Annual Report 2009 - Istituto di Ricerche Farmacologiche Mario Negri
Annual Report 2009 - Istituto di Ricerche Farmacologiche Mario Negri
Annual Report 2009 - Istituto di Ricerche Farmacologiche Mario Negri
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IRFMNPREFACEANNUAL REPORTMARIO NEGRI INSTITUTE, MILANwww.marionegri.itDEPARTMENTSDepartment of Oncology ………………….………………………….……………………… 7Department of Environmental Health Sciences ……….………….……….……………… 53Department of Neuroscience ………………….………………………….………………… 73Department of Car<strong>di</strong>ovascular Research ………………….…………………….………… 123Department of Molecular Biochemistry and Pharmacology .…….………….………… 155Department of Epidemiology……………………………..…….………….……………….. 183Department of Public Health............................................................................. 231LABORATORIES AND CENTERSLaboratory of Regulatory Policies ……….………………………..……….………….……… 253Centre of Computer Science Engineering………………………………………….………… 259Italian Cochrane Center …….….……………………………………………………………… 263The Catullo and Daniela Borgomainerio Center…………………………………………… 271Library ……….….…………………………………………………………….………….………… 273NEGRI BERGAMO LABORATORIESDEPARTMENTSDepartment of Molecular Me<strong>di</strong>cine ……….……………………………………….………… 279Department of Biome<strong>di</strong>cal Engineering……….……………………………………………… 399Laboratory of Biology and Therapy of Metastasis…………………………………….. 315ALDO and CELE DACCO’ CENTERDEPARTMENTDepartment of Renal Me<strong>di</strong>cine…………….…………………………………………………… 319LABORATORIES AND CENTERSRare Diseases Documentation and Research..................................................…..… 343International Relations Office of rare Diseases........................................................ 353T he Transplant Research Center…………….………………………………………………… 357EDUCATION ACTIVITIES 359STAFF 361All the staff of the Institute is listed on its website www.marionegri.itPUBLICATIONSA comprehensive list of the Institute’s publications is available on the www.marionegri.itwebsite – Section Publications1ANNUAL REPORT <strong>2009</strong>
IRFMNE<strong>di</strong>ted by Isabella Bordognaprinted May 20102ANNUAL REPORT <strong>2009</strong>
2. April 2011- Amtsblatt 2/2011 - 4-Beschluss-Nr. 09-03/2011Feststellung des Jahresabschluss 2004 des ehemaligen Abwasserbetriebesder Stadt Blankenhain und Entlastung des BürgermeistersDer Stadtrat der Stadt Blankenhain stellt den Jahresabschluss 2004 desehemaligen Abwasserbetriebes fest und erteilt dem Bürgermeister <strong>di</strong>eEntlastung für <strong>di</strong>eses Geschäftsjahr. Auf eine Beschlussfassung zurVerwendung des Gewinnes oder Verlustes gemäß § 25 (3) ThürEBVwird verzichtet, da der Abwasserbetrieb aufgelöst und sämtliche Buchungsvorgängein den Haushalt 2006 übernommen wurden.Der beiliegende Auszug aus dem Bericht über <strong>di</strong>e Prüfung des Jahresabschlussesdes Jahres 2004 ist Bestandteil <strong>di</strong>eses Beschlusses.Beschluss-Nr. 10-03/2011Feststellung des Jahresabschluss 2005 des ehemaligen Abwasserbetriebesder Stadt Blankenhain und Entlastung des BürgermeistersDer Stadtrat der Stadt Blankenhain stellt den Jahresabschluss 2005 desehemaligen Abwasserbetriebes fest und erteilt dem Bürgermeister <strong>di</strong>eEntlastung für <strong>di</strong>eses Geschäftsjahr. Auf eine Beschlussfassung zurVerwendung des Gewinnes oder Verlustes gemäß § 25 (3) ThürEBVwird verzichtet, da der Abwasserbetrieb aufgelöst und sämtliche Buchungsvorgängein den Haushalt 2006 übernommen wurden.Der beiliegende Auszug aus dem Bericht über <strong>di</strong>e Prüfung des Jahresabschlussesdes Jahres 2005 ist Bestandteil <strong>di</strong>eses Beschlusses.Die Jahresrechnungen 2001 - 2005 liegen in der Zeit vom 04.04. -14.04.2011 während der Dienstzeiten in der Kämmerei - Zimmer-Nr.215 zu jedermanns Einsichtnahme aus.Die erteilten Bestätigungsvermerke der Abschlussprüfer für <strong>di</strong>e genanntenJahresabschlüsse können ebenfalls in <strong>di</strong>esem Zeitraum eingesehenwerden.Die Bestätigungsvermerke für <strong>di</strong>e angegebenen Jahresrechnungenwurden erteilt.Beschluss-Nr. 11-03/2011Gründung „Stiftung Blankenhain für gesellschaftliches Engagement“als Projektträger für <strong>di</strong>e Realisierung gemeindlicher Projektezur Verbesserung der InfrastrukturDer Stadtrat der Stadt Blankenhain beschließt:1. Der Bürgermeister wird beauftragt, das Projekt der Gründung einer„Stiftung Blankenhain für gesellschaftliches Engagement“ zubetreiben und <strong>di</strong>e notwen<strong>di</strong>gen Vorbereitungen für <strong>di</strong>e Stiftungsgründungzu treffen.2. Der Bürgermeister soll für eine der nächsten Stadtratssitzungen einenüberarbeiteten Satzungsentwurf für <strong>di</strong>e Stiftung und einenEntwurf des Stiftungsgeschäfts vorlegen, in denen <strong>di</strong>e Vorschlägeder Mitglieder des Stadtrates eingearbeitet werden.3. Der Bürgermeister wird beauftragt, alle Vorbereitungen für <strong>di</strong>e Kapitalausstattungder Stiftung aus Gemeindevermögen und Privatvermögenvorzuschlagen.4. Der Bürgermeister wird beauftragt, alle vorbereitenden Maßnahmenfür einen förmlichen Gründungsbeschluss der Stiftung zu veranlassenund <strong>di</strong>e ersten konkreten Projekte zu benennen.5. Der Bürgermeister wird beauftragt, in Zusammenarbeit mit anderenFachleuten <strong>di</strong>e Investitionsmaßnahmen über <strong>di</strong>e Aufnahme indas Bund-Länder-Förderprogramm „Kleine Städte und Gemeinden!“zu beantragen und hierfür <strong>di</strong>e erforderlichen Antragsunterlagenausarbeiten zu lassen. Die entstehenden Kosten sind als Projektvorlaufkostender Stiftung zu behandeln.6. Folgende Anlagen sind Bestandteil <strong>di</strong>eses Beschlusses:1. Information, insbesondere zwecks Vorlage im Stadtrat, bei derKommunalaufsicht bzw. dem Landrat Modell „Stiftung Blankenhainfür gesellschaftliches Engagement“ vom 24.02.20112. Entwurf vom 24.02.2011 - Stiftungsgeschäft3. Entwurf vom 24.02.2011 - Satzung der „Stiftung Blankenhainfür gesellschaftliches Engagement“Beschluss-Nr. 12-03/2011Unbefristete Verlängerung des Mietvertrages für <strong>di</strong>e KindertageseinrichtungBlankenhain „Waldgeister am Steintisch“Der Stadtrat der Stadt Blankenhain beschließt <strong>di</strong>e unbefristete Verlängerungdes Mietvertrages für <strong>di</strong>e Kindertageseinrichtung in Blankenhain„Waldgeister am Steintisch“. Der § 2 - Mietzeit - Satz 1 des Mietvertragesvom 25.03.<strong>2009</strong> ändert sich entsprechend.Beschluss-Nr. 13-03/2011Unbefristete Verlängerung des Mietvertrages für <strong>di</strong>e Kindertageseinrichtung„Zwergenvilla“ ThangelstedtDer Stadtrat der Stadt Blankenhain beschließt <strong>di</strong>e unbefristete Verlängerungdes Mietvertrages für <strong>di</strong>e Kindertageseinrichtung „Zwergenvilla“Thangelstedt. Der § 2 - Mietzeit - Satz 1 des Mietvertrages vom25.03.<strong>2009</strong> ändert sich entsprechend.BekanntmachungBeschlüsse des Haupt- und FinanzausschussesDie Veröffentlichung nachfolgender Beschlüsse erfolgt vorbehaltlichder Genehmigung der Niederschrift durch den Haupt- undFinanzausschussIn der Sitzung des Haupt- und Finanzausschusses am 01.03.2011 wurdennachfolgende Beschlüsse gefasst. Die in öffentlicher Sitzung gefasstenBeschlüsse liegen nach Genehmigung der Niederschrift zu denDienstzeiten zu jedermanns Einsichtnahme in der StadtverwaltungBlankenhain, Marktstraße 4, 99444 Blankenhain aus.In der öffentlichen Sitzung wurden folgende Beschlüssegefasst:Genehmigung der Niederschrift der öffentlichen Sitzung desHaupt- und Finanzausschusses vom 07.12.2010Gemäß § 42 ThürKO sowie § 14 der Geschäftsordnung für <strong>di</strong>e Stadträteund Ausschüsse (sowie Ortsteilräte) der Stadt Blankenhain wird<strong>di</strong>e Niederschrift der öffentlichen Sitzung des Haupt- und Finanzausschussesvom 07.12.2010 genehmigt.Beschluss-Nr. HFA 01-03/2011Vergabe Baumaßnahme - Fassade Gemeindehaus KeßlarDer Haupt- und Finanzausschuss beschließt <strong>di</strong>e Vergabe der Baumaßnahmean der Fassade des Gemeindehauses Keßlar an <strong>di</strong>e Fa. TinoBehr, Krakendorf, Unter dem Bornberge 37, 99444 Blankenhain. DieAuftragssumme beträgt 7.524,93 EUR.Beschluss-Nr. HFA 02-03/2011Vergabe Baumaßnahme - Abriss und Neuaufbau Außentreppe„Am Markt 3“ (Rathaus)Der Haupt- und Finanzausschuss beschließt <strong>di</strong>e Vergabe der BaumaßnahmeAbriss und Neuaufbau Außentreppe „Am Markt 3“ (Rathaus)an <strong>di</strong>e Fa. Schweiger GmbH, Vor dem Tor 25, 07768 Orlamünde. DieAuftragssumme beträgt ca. 10.000,00 EUR.Beschluss-Nr. 03-03/2011Beschilderung/Verkehrsführung in Söllnitz „An der Magdel“ 10 - 14Der Haupt- und Finanzausschuss beschließt <strong>di</strong>e im Sachverhalt geschilderteBeschilderung/Verkehrsführung in Söllnitz „An der Magdel“10 - 14.Blankenhain, 02.03.2011gez. KellnerKlaus-Dieter KellnerBürgermeisterBekanntmachung Beschlüssedes Bau- und GrundstücksausschussesDie Veröffentlichung nachfolgender Beschlüsse erfolgt vorbehaltlichder Genehmigung der Niederschrift durch den Bau- undGrundstücksausschussIn der Sitzung des Bau- und Grundstücksausschusses am 15.02.2011wurden folgende Beschlüsse gefasst. Die in öffentlicher Sitzung gefasstenBeschlüsse liegen zur Einsichtnahme in der StadtverwaltungBlankenhain, Marktstraße 4, 99444 Blankenhain, nach Genehmigungder Niederschrift öffentlich aus.Blankenhain, 21.02.2011gez. KellnerBürgermeisterIn öffentlicher Sitzung wurden folgende Beschlüsse gefasst:Genehmigung der Niederschrift der öffentlichen Sitzung des BauundGrundstücksausschusses vom 30.11.2011Gemäß § 42 ThürKO sowie § 14 der Geschäftsordnung für <strong>di</strong>e Stadträteund Ausschüsse (sowie Ortschaftsräte) der Stadt Blankenhainwird <strong>di</strong>e Niederschrift der öffentlichen Sitzung des Bau und Grundstücksausschussesvom 30.11.2011 genehmigt.Eilentscheidung-Nr. BGA 06-12/2010Vergabe von Bauleistungen Straßenbauarbeiten - Gewerbegebiet„Rottdorfer Straße“ Blankenhain - Herstellung WendehammerDer Bau- und Grundstücksausschuss nimmt <strong>di</strong>e Vergabe der Straßenbauarbeitenzur Herstellung Wendehammer im Gewerbegebiet „RottdorferStraße“ Blankenhain an <strong>di</strong>e Firma Wachenfeld Bau GmbH,Waldecker Straße 3, 99444 Blankenhain, mit einer Angebotssummevon 16.468,67 EUR Brutto zur Kenntnis.
IRFMN4ANNUAL REPORT <strong>2009</strong>
IRFMN<strong>Mario</strong> <strong>Negri</strong> INSTITUTE FORPHARMACOLOGICAL RESEARCH MilanANNUALREPORT <strong>2009</strong>departments and laboratories5ANNUAL REPORT <strong>2009</strong>
IRFMN6ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF ONCOLOGYSTAFFChiefMaurizio D’INCALCI, M.D.Oncological Stu<strong>di</strong>es Office and DocumentationScientific DocumentalistStefania FILIPPESCHI, ChemistLaboratory of Cancer PharmacologyHeadBiophysics UnitHeadFlow Citometry UnitHeadCancer Clinical Pharmacology UnitHeadMaurizio D’INCALCI, M.D.Paolo UBEZIO, Phys.D.Eugenio ERBA, Biochem.DMassimo ZUCCHETTI, Chem.Pharm.D.Laboratory of Molecular PharmacologyHeadDNA Repair UnitHeadMassimo BROGGINI, Ph.D.Giovanna DAMIA, M.D.Laboratory of Biology and Therapy of MetastasisHeadTumor Angiogenesis UnitHeadUnit located in BergamoMolecular Cancer Therapeutics UnitHeadRaffaella GIAVAZZI, Biol.Sci.D., Ph.D.Giulia TARABOLETTI, Biol.Sci.D.Maria Rosa BANI, Biol.Sci.D., Ph.D.7ANNUAL REPORT <strong>2009</strong>
IRFMNLaboratory for the development of new pharmacological strategiesHeadValter TORRI, M.D.Laboratory of Clinical TrialsHeadIrene FLORIANI, Dr.Sci.Biol., Dr.Stat., Ph.D.Laboratory of Translational and Outcome Research in OncologyHeadGynecology Oncology UnitHeadGiovanni APOLONE, M.D.Roldano FOSSATI, M.D.CERP: Center for the Evaluation and Research on PainHeadGiovanni APOLONE, M.D.Oscar CORLI, M.D.Laboratory of Me<strong>di</strong>cal Research and Consumer InvolvementHeadPaola MOSCONI, Biol.Sci.D.8ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAMaurizio D'Incalci obtained his Me<strong>di</strong>cal Degree cum Laude from the University of Milan in 1977. Afterspecializing in Pharmacology at the <strong>Mario</strong> <strong>Negri</strong> Institute of Milan and in Oncology at the University ofGenoa, he worked in the Laboratory of Molecular Pharmacology of the National Cancer Institute inBethesda, MD, USA. Since 1986 he has been chief of the Laboratory of Cancer Chemotherapy at the<strong>Mario</strong> <strong>Negri</strong> Institute and since 1996 he has become chief of the Department of Oncology at the <strong>Mario</strong><strong>Negri</strong> Institute.He has been President of the Pharmacology and Molecular Mechanisms Group of the EuropeanOrganization for Research and Treatment of Cancer (EORTC). From 1994 to 1997 he was Chairman ofthe New Drug Development Coor<strong>di</strong>nating Committee and from 1997 to 2000 he was chairman of theResearch Division of the EORTC. He has been member of the Board of the EORTC from April 2000 to2003. From 1997 he is the Preclinical Coor<strong>di</strong>nator of the Southern Europe New Drug Organization(SENDO) and since 2006 the Chairman of the New Agents Committee (NAC). From 2006 he ispresident of the Scientific Committee of the <strong>Mario</strong> <strong>Negri</strong> Gynecologic Oncology group (MaNGO).From 2007 he is member of the Scientific Committee of the Italian Association for Cancer Research(AIRC). He is on the e<strong>di</strong>torial board of many international cancer-related scientific journals and sinceSeptember 2000 he is E<strong>di</strong>tor for Experimental Oncology of the European Journal of Cancer. Dr D'Incalciis author of more than 440 papers on cancer chemotherapy published in peer reviewed internationaljournals, and of several chapters in books on cancer chemotherapy.Selected publications• Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' L, Locatelli A, Rulli E, Compagnoni A, Bello E, Pisano C,Carminati P, D'Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patientvariability is related to α(1)-acid glycoprotein plasma levels. Eur J Cancer <strong>2009</strong> E-pub.• Forni C, Minuzzo M, Vir<strong>di</strong>s E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A, Aman P, Casali P,D'Incalci M, Pilotti S, Mantovani R. Trabecte<strong>di</strong>n (ET-743) promotes <strong>di</strong>fferentiation in myxoid liposarcoma tumors. MolCancer Ther, 8 : 449-457 (<strong>2009</strong>).• Marchini S, Mariani P, Chiorino G, Marrazzo E, Bonomi R, Fruscio R, Clivio L, Garbi A, Torri V, Cinquini M,Dell'Anna T, Apolone G, Broggini M, D'Incalci M. Analysis of gene expression in early-stage ovarian cancerClin Cancer Res, 14 : 7850-7860 (2008).• Grosso F., Jones R.L. Demetri G.D., Judson I.R., Blay J.Y., Le Cesne A., Sanfilippo R., Casieri P., Collini P., Dileo P.,Spreafico C., Stacchiotti S., Tamborini E., Tercero J.C., Jimeno J., D’Incalci M., Gronchi A., Fletcher J.A., Pilotti S.,Casali P.G. Efficacy of Trabecte<strong>di</strong>n (ET-743) in advanced pre-treated myxoid liposarcomas. Lancet Oncology, 2007;8:595-602.• Salvati E., Leonetti C., Rizzo A., Scarsella M., Mottolese M., Galati R., Sperduti I., Stevens M., D’Incalci M., BlascoM., Chiorino G., Horard B., Gilson E., Zupi G., Biroccio A. Telomere damage promotes antitumoral activity of the G-quadruplex ligand RHPS4. J. Clin. Invest., 2007; 117:3236-3247.• Tavecchio M., Natoli C., Ubezio P., Erba E., D’Incalci M. Dynamics of cell cycle phase perturbations by Trabecte<strong>di</strong>n(ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematicalsimulation approach. Cell proliferation, 2007; 40: 885-904.Giovanni Apolone, got his Me<strong>di</strong>cal degree in 1982 (Pavia, Italy) and his post-doctoral specializations inInternal Me<strong>di</strong>cine in 1987 (Pavia, Italy) and Pharmacological Research (1992). He is Head of theLaboratory of Translational and Outcome Research. He is also Vice-President of the Ethics Committeeof the European Institute of Oncology in Milan (Italy) and listed as National Expert at the EuropeanAgency for the Evaluation of Me<strong>di</strong>cinal products (EMEA) in London (UK). His main fields of interestare:• Methodological, ethical and regulatory aspects of clinical research, with special emphasis on oncologyand the cancer pain.• Health care evaluation with special emphasis on oncology;• Development and validation of case-mix and patient-reported outcome measures;• Education and health promotion research and programs.He is author or co-author of more than 270 publications, mostòy in International peer-reviewed Journals.Mean Impact Factor, computed on peer-reviewed papers: 3.2. H-index (from ISI-Web of knowledge,March 2010): 30. Number of citations: 4111. Average citation per item: 32.37. Number of papers with>50 citations: 19.9ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Corli O, Apolone G, Pizzuto M, Cesaris L et al. Illness awareness in terminal cancer patients: an Italian study. PalliativeMe<strong>di</strong>cine, 23: 354-9, <strong>2009</strong>• Riva E, Tettamanti M, Mosconi M, Apolone, G et al. Association of Mild Anemia with Hospitalization and Mortalityin the Elderly The “Health and Anemia” Population-Based Study. Haematologica, 94 (1): 22-28, <strong>2009</strong>• Apolone G, Corli O, <strong>Negri</strong> E, Mangano S, Montanari M, Greco MT. Effects of transdermal buprenorphine on patientsreportedoutcomes in cancer patients. Results from the Cancer Pain Outcome Research (CPOR) Study Group.Clinical J Of Pain, 25:671-682, <strong>2009</strong>• Apolone G, Corli O, et al. Pattern and quality of care of cancer pain management. Results from the Cancer Pain OutcomeResearch Study Group (CPOR SG). Br J Cancer, 100:1566-74, <strong>2009</strong>.• Apolone G, on behalf of the 2008 Erice Group. The 2008 Erice Statement toward a more humanistic oncology. J Ambcare Manage 32:252-258,<strong>2009</strong>.• De Andrea S, Corli O, Moschetti I, Apolone G. Managing severe cancer pain. The role of TDS buprenorphine: asystematic review. Therapeutics and Clinical Risk management, 5:1-12, <strong>2009</strong>.• Gallus S, Tramacere I, La Vecchia C, Colombo P, Zuccaro P, Paleari L, Cesario A, Russo P, Apolone G. Use ofpharmacotherapy for smoking cessation in Italy. Arch Intern Med 169: 1927-1928, <strong>2009</strong>.Massimo Broggini followed the faculty of Science of the University of Milan, got the specialization inBiochemistry at <strong>Mario</strong> <strong>Negri</strong> Institute, and the PhD degree at the Open University, London,UK.He worked in the laboratory of Molecular Pharmacology of the National Cancer Institute of Bethesda,Md, in 1986. From 1991 he is the head of the Molecular Pharmacology Unit of the <strong>Mario</strong> <strong>Negri</strong> Instituteand from 1999 he his the head of the Laboratory of Molecular Pharmacology of the same Institute.His main fields of interest are the study of the mechanism of action of new anticancer agents, the searchof altered proteins and genes in human cancer and the study of oncosuppressor genes. He is member ofthe "Pharmacology and Molecular Mechanisms Group" of the European Organisation for the Researchand Treatment of Cancer (EORTC) and of the American Association for Cancer Research. He is in theE<strong>di</strong>torial board of the European Journal of Cancer.He is author of more than 100 articles published in international journals.Principali pubblicazioni• Zangrossi S, Marabese M, Broggini M, Giordano R, D'Erasmo M, Montelatici E, Intini D, Neri A, Pesce M, Rebulla P,Lazzari L. Oct-4 expression in adult human <strong>di</strong>fferentiated cells challenges its role as a pure stem cell marker. Stem Cells.2007;25(7):1675-80.• Marrazzo E, Marchini S, Previ<strong>di</strong> S, Broggini M. Questioning the oncogenic role of DeltaNp73alpha in <strong>di</strong>fferent cell linesexpressing p53 or not. Cancer Biol Ther. 2006;5(7):794-803.• Polato F, Codegoni A, Fruscio R, Perego P, Mangioni C, Saha S, Bardelli A, Broggini M. PRL-3 phosphatase isimplicated in ovarian cancer growth. Clin Cancer Res. 2005 11:6835-9.• Maffucci T, Piccolo E, Cumashi A, Iezzi M, Riley AM, Saiar<strong>di</strong> A, Godage HY,Rossi C, Broggini M, Iacobelli S, PotterBV, Innocenti P, Falasca M. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway by inositol pentakisphosphateresults in antiangiogenic and antitumor effects. Cancer Res. 2005;65:8339-49.• Marabese M, Marchini S, Sabatino MA, Polato F, Vikhanskaya F, Marrazzo E, Riccar<strong>di</strong> E, Scanziani E, Broggini M.Effects of inducible overexpression of DNp73alpha on cancer cell growth and response to treatment in vitro and in vivo.Cell Death Differ. 2005;12:805-14.• Sabatino MA, Colombo T, Geroni C, Marchini S, Broggini M. Enhancement of in vivo antitumor activity of classicalanticancer agents by combination with the new, glutathione-interacting DNA minor groove-binder, brostallicin. ClinCancer Res. 2003;9:5402-8.Irene Floriani got her degree in Biological Sciences at the University of Milan in 1988, her degree inBiostatistics and Experimental Statistics at the University of Milan in 2003 and her phD in Life Sciencesat Open University of London (UK) in 2005. After ten-year experience in pharmaceutical industry, in2002 she became Head of the Biometry and Data Management Unit of the Laboratory of ClinicalResearch in Oncology and since 2006 she is Head of Laboratory of Clinical Trials. She is also member asbio-statistician of three Italian Ethics Committees. Her main fields of interest are: statistical aspects ofmethodology of clinical research with focus on Controlled Clinical Trials in Oncology; SystematicOverview of the me<strong>di</strong>cal literature and Methodological aspects of <strong>di</strong>agnostic test evaluation.Selected publications• Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E, Rulli E, Floriani I,Bencar<strong>di</strong>no K, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, Basolo F, Falcone A, Graziano F. KRAScodon 61, 146 and BRAF mutations pre<strong>di</strong>ct resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-typemetastatic colorectal cancer. Br J Cancer <strong>2009</strong> 101 : 715-72110ANNUAL REPORT <strong>2009</strong>
IRFMN• Signorelli M, Lissoni AA, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R,Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, and Fossati R. Mo<strong>di</strong>fied ra<strong>di</strong>cal hysterectomy versusextrafascial hysterectomy in the treatment of stage I endometrial cancer: results from the ILIADE randomized study. AnnSurg Oncol <strong>2009</strong> 16 : 3431-3441• Floriani I, Santini D, Torri V, Cremolini C, Falcone A, Loupakis F. Do we need biopsies of metastases for colorectalcancer patients? Br J Cancer <strong>2009</strong> 101 : 374-375• Garattini S, Torri V, Floriani I. Cetuximab for metastatic colorectal cancer. N Engl J Med <strong>2009</strong> 361 : 96• Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi G, Graziano F, Cremolini C, Rulli E, Canestrari E,Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I, Cascinu S, Falcone A. PTEN expressionand KRAS mutations on primary tumors and metastases in the pre<strong>di</strong>ction of benefit from cetuximab plus irinotecan forpatients with metastatic colorectal cancer. J Clin Oncol <strong>2009</strong> 27 : 2622-2629• Ferrari D, Fiore J, Codecà C, Di Maria G, Bozzoni S, Bor<strong>di</strong>n V, Cal<strong>di</strong>era S, Luciani A, Zonato S, Floriani I, Foa P. Aphase II study of carboplatin and paclitaxel for recurrent or metastatic head and neck cancer. Anticancer Drugs <strong>2009</strong> 20 :185-190• Lissoni AA, Colombo N, Pellegrino A, Parma G, Zola P, Katsaros D, Chiari S, Buda A, Landoni F, Peiretti M, Dell'annaT, Fruscio R, Signorelli M, Grassi R, Floriani I, Fossati R, Torri V, Rulli E. A phase II, randomized trial of neo-adjuvantchemotherapy comparing a three-drug combination of paclitaxel, ifosfamide, and cisplatin (TIP) versus paclitaxel andcisplatin (TP) followed by ra<strong>di</strong>cal surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study. Ann Oncol <strong>2009</strong> 20 : 660-665• Graziano F, Ruzzo A, Canestrari E, Loupakis F, Santini D, Rulli E, Humar B, Galluccio N, Bisonni R, Floriani I,Maltese P, Falcone A, Tonini G, Catalano V, Fontana A, Giustini L, Masi G, Vincenzi B, Alessandroni P, MagnaniM.Variations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectalcancer. Pharmacogenomics J <strong>2009</strong> 9 : 78-84• Mandalà M, Barni S, Floriani I, Isa L, Fornarini G, Marangolo M, Mosconi S, Corsi D, Rulli E, Frontini L, Cortesi E,Zaniboni A, Aglietta M, Labianca R. Incidence and clinical implications of venous thromboembolism in advancedcolorectal cancer patients: The 'GISCAD-alternating schedule' study fin<strong>di</strong>ngs. Eur J Cancer <strong>2009</strong> 45 : 65-73Raffaella Giavazzi got her Biological Sciences degree (1979) at the University of Milan, and her Ph.D.in Pharmacology at the <strong>Mario</strong> <strong>Negri</strong> Institute of Milan (1984), followed by a specialization inpharmacology (1994) at the University of Milan. From 1981 to 1983 she was a Fellow in the CancerMetastasis and Treatment Laboratory, NCI-FCRDC, Frederick, MD., and from 1983 to 1985 AssistantProfessor at the Department of Cell Biology of M.D. Anderson Hospital and Tumour Institute,University of Texas System Cancer Centre in Houston (TX).Raffaella Giavazzi’s research interests are in the field of tumour biology and pharmacology. Specifically,she is studying aspects related to the metastatic process and angiogenesis. She is involved in the preclinicalevaluation of new therapeutic strategies against cancer focusing on the angiogenesis inhibitorsand combination therapies.From 1986 to 1993 she was Head of the Cancer Metastasis Treatment Unit and since 1993 she has beenthe Head of the Laboratory of Biology and Treatment of Metastasis at <strong>Mario</strong> <strong>Negri</strong> Institute forPharmacological Research.She is also adjutant Professor in Oncology, Me<strong>di</strong>cal School-University of Brescia, member of theTeaching Committee for the PhD course in Physiology-Pharmacology-Molecular and CellularTossicology-University of Siena, member of the Executive Committee at SENDO (South Europe NewDrug Development Organization) and member of the Executive Committee of the European Associationfor Cancer Research (EACR).She was consulting scientist for the NCI-Drug Therapeutics Program, USA (1996-2006);She is a member of the American Association for Cancer Research (AACR), International MetastasesResearch Society, EORTC-Screening and Pharmacology Group, European Association for CancerResearch (EACR), Italian Cancer Society (SIC) of which she was President (2006-2007).She is on the E<strong>di</strong>torial Board of international scientific journals such as the European Journal of Cancer,Journal of Clinical & Experimental Metastasis, and The International Journal of Biological Markers.She has published approximately 200 articles on “peer reviewed” scientific journals.Selected publications• Rösli C., Borgia B., Schliemann C., Gunther M., Wunderli-Allenspach H., Giavazzi R., Neri D. Comparative analysis ofthe membrane protome of closely related metastatic and non-metastatic tumor cells. Cancer Research, 69(13):5406-14,<strong>2009</strong>.• Cesca M., Frapolli R., Berndt A., Scarlato V., Richter P., Kosmehl H., D’Inclaci M., Ryan A.J., Giavazzi R. The effectsof vandetanib on paclitaxel tumor <strong>di</strong>stribution and antitumor activity in a xenograft model of human ovarian carcinoma.Neoplasia, 11(11):1155-64, <strong>2009</strong>.• Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular <strong>di</strong>srupting activity of tubulin-bin<strong>di</strong>ng1,5-Diaryl-1H-imidazoles. Journal of Me<strong>di</strong>cal Chemistry, 52:7906-10, <strong>2009</strong>.11ANNUAL REPORT <strong>2009</strong>
IRFMN• Borgia B., Rösli C., Fugmann T., Schliemann C., Cesca M., Neri D., Giavazzi R. A proteomic approach for theidentification of vascular markers of liver metastasis. Cancer Research, 70(1):309-18, 2010.• Ghilar<strong>di</strong> C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers throughgene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008.• Giavazzi R., Bani M.R.,Taraboletti G.: Tumor–host interaction in the optimization of paclitaxel-based combinationtherapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481–88, 2007Paola Mosconi got her Biological Science degree (Milan 1982) and the specialisation in PharmacologicalResearch (Milan 1984). Her main areas of interest are:• development of strategies to involve patients-consumer associations in the health debate, andresearch projects;• assessment of the quality of life, translation and cultural adaptation of questionnaires for quality oflife;• stu<strong>di</strong>es to evaluate the type of information on <strong>di</strong>seases and treatments received by patients, mainlycancer patients; set-up of websites targeted on consumers/patients www.partecipasalute.it,www.paincare.it, www.fondazioneMattioli.it ;• stu<strong>di</strong>es to evaluate the consumers’ level of satisfaction with the health services and care.Paola Mosconi has participated as a teacher, or coor<strong>di</strong>nator, to the realization of training course on“Methodological aspects of clinical research” or “Evaluation of quality of life” for health careprofessionals and representatives of voluntary associations.Selected publications• Mosconi P, Donati S, Colombo C, Mele A, Liberati A, Satolli R. The Consensus Conference WorkingGroup. Informingwomen about hormone replacement therapy: the Consensus conference statement. BMC Woman Health Journal <strong>2009</strong>;9:14 doi:10.11886/1472-6874-9-14• Donati S, Cotichini R, Mosconi P, Satolli R, Colombo C, Liberati A, Mele A Menopause: knowledge, attitude andpractice among Italian women.Maturitas <strong>2009</strong>; 20; 63(3):246-52.• Mosconi P, Colombo C, Satolli R, Liberati A. PartecipaSalute, an Italian project to involve lay people,patients’ associations and scientific-me<strong>di</strong>cal representatives on the health debate. Health Expectations 10: 194-204, 2007.O’Connel D, Mosconi P. An active role for patients in clinical research? Drug Development Research 67 (3): 188-192,2006.• Mosconi P, Colombo Cinzia, La Bianca R, Apolone G. Oncologists' opinions about research ethics committees in Italy:an update, 2004. Eur J Cancer Prev 2006; 15: 91-94• Mosconi P, Poli P, Giolo A, Apolone G. How health consumers feel about clinical research: a questionnairesurvey. European Journal of Public Health 15: 372-379, 2005.• Mosconi P, Buchanan M, Kyriakides S, Fernandez-Marcos A, Horvatin J, O'Connell D, Zernik N, on behalf of EUROPADONNA. EUROPA DONNA: has strength in its heterogeneity. European J Cancer 40: 1145-1149, 2004.Valter Torri got his Me<strong>di</strong>cal degree in 1985 and the specialization in me<strong>di</strong>cal Oncology in 1989 at theUniversity of Milano.Education: 1985: MD Degree with full honors cum Laude, University of Milano; 1988 Post-DoctoralDegree in Pharmacological Research, <strong>Mario</strong> <strong>Negri</strong> Institute, Milano; 1989 Post-Doctoral Degree inMe<strong>di</strong>cal Oncology, University of Milano; 1989-1991 Research Fellow at the Biometric Research Branchof Cancer Treatment Evaluation Program, NCI, Bethesda, MD (USA)Areas of Interest: Statistical aspects of clinical research methodology with focus on Controlled ClinicalTrials in Oncology; Systematic Overview of the me<strong>di</strong>cal literature; Methodological aspects of <strong>di</strong>agnostictest evaluation.Present Position: Head of Laboratory of Clinical Research In Oncology, Oncology Department, <strong>Mario</strong><strong>Negri</strong> Institute, Milano.Chronology of Professional Appointments: 1983-1985: Clinical research Fellow in Internal Me<strong>di</strong>cine atthe University Hospital, University of Milan; 1985-1989: Research assistant at the Clinical Trial Unit ofthe Laboratory of Clinical Epidemiology, <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, Milano;1989-1991: Research fellow at the Biometric Research Branch of Cancer Treatment Evaluation Program,NCI, Bethesda, MD (USA); 1994: Head of Biometric Unit of the Laboratory of Cancer ClinicalEpidemiology, Oncology Department, <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, Milano, Italy;1995 Vice Director of the Italian “Cochrane” Center; 2001: Head of Laboratory of Clinical Research InOncology, Oncology Department, <strong>Mario</strong> <strong>Negri</strong> Institute, Milano. 2006: Head of Laboratory for thedevelopment of new pharmacological strategies , Oncology Department, <strong>Mario</strong> <strong>Negri</strong> Institute, Milano.Member of Consiglio Direttivo Nazionale dell’Associazione Italiana <strong>di</strong> Oncologia Me<strong>di</strong>ca12ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, Santoro A, MantovaniA, Roncalli M, Malesci A. CD3+ cells at the invasive margin of deeply inva<strong>di</strong>ng (pT3-T4) colorectal cancer and risk ofpost-surgical metastasis: a longitu<strong>di</strong>nal study. Lancet Oncol. <strong>2009</strong>; 10 (9): 877-84.• Garassino MC, Borgonovo K, Rossi A, Mancuso A, Martelli O, Tinazzi A, Di Cosimo S, La Verde N, Sburlati P,Bianchi C, Farina G, Torri V. Biological and clinical features in pre<strong>di</strong>cting efficacy of epidermal growth factor receptortyrosine kinase inhibitors: a systematic review and meta-analysis. Anticancer Res. <strong>2009</strong>; 29 (7): 2691-701.• Marchini S, Mariani P, Chiorino G, Marrazzo E, Bonomi R, Fruscio R, Clivio L, Garbi A, Torri V, Cinquini M,Dell'Anna T, Apolone G, Broggini M, D'Incalci M. Analysis of gene expression in early-stage ovarian cancer. ClinCancer Res. 2008 Dec 1;14(23):7850-60.• Benedetti Panici P, Basile S, Maneschi F, Alberto Lissoni A, Signorelli M,Scambia G, Angioli R, Tateo S, Mangili G,Katsaros D, Garozzo G, Campagnutta E,Donadello N, Greggi S, Melpignano M, Raspagliesi F, Ragni N, Cormio G,Grassi R,Franchi M, Giannarelli D, Fossati R, Torri V, Amoroso M, Crocè C, Mangioni C. Systematic pelvic lymphadenectomyvs. no lymphadenectomy in early-stage endometrial carcinoma: randomized clinical trial. J Natl Cancer Inst. 2008 Dec3;100(23):1707-16.• Mitry E, Fields AL, Bleiberg H, Labianca R, Portier G, Tu D, Nitti D, Torri V,Elias D, O'Callaghan C, Langer B,Martignoni G, Bouché O, Lazorthes F, Van Cutsem E, Bedenne L, Moore MJ, Rougier P. Adjuvant chemotherapy afterpotentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials. J ClinOncol. 2008 Oct 20;26(30):4906-11.• Cascinu S, Labianca R, Barone C, Santoro A, Carnaghi C, Cassano A, Beretta GD, Catalano V, Bertetto O, Barni S,Frontini L, Aitini E, Rota S, Torri V, FlorianiI; Italian Group for the Study of Digestive Tract Cancer, Adjuvanttreatment of high-risk, ra<strong>di</strong>cally resected gastric cancer patients with 5-fluorouracil, leucovorin, cisplatin, andepidoxorubicin in a randomised controlled trial. J Natl Cancer Inst. 2007;99(8):601-7.• Graziano F, Kawakami K, Ruzzo A, Watanabe G, Santini D, Pizzagalli F, Bisonni R, Mari D, Floriani I, Catalano V,Silva R, Tonini G, Torri V, Giustini L, Magnani M Methylenetetrahydrofolate reductase 677C/T gene polymorphism,gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population. Int J Cancer 2006 118 :628-632• Torri V: Clinical trials and data management In: Oxford textbook of oncology, 2nd. ed. Vol. 1. Oxford Univ. Press,Oxford; 2002 : 1123-1134Maria Rosa Bani got her Biological Sciences degree at the University of Milan in 1998 attaining theItalian Government Qualification to practice as Biologist in 1990. She obtained the specialization inPharmacological Research from the Department of Education of the Regional Government ofLombar<strong>di</strong>a in 1991 and the specialization in Biome<strong>di</strong>cal Research from the Department of Education ofthe Regional Government of Abruzzo in 1993.In 2005 she was awarded the degree of Doctor of Philosophy (PhD), Discipline of Life Sciences of theOpen University Research School (UK).From 1991 to 1995 she was a Post Doctoral Fellow in the Cancer Research Division, Sunnybrook HealthScience Centre, University of Toronto (Canada); from 2000 to 2001 she was Guest Scientist at theAdvance Technology Centre, National Cancer Institute, National Institute of Health (USA).At the <strong>Mario</strong><strong>Negri</strong> Institute for Pharmacological Research she was a Fellow Research Scientist in theLaboratory of Biology and Treatment of Metastasis, Bergamo from 1996 to 2002 and she became a StaffResearch Scientist in 2003. In April 2004 she became Head of the Molecular Cancer Therapeutics Unit.She is the Scientific Manager of STROMA(since 2004) and ADAMANT(since2008), two IntegratedProjects within the 6 th and 7 th Framework Programs of the European Commission.She is a member of the American Association for Cancer Research (AACR), the European Associationfor Cancer Research (EACR) and the Italian Cancer Society (SIC).Maria Rosa Bani research interests are in the field of cancer biology and molecular therapeutics. She isco-author of 34 peer reviewed publications, 2 book chapters and 65 procee<strong>di</strong>ngs of which 15 selected fororal presentation at international meetings.Selected publications• Ghilar<strong>di</strong> C., Chiorino G., Dossi R., Nagy Z., Giavazzi R., Bani M.R. Identification of novel vascular markers throughgene expression profiling of tumor-derived endothelium. BMC Genomics, 30(9), 201, 2008.• Giavazzi R., Bani M.R.,Taraboletti G.: Tumor–host interaction in the optimization of paclitaxel-based combinationtherapies with vascular targeting compounds. Cancer Metastasis Rev. 26:481–88, 2007.• Naumova E., Ubezio P., Garofalo A., Borsotti P., Cassis L., Riccar<strong>di</strong> E., Scanziani E., Eccles S.A., Bani M.R. &Giavazzi R. The vascular targeting property of paclitaxel is enhanced by SU6668, a receptor tyrosine kinase inhibitor,causing apoptosis of endothelial cells and inhibition of angiogenesis. Clinical Cancer Research 12: 1839-1849, 2006.• Bani M.R., Nicoletti M.I., Alkharouf N.W., Ghilar<strong>di</strong> C., Petersen D., Erba E., Sausville E.A., Liu E.T. and Giavazzi R.Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts. Molecular Cancer Therapeutics3: 111-121, 2004.13ANNUAL REPORT <strong>2009</strong>
IRFMN• Vikhanskaya F.*, Bani M.R.*., Borsotti P., Ghilar<strong>di</strong> C., Ceruti R., Ghisleni G., Marabese M., Giavazzi R., Broggini M.& Taraboletti G. p73 overexpression increases VEGF and reduces thrombospon<strong>di</strong>n-1 production: implication for tumorangiogenesis. Oncogene 20 : 7293-7300, 2001.• Taraboletti G., Sonzogni L., Vergani V., Hosseini G., Ceruti R., Ghilar<strong>di</strong> C., Bastone A., Toschi E., Borsotti P.,Scanziani E., Giavazzi R., Pepper M.S., Stetler-Stevenson W.G. & Bani M.R. Post-transcriptional stimulation ofendothelial cell matrix metalloproteinases 2 and 1 by endothelioma cells. Experimental Cell Research 258 : 384-394,2000.Giovanna Damia obtained her Me<strong>di</strong>cal Degree cum Laude from the University of Milan in 1985. Afterspecializing in Pharmacology at the <strong>Mario</strong> <strong>Negri</strong> Institute of Milan and in Oncology at the University ofMilan, she worked as a post-doctoral fellow in the Laboratory of Experimental Immunology of theNational Cancer Institute, Frederick, USA. She worked as a research fellow in the Laboratory of CancerChemotherapy at the <strong>Mario</strong> <strong>Negri</strong> Institute and since April 2003 she has become chief of the DNA RepairUnit at the <strong>Mario</strong> <strong>Negri</strong> Institute. From 1992 to1995 she has been consultant of the General Secretariat ofthe Progetto Finalizzato CNR "Applicazioni Cliniche della Ricerca Oncologica". Since September 2005she is Deputy E<strong>di</strong>tor for Experimental Oncology of the European Journal of Cancer.Her main fields of interest are: mechanism of action of anticancer drugs, cell cycle checkpointsand natural compounds.Selected publications• Simone M, Erba E, Damia G, Vikhanskaya F, Di Francesco A M, Riccar<strong>di</strong> R, Baldeyrou B, Bailly C, Cuevas C, Sousa-Faro J MF, D'Incalci M. Variolin B and its derivate deoxy-variolin B: New marine natural compounds with cyclin-dependent kinaseinhibitor activity. Eur J Cancer 2005; 41: 2366-2377• Carrassa L, Broggini M, Erba E, Damia G. Chk1, but not Chk2, is involved in the cellular response to DNA damaging agents.Differential activity in cells expressing or not p53. Cell Cycle 2004; 3: 1177-1181• Damia G, Broggini M. Improving the selectivity of cancer treatment by interfering with cell response pathways. Eur J Cancer2004; 40: 2550-2559• Damia G, Broggini M. Cell cycle checkpoint proteins and cellular response to treatment by anticancer agents. Cell Cycle 2004;3: 46-50• Carrassa L, Broggini M, Vikhanskaya F, Damia G. Characterization of the 5' flanking region of the human chk1 gene.Identification of E2F1 functional sites. Cell Cycle 2003; 2: 604-609• Damia G, Sanchez Y, Erba E, Broggini M. DNA damage induces p53-dependent down-regulation of hCHK1. J Biol Chem 2001;276: 10641-10645Eugenio Erba has obtained his Biological and Biochemmistry Analysis Degree at the University ofUrbino. He worked as a research fellow in the Laboratory of Cancer Chemotherapy at the <strong>Mario</strong> <strong>Negri</strong>Institute and since 1984 he is head of the Flow Cytometry Unit in the Department of Oncology at the<strong>Mario</strong> <strong>Negri</strong> Institute of Milan. He has worked as a visiting fellow in the Department of Istochemistryand Cytochemistry of the University of Leiden, The Netherlands in 1983. Since 1997 he is Teacher ofPost-Graduate Stu<strong>di</strong>es in Cytometry at the University of Milan and Co-or<strong>di</strong>nator and Teacher of Post-Graduate Stu<strong>di</strong>es in Cytometry for the Italian Cytometry Group. He has been President of the ItalianCytometry Group from 1999 to 2001. Since 2001 he is member of the Executive Board of the ItalianCytometry Group.Scientific areas of interest: stu<strong>di</strong>es on the mechanism of action of <strong>di</strong>fferent compounds with providedantitumoral activity evaluating the mechanism of cell death and cell cycle phase perturbations inducedon <strong>di</strong>fferent human cancer cell lines by using flow cytometry. Co-or<strong>di</strong>nator of working-group in aquality control study on flow cytometric DNA content analysis in human tumors.Selected publications• C. Forni, M Minuzzo, E. Vir<strong>di</strong>s, E. Tamburini, M. Simone, M. Tavecchio, E. Erba, F. Grosso, A. Gronchi, P.Aman, P.Casali, M. D’Incalci, S. Pilotti , R. Mantovani. Trabecte<strong>di</strong>n (ET-743) promotes <strong>di</strong>fferentiation in myxoid liposarcomatumors. Mol. Ca. Ther. 8(2), 449-57, <strong>2009</strong>• E. Marrazzo, S. Marchini, M. Tavecchio, T. Alberio, S. Previ<strong>di</strong>, E. Erba, V. Rotter, M. BrogginiThe expression of the ΔNp73β isoform of p73 leads to tetraploidy. Eur J Ca 45, 443-53, <strong>2009</strong>• C. Valli, G. Paroni, A. Di Francesco, R. Riccar<strong>di</strong>, M. Tavecchio, E. Erba, A. Boldetti, M. Giannì, M. Fratelli, C. Pisano,L. Merlini, A. Antoccia, C. Cenciarelli, M. Terao, E. Garattini. Atypical retinoids ST1926 and CD437 are S-phasespecific agents causing DNA double-strand breaks: significance for the cytotoxic and antiproliferative activity. Mol.Ca. Ther. 7(9),2941-54, 2008• L. Roncoroni, L. Elli, E. Delfini, E. Erba, E. Dogliotti, C. Terrai, L. Doneda, MG. Grimol<strong>di</strong>, MT. Bardella. Resveratrolinhibits cell growth in a human cholangiocarcinoma cell line. Liver Int. 28(10),1426-36, 2008• M.Tavecchio, M. Simone, E.Erba, I. Chiolo, G. Liberi, M. Foiani, M. D’Incalci, G. Damia. Role of homologousrecombination in trabecte<strong>di</strong>n-induced DNA damage. Eur. J. Ca 44:609-618 (2008)• Paulis M., Bensi M., Orioli D., Mondello C., Mazzini G., D’Incalci M., Falcioni C., Radaelli E., Erba E.,Raimon<strong>di</strong> E., De Carli L. Transfer of a Human Chromosomal Vector from a Hamster Cell Line to a MouseEmbryonic Stem Cell Line. Stem Cell , 25:2543-2550 (2007)14ANNUAL REPORT <strong>2009</strong>
IRFMN• Tavecchio M., Natoli C., Ubezio P., Erba E., D’Incalci M. Dynamics of cell cycle perturbations by trabecte<strong>di</strong>n(ET-743) in nucleotide excision repair (NER) –deficient and NER-proficient cells, unravelled by a novelmathematical simulation approach. Cell Prolif., 40:885-904 (2007)• Tognon G., Bernasconi S., Celli N., Faircloth G.T. Cuevas C., Jimeno J., Erba E., D’Incalci M. Induction ofresistance to Apli<strong>di</strong>n® in a human ovarian cancer cell line related to MDR expression. Cancer Biology andTherapy, 4(12): 1325-1330 (2005).Roldano Fossati got his Me<strong>di</strong>cal Degree cum Laude from the University of Milan in 1980, his Post-Doctoral Degree in Endocrinolgy cum Laude from the University of Verona in 1983 and his Post-Doctoral Degree in Me<strong>di</strong>cal Statistics from the University of Milan in 1992. He has been consultant atthe <strong>Mario</strong> <strong>Negri</strong> Institute since 1983 and, at present, he is head of the Gynecology and Oncology Unit ofthe Laboratory of Translational and Outcome Research.Areas of Interest: Statistical and methodologic aspects of clinical research with focus on ControlledClinical Trials in Oncology; Systematic Overview of the me<strong>di</strong>cal literature.Selected publications• P. Benedetti Panici, A. Maggioni, N. Hacker, F. Landoni, S. Ackermann, E. Campagnutta, K. Tamussino, R. Winter, A.Pellegrino, S. Greggi, R. Angioli, N. Manci, G. Scambia, T. Dell'Anna, R. Fossati, I. Floriani, R.S. Rossi, R. Grassi, G.Favalli, F. Raspagliesi, D. Giannarelli, L. Martella, C. Mangioni. Systematic Aortic and Pelvic Lymphadenectomy versusResection of Bulky Nodes Only in Optimally Debulked Advanced Ovarian Cancer: A Randomized Clinical Trial J NatlCancer Inst 97:1-6;2005• Buda A, Fossati R, Colombo N, Fei F, Floriani I, Gueli Alletti D, Katsaros D, Landoni F, Lissoni A, Calzoni C, Sartori E,Scollo P, Torri V, Zola P, Mangioni C. Randomized trial of neoadjuvant chemotherapy comparing paclitaxel, ifosfamide,and cisplatin with ifosfamide and cisplatin followed by ra<strong>di</strong>cal surgery in patients with locally advanced squamous cellcervical carcinoma: The SNAP01 (Stu<strong>di</strong>o Neo-Adjuvante Por. J Clin Oncol 2005; 23: 4137-4145.• Maggioni A, Benedetti Panici P, Dell'anna T, Landoni F, Lissoni A, Pellegrino A, Rossi RS, Chiari S, Campagnutta E,Greggi S, Angioli R, Manci N, Calcagno M, Scambia G, Fossati R, Floriani I, Torri V, Grassi R, Mangioni C.Randomisedstudy of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis. BrJ Cancer. 2006 Sep 18;95(6):699-704.• Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, Colombo A, Fossati R. Adjuvant chemotherapy vsra<strong>di</strong>otherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006 Aug 7;95(3):266-71• Fruscio R, Colombo N, Lissoni AA, Garbi A, Fossati R, Ieda' N, Torri V, Mangioni C.A phase II randomised clinical trialcomparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly <strong>di</strong>agnosed advancedepithelial ovarian cancer: long-term survival analysis. Br J Cancer. 2008 Feb 5.• Andrea Alberto Lissoni , Nicoletta Colombo, Antonio Pellegrino, Gabriella Parma, Paolo Zola, Dionyssios Katsaros,Stefania Chiari, Alessandro Buda, Fabio Landoni , Michele Peiretti, Tiziana Dell’Anna, Robert Fruscio, Mauro Signorelli,Roberto Grassi, Irene Floriani, Roldano Fossati , Valter Torri, Eliana Rulli . A phase II, randomized trial of neoadjuvantchemotherapy comparing a three-drug combination of paclitaxel, ifosfamide and cisplatin (TIP) versus paclitaxel andcisplatin (TP) followed by ra<strong>di</strong>cal surgery in patients with locally advanced squamous cell cervical carcinoma: the Snap-02 Italian Collaborative Study. Annals of Oncology, 20:660-665;<strong>2009</strong>• Signorelli M, Lissoni AA, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, Zola P, Grassi R,Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, Fossati R. Mo<strong>di</strong>fied Ra<strong>di</strong>cal Hysterectomy VersusExtrafascial Hysterectomy in the Treatment of Stage I Endometrial Cancer: Results From the ILIADE Randomized Study.Ann Surg Oncol. <strong>2009</strong> Oct 16Giulia Taraboletti got her degree cum laude in Biological Sciences at the University of Pavia(Pavia, Italy) in 1983, and the specialization in Pharmacological Research at the <strong>Mario</strong> <strong>Negri</strong>Institute, Milano, Italy in 1986. From 1986 to 1988 she was a post-doctoral fellow at theLaboratory of Pathology, NCI, NIH, Bethesda, MD, and from 1988-1995 research scientist at<strong>Mario</strong> <strong>Negri</strong> Institute in Bergamo, Italy. Since 1995 she is Head of the Unit of TumorAngiogenesis, at <strong>Mario</strong> <strong>Negri</strong> Institute, in Bergamo. Research interests include tumorangiogenesis, endogenous inhibitors of angiogenesis (thrombospon<strong>di</strong>n-1) and preclinical stu<strong>di</strong>esof antiangiogenic and vascular <strong>di</strong>srupting compounds, inclu<strong>di</strong>ng tubulin-targeting agents. She ismember of Metatasis Research Society (MRS), American Association for Cancer Research(AACR), European Association for Cancer Research (EACR), and the Italian Society ofOncology (SIC). She is on the e<strong>di</strong>torial board of European Journal of Cancer.Selected publications• Bonezzi K., Taraboletti G., Borsotti P., Bellina F., Rossi R., Giavazzi R. Vascular <strong>di</strong>srupting activity of tubulin-bin<strong>di</strong>ng1,5-<strong>di</strong>aryl-1H-imidazoles. J Med Chem 52, 7906–7910, <strong>2009</strong>.• Margosio B, Rusnati M, Bonezzi K, Cordes B-lA, Annis DS, Urbinati C, Giavazzi R, Presta M, Ribatti D, Mosher DF,and Taraboletti G. Fibroblast growth factor-2 bin<strong>di</strong>ng to the thrombospon<strong>di</strong>n-1 type III repeats, a novel antiangiogenicdomain. Int J Biochem Cell Biol 40: 700-709, 2008.15ANNUAL REPORT <strong>2009</strong>
IRFMN• Giavazzi R., Bani M.R.,Taraboletti G. Tumor–host interaction in the optimization of paclitaxel-basedcombination therapies with vascular targeting compounds. Cancer Metastasis Rev, 26:481–88, 2007.• Martinelli M., Bonezzi K., Riccar<strong>di</strong> E., Kuhn E., Frapolli R., Zucchetti M., Ryan A.J., Taraboletti G., Giavazzi R.Sequence dependent antitumour efficacy of the vascular <strong>di</strong>srupting agent ZD6126 in combination with paclitaxel. Br JCancer 97:888-94, 2007.• Margosio B., Marchetti D., Vergani V., Giavazzi R., Rusnati M., Presta M., and Taraboletti G. Thrombospon<strong>di</strong>n-1 as ascavenger for matrix-associated fibroblast growth factor-2. Blood 102: 4399-4406, 2003.• Taraboletti G. Micheletti G, Rieppi M, Poli M, Turatto M, Rossi C, Borsotti P, Roccabianca P, Scanziani E, Nicoletti MI,Bombardelli E, Morazzoni P, Riva A, and Giavazzi R. Antiangiogenic and antitumor activity of IDN 5390, a new taxanederivative. Clin Cancer Res. 8: 1182-1188, 2002Paolo Ubezio got his B.Sc. degree in Physics at the University of Milan, in 1982, and the specialisationin Pharmacological Research Specialist" at the <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research in1986.Main activities are: i) Computer simulation of tumor proliferation during/after treatments using modelsbased on the cell cycle; ii) Development of new methods and data analysis tools in flow cytometry and intime-lapse imaging of living cells; iii) Optimization of anticancer drug scheduling.Since 1991 is Head of the Unit of Biophysics at the <strong>Mario</strong> <strong>Negri</strong> InstituteSelected publications• Ubezio, P.; Lupi, M., Branduar<strong>di</strong>, D.; Cappella, P., Cavallini, E., Colombo, V., Matera, G., Natoli, C., Tomasoni, D.,D’Incalci, M. (<strong>2009</strong>) Quantitative assessment of the complex dynamics of G1, S and G2M checkpoint activities. CancerRes. 69: 5234-5240• Valentini, G., D’Andrea, C., Ferrari, R., Pifferi, A., Cubeddu, R., Martinelli, M., Natoli, C., Ubezio, P. and Giavazzi R.(2008) In-vivo measurement of vascular modulation in experimental tumors using a fluorescent contrast agent.Photochem. Photobiol. 84:1249-1256.• Ubezio, P. and Cameron, D. (2008) Cell killing and resistance in pre-operative breast cancer chemotherapy. BMC Cancer8:201.• Basse, B., Ubezio, P. (2007) A generalised age and phase structured model of human tumour cell populations bothumperturbed and exposed to a range of cancer therapies. Bull. Math. Biol. 69:1673-90.• Lupi, M., Matera, G., Natoli, C., Colombo, V., Ubezio, P. (2007) The Contribution of p53 in the Dynamics of Cell CycleResponse to DNA Damage Interpreted by a Mathematical Model. Cell Cycle 6:943-950.• Lupi, M., Matera, G., Branduar<strong>di</strong>, D., D'Incalci M. and Ubezio, P. (2004) Cytostatic and cytotoxic effects of topotecandecoded by a novel mathematical simulation approach. Cancer Res. 64: 2825-2832.Massimo Zucchetti obtained his Chem. Pharm. Degree from the University of Milan in 1982. Afterspecializing in Pharmacology at the <strong>Mario</strong> <strong>Negri</strong> Institute of Milan (1988), he worked in the Laboratoryof Clinical Pharmacology of Department of Oncology at San Giovanni Hospital, Bellinzona, Switzerland(1988-1990). Since 1996 he has been chief of the Cancer Clinical Pharmacology Unit at the <strong>Mario</strong> <strong>Negri</strong>Institute. He is member of the Pharmacology and Molecular Mechanisms Group of the EuropeanOrganization for Research and Treatment of Cancer (EORTC) from 1988 up to date. His main field ofinterest are:- Clinical pharmacology, phase I and Phase II stu<strong>di</strong>es- Analysis of drugs, development of new analytical method, pharmacokinetic andpharmacodynamic stu<strong>di</strong>es in humans in GCP and GLP con<strong>di</strong>tions- Pharmacokinetic, toxicokinetic and metabolic stu<strong>di</strong>es in animals- Pharmacokinetic drug interactionDr Zucchetti is author of more than 90 papers on pre-clinical and clinical cancer chemotherapy publishe<strong>di</strong>n peer reviewed international journals.Selected publications• Frapolli R., Zucchetti M., Sessa C., Marsoni SA., Viganò L., Locatelli A., Rulli E., Compagnoni A., Bello E., Pisano C.,Carminati P., D’Incalci M. Clinical pharmacokinetics of the new oral camptothecin gimatecan: the intra-patientsvariability is related to α1-acid glycoprotein plasma levels. Eur J Cancer 2010; 46: 505-516.• Sala F., Zucchetti M., Bagnati R., D’Incalci M., Pace S., Capocasa F., Marangon E. Development and validation of aHPLC-MS/MS m,ethod for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative, inhuman plasma of patients partecipatig in a phase I study. J Chromatogr B: Anal. Tecnol. Biomed. Life Sci. <strong>2009</strong>; 31: 18-26.• Gambacorti-Passerini CB, Tornaghi L, Marangon E, Franceschino A, Pogliani EM, D'Incalci M, Zucchetti M.. Imatinibconcentrations in human milk Blood. 2007 Feb 15;109(4):1790.• Marangon E, Sala F, Caffo O, Galligioni E, D'Incalci M, Zucchetti M. Simultaneous determination of gemcitabine an<strong>di</strong>ts main metabolite, dFdU, in plasma of patients with advanced non-small-cell lung cancer by high-performance liquidchromatography-tandem mass spectrometry. J Mass Spectrom. 2008 Feb;43(2):216-23.16ANNUAL REPORT <strong>2009</strong>
IRFMN• Frapolli R., Marangon E., Zaffaroni M., Colombo T., Falcioni C., Bagnati R., Simone M., D’Incalci M., Manzotti C.,Fontana G., Morazzoni P., Zucchetti M. Pharmacokinetics and metabolism in mice of IDN 5390 (13-(N-Boc-3-ibutylisoserinoyl)-C-7,8-seco-10-deacetylbaccatinIII), a new oral C-seco-taxane derivative with antiangiogenic propertyeffective on paclitaxel-resistant tumors. Drug Metabolism and Disposition, 34(12):2028-2035 (2006).• Rizzari C., Citterio M., Zucchetti M., Conter V., Chiesa R., Colombini A., Malguzzi S., D’Incalci M. Pharmacologicalstudy on pegylated asparaginase used in front-line treatment of children with acute lymphoblastic leukemia.Hematologica, 91: 24-31 (2006).ACTIVITIESThe Oncology Department comprises three preclinical experimental laboratories (Laboratory ofCancer Pharmacology, Laboratory of Molecular Pharmacology and Laboratory of Biology andTherapy of Metastasis) and four laboratories dealing with clinical research and clinical trials(Laboratory for the Development of New Pharmacological Strategies, Laboratory of ClinicalTrials, Laboratory of Translational and Outcome Research in Oncology and Laboratory forMe<strong>di</strong>cal Research and Consumer Involvement).The Oncology department hosts the coor<strong>di</strong>nation center of two networks of hospitals that carryon clinical research in gynecologic cancer (MaNGO: <strong>Mario</strong> <strong>Negri</strong> Gynecologic Oncology) an<strong>di</strong>n cancer pain (CPOR-SG: Cancer Pain Outcome Research Study Group) and a center forcancer pain assessment and research (CERP:Center for the Evaluation and Research on Pain).In some cases research projects are carried out by single laboratories or research units, in othercases by collaborations between <strong>di</strong>fferent laboratories of the Oncology Department or otherdepartments, or other groups outside the Institute (see National and InternationalCollaborations).Preclinical laboratories focus on the <strong>di</strong>scovery and development of new antitumor andantimetastatic drugs and their new combinations; on tumor biology, not only to acquire newscientific knowledge, but particularly as a base for more selective therapeutic approaches and toidentify and evaluate experimental models for <strong>di</strong>scovering and studying new drugs ortreatments.Clinical new drug development involves close participation in the activity of SENDO (SouthEurope New Drug Development Organization) and stu<strong>di</strong>es driven by the Laboratory of CancerPharmacology, the Laboratory of Molecular Pharmacology and the Laboratory of Biology andTherapy of Metastasis. The Laboratory for the Development of New PharmacologicalStrategies, the Laboratory of Clinical Trials, the Laboratory of Translational and OutcomeResearch in Oncology and the Laboratory for Me<strong>di</strong>cal Research and Consumer Involvement areinvolved in the evaluation of the effects of new therapeutic modalities in phase I/II and in phaseIII comparative and effectiveness outcome stu<strong>di</strong>es.Outcome Research implies organizing trials to clarify the results of certain health care practicesand interventions in clinical practice. Observational (surveys) and outcome research(effectiveness) stu<strong>di</strong>es are carried out, in collaboration with regional and national healthauthorities and other scientific associations.At the preclinical and clinical level there are stu<strong>di</strong>es of various human tumors, with particularemphasis on ovarian tumors and more recently on soft tissue sarcomas.MAIN FINDINGSAt nanomolar concentrations, Trabecte<strong>di</strong>n affects the regulatory mechanisms of thetranscription. Nucleotide excision repair deficient cells that are hypersensitive to UV rays and toother DNA damaging drugs are resistant to Trabecte<strong>di</strong>n.The selective activity of Trabecte<strong>di</strong>n against human myxoid liposarcoma appears related to thedrug ability to modulate the transcription of genes involved in a<strong>di</strong>pocytic <strong>di</strong>fferentiation.17ANNUAL REPORT <strong>2009</strong>
IRFMNTrabecte<strong>di</strong>n modulates the transcription of genes involved in pro-inflammatory mechanisms thatare potentially relevant for tumor growth and progression.New sarcoma experimental models have been obtained. They will be useful to investigate newdrugs for these <strong>di</strong>seases.Use of mathematical models of tumor growth and anticancer treatment to interpret experimentaldata and to manage the complexity of underlying biological phenomena.A new method enabling to perform dynamical measures of cell cycle checkpoint activities inresponse to anticancer treatments.Gene profiling analysis shows specific molecular signatures accor<strong>di</strong>ng to the histotype andprognosis of stage I ovarian carcinoma.The expression of a truncated form of p63 (DNp63) increases with the increased malignancy ofovarian cancer. Patients expressing high levels of DNp63 have a worst prognosis. DNp63represents therefore a new potential target for selective therapies in this malignancy.CHK1 downregulation by specific inhibitors or siRNA, increases the antitumor activity of 5-fluorouracil in vivo. This effect is particularly evident in p53 deficient tumors in<strong>di</strong>cating thatthis combination increases the selectivity of this anticancer agent.An anthracycline derivative, Nemorubicin, has a peculiar mechanism of action and is activeagainst tumors resistant to drugs such as cisplatin. A mechanism of resistance against this drughas been identified, which involves the abrogation of the expression of a nucleotide excisionrepair gene.Overexpression of a truncated form of p73 (DNp73beta) in human cancer cells leads to growtharrest and formation of tetraploid cells, suggesting a role of this isoform in mitosis.A new mechanism of p73 activation me<strong>di</strong>ated by the protease HtrA2 has been identified. Afterapoptotic stimuli this protease cleaves p73 in the C-terminal region increasing its apoptoticpotential.Inositol pentaphosphate analogues interfere with the PI3-kinase-induced phosphorylation of aktand possess antitumor activity in vitro and in vivo, particularly when combined with otheranticancer agents.Human umbilical cord-derived stem cells express checkpoints proteins only in specific<strong>di</strong>fferentiation stages. It is likely that this is related to the <strong>di</strong>fferent susceptibility of the cells.Inhibition of PLC gamma, through siRNA technology, reduces the in vivo growth of tumors andreduces the formation of metastasis.Identification of gene transcripts preferentially expressed by tumor associated endothelial cells.Demonstration that the correspon<strong>di</strong>ng proteins localize within the tumor stroma.VEGF released by cancer cells modulates the gene expression of the tumor microenvironment(stroma). Identification of transcripts.Soluble human VEGFC levels in serum and ascites correlate with tumor progression andmetastatic capability in human ovarian carcinoma models.18ANNUAL REPORT <strong>2009</strong>
IRFMNA new antiangiogenic domain of thrombospon<strong>di</strong>n-1 (an endogenous inhibitor of angiogenesis)that binds the angiogenic factor FGF-2 has been identified and characterized. Non pepti<strong>di</strong>csmall molecules, mimetic of this domain have been designed as potential inhibitors ofangiogenesis.New antineoplastic compounds <strong>di</strong>rected against the tumor vasculature (vascular <strong>di</strong>sruptingagents) have been identified.Proteins for which expression is selectively associated with liver metastasis have been identifie<strong>di</strong>n preclinical models of advanced cancer.The expression of protease-activated receptor-1 (PAR-1) correlates with the malignantphenotype of human melanomas and is accountable for their motility and invasive featuresThe response to chemotherapy was a good surrogate endpoint of survival in patients withlocally advanced cervix carcinoma.Adjuvant chemotherapy with the regimen vindesin, mitomycin C and cisplatin (MVP) <strong>di</strong>d notimprove survival of non small cell lung cancer (NSCLC) patients compared with surgery alone.The website of the project PartecipaSalute (www.partecipasalute.it) has a very innovativecharacter in comparison with the other health Italian sites because it introduces and developsinformation in a very active way with specific instruments.A randomized phase III trial has shown that pelvic systematic lymphadenectomy in earlyendometrial cancer does not improve overall survival. As pelvic systematic lymphadenectomyis not devoid of side effects, this trial will spare patients with early endometrial cancerimportant early and late surgical morbi<strong>di</strong>ties. A twin trial in ovarian carcinoma, published in2005, came to similar conclusions.Results from a systematic review of literature and from a prospective epidemiologic studysuggest that an important proportion of patients with cancer pain (up to 43%) receive ananalgesic treatments that is not appropriate with the intensity of painResults from a survey carried out on a national level on a sample of 1801 patients with cancerpain confirm that in Italy a relevant part of cancer patients does not receive an appropriateinformation about their prognosis: physicians reported that accor<strong>di</strong>ng to their knowledge only31% received information about their prognosis. An independent survey carried out in aNorthern Italian Region confirmed this fin<strong>di</strong>ng: among 550 patienst treated at home for cancerpain with palliative care , only 58% were classified to be fully aware of ther prognosis.An observational longitu<strong>di</strong>nal study carried out in 110 Italian centers and involving about 1800patients with metastatic cancer and pain have documented that that in terms of analgesicseffectiveness, that each drugs prescribed by investigators (morphine, fentanyl, buprenorphineand oxycodone) were able to reduce the intensity of pain of about 2 points on a 11-eleven pointnumerical rating scale (p50%,and III) endometrial carcinoma showed the substantial equivalence between ra<strong>di</strong>otherapy or19ANNUAL REPORT <strong>2009</strong>
IRFMNchemotherapy as an adjuvant therapy after surgery. Although both ra<strong>di</strong>otherapic andchemotherapic approaches are still unsatisfactory, since the risk of progression or death remainshigh, this encouraging evidence of clinical activity suggest a possible use of their concurrent orsequential use in an adjuvant setting.A randomized phase III trial has shown that a mo<strong>di</strong>fied ra<strong>di</strong>cal (Piver-Rutledge class II)hysterectomy does not improve survival and locoregional control compared to the standardextrafascial (Piver-Rutledge class I) hysterectomy in patients with stage I endometrial cancer .This trial has enrolled 520 patients who have been followed-up for over 5 yearsThe training and information activity organized with the associations of citizens & patients inthe framework of the PartecipaSalute project has been finalized to the organization of the Paritatask “Participate to the research project with the associations”. Parita is organised to <strong>di</strong>scusswith the scientific community the grey areas of the me<strong>di</strong>cal assistance and clinical researchidentified from the patients and their associations, and to develop specific protocols for futureresearch programs.NATIONAL COLLABORATIONSASR, Agenzia Sanitaria Regionale, BolognaAIFA, Agenzia Italiana del Farmaco (Roma)Azienda Sanitaria Locale, RiminiAssessorato Sanità, Regione Emilia RomagnaAzienda Sanitaria Unica Regionale, Regione MarcheCasa Sollievo della Sofferenza, San Giovanni Rotondo (IRCCS)CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, MilanoCNR IGBE, PaviaCNR, <strong>Istituto</strong> <strong>di</strong> Chimica del Riconoscimento Molecolare, MilanoCochrane CollaborationENEA Centro <strong>Ricerche</strong>, Unità <strong>di</strong> Tossicologia e Scienze Biome<strong>di</strong>che, RomaFondazione IRCCS <strong>Istituto</strong> Nazionale dei Tumori (INT), MilanoFondazione <strong>Istituto</strong> FIRC <strong>di</strong> Oncologia Molecolare (IFOM), MilanoFondazione LUVI, MilanoFondazione Nerina e <strong>Mario</strong> Mattioli Onlus, MilanoFondazione Salvatore Maugeri, PaviaFondazione SmithKline (FSK), MilanoFondo Edo Tempia, Laboratorio <strong>di</strong> Farmacogenomica, BiellaI.A.S.I., Roma<strong>Istituto</strong> Clinico Humanitas, Rozzano MI<strong>Istituto</strong> Dermopatico dell'Immacolata, Roma<strong>Istituto</strong> Ortope<strong>di</strong>co Galeazzi, MilanoIstituti Ortope<strong>di</strong>ci Rizzoli, Bologna<strong>Istituto</strong> Europeo <strong>di</strong> Oncologia (IEO), Milano<strong>Istituto</strong> <strong>di</strong> Fisica, Politecnico <strong>di</strong> Milano<strong>Istituto</strong> <strong>di</strong> Genetica Molecolare CNR, Sezione <strong>di</strong> Istochimica e Citometria, Pavia<strong>Istituto</strong> Nazionale per la Ricerca sul Cancro (IST), Genova<strong>Istituto</strong> Nazionale Tumori Fondazione G. Pascale, Napoli<strong>Istituto</strong> Regina Elena, Roma<strong>Istituto</strong> Superiore <strong>di</strong> Sanità20ANNUAL REPORT <strong>2009</strong>
IRFMNLaboratorio Cell factory, Policlinico <strong>di</strong> MilanoOspedale San Gerardo, Monza, MilanoOspedale San Matteo, PaviaOspedale Santa Chiara, TrentoRete Oncologica Lombarda (ROL), MilanoUniversità Cattolica del Sacro Cuore, RomaUniversità <strong>di</strong> BariUniversità <strong>di</strong> BresciaUniversità <strong>di</strong> ChietiUniversità <strong>di</strong> L’AquilaUniversità <strong>di</strong> MilanoUniversità <strong>di</strong> Modena e Reggio EmiliaUniversità <strong>di</strong> MonzaUniversità <strong>di</strong> CataniaUniversità <strong>di</strong> PadovaUniversità <strong>di</strong> PisaUniversità <strong>di</strong> SienaUniversità “La Sapienza”, RomaZa<strong>di</strong>g, Agenzia <strong>di</strong> Giornalismo scientificoINTERNATIONAL COLLABORATIONSADAMANT Consortium, IP 7th FP, ECARCAGY (Association de Recherche sur les Cancers Gynécologiques), FranceBreakthrough Breast Cancer Center, Instutite of Cancer Reasearch, London, U.K.Cancer Biomarkers and Prevention Group, University of Leicester, U.K.Cancer Research UK, London, U.K.EORTC, Brussels, BelgiumEUROPA DONNAEuropean Agency for the Evaluation of Me<strong>di</strong>cinal Products (EMEA), London, U.K.European Association for Palliative Care (EAPC)European Network of Gynaecological Oncology Trials groups (ENGOT)Eusoma – (EuropeanSociety of Breast Cancer Specialist) Florence, ItalyExecutive Board of GCIG (Gynecologic Cancer Intergroup)Frontier science & technology Research Foundation Southern Europe (FSE)Genome Institute of Singapore (GIS), SingaporeGerman Cancer Research Center, Division of Toxicology and Cancer Risk Factors, Heidelberg,GermanyGoteborg University, Lundberg Laboratory for Cancer Research, Goteborg, SwedenGynecologic Cancer Intergroup (GCIG)Helios Klinikum Erfurt GmbH, Institute of Pathology, GermanyInstitute of Pathology, Friedrich Schiller University, Jena, Germany<strong>Istituto</strong> Oncologico della Svizzera ItalianaJohns Hopkins University, USALudwig Institute for Cancer Research, London, U.K.National Cancer Center, SingaporeStony Brook University, NY, USAMassachusetts General Hospital and Harvard Me<strong>di</strong>cal School, USAMD Anderson Cancer Center, Houston, Texas, USAMRC, London, U.K.21ANNUAL REPORT <strong>2009</strong>
IRFMNNational Cancer Institute (NCI), Bethesda and Frederick, MD, USAOspedale San Giovanni, Bellinzona, SwitzerlandPaterson Institute for Cancer Research, Manchester, U.K.Southern Europe New Drug Organization (SENDO), Milan, ItalySwiss Federal Institute of Technology, Zurich, SwitzerlandThe Sackler Institute, University College London, U.K.Tumor Biology and Metastasis Institute of Cancer Research, Sutton, U.K.University College, London Me<strong>di</strong>cal School, London, U.K.University of Birmingham, U.K.University of Cincinnati, USAUniversity of Crete Me<strong>di</strong>cal School, GreeceUniversity of Newcastle, U.K.University of Pau, FranceUniversity of Wisconsin, Ma<strong>di</strong>son, WI, USAKyoto University, JapanWeizmann Institute of Science, IsraelEDITORIAL BOARD MEMBERSHIPAttualità in Senologia (Paola Mosconi)British Journal of Cancer (Maurizio D’Incalci)Chemotherapy (Maurizio D’Incalci)Clinical Experimental Metastasis (Raffaella Giavazzi)Current Opinion in Oncologic, Endocrine and Metabolic Drugs (Maurizio D’Incalci)Current Cancer Therapy Reviews (Raffaella Giavazzi)European Journal of Cancer (Maurizio D’Incalci, Giovanna Damia, Raffaella Giavazzi,Massimo Broggini e Giulia Taraboletti)Health and Quality of Life Outcomes (Giovanni Apolone, Paola Mosconi)International Journal of Biological Markers (Raffaella Giavazzi)International Journal for Quality in Health Care (Giovanni Apolone)Journal of Ambulatory Care and Management (Giovanni Apolone)Journal of B.U.ON. (Maurizio D’Incalci)Journal of Cancer Microenvironment (Raffaella Giavazzi)Journal of Chemotherapy (Raffaella Giavazzi)Journal of Experimental Therapeutics and Oncology (Raffaella Giavazzi)Journal of Me<strong>di</strong>cine and the Person (Giovanni Apolone)Journal of Preventive Me<strong>di</strong>cine anf Hygiene (Giovanni Apolone)Molecular Cancer Therapeutics (Maurizio D’Incalci)Oncology Research (Maurizio D’Incalci)Tumori (Maurizio D’Incalci, Raffaella Giavazzi)www.PartecipaSalute.it (Paola Mosconi)www.fondazionemattioli.it (Paola Mosconi)PEER REVIEW ACTIVITIESAmerican Journal of Pathology, Annals of Oncology, Anti-cancer Drugs, BiochemicalPharmacology, BioMed Central E<strong>di</strong>torial, British Journal of Cancer, British Journal ofPharmacology, British Me<strong>di</strong>cal Journal, Cancer Chemotherapy and Pharmacology, CancerDetection and Prevention, Cancer Letters, Cancer Research, Carcinogenesis, Chemico-Biological Interactions, Clinical & Experimental Metastasis, Clinical Cancer Research,22ANNUAL REPORT <strong>2009</strong>
IRFMNCytometry, European Journal of Cancer, European Journal of Immunology, European Journal ofNeurology, Faseb Journal, Gynecologic Oncology, Health and Quality of Life Outcomes,Health Expectations, European Journal of Neurology, Intensive Care Me<strong>di</strong>cine, InternationalJournal of Biological Markers, International Journal of Cancer, International Journal for Qualityin Health Care, Journal of Ambulatory Care and Management, Journal of Biological Chemistry,Journal of Biological Markers, Journal of Cell Biochemistry, Journal of Clinical Oncology,Journal of Experimental Therapeutics and Oncology, Journal of Me<strong>di</strong>cinal Chemistry, Journalof Me<strong>di</strong>cine and the Person, Journal of the National Cancer Institute, Journal of Neurology,Journal of Preventive Me<strong>di</strong>cine and Hygiene, Journal of the National Cancer Institute,Leukemia, Molecular Cancer Therapeutics, Nature Biotechnology, Nature Reviews, OncologyResearch, PharmacoEconomics, Quality of Life Research, Science, The Patient: patientcenteredoutcomes research, Tumori, ZEG Centre for Epidemiology & Health Research.NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPEthical Committee, Centro <strong>di</strong> Riferimento Oncologico, Aviano PN, ItalyEthical Committee, Ente Ospedaliero San Paolo, Milan, ItalyEthical Committee, <strong>Istituto</strong> Europeo <strong>di</strong> Oncologia, Milan, ItalyEthical Committee, <strong>Istituto</strong> Neurologico Carlo Besta, Milan, ItalyEthical Committee, <strong>Istituto</strong> Scientifico Eugenio Medea, Bosisio Parini, Lecco, ItalyEthical Committee, Ospedale San Gerardo, Monza, Milan, ItalyEthical Committee, Ospedale Sant’Anna, Como, ItalyEthical Committee, Ospedale della Valtellina e Valchiavenna, Sondrio, ItalyEthical Committee, IRCCS MultiMe<strong>di</strong>ca, Sesto San Giovanni, Milan, ItalyEthical Committee, Azienda USL <strong>di</strong> Bologna, ItalyExecutive Board of GCIG (Gynecologic Cancer Intergroup)Scientific Committee, Associazione Italiana Ematologia e Oncologia Pe<strong>di</strong>atrica, Monza, Milan,ItalyScientific Committee, Pezcoller Foundation, Trento, ItalyTechnical-Scientific Commitee, Associazione Italiana per la Ricerca sul Cancro, Milan, ItalyBoard of Directors, Fondazione Nerina e <strong>Mario</strong> Mattioli Onlus, Milan, ItalyBoard of Directors, Società Italiana <strong>di</strong> Cancerologia (SIC)Board of Directors, Società Italiana <strong>di</strong> Citometria (GIC)Directional Council Areas-CCINational Advisory Board 8th World Congress of Psycho-OncologyDevelopmental Therapeutics Program, National Cancer Institute (NCI)Decision Network and Executive Committee, South Europe New Drug Organization (SENDO)Executive Board, Europa DonnaExecutive Committee, European Asociation for Cancer Research (EACR)Fondazione Attilia Pofferi, Pistoia, ItalyNHS R&D National Coor<strong>di</strong>nating Centre for Health Technology Assessment, UKPezcoller Foundation-ECCO AwardUniversity Me<strong>di</strong>cal School of Siena, ItalyEVENT ORGANIZATIONIl Comitato etico: luogo <strong>di</strong> partecipazione tra laici e tecnici?Fondazione IRCCS <strong>Istituto</strong> Nazionale dei Tumori, Milan, January 13, <strong>2009</strong>.23ANNUAL REPORT <strong>2009</strong>
IRFMNInvestigators’ Meeting “Cetuximab”, <strong>Istituto</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong> ”, MilanMarch 30, <strong>2009</strong>.International Clinical Trials’ Day.<strong>2009</strong> Strategie <strong>di</strong> promozione della salute e delle malattie:quale spazio per le evidenze degli stu<strong>di</strong> clinici. Milan, May 20, <strong>2009</strong>.Meeting: Assessment of cancer pain in clinics and in research. Need for a common internationalmethodology? <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> Faramacologiche <strong>Mario</strong> <strong>Negri</strong>, Milan, September 9-10, <strong>2009</strong>.Investigators’ Meeting “Head & Neck trial” Congresso AIOM, Milan, October 12, <strong>2009</strong>.Investigators’ Meeting “Tailor trial” Congresso AIOM, Milan, October 11, <strong>2009</strong>.Investigators’ Meeting “TOSCA” Congresso AIOM, Milan, October 11, <strong>2009</strong>.Investigators’ Meeting “COMETS” Congresso AIOM, Milan, October 11, <strong>2009</strong>.XXVII Conferenza Nazionale <strong>di</strong> Citometria, Centro Congressi Ferrara, October 14-17, <strong>2009</strong>.IV e<strong>di</strong>zione percorso <strong>di</strong> formazione PartecipaSalute - “L’Accademia del Citta<strong>di</strong>no”. Milan,Montecatini Terme, October <strong>2009</strong>-March 2010.CONFERENCE AND WORKSHOP CONTRIBUTIONSWorkshop: Chemoresistance - a major treatment failure in oncology. “Experimental bases”.Milan (Italy), January 21, <strong>2009</strong>.Update sull’angiogenesi ad un anno dalla scomparsa <strong>di</strong> Judah Folkman. Rome (Italy), January24, <strong>2009</strong>. “Stu<strong>di</strong> preclinici con inibitori dell’angiogenesi”.Meeting: Trabecte<strong>di</strong>n: Soft Tissue Sarcoma Treatment. New Horizons in Oncology. ”Drugs ofMarine Origin”. Antequera, Malaga (Spain), February 12, <strong>2009</strong>.Conference: Exploitation of research outcomes towards cancer patients’ expectations: Europeanperspectives. ”The importance of translational research for drug development: the example ofthe marine natural product ET-743”. Bruxelles (Belgium), March 17, <strong>2009</strong>.Conference: IV Assemblea Plenaria, Conferenza Provinciale sulla Salute “La malattia cheimpoverisce. La povertà che fa ammalare “Per <strong>di</strong>scutere del valore del risultato dell’indagineper l’introduzione <strong>di</strong> nuovi strumenti <strong>di</strong> misura nella pratica me<strong>di</strong>ca”, Turin (Italy), March 26,<strong>2009</strong>.CNIO Scientific Symposium: Molecular markers in cancer therapy: present use and futureperspectives. San Lorenzo de El Escorial, Madrid (Spain), March 26-27, <strong>2009</strong>.“Gene expression analysis of endothelial cells revealed novel markers of tumor vasculature”.“Human Ovarian carcinoma xenografts equipped with <strong>di</strong>fferent angiogenic phenotype <strong>di</strong>ffer inthe transcriptional profile profile of their stroma”.Conference: XVII Conferenza Nazionale AIOM: Clinical pathways nel carcinoma del colonretto: dalle linee guida alla pratica clinica. Florence (Italy), April 2-4, <strong>2009</strong>.24ANNUAL REPORT <strong>2009</strong>
IRFMNConference: IV Giornata <strong>di</strong> Stu<strong>di</strong>o Novarese “Il Carcinoma Ovarico: conoscenze attuali eprospettive future” La ricerca collaborativa del tumore ovarico: l’esperienza del MaNGO. SantaMargherita Ligure (Italy), April 18, <strong>2009</strong>.Meeting: 100 th AACR <strong>Annual</strong> Meeting. Denver (USA), April 18-22, <strong>2009</strong>.“PTX-008, a non-pepti<strong>di</strong>c topomimetic of the antiangiogenic galectin-1-targeting anginex:<strong>di</strong>fferential antiproliferative activity on cancer and endothelial cells”.“Identification of novel markers of tumor-associated vasculature”.XIII Riunione scientifica annuale, Italian Sarcoma Group. ”Meccanismo d’azione e selettivitàper alcuni subset <strong>di</strong> pazienti”. Turin (Italy), April 20-21, <strong>2009</strong>.Meeting AGO-OVAR 12 VARGATEF, Frankfurt (Germany) April 28, <strong>2009</strong>.Course: Corso <strong>di</strong> perfezionamento “Formazione clinica, comunicazione e management inCar<strong>di</strong>ologia": Novità nella ricerca farmacologica car<strong>di</strong>ovascolare. <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milan (Italy), May 27, <strong>2009</strong>.Meeting: 45° Meeting ASCO, Orlando (USA) May 29 – June 2, <strong>2009</strong>.Conference: ESH Conference on Angiogenesis. Helsinki (Finlan<strong>di</strong>a), June 5-8, <strong>2009</strong>.“Ovarian tumor models to study lymphatic spread”.Assembly: VI Assemblea Gruppo Mango, Turin (Italy), June 12, <strong>2009</strong>.Symposium: 21 th Pezcoller Symposium. Trento (Italy), June 11-13, <strong>2009</strong>.Novel “vascular markers” highly expressed by human tumor endothelial cells.Meeting: Young Life Scientist <strong>2009</strong> - Networking Angiogenesis: bridging young researchers inthe vascular biology field. University of Chester (UK), July 14, <strong>2009</strong>.“The rational for combination treatments with vascular targeting therapy”.Meeting: Assessment of cancer pain in clinics and in research. Need for a common internationalmethodology? <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> Faramacologiche <strong>Mario</strong> <strong>Negri</strong>, Milan (Italy), September 9-10, <strong>2009</strong>.Course: Emerging Issues nei Sarcomi dei Tessuti Molli. “Trabecte<strong>di</strong>na: meccanisco <strong>di</strong> azione easpetti farmacologici”. Brescia (Italy), September 28, <strong>2009</strong>.Congress: XI Congresso Nazionale SIPO “Professionalità ed Innovazione in Psico-Oncologia”Dolore Oncologico: coinvolgere i pazienti nella valutazione e nel trattamento. Senigallia (AN,Italy) October 1-3, <strong>2009</strong>.Congress: XI Congresso Nazionale dell’Associazione Italiana <strong>di</strong> Oncologia Me<strong>di</strong>ca (AIOM),Simposio Satellite: Farmaci dal mare: realtà emergente. “Nuovi prodotti naturali marini: statodell’arte e prospettive”. Milan (Italy), October 10-13, <strong>2009</strong>.Meeting: XVI Meeting Internazionale della Società Europea <strong>di</strong> Ginecologia Oncologica,Belgrado, October 11-14, <strong>2009</strong>.Conference: XXVII Conferenza Nazionale <strong>di</strong> Citometria, Centro Congressi Ferrara (Italy),October 14-17, <strong>2009</strong>.25ANNUAL REPORT <strong>2009</strong>
IRFMNConference: International Conference on Tumor Microenvironment: Progression, Therapy &Prevention.Versailles (France), October 20-24, <strong>2009</strong>.“Interactions of Tumor Cells with Microenvironmental Cells & Molecules I”.Congress: XVI Congresso Nazionale della Società Italiana <strong>di</strong> Cure Palliative. Stu<strong>di</strong>o <strong>di</strong>Outcome <strong>Mario</strong> <strong>Negri</strong>: dati <strong>di</strong> confronto nel dolore da cancro. Lecce (Italy), October 27-30,<strong>2009</strong>.Congress: II° Convegno <strong>di</strong> Oncologia Interventistica: Tecniche innovative nel trattamento deitumori primitivi epatici. ”Importanza degli stu<strong>di</strong> <strong>di</strong> farmacocinetica per ottimizzare le terapieoncologiche”. Cervesina (PV, Italy), November 6-7, <strong>2009</strong>.Congress: II Congresso del Gruppo Oncologico Chirurgico Cooperativo Italiano: TerapieMe<strong>di</strong>che Innovative in Oncologia. ”Progressi nella terapia me<strong>di</strong>ca dei sarcomi dei tessutimolli”. Florence (Italy), November 6-7,<strong>2009</strong>.Congress: VIII Convegno ACD SIAARTI <strong>2009</strong>. Oppioi<strong>di</strong> a rapido onset nel breakthroughcancer pain. Rome (Italy), November 11-13, <strong>2009</strong>Conference: AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics. Boston (USA),November 15-19, <strong>2009</strong>.“Antiangiogenic proprieties of E-3810, a new dual inhibitor of VEGF and FGF receptors”.51 st <strong>Annual</strong> Meeting of the Italian Cancer Society (SIC). Sesto S. Giovanni (Milan, Italy)November 23-26, <strong>2009</strong>.“Protease-activated receptor-1 (PAR-1) expression contributes to the metastatic capabilities ofprimary melanoma lesions”.“Renal carcinoma as model for anti-angiogenic therapy”.“Antiangiogenic and antineoplastic activity of PTX-008, a nonpepti<strong>di</strong>c topomimetic ofAnginex”.“Lymphatic spread: models of ovarian carcinoma xenografts”.“The effect of vandetanib on tumor vasculature remodeling and paclitaxel uptake reflects theantitumor activity in a xenograft model of human ovarian carcinoma”.“Human Vascular Endothelial Growth Factor affects response to paclitaxel treatment in a modelof ovarian carcinoma”.“Dual targeting of cancer and endothelial cells by gonadotropin-releasing hormone agonist toreduce melanoma angiogenesis”.“The isothiocyanate produced from glucomoringin inhibits NF-KB and reduces myelomagrowth in nude mice in vivo”.“Molecular mechanisms of resistance to trabecte<strong>di</strong>n of a myxoid liposarcoma cell line”.“Stu<strong>di</strong>es on the ‘tumor initiating cell’ of ovarian cancer”.“Generation-wise cell cycle analysis: a new insight into antiproliferative activity of anticancertreatments”.”From sea to bedside: trabecte<strong>di</strong>n, a success story of translational research”.Congress: V Congresso Nazionale “Approccio globale la paziente oncologico”, Forlì (Italy),November 25-27, <strong>2009</strong>.Conference: Nuovi orizzonti nella gestione del paziente oncologico con BTcP: Valutazionedella frequenza e dell’impatto del BTcP in uno stu<strong>di</strong>o longitu<strong>di</strong>nale. Rome (Italy), December 4,<strong>2009</strong>.26ANNUAL REPORT <strong>2009</strong>
IRFMNCongress: VII congresso COMU: Problematiche emergenti sull’uso dei nuovi farmaci inoncologia. ”La Trabecte<strong>di</strong>na”. Florence (Italy), December 17-18, <strong>2009</strong>.GRANTS AND CONTRACTSAIFA Agenzia Italiana del FarmacoArcispedale Santa Maria Nuova <strong>di</strong> Reggio-EmiliaAzienda Sanitaria Locale - RiminiAzienda Sanitaria Unica Regionale - MARCHEAIFA Agenzia Italiana del FarmacoAmgem SpA, MilanoAIRC Associazione Italiana per la Ricerca sul CancroASL PadovaASL Provincia <strong>di</strong> Lo<strong>di</strong>Astra Zeneca SpAAstra Zeneca UKAVAPO (Associazione Volontari Assistenza Pazienti Oncologici)Aventis PharmaAzienda Ospedaliera Fatebenefratelli e Oftalmico- MilanoAzienda Sanitaria Locale, RiminiAzienda Sanitaria Unica Regionale, MarcheAzienda Ospedaliera “Spedali Civili <strong>di</strong> Brescia”Bracco Imaging SpA, MilanCentro Cochrane ItalianoChiesi Farmaceutici SpACIPOMO (Collegio Italiano dei Primari Oncologi Me<strong>di</strong>ci Ospedalieri)CNPDS, Centro Nazionale per la prevenzione e Difesa Sociale, MilanoCNR Consiglio Nazionale delle <strong>Ricerche</strong>CNR-MIUR Ministero Istruzione Università e RicercaCompagnia <strong>di</strong> San PaoloDompéEli Lilly Italia SpAElsevier Science Ltd.EORTC-European Organization for Research and Treatment of CancerEOS SpAEuropean Commission - 7th Framework Programme (ADAMANT)FIRB-MIUR Fondo per gli Investimenti della Ricerca <strong>di</strong> Base-Ministero Istruzione Università eRicercaFIRC Fondazione Italiana per la Ricerca sul CancroFondazione Cassa <strong>di</strong> Risparmio delle Province LombardeFondazione SmithKline, RomaFondazione Lu.V.I.Fondazione Nerina e <strong>Mario</strong> Mattioli OnlusFSE Frontier Southern EuropeGISCAD(Gruppo Italiano Stu<strong>di</strong> <strong>di</strong> Carcinomi Apparato Digerente)GlaxoSmithKline, VeronaGrunenthal Italia, MilanoIndena SpA27ANNUAL REPORT <strong>2009</strong>
IRFMNInstitut de Recherche Pierre Fabre<strong>Istituto</strong> Clinico Humanitas – Rozzano<strong>Istituto</strong> Nazionale dei Tumori, Milano<strong>Istituto</strong> Superiore <strong>di</strong> SanitàKomen Italia OnlusLottomaticaMedacMerck Sharp & DomeMinistero della SaluteNerviano Me<strong>di</strong>cal Science S.r.l.NovartisNovartis Farma SpANovartis Pharmaceuticals Corporation, East Hanover, NJ, USAOncoethixOptigenex Inc.Pfizer Global Research and DevelopmentPfizer ItaliaPharma Mar, SAPharminox Ltd, UKPoliclinico <strong>di</strong> Padova / C.O.R.Regione Emilia RomagnaRegione Lombar<strong>di</strong>aRegione ToscanaRegione VenetoSanofi-Aventis PharmaSara Bet, RomaSENDO-Tech SrlSigma-Tau SpAUniversità degli Stu<strong>di</strong> <strong>di</strong> PadovaUniversità Federico II – Napoli (Dipartimento <strong>di</strong> Endocrinologia ed Oncologia molecolare eclinica)SCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Frapolli R, Zucchetti M, Sessa C, Marsoni S, Vigano' L, Locatelli A, Rulli E, Compagnoni A, Bello E,Pisano C, Carminati P, D'Incalci MClinical pharmacokinetics of the new oral camptothecin gimatecan: The inter-patient variability is related to α(1)-acidglycoprotein plasma levelsEur J Cancer <strong>2009</strong> E-pub :Cesca M, Frapolli R, Berndt A, Scarlato V, Richter P, Kosmehl H, D’Inclaci M, Ryan AJ, Giavazzi RThe effects of vandetanib on paclitaxel tumor <strong>di</strong>stribution and antitumor activity in a xenograft model of humanovarian carcinomaNeoplasia <strong>2009</strong> 11(11) : 1155-64Ferketich A K, Gallus S, Colombo P, Apolone G, Rossi S, Zuccaro P, La Vecchia CUse of pharmacotherapy while attempting cessation among Italian smokersEur J Cancer Prev <strong>2009</strong> 18 : 90-92Carrassa L, Sanchez Y, Erba E, Damia GU2OS cells lacking Chk1 undergo aberrant mitosis and fail to activate the spindle checkpointJ Cell Mol Med <strong>2009</strong> 13 : 1565-1576Forni C, Minuzzo M, Vir<strong>di</strong>s E, Tamborini E, Simone M, Tavecchio M, Erba E, Grosso F, Gronchi A,Aman P, Casali P, D'Incalci M, Pilotti S, Mantovani R28ANNUAL REPORT <strong>2009</strong>
IRFMNTrabecte<strong>di</strong>n (ET-743) promotes <strong>di</strong>fferentiation in myxoid liposarcoma tumorsMol Cancer Ther <strong>2009</strong> 8 : 449-457Corli O, Apolone G, Pizzuto M, Cesaris L, Cozzolino A, Orsi L, Enterri LIllness awareness in terminal cancer patients: an Italian studyPalliat Med <strong>2009</strong> 23 : 354-359Lissoni A A, Colombo N, Pellegrino A, Parma G, Zola P, Katsaros D, Chiari S, Buda A, Landoni F,Peiretti M, Dell'Anna T, Fruscio R, Signorelli M, Grassi R, Floriani I, Fossati R, Torri V, Rulli EA phase II, randomized trial of neo-adjuvant chemotherapy comparing a three-drug combination of paclitaxel,ifosfamide, and cisplatin (TIP) versus paclitaxel and cisplatin (TP) followed by ra<strong>di</strong>cal surgery in patients withlocally advanced squamous cell ceAnn Oncol <strong>2009</strong> 20 : 660-665Marangon E, Citterio M, Sala F, Barisone E, Lippi A A, Rizzari C, Bion<strong>di</strong> A, D'Incalci M, Zucchetti MPharmacokinetic profile of imatinib mesylate and N-desmethyl-imatinib (CGP 74588) in children with newly<strong>di</strong>agnosed Ph+ acute leukemiasCancer Chemother Pharmacol <strong>2009</strong> 63 : 563-566Sessa C, Perotti A, Noberasco C, de Braud F, Gallerani E, Cresta S, Zucchetti M, Vigano' L, Locatelli A,Jimeno J, Feilchenfeldt J W, D'Incalci M, Capri G, Ielmini N, Gianni LPhase I clinical and pharmacokinetic study of trabecte<strong>di</strong>n and doxorubicin in advanced soft tissue sarcoma and breastcancerEur J Cancer <strong>2009</strong> 45 : 1153-1161Nal<strong>di</strong>ni A, Filippi I, Ar<strong>di</strong>nghi C, Silini Antonietta, Giavazzi R, Carraro FIdentification of a functional role for the protease-activated receptor-1 in hypoxic breast cancer cellsEur J Cancer <strong>2009</strong> 45 : 454-460Marrazzo E, Marchini S, Tavecchio M, Alberio T, Previ<strong>di</strong> S, Erba E, Rotter V, Broggini MThe expression of the ΔNp73β isoform of p73 leads to tetraploidyEur J Cancer <strong>2009</strong> 45 : 443-453Apolone G, Corli O, Caraceni A, <strong>Negri</strong> E, Deandrea S, Montanari M, Greco M T, CPOR SGInvestigatorsPattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome Research StudyGroupBr J Cancer <strong>2009</strong> 100 : 1566-1574Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, Masi Gianluca, Graziano F, Cremolini C,Rulli E, Canestrari E, Funel N, Schiavon G, Petrini I, Magnani M, Tonini G, Campani D, Floriani I,Cascinu S, Falcone APTEN Expression and KRAS Mutations on Primary Tumors and Metastases in the Pre<strong>di</strong>ction of Benefit FromCetuximab Plus Irinotecan for Patients With Metastatic Colorectal CancerJ Clin Oncol <strong>2009</strong> 27 : 2622-2629Mandalà M, Barni S, Floriani I, Isa L, Fornarini L, Marangolo M, Mosconi P, Corsi D, Rulli E, FrontiniL, Cortesi E, Zaniboni A, Aglietta M, Labianca R, GISCADIncidence and clinical implications of venous thromboembolism in advanced colorectal cancer patients: the'GISCAD-alternating schedule' study fin<strong>di</strong>ngsEur J Cancer <strong>2009</strong> 45 : 65-73Riva E, Tettamanti M, Mosconi P, Apolone G, Gan<strong>di</strong>ni F, Nobili A, Tallone M V, Detoma P, GiacominA, Clerico M, Tempia P, Guala A, Fasolo G, Lucca UAssociation of mild anemia with hospitalization and mortality in the elderly: the Health and Anemia population-basedstudyHaematologica <strong>2009</strong> 94 : 22-28Graziano F, Ruzzo A, Canestrari E, Loupakis F, Santini D, Rulli E, Humar B, Galluccio N, Bisonni R,Floriani I, Maltese P, Falcone A, Tonini G, Catalano V, Fontana A, Giustini L, Masi G, Vincenzi B,Alessandroni P, Magnani M29ANNUAL REPORT <strong>2009</strong>
IRFMNVariations in the interleukin-1 receptor antagonist gene impact on survival of patients with advanced colorectalcancer Pharmacogenomics J <strong>2009</strong> 9 : 78-84Marano R, De Cobelli F, Floriani I, Becker C, Herzog C, Centonze M, Morana G, Gual<strong>di</strong> G F, LigabueG, Pontone G, Catalano C, Chiappino D, Mi<strong>di</strong>ri M, Simonetti G, Marchisio F, Olivetti L, Fattori R,Bonomo L, Del Maschio Alessandro, NIMISCAD Study GroupItalian multicenter, prospective study to evaluate the negative pre<strong>di</strong>ctive value of 16- and 64-slice MDCT imaging inpatients scheduled for coronary angiography (NIMISCAD-Non Invasive Multicenter Italian Study for CoronaryArtery Disease)Eur Ra<strong>di</strong>ol <strong>2009</strong> 19 : 1114-1123D'Incalci MThe potential impact of marine compounds in the era of targeting therapiesIn :International Oncology Updates Permanyer Publications, Mallorca (Spain), <strong>2009</strong>; 1-18Corich L, Aranda A, Carrassa L, Bellarosa C, Ostrow J D, Tiribelli CThe cytotoxic effect of unconjugated bilirubin in human neuroblastoma SH-SY5Y cells is modulated by theexpression level of MRP1 but not MDR1Biochem J <strong>2009</strong> 417 : 305-312D'Incalci MAdjuvant 5-FU based chemotherapy for colon cancer: match or miss the mismatch?Eur J Cancer <strong>2009</strong> 45 : 316-317Mosconi P, Donati S, Colombo Cinzia, Mele A, Liberati A, Satolli R, Consensus Conference WorkingGroupInforming women about hormone replacement therapy: the Consensus conference statemenBMC Womens Health <strong>2009</strong> 9 : 14Apolone G, Corli O, <strong>Negri</strong> Emanuele, Mangano S, Montanari M, Greco M T, CPOR SG InvestigatorsEffect of transdermal buprenorphine on patients-reported outcomes in cancer patients. Results from the Cancer PainOutcome Research (CPOR) Study GroupClin J Pain <strong>2009</strong> 25 : 671-682De Vargas Macciucca M, Casale A, Manganaro L, Floriani I, Fiore F, Marchetti L, Panzironi GRectal villous tumours: MR features and correlation with TRUS in the preoperative evaluationEur J Ra<strong>di</strong>ol <strong>2009</strong> E-pub :Sessa C, Cresta S, Noberasco C, Capri G, Gallerani E, de Braud F, Zucchetti M, D'Incalci M, Locatelli A,Marsoni S, Corra<strong>di</strong>no I, Minoia C, Zintl P, Gianni LPhase I clinical and pharmacokinetic study of trabecte<strong>di</strong>n and cisplatin in solid tumoursEur J Cancer <strong>2009</strong> 45 : 2116-2122Pace S, Capocasa F, Tallarico C, Frapolli R, Zucchetti M, Longo ADetermination of total and lactone form of a new camptothecin derivative gimatecan (ST1481) and its metaboliteST1698 in human plasma by high-performance liquid chromatography with fluorimetric detectionJ Pharm Biomed Anal <strong>2009</strong> 50 : 507-514Ferrari D, Fiore J, Codecà C, Di Maria G, Bozzoni S, Bor<strong>di</strong>n V, Cal<strong>di</strong>era S, Luciani A, Zonato S,Floriani I, Foa PA phase II study of carboplatin and paclitaxel for recurrent or metastatic head and neck cancerAnticancer Drugs <strong>2009</strong> 20 : 185-190Garattini S, Bertele' V, Floriani I, Torri VExenatide for type 2 <strong>di</strong>abetesLancet <strong>2009</strong> 373 : 12230ANNUAL REPORT <strong>2009</strong>
IRFMNBardella M T, Elli L, De Matteis S, Floriani I, Torri V, Pio<strong>di</strong> LAutoimmune <strong>di</strong>sorders in patients affected by celiac sprue and inflammatory bowel <strong>di</strong>seaseAnn Med <strong>2009</strong> 41 : 139-143Infante M, Lutman R F, Imparato S, Di Rocco M, Ceresoli G L, Torri V, Morenghi E, Minuti F, CavutoS, Bottoni E, Inzirillo F, Cariboni U, Errico V, Incarbone M, Ferraroli G, Brambilla G, Alloisio M,Ravasi GDifferential <strong>di</strong>agnosis and management of focal ground-glass opacitiesEur Respir J <strong>2009</strong> 33 : 821-827Stacchiotti S, Collini P, Messina A, Morosi C, Barisella M, Bertulli R, Piovesan C, Dileo P, Torri V,Gronchi A, Casali P GHigh-grade soft-tissue sarcomas: tumor response assessment--pilot study to assess the correlation between ra<strong>di</strong>ologicand pathologic response by using RECIST and Choi criteriaRa<strong>di</strong>ology <strong>2009</strong> 251 : 447-456Mazziotti G, Floriani I, Bonadonna S, Torri V, Chanson P, Giustina AEffects of somatostatin analogs on glucose homeostasis: a metaanalysis of acromegaly stu<strong>di</strong>esJ Clin Endocrinol Metab <strong>2009</strong> 94 : 1500-1508Donati S, Cotichini R, Mosconi P, Satolli R, Colombo Cinzia, Liberati A, Mele AMenopause: knowledge, attitude and practice among Italian womenMaturitas <strong>2009</strong> 63 : 246-252Bonezzi K, Taraboletti G, Borsotti P, Bellina F, Rossi R, Giavazzi RVascular <strong>di</strong>srupting activity of tubulin-bin<strong>di</strong>ng 1,5-<strong>di</strong>aryl-1H-imidazolesJ Med Chem <strong>2009</strong> 52 : 7906-7910Roesli C, Borgia B, Schliemann C, Gunthert M, Wunderli-Allenspach H, Giavazzi R, Neri DComparative analysis of the membrane proteome of closely related metastatic and non-metastatic tumor cellsCancer Res <strong>2009</strong> 69 : 5406-5414Apolone G, Corli O, Mosconi P, et al, The 2008 Erice GroupThe 2008 Erice statement toward a more humanistic oncologyJ Ambul Care Manage <strong>2009</strong> 32 : 252-258Deandrea S, Corli O, Moschetti I, Apolone GManaging severe cancer pain: the role of transdermal buprenorphine: a systematic reviewTher Clin Risk Manag <strong>2009</strong> 5 : 707-718Mosconi P, Donati S, Colombo C, Mele A, Liberati A, Satolli R, Consensus Conference Working GroupInforming women about hormone replacement therapyCancer Journal <strong>2009</strong> 15 : 344Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F, Allavena P, Torri V, Repici A, SantoroA, Mantovani A, Roncalli M, Malesci ACD3+ cells at the invasive margin of deeply inva<strong>di</strong>ng (pT3-T4) colorectal cancer and risk of post-surgical metastasis:a longitu<strong>di</strong>nal studyLancet Oncol <strong>2009</strong> 10 : 877-884Garattini S, Torri V, Floriani ICetuximab for metastatic colorectal cancerN Engl J Med <strong>2009</strong> 361 : 96Floriani I, Santini D, Torri V, Cremolini C, Falcone A, Loupakis FDo we need biopsies of metastases for colorectal cancer patients?Br J Cancer <strong>2009</strong> 101 : 374-375Taraboletti G, Bonezzi KInhibitors of angiogenesis based on thrombospon<strong>di</strong>n-131ANNUAL REPORT <strong>2009</strong>
IRFMNIn :Recent advances in angiogenesis and antiangiogenesis Bentham, United Arab Emirates, <strong>2009</strong>; 112-126Coltrini D, Ronca R, Belleri M, Zar<strong>di</strong> L, Indraccolo S, Scarlato V, Giavazzi R, Presta MImpact of VEGF-dependent tumour micro-environment on EDB fibronectin expression by subcutaneous humantumour xenografts in nude miceJ Pathol <strong>2009</strong> 219 : 455-462Marangon E, Falcioni C, Manzotti C, Fontana G, D'Incalci M, Zucchetti MDevelopment and validation of a LC–MS/MS method for the determination of the novel oral 1,14 substituted taxanederivatives, IDN 5738 and IDN 5839, in mouse plasma and its application to the pharmacokinetic studyJ Chromatogr B Analyt Technol Biomed Life Sci <strong>2009</strong> 877 : 4147-4153Sala F, Zucchetti M, Bagnati R, D'Incalci M, Pace S, Capocasa F, Marangon EDevelopment and validation of a HPLC-MS/MS method for the determination of ST1926, a novel oral antitumoragent, adamantyl retinoid derivative, in human plasma of patients participating in a Phase I studyJ Chromatogr B Biomed Appl <strong>2009</strong> 877 : 3118-3126Loupakis F, Ruzzo A, Cremolini C, Vincenzi B, Salvatore L, Santini D, Masi G, Stasi I, Canestrari E,Rulli E, Floriani I, Bencar<strong>di</strong>no K B, Galluccio N, Catalano V, Tonini G, Magnani M, Fontanini G, BasoloF, Falcone A, Graziano FKRAS codon 61, 146 and BRAF mutations pre<strong>di</strong>ct resistance to cetuximab plus irinotecan in KRAS codon 12 and 13wild-type metastatic colorectal cancerBr J Cancer <strong>2009</strong> 101 : 715-721Garassino M C, Borgonovo K, Rossi A, Mancuso A, Martelli O, Tinazzi A, Di Cosimo S, La Verde N,Sburlati P, Bianchi C, Farina G, Torri VBiological and clinical features in pre<strong>di</strong>cting efficacy of epidermal growth factor receptor tyrosine kinase inhibitors: asystematic review and meta-analysisAnticancer Res <strong>2009</strong> 29 : 2691-2701Signorelli M, Lissoni A A, Cormio G, Katsaros D, Pellegrino A, Selvaggi L, Ghezzi F, Scambia G, ZolaP, Grassi R, Milani R, Giannice R, Caspani G, Mangioni C, Floriani I, Rulli E, Fossati RMo<strong>di</strong>fied ra<strong>di</strong>cal hysterectomy versus extrafascial hysterectomy in the treatment of stage I endometrial cancer:Results from the ILIADE randomized studyAnn Surg Oncol <strong>2009</strong> 16 : 3431-3441De Pangher V, Recchia L, Cafferata M, Porta C, Siena S, Giannetta L, Morelli F, Oniga F, Bearz A, TorriV, Cinquini MMalignant peritoneal mesothelioma: a multicenter study on 81 casesAnn Oncol <strong>2009</strong> E-pub :Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli EAntibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive careCochrane Database Systematic Reviews <strong>2009</strong> CD000022Ubezio P, Lupi M, Branduar<strong>di</strong> D, Cappella P, Cavallini E, Colombo V, Matera G, Natoli C, Tomasoni D,D'Incalci MQuantitative assessment of the complex dynamics of G1, S, and G2-M checkpoint activitiesCancer Res <strong>2009</strong> 69 : 5234-5240Damia G, D'Incalci MContemporary pre-clinical development of anticancer agents - What are the optimal preclinical models?Eur J Cancer <strong>2009</strong> 45 : 2768-2781Cazzola M, Floriani I, Page C PThe therapeutic efficacy of erdosteine in the treatment of chronic obstructive bronchitis: a meta-analysis of in<strong>di</strong>vidualpatient dataPulm Pharmacol Ther <strong>2009</strong>32ANNUAL REPORT <strong>2009</strong>
IRFMNCervellini I, Bello E, Frapolli R, Porretta-Serapiglia C, Oggioni N, Canta A, Lombar<strong>di</strong> R, Camozzi F,Roglio I, Melcangi R C, D'Incalci M, Lauria G, Ghezzi P, Cavaletti G, Bianchi RThe neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction ofantitumor activity in 13762 adenocarcinoma-bearing ratsNeurotox Res <strong>2009</strong> E-pub :LAY PRESS SELECTION (<strong>2009</strong>)Can<strong>di</strong>ani G, Colombo C, Daghini R, Magrini N, Mosconi P, Nonino F, Satolli R.Manuale metodologico: come organizzare una conferenza <strong>di</strong> consenso<strong>Istituto</strong> Superiore <strong>di</strong> Sanità, Sistema Nazionale Linee Guida SNLG, Roma, Novembre <strong>2009</strong>Mosconi P, Satolli R, Donati S, Colombo C, Liberati A, Mele A.TOS: quale informazione alle donne? La conferenza <strong>di</strong> consenso <strong>di</strong> TorinoDialogo sui Farmaci 6/2008 dossier:264-269http://www.torinome<strong>di</strong>ca.com/allegati/<strong>2009</strong>/All.%20a%20(23)%20Ferraro_PROCEDURE_Prevenzione_01%20febbraio%20<strong>2009</strong>.pdfMosconi PAncora a proposito <strong>di</strong> mammografia e buona informazionehttp://www.partecipasalute.it/cms_2/node/1101 ; 23/2/<strong>2009</strong>Braun C, Mosconi PIl punto sulla pubblicità <strong>di</strong>retta ai consumatoriRicerca & Pratica <strong>2009</strong> Numero 145 anno 25: 19-28Mosconi P, Colombo CI citta<strong>di</strong>ni e l’innovazione. L’innovazione nell’assistenza e nuovi strumenti <strong>di</strong> valutazioneIl Pensiero Scientifico E<strong>di</strong>tore, Suppl. 3 Politiche Sanitarie Vol 10 N°.1, <strong>2009</strong>Mosconi P, Satolli R, Liberati A, Donati S, Mele A et al.Quale informazione per la donna in menopausa sulla terapia ormonale sostitutiva? ConsensusConference Torino, 16-17 maggio 2008Sistema Nazionale per le Linee Guida SNLG-ISShttp://www.pnlg.it/cms/files/CC_TOS.pdf giugno <strong>2009</strong>: 1-48Mosconi PLa tutela del citta<strong>di</strong>no nelle attività del comitato eticoJanus Numero 34, estate <strong>2009</strong>, Za<strong>di</strong>g e<strong>di</strong>tore: 15-16Mosconi PMilano, capitale morale dell’impegno volontarioIn: Milano capitale della salute, a cura <strong>di</strong> Roberto Satolli. E<strong>di</strong>trice Abitare Segesta, Milano,<strong>2009</strong>Giavazzi R. ADAMANT. In: The Parliament Magazine, issue 285, pag.50, 30 marzo <strong>2009</strong>33ANNUAL REPORT <strong>2009</strong>
IRFMNRESEARCH ACTIVITIESLaboratory of Cancer PharmacologyMode of action of Ecteinasci<strong>di</strong>nsA project ongoing since several years is about the characterization of marine natural productspossessing antitumor activity. In particular we carried on the stu<strong>di</strong>es on the effects of ET-743 incells defective for some DNA repair mechanisms. Cells deficient for HomologousRecombination (HR) are very sensitive to the drug, while cells deficient for Non HomologousEnd-Joining (NHEJ) are only slightly more sensitive, but surpraisingly cell lines defective forNucleotide Excision Repair (NER) are less sensitive to ET-743. Flow cytometric analysiscoupled to a software of computer simulation, developed in our laboratory, has demonstratedthat NER defective cells showed, after ET-743 treatment, cell cycle perturbations <strong>di</strong>fferent thanthose occurring in NER proficient cells, probably for the activation of <strong>di</strong>fferent and moreefficient repair mechanisms.We study also a functional evaluation of the DNA repair mechanisms by the cell capacity torecognize and repair double helix breaks with a recently introduced test that is very sensitive todetect the phosphorylation of histone H2AX. An in vitro study is ongoing with flow cytometryand immunofluorescence techniques to evaluate in <strong>di</strong>fferent tumor cell lines the phosphorylationlevel of histone H2AX in relation to the <strong>di</strong>stribution of the cells in the <strong>di</strong>fferent phases of thecell cycle and the cytotoxic effect induced after treatment with ET-743.Stu<strong>di</strong>es are in progress on the mechanism of action of new ET-743 derivates compounds thathave shown antitumoral activity on cell lines with <strong>di</strong>fferent DNA repair mechanisms.A new project is the study of the selective action of ET-743 on mixoid lyposarcoma, apathology representing 10% of all soft tissue sarcomas, trying to understand if the significativeantitumor effect is due to a selective action of the compound on pathogenetic alterationscharacteristic of this pathology. In particular we are trying to evaluate how ET-743 interact withthe transcriptional mo<strong>di</strong>fications of specific genes due to the translocation FUS-CHOP thatcharacterizes mixoid sarcomas or those caused by the interaction host-tumor, mo<strong>di</strong>fyinginflammatory and angiogenetic processes. Stu<strong>di</strong>es are in progress to obtain cell lines andxenografts of mixoid lyposarcomas exhibiting the same molecular features of the patients’tumors.Combinations of natural products of marine origin with other anticancerdrugsWe have observed ad<strong>di</strong>tive or synergistic activity of ET-743 combined with other anticancerdrugs such as cisplatin, doxorubicin, campthotecin and inhibitors of telomerase.Flow Cytometric analysis of the DNA content in human ovarian cancer:clinical correlationsConflicting results have been published on the prognostic significance of DNA aneuploidy onadvanced ovary carcinoma (stage III or IV). The Citometry unit has reported one of the largeststu<strong>di</strong>es of the scientific literature in<strong>di</strong>cating that the aneuploidy in the advanced ovarycarcinoma is not an independent prognostic factor. In a large number of cases of stage I and IIovary tumors DNA content and the percentage of cells in S phase of the cell cycle, has beenmeasured with flow cytometry, demonstrating that in the early stages of the <strong>di</strong>sease DNAcontent is a prognostic factor important for ovary tumor.Analysis of cell cycle data and interactions of <strong>di</strong>fferent drugsThe Biophysics Unit is engaged in theoretical and methodological stu<strong>di</strong>es aimed at a criticalevaluation of current techniques of investigation of drug effects on heterogeneous cell34ANNUAL REPORT <strong>2009</strong>
IRFMNpopulations. Several computing tools have been produced to simulate the cell proliferation at<strong>di</strong>fferent levels (from molecular interactions to in vivo growth of solid tumours) and the processof measure.Collaborations are ongoing with other research groups for design and data analysis of drugcombination stu<strong>di</strong>es in vitro. In this field, a number of computer programs have been developed,allowing comparative data analysis with the most common models of drug interaction.Evaluation of the complexity of the response of cell populations totreatment with anticancer drugsThis project of the Biophysics Unit addresses the issue of establishing a connection between theintracellular drug interactions and the resulting cell cycle perturbations. It starts from the singlecelllevel of investigation to reach the cell-population level where the relevant end points oftreatment efficacy are evaluated by flow cytometry and growth inhibition/cytotoxicity assays.The model adopted for data analysis and interpretation is the result of the merging of twomathematical models. One model describes the cell cycle, exploiting the results of the theory ofage-structured cell population dynamics. The second model describes the response to the drug'schallenge, using <strong>di</strong>stinct parameters ("effect descriptors") measuring either the strength of cellcycle arrest, damage repair or cell death in every phase (G1, S and G2M). In this way, it ispossible to reach a quantitative interpretation of the experimental results, overcoming thecurrent qualitative and partial approaches to this problem, which are unable to resolve theoverlapping of cytostatic and cytotoxic effects, and to establish a connection with phase-relatedevents.Applying this procedure we demonstrated complex but biologically consistent patterns of timeand dose-dependence for each cell cycle effect descriptor, on a reference cell line of ovariancarcinoma, following a short treatment with melphalan, doxorubicin, topotecan, cisplatin andtaxol. Within this project we produced a database containing the values associated to the neweffect descriptors, related to few compounds but rich of information about them, especially inthe dose and time dependence of the effects. This database will be used to compare thetreatment response of the most common drugs adopted in the ovarian carcinoma.Cell cycle dYsregulation in erlotinib-based treatments decoded by flowcytometry and mathematical modelingEpidermal growth factor receptor (EGFR) inhibitors represent one of the most promising classof anticancer compounds, some of them, like erlotinib, are already used for clinical therapy.Nevertheless, so far, the research has focused on molecular interaction of these compounds,somewhat neglecting the study of the dynamics of cell cycle perturbations and underscoring theimportance of this issue for the optimization of both single and multidrug therapies.In order to fill this gap, the Biophysics Unit will apply the multi<strong>di</strong>sciplinary approach,exploiting cell cycle simulation tools, to the study of cell cycle perturbations induced byerlotinib as a representative EGFR inhibitor. Stu<strong>di</strong>es of the time- and dose-dependence ofperturbations induced by treatments are ongoing for single erlotinib treatment or for erlotinibcombined with gemcitabine, irinotecan and oxaliplatin. The appreciation and the quantificationof these effects will provide an important contribution to the comprehension of the mode ofaction of erlotinib alone or in combination. Such perspectives are vital if the events are to bedecoded and used in pre<strong>di</strong>ctive models for the exploration of pharmacodynamic actions and inunderstan<strong>di</strong>ng the origins of treatment failure.Anticancer Drug Effects Decoded by Time-Lapse Imaging, Flow Cytometryand ModelingWe aim to use flow cytometric (cell-population based analysis) and time-lapse imaging (singlecell lineage based analysis) techniques to generate data that will be used to pre<strong>di</strong>ct drug35ANNUAL REPORT <strong>2009</strong>
IRFMNresponses in term of the two major determinant of cytostatic/cytotoxic actions of anticancerdrugs: specific cell cycle perturbations (detecting accumulation or depletion of cells in G1, Sand G2M phases) and the commitment to cell death (apoptosis).The working hypothesis is that quantitative analysis of time-lapse microscopy data could beintegrated with the information provided by flow cytometry - allowing for the first time a jointinterpretation of both kind of experiments through a common mathematical model that simulatethe underlying phenomena. The final goal is to provide new levels of understan<strong>di</strong>ng andsimulation tools to the cancer research community.Timing the changes of the cellular content of specific proteins inside G1,in exponentially growing cellsWe developed a method for measuring the content of immunocytochemically detected proteinsin in<strong>di</strong>vidual cells progressing through G1 phase. The feasibility was demonstrated in theanalysis of cyclin E levels. The sequence of G1 events is tracked in unaltered cyclingcon<strong>di</strong>tions, in a cell line in the phase of balanced growth in vitro, to avoid the pitfalls ofsynchronization.The method is based on i) a bromodeoxyuri<strong>di</strong>ne (BrdUrd) pulse-and-chase experimental plan;ii) triparametric flow cytometric detection of DNA, BrdUrd and cyclin E; iii) data analysissupported by the basic mathematical theory of asynchronous growing populations with variablecell cycle phase durations.Pharmacokinetic of new taxane derivatesWe have performed a study on a new taxane derivative, chemically and biologically <strong>di</strong>fferentfrom the conventional ones. For two of this compound, IDN6140, we evaluated thepharmacokinetic profile applying analytical methods based on HPLC/MS/MS techniquedeveloped in the Cancer Clinical Pharmacology Unit. It showed high ability to cross the bloodbrain barrier, high <strong>di</strong>stribution in brain and biological activity even in tumors with lowsusceptibility to other taxanes (cerebral tumor), suggesting a potential clinical interest- for thetherapy of Central Nervous System tumors and metastasis.Clinical pharmacology of CEP-18770 (a new proteasome inhibitor)The study in collaboration with SENDO, was performed in 40 patients defining thepharmacokinetic and the pharmacodynamic profiles of the new proteasoma inhibitor, CEP-18770, in patients enrolld in the phase I clinical study. This study evidencied for this compounda very long plasma half-life assuring a prolonged drug espostion.Pharmacokinetic/pharmacodynamic correlations showed in the patients stu<strong>di</strong>ed a significativeinhibition of the proteasome activity.Quality assurance programDuring this last year we started a project aimed to achieve a quality system to bring thePharmacokinetic Unit inside the Laboratory of Cancer Pharmacology in compliance with GoodLaboratory Practice (GLP). On this purpose, as first step, we organized spaces and tools todevelop this process starting from the preparation of the standard operating procedures andwith the training of the personnel involved.Antitumoral activity and pharmacokinetic properties of new drugs andcombinationsThe antitumor activity, pharmacokinetic properties and toxicity of novel anticancer drugs withspecific targets (e.g. <strong>di</strong>fferent kinase inhibitors), conventional anticancer drugs (taxanes andcamptothecins) and combinations is being investigated using rodent tumors and human tumorxenografts.36ANNUAL REPORT <strong>2009</strong>
IRFMNDevelopment of a software framework for a rationalized process ofMicroarrays analysisIt is currently active in the Institute a multi<strong>di</strong>sciplinary group involved in the rationalization ofthe various microarray analysis aspects, with many external collaborations.The <strong>di</strong>fferent possible analysis procedures have been <strong>di</strong>scussed, compared and formalized inorder to obtain a common work flow to be accepted from the scientific community.Thanks to this activity it is now possible to automate some aspects of the analysis making themfaster end better reproducible for people managing the analysis itself.This activity has involved the development of the necessary software for data analysis and theimplementation of a Beowulf computer cluster, using the old computers <strong>di</strong>smissed by thedesktop users in order to obtain a sufficient power.Internal collaborations:Department of Biochemistry and Molecular Pharmacology (ref.: Maddalena Fratelli, <strong>Mario</strong>Salmona)Department of Oncology (ref.: Sergio Marchini, Mariarosa Bani, Maurizio D'Incalci)External collaborations:Fondo Edo Tempia (ref.: Giovanna Chiorino)<strong>Istituto</strong> Toscano Tumori (ref: Duccio Cavalieri)<strong>Istituto</strong> Weizmann (ref. Eytan Domany)Università <strong>di</strong> Birmingham (ref. Francesco Falciani)Università <strong>di</strong> Aberdeen (ref. Tony Travis)Microarray data analysis for the Oncology DepartmentThe data analysis activities concern the biology of sensible versus resistant to therapy humanovarian carcinoma and the study of the ET-743 working mechanism in human sarcoma, sensibleand resistant.Related to the projects:Department of Oncology (ref. Sergio Marchini, Maurizio D'Incalci, Massimo Broggini, MirkoMarabese) –Agilent platformMetastasis/Relapses Project (phase III ovarian)LPS2 Project (cell lines, response to ET-743)Department of Oncology (ref. Mariarosa Bani, Raffaella Giavazzi) –Affymetrics platformStroma ProjectParenchyma Project־־־־External collaborations:Osp. S.Gerardo, Monza (ref. Robert Fruscio)Development of the new database handling software for the ovariantumors bio-bank, compliant with the new privacy related laws for datahandling for clinical trials and with a new reporting engine for a betterdata extrationInternal collaborations:Department of Oncology (ref.: Sergio Marchini, Mariarosa Bani, Raffaella Giavazzi, MaurizioD'Incalci, Massimo Broggini, Mirko Marabese)External collaborations;Ospedale S.Gerardo, Monza (ref. Robert Fruscio)37ANNUAL REPORT <strong>2009</strong>
IRFMNImplementation of the data management engine for the Italian RegistryDomiciliar Artificial Nutrition, in collaboration with the Scientific SocietySINPE (ref. Loris Pironi, S.Orsola, Bologna)This activity involves all aspects of the data management, statistical analysis, help desk,informatic infrastructures and software for handling an observational clinical study.For this purpose a new ibrid online/offline database has been developed, compliant with the newprivacy related laws about the data protection issues.External collaborations:Osp. S. Orsola, Bologna (ref. Loris Pironi)Società Scientifica SINPELaboratory of Molecular PharmacologyG2 checkpoint and cell cycleThe requirement of Chk1 for both S and G2/M checkpoints has been elucidated while onlyfew stu<strong>di</strong>es have connected Chk1 to the mitotic spindle checkpoint. This checkpoint ensuresproper chromosome segregation by delaying anaphase until chromosomes are aligned on thespindle thus preventing chromosomal instability, aneuploidy and cancer pre<strong>di</strong>sposition. Werecently found that Chk1 depletion in U2OS human osteosarcoma cells inhibited cellproliferation and raised the percentage of cells with a 4N DNA content, which correlated withaccumulation of giant polynucleated cells morphologically <strong>di</strong>stinct from apoptotic cells,while no increased number of cells in G2 or mitosis could be detected. Downregulation ofChk1 also caused accumulation of cells in the last step of cytokinesis, and of tetraploid cellsin G1 phase, which coincided with activation of p53 and increased levels of p21. In ad<strong>di</strong>tion,Chk1 depleted U2OS cells failed to arrest in mitosis after spindle <strong>di</strong>sruption by nocodazole andshowed decreased protein levels of Mad2 and BubR1, two mitotic checkpoint components.These stu<strong>di</strong>es show that U2OS cells lacking Chk1 undergo abnormal mitosis and fail to activatethe spindle checkpoint, suggesting a role of Chk1 in this checkpoint. It will be now interestingto further investigate the inter relationship existing among Chk1 and mitotic checkpointcomponents.Characterization of new potential oncosuppressor genesDRAGO gene, identified and cloned in our laboratory is one of the most interesting projects ofthe group. The characterization of the response of KO mice for DRAGO to ionising ra<strong>di</strong>ation issimilar to normal mice.Mice KO for DRAGO have been crossed with with p53 KO mice to evaluate the potentialoncosuppressive function of DRAGO. The double mutants are viable and the genotypes arisingfrom the crossing are at the normal Mendelian ratio, in<strong>di</strong>cating that no specific genotypes(p53;DRAGO) are favoured. The mice will be followed for tumor onset and survival and thedevelopment of tumors in the double KO mice will be compared with p53 KO mice.Molecular characterization of ovarian carcinomaMicro RNAs are small non co<strong>di</strong>ng RNAs playing an important role in the regulation of mRNAtranscription. They have been found deregulated in several human cancer. We have started astudy aimed at evaluating the expression of approximately 600 microRNAs in ovarian cancerfrom patients with a very high response to treatment (surviving more than 10 years from<strong>di</strong>agnosis) compared to patients not respon<strong>di</strong>ng at first line therapy. The analysis of the tumorsso far characterised in<strong>di</strong>cates that the are microRNAs <strong>di</strong>fferentially expressed in the twosubgroups that, if confirmed in a larger sample size, could represent a potential therapeutictarget.38ANNUAL REPORT <strong>2009</strong>
IRFMNIn parallel we have characterised retrospectively, polymorphisms in genes participating in theresponse to damage such as mdm2, ERCC1 and XPG as possible pre<strong>di</strong>ctors of response totreatment in patients with ovarian cancer. 420 patients have been genotyped and the allelicfrequency found is the expected one for a Caucasian population. The data generated will beanalysed together with the clinical parameters and with the follow-up data available for all thesamples analysed.Expression of gene involved in DNA repair in human ovarian cancerBy Real Time PCR, the expression of genes involved in DNA repair has been evaluated in 77stage I, 81 stage III and 13 borderline samples of ovarian cancer. The genes analysed includethose belonging to the nucleotide excision repair, in the fanconi anemia repair, in the baseexcision repair. In ad<strong>di</strong>tion, genes important for the cellular response to damage, such as chk1and claspin have been stu<strong>di</strong>ed.Two were the aims of the study: 1) to understand whether there are genes <strong>di</strong>fferentiallyexpressed in the three categories analysed that could help us in understan<strong>di</strong>ng the biology ofovarian cancer; 2) to correlate mRNA levels of the <strong>di</strong>fferent genes with the response totreatment with the idea of fin<strong>di</strong>ng new possible response markers.Data analysis showed that genes involved in the Fanconi Anemia pathway and some of thegenes involved in checkpoints are more expressed in stage I carcinoma than stage I borderlinetumors. These data might suggest that the malignant phenotype is associated with an upregulationof these genes that would endow tumor ovarian cell with higher growth andmetastatic potentials. In Stage III ovarian patients a number of correlation between theexpression of the repair genes and the response to therapy have been performed; however noclear cut statistically significant correlation could be found. The data, even if negative, havebeen obtained in a quite large sample size and we think pose some doubts on role of theexpression of single gene as pre<strong>di</strong>ctive of response, as suggested by other stu<strong>di</strong>es.Inhibition of the signal me<strong>di</strong>ated by PI3K/aktPi3K/akt axis represents one of the major altered pathway in human cancer and therefore is agood target for the development of new drugs. The laboratory has been involved in thepharmacological characterisation of new molecules able to inhibit the pathway.The encouraging study on the natural derivatives of inositol phosphates (IP5) had as aconsequence the synthesis of new derivatives which have been charcterised in vitro for theiractivity. One of these derivatives, HYG9 (2-O-benzil-myo-inositol 1,3,4,5,6-pentakisphosphate)has been further investigated because of its good pharmacological profile in vitro. In particular,HYG9 showed activity also in cell lines resistant to IP5.We have therefore evaluated the activity in vivo of HYG9 in a model of human prostate cancer,PC3 were the drug showed a dose dependent inhibition of tumor growth. The pharmacodynamicstudy prformed in parallel, showed that at the active doses, HYG9 was able to significantlyreduce in the tumor the phosphorylation of akt (in<strong>di</strong>cative of an inhibition of the pathway).From a mechanistic point of view, HYG9 has been shown to compete for the PH domain of aktbut also to <strong>di</strong>rectly inhibit PDK1, a kinase responsible for akt phosphorylation.We have also stu<strong>di</strong>ed other inhibitors, such as PIK-75 and PI-103 as isoform specific ad dualPI3K mTOR inhibitors, respectively. Both drugs showed activity against human cancer celllines constitutively expressing activated akt and showed interesting results in combinationstu<strong>di</strong>es with drugs acting with a <strong>di</strong>fferent mechanism of action.Role of phospholipase C γ1 in the development of metastasisThe already performed stu<strong>di</strong>es on the role of phospholipase C γ1 in favouring the metastaticprocess, have been extended in a human breast cancer model with a strong ability to metastatizeto the bones. In this model we have reproduced the systes previously utilized to inhibit39ANNUAL REPORT <strong>2009</strong>
IRFMNphospholipase C γ1 and new clones with inducible expression of phospholipase C γ1 have beenconsequently generated. These models will will be extremely useful for better understan<strong>di</strong>ng therole of this protein in the metastatic process.Oncosuppressors p53, p63 and p73The p63 protein, belonging together with p73 to the p53 family, can be expressed in cells in<strong>di</strong>fferent isoforms. Among these the DN isoform , which originates from an alternative internalpromoter, seems to have a role in the development and progression of cancer.In the previous year, our laboratory the expression of p63 members in human ovarian cancer,both at early and advanced stage, has been evaluated. We have shown that the advanced stageexpresses much higher levels of DNp63 than early stage tumors. Following these results, wehave generated cellular clones in vitro which express a <strong>di</strong>fferential, inducible expression ofDNp63. These clones which have been characterised for their protein expression, will allow usto define the role of this protein in the growth and response to treatment of cancer cells. Inparallel we are evaluating the molecular mechanism responsible for the modulation of DNp63levels in human ovarian cancers. To date we have been able to exclude an involvement of achromosomal rearrangement in the area where the p63 gene is present.In this chromosomal area,in fact, we <strong>di</strong>d not find duplication, amplification of genetic material both in early and advancedovarian cancer.Mechanisms of action of new antitumor drugsWe have identified a new mechanism through which cancer cells become resistant to theanthracycline derivative, nemorubicin (methoxy morpholino doxorubicin). In resistant cells, infact, we have a a reduced DNA repair ability particularly they show defects in the nucleotideexcision repair (NER) due to the lack of expression of one of the NER genes, XPG.The lack of XPG expressionin resistant cells is due to methylation of DNA in the regulatoryregions of the gene which blocks the transcription of the gene and consequently proteinformation. All the cells of <strong>di</strong>fferent origin presenting resistance to nemorubicin show thismechanism. This represent sthe first experimental evidence that a NERR gene can beinactivated through methylation and offers new possibilties to revert the resistance mechanismsby using demethylating and/or histone deacetylating inhibitors.Generation of new cellular systems for in vivo imagingWe have generated new cell clones derived from human cancer cells growing in vitro, whichstably express fluorescent or luminescent probes which can allow us to follow in vivo thegrowth of primary tumors and metastasis in mice. These systems generated in human ovarian ,breast and prostate cancer cell lines, can be implanted in nude mice and the growth and responseto therapy followed by either optical and luminescent imaging or microTAC analysis.We have in particular set up models derived from human breast cancer, which are able tometastasis to the bone which can be evidentiated by optical imaging and microTC techniques inlaboratory animals. Utilising <strong>di</strong>fferent reporter genes, we have generated fluorescent andluminiscent human cancer cell lines which can be transplanted in immunodeficient mice. Thesecells can then be visualised in organs such as peritoneum and lungs were these cells werepreviously be observed only after sacrifice of the animal. The cells generated to be fluorescentor bioluminiscent will also have specific gene defects which will be useful for understan<strong>di</strong>ng themechanism of action of new molecules. These systems will be particularly useful to study theantimetastatic potential of new drugs.40ANNUAL REPORT <strong>2009</strong>
IRFMNStu<strong>di</strong>es on the bone metastatic processesUsing a model of human breast cancer cells metastatizing to the bones, we have characterisedsome molecular pathways involved in the colonisation and metastatic growth. In particular, wehave evaluated the role of cMet receptor and of its activation both in vitro and in vivo.The in vivo model utilized develops bone metastasis following intraventricular injection ofcancer cells. The bone metastasis can be visualized by optical imaging already after 10 daysfrom cancer cell inoculum. By microTC analysis, bone osteolytic lesions can be evidentiatedafter 3-4 weeks from tumor cells injection.With this model we have shown that c-met plays an important role in the process and we havebeen able to demonstrate a cross-talk in vivo between human cancer cells and host cells. Inparticular we have found that inside cancer cells growing in the bone, there is HGF, the ligandof c-met, both produced by the cancer cells themselves and by the murine host cells. HGFpresentin the bone can therefore be activated by human cancer cells there have colonized in thebones, thus activating an autoregulatory loop able to stimulate tumor growth. These data suggestthe possibility to act with molecules able to inhibit HGF or c-met as possible boneantimetastatic agents.Characterization of response of stem cells to damageA number of stu<strong>di</strong>es have been conducted in our laboratory aimed at investigating the activationof the DNA damage checkpoints after IR in hematopoietic stem cell obtained from umbilicalcord. Stem cells can be obtained from umbilical cord and expanded and partially <strong>di</strong>fferentiate<strong>di</strong>n vitro with a specific cytokine cocktails, having a system in which two <strong>di</strong>fferent cellpopulation (staminal and more <strong>di</strong>fferentiated progenitors) can be stu<strong>di</strong>ed. We could demonstratethat the IR-DNA damage checkpoint is similar in hematopoietic stem cells and in the more<strong>di</strong>fferentiated cells derived from them. We could also demonstrate that during this in vitroexpansion, the expression of the Chk1 protein (a master protein in the control of S and G2checkpoints in cells) has a peculiar pattern of expression, being expressed only at the beginningof the culture. Interfering with the activity of the protein with a specific inhibitors at the timewhen the protein is expressed, induced a shift from myeloid to lymphoid <strong>di</strong>fferentiation,unravelling a new role of chk1 in <strong>di</strong>fferentiation.Identification of cancer stem cells from ovarian cancerThis project is aimed at isolating and characterizing a possible cancer stem cell from ovariancancers. There are increasing evidences supporting the idea that few important multipotentcancer cells, termed cancer stem cells, are among the most relevant cells to be killed in a tumor.Normally present as quiescent cells inside the tumors, they are able to rapidly generate <strong>di</strong>vi<strong>di</strong>ngand growing cancer cells. The current hypothesis is that normally <strong>di</strong>vi<strong>di</strong>ng cancer cells can bepreferentially killed by chemotherapy while the cancer stem cells would be more <strong>di</strong>fficult to killand would be responsible for the relapse following treatment. The possibility to identify andcharacterize the cancer stem cell would theoretically open the way to the selection of newgeneration molecules able to preferentially kill these cells.Several stu<strong>di</strong>es have been conducted in ovarian fresh tumor samples, obtained from theGynecological Department of Ospedale San Gerardo <strong>di</strong> Monza, <strong>di</strong>rected by Prof Mangioni, thatlead to the identification of a cell bearing the characteristic of a tumor initiating cells. We arenow performing a detailed phenotypical, molecular and pharmacological characterization.Indeed all these stu<strong>di</strong>es will possibly lead to the identification of specific genes that could betargeted in the opvarian tumor initiating cells with the final aim to improve the therapy of thistumor.41ANNUAL REPORT <strong>2009</strong>
IRFMNDetermination of the impact of EGFR mutations in the activity of tyrosinekinase inhibitors in patients with NSCLCThe study on the characterisation of the response of patients with NSCLC to therapy with orwithout EGFR inhibitors is ongoing. The data available so far show that among the patientsenrolled in the study, the percentage with mutations in the EGFR gene is 8-9%, in line withwhat previously reported for this tumor in the Caucasian population.The study aims also to evaluate the role of mutations in another gene, K.RAS , in determiningthe response to treatments. This gene is mutated in a significantly higher proportion of patientsthan EGFR. The mutational spectrum found in this tumor is <strong>di</strong>fferent from that reported in othertumor types, such as the colrectal cancer. These <strong>di</strong>fferences could be responsible for a <strong>di</strong>fferenteffect on tumor growth and response to treatment and this hypothesis will be tested bygenerating new cellular models harbouring <strong>di</strong>fferent mutations of the K-RAS gene in NSCLCcell lines.Laboratory of Biology and Therapy of MetastasisPhysiologic regulation of angiogenesisAngiogenesis, the formation of blood vessels from existing ones is a fundamental process intumor progression. A delicate balance between pro- and antiangiogenic factors finely tunes thisprocess. In the last years we have been interested in endogenous angiogenesis-regulatoryfactors. During <strong>2009</strong> we have continued the study of trombospon<strong>di</strong>n-1 (TSP-1), an endogenousinhibitor of angiogenesis. TSP-1 <strong>di</strong>rectly binds to angiogenic factors, in particular FGF-2(Fibroblast Growth Factor-2), inhibiting their bioavailability and activity. In a structure/functionrelationship analysis of <strong>di</strong>fferent active domains of TSP-1, we have identified the FGF-2bin<strong>di</strong>ng site of TSP-1. This sequence has beenused as a model to design new antiangiogeniccompounds based on the active sequence of TSP-1.Lymphangiogenesis in ovarian carcinomaLymphatic spread in early ovarian cancer is a pre<strong>di</strong>ctor of outcome with potential clinical value.With the aim to clarify the molecular mechanisms involved in the process of lymphangiogenesisin ovarian cancer, the expression of VEGFC, a factor that stimulates lymphangiogenesis, hasbeen measured in serum and ascites of mice bearing human ovarian carcinoma xenografts andcorrelated with lymphonode infiltration by neoplastic cells.To better represent the clinical features of ovarian neoplasia, an orthotopic model of humanovarian carcinoma xenograft has been created by injecting ovarian tumor cells under the bursaof the ovary. Infection of ovarian carcinoma cells with lentivirus vectors carrying the co<strong>di</strong>ngsequence of VEGFC together with the firefly luciferease gene and fluorescent probes has beenperformed; the invasive and metastatic potential of tumor cells producing VEGFC will beevaluated using optical imaging techniques, in mice bearing tumor.How the microenvironment affects endothelial cell gene expressionIt is fundamental to understand qualitative and functional <strong>di</strong>fferences between tumor and normaltissue endothelial cells (EC) and the molecular mechanisms that drive the angiogenic process.This could lead to the identification of selective markers of the vascular endothelium associatedto pathologies and/or of target molecules for the development of novel therapeutic strategies. Tothis purpose we analysed the gene expression profile of endothelial cells isolated from ovariancarcinoma exposed or not to an “angiogenic/tumor” environment reconstituted in vitro. We havefound that:i) the “angiogenic/tumor” environment is able to modulate EC gene expressionii) a few genes are preferentially expressed by tumor associated endothelial cells.Results suggest that those “genes” might be of interest as markers of tumor endothelium. Their42ANNUAL REPORT <strong>2009</strong>
IRFMNexpression is higher in endothelial cells from tumor specimens than from normal tissues. Theputative new tumor endothelial markers have been further validated by in situ hybri<strong>di</strong>zationanalysis of normal and tumor tissues (as mRNA transcript). Antibo<strong>di</strong>es, <strong>di</strong>rected against theputative targets proteins, have indeed demonstrated the localization within the tumor stroma.Preclinical models: role of Vascular Endothelial Growth Factor (VEGF) ontumor growth, vascularization and response to therapyTo study the role of VEGF induced angiogenesis in the response of cancer to chemotherapy wehave generated a variant of the human ovarian carcinoma A2780/1A9 by stable transfectionwith the VEGF121 isoform (1A9-VS1). In mice 1A9-VS1 xenografts show an angiogenicphenotype associated to the high production of VEGF.We have found that the response to chemotherapy (e.g. paclitaxel) <strong>di</strong>ffer in xenograftsproducing <strong>di</strong>fferent levels of VEGF. The blockade of VEGF, by the administration ofAvastin®, greatly improved the antitumor activity by paclitaxel treatment of 1A9-VS1.Stu<strong>di</strong>es are ongoing to elucidate the mechanism, associated to mo<strong>di</strong>fication of the tumormicroenvironment, that are responsible of these <strong>di</strong>fferences.This model is therefore being used to study gene expression. Based on circulating VEGF levelsand morphological analysis of the tumor vasculature, tissue samples of the 1A9-VS1 weremicro<strong>di</strong>ssected (PALM Microlaser system, in collaboration with the Institute of Pathology atHelios Klinikum, Germany) in order to isolate the stroma compartment to be evaluated by meanof Affymetrix’s GeneChip® Arrays technology. The microarray hybri<strong>di</strong>sation data wereanalyzed with the aid of specialized software (i.e. GeneSpring and Rosetta Resolver) and<strong>di</strong>fferentially expressed genes were identified. Specifically, we have <strong>di</strong>scovered that in thestroma of tumors 294 genes were up- and 162 were down-regulated in consequence of theVEGF produced by the cancer cells. Gene Ontology (GO) enquiry, identified over-representedcategories of potentially biologically relevant genes in the stroma of 1A9VS1 (high VEGF)tumors. Structural molecule activity, cell organization and biogenesis, and basement membranewere among the up-regulated categories.Preclinical evaluation of inhibitors of angiogenesis and vascular targetingagentsAntineoplastic therapies <strong>di</strong>rected against the tumor vascular system may be designed with two<strong>di</strong>fferent strategies. Antiangiogenic therapy prevents the formation of new vessels, whilevascular <strong>di</strong>srupting agents (VDA) aim to selectively destroy the already formed tumor vessels.In <strong>2009</strong> we have investigated the activity of several inhibitors of angiogenesis and VDA.We have investigated the antiangiogenic activity and mechanism of action of new molecules –peptides or non-pepti<strong>di</strong>c small molecules – which mimic endogenous inhibitors of angiogenesis,inclu<strong>di</strong>ng thrombospon<strong>di</strong>n (TSP-1).Among the VDA, we have stu<strong>di</strong>ed the properties of novel tubulin bin<strong>di</strong>ng agents (analogues ofcolchicines and combretastatins), which cause microtubules depolymerization, selective damageto tumor blood vessels and tumor necrosis in experimental models in vivo. In collaboration withProf. Bellina at the Department of Chemistry, University of Pisa , we have screened classes ofcompounds with such properties. The lead compound/s will be further characterized forpharmacological and vascular targeting/antineoplastic properties.The challenge of the combinationsThe optimization of biological therapies against selective targets in combinations withchemotherapy is one of the interest of this laboratory. We are investigating small moleculereceptor tyrosine kinase inhibitors, that affects angiogenesis. We are studying vandetanib, an43ANNUAL REPORT <strong>2009</strong>
IRFMNinhibitor of VEGFR, EGFR and Ret in combination with pacltaxel (PTX) on a model of humanovarian carcinoma xenograft.As expected we found vandetanib influences the tumor vasculature (decreased vascular volumeand increased maturation). This was associated to a decreased <strong>di</strong>stribution of paclitaxel in thetumor. Accor<strong>di</strong>ngly, a therapeutic advantage has been observed by the combination ofvandetanib administrated together with or after paclitaxel. These fin<strong>di</strong>ngs imply that the analysisof vascular changes and chemotherapeutic drug uptake in vandetanib treated tumors may assistto guide the schedule of this combination.Identification of vascular markers of liver metastasisUsing mouse models of liver metastasis, vascular structure were biotinylated in vivo by terminalperfusion methodology and biotinylated proteins analyzed by mass spectrometry (collaborationwith Dario Neri, ETH Zürich). A number of proteins selectively expressed at the level of themetastatic nodules have been identified and confirmed by immunofluorescence analysis.High PAR-1 expression is associated to a malignant phenotypeProtease-activated receptor-1 (PAR-1) over-expression has been associated to a variety ofhuman cancers, and increasing evidence implicates PAR-1 as a contributor to human melanomamalignancy. We investigated melanoma cells, isolated from patient lesions representing variousstages of <strong>di</strong>sease progression, for the expression of PAR-1 and evaluated their migratory andmetastatic capabilities. Cells from advanced stage melanomas expressed higher levels of PAR-1than those from early stages. The metastatic capability showed by the melanoma cells whichoverexpressed PAR-1 allowed these cells to colonize the lungs in 70-100% of the mice.Accor<strong>di</strong>ngly, melanoma cells over-expressing PAR-1 had higher migrated (chemotaxis assay)and inva<strong>di</strong>ng (invasion assay-matrigel) cell counts than those expressing low PAR-1. Migrationand invasion were decreased by silencing PAR-1 (siRNA) and treating with SCH9797, a PAR-1specific inhibitor.Laboratory for the development of new pharmacologicalstrategiesThe laboratory was born out of the consideration that the advent of oncological drugs endowedwith mechanisms of action <strong>di</strong>fferent from those of tra<strong>di</strong>tional chemiotherapics, introduces newtreatment opportunities. At the same time, new problems arise concerning the choice of themost appropriate and effective design for research into the clinical activity profile of these newtreatments.The tra<strong>di</strong>tional para<strong>di</strong>gm where the choice of dose is based on the maximal tolerated toxicity,and the screening of therapeutic activity focus on tumor mass reduction, may not necessarily besuitable for the evaluation of new agents whose targets may include the extracellularcompartment or specific molecular targets.The clinical development of ‘non toxic’ anti tumor molecules requires a critical review of theexisting models as well as of all the aspects relative to the conduction of clinical trialsinclu<strong>di</strong>ng: dose selection criteria, methods for determination and confirmation ofpharmacological activity, and the validation of new technologies and laboratory methods.This is where the need for a profound integration of the ‘clinical screening’ and the preclinicalresearch lies. It is a prerequisite for the construction of the pharmacological rationale for theidentification of the most interesting molecules, the choice of dose, the hypotheses ofcombination with other drugs, and of the most appropriate in<strong>di</strong>cators of clinical activity.44ANNUAL REPORT <strong>2009</strong>
IRFMNThe acquisition of know how and the development and application of new designs for clinicalactivity stu<strong>di</strong>es, inclu<strong>di</strong>ng the use of randomization, the introduction of groups of patientstreated with placebo, and new <strong>di</strong>scontinuation designs, proceed in parallel to the above.Another fundamental issue in laboratory research is the recognition that the genomiccharacterization of any single tumor may now play a more relevant role in drug developmentand treatment identification.This notwithstan<strong>di</strong>ng, numerous uncertainties remain regar<strong>di</strong>ng the role of biomarkers in drugdevelopment and in the implementation of genomic technologies in clinical trials. It is thereforenecessary to improve the methodology and more biomarkers evaluation already in the earlystages of research, thus shifting translational research from a simple process of correlationsearch to one producing knowledge regar<strong>di</strong>ng the pre<strong>di</strong>ctive role of the clinical activity of theinvestigational treatments.Therefore, the primary focus of the laboratory is the optimization of the methods for evaluatingthe activity of cytotoxic drugs, but mostly for those therapies aimed at specific moleculartargets, as well as the identification of factors pre<strong>di</strong>ctive of therapeutic response.Since 2008 two phase II stu<strong>di</strong>es exploring the activity of sorafenib in patients with pancreaticcancer and of Panitumubab in colorectal cancer have been initiated.Laboratory of Clinical TrialsThe Laboratory of Clinical Trials is involved in the planning, coor<strong>di</strong>nation and analysis ofrandomized clinical trials in oncology, conducted in cooperation with a network of me<strong>di</strong>caloncologists. Main covered research areas are gastric, colo-rectal, breast and lung cancer.Moreover the laboratory works on a second line study in patients with pe<strong>di</strong>atric glaucoma incollaboration with Azienda Ospedaliera “Spedali Civili Di Brescia” and supported by AIFA.Gastric cancerITACAS ”Intergruppo Nazionale A<strong>di</strong>uvante Gastrico” study is a randomised, open-label,multicenter, trial aimed at assessing the role of adjuvant chemotherapy in the treatment ofgastric cancer. It compares the efficacy and safety of a sequential treatment (campto plusflurouracil/leucovorin, followed by taxotere and cisplatin) versus flurouracil/leucovorinregimen, used as standard reference in patients with ra<strong>di</strong>cally resected adenocarcinoma of thestomach or gastroesophageal junction. The study, sponsored by <strong>Mario</strong> <strong>Negri</strong> Institute, involves11 oncological collaborative groups and is being conducted in more than 110 Italianexperimental centers. From February 2005 to August <strong>2009</strong>, 1107 patients have been enrolled.The follow-up ends for all patients after the achievement of the target number of events. Firstresults about feasibility and tollerability will be published after the mid-2010. The expertise ofITACA-S will be followed by another study “ ITACA-S2” conducted in patients withadenocarcinoma of the stomach. This randomized, multicentre, 2x2 factorial study, supportedby a grant of AIFA, evaluates the efficacy of a peri-operative versus a post-operativechemotherapy treatment and the efficacy of a post-surgical chemo-ra<strong>di</strong>otherapy treatmentversus no other treatment , irrespectively of the timing of chemotherapy. The study is inprogress and the first patient is expected to be enrolled on the mid-2010.Lung cancerOn September 2007 the accrual of a multicentre, randomized, Italian study started. The aim ofthis project (TAILORAIFA trial) is the optimization of second line therapy in patientswith advanced NSCLC.The development of target-therapy suggested evaluating the treatment efficacy molecularfeatures based on. In particular the epidermal growth factor (EGFR) is a promising target for45ANNUAL REPORT <strong>2009</strong>
IRFMNanticancer therapy. A "tailored therapy" based on in<strong>di</strong>vidual molecular features may result inbetter responses and optimization of sources and costs. The study select specific patientsubgroups based on clinical and biological features. In this patients the target therapy may resultin better responses. In particular, the pre<strong>di</strong>ctive value of PTEN mutations, EGFR proteinexpression and EGFR gene amplification and KRAS mutations in determining the effect oferlotinib as compared to chemotherapy will be assessed .TAILORAIFA trial sponsored by Azienda Ospedaliera Fatebenefratelli e Oftalmico of Milanand supported by the Agenzia Italiana del Farmaco (AIFA), will enroll approximately 1500patients in three years.Colon cancerOn June 2007 started the accrual of a randomised, phase III clinical trial aimed at identifying thebest therapeutic adjuvant strategy in ra<strong>di</strong>cally resected colon cancer patients is starting. Thestudy, sponsored by Fondazione Giscad per la Cura dei Tumori and supported by the AgenziaItaliana del Farmaco (AIFA), will assess the following two questions:1) Optimal duration of FOLFOX-4 regimen (3 vs 6 months)2) Efficacy of the ad<strong>di</strong>tion of Bevacizumab to FOLFOX-4 regimen (only in high risk stageIII patients)For both questions, primary efficacy endpoint will be recurrence free survival.Another phase III clinical trial has started. This study aimed at comparing the efficacy in termsof PFS of the ad<strong>di</strong>tion of cetuximab to FOLFIRI vs. FOLFIRI alone given as first line therapyin patients with advanced CRC KRAS wild-type. In particular, the pre<strong>di</strong>ctive value of PTENmutation will be assessed in determining the effect of cetuximab+FOLFIRI as compared tochemotherapy alone.The patient accrual period is planned for approximately 30 months. To assess PFS, all patientswill be followed for up to 24 months after the last patient is randomized. The maximumestimated study duration is approximately 54 months.This study, sponsored by Regione Lombar<strong>di</strong>a, forsees the involvement of 30 centers and theenrollment of 290 KRAS negative patients.At last a phase III clinical trial has been activated. This study (COMETS), sponsored byFondazione Giscad per la Cura dei Tumori and supported by AIFA, aimed at identifying thebest sequence of treatment (Irinoteca/Cetuximab followed by FOLFOX-4 vs FOLFOX-4followed by Irinotecan/Cetuximab) in KRAS negative patients with advanced colorectal cancerafter a first line chemotherapy with FOLFIRI/Bevacizumab.Primary efficacy endpoint will be overall survival. The maximum estimated study duration isapproximately 52 months and about 350 patients will be enroll.Breast cancerTOP (Trastuzumab Optimisation trial) study is aimed at increasing the knowledge on theefficacy of herceptin in the treatment of locally advanced or metastatic breast cancer patients. Itincludes two randomised, open label, phase III clinical trials: the first addresses the impact of amaintenace therapy with herceptin in patients previously treated with chemotherapy plusherceptin, the second is focused on the efficacy in term of overall survival of a second-line ofchemotherapy plus herceptin versus chemotherapy alone in patients progressed to a first-linecontaining herceptin. The results of TOP study will allow to evaluate the cost/benefit ratio ofherceptin treatment and to optimise the therapeutic effectiveness of such a drug, alreadyapproved in Italy, but used without clear data supporting evidence of benefit in the consideredsetting. This study is sponsored by Regione Lombar<strong>di</strong>a and supported by the Agenzia Italianadel Farmaco (AIFA).46ANNUAL REPORT <strong>2009</strong>
IRFMNHead and neckOn March 2008 started the accrual of a randomized multicenter open label phase 3 factorial trialevaluating the overall survival in patients with locally advanced squamous cell carcinoma ofhead and neck treated with locoregional treatment (ra<strong>di</strong>otherapy plus concomitant chemotherapyor cetuximab) with or without neoadjuvant chemotherapy. Patients will be randomized toreceive 3 cycles of neoadjuvant chemotherapy (TPF) followed by ra<strong>di</strong>otherapy plus concomitantchemo or cetuximab, or ra<strong>di</strong>otherapy plus concomitant chemo or cetuximab alone. The primaryobjectives of the study are to compare the overall survival between neoadjuvant and noneoadjuvant arm and to compare the toxicity between concomitant chemora<strong>di</strong>otherapy andra<strong>di</strong>otherapy plus Cetuximab. The study will be conducted by a multi<strong>di</strong>sciplinary team,composed by oncologists, ra<strong>di</strong>otherapists and othorinolaryngologists and will enrollapproximately 350 patients in Italian centers.Laboratory of Translational and Outcome Research in OncologyThe Laboratory is mainly aimed at documenting, by using either Systematic Literature Review,Randomized or Outcome Research stu<strong>di</strong>es, the value of new <strong>di</strong>agnostic and therapeuticinterventions in oncology, paying particular attention to two critical steps: the passage fromearly to late clinical research (from the activity to efficacy evaluation) and from phase III toclinical practice (from efficacy to effectiveness). The principal lines of research are three:cancer pain evaluation, clinical research on gynecologic cancers and evalution of theeffectiveness of complex clinical programs in oncology care. In order to facilitate the researchactivities and optimize the outputs, the Laboratory hosts the Coor<strong>di</strong>nation Centers of two multi<strong>di</strong>sciplinaryGroups (MANGO: <strong>Mario</strong> <strong>Negri</strong> Gynecologic Oncology and the CP-OR: CancerPain Outcome Research Study Groups). As from 2007 on, all the activities of research andtraining in the field of chronic pain has been coor<strong>di</strong>nated by a de<strong>di</strong>cated center (CERP:Centerfor the Evaluation and Research on Pain).The Center for Evaluation and Research on Pain named CERPCERP is active since early 2008. It coor<strong>di</strong>nates several stu<strong>di</strong>es and other activities regar<strong>di</strong>ngchronic pain, particularly of oncologic nature. CERP is aimed at advancing the scientificknowledge in this field and at improving the quality of palliative care and pain treatment. CERPactivities mainly focus on clinical research, but pre-clinical research (in vivo), information andeducational activities are also considered.Major activities in <strong>2009</strong>:• Publication of scientific articles on international journals: 4 published and 2submitted• Publication of the volume “Guida ragionata all’impiego dei farmaci oppioi<strong>di</strong> neldolore da cancro” (“The rational guide to use opioids in cancer pain”) written byO.Corli and M.Pizzuto - CIC E<strong>di</strong>tore;• Educational activity: “2° Corso <strong>di</strong> Epidemiologia Clinica e Metodologia dellaRicerca” (“2nd Course of Clinical Epidemiology and Researching Methodology” – Naples, feb. <strong>2009</strong>;• Organization of International Conference “Pain classification and assessment” -Milan, sept. <strong>2009</strong>;• Participation in EAPC (European Association of Palliative Care) – Wien, May<strong>2009</strong> – and in EPIC Congress - Lisbon, Sept. <strong>2009</strong>;• Joining in the EuropeanPCR-network (Palliative Care Research Network);• Initial planning and organization of new stu<strong>di</strong>es:47ANNUAL REPORT <strong>2009</strong>
IRFMN‐ A comparison RTC between strong opioids used in cancer pain treatment(multicentric Italian/European study)‐ A validation research of an algorithm for chronic pain management ingeneral me<strong>di</strong>cine‐ Planning of a HTA for a new opioid molecule: tapentadol‐ A systematic review on breakthrough cancer pain.The collaborative group in clinical gynecologic oncology named MaNGOThe <strong>Mario</strong> <strong>Negri</strong> Gynecologic Oncology group (MaNGO) is a new name for a collaborativegroup that has been active in clinical gynecologic oncology for several years. Infact, this groupconsolidated its network and logistics while running the ICONs stu<strong>di</strong>es which were conducte<strong>di</strong>n very close partnership with researchers at the Me<strong>di</strong>cal Research Council, Clinical Trial Unit,UK. MaNGO was formally set up in May 2006 and is mainly representative of the northernpart of Italy, although there are important sites in the central and southern part of the countrytoo. Participating centers are either general public and private hospitals or university clinics.One of MaNGO’s main statutory objectives was to foster an active collaboration with theGynecologic Cancer Intergroup (GCIG), and the European Network of GynaecologicalOncology Trials groups (ENGOT) that represent two International Forum circulating thescientific proposals from many national collaborative groups. MaNGO group is activelyinvolved in many international phase III trials. In <strong>2009</strong> the main results of CALYPSO studywere presented at ASCO meeting in Orlando. MaNGO has been coor<strong>di</strong>nating the Italianparticipation to the PORTEC 3 study: this is an academic randomized phase III trial inendometrial cancer promoted by the Dutch collaborative group. MaNGO received governmentfunds from the Italian Agency for Drugs (AIFA) supporting its national coor<strong>di</strong>nating role. In<strong>2009</strong> two randomized clinical trials in ovarian cancer with new antiangiogenic drugs (pazopaniband vargatef) and internationally coor<strong>di</strong>nated by the German onco-gynecologic group namedAGO were finalised and one started accrual MaNGO group is the promoter of an ancillarystudy for the vargatef trial aimed at clarifying the role of angiogenic markers such as VEGFC,VEGFB, VEGFA and their receptors VEGFR3, VEGFR2) This translational study will bereceiving specific funds. In <strong>2009</strong> MaNGO launched a randomized phase II trial aimed toevaluate the efficacy of trabecte<strong>di</strong>na in the treatment of patients with uterine leiomyosarcoma.In <strong>2009</strong> the data collection for two observational stu<strong>di</strong>es was concluded: a retrospective studydescribing the therapeutic approach to ovarian cancer relapsing after 6-12 months form a firstline platinum-based chemotherapy and a prospective study aimed at evaluating the reliability oftrans-vaginal echography to assess the depth of endometrial cancer miometrial invasion. During<strong>2009</strong> the data of the ILIADE III trial (chemo-ra<strong>di</strong>otherapy compared with ra<strong>di</strong>otherapy only inhigh risk endometrial cancer patients ) were pooled with data coming form a similar Nor<strong>di</strong>cSociety of Gynecologic Oncology (NSGO)’s trialDuring 2008, MaNGO’s Technical-Scientific Committe met quarterly while MaNGO affiliateswere conveyed in one General Assembly.As to the third lineof activities (development and evaluation of complex healthcarevinterventions) two activites are at the moment ongoing on colo-rectal and breast cancerpatients.Colo-rectal cancerThe assessment of efficacy of screening for relapses of colorectal carcinoma has been debatedfor a long time, with controversial results. GILDA is an open label, international, randomisedstudy comparing two <strong>di</strong>fferent strategies of post surgical surveillance in colorectal cancer(Dukes B2-C stage): minimalist versus intensive. Primary endpoints of this trial are <strong>di</strong>sease freesurvival (which is used to assess <strong>di</strong>agnostic anticipation of metastases), overall survival, healthrelated quality of life, <strong>di</strong>rect and in<strong>di</strong>rect costs evaluation. At present, GILDA trial is the largest48ANNUAL REPORT <strong>2009</strong>
IRFMNrandomised study evaluating the efficacy of two follow-ups in colorectal carcinoma. The trialwas closed to patient entry in September 2006 when a total of 1200 patients had been enrolled.At the end of 2008 a manuscript for an Italian journal has been prepared to present the progressof the trial, in <strong>2009</strong> the final analyses will be finished and in 2010 results will be submitted toan international peer reviewed journal.Breast cancerIn the context of a multi-regional project sponsored by the Italian Ministery of Health (6°Progetto Integrato Oncologia) LaTOR is coor<strong>di</strong>nating 2 multi-center RCTs testing the efficacyof <strong>di</strong>fferent follw-up regimens in low and high riskpatienst with breast cancer.Other research activitiesLaTOR has continued on <strong>2009</strong> colklaboration with other laboratories of the <strong>Mario</strong> <strong>Negri</strong>Institute. The most important collaboration are thos eeprtaining the evaluation of incidence an<strong>di</strong>mpact of mild anemia in elderly patients and on the attitude of smokers in the utilization ofpharmacological interventions to quit smoking. Resulst of these collaboration have beebnextensivlely published on interbationala peweer-reviwed journals.Laboratory of Me<strong>di</strong>cal Research and Consumer InvolvementThis Laboratory promotes activities of research in the field of involvement of citizens andpatients and their associations in decision making in health and me<strong>di</strong>cal issues. The activities ofthis laboratory include: researches on information conveyed to patients on illness and treatment,implementation of web site on the topics of the health and the information(www.partecipasalute.it; www.paincare.it; www.fondazionemattioli.it); strategy of involvementof groups of patients for the publication of educational material; research on the evaluation ofthe quality of the life and satisfaction with care through stu<strong>di</strong>es on ad hoc selected groups, an<strong>di</strong>mplementation on validated ad hoc questionnaires.PartecipaSalute (“Participate in Health Care”) - fostering a strategicalliance between consumers’ associations and me<strong>di</strong>cal communityThe project, started in 2003, has been extended over <strong>2009</strong> within a three years planning. It iscoor<strong>di</strong>nated by <strong>Mario</strong> <strong>Negri</strong> Institute, with the collaboration of the Italian Cochrane Centre andZa<strong>di</strong>g, an e<strong>di</strong>torial and publishing company. It is supported by Compagnia <strong>di</strong> San Paolo, a nonprofit private-law foundation. The project develops initiatives de<strong>di</strong>cated both to patients,citizens and their organizations, and to clinicians, researchers and me<strong>di</strong>cal societies.The main aims of the project are to boost patients’ participation to health care debate anddecision making processes - also through their organizations - and to increase me<strong>di</strong>cal societies’attention to patients demands related to clinical research and <strong>di</strong>ssemination of me<strong>di</strong>calinformation. Different stakeholders are involved: patients and consumers’ associations, me<strong>di</strong>calsocieties, researchers, me<strong>di</strong>cal journalists, experts in me<strong>di</strong>cal communication.During <strong>2009</strong> the fourth e<strong>di</strong>tion of the training course for consumers and patients’ representatives- called “Accademia del citta<strong>di</strong>no” - has been organized together with the Centro GestioneRischio Clinico e Sicurezza dei Pazienti ed il Settore Equità e Accesso della Direzione GeneraleDiritto alla Salute della Toscana. The program is structured into three standard modules of thePartecipasalute framework and two modules focused on the training goals of the CentroGestione Rischio Clinico. Participants are 33, coming mainly from Toscana. One of the futureaims of the project is to promote joint initiatives with national and regional institutions in orderto foster their collaborations and partnership with citizens and patients.49ANNUAL REPORT <strong>2009</strong>
IRFMNDuring <strong>2009</strong>, a training course de<strong>di</strong>cated to lay members of ethic committees in Lombar<strong>di</strong>a hasbeen organized, together with the Rete Oncologica Lombarda and the Fondazione <strong>Istituto</strong> deiTumori <strong>di</strong> Milano. The main issues covered were the clinical relevance of research stu<strong>di</strong>es andthe critical aspects of information and informed consent for patients. The course was structure<strong>di</strong>nto three modules of two days each and ended in a final congress.The website of the project has been developed into the PartecipaSalute web 2.0http://www.partecipasalute.it/cms_2/drigg_home where users can post comments, articles andshare documents. Every article published on the website can be commented and rated by users.Areas restricted to participants of the training course have been created, where online formswith exercises are available.Project “ConMe Conoscere la menopausa”The Partecipasalute project together with the National Guidelines System (SNLG) based at the<strong>Istituto</strong> Superiore <strong>di</strong> Sanità organized in 2008 the Consensus conference (CC) “Informingwomen on hormone replacement therapy” in order to assess the current status of the quality ofinformation on hormone replacement therapy (HRT) and re-visit recent research fin<strong>di</strong>ngs on itsrisks/benefits. The final recommendations concern menopause, HRT and information to conveyto women (http://www.partecipasalute.it/cms/files/Documento-definitivo-consenso.pdf).The Laboratory of Me<strong>di</strong>cal research on consumer involvement, Za<strong>di</strong>g - e<strong>di</strong>torial and publishingcompany, and the <strong>Istituto</strong> Superiore <strong>di</strong> Sanità developed the project CONoscere la MEnopausato evaluate the impact of training and information initiatives targeted to women and healthcareoperators, focused on the CC recommendations. The project is funded by the Agenzia italianadel farmaco. Four regions participate in the project: Lombar<strong>di</strong>a, Toscana, Lazio, Sicilia. Thetraining and information interventions are carried out in four local healthcare agencies: ASL <strong>di</strong>Bergamo, ASL 7 <strong>di</strong> Siena, ASL RMH, ASL <strong>di</strong> Enna.Education programs on this issue are organized trough residential sessions and online modulesde<strong>di</strong>cated to me<strong>di</strong>cal practitioners, gynecologists, pharmacists, obstetricians. A booklet forwomen and information material for healthcare operators are also provided.Three main outcomes will be considered: HRT prescriptions, healthcare operators’ and womenknowledge about menopause and HRT, quality of information conveyed to women through thepress.In <strong>2009</strong> the project started, the persons in charge for the project in each local agency werecontacted and the information materials were draft. The booklet for women was also pilotedthrough three focus groups. Residential courses for the persons in charge of the project wereorganized. The project lasts two years.SNAP project - Smoke, Nutrition, Alcohol and Physical ActivitySNAP - Smoke, Nutrition, Alcohol and Physical Activity - is a campaign for the healthaddressed to the whole population of the province of Como, with particular attention to youngpeople between 11 and 20 years. This project, commissioned by FSE - Frontier Science &Technology Research Foundation, Southern Europe, a foundation to support independentresearch - in collaboration with the <strong>Mario</strong> <strong>Negri</strong> Institute, has been launched with the aim ofincreasing knowledge and changing opinions, attitudes and behaviors of young people on thefour issues examined, with an active process of information through the <strong>di</strong>stribution of writtenmaterial, a website built ad hoc and a public event.Between 2008 and <strong>2009</strong>, a prototype phase was carried out in a company furnishing accessoriesin Brianza, to assess the effectiveness of training-information. A questionnaire on the 4 themesSNAP, on knowledge, opinions and attitudes has been <strong>di</strong>stributed to more than 500 employeesbefore a formation-information public event and then 3 months and one year after the event.Data from the first and second survey have been analyzed and data were presented to employees50ANNUAL REPORT <strong>2009</strong>
IRFMNthrough a brochure. Data from the third questionnaire will be analyzed and compared with thoseof the first two.In <strong>2009</strong> a protocol for an intervention in secondary schools in Lombar<strong>di</strong>a was written incollaboration with FSE and IFOM.Programma 1, WP5 -Alleanza contro il cancro – Servizio nazionale <strong>di</strong>accoglienza e informazione sul cancro. Gruppo per l'Informazione ACCP1WP5The project is coor<strong>di</strong>nated by the <strong>Istituto</strong> superiore <strong>di</strong> sanità. Other partners are the Centro <strong>di</strong>Riferimento Oncologico - Aviano, AIMaC Associazione italiana malati <strong>di</strong> cancro, <strong>Istituto</strong>Nazionale dei Tumori, <strong>Istituto</strong> Europeo <strong>di</strong> Oncologia.The Laboratory of Me<strong>di</strong>cal research on consumer involvement refers to the working groupfocusing on information. It planned to evaluate the quality of websites dealing with breastcancer, colon rectal cancer, cervical cancer. An ad hoc evaluation form was created, consideringthe quality of the website and some issues related to the contents.The websites were collected through a research by key words on the search engine google. 72websites were included in the sample. Each website was independently evaluated by tworeviewers, using the defined form. Discrepancies were settled by <strong>di</strong>scussion between reviewersand a third reviewer settled any remaining <strong>di</strong>sagreement. Data collected were analyzed and<strong>di</strong>scussed by the Laboratory.Each evaluation form was included in Cignoweb, a website developed within the project thatpublishes a database collecting websites and information materials about cancer.FSK projectThe project "Inquire, know and participate to improve the quality of life. The case of asthma,type 2 <strong>di</strong>abetes and breast cancer" is a study on the quality of information provided to citizensand patients.This project, sponsored by the Smith Kline Foundation, has been launched with the aim ofevaluating the quality of the brochures produced and <strong>di</strong>stributed by the associations of patientsdealing with the three <strong>di</strong>seases and to produce a core of information on which associations candraw evidence-based information to produce their brochures.In February <strong>2009</strong>, associations were contacted in Lombardy, Veneto, Tuscany, EmiliaRomagna, Puglia and Sar<strong>di</strong>nia.All the brochures, produced or <strong>di</strong>stributed by the associations contacted, arrived at the Instituteand were evaluated twice. Analysis of data was carried out: most of the brochures are written ina clear language, but only few raise awareness of the reader because the information does notfollow data reported in the literature. The core of information will be produced in collaborationwith representatives of patients’ associations contacted.Follow-up in oncology settingTwo stu<strong>di</strong>es on follow-up have been designed and carried out in collaboration with thelaboratory of Giovanni Apolone.The first in collaboration with the Network Oncologica Piemontese regards the follow-up ofpatients with endometrial cancer organization for which the evidence available is not sufficientto draw a path of sure effectiveness. TOTEM study that has the characteristics of an openrandomized multicenter study comparing two <strong>di</strong>fferent modulations of visits and examinationsand in 2008 was <strong>di</strong>scussed and developed the protocol and all related forms, inclu<strong>di</strong>ng from thepoint of fair and comprehensive information to patients who will be invited to participate in thestudy.The second study that takes place in the context of the 6th Integrated Project Oncology (HealthMinistry) provides for the comparative assessment of two follow-up for women at moderate-51ANNUAL REPORT <strong>2009</strong>
IRFMNlow risk with a <strong>di</strong>agnosis of breast cancer and lead to a randomization minimalist follow-upcoor<strong>di</strong>nated by the oncologist or by general practitioner. The study will be operational from<strong>2009</strong>.Quality of life projectsNo specific research projects have been carried out on quality of the life evaluation. Howeverwe have been supporting and coor<strong>di</strong>nating other groups using the instruments of quality of lifetranslated and validated by our research group, SF-36, SF-12, PGWBI. During the year thewebsite http://crc.marionegri.it/qod. has been perio<strong>di</strong>cally updated.52ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF ENVIRONMENTALHEALTH SCIENCESSTAFFHeadRoberto FANELLI, Biol.Sci.D.Laboratory of Analytical BiochemistryHeadChiara CHIABRANDO, Biol.Sci.D.Laboratory of Environmental Chemistry and ToxicologyHeadEmilio BENFENATI, Chem.D.Industrial and Environmental Health UnitHeadLaboratory of Food ToxicologyMarco LODI, ChemistHeadEttore ZUCCATO, M.D.Laboratory of Mass SpectrometryHeadEnrico DAVOLI, Anim.Sci.D.Laboratory of Molecular ToxicologyHeadProtein and Gene Biomarkers UnitHeadLuisa AIROLDI, Pharm.D.Roberta PASTORELLI, Biol.Sci.DDepartment’s UnitsEnvironmental Pollutants Risk Assessment UnitHeadElena FATTORE, Biol.Sci.DAnalytical Instrumentation UnitHeadRenzo BAGNATI, Chem.D.53ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULARoberto Fanelli, Head of the Environmental Health Sciences Department since 1997, Laboratory Head1978-97, Researcher 1975-78, Research fellow 1969-74 at the <strong>Mario</strong> <strong>Negri</strong> Institute.Doctoral Degree in Biological Sciences (University of Milan, 1973), Assistant Professor in Biochemistryat Baylor College of Me<strong>di</strong>cine (Houston, Texas). Member of the Commissione Consultiva ProdottiFitosanitari (Ministero Salute), Member of the Scientific Panel on Contaminants in the Food Chain(European Food Safety Authority, 2003-2006), Certified Italian Toxicologist. Member of the ComitatoScientifico Ente Risi.Research areas: Sources, <strong>di</strong>ffusion, toxicology, human exposure and risk assessment of persistentenvironmental pollutants. Environmental risk of plant protection products. Development of analyticalmethods for identification and measurement of biomarkers in toxicology. Mechanisms of toxic action byproteomic techniques.Selected publications:1. Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S, Zoja C, Corna D, Mele C, FanelliR, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am SocNephrol <strong>2009</strong> ; 20 : 123-130.2. Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometric analysis of illicit drugs in wastewater andsurface water. Mass Spectrom Rev 2008 ; 27 : 378-3943. Zuccato E, Chiabrando C, Castiglioni S, Bagnati R, Fanelli R. Estimating community drug abuse by wastewater analysis.Environ Health Perspect 2008 ; 116 : 1027-10324. Hodgson S, Thomas Laura, Fattore E, Lind P M, Alfven T, Hellstrom L, Hakansson H, Carubelli G, Fanelli R, Jarup L. Bonemineral density changes in relation to environmental PCB exposure. Environ Health Perspect 2008 ; 116 : 1162-11665. Pastorelli R, Carpi D, Campagna R, Airol<strong>di</strong> L, Pohjanvirta R, Viluksela M, Hakansson H, Boutros P C, Moffat I D, Okey A B,Fanelli R. Differential expression profiling of the hepatic proteome in a rat model of <strong>di</strong>oxin resistance: correlation withgenomic and transcriptomic analyses. Mol Cell Proteomics 2006; 5: 882-8946. Zuccato E, Chiabrando C, Castiglioni S, Calamari D, Bagnati R, Schiarea S, Fanelli R. Cocaine in surface waters: a newevidence-based tool to monitor community drug abuse. Environ Health 2005; 4: 14(http://www.ehjournal.net/content/4/1/14 2005)Luisa Airol<strong>di</strong>, Head of the Molecular Toxicology Laboratory since 1994, Unit Head 1987-94, Researcher1978-87, Technician 1967-75 at the <strong>Mario</strong> <strong>Negri</strong> Institute.Doctoral Degree in Pharmacy (University of Milan, 1975), Postdoctoral fellow at the MassachusettsInstitute of Technology (Cambridge, MA, 1976) and at the Northwestern University Me<strong>di</strong>cal School(Chicago, Il, 1977), Researcher at the Yale University Me<strong>di</strong>cal School (New Haven, CT, 1980-81).Research areas: Proteomics in toxicology with particular interest on the study of proteome changes intissues and biological fluids from animals and humans after exposure to toxic compounds; clinicalproteomics aimed at the identification of protein biomarkers as <strong>di</strong>agnostic tools; molecular epidemiologyfocused on the identification and measurement of biomarkers of exposure to environmental carcinogensand <strong>di</strong>sease susceptibility.Selected publications:1. Airol<strong>di</strong> L, Magagnotti C, Iannuzzi AR, Marelli C, Bagnati R, Pastorelli R, Colombi A, Santaguida S, Chiabrando C, SchiareaS, Fanelli R. Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun. <strong>2009</strong> 381: 397-402.2. Carpi D, Korkalainen M, Airol<strong>di</strong> L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R. Dioxinsensitiveproteins in <strong>di</strong>fferentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci. <strong>2009</strong> 108: 330-43.3. Peluso M, Airol<strong>di</strong> L, Colombi A, Munnia A, Veglia F, Autrup H, Dunning A, Garte S, Gormally E, Malaveille C, Matullo G,Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Linseisen J, Boeing H, Trichopoulou A, Palli D, Krogh V, Tumino R,Panico S, Bueno-De-Mesquita H B, Peeters P H, Kumle M, Gonzalez C A, Martinez C, Dorronsoro M, Barricarte A, Tormo MJ, Quiros J R, Berglund G, Janzon L, Jarvholm B, Day N E, Key T J, Saracci R, Kaaks R, Riboli E, Bingham S, Vineis P.Bulky DNA adducts, 4-aminobiphenyl hemoglobin adducts, <strong>di</strong>et and air pollution in a healthy European population. Br J Nutr2008 100: 489-495.4. Veglia F, Loft S, Matullo G, Peluso M, Munnia A, Perera F, Phillips D H, Tang D, Autrup H, Raaschou-Nielsen O,Tjonneland A, Vineis P, Genair-EPIC Investigators. DNA adducts and cancer risk in prospective stu<strong>di</strong>es: a pooled analysis anda meta-analysis. Carcinogenesis 2008 ; 29 : 932-936.5. Pastorelli R, Saletta F, Campagna R, Carpi D, Dell'Osta C, Schiarea S, Vineis P, Airol<strong>di</strong> L, Matullo G Proteomecharacterization of a human urothelial cell line resistant to the bladder carcinogen 4-aminobiphenyl Proteome Sci 2007 5: 654ANNUAL REPORT <strong>2009</strong>
IRFMN6. Pastorelli R, Carpi D, Campagna R, Airol<strong>di</strong> L, Pohjanvirta R, Viluksela M, Hakansson H, Boutros P C, Moffat I D, Okey A B,Fanelli R. Differential expression profiling of the hepatic proteome in a rat model of <strong>di</strong>oxin resistance: correlation withgenomic and transcriptomic analyses. Mol Cell Proteomics 2006; 5: 882-894Emilio Benfenati, Head of the Laboratory of Environmental Chemistry and Toxicology since 1997, UnitHead 1987-97, Researcher 1986-87, Research fellow 1981-86 at the <strong>Mario</strong> <strong>Negri</strong> Institute. Researcher at<strong>Istituto</strong> Biochimico Italiano 1979-1981.Doctoral Degree in Chemistry (University of Milan, 1979).Member of Commissione Consultiva Prodotti Fitosanitari (Ministero Salute 1997-99), Certified ItalianChemist.Research areas: Computer-based models for chemistry and toxicology; Molecular descriptors; QSAR;Toxicity pre<strong>di</strong>ction; Metabolism stu<strong>di</strong>es; Characterization and assessment of wastes, industrial effluents,emissions from landfill and incinerator; Integration of chemical analysis and eco-toxicological data;Chemical analysis of organic compounds by mass spectrometry.Principali pubblicazioni:1. Benfenati E, Benigni R, DeMarini D M, Helma C, Kirkland D, Martin T M, Mazzatorta P, Ouédraogo-Arras G, Richard A,Schilter B, Schoonen W G E J, Snyder R D, Yang C. Pre<strong>di</strong>ctive models for carcinogenicity and mutagenicity: frameworks,state-of-the-art, and perspectives. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev <strong>2009</strong> ; 27 : 57-90.2. Zhao C, Boriani E, Chana A, Roncaglioni A, Benfenati E, A new hybrid QSAR model for the pre<strong>di</strong>ction ofbioconcentration factors (BCF), Chemosphere 2008 73 : 1701-17073. Fjororova N, Novich M, Vrachko M, Kharchevnichova N, Zholdakova Z, Sinitzyna O, Benfenati E, Regulatoryassessment of chemicals within OECD Member Countries, EU and in Russia, J Environ Sci Heal C 2008 26: 40-884. Roncaglioni A, Benfenati E, In silico-aided pre<strong>di</strong>ction of biological properties of chemicals: oestrogen receptorme<strong>di</strong>atedeffects, Chem Soc Rev 2008 37: 441-4505. Porcelli C, Boriani E, Roncaglioni A, Chana A, Benfenati E, Regulatory perspectives in the use and validation ofQSAR. A case study: DEMETRA model for daphnia toxicity, Environ Sci Technol 2008 42 : 491-4966. Benfenati E (Ed.), Quantitative Structure-Activity Relationships (QSAR) for Pesticide Regulatory Purposes,Elsevier Science Ltd, Amsterdam, The Netherlands (2007), 1-510Chiara Chiabrando, Head of the Analytical Biochemistry Laboratory since 1997, Unit Head 1987-97,Researcher 1978-87, Research fellow 1975-78 at the <strong>Mario</strong> <strong>Negri</strong> Institute.Doctoral degree in Biological Sciences (University of Milan, 1974), Postdoctoral fellow at the BaylorCollege of Me<strong>di</strong>cine (Houston, Texas, 1974-75). Postgraduate degree in Pharmacological Research,<strong>Mario</strong> <strong>Negri</strong> Institute (1977).Research areas: Development and application of bio-analytical methods based on mass spectrometry inthe fields of biochemistry, metabolism, clinical chemistry and pharmacology. Identification andcharacterization of proteins and peptides of biome<strong>di</strong>cal interest by proteomic approaches and massspectrometry. Proteomics in oncology.Selected publications1. Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S, Zoja C, Corna D, Mele C, FanelliR, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am SocNephrol <strong>2009</strong> ; 20 : 123-130.2. Zuccato E, Chiabrando C, Castiglioni S, Bagnati R, Fanelli R. Estimating community drug abuse by wastewater analysis.Environ Health Perspect 2008; 116: 1027-1032.3. Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometric analysis of illicit drugs in wastewater andsurface water. Mass Spectrom Rev 2008; 27: 378-394.4. Castiglioni S, Zuccato E, Crisci E, Chiabrando C, Fanelli R, Bagnati R. Identification and measurement of illicit drugs andtheir metabolites in urban wastewaters by liquid chromatography tandem mass spectrometry (HPLC-MS-MS). Anal Chem2006;78: 8421-8429.5. Pastorelli R, Carpi D, Airol<strong>di</strong> L, Chiabrando C, Bagnati R, Fanelli R, Moverare S, Ohlsson C. Proteome analysis for theidentification of in vivo estrogen-regulated proteins in bone. Proteomics. 2005; 5:4936-4945.6. Chiabrando C, Rivalta C, Bagnati R, Valagussa A, Durand T, Guy A, Villa P, Rossi JC, Fanelli R. Identification ofmetabolites from type III F2-isoprostane <strong>di</strong>astereoisomers by mass spectrometry. J Lipid Res. 2002;43:495-509.55ANNUAL REPORT <strong>2009</strong>
IRFMNEnrico Davoli, Head of the Mass Spectrometry Laboratory since 1997, Unit Head 1994-97, Researcher1989-94, Research Fellow 1985-87 at the <strong>Mario</strong> <strong>Negri</strong> Institute. Fellow at USDA, Beltville, MD 1977-78.Doctoral Degree in Animal Sciences (University of Milan, 1983), Postdoctoral fellow at the University ofNebraska (Lincoln, NE, 1987) and at the University of Colorado Health Sciences Center (Denver, CO,1988). Postgraduate degree in Pharmacological Research, <strong>Mario</strong> <strong>Negri</strong> Institute (1988). Member of theAmerican Association for Mass Spectrometry (ASMS) of the Environment and Safety Commission ofIGQ and of the ETS (Emission Tra<strong>di</strong>ng System) commission. Member of the National Biomass ResearchCenter Scientific Committee. Environmental Applications Interest Group Coor<strong>di</strong>nator (ASMS).Research areas: Development of methodology, instrumentation and software for environmental research.Stu<strong>di</strong>es of urban air pollution and characterization of environmental odor annoyance.Selected Publications1. Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Fanelli R, Rossi A N, Il Grande M. Waste management health riskassessment: A case study of a solid waste landfill in South Italy. Waste Manag <strong>2009</strong>, DOI 10.1016/j.wasman.<strong>2009</strong>.10.013.2. Davoli E, Bianchi G. Odour emission rates from a waste treatment plant: results from a multi year follow-up study. ChemicalEngineering Transactions 2008; 15 : 95-102.3. Zuccato E, Grassi P, Davoli E, Val<strong>di</strong>celli L, Wood D, Reitano G, Fanelli R. PCB concentrations in some food from Europeancountries. Food Chem Toxicol 2008, 46: 1062-1067.4. Bagnati R, Bianchi G, Marangon E, Zuccato E, Fanelli R, Davoli E. Direct analysis of isopropylthioxanthone (ITX) in milk byhigh-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007 ; 21 : 1998-20025. Riservato M, Rolla A, Davoli E . An isotopic <strong>di</strong>lution approach for 1,3-buta<strong>di</strong>ene tailpipe emissions and ambient airmonitoring. Rapid Commun Mass Spectrom 2004; 18: 399-4046. Davoli E, Gangai L, Morselli P, Tonelli D. Characterisation of Odorant emissions from Landfills by SPME and GC/MS.Chemosphere 2003; 51: 357-368Ettore Zuccato, Head of the Food Toxicology Laboratory since 2005, Unit Head 1997-2005, Researcher1986-97, Technician 1975-86 at the <strong>Mario</strong> <strong>Negri</strong> Institute.Doctoral degree in Me<strong>di</strong>cine (University of Milan, 1986), Postdoctoral degree in Human Nutrition(1999), Postdoctoral fellow at the King’s College School of Me<strong>di</strong>cine (London, UK, 1988-89).Member of the ANSISA, EMEA expert, member of the Commissione Consultiva per i ProdottiFitosanitari, and expert for the evaluation of plant protection products for registration within the EU.Research areas: Food safety, inclu<strong>di</strong>ng the study of <strong>di</strong>etary chemical contaminants, safety assessment ofGMO in human nutrition, food allergens and toxicants, emerging issues in food toxicology, riskperception and risk communication to the consumers, and evaluation of plant protection products forregistration within the European Union. Environmental pollution by pharmaceuticals, and monitoring ofillicit drugs in surface waters to estimate community drug abuse.Selected publications1. Zuccato E, Castiglioni S. Illicit drugs in the environment. Philos Transact A Math Phys Eng Sci <strong>2009</strong> ; 367 : 3965-3978.2. Zuccato E, Chiabrando C, Castiglioni S, Bagnati R, Fanelli R. Estimating community drug abuse by wastewater analysis.Environ Health Perspect 2008, 116: 1027-1032.3. Castiglioni S, Zuccato E, Chiabrando C, Fanelli R, Bagnati R. Mass spectrometry analysis of illicit drugs in wastewater andsurface water. Mass Spectrom Rev, 2008, 27: 378-394.4. Zuccato E, Grassi P, Davoli E, Val<strong>di</strong>celli L, Wood D, Reitano G, Fanelli R. PCB concentrations in some food from Europeancountries. Food Chem Toxicol 2008, 46: 1062-1067.5. Castiglioni S, Zuccato E, Crisci E, Chiabrando C, Fanelli R, Bagnati R. Identification and measurement of illicit drugs andtheir metabolites in urban wastewaters by liquid chromatography tandem mass spectrometry (HPLC-MS-MS). Anal Chem2006, 78: 8421-8429.6. Zuccato E, Calamari D, Castiglioni S, Chiabrando C, Bagnati R, Fanelli R. Cocaine in surface water: a new evidence-basedtool to monitor community drug abuse. Environmental Health: A Global Access Science Source 2005, 4:14Renzo Bagnati, Head of the Analytical Instrumentation Unit since 2005, Researcher 1992-2005,Research fellow 1986-92 at the <strong>Mario</strong> <strong>Negri</strong> Institute.Doctoral degree in Chemistry (University of Turin, 1985), Postgraduate degree in PharmacologicalResearch, <strong>Mario</strong> <strong>Negri</strong> Institute (1989).Research areas: Mass spectrometry applied to the analysis of biological and environmental relevantsubstances (proteins, peptides, hormones, pharmaceuticals, drugs of abuse, pesticides).Selected Publications1. Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giu<strong>di</strong>ce C, Scanziani E, Mancuso A, Tiveron C,Garattini E. Role of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoic acid: generation andcharacterization of a knockout mouse. Mol Cell Biol <strong>2009</strong> ; 29 : 357-377.56ANNUAL REPORT <strong>2009</strong>
IRFMN2. Zuccato E, Castiglioni S, Bagnati R, Chiabrando C, Grassi P, Fanelli R. Illicit drugs, a novel group of environmentalcontaminants. Water Res 2008 ; 42 : 961-968.3. Analysis of phosphoinositides and their aqueous metabolites. Berrie CP, Iurisci C, Piccolo E, Bagnati R, Corda D. MethodsEnzymol. 2007;434:187-232.4. Bagnati R, Bianchi G, Marangon E, Zuccato E, Fanelli R, Davoli E. Direct analysis of isopropylthioxanthone (ITX) in milk byhigh-performance liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007 ; 21 : 1998-2002.5. Castiglioni S, Zuccato E, Crisci E, Chiabrando C, Fanelli R, Bagnati R. Identification and measurement of illicit drugs andtheir metabolites in urban wastewater by liquid chromatography-tandem mass spectrometry. Anal Chem 2006; 78: 8421-8429.6. Zuccato E, Chiabrando C, Castiglioni S, Calamari D, Bagnati R, Schiarea S, Fanelli R. Cocaine in surface waters: a newevidence-based tool to monitor community drug abuse. http://www.ehjournal.net/content/4/1/14 2005.Elena Fattore, Head of the Environmental Pollutants Risk Assessment Unit since 2005, Researcher2001-2004, Research fellow 1991-1997 at the <strong>Mario</strong> <strong>Negri</strong> Institute.Doctoral Degree in Biological Sciences (University of Milan, 1991), Postgraduate degree inPharmacological Research, <strong>Mario</strong> <strong>Negri</strong> Institute (1994), Postdoctoral fellow at the National Institute ofEnvironmental Me<strong>di</strong>cine, Karolinska Institutet, Stockholm (1998-2000). Member of the Working Groupof External Scientific Experts to externally review the quality of the scientific outputs of the EuropeanFood Safety Authority (EFSA) in the area of activity of chemical risk assessment and connected fields.Research areas: Environmental chemistry, toxicology, assessment of human exposure and risk fromenvironmental pollutants with emphasis on <strong>di</strong>oxins and <strong>di</strong>oxin-like compounds.Selected publications1. Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Fanelli R, Rossi A N, Il Grande M. Waste management health riskassessment: A case study of a solid waste landfill in South Italy. Waste Manag <strong>2009</strong>, DOI 10.1016/j.wasman.<strong>2009</strong>.10.013.2. Colombo A, Benfenati E, Mariani G, Lo<strong>di</strong> M, Marras R, Rotella G, Senese V, Fattore E, Fanelli R. PCDD/Fs in ambient air innorth/east Italy: The role of a MSWI inside an industrial area. Chemosphere <strong>2009</strong>; 77: 1224-12293. Fattore E, Fanelli R, Dellatte E, Turrini A, Di Domenico A. Assessment of the <strong>di</strong>etary exposure to non-<strong>di</strong>oxin-like PCBs of theItalian general population. Chemosphere 2008, 73: S278-S283.4. Hodgson S, Thomas L, Fattore E, Lind P M, Alfven T, Hellstrom L, Hakansson H, Carubelli G, Fanelli R, Jarup L Bonemineral density changes in relation to environmental PCB exposure. Environmental Health Perspective 2008, 116: 1162-1166.5. Carubelli G, Fanelli R, Mariani G, Nichetti S, Crosa G, Calamari D, Fattore E. PCB contamination in farmed and wild sea bass(Dicentrarchus labrax L.) from a coastal wetland area in central Italy. Chemosphere 2007 ; 68 : 1630-1635.6. Fattore E, Fanelli R, Turrini A, Di Domenico A. Current <strong>di</strong>etary exposure to polychloro<strong>di</strong>benzo-p-<strong>di</strong>oxins,polychloro<strong>di</strong>benzofurans, and <strong>di</strong>oxin-like polychlorobiphenyls in Italy. Mol Nutr Food Res 2006; 50: 915-921Marco Lo<strong>di</strong>, Head of the Industrial and Environmental Unit since 2002, Consultant 1997-2002 at the<strong>Mario</strong> <strong>Negri</strong> Institute.General Certificate of Education in Industrial Chemistry (Milan, 1974).Member of AIDII (Italian Industrial Hygiene Association), certified by ACGIH (American Conference ofGovernmental Industrial Hygienist).Research areas: Emission sources, environmental <strong>di</strong>ffusion, toxicology, human exposure and riskassessment of persistent environmental pollutants. Environmental risk of chemical pollution products.Development of sampling methods for environmental toxic compounds.Selected publications1. Colombo A, Benfenati E, Mariani G, Lo<strong>di</strong> M, Marras R, Rotella G, Senese V, Fattore E, Fanelli R. PCDD/Fs in ambient air innorth/east Italy: The role of a MSWI inside an industrial area. Chemosphere <strong>2009</strong> ; 77 : 1224-1229.2. Benfenati E, Azimonti G, Auteri D, Lo<strong>di</strong> M Environmental and ecological toxicology: computational risk assessment.Computational toxicology. Risk assessment for pharmaceutical and environmental chemicals John Wiley, Hoboken, NJ, 2007;625-6503. Grosso M, Cernuschi S, Palini E, Lo<strong>di</strong> M, Mariani G. PCDD/Fs release during normal and transient operation of a full scaleMSWI plant. Organohalogen Compounds 2004; 66: 1243-12494. Benfenati E, Mariani G, Lo<strong>di</strong> M, Reitano G, Fanelli R. Is bioexsiccation releasing <strong>di</strong>oxins? Organohalogen Compounds2004; 66: 955-9615. Fattore E, Mariani G, Guzzi A, Di Guardo A, Benfenati E, Lo<strong>di</strong> M, Fanelli R. Air <strong>di</strong>oxin concentrations in Seveso area. In:Halogenated Environmental Organic Pollutants, 18th. Symp., Stockholm, Sweden, august 17-21, 1998. 1998 : 237-2406. Benfenati E, Mariani G, Schiavon G, Lo<strong>di</strong> M, Fanelli R. Diurnal, weekly and seasonal air concentrations of PCDD and PCDFin an industrial area. Fresenius Journal Analytical Chemistry 1994; 348: 141-14357ANNUAL REPORT <strong>2009</strong>
IRFMNRoberta Pastorelli, Head of Protein and Gene Biomarkers Unit since 2004, Researcher 1992-2003,Research fellow 1983-92 at the <strong>Mario</strong> <strong>Negri</strong> Institute.Doctoral Degree in Biological Sciences (University of Milan, 1982), Postgraduate degree inPharmacological Research, <strong>Mario</strong> <strong>Negri</strong> Institute (1986), Postdoctoral fellow at the MassachusettsInstitute of Technology, Cambridge, MA (1987-89 and 1991).Research areas: Toxicoproteomic investigation of global protein expression profiles and their modulationevoked by environmental compounds in <strong>di</strong>fferent biological compartments. Critical targets and pathwaysin toxicology. Pharmacogenetics: effects of genetic polymorphisms in the human population on thein<strong>di</strong>vidual susceptibility to environmental xenobiotic and carcinogen effects.Selected publications:1. Airol<strong>di</strong> L, Magagnotti C, Iannuzzi AR, Marelli C, Bagnati R, Pastorelli R, Colombi A, Santaguida S, Chiabrando C, SchiareaS, Fanelli R. Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun. <strong>2009</strong> 381: 397-402.2. Carpi D, Korkalainen M, Airol<strong>di</strong> L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R. Dioxinsensitiveproteins in <strong>di</strong>fferentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci. <strong>2009</strong> 108: 330-43.3. Pastorelli R, Saletta F, Campagna R, Carpi D, Dell’Osta C, Schiarea S, Vineis P, Airol<strong>di</strong> L, Matullo G. Proteomecharacterization of a human urothelial cell line resistant to the bladder carcinogen 4-aminobiphenyl. Proteome Science 2007.4. Moretti M, Dell'omo M, Villarini M, Pastorelli R, Muzi G, Airol<strong>di</strong> L, Pasquini R. Primary DNA damage and geneticpolymorphisms for CYP1A1, EPHX and GSTM1 in workers at a graphite electrode manufacturing plant. BMC Public Health.2007 7: 2705. Pastorelli R, Carpi D, Campagna R, Airol<strong>di</strong> L, Pohjanvirta R, Viluksela M, Hakansson H, Boutros P C, Moffat I D, Okey A B,Fanelli R. Differential expression profiling of the hepatic proteome in a rat model of <strong>di</strong>oxin resistance: correlation withgenomic and transcriptomic analyses. Mol Cell Proteomics 2006; 5: 882-8946. Pastorelli R, Carpi D, Airol<strong>di</strong> L, Chiabrando C, Bagnati R, Fanelli R, Moverare S, Ohlsson C.Proteome analysis for theidentification of in vivo estrogen-regulated proteins in bone. Proteomics 2005; 5: 4936-4945ACTIVITIESThe Department works to investigate environmental factors and their effects on human health.The main research lines focus on the survey of environmental contaminants, the assessment ofhuman exposure with related health risks, and toxicity mechanisms of pollutants.The assessment of environmental contamination is carried out not only for well-known andwidespread compounds, like <strong>di</strong>oxins and PCBs, but also for new classes of "unconventional"pollutants, e.g., endocrine <strong>di</strong>sruptors, potentially toxic "natural" compounds, and drugs enteringthe environment after human or veterinary use. The identification –for the first time– of illicitdrugs in urban waste and river waters, led to a new original tool for the evidence-basedmonitoring of community drug abuse. For all these survey activities sophisticated analyticalmethods based on advanced mass spectrometric techniques are developed.The Department is active in the assessment of human exposure to toxic compounds in theatmosphere and the <strong>di</strong>et, which is the main source of priority pollutants (PCBs, <strong>di</strong>oxins andother endocrine <strong>di</strong>sruptors). Assessment of the risk associated to contamination in real-lifescenarios has recently gained much importance. In order to respond to the growing demand forinformation, the Department is more and more involved in toxicological and ecotoxicologicalrisk analysis, based on stu<strong>di</strong>es in field and pre<strong>di</strong>ctive models of toxicity.Molecular epidemiology stu<strong>di</strong>es are used to identify genetic and/or environmental factorsposing risks to human health. By this approach, we search for new useful “biological markers"to identify susceptible subjects, in view of fin<strong>di</strong>ng appropriate preventive strategies.The Department has implemented an advanced technological proteomic platform, in order toidentify proteins <strong>di</strong>fferentially expressed in biological compartments in various experimentaland clinical con<strong>di</strong>tions. This approach is particularly relevant in toxicology, since it cancontribute to find new biomarkers of toxicity or pathology, and to identify molecular targets andtoxic effect mechanisms of pollutants and drugs. To integrate our proteomic stu<strong>di</strong>es, we havenow introduced among our activities metabolomics, i.e., the study of small molecules, such asamino acids, carbohydrates, lipids, hormones etc., the final products of protein expression andactivity which contribute to define the biochemical phenotype of a biological system.58ANNUAL REPORT <strong>2009</strong>
IRFMNMass spectrometry (MS) is a central analytical technique at the Department, where a completeset of state-of-the-art instrumentation is available, from GC-MS and LC-MS to MALDI-TOF-MS. These instruments are provided with modern solutions for sample introduction (chip-basednanoLC), sample ionization (ESI, DESI and MALDI), tandem MS (MSn) by triple quadrupoleand TOF-TOF instruments, high mass resolution analysis (hybrid ion trap/orbitrap).FINDINGS/MAIN RESULTSEvidence of new molecular players in the effects of TCDD on bone development provided byproteomics coupled to networks analysis.Resistance to the bladder carcinogen 4-aminobiphenyl in human urothelial cells is me<strong>di</strong>ated byderegulation of apoptosis and membrane trafficking proteins.Bone protein profile in a murine model of osteoporosis.Identification of novel protein targets responsive to the effects of estrogens in bone.TCDD's effect on the liver proteome profile of exposed rats. Determination of a subset of rathepatic proteins in<strong>di</strong>cative of <strong>di</strong>fferences in <strong>di</strong>oxin susceptibility.The presence of 4-aminobiphenyl-hemoglobin adducts may help identify nonsmokers at highrisk of cancers related to environmental tobacco smoke exposure.Reference values of allele and genotype frequency of several metabolic genes in 15,000 controlsubjects.CYP1A1 polymorphism affects lung tumor risk.Identification of CYP2C9 genetic polymorphism as a determinant of severe adverse reactions tophenytoin.On-line in silico models to pre<strong>di</strong>ct ecotoxicity of pesticides for regulatory purposes.New in silico models, freely available on-line, to pre<strong>di</strong>ct toxicity and ecotoxicity of chemicalsfor the REACH European legislation.A new model for identification of endocrine <strong>di</strong>sruptors using molecular docking.A method aimed at characterizing environmental odors to identify odor sources in complexenvironments.Albumin can become a source of potentially antigenic peptides in proteinuric nephropaties.Proteomic/bionformatic workflow for comparative secretome analysis to highlight perturbedfunctional networks in cancer cell lines.Moderate-to-high fish consumption can result in excee<strong>di</strong>ng the daily intake safety levels ofPCBs and <strong>di</strong>oxin-like compounds established by the European Commission.The same food type may contain significantly <strong>di</strong>fferent concentrations of PCBs and <strong>di</strong>oxin-likecompounds, depen<strong>di</strong>ng on the geographic origin (this may help lower the risk for the consumersby understan<strong>di</strong>ng and controlling the causes of the <strong>di</strong>fferences).The environmental levels of several drugs exceed the “safety limits” established for them.Environmental pollution from pharmaceuticals is a general phenomenon that can be describedby controllable variables (environmental load and mass balance).Illicit drug residues and their metabolites were found in urban waste and river waters.Environmental levels can be used as a new tool to estimate illicit drugs consumption in thepopulation.The <strong>di</strong>stribution of <strong>di</strong>etary intake values of <strong>di</strong>oxins, <strong>di</strong>oxin-like PCBs and non <strong>di</strong>oxin-like PCBswas characterized for the general Italian population.The higher intake of PCBs due to consumption of farmed fish vs. wild fish is mainly due to thehigher fat content in farmed fish.Development of novel mass spectrometric methods for the selective measurement of therapeuticand illicit drugs in environmental samples.59ANNUAL REPORT <strong>2009</strong>
IRFMNNATIONAL COLLABORATIONSARPA Emilia RomagnaARPA VenetoASL <strong>di</strong> BresciaASL <strong>di</strong> ComoASL <strong>di</strong> CagliariASL <strong>di</strong> NapoliCNR - IRSAComune <strong>di</strong> Rosignano Marittimo (LI)Comune <strong>di</strong> Sant’Urbano (PD)CSRA-AstiFederchimicaFondazione 'S. Maugeri'Fondazione ISI, TurinGruppo Collaborativo sulla Suscettibilità Genetica ai Cancerogeni Ambientali (GSEC), Milan,ItaliaINRAN-<strong>Istituto</strong> Nazionale <strong>di</strong> Ricerca sugli Alimenti e la NutrizioneISPO, Florence<strong>Istituto</strong> Clinico Humanitas, Milan<strong>Istituto</strong> Superiore <strong>di</strong> SanitàI.Z.S.L.T - <strong>Istituto</strong> Zooprofilattico Sperimentale del Lazio e ToscanaMinistero dell'AmbientePolitecnico <strong>di</strong> MilanoPolitecnico <strong>di</strong> TorinoProvincia <strong>di</strong> VercelliProvincia PordenoneStazione Sperimentale dei Combustibili, MilanUniversità degli Stu<strong>di</strong> del Piemonte OrientaleUniversità degli Stu<strong>di</strong> <strong>di</strong> CagliariUniversità degli Stu<strong>di</strong> <strong>di</strong> GenovaUniversità degli Stu<strong>di</strong> <strong>di</strong> MilanoUniversità degli Stu<strong>di</strong> <strong>di</strong> Napoli "Federico II"Università degli Stu<strong>di</strong> <strong>di</strong> PalermoUniversità degli Stu<strong>di</strong> <strong>di</strong> PaviaUniversità degli Stu<strong>di</strong> <strong>di</strong> PerugiaUniversità degli Stu<strong>di</strong> <strong>di</strong> Roma "La Sapienza"Università degli Stu<strong>di</strong> <strong>di</strong> SienaUniversità degli Stu<strong>di</strong> <strong>di</strong> TorinoUniversità dell’Insubria, VareseUniversità degli Stu<strong>di</strong> <strong>di</strong> VeronaINTERNATIONAL COLLABORATIONSBASF Agricultural Centre, Limburgerhof, GermanyCentre for Environmental Policy, Imperial College, London, UKDanish Institute of Agricultural Sciences, Research Centre Foulum, Tjele, DenmarkDepartment of Analytical and Pharmaceutical Chemistry, The Royal Danish School of60ANNUAL REPORT <strong>2009</strong>
IRFMNPharmacy, DenmarkDepartment of Anatomy and Cell Biology, University of Oulu, Oulu, FinlandDepartment of Computer Science and Engineering, University of Galati, RomaniaDepartment of Electrical and Computer Engineering, University of Patras, GreeceDepartment of Environmental Health, National Public Health Institute, Kuopio, FinlandDepartment of Epidemiology & Public Health, Imperial College, London, UKDepartment of Inland Fisheries, Institute of Freshwater Ecology and Inland Fisheries, Berlin,GermanyDepartment of Molecular Biology, University of Bergen, Bergen, NorwayDepartment of Organic Chemistry, Universidad de Ca<strong>di</strong>z, Ca<strong>di</strong>z, SpainDivision of Endocrinology, Department of Internal Me<strong>di</strong>cine, Sahlgrenska University Hospital,Gothenburg, SwedenEnvironmental Chemistry, IIQAB-CSIC, Barcelona, SpainEnvironmental Hygiene and Chemistry Department, Institute of Environmental Me<strong>di</strong>cine andHospital Epidemiology, University of Freiburg, GermanyEnvironmental Protection Agency, US EPA - National Risk Management Research Laboratory(NRMRL), Cincinnati OH, USAEuropean Monitoring Centre for Drugs and Drug Ad<strong>di</strong>ction (EMCDDA), Lisbon, PortugalFaculté de Mé<strong>di</strong>cine et de Pharmacie, Université de Mons-Hainaut, Mons, BelgiumFaculty of Veterinary Me<strong>di</strong>cine, Utrecht University, Utrecht, NetherlandsFood and Environment Research Agency, York, UKForschungzentrum Jülich Gmbh, Jülich, GermanyHelmholtz-Zentrum für Umweltforschung UFZ, Leipzig, GermanyInstitute of Environmental Me<strong>di</strong>cine. Karolinska Institute, Stockholm, SwedenInstitute of Pharmaceutical Chemistry, University of Pécs, Pecs, HungaryInstitute of Phytome<strong>di</strong>cine, Biological Control, Horticulture and Nematology, Vienna, AustriaInstitute of Soil Science and Plant Cultivation, Pulawy, PolandInteruniversitaeres Forchunginstitut fuer Agrarbiotechnologie, Tulln, Austria<strong>Istituto</strong> <strong>di</strong> Chimica <strong>di</strong> São Carlos, Università <strong>di</strong> São Paulo, BrazilKnowledgeMiner Software, Berlin, GermanyIn Vitro Testing Industrial Platform, Tres Cantos (Madrid), SpainLaboratory of Chemometrics & Bioinformatics, University of Orléans, Orléans, FranceLaboratory of Neurobiology, Centro de Investigation Principe Felipe, Valencia, SpainLithuanian Institute of Agricultrure, Vilnius, LithuaniaLiverpool John Moores University, Liverpool, UKNational Institute of Chemistry, Kemijski Institut Ljubljana, Ljubliana, SloveniaNatural Resources Research Institute, University of Minnesota, Duluth, USANational Institute for Public Health and the Environment (RIVM), Bilthoven, NetherlandsPesticide Safety Directorate, York, UKPlant Protection Institute, Hungarian Academy of Sciences, Budapest, HungaryPublicSpace Ltd, Ulverstone, UKSchool of Biome<strong>di</strong>cal Sciences, University of Ulster, Coleraine, UKSymlog, Paris, FranceSyngenta Crop Protection AG, Basel, SwitzerlandTNO, Delft, NetherlandsUniversity of Tartu, Tartu, EstoniaEDITORIAL BOARD MEMBERSHIPJournal of Environmental Science and Health, Part B (Emilio Benfenati), Journal of61ANNUAL REPORT <strong>2009</strong>
IRFMNEnvironmental Science and Health, Part C (Emilio Benfenati), International Journal ofComputational Intelligence (Emilio Benfenati), International Journal of Information Technology(Emilio Benfenati), International Journal of Signal Processing (Emilio Benfenati), ChemistryCentral Journal (Emilio Benfenati), Current Computer Aided Drug Design (Emilio Benfenati),Advances in Chemoinformatics and Computational Methods (Emilio Benfenati), The OpenBiomarkers Journal (Luisa Airol<strong>di</strong>).PEER REVIEW ACTIVITIESAd<strong>di</strong>ction, Analytical and Bioanalytical Chemistry, Chemical Biology & Drug Design,Chemical Research Toxicology, Chemometrics and Intelligent Laboratory Systems,CHEMOLAB, Chemosphere, Clinical Biochemistry, , Environment International,Environmental Pollution, Environmental Modeling & Software, Environmental Science &Technology, Journal of Chemical Information and Modeling, International Journal of MolecularScience, Journal Computer-Aided Molecular Design, Journal of Hazardous Materials, LungCancer, Molecular Diversity, Proteomics, Royal Society's Philosophical Transactions,Toxicology Letters, Waste Management, Water Research, International Journal ofEnvironmental Analytical Chemistry, Molecular Nutrition and Food Research, Journal ofChromatography A, External review of the quality of the scientific outputs of the EuropeanFood Safety Authority (EFSA).NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPCCPF - Commissione Consultiva Prodotti Fitosanitari (Ministero della Salute, Ministerodell'Ambiente)ECCO - European Commission Coor<strong>di</strong>nationEFSA - European Food Safety AuthorityIGQ - Commissione Ambiente e SicurezzaEVENT ORGANIZATIONWorkshop of the CAESAR EC project on QSAR models for REACH, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong>Farmacologìche <strong>Mario</strong> <strong>Negri</strong>, Milan, Italy, 10-11 March <strong>2009</strong>.4th annual meeting of the ATHON EC project, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> Farmacologìche <strong>Mario</strong><strong>Negri</strong>, Milan, Italy, 24-26 March <strong>2009</strong>.OSIRIS Training Course on Integrated Testing Strategies (ITS), <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong>Farmacologìche <strong>Mario</strong> <strong>Negri</strong>, Milan, Italy, 23-25 September <strong>2009</strong>.Workshop “Alta risoluzione, imaging, ion mobility: le sfide della spettrometria <strong>di</strong> massamoderna”, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> Farmacologìche <strong>Mario</strong> <strong>Negri</strong>, Milan, Italy, 16 December <strong>2009</strong>.62ANNUAL REPORT <strong>2009</strong>
IRFMNCONFERENCE AND WORKSHOP CONTRIBUTIONSWorkshop “Alta risoluzione, imaging, ion mobility: le sfide della spettrometria <strong>di</strong> massamoderna”, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> Farmacologìche <strong>Mario</strong> <strong>Negri</strong>, Milan, Italy, 16 December <strong>2009</strong>.International Meeting on health and environment: challenges for the future. <strong>Istituto</strong> Superiore <strong>di</strong>Sanità, Rome, Italy, 9-11 December <strong>2009</strong>.Milano Focus Salute. Seminari e Dibattiti sui temi della prevenzione e dei corretti stili <strong>di</strong> vita,Milan, Italy, 25-27 November <strong>2009</strong>.Master <strong>di</strong> II livello anno accademico <strong>2009</strong> - 2010 “Management of chemicals: la normativaREACH”, Teoria sui meto<strong>di</strong> <strong>di</strong> non testing e meto<strong>di</strong> in silico nel REACH, Genoa, Italy, 10November <strong>2009</strong>.EPAA <strong>Annual</strong> Conference "Dissemination of 3Rs information", Brussels, Belgium, 6November <strong>2009</strong>.3rd Meeting of the Extended OECD/IPCS Advisory Group on Molecular Screening andToxicogenomics, Paris, France, 26 October <strong>2009</strong>.XXXIII Congresso Nazionale dell’Associazione Italiana Stu<strong>di</strong>o Pancreas, Rozzano (Milan),Italy, 15-17 October <strong>2009</strong>.34° Congresso Nazionale della Società Italiana <strong>di</strong> Farmacologia, Rimini, Italy, 14-17 October<strong>2009</strong>.Course “Philosophy of Risk in Health Risk Assessment”, Stockholm, Sweden, 12-16 October<strong>2009</strong>.Scuola <strong>di</strong> Alta Formazione - Università del Piemonte Orientale, Alessandria, Italy, 12 October<strong>2009</strong>.Sar<strong>di</strong>nia 2010 International Symposium on Energy from Biomass and Waste. Cagliari, Italy, 5-8October <strong>2009</strong>.National Congress of the Italian Society for Neuroscience (SINS), Milan, Italy, 2-5October <strong>2009</strong>.WATERMED - Salone sulle Tecnologie dell'Acqua per il Me<strong>di</strong>terraneo, Rome, Italy, 1 October<strong>2009</strong>.ECNIS Workshop on Biomarkers and Cancer, Porto, Portugal, 21-23 September <strong>2009</strong>.International workshop “Illicit drug market” Università <strong>di</strong> Roma “la Sapienza”, Rome, Italy, 16-17 September <strong>2009</strong>.63ANNUAL REPORT <strong>2009</strong>
IRFMNVII World Congress on Alternatives & Animal Use in the Life Sciences, Rome, Italy, 30August-3 September <strong>2009</strong>.10th International Conference on Environmental Mutagens, Florence, Italy, 20-25 August <strong>2009</strong>.EC Project Coor<strong>di</strong>nators Meeting, Sintra, Portugal, 30-31 July <strong>2009</strong>.Hydrica - Salone Internazionale biennale Tecnologie per l’Acqua, Padua, Italy, 25 June <strong>2009</strong>.Italian Proteomics Association, 4th <strong>Annual</strong> National Conference, Milan, Italy, 22-25 June <strong>2009</strong>.57th American Society for Mass Spectrometry Conference, Philadelphia, PA, USA, 1-5 June<strong>2009</strong>.SETAC Europe 19 th <strong>Annual</strong> Meeting, Gothenburg, Sweden, 31 May-4 June <strong>2009</strong>.Triple Quadrupole User Meeting, Florence, Italy, 22-23 May <strong>2009</strong>.International Society of Pharmacovigilance, Training Courses ‘Ecopharmacovigilance’, Verona,Italy, 26-27 March <strong>2009</strong>.Workshop of the CAESAR EC project on QSAR models for REACH, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong>Farmacologìche <strong>Mario</strong> <strong>Negri</strong>, Milan, Italy, 10-11 March <strong>2009</strong>.13° Congreso de Investigacion en Salud Publica, Cuernavaca, Mexico, 3-6 March <strong>2009</strong>.GRANTS AND CONTRACTSA2A BresciaACEGAS S.p.A, TriesteAIIPA (Associazione Italiana Industrie Prodotti Alimentari)AMA, RomaASL ComoASL MantovaASL Napoli 2Associazione Italiana Ricerca sul CancroASSOFOODTEC/UCIMAC (Costruttori Italiani Macchine per Caffè Espresso ed Attrezzatureper Bar)Bluegreen BiotechCatanzaro Costruzioni S.r.l.CLIR S.p.A.COGEIDE S.p.A.COOP ItaliaCSRAComune <strong>di</strong> Lomello (PV)Comune <strong>di</strong> Mazzano e Rezzato (BS)64ANNUAL REPORT <strong>2009</strong>
IRFMNComune <strong>di</strong> Rosignano Marittimo (LI)Comune <strong>di</strong> Sant’Urbano (PD)Consorzio Quadrifoglio S.p.A.Dipartimento delle Politiche Antidroga, Presidenza del Consiglio dei MinistriECODECO, PaviaEnergyGreen S.r.l.European Commission (ATHON, CASCADE, CAESAR, CHEMOMENTUM,CHEMPREDICT, OSIRIS, ORCHESTRA)Federchimica, MilanoFIAT Auto S.p.A.Fondazione CARIPLO, MilanoFondazione Italo Monzino, MilanoGruppo CSA, S.p.a. Rimini (RN)HERA S.p.A. (Hol<strong>di</strong>ng Energia Risorse Ambiente)I.Z.S.L.T - <strong>Istituto</strong> Zooprofilattico Sperimentale del Lazio e ToscanaLachifarma, Zollino (LE)Lucart, Cartiera Lucchese S.p.A. Porcari, LuccaMinistero della Salute, ItaliaMinistero dell'Ambiente, ItaliaNufarm S.A.S., FranciaOxon Italia S.p.A., Pero (MI)Provincia <strong>di</strong> PordenoneProvincia <strong>di</strong> VercelliSO.GE.NU.S. S.p.ATenacta GroupTM.E. S.p.A.Veolia Servizi Ambientali S.p.A.SCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Vaissière T, Cuenin C, Paliwal A, Genair-EPIC Investigators, Hainaut P, Herceg Z. Quantitative analysis of DNAmethylation after whole bisulfitome amplification of a minute amount of DNA from body fluids. Epigenetics <strong>2009</strong> ;4 : 221-230.Carpi D, Korkalainen M, Airol<strong>di</strong> L, Fanelli R, Hakansson H, Muhonen V, Tuukkanen J, Viluksela M, Pastorelli R.Dioxin-sensitive proteins in <strong>di</strong>fferentiating osteoblasts: effects on bone formation in vitro. Toxicol Sci <strong>2009</strong> ; 108 :330-343.Airol<strong>di</strong> L, Magagnotti C, Iannuzzi A R, Marelli C, Bagnati R, Pastorelli R, Colombi A, Santaguida S, Chiabrando C,Schiarea S, Fanelli R Effects of cigarette smoking on the human urinary proteome. Biochem Biophys Res Commun<strong>2009</strong> ; 381 : 397-402.Maggioni S, Benfenati E, Colosio C, Moretto A, Roots O, SAFEFOODNET Consortium. Food contamination controlin European new Member States and associated can<strong>di</strong>date countries: data collected within the SAFEFOODNETproject. J Environ Sci Health B <strong>2009</strong> 44 : 407-414.Toropov A A, Toropova A P, Benfenati E. QSAR modelling for mutagenic potency of heteroaromatic amines byoptimal SMILES-based descriptors. Chem Biol Drug Des <strong>2009</strong> ; 73 : 301-312.Colombo A, Benfenati E, Mariani G, Lo<strong>di</strong> M, Marras R, Rotella G, Senese V, Fattore E, Fanelli R. PCDD/Fs inambient air in north/east Italy: The role of a MSWI inside an industrial area. Chemosphere <strong>2009</strong> ; 77 : 1224-1229.65ANNUAL REPORT <strong>2009</strong>
IRFMNToropov A, Toropova A P, Benfenati E. Simplified molecular input line entry system-based optimal descriptors:quantitative structure-activity relationship modeling mutagenicity of nitrated polycyclic aromatic hydrocarbons.Chem Biol Drug Des <strong>2009</strong> ; 73 : 515-525.Toropov A A, Toropova A P, Benfenati E. QSPR modeling bioconcentration factor (BCF) by balance of correlations.Eur J Med Chem <strong>2009</strong> ; 44 : 2544-2551.Benfenati E, Benigni R, DeMarini D M, Helma C, Kirkland D, Martin T M, Mazzatorta P, Ouédraogo-Arras G,Richard A, Schilter B, Schoonen W G E J, Snyder R D, Yang C. Pre<strong>di</strong>ctive models for carcinogenicity andmutagenicity: frameworks, state-of-the-art, and perspectives. J Environ Sci Health C Environ Carcinog EcotoxicolRev <strong>2009</strong> ; 27 : 57-90.Toropov A A, Toropova A P, Benfenati E, Manganaro A. QSPR modeling of enthalpies of formation fororganometallic compounds by SMART-based optimal descriptors. J Comput Chem <strong>2009</strong> ; 30 : 2576-2582.Toropov A A, Toropova A P, Benfenati E. QSPR modeling of octanol water partition coefficient of platinumcomplexes by InChI-based optimal descriptors. J Math Chem <strong>2009</strong> ; 46 : 1060-1073.Bala P, Ostropytskyy V , Baldridge K, Rasch K, Benfenati E, Sild S, Casalegno M, Schone R, Maran U, Schuller B,Miroslaw L, Williams N. UNICORE: A middleware for life sciences grids. In: Handbook of research oncomputational grid technologies for life sciences, biome<strong>di</strong>cine, and healthcare. Vol. I, <strong>2009</strong>; 615-643.Roncaglioni A, Benfenati E. Computer-aided methodologies to pre<strong>di</strong>ct endocrine-<strong>di</strong>srupting potency of chemicals. In:Endocrine-<strong>di</strong>srupting chemicals in food. CRC Press, Boca Raton, <strong>2009</strong>; 306-321.Toropov A A, Toropova A P, Benfenati E, Leszczynska D, Leszczynksy J. Ad<strong>di</strong>tive InChI-based optimal descriptors:QSPR modeling of fullerene C60 solubility in organic solvents. J Math Chem <strong>2009</strong> ; 46 : 1232-1251.Toropov A A, Toropova A P, Benfenati E. QSPR modelling of the octanol/water partition coefficient oforganometallic substances by optimal SMILES-based descriptors. Central European Journal Chemistry <strong>2009</strong> ; 7 :846-856.Toropov A A, Toropova A P, Benfenati E, Manganaro A. QSAR modelling of carcinogenicity by balance ofcorrelations. Mol Divers <strong>2009</strong> ; 13 : 367-373.Toropov A A, Toropova A P, Benfenati E. Ad<strong>di</strong>tive SMILES-based carcinogenicity models: probabilistic principlesin the search for robust pre<strong>di</strong>ctions. Int J Mol Sci <strong>2009</strong> ; 10 : 3106-3127.Toropov A A, Toropova A P, Benfenati E, Manganaro A. QSAR modelling of the toxicity to Tetrahymena pyriformisby balance of correlations. Mol Divers <strong>2009</strong>, DOI 10.1007/s11030-009-9186-0.Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S, Zoja C, Corna D, MeleC, Fanelli R, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenicpeptides. J Am Soc Nephrol <strong>2009</strong> ; 20 : 123-130.Davoli E, Fattore E, Paiano V, Colombo A, Palmiotto M, Fanelli R, Rossi A N, Il Grande M. Waste managementhealth risk assessment: A case study of a solid waste landfill in South Italy. Waste Manag <strong>2009</strong>, DOI10.1016/j.wasman.<strong>2009</strong>.10.013.Zuccato E, Castiglioni S. Illicit drugs in the environment. Philos Transact A Math Phys Eng Sci <strong>2009</strong> ; 367 : 3965-3978.Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giu<strong>di</strong>ce C, Scanziani E, Mancuso A,Tiveron C, Garattini E. Role of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoicacid: generation and characterization of a knockout mouse. Mol Cell Biol <strong>2009</strong> ; 29 : 357-377.Sala F, Zucchetti M, Bagnati R, D'Incalci M, Pace S, Capocasa F, Marangon E. Development and validation of aHPLC-MS/MS method for the determination of ST1926, a novel oral antitumor agent, adamantyl retinoid derivative,in human plasma of patients participating in a Phase I study. J Chromatogr B Biomed Appl <strong>2009</strong> ; 877 : 3118-312666ANNUAL REPORT <strong>2009</strong>
IRFMNLAY PRESS SELECTION (<strong>2009</strong>)Zuccato E, Castiglioni S, Chiabrando C, Bagnati R, Fanelli R Valutazione dell'uso <strong>di</strong> droga nelle città. Residui nelleacque <strong>di</strong> scarico e consumi nella popolazione. Ricerca & Pratica, <strong>2009</strong> 145 : 3-11Fattore E. Effetto accumulo attraverso la catena alimentare, occorre ridurre l'esposizione, ARPA <strong>2009</strong>, n. 1: 32.Fattore E. Esposizione acuta a pestici<strong>di</strong>: e i bambini? Ricerca & Pratica, <strong>2009</strong> 149 : 193-199OTHER PUBLICATIONS (<strong>2009</strong>)Brambilla G, Abate V, Davoli E, De Filippis S P, De Luca S, Dellatte E, Fanelli R, Fattore E, Fochi I, Fulgenzi A R,Iacovella N, Iamiceli A L, Lucchetti D, Melotti P, Miniero R, Moret I, Pignata S, Roncarati A, Triboni P, Ubal<strong>di</strong> A,Zambon S, Di Domenico A. Occurrence of persistent organic pollutants in wild and farmed Italian fish in theMe<strong>di</strong>terranean Sea. 29th International Symposium on Halogenated Persistent Organic Pollutants (Dioxin <strong>2009</strong>)August 23-28, <strong>2009</strong> Beijing. Organohalogen Compounds <strong>2009</strong>, 71 : 1070-1074.RESEARCH ACTIVITIESLaboratory of Molecular ToxicologyProteome AnalysisProteome analysis includes protein separation by one- and two-<strong>di</strong>mensional gel electrophoresis,protein excision from the gel, their <strong>di</strong>gestion with proteolytic enzymes and their identificationby mass spectrometry (MALDI-TOF-MS, LC-ESI-MS/MS) coupled to the use of existingdatabases. Alternatively, peptides resulting from the <strong>di</strong>gestion of protein mixtures with specificproteases are separated by two-<strong>di</strong>mensional liquid chromatography.ToxicoproteomicsStu<strong>di</strong>es are ongoing on the characterization of changes in the proteome profile induced byenvironmental toxic compounds, with the aim of obtaining protein biomarkers with the abilityto <strong>di</strong>fferentiate two or more biological states. Proteome changes in tissues and target organs ofanimals, and cells treated with endocrine <strong>di</strong>sruptors, estrogens, or environmental carcinogens,are related to functional changes during toxicological processes.Clinical ProteomicsQualitative and quantitative proteome changes resulting from the exposure to environmentaltoxic compounds or in pathological con<strong>di</strong>tions are monitored in human biological plasma andurine. Ongoing stu<strong>di</strong>es aim at the characterization of protein biomarkers for early <strong>di</strong>agnosis of<strong>di</strong>seases and for the identification of therapeutic targets.Pathways analysisAn integrated data-mining platform such as MetaCore (GeneGo Inc., USA) is used in order tomap the <strong>di</strong>fferentially expressed proteins into biological networks and for functionalinterpretation of the protein data.MetabolomicsMetabolites are the biological endpoints of gene expression and enzyme activity and includesmall molecules such as amino acids, carbohydrates, fatty acids, hormones, etc., that provide themetabolic phenotype of in<strong>di</strong>viduals. Metabolomic research focuses on the quantitative analysis67ANNUAL REPORT <strong>2009</strong>
IRFMNof metabolites in biological fluids to link human metabolic profile variations to endogenous orexogenous pathophysiological stimuli and to genetic mo<strong>di</strong>fications.Selected metabolites are extracted from plasma or urine by solid phase extraction and analyzedby HPLC coupled to high-resolution mass spectrometry.The integration of proteomic and metabolomic stu<strong>di</strong>es will provide information that can help tobetter understand <strong>di</strong>sease development and to identify preventive interventions.Molecular EpidemiologyThe laboratory works mainly on the measurement of biological markers used to assess humanexposure to environmental toxic compounds. Our stu<strong>di</strong>es include DNA- and blood proteinadductformation by several environmental carcinogens. In ad<strong>di</strong>tion, we study whether thepolymorphism of genes co<strong>di</strong>ng for enzymes involved in the activation and detoxification ofcarcinogens are determinants of adduct formation. Genotypes are detected by restrictionfragment length polymorphism analysis, after the amplification by polymerase chain reaction ofspecific nucleotide sequences of the genes under study.The laboratory participates in an international cooperation study aimed at the collection ofreference values on allele and genotype frequency of the most common metabolic enzymepolymorphisms in control populations.Laboratory of Analytical BiochemistryIdentification and characterization of proteins by mass spectrometryOur laboratory is developing <strong>di</strong>fferent analytical and instrumental techniques, based onchromatography, electrophoresis and mass spectrometry, for the identification andcharacterization of proteins and peptides in biological samples. This activity is mainly aimed at1) global characterization and comparison of secretomes from human cancer cell lines toidentify proteins that may be functionally relevant for tumor growth and spread; 2) profilingproteins in biological fluids for <strong>di</strong>scovery and identification of biomarkers of physiopathologicaland toxicological relevance, 3) identifying and characterizing endogenous degradation productsof proteins, 4) identifying proteins produced by cells in vitro in response to given stimuli, 5)selectively isolating biologically relevant proteins by immunoaffinity-based micro-techniques.Ongoing projects include the study of exogenous protein degradation in renal tubular cells inrelation to antigen presentation mechanisms, and the characterization of the secretome of cancercell lines in vitro to identify factors affecting immune cells.Method development in proteomicsThe laboratory works on the optimization of various analytical methodologies for proteomics,i.e. various complementary techniques for protein isolation and identification by massspectrometry (MALDI-TOF-MS, LC-ESI-MS/MS).Inflammation and neurodegeneration induced by environmental agentsWe are studying the neurotoxic effects of endotoxin (LPS) and other environmental proinflammatoryagents on neuronal cell primary cultures. The mechanisms lea<strong>di</strong>ng to theactivation of the inflammatory reaction are stu<strong>di</strong>ed by biochemical and immunochemicalmethods, and proteomic approaches. Novel anti-inflammatory drugs of natural origin are beingtested in this model, with the aim of evaluating their neuroprotective effects.68ANNUAL REPORT <strong>2009</strong>
IRFMNLaboratory of Environmental Chemistry and ToxicologyDevelopment and use of analytical methods to evaluate contamination inwater bo<strong>di</strong>es, soil, biota, human samples in exposed populationAnalytical methods are developed to study environmental pollutants in water ecosystems,landfills, contaminated sites. Qualitative and quantitative analyses of organic pollutants are doneby mass spectrometry (GC-MS, LC-MS, LC-MS/MS). Typical analyses include PCDD/F, PCB,PAH, polybrominated <strong>di</strong>phenylethers, pesticides, endocrine <strong>di</strong>sruptor chemicals, and industrialpollutants.Stu<strong>di</strong>es on environmental, toxicological and ecotoxicological propertiesof chemicalsResearch is carried out on pollutant properties, searching literature data, comparing andevaluating <strong>di</strong>fferent sources, and mainly developing pre<strong>di</strong>ctive models to cope with the lack ofexperimental data. Thus, we develop models starting merely from the chemical structure. Theresearch addresses the <strong>di</strong>fferent kinds of chemical descriptors and chemical fragments, obtainedwith <strong>di</strong>fferent software. Then, we develop models using algorithms such as neural network,fuzzy logic, genetic algorithms, classifiers, multivariate analysis, etc. Different methods arecompared and integrated within a structured ensemble. Standar<strong>di</strong>zed methods for pesticideswere developed and validated accor<strong>di</strong>ng to OECD guidelines.Risk assessment of pollutantsStu<strong>di</strong>es are aimed at assessing the risk of pollutants for human population and environment. Forthis we model transport and <strong>di</strong>ffusion of pollutants, to obtain a pre<strong>di</strong>cted concentration on givenspace and time scales. Such an activity is integrated with those above described on chemicalanalyses and toxicity pre<strong>di</strong>ction, to achieve a continuous transfer of data and research.Research on pollutants emitted in the atmosphere (Unit of Industrial andEnvironmental Hygiene)Stu<strong>di</strong>es address <strong>di</strong>fferent aspects of atmospheric pollution. Research deals with: sampling areasaround the pollution source, chemical analyses, transport modeling depen<strong>di</strong>ng onmeteorological con<strong>di</strong>tions and orography, risk assessment for population and environment.Qualitative and quantitative analyses are done by gas chromatography-mass spectrometry usinghigh resolution for PCDDs/PCDFs, and negative ion-chemical ionization for PCBs.Laboratory of Mass SpectrometryParticulate air pollutionEpidemiological stu<strong>di</strong>es consistently show an association between an increasing number ofpathologies, both acute and chronic, and particulate air pollution. This has been shown not onlyin respiratory, but in car<strong>di</strong>ovascular <strong>di</strong>seases as well. Airborne particulate sampling and analysisstrategies are developed to characterize both adsorbed compounds and exposition in <strong>di</strong>fferentactivities.Method development in environmental sciencesMethods, analytical methodologies, instrumentation and software for data acquisition andreduction, are developed for environmental stu<strong>di</strong>es. High-sensitivity instrumentation, mainlybased on mass spectrometry, is developed for trace and ultra-trace analysis. Also, transportableinstrumentation is developed for field stu<strong>di</strong>es or continuous monitoring.69ANNUAL REPORT <strong>2009</strong>
IRFMNCharacterization of environmental odor annoyanceCharacterization of odors poses several analytical problems because they result from a complexmixture of compounds (odorants) stimulating receptors in the nasal cavity. Most odorants arevolatile organic compounds (VOC) generated by bacterial degradation of organic matter. Theyare often present at trace levels, while numerous sources can contribute to the total odor. Usingsampling techniques specifically developed for olfactometry, solid phase microextraction andGC/MS analysis, we can detect traces (low ppb to high ppt) of a wide polarity/volatility range ofairborne VOC odorant compounds. With a chemometric approach, we can characterize thesources of emissions, assess odor control methods, and identify emissions that contribute toodors in ambient air.Laboratory of Food ToxicologyChemical contaminants in foodWe are studying human exposure to <strong>di</strong>etary PCBs and <strong>di</strong>oxins. PCBs were measured in foo<strong>di</strong>tems in <strong>di</strong>fferent European countries, showing <strong>di</strong>fferences in PCBs exposure of Europeanconsumers. Further stu<strong>di</strong>es were aimed at measuring PCBs and <strong>di</strong>oxins in samples of fishcaught in Italy and in food items from an Italian area at high risk of contamination. Ongoingstu<strong>di</strong>es are focused to assess levels of PCBs and <strong>di</strong>oxins in samples of human milk collectedfrom mothers living in highly contaminated areas.Therapeutic and illicit drugs in the environmentPharmaceuticals are a class of emerging environmental pollutants. We have organized acampaign to detect the presence of pharmaceuticals and their metabolites in Italian rivers andsewage treatment plants, with the aim of better characterizing the contamination and assessingrelated risks.Human and environmental risks are evaluated by studying the toxic effects of pharmaceuticalsat environmental levels, on cultures of human and zebra fish cells. Further ongoing stu<strong>di</strong>es areaimed at investigating a possible relationship between antibiotic occurrence and resistance inenvironmental bacteria.The possible presence of illicit drugs in water samples from sewage treatment plants and riverswas investigated, starting with cocaine and its metabolites. Their levels, used to estimate drugabuse in the local population, revealed that cocaine consumption greatly exceeds officialestimates. This approach has been subsequently extended to include other common drugs ofabuse such as cannabis, opiates (heroin, morphine), and amphetamines (amphetamine,methamphetamine, ecstasy). Consumption of these drugs have been subsequently estimated insome European cities. Our evidence-based method allows monitoring of patterns and trends ofdrug abuse in local communities, and is able to detect qualitative and quantitative consumptionchanges in real time. This tool can therefore complement survey methods in more realisticallydescribing the drug abuse phenomenon.Regulatory activitiesOn behalf of the Ministry of Health, we carried on the evaluation of the dossiers required forpesticide registration within the European Union.Unit of Environmental Pollutants Risk AssessmentToxicological risk assessmentStarting from real cases of contamination the unit aims to develop methods for the exposureassessment also employing probabilistic approaches, and more refined statistical models.70ANNUAL REPORT <strong>2009</strong>
IRFMNThe activities focus on risk assessment related to specific environmental con<strong>di</strong>tions or humanactivities which pose a risk for human health. These stu<strong>di</strong>es include risk assessments related tothe emissions of pollutants from incinerators and landfills, inclu<strong>di</strong>ng transfer of thesecompounds into the food chain. During the <strong>2009</strong> a health impact assessment due toconcentrations of particulate matter, ozone, and nitrogen <strong>di</strong>oxide, in an highly industrializedarea, in northern Italy, and another study on the toxicological risk for consumers, due to therelease of heavy metals from the professional coffee machines have been completed.Exposure to environmental pollutantsResearch activities also include measurement of contaminants in environmental samples, andassessment of human exposure. Specific research projects focuses on the analysis ofpolychlorinated and polybrominated <strong>di</strong>oxins and furans (PCDD, PBDD, PCDF and PBDF),polychlorinated biphenyls (PCBs), perfluorooctanoic acid (PFOA), and perfluorooctanesulphonate (PFOS), in aquatic organisms at <strong>di</strong>fferent levels of the food chain, and farmed fishcoming from <strong>di</strong>fferent areas of the Me<strong>di</strong>terranean sea. The purpose is to estimate, for thegeneral Italian population , the exposure to these pollutants trough fish consumption.Evaluation of toxicological dataToxicological data resulting from in vivo sub-chronic stu<strong>di</strong>es in rats exposed to in<strong>di</strong>vidual<strong>di</strong>oxin-like and non <strong>di</strong>oxin-like PCBs are evaluated in detail, in order to investigate the doseresponserelationship and the applicability of the “benchmark dose” approach.Unit of Analytical InstrumentationDevelopment and application of analytical methods for compounds ofbiological and environmental interest.Methods are developed mainly using solid phase extraction (SPE) followed by liquidchromatography - mass spectrometry (LC-ESI-MS/MS) or gas chromatography - massspectrometry (GC-MS). Available instruments include mass spectrometers equipped with<strong>di</strong>fferent analyzers: magnetic fields, time of flight (TOF), quadrupoles (single and triple), iontraps and high resolution orbitrap. The main ionization techniques are electron ionization (EI),chemical ionization (CI), MALDI, ACPI and Electrospray (conventional and nanoSpray).Substances of interest include proteins, peptides, hormones, pharmaceuticals, drugs of abuse,pesticides, and other environmental contaminants (PCBs, hydroxy-PCBs, perfluorinatedcompounds).Work has been started for the development of imaging methods in biological tissues with theMALDI-TOF technique.71ANNUAL REPORT <strong>2009</strong>
IRFMN72ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF NEUROSCIENCESTAFFHeadGianluigi FORLONI, Biol.Sci.D.Laboratory of Biology of Neurodegenerative DisordersHeadCell Death and Neuroprotection UnitHeadGianluigi FORLONI, Biol.Sci.D.Tiziana Borselllo, Biol.Sci.D.Laboratory of Drug MetabolismHeadSilvio CACCIA, Farm.D.Laboratory of Experimental NeurologyHeadAnnamaria VEZZANI, Biol.Sci.D.Laboratory of Experimental PsychopharmacologyHeadLuigi CERVO, Ph.D.Laboratory of Geriatric NeuropsychiatryHeadUgo LUCCA, MScEpidemiology and Social Psychiatry UnitHeadBarbara D’AVANZO, Philos.D.Geriatric Epidemiology UnitHeadGeriatric Pharmacology UnitHeadMauro TETTAMANTI, Biol.Sci.D.Emma RIVA, M.D.Laboratory of Inflammation and Nervous System DiseasesHeadPharmacology of septic shockHeadMaria Grazia DE SIMONI, Biol.Sci.D.Pia VILLA, Biol. Sci. DLaboratory of Molecular NeurobiologyHeadCaterina BENDOTTI, Farm.D.73ANNUAL REPORT <strong>2009</strong>
IRFMNLaboratory of Neurobiology of PrionsHeadRoberto Chiesa, Biol. Sci. DLaboratory of Neurochemistry and BehaviorHeadRoberto William INVERNIZZI, Biol. Sci DPharmacology of Cognitive Behavior UnitHeadMirjana CARLI, Ph.D.Laboratory of Neurological DisordersHeadEttore BEGHI, M.D.Laboratory of Quality Assessment of Geriatric Services UnitHeadAlessandro NOBILI, M.D.74ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAGianluigi Forloni, obtained the Degree of Biological Science at the University of Milan in 1985. Aftertwo years of post doc at the Department of Neuroscience and Psychiatry at Johns Hopkins University inBaltimore, USA, he came back to the <strong>Mario</strong> <strong>Negri</strong> Institute and between 1992 and 1996 he was the headof the Neurobiology of Alzheimer's <strong>di</strong>sease Unit; since 1996 he is the Head of the Biology ofNeurodegenerative Diseases Lab and since 2002 the Head of the Neuroscience Department. His scientificinterest is focused on the biological and genetic bases of aging-related <strong>di</strong>sorders in particular Alzheimer’s<strong>di</strong>sease, Prion-related encephalopathies and Parkinson’s <strong>di</strong>sease. He has been member of severalEuropean committees for the examination of projects in the neuroscience field. He is now member of thecoor<strong>di</strong>nation group of the European IMI Consortium Pharmacog. He is President of the ItalianAssociation on Brain Aging Research (AIRIC) and member of the European Academy of Sciences. He isthe author of more than 170 peer-reviewed scientific articles and about 30 reviews or book chapters.Selected publications• Forloni G. Angeretti N., Chiesa R., Monzani E., Salmona M., Bugiani O.,Tagliavini F. Neurotoxicity of a prion proteinfragment. Nature 362: 543-546 (1993)• Forloni, G., Tagliavini, F.,Bugiani, O. and Salmona, M. Amyloid in Alzheimer’s <strong>di</strong>sease and prion-relatedencephalopathies: Stu<strong>di</strong>es with synthetic peptides. Progr. Neurobiol. 49: 287- 315 (1996)• Forloni, G., Bertani, I. Calella, AM., Thaler, F.Invernizzi. R. Alpha-synuclein and Parkinson's <strong>di</strong>sease selectiveneurodegeneration effect of alpha synuclein fragment on dopaminergic neurons in vitro. Ann. Neurol. 47: 632-640(2000)• Forloni G. Iussich, S. Awan T. Colombo L. Angeretti, N. Girola, L. Bertani, I. Poli, G. Caramelli, M. Bruzzone,MG.Farina, L. Limido, L. Rossi, G. Giaccone G. Ironside, JW. Bugiani, O.Salmona M. and Tagliavini, F. Tetracyclinesaffect prion infectivity Proc. Natl. Acad. Sci . New York 99: 10849-10854 (2002)• Pesaresi M, Lovati C, Bertora P, Mailland E, Galimberti D, Scarpini E, Quadri P, Forloni G, Mariani C. Plasma levels ofbeta-amyloid (1-42) in Alzheimer's <strong>di</strong>sease and mild cognitive impairment. Neurobiol Aging., 27:904-5 (2006)• Fioriti, L. Angeretti, N.. Colombo, L., De Luigi A., Manzoni, C., Colombo A., Morbin, M., Tagliavini, F., Salmona, M.Chiesa, R. Forloni, G. Neurotoxic and gliotrophic activity of a synthetic peptide homologous to Gerstmann-Sträussler-Scheinker <strong>di</strong>sease amyloid protein. J. Neurosci. 27: 576-83 (2007)• Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, Restelli E, Balducci C, Fiordaliso F, Salio M,Bianchi S, Fioriti L, Morbin M, Pincherle A, Marcon G, Villani F, Carli M, Tagliavini F, Forloni G, Chiesa Mutant prionprotein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model.Neuron ; 60 : 598-609 (2008)• Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C, Salmona M, Caccia S, NegroA, Forloni G. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity causedby alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem. 110:1445-56 (<strong>2009</strong>).Ettore Beghi (EB) graduated in Me<strong>di</strong>cine in 1972 and received his specialty in neurology in 1976 at theUniversity of Milan. He trained in epidemiology with a fellowship at the Department of statistics andEpidemiology of the Mayo Clinic in Rochester, MN (USA). He is Head of the Laboratory ofNeurological Disorders at the <strong>Mario</strong> <strong>Negri</strong> Institute, Director of the Neurophysiology/Epilepsy Unit andProfessor of Neuroepidemiology at the University of Milano-Bicocca, Monza. He is member of thee<strong>di</strong>torial board of the journals Epilepsia, Neuroepidemiology, Inpharma, Drugs in R & D, Clinical DrugInvestigation, Neurological Sciences and is a referee of several national and international me<strong>di</strong>caljournals. The main areas of interest and research include stu<strong>di</strong>es on the descriptive, analytic, andexperimental epidemiology in the field of epilepsy, peripheral neuropathies, headache, and amyotrophiclateral sclerosis.Selected publications• Leone, MA. Solari, A.,Beghi, E. for the FIRST Group. Treatment of the first tonic-clonic seizure does not affect longtermremission of epilepsy. Neurology 2006; 67: 2227-2229• Millul, A., E. Beghi, G. Logroscino, A. Micheli, E. Vitelli, A. Zar<strong>di</strong>, for the “Registro Lombardo SLA”(SLALOM).Survival of patients with amyotrophic lateral sclerosis in a population-based registry. Neuroepidemiology 2005; 25: 114-119.• Tonini, C., E. Beghi, A.T. Berg, G. Bogliun, L. Giordano, R.W. Newton, A. Tetto, E. Vitelli, D. Vitezic, S. Wiebe.Pre<strong>di</strong>ctors of epilepsy surgery outcome: a meta-analysis. Epilepsy Res 2004; 62: 75-87.• Van den Broek, M., and Beghi E., for the RESt-1 Group. Morbi<strong>di</strong>ty in patients with epilepsy: type and complications. AEuropean Cohort Study. Epilepsia 2004; 45: 71-76.• Van den Broek, M. and Beghi E. for the RESt-1 Group. Accidents in patients with epilepsy: type and complications. AEuropean Cohort Study. Epilepsia 2004; 45: 667-672.75ANNUAL REPORT <strong>2009</strong>
IRFMN• Musico, M., E. Beghi, A. Solari, F. Viani for the First Seizure Trial Group. Treatment of the first tonic-clonic seizuredoes not improve the prognosis of epilepsy. Neurology 1997; 49: 991-998.Caterina Bendotti, got her degree in Pharmacy at the University of Milano in 1984; In 1986 -1988 she waspost doc at the Genetic developmental Lab, Dept. of Physiology of the Johns Hopkins University, Baltimore,USA. In 1988 -1992 she was research fellow in the laboratory of Neuropharmacology and in the 1992, shebecame head of the Molecular Neurobiology Unit in Institute, since 1998 she is head of laboratory. Themajor research interest is the study of pathogenetic mechanisms of familial Amyotrophic Lateral Sclerosis..Since 2002 she is a member of the e<strong>di</strong>torial board of Journal of Neurochemistry. In 2002-2003 has beenMember of Scientific Committees of the International Symposia on ALS held in Milano, 17-19Novembre,2003. In 2003-2007 has been member of the Italian Ministry of Health Committees for the<strong>di</strong>agnosis, cure, care and assistance of patients with ALS. Since 2005 is member of the Board of Directors ofthe Italian Society of Neuroscience. Since 2006 is member of the Research Advisory Panel of the MNDAssociation, UK. Scientific reviewer of 11 international scientific journals. In 2007 she has co-organised thefirst international meeting on” Mutant SOD1 and familial ALS:from the molecule to man” held inMilano(13-16 September). She is author and co-author of 110 articles 100 of which with peer-review.Rapporteur of many communications in national and international meetings.Selected publications• Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M, Simeoni S, Crippa V, Onesto E, Palazzolo I,Rusmini P, Bolzoni E, Bendotti C, Poletti A. Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet.16(13):1604-18, 2007.• Massignan T, Casoni F, Basso M, Stefanazzi P, Biasini E, Tortarolo M, Salmona M, Gianazza E, Bendotti C, Bonetto V.Proteomic analysis of spinal cord of presymptomatic amyotrophic lateral sclerosis G93A SOD1 mouse.Biochem BiophysRes Commun. 353(3):719-25, 2007• Peviani M, Cheroni C, Troglio F, Quarto M, Pelicci G, Bendotti C. Lack of changes in the PI3K/AKT survival pathwayin the spinal cord motor neurons of a mouse model of familial amyotrophic lateral sclerosis.Mol Cell Neurosci. 34:592-602, 2007• Carri MT, Grignaschi G, Bendotti C. Targets in ALS: designing multidrug therapies. Trends Pharmacol Sci. 27(5):267-73, 2006• Cheroni C., Peviani M., Cascio P., Debiasi S., Monti C. and Bendotti C. Accumulation of human SOD1 andubiquitinated deposits in the spinal cord of SOD1G93A mice during motor neuron <strong>di</strong>sease progression correlates with adecrease of proteasome. Neurobiol. Disease. 18(3): 509-522, 2005• Bendotti C and MT Carri. Lessons from models of SOD1-linked familial ALS. Trends Mol Med. 10(8):393-400, 2004• Bendotti C., Tortarolo M., Suchak S.K., Calvaresi N., Carvelli L., Bastone A., Rizzi M., Rattray M. and Mennini T.Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamatelevels. J. Neurochem.,79, 737-746, 2001• Migheli A., Atzori C., Piva R., Tortarolo M., Girelli M., Schiffer D. and Bendotti C. Lack of apoptosis in mice withALS. Nature Me<strong>di</strong>cine: 5, 966-967, 1999.Silvio Caccia. Laurea in Pharmacy at the University of Milan. Diploma in Industrial Chemistry at the L.Cobianchi Technical Institute (Verbania, NO) and Diploma in Biochemical Research at the <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>” (Milan).Research fellow, Laboratory of General Pharmacology at the <strong>Mario</strong> <strong>Negri</strong> Institute, 1970-1973;Permanent Researcher, Laboratory of Neuropharmacology, 1975; Head of Pharmacokinetic Unit, 1983;Head of Drug Metabolism Laboratory, 1988 to date, doing research in the field of pharmacology andtoxicology with particular focus on pharmacokinetic aspects, both at the pre-clinical and clinical level.He has been member of the scientific assessment teams (acting as expert) for the evaluation of marketingauthorisation applications submitted to the European and Italian Agencies.He is author and co-author ofmore than 200 articles, inclu<strong>di</strong>ng reviews, monographs and book chapters.Selected publications• Caccia S. N-dealkylation of arylpiperazine derivatives: <strong>di</strong>sposition and metabolism of the 1-aryl-piperazines formed.Curr Drug Metab 2007 ; 8 : 612-622.• Caccia S. Main active components of St. John's Wort (Hypericum Perforatum) extracts: current analytical procedures forpharmacokinetics and concentration-response stu<strong>di</strong>es. Curr Pharm Anal 2006; 2: 59-68.• Caccia S. Antidepressant-like components of Hypericum perforatum extracts: An overview of their pharmacokineticsand metabolism. Curr Drug Metab 2005; 6: 531-543• Caccia S. Metabolism of the newest antidepressants: Comparisons with related predecessors IDrugs 2004; 7: 143-150.• Caccia S. Biotransformation of post-clozapine antipsychotics. Pharmacological implications. Clin Pharmacokinet2000; 38: 39.76ANNUAL REPORT <strong>2009</strong>
IRFMN• Caccia S. Metabolism of the newer antidepressants. An overview of the pharmacological and pharmacokineticimplications. Clin Pharmacokinet 1998; 34: 281-302.Luigi Cervo was awarded the degree of Doctor of Philosophy (Ph.D.) from the Open University, MiltonKeynes, U. K. in 2005. Since 2006 he has been the head of the Experimental PsychopharmacologyLaboratory. From 1978 to 2001 he has been a research fellow and then Chief of the BehaviouralPharmacology Unit in the laboratory of Neuropharmacology and in 1981 he was awarded the degree inBiochemical Research from the “M. <strong>Negri</strong>” Institute. Between 1981 and 1983 he spent two years as aresearch fellow in the Department of Psychiatry at the Chicago University, Illinois, U.S.A. His mainresearch interests concern Neuropsychopharmacology and the mechanism of action of psychotropicdrugs. In particular the role of receptors subtypes for serotonin, dopamine, noradrenaline and glutamatein drug dependence and drug craving, depression, anxiety. Author and co-author of several peer-reviewarticles, author of communications in international meetings, he is scientific reviewer of severalinternational scientific journals. Member of Society for Neuroscience, European BehaviouralPharmacological Society, Italian Society for Neuroscience and Italian Society ofNeuropsychopharmacology.Selected publications• Cervo L, Carnovali, F, Stark JA, Mennini T. Cocaine-seeking behavior in response to drug-associated stimuli in rats:involvement of D 3 and D 2 dopamine receptors. Neuropsychopharmacology 2003; 28: 1150-1159• Grignaschi G, Burbassi S, Zennaro E, Bendotti C, Cervo L. A single high dose of cocaine induces behaviouralsensitization and mo<strong>di</strong>fies mRNA enco<strong>di</strong>ng GluR1 and GAP-43 in rats. Eur J Neurosci 2004; 20:2833-2837• Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, Invernizzi R.Deficits of serotonin synthesis cause resistance to antidepressants, J Neuroscience 2005; 25: 8165-8172• Cervo L, Cocco A, Petrella C, Heidbreder CA. Selective antagonism at dopamine D3 receptors attenuates cocaineseekingbehaviour in the rat. Int J Neuropsychopharmacol. 2007; 10: 167-181.• Burbassi S, Cervo L. Stimulation of serotonin(2C) receptors influences cocaine-seeking behavior in response to drugassociatedstimuli in rats. Psychopharmacology (Berl). 2008; 196: 15-27.• Burattini C, Burbassi S, Aicar<strong>di</strong> G, Cervo L. Effects of naltrexone on cocaine- and sucrose-seeking behaviour inresponse to associated stimuli in rats. Int J Neuropsychopharmacol. 2008; 11, 103-109.• Marchesi F, Piemonti L, Fedele G, Destro A, Roncalli M, Albarello L, Doglioni C, Anselmo A, Doni A, Bianchi P,Laghi L, Malesci A, Cervo L, Malosio M, Reni M, Zerbi A, Di Carlo V, Mantovani A, Allavena P. The chemokinereceptor CX3CR1 is involved in the neural tropism and malignant behavior of pancreatic ductal adenocarcinoma. CancerRes. 2008; 68, 9060-9069.• Fumagalli F, Franchi C, Caffino L, Racagni G, Riva MA, Cervo L. Single session of cocaine intravenous selfadministrationshapes goal-oriented behaviours and up-regulates Arc mRNA levels in rat me<strong>di</strong>al prefrontal cortex. Int JNeuropsychopharmacol. <strong>2009</strong>; 12:423-9..• Calcagno E, Guzzetti S, Canetta A, Fracasso C, Caccia S, Cervo L, Invernizzi RW. Enhancement of cortical extracellular5-HT by 5-HT1A and 5-HT2C receptor blockade restores the antidepressant-like effect of citalopram in non-respondermice. Int J Neuropsychopharmacol. <strong>2009</strong>; 12:793-803.Roberto Chiesa graduated in Biological Sciences with major in Genetics at the University of Pavia in1991, and obtained a Ph.D. in Pharmacology at the <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research ofMilan in 1994. From 1996 through 2000 he was Research Associate at the Department of Cell Biologyand Physiology of Washington University in St. Louis, MO, USA. In 2001 Dr. Chiesa moved back to the<strong>Mario</strong> <strong>Negri</strong> Institute where he is currently head of the Prion Neurobiology lab in the Department ofNeuroscience. He also holds an Associate Telethon Scientist position (Dulbecco Telethon Institute,Telethon Foundation).Selected publications° Chiesa R, Piccardo P, Ghetti B, Harris DA Neurological illness in transgenic mice expressing a prion protein with aninsertional mutation.Neuron. 21:1339-51 (1998)° Chiesa R, Drisal<strong>di</strong> B, Quaglio E, Migheli A, Piccardo P, Ghetti B, Harris DA Accumulation of protease-resistant prionprotein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation. Proc NatlAcad Sci U S A. 97:5574-9 (2000)° Chiesa R, Harris DA.Prion <strong>di</strong>seases: what is the neurotoxic molecule? Neurobiol Dis. 8:743-63 (2001)° Fioriti L, Dossena S, Stewart LR, Stewart RS, Harris DA, Forloni G, Chiesa R.Cytosolic prion protein (PrP) is not toxicin N2a cells and primary neurons expressing pathogenic PrP mutations. J Biol Chem. 280:11320-8 (2005)77ANNUAL REPORT <strong>2009</strong>
IRFMN° Biasini E, Massignan T, Fioriti L, Rossi V, Dossena S, Salmona M, Forloni G, Bonetto V, Chiesa R Analysis of thecerebellar proteome in a transgenic mouse model of inherited prion <strong>di</strong>sease reveals preclinical alteration of calcineurinactivity. Proteomics. 6:2823-34 (2006)° Li A, Christensen HM, Stewart LR, Roth KA, Chiesa R, Harris DA.Neonatal lethality in transgenic mice expressingprion protein with a deletion of residues 105-125. EMBO J. 26:548-58 (2007)° Dossena S, Imeri L, Mangieri M, Garofoli A, Ferrari L, Senatore A, Restelli E, Balducci C, Fiordaliso F, Salio M,Bianchi S, Fioriti L, Morbin M, Pincherle A, Marcon G, Villani F, Carli M, Tagliavini F, Forloni G, Chiesa R. Mutantprion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model.Neuron. 2008, 60:598-609 (2008).° Chiesa R, Harris DA.Fishing for prion protein function. PLoS Biol. <strong>2009</strong> Mar 31;7(3):e75Maria Grazia De Simoni got the Doctoral Degree in Biological Sciences in 1977 at the University ofMilano, Italy. 1981: Research Specialist in Pharmacology (PhD), <strong>Mario</strong> <strong>Negri</strong> Institute, Milan, Italy.1981-1982: European Community fellowship for "Advanced Professional Training", INSERM U 171,Universitè Claude Bernard, Lyon, France; 1984 Department of Histology, Karolinska Institute,Stockholm. Working experience:1987-1997: Chief of the Neurochemistry Unit, <strong>Mario</strong> <strong>Negri</strong> Institute,Milano; 1998-present: Chief of the Laboratory of Inflammation and Nervous System Diseases, <strong>Mario</strong><strong>Negri</strong> Institute. Scientific interests: pathogenesis of cerebral ischemia/reperfusion and traumatic braininjury; inflammatory response and apoptotic mechanisms as targets of therapeutic strategies; animalmodels and clinical stu<strong>di</strong>es. She is member of the board of “Master in Tecnologie Avanzate Applicatealle Patologie Neurodegenerative", University of Milan and member of the board of “AssociazioneItaliana per la Ricerca sull’Invecchiamento Cerebrale” (AIRIC).Selected pubblications• De Simoni MG, Storini C, Barba M, Catapano L, Arabia AM, Rossi E, Bergamaschini L. Neuroprotection bycomplement (C1)-inhibitor in mouse transient brain ischemia. J Cereb Blood Flow Metab, 23: 232-239, 2003.• De Simoni M G, Rossi E, Storini C, Pizzimenti S, Echart C, Bergamaschini L. The powerful neuroprotective action ofC1-inhibitor on brain ischemia-reperfusion injury does not require C1q. Am J Pathol., 164: 1857-1863, 2004.• Bergamaschini L, Rossi E, Storini C, Pizzimenti S, Distaso M, Perego C, De Luigi A, Vergani C and De Simoni MG.Peripheral treatment with enoxaparin, a low-molecular weight heparin, reduces plaques and β-amyloid accumulation in amouse model of Alzheimer’s <strong>di</strong>sease. J. Neurosci. 24: 4181-4186, 2004• Troglio F, Echart C, Gobbi A, Pawson T, Pelicci PG, De Simoni MG & Pelicci G. The neuron-specific Rai (Shc C)adaptor regulates the PI3K-Akt pathway in vivo and protects against cerebral ischemia. Proc Natl Acad Sci U S A101(43): 15476-15481, 2004.• Storini C, Bergamaschini L, Gesuete R, Rossi E, Maiocchi D, De Simoni MG. Selective inhibition of plasma kallikreinprotects brain from reperfusion injury. JPET 318: 849-854, 2006• Capone C, Fabrizi C, Piovesan P, Principato MC, Marzorati C, Ghirar<strong>di</strong> O, Fumagalli L, Carminati P and De SimoniMG. 2-Aminotetraline derivative protects from ischemia/reperfusion brain injury with a broad therapeutic window,Neuropsychopharmacology, 32: 1302-1311, 2007• Capone C, Frigerio S, Fumagalli S, Gelati M, Principato M C, Storini C, Montinaro M, Kraftsik R, De Curtis M, ParatiE, De Simoni MG. Neurosphere - derived cells exert a neuroprotective action by changing the ischemicmicroenvironment. PLoS ONE 2 e373, 2007.• Pastori C, Librizzi L, Breschi GL, Regon<strong>di</strong> C, Frassoni C, Panzica F, Frigerio S, Gelati M, Parati E, De Simoni MG, deCurtis M.Arterially perfused neurosphere-derived cells <strong>di</strong>stribute outside the ischemic core in a model of transient focalischemia and reperfusion in vitro.PLoS ONE. 3(7):e2754. 2008Roberto W. Invernizzi started his career in the laboratory of Neuropharmacology of the “<strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>” in 1976, where, at present, he heads the Laboratory ofNeurochemistry and Behavior. In 1986 he got his degree in Biological Sciences at the Università Statale <strong>di</strong>Milano and in 1996 he was nominated head of the Intracerebral Micro<strong>di</strong>alysis Unit. Of particular interestto Invernizzi’s research team is the study of the neurochemical mechanisms and neuronal circuitriesinvolved in the pathology of the main psychiatric <strong>di</strong>seases, such as depression and schizophrenia and inthe mechanism of action of psychotropic drugs. Since 1987 he applied the intracerebral micro<strong>di</strong>alysistechnique to study the in vivo release of monoamines. Using this technique, Invernizzi’s team firstcontributed to clarifying the role of serotonergic and adrenergic autoreceptors in the effect ofantidepressant drugs suggesting new hypotheses on their mechanism of action. Currently, Invernizzi’slaboratory is involved in two main collaborative projects aimed at clarifying the neurochemicalmechanisms involved in the “resistance” to antidepressant drugs and the role of glutamatergic andserotonergic mechanisms in attentional processes. Reviewer for various international journals in the fieldof pharmacology and neurochemistry. Author and co-author of more than 60 peer-reviewed articles.Member of the Italian Society of Neuroscience and the Italian Society of Pharmacology.78ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Baviera M, Invernizzi RW, Carli M. Haloperidol and clozapine have <strong>di</strong>ssociable effects in a model of attentionalperformance deficits induced by blockade of NMDA receptors in the mPFC. Psychopharmacology 2008; 196: 269-280.• Guzzetti S, Calcagno E, Canetta A, Sacchetti G, Fracasso C, Caccia S, Cervo L, Invernizzi RW Strain <strong>di</strong>fferences inparoxetine-induced reduction of immobility time in the forced swimming test in mice: Role of serotonin. Eur. J.Pharmacol. 2008; 594: 117-124• Calcagno E, Canetta A, Guzzetti S, Cervo L, Invernizzi RW. Strain <strong>di</strong>fferences in basal and post-citalopram extracellular5-HT in the mouse me<strong>di</strong>al prefrontal cortex and dorsal hippocampus: relation with tryptophan with tryptophanhydroxylase-2 activity. J Neurochem 2007; 103 : 1111-1120• Invernizzi RW, Pierucci M, Calcagno E, Di Giovanni G, Di Matteo V, Benigno A, Esposito E. Selective activation of5HT2C receptors stimulates GABA-ergic function in the rat substantia nigra pars reticulata: a combined in vivoelectrophysiological and neurochemical study. Neuroscience 2007 144 : 1523-1535• Calcagno E, Carli M, Invernizzi RW The 5-HT1A receptor agonist 8-OH-DPAT prevents prefrontocortical glutamateand serotonin release in response to blockade of cortical NMDA receptors J Neurochem 2006; 96: 853-860• Cervo L, Canetta A, Calcagno E, Burbassi S, Sacchetti G, Caccia S, Fracasso C, Albani D, Forloni G, InvernizziRWGenotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse modelof depression J Neurosci 2005; 25: 8165-8172• Greco B, Invernizzi RW, Carli M Phencycli<strong>di</strong>ne-induced impairment in attention and response control depends on thebackground genotype of mice: reversal by the mGLU2/3 receptor agonist, LY379268 Psychopharmacology (Berl) 2005;179: 68-76Ugo Lucca got his Master of Science, University of Aberdeen - UK, 1999. At the <strong>Mario</strong> <strong>Negri</strong> Institutehe was investigator from 1986- 1995, head of the "Clinical Evaluation of Antidementia Drugs Unit"(1995-1996) and, since 1996, head of the "Laboratory of Geriatric Neuropsychiatry".The main areas of interests include epidemiology and clinic features of dementia; natural history ofdementia; neuropsychiatric <strong>di</strong>sorders of the elderly; instruments for the screening <strong>di</strong>agnosis and clinicalcourse assessment of dementia; clinical evaluation of anti dementia treatments and CNS active drugs(phase I, II, III, IV and observational stu<strong>di</strong>es).Selected publications• Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, et al. Long-term acetyl-L-carnitinetreatment in Alzheimer's <strong>di</strong>sease. Neurology 1991; 41:1726-1732• Lucca U, Comelli M, Tettamanti M, Tiraboschi P, Spagnoli A. Rate of progression and prognostic factors in Alzheimer’s<strong>di</strong>sease: a prospective study. J Am Geriats Society 1993; 41: 45-49.• Lucca U, Tettamanti M, Forloni G, Spagnoli A. Nonsteroidal anti-inflammatory drug use in Alzheimer’s <strong>di</strong>sease.Biological Psychiatry 1994; 36: 854-856.• Imbimbo BP, Martelli P, Troetel WM, Lucchelli F, Lucca U, Thal LJ, and the Eptastigmine Study Group. Efficacy andsafety of eptastigmine for the treatment of patients with Alzheimer’s <strong>di</strong>sease. Neurology 1999; 52: 700-708.• Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer’s <strong>di</strong>sease and Vascular Dementia. Am J Clinical Nutr 2004; 80: 114-122.• Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. New England Journal ofMe<strong>di</strong>cine 2006; 355: 1390.• Lucca U, Tettamanti M, Mosconi P, Apolone G, Gan<strong>di</strong>ni F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M,Tempia P, Guala A, Fasolo G, Riva E.Association of mild anemia with cognitive, functional, mood and quality of lifeoutcomes in the elderly: the "Health and Anemia" study. PLoS ONE. 3(4):e1920 (2008)Alessandro Nobili got his degree in Me<strong>di</strong>cine (Milan, 1990). Master in Biotechonological Research,Regione Lombar<strong>di</strong>a, Milan 1988. International School of Pharmacology, 31° Course on: DrugEpidemiology and Post-marketing Surveillance, Erice, September 1990. Course on: Methods inEpidemiological Research, Milan, October 1990. Course: Long Term Clinical Trials, Cogne January1991.Main areas of interest Methodology of Randomized Clinical Trials; Pharmacoepidemiology and postmarketingsurveillance research; Drug utilization stu<strong>di</strong>es; Quality assessment of geriatric services;Qualitative stu<strong>di</strong>es on caregiver role in the care of patients with dementia; Methodological evaluation ofthe Special Care Unit for Alzheimer Disease patients; Methodology of drug information. Employmentand research experience Chief of the Unit of Quality Assessment of Geriatric Services Chief of the DrugInformation Services for the Elderly, Laboratory of Geriatric Neuropsychiatry, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milan. E<strong>di</strong>torial Board of the MICROMEDEX Inc., Englewood,Colorado 80111-4740 USA. National Expert accre<strong>di</strong>ted by Italian Ministry of Health for The Italian(AIFA) and European Agency for the Evaluation of Me<strong>di</strong>cinal Products (EMEA). Head of theLaboratory of the Quality Assessment of Geriatric Services at the <strong>Mario</strong> <strong>Negri</strong> Institute since 2007.79ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Nobili A, Tettamanti M, Frattura L, et al. Drug use in the elderly in Italy. Ann Pharmacother 1997; 31:416-422.• Nobili A, Gebru F, Rossetti A, et al. Doctorline a private toll-free telephone me<strong>di</strong>cal information service. AnnPharmacother 1998; 32:120-5.• Nobili A, Riva E, Tettamanti M, et al. The effect of a structured intervention on caregivers of patients with dementia andproblem behavior: a randomized controlled pilot study. Alzheimer Dis Assoc Disord 2004; 18: 75-82.• Lucca U, Nobili A, Riva E, Tettamanti M. Low level of B vitamins and the risk of cognitive and functional decline in thevery-old: results from the Monzino 80-Plus Study. Neurobiol Aging 2004; 25: 31.• Lucca U, Nobili A, Riva E, Tettamanti M Cholinesterase inhibitor use and age in the general population Arch Neurol2006; 63: 154-155.• Tettamanti M, Garri' M T, Nobili A, Riva E, Lucca U Low folate and the risk of cognitive and functional deficits in thevery old: The Monzino 80-plus study J Am Coll Nutr 2006; 25: 502-508• Nobili A, Piana I, Balossi L, Pasina L, Matucci M, Tarantola M, Trevisan S, Riva E, Lucca U, Tettamanti M.Alzheimerspecial care units compared with tra<strong>di</strong>tional nursing home for dementia care: are there <strong>di</strong>fferences at admission and inclinical outcomes?Alzheimer Dis Assoc Disord. 22:352-6 (2008).Annamaria Vezzani got her Degree in Biological Science at the University of Milan in 1978 and shespecialized in Neuropharmacology at the <strong>Mario</strong> <strong>Negri</strong> Institute in 1982. She spent her post-doctoralperiod in Baltimore at the University of Maryland in 1983-1984 working on the mechanisms ofepileptogenesis in experimental models of epilepsy. She spent ad<strong>di</strong>tional post-doctoral periods at theUniversity of Stockholm and at the Karolinska Institute between 1985 and 1999. She was onsabbatical at the Albert Einstein College of Me<strong>di</strong>cine in 2002 in the laboratory of DevelopmentalEpilepsy. She is involved in stu<strong>di</strong>es on the biochemical and molecular mechanisms involved in theetiopathogenesis of seizures <strong>di</strong>sorders using experimental models of epilepsy. The present research isfocused on the functional role of neuroactive peptides and inflammatory me<strong>di</strong>ators in the modulationof neuronal excitability and seizure-related neurodegeneration. Focus of the research is also on themechanisms of pharmacoresistance. Since 1997 she is the Head of the Laboratory of ExperimentalNeurology at the <strong>Mario</strong> <strong>Negri</strong> Institute. She is member of the E<strong>di</strong>torial Board of Epilepsy Currentsand Neuroscience and Associate E<strong>di</strong>tor for Exp Models of Epilepsia. She is appointed of the Chair ofthe Commission on Neurobiology of International League Against Epilepsy which is promotinginitiatives for improving translational research in epilepsy.Selected publicationsBalosso S, Maroso M, Sanchez-Alavez M, Ravizza T, Frasca A, Bartfai T, Vezzani A. A novel non-transcriptionalpathway me<strong>di</strong>ates the proconvulsive effects of interleukin-1 beta (2008) Brain, 131: 3256-65• Balosso S, Ravizza T, Perego C, Peschon J, Campbell I, De Simoni MG, Vezzani A. TNF-alpha inhibits kainic aci<strong>di</strong>nducedseizures in mice via p75 receptors (2005) Ann Neurol, 57, 804• Dube’ C., Vezzani A., Behrens M., Bartfai T., Baram TZ. (2005) Interleukin-1beta contributes to the generation ofexperimental febrile seizures. Ann Neurol, 57,152.• Richichi C, E-J. D. Lin, D. Stefanin, D. Colella, T. Ravizza,G. Grignaschi, G. Sperk, M. J. During and A. Vezzani “Anticonvulsant and antiepileptogenic effects me<strong>di</strong>ated by adeno-associated virus vector neuropeptide Y expression inthe rat hippocampus” (2004) J Neurosci, 24,3051• Rizzi M, Caccia S, Guiso G, Richichi C, Gorter JA, Aronica E, Alipran<strong>di</strong> M, Bagnati R, Fanelli R, D'Incalci M,Samanin R, Vezzani A.“Limbic seizures induce P-glycoprotein in rodent brain: functional implications forpharmacoresistance” (2002) J Neurosci, 22, 5833• Vezzani A., Moneta D., Conti M., Richichi C., Ravizza T., De Luigi A., De Simoni M.G., Sperk, Andell-Jonsson S.,Lundkvist J., Iverfeldt K. and Bartfai T. (2000) "Powerful anticonvulsant action of IL-1 receptor antagonist uponintracerebral injection and astrocytic overexpression in mice" Proc. Natl. Acad. Sci. USA, 97, 11534.• Vezzani A., Moneta D., Conti M., Richichi C., Ravizza T., De Luigi A., De Simoni M.G., Sperk, Andell-Jonsson S.,Lundkvist J., Iverfeldt K. and Bartfai T. (2000) "Powerful anticonvulsant action of IL-1 receptor antagonist uponintracerebral injection and astrocytic overexpression in mice" Proc. Natl. Acad. Sci. USA, 97, 11534.Tiziana Borsello got her Degree in Biological Science at the University of Torino in 1990 and she thenobtained a PhD in Neuroscience at the University of Turin Me<strong>di</strong>cal School. She won 1 year fellow of theEuropean Science Foundation scholarship for work at the Netherlands Research Institute of Amsterdam. From1997 to 1999 she was a Researcher at the Institute of Neurobiology, CNR, Rome Italy. In the period 1999-2003she was Premier Assistant, Département de Biologie Cellulaire et de Morphologie, Université de Lausanne,Switzerland, and then became Maitre Assistant and group leader in the same institute. In 2004 joined the Biol.Neurodeg. Disorders Lab at the "<strong>Mario</strong> <strong>Negri</strong>” Institute. In 2005 won the Prize of the Pfizer Foundation,Neuroscience and Diseases Nervous System. Since 2006 she is the Head of the Unit: Neuronal Death andNeuroprotection. Her main scientific interest is understan<strong>di</strong>ng the role of signaling pathways in neuronal death80ANNUAL REPORT <strong>2009</strong>
IRFMNafter <strong>di</strong>fferent stress-stimuli and the neuroprotection. In particular, the present research is focused on the studyof the mechanisms of excitotocic stress, ischemia, Traumatic Brain Injury and the cell death pathways inneurodegenerative <strong>di</strong>seases as Alzheimer, with the challenge to define the neuronal death pathways to designmore specific methods of neuroprotection.Selected pubblications• Repici M, Centeno C, Tomasi S, Forloni G, Bonny C, Vercelli A, Borsello T.Activation After Cerebral Ischemia AndEffect Of D-Jnki1 On C-Jun And Caspase-3 Activation. Neuroscience. 2007, 150: 40-9• Borsello T., Centeno C., Riederer IM, Haeflinger JA and Riedere BM. Phosphorylation-dependent <strong>di</strong>merization andsubcellular localization of islet-brain 1/c-Jun N-terminal kinase-interacting protein 1. J Neurosci Res. 2007, 85:3632-41.• Borsello T Ed “Neuroprotection: Methods In Molecular Biology” Published By Humana Press, Usa Humana Press,USA, Methods in Molecular Biology, June 2007• Colombo A, Repici M, Pesaresi M, Santambrogio S, Forloni G, Borsello T. The Tat-Jnk Inhibitor Peptide Interferes WithBeta Amyloid Protein Stability Cell Death Differ. 2007, 14:1845-8.• Borsello T and Forloni G. JNK signalling: a possible target to prevent neurodegeneration. Current PharmaceuticalDesign 2007, 13, 1875-1886• Centeno C., Repici M., Chatton J. Y., Riederer B. M., Bonny C., Nicod P., Price M., Clarke P. G., Papa S., Franzoso G.and Borsello T. Role of the JNK pathway in NMDA-me<strong>di</strong>ated excitotoxicity of cortical neurons. Cell Death Differ ,2007, 14: 240-253.• Borsello T. and Bonny C.Use of cell-permeable peptides to prevent neuronal degeneration. Trend in Mol. Med. 2004, 10:239-44• Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C. A peptide inhibitor ofc-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia. Nature Med. 2003, 9: 1180-6Mirjana Carli started his scientific career in the laboratory of Neuropharmacology of the “<strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> <strong>Mario</strong> <strong>Negri</strong>” Milan in 1977, where, at present, she is head of thePharmacology of Cognitive Behaviour Unit. She spent a few years in the laboratory of CognitiveNeuroscience, Dept. of Experimental Psychology, University of Cambridge (UK) <strong>di</strong>rected by Prof.Trevor W. Robbins. Here she took interest in the role of brain monoamines in attention, and for thispurpose developed several behavioral tests for rats. In 1986 she returned to the laboratory ofNeuropharmacology of the “<strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> <strong>Mario</strong> <strong>Negri</strong>”. Here she devoted herefforts to the study of the role played by neuronal mechanisms in cognitive processes such as memory,attention and executive functions. Her work has improved the knowledge of the role played by someserotonin receptors in cognitive processes.Selected publications• Carli M, Baviera M, Invernizzi R, Balducci C Dissociable contribution of 5-HT1A and 5-HT2A receptors in the me<strong>di</strong>alprefrontal cortex to <strong>di</strong>fferent aspects of executive control such as impulsivity and compulsive perseveration in ratNeuropsychopharmacology 2006; 31: 757-767• Greco B, Carli M Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: Relation to anxiolyticlikephenotype Behav Brain Res 2006; 169: 325-334• Carli M, Baviera M, Invernizzi R, Balducci C The serotonin 5-HT2A receptors antagonist MI00907 prevents impairmentin attentional performance by NMDA receptor blockade in the rat prefrontal cortex Neuropsychopharmacology 2004;29: 1637-1647• Balducci C, Nurra M, Pietropoli A, Samanin R, Carli M Reversal of visual attention dysfunction after AMPA lesions ofthe nucleus basalis magnocellularis (NBM) by the cholinesterase inhibitor donepezil and by a 5-HT(1A) receptorantagonist WAY 100635 Psychopharmacology (Berl) 2003; 167: 28-36• Carli M, Balducci C, Samanin R. Stimulation of 5-HT1A receptors in the dorsal raphe ameliorates the impairment ofspatial learning caused by intrahippocampal 7-chloro-kynurenic acid in naive and pretrained rats Psychopharmacology(Berl) 2000; 158: 39-47• Carli M, Samanin R The 5-HT1A receptor agonist 8-OH-DPAT reduces rats' accuracy of attentional performance andenhances impulsive respon<strong>di</strong>ng in a five-choice serial reaction time task: Role of presynaptic 5-HT1A receptorsPsychopharmacology (Berl) 2000; 149: 259-268Barbara D’Avanzo obtained her master in Philosophy in 1989 at the University of Milan. Her main fieldof interest is epidemiologic research in mental health. She was involved in the analysis of theimplementation of the psychiatric reform in Italy and quality evaluation of services and their recentmo<strong>di</strong>fications with specific attention to the role of psychiatric residential facilities in the communityservice networks; evaluation of effectiveness of the most common psychosocial interventions; suicidetrend monitoring and study of suicide prevention programs and initiatives. More recently, she is workingon issues like recovery-oriented services, consumers’ empowerment, and methods of participation ofconsumers to evaluation of services, and acknowledgment of the value of the consumers’ point of viewabout psychiatric treatments and services.81ANNUAL REPORT <strong>2009</strong>
IRFMNShe worked as researcher in the Laboratory of General Epidemiology between 1991 and 1996, and she isChief of the Unit of Epidemiology and Social Psychiatry since 2002. Member of the Scientific NationalBoard of WAPR Italy and of the World Head Office of the WAPR.Selected publications• Barbato A, D'Avanzo B. Efficacy of couple therapy as a treatment for depression: a meta-analysis. Psychiatr Q. 2008,79:121-32.• Barbato A, D'Avanzo B. Marital therapy for depression. Cochrane Database Systematic Reviews 2006; Issue 2.• Parabiaghi A, Barbato A, D'Avanzo B, Erlicher A, Lora A. Assessing reliable and clinically significant change on Healthof the Nation Outcome Scales: method for <strong>di</strong>splaying longitu<strong>di</strong>nal data. Aust N Z J Psychiatry 2005; 39: 719-725.• Barbato A, D'Avanzo B. Involuntary placement in Italy. Br J Psychiatry 2005; 186: 542-543.• Guaiana G, Andretta M, Corbari L, Mirandola M, Sorio A, D'Avanzo B, Barbui C. Antidepressant drug consumption andpublic health in<strong>di</strong>cators in Italy, 1955-2000. J Clinical Psychiatry 2005; 66: 750-755.• D'Avanzo B, Battino R N, Gallus S, Barbato A. Factors pre<strong>di</strong>cting <strong>di</strong>scharge of patients from community residentialfacilities: A longitu<strong>di</strong>nal study from Italy. Aust N Z J Psychiatry 2004; 38: 619-628.• D'Avanzo B, Barbato A, Barbui C, Battino N, Civenti G, Frattura L. Discharges of patients from public psychiatrichospitals in Italy between 1994 and 2000. Int J Social Psychiatry 2003; 49: 27-3Emma Riva, Me<strong>di</strong>cal Doctor degree in 1984 University of Milan, PhD in 1990 in Car<strong>di</strong>ovascularPathophysiology at the University of London (UK) Training: Research Assistant, Department ofPharmacology, Me<strong>di</strong>cal School, University of Ottawa, Canada; Internship in Internal Me<strong>di</strong>cine, OspedaleLuigi Sacco, Milan; Car<strong>di</strong>ac Fellow, St Thomas' Hospital, London, UK. Field of interest: Prevalence andeffects of anemia on cognitive, functional and clinical variables in the elderly; Problem behaviors indementia; Burden for care-givers of Alzheimer Disease patients; End of life care. Present and past rolesin Institute Head of the Geriatric Pharmacology Unit, <strong>Istituto</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milan; Scientific Directorof the hospice “Via <strong>di</strong> Natale Franco Gallini”, Aviano, Italy; Consultant <strong>Istituto</strong> Geriatrico “Pio AlbergoTrivulzio”, Milan: Project member of PREDICT (Policy Review and Evaluation of Dementia andInstitutional Care Trends): a Transnational Comparison.Selected publications• Lucca U, Tettamanti M, Mosconi P, Apolone G, Gan<strong>di</strong>ni F, Nobili A, Tallone MV, Detoma P, Giacomin A, Clerico M,Tempia P, Guala A, Fasolo G, Riva E.Association of mild anemia with cognitive, functional, mood and quality of lifeoutcomes in the elderly: the "Health and Anemia" study. PLoS ONE. 3(4):e1920 (2008)• Tettamanti M, Garrì MT, Nobili A, Riva E, Lucca U. Low folate and risk of cognitive and functional deficits in the veryold: The Monzino 80-plus study. J Am Coll Nutr 2006;25:502-508• Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch Neurol2006;63:154-155• Nobili A, Riva E, Tettamanti M, Lucca U, Liscio MR, Petrucci B, Salvini Porro G. The effect of a structured interventionon caregivers of patients with dementia. Results of a Randomized Controlled Study. Alzheimer Dis and AssociatedDisorders 2004;18:75-82• Il malato terminale oncologico. Esperienze dall’hospice. Ed. Emma Riva. Il Pensiero Scientifico, 2001• Riva E, Tettamanti M, Gallini C. Il ruolo del me<strong>di</strong>co <strong>di</strong> me<strong>di</strong>cina generale nella gestione dei malati terminali oncologici.Indagine svolta tra i me<strong>di</strong>ci <strong>di</strong> me<strong>di</strong>cina generale in Friuli Venezia Giulia. Ricerca & Pratica 2001• Riva E, Nobili A, Trecate F. Per un impiego "ragionato" dei neurolettici, per la gestione dei <strong>di</strong>sturbi del comportamentoin corso <strong>di</strong> Malattia <strong>di</strong> Alzheimer. Rec Prog Med 1998;89:598-603Mauro Tettamanti got his Biology Degree at the Università degli Stu<strong>di</strong> <strong>di</strong> Milano in 1986, and thespecialisation in Epidemiology and Me<strong>di</strong>cal Statistics in 1993, at the Università degli Stu<strong>di</strong> <strong>di</strong> Pavia.Teaching experience Introduction course to statistics, Master in Ergonomy, Politecnico <strong>di</strong> Milano, years2001-2004 Areas of interest: Planning, conduction and analysis of clinical trials and epidemiologicresearches in the geriatric field: Phase I, II, III and observational stu<strong>di</strong>es on the efficacy of drugs onneurologic <strong>di</strong>sorders, with special emphasis on dementia; Effects of multi-<strong>di</strong>sciplinary interventions ongeriatric/dementia patients; Epidemiology and risk factors of dementia; Care of patients with terminalillness; Association of anemia with prevalence of <strong>di</strong>seases and cognitive problems Scholarship between1989 and 1998, Senior Researcher since 1999 and Head of the Unit of Geriatric Epidemiology at the<strong>Mario</strong> <strong>Negri</strong> Institute since 2001.82ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Spagnoli A, Lucca U, Menasce G, Bandera L, Cizza G, Forloni G, Tettamanti M, et al. Long-term acetyl-L-carnitinetreatment in Alzheimer's <strong>di</strong>sease. Neurology 1991; 41:1726-1732.• Lucca U, Comelli M, Tettamanti M, Tiraboschi P, Spagnoli A. Rate of progression and prognostic factors in Alzheimer's<strong>di</strong>sease: A prospective study. J Am Geriatr Soc 1993; 41:45-49• Quadri P, Fragiacomo C, Pezzati R, Zanda E, Forloni G, Tettamanti M, Lucca U. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer <strong>di</strong>sease, and vascular dementia. Am J Clin Nutr 2004; 80: 114-122• Lucca U, Nobili A, Riva E, Tettamanti M. Cholinesterase inhibitor use and age in the general population. Arch Neurol2006; 63:154-155• Lucca U, Tettamanti M, Quadri P. Homocysteine lowering and cognitive performance. N Engl J Med 2006; 355:1390• Tettamanti M, Garri' M T, Nobili A, Riva E, Lucca U. Low folate and the risk of cognitive and functional deficits in thevery old: The Monzino 80-plus study. J Am Coll Nutr 2006; 25: 502-508• Nobili A, Piana I, Balossi L, Pasina L, Matucci M, Tarantola M, Trevisan S, Riva E, Lucca U, Tettamanti M.Alzheimerspecial care units compared with tra<strong>di</strong>tional nursing home for dementia care: are there <strong>di</strong>fferences at admission and inclinical outcomes? Alzheimer Dis Assoc Disord. 22:352-6 (2008).ACTIVITIESThe Department of Neuroscience is formed by ten Laboratories; the activities of research aredevoted to the study of neurological and psychiatric <strong>di</strong>seases, evaluated by the biological pointof view, clinical and epidemiological aspects and the quality of care. Together with theseactivities, in the Department other more general expertise are present. Pharmacokinetics stu<strong>di</strong>es,drug information service and preparation of protocols for clinical trial and epidemiologicalstu<strong>di</strong>es are activities in charge of the Neuroscience Department. Tra<strong>di</strong>tionally part of theDepartment was devoted to the creation of experimental models for the pharmacological,neurochemical and pathogenetic stu<strong>di</strong>es in Alzheimer or prion's <strong>di</strong>seases, epilepsy, depressionand cognitive impairment. More recently, consolidated expertise were created in thepathogenesis of amyotrophic lateral sclerosis (ALS), cerebral stroke and drug abuse. Some ofthese <strong>di</strong>sorders, like epilepsy, ALS and Alzheimer's <strong>di</strong>sease are investigated from the clinicaland epidemiological points of view for the evaluation of drug and care efficacy. The activities ofthe Department are aimed to an integration of the <strong>di</strong>fferent expertise to developmulti<strong>di</strong>sciplinary approaches. The purpose is to address at <strong>di</strong>fferent levels, knowledge, therapyand clinical practice to the numerous questions, largely unresolved, proposed by the <strong>di</strong>sorders ofnervoussystem.MAIN FINDINGSIn a cellular model it has been shown that the peptide of D-JNK-1-TAT inhibiting the JNKphosphorylation activity me<strong>di</strong>ated by the enzyme JNK, exerts a control on β amyloidproduction, these data in<strong>di</strong>cate possible therapeutic perspectives in Alzheimer’s <strong>di</strong>seaseThe intracerebral application of synthetic β amyloid 1-40 e 1-42 in oligomeric form isassociated with a cognitive damage that does not occur when the pepetides are applied inmonomeric form of fibrils species.The exposure of cultured hippocampal cells to β amyloid 1-42 in oligomeric form induces analteration of dendritic spines.The resveratrol, a well-known antioxidant induces its neuroprotective effect through theactivation of SIRT.183ANNUAL REPORT <strong>2009</strong>
IRFMNIn the transgenic mice overexpressing a mutated form of human prion protein associated withCJD generated in the Institute has been found a significant alteration of endoplasmic reticulumassociated with the presence of mutated prion protein.Polymorphisms in gene encoded for serotonin transporter protein influenced the risk to developParkinson’s <strong>di</strong>seaseIn a prospective population-based study in the very old (Monzino 80-plus Study), behavioral<strong>di</strong>sturbances are uncommon prior to clinical dementia onset. After dementia <strong>di</strong>agnosis,behavioral <strong>di</strong>sturbances affect a large proportion of subjects, increasing with <strong>di</strong>sease severitywhile decreasing in the oldest-olds.The same prospective population-based study (Monzino 80-plus Study) failed to demonstrate asignificant association between <strong>di</strong>abetes or glucose concentration and dementia in the very old.In a prospective ambulatory population of cognitively normal or mildly cognitively impairedelderly, <strong>di</strong>ssecting mild cognitive impairment into severity levels was found to increase theaccuracy of progression pre<strong>di</strong>ctions to dementia.More than one out of 10 elderly persons (65 years or older) were anemic and most of the caseshad a mild grade anemia. Hemoglobin concentrations decreased and prevalence of (mild)anemia increased with increasing age.After controlling for many potential confounders, mild anemia was found to be associated withpoorer health con<strong>di</strong>tions and with increased risk of clinically relevant outcome such ashospitalization and mortality.An intervention of common mental health <strong>di</strong>sorders prevention in schools have produced nochange in information, attitudes and help seeking behaviour in students, partly because of thehigh baseline levels.In the period 2000-2007, antidepressant prescription doubled. In 2000 it concerned 5.5% of theaging population, 11.4% seven years after. This increase is connected with SSRI, whoseprescription rose from 2.5% to 8.6%. No proportional decrease in the prescription of trycliclicsor the so-called atipical antidepressants was observed.Patients with dementia resident in Alzheimer’s special care units (ASCU) had a lower rate ofhospitalisation and use of physical restraints than those in tra<strong>di</strong>tional nursing homes.In ASCU 60% of patients with dementia were taking at least one antipsychotic, 49% typical and51% atypical.More than 50% of patients exposed to antipsychotics at baseline, were still taking the drug after18 months of follow-up. The use of antipsychotic agents was strongly related to the presence ofagitation, irritability, delusions, anxiety, night-time behaviour and aberrant motor behaviour.In the Lecco Local Health Authority 16% of elderly patients were exposed to potential severedrug-drug interactions; age and number of chronic drugs were associated with an increasing riskof DDIs. Since physicians still have some <strong>di</strong>fficulty in managing this topic, it is essential toprovide them with adequate information on which factors raise the risk of DDIs..84ANNUAL REPORT <strong>2009</strong>
IRFMNDuring 2005 in Lombardy Region, 76% of the elderly aged 65 years ore more (76% women and75% men) received at least one chronic drug, 46% were exposed to polypharmacy (46% womenand 45% men) and 20% to chronic polypharmacy (18% women and 22% men). Elderly in theage groups of 75-79, 80-84 and 85-89 years had the highest risk to be exposed to chronicpolypharmacy (OR 2.25; 95%CI: 2.23-2.27, OR 2.68; 95%CI: 2.65-2.71, and OR 2.84; 95%CI:2.79-2.89 respectively).In a sample of 38 internal me<strong>di</strong>cine and geriatric wards, at hospital admission 52% of 1332elderly patients aged 65 years or older taken five or more <strong>di</strong>fferent drugs (polypharmacy) andwere in the ward for averagely 11 days. At hospital <strong>di</strong>scharge there was an increase in the rateof patient with polypharamacy (+13%) and with multiple <strong>di</strong>sease (+16%).The long-term prognosis of epilepsy is the same in patients treated at the first seizure and thosetreated at the recurrence. These fin<strong>di</strong>ngs suggest that treatment should be started at the firstseizure only on a case-by-case basis. The use of a third drug in children refractory to twoanticonvulsants does not affect the chance of seizure remission, suggesting that drug resistancein epilepsy can be identified at the time of failure of two drugs.The treatment of the first unprovoked seizure does not affect short and long-term mortality inpatients with epilepsy.The prevalence of some neurological <strong>di</strong>sorders in Albania <strong>di</strong>ffers from that of other Europeancountries. Differences can be explained by the study methodology and by the <strong>di</strong>verse<strong>di</strong>stribution of genetic and environmental risk factors.The incidence of acute symptomatic seizures in patients with a firstly <strong>di</strong>agnosed stroke followedprospectively is low. Cerebral hemorrhage is the only independent pre<strong>di</strong>ctor of acutesymptomatic seizures.Psychiatric comorbi<strong>di</strong>ty is <strong>di</strong>fferent when comparing patients with migraine to patients withtension-type headache. This can be explained the severity of the <strong>di</strong>sease and the underlyingpathophysiologic mechanisms. Patients with epilepsy-headache comorbi<strong>di</strong>ty <strong>di</strong>ffer from patientswith epilepsy or headache alone in terms of family history and severity of the clinical picture.We have demonstrated the crucial involvement of some pro- and anti-inflammatory cytokines inseizures using experimental models of epilepsy in rodents, thus describing a newetiopathological mechanism which may be relevant for human epilepsy.We have demonstrated that membrane-bound drug transport proteins are functionally activatedby seizures and have a significant role in decreasing the brain concentrations of antiepilepticdrugs in experimental models. Pharmacological intervention to block the activity of theseproteins may contribute to reverse multidrug resistance in epilepsy.Gene therapy stu<strong>di</strong>es highlight the possibility to significantly reduced spontaneous seizure thatare refractory to anticonvulsant drugs opening the perspective of using gene therapy inpharmacoresistant forms of epilepsy.Recombinant complement inhibitor (rhC1-INH) has a powerful neuroprotective action and awide therapeutic window in brain ischemia/reperfusion injury85ANNUAL REPORT <strong>2009</strong>
IRFMNMannose-bin<strong>di</strong>ng lectin (MBL), a key protein in the complement lectin pathway, is a noveltarget for stroke treatmentMicroglia can favour protective actions in the ischemic environmentStem cells from umbilical cord blood decrease post-traumatic brain functional defictsand lesion in injuried miceA dysfunction of proteasome is found in the motor neurons of SOD1 mutant mice, which mightcontribute to the accumulation of intracellular protein aggregates. This <strong>di</strong>scovery open a routefor a possible therapeutic strategy based on the application of substance that may increase theactivity of proteasomeDifferences in feedback control of serotonergic transmission influence the efficacy of SSRIsCo-treatment with 5-HT 2C receptor antagonists enhance the effects of SSRI on serotonergictransmission and restore their antidepressant-like effect in “non-responder” miceThe blockade of NMDA receptors of the rat prefrontal cortex induces an increase of glutamaterelease, activates the transcription factor CREB in the dorsal striatum and is deleterious forprefrontal cortex-dependent cognitive functions5-HT 2A receptor antagonists and 5-HT 1A and 5-HT 2C receptor agonists prevent the increase ofglutamate release and attentional deficits caused by NMDA receptors blockade suggesting thatsome serotonin receptor subtypes might constitute a molecular target for the development ofdrugs for the treatment of cognitive deficits of schizophreniaWe show that in a glutamate NMDA model of cognitive deficit of schizophrenia antipsychoticsmay be <strong>di</strong>fferentiated by a selective effect of typical antipsychotics on compulsiveperseveration, and atypical antipsychotics on impulsivity.A single session of cocaine self-administration is sufficient to shape rat behavior towards goal<strong>di</strong>rectedbehaviors and selectively up-regulate Arc expression in mPFC. This is the firstevidence that the mPFC's function is already profoundly influenced by the first voluntarycocaine exposure.Gamma-hydroxybutyric acid (GHB) does not maintain self-administration but inducescon<strong>di</strong>tioned place preference when injected in the ventral tegmental area.Environmental stimuli associated to drug self-administration induce drug seeking behaviorwhen present to rodents after a long period of abstinence.Genetic <strong>di</strong>fferences in serotonin synthesis may contribute to the efficacy of SSRIs in a murinemodel pre<strong>di</strong>ctive of the antidepressant activity.In non-responder mice, 5-HT 1A and 5-HT 2C receptor antagonists restore the antidepressant-liketo the SSRI.86ANNUAL REPORT <strong>2009</strong>
IRFMNNATIONAL COLLABORATIONSAssociazione Familiari Insonnia Familiare Fatale malattie da prioni, TrevisoAssociazione Italiana GIST A.I.G.Associazione per la Ricerca Neurogenetica, Lamezia Terme (CS) e ASL 6, Regione CalabriaAgenzia <strong>di</strong> Sanità Pubblica del Lazio, Regione LazioAssessorato alla Salute, Comune <strong>di</strong> MilanoAzienda Ospedaliera Ospedali Riuniti <strong>di</strong> BergamoAzienda Sanitaria Locale <strong>di</strong> BergamoAzienda ULS TO2, TorinoCEND, Centro Eccellenza per le Malattie Neurodegenerative, Università <strong>di</strong> MilanoCentro <strong>di</strong> Terapie per l’Adolescenza, MilanoCentro Fatebenefratelli San Giovanni <strong>di</strong> Dio, Cernusco sul NaviglioCentro <strong>di</strong> Neurofarmacologia, Dipartimento <strong>di</strong> Scienze <strong>Farmacologiche</strong>, Università <strong>di</strong> MilanoCentro Stu<strong>di</strong> in Psichiatra, ASL 2, TorinoCentro Parkinson-Istituti Clinici <strong>di</strong> PerfezionamentoClinica IRCSS S. Maria Nascente, MilanoClinica Neurologica III Università <strong>di</strong> Milano, Azienda Ospedaliera S. Paolo, MilanoClinica Psichiatrica, Università Milano BicoccaConsorzio <strong>Ricerche</strong> Luigi Amaducci, CRIC, Arcugnano (Vc)Consorzio MIA, MilanoDIBIT, San Raffaele Scientific Insitute, Milano.Dipartimento <strong>di</strong> Chimica Biologica, Università <strong>di</strong> PadovaDipartimento <strong>di</strong> Chimica, Università egli Stu<strong>di</strong> <strong>di</strong> FirenzeDipartimento <strong>di</strong> Chirurgia "P. Valdoni" - Lab., Ricerca Center for Research in Neurobiology"Daniel Bovet" (CRiN), "Sapienza" Università <strong>di</strong> RomaDipartimento En<strong>di</strong>cronologia, Università <strong>di</strong> MilanoDipartimento Farmaco Chimico Tecnologico, Università <strong>di</strong> SienaDipartimento <strong>di</strong> Farmacologia Me<strong>di</strong>ca, Università <strong>di</strong> MilanoDipartimento <strong>di</strong> Fisiologia Umana, Facoltà <strong>di</strong> Me<strong>di</strong>cina, Università <strong>di</strong> MilanoDipartimento <strong>di</strong> Me<strong>di</strong>cina e Sanità Pubblica, Sezione <strong>di</strong> Psichiatria e Psicologia Clinica,Università <strong>di</strong> VeronaDip. <strong>di</strong> Morfofisiologia, Scuola <strong>di</strong> me<strong>di</strong>cina Veterinaria, Università <strong>di</strong> Torino, Grugliasco (TO).Dip. Neurologia, IRCCS Fondazione Maugeri, PaviaDipartimento Neurologia, Ospedale Molinette, TorinoDipartimento <strong>di</strong> Neurologia Università <strong>di</strong> Milano, Ospedale Luigi Sacco.Dipartimento <strong>di</strong> Neuroscienze, Università <strong>di</strong> Parma, ParmaDipartimento <strong>di</strong> Salute Mentale <strong>di</strong> Niguarda, MilanoDipartimento <strong>di</strong> Salute Mentale ASL 3 ”Genovese”, GenovaDipartimento <strong>di</strong> Salute Mentale San Carlo, MilanoDipartimento <strong>di</strong> Salute Mentale della Ulss 5 Ovest VicentinoDip. <strong>di</strong> Scienze Biomolecolari e Biotecnologie, Università <strong>di</strong> MilanoDipartimento <strong>di</strong> Scienze Fisiologiche Università <strong>di</strong> Pavia, PaviaDipartimento Scienze Neurologiche, Università <strong>di</strong> Genova, GenovaDipartimento Scienze Neurologiche, Ospedale Maggiore Policlinico <strong>di</strong> MilanoDirezione Generale Famiglia e Solidarietà Sociale, Regione Lombar<strong>di</strong>a, MilanoDirezione Generale Sanità, Regione Lombar<strong>di</strong>a, MilanoDirezione Regionale Sanità e Servizi Sociali, Regione UmbriaDivisione <strong>di</strong> Ematologia, Università <strong>di</strong> Pavia e Fondazione IRCCS Policlinico S. Matteo, PaviaDivisione Neurologica, Università <strong>di</strong> Bologna87ANNUAL REPORT <strong>2009</strong>
IRFMNEPAPSY, Scientific Association for Regional Development and Mental Health, Athens, GreeceEvidentia Me<strong>di</strong>ca, Grottaferrata, RomaFederazione Alzheimer Italia, MilanoFranco Calori Cell Factory, Centro Trasfusionale e <strong>di</strong> Immunologia dei Trapianti, IRCCSOspedale Maggiore, MilanoFondazione Clelio AngelinoFondazione Cecchini Pace, MilanoFondo Edo TempiaHospice “Franco Gallini”, Aviano (PN)IRCSS "Casa Sollievo della Sofferenza", San Giovanni RotondoIRCCS <strong>Istituto</strong> Auxologico Italiano, Milano<strong>Istituto</strong> <strong>di</strong> Ricovero e Cura a Carattere Scientifico IRCCS (I.N.R.C.A.), AnconaIRCSS Fatebenefratelli <strong>di</strong> BresciaIRCSS "San Raffaele", Milano<strong>Istituto</strong> Europeo <strong>di</strong> Oncologia, IRCCS, Milano<strong>Istituto</strong> <strong>di</strong> Farmacologia e Farmacognosia, Università <strong>di</strong> Urbino<strong>Istituto</strong> <strong>di</strong> Farmacologia, Università <strong>di</strong> Milano<strong>Istituto</strong> <strong>di</strong> Fisiologia Umana II Università degli Stu<strong>di</strong> <strong>di</strong> Milano, Milano<strong>Istituto</strong> “G. Ronzoni”, Milano<strong>Istituto</strong> Nazionale Neurologico “Carlo Besta”, Milano<strong>Istituto</strong> Scientifico Humanitas<strong>Istituto</strong> <strong>di</strong> Scienze e Tecnologie della Cognizione, CNR, Roma<strong>Istituto</strong> "Stella Maris", IRCCS, Calambrone (PI)<strong>Istituto</strong> Superiore <strong>di</strong> Sanità, Roma<strong>Istituto</strong> Zooprofilattico Piemonte Liguria Val D'Aosta,TorinoLaboratorio <strong>di</strong> Immunopatologia Renale, Ospedale San Carlo, MilanoLaboratorio <strong>di</strong> Neuroscienze, Centro Dino Ferrari, Università <strong>di</strong> MilanoLega Italiana per la Lotta contro i TumoriNeuroscience and Brain Technologies, <strong>Istituto</strong> Italiano <strong>di</strong> Tecnologia, GenovaOspedale del Bambin Gesu’, RomaOspedale Regionale Ca Fondello, TrevisoOspedale "Molinette", TorinoPolo Oncologico, ASL 12, BiellaPolo Tecnologico, IRCCS S. Maria Nascente, Fondazione Don Carlo Gnocchi Onlus, MilanoProvincia Lombardo-Veneta Or<strong>di</strong>ne Ospedaliero San Giovanni <strong>di</strong> Dio, Fatebenefratelli <strong>di</strong>Cernusco sul NaviglioProgetto Itaca, associazione Volontari per la Salute Mentale – ONLUS, MilanoScuola <strong>di</strong> Specializzazione in Psicoterapia IRIS-Insegnamento e Ricerca In<strong>di</strong>viduo e Sistemi,MilanoScuola <strong>di</strong> Terapia Cognitiva “Stu<strong>di</strong> Cognitivi”, MilanoSocietà Italiana Me<strong>di</strong>cina Interna, RomaUnione Nazionale delle Associazioni per la Salute Mentale (UNASAM), MilanoUnità <strong>di</strong> Geriatria, Ospedale Maggiore IRCCS, Università <strong>di</strong> MilanoUnità Operativa <strong>di</strong> Psichiatria, Azienda Ospedaliera Luigi Sacco <strong>di</strong> Milano, MilanoUnità Operativa <strong>di</strong> Psichiatria, Azienda Ospedaliera San Gerardo <strong>di</strong> Monza, Monza, UnitàOperativa <strong>di</strong> Psichiatria <strong>di</strong> Garbagnate, Azienda Ospedaliere Salvini <strong>di</strong> Garbagnate, GarbagnateMilaneseUnità Operativa <strong>di</strong> Psichiatria, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagallie Regina Elena <strong>di</strong> Milano, MilanoUniversità degli Stu<strong>di</strong> <strong>di</strong> FoggiaUniversità Cattolica del Sacro Cuore <strong>di</strong> Roma88ANNUAL REPORT <strong>2009</strong>
IRFMNUniversità dell’Insubria, VareseUniversità del Piemonte Orientale, NovaraUniversità <strong>di</strong> Milano, IRCCS Ospedale Maggiore, MilanoUniversità Milano-Bicocca, MonzaUniversità La Sapienza, RomaU.O. Neurologia, Clinica S. Maria, IRCCS, Castellanza (VA).UNASAM, Unione Nazionale delle Associazioni per la Salute MentaleUnità Operativa <strong>di</strong> Psichiatria, Azienda Ospedaliera Luigi Sacco <strong>di</strong> Milano, MilanoWeb Me<strong>di</strong>ca, Grottaferrata, RomaINTERNATIONAL COLLABORATIONSAlbert Einstein College of Me<strong>di</strong>cine, Bronx, NY, USAAtomic Energy Commission, Service de Neurovirologie, Fontenay-aux-Roses, FranceBeaumont Hospital, Dublin, IrelandBrain Repair Centre, University of Cambridge, Cambridge, UKCambridge Centre for Brain Repair, University of Cambridge, UKCentre for Neuroscience Research and Division of Biomolecular Sciences, GKT School, King’sCollege, London, UKCentre National de la Recherche Scientifique, Paris. FranceChorley & South Ribble General Hospital, Chorley,Cochrane Schizophrenia Group, Università <strong>di</strong> Nottingham, Nottingham, UKColumbia Univ, Haverstraw, NY, USADepartment of Anatomy and Physiology, Laval University, QuebecDepartment of Biochemistry, Boston University, Boston USADepartment of Cell Biology, Washington University, St Louis, USADepartment of Chemistry, The Australian National University, Canberra City, AustraliaDepartment of Experimental Psychology, University of Cambridge, UKDepartment of Neuroscience, Physiology & Pharmacology University College London, , UKDepartment of Pathology and Infectious Diseases Royal Veterinary College, Herts, UKDepartment of Psychiatry, Me<strong>di</strong>cal Center University of Mississippi, Jackson, USA DirectorateGeneral for the Health and Consumer Protection, European Commission, LuxembourgDivision of Me<strong>di</strong>cal Genetics, CHUV Lausanne, SwitzerlandDivisione <strong>di</strong> Geriatria, Ospedali Regionali <strong>di</strong> Lugano e Mendrisio, SvizzeraEPAPSY, Scientific Association for Regional Development and Mental Health, Athens, GreeceEuropean Union of Family Associations of People with Mental Illness (EUFAMI)Geriatric Division and Department of Metabolic Diseases, Ospedali Regionali of Lugano andMendrisio, SwitzerlandHSPH Harvard University, Boston, USAIBCM, University of Lausanne, Lausanne, SwitzerlandINSERM U 751, Marseille, FranceInstitut de Génétique Humaine du CNRS, Montpellier, FranceJefferson Med Coll, Philadelphia, USAKarolinska Institutet, Stockholm, SwedenKing’s College Hospital, London, UKLancaster University, Lancaster, UK.Lexicon Pharmaceuticals Texas, USAMax-Delbrück-Center for Molecular Me<strong>di</strong>cine, Berlin, GermanyMPRC, Univ Baltimore, Baltimore, MD, USA89ANNUAL REPORT <strong>2009</strong>
IRFMNNational Insitute on Aging, NIH, Baltimore, USANeuroprion, Network of Excellence, WP VI, ECNeurological Department of the University of Tirana, AlbaniaNeurology, GlaxoSmithKline, New Frontiers Science Park North, Harlow UKNinewells Hospital and Me<strong>di</strong>cal School, Dundee, Scotland UKNorthern Illinois University, DeKalb, IL, USANovartis Pharma, Basel, SwitzerlandNYU, NY, USAObservatoire National Santé mentale et Précarité, Région Rhône-Alpes, Lione, FranciaOhio State Univ, Columbus, Ohio, USARobarts Research Institute, London, Ontario, CanadaRoyal Manchester Children's Hospital, Manchester, UKRoyal Preston Hospital, Preston, UKSergievsky Center, Columbia University, New York, NY, USAServizio <strong>di</strong> Geriatria, Ospedale della Beata Vergine, Mendrisio, SwitzerlandThe Scripps Research Institute, Jupiter, Florida, USATechnology Park of Bizkaia, Bizkaia, SpainToxicology Unit MRC, Leicester, UKUniversity of Alberta, CanadaUniversity of Bristol, Frenchay Hospital, Frenchay, Bristol, UK.University of Bristol, School of Me<strong>di</strong>cal Sciences, UKUniv of California at Irvine, Irvine, CA, USAUniversity of Car<strong>di</strong>ff, United KingdomUniversity of Chicago, Chicago, IL , USA.Univ of Colorado, Denver, USAUniversity Hospital, London, ON, CanadaUniv of Innsbruck, Innsbruck, AustriaUniversity of Lausanne, Lausanne SwitzerlandUniv of Maryland, Baltimore, USAUniversity of Maastricht, the NetherlandsUniversity of Rijeka Me<strong>di</strong>cal School, Rijeka, CroatiaUniversity of Szeged, UngaryUniversité de la Mé<strong>di</strong>terranée -Hôpital de la Timone Marseille, FranceUniversité Victor Segalen, Bordeaux, FranceUnit of Molecular Genetics, CHUV Lausanne, SwitzerlandVirtanen Institute for Molecular Sciences, University of Kuopio, FinlandVrije Universiteit Me<strong>di</strong>cal Center, Amsterdam, The NetherlandsWalton Hospital, Liverpool, UKWAPR (World Association for Psychosocial Rehabilitation)Washington University, St Louis, MI,USAWeill Cornell Me<strong>di</strong>cal College, New York, USAWorld Mental Health, Department of Mental Health and Substance Abuse, Geneva,SwitzerlandWorld Association for Psychosocial RehabilitationWorld Health Organization, Disability and Rehabilitation TeamAnnals Pharmacotherapy (Nobili)Biochemical Journal (Chiesa)Brain Aging (Forloni)EDITORIAL BOARD MEMBERSHIP90ANNUAL REPORT <strong>2009</strong>
IRFMNClinical Drug Investigation (Beghi)Clinical Neurology and Neurosurgery (Beghi)Cochrane Collaboration, Epilepsy (Beghi)Dialogo sui Farmaci (Nobili)Drugs in the R&D (Beghi)Early Intervention in Psychiatry (Barbato)Epidemiologia e Prevenzione (Lucca)Epilepsia (Beghi, Vezzani. Assistant e<strong>di</strong>tor)Epilepsy Current (Vezzani)Epilepsy Research (Vezzani)Inpharma (Beghi)International Journal of Mental Health (Barbato)International Journal of Molecular Epidemiology and Genetics (Forloni, senior, Albaniassociate)Journal of Neurochemistry (Bendotti)Journal of Neuroscience Online (Forloni)Neurological Sciences (Beghi)Neuroepidemiology (Beghi)Neuroscience (Vezzani)Open Aging Journal (Forloni)Open Geriatric Me<strong>di</strong>cine Journal (Forloni)Psichiatria <strong>di</strong> Comunità (Barbato)Quality of Life Research (Barbato)Ricerca & Pratica (Nobili)Stroke (De Simoni, Associate e<strong>di</strong>tor)Acta Neurologica Scan<strong>di</strong>navicaActa Psychiatrica Scan<strong>di</strong>navicaAlzheimer Disease and Associated DisordersAmerican Journal of Clinical NutritionAmerican Journal of HematologyAmerican Journal of Human GeneticsAmerican Journal of PathologyAmerican Journal of PhysiologyAnnals of NeurologyAnnals of PharmacotherapyArchives of Internal Me<strong>di</strong>cineBehavioural Brain ResearchBehavioural NeuroscienceBiochimica et Biophysica ActaBiochemical JournalBiochemistryBioMed Central NeurologyBiological PsychiatryBrain ResearchBrain Research BulletinBrain Research ReviewClinical Drug InvestigationClinical Neurology and NeurosurgeryPEER REVIEW ACTIVITIES91ANNUAL REPORT <strong>2009</strong>
IRFMNClinical PharmacokineticsClin Pharm TherapyCNS DrugsDialogo sui farmaciDrugsEpidemiologia e Psichiatria SocialeEpilepsiaEpilepsy & BehaviorEuropean Journal of ImmunologyEuropean Journal of NeuroscienceEuropean Journal of PharmacologyEuropean Journal of Public HealthExperimental NeurologyEuropean NeuropsychopharmacologyExpert Opinion on PharmacotherapyFASEB JournalFEBS lettersFundamental Clinical PsychopharmacologyFuture DrugsGiornale <strong>di</strong> Neuropsichiatria dell’Età EvolutivaGliaInternational Journal of NeuropsychopharmacologyJournal of Alzheimer’s <strong>di</strong>seaseJAMAJournal of the American Board of Family PracticeJournal of Biological ChemistryJournal of Cell. BiologyJournal of Cell PhysiologyJournal of Cerebral Blood Flow and MetabolismJournal of Chemical NeuroanatomyJournal of Chromatography B: Analytical Technologies in the Biome<strong>di</strong>cal and Life ScienceJournal of GerontologyJournal of Headache and PainJournal of Histochemistry and CytochemistryJournal of ImmunologyJournal of Internal Me<strong>di</strong>cineJournal of NeurochemistryJournal of NeuroimmunologyJournal of Neurology, Neurosurgery and PsychiatryJournal of NeuroscienceJournal of Pharmacology and Experimental TherapeuticsJournal of Pharmacy and PharmacologyJournal of PsychopharmacologyJournal of Psychosomatic ResearchJournal of Structural BiologyJournal of VirologyLife SciencesLancetLancet NeurologyMolecular Brain ResearchMolecular and Cellular NeuroscienceMolecular Therapy92ANNUAL REPORT <strong>2009</strong>
IRFMNNature NeuroscienceNeuroepidemiologyNeurologyNeurological SciencesNeurobiology of AgingNeurobiology of DiseasesNeuropharmacologyNeuropsychopharmacologyNeuroscienceNeuroscience LettersN.S. Archives PharmacologyParkinsonism & Related DisordersPharmacological ResearchPharmacoepidemiology and Drug SafetyPharmacology Biochemistry & BehaviorPlosONEProc Natl Acad Sci, USAProgress in Neuro-Psychopharmacology & Biological ResearchPsychopharmacologySynapseTrends Molecular Me<strong>di</strong>cineNATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPAgenzia Europea <strong>di</strong> Valutazione dei Me<strong>di</strong>cinali (EMEA)Agenzia Italiana per il Farmaco (AIFA)Associazione Italiana <strong>di</strong> Neuroepidemiologia (Presidente Uscente)Associazione Italiana per la Ricerca sull’Invecchiamento Cerebrale (AIRIC, Presidenza)Board of "Master in Advanced Technologies for the Study of Neurodegenerative Diseases",Milan UniversityComitato <strong>di</strong> coor<strong>di</strong>namento internazionale del progetto europeo”Quelles professionnalités ensanté mentale. Perspectives croisées, usagers, élus professionnels”.Commissione sulla Health Care Policy della Lega Internazionale contro l’Epilessia (ILAE)Comitato Or<strong>di</strong>natore del Master in "Tecnologie Avanzate Appicate alle PatologieNeurodegenerative", Università <strong>di</strong> MilanoCommittee for Proprietary Me<strong>di</strong>cinal Products (CPMP) presso L’EMEAConsiglio Direttivo AIRICConsiglio Direttivo della Società Italiana <strong>di</strong> Neuroscienze (SINS)Coor<strong>di</strong>nation Group IMI-PharmaCog projectDirettivo della Lega Italiana contro l’Epilessia (LICE)E<strong>di</strong>torial Committee, Guidelines of community based rehabilitation, World HealthOrganization.National Expert, recognized by AIFA (Agenzia Italiana del Farmaco), per l’EMEA (The Expertfor the Me<strong>di</strong>cal Research Council (MRC), UKGruppo <strong>di</strong> Approfon<strong>di</strong>mento Tecnico per lo sviluppo dell’area ‘Promozione della salutementale’, Regione Lombar<strong>di</strong>aGruppo <strong>di</strong> lavoro sull'epilessia dell'Organizzazione Mon<strong>di</strong>ale della SanitàGruppo <strong>di</strong> Stu<strong>di</strong>o sull’Epilessia della Società Italiana <strong>di</strong> Neurologia (SIN)Gruppo <strong>di</strong> Stu<strong>di</strong>o sulla Qualità della Vita della Società Italiana <strong>di</strong> Neurologia (SIN)Gruppo <strong>di</strong> Stu<strong>di</strong>o sulla Sclerosi Laterale Amiotrofica della Società Italiana <strong>di</strong> Neurologia (SIN)93ANNUAL REPORT <strong>2009</strong>
IRFMNMe<strong>di</strong>cal Research Council Strategic Grant Application, UKMental Health Working Party, work group created by the Directorate General for health andConsumer Protection (DG-SANCO), Bruxelles.Coor<strong>di</strong>nation Group Neuroprion NoE, EUInternational Committee on “Epilepsy and the Law”International Organizing Committee and Secretariat coor<strong>di</strong>nator for the Global Forum forCommunity Mental Health, managed by the Department of Mental Health of the World HealthOrganization.International Subcommittee of the American Academy of NeurologyInternational Steering Committee of the ’European Network on mental health promotion andmental <strong>di</strong>sorder prevention (EMHPA).International Subcommittee of the American Academy of NeurologyNational Institutes of Health of the USA and World Health Organization supported project onThe Future of Psychiatric Diagnosis: Refining the Research Agenda.Neurobiology Commission of the International League Against EpilepsyNeuroepidemiology Section of the American Academy of Neurology (Exiting Chair)Research Advisory Panel, MND Association, UKTask Force sull’epidemiologia dell’epilessia della ILAEScientific Advisory Board of Sheffield Institute Foundation for MNDScientific Advisory Board del Thierry Latran Foundation, FranceWorking Group on Epilepsy of the World Health Organization (WHO)EVENT ORGANIZATION7 a Giornata <strong>di</strong> stu<strong>di</strong>o sulla malattia <strong>di</strong> AlzheimerProblemi etici nella cura della persona affetta da demenzaMarch 14 <strong>2009</strong>, Ateneo Veneto, VeneziaWorkshopLa società della pauraMay 22nd, <strong>2009</strong>, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> <strong>Mario</strong> <strong>Negri</strong>, MilanoCorso sull’epidemiolgia e metodologia della ricerca.“Me<strong>di</strong>cina basata sull’evidenza in neuropsichiatria dello sviluppo: la <strong>di</strong>agnosi come strumento<strong>di</strong> co<strong>di</strong>fica per una banca-dati. <strong>Istituto</strong> Scientifico Stella Maris, Calabrone (Pisa) June 7-9,<strong>2009</strong>.Secondo Investigators’ Meeting Stu<strong>di</strong>o GiSASJune 9, <strong>2009</strong>, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> <strong>Mario</strong> <strong>Negri</strong>, MilanoCorso per me<strong>di</strong>ci e operatori sanitari:Associazione Nazionale Dentisti Italiani (ANDI)Il supporto farmacologico per una terapia <strong>di</strong> successo- Meccanismi delle interazioni tra farmaci- Valutazione e significato clinico delle interazioniMay 4-11, <strong>2009</strong> - Milano.ASL Provincia <strong>di</strong> Lecco, Lecco94ANNUAL REPORT <strong>2009</strong>
IRFMNTrattamento delle infezioni delle vie urinarie nell’anziano istituzionalizzato: tra evidenze eincertezzeMay 16, <strong>2009</strong> - Lecco.Serate <strong>di</strong> aggiornamento in Patologia e Me<strong>di</strong>cina OraleUniversità degli Stu<strong>di</strong> <strong>di</strong> MilanoInterazioni tra farmaci: una valutazione della rilevanza clinicaMay 19, <strong>2009</strong> - Milano.ASL Provincia <strong>di</strong> Bergamo, BergamoReazioni avverse e interazioni tra farmaci: valutazione della rilevanza clinica.September 19, <strong>2009</strong> – ASL Bergamo (BG)Me<strong>di</strong>cal Evidence, AreseLe interazioni tra farmaciDecember 11, <strong>2009</strong>, AreseGFCMH Meeting regionaleJune, 10-11 <strong>2009</strong>, Entebbe, UgandaWorkshop “Identification of molecular targets for next-generation treatments of Motor NeuronDisease”4th ESN Conference on Advances in Molecular Mechanisms of NeurologicalDisorders Leipzig, Germany; July 11-19, <strong>2009</strong>Workshop “Il ruolo degli utenti nella tutela della salute mentale”10° Congresso Mon<strong>di</strong>ale della WAPRNovember, 14th <strong>2009</strong>, Bangalore, In<strong>di</strong>aGRANTS AND CONTRACTSAbbott GmbH & Co. KGAgenzia <strong>di</strong> Sanità Pubblica del LazioAmgen, MilanoASL 2 Piemonte.ASL TO1 TorinoAssessorato alla Salute, Comune <strong>di</strong> MilanoAssociation pour la recherché sur la SLA, FranceAzienda USL 3 Pistoia e Val<strong>di</strong>nievoleBristol-Myers SquibbBoehringer IngelheimCUREEISAIEpilepsyDipartimento <strong>di</strong> Salute Mentale, Azienda Ospedaliera Niguarda Ca’ Granda, MilanoDana FoundationEvidentia Me<strong>di</strong>ca, Grottaferrata (Roma)Fondazione Cariplo, MilanoFondazione Mariani, MilanoFondazione Italo Monzino, Milano95ANNUAL REPORT <strong>2009</strong>
IRFMNFondazione Vialli e Mauro per la RicercaFP6, European UnionGlaxo-SmithKline, ItalyHospice "via <strong>di</strong> Natale Franco Gallini", Aviano (PN)Human Frontiers Scientific ProgrammeIMPHA II, DG-SANCO, Public Health and Consumers' Protection (Directorate General<strong>Istituto</strong> Comprensivo Statale "G.D. Romagnosi", Carate Brianza (MI)<strong>Istituto</strong> per la Ricerca e l’Educazione Regionale (Regione Lombar<strong>di</strong>a)I.R.I.S<strong>Istituto</strong> Superiore <strong>di</strong> SanitàJanssen-CilagH. Lundbeck A/S, DanimarkHoffmann-La Roche AG, SvizzeraMinistero della Ricerca ScientificaMinistero della SaluteMND Association, UKNewronOspedale “Casa Sollievo” <strong>di</strong> San Giovanni RotondoPharmingProgetto Itaca, MilanoRegione Lombar<strong>di</strong>a, Assessorato alla Famiglia e Solidarietà Sociale e Assessorato alla Sanità,MilanoRimol<strong>di</strong> e BergaminiRotary Clubs Gruppo 1, MilanoRotary Clubs Milano Naviglio Grande San Carlo, Milano Scala, Inner Wheel Milano San CarloSanofi-AventisSELECTA MEDICA, PaviaServier Laboratories, ParigiSigma-TauTelethonUnione Nazionale Associazioni per la Salute Mentale – UNASAMVertexWebMe<strong>di</strong>ca, Grottaferrata (Roma).World Health OrganisationSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Albani, D., Prato, F., Tettamanti, M., Lovati, C., Galimberti, D., Mariani, C., Lucca, U., Quadri,PL., Scarpini, E., Forloni, G. The Serotonin Transporter Promoter Polymorphic Region is not aRisk Factor for Alzheimer Disease Related Psychological J Alzheimers Dis 18:125-30 (<strong>2009</strong>)Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni C,Salmona M, Caccia S, Negro A, Forloni G. The SIRT1 activator resveratrol protects SK-N-BEcells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem. <strong>2009</strong>;110:1445-56Albani D, Vittori A, Batelli S, Polito L, De Mauro S, Galimberti D, Scarpini E, Lovati C,Mariani C, Forloni G.Serotonin transporter gene polymorphic element 5-HTTLPR increases therisk of spora<strong>di</strong>c Parkinson's <strong>di</strong>sease in Italy.Eur Neurol. <strong>2009</strong>; 62:120-396ANNUAL REPORT <strong>2009</strong>
IRFMNAlbani D, Batelli S, Polito L, Prato F, Pesaresi M, Gajo GB, De Angeli S, Zanardo A,Galimberti D, Scarpini E, Gallucci M, Forloni G. Interleukin-6 plasma level increases with agein an Italian elderly population ("The Treviso Longeva"-Trelong-study) with a sex-specificcontribution of rs1800795 polymorphism.Age (Dordr). <strong>2009</strong>, 31:155-6Antoniou X, Sclip A, Ploia C, Colombo A, Moroy G, Borsello T. JNK Contributes to Hif-1alpha Regulation in Hypoxic Neurons. Molecules. <strong>2009</strong>; 15:114-27.Balosso S, Ravizza T, Pierucci M, Calcagno E, Invernizzi R, Di Giovanni G, Esposito E,Vezzani A Molecular and functional interactions between tumor necrosis factor-alpha receptorsand the glutamatergic system in the mouse hippocampus: Implications for seizure susceptibilityNeuroscience <strong>2009</strong> 161 : 293-300Barbato A, Aresu A, Battino RN, Troisi E, Tettamanti M, Parabiaghi A. Uno strumento per laricerca transculturale in psichiatria: stu<strong>di</strong>o pilota sull’adattamento del Chinese HealthQuestionnaire a 12 item (CHQ-12) per i cinesi residenti in Italia. Rivista <strong>di</strong> Psichiatria <strong>2009</strong>; 44:1-9.Barbato A, D’Avanzo B. Efficacy of couple therapy as a treatment for depression, in Directionsin Psychiatry, ed. by Frederic Flach, Heatherleigh Press, New York, <strong>2009</strong>.Basso M, Samengo G, Nardo G, Massignan T, D'Alessandro G, Tartari S, Cantoni L, Marino M,Cheroni C, De Biasi S, Giordana MT, Strong MJ, Estevez AG, Salmona M, Bendotti C, BonettoV.Characterization of detergent-insoluble proteins in ALS in<strong>di</strong>cates a causal link betweennitrative stress and aggregation in pathogenesis. PLoS One. <strong>2009</strong> Dec 2;4(12):e8130.Beghi, M., R. Savica, E. Beghi, A. Nobili, L. Garattini. Utilization and costs of antiepilepticdrugs in the elderly. Drugs Aging <strong>2009</strong>; 26: 157-168.Beghi. E. Accidents and injuries in patients with epilepsy. Expert Rev. Neurother. <strong>2009</strong>;9(2):291-298.Beghi. E., The concept of the epilepsy syndrome: How useful is it in clinical practice? Epilepsia<strong>2009</strong>; 50 (Suppl.5): 4-10.Beghi, E. Pupillo, S. Zoccolella, On behalf of the European Amyotrophic Lateral SclerosisConsortium (EURALS). 148 th ENMC international workshop on the scientific contributions ofthe EURALS consortium on amyotrophic lateral sclerosis. Neuromuscular Disorders <strong>2009</strong>; 19:379-381.Bendotti C, Carrì MT. Amyotrophic lateral sclerosis: mechanisms and countermeasures.Antioxid Redox Signal. <strong>2009</strong>; 11:1519-22.Biasini E., Tapella L., Mantovani S., Stravalaci M., Gobbi M., Harris D.A. and Chiesa R. (<strong>2009</strong>)Immunopurification of pathological prion protein aggregates. PloS ONE, 4(11): e7816Colombo, A., Bastone, A., Ploia, C., Sclip, A., Salmona, M. Forloni, G. Borsello, TJNKregulates APP cleavage and degradation in a model of Alzheimer's <strong>di</strong>sease Neurobiol Dis 33:518-25. (<strong>2009</strong>)97ANNUAL REPORT <strong>2009</strong>
IRFMNCaccia S, Garattini S, Pasina S, and Nobili A. Pre<strong>di</strong>cting the clinical relevance of drug interactionsfrom pre-approval stu<strong>di</strong>es. Drug Safety <strong>2009</strong>; 32: 1017-1039.Calcagno E, Guzzetti S, Canetta A, Fracasso C, Caccia S, Cervo L, Invernizzi RW.Enhancement of cortical extracellular 5-HT by 5-HT1A and 5-HT2C receptor blockade restoresthe antidepressant-like effect of citalopram in non-responder mice.Int J Neuropsychopharmacol. <strong>2009</strong>; 12:793-803Calcagno E, Carli M, Baviera M, Invernizzi RWEndogenous serotonin and serotonin2C receptors are involved in the ability of M100907 tosuppress cortical glutamate release induced by NMDA receptor blockadeJ Neurochem <strong>2009</strong> 108 : 521-532Cheroni C, Marino M, Tortarolo M, Veglianese P, De Biasi S, Fontana E, Vitellaro ZuccarelloL, Maynard CJ, Dantuma NP, Bendotti C. Functional alterations of the ubiquitin proteasomesystem in motor neurons of a mouse model of familial Amyotrophic Lateral Sclerosis. Hum MolGenet. <strong>2009</strong>; 18:82-96A.Chiò, G. Logroscino, O. Har<strong>di</strong>man, R. Swingler, D. Mitchell, E. Beghi, B.G. Traynor, onbehalf of the EURALS Consortium. Prognostic factors in ALS: a critical review. AmyotrophLateral Scler <strong>2009</strong>; 10(5-6): 310-323.Chiesa R. and Harris D.A. (<strong>2009</strong>) Fishing for prion protein function. PloS Biol., 7(3):e1000075.Citterio,A., E. Beghi, A. Millul, A Evoli, R. Mantegazza, C. Antozzi, et al. Risk factors fortumor occurrence in patients with myasthenia gravis. J. Neurol <strong>2009</strong>; 256: 1221-1227Colombo L, Piovesan P, Ghirar<strong>di</strong> O, Salmona M, Forloni G.ST1859 reduces prion infectivity and increase survival in experimental scrapie.Arch Virol. <strong>2009</strong>; 154:1539-44..Di Lazzaro, V., F. Pilato, P. Profice, F. Ranieri, G. Musumeci, L. Florio, E. Beghi, et al. Motorcortex stimulation for ALS: a double blind placebo-controlled study. Neuroscience Letters<strong>2009</strong>; 464: 18-21.Feigin, AV. , J.F. Kurtzke, A. Korczyn, E. Beghi, A. Brown. Bridging the gap betweenexperimental and nonexperimental neuroepidemiology, and ultimately-betweenneuroepidemiological research and practice: round table <strong>di</strong>scussion at the First InternationalCongress on Clinical Neurology and Epidemiology. Neuroepidemiology <strong>2009</strong>; 33: 296-304.Forloni G, Salmona M, Marcon G, Tagliavini F.Tetracyclines and prion infectivity.Infect Disord Drug Targets. <strong>2009</strong>; 9: 23-30.Fumagalli F, Franchi C, Caffino L, Racagni G, Riva MA, Cervo L.Single session of cocaine intravenous self-administration shapes goal-oriented behaviours andup-regulates Arc mRNA levels in rat me<strong>di</strong>al prefrontal cortex.Int J Neuropsychopharmacol. <strong>2009</strong>; 12:423-9Gesuete R., Storini C. Fantin A., Stravalaci M., Zanier E.R., Orsini F, Vietsch H., Mannesse M.L. M., Ziere B., Gobbi M. and De Simoni M.G. “Recombinant C1-inhibitor in Brain IschemicInjury” Annals of Neurology, 66:332-342, <strong>2009</strong>98ANNUAL REPORT <strong>2009</strong>
IRFMNGiordano C, Albani D, Gloria A, Tunesi M, Batelli S, Russo T, Forloni G, Ambrosio L, CigadaA.Multi<strong>di</strong>sciplinary perspectives for Alzheimer's and Parkinson's <strong>di</strong>seases: hydrogels for proteindelivery and cell-based drug delivery as therapeutic strategies.Int J Artif Organs. <strong>2009</strong>; 32:836-50.Guerini, F.R., E. Beghi, G. Riboldazzi, et al. BDNF Val66Met polymorphism is associated withcognitive impairment in Italian patients with Parkinson’s <strong>di</strong>sease. Eur J Neurol <strong>2009</strong>; 16:1240-1245.Longhi L, Perego C, Ortolano F, Zanier E R, Bianchi P, Stocchetti N, McIntosh T and De SimoniMG .C1-Inhibitor attenuates neurobehavioral deficits and reduces contusion volume followingcontrolled cortical impact brain injury in mice. Critical Care Me<strong>di</strong>cine, 37:659-665, <strong>2009</strong>Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, Bendotti C, Mora G.Immune system alterations in spora<strong>di</strong>c amyotrophic lateral sclerosis patients suggest an ongoingneuroinflammatory process. J Neuroimmunol. <strong>2009</strong>; 210:73-9.Marcon J, Gagliar<strong>di</strong> B, Balosso S, Maroso M, Noé F, Morin M, Lerner-Natoli M, Vezzani A,Ravizza T. Age-dependent vascular changes induced by status epilepticus in rat forebrain:implications for epileptogenesis (<strong>2009</strong>) Neurobiol Dis, 34:121Mennini, T., L.Giordano, M. Mengozzi, P.Ghezzi, R. Tonelli, R. Mantegazza, V. Silani,M.Corbo, C. Lunetta, E. Beghi. Increased IL-8 levels in the cerebrospinal fluid of patients withamyotrophic lateral sclerosis. European Journal of Inflammation <strong>2009</strong>;7:39-44.Nardo G, Pozzi S, Mantovani S, Garbelli S, Marinou K, Basso M, Mora G, Bendotti C, BonettoV. Nitroproteomics of peripheral blood mononuclear cells from patients and a rat model ofALS. Antioxid Redox Signal. <strong>2009</strong>; 11:1559-67.Nobili A, Pasina L, Trevisan S, Riva E, Lucca U, Tettamanti M, Matucci M, Tarantola M. Useand misuse of antipsychotic drugs in patients with dementia in Alzheimer special care units.International Clinical Psychopharmacology <strong>2009</strong>; 24: 97-104.Nobili A, Pasina L, Tettamanti M, Lucca U, Riva E, Marzona I, Monesi L, Cucchiani R,Bortolotti A, Fortino I, Merlino L, Locatelli GW, Giuliani G. Potentially severe druginteractions in elderly outpatients: results of an observational study of an administrativeprescription database. Journal Clinical Pharmacy Therapeutics <strong>2009</strong>; 34: 1-10.Noé F, Frasca A, Balducci C, Carli M, Sperk G, Ferraguti F, Pitkänen A, Bland R, FitzsimonsH, During M, Vezzani A. Neuropeptide Y overexpression using recombinant adeno-associatedviral vectorsNeurotherapeutics. <strong>2009</strong>; 6:300-6.Ortolano F, Colombo A, Zanier E R, Sclip A, Longhi L, Perego C, Stocchetti N, Borsello T, DeSimoni M G.Human and experimental cerebral contusion: relevance of JNK pathway activation. JNeuropathol Exp Neurol, 68:964-971, <strong>2009</strong>Papantonio, A.M., E. Beghi, D. Fogli, M. Zarrelli, G. Logroscino, A. Bentivoglio, P. Simone,P. Tonali, L.M. Specchio. Prevalence of primary focal or segmental dystonia in adults in the99ANNUAL REPORT <strong>2009</strong>
IRFMN<strong>di</strong>strict of Foggia, Southern Italy: A service-based study. Neuroepidemiology <strong>2009</strong>; 33: 117-123.Pizzasegola C, Caron I, Daleno C, Ronchi A, Minoia C, Carri MT, Bendotti C. Treatment withlithium carbonate does not improve <strong>di</strong>sease progression in two <strong>di</strong>fferent strains of SOD1 mutantmice.Amyotroph Lateral Scler. Amyotroph Lateral Scler. <strong>2009</strong>; 10:221-8.Relja B, Schwestka B, Lee VS, Henrich D, Czerny C, Borsello T, Marzi I, Lehnert M.Inhibitionof c-Jun N-terminal kinase after hemorrhage but before resuscitation mitigates hepatic damageand inflammatory response in male rats.Shock. <strong>2009</strong>; 32:509-16.Riva E, Tettamanti M, Mosconi P, Apolone G, Gan<strong>di</strong>ni F, Nobili A, Tallone MV, Detoma P,Giacomin A, Clerico M, Tempia P, Guala A, Fasolo G, Lucca U. Association of mild anemiawith hospitalization and mortality in the elderly: the Health and Anemia Population-BasedStudy. Haematologica <strong>2009</strong>; 94: 22-3Serretti A, Olgiati P, Politis A, Malitas P, Albani D, Dusi S, Polito L, De Mauro S, Zisaki A,Piperi C, Liappas I, Stamouli E, Mailis A, Atti AR, Morri M, Ujkaj M, Batelli S, Forloni G,Soldatos CR, Papa<strong>di</strong>mitriou GN, De Ronchi D, Kalofoutis A.Lack of association betweeninterleukin-1 alpha rs1800587 polymorphism and Alzheimer's <strong>di</strong>sease in two IndependentEuropean samples. J Alzheimers Dis. <strong>2009</strong>;16:181-7.Striano,S., Beghii, E.,Epilepsy Syndromes in Development. Introduction. Epilepsia <strong>2009</strong>; 50(Suppl. 5): 1-3.Valerio A, Dossena M, Bertolotti P, Boroni F, Sarnico I, Delbalba A, Faraco G, Chiarugi A,Giordano A, Frontini A, Tonello C, Liou H C, De Simoni M G, Spano P F, Carruba M O, PizziM, Nisoli E Leptin protects against cerebral ischemia through inhibition of glycogen synthasekinase-3Beta and activation of NF-kB/c-Rel-dependent transcription. Stroke, 40: 610-617, <strong>2009</strong>Zoccolella S, Bendotti C, Beghi E, Logroscino G. Homocysteine levels and amyotrophic lateralsclerosis: A possible link. Amyotroph Lateral Scler. <strong>2009</strong> Jun 23:1-8LAY PRESS SELECTION (<strong>2009</strong>)Nobili A, Pasina L, Garattini S. Il paziente oncologico in trattamento con i farmaci inibitoridelle chinasi. Aggiornamento Me<strong>di</strong>co <strong>2009</strong> ; 33 : 28-32.Nobili A, Pasina L, Garattini S. Il paziente affetto da artrite reumatoide. Aggiornamento Me<strong>di</strong>co<strong>2009</strong> ; 33 : 104-114.Nobili A, Pasina L, Garattini S. Il paracetamolo. Aggiornamento Me<strong>di</strong>co <strong>2009</strong> ; 33 : 173-175.Camporese M, Frau S, Zimol R, Zermiani G, Nobili A, Conforti A, Giustetto G, Converso F,Lombardo G, Del Zotti F, Font M, Mezzalira L. L'informazione sui farmaci nei software <strong>di</strong>gestione delle cartelle cliniche. Dialogo sui Farmaci <strong>2009</strong>; n. 3 : 108-112.Nobili A, Pasina L, Garattini S. Il paziente con impotenza. Aggiornamento Me<strong>di</strong>co <strong>2009</strong> ; 33 :232-236.100ANNUAL REPORT <strong>2009</strong>
IRFMNNobili A, Pasina L, Garattini S. Farmaci antidemenza. Aggiornamento Me<strong>di</strong>co <strong>2009</strong> ; 33 : 290-293.Marcucci M, Iorio A, Agnelli G, Nobili A, Salerno F, Corrao S, Mannucci PM, a nome delpartecipanti al Progetto Registro Politerapie SIMI. Somministrazione <strong>di</strong> FANS in pazienti intrattamento anticoagulante orale ed eventi emorragici correlati in una coorte <strong>di</strong> anziani ricoveratiin reparti <strong>di</strong> me<strong>di</strong>cina interna. Intern Emerg Med <strong>2009</strong>; 4: S11.Salerno F, Pasina L, Gobbo G, Cazzaniga M, Nobili A, Tettamanti M, Corrao S, Bonazzi J,Vicidomini R, Mannucci PM, a nome del partecipanti al Progetto Registro Politerapie SIMI.Utilizzo cronico <strong>di</strong> farmaci anti-ulcera peptica/reflusso gastroesofageo e infezione battericacome causa <strong>di</strong> ricovero in soggetti anziani ricoverati in reparti <strong>di</strong> me<strong>di</strong>cina interna. Intern EmergMed <strong>2009</strong>; 4: S12.Nobili A, Tettamanti M, Salerno F, Corrao S, Pasina L, Spirito V, Bonazzi J, Noce D, MannucciPM, a nome del partecipanti al Progetto Registro Politerapie SIMI. Stu<strong>di</strong>o sulla prevalenza <strong>di</strong>polipatologie e politerapie nei reparti <strong>di</strong> me<strong>di</strong>cina interna. Intern Emerg Med <strong>2009</strong>; 4: S13.Nobili A, Tettamanti M, Salerno F, Corrao S, Pasina L, Spirito V, Bonazzi J, Noce D, MannucciPM, a nome del partecipanti al Progetto Registro Politerapie SIMI. Analisi dei pre<strong>di</strong>ttori <strong>di</strong>mortalità e durata della degenza in anziani ricoverati in reparti <strong>di</strong> me<strong>di</strong>cina interna. InternEmerg Med <strong>2009</strong>; 4: S124-S125.Iorio A, Marcucci M, Agnelli G, Nobili A, Salerno F, Corrao S, Mannucci PM, a nome delpartecipanti al Progetto Registro Politerapie SIMI. Terapia antitrombotica combinata e correlatieventi emorragici in una coorte <strong>di</strong> anziani ricoverati in reparti <strong>di</strong> me<strong>di</strong>cina interna. Intern EmergMed <strong>2009</strong>; 4: S14.Iorio A, Mannucci PM, Pasina L, Marcucci M, Bonazzi J, Agnelli G, Salerno F, Corrao S,Nobili A, a nome del partecipanti al Progetto Registro Politerapie SIMI. La profilassiantitrombotica in pazienti con fibrillazione o flutter atriale (FFA) preesistente ricoverati inreparti <strong>di</strong> me<strong>di</strong>cina interna. Intern Emerg Med <strong>2009</strong>; 4: S26.Pasina L, Nobili A, Tettamanti M, Salerno F, Corrao S, Bonazzi J, Vicidomini R, MannucciPM, a nome del partecipanti al Progetto Registro Politerapie SIMI. Utilizzo e appropriatezzad’uso dei farmaci anti-ulcera peptica/reflusso gastroesofageo in una coorte <strong>di</strong> anziani ricoveratiin reparti <strong>di</strong> me<strong>di</strong>cina interna. Intern Emerg Med <strong>2009</strong>; 4: S69.Marengoni A, Bonometti F, Mannucci PM, Salerno F, Corrao S, Nobili A, Tettamanti M, anome del partecipanti al Progetto Registro Politerapie SIMI. Politerapioa, eventi avversi duranteil ricovero e out come alla <strong>di</strong>missione in relazione a <strong>di</strong>versi clusters <strong>di</strong> malattie. Intern EmergMed <strong>2009</strong>; 4: S124.RESEARCH ACTIVITIESLaboratory of Biology of Neurodegenerative DisordersAlzheimer's <strong>di</strong>sease: genetic stu<strong>di</strong>es and clinical investigations101ANNUAL REPORT <strong>2009</strong>
IRFMNIn collaboration with <strong>di</strong>fferent neurological centers and the laboratory of GeriatricNeuropsychiatry it has been created a bank of blood samples for DNA of patients withAlzheimer’s <strong>di</strong>sease (AD), in familial (FAD) or spora<strong>di</strong>c form (SAD), and patients withvascular dementia (VD). In all subjects the <strong>di</strong>agnosis of dementia is performed accor<strong>di</strong>ng to theinternational guidelines. Since 2005 we started also the collection of blood samples fromsubjects with front-temporal dementia. The genetic stu<strong>di</strong>es are aimed to the identification ofcausal factors in FAD and risk factors in SAD. Mutations on genes enco<strong>di</strong>ng proteins involve<strong>di</strong>n the physiopathology of AD were investigated. The pathogenic role of these mutations isunder investigation using fibroblasts obtained from skin biopsy. Furthermore, we continued thescreening of FAD samples for the genes enco<strong>di</strong>ng for presenilin 1 and 2 (PS-1 and PS-2) andAPP, missense mutations in these three genes were associated with AD.Alzheimer's <strong>di</strong>sease: preclinical stu<strong>di</strong>esThe formation of β amyloid (Aβ) deposits in brain parenchyma and on the wall of cerebral bloodvessels is an early event in AD and there are now numerous genetic, biochemical andneuropathological stu<strong>di</strong>es pointing to a causal role of Aβ in the pathogenesis of AD. Thus,prevention the formation of Aβ aggregates or their elimination once formed is a potentialtherapeutic approach to the <strong>di</strong>sease. This aim is strongly persecuted with <strong>di</strong>fferent strategiesinclu<strong>di</strong>ng the regulation of enzymes responsible of the synthesis and degradation of Aβ and theenzymes influencing the metabolism of amyloid precursor protein (APP). In the lab, we developedthe idea to interfere <strong>di</strong>rectly with the Aβ deposits formation using anti-amyloidogenic drugs. Theexperimental stu<strong>di</strong>es have shown the potential therapeutic activity of these drugs in AD, and nowthey will be tested in a clinical setting.The role of oligomers in the Alzheimer pathogenesisRecent data have shown the essential role plays by oligomers, small and soluble aggregates ofAβ, in the Alzheimer pathogenesis and in particular in the cognitive decline associated to the<strong>di</strong>sease. In collaboration with the Department of Biochemistry an Molecular Pharamacology wedeveloped some in vivo models to analyze the neuronal dysfunction induced by Aβ 1−42 butnot in monomeric or fibrillar species. The intracerebral application of these <strong>di</strong>fferent formsconfirmed that Aβ oligomers induced behavioral impairment while monomeric or fibrillar formsof Aβ <strong>di</strong>d not affect the cognitive behavior,The intracellular signaling pathways, by which Aβ oligomers induce synaptic failure andconsequently neuronal degeneration are poorly understood. Nevertheless increasing evidencein<strong>di</strong>cate the involvement of kinases-dependent signaling pathways, and more specifically theJNK signaling pathway in these early degenerative events.The JNK kinase phosphorylates APP (amyloid precursor protein) and its relevance in bothneuronal death and brain plasticity is well established. We recently demonstrated, by using thespecific cell penetrating JNK inhibitor peptide (D-JNKI1) characterized by dr. Borsello, thatJNK is responsible for APP phosphorylation at Thr668, and that its specific inhibition reducedthe βAPPs and Aβ fragments production in primary cortical neurons. In ad<strong>di</strong>tion, we couldshow that JNK inhibition leads to a shift from the amyloidogenic to the non-amyloidogenicpathway, a result with potentially important therapeutic implications.Synaptic DysfunctionNowadays it is assumed that AD is a synapse-related pathology lea<strong>di</strong>ng to synaptic dysfunctionand loss, a phenomenon that precedes extensive amyloid deposition in the brain. At the sametime, soluble <strong>di</strong>ffusible forms of Aβ can perturb in an early stage of the <strong>di</strong>sease the synapticfunction causing a reduction of dendritic spines density in the cortex and hippocampus, an acuteinhibition of long term potentiation (LTP) and the loss of critical spine proteins (e.g. membraneexpression of NMDA receptors).102ANNUAL REPORT <strong>2009</strong>
IRFMNHowever, the relationship between Aβ and synapses loss remains unclear and more efforts arenecessary to better understand the mechanisms underlying Aβ synaptic toxicity. Our aim is tostudy the effects of Aβ oligomers on MAPKs pathways and elucidate the link betweensynaptopathies and the activation/inhibition of the JNK, p38 and ERK cascades. This study canpotentially be a breakthrough in the comprehension of AD pathogenesis: understan<strong>di</strong>ng thecellular and molecular alterations that lead to AD will help in developing effective andpreventive therapeutic strategies in order to counteract or nullify the degenerative processesactivated by Aβ.MAPKs (ERK, p38 and JNK) are also implicated in the regulation of the imme<strong>di</strong>ate earlysignaling events that modulate synaptic plasticity by controlling LTP, LTD and the recycling ofglutamate receptors (NMDAR and AMPAR) as well as their expression. Nevertheless, MAPKsinvolvement in the regulation of synaptic function and dysfunction and the mechanisms bywhich they trigger the synaptic loss induced by Aβ oligomers are largely unknown.The cargo strategy as a key tool in neuroprotectionThe possibility to target protein complexes and enzymes involved in intracellular signalingpathways by means of cell permeable peptide (CPP) conjugates represents a novel, versatile andextremely powerful way of blocking the propagation of intracellular signaling events orintracellular processes, with an unprecedented specificity allowing for reduction of side effects.D-JNKI1 is a cell-permeable, biologically-active peptide consisting of a carboxyl terminalsequence derived from the JNK bin<strong>di</strong>ng domain of the scaffold protein JIP-1/IB1 (JBD20), andan amino terminal portion containing the HIV-TAT 48-57 transporter sequence. D-JNKI-1 hasbeen designed to block the interaction, me<strong>di</strong>ated by JBD domain, between JNK and its targets.D-JNKI1 afforded powerful protection against NMDA excitotoxicity in cortical neurons andagainst cerebral ischemia in vivo, as well as in two other neurodegenerative models (hair-cellloss in animal models of sudden deafness and retinal ganglion cell loss following optic nervecrush in vivo. The peptide progressed in clinical trails for preventing brain ischemia/stroke (seeCHUV/Xigenpharma Lausanne web-link). Among the possible targets for neuroprotection thereis MKK7, that is activated, unlikely MKK4, during NMDA-stress,. To inactivate MKK7 we uselentiviruses because of the particular capability of integrating genetic material into the genomeof non-<strong>di</strong>vi<strong>di</strong>ng cells stably. Our lentiviral vector will carry a single si-RNA duplex of MKK7.A second approach is to test in vitro the specific inhibitor: Gadd45, a molecule active onMKK7. Gadd45β binds to MKK7 <strong>di</strong>rectly and blocks its catalytic activity, the bin<strong>di</strong>ng betweenGadd45β/MKK7 being tighter than JIP1/MKK7. The endogenous Gadd45 interacts to MKK7through <strong>di</strong>rect, high-affinity contact but not with the other JNK upstream kinase, MKK4. Forthis study we initially plan to use a viral system that will allow us to observe the role of thispathway in excitotoxicity, with a final goal of producing a cell-permeable peptide with a morespecific effect in the prevention of neuronal death.SUMOlization in acute and chronic <strong>di</strong>seasesSmall ubiquitin-like mo<strong>di</strong>fier (SUMO) is a group of proteins responsible for post translationalmo<strong>di</strong>fications influencing protein function, localization and stability. Recently, proteinSumoylation has attracted neuroscientists since it is implicated in the altered protein dynamicsthat are associated with various aspects of neurodegenerative <strong>di</strong>sease, inclu<strong>di</strong>ng stroke andAlzheimer's Disease (AD). Our hypothesis is that SUMOylation confers neuroprotection againststressful stimuli through regulation of important stress signaling pathways. The aim of thisstudy is to investigate the role of SUMOylation in models of acute (ischemia) and chronic brain<strong>di</strong>seases (AD). At present we are characterising the changes in expression and localisation ofSUMO1-2/3 in an in vitro model of ischemia (NMDA application) as well as in a model of AD(oligomers application).103ANNUAL REPORT <strong>2009</strong>
IRFMNSirtuins and agingThe sirtuins are a family of conserved proteins with de-acetylation activity. In human thesirtuins are coded by 7 <strong>di</strong>fferent genes and are localized in the citosol, within the nuclei and inthe cellular mitochondria. SIRT-1, the better known sirtuin, is involved in the aging physiologyand energetic metabolism, its activation induced beneficial effects in Alzheimer and Parkinsonexperimental models. We stu<strong>di</strong>ed sirtuins from <strong>di</strong>fferent points of view, genetic, cellular andbehaviorally. The genetic stu<strong>di</strong>es are devoted to identify alterations associated to AD in Italianpopulations. During the screening of all sirtuin genes, we found several single nucleicpolymorphisms that now are investigated in larger population (560 AD subjects). The cellularstu<strong>di</strong>es are focused on the role of SIRT-1 and SIRT-2 in the cell death mechanisms andoxidative stress in cellular models of AD. Since sirtuins have been involved in the energeticmetabolism, and mental as well as physical exercise exert protective effect in AD, we areevaluating in AD animal models if sirtuins are able to me<strong>di</strong>ate the beneficial effects of physicalexercise and environmental stimulation.Genetics of agingIn collaboration with Geriatric Neuropsychiatry Lab for the Monzino 80-plus study and with dr.Maurizio Gallucci from the ARGel Association in Treviso for Trelong study we collected alarge number of blood samples from subjects over seventy. In these samples we are performinga genetic analysis to identify genetic profiles associate to the longevity and /or to the agingassociatedpathologies with specific attention to the dementias. The aim is to cross thegenotype/phenotype profile with pathologies and environmental aspects inclu<strong>di</strong>ng style of life,<strong>di</strong>et and economical con<strong>di</strong>tions to identify risks and protective factors. Initially the subjectswere genotypized for ApoE, whom allele E4 is a well-known risk factor for Alzheimer’s <strong>di</strong>seaseand several other <strong>di</strong>sorders and sirt-1 a gene co<strong>di</strong>fied for protein member of a enzymatic familyof sirtuins associated to the longevity in several experimental models. The results are interestingbut before drawing any conclusion we need to consider the numerous other parameters collecte<strong>di</strong>n our database.Prion's <strong>di</strong>sease: in vitro stu<strong>di</strong>esImmunopurification of pathological PrP aggregatesA great deal of effort has been devoted to developing protocols for purifying the abnormal PrPisoform for structural stu<strong>di</strong>es, and testing its biological properties. Most procedures rely onprotease <strong>di</strong>gestion, allowing efficient purification of PrP27-30, the protease-resistant core ofmisfolded PrP. However, protease treatment cannot be used to isolate abnormal forms of PrPlacking conventional protease resistance, such as those found in several genetic and atypicalspora<strong>di</strong>c cases. We developed a method for purifying pathological PrP molecules based onsequential centrifugation and immunoprecipitation with a monoclonal antibody selective foraggregated PrP. With this procedure we purified pathological PrP aggregates at electrophoretichomogeneity and demonstrated that they retain their native biological activity. Thesepreparations may be useful for investigating the structural and chemico-physical properties ofinfectious and neurotoxic PrP aggregates.Development of a novel drug-based, cellular assay for the activity of neurotoxic PrP mutantsSeveral mutated forms of PrP induce neurodegeneration when expressed in transgenic mice;however, they are not toxic when expressed in cultured cells. We found that some PrP mutantssensitize cultured cells to the toxic activity of two classes of antibiotics. Based on this result,we developed a new assay allowing the screening of the cytotoxic activity of mutant PrP inimmortalized cell lines. This assay could be useful for <strong>di</strong>ssecting the molecular mechanisms ofPrP toxicity, and to test the efficacy of potential therapeutic agents.104ANNUAL REPORT <strong>2009</strong>
IRFMNPrion's <strong>di</strong>sease: in vivo stu<strong>di</strong>esProteomic analysis of a cellular model of fatal familial insonniaThe PrP mutation D178N/M129 is linked to fatal familial insomnia, characterized by severesleep abnormalities and autonomic dysfunction. We showed by immuno-electron microscopythat this mutant PrP accumulates abnormally in the endoplasmic reticulum and Golgi oftransfected neuroblastoma N2a cells. To investigate the impact of intracellular PrPaccumulation on cellular homeostasis, we <strong>di</strong>d a 2D gel-based <strong>di</strong>fferential proteomic analysis incollaboration with the Translational Proteomics Lab of the <strong>Mario</strong> <strong>Negri</strong> Institute. We foundchanges in proteins involved in energy metabolism, redox regulation and vesicular transport.Rab GDP <strong>di</strong>ssociation inhibitor alpha (GDI) was one of the proteins that changed most. GDIregulates vesicular protein trafficking by acting on the activity of several Rab proteins. Wefound a specific reduction in the level of functional Rab11 in mutant PrP expressing cells,associated with impaired post-Golgi trafficking. These data are consistent with a model bywhich mutant PrP induces over-expression of GDI activating a cytotoxic feedback loop whichleads to protein accumulation in the secretory pathway.Parkinson’s Disease: genetic stu<strong>di</strong>esParkinson’s <strong>di</strong>sease (PD) is the second more <strong>di</strong>ffuse neurodegenerative <strong>di</strong>sorder with anunknown pathogenesis, however for PD several therapies are available and, although at thesymptomatic level, their efficacies is well-established. In the etiological stu<strong>di</strong>es on PD thegenetic component has been tra<strong>di</strong>tionally considered with scarce interest whereas theenvironmental causes were carefully evaluated. This orientation was based on the evidence thatthe exposure to several toxins can mimic the PD pathology. However the genetic stu<strong>di</strong>es in thelast few years have completely changed the perspective with the identification of mutations ontwo genes, enco<strong>di</strong>ng for alpha-synuclein and parkin, associated to the juvenile forms of the<strong>di</strong>sease. A mutation on alpha synuclein gene is an event extremely rare, only three mutationsidentified until now, the parkin mutations are numerous ether in puntiform or in deletion form.The mutations on alpha-synuclein gene are dominant while the parkin mutations are associatedwith PD in recessive form. We collected, in collaboration with several neurological centers,blood samples from PD subjects and the screening of the samples involved genes like alphasynuclein,parkin, DJ-1 and other factors potentially involved in PD. Recently, an associationbetween polymorphisms occurring in gene for serotonin transporter and the appearance ofdepression in PD subjects has been investigated. The results in<strong>di</strong>cate no association between theserotonin transporter gene polymorphisms and depression in PD, but a <strong>di</strong>rect associationbetween these polymorphisms and PD itself. This in<strong>di</strong>cate a more relevant involvement oserotonergic system in PD pathogenesis compared to whom is generally considered.Parkinson’s <strong>di</strong>sease: stu<strong>di</strong>es in vitroThe identification of the mutations associated to Parkinson’s <strong>di</strong>sease (PD) gave a substantialcontribute to understand the <strong>di</strong>sease and allowed the develop of cellular models to investigatethe pathogenesis of the <strong>di</strong>sease. In past we showed the potential neurotoxic activity of alphasinucleinusing the synthetic peptide homologous to the fibrillogenic fragment 61-95 (NAC) ofthe protein. Successively with help of dr. Negro at the Department of Biochemistry at theUniversity of Padova we prepared cDNA vectors inclu<strong>di</strong>ng the sequence of wild type andmutated alpha-synuclein Their transfection to the PC12 cells induced in specific con<strong>di</strong>tions acellular damage. More recently alpha-synuclein was associated to a TAT sequence capable totransport inside the cells the protein. With this method the intracellular concentration of alphasinucleinwas better controlled. In a micromolar range alpha-synuclein was toxic, but innanomolar range, it exerted neuroprotective effect against oxidative stress induced by hydrogenperoxide. This double effect dose-dependent was confirmed in an “inducible” model. More105ANNUAL REPORT <strong>2009</strong>
IRFMNrecently again in collaboration with Dr. Negro (Padua University), we obtained the recombinantform of DJ-1 associated with TAT (TAT-DJ-1). This protein is similar to alpha-synuclein,mutations of its sequence has been associated to PD. TAT-DJ-1 silencing by small interferenceRNA (siRNAi) were used to study the interaction between DJ-1 and alpha synuclein..Laboratory of Neurological DisordersEpidemiological stu<strong>di</strong>es on amyotrophic lateral sclerosis (ALS)Included are stu<strong>di</strong>es on the incidence, risk factors and mortality of ALS. The data are obtainedfrom a regional registry of the <strong>di</strong>sease activated in 1998 and inclu<strong>di</strong>ng all patients with newly<strong>di</strong>agnosed ALS identified in the Lombardy region. Using similar study protocols, the same dataare collected in two ad<strong>di</strong>tional regional registries (from Piemonte and Puglia) included in anetwork with the Lombard registry. Information obtained from patients enrolled in the Lombardregistry and from cases examined by members of the Italian ALS Study Group has been used toassess the vali<strong>di</strong>ty and reliability of <strong>di</strong>agnostic criteria for ALS and selected <strong>di</strong>sability scales.Based on the data recorded, the annual incidence of ALS is comparable to that obtained in otherWestern countries where ALS registries have been activated, and is among the highest everpublished (1.9 per 100,000). Mortality of ALS has been found to be comparable to that ofstu<strong>di</strong>es from similar populations stu<strong>di</strong>ed with the same protocol. The study on the validation ofthe current <strong>di</strong>agnostic criteria for ALS (the El Escorial criteria) showed that to be consideredvalid and reliable, the criteria should be used after proper training of the investigators.In October 2004, the Laboratory of Neurological Disorders has started a European collaborativegroup for the ALS registries (EURALS) with the intent to create a common database(completed in the year 2005) with the participation of the existing regional and national <strong>di</strong>seaseregistries. With the collaboration of the UK and Irish groups participating in the EURALScollaboration, a scientific report has been published on a meta-analysis of the incidence of ALS,performed by pooling data from the 1998-99 cohorts of patients enrolled in the populationbasedregistries. Other stu<strong>di</strong>es are ongoing under the coor<strong>di</strong>nation of the Laboratory ofNeurological Disorders: 1. A case-control study on trauma and risk of ALS (in collaborationwith the Italian registries); 2. A case-control study on ALS, physical exercise and sport (incollaboration with the EURALS Consortium). 3. A survey of the prevalence of cognitiveimpairment and extrapyramidal signs in patients with newly <strong>di</strong>agnosed ALS (Italian registries);4. A study of the mortality of ALS in the 1998-99 cohort of patients from the Europeanpopulation-based registries (EURALS Consortium).Treatment of the first epileptic seizure and short and long-term mortalityA cohort of 419 patients with a first unprovoked seizure, randomized to imme<strong>di</strong>ate treatment ofto treatment at the time of relapse, were followed for up to 20 years in search of short-term andlong-term mortality. The mortality in this cohort was compared to that of the Italian populationand measured with the Standar<strong>di</strong>zed Mortality Ratio (SMR). The SMR was not significant (1.2;95% CI 0.9-1.7) and was not changed for patients in whom the treatment of the first seizure waswithhold.Innovative therapeutic strategies in patients with epilepsyA cohort of patients with a first unprovoked seizure, randomised since 1988 by several Italiancenters to imme<strong>di</strong>ate treatment or to treatment only at the time of a seizure relapse, wasfollowed to verify the impact of the two therapeutic strategies on the long-term prognosis ofepilepsy, measured by the chance of achieving 5-year remission.106ANNUAL REPORT <strong>2009</strong>
IRFMNTo provide a pragmatic definition of drug resistance in childhood epilepsy, children refractoryto two antiepileptic drugs (in sequence or in combination) were randomised to the use of a thirddrug or to the optimization of the existing treatment and followed for up to three years.Therapeutic response was measured by the achievement of a six-month period of remission. Thestudy has been conducted in collaboration with the IRCCS “Stella Maris” of Calambrone (PI).The study has been concluded prior to completing patient recruitment because the eligiblepatients could not be easily traced. The available data have processed and analyzed and ascientific manuscript is in preparationEpidemiology of neurological <strong>di</strong>sorders in AlbaniaWith the collaboration of the Fondazione Mariani and the Neurological Department of theUniversity of Tirana, an epidemiological survey has been started to assess the prevalence an<strong>di</strong>ncidence of several neurological con<strong>di</strong>tions (stroke, epilepsy, headache, dementia, peripheralneuropathy, multiple sclerosis) comparing an urban and a rural community (Tirana andSaranda). In 2005, a study on the validation of the <strong>di</strong>agnostic criteria was conducted.A total of 9869 persons (Tirana 4953; Saranda 4916) were screened. The prevalence rates of theclinical con<strong>di</strong>tions (expressed as number per 1000) are, in decreasing order, 258 (headache), 36(polyneuropathy), 15 (epilepsy), 13 (stroke), 11 (dementia), 9 (parkinsonisms), 5 (cerebralpalsy), and 0.3 (multiple sclerosis).Headache and comorbi<strong>di</strong>tyHeadache is frequently associated with other comorbid <strong>di</strong>sorders. Anxiety, depression andepilepsy are the commonest clinical con<strong>di</strong>tions. On this background, two observational stu<strong>di</strong>eshave been completed to assess the correlation between headache, anxiety and depression and,respectively, between headache and epilepsy. The aim of the first study was to assess theprevalence and characteristics of anxiety and depressive <strong>di</strong>sorders in cohorts of patients withmigraine (with or without aura), tension-type headache (episo<strong>di</strong>c or chronic) or both. Thesample included 158 patients with migraine and 216 patients with tension-type headache with orwithout migraine. Psychiatric <strong>di</strong>sorders were <strong>di</strong>fferent in the two groups. The greatest<strong>di</strong>fferences were observed for panic and obsessive-compulsive <strong>di</strong>sorders (predominating inpatients with migraine). The second study aimed at showing any <strong>di</strong>fferences between patientswith epilepsy-headache comorbi<strong>di</strong>ty and those with epilepsy or headache alone. A total of 1167patients were examined (156 with epilepsy-headache comorbi<strong>di</strong>ty, 675 with headache alone,and 336 with epilepsy alone). Differences between the three groups were found for familyhistory of epilepsy (prevailing in patients with epilepsy-headache comorbi<strong>di</strong>ty) or headache(prevailing in patients with headache alone) and for clinical features (less severe in patients withepilepsy-headache comorbi<strong>di</strong>ty).Cerebrovascular <strong>di</strong>sorders and risk of epilepsyEpilepsy is a frequent complication of stroke. Acute symptomatic seizures (i.e. seizuresoccurring in the seven days after stroke) can occur in up to two-thirds of cases and epilepsy (i.e.repeated unprovoked seizures) in 2-4%. There are no consistent fin<strong>di</strong>ngs on the risk factors foracute symptomatic seizures, unprovoked seizures and epilepsy in patients with stroke. For thesereasons, in 2007 a multicenter national prospective survey has been started to assess the risk ofseizures and epilepsy (and the main risk factors) in a cohort of patients with a first ischemic orhemorrhagic stroke followed for a maximum period of 24 months. The study was alsoimplemented to assess the feasibility of a pragmatic therapeutic trial on the prophylaxis ofseizures and epilepsy in stroke. Based on a preliminary analysis of 583 patients, the incidence ofacute symptomatic seizures (5.7%) and the independent pre<strong>di</strong>ctors of seizures (cerebralhemorrhage).107ANNUAL REPORT <strong>2009</strong>
IRFMNTherapeutic trials in neurological <strong>di</strong>sordersDuring the year <strong>2009</strong> six therapeutic trials sponsored by the Italian Drug Agency (AIFA) and atherapeutic trial sponsored by the Italian Ministry of Health were started or continued. Includedare: 1. A randomized double-blind parallel-group placebo-controlled trial on the efficacy andtolerability of L-acetylcarnitine in ALS; 2. A randomized open-label parallel-group trialcomparing Erythropoietine to Metyl-prednisolone in patients with acute spinal cord injury; 3. Arandomized double-blind parallel-group placebo-controlled trial on the efficacy and safety ofvalproate in me<strong>di</strong>cation-overuse headache; 4. A randomized open-label trial of the efficacy of acomprehensive rehabilitation program for the prevention of falls in Parkinson’s <strong>di</strong>sease; 5. Arandomized open-label trial on the efficacy of an active monitoring of the adverse effects ofantiepileptic drugs and of relevant drug interactions; 6. A randomized open-label trial on theefficacy of an educational program for physicians working in nursing homes.. The first trialaims at fin<strong>di</strong>ng a potentially effective drug in a clinical con<strong>di</strong>tion for which there is only oneproduct (Riluzole) with at best modest efficacy on survival. L-acetylcarnitine has been found toimprove survival in experimental models of motor neuron <strong>di</strong>sease. The second trial intends toverify the efficacy of erythropoietin, a drug shown to mitigate the effects of traumatic spinalshock and accelerate recovery in experimental animals. The drug chosen for comparison(Methylprednisolone at high doses) has been selected for being the present gold standard inclinical practice. The third trial aims at verifying whether valproate (a drug commonly used forthe prophylaxis of migraine) abates symptoms occurring in drug-overuse headache, a commonand frequently invalidating variety of chronic i<strong>di</strong>opathic headache. The fourth trial aims atassessing whether a comprehensive rehabilitation program compared to usual care is followedby a reduction in the incidence of falls in patients with Parkinson’s <strong>di</strong>sease at risk of falls. Thefifth trial aims at verifying the added value of an active monitoring of adverse drug interactionscompared to usual care in patients receiving antiepileptic drugs associated to other compounds.The sixth trial aims to verify the added value of a web-based educational program in reducingthe number of inappropriate prescriptions compared to usual care.The laboratory of neurological <strong>di</strong>sorders is the coor<strong>di</strong>nator of the first trial and a partner in theother trials, where the main tasks include protocol and CRF preparation, statistical analysis, andpreparation of the final scientific report.Laboratory of Drug Metabolism1-Aryl-piperazine as active metabolites of centrally acting drugStarting from the previously reported 5-HT 7 receptor compounds with N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazineexanamide structure (Leopoldo et al., J. Med. Chem.,2007, 50, 4214), a new series of 1-(2-methythiophenyl)-, 1-(2-biphenyl)-, 1-(2-isopropylphenyl)- and1-(2-methoxyphenyl)-piperazine derivatives were designed with the aim to obtain new potentderivatives endowed with suitable physicochemical properties for rapid and extensive penetration intothe brain. The newly synthesized compounds underwent ra<strong>di</strong>oligand bin<strong>di</strong>ng assays to assess theiraffinities for 5-HT 7 , 5-HT 1A , and D 2 receptors. The intrinsic activities at 5-HT 7 receptor as well asthose for serotonin 5-HT 1A and dopamine D 2 of the most potent compounds were determined(Leopoldo et al., J. Med. Chem., 2008; 51: 5813).The proposed structural mo<strong>di</strong>fications on the tetrahydronaphthalenyl ring of the original compoundswere, in most cases, detrimental for 5-HT 7 receptor, whereas had limited impact on the affinity for 5-HT 1A and D 2 receptors. Nonetheless, the pursued strategy led to the identification of the 1-(2-biphenyl)piperazine derivatives which retained nanomolar affinity at 5-HT 7 receptor, still showing lipophilicitywithin the target range. Among these, the N-(4-cyanophenylmethyl)-4-(2-<strong>di</strong>phenyl)-1-piperazinehexanamide derivative also demonstrated high selectivity over 5-HT 1A and D 2 receptors(324- and 245-fold, respectively) and showed full competitive agonism at 5-HT 7 receptor in an108ANNUAL REPORT <strong>2009</strong>
IRFMNisolated guinea-pig ileum assay. It rapidly reached the systemic circulation and entered the brain,achieving concentrations in the low micromolar range after intraperitoneal doses in mice. Its brainconcentration-time profile paralleled that in plasma, in<strong>di</strong>cating that it rapidly and freely <strong>di</strong>stributesacross the blood-brain barrier. Similar stu<strong>di</strong>es were performed on the most potent and selective 5-HT 7agonist derivative of the previous series - which had lipophilicity comparable to the new derivative -which, however, was cleared more rapidly from mouse plasma. Moreover, the potential formation ofthe 1-aryl-piperazine metabolite and its brain-to-plasma concentration ratio were also examinated,because arylpiperazine derivatives generally undergo CYP3A-me<strong>di</strong>ated N-dealkylation of the aliphaticchain attached to the piperazine nitrogen. While the plasma concentrations of the metabolites werealways below the detection limit of the analytical procedure, their brain concentrations exceeded thatof their parent compound, by about 1.6 and 4 times for the new and original derivative, respectively.This was not surprising as previous stu<strong>di</strong>es have shown that 1-arylpiperazines concentrate in braintissue. Future stu<strong>di</strong>es will focus on characterization of the neuropharmacological profile of the 1-arylpiperazinemetabolite compared with its parent compound.Pharmacological role of the constituents of Hypericum perforatumextractsThe chemical composition of extracts of hypericum perforatum L. (St. John’s wort) is essentiallyknown but is still not clear which constituent(s) account, wholly or in part, for the antidepressantactivity of the extracts, and through what neurochemical mechanism(s). The phloroglucinol hyperforinshares most of the in vitro and in vivo pharmacological properties of the extracts, and is possibly amain “antidepressant” component, but there is also evidence for other pharmacologically activecomponents. However, identifying the roles of the various derivatives and the mechanism(s) of theiractivity is complicated by the scarcity of information about their ability to cross the blood-brainbarrier and the concentrations reached in brain after administration of the extracts. This is also true forthe biflavone biapigenin and particularly its I3’,II8 analog amentoflavone which, although present insmaller amounts in extracts, shows a multitude of pharmacological actions in vitro and in vivo inanimal models. The lack of pharmacokinetic data in man and animals and questions about the brainuptake of amentoflavone and biapigenin prompted us to examine their brain uptake and concentrationsand the relationships with plasma concentrations after pharmacologically effective doses in mice.After doses of Hypericum perforatum extracts the brain concentrations of biapigenin andamentoflavone were below the limit of quantification. The same was true for amentoflavone after abiflavone-enriched extract of Ginkgo biloba. Levels were consistently detected only afterintraperitoneal biapigenin or amentoflavone but were low and mostly related to the residual biflavonein the circulation. Poor brain-to-blood permeability is common to other polar components ofHypericum perforatum, resulting in brain concentrations generally too low for any <strong>di</strong>rect interactionwith neurotransmitter transporters and receptors which are obviously important for the action ofconventional antidepressants. Likewise, the in vitro interactions of biapigenin and amentoflavone withknown central mechanisms are apparently not relevant for the in vivo effects of the extracts becausethey occur at biflavone concentrations far excee<strong>di</strong>ng those found in the brain after pharmacologicallyeffective doses. However, this does not exclude that tissues other than brain may concentratebiapigenin or amentoflavone sufficiently to exert beneficial effects after daily intake of the extracts.Resistence to antidepressant drugs: stu<strong>di</strong>es in animal modelsThe selective serotonin reuptake inhibitors are the drugs of choice in the treatment of depression.However, they are not or only partially effective in a fraction of depressed patients. The reasons aresubstantially unknown, though pharmacogenetic stu<strong>di</strong>es have linked the response to serotonin reuptakeinhibitors to polymorphisms in various genes co<strong>di</strong>ng for serotonin mechanisms, particularly thepromoter of the serotonin transporter molecule. These stu<strong>di</strong>es are therefore aimed to investigate theneurobiological mechanism(s) of resistance to antidepressant drugs in strains of mice carrying109ANNUAL REPORT <strong>2009</strong>
IRFMN<strong>di</strong>fferent isoforms of tryptophan hydroxylase-2, the enzyme responsible for the synthesis of brainserotonin.These stu<strong>di</strong>es are conducted in collaboration with the laboratory of Experimental Psycopharmacology(L. Cervo) and the laboratory of Neurochemistry and Behaviour (R.W. Invernizzi), who will provide abrief description of recent results with the potent serotonin reuptake inhibitors citalopram andparoxetine.Laboratory of Experimental NeurologyRole of inflammatory molecules in ictogenesis and epileptogenesisWe are studying the role of IL-1beta, TNF-alpha and HMGB1 systems in the genesis andpropagation of seizures and in the associated neurodegenerative phenomena. We havedemonstrated that epileptic activity induces the synthesis of these pro-inflammatory moleculesand their specific receptors. In particular, IL-1beta and HMGB1 have proconvulsant actionswhile their receptor antagonist (IL-1Ra, BOX-A, Toll-like receptors inhibitors) or IL-1betasynthesis inhibitors, have anticonvulsant activities. We are actively studying the role of thesemolecules in epilepsy models with the intent of promoting their clinical applications in drugresistantepileptic patients. This possibility is encouraged by the clinical use of some of thesemolecules in chronic inflammatory and autoimmune <strong>di</strong>seases in humans (e.g. anakinra, the IL-1R antagonist). We are studying pharmacological approaches to block IL-1beta- and HMGB1-signaling involved in the proconvulsant effects of these molecules.Epilepsy and postnatal developmentSeizure susceptibility is higher in early infancy although the immature brain appears to be lesssusceptible to epileptogenesis. Using experimental models of seizures induced during postnataldevelopment in rodents, we study the mechanisms involved in age-dependent seizuresusceptibility and the associated neuronal injury. Our stu<strong>di</strong>es are primarily focused oninflammatory pathways, angiogenic processes and blood-brain barrier damage.Blood-brain barrier and epileptogenesisWe are studying BBB permeability and microvasculature changes induced in the brain byseizures or by neurotrauma or infection and how these mo<strong>di</strong>fications may affect the process ofepileptogenesis. Experimental models of symptomatic epilepsy are used.New therapeutic approaches of In vivo gene transferThis study concerns the use of adeno-associated viral vectors to introduce genes withtherapeutic potential in the brain, thus increasing the synthesis of specific proteins to producelong-lasting anticonvulsant effects. We have demonstrated that adeno-associated viral vectorcarrying the human neuropeptide Y gene, significantly increases the brain concentration of thispeptide after its intrahippocampal injection for a prolonged time (at least up to 5 months after asingle intracerebral injection). The rats overexpressing this peptide are less susceptible toseizures. Future development of this study concerns the optimization of the transgene transfertechnology to envisage a possible clinical application.110ANNUAL REPORT <strong>2009</strong>
IRFMNLaboratory of Geriatric NeuropsychiatryPopulation study on the prevalence of dementias in the older-oldParallel to the progressive increase of in<strong>di</strong>viduals aged 80 years or older within the elderlypopulation (65+), the number of demented patients of 80 years or older makes up an everincreasing fraction of the total population affected by dementia. As very often happens,the exclusion from stu<strong>di</strong>es of subjects in the oldest age classes tends to inevitablyunderestimate the total number of in<strong>di</strong>viduals affected by dementia present in thepopulation. To fill this gap, a door-to-door population study on the prevalence, incidence,risk factors and evolution of dementias and age-associated cognitive deficits has been setup in an elderly population aged 80 years or older living in eight small towns of VareseProvince. The study is funded by a grant from the Fondazione Italo Monzino, Milano.Effects of anemia in the elderlyA previous large survey in old resident of Biella (65-84 years old) has been conducted incollaboration with the Local Health Authority of Biella (ASL 12) to determine theprevalence of anemia. We have now extended the investigation to the oldest old residents(about 1500 85 years or older in<strong>di</strong>viduals) in order to estimate the prevalence and impactof mild anemia also in this segment of the elderly population.Evaluating risk profiles in hospitalised elderly subjectsIn collaboration with the Geriatric Division of the Ospedali Regionali of Lugano andMendrisio, Switzerland, hospitalized and ambulatory patients are evaluated from aneuropsychological, functional and mobility point of view to estimate the impact of thesefactors on heath-related outcomes and <strong>di</strong>sease progression.Longitu<strong>di</strong>nal follow-up of in<strong>di</strong>viduals with mild cognitive impairment(MCI)In collaboration with the Geriatric Unit of Ospedali Regionali of Lugano and Mendrisio,Switzerland, the follow-up study of all Mild Cognitive Impairment or QuestionableDementia (CDR 0.5) patients seen at the Memory Clinic of the Hospitals is continuing toestimate the rate of conversion to dementia and to evaluate the possible risk factorsassociated with conversion.Quality of care of terminally ill oncological subjectsIn 1999 we started a collaborative program with the hospice “via <strong>di</strong> Natale FrancoGallini” in Aviano (PN). The aim of the research project was to assess the quality of caregiven in hospice to terminally ill oncological patients at the end of life. Present aim of thecollaboration is the assessment of the hospice activities after its opening and to providenurses with continuous training on use of databank.Randomised controlled trial of the Italian Group for the Study of theSecond Generation Antipsychotics – GISASThe study aims at evaluating efficacy and safety of three antipsychotic drugs - aripiprazole,olanzapine and haloperidol – by a pragmatic design involving a large sample of patients withschizophrenia treated in community psychiatric services across Italy. This is the first largemulticentre trial on this subject ever realized in Italy. The target is to recruit 250 patients. Thirty111ANNUAL REPORT <strong>2009</strong>
IRFMNservices are currently participating and 150 patients already entered the study, among whom 74completed one-year follow-upMonitoring of self-harm and suicide attemptsIn the framework of a wider project financed by the Ministry of Health (Call 2006) and led bythe Public Health Agency of the Lazio Region, the Unit of Epidemiology and Social Psychiatryhas reviewed the scientific literature on the prevalence and determinants of the psychosocialassessment of cases of self-harm and suicide attempts in the emergencies, and enlarged thenetwork of services where the Schedule for Hospital Assessment of Self-Harm and SuicideAttempts is used. Data collection has started in various centres, covering a total of more than 1million inhabitants in various areas of North Italy. More areas have been involved in <strong>di</strong>scussionof the schedule and Ethical Committees contacted. In the Province of Trentino, services foradolescents have adopted the schedule after the necessary mo<strong>di</strong>fications. The Unit is alsoinvolved on a project financed by the Italian Centre for Disease Control, where the schedule willbe further introduced and family practitioners will be trained about depression identification andsuicide risk detection.European Network of Bipolar Research Export CentresENBREC is designed to build an EU-wide network of expert centres specialising in researchand care on bipolar <strong>di</strong>sorders, in order to integrate research efforts on the mechanism of <strong>di</strong>sease,and optimized <strong>di</strong>agnostic and treatment. Common tools and practice, training and informationwill help structuring the European bipolar <strong>di</strong>sorders research community and translate researchoutcome into healthcare. Epidemiology and Social Psychiatry Unit reviewed research fin<strong>di</strong>ngson effective psychosocial interventions and planned, in collaboration with the Department ofMental Health of San Carlo Hospital in Milan, an investigation on use of psychosocialinterventions for bipolar <strong>di</strong>sorders in routine clinical practice. On the basis of the abovementioned research review the implementation of psychoeducation groups for bipolar patients isin progress in the Department of Mental Health of San Carlo Hospital.Quality Evaluation of a Department of Mental Health with the participationof usersThe study investigates the quality of assistance offered to patients with severe mental illnessesand intensively cared by the mental health services, through an instrument developed with ameaningful contribution of users and <strong>di</strong>stributed by them. Various focus groups were hel<strong>di</strong>nvolving 12 users. A sample of 250 patients with severe mental illnesses and intensively caredwere described and the questionnaire was administered by a group of trained patients.Evaluation of an intervention of common psychiatric <strong>di</strong>sorders preventionin schoolsThe intervention delivered by an association for mental health through psychiatrists to studentsof various school types aged 16 years was mo<strong>di</strong>fied in order to include components suggestedby the available literature as evidence based (videos and testimonial). Its efficacy in terms ofinformation, attitudes and help seeking behaviour was tested at end of treatment and after threemonths.Prevalence and incidence of antidepressant prescribing in an agingpopulationThe study investigates prevalence and incidence of antidepressant use and changes in thepatterns of antidepressant prescribing from 2000 to 2007 in the elderly population of a largearea in Lombardy by using a population-based prescription dataset.112ANNUAL REPORT <strong>2009</strong>
IRFMNHoNOS-5 Study: towards the development of a clinically oriente<strong>di</strong>nformative systemThe study was approved by the Italian Health Department (Call 2008) and adopted as outcomemeasure the Health of the Nation Outcome Scale (HoNOS). Its aim is to evaluate the clinicaloutcomes of a cohort of subjects referring to a group of eight Italian mental health services andto create a dataset containing all available information drawing on already operating informativeflows, thus developing a clinically oriented informative system.Michel’s game: a table game for group cognitive-behavioural therapy ofpsychotic symptoms.Cognitive therapies of psychotic symptoms (CBT) have shown a certain efficacy in thetreatment of psychoses. Their sprea<strong>di</strong>ng within naturalistic settings is, however, limited.“Michael’s Game”, a training module for hypothetical reasoning, which comes in the form of agame of cards, is a treatment inspired by CBT approach. It was conceived as a tool to promotethe sprea<strong>di</strong>ng of CBT in natural clinical settings.The Unit coor<strong>di</strong>nates the participation of three centers in Italy to a multi-center internationalnon-profit clinical trial evaluating the effectiveness of “Michael’s Game” program (training toreason with hypotheses) on adult patients who show residual psychotic symptoms.Laboratory of Inflammation and Nervous System DiseasesInhibition of selected aspects of the inflammatory response powerfullyreduces ischemia/reperfusion injuryPrevious stu<strong>di</strong>es of ours have in<strong>di</strong>cated that complement and related inflammatory systems suchas contact/kinin and fibrinolytic systems may represent novel targets for reducingischemia/reperfusion injury. We have shown that C1-INH, a serine-protease inhibitor that actsas a major regulator of both complement and kinin systems, markedly improves neurologicaldeficits and reduces infarct volume in mice with focal transient as well as permanent ischemiainduced by middle cerebral artery occlusion. We have further extended this fin<strong>di</strong>ng defining itseffectivness on <strong>di</strong>fferent strains of mice (<strong>di</strong>splaying <strong>di</strong>fferent levels of complement expression),the time-window and the dose-response curves. Since C1-INH may act on <strong>di</strong>fferent substrates,we have evaluated the specific involvement of the <strong>di</strong>fferent complement pathways and of theother inflammatory systems, ie kinin and coagulation systems. To explore the mechanisms ofC1-INH neuroprotection, we have also investigated the expression (protein and mRNA) ofinflammatory cytokines, adhesion molecules, NO synthase isoforms, apoptosis markers.In sum the results obtained show that: i) C1-INH effectively and markedly reduces brainischemia/reperfusion injury, inducing a decrease of the 90% of the ischemic lesion; ii) C1-INHactions lead to inhibition of cell recruitment, inflammation and apoptosis; iii) a major target ofC1-INH neuroprotection is mannose-bin<strong>di</strong>ng lectin (MBL), a key protein in the complementlectin pathway; iv) C1-INH protective effects can be observed also in traumatic brain injurymodels.Thus C1-INH, which is presently used as replacement therapy in patients with C1-INHdeficiency, possesses potent, multi-faceted neuroprotective actions that may be beneficial inacute brain injury (De Simoni et al. 2003; De Simoni et al. 2004; Storini et al. 2005; Storini etal. 2006, Longhi et al. 2008, Gesuete et al, <strong>2009</strong>). Ongoing stu<strong>di</strong>es are focussed on MBL as anovel target for stroke and traumatic brain injury.113ANNUAL REPORT <strong>2009</strong>
IRFMNStem cells as a therapeutic approach in stroke and traumatic brain injuryIn the past years we have demontrated a beneficial effect of neural stem cells after transientbrain ischemia (Capone et al. 2007, Pastori et al. 2008). However, ethical issues involved instem cell research and the limited availability of most adult stem cells outline the need to lookfor other cell populations. We are presently focussing on stem cells obtained from humanumbilical cord blood that are an easily available source of progenitors with multilineagecapacity and could represent an ideal can<strong>di</strong>date for cell-based therapy after acute brain injury.The aim of the research is to verify the con<strong>di</strong>tions for the effectivenss of Human Umbilical CordBlood Mesenchymal Stem Cells (CB-MSC, in collaboration with Cell Factory, OspedaleMaggiore Policlinico <strong>di</strong> Milano) in reducing the ischemic and traumatic brain injury and toinvestigate the mechanisms triggered by their infusion in the injured brain. CB-MSC are infuse<strong>di</strong>nto the brain ventricle of injured mice. At <strong>di</strong>fferent time points and up to 3 months, severalparameters are evaluated: <strong>di</strong>stribution and phenotype of injected cells, neurodegeneration,behavioral deficits, cytokine and trophic factor gene expression, microglia activation. In ourtraumatic brain injury (TBI) model the results obtained show that CB-MSC: 1) migrate towardsthe contused tissue and survive in the injured brain up to 4 weeks postinjury 2) effectivelydecrease anatomical damge and induce an early and persistent attenuation of functionalimpairments related to sensory/motor activity and cognitive functions up to 6 weeks post-TBI.In our focal ischemia model the results obtained in<strong>di</strong>cate a similar protective effect onsensorymotor functions. Ongoing stu<strong>di</strong>es include: 1) definition of the long term effects onbehavioural and anatomical damage after ischemia 2) evaluation of the trophic effects of CB-MSC and of the reciprocal interaction between CB-MSC and injured environment with specificanalysis of the protective/toxic role of microglia (Capone et al, 2007); 2) definition of themechanisms of homing of stem cells in the injured brain; 3) evaluation of the ability of CB-MSC to <strong>di</strong>fferentiate into functional neural progeny 3 months after transplantation.In vivo real time imaging in ischemic mouse brain by two-photonmicroscopyIschemic stroke triggers vascular responses inclu<strong>di</strong>ng blood flow rearrangements, blood brainbarrier <strong>di</strong>sruption and expression of adhesion molecules that stimulate immune cell infiltration.These mechanims contribute to the progression of the ischemic damage after the acute event andrepresent potential therapeutic targets. In vivo imaging of the brain at cellular resolution in 3Dprovides an ideal tool to get insight of these dynamic events.In collaboration with the Centre For Biophotonics at the Strathclyde University of Glasgow, wehave recently established an original approach by means of two-photon microscopy that allowsthe visualisation and measurement of dynamic events taking place in the brain. Two-photonmicroscope benefits from high-energy electronic transition in a fluorescent molecule due to thecooperation of two low-energy photons, thus enabling imaging over long periods in livinganimals.On-going projects focus on the blood flow dynamics following focal brain ischemia and on thetracking of lymphocytes infiltrated in the ischemic territory. We obtained high detailed imagingand quantification of vascular dynamics and moving lymphocytes in the brain in vivo afterstroke. In particular we: 1) measured the massive vascular rearrangement occurring during andafter ischemia, such as blood flow speed variations and temporal dynamics of extravasationappearance; 2) collected data as number of infiltrated lymphocytes, their track velocity,<strong>di</strong>splacement rate and meandering index thus provi<strong>di</strong>ng a comprehensive description oflymphocyte behaviour in the brain.The final aim of the project will be to elucidate dynamic events associated with the evolution ofischemic damage over time thus provi<strong>di</strong>ng the bases for a rational manipulation of blood supplyand immune responses for therapeutic intervention in stroke.114ANNUAL REPORT <strong>2009</strong>
IRFMNIschemic precon<strong>di</strong>tioning and the blood-brain barrierRecent stu<strong>di</strong>es in<strong>di</strong>cate that cell death resulting from ischemic injury can be reduced when asublethal injurious stimulus or ischemic episode occur hours or days before a severe ischemicinsult. This phenomenon is known as Ischemic PreCon<strong>di</strong>tioning (IPC). Elucidating themechanisms responsible of ischemic precon<strong>di</strong>tioning provides an opportunity to identify theputative can<strong>di</strong>dates that can confer neuroprotection against acute brain injury. A major goal is toidentify the underlying endogenous protective cellular receptor/signaling cascades, with thelong-term goal to allow therapeutic augmentation of the endogenous protective mechanisms incerebral ischemia.Although most attention has focussed on the neuronal effects of IPC, recent stu<strong>di</strong>es have shownthat IPC reduces ischemia-induced cerebrovascular damage. The major goal of the research is toidentify the underlying endogenous protective cellular receptor/signaling cascades, byaddressing the specific role of BBB in cerebral ischemia and precon<strong>di</strong>tioning. To this purposewe have established a bi<strong>di</strong>mensional BBB model by means of co-cultures of mouse brainendothelial cells and glial cells. We are specifically addressing the following aspects: 1)elucidation of BBB involvement in cerebral ischemia and precon<strong>di</strong>tioning in in vivo and in vitromouse models; 2) identification of me<strong>di</strong>ators and/or pathways involved in activation andmaintenance of ischemic tolerance in the cerebrovascular unit; 3) characterization of the effectsand identification of the mechanisms involved in precon<strong>di</strong>tioning induced by <strong>di</strong>fferent stimuli inBBB models; 4) identification of new pathways and molecular targets useful for a potentialtherapeutical stroke treatment.Blood-brain barrier and ischemic precon<strong>di</strong>tioningThe endothelial cells belonging to the cerebral microvasculature are the main component of theBlood-Brain Barrier (BBB). These cells are attached to each other by intercellular TightJunctions and are closely associated with the endfeet of astrocytes, with pericytes and withmicroglia, resulting in a complex network of cellular interactions. The integrity of this structureis essential for the maintenance of the ischemic environment. We have recently established abi<strong>di</strong>mensional BBB model by means of co-cultures of mouse brain endothelial cells and mixedglial cells. These coltures retain the BBB typical features, namely they express thight junctions,they present typical transendothelial electrical resistence (TEER), and paracellular andtranscellular permeability values. To mimic the ischemic insult, the BBB coltures are exposed tooxygen-glucose deprivation (ODG) protocols. The ongoing project is aimed at studying theinvolvement of BBB in ischemic precon<strong>di</strong>tiong (IPC, see previous research topic). Albeit IPChas been reported to reduce edema formation and thus BBB <strong>di</strong>sruption following ischemia, noinformation about a <strong>di</strong>rect role of BBB cells in IPC is presently available. The major goal of theresearch has been to assess if BBB cells may be precon<strong>di</strong>tioned. To this purpose a brief OGDstimulus was delivered before a severe OGD exposure. The results obtained have shown that amild OGD stimulus may actually dampen the effects of a subsequent severe OGD exposureshowing that BBB cells can be effectively precon<strong>di</strong>tioned. Ongoing stu<strong>di</strong>es are presently aimedat identifying me<strong>di</strong>ators and/or pathways involved in activation and maintenance of IPC in thecerebrovascular unit with the final aim of selecting new pathways and molecular targets usefulfor a therapeutic stroke strategies.Laboratory of Molecular NeurobiologyStudy on pathogenic mechanisms of Amyotrophic Lateral SclerosisRole of protein aggregation115ANNUAL REPORT <strong>2009</strong>
IRFMNA pathological feature of ALS is the accumulation of protein aggregates in the perykaria andaxons of motor neurons. Our hypothesis is that this may be due to an impairment of theubiquitin/proteasome system (UPS). To functionally investigate the UPS in ALS motor neuronsin vivo, we crossed SOD1G93A mice with transgenic mice that express a fluorescently-taggedreporter substrate of the UPS (Ub G76V -GFP, from now on in<strong>di</strong>cated as GFP mice). In doubletransgenic GFP/SOD1G93A mice an increase in Ub G76V -GFP reporter, in<strong>di</strong>cative of UPSimpairment, was detectable in a few spinal motor neurons and not in reactive astrocytes ormicroglia, at symptomatic stage but not before symptom onset. These data suggest that UPSimpairment occurs in motor neurons of mutant SOD1-linked ALS mice and may play a role inthe <strong>di</strong>sease progression.Another major route for intracellular protein degradation is the autophagy−lysosomal pathway.The rat microtubule-associated protein 1 light chain 3 (LC3), plays a critical role in theformation of autophagosomes and its conversion from LC3I into LC3II is accepted as a simplemethod for monitoring authophagy. Recently, we have observed that levels of LC3II which isknown to be correlated with the extent of autophagosome formation, was increased inSOD1G93A mice with at an advanced stage of <strong>di</strong>sease compared with non transgenic mice.This in<strong>di</strong>cates that the activation of autophagy may be an alternative mechanism of celldefense to eliminate the proteins misfolded when the proteasome is partially inhibited asdemonstrated above. We are now examining the autophagy at earlier times of the pathology.In collaboration with the Molecular Biochemistry and Pharmacology department we carried outa proteomic analysis of the protein composition of the Triton-insoluble fraction (TIF), as amodel of protein aggregates, from the SOD1G93A mice at <strong>di</strong>fferent <strong>di</strong>sease stages. Weidentified several proteins enriched in TIF of ALS mice already at preclinical stage, inclu<strong>di</strong>nginterme<strong>di</strong>ate filaments, chaperones and mitochondrial proteins. Some of them, HSP90,aconitase, HSC70 and cyclophilin A, were also analyzed in TIF of spinal cord of ALS patientsand found significantly enriched. Interestingly, the majority of proteins in mice and at leastHSP90 in patients were tyrosine nitrated. We therefore investigated the role of nitrative stress inaggregate formation in a cellular model of ALS. We could demonstrate that by inhibiting nitricoxide synthesis it is possible to substantially reduce the amount of insoluble proteins and inparticular of aconitase, HSC70, cyclophilin A and SOD1. In conclusion, the analysis of theinsoluble fractions from cellular/mouse models and human tissues could reveal novel aggregateproneproteins in ALS and suggest that nitrative stress may contribute to protein aggregateformation. These results are in a manuscript submitted to Brain.Role of glutamate AMPA receptors in the pathogenesis of ALSTo further study the role of glutamate AMPA receptors in the susceptibility of motor neuronswe have examined the expression and <strong>di</strong>stribution of GluR2 subunit in motor neurons stillmaintaining a functional connection with muscle fibers. We found a significant decrease ofGlur2 suggesting that this is a very early event that may play an important role in thepathogenesis of the <strong>di</strong>sease. The analysis of all these data are under completion.In vitro stu<strong>di</strong>es on neuron-glia interactionTo investigate further the role of inflammatory mechanisms, we have set up an in vitro cocultureof spinal neurons and astrocytes derived from SOD1G93A mice embryos. We areverifying in this model the alterations observed in vivo such as the activation of TNFalphap38MAPKpathway. This model, hopefully, will allow to examine more rapidly the protectiveeffect of various strategies interfering with this pathway and will provide a model to test newpathogenic mechanisms.Altered axonuclear communication in motor neurons of a mouse model offamilial amyotrophic lateral sclerosis (European collaborative project FP6program EU-NES AXON SUPPORT))116ANNUAL REPORT <strong>2009</strong>
IRFMNImpairment in the maintenance of axon-nuclear communication, and viceversa, due to motorproteins defects may play a primary role in the ALS.To assess this hypothesis we examined the expression and the <strong>di</strong>stribution of <strong>di</strong>fferentcomponents of the nucleocytoplasmic-transport system, such as importins and vimentin, in theventral horn spinal cord and in the peripheral nerves of transgenic mice and rats carrying humanSOD1G93A. We found reduction of importin beta and slight increase of vimentin protein levelsin homogenates from ventral horn spinal cord concomitantly with the appearance of firstsymptoms of the pathology. Using confocal miscroscopy, we detected abnormal accumulationof vimentin in the perikaria of motor neurons at the presymptomatic stage; moreover weobserved a reduction of importin beta staining in the cytoplasm of motor neurons showingaccumulation of phosphorylated neurofilaments, a hallmark of neuronal damage, and defects inretrograde transport. Based on these evidences we suggest that alterations of nucleocytoplasmictransport-related proteins are linked with the degenerative process of motor neurons and mayplay a role in ALS pathology.Therapeutical interventions in mouse model of ALSDevelopment of target genes-based therapies for the protection of motorneuronsIt is emerging evidence that in the motoneurons of patients with spora<strong>di</strong>c ALS and inanimal models of the <strong>di</strong>sease, there is a remarkable activation of pro-degenerativepathways (like p38 MAP-Kinase). On the other side, the mechanisms involved in themodulation of cell survival (like PI3K/Akt pathway) are not activated, thus suggestingan impairment in the induction of neuroprotective responses.These pathways may beconsidered as potential therapeutic targets. Based on these evidences, with this projectwe propose: 1) to develop gene-targeted strategies aimed at counteracting p38 prodegenerativepathway and activating Akt pro-survival cascade inside motorneurons ofspinal cord; 2) to evaluate efficacy and safety of these potential therapeuticinterventions in an animal model of ALS. We have developed lentiviral vectorsexpressing can<strong>di</strong>date p38-targeted shRNA sequences. These shRNAs were tested inprimary mouse astrocyte-motoneuronal cell co-cultures or in cultures of rat corticalneurons. They were able to prevent activation of p38 and its downstream targets afterTNFalpha stimulation, and to reduce neuronal loss after toxic stimuli. In parallel, wehave developed constructs that express constitutively active forms of Akt1 and Akt3(caAkt1 and caAkt3). Preliminary experiments in cell lines showed that either caAkt1 orcaAkt3 efficiently phosphorylates and inhibits downstream pro-apoptotic targets, suchas GSK3beta. Current stu<strong>di</strong>es aim to selectively drive the expression of p38-shRNA andAkt1 to motor neurons and to increase the efficiency of their cellular expression.Stu<strong>di</strong>es on the effects of the long-chain omega-3 polyunsaturated fatty acidseicosapentaenoic acid and docosahexaenoic acid in the G93A SOD1 mouse(This is a project in collaboration with Dr. A. Michael-Titus del Queen Mary Universityof London supported by MND Association) Based on the observations by Dr. A.Michael-Titus that a <strong>di</strong>et enriched of omega 3 is neuroprotective in a model of spinalcord trauma in rat we decided to investigate if such treatment could have a beneficialeffect on SOD1G93A mice. The study is in progress.117ANNUAL REPORT <strong>2009</strong>
IRFMNTreatment with lithium carbonate does not improve <strong>di</strong>sease progression in two<strong>di</strong>fferent strains of SOD1 mutant miceFemale SOD1G93A mice on <strong>di</strong>fferent genetic background and <strong>di</strong>fferent phenotype of<strong>di</strong>sease severity were treated daily with Li 2 CO 3 37mg/kg (1 mEq /kg) i.p. starting fromage 75 days until death. We observed a significant anticipation of the onset and reducedsurvival in 129Sv/G93A and no effect in C57G93A mice treated with lithium ascompared to vehicle treated mice. Moreover, lithium neither exerted neuroprotectiveeffects not increased the expression of LCII and the activity of mitochondrial complexIV in the spinal cord. The present study does not identify any therapeutic orneuroprotective effect of lithium in SOD1G93A female mice. This study is in press inAmyotrophic Lateral Sclerosis.Stu<strong>di</strong>es aimed to identify biomarkers for the <strong>di</strong>agnosis and progression ofthe <strong>di</strong>sease in ALS patientsIn collaboration with the department of Neurology of the Fondazione Salvatore Maugeri,IRCCS, of Pavia, we have started a series of stu<strong>di</strong>es aimed to investigate the immunesystem and the oxidative stress products in the PBMC of spora<strong>di</strong>c ALS patients incomparison to healthy age matched controls. The results show that spora<strong>di</strong>c ALSpatients exhibit immunological alterations in their blood, in respect to healthy controls.This study strengthens the hypothesis of an involvement of the adaptive immune systemassociated with a neuroinflammatory process in the pathobiology of ALS. Themanuscript describing these data is under revision for the J. of Neuroimmunology.In parallel, we are examining the levels and the characterisation of the nitrated proteinin the PBMC of ALS patients compared to healthy controls. We also evaluated thePBMC of SOD1G93A transgenic rats. The protein nitration on tyrosine is an oxidativemechanism that alters the function of proteins inducing their inactivation or a gain oftoxic functions. Using a proteomic approach we have observed that a series of proteinsare overnitrated in ALS patients and in SOD1G93A rats in respect to controls. Someproteins are the same in rat and patients suggesting that they could be a reliablebiomarkers for the <strong>di</strong>agnosis and prognosis of the <strong>di</strong>sease. These data are in amanuscript under revision for the Antioxidant and Redox Signalling.Another approach to identify potential specific <strong>di</strong>agnostic and prognostic markers ofthe <strong>di</strong>sease has been set up in collaboration with the department of neurology of the<strong>Istituto</strong> Auxologico , IRCCS of Milano. In particular, we have used genomic andproteomic analyses to identify and characterize genes and proteins specifically mo<strong>di</strong>fie<strong>di</strong>n the muscles of ALS transgenic mouse models, at the onset of <strong>di</strong>sease, in respect tocontrol mice. We have completed the examinations and the data are now under analysis.Laboratory of Experimental PsychopharmacologyDrug AbuseNeural basis of drug self-administrationTo separate the <strong>di</strong>rect pharmacological effects of cocaine from those associated withactive drug self-administration we employed a yoked control-operant para<strong>di</strong>gm an<strong>di</strong>nvestigated the expression of well established markers of the rapid action of cocaine,i.e. the inducible early genes and trophic factors, in rats after a single intravenous (i.v.)118ANNUAL REPORT <strong>2009</strong>
IRFMNcocaine self-administration session. Animals self-administering cocaine <strong>di</strong>d more activelever-presses than yoked-cocaine (YC) and yoked-vehicle (YV) animals. This goalorientedbehavior was accompanied by a selective increase in Arc mRNA levels in theme<strong>di</strong>al prefrontal cortex (mPFC). These fin<strong>di</strong>ngs demonstrate that a single session ofcocaine i.v. self-administration is sufficient to shape rat behavior towards goal-<strong>di</strong>rectedbehaviors and selectively up-regulate Arc expression in mPFC (of SA animals),provi<strong>di</strong>ng the first evidence that the mPFC's function is already profoundly influencedby the first voluntary cocaine exposure. Ongoing stu<strong>di</strong>es are evaluating whether thiseffect is peculiar to cocaine or common to other drugs of abuse.GHB mechanism of actionGamma-hydroxybutyric acid (GHB) is an endogenous brain substance that has <strong>di</strong>verseneuropharmacological actions, inclu<strong>di</strong>ng rewar<strong>di</strong>ng properties in <strong>di</strong>fferent animalspecies and in humans. As other drugs of abuse, GHB affects the firing of ventraltegmental neurons (VTA) in anaesthetized animals and hyperpolarizes dopaminergicneurons in VTA slices. We investigated the effects of various doses of intravenousGHB in maintaining self-administration and its ability to induce con<strong>di</strong>tioned placepreference (CPP) in rats when given orally or injected <strong>di</strong>rectly either in the VTA orNAc. Our results in<strong>di</strong>cate that GHB <strong>di</strong>d not maintained self-administration, while givenorally induced CPP. CPP was also observed when GHB was injected in the VTA butnot in the NAc. Together with recent in-vitro fin<strong>di</strong>ngs, these results suggest that therewar<strong>di</strong>ng properties of GHB mainly occur via <strong>di</strong>sinhibition of VTA dopaminergicneurons.Neural basis of “drug craving” and “relapse” in the drug abuseassumptionDrug craving, defined as “the desire to experience the effect(s) of a previouslyexperienced psychoactive substance” is a car<strong>di</strong>nal feature of drug ad<strong>di</strong>ction and isclinically significant because of its potential link to relapse. To provide usefulin<strong>di</strong>cations to the development of novel therapeutic approaches to prevent the use andabuse and the relapse of drug assumption following the outcome of “craving”, weelaborated experimental models of self-administration and “relapse” induced bycocaine, nicotine and alcohol-associated cues, after a period of abstinence. Ongoingstu<strong>di</strong>es are evaluating the role of several neurochemical mechanisms potentiallyinvolved in the drug-seeking behavior.Resistance to antidepressant drugs: experimental and clinical stu<strong>di</strong>esThis project arises from a collaboration between the laboratories of Neurochemistry andBehavior (R.W. Invernizzi), Drug Metabolism (Silvio Caccia), Biology ofNeurodegenerative Disorders (GianLuigi Forloni) and focus on behavioral andbiochemical characterization of an experimental model of resistance to theantidepressant drugs.Using an animal model pre<strong>di</strong>ctive of the antidepressant activity, the effects of selectiveserotonin reuptake blockers (SSRI) was evaluated in several mice strains. It was foundthat DBA/2J and BALB/c do not respond to the antidepressant-like activity of the SSRI.The lack of effect was attributed to genotype-dependent impairment of 5-HT synthesis119ANNUAL REPORT <strong>2009</strong>
IRFMNsince DBA/2J and BALB/c carring a single nucleotide polymorphism (C1473G mice) inthe gene for the brain-specific isoform of tryptophan hydroxylase-2, the rate-limitingenzyme in the synthesis of serotonin are characterized by a decreased serotoninsynthesis. This hypothesis seems to be supported by the observation that DBA/2J andBALB/c mice had less <strong>di</strong>alysate 5-HT in the me<strong>di</strong>al prefrontal cortex and dorsalhippocampus than C57BL/6J mice. Moreover, in DBA/2J and BALB/c the SSRI raisedsignificantly less extracellular 5-HT when compared to C57BL/6J mice. More recentlyit was found that 5-HT 1A and 5-HT 2C receptor antagonists restored the SSRIs’ effect oneither the antidepressant-like activity and the extracellular 5-HT.Laboratory of Neurochemistry and Behavior“Resistance” to antidepressant drugsIn collaboration with the Laboratories of “Experimental Psychopharmacology” and“Drug Metabolism” we set up a murine model of resistance to antidepressant drugsbased on the comparison between mice strains in the forced swimming test (FST), abehavioural procedure widely used to screen potential antidepressant compounds Weshowed that mice carrying a genetic mutation of the brain-specific isoform oftryptophan hydroxylase-2, the rate-limiting enzyme in the synthesis of serotonin, <strong>di</strong>d notrespond to antidepressants inhibiting selectively the reuptake of serotonin (SSRI). In<strong>2009</strong> we found that in “non-responder” mice serotonergic autoregulatory feedbackmechanisms are defective. Particularly, we found that 5-HT 2C receptors are overactive.Blockade of 5-HT 2C receptors with a selective antagonist restored the effects of SSRI.These results suggest that overactive feedback control suppresses the effects of SSRIand identify pharmacological strategies that may enhance the response in treatmentresistantdepressed patients.Animal model of cognitive deficit of schizophrenia; typical and atypicalantipsychoticsThe cognitive deficit is a core symptom of schizophrenia, which has been linked tofunctional outcome and is relatively independent of psychotic symptoms. Theantipsychotics, either typical or atypical, are able to control positive symptoms such asdelirium, hallucinations and paranoia. However, the currently available atypicalantipsychotics when compared to conventional antipsychotics show somewhat superiorefficacy for the management of cognitive deficits in patients with schizophrenia.The cognitive deficit of schizophrenia was modelled in rats and mice, by using a test ofattention such as the 5-choice serial reaction time task (5-CSRTT) and injections ofglutamate NMDA receptor antagonists into the me<strong>di</strong>al prefrontal cortex (mPFC). Thismodel makes clear links with psychopathology as dysfunctional glutamateneurotransmission in the mPFC has been implicated in cognitive deficits ofschizophrenia and the 5-CSRTT is the rat analogue of the continuous performance testused to assess attention and vigilance in schizophrenic patients.Antipsychotics possess a complex pharmacology across the biogenic amine receptorfamilies as shown by affinity constants derived from ra<strong>di</strong>oligand-bin<strong>di</strong>ng techniques.The ability to antagonise the DA D 2 receptor function is shared by the conventional andby the atypical antipsychotics. However, atypical antipsychotics show a high affinityalso for serotonin 5-HT 2A , 5-HT 2C and 5-HT 1A receptors. Our stu<strong>di</strong>es compared the120ANNUAL REPORT <strong>2009</strong>
IRFMNeffects of conventional and atypical antipsychotics in this model of cognitive deficit ofschizophrenia. The results show that antipsychotics may be <strong>di</strong>fferentiated by a selectiveeffect of typical antipsychotics on compulsive perseveration, and atypical antipsychoticson impulsivity. Biochemical stu<strong>di</strong>es show that attentional deficits induced by NMDAreceptor antagonists are associated with excessive glutamate in the me<strong>di</strong>al prefrontalcortex of the rat and activation of the transcription factor CREB in the dorsal striatum.121ANNUAL REPORT <strong>2009</strong>
IRFMN122ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF CARDIOVASCULARRESEARCHSTAFFHeadMaria Grazia FRANZOSI, Biol.Sci.D.Laboratory of Car<strong>di</strong>ovascular Clinical PharmacologyHeadRoberto LATINI, M.D.Bio-imaging UnitHeadCar<strong>di</strong>ovascular Endocrine UnitHeadTissue Culture UnitHeadFabio FIORDALISO, Biol.Sci.D.Serge MASSON, Ph.D.Giovanna BALCONI, BSc.Laboratory of Clinical Drug EvaluationHeadMaria Grazia FRANZOSI, Biol.Sci.D.Bioinformatics UnitHeadEnrico NICOLISLaboratory of General Practice ResearchHeadMaria Carla RONCAGLIONI, Biol.Sci.D.Laboratory of Me<strong>di</strong>cal StatisticsHeadSimona BARLERA, Dr.Sci.Pol., MSc.Laboratory of Clinical PharmacologyHeadNursing Research UnitHeadGianni TOGNONI, M.D.Paola DI GIULIO, R.N., MSc123ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAMaria Grazia Franzosi got her Biological Science degree in 1972 at the University of Milan.Education1972 Doctoral degree in Biological Sciences, University of Milan, Italy1978 Postdoctoral degree in Pharmacological Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong><strong>Negri</strong>” <strong>di</strong> Milano, ItalyMain fields of activityCoor<strong>di</strong>nation of multicentric randomised clinical trials. Relationship between genetic and environmental riskfactors in coronary events. Pharmacogenetics. Car<strong>di</strong>ovascular genetic epidemiology. Pharmacoeconomics.Drug Epidemiology and Post-Marketing Surveillance.Positionfrom 2002 Director of the Department of Car<strong>di</strong>ovascular Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong>"<strong>Mario</strong> <strong>Negri</strong>", Milano, Italyfrom 2005 Member of the Coor<strong>di</strong>nating Committee of Master course in Clinical Research – University ofMilanofrom 2004 Member of Steering Committee, Stu<strong>di</strong>o GISSI-AF Study, Milano, Italyfrom 2001from 1998Member of Steering Committee, Stu<strong>di</strong>o GISSI-HF Study, Milano, ItalyMember of Steering Committee of the PROCARDIS Research Programme - A genome-widestrategy to identify susceptibility loci in precocious coronary artery <strong>di</strong>sease - University ofOxford, UKfrom 1997 Member of “Antithrombotic Trialists’ Collaboration”, Oxford, UKfrom 1996 Member of the Steering Committee e National Coor<strong>di</strong>nator for Italy of the Organization toAssess Strategies for Ischemic Syndromes (OASIS-2, OASIS-4 CURE, MichelangeloOASIS-5 e OASIS 6, , CURRENT OASIS-7, FUTURA OASIS-8), of the INTER-HEARTstudy and of the ACTIVE, RELY and AVERROES stu<strong>di</strong>es, Population Health ResearchInstitute, McMaster University, Hamilton, Canada1994-1996 Director of European Coor<strong>di</strong>nating Centre and Member of Steering Committee, Collaborativefrom 1993from 2002Organization for RheothRx Evaluation (CORE), McMaster University, Hamilton, CanadaMember of Steering Committee, Stu<strong>di</strong>o GISSI-Prevenzione, Milano, ItalyMember of “Fibrinolytic Therapy Trialists’s Collaboration”, Oxford, UK e del “CollaborativeGroup on Angiotensin Converting Enzyme Inhibitors Trials”, National Institutes of Health,Bethesda, Washington, USA1989-2001 Head of the Laboratory of Clinical Drug Evaluation, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong><strong>Negri</strong>"1985-1988 Head of the Clinic Drug Evaluation Unit of the Laboratory of Clinical Pharmacology, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>"from 1984Member of the Scientific and Organising Secretariat, Gruppo Italiano per lo Stu<strong>di</strong>o dellaSopravvivenza nell'Infarto Miocar<strong>di</strong>co (GISSI-1, GISSI-2, GISSI-3 stu<strong>di</strong>es) Milano, Italy1975-1984 Researcher at the Laboratory of Clinical Pharmacology, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong>"<strong>Mario</strong> <strong>Negri</strong>" and at the Regional Center for Drug Information of the Lombardy RegionSelected publications• Chio<strong>di</strong>ni B, Franzosi MG, Barlera S, Signorini S, Lewis CM, D'Orazio A, Mocarelli P, Nicolis E, Marchioli R, TognoniG, on behalf of the GISSI Investigators, SIBioC-GISSI Prevenzione Group. Apolipoprotein E polymorphisms influenceeffect of pravastatin on survival after myocar<strong>di</strong>al infarction in a Me<strong>di</strong>terranean population: the GISSI-Prevenzione study.Eur Heart J 2007 ; 28: 1977-1983• Anand SS, Islam S, Rosengren A, Franzosi MG, Steyn K, Yusufali AH, Keltai M, Diaz R, Rangarajan S, Yusuf S, onbehalf of the INTERHEART Investigators. Risk factors for myocar<strong>di</strong>al infarction in women and men: insights from theINTERHEART study. Eur Heart J 2008 29 : 932-940• Broadbent HM, Peden JF, Lorkowski S, Goel A, Ongen H, Green F, Clarke R, Collins R, Franzosi MG, Tognoni G,Seedorf U, Rust S, Hamsten A, Farrall M, Watkins H, for the PROCARDIS Consortium. Susceptibility to coronaryartery <strong>di</strong>sease and <strong>di</strong>abetes is encoded by <strong>di</strong>stinct, tightly linked, SNPs in the ANRIL locus on chromosome 9p. HumMol Genet 2008; 17: 806-814• GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of n-3 polyunsaturated fatty acids in patients with chronic heartfailure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223-1230• GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HFtrial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1231-1239• Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D,Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R,124ANNUAL REPORT <strong>2009</strong>
IRFMNWatkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level andcoronary <strong>di</strong>sease. N Engl J Med <strong>2009</strong>; 361: 2518-2528• GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, MaggioniAP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med <strong>2009</strong>;360: 1606-1617Simona Barlera got her degree in Political Science, area Statistics at the “Università degli Stu<strong>di</strong> <strong>di</strong>Milano” in Milano in 1992, followed by a master in Me<strong>di</strong>cal Statistics at the London School of Hygieneand Tropical Me<strong>di</strong>cine, “University of London” in 1998.Education and training1987-1992 Degree in Political Science, course of stu<strong>di</strong>es Statistics, Università degli Stu<strong>di</strong> <strong>di</strong> Milano,Milano (Italy)1993-1995 Post-degree Specialization in Pharmacological Research. School of Specialization inPharmacological Research Of Lombar<strong>di</strong>a Region, Milan1997-1998 Master of Science in Me<strong>di</strong>cal Statistics at the London School of Hygiene and TropicalMe<strong>di</strong>cine, University of London, London.1998-1999 Visiting Scientist in the Department of Statistical Genetics, Wellcome Trust Centre forHuman Genetics, University of Oxford (UK).Main fields of activityMethodology of Clinical Trials in the car<strong>di</strong>ovascular field. Preparation and viewing of research protocols,planning and conduct of statistical analyses and the reporting of fin<strong>di</strong>ngs on scientific journals.Genetic epidemiology: genome-wide strategies (linkage analysis) to identify susceptibility genes incoronary artery <strong>di</strong>sease; case-control stu<strong>di</strong>es in order to identify can<strong>di</strong>date genes involved in thecar<strong>di</strong>ovascular pathology.Position Heldfrom Oct 2006Head of the Laboratory of Me<strong>di</strong>cal Statistics, Department of Car<strong>di</strong>ovascular Research,<strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, Italy1999 -2006 Head of the Me<strong>di</strong>cal Statistics Unit, Department of Car<strong>di</strong>ovascular Research, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, Italy1992-1997 Researcher in the Unit of Applied Statistics and Information Technology, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalySelected publications• Barlera S, Specchia C, Farrall M, Chio<strong>di</strong>ni BD, Franzosi MG, Rust S, Green F, Nicolis E, Peden J, Assmann G, CollinsR, Hamsten A, Tognoni G, PROCARDIS Consortium. Multiple QTL influence the serum Lp(a) concentration: agenome-wide linkage screen in the PROCARDIS study. Eur J Hum Genet 2007; 15: 221-227• GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of n-3 polyunsaturated fatty acids in patients with chronic heartfailure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223-1230• GISSI-HF Investigators (Writing Commitee:Tavazzi L, Maggioni A P, Marchioli R, Barlera S, Franzosi M G, Latini R,Lucci D, Nicolosi G L, Porcu M, Tognoni G) Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HFtrial): a randomised, double-blind, placebo-controlled trial. Lancet 2008 372: 1231-1239• Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D,Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R,Watkins H, Farrall M, for the PROCARDIS Consortium. Genetic variants associated with Lp(a) Lipoprotein Level andCoronary Disease. N Engl J Med <strong>2009</strong>; 361: 2518-2528• GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, MaggioniAP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med <strong>2009</strong>;360: 1606-1617• Malarstig A, Buil A , Souto JC, Clarke R, Blanco-Vaca F , Fontcuberta J, Peden J, Andersen M, Silveira A, Barlera S,Seedorf U, Watkins H, Almasy L, Hamsten A, Soria JM ,on behalf of the Genetic Analysis of I<strong>di</strong>opathic Thrombophilia(GAIT) and Precocious Coronary Artery Disease (PROCARDIS) consortia. Identification of ZNF366 and PTPRD asnovel determinants of plasma homocysteine in a family-based genome-wide association study. Blood <strong>2009</strong>; 114: 1417-1422Roberto Latini got his Me<strong>di</strong>cal Doctor degree in 1978 at the University of Milan.Education1970-1978 University of Milan School of Me<strong>di</strong>cine, degree in Me<strong>di</strong>cine1981-1983 Merck Sharp & Dohme International Fellow in Clinical Pharmacology125ANNUAL REPORT <strong>2009</strong>
IRFMNMain fields of activityMechanisms of car<strong>di</strong>ac damage following ischemia, with focus on eurohumoral activation. Use of stemcells for car<strong>di</strong>ac repair. Biohumoral investigations within large scale clinical trials in heart failure andatrial fibrillation.Positionsfrom 1990 Head of the Car<strong>di</strong>ovascular Clinical Pharmacology Laboratory (Car<strong>di</strong>ovascular ResearchDepartment) <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milan, Italyfrom 2001 Member of the GISSI-HF Steering Committeefrom 2004 Member of the GISSI-AF Steering Committeefrom 2005 Member of the CandHeart Steering Committee1999-<strong>2009</strong> Visiting Professor Dept of Me<strong>di</strong>cine, New York Me<strong>di</strong>cal College, Valhalla, NY, USA1981-1983 Car<strong>di</strong>ology Fellow (Dr. R. E. Kates, Laboratory) Stanford University Me<strong>di</strong>cal Center,CA, USA1976-1981 Member of the Sub-Group RMs for Drugs (Community Bureau of Reference,Commission of the European Communities)1973-1990 Fellow at the Laboratory of Clinical Pharmacology of the <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalySelected publications• Latini R, Masson S, Anand I S, Missov E, Carlson M, Vago T, Angelici L, Barlera S, Parrinello G, Maggioni A P,Tognoni G, Cohn J N, Val-HeFT Investigators. Prognostic value of very low plasma concentrations of troponin T inpatients with stable chronic heart failure. Circulation 2007; 116: 1242-1249• Masson S, Latini R, Anand IS, Barlera S, Angelici L, Vago T, Tognoni G, Cohn J N, for the Val-HeFT Investigators.Prognostic value of changes in N-termianl pro-brain natriuretic peptide in the Val-HeFT (Valsartan Heart Failure Trial).J Am Coll Car<strong>di</strong>ol 2008; 52: 997-1003• Salio M, Chimenti S, De Angelis N, Molla F, Maina V, Nebuloni M, Pasqualini F, Latini R, Garlanda C, Mantovani A.Car<strong>di</strong>oprotective function of the long pentraxin PTX3 in acute myocar<strong>di</strong>al infarction. Circulation 2008; 117: 1055-1064• Galvez BG, Covarello D, Tolorenzi R, Brunelli S, Dellavalle A, Crippa S, Mohammed SAA, Scialla L, Cuccovillo I,Molla F, Staszewsky L, Maisano F, Sampaolesi M, Latini R, Cossu G. Human car<strong>di</strong>ac mesoangioblasts isolated fromhypertrophic car<strong>di</strong>omyopathies are greatly reduced in proliferation and <strong>di</strong>fferentiation potency. Car<strong>di</strong>ovasc Res <strong>2009</strong>, 83:707-716• GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, MaggioniAP, Lucci D, Di Pasquale G, Tognoni G), Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med <strong>2009</strong>;360: 1606-1617• Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, Caspani L, Raimon<strong>di</strong> F, Bordone G, Iapichino G,Mancebo J, Guerin C, Ayzac L, Blanch L, Fumagalli R, Tognoni G, Gattinoni L, for the Prone-Supine II Study Group.Prone positioning in patients with moderate and severe acute respiratory <strong>di</strong>stress syndrome. A randomized controlledtrial. JAMA <strong>2009</strong>; 302: 1977-1984Maria Carla Roncaglioni got her Biological Science degree in 1987 at the University of Milan.Education1987 Doctoral degree in Biological Sciences, University of Milan, Italy1982-1983 “Research Fellow” at the Dept. of Biochemistry, Faculty of Me<strong>di</strong>cine, Rijksuniversiteit ofLimburg, Maastricht , The Netherland (Prof. C.Hemker);1998-1999 “Visiting Scientist” at the Car<strong>di</strong>ovascular Research Unit, Hammersmith Hospital, London,UK (Prof. A. Maseri)Main fields of activityCoor<strong>di</strong>nation of multicenter clinical trials and observational stu<strong>di</strong>es in <strong>di</strong>fferent car<strong>di</strong>ovascular areas(neurological, angiological, car<strong>di</strong>ological). Coor<strong>di</strong>nation of a network of more than 1000 GPs activelyinvolved in epidemiological and experimental stu<strong>di</strong>es in the prevention of car<strong>di</strong>ovascular <strong>di</strong>seases.Positionfrom 2001 Head of the Laboratory for General Practice Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong>"<strong>Mario</strong> <strong>Negri</strong>", Milano, Italyfrom 1989 Senior Researcher in the Clinical Pharmacology Laboratory, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, Italyfrom 1974 Researcher in the Laboratory for the Study of Haemostasis and Thrombosis, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, Italy126ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Tognoni G, Avanzini F, Pangrazzi J, Roncaglioni M C, Bertele V, de Gaetano G, Caimi V, Tombesi M, Colombo Fabio,Barlera S, PPP - Primary Prevention Project. Low-dose aspirin and vitamin E in people at car<strong>di</strong>ovascular risk: Arandomized trial in general practice. Lancet 2001; 357: 89-95• Sacco M, Pellegrini F, Roncaglioni MC, Avanzini F, Tognoni G, Nicolucci A, PPP - Primary Prevention Project.Primary prevention of car<strong>di</strong>ovascular events with low-dose aspirin and vitamin E in type 2 <strong>di</strong>abetic patients. Results ofthe Primary Prevention Project (PPP) trial. Diabetes Care 2003; 26: 3264-3272• Roncaglioni MC, Avanzini F, Roccatagliata D, Monesi L, Tamayo-Benitez D, Tombesi M, Caimi V, Longoni P, LauriD, Barlera S, Tognoni G, Collaborative Group Risk Prevention Study. How general practitioners perceive and grade thecar<strong>di</strong>ovascular risk of their patients Eur J Car<strong>di</strong>ovasc Prev Rehabil 2004; 11: 233-238• Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi J, Tognoni G, Brown DL. Aspirin for the primary prevention ofcar<strong>di</strong>ovascular events in women and men: A sex-specific meta-analysis of randomized controlled trials. JAMA 2006;295: 306-313• Montalvo G, Avanzini F, Anselmi M, Pran<strong>di</strong> R, Ibarra S, Marquez M, Armani D, Moreira J M, Caicedo C, RoncaglioniMC, Colombo Fabio, Camisasca P, Milani V, Quimi' S, Gonzabay F, Tognoni G. Diagnostic evaluation of people withhypertension in low income country: cohort study of "essential" method of risk stratification. BMJ 2008;337: a1387• Antithrombotic Trialists' (ATT) Collaboration, Roncaglioni MC. Aspirin in the primary and secondary prevention ofvascular <strong>di</strong>sease: collaborative meta-analysis of in<strong>di</strong>vidual participant data from randomised trials. Lancet <strong>2009</strong>; 373:1849-1860Gianni Tognoni got his Me<strong>di</strong>cal Doctor in 1970, University of Milan.Main areas of methodologyRandomized clinical trials; outcomes stu<strong>di</strong>es; pharmacoepidemiology; pharmacoeconomics;epidemiological monitoring and assessment of health care systems, drug policy; genetic epidemiology;community epidemiology; transfer of technology; health and human rights.Main clinical areasAcute and chronic CV <strong>di</strong>seases; psychiatry; aging; intensive care; neurodegenerative <strong>di</strong>sordes; hematooncology.Positionfrom 2004 Member, Commission of Human Experimentation of the Italian Drug Agency (AIFA)2001-2003 Member, Commissione Unica del Farmaco (CUF), Ministry of Healthfrom 2002 Director, Consorzio <strong>Mario</strong> <strong>Negri</strong> Sud, S. Maria Imbaro, Chieti.1996-2002 Coor<strong>di</strong>nator, Department of Car<strong>di</strong>ovascular Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong>"<strong>Mario</strong> <strong>Negri</strong>", Milanofrom 1990 Co-Director, Scuola Superiore <strong>di</strong> Ricerca in Me<strong>di</strong>cina Generale (CSeRMEG)from 1976 Foun<strong>di</strong>ng member of the International Society of Drug Bulletins (ISDB)Coor<strong>di</strong>nator, Commission of Human Experimentation, Regione Lombar<strong>di</strong>afrom 1983 Founder and in the E<strong>di</strong>torial Board of the nursing research Journal Rivistadell'Infermiere/Assistenza Infermieristica e Ricercafrom 1977 Consultant to WHO and other UN agencies for drug selection and policy; training inmethods of clinical and epidemiological research in developing countries mainly in LatinAmerica and Africa1976-1999 Head, Laboratory of Clinical Pharmacology of the <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong>from 1975"<strong>Mario</strong> <strong>Negri</strong>", MilanoHead, Regional Centre for Drug Information (CRIF), Regione Lombar<strong>di</strong>a, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano1969-1974 Research Assistant, Laboratory of Clinical Pharmacology, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", MilanoSelected publications• Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, Marilus R, Villegas A, Tognoni G, Barbui T.Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J. Clin. Oncol. 2005; 23: 2224-2232• Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention ofcar<strong>di</strong>ovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA. 2006 Jan18;295(3):306-13. Erratum in: JAMA. 2006 May 3;295(17):2002• Strippoli GF, Tognoni G, Navaneethan SD, Nicolucci A, Craig JC. Haemoglobin targets: we were wrong, time to moveon. Lancet 2007;369:346-350• GISSI-HF Investigators (Writing Committee: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,Lucci D, Nicolosi GL, Porcu M, Tognoni G). Effect of n-3 polyunsaturated fatty acids in patients with chronic heartfailure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008; 372: 1223-1230127ANNUAL REPORT <strong>2009</strong>
IRFMN• GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L, MaggioniAP, Lucci D, Di Pasquale G, Tognoni G). Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med <strong>2009</strong>;360: 1606-1617• Maggioni AP, Fabbri G, Lucci D, Marchioli R, Franzosi MG, Latini R, Nicolosi GL, Porcu M, Cosmi F, Stefanelli S,Tognoni G, Tavazzi L, on behalf of the GISSI-HF Investigators. Effects of rosuvastatin on atrial fibrillation occurrence:ancillary results of the GISSI-HF trial. Eur Heart J <strong>2009</strong>; 30: 2327-2336Giovanna Balconi got her degree at the School for Technicians of Biome<strong>di</strong>cal Institutes of theUniversity of Milan, with a specialisation in Histology in the Pathological Anatomy Laboratory of thesame University (1968).Main fields of interestIsolation, culture and characterization of peripheral blood circulating progenitor cells of patients withheart failure. Isolation, culture and characterization of peripheral blood circulating progenitor cells inrodents affected by <strong>di</strong>abetic car<strong>di</strong>omyopathy. “In vitro” culture and characterization of stem cells forrepair of myocar<strong>di</strong>al infarction in experimental animal models.Positionsfrom July 2005 Head of Tissue Culture Unit, Car<strong>di</strong>ovascular Clinical Pharmacology Laboratory,<strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalyOct 1995 - June 2005 Head of Tissue Culture Unit, Vascular Biology Laboratory, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalyDec 1983 - Oct 1995 Head of Tissue Culture Unit, Anticancer Chemotherapy Laboratory, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalyOct 1968 - Nov 1983 Researcher, Anticancer Chemotherapy Laboratory, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalySelected publications• Cattelino A, Liebner S, Gallini R, Zanetti A, Balconi G, Corsi A, Bianco P, Wolburg H, Moore R, Oreda B, Kemler R,Dejana E. The con<strong>di</strong>tional inactivation of the beta-catenin gene in endothelial cells causes a defective vascular patternand increased vascular fragility. J Cell Biol 2003; 162: 1111-1122• Cusella De Angelis MG, Balconi G, Bernasconi S, Zanetta L, Boratto R, Galli D, Dejana E, Cossu G. Skeletal myogenicprogenitors in the endothelium of lung and yolk sac. Exp Cell Res 2003; 290: 207-216• Galli D, Innocenzi A, Staszewsky L, Zanetta L, Sampaolesi M, Bai A, Martinoli E, Carlo E, Balconi G, Fiordaliso F,Chimenti S, Cusella G, Dejana E, Cossu G, Latini R. Mesoangioblasts, vessel-associated multipotent stem cells, repairthe infarcted heart by multiple cellular mechanisms. A comparison with bone marrow progenitors, fibroblasts, andendothelial cells. Arterioscler Thromb Vasc Biol 2005; 25: 692-697• Sarto P, Balducci E, Balconi G, Fiordaliso F, Merlo L, Tuzzato G, Pappagallo GL, Frigato N, Zanocco A, Forestieri C,Azzarello G, Mazzucco A, Valenti M T, Alborino F, Noventa D, Vinante O, Pascotto P, Sartore S, Dejana E, Latini R.Effects of exercise training on endothelial progenitor cells in patients with chronic heart failure. J Card Fail 2007; 13:701-708• Galvez BG, Sampaolesi M, Barbuti A, Crespi A, Covarello D, Brunelli S, Dellavalle A, Crippa S, Balconi G, CuccovilloI, Molla F, Staszewsky L, Latini R, DiFrancesco D, Cossu G. Car<strong>di</strong>ac mesoangioblasts are committed, self-renewableprogenitors, associated with small vessels of juvenile mouse ventricle. Cell Death Differ 2008; 15: 1417-1428• Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, Angelici L,Masson S, Mohammed SAA, Dejana E, Gorini M, Zeiher AM, Latini R, GISSI-HF Investigators. Levels of circulatingpro-angiogenic cells pre<strong>di</strong>ct car<strong>di</strong>ovascular outcomes in patients with chronic heart failure. J Car<strong>di</strong>ac Fail <strong>2009</strong>; 15: 747-755Paola Di Giulio got her Nursing Diploma at the Nursing School of <strong>Istituto</strong> Nazionale dei Tumori inMilano and her Master in Oncology Nursing at Guildford University (UK) in 1995.Main fields of activityCoor<strong>di</strong>nation of multicentre and observational stu<strong>di</strong>es in car<strong>di</strong>ology and palliative care. Coor<strong>di</strong>nation ofnursing networks.Positionfrom March 2001 Associated professor at the Turin University.from 1997 Responsible of the Nursing Research Unitfrom 1995 Senior researcher of the Car<strong>di</strong>ovascular Research Departmentfrom 1989 Consultant of the Clinical Phrmacology Laboratorysince 1998 Coor<strong>di</strong>nator of the E<strong>di</strong>torial Board of Assistenza Infermieristica e Ricerca128ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Saiani L, Di Giulio P, Gruppo PARI-FV (Percorsi Assistenziali e Ricerca Infermieristica-Farmaco Vigilanza).Epidemiologia dei problemi assistenziali legati a farmaci e presi<strong>di</strong> in RSA e <strong>di</strong>stretto. Assistenza Infermieristica eRicerca 2007; 26: 123-164• Lepore V, Cecchetto G, Di Giulio P, Saiani L, Samarelli V, Saugo M, Romero M, Scurti V, Tognoni G, Valerio M. Etàanziana-molto-anziana, e “aspettativa <strong>di</strong> vita”? Assistenza Infermieristica e Ricerca 2007; 26: 234-242• Di Giulio P, Toscani F, Villani D, Brunelli C, Gentile S, Spa<strong>di</strong>n P. Dying with advanced dementia in long-term caregeriatric institutions: a retrospective study. J Palliat Med 2008; 11: 1023-1028• Amodeo R, De Ponti A, Sorbara L, Avanzini F, Di Giulio P, De Martini M. Come aumentare le conoscenze dei pazienticon car<strong>di</strong>opatia ischemica sulla loro malattia? Utilità <strong>di</strong> un incontro educazionale tenuto da infermieri. G Ital Car<strong>di</strong>ol<strong>2009</strong>; 10: 249-255• Di Giulio P, Pera C, Scarano M, Ferri B, Lepore V, Miani D, Tognoni G. Rapporto finale dello stu<strong>di</strong>o QDF (Qualità <strong>di</strong>vita, Depressione e Funzioni cognitive) nei pazienti con scompenso car<strong>di</strong>aco. Assistenza Infermieristica e Ricerca <strong>2009</strong>;28: 5-38• Toscani F, Di Giulio P, Campi R, Pellerin I, De Luca A, Casale G, on behalf of the End of Life Observatory ResearchGroup. Off-label prescriptions in Italian hospices: a national survey. J Pain Symptom Manage <strong>2009</strong>; 38: 365-371Fabio Fiordaliso got his Biological Science degree in 1995 at the University of Milan.Education1998 Postdoctoral degree in Pharmacological Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong>“<strong>Mario</strong> <strong>Negri</strong>”, Milan, Italy1995 Doctoral degree in Biological Sciences, University of Milan, ItalyMain fields of activityTherapeutical potential of stem cell and antioxidant treatments in experimental model of <strong>di</strong>abeticcar<strong>di</strong>omyopathy and in primary myocyte cultures exposed to hyperglycemia.Morphological and structrural analysis of cells and tissue by optical, confocal and electron microscopy.Positionsfrom 2007 Head of Bio-imaging Unit, Department of Car<strong>di</strong>ovascular Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milanfrom 2006 Member of the Heart Failure Association (HFA) of the European Society of Car<strong>di</strong>ologyfrom 2005 Member of the Working group on myocar<strong>di</strong>al function (WG 4) of the European Society ofCar<strong>di</strong>ologyfrom 2005 Member of the steering committee of the Consorzio of Microscopy and Image Analysisfrom 2001(MIA)Senior Research Scientist, Laboratory of Car<strong>di</strong>ovascular Clinical Pharmacology(Department of Car<strong>di</strong>ovascular Research), <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong><strong>Negri</strong>”, Milan1997-2001 Post-Doctoral Research Fellow at Car<strong>di</strong>ovascular Research Institute (Department ofMe<strong>di</strong>cine), New York Me<strong>di</strong>cal College, Valhalla, New York1994-1997 Research Fellow, Laboratory of Car<strong>di</strong>ovascular Clinical Pharmacology (Department ofCar<strong>di</strong>ovascular Research), <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milan1992-1994 Research training, Institute of General Pathology, University of Milan (Italy)Selected publications• Fiordaliso F, Chimenti S, Staszewsky L, Bai A, Carlo E, Cuccovillo I, Doni M, Mengozzi M, Tonelli R, Ghezzi P,Coleman T, Brines M, Cerami A, Latini R. A non-erythropoietic derivative of EPO effectively ameliorates experimentalcar<strong>di</strong>ac ischemia with reperfusion. Proc Natl Acad Sci USA 2005; 102: 2046-2051• Fiordaliso F, Cuccovillo I, Bianchi R, Bai A, Doni M, Salio M, De Angelis N, Ghezzi P, Latini R, Masson S.Car<strong>di</strong>ovascular oxidative stress is reduced by an ACE inhibitor in a rat model of streptozotocin-induced <strong>di</strong>abetes . Life Sci2006; 79: 121-129• Fiordaliso F, De Angelis N, Cuccovillo I, Bai A, Salio M, Serra DM, Bianchi R, Razzetti R, Latini R, Masson S. Effectof β-adrenergic and renin-angiotensin system blockade on myocyte apoptosis and oxidative stress in <strong>di</strong>abetichypertensive rats. Life Sci 2007; 81: 951-959• Latini R, Brines M, Fiordaliso F. Do non-hemopoietic effects of erythropoietin play a beneficial role in heart failure?Heart Fail Rev 2008; 13: 415-423• Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, Angelici L,Masson S, Mohammed SAA, Dejana E, Gorini M, Zeiher AM, Latini R, GISSI-HF Investigators. Levels of circulatingpro-angiogenic cells pre<strong>di</strong>ct car<strong>di</strong>ovascular outcomes in patients with chronic heart failure. J Car<strong>di</strong>ac Fail <strong>2009</strong>; 15: 747-755• Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V, Crippa L, Avezza F,Fiordaliso F, Salio M, Lauria G, Lombar<strong>di</strong> R, Cavaletti G. Regression of <strong>di</strong>abetic complications by islet transplantationin the rat. Diabetologia <strong>2009</strong>; 52: 2653-2661129ANNUAL REPORT <strong>2009</strong>
IRFMNSerge Masson obtained his doctorate (PhD) in Biochemistry and Cellular Biology in 1990 at theUniversity of Marseilles (France), followed by a postdoctoral stay at the Panum Institute in Copenhagen(Denmark).Education1988-1990 Doctorate fellow, Faculty of Me<strong>di</strong>cine, University of Aix-Marseilles, France1990-1993 Post-doctoral Researcher, Panum Institute and Assistant Lecturer, University ofCopenhagen, Denmark1993 Research Scientist, NMR Laboratory, Hospital “San Raffaele”, Milan, Italyfrom 1994Research Scientist, Department of Car<strong>di</strong>ovascular Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalyMain fields of activityPhysiopathology, <strong>di</strong>agnostic and prognostic role of the activation of neuroendocrine systems incar<strong>di</strong>ovascular <strong>di</strong>seasePositionfrom 2002from 2002from 2002Head of the Car<strong>di</strong>ovascular Endocrine Unit, responsible for Quality Assurance for theDepartment of Car<strong>di</strong>ovascular Research, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong><strong>Negri</strong>", Milano, ItalyTutor of fellows of the School of Specialists in Pharmacological Research, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalyFellows of the American Heart Association (Basic Council) and the Working Group onMyocar<strong>di</strong>al Function of the European Society of Car<strong>di</strong>ologySelected publications• Masson S, Latini R, Anand I S, Barlera S, Judd D, Salio M, Perticone F, Perini G, Tognoni G, Cohn JN, on behalf of theVal-HeFT Investigators. The prognostic value of Big endothelin-1 in more than 2,300 patients with heart failure enrolledthe Valsartan in Heart Failure Trial (Val-HeFT). J Card Fail 2006; 12: 375-380.• Latini R, Masson S, Anand I S, Missov E, Carlson M, Vago T, Angelici L, Barlera S, Parrinello G, Maggioni AP,Tognoni G, Cohn J N, Val-HeFT Investigators. Prognostic value of very low plasma concentrations of troponin T inpatients with stable chronic heart failure. Circulation 2007; 116: 1242-1249.• Masson S, Latini R, Anand IS, Vago T, Angelici L, Barlera S, Missov ED, Clerico A, Tognoni G, Cohn JN, on behalf ofthe Val-HeFT Investigators. Direct comparison of B-type natriuretic peptide (BNP) and amino-terminal proBNP in alarge population of patients with chronic and symptomatic heart failure. The Valsartan Heart Failure (Val-HeFT) data.Clin Chem 2006; 52: 1528-1538.• Staszewsky L, Wong M, Masson S, Barlera S, Carretta E, Maggioni AP, Anand IS, Cohn JN, Tognoni G, Latini R,Valsartan Heart Failure Trial Investigators. Clinical, neurohormonal, and inflammatory markers and overall prognosticrole of chronic obstructive pulmonary <strong>di</strong>sease in patients with heart failure: data from the Val-HeFT Heart Failure Trial.J Card Fail 2007; 13: 797-804.• Masson S, Latini R, Anand IS, Barlera S, Angelici L, Vago T, Tognoni G, Cohn J N, for the Val-HeFT Investigators.Prognostic value of changes in N-termianl pro-brain natriuretic peptide in the Val-HeFT (Valsartan Heart Failure Trial).J Am Coll Car<strong>di</strong>ol 2008; 52: 997-1003• Boccanelli A, Mureddu GF, Cacciatore G, Clemenza F, Di Lenarda A, Gavazzi A, Porcu M, Latini R, Lucci D,Maggioni AP, Masson S, Vanasia M, De Simone G, AREA IN-CHF Investigators. Anti-remodelling effect of canrenonein patients with mild chronic heart failure (AREA IN-CHF study): final results. Eur J Heart Fail <strong>2009</strong>; 11: 68-76Enrico Bjørn Nicolis has attended the courses in Computer Science at the University of Milan.Education1991-1999 “Research fellow”, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, ItalyMain fields of activityData management and analysis of randomized clinical trials. Developing of database and tools for stu<strong>di</strong>esof population genetics, particularly for linkage analysis.Positionfrom 2001 Head of the Bioinformatics Unit, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>",Milano, Italyfrom 1999 Research fellow of the Laboratory of Clinical Drugs Evaluationfrom 1997 System administrator at the EDP center, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>",Milano, Italyfrom 1991 Research fellow at the Me<strong>di</strong>cal Informatics and Applied Statistics Unit, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong><strong>Farmacologiche</strong> "<strong>Mario</strong> <strong>Negri</strong>", Milano, Italy130ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Nobili A, Gebru F, Rossetti A, Schettino F, Zahn R W, Nicolis E, Macario G, Celani L, Acik V O, Farina ML, Nal<strong>di</strong> L.Doctorline: A private toll-free telephone me<strong>di</strong>cal information service. Five years of activity: Old problems and newperspectives. Ann Pharmacother 1998; 32: 120-125• Santoro E, Nicolis E, Franzosi MG.Telecommunication technology for the management of large scale clinical trials: TheGISSI experience. Comput Methods Programs Biomed 1999; 60: 215-223• Tognoni G, Franzosi MG, Nicolis E, Barlera S, Specchia C, Chio<strong>di</strong>ni B, Crociati L, Ferrario L, PROCARDISConsortium. A trio family study showing association of the lymphotoxin-alfa N26 (804A) allele with coronary artery<strong>di</strong>sease. Eur J Hum Genet 2004; 12: 770-774• Barlera S, Specchia C, Farrall M, Chio<strong>di</strong>ni BD, Franzosi MG, Rust S, Green F, Nicolis E, Peden J, Assmann G, CollinsR, Hamsten A, Tognoni G, PROCARDIS Consortium. Multiple QTL influence the serum Lp(a) concentration: agenome-wide linkage screen in the PROCARDIS study. Eur J Hum Genet 2007; 15: 221-227• Specchia C, Barlera S, Chio<strong>di</strong>ni BD, Nicolis EB, Farrall M, Peden J, Collins R, Watkins H, Tognoni G, Franzosi MG,PROCARDIS Consortium. Quantitative trait genetic linkage analysis of body-mass index in familial coronary artery<strong>di</strong>sease. Hum Hered 2008; 66: 19-24• Disertori M, Latini R, Maggioni AP, Barlera S, Di Pasquale G, Franzosi MG, Lucci D, Staszewsky L, Masson S, BavieraM, Nicolis E, Tognoni G, GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med<strong>2009</strong>; 360: 1606-1617ACTIVITIESThe areas of interest of the Department of Car<strong>di</strong>ovascular Research include the experimental,clinical, genetic, epidemiological aspects of acute myocar<strong>di</strong>al infarction, car<strong>di</strong>ac failure, car<strong>di</strong>acarrhythmias, as well as the clinical and epidemiological investigation of car<strong>di</strong>ovascularprevention, hypertension and stroke. Following the successful experience of the GISSI-trials(Gruppo Italiano per lo Stu<strong>di</strong>o della Sopravvivenza nell'Infarto), the activation of largecollaborative networks in the setting of the National Health Service hospitals and in generalpractice has become a key characteristics of the Department, which can now rely on thepermanent collaboration of over 300 clinical groups and of several hundred generalpractitioners. Over the years, firm links have also been established with international lea<strong>di</strong>ngresearch groups.The experimental research activity concerns the physiopathology, the pharmacologicalmodulation and the prognostic role of the activation of the renin-angiotensin-aldosteronesystem, as well as other neurohormonal systems, in myocar<strong>di</strong>al infarction and heart failure, thephysiopathology, the pharmacological modulation and prognostic role of the activation of theinflammatory processes in myocar<strong>di</strong>al infarction and heart failure; a more recent research topicis the cell therapy of experimental myocar<strong>di</strong>al infarction.The activity in clinical research includes the clinical assessment of therapeutic strategies and ofbiomarkers of car<strong>di</strong>ovascular risk with large scale clinical trials in the field of acute coronarysyndromes, congestive heart failure and atrial fibrillation. A recently developing area is thegenetic epidemiology of myocar<strong>di</strong>al infarction and heart failure. Several stu<strong>di</strong>es have beenconducted in the area of clinical epidemiology and risk factors assessment of myocar<strong>di</strong>alinfarction.The collaboration with a large network of General Practitioners in the area of car<strong>di</strong>ovascularprevention allowed to test new hypotheses through large scale clinical trials and to evaluate theactual transferability of evidence based interventions in the every day practice throughepidemiological or outcome research stu<strong>di</strong>es. Pharmacoepidemiological stu<strong>di</strong>es through theanalysis of a large sample of Local Health Units drug prescriptions were also performed. Aresearch network of nurses has been developed with the main focus on the assessment of healthrelatedquality of life of patients and on the epidemiology of nursing interventions and theirimplications for patients' well being and outcomes.MAIN FINDINGSGISSI-AF, a randomized, prospective, parallel group, placebo-controlled, multicenter study on131ANNUAL REPORT <strong>2009</strong>
IRFMNthe use of valsartan, an angiotensin II AT1-receptor blocker (ARBs) in the prevention of AtrialFibrillation (AF) recurrence, has recruited and treated for 12 months 1400 patients with ahistory of recent AF associated with car<strong>di</strong>ovascular <strong>di</strong>seases/comorbi<strong>di</strong>ties. In GISSI-AF, thelargest trial ever conducted with ARBs in pts with AF, Valsartan <strong>di</strong>d not reduce AF recurrence.The ongoing analyses on echocar<strong>di</strong>ographic and biohumoral data of 382 pts from GISSI-AF ledto the identification of some pre<strong>di</strong>ctors of recurrence of AF such as natriuretic peptides, highsensitivetroponin T and atrial volumes measured by echocar<strong>di</strong>ography.The GISSI-HF Study, a randomized multicenter trial conducted in nearby 7000 patients from357 car<strong>di</strong>ology sites in Italy, showed that a simple, safe, one-a-day capsule of n-3polyunsaturated fatty acids (PUFA) can reduce mortality (9%) and admission to hospital forcar<strong>di</strong>ovascular reasons (8%) in patients with heart failure. Patients received either n-3 PUFA ina capsule once daily (3494 patients) or placebo (3481). 955 patients in the PUFA group (27%)<strong>di</strong>ed, compared with 1014 (29%) in the placebo group, meaning a relative risk reduction of 9%in the PUFA group. A higher proportion of patients in the placebo group (2053/59%) <strong>di</strong>ed orwere admitted to hospital for car<strong>di</strong>ovascular reasons than in the PUFA group (1981/57%) arelative reduction of 8% in the PUFA group. In absolute terms, 56 patients needed to be treatedwith PUFA for four years to avoid one death, or 44 patients to avoid one event of either death oradmission to hospital for car<strong>di</strong>ovascular causes. Statin treatment with rosuvastatin does notaffect clinical outcomes in patients with chronic heart failure.The PROCARDIS study identified risk loci for coronary <strong>di</strong>sease by using a novel gene chipconsisting of48,742 SNPs for 2100 can<strong>di</strong>date genes that were selected for their potential relevance tocoronary artery<strong>di</strong>sease (CAD). With this gene chip, PROCARDIS confirmed the previous identification ofthree chromosomal regions that were correlated with the risk of coronary <strong>di</strong>sease: 6q26–27,9p21, and 1p13.In the chromosome 9p21 region PROCARDIS has identified two SNPs, rs2891168 andrs10811661, that are independently associated with CAD and with type 2 <strong>di</strong>abetes (T2D)respectively.The PROCARDIS study has identified two single nucleotide polymorphisms (SNPs) at the LPAlocus, strongly associated to coronary <strong>di</strong>sease, with an odds ratio of 1.70 (95% CI 1.49-1.95) forrs10455872,and with an odds ratio of 1.92 (95% CI 1.48-2.49) for rs3798220. Both variantswere strongly associated also with an increased level of lipoprotein(a), a reduced copy numberin LPA, and a small lipoprotein(a) size. These common variants explain over a third of thevariance in lipoprotein(a) levels in in<strong>di</strong>viduals of European descent. After adjustment for theplasma lipoprotein(a) level, the association between these genotypes and coronary <strong>di</strong>sease wasabolished, in<strong>di</strong>cating a causal role of lipoprotein(a) in coronary <strong>di</strong>sease.NATIONAL COLLABORATIONSAngiogenesis and Tumor Targeting Research Unit & Telethon Institute for Gene Therapy,Ospedale San Raffaele, MilanoAMD (Associazione Me<strong>di</strong>ci Diabetologi) - Lombar<strong>di</strong>aANMCO (Associazione Nazionale Me<strong>di</strong>ci Car<strong>di</strong>ologi Ospedalieri)Centro Car<strong>di</strong>ologico Monzino IRCCS, MilanoCINECA (Consorzio Interuniversitario per il Calcolo Automatico dell'Italia Nord-Orientale)CSeRMEG (Centro Stu<strong>di</strong> e <strong>Ricerche</strong> in Me<strong>di</strong>cina Generale)Dipartimento Car<strong>di</strong>o-Vascolare ed Endocrino-Metabolico, Ospedale Casa Sollievo della132ANNUAL REPORT <strong>2009</strong>
IRFMNSofferenza IRCCS, San Giovanni RotondoDipartimento <strong>di</strong> Car<strong>di</strong>ologia e UTIC, <strong>Istituto</strong> Clinico Humanitas IRCCS, MilanoDipartimento <strong>di</strong> Immunologia, <strong>Istituto</strong> Clinico Humanitas IRCCS, MilanoEmatologia, Ospedale Sant’Anna, TorinoFondazione Don Gnocchi IRCCS, MilanoGruppi organizzati <strong>di</strong> MMG (FIMMG, CoS, Ass.Cu.M.I., AMISI)IEO (<strong>Istituto</strong> Europeo <strong>di</strong> Oncologia), MilanoIFOM-FIRC, Milano<strong>Istituto</strong> <strong>di</strong> Anestesiologia e Rianimazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli,Regina Elena, Milano<strong>Istituto</strong> <strong>di</strong> Anestesia e Rianimazione, Ospedale San Gerardo, Monza<strong>Istituto</strong> <strong>di</strong> Ricerca in Cure palliative Lino Maestroni, CremonaLaboratorio <strong>di</strong> Endocrinologia, Ospedale Luigi Sacco, MilanoRegione Lombar<strong>di</strong>aSIBioC (Società Italiana <strong>di</strong> Biochimica Clinica e Biologia Molecolare)SIFO (Società Italiana <strong>di</strong> Farmacia Ospedaliera)Stem Cell Research Institute, Ospedale San Raffaele, MilanoUnità Operativa Semplice <strong>di</strong> Neuroanestesia e Neurorianimazione, Dipartimento <strong>di</strong> Me<strong>di</strong>cinaPerioperatoria e Terapie Intensive, Ospedale San Gerardo, MonzaUnità <strong>di</strong> Car<strong>di</strong>ologia, IEO, MilanoUniversità degli Stu<strong>di</strong> <strong>di</strong> Milano, Dipartimento <strong>di</strong> Me<strong>di</strong>cina InternaUniversità degli Stu<strong>di</strong> <strong>di</strong> Milano, Dipartimento <strong>di</strong> Scienze <strong>Farmacologiche</strong>Università degli Stu<strong>di</strong> <strong>di</strong> Torino, Dipartimento <strong>di</strong> Anatomia, Farmacologia e Me<strong>di</strong>cina ForenseUniversità degli Stu<strong>di</strong> <strong>di</strong> Torino, Dipartimento <strong>di</strong> Sanità Pubblica e MicrobiologiaUniversità degli Stu<strong>di</strong> <strong>di</strong> Verona, Dipartimento <strong>di</strong> Sanità PubblicaUniversità degli Stu<strong>di</strong> <strong>di</strong> Verona, <strong>Istituto</strong> <strong>di</strong> Anatomia UmanaINTERNATIONAL COLLABORATIONSCecomet (Centro de Epidemiologia comunitaria y Me<strong>di</strong>cina tropical, Esmeraldas) EcuadorCochrane Collaboration, Oxford, UKClinical Trial Research Unit, Auckland University, New ZealandCTSU (Clinical Trial Service Unit) /ISIS (International Stu<strong>di</strong>es on Infarct Survival), Oxford,UKDivision of Genetics and Development, Guy's, King's and St Thomas' School of Me<strong>di</strong>cine,King's College, London, UKDSAN SUPSI (Scuola Universitaria Professioni Sanitarie), Lugano CHECLA (Estu<strong>di</strong>os Car<strong>di</strong>ologicos de Latino-America)JW Goethe University, Department of Car<strong>di</strong>ology, Frankfurt, GermanyKarolinska Institutet, Stockholm, SwedenPHRI (Population Health Research Institute), McMaster University, Hamilton, Ontario, CanadaSIOP Europe (European Society for Pae<strong>di</strong>atric Oncology)University of Cambridge, UKUniversity of Minnesota, Minneapolis, USAUniversity of Oslo, NorwayUniversity Me<strong>di</strong>cal Center, Groningen, The NetherlandsWellcome Trust Centre for Human Genetics, University of Oxford, UKWONCA (World Organization of Family Doctors)133ANNUAL REPORT <strong>2009</strong>
IRFMNEDITORIAL BOARD MEMBERSHIPCirculation, International Journal of Health Services, European Heart Journal (Gianni Tognoni)Journal of Car<strong>di</strong>ac Failure, Journal of Car<strong>di</strong>ovascular Me<strong>di</strong>cine (Roberto Latini)Assistenza Infermieristica e Ricerca, European Journal of Cancer Care, European Journal ofOncology Nursing, International Nursing Perspectives (Paola Di Giulio)PEER REVIEW ACTIVITIESAmerican Heart Journal, American Journal of Car<strong>di</strong>ology, American Journal of Me<strong>di</strong>cine,Archives of Me<strong>di</strong>cal Research, Atherosclerosis Thrombosis and Vascular Biology,Car<strong>di</strong>ovascular Drugs and Therapy, Car<strong>di</strong>ovascular Research, Circulation, Circulation Research,Clinical Pharmacology and Therapeutics, European Heart Journal, European Journal of CancerCare, European Journal of Car<strong>di</strong>ovascular Nursing, European Journal of Oncology Nursing,Free Ra<strong>di</strong>cal Biology & Me<strong>di</strong>cine, Health and Quality of Life, Heart Vessels, InternationalJournal of Car<strong>di</strong>ology, International Journal of Obesity, Italian Journal of Car<strong>di</strong>ology, Journal ofAmerican College of Car<strong>di</strong>ology, Journal of Car<strong>di</strong>ac Failure, Journal of Clinical LaboratoryAnalysis, Journal of Internal Me<strong>di</strong>cine, Journal of Car<strong>di</strong>ovascular Me<strong>di</strong>cine, Life Sciences, TheLancet, PharmacoEconomics, Pharmacological Research, Redox <strong>Report</strong>, Value in Health.NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPEthical Committee of the ASL of MilanEthical Committee of Lombardy RegionEthical Committee of the Provincia of VeronaEthical Committee of the A.O. Fatebenefratelli e Oftalmico of MilanAgenzia Italiana del Farmaco, Direzione Generale Farmaci e Dispositivi Me<strong>di</strong>ciEVENT ORGANIZATIONPROCARDIS <strong>Annual</strong> Meeting21-22/04/09, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoInvestigator's Meeting – Riunione <strong>di</strong> avvio dello stu<strong>di</strong>o GLICINE SPIDER27/04/09, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoSeminar - Fabio Di Lisa: Mitochondrial ROS formation and car<strong>di</strong>ac <strong>di</strong>seases02/07/09, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoSeminar - Michel Ovize: Cyclosporine A to prevent ischemia/reperfusion injury06/07/09, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoSeminar – Salim Yusuf: Risk factors, management challenges, and new data on treatmentoptions for patients with Atrial Fibrillation28/09/09, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoInvestigator's Meeting – Riunione degli Sperimentatori dello stu<strong>di</strong>o GLICINE SPIDER134ANNUAL REPORT <strong>2009</strong>
IRFMN01/10/09, sala ARIES – Polo Fieristico Rho-Pero, MilanoInvestigator's Meeting – Stato <strong>di</strong> avanzamento dello stu<strong>di</strong>o "NeuroMorfeo"05/11/09, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoMaster <strong>di</strong> I° Livello in Ricerca Clinica dell’Università degli Stu<strong>di</strong> <strong>di</strong> Milano, Facoltà <strong>di</strong>Me<strong>di</strong>cina e Chirurgia, Dipartimento <strong>di</strong> Me<strong>di</strong>cina Interna (Anno Accademico <strong>2009</strong>-2010)03/11/09 Introduzione al corsoLa ricerca clinica oggi: profit e no-profitCorso <strong>di</strong> introduzione alla statistica04/11/09 La variabilità dei fnomeni biologiciElementi <strong>di</strong> statistica descrittiva05/11/09 Test <strong>di</strong>agnosticiEsercitazione <strong>di</strong> statistica descrittiva06/11/09 Legislazione sulla sperimentazione clinica e ruolo dei Comitati Etici09/11/09 Il <strong>di</strong>segno dello stu<strong>di</strong>o in epidemiologiaIl <strong>di</strong>segno degli stu<strong>di</strong> clinici10/11/09 Misure <strong>di</strong> rischio in epidemiologia11/11/09 Monitoraggio degli stu<strong>di</strong> clinici no-proft<strong>Report</strong> delle Reazioni avverse negli stu<strong>di</strong> clinici no-profit12/11/09 Stu<strong>di</strong> <strong>di</strong> fase 2: Obiettivi, <strong>di</strong>segno e stima del campione in oncologia16/11/09 Analisi della sopravvivenzaInferenza statistica17/11/09 FarmacovigilanzaEsercitazione <strong>di</strong> Inferenza Statistica18/11/09 Ricerca clinica nel campo dell'epilessiaRicerca clinica nell'ictusInternet e le nuove tecnologie per l'aggiornamento me<strong>di</strong>co-scientifico23/11/09 Stu<strong>di</strong> <strong>di</strong> fase 3: Obiettivi, <strong>di</strong>segno e in<strong>di</strong>catori in oncologiaRevisioni sistematiche e metaanalisi24/11/09 Monitoraggio degli stu<strong>di</strong> clinici profit<strong>Report</strong> delle Reazioni AvverseLa ricerca bibliografica oggiLe interazioni tra farmaci25/11/09 Ricerca in me<strong>di</strong>cina generale30/11/09 Ricerca TraslazionaleOutcome ResearchDalla preclinica alla clinica: sviluppo <strong>di</strong> nuovi farmaci car<strong>di</strong>ovascolari<strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoSeminar – Domenico Corra<strong>di</strong>: Basi anatomopatologiche della fibrillazione atriale20/11/09, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, MilanoCONFERENCE AND WORKSHOP CONTRIBUTIONSDipartimento <strong>di</strong> Genetica Biologia e Biochimica-Centro <strong>di</strong> Biotecnologie Molecolari,Università <strong>di</strong> Torino. I Car<strong>di</strong>onetwork meeting, 5-6/03/09, Torino, Italy- Translational approaches to myocar<strong>di</strong>al infarction: pentraxins and stem cells135ANNUAL REPORT <strong>2009</strong>
IRFMNSMART-Organizing and Scientific Committee. 20° SMART – Simposio Mostra Anestesia,Rianimazione e Terapia Intensiva, 6-8/05/09, Milano, Italy- Troponina e proBNP come marker <strong>di</strong> <strong>di</strong>sfunzione car<strong>di</strong>acaUniversità degli stu<strong>di</strong> <strong>di</strong> Padova - Fondazione Livia e Vitttorio Tonolli. Formazione clinica,comunicazione, management in car<strong>di</strong>ologia. Corso <strong>di</strong> perfezionamento post laurea – Modulo 16,27/05/09, Milano, Italy- L’impiego delle cellule staminali: dai modelli animali all’applicazione nell’uomo nellelesioni del miocar<strong>di</strong>o- Gli stu<strong>di</strong> clinici nello scompenso car<strong>di</strong>aco- Novità vere e apparenti in car<strong>di</strong>ologiaEuropean Society of Car<strong>di</strong>ology. Heart Failure <strong>2009</strong>, 30/05-02/06/09, Nice, France- Emerging targets from basis mechanisms. PentraxinsAssociazione Nazionale Me<strong>di</strong>ci Car<strong>di</strong>ologi Ospedalieri. 40° Congresso Nazionale <strong>di</strong>Car<strong>di</strong>ologia, 04-07/06/09, Firenze, Italy- Valore prognostico della variabilità della frequenza car<strong>di</strong>aca nello stu<strong>di</strong>o GISSI-HF- La concentrazione plasmatica <strong>di</strong> pentraxina-3 pre<strong>di</strong>ce la mortalità in pazienti coninsufficienza car<strong>di</strong>aca cronica. Dati dallo stu<strong>di</strong>o GISSI-HF- Aci<strong>di</strong> grassi plasmatici e mortalità in pazienti con insufficienza car<strong>di</strong>aca cronica. Dati dallostu<strong>di</strong>o GISSI-HF- Prevalenza <strong>di</strong> <strong>di</strong>sfunzione sistolica asintomatica su popolazione: risultati preliminari dellostu<strong>di</strong>o PREDICTOR (valutazione della prevalenza <strong>di</strong> <strong>di</strong>sfunzione car<strong>di</strong>aca asintomatica e <strong>di</strong>scompenso car<strong>di</strong>aco conclamato in un campione <strong>di</strong> popolazione <strong>di</strong> età ≥ 65 anni nel Lazio)- Prevalenza <strong>di</strong> <strong>di</strong>sfunzione sistolica asintomatica su popolazione anziana: risultati preliminaridello stu<strong>di</strong>o PREDICTOR- Profilo <strong>di</strong> sicurezza e tollerabilità <strong>di</strong> Aliskiren quando aggiunto alla terapia ottimizzata <strong>di</strong>pazienti con scompenso car<strong>di</strong>aco e <strong>di</strong>sfunzione renale- Valutazione della prevalenza <strong>di</strong> <strong>di</strong>sfunzione car<strong>di</strong>aca asintomatica e <strong>di</strong> scompenso car<strong>di</strong>acosu popolazione <strong>di</strong> età ≥ 65 anni nel Lazio: risultati preliminari dello stu<strong>di</strong>o PREDICTOR- Efficacia e tollerabilità <strong>di</strong> Aliskiren aggiunto alla terapia ottimizzata <strong>di</strong> pazienti con <strong>di</strong>abetemellito e scompenso car<strong>di</strong>aco- Vi sono <strong>di</strong>fferenze tra la popolazione <strong>di</strong> un trial e quella arruolata da un singolo centro?Un’analisi all’interno del GISSI-HF- Concentrazioni <strong>di</strong> NT-proBNP in 537 soggetti anziani nel Lazio: risultati preliminari dellostu<strong>di</strong>o e<strong>di</strong>demiologico PREDICTOREuropean Society of Car<strong>di</strong>ology. ESC Congress <strong>2009</strong>, 29/08-02/09/09, Barcellona, Spain- Aldosterone escape is associated with insulin resistance in patients with heart failure –fin<strong>di</strong>ngs in the ALiskiren Observation of heart Failure Treatment trial (ALOFT)- Plasma renin activity retains a strong prognostic value in patients with chronic HF,independent of ACE inhibitor or beta-blocker therapy. Data from the Valsartan Heart Failure(Val-HeFT)- Time course analysis of the effect of n-3 PUFA on fatal and non fatal arrhythmias in heartfailure: secondary results of the GISSI-HF trial- Safety and tolerability profile of aliskiren added to optimized therapy in elderly and veryelderly patients with heart failure- Prevalence of heart failure in the community: preliminary results of an epidemiologicalsurvey in the elderly population in Italy. The PREDICTOR Study- Effect of n-3 PUFA in heart failure patients with <strong>di</strong>fferent <strong>di</strong>etary habits: preliminary resultsof the GISSI-Heart Failure trial136ANNUAL REPORT <strong>2009</strong>
IRFMN- Pre<strong>di</strong>ctive role of QRS duration in patients with chronic heart failure. Data from the GISSI-HF trial- Prognostic ability of a Me<strong>di</strong>terranean <strong>di</strong>etary score in heart failure: preliminary analysis ofthe GISSI-Heart Failure trial- Antiarrhythmic effects of n-3 PUFA in patients with heart failure and an implantablecar<strong>di</strong>overter defibrillator in the GISSI-HF trial- Epidemiology and prognosis of <strong>di</strong>abetes in acute and chronic heart failure- Erythropoieting as a car<strong>di</strong>oprotectant with clinical potential- Pre<strong>di</strong>ctors of change of <strong>di</strong>etary habits in cohort of 12,513 patients at high risk ofcar<strong>di</strong>ovascular risk followed by 860 Italian general Practitioners: preliminary analysis of theRisk & Prevention trial- Prognostic ability of a simple <strong>di</strong>etary score in cohort of 12,513 patients at high risk ofcar<strong>di</strong>ovascular risk followed by 860 Italian GPs: preliminary analysis of the Risk & PreventiontrialIEO European Institute of Oncology. Car<strong>di</strong>oncology <strong>2009</strong>. 25-26/09/09, Milano, Italy- Markers of inflammation in heart <strong>di</strong>seasesDipartimento Car<strong>di</strong>ovascolare “A. De Gasperis” – Azienda Ospedaliera Ospedale Niguarda Ca’Granda. 43° Convegno Car<strong>di</strong>ologia <strong>2009</strong>, 28/09-02/10/09, Centro Congressi Stella Polare.Porta Sud, Nuovo Polo della Fiera <strong>di</strong> Milano, Pero-Rho, Italy- La fragilità sociale e la compliance farmacologicaHeart Care Foundation. Integriamo l’evidence based me<strong>di</strong>cine con le cure “su misura”. Il ruolodella clinica nella pratica e nella ricerca car<strong>di</strong>ovascolare, 22-23/10/09, Grand Hotel Dino,Baveno, Italy- Il “rinascimento” dell’osservazione clinica – parte 2. Risposta neuro umonaleSIGU Società Italiana <strong>di</strong> Genetica Umana. XII Congresso Nazionale SIGU, 8-10/11/09,Lingotto, Torino, Italy- Common genetic variants on chromosome 9p21 are associated with myocar<strong>di</strong>al infarctionand type 2 <strong>di</strong>abetes in an Italian populationAmerican Heart Association. AHA Scientific Session <strong>2009</strong>, 14-18/11/09, Orlando, Florida,USA- Significant association between atrial and ventricular echocar<strong>di</strong>ographic fin<strong>di</strong>ngs and car<strong>di</strong>accirculatin biomarkers in patients with a history of atrial fibrillation. Data from the GISSI-AFTrial- Transthoracic echocar<strong>di</strong>ographic parameters as pre<strong>di</strong>ctors of atrial fibrillation recurrence.Data from the GISSI-AF Echocar<strong>di</strong>ographic Study- Prognostic value and serial changes of plasma a<strong>di</strong>ponectin concentration in patients withchronic heart failure. Data from GISSI-HF TrialCar<strong>di</strong>ologia Prof. M Viecca - Ospedale Luigi Sacco, ARCA, AIMEF. I° Convegno - Breakingnews in interventistica car<strong>di</strong>ovascolare e nuove frontiere terapeutiche nel trattamento dellepatologie car<strong>di</strong>ovascolari, 21/11/09, Milano. Italy- Terapia farmacologica non antiaritmica della fibrillazione atriale: quale ruolo per i Sanitari egli ACE-inibitori?Società Italiana <strong>di</strong> Gerontologia e Geriatria. 54° Congresso Nazionale, Salute e benesseredell’anziano: la nostra missione, 2-5/12/09, Palazzo dei Congressi, Firenze Italy- In<strong>di</strong>ce <strong>di</strong> complessità assistenziale (ICA): stu<strong>di</strong>o <strong>di</strong> validazione137ANNUAL REPORT <strong>2009</strong>
IRFMNGRANTS AND CONTRACTSAIFA (Agenzia Italiana del Farmaco), AstraZeneca, Azienda Ospedaliera San Gerardo Monza,Chiesi Farmaceutici, Boehringer Ingelheim Italia SpA, BRAHAMS AG, Centro Car<strong>di</strong>ologicoMonzino IRCCS Milano, Cambridge University, CONGENIA, Fondazione Don GnocchiMilano, Fondazione San Raffaele Milano, Heart Care Foundation, International Biome<strong>di</strong>calSystem SpA, <strong>Istituto</strong> Auxologico <strong>di</strong> Milano, <strong>Istituto</strong> Dermopatico dell’Immacolata <strong>di</strong> Roma,LACHIFARMA, Ministero della Salute, NOEMALIFE GmbH, Novartis Pharma, OspedaleCasa Sollievo della Sofferenza IRCCS San Giovanni Rotondo, Oxford University, PopulationHealth Research Institute-Mc Master University, Pfizer Italia, Regione Lombar<strong>di</strong>a, Sanofi-Aventis, Sigma Tau, SPA Società Prodotti Antibiotici S.p.A., Takeda Italia S.p.A., Universitàdegli Stu<strong>di</strong> TorinoSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)ACTIVE InvestigatorsEffect of clopidogrel added to aspirin in patients with atrial fibrillationN Engl J Med <strong>2009</strong>; 360: 2066-2078Antithrombotic Trialists' (ATT) CollaborationAspirin in the primary and secondary prevention of vascular <strong>di</strong>sease: collaborative meta-analysis of in<strong>di</strong>vidualparticipant data from randomised trialsLancet <strong>2009</strong>; 373: 1849-1860Avanzini F, Marelli G, Donzelli W, Sorbara L, Palazzo E, Bellato L, Colombo EL, Roncaglioni MC, Riva E, DeMartini M, on behalf of the DDD study groupHyperglycemia during acute coronary syndrome: A nurse-managed insulin infusion protocol for stricter and safercontrolEur J Car<strong>di</strong>ovasc Nurs <strong>2009</strong>; 8: 182-189Balconi G, Lehmann R, Fiordaliso F, Assmus B, Dimmeler S, Sarto P, Carbonieri E, Gualco A, Campana C, AngeliciL, Masson S, Mohammed SAA, Dejana E, Gorini M, Zeiher AM, Latini R, GISSI-HF InvestigatorsLevels of circulating pro-angiogenic cells pre<strong>di</strong>ct car<strong>di</strong>ovascular outcomes in patients with chronic heart failureJ Car<strong>di</strong>ac Fail <strong>2009</strong>; 15: 747-755Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M,Coffman TM, Remuzzi GDisruption of the Ang II type 1 receptor promotes longevity in miceJ Clin Invest <strong>2009</strong>; 119: 524-530Boccanelli A, Mureddu GF, Cacciatore G, Clemenza F, Di Lenarda A, Gavazzi A, Porcu M, Latini R, Lucci D,Maggioni AP, Masson S, Vanasia M, de Simone G, on behalf of AREA IN-CHF InvestigatorsAnti-remodelling effect of canrenone in patients with mild chronic heart failure (AREA IN-CHF study): final resultsEur J Heart Fail <strong>2009</strong>; 11: 68-76Citerio G, Franzosi MG, Latini R, Masson S, Barlera S, Guzzetti S, Pesenti AAnaesthesiological strategies in elective craniotomy: randomized, equivalence, open trial - The NeuroMorfeo trialTrials <strong>2009</strong>; 10: 19Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, BennettD, Silveira A, Malarstig A , Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, CollinsR, Watkins H, Farrall M, for the PROCARDIS ConsortiumGenetic variants associated with Lp(a) lipoprotein level and coronary <strong>di</strong>seaseN Engl J Med <strong>2009</strong>; 361: 2518-2528Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, VarroneJ, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener H-C, Joyner CD, Wallentin L, the RE-LY Steering Committee and Investigators.Dabigatran versus Warfarin in patients with atrial fibrillation138ANNUAL REPORT <strong>2009</strong>
IRFMNN Engl J Med <strong>2009</strong>; 361: 1139-1151Freel EM, Tsorlalis IK, Lewsey JD, Latini R, Maggioni AP, Solomon S, Pitt B, Connell JMC, McMurray JJVAldosterone status associated with insulin resistance in patients with heart failure - data from the ALOFT studyHeart <strong>2009</strong>; 95: 1920-1924Galvez BG, Covarello D, Tolorenzi R, Brunelli S, Dellavalle A, Crippa S, Mohammed SAA, Scialla L, Cuccovillo I,Molla F, Staszewsky L, Maisano F, Sampaolesi M, Latini R, Cossu GHuman car<strong>di</strong>ac mesoangioblasts isolated from hypertrophic car<strong>di</strong>omyopathies are greatly reduced in proliferation and<strong>di</strong>fferentiation potencyCar<strong>di</strong>ovasc Res <strong>2009</strong>, 83: 707-716GISSI-AF Investigators (Writing Committee: Disertori M, Latini R, Barlera S, Franzosi MG, Staszewsky L,Maggioni AP, Lucci D, Di Pasquale G, Tognoni G),Valsartan for prevention of recurrent atrial fibrillationN Engl J Med <strong>2009</strong>; 360: 1606-1617Heymans S, Hirsch E, Anker SD, Aukrust P, Balligand J-L, Cohen-Tervaert JW, Drexler H, Filippatos G, Felix SB,Gullestad L, Hilfiker-Kleiner D, Janssens S, Latini R, Neubauer G, Paulus WJ, Pieske B, Ponikowski P, Schroen B,Schultheiss H-P, Tschöpe C, Van Bilsen M, Zannad F, McMurray J, Shah AMInflammation as a therapeutic target in heart failure? A scientific statement from the Translational ResearchCommittee of the Heart Failure Association of the European Society of Car<strong>di</strong>ologyEur J Heart Fail <strong>2009</strong>; 11: 119-129Joyner CD, Peters RJG, Afzal R, Chrolavicius S, Mehta SR, Fox KAA, Granger CB, Franzosi MG, Flather M, BudajA, Bassand JP, Yusuf SFondaparinux compared to enoxaparin in patients with acute coronary syndromes without ST-segment elevation:outcomes and treatment effect across <strong>di</strong>fferent levels of riskAm Heart J <strong>2009</strong>; 157: 502-508Latini L, Masson SBiomarkers of myocyte injury in heart failureHeart Fail Clin <strong>2009</strong>; 5: 529-536Maggioni AP, Fabbri G, Lucci D, Marchioli R, Franzosi MG, Latini R, Nicolosi GL, Porcu M, Cosmi F, Stefanelli S,Tognoni G, Tavazzi L, on behalf of the GISSI-HF InvestigatorsEffects of rosuvastatin on atrial fibrillation occurrence: ancillary results of the GISSI-HF trialEur Heart J <strong>2009</strong>; 30: 2327-2336Maggioni AP, Franzosi MG, Latini RBeta-adrenoceptor antagonists and antianginal drugsIn: Side effects of drugs, <strong>Annual</strong> 31Elsevier, Amsterdam, <strong>2009</strong>; 339-343Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo ESemaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculaturein transgenic mouse modelsJ Clin Invest <strong>2009</strong>; 119: 3356-3372Malarstig A, Buil A , Souto JC, Clarke R, Blanco-Vaca F , Fontcuberta J, Peden J, Andersen M, Silveira A, BarleraS, Seedorf U, Watkins H, Almasy L, Hamsten A, Soria JM ,on behalf of the Genetic Analysis of I<strong>di</strong>opathicThrombophilia (GAIT) and Precocious Coronary Artery Disease (PROCARDIS) consortiaIdentification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wideassociation studyBlood <strong>2009</strong>; 114: 1417-1422Marchioli R, Levantesi G, Silletta MG, Barlera S, Carbonieri E, Cosmi F, Franzosi MG, Latini R, Lucci D, MaggioniAP, Moretti L, Nicolosi GL, Porcu M, Rossi MG, Tognoni G, Tavazzi L, on behalf of the GISSI-HF InvestigatorsEffect of n-3 polyunsaturated fatty acids and rosuvastatin in patients with heart failure: results of the GISSI-HF trialExpert Rev Car<strong>di</strong>ovasc Ther <strong>2009</strong>; 7: 735-748Nobili A, Pasina L, Tettamanti M, Lucca U, Riva E, Marzona I, Monesi L, Cucchiani R, Bortolotti A, Fortino I,Merlino L, Locatelli GW, Giuliani G139ANNUAL REPORT <strong>2009</strong>
IRFMNPotentially severe drug interactions in elderly outpatients: results of an observational study of an administrativeprescription databaseJ Clin Pharm Ther <strong>2009</strong>; 34: 377-386Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V, Crippa L, Avezza F,Fiordaliso F, Salio M, Lauria G, Lombar<strong>di</strong> R, Cavaletti GRegression of <strong>di</strong>abetic complications by islet transplantation in the ratDiabetologia <strong>2009</strong>; 52: 2653-2661Taccone P, Pesenti A, Latini R, Polli F, Vagginelli F, Mietto C, Caspani L, Raimon<strong>di</strong> F, Bordone G, Iapichino G,Mancebo J, Guerin C, Ayzac L, Blanch L, Fumagalli R, Tognoni G, Gattinoni L, for the Prone-Supine II StudyGroupProne positioning in patients with moderate and severe acute respiratory <strong>di</strong>stress syndrome. A randomized controlledtrialJAMA <strong>2009</strong>, 302: 1977-1984Toscani F, Di Giulio P, Campi R, Pellerin I, De Luca A, Casale G, on behalf of the End of Life Observatory ResearchGroupOff-label prescriptions in Italian hospices: a national surveyJ Pain Symptom Manage <strong>2009</strong>; 38: 365-371LAY PRESS SELECTION (<strong>2009</strong>)Amodeo R, De Ponti A, Sorbara L, Avanzini F, Di Giulio P, De Martini MCome aumentare le conoscenze dei pazienti con car<strong>di</strong>opatia ischemica sulla loro malattia? Utilità <strong>di</strong> un incontroeducazionale tenuto da infermieriG Ital Car<strong>di</strong>ol <strong>2009</strong>; 10: 249-255Di Giulio P, Pera C, Scarano M, Ferri B, Lepore V, Miani D, Tognoni GRapporto finale dello stu<strong>di</strong>o QDF (Qualità <strong>di</strong> vita, Depressione e Funzioni cognitive) nei pazienti con scompensocar<strong>di</strong>acoAssistenza Infermieristica e Ricerca <strong>2009</strong>; 28: 5-38Franzosi MGIl modello GISSI e la scoperta della cura per l’infartoIn: Milano capitale della salute. E<strong>di</strong>trice Abitare Segesta, Milano, <strong>2009</strong>; 176Nobili A, Latini RInterazioni pericolose in car<strong>di</strong>ologiaIn: Car<strong>di</strong>ologia <strong>2009</strong>. Atti del 43° convegno internazionale del <strong>di</strong>partimento car<strong>di</strong>ologico A. De Gasperis. 28settembre-2 ottobre <strong>2009</strong>, Milano. Fond. Centro Car<strong>di</strong>ologia e Car<strong>di</strong>ochirurgia A. De Gasperis, Milano, <strong>2009</strong>; 152-160Oliva F, Macera F, Verde A, Vittori C, Cipriani M, Masciocco G, Garascia A, Foti G, Turazza F, Frigerio MValore scientifico e limiti epidemiologici dei registri <strong>di</strong> patologia come fonte <strong>di</strong> informazione: l’esempio delloscompenso car<strong>di</strong>acoIn: Car<strong>di</strong>ologia <strong>2009</strong>. Atti del 43° convegno internazionale del <strong>di</strong>partimento car<strong>di</strong>ologico A. De Gasperis. 28settembre-2 ottobre <strong>2009</strong>, Milano. Fond. Centro Car<strong>di</strong>ologia e Car<strong>di</strong>ochirurgia A. De Gasperis, Milano, <strong>2009</strong>; 6-9Tognoni GQDF: Qualità <strong>di</strong> vita, Depressione, Funzioni cognitive. Un progetto <strong>di</strong> ricerca car<strong>di</strong>ologica che può essere letturaobbligatoria e strumento <strong>di</strong> lavoro <strong>di</strong> interesse generaleAssistenza Infermieristica e Ricerca <strong>2009</strong>; 28: 2-4140ANNUAL REPORT <strong>2009</strong>
IRFMNRESEARCH ACTIVITIESLaboratory of Car<strong>di</strong>ovascular Clinical PharmacologyThe effects of mesoangioblasts and of <strong>di</strong>fferent progenitor cells on injuryafter experimental myocar<strong>di</strong>al infarction in the mouseMany stu<strong>di</strong>es have demonstrated that autologous and homologous cells of various origins canrepair myocar<strong>di</strong>um damaged due to an acute ischemic insult. Mesangioblasts are potentiallyinteresting when compared with bone marrow precursors because (a) they are easily expandedand (b) obtainable by a biopsy of skeletal muscle in man. Mesoangioblasts isolated from humanheart biopsies migrate and home in the heart of immunodeficient mice after coronary ligation,and they survive for at least 4 weeks; however, there are no evidences of myocar<strong>di</strong>alregeneration, and improvement in car<strong>di</strong>ac function was modest. The same model of coronaryligation in immunodeficient mice is being used for testing in vivo the angiogenic potential ofother progenitor cells such as CD34+ (collaboration with F Fagioli, Ospedale S. Anna, Torino),CD133+ (collaboration with M Pesce and G Pompilio, Centro Car<strong>di</strong>ologico Monzino, Milano).Stu<strong>di</strong>es are ongoing using genetically mo<strong>di</strong>fied mesoangioblasts (transfected with lentivirusco<strong>di</strong>fying for PlGF or MMP9) derived from mice in the treatment of experimental myocar<strong>di</strong>alinfarction in immunocompentent mice.Pulmonary injury by hydrochloric acid in the mouse: a model ofAspiration pneumonitis to test protective interventionsAspiration pneumonitis (AP) occurs when the acid content of the stomach makes his waythrough the larynx in the lower respiratory tract. Patients with consciousness <strong>di</strong>sturbance are atrisk for this event. Specifically, it has been shown that Pulmonary Aspiration can complicatebetween 0.47-1.41% general anesthesia procedures.The main injurious mechanism of AP is the chemical insult due to the low pH of gastricsecretions, which causes a chemical burn of the airway tree and of the alveolar structures. Thecourse of AP can be extremely variable, ranging from the “silent aspiration” characterized by amodest desaturation to the dramatic sequelae of Acute Lung Injury (ALI) and Acute RespiratoryDistress Syndrome (ARDS), requiring prolonged mechanical ventilation and potentially lea<strong>di</strong>ngto death. In a murine model of monolateral acid instillation established in our laboratory, wehave shown the protective effect of exogenous pulmonary surfactant instillation. We arecurrently working on a model of ventilation-induced lung injury (VILI) to assess the effect ofexogenous surfactant. A study completed recently has shown that PTX3 modulatesinflammation in a murine model of ALI by interacting with P-selectin.Con<strong>di</strong>tional transgenic model of car<strong>di</strong>ac HGF expression to promoteneovascularization and to recruit stem cells in the myocar<strong>di</strong>al infarctionGrowth factors such as hepatocyte growth factor (HGF) through angiogenic and anti-apoptoticeffects may promote car<strong>di</strong>ac repair after myocar<strong>di</strong>al infarction and in heart failure. The car<strong>di</strong>acspecificα-Myosin Heavy Chain (MHC-α) transactivator was used to <strong>di</strong>rect expression of HGFto car<strong>di</strong>omyocytes: by this way the effects of HGF can be tested under car<strong>di</strong>ac ischemia andreperfusion, without the need for administration of exogenous HGF. In the first half of 2010 it isexpected the conclusion of the experiments aimed at verifying the ability of HGF in vivo topromote neovascularisation, to protect car<strong>di</strong>omyocytes from apoptosis, to recruit and activateendogenous or transplanted stem cells and to sustain their cellular replication and <strong>di</strong>fferentiationinto car<strong>di</strong>omyocytes after ischemia followed by reperfusion.141ANNUAL REPORT <strong>2009</strong>
IRFMNRoles of macrophages in car<strong>di</strong>ac ischemia/reperfusion injury and incar<strong>di</strong>ac repairMacrophages either resident or from blood-borne monocytes play several key roles in theresponse of the heart to ischemic injury. They may be useful in particular during car<strong>di</strong>ac repair,when collagen deposition occurs and neonagiogenesis, stimulated by growth factors producedby macrophages. The aim of the project is to assess the relevance of macrophages in myocar<strong>di</strong>alrepair and scar formation after myocar<strong>di</strong>al infarction, in the attempt to <strong>di</strong>ssect the role ofinflammatory cells in myocar<strong>di</strong>al injury vs repair.Experiments of experimental infarction in transgenic mice expressing human Dyphtheria toxinreceptor (hDTR) in (CD11b-DTR) have shown (a) the halving of circulating monocytes, andhence of car<strong>di</strong>ac macrophages, but at the same time (b) serious wasting of mice receivingDyphtheria toxin right after car<strong>di</strong>ac ischemia. The high mortality <strong>di</strong>d not allow to continue theexperiments, and another model based on clodronate liposomes is now being tested. We arenow running experiments to evaluate the structural and functional consequences of the reductionin circulating monocytes and in car<strong>di</strong>ac macrophages induced by clodronate.Effects of <strong>di</strong>peptidyl peptidase-4 (DPP-4) inhibition on endothelialprogenitor cells and hypoxic injury in type 2 <strong>di</strong>abetesDiabetic patients have a two- to threefold greater risk of developing congestive heart failureafter myocar<strong>di</strong>al infarction. Decreased microvascular density, one of major vascularcomplications in <strong>di</strong>abetes, is accompanied by increased susceptibility to myocar<strong>di</strong>al ischemiaand by progressive left ventricular dysfunction. Circulating Endothelial Progenitor Cells (EPCs)are incorporated into new vessels and promoted neo-vascularization. Insufficient numbers ofendothelial progenitor cells (EPCs) are reported in both type 1 and type 2 <strong>di</strong>abetic patients.The present study aims at evaluating whether the administration to <strong>di</strong>abetic ob/ob mice of a<strong>di</strong>peptidyl peptidase-4 (DPP-4) inhibitor, an antihyperglycemic drug, with the ability to preservethe active form of the SDF-1 (Stromal cell-Derived Factor-1), me<strong>di</strong>ator of progenitor cellmobilization increases EPC circulating levels, which, in turn, may contribute to theregeneration of blood vessels and reducing myocar<strong>di</strong>al ischemic stress induced by strenuousexercise.Effects of propionyl-L-carnitine on vascular damage and car<strong>di</strong>ovascularoxidative stress in type 2 <strong>di</strong>abetic mouseExperimental and clinical evidence suggest that the generation of reactive oxygen species(ROS) is increased in both types of <strong>di</strong>abetes and that the onset of <strong>di</strong>abetes and <strong>di</strong>abetic car<strong>di</strong>accomplications are closely associated with oxidative stress which is exacerbated during strenuousexercise.Oxidative stress represents a primary cause of the microvascular and macrovascularcomplications in <strong>di</strong>abetes. Among these complications, reduced neovascularization in <strong>di</strong>abetesis not solely the result of reduced proliferation of local endothelial cells but is also due to adecrease of the number of circulating Endothelial Progenitor Cells (EPCs) observed in both typeI and type 2 <strong>di</strong>abetic patients. The mechanism involved in the impairment of the function ofthese cells in <strong>di</strong>abetic patients might be related to eNOS-me<strong>di</strong>ated superoxide anion production.L-Carnitine is essential for the transfer of long-chain fatty acids from cytosol into themitochondrial matrix where β-oxidation and production of cellular energy occur. Anabnormality in myocar<strong>di</strong>al energy metabolism is a reported factor in the development of<strong>di</strong>abetes-induced heart dysfunction. L-Carnitine is present in both plasma and tissue as eitherfree carnitine or bound to fatty acids as acyl-carnitine derivatives, such as propionyl-L-carnitinewhich has a higher affinity for the muscular carnitine transferase and is rea<strong>di</strong>ly converted into142ANNUAL REPORT <strong>2009</strong>
IRFMNpropionyl-coenzyme A and free carnitine, increasing the intracellular pool of L-carnitine andfree fatty acid oxidation in carnitine-deficient-states.Propionyl-L-carnitine has been shown to act as an intracellular superoxide scavenger, improvingmitochondrial function and reducing DNA damage and these properties might in part accountfor the functional improvement of <strong>di</strong>abetic heart. Similarly, the antioxidant activity ofpropionyl-L-carnitine has been reported to determine an improvement in the aortic endothelialdysfunction based on the evidences that the enhanced production of superoxide anions invascular endothelium is responsible for endothelial dysfunction, due to NO inactivation.The present study aims at evaluating whether the propionyl-L-carnitine treatment for 8 weeks inobese/<strong>di</strong>abetic ob/ob mice improves mobilization/homing of endogenous progenitor cells (socalled EPCs) and <strong>di</strong>minishes the vascular damage in myocar<strong>di</strong>um and aorta by reducingsuperoxide anion production at cellular levels and consequently increasing NO availability in amodel of swimming exercise-induce oxidative stress.GISSI-HF: biohumoral substudy and urinary markers of renal injuryThe GISSI-HF trial was designed to assess whether two treatments (a statin and n-3polyunsaturated fatty acids or PUFA) can improve the prognosis of patients with heart failure ofany etiology, with preserved or compromised left ventricular ejection fraction. Main resultshave recently been published (Lancet 2008; 372: 1223-1230 e Lancet 2008; 372: 1231-1239).The biomarker substudy aims at exploring the pathophysiology of heart failure and mechanismsof action of the treatments in study. Overall, 1237 patients have been enrolled in the substudy.Blood samples were collected at enrolment and after three months to measure plasma PUFA,and markers of ventricular myocyte stress (brain natriuretic peptides, BNP and N-terminalproBNP, MR-proANP), myocar<strong>di</strong>al damage (car<strong>di</strong>ac troponin T, measured with the standardassay or with a newly developed high sensitive method) and inflammation (C-reactive protein,CRP, pentraxin-3, PTX3). Baseline fraction of n-3 PUFA averages 3.4 and increases by about50% over 3 months. Baseline BNP concentration in 1223 patients is 141 pg/mL (me<strong>di</strong>an) andcorrelates with the severity of heart failure. The number of circulating endothelial progenitor hasbeen measured in a smaller group of 68 patients, in collaboration with the laboratory of E.Dejana (IFOM). Number of endothelial progenitor cells in patients with heart failure is 30-50%lower than in healthy volunteers was inversely correlated to morbi<strong>di</strong>ty/mortality in a populationof patients from 5 Italian centers and a Car<strong>di</strong>ology center in Frankfurt (collaboration withAndreas Zeiher). Microalbuminuria (defined as the ratio between urinary concentrations ofalbumin and creatinine) is being measured in more than 2000 patients enrolled in the GISSI-HFtrial as an in<strong>di</strong>cator of renal endothelial dysfunction. Microalbuminuria (albumin/creatinine =30-299 mg/g) is present in 19% of the patients and is a robust marker of bad outcome. New andearly markers of renal tubular injury (KIM-1, N-GAL e NAG) have been assayed in the urinesamples. Preliminary analyses in<strong>di</strong>cate that these markers are strongly associated with death,independently of microalbuminuria or renal glomerular filtration rate. Novel and more stablecirculating biomarkers have been successively assayed. They belong to the family of natriureticpeptides (mid-regional pro-atrial natriuretici peptide, MR-proANP), endothelin (C-terminal proendothelin-1,CT-proET-1), vasopressin (C-terminal pro-vasopressin, CT-proAVP) andadrenomedullin (mid-regional pro-adrenomedullin, MR-proADM). Other markers related toinfection and innate immunity are currently measured (chromogranin A, mannose-bin<strong>di</strong>nglectin, osteoprotegerin, and alpha-defensin). We are currently performing stu<strong>di</strong>es on therelationship between circulating levels of a<strong>di</strong>ponectin, single nucleotide polymorphisms of thegene enco<strong>di</strong>ng this peculiar cytokine (in collaboration with the Laboratory of Clinical DrugEvaluation of the Department), and outcome.PTX-3, a novel long pentraxin is a marker of severity of <strong>di</strong>sease and ofoutcome in car<strong>di</strong>ovascular <strong>di</strong>seases, independent of C-reactive proteinPTX-3 is a novel long pentraxin whose expression is induced by cytokines in endothelial and143ANNUAL REPORT <strong>2009</strong>
IRFMNmononuclear cells, mostly in striated muscle and heart, while C-reactive protein (CRP) ismainly synthesized in the liver. PTX3 was shown to peak in plasma around 7 h after onset ofsymptoms of MI and to be an independent pre<strong>di</strong>ctor of 3-month mortality. PTX3 has beenassayed with a more accurate method in 1200 patients with symptomatic heart failure (GISSI-HF) and in 380 patients with atrial fibrillation (GISSI-AF) to explore its role in othercar<strong>di</strong>ovascular <strong>di</strong>seases. First results in<strong>di</strong>cate that PTX3 is associated with <strong>di</strong>fferent clinicalcharacteristics in patients with heart failure, inclu<strong>di</strong>ng advanced age, ventricular dysfunction,functional class (NYHA class), and comorbi<strong>di</strong>ties such as atrial fibrillation and <strong>di</strong>abetes. PTX3independently pre<strong>di</strong>cts mortality and morbi<strong>di</strong>ty in the patients with chronic heart failure. Plasmaconcentrations of PTX3 have been measured, in collaboration with the laboratory headed byAlberto Mantovani (<strong>Istituto</strong> Clinico Humanitas, Rozzano) in samples collected in the GISSI-HFtrial, but also in samples collected in another large-scale clinical study (CORONA), thatenrolled elderly patients with heart failure of ischemic origin, randomized to rosuvastatin orplacebo. Results from both trials will be examined together to evaluate the effect of a statin onPTX3 circulating levels and the prognostic value of this marker in a population of more than3500 patients.Echocar<strong>di</strong>ographic and biohumoral substudy – GISSI-AF trialThe GISSI Atrial Fibrillation trial (GISSI-AF) tested the efficacy of Valsartan, an angiotensin IIAT1-receptor blocker, in the prevention of atrial fibrillation recurrence in 1400 patients. Asubstudy of the GISSI-AF has recently been concluded; it evaluated the potential role ofbiohumoral factors and car<strong>di</strong>ac structural remodelling in the reoccurrence and severity of atrialfibrillation. In approx. 400 patients three serial echocar<strong>di</strong>ographic exams (at randomization, 6months and 1 year) and contemporaneous blood collection were performed. Left ventricular andatrial <strong>di</strong>mensions were determined by echocar<strong>di</strong>ography, whereas plasma levels of natriureticpeptides (BNP, NT-proBNP and MR-proANP), troponin T (high sensitive method), stablevasopactive peptides (endothelin-1, Adrenomedullin and vasopressin), and inflammatorymarkers (C-reactive protein, interleukin-6 and pentraxin-3) have been measured. Besides givingclues on the pathophysiology of atrial fibrillation, the most common arrhythmia in elderly, thissubstudy aims at provi<strong>di</strong>ng mechanical insights of the potential benefits of the study drug. Thestudy was completed on January 31, 2008 and results being analyzed. Two papers, one oncar<strong>di</strong>ac markers and the other on inflammatory markers, have been prepared and are currentlyunder evaluation.CandHeart: effects of candesartan on BNP and left ventricular function inpatients with symptomatic heart failureCandesartan, an antagonist of angiotensin II type 1 receptors, significantly reduces mortalityand morbi<strong>di</strong>ty in heart failure, as shown by the CHARM trials. The principal objective of theCandHeart trial is to assess the effects of Candesartan on circulating levels of brain natriureticpeptide (BNP) in patients suffering from CHF with depressed or preserved left ventricular (LV)systolic function. The study enrolled 487 patients in 70 clinical centers with a follow-up of 1-year. Serial circulating blood samples and echocar<strong>di</strong>ographic examinations have beenperformed at baseline and after 3 and 12 months (end of study). Besides BNP, other prognosticbiomarkers such as aldosterone and microalbuminuria have been assayed. Main statisticalanalyses have been performed and a paper is being drafted.Trial Prone/Supine 2: effects of prolonged prone position on survival insevere acute respiratory <strong>di</strong>stress syndrome (ARDS)After the publication of the results of the trial, a collaborative meta-analysis has been conductedand published of all published stu<strong>di</strong>es on postural changes in adult ARDS. The meta-analysisshowed that prone position for several hours each day improves survival of patients with severe144ANNUAL REPORT <strong>2009</strong>
IRFMNARDS.DyDa: left ventricular dysfunction in <strong>di</strong>abetes. Prevalence and incidenceof left ventricular dysfunction in <strong>di</strong>abetics patients without clinical car<strong>di</strong>ac<strong>di</strong>seaseThis is a prospective, multicentric, national and epidemiological trial aimed at evaluating theprevalence of left ventricular dysfunction (systolic or <strong>di</strong>astolic) in 1000 patients with type 2<strong>di</strong>abetes mellitus but no clinical car<strong>di</strong>ovascular <strong>di</strong>sease at enrolment. The incidence of leftventricular dysfunction is monitored during a 2-year follow-up using ECG andechocar<strong>di</strong>ography. The Biomarker Core Laboratory evaluated the biohumoral profile of thesepatients at study entry, measuring the circulating levels of brain natriuretic peptide, C-reactiveprotein, microalbuminuria and glycated hemoglobin. Enrolment started in July 2006 and ende<strong>di</strong>n March 2008 with 970 patients recruited. The assays of the biomarkers are concluded and firstdata on the association between theses markers and baseline clinical characteristics are underanalysis. The follow-up phase of the study should be concluded in 2010 to get data on incidentleft ventricular dysfunction. Two manuscripts on baseline data have been drafted and arecurrently evaluated. In a subgroup of patients from the study, levels of circulating progenitorcells and their angiogenic potential in vitro will be measured to assess whether they areassociated to risk of developing car<strong>di</strong>ovascular <strong>di</strong>sorders in <strong>di</strong>abetics.Albumin Italian Outcome Sepsis Study. The ALBIOS Study (AIFA)ALBIOS is a multicenter, controlled, randomized clinical trial that compares the efficacy ofhuman albumin and a crystalloid solution for volume replacement in patients with severe sepsisor septic shock. The primary endpoint is survival at 28 and 90 days after enrolment. Secondaryendpoints include the number of organ dysfunctions, severity of organ dysfunction (SOFAscale), and lengths of stay in (intensive care unit) ICU and in hospital. More than 150 ICU inItaly are expected to participate to this large study, coor<strong>di</strong>nated by the Ospedale MaggiorePoliclinico in Milan and the Consorzio <strong>Mario</strong> <strong>Negri</strong> Sud. A group of 48 ICUs participates to abiomarkers substudy, coor<strong>di</strong>nated by the laboratory of Clinical Car<strong>di</strong>ovascular Pharmacology,with the aims of enrolling 800 patients. Serial blood samples are collected to measure thepossible effects of albumin on markers of inflammation, infection, car<strong>di</strong>ac function andcoagulation. 704 patients have been randomized by the end of <strong>2009</strong>, and blood samplescollected in at least 350 of them.Clinical, biochemical and instrumental pre<strong>di</strong>ctors of outcome inrehabilitation after car<strong>di</strong>ac surgery (MIUR)Due to the short length of hospital recovery in patients with car<strong>di</strong>ac <strong>di</strong>sease, the period ofrehabilitation becomes crucial and is in<strong>di</strong>cated for almost all the car<strong>di</strong>omyopathies, inclu<strong>di</strong>ngmyocar<strong>di</strong>al revascularization and surgery of car<strong>di</strong>ac valves. The objective of this study is toevaluate the prognostic role of circulating biomarkers in 250 patients enrolled in 5 Centers forrehabilitation after car<strong>di</strong>ac surgery. A plasma bank will be collected under the responsibility ofthe Laboratory of Car<strong>di</strong>ovascular Clinical Pharmacology from the <strong>Mario</strong> <strong>Negri</strong> Institute to assaypotential markers of interest. The project is coor<strong>di</strong>nated by the Fondazione Don Gnocchi inMilan. About 500 samples of blood and urine have been collected. Assays of high sensitivitycar<strong>di</strong>ac troponin T and microalbuminuria are concluded and statistical analyses under way.Evaluation of <strong>di</strong>fferent anesthesiological strategies for supratentorialneurosurgery. The NeuroMorfeo Study (AIFA)The aim of the study is to evaluate whether an anesthesia with volatile anesthetics is equivalentto endovenous anesthetics for elective supratentorial surgery. This is a multicenter, randomized,controlled and opened study, based on a design of equivalence for comparison of <strong>di</strong>fferent145ANNUAL REPORT <strong>2009</strong>
IRFMNanesthesiological strategies (see Laboratory of Clinical Drug Evaluation for details). Thebiohumoral response to surgical stress will be measured as an in<strong>di</strong>cator of homeostasis andneurovegetative status. The urinary excretion of catecholamines and cortisol and the plasmaconcentration of cortisol will be measured in a central laboratory. Plasma concentrations ofcortisol and urine excretion of cortisol, adrenaline and noradrenaline have been measured, incollaboration with the Laboratory of Pharmacokinetics and Clinical Chemistry from the <strong>Istituto</strong><strong>Mario</strong> <strong>Negri</strong> at Ranica. Statistical analyses and drafting of manuscripts are ongoing.Prevalence of asymptomatic car<strong>di</strong>ac dysfunction and heart failure in apopulation of elderly subjects from Lazio. The PREDICTOR StudyThis observational study aims at evaluating the prevalence of asymptomatic car<strong>di</strong>ac dysfunctionand heart failure in a random sample of elderly subjects from the Lazio area. The secondaryobjective is to identify clinical, biohumoral (natriuretic peptides) and non-invasive instrumental(echocar<strong>di</strong>ography and ECG) markers of asymptomatic car<strong>di</strong>ac dysfunction and heart failure.The population under observation is a randomly selected sample of elderly subjects (age rangingfrom 65 and 84 years) resident in the area of 10 hospital car<strong>di</strong>ology centers. In a first phase,1000 subjects have been recruited; a second phase has recently started with the objective ofenrolling another 2000 subjects. Blood samples are collected for each subject and stored in thebiobank in the Laboratory of Clinical Car<strong>di</strong>ovascular Pharmacology. Preliminary data obtaine<strong>di</strong>n the first 1000 subjects show a good pathophysiological agreement between the circulatinglevels of NT-proBNP and indexes of left or right asymptomatic car<strong>di</strong>ac dysfunction or theseverity of heart failure. By the end of <strong>2009</strong>, almost 2000 subjects have been enrolled, a figureclose to the final objective of this study.Laboratory of Clinical Drug EvaluationPROCARDIS: A genome-wide strategy to identify susceptibility loci inprecocious coronary artery <strong>di</strong>seaseThe PROCARDIS research programme, a genome-wide strategy to identify susceptibility lociin precocious coronary artery <strong>di</strong>sease (CAD) supported by the 5th Framework Programme ofthe EC, was initiated as a collaboration between the Universities of Oxford and Munster, theKarolinska Institute, the <strong>Mario</strong> <strong>Negri</strong> Institute with the support of the GISSI group, Oxagen, abiotechnology company, and AstraZeneca. The objectives of the first stage of this programmewere to collect a minimum of 2000 affected sibling pairs (ASPs) and families with precociousCAD and to apply genome-wide linkage mapping techniques, by typing anonymous highlyinformative markers spaced throughout the genome, to identify chromosomal regions which arelinked to the susceptibility to early-onset CAD. The study design is based on familyascertainment, to allow non-parametric linkage analyses (in ASPs). The PROCARDIS collected2,036 CAD families from four European countries, in order to maximise the power of detectinggenes that confer modest risks. A genome-wide linkage scan identified three promising regionsfor intensive study; one of the linked regions (Chromosome 17) was confined to families withmultiple cases of myocar<strong>di</strong>al infarction and was replicated in a second independent series offamilies. In ad<strong>di</strong>tion the linkage scan confirmed a previously identified locus on Chromosome 2.Ad<strong>di</strong>tionally, the program has collected nuclear families (e.g. parent-offspring trios) fortransmission-based tests of association for fine mapping by linkage <strong>di</strong>sequilibrium analysis andtesting of positional can<strong>di</strong>date genes. Extensive clinical and biochemical interme<strong>di</strong>atephenotype data have also been collected and assessed.The second stage of PROCARDIS, supported by the EC 6th Framework Programme, isconducting a large GWAS (genome wide association study), where the patients with myocar<strong>di</strong>alinfarction enrolled in the first stage are compared with control subjects to identify novel146ANNUAL REPORT <strong>2009</strong>
IRFMNcan<strong>di</strong>date genes. The results are replicated in <strong>di</strong>fferent populations. The collaboration has beenextended to include complementary expertise, as proteomics, bioinformatics, functionalanalysis.The PROCARDIS study identified risk loci for coronary <strong>di</strong>sease by using a novel gene chipconsisting of48,742 SNPs for 2100 can<strong>di</strong>date genes that were selected for their potential relevance tocoronary artery<strong>di</strong>sease. With this gene chip, PROCARDIS confirmed the previous identification of threechromosomal regions that were correlated with the risk of coronary <strong>di</strong>sease: 6q26–27, 9p21, and1p13.In the chromosome 9p21 region PROCARDIS has identified two SNPs, rs2891168 andrs10811661, that are independently associated with CAD and with type 2 <strong>di</strong>abetes (T2D)respectively.Recently, the PROCARDIS study has identified two single nucleotide polymorphisms (SNPs) atthe LPA locus, strongly associated to coronary <strong>di</strong>sease, with an odds ratio of 1.70 (95% CI 1.49-1.95) for rs10455872,and with an odds ratio of 1.92 (95% CI 1.48-2.49) for rs3798220. Bothvariants were strongly associated also with an increased level of lipoprotein(a), a reduced copynumber in LPA, and a small lipoprotein(a) size. These common variants explain over a third ofthe variance in lipoprotein(a) levels in in<strong>di</strong>viduals of European descent. After adjustment for theplasma lipoprotein(a) level, the association between these genotypes and coronary <strong>di</strong>sease wasabolished, in<strong>di</strong>cating a causal role of lipoprotein(a) in coronary <strong>di</strong>sease.GISSI-HF Genetic SubstudyThe GISSI (Gruppo Italiano per lo Stu<strong>di</strong>o della Sopravvivenza nell'Insufficienza car<strong>di</strong>aca) is acollaborative group endorsed by ANMCO (Associazione Nazionale Me<strong>di</strong>ci Car<strong>di</strong>ologiOspedalieri) and by the <strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong>, active from 20 years in the car<strong>di</strong>ovascular researchfield. The GISSI-HF was the fifth large scale clinical trial conducted by the Group and was aprospective, multicenter, randomized, double blind, placebo controlled study, with randomizedallocation of patients with a clinical <strong>di</strong>agnosis of heart failure ton-3 PUFA and/or to rosuvastatin to assess the effects of long-term administration of n-3 PUFAand/or rosuvastatin on all-cause mortality and car<strong>di</strong>ovascular hospitalizations.The study randomized more than 7000 patients with the participation of 357 departments ofcar<strong>di</strong>ology; in a follow-up time of four years, 27% of patients in the PUFA group <strong>di</strong>ed,compared with 29% in the placebo group, meaning a relative risk reduction of 9% in the PUFAgroup. A higher proportion of patients in the placebo group <strong>di</strong>ed or were admitted to hospital forcar<strong>di</strong>ovascular reasons than in the PUFA group. Statin treatment with rosuvastatin <strong>di</strong>d not affectclinical outcomes in patients with chronic heart failure.Several substu<strong>di</strong>es focus on possible mechanistic effects of the study treatments. Among them ageneticsubstudy conducted by nearly 100 Centres that have included 2200 patients, gives theopportunity to improve knowledge on the role of genetic factors involved in heart failure,through a collection of blood samples of a large population of patients, involving cases of heartfailure of <strong>di</strong>fferent etiologies, i.e. non-ischaemic and ischaemic heart <strong>di</strong>sease.The role of genetic factors in causes, evolution, prognosis and treatment of heart failure islargely unexplored, with the exception of heart failure originated by specific car<strong>di</strong>omyopathies(such as <strong>di</strong>lated, hypertrophic, arrhythmogenic right ventricular car<strong>di</strong>omyopathies), for whichthe role of heritable gene mutations is increasingly well understood. Heart failure (HF) is asyndrome with <strong>di</strong>fferent etiologies, and more than one half is caused by coronary heart <strong>di</strong>sease(CHD). The objective of the genetic substudy is 1) to assess the relationships between thepolymorphysms of various can<strong>di</strong>date genes and the clinical outcome in patients enrolled inGISSI-HF study; 2) to assess whether these relationships are mo<strong>di</strong>fied by the experimentaltreatments.147ANNUAL REPORT <strong>2009</strong>
IRFMNGISSI-Prevenzione-Genetic StudyMyocar<strong>di</strong>al infarction is a multifactorial <strong>di</strong>sease. While the role of known risk factors oncoronary heart <strong>di</strong>sease susceptibility is well defined, the impact of the genetic components an<strong>di</strong>ts interaction with environmental factors need investigation. The GISSI-Prevenzione trialinvestigated the effects of pharmacological treatments with n-3 PUFA and pravastatin onmorbi<strong>di</strong>ty and mortality after myocar<strong>di</strong>al infarction. During the study more than 8000 samplesof a large population of patients affected by this <strong>di</strong>sease have been collected and stored with thecollaboration of SIBioC (Societê Italiana <strong>di</strong> Biochimica Clinica e Biologia Molecolare). TheGISSI-Prevenzione-Genetic Study investigates the role of genetic factors in ischaemic heart<strong>di</strong>sease. The objectives of the project are 1) to assess the relationships between thepolymorphysms of various can<strong>di</strong>date genes and the clinical outcome in patients enrolled in thelarge clinical trial GISSI-Prevenzione study; 2) to assess whether these relationships aremo<strong>di</strong>fied by the pharmacological treatments. Accor<strong>di</strong>ng to these objectives, we investigated therelationship between APOE, mortality and the response to treatment in 3300 myocar<strong>di</strong>alinfarction survivors randomized to pravastatin or no treatment. We found that epsilon 4 allele isa determinant of pravastatin response in terms of survival (Eur Heart J 2007; 28:1977-1983).Association stu<strong>di</strong>es in the same population on the a<strong>di</strong>ponectin gene variants, the CRP (Creactiveprotein) gene variants, some genetic variants on Chromosome 9p21 are in progress. Agenetic assessment of PTX3 protein, a novel long pentraxin whose expression is induced bycytokines in endothelial and mononuclear cells, and involved in the atherogenesis process, isongoing in collaboration with the <strong>Istituto</strong> Clinico Humanitas and the IRCCS San GiovanniRotondo.GISSI-AF. Clinical trial testing the efficacy of an angiotensin II AT1-receptor blocker in Atrial FibrillationThe GISSI-AF is a randomized, prospective, parallel group, placebo-controlled, multicenterstudy on the use of valsartan, an angiotensin II AT1-receptor blocker in the prevention of AtrialFibrillation (AF) recurrence.Atrial fibrillation is the most frequent form of arrhythmia in clinical practice, affecting 6% ofpeople over 65 years old. The tra<strong>di</strong>tional therapies are often able to restore the sinus rhythm butare subject to a very high percentage of relapses, above all when the AF has been present for along time and when there are structural changes at both atrial and ventricular level. The reninangiotensin-aldosteronesystem (RAAS) plays a key role in the “remodelling” phenomenon,which makes increasingly irreversible the electrical, mechanical and structural properties of theatrial tissue. Existing experimental and clinical data do not allow any definite conclusionregar<strong>di</strong>ng the efficacy of an angiotensin II AT1-receptor blocker in the prevention of AF. TheGISSI group decided to conduct a specific trial of adequate size versus placebo aimed to assessif the ad<strong>di</strong>tion of valsartan on top of established therapies can reduce the recurrence of atrialfibrillation in patients with a history of recent AF associated with car<strong>di</strong>ovascular<strong>di</strong>seases/comorbi<strong>di</strong>ties. The study has recruited and treated for 12 months 1400patients with ahistory of recent AF associated with car<strong>di</strong>ovascular <strong>di</strong>seases/comorbi<strong>di</strong>ties. In GISSI-AF, thelargest trial ever conducted with ARBs in pts with AF, Valsartan <strong>di</strong>d not reduce AF recurrence.A trend favouring valsartan was observed only in the small group of pts with heart failureand/or left ventricular dysfunction.The project was conducted in collaboration with the Laboratory of Car<strong>di</strong>ovascular ClinicalPharmacology.148ANNUAL REPORT <strong>2009</strong>
IRFMNEvaluation of <strong>di</strong>fferent anesthesiological strategies for supratentorialneurosurgery. The NeuroMorfeo Study (AIFA)NeuroMorfeo is a multicenter, randomized, controlled and open study, based on an equivalencedesign, with the aim to assess whether an anesthesia with volatile anesthetics is equivalent toendovenous anesthetics for elective supratentorial surgery. The study is financed by the AIFAand is coor<strong>di</strong>nated by the San Gerardo Hospital in Monza, with the support of the Department ofCar<strong>di</strong>ovascular Research of the <strong>Mario</strong> <strong>Negri</strong> Institute.The study recruitment has been completed by 14 neurosurgical centers in Italy that haverandomized 411 patients admitted for elective intracranial surgery with supratentorial lesionswithout signs of endocranial hypertension (range of age 18-75 years).Statistical analyses and drafting of manuscripts are ongoing.Collaboration with the Population Health Research Institute (PHRI)The Population Health Research Institute (PHRI), McMaster University, Hamilton, Ontario, isthe coor<strong>di</strong>nating center of a multinational network of car<strong>di</strong>ology clinics that collaborate tomulticenter large scale clinical trials (nearly 40 Countries and more than 600 car<strong>di</strong>ology clinics).The Laboratory of Clinical Drug Evaluation is responsible for the scientific coor<strong>di</strong>nation in Italyof some of these trials (INTER-HEART, CURE, ACTIVE, RE-LY, CURRENT, OASIS-8FUTURA, AVERROES).ACTIVE study (Atrial Fibrillation Clopidogrel Trial with Irbesartan forprevention of Vascular Events)The aims of the study were to evaluate whether clopidogrel plus acetylsalicylic acid (ASA) issuperior to ASA alone (A study) and non-inferior to standard oral anticoagulant therapy (Wstudy) in preventing vascular events in patients with atrial fibrillation and to evaluate whetherblood pressure lowering with irbesartan is superior to placebo in preventing vascular events inpatients with atrial fibrillation (I study). The primary efficacy outcome is the first occurrence ofstroke, myocar<strong>di</strong>al infarction, vascular death over the duration of follow-up, (a minimum of 2and maximum of 4 years approximately). A sample size of 14000 patients was planned, 6500 inthe W study (testing the efficacy of warfarin vs ASA + clopidogrel) and 7500 in the A study(testing the efficacy of ASA + clopidogrel vs ASA alone). The W study was stopped early bythe Data and Safety Monitoring Board in September 2005 after an interim analysis showing asignificant <strong>di</strong>fference in favour of warfarin over the combination of ASA + clopidogrel. Thedetails of the ACTIVE W have been published (Lancet 2006; 367:1903-1912). The A and the Istu<strong>di</strong>es have been now completed: the ACTIVE A showed that the ad<strong>di</strong>tion of clopidogrel toaspirin reduces the risk of major car<strong>di</strong>ovascular events and car<strong>di</strong>ovascular deaths by 11% withrespect to a treatment with aspirin alone. In the ACTIVE I the irbesartan treatment <strong>di</strong>d not affectthe primary endpoint (a composite of stroke, MI and vascular death); however, the secondaryendpoint of the study (hospitalization for car<strong>di</strong>ac failure) was reduced.RE-LY Study (Randomized Evaluation of Long term anticoagulanttherapY)Non-valvular atrial fibrillation is implicated in nearly 15% of strokes. Dose-adjusted warfarindecreases the risk of stroke by 62%. However, in practice, the risk of blee<strong>di</strong>ng, the variability ofanticoagulation intensity and the need of frequent monitoring and dose adjustments limit thetreatment with warfarin, leaving patients outside the therapeutic range almost half the time.Underuse of warfarin in patients with atrial fibrillation at high risk of blee<strong>di</strong>ng calls for safer,more reliable alternatives. For these reasons an international multicentre, randomized, activecontrolled, parallel group, non-inferiority, clinical trial (RE-LY study) was designed to evaluate149ANNUAL REPORT <strong>2009</strong>
IRFMNthe efficacy and safety of dabigatran etexilate, a <strong>di</strong>rect thrombin inhibitor, compared with openlabel adjusted warfarin for the prevention of stroke and systemic embolism in patients with nonvalvularatrial fibrillation. The study recruited more than18000 patients. The me<strong>di</strong>an duration ofthe follow-up period was 2.0 years. Dabigatran given at a dose of 110 mg was associated withrates of stroke and systemic embolism that were similar to those associated with warfarin, aswell as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, ascompared with warfarin, was associated with lower rates of stroke and systemic embolism butsimilar rates of major hemorrhage. The <strong>di</strong>rect thrombin inhibitor dabigatran may offer fixed oraldosing without need for coagulation monitoring, rapid onset and offset of action, stablepharmacokinetics with little potential for drug interactions, and no known food interactions.AVERROES Study (Apixaban VErsus ASA to Reduce the Rate Of EmbolicStroke)Although vitamin K antagonists (VKA) are effective for preventing stroke or systemicembolism in patients with atrial fibrillation (AF), complexity of use and blee<strong>di</strong>ng risk limit theirpotential benefit. Many patients not treated with VKA receive aspirin.There are two main groups of patients with AF who could benefit from a better antithromboticthan ASA: (1) Those not expected to do well on VKA; and (2) Those with only a moderate riskfor stroke.Aspirin is presently the only alternative to VKA to prevent stroke in patients with AF but isrelatively ineffective, reducing the risk of stroke or systemic embolism by about one-fifthcompared with a two-thirds reduction by VKA. New treatments that are more effective thanASA but do not share the many limitations of VKA are required. AVERROES is the only studyof a new anticoagulant that <strong>di</strong>rectly addresses this important unmet need. Patients with AF(n=5600) not suitable for VKA, for one or more of the reasons given above, are randomized toreceive a new oral anticoagulant, Apixaban, or aspirin. Apixaban is simple to use, convenient,does not require laboratory monitoring, does not interact with foods, and has very few druginteractions. Successful completion of the AVERROES trial will potentially establish Apixabanas an effective alternative to ASA for those unsuitable for oral anticoagulation and also for thoseat moderate risk.CURRENT OASIS-7 StudyOASIS 7 is a randomized, multinational, 2X2 factorial design, parallel-group, double-blindstudy, comparing a high loa<strong>di</strong>ng dose regimen of clopidogrel versus standard dose and highdose regimen of aspirin versus standard dose, in patients with acute coronary syndrome (ACS)managed with an early invasive strategy. The study recruited more than 25000 patients in 800clinical centers worldwide, 17232 of them undergone planned angioplasty (PCI). The primaryobjective of the study was to determine whether a high dose regimen of clopidogrel is superiorto a standard dose of clopidogrel in preventing CV death, myocar<strong>di</strong>al infarction or stroke and todetermine if high dose of aspirin is as safe as low dose in terms of TIMI major blee<strong>di</strong>ng rate.In terms of efficacy, there was no significant <strong>di</strong>fference in the primary outcome or itscomponents, although there was a numerical reduction with the higher dose of aspirin.However, doubling the loa<strong>di</strong>ng and maintenance doses of clopidogrel in ACS patientsundergoing planned PCI significantly reduced stent thrombosis and car<strong>di</strong>ovascular events,largely driven by reductions in MI, without a significant increase in major blee<strong>di</strong>ng.FUTURA OASIS-8 StudyFUTURA is the eighth in the series of Organization to Assess Strategies in Acute IschemicSyndromes (OASIS) trials.FUTURA builds upon the MICHELANGELO: OASIS 5 & 6 trials to determine the optimaldose of adjunctive UFH during PCI in patients with unstable angina or myocar<strong>di</strong>al infarction150ANNUAL REPORT <strong>2009</strong>
IRFMNwithout ST-segment elevation on a background of fondaparinux. While the existing safetyexperience from OASIS 5 and OASIS 6 supports the use of UFH during PCI in patients initiallytreated with fondaparinux, it is based on relativelylimited patient numbers and on retrospective analyses.The FUTURA study will expand the safety experience in UA/NSTEMI patients initially treatedwith fondaparinux who undergo PCI with adjunctive UFH, while also addressing the questionof the optimal dosing strategy with adjunctive UFH during the procedure. The study design willconsist of:• An international, prospective cohort study of high risk patients presenting to hospital withUA/NSTEMI who are treated with s.c. fondaparinux as initial me<strong>di</strong>cal therapy and referredfor early coronary angiography and potentially PCI.• A double-blind, international, randomized, parallel-group study evaluating standard versus lowdose adjunctive i.v. UFH in those patients where a PCI procedure is in<strong>di</strong>cated.In ad<strong>di</strong>tion, subjects with multi-vessel <strong>di</strong>sease will be further randomised in a partial 2x2factorial sub-study, assessing culprit vessel only revascularization or completerevascularization.Laboratory of General Practice ResearchRisk and Prevention Study (R&P)R&P is a study on the optimization of car<strong>di</strong>ovascular prevention of subjects at high riskperformed at national level by General Practitioners.Study objective and design- Controlled clinical trial, double-blind and randomised, of the efficacy of a n-3 PUFA treatmentin reducing the incidence of car<strong>di</strong>ovascular events, both fatal and non-fatal, in a populationdefined as at high risk by participating GPs.- Practicability and overall yield of the preventive interventions adopted (outcome study) Theepidemiological and care history of this population shall form the object of a specific evaluationaccor<strong>di</strong>ng to a plan of formal predefined analyses.Study populationInclusion criteriaAmong the subjects deemed by GPs to be at high car<strong>di</strong>ovascular risk, patients are selected ifpresenting:- multiple risk factors (e.g. hypertension, hypercholesterolemia, <strong>di</strong>abetes, smoking, familyhistory of myocar<strong>di</strong>al infarction, obesity, sex and old age)- previous car<strong>di</strong>o-cerebrovascular events or clinical manifestations of atherosclerotic <strong>di</strong>sease(stroke, TIA, peripheral arteriopathy, previous arterial revascularisation procedures, anginapectoris).Exclusion criteria- serious co morbi<strong>di</strong>ty with an unfavourable prognosis over the short term (e.g. cancer)- expected non-compliance over a long period of time; contrain<strong>di</strong>cations (known allergies to n-3PUFA)- in<strong>di</strong>cations (previous MI) for treatment with n-3 PUFA.Efficacy measuresThe primary objective is to evaluate if a long-term administration of n-3 PUFA is more effectivethan the correspon<strong>di</strong>ng placebo in reducing car<strong>di</strong>ovascular mortality and hospitalization forcar<strong>di</strong>ovascular causes (primary end-point).Randomisation is central, stratified by GP.The experimental treatment consists of one capsule containing 1g of n-3 PUFA, or thecorrespon<strong>di</strong>ng placebo, to be taken daily.The duration of follow-up is 5 years.151ANNUAL REPORT <strong>2009</strong>
IRFMNIn order to document with sufficient statistical reliability that the experimental treatment with n-3 PUFA reduces of 15% the incidence of the events considered in the primary end-point, a totalof 12,000 patients is required.Up-date of the study: From February 2004 to March 2007 12,521 patients have been enrolledby a network of 860 GPs. The Local Health Authorities involved are 57 and in each oneinvestigator’s meeting has been organized. The characteristics of the population so far enrolledare the following: mean age 65 years, males 62%, hypertension 79%, hypercholesterolaemia62%, <strong>di</strong>abetes 56%, smokers 16%, obesity 35%, family history of premature myocar<strong>di</strong>alinfarction 20%. Twenty five% of patients have a clinical manifestation of atherosclerotic<strong>di</strong>seases, 50% have <strong>di</strong>abetes in association with another risk factor and 23% have multiple riskfactors.The trial will continue until the minimum expected number of 1,383 events will occurred.More information available on the website www.rischioeprevenzione.it.Epidemiological and clinical profile of <strong>di</strong>abetic patients in LombardyRegion using administrative databases.The study is part of an ongoing pharmacoepidemiological project in collaboration with theHealth Department of the Lombardy Region. Its main objective is the definition of a model toassess and control the use of health resources of <strong>di</strong>abetic patients by means of integratedadministrative database.Specific aims of the study are:• To describe prevalence, incidence, hospitalization and mortality of the <strong>di</strong>abetic populationeach year, from 2000 to 2007.• To assess the prescriptions of both anti-<strong>di</strong>abetic and car<strong>di</strong>ovascular drugsDiabetic patients have been identified each year if they met one of the three following criteria: -a prescription of an A10 drug: insulin and/or oral glucose lowering agent ; - the occurrence of atleast one hospitalization with Disease Related Group (DRG)=294 or DRG=295; presence of theexemption code number 013.250 in<strong>di</strong>cating <strong>di</strong>abetes. Data from prescription database, hospitaladmission and outpatient clinic visits and examinations were also included in the analysis vialinkage to the personal identification number (national identifiers). Results are in the processingphase.“Glicine-Spider” Study“Glicine-Spider” is an observational study, carried out in the Coronary Care Unit (CCU) ofLombardy. The protocol is the result of a collaboration between the ANMCO (ItalianAssociation of Hospital Car<strong>di</strong>ologists) Lombar<strong>di</strong>a , AMD (Association of Me<strong>di</strong>calDiabetologists) Lombar<strong>di</strong>a and the <strong>Mario</strong> <strong>Negri</strong> Institute. The study is coor<strong>di</strong>nated by the“General Practice Research Laboratory” and the “Clinical Drug Evaluation Laboratory”.Hyperglycemia at the onset of an acute coronary syndrome (ACS) constitutes a negativeprognostic factor in <strong>di</strong>abetic and non-<strong>di</strong>abetic patients and a poor control of blood glucose in theearly hours after hospital admission for ACS is an ad<strong>di</strong>tional unfavourable prognostic factor.Recent guidelines, although recognizing the importance of controlling blood glucose in ACS, donot clearly define therapeutic strategies to apply and target range.Patients with and without <strong>di</strong>abetes hospitalized in CCU for a confirmed ACS.The aim of the study is to describe in a large sample of patients hospitalized in CCU for a ASC:• the prevalence of <strong>di</strong>abetes and hyperglycemia• the type of treatment and blood glucose control during the acute phase• the incidence of mortality and car<strong>di</strong>ovascular complications occurred during thehospitalization accor<strong>di</strong>ng to <strong>di</strong>agnosis and blood glucose levelIt was estimated a sample of about 1300 patients. The study is currently ongoing.152ANNUAL REPORT <strong>2009</strong>
IRFMNThe stratification of global car<strong>di</strong>ovascular risk in hypertensive patients ofthe <strong>di</strong>strict of Borbon – EcuadorThe Laboratory is involved in a collaborative project with the Cecomet (Centro deEpidemiologia comunitaria y Me<strong>di</strong>cina tropical) in Esmeralda, Ecuador, on the prevalence andtreatment of hypertension in the <strong>di</strong>strict of Borbon, a rural zone of Ecuador in the northern partof the country.In this area, 36% of the adult population is affected by hypertension and more than half ofhypertensive patients present blood pressure levels > 160/110 mmHg.From 2001, in the District is ongoing an intensive follow-up of the hypertensive population withthe following aims: to evaluate the global car<strong>di</strong>ovascular risk of the population, to better controlblood pressure levels increasing the number of subjects treated with hypertensive therapy (inparticular those at high car<strong>di</strong>ovascular risk) and monitoring of the clinical complications.Preliminary data show that:• Patients treated with hypertensive therapy are increased from 39% to 59%• Antihypertensive drugs are mainly prescribed to subjects with high blood pressure levels(80% of those with systolic blood pressure >180mmHg are actually under treatment) or athigh car<strong>di</strong>ovascular risk (82%)• Blood pressure control is improved (patients with systolic blood pressure levels> 180mmHg decreased from 33% to 24% and those with levels
IRFMNThe study of the genetic component of multifactorial <strong>di</strong>seases, such as the car<strong>di</strong>ovascular<strong>di</strong>sease, has been dealt with in the PROCARDIS study, by means of the genome-widescreening. This technique aims at identifying genes that can cause coronary <strong>di</strong>sease.PROCARDIS database gave the opportunity of studying some quantitative traits such as thelevel of lipids or body max indexes.During the second step of the PROCARDIS project, supported by the 6 th Framework Programof EEC, a screening on the whole genome has been carried out by means of the “genome-wideassociation” technique. For this project about 1 million of polymorphisms (SNPs) have beenanalyzed in order to identify a possible relationship with coronary <strong>di</strong>sease.Concerning the GISSI-Genetic Prevention study, the laboratory has developed statisticsgenetics techniques to analyze case control stu<strong>di</strong>es in order to assess the association of geneticvariants linked to a<strong>di</strong>ponectin, HsCRP, PTX3 with coronary <strong>di</strong>sease. Besides, the associationbetween some polymorphisms of chromosome 9p area and coronary <strong>di</strong>sease has been evaluate<strong>di</strong>n <strong>di</strong>abetic patients.From a strictly epidemiologic point of view, the epidemiologic and health-care history of<strong>di</strong>abetes mellitus in Regione Lombar<strong>di</strong>a has been investigated by means of administrativedatabases.Laboratory of Clinical PharmacologyQuality of Life, Depression and Cognitive problems in heart failurepatients (QDF-GISSI-HF)The project is a sub-project of the GISSI-HF study. The aims of the study are 1) to describe theevolution of depression, cognitive problems and the quality of life in a sample of 1500 heartfailure patients; 2) to assess the use of common instruments that measure QDF variables; 3) tocompare the assessment of the instrument (Geriatric Depression scale, Mini Mental StateExamination, Kansas City Car<strong>di</strong>omiopathy Questionnaire) with the clinical perception of thenurses; 4) to describe if assessed or perceived patients' problems (low quality of life, highdepression or compromised cognitive function) lead to any caring intervention.The baseline clinical characteristics of the 1564 patients included in the QDF study are closelycomparable with those of the GISSI-HF population. The study instruments could be validlyadministered to the greatest majority of patients (KCQQ 97.2%, GDS 94.9%, MMSE 80.6% ofpatients >70 years).The nurses network nested in a major clinical trial, has produced one of the largest prospectivecohort of HF patients who are comprehensively assessed and prospectively monitored, to allowan integrated evaluation of the relevance and implications of QDF measurements also on theclinical outcomes of this population.154ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF MOLECULARBIOCHEMISTRY ANDPHARMACOLOGYSTAFFHead<strong>Mario</strong> SALMONA, Food Technology D, Ph.D.Laboratory of Biochemistry and Protein ChemistryHead <strong>Mario</strong> SALMONA, Food Technology D,Ph.D.Synaptic Transmission UnitHeadMarco GOBBI, Pharm.D.Laboratory of Molecular BiologyHeadEnrico GARATTINI, M.D.Pharmacogenomics UnitHeadMaddalena FRATELLI, Biol.Sci.D.Gene Structure and Regulation UnitHeadMineko TERAO, Bioch.D., Ph.D.Laboratory of Receptor PharmacologyHeadTiziana MENNINI, Pharm.D.Laboratory of Molecular PathologyHeadLavinia CANTONI, Biol.Sci.D.Laboratory of Translational ProteomicsHeadValentina BONETTO, Chem.Pharm.D.Laboratory of Systems BiologyHeadGianfranco BAZZONI, M.D.155ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULA<strong>Mario</strong> Salmona obtained his doctorate degree in Biochemistry and Food Technology atthe University of Milan in 1971. His background is in biochemistry, biophysics andpharmacology. His scientific interests relate to problems of human and animal <strong>di</strong>seasesoriginating from the aberrant fol<strong>di</strong>ng of proteins. In this context, a major portion of hisstu<strong>di</strong>es was devoted to the etiopathogenesis and therapy of prion <strong>di</strong>seases. He haspublished over 200 articles on peer reviewed scientific journals.1971-1975 Ph.D in Pharmacology, <strong>Mario</strong> <strong>Negri</strong> Institute1975 Visiting Fellow in the Department of Biology of the Weizmann Institute ofScience, Rehovot, Israel1976-1997 Head, Laboratory of Enzyme Research, <strong>Mario</strong> <strong>Negri</strong> Institute1995 to date Dean of the School of Advanced Pharmacology, <strong>Mario</strong> <strong>Negri</strong> Institute1997 to date Head, Department of Biochemistry and Molecular Pharmacology, <strong>Mario</strong><strong>Negri</strong> Institute2003 to date Member of the American Society of Biochemistry and Molecular BiologyReferee for international scientific journals.Selected publications• Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T,Chiesa R, Gobbi M, Salmona M, Forloni GSynthetic amyloid-beta oligomers impair long-term memory independently of cellular prion proteinProc Natl Acad Sci U S A.[Epub ahead of print], <strong>2009</strong>• Di Fede G, Catania M, Morbin M, Rossi G, Suar<strong>di</strong> S, Mazzoleni G, Merlin M, Giovagnoli A R, Prioni S, Erbetta A,Falcone C, Gobbi M, Colombo L, Bastone A, Beeg M, Manzoni Clau<strong>di</strong>a, Francescucci B, Spagnoli A, Cantu' L, DelFavero A, Levy E, Salmona M, Tagliavini FA recessive mutation in the APP gene with dominant-negative effect on amyloidogenesisScience 323: 1473-1477, <strong>2009</strong>• Saracino GA, Villa A, Moro G, Cosentino U, Salmona M.Spontaneous beta-helical fold in prion protein: The case of PrP(82-146)Proteins 75: 964-76, <strong>2009</strong>• De Luigi A, Colombo L, Diomede L, Capobianco R, Mangieri M, Miccolo C, Limido L, Forloni G, Tagliavini F,Salmona M.The efficacy of tetracyclines in peripheral and intracerebral prion infection.PLoS ONE 3(3):e1888, 2008• Cosentino U, Pitea D, Moro G, Saracino GA, Caria P, Varì RM, Colombo L, Forloni G, Tagliavini F, Salmona M.The anti-fibrillogenic activity of tetracyclines on PrP 106-126: a 3D-QSAR study.J Mol Model. 14: 987-94, 2008• Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantù L, Kirschner DA, ManzoniC, Beeg M, Ceci P, Ubezio P, Forloni G, Tagliavini F, Salmona M.Gerstmann-Sträussler-Scheinker <strong>di</strong>sease amyloid protein polymerizes accor<strong>di</strong>ng to the "dock-and-lock" model.J Biol Chem 281: 843-9, 2006Gianfranco Bazzoni got his Me<strong>di</strong>cine and Surgery degree in 1988 (at the Universityof Milan) and the specialisation in Pharmacological Research in 1992 (at the <strong>Mario</strong><strong>Negri</strong> Institute, Milan). His area of expertise is cell biology, with focus on theprocesses of cell adhesion and migration.1988-2000 Research Fellow, <strong>Mario</strong> <strong>Negri</strong> Institute1993-1997 Post-doctoral Fellow, Dana Farber Cancer Institute and Harvard Me<strong>di</strong>calSchool, Boston, MA2000-2002 Research Scientist, <strong>Mario</strong> <strong>Negri</strong> Institute2003 Head, Unit of Cell Adhesion, <strong>Mario</strong> <strong>Negri</strong> Institute2004 to date Head, Laboratory of Systems Biology, <strong>Mario</strong> <strong>Negri</strong> Institute2004 Regular Member of The American Physiological Society, Bethesda, MDReferee for international scientific journals156ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Paris L, Bazzoni GThe protein interaction network of the epithelial junctional complex: a system-level analysis Mol Biol Cell 19: 5409-5421, 2008• Paris L, Tonutti L, Vannini C, Bazzoni GStructural organization of the tight junctionBiochim Biophys Acta 1778: 646-659, 2008• Huang H, Cruz F, Bazzoni GJunctional adhesion molecule-A regulates cell migration and resistance to shear stressJ. Cell Physiol 209; 122-130, 2006• Martinez-Estrada OM, Manzi L, Tonetti P, Dejana E, Bazzoni GOpposite effects of Tumor Necrosis Factor and soluble fibronectin on Junctional Adhesion Molecule-A in endothelialcellsAm J Physiol (Lung Cell Mol Physiol) 288: L1081-L1088, 2005• Bazzoni G, Tonetti P, Manzi L, Cera MR, Balconi G, Dejana EExpression of Junction Adhesion Molecule-A prevents spontaneous and random motility.J Cell Sci 118: 623-632, 2005• Bazzoni G, Dejana EEndothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84: 869-901,2004Valentina Bonetto has got the degree in Pharmaceutical Chemistry and Technology atthe University of Padua, Italy in 1993. She has got the Ph.D in Me<strong>di</strong>cal Biochemistryand Biophysics at Karolinska Institutet, Stockholm, Sweden.Her principal lines of research are: 1) Study of the pathogenetic mechanisms at the basisof amyotrophic lateral sclerosis (ALS); 2) Identification of biomarkers of ALS; 3) Roleof the oxidative mo<strong>di</strong>fication in neurological <strong>di</strong>sorders. These issues are investigated by<strong>di</strong>fferent experimental approaches, inclu<strong>di</strong>ng proteomics and mass spectrometry.2000-<strong>2009</strong> Research Scientist, Laboratory of Biochemistry and Protein Chemistry,<strong>Mario</strong> <strong>Negri</strong> Institute2002-<strong>2009</strong> also Assistant Telethon Scientist at Dulbecco Telethon Institute2007-<strong>2009</strong> Head, Unit of Me<strong>di</strong>cal Biochemistry, Laboratory of Biochemistry andProtein Chemistry, <strong>Mario</strong> <strong>Negri</strong> InstituteFrom <strong>2009</strong> to date, Head Laboratory of Translational Proteomics and AssociateTelethon Scientist.She is author of 26 publications from 1994 to 2007, in peer-reviewed journals. Amongthem she is first author in 11 and last author in 4. She is also author of 2 reviews. She isreviewer for scientific journals in the field of Proteomics and Neuroscience.Selected publications• Massignan T, Biasini E, Lauranzano E, Veglianese P, Pignataro M, Fioriti L, Harris DA, Salmona M, Chiesa R, BonettoVMutant prion protein expression is associated with an alteration of the Rab GDP <strong>di</strong>ssociation inhibitor alpha (GDI)/Rab11pathway.Mol Cell Proteomics [Epub ahead of print], <strong>2009</strong>• Basso M, Samengo G, Nardo G, Massignan T, D’Alessandro G, Tartari S, Cantoni L, Marino M, Cheroni C, De Biasi S,Giordana MT, Strong MJ, Estevez AG, Salmona M, Bendotti C, Bonetto VCharacterization of detergent-insoluble proteins in ALS in<strong>di</strong>cates a causal link between nitrative stress and aggregation inpathogenesisPLoS ONE 4:e8130, <strong>2009</strong>• Nardo G, Pozzi S, Mantovani S, Garbelli S, Marinou K, Basso M, Mora G, Bendotti C, Bonetto VNitroproteomics of peripheral blood mononuclear cells from patients and a rat model of ALSAntioxid. Redox Signal 11: 1559-1567, <strong>2009</strong>• Massignan T, Casoni F, Basso M, Stefanazzi P, Biasini E, Tortarolo M, Salmona M, Gianazza E, Bendotti C, Bonetto VProteomic analysis of spinal cord of presymptomatic amyotrophic lateral sclerosis G93A SOD1 mouseBiochem. Biophys. Res. Commun. 353: 719-25, 2007• Basso M, Massignan T, Samengo G, Cheroni C, De Biasi S, Salmona M, Bendotti C, Bonetto VInsoluble mutant SOD1 is partly oligoubiquitinated in amyotrophic lateral sclerosis mice157ANNUAL REPORT <strong>2009</strong>
IRFMNJ. Biol. Chem. 281:33325-33335, 2006• Casoni F, Basso M, Massignan T, Gianazza E, Cheroni C, Salmona M, Bendotti C, Bonetto VProtein nitration in a mouse model of familial amyotrophic lateral sclerosis: Possible multifunctional role in thepathogenesis. J. Biol. Chem., 280: 16295-16304, 2005Lavinia Cantoni obtained her degree in Biological Sciences in 1973 at the Universityof Milan. Then she specialized in pharmacological research at the <strong>Mario</strong> <strong>Negri</strong> Institute(1974-1977).Research areas 1) biochemical-molecular mechanisms activated by oxidative stress 2)drug metabolism 3) porphyrias.1977-1978 Post-doctoral Fellow, Me<strong>di</strong>cal Research Council, Toxicology Unit,Carshalton, UK (Winner of a Welcome Trust Research Fellowship)1979-1982 Research Scientist, <strong>Mario</strong> <strong>Negri</strong> Institute1980-1990 Visiting Scientist, Toxicology Unit, Carshalton, UK, and Cornell Me<strong>di</strong>calCenter, New York, NY (short periods)1983-1997 Head, Unit of Heme and Hemoprotein Metabolism, <strong>Mario</strong> <strong>Negri</strong> Institute1998 to date, Head, Laboratory of Molecular Pathology, <strong>Mario</strong> <strong>Negri</strong> Institute1975 to date Member of the National Roll of Biologists1983 to date Member of the Italian Toxicology SocietyReferee for international scientific journals.Selected publications• Tartari S, D’Alessandro G, Babetto E, Rizzar<strong>di</strong>ni M, Conforti L, Cantoni L.Adaptation to G93Asuperoxide <strong>di</strong>smutase 1 in a motor neuron cell line model of amyotrophic lateral sclerosis. The roleof glutathioneFEBS J. 276: 2861-2874, <strong>2009</strong>• Raimon<strong>di</strong> A, Mangolini A, Rizzar<strong>di</strong>ni M, Tartari S, Massari S, Bendotti C, Francolini M, Borghese N, Cantoni L,Pietrini G.Cell culture models to investigate the selective vulnerability of motoneuronal mitochondria to familial ALS-linkedG93ASOD1Eur. J. Neurosci. 24: 387-399, 2006• Babetto E, Mangolini A, Rizzar<strong>di</strong>ni M, Lupi M, Conforti L, Poletti A, Rusmini P, Cantoni L. Tetracycline-regulated geneexpression in the NSC-34-tTA cell line for investigation of motor neuron <strong>di</strong>seasesMol. Brain Res. 140: 63-72, 2005• Cantoni L,Valaperta R, Ponsoda X, Castell JV, Barelli D, Rizzar<strong>di</strong>ni M, Mangolini A, Hauri L, Villa P.Induction of hepatic heme oxygenase-1 by <strong>di</strong>clofenac in rodents: role of oxidative stress and cytochrome P-450 activityJ. Hepatology 38: 776-783, 2003• Cantoni L, Rozio M, Mangolini A, Hauri L, Caccia S.Hyperforin contributes to the hepatic CYP3A-inducing effect of Hypericum perforatum extract in the mouse.Toxicol.Sci. 75:25-30, 2003• Rizzar<strong>di</strong>ni M, Zappone M, Villa P, Gnocchi P, Sironi M, Diomede L, Meazza C, Monshouwer M, Cantoni L.Kupffer cell depletion partially prevents hepatic heme oxygenase 1 messenger RNA accumulation in systemicinflammation in mice: role of interleukin 1 betaHepatology 27: 703-710, 1998Enrico Garattini obtained his degree in Me<strong>di</strong>cine and Surgery with full marks(110/110) in 1982 at the University of Milan. His scientific interests relate to problemsof Cellular Biology and Molecular Biology.1982-1990 Research Fellow of the National Research Council, <strong>Mario</strong> <strong>Negri</strong> Institute1983-1987 Postdoctoral Researcher at the Roche Institute of Molecular Biology,Department of Neurosciences Nutley, New Jersey, US1991-1997 Senior Researcher Regione Lombar<strong>di</strong>a and Head of the Molecular BiologyUnit, <strong>Mario</strong> <strong>Negri</strong> Institute1997 to date Head, Laboratory of Molecular Biology, <strong>Mario</strong> <strong>Negri</strong> InstituteFrom 2005 Dean, Advanced School of Pharmacology (Philosophy Doctor), <strong>Mario</strong> <strong>Negri</strong>158ANNUAL REPORT <strong>2009</strong>
IRFMNInstituteMember of the E<strong>di</strong>torial Board of the European Journal of Cancer and of CurrentCancer Therapy ReviewsMember of the American Society of Biochemistry and Molecular Biology (ASBMB)Selected publications• Gianni M, Boldetti A, Guarnaccia V, Rambal<strong>di</strong> A, Parrella E, Raska I Jr, Rochette-Egly C, Del Sal G, Rustighi A, TeraoM, Garattini EInhibition of the peptidyl-propyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoicacid via stabilization of RARα and PML-RARα.Cancer Res 69 : 1016-1026, <strong>2009</strong>• Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giu<strong>di</strong>ce C, Scanziani E, Mancuso A, Tiveron C,Garattini ERole of the molybdo-flavoenzyme, aldehyde oxidase homolog 2, in the biosynthesis of retinoic acid: generation andcharacterization of a knock-out mouseMol Cell Biol 29: 357-77, <strong>2009</strong>• Gianni M, Parrella E, Raska I Jr, Gaillard E, Nigro EA, Gaudon C, Garattini E, Rochette-Egly C. P38MAPK-dependentphosphorylation and degradation of SRC-3/AIB1 and RARalpha-me<strong>di</strong>ated transcriptionEMBO J. 25:739-51, 2006• Garattini E, Parrella E, Diomede L, Gianni M, Kalac Y, Merlini L, Simoni D, Zanier R, Ferrara F F, Chiarucci I,Carminati P, Terao M, Pisano CST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: Modulation ofintracellular calcium homeostasisBlood 103: 194-207, 2004• Kurosaki M, Terao M, Barzago M M, Bastone A, Bernar<strong>di</strong>nello D, Salmona M, Garattini E. The aldehyde oxidase genecluster in mice and rats: Aldehyde oxidase homologue 3, a novel member of the molybdo-flavoenzyme family withselective expression in the olfactory mucosaJ Biol Chem 279: 50482-50498, 2004• Pisano C, Kollar P, Gianni M, Kalac Y, Giordano V, Ferrara F F, Tancre<strong>di</strong> R, Devoto A, Rinal<strong>di</strong> A, Rambal<strong>di</strong> A, PencoS, Marzi M, Moretti G, Vesci L, Tinti O, Carminati P, Terao M, Garattini EBis-indols a novel class of molecules enhancing the cyto<strong>di</strong>fferentianting properties of retinoids in myeloid leukemiacellsBlood 100: 3719-3730, 2002Tiziana Mennini got her degree in Pharmacy at the University of Milano (1975). Inthe same year she obtained a fellowship from the European Molecular BiologyOrganization, to learn sub-cellular fractionation techniques and synaptosomesutilization in neurochemistry, at the laboratory of Prof. VP Whittaker ( Stockholm,Sweden). In 1882 she spent a further period in Prof. Whittaker’s laboratories (Max-Plank-Institut fur Biophysikalische Chemie, Abteilung Neurochemie Am Fassberg,Gottingen, Germany). She spent all her scientific career at the <strong>Mario</strong> <strong>Negri</strong> Institute:1967- 1975 Research Assistant in the Laboratory of Drug Metabolism1975-1987 Chief of the Unit of Neurochemical Transmission,1988 to date Chief of the Laboratory of Receptor PharmacologySpeaker, chairman and organizer at many congresses and courses, author of more than200 articles published in international journals in the area of receptor pharmacology andneuropharmacology.Selected publications• Bastone A, Fumagalli E, Bigini P, Perini P, Bernar<strong>di</strong>nello D, Cagnotto A, Mereghetti I, Curti D, Salmona M, Mennini TProteomic profiling of cervical and lumbar spinal cord reveals potential protective mechanisms in the wobblermouse, a model of motor neuron degenerationJ Proteome Res 8: 5229-40, <strong>2009</strong>• Beghi E, Bendotti C, Mennini T.Merits of a new drug trial for ALS?Science 308:632-633, 2005• Gobbi M, Mennini T.Is St John's wort a 'Prozac-like' herbal antidepressant?Trends Pharmacol Sci 22:557-559, 2001• The Italian ALSSG.Ceftriaxone in amyotrophic lateral sclerosis159ANNUAL REPORT <strong>2009</strong>
IRFMNEur J Neurol 3:295-298, 1996• Mennini T, Mocaer E, Garattini S.Tianeptine, a selective enhancer of serotonin uptake in rat brain.Naunyn-Schmiedebergs Arch Pharmacol 336:478-482, 1987• Mennini T, Garattini S.Benzo<strong>di</strong>azepines receptor bin<strong>di</strong>ng in vivo: pharmacokinetic and pharmacologicalSignificanteAdvances Biochemical Psychopharmacol 38:189-199,1983Maddalena Fratelli got her degree in Biological Sciences at the University of Pisa andat the Scuola Normale Superiore <strong>di</strong> Pisa in 1983. Then the specialization inPharmacological Research at the <strong>Mario</strong> <strong>Negri</strong> Institute in 1986.Her main fields of interest are: 1. High throughput genomic systems for the study ofdrug action and pharmacoresistance. 2. Redox regulation of protein function and geneexpression: glutathionylation and gene expression profiling of glutathione dependentresponses to oxidant challenge.1988-1989 Postdoctoral Research Fellow in the Me<strong>di</strong>cal Research Council,Neurobiology Unit, Cambridge, UK.Since 1995, Head, Unit of Me<strong>di</strong>ators of inflammation, Laboratory ofNeuroimmunology, <strong>Mario</strong> <strong>Negri</strong> InstituteSince 2005, Head, Unit of Pharmacogenomics, Laboratory of Molecular Biology, <strong>Mario</strong><strong>Negri</strong> InstituteSelected publications• Garattini E, Fratelli M, Terao M.The mammalian aldehyde oxidase gene familyHum Genomics. 4: 119-30, <strong>2009</strong>• Fratelli M, Goodwin LO, Orom UA, Lombar<strong>di</strong> S, Tonelli R, Mengozzi M, Ghezzi P. Gene expression profiling revealsa signaling role of glutathione in redox regulation.Proc Natl Acad Sci U S A 102:13998-4003, 2005• Brines M, Grasso G, Fiordaliso F, Sfacteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E,Diaz D, Gomez D, Hand C, Coleman T, Cerami A. Erythropoietin me<strong>di</strong>ates tissue protection through an erythropoietinand common beta-subunit heteroreceptorProc Natl Acad Sci U S A 101:14907-12, 2004• Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P,Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S,Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M.Derivatives of erythropoietin that are tissue protective but not erythropoieticScience 305:239-42, 2004• Fratelli M, Minto M, Crespi A, Erba E, Vandenabeele P, Del Soldato P, Ghezzi P. Inhibition of nuclear factor-kappaBby a nitro-derivative of flurbiprofen: a possible mechanism for antiinflammatory and antiproliferative effectAntioxid Redox Signal. 5:229-35, 2003• Fratelli M, Demol H, Puype M, Casagrande S, Eberini I, Salmona M, Bonetto V, Mengozzi M, Duffieux F, Miclet E,Bachi A, Vandekerckhove J, Gianazza E, Ghezzi P.Identification by redox proteomics of glutathionylated proteins in oxidatively stressed human T lymphocytesProc Natl Acad Sci U S A 99:3505-10, 2002Marco Gobbi got his degree in Pharmacy at the University of Milan, Italy, in 1989.His main fields of interest are: 1) neuropharmacology, in particular with stu<strong>di</strong>es on theinteraction of drugs and neurotransmitters with receptors and transporters; 2)neurodegenerative <strong>di</strong>seases associated to misfol<strong>di</strong>ng and aggregation ofpeptides/proteins, such as beta-amyloid and prions; 3) biomolecular interactions,stu<strong>di</strong>ed using Surface Plasmon Resonance (SPR). Dr. Gobbi is now the responsible forthe SPR apparatus present at <strong>Mario</strong> <strong>Negri</strong> Institute.1981-1989 Researcher, Laboratory of Neuropharmacology and, from 1988, in theLaboratory of Receptor Pharmacology, <strong>Mario</strong> <strong>Negri</strong> Institute1989 to date Head, Unit of Synaptic Transmission, <strong>Mario</strong> <strong>Negri</strong> Institute160ANNUAL REPORT <strong>2009</strong>
IRFMNCo-author in more than 90 scientific publications on peer-reviewed internationaljournals. First or last author in more than 40 of them. Reviewer for internationalscientific journals operating in the Neuroscience/Neuropharmacology fields.Selected publications• Colleoni S, Jensen AA, Fumagalli E, Conti P, De Amici M, Pellegrini-Giampietro DE, De Micheli C, Mennini T, GobbiMNeuroprotective effects of the novel glutamate transporter inhibitor (-)-HIP-A which acts on reverse transport (glutamaterelease) more than on glutamate reuptakeJ. Pharmacol. Exp. Ther. 326: 646:656, 2008• Gobbi M, Colombo L, Morbin M, Mazzoleni G, Accardo E, Vanoni M, Del Favero E, Cantù L, Kirschner D A, Ceci P,Ubezio P, Manzoni C, Forloni G, Tagliavini F, Salmona M. Gerstmann-Straussler-Scheinker <strong>di</strong>sease amyloid proteinpolymerizes accor<strong>di</strong>ng to the "dock-and-lock" modelJ Biol Chem 281: 843-9, 2006• Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T.p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, <strong>di</strong>ffer fromneurotoxic amphetamine derivatives in their mode of action at 5-HT nerve en<strong>di</strong>ngs in vitroJ Neurochem 82:1435-1443, 2002• Gobbi M, Mennini T.Is St John's wort a 'Prozac-like' herbal antidepressant?Trends Pharmacol Sci 22:557-559, 2001• Gobbi M, Garibol<strong>di</strong> M, Piwko C, Hoyer D, Sperk G, Vezzani A.Distinct changes in peptide YY bin<strong>di</strong>ng to, and mRNA levels of, Y1 and Y2 receptors in the rat hippocampusassociated with kindling epileptogenesis.J Neurochem 70:1615-1622, 1998• Crespi D, Mennini T, Gobbi M.Carrier-dependent and Ca(2+)-dependent 5-HT and dopamine release induced by (+)-amphetamine, 3,4-methylen<strong>di</strong>oxymethamphetamine, p-chloroamphetamine and (+)-fenfluramineBr J Pharmacol 121:1735-1743, 1997Mineko Terao obtained her doctorate degree in Pharmaceutical Science from the KobeWomen’s College of Pharmacy, Japan in 1978. Her scientific interests relate toproblems of Cellular Biology and Molecular Biology.1983 Ph.D in Molecular Biology, Kyoto University, Japan1982-1983 Research Fellow, Department of Me<strong>di</strong>cal Chemistry, Kyoto UniversityFaculty of Me<strong>di</strong>cine, Japan1983-1987 Postdoctoral Associate of the Institute for Cancer Research, Philadelphia,USFrom 1987 Visiting Scientist of <strong>Mario</strong> <strong>Negri</strong> InstituteFrom 1998 Head of the Unit of Gene Structure and Regulation, <strong>Mario</strong> <strong>Negri</strong> InstituteSelected publications• Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giu<strong>di</strong>ce C, Scanziani E, Mancuso A,Tiveron C, Garattini ERole of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoic acid: generation andcharacterization of a knockout mouseMol Cell Biol 29 : 357-377, <strong>2009</strong>• Terao M, Kurosaki M, Barzago MM, Varasano E, Boldetti A, Bastone A, Fratelli M, Garattini E.Avian and canine aldehyde oxidases. Novel insights into the biology and evolution of molybdo-flavoenzymes.J Biol Chem. 281: 19748-61, 2006• Garattini E, Parrella E, Diomede L, Gianni M, Kalac Y, Merlini L, Simoni D, Zanier R, Ferrara F F, Chiarucci I,Carminati P,Terao M, Pisano C.ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: Modulation ofintracellular calcium homeostasis.Blood 103: 194-207, 2004• Vila R, Kurosaki M, Barzago M M, Kolek M, Bastone A, Colombo L, Salmona M, Terao M, Garattini E.Regulation and biochemistry of mouse molybdo-flavoenzymes. The DBA/2 mouse is selectively deficient in theexpression of aldehyde oxidase homologues 1 and 2 and represents a unique source for the purification andcharacterization of aldehyde oxidase.J Biol Chem 279: 8668-8683, 2004161ANNUAL REPORT <strong>2009</strong>
IRFMN• Kurosaki M, Terao M, Barzago M M, Bastone A, Bernar<strong>di</strong>nello D, Salmona M, Garattini E. The aldehyde oxidase genecluster in mice and rats: Aldehyde oxidase homologue 3, a novel member of the molybdo-flavoenzyme family withselective expression in the olfactory mucosaJ Biol Chem 279: 50482-50498, 2004• Parrella E, Gianni’ M, Cecconi V, Nigro E, Barzago MM, Rambal<strong>di</strong> A, Rochette-Egly C, Terao M and Garattini E.Phospho<strong>di</strong>esterase 4 inhibition by piclamilast potentiates the cyto-<strong>di</strong>fferentiating action of retinoids in myeloid leukemiacells.J Biol Chem 279: 42026-42040, 2004ACTIVITIESThe Department comprises six laboratories. Research is heterogeneous in terms ofscientific interests and aims, but it is unified by the structural and functional study ofspecific, pharmacologically important gene products, using a common body oftechniques. Classical biochemistry and molecular biology methods are used to defineproteins that might be targets for the pharmacological activity of drugs. Potential <strong>di</strong>rectinteractions between drugs and proteins are stu<strong>di</strong>ed at the molecular level by a variety ofapproaches ranging from animal stu<strong>di</strong>es to computer simulation.MAIN FINDINGSIdentification of the molecular mechanisms responsible of oligomer formation ofamyloidogenic proteins.Identification of tetracyclines as potential therapeutic agents for prion <strong>di</strong>seases.Synthesis, biological and chemico-physical characterization of peptides deduced fromprion protein sequence.Identification of a correlation between cholesterol synthesis and prion proteinproduction.Protein identifications by mass spectrometry and data base searching using acombination of techniques.Characterization of the Pentraxin 3 role in the organization of the cumulus oophorusextracellular matrix and in female fertility.System-level analysis of protein interactions in the epithelial junctional complex.Characterization of the role of Junctional Adhesion Molecule-A (JAM-A) in the controlof cell motility.Characterization of the effect of inflammatory cytokines on JAM-A function.Proteomic analysis of the aggregates isolated from spinal cord of a mouse model ofamyotrophic lateral sclerosis (ALS)Identification of nitroprotein biomarkers in peripheral blood mononuclear cells of ALSpatients and a rat model of ALSProteomic analysis of a cellular model of fatal familial insomniaDevelopment of constitutive and con<strong>di</strong>tional motor neuronal cell models to unravel thetoxicity of mutant G93A superoxide <strong>di</strong>smutase 1 responsible for some forms of familialamyotrophic lateral sclerosis.Drugs or exogenous compounds impairing the electron transport chain are a risk factorto motor neurons of in<strong>di</strong>viduals carrying mutant forms of superoxide <strong>di</strong>smutase 1.Mitochondrial damage due to mutant G93A superoxide <strong>di</strong>smutase 1 occurs selectivelyin motor neurons.162ANNUAL REPORT <strong>2009</strong>
IRFMNSynthesis of glutathione, the main cellular antioxidant, is altered in motor neuronal cellsby human G93A mutant superoxide <strong>di</strong>smutase 1.Identification and characterization of a novel class of retinoids endowed with strong andselective apoptogenic activity on the neoplastic cell. Pre-clinical development of theseagents for the treatment of acute leukemia.Identification and characterization of novel retinoid-based pharmacologicalcombinations for the treatment of acute myelogenous leukemia.Molecular cloning and characterization of the cDNAs and genes of four novel membersof the mammalian molybdo-flavoprotein family. Definition of a novel gene cluster onhuman chromosome 2 and mouse chromosome 1.Development of knok-out animals for molybdo-flavoproteins: AOX1, AOH1, AOH2,AOH3.Creation of integrated instruments for the rationalization of Microarray analysisprocesses.The treatment with a non haematopoietic derivate of Erythropoietin (CEPO) reducesmotor neuron loss and clinical progression in a mouse model of ALS related toalterations in vesicle trafficking, the wobbler mouse.Treatment with a soluble TNF receptor in the wobbler mouse, reduces motor neurondegeneration and the phosphorylation of the two main stress kinases (p38 e JNK)activated by TNF receptors.Riluzole treatment reduces motor neuron loss and clinical progression of wobblermouse by increasing the endogenous BDNF expression .Oxidative stress, glial activation and inflammation occur in the retinopathy as well asin cerebral and spinal cord dysfunction in the mnd mouse, a model of progressiveepilepsy with mental retardation related to mutation in the CLN8 gene. These fin<strong>di</strong>ngsprovide further evidence for the implication of TNF death receptor signalling in thepathology of Neuronal Ceroid LipofuscinosisNew conformationally constrained aspartate and glutamate analogues <strong>di</strong>ssociateglutamate uptake inhibition and reverse transport-me<strong>di</strong>ated release.Dimethyl sulfoxide, a solvent commonly utilized to <strong>di</strong>ssolve hydrophobic compoundfor in vitro experiments, interferes with the 5-HT6 agonists activity when thescintillation proximity assay is used for evaluating 35S-GTP-γ-S bin<strong>di</strong>ng; but does notinterfere with the europium labelled GTP bin<strong>di</strong>ng determined by “time-resolvedfluorescence” .Evidence that the glutamate release me<strong>di</strong>ated by excitatory amino acid transporters(EAAT) (reverse transport) might be <strong>di</strong>ssociated from the EAAT-me<strong>di</strong>ated glutamatereuptake. Identification of novel glutamate transporter inhibitors, with neuroprotectiveproperties, which preferentially inhibits glutamate release compared to glutamatereuptake.Evidence that the monoamine release induced by amphetamine derivatives is mainlycalcium-dependent. Neurotoxic amphetamine derivatives, such asmethylen<strong>di</strong>oxymethamphetamine (MDMA, ecstasy), <strong>di</strong>ffer from non-neurotoxic ones intheir interaction with presynaptic nerve en<strong>di</strong>ngs.Stu<strong>di</strong>es on the mechanism of action underlying the antidepressant effects of Hypericumperforatum extracts and its main putative active principle Hyperforin: no interactionwith central monoamine transporters (as classic antidepressants) but possible action at aperipheral level by modulation of IL6 release.163ANNUAL REPORT <strong>2009</strong>
IRFMNCellular localization of neuropeptide Y (NPY) receptor subtypes Y1 and Y2, and theiradaptive changes following epileptic seizures.Recombinant C1-inhibitor binds with high affinity with Mannose Bin<strong>di</strong>ng Lectins, aninteraction possibly underlying its superior anti-ischemic properties in animal models.NATIONAL COLLABORATIONSAdvanced Biology Center, GenoaCentro Clinico Nemo, Ospedale Niguarda, MilanDip. Anatomia, Farmacologia, Me<strong>di</strong>cina Legale, University of TurinDip. Biotecnologie, Università degli Stu<strong>di</strong>, MilanDip. Chimica Biochimica e Biotecnologie per la Me<strong>di</strong>cina, Università degli Stu<strong>di</strong>,MilanDip. Chimica Farmaceutica e Tossicologica, Università degli Stu<strong>di</strong>, MilanDip. Farmaco-Chimico, Università degli Stu<strong>di</strong>, MessinaDip. Farmaco-Chimico-Tecnologico, University of SienaDip. Farmacologia Me<strong>di</strong>ca, Università degli Stu<strong>di</strong>, MilanDip. Scienze Biochimiche, University of FlorenceDip. Scienze Farmaceutiche, University of CataniaDip. Scienze Farmaceutiche, University of GenoaDip. Scienze <strong>Farmacologiche</strong>, Università degli Stu<strong>di</strong>, MilanDip. Scienze Fisiologiche e <strong>Farmacologiche</strong>, University of PaviaDip. Scienze Molecolari, University of MilanDip. Stu<strong>di</strong> pre-clinici, University of MilanFacoltà <strong>di</strong> Biologia, Università degli Stu<strong>di</strong>, MilanFacoltà <strong>di</strong> Chimica, Università degli Stu<strong>di</strong>, MilanFacoltà <strong>di</strong> Chimica, University of FerraraFondazione S. Maugeri, MilanFondo Edo Tempia, BiellaIFOM Fondazione <strong>Istituto</strong> FIRC <strong>di</strong> Oncologia Molecolare, MilanIRCCS Fondazione "<strong>Istituto</strong> C. Mon<strong>di</strong>no", Laboratorio <strong>di</strong> Neurobiologia Sperimentale,Pavia<strong>Istituto</strong> <strong>di</strong> Biologia Molecolare Buzzati Traverso, Naples<strong>Istituto</strong> <strong>di</strong> Biome<strong>di</strong>cina e Immunologia Molecolare CNR, Palermo<strong>Istituto</strong> <strong>di</strong> Endocrinologia, Centro <strong>di</strong> Eccellenza per le Malattie Neurodegenerative,Università degli Stu<strong>di</strong>, Milan<strong>Istituto</strong> <strong>di</strong> Clinica Neurologica, Ospedale Maggiore Policlinico, Milan<strong>Istituto</strong> Clinico Humanitas, Milan<strong>Istituto</strong> <strong>di</strong> Neuroscienze C.N.R., Pisa<strong>Istituto</strong> Nazionale dei Tumori, Milan<strong>Istituto</strong> Nazionale dei Tumori, Naples<strong>Istituto</strong> Nazionale Neurologico "C. Besta", Milan<strong>Istituto</strong> Oncologico Europeo, Milan<strong>Istituto</strong> Regina Elena, Rome<strong>Istituto</strong> Toscano Tumori, Florence164ANNUAL REPORT <strong>2009</strong>
IRFMNNewron Pharmaceuticals, MilanOspedale Maggiore Policlinico, MilanOspedale Pe<strong>di</strong>atrico Bambino Gesu', RomeOspedale Pe<strong>di</strong>atrico "Gaslini", GenoaOspedale S. Gerardo, Monza, MilanSigma-Tau, Pomezia, RomeZambon, MilanINTERNATIONAL COLLABORATIONSThe Babraham Institute, Cambridge, UKBoston College, Boston, MA, USABurke Me<strong>di</strong>cal Research Institute, White Plains, new York, USACase Western Research University, Cleveland, OH, USADept. de Quimica-Fisica de Macromoleculas Biologicas, CSIC, Madrid, SpainFaculdad de Ciencias Me<strong>di</strong>cas, Universidad de Santiago de Chile, ChileETH, Zurig, SwitzerlandFMP, Berlin, GermanyGiessen Polyclinic University, Giessen, GermanyHouston University, TX, USAKeio University, Tokyo, JapanIBSN CNRS, Marseille, FranceIn<strong>di</strong>ana University, In<strong>di</strong>anapolis, IN, USAInstitut de Genetique et Biologie Moleculaire et Cellulaire, Strasbourg, FranceInstitut Pasteur, Paris, FranceJohn Innes Centre, Norwich, UKLundbeck, USAMayo Clinic College of Me<strong>di</strong>cine, Jacksonville, FL, USANational Institute of Health, Bethesda, MD, USANippon University, Tokyo, JapanPepscan System BV, Lelystad, HollandPolichem S.A., Lugano, SwitzerlandTechnical University Braunschweig, GermanyThe Alexander Silberman Institute of Life Sciences, The Hebrew University ofJerusalem, Jerusalem, IsraelTrinity College, Dublin, IrelandUniversidad de La Laguna, Tenerife, SpainUniversidad Nova, Lisbon, PortugalUniversitat des Saarlandes, Hamburg, GermanyUniversitat Freiburg, GermanyUniversité Paris, FranceUniversité Victor Segalen Bordeaux 2, Bordeaux, FranceUniversity of Aberdeen, UKUniversity of Amsterdam, The NetherlandsUniversity of Birmingham, UKUniversity of Car<strong>di</strong>ff, UK165ANNUAL REPORT <strong>2009</strong>
IRFMNUniversity of Glasgow, UKUniversity of Gottingen, GermanyUniversity of Muenster, GermanyUniversity of Patrasso, GreceUniversity of Southampton, UKUniversity of Sussex, UKUniversity of Vienna, AustriaWaring-Webb Institute, University of Colorado, Denver CO, USAWeizmann Institut, Rehovot, IsraelWestfaelische Wilhelms-Universitaet Muenster, GermanyNeurobiology of Lipids (L. Diomede)European Journal of Cancer (E. Garattini)EDITORIAL BOARD MEMBERSHIPPEER REVIEW ACTIVITIESAmerican Journal Physiology, Antioxidants and Redox Signaling, BBA-Proteomics,Biochemical Journal, Biochemical Pharmacology, Biochimica Biophysica Acta, BMC-Biochemistry, Brain Research, Cancer Research, Cell Death and Differentiation, CellResearch, Cellular and Molecular Life Sciences, Circulation, Drug Investigation,European Journal of Cancer, European Journal of Immunology, European Journal ofNeuroscience, InternationalJournal of Cancer, Journal of Cell Biology, Journal of Hepatology, Journal ofImmunology,Journal of Investigative Dermatology, Journal of Lipid Me<strong>di</strong>ators, Journal ofNeurochemistry,Journal of Neuroimmunology, Journal of Translational Me<strong>di</strong>cine, Neuroscience,NeuroscienceLetters, Pharmacological Research, Physiological Genomics, PLoS ONE, Procee<strong>di</strong>ngsof theNational Academy of Sciences, Life Sciences, Proteomics, Proteome Science.CONFERENCE AND WORKSHOP CONTRIBUTIONSCourse: “Nanoparticles in Me<strong>di</strong>cine”, “Pharmacokinetics and bioavailability ofNanoparticles based drug delivery system”, 11-13 March, Milan, ItalyMeeting: “XIII Riunione del GSSNP”, "Hyperglycemia and nerve functional parametersare normalized by syngenically transplanted microcapsulated rat pancreatic islets in ratswith streptozotocin-induced <strong>di</strong>abetes”, “The neuroprotective effect of erythropoietin(EPO) in docetaxel (DOCE)-induced peripheral neuropathy (PN) in exerted with no166ANNUAL REPORT <strong>2009</strong>
IRFMNreduction of antitumor activity in 13762 breast carcinoma bearing rats” 14 May,Otranto, ItalyMeeting: “4th Meeting, Molecular Mechanisms of Neurodegeneration”, “Mutant prionprotein expression causes impairment of voltage-gated calcium channels in a transgenicmouse model”, “The expression of the steroidogenic acute regulatory protein (STAR) isincreased in degenerating trait of spinal cord of wobbler mice”, “Role of the axonal-SMN (a-SMN) protein in axon growth and spinal muscular atrophy (SMA)pathogenesis”, “Good gene, bad gene: new APP variant may be both”, “Protein toxicityin Alzheimer and Parkinson Disease”, “Nitroproteomics of peripheral bloodmononuclear cells from patients and rat model of ALS”, “Mutant prion proteinexpression is associated to an alteration of the RAB GDP <strong>di</strong>sassociation inhibitoralpha(GDI)RAB11 pathway”, “Characterization of detergent-insoluble proteins in ALSmodels and patients in<strong>di</strong>cates a possible causal link between nitrative stress andaggregation in pathogenesis”, 8-10 May, Milan, ItalyMeeting: “EuroNanoForum <strong>2009</strong>”, “The NAD project: Nanoparticles for therapy and<strong>di</strong>agnosis of Alzheimer’s <strong>di</strong>sease. Preliminary results with nanoliposomes”, 2-5 June,Prague, Czech RepublicMeeting: “Joint Meeting on Me<strong>di</strong>cinal Chemistry”, “New benzoxazole andbenzothiazole derivatives as potential 5-HT7 receptor ligands”, 25 June, Budapest,HungaryMeeting “PNS Meeting”, “ Evaluation of the continuous buprenorphine deliveryanalgesic effect in an experimental rat model of painful <strong>di</strong>abetic neuropathy”,“Functional recovery with syngenically transplanted microcapsulated pancreatic islets instreptozotocin-induced <strong>di</strong>abetic rats”, 9 July, Wurzburg, GermanyConference: “ICAD <strong>2009</strong> - Alzheimer’s Associations International Conference onAlzheimer’s Disease”, “A novel approach to control Abeta peptide aging during storageand handling”, “Membrane protein and Abeta peptide toxicity”, 10 July, Wien, AustriaCourse: “First training course <strong>2009</strong> for NAD - Nanoparticles for therapy and <strong>di</strong>agnosisof Alzheimer <strong>di</strong>sease”, 5-10 September, Patras, GreeceConference: “VI International Conference on Proteoglycan”, “Re-appraisal of the roleof NG2-expressing olygodendrocyte subsets in the pathogenesis of Multiple Sclerosis”,13 September, Aix-les-Bains, FranceCongress: “2nd European Congress of Immunology”, “PTX3 acts as a regulator ofleukocyte rolling and extravasation via P-selectin bin<strong>di</strong>ng”, 13-16 September, Berlin,GermanyMeeting: “Tetracycline Day”, “Caenorhab<strong>di</strong>tis elegans come modello <strong>di</strong> malattia <strong>di</strong>Alzheimer e <strong>di</strong> altre amiloidosi per lo sviluppo <strong>di</strong> nuove strategie terapeutiche”, 15September, Pavia, Italy167ANNUAL REPORT <strong>2009</strong>
IRFMNConference: “2nd National Nanome<strong>di</strong>cine Conference”, “The NAD project:Nanoparticles for therapy and <strong>di</strong>agnosis of Alzheimer’s <strong>di</strong>sease. Preliminary resultswith nanoliposomes”, 21 September, Pavia, ItalyConference: “Prion <strong>2009</strong>”, “Characterization of the molecular heterogeneity of mutantprion proteins”, 23-25 September, Chalki<strong>di</strong>ki, GreeceCongress: “XIII National Congress of the Italian Society for Neuroscience”,“Cholesterol in PrP and Aβ amyloid formation”, “C-jun N-terminal kinase regulatessynaptic dysfunction”, “Artificial chaperone, ciclodextrin, decreases accumulation ofmisfolded proteins in intracellular inclusions in motoneuron <strong>di</strong>seases”, 2-5 October,Milan, ItalyGRANTS AND CONTRACTSAgenzia Italiana del Farmaco, Rome, ItalyAssociazione Italiana Ricerca sul Cancro (AIRC), Milan, ItalyBiotecnologie BT - Perugia, ItalyComunità Europea (EU), Bruxelles, BelgiumConsiglio Nazionale delle <strong>Ricerche</strong> (CNR), Palermo, ItalyFondazione Don Gnocchi, Milan, ItalyFondazione Cariplo, Milan, ItalyFondazione Mariani, Milan, ItalyFondazione Monzino, Milan, ItalyFondazione Weizmann-Pasteur-<strong>Negri</strong>, Paris, France<strong>Istituto</strong> Auxologico Italiano, Milan, Italy<strong>Istituto</strong> Nazionale Neurologico "C. Besta", Milan, ItalyLundbeck A/S, Copenhagen, DenmarkMinistero della Salute, Roma, ItalyMinistero dell'Istruzione, Università e Ricerca Scientifica (MIUR), Rome, ItalyNorth Shore University Hospital, NY, USAPerfetti-Van Melle, Lainate, Milan, ItalySigma Tau, Pomezia, Rome, ItalyTelethon, Milan, ItalyUniversità <strong>di</strong> Firenze, ItalyUniversità <strong>di</strong> Milano-Bicocca, ItalyUniversità <strong>di</strong> Siena, ItalyZambon Group, Bresso (Mi), ItalySCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, Colombo L, Manzoni Clau<strong>di</strong>a, Salmona M,Caccia S, Negro A, Forloni GThe SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by α-synuclein or amyloid-β (1-42) peptideJ Neurochem <strong>2009</strong> 110 : 1445-1456168ANNUAL REPORT <strong>2009</strong>
IRFMNBalducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T,Chiesa R, Gobbi M, Salmona M, Forloni GSynthetic amyloid-beta oligomers impair long-term memory independently of cellular prion proteinProc Natl Acad Sci U S A. <strong>2009</strong>, [Epub ahead of print]Basso M, Samengo G, Nardo G, Massignan T, D'Alessandro G, Tartari S, Cantoni L, Marino M, Cheroni C, DeBiasi S, Giordana M T, Strong M J, Estevez A G, Salmona M, Bendotti C, Bonetto VCharacterization of detergent-insoluble proteins in ALS models in<strong>di</strong>cates a causal link between nitrative stressand aggregation in pathogenesisPLoS One <strong>2009</strong> 4: e8140Bastone A, Fumagalli E, Bigini P, Perini P, Bernar<strong>di</strong>nello D, Cagnotto A, Mereghetti I, Curti D, Salmona M,Mennini TProteomic profiling of cervical and lumbar spinal cord reveals potential protective mechanisms in the wobblermouse, a model of motor neuron degenerationJ Proteome Res <strong>2009</strong> 8: 5229-5240Bate C, Tayebi M, Diomede L, Salmona M, Williams AGlimepiride reduces the expression of PrPc, prevents PrPSc formation and protects against prion me<strong>di</strong>atedneurotoxicity in cell linesPLoS One <strong>2009</strong> 4 : e8221Bate C, Tayebi M, Salmona M, Diomede L, Williams APolyunsaturated fatty acids protect against prion-me<strong>di</strong>ated synapse damage in vitroNeurotox Res 2010 17 : 203-214Biasini E, Tapella L, Mantovani S, Stravalaci M, Gobbi M, Harris D A, Chiesa RImmunopurification of pathological prion protein aggregatesPLoS One <strong>2009</strong> 4 : e7816Bonanno G, Fumagalli E, Milanese M, Zappettini S, Mennini TRelease of [3H]D-aspartate induced by K+-stimulation is increased in the cervical spinal cord of the wobblermouse: a model of motor neuron <strong>di</strong>seaseNeurochem Int <strong>2009</strong> 55 : 302-306Butini S, Budriesi R, Hamon M, Morelli E, Gemma S, Brin<strong>di</strong>si M, Borrelli G, Novellino E, Fiorini I, Ioan P,Chiarini A, Cagnotto A, Mennini T, Fracasso C, Caccia S, Campiani GNovel, potent and selective quinoxaline-based 5-HT3 receptor ligands. 1. Further structure-activity relationshipsand pharmacological characterizationJ Med Chem <strong>2009</strong> 52 : 6946-6950Butini S, Gemma S, Campiani G, Franceschini S, Trotta F, Borriello M, Ceres N, Ros S, Sanna Coccone S,Bernetti M, De Angelis M, Brin<strong>di</strong>si M, Nacci V, Fiorini I, Novellino E, Cagnotto A, Mennini T, Sandager-Nielsen K, Andreasen J T, Scheel-Kruger J, Mikkelsen J D, Fattorusso CDiscovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 andserotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavioJ Med Chem <strong>2009</strong> 52 : 151-169Caccia S, Gobbi MSt. John's wort components and the brain: Uptake, concentrations reached and the mechanisms underlyingpharmacological effectsCurr Drug Metab <strong>2009</strong> 10: 1055-1065Calabro' M L, Raneri D, Ficarra P, Mennini T, Colleoni S, Grazioso G, Micale N, Zappala' M, Grasso SSynthesis, chiral resolution and pharmacological evaluation of a 2,3-benzo<strong>di</strong>azepine-derived noncompetitiveAMPA receptor antagonistChemMedChem <strong>2009</strong> 4 : 415-420Cervellini I, Bello E, Frapolli R, Porretta-Serapiglia C, Oggioni N, Canta A, Lombar<strong>di</strong> R, Camozzi F, Roglio I,Melcangi R C, D'Incalci M, Lauria G, Ghezzi P, Cavaletti G, Bianchi RThe neuroprotective effect of erythropoietin in docetaxel-induced peripheral neuropathy causes no reduction ofantitumor activity in 13762 adenocarcinoma-bearing ratsNeurotox Res <strong>2009</strong> [Epub ahead of print]169ANNUAL REPORT <strong>2009</strong>
IRFMNChiorazzi A, Nicolini G, Canta A, Oggioni N, Rigolio R, Cossa G, Lombar<strong>di</strong> R, Roglio I, Cervellini I, Lauria G,Melcangi R C, Bianchi R, Crippa D, Cavaletti GExperimental epothilone B neurotoxicity: results of in vitro and in vivo stu<strong>di</strong>esNeurobiol Dis <strong>2009</strong> 35 : 270-277Colombo A, Bastone A, Ploia C, Sclip A, Salmona M, Forloni G, Borsello TJNK regulates APP cleavage and degradation in a model of Alzheimer's <strong>di</strong>seaseNeurobiol Dis <strong>2009</strong> 33 : 518-525Colombo G, Margosio B, Ragona L, Neves M, Bonifacio S, Annis D S, Stravalaci M, Tomaselli S, Giavazzi R,Rusnati M, Presta M, Zetta L, Mosher D F, Ribatti D, Gobbi M, Taraboletti GNon-pepti<strong>di</strong>c thrombospon<strong>di</strong>n-1-mimics as fibroblast growth factor-2 inhibitors: an integrated strategy for thedevelopment of new antiangiogenic compoundsJ Biol Chem <strong>2009</strong>, in pressColombo L, Piovesan P, Ghirar<strong>di</strong> O, Salmona M, Forloni GST1859 reduces prion infectivity and increase survival in experimental scrapieJ Virol <strong>2009</strong> 154: 1539-1544Di Fede G, Catania M, Morbin M, Rossi G, Suar<strong>di</strong> S, Mazzoleni G, Merlin M, Giovagnoli A R, Prioni S, ErbettaA, Falcone C, Gobbi M, Colombo L, Bastone A, Beeg M, Manzoni Clau<strong>di</strong>a, Francescucci B, Spagnoli A, Cantu'L, Del Favero A, Levy E, Salmona M, Tagliavini FA recessive mutation in the APP gene with dominant-negative effect on amyloidogenesisScience <strong>2009</strong> 323 : 1473-1477Ferry C, Giannì M, Lalevée S, Bruck N, Plassat J - L, Raska I Jr, Garattini E, Rochette-Egly CSUG-1 plays proteolytic and non-proteolytic roles in the control of retinoic acid target genes via its interactionwith SRC-3J Biol Chem <strong>2009</strong> 284 : 8127-8135Forloni G, Salmona M, Marcon G, Tagliavini FTetracyclines and prion infectivityInfect Disord Drug Targets <strong>2009</strong> 9 : 23-30Garattini E, Fratelli M, Terao M.The mammalian aldehyde oxidase gene familyHum Genomics. <strong>2009</strong> 4: 119-30Gesuete R, Storini C, Fantin A, Stravalaci M, Vitsch H, Mannesse M L M, Ziere B, Gobbi M and De Simoni MGRecombinant C1-inhibitor in Brain Ischemic InjuryAnnals of Neurology <strong>2009</strong> 66: 332-342Gianazza E, Eberini I, Ghezzi PDetection of protein glutathionylationMethods Mol Biol <strong>2009</strong> 519 : 397-415Gianni M, Boldetti A, Guarnaccia V, Rambal<strong>di</strong> A, Parrella E, Raska I Jr, Rochette-Egly C, Del Sal G, Rustighi A,Terao M, Garattini EInhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells toretinoic acid via stabilization of RARα and PML-RARαCancer Res <strong>2009</strong> 69 : 1016-1026Manzoni Clau<strong>di</strong>a, Colombo L, Messa M, Cagnotto A, Cantu' L, Del Favero E, Salmona MOvercoming Aβ peptides aging: a new approach to an age-old problemAmyloid <strong>2009</strong> 16 : 71-80Massignan T, Biasini E, Veglianese P, Fioriti L, Harris D A, Salmona M, Chiesa R, Bonetto VMutant prion protein expression is associated with an alteration of the Rab GDP <strong>di</strong>ssociation inhibitor alpha(GDI)/Rab11 pathwayMol Cell Proteomics <strong>2009</strong> [Epub ahead of print]Massignan T, Stewart R S, Biasini E, Solomon I H, Bonetto V, Chiesa R, Harris D A170ANNUAL REPORT <strong>2009</strong>
IRFMNA novel, drug-based, cellular assay for the activity of neurotoxic mutants of the prion proteinJ Biol Chem <strong>2009</strong> [Epub ahead of print]Ma Y J, Doni A, Hummelshøj T, Bastone A, Mantovani A, Thielens N M, Garred PSynergy between Ficolin-2 and PTX3 boost innate immune recognition and complement depositionJ Biol Chem <strong>2009</strong> 284 : 28263-28275Mennini T, Giordano L, Mengozzi M, Ghezzi P, Tonelli R, Mantegazza R, Silani V, Corbo M, Lunetta C, BeghiEIncreased IL-8 levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosisAmyotroph Lateral Scler <strong>2009</strong> 7 : 39-44Mennini T, Testa RAre descen<strong>di</strong>ng control pathways of the lower urinary tract and pain overlapping systems?Central Nervous System Agents Me<strong>di</strong>cinal Chemistry <strong>2009</strong>, in pressMorelli E, Gemma S, Budriesi R, Campiani G, Novellino E, Fattorusso C, Catalanotti B, Sanna Coccone S, RosS, Borrelli G, Kumar V, Persico M, Fiorini I, Nacci V, Ioan P, Chiarini A, Hamon M, Cagnotto A, Mennini T,Fracasso C, Colovic M, Caccia S, Butini SSpecific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structureactivityrelationshipsJ Med Chem <strong>2009</strong> 52 : 3548-3562Nardo G, Pozzi S, Mantovani S, Garbelli S, Marinou K, Basso M, Mora G, Bendotti C, Bonetto VNitroproteomics of peripheral blood mononuclear cells from patients and a rat model of ALS.Antioxid. Redox Signal. <strong>2009</strong> 11: 1559-1567Oliva A, Sanchez Ashen D, Salmona M, Farina J B, Llabres MSolid-state stability stu<strong>di</strong>es of cholecystokinin (CCK-4) peptide under nonisothermal con<strong>di</strong>tions using thermalanalysis, chromatography and mass spectrometryEur J Pharm Sci <strong>2009</strong>, in pressParis L, Bononi E, Bazzoni GNetwork analysis of cell adhesion: Adhesomes as context-defined subnetworksCommunicative & Integrative Biology <strong>2009</strong> 2 : 20-22Pera M, Martinez-Otero A, Colombo L, Salmona M, Ruiz-Molina D, Ba<strong>di</strong>a A, Clos M VAcetylcholinesterase as an amyloid enhancing factor in PrP82-146 aggregation processMol Cell Neurosci <strong>2009</strong> 40 : 217-224Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V, Crippa L, AvezzaF, Fiordaliso F, Salio M, Lauria G, Lombar<strong>di</strong> R, Cavaletti GRegression of <strong>di</strong>abetic complications by islet transplantation in the ratDiabetologia <strong>2009</strong> 52 : 2653-2661Repici M, Mare L, Colombo Alessio, Ploia C, Sclip A, Bonny C, Nicod P, Salmona M, Borsello Tc-Jun N-terminal kinase bin<strong>di</strong>ng domain-dependent phosphorylation of mitogen-activated protein kinase kinase 4and mitogen-activated protein kinase kinase 7 and balancing cross-talk between c-Jun N-terminal kinase andextracellular signal-regulated kinaseJ Neurochem <strong>2009</strong> 159 : 94-103Roglio I, Bianchi R, Camozzi F, Carozzi V, Cervellini I, Crippa D, Lauria G, Cavaletti G, Melcangi R CDocetaxel-induced peripheral neuropathy: protective effects of <strong>di</strong>hydroprogesterone and progesterone in anexperimental modelJ Peripher Nerv Syst <strong>2009</strong> 14 : 36-44Saracino GA, Villa A, Moro G, Cosentino U, Salmona MSpontaneous beta-helical fold in prion protein: The case of PrP(82-146)Proteins <strong>2009</strong> 75: 964-976Schumann S, Terao M, Garattini E, Saggu M, Lendzian F, Hildebrandt F, Leimkuhler SSite <strong>di</strong>rected mutagenesis of amino acid residues at the active site of mouse aldehyde oxidase AOX1PLoS One <strong>2009</strong> 4 : e5348171ANNUAL REPORT <strong>2009</strong>
IRFMNTartari S, D'Alessandro G, Babetto E, Rizzar<strong>di</strong>ni M, Conforti L, Cantoni LAdaptation to G93Asuperoxide <strong>di</strong>smutase 1 in motor neuron cell line model of amyotrophic lateral sclerosis. Therole of glutathione.FEBS J <strong>2009</strong> 276: 2861-2874Tamborini L, Conti P, Pinto A, Colleoni S, Gobbi M, De Micheli CSynthesis of new β- and γ-benzyloxy-S-glutamic acid derivatives and evaluation of their activity as inhibitors ofexcitatory amino acid transportersTetrahedron <strong>2009</strong> 65: 6083-6089Terao M, Kurosaki M, Barzago M M, Fratelli M, Bagnati R, Bastone A, Giu<strong>di</strong>ce C, Scanziani E, Mancuso A,Tiveron C, Garattini ERole of the molybdoflavoenzyme aldehyde oxidase homolog 2 in the biosynthesis of retinoic acid: generation andcharacterization of a knockout mouseMol Cell Biol <strong>2009</strong> 29 : 357-377RESEARCH ACTIVITIESLaboratory of Biochemistry and Protein ChemistryDevelopment of new therapeutic strategies for the treatment of centraland peripheral amyloidosisThe development of an effective strategy for the prevention and cure of Alzheimer<strong>di</strong>sease and systemic amyloidosis is of great importance due to the absence of aneffective therapy. Their severity affects seriously the life of patients and their relatives.The formation of amyloid fibrils and their deposition in specific tissues were for longtimeconsidered the cause of the <strong>di</strong>sease, however recent stu<strong>di</strong>es showed that solubleoligomeric species are the actual culprits of the toxicity. The kinetics of proteinaggregation due to conformational mo<strong>di</strong>fications and the comprehension of genetic,biochemical and structural determinants at the basis of this transformation are veryimportant for unveiling the pathogenic process and the development of therapeuticstrategies. Aiming at developing simple models that enable monitoring theconformational changes that preceds fibril deposition, we have designed and developeda variety of synthetic peptides as deduced from the primary sequence of humanamyloidogenic proteins in their wild-type or mutated forms.In collaboration with the <strong>Istituto</strong> Neurologico “Carlo Besta” of Milan we have identifieda mutated form of beta-amyloid (A673V) that <strong>di</strong>splays amazing biological featuressince it binds to wild-type beta-amyloid and inhibits amyloid formation and the onset ofthe <strong>di</strong>sease. This observation opens new therapeutic perspectives both for genetic andspora<strong>di</strong>c forms of Alzheimer <strong>di</strong>sease based upon the use of protein fragmentscontaining this mutation or peptide-mimetic compounds. Moreover, we havesynthesized several Abeta peptides containing the same mutation and we have evaluate<strong>di</strong>ts importance in the aggregation and amyloidogenic properties. Similar stu<strong>di</strong>es havebeen carried out with prion protein and some amyloidogenic proteins responsible ofperipheral amyloidosis. The first approach for the development of can<strong>di</strong>date drugscontemplates the development of molecules capable to interfere with oligomeric speciesfollowing <strong>di</strong>rect interaction with protein molecules <strong>di</strong>srupting its beta-sheetconformation or the fibrillary aggregates. This activity requires in vitro stu<strong>di</strong>es with cellfree models to determine the conformational features of amyloidogenic peptides, their172ANNUAL REPORT <strong>2009</strong>
IRFMNsecondary structure, the hydrogen-deuterium exchange, the resistance to <strong>di</strong>gestion byproteases, the aggregation propensity and amyloidogenic characteristcs.To understand the molecular and biochemical mechanisms of action underlying thecause of the cytotoxic action, peptides are used for in vitro stu<strong>di</strong>es in variety of cellularmodels trying to correlate their physical features and the biological effect. Moreover,the subcellular <strong>di</strong>stribution of peptides and their molecular targets are also investigated.In cooperation with the Laboratory of Biology of Neurodegenerative Disease, moleculesthat are potentially active are evaluated in <strong>di</strong>fferent experimental models of central andperipheral amyloidosis. We have reported that tetracyclines are new can<strong>di</strong>dates as antiamyloidogenesisdrugs, in particular they <strong>di</strong>srupt amyloid tangles and increase thesensitivity of PrP to proteinase K <strong>di</strong>gestion. Tetracycline are able to inhibit neuronal celldeath and astroglial prolipheration induce by PrP peptides and, in animal model of<strong>di</strong>sease, they prolong the survival of animals inoculated with PrP.Another therapeutic strategy is based on the development of molecules which inhibitPrP formation by interacting with the lipid metabolism or by destabilizing particularcellular membrane domains. In collaboration with the Department of Pathology andInfective Disease of the Royal Veterinary School (Hawkshead, UK) we have shownthat statins, able to inhibit the cellular cholesterol synthesis and levels, reduced the invitro prion protein production. On the other hands, other molecules known for theiractivity in decreasing cholesterol levels, such as polyunsaturated fatty acids, increasedPrP production. Our stu<strong>di</strong>es are aimed to the comprehension of the relationshipbetween the cholesterol cellular membrane <strong>di</strong>stribution, the stability of lipid domainsand the conversion of the prion protein from the cellular to the pathological form.The nematode Caenorhab<strong>di</strong>tis elegans as experimental model toinvestigate in vivo the molecular mechanisms underlying the aggregationof amyloidogenic proteinsThe description of the molecular events underlying the in vivo amyloidogenesis iscrucial for the design of effective therapeutic strategies. To this end, in our laboratorywe use Caenorhab<strong>di</strong>tis elegans as experimental model since it offers the uniqueopportunity to analyze the genetic and molecular functions of human <strong>di</strong>sease-relatedgenes in vivo. This nematode offers also the major advantages of the easy generation oftransgenic strains expressing human genes, the production of <strong>di</strong>stinct phenotypes offersinsight into the biology of the <strong>di</strong>sease and help to elucidate fundamental cellularprocesses related to it. In particular, it is possible to correlate the phenotype of thetransgene with the <strong>di</strong>sease insurgence, the degeneration, the protein expression and itsaggregation into the oligomeric or fibrillar forms.Different transgenic strains expressing various fragments of human β amyloid inneurons or in muscles are available in our laboratory. We also developed newtransgenic strains expressing A-V or A-T mutated peptides in position 2 under aneuronal promoter, to evaluate their in vivo effects.The expression of these peptides results in the cytoplasmic amyloid β inclusion and inthe appearance of progressive phenotypes related to the <strong>di</strong>sease. In these C. elegansstrains, amyloid aggregates were observed and they are similar to those observed in thebrain of patients with AD or in muscles of patients with spora<strong>di</strong>c forms of InclusionBody Myositis, the most common myopathy. These models were already used to studythe relationship between Aβ sequence, amyloid formation and toxicity. A transgenic C.173ANNUAL REPORT <strong>2009</strong>
IRFMNelegans strain producing only the oligomeric form of the β amyloid protein was alsoavailable representing a good pre<strong>di</strong>ctive model for the investigation of drugsspecifically interfering with oligomers. C. elegans is also applied to investigate themolecular mechanisms underlying some systemic amyloidosis, like those caused bytissue deposition of immunoglobulin light chain or β 2 microglobuline. Using thismulti<strong>di</strong>sciplinary genomic and molecular integrated approach, we will obtain importantinformations for the development and validation of innovative therapeutic strategies andfor the comprehension of the in vivo molecular functions of genes related to humanamyloidosis.Nanoparticles in pharmacology: new <strong>di</strong>agnosis and therapy systemsThe clinical development of molecules with promising therapeutic activity for thetreatment of <strong>di</strong>seases with unfavorable prognosis, is sometimes limited by themolecules’ scarse bioavailability, by a rapid clearance, or the <strong>di</strong>fficulty to cross certainbiological barriers, and last but not least, by the onset of severe side effects. Toovercome those hurdles the usage of biocompatible and biodegradable nanoparticles(NPs) has been suggested. These NPs “protect” the active compounds loaded in the NPsand act as controlled release devices.Various types of NPs, both lipi<strong>di</strong>c and polymeric, have been used in our laboratories toenhance the release kinetics of the loaded molecules. Mo<strong>di</strong>fying the NPs’ surfaces withparticular peptides, antibo<strong>di</strong>es and ligands, it has been possible to change theirbio<strong>di</strong>stribution with respect to healthy and tumoral tissuesOur laboratory has evaluated, within the European project “Nanoparticles for therapyand <strong>di</strong>agnosis of Alzheimer Disease” (NAD), the ability of <strong>di</strong>fferent NPs of lipi<strong>di</strong>c andpolymeric nature to cross the blood-brain-barrier in vivo, to deliver anti-amiloidogenicdrugs to the brain. Furthermore, in collaboration with Politecnico <strong>di</strong> Milano and theSwiss Federal Institute of Technology (ETH), new polymeric NPs have beensynthesized and their stability has been evaluated in biological fluids. Utilizing nondegradable NPs loaded with fluorescent dyes and/or paramagnetic molecules,bio<strong>di</strong>stribution stu<strong>di</strong>es have been performed in vivo employing Optical Imagingtechniques, Magnetic Resonance Imaging, optical and fluorescence microscopy. Theseresults will represent the basis for the design of NPs for early <strong>di</strong>agnosis of specific<strong>di</strong>seases and for monitoring the therapy’s efficacy.A deeper analysis of the parameters influencing the in vitro and in vivo drug releasefrom NPs are currently in progress. All obtained data will be used for the developmentof mathematical models able to describe the pharmacokinetics of the NPs and of thereleased compounds.Preclinical imaging to improve the translation of results from mice topatientsOne of the main goal of the modern pharmacological research is to translate the resultsobtained form preclinical models (cells and animals) to the clinical practice. The use ofnon invasive instruments of screening has been more and more taking place either forthe <strong>di</strong>agnosis or to follow the efficacy of therapy in <strong>di</strong>fferent clinical fields. The recentdevelopment of in vivo imaging instruments de<strong>di</strong>cated to small rodents may thereforeallow to perform the same strategy of investigation already at preclinical level.174ANNUAL REPORT <strong>2009</strong>
IRFMNThe Department of Biochemistry and Molecular Pharmacology has been developing aseries of experimental procedures aimed at coupling the results obtained by <strong>di</strong>fferent invivo analyses (Magnetic Resonance Imaging, micro Computerized Tomography,Fluorescent Molecular Tomography, Ocular Coherence Tomography) to the dataobtained by ex vivo stu<strong>di</strong>es (histology and/or immunohistochemistry). The integrationof these two areas can be identified as “preclinical imaging”.This approach has been recently exploited to better investigate the clinical progressionof an interesting of model of neuronal ceroid lipofuscinosis, the mnd mouse. Analysescarried out by fluoro-angiography and ocular coherence tomography allowed us tocharacterize the progressive ocular inflammation and retinal degeneration affecting mndmice by simply following the same group animals during the time. Histologicalcharacterization, performed by sacrificing animals at <strong>di</strong>fferent time points, confirmedthese data and highlighted that lipofuscin accumulation, apoptosis of retinal cells andreactive gliosis, are the cellular bases for the alteration revealed by in vitro imaginganalyses. A series of experiments will be carried out, by three <strong>di</strong>fferent degree ofresolution, to better characterize this peculiar accumulation of autofluorescent ceroidand lipofuscin-like material in brain and in eyes of mnd mice. In collaboration with theDepartment of Oncology, we investigated about the anatomical localization ofautofluorescent material by a non invasive approach (fluorescent moleculartomography). Such strategy allowed us to follow the progressive deposition ofautofluorescent material in the same group of mice at <strong>di</strong>fferent ages. A markedfluorescence was first observed in the posterior area of forebrain and in the cerebellarregion. In older animals the fluorescent signal spread in the whole brain parenchymaand in other peripheral organs.Histological analysis (by the observation of the autofluorescence in 20 µm thicksections) confirmed the reliability of in vivo imaging and evidenced a selectivedeposition of autofluorescent material in neurons. Finally, electron microscopy stu<strong>di</strong>es(in collaboration with the Department of Car<strong>di</strong>ovascular Diseases) showed thatlipofuscin-like bo<strong>di</strong>es were mainly segregated in swollen lysosomes and <strong>di</strong>stributed inthe whole cytoplasm of neurons.Contrast Enhanced (MnCl 2 ) MRI experiments have demonstrated that in thehippocampus of mnd micea marked process of hyperexcitability occurs before motorsymptom onset. Hippocampal hyperexcitabilty was further confirmed by EEG analysis(in collaboration with the Laboratory of Experimental Neurology) and by c-fosimmunohistochemistry. The body of knowledge emerging from all these experimentsallow us to propose the mnd mouse as a reliable model of Epilepsy with mentalretardation, one of the most common form of neuronal ceroid lipofuscinosis andassociated with mutation(s) of the same gene (cln8) responsible for the phenotypicchanges found in mnd mice.In collaboration with the Unit of Cancer Clinical Pharmacology we evaluated, byGadolinium enhanced MRI, the growth of an orthotopically implanted humanglioblastoma in the brain parenchyma of nude mice.In ad<strong>di</strong>tion, the internalization of paramagnetic and fluorescent probes in human foetalstem cells has allowed to track the fate of these cells once transplanted in cerebralventricles of healthy and <strong>di</strong>seased mice (more specifically in a model of amyotrophiclateral sclerosis: the wobbler mouse). Other stu<strong>di</strong>es with dual “paramagneticfluorescent”are now in progress to follow the route of human fetal stem cells by MRI175ANNUAL REPORT <strong>2009</strong>
IRFMNand fluorescent molecular tomography in the same group of animals at <strong>di</strong>fferent timesafter transplantation.Laboratory of Molecular BiologyThe family of molybdo-enzymesMolybdo-enzymes are proteins requiring a molybdo-pterin cofactor (molybdenumcofactor,MoCo) for their catalytic activity. Until a few years ago, it was believed thatthe family of molybdo-enzymes consisted only of three members: sulfite oxidase,aldehyde oxidase and xanthine oxidoreductase. In the last few years of research, ourlaboratory has determined the structure of the genes co<strong>di</strong>ng for <strong>di</strong>fferentmolybdoenzymes in rodents and humans. In particular, we demonstrated that rodentsare endowed with four <strong>di</strong>fferent aldehyde oxidase (AOX1, AOX3, AOX4 andAOX3L1) characterized by remarkable structural and functional similarity. Thephysiological substrate(s) and the physiological function(s) of this group of protein havenot yet been identified, although it is known that aldehyde oxidases can oxi<strong>di</strong>zealiphatic and aromatic aldehydes into the correspon<strong>di</strong>ng carboxylic acids and tohydroxylate <strong>di</strong>fferent types of n-heterocyclic aromatic rings. The four <strong>di</strong>fferentaldehyde oxidases of rats and mice are the product of an equivalent number of geneslocated at the short <strong>di</strong>stance one from the other on the same chromosome. These genesoriginated through a number of a synchronous gene duplication events. Our stu<strong>di</strong>esaimed at the determination of the evolutionary processes underlying the development ofthe genes co<strong>di</strong>ng for aldehyde oxidases allowed us to establish that the natural history ofthis gene family is made of duplication and suppression events. These evolutionaryprocesses resulted in the presence of variable number of aldehyde oxidases in <strong>di</strong>fferentgenomes. Man is characterized by the presence of a single active gene (AOX1) and twoinactive pseudo genes clustered on chromosome 2. In the last years we have focused onthe functional definition of the <strong>di</strong>fferent mouse aldehyde oxidases and our long termaim is to establish the reasons underlying the <strong>di</strong>sparity in the number of these enzymesbetween humans and rodents. To this purpose, we generated two knockout animals forthe AOX4 and AOX3L1 genes. The AOX4 knockout mouse was characterizedphenotypically demonstrating minimal alterations of the epidermis. Indeed, the AOX4knockout animal shows epidermal hypertrophy, which is associated with a peculiarfragility of the corneal layer. At the biochemical level, we observed a deficiency in thesynthesis of retinoic acid in the two organs where AOX4 is present in significantamounts (skin and Harderian glands). This observation is in line with the idea thatAOX4 may have a role in the metabolism of retinaldehyde to retinoic acid, the activemetabolite of vitamine A. Recently we gathered novel data in<strong>di</strong>cating a role for AOX4in the control of the a<strong>di</strong>pose tissue homeostasis. The observation is of particularimportance also in man as human AOX1 seems to exert a similar effect in the synthesisand deposition of lipids. Currently we are performing similar stu<strong>di</strong>es in a knockoutmouse for AOX3L1.176ANNUAL REPORT <strong>2009</strong>
IRFMNRetinoids in the treatment and chemoprevention of myeloid leukemia andmammary carcinomaOur laboratory has a long stan<strong>di</strong>ng interest in defining the therapeutic potential ofnatural and synthetic derivatives of retinoic acid, the active metabolite of vitamin A.These compounds, commonly defined as retinoids, are characterized by cyto<strong>di</strong>fferentiating,anti-proliferative and apoptotic effects which are at the bases of theirtherapeutic activity in the context of myeloid leukemia and mammary carcinoma.Retinoids are very active therapeutic agents, although they are endowed with doselimiting side effects, particularly chronic administration. A rational clinical use ofretinoids calls for a better knowledge of the mechanisms of action underlying the antineoplasticaction exerted by these compounds. In-depth knowledge is of fundamentalvalue for the design of novel retinoid-based treatment strategies characterized byincreased therapeutic index. We have a long-stan<strong>di</strong>ng interest in the definition of themolecular mechanisms regulating the activity of retinoic acid nuclear receptors, as theymay lead to the identification of pharmacological targets to be modulated in a specificmanner. Indeed, we believe that knowledge in this field may lead to the development ofrational combinations between retinoids and other pharmacologically active agents to beused in the treatment of <strong>di</strong>fferent tumor types. Such an approach has led us to the recentidentification of the prolyl-isomerase, PIN1 as a negative regulator of the retinoic acidreceptor, RARα. Pharmacological inhibitors PIN1 proved to be particularly effective insensitizing the leukemic cell to the anti-neoplastic activity of retinoids. These resultsopen up the possibility to develop combinations based on PIN1 inhibitors and retinoidsfor the treatment of acute myeloid leukemia. Following the same type of logic, we haverecently demonstrated that the inhibition of the microRNA, miR21 in mammarycarcinomas positive for estrogen receptor is of the utmost importance in potentiating theanti-proliferative activity of retinoids in this particular type of tumor. Finally, weobserved that the peculiar subgroup of mammary cancer positive for HER2 may benefitfrom retinoid-based treatment or associations between retinoids and inhibitors of HER2receptor tyrosine kinase activity.Laboratory of Receptor PharmacologyStu<strong>di</strong>es on the role of dysfunction of the endoplasmic reticulum (ER) orthe Golgi apparatus (GA) in neurodegenerative <strong>di</strong>seaseThe secretory pathway starts at the endoplasmic reticulum (ER) where proteins aresynthesized and folded and chaperone–me<strong>di</strong>ated quality control prevents misfoldedproteins to reach their destination and interfere with normal metabolism. Proteintransport by mean of vesicles continues through the Golgi Apparatus (GA), that is mostabundant in neurons, and finishes in the plasma membrane, secretory vesicles orlysosomes. The endocytic pathway enables internalized macromolecules to be deliveredvia endosomes to lysosomes where they are enzymatically <strong>di</strong>gested.In mammalian cells, the Golgi-associated retrograde protein (GARP) complex isinvolved in retrograde transport of endosomes to the trans GA network. Defectiveintracellular membrane trafficking is common to several neurodegenerative <strong>di</strong>seases.Among the neuronal population, motor neurons, due the their high energy requirementand long axons are, together with retinal cells, the most sensitive ones.177ANNUAL REPORT <strong>2009</strong>
IRFMNThe Laboratory of Receptor Pharmacology utilizes two mouse models ofneurodegeneration related to cellular transport <strong>di</strong>sruption, carrying mutation in proteinsresident in the ER (the mnd mouse) or in the GARP complex (the wobbler mouse),models, respectively, of EPMR, a form of neuronal ceroid lipofuscinosis, andAmyotrophic Lateral Sclerosis.We have found that mnd mice are more sensitive to convulsions induced by intrahippocampalkainic acid or i.p. pentylenetetrazole. New non-invasive approaches, likeOptical Imaging , MRI, MicroCT and Confocal Angiography are in progress, in orderto allow a better translation of the results to the human <strong>di</strong>sease.In the wobbler mice we have tested two <strong>di</strong>fferent approaches of cell therapy.Un<strong>di</strong>fferentiated adult neural stem cells (in collaboration with Dr. Parati, <strong>Istituto</strong> Besta)produced a weak and transient protective effect in clinical progression but significantlyreduced motor neuron loss occurring in the wobbler mouse. Transplantation ofmononucleate cells from human cord blood (in collaboration with Dott. Lazzari,Policlinico), although <strong>di</strong>d not replace degenerating motor neurons, produced a markedneuroprotective effect by slowing the clinical progression and reducing motor neuronloss, biceps atrophy and neuroinflammation (reactive gliosis). Finally, we have trackedby MRI cells obtained from human amniotic fluid or chorioid villi labelled withparamagnetic nanoparticles (SPIO), and found that they can be detected for two monthsafter transplantation.Neuropharmacology of serotonergic transporterWe have ongoing collaborative stu<strong>di</strong>es with Dr. Gobbi (Lab. biochemistry and proteinchemistry, IRFMN), Lundbeck and Vanderbilt University to characterize the role of theallosteric site at the serotonin transporter on the mechanism of action of SSRI (selectiveserotonin reuptake inhibitors) antidepressant, like escitalopram.Laboratory of Molecular PathologyIn vitro models for investigating motor neuron pathologiesMutant forms of specific proteins play a key role in many neurodegenerative <strong>di</strong>seases.Experimental models in vivo and in vitro are sorely needed to study the effects of thesetoxic proteins. The motor neuronal cell line NSC-34, a widely used model to studymotor neuron degeneration, is available in the laboratory. We have applied the pTet-Offsystem to control gene expression through the level of tetracyclines to the NSC-34 cellline establishing a new cell line (NSC-34 tTA40) that stably expresses thetransactivating protein tTA. This cell line is suitable to study the pathogenicmechanisms of motor neuron <strong>di</strong>seases after transient/stable transfection with genes ofinterest for these pathologies.The NSC-34 and the NSC-34 tTA40 cell lines were used to obtain in vitro models tostudy the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). Mutant formsof superoxide <strong>di</strong>smutase 1 are responsible for some of the familial forms of ALS. Wedeveloped NSC-34-based cell lines expressing constitutively or con<strong>di</strong>tionally humanG93A mutant superoxide <strong>di</strong>smutase 1 (G93ASOD1).178ANNUAL REPORT <strong>2009</strong>
IRFMNNovel intracellular targets in the selective degeneration of motor neuronsin amyotrophic lateral sclerosisAmyotrophic lateral sclerosis (ALS) is a rapidly fatal neurodegenerative <strong>di</strong>seasecharacterized by loss of motor neurons. The management of this <strong>di</strong>sease remainsessentially supportive and symptomatic. Understan<strong>di</strong>ng the mechanisms underlying the<strong>di</strong>sease is a way to favor more efficient therapeutic strategies. We utilized our cellmodels to investigate the biochemical-molecular mechanisms underlying the alterationsof mitochondrial morphology observed in the early stages of the <strong>di</strong>sease in the motornerve terminals of ALS patients and in the murine models of the <strong>di</strong>sease. We showedthat motor neurons are selectively susceptible to mitochondrial damage induced by amutant form of human superoxide <strong>di</strong>smutase 1 (G93ASOD1) and that this damage wasmodulated by the extent of expression of the mutant protein.Furthermore the expression of G93ASOD1 protein increased the susceptibility of motorneurons to inhibitors of the electron transport chain (ETC) and to oxidants. Exposure todrugs or exogenous compounds impairing the ETC could thus be a risk factor to motorneurons of in<strong>di</strong>viduals carrying mutant superoxide <strong>di</strong>smutase 1.We have shown that in motor neuronal cells the activity of glutamate cysteine ligase,the rate limiting enzyme for glutathione biosynthesis, was modulated by the level ofG93ASOD1. As a consequence, the level of glutathione, the main cell antioxidant,increased or decreased. A variation in the level of glutathione may influence theformation of nitrated proteins, a pathogenic mechanism in ALS, which was investigate<strong>di</strong>n collaboration with the laboratory of Translational Proteomics.Cytochrome P-450 superfamilyCytochrome(s) P-450 have evolved into a large superfamily which plays a major role inthe metabolism of drugs and other chemicals. The majority of existing drugs depends onthe P-450 system for terminating their biological effects or for side effects or adversereaction. The laboratory has a long-stan<strong>di</strong>ng interest in the induction/degradationmechanisms of specific cytochrome P-450 families due to drug administration or to<strong>di</strong>sease states.Activation of enzymes of the heme metabolic pathway (heme oxygenasesystem, biliver<strong>di</strong>n reductase) as a protective response to stressThe enzymatic system of heme oxygenase (HO) is devoted to cellular degradation ofheme containing molecules, like cytochromes and hemoglobin, and to recycling of iron.Products formed by the catalytic activity of HO - carbon monoxide and bile pigments -are important regulating factors in the cell. An increase of HO activity (which is usuallysustained by activation of the inducible form HO-1) is now considered a protectivemechanism against untoward stimuli particularly when oxidative stress is involved. Inthe past, the laboratory of Molecular Pathology identified cytokines as inducers of HOactivity and as transcriptional activators of the HO-1 gene. We are currentlyinvestigating the functional significance of HO-1 activation in neurodegeneration.Laboratory of Translational ProteomicsNitrative stress and protein aggregation in amyotrophic lateral sclerosis: aproteomic approach179ANNUAL REPORT <strong>2009</strong>
IRFMNThe molecular mechanisms at the basis of neurodegenerative <strong>di</strong>seases inclu<strong>di</strong>ng thegenetically linked ones, such as amyotrophic lateral sclerosis (ALS), are still unknown.However, there is evidence that nitrative stress and protein aggregation play centralroles in the pathogenesis of such <strong>di</strong>seases. In collaboration with the Laboratory ofMolecular Neurobiology at the <strong>Mario</strong> <strong>Negri</strong> Institute in Milano we conducted proteomeanalysis of an animal model of familial ALS (fALS). We focused the attention on theanalysis of protein expression changes and protein mo<strong>di</strong>fications, such as tyrosinenitration (marker of nitrative stress), in a transgenic mouse, which over-express humanmutated (G93A) superoxide <strong>di</strong>smutase (SOD1). We analyzed, by proteomic tools,spinal cord of presymptomatic G93A SOD1 mice, we identified nitrated proteins andquantified the level of nitration for each protein in comparison with healthy controls.We revealed that there was a substantial increase of the nitration level in at least fiveproteins: actin, alpha and gamma enolase, ATP synthase and a chaperone protein,HSC71. The alteration of the function of these proteins, due to the oxidativemo<strong>di</strong>fication, may have important consequences on the cellular metabolism/catabolism,signaling pathways and phosphorylation cascades, therefore may be at the basis of themolecular mechanisms lea<strong>di</strong>ng to neurodegeneration. Regar<strong>di</strong>ng the aggregationstu<strong>di</strong>es, we carried out a proteomic analysis of the protein composition of the insolublefraction, as a model of protein aggregates, from the fALS mouse model at <strong>di</strong>fferent<strong>di</strong>sease stages. We identified several proteins enriched in the detergent-insolublefraction already at a preclinical stage, inclu<strong>di</strong>ng interme<strong>di</strong>ate filaments, chaperones andmitochondrial proteins. Aconitase, HSC70 and cyclophilin A were also significantlyenriched in the insoluble fraction of spinal cords of ALS patients. Moreover, we foundthat the majority of proteins in mice and HSP90 in patients were tyrosine-nitrated. Incollaboration with the Laboratory of Molecular Pathology at the <strong>Mario</strong> <strong>Negri</strong> Institutein Milan we therefore investigated the role of nitrative stress in aggregate formation infALS-like murine motor neuron-neuroblastoma (NSC-34) cell lines. By inhibiting nitricoxide synthesis the amount of insoluble proteins, particularly aconitase, HSC70,cyclophilin A and SOD1 can be substantially reduced. In conclusions, analysis of theinsoluble fractions from cellular/mouse models and human tissues revealed novelaggregation-prone proteins and suggests that nitrative stress contribute to proteinaggregate formation in ALS.Identification of biomarkers of ALSIn collaboration with the Laboratory of Molecular Neurobiology at the <strong>Mario</strong> <strong>Negri</strong>Institute, “Fondazione Salvatore Maugeri”, IRCCS, in Pavia and Milan we areconducting a series of stu<strong>di</strong>es with the aim to identify biomarkers of ALS useful in<strong>di</strong>agnosis and prognosis and to unravel pathogenetic mechanisms, still unknown.Increased levels of nitrotyrosine in the central nervous system have been found inpatients and mouse models of fALS, suggesting a possible use of nitrated proteins asbiomarkers. We analyzed peripheral blood mononuclear cells (PBMCs), easilyaccessible samples, from spora<strong>di</strong>c ALS (sALS) patients and a rat model of fALS (a) toestablish whether an increased level of nitrated proteins was present in PBMCs, too, and(b) to identify possible can<strong>di</strong>date biomarkers. With a proteomic approach, we identifiedfor the first time the major over-nitrated proteins in PBMCs from patients and rats at<strong>di</strong>fferent <strong>di</strong>sease stages. In the rats, their increased levels already were measured at apresymptomatic stage. Among them, actin, ATP synthase, and vinculin overlap between180ANNUAL REPORT <strong>2009</strong>
IRFMNsALS patients and the rat model. Both in patients and in rats the nitration level is at leasttwice than the one in the controls. Interestingly, in a previous study, actin and ATPasehave been found over nitrated in the spinal cord of a mouse model of fALS before<strong>di</strong>sease onset, suggesting their possible involvement in motor neuron degeneration. Inconclusion, we observed that an increased level of nitrated proteins was not restricted tothe spinal cord but also was present in peripheral cells of patients and an animal model,and that nitrated proteins are promising can<strong>di</strong>date biomarkers for early <strong>di</strong>agnosis ofALS.Proteomic analysis of a cellular model of fatal familial insomniaThe prion protein (PrP) is a glycosyl-phosphatidyl-inositol (GPI)-anchored membraneglycoprotein that plays a vital role in prion <strong>di</strong>seases, a class of fatal neurodegenerative<strong>di</strong>sorders of humans and animals. Approximately 20% of human prion <strong>di</strong>seases <strong>di</strong>splayautosomal dominant inheritance and are linked to mutations in the PrP gene onchromosome 20. PrP mutations are thought to favor the conformational conversion ofPrP into a misfolded isoform that causes <strong>di</strong>sease by an unknown mechanism. The PrPmutation D178N/M129 is linked to fatal familial insomnia, which causes severe sleepabnormalities and autonomic dysfunction. In collaboration with the Laboratory ofNeurobiology of Prions at the <strong>Mario</strong> <strong>Negri</strong> Institute in Milan we found that mutant PrPaccumulates abnormally in the endoplasmic reticulum and Golgi of transfectedneuroblastoma N2a cells. We then investigated the impact of intracellular PrPaccumulation on cellular homeostasis, we <strong>di</strong>d a 2D gel-based <strong>di</strong>fferential proteomicanalysis. We used wide-range immobilized pH gra<strong>di</strong>ent strips, pH 4-7 and 6-11, toanalyze a large number of proteins. We found changes in proteins involved in energymetabolism, redox regulation and vesicular transport. Rab GDP <strong>di</strong>ssociation inhibitoralpha (GDI) was one of the proteins that changed most. GDI regulates vesicular proteintrafficking by acting on the activity of several Rab proteins. We found a specificreduction in the level of functional Rab11 in mutant PrP expressing cells, associatedwith impaired post-Golgi trafficking. Our data are consistent with a model by whichmutant PrP induces over-expression of GDI activating a cytotoxic feedback loop whichleads to protein accumulation in the secretory pathway.Laboratory for the Study of Biological SystemsSystem-level analysis of protein interactions in the epithelial junctionalcomplexInter-cellular junctions form the apical junctional complex and me<strong>di</strong>ate adhesionbetween adjacent cells, thus representing the cellular basis for tissue cohesion (forinstance, the epithelial lining of the intestine). In order to acquire system-levelunderstan<strong>di</strong>ng of the apical junctional complex, we have stu<strong>di</strong>ed (using amethodological approach of ‘network analysis’) all the protein interactions that havebeen described at the junctions in epithelial cells of human origin. We also found thatproper ‘hubs’ (i.e., very rare proteins with an excee<strong>di</strong>ngly high number of interactionswith other proteins) were absent from the junctional network. Nevertheless, weobserved that the most connected (albeit non-hub) proteins were also essential proteins.In ad<strong>di</strong>tion, we have detected modules within the junctional networks (i.e., denselyinter-connected groups of proteins). Analysis of the modules has highlighted general181ANNUAL REPORT <strong>2009</strong>
IRFMNorganizing principles of the junctional complex, thus confirming the usefulness ofnetwork analysis for studying the components and the interactions of the cell.Novel regulators of cell motilityCell motility plays a central role in several biological processes, under both normal (e.g.embryonic development) and pathological con<strong>di</strong>tions (e.g. tumor cell <strong>di</strong>ssemination).Thus, it is important to identify the molecular mechanisms that regulate cell motility. Inrecent years, we have characterized Junctional Adhesion Molecule-A (JAM-A), amembrane molecule that localizes to the intercellular tight junctions and binds PDZtypeintracellular proteins. In the course of these stu<strong>di</strong>es, we have <strong>di</strong>scovered that JAM-A expression reduces cell motility. In ad<strong>di</strong>tion, we have found that JAM-A enhancesmicrotubule stability and focal adhesion formation, which are the adhesive points ofcontact between cells and extracellular matrix. All these functional changes requireamino acid residues that me<strong>di</strong>ate bin<strong>di</strong>ng to PDZ-type intracellular proteins. Thesefin<strong>di</strong>ngs have highlighted a novel mechanism of motility inhibition that requires theinteraction between a membrane protein and PDZ-type intracellular proteins.Effect of inflammatory cytokines on Junctional Adhesion Molecule-A(JAM-A)In the course of inflammatory responses, JAM-A contributes to the leakage of plasmaproteins and the transmigration of circulating leukocytes. Although it has been reportedthat the inflammatory cytokine Tumor Necrosis Factor (TNF) causes the <strong>di</strong>sassembly ofJAM-A from the intercellular junctions, the mechanism has not been elucidated fully.Recently, we found that TNF enhances the solubility of JAM-A in non-ionic detergentsand increases the amount of detergent-soluble JAM-A at the cell surface. In ad<strong>di</strong>tion,we found that, upon cell treatment with TNF, higher levels of JAM-A becomedetectable at the cell surface (by FACS analysis). As these higher levels of JAM-Aderive from the intercellular junctions (and not from intracellular stores), we proposethat TNF causes not only the <strong>di</strong>sassembly of JAM-A from the junctions and itssubsequent re<strong>di</strong>stribution to the cell surface, but also its <strong>di</strong>spersal in such a way thatJAM-A becomes more easily accessible to the antibo<strong>di</strong>es used for FACS analysis.These fin<strong>di</strong>ngs are important to highlight potential mechanisms of permeabilityregulation during inflammation that might be modulated by inflammatory interventions.182ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF EPIDEMIOLOGYSTAFFHeadCarlo LA VECCHIA, M.D.Laboratory of General EpidemiologyHeadCarlo LA VECCHIA, M.D.Cancer Epidemiology UnitHeadCristina BOSETTI, Mat.Sci.D.Lifestyle Habits and Prevention UnitHeadLiliane CHATENOUD, Biol.Sci.D.Epidemiology for Clinical Research UnitHeadSilvano GALLUS, Comp.Sci.D.Laboratory of Epidemiological MethodsHeadEva NEGRI, Mat.Sci.D.Laboratory of Epidemiology of Chronic DiseasesHeadAlessandra TAVANI, Biol.Sci.D.Laboratory of Me<strong>di</strong>cal InformaticsHeadEugenio SANTORO, Comp.Sci.D.183ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULACarlo La Vecchia holds a Doctor of Me<strong>di</strong>cine from the University of Milan, a Master of Science inClinical Me<strong>di</strong>cine (epidemiology) from Oxford University and a Diploma from the Post-Graduate Schoolof Pharmacological Research at the “<strong>Mario</strong> <strong>Negri</strong>” Institute for Pharmacological Research in Milan.Work experiences: He is Head of the Department of Epidemiology at the <strong>Mario</strong> <strong>Negri</strong> Institute forPharmacological Research in Milan, Italy. He is also Associate Professor of Epidemiology at theUniversity of Milan, Adjunct Professor of Epidemiology, University of Lausanne, Switzerland (since2002) and Adjunct Professor of Me<strong>di</strong>cine, School of Me<strong>di</strong>cine, Vanderbilt University, Nashville, TN(2002-<strong>2009</strong>).Dr. La Vecchia is a temporary advisor at the International Agency for Research on Cancer IARC/WHO inLyon and at the WHO in Geneva, and a registered journalist in Milan. He was an Honorary SeniorLecturer in Oral Me<strong>di</strong>cine at the Eastman Dental Institute at the University College of London (1996-2003) and Adjunct Associate Professor of Epidemiology at the Harvard School of Public Health (1996-2001).He is Associate E<strong>di</strong>tor to: European Journal of Cancer Prevention and Annals of Oncology, and serves onthe e<strong>di</strong>torial boards of the Jornals: Alimentazione e Prevenzione; Archives of Me<strong>di</strong>cal Science; AsianPacific Journal of Cancer Prevention; Current Cancer Therapy Reviews; Dermatology Research andPractice; Digestive and Liver Disease; Economia Politica del Farmaco; European Journal of Nutrition; InScope Oncology & Haematology; Maturitas; Nutrition and Cancer; Oncology; Open Cancer Journal; OralOncology; Revisiones en Ginecologia y Obstetricia; Revista Española de Nutrición Comunitaria; Revued'Epidémiologie et de Santé Publique;Tumori. In 1993, he received the Glaxo Prize for me<strong>di</strong>calpublication.He has authored or co-authored over 2000 publications in peer reviewed journals (1500 included inPubmed), with a mean Impact Factor of 3.8 and a total Impact Factor over 5000 (1995-2006). He has over62.000 citations, and 380 publications quoted more than 30 times (H-index 81).Eva <strong>Negri</strong> got a degree in Mathematics in 1985 at the University of Milan, School of Mathematics.Awards: EEC scholarship for postgraduate training in Epidemiology (1988).Areas of interest: Design, conduction and analysis of epidemiologic stu<strong>di</strong>es on chronic <strong>di</strong>seases (e.g.cancer and myocar<strong>di</strong>al infarction) and injuries, analysis of mortality of cohorts of workers, analysis oftemporal trends and geographic <strong>di</strong>stribution of mortality from cancer, car<strong>di</strong>ovascular <strong>di</strong>sease, injuries andother selected con<strong>di</strong>tions, analysis of national health surveys, application of linear modeling techniques tothe analysis of epidemiological data, collaborative re-analyses and meta-analyses of epidemiologicalstu<strong>di</strong>es.Work experiences: Since 2007: Laboratory Chief, Unit of Epidemiologic Methods, Department ofEpidemiology; 1992-2006: Unit Chief, Unit of Epidemiologic Methods, Laboratory Epidemiology; since1990-1992: Researcher at the Laboratory of Epidemiology; 1984-1990: Collaborator of the Laboratory ofEpidemiology.Selected publications• <strong>Negri</strong> E, La Vecchia C, Pelucchi C, Tavani A The risk of acute myocar<strong>di</strong>al infarction after stopping drinking Prev Med2005; 40: 725-728• <strong>Negri</strong> E, Pelucchi C, Talamini R, Montella M, Gallus S, Bosetti C, Franceschi S, La Vecchia C Family history of cancerand the risk of prostate cancer and benign prostatic hyperplasia Int J Cancer 2005; 114: 648-652• <strong>Negri</strong> E, Little D, Boiocchi M, La Vecchia C, Franceschi S. B-cell non-Hodgkin’s lymphoma and hepatitis C virusinfection: A systematic review Int J Cancer 2004; 111: 1-8• <strong>Negri</strong> E, Ron E, Franceschi S, La Vecchia C, Preston-Martin S, Kolonel L, et al. Risk factors for medullary thyroidcarcinoma: A pooled analysis Cancer Causes Control 2002; 13: 365-372• Levi F, La Vecchia C, Boyle P, Lucchini F, <strong>Negri</strong> E Western and eastern European trends in testicular cancer mortalityLancet 2001; 357: 1853-1854184ANNUAL REPORT <strong>2009</strong>
IRFMNAlessandra Tavani degree in Biological Sciences, University of Milan, Italy (July 1977);Pharmacological Research Specialist, “<strong>Mario</strong> <strong>Negri</strong>” Institute for Pharmacological Research, Milan,Italy (July 1979).Work experiences: 1979-81: Researcher at the laboratory of Drug Metabolism, “<strong>Mario</strong> <strong>Negri</strong>” Institutefor Pharmacological Research. 1981: Researcher at the Unit for Research on Ad<strong>di</strong>ctive Drugs (<strong>di</strong>rectorprof. H.W. Kosterlitz), University of Aberdeen, Scotland, U.K. 1982-1990: Head of the Unit of OpioidNeuropharmacology, “<strong>Mario</strong> <strong>Negri</strong>” Institute for Pharmacological Research. 1990: Researcher at theUnit of Clinical Perinatal Pharmacology, “<strong>Mario</strong> <strong>Negri</strong>” Institute for Pharmacological Research. From1991-2006: Head of the Unit of Epidemiology of Chronic Diseases of the Laboratory of Epidemiology,“<strong>Mario</strong> <strong>Negri</strong>” Institute for Pharmacological Research. 2007-: Head of the Laboratory of Epidemiologyof Chronic Diseases of the Department of Epidemiology, “<strong>Mario</strong> <strong>Negri</strong>” Institute for PharmacologicalResearch.Awards: "Rafaelsen Scholar Award" from the Collegium Internationale Neuro-Psychopharmacologicum(CINP), 16th Meeting, Munich (F.R.G.), 1988.Areas of interest: Epidemiology of cancer and coronary heart <strong>di</strong>sease. Organization of case-controlstu<strong>di</strong>es and cohort stu<strong>di</strong>es on cancer and coronary heart <strong>di</strong>sease, inclu<strong>di</strong>ng biological sample collection.Analyses of risk factors related to genetic factors and lifestyles, particularly coffee, <strong>di</strong>et, physical activity.Selected publications• Bravi F, Scotti L, Bosetti C, Gallus S, <strong>Negri</strong> E, La Vecchia C, Tavani A. Coffee drinking and endometrial cancer risk: ametaanalysis of observational stu<strong>di</strong>es. Am J Obstet Gynecol <strong>2009</strong>; 200: 130-135• Tavani A, Bravi F, Dal Maso L, Zucchetto A, Bosetti C, Pelucchi C, Montella M, Franceschi S, La Vecchia C. Physicalactivity and risk of endometrial cancer: an Italian case-control study. Eur J Cancer Prev <strong>2009</strong>; 18: 303-306• Tavani A, Pelucchi C, Parpinel M T, <strong>Negri</strong> E, Franceschi S, Levi F, La Vecchia C. n-3 Polyunsaturated fatty acid intakeand cancer risk in Italy and Switzerland. Int J Cancer 2003; 105: 113-116• Herrero R, Castellsague X, Pawlita M, Lissowska J, Kee F, Balaram P, Rajkumar T, Sridhar H, Rose B, PintosJ, Fernandez L, Idris A, Sanchez M J, Nieto A, Talamini R, Tavani A, et al. Human papillomavirus and oral cancer: TheInternational Agency for Research on Cancer Multicenter Study. J Natl Cancer Inst 2003; 95: 1772-1783• Tavani A, Pelucchi C, <strong>Negri</strong> E, Bertuzzi M, La Vecchia C. n-3 polyunsaturated fatty acids, fish, and nonfatal acutemyocar<strong>di</strong>al infarction. Circulation 2001; 104: 2269-2272Eugenio Santoro got his degree in Computer Science in 1990 at the Milan University. He started towork at the “<strong>Mario</strong> <strong>Negri</strong>” Institute in 1985 as a research fellow. He was Head of the Applied Statisticsand Informatics Unit and of the Applied Statistics and Informatics laboratory, which was part of theDepartment of Car<strong>di</strong>ovascular Research. Since 2001 he is Head of the Laboratory of Me<strong>di</strong>calInformatics that is currently part of the Department of Epidemiology. His main areas of interest havebeen biostatistics and clinical informatics with the development of software for data management anddata analyses of large scale clinical trials in car<strong>di</strong>ology, such as the GISSI stu<strong>di</strong>es (Gruppo Italiano perlo Stu<strong>di</strong>o della Sopravvivenza nell’Infarto miocar<strong>di</strong>co). His main current area of interest is the Internet,and more recently the web 2.0, and their application in the me<strong>di</strong>cal field, in clinical research, and inme<strong>di</strong>cal education through the development of health related websites. He is author or co-author of morethan 180 scientific papers published in peer reviewed journals, and of more than 70 scientific abstractssubmitted to the main international meetings in the car<strong>di</strong>ology and in the computer science fields. He isalso author of three books (available in Italian) about the use of the Internet in me<strong>di</strong>cine (“Web 2.0 andme<strong>di</strong>cine”, “Guida alla me<strong>di</strong>cina in rete” and “Internet in me<strong>di</strong>cina. Guida all’uso e applicazionipratiche”, published by the Pensiero Scientifico E<strong>di</strong>tore, Rome) and of one section about Internet andme<strong>di</strong>cine, included in one of the most important italian me<strong>di</strong>cal encyclope<strong>di</strong>a (“Enciclope<strong>di</strong>a Me<strong>di</strong>caItaliana”, UTET 2007). He also collaborates to the publication of the Italian National BioethicsCommittee’s guidelines about ethics, health, and the new information technologies.Selected publications• Santoro E. "Web 2.0 e Me<strong>di</strong>cine: how social networks, podcasts, wikis and blogs are transforming communication,care, and education in health”. Il Pensiero Scientifco E<strong>di</strong>tore, Roma <strong>2009</strong>.• Santoro E., Tinazzi A.“Clinical Trials Data Management”. In “Clinical Trials Handbook” (Wiley <strong>2009</strong>, E<strong>di</strong>ted by GadS.C.).• Santoro E. Podcast, wiki e blog: il web 2.0 al servizio della formazione edell’aggiornamento del me<strong>di</strong>co. Recenti Prog Med 2007;98:484-494.185ANNUAL REPORT <strong>2009</strong>
IRFMN• Santoro E, Rossi Valentina, Pandolfini C, Bonati M. DEC-NET: The development of the European register of clinicaltrials on me<strong>di</strong>cines for children. Clin Trials 2006; 3: 366-375• Clivio L, Tinazzi A, Mangano S, Santoro E. The contribution of information technology: Towards a better clinical datamanagement. Drug Dev Res 2006; 67: 245-250• Santoro E. Internet and information on breast cancer: an overview. Breast 2003; 12: 424-431Cristina Bosetti got her degree in Mathematics in 1994 at the University of Milan, School ofMathematics, and the Post-Graduate Diploma in Pharmacological Research in 1999 at the “<strong>Mario</strong> <strong>Negri</strong>”Institute for Pharmacological Research in Milan.Areas of interest: Epidemiology of cancer, car<strong>di</strong>ovascular <strong>di</strong>seases and other chronic con<strong>di</strong>tions. Inparticular case-control stu<strong>di</strong>es on cancers of the upper respiratory and <strong>di</strong>gestive sites, thyroid, breast,hormone-related cancers, and on ischemic heart <strong>di</strong>sease. Analysis of risk related to <strong>di</strong>et, alcohol, tobacco,reproductive and hormonal factors, occupational and environmental exposure to toxic substances, throughthe application of generalized linear models.She is author/coauthor of more than 130 publications on these issues on peer-reviewed scientific journals.Work experiences: Visiting scientist at the”Life style and cancer group” of the International Agency forResearch on Cancer (IARC), Lyon, France (Oct <strong>2009</strong>); Unit Head, Unit of Cancer Epidemiology,Department of Epidemiology, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milan (since Sept.2005); Collaboration with the “International Epidemiology Institute”, Rockville, MD, USA (since 2002-); Visiting scientist at the Unit of “Field and intervention stu<strong>di</strong>es”, IARC, Lyon, France (sett-2000-giu.2001); Visiting scientist at the Department of Epidemiology, Harvard School of Public Health, Boston,MA (sett-nov. 1998); Researcher at the Laboratory of Epidemiology, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong>“<strong>Mario</strong> <strong>Negri</strong>”, Milan (1998-2005); Researcher at the Laboratory of Mother and Child Health, <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milan (1996-1997). She has over 200 publications on peerreviewedscientific Journals cited in PubMed/MEDLINE. Mean I.F.: 3.68. H-index: 30 (on GoogleScholar or SCOPUS).Selected publications:• Bosetti C, Bertuccio P, Chatenoud L, <strong>Negri</strong> E, Levi F, La Vecchia C. Childhood cancer mortality in Europe, 1970-2007.Eur J Cancer. <strong>2009</strong> Oct 7. [Epub ahead of print]• Bosetti C, Gallus S, Peto R, <strong>Negri</strong> E, Talamini R, Tavani A, Franceschi S, La Vecchia C. Tobacco Smoking, SmokingCessation, and Cumulative Risk of Upper Aero<strong>di</strong>gestive Tract Cancers.Am J Epidemiol. 2007; 167:468-73.• Bosetti C, Malvezzi M, Chatenoud L, <strong>Negri</strong> E, Levi F, La Vecchia C. Trends in cancer mortality in the Americas, 1970-2000. Ann Oncol 2005; 16: 489-511.• Bosetti C, Spertini L, Parpinel M T, Gnagnarella P, Lagiou P, <strong>Negri</strong> E, et al. Flavonoids and breast cancer risk in Italy.Cancer Epidemiol Biomarkers Prev 2005; 14: 805-808.• Bosetti C, Micelotta S, Dal Maso L, Talamini R, Montella M, <strong>Negri</strong> E, et al. Food groups and risk of prostate cancer inItaly. Int J Cancer 2004; 110: 424-428.• Smith J S, Herrero R, Bosetti C, Munoz N, Bosch F X, Eluf-Neto J, et al. IARC Multicentric Cervical Cancer StudyGroup Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J NatlCancer Inst 2002; 94: 1604-1613.Liliane Chatenoud, Doctor in Science Biology, University of Milan (1987); Postgraduate Doctor inHealth Statistics University of Milan (1995).Areas of interest: Epidemiological stu<strong>di</strong>es on obstetric <strong>di</strong>seases. Dermato-epidemiology. Cancerepidemiology (case-control stu<strong>di</strong>es on cancers of the breast, female genital tract). Analysis of temporaltrends and geographical <strong>di</strong>stribution of perinatal, infant mortality, cancer and other selected con<strong>di</strong>tions(over 150 publications on these topics, 1993-2005).Work experiences: Since Sept. 2005: Unit Head, “Lifestyle and Prevention”, Department ofEpidemiology. 1993-2005: Researcher at the Laboratory of Epidemiology; 1988-1990: Staff StatisticianBracco S.p.A., Milan.Selected publications• Chatenoud L, Malvezzi M, Pitrelli A, La Vecchia C, Bamfi F. Asthma mortality and long-acting beta2-agonists in fivemajor European countries, 1994-2004. J Asthma <strong>2009</strong> 46 : 546-551• Nal<strong>di</strong> L, Chatenoud L Registry research in dermatology. Dermatol Clin <strong>2009</strong> 27 : 185-19• Nal<strong>di</strong> L, Chatenoud L, Belloni A, Peserico A, Balato N, Virgili A R, Bruni P L, Ingordo V, Lo Scocco G, Solaroli C,Schena D, Di Landro A, Pezzarossa E, Arcangeli F, Gianni C, Betti R, Carli P, Farris A, Barabino G F, La Vecchia C,Parazzini F Me<strong>di</strong>cal history, drug exposure and the risk of psoriasis. Evidence from an Italian case-control studyDermatology 2008 216 : 125-132186ANNUAL REPORT <strong>2009</strong>
IRFMN• Valentini L G, Casali C, Chatenoud L, Chiaffarino F, Uberti Foppa C, Broggi G Surgical site infections after electiveneurosurgery: a survey of 1747 patients. Neurosurgery 2008 62 : 88-95• Chatenoud L, Mosconi P, Malvezzi M, Colombo P, La Vecchia C, Apolone G. Impact of a major thermoelectric plant onself-perceived health status. Prev Med. 2005;41:328-33.• Nal<strong>di</strong> L, Chatenoud L, Linder D, Belloni Fortina A, Peserico A, Virgili AR, et al. Cigarette smoking, body mass index,and stressful life events as risk factors for psoriasis: results from an Italian case-control study. J Invest Dermatol.2005;125:61-7.• Bosetti C, Malvezzi M, Chatenoud L, <strong>Negri</strong> E, Levi F, La Vecchia C. Trends in cancer mortality in the Americas, 1970-2000. Ann Oncol 2005; 16: 489-511.Silvano Gallus was born in Milan on the 20th of November 1970, and got his degree in ComputerScience in 1999 at the University of Milan.Areas of interest: Design, data managing, and statistical analyses of case-control stu<strong>di</strong>es on theassociations between several risk factors (inclu<strong>di</strong>ng in particular tobacco smoking, alcohol drinking andMe<strong>di</strong>terranean <strong>di</strong>et) and risk of cancer, coronary heart <strong>di</strong>sease and several other con<strong>di</strong>tions. Analyses ofoccupational cohort stu<strong>di</strong>es. Monitoring of prevalence and trends of smoking habit and obesity in Italyand Europe. Author/coauthor of over 160 publications in peer-reviewed journals since 1998.Work experiences: Chief of the Unit of Epidemiology for Clinical Research of the Department ofEpidemiology (since 2006); computer analyst, graphic designer, and statistical and epidemiologicalconsultant, Milan and Bergamo (since 2002); researcher at the Laboratory of Epidemiology (since 1997);creator, designer and webmaster of the website of one of the major Italian public hospital, Milano (1999-2002).Since 2008, Dr Gallus is Associate E<strong>di</strong>tor of the journal BMC Public Health, and is member of thee<strong>di</strong>torial board of The Open Obesity Journal (since <strong>2009</strong>) and the World Journal of GastrointestinalOncology (since <strong>2009</strong>).Selected publications• Gallus S, Tramacere I, La Vecchia C, Colombo P, Zuccaro P, Paleari L, Cesario A, Russo P, Apolone G. Use ofpharmacotherapy for smoking cessation in Italy. Arch Intern Med. <strong>2009</strong>;169:1927-8.• Gallus S, Nal<strong>di</strong> L, Carli P, La Vecchia C; Italian Group for Epidemiologic Research in Dermatology (GISED). Nevuscount on specific anatomic sites as a pre<strong>di</strong>ctor of total body count: a survey of 3,406 children from Italy. Am JEpidemiol. 2007;166:472-8.• Gallus S, Scotti L, <strong>Negri</strong> E, Talamini R, Franceschi S, Montella M, Giacosa A, Dal Maso L, La Vecchia C. Artificialsweeteners and cancer risk in a network of case-control stu<strong>di</strong>es. Ann Oncol. 2007;18:40-4.• Gallus S, Schiaffino A, La Vecchia C, Townsend J, Fernandez E. Price and cigarette consumption in Europe. TobControl. 2006;15:114-9.• Gallus S, Zuccaro P, Colombo P, Apolone G, Pacifici R, Garattini S, La Vecchia C. Effects of new smoking regulationsin Italy. Ann Oncol. 2006;17:346-7.• Clifford GM, Gallus S, Herrero R, Muñoz N, Snijders PJ, Vaccarella S, Anh PT, Ferreccio C, Hieu NT, Matos E,Molano M, Rajkumar R, Ronco G, de Sanjosé S, Shin HR, Sukvirach S, Thomas JO, Tunsakul S, Meijer CJ, FranceschiS; IARC HPV Prevalence Surveys Study Group. Worldwide <strong>di</strong>stribution of human papillomavirus types in cytologicallynormal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet.2005;366:991-8.ACTIVITIESThe Department of Epidemiology is involved in the epidemiology of several common cancers(inclu<strong>di</strong>ng cancers of the breast, female genital tract, respiratory and <strong>di</strong>gestive sites, prostate andurinary organs, lymphoid malignancies, melanoma, etc.) and of car<strong>di</strong>ovascular <strong>di</strong>seases, boththrough a descriptive and an analytical approach. Among the activities of descriptiveepidemiology are the analysis of temporal trends and geographical <strong>di</strong>stribution of mortalityfrom cancer, car<strong>di</strong>ovascular <strong>di</strong>seases, and other selected con<strong>di</strong>tions, in Italy and Europe; theanalysis of trends in tobacco consumption in the Italian population, and the correspon<strong>di</strong>ngeffects on incidence and mortality from lung and other tobacco-related neoplasms. The analyticepidemiology activities include the conduction and analysis of case-control stu<strong>di</strong>es, aimed atidentifying and better quantifying the association between genetic factors (family history),selected lifestyle habits (<strong>di</strong>et, tobacco, alcohol, etc.), use of exogenous hormones and exposure187ANNUAL REPORT <strong>2009</strong>
IRFMNto various substances and the development of various forms of cancers and car<strong>di</strong>ovascular<strong>di</strong>seases. In particular, the Department works on the analysis of <strong>di</strong>etary correlates of cancer andcar<strong>di</strong>ovascular <strong>di</strong>sease risk; quantification of health effects of tobacco smoking, alcoholconsumption and implications for prevention; epidemiological stu<strong>di</strong>es on the risk related to oralcontraceptive and hormone replacement therapy use; evaluation of the impact of screening inthe early <strong>di</strong>agnosis and prevention of cancer. Other activities include: the conduction ofquantitative reviews and meta-analysis of published data; the re-analysis of original data fromepidemiological stu<strong>di</strong>es of cancers of the oral cavity and pharynx, pancreas, thyroid, breast,ovary, and cervix; epidemiological and clinical stu<strong>di</strong>es in dermatology in collaboration with the“Gruppo Italiano per gli Stu<strong>di</strong> Epidemiologici in Dermatologia” (GISED); the analysis ofhistorical cohort stu<strong>di</strong>es of occupational exposures to aromatic amines, asbestos, herbicides andother known or potential carcinogens; monitoring and prevention of injuries. OtherDepartment’s activities are related to the development of me<strong>di</strong>cal websites, the study of thequality of me<strong>di</strong>cal information available on the Internet, and the training and research on issuesrelated to me<strong>di</strong>cal informatics and those concerning the use in the me<strong>di</strong>cal field of the Internet,the social me<strong>di</strong>a, and the web 2.0 applications.MAIN FINDINGSInverse associations between <strong>di</strong>etary vitamin D intake and the risk ofoesophageal/oral/pharyngeal cancers were found.Gastric cancer was inversely associated with intake of vitamin E, alpha-carotene and betacarotene,and positively associated with so<strong>di</strong>um intake in our study conducted in Milan.Besides micronutrients, we evaluated the association between macronutrients and gastric cancer,and found a protective effect of selected vegetable fats, which are common in the Me<strong>di</strong>terranean<strong>di</strong>et.High glycemic index and load increase the risk of gastric cancer. The risk is particularly whenhigh levels of glycemic load are combined to low intake of fruit and vegetables.In the same study of gastric cancer, we found a protective effect of total fiber intake. Withreference to the source of fiber intake, vegetable and fruit fiber, but not grain fiber, decreasedgastric cancer risk.In a case-control study from China, we found an inverse relation between green tea drinking andgastric cancer risk limited to the intake of cold tea.We found a protective effect against gastric cancer risk of <strong>di</strong>etary patterns rich in fruits andvegetables, and a positive association of <strong>di</strong>etary patterns rich in meats and animal fats andstarchy foods.Subjects in the highest decile of vitamin D intake had an about 30% decreased risk of coloncancer. Rectal cancer was unrelated to vitamin D intake in the investigated population.Inverse associations between proanthocyani<strong>di</strong>ns and the risk of colorectal cancer may explainthe protective effect of vegetables and fruit on colorectal cancer.188ANNUAL REPORT <strong>2009</strong>
IRFMNA <strong>di</strong>et with a high glycemic load was <strong>di</strong>rectly associated with the risk of hepatocellularcarcinoma in two stu<strong>di</strong>es from Italy and Greece.Obesity and <strong>di</strong>abetes increase HCC risk, and that these factors may explain a relevantproportion of cases among subjects without markers of HBV/HCV infection.Besides colon cancer, very high levels of vitamin D intake might have a protective effect againstbreast cancer, too.Our study <strong>di</strong>d not lend support to the hypothesis that alcohol or wine consumption improves thesurvival of women with breast cancer.We found a <strong>di</strong>rect association between consumption of red meat and endometrial cancer, and amoderate increase in risk for consumption of sweets and poultry. A high consumption of cerealsand vegetables decreased the risk of endometrial cancer by 44% and 41%, respectively.Our study confirmed the results of previous reports that a family history of endometrial, uterineand colorectal cancer increases the risk of endometrial cancer.The study of endometrial cancer confirmed the importance of multiparity, years ofmenstruation, and oral contraceptives use in endometrial cancer aetiology, thus contributing toidentify women at elevated risk of such neoplasm.The cluster of subjects mainly consuming bread and pasta was unfavourable for breast andovarian cancers. The group inclu<strong>di</strong>ng subjects mainly consuming fruits and vegetables wasprotective against ovarian cancer.We found <strong>di</strong>rect relations between <strong>di</strong>etary levels of glycemic index and load and renal cellcancer risk. This positive association can be related to mechanisms related to insulin resistanceand sensitivity.Regular use of aspirin for at least six months was not related with risk of renal cell cancer.The data on renal cell carcinoma provided evidence that a <strong>di</strong>et rich in beta-carotene andlutein/zeaxanthin may play a role in renal cell cancer prevention.Tobacco smoking and alcohol drinking are two independent risk factors for pancreatic cancerwhich may be responsible for approximately one third of these cancers in Italy.There is a positive association between pancreatic cancer risk and the intake of animal protein,and a negative one with sugars.A <strong>di</strong>et rich in meat, sugar and potatoes has an unfavourable role on pancreatic cancer. Noncitrusfruit, cooked vegetables and pulses have a protective effect on this cancer.A varied <strong>di</strong>et has a beneficial effect on laryngeal cancer. Diversity within vegetables and fruithas also a protective effect.Citrus fruit showed a protective effect against cancers of the <strong>di</strong>gestive and respiratory tract,whereas no association was found with breast, endometrial, ovarian, prostate and renal cellcancer.189ANNUAL REPORT <strong>2009</strong>
IRFMNSeveral aspects of the Me<strong>di</strong>terranean <strong>di</strong>et might be favourable not only on car<strong>di</strong>ovascular<strong>di</strong>sease, but also on cancer risk. This hypothesis was supported by fin<strong>di</strong>ngs from our network ofcase-control stu<strong>di</strong>es.There is no evidence of an adverse effect of low-calorie sweetener (inclu<strong>di</strong>ng aspartame)consumption on the risk of common neoplasms in the Italian population.In a review of epidemiological stu<strong>di</strong>es on selected aspects of <strong>di</strong>et and oral and pharyngealcancer risk, we confirmed and quantified the protective role of vegetable and fruit consumption.Given the absence of apparent effect of moderate alcohol drinking and pancreatic cancer risk,and the moderate association observed with heavy drinking, alcohol would be responsible for asmall fraction of all pancreatic cancer.In a meta-analysis on oral contraceptives use and colorectal cancer we observed that oralcontraceptive users have a reduced risk of colorectal cancer, with a greater protection for recentusers.In a meta-analysis of published stu<strong>di</strong>es on coffee and hepatocellular carcinoma, we observed adecreased risk of 31% for moderate coffee drinkers, and of 56% for heavy coffee drinkers, ascompared to non-drinkers.Recent stu<strong>di</strong>es conducted in <strong>di</strong>fferent areas of North America and Europe showed a 5-10%decline in the incidence of breast cancer, that might be explained by an effect of reducedhormone therapy use. However, the reasons of the falls in incidence of breast cancer remainopen to <strong>di</strong>scussion.Epidemiological data on coffee and alcohol drinking and bladder cancer are suggestive of noassociation.We reviewed epidemiological evidence on risk factors for thyroid cancer. At present, the onlyrecognized measures for reducing thyroid cancer risk is to avoid ionizing ra<strong>di</strong>ation and io<strong>di</strong>nedeficiency, particularly in childhood and young women, and to increase vegetable consumption.Aspirin has emerged as the most likely NSAID for use in chemoprevention of colorectal andother selected neoplasms because of its known car<strong>di</strong>ovascular benefit and available safety andefficacy data.In 2008, smoking prevalence was the lowest observed over the last 50 years, in Italy. Subjectswith less privileged socio-economic characteristics should be considered target populations fortobacco control.In Italy, in 2007, the highest prevalence of hardcore smoking that has been reported in theliterature to date has been observed.Analyzing data from 7 tobacco surveys conducted between 2002 and 2008, we observed thatfurther methods to increase the use of pharmacotherapy for smoking cessation are needed inItaly.Using data from 4 surveys conducted annually between 2005 and 2008, we showed that in Italycigarette smuggling now contributes only a small proportion of total tobacco sales and thatinternet is not yet used as source for cigarette sales.190ANNUAL REPORT <strong>2009</strong>
IRFMNIn Italy, 3 years after the law came into force, the smoke-free legislation remains respected andappears to have favourably affected the business of restaurants and bars.An updated analysis of cancer mortality in Europe showed a persistent favourable trend over thelast years.Updated trends for cancer mortality in Italy remained favourable for most cancer sites, mainlyfor male tobacco-related cancers, and female cancers for which screening practices are morewidespread (uterus and female breast).Mortality from childhood cancer continued to decline over more recent years in most Europeancountries. Some further improvement in childhood cancer mortality in Eastern and SouthernEurope is achievable through more widespread and better adoption of currently availabletreatments.Though oral and pharyngeal mortality in Europe has declined in the last decade in men, therewere still rises in a few central and eastern European countries, reaching excee<strong>di</strong>ngly high ratesin Hungary and Slovakia.Steady downward trends persist in gastric cancer mortality worldwide even in middle agedpopulation, and hence further appreciable declines are likely in the near future.Falling rates for biliary tract cancer mortality were recorded throughout the Americas, Europeand Asia, there are however some high risk areas, mainly in South America and In<strong>di</strong>a whereaccess to gall-bladder surgery remains inadequateThere are persistent declines in HL mortality in western European countries, and favourablepatterns over more recent calendar years in central/eastern ones, where rates, however, are stillat levels observed in western Europe in the early 1990s.Though mortality from car<strong>di</strong>o- and cerebrovascular <strong>di</strong>seases continued to decline in severalareas of the world, unfavourable trends were still observed in the Russian Federation and othercountries of the former Soviet Union, whose recent rates remain excee<strong>di</strong>ngly high.The most reliable estimate of incident kidney cancer cases in Italy over the period 2007-2012 islikely to range between 7000 and 9000. Of these, between 6000 and 8000 are renal cell cancercases.The most reliable estimate of hepatocellular carcinoma incident cases in Italy in 2007 isbetween 5500 and 6000, and this figure is likely to decline to 5000-5500 in 2012.In a meta-analysis of stu<strong>di</strong>es on interventions for the prevention of falls in elderly people,intervention based on exercise alone resulted more effective as compared to multifactorialinterventions.Our investigation on gastric cancer provided convincing evidence that coffee and teaconsumption are unlikely to be strongly associated with this neoplasm.Results from our case-control study ruled out a strong relation between physical activity andendometrial cancer risk.191ANNUAL REPORT <strong>2009</strong>
IRFMNWe provided further evidence that coffee, decaffeinated coffee and tea consumption is notrelated to renal cell cancer risk.A <strong>di</strong>et rich in onion, and not in garlic, may have a favourable effect on the risk of acutemyocar<strong>di</strong>al infarction.A meta-analysis of case-control stu<strong>di</strong>es provided quantitative evidence of an inverse relationbetween coffee drinking and colorectal (mainly colon) cancer risk.In another meta-analysis of two cohort and seven case-control stu<strong>di</strong>es, an inverse relationbetween coffee drinking and endometrial cancer risk emerged.NATIONAL COLLABORATIONSAgenzia giornalismo scientifico Za<strong>di</strong>g, MilanoAssociazione Nazionale dei Me<strong>di</strong>ci Car<strong>di</strong>ologi Ospedalieri (ANMCO)Associazioni Sguazzi OnlusAssociazione Chirurghi Ospedalieri Italiani (ACOI),Centro <strong>di</strong> Riferimento Oncologico, Servizio <strong>di</strong> Epidemiologia, Aviano (PN)Comune <strong>di</strong> Milano, Direzione centrale salute, Settore politiche per la saluteFondazione LuVIFondazione Politecnico <strong>di</strong> MilanoFondazione SmithKline, MilanoGruppo Italiano per lo Stu<strong>di</strong>o della Sopravivenza nell’Infarto miocar<strong>di</strong>co (GISSI)Gruppo Italiano Stu<strong>di</strong> Epidemiologici in Dermatologia GISED, BergamoGruppo Italiano Documentalisti dell’Industria Farmaceutica e degli Istituti <strong>di</strong> RicercaBiome<strong>di</strong>ca International Centre for Pesticides and Health Risk Prevention, Milano<strong>Istituto</strong> Auxologico Italiano, Divisione Malattie Metaboliche III, IRCCS, Piancavallo (VB)<strong>Istituto</strong> Auxologico Italiano, Laboratorio Sperimentale <strong>di</strong> <strong>Ricerche</strong> Endocrinologiche (LSRE),IRCCS, Milano<strong>Istituto</strong> DOXA, Milano<strong>Istituto</strong> Europeo <strong>di</strong> Oncologia, Divisione <strong>di</strong> Epidemiologia e Biostatistica, Milano<strong>Istituto</strong> Europeo <strong>di</strong> Oncologia, Divisione <strong>di</strong> Chirurgia Cervico Facciale, Milano<strong>Istituto</strong> Nazionale <strong>di</strong> Ricerca per gli Alimenti e la Nutrizione (INRAN), Roma<strong>Istituto</strong> Nazionale Neurologico “Carlo Besta”, Milano<strong>Istituto</strong> Nazionale per lo Stu<strong>di</strong>o e la Cura dei Tumori, Oncologia Sperimentale, Unità <strong>di</strong> Ere<strong>di</strong>tàPoligenica, Milano<strong>Istituto</strong> Superiore <strong>di</strong> Sanità, Osservatorio Fumo Alcol Droga, Roma<strong>Istituto</strong> Tumori “Fondazione Pascale”, Servizio <strong>di</strong> Epidemiologia, NapoliNovartis Vaccines SpA, SienaOspedale Casa Sollievo della Sofferenza San Giovanni RotondoOspedale Niguarda Ca’ Granda, Dipartimento Trapianti <strong>di</strong> Fegato, MilanoOspedale Niguarda Ca’ Granda, <strong>Istituto</strong> <strong>di</strong> Fisiologia Clinica CNR, Sezione <strong>di</strong> Milano, MilanoOspedali Riuniti <strong>di</strong> BergamoOspedale Alessandro Manzoni, Unità <strong>di</strong> Gastroenterologia, Lecco (LC)Ospedale Luigi Sacco, Az Osp - Polo UniversitarioPoliclinico <strong>di</strong> Monza, Unità Operativa <strong>di</strong> Endoscopia I, Monza (MB)Prima Clinica Ostetrico Ginecologica, Mangiagalli, MilanoRegione Lombar<strong>di</strong>a, U.O. Governo dei servizi sanitari territoriali e politiche <strong>di</strong> appropriatezza econtrollo Società Italiana Attività Regolatorie192ANNUAL REPORT <strong>2009</strong>
IRFMNUniversità Bocconi <strong>di</strong> Milano, Dipartimento <strong>di</strong> Analisi Istituzionale e Management PubblicoUniversità degli Stu<strong>di</strong> <strong>di</strong> Milano-Bicocca, Dipartimento <strong>di</strong> Statistica, MilanoUniversità degli Stu<strong>di</strong> <strong>di</strong> Milano-Bicocca, I Clinica Otorinolaringoiatria, DNTB, MonzaUniversità <strong>di</strong> Milano, Clinica Pe<strong>di</strong>atrica De Marchi, MilanoUniversità <strong>di</strong> Milano, <strong>Istituto</strong> <strong>di</strong> Statistica Me<strong>di</strong>ca e Biometria “G.A. Maccacaro”, MilanoUniversità <strong>di</strong> Milano, Prima Clinica Ostetrico Ginecologica, MilanoUniversità <strong>di</strong> Pavia, Azienda <strong>di</strong> Servizi alla Persona, PaviaUniversità <strong>di</strong> Torino, <strong>Istituto</strong> <strong>di</strong> Me<strong>di</strong>cina del Lavoro, CTO, TorinoUniversità <strong>di</strong> Verona, Clinica Ostetrico Ginecologica, VeronaINTERNATIONAL COLLABORATIONSCatalan Institute of Oncology, Institut d’Investigaciò Biomé<strong>di</strong>ca de Bellvitge (IDIBELL),Cancer Prevention and Control Unit, L’Hospitalet de Llobregat, SpainCenter of Oncology, Dept. of Epidemiology and Cancer Prevention, Varsavia, PolandCentre for Research in Environmental Epidemiology (CREAL) and Municipal Institute ofMe<strong>di</strong>cal Research (IMIM), Barcellona, SpainEvidence and Risk Assessment Division, Centre for Chronic Disease Prevention and Control,Public Health Agency of Canada, Ottawa, Ontario, CanadaFaculty of Me<strong>di</strong>cal Sciences, University of Córdoba, ArgentinaHarvard School of Public Health, Department of Epidemiology, Boston, USAHellenic Health FoundationHôpital Necker - Enfants Malades, Centre of the Association Claude Bernard on Auto-immunes<strong>di</strong>seases, Parigi, FranceInternational Agency for Research on Cancer, Lione, FranceInternational Epidemiology Institute (IEI), Rockville, USAInternational Life Science Institute (ILSI), Bruxelles, BelgiumInternational Prevention Research Institute (IPRI), Lyon, FranceKarolinska Institute, Department of Me<strong>di</strong>cal Epidemiology and Biostatistics, Stockholm,SwedenNational Cancer Institute, Environmental Stu<strong>di</strong>es Section, Bethesda, USANational Cancer Institute, Ra<strong>di</strong>ation Epidemiology Branch, Bethesda, USANational School of Public Health, WHO, Atene, GreeceRegistre Vaudois des Tumeurs, Institut Universitaire de Médecine Sociale et Préventive,Losanna, SwitzerlandSenologic International SocietySociety for Internet in Me<strong>di</strong>cineTobaccoFree Research Institut, Dublin, IrelandeUNDP/UNFPA/WHO/WORLD Bank special programme of research development andresearch training in human reproduction, Ginevra, SwitzerlandUniversitat Pompeu Fabra, Department of Experimental and Health Sciences, Barcellona, SpainUniversity of Athens Me<strong>di</strong>cal School, Department of Hygiene and Epidemiology, Atene,GreeceUniversity of Las Palmas de Gran Canaria, Department of Clinical Sciences, Las Palmas deGran Canaria, SpainVanderbilt University, Department of Me<strong>di</strong>cine, School of Me<strong>di</strong>cine, Nashville, USA193ANNUAL REPORT <strong>2009</strong>
IRFMNEDITORIAL BOARD MEMBERSHIPAdvances in Therapy (Eva <strong>Negri</strong>)Alimentazione e Prevenzione (Carlo La Vecchia)Annals of Oncology (Carlo La Vecchia)Archives of Me<strong>di</strong>cal Science (Carlo La Vecchia)BMC Public Health (Silvano Gallus, Associate E<strong>di</strong>tor)Cancer Letter (Carlo La Vecchia, Associate E<strong>di</strong>tor)Current Cancer Therapy Reviews (Carlo La Vecchia)Dermatology Research and Practice (Carlo La Vecchia)Digestive and Liver Disease (Carlo La Vecchia)Economia Politica del Farmaco (Carlo La Vecchia)European Journal of Cancer Prevention (Carlo La Vecchia, Associate E<strong>di</strong>tor)European Journal of Clinical Nutrition (Carlo La Vecchia)European Journal of Nutrition (Carlo La Vecchia)Evidence Based Dermatology (Carlo La Vecchia, Liliane Chatenoud)In Scope Oncology & Haematology (Carlo La Vecchia)Maturitas (Carlo La Vecchia)Nutrition and Cancer (Carlo La Vecchia)Open Cancer Journal (Carlo La Vecchia)Oral Oncology (Carlo La Vecchia)Portale Partecipasalute.it – http://www.partecipasalute.it (Eugenio Santoro)Revisiones en Ginecologìa y Obstetricia (Carlo La Vecchia)Revista Española de Nutriciò Comunitaria (Carlo La Vecchia)Revue d’Epidémiologie et de Santé Publique (Carlo La Vecchia)Società Italiana Attività Regolatorie News, SIARNews (Eugenio Santoro)The Open Obesity Journal (Silvano Gallus)Tumori (Carlo La Vecchia)World Journal of Gastrointestinal Oncology (Silvano Gallus)PEER REVIEW ACTIVITIESActa Dermato-Venereologica, Acta Psychiatrica Scan<strong>di</strong>navica, Alcologia, American Journal ofClinical Nutrition, American Journal of Epidemiology, Annals of Epidemiology, Annals ofOncology, Archives of Internal Me<strong>di</strong>cine, BMC Public Health, British Journal of Cancer,British Journal of Nutrition, British Me<strong>di</strong>cal Journal, Bulletin of the World Health Organization,Cana<strong>di</strong>an Journal of Physiology and Pharmacology, Cancer, Cancer Causes and Control, CancerDetection and Prevention, Cancer Epidemiology Biomarkers and Prevention, ComputerMethods and Programs in Biome<strong>di</strong>cine, Diabetes/Metabolism Research and Reviews, DigestiveLiver Disease, Epidemiologia & Prevenzione, Epidemiology, Epidemiology & Biostatistic,European Heart Journal, European Journal of Cancer, European Journal of Cancer Prevention,European Journal of Clinical Nutrition, European Journal of Epidemiology, European Journal ofPublic Health, Evidence-Based Healthcare and Public Health, Gynecological Endocrinology,Gut, Hepatology, Human Reproduction, International Journal of Cancer, International Journalof Environmental Research and Public Health, International Journal of Epidemiology,International Journal of Obesity, JAMA, Journal of American College of Nutrition, Journal ofClinical Endocrinology and Metabolism, Journal of Clinical Epidemiology, Journal ofEpidemiology and Community Health, Journal of Investigative Dermatology, Journal of194ANNUAL REPORT <strong>2009</strong>
IRFMNMe<strong>di</strong>cal Internet Research , Journal of the National Cancer Institute, Lancet Oncology,Maturitas, Melanoma Research, Nicotine & Tobacco Research, Nutrition and Cancer, Obstetricand Gynecology, Oncology, Preventive Me<strong>di</strong>cine, Public Health, Public Health Nutrition, QJM,Ra<strong>di</strong>ation Research, Revue d’Epidèmiologie et de Santé Publique, The Breast, The CancerJournal, The Lancet, The Open Obesity Journal, Tobacco Control, Tumori.NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPAdvisory Committee of the Oxford Collaborative group on Aetiological Factors in Cancers ofthe Female Genital TractComitato Scientifico del Gruppo Italiano Stu<strong>di</strong> Epidemiologici in DermatologiaComitato Scientifico della Società Italiana <strong>di</strong> Colposcopia e Patologia Cervico VaginaleComitato Scientifico del portale www.familyhealth.itData and Safety Monitoring Board of the “Phase II therapeutic trial with a humanizednonmitogenic CD3 (ChAgly CD3) monoclonal antibody in recently <strong>di</strong>agnosed type I <strong>di</strong>abeticpatients”Executive Committee, International Head and Neck Cancer Epidemiology (INHANCE)consortiumIARC/OMS <strong>di</strong> Lione e OMS <strong>di</strong> GinevraMinistero della Salute, Sottocomitato fumo.Ministero della Salute, Commissione Oncologica Nazionale.Scientific Review Committee del UND/WHO/World Bank Human Reproduction ProgrammeSocietà Italiana della RiproduzioneEVENT ORGANIZATIONCorso “Clinical Trials, HTA reports, practice guidelines. Where and how to search”,organizzato dal personale del <strong>di</strong>partimento nel corso dell’European Association for HealthInformation and Libraries Workshop, Dublino 2-5 giugno <strong>2009</strong>.III° e<strong>di</strong>zione del corso ECM “"La ricerca bibliografica su database biome<strong>di</strong>ci", <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milano, 8 giugno <strong>2009</strong>III° e<strong>di</strong>zione del corso ECM "Internet e l’aggiornamento professionale in ambito me<strong>di</strong>co",<strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milano, 9 giugno <strong>2009</strong>III° e<strong>di</strong>zione del corso ECM "Il web 2.0 al servizio della formazione e dell’aggiornamento delme<strong>di</strong>co", <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milano, 10 giugno <strong>2009</strong>IV° e<strong>di</strong>zione del corso ECM “"La ricerca bibliografica su database biome<strong>di</strong>ci", <strong>Istituto</strong> <strong>di</strong><strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milano, 10 novembre <strong>2009</strong>IV° e<strong>di</strong>zione del corso ECM "Internet e l’aggiornamento professionale in ambito me<strong>di</strong>co",<strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milano, 11 novembre <strong>2009</strong>IV° e<strong>di</strong>zione del corso ECM "Il web 2.0 al servizio della formazione e dell’aggiornamento delme<strong>di</strong>co", <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> “<strong>Mario</strong> <strong>Negri</strong>”, Milano, 12 novembre <strong>2009</strong>195ANNUAL REPORT <strong>2009</strong>
IRFMNCONFERENCE AND WORKSHOP CONTRIBUTIONSWorkwhop on Environment and Health: Evaluating European air quality research andtranslating priorities into actions. CONCAWE. Brusselles, Belgio 19-20 January <strong>2009</strong>Pancreatic Cancer case-control (PANC4) consortium. “PANC4 plans and potentialcollaboration with Cohort stu<strong>di</strong>es”. Rockville, MD, 26 February <strong>2009</strong>.PPACTE Kickoff Meeting. Dublino, Irlanda, 26-27 February <strong>2009</strong>.Seminario “ Internet e giovani: potenzialità e pericoli”, promosso dal Laboratorio Salute Socialee Comune <strong>di</strong> Milano. Titolo relazione “Internet e salute: come evitare i pericoli”. Milano,February 18 <strong>2009</strong>.Lo stress ossidativo: dal laboratorio alla pratica. “Componenti antiossidanti <strong>di</strong> frutta e verdura erischio <strong>di</strong> tumore.” Bologna, 21 March <strong>2009</strong>.6 th <strong>Annual</strong> INHANCE Meeting. “Principal components analysis for <strong>di</strong>et”. Paris, France, 24-25March <strong>2009</strong>International experts workshop on the risk of hepatocellular carcinoma caused by exposure tovinyl chloride monomer. Leuven, Belgium., 21 April <strong>2009</strong>Workshop on Nutrition and Cancer: from epidemiology to molecular mechanisms. “Diet andCancer Prevention: Italian data”. Padova, 30 April <strong>2009</strong>Tavola rotonda “Prevenzione nei me<strong>di</strong>a: responsabilità o business”, promossa nell’ambito delFestival Internazionale del Giornalismo, Perugia, April, 1-5.Corso “Internet e l’aggiornamento professionale in ambito me<strong>di</strong>co”, promosso dal servizioformazione del personale me<strong>di</strong>co della Provincia Autonoma <strong>di</strong> Bolzano, Bolzano, April 16 <strong>2009</strong>La metodologia della ricerca clinica. “Gli stu<strong>di</strong> osservazionali”. Università degli Stu<strong>di</strong> <strong>di</strong>Milano, Ospedale Niguarda. Milano, 6 May <strong>2009</strong>.Partecipation to a special expert panel meeting to evalute the proposals in the January <strong>2009</strong> call.Helsinki, Finlan<strong>di</strong>a 11-12 May <strong>2009</strong>2nd International Congress on Nutrition and Cancer. “Overweight, a<strong>di</strong>ponectin andginecological cancer”, “Diet and cancer in Me<strong>di</strong>terranean countries: carbohydrates, fats andflavonoids”, “Sun exposure, vitamin D and lymphohaemopoietic cancers”. Antalya, Turchia,18-22 May <strong>2009</strong>Sweden Research Council for Working Life and Social Research. Allocation of resources tonational and international research infrastructures within the framework of the strategic researchareas. Evaluation form Strategic research areas <strong>2009</strong>. Stockholm, Sweden, 24-25 May <strong>2009</strong>XI Convegno Nazionale tabagismo e Servizio sanitario nazionale. “Dimezzare i morti e i tumorida fumo”. Roma, 29 May <strong>2009</strong>196ANNUAL REPORT <strong>2009</strong>
IRFMNConvegno “Crisi ed e<strong>di</strong>toria: vecchi problemi e nuove soluzioni, XXVI convegno GIDIF, RBM(Gruppo Italiano Documentalisti dell’Industria Farmaceutica e degli Istituti <strong>di</strong> RicercaBiome<strong>di</strong>ca). Titolo della relazione “I blog e le loro opportunità nel campo della e<strong>di</strong>toria me<strong>di</strong>coscientifica”,Monza, May 26 <strong>2009</strong>.Corso “Internet e l’uso dei nuovi strumenti del web 2.0 in ambito me<strong>di</strong>co: potenzialità eapplicazioni”, <strong>Istituto</strong> Nazionale dei Tumori, Milano, May 7 <strong>2009</strong>Corso, “Me<strong>di</strong>cina basata sulle prove <strong>di</strong> efficacia” promosso dall’Azienda Unità Sanitaria Localen.1 <strong>di</strong> Sassari, Titolo della lezione “Siti e applicazioni Internet in ambito me<strong>di</strong>co: tipologia <strong>di</strong>informazione e modalità <strong>di</strong> reperimento”. Sassari, May 22 <strong>2009</strong>.PSONET Steering Group Meeting. Roma, 4-5 June <strong>2009</strong>VII Congresso Nazionale SIB - Società Italiana <strong>di</strong> Biometria. “Confidence intervals for thecost-effectiveness ratio: a new methodological proposal”. Ponte <strong>di</strong> Legno (BS), 10-12 June<strong>2009</strong>,Meeting. Caffè e rischio <strong>di</strong> cancro: il ruolo protettivo su alcune patologie tumorali. “Caffè erischio <strong>di</strong> tumore all’endometrio e altri tumori”. Milano, 16 June <strong>2009</strong>.Master Universitario <strong>di</strong> II livello in “Informatica me<strong>di</strong>ca”, Università <strong>di</strong> U<strong>di</strong>ne, annoaccademico 2008-<strong>2009</strong>. Ruolo <strong>di</strong> docenza nel modulo “Internet, web 2.0 e sanità; strumenti eapplicazioni al servizio del me<strong>di</strong>co e del citta<strong>di</strong>no”, U<strong>di</strong>ne, June 18, 19 <strong>2009</strong>.Seminario “Cartella clinica informatizzata”, promosso dall’Associazione Nazionale Me<strong>di</strong>ciCar<strong>di</strong>ologi Ospedalieri nel corso del congresso ANMCO <strong>2009</strong>. Titolo relazione “Utilitàdell’informatizzazione per la riduzione del rischio clinico”, Firenze, June 5 <strong>2009</strong>.Expert Meeting. Rischio car<strong>di</strong>ovascolare e valutazione del paziente HIV. “Il punto <strong>di</strong> vistadell’epidemiologo-analisi dati”. Milano 1 July <strong>2009</strong>.Meeting HiWATE. Dublino, Irlanda. 25 August <strong>2009</strong>Gordon conference. “Colorectal cancer and <strong>di</strong>sinfection by-products. Exposure measurement inan on-going case-control study in Spain and Italy. Dublino, August <strong>2009</strong>Meeting. Bone fractures after menopause. “Chairman Session 3” and“Frequency of falls andprevalence of fractures in postmenopausal women”. Capri, 30-31 August <strong>2009</strong>Workshop on the enhancement of the scientific process and transparency of observationalepidemiology stu<strong>di</strong>es. ECETOC. Londra, UK 24-25 September <strong>2009</strong>Convegno. Le <strong>di</strong>ossine Taranto tra ambiente e salute. Le <strong>di</strong>ossine a Taranto tra ambiente esalute. Taranto, 26 September <strong>2009</strong>Convegno. Alcohol & collutori. “Review stu<strong>di</strong> epidemiologici su rischio cancro orale e utilizzocollutori a base <strong>di</strong> alcohol”. Milano, 29 September <strong>2009</strong>Corso, “Me<strong>di</strong>cina basata sulle prove <strong>di</strong> efficacia. Corso avanzato” promosso dall’Azienda UnitàSanitaria Locale n.1 <strong>di</strong> Sassari. Titolo della lezione “Siti e applicazioni web 2.0 in ambitome<strong>di</strong>co: tipologia <strong>di</strong> informazioni e metodologia d’uso”. Sassari, September 10,11 <strong>2009</strong>.197ANNUAL REPORT <strong>2009</strong>
IRFMNCorso, “Siti, strumenti ed applicazioni web 2.0 in ambito me<strong>di</strong>co” promosso dalla BibliotecaMe<strong>di</strong>ca della AIL Biella-Fondazione Clelio Angelino onlus, Biella, September 8 <strong>2009</strong>.Congresso. Integrazione <strong>di</strong> un nuovo farmaco antifumo nei programmi <strong>di</strong> <strong>di</strong>agnosi precoce neiforti fumatori. “Tavola rotonda: l’esperienza del MILD”. Milano, 9 October <strong>2009</strong>Il carcinoma epatocellulare. Opera e<strong>di</strong>toriale Prof. Massimo Colombo. Milano, 11 October <strong>2009</strong>XXXIII Congresso nazionale della Associazione Italiana <strong>di</strong> Epidemiologia (AIE). “Acceptanceof HPV vaccination among parents and adolescents in Italy”. Modena, 22-24 October <strong>2009</strong>.XI Congresso Nazionale della Associazione Italiana Oncologi Me<strong>di</strong>ci (AIOM). Titolo relazione:“RSS technology and podcasts in oncology: a new way to deliver scientific information”.Milano, October 10-13 <strong>2009</strong>.Corso “Accesso, <strong>di</strong>stribuzione e valutazione dell’informazione me<strong>di</strong>ca e il ruolo degli strumentiweb 2.0”, promosso dall’Arcispedale Santa Maria Nuova, Azienda Ospedaliera <strong>di</strong> ReggioEmilia, Reggio Emilia, October 2 <strong>2009</strong>.Seminario “Il ruolo degli strumenti del web 2.0 nell’aggiornamento professionale del me<strong>di</strong>co edel ricercatore”, <strong>Istituto</strong> Superiore <strong>di</strong> Sanità, Roma, October 9 <strong>2009</strong>Convegno “Web 2.0 per guadagnare salute”, promosso dall'Associazione Italiana dellaComunicazione Pubblica e Istituzionale nell’ambito <strong>di</strong> COM.Lab <strong>2009</strong>. Bologna, October 15<strong>2009</strong>Seminario “Siti, strumenti e applicazioni web 2.0 in ambito me<strong>di</strong>co”, Biblioteca OspedaleBellaria, Bologna, October 26 <strong>2009</strong>XIII Weekend clinico. Tumori Ginecologici e della Mammella: stile <strong>di</strong> vita, ormoni eriproduzione. “Soprappeso A<strong>di</strong>ponectina e Tumori Ginecologici”. Castrocaro Terme, 6-7November <strong>2009</strong>Milano Focus Salute. “Epidemiologia del fumo e dell’alcool”, “Asbesto e mesotelioma pleurico:rischi attuali e futuri”. Milano, 26-27 November <strong>2009</strong>Conferenza AIRC. “I tumori: cause e prevenzione”. Bellinzago, 26 November <strong>2009</strong>Master Universitario <strong>di</strong> I° livello in Ricerca Clinica, Università <strong>di</strong> Milano, anno accademico<strong>2009</strong>-2010. Ruolo <strong>di</strong> docenze nel modulo “Internet e le nuove tecnologie per l’aggiornamentome<strong>di</strong>co-scientifico”, Milano, November 18 <strong>2009</strong>Tavola rotonda “Internet e le nuove tecnologie del web: applicazioni e ricadute in chirurgia”,congresso <strong>di</strong> videochirurgia della Associazione Chirurghi Ospedalieri Italiani (ACOI),Conegliano, November 24 <strong>2009</strong>70° Congresso Nazionale della Società Italiana <strong>di</strong> Car<strong>di</strong>ologia. Titolo relazioni: “L’uso dellatecnologia RSS in car<strong>di</strong>ologia: un nuovo modo <strong>di</strong> <strong>di</strong>stribuire l’informazione scientifica” e“Twitter, il web 2.0 e loro applicazioni in ambito car<strong>di</strong>ovascolare”. Roma, December 12 – 15<strong>2009</strong>198ANNUAL REPORT <strong>2009</strong>
IRFMNXXXIV Congresso Nazionale SINU. Nutrizione, la pietra d’angolo. Fabbisogni nutrizionali esalute nell’epoca del genoma. “Alcool e tumori”. Firenze, 11-12 December <strong>2009</strong>GRANTS AND CONTRACTSAIFAAssociazioni Sguazzi OnlusAssociazione Italiana per la Ricerca sul CancroComune <strong>di</strong> MilanoLega Italiana Lotta contro i TumoriEuropean Commission (FP7)European Research Council (ERC)Fondazione Politecnico <strong>di</strong> MilanoGISEDMinistero della SaluteRegione Lombar<strong>di</strong>aWeber ShandwichConsorzio AssomelaISAPerfetti Van MelleSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Gallus S, Tramacere I, Tavani A, Bosetti C, Bertuccio P, <strong>Negri</strong> E, La Vecchia CCoffee, black tea and risk of gastric cancer.Cancer Causes Control, 20: 1303-1308 (<strong>2009</strong>).Montella M, Tramacere I, Tavani A, Gallus S, Crispo A, Talamini R, Dal Maso L, RamazzottiV, Galeone C., Franceschi S, La Vecchia C.Coffee, decaffeinated coffee, tea intake and risk of renal cell cancer.Nutr. Cancer, 61: 76-80 (<strong>2009</strong>).Gallus S, Tavani A, La Vecchia C.Response to Chocolate, well-being and health among elderly men: chocolate and acutemyocar<strong>di</strong>al infarction in a case-control study from Italy.Eur. J. Clin. Nutr., 63: 588-589 (<strong>2009</strong>).Lucenteforte E, Talamini R, Montella M, Dal Maso L, Pelucchi C, Franceschi S, La Vecchia C,<strong>Negri</strong> E.Family history of cancer and the risk of endometrial cancer.Eur. J. Cancer Prev., 18: 95-99 (<strong>2009</strong>).Bravi F, Scotti L, Bosetti C, Zucchetto A, Talamini R, Montella M, Greggi S, Pelucchi C, <strong>Negri</strong>E, Franceschi S, La Vecchia C.Food groups and endometrial cancer risk: a case-control study from Italy.Am. J. Obstet. Gynecol, 200: 293.e1-293.7 (<strong>2009</strong>).199ANNUAL REPORT <strong>2009</strong>
IRFMNTavani A, Bravi F, Dal Maso L, Zucchetto A, Bosetti C, Pelucchi C, Montella M, Franceschi S,La Vecchia C.Physical activity and risk of endometrial cancer: an Italian case-control study.Eur. J. Cancer Prev., 18: 303-306 (<strong>2009</strong>).Ferketich AK, Gallus S, Colombo C, Pacifici R, Zuccaro P, La Vecchia C.Hardcore smoking among Italian men and women.Eur. J. Cancer Prev., 18: 100-105 (<strong>2009</strong>).<strong>Negri</strong> E, Boffetta P, Berthiller J, Castellsague X, Curado MP, Dal Maso L, Daudt AW,Fabianova E, Fernandez L, Wünsch-Filho V, Franceschi S, Hayes RB, Herrero R, Koifman S,Lazarus P, Lence JJ, Levi F, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Olshan AF,Rudnai P, Shangina O, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM,Zaridze D, Lissowska J, Zhang ZF, Ferro G, Brennan P, La Vecchia C, Hashibe M.Family history of cancer: Pooled analysis in the International Head and NeckCancer Epidemiology Consortium.Int. J. Cancer, 124: 394-401 (<strong>2009</strong>).Hashibe M, Brennan P, Chuang S-, Boccia S, Castellsague X, Chen C, Curado MP, Dal MasoL, Daudt AW, Fabianova E, Fernandez L, Wünsch-Filho V, Franceschi S, Hayes RB, HerreroR, Kelsey K, Koifman S, La Vecchia C, Lazarus P, Levi F, Lence JJ, Mates D, Matos E,Menezes E, McClean MD, Muscat J, Eluf-Neto J, Olshan AF, Pudue A, Rudnai P, SchwartzSM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, ShanginaO, Pilarska A, Zhang Z-, Ferro G, Berthiller J, Boffetta P.Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooledanalysis in the International Head and neck Cancer Epidemiology Consortium.CEBP, 18: 541-550 (<strong>2009</strong>).Bosetti C, Bianchi C, <strong>Negri</strong> E, La Vecchia C.Estimates of the incidence and prevalence of renal cell carcinoma in Italy in 2002 andprojections for the years 2007 and 2012.Tumori, 95: 142-145 (<strong>2009</strong>).Bosetti C, Bianchi C, <strong>Negri</strong> E, La Vecchia C.Estimates of the incidence and prevalence of hepatocellular carcinoma in Italy in 2002 andprojections for the years 2007 and 2012.Tumori, 95:23-27 (<strong>2009</strong>).Pelucchi C, La Vecchia CAlcohol, coffee, and bladder cancer risk: a review of epidemiological stu<strong>di</strong>es.Eur. J. Cancer Prev. 18: 62-68 (<strong>2009</strong>).Rossi M, McLaughlin JK, Lagiou P, Bosetti C, Talamini R, Lipworth L, Giacosa A,Montella M, Franceschi S, <strong>Negri</strong> E, La Vecchia C.Vitamin D intake and breast cancer risk: a case-control study in Italy.Ann. Oncol., 20: 374-378, <strong>2009</strong>.Bosetti C, Pelucchi P, La Vecchia C.Diet and cancer in Me<strong>di</strong>terranean countries: carbohydrates and fats.Publ. Health Nutr., 12 (9A): 1595-1600 (<strong>2009</strong>).Ferketich AK, Gallus S, Colombo C, Apolone G, Rossi S, Zuccaro P, La Vecchia C.200ANNUAL REPORT <strong>2009</strong>
IRFMNUse of pharmacotherapy while attempting cessation among Italian smokers.Eur. J. Cancer Prev., 18: 90-92 (<strong>2009</strong>).Garavello W, Lucenteforte E, Bosetti C, Talamini R, Levi F, Tavani A, Franceschi S, <strong>Negri</strong> E,La Vecchia C.Diet <strong>di</strong>versity and the risk of laryngeal cancer: a case-control study from Italy and Switzerland.Oral Oncol., 45: 85-89 (<strong>2009</strong>).Lipworth L, Bender TJ, Rossi M, Bosetti C, <strong>Negri</strong> E, Talamini R, Giacosa A, Franceschi S,McLaughlin JK, La Vecchia C.Dietary vitamin D intake and cancers of the colon and rectum: a case-control study in Italy.Nutr. Cancer, 61: 70-75 (<strong>2009</strong>).Purdue MP, , Hashibe M, Berthiller J, La Vecchia C, Dal Maso L, Herrero R, Franceschi S,Castellsague X, Wei Q, Sturgis EM, Morgenstern H, Zhang Z-F, Levi F, Talamini R, Smith E,Muscat J, Lazarus P, Schwartz SM, Chen C, Eluf Neto J, Wünsch-Filho V, Zaridze D, KoifmanS, Curado MP, Benhamou S, Matos E, Szeszenia-Dabrowska N, Olshan AF, Lence J, MenezesA, Daudt AW, Mates IN, Pilarska A, Fabianova E, Rudnai P, Winn D, Ferro G, Brennan P,Boffetta P, Hayes RB.Type of alcoholic beverage and risk of head and neck cancer - A pooled analysis within theINHANCE consortium.Am. J. Epidemiol., 169: 132-142 (<strong>2009</strong>).Lucenteforte E, Bosetti C, Gallus S, Bertuccio P, Pelucchi C, Tavani A, La Vecchia C, <strong>Negri</strong> E.Macronutrients, fatty acids and cholesterol intake and stomach cancer risk.Ann. Oncol., 20: 1434-1438 (<strong>2009</strong>).Maconi G, Sainaghi M, Molteni M, Bosani M, Gallus S, Ricci G, Alvisi V, Bianchi Porro GPre<strong>di</strong>ctors of long-term outcome of functional dyspepsia and duodenal ulcer after successfulHelicobacter pylori era<strong>di</strong>cation - a 7-year follow-up studyEur. J. Gastroenterol. Hepatol., 21: 387-393 (<strong>2009</strong>).Nal<strong>di</strong> L, Parazzini F, Gallus S, and GISED study centres.Prevalence of atopic dermatitis in Italian schoolchildren: factors affecting its variationsActa Derm.Venereol., 89: 122-123 (<strong>2009</strong>).Bravi F, Scotti L, Bosetti C, Bertuccio P, <strong>Negri</strong> E, La Vecchia C.Dietary fiber and stomach cancer risk: a case-control study from Italy.Cancer Causes Control, 20: 847-853 (<strong>2009</strong>).Levi F., Ran<strong>di</strong>mbison L., Te VC, Maspoli Conconi M., La Vecchia C.RE: Risk of prostate, breast and colorectal cancer after skin cancer <strong>di</strong>agnosis.Int. J. Cancer, 123: 2899-2901 (<strong>2009</strong>).Bosetti C., Levi F., Ferlay J., Lucchini F., <strong>Negri</strong> E., La Vecchia C.The recent decline in mortality from Hodgkin lymphomas in Central and eastern Europe.Ann. Oncol., 20: 767-774 (<strong>2009</strong>).Gallus S, Tramacere I, Zuccaro P, Colombo P, La Vecchia C.Tobacco sales to minors in Italy.Tumori, 95:283-285 (<strong>2009</strong>).201ANNUAL REPORT <strong>2009</strong>
IRFMNChatenoud L, Malvezzi M, Pitrelli A, La Vecchia C, Bamfi F.Asthma mortality and long-acting beta 2 -agonists in five major European countries, 1994-2004.J. Asthma, 46: 546-551 (<strong>2009</strong>).Polesel J, Zucchetto A, Montella M, Dal Maso L, Crispo A, La Vecchia C, Serraino D,Franceschi S, Talamini R.The impact of obesity and <strong>di</strong>abetes mellitus on the risk of hepatocellular carcinoma.Ann. Oncol., 20: 353-357 (<strong>2009</strong>).Galeone C, Pelucchi C, Dal Maso L, <strong>Negri</strong> E, Talamini R, Montella M, Ramazzotti V, BelloccoR, Franceschi S, La Vecchia C.Glycemic index, glycemic load and renal cell carcinoma risk.Ann. Oncol., 20: 1881-1885 (<strong>2009</strong>)Pira E, Manzari M, Gallus S, <strong>Negri</strong> E, Bosetti C, Romano C,McLaughlin JK, Boffetta P, La Vecchia C.Cancer mortality in a cohort of continuous glass filament workers.J. Occup. Environ. Med. J. Occup Environ. Med., 51:239-242 (<strong>2009</strong>)La Vecchia C, <strong>Negri</strong> E, International Collaboration of Epidemiological Stu<strong>di</strong>es of Cervicalcancer.Cervical carcinoma and sexual behaviour: collaborative reanalysis of in<strong>di</strong>vidual dataon 15,461 women with cervical carcinoma and 29,164 women without cervicalcarcinoma from 21 epidemiological stu<strong>di</strong>es.Cancer Epidemiol. Biomarkers Prev., 18: 1060-1069 (<strong>2009</strong>).Galeone C, Tavani A., Pelucchi C, <strong>Negri</strong> E, La Vecchia C:Allium vegetable intake and risk of acute myocar<strong>di</strong>al infarction in Italy.Eur. J. Nutr., 48: 120-123 (<strong>2009</strong>).Pelucchi C, Tramacere I, Bertuccio P, Tavani A, <strong>Negri</strong> E, La Vecchia C.Dietary intake of selected micronutrients and gastric cancer risk: an Italian case-control study.Ann. Oncol., 20: 160-165 (<strong>2009</strong>).Ran<strong>di</strong> G, Malvezzi M, Levi F, Ferlay J, <strong>Negri</strong> E, Franceschi S, La Vecchia C.Epidemiology of biliary tract cancers: an update.Ann. Oncol., 20: 146-159 (<strong>2009</strong>).Dal Maso L, Bosetti C, La Vecchia C, Franceschi S.Risk factors for thyroid cancer: an epidemiological review focused on nutritional.Cancer Causes Control, 20: 75-86 (<strong>2009</strong>).Bravi F, Scotti L, Bosetti C, Gallus S, <strong>Negri</strong> E, La Vecchia C, Tavani A.Coffee drinking and endometrial cancer risk: a meta-analysis of observational stu<strong>di</strong>es.Am. J. Obstet. Gynecol., 200: 130-134 (<strong>2009</strong>).Edefonti V, Ran<strong>di</strong> G, Decarli A, La Vecchia C, Bosetti C, Franceschi S, Dal Maso L, FerraroniM.Clustering <strong>di</strong>etary habits and the risk of breast and ovarian cancers.Ann. Oncol., 20: 581-590 (<strong>2009</strong>).202ANNUAL REPORT <strong>2009</strong>
IRFMNBertuccio P, Praud D, Chatenoud L, Lucenteforte E, Bosetti C, Pelucchi C, Rossi M, <strong>Negri</strong> E,La Vecchia C.Dietary glycemic load and gastric cancer risk in Italy.Br. J. Cancer, 100: 558-561 (<strong>2009</strong>).Vaj<strong>di</strong>c CM, Falster MO, de Sanjose S, Martinez-Maza O, Becker N, Bracci PM, Melbye M,Smedby KE, Engels EA, Turner J, Vineis P, Seniori Constantini A, Holly EA, Kane E, SpinelliJJ, La Vecchia C, Zheng T, Chiu BCH, Dal Maso L, Cocco P, Mayna<strong>di</strong>é M, Foretova L, StainesA, Brennan P, Davis S, Severson R, Cerhan JR, Breen EC, Birmann B, Cozen W, Grulich AE.Atopic <strong>di</strong>sease and risk of non-Hodgkin lymphoma: an InterLymph pooled analysis.Cancer Res., 69: 6482-6489 (<strong>2009</strong>).Esposito S, Pelucchi C, Tel F, Chiarelli F, Sabatini C, Semino M, Marseglia GL, De Mattia D,Principi N.Factors con<strong>di</strong>tioning effectiveness of a remainder/recall system to improve influenzavaccination in asthmatic children.Vaccine., 27: 633-635 (<strong>2009</strong>).Bertuccio P, Chatenoud L, Levi F, Praud D, Ferlay J, <strong>Negri</strong> E, Malvezzi M, La Vecchia C.Recent patterns in gastric cancer: a global overview.Int. J. Cancer, 125: 666-673 (<strong>2009</strong>).Gallus S., Nal<strong>di</strong> L.Longitu<strong>di</strong>nal stu<strong>di</strong>es of melanocytic nevi in children. A clue to improve understan<strong>di</strong>ng ofmelanoma in adults.Arch. Dermatol., 145: 191-193 (<strong>2009</strong>).Levi F, Chatenoud L, Bertuccio P, Lucchini F, <strong>Negri</strong> E, La Vecchia C.Mortality from car<strong>di</strong>ovascular and cerebrovascular <strong>di</strong>seases in Europe and other areas of theworld: an update.Eur. J. Car<strong>di</strong>ovasc. Prev. Rehabil., 16: 333-350 (<strong>2009</strong>).Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, Jankowski J, La Vecchia C,Meyskens F, Senn HJ, Thun M.Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: An internationalconsensus statement.Lancet Oncol., 10: 501-507 (<strong>2009</strong>).Levi F, Ran<strong>di</strong>mbison L, Blanc-Moya R, La Vecchia C.Second neoplasms following invasive and borderline ovarian cancer.Eur. J. Cancer Prev., 18:216-219 (<strong>2009</strong>).Lucenteforte E, Garavello W, Bosetti C, La Vecchia C.Dietary factors and oral and pharyngeal cancer risk.Oral Oncol. <strong>2009</strong>;45:461-7 (<strong>2009</strong>)Tramacere I, Gallus S, Zuccaro P, Colombo P, Rossi S, Boffetta P, La Vecchia C.Socio-demographic variation in smoking habits. Italy 2008.Prev. Med., 48: 213-217 (<strong>2009</strong>).Lipworth L, Rossi M, McLaughlin JK, <strong>Negri</strong> E, Talamini R, Levi F, Franceschi S, La VecchiaC.203ANNUAL REPORT <strong>2009</strong>
IRFMNDietary vitamin D and cancers of the oral cavity and esophagus.Ann. Oncol., 20: 1576-1581 (<strong>2009</strong>).Lagiou P, Rossi M, Tzonou A, Georgila C, Trichopoulos D, La Vecchia C.Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatititsinfection.Ann. Oncol., 20: 1741-1745 (<strong>2009</strong>).Gallus S, Tramacere I, Zuccaro, Colombo P, La Vecchia CCigarette smuggling in Italy, 2005-8.Tobacco Control,18: 159-160 (<strong>2009</strong>).del Pilar Diaz M, Osella AR, Aballay LR, Munoz SE, Lantieri MJ, Butinof M, Meyer Paz R,Pou S, Eynard AR, La Vecchia C.Cancer incidence pattern in Cordoba, Argentina.Eur. J. Cancer Prev., 18: 259-266 (<strong>2009</strong>).Zucchetto A, Serraino D, Polesel J, <strong>Negri</strong> E, De Paoli A, Dal Maso L, Montella M, La VecchiaC, Franceschi S, Talamini R.Hormone-related factors and gynecological con<strong>di</strong>tions in relation to endometrial cancer risk.Eur. J. Cancer Prev., 18: 316-321 (<strong>2009</strong>).Lubin JH, Purdue M, Kelsey K, Zhang Z-F, Winn D, Wei Q, Talamini R, Szeszenia-DabrowskaN, Sturgis EM, Smith E, Shangina O, Schwartz SM, Rudnai P, Neto JE, Muscat J, MorgensternH, Menezes A, Matos A, Mates IN, Lissowska J, Levi F, Lazarus P, La Vecchia C, Koifman S,Herrero R, Franceschi S, Wunsch-Filho V, Fernandez L, Fabianova E, Daudt AW, Dal Maso L,Curado MP, Chen C, Castellsague X, Brennan P, Boffetta P, Hashibe M, Hayes RB.Total exposure and exposure rate effects for alcohol and smoking and risk of head and neckcancer: a pooled analysis of case-control stu<strong>di</strong>es.Am. J. Epidemiol., 170: 937-947 (<strong>2009</strong>).Rossi M, Lipworth L, Dal Maso L, Talamini R, Montella M, Polesel J, McLaughlin JK,Parpinel M, Franceschi S, Lagiou P, La Vecchia C.Dietary glycemic load and hepatocellular carcinoma with or without chronic hepatitis infection.Ann. Oncol., 20: 1736-1740 (<strong>2009</strong>).Tramacere I, Gallus S, Fernandez E, Zuccaro P, Colombo P, La Vecchia C.Me<strong>di</strong>um-term effects of the Italian smoke-free legislation: fin<strong>di</strong>ngs from 4 annual populationbased surveys.J Epidemiol Community Health, 63: 559-562 (<strong>2009</strong>).Paleari L, <strong>Negri</strong> E, Catassi A, Cilli M, Servent D, D’Angelillo R, Cesario A, Russo P, Fini M.Inhibition of nonneuronal α7-nicotinic receptor for lung cancer treatment.Am. J. Respir. Crit. Care Med., 179: 1142-1150 (<strong>2009</strong>).Polesel J, Serraino D, Zucchetto A, Lucenteforte E, Dal Maso L, Levi F, <strong>Negri</strong> E, Montella M,Franceschi S, Talamini R, La Vecchia C.Cigarette smoking and endometrial cancer risk: the mo<strong>di</strong>fying effect of obesity.Eur. J. Cancer Prev., 18: 476-481 (<strong>2009</strong>).Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ.204ANNUAL REPORT <strong>2009</strong>
IRFMNA further plea for adherence to the principles underlying science in general and theepidemiologic enterprise in particular. (Authors’response)Int. J. Epidemiol., 38: 678-679 (<strong>2009</strong>).Sverzellati N, Calabrò E, Ran<strong>di</strong> G, La Vecchia C, Marchianò A, Kuhnigk J-M, Zompatori M,Spagnolo P, Pastorino U.Sex <strong>di</strong>fferences in emphysema phenotype in smokers without airflow obstruction.Eur. Resp. J., 33: 1320-1328 (<strong>2009</strong>).Lam TK, Cross AJ, Consonni D, Ran<strong>di</strong> G, Bagnar<strong>di</strong> V, Bertazzi PA, Caporaso NE, Sinha R,Subar AF, Lan<strong>di</strong> MT.Intakes of red meat, processed meat, and meat mutagens increase lung cancer risk.Cancer Res., 69: 932-939 (<strong>2009</strong>).Bosetti C, Gallus S, Talamini R. Montella M, Franceschi S, <strong>Negri</strong> E, La Vecchia C.Artificial sweeteners and the risk of gastric, pancreatic and endometrial cancers in Italy.CEBP, 18: 2235-2238 (<strong>2009</strong>)La Vecchia C.Mouthwash and oral cancer risk: An update.Oral Oncol., 45: 198-200 (<strong>2009</strong>).Boffetta P, McLaughlin JK, La Vecchia C, Tarone RE, Lipworth L, Blot WJ.Response: Re: False-positive results in cancer epidemiology: A plea for epistemologicalmodesty.JNCI,101: 213-214 (<strong>2009</strong>).Conway DI, Hashibe M, Wunsch-Filho V, Muscat J, La Vecchia C, Winn D, Boffetta P, onbehalf of the INHANCE consortium.Enhancing epidemiologic research on head and neck cancer: INHANCE – the international headand neck cancer epidemiology consortium.Oral Oncol., 45: 743-746 (<strong>2009</strong>).Bosetti C, Gallus S, La Vecchia C.Aspirin and cancer risk: a summary review to 2007.Recent Results Cancer Res. 181: 231-251 (<strong>2009</strong>).Petracci E, Farella M, Galeone C, Albano A, Ferraroni M, Decarli A.Survival analysis with clustered observations of orthodontic brackets.Stat. Med., 28: 3483-3491 (<strong>2009</strong>).Nieuwenhujisen MJ, Smith R., Golfinopoulos S, Best N, Bennett J, Aggazzotti G, Righi E,Fantuzzi G, Buchini L, Cor<strong>di</strong>er S, Villanueva CM, Moreno V, La Vecchia C, Bosetti C,Vartiainen T, Rautiu R, Toledano M, Iszatt N, Grazuleviciene R, Kogevinas M.Health impacts of long-term exposure to <strong>di</strong>sinfection by-products in drinking water in Europe:HIWATE.J. Water Health, 7: 185-207 (<strong>2009</strong>).Nal<strong>di</strong> L, Chatenoud L.Registry research in dermatology.Dermatol. Clin., 27: 185-191, vii (<strong>2009</strong>).205ANNUAL REPORT <strong>2009</strong>
IRFMNFranceschi S, Dal Maso L, Zucchetto A, Talamini R, Bidoli E, Lise M, Polesel J, Serraino D,Bosetti C, Galeone C, Gallus S, La Vecchia C, <strong>Negri</strong> E, Pelucchi C, Zanier L, de Dottori M,Stocco CF, Zambon P, Puppo A, Vercelli M, Falcini F, Ravaiolo A, Prospective Analysis ofCase-control stu<strong>di</strong>es on Environmental factors and health (PACE) study group.Alcohol consumption and survival after breast cancer.Cancer Epidemiol. Biomarkers Prev., 17: 1988-1996 (<strong>2009</strong>).Edefonti V, Ran<strong>di</strong> G, La Vecchia C, Ferraroni M, Decarli A.Dietary patterns and breast cancer: a review with focus on methodological issues.Nutr. Rev., 67: 297-314 (<strong>2009</strong>).Hu J, La Vecchia C, <strong>Negri</strong> E, DesMeules M, Mery L, The Cana<strong>di</strong>an Cancer RegistriesEpidemiology Research Group.Dietary vitamin C, E, and carotenoid intake and risk of renal cell carcinoma.Cancer Causes Control, 20: 1451-1458 (<strong>2009</strong>).Gallus S, Tramacere I, La Vecchia C, Colombo P, Zuccaro P, Paleari L, Cesario A, Russo P,Ferketich A, Apolone G.Use of pharmacotherapy for smoking cessation in Italy.Arch. Int. Med., 169: 1927-1928 (<strong>2009</strong>)Boccar<strong>di</strong> D, Menni S, La Vecchia C, Nobile M, Decarli A, Volpi G, Ferraroni M.Overweight and childhood psoriasis. Letter.Br. J. Dermatol.,161: 484-486 (<strong>2009</strong>).Garavello W, Lucenteforte E, Bosetti C, La Vecchia C.The role of foods and nutrients on oral and pharyngeal cancer risk.Minerva Stomatol., 58: 25-34 (<strong>2009</strong>).La Vecchia C.Association between Me<strong>di</strong>terranean <strong>di</strong>etary patterns and cancer risk.Nutr. Rev., 67 (suppl.1): S126-S129. (<strong>2009</strong>)Bertuccio P, Edefonti V, Bravi F, Ferraroni M, Pelucchi C, <strong>Negri</strong> E, Decarli A, La Vecchia C.Nutrient <strong>di</strong>etary patterns and gastric cancer risk in Italy.CEBP, 18: 2882-2886 (<strong>2009</strong>)Bravi F, Bosetti C, Tavani A, La vecchia C.Coffee drinking and hepatocellular carcinoma: an update.Hepatology, 50: 1317-1318 (<strong>2009</strong>).Boffetta P, La Vecchia C.Neoplasms.In: “Oxford Texbook of Public Health”, vol. 3, V e<strong>di</strong>tion “The Practice of Public Health”,Detels R, Beaglehole R, Lansang MA, Gulliford M , New York: Oxford Univ. Press,Chapter 9.3, pp. 997-1020 (<strong>2009</strong>).La Vecchia C, Bosetti C.Oral contraceptives and neoplasms other than breast and female genital tract.Eur. J. Cancer Prev., 18: 407-411 (<strong>2009</strong>).Petridou E Th, Manti EG, Ntinapogias AG, <strong>Negri</strong> E, Szczerbinska K.206ANNUAL REPORT <strong>2009</strong>
IRFMNWhat works better for community-dwelling older people at risk to fall? A meta-analysis ofmultifactorial versus physical exercise-alone interventions.J. Aging Health, 21: 713-729 (<strong>2009</strong>).Santoro E, Tinazzi A.Clinical trials data management.In: Clinical Trials Handbook, Gad S.C. ed.Wiley & Sons, Inc., Hoboken, New Jersey, <strong>2009</strong>, Ch. 8, pp.203-225.Lipworth L, La Vecchia C, Bosetti C, McLaughlin JK.Occupational exposure to rock wool and glass wool and risk of cancers of the lung and the headand neck: a systematic review and meta-analysis.J. Occup. Environ. Med., 51: 1075-1087 (<strong>2009</strong>).Bosetti C, Bravi F, <strong>Negri</strong> E, La Vecchia C.Oral contraceptives and colorectal cancer risk: a systematic review and meta-analysis.Human Repr. Update, 15: 489-498 (<strong>2009</strong>).Pelucchi C, Bosetti C, Rossi M, <strong>Negri</strong> E, La Vecchia C.Selected aspects of Me<strong>di</strong>terranean <strong>di</strong>et and cancer risk.Nutr. Cancer, 61: 756-766 (<strong>2009</strong>)Parente F, Molteni M, Marino B, Colli A, Ar<strong>di</strong>zzone S, Greco S, Sampietro G, Gallus S.Bowel ultrasound and mucosal healing in ulcerative colitis.Dig. Dis., 27: 285-290 (<strong>2009</strong>).Chuang S-C, La Vecchia C, Boffetta P.Liver cancer: descriptive epidemiology and risk factors other than HBV and HCV infection.Cancer Letters, 286: 9-14 (<strong>2009</strong>).Pelucchi C, <strong>Negri</strong> E, Gallus S, Boffetta P, Tramacere I, La Vecchia C.Long-term particulate matter exposure and mortality: a review of European epidemiologicalstu<strong>di</strong>es.BMC Publ. Health, 9:453 (<strong>2009</strong>).Levi F, Ran<strong>di</strong>mbison L, Te VC, Maspoli Conconi M, La Vecchia C.Re: Risk of prostate, breast, and colorectal cancer after skin cancer <strong>di</strong>agnosis.Int. J. Cancer, 124: 1743-1744 (<strong>2009</strong>).Bosetti C, Levi F, Boffetta P, Lucchini F, <strong>Negri</strong> E, La Vecchia C.Re: Mislea<strong>di</strong>ng figures on trends in mortality from hepatocellular carcinoma in Europe.Hepatology, 49: 336 (<strong>2009</strong>).Santoro E. RSS technology and podcasts in oncology: a new way to deliver scientificinformation. Annals of Oncology <strong>2009</strong>; 20 (Supplement 8):viii43.207ANNUAL REPORT <strong>2009</strong>
IRFMNLAY PRESS SELECTION (<strong>2009</strong>)Gallus S, Apolone G.Tumore al polmone: prevenzione primaria e secondaria.In: “La Salute del Respiro. Fattori <strong>di</strong> rischio, epidemiologia, costi e impatto sociale dellemalattie respiratorie nella realtà sanitaria italiana”, a cura <strong>di</strong> Testi R. et al.,Milano, Franco Angeli, <strong>2009</strong>, pp. 267-298.Gallus S, La Vecchia CFumo e malattie dell’apparato respiratorio.In: “La Salute del Respiro. Fattori <strong>di</strong> rischio, epidemiologia, costi e impatto sociale dellemalattie respiratorie nella realtà sanitaria italiana”, a cura <strong>di</strong> Testi R. et al., Milano,Franco Angeli, <strong>2009</strong>, pt. II “Fattori <strong>di</strong> rischio per le malattie polmonari croniche”,Cap. 1, pp. 31-46.Testi R, Rizzini P, Bosetti C, La Vecchia C, Bettoncelli G, Dal Negro RW.Terapie farmacologiche per asma e BCPO in Italia: farmaco utilizzazione e stima dellenecessità terapeutiche.In: “La Salute del Respiro. Fattori <strong>di</strong> rischio, epidemiologia, costi e impatto sociale dellemalattie respiratorie nella realtà sanitaria italiana”, a cura <strong>di</strong> Testi R. et al., Milano,Franco Angeli, <strong>2009</strong>, pt. IV “Prevenzione, programmazione e cura delle patologie respiratorie”,Cap. 2, pp. 267-298.Tavani ACaffè e tumori<strong>2009</strong>; Weber Shandwick Italia, MilanoZocchetti C, Chatenoud L, La Vecchia C.Una città che invecchia e si ripopola.In: Milano capitale della saluteE<strong>di</strong>trice Abitare Segesta, Milano, <strong>2009</strong>; 70-81Santoro E. L'uso delle cartelle cliniche elettroniche negli ospedali americani: i risultati <strong>di</strong>un'indagineCARE <strong>2009</strong>; 2: 13-14Santoro E. Il web 2.0 e l'influenza A. Ricerca & Pratica <strong>2009</strong> n.148 : 154-155Santoro E. Il web 2.0 per capire la nuova influenza. Partecipasalute <strong>2009</strong>;http://www.partecipasalute.it/cms_2/node/1269Santoro E. I tassi <strong>di</strong> mortalità dell'influenza da virus H1N1: una questione <strong>di</strong> numeri.Partecipasalute <strong>2009</strong>. http://www.partecipasalute.it/cms_2/node/1307Santoro E. I servizi socio-sanitari della Carta Regionale della Lombar<strong>di</strong>a non decollano.Partecipasalute <strong>2009</strong>; http://www.partecipasalute.it/cms_2/node/1243Santoro E. I Personal Health Record integrati (versione online). Ricerca & Pratica <strong>2009</strong> n.147 :4-5Santoro E. Google Flu Trends: un nuovo strumento. Ricerca & Pratica <strong>2009</strong> n.145 : 13-14208ANNUAL REPORT <strong>2009</strong>
IRFMNSantoro E. La Carta regionale dei servizi della regione: prova su strada. Partecipasalute <strong>2009</strong>;http://www.partecipasalute.it/cms_2/node/1022Santoro E. Guarire insieme. Corriere Salute 12 aprile <strong>2009</strong>; 134/87: 52Santoro E. Pharma 2.0. Notiziario Chimico Farmaceutico <strong>2009</strong> 4 : 46-54Santoro E. Me<strong>di</strong>ci e social network: un connubio che avanza. Ricerca & Pratica <strong>2009</strong> n.146 :65-67Santoro E. Doc2Doc: il nuovo social network del BMJ.Ricerca & Pratica <strong>2009</strong> n.147 : 101-102Santoro E. “L’uso della tecnologia RSS in car<strong>di</strong>ologia: un nuovo modo <strong>di</strong> <strong>di</strong>stribuirel’informazione scientifica”. Giornale Italiano <strong>di</strong> Car<strong>di</strong>ologia <strong>2009</strong>; 10 (Suppl 1):252.Santoro E. “Twitter, il web 2.0 e loro applicazioni in ambito car<strong>di</strong>ovascolare”. Giornale Italiano<strong>di</strong> Car<strong>di</strong>ologia <strong>2009</strong>; 10 (Suppl 1):252.Santoro E. Pazienti più forti grazie ai blog e ai social network. Corriere Salute 13 <strong>di</strong>cembre<strong>2009</strong>: 60Santoro E. La salute viaggia su Twitter. Ricerca & Pratica <strong>2009</strong> n.150 : 235-236Santoro E. L’uso <strong>di</strong> Wikipe<strong>di</strong>a per cercare informazioni sanitarie. Care <strong>2009</strong>; 4: 13-14Santoro E. La gestione delle malattie croniche attraverso il web. Care <strong>2009</strong>; 5: 13-14OTHER PUBLICATIONS (<strong>2009</strong>)Santoro E. Web 2.0 e Me<strong>di</strong>cina: come social network, podcast, wiki e blog trasformano lacomunicazione, l’assistenza e la formazione in sanità. Il Pensiero Scientifco E<strong>di</strong>tore, Roma<strong>2009</strong>.Santoro E, Tinazzi A. Clinical trials data management. In :Clinical Trials Handbook, (Wiley<strong>2009</strong>, E<strong>di</strong>ted by Gad S.C.); 203-225.RESEARCH ACTIVITIESLaboratory of General EpidemiologyCASE-CONTROL STUDIES ON CANCERDigestive tract neoplasmsDietary vitamin D and cancers of the oral cavity and esophagus209ANNUAL REPORT <strong>2009</strong>
IRFMNData on the association between vitamin D and upper <strong>di</strong>gestive tract neoplasms are limited. Weexamined the relation between <strong>di</strong>etary vitamin D intake and risk of oesophageal andoral/pharyngeal cancers in two case-control stu<strong>di</strong>es conducted in Italy between 1992 and 2005.Using data on 304 incident cases of oesophageal cancer and 804 cases of oral/pharyngeal cancerwith correspon<strong>di</strong>ng 743 and 2,080 hospital controls, respectively. We reported inverseassociations between <strong>di</strong>etary vitamin D intake and risk of oesophageal cancer and, perhaps,oral/pharyngeal cancer, which were most pronounced among heavy current smokers and heavyconsumers of alcohol.Micronutrients and gastric cancerNo specific constituent of plant foods has been consistently identified to explain the inverseassociation between non-starchy vegetables and fruit and gastric cancer. In our study, weestimated micronutrient intake using information from a validated and reproducible foodfrequency questionnaire, through an Italian food composition database. We found decreasedodds ratios (ORs) for the highest vs. lowest quartile of vitamin E (OR = 0.50), alpha-carotene(OR = 0.52) and beta-carotene (OR = 0.42) intake. Gastric cancer was <strong>di</strong>rectly associated withso<strong>di</strong>um, with ORs of 2.22 for the second, 2.56 for the third and 2.46 for the fourth quartile ofintake. No significant relation emerged with iron, calcium, potassium, zinc, vitamin C, thiamin,riboflavin, niacin, vitamin B6, folate, vitamin D, retinol, beta-cryptoxanthin, lycopene andlutein plus zeaxanthin.Macronutrients, fatty acids and cholesterol intake and gastric cancerBesides micronutrients, we also evaluated the association between specific macronutrients(inclu<strong>di</strong>ng total energy, various macronutrients and fatty acids) and stomach cancer risk. Themultivariate ORs were 1.79 (95% confidence interval, CI, 1.16-2.76) in the highest versuslowest tertile of total energy intake, 0.65 (95% CI, 0.43-0.98) for vegetable fats, and 0.66 (95%CI, 0.44-0.97) for polyunsaturated fatty acids. No significant association was found for proteins,sugars, starch, total and animal fats, saturated and monounsaturated fatty acids and cholesterol.Our study thus in<strong>di</strong>cated that selected vegetable fats, which are common in the Me<strong>di</strong>terranean<strong>di</strong>et, have a potential for prevention through <strong>di</strong>etary changes in stomach cancer.Glycemic index and load and gastric cancerWe further investigated gastric cancer risk in relation to <strong>di</strong>etary glycemic index (GI) andglycemic load (GL). We found that adjusted ORs in the highest versus the lowest quintile were1.9 (95% CI, 1.0–3.3) for GI and 2.5 (95% CI, 1.3–4.9) for GL. Compared with participantsreporting low GL and high fruit/vegetables intake, the OR rose across strata of high GL and lowfruit/vegetables, to reach 5.0 (95% CI, 2.2–11.5) for those reporting low fruit/vegetables intakeand high GL.Dietary fiber and gastric cancerFiber intake has been inversely related to stomach cancer risk in some stu<strong>di</strong>es, although thisissue is still controversial. In our study, the multivariate OR for total fiber was 0.47 (95% CI,0.28-0.79 for the highest quintile of intake as compared to the lowest). With reference to thesources of <strong>di</strong>etary fiber, an inverse association was found for fiber from vegetable (OR=0.42,95% CI, 0.24-0.72) and to a lesser extent from fruit (OR=0.65, 95% CI, 0.38-1.10), but not forfiber from grain (OR=1.25, 95% CI, 0.77-2.03).Green tea intake and the risk gastric cancer risk in ChinaWe considered the relationship between green tea and gastric cancer risk in Harbin,Heilongjiang province, northeast China, an area with high baseline risk of stomach cancer. We210ANNUAL REPORT <strong>2009</strong>
IRFMNused data from a case-control study conducted from 1987 to 1989 among 266 incident cases ofstomach cancer and 533 controls admitted to the same hospitals as cases. No associationemerged when tea consumption alone was considered: the OR for green tea consumption was0.87 (95% CI: 0.60-1.25) for green tea intake ≥750 g/year versus no intake and 0.99 (95% CI:0.97-1.02) for an increment of 500 g of tea per year. When tea consumption was furtherclassified accor<strong>di</strong>ng to the temperature, however, the OR was 0.19 (95% CI: 0.07-0.48) for coldtea intake ≥750 g/year and 1.27 (95% CI: 0.85-1.90) for hot tea intake (p value for interaction
IRFMNassociation between GL and HCC, which was exclusively accounted for by a positiveassociation between GL and HCC cases with chronic infection with hepatitis B and/or C. Forthe latter group of patients, the OR at the highest compared to the lowest GL quintile was 1.95(95% CI, 1.09-3.48). The association was strengthened after exclusion of subjects with <strong>di</strong>abetes.Diabetes and hepatocellular carcinomaWe also considered the impact of obesity and <strong>di</strong>abetes mellitus (DM) on the risk of HCC inItaly, provi<strong>di</strong>ng further evidence that obesity and DM increase HCC risk and that these factorsmay explain a relevant proportion of cases (over a trend) among subjects without markers ofHBV/HCV infection.Female breast and genital neoplasmsVitamin D and breast cancer riskWe investigated whether vitamin D was associated with risk of breast cancer in our studyinclu<strong>di</strong>ng 2569 cases of breast cancer and 2588 hospital controls. After allowance for major riskfactors for breast cancer and <strong>di</strong>etary covariates, inclu<strong>di</strong>ng calcium and energy intake, there wasno association up to the seventh decile between vitamin D intake and breast cancer. Thereafter,the OR declined, so that the overall trend was statistically significantly inverse. The OR forsubjects in the three highest deciles of consumption of vitamin D compared with those in thelowest ones combined was 0.79 (95% CI, 0.70-0.90). Only intake of vitamin D over 3.57 μg or143 IU appeared to have a protective effect against breast cancer.Alcohol and survival after breast cancerA recent study from the United Kingdom reported that alcohol consumption may improve breastcancer survival. To provide information on this issue, we used follow-up information (me<strong>di</strong>an,12.6 years) from 1,453 women with incident invasive breast cancer, <strong>di</strong>agnosed between 1991and 1994 and interviewed in our case-control study. We observed 503 deaths, and estimatedhazard ratios (HR) for all-cause mortality using Cox proportional hazard models, adjusted formajor tumor characteristics (tumor, node, and metastasis stage, and estrogen and progesteronereceptor status) and potential lifestyle factors associated with survival. The HR in the fullyadjusted model were 0.98 (95% CI, 0.79-1.22) for all drinkers and 1.17 (95% CI, 0.85-1.61) for≥21 drinks/wk, compared with nondrinkers. The correspon<strong>di</strong>ng figures for wine consumption,which accounted for 79% of all alcohol consumption in our study, were 0.94 (95% CI, 0.76-1.16) and 1.11 (95% CI, 0.71-1.73). In no category of alcohol consumption <strong>di</strong>d drinkers surviveany longer than nondrinkers. Our study <strong>di</strong>d not lend support to the possibility that alcohol orwine consumption improves the survival of women with breast cancer.Diet and endometrial cancerWe analyzed data from a case-control study on endometrial cancer, conducted during 1992-2006 in three areas of Italy, inclu<strong>di</strong>ng 454 cases and 908 controls, to investigate the relationshipbetween various aspects of <strong>di</strong>et and risk of endometrial cancer. With reference to main foodgroups, we found a significant <strong>di</strong>rect association with consumption of red meat, and a moderateincrease in risk for consumption of sweets and poultry. On the other hand, a high consumptionof cereals and vegetables decreased the risk of endometrial cancer by 44% and 41%,respectively, while other food groups investigated were not associated with the risk of thiscancer. Another study considered the role of allium vegetables, which were found to beinversely related with risk of various other cancers in an earlier Italian study. For endometrialcancer too, we found significant inverse associations with consumption of both onions (OR =0.40 for the highest vs. lowest level of consumption) and garlic (OR = 0.62).212ANNUAL REPORT <strong>2009</strong>
IRFMNFamily history of cancer and endometrial cancer riskWith reference to family history of cancer, our questionnaires had detailed information onhistory of all cancers in first-degree relatives and thus allowed a thoroughly investigation of therelation with endometrial cancer risk. The OR of endometrial cancer for women with at leastone first-degree relative <strong>di</strong>agnosed the same neoplasm was 2.13, while those who had relativeswith a <strong>di</strong>agnosis of uterine and colorectal cancer had OR of endometrial cancer of 1.76 and1.62, respectively. Risks were also increased in women younger than 55 years at <strong>di</strong>agnosis (OR= 2.60 for family history of uterine cancer, OR = 2.79 for family history of colorectal cancer).We found <strong>di</strong>rect associations with some other cancer sites, while there was no association withthe family history of breast cancer. Thus, our study confirmed that a family history ofendometrial, uterine and colorectal cancer increases the risk of endometrial cancer.Hormone-related factors, gynecological con<strong>di</strong>tions and endometrialcancer riskThe objectives of this study were to investigate the effect of menstrual and reproductivevariables, breastfee<strong>di</strong>ng, exogenous hormones, and gynaecological con<strong>di</strong>tions on endometrialcancer risk. Endometrial cancer risk was inversely associated with parity (OR=0.5, 95% CI 0.4-0.8, for ≥3 deliveries vs. none) and age at menarche (OR=0.7, 95% CI 0.5-1.0, for ≥14 vs.
IRFMNAspirin use and renal cell cancerAspirin and non-steroideal anti-inflammatory drugs (NSAIDs) have been related to decreasedrisk of several cancers, but stu<strong>di</strong>es on the relation with the risk of RCC are inconsistent. Wehave analyzed data of our case-control study conducted in Italy in 1992-2004, based on 755cases and 1,297 controls. Regular use of aspirin for at least six months was reported by 67 casesand 99 controls and was not related with risk of RCC (OR = 0.98). The lack of association wasconsistent in both sexes, in two strata of age, in users for less than 3 years or 3 years or longer,and among users of aspirin as analgesic or for car<strong>di</strong>ovascular <strong>di</strong>sease prevention.Micronutrients and renal cell cancerWe contributed to the analysis of a nationwide multi-site population-based case-control studybased on cancer registration in Canada. The data on RCC provide evidence that a <strong>di</strong>et rich inbeta-carotene and lutein/zeaxanthin may play a role in RCC prevention.Other neoplasmsDiet <strong>di</strong>versity and the risk of laryngeal cancerDiet <strong>di</strong>versity (defined as the number of <strong>di</strong>fferent foods consumed) has been considered anin<strong>di</strong>cator of a healthy <strong>di</strong>et, and favorably related to the risk of several <strong>di</strong>gestive tract cancers.We analyzed the relation between <strong>di</strong>et <strong>di</strong>versity and the risk of laryngeal cancer using data froma case-control study carried out between 1992 and 2000 in Italy and Switzerland. The subjectsof the study were 527 patients with histologically confirmed incident cancers of the larynx and1297 patients admitted for acute, non-neoplastic <strong>di</strong>seases, unrelated to tobacco or alcoholconsumption. Total <strong>di</strong>versity was computed as the number of <strong>di</strong>fferent foods (overall and withinfour food groups, i.e., vegetables, fruit, meat, and cereals) consumed at least once per week. Asignificant inverse association was observed for vegetable <strong>di</strong>versity (OR=0.41, 95% CI: 0.28-0.59, for the highest versus the lowest quartile) and fruit <strong>di</strong>versity (OR=0.40, 95% CI: 0.27-0.59). Conversely, a <strong>di</strong>rect association was found for meat <strong>di</strong>versity (OR=1.67, 95% CI: 1.11-2.50), while no meaningful association was found for total <strong>di</strong>et and cereal <strong>di</strong>versity.Tobacco, alcohol and pancreatic cancer riskTobacco smoking is the major established risk factor for pancreatic cancer, whereas the role ofalcohol consumption is still open to debate. Between 1991 and 2008, we conducted a hospitalbasedcase-control study in northern Italy on 326 cases with pancreatic cancer, and 652 controls.Pancreatic cancer was associated to current smoking (OR=1.68; 95% CI, 1.13-2.48), and therisk rose with increasing number of cigarettes/day (OR=2.04; 95% CI, 1.14-3.66 for 20cigarettes/day). No association emerged for former smokers (OR=0.98; 95% CI, 0.66-1.45).Alcohol consumption was associated to increased pancreatic cancer risk, but ORs weresignificant only among heavy drinkers (ORs = 2.03 and 3.42 for 21-34 and ≥35 drinks/week,respectively). Pancreatic cancer risk was 4.3-fold higher in heavy smokers (≥20 cigarettes/day)and heavy drinkers (≥21 drinks/week) in comparison with never smokers who drunk
IRFMNcolorectal, and 0.55 (95% CI, 0.37-0.83) for laryngeal cancer. No consistent association wasfound with breast, endometrial, ovarian, prostate and RCC. Thus, our fin<strong>di</strong>ngs in<strong>di</strong>cated thatcitrus fruit has a protective role against cancers of the <strong>di</strong>gestive and upper respiratory tract.Selected aspects of Me<strong>di</strong>terranean <strong>di</strong>et and cancer riskSeveral aspects of the Me<strong>di</strong>terranean <strong>di</strong>et are considered favourable not only on car<strong>di</strong>ovascular<strong>di</strong>sease, but also on cancer risk. We reviewed the role of various aspects of the Me<strong>di</strong>terranean<strong>di</strong>et on cancer risk in our series of case-control stu<strong>di</strong>es conducted between 1991 and 2007. Formost epithelial cancers, the risk decreased with increasing vegetable consumption, with ORsbetween 0.3 and 0.8 for the highest versus the lowest level. Allium vegetables were alsofavourably related to cancer risk. The risk of a few cancer sites, mainly of <strong>di</strong>gestive tract andlarynx, was inversely associated with fruit intake. For <strong>di</strong>gestive tract cancers, the populationattributable risks for low intake of vegetables and fruit ranged between 15 and 40%. Fish, andconsequently a <strong>di</strong>et rich in n-3 polyunsaturated fatty acids, was another favourable <strong>di</strong>etin<strong>di</strong>cator, while red meat intake was <strong>di</strong>rectly related to some common neoplasms. Olive oil andunsaturated fats, which are also typical aspects of the Me<strong>di</strong>terranean <strong>di</strong>et, were inversely relatedto the risk of several cancer sites, particularly of the upper aero<strong>di</strong>gestive tract. Whole grain food(and hence possibly fiber) intake was also related to reduced risk of upper aero<strong>di</strong>gestive tractand various other cancers. In contrast, refined grain intake and, consequently, glycemic load andglycemic index were associated to increased risk for several cancer sites. A number ofantioxidants and other micronutrients and food components (inclu<strong>di</strong>ng folate, flavonoids andcarotenoids) showed an inverse relation with cancer risk, but the main component(s) responsiblefor the favourable effect of a <strong>di</strong>et rich in vegetables and fruit remain undefined.Artificial sweeteners and the risk of gastric, pancreatic, and endometrialcancersThe role of sweeteners on cancer risk has been widely debated over the last few decades. Weprovided ad<strong>di</strong>tional information on saccharin and other artificial or low-calorie sweeteners(mainly aspartame), using data from a network of case-control stu<strong>di</strong>es conducted in Italybetween 1991 and 2004 inclu<strong>di</strong>ng data on 230 cancers of the stomach, 326 of the pancreas, and454 of the endometrium. After allowance for various confoun<strong>di</strong>ng factors, ORs for ever users ofsweeteners versus nonusers were 0.80 (95% CI, 0.45-1.43) for gastric cancer, 0.62 (95% CI,0.37-1.04) for pancreatic cancer, and 0.96 (95% CI, 0.67-1.40) for endometrial cancer.Correspon<strong>di</strong>ng ORs for saccharin were 0.65, 0.19, and 0.71, and for other sweeteners were 0.86,1.16, and 1.07, respectively, for the three cancer sites.META-ANALYSES AND REVIEW PAPERSDietary factors and oral and pharyngeal cancerWe reviewed data from six cohort stu<strong>di</strong>es and approximately 30 case-control stu<strong>di</strong>es on therelation between selected aspects of <strong>di</strong>et and the risk of oral and pharyngeal cancer. The pooledrelative risk (RR) for high vegetable consumption were 0.65 from three cohort stu<strong>di</strong>es onUADT cancer, and 0.52 from 18 case-control stu<strong>di</strong>es of oral and pharyngeal cancer.Correspon<strong>di</strong>ng RRs for fruit consumption were 0.78, and 0.55.Oral contraceptives and colorectal cancer riskIn order to quantify the association between oral contraceptive (OC) use and colorectal cancerrisk, we performed a systematic review and meta-analysis of stu<strong>di</strong>es on this issue. We identifiedall relevant stu<strong>di</strong>es published, in English, as original articles up to December 2008 through asearch of the literature using PubMed and EMBASE, and by reviewing the references from theretrieved articles.The summary relative risk of colorectal cancer for ever versus never OC use215ANNUAL REPORT <strong>2009</strong>
IRFMNwas 0.82 (95% confidence interval, CI, 0.69-0.97) from 11 case-control stu<strong>di</strong>es, 0.81 (95% CI,0.75-0.89) from seven cohort stu<strong>di</strong>es, and 0.81 (95% CI, 0.72-0.92) from all stu<strong>di</strong>es combined.The results were similar for colon and rectal cancer. No <strong>di</strong>fference was evident accor<strong>di</strong>ng toduration of OC use both for colon and rectal cancer, although there is an in<strong>di</strong>cation that theprotection is stronger for more recent use (OR = 0.70, 95% CI, 0.53-0.90, on the basis of fourstu<strong>di</strong>es).Alcohol drinking and pancreatic cancer riskWe performed a meta-analysis of relevant dose-risk results on the association between alcoholconsumption and pancreatic cancer risk. We conducted a PubMed search of all case-control(N=21) and cohort (N=11) stu<strong>di</strong>es published up to March <strong>2009</strong>. The pooled RR was 0.92 (95%CI, 0.86-0.97) for
IRFMNassociation with TC. Among other food groups, vegetables other than cruciferous are the onlyfood group showing a favourable effect on TC, with an approximate 20% reduction in risk forsubjects with the highest consumption. No effect on TC risk of alcohol, coffee, or other foodgroups/nutrients emerged. Height and weight at <strong>di</strong>agnosis show a moderate positive associationwith TC risk. At present, the only recognized measures for reducing TC risk is to avoid ionizingra<strong>di</strong>ation and io<strong>di</strong>ne deficiency, particularly in childhood and young women, and to increasevegetable consumption.Aspirin and cancer riskIn two papers, we reviewed aspirin and cancer risk. Aspirin has emerged as the most likelyNSAID for use in chemoprevention of colorectal and other selected neoplasms because of itsknown car<strong>di</strong>ovascular benefit and available safety and efficacy data. Other tra<strong>di</strong>tional NSAIDs,particularly sulindac, and selective COX-2 inhibitors are now given to patients at high risk ofcolorectal cancer, although these drugs do not provide car<strong>di</strong>oprotection.TOBACCO CONTROLSmoking prevalence in 2008We provided updated information on smoking prevalence in Italy, with a focus on demographicand socio-economic characteristics, using a representative survey conducted in 2008 on asample of 3035 Italian in<strong>di</strong>viduals (1459 men and 1576 women) aged 15 years or over. Overall,22.0% of Italians described themselves as current cigarette smokers (26.4% of men, 17.9% ofwomen); ex-smokers were 18.4% (24.1% of men, 13.2% of women). Smoking prevalence in theyoung (15-24 years) was around 30% in males, and almost 20% in females. For both sexes,current smoking was less prevalent in higher (22.9% of men, 20.1% of women) than in lowereducated participants (34.8% of men, 22.1% of women), and in northern (22.5% of men, 16.1%of women) than southern Italy (31.8% of men, 18.4% of women).Hardcore smoking among Italian women and menHardcore smokers are described as heavy smokers who have not attempted to quit and have nofuture intentions to quit. In 2007, we collected data from 3057 Italians aged 15 years and older,who were randomly selected to be representative of the population. The smoking prevalenceoverall was 23.5% (27.9% among males and 19.3% among females). An estimated 7.8% ofin<strong>di</strong>viduals were hardcore smokers (9.7% among males and 6% among females), whichtranslates into 33.1% of all smokers in Italy. Age at smoking initiation, occupation (amongmales), home smoking rules, and perceived stress (among females) <strong>di</strong>stinguished hardcore fromnon hardcore smokers.Tobacco sales to minorsOne of the strategies to control tobacco is to limit purchase of cigarettes to minors. Tounderstand the attitudes of Italian adults towards regulations to prevent minors from purchasingtobacco products, we considered data from a representative tobacco survey on 3057 subjects,conducted in 2007. Overall, 78% of Italians believed that a restriction of the current tobaccosales-to-minors law could be moderately to extremely effective as a strategy to decreasesmoking prevalence and consumption. More than 90% of Italians reported that they had neverseen in their lifetime a retailer refusing to sell cigarettes to an adolescent or requesting theminor's identification or age.Use of pharmacotherapy for smoking cessationWe examined the use of pharmacotherapy while attempting smoking cessation among currentsmokers and also the prevalence of use among former smokers in Italy, using data from six217ANNUAL REPORT <strong>2009</strong>
IRFMNrepresentative surveys conducted between 2002 and 2007 on a total of 19,459 Italians aged 15years and older. Among 1854 smokers who had made at least one quit attempt in the past, 9.4%reported using pharmacotherapy during at least one attempt. Use of pharmacotherapy wasrelated to smoking intensity, education level, and age. Among former smokers,pharmacotherapy use for cessation ranged between 0 and 4.9%. Analyzing data from asubsequent survey conducted in 2008 we found similar results. Therefore, methods to increasethe use of pharmacotherapy for smoking cessation need to be enhanced in Italy because theseproducts are not reaching a large majority of smokers. One possible solution is to addpharmacotherapy to the list of me<strong>di</strong>cations covered by the National Health Service.Cigarette smugglingWe updated information on cigarette smuggling in Italy, using data from 4 surveys annuallyconducted between 2005 and 2008. Of the total of cigarettes smoked, 90.9% had been boughtfrom tobacco shops, 6.9% from ven<strong>di</strong>ng machines, 0.7% from smugglers, 0.0% from theinternet, and 1.5% from peers. The proportion of smuggled tobacco consumption appeared to begreater in heavy smokers, while no significant <strong>di</strong>fference was found accor<strong>di</strong>ng to sex, agegroup, geographic area, education and survey. Among 2893 current smokers, only 46 subjects(1.6%) bought their cigarettes through illicit trade. Of these, 11 (0.4%) bought cigarettesexclusively from smugglers. Only 2 subjects, both in 2008, reported purchasing cigarettes fromthe internet.Me<strong>di</strong>um-term effects of the Italian smoke-free legislationIn order to quantify, 3 years after the law came into force, the effects of the smoking ban interms of observance of the legislation and change of habits, we considered data from fourrepresentative surveys on smoking, conducted between 2005 and 2008 on a total of 12,245in<strong>di</strong>viduals (5906 men and 6339 women) aged 15 years or over. In 2008, more than 80% ofItalians (more than 90% in northern Italy) had the perception that the smoking ban wasrespected in bars/cafes and restaurants, despite a slight reduction since 2005. In all the surveyscombined, 75% of the Italian population reported that the smoking ban was respected inworkplaces. Overall, approximately 10% of Italians reported that, after the implementation ofthe tobacco regulation, they went to bars/cafes and restaurants more frequently, andapproximately 7% less frequently, than before. Our study shows that in Italy the smoke-freelegislation <strong>di</strong>d not affect the business of restaurants and bars, and remains widely respected 3years after the law came into force.Lung <strong>di</strong>seases in smokersWe are involved in the conduction and analysis of the MILD study of CT scan in heavysmokers. In this investigation, bronchial <strong>di</strong>verticula are a frequent fin<strong>di</strong>ng in the major airwaysof smokers, and they are associated with other markers of smoking-related damage.In the same study, compared with males, females exhibited an emphysema phenotype lessextensive in each pulmonary lobe. However, in females, the increase of emphysema with agewas more pronounced and <strong>di</strong>splayed a more significant relationship with FEV(1)% decline.Males and females responded <strong>di</strong>fferently to the type and location of lung damage due to tobaccoexposure. In smokers, sex influences the relationship between emphysema and clinical features.Likewise, lung function production lung cancer risk in smokers.OTHER PROJECTSHI-WATE project on colorectal cancer and drinking water by-productsThere appears to be very good epidemiological evidence for a relationship between chlorinationby-products, as measured by trihalomethanes (THMs), in drinking water and bladder cancer, but218ANNUAL REPORT <strong>2009</strong>
IRFMNthe evidence for other cancers, inclu<strong>di</strong>ng colorectal cancer appears to be inconclusive an<strong>di</strong>nconsistent. There appears to be some evidence for a relationship between chlorination byproducts,as measured by THMs, and small for gestational age (SGA)/intrauterine growthretardation (IUGR) and preterm delivery, but evidence for other outcomes such as low birthweight (LBW), stillbirth, congenital anomalies and semen quality appears to be inconclusiveand inconsistent.The overall aim of the HIWATE study (supported by th EU FP-6) is toinvestigate potential human health risks (e.g. bladder and colorectal cancer, premature births,SGA, semen quality, stillbirth, congenital anomalies) associated with long-term exposure to lowlevels of <strong>di</strong>sinfectants (such as chlorine) and DBPs occurring in water for human consumptionand use in the food industry. The study will comprise risk-benefit analyses inclu<strong>di</strong>ngquantitative assessments of risk associated with microbial contamination of drinking waterversus chemical risk and will compare alternative treatment options. The outcome will beimproved risk assessment and better information for risk management. The work is <strong>di</strong>vided into<strong>di</strong>fferent topics (exposure assessment, epidemiology, risk assessment and management) andstu<strong>di</strong>es.In 2008, the Department started the collection of data for a case-control study on colorectalcancer within the HI-Wate project. The study is conducted in the greater Milan area and in theProvinces of Pordenone and U<strong>di</strong>ne, and includes incident, histologically confirmed casesenrolled in the major general and teaching hospital of the study area, and frequency-matchedcontrols, admitted to the same hospital as cases for acute, nonneoplastic con<strong>di</strong>tions. Cases andcontrols are interviewed using an extensive questionnaire. Detailed information on water useand water-related habits for etiologically relevant time periods is collected, inclu<strong>di</strong>ng not onlywater consumption, but also water related activities, such as showering, bathing and swimming,that may influence exposure assessment. Moreover, in order to assess the subjects’ exposure toDBPs and THMs in water, current and historical THM levels, water source and year of startingchlorination in the study area will be collected from local companies, authorities andmunicipalities. About 250 colorectal cancer cases and 250 correspon<strong>di</strong>ng controls have beencollected, i.e., about half of the total number of cases and controls which should be enrolled atthe end of the study. Giving the large number of people exposed to chlorinated drinking-waterand its DBPs, the study has potentially important implications in terms of public health. Evenmodest excess risk in relation to DBP exposure may in fact have a relevant impact on apopulation level, and may be responsible of a considerable number of colorectal cancer cases.Mortality from cancer and other causes in a cohort of chrysotile asbestosminersWe updated the analyses from the cohort of Balangero mine workers, inclu<strong>di</strong>ng 1056 males anda total of 34,432 man-years of observation, using follow-up data to the end of 2003. Aim of thestudy was to investigate mortality from cancer and other causes among chrysotile asbestosminers several years after stopping exposure. We obtained employment data from personnelrecords at the factory, and ascertained vital status and causes of death through populationregisters and death certificates from municipal registration offices. We found a significantexcess mortality from pleural and peritoneal cancers combined (5 deaths, standar<strong>di</strong>zed mortalityratio, SMR=3.16). All pleural and peritoneal cancer deaths occurred 30 or more years after firstexposure. The SMRs were 1.27 for lung cancer (45 deaths), 1.82 for laryngeal cancer (8 deaths)and 1.12 for all cancers (142 deaths). There were 57 deaths from cirrhosis (SMR=2.94) and 54from accidents and violence (SMR=1.88). Overall, we observed a total of 590 deaths ascompared to 412.9 expected (SMR=1.43). This updated analysis, with almost 60% of workersof the cohort who had <strong>di</strong>ed, confirmed the excess mortality from pleural and peritoneal cancersand from several alcohol-related causes.219ANNUAL REPORT <strong>2009</strong>
IRFMNINHANCE studyWe were actively involved in the International Head and Neck Cancer (HNC) Epidemiology(INHANCE) consortium, which includes data from 33 HNC stu<strong>di</strong>es worldwide, and a total ofabout 25,000 cases of 33,000 controls. During <strong>2009</strong>, we published a paper summarizing scope,aims, design and motivation of the study, and a number of pages on selected topics. Theseinclude family history, since family history of HNC in first-degree relatives increased the risk ofHNC (OR=1.7, 95% CI, 1.2-2.3). The risk was higher when the affected relative was a siblingrather than a parent and for more <strong>di</strong>stal HNC anatomic sites (hypopharynx and larynx). The riskwas also higher, or limited to, in subjects exposed to tobacco. The OR rose to 7.2 (95% CI 5.5-9.5) among subjects with family history, who were alcohol and tobacco users.With reference to type of alcoholic beverage there were similar associations with ethanolstandar<strong>di</strong>zedconsumption frequency for beer-only drinkers and liquor-only drinkers. Amongwine-only drinkers, the ORs for moderate levels of consumption approached the unity, whereasthose for higher consumption levels were comparable to those of drinkers of other beveragetypes. These study fin<strong>di</strong>ngs suggest that the RRs of HNC for beer and liquor are comparable. Agreater than multiplicative effect between ever tobacco and alcohol use was observed for headand neck cancer risk. The population attributable risk for tobacco or alcohol was 72% for HNC,of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due totobacco and alcohol combined Quitting tobacco smoking resulted in a HNC risk reduction in theshort-term (OR 0.70, CI 0.61-0.81 after 1-4 years compared with current smoking). For alcoholuse, a beneficial effect on the risk of head and neck cancer was only observed after ≥20 years ofquitting. We also modeled the excess OR (EOR) for total exposure to alcohol and tobacco.Above 15 cigarettes/day, the EOR/pack-year decreased with increasing cigarettes/day,suggesting that greater cigarettes/day for a shorter duration was less deleterious than fewercigarettes/day for a longer duration. EOR/drink-year estimates increased through 10 drinks/day,suggesting that greater drinks/day for a shorter duration was more deleterious than fewerdrinks/day for a longer duration.InterLymph studyWe also participated to another consortium study of non-Hodgkin lymphoma (NHL) worldwide.A study on allergy and NHL showed evidence of a modest but consistent reduction in the risk ofB-cell NHL associated with atopy.DERMATO EPIDEMIOLOGYFrequency of atopic dermatitis in Italian childrenThe frequency of atopic dermatitis in Italian children and its relationship with selectedvariables were analysed in a large survey of skin health conducted in Italy on more than3,000 schoolchildren. A <strong>di</strong>agnosis of atopic dermatitis was reported in 224 cases(7.0%). The frequency of reported atopic dermatitis was significantly higher in childrenwith asthma. The lifetime prevalence of a <strong>di</strong>agnosis of atopic dermatitis was higheramong schoolchildren reporting a <strong>di</strong>agnosis of psoriasis and vitiligo.Longitu<strong>di</strong>nal stu<strong>di</strong>es of melanocytic nevi in childrenIn an e<strong>di</strong>torial, we revised the literature on longitu<strong>di</strong>nal stu<strong>di</strong>es of melanocytic nevi inchildren. The number of nevi represents the strongest independent risk factor forcutaneous malignant melanoma, and risk factors for the number of melanocytic neviparallel those for cutaneous malignant melanoma, inclu<strong>di</strong>ng intensive sun exposure,high propensity to sunburn, and pale skin. Nevi usually develop during childhood andadolescence, and their body site <strong>di</strong>stribution is influenced by sun exposure. Thus,monitoring the evolution of nevi in children from <strong>di</strong>fferent geographic areas with220ANNUAL REPORT <strong>2009</strong>
IRFMNvarying sun exposure patterns and behavioural norms might offer ad<strong>di</strong>tional clues tounderstan<strong>di</strong>ng melanoma development. Further data are also needed from geographicareas other than the United States and Australia, particularly Europe, where the lack oflongitu<strong>di</strong>nal stu<strong>di</strong>es is of concern.PUBLIC HEALTH PREVENTION AND INFORMATIONThe major products of our activity have also been published in the lay press, in order to increasethe project impact on prevention and public health.Laboratory of Epidemiological MethodsMONITORING OF CANCER MORTALITY IN EUROPECancer mortality in Europe, 2000-2004We updated the pattern of cancer mortality in 34 European countries during 2000-2004, with anoverview of trends in 1975-2004, using data from the WHO. From 1990-1994 to 2000-2004,overall cancer mortality in the European Union (EU) declined from 185.2 to 168.0/100 000(world standard, -9%) in men and from 104.8 to 96.9 (-8%) in women, with larger falls inmiddle age. Total cancer mortality trends were favourable, though to a variable degree, in allmajor European countries, inclu<strong>di</strong>ng Russia, but not in Romania. The major determinants ofthese favourable trends were the decline of lung (-16%) and other tobacco-related cancers inmen, together with the persistent falls in gastric cancer, and the recent appreciable falls incolorectal cancer. In women, relevant contributions came from the persistent decline in cervicalcancer and the recent falls in breast cancer mortality, particularly in northern and westernEurope. Favourable trends were also observed for testicular cancer, Hodgkin lymphomas,leukaemias, and other neoplasms amenable to treatment, though the reductions were stillappreciably smaller in eastern Europe.Cancer mortality in Italy, 2003Italian Cancer mortality was updated with data for 2003, with a change of classification from 9 the<strong>di</strong>tion to the 10 th e<strong>di</strong>tion of the International Classification of Diseases (ICD). The total numberof cancer deaths was 167,144 (96,127 men and 71,017 women), the age standar<strong>di</strong>sed death rateswere 160.63 and 89.32/100,000 for men and women respectively for all cancers. Most tobaccorelatedcancers confirmed their declining trends in men, but not in women. Male lung cancermortality was 43.72/100,000. Cancers of the uterus and female breast also confirmed theirfavourable trends with rates of 17.11 and 3.71/100,000 respectively. Falls in mortality were alsorecorded for stomach and testis cancers. Some cancers such as prostate and multiple myelomaappeared to rise, but this is mainly due to the change in ICD and the stricter age standar<strong>di</strong>sationadopted.Childhood cancer mortality in Europe, 1970-2007We updated trends in childhood cancer mortality in 30 European countries up to 2007, usingdata from the WHO for all childhood neoplasms, bone and kidney cancers, NHL andleukaemias. Between 1990-1994 and 2005-2007, mortality from all neoplasms stea<strong>di</strong>ly decline<strong>di</strong>n most European countries (from 5.2 to 3.5/100,000 boys and from 4.3 to 2.8/100,000 girls inthe EU). In 2005-2007, however, mortality rates from childhood cancers were still higher incountries from Eastern (4.9/100,000 boys and 3.9/100,000 girls) and Southern (4.0/100,000boys and 3.1/100,000 girls) Europe than in those from Western (3.1/100,000 boys and2.5/100,000 girls) and Northern (3.2/100,000 boys and 2.5/100,000 girls) Europe. Similartemporal trends and geographic patterns were observed for leukaemias, with declines from 1.7221ANNUAL REPORT <strong>2009</strong>
IRFMNto 0.9/100,000 boys and from 1.3 to 0.7/100,000 girls between 1990-1994 and 2005-2007 in theEU. For kidney cancer and NHL mortality rates were low and have been declining in largerEuropean countries over the last 15 years. The pattern of trends was less clear for bone cancer,with no systematic downward trends at age 0-14, though some fall was evident at age 15-19.The oral cancer epidemic in central and eastern EuropeWe analyzed oral and pharyngeal cancer mortality in 38 European countries over the period1975–2004. Joinpoint analysis was used to identify significant changes in trends. In the EU,male mortality rates rose by 2.1% per year between 1975 and 1984, by 1.0% between 1984 and1993, and declined by 1.3% between 1993 and 2004, to reach an overall age-standar<strong>di</strong>zed rateof 6.1/100,000 in 2000–2004. Mortality rates were much lower in women, and the rate in theEU rose by 0.9% per year up to 2000, and levelled off to 1.1/100,000 in 2000–2004. In Franceand Italy, which had the highest rates in the past, male rates have stea<strong>di</strong>ly declined during thelast two decades (annual percent change, APC=-4.8% in 1998–2004 in France and -2.6% in1986–2003 in Italy). Persisting rises were, however, observed in several central and easternEuropean countries, with excee<strong>di</strong>ngly high rates in Hungary (21.1/100,000; APC=6.9% in1975–1993 and 1.4% in 1993–2004) and Slovakia (16.9/100,000; APC=0.1% in 1992–2004).The highest rates for women were in Hungary (3.3/100,000; APC=4.7% in 1975–2004) andDenmark (1.6/100,000; APC=1.3% in 1975–2001). Oral and pharyngeal cancer mortalityessentially reflects the <strong>di</strong>fferent patterns in tobacco smoking and alcohol drinking, inclu<strong>di</strong>ngdrinking patterns and type of alcohol in central Europe.Gastric cancer mortality: a global overviewWe analyzed gastric cancer mortality in Europe and other areas of the world from 1980 to 2005using joinpoint regression analysis, and provided updated site-specific incidence rates from 51selected registries. Over the last decade, the APC in mortality rate was around -3, -4% for themajor European countries. The APC were similar for the Republic of Korea (APC=-4.3%),Australia (-3.7%), the USA (-3.6%), Japan (-3.5%), Ukraine (-3%) and the Russian Federation(-2.8%). In Latin America, the decline was less marked, but constant with APC around -1.6% inChile and Brazil, -2.3% in Argentina and Mexico and -2.6% in Colombia. Cancers in the fundusand pylorus are more common in high incidence and mortality areas and have been decliningmore than car<strong>di</strong>a gastric cancer.Biliary tract cancer mortalityBiliary tract cancer mortality and incidence data were updated, and analysed using joinpointregression analysis. Biliary tract cancer mortality is characterised by a wide geographicalvariation and a female to male mortality ratio greater than unity in most countries. In Europeand North America it is a rare cancer, while it has a high incidence in some areas Latin Americaand Asia. Decreasing biliary tract cancer mortality rates were observed since the 1980s inAustralia, Hong Kong, New Zealand, Israel, Canada, the United States and the EU as a whole,as well as high risk countries such as Japan and Venezuela, with joinpoint regression in<strong>di</strong>catingthat the decreasing trends are more favourable in more recent calendar periods. However, highmortality rates were still observed, particularly in women, in some central and eastern Europeancountries and Japan (4-5/100,000 female mortality rate) and Chile (16.6/100,000 femalemortality rate). The study of incidence rates identified other high-risk areas in In<strong>di</strong>a(8.5/100,000 women), Korea (5.6/100,000 women) and Shanghai in China (5.2/100,000women). The observed decreases in biliary tract cancer mortality are a consequence of the morewidespread adoption of cholecystectomy, since the main risk factor for this cancer is gallstones.However in some high-risk areas of South America and In<strong>di</strong>a, access to gall-bladder surgeryremains inadequate.222ANNUAL REPORT <strong>2009</strong>
IRFMNThe recent decline in mortality from Hodgkin lymphomas in central andeastern EuropeHodgkin lymphoma (HL) is a largely curable <strong>di</strong>sease and its mortality had stea<strong>di</strong>ly declined inWestern Europe since the late 1960s. Only modest declines were, however, observed incentral/eastern Europe. We updated trends in mortality from HL in various European areas up to2004 and analyzed patterns in incidence for selected European countries provi<strong>di</strong>ng nationaldata. In most western European countries, HL mortality continued to stea<strong>di</strong>ly decline up to themid 2000s. More recent reductions were also observed in eastern European countries. Overall,mortality from HL declined from 1.17/100,000 (age-standar<strong>di</strong>zed, world population) in 1980-1989 to 1.42/100,000 in 2000-2004 in men from the 15 member states of the EU from westernand northern Europe. In the EU 10 accession countries of central and eastern Europe, malemortality from HL was 1.42/100,000 in 1980-1984, 1.32 in 1990-1994, and declined to 0.76 in2000-2004. Similar trends were observed in women. No consistent patterns were found for HLincidence.Mortality from coronary heart <strong>di</strong>seases and cerebrovascular <strong>di</strong>seasesWe updated trends in mortality from coronary heart <strong>di</strong>seases (CHD) and cerebrovascular<strong>di</strong>seases (CVD) over the period 1981 to 2004 in Europe, the USA, Latin America, Japan andother selected areas of the world. Though mortality from CHD and CVD continue to decline inseveral areas of the world inclu<strong>di</strong>ng most countries of Europe and of the Americas provi<strong>di</strong>ngdata, and Australia, unfavourable trends were still observed in the Russian Federation and othercountries of the former Soviet Union, whose recent rates remain excee<strong>di</strong>ngly high.Estimates of the incidence and prevalence of renal cell carcinoma in ItalyWe provided estimates of the number of incident and prevalent cases of kidney and RCC inItaly overall and in various regions in 2002 and gave projections for the years 2007 and 2012. In2002, there were about 8000 incident cases and 26,800 prevalent cases of kidney cancer in Italy.Of these, approximately 6800 and 22,750 were incident and prevalent cases of RCC,respectively. The most reliable estimate of incident kidney cancer cases in Italy over the period2007-2012 is likely to range between 7000 and 9000. Of these, between 6000 and 8000 areRCC cases. The best estimate of prevalence of kidney cancer is between 20,000 and 34,000cases and that of RCC between 17,000 and 29,000 cases. Incidence and prevalence of RCC arelikely to remain approximately stable between 2002 and 2007. Increased <strong>di</strong>agnostic attentiondue to widespread use of echography and other <strong>di</strong>agnostic techniques may, however, lead toearlier detection of kidney neoplasms and consequently to an apparent increase in the incidenceof RCC.Estimates of the incidence and prevalence of hepatocellular carcinoma inItalyUsing the same methodology adopted for RCC, we provided estimates of the number of incidentand prevalent cases for HCC in Italy overall and in various regions in 2002 and gave projectionsfor the years 2007 and 2012. In 2002, there were about 5800 incident cases and 4300 prevalentcases of HCC in Italy. The most reliable estimate of HCC incident cases in Italy in 2007 isbetween 5500 and 6000, and this figure is likely to decline to 5000-5500 in 2012. The bestestimate of prevalence is about 4000 cases in 2007, which is likely to decline to 3700 in 2012.Incidence and prevalence of HCC are likely to remain approximately stable between 2002 and2007 and slightly decrease in the subsequent quinquennia. These projections are, however,subject to large uncertainties because of the problems in <strong>di</strong>agnosis and death certification forthis neoplasm, particularly for the elderly.223ANNUAL REPORT <strong>2009</strong>
IRFMNOTHER PROJECTSStrategies and best practices for the reduction of injuriesSince 2006, our Department is involved in the Apollo project, a European project aiming atidentifying strategies and best practices for the reduction of injuries. Within this project, ourDepartment is coor<strong>di</strong>nator of the Workpackage 4 on the development and implementation ofrecommendations for the prevention of falls among elderly people in the EU.The majority of falls in elderly people are due to a combination of several interacting factors.Many stu<strong>di</strong>es have investigated the role several factors on the risk of falling. Thus we conducteda systematic review and a quantitative meta-analysis of risk factors for falls in communitydwellingelderly people, inclu<strong>di</strong>ng relevant stu<strong>di</strong>es published up to 2006. Fifty-nine stu<strong>di</strong>es wereincluded and 28 risk factors were analyzed, inclu<strong>di</strong>ng socio-demographic characteristics,mobility, sensory, psychological and me<strong>di</strong>cal factors, and me<strong>di</strong>cation use. The strongestassociations were found for history of falls, vertigo, gait problems, use of walking aids, and useof antiepileptics.Moreover, we investigated the amount of information on the participation rates reported fromstu<strong>di</strong>es investigating the effectiveness of selected intervention for the prevention of falls amongcommunity-dwelling elderly people. We identified 32 stu<strong>di</strong>es implementing interventions basedon an exercise program, an exercise program in combination with other measures, or other typesof interventions. Fourteen stu<strong>di</strong>es <strong>di</strong>d not report information on the refusal rate; most stu<strong>di</strong>esreporting the information had a refusal rate between 25 and 50%. We also conducted a survey toinvestigate the attitudes of elderly people towards selected intervention for the prevention offalls. The study was conducted in Italy, Poland, Greece, Hungary, and Slovenia, countries forwhich limited data is available on this issue. A total of 1497 subjects aged 65 to 89 years wereinterviewed to evaluate their beliefs and attitudes towards two evidence-based interventions, i.e.a social activity aimed at improving muscle strength and balance (such as exercise class ordancing), and a home safety assessment and mo<strong>di</strong>fication program. Among the respondentsabout 47% would accept to participate to a social activity, and about 38% would accept aprogram of home hazard assessment and mo<strong>di</strong>fication. However, we found marked <strong>di</strong>fferencesbetween countries in the acceptability of the two proposed interventions.Finally, we conducted a meta-analysis of stu<strong>di</strong>es for the prevention of falls in elderly people. Acomputerized search in several me<strong>di</strong>cal databases allowed to identify 52 published stu<strong>di</strong>es,inclu<strong>di</strong>ng 10 stu<strong>di</strong>es complying with the inclusion criteria (absence of comorbi<strong>di</strong>ty, noninstitutionalizedsubjects, previous history of falls). These stu<strong>di</strong>es included interventions basedon exercise only and multifactorial interventions, and showed a reduction in the risk of falling,with an overall estimate of 0.67 (95% CI: 0.52-0.85). Considering 5 stu<strong>di</strong>es based on physicalexercise, the overall estimate was 0.45 (95% CI: 0.28-0.71), while considering 5 stu<strong>di</strong>es basedon multifactorial interventions the estimate was 0.90 (95% CI: 0.82-1.00).Record-linkage for cohort analysesThe main aim of this project is to collect follow-up information to the end of 2008 on vitalstatus and, when needed, cause of death for each subject included in the case-control stu<strong>di</strong>es, inorder to obtain a prospective study from retrospectively collected data. During recent years, weincluded in a single large database the data of the case-control surveillance collected in thegreater Milan area during the last 25 years. We made uniform the information coming from<strong>di</strong>fferent generations of structured and validated questionnaires, and assigned a singleidentification number to each subject interviewed. In <strong>2009</strong>, we added further data for stu<strong>di</strong>es oncancers of the oral cavity, pharynx, stomach, pancreas and endometrium, that have beenrecently finalized. This added to the unique database of subjects about 1500 further cancer casesand 1500 controls, so that the total number of subjects now exceed 29,000. We organized thestrategy to obtain and manage information on vital status and death certificates of the subjectsincluded in our database, by contacting the competent institutional sources (Municipalities,224ANNUAL REPORT <strong>2009</strong>
IRFMNLocal Health Units, General Registry Offices) and through the use of an ad hoc developedsoftware.Laboratory of Epidemiology of Chronic DiseasesCASE-CONTROL STUDIESOrganization for data and biological sample collection for case-controlstu<strong>di</strong>esData collection of epidemiological data is going on and it includes: 1) interview and interviewermanagement and training activity for new interviewers; 2) contacts with hospital departmentand ethical committee for study approval and conduction; 3) check and co<strong>di</strong>fication of patientquestionnaires; 4) <strong>di</strong>agnosis and histological exam check; 5) organization and management ofbiological sample collection; 6) data input management.Ongoing case-control stu<strong>di</strong>es include: cancer of the oral cavity, pharynx, larynx, esophaguscar<strong>di</strong>as,biliary tract, colorectum, bladder, lymphomas, myelomas and sarcomas.The overall updated dataset include about: 1250 cases of cancers of oral cavity and pharynx,700 of the esophagus, 1100 of the stomach, 6500 of the colorectum, 600 of the liver, 120 of thebiliary tract, 600 of the pancreas, 850 of the larynx, 500 cutaneous malignant melanoma, 7000of the breast, 1000 of the cervix, 1000 of the endometrium, 200 of trophoblastic gestational<strong>di</strong>sease, 200 of the vulva, 2000 of the ovary, 1300 of the prostate, 700 of the bladder, 800 of thekidney and renal pelvis, 600 of the thyroid, 200 of Hodgkin <strong>di</strong>sease, 500 of non-Hodgkin<strong>di</strong>sease, 200 of sarcomas, 300 of myelomas and about 18,000 controls. Biological samplecollection, aimed to study genetic polymorphisms, includes cancers of the oral cavity, pharynx,larynx, bladder and colorectum.Coffee, black tea and gastric cancerTo provide further information on the association between coffee, tea and gastric cancer risk, wepooled data from 2 hospital-based case-control stu<strong>di</strong>es from northern Italy, on a total of 999cases with gastric cancer and 2,628 controls. As compared to non coffee drinkers, themultivariate OR was 0.94 for drinkers of 1 cup of coffee per day, 1.03 for 2, 1.07 for 3, and 1.24for 4 or more cups per day. No association was found with reference to duration of coffeeconsumption, nor to consumption of decaffeinated coffee. As compared to non tea drinkers, theOR was 0.89 for 2 or more cups of black tea per day. Our investigation provided convincingevidence that coffee and tea consumption are unlikely to be strongly associated to gastric cancerrisk.Physical activity and endometrial cancerIn the case-control study of endometrial cancer, we investigated the relation with physicalactivity at <strong>di</strong>fferent ages. Taking into account various potential confoun<strong>di</strong>ng factors, inclu<strong>di</strong>ngage, body mass index, <strong>di</strong>abetes, hormonal/reproductive factors and energy intake, the OR ofendometrial cancer in women at high level of occupational physical activity, as compared withthose at the lowest level, were 1.69 at 12 years of age, 1.33 between 15 and 19 years, 1.17between 30 and 39 years and 0.82 between 50 and 59 years. No significant trend in risk withlevel of occupational physical activity was found at any age. Similarly, no significantassociation was detected with recreational physical activity in <strong>di</strong>fferent periods of life, since theOR for the highest vs. lowest level of physical activity were 0.82 at 12 years of age, 0.78between 15 and 19 years, 1.12 between 30 and 39 years and 0.97 between 50 and 59 years.Therefore, our results ruled out a strong relation between physical activity and endometrialcancer.225ANNUAL REPORT <strong>2009</strong>
IRFMNCoffee, decaffeinated coffee, tea intake and risk of renal cell cancerThe relation between coffee, decaffeinated coffee and tea intake and RCC risk was analyzed inour case-control study on 767 cases with RCC and 1534 controls. Coffee intake (mostlyespresso and mocha) was not associated with RCC (OR = 1.02 in drinkers of 4 or morecups/day compared with drinkers of less than 1 cup/day). No relation was observed withdecaffeinated coffee and tea intake, the ORs being 1.38 and 0.78 for drinkers compared withnondrinkers respectively, although these two estimates were based on a low number of drinkers.This study, based on a large dataset, provided further evidence that coffee, decaffeinated coffeeand tea consumption is not related to RCC risk.Allium vegetables and the risk of acute myocar<strong>di</strong>al infarctionOnly two previous epidemiological stu<strong>di</strong>es considered the relation between <strong>di</strong>etary intake ofallium vegetables and car<strong>di</strong>ovascular <strong>di</strong>seases. To provide further information we analysed therelationship between onion and garlic intake and acute myocar<strong>di</strong>al infarction (AMI). We useddata from a case-control study of 760 patients with a first episode of non-fatal AMI and 682controls admitted to the same hospitals. Compared with nonusers, the ORs of AMI forsubsequent categories of onion intake were 0.90 (95% CI, 0.68-1.22) for
IRFMNLaboratory of Me<strong>di</strong>cal Informatics“A library for the Hospital of Man” projectThe project is based on a collaboration between the “Associazione Sguazzi Onlus” of Bergamo,the association ACIM of Man (Côte d'Ivoire – Ivory Coast), and the Sistema BibliotecarioBiome<strong>di</strong>co Lombardo (SBBL) of the Regione Lombar<strong>di</strong>a. It’s aim is to provide the Hospital ofMan (Côte d'Ivoire) with a modern and efficient me<strong>di</strong>cal (e)library where people can access tome<strong>di</strong>cal information (journal publications, grey literature, etc.) and use e-learning, <strong>di</strong>stancelearning and teleme<strong>di</strong>cine tools. The <strong>Mario</strong> <strong>Negri</strong> Institute is a partner of the project with theEuropean Space Agency (ESA), the Università of Bergamo, and the Ospedali Riuniti ofBergamo. During <strong>2009</strong>, the Laboratory of Me<strong>di</strong>cal Informatics has been involved in trainingcourses that were provided through e-learning and au<strong>di</strong>o/video conferences tools (more than 50people in Côte d'Ivoire have been trained remotely). The use of me<strong>di</strong>cal databases (such asPubMed-Medline) and the Internet tools to locate me<strong>di</strong>cal information on the Web were someof the issues covered in the lessons.The equipment for the video-conferences and the <strong>di</strong>stance learning sessions has been providedand programmed by the <strong>Mario</strong> <strong>Negri</strong> Institute.Maintenance of the CARDIO.CARE, ONCO.CARE, GASTRO.CARE,NEURO.CARE, PNEUMO.CARE, BPCO.CARE, PAIN.CARE andDERMA.CARE websitesThese indexes have been developed by the Laboratory of Me<strong>di</strong>cal Informatics in order tocollect, classify, evaluate, and describe the most useful me<strong>di</strong>cal information on the web, and toprovide Internet users with an easy means to surf the net. Several me<strong>di</strong>cal areas are covere<strong>di</strong>nclu<strong>di</strong>ng oncology (http://www.oncocare.it), neurology (http://www.neurocare.it),gastroenterology (http://www.gastrocare.it), car<strong>di</strong>ology (http://www.car<strong>di</strong>ocare.it),pulmonology (http://www.pneumocare.it, http://www.bpcocare.it ), the pain care andmanagement (http://www.paincare.it), and dermatology (http://www.dermacare.it). The projectis in collaboration with intramural departments (Department of Oncology, Laboratory ofNeurological Disorders and Department of Car<strong>di</strong>ovascular Research, Laboratory of GeneralPractice Research, Laboratory of Translational and Outcome Research in Oncology) andextramural research groups (Italian Group for Epidemiologic Research in Dermatology,GISED). During <strong>2009</strong>, information about the use of web 2.0 tools and technologies (such aspodcast, RSS feeds, blogs, webcasts, and webinars) by the indexed websites has been collected.RSS feeds and podcasting services have been activated on the CARE websites in order to allowthe users to access to the correspon<strong>di</strong>ng applications available on the classified websites.Stu<strong>di</strong>es on the typology of the web 2.0 applications in me<strong>di</strong>cineThe Laboratory of Me<strong>di</strong>cal Informatics is involved in stu<strong>di</strong>es and surveys which aim is todescribe the typology of the web 2.0 applications and tools (inclu<strong>di</strong>ng social networks, podcasts,feed RSS, blogs, and wikis) in me<strong>di</strong>cine available on the net, and how these are perceived bythe me<strong>di</strong>cal community.Internet as a research and formative tool on the chronic pain in cancerpatientThis research project was born in the framework of the project "Pain in the patient with cancer",in collaboration with the Laboratory of Me<strong>di</strong>cal Research and Consumer Involvement and theLaboratory of Translational and Outcome Research in Oncology. Its aim is to make availablefor doctors, patients and families correct information about therapies for cancer pain and toproduce greater tests on the effectiveness of therapies based on the use of analgesic drugs. This227ANNUAL REPORT <strong>2009</strong>
IRFMNproject is articulated in two main activities:Paincare, set-up a catalogue of selected web pages de<strong>di</strong>cated to the cancer pain and relativeperio<strong>di</strong>cal up-to-date, http://www.paincare.it;Adaptation of the methods and instruments of Evidence Based Me<strong>di</strong>cine to the resourcesavailable on the Internet about chronic pain in patients with cancer. This is done through aspecific questionnaire. We are also considering the opportunity to set up a new Italian cancerpain website.Training activitiesIn <strong>2009</strong>, the Laboratory of Me<strong>di</strong>cal Informatics continued its training activity on issues relatedto the use of the Internet in me<strong>di</strong>cine, and extended it to the use of the recent web 2.0technologies and tools in the me<strong>di</strong>cine area. The members of the laboratory staff activated (orattended as invited teachers) a number of training courses, workshops, and master courses.Onsite CME courses for the Italian physicians have also been organized using thetraining/educational facilities and equipment available at the <strong>Mario</strong> <strong>Negri</strong> Institute.228ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF PUBLIC HEALTHSTAFFHead DepartmentMaurizio BONATI, MD."Angelo & Angela Valenti" Centre for Health Economics (CESAV)Head of LaboratoryLivio GARATTINI, Econ.D.Laboratory of Clinical EpidemiologyHead of LaboratoryGuido BERTOLINI, MD.Clinical Knowledge Engineering UnitHead UnitDavide LUCIANI, MD.Computer Methods and Programs for Clinical Research UnitHead UnitAbramo ANGHILERI, IT.Laboratory for Mother and Child HealthHead LaboratoryMaurizio BONATI, MD.229ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAMaurizio Bonati has a Me<strong>di</strong>cal School degree at the University of Milan.Areas of interest: Monitoring and epidemiological evaluation of drug utilisation and effects of drugs andvaccines in motherhood and childhood. Research methodology in general hospital and pae<strong>di</strong>atriccommunity practice. Transfer of information to the community. Epidemiology of pae<strong>di</strong>atric and perinatalcare.Past and present roles both at the <strong>Mario</strong> <strong>Negri</strong> Institute and in other institutions: 1973-77 Research Fellowat the IRFMN, within the Neurochemistry Lab.; 1977-85 Research Assistant at the IRFMN, within theClinical Pharmacology Lab.; 1986-93 Chief of the Perinatal Clinical Pharmacology Unit at the IRFMN;Advisor to WHO for the Drug Utilization Research Group (pregnancy, pae<strong>di</strong>atrics and breastfee<strong>di</strong>ng);1987-92 coor<strong>di</strong>nator of the International Cooperative Study of Drug Use in Pregnancy, under the auspicesof WHO and the support of EEC; 1992-93 co-e<strong>di</strong>tor of The Kangaroo; 2000-05 coor<strong>di</strong>nator of theEuropean Cooperative Study: “Development of the European register of clinical trials on me<strong>di</strong>cines forchildren” (DEC-net), under the 5 th Framework Programme’s Quality of life and Management of LivingResources; since 1989 he has been <strong>di</strong>rector of the Centre for Drug Information; since 1993 head of theLab. for Mother and Child Health; since 1997 teacher for the Lombardy region’s professional trainingcourses; since 2000 teacher for the Lombardy region’s professional training courses; since 2002 E<strong>di</strong>tor ofthe Ricerca & Pratica scientific journal; since 2003 professor of the School of Specialisation inPae<strong>di</strong>atrics - University of Milan Bicocca; teacher at the annual European course “Evaluation ofMe<strong>di</strong>cinal Products in Children” (promoted by ESDPPP and Eu<strong>di</strong>pharm); from May 2008 Head ofDepartment Public Health"<strong>Mario</strong> <strong>Negri</strong>" Institute for Pharmacology Research.Selected publications• Bonati M, Campi R. What Can We Do to Improve Child Health in Southern Italy? PLos Me<strong>di</strong>cine 2005;2(9):e250.• Santoro E, Rossi V, Pandolfini C, Bonati M. DEC-net: the development of the European Register of Clinical Trials onMe<strong>di</strong>cines for Children. Clinical Trials 2006;3:366-375.• Clavenna A, Rossi E, De Rosa M, Bonati M. Use of Psychotropic Me<strong>di</strong>cations in Italian Children and adolescents. Eur JPe<strong>di</strong>atr 2007;166:339-47.• Maschi S, Clavenna A, Schiavetti B, Campi R, Bernat M, Bonati M. Neonatal outcome following pregnancy exposure toantidepressants: a prospective controlled cohort study. BJOG 2008;115:283-289.• Usala T, Clavenna A, Zuddas A, Bonati M. Randomised controlled trials of Selective Serotonin Reuptake Inhibitors intreating depression in children and adolescents: a systematic review and meta-analysis. EuropeanNeuropsychopharmacology 2008;18:62-73.• Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfee<strong>di</strong>ng: a review of the evidence. Pe<strong>di</strong>atrics<strong>2009</strong>;124:e547-e556.Livio Garattini: got his degree in Economics in March 1983 at the Bocconi University in Milan.Educational activities: “King’s Fund College”, London: courses of health care management; “Centre forHealth Economics”, York: review of publications on the English NHS; “Ecole Nationale de la SantéPublique”, Rennes: courses of health policy.Areas of interest: Health Economics and Health Policy Analysis.At present he is the Director of CESAV (Centre of Health Economics A. e A. Valenti - M. <strong>Negri</strong>Institute); 1981-1983: researcher at M. <strong>Negri</strong> Institute; 1983-1984: clerk at Banca Commerciale Italianain Milan; 1984- 1985: junior consultant at “Sogess srl” in Milan; 1985-1990: researcher at BocconiUniversity in Milan.Selected publications:• Cornago D, Li Bassi L, De Compadri P, Garattini L. Pharmacoeconomic stu<strong>di</strong>es in Italy: a critical review of theliterature. The European Journal of Health Economics 2007;8(2):89-95.• Garattini L, Cornago D, De Compadri P. Pricing and reimbursement of in-patent drugs in seven European countries: Acomparative analysis. Health Policy 2007;82:330-339.• Garattini L, Motterlini N, Cornago D. Prices and <strong>di</strong>stribution margins of in-patent drugs in pharmacy: A comparison inseven European countries. Health Policy 2008;85(3):305-313.• Garattini L, Casadei G. Health technology assessment: for whom the bell tolls? The European Journal of HealthEconomics 2008;9(4):311-312.• Garattini L, Casadei G, Freemantle N. Continuing me<strong>di</strong>cal education fun<strong>di</strong>ng and management in Europe: room forimprovement? (E<strong>di</strong>torial) JME <strong>2009</strong>;12(1):56-59.• Garattini L, Gritti S, De Compadri P, Casadei G. Continuing Me<strong>di</strong>cal Education in six European countries: A230ANNUAL REPORT <strong>2009</strong>
IRFMNcomparative analysis. Health Policy (online from November <strong>2009</strong>).Guido Bertolini got his Me<strong>di</strong>cal degree in 1989 at the University of Bologna, and the specialization inPharmacological Research in 1993 at the “<strong>Mario</strong> <strong>Negri</strong>” Institute and in Gastroenterology in 1994 at theUniversity of Pavia.He founded and chaired from 1997 to 2000 the School of Clinical Methodology and Quality of CareImprovement at the Ospedali Riuniti <strong>di</strong> Bergamo and the <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> <strong>Mario</strong><strong>Negri</strong>. From 1999 to 2003 he has been contract professor at the post-doctoral schools in Anaesthesia andIntensive Care, University of Brescia and Milano; from 2002 to 2005 he has been contract professor ofEducational Science at the Faculty of Lettere e Filosofia, University of Bergamo.Current research interests: Clinical Research Methodology, Continuous Quality of Care Assessment andImprovement, Health services research and outcome, Me<strong>di</strong>cal decision making, Me<strong>di</strong>cal Education.These interests are mainly developed within the fields of Intensive Care Me<strong>di</strong>cine and Rare Diseases.Since 1997 he chairs the GiViTI Coor<strong>di</strong>nating Center for research in intensive care me<strong>di</strong>cine. He has beenHead of the Unit of Epidemiology and Education for Clinical Practice at the “<strong>Mario</strong> <strong>Negri</strong>” Institute andsince 2001 he is the Head of the Laboratory of Clinical Epidemiology. From 2001 to 2005 he has beenVice-chairman of the Research Group on Cost-effectiveness, Section on Health Services Research andOutcomes – European Society of Intensive Care Me<strong>di</strong>cine and, from 2001 to 2005, he has been Presidentof the Scientific Committee of the “Ospedale maggiore” in Crema.Selected publications• Simini B, Bertolini G. Should same anaesthetist do preoperative anaesthetic visit and give subsequent anaeshetic?Questionnaire survey of anaesthetists. BMJ 2003;327:79-80.• Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibo<strong>di</strong>es, and the risk ofthrombosis in the antiphospholipid syndrome. Blood 2003;102:2717-2723.• Vanoli M, Daina E, Salvarani C, Sabba<strong>di</strong>ni MG, Rossi C, Bacchiani G, Schieppati A, Bal<strong>di</strong>ssera E, Bertolini G.Takayasu's arteritis: A study of 104 Italian patients. Arthritis Rheum 2005;53:100-107.• Bertolini G, Rossi C, Anghileri A, Livigni S, Ad<strong>di</strong>s A, Poole D. Use of drotrecogin alfa (activated) in Italian intensivecare units: the results of a nationwide survey. Intensive Care Med 2007;33:426-434.• Malacarne P, Langer M, Nascimben E, Moro ML, Giu<strong>di</strong>ci D, Lampati L, Bertolini G, GiViTI. Buil<strong>di</strong>ng a continuousmulticenter infection surveillance system in the intensive care unit: fin<strong>di</strong>ngs from the initial data set of 9,493 patientsfrom 71 Italian intensive care units. Crit Care Med 2008;36:1105-1113.• Poole D, Bertolini G, Garattini S. Errors in the approval process and post-marketing evaluation of drotrecogin alfa(activated) for the treatment of severe sepsis. Lancet Infect Dis <strong>2009</strong>;9:67-72.Davide Luciani got his Me<strong>di</strong>cal Degree at the University of Bologna in 1995, and the post-doctoralcertificate in "Tropical Me<strong>di</strong>cine and Hygiene" at the University of Liverpool in 1997. In 2001, he spentone year at the Department of Statistical Science (University College London). Bayesian probabilisticapplications, decision theory and the graphical approach to pathophysiological modelling represent hismain interests. Within his research activity, these skills are meant as the main methodologicalingre<strong>di</strong>ents in the formalization of clinical reasoning, in order to improve its effectiveness and to exploitits educational value.Since 2005 he is responsible of the Unit of Clinical Knowledge Engineering.Selected publications• Luciani D, Marchesi M, Bertolini G. The role of Bayesian Network in the <strong>di</strong>agnosis of pulmunary embolism. J ThrombHaemost 2003;1:698-707.• Galli M, Luciani D, Bertolini G, Barbui T. Anti-beta 2-glycoprotein I, antiprothrombin antibo<strong>di</strong>es, and the risk ofthrombosis in the antiphospholipid syndrome. Blood 2003;102 (8):2717-23.• Luciani D, Cavuto S, Antiga L, Miniati M, Monti S, Pistolesi M, Bertolini G. Bayes pulmonary embolism assisted<strong>di</strong>agnosis: a new expert system for clinical use. Em Med J 2007;24:157-164.• M.Cesana, R.Cerutti, E.Grossi, E.Fagiuoli, M.Stabilini, F.Stella, D Luciani. Bayesian Data Mining Techniques: TheEvidence Provided by Signals Detected in Single-Company Spontaneous <strong>Report</strong>s Databases. Drug Information Journal2007;41:11-21.• Latronico N, Bertolini G, Guarneri B, Botteri M, Peli E, Andreoletti S, Bera P, Luciani D, Nardella A, Vittorielli E,Simini B, Can<strong>di</strong>ani A Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italianmulti-centre CRIMYNE study. Crit Care 2007;11(1):R11.• Bertolini G, Luciani D, Biolo G Immunonutrition in septic patients: A philosophical view of the current situation. ClinNutr 2007;26:25-29.Abramo Anghileri got his high-school certificate at the ITIS P. Paleocapa of Bergamo in 1997 andattended several courses in information technology (IT) applied to health care. Since 2001 he coor<strong>di</strong>natesthe IT activities of the Laboratory of Clinical Epidemiology at the <strong>Mario</strong> <strong>Negri</strong> Institute forPharmacological Research. His main area of interest is informatics applied to clinical research. Since231ANNUAL REPORT <strong>2009</strong>
IRFMN<strong>2009</strong>, he is the head of the Unit of Computer Methods and Programs for Clinical Research of theLaboratory of Clinical Epidemiology• Boffelli S, Rossi C, Anghileri A, Giar<strong>di</strong>no M, Carnevale L, Messina M, Neri M, Langer M, Bertolini G. Continuousquality improvement in intensive care me<strong>di</strong>cine. The GiViTI Margherita project - <strong>Report</strong> 2005. Minerva Anestesiol 2006;72: 419-432.• Bertolini G, Rossi C, Anghileri A, Livigni S, Ad<strong>di</strong>s A, Poole D. Response to the letter by Williams et al. Intensive CareMed 2007; 33(8): 1490-1• Bertolini G, Rossi C, Anghileri A, Livigni S, Ad<strong>di</strong>s A, Poole D. Use of drotrecogin alfa (activated) in Italian intensivecare units: the results of a nationwide survey. Intensive Care Med 2007; 33(3): 426-34• Di Bartolomeo S, Valent F, Rossi C, Beltrame F, Anghileri A, Barbone F. Geographical <strong>di</strong>fferences in mortality ofseverely injured patients in Italy. Eur J Epidemiol 2008• Poole D, Rossi C, Anghileri A, Giar<strong>di</strong>no M, Latronico N, Radrizzani D, Langer M, Bertolini G. External validation ofthe simplified acute physiology score (SAPS3) in a cohort of 28.357 patients from 147 Italian intensive care units.Intensive Care Me<strong>di</strong>cine (<strong>2009</strong>)35:1916-1924ACTIVITIESThe main aim of the Public Health Department is to understand which factors affect the healthof in<strong>di</strong>viduals or entire populations and to define effective interventions for respon<strong>di</strong>ng to theirhealth needs. Special emphasis is therefore placed on prevention, so that the risks of contractingillness are lowered, and on the <strong>di</strong>ssemination of independent, evidence-based information.The department’s effort cannot <strong>di</strong>sregard the National Health System, however, which mustguarantee access to, and quality of, care that is based on principles of equity and appropriatenessand must guarantee it especially to the more vulnerable patient groups. It is in this context thatthe Public Health Department carries out its activities.In ad<strong>di</strong>tion to its formal research activity, the department participates in, and organises,initiatives involving information <strong>di</strong>ssemination, training, and debate aimed at healthcareoperators and social care workers, but also at the general population. These activities are alsosupported by the publication of the department’s two journals: Ricerca&Pratica and Quaderni<strong>di</strong> Farmaco Economia.During <strong>2009</strong>, 34 people worked in the Department"A. and A. Valenti" Centre for Health Economics (CESAV)The "Angelo e Angela Valenti" Centre for Health Economics (CESAV) was established in 1992at the "M. <strong>Negri</strong> Institute" and based at Villa Camozzi- Ranica (Bergamo)-Italy. CESAV isprimarily a research centre, but also does educational work. The centre is involved in healtheconomics and health policy research. The main areas of research are: Economic Evaluation ofHealth Care Programs (i.e. assessment of costs and benefits of alternative health care treatmentsand services) and Comparative Health Policy Analysis (i.e. study of domestic and foreign healthcare systems, in particular aimed at identifying possible innovations for European countries).The general aim of the Laboratory of Clinical Epidemiology is to contribute to the improvementof health care in <strong>di</strong>fferent me<strong>di</strong>cal fields. The gui<strong>di</strong>ng principles are mainly two: to helpphysicians use the available knowledge and resources at their best; to play a role in the growthof useful knowledge for clinical practice. The Laboratory operates particularly in the field ofIntensive Care Me<strong>di</strong>cine and Rare Diseases.Within the Laboratory, the Unit of Clinical Knowledge Engineering aims to bring the value ofclinical reasoning out, through the implementation of probabilistic models for its formalization,thus favouring the evaluation and the continuous improvement of complex clinical activities.232ANNUAL REPORT <strong>2009</strong>
IRFMNLaboratory of Clinical EpidemiologyThe general aim of the Laboratory of Clinical Epidemiology is to contribute to the improvementof health care in <strong>di</strong>fferent me<strong>di</strong>cal fields. The gui<strong>di</strong>ng principles are mainly two: to helpphysicians in using the available knowledge and resources at their best, and to contribute to thegrowth of applied knowledge for clinical practice. The Laboratory operates in the field ofIntensive Care Me<strong>di</strong>cine and Rare Diseases.Within the Laboratory, the Unit of Clinical Knowledge Engineering aims to bring the value ofclinical reasoning out, through the implementation of probabilistic models for its formalization,thus favouring the evaluation and the continuous improvement of complex clinical activities.The main area of activity of the Unit of Computer Methods and Programs for Clinical Researchis the development of an electronic health record for the ICU that would be able to conjugate theneeds of clinical practice with those of clinical research, with the aim of closing the gapbetween the two.Laboratory for Mother and Child HealthThe main objective of the Laboratory for Mother and Child Health is to ensure a better motherand child well-being by undertaking inter<strong>di</strong>sciplinary and collaborative work in the field.Four broad areas, or spheres, of research have been selected:- monitoring and epidemiological evaluation of utilisation and effects of drugs and vaccines;- research methodology in general hospital and pae<strong>di</strong>atric community practice;- public health determinants of children’s well-being;- transfer of health information to the community.Special attention is given to activities involving countries in the north and south of the world.In ad<strong>di</strong>tion to the formal research activities, the Laboratory promotes initiatives in the publichealth field, in particular those involving mother and child health care.The initiatives involve the participation in, and the organisation of, educational, training, an<strong>di</strong>nformation-<strong>di</strong>ssemination activities.The critical and active transfer of scientific knowledge is a continuous, daily stimulus to theLaboratory’s activity.NATIONAL COLLABORATIONS"A. and A. Valenti" Centre for Health Economics (CESAV)Public and private institutions, other health care organizations (Ministry of Health, Regional andLocal Health Authorities, Hospital Trusts).Laboratory of Clinical Epidemiology−−−−−−<strong>Istituto</strong> Me<strong>di</strong>terraneo per i Trapianti e Terapie ad Alta Specializzazione, PalermoOspedale A. Manzoni, U.O. Anestesia e Rianimazione 1, Lecco.Ospedale Regionale S. Maria dei Battuti Cà Foncello, Dipartimento <strong>di</strong> Neurologia,TrevisoOspedale San Giovanni Bosco, Servizio Anestesia e Rianimazione, TorinoUniversità degli Stu<strong>di</strong> <strong>di</strong> Brescia, Dipartimento <strong>di</strong> Specialità Chirurgiche, ScienzeRa<strong>di</strong>ologiche e Me<strong>di</strong>co Forensi, Cattedra <strong>di</strong> Anestesia.Università <strong>di</strong> Firenze, Facoltà <strong>di</strong> Me<strong>di</strong>cina e Chirurgia,Cattedra <strong>di</strong> Fisica e InformaticaMe<strong>di</strong>ca.233ANNUAL REPORT <strong>2009</strong>
IRFMN− Università <strong>di</strong> Milano Bicocca, Dipartimento <strong>di</strong> Informatica Sistemistica eComunicazione.− Me<strong>di</strong>cina Interna e Geriatria, Università Cattolica del Sacro Cuore, RomaLaboratory for Mother and Child Health− Centre for Child Health, (CSB)− Cultural Pae<strong>di</strong>atric Association, (ACP)− Federfarma Lombar<strong>di</strong>a− Hospital of Bergamo “Ospedali Riuniti”, Poison Control Centre, Unit ClinicalToxicology− Italian Drug Agency, (AIFA)− Italian Global Health Watch (OISG)− Italian National Institute of Health (ISS)− Italian Society of Preparers Pharmacists (SIFAP)− Italian Society of Clinical Pharmacy (SIFO)− Il Pensiero Scientifico E<strong>di</strong>tore− Lombardy Region, Ministry of Health− Operating unity of Neuropsychiatry of the childhood and of the adolescence,Foundation “Policlinico <strong>di</strong> Milano”, (UONPIA)− University of Cagliari, Department of Neuroscience, Clinic of Child and AdolescentNeuropsychiatry− University of Milan-Bicocca, Faculty Me<strong>di</strong>cine, Pae<strong>di</strong>atric ClinicINTERNATIONAL COLLABORATIONS"A. and A. Valenti" Centre for Health Economics (CESAV)− CES (Collège des Economistes de la Santé) of Paris− Corvinus University of Budapest− Global Fund of Geneva− WidO of Bonn− Servicio Canario de la Salud, S/C de Tenerife− University of Birmingham− University of Hannover− University of York− University Pompeu Fabra of Barcelona− University Erasmus of RotterdamLaboratory of Clinical Epidemiology−−−−−−−Centre for Intensive Care Me<strong>di</strong>cines, Bloomsbury Institute, London, UKClinic of Anesthesiology and Intensive Therapy, Jena, GermanyDepartment of Anesthesiology and Intensive Cares, University of Toronto, CanadaDepartment of Anesthesiology and Intensive Cares, University of Warsaw, PolandDepartment of Intensive Care, Hospital Generale <strong>di</strong> Novo Mesto, SloveniaDepartment of Pneumologia and Intensive Cares, Hospital Generale <strong>di</strong> Nicosia, CyprusIntensive Me<strong>di</strong>cine, Regional Hospital of Lugano, Switzerland234ANNUAL REPORT <strong>2009</strong>
IRFMN−−−−Intensive Me<strong>di</strong>cine, Regional Hospital Beata Vergine, Mendrisio - Ticino, SwitzerlandInstitute of Anesthesia and Intensive Cares, Semmelweis University, Budapest,HungaryLaboratory of Experimental Physiopathology, Academic Unity of Sciences of theHealth, University of the Stu<strong>di</strong>es Extremo Sul Catarinense, Criciúma, SC, BrasilMachine Intelligence Group, University <strong>di</strong> Aalborg, DenmarkLaboratory for Mother and Child Health− Centre for Tropical Diseases (CECOMET), Ecuador− Clínica Infantil Colsubsi<strong>di</strong>o, Bogotà, Colombia− European Me<strong>di</strong>cines Agency (EMA)− European Society for Developmental, Perinatal and Pae<strong>di</strong>atric Pharmacology.(ESDPPP)− European Union (EU)− Hospital Robert Debré, Paris, France− International Society of Drug Bulletins (ISDB)− World Health Organization (WHO)− University of Nottingham, Derbyshire Children’s Hospital, Derby, United KingdomEDITORIAL BOARD MEMBERSHIP"A. and A. Valenti" Centre for Health Economics (CESAV)INTERNATIONAL:Acta Bio Me<strong>di</strong>ca; Applied Health Economics and Health Policy; Biome<strong>di</strong>cal Statistics andClinical Epidemiology; BMC-Health Services Research; Health Policy; Journal of Me<strong>di</strong>calEconomics; The European Journal of Health Economics.NATIONAL:FarmacoEconomia News; Farmeconomia e Percorsi Terapeutici; L'Internista;PharmacoEconomics Italian Research Articles; Quaderni <strong>di</strong> FarmacoEconomia.Laboratory of Clinical EpidemiologyINTERNATIONAL:Intensive Care Me<strong>di</strong>cineNATIONAL:Ricerca & Pratica;Dedalo. Gestire i sistemi complessi in sanità.Laboratory for Mother and Child HealthINTERNATIONAL:European Journal Clinical Pharmacology; Journal of Clinical Pharmacology & Pharmacoepidemiology;Pae<strong>di</strong>atric & Perinatal Drug Therapy; Saludarte.NATIONAL:Dialogo sui Farmaci; Disturbi d’Attenzione e Iperattività; Quaderni ACP; Quaderni <strong>di</strong>Farmacoeconomia; Ricerca & Pratica.235ANNUAL REPORT <strong>2009</strong>
IRFMNPEER REVIEW ACTIVITIES"A. and A. Valenti" Centre for Health Economics (CESAV)Applied Health Economics and Health Policy; BMC-Health Services Research; Health Policy;PharmacoEconomics; The European Journal of Health Economics.Laboratory of Clinical EpidemiologyINTERNATIONAL:British Me<strong>di</strong>cal Journal; Intensive Care Me<strong>di</strong>cine; Critical Care Me<strong>di</strong>cine; American Journal ofrespiratory and Critical Care Me<strong>di</strong>cine.NATIONAL:Ricerca & PraticaLaboratory for Mother and Child HealthINTERNATIONAL:Archives of Diseases Childhood; BMC Health Services Research; BMC Psychiatry; BMCPublic Health; British Me<strong>di</strong>cal Journal; European Child & Adolescent Psychiatry; EuropeanJournal of Clinical Pharmacology; Human Psychopharmacology; Clinical and Experimental;Journal of Child and Adolescent Psycopharmacology; Pharmacoepidemiology and Drug Safety;Prescrire; Trials Journal.NATIONAL:Assistenza Infermieristica e Ricerca; Dialogo sui Farmaci; Giornale Italiano <strong>di</strong> FarmaciaClinica; Me<strong>di</strong>co e Bambino; Quaderni ACP.NATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIP"A. and A. Valenti" Centre for Health Economics (CESAV)− Comitato <strong>di</strong> Bioetica, Provincia Autonoma <strong>di</strong> TrentoLaboratory of Clinical Epidemiology− Ethical committee A.O. “Bolognini” in Seriate (Bergamo)− National Health Plan Research Commission, Trent Autonomous Province− Scientific Council of the Health and Illness Inter<strong>di</strong>sciplinary Research CentreLaboratory for Mother and Child Health− Ethical committee A.O. "Ospedale Maggiore" of Crema− ADHD Scientific committee, Superior Institute of Health (ISS)− Technical-scientific Commission for the planning and verification ofvaccinations, Lombardy Region− Technical Commission for the management, update, and elaboration of theRegional Therapeutic Formulary, Valle d'Aosta Autonomous Region− Breastfee<strong>di</strong>ng Promotion Work Group, Lombardy Region236ANNUAL REPORT <strong>2009</strong>
IRFMN− Expert Group, EMA− Scientific Advisory Board (PRIOMEDCHILD)EVENT ORGANIZATION"A. and A. Valenti" Centre for Health Economics (CESAV)Congress: Convegno Nazionale <strong>di</strong> Farmacoeconomia: “Economia del farmaco: fra soluzionitecniche e decisioni politiche”, June 9-10, Ranica (BG)Congress: Convegno Regionale <strong>di</strong> Farmacoeconomia: “Politiche vaccinali regionali: esperienzea confronto”, October 6, Milan.Laboratory of Clinical EpidemiologyCongress, GiViTI <strong>Annual</strong> Meeting, October 28-30, Pesaro.Workshop, Meeting Compact, June 15, Milan.Laboratory for Mother and Child HealthSeminary “Children’s me<strong>di</strong>cines: a global problem”. 11 November, Milan.Meeting of the ADHD referral centres: “ADHD: registro e stateìo dell'arte in Lombar<strong>di</strong>a” 20March, Milan.CONFERENCE AND WORKSHOP CONTRIBUTIONS"A. and A. Valenti" Centre for Health Economics (CESAV)MarchCongress: “HIV Summit Italia <strong>2009</strong>-Diagnosi precoce, qualità della vita”. “Prevenzione eaccesso alle cure nell’era del federalismo”; Rome.AugustWorkshop: “Depression workgroup” (expert panel); Milan.OctoberCongress: “La farmacovigilanza in pe<strong>di</strong>atria” (round table); Milan.NovemberCongress: “La valutazione economica delle nuove tecnologie in sanità- Modelli eapplicazioni”. “Lo stato dell’arte dell’HTA in Italia tra Stato e Regioni”; Verona.DecemberCongress: “Respiratory Advisory Board” (tavola rotonda); London.237ANNUAL REPORT <strong>2009</strong>
IRFMNCourse: “Approfon<strong>di</strong>menti in tema <strong>di</strong> farmacoeconomia e HTA”. “Impiego dei costi in<strong>di</strong>rettinelle valutazioni economiche”. “Evoluzione dell’organizzazione del SSN e degli SSR”.“Analisi della gestione della spesa farmaceutica ospedaliera regionale”; Rome.Laboratory of Clinical EpidemiologyFebruaryCongress, Trauma e Subintensive, BolognaCongress, "Riusciremo a morire in pace?", MilanoCongress, Emorragia intracerebrale (ICH): quale paziente si giova <strong>di</strong> un trattamento intensivoin ambiente neurochirurgico? TorinoCourse, Statistica <strong>di</strong> Base, TorinoMarchCongress, Fine Vita, PadovaCourse, Statistica <strong>di</strong> Base, TorinoCourse, Statistica <strong>di</strong> Base, TorinoCourse, Excel e MargheritaDue: applicazione pratica, TorinoCongress, GiViTI Bergamo, Zingogna (BG)Congress, La sorveglianza delle infezioni in TI, ZingoniaAprilCourse, Statistica <strong>di</strong> Base, TorinoCongress, Le infezioni in TI: Presentazione dei dati regionali del gruppo GiViTI, BolognaCourse, Statistica <strong>di</strong> Base, TorinoCourse, Statistica <strong>di</strong> Base, TorinoCourse, Margherita Due (Course, avanzato), TorinoMayCongress, Analgesia, anestesia, terapia intensiva in ostetricia, TorinoWorkshop, Perfezionamento e aggiornamento in me<strong>di</strong>cina intensiva , MendrisioCourse, Statistica <strong>di</strong> Base, TorinoCongress, Appropriatezza dei ricoveri in terapia intensiva, TorinoJuneCongress, Valutazione della qualità della Assistenza sulla base degli in<strong>di</strong>catori <strong>di</strong> gravità delpaziente, AvezzanoSeptemberCongress, ESPEN Congress, FirenzeCongress, Sepsi nel trauma - Trauma Update, RomaCourse, MargheritaTre: stato dell'arte e pianificazione dei lavori, IvreaOctoberCongress, Incontri GiViTI-Piemonte, TorinoCourse, Migliorare la compilazione <strong>di</strong> Margherita Due ed imparare a leggere il report, TorinoCourse, Migliorare la compilazione <strong>di</strong> Margherita Due ed imparare a leggere il report, TorinoWorkshop, Accademia della cura, Rho (MI)Congress, Meeting GiViTI, PesaroNovemberCongress, Trauma Update, CesenaCourse, Margherita Tre: presentazione dei nuovi moduli, TorinoDecemberWorkshop, PNS: Euronetwork Sindromi Paraneoplastiche, TrevisoCongress, Sorveglianza delle infezioni in ti con margherita due: Presentazione dei dati 2007,Torino238ANNUAL REPORT <strong>2009</strong>
IRFMNLaboratory for Mother and Child HealthJanuaryCourse. Università degli Stu<strong>di</strong> <strong>di</strong> Milano, Facoltà <strong>di</strong> Farmacia; Milan.Congress: “Scegliere per la propria salute prima dei 18 anni: troppo giovane per <strong>di</strong>re la mia”.Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, U.O.N.P.I.A. (Childand Adolescent, Neuropsychiatry Unit); Milan.II ACP Regional Congress: “Etica della responsabilità in pe<strong>di</strong>atria”. Pe<strong>di</strong>atricians’ CultiralAssociation, Campania Region, CEINGE biotecnologie avanzate; Naples.FebruaryXVIII Tabiano Congress: “A volte ritornano”. Pe<strong>di</strong>atricians’ Cultiral Association (ACP);Tabiano (PR).MarchCourse: “Migrazione e salute mentale dall’età evolutiva all’età adulta: un progetto perMilano”. Milan Province, Lombardy Region, Municipality of Milan, Asl of Milan, MaggiorePoliclinico Mangiagalli e Regina Elena Hospital; Milan.Congress: “Autismo e sindromi correlate: la realtà dei servizi e della ricerca in Italia”. ISS(<strong>Istituto</strong> Superiore <strong>di</strong> Sanità), ANGSA (Autismo Italia, Società Italiana <strong>di</strong> Pe<strong>di</strong>atria,Federazione Italiana Me<strong>di</strong>ci Pe<strong>di</strong>atri); Rome.Meeting of the ADHD Register’s Referral Centres. ISS (<strong>Istituto</strong> Superiore <strong>di</strong> Sanità); Rome.III <strong>Annual</strong> Seminary of the Corporate Therapeutic Commission: “L’uso dei farmaci dalla partedei bambini”. Azienda Provinciale per i servizi Sanitari, Provincia Autonoma <strong>di</strong> Trento; Trent.Congress: “Incontro su farmaci e neonato. Luci, ombre e ... prospettive”. SIN (Società Italiana<strong>di</strong> Neonatologia); Rome.Meeting: “Artemisia and fight against malaria”. ICEI (Ist. Cooperazione EconomicaInternazionale); Rome.AprilMeeting: ENBe Study (Efficacia del Beclometasone versus placebo nella profilassi delwheezing virale in età prescolare). Meeting between local coor<strong>di</strong>nators and the ResearchMonitoring Committee; Rome.Round Table: il conflitto <strong>di</strong> interessi e il ruolo dell’Università e della ricerca nello sviluppo deifarmaci per le malattie <strong>di</strong>menticate. C.S.I. (Centro Salute Internazionale) Università <strong>di</strong>Bologna, Gruppo Prometeo; Bologna.MayMeeting: Uso e abuso degli psicofarmaci nella ricerca e nell’assistenza ai minori e agli adulti.Trattamenti psicofarmacologici in gravidanza. ADHD: registro e stato dell’arte. Nuovefrontiere psicofarmacologiche nell’infanzia nell’adolescenza e nell’adulto dalle sinapsi allaterapia integrata. Farmaci e allattamento cosa chiedono le madri. Progetto formativo/Eventoresidenziale “Nuove frontiere psicofarmacologiche nell’Infanzia nell’adolescenza enell’adulto”. Regione Piemonte ASL TO5; Moncaglieri (TO).Course: pharmacovigilance SEFAP (Servizio <strong>di</strong> Epidemiologia e Farmacologia Preventiva);Milan.26° National Congress S.I.O.P. (Società Italiana <strong>di</strong> Oftalmologia Pe<strong>di</strong>atrica); Milan.JuneCongress: “GENITORI PIU’: Stato dell’Arte. Un rilancio per il futuro? Genitoripiù, Ministerodel Lavoro della Salute e delle Politiche Sociali, Regione Veneto, Azienda ULSS 20 Verona;Verona12th ESDPPP Biannual Congress. European Society for Developmental Perinatal & Pae<strong>di</strong>atricPharmacology; Chamonix, France.239ANNUAL REPORT <strong>2009</strong>
IRFMNMeeting: "Tubercolosi: omissione <strong>di</strong> soccorso - L'impegno per gli investimenti italiani nellaricerca e lo sviluppo <strong>di</strong> nuove terapie contro una malattia globale". Medecins Sans Frontieres,Rome.July9th Congress of the EACPT. European Association of Clinical Pharmacology & Therapeutics(EACPT); E<strong>di</strong>mburgh, Scotland.September1° National Congress: “Con ragione e Sentimento”. Società Italiana <strong>di</strong> Neonatologia (Gruppo<strong>di</strong> stu<strong>di</strong>o sulla Care - Gruppo <strong>di</strong> stu<strong>di</strong>o QCN); Turin.Meeting APCP (Associazione per la Promozione della Cultura Pe<strong>di</strong>atrica); Verona.3° International Congress: "La Vita dei Farmaci: Prospettive scientifiche e analisiinter<strong>di</strong>sciplinare <strong>di</strong> un prodotto in trasformazione". Medecins Sans Frontieres, Milan.OctoberXXX National SIFO Congress: “L’assistenza come occasione <strong>di</strong> ricerca”. Società Italiana <strong>di</strong>Farmacia Ospedaliera (SIFO); Ascoli Piceno.XXI National ACP Congress: “I bambini e il dottore”. Associazione Culturali Pe<strong>di</strong>atri (ACP),Servizio Sanitario Regionale Emilia-Romagna; Cesenatico (FC).Meeting. Città <strong>di</strong> Garbagnate Milanese Assessorato alle Politiche Culturali; GarbagnateMilanese (MI).Congress: “La farmacovigilanza in pe<strong>di</strong>atria”. Università <strong>di</strong> Milano - Ospedale Luigi Sacco;Milano.Meeting. Comune <strong>di</strong> Capiago Intimiano, Assessorato ai Servizi Sociali; Capiago Intimiano(CO).Course: “L’Accademia del citta<strong>di</strong>no: valutare la qualità e la sicurezza dei servizi sanitari perfare scelte consapevoli e partecipare al miglioramento”. Regione Toscana Settore Equità eAccesso, Regione Toscana Gestione Rischio Clinico Sicurezza del Paziente, Partecipasalute;Milan.Meeting: “Un metodo vincente per riconoscere ed ostacolare il <strong>di</strong>sagio infantile”. Per laFamiglia, Centro <strong>di</strong> Consulenza e Formazione; Orzinuovi (BS).Course: Farmacologia pe<strong>di</strong>atrica. Scuola <strong>di</strong> Specializzazione in Pe<strong>di</strong>atria. Università degliStu<strong>di</strong> Milano-Bicocca, Facoltà <strong>di</strong> Me<strong>di</strong>cina e Chirurgia; Monza (MB).November89° National Congress: Società oftalmologica Italiana “Simposio ROP - Gruppo <strong>di</strong> stu<strong>di</strong>o perla ROP. Attualità in tema <strong>di</strong> ROP ELBW”. Milan.Congress: “I percorsi <strong>di</strong> cura e <strong>di</strong> inclusione sociale della salute mentale nella regione FriuliVenezia Giulia”. Regione Autonoma Friuli Venezia Giulia, Centro Regionale <strong>di</strong> Formazioneper l’Area delle Cure Primarie (ARS); U<strong>di</strong>ne.Meeting: Ospedale-Territorio. Struttura Complessa <strong>di</strong> Pe<strong>di</strong>atria, Azienda OspedalieraOspedale <strong>di</strong> Circolo <strong>di</strong> Melegnano; Melegnano (MI).Course on corporate training. ASL Salerno 1. Nocera Inferiore (SA).Course: “Le incertezze in me<strong>di</strong>cina e i conflitti <strong>di</strong> interesse”. Regione Toscana Settore Equitàe Accesso, Regione Toscana Gestione Rischio Clinico Sicurezza del Paziente, Partecipasalute;Milan.65° Congress SIP “Nuove frontiere della moderna pe<strong>di</strong>atria”. Società Italiana <strong>di</strong> Pe<strong>di</strong>atria(SIP); Padua.Course: Principi <strong>di</strong> terapia in età pe<strong>di</strong>atrica. Scuola <strong>di</strong> Specializzazione in Pe<strong>di</strong>atria. Universitàdegli Stu<strong>di</strong> Milano-Bicocca, Facoltà <strong>di</strong> Me<strong>di</strong>cina e Chirurgia; Monza (MB).DecemberCourse for the pharmacy degree “Attività <strong>di</strong> preparazione in farmacia”. Università degliStu<strong>di</strong>; Milan.Meeting: Me lo <strong>di</strong>ci in … bambinese. Presentazione del libro in oggetto. E<strong>di</strong>zioni Paoline;Milan.240ANNUAL REPORT <strong>2009</strong>
IRFMNSymposium: AIPO - Medecins Sans Frontieres "Tubercolosi:omissione <strong>di</strong> soccorso". Me<strong>di</strong>cisenza Frontiere, Milan.GRANTS AND CONTRACTS"A. and A. Valenti" Centre for Health Economics (CESAV)− Abbott− AIFA− Grunenthal-Prodotti Formenti− Merck Serono− Sanofi Aventis− Sanofi Pasteur MSD− Schering Plough− VivisolLaboratory of Clinical Epidemiology− ARESS Piemonte− ASL TO-2 Piemonte− AstraZeneca− Azienda ULSS 16, Padova – Italia− Bellco SpA− Draeger Italia− Regione Lombar<strong>di</strong>a− Regione Toscana− Commissione Europea DG SANCO− Hill-Rom− Brahms− AstellasLaboratory for Mother and Child Health−−−−−−−Boehringer IngelheimEuropean UnionHospital of Bergamo “Ospedali Riuniti”Italian Drug Agency, (AIFA)Provinve of MilanRegional Health Ministry - Lombardy RegionRegional Health Ministry - Valle d’Aosta Region241ANNUAL REPORT <strong>2009</strong>
IRFMNSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)"A. and A. Valenti" Centre for Health Economics (CESAV)Koleva D, De Compadri P, Virgili G, Nobili A, Garattini L. A critical review of the full economic evaluations ofpharmacological treatments for glaucoma. JME 2008 [published in <strong>2009</strong>];11(4):719-741.Beghi M, Savica R, Beghi E, Nobili A, Garattini L. Utilization and Costs of Antiepilectic Drugs in the Elderly. Drugs &Aging <strong>2009</strong>;26(2):157-168.Garattini L, Casadei G, Freemantle N. Continuing me<strong>di</strong>cal education fun<strong>di</strong>ng and management in Europe: room forimprovement? [E<strong>di</strong>torial] JME <strong>2009</strong>;12(1):56-59.Garattini L, Casadei G. Letter to the E<strong>di</strong>tor. Vaccine <strong>2009</strong>;27(38):5171.Garattini L, Gritti S, De Compadri P, Casadei G. Continuing Me<strong>di</strong>cal Education in six European countries: A comparativeanalysis. Health Policy <strong>2009</strong> [online from November <strong>2009</strong>].Garattini L, Casadei G. Letter to the E<strong>di</strong>tor. (2nd) Vaccine <strong>2009</strong> [online].Laboratory of Clinical EpidemiologyPoole D, Rossi C, Anghileri A, Giar<strong>di</strong>no M, Latronico N, Radrizzani D, Langer M, Bertolini G. External validation of thesimplified acute physiology score (SAPS3) in a cohort of 28.357 patients from 147 Italian intensive care units. IntensiveCare Me<strong>di</strong>cine <strong>2009</strong>;35:1916-1924.J.C. Marchall, K. Reinhart, D. Angus, A. Argent, G. Bernard, G. Bertolini, S. Bhagwanjee, J.P. Cobb, D.J. cook, D. Fedson,S. Finfer, R. Fowler, C. Gomersall, E. Jimenez, N. Kissoon, D. McAuley, S. Opal, J.L. Vincent, S. Webb. InFACT: a globalvritical care clinical research reponse to severe pendemic H1N1. <strong>2009</strong> Lancet.Poole D, Bertolini G. Outcome-based benchmarking in the ICU Part II: Use and limitations of severity scores in critical care.Patient Safety and Quality of Care in Intensive Care Me<strong>di</strong>cine <strong>2009</strong>;151-159Poole D, Bertolini G. Outcome-based benchmarking in the ICU Part I: Statistical tools for the creation and validation ofseverity scores. Patient Safety and Quality of Care in Intensive Care Me<strong>di</strong>cine <strong>2009</strong>;141-149.Foltran F, Bal<strong>di</strong> I, Bertolini G, Merletti F, Gregori D. Monitoring the performance of intensive care units using the variablelife-adjusted <strong>di</strong>splay: a simulation study to explore its applicability and efficiency. J Eval Clin Prac <strong>2009</strong>;15: 506–51.G. Bertolini, M. Langer, D. Poole. The project Margherita for assessing italian ICU performance. ICU-management2008/<strong>2009</strong>;8;(4):42-43.Angermayr B, Luca A, König F, Bertolini G, Ploner M, Gridelli B, Ulbrich G, Reiberger T, Bosch J, Peck-Radosavljevic M.Aetiology of cirrhosis of the liver has an impact on survival presicted by the Model of End-stage Liver Disease score.European Journal of Clinical Investigation <strong>2009</strong>;39(1):65-71.Poole D, Guido B, Silvio G. Errors in the approval process and post-marketing evaluation of drotrecogin alfa (activated) forthe treatment of severe sepsis. The Lancet Infectious Diseases <strong>2009</strong>;9(1):67-72.Laboratory for Mother and Child HealthBianchi M, Clavenna A, Labate L, Bortolotti A, Fortino I, Merlino L, Locatelli WG, Giuliani G, Bonati M. Antiasthmaticdrug prescriptions to an Italian paedriatic population. Pe<strong>di</strong>atric Allergy Immunology <strong>2009</strong>;20:585-591.Bonati M. Once again, children are the main victims of fake drugs. Arch Dis Child <strong>2009</strong>;94:468.Bonati M, Garattini S. Controlling Cervical Cancer. PharmacoEconomics <strong>2009</strong>;27:91-93.Campi R, Barbato A, D’Avanzo B, Guaiana G, Bonati M. Suicide in Italian children and adolescents. Journal ofAffective Disorders <strong>2009</strong>;113:291-295.242ANNUAL REPORT <strong>2009</strong>
IRFMNClavenna A, Berti A, Gualan<strong>di</strong> L, Rossi E, De Rosa M, Bonati M. Drug utilisation profile in the Italian pae<strong>di</strong>atricpopulation. Eur J Pe<strong>di</strong>atr <strong>2009</strong>;168:173-180.Clavenna A, Bonati M. Adverse drug reactions in childhood: a review of prospective stu<strong>di</strong>es and safety alerts. ArchDis Child <strong>2009</strong>;94:724-728.Clavenna A, Bonati M. Drug prescriptions to outpatient children: a review of the literature. Eur J Clin Pharmacol<strong>2009</strong>;65:749-755.Clavenna A, Sequi M, Bortolotti A, Merlino L, Fortino I, Bonati M. Determinants of the drug utilisation profile in thepae<strong>di</strong>atric population in Italy’s Lombardy Region. Br J Clin Pharmacol <strong>2009</strong>;67:565-571.Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfee<strong>di</strong>ng: a review of the evidence.Pe<strong>di</strong>atrics <strong>2009</strong>;124:e547-e556.Pandolfini C, Bonati M. Children’s presence in research. A review of online registers. Eur J Clin Pharmacol<strong>2009</strong>;65:873-880.Pandolfini C, Bonati M, Sammons HM. Registration of trials in children. Update of current international initiatives.Arch Dis Child <strong>2009</strong>;94:717-719.Pandolfini C, Clavenna A, Bonati M. Quality of cystic fibrosis information on Italian websites. Informatics HealthSocial Care <strong>2009</strong>;34:10-17.Toscani F, Di Giulio P, Campi R, Pellerin I, De Luca A, Casale G, on behalf of the end of life observatory ResearchGroup. Off-label prescriptions in Italian hospices: a national survey. Journal of Pain and Symptom Management<strong>2009</strong>;34:10-17.LAY PRESS SELECTION (<strong>2009</strong>)"A. and A. Valenti" Centre for Health Economics (CESAV)Garattini L. Extra sconti generici: una proposta nella giusta <strong>di</strong>rezione? [E<strong>di</strong>torial] Quaderni <strong>di</strong> Farmaco Economia <strong>2009</strong>;8:5-6.De Compadri P, Koleva D, Garattini L. Revisione critica della valutazioni economiche sull’estensione del vaccinoantinfluenzale alla fascia <strong>di</strong> età 50-64 anni. Quaderni <strong>di</strong> Farmaco Economia <strong>2009</strong>;8:7-15.Casadei G, Gritti S, Garattini L. La gestione dei vaccini nelle ASL lombarde: un’indagine in nove province. Quaderni <strong>di</strong>Farmaco Economia <strong>2009</strong>;8:17-25.De Compadri P, Koleva D, Garattini L. Analisi costo-beneficio del vaccino anti-influenzale per soggetti <strong>di</strong> età compresa tra50 e 64 anni: un tentativo <strong>di</strong> stima a livello nazionale. Quaderni <strong>di</strong> Farmaco Economia <strong>2009</strong>;9:9-18.Casadei G, De Compadri P, Gritti S, Garattini L. ASL e controllo della spesa farmaceutica: un’indagine conoscitiva.Quaderni <strong>di</strong> Farmaco Economia <strong>2009</strong>;9:19-24.Casadei G, Garattini L. Costi <strong>di</strong> <strong>di</strong>stribuzione, ma quando mai una seria riforma strutturale? Quaderni <strong>di</strong> Farmaco Economia<strong>2009</strong>;9:27-31.Casadei G, Garattini L. Questioni <strong>di</strong> interesse [E<strong>di</strong>torial] Quaderni <strong>di</strong> Farmaco Economia <strong>2009</strong>;10:5-6.De Compadri P, Koleva D, Mangia A, Motterlini N, Garattini L. Analisi costo minimizzazione della terapia <strong>di</strong> durata 12 o 24settimane <strong>di</strong> peginterferone alfa-2b e <strong>di</strong> ribavirina nell’infezione da virus dell’epatite C. Quaderni <strong>di</strong> Farmaco Economia<strong>2009</strong>;10:7-16.Garattini L. Extrasconti generici-Una proposta nella giusta <strong>di</strong>rezione? Dialogo sui farmaci <strong>2009</strong>;1:29-30.Garattini L. Via le alternative per la bolla “extrasconto. Sanità del Sole 24 Ore 7-13 Aprile <strong>2009</strong>:12.243ANNUAL REPORT <strong>2009</strong>
IRFMNCasadei G, Garattini L. Spesa farmaceutica territoriale e costi <strong>di</strong> <strong>di</strong>stribuzione- E’ tempo <strong>di</strong> pensare ad una riformastrutturale? Ricerca & Pratica <strong>2009</strong>;25(3):91-99.Garattini L. ECM, nessuna sanzione vera per chi non la fa. Sanità del Sole 24Ore 13-19 October <strong>2009</strong>:18-19.Casadei G, Garattini L. Farmaci, trasparenza all’innovatività. Sanità del Sole 24Ore 3-9 November <strong>2009</strong>:16.Laboratory of Clinical EpidemiologyBertolini G. Imparare dall’errore. Appunti per una riflessione in me<strong>di</strong>cina. R&P <strong>2009</strong>; 25: 127-130Bertolini G, Luciani D, Tavola M, Livigni S, Bertoni C, Tetamo, Radrizzani D, Biolo G, GiViTI. PROMISED:protocollo <strong>di</strong> ricerca GiViTI per stu<strong>di</strong>are il profilo metabolico del glucosio nel paziente critico e nel paziente<strong>di</strong>abetico. EsaDia <strong>2009</strong>;11: 42-48Bertolini G. L'articolo 32. R&P <strong>2009</strong>;146:82Laboratory for Mother and Child HealthBonaccorsi A. Marketing farmaceutico in Internet. R&P <strong>2009</strong>;25:104-117.Bonaccorsi A. Universities Allied For Essential Me<strong>di</strong>cines (UAEM). GIFC <strong>2009</strong>;23:118-19.Bonati M. La guerra dei bambini. R&P <strong>2009</strong>;25:1-2.Bonati M, Panei P. Il registro dell’ADHD:lo stato dell’arte. Me<strong>di</strong>co e Bambino <strong>2009</strong>;8:279-281.Clavenna A. Tra nuova influenza e vecchie questioni irrisolte. Ricerca&Pratica <strong>2009</strong>;25:133-135.Clavenna A, Andretta M, Pilati P, Dusi M, Gangemi M, Gattoni M B, Lombardo G, Zoccante L, Mezzalira L, BonatiM. I percorsi <strong>di</strong>agnostico-terapeutici e assistenziali <strong>di</strong> bambini e adolescenti con <strong>di</strong>sturbi psichiatrici nell'AziendaULSS 20 <strong>di</strong> Verona. R&P <strong>2009</strong>;149:179-189.Clavenna A, Bonati M. Profilo epidemiologico delle ADR in pe<strong>di</strong>atria. Me<strong>di</strong>co e Bambino <strong>2009</strong>;28:503-504.Clavenna A, Fortinguerra F. Aumentano le evidenze contro la profilassi antibiotica delle infezioni delle vie urinarie.Quaderni acp <strong>2009</strong>;16:33.Clavenna A, Fortinguerra F. Una formulazione adatta ai bambini per la cura della malaria. Quaderni acp <strong>2009</strong>;16:82.Clavenna A, Fortinguerra F. Uso degli antivirali nei bambini: il punto della situazione. Quaderni acp <strong>2009</strong>;16:269.Clavenna A, Fortinguerra F. Aumentano le segnalazioni <strong>di</strong> reazioni avverse: solo una su <strong>di</strong>eci dai pe<strong>di</strong>atri <strong>di</strong> famiglia.Quaderni acp <strong>2009</strong>;16:132.Clavenna A, Fortinguerra F. Novità sugli psicofarmaci per uso pe<strong>di</strong>atrico, ma con molte perplessità. Quaderni acp<strong>2009</strong>;16:184.Clavenna A, Fortinguerra F. Gli psicostimolanti aumentano il rischio <strong>di</strong> morte improvvisa. Quaderni acp<strong>2009</strong>;16:219.Fortinguerra F, Bianchi M, Clavenna A, Bonati M. Il destino dei me<strong>di</strong>cinali dopo la prescrizione me<strong>di</strong>ca. R&P<strong>2009</strong>;25:47-56.Garattini S, Bonati M. La ricerca in Italia contro una malattia globale. In: Tubercolosi: omissioni <strong>di</strong> soccorso. Me<strong>di</strong>ciSenza Frontiere <strong>2009</strong>;3.244ANNUAL REPORT <strong>2009</strong>
IRFMNOTHER PUBLICATIONS (<strong>2009</strong>)"A. and A. Valenti" Centre for Health Economics (CESAV)Garattini L “Aspetti economici: analisi dei gap <strong>di</strong> conoscenza” in chapter “Prevenzione e accesso alle cure nell’eradel federalismo” in “HIV Summit Italia <strong>2009</strong>- Diagnosi precoce, qualità della vita” [conference documentation].Roma: Weber Shandwick;<strong>2009</strong> (pag. 66).Laboratory of Clinical EpidemiologyRossi C, Pezzi A, Bertolini G. Progetto Margherita - Promuovere la ricerca e la valutazione in Terapia IntensivaRAPPORTO 2008. Bergamo: E<strong>di</strong>zioni Sestante, <strong>2009</strong>Laboratory for Mother and Child HealthBonati M. Cuba. In: Global health and Development Assistance. Rights, Ideologies and Deceit. E<strong>di</strong>zioni ETS, Pisa.<strong>2009</strong>;267-275. [Chapter Book]Clavenna A, Braguglia A. Peculiarità della farmacocinetica nel neonato. In: Farmacoterapia Neonatale. Guida praticacon supporto interattivo. I e<strong>di</strong>zione <strong>2009</strong>. E<strong>di</strong>tore Biome<strong>di</strong>a, Milano <strong>2009</strong>;4-6. [Chapter Book]Bianchi M, Clavenna A, Bonati M. Anti-asthmatic prescription and prevalence rate in the outpatient pae<strong>di</strong>atricpopulation. Analysis of stu<strong>di</strong>es published during 2000-2008. In: ESDPPP Chamonix Congress. June 17th to 20th<strong>2009</strong>. [abstract]Bonati M. Current issues in pae<strong>di</strong>atric prescribing. In:Basic & Clinical Pharmacology & Toxicology. Abstarcts of the9th Congress of the European Association for Clinical Pharmacology and Therapeutics; 12-15 July <strong>2009</strong>, E<strong>di</strong>mburgo,UK. <strong>2009</strong>;105:18. [abstract]Clavenna A, Fortinguerra F, Bonati M, Study Working Group. Diagnostic and therapeutic approaches in children andadolescents with neuropsychiatric <strong>di</strong>sorders. In: ESDPPP Chamonix Congress. June 17th to 20th <strong>2009</strong>. [abstract]Clavenna A, Sequi M, Bonati M. Children taking antiepileptic drugs have an increased risk of death. In: ESDPPPChamonix Congress. June 17th to 20th <strong>2009</strong>. [abstract]Didoni A, Costantino A, Panei P, Clavenna A, Bonati M. Pharmacological treatment ADHD children of LombardyRegion (Italy). In: ESDPPP Chamonix Congress. June 17th to 20th <strong>2009</strong>. [abstract]Per un uso razionale dei farmaci. Controparte: Assessorato alla Sanità, Regione Lombar<strong>di</strong>a. [report]Registro Nazionale ADHD. Controparte : AIFA. [report]Analisi delle richieste riguardanti pazienti pe<strong>di</strong>atrici giunte al Centro Antiveleni <strong>di</strong> Bergamo nel corso dell’anno2007. (Progetto REAPEDINPS) Controparte: Regione Lombar<strong>di</strong>a. [report]Formazione farmaco epidemiologia pe<strong>di</strong>atrica. Controparte: Boehringer Ingelheim S.p.A. [report]During <strong>2009</strong> the laboratory’s activities were covered by the national me<strong>di</strong>a 91 timesRESEARCH ACTIVITIES"A. and A. Valenti" Centre for Health Economics (CESAV)Educational activityEducational activities are developed only if related to research stu<strong>di</strong>es, in order to offeroriginal contributions which naturally reinforce the research aims.245ANNUAL REPORT <strong>2009</strong>
IRFMNEconomic Evaluation of Health Care ProgramsThe aim of this research area is to assess the costs of pathologies and the cost-effectivenessratios of the <strong>di</strong>agnostic/therapeutic existing alternatives. In general, analyses can beclassified into two groups: partial economic evaluations (e.g. cost of illness analysis) and fulleconomic evaluations (e.g. cost-effectiveness analyses).Comparative Health Policy AnalysisThe aim of this research area is to study the organization of health care systems, in order todraw lessons from international comparisons. This is particularly important in a "market"like health care where economic competition lacks by definition and therefore publicregulation plays a crucial role.Laboratory of Clinical EpidemiologyQuality of care in the Intensive Care UnitsThe main purpose of these research projects is the assessment and improvement of thequality of care in Italian Intensive Care Units (ICUs). It is a multi-annual project promotedon behalf of GiViTI, a collaborative network composed by more than half of the Italian ICUsand coor<strong>di</strong>nated by the Laboratory. The main focus is the Project Margherita. Its aim is thecontinuous evaluation of the quality of care and it is based on a free software developed bythe Laboratory and <strong>di</strong>stributed to all the ICUs adhering to the GiViTI group. The softwarehas been realized on a modular structure, which enables to easily integrate the basic datacollection (the “core” of Margherita) with the data collection of specific research projects(the “petals” of Margherita).Ad<strong>di</strong>tionally, in the current year, a software based on a probabilistic model (bayesiannetwork) covering a large set of clinical variables, has been further implemented. Such anactivity, lead by the Unit of Clinical Knowledge Engineering, and also involving theMachine Intelligence Group of the University of Aalborg (Denmark), pursues the realizationof tools for the retrospective evaluation of specific treatments in ICU. By means of thismodel, it is meant to overcome the current limits of an overall evaluation of ICU, likewise ithappens when the tra<strong>di</strong>tional models for mortality pre<strong>di</strong>ction are adopted. Within thisactivity, a bayesian system to monitor the Standar<strong>di</strong>sed Mortality Ratio of the single ICU.This system, which resembles the bayesian pharmacovigilance system currently in use at theWHO and FDA, will identify periods during which some problems occurred, allowing thephysicians of the Center to promptly and efficacy react.Appropriateness of the Intensive Care UnitsICU is a high technology environment, that requires a high number of high-level personnel.Hence, the cost of these units is extremely important and a special attention not to wasteresources is mandatory. In this field, the Laboratory launched a study to assess the level ofappropriateness of the use of ICU beds, in four Italian regions: Lombar<strong>di</strong>a, Piemonte,Toscana e Campania. Such an evaluation is based on the understan<strong>di</strong>ng that the level of careprovided by an ICU should correspond to the level of care it can theoretically provide, giventhe available resources. In this framework, patients are classified as requiring high-, low-, oror<strong>di</strong>nary-care, and beds are independently classified are high- or low-level. Theappropriateness evaluation protocol adopted verify the concordance between these twoseparate classifications.Influenza A/H1N1 in ICUOn June <strong>2009</strong> the World Health Organization confirmed the presence of a new pandemicinfluenza A, caused by a H1N1 virus. The first experiences showed that this influenza was246ANNUAL REPORT <strong>2009</strong>
IRFMNcharacterized by a higher incidence of severe viral pneumonia in children, middle-agedpatients, and pregnant women and, apparently, by a higher mortality than expected in anormal influenza season. This caused a generalized alarm all over the world.On October <strong>2009</strong> the GiViTI group, coor<strong>di</strong>nated by the Laboratory of ClinicalEpidemiology, set up the H1N1 registry, with the aim to assess the characteristics andoutcome of affected patients, the impact of the pandemic influenza on the activity of ItalianICUs, and the correspondence between the generalized alarm on this phenomenon and whatreally took place in Italian ICUs.Stu<strong>di</strong>es on Multiple Organ Failure pathological processesThe Laboratory of Clinical Epidemiology has lead several investigations to clarify whichpathophysiological mechanisms induce multiple organ failure, a con<strong>di</strong>tion still burdenedwith high mortality. Among these, the investigation on the neuromuscular impairment incritical patients (the observational study 'Crimyne'), the study on the impact of enteralfee<strong>di</strong>ng, and the new treatments proposed for severe sepsis (Xigris and the removal ofinflammation me<strong>di</strong>ators through specific filter applied to circuit of plasma-filtration).The value of a strict glycemic control of critical patients has been recently emphasized, givenits connection to a drug like insulin that, in spite of its large availability and low cost,induces a relevant reduction of mortality in ICU. The Unit of Clinical KnowledgeEngineering has developed a model based on a <strong>di</strong>fferential equations system whose aim is tosupport the physician in dosing both insulin and glucose infusions, in order to extend thepossibility of a strict control even to patients with a high risk of hypoglycaemia. This modelrepresents a precious opportunity to investigate the pathophysiological mechanisms behindthe benefits of insulin already demonstrated at an empirical level, allowing the explanationof the dynamic behaviour of glycemic fluctuations on the basis of the patient's metabolicprofile.The reconstruction of clinical reasoning in the me<strong>di</strong>cal practice andeducationThis area represents the main concern of the Unit of Clinical Knowledge Engineering, whoseobjective is the valorization of clinical reasoning in solving complex clinical problems.The <strong>di</strong>agnosis of pulmonary embolism still represents a relevant clinical challenge, due tothe complexity of the patient's clinical presentation and the variability of <strong>di</strong>agnosticresources among Centres. In this regards, we are conducting an Italian multicenter study,involving mainly Emergency Units, with the aim of prospectively validating the <strong>di</strong>agnosticsoftware BayPAD (Bayes Pulmonary embolism Assisted Diagnosis). Such a tool, relying ona probabilistic model covering 72 clinical variables and doing without the need to input allthe contemplated observations, would overcome the main reasons which prevented or<strong>di</strong>naryclinical guidelines to be largely accepted. Moreover, the results of the retrospectivevalidation of the system have been obtained.The Unit started a project for the realization of a software assisting the physician in tracingback the basis of his clinical decisions before the description provided by clinical reports,among those that are typical of particular me<strong>di</strong>cal specialty. The software has the doubletarget to create specific applications based on probabilistic models representing complexclinical decision problems, and to involve physicians in their construction. The last target isachievable given the strong analogy between the causal structure of the exploited models(bayesian networks) and the pathophysiological structure of me<strong>di</strong>cal knowledge. By this, itwill be given the chance to adopt this system within me<strong>di</strong>cal training projects, with a specialattention to e-learning programs.247ANNUAL REPORT <strong>2009</strong>
IRFMNClinical Epidemiology of rare <strong>di</strong>seases and orphan me<strong>di</strong>cineOur purpose is to find out and describe clinical and research problems related either to rare<strong>di</strong>seases or to neglected aspects of well-known <strong>di</strong>seases. We also focus on the needs of thepatients with rare <strong>di</strong>seases. A specific project is connected with this research activity: “PNS– Euronetwork”. It is a European project on paraneoplastic neurological syndromes that isfinanced by the Fifth and Sixth Framework Program of the European Community. Itspurposes are various: to develop a network of reference centers for these pathologies allsharing a common database; to organize a sample bank of biological fluids and cerebrospinalliquid to point out the best antibody in<strong>di</strong>cators for the <strong>di</strong>agnosis and prognosis of thesepatients; to realize some research projects on the treatment of this syndrome.An electronic health record to promote research in Intensive CareMe<strong>di</strong>cineThe main aim of this project is to develop an electronic health record (EHR) the allows theassessment of in<strong>di</strong>cators of the process of care in the ICU. A multi<strong>di</strong>sciplinary team ofintensivists, ICU nurses, epidemiologists, statisticians, and IT specialists, had theresponsibility of planning the HER, that is now already shared by 15 Italian ICUs.Laboratory for Mother and Child HealthPharmacoepidemiology in the Lombardy RegionThe Laboratory for Mother and Child Health is involved in the analysis of the drugprescription profile in children and adolescents in the EPIFARM (Epidemiologia delfarmaco) project funded by the Lombardy Region.In this regard, the prescriptions <strong>di</strong>spensed during 2005 by 1107 family pae<strong>di</strong>atricians to486,406 children
IRFMNPrescription, efficacy, and safety of psychotropic drugs in the Italianpae<strong>di</strong>atric populationDiagnostic and therapeutic approaches in children and adolescents withneuropsychiatric <strong>di</strong>sorders in the Local Health Unit of Verona, Italy.Aims. The safety and effectiveness of psychotropic drug use in the pae<strong>di</strong>atric population arewidely debated, in particular because of the lack of data concerning the long term effects. InItaly the prevalence of psychotropic drug prescriptions increased in the 2000-2002 periodand decreased afterwards. In such a context, a study with the aim to estimate the prevalenceof psychotropic drug prescription in the pae<strong>di</strong>atric population and to describe <strong>di</strong>agnostic andtherapeutic approaches was performed.Methods. The study population was composed of 76,000 youths
IRFMNBeclometasone is the second most prescribed drug in Italian children among the me<strong>di</strong>cationsreimbursed by the National Health Service, with a prevalence estimated around 15% (9-22%depen<strong>di</strong>ng on the setting), and the fourth drug in order of expen<strong>di</strong>ture. No changes wereobserved in beclometasone prevalence rate in the 2000-2006 period. In such a context, arigorous evaluation of current practice is fundamental. A randomised controlled trial wastherefore planned with the aim to evaluate the safety and effectiveness of beclometasone inpreventing wheezing in respiratory tract infection.The study will be performed in the primary care setting and will involve 36 familypae<strong>di</strong>atricians in 9 Italian local health units representative of geographical <strong>di</strong>stribution andsetting.A total of 576 children 1-5 years old, with at least one episode of viral wheezing in theprevious 12 months, will be enrolled. Children with steroid hypersensitivity, chronicrespiratory <strong>di</strong>sease (e.g. cystic fibrosis, broncho-pulmonary dysplasia), presence of wheezingat the entry visit or using inhaled and/or oral corticosteroid use in the prece<strong>di</strong>ng month willbe excluded. Patients will be randomly allocated to receive beclometasone suspension 400mcg b.i.d or placebo b.i.d.Active drug and placebo will be administered through a nebuliser, in the morning and in theevening. The duration of the treatment will be 10 days, and a 6-month follow up period willbe performed to monitor the recurrence of respiratory tract infections and viral wheezing.The percentage of children with wheezing (<strong>di</strong>agnosed by the pae<strong>di</strong>atrician) during the URTIepisode will be the primary outcome measure.The expected results are: to evaluate the efficacy of a widespread practice; to assess viralwheezing incidence and the <strong>di</strong>sease's natural history; to assess therapeutic approaches usedby the pae<strong>di</strong>atricians; to collect useful evidence to plan interventions for improving rationaldrug use in children.National ADHD RegisterThe National Register for ADHD in children has been active since June 2007. The registermonitors the <strong>di</strong>agnostic, therapeutic and health care approaches and evaluates the adverseeffects of two drugs: methylphenidate and atomoxetine. These two drugs are marketed inItaly for the treatment of ADHD in children and adolescents. The register was initiallysupposed to be active for two years (2008-9), but its duration was extended to three (to theend of June 2010).The register is a tool with great potential for respon<strong>di</strong>ng, in an appropriate manner and at thenational level, to specific, unmet health needs in youth with ADHD (and their families).The Laboratory for Mother and Child Health, as part of the scientific committee, participate<strong>di</strong>n writing the protocol that defines the National ADHD Register’s structure and activitiesand in monitoring it. The laboratory is currently involved in monitoring the data present inthe register and in creating the data reports for the health operators working in the servicesinvolved. The lab is especially involved in supporting the creation of a functional network ofreferral centres.The Lombardy Region, with 272 patients, is second only to the Veneto Region in number ofpatients monitored by the register.There are 181 patients with a first methylphenidate or atomoxetine prescription (86%),reported by 14 of 21 referral centres (70%) in<strong>di</strong>cated by the Lombardy Region (4-40; me<strong>di</strong>an7,5). Of these patients: 57 were present in 2007, 82 in 2008, and 42 in <strong>2009</strong>. In all, 86% ofpatients are male, aged between 5 and 16 years (me<strong>di</strong>an 10 years, mode 8). For 118 patients(65%) at least one familiarity was found: 6 with ADHD, 12 with ADHD and learning<strong>di</strong>sabilities, 8 with ADHD, learning <strong>di</strong>sabilities, and other positive familiarities, 12 withlearning <strong>di</strong>sabilities.In agreement with the protocol’s in<strong>di</strong>cations, 53 patients were evaluated with amulti<strong>di</strong>mensional approach (29% of the total, with K-SADS, CPRS, CTRS e WISC). The250ANNUAL REPORT <strong>2009</strong>
IRFMNmost common <strong>di</strong>agnosis was complex ADHD (80%) compared to the <strong>di</strong>sorder characterisedprevalently by attention deficit (16%) or hyperactivity (4%). In 42 cases (23% of the total)no comorbi<strong>di</strong>ties were found, while in 95 cases one was found and in 1case five were found.The most common comorbi<strong>di</strong>ties were learning <strong>di</strong>sorders (44%) and oppositional defiant<strong>di</strong>sorder (35%). Both were <strong>di</strong>agnosed in 25 patients (15% of total). In all, 129 patients begantreatment with atomoxetine (71%) and 52 with methylphenidate. Adverse effects were foun<strong>di</strong>n 65 patients (36% of total). A total of 22 adverse events were found duringpharmacological treatment in 14 patients (8%, 5 of whom had more than one adverse effect).The Laboratory set up ADHDNews, a newsletter aimed at provi<strong>di</strong>ng interested health careoperators a monthly bibliographic update of the recent scientific literature via email. Thisinitiative is part of the Italian Drug Agency’s (AIFA) independent research projectimplemented in collaboration with the <strong>Istituto</strong> Superiore <strong>di</strong> Sanità and called “Long termsafety of drugs used to treat school-aged children with Attention Deficit HyperactivityDisorder and epidemiology of the <strong>di</strong>sorder in the Italian population”. A total of 24 issues ofADHDNews have been produced so far, identifying 1010 scientific articles. 277 people haveregistered to receive the update (125 psychiatrists and neuropsychiatrists; 48 MD; 36psychologists and speech therapist; 32 pe<strong>di</strong>atricians; 7 pharmacists; 7 operating scholastic;22 other). The newsletter is also viewable on the <strong>Mario</strong> <strong>Negri</strong>’s website under the section“The <strong>Mario</strong> <strong>Negri</strong> Institute for the physician” (L’<strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong> per il Me<strong>di</strong>co):http://www.marionegri.it/mn/it/index.htmlMigration and psychological <strong>di</strong>fficulties in growth and adulthoodThe primary goal of the project is the creation of shared, coor<strong>di</strong>nated practices that areintegrated among the <strong>di</strong>fferent services available, for an appropriate management of themental health needs of migrant children and adolescents.The project involves the Childhood and Adolescence Neuropsychiatry Units (7 UONPIAs), amental health service of one of Milan’s local health units, and 11 third-sector organisations.The Laboratory is a member of the Scientific and Technical Committee and is involved inthe project’s epidemiological analyses and in the development of its information system.TINN – Treat Infections in NeoNatesCiprofloxacin and Fluconazole are two anti-infectious drugs included in the EuropeanMe<strong>di</strong>cines Agency’s (EMEA) priority list of therapeutic areas that need specific drugevaluation in preterm and term neonates. More specifically, ciprofloxacin is an antibioticused in newborns with sepsis caused by multiple resistant organisms and fluconazole is anantimicotic used to prevent or treat invasive can<strong>di</strong><strong>di</strong>asis. These two drugs are prescribed offlabelto treat infections that can make babies seriously ill or even kill them. To improve thesituation, the Tinn project will conduct two clinical trials to evaluate the utility and safety ofCiprofloxacin and Fluconazole, administered as formulations adapted to preterm and termneonates.The project will coor<strong>di</strong>nate and integrate the experience of numerous European countries incarrying out research in neonates in order to produce detailed evidence on the safety andefficacy of these two drugs in infants. One of the final goals of the project is to apply for aPea<strong>di</strong>atric-Use Marketing Authorization (PUMA).Analysis of the requests of information concerning pae<strong>di</strong>atric patientscollected by the Poisons Information Centre in Bergamo during 2007.As part of a pharmacovigilance project funded by the Lombardy region and a long lastingcollaboration, 1,579 phone calls received during 2007 by the Unità <strong>di</strong> Tossicologia Clinica,Ospedali Riuniti <strong>di</strong> Bergamo (a poisons information centre) concerning 1,591 children andadolescents < 18 years old with a suspect intoxication, were analysed.251ANNUAL REPORT <strong>2009</strong>
IRFMNDrugs were the most commonly involved substances (36% of the cases), followed by homeproducts (19%). 65% of the queries regar<strong>di</strong>ng drugs were due to accidental ingestions, 25%to therapeutic errors and 5% to intentional ingestion and to adverse drug reactions (ADRs).In all, the 141 queries related to therapeutic errors concerned a total of 75 drugs. An error inthe dosage was the most frequent cause of therapeutic error (67% of the queries). Antibioticsand analgesics were the therapeutic class most commonly involved. Paracetamol (20 cases)and cetirizine (9 cases) were the drugs with the greatest number of queries.In 10 out of 19 cases of suspect ADR the call was made by a physician and in 9 cases by aparent. In 7 cases the child was hospitalized; and when child was at home, parents wereadvised to consult a physician. 20 drugs were associated to the ADRs: antibiotics (8 out 19cases) and prokinetics (4 cases) were the drugs most commonly suspected as the cause of theADR. Symptoms most frequently reported regarded the central nervous system and skin (5cases each). These fin<strong>di</strong>ngs are consistent with the results of retrospective and prospectivestu<strong>di</strong>es that monitored ADR incidence in the pae<strong>di</strong>atric population.Mechanical ventilation in childrenThe Laboratory for Mother and Child Health takes part, in collaboration with the Departmentof Anesthesiology and Intensive Care Me<strong>di</strong>cine, San Giovanni Battista-Molinette Hospital,in the first national study of home mechanical ventilation of children < 18 years old.The main purpose was to identify the number of children who need long-term homeventilation and clinical variables associated with primary care after hospital <strong>di</strong>scharge.Information was collected on 378 patients <strong>di</strong>scharged from 30 hospitals.Ricerca & PraticaRicerca & Pratica was born in January, 1985, as a manifestation of the “<strong>Mario</strong> <strong>Negri</strong>”Institute for Pharmacological Research. Today, the journal is part of the International Societyof Drug Bulletins (ISDB), which represents independent journals.For more than twenty years, the journal has represented an arena for all those professionalswho collect data and carry out stu<strong>di</strong>es in general practice with the aim to increase theirknowledge and to improve their practice. Ricerca & Pratica is also appreciated for its abilityto go beyond the merely clinical aspect of me<strong>di</strong>cine, without, however, forgetting that it is tothis aspect that the readers de<strong>di</strong>cate most of their time and effort.Through its activity, Ricerca & Pratica can therefore represent an exclusive, independentobservation point. It is also an area that promotes contemplation, evaluation, an<strong>di</strong>nformation by applying “tools” such as data trustworthiness and importance, the balancebetween benefits and risks and between benefits and costs, independence from conflicts ofinterest, and the realistic objective to contribute to a progressive, equally <strong>di</strong>stribute<strong>di</strong>mprovement in the population’s health.Co-operation with countries with limited resourcesAs an expression, test, and original method of expression of the choice to make theLaboratory’s research transferable and accessible to all populations, the Laboratorypromoted and provided assistance to projects in, and for, the “South of the world”, also incollaboration with the World Health Organization. The technical and organisational supportfor local groups and international non-governmental organisations for carrying out sociosanitaryprojects in countries with limited resources, especially Colombia, Ecuador, Brazil,Bolivia, Cuba, Vietnam e the Balkans, continues.252ANNUAL REPORT <strong>2009</strong>
IRFMNLABORATORY OF REGULATORYPOLICIESSTAFFHeadVittorio BERTELE’, M.D.253ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAVittorio Bertele’ is a clinical pharmacologist. He got his MD degree in 1977 and the specialization inInternal Me<strong>di</strong>cine in 1982, both at the Milan University Me<strong>di</strong>cal School. He was research fellow at theHarvard Me<strong>di</strong>cal School and then worked at the Milan University and the “<strong>Mario</strong> <strong>Negri</strong>” Institute.His main areas of interest have been clinical pharmacology of drugs active on the haemostatic andvascular system 1,2 , epidemiology of interventions in the car<strong>di</strong>ovascular area, and clinical trials and drugutilization stu<strong>di</strong>es in the car<strong>di</strong>ovascular area 3,4 . He was CPMP expert at the EMEA, member of theCommittee for Drug Price Negotiation at the Italian Ministry of Health, and member of the Technical-Scientific Committee at the Italian Drug Agency. At present he is head of the Regulatory PoliciesLaboratory at the "<strong>Mario</strong> <strong>Negri</strong>" Institute 5-10 .Selected publications1. Bertele' V., Falanga A., Tomasiak M., Dejana E., Cerletti C., De Gaetano G. Plateletthromboxane synthetase inhibitors with low doses of aspirin: Possible resolution of the"aspirin <strong>di</strong>lemma". Science 1983; 220: 517-5192. Bertele' V., Falanga A., Tomasiak M., Chiabrando C., Cerletti C., De Gaetano G.Pharmacological inhibition of thromboxane synthetase and platelet aggregation:Modulatory role of cyclooxygenase products. Blood 1984; 63: 1460-1466 (1984).3. The i.c.a.i. Group (Gruppo <strong>di</strong> stu<strong>di</strong>o dell'Ischemia cronica Critica degli Arti Inferiori).Prostanoids for chronic critical leg ischemia: A randomized, controlled, open-label trial withprostaglan<strong>di</strong>n E 1 . Ann Int Med 1999; 130: 412-4214. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin and vitamin Ein people at car<strong>di</strong>ovascular risk: a randomised trial in general practice. Lancet 2001; 357: 89-955. Garattini S, Bertele’ V. Adjusting regulatory rules to public health needs. Lancet 2001; 358: 64-676. Garattini S, Bertele' V. Efficacy, safety, and cost of new anticancer drugs. BMJ 2002; 325: 269-2717. Garattini S, Bertele’ V, Li Bassi L. How can research ethics committees protect patients better?BMJ 2003; 326:1199–2018. Joppi R, Bertele' V, Garattini S. Disappointing biotech. BMJ 2005; 331: 895-8979. Garattini S, Bertele' V. Non-inferiority trials are unethical because they <strong>di</strong>sregard patients'interests. Lancet 2007; 370 : 1875-187710. Garattini S, Bertele' V. Homoeopathy: not a matter for drug-regulatory authorities. Lancet <strong>2009</strong>;374 : 1578-1580ACTIVITIESCritical appraisal of clinical methodologyCooperation to the development and functioning of the pan-European Infrastructure for clinicaltrials (ECRIN, European Clinical Research Infrastructure Network)Critical evaluation of the benefit-risk profile of drugsAssessment of emerging technologiesOptimisation of drug use and healthcare fund stewardship inclu<strong>di</strong>ng potential reforms an<strong>di</strong>nitiatives to achieve thisCritical appraisal and recommendations for European Pricing and Reimbursement systemsinclu<strong>di</strong>ng generics, interchangeable products within a class and new innovative me<strong>di</strong>cines254ANNUAL REPORT <strong>2009</strong>
IRFMNEvaluation of marketing authorization applications submitted to the European or the Italianregulatory agency (respectively, EMA and AIFA) and of subsequent variationsCooperation to the design and conduct of pharmacovigilance and pharmacoepidemiologystu<strong>di</strong>es in EuropeEvaluation of the appropriateness of drug legislation, institutions, and regulatory procedureswith respect to public health needs.Cooperation to the development and to the solution of regulatory issues in developing countries.MAIN FINDINGSCritical appraisal of clinical research methodological aspects as the adoption ofequivalence/non-inferiority design in clinical trialsCritical evaluation of transnational clinical research projects to be conducted with themethodological and operating support of ECRIN (European Clinical Research InfrastructureNetwork).Development of Pan-European strategies for the rational use of new and existing drugsinclu<strong>di</strong>ng policies to enhance the managed entry of new drugs as well as reduce prescribing ofmore expensive interchangeable single sourced products in a class once generics are available:establishment of the Piperska GroupRecommendations for Pan-European pricing policies for generics as well as interchangeablebrands in a class once generics are availableAssessment of emerging technologies in the frame of the Italian Horizon Scanning Projectwhich provides decision makers with timely information on the potential clinical impact andcost-effectiveness of new health technologiesCritical review of drug documentation at the basis of marketing authorizations.Critical review of the criteria to assess pharmaceutical innovation and include new drugs in thenational reimbursement schemes.Participation in the ENCePP (European Network of Centres of Pharmacovigilance andPharmacoepidemiology) and the PROTECT consortium which under the coor<strong>di</strong>nation of theEuropean Me<strong>di</strong>cines Agency (EMA) aims at improving design and conduct ofpharmacovigilance activities and pharmacoepidemiological stu<strong>di</strong>es in Europe. The PROTECTconsortium is also developing and testing innovative methods to integrate and presentinformation on drug-related benefits and risksRaising awareness among interested parties about the deficiencies of the present EUpharmaceutical legislation and about our proposals to improve it in the public health interest.255ANNUAL REPORT <strong>2009</strong>
IRFMNNATIONAL COLLABORATIONSItalian Drug Agency (AIFA)<strong>Istituto</strong> Superiore <strong>di</strong> SanitàDepartment of Health Lombardy RegionItalian Horizon Scanning ProjectEuropean Me<strong>di</strong>cine Agency (EMA)INTERNATIONAL COLLABORATIONSEuropean Clinical Research Infrastructure Network (ECRIN)European Network of Centres in Pharmacoepidemiology and Pharmacovigilance (ENCePP)Karolinska Institutet, Division of Clinical Pharmacology, Department of Laboratory Me<strong>di</strong>cine,and Centre for Pharmacoepidemiology; Department of Drug Management and Informatics, SEUniversity of Liverpool Management School, Prescribing Research Group, UKInternational Information Network on New and Emerging Health Technologies (EuroScan)World Health Organisation (Department of Essential Drugs and Me<strong>di</strong>cines Policy)Association of South East Asian Nations (ASEAN)EDITORIAL BOARD MEMBERSHIPRicerca & PraticaDialogo sui FarmaciNATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPTechnical Scientific Committee at the Italian Drug Agency (AIFA)European Clinical Research Infrastructure Network (ECRIN) Scientific Board, SecretariatScientific Committee of the Italian Horizon Scanning Project256ANNUAL REPORT <strong>2009</strong>
IRFMNSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)• Comma A, Zara C, Godman B, Augusti A, Diogene E, Wettermark B, Haycox A. Policies to enhancethe efficiency of prescribing in the Spanish Catalan Region: impact and future <strong>di</strong>rection. Exp Reviewof Pharmacoeconomics and Outcomes Research <strong>2009</strong>; 9: 569-581• Garattini S, Bertele' V. Homoeopathy: not a matter for drug-regulatory authorities. Lancet <strong>2009</strong>; 374: 1578-1580• Garattini S, Bertele' V. Ethics in clinical research. J Hepatol <strong>2009</strong>; 51 : 792-797• Garattini S, Bertele' V, Floriani I, Torri V. Exenatide for type 2 <strong>di</strong>abetes. Lancet <strong>2009</strong>; 373 : 122• Godman B, Wettermark B, Vlahovic-Palcevski V, Schwabe U, Gulbinovic J, Laius O, Diogene E,Paterson K, Martikainen J, Bennet K, Gustafsson LL. Impact of reforms to enhance the quality andefficiency of statin prescribing across 20 European countries. Basic & Clin Pharm & Toxicology<strong>2009</strong>; 105 (Suppl 1):35• Godman B, Vlahovic-Palcevski V, Laius O, Bennet K et al. Trends in consumption and expen<strong>di</strong>tureof proton pump inhibitors (PPIs) in 20 European countries. Basic & Clin Pharm & Toxicology <strong>2009</strong>;105 (Suppl 1):37• Godman B., Burkhardt T, Bucsics A et al. Impact of recent reforms in Austria on utilisation andexpen<strong>di</strong>ture of PPIs and lipid lowering drugs; implications for the future. Expert RevPharmacoeconomics Outcomes Research <strong>2009</strong>; 9:475-484• Godman B, Schwabe U, Selke G, Wettermark B. Update of recent reforms in Germany to enhancethe quality and efficiency of prescribing of proton pump inhibitors and lipid lowering drugs.Pharmacoeconomics <strong>2009</strong>; 27: 435-438• Godman B, Wettermark B, Hoffman M, Andersson K, Haycox A, Gustafsson LL. Multifacetednational and regional drug reforms and initiatives in ambulatory care in Sweden; global relevance.Expert Rev Pharmacoeconomcis Outcomes Research <strong>2009</strong>; 9:65-83• Joppi R, Bertele' V, Garattini S. Orphan drug development is not taking off. Br J Clin Pharmacol <strong>2009</strong>; 67 : 494-502• Joppi R, Demattè L, Menti AM, Pase D, Poggiani C, Mezzalira L, on behalf of the Italian HorizonScanning Project Group. The Italian Horizon Scanning Project. Eur J Clin Pharmacol <strong>2009</strong>; 65:775–781• Ottolenghi L, Bertele' V, Garattini S. Limits of add-on trials: antirheumatic drugs. Eur J ClinPharmacol <strong>2009</strong> 65 : 33-41• Vitry A, Bertele' V, Garattini S. Drug regulation and the need for greater transparency. RAJ Pharma<strong>2009</strong> March; 1-4• Wettermark B, Godman B, Jacobsson B, Haaijer-Ruskamp F. Soft regulations in pharmaceuticalpolicymaking - an overview of current approaches and their consequences. Appl. Health Econ HealthPolicy <strong>2009</strong>; 7: 1-11• Wettermark B, Pehrsson A, Juhasz-Haverinen M, Veg A, Edlert M, Törnwall-Bergendahl G,Almkvist H, Godman B, Granath F, and Bergman U. Financial incentives linked to self-assessmentof prescribing patterns – a new approach for quality improvement of drug prescribing in primarycare. Quality in Primary Care <strong>2009</strong>;17:179–89257ANNUAL REPORT <strong>2009</strong>
IRFMNRESEARCH ACTIVITIESCritical appraisal of clinical methodologyRaising awareness about potential biases in clinical researchCritical evaluation of the EU pharmaceutical legislationRaising awareness among interested parties about the deficiencies of the present EUpharmaceutical legislation and about our proposals to improve it in the public health interestDevelopment of a Pan-European Infrastructure for clinical trialsParticipation in a <strong>di</strong>stributed infrastructure linking national networks of clinical research centresand clinical trials units (ECRIN, European Clinical Research Infrastructure Network) whichprovides integrated ‘one-stop shop’ services to investigators and sponsors in multinationalstu<strong>di</strong>esCritical appraisal of ongoing reforms inclu<strong>di</strong>ng pricing reforms in majorEuropean countriesEvaluation of ongoing reforms across Europe to enhance generic prescribing rates, drive downgeneric prices and correspon<strong>di</strong>ng originator brands, as well as potential prices ofinterchangeable brands once standards become available as generics, and the potential for crosscultural learnings to release valuable resources to fund increased volumes and new innovativedrugs in the future without prohibitive increases in general taxation or health insurances tocontinue to provide equitable and comprehensive healthcare in EuropeDevelopment of Pan-European strategies for rational use of drugsEnhancing rational use in line with an approach that has become known as the ‘five Es’,namely: evaluation; economics; enforcement; education and engineering to further fun<strong>di</strong>ncreased volumes and new valuable innovative drugsDevelopment of Pan-European strategies for pharmacovigilanceDeveloping and testing innovative methods to integrate and present information on benefits andrisks in order to provide all stakeholders (patients, prescribers, regulators and pharmaceuticalcompanies) with accurate and useful information on drug-related risks and benefitsAssessment of emerging technologiesCollecting information on emerging me<strong>di</strong>cines with respect to their potential clinical impact andtheir cost effectiveness and ranking the new products accor<strong>di</strong>ng to their possible marketingauthorization date, their potential innovation grade, therapeutic and economic impact, possibleprice and NHS sustainability with the aim to provide decision makers with timely informationon the potential clinical impact and cost effectiveness of new health technologiesAssessment of drug dossiers for regulatory approvalsExpert support to the Rapporteurship for marketing authorisation applications and variations tothe con<strong>di</strong>tions of marketing authorisationActivities for the Technical Scientific Committee at the AIFAConsultative activities for the Italian Drug Agency regar<strong>di</strong>ng regulatory duties with respect todrug quality, safety, efficacy, and cost258ANNUAL REPORT <strong>2009</strong>
IRFMNCENTRE OF COMPUTER SCIENCEENGINEERING−STAFFResearch and Communication InformaticsHead of DivisionROSSI Lorenzo MarcoDivision of I.C.T. Services and ManagementHead of DivisionBAZZI Davide259ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULALorenzo Marco Rossi graduated in Biome<strong>di</strong>cal Engineering with specialization in Hospital ClinicalInstrumentation at Politecnico of Milan. He has been working with the Institute <strong>Mario</strong> <strong>Negri</strong> since 1998.Main areas of interest:1. Planning and realization of software for clinical research2. Planning and realization of software system for in-plant automatization3. Planning and realization of products for multime<strong>di</strong>al <strong>di</strong>vulgationDavide Bazzi graduated in Informatics with specialization in ABACUS at <strong>Istituto</strong> Tecnico IndustrialeStatale of Corsico. He has been working with the Institute of <strong>Mario</strong> <strong>Negri</strong> since 1997.Main areas of interest:1. Planning, realization and management of communication Network and Data Center2. Definition and management of quality levels in ICT services <strong>di</strong>stribution3. Planning and realization of technological innovation for ICT systems4. Definition and application of organization’s methodologies and processes for the informatics securitymanagementACTIVITIESIn order to fulfil even more specialization needs in informatics development, the Centreof Computer Science Engineering is organized, considering the acquired skills, in three<strong>di</strong>stinct <strong>di</strong>vision bound each other by a strong collaborative relationship.The Centre of Computer Science Engineering gathering informatics multi<strong>di</strong>sciplinaryaspects promotes and propose itself to coor<strong>di</strong>nate and harmonize the development of thetools for the management information, improving the integration between informativeprocedures making more efficacious communication process and management ofscientific and administrative datas, in order to support and fasten decisional,management, clinical trials and scientific processes.RESEARCH ACTIVITIESImplementation e of Clinical Trials’ gathering forms (E-CRF)−−−Lab. Clinical Trialso GLAUCOMA PEDIATRICOo Amendment of Trial TAILORo Trial HEAD & NECKLab. New Drug Development Strategies (Dep. Oncology)o Trial MUCOSITISo Trial TRIACLab. Neurological Disorders (Dep. Neuroscience):o Trial ANTIEPILETTICIo Trial ADONEo Trial EDU-COM260ANNUAL REPORT <strong>2009</strong>
IRFMNMaintenance and management of data gathering forms for the followingclinical trials−−−−−Lab. Neurological Disorders (Dep. Neuroscience):• Estensione Registro Europeo SLA• Trial L-ACETYLCARNITINE• Trial ANTIEPILETTICI• Trial EPILESSIA E STROKE• Trial EPO VS MP IN SPINAL SHOCK• Trial VALPROATO• Trial THEOREMLab. Clinical Trials (Dep. Oncology)o Trial FOLFOXo Trial TOPo Trial COMETSo Trial TAILORo Trial HEAD & NECKLab. New Drug Development Strategies (Dep. Oncology)• Trial MAPS• Trial STARPANDep. Epidemiology− Trial CADASILLab. Quality Assessment of Geriatric Therapies and Services (Dep. Neuroscience)− Trial GISAS− Patients registry for Polipathologies and Politherapies – SIMI webWeb based applications connected to the projects- Utility system for the current trials gathering data program (realized)- Redesign of the database concerning hospitalizations, recipes and me<strong>di</strong>calvisitation provided from Regione Lombar<strong>di</strong>a for covenant data analysis- Support to data processing in recipes analysis for Regione Lombar<strong>di</strong>a- Creation of a feedback system for TINN study- Analysis software for interaction between drugs and integrations betweeninteraction database and drugs reference book (in collaboration with Lab.Quality Assessment of Geriatric Therapies and Services).Other projectsWeb based application for in-plant automation• New database for the Institute Orders261ANNUAL REPORT <strong>2009</strong>
IRFMN• New database for the Institute Distributed Publications• Management of the database and cre<strong>di</strong>ts of ECM• New clinical trial Register for the Institute• Creation of a management system for the entrance exams of the RegioneLombar<strong>di</strong>a school• Creation of a management system for the entrance exams for PhDMultime<strong>di</strong>al communication- Management of multime<strong>di</strong>a contents for the Institute website- DVD video e<strong>di</strong>ting and realization for presentations- Creation of promotional videos for the “5xmille” annual campaignWebsites−−−Management of the Institute websiteManagement of the related websitesRestyling of "Fondazione Mattioli" websiteInformatics infrastructures- Realization of the virtualization platform of the Institute server systems- Planning and realization of the accesses and management and supportingprocesses control system- Migration to the new e-mail system262ANNUAL REPORT <strong>2009</strong>
IRFMNITALIAN COCHRANE CENTRESTAFFHeadAlessandro LIBERATI, M.D.263ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAAlessandro Liberati obtained his MD Degree in 1978 at the University of Milano and his post doctoraldegree in Hygiene and Preventive Me<strong>di</strong>cine in 1981 at the same university.Teaching activities: Primary responsibility of several academic and non academic training courses on themethodology of clinical research and systematic reviews/metanalyses. He is Director of the advancedMaster “Evidence based me<strong>di</strong>cine e metodologia della ricerca sanitaria”, at the Università degli Stu<strong>di</strong> <strong>di</strong>Modena e Reggio Emilia.Areas of scientific expertise: methodology of clinical research with particular reference to controlledclinical trials, epidemiological methods for research synthesis (systematic reviews and metanalyses);methods of practice guidelines production and implementation, evaluation of ethical implications ofclinical research.Past and current roles at the <strong>Mario</strong> <strong>Negri</strong> Institute: 1980-1986 Junior researcher at the Laboratory ofClinical pharmacology; 1987-1989 Head, Unit of Clinical Epidemiology and Health Services Research;1990-1998 Head Laboratory of Clinical Epidemiology; since 1994 he is Director of the Italian CochraneCentre; since 1998 he is Associate Professor of Clinical Biostatistics and Epidemiology at the Universityof Modena and Reggio Emilia; since 1997 he is President of the Associazione per la Ricerca sullaEfficacia dell’Assistenza Sanitaria - Centro Cochrane Italiano (AREAS-CCI); he collaborates since 2004with the Social and Health Regional Agency of Emilia Romagna; since 2004 he is Member of theCommissione Nazionale Ricerca Sanitaria; since 2005 he is Member of the Commissione Ricerca eSviluppo dell’Agenzia Italiana del Farmaco (AIFA).Selected publications• Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis to reduce respiratory tractinfections and mortality in adults receiving intensive care. Cochrane Database Syst Rev. <strong>2009</strong>• Donati S., Cotichini R., Mosconi P., Satolli R., Colombo C., Liberati A., Mele A. Menopause: knowledge, attitude andpractice among Italian women Maturitas <strong>2009</strong>;63:246-252• Mosconi P., Donati S., Colombo C., Mele A., Liberati A., Satolli R., Consensus Conference Working Group. Informingwomen about hormone replacement therapy: the Consensus Conference statement. BMC Women’s Health <strong>2009</strong>;9:14• Mosconi P., Donati S., Colombo C., Mele A., Liberati A., Satolli R., Consensus Conference Working Group. Informingwomen about hormone replacement therapy. Cancer Journal <strong>2009</strong>;15:344• Moher D., Liberati A., Tetzlaff J., Altman D.A. Preferred reporting items for systematic reviews and metanalysis: thePRISMA Statement. Ann Intern Med <strong>2009</strong>;151:264-269• Banzi R., Moja L., Liberati A., Gensini G.F., Gusinu R., Conti A.A. Measuring the impact of evidence: the Cochranesystematic review of organized stroke care. Intern Emerg Med <strong>2009</strong>;4:507-510• Liberati A., Altman D.A., Tetzlaff J., et al. The PRISMA Statement for reporting systematic reviews and metanalyses ofstu<strong>di</strong>es that evaluate health care interventions: explanation and elaboration. Annals of Internal Me<strong>di</strong>cine <strong>2009</strong>;151:w1-w30• Moja L., Moschetti I., Nurbhai M., Compagnoni A., Liberati A. et al. Compliance of clinical trial registries with theWorld Health Organization minimum data set: a survey. Trials <strong>2009</strong>;10:56ACTIVITIESThe Italian Cochrane Centre (ICC) (http://www.cochrane.it) was founded in 1994 and isaffiliated to the Cochrane Collaboration (CC). The CC is an international non profitorganization that prepares, maintains and promotes systematic reviews of the effects of healthcare interventions. The main product of the Cochrane Collaboration is the Cochrane Library, aquarterly publication containing Cochrane systematic reviews and other relevant databases ofother siblings international organizations.The objectives of the ICC are centered around supporting various activities of the CochraneCollaboration within Italy. In particular:a) to <strong>di</strong>sseminate the knowledge of CC and CC activities throughout Italy;b) to provide methodological and practical support to all in<strong>di</strong>viduals and groups who areinterested in collaborating with the CC;c) to contribute to the adoption and <strong>di</strong>ssemination of Evidence-based Me<strong>di</strong>cine in Italy.d) to collaborate with NHS to improve the quality of clinical and epidemiological research.264ANNUAL REPORT <strong>2009</strong>
IRFMNMAIN FINDINGSThe ICC has created a national network with researchers and health care providers who areproducing systematic reviews for the Cochrane Collaboration and are actively involved in otheractivities related to the <strong>di</strong>ssemination of evidence based me<strong>di</strong>cine.NATIONAL COLLABORATIONS<strong>Istituto</strong> Neurologico "Carlo Besta", MilanoAgenzia Sanitaria Regionale, Regione Emilia Romagna, BolognaUniversità degli Stu<strong>di</strong> <strong>di</strong> Modena e Reggio Emilia, ModenaUniversità degli Stu<strong>di</strong> <strong>di</strong> Milano, MilanoDipartimento <strong>di</strong> Epidemiologia della Regione Lazio, RomaOsservatorio epidemiologico della Direzione sanità e servizi sociali della Regione Umbria,Perugia<strong>Istituto</strong> Ortope<strong>di</strong>co “Galeazzi”, MilanoIstituti Ortope<strong>di</strong>ci Rizzoli, BolognaINTERNATIONAL COLLABORATIONSThe Cochrane Collaboration, Oxford, UKCentre for Reviews and Dissemination, University of York, York, UKBritish Me<strong>di</strong>cal Journal Publishing Group, London, UKCentre for Statistics in Me<strong>di</strong>cine, Oxford, UKThomas Chalmers Centre for Systematic Reviews, Ottawa, CanadaThe Campbell Collaboration, Philadelphia, USACentre for Evidence-Based Me<strong>di</strong>cine, Oxford, UKInstitute of Health and Society, Newcastle University, Newcastle, UKClinical Epidemiology, Ottawa Hospital Research Institute, Ottawa, CanadaDepartment of Epidemiology and Community Me<strong>di</strong>cine, Faculty of Me<strong>di</strong>cine, University ofOttawa, Ottawa, CanadaEDITORIAL BOARD MEMBERSHIPEvidence Based Health Policy and Research, Journal of Clinical Epidemiology, Journal ofHealth Services Research, BMJ Evidence Centre (BMJ Publishing Group), European Journal ofClinical InvestigationPEER REVIEW ACTIVITIESAnnals of Internal Me<strong>di</strong>cine, British Me<strong>di</strong>cal Journal, JAMA, Evidence Based Health Policyand Research, Cana<strong>di</strong>an Me<strong>di</strong>cal Association Journal, PLoS Me<strong>di</strong>cine. International Journal ofEpidemiology.265ANNUAL REPORT <strong>2009</strong>
IRFMNEVENT ORGANIZATIONI° E<strong>di</strong>tion Master in “Promozione e governo della ricerca nelle aziende sanitarie”February - December <strong>2009</strong> - ModenaCourse EBM - I.R.C.C.S. <strong>Istituto</strong> Ortope<strong>di</strong>co Galeazzi, Febbraio – March <strong>2009</strong> - MilanCorso <strong>di</strong> perfezionamento avanzato in “Revisioni sistematiche e meta-analisi – metodologiaCochrane” –November <strong>2009</strong>- March 2010Workshop: November 20-21, <strong>2009</strong> - Perugia- Quando i comitati etici possono interferire nella valutazione del <strong>di</strong>segno e delsignificato <strong>di</strong> uno stu<strong>di</strong>o clinico- La me<strong>di</strong>cina non convenzionale: il ruolo delle revisioni sistematicheXIV <strong>Annual</strong> Meeting of the Italian Cochrane Network “Le priorità della ricerca nei sistemisanitari” –November 20-2, <strong>2009</strong>- PerugiaCONFERENCE AND WORKSHOP CONTRIBUTIONSII° E<strong>di</strong>tion “Corso <strong>di</strong> epidemiologia clinica e metodologia della ricerca: il dolore nel pazientecon cancro”20-21 February <strong>2009</strong>, NapoliMeeting “Evidence-based veterinary me<strong>di</strong>cine” March 14 ,<strong>2009</strong> - BolognaMaster in “Ricerca Organizzativa nelle strutture sanitarie” May 22-23 <strong>2009</strong>, Università degliStu<strong>di</strong> <strong>di</strong> FerraraMaster in Scienze Me<strong>di</strong>che <strong>di</strong> II livello “Metodologia della Ricerca”, February <strong>2009</strong>,Università degli Stu<strong>di</strong> <strong>di</strong> Parma“Evidence-based clinical practice workshop: architecture of prognostic and <strong>di</strong>agnostic stu<strong>di</strong>es” 2October <strong>2009</strong>, Gargnano<strong>2009</strong> Mid-Year Steering Group and Centre Directors’ Meeting April 20-25, <strong>2009</strong> - Copenhagen<strong>Annual</strong> Continental European Cochrane Entities Meeting (CECEM), June 10-12, <strong>2009</strong> -MaastrichtFirst <strong>Annual</strong> Croatian Cochrane Symposium, June 26-27- SpalatoXVI Cochrane Colloquium, October 11-14, <strong>2009</strong> - SingaporeWorskhop del Centre for Evidence based Me<strong>di</strong>cine <strong>di</strong> Oxford (CEBM) per la revisione della“CEBM Level of Evidence classification”; Oxford (UK) December 17, <strong>2009</strong>266ANNUAL REPORT <strong>2009</strong>
IRFMNTrenta Anni del Dipartimento <strong>di</strong> Epidemiologia della Regione Lazio, December 18,<strong>2009</strong> -RomeGRANTS AND CONTRACTS<strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> <strong>Mario</strong> <strong>Negri</strong>, MilanoUniversità degli stu<strong>di</strong> <strong>di</strong> Modena e Reggio EmiliaAgenzia sanitaria e sociale regionale, Regione Emilia-Romagna, BolognaUniversità degli Stu<strong>di</strong> <strong>di</strong> Milano, MilanoSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)All publications of the Italian Cochrane Center are available on web site www.cochrane.it.Virgili G, Conti AA, Moja L, Gensini GF, Gusinu R. Heterogeneity and meta-analyses: dostudy results truly <strong>di</strong>ffer? Internal and Emergency Me<strong>di</strong>cine <strong>2009</strong>;4:423-427Sirtori V, Corbetta D, Moja L, Gatti R. Constraint-induced movement therapy for upperextremities in stroke patients. Cochrane Database of Systematic Reviews <strong>2009</strong>, Issue 4. Art.No.: CD004433Amato B, Moja L, Panico S, Persico G, Rispoli C, Rocco N, Moschetti I. Shoul<strong>di</strong>ce techniqueversus other open techniques for inguinal hernia repair. Cochrane Database of SystematicReviews <strong>2009</strong>, Issue 4. Art. No.: CD001543Banzi R, Moja L, Liberati A, Gensini GF, Gusinu R, Conti AA. Measuring the impact ofevidence: the Cochrane systematic review of organised stroke care. Internal and EmergencyMe<strong>di</strong>cine <strong>2009</strong>;4:507-510Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche P, et al. The Prisma Group. ThePRISMA statement for reporting systematic reviews and meta-analyses of stu<strong>di</strong>es that evaluatehealth care interventions: explanation and elaboration. PLoS Med <strong>2009</strong>;6Liberati A, D'Amico R, Pifferi S, Torri V, Brazzi L, Parmelli E. Antibiotic prophylaxis toreduce respiratory tract infections and mortality in adults receveing intensive care. CochraneDatabase of Systematic Review, <strong>2009</strong> (4)Moher D, Liberati A, Tetzlaff J, Altman DG, The Prisma Group. Preferred reporting items forsystematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med<strong>2009</strong>;18:151(4):264-9Li LC, Moja L, Romero A, Sayre EC, Grimshaw JM. Nonrandomized quality improvementtrials might overstate the strenght of causal inference of their fin<strong>di</strong>ngs. Journal of clinicalepidemiology <strong>2009</strong>;62(9):959-66Banzi R, Moschetti I, Moja L. Internet-based education for health professionals. JAMA<strong>2009</strong>;301(6):599-600267ANNUAL REPORT <strong>2009</strong>
IRFMNSquizzato A, Moja L, Gensini GF, Gusinu R, Conti AA. Is thrombolysis for interme<strong>di</strong>ate-riskpulmonary embolism beneficial? The case of Emeritus Professor Crow. Internal and EmergencyMe<strong>di</strong>cine <strong>2009</strong>;4:339-41Moja L, Moschetti I, Nuebhai M, Compagnoni A, Liberati A; Grimsha JM, Chan AW,Dickersin K, Krleza-Jeric K, Moher D, Sim I, Volmink J. Compliance of clinical trial registrieswith the World Health Organitation minimum data set: a survey. Trials <strong>2009</strong>; 22 :10-56Deandrea S, Corli O, Moschetti I, Apolone G Managing severe cancer pain: the role oftransdermal buprenorphine: a systematic review. Therapeutics and clinical risk management<strong>2009</strong>; 5: 707-18.RESEARCH ACTIVITIESEducational and <strong>di</strong>ssemination activitiesThe ICC is a partner of the Thomas C. Chalmers Interuniversity Center together with eightItalian schools of me<strong>di</strong>cine. This network’s main objective is to <strong>di</strong>sseminate systematic reviewsknowledge, production and use within the academia activities. In particular, many post-graduatecourses were organized on EBM, clinical trial and systematic review methodology, and theGRADE approach to develop clinical guideline. In the context of the Thomas C. Chalmersactivities, the ICC has organized a post-graduate advanced course on systematic reviews,“Corso <strong>di</strong> Perfezionamento avanzato in revisioni sistematiche e meta-analisi per la produzione<strong>di</strong> linee guida – metodologia Cochrane”.The ICC offered in<strong>di</strong>vidual training and support to reviewers involved in specific researchprojects aimed at producing Cochrane systematic reviews (see scientific publication section).The ICC researchers collaborate with the Social and Health Regional Agency of EmiliaRomagna to produce clinical recommendations in oncology.In collaboration with PartecipaSalute project, the ICC translates the Cochrane Library pressreleases and <strong>di</strong>sseminates them to scientific journalists, doctors and consumers (through thePartecipaSalute website). In <strong>2009</strong> 54 press releases were cited by relevant Italian newspapersand ra<strong>di</strong>o programs.Research activitiesICC researchers are involved in methodological projects focused on the study of the quality ofSystematic Reviews.The ICC is involved in many multi<strong>di</strong>sciplinary projects:- Point-of-Care information tools: to describe and evaluate information tools used byclinicians during their practice. Specifically the project focuses on e<strong>di</strong>torial quality,evidence-based methodology and updating of Point-of-Care products.- Users’ guide on <strong>di</strong>scordant systematic reviews: to investigate the scientific vali<strong>di</strong>ty andreliability of systematic review’s results. The project final output will be a critical tooldeal with <strong>di</strong>scordant systematic reviews in order to inform clinical and policy decisionmaking.- ICEKUBE: randomized controlled trial to evaluate the effectiveness of the <strong>di</strong>stantlearning project ECCE, based on the Clinical Evidence contents, to improve clinician268ANNUAL REPORT <strong>2009</strong>
IRFMNknowledge. In <strong>2009</strong> the trial was concluded and the preliminary results are nowavailable.- GRADE: international collaboration with the GRADE working Group to develop andtransparent methodology on evidence quality and strength of recommendationassessment, used in the production of the clinical guideline.- PRISMA: publication of a reporting guideline to evaluate the completeness ofsystematic review reporting.- AFO (progetto Appropriatezza Farmaci Oncologici): methodological support to theSocial and Health Regional Agency of Emilia Romagna to produce clinicalrecommendations in oncology.In <strong>2009</strong> the ICC continued its collaboration with the PartecipaSalute ("Participate in HealthCare") project to foster a strategic alliance between patients’ groups and professional societieswith the common goal of promoting better health and shared decision-making. The project’smain aims are:- to increase patients’ associations’ involvement in healthcare assistance and in decisionmaking processes;- to promote a partnership between patients’ associations and me<strong>di</strong>cal societies solicitingme<strong>di</strong>cal societies’ attention to patients’ need and perspectives- to develop a partnership between citizens, patients and healthcare system.269ANNUAL REPORT <strong>2009</strong>
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IRFMNTHE CATULLO AND DANIELABORGOMAINERIO CENTEROne of the buil<strong>di</strong>ngs on the <strong>Mario</strong> <strong>Negri</strong> Institute campus is The Catullo and DanielaBorgomainerio Center built in 1987 thanks to a donation from Mrs. Angela MarchegianoBorgomainerio. This is a Center for the study of rare childhood <strong>di</strong>seases and even today some ofthe laboratories housed in the buil<strong>di</strong>ng still conduct this research. For example, the study of newtherapies used to treat a very rare form of acute myeloid leukemia, know as acute promyelocyticleukemia. A number of new stu<strong>di</strong>es are being done to identify new drugs having <strong>di</strong>fferentmechanisms able to synergize with trans retinoic acid.Research on epidemiological childhood leukemia is also done at the Borgomainerio and asimilar line of research involves testicular cancer in adolescents and young adults.We also do research aimed at fin<strong>di</strong>ng evidence based therapies for children.Pae<strong>di</strong>atric research activities done at the Borgomainerio Center are also performed incollaboration with groups located at other Institute locations inclu<strong>di</strong>ng, The Aldo and CeleDaccò Center for Clinical Research on Rare Diseases at Ranica in Bergamo, the RegionalCentre for Drug Information (CRIF) and the Laboratory for Mother and Child Health(Department of Public Health) which are both located in Milan.271ANNUAL REPORT <strong>2009</strong>
IRFMN272ANNUAL REPORT <strong>2009</strong>
IRFMNTHE LIBRARYSTAFFHead LibrarianVanna Pistotti273ANNUAL REPORT <strong>2009</strong>
IRFMNThe Library, specialised in pharmacology and clinical epidemiology, was founded in 1963thanks to a generous donation from the Gustavus and Louise Pfeiffer Research Foundation, inDenville, New Jersey, USA.Numerous public and private organisations help keep it operative, through donations in moneyor books, and subscriptions to perio<strong>di</strong>cals.STAFFOne Head and two Assistants plus a clerical workerWHAT THE LIBRARY OFFERSThe library has a collection of about 5000 textbooks, monographs and congressionalprocee<strong>di</strong>ngs, and 150 perio<strong>di</strong>cals of which a major part are in an electronic format. The booksare classified accor<strong>di</strong>ng to the US National Library of Me<strong>di</strong>cine Classification and the Me<strong>di</strong>calSubject hea<strong>di</strong>ngs of Medline (MeSH). Besides the internal collection, the Library has access tothe National Perio<strong>di</strong>cal Catalogue and to other Library systems (SBBL, GIDIF-RBM).DATABESES AND ELECTRONIC JOURNALSFrom every computer in the Institute it is now possible to have access to more than 2000electronic journals and to three of the most important databases, PubMed, the Cochrane Libraryand Embase.SPECIAL PROJECTSThe Library cooperates to the realisation of the Italian Information Specialists’ (GIDIF,RBM) journal catalog which is updated annually and to the catalog of the LombardyBiome<strong>di</strong>cal Library Consortium, a network that serves, through Internet, the scientificcommunity in this District.It collaborates to the Institute web site, particularly taking care of the Publications section, bothscientific and lay press.TRAININGEvery year courses on the use of the database and electronic journals are organised. Thesecourses are designed for use by those working at the Institute but outsiders who are interestedmay attend.274ANNUAL REPORT <strong>2009</strong>
IRFMNCONTRACTSSince 1994 the library has been part of the Lombard Biome<strong>di</strong>cal Library System. 14 universityand research organisation libraries in Lombardy take part in this project, which allows easy, freeaccess to scientific information to over 140 centres and institutions the Lombardy Region.275ANNUAL REPORT <strong>2009</strong>
IRFMN276ANNUAL REPORT <strong>2009</strong>
IRFMN<strong>Negri</strong> Bergamo LaboratoriesANNUALREPORT <strong>2009</strong>departments and laboratories277ANNUAL REPORT <strong>2009</strong>
IRFMN278ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF MOLECULARMEDICINESTAFFHeadAriela BENIGNI, Biol.Sci.D., Ph.D.Unit of Gene TherapyHeadSusanna TOMASONI, Biol.Sci.D., Ph.D.Laboratory of Cell Biology and XenotransplantationHeadMarina MORIGI, Biol.Sci.D., Ph.D.Unit of Platelet-Endothelial Cell InteractionHeadMiriam GALBUSERA, Biol.Sci.D.Laboratory of Immunology and Genetics of Organ Transplantation andRare DiseasesHeadMarina NORIS, Chem.Farm.D., Ph.D.Unit of Cellular biology of Autoimmunity and Transplant RejectionHeadSistiana AIELLO, Biol.Sci.DUnit of Cellular and Molecular Biology of Transplantation ToleranceHeadFederica CASIRAGHI, ChemistLaboratory of Experimental Models of Kidney DiseasesHeadCarla ZOJA, Biol.Sci.D., Ph.D.Unit of Pathology and ImmunophatologyHeadMauro ABBATE, M.D.279ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAAriela Benigni got the Biol.Sci. degree in 1979 at the University of Milano, Italy, and the Ph.D. atMaastricht University, Netherlands, in 2001.Educational training: in 1979 Post Doctoral Fellow, <strong>Istituto</strong> <strong>di</strong> <strong>Ricerche</strong> <strong>Farmacologiche</strong> <strong>Mario</strong> <strong>Negri</strong>(IRFMN), Laboratory of Cancer Chemotherapy, Milan, Italy; in 1980-1981 Post Doctoral Fellow,Associazione Bergamasca per lo Stu<strong>di</strong>o delle Malattie Renali, Laboratory of the Division of Nephrologyand Dialysis, Ospedali Riuniti <strong>di</strong> Bergamo, Italy; in 1982 Post Doctoral Fellow, Centre Regional deTransfusion Sanguigne de Strasbourg, France.Areas of interest: vasoactive and inflammatory me<strong>di</strong>ators of progressive renal injury with a particularemphasis on endothelin-1; combined treatment of antipertensive and renoprotective drugs to haltprogressive renal injury; use of stem cells for tissue regeneration in acute renal failure in vivo e in vitrogene transfer; prevention of acute graft rejection through gene therapy; induction of kidney transplanttolerance by gene therapy; correction of genetic deficiency in rare <strong>di</strong>seases.Employement: in 1983 Scientist, IRFMN, Laboratory of Kidney Disease, Bergamo, Italy; in 1990-1994 Head Laboratory of Prostaglan<strong>di</strong>n and Leukotriene Metabolism, IRFMN, Bergamo, Italy;from January 1991 Scientific Secretary, IRFMN, Bergamo, Italy; in 1994-1999 Head Laboratory ofVasoactive and Inflammatory Me<strong>di</strong>ators of Tissue damage, IRFMN, Bergamo, Italy; from January2000 Head, Department of Molecular Me<strong>di</strong>cine, IRFMN, Bergamo, Italy; from March 2007Consultant World Health Organization (WHO) for the multicentre observational study “Screeningfor Pre-eclampsia: evaluation of the pre<strong>di</strong>ctive ability of angiogenic factors for Pre-eclampsia”;during 2007 Senior Fellow at the University of Oxford, Nuffield Department of Obstetrics &Gynaecology.Selected publications:− Schiffmann R, Waldek S, Benigni A, Auray-Blais C. Biomarkers of Fabry Disease Nephropathy. Clin J Am Soc Nephrol.<strong>2009</strong> Nov 5. [Epub ahead of print].− Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C, Mazzinghi B,Ronconi E, Becherucci F, Benigni A, Steenbergen E, Lasagni L, Remuzzi G, Wetzels J, Romagnani P. Renal progenitor cellscontribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol. <strong>2009</strong>Dec;20(12):2593-603.− Trionfini P, Tomasoni S, Galbusera M, Motto D, Longaretti L, Corna D, Remuzzi G, Benigni A. Adenoviral-me<strong>di</strong>ated genetransfer restores plasma ADAMTS13 antigen and activity in ADAMTS13 knockout mice. Gene Ther. <strong>2009</strong> Nov;16(11):1373-9.− Gagliar<strong>di</strong>ni E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti L, Remuzzi A, Remuzzi G,Benigni A. Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental<strong>di</strong>abetes. Am J Physiol Renal Physiol. <strong>2009</strong> Nov;297(5):F1448-56.− Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, CoffmanTM, Remuzzi G. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. <strong>2009</strong> Mar;119(3):524-30.− Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S, Zoja C, Corna D, Mele C, FanelliR, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am SocNephrol. <strong>2009</strong> Jan;20(1):123-30. Epub 2008 Dec 17.Marina Morigi got her Biol.Sci. degree in 1987 at the University of Milano, Milano, Italy and the Ph.D.at Maastricht University, Netherlands, in 2005.Educational training: in 1984-1987 Research training, IRFMN, Bergamo, Italy; in 1987 1995 PostDoctoral Fellow, IRFMN, Bergamo, Italy; in 1991 Stage at Brigham and Women’s Hospital, Laboratoryof Dr. P. Marsden, Boston, USA.Employement: since 1995 Scientist, IRFMN, Bergamo, Italy; in 1996-1999 Head, Unit of Renal andEndothelial Cell Biology; since 2000 Head, Laboratory of Cell Biology and Xenotransplantation,IRFMN, Bergamo, Italy.Areas of interest: role of Shigatoxin in the pathogenesis of endothelial dysfunction and microvascularthrombosis in Hemolytic Uremic Syndrome; in vitro model of hyperacute xenograft rejection (porcineendothelium exposed to human serum as a source of xenoreactive natural antibo<strong>di</strong>es and complement);renal toxicity of the proteins filtered through the capillary barrier. In vitro model to study intracellularsignals, gene expression and production of inflammatory me<strong>di</strong>ators in cultured proximal tubular cellsand glomerular epithelial cells; cell therapy and tissue regeneration: Capability of adult stem cells to<strong>di</strong>fferentiate and to regenerate renal tissue in acute and chronic experimental models of renal <strong>di</strong>sease.280ANNUAL REPORT <strong>2009</strong>
IRFMNMurine embryonic stem cell therapy to correct the genetic defect characteristic of Fabry <strong>di</strong>sease in anexperimental mouse model.Selected publications- Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, Remuzzi A, Benigni A. Bone marrow-derivedmesenchymal stem cells improve islet graft function in <strong>di</strong>abetic rats.Transplant Proc. <strong>2009</strong> Jun;41(5):1797-800.- Buelli S, Abbate M, Morigi M, Moioli D, Zanchi C, Noris M, Zoja C, Pusey CD, Zipfel PF, Remuzzi G. Protein load impairsfactor H bin<strong>di</strong>ng promoting complement-dependent dysfunction of proximal tubular cells. Kidney Int. <strong>2009</strong> May;75(10):1050-9. Epub <strong>2009</strong> Feb 25.- Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, Sonzogni A, PericoN, Remuzzi G, Noris M. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic hearttransplant through the generation of regulatory T cells. J Immunol. 2008 Sep 15;181(6):3933-46.- Morigi M, Introna M, Imberti B, Corna D, Abbate M, Rota C, Rottoli D, Benigni A, Perico N, Zoja C, Rambal<strong>di</strong> A, RemuzziA, Remuzzi G. Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival inmice. Stem Cells. 2008 Aug;26(8):2075-82.- Imberti B, Morigi M, Tomasoni S, Rota C, Corna D, Longaretti L, Rottoli D, Valsecchi F, Benigni A, Wang J, Abbate M, ZojaC, Remuzzi G. Insulin-like growth factor-1 sustains stem cell me<strong>di</strong>ated renal repair. J Am Soc Nephrol. 2007Nov;18(11):2921-8. Epub 2007 Oct 17.- Geelen J Valsecchi F, van der Velden T, van den Heuvel L, Monnens L, Morigi M. Shiga-toxin-induced firm adhesion ofhuman leukocytes to endothelium is in part me<strong>di</strong>ated by heparan sul fate. Nephrol Dial Transplant. 2008 Oct;23(10):3091-5.Marina Noris got her degree in Pharmaceutical Chemistry and Technologies in 1986 at the Universityof Rome “La Sapienza) and the Ph.D. at Maastricht University, Netherlands, in 2005.Educational training: in 1984-1986 Fellow, <strong>Istituto</strong> <strong>di</strong> Chimica Farmaceutica e Tossicologica, Universityof Rome, Italy; in 1986-1987 Post Doctoral Fellow, <strong>Istituto</strong> <strong>di</strong> Chimica Farmaceutica e Tossicologica,University of Rome, Italy; in September 1987-March 1994 Post Doctoral Fellow, IRFMN, Unit ofMe<strong>di</strong>ators of Inflammation and Tissue Damage, Laboratory of Kidney Disease, Bergamo, Italy.Areas of interest: immunology of transplantation, tolerance induction; genetics of hemolytic uremicsyndrome, thrombotic thrombocytopenic purpura, focal segmental glomerulosclerosis, <strong>di</strong>abeticnephropathy, role of nitric oxide and arginine dysfunctions in uremia and in pre-eclampsia.Employment: in 1994-1996 Head, Unit of Endothelial Cell Pathophysiology, IRFMN, Bergamo, Italy;1996-1999 Head, Laboratory of Cellular and Molecular Biology of the immune response andautoimmunity, IRFMN, Italy; from January 2000: Head, Laboratory of Immunology and Genetics of RareDiseases and Organ Transplantation, Department of Molecular Me<strong>di</strong>cine, IRFMN, Bergamo, Italy.Selected publications• Noris M, Remuzzi G. Atypical Hemolytic Uremic Syndrome N Engl J Med. <strong>2009</strong> Oct 22;361(17):1676-87.• Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, TodeschiniM, Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. TheToll-IL-1R member Tir8/SIGIRR negatively regulates adaptive immunity against kidney grafts. J Immunol. <strong>2009</strong> Oct1;183(7):4249-60.• Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, LambrechtsD, Zoja C, Remuzzi G, Conway EM. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl JMed. <strong>2009</strong> Jul 23;361(4):345-57.• Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M,Caprioli J, Caruso RM, Artuso R, Remuzzi G, Noris M. Mutations in FN1 cause glomerulopathy with fibronectindeposits. Proc Natl Acad Sci U S A. 2008;105(7):2538-43.• Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, Sonzogni A,Perico N, Remuzzi G, Noris M. Pretransplant infusion of mesenchymal stem cells prolongs the survival of asemiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008;181(6):3933-46.• Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F,Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: theimpact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108(4):1267-79.• Noris M, Casiraghi F, Todeschini M, Crave<strong>di</strong> P, Cugini D, Monteferrante G, Aiello S, Cassis L, Gotti E, Gaspari F,Cattaneo D, Perico N, Remuzzi G. Regulatory T Cells and T Cell Depletion: Role of Immunosuppressive Drugs. J AmSoc Nephrol. 2007; 18 (3):1007-18.• Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G, on behalf of the InternationalRegistry of Familial and Recurrent HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet.2003; 362:1542-47.281ANNUAL REPORT <strong>2009</strong>
IRFMNCarlamaria Zoja got her Biol.Sci. degree at the University of Milano, Italy, in 1979 and the Ph.D. atthe University of Maastricht, The Netherlands in 2001.Educational Training: in 1979-1981 Post Doctoral Fellow, ‘Associazione Bergamasca per lo stu<strong>di</strong>o delleMalattie Renali’, Laboratory of the Division of Nephrology and Dialysis, Ospedali Riuniti <strong>di</strong> Bergamo,Italy; in 1981-1983 Post Doctoral Fellow, Center for Thrombosis and Vascular Research, Department ofResearch Katholieke Universiteit, Leuven, Belgium; in 1983-1985: Post Doctoral Fellow, IRFMN,Laboratory of Kidney Disease, Bergamo, Italy; in 1988 stage at Case Western Reserve University,Cleveland, Ohio, USA; in 1989 stage at Brigham and Women’s Hospital, Boston, USA.Areas of interest: experimental models of kidney <strong>di</strong>seases of immunological and non immunologicalorigin; vasoactive and inflammatory me<strong>di</strong>ators of renal <strong>di</strong>sease progression; role of proteinuria inprogressive kidney damage; protection of renal <strong>di</strong>sease progression by a multidrug approach; novelimmunosuppressive and anti-inflammatory strategies for the treatment of lupus nephritis; role ofShigatoxin in the pathogenesis of endothelial dysfunction in Hemolytic Uremic Syndrome.Employement: since 1985 Scientist, IRFMN, Bergamo, Italy; in 1990-1994: Head, Unit of ExperimentalModelling for Human Renal Diseases, Laboratory of Kidney Diseases, IRFMN, Bergamo, Italy; since1995: Head, Laboratory of Experimental Models of Kidney Diseases, IRFMN, Bergamo, Italy. In 2004-2007 member E<strong>di</strong>torial Board, Journal of the American Society of Nephrology.Selected publications− Perico N, Zoja C, Corna D, Rottoli D, Gaspari F, Haskell L, Remuzzi G.V1/V2 Vasopressin receptor antagonismpotentiates the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction. Kidney Int. <strong>2009</strong>;76:960-7.− Zanchi C, Zoja C, Morigi M, Valsecchi F, Liu XY, Rottoli D, Locatelli M, Buelli S, Pezzotta A, Mapelli P, Geelen J,Remuzzi G, Hawiger J. Fractalkine and CX3CR1 me<strong>di</strong>ate leukocyte capture by endothelium in response to Shiga toxin. JImmunol. 2008; 181:1460-9.− Abbate M, Zoja C, Corna D, Rottoli D, Zanchi C, Azzollini N, Tomasoni S, Berlingeri S, Noris M, Morigi M, RemuzziG. Complement-me<strong>di</strong>ated dysfunction of glomerular filtration barrier accelerates progressive renal injury. J Am SocNephrol. 2008; 19:1158-67.− Zoja C, Casiraghi F, Conti S, Corna D, Rottoli D, Cavinato RA, Remuzzi G, Benigni A. Cyclin-Dependent kinaseinhibition limits glomerulonephritis and extends lifespan of mice with systemic lupus. Arthr.Rheumatism 2007; 56;1629-37.− Donadelli R, Zanchi C, Morigi M, Buelli S, Batani C, Tomasoni S, Corna D, Rottoli D, Benigni A, Abbate M, RemuzziG, Zoja C. Protein overload induces fractalkine upregulation in proximal tubular cells through NF-kB and p38 MAPKdependent pathways. J Am Soc Nephrol. 2003;14:2436-46.− Zoja C, Corna D, Camozzi D, Cattaneo D, Rottoli D, Batani C, Zanchi C, Abbate M, Remuzzi G. How to fully protectthe kidney in a severe model of progressive nephropathy: a multidrug approach. J Am Soc Nephrol. 2002;13:2898-908.Mauro Abbate obtained his M.D. degree in 1988 at the University of Brescia, Italy.Educational training: in 1984-1988 Graduate Student, IRFMN, Bergamo, Italy; in 1988-1992 PostDoctoral Fellow, IRFMN, Bergamo, Italy; in 1992-1994 Research Fellow, The Renal Unit,Massachusetts General Hospital, HMS, Boston, USA.Areas of interest: renal <strong>di</strong>sease progression: the role of proteinuria, complement, and me<strong>di</strong>ators of injuryin progressive kidney damage; mechanisms of glomerular injury; anti-GBM glomerulonephritis;mechanisms of tubular injury; kidney fibrosis; the renal biopsy; membranous nephropathy.Employement: in 1996 - 2000: Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of RenalPathology and Immunopathology, IRFMN, Bergamo, Italy.Selected publications− Buelli S, Abbate M, Morigi M, Moioli D, Zanchi C, Noris M, Zoja C, Pusey CD, Zipfel PF, Remuzzi G. Protein loa<strong>di</strong>mpairs factor H bin<strong>di</strong>ng promoting complement-dependent dysfunction of proximal tubular cells. Kidney Int. <strong>2009</strong>May;75(10):1050-9.− Ruggenenti P, Crave<strong>di</strong> P, Sghirlanzoni MC, Gagliar<strong>di</strong>ni E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G.Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol. 2008Nov;3(6):1652-9.− Abbate M, Zoja C, Corna D, Rottoli D, Zanchi C, Azzollini N, Tomasoni S, Berlingeri S, Noris M, Morigi M, RemuzziG. Complement-me<strong>di</strong>ated dysfunction of glomerular filtration barrier accelerates progressive renal injury. J Am SocNephrol. 2008 Jun;19(6):1158-67.− Macconi D, Abbate M, Morigi M, Angioletti S, Mister M, Buelli S, Bonomelli M, Mundel P, Endlich K, Remuzzi A,Remuzzi G. Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular targetfor renoprotective intervention. Am J Pathol. 2006 Apr;168(4):1073-85.282ANNUAL REPORT <strong>2009</strong>
IRFMN− Abbate M, Zoja C, Remuzzi G. How does proteinuria cause progressive renal damage? J Am Soc Nephrol. 2006Nov;17(11):2974-84. Review− Abbate M, Zoja C, Morigi M, Rottoli D, Angioletti S, Tomasoni S, Zanchi C, Longaretti L, Donadelli R, Remuzzi G.Transforming Growth Factor-beta 1 Is Up-Regulated by Podocytes in Response to Excess Intraglomerular Passage ofProteins: A Central Pathway in Progressive Glomerulosclerosis. Am J Pathol. 2002;161,2179-93.Sistiana Aiello got the Biol.Sci. degree in 1993 at the University of Milano, Italy, and the Specializationin Pharmacology Research in 1996, at IRFMN, Bergamo, Italy.Educational training: in 1990-1993 research training, IRFMN, Bergamo; in 1993-2000 post doctoralfellow, IRFMN, Bergamo.Areas of interest: transplant immunology with a particular interest on dendritic cell biology andmechanisms by which T regulatory cells arise and work; in vitro and in vivo stu<strong>di</strong>es on new compoundswith immunosuppressive capacity or capable to prevent ischemia/reperfusion tissue injury; vasoactive an<strong>di</strong>nflammatory me<strong>di</strong>ators of progressive renal injury with a particular emphasis on platelet activating factor(PAF) and nitric oxide (NO).Employment: since 2000 Scientist within Laboratory of Immunology and Genetics of Rare <strong>di</strong>sease andOrgan Transplantation; IRFMN, Bergamo; since 2006 Head, Unit of Cellular Biology of Autoimmunityand Transplant Rejection, IRFMN, Transplant Research Center “Chiara Cucchi de Alessandri e GilbertoCrespi”, Ranica.Selected publications:- Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, Todeschini M,Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. The Toll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts. J Immunol. <strong>2009</strong>, 183(7): 4249-60.- Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S, Zoja C, Corna D, Mele C, FanelliR, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am SocNephrol. <strong>2009</strong>;20(1):123-30.- Pezzotta A, Mister M, Monteferrante G, Cassis L, Azzollini N, Aiello S, Satta M, Benigni A, Remuzzi G, Noris M. Effect ofseliciclib (CYC202, R-roscovitine) on lymphocyte alloreactivity and acute kidney allograft rejection in rat. Transplantation.2008; 85(10):1476-82.- Aiello S, Cassis P, Cassis L, Tomasoni S, Benigni A, Pezzotta A, Cavinato RA, Cugini D, Azzollini N, Mister M, LongarettiL, Thomson AW, Remuzzi G, Noris M. DnIKK2-transfected dendritic cells induce a novel population of iNOS-expressingCD4 + CD25 - cells with tolerogenic properties. Transplantation. 2007; 83:474-84.- Tomasoni S, Aiello S, Cassis L, Noris M, Longaretti L, Cavinato RA, Azzollini N, Pezzotta A, Remuzzi G, Benigni A.Dendritic cells genetically engineered with adenoviral vector enco<strong>di</strong>ng dnIKK2 induce the formation of potent CD4 + Tregulatory cells. Transplantation. 2005;79:1056-61.Federica Casiraghi has obtained his degree in Industrial Chemistry in 1988, and the degree in ClinicalMonitoring and in Biochemical Research in 1993-1994 at IRFMN, Bergamo, Italy.Educational Training: 1989-1994 research fellow, IRFMN, Bergamo.Areas of interest: Transplant immunology with particular focus on pharmacological and cellular therapiesfor induction and maintenance of transplantation tolerance. Characterization of regulatory T cells in renaltransplant patients and in experimental models of allograft tolerance. Impact of <strong>di</strong>fferentimmunosuppressive drugs on T cell function in renal transplant patients. Vasoactive and inflammatoryme<strong>di</strong>ators of progressive renal injury with a particular emphasis on arachidonic acid metabolites.Employment: since 1994 Scientist within Laboratory of Immunology and Genetics of Rare Disease andOrgan Transplantation, IRFM, Bergamo; since 2006 Head, Unit of Cellular and Molecolar Biology ofTransplantation Tolerance, Transplant Research Center “Chiara Cucchi de Alessandri e Gilberto Crespi”,Ranica.Selected Publications:− Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, Mister M, TodeschiniM, Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N, Mantovani A, Remuzzi G. TheToll-IL-1R Member Tir8/SIGIRR Negatively Regulates Adaptive Immunity against Kidney Grafts. J Immunol. <strong>2009</strong>183(7): 4249-60.− Casiraghi F, Azzollini N, Cassis P, Imberti B, Morigi M, Cugini D, Cavinato RA, Todeschini M, Solini S, Sonzogni A,Perico N, Remuzzi G, Noris M. Pretransplant infusion of mesenchymal stem cells prolongs the survival of asemiallogeneic heart transplant through the generation of regulatory T cells. J Immunol. 2008;181(6):3933-46.− Noris M, Casiraghi F, Todeschini M, Crave<strong>di</strong> P, Cugini D, Monteferrante G, Aiello S, Cassis L, Gotti E, Gaspari F,Cattaneo D, Perico N, Remuzzi G. Regulatory T Cells and T Cell Depletion: Role of Immunosuppressive Drugs. J AmSoc Nephrol. 2007; 18 (3):1007-18.283ANNUAL REPORT <strong>2009</strong>
IRFMN− Ruggenenti P, Perico N, Gotti E, Crave<strong>di</strong> P, D'Agati V, Gagliar<strong>di</strong>ni E, Abbate M, Gaspari F, Cattaneo D, Noris M,Casiraghi F, Todeschini M, Cugini D, Conti S, Remuzzi G. Sirolimus versus cyclosporine therapy increases circulatingregulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograftinjury. Transplantation. 2007, 84(8):956-64.− Cavinato RA, Casiraghi F, Azzollini N, Cassis P, Cugini D, Mister M, Pezzotta A, Aiello S, Remuzzi G, Noris M.Pretransplant donor peripheral blood mononuclear cells infusion induces transplantation tolerance by generatingregulatory T cells. Transplantation. 2005;79(9):1034-9.Miriam Galbusera got her Biol.Sci. degree in 1981 at the Università degli Stu<strong>di</strong> <strong>di</strong> Milano.Educational training: in 1981-1983 Post Doctoral Fellow, <strong>Istituto</strong> <strong>di</strong> Patologia Speciale Me<strong>di</strong>cadell'Università degli Stu<strong>di</strong> <strong>di</strong> Milano, Italy; in 1985 - 1989 Post Doctoral Fellow, IRFMN, Bergamo,Italy; in 1989-1991 Post Doctoral Fellow at Scripps Clinic and Research Foundation, Laboratory ofThrombosis and Hemostasis, La Jolla, CA, USA; in 1991-1995 Post Doctoral Fellow, IRFMN, Bergamo,Italy.Areas of interest: ADAMTS-13 and VWF in thrombotic microangiopathies, VWF biochemistry,xenotransplantation, platelet-endothelial cell interaction under flow con<strong>di</strong>tion, platelet pathophysiology inuremia, receptor stu<strong>di</strong>es in kidney and platelets.Employement: 1995 - 1999: Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of Platelet-Endothelial Cell Interaction, IRFMN, Bergamo, Italy.Selected publications− Trionfini, P, Tomasoni S, Galbusera M, Motto D, Longaretti L, Corna D, Remuzzi G, Benigni A. Adenoviral-me<strong>di</strong>ated genetransfer restores ADAMTS13 plasma levels and activity in knockout mice. Gene Therapy. <strong>2009</strong>; 16:1373-9.− Galbusera M, Remuzzi G, Boccardo P. Treatment of blee<strong>di</strong>ng in the <strong>di</strong>alysis patients. Semin Dial. <strong>2009</strong>; 22:279-86.− Galbusera M, Noris M, Remuzzi G. Inherited thrombotic thrombocytopenic purpura. Haematologica. <strong>2009</strong>; 94:166-70.− Bresin E, Gastol<strong>di</strong> S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G, GalbuseraM. Rituximab to prevent relapses in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13autoantibo<strong>di</strong>es. Thromb Haemost. <strong>2009</strong>; 101:233-8.− Benigni A, Caroli C, Longaretti L, Gagliar<strong>di</strong>ni E, Zoja C, Galbusera M, Moioli D, Romagnani P, Tincani A, Andreoli L,Remuzzi G. Renal tubular TLR9 is involved in the development of tubulointerstitial injury of systemic lupus. Arthritis Rheum.2007; 56:1569-78.− Donadelli R, Banterla F, Galbusera M, Capoferri C, Bucchioni S, Gastol<strong>di</strong> S, Ruggeri ZM, Bresin E, Scheiflinger F, Rossi E,Remuzzi G, Noris M. In vitro and in vivo consequences of mutations in the von Willebrand factor cleaving proteaseADAMTS13 in thrombotic microangiopathies. Thromb Haemost. 2006; 96:454-64.Susanna Tomasoni got her Biological Science degree in 1991 at the University of Milan and the Ph.D. atthe University of Bologna in 1995.Educational training: in 1989-1991 Graduate student, University of Milan; in 1991-1994 PhD student,University of Milan; in 1994 Research Fellow, Renal Division, Brigham & Women’s Hospital, HarvardMe<strong>di</strong>cal School, Boston, USA; 1995-1998: Post Doctoral Fellow, IRFMN, Bergamo, Italy.Areas of interest: construction of adenoviral vectors for gene therapy; in vitro and in vivo gene transfertechniques; use of adenoviral and adeno-associated viral vectors to prevent acute and chronic allograftrejection; induction of kidney transplant tolerance by cell and gene therapy; correction of geneticdeficiency in rare <strong>di</strong>seases by gene therapy; involvement of microRNAs in the progression of renal<strong>di</strong>sease; generation of induced-pluripotent stem cell from adult somatic cells; mesenchymal stem cellderivedexosomes as me<strong>di</strong>ators of cell-to-cell communication.Employment: in 1998-2000 Scientist, IRFMN, Bergamo, Italy; from 2000 Head, Unit of Gene Therapy,IRFMN, Bergamo, ItalySelected publications• Trionfini P, Tomasoni S, Galbusera M, Motto D, Longaretti L, Corna D, Remuzzi G, Benigni A. Adenoviral-me<strong>di</strong>atedgene transfer restores plasma ADAMTS13 antigen and activity in ADAMTS13 knockout mice. Gene Therapy. <strong>2009</strong>; 16:1379-85.• Tomasoni S, Remuzzi G, Benigni A. Allograft rejection: acute and chronic stu<strong>di</strong>es. Contrib Nephrol. 2008; 159:122-34.Review.• Imberti B, Morigi M, Tomasoni S, Rota C, Corna D, Longaretti L, Rottoli D, Valsecchi F, Benigni A, Wang J, AbbateM, Zoja C, Remuzzi G. Insulin-like growth factor-1 sustains stem cell me<strong>di</strong>ated renal repair. J Am Soc Nephrol. 2007;18: 2921-8.• Benigni A, Tomasoni S, Turka LA, Longaretti L, Zentilin L, Mister M, Pezzotta A, Azzollini N, Noris M, Conti S,Abbate M, Giacca M, Remuzzi G. Adeno-associated virus-me<strong>di</strong>ated CTLA4Ig gene transfer protects MHC-mismatchedrenal allografts from chronic rejection. J Am Soc Nephrol. 2006, 17: 1665-72.284ANNUAL REPORT <strong>2009</strong>
IRFMN• Tomasoni S, Aiello S, Cassis L, Noris M, Longaretti L, Cavinato R, Azzollini N, Pezzotta A, Remuzzi G, Benigni A.Dendritic cells genetically engineered with adenoviral vector enco<strong>di</strong>ng dnIKK2 induce the formation of potent CD4+ T-regulatory cells. Transplantation. 2005; 79: 1056-61.• Tomasoni S, Azzollini N, Casiraghi F, Capogrossi M C, Remuzzi G, Benigni A. CTLA4Ig gene transfer prolongssurvival and induces donor-specific tolerance in a rat renal allograft. J Am Soc Nephrol. 2000; 11: 747-52.ACTIVITIESThe Department of Molecular Me<strong>di</strong>cine was established in 1999 at the <strong>Negri</strong> Bergamolaboratories to coor<strong>di</strong>nate the work of three laboratories and three units. The activities of theDepartment of Molecular Me<strong>di</strong>cine are strictly interrelated with those of the Department ofRenal Me<strong>di</strong>cine of the Clinical Research Center for Rare Diseases Aldo e Cele Daccò.The following major objectives have been pursued:1) identification of me<strong>di</strong>ators and mechanisms responsible for the relentless decline of renalfunction in kidney <strong>di</strong>seases and development of therapeutic interventions to slow or even haltthe <strong>di</strong>sease progression to end-stage renal failure;2) understan<strong>di</strong>ng the mechanisms underlying endothelial cell dysfunction in thromboticmicroangiopathies and hyperacute rejection of xenograft3) fin<strong>di</strong>ng new strategies for modulating the immune response and preventing acute and chronicrejection of kidney allograft as well as exploration of immunological pathways lea<strong>di</strong>ng to donorspecific unresponsiveness and tolerance of the graft;4) investigation of the molecular and genetic basis of rare <strong>di</strong>seases such as hemolytic uremicsyndrome/thrombotic thrombocytopenic purpura and pre-eclampsia and search for <strong>di</strong>seasesusceptibilitygenes or gene polymorphisms pre<strong>di</strong>cting the patient's response to drug therapy inmore common and complex polygenic <strong>di</strong>sorders.Such goals have been pursued using various approaches: 1) experimental models of kidney<strong>di</strong>seases of immunological and non-immunological origin mimicking human renal <strong>di</strong>seases tostudy vasoactive and inflammatory me<strong>di</strong>ators and to test novel antiproteinuric andrenoprotective drugs; 2) in vitro cultures of renal cells to address the toxicity of protein overloadreproducing the con<strong>di</strong>tion of exaggerated protein traffic of proteinuric progressivenephropathies; 3) in vitro models to assess the interaction of vascular endothelial cells withleukocytes and platelets under controlled flow con<strong>di</strong>tions; 4) experimental models of kidneyallotransplant to study immunological processes responsible for acute and chronic rejection, thenephrotoxicity of immunosuppressor drugs as well as to explore pathways responsible foraccomodation; 5) gene transfer of viral constructs carrying genes enco<strong>di</strong>ng immunomodulatorymolecules to overcome acute rejection of allotransplantation avoi<strong>di</strong>ng immunosuppression; 6)identification of can<strong>di</strong>date genes with linkage analysis and search for mutations as well asassessment of gene polymorphisms.MAIN FINDINGSKnocking out angiotensin II type 1 receptor prolongs survival of mice.A new drug association to slow the progression of chronic renal <strong>di</strong>sease.Thrombomodulin modulates complement activation on the surface of endothelial cells: a novellink between complement and coagulation systems.285ANNUAL REPORT <strong>2009</strong>
IRFMNCord blood mesenchymal stem cells are more effective than bone marrow mesenchymal stemcells in repairing acute renal injury and in prolonging survival of mice.A new approach to improve mesenchymal stem cells tissue regeneration capability in acuterenal failure.Gene therapy restores ADAMTS13 deficiency: new hope for gene therapy for ThromboticThrombocytopenic Purpura.TIR8 modulates innate immune response against kidney transplantation.Genetic abnormalities in thrombomodulin – a coagulation protein -pre<strong>di</strong>spose to atypicalHeamolitic Uremic Syndrome (aHUS).Complement factors mutations in atypical HUS (aHUS) cause massive complement systemactivation responsible for endothelial cells injury.NATIONAL COLLABORATIONSLaboratorio <strong>di</strong> Terapia genica e cellulare, G. Lanzani, Divisione <strong>di</strong> Ematologia, Ospedali Riuniti<strong>di</strong> BergamoLaboratorio <strong>di</strong> Tecnologie riproduttive, <strong>Istituto</strong> Sperimentale Lazzaro Spallanzani, CremonaLaboratorio <strong>di</strong> Virologia, <strong>Istituto</strong> Nazionale per le Malattie Infettive L. Spallanzani, RomaCentro Trasfusionale e <strong>di</strong> Immunologia dei Trapianti, IRCCS Ospedale Maggiore, MilanoDipartimento <strong>di</strong> Istologia Microbiologia e Biotecnologie Me<strong>di</strong>che, Università <strong>di</strong> PadovaDipartimento <strong>di</strong> Biotecnologie, Università <strong>di</strong> VeronaInternational Centre for Genetic Engineering and Biotechnology, Molecular Me<strong>di</strong>cine Group,TriesteU.O. <strong>di</strong> Ostetricia e Ginecologia, Ospedale San Gerardo <strong>di</strong> MonzaU.O. <strong>di</strong> Ostetricia e Ginecologia, Azienda Ospedaliera Ospedali Riuniti <strong>di</strong> BergamoU.O. <strong>di</strong> Ostetricia e Ginecologia, Azienda Ospedaliera Spedali Civili <strong>di</strong> BresciaI.R.C.C.S. Policlinico San Matteo, PaviaConsorzio per la Ricerca sul Trapianto <strong>di</strong> Organi, Tessuti, Cellule e Me<strong>di</strong>cina RigenerativaCORIT, PadovaINTERNATIONAL COLLABORATIONSAcademisch Ziekenhuis Maastricht, Interne Geneeskunde, Maastricht, The NetherlandsBeth Israel Deaconess Me<strong>di</strong>cal Center and Harvard Me<strong>di</strong>cal School, Boston, USACharitè Campus Virchov Klinikum, Berlin, GermanyChildren's Hospital and Regional Me<strong>di</strong>cal Center, University of Washington, Seattle, USADepartements of Pe<strong>di</strong>atrics and Human Genetics, University of Michigan, Ann Arbor, USADeparment of Me<strong>di</strong>cine, Division of Rheumatology, Washington University School ofMe<strong>di</strong>cine, St. Louis, USADuke University Me<strong>di</strong>cal Center and Durham Veterans Affairs Me<strong>di</strong>cal Center, Durham, NorthCarolina, USAErasmus University of Rotterdam, The NetherlandsHans-Knoll Institute for Natural Products Research, Jena, GermanyINSERM, Paris, FranceKlinikum der Ludwig Maximillians Universitat Munchen, Germany286ANNUAL REPORT <strong>2009</strong>
IRFMNMax Delbruck Center for Molecular Me<strong>di</strong>cine, Berlin, GermanyMax-Plank Gesellschaft zur Forderung der Wissenshaften, Hpi of experimental endocrinology,Hannover, GermanyNecker Hospital, Paris, FranceRenal Transplant Unit, Hospital de Bellvitge, Barcelona, SpainRosalind Franklin University of Me<strong>di</strong>cine and Science, Chicago, USAUniversitaet Hamburg, Institut fur Molekulare Neuropathobiologie, Hamburg, GermanyUniversity of Aarhus, DenmarkUniversity of British Columbia, Vancouver, CanadaUniversity of Colorado Car<strong>di</strong>ovascular Institute, Denver, USAUniversity of Groningen, The NetherlandsUniversity of Liverpool, School of Biological Sciences, UKUniversity of Oulu, DenmarkUniversity of Pittsburgh School of Me<strong>di</strong>cine, Pittsburgh, USAUniversity of Zurich, SwitzerlandWeizmann Institute of Science, Rehovot, IsraelWorld Health Organization, Geneva, SwitzerlandJournal of American Society of NephrologyInternational Journal of Artificial OrgansEDITORIAL BOARD MEMBERSHIPPEER REVIEW ACTIVITIESAmerican Journal of PathologyAmerican Journal of PhysiologyCell ProliferationDiabetologiaHypertensionImmunologyKidney InternationalJournal of Clinical InvestigationJournal of the Renin Angiotensin Aldosterone SystemJournal of the American Society of NephrologyJournal of Thrombosis and HaemostasisNature Me<strong>di</strong>cineNephrology, Dialysis and TransplantationNephron Clinical PracticeNew England Journal of Me<strong>di</strong>cinePe<strong>di</strong>atric NephrologyPlos Me<strong>di</strong>cineThe American Journal of PathologyThe Cana<strong>di</strong>an Journal of Physiology and PharmacologyThe Journal of Experimental Me<strong>di</strong>cineThe LancetThe Open Urology & Nephrology JournalTransplant Immunology287ANNUAL REPORT <strong>2009</strong>
IRFMNTrends in molecular me<strong>di</strong>cineCONFERENCE AND WORKSHOP CONTRIBUTIONS33° Congresso Nazionale Società Italiana Trapianto d’Organo, Milano, 13-15 December <strong>2009</strong>Grandangolo <strong>2009</strong> in nefrologia, <strong>di</strong>alisi e trapianto, Bologna, 17 December<strong>2009</strong>Stem cell-based therapies: background and practice, Università degli Stu<strong>di</strong> <strong>di</strong> Milano, 3December <strong>2009</strong>XVI Symposium of the “Reina Sofia”, Madrid, 19-20 November <strong>2009</strong>XII Corso Educazionale SISET: Microangiopatie trombotiche e coagulopatie da consumo,Bosco Marengo, 6-7 November <strong>2009</strong>Meeting American Society of Nephrology, San Diego, 29 October -2 November <strong>2009</strong>The Cord meeting , Policlinico Mangiagalli, Cell Factory, Milano, 19 October <strong>2009</strong>Joint Meeting IPITA-IXA <strong>2009</strong>, Venezia, 12-16 October <strong>2009</strong>Focus on cell therapy: Transplantation and tissue repair, Bergamo, 8-10 October <strong>2009</strong>50° Congresso Nazionale Società Italiana <strong>di</strong> Nefrologia (SIN), Bologna, 7-10 October<strong>2009</strong>4 th International Workshop on Thrombotic Microangiopathies, Weimar, 1-3 October<strong>2009</strong>Meeting per progetto GENECURE, FP6, Stoccolma, 16-17 September <strong>2009</strong>Congresso Europeo <strong>di</strong> Immunologia, Berlino, September13-16, <strong>2009</strong>ET-11, 11° International Conference on Endothelin, Montreal, 9-12 September <strong>2009</strong>12th European Meeting on Complement in Human Disease, Visegrad, 5-8 September <strong>2009</strong>FRR-E Society for Free Ra<strong>di</strong>cals Research Europe Meeting <strong>2009</strong>, Roma, 27-28 August <strong>2009</strong>University of Florence Workshops Series “Systemic Sclerosis and its vascular complications:state of the art in <strong>di</strong>agnosis and therapy”, Firenze, 22 June <strong>2009</strong>KIDSTEM International Conference, E<strong>di</strong>nburgh, 29-31 July <strong>2009</strong>American Transplant Congress, Boston, 30 Maggio-3 June <strong>2009</strong>WCN <strong>2009</strong> World Congress of Nephrology, Milano, 22-29 May <strong>2009</strong>Serono Symposia International Foundation, Progress in stem cell biology and me<strong>di</strong>calapplications’, Stresa, 14-16 Maggio <strong>2009</strong>288ANNUAL REPORT <strong>2009</strong>
IRFMNConference on “HUS- Current <strong>di</strong>agnosis and therapy of haemolytic uremic syndrome”,Innsbruck, 18-20 May <strong>2009</strong>EuReGene Meeting, FP6, Berlino, 14-16 May <strong>2009</strong>EuroKup European Kidney and Urine Proteomics, European Science Foundation, Nafplio, 29-30 March <strong>2009</strong>21st <strong>Annual</strong> Meeting of the European Renal Cell Study Group ERCSG, Delphi, 26-28 March<strong>2009</strong>KIDSTEM meeting Vienna, 26-27 March <strong>2009</strong>Cellule staminali e me<strong>di</strong>cina rigenerativa <strong>2009</strong>, attualità e prospettive, Pavia, 16-20 March <strong>2009</strong>Atrasentam (M10-815) Protocol Advisory meeting, 6-7 March <strong>2009</strong>, Atlanta,12° Convegno Patologia Immune e malattie orfane <strong>2009</strong>, Torino, 22-24 JanuaryStar-T Rek kick off Meeting, Siena, 14-15 January <strong>2009</strong>GRANTS AND CONTRACTSComitato Telethon Fondazione ONLUSEuropean Commission FP6 and FP7Fondazione Aiuti per la Ricerca sulle Malattie Rare (ARMR)Fondazione ART per la Ricerca sui Trapianti ONLUSFondazione CariploFondazione Compagnia <strong>di</strong> San PaoloFondazione Chiesi<strong>Istituto</strong> Superiore <strong>di</strong> SanitàAblynx NVACRAF (Aziende Chimiche Riunite Angelini Francesco Spa)Alexion PharmaceuticalsEvolva AGGenzyme CorporationLFB BiotechnologiesTaligen TherpeuticsSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Schiffmann R, Waldek S, Benigni A, Auray-Blais C. Biomarkers of Fabry Disease Nephropathy. Clin JAm Soc Nephrol. <strong>2009</strong> Nov 5. [Epub ahead of print].Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C,Mazzinghi B, Ronconi E, Becherucci F, Benigni A, Steenbergen E, Lasagni L, Remuzzi G, Wetzels J,Romagnani P. Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescenticglomerulonephritis. J Am Soc Nephrol. <strong>2009</strong> Dec;20(12):2593-603.289ANNUAL REPORT <strong>2009</strong>
IRFMNNoris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. <strong>2009</strong> Oct 22;361(17):1676-87. Review.Cassis P, Conti S, Remuzzi G, Benigni A. Angiotensin receptors as determinants of life span. PflugersArch. <strong>2009</strong> Sep 11. [Epub ahead of print].Dahlke MH, Hoogduijn M, Eggenhofer E, Popp FC, Renner P, Slowik P, Rosenauer A, Piso P, GeisslerEK, Lange C, Chabannes D, Mazzanti B, Bigenzahn S, Bertolino P, Kunter U, Introna M, Rambal<strong>di</strong> A,Capelli C, Perico N, Casiraghi F, Noris M, Gotti E, Seifert M, Saccar<strong>di</strong> R, Verspaget HW, van Hoek B,Bartholomew A, Wekerle T, Volk HD, Remuzzi G, Deans R, Lazarus H, Schlitt HJ, Baan CC; MISOTStudy Group. Toward MSC in solid organ transplantation: 2008 position paper of the MISOT studygroup. Transplantation. <strong>2009</strong> Sep 15;88(5):614-9.Noris M, Cassis P, Azzollini N, Cavinato R, Cugini D, Casiraghi F, Aiello S, Solini S, Cassis L, MisterM, Todeschini M, Abbate M, Benigni A, Trionfini P, Tomasoni S, Mele C, Garlanda C, Polentarutti N,Mantovani A, Remuzzi G. The Toll-IL-1R member Tir8/SIGIRR negatively regulates adaptive immunityagainst kidney grafts. J Immunol. <strong>2009</strong> Oct 1;183(7):4249-60.Trionfini P, Tomasoni S, Galbusera M, Motto D, Longaretti L, Corna D, Remuzzi G, Benigni A.Adenoviral-me<strong>di</strong>ated gene transfer restores plasma ADAMTS13 antigen and activity in ADAMTS13knockout mice. Gene Ther. <strong>2009</strong> Nov;16(11):1373-9.Gagliar<strong>di</strong>ni E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti L,Remuzzi A, Remuzzi G, Benigni A. Unlike each drug alone, lisinopril if combined with avosentanpromotes regression of renal lesions in experimental <strong>di</strong>abetes. Am J Physiol Renal Physiol. <strong>2009</strong>Nov;297(5):F1448-56.Perico N, Zoja C, Corna D, Rottoli D, Gaspari F, Haskell L, Remuzzi G. V1/V2 Vasopressin receptorantagonism potentiates the renoprotection of renin-angiotensin system inhibition in rats with renal massreduction. Kidney Int. <strong>2009</strong> Nov;76(9):960-7.Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, ClaesB, Lambrechts D, Zoja C, Remuzzi G, Conway EM. Thrombomodulin mutations in atypical hemolyticuremicsyndrome. N Engl J Med. <strong>2009</strong> Jul 23;361(4):345-57.Goumenos DS, Kawar B, El Nahas M, Conti S, Wagner B, Spyropoulos C, Vlachojannis JG, Benigni A,Kalfarentzos F. Early histological changes in the kidney of people with morbid obesity. Nephrol DialTransplant. <strong>2009</strong> Dec;24(12):3732-8.Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, Remuzzi A, Benigni A. Bone marrowderivedmesenchymal stem cells improve islet graft function in <strong>di</strong>abetic rats. Transplant Proc. <strong>2009</strong>Jun;41(5):1797-800.Benigni A, Remuzzi G. Treatment of chronic proteinuric kidney <strong>di</strong>sease: what next? Hypertension. <strong>2009</strong>Jul;54(1):29-31.Longaretti L, Benigni A. Endothelin receptor selectivity in chronic renal failure. Eur J Clin Invest. <strong>2009</strong>Jun;39 Suppl 2:32-7. Review. Erratum in: Eur J Clin Invest. <strong>2009</strong> Jul;39(7):630.Noris M, Remuzzi G. Thrombotic microangiopathy: what not to learn from a meta-analysis. Nat RevNephrol. <strong>2009</strong> Apr;5(4):186-8.Zoja C, Garcia PB, Remuzzi G. The role of chemokines in progressive renal <strong>di</strong>sease. Front Biosci. <strong>2009</strong>Jan 1;14:1815-22. Review. PubMed PMID: 19273165.290ANNUAL REPORT <strong>2009</strong>
IRFMNBuelli S, Abbate M, Morigi M, Moioli D, Zanchi C, Noris M, Zoja C, Pusey CD, Zipfel PF, Remuzzi G.Protein load impairs factor H bin<strong>di</strong>ng promoting complement-dependent dysfunction of proximal tubularcells. Kidney Int. <strong>2009</strong> May;75(10):1050-9.Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P,Morigi M, Coffman TM, Remuzzi G. Disruption of the Ang II type 1 receptor promotes longevity inmice. J Clin Invest. <strong>2009</strong> Mar;119(3):524-30.Galbusera M, Noris M, Remuzzi G. Inherited thrombotic thrombocytopenic purpura. Haematologica.<strong>2009</strong> Feb;94(2):166-70. Review.Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S, Zoja C,Corna D, Mele C, Fanelli R, Remuzzi G, Benigni A. Proteasomal processing of albumin by renaldendritic cells generates antigenic peptides. J Am Soc Nephrol. <strong>2009</strong> Jan;20(1):123-30.Vlahou A, Charonis A, Benigni A. <strong>Report</strong> on the first combined working group and managementcommittee meeting of EuroKUP (Urine and Kidney Proteomics cost action). J Proteomics. <strong>2009</strong> Jan30;71(6):682-4.RESEARCH ACTIVITIESLaboratory of Cell Biology and XenotransplantationHuman amniotic fluid stem cells accelerate recovery of acute kidneyinjury and prolong survival in miceTransplantation of bone marrow or cord blood-derived mesenchymal stem cells (MSCs) hasbeen in<strong>di</strong>cated as a new approach for the cure of acute kidney injury (AKI). However, bonemarrow collection is associated with considerable patient’s <strong>di</strong>scomfort and isolation of MSCsfrom cord blood is not invariably successful. By contrast, various progenitors have been easilyobtained from amniotic fluid. Here we investigated the potential of human amniotic fluidderivedstem (hAFS) cells to prevent AKI induced by cisplatin and prolong survival inimmunodeficient mouse model. Human AFS cells were obtained by amniotic fluid takenbetween 14-18 weeks of gestation from amniocentesis. Cells were immunoselected for CD117positivity. Results showed that infusion of human AFS cells significantly protected cisplatinmicefrom renal function deterioration as documented by low levels of serum blood ureanitrogen in respect to mice given saline at 4 days. In parallel, human AFS cell injectionmarkedly reduced tubular damage in terms of less number of luminal casts and necrotic tubuli.Improvement of function and preservation of tubular structures resulted in a significantprolongation (p
IRFMNtransplanted under the kidney capsule of 25 weeks-old rats exhibiting proteinuria andhistological changes. At sacrifice, 6 weeks later, macroscopic views revealed that MET haddeveloped into large structures, some of them with cysts containing fluid with a concentration ofcreatinine much higher as compared to the serum suggesting a filtering action of MET to form<strong>di</strong>luted urine. Histological analysis of grafted MET showed the presence of glomeruli andtubuli. Blood vessels within grafts exhibited intraluminal FITC-albumin upon intravenousinjection of the tracer, in<strong>di</strong>cating vascular connection to the host. FITC-BSA in the tubular cellsof the graft suggested a basic absorptive capacity. Our data provide evidence that, in the contextof chronic renal <strong>di</strong>sease, MET can mature into new nephrons. Whether these neo-kidneys areable of creating pro-regenerative environment is presently matter of investigation.Atypical Haemolytic Uremic Syndrome (aHUS)-associated geneticcomplement abnormalities cause C3 deposition on endothelial cells.In collaboration with the Laboratory of Immunology and Genetic of Rare Diseases andOrgan TransplantationaHUS is a rare <strong>di</strong>sease characterized by microangiopathic hemolytic anemia, thrombocytopeniaand renal dysfunction due to endothelial cell damage and thrombus formation in renalmicrocirculation. Genetic abnormalities of complement regulators and of the components of thealternative pathway C3 convertase, CFB and C3, have been reported in aHUS. To investigatewhether these mutations cause C3 deposition on endothelial cells and whether complementinhibitors prevent C3 accumulation, we selected 25 aHUS patients carrying mutations in CFH,CFI, C3 and mutations or the risk R32W polymorphism in CFB. Human microvascularendothelial cells (HMEC-1) pre-activated with ADP were incubated with serum from patients orhealthy controls, C3 deposits were visualized by immunofluorescence and the area measured.HMEC-1 exposed to patient serum showed intense deposition of C3 on cell surface. Indeed, thearea covered by C3 was significantly higher on cells exposed to aHUS serum than on cellsexposed to control serum. Soluble complement receptor1 (sCR1) -an inhibitor of all the threepathways (classical, alternative and lectin) of complement activation- markedly inhibited C3deposits. No appreciable C4 or IgG staining was observed on cells exposed to the same aHUSsera, in<strong>di</strong>cating a selective activation of the alternative pathway of complement. We thenevaluated whether two specific inhibitors of the alternative pathway of complement, an anti-CFB antibody (TA106) and the C3d-targeted complement inhibitor CR2-FH (TT30) were ableto inhibit aHUS-serum induced C3 deposition on HMEC-1. Ad<strong>di</strong>tion of either TT30 or TA106to patients’ serum (with CFH mutations) lead to a significant reduction of area covered by C3 ascompared to untreated serum. In conclusion, we documented that aHUS-associated mutations incomplement components cause alternative pathway-me<strong>di</strong>ated complement hyperactivation an<strong>di</strong>mpair the natural resistance of endothelial cells to complement attack. These fin<strong>di</strong>ngs offer therationale for the development of new mechanism-based complement inhibitors to cure this lifethreatening<strong>di</strong>sease.Laboratory of Experimental Models of Kidney DiseasesDisruption of the Ang II type 1 receptor promotes longevity in miceThe renin-angiotensin system plays a role in the etiology of hypertension and thepathophysiology of car<strong>di</strong>ac and renal <strong>di</strong>seases in humans. Ang II is the central product of thissystem and is involved in regulating immune responses, inflammation, cell growth, andproliferation by acting through Ang II type 1 receptors (AT 1 ). Our recent study shows thattargeted <strong>di</strong>sruption of the Agtr1a gene that encodes AT 1A results in marked prolongation of lifespan in mice. Agtr1a–/– mice developed less car<strong>di</strong>ac and vascular injury, and heart, aorta andkidney from these mice <strong>di</strong>splayed less oxidative damage than wild-type mice. The longevityphenotype was associated with an increased number of mitochondria and upregulation of the292ANNUAL REPORT <strong>2009</strong>
IRFMNprosurvival genes nicotinamide phosphoribosyltransferase (Nampt) and sirtuin 3 (Sirt3) in thekidney. In cultured tubular epithelial cells, Ang II downregulated Sirt3 mRNA, and this effectwas inhibited by an AT 1 antagonist. These results demonstrated that <strong>di</strong>sruption of AT 1 promoteslongevity in mice, possibly through the attenuation of oxidative stress and overexpression ofprosurvival genes. AT 1 receptor antagonists have been proven safe and are used as a keycomponent of the modern therapy for hypertension and car<strong>di</strong>ac failure. Whether the resultsobtained in mice were confirmed in humans, AT 1 receptor antagonists could represent a possibletherapeutic strategy for <strong>di</strong>seases of aging and to extend life span. Further stu<strong>di</strong>es are necessaryto deepen the role of AT 1 receptor in humans and to understand whether its function is similar tothat found in animals.Combined treatment of angiotensin converting enzyme inhibitor withendothelin receptor antagonist induces a complete renoprotection inexperimental <strong>di</strong>abetesIn collaboration with the Department of Biome<strong>di</strong>cal EngineeringProteinuria is one of the major risk factors for renal <strong>di</strong>sease progression in patients with chronicnephropathies. The hyperfiltration of proteins through the glomerular barrier is associated withalterations in structure and function of visceral epithelial cells, the podocytes, with theconsequent increased <strong>di</strong>mension of pores perforating the glomerular capillary. The increasedglomerular filtration of plasma proteins leads to damage of tubuli, which try to recover theexaggerated amount of proteins escaped from the glomerular filter with the consequentaccumulation of inflammatory cells in the interstitium. Angiotensin converting enzymeinhibitors (ACEi) represent the current gold standard for renoprotection. However, an imperfectprotection was observed when these drugs were given in the advanced phase of the <strong>di</strong>sease.From previous stu<strong>di</strong>es, a role for endothelin-1 in proteinuric chronic renal <strong>di</strong>seases has beensuggested, thus provi<strong>di</strong>ng the rationale for novel therapeutic approaches with endothelinreceptor antagonists (ETRA). In experimental <strong>di</strong>abetes we recently observed a completerenoprotection with the combined treatment of ACEi with ETRA. Renoprotection resulted in anormalization of proteinuria and regression of glomerular lesions in terms of reducedaccumulation of extracellular matrix. The effect of the drug combination of fully protectinganimals from renal injury is the result of two <strong>di</strong>verse mechanisms acting synergistically. TheACEi preserved the glomerular permselective properties restoring the pore <strong>di</strong>mension of theglomerular barrier and improving the integrity and function of podocytes with the consequentreduction of proteinuria. ETRA improved the architecture of peritubular capillaries and,therefore, renal interstitial blood perfusion, and preserved tubulointerstitial structure whichwould possibly lead to amelioration of tubular function and protein reabsorption. In conclusion,combined administration of ACEi and ETRA could provide a novel opportunity to treat patientswith <strong>di</strong>abetes and overt nephropathy who have incomplete benefit from ACE inhibitor alone.Renal progenitor cells contribute to hyperplastic lesion of <strong>di</strong>fferent human<strong>di</strong>seasesA wide variety of renal <strong>di</strong>seases, inclu<strong>di</strong>ng collapsing glomerulopathy, focal segmentalglomerulosclerosis and extracapillary glomerulonephritis, is characterized by glomerularlesions. In the early stage of the injury, an excessive proliferation of glomerular epithelial cellsleads to obliteration of the space between Bowman’s capsule and capillary tuft. This generatespathological bridges connecting these <strong>di</strong>fferent glomerular <strong>di</strong>stricts, and subsequent hyperplasticlesions called crescents. Progression of glomerular injury toward glomerulosclerosis ischaracterized by the evolution from an early hyperplastic lesion to a fibrous lesion, related to agradual accumulation of extracellular matrix (ECM). Theories explaining the origin of crescentsare controversial, and which cells contribute to the formation of these lesions is still unknown.A previous study described along the Bowman’s capsule of healthy human glomeruli the293ANNUAL REPORT <strong>2009</strong>
IRFMNpresence of three subsets of cell populations: immature renal progenitors, visceral epithelialcells or podocytes, and transitional cells which co-express markers of both the other cellpopulations. Progenitor cells were able to replace injured podocytes. In a recent study wecharacterized the phenotype of the cell populations of hyperplastic lesions of patients sufferingfrom <strong>di</strong>fferent types of glomerulopathies. We have observed that most of the cells withincrescents <strong>di</strong>splay features of immature progenitors and transitional cells sometimesproliferating, but a high percentage of <strong>di</strong>fferentiated podocytes, which can even represent 50%of total cells in the lesions, are present. Through in vitro study we have observed that thesecells, and in particular progenitors, when exposed to transforming growth factor-b (TGFb), areable to produce type IV collagen, fibronectin and laminin, which are the main constituents ofECM. Taken together, these results suggest that, while in the early phase of the <strong>di</strong>sease renalprogenitors of the Bowman’s capsule <strong>di</strong>fferentiate into podocytes thus replacing injured cells, inpresence of a severe glomerular damage, they excessively proliferate lea<strong>di</strong>ng to formation ofhyperplastic lesions.V 1 /V 2 vasopressin receptor antagonism potentiates the renoprotection ofrenin-angiotensin system inhibition in a rat model of proteinuric chronicnephropathy.In collaboration with the Department of Renal Me<strong>di</strong>cineThe current therapy for chronic proteinuric nephropathy is based on blockade of the reninangiotensinsystem (RAS) which slows, but may not halt, the progression of <strong>di</strong>sease particularlywhen pharmacologic intervention is started late. Besides RAS, vasopressin has been suggestedto play a role in the progression of renal <strong>di</strong>sease by increasing intraglomerular capillary pressureand stimulation of mesangial cells proliferation. Vasopressin exerts its biological effects by theinteraction with a specific subtype of receptors, inclu<strong>di</strong>ng vascular V 1 and renal V 2 receptors.Thus, V 1 and/or V 2 receptor antagonists could be included in a multimodal strategy toimplement renoprotection obtained by blockade of RAS. We stu<strong>di</strong>ed the effect of a dual V 1 andV 2 vasopressin receptor antagonist (RWJ-676070) alone or combined with ACE inhibitor onproteinuria and renal <strong>di</strong>sease progression in rats with 5/6 nephrectomy starting during overtnephropathy. This model is characterized by severe hypertension, proteinuria,glomerulosclerosis, tubulointerstitial damage and progressive renal function deterioration. Ourresults demonstrate that RWJ-676070 afforded a partial antiproteinuric effect, which wasenhanced by the ad<strong>di</strong>tion of ACE inhibitor. Renal function impairment, and glomerular andtubular changes were partially ameliorated by RWJ-676070. These parameters weresignificantly improved by ACE inhibitor and to a greater extent by the combined therapy. Thepresent fin<strong>di</strong>ngs suggest that vasopressin receptor antagonists combined with ACE inhibitorcould be considered a valid therapeutic approach for those patients who do not completelybenefit by ACE inhibiton.Laboratory of Immunology and Genetic of Rare Diseases andOrgan TransplantationThe Toll-Interleukin-1 Receptor member Tir8/SIGIRR negatively regulatesadaptive immunity against kidney graftsMembers of the Toll-like receptor (TLR)/interleukin-1 receptor (IL-1R) superfamily me<strong>di</strong>ateischemia/reperfusion injury and initiate immune response in transplanted organs. Here we testedthe hypothesis that Toll-IL-1R8 (TIR8), a negative regulator of TLR/IL-1R highly expressed inthe kidney, modulates immune cell activation underlying kidney rejection. In a mouse model offully mismatched kidney allotransplantation in which the graft is spontaneously accepted, intragraftTir8 expression was enhanced compared to naïve kidneys. Targeted deletion of Tir8 in the294ANNUAL REPORT <strong>2009</strong>
IRFMNgraft exerted a powerful anti-tolerogenic action lea<strong>di</strong>ng to acute rejection. Despite similar levelsof TLR4, IL-1R and their ligands, post-transplant ischemia/reperfusion-induced inflammatoryresponse was more severe in Tir8-/- than in Tir8+/+ grafts and was followed by expansion andmaturation of resident dendritic cell (DC) precursors. In vitro, Tir8-/- DC precursors acquiredhigher allostimulatory activity and released more IL-6 upon stimulation with a TLR4 ligand andTNF-alpha than Tir8+/+ cells, which may explain the increased frequency of anti-donorreactive T cells and the block of regulatory T cell formation we found in vivo in recipients of aTir8-/- kidney. Thus, TIR8 acts locally as a key regulator of allogeneic immune response in thekidney. Tir8 expression and/or signalling in donor tissue are envisaged as a novel target forcontrol of innate immunity and amelioration of graft survival.Toward MSC in solid organ transplantation: 2008 position paper of theMISOT study group.Mesenchymal Stem Cells (MSC) have emerged as a promising cell population forimmunomodulatory therapy. A variety of promising results have been reported in vitro and inanimal models of (auto-) immunity. Notwithstan<strong>di</strong>ng these early promising results with MSCtherapy, moving this concept forward clinical application in solid organ transplantation shouldbe critically assessed by experts in the field. Our initiative focuses on the application of MSC tosolid organ transplantation for the purpose of inducing operational immunologic tolerance or atleast enabling the reduction of pharmacological immunosuppression. For this purpose, we haveformed a study group, MISOT (Mesenchymal Stem Cells in Solid Organ Transplantation,www.misot.de) to <strong>di</strong>scuss our current base of knowledge and to consider if, and how, to proceedwith ethical clinical trial using MSC. This is the position paper summarizes therecommendations for early clinical trials and ongoing basic research in the field ofmesenchymal stem cell-induced solid organ graft acceptance--agreed upon on the first meetingof the Mesenchymal Stem Cells In Solid Organ Transplantation (MISOT) study group in late2008.Atypical haemolytic-uremic syndromeThe haemolytic–uremic syndrome is characterized by non immune haemolytic anemia,thrombocytopenia, and renal impairment. The <strong>di</strong>sorder occurs most frequently in children underthe age of 5 years, with an annual incidence of 6.1 cases per 100,000 children under 5 years, ascompared with an overall incidence of 1 to 2 cases per 100,000. The presentation is generallyheralded by <strong>di</strong>arrhea, which is often bloody. Most cases (inclu<strong>di</strong>ng more than 90% of those inchildren) are secondary to infection with Escherichia coli serotypes O157:H7, O111:H8,O103:H2, O123, O26, or others, which produce Shiga-like toxin (Stx), and several otherbacteria, such as Streptococcus pneumoniae. Approximately 10% of cases of the haemolytic–uremic syndrome are classified as atypical, since they are not caused by either Stx-producingbacteria or streptococci. Atypical hemolytic–uremic syndrome has a poor prognosis, with deathrates as high as 25% and progression to end-stage renal <strong>di</strong>sease in half the patients. Researchhas linked atypical haemolytic–uremic syndrome to uncontrolled activation of the complementsystem. This article reviews current concepts about the pathobiology of this syndrome and its<strong>di</strong>agnosis and management.Thrombomodulin mutations in atypical hemolytic-uremic syndromeThe hemolytic-uremic syndrome consists of the triad of microangiopathic hemolytic anemia,thrombocytopenia, and renal failure. The common form of the syndrome is triggered byinfection with Shiga toxin-producing bacteria and has a favourable outcome. The less commonform of the syndrome, called atypical haemolytic-uremic syndrome, accounts for about 10% ofcases, and patients with this form of the syndrome have a poor prognosis. Approximately half ofthe patients with atypical haemolytic-uremic syndrome have mutations in genes that regulate the295ANNUAL REPORT <strong>2009</strong>
IRFMNcomplement system. Genetic factors in the remaining cases are unknown. We stu<strong>di</strong>ed the role ofthrombomodulin, an endothelial glycoprotein with anticoagulant, antiinflammatory, andcytoprotective properties, in atypical haemolytic-uremic syndrome. We sequenced the entirethrombomodulin gene (THBD) in 152 patients with atypical haemolytic-uremic syndrome an<strong>di</strong>n 380 controls. Using purified proteins and cell-expression systems, we investigated whetherthrombomodulin regulates the complement system, and we characterized the mechanisms. Weevaluated the effects of thrombomodulin missense mutations associated with atypicalhaemolytic-uremic syndrome on complement activation by expressing thrombomodulin variantsin cultured cells. Of 152 patients with atypical haemolytic-uremic syndrome, 7 unrelatedpatients had six <strong>di</strong>fferent heterozygous missense THBD mutations. In vitro, thrombomodulinbinds to C3b and factor H (CFH) and negatively regulates complement by accelerating factor I-me<strong>di</strong>ated inactivation of C3b in the presence of cofactors, CFH or C4b bin<strong>di</strong>ng protein. Bypromoting activation of the plasma procarboxypeptidase B, thrombomodulin also acceleratesthe inactivation of anaphylatoxins C3a and C5a. Cultured cells expressing thrombomodulinvariants associated with atypical hemolytic-uremic syndrome had <strong>di</strong>minished capacity toinactivate C3b and to activate procarboxypeptidase B and were thus less protected fromactivated complement. Mutations that impair the function of thrombomodulin occur in about 5%of patients with atypical haemolytic-uremic syndrome.Unit of Gene TherapyGene therapy to correct Thrombotic Thrombocytopenic PurpuraThrombotic Thrombocytopenic Purpura is a thrombotic microangiopathy characterized byanemia and thrombocytopenia caused by erythrocytes fragmentation in the microcirculation andby the formation of intravascular thrombi, respectively. The <strong>di</strong>sease manifests prevalent, but notexclusive, neurologic symptoms and renal dysfunction. TTP patients show deposition ofultralarge multimers of von Willebrand (vWF) factor due to the deficiency of ADAMTS13protease, a plasma protein able to cleave VWF secreted from endothelial cells. ADAMTS13deficiency may be constitutive due to mutations in the correspon<strong>di</strong>ng gene, or acquired, due tothe presence of circulating autoantibo<strong>di</strong>es. Plasma infusion is the treatment of choice forpatients with familial TTP, however, it exposes patients to high risk of infections, fluid volumeoverload and allergies. These main limitations prompted us to look for an alternative therapy.One of the project research of the Department is to evaluate if a gene therapy approach is able torestore ADAMTS13 production in Adamts13 -/- knockout mice. We first generated a recombinantadenoviral vector enco<strong>di</strong>ng for human ADAMTS13 and tested its efficacy in vitro. In vivoexperiments on Adamts13 -/- mice were subsequently performed. A systemic injection ofadenoviral vector induced transgene expression in liver, kidney, heart, lung, and spleen oneweek after injection with concomitant release into the plasma of large amounts of functionallyactive ADAMTS13 protein. ADAMTS13 protein persisted in plasma for at least 12 weeks.Moreover, by mean of an ex vivo thrombogenesis test, we demonstrated that the protein secrete<strong>di</strong>n the blood of treated mice reduced the area covered by thrombi in respect to blood fromcontrol mice. The use of an adenoviral vector as a gene transfer tool, however, causes theproduction of antibo<strong>di</strong>es against both the adenovirus and the transgene that may be responsiblefor the reduction in the expression and activity of the recombinant protein in the long term. Inorder to reduce the activation of the immune system, we are now evaluating alternative genedelivery strategies. Moreover, since ADAMTS13 deficiency in mice does not cause TTP , weare trying to obtain a mouse TTP model to test if gene therapy approach is able to cure the<strong>di</strong>sease.Mechanism of cell-to-cell communication between MSc and tubular cellsinjury296ANNUAL REPORT <strong>2009</strong>
IRFMNIn collaboration with the Laboratory of Cell Biology and XenotransplantationRecent stu<strong>di</strong>es demonstrated that exogenous bone marrow mesenchymal stem cells (MSCs) maycontribute to the recovery of tissue injury in several organs. We demonstrated thatadministration of mouse primary bone marrow-derived MSC in a mouse model of cisplatininducedacute kidney injury (AKI) ameliorates renal dysfunction and repairs tubular damage.This effect is possibly due to the ability of MSCs to promote renal tubular cell proliferation. Thelow number of MSC found within the renal tissue after injury together with the increasedproliferation of tubular cells suggest that MSCs may exert their effects by a paracrine action onresident cells.Further stu<strong>di</strong>es of the Department will be performed to characterize the signaling me<strong>di</strong>atorsinvolved in the mechanism of cell-to-cell communication between MSCs and damage tubularcells (growth factors, antiinflammatory cytokines and exosomes).MicroRNAs Involvement in the progression of the renal <strong>di</strong>seaseIn collaboration with the Laboratory of Renal Biophysics (Department of Bioengineering)MicroRNAs are small, endogenously expressed non-co<strong>di</strong>ng RNA molecules that regulate targetgene expression through translation repression or messenger RNA degradation. MicroRNAs areinvolved in a number of physiological processes like development, cellular proliferation, andapoptosis but also in pathological con<strong>di</strong>tions such as in car<strong>di</strong>ovascular <strong>di</strong>seases and in cancer.One of the research of the Department is the identification of possible microRNAs modulatedduring the progression of renal <strong>di</strong>sease in order to find gene and mechanisms pre<strong>di</strong>sposing to therenal damage.Induction of pluripotent stem cells from somatic cellsIn collaboration with the Laboratory of Renal Biophysics (Department of Bioengineering)The therapeutic effects of human embryonic stem cells (hES cells) have been reported in severalanimal models of degenerative <strong>di</strong>seases, but only in January <strong>2009</strong> the US FDA approved thefirst clinical trial for treating patients affected by spinal cord injury with hES cells. The clinicalapplications of hES cells are associated with some obstacles: the immune rejection aftertransplantation and ethical concerns about the use of embryos. The induced pluripotent stemcells (iPS) technology could overcome the obstacles associated with hES cells. The iPS cellsrefer to pluripotent stem cells that are artificially induced from <strong>di</strong>fferentiated cells byintroducing four transcription factors (OCT4, KLF4, SOX2 and cMyc) highly expressed in hEScells. Several methods have been used to deliver the four transcription factors into the somaticcells, but the plasmid based transfection seems to be the more safe, because it can avoid theintegration into the house genome. On the basis of these evidences, our group cloned the fourtranscription factors in a single plasmid vector that assures the same expression levels for thefour factors in the <strong>di</strong>fferentiated cells. In particular, we have chosen to reprogram human adultdermal fibroblast cells because they are easy to obtain from patients. The final goal of ourresearch will be to obtain iPS cells from patients affected from rare genetics <strong>di</strong>seases in order tocorrect their pathology.297ANNUAL REPORT <strong>2009</strong>
IRFMN298ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF BIOMEDICALENGINEERINGSTAFFHead Andrea REMUZZI, Eng. D.Laboratory of Renal BiophysicsHeadDaniela MACCONI, Biol.Sci.D.Laboratory of Biome<strong>di</strong>cal TechnologiesHeadBogdan ENE-IORDACHE, Eng.D.Unit of Tissue EngineeringHeadMarina FIGLIUZZI, Biol.Sci.D.Unit of Me<strong>di</strong>cal ImagingHeadLuca ANTIGA, Ph.D.299ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAAndrea Remuzzi got his degree in Mechanical (Biome<strong>di</strong>cal) Engineering in 1979, Politecnico <strong>di</strong> Milano.Research experience: 1980 Politecnico <strong>di</strong> Milano, Dipartimento <strong>di</strong> Ingegneria Biome<strong>di</strong>ca; 1981 <strong>Istituto</strong><strong>Mario</strong> <strong>Negri</strong> (Milano), Laboratorio <strong>di</strong> Farmacologia Car<strong>di</strong>ovascolare; 1982-83 Massachusetts Institute ofTechnology, Mechanical Engineering Department, Cambridge, USA.Areas of interest: biological transport phenomena, mathematical models, renal pathophysiology, cellularresponse to mechanical stimulation, tissue engineering, pancreatic islet transplantation, clinical databases,computational fluid dynamics.Chronology of appointment: From 1984 to 1986 Ricercatore <strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong> (Bergamo), Laboratorio<strong>di</strong> malattie renali, 1986-1989 Head, Unità <strong>di</strong> Bioingegneria, <strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong>, 1989-1993 Head,Laboratorio <strong>di</strong> Bioingegneria, <strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong>, 1993-1999 Head, Dipartimento <strong>di</strong> Ricerca Renale,<strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong>, from 2000 Head, Dipartimento <strong>di</strong> Bioingegneria, <strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong>. From 1998 to2007 contract professor of Bioengineering, Politecnico <strong>di</strong> Milano. For 2007 Professor of Bioengineering,University of Bergamo.Selected publications• Davies PF, Remuzzi A, Gordon EJ, Dewey CF Jr, Gimbrone MA Jr. Turbulent fluid shear stress induces vascularendothelial cell turnover in vitro. Proc Natl Acad Sci U S A. 1986 Apr;83(7): 2114-7. PMID: 3457378• Remuzzi A, Puntorieri S, Battaglia C, Bertani T, Remuzzi G. Angiotensin converting enzyme inhibition amelioratesglomerular filtration of macromolecules and water and lessens glomerular injury in the rat. J Clin Invest. 1990Feb;85(2):541-9. PMID: 1688888• Noris M, Morigi M, Donadelli R, Aiello S, Foppolo M, Todeschini M, Orisio S, Remuzzi G, Remuzzi A. Nitric oxidesynthesis by cultured endothelial cells is modulated by flow con<strong>di</strong>tions. Circ Res. 1995 Apr;76(4):536-43. PMID:7534657• Giavazzi R, Foppolo M, Dossi R, Remuzzi A. Rolling and adhesion of human tumor cells on vascular endotheliumunder physiological flow con<strong>di</strong>tions. J Clin Invest. 1993 Dec;92(6):3038-44. PMID: 7504697• Antiga L, Ene-Iordache B, Remuzzi A. Computational geometry for patient-specific reconstruction and meshing ofblood vessels from MR and CT angiography. IEEE Trans Med Imaging. 2003 May;22(5):674-84. PMID: 12846436• Remuzzi A, Gagliar<strong>di</strong>ni E, Sangalli F, Bonomelli M, Piccinelli M, Benigni A, Remuzzi G. ACE inhibition reducesglomerulosclerosis and regenerates glomerular tissue in a model of progressive renal <strong>di</strong>sease. Kidney Int. 2006Apr;69(7):1124-30.• Ruggenenti P, Remuzzi A, Remuzzi G. Decision time for pancreatic islet-cell transplantation. Lancet. 2008 371:883-4.• Antiga L, Piccinelli M, Fasolini G, Ene-Iordache B, Ondei P, Bruno S, Remuzzi G, Remuzzi A. Computed tomographyevaluation of autosomal dominant polycystic kidney <strong>di</strong>sease progression: a progress report. CJASN 2006 1:754-60.• Cornolti R, Figliuzzi M, Remuzzi A. Effect of micro-and macroencapsulation on oxygen consumption by pancreaticislets. Cell Transplant. <strong>2009</strong>; 18(2): 195-201.• Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V, Crippa L, Avezza F,Fiordaliso• F, Salio M, Lauria G, Lombar<strong>di</strong> R, Cavaletti G. Regression of <strong>di</strong>abetic complications by islet transplantation in the rat.• Diabetologia <strong>2009</strong> sep 30; 52: 2653-2661.• Cornolti R, Cattaneo I, Trudu M, Figliuzzi M, Remuzzi A. Effect of islet transplantation on metabolic glucose control inrats• with <strong>di</strong>abetes. Diabetes Technol Ther. <strong>2009</strong> Dec; 11(12):805-11Daniela Macconi got her Biol.Sci.D. degree in Milan in the 1983.Research experience: 1977-81 CNR Institute of Neuroscience - Cell Mol Pharmacology - and Departmentof Me<strong>di</strong>cal Pharmacology, University of Milan, Milan, Italy;1982-83 Laboratory of the Division ofNephrology and Dialysis, Ospedali Riuniti <strong>di</strong> Bergamo, Bergamo, Italy; 1984-85 University of Michigan,Me<strong>di</strong>cal School, Department of Pathology, Me<strong>di</strong>cal Science I, Ann Arbor Michigan, USA; 1985-89<strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, Laboratory of Kidney Disease, Bergamo, Italy.Areas of interest: glomerular permeability, renal <strong>di</strong>sease progression, podocytes, angiotensin II, reactiveoxygen speciesChronology of appointment: From 2000 Head Laboratory of Renal Biophisics, Department ofBiome<strong>di</strong>cal Engineering; 1994-2000 Head, Unit of Inflammatory Me<strong>di</strong>ator of Leucocyte Origin; 1989- 94Scientist, 1985-89 post-doctoral fellow <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, Bergamo,Italy; 1982-83 fellow Laboratory of the Division of Nefrology e Dialysis, Ospedali Riuniti <strong>di</strong> Bergamo,Bergamo, Italy300ANNUAL REPORT <strong>2009</strong>
IRFMNSelected publications• Macconi D, Sangalli F, Bonomelli M, Conti S, Condorelli L, Gagliar<strong>di</strong>ni E, Remuzzi G, Remuzzi A. Podocyterepopulation contributes to regression of glomerular injury induced by ACE inhibition. Am J Pathos 174:797-807, <strong>2009</strong>• Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S, Zoja C, Corna D, Mele C,Fanelli R, Remuzzi G, Benigni A. Proteasomal processing of albumin by renal dendritic cells generates antigenicpeptides. J Am Soc Nephrol 20:123-30, <strong>2009</strong>.• Macconi D, Abbate M, Morigi M, Angioletti S, Mister M, Buelli S, Bonomelli M, Mundel P, Endlich K, Remuzzi A,Remuzzi G: Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular targetfor renoprotective intervention. Am J Pathol 168:1073-85, 2006.• Macconi D, Bonomelli M, Benigni A, Plati T, Sangalli F, Longaretti L, Conti S, Kawachi H, Hill P, Remuzzi G,Remuzzi A. Pathophysiologic implications of reduced podocyte number in a rat model of progressive glomerular injury.Am J Pathol 68:42-54, 2006.• Morigi M, Buelli S, Zanchi C, Longaretti L, Macconi D, Benigni A, Moioli D, Remuzzi G, Zoja C. Shigatoxin –inducedendothelin-1 expression in cultured podocytes autocrinally me<strong>di</strong>ates actin remodeling. Am J Pathol 169:1965-75, 2006• Morigi M, Macconi D, Zoja C, Donadelli R, Buelli S, Zanchi C, Ghilar<strong>di</strong> M, Remuzzi G: Protein overload-induced NFkappaBactivation in proximal tubular cells requires H(2)O(2) through a PKC-dependent pathway. J Am Soc Nephrol13:1179-89, 2002• Macconi D, Ghilar<strong>di</strong> M, Bonassi ME, Mohamed EI, Abbate M, Colombi F, Remuzzi G, Remuzzi A: Effect ofangiotensin-converting enzyme inhibition on glomerular basement membrane permeability and <strong>di</strong>stribution of zonulaoccludens-1 in MWF rats. J Am Soc Nephrol 11:477-89, 2000.Bogdan Ene-Iordache got a MSc in Mechanical Engineering in 1990 at the Oil & Gas Institute inPloiesti (Romania). In 1992 he joined the Bioengineering Laboratory at <strong>Negri</strong>BERGAMO Laboratories.Main interests: renal research (hemodynamics and remodeling of arteriovenous fistula for vascular access,morfometrical analysis of glomerular capillaries) and controlled clinical trials (data management and dataanalysis); clinical research informatics (local and web-based application development), coor<strong>di</strong>nation of ITactivity in the Clinical Research Center for Rare Diseases ‘Aldo e Cele Daccò’, applied clinicalinformatics (development and maintenance of Electronic Health Records - EHR).Roles: since January 2000 is head of the Biome<strong>di</strong>cal Technologies Laboratory, Department of Biome<strong>di</strong>calEngineering.Selected publications• Ene-Iordache B, Imberti O, Foglieni O, Remuzzi G, Bertani T and Remuzzi A. Effects ofangiotensin-converting enzyme inhibition on glomerular capillary wall ultrastructure inMWF/Ztm rats. J Am Soc Nephrol 5: 1378-1384, 1994.• Ene-Iordache B and Remuzzi A. Numerical analysis of blood flow in reconstructed glomerularcapillary segments. Microvasc Res 49: 1-11, 1995.• Remuzzi A and Ene-Iordache B. Capillary network structure does not affect theoretical analysisof glomerular size selectivity. Am J Physiol 268: F972-F979, 1995.• Ene-Iordache B, Mosconi L, Remuzzi G, Remuzzi A. Computational fluid dynamics of avascular access case for hemo<strong>di</strong>alysis. J Biomech Eng 123(3): 284-292, 2001.• Ene-Iordache B, Mosconi L, Antiga L, Bruno S, Anghileri A, Remuzzi G, Remuzzi A. Ra<strong>di</strong>alartery remodeling in response to shear stress increase within arteriovenous fistula forhemo<strong>di</strong>alysis access. Endothelium 10(2): 95-102, 2003.• Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherar<strong>di</strong> G, Arnol<strong>di</strong>F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, RemuzziG for the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators.Preventing microalbuminuria in type 2 <strong>di</strong>abetes. NEJM 351(19): 1941-1951, 2004.• Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G and Remuzzi A.Developing regulatory-compliant electronic case report forms for clinical trials: experience withthe DEMAND trial. J Am Med Inform Assoc, 16(3):404-408, <strong>2009</strong>.Marina Figliuzzi got her Biol.Sci.D. degree in Milan in the 1991.Research experience :1991-94 <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, Bergamo, Italy.Areas of interest: isolation of pancreatic islets from human, bovine , pig and rat pancreas, cell culture,immunoisolation devices for pancreatic islets, <strong>di</strong>fferentiation of progenitor pancreatic cells in insulincontaining cells, immunhistochemistry.301ANNUAL REPORT <strong>2009</strong>
IRFMNChronology of appointment: From 2000 Head Unit of Tissue Engineering, Department of Biome<strong>di</strong>calEngineering; 1991-2000 fellow laboratory of Renal research, <strong>Mario</strong> <strong>Negri</strong> Institute for PharmacologicalResearch, Bergamo, Italy.Selected publications• Cornolti R, Cattaneo I, Trudu M, Figliuzzi M, Remuzzi A.Effect of islet transplantation on metabolic glucose control inrats with <strong>di</strong>abetes.Diabetes Technol Ther. <strong>2009</strong> Dec;11(12):805-11.• Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V, Crippa L, Avezza F,Fiordaliso F, Salio M, Lauria G, Lombar<strong>di</strong> R, Cavaletti G. Regression of <strong>di</strong>abetic complications by islet transplantationin the rat. Diabetologia. <strong>2009</strong> Dec;52(12):2653-2661.• Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, Remuzzi A, Benigni A. Bone marrow-derivedmesenchymal stem cells improve islet graft function in <strong>di</strong>abetic rats. Transplant Proc. <strong>2009</strong> Jun;41(5):1797-800.• Cornolti R, Figliuzzi M, Remuzzi A. Effect of micro- and macroencapsulation on oxygen consumption by pancreaticislets.Cell Transplant. <strong>2009</strong>;18(2):195-201.• Figliuzzi M, Adobati F, Cornolti R, Cassis P, Remuzzi G, Remuzzi A.Assessment of in vitro <strong>di</strong>fferentiation of bovinepancreatic tissue in insulin-expressing cells. JOP 9(5):601-11, 2008.• Figliuzzi M, Plati T, Cornolti R, Adobati F, Fagiani A, Rossi L, Remuzzi G, Remuzzi A. Biocompatibility and functionof microencapsulated pancreatic islets. Acta Biomater. 2006 Mar;2(2):221-7.• Figliuzzi M, Cornolti R, Plati T, Rajan N, Adobati F, Remuzzi G, Remuzzi A: Subcutaneous xenotransplantation ofbovine pancreatic islets. Biomaterials. 26:5640-47, 2005.• Figliuzzi M, Zappella S, Morigi M, Rossi P, Marchetti P, Remuzzi A: Influence of donor age on bovine pancreatic isletisolation. Transplantation. 70:1032-37, 2000Luke Antiga graduated in 1999 in Biome<strong>di</strong>cal Engineering and got his PhD in Bioengineering in 2003,Politecnico <strong>di</strong> Milano, having worked at the research laboratory of Biome<strong>di</strong>cal Technology, Departmentof Bioengineering Institute <strong>Mario</strong> <strong>Negri</strong>.Training activities: 2003 Post-doctoral fellow at Imaging Research Laboratories, Robarts ResearchInstitute, London, Ontario.Areas of interest: acquisition and image processing for me<strong>di</strong>cal and microscopy applications, numericalmodeling of transport phenomena.Roles: from 2000 to 2002 Doctoral Student at the Laboratory of Biome<strong>di</strong>cal Technology, Department ofBioengineering, from 2002 to 2003 visiting scientist Robarts Institute for me<strong>di</strong>cal Imaging, London,Ontario, Canada, from 2004 to 2006 resercher at the Laboratory of Biome<strong>di</strong>cal Technology, Departmentof Bioengineering, from 2007 Head Unit of Me<strong>di</strong>cal Imaging, Department of Bioengineering.Selected publications• Antiga L, and Steinman DA. Rethinking turbulence in blood. Biorheology, 46(2): 77-81, <strong>2009</strong>.• Piccinelli M, Veneziani A, Steinman DA, Remuzzi A and Antiga L. A framework for geometric analysis of vascularstructures: application to cerebral aneurysms. IEEE Transactions on Me<strong>di</strong>cal Imaging, 28(8): 1141-55, <strong>2009</strong>.• Botti L, Piccinelli M, Ene-Iordache B, Remuzzi A and Antiga L. An adaptive mesh refinement solver for large-scalesimulation of biological flows. Communications in Numerical Methods in Engineering, 26(1): 86-100, 2010.• Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G, Remuzzi A. Developing regulatorycompliantelectronic case report forms for clinical trials: the DEMAND trial. JAMIA, 16(3): 404-408, May-Jun <strong>2009</strong>.• Lee SW, Antiga L and Steinman DA. Correlations among in<strong>di</strong>cators of <strong>di</strong>sturbed flow at the normal carotid bifurcation.Journal of Biomechanical Engineering, 131(6): , Jun <strong>2009</strong>.• Antiga L, Piccinelli M, Botti L, Ene-Iordache B, Remuzzi A and Steinman DA. An image-based modeling frameworkfor patient-specific computational hemodynamics. Me<strong>di</strong>cal and Biological Engineering and Computing, 46: 1097-1112,Nov 2008.• Antiga L, Wasserman B, Steinman D. On the overestimation of early wall thickening at the carotid bulb by black bloodMRI, with implications for coronary and vulnerable plaque imaging. Magnetic Resonance in Me<strong>di</strong>cine, 60(5): 1020-1028, Nov 2008.• Antiga L, Piccinelli M, Fasolini G, Ene-Iordache B, Ondei P, Ruggenenti P, Remuzzi G and Remuzzi A. Computedtomography evaluation of ADPKD progression: a progress report. Clinical Journal of the American Society ofNephrology (CJASN), 1(4): 754-760, Jul 2006.• Thomas JB, Antiga L, Che S, Milner JS, Hangan Steinman DA, Spence JD, Rutt BK and Steinman DA. Variation in thecarotid bifurcation geometry of young vs. older adults: Implications for "geometric risk" of atherosclerosis. Stroke,36(11): 2450-2456, Nov 2005.• Antiga L, Steinman DA. Robust and objective decomposition and mapping of bifurcating vessels. IEEE Transactions onMe<strong>di</strong>cal Imaging, 23(6): 704-713, June 2004.• Antiga L, Ene-Iordache B and Remuzzi A. Computational geometry for patient-specific reconstruction and meshing ofblood vessels from MR and CT angiography. IEEE Transactions on Me<strong>di</strong>cal Imaging, 22(5): 674-684, May 2003.• Antiga L, Ene-Iordache B, Remuzzi G and Remuzzi A. Automatic generation of glomerular capillary topologicalorganization. Microvascular Research, 62: 346-354, June 2001.302ANNUAL REPORT <strong>2009</strong>
IRFMNACTIVITIESThe Department of Bioengineering conducts research and development in biome<strong>di</strong>cine, both atexperimental and clinical level. Physiopathological processes are stu<strong>di</strong>ed through the use ofengineering techniques and to develop innovative treatment strategies. Several lines of researchin basic, applied research and clinical are currently active within the Department . The maininstruments used for this research consist of: theoretical models; <strong>di</strong>agnostic imaging;histological measures; physical and chemical parameters in both experimental and clinicalstu<strong>di</strong>es; cell culture techniques; biomaterials; technologies for archiving and processing ofclinical data. The ongoing stu<strong>di</strong>es relate to four main areas: 1) study of the mechanismsinvolved in the progression of chronic nephropathy; 2) stu<strong>di</strong>es on the role hemodynamics in thedevelopment of vascular <strong>di</strong>seases; 3) development of laboratory techniques for tissueengineering, 4 ) developement of information systems to manage clinical data and imagesgenerated in the context of controlled clinical trials and in routine clinical practice.MAIN FINDINGSWe produced evidence demonstrating a possible relationship between the geometry of thecerebral arterial vessels, hemodynamic con<strong>di</strong>tions and location of cerebral aneurysms. Thesefin<strong>di</strong>ngs are opening new perspectives in the understan<strong>di</strong>ng of the mechanisms responsible forthis <strong>di</strong>sease.Demonstration of a significant relationship between morphometric parameters of the renalparenchyma, quantified through elaboration of CT images, and the loss of renal function inpatients with polycystic kidney <strong>di</strong>sease.Demonstration that the mechanism responsible for regeneration of the glomerular capillary,induced by drugs that inhibit the angiotensin II, depends on the proliferation of parietal cells ofBowman capsule and their migration on the glomerular capillary loops.Implementation of a web-based system for the management, in compliance with GCP, ofclinical data generated in controlled clinical trials.Set up a new network of specialists in Nephrology for data collection aimed at monitoring thequality of treatment of chronic progressive nephropathy in current clinical practice.NATIONAL COLLABORATIONSDipartimento <strong>di</strong> Bioingegneria, Politecnico <strong>di</strong> Milano, Milano.Fi<strong>di</strong>a Advanced Biopolymers, Abano Terme, Padova.Unità <strong>di</strong> Diabetologia, Ospedali Riuniti, Bergamo.STMicroelectronics , Agrate Brianza, MilanoUniversità <strong>di</strong> BergamoDipartimento <strong>di</strong> scienze Neurologiche e della visione, Università <strong>di</strong> Verona.Dipartimento <strong>di</strong> Ingegneria Industriale e Dipartimento <strong>di</strong> Ingegneria dell’informazione e meto<strong>di</strong>MatematiciFacoltà <strong>di</strong> Me<strong>di</strong>cina e Chirurgia, Università degli stu<strong>di</strong> <strong>di</strong> Milano303ANNUAL REPORT <strong>2009</strong>
IRFMNINTERNATIONAL COLLABORATIONSMassachussetts Institute of Technology, Cambridge MA, USA.National Alliance for Me<strong>di</strong>cal Imaging Computing, USA.Harvard Me<strong>di</strong>cal School, Cambridge MA, USA.Department of Mathematics and Computer Science, Emory University, Atlanta, Georgia, US.Simula Laboratories, Oslo, NorwayAcademisch Me<strong>di</strong>sch Centrum, Amsterdam, the NetherlandsUniversity of Toronto, Ontario, Canada.Ghent University, Ghent, Belgium.Technical University, Eindhoven, The Netherlands.University Hospital, Maastricht, The Netherlands.Universzitetni Klinikni Center Lubjana, Ljubljana, Slovenia.The University of Sheffield, Sheffield, United Kingdom.EDITORIAL BOARD MEMBERSHIPInternational Journal of Artificial Organs, (Andrea Remuzzi)PEER REVIEW ACTIVITIESAnnals of Biome<strong>di</strong>cal EngineeringASME Journal of Biomechanical EngineeringJournal of Vascular ResearchMagnetic Resonance in Me<strong>di</strong>cineStrokeJournal of the American Society of NephrologyKidney InternationalAmerican Journal of Kidney DiseasesAmerican Journal of PathologyAmerican Journal of PhysiologyMe<strong>di</strong>cal & Biological Engineering & ComputingNew England Journal of Me<strong>di</strong>cineIEEE Transactions on Me<strong>di</strong>cal ImagingIEEE Transactions on Biome<strong>di</strong>cal EngineeringMe<strong>di</strong>cal PhysicsJournal of BiomechanicsMe<strong>di</strong>cal Engineering and PhysicsArtificial OrgansInternational Journal of Artificial OrgansBiomaterialsContemporary Clinical TrialsJournal of Endocrinological Investigation304ANNUAL REPORT <strong>2009</strong>
IRFMNEVENT ORGANIZATIONSeminar: “High resolution micro-CT in biological and biome<strong>di</strong>cal applications", Dr. JeroenHostess, SkyScan (http://www.skyscan.be/home.htm) (seminario organizzato in collaborazionecon Assing S.p.A. - Roma) September, Sala Conferenze Centro Daccò, Ranica, Bergamo.Seminar: "Uno strumento web-base per la randomizzazione negli stu<strong>di</strong> clinici controllati.Presentazione del nouvo portale degli stu<strong>di</strong> clinici del centro Daccò" Simone Manini,September, Sala Conferenze Centro Daccò, Ranica, Bergamo.Seminar: "Developing regulatory-compliant eletronic case report forms for clinical trials: theDEMAN rats." Journal of the American Me<strong>di</strong>cal Informatics Association, Bogdan Ene-Iordache, May, Sala Conferenze Centro Daccò, Ranica, Bergamo.Mini Course: Utilizzo del programma per analisi <strong>di</strong> immagini "ImageJ", DipartimentoBioingegneria Luca Antiga, Aprile, Sala conferenze Centro Daccò, Ranica Bergamo.Seminar: “The Pathobiology of the Saccular Cerebral Artery Aneurysm Rupture and Repair”,Juhana Frösén, Department of Neurosurgery, Helsinki University Central Hospital, February,Sala Conferenze Centro Daccò, Ranica, Bergamo.Course for nephrologists and <strong>di</strong>abetologists: “La Remission Clinic nella pratica clinica: nuoveprospettive <strong>di</strong> prevenzione e trattamento per le nefropatie croniche progressive”.Dicember, Sala Conferenze Centro Daccò, Ranica, Bergamo.CONFERENCE AND WORKSHOP CONTRIBUTIONS1 st Open Clinica European Summit, April <strong>2009</strong>, Brussels; Presentations were given byin<strong>di</strong>viduals involved in both industry and academic clinical trials.Vascular Access Society 6 th Congress, April <strong>2009</strong>, Roma; Hemodynamics of vascular access:technical aspects.The 15th ERCIM Environmental Modelling Group Workshop took place on 27 May <strong>2009</strong>during the ERCIM Spring Days Meeting & 20th Anniversary Celebration, Les Jar<strong>di</strong>ns duMarais Hotel, Paris, France.2 nd ICT Coor<strong>di</strong>nators Day on Project Management in FP7, June <strong>2009</strong>, Brussels.VPH IM2IM Meeting, July <strong>2009</strong>, Berlin. 7th <strong>Annual</strong> HealthGrid International Conference“Car<strong>di</strong>ovascular flow, function e tissue Mechanics”, International society for Magneticresonance in Me<strong>di</strong>cine ISMRM, September <strong>2009</strong>, Sintra Portugal.ASN 42st <strong>Annual</strong> Renal Week <strong>2009</strong>, November <strong>2009</strong>, San Diego, CA.305ANNUAL REPORT <strong>2009</strong>
IRFMNOpen Information Day – IMI Joint Undertaking, November <strong>2009</strong>, BrusselsIPITA-IXA Joint Meeting Venice Italy, October <strong>2009</strong>.International pancreas and islet transplantassociation.Poster: Regression of <strong>di</strong>abetic complications by singenically transplanted ratpancreatic islets.DEMAND 30 th <strong>Annual</strong> Meeting of the Society for Clinical Trials – Atlanta USA, May <strong>2009</strong>ATTD 2 nd International Conference on Advance Technologies & Treatments for Diabetes,February <strong>2009</strong>, Athens, Greece.WC<strong>2009</strong> World Congress Me<strong>di</strong>cal on Me<strong>di</strong>cal Physics and Biome<strong>di</strong>cal Engineering, September<strong>2009</strong>, Munich.XXVIII Scuola <strong>Annual</strong>e <strong>di</strong> Bioingegneria, Bioingegneria per le neuroscienze cognitive,Università degli stu<strong>di</strong> <strong>di</strong> Padova, Bressanone Settembre <strong>2009</strong>.GRANTS AND CONTRACTSResearch grants AIFA - trial clinici controllati (VARIETY, VALID, ATHENA, ARCADIA,NEMO).Research grant PKD foundation - ALADIN trial “Effect of long-acting somatostatin on <strong>di</strong>seaseprogression in ADPKD: a long-term three year follow-up study”.Research grant Baxter – ASAP trial “Acute Start Access Programme”.Research grant ISN per il Kidney Disease Data Center (KDDC ) del COMGAN.Contributo Regione Lombar<strong>di</strong>a per data management del Centro <strong>di</strong> Coor<strong>di</strong>namento della ReteRegionale per le Malattie Rare.Progetto <strong>di</strong> ricerca - FP6 UE-STEPS "A system approach to tissue engineering products andprocesses" FP6-500465Progetto <strong>di</strong> ricerca - FP7 UE - ARCH "Patient specific image-based computational modellingfor improvement of acute and long-term outcomes of vascular access for hemo<strong>di</strong>alysis”FP7-224390 - Project Coor<strong>di</strong>nation.VASCOSILK, Fondazione Cariplo - N.536/5314 - Protesi vascolari in fibroina elettrofilata perla rigenerazione in vivo <strong>di</strong> arterie <strong>di</strong> piccolo calibro.LIGASILK, Regione Lombar<strong>di</strong>a - N.534/5287 - Bioingegnerizzazione <strong>di</strong> ten<strong>di</strong>ni e legamenti:impiego combinato <strong>di</strong> supporti tessili in seta e cellule staminali adulte.306ANNUAL REPORT <strong>2009</strong>
IRFMNSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliar<strong>di</strong>ni E, Noris M, Buelli S,Zoja C, Corna D, Mele C, Fanelli R, Remuzzi G, Benigni A. Proteasomal Processing ofAlbumin by Renal Dendritic Cells Generates Antigenic Peptides. J Am Soc Nephrol, <strong>2009</strong>20:123-130.Macconi D, Sangalli F, Bonomelli M, Conti S, Condorelli L, Gagliar<strong>di</strong>ni E, Remuzzi G,Remuzzi A. Podocyte repopulation contributes to regression of glomerular injury induced byACE inhibition. Am J Pathol. <strong>2009</strong>; 174(3): 797-807.Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G, Remuzzi A.Developing regulatory-compliant electronic case report forms for clinical trials: experience withthe DEMAND trial. J Am Med Inform Assoc. <strong>2009</strong> 16(3):404-408.Figliuzzi M, Cornolti R, Perico N, Rota C, Morigi M, Remuzzi G, Remuzzi A, Benigni A. BoneMarrow-Derived Mesenchymal Stem Cells Improve Islet Graft Function in Diabetic Rats.Transplantation Procee<strong>di</strong>ngs <strong>2009</strong> 41, 1797-1800.Morbelli S, Piccardo A, Villavecchia G, Dessi B, Brugnolo A, Piccini A, Caroli A, Frisoni G,Ridriguez G, Nobili F. Mapping brain morphological and functional conversion patterns inamnestic MCI: a voxel-based MRI and FDG-PET study. Eur J Nucl Med Mol Imaging <strong>2009</strong>;37(1): 36-45.Piccinelli M, Veneziani A, Steinman DA, Remuzzi A, Antiga L. Framework for geometricanalysis of vascular structures: application to cerebral aneurysms. IEEE Trans Med Imaging<strong>2009</strong>; 28(8): 1141-55.Cornolti R, Figliuzzi M, Remuzzi A. Effect of micro-and macroencapsulation on oxygenconsumption by pancreatic islets. Cell Transplant. <strong>2009</strong>; 18(2): 195-201.Casagrande G, Lanzarone E, Miglietta F, Remuzzi A, Fumero R, Costantino ML. Determinationof Car<strong>di</strong>ovascular Mechanics Evolution in the Presence of the Arteriovenous Fistula. ASAIO J.<strong>2009</strong>; 55(5): 484-93.Gagliar<strong>di</strong>ni E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, LongarettiL, Remuzzi A, Remuzzi G, Benigni A. Unlike each drug alone, lisinopril if combined withavosentan promotes regression of renal lesions in experimental <strong>di</strong>abetes. Am J Physiol RenalPhysiol. <strong>2009</strong>; 297(5): F1448-56.Lee SW, Antiga L, Steinman DA. Correlations among in<strong>di</strong>cators of <strong>di</strong>sturbed flow at the normalcarotid bifurcation. J Biomech Eng. <strong>2009</strong>; 131: 061013.Antiga L, Steinman DA. Rethinking turbolence in blood. Biorheology <strong>2009</strong>; 46(2): 77-81.Caroli A, Frisoni GB. Quantitative evaluation of Alzheimer's <strong>di</strong>sease.Expert Rev Med Devices <strong>2009</strong>; 6(5): 569-588.Frisoni GB, Lorenzi M, Caroli A, Kemppainen N, Någren K, Rinne JO. In vivo mapping ofamyloid toxicity in Alzheimer <strong>di</strong>sease. Neurology. <strong>2009</strong> Apr 28;72(17):1504-11.307ANNUAL REPORT <strong>2009</strong>
IRFMNNobili F, De Carli F, Frisoni GB, Portet F, Verhey F, Rodriguez G, Caroli A, Touchon J,Morbelli S, Guerra UP, Dessi B, Brugnolo A, Visser PJ. SPECT Pre<strong>di</strong>ctors of CognitiveDecline and Alzheimer's Disease in Mild Cognitive Impairment. J A Dis. <strong>2009</strong>;Duchesne S, Caroli A, Gerol<strong>di</strong> C, Collins DL, Frisoni GB. Relating one-year cognitive changein mild cognitive impairment to baseline MRI features. Neuroimage. <strong>2009</strong> Oct 1;47(4):1363-70.Remuzzi A, Cornolti R, Bianchi R, Figliuzzi M, Porretta-Serapiglia C, Oggioni N, Carozzi V,Crippa L, Avezza F, Fiordaliso F, Salio M, Lauria G, Lombar<strong>di</strong> R, Cavaletti G. Regression of<strong>di</strong>abetic complications by islet transplantation in the rat. Diabetologia <strong>2009</strong>; 52: 2653-2661.Cornolti R, Cattaneo I, Trudu M, Figliuzzi M, Remuzzi A.Effect of islet transplantation on metabolic glucose control in rats with <strong>di</strong>abetes. DiabetesTechnol Ther. <strong>2009</strong>; 11(12):805-11.RESEARCH ACTIVITIESLaboratory of Renal BiophysicsThree <strong>di</strong>mensional reconstruction of the glomerular capillary networkWe have recently documented that angiotensin II blockade not only retards the progression ofrenal <strong>di</strong>seases, but also induces regression of the glomerular lesions. To quantify the extent ofthe regression of sclerotic lesions and the potential regeneration of the glomerular capillaryinduced by a therapy with angiotensin converting enzyme (ACE) inhibitors we are developingthree <strong>di</strong>mensional (3D) reconstruction of tissues by several approaches: one of them is thevascular corrosion casting technique, using a polyurethane resin, that allows to obtain casts ofthe vascular architecture of the glomerular capillary to be analyzed by scanning electronmicroscopy. We are also setting up a new technique to study the morphology of the glomerularcapillary and its wall by electron microscopy, based on a combination of an electron beam withan ionic one, in order to achieve sectioning of samples and acquisition of serial images for 3Dreconstruction of the ultrastructure by mathematical algorithms.Study of the role of the AcSDKP peptide in the regression of renal damageinduced by angiotensin II blockadeClinical and experimental stu<strong>di</strong>es have documented that lowering proteinuria bypharmacological interventions retards renal <strong>di</strong>sease progression and even inducesremission. We have recently shown in MWF rats, a genetic model of spontaneousglomerular damage, that the ACE inhibitor, lisinopril, induces regression of proteinuriaand of existing glomerulosclerosis, ameliorates interstitial damage and stabilizes renalfunction even when given in advanced stages of nephropathy. Given the key role ofangiotensin II (Ang II) in renal <strong>di</strong>sease progression, the renoprotective effect of ACEinhibition has been attributed to the suppression of Ang II formation. However, thepossibility that other substrates that are processed by ACE may contribute to thetherapeutic benefits of ACE inhibition cannot be ruled out.308ANNUAL REPORT <strong>2009</strong>
IRFMNSomatic ACE in vertebrate is a zinc metallo peptidyl–<strong>di</strong>peptidase that <strong>di</strong>splays activity toward abroad range of substrates and has two homologous N- and C-terminal active domains. Bothdomains contribute to Ang II formation by hydrolysis of angiotensin I and to the inactivation ofbradykinin. Very recently, experiments of gene targeting revealed that the ACE C-terminalcatalytic domain is the main site of angiotensin I cleavage in vivo. N-terminal active domain ofACE specifically cleaves its natural substrate N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) atetrapeptide that reduces inflammation, fibrosis and target organ damage induced byhypertension. Moreover, the peptide likely induces regeneration of myocar<strong>di</strong>al endothelial cells.Ac-SDKP is rapidly cleared from plasma by two <strong>di</strong>fferent mechanisms: enzymatic cleavage ofthe Asp-Lys peptide bound by ACE and by glomerular filtration. Basing on the above evidencewe have pursued a study aimed at evaluating whether the ACE inhibitor protects from advancednephropathy also through the regulation of endogenous Ac-SDKP. The peptide levels will bemeasured in the plasma, urine, and kidney by EIA assay and correlated with the extent ofcollagen deposition and inflammation.Application of confocal microscopy to the study of cells and tissuesFluorescent probes to investigate the <strong>di</strong>stribution and co-localization of proteins and otherspecific antigens in cell monolayers and tissue specimens are commonly used in the majority ofexperimental applications. Bi<strong>di</strong>mensional images are not of high resolution to provide correctinformation, thus the use of 3D reconstruction of fluorescent signal becomes mandatory. Theseproblems can not be solved by the classic fluorescent microscopy that has some limitations. Forthese reasons we have optimized the laser confocal microscopy by using the LSM510 METAmicroscope from Zeiss (Germany). The microscope is equipped with four laser lines that excitethe sample within the whole visible spectrum plus the characteristic “META scan head” thatallow to analyze the emission spectrum of <strong>di</strong>fferent fluorophores to optimally separate them.The instrument is characterized by and used for its high specificity and for the excellence of therevealed and elaborated signal.Laboratory of Biome<strong>di</strong>cal TechnologiesRemission Clinic NetworkMany forms of chronic kidney <strong>di</strong>seases progress with a constant rate of glomerular filtrationrate towards the end stage renal <strong>di</strong>sease (ESRD). Often, even when the responsible cause for theonset of the <strong>di</strong>sease is removed or <strong>di</strong>sappears, we are witnessing the progressive loss of renalfunction. These forms of kidney <strong>di</strong>sease are frequently associated with arterial hypertension andurine proteins, known as aggravating factors in the progression of the <strong>di</strong>sease. Controlledclinical trials have demonstrated that specific treatment of hypertension by using drugs thatreduce the urinary excretion of proteins (ACE-inhibitors), are effective in reducing the rate ofdecline of glomerular filtration rate (GFR) and even in obtaining stabilization or recovery ofGFR. These kind of treatments allow to delay the start of <strong>di</strong>alysis or need of kidney transplant insubjects with CKD. It is therefore essential to assess to what extent the results obtained incontrolled clinical trials may actually be achieved also in clinical practice. With this purpose, incollaboration with the Renal Department, we started a quality control and monitoringprogramme of patients affected by proteinuric nephropathies (Remision Clinic protocol) aimedat verifying that GFR improvement might be obtained in routine clinical practice as well. Ourlaboratory developed a web-based application and established a network of specialists involve<strong>di</strong>n the treatment of chronic progressive nephropathies <strong>di</strong>stributed nationally(http://clinicalweb.marionegri.it/remission). Our tool offers computer support to me<strong>di</strong>calspecialists from all participating centers to gather, extract and analyze real time clinical data for309ANNUAL REPORT <strong>2009</strong>
IRFMNpatients with chronic kidney <strong>di</strong>seases treated accor<strong>di</strong>ng to the guidelines of Remission Clinicprotocol. In ad<strong>di</strong>tion, our tool allows report analyses and quality controls of this clinical activityto assess in what extent adherence to the protocol factors, may itself affect the progression ofnephropathy in time.KDDC – a coor<strong>di</strong>nating centre for data collection and surveillance ofprevention programs on non-communicable chronic <strong>di</strong>seases in emergingcountriesChronic kidney <strong>di</strong>seases are emerging as a global threat to human health. Prevalence an<strong>di</strong>ncidence of renal <strong>di</strong>seases in developing countries are not known, and this is an obstacle to theadoption of preventive measures. Prevention is the only hope for these countries wheretreatment options for end stage renal failure are simply not available to the vast majority of thepopulation because of their costs.The International Society of Nephrology (ISN), through the Commission for GlobalAdvancement of Nephrology (COMGAN), has established a research committee in order to facethe problems about prevention of kidney <strong>di</strong>seases in developing countries. The coor<strong>di</strong>nation ofthe team and intervention programs was committed to the <strong>Mario</strong> <strong>Negri</strong> Institute forPharmacological Research at the Clinical Research Centre “Aldo e Cele Daccò”. The generalaim of the project is to define programs in developing countries to identify those subjects whoare at risk of developing a renal <strong>di</strong>sease later in life, in order to design a prevention strategy onnational basis by means of interventions of the local ministries of health to governmental andfinancial level.The Kidney Disease Data Centre (KDDC) established in our Laboratory, is de<strong>di</strong>cated to datamanagement for the prevention programs underway in emerging countries. We have set up an atool to collect clinical data from <strong>di</strong>fferent centres located world-wide(http://comgan.marionegri.it). Data are stored in a de<strong>di</strong>cated server in our Laboratory. Results ofour epidemiological analyses, shared also with me<strong>di</strong>cal staff of the center, allow us to have ageneral overview on the health of population under study. The prevention program is underwayand we have already collected data from participating centres from Nepal, Mongolia, In<strong>di</strong>a,China, Moldova, Bosnia-Herzegovina, Bolivia, Panama and Mozambique. Initial results onscreening on several thousands of subjects, confirm the need to proceed with preventionprograms in theses countries. Through the activity of KDDC it is possible to monitor the courseof the prevention programs and to tailor them to fit the needs of each participating country.Development of computerized systems for controlled clinical trialsNumerous clinical trials are conducted in the Clinical Research Center for Rare Diseases “Aldoe Celè Daccò”. These stu<strong>di</strong>es must be carried out with respect to the GCP (Good ClinicalPractice) guidelines and require high quality of data. Every clinical study requires a paper casereport form (CRF) for collection of patients’ clinical observations. These data must be verifiedfor inconsistency by de<strong>di</strong>cated monitoring staff, and then recorded electronically. In our Lab wehave developed applications tailored for data management of clinical stu<strong>di</strong>es using relationaldatabases systems (RDBMS) and specific programs aimed to data elaboration, validation andextraction for subsequent statistic analyses. REIN, BENEDICT MYSS REIN2, DKG are justfew of the trials concluded successfully and published in prestigious me<strong>di</strong>cal journals. Thisaccomplishment is, in part, due to the contribution of our Lab. For the DEMAND study we havedeveloped an innovative electronic CRFs based on laptop computers. We are implementing alsoa web-based framework for electronic data capture and clinical data management for clinicaltrials. Thus, recently we have set-up a de<strong>di</strong>cated portal (http://clintrials.marionegri.it) as ashow-case for the clinical trials conducted at the Clinical Research Center “Aldo e Cele Daccò”and a platform for the new web-tools developed in our Lab.310ANNUAL REPORT <strong>2009</strong>
IRFMNData Management for the Registry for Rare Disease - LombardyOur laboratory contributes to the management of the Regional Network for Rare Diseases ofLombardy. We are <strong>di</strong>rectly involved for the development and maintenance of the web site of thecentre and management of a regional Registry for Rare Diseases. We have set-up the databasesand developed related web-pages for centers, rare <strong>di</strong>seases archive, associations of patients andcongenital rare <strong>di</strong>seases. These are published on the homepage of the web-site(http://malattierare.marionegri.it/).The Registry for Rare Diseases was born in 2007 as a collaboration between <strong>Mario</strong> <strong>Negri</strong>Institute, Lombar<strong>di</strong>a Informatica (LI) and Regione Lombar<strong>di</strong>a. The aim was to create a regionalregistry for rare <strong>di</strong>seases where all me<strong>di</strong>cal staff from Lombardy could register informationregar<strong>di</strong>ng rare <strong>di</strong>seases. The application (Sistema Malattie Rare - SMR) was developed by LI incollaboration with our group. SMR application is using web-based technology and can be usedjointly with the health patient card. It is actually in use in almost all centres de<strong>di</strong>cated for rare<strong>di</strong>seases in Lombardy. Our laboratory is involved in the maintenance of SMR, statisticalanalyses of registry data and creation of a minimal set of data that are shared at national level bythe <strong>Istituto</strong> Superiore <strong>di</strong> Sanità (ISS).Hemodynamics and vascular pathologyDuring the last ten years the presence of a close relationship between hemodynamics andvascular pathology has been pointed out both in the biological and in the clinical field. Twotypical examples of such relationship are atherosclerosis and intracranial aneurysm <strong>di</strong>sease. Inatherosclerosis, a pathology lea<strong>di</strong>ng to lipid-rich and fibrotic plaque formation in artery walls,lesions tend to form mainly in correspondence to bifurcations (e.g. carotid bifurcation) and greatcurvature tracts (e.g. coronary arteries). In intracranial aneurysm <strong>di</strong>sease, characterized by theformation of one (or more) artery wall protrusions in the cerebral arterial circulation, cerebralaneurysms tend to locate at the <strong>di</strong>stal wall of main bifurcations and at the exteral wall ofsegments characterized by large curvature.Besides being involved in pathogenesis, hemodynamics also plays a role at a mechanical levelfor the determination of atherosclerotic plaque rupture, responsible for heart attacks and stroke,or cerebral aneurysm rupture with consequent intracranial hemorrhage.It has been experimentally shown that endothelial cells (lining vessel walls) and smooth musclecells (the vasoactive component of the wall) exposed to flow exhibit changes in geneexpression, cytoskeleton reorganization and permeability accor<strong>di</strong>ng to the characteristics of theimposed flow (e.g. laminar vs turbulent).In spite of this data supporting the hypothesis of a close relationship between hemodynamicsand vascular pathology, the nature of such relationship is still under scrutiny, mainly due to the<strong>di</strong>fficulty of measuring in-vivo hemodynamics-related quantities.Thanks to innovative technologies developed during the last few years in the me<strong>di</strong>cal imagingand mathematical modelling fields, also within the Biome<strong>di</strong>cal Engineering Department, it isnow possible to accurately reproduce patient-specific hemodynamic force <strong>di</strong>stribution fromcomputed tomography (CT) or magnetic resonance (MR) acquisitions.Within the Department of Biome<strong>di</strong>cal Engineering such technologies have three mainapplications: atherosclerosis (carotid bifurcation and renal artery level), intracranial aneurysm<strong>di</strong>sease and complications of vascular access in hemo<strong>di</strong>alysis. In particular, the Department iscurrently involved in an international collaborative project: (ARCH) funded by the EuropeanUnion within the Seventh Framework Programme, starting from 2008, aimed at improving thefunctionality of vascular access in hemo<strong>di</strong>alysis patients, for which the Department is thecoor<strong>di</strong>nator centre.311ANNUAL REPORT <strong>2009</strong>
IRFMNTheoretical and experimental study of filtration of 'albumin in the kidneyThe Department is studying the mechanisms responsible for glomerular filtration of albumin.Recently we have been de<strong>di</strong>cated to the experimental measurement and theoretical modelling offiltration of albumin and its concentration at the renal tubule. In an experimental model ofnephropathy, we stu<strong>di</strong>ed the variations in the concentration of albumin in the tubules andstu<strong>di</strong>ed the effect of treatment with an ACE inhibitor. The combination of the experimentalapproach with the theoretical modelling allowed to elucidate an aspect of renal pathophysiologystill not highlighted.Imaging and quantification in renal physiopathologyThe use of imaging techniques such as CT, MR, and echography, and the application ofadvanced image processing tools make it possible to perform non-invasive in-vivo quantitativeanalysis of biological phenomena. Within the Department of Biome<strong>di</strong>cal Engineering, thisapproach is applied to the investigation of renal physiopathology. Through CT and MR imagebasedquantification, new therapies for autosomal dominant polycystic kidney <strong>di</strong>sease(ADPKD) are currently being evaluated. To this purpose, the Me<strong>di</strong>cal Imaging Unit is involve<strong>di</strong>n three clinical trials one of which funded by the Polycystic Kidney Foundation, aimed atreducing the overall kidney cyst volume with the use of novel therapies. In this context, CTimage quantification has recently led to the <strong>di</strong>scovery of a high correlation between a specificportion of polycystic kidney tissue and renal function, showing for the first time a likely <strong>di</strong>rectrelationship between structure and function, thus opening the way to new therapeutic targets.Beyond ADPKD stu<strong>di</strong>es, new methodologies for noninvasive characterization of renalfunctionality from <strong>di</strong>ffusion-weighted MR images are currently under study.Development of biome<strong>di</strong>cal image analysis and computational modellingtoolsThe employment of quantitative imaging and mathematical modelling techniques aimed at thestudy of physiopathological processes is <strong>di</strong>rectly linked to me<strong>di</strong>cal image management andprocessing methodologies. Within the Department, research activity related to the developmentof new image processing algorithms and mathematical models for the numerical simulation ofbiological phenomena, both theoretical and in terms of software development, is activelyperformed.The department contributes to the development of three main open-source projects in thebiome<strong>di</strong>cal imaging field: Vascular Modelling Toolkit (www.vmtk.org), as main developer,Insight Toolkit (www.itk.org), a state-of-the-art library for me<strong>di</strong>cal image analysis, and Slicer3D (www.slicer.org), one of the main me<strong>di</strong>cal imaging applications. The Department is <strong>di</strong>rectlyinvolved in the development activities carried out within the National Alliance for Me<strong>di</strong>calImage Computing, an inter-university consortium gathering the main academic institutions ofthe United States.Development of devices for the transplantation of immunoisolated isletsThe project’s main objective is to develop an immunisolation device for pancreaticislets that can be implanted in <strong>di</strong>abetic patients permitting allo-islet transplantationwithout the use of pharmacological immunosuppression and avoi<strong>di</strong>ng allosensitizationof the patient. The study started from the design and characterization of the semipermeablemembrane used for the device construction. The device that we aredeveloping can be implanted with minimally invasive surgical procedures and easy toretry. We have also developed a method for subcutaneous implantation as alternativesite for transplantation. We are tested <strong>di</strong>fferent types of material to be used aspolysulfone hollow fiber or tubular membranes of polyvinyl alcohol. The aims of our312ANNUAL REPORT <strong>2009</strong>
IRFMNstu<strong>di</strong>es in the next months will be to improve functionality using nanotechnologies formaterials characterization. Moreover we will develop new kinds of device and we willtest new implantation sites.Effect of pancreatic islet transplantation on <strong>di</strong>abetic complicationsDiabetes type 1 is taking place as one of the most important worldwide public health problemswith a high morbi<strong>di</strong>ty and mortality. Diabetes is associated with increased risk of a number ofmicrovascular, neurologic and macrovascular complications due to poor glycemic control. Theaim of this project is to evaluate whether the transplantation of pancreatic islets can induceregression of <strong>di</strong>abetic complications in a model of rats with chemically induced <strong>di</strong>abetes. Forthis study, we used three groups of rats: healthy controls, <strong>di</strong>abetics and <strong>di</strong>abetics withtransplanted islet two months after induction of <strong>di</strong>abetes. At this time, the behavioural tests fordetermination of thermal and mechanical nociceptive threshold and the measurement of nerveconduction velocity in the nerves of the tail (NCV) show a significant neuropathic damage. Atthe end of the experiment a morphometrical analysis of the number of myocytes in the heart wascarried out. Transplantation of islet induces a lowering of blood glucose within a few days aftertransplantation, accompanied by an increase in body weight. All the neurological parametersobserved in <strong>di</strong>abetic rats return to values similar to the control in transplanted rats. The loss ofmyocytes and their hypertrophy is reduced after islet transplantation. In conclusion, thetransplantation of pancreatic islets not only normalizes blood glycemia levels in <strong>di</strong>abeticanimals, but also stop the neuropathy getting worse and improves car<strong>di</strong>ovascular complications.(In collaboration with the Department of Biochemistry and Molecular Pharmacology and theDepartment of Car<strong>di</strong>ovascular Research).Mesenchymal stem cells improve vascolarization in pancreatic islettransplantationPancreatic islet transplantation represents a cure for type I <strong>di</strong>abetes but there are still biglimitations inclu<strong>di</strong>ng the lack of metabolic capacity of transplanted islets in the long-run. Thisphenomenon must be mainly attributed to delayed and insufficient islet revascularization thatcan deprive newly transplanted islets of oxygen, resulting in permanent cell death. Promotion ofislet revascularization through locally increased expression of growth factors, such as vascularendothelial growth factor (VEGF), could improve the efficiency of islet transplantation. On thisbasis, we elected to investigate whether rat MSCs co-transplanted with pancreatic islets mayserve as cell therapy to promote therapeutic angiogenesis ultimately lea<strong>di</strong>ng to an effectivemetabolic activity of islet grafts. 2,000 syngenic islets alone or in combination with MSCs weretransplanted under the kidney capsules of <strong>di</strong>abetic Lewis rats. Animals transplanted with isletsalone never reached normoglycemia. In contrast, in rats transplanted with islets and MSCs,glycemia gradually fell after transplantation and normoglycemia was maintained for a longtime. In transplanted animals, islet vascularization was quantified by morphometrical analysis.Mean capillary density was significantly increased in islet co-transplanted with MSCs in<strong>di</strong>catingthat co-transplantation of MSCs with pancreatic islets improves islet graft function bypromoting graft vascularization. (In collaboration with Laboratory of Cellular Biology andXenotransplantation).Vascular tissue engineeringThe synthetic vascular grafts are stu<strong>di</strong>ed for the replacement of large caliber vessels damaged bypathological events. Currently available synthetic vascular grafts are limited to large internal<strong>di</strong>ameter grafts because of frequent thrombosis and occlusion. The alternative is representedfrom the use of autologous vascular graft, but they are not always available in patients affectedfrom vascular pathology. Vascular tissue engineering has the objective to generate cellularized313ANNUAL REPORT <strong>2009</strong>
IRFMNvascular prosthesis made of biodegradable materials that can be colonized by endothelial cells.For this purpose (in collaboration with Stazione Sperimentale della Seta in Milano andPolitecnico d Milano), we have stu<strong>di</strong>ed an innovative strategy for the vascular prosthesisrealization using biodegradable material, the fibroin of the silk. Tubular structures wereproduced through elettrospinning of the fibrin of the silk, and stu<strong>di</strong>es of biocompatibility andbiodegradation in vivo were performed, The structures were implanted into the subcutaneoustissue of rat and retrieved 15 days after transplantation for morphological evaluation of tissue.The analysis by light microscopy showed that fibroin tissue was completely enveloped in a verythick fibrous capsule, with cells infiltrating into the fibers of fibroin. These data confirmed thebiocompatibility of fibroin. The vascular prosthesis will be implanted in small animals (rats) toreplace abdominal aorta and, therefore, to evaluate the functionality of the prosthesis.The effect of flow on renal tubular cellsADPKD (Autosomal Dominant Policystic Kidney Disease) is one of the major genetic renalpathologies with an incidence of 1 in 1000 and it represents the main genetic cause of renalinsufficiency in adult. It is characterized by cysts growth in the tubular segment, which increasein size and in number throughout an in<strong>di</strong>vidual's lifetime, that leads to renal failure requiring<strong>di</strong>alysis or transplant. This pathology is due to the mutation of two genes:PKD1 and PKD2. Themutation of PKD1 gene is the most common, and is responsible of the 85% of cases, the geneenco<strong>di</strong>ng for a protein, a membrane receptor, the polycystin 1, which is involved in themaintenance of cell/cell or cell/matrix interactions while the PKD2 gene product, polycystin 2,is a ionic channel.Both the protein are localized in the cilia of renal tubular epithelial cells andact as a mechanosensory organs. The ben<strong>di</strong>ng of the cilium, caused by tubular flow, leads to theactivation of the polycystin 1 and to the generation of a peak of intracellular calciumconcentration. This increase in intracellular calcium activates signalling pathways that mo<strong>di</strong>fycellular proliferation and other cellular functions. In pathologic con<strong>di</strong>tions, polycystinmo<strong>di</strong>fication impairs the mechanosensitive function of cilia, altering tubular cellular functions.The aim of this project is the in vitro study of renal tubular cells (MDCK2) in laminar flowcon<strong>di</strong>tions, to investigate the role of mechanical stimulation in the pathology development.Preliminary results showed that the application of a constant laminar flow to MDCK2 causes a<strong>di</strong>fferent tri<strong>di</strong>mensional organization of the cellular layer, as compared to static control.Furthermore, the inhibition of intracellular calcium increase impairs this reorganization whenflow is applied.314ANNUAL REPORT <strong>2009</strong>
IRFMNLABORATORY OF BIOLOGY ANDTHERAPY OF METASTASIS*STAFFHeadRaffaella GIAVAZZI, Biol.Sci.D., Ph.D.HeadGiulia TARABOLETTI, Biol.Sci.D.* Research activities of this Laboratory are listed in the Department of Oncology section (pag. 7)315ANNUAL REPORT <strong>2009</strong>
IRFMN316ANNUAL REPORT <strong>2009</strong>
IRFMNAldo and Cele Daccò CenterRanica (Bg)ANNUALREPORT <strong>2009</strong>departments and laboratories317ANNUAL REPORT <strong>2009</strong>
IRFMN318ANNUAL REPORT <strong>2009</strong>
IRFMNDEPARTMENT OF RENAL MEDICINESTAFFHeadPiero RUGGENENTI, M.D.Laboratory of BiostatisticsHeadAnnalisa PERNA, Stat.Sci.D.Laboratory of Coor<strong>di</strong>nation and Conduction of Controlled Clinical TrialsHeadGiulia GHERARDI, Res.N.Unit of Drug MonitoringHeadNa<strong>di</strong>a RUBIS, Res.N.Laboratory of Pharmacokinetics and Clinical ChemistryHeadFlavio GASPARI, Chem.D.Laboratory of Advanced Development of DrugsHeadNorberto PERICO, M.D.Unit of Pharmacology and PharmacogeneticsUnit of Early Clinical Evaluation of DrugsHeadAneliya ILIEVA PARVANOVA, M.D.Laboratory of Clinical Pathophysiology of Renal Disease andTransplantationHeadPaolo CRAVEDI, M.D., PhD.Laboratory of Regulatory Affairs for Clinical Stu<strong>di</strong>esHeadPaola BOCCARDO, Bio.Sci.D.319ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAPiero Ruggenenti got his Me<strong>di</strong>cine degree in 1983 at the University of Milan, Italy; he got hisspecialization in Car<strong>di</strong>ology in 1985 and in Clinical Nephrology in 1989 at the same University; hespecialized in Pharmacological Research in 1988 at IRFMN.Educational training: in 1980-1983 researcher at "Centro <strong>di</strong> Fisiologia Clinica e Ipertensione, ClinicaMe<strong>di</strong>ca IV", Università degli Stu<strong>di</strong> <strong>di</strong> Milano; in 1984 Researcher at IRFMN, Bergamo, Italy in 1987-1988 Honorary Registrar of the Unit for Metabolic Me<strong>di</strong>cine, Division of Me<strong>di</strong>cine (University ofLondon) of Guy's and St. Thomas's Hospitals, London; in 1988-1989 Assistant Professor of the Divisionof Nephrology and Dialysis of the Ospedali Riuniti <strong>di</strong> Bergamo.Areas of interest: mechanisms of chronic renal <strong>di</strong>sease progression, <strong>di</strong>abetes and <strong>di</strong>abetic complications,clinical transplantation, thrombotic microangiopathies, car<strong>di</strong>ovascular complications of chronic renal<strong>di</strong>sease, clinical trials, clinical pharmacology.Employment: from 1990 Assistant Professor of the Division of Nephrology and Dialysis of theOspedali Riuniti <strong>di</strong> Bergamo; in 1994-1999 Head, Unit of Advanced Development of Drugs, DaccòCenter, Ranica, Bergamo, Italy; since 2000 Head, Department of Renal Me<strong>di</strong>cine, Daccò Center,Bergamo, Italy.Selected publications:• Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherar<strong>di</strong> G, Orisio S, Remuzzi G. Ameliorating hypertensionand insulin resistance in subjects at increased car<strong>di</strong>ovascular risk: effects of acetyl-L-carnitine therapy. Hypertension, <strong>2009</strong>Sep; 54(3): 567-74.• Remuzzi G, Crave<strong>di</strong> P, Perna A, Dimitrov BD, Turturro M, Locatelli G, Rigotti P, Baldan N, Beatini M, Valente U,Scalamogna M, Ruggenenti P Dual Kidney Transplant Group. Long-term outcome of renal transplantation from olderdonors. N Engl J Med, 2006; 354: 343-352.• Ruggenenti P, Fassi A, Parvanova A, Bruno S, Iliev I, Brusegan V, Rubis N, Gherar<strong>di</strong> G, Arnol<strong>di</strong> F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G for the Bergamo Nephrologic DiabetesComplications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 <strong>di</strong>abetes. N Engl J Med, 2004;351: 1941-1951.• Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, Gherar<strong>di</strong> G, Donati D, Salvadori M, Sandrini S,Valente U, Segoloni G, Mourad G, Federico S, Rigotti P, Sparacino V, Bosmans JL, Perico N, Ruggenenti P.Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomisedtrial. Lancet, 2004 Aug 7-13; 364 (9433): 503-12.• Remuzzi G, Chiurchiu C, Abbate M, Brusegan V, Bontempelli M, Ruggenenti P. Rituximab for i<strong>di</strong>opathic membranousnephropathy. Research Letter. Lancet, 2002; 360: 923-924.• Ruggenenti P, Perna A, Gherar<strong>di</strong> G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotectiveproperties of ACE-inhibition in non-<strong>di</strong>abetic nephropathies with non-nephrotic proteinuria. Lancet ,1999; 354: 359-364.Paola Boccardo got her classic High School Diploma in 1979 and the Biol. Sci. Degree at the Universityof Pisa in 1985. In 1987 she passed the qualifying examination and got the license of Biologist.Educational training: she performed her training first at Mutagenesis and Differentiation Institute, CNR,of Pisa, and then at <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, where in 1990, got her <strong>di</strong>plomaof “Specialist in Pharmacological Research”. Since 1987 has been working as full-time researcher at<strong>Mario</strong> <strong>Negri</strong> Institute, till 1995 at Molecular Me<strong>di</strong>cine Department and then at Renal Me<strong>di</strong>cineDepartment.Area of interest: since 1995 she is in charge of Regulatory Affairs and attends to the planning, organizingand conducting of clinical stu<strong>di</strong>es in accordance with the principles of Good Clinical Practice and withthe laws in force.Employment: since June 2006 to October <strong>2009</strong> Responsible of Clinical Trials Office; since November<strong>2009</strong> Head, Laboratory of Regulatory Affairs for Clinical Stu<strong>di</strong>es. Member of Internal Staff for Security,since May 2008 she is Security Manager at Clinical Research Center for Rare Diseases Aldo e CeleDaccò.Selected publications:• Perico N, Delaini F, Lupini C, Benigni A, Galbusera M, Boccardo P, Remuzzi G. Blunted excretory response to atrialnatriuretic peptide in experimental nephrosis. Kidney Int, 1989; 36: 57-64.• Benigni A, Perico N, Dadan J, Gabanelli M, Galbusera M, Boccardo P, Mennini T, Remuzzi G. Functional implications ofdecreased renal cortical ANP bin<strong>di</strong>ng in experimental <strong>di</strong>abetes. Circ Res, 1990; 66: 1453-60.320ANNUAL REPORT <strong>2009</strong>
IRFMN• Benigni A, Boccardo P, Noris M, Remuzzi G, Siegler RL. Urinary excretion of platelet-activating factor in hemolyticuremic syndrome. Lancet, 1992; 339: 835-6.• Noris M, Benigni A, Boccardo P, Aiello S, Gaspari F, Todeschini M, Figliuzzi M, Remuzzi G. Enhanced nitric oxidesynthesis in uremia: implications for platelet dysfunction and <strong>di</strong>alysis hypotension. Kidney Int, 1993; 44: 445-450.• Benigni A, Boccardo P, Galbusera M, Monteagudo J, De Marco L, Remuzzi G, Ruggeri ZM. Reversible activation defectof the platelet glycoprotein IIb-IIIa complex in patients with uremia. Am J Kidney Dis, 1993; 22: 668-676.• Boccardo P, Noris M, Remuzzi G. Prevention and therapeutic management of blee<strong>di</strong>ng in <strong>di</strong>alysis patients. In: DialysisTherapy, 3 rd e<strong>di</strong>tion. E<strong>di</strong>ted by Nissenson A.R., Fine R.N. Hanley & Belfus, Inc., Philadelphia 2001; 3: 190-194.• Remuzzi G, Galbusera M, Boccardo P. Disorders of hemostasis in <strong>di</strong>alysis patients. In: Heinrich, W.L. Ed. Principles andPractice of Dialysis, 4 th ed. Philadelphia, PA: Lippincot W & W, <strong>2009</strong>.Paolo Crave<strong>di</strong> got his Me<strong>di</strong>cine degree (cum laude) in 1999 at the University of Milan, Italy; he got hisspecialization in Nephrology (cum laude) in 2004 at the University of Parma. In <strong>2009</strong> got a Ph.D. degreefrom the Open University of London.Educational training: in 2005 Master on Organ Transplant at the University of Milano Bicocca; in 2006researcher at the <strong>Mario</strong> <strong>Negri</strong> Institute, Bergamo; since 2007 to 2008 Research Fellow at the TransplantBranch of the National Institutes of Health (NIH) (Mentor Dr. Roslyn Mannon); since <strong>2009</strong> researcher atthe <strong>Mario</strong> <strong>Negri</strong> Institute, Bergamo.Areas of interest: mechanisms of chronic renal <strong>di</strong>sease progression, <strong>di</strong>abetes and <strong>di</strong>abetic complications,clinical transplantation, membranous nephropathy, clinical pharmacology.Employment: since 2010, Head Laboratory of Clinical Pathophysiology of Renal Disease andTransplantation.Selected publications:• Remuzzi G, Crave<strong>di</strong> P, Perna A, Dimitrov BD, Turturro M, Locatelli G, Rigotti P, Baldan N, Beatini M, Valente U,Scalamogna M, Ruggenenti P Dual Kidney Transplant Group. Long-term outcome of renal transplantation from olderdonors. N Engl J Med, 2006; 354: 343-352.• Crave<strong>di</strong> P, Ruggenenti P, Remuzzi G. Sirolimus to replace calcineurin inhibitors? Too early yet. Lancet, <strong>2009</strong>; 373:1235-6.• Ruggenenti P, Crave<strong>di</strong> P, Sghirlanzoni MC, Gagliar<strong>di</strong>ni E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G.Effects of rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol, 2008; 3:1652-9.• Crave<strong>di</strong> P, Ruggenenti P, Sghirlanzoni MC, Remuzzi G. Titrating rituximab to circulating B cells to optimizelymphocytolytic therapy in i<strong>di</strong>opathic membranous nephropathy. Clin J Am Soc Nephrol, 2007; 2: 932-7.• Remuzzi G, Crave<strong>di</strong> P, Costantini M, Lesti M, Ganeva M, Gherar<strong>di</strong> G, Ene-Iordache B, Gotti E, Donati D, Salvadori M,Sandrini S, Segoloni G, Federico S, Rigotti P, Sparacino V, Ruggenenti P. Mycophenolate mofetil versus azathioprine forprevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinicaltrial. J Am Soc Nephrol, 2007; 18: 1973-85.Flavio Gaspari got his Chemistry degree in 1977 at the University of Milano, Italy, and thespecialization in the same University in 1979.Educational training: in 1981-1985 Fellow and Researcher at IRFMN, Milan; in 1985-1991 at IRFMN,Bergamo, Italy.Areas of interest: pharmacokinetics and the metabolism of xanthines in <strong>di</strong>fferent animal species; drugpharmacokinetics in uremic patients and in subjects with <strong>di</strong>fferent degrees of renal function; analyticalmethods to measure the most important immunosuppressive drugs to determine their pharmacokinetics inkidney, heart, and liver transplant recipients; evaluation of the renal function by using <strong>di</strong>fferentapproaches, in the study of renal <strong>di</strong>sease progression, and in the comparison of <strong>di</strong>fferent methods foralbuminuria determination.Employement: he is Head of Laboratory of Pharmacokinetics and Clinical Chemistry since January 2000and he was Head of this Unit since 1991.Selected publications:• Perico N, Zoja C, Corna D, Rottoli D, Gaspari F, Haskell L, Remuzzi G. V1/V2 Vasopressin receptor antagonismpotentiates the renoprotection of renin-angiotensin system inhibition in rats with renal mass reduction. Kidney Int, <strong>2009</strong>Nov; 76(9): 960-7.• Ruggenenti P, Crave<strong>di</strong> P, Sghirlanzoni MC, Gagliar<strong>di</strong>ni E, Conti S, Gaspari F, Marchetti G, Abbate M, Remuzzi G. Effectsof rituximab on morphofunctional abnormalities of membranous glomerulopathy. Clin J Am Soc Nephrol, 2008 Nov; 3(6):1652-9.• Gotti E, Perico N, Gaspari F, Cattaneo D, Lesti MD, Ruggenenti P, Segoloni G, Salvadori M, Rigotti P, Valente U, DonatiD, Sandrini S, Federico S, Sparacino V, Mourad G, Bosmans JL, Dimitrov BD, Iordache BE, Remuzzi G. Blood321ANNUAL REPORT <strong>2009</strong>
IRFMNcyclosporine level soon after kidney transplantation is a major determinant of rejection: insights from the MycophenolateSteroid-Sparing Trial. Transplant Proc, 2005 Jun; 37(5): 2037-40.• Perico N, Gaspari F, Remuzzi G. Assessing renal function by GFR pre<strong>di</strong>ction equations in kidney transplantation. Am JTransplant, 2005 Jun; 5(6): 1175-6.• D. Cattaneo, F. Gaspari, S. Zanoni, S. Baldelli, E.Gotti, A. Perna, N. Perico, G. Remuzzi. Two-hour post-dose cyclosporinemonitoring does not fit all in kidney transplantation. Therapy, 2005; 2: 95-105.• Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherar<strong>di</strong> G, Arnol<strong>di</strong> F, Ganeva M, Ene-IordacheB, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabetes ComplicationsTrial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 <strong>di</strong>abetes. N Engl J Med, 2004 Nov 4; 351 (19):1941-51.• Gaspari F, Ferrari S, Stucchi N, Centemeri E, Carrara F, Pellegrino M, Gherar<strong>di</strong> G, Gotti E, Segoloni G, Salvadori M,Rigotti P, Valente U, Donati D, Sandrini S, Sparacino V, Remuzzi G, Perico N; MY.S.S. Study Investigators. Performanceof <strong>di</strong>fferent pre<strong>di</strong>ction equations for estimating renal function in kidney transplantation. Am J Transplant, 2004 Nov; 4(11): 1826-35.Giulia Gherar<strong>di</strong> got her Scientific High School Diploma in 1989 at the Liceo Scientifico Marie Curie inZogno (Bergamo), the Nurse Diploma in 1995 at the Scuola per Infermieri Professionali, OspedaliRiuniti, Bergamo and the 1st Level Master in Clinical Research in 2008 at the Me<strong>di</strong>cine and SurgeryFaculty of the University in Milan.Educational training: Clinical Research Nurse Diploma on 1997 at IRFMN –Daccò Center.Areas of interest: statistical methodology of long-term randomised clinical trials in nephrology, and<strong>di</strong>abetology; the coor<strong>di</strong>nation, conduction and monitoring of controlled clinical trials.Employement: in 1997-2003 involved as co-organizing, speaker, co-speaker and tutor for the ClinicalResearch Course for Nurse at IRFMN – Daccò Center (Ranica – Bergamo). Several training activities forNurses in Clinical Research area. In 1997-1999, Clinical Research Monitor at IRFMN – Daccò Center; in2000-2008 Head of the Monitoring Drug Unit at IRFMN – Daccò Center. Since <strong>2009</strong> Head of theLaboratory of Coor<strong>di</strong>nation and Conduction of Controlled Clinical Trials at IRFMN – Daccò Center.Selected publications:• Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherar<strong>di</strong> G, Orisio S, Remuzzi G. Ameliorating hypertensionand insulin resistance in subjects at increased car<strong>di</strong>ovascular risk: effects of acetyl-L-carnitine therapy. Hypertension, <strong>2009</strong>Sep; 54 (3): 567-74.• Remuzzi G, Crave<strong>di</strong> P, Costantini M, Lesti M, Ganeva M, Gherar<strong>di</strong> G, Ene-Iordache B, Gotti E, Donati D, Salvadori M,Sandrini S, Segoloni G, Federico S, Rigotti P, Sparacino V, Ruggenenti P. Mycophenolate mofetil versus azathioprine forprevention of chronic allograft dysfunction in renal transplantation: the MYSS follow-up randomized, controlled clinicaltrial. J Am Soc Nephrol, 2007 Jun; 18 (6): 1973-85.• Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherar<strong>di</strong> G, Arnol<strong>di</strong> F, Ganeva M, Ene-IordacheB, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabetes ComplicationsTrial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 <strong>di</strong>abetes. N Engl J Med, 2004 Nov 4; 351 (19):1941-51.• Remuzzi G, Lesti M, Gotti E, Ganeva M, Dimitrov BD, Ene-Iordache B, Gherar<strong>di</strong> G, Donati D, Salvadori M, Sandrini S,Valente U, Segoloni G, Mourad G, Federico S, Rigotti P, Sparacino V, Bosmans JL, Perico N, Ruggenenti P.Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomisedtrial. Lancet, 2004 Aug 7-13; 364 (9433): 503-12.• Ruggenenti P, Perna A, Gherar<strong>di</strong> G, Benini R, Remuzzi G. Chronic proteinuric nephropathies: outcomes and response totreatment in a prospective cohort of 352 patients with <strong>di</strong>fferent patterns of renal injury. Am J Kidney Dis, 2000 Jun; 35 (6):1155-65.• Ruggenenti P, Perna A, Gherar<strong>di</strong> G, Garini G, Zoccali C, Salvadori M, Scolari F, Schena FP, Remuzzi G. Renoprotectiveproperties of ACE-inhibition in non-<strong>di</strong>abetic nephropathies with non-nephrotic proteinuria. Lancet, 1999 Jul 31; 354(9176): 359-64.• Ruggenenti P, Perna A, Gherar<strong>di</strong> G, Gaspari F, Benini R, Remuzzi G. Renal function and requirement for <strong>di</strong>alysis inchronic nephropathy patients on long-term ramipril: REIN follow-up trial. Gruppo Italiano <strong>di</strong> Stu<strong>di</strong> Epidemiologici inNefrologia (GISEN). Ramipril Efficacy in Nephropathy. Lancet, 1998 Oct 17; 352 (9136): 1252-6.Norberto Perico got his Me<strong>di</strong>cine degree in 1983 at the University of Milano, Italy. He got hisspecialization in Pharmacological Research in 1986 at IRFMN, Bergamo and in Clinical Nephrology in1989 at the University of Verona, Italy.Educational training: in 1982 Fellow, Department of Pharmacology, New York Me<strong>di</strong>cal College,Valhalla, New York, USA; in 1984-1988 Post Doctoral Fellow, Laboratory of Kidney Diseases, IRFMN,Bergamo, Italy; in 1988-1989 Researcher in the same laboratory.Areas of interest: pathophysiology and pharmacology of cyclosporine nephrotoxicity; newimmunosuppressive strategies to prevent renal graft rejection; innovative approach to induce tolerance to322ANNUAL REPORT <strong>2009</strong>
IRFMNorgan transplantation; mechanism(s) and management of progression of chronic renal <strong>di</strong>seases.Employment: in 1990-1994 Head, Renal Physiology Unit, Laboratory of Kidney Diseases, IRFMN,Bergamo, Italy; in 1990-2000 Assistant Professor, Division of Nephrology and Dialysis, Ospedali Riuniti<strong>di</strong> Bergamo, Italy; in 1994 –1999 Head, Laboratory of Transplant Immunology, IRFMN, Bergamo, Italy;from January 2000 Head, Laboratory of Drug Development, Department of Renal Me<strong>di</strong>cine, IRFMN,Bergamo, Italy; from September 2000 Health Director, Daccò Center, IRFMN, Bergamo, Italy. FromOctober 2002 he’s Member, ISN-COMGAN Research Committee of the International Society ofNephrology.Selected publications:• Dahlke MH, Hoogduijn M, Eggenhofer E, Popp FC, Renner P, Slowik P, Rosenauer A, Piso P, Geissler EK, Lange C,Chabannes D, Mazzanti B, Bigenzahn S, Bertolino P, Kunter U, Introna M, Rambal<strong>di</strong> A, Capelli C, Perico N, Casiraghi F,Noris M, Gotti E, Seifert M, Saccar<strong>di</strong> R, Verspaget HW, van Hoek B, Bartholomew A, Wekerle T, Volk HD, Remuzzi G,Deans R, Lazarus H, Schlitt HJ, Baan CC; MISOT Study Group. Toward MSC in solid organ transplantation: 2008position paper of the MISOT study group. Transplantation, <strong>2009</strong> Sep 15; 88 (5): 614-9.• Cattaneo D, Cortinovis M, Baldelli S, Gotti E, Remuzzi G, Perico N. Limited sampling strategies for the estimation ofsirolimus daily exposure in kidney transplant recipients on a calcineurin inhibitor-free regimen. J Clin Pharmacol, <strong>2009</strong> Jul;49 (7): 773-81.• Cattaneo D, Ruggenenti P, Baldelli S, Motterlini N, Gotti E, Sandrini S, Salvadori M, Segoloni G, Rigotti P, Donati D,Perico N, Remuzzi G; Mycophenolate Steroids Sparing (MYSS) Genetics Study Group. ABCB1 genotypes pre<strong>di</strong>ctcyclosporine-related adverse events and kidney allograft outcome. J Am Soc Nephrol, <strong>2009</strong> Jun; 20 (6): 1404-15.• Perico N, Bravo RF, De Leon FR, Remuzzi G. Screening for chronic kidney <strong>di</strong>sease in emerging countries: feasibility andhurdles. Nephrol Dial Transplant, <strong>2009</strong> May; 24 (5): 1355-8.• Perico N, Benigni A, Remuzzi G. Present and future drug treatments for chronic kidney <strong>di</strong>seases: evolving targets inrenoprotection. Nat Rev Drug Discov, 2008 Nov; 7 (11): 936-53.• Ruggenenti P, Perico N, Gotti E, Crave<strong>di</strong> P, D'Agati V, Gagliar<strong>di</strong>ni E, Abbate M, Gaspari F, Cattaneo D, Noris M,Casiraghi F, Todeschini M, Cugini D, Conti S, Remuzzi G. Sirolimus versus cyclosporine therapy increases circulatingregulatory T cells, but does not protect renal transplant patients given alemtuzumab induction from chronic allograft injury.Transplantation, 2007 Oct 27; 84 (8): 956-64.• Baldelli S, Merlini S, Perico N, Nicastri A, Cortinovis M, Gotti E, Remuzzi G, Cattaneo D. C-440T/T-331Cpolymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation.Pharmacogenomics, 2007 Sep; 8 (9): 1127-41.Annalisa Perna got her Statistical Sciences degree in 1984 at the University of Bologna, Italy.Educational training: She completed her research training at IRFMN, Bergamo Labs. and at the DaccòCenter.Areas of interest: statistical methodology of long-term randomised clinical trials in nephrology, statisticalmethods for calculating sample size and for meta-analytic techniques. She is also involved in performingsystematic reviews for the Cochrane Collaboration – Renal Review Group. Employment: she is Head ofthe Laboratory of Biostatistics - Department of Renal Me<strong>di</strong>cine at Daccò Center, Ranica (Bergamo).Selected publications:• Rigotti P, Ekser B, Furian L, Baldan N, Valente ML, Boschiero L, Motterlini N, Perna A, Remuzzi G, Ruggenenti P.Outcome of renal transplantation from very old donors, N Engl J Med, <strong>2009</strong>; 360 (14): 1464-5.• Vegter S, Perna A, Hiddema W, Ruggenenti P, Remuzzi G, Navis G, Postma MJ. Cost-effectiveness of ACE inhibitortherapy to prevent <strong>di</strong>alysis in non<strong>di</strong>abetic nephropathy: influence of the ACE insertion/deletion polymorphism.Pharmacogenet Genomics, <strong>2009</strong>. 19(9): 695-703.• Crave<strong>di</strong> P, Perna A, Ruggenenti P, Remuzzi G. Mycophenolate Mofetil Versus Azathioprine in Organ Transplantation.Am J Transplant, <strong>2009</strong>; 9 (12): 2856-7.• De Cosmo S, Motterlini N, Prudente S, Pellegrini F, Trevisan R, Bossi A, Remuzzi G, Trischitta V, Ruggenenti P;BENEDICT Study Group. Impact of the PPAR-gamma2 Pro12Ala polymorphism and ACE inhibitor therapy on newonsetmicroalbuminuria in type 2 <strong>di</strong>abetes: evidence from BENEDICT. Diabetes, <strong>2009</strong> Dec; 58 (12): 2920-9.• Ruggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherar<strong>di</strong> G, Orisio S, Remuzzi G. Amelioratinghypertension and insulin resistance in subjects at increased car<strong>di</strong>ovascular risk: effects of acetyl-L-carnitine therapy.Hypertension, <strong>2009</strong> Sep; 54 (3): 567-74.• Cattaneo D, Ruggenenti P, Baldelli S, Motterlini N, Gotti E, Sandrini S, Salvadori M, Segoloni G, Rigotti P, Donati D,Perico N, Remuzzi G; Mycophenolate Steroids Sparing (MYSS) Genetics Study Group. ABCB1 genotypes pre<strong>di</strong>ctcyclosporine-related adverse events and kidney allograft outcome. J Am Soc Nephrol, <strong>2009</strong> Jun; 20 (6): 1404-15.Aneliya Parvanova Ilieva got her Me<strong>di</strong>cal Doctor degree at the Faculty of Me<strong>di</strong>cine, ThracianUniversity (former Higher Me<strong>di</strong>cal Institute), Stara Zagora, Bulgaria in 1988, and the specialization inPharmacology in Department of Pharmacology, University of Me<strong>di</strong>cine, Sofia in 1992. Her me<strong>di</strong>caldegree is recognized in Italy in <strong>2009</strong>.323ANNUAL REPORT <strong>2009</strong>
IRFMNEducational training: in 1989-1998 teaching of 3 rd , 4 th and 5 th -year me<strong>di</strong>cal students and 2 nd and 3 rd -yearclinical nurses in a general pharmacology and clinical pharmacology, Thracian University, Stara Zagora,Bulgaria; examiner of these students in theoretical and practical, oral and written exams and tests andState examination. In 1993 Course on investigation of isolated organs – Bulgarian Academy of Sciences,Sofia. In 1998 visiting scientist, IRFMN, Ranica, Bergamo, Italy. In 1998 proficiency in the methods forinsulin sensitivity evaluation (hyperinsulinemic euglicaemic clamp technique), in renal hemodynamicmeasurements -glomerular filtration rate (plasma clearance of iohexol and insulin), in renal plasma flow(plasma clearance of para-aminohippuric acid), glomerular size selectivity (plasma clearance of neutraldextrans) and in twenty four-hour blood pressure monitoring.Areas of interest: primary and secondary prevention of the chronic microvascular <strong>di</strong>abetic complications(<strong>di</strong>abetic nephropathy, <strong>di</strong>abetic retinopathy and <strong>di</strong>abetic neuropathy); role of insulin resistance, arterialhypertension, dyslipidemia and hyperhomocysteinemia in micro- and macrovascular <strong>di</strong>abeticcomplications; possibilities for pharmacological treatment of these pathological con<strong>di</strong>tions.Employment: she participates as investigator in several clinical stu<strong>di</strong>es. She is Head of The Unit of EarlyClinical Evaluation of Drugs at IRFMN since 2000. She is a member of the Union of Bulgarian Doctors(since 1989), of the Union of Pharmacologists in Bulgaria (since 1990), of the Union of Scientists inBulgaria (since 1991), and member of the Union of Me<strong>di</strong>cal Doctors and Dentists, Bergamo, Italy (since05.03.<strong>2009</strong>).Selected publications:• Ruggenenti P, Iliev I, Costa GM, Parvanova A, Perna A, Giuliano GA, Motterlini N, Ene-Iordache B, Remuzzi G.Preventing left ventricular hypertrophy by ACE inhibition in hypertensive patients with type 2 <strong>di</strong>abetes: a perspecifiedanalysis of the Bergamo Nephrologic Diabetes Complications Trial (BENEDICT). Diabetes Care, 2008 Aug; 31 (8): 1629-34.• Parvanova A, Trevisan R, Iliev I, Dimitrov BD, Vedovato M, Tiengo A, Remuzzi G, Ruggenenti P. Insulin resistance andmicroalbuminuria, A Cross-sectional, case-control study of 158 patients with type 2 <strong>di</strong>abetes and <strong>di</strong>fferent degrees ofurinary albumin excretion. Diabetes, 2006; 55: 1456-1462.• Parvanova A, Chiurchiu C, Ruggenenti P, Remuzzi G. Inhibition of the renin-angiotensin system and car<strong>di</strong>o-renalprotection: focus on losartan and angiotensin receptor blockade. Expert Opinion on Pharmacotherapy, 2005 Sep; 6(11):1931-1942.• Ruggenenti P, Fassi A, Parvanova A, Bruno S, Iliev I, Brusegan V, Rubis N, Gherar<strong>di</strong> G, Arnol<strong>di</strong> F, Ganeva M, Ene-Iordache, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini A, Remuzzi G. Preventing Microalbuminuria in Type 2Diabetes. NEJM, 2004;351 (19): 1941-51.• Parvanova A, Iliev I, Filipponi M, Dimitrov BD, Vedovato M, Tiengo A, Trevisan R, Remuzzi G, Ruggenenti P. Insulinresistance and proliferative retinopathy: a cross-sectional, case-control study in 115 patients with type 2 <strong>di</strong>abetes. J ClinEndocrinol Metab, 2004 Sep; 89 (9): 4371-6.• The BENEDICT Group. The Bergamo Nephrologic DIabetes Complications Trial (BENEDICT): design and baselinecharacteristics. Controlled Clinical Trials, 2003; 24: 442-461.• Parvanova A, Iliev I, Dimitrov BD, Arnol<strong>di</strong> F, Zaletel J, Remuzzi G, Ruggenenti P. Hyperhomocysteinemia and increasedrisk of retinopathy: a cross-sectional, case-control study in patients with type 2 <strong>di</strong>abetes. Diabetes Care, 2002; 25 (12):2361.Na<strong>di</strong>a Rubis got her degree in licensed practical nurse in 1995 at the Nursing School of AziendaOspedaliera Ospedali Riuniti <strong>di</strong> Bergamo.Education training: she completed her research training at IRFMN - Centro <strong>di</strong> <strong>Ricerche</strong> Cliniche per leMalattie Rare Aldo e Cele Daccò – Bergamo, Clinical Research Nurse Course (1998).Areas of interest: coor<strong>di</strong>nation of clinical stu<strong>di</strong>es, monitoring activities and data management,pharmacovigilance.Employment: in 1998-2003 involved as co-promoter and tutor for the Clinical Research Course for Nurseat IRFMN - Centro Daccò. In 1998-2008 clinical monitor, Drug Monitoring Unit of Centro Daccò. SinceSeptember 2008 Head of the Drug Monitoring Unit.Selected publications:• Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G and Remuzzi A. Developing regulatorycompliantelectronic case report forms for clinical trials: experience with the demand trial. J Am Med Inform Assoc, <strong>2009</strong>May-Jun;16 (3): 404-8.• Fassi A, Rubis N, Parvanova A, Iliev I, Zamora J, Giuliano GA, Ene-Iordache B, Perna A, Anabaya A, Motterlini N,Ruggenenti P, Remuzzi G for the BENEDICT Study Investigators. Randomized and non-randomized patients in theBergamo Nephrologic Diabetes Complications Trial (BENEDICT). Abstract. 29th <strong>Annual</strong> Meeting of the Society forClinical Trials St Louis, Missouri, May 18-21, 2008.• Ruggenenti P, Fassi A, Parvanova Ilieva A, Bruno S, Petro Iliev I, Brusegan V, Rubis N, Gherar<strong>di</strong> G, Arnol<strong>di</strong> A, GanevaM, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G, for the Bergamo NephrologicDiabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 <strong>di</strong>abetes. N Engl J Med,2004; 351: 1941-51.324ANNUAL REPORT <strong>2009</strong>
IRFMN• Ruggenenti P, Perna A, Gherar<strong>di</strong> G, Benini R, Rubis N, Gritti D, Ciocca I, Stucchi N and Remuzzi G for the GISENGroup. In chronic renal <strong>di</strong>sease, hypertension and type 2 <strong>di</strong>abetes pre<strong>di</strong>ct fast progression. Proteinuria < 2 g/24 hours, type2 <strong>di</strong>abetes and polycystic kidneys are associated with poor response to ACE inhibition. ASN, November 5-8, 1999.ACTIVITIESThe Department of Renal Me<strong>di</strong>cine was established on 1999 at the Clinical Research Center forRare Diseases “Aldo e Cele Daccò” – Villa Camozzi, Ranica to coor<strong>di</strong>nate the activities of sixLaboratories and three Units.The activities of the Department are mainly focused on the study of the mechanisms ofprogression of chronic nephropathies, of new prevention and intervention strategies for <strong>di</strong>abeticnephropathy, non <strong>di</strong>abetic chronic nephropathies, chronic allograft dysfunction, ofcar<strong>di</strong>ovascular complications of <strong>di</strong>abetes, chronic renal <strong>di</strong>sease, <strong>di</strong>alysis and transplantation andof thrombotic microangiopathies.The main aims of these activities are:1. To identify screening and intervention strategies aimed to prevent the onset of nephropathyand of other chronic complications of <strong>di</strong>abetes and/or hypertension.2. To define intervention strategies to prevent or slow the progression of chronic nephropathiesand eventually obtain remission/regression of renal dysfunction.3. To optimize immunosuppressive protocols in kidney transplantation and to define new donorselection criteria in order to expand the pool of available organs.These aims will be pursued through the following modalities:1. Pilot pathophysiology and clinical pharmacology stu<strong>di</strong>es fully finalized at the ClinicalResearch Center to test new pathogenetic hypotheses and new treatment modalities.2. National and international networks and multicenter trials aimed to verify the efficacy oftreatments of potential interest identified as described at point 1.3. Meta-analyses and probabilistic models to test new risk factors and treatments in largesamples of patients and to transfer this information at in<strong>di</strong>vidual level.Many of these activities rest on the possibility of a tight cooperation with the Department ofMolecular Me<strong>di</strong>cine, the Department of Bioengineering and the Public-Private Department ofSpecialist and Transplant Me<strong>di</strong>cine. This cooperation allows to plan the research activities ofthe Department on the basis of new information derived from basic research and of problems ofmajor clinical relevance emerging from routine clinical activities.MAIN FINDINGSDefinition and validation of specific treatments aimed to prevent the development andprogression of nephropathy and related micro and macrovascular complications in subjects withtype 2 <strong>di</strong>abetes.Definition and validation of new integrated treatment protocols aimed to slow the progressionand/or to achieve remission/regression of <strong>di</strong>abetic and non-<strong>di</strong>abetic chronic nephropathies.Institution of a standar<strong>di</strong>zed protocol “on line” (The “Remission Clinics”) finalized to achieveregression/remission of chronic nephropathies and limit overall renal and ra<strong>di</strong>ovascular risk inhospital practice in the setting of a multicenter Network.Characterization of the antiproteinuric, nephroprotective and car<strong>di</strong>oprotective effect of325ANNUAL REPORT <strong>2009</strong>
IRFMNmaximized and polypharmacologic renin-angiotensin system inhibition, intensified bloodpressure and lipid control and identification of novel treatments to reduce the blood pressureand ameliorate insulin sensitivity in subjects at increased car<strong>di</strong>ovascular risk.Identification of acquired or congenital risk factors for chronic complications of <strong>di</strong>abetes andcar<strong>di</strong>ovascular morbi<strong>di</strong>ty and mortalityIdentification and validation of early markers of acute kidney failure and of methods for <strong>di</strong>rectand in<strong>di</strong>rect measurements of kidney function and GFR decline.Definition and validation of new, specific treatments for i<strong>di</strong>opathic membranous nephropathyand for HUS forms associated with genetic defect of complement factors inclu<strong>di</strong>ng thestandar<strong>di</strong>zation of combined liver and kidney transplantation to prevent post transplantrecurrence of genetic associated HUS.Definition and validation of new laboratory procedures and pre<strong>di</strong>ctive models to helpmonitoring and optimizing immunosuppressive therapy in clinical transplantation withparticular focus on pharmacokynetic markers of drug exposure and genetic pre<strong>di</strong>ctors of drugtolerability and efficacy.Definition and validation of selection and allocation criteria of kidneys from marginal and oldveryold donors to increase the donor pool and the transplant activity.Finalization and activation of multicenter clinical trials aimed to prevent onset and progressionof <strong>di</strong>abetic and non-<strong>di</strong>abetic chronic nephropathies, to achieve remission of the nephroticsyndrome in primary glomerular <strong>di</strong>seases, minimize maintenance immunosuppression in kidneytransplantation and prevent car<strong>di</strong>ovascular morbi<strong>di</strong>ty and mortality in chronic hemo<strong>di</strong>alysis.Computerization of data acquisition and monitoring procedures for the conduction of controlledclinical trials.NATIONAL COLLABORATIONSLombar<strong>di</strong>a- AO Bolognini Seriate, Ospedale Bolognini, Seriate (BG)- AO Bolognini Seriate, Ospedale Briolini, Gazzaniga (BG)- AO Bolognini Seriate, Ospedale M. O. A. Locatelli, Piario (BG)- AO Bolognini Seriate, Ospedale Pesenti Fenaroli, Alzano Lombardo (BG)- AO Ospedali Riuniti, Bergamo- AO Treviglio, Ospedale <strong>di</strong> Treviglio, Treviglio (BG)- AO Treviglio, Ospedale SS. Trinità, Romano <strong>di</strong> Lombar<strong>di</strong>a (BG)- AO Treviglio, Poliambulatorio extra-ospedaliero, Ponte San Pietro (BG)- ASL Bergamo, Bergamo- AO Spedali Civili <strong>di</strong> Brescia, Presi<strong>di</strong>o Ospedaliero <strong>di</strong> Montichiari, Montichiari (BS)- AO Spedali Civili, Spedali Civili, Brescia- AO Ospedale Sant’Anna, Presi<strong>di</strong>o Ospedaliero Sant’Anna, Como- Azienda Istituti Ospedalieri, Cremona- AO Lecco, Presi<strong>di</strong>o Ospedaliero Alessandro Manzoni, Lecco- AO Ospedale <strong>di</strong> Lecco, Presi<strong>di</strong>o <strong>di</strong> Merate Leopoldo Man<strong>di</strong>c, Merate (LC)- AO Desio e Vimercate, Ospedale <strong>di</strong> Desio (MI)326ANNUAL REPORT <strong>2009</strong>
IRFMN- AO Melegnano, Presi<strong>di</strong>o Ospedaliero <strong>di</strong> Vizzolo Predabissi (MI)- AO e Polo Universitario, Ospedale Luigi Sacco, Milano- AO Ospedale Civile <strong>di</strong> Legnano, Ospedale Cesare Cantù, Abbiategrasso (MI)- AO Guido Salvini, Ospedale Caduti Bollatesi, Bollate (MI)- AO Ospedale Fatebenefratelli e Oftalmico, Milano- AO Ospedale Niguarda Cà Granda, Milano- AO Ospedale San Carlo Borromeo, Milano- AO San Gerardo, Ospedale Bassini, Cinisello Balsamo (MI)- AO San Gerardo, Ospedale San Gerardo, Monza (MI)- ASL Provincia <strong>di</strong> Milano 2, Ospedale A. Uboldo, Cernusco sul Naviglio (MI)- Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, ClinicaPe<strong>di</strong>atrica Giu<strong>di</strong>tta e Demetrio De Marchi, Milano- Gruppo Ospedaliero San Donato, Istituti Clinici Zucchi, Monza (MI)- IRCCS Fondazione Centro San Raffaele del Monte Tabor, Milano- IRCCS <strong>Istituto</strong> Clinico Humanitas, Rozzano (MI)- IRCCS Multime<strong>di</strong>ca <strong>di</strong> Sesto San Giovanni, Sesto San Giovanni (MI)- IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milano- AO Desio e Vimercate, Ospedale <strong>di</strong> Vimercate (MB)- AO Ospedale Carlo Poma, Ospedale Civile <strong>di</strong> Asola, Asola (MN)- AO Pavia, Ospedale Civile <strong>di</strong> Voghera, Voghera (PV)- Università degli Stu<strong>di</strong> <strong>di</strong> Pavia, Dipartimento <strong>di</strong> Me<strong>di</strong>cina Interna e Terapia Me<strong>di</strong>ca, Pavia- AO Valtellina e Valchiavenna, Ospedale <strong>di</strong> Sondrio, Sondrio- AO Universitaria, Ospedale <strong>di</strong> Circolo e Fondazione Macchi, VaresePiemonte- ASO Santa Croce e Carli, Cuneo- AO Universitaria Maggiore della Carità, Novara- AO Ospedale Infantile Regina Margherita-Sant’Anna <strong>di</strong> Torino, Ospedale Infantile ReginaMargherita, Torino- AO Or<strong>di</strong>ne Mauriziano, Ospedale Mauriziano Umberto I, Torino- AO Universitaria, Ospedale San Giovanni Battista, Torino- ASL TO1, Presi<strong>di</strong>o Ospedaliero Martini, Torino- ASL TO4, Ospedale <strong>di</strong> Ivrea, Ivrea (TO)- Ospedale Luigi Einau<strong>di</strong>, TorinoVeneto, Trentino Alto-A<strong>di</strong>ge e Friuli Venezia Giulia- AO Padova, Ospedale Civile, Padova- AO Padova, Ospedale Giustinianeo, Padova- AULSS 17 Este, Ospedale <strong>di</strong> Monselice, Monselice (PD)- Policlinico Abano Terme, Presi<strong>di</strong>o Ospedaliero Regione Veneto, Abano Terme (PD)- Università degli Stu<strong>di</strong> <strong>di</strong> Padova, <strong>Istituto</strong> <strong>di</strong> Anatomia Patologica, Padova- AULSS 4 Alto-Vicentino, Ospedale San Camillo de Lellis, Schio (VI)- AULSS 8 Asolo, Ospedale San Giacomo Apostolo, Castelfranco Veneto, Treviso- AULSS 9 <strong>di</strong> Treviso, Ospedale Regionale Santa Maria dei Battuti, Treviso- AULSS 9 <strong>di</strong> Treviso, Ospedale Santa Maria <strong>di</strong> Ca' Foncello, Treviso- AULSS 12 Veneziana, Ospedale Civile Umberto I, Mestre (VE)- AULSS 12 Veneziana, Ospedale Civile Maggiore-Borgo Trento, Verona- AULSS 12 Veneziana, Ospedale Policlinico Gianbattista Rossi-Borgo Roma, Verona- AULSS 6 <strong>di</strong> Vicenza, Ospedale San Bortolo, Vicenza- AO Universistaria degli Ospedali Riuniti <strong>di</strong> Trieste, Ospedale <strong>di</strong> Cattinara, Trieste- IRCCS materno-infantile Burlo Garofalo, Trieste- ASS 4 Me<strong>di</strong>o Frìuli, Ospedale <strong>di</strong> San Daniele, San Daniele del Frìuli (UD)327ANNUAL REPORT <strong>2009</strong>
IRFMN- Università degli Stu<strong>di</strong> <strong>di</strong> U<strong>di</strong>ne, Centro Trapianti Fegato-Rene-Pancreas, U<strong>di</strong>ne- AULSS 1, Ospedale Civile <strong>di</strong> Belluno, Belluno- APSS, Presi<strong>di</strong>o Ospedaliero Santa Chiara, TrentoLiguria, Emilia Romagna e Toscana- AO Universitaria San Martino, Genova- IRCCS Pe<strong>di</strong>atrico <strong>Istituto</strong> Giannina Gaslini, Genova- AO Universitaria <strong>di</strong> Bologna, Policlinico Sant’Orsola-Malpighi, Bologna- AUSL Bologna, Ospedale Maggiore, Bologna- AUSL Imola, Ospedale Civile, Imola (BO)- AO Universitaria <strong>di</strong> Ferrara, Arcispedale Sant’Anna, Ferrara- AUSL Forlì, Ospedale G. B. Morgagni - L. Pierantoni, Forlì- AO Universitaria <strong>di</strong> Modena, Policlinico, Modena- AO Universitaria <strong>di</strong> Parma, Ospedale <strong>di</strong> Parma, Parma- AUSL Ravenna, Ospedale Santa Maria delle Croci, Ravenna- AUSL Ravenna, Ospedale <strong>di</strong> Ravenna, Ravenna- AO Reggio Emilia, Arcispedale Santa Maria Nuova, Reggio Emilia- AUSL Rimini, Ospedale Infermi, Rimini- AS Firenze, Ospedale Nuovo San Giovanni <strong>di</strong> Dio, Firenze- AS Firenze, Ospedale Santa Maria Annunziata, Bagno a Ripoli (FI)- AO Universitaria Careggi, Firenze- AO Universitaria, Ospedale Pe<strong>di</strong>atrico Meyer, Firenze- AUSL 11 Empoli, Ospedale degli Infermi San Miniato, San Miniato (FI)- AUSL 2 Lucca, Ospedale Campo <strong>di</strong> Marte, Lucca- AO Universitaria Pisana, Stabilimento Ospedaliero <strong>di</strong> Cisanello, Cisanello (PI)- AO Universitaria Pisana, Ospedale Santa Chiara, Pisa- AUSL 3 Pistoia, Ospedale del Ceppo, PistoiaMarche- AO Universitaria Ospedali Riuniti, Ospedale Umberto I - G.M. Lancisi - G. Salesi, Ancona- IRCCS <strong>Istituto</strong> Nazionale <strong>di</strong> Ricovero e Cura per Anziani, Ancona- ASUR Zona Territoriale 13, Ospedale Mazzoni, Ascoli Piceno- AO San Salvatore, PesaroLazio, Basilicata e Campania- AO San Camillo-Forlanini, Ospedale San Camillo, Roma- ASL Roma H, Ospedale <strong>di</strong> Anzio, Anzio (RM)- IRCCS Pe<strong>di</strong>atrico Bambino Gesù, Roma- Ospedale Policlinico Umberto I, Roma- Ospedale San Giovanni Calibita Fatebenefratelli, Roma- Università Cattolica del Sacro Cuore, Policlinico Universitario Agostino Gemelli, Roma- Università La Sapienza, Dipartimento <strong>di</strong> Biopatologia Umana, Roma- AUSL Latina, Presi<strong>di</strong>o <strong>di</strong> Formia, Latina- AUSL Rieti, Rieti- AUSL Viterbo, Ospedale Grande degli Infermi, Viterbo- ASL Matera, Ospedale Riuniti, Matera- AO Ospedale San Giuseppe Moscati, Avellino- AO Cardarelli, Napoli- AO Ospedale Monal<strong>di</strong>, Napoli- AO Sant’Anna e San Sebastiano, Ospedale Civile, Caserta (NA)- Università Azienda Ospedaliera Universitaria Federico II, Napoli- Università Azienda Ospedaliera Universitaria Federico II, Policlinico Nuovo, Napoli328ANNUAL REPORT <strong>2009</strong>
IRFMN- AO Universitaria <strong>di</strong> Salerno, Ospedali Riuniti San Giovanni <strong>di</strong> Dio e Ruggi d’Aragona,SalernoAbruzzo- Ospedale Civile San Massimo, Penne (PE)- ASL Chieti, Ospedale G. Bernabeo, Ortona (CH)- ASL Teramo, Presi<strong>di</strong>o Ospedaliero Giuseppe Mazzini, TeramoPuglia, Calabria, Sicilia e Sardegna- AO Pugliese Ciaccio, Ospedale Pugliese Ciaccio, Catanzaro- AO Cosenza, Ospedale Civile dell'Annunziata, Cosenza- AS 3 Rossano, Ospedale Civile Nicola Giannettasio, Rossano (CS)- AO Bianchi-Melacrino-Morelli, Reggio Calabria- CNR Reggio Calabria, Reggio Calabria- AO Ospedale Cannizzaro, Catania- AO Universitaria Policlinico-Vittorio Emanuele, Presi<strong>di</strong>o Ospedaliero Vittorio Emanuele,Catania- AUSL 3 Catania, Presi<strong>di</strong>o Ospedaliero <strong>di</strong> Acireale, Acireale (CT)- ASP 5 Messina, Ospedale <strong>di</strong> Milazzo, Milazzo (ME)- AO Civico-Di Cristina-Benfratelli, Presi<strong>di</strong>o Ospedaliero Civico e Benfratelli, Palermo- AO Ospedali Riuniti Villa Sofia-Cervello, Ospedale Vincenzo Cervello, Palermo- AO Universitaria Policlinico Paolo Giaccone, Università degli Stu<strong>di</strong>, Palermo- <strong>Istituto</strong> Me<strong>di</strong>terraneo per i Trapianti e Terapie ad Alta Specializzazione (IsMeTT), Palermo- ASP 7 Ragusa, Ospedale Maggiore, Mo<strong>di</strong>ca (RG)- Azienda Ospedaliera, Ospedale Umberto I, Siracusa- AO Universitaria Consorziale Policlinico <strong>di</strong> Bari, Ospedale Giovanni XXIII, Bari- Ospedale Generale Regionale Francesco Miulli, Acquaviva delle Fonti (BA)- Policlinico <strong>di</strong> Bari, Ospedale Pe<strong>di</strong>atrico Giovanni XXIII, Bari- AO Universitaria <strong>di</strong> Foggia, Ospedali Riuniti, Foggia- IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG)- AUSL Le/1, Ospedale Vito Fazzi, Lecce- ASL Taranto, Ospedale <strong>di</strong> Martina Franca, Martina Franca (TA)- AO Brotzu, Ospedale San Michele, Cagliari- Università degli Stu<strong>di</strong> <strong>di</strong> Cagliari, <strong>Istituto</strong> <strong>di</strong> Clinica e Biologia dell’Età Evolutiva, Cagliari- ASL Sanluri, Presi<strong>di</strong>o Ospedaliero Nostra Signora <strong>di</strong> Bonaria, San Gavino Monreale (VS)- ASL Olbia, Ospedale San Giovanni <strong>di</strong> Dio, Olbia (OT)- ASL Sassari, Azienda Ospedaliero-Universitaria <strong>di</strong> Sassari, Sassari- ASL Sassari, Ospedale Antonio Segni, Ozieri (SS)- ASL Sassari, Ospedale Civle SS. Annunziata, Sassari- Policlinico Sassarese, SassariUmbria- AO Perugia, PerugiaINTERNATIONAL COLLABORATIONS- University Me<strong>di</strong>cal Center, Ljubljana Slovenia- University Hospital Ziekenhuius, Edegem Antwerpen, Belgium- Clinique de Nephrologie-Dialyse Chu Brugmann, Bruxelles, Belgium- University Ziekenhuius Gent, Gent, Belgium329ANNUAL REPORT <strong>2009</strong>
IRFMN- U.Z. Gasthuisberg, Leuven, Belgium- General Hospital Maria Middelares, Sint Niklaas, Belgium- University of Groningen, AV Groningen, The Netherlands- Academisch Ziekenhuis, Maastricht, The Netherlands- Thracian University, Stara Zagora, Bulgaria- The Birmingham Children's Hospital, Birmingham, UK- Guy’s Hospital, London, UK- Manchester Children's Hospital, Manchester, UK- Nottingham City Hospital, Nottingham, UK- Aalborg Hospital, Aalborg, Denmark- Nephrological Department, University of Copenaghen, Copenaghen, Denmark- Steno Diabetes Center, Gentofte, Denmark- Department of Nephrology, Odense University Hospital, Odense, Denmark- Department of Nephrology, Sahlgrenska University Hospital, Goteborg, Sweden- Ospedale San Giovanni, Bellinzona, Switzerland-- Department of Nephrology, University of Wien, Wien, Austria- Carl Thiem Klinikum, Cottbus, Germany- Klinikum der Johann Wolfgang, Frankfurt am Main, Germany- Arbeitsgruppe fyr Biomolekulare Me<strong>di</strong>zin, Hamburg, Germany- Univeristatklinik Heidelberg, Heidelberg, Germany- Me<strong>di</strong>zinische Klinik, Mannheim, Germany- Luitpold Krankenhaus Med. Universitatklinik/Dialyse, Wurzburg, Germany- Fundacion Jimenez Diaz, Madrid, Spain- Hospital 12 de Octubre, Madrid, Spain- Hospital Clinico Martin Logas, Madrid, Spain- Hospital Gregorio Maranon, Madrid, Spain- Hospital La Paz, Madrid, Spain- Hospital Ntra Sra. de Sonsoles, Avila, Spain- Hospital Puerta de Hierro, Madrid, Spain- Hospital Ramon y Cajal, Madrid, Spain- Hospital Severo Ochoa, Leganes, Madrid, Spain- Hospital Universitario de Canarias, Tenerife, Spain- Hospital Universitario de Tarragona Joan XXIII, Tarragona, Spain- Hospitalet de Llobregat, Institut Català de la Salut, Barcellona, Spain- Hospital Garcia de Orta, Almada, Portugal- Department of Pharmacy, Unit of PharmacoEpidemiology & PharmacoEconomics,University Me<strong>di</strong>cal Center Groningen, Groningen, The Netherlands- GENomic stratEgies for treatment and prevention of Car<strong>di</strong>ovascular death in Uraemia andend-stage REnal <strong>di</strong>sease (GENECURE) University Me<strong>di</strong>cal Center Groningen, Groningen,The Netherlands330ANNUAL REPORT <strong>2009</strong>
IRFMN- Moscow State University of Me<strong>di</strong>cine and Dentistry, Mosca, Russian Federation- Chişinău Hospital, Chişinău, Moldavia- Damanhour Me<strong>di</strong>cal National Institute, Damanhour, Beheira, Egypt- Health Sciences University, Ulaanbaator, Mongolia- BP Kerala Institute of Health, Dharan, Nepal- Brigham & Women's Hospital, Boston, USA- CKD Prognosis Consortium, Department of Epidemiology, Johns Hopkins BloombergSchool of Public Health, Baltimore, MD, USA- Hennepin County Me<strong>di</strong>cal Center, Minneapolis, USA- SIU School of Me<strong>di</strong>cine, Springfield, USA- Complejo Hosp Metropolitano de la Caja de Seguro Social, Panama City, Panama- The Toronto Hospital, Toronto, Canada- INCUCAI, Buenos Aires, Argentina- Hospital Italiano de Buenos Aires, Buenos Aires, Argentina- Hospital Juan XXIII, La Paz, Bolivia- Hospital Regional de Val<strong>di</strong>via, Val<strong>di</strong>via, Cile- <strong>Istituto</strong> de Me<strong>di</strong>cina – Universidad Austral de Chile, Val<strong>di</strong>via, Cile- Soroka Me<strong>di</strong>cal Center, Beer Sheva, IsraelEDITORAIL BOARD MEMBERSHIPCurrent Diabetes Reviews (Piero Ruggenenti)Clinical Journal of the American Society of Nephrology (Piero Ruggenenti)Journal of Nephrology (Piero Ruggenenti)Nephron (Norberto Perico)The Open Hypertension Journal (Paolo Crave<strong>di</strong>)PEER REVIEW ACTIVITIESActa Pharmacologica SinicaAmerican Journal of Kidney DiseasesAmerican Journal of PhysiologyAmerican Journal of TransplantationAmerican Transplant JournalArchives of Me<strong>di</strong>cal Science331ANNUAL REPORT <strong>2009</strong>
IRFMNClinical Journal of the American Society of Nephrology (CJASN)International Journal of Clinical PracticeJournal of the American Society of Nephrology (JASN)Kidney InternationalLancetNephrology Dialysis and TransplantationNephron Clinical PracticeTransplantationTransplant InternationalCONFERENCE AND WORKSHOP CONTRIBUTIONS”Trapianto <strong>di</strong> pancreas o solo delle isole?”. In “Bergamo, i trapianti e GiuseppeLocatelli”. Bergamo, Italy. March 14 th , <strong>2009</strong>.“Stu<strong>di</strong>o randomizzato, prospettico, multicentrico, double-blinded per valutare l’efficaciae la sicurezza della Propionill-carnitina nella prevenzione della <strong>di</strong>sfunzione posttrapiantodel graft in riceventi <strong>di</strong> trapianto renale ad alto rischio <strong>di</strong> ritardata ripresafunzionale“. In the 2 nd Meeting “Scientific Clubs Fair & Exhibition della SocietàItaliana <strong>di</strong> Nefrologia”. Roma, Italy. March 23 th -24 th , <strong>2009</strong>.“Prevention and treatment of <strong>di</strong>abetic nephropathy”. In “XXV Congreso Internacionalde Me<strong>di</strong>cina ITESM”. Monterrey, Mexico. April 16 th -18 th . <strong>2009</strong>.“La modulazione del continuum car<strong>di</strong>orenale, microalbuminuria e rischio car<strong>di</strong>ovascolare”.In “Congresso Nazionale Associazioni Regionali Car<strong>di</strong>ologi Ambulatoriali(A.R.C.A.)”. Sorrento, Italy. May 13 th -16 th , <strong>2009</strong>.“Transplantation”. In “CNE Course of World Congress of Nephrology”. Milano, Italy.May 25 th , <strong>2009</strong>.“Clinical and therapeutic aspects on cystic <strong>di</strong>seases”. In “5 th international course ongenetics and renal <strong>di</strong>seases”. Genova, Italy. May 29 th , <strong>2009</strong>.“Immunosuppressive drugs in renal transplantation”. In “Scuola <strong>di</strong> Specializzazione inNefrologia dell’Università degli Stu<strong>di</strong> <strong>di</strong> Firenze”. Firenze, Italy. June 9 th , <strong>2009</strong>.“Trials clinici con terapie innovative”. Colli del Tronto (Ascoli Piceno), Italy. June 13 th ,<strong>2009</strong>.”Diabetic Glomerulopathy: Pathogenesis, Mechanisms of Progression andManagement”. In the 15 th “Nantes/Actualités/Transplantation (N.A.T.)”. Nantes,France. June 18 th -19 th , <strong>2009</strong>.“The protection of the kidney with reduced mass”. In “12 th International Symposium onPerinatal Nephrology”. Brescia, Italy. June 26 th -27 th , <strong>2009</strong>.332ANNUAL REPORT <strong>2009</strong>
IRFMN“Albuminuria/proteinuria as risk factors fo CKD progression”. In “1 st InternationalCourse in Nephrology, prevention and management of CKD”. La Paz, Bolivia. August20 th , <strong>2009</strong>.“The ISN COMGAN prevention programs for emerging countries”. In “1 stInternational Course in Nephrology, prevention and management of CKD”. La Paz,Bolivia. August 20 th , <strong>2009</strong>.“Remission and regression of proteinuric nephropathies”. In “1 st International Course inNephrology, prevention and management of CKD”. La Paz, Bolivia. August 21 st , <strong>2009</strong>.“Therapeutic perspectives in polycystic kidney <strong>di</strong>sease”. In “Advances in therapy innephrology <strong>di</strong>alysis and Transplantation Congress”. Lucca, Italy. September 12 th , <strong>2009</strong>.“Regression of chronic renal <strong>di</strong>sease and the case of kidney self repairing” and “TTPand HUS: are they separate <strong>di</strong>seases? Vitamina D e proteinuria”. In “XXVII Congress& XLIII <strong>Annual</strong> Meeting”. México City, Mexico. September 12t h -14 th , <strong>2009</strong>.“Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference”. London,England. October 4 th -6 th , <strong>2009</strong>.“Terapia della malattia policistica del rene autosomica dominante”. In the “50 thNazionale della Società Italiana <strong>di</strong> Nefrologia”. Bologna, Italy. October 8 th , <strong>2009</strong>.Congresso“Vitamina D e proteinuria”. In “Corso Residenziale Vitamina D e Analoghi”. Torino,Italy. October 20th-21 st , <strong>2009</strong>.“Immunosuppression minimization: less side effects, more prolonged graft survival?”.In “WWVI Congreso conjunto Sociedades Chilenas de Nefrología Hipertensíon yTransplantes”. Puerto Vara, Chile. November 5 th , <strong>2009</strong>.“Remission/regression of chronic proteinuric nephropathies”. In “WWVI Congresoconjunto Sociedades Chilenas de Nefrología Hipertensíon y Transplantes”. Puerto Vara,Chile. November 5 th , <strong>2009</strong>.“Inducing transplant tolerance: progress and challenges”. In “WWVI Congreso conjuntoSociedades Chilenas de Nefrología Hipertensíon y Transplantes”. Puerto Vara, Chile.November 5 th , <strong>2009</strong>.“L’attività <strong>di</strong> farmacovigilanza per i promotori no-profit. L’esperienza del Centro <strong>di</strong> <strong>Ricerche</strong>Cliniche Aldo e Cele Daccò.” In “Master <strong>di</strong> I° livello in Ricerca Clinica” dell’Università degliStu<strong>di</strong> <strong>di</strong> Milano. Milano, Italy. November 11 th , <strong>2009</strong>.“Remission/regression of chronic proteinuric nephropathies”. In “ISN COMGANCourse”. Dharan, Nepal. DEcember, <strong>2009</strong>.“Hemolytic uremic syndrome” al “ISN COMGAN Course”. Dharan, Nepal. DEcember,<strong>2009</strong>.333ANNUAL REPORT <strong>2009</strong>
IRFMN“Immunosuppressive regimens for kidney transplantation affordable for emergingcountries”. In “ISN COMGAN Course”. Dharan, Nepal. DEcember, <strong>2009</strong>.“Quali dati per <strong>di</strong>segnare uno stu<strong>di</strong>o clinico”. In “Corso Sperimentazione Clinica eMonitoraggio”.Torino, Italy. Dicember 10 th , <strong>2009</strong>.“L’estensione del network: la Remission Clinic internazionale”. In “La Remission Clinic nellapratica clinica: nuove prospettive <strong>di</strong> prevenzione e trattamento per le nefropatie cronicheprogressive”. Ranica (Bergamo), Italy. DEcember 12 th , <strong>2009</strong>.GRANTS AND CONTRACTSAIFA (Agenzia Italiana del Farmaco)International Society of Nephrology (ISN)<strong>Istituto</strong> Superiore <strong>di</strong> Sanità (ISS)Regione PugliaUniversità degli Stu<strong>di</strong> <strong>di</strong> Firenze / Regione ToscanaAbbott GmbH & Co.AstraZeneca SpAACRAF Spa (Aziende Chimiche Riunite Angelini Francesco)Baxter SpABoheringer Ingelheim Italia SpAGenzyme Europe BVSanofi-Aventis SpASigma-Tau Industrie Farmaceutiche Riunite SpASolvay PharmaceuticalsSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Crave<strong>di</strong> P, Perna A, Ruggenenti P, Remuzzi G. Mycophenolate mofetil versus azathioprine inorgan transplantation. Am J Transplant. <strong>2009</strong> Dec; 9 (12): 2856-7.De Cosmo S, Motterlini N, Prudente S, Pellegrini F, Trevisan R, Bossi A, Remuzzi G, TrischittaV, Ruggenenti P; BENEDICT Study Group. Impact of the PPAR-gamma2 Pro12Alapolymorphism and ACE inhibitor therapy on new-onset microalbuminuria in type 2 <strong>di</strong>abetes:evidence from BENEDICT. Diabetes. <strong>2009</strong> Dec; 58 (12): 2920-9.Vegter S, Perna A, Hiddema W, Ruggenenti P, Remuzzi G, Navis G, Postma MJ. Costeffectivenessof ACE inhibitor therapy to prevent <strong>di</strong>alysis in non<strong>di</strong>abetic nephropathy: influenceof the ACE insertion/deletion polymorphism. Pharmacogenet Genomics. <strong>2009</strong> Sep; 19 (9): 695-703.Ruggenenti P, Remuzzi G. Proteinuria: Is the ONTARGET renal substudy actually off target?Nat Rev Nephrol. <strong>2009</strong> Aug; 5 (8): 436-7.334ANNUAL REPORT <strong>2009</strong>
IRFMNRuggenenti P, Cattaneo D, Loriga G, Ledda F, Motterlini N, Gherar<strong>di</strong> G, Orisio S, Remuzzi G.Ameliorating hypertension and insulin resistance in subjects at increased car<strong>di</strong>ovascular risk:effects of acetyl-L-carnitine therapy. Hypertension. <strong>2009</strong> Sep; 54 (3): 567-74.Ruggenenti P, Crave<strong>di</strong> P, Remuzzi G. Proteinuria: Increased angiotensin-receptor blocking is notthe first option. Nat Rev Nephrol. <strong>2009</strong> Jul; 5 (7): 367-8.Cattaneo D, Ruggenenti P, Baldelli S, Motterlini N, Gotti E, Sandrini S, Salvadori M, SegoloniG, Rigotti P, Donati D, Perico N, Remuzzi G; Mycophenolate Steroids Sparing (MYSS)Genetics Study Group. ABCB1 genotypes pre<strong>di</strong>ct cyclosporine-related adverse events andkidney allograft outcome. J Am Soc Nephrol. <strong>2009</strong> Jun; 20 (6): 1404-15.Crave<strong>di</strong> P, Ruggenenti P, Remuzzi G. Sirolimus to replace calcineurin inhibitors? Too early yet.Lancet. <strong>2009</strong> Apr 11; 373 (9671): 1235-6.Rigotti P, Ekser B, Furian L, Baldan N, Valente ML, Boschiero L, Motterlini N, Perna A,Remuzzi G, Ruggenenti P. Outcome of renal transplantation from very old donors. N Engl JMed. <strong>2009</strong> Apr 2; 360 (14): 1464-5.Crave<strong>di</strong> P, Ruggenenti P, Remuzzi G. Intensified inhibition of renin-angiotensin system: a wayto improve renal protection? Curr Hypertens Rep. <strong>2009</strong> Apr; 11 (2): 118-24.Ene-Iordache B, Carminati S, Antiga L, Rubis N, Ruggenenti P, Remuzzi G, Remuzzi A.Developing regulatory-compliant electronic case report forms for clinical trials: experience withthe demand trial. J Am Med Inform Assoc. <strong>2009</strong> May-Jun; 16 (3): 404-8.Crave<strong>di</strong> P, Ruggenenti P, Mingar<strong>di</strong> G, Sghirlanzoni MC, Remuzzi G. Thrice-weekly in-centernocturnal hemo<strong>di</strong>alysis: an effective strategy to optimize chronic <strong>di</strong>alysis therapy. Int J ArtifOrgans. <strong>2009</strong> Jan; 32 (1): 12-9.Saland JM, Ruggenenti P, Remuzzi G; Consensus Study Group. Liver-kidney transplantation tocure atypical hemolytic uremic syndrome. J Am Soc Nephrol. <strong>2009</strong> May; 20 (5): 940-9.Ruggenenti P, Crave<strong>di</strong> P, Remuzzi G. Rituximab for membranous nephropathy and immune<strong>di</strong>sease: less might be enough. Nat Clin Pract Nephrol. <strong>2009</strong> Feb; 5 (2): 76-7.Warnock DG, Remuzzi G, Brenner BM, Levin A, Wanner C. Introduction to Focus on FabryNephropathy: Biomarkers, Progression, and Disease Severity. Clin J Am Soc Nephrol. <strong>2009</strong> Dec17.Cattaneo D, Cortinovis M, Baldelli S, Gotti E, Remuzzi G, Perico N. Limited sampling strategiesfor the estimation of sirolimus daily exposure in kidney transplant recipients on a calcineurininhibitor-free regimen. J Clin Pharmacol. <strong>2009</strong> Jul; 49 (7): 773-81.Perico N, Bravo RF, De Leon FR, Remuzzi G. Screening for chronic kidney <strong>di</strong>sease in emergingcountries: feasibility and hurdles. Nephrol Dial Transplant. <strong>2009</strong> May; 24 (5): 1355-8.Remuzzi G, Chiaramonte S, Perico N, Ronco C. Humoral immunity in kidney transplantation:what clinicians need to know. Preface. Contrib Nephrol. <strong>2009</strong>; 162: vii-ix.Cortinovis M, Perico N, Cattaneo D, Remuzzi G. Aldosterone and progression of kidney <strong>di</strong>sease.Ther Adv Car<strong>di</strong>ovasc Dis. <strong>2009</strong> Apr; 3 (2): 133-43.335ANNUAL REPORT <strong>2009</strong>
IRFMNPerico N, Cattaneo D, Bikbov B, Remuzzi G. Hepatitis C infection and chronic renal <strong>di</strong>seases.Clin J Am Soc Nephrol. <strong>2009</strong> Jan; 4 (1): 207-20.Perico N, Cattaneo D, Remuzzi G. Kidney injury molecule 1: in search of biomarkers of chronictubulointerstitial damage and <strong>di</strong>sease progression. Am J Kidney Dis. <strong>2009</strong> Jan; 53 (1): 1-4.Saland JM, Ruggenenti P, Remuzzi G; Consensus Study Group. Liver-kidney transplantation tocure atypical hemolytic uremic syndrome. J Am Soc Nephrol. <strong>2009</strong> May; 20 (5): 940-9.Saland JM, Shneider BL, Bromberg JS, Shi PA, Ward SC, Magid MS, Benchimol C, SeikalyMG, Emre SH, Bresin E, Remuzzi G. Successful split liver-kidney transplant for factor Hassociated hemolytic uremic syndrome. Clin J Am Soc Nephrol. <strong>2009</strong> Jan; 4 (1): 201-6.RESEARCH ACTIVITIESLaboratory of BiostatisticsDElapril and MAni<strong>di</strong>pine for Nephroprotection in Diabetes (DEMAND)clinical trial: final analysesThe DEMAND study is a multicenter, double-blind, placebo-controlled, randomized trialassessing whether angiotensin-converting-enzyme inhibitors and third-generation<strong>di</strong>hydropyri<strong>di</strong>ne calcium-channel-blockers ameliorate chronic complications in hypertensivetype 2 <strong>di</strong>abetic patients without nephropathy. Three-hundred-eighty patients were randomized toat least three-year treatment with mani<strong>di</strong>pine (10 mg/day) plus delapril (30 mg/day), delapril (30mg/day), or placebo. Target blood pressure was 120/80 mmHg. Primary comparison wasbetween combined therapy and placebo. During <strong>2009</strong> we performed statistical analysis of finaldata.DElapril and MAni<strong>di</strong>pine for Nephroprotection in Diabetes (DEMAND) –Neuropathy substudy: final analysesA total of 243 subjects were included in the DEMAND – Neuropathy substudy. Peripheralnerve involvement at inclusion and 3 years was centrally graded by examiners blinded to studydata by means of the Total Neuropathy Score (TNS) scale. TNS combines symptoms (sensory,motor, and autonomic), signs (pin and vibration sensibility, strength, and tendon reflexes),vibratory threshold measured by the quantitative sensory testing, and nerve conduction study(sural and peroneal amplitude) fin<strong>di</strong>ngs. Neuropathy was defined with score greater than 2.Quantitative sensory testing was performed at the first metatarsal phalanx of the big toe usingthe Computed-Assisted Sensory Examinator (CASE IV) device (W.R. Me<strong>di</strong>cal Electronics Co.,Stillwater, MN). Data were referred to the normative ranges provided by the software. Nerveconduction stu<strong>di</strong>es were performed in a warm room with temperature between 25 and 28°C andcontrolled skin temperature using a Keypoint (Medtronic, Copenhagen, Denmark). Peronealnerve compound motor action potential amplitude (normal >4 mV) and antidromic sural nerveaction potential amplitude (peak-to-peak value; normal >6 μV) were recorded in the dominantleg using surface stimulating and recor<strong>di</strong>ng electrodes with standard placement. During the<strong>2009</strong> we performed statistical analysis of final data.DElapril and MAni<strong>di</strong>pine for Nephroprotection in Diabetes (DEMAND) –Retinopathy substudy: final analysesA total of 258 subjects were included in the DEMAND – Retinopathy substudy. All subjectsconsenting to funduscopy evaluation were centrally assessed at the Unit of Ophtalmology of theAzienda Ospedaliera of Ospedali Riuniti (Bergamo, Italy) by ophthalmologists blinded to study336ANNUAL REPORT <strong>2009</strong>
IRFMNdata. In<strong>di</strong>rect binocular ophthalmoscopy was performed by a L-0185 slit-lamp biomicroscope(magnification 10x and 16x) and hand-held lens (magnification 90x) (27). Photographs of fourstandard 30° fields of each eye were taken through <strong>di</strong>lated pupils in stereo pairs (lateral tomacula, macula, <strong>di</strong>sc, and nasal) with Canon CF 60 UV fundus camera (Tokio, Japan). Retinalinvolvement was graded from no apparent retinopathy to mild, moderate or severe preproliferativeretinopathy and to proliferative retinopathy. The eye with the higher grade wasconsidered for statistical analysis. New onset retinopathy was <strong>di</strong>agnosed when any grade ofretinopathy was observed in two consecutive evaluations in eyes with no retinopathy atbaseline. During the <strong>2009</strong> we performed statistical analysis of final data.BErgamo NEphrologic DIabetes Complications Trial (BENEDICT) – Followup ExtensionThe main objective of the follow up extension of the BENEDICT study was to evaluate theeffect of low albuminuria levels (among the normoalbuminuric range) on car<strong>di</strong>ovascular <strong>di</strong>sease(CVD) in the long term in type 2 <strong>di</strong>abetic patients. The BENEDICT phase A core study was arandomized, double blind clinical trial that evaluated <strong>di</strong>verse therapeutic strategies to preventmicroalbuminuria in 1209 patients. A post-hoc follow-up evaluation was undertaken in order toanalyse the long-term impact of albuminuria in CVD. The follow-up evaluation consisted in thefollowing: a.- scheduled visits offered to all eligible participants at the end of the trial (n= 1194)which were accepted by 645 (54%) and ii.- an evaluation of clinical charts in the whole group ofpatients. Through this approach, extended follow-up data was obtained in 993 patients (83.16%). For the remaining group of 201 patients, information was obtained by telephone calls in 62.So, from the initial cohort of 1209 patients, complete follow-up information was available in1055 patients (87%) and 139 (11%) only had follow-up data during the core study. Severalmultivariable models were developed to evaluate the independent impact of low and even verylow levels of albuminuria in car<strong>di</strong>ovascular <strong>di</strong>sease. During the <strong>2009</strong> we performed statisticalanalysis of preliminary data.Laboratory of Coor<strong>di</strong>nation and Conduction of Controlled ClinicalTrialsThe main aim of the Laboratory is to implement and coor<strong>di</strong>nate all the activities needed to fulfilthe trials planned by the Renal Me<strong>di</strong>cine Department, accor<strong>di</strong>ng to the study protocols and theGood Clinical Practice (GCP).To Laboratory staff collaborates with all the Laboratories/Unit of the <strong>Mario</strong> <strong>Negri</strong> Instituteinvolving in the clinical stu<strong>di</strong>es coor<strong>di</strong>nated by the Renal Me<strong>di</strong>cine Department taking care of:to guarantee the flow of the information between the Laboratories/Units of the Renal Me<strong>di</strong>cineDepartment and to guarantee a continuous updating of the trial status; to develop the case reportform of stu<strong>di</strong>es; to develop the database of stu<strong>di</strong>es; to implement and update a centralizedsystem of data management easily enjoyable by researchers of the Renal Me<strong>di</strong>cine Department;to promote training activities for young investigators; to implement and update the SOPs neededfor the trial protocols.Moreover part of the Laboratory staff is specifically devoted to the clinical study monitoringwhich purposes are to verify that: the rights and well-being of human subjects are protected; thereported trial data are accurate, complete, and verifiable from source documents; and theconduct of the trial is in compliance with the currently approved protocol/ amendments, withGCP, and with applicable regulatory requirements.Clinical monitors acting as the main line of communication between the sponsor and theinvestigator; verifying that the investigator has adequate qualifications and resources and theseremain adequate throughout the trial period, and that the staff and facilities, inclu<strong>di</strong>ng337ANNUAL REPORT <strong>2009</strong>
IRFMNlaboratories and equipment, are adequate to safely and properly conduct the trial and theseremain adequate throughout the trial period; verifying that the investigator follows the approvedprotocol and all approved amendments; <strong>di</strong>scussing with the investigator any protocol deviation;verifying that each adverse event is well-documented and timely notified to Authorities asrequired by GCP; verifying the subjects recruitment rate and <strong>di</strong>scussing with Sponsor an<strong>di</strong>nvestigator new strategies to implement the enrolment. For the investigational me<strong>di</strong>cinalproduct (IMP), verifying: that storage times and con<strong>di</strong>tions are acceptable, and that supplies aresufficient throughout the trial; that the IMP are supplied only to subjects who are eligible toreceive it and at the protocol specified doses; that subjects are provided with necessaryinstruction on properly using, handling, storing, and returning the IMP; that the receipt, use, andreturn of the IMP at the trial sites are controlled and documented adequately; that the <strong>di</strong>spositionof unused IMP the trial sites complies with applicable regulatory requirements and is inaccordance with the sponsor’s authorized procedures.In <strong>2009</strong> the Laboratory coor<strong>di</strong>nated and monitored 20 clinical stu<strong>di</strong>es performed incollaboration with 84 Italian Hospital where 250 monitoring visits have been done.Laboratory of Pharmacokinetics and Clinical ChemistryHyperfiltration and renal function decline in patients with type 2 <strong>di</strong>abetesType 2 <strong>di</strong>abetes mellitus is a public health concern. Accor<strong>di</strong>ng to the World HealthOrganization (WHO), <strong>di</strong>abetes affects more than 170 million people worldwide, and thisnumber will rise to 370 million by 2030. One third of <strong>di</strong>abetic patients will eventually develop<strong>di</strong>abetic nephropathy, a syndrome of macroalbuminuria, declining glomerular filtration rate(GFR) and increased car<strong>di</strong>ovascular mortality. Untreated, these patients progress to end stagerenal <strong>di</strong>sease (ESRD) requiring renal replacement therapy in about ten years. Early GFRelevation, commonly referred to as hyperfiltration (GFR > 120 mL/min/1.73m 2 ), has beenconsistently found to play a central role in the pathogenesis and progression of renal <strong>di</strong>sease inexperimental models of both type 1 and type 2 <strong>di</strong>abetes. Some stu<strong>di</strong>es found an acceleratedrenal function loss in hyperfiltering patients compared to those with normal or reduced GFR,but these fin<strong>di</strong>ngs were not confirmed in other stu<strong>di</strong>es. To address this issue we examined anhomogeneous cohort of 600 normo- and microalbuminuric patients with type 2 <strong>di</strong>abetesincluded in the BENEDICT and DEMAND stu<strong>di</strong>es and allocated to ACE inhibitors therapy ornot who had their GFR prospectively monitored with serial measurements of at least 4 iohexolplasma clearance. In ad<strong>di</strong>tion we estimated the renal function of the patients and its decline overtime by means of 14 pre<strong>di</strong>ction equations developed to provide an estimate of GFR from serumcreatinine and demographic characteristics. Overall, we performed 4593 GFR measurements byiohexol plasma clearance over a me<strong>di</strong>an follow-up of 4.3 ± 1.4 years and each patient had up to18 GFR determinations. Of these patients, 449 (74.8%) had at least four GFR measurements onfollow up available for renal function decline analyses. The total GFR slope was of -3.37mL/min/1.73m 2 per year. Hyperfiltering patients showed a significantly faster total GFR slope: -4.39 mL/min/1.73m 2 /y than non-hyperfiltering -3.23 mL/min/1.73m 2 /y. Conversely, no<strong>di</strong>fferences in total GFR slope were observed in patients with micro- or normoalbuminuria an<strong>di</strong>n those receiving ACE inhibitors or not. However, an in depth analysis of the data, showed thathyperfiltering patients had a non linear GFR decline characterized by an acute followed by aslower decrease. The acute GFR change from baseline to 6 months was significantly deeper inhyperfiltering patients: -13.64±19.04 mL/min/1.73m 2 when compared to non-hyperfiltering: -1.18±13.65. The chronic GFR slope, calculated from month 6, was not <strong>di</strong>fferent betweenhyperfiltering (-2.49 mL/min/1.73m 2 /y) and non-hyperfiltering patients (-3.38mL/min/1.73m 2 /y) or when comparing micro- and normoalbuminuric patients or in thoseallocated to ACE inhibitors or not.338ANNUAL REPORT <strong>2009</strong>
IRFMNIn the stu<strong>di</strong>ed patients as a whole, all pre<strong>di</strong>ction equations, with the single exception of theIbrahim model, significantly underestimated baseline GFR. GFR underestimation ranged from1.48 to 29.72 mL/min/1.73m 2 and the percentage of estimates with less than 10% deviationfrom measured GFR ranged from 8.3% to 48.2%. The largest deviations from measured GFRwere observed in the subgroup of hyperfiltering patients where all formulas significantlyunderestimated the GFR and the proportion of hyperfiltering subjects correctly identified rangedfrom 0 to 27%. In ad<strong>di</strong>tion, none of the 14 GFR models reliably pre<strong>di</strong>cted GFR decline in<strong>di</strong>abetics with micro- or normoalbuminuria. Underestimation of the decline ranged from 2.09mL/min/1.73m 2 /y to 3.11 mL/min/1.73m 2 /y and similar trends were observed in hyperfilteringand non-hyperfiltering patients considered separately. Acute GFR decrease was underestimatedby all tested formulas and in particular in hyperfiltering patients where the underestimationranged from 11.54 to 13.16 mL/min/1.73m 2 . Chronic GFR slope was also markedlyunderestimated in the whole population, (from 2.03 to 3.02 mL/min/1.73m 2 /y) as well as inhyperfiltering subjects (2.21 to 3.59 mL/min/1.73m 2 /y) and in non-hyperfiltering patients (2.00to 3.00 mL/min/1.73m 2 /y).These fin<strong>di</strong>ngs showed that in hyperfilterng and non-hyperfiltering patients measured GFRchronic decline was similar and all considered pre<strong>di</strong>ction formulas underestimated GFR andGFR decline to a substantial extent. This is true particularly in patients with hyperfiltration, butformulas were imprecise also in subjects with normal or decreased GFR with large deviationsfrom actual values.Sirolimus therapy to halt the progression of Autosomal DominantPolycystic Kidney DiseaseActivation of mammalian target of rapamycin (mTOR) pathways may contribute touncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominantpolycystic kidney <strong>di</strong>sease (ADPKD). We planned to assess the effects of mTOR inhibition on<strong>di</strong>sease progression, in a prospective, randomized, cross-over study comparing by computedtomography the effects of six-month treatment with sirolimus or conventional therapy alone onthe growth of kidney volume and its compartments in 21 patients with ADPKD and aglomerular filtration rate (GFR) >40 mL/min/1.73m 2 . Total kidney volume increased less onsirolimus than on conventional therapy, but the <strong>di</strong>fference between the two treatments <strong>di</strong>d notreach statistical significance; cyst volume was stable on sirolimus and increased by onconventional therapy, whereas parenchyma volume increased on sirolimus and was stable onconventional therapy. Percent changes in cyst and parenchyma volumes were significantly<strong>di</strong>fferent between the two treatment periods. Sirolimus had no appreciable effects oninterme<strong>di</strong>ate volume and GFR. Sirolimus halted cyst growth and increased parenchyma volumein patients with ADPKD, and was well tolerated. These fin<strong>di</strong>ngs provide the rationale foradequately powered trials aimed to assess whether and to which extent chronic sirolimustherapy may improve clinical outcomes of ADPKD patients in the long run.Laboratory of Advanced Development of DrugOmega-3 polyunsaturated fatty acids affect sirolimus exposure in kidneytransplant recipients on calcineurin inhibitor-free regimenSirolimus (SRL) is an immunosuppressive drug extensively metabolized by the cytochromeP450 (CYP3A4) system. Therefore, its pharmacokinetics is influenced by drugs that interferewith CYP3A4 activity, such as cyclosporine. Patients on SRL therapy frequently requireomega-3 polyunsaturated fatty acids (PUFA) to control hypertriglyceridemia, a common sideeffect of chronic treatment with mammalian target of rapamycin inhibitors. Althoughexperimental stu<strong>di</strong>es have shown that PUFA inhibit CYP3A4 activity, the impact of these lipid-339ANNUAL REPORT <strong>2009</strong>
IRFMNlowering agents on SRL exposure in kidney transplant recipients has not been investigated sofar.To address this issue, we performed a retrospective analysis of a pharmacokinetic data set oftwo groups of patients: one with and one without PUFA treatment. 445 SRL trough levels and55 daily pharmacokinetic profiles were collected from 22 kidney transplant recipients givenlow-dose SRL and low-dose MMF as maintenance immunosuppressive regimen up to 36months post-transplant. Nine out of 22 patients started PUFA administration at <strong>di</strong>fferent timepointsafter surgery to control hypertriglyceridemia. We found that from month 4 posttransplantdose-normalized SRL trough levels were higher in patients given PUFA incomparison to those not receiving the lipid-lowering agents. The <strong>di</strong>fference became statisticallysignificant from month 7 after surgery and it remained significant throughout the study.Moreover, when we compared mean dose-adjusted SRL trough levels in the same patientsbefore and after starting PUFA administration, we found that the treatment resulted in asignificant increase of dose-adjusted SRL concentrations. Pharmacokinetic stu<strong>di</strong>es demonstratedthat concomitant PUFA administration also increased dose-adjusted SRL AUC 0-24 valuescompared with those observed in untreated patients. Interestingly, the major <strong>di</strong>fferences in thepharmacokinetic profiles were observed from 240 to 480 minutes after SRL administration,namely during the phase of drug metabolism. Nearly 25% reduction in the SRL dose wasrequired in patients given PUFA to reach trough concentrations and AUC 0-24 comparable withthose found in patients not receiving the lipid-lowering agents. Altogether, these clinical datasuggest that daily SRL exposure was significantly increased by concomitant administration ofPUFA and extend previous in vivo experimental observation showing the inhibitory effect ofPUFA on the activity of CYP3A4 , the main enzyme involved in SRL metabolism. Thesefin<strong>di</strong>ngs might be helpful to better in<strong>di</strong>vidualize SRL therapy in kidney transplant recipients.The results of this study have been published in Transplantation (2010; 89:126-127).Limiting sampling strategies for the estimation of daily sirolimusexposure in kidney transplant recipients on a calcineurin inhibitor-freeregimenSirolimus (SRL) in an immunosuppressive drug characterized by a narrow therapeutic index.Monitoring of SRL blood concentrations is mandatory to optimize drug dosing. The area underthe concentration-time curve (AUC) is generally accepted as the best surrogate marker of SRLexposure. Assessment of full SRL AUC, however, requires the collection of multiple bloodsamples, imposing both time and cost constrains. Limiting sample strategies (LSS) may be ofclinical relevance to improve the therapeutic drug monitoring of SRL. In this study <strong>di</strong>fferentLSS equations have been identified based on 2 or 3 sample points collected within the first 6hours after drug intake. Most of the proposed algorithms are associated with good correlationswith the measured AUC and acceptable bias and imprecision. In particular, two equations, basedon two time points collected within the first 4 hours after dosing, have been identified thatreliably pre<strong>di</strong>ct SRL exposure in routine clinical practice compared with tra<strong>di</strong>tional C 0 -basedapproach. These tools provide ad<strong>di</strong>tional information to optimize SRL therapeutic drugmonitoring in renal transplant recipients.The results of this study have been published in The Journal of Clinical Pharmacology (<strong>2009</strong>;49: 773-781).ABCB1 genotypes pre<strong>di</strong>ct cyclosporine-related adverse events and kidneyallograft outcomeCyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by theABCB1 gene. Previous stu<strong>di</strong>es have shown that, compared with carriers of wild-type gene,carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and,secondarily, increased intracellular CsA concentrations. Therefore, at comparable CsA340ANNUAL REPORT <strong>2009</strong>
IRFMNexposure, carriers of T allelic variants might be at increased risk for CsA-related adverse events.To test this hypothesis, we evaluated the association between ABCB1 genotype (in exons 12, 21and 26) and clinical outcomes in 147 kidney transplant recipients who were receiving CsAbase<strong>di</strong>mmunosuppression regimen and were included in the Mycophenolate Steroids Sparingstudy. During a me<strong>di</strong>an follow-up of 65.5 mo, carriers of T allelic variants in exons 21 or 26 hada three-fold higher risk for delayed graft function (DGF), a trend to slower recovery of renalfunction and lower glomerular filtration rate at study end, significantly higher incidences ofnew-onset <strong>di</strong>abetes and cytomegalovirus reactivation compared with carriers of the wild-typegenotype. In particular, T variants in both exons 21 and 26 were independently associated with3.8- and 3.5-fold higher risk for DGF, respectively (p = 0.022 and p = 0.034). The incidence ofacute rejection episodes, mean CsA dose and blood levels were comparable in genotype groups.In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are atincreased risk for CsA-related adverse events. Pre-transplant genetic evaluation may help toidentify patients at increased risk of side effects and to modulate CsA therapy in order tooptimize graft and patient outcomes. The results of this study have been published in J Am SocNephrol (<strong>2009</strong>; 20:1404-15).Mesenchymal stem cells in living-related kidney transplant recipientsCurrently available immunosuppressive drugs are associated with long-term complicationsinclu<strong>di</strong>ng premature car<strong>di</strong>ovascular <strong>di</strong>sease, metabolic <strong>di</strong>sorders, infections and malignancy.Moreover, although these drugs have reduced the incidence of acute rejections and one-yeargraft survival rate, they failed to increase long-term renal allograft survival. Thus, the ultimatelygoal of kidney transplantation is to find strategies to induce allograft “tolerance”, a con<strong>di</strong>tion inwhich the transplanted organ is accepted without long-term maintenance immunosuppressivetreatment. In this context, mesenchymal stem cells (MSC) have attracted attention because theyavoid recognition by the immune system and they also exert immunomodulatory functions. Oneof our experimental stu<strong>di</strong>es published in Journal of Immunology (2008; 181: 3933-3946) hasevaluated the effect of MSC infusion on the incidence of acute rejection episodes in asemiallogenic heart transplant mouse model. We found that either single (day -7) or a double(day -7 and day -1) pretransplant infusion of donor-derived MSC induced a profound T cellhyporesponsiveness and prolonged car<strong>di</strong>ac allograft survival. MSC-induced tolerance wasassociated with CD4 + CD25 + FOXP3 + T cells (Treg) expansion. MSC-induced Treg were donorspecificsince adoptive transfer of splenocytes from tolerant mice prevented rejection of donorspecificsecondary allografts but not of third-party grafts. Based on these results a pilot,exploratory study has started to define the safety and biological/mechanistic effects of thesystemic infusion of autologous ex-vivo expanded human MSC in living-related kidneytransplant recipients. The con<strong>di</strong>tion of donor-specific immune tolerance that might be achievedthrough MSC infusion might allow tapering and <strong>di</strong>scontinuation of maintenanceimmunosuppressive drugs.Laboratory of Clinical Pathophysiology of Renal Disease andTransplantationMain objective of the Laboratory of Clinical Pathophysiology of Renal Disease andTransplantation is the study of pathophysiological mechanisms underlying the progression ofchronic kidney <strong>di</strong>sease and the identification of new therapeutic strategies for <strong>di</strong>abetic kidney<strong>di</strong>sease and non<strong>di</strong>abetic proteinuric nephropathies and chronic rejection. The multi<strong>di</strong>sciplinarynature of these lines of research necessarily requires a close integration between various skills ofclinical physiology and clinical pharmacology, and of molecular biology. For this reason, thelaboratory includes not only researchers from the Department of Renal Me<strong>di</strong>cine, which touchon the laboratory, but also the Department of Public-Private Me<strong>di</strong>cal Specialist and Transplants.341ANNUAL REPORT <strong>2009</strong>
IRFMNFrom an operational standpoint, the laboratory interacts closely with the Laboratory for thecoor<strong>di</strong>nation and conduct of controlled clinical trials which finalizes the protocols designed forclinical research within the Department of Renal Me<strong>di</strong>cine.Laboratory of Regulatory Affairs for Clinical Stu<strong>di</strong>esSince 1999, the Department of Renal Me<strong>di</strong>cine, in collaboration with other Departments of theInstitute and with the Hospital of Bergamo, within the framework of activities of the Public-Private Department of Specialist and Transplant Me<strong>di</strong>cine, designs, promotes and coor<strong>di</strong>natesprojects of clinical research. These are mainly independent research projects; some of them arecarried out exclusively in the Daccò Centre, but most of them are multi-centre trials, incollaboration with Hospitals, Research Centres and Universities, both Italian and foreign.The Laboratory of Regulatory Affairs for Clinical Stu<strong>di</strong>es has been created in relation to thisactivity, to verify that the stu<strong>di</strong>es are conducted in compliance with patient’s safety and rightsand accor<strong>di</strong>ng to the legislation in force.In the execution of its activities, the Laboratory, interacts with several interlocutors, amongthem the Ministry of Health, the Italian Agency for Drugs (AIFA), the Local Ethic Committees,the ASL and the Pharmaceutical companies.The Laboratory, supported by a secretariat, participates in all the phases of planning, organizing,conducting and managing the clinical stu<strong>di</strong>es.During the preparatory phase, prece<strong>di</strong>ng the onset of the study, the Laboratory collaborates withthe researchers in order to establish the protocol and the study’s documents in accordance withthe principles of Good Clinical Practice. In ad<strong>di</strong>tion it verifies the adherence of these documentsto regulatory and ethical aspects. Once the protocol has been established, the Laboratoryproceeds to the input of the trial in the National Monitoring Centre on Clinical Research withMe<strong>di</strong>cines (OsSC) and subsequently submits all the documents to the competent authorities, inorder to obtain the ethical and administrative approvals and manages all the bureaucraticprocedures.During the course of the study, the Laboratory is responsible for complying with the legalobligations to keep AIFA and the Ethic committees constantly updated on the progress of theexperimentation. Moreover, it occupies with the collection and maintenance of all essentialdocuments for the conduction of clinical stu<strong>di</strong>es.Since 2005, accor<strong>di</strong>ng to the rules set by the International Committee of Me<strong>di</strong>cal JournalE<strong>di</strong>tors, the Laboratory ensures that all the clinical stu<strong>di</strong>es promoted by the Centre Daccò areregistered to the NIH international registry, “clinicaltrials.gov”.The Laboratory develops its activities within a research frame that promotes primarily academicstu<strong>di</strong>es, therefore, particular attention is paid to the creation of networks of Italian and foreignresearchers, who are interested in collaborating with the institute on specific topics. Theresearchers are involved in collaborative stu<strong>di</strong>es and are supported in the beginning and duringthe conduction of the stu<strong>di</strong>es and constantly updated through workshops and investigatormeetings.Finally, it falls into the responsibilities of the Laboratory Head, to be constantly updated on thenational and international norms and procedures that regulate the clinical stu<strong>di</strong>es.In respect to the recent sanitary accre<strong>di</strong>tation of Daccò Centre, the Laboratory interfaces withASL and other competent authorities, in order to comply with the legal and administrativerequirements.342ANNUAL REPORT <strong>2009</strong>
IRFMNRARE DISEASES DOCUMENTATIONAND RESEARCHSTAFFHeadErica DAINA, M.D.Genetics for Clinical ResearchHeadElena BRESIN, M.D.Network Development for Rare DiseasesHeadSara GAMBA, Research Nurse343ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAErica Daina got her degree in Me<strong>di</strong>cine at the University of Milan in 1987 and the specialisation inMe<strong>di</strong>cal Nephrology in 1990 at the same University.She performed her training at the II° Me<strong>di</strong>cal Division - San Raffaele Hospital - Milan, and at theDivision of Nephrology and Dialysis - Riuniti Hospital - Bergamo.In March 1988 she started her collaboration with the <strong>Mario</strong> <strong>Negri</strong> Institute and since June 1993 she worksas full-time clinical researcher at the Clinical Research Center for Rare Diseases Aldo e Cele Daccò.1996 – <strong>2009</strong>: Chief, Information Center for Rare DiseasesJune <strong>2009</strong>: Chief, Laboratory of Rare Diseases Documentation and ResearchAreas of interest: Rare <strong>di</strong>seases, Takayasu’s Arteritis, Hemolytic Uremic Syndrome/ThromboticThrombocytopenic Purpura, genetic kidney <strong>di</strong>seases.Selected publications1. Warnock DG, Daina E, Remuzzi G, West M. Enzyme Replacement Therapy and Fabry Nephropathy. Clin J Am SocNephrol. Epub <strong>2009</strong> Dec. 10. 2010 feb; 5(2):371-82. Bresin E, Gastol<strong>di</strong> S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G,Galbusera M. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence ofanti-ADAMTS13 autoantibo<strong>di</strong>es. Thromb Haemost <strong>2009</strong>; 101(2):233-83. Schieppati A, Henter JI, Daina E, Aperia A. Why rare <strong>di</strong>seases are an important me<strong>di</strong>cal and social issue. Lancet. 2008Jun 14;371(9629):2039-41.4. Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship T H J, Remuzzi G, International RegistryRecurrent Familial HUS/TTP. Outcome of renal transplantation in patients with non-Shiga toxin-associated HemolyticUremic Syndrome: Prognostic significance of genetic background. Clinical Journal American Society Nephrology 2006;1: 88-995. Daina E, Schieppati A, Remuzzi G. Mycophenolate mofetil for the treatment of Takayasu arteritis: report of three cases.Ann Intern Med. 1999 Mar 2;130(5):422-6.Elena Bresin got her degree in Me<strong>di</strong>cine at the University of Padua in 1994 and the specialisation inMe<strong>di</strong>cal Genetics at the University of Verona in 2000.She performed her training at the Department of Pe<strong>di</strong>atrics of the University Policlinic of Padua, then atthe Department of Biology and Genetics of the University Policlinic of Verona and since 2000 at t theClinical Research Center for Rare Diseases Aldo e Cele Daccò.Since January 2001 she works as full-time clinical researcher at the Clinical Research Center for RareDiseases Aldo e Cele Daccò and since June <strong>2009</strong> she is Unit Head of Genetics for Clinical Research.Areas of interest: thrombotic microangiopathies, membranoproliferative glomerulonephritis, familialfocal segmental glomerulosclerosis.Selected publications1. Bresin E, Gastol<strong>di</strong> S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R, Remuzzi G,Galbusera M. Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence ofanti-ADAMTS13 autoantibo<strong>di</strong>es. Thromb Haemost <strong>2009</strong>; 101(2):233-82. Castelletti F, Donadelli R, Banterla F, Hildebrandt F, Zipfel PF, Bresin E, Otto E, Skerka C, Renieri A, Todeschini M,Caprioli J, Caruso RM, Artuso R, Remuzzi G, Noris M. Mutations in FN1 cause glomerulopathy with fibronectindeposits. Proc Natl Acad Sci U S A 2008 Feb 19;105(7):2538-433. Monteferrante G, Brioschi S, Caprioli J, Pianetti G, Bettinaglio P, Bresin E, Remuzzi G, Noris M Genetic analysis of thecomplement factor H related 5 gene in haemolytic uraemic syndrome. Mol Immunol 2007; 44:1704-17084. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F,Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: theimpact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood2006;108(4):1267-795. Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship T H J, Remuzzi G, International RegistryRecurrent Familial HUS/TTP. Outcome of renal transplantation in patients with non-Shiga toxin-associated HemolyticUremic Syndrome: Prognostic significance of genetic background. Clinical Journal American Society Nephrology 2006;1: 88-99Sara Gamba got her Nurse Diploma on 1994 at Bolognini Hospital Nurses School, Seriate (Bergamo).Educational training: Clinical Research Nurse Diploma on 1996 at IRFMN – Daccò Center.First Level Master on Clinical Research at Milan University on 2008.344ANNUAL REPORT <strong>2009</strong>
IRFMNAreas of interest: rare <strong>di</strong>seases stu<strong>di</strong>ed by the Laboratory staff. She is involved with the Italian rare<strong>di</strong>seases patients’ Associations and she coor<strong>di</strong>nates the documentation service addressed to the patientwith rare con<strong>di</strong>tions, their relatives and the health care professionals.Employment: In 1997-2003 she was involved as co-organizing, speaker, co-speaker and tutor for theClinical Research Course for Nurses at IRFMN – Daccò Center.Since <strong>2009</strong> she is Chief of the Unit Network Development for Rare Diseases.Selected publications1. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F,Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: theimpact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood2006;108(4):1267-792. Krulichova I, Gamba S, Ricci E, Garattini L on behalf of the Italian Takayasu Arteritis Study Group. Direct me<strong>di</strong>calcosts of monitoring and treating patients with Takayasu arteritis in Italy. Eur J Health Econ Vol. 49, August 20043. Noris M, Brioschi S, Caprioli J, Todeschini M, Porrati F, Gamba S, Remuzzi G for the International Registry ofRecurrent and Familial HUS/TTP. Familial haemolytic uraemic syndrome and an MCP mutation. The Lancet, Vol. 362,November 8, 20034. Gamba S, Cicci L, Stefanov R. Qualità della vita in pazienti con malattie rare:l’esperienza degli infermieri del Centro <strong>di</strong><strong>Ricerche</strong> Cliniche per le Malattie Rare Aldo e Cele Daccò. Assistenza Infermieristica e Ricerca, Vol. 22, N. 3, July-September 2003.5. Remuzzi G, Galbusera M, Noris M, Canciani MT, Daina E, Bresin E, Contaretti S, Caprioli J, Gamba S, Ruggenenti P,Perico N, Mannucci PM; Italian Registry of Recurrent and Familial HUS/TTP. von Willebrand factor cleaving protease(ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremicsyndrome. Blood. 2002 Aug 1;100(3):778-85.ACTIVITIESRare Diseases (RD) represent about ten percent of all human me<strong>di</strong>cal illnesses and infirmities. Itis <strong>di</strong>fficult to define what exactly is intended as a RD. The US Congress in the Orphan Drug Acthas given the first definition in 1983. Under this law it is considered rare a <strong>di</strong>sease that affectsless than 200 000 Americans (prevalence 0.75 per 1 000).The European Parliament adopted a more strict definition; they consider rare a con<strong>di</strong>tion thataffects not more than five in<strong>di</strong>viduals per 10 000 in the European Community (prevalence 0.5per 1 000).Accor<strong>di</strong>ng to the WHO, there are 5-7 000 rare <strong>di</strong>seases and most of them (about 4 000) are ofgenetic origin.Rarity often brings a <strong>di</strong>fficult and/or late <strong>di</strong>agnosis, and represents a <strong>di</strong>fficulty in implementingexperimental and clinical research stu<strong>di</strong>es.RD comprehend heterogeneous groups of <strong>di</strong>seases and often require a multi<strong>di</strong>sciplinaryapproach.The greatest barrier to prevention, <strong>di</strong>agnosis and treatment of RD is inadequate knowledge.Once a <strong>di</strong>agnosis of RD is made, a major complaint of patients and of those involved in theircare is the <strong>di</strong>fficulty to obtain pertinent information about causes, symptoms and eitherestablished or experimental treatments. Often, patients with RD are willing to participate inclinical stu<strong>di</strong>es, but they do not know where and how, and physicians or health authorities areseldom able to help them.RD is not a very attracting field for basic and clinical investigators for several reasons: it is<strong>di</strong>fficult to find adequate animal models for many rare <strong>di</strong>sorders; clinical trials may requiremore patients than available; financial support is insufficient.Few countries have a central body or system to <strong>di</strong>sseminate information on RD. Accurateinformation on the incidence and prevalence of RD is extremely important for both basic andclinical investigators. Invaluable help to research advances in RD would come from theavailability of registries and databases containing <strong>di</strong>agnostic, clinical and biological data ofpatients with rare <strong>di</strong>sorders.345ANNUAL REPORT <strong>2009</strong>
IRFMNThe Laboratory has been established whit the aim to collect <strong>di</strong>fferent skills to support patientswith rare <strong>di</strong>seases.Since the beginning of the activities, a Database for rare <strong>di</strong>seases was created with update<strong>di</strong>nformation for patients, their families and professionals. Specific research projects has beendeveloped for some rare con<strong>di</strong>tions such as familial and recurrent forms of Hemolytic UremicSindrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP), Fabry <strong>di</strong>sease, AlportSyndrome, Takayasu arteritis, here<strong>di</strong>tary nephrotic syndromes.During the years the Laboratory role has changed, because of the major attention on rare<strong>di</strong>seases developed at the Institutional level.In 2001 it has been nominated Coor<strong>di</strong>nating Centre of the Regional Network for Rare Diseasesin the Lombardy Region, an area of 9 million people in Northern Italy. As Coor<strong>di</strong>nating Centre,it is also working with the National Centre of Rare Diseases at <strong>Istituto</strong> Superiore <strong>di</strong> Sanità inRome. All the information regar<strong>di</strong>ng the activities of the Coor<strong>di</strong>nating Centre are available atthe web site: http://malattierare.marionegri.itIn <strong>2009</strong> the Genetics for Clinical Research Unit was established with the aim to supportresearch projects on here<strong>di</strong>tary rare <strong>di</strong>seases ongoing at the Daccò Centre, through a closecollaboration with the Laboratory of Immunology and Genetic of Rare Diseases and OrganTransplantation and the Laboratory of Cell Biology and Xenotransplantation – <strong>Negri</strong> Bergamo.The Network Development for Rare Diseases Unit (also established in <strong>2009</strong>) represents asuitable tool for the enhancement of collaborations already activated in the past years and forthe development of new network on rare <strong>di</strong>seases. In ad<strong>di</strong>tion, very important are thecollaborations with Italian patients’ organisations and whit national (UNIAMO-FIMR) an<strong>di</strong>nternational (NORD, EURORDIS) Federations for rare <strong>di</strong>seases. Moreover, particular attentionis de<strong>di</strong>cated to keep up-to-date documentation and scientific bibliography on rare <strong>di</strong>seases. Anhelp-line service to the public it is also maintained.MAIN FINDINGSThe database of the Information Centre for Rare Diseases contains data about 11160 patientsaffected by 897 <strong>di</strong>fferent rare <strong>di</strong>sorders.In the Bank of biological materials, samples from 1541 patients with rare con<strong>di</strong>tions and theirfamilies have been collected.The Centre has established contacts with 346 Italian Associations for rare <strong>di</strong>seases. It was evenpossible that patients with 90 <strong>di</strong>fferent rare <strong>di</strong>seases - for which no Associations have beenestablished in Italy yet - to meet among themselves.In 2000, the European Commission recognized the Laboratory as a site for "Postgraduatetraining on rare <strong>di</strong>seases" (contract No. QLK4-1999-50547).In December 2001 (Delibera della Giunta Lombarda N. 7328), the Centre was identified as"Coor<strong>di</strong>nating Centre of the Regional Network for Rare Diseases".The Laboratory coor<strong>di</strong>nates the International Registry of Recurrent and Familial HemolyticUremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP), since 1996. Theresearch projects developed in collaboration with the Laboratory of Immunology and Genetic ofRare Diseases and Organ Transplantation and with the Laboratory of Cell Biology andXenotransplantation, have allowed to better comprehend the pathogenesis of these <strong>di</strong>seases.346ANNUAL REPORT <strong>2009</strong>
IRFMNNATIONAL COLLABORATIONSItalian National Institute of HealthG. Bosco Hospital, Turin, Regional Coor<strong>di</strong>nating Center for Rare DiseasesRiuniti Hospital, BergamoItalian Registry of Membranoproliferative GlomerulonephritisRegistry of Steroid-Resistant Nephrotic SyndromeBiotechnology Laboratory, IRCCS Policlinico San Matteo, PaviaAssessorato alla Sanità, Lombar<strong>di</strong>a RegionUniversity of Turin, School of Clinical Pathology, Faculty of Me<strong>di</strong>cine and SurgeryItalian Network for Promotion of Folic Acid to Prevent Birth DefectsUniversity of Turin, Department of Experimental Me<strong>di</strong>cine and Oncology, 2 nd Level Master inRare DiseasesItalian Society of Neonatology (Lombardy section), Rare Congenital Respiratory DiseasesStudy GroupUniversity of Milan, 1 st Level Master in Clinical Research“BergamoScienza” AssociationINTERNATIONAL COLLABORATIONSInternational Registry of Recurrent and Familial Hemolytic Uremic Syndrome and ThromboticThrombocytopenic PurpuraInformation Centre for Rare Diseases and Orphan Drugs – ICRDOD, BulgariaPodonet: Consortium for Clinical, Genetic and Experimental Research into Here<strong>di</strong>tary Diseasesof the Podocyte – Coor<strong>di</strong>nator: Heidelberg University Hospital, GermanyInternational Network and Registry for Thrombotic Microangiopathy (TMA) – Coor<strong>di</strong>nator:Schneider Children’s Hospital, Albert Einstein College of Me<strong>di</strong>cine, USAQuaderni <strong>di</strong> FarmacoeconomiaEDITORIAL COMMITTEE MEMBERSHIPNATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPNetwork for Rare Diseases – Lombardy Region (Delibera Regione Lombar<strong>di</strong>a N°7328,11/12/2001)Working group “Classification and co<strong>di</strong>ng of rare <strong>di</strong>seases” coor<strong>di</strong>nated by Italian NationalInstitute of HealthEVENT ORGANIZATIONRiunione Tecnica del Gruppo <strong>di</strong> Lavoro Rete Regionale Malattie RareCentro <strong>di</strong> <strong>Ricerche</strong> Cliniche per le Malattie Rare Aldo e Cele Daccò – <strong>Istituto</strong> <strong>Mario</strong> <strong>Negri</strong>Ranica (Bergamo), april 21, <strong>2009</strong>347ANNUAL REPORT <strong>2009</strong>
IRFMNCONFERENCE AND WORKSHOP CONTRIBUTIONS12° Convegno “Patologia Immune e Malattie Orfane”Torino, january 22-24, <strong>2009</strong>La Rete Regionale per le Malattie Rare: un cantiere apertoMilano, february 28, <strong>2009</strong>XV Convention Scientifica TelethonRiva del Garda (Trento), march 9-11, <strong>2009</strong>Congresso Bergamo, i trapianti e Giuseppe LocatelliBergamo, march 14, <strong>2009</strong>XVIII Riunione <strong>Annual</strong>e SIN SNO Lombar<strong>di</strong>a: Updates in clinical neurologyRozzano (Milano), april 2-4, <strong>2009</strong>VII Meeting Associazione Italiana Pazienti Anderson Fabry (AIPAF)Bologna, april 4, <strong>2009</strong>Advisory board ITP e le malattie Rare in ItaliaMilano, april 16, <strong>2009</strong>Febbri Perio<strong>di</strong>che: impariamo a conoscerleMalattie Rare: un’emergenza che emerge pocoMogliano Veneto (Treviso), april 18, <strong>2009</strong>Focus on Fabry Nephropathy: Biomarkers, progression and Disease severityBergamo, may 27-28, <strong>2009</strong>Le problematiche del malato <strong>di</strong> sclerosi sistemica: dalla malattia alla <strong>di</strong>sabilitàMilano, june 06, <strong>2009</strong>Immunodeficienze primitive in età adulta: una rete per l’assistenzaGrumello del Monte (Bergamo), july 03, <strong>2009</strong>2° Congresso Nazionale Congiunto “Microangiopatie Trombotiche primitive. Geneticamolecolare delle SEU atipiche e MTP”Genova, september 16-19, <strong>2009</strong>La malattia <strong>di</strong> Kawasaki tra presente e futuroPavia, september 18, <strong>2009</strong>Convengo Nazionale Rete Nazionale malattie Rare: Il registro nazionale e i registri regionaliRoma, october 7-9, <strong>2009</strong>Festival della scienzaGenova, october 27, <strong>2009</strong>XII Congresso Nazionale della Società Italiana <strong>di</strong> Genetica Umana (SIGU)Torino Lingotto, november 8-10, <strong>2009</strong>348ANNUAL REPORT <strong>2009</strong>
IRFMNFarmaci orfani per la Malattie Rare da accumulo <strong>di</strong> lisosomialeMilano, november 11, <strong>2009</strong>25 Anni <strong>Negri</strong> BergamoCentro Congressi, Bergamo, november 23, <strong>2009</strong>Aggiornamenti in gastroenterologia dall’Ipertransaminasemia al cancro al fegatoTreviso, december 11-12, <strong>2009</strong>Progetto <strong>di</strong> formazione sul campo: registro Regionale Malattie RarePresi<strong>di</strong> Rete Regionale, <strong>2009</strong>GRANTS AND CONTRACTS"Fondazione Aiuti per la Ricerca sulle Malattie Rare", BergamoLombardy RegionFondazione TelethonSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Warnock DG, Daina E, Remuzzi G, West M.Enzyme Replacement Therapy and Fabry Nephropathy.Clin J Am Soc Nephrol. Epub <strong>2009</strong> Dec. 10. 2010 feb; 5(2):371-8Saland JM, Ruggenenti P, Remuzzi G, Consensus Study Group*Liver-kidney transplantation to cure atypical hemolytic uremic syndrome.*Collaborators:Bekassy Z, Bensman A, Bresin E, Colledan M, Camilla R, Coppo R, Cruzado-Garrit JM, Daina E,Fremeaux-Bacchi V, Goodship TJ, Gridelli B, Hugo C, Karpman D, Jalanko H, Loirat C, Melgosa HijosaM, Mc Kiernan PJ, Noris M, Remuzzi G, Rodriguez de Cordoba S, Rota G, Ruggenenti P, Saland JM,Sanchez-Corral P, Skerka C, Tartufari A, Zipfel PF.J Am Soc Nephrol <strong>2009</strong> May; 20(5):940-9.Saland JM, Shneider BL, Bromberg JS, Shi PA, Ward SC, Magid MS, Benchimol C, Seikaly MG, EmreSH, Bresin E, Remuzzi G.Successful Split Liver-Kidney Transplant for Factor H Associated Hemolytic Uremic Syndrome.CJASN <strong>2009</strong>; 4(1):201-6Bresin E, Gastol<strong>di</strong> S, Daina E, Belotti D, Pogliani E, Perseghin P, Scalzulli PR, Paolini R, Marcenò R,Remuzzi G, Galbusera M.Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidenceof anti-ADAMTS13 autoantibo<strong>di</strong>es.Thromb Haemost <strong>2009</strong>; 101(2):233-8OTHER PUBLICATIONS (<strong>2009</strong>)Barcella L, Ene-Iordache B, Scarpato M, Beccaria L, Citterio A, Baraldo G, Daina E.Registri <strong>di</strong> malattie rare: l’esperienza della Regione Lombar<strong>di</strong>aRicerca e Pratica, Anno 25, N. 6, nov-<strong>di</strong>c <strong>2009</strong>, Il Pensiero Scientifico E<strong>di</strong>tore349ANNUAL REPORT <strong>2009</strong>
IRFMNRESEARCH ACTIVITIESBank of biological samples and description of here<strong>di</strong>tary nephropathiesThe aim of this project is to collect clinical data and biological samples from patients and theirfamilies with rare genetic con<strong>di</strong>tions. A database with clinical data and a Bank for biologicalsamples collection and preservation has been created.The availability of clinical data and biological samples is useful to perform new biochemicaland genetic tests within specific research projects aimed to better reveal the mechanisms of the<strong>di</strong>seases, their manifestation and therapeutic opportunities.In particular, the attention is focused on rare genetic <strong>di</strong>sorders of the kidney. A thorough clinicalevaluation, inclu<strong>di</strong>ng clinical data collection, me<strong>di</strong>cal physical examination, renalultrasonography, laboratory tests of blood and urine is offered to patients, affected by here<strong>di</strong>tarynephropathies (Alport syndrome, Fabry <strong>di</strong>sease, Familial Focal Glomerulosclerosis,Glomerulopathy with Fibronectin deposits, Membranoproliferative glomerulonephritis,Medullary Cystic Kidney <strong>di</strong>sease), who are addressing our Centre. After obtaining a writteninformed consent, biological samples from patients and their relatives are collected, labelledwith specific codes to assure the anonymity and conserved in the Bank for biological samples.In case the responsible gene for a here<strong>di</strong>tary nephropathy is known (Alport syndrome, Fabry<strong>di</strong>sease, Medullary Cystic Kidney <strong>di</strong>sease), the blood samples are re<strong>di</strong>rected to the relevantLaboratory of reference. For other nephropathies, where the identification of the gene mutationis unknown or still in course, the blood samples are conserved with the aim to be used inspecific future research projects.International Registry of Recurrent and Familial Hemolytic UremicSyndrome and Thrombotic Thrombocytopenic PurpuraHemolytic Uremic Syndrome (HUS) and Thrombotic Thrombocytopenic Purpura (TTP) arerare <strong>di</strong>seases of microangiopathic haemolytic anemia and thrombocytopenia with signs of renal(most prevalent in HUS) and cerebral (most prevalent in TTP) damage. There are extremely rareforms of HUS and TTP, often occurring in families, in which the patients relapse even aftercomplete recovery of the first episode with permanent renal and neurological sequelae. In thefamilial and recurrent forms of HUS and TTP, the attention is concentrated mainly on thegenetic pre<strong>di</strong>sposition to the <strong>di</strong>sease.The Laboratory coor<strong>di</strong>nates the International Registry of Recurrent and Familial HUS/TTP,since 1996. The Registry has collected more than 600 cases of HUS/TTP referred from 100Italian and 80 European and extra-European Centres. Clinical and laboratory data of all patientsreferred to the Registry are collected by a uniform data extraction form. The family history andalso the personal data of the unaffected relatives are collected, when possible. Biologicalsamples are collected from all patients and available relatives, for the biochemical and geneticanalyses. Many research projects in collaboration with the Laboratory of Immunology andGenetic of Rare Diseases and Organ Transplantation and the Laboratory of Cellular Biology andXenotransplantation – <strong>Negri</strong> Bergamo are developed and have still allowed to identify somegenetically determined forms of HUS and TTP. The maintenance of a centralised bank ofbiological samples ensure the availability of clinical material for new investigative approachesas they will be developed.Rituximab in relapsing and chronic thrombotic thrombocytopenic purpuraIn most cases, TTP is related to an acquired deficiency of ADAMTS13 activity, due to thepresence of autoantibo<strong>di</strong>es anti-ADAMTS13. The absence of ADAMTS13 activity leads to theaccumulation of von Willebrand Factor ultralarge multimers (normally cleaved to smallermolecular forms by ADAMTS13 enzyme), which probably induces platelets aggregation andthe ensuing process of thrombotic microangiopathy.350ANNUAL REPORT <strong>2009</strong>
IRFMNThe purpose of the project is to evaluate the use of a monoclonal anti-CD20 antibody(Rituximab) in patients with relapsing and chronic thrombotic thrombocytopenic purpura,related to the presence of anti-ADAMTS13 antibo<strong>di</strong>es. Rituximab is a humanized monoclonalantibody that targets the CD20 molecule on B cells (white cells producing antibo<strong>di</strong>es).Administration of Rituximab leads to a selective B cell depletion that usually lasts 6 to 9months. Inhibition of B cell activation or growth by rituximab treatment limit the uncontrolledsynthesis of autoantibo<strong>di</strong>es, that may pre<strong>di</strong>spose to chronic relapsing TTP.After Rituximab treatment, the patients are perio<strong>di</strong>cally controlled with me<strong>di</strong>cal examination,blood and urine exams, and with ADAMTS13 plasma activity assay and research of anti-ADAMTS13 autoantibo<strong>di</strong>es, in collaboration with the Laboratory of Cellular Biology andXenotransplantation – <strong>Negri</strong> Bergamo. Observational period lasts 12 months.MA.RES.CO.: Congenital Respiratory Malformations databaseThe Project originated from the collaboration between the Italian Society of Neonatology(Lombardy section) and the Regional Coor<strong>di</strong>nating Centre for Rare Diseases.The MA.RES.CO (Congenital Respiratory Malformations) Database is conceived to facilitatethe <strong>di</strong>agnostic and assistance procedures for pe<strong>di</strong>atricians facing with respiratory malformations.For each syndrome a description is available with in<strong>di</strong>cations about Reference Centres. A linkwith the OMIM database is also provided. The Database is available at the web site of theRegional Coor<strong>di</strong>nating Center for Rare Diseases: http://malattierare.marionegri.it/.Identification of new genes associated to the Autosomal DominantFamilial form of Focal Segmental GlomerulosclerosisFocal segmental glomerulosclerosis (FSGS) is a pathological entity, and is a significant cause ofend-stage renal <strong>di</strong>sease (ESRD). Glomerular <strong>di</strong>sease is the third lea<strong>di</strong>ng cause of ESRD, andFSGS comprises a significant proportion of this subgroup: up to 5% of adults and 20% ofchildren with ESRD.The <strong>di</strong>agnosis of FSGS is based on renal pathology. The clinical hallmarks include proteinuria,nephrotic syndrome, occasional hematuria and frequent progression to ESRD. Hypertension isalso a common fin<strong>di</strong>ng. At present, there are no consistently reliable treatments for FSGS andresponse rates to available treatments have been estimated at
IRFMNCoor<strong>di</strong>nating Center is in charge of Registry management which consists in analyzing data andsen<strong>di</strong>ng “minimum dataset” (data required by the National Registry of Rare Diseases) to <strong>Istituto</strong>Superiore <strong>di</strong> Sanità. On 31 December <strong>2009</strong>, the Registry contains 5.761 records of <strong>di</strong>agnosis ofrare <strong>di</strong>sease. Most reported Rare Diseases are those in the category of the endocrine glands,nutrition, metabolism and immune <strong>di</strong>sorders. Twenty-five percent of the patients received oneor more me<strong>di</strong>cations for the treatment of their Rare Diseases. Fifteen percent of reportedpatients live in another Italian region. The Registry of Rare Diseases of Lombardy represent aremarkable resource for the study of epidemiology and health planning for rare <strong>di</strong>seases.Perio<strong>di</strong>c Review <strong>Report</strong>s has been implemented and are available at the Coor<strong>di</strong>nating Centreweb site (http://malattierare.marionegri.it).Complement abnormalities in primary MembranoproliferativeglomerulonephritisPrimary membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronicrenal <strong>di</strong>sease that occurs principally in children and young adults, and that often has anunfavourable prognosis.Data on incidence and prevalence of MPGN are scanty, thus a first aim of this project is tocollect through a Registry clinical data and biological samples from well characterized patientswith primary MPGN. Since 2006 the Laboratory coor<strong>di</strong>nates the Italian Registry of primaryform of MPGN and till now 60 cases (17 of type II MPGN, the rarest form) have been collected.The Registry contains homogeneous clinical data for all recruited patients. The family history isalso recorded and biological samples are collected from the patients to perform biochemical andgenetic analyses. Genetic counselling is provided to all patients and relatives.The pathogenesis of primary MPGN is ill defined. The available data in<strong>di</strong>cate that excessiveactivation of complement due to autoimmune and genetic abnormalities plays a role in inducingdamage to the kidney and other organs. The complement is a complex system that me<strong>di</strong>ates theimmune response against bacteria and viruses. In normal con<strong>di</strong>tions human cells are protectedfrom complement attack by several inhibitors that restrict complement activation to the surfaceof pathogens. Such regulatory system is defective in MPGN. Thus a major goal of this project,in collaboration with the Laboratory of Immunology and Genetic of Rare Diseases and OrganTransplantation, will be the identification of the genetic and acquired defects underlyingcomplement activation in MPGN and to establish whether specific complement abnormalitiesare associated with <strong>di</strong>sease progression, response to therapy and recurrence on a transplantedkidney. As yet, a genetic pre<strong>di</strong>sposing factor of complement system has been identified in 10%of cases (50% are patients with MPGN type II). Otherwise, a positive activity of C3Nef (anantibody bin<strong>di</strong>ng C3-convertase) has been in 30% of cases.352ANNUAL REPORT <strong>2009</strong>
IRFMNINTERNATIONAL RELATIONS OFFICEOF RARE DISEASESSTAFFHeadArrigo SCHIEPPATI, M.D.353ANNUAL REPORT <strong>2009</strong>
IRFMNCURRICULAArrigo Schieppati got his degree in Me<strong>di</strong>cine at the University of Milan in 1978 and the specialisation inMe<strong>di</strong>cal Nephrology in 1984 at the same University.He performed his training at the <strong>Mario</strong> <strong>Negri</strong> Bergamo Laboratories with Dr. Remuzzi, and completed itwith stages at the laboratories of prof. Patrono (Catholic University in Rome), prof. John Gordon(Cambridge, GB), and at the Division of Renal Diseases - University of Colorado Me<strong>di</strong>cal School,<strong>di</strong>rected by Dr. Schrier (Denver, USA). Since 1982 he works at the Division of Nephrology and Dialysis– Riuniti Hospital – Bergamo, where he is in charge of Outpatients Clinic and Day Hospital.1991-1995: Chief, Information Center for Rare Diseases1996- 2008: Chief, Laboratory for Coor<strong>di</strong>nation of Information and Diagnosis of Rare Diseases<strong>2009</strong> to date: Chief, International Relations Office of Rare Diseases.Areas of interest: <strong>di</strong>agnosis and therapy of chronic renal <strong>di</strong>seases, hypertension and rare kidney <strong>di</strong>seases.Affiliations: ethical committee Riuniti Hospital - Bergamo; member of the working group of the regionalnetwork for rare <strong>di</strong>seases in Lombardy; scientific committee Bolognini Hospital – Seriate (BG); memberof the Task Force on Rare Diseases (DG Health and Consumer Protection); International Society ofNephrology; American Society of Nephrology; E<strong>di</strong>torial Board Journal of Nephrology.Principali pubblicazioni1. Schieppati A, Henter J I, Daina E, Aperia A. Why rare <strong>di</strong>seases are an important me<strong>di</strong>cal and social issue. Lancet. 2008 June14; 371:2039-55.2. Schieppati A, Remuzzi G. Chronic renal <strong>di</strong>seases as a public health problem: epidemiology, social, and economicimplications. Kidney Int Suppl. 2005 Sep;(98):S7-S10.3. Remuzzi G, Schieppati A, Boissel JP, Garattini S, Horton R. Independent clinical research in Europe. Lancet. 2004 Nov 6-12;364(9446):1723-6.4. Schieppati A, Perna A, Zamora J, Giuliano GA, Braun N, Remuzzi G. Immunosuppressive treatment for i<strong>di</strong>opathicmembranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004293.5. Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 <strong>di</strong>abetes. N Engl J Med. 2002Apr 11;346(15):1145-51.6. Schieppati A, Remuzzi G, Garattini S. Modulating the profit motive to meet needs of the less-developed world. Lancet. 2001Nov 10;358(9293):1638-41.INTRODUCTION TO THE LABORATORY’S ACTIVITIESThe International Relations Office of Rare Diseases has been established in <strong>2009</strong>. It representsthe evolution of the previous Laboratory mainly de<strong>di</strong>cated to information about rare <strong>di</strong>seases.The Laboratory represents also the evolution of the <strong>Mario</strong> <strong>Negri</strong> Institute activities in the fieldof rare <strong>di</strong>seases, with particular attention to the European collaborations.The International Relations Office of Rare Diseases is involved in the EUROPLAN project forrare <strong>di</strong>seases national plans development.Italian National Institute of HealthAssessorato alla Sanità, Lombar<strong>di</strong>a RegionUNIAMO - Rare Diseases Italian FederationRiuniti Hospital, Bergamo“BergamoScienza” AssociationNATIONAL COLLABORATIONS354ANNUAL REPORT <strong>2009</strong>
IRFMNINTERNATIONAL COLLABORATIONSICORD Society - International Conference on Rare Diseases and Orphan DrugsEURORDIS Rare Diseases Europe, non-governmental patient-driven allianceECRIN - European Clinical Research Infrastructures NetworkICRDOD - Information Centre for Rare Diseases and Orphan Drugs, BulgariaJournal of NephrologyEDITORIAL COMMITTEE MEMBERSHIPNATIONAL AND INTERNATIONAL COMMITTEE MEMBERSHIPTask Force on Rare Diseases (established by DG Health and Consumer Protection on 21January 2004).External Advisory Board E-Rare (ERA-Net for research programs on rare <strong>di</strong>seases).Network for Rare Diseases – Lombardy Region (Delibera Regione Lombar<strong>di</strong>a N°7328,11/12/2001)Scientific Committee A.O. Bolognini <strong>di</strong> SeriateEthical Committe, A.O. Ospedali Riuniti <strong>di</strong> BergamoEVENT ORGANIZATIONFocus on Fabry Nephropathy: Biomarkers, progression and Disease severityBergamo, may 27-28, <strong>2009</strong>CONFERENCE AND WORKSHOP CONTRIBUTIONS12° Convegno “Patologia Immune e Malattie Orfane”Torino, january 22-24, <strong>2009</strong>International Conference on Rare Diseases and Orphan Drugs in Rome (ICORD <strong>2009</strong>)Roma, february, 23-25, <strong>2009</strong>La Rete Regionale per le Malattie Rare: un cantiere apertoMilano, february 28, <strong>2009</strong>XVIII Riunione <strong>Annual</strong>e SIN SNO Lambar<strong>di</strong>a: Updates in clinical neurologyRozzano (Milano), april 2-4, <strong>2009</strong>Focus on Fabry Nephropathy: Biomarkers, progression and Disease severityBergamo, may 27-28, <strong>2009</strong>Festival della scienzaGenova, october 27, <strong>2009</strong>Farmaci orfani per la Malattie Rare da accumulo <strong>di</strong> lisosomialeMilano, november 11, <strong>2009</strong>355ANNUAL REPORT <strong>2009</strong>
IRFMNGRANTS AND CONTRACTSEuropean CommissionSCIENTIFIC PUBLICATIONS (<strong>2009</strong>)Kubiak C, de Andres-Trelles F, Kuchinke W, Huemer KH, Thirstrup S, Whitfield K, Libersa C, Barraud B, GrählertX, Dreier G, Grychtol R, Temesvari Z, Blasko G, Kardos G, O'Brien T, Cooney M, Gaynor S, Schieppati A, Sanz N,Hernandez R, Asker-Hagelberg C, Johansson H, Bourne S, Byrne J, Asghar A, Husson JM, Gluud C, Demotes-Mainard J.Common definition for categories of clinical research: a prerequisite for a survey on regulatory requirements by theEuropean Clinical Research Infrastructures Network (ECRIN). Trials. <strong>2009</strong> Oct 16;10:95.Lauder A, Schieppati A, Conte F, Remuzzi G, Batlle D.Low mortality and key aspects of delivery of care for end-stage renal <strong>di</strong>sease in Italy.ScientificWorldJournal. <strong>2009</strong> May 21;9:349-59.RESEARCH ACTIVITIESEUROPLAN - European Project for Rare Diseases National PlansDevelopmentEUROPLAN is a three-year project of the Programme of Community action in the field ofPublic Health (2003 - 2008), which began in April 2008. The main goal is to provide NationalHealth Authorities with a supporting tools for the development and implementation of NationalPlans and Strategies for rare <strong>di</strong>seases (RDs) following the recently agreed European CouncilRecommendation on an action in the field of RDs (<strong>2009</strong>/C 151/02). This supporting tools willbe composed of three documents focused on defined priority areas: the Guidance document onrecommendations for the definition and implementation of National Plans and Strategies forrare <strong>di</strong>seases; the report on current practices and relevant cases in the field of rare <strong>di</strong>seases; andthe document on the recommended set of in<strong>di</strong>cators for monitoring and evaluating theimplementation of national initiatives.The National Centre for Rare Diseases (Italian Institute of Health - <strong>Istituto</strong> Superiore <strong>di</strong> Sanità,Italy) is the lea<strong>di</strong>ng partner that organize the contributions from 31 countries and Euror<strong>di</strong>s (theEuropean Organisation for rare <strong>di</strong>seases) ensuring a broad representation of <strong>di</strong>fferent EUcontexts and experiences and patients’ point of view. The <strong>Mario</strong> <strong>Negri</strong> Institute collaborates inthe EUROPLAN Project as scientific counsellor.In ad<strong>di</strong>tion, the project ensures an inclusive and wide engagement of stakeholders - Ministries,regional and local authorities, health care planners, programme managers, health careprofessionals, researchers and patients.EUROPLAN Projects is <strong>di</strong>vided in eight work-packages. Till now have been completed some ofthe activities requested by the work-package (i.e. information about initiatives for rare <strong>di</strong>seasesalready implemented by the Member States, development of monitoring tools of national plansand creation of contents for EUROPLAN recommendations).During 2010 National Conferences will be organized with the contribution of patientsorganisations.356ANNUAL REPORT <strong>2009</strong>
IRFMNThe Transplant Research CenterChiara Cucchi De Alessandri eGilberto CrespiThe Transplant Research Center (CRT) was set up in 2002 to support and promote the work ofoutstan<strong>di</strong>ng research scientists throughout the world and to carry out major organ transplantresearch programs.The Center is housed in the Villa Camozzi, at Ranica, under the same roof as the <strong>Mario</strong> <strong>Negri</strong>Institute in Bergamo and is managed in collaboration with the Institute.The Center’s staff is mainly made up of senior and junior researchers that were trained in thelaboratories of the <strong>Mario</strong> <strong>Negri</strong> Institute in Bergamo, focusing on transplant immunology,research for less toxic immunosuppressant drugs, and new gene therapy techniques to preventacute rejection of transplanted organs.Information on the Center’s activities can be found in the sections addressed to the Departmentof Molecular Me<strong>di</strong>cine (Laboratory of Immunology and Genetics of Organ Transplantation andRare Diseases) and the Department of Renal Me<strong>di</strong>cine (Laboratory of Pharmacokinetics andClinical Chemistry).357ANNUAL REPORT <strong>2009</strong>
IRFMN358ANNUAL REPORT <strong>2009</strong>
IRFMNEDUCATIONAL ACTIVITIESDean, Educational Activities – Dr. <strong>Mario</strong> SalmonaThe Institute's training programs fall under the hea<strong>di</strong>ng of biome<strong>di</strong>cal science, and are part ofthe Lombardy Region's professional training schemes. There are courses for specializedlaboratory technicians, and for graduates inten<strong>di</strong>ng to do research. In 1999 the Institute set up aPhD course, in collaboration with the Open University (UK). This degree is recognisedthroughout Europe and in the USA. In 2006 the Institute also set up a First Level master Coursein Clinical Research, in collaboration with the Milan University and a Second Level masterCourse in Rare Diseases, in collaboration with the University of Turin.In <strong>2009</strong> the Lombardy Region started reviewing its occupational training courses andestablished an ad hoc register for “Regional Occupational Standards” (Quadro Regionale degliStandard Professionali - QRSP) , This lists all the training courses and the standards reachedby pupils. The Lombardy Region Decree No. 14355 dated 22/12/<strong>2009</strong> approved the newoccupational profile known as Biome<strong>di</strong>cal Research Specialists (formerly PharmacologicalResearch Specialists) presented by the <strong>Mario</strong> <strong>Negri</strong> Institute.Students enrolled in formal courses receive one month’s preparatory training, after which theyare assigned study grants. Between 1963 and 2008 the <strong>Mario</strong> <strong>Negri</strong> Institute awarded 6799grants, 720 of them to foreign researchers who came to the Institute for special training.Everything possible is done to help students find work once they finish the course.The main feature of these courses is that technicians and researchers receive their training "onsite". They work full-time in research programs of a high scientific standard, using advancedequipment and learning the latest methods, in regular contact with colleagues in <strong>di</strong>fferentcountries. Besides its scientific value, this approach provides an excellent preparation on thehuman and personal scale.Students are usually assigned to one of the Institute’s laboratories, where they gradually gainspecialized skills by working on specific research projects. They are expected to attend lessons,seminars, courses and congresses and learn to make full use of the Institute’s well-stockedlibrary. Students all have access to the internet and to biome<strong>di</strong>cal databases and can print outarticles they need to consult, from major international journals. Should the opportunity arise,students are expected to be available for trips abroad, to participate in conferences or courses.The Biome<strong>di</strong>cal Research Specialists will receive <strong>di</strong>plomas issued officially by the LombardyRegion and the <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research. These have legal valuethroughout Italy, and are recognised in competitions for public posts, where they are worth acertain number of points. <strong>Mario</strong> <strong>Negri</strong> Institute <strong>di</strong>plomas are widely considered a guarantee ofan excellent theoretical and practical training. The Open University PhD degree earned at theInstitute has legal value throughout Europe and in the USA. Once they have their <strong>di</strong>ploma orPhD, graduates who want to continue doing research at the Institute may be offered a chance tospend a year or two abroad.359ANNUAL REPORT <strong>2009</strong>
IRFMNIn 2008 the Institute started a two-year Advanced School in Applied Pharmacology (SAFA).The course provides advanced teaching and practical experience with experimental work in thelaboratories. The SAFA course is aimed at preparing young researchers and enabling them tospecialize and work for the pharmaceutical industry, for other research institutes and for publicinstitutions, such as the Regions for instance. Some of the SAFA graduates decide to enroll inthe PhD programs offered by the Institute, while others decide to study abroad.In January 2010, the Institute started running courses for Pharmacological Research Doctorates,recognised by the Ministry for the University and Research with Ministerial Decree dated 11November 2008.At the moment the following courses are available:• Three-year course for graduates, in Milan or Bergamo, lea<strong>di</strong>ng to a <strong>di</strong>ploma asBiome<strong>di</strong>cal Research Specialist.• Three-year course for <strong>di</strong>ploma-holders, in Milan or Bergamo, lea<strong>di</strong>ng to a <strong>di</strong>ploma asBiochemical Research Technician.• Research doctorates (PhD), run under an agreement with the Open University (UK)and the Universities of Maastricht and Groningen (NL).• Two-year Advanced School in Applied Pharmacology (SAFA) for graduate students,in Milan and Bergamo.• Three-year course for Pharmacological Research Doctorates, in Milan or Bergamo,recognised by the Ministry for the University and Research.• First Level Master in Clinical Research, in collaboration with the University of Milan.• Second Level Master Course in Rare Diseases, in collaboration with the University ofTurin.Other training opportunitiesPREPARING A DEGREE THESISStudents can prepare their thesis in scientific subjects at the Institute, with the approval of theiruniversity faculty. These students must work at the Institute for at least two years.SUMMER STUDENTSIn June and July each year the Institute accepts a certain number of students in their last twoyears at high school, to give them experience as part of school/work programs.Since 2003 the Institute’s training schemes have been certified accor<strong>di</strong>ng to UNI EN ISO9001:2008 requirements for the “Design and provision of specialized training courses inbiological and me<strong>di</strong>cal fields”.360ANNUAL REPORT <strong>2009</strong>
IRFMNSTAFFExecutive OfficesServices and Offices361ANNUAL REPORT <strong>2009</strong>
IRFMN362ANNUAL REPORT <strong>2009</strong>
IRFMNProf. Silvio GarattiniSilvio Garattini was born in Bergamo (Italy) on 12 November 1928. He earned a <strong>di</strong>ploma in Chemistry,then a degree in Me<strong>di</strong>cine and was appointed lecturer in Chemotherapy and Pharmacology. He held thepost of Assistant then Deputy Professor at the Milan University Institute of Pharmacology, until 1962.A founder of the <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, when it opened in 1963 he was its<strong>di</strong>rector. The Institute now has four locations (Milan, Bergamo, Ranica (Bg), S. Maria Imbaro (Ch)) andmore than 950 people work there. Professor Garattini is a member of the Gruppo 2003 (a group of themost cited Italian scientists in international scientific literature) and has hundreds of publications inItalian and English in international scientific journals, and texts on pharmacology. He was a founder ofthe European Organisation for Research and Treatment of Cancer (EORTC).In the last ten years Professor Garattini has acted in various organizations, inclu<strong>di</strong>ng the Italian NationalResearch Council (CNR) - Committee on Biology and Me<strong>di</strong>cine; the National Health Council, theCommittee for Italian Research Policy, set up by the Presidency of the Council of Ministers; the Ministryof Health Commissione Unica del Farmaco (CUF).He has held the following posts: President of the UICC Committee on Antitumoral Chemotherapy,President of the European Organisation for Research and Treatment of Cancer (EORTC), Consultant tothe World Health Organisation; President of the European Society of Biochemical Pharmacology;member of the Committee for Proprietary Me<strong>di</strong>cinal Products (CPMP) of the European Agency for theEvaluation of Me<strong>di</strong>cinal Products (EMEA); member of the Committee of Experts of Research Policy –CEPR - at the Ministry for University and Scientific and Technological Research; member of theScientific Committee of the Lega Italiana per la Lotta Contro i Tumori; member of the Board of the<strong>Istituto</strong> Superiore <strong>di</strong> Sanità; Chairman of the Committee for Research of the Italian Agency for Drugs(AIFA).Other appointments include: Vice-president of the Consiglio Superiore <strong>di</strong> Sanità; President of theResearch and Development Commission of the Agenzia Italiana del Farmaco (AIFA); President of theAngelo and Angela Valenti Foundation and the "Via <strong>di</strong> Natale" Foundation; President of the TechnicalCommission for Pharmaceutical Assistance of the Regione Autonoma of Sar<strong>di</strong>nia. He is a member of theStrategic Committee for Welfare, Regione Lombar<strong>di</strong>a, the Consiglio Superiore <strong>di</strong> Sanità and theComitato Nazionale <strong>di</strong> Bioetica, the International Scientific Committee, Centro <strong>di</strong> RiferimentoOncologico, Aviano, and the Scientific Committee of AISLA, Member Comitato Scientifico,Dipartimento Politiche Antidroga Presidenza del Consiglio dei Ministri, Member, Advisory BoardADAMO Onlus, Milan, Member of Committee of the Recommendation for the Call, Wemos Foundation,Amsterdam, , Member, Development Advisory Board of the International Center for Biome<strong>di</strong>calSciences (ICBMS), Luxu Town, Wujiang City, China, Honorary Member AREAS-CCI Onlus.Silvio Garattini is a Fellow of the New York Academy of Sciences, the American Association for theAdvancement of Science, Honorary Fellow of the Royal College of Physicians (PharmaceuticalMe<strong>di</strong>cine), London, Honorary Fellow of the Italian Society of Pharmacology and a member of numerousother Italian and international scientific societies.He has received many awards for his work, inclu<strong>di</strong>ng the French Legion d'Honneur for scientific merit,and the Grand Ufficiale della Repubblica Italiana, and holds honorary degrees from the Universities ofBialystok in Poland, and Barcelona in Spain. Recent awards include the Ippocrate Prize, 2003; MensSana in Corpore Sano; Nuova Spoleto, 2003; Angelo dell’anno; Alkmeon International Prize;International Prize Sant’Agostino Città <strong>di</strong> Bergamo; Il Campione della Scienza; Natta Medal; CoppolaPrize, Scienza e Società in the framework of the Premio Città <strong>di</strong> Firenze and Premio Rana d’Oro,Casalbeltrame (Novara), Premio Barocco Città <strong>di</strong> Lecce, Premio Nazionale Tv L’Altra Italia, Caserta;Premio Chirone <strong>2009</strong>, Centro <strong>Ricerche</strong> e Stu<strong>di</strong> Direzionali (Ceris<strong>di</strong>), Palermo.In its 47 years, the <strong>Mario</strong> <strong>Negri</strong> Institute for Pharmacological Research, under Professor Garattini'sleadership, has published more than 11,105 scientific papers and more than 250 books, on topics rangingfrom cancer and its treatment to tumour immunology, neuropsychopharmacology, and car<strong>di</strong>ovascular andrenal pharmacology. More than 6100 young Italian and 670 foreign graduates and technicians haveobtained specialist qualifications at the Institute.363ANNUAL REPORT <strong>2009</strong>
IRFMN364ANNUAL REPORT <strong>2009</strong>
IRFMNProf. Giuseppe RemuzziGiuseppe Remuzzi was born in Bergamo, Italy in 1949. Upon completion of his me<strong>di</strong>cal training at theUniversity of Pavia in 1974, he received specialty training in Hematology and Nephrology at theUniversity of Milan.Since 1975, he has pursued his academic career at the Ospedali Riuniti of Bergamo, where he wasappointed Professor of Nephrology and Director of the Department of Me<strong>di</strong>cine and Transplantation in1996. Since 1999, he is Director of the Department of Nephrology and Dialysis of the same hospital. The<strong>Negri</strong> Bergamo Laboratories, which he has <strong>di</strong>rected since 1984, is a group of basic scientists,physiologists, pharmacologists, molecular and cellular biologists, pathologists and clinicians devoted tothe study of renal <strong>di</strong>sease. As Research Coor<strong>di</strong>nator of the <strong>Negri</strong> Bergamo Laboratories and the affiliatedClinical Research Center for Rare Diseases "Aldo e Cele Dacco", both <strong>di</strong>visions of the <strong>Mario</strong> <strong>Negri</strong>Institute for Pharmacological Research, he conduct a <strong>di</strong>verse team of researchers studying human renal<strong>di</strong>seases and their correspon<strong>di</strong>ng experimental models from the perspective of pathophysiology andtherapeutic intervention. He touched major advances in many areas of nephrology, with particular focuson platelet endothelial interactions, vascular prostaglan<strong>di</strong>n biology, coagulation and renal <strong>di</strong>sease,progression of renal <strong>di</strong>sease, experimental models of glomerular damage, and transplant immunology andtolerance. Particularly his contributions to the understan<strong>di</strong>ng of the pathophysiology of hemolytic uremicsyndrome, prostaglan<strong>di</strong>n metabolism in pregnancy, renal vascular biology in uremia, the role of proteintrafficking in renal <strong>di</strong>sease progression, the induction of graft tolerance by intrathymic injection of donorantigens, the role of the co-stimulatory CD28-B67 pathway in transplant rejection and the prevention ofrenal and car<strong>di</strong>ovascular damage in <strong>di</strong>abetes.Prof. Remuzzi serves on e<strong>di</strong>torial boards of numerous journals inclu<strong>di</strong>ng the prestigious New EnglandJournal of Me<strong>di</strong>cine and is member of the International Advisory Board of The Lancet.In recognition of his achievements, he has been awarded in 1998 honorary memberships of theAssociation of American Physicians and the British Royal College of Physicians. In 2001 he wasnominated Chairman of the Research Committee of the COMGAN (Commission on Global Advancementof Nephrology) of the International Society of Nephrology (ISN). He received an Honorary Professorshipat the University of Maastricht in 2003.In 2005 during the World Congress of Nephrology in Singapore he received the ISN Jean HamburgerAward and in November 2007 he received during the annual congress of the American Society ofNephrology the precious John P. Peters Award.On August 2008, he was appointed "Honoris Causa Professor" by the Catholic University of Cordoba(Argentina).Prof. Remuzzi has authored and co-authored more than 1030 scientific articles, reviews and monographs.365ANNUAL REPORT <strong>2009</strong>
IRFMN366ANNUAL REPORT <strong>2009</strong>
IRFMN<strong>Mario</strong> <strong>Negri</strong> Institute MilanExecutive OfficeDirectorProf. Silvio GARATTINI, M.D.Administrative OfficeMaria Grazia PEZZONI, ChiefTechnical OfficeFabio BRIGHENTI, D. Arch.General MaintenanceEmanuele SINELLIStu<strong>di</strong>es OfficeArmanda JORI, Pharm.D.Press OfficeIsabella BORDOGNA, Phil. D.Public Relations OfficeClau<strong>di</strong>o PANTAROTTO, Comm.Prevention and Safety OfficeEmilio BENFENATI, Chem.D.Annamaria SEGALINI, Phys.D.English Style E<strong>di</strong>torJu<strong>di</strong> BAGGOTTPhotography and Au<strong>di</strong>o-Visual ServiceFelice DE CEGLIEPurchasing OfficeEufrasia COVIELLODirector’s OfficeRosanna MAPELLI, ChiefGeneral SecretariatElena POZZOLI367ANNUAL REPORT <strong>2009</strong>
IRFMN368ANNUAL REPORT <strong>2009</strong>
IRFMN<strong>Negri</strong> Bergamo LaboratoriesExecutive OfficesDirectorResearch Coor<strong>di</strong>natorScientific SecretariatProf. Silvio GARATTINI, M.D.Giuseppe REMUZZI, M.D.Ariela BENIGNI, Biol.Sci.D., Ph.D.Administration of Research Projects/Admn. AssistanceDaniela MELACINI, Biol.Sci.D.Press and Communication OfficeFrancesca Di Fronzo, Mod. Lit. D.Au<strong>di</strong>o-Visual ServiceAntonella PICCINELLI, Biol.Sci.D.Prevention and Safety OfficeChiefAnnamaria SEGALINI, Phys.D.LibraryChiefValeria MIGLIOLIGeneral MaintenanceGiancarlo GASPARIDirector’s OfficeAntoinette van ENGELEN, Chief369ANNUAL REPORT <strong>2009</strong>
IRFMN370ANNUAL REPORT <strong>2009</strong>
IRFMNCentro Aldo e Cele Daccò Ranica (Bg)Executive OfficesDirectorResearch Coor<strong>di</strong>natorScientific SecretariatHealth DirectorProf. Silvio GARATTINI, M.D.Giuseppe REMUZZI, M.D.Ariela BENIGNI, Biol.Sci.D., Ph.D.Norberto PERICO,M.D.Press and Communication OfficeFrancesca Di Fronzo, Mod. Lit. D.Prevention and Protection OfficeChiefAnnamaria SEGALINI, Phys.D.Paola BOCCARDO, Biol.Sci.D.Library ‘Mansueto Astori’ChiefValeria MIGLIOLIMonica MINALIDirector’s OfficeBarbara REMONTI, Oriental Languages D.Clinical Trials OfficePaola BOCCARDO, Biol.Sci.D.Custo<strong>di</strong>an/general maintenaceGiampiero CUGUSI371ANNUAL REPORT <strong>2009</strong>
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