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tropic virus were individual virus clones selected by the microtiter procedure for further analysis. IV. Immunologie Identifieation 01 Reeombinant Viruses Type-specific antigenic determinants have been readily demonstrated in the p15 and p12 gag gene coded proteins as weB as in the reverse transcriptase and envelope glycoprotein (gp70) of mouse leukemia viruses (for review see Stephenson et al. 1977). Furthermore, using appropriate antisera, type-specific determinants have also been demonstrated even in the more broadly immunoreactive proteins such as p30 (Boiocchi and Nowinski 1978) and p10 (M. Barbacid and S. A. Aaronson, unpublished observations). We submitted clonal viruses isolated according to the above protocol to immunologic analysis. Tbe origin of the viral sequences of each recombinant virus was determined by the ability of its respective gene products to compete in corresponding Rauscher MuLV or BALB : virus-2 homologous radioimmunoassays. Tbe results, summarized in Figure 1, indicate the generation of individual recombinants that contained different amounts of genetie information of each parent. In some cases, as with rec 25e-8, recombination appeared to involve more than one cross-over. V. Oncogenicity 01 Reeombinants Between Rauscher MuLV and Balb: Virus-2 We have investigated the biologie properties of some of the recombinant viruses so far generated. Tbeir infectivity in tissue culture for NIH/3T3 cells was found to be similar (data not shown). However we observed striking differences in their ability to infect and replicate in newborn NIH/Swiss miee. As shown in Table 1, the Rauscher MuLV parental virus induced readily detectable levels of MuLV p30 in serum within 5 months with as few as 10 XC pfu inoculated. Rec 25b-14 showed almost comparable infectivity. In contrast, recombinants, including rec 25c-3, rec 25d-22, and rec 25e-8, were markedly less able to induce sustained virus replication in vivo. It should be noted that these viruses each contain substantially more genetie information of the xenotropic parental virus than did rec 25b-14. Tbe ability of a given virus to chronieally replicate in vivo was highly predictive of subsequent tumor formation. As shown in Table 2, both Rauscher MuLV and rec 25b-14 induced tumors by 10 months with as few as 10 2 XC pfu inoculated, whereas each of the other recombi- GENETIC MAPPING OF IN VITRO GENERATED RECOMBINANTS BETWEEN RAUSCHER-MuLV ts 25 AND BALB:VIRUS 2 5' gag gene pol gene env gene 3' pm 7G -t-I 1-1 -+-1 -41---+1 -+-1111-+1 +-1 ----4I-tI-lIHI----tI-+1 +1- (A)n p15p12 p30 pl0 Rev. Transcrip. gp 70 p15E ree 25a-3 --~ ...... .---...... --~==~~~ ree 25a-8 --~ ...... ~~ .... __ _c====~~ ree 25b-14 --j ree 25e-3 ---,--'f___ ree 25e-6 ree 25e-14 - ree 25d-4 ree 25d-l0 - ree 25d-22 - ______ ~ ______ II_-{===:J=::Jf___ --~ ...... ~ __ ...... --~==~~f___ ___-==_--c:===:::J ___-===_--c:===:::J ree 25d-25 --___ ===-I---C====:l ree 25e-8 '---__ -'-----'f___ '---__ -'-----'f___ Fig. 1. Proteins exhibiting parental Rauscher-MuLV (c:::::J) or BALB : virus-2 (_) antigenic determinants are indicated. Where intracistronic crossingovers are depicted, the relative localization and extent of Rauscher-MuLv and BALB:virus-2 derived genetic information have been arbitrarily assigned 457
Table 2. In vivo growth and oneogenieity of reeombinants between Rauscher MuLV and BALB :virus-2 Virus In vivo infeetivitya Tumorigenicity MuLV p30 in serum at 5 months b Tumor at 10 months b XC pfu inoeulated XC pfu inoeulated 10 4 10 3 10 2 10 1 10 4 103 10 2 Rauscher MuLV 10/10 10/10 10/10 7/10 9/10 7/7 3/7 ree 25b-14 10/10 10/10 9/10 1/10 5/9 5/7 1/8 ree 25e-3 0/10 ND ND ND 0/9 ND ND ree 25d-22 7/10 0/10 ND ND 0/10 ND ND ree 25e-8 0/10 ND ND ND 0/10 ND ND a NIH/Swiss mice were injeeted at birth with 0.2 ml of the appropriate virus dilution b Animals positive/total animals inoeulated nant viruses tested was at least 100-fold less tumorigenie. c. Discussion The present studies demonstrate that the target cells for transformation by two donal mouse leukemia virus strains, Rauscher and Moloney MuLV, contain markers that differentiate them readily within the lymphoid cell lineage. Our finding that Moloney MuLV caused tumors in NIH/Swiss mice containing T but not B cell markers (Reddy et al. 1980) confirms previous studies indicating that T cells are the in vivo target for transformation by this virus (Moloney 1960). Rauscher MuLV tumors of the same strain, tested either directly or as ceIllines established in culture, invariably contained markers of B lymphoid cells. This in combination with their lack of Thy. 1 antigen, a weIl established marker of T lymphoid ceIls, provides the first demonstration of aBceIl target for neoplastie transformation by a replication-competent MuLV (Reddy et al. 1980). Among the most important biologie questions pertaining to replication-competent type-C viruses concerns the mechanism by whieh they cause neoplasia. Recombinants generated and characterized in this report should be useful in determining what regions of the viral genome are essential for oncogenicity. Our preliminary data indicate that recombinant viruses, whieh have a similar capacity to infect and replicate in mouse cells in tissue culture, show striking differences in their abilities to replicate and induce tumors in the animal. In collaborative studies with P. Arnstein (National Cancer Institute), it has been possible to show that each recombinant virus was capable of inducing tumors in (Nu/Nu) miee on an NIH/Swiss genetic background. Under the same conditions only the parental Rauscher MuLV and rec 25b-14 produced tumors in (Nu+ /Nu) heterozygous mice. These results indicate that the ability of the host to mount an immune response plays an important role in the ability of recombinant viruses to replicate in the mouse. Further studies will be necessary to dissect other host genetic factors that may also influence the expression of the virus es in vivo. Nonetheless, our studies to date argue for the importance of active virus replication in order for mouse type-C viruses to induce disease in their host. Leukemia viruses might be postulated to induce transformation as a result of their site of integration or due to their coding for a specifie transforming gene product from an already identified structural gene or an as yet unidentified transforming gene. Accumulating evidence indicates that there is no specificity with respect to the site of virus integration. This conclusion is derived both from analysis of the arrangement of added viral information in the cellular genome of individual virus-induced leukemias (Canaani and Aaronson 1979; Steffen and Weinberg 1978) and by DNA sequence analysis of cellular junctions of individual molecularly doned integrated DNA proviruses (McClements et al. 1980; Shimotohno et al. 1980). Recently, Hayward (this volume) has obtained evidence that at least some cellular messages found in leukemia virus 458
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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
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11. Treatment Program Chemotherapy
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efractory congestive heart failure
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period (Sequence II) was gene rally
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children with a multiple drug proto
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DAYS 1 5 10 15 20 25 30 35 , I I I
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Biologically Drug Outcome fit" sens
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may counterbalance the potential be
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Ht (0--0) 50 40 30 20 10 0 Platelet
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10 7 ,-----------------------------
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11. Haematological and Biochemical
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0\ 0\ INTERFERON ... 10 3 rl E "'
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("pre-B" phenotype) has been descri
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human bone marrow cells exhibit the
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10 9.,0 MBKCC .. .,4 B prot:oool 1'
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demann W, Büehner T, Arlin Z, Gee
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-...l 00 a-tLDRENS CAt«:ER S TU>Y
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prognostic characteristics under in
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significantly higher in HR} (14.5%,
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normal or elevated immunoglobulin l
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References Andreeff M, Darzynkiewic
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R GROUP 1 ( 1970 - 1971 ) 17 PTS. R
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Table 3. Influence of initial featu
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LIJ (f) a.. < -1 LIJ Q: u. 0 >- I-
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me nt indicated that additional the
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42:2123-2134 - Chessells JM, Cornbl
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Baum et al. 1979). This study was b
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1. 0 '--'1--" 0.9 e: o .- VI VI E C
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e: o e: 1. 0 ,.--...-- 1'"'\ ......
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In conclusion, we can state that th
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Haematology and Blood Transfnsion V
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INDUCTION VCR + PRED + ASNASE (wk 3
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SCHED.INT 1 MTX • ! Adria MTX •
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~ looh---------ooooc>----o---c>----
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Consoll- Irra .tlon t) .tlon Indu
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Highrisk Standard risk Table 1. Cli
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Cumulo/ive comp/el9 remission 1.0 .
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10° 8 = 6 ö 4 Non T Cell .~ :ö
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% SURVIVAL 100 ~ ~II 0 80 60 40 - -
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a) Percentage of donor cell mitoses
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Table 5. Results of bone marrow tra
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...... w N Table 7. Clinical result
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agent had to be added and that in t
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C. Chronic Myelogenous Leukemia The
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Patients with a suitable donor rece
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No. Recurrent Leukaemia Other death
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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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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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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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munized animals to 1316 tumor cells
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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
Page 415 and 416: DEAE (o(lJmn 'liI GI -2 2 o e s 1
Page 417 and 418: vity was deterrnined. For endogenou
Page 419 and 420: pr 180 - - - P 12/15 - A B c D E F
Page 421 and 422: 85,- 66- -27 - -66 40- 27- -1'9 19-
Page 423 and 424: Haematology and Blood Transfusion V
Page 425 and 426: = 0.5 o E Q. o ILI 0.4 (J) « ILI .
Page 427 and 428: Table 1. Oncogenic potential of avi
Page 429 and 430: 100 III GI c: o "8 80 > w
Page 431 and 432: Expt. No. Infecting virus Proportio
Page 433 and 434: Haematology and Blood 'fransfusion
Page 435 and 436: sequences, provided its gag portion
Page 437 and 438: 77:3009-3013 - Hu SSF, Moscoviei C,
Page 439 and 440: RI 2.2 md and Hind III 2.6 md leuke
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
Page 455 and 456: a :Sa,C! + . ~ 111 i' ( " '~ .J. b
Page 457 and 458: Table 1 Sampie Tissue TS fragment"
Page 459 and 460: 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: Lymphoma cellline Table 1. T and B
Page 471 and 472: Table 1. Transforming aetivity of c
Page 473 and 474: 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 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 499 and 500: le of reacting in sensitive radioim
Page 503 and 504: gic approach. In: Hiatt HH, Watson
Page 505 and 506: 12 Eco R [ Fig. 1. Hybridization pa
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
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Fig. 3. Thin-section electron micro
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Table 3. Lack of detectable related
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J. HTLV Was Present in the Primary
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specific signals into nonspecific s
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Table 2. Distribution of HTLV-relat
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u 10 ~ 20 ~ :c 30 a 40 o Fig. 1. Ki
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SSV TrS-gp labeled effectively with
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60 HFF/SSV cDNA CELL RNAs: 0 HF/SSV
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Antisera a Table 1. Immunofluoresce
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Haematology and Blood 'ftansfusion
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y competition RIA yielded virtually
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SiS'V' gp70: ANTIGEN, ANTI BODY, IM
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type-C virus p30 antigen in cells f
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c. Results The fractionated whole-b
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induced antibodies as well as exper
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- Fig. la-f. Retravirus particles p
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eplication of infecting murine leuk
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immunodeficiency, multic10nal lymph
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Bovine leukemia --, proteins of 499
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Human T- cell - -, characterization
Page 563 and 564:
RNA -, of tumor virus 439 Rous sarc
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Haematology andBlood Transfusion Su
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