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seven are in second remission for 6 to 23 + months and two have been reinduced into new remissions after a second relapse off therapy. The durations of their third hematologie remissions are 7 + and 18 + months. Of the eight patients who had treatment stopped for a second time, one completed therapy only recently and six are in unmaintained second remissions for 12 + to 51 + months. Another child who also developed a second relapse off therapy attained a third remission and is now off treatment a third time for 6 + months. Among the 17 survivors, 14 have had long-term leukemia-free remissions. Their median survival since diagnosis is 9 years (range 5-14 years), with a median of 33 + months (range 19+ to 76+ mo) of continuous complete remission since their last relapse. F. Discussion These results demonstrate that prolonged second remissions are attainable in about onethird of the patients who develop a marrow relapse after elective cessation of initial cureoriented therapy. Most importantly, in a certain proportion of children therapy may be stopped altogether for a second time. Although it is still not possible to prediet the likelihood of relapse in individual patients after cessation ot treatment (Sirnone et al. 1978), statistical analysis of patient variables at the time of relapse can provide a reliable estimate of prognosis. Patients whose first complete remission lasts Ion ger than 3 years, whose first relapse occurs more than 6 months after cessation of therapy, and whose si te of relapse is exclusively hematologic have a significantly better chance to attain a extended second remission. Other large series of patients are not available for comparison. Instances of extended se co nd remissions have been reported, but only in patients who relapsed after unmaintained remissions following short-term initial therapy, i.e., 3-13 months (Leventhal et al. 1975). When first diagnosed with ALL, none of the children in these studies had clinical or biologie features that are today regarded as carrying a "high risk" for early treatment failure. The most plausible explanation for their variable therapeutic responsiveness is that subpopulations of leukemic cells not eradicated by initial treatment have different growth potentials, which would account for the wide range in duration of second remissions (3 to 78 + months). For the few patients who remain free of leukemia after completing a second course of therapy, one could speculate that there relapses stemmed from the emergence of a new (and hence more drug-sensitive) clone of leukemic cells. Evidence for the emergence of different clones of leukemic cells in previously treated patients is supported by several re cent reports (Fisher et al. 1977; Merteksmann et al. 1978; Spector et al. 1979). The treatment results presented here were obtained by administering a second program of thera y :omparable to that originally given to these children. The only notable exception was that CNS prophylaxis was not repeated in about one-half of the subjects, because at the onset of the study the need for such additional treatment was unknown. Repeating a treatment that has be co me ineffective would not be recommended today. It should be stressed, however, that even in this circumstance about onethird of our patients responded weIl to therapy, an outcome that compares favorably to results for initially treated childhood ALL. Ultimately, the prospects for obtaining larger proportions of long-term remissions following relapse will depend on the development of more effective chemotherapy, preferably with agents not used earlier, to suppress the emergen ce of drug-resistant disease. A new protocol study to test the value of cyclie combination chemotherapy for maintenance of second remissions is underway at this center. We conclude that children with ALL who develop marrow relapses during unmaintained remissions should be retreated just as aggressively as newly diagnosed patients. Acknowledgments I thank J.R. Gilbert for criticisms and editorial suggestions throughout preparation of this paper. References Aur RJA, Simone JV, Verzosa MS, Hustu HO, Barker LS, Pinkel DP, Rivera G, Dahl GV, Wood A, Stagner S, Mason C (1978) Childhood acute lymphocytic leukemia. Study VIII. Cancer 97
42:2123-2134 - Chessells JM, Cornbleet M (1979) Combination chemotherapy for bone marrow relapse in childhood Iymphoblastic leukemia (ALL). Med Pediatr Oncol 6: 359-365 - Ekert H, EIIis WM, Waters KD, Matthews RN (1979) Poor outlook for childhood acute lymphoblastic leukemia with relapse. Med JAust 2: 224-226 - Fisher EL, Lyons RM, Sears DA (1977) Development of chronic myelocytic leukemia du ring the course of acute lymphatic leukemia in an adult. Am J Hematol 2:291-297 - Kearney PJ, Baumer JH, Howlett BC (1979) Marrow relapse on maintenance chemotherapy in childhood acute lymphoblastic leukemia. Br J Cancer 40: 890-897 - Leventhal BG, Levine AS, Graw RG, Simon R, Freireich EJ, Henderson ES (1975) Long-term second remissions in acute lymphocytic leukemia. Cancer 35: 1136-1140 - Merteksmann R, Koziner B, Ralph P, Fillipa D, McKenzie S, Arlin ZA, Gee TS, Moore MAS, Clarkson BD (1978) Evidence for distinct Iymphocytic and monocytic populations in a patient with terminal transferasepositive acute leukemia. Blood 51: 1051 - Price R, Jamieson P (1975) The central nervous system in childhood leukemia. H. Leukoencephalopathy. Cancer 35:306-318 - Rivera G, Pratt CB, Aur RJA, Verzosa M, Hustu HO (1976) Recurrent childhood Iymphocytic leukemia following cessation of therapy. Treatment and response. Cancer 37:1679-1686 - Rivera G, Murphy SB, Aur RJA, Verzosa MF, Dahl GV, Mauer AM (1978) Recurre nt childhood lymphocytic leukemia. Clinical and cytokinetic studies of cytosine arabinoside and methotrexate for maintenance of second hematologic remission. Cancer 42:2521-2528 - Rivera G, Aur RJA, Dahl GV, Pratt CB, Hustu HO, George SL, Mauer AM (1979) Second cessation of therapy in childhood Iymphocytic leukemia. Blood 53:1114-1120 - Simone J, Aur RJA, Hustu HO, Pinkel D (1972) "Total-Therapy" studies of acute lymphocytic leukemia in children. Current results and prospects for cure. Cancer 30: 1488-1494 - Simone JV, Aur RJA, Hustu HO, Verzosa M, Pinkel D (1978) Three to ten years after cessation of therapy in children with leukemia. Cancer 42:839-842 - Spector G, Youness E, Culbert SJ (1979) Acute lymphoblastic leukemia followed by acute agranulocytic leukemia in a pediatric patient. Am J Clin Pathol 72: 242-245 98
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Haematology and Blood Transfusion 2
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Dr. Rolf Neth, Universitäts-Kinder
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Participants of the Meeting Aaronso
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Kurth, R, Friedrich-Miescher-Labora
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Wilsede Scholarship Holders (Grante
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Preface Gut ist eine Lehrart, wo ma
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Personal and scientific discussion
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Acknowledgement We should like to t
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Wilsede, June 21 1978 Memorial Trib
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limiting benign lymphoproliferative
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this most unlikely, however (for re
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longer subject to the same control
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Bregula U, Wiener F, Harris H (1971
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fresh lymph node biopsies from ten
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Fig. 3. Binucleate mitosis in an ob
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y Fig. 4. Schematic diagram of post
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than that among patients with Stage
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Tests of binding affinity, agglutin
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N Engl J Med 297: 963-968 - Green I
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Clinical Aspects
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"ring chromosome". "Mar" is marker,
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191 chromosomally abnormal patients
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tumors of both African and non-Afri
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Haematology and Blood Transfusion V
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Retrospective group 26/93 evolved l
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Treatment
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advantage in terms of duration of f
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leukaemia. An analysis of 168 patie
Page 59 and 60: 11. Treatment Program Chemotherapy
Page 61 and 62: efractory congestive heart failure
Page 63 and 64: period (Sequence II) was gene rally
Page 65 and 66: children with a multiple drug proto
Page 67 and 68: DAYS 1 5 10 15 20 25 30 35 , I I I
Page 69 and 70: Biologically Drug Outcome fit" sens
Page 71 and 72: may counterbalance the potential be
Page 73 and 74: Ht (0--0) 50 40 30 20 10 0 Platelet
Page 75 and 76: 10 7 ,-----------------------------
Page 77 and 78: 11. Haematological and Biochemical
Page 79 and 80: 0\ 0\ INTERFERON ... 10 3 rl E "'
Page 81 and 82: Haematology and Blood Transfusion V
Page 83 and 84: ("pre-B" phenotype) has been descri
Page 85 and 86: human bone marrow cells exhibit the
Page 87 and 88: 10 9.,0 MBKCC .. .,4 B prot:oool 1'
Page 89 and 90: demann W, Büehner T, Arlin Z, Gee
Page 91 and 92: -...l 00 a-tLDRENS CAt«:ER S TU>Y
Page 93 and 94: prognostic characteristics under in
Page 95 and 96: significantly higher in HR} (14.5%,
Page 97 and 98: normal or elevated immunoglobulin l
Page 99 and 100: References Andreeff M, Darzynkiewic
Page 101 and 102: R GROUP 1 ( 1970 - 1971 ) 17 PTS. R
Page 103 and 104: Table 3. Influence of initial featu
Page 105 and 106: LIJ (f) a.. < -1 LIJ Q: u. 0 >- I-
Page 109: me nt indicated that additional the
Page 113 and 114: Baum et al. 1979). This study was b
Page 115 and 116: 1. 0 '--'1--" 0.9 e: o .- VI VI E C
Page 117 and 118: e: o e: 1. 0 ,.--...-- 1'"'\ ......
Page 119 and 120: In conclusion, we can state that th
Page 121 and 122: Haematology and Blood Transfnsion V
Page 123 and 124: INDUCTION VCR + PRED + ASNASE (wk 3
Page 125 and 126: SCHED.INT 1 MTX • ! Adria MTX •
Page 127 and 128: ~ looh---------ooooc>----o---c>----
Page 129 and 130: Consoll- Irra .tlon t) .tlon Indu
Page 131 and 132: Highrisk Standard risk Table 1. Cli
Page 133 and 134: Cumulo/ive comp/el9 remission 1.0 .
Page 135 and 136: 10° 8 = 6 ö 4 Non T Cell .~ :ö
Page 139 and 140: % SURVIVAL 100 ~ ~II 0 80 60 40 - -
Page 141 and 142: a) Percentage of donor cell mitoses
Page 143 and 144: Table 5. Results of bone marrow tra
Page 145 and 146: ...... w N Table 7. Clinical result
Page 147 and 148: agent had to be added and that in t
Page 151 and 152: C. Chronic Myelogenous Leukemia The
Page 153 and 154: Patients with a suitable donor rece
Page 155 and 156: No. Recurrent Leukaemia Other death
Page 157 and 158: followed by dialysis against isoton
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HS, HL- Heme >_ 40 0 HS I ;:. =====
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knowing at present. These genes may
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esistance to antifolates. In Vitro
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a DNA probe specific for the gene t
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translocation between chromosomes 9
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Table 1. Subdivision of 1827 Myelo-
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NORMAL CELL ®
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some change of the primary type, in
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F. Transformation of Mouse Bone Mar
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were carried out with 3H-MTX in the
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the lysozyme cDNA prepared from ovi
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et al. 1976). The BJAB cellline in
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dalton bands corresponding to light
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1979). The EBV-carrying cell lines
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producer lines (DAUDI and P3HR-1),
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G, Giovanella B, Westman A, Stehlin
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Dc;bt CT + i J.I9 Raji; 1. i .. 100
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c. Discussion During infectious mon
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C. Nonepisomal Viral DNA We have us
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A 260 3.0 A B 1670 70 N2 2.0 c: E .
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vivo. Nature 260:302-306 - Kirk JTO
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Fig. 1. a Polyacrylamide gelelectro
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1979). The lymphocyte subpopulation
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lysin 0 antigens are found, and mix
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Pope JH (1978) Long-term T cell-med
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Haematology and Blood Transfnsion V
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Charaeteristie Morphologie maturati
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after TPA-induction (Table 3). The
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PA (1978) Reactivity of a rabbit an
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Blood Monocyte. B lood Monocytes 1-
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and nonhistone proteins can serve a
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The findings of the evaluation of s
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Fig. 3. Tumor grawth of L 428 cells
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Cell biological and Immunological A
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consideration. Sanel (1973) obtaine
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endotoxin serum, were used. A parti
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monocytic leukemia cell line in cul
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B. Isolation, Characterization and
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don al hemopathies generally displa
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nitors. Blood Cells 6:595-607 - Min
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\I) ....I ....I IU Jl 200 r 100 90
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their haemopoietic cells' ability t
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normal normal ALL ALL ALL persons p
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64.5 { V)
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References Biermann E, Neth R, Gros
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ehambers, the growth pattern observ
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References Anderssen LC, 10kinen M,
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REH CELL UNE TO CALLb~Ö ~q~ V.M. c
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the macrophage series in which the
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Table 1. Production of factor depen
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Table 1. Characteristics of the adh
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Fig. 3. A human marrow culture at 6
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300 250 • HYPERPROLIFERATIVE PATT
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Fig. 9. Nonadherent population from
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The cobblestone areas were often no
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L (1976) Induction of colony format
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B. Materials and Methods J. Tissue
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Fig. 2. Ultrastructural appearance
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Page 307 and 308:
Page 309 and 310:
Table 1. Monoclonal antibody reacti
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al. 1979; Janossy et al. 1979) is e
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to which this is an exact replica o
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inger JL (1976) Distribution of la-
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I region antigens were found to be
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have been reported to be present on
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V. FunctionalAssays Assays for PHA
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Functional studies of UCHT1 separat
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40 ,...... (5 L.. C o u 30 .9 ~ .~
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with immunohistochemieal methods (L
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can be dissected by cloning. Utiliz
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Table 1. Origin and marker profile
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complete identity of gp 100 from no
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Table 1. Reaction of single anti se
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media. Following 24-h incubation, c
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nonleukemic eells (Greaves 1979). L
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Fig. 2. Cytocentrifuged smears of b
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Modification of amino-groups of hum
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disturb this balance in the directi
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The majority of human blood lymphoc
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of the EBV infected B cells. Howeve
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and immunoglobulins. J Immunol 120:
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" K 10 • j ~ ALL RNlL AL wtfh les
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tion akuter Leukämiezellen in "spo
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D. Results and Discussion J. Acute
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selectively responsive to different
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l1J ~ 100 ~ Q. ::) l1J Z 0 ~ z >- .
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Table 2. Growth inhibition of S49 e
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Reverse Infectious ASC/2X1Q6 transc
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Page 381 and 382:
munized animals to 1316 tumor cells
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Haematology and Blood Transfnsion V
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Fig. 3. Expression of retroviral gp
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pg70. J Exp Med 143: 151-166 - McGr
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Table 1. Expression of tumor antige
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Virological and Molecularbiological
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Table 1. Oncogenic properties of re
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also Fig. 1). It followed that the
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whether this sequence is related to
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zed in infected cells argue that th
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a specific viral transforming prote
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detect viral RNA as the only charac
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Eisen H (1980) Myeloproliferate vir
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p,60- -34K - 1 2 3 4 Fig. 1. In vit
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.. p - • a'T ... I .t'l Fig. 4. D
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Fig. 2. Photomicrographs of NY68 in
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DEAE (o(lJmn 'liI GI -2 2 o e s 1
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vity was deterrnined. For endogenou
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pr 180 - - - P 12/15 - A B c D E F
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85,- 66- -27 - -66 40- 27- -1'9 19-
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= 0.5 o E Q. o ILI 0.4 (J) « ILI .
Page 427 and 428:
Table 1. Oncogenic potential of avi
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100 III GI c: o "8 80 > w
Page 431 and 432:
Expt. No. Infecting virus Proportio
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Haematology and Blood 'fransfusion
Page 435 and 436:
sequences, provided its gag portion
Page 437 and 438:
77:3009-3013 - Hu SSF, Moscoviei C,
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RI 2.2 md and Hind III 2.6 md leuke
Page 441 and 442:
Page 443 and 444:
RELATIONSHIP OF ENDOGENOUS AND EXOG
Page 445 and 446:
E ........ E Cl. U E :::l .... Q) (
Page 447 and 448:
References Astrin S (1978) Endogeno
Page 449 and 450:
the same animal were examined (e.g.
Page 451 and 452:
I) 'IQ a \0 - CL -- Fig. 2. Restrie
Page 453 and 454:
~ ..................... ~ Cell 3' 5
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a :Sa,C! + . ~ 111 i' ( " '~ .J. b
Page 457 and 458:
Table 1 Sampie Tissue TS fragment"
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a b Sac I / rep ._-_.-_ K J nl rep
Page 461 and 462:
Haematology and Blood 'fiansfusion
Page 463 and 464:
Osteopetrosis and osteosarcomas occ
Page 465 and 466:
Lymphoma cellline Table 1. T and B
Page 467 and 468:
Table 2. In vivo growth and oneogen
Page 469 and 470:
Page 471 and 472:
Table 1. Transforming aetivity of c
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Table 3. Transformation aetivity of
Page 475 and 476:
- Shoemaker C, Goff S, Gilboa E, Pa
Page 477 and 478:
indieate a shifting of target eell
Page 479 and 480:
Table 2. Expression of Jl and Sourc
Page 481 and 482:
Page 483 and 484:
~ i ,..1---------,,':::::::::::::::
Page 485 and 486:
fragment of pBR322 DNA, a 3.0-kbp S
Page 487 and 488:
Mak TW (1979) Proc Natl Acad Sci US
Page 489 and 490:
Table 1. Transformation of 3T3 cell
Page 491 and 492:
inserts in the genome of rapidly tr
Page 493 and 494:
pulations, it seemed likely that th
Page 495 and 496:
contains antigens which react with
Page 497 and 498:
Page 499 and 500:
le of reacting in sensitive radioim
Page 501 and 502:
Page 503 and 504:
gic approach. In: Hiatt HH, Watson
Page 505 and 506:
12 Eco R [ Fig. 1. Hybridization pa
Page 507 and 508:
Page 509 and 510:
10 - '1~ )( -~ S:! E A U I o 1 2
Page 511 and 512:
Haematology and Blood 'fransfusion
Page 513 and 514:
cultures. These cells did not conta
Page 515 and 516:
indication of malignant T-cells in
Page 517 and 518:
Fig. 3. Thin-section electron micro
Page 519 and 520:
Table 3. Lack of detectable related
Page 521 and 522:
J. HTLV Was Present in the Primary
Page 523 and 524:
specific signals into nonspecific s
Page 525 and 526:
Table 2. Distribution of HTLV-relat
Page 527 and 528:
u 10 ~ 20 ~ :c 30 a 40 o Fig. 1. Ki
Page 529 and 530:
Page 531 and 532:
SSV TrS-gp labeled effectively with
Page 533 and 534:
Page 535 and 536:
60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
Page 537 and 538:
Antisera a Table 1. Immunofluoresce
Page 539 and 540:
Haematology and Blood 'ftansfusion
Page 541 and 542:
y competition RIA yielded virtually
Page 543 and 544:
SiS'V' gp70: ANTIGEN, ANTI BODY, IM
Page 545 and 546:
type-C virus p30 antigen in cells f
Page 547 and 548:
c. Results The fractionated whole-b
Page 549 and 550:
induced antibodies as well as exper
Page 551 and 552:
- Fig. la-f. Retravirus particles p
Page 553 and 554:
eplication of infecting murine leuk
Page 555 and 556:
Page 557 and 558:
immunodeficiency, multic10nal lymph
Page 559 and 560:
Bovine leukemia --, proteins of 499
Page 561 and 562:
Human T- cell - -, characterization
Page 563 and 564:
RNA -, of tumor virus 439 Rous sarc
Page 565 and 566:
Haematology andBlood Transfusion Su
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