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5' most vlflon gene that they partially or completely replace (Fig. 1). To determine whether the gag-related elements of the hybrid onc genes are indeed essential for the probable transforming function of their proteins as our analyses suggest, it would be necessary to find transforming viruses in which the specific sequences of hybrid onc genes are not linked to gag or pol sequences. Conversely it would be interesting to know whether src or the amv sequence would have a transforming function if inserted into gag or pol genes. It is thought that the 60-kd src gene product functions catalytically, probably as a phosphokinase (Erikson et al. 1980; Bishop et al. 1980), although there is evidence that kin ase activity may not be the only function of the src gene product (Rübsamen et al. 1980; Bishop et al. 1980). By contrast the function of the gag-related proteins of avian acute leukemia and Fujinami sarcoma viruses, of the Abelson MuLV, and of the feline sarcoma viruses may not be solely catalytic. Although a kinase activity again appears as a candidate for a catalytic function of these proteins, this has not been demonstrated in each of these proteins. It appears associated with the gag-related proteins of some strains of Abelson virus (Witte et al. 1980) and, with some uncertainty, also with the proteins of the Gardner and Snyder-Theilen strains of feHne sarcoma virus (Reynolds et al. 1980) but has not been found in some avian viruses with onc genes of MC29 design (Bister et al. 1980b) and in the McDonough strain of feHne sarcoma virus (Van de Yen et al. 1980). I t is possible that these onc gene products have in addition to a possible catalytic function a structural function involving their gag-related elements. Analogous to the function of virion gag proteins, the gag portions of the nonstructural pro teins of these virus es may function by binding to specific cellular and also to intracellular viral nucleic acid sequences. This specific binding may represent a regulatory function of a cellular catalytic activity or perhaps of a yet to be discovered catalytic activity of the gag-related proteins. This function would then correspond to one of the two domains diagnosed in the proteins of the MC29 subgroup viruses described above. The consistent difficulties in isolating temperature-sensitive onc mutants of these viruses that respond fast to temperature shifts (unpublished experiments and personal communications) support the view that onc genes of the MC29 design may have a structural function. F. Multiple one Genes: Multiple Meehanisms and Multiple Targets of Transformation Despite some insufficiencies in the definition of onc genes of defective viruses, it is clear that multiple, at least five different classes of specific sequences (src, mev, aev,fsv, and amv) and hence probably five different onc genes exist in the avian tumor virus group alone. The number will increase if other viruses are analyzed and if viruses of other taxonomic groups are included. Some of these onc genes cause specific cancers in the animal: for example, RSV and FSV, which cause predominantly sarcomas, and AMV and E26, which cause specifically leukemias affecting myeloid or erythroid precursor cells or more primitive stern cells depending on the host [chicken or quail (Moscovici and Löliger, personal communication)]. Other onc genes like those of MC29 and AEV may in addition to acute leukemias cause sarcomas and carcinomas (Table 1). The fact that different onc genes vary in specificity yet may cause the same cancer argues against a unique mechanism to transform a given class of differentiated cells. For example RSV, FSV, MC29, AEV, and even Kirsten MuSV (Galehouse and Duesberg 1976) all may cause sarcomas in birds and can also transform mammalian fibroblasts (not tested for FSV) (Quade 1979), although they contain totally different onc genes. Likewise, AEV, MC29, and E26 and AMV may cause erythroblastosis (Table 1) (Beard et al. 1973; Graf and Beug 1978), although their onc genes, except for those of AMV and E26 (Duesberg et al. 1980), are different. It is concluded that multiple mechanisms, involving multiple onc genes and onc gene products and presumably multiple cellular targets, exist for sarcomagenic and leukemogenic transformation. The fact that different onc genes cause the same cancers or that one onc gene may cause multiple cancers argues against the hypothesis that the transforming proteins of these viruses c10sely resemble specific cellular differentiation proteins and that transformation is a consequence of a competition between 391
a specific viral transforming protein and a specific related cellular counterpart (Graf et al. 1980). The overlap among the oncogenic spectra of different onc genes suggests that different onc genes either interact with different specific cellular targets or that onc genes interact with nonspecific targets. A unique target for a given form of cancer would fail to explain why different onc genes may cause the same disease and why in some cases one onc gene may cause different cancers. The nature of cellular targets for viral transformation remains to be elucidated; it is believed to include factors determining susceptibility to virus infection and replication as well as intracellular substances that interact directly with viral transforming proteins. G. On the Relationship Between Viral one Genes and CeUular Chromosomal Sequenees The helper virus unrelated specific sequences of acutely transforming avian, murine, and feline viruses have been shown to have elosely related cellular counterparts (Scolnick et al. 1973, 1975; Tsuchida et al. 1974; Frankeland Fischinger 1976; Stehelin et al. 1976b; Spector 1978a; Frankel et al. 1979; Sheiness and Bishop 1979; Hughes et al. 1979a,b; Souza et al. 1980; Oskarsson et al. 1980). This has lent support to the hypothesis that normal cells contain viral onc genes and that viral onc genes are transduced cellular genes (Huebner and Todaro 1969; Stephenson et al. 1979; Bishop et al. 1980). If correct, this hypothesis would predict paradoxically, that normal cells contain a number of viral or cellular onc genes that apparently are not subject to negative selection. (At present this number is around a dozen and is going up as more onc genes are defined.) Thus normaly would be an admirable effort of cellular suppression of endogenous onc genes. Although their cellular relatives are even less weIl defined than most viral onc genes themselves, enough is known about them to deduce that viral onc genes are not in the cell but that some or most of their coding sequences have related counterparts in cellular DNA. 1. One example is src of RSV: The only form in which the specific sequence of RSV has ever been shown to have transforming function is if it is part of the viral src gene. As such, this sequence is expressed via a mRNA that shares 5' leader and 3' terminal c-region sequences with other virion genes (MelIon and Duesberg 1977). These virion sequences are not found in all veterbrates said to contain src-related sequences (Spector et al. 1978a) except in some strains of chicken. Moreover in chicken src-related and endogenous virion gene-related sequences are not located on the same restriction fragments of cellular DNA (Hughes 1979b) nor on the same chromosomes (Hughes 1979a). In addition the cellular src-related mRNA and DNA sequences appear not to be colinear with those of RSVs (Wang et al. 1977; Spector et al. 1978b; Hughes et al. 1979b). Hence concrete qualitative differences set apart the src of RSV and its relatives in normal vertebrate cells. 2. Another example of a elose relationship between a viral onc gene and cellular alleles is the case of MuSV: Most of the helper virus unrelated 1.5-kb sequence of MuSV has a closely related, perhaps identical counterpart in the cell (Oskarsson et al. 1980; Blair et al. 1980). However, molecularly cloned "MuSVspecific" DNA from the cell or from MuSV can only transform cultured mouse fibroblasts if it is first linked with (presumably noncoding) terminal sequences from MuSV or hel per MuLV. Again concrete qualitative differences exist between the onc gene of MuSV and related DNA sequences of the cello Moreover transformation by these modified MuSV -related sequences from the cell is abortive, and no infectious virus is recovered. Thus transformation by this kind of DNA and by infectious virus may prove not to be the same, although they appear indistinguishable based on the fibroblast assay. 3. The transforming genes of viruses which appear to be hybrids of structural and nonstructural viral genetic elements provide even more convincing evidence that viral onc genes and their cellular relatives are not the same thing: Although it has been shown that most but not all vertebrate cells contain sequences related to the hel per virus unrelated part of MC29 and AEV, the helper virus-related elements of these viruses, in particular gag-related elements, do not have the same distribution and are not found in the same cells (Sheiness and Bishop 1979; Roussell et al. 1979). Hence gag-related sequences, thought to be an essential element of the onc genes of MC29 and AEV, are not part of the cellular 392
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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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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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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
Page 349 and 350: Haematology and Blood Transfusion V
Page 351 and 352: Fig. 2. Cytocentrifuged smears of b
Page 353 and 354: Modification of amino-groups of hum
Page 355 and 356: disturb this balance in the directi
Page 357 and 358: The majority of human blood lymphoc
Page 359 and 360: of the EBV infected B cells. Howeve
Page 361 and 362: and immunoglobulins. J Immunol 120:
Page 363 and 364: " K 10 • j ~ ALL RNlL AL wtfh les
Page 365 and 366: tion akuter Leukämiezellen in "spo
Page 367 and 368: D. Results and Discussion J. Acute
Page 369 and 370: selectively responsive to different
Page 373 and 374: l1J ~ 100 ~ Q. ::) l1J Z 0 ~ z >- .
Page 375 and 376: Table 2. Growth inhibition of S49 e
Page 377 and 378: Reverse Infectious ASC/2X1Q6 transc
Page 381 and 382: munized animals to 1316 tumor cells
Page 383 and 384: Haematology and Blood Transfnsion V
Page 385 and 386: Fig. 3. Expression of retroviral gp
Page 387 and 388: pg70. J Exp Med 143: 151-166 - McGr
Page 389 and 390: Table 1. Expression of tumor antige
Page 391 and 392: Virological and Molecularbiological
Page 393 and 394: Table 1. Oncogenic properties of re
Page 395 and 396: also Fig. 1). It followed that the
Page 397 and 398: whether this sequence is related to
Page 399: zed in infected cells argue that th
Page 403 and 404: detect viral RNA as the only charac
Page 405 and 406: Eisen H (1980) Myeloproliferate vir
Page 407 and 408: p,60- -34K - 1 2 3 4 Fig. 1. In vit
Page 409 and 410: .. p - • a'T ... I .t'l Fig. 4. D
Page 413 and 414: 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 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.
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I) 'IQ a \0 - CL -- Fig. 2. Restrie
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~ ..................... ~ Cell 3' 5
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a :Sa,C! + . ~ 111 i' ( " '~ .J. b
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Table 1 Sampie Tissue TS fragment"
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a b Sac I / rep ._-_.-_ K J nl rep
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Haematology and Blood 'fiansfusion
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Osteopetrosis and osteosarcomas occ
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Lymphoma cellline Table 1. T and B
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Table 2. In vivo growth and oneogen
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Table 1. Transforming aetivity of c
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Table 3. Transformation aetivity of
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- Shoemaker C, Goff S, Gilboa E, Pa
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indieate a shifting of target eell
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Table 2. Expression of Jl and Sourc
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~ i ,..1---------,,':::::::::::::::
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fragment of pBR322 DNA, a 3.0-kbp S
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Mak TW (1979) Proc Natl Acad Sci US
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Table 1. Transformation of 3T3 cell
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inserts in the genome of rapidly tr
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pulations, it seemed likely that th
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contains antigens which react with
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le of reacting in sensitive radioim
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gic approach. In: Hiatt HH, Watson
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12 Eco R [ Fig. 1. Hybridization pa
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10 - '1~ )( -~ S:! E A U I o 1 2
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Haematology and Blood 'fransfusion
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cultures. These cells did not conta
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indication of malignant T-cells in
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Fig. 3. Thin-section electron micro
Page 519 and 520:
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
Page 525 and 526:
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
Page 547 and 548:
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
Page 565 and 566:
Haematology andBlood Transfusion Su
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