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Murine leukemia viruses capable of malignant transformation of mink tissue culture cells have been isolated from an AKR thymoma cell line and from a spontaneous reticulum cell sarcoma in an NIH Swiss mouse partially congenic for the AKR ecotropic virus-inducing locus Akv-2. In contrast to the recently described mink cell focus-inducing strains of murine leukemia virus, at least one of the two transforming strains is replication defective. Nonproducer mink cells carrying the genome of the transforming virus of AKR origin have been isolated, and pseudotype transforming viruses generated.

Moloney murine leukemia virus induces T cell lymphomas after injection into NFS mice, whereas the nondefective Friend virus induces erythroleukemias. Previous studies showed that sequences encompassing the viral transcriptional signals in U3 are the primary determinant of this phenotype in recombinants between these two viruses. To more precisely identify the sequences responsible, we constructed additional recombinants, within U3, between Friend and Moloney viruses and assayed these recombinants for for their disease specificity. We found that a fragment 191 bases long that included the direct repeat (enhancer) region plus 22 nucleotides to its 3' side from Friend virus was sufficient to convert Moloney virus to a virus that induced only erythroleukemias. A 171-base-long fragment of Moloney virus, including just the direct repeat, converted Friend virus to a virus that induced primarily lymphomas (about 85% of mice injected). We also constructed Moloney and Friend virus variants with one rather than two copies of the enhancer element. These viruses retained their disease specificity, although they exhibited a marked increase in the latent period of disease induction. Together the results suggest that 25 or fewer nucleotide differences, lying within and also just 3' of the direct repeat, are the primary determinant of the distinct disease specificities of nondefective Friend and Moloney viruses.

A high proportion of lymphocytes from F/St mice produce infectious xenotropic murine leukemia virus (X-MuLV) and express high levels of cell surface antigens, termed XenCSA, related to the major glycoprotein of X-MuLV. In crosses of F/St with AKR, the high-virus phenotype of F/St was found to be recessive and was shown to be governed by a single locus, Cxv-1, less than 2 centimorgans from H-2K. The close association of Cxv-1 with the H-2 complex was confirmed by the observation that B10.F mice, congeneic for the H-2 region of F/St, expressed high levels of infectious X-MuLV and XenCSA, whereas C57BL/10 mice and other C57BL/10 H-2 congeneic strains did not. Studies of hybrid mice homozygous for Cxv-1s, but segregating for a chromosome 1 X-MuLV induction locus (V locus) of F/St, demonstrated that the high-virus phenotype of F/St was dependent on the interaction between Cxv-1 and the chromosome 1 V locus.

An NFS/N mouse inoculated at birth with an ecotropic murine leukemia virus (MuLV) obtained from wild mice (Cas-Br-M MuLV) developed a lymphoma after 18 weeks. An extract prepared from the lymphomatous spleen was inoculated into newborn NFS/N mice, and these mice developed erythroleukemia within 9 weeks. Spleens from the erythroleukemic mice contained ecotropic and mink cell focus-inducing (MCF) MuLVs; however, when these viruses were biologically cloned and reinoculated into newborn NFS/N mice, no erythroleukemia was induced. In contrast, cell-free extracts prepared from the erythroleukemic spleens induced erythroleukemia within 5 weeks. Analysis of cell-free extracts prepared from the erythroleukemic spleens showed that they contained a viral species that induced splenomegaly and spleen focus formation in adult mice, with susceptibility controlled by alleles at the Fv-2 locus. The spleen focus-forming virus coded for a 50,000-dalton protein precipitated by antibodies specific to MCF virus gp70. RNA blot hybridization studies showed the genomic viral RNA to be 7.5 kilobases and to hybridize strongly to a xenotropic or MCF envelope-specific probe but not to hybridize with an ecotropic virus envelope-specific probe. The virus described here appears to be the fourth independent isolate of a MuLV with spleen focus-forming activity.

XenCSA and GIX are two cell surface antigens related to the major envelope glycoproteins (gp70) of murine leukemia viruses. The levels of expression of these gp70 determinants were assessed in 36 recombinant inbred mouse strains and selected backcrosses derived from crosses between C57BL/6 with DBA/2 and C3H/He. These two antigens segregated in backcross mice and showed a different strain distribution pattern among the recombinant inbred mice, demonstrating that XenCSA and GIX are distinct genetic markers for different endogenous gp70 sequences. It was also shown that independent sets of gene regulate the expression of XenCSA and GIX.

Nondefective Friend helper murine leukemia virus (Fr-MuLV) induces primarily erythroleukemias in NFS mice, whereas Moloney murine leukemia virus (Mo-MuLV) induces T cell lymphomas. Using molecular clones of these two viruses, we constructed a recombinant in which a 0.62-kilobase fragment encompassing the U3 region at the 3' end of the Fr-MuLV genome replaced the corresponding region of Mo-MuLV. The recombinant virus obtained by transfection of this clone, whose genome is derived primarily from Mo-MuLV, induces almost exclusively erythroleukemias in NFS mice. This and the previous result of Chatis et al. (Proc. Natl. Acad. Sci. U.S.A. 80:4408-4411), showing that the reciprocal recombinant whose genome is primarily derived from Fr-MuLV induces almost exclusively lymphomas, argue that a strong determinant of the distinct disease specificities of Fr-MuLV and Mo-MuLV lies in this 3' end 0.62-kilobase fragment which contains the putative virus enhancers. To more precisely define this determinant, we have begun to construct recombinants in which smaller 3' end fragments of the Fr-MuLV and Mo-MuLV genomes are exchanged. Analysis of the first such recombinant showed that Fr-MuLV can be converted to a lymphoma-inducing virus in NFS mice by substitution of a 0.38-kilobase fragment encompassing the virus enhancers in U3 with the corresponding region of the Mo-MuLV genome.

AKXD-23 recombinant inbred mice develop myeloid tumors at a high frequency, unlike other AKXD recombinant inbred strains which develop B-cell lymphomas, T-cell lymphomas, or both. AKXD-23 myeloid tumors are monoclonal, and their DNA contains somatically acquired proviruses, suggesting that they are retrovirally induced. We identified a common site of ecotropic proviral integration that is present in the DNA of all AKXD-23 myeloid tumors that were analyzed and in the DNA of all myeloid tumors that occur in AKXD strains other than AKXD-23. We designated this locus Evi-1 (ecotropic viral integration site 1). Rearrangements in the Evi-1 locus were also detected in the DNA of a number of myeloid tumors and myeloid cell lines isolated from strains other than AKXD. In contrast, few Evi-1 rearrangements were detected in the DNA of T- or B-cell tumors. Evi-1 may thus identify a new proto-oncogene locus that is involved in myeloid disease.

A portable apparatus for performing repeated, brief coronary artery occlusions automatically in long-term chronic studies involving dogs and larger animals is described. The battery-operated, back-pack-carried device uses a motorized syringe driven by a digital-programmable timing circuit to inflate a coronary artery occluder for durations of 10 s to 3 min at intervals from 14 s to 16 h. A single battery charge produces 450 occlusions. The generated pressure is adjustable to 1,000 mmHg maximum. A separate fail-safe circuit monitors system operation to open a pressure-relief valve if occlusions exceed a preset duration.

The recently described amphotropic group of murine leukemia viruses constitutes a distinct biological group, differing from the ecotropic and xenotropic groups in host range, cross interference, and serological reactivity. Viruses of this group have been detected only in wild mice from certain areas in California. By using a [3H]DNA probe synthesized in an endogenous reaction from detergent-lysed amphotropic virus (strain 1504-A), it was demonstrated that the amphotropic murine leukemia viruses are distinct biochemically, in that 20% of the viral genome sequences are not shared by AKR-type ecotropic or nay of three types of xenotropic murine leukemia virus tested. A subset of these amphotropic unique sequences, comprising one half of them, is present in the genome of wild mouse ecotropic viruses and in Moloney and Rauscher viruses as well. Sequences homologous to the entire genome of 1504-A amphotropic virus are present in the cellular DNA of all eight inbred mouse strains tested, as well as in wild Mus in Asia, in amounts varying from three to six complete viral genomes per haploid cell genome. Evidence is presented that at least 20% of the DNA sequences in both mouse- and mink-grown murine leukemia virus probes are of host-cell origin.

Cas NS-1 is an acutely transforming murine retrovirus that induces pre-B and pro-B cell lymphomas. Molecular cloning showed it was generated from the ecotropic Cas-Br-M virus by sequential recombinations with endogenous retroviral sequences and a cellular oncogene. The oncogene sequence shows no homology with known oncogenes but some similarity to the yeast transcriptional activator GCN4. A 100-kDa gag-cbl fusion protein, with no detectable kinase activity, is responsible for the cellular transformation. The cellular homologue of v-cbl, present in mouse and human DNA, is expressed in a range of hemopoietic lineages.

C57BL/6 mice infected with a mixture of murine leukemia viruses (MuLV) develop a syndrome characterized by lymphoproliferation and profound immunodeficiency. Analyses of this viral mixture (LP-BM5 MuLV) showed that it includes replication-competent ecotropic and mink cell focus-inducing MuLV and defective viruses with genome sizes of 3.8-6.5 kilobases. The ecotropic and mink cell focus-inducing MuLV biologically cloned from the mixture did not induce disease, whereas viral preparations containing the ecotropic MuLV and 4.8-kilobase defective virus were active. Cells producing the 4.8-kilobase defective virus expressed an unusual gag-encoded polyprotein of Mr 60,000.

A murine sarcoma virus (MSV) was recovered from an (NFS X NS.C58v-1) F1 mouse which developed splenic sarcoma and erythroleukemia 6 months after inoculation with a mink cell focus-inducing murine leukemia virus (MuLV) isolated from an NFS mouse infected with a wild mouse ecotropic MuLV. The MSV, designated NS.C58 MSV-1, induced foci of transformation in mouse and rat fibroblasts, and inoculation of mice of various strains 2 weeks of age or younger resulted in erythroleukemia and sarcomatous lesions in spleen, lymph node, and brain. The MSV provirus was molecularly cloned from a genomic library prepared from transformed non-producer rat cells. The 8.8-kilobase proviral DNA contained a 1.0-kilobase p21 ras coding segment which replaced most of the gp70-encoding portion of an MuLV, most likely the endogenous C58v-1 ecotropic virus. The ras oncogene is closely related to v-Ha-ras by hybridization, expression of p21 protein, and nucleotide sequence. It is nearly identical in sequence to v-bas, the only previously described transduced, activated mouse c-ras. At position 12 in the p21 coding region, arginine is substituted for the naturally occurring glycine present in c-ras. A second MSV isolate is described which is similar to NS.C58 MSV-1 except for a 100- to 200-base-pair deletion in the noncoding region of the ras-containing insert.

NFS/N mice were infected within 48 hr of birth with pseudotypes of recombinant murine leukemia viruses containing avian v-myc developed T-cell, pre-B-cell, and B-cell lymphomas and epithelial tumors including pancreatic and mammary adenocarcinomas. Primary hematopoietic and epithelial tumors and continuous in vitro cell lines derived from some of these tumors, established in the absence of added growth factors, exhibited clonal integrations of v-myc and expressed v-myc RNA. These results show that deregulated expression of the myc oncogene in mammalian cells can initiate a wide variety of neoplasms.

Nucleotide sequences encoding gp70, Prp15E, and the U3 region of the long terminal repeat (LTR) distinguish mink cell focus-forming (MCF) retroviruses that can induce leukemia in AKR mice from closely related MCF and ecotropic murine retroviruses that are nonleukemogenic in all inbred mouse strains tested (Lung et al., Cold Spring Harbor Symp. Quant. Biol. 44:1269-1274, 1979; Lung et al., J. Virol. 45:275-290, 1983). We used a set of recombinants constructed in vitro from molecular clones of leukemogenic MCF 247 and nonleukemogenic ecotropic Akv to separate and thereby directly test the role of these genetic elements in disease induction. Leukemogenicity tests of recombinants in AKR mice show that introduction of fragments containing either an MCF LTR or MCF gp70 coding sequences can confer only a very low incidence of disease induction on Akv virus, whereas an MCF type Prp15E alone is completely ineffective. Recombinants with an MCF 247 LTR in combination with MCF Prp15E are moderately oncogenic, whereas those with an MCF 247 LTR plus MCF gp70 coding segment are quite highly leukemogenic. Mice infected with the latter virus show a substantial increase in latent period of disease induction relative to MCF 247; this delay can be reduced when Prp15E, and hence the entire 3' half of the genome, is from MCF 247. Surprisingly, sequences in the 5' half of the genome can also contribute to disease induction. We found a good correlation between oncogenicity and recovery of MCF viruses from thymocytes of injected mice, with early recovery and high titers of MCF in the thymus being correlated with high oncogenicity. This correlation held for recombinants with either an MCF or ecotropic type gp70. Together, these results (i) demonstrate that at least four genes contribute to the oncogenicity of MCF viruses in AKR mice and (ii) suggest that recombinants with only some of the necessary MCF type genes induce leukemia because they recombine to generate complete MCF genomes. Although neither Akv nor MCF 247 is leukemogenic in NFS mice, recombinant viruses whose gp70 gene was derived from Akv but whose LTRs were derived from MCF 247 induced a low incidence of leukemia in this mouse strain.

We derived an amphotropic murine leukemia virus (MuLV) type-specific probe for use in Southern blot hybridizations with cloned and genomic DNAs. A 133-base-pair RsaI-RsaI fragment from the 5' env region of the amphotropic viral isolate 4070A was subcloned into M13mp18 and radiolabeled in vitro. The probe detected the proviral DNAs in mink cells infected with seven different amphotropic MuLV isolates. The probe did not cross hybridize with the DNAs of molecular clones of ecotropic, mink cell focus-forming, or xenotropic MuLVs; nor did it anneal to the proviral DNAs of four xenotropic or six mink cell focus-forming viral isolates grown in mink cells. DNAs of 12 inbred laboratory mouse strains and more than 15 different wild mouse species and subspecies were examined for the presence of endogenous amphotropic env-related fragments. Amphotropic env-related sequences were found only in the DNAs of wild mice trapped in southern California in an area previously shown to harbor mice producing infectious amphotropic virus. Restriction enzyme analyses of DNAs from these mice showed that amphotropic sequences were not present as germ line copies but were the result of congenital or horizontal infection or both in this population. The DNAs of 11 various mammalian and avian species, including both natural predators of mice and squabs from the farms with virus-positive mice, lacked amphotropic envelope-related sequences.

The syndrome of intrahepatic inferior vena cava obstruction has neither been commonly recognized nor adequately described. Symptoms include the abrupt onset of ascites, hepatomegaly, and fluid retention below the diaphragm with edema of the lower extremity. Proteinuria can be associated with these symptoms. When this syndrome has been caused by malignant hepatic enlargement, it has not been well characterized in the literature, and its treatment has been ignored. We have diagnosed the inferior vena cava syndrome due to metastatic liver involvement in 34 patients before death. Thirty-three of these patients were treated using a combination of strip radiotherapy to the hepatic vena cava, with or without hepatic arterial infusion of chemotherapy. Fifty-six percent of the patients completed a full course of radiotherapy, with an 83 percent response rate. A dose of 3,000 to 4,500 rads was found to be safe and provided excellent palliation of ascites and edema. Tumors known to be radiosensitive had the best responses and side effects were few and mild in nature. Recognition and treatment of this condition will assume greater importance as survival is prolonged in more patients with advanced malignancy.

Distinct type-specific antigens were detected on cells infected with cloned mink cell focus-inducing (MCF) murine leukemia viruses by means of cell surface immunofluorescence absorption assays with rabbit antisera raised against naturally-occurring AKR MCF viruses. The MCF type-specific antibodies were present in high titer and not absorbable by cells infected with ecotropic, xenotropic, or wild mouse amphotropic murine leukemia viruses, or combinations of ecotropic and xenotropic viruses. Three MCF subtype-specific reactions were identified. One subspecificity (operationally designated MCFA-1) defined antigenic determinant(s) distributed among MCF viruses in general. Another (MCFA-2) specified determinant(s) induced by all naturally occurring MCF isolates not of Friend or Moloney origin. A third subspecificity (MCFA-3) was induced by some MCF isolates, and not by others; the presence of this antigen did not correlate with the source of any presently known biological property of the viruses. In addition, type-specific antigenic determinants of ecotropic and xenotropic murine leukemia viruses were expressed on MCF virus-infected cells. The serological profile of MCF viruses thus supports the contention that they are env gene recombinants between ecotropic and xenotropic murine leukemia viruses. However, new, distinct MCF-specific determinants are also generated, and these could be useful markers in studying MCF viruses.

Selected conserved amino acids in the putative RNase H domain of reverse transcriptase (RT) were modified in a molecularly cloned infectious provirus and in a Moloney murine leukemia virus RT expression vector by site-directed mutagenesis. Substitution of either of two conserved aspartic acid residues in proviral DNA prevented production of infectious particles in transfected NIH 3T3 cells, and the same modifications depressed RT-associated RNase H activity by more than 25-fold with little or no effect on polymerase activity.

An 8.9-kilobase EcoRI restriction fragment was cloned from mink cells chronically infected with NFS-Th-1 xenotropic murine leukemia virus by using a lambda phage host vector system. After its transfer into pBR322, the EcoRI DNA insert was characterized and found to contain 6.7 kilobases of proviral DNA sequences and 2.2 kilobases of mink cellular DNA flanking the 5' end of the viral genome. A 500-base pair fragment which was located at the 3' terminus of the cloned DNA insert and which mapped to the env region of xenotropic proviral DNA was subcloned into pBR322. This xenotropic envelope proviral DNA segment did not hybridize to ecotropic murine leukemia proviruses but did anneal to representative alpha and beta xenotropic and seven different mink cell focus-inducing proviral DNAs. The cloned xenotropic envelope-specific probe was also used in blot hybridization experiments to analyze the arrangement of related sequences in preparations of different mouse liver DNAs.

The directly transforming murine retrovirus, AKT8, was isolated from a spontaneous AKR thymoma and carries the cell-derived viral oncogene, akt. We have now shown that this virus produces thymic lymphomas after inoculation of susceptible mouse strains. The presence of the AKT8 genome in the DNA of the virus-induced tumors was demonstrated by Southern blotting using an akt-specific probe. These results establish the in vivo pathogenicity of the AKT8 virus and its akt oncogene, and imply a potential role for the cellular akt proto-oncogene in tumor development.

F/St mice are unique in producing high levels of both ecotropic and xenotropic murine leukemia virus. The high ecotropic virus phenotype is determined by three or more V (virus-inducing) loci. A single locus for inducibility of xenotropic murine leukemia virus was mapped to chromosome 1 close to, but possibly not allelic to, Bxv-1. Although the high ecotropic virus phenotype is phenotypically dominant, the high xenotropic virus phenotype was recessive in all crosses tested. Suppression of xenotropic murine leukemia virus is governed by a single gene which is not linked to the xenotropic V locus.

The role of spreading somatic cell infections with ecotropic MuLV viruses in the induction of plasmacytomas in BALB/cAN pi mice was determined by constructing congenic mice that lacked the gene locus Cv that codes for ecotropic virus. DBA/2 mice that lack Cv on chromosome (chr) 5 carry a closely linked gene Rmcfr that determines resistance to infection with mink cell focus-forming viruses (MCF). Rmcfr was retrogressively back-crossed onto BALB/c for six successive generations to produce N6 mice. N6 mice were mated to each other to produce BALB/c.DBA/2 Rmvfr/Rmcfr homozygotes. This stock of mice lacked Cv, as demonstrated by DNA hybridization and were as fully susceptible to developing plasmacytomas as the parental BALB/c. A second congenic stock BALB/c.DBA/2 Rmcfr/Rmcfr Fv-1n/Fv-1n was also developed, but the mice of this stock showed a reduced incidence of plasmacytomas, as did BALB/c.DBA/2 Fv-1n/Fv-1n mice. These findings indicated Fv-1 or a gene closely linked to it conferred partial resistance to plasmacytomagenesis. In constructing the BALB/c.DBA/2 Fv-1n/Fv-1n stock, a "control" congenic BALB/c.DBA/2 Fv-1b/Fv-1b was also developed at N6. Surprisingly, this stock carried the Qa2+ trait. These mice were also partially resistant to plasmacytomagenesis, suggesting a gene on chromosome 17 (the location of Qa2) or a gene located elsewhere that regulates Qa2 expression is linked to a gene controlling partial resistance to plasmacytoma development.

Lymphocytes from Thy, Sp, LN, and BM and NZB mice were tested for expression of X-MuLV genomes as cell surface gp70 (XenCSA) or infectious virus. The results demonstrate major dissociations for these parameters of X-MuLV expression in different lymphoid compartments and suggest that factors involved in T lymphocyte differentiation modify the levels of expression in these two modes.

A new type of murine leukemia virus has been detected in thymuses of leukemic and late preleukemic AKR mice, in lymphomas developing in NIH Swiss mice carrying the AKR ectopic virus-inducing loci Akv-I or Akv-2, and in the thymus of a preleukemic C58 mouse. The viruses induce focal areas of morphologic alteration in a mink lung cell line and are tentatively referred to as "mink cell focus-inducing" (MCF) strains. They have the host range of both xenotropic and N-tropic ecotropic murine leukemia viruses, are neutralized by antisera to both ecotropic and xenotropic viruses, and are interfered with by both viruses. They may represent a particular type of genetic recombinant which emerges during the preleukemic period in high-ecotropic-virus mouse strains, and they may play a significant role in the etiology of spontaneous lymphomas.

In contrast to the original B10.BR/SgSn congenic mouse strain, adult mice of the B10.BR/SgLi subline showed a high level of expression of B-tropic ecotropic murine leukemia virus (MuLV). Both B-tropic and N-tropic ecotropic MuLV could be included in cultures of virus-free cell lines derived from embryos of B10.BR/SgLi mice. Both various were also inducible from each of several clonal cell lines and from cultures of F1 embryos of matings of B10.BR/SgLi males with females of strains NFS/N and A/J, which are negative for B-tropic virus. Thus the information for B-tropic MuLV as well as that for N-tropic MuLV was transmitted as a genetic element in the B10.BR/SgLi subline.

Flow microfluorometry was used to assess levels of xenotropic murine leukemia virus envelope-related cell-surface antigens (XenCSA) expressed on lymphocytes of mice derived from crosses between C57BL/6 (B6) and DBA/2 (D2); 24 recombinant inbred strains (BXD RIs) and 62 backcross mice were studied. The results suggest that XenCSA expression is affected by more than one gene but that the predominant influence is exerted by a single semidominant gene apparently located on chromosome 4 at or in close proximity to the Fv-1 locus. Studies of spontaneous virus production in B6D2F1 X D2 mice suggest that this locus may also affect production by spleen cells of xenotropic MuLV registering in a fluorescent antibody assay of mink lung cells.

Cas-Br-M is an ecotropic murine leukemia virus isolated from wild mice that induces a wide spectrum of hematopoietic neoplasms, including T and B cell lymphomas, myelogenous leukemias, and erythroleukemias. The purpose of this study was to determine if the induction of neoplasms belonging to multiple lineages was due to the ecotropic virus itself or to the generation of cell lineage-specific recombinant viruses. The results demonstrate that in some instances (two of 12 tumor extracts tested), recombinant viruses can be recovered from primary Cas-Br-M-induced tumors that will induce lymphomas of single lineages in mice inoculated as newborns. One of these viruses is a recombinant mink cell focus-forming virus that induces T cell lymphomas, and the other is a replication-defective, fibroblast-transforming virus that induces early B lineage lymphomas in mice. Histologic and flow microfluorometric cell surface antigen analyses of primary and in vitro adapted tumors are presented in support of a modified scheme of hematopoietic cell development.

DBA/1, DBA/2, CBA/N, and CBA/Ca mice carry a gene which specifically restricts infectivity of mink cell focus-forming (MCF) murine leukemia viruses. The gene, designated Rmcfr, is dominant or semidominant and maps to chromosome 5; it is closely linked to the morphologic marker gene Hm. The Rmcf gene may be of much use as a means of determining the role of MCF viruses in various forms of leukemogenesis.

C57BL mice (Fv-1b) develop a severe immunodeficiency disease following inoculation as adults with LP-BM5 murine leukemia virus (MuLV), a derivative of Duplan-Laterjet virus which contains B-tropic ecotropic and mink cell focus-inducing MuLVs and a putative defective genome which may be the proximal cause of disease. The stages of development of this disease were defined for C57BL mice on the basis of lymphadenopathy and splenomegaly; histopathological changes consistent with B-cell activation; and alterations in expression of cell surface antigens affected by proliferation of T cells, B cells, and macrophages. By using this disease profile as a standard, the response of adult mice of various inbred strains and selected F1 hybrids was compared. We show that although the strains which are highly sensitive are of the Fv-1b genotype (i.e., permissive for B-tropic MuLVs), certain Fv-1b strains, e.g., BALB/c and A/J, are resistant to murine acquired immunodeficiency syndrome, whereas certain Fv-1n strains (permissive for N-tropic MuLVs but restrictive for B-tropic MuLVs), notably P/N, BDP, and AKR, show moderate sensitivity and (C57BL/6 x CBA/N)F1 mice (Fv-1n/b and thus dually restrictive) are of relatively high susceptibility. The results of virus recovery tests suggest that apparently anomalous sensitivity, based on predicted Fv-1 restriction, may reflect MuLV induction and/or mutation to provide a helper virus for which the host is permissive.

The species host range of the recombinant, mink cell focus-inducing (MCF) class of murine retroviruses was determined in vitro and compared to the host range properties of xenotropic and amphotropic murine viruses. In contrast to xenotropic and amphotropic viruses, MCF viruses were restricted in the number of mammalian species they would infect. Cell lines from mouse, rat, mink, ferret, and cat were susceptible to MCF infection and certain virus isolates could infect rabbit cells, but cells from Chinese hamster, buffalo, bat, dog, monkey, and human were resistant to infection by most MCF viruses. The resistance of some of the latter cells was abrogated by phenotypic mixing with xenotropic virus, which demonstrated that MCF species host range was mediated by virus envelope-cell surface interaction. The host range uniformity of the various MCF isolates and the unique species distribution of sensitivity are consistent with the conclusion from other evidence that the MCF viruses comprise a class distinct from xenotropic and amphotropic viruses.

Objective: To define an outbreak of bacteraemia due to coagulase negative staphylococci highly resistant to ciprofloxacin in a leukaemia unit, investigate the source and mode of spread of the outbreak strain, and assess control measures., Design: The outbreak strain was characterised by five different typing methods. Surveillance of patients, staff, and environment was carried out during the outbreak and five months after control measures were introduced., Setting: A unit with 10 beds for adults with leukaemia and patients receiving bone marrow transplants. The outbreak occurred during a trial of ciprofloxacin for empirical treatment of neutropenic fevers., Interventions: Ciprofloxacin was withdrawn from use in the unit and daily bathing with chlorhexidine gluconate solution started. Main outcome measure--The absence of bacteraemia due to the outbreak strain for five months after control measures., Results: During the study 49 patients developed 21 episodes of bacteraemia due to the outbreak strain, which was ciprofloxacin resistant (minimum inhibitory concentration greater than or equal to 128 mg/l), susceptible to phage 155 A9C, and SII biotype and had characteristic immunoblot and DNA fingerprint features. There was a high amount of colonisation of patients but not staff with this strain, which was also wide spread in the environment. The control measures led to rapid resolution of the outbreak and disappearance of the strain from the unit., Conclusions: In areas where coagulase negative staphylococcal infections are common doctors must be aware of the possibility of cross infection with single strain, and the availability of more discriminatory methods of typing will facilitate the identification and control of such episodes.

A variety of transplantable mouse tumor lines were shown to contain murine type C viruses and virus-associated antigens. The type of virus isolated and antigens detected could not invariably be correlated with the original method of tumor induction, but testing of the majority of tumor lines for infectious virus at various levels of in vivo or in vitro passage yielded isolates that were consistent in tissue culture host range for each tumor. In contrast, during the course of in vivo transplantation, some of the lines underwent considerable change in the pattern of virus-associated cell-surface antigens. When the transplanted tumor lines were placed into culture, all showed some alteration in the detectable surface antigens. Upon retransplantation and passage of the cultured cells in mice, the surface antigens gradually returned to the original in vivo patterns and occasionally acquired additional type C virus-associated antigens not detected in the original tumor line. To test for association of antigens with infectious virus, appropriate tissue culture cell lines were infected with the viruses isolated from the tumors. In these infected indicator cells, some new virus-associated cell-surface and virion evelope antigens were detected, but the complete array of antigens found in the original tumor lines was not acquired. These findings indicated the presence of several different type C viruses in long transplanted cell lines and demonstrated that environmental and host cell factors may have major influences on expression of virus-associated antigens.

The validity of the ultrasonic Doppler technic for indirectly measuring arterial blood pressure over a wide range was tested in anesthetized dogs. Correlation coefficents of 0.99 and 0.97 for systolic and diastolic pressure were verified on the basis of 316 comparisons of direct and indirect measurements. Utility of the method for detecting hypotensive, normotensive, and hypertensive arterial blood pressures was demonstrated. Potential applications of the method by life scientists and veterinarians includes routine monitoring of anesthesia, characterization of disease, and documentation of pharmacologic states.

A high-titered non-focus-forming virus, FBJ-MuLV (murine leukemia virus), present in FBJ tumor preparations, inhibited significantly the expression and production of FBJ-MuSV (murine sarcoma virus) in tissue culture. This "autoinhibition" was comparable to that observed when a 3- to 4-log excess of infectious MuLV was added to standard MuSV. The degree of inhibition was influenced by the tropism of the MuLV (or the ease of spread and propagation of MuLV in certain cells), multiplicity of infection by MuLV, amount of excess MuLV, and ability of the MuSV-transformed cells to replicate independently. The FBJ MuLV-MuSV complex may be a model system for the detection of sarcoma viruses in spontaneous tumors in various animals where inhibition by excess nontransforming virus could be an important biologic phenomenon.

Usage of tamoxifen in the treatment of advanced breast cancer is increasing and is advocated by some authors as primary therapy in all estrogen receptor positive cancer patients. Tamoxifen is an incomplete estrogen antagonist with partial estrogen agonist activity as well. Tamoxifen-induced exacerbation of breast cancer ("tamoxifen flare") is reported to occur in 4-20% or more of treated patients. Management of this condition has varied from stopping treatment to continued administration or reinstitution of tamoxifen after flare symptoms subside. Responses have occurred in some patients so treated, although the remissions do not appear durable. The seven patients with advanced breast cancer in this report experienced disease exacerbation with tamoxifen therapy. Endocrine ablation afforded all patients excellent pain relief and disease control with prolonged survival in six of the seven. There have been no studies directly examining the disease course in flare patients continuing on tamoxifen. Persistence in treating these patients with an incomplete antagonist-agonist may deprive them of full survival benefit possible through ablative procedures when used in sequential treatment.

Cas-Br-M, a cloned ecotropic murine leukemia virus (MuLV) of wild mouse origin that induces both neurogenic hindlimb paralysis and lymphomas, was injected into NFS/N inbred mice neonatally. Then the mice were observed for the development of neurologic disease and tumors. All mice manifested neurologic abnormalities by 6 months of age, and 58% of the animals died with hematopoietic neoplasms. The tumors included T- and B-cell lymphomas, lymphoblastic lymphoma, erythroleukemias, myelogenous leukemias, and a megakaryocytic leukemia. Cas-Br-M thus appeared to be unique among ecotropic MuLV in inducing a wide spectrum of hematopoietic tumors.

Infectious tissue culture fluids of the majority of serotypes of adenovirus at low dilutions detach HeLa or KB cells from glass surfaces within a few hours after inoculation. A reproducible method for testing cell detachment was devised. The factor present in infectious tissue culture fluids and responsible for cell detachment is trypsin-sensitive and non-dialyzable; it is smaller and more resistant to the effect of heat or ultraviolet light than the infectious virus particle. Cell detachment activity was found to be temperature-dependent, and the cell-detaching titer of infectious tissue culture fluids was not affected by repeated exposure to HeLa cells. Inhibition of cell detachment by human or rabbit sera was observed only when other antibodies to adenovirus antigens were also present, but the antibody inhibiting cell detachment could not be correlated quantitatively with complement-fixing or homologous neutralizing antibody.