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Studies of tumor incidence and assorted lesions found in 187 C3H-Avy mice throughout their natural life-spans revealed the following: Hepatocellular carcinomas occurred in 54.3% of males, mammary carcinomas in 95% of females, pancreatic islet cell adenomas in 9.4% of males and in no females, and pancreatic islet cell hyperplasia in 41% of males and 23% of fefemales. Islet cell hyperplasia and adenomas appeared to consist predominantly of alpha and delta cells. Multiple tumors, or hyperplasia, or both, of a single site or of multiple sites occurred as frequently in males as they did in females--49.6% and 51.7% respectively. The most frequent neoplasms were hepatocellular carcinomas and islet cell tumors or hyperplasia in males (45.7%) and multiple mammary tumors in females (30%). Heretofore unreported tumors found in this strain of mouse were 12 islet cell adenomas, 2 spindle cell tumors of the meninges and olfactory lobes, a squamous cell carcinoma of the nasal turbinates, and a schwannoma of the spermatic cord.

Two types of particles resembling virions were observed in biopsy tissue from each of two patients with Creutzfeldt-Jakob disease. In addition, aggregates of nucleoprotein-type filaments were seen in scattered unidentifiable cytoplasmic fragments or in extracellular spaces. A plaque was present in the white matter of one of the specimens and in the neuropil of the second. Status spongiosus was observed in the grey matter in both cases.

Electron microscopic examination of lymph nodes from “normal” subjects and diseased patients revealed the presence of Birbeck granules in histiocytes in 8 of 12 patients with subacute sclerosing panencephalitis (SSPE), 1 of 6 patients with other diseases, and 1 of 4 “normal” subjects. The one apparently “normal” subject who had Birbeck granules was the sibling twin of a patient with subacute sclerosing panencephalitis. The significance of Birbeck granules is not fully known, and the possible relationship to SSPE is speculative at this time. The data are interpreted as supporting the concept of Prunieras28 that Birbeck granules may play an important role in the primary response to antigenic substances.

SummaryNeoplastic transformation of rat embryo cells in vitro by Rauscher leukemia virus (RLV) is reported. Rat embryo cells infected initially with RLV have replicated infectious virus and produced complement-fixing (CF) antigen characteristic of the murine leukemia-sarcoma virus complex for more than 18 months. Cells from these cultures underwent neoplastic transformation in vitro and produced tumors when injected into homologous hosts. The tumors were serially transplantable, and subsequent transplants continued to carry the initial RLV and to yield CF antigen.The authors wish to thank Mr. H. C. Turner, National Institutes of Health, for supervising CF tests, and Mrs. Ersell S. Richardson and Mrs. M. H. Joglekar for excellent technical assistance. We are also grateful to Dr. L. Rabstein, Microbiological Associates, Inc., for histological examination of tumors.

Low-passage rat-embryo cells were not transformed by 3-methylcholanthrene or by 5-bromo-2′ deoxyuridine. However, prior treatment with bromodeoxyuridine, followed by treatment with methylcholanthrene, resulted in cell transformation about three subpassages after removal of the carcinogen. RNA-directed DNA polymerase activity could not be detected in either normal or transformed cells. However, gs-1 antigen specific for rat C-type RNA virus was detected in cultures derived from bromodeoxyuridine-treated cells. No gs-1 antigen for the C-type RNA virus was detected in cultures that had not been treated with bromodeoxyuridine during the 25 subpassages of these experiments. High-passage rat-embryo cells, derived from a different cell pool, were transformed by either methylcholanthrene or dimethylbenzanthracene without prior infection with an exogenous virus, and without prior treatment with bromodeoxyuridine, gs-1 antigen for C-type RNA virus was also detected in 4 of 4 randomly selected transformed cell lines; the gs-1 antigen was not detected in any of 4 nontransformed control cultures. Considering these and previously published findings, we conclude that the lowpassage cells cannot be transformed by methylcholanthrene because of powerful cellular controls over the endogenous virus. Bromodeoxyuridine triggers some expressions of the endogenous virus; thus, the bromodeoxyuridine-treated cells are more susceptible to the transforming effects of methylcholanthrene. High-passage rat cells do not maintain perfect control over expression of their endogenous virus; the cell cultures are susceptible to the transforming effects of chemical carcinogens.

Tubuloreticular structures of the geometric type were observed in dog osteosarcoma cells (D17a) before and after cocultivation with human placenta cells and before and after passage of the cocultivated cells through NIH nude mice. After passage through NIH nude mice, the reestablished cultures regularly produced conventional murine type-C particles and displayed budding virus-like particles (VLP) within the tubuloreticular structures. VLP, tentatively considered an aberrant form of type-C particles, were presumably of murine origin since they were not observed in the osteosarcoma cells before passage through NIH nude mice.

SummaryParticles resembling guinea pig leukemia virus were activated from guinea pig nonproducer cells and cultured normal guinea pig cells after chemical treatment. These particles were approximately 100 nm in the mature form, had a density of 1.16-1.17 g/ml, and contained RNA-dependent DNA polymerase activity. The peak of polymerase production was observed between 6 and 8 days after 1-day bromodeoxyruidine (BrdU) treatment. Polymerase activity was reinducible and was always detectable in the BrdU-containing medium of the cultures in prolonged cultivation. The results of screening various chemicals demonstrated that thymidine analogs (BrdU and 5-iododeoxyuridine) were by far the most efficient inducers of guinea pig leukemia-like virus in the cells. Antigenic relationship to known type C viruses has been discussed.

Eight food dyes or commercial color mixtures certified for use in the United States were tested for their ability to transform in vitro a serial line of Fischer rat embryo cells previously reported to be a sensitive indicator of chemicals having carcinogenic potential. Malignant cell transformation was induced by a commercial mixture (G2024) of two of these dyes (Blue 1 and Yellow 5) and by Blue 2, Green 3 (one of two experiments) and Red 4. Food dyes Blue 1, Red 3, Yellow 5 and Yellow 6 did not induce cell transformation. One to 1.5 mg of each dye was injected into suckling LVG or Graffi hamsters which were monitored for tumor induction and/or death over a 330-day period. None of the non-transforming dyes (Blue 1, Red 3, Yellow 5, Yellow 6) or Green 3 induced a significant increase in tumor (mostly lymphoma) incidence or animal mortality. Three of the transforming dyes (Blue 2, Green 2024, Red 4) did increase tumor incidence and/or mortality in at least one strain of hamster. We conclude the the in vitro assay suggested that certain food dyes were carcinogens and that in vivo studies in hamsters supported this interpretation.

Non-producer (NP) human cells induced by the Kirsten sarcoma virus were characterized. These morphologically altered NP cells produced neither infectious virus nor complement-fixing antigens of the murine sarcoma-leukemia virus complex. The NP cells did not release RNA-dependent DNA polymerase and type-C virus particles with a density of approximately 1.15 g/ml in sucrose gradients by 3H-uridine labelling. The NP cells produced tumors when transplanted subcutaneously into athymic nude mice. The tumor cells re-established in culture resembled the orginal NP cells, were confirmed as human cells by karyological analysis and were also found to be "non-producer". The sarcoma virus genome in NP cells could be rescued not only by co-cultivation with "helper virus"-releasing cells but also by superinfection with helper type-C viruses. Murine (Rauscher, Ki-MuLV, AT-124 and two other xenotropic viruses), feline, RD-114 and Simian (woolly monkey and baboon) type-C viruses possessed the ability to rescue the sarcoma genome from NP cells but not AKR leukemia virus. In addition, the feline leukemia virus titer obtained by the rescuing technique in NP cells was the same as those obtained in feline embryo and NP cells by CF induction assay.

Cultures of canine, rabbit, porcine, avian, feline, bovine, simian and human origin were tested for their susceptibility to the Kirsten murine sarcoma virus (Ki-MSV). Data indicated that Ki-MSV replicates and transforms the cultures of canine embryo, rabbit kidney, porcine kidney, feline embryo, bovine embryo and human tumor cells. These morphologically altered cells contained infectious virus and group-specific (gs) complement-fixing (CF) antigen characteristic of viruses of the murine sarcoma-leukemia complex. The infected cultures produced type-C virus particles. RNA-dependent DNA polymerase activity was also demonstrable in the altered cells. The present results indicate that members of the murine sarcoma-leukemia virus complex, particularly Ki-MSV, exhibit a wider host range than was hitherto believed.

SummaryCanine embryo cells were transformed in vitro by Kirsten murine sarcoma virus (Ki-MSV). The transformed cells contained group-specific complement-fixing antigen characteristic of the murine leukemiasarcoma virus complex. Cell-free supernatant fluids from the transformed cultures were infectious for rat, guinea pig, and canine embryo cells. RNA-dependent DNA polymerase activity was demonstrated in the transformed cells. Electron microscope observation showed that the transformed cells produced type C virus particles. The present results indicate that members of the murine sarcomaleukemia virus complex, particularly Ki-MSV, exhibit a broader host range than was hitherto believed.

Several types of tumors from various species were propagated in NIH athymic nude mice. Subsequently, cell lines were established from the tumors and examined for evidence of type-C virus activity. Hybrid mice (NIH Swiss and BALB/c) harbored murine type-C viruses of three categories: N-tropic, B-tropic and X-tropic.

Measles virus was isolated in mixed cultures of lymph node cells and HeLa cells. The agent was isolated by cocultivation from biopsy specimens of two of five patients with subacute sclerosing panencephalitis. The virus was identified by hemagglutination-inhibition, immunofluorescent, and neutralization tests. Biopsies from controls did not show evidence of measles virus.