[Three cases in a family of congenital protein S deficiency associated with cerebral infarction].
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Biomedical subjects
Publications and source records attributed to Y Tsubura.
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A new murine mammary tumor cell line (BALB/c-MC) was established from a spontaneous mammary tumor in a 17-mo.-old female mouse of the low mammary cancer strain BALB/cHe. The cell line was derived from a papillary adenocarcinoma. In monolayer culture the line exhibits a pavementlike arrangement of cells and forms "domes" or "hemicysts" as the cells become confluent. The cell line rapidly forms tumors when transplanted into young syngeneic BALB/cHe mice. The subcutaneous injection of 10(6) cells resulted in the development of mammary tumors (typical papillary adenocarcinomas) in 33 of 37 (87%) recipients within 2 to 3 mo. after injection. These mammary tumors also metastasize to lung [14 of 33 (42%) of recipients] during this time. The number of chromosomes in this cell line is hyperdiploid (average of 43, range 39 to 44).
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Histological localization of mammary tumor virus (MTV) antigen was investigated using a variety of organs high (DD/Tbr, SHN, SLN, GR) and low (BALB/c) mammary cancer mice strains and immuno-peroxidase staining with MTV antigen. Except for BALB/c strain mice, the mammary gland and mammary tumors were generally positive. Accessory male genital organs including the prostate, seminal vesicle, and coagulating gland also demonstrated a positive reaction, but the testis and female genital organs including uterus and ovaries did not. MTV antigen was also revealed in the serous acini of the salivary gland in both sexes. The site of positive reaction in the accessory male sex organs and salivary gland was located in the apical portion of the secretory epithelial cells and their secretory substance. Localization and intensity of antigenic expression of MTV detected histologically were comparable to results obtained by immunodiffusion test and radioimmunoassay. These evidences support the idea that MTV is transmitted horizontally via seminal fluid or saliva.
A case of pancreatic carcinoma in a 14-year-old Japanese boy is reported. He complained of general fatigue, anorexia, abdominal distension, and abdominal mass. At autopsy, a whitish tumor was found from the head to the body of the pancreas. Metastasis was found in the liver, lungs, gall bladder, and various lymph nodes such as stomach, hilus, and periaorta. The tumor was histologically determined to be moderately differentiated adenocarcinoma (cribriform type) of duct cell origin. However, the tumors showed PAS-positive diastase-resistant mucus in the cytoplasm. Histocytology showed the positivity for alpha 1-antitrypsin, secretory component (sc), and CEA, but no S-amylase was detected in the cytoplasm. Electron microscopy revealed zymogen-like granules in the cytoplasm suggesting acinar differentiation.
Monoclonal antibodies which are considered to be able to differentiate epithelial and myoepithelial cells in the breast have been developed. Human mammary carcinoma cell line (HBC-4W) was used for immunization. Monoclonal antibodies-B4B2F10 (epi-1), E9E8B7 (myo-1)-with IgM was examined using tissues from diseased breast by avidin-biotin-peroxidase assay. Epi-1 antibody reacted with epithelial cells while myo-1 antibody reacted with myoepithelial cells in the mammary glands, respectively. The reaction was markedly visible, in particular, in fibroadenoma, mastopathy, and papilloma, which showed clear two-cell-type structures. In the infiltrating ductal carcinoma, epi-1 antibody reacted with carcinoma cells, while myo-1 antibody reacted with stromal cells rather than carcinoma cells suggesting that infiltrating ductal carcinoma was mainly of epithelial origin. In the infiltrating lobular carcinoma, however, myo-1 as well as epi-1 antibodies reacted with carcinoma cells. It is suggested that infiltrating lobular carcinoma was of a mixture of epithelial and myoepithelial cell origin.
In order to establish the genetic relatedness of the inbred mouse strains kept in Nara, genetic marker patterns were determined in conjunction with a study on endogenous mammary tumor viral genes in these strains. Isoenzyme patterns combined with patterns of other genetic markers, show that the unrelatedness between various inbred strains of the dd stock is as high or even higher as between strains of known different origin and geneology. Based on endogenous viral gene patterns the dd stock derived mice can be subdivided into three group, DDD, DDN, DDO, KF and DD/Tbr. The DD/Tbr and its foster-nursed substrain (DD/Tbrf) have the lowest number of endogenous viral genes, i.e. two, while the other strains carry 4-6 such genes. The SLN and SHN strains, derived from a Swiss stock, have a similar pattern of viral genes different that of all other strains studied, also strains of Swiss origin from other sources, such as the NFS and the GR.
F344/Slc and F344/JCL rats 2 years of age were histologically examined for the incidence and distribution of calcification. In the male rats of both strains, calcification was observed in the testis, lung, brain, kidney, heart, aorta, cornea, prostate and seminal vesicle respectively. In the female F344/JCL rats, calcification appeared in the kidney, lung, cornea, brain, stomach, ovary and heart. Among these of both sexes, the lung was one of the most affected organs for calcification. On the other hand, calcification in the kidney was more severe and frequent in the females than in the males, suggesting that the sex may be one of enhancing factors for calcification.
Horizontal transmission of mouse mammary tumor virus (MTV) was investigated in cage mates of the same and opposite sex of low (BALB/c) and high mammary cancer strains (DD/Tbr, SHN and GR). By MTVp27 and MTVgp52 radioimmunoassay, MTV antigen expression was found in the salivary glands, mammary glands and secondary male genital organs of the MTV-free BALB/c strain. Infectivity and oncogenicity were also found in DDf or BALB/c mice by inoculating extracts of salivary gland and/or seminal vesicle in high mammary cancer strains. It is suggested that the primary source of the infectious agent in cases of caged animals of the same sex is saliva, while the primary source in cases of caged animals of the opposite sex is the seminal fluid, although additional infection through saliva cannot be ruled out in the latter case.
The expression of the type-C retrovirus and the virus-related components in NFS mice were examined during preleukemic and leukemic phases after fractionated whole-body X irradiation. The NFS mice were highly susceptible to induction of thymoma by fractionated X irradiation. The leukemic tissues were negative for infectious type-C virus, as detected by both the XC-plaque test and mink S+ L- focus-inducing assays, but contained a substantially higher level of viral-specific RNA-dependent DNA polymerase activity and a major core protein p30 than the corresponding tissues from unirradiated age-control mice. In the preleukemic phase, the amount of p30-related antigen increased transiently in spleen. The leukemic cell lines established from radiation-induced lymphomas produced particulate entities with a buoyant density of about 1.15 g/ml. These virus-like particles lacked in vitro infectivity to mouse cells and mink lung cells and leukemogenicity in syngeneic mice. The p30-related antigens of these particles were immunologically similar to that of xenotropic virus derived from NZB mouse.
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The antispermatogenic effects of 2, 4-dinitro-6-tert-. butylphenyl methanesulfonate (HE-166) were studied in Sprague-Dawley rats. They were fed 25, 100 and 400 ppm of HE-166 in the basal died for one year. Laboratory data showed no significant changes except for increases in gamma-globulin, alkaline phosphatase, GOT and GPT values in the 100 ppm group. Macroscopically, significant changes were found in the testes in the experimental group, which showed marked atrophy. Histologically, the testes were filled with fibrin exudate in the stroma and there was reduced spermatogonia, cellular debris and giant cells, and even calcification, depending on the dose of HE-166. The anti-fertility effects of HE-166 were also observed by mating rats and checking the pregnancy rate during three generations. These effects might be due to the direct cytotoxic effect of HE-166 on post-meiotic cells as epididymal spermatozoa and testicular sperm and spermatids. As far as tumor incidence was concerned, one case of fibroadenoma of the mammary gland, one case of leiomyosarcoma in the uterus in the 100 ppm group and one case of leiomyoma in the uterus in the 25 ppm group developed at around 8 months, but no other tumors developed.
Administration of urethan (CAS: 51-79-6; carbamic acid, ethyl ester) in the drinking water of breeding female mice of the murine mammary tumor virus (MuMTV)-positive DD/Tbr strain and the MuMTV-negative DDf strain induced so-called keratinized nodules, which were demonstrable in wholemount preparations of mammary glands. It also induced squamous cell tumors (also called adenoacanthoma) at an extremely early age. The keratinized lesions appearing in the lobular areas of the mammary glands showed heavy infiltration with lymphocytes and as such were very different from hyperplastic alveolar nodules, the preneoplastic lesions for adenocarcinomas. Immunoperoxidase tests with antibodies against the MuMTV revealed that positivity of normal mammary gland epithelium in the DD/Tbr strain was not found in the keratinized nodules, which was further evidence that in squamous cell tumorigenesis of the mammary gland the MuMTV is not expressed overtly even at an early stage in tumorigenesis, in contrast to the case with adenocarcinoma tumorigenesis. These findings substantiate previous conclusions that the MuMTV is not involved in chemical carcinogenesis of the mouse mammary gland.
Expression of mammary tumor virus (MTV) antigen was measured in a wide variety of organs and tissues of a series of high (GR, SHN, SHNf, DD, SLN, SLNf) and low (DDf, DDD, DDDf, KF, KFf, ddY, C57BL, BALB/c) mammary cancer strain mice. Tests were carried out by microimmunodiffusion (micro-ID) and immunoperoxidase tests on formalin-fixed tissues and radioimmunoassays in extracts for 2 viral proteins, MTVp27 from the viral core and MTVgp52 from the viral envelope. Organs with exocrine function, i.e. the mammary gland, salivary gland, coagulating gland and prostate, were mostly positive. The secretory epithelial cells of these organs showed viral antigen expression. Less positivity was encountered in brain, pancreas, stomach, urinary bladder, epididymis, uterus, thymus, spleen, lymph nodes and kidney, plasma and blood cell pools. Unexpectedly the uterus extracts showed MTV antigen expression, occasionally even by immunodiffusion, especially in mice of various DD stocks, but also in the GR strain. Another striking observation was the detection of MTV antigen expression in salivary glands in C57BL strain mice; most other organs of this strain (including the mammary glands) were negative. The implications of results of this extensive survey for MTV antigen expression are discussed for tumorigenesis by MTV of mammary gland and perhaps other tissues in the mouse.
Carcinogenicity study on cholestyramine, an anti-hypercholesterolemic agent, was carried out using Fischer rats by feeding with a normal pellet diet (control) and with three sorts of the pellet diets in which cholestyramine was admixed in the common diet at the rates of 1.25, 2.5 and 5%, respectively. The animals were fed with these diets for 26 months and a normal diet for subsequent 2 months. Some of the male rats fed with the 5% admixed diet revealed a slight growth retardation and occasionally hemorrhagic tendency, without resulting in severe macroscopic and microscopic lesions of the internal organs and in shortening of the mean survival time as compared with that of the control group. The rates of tumor-bearing animals were high in all experimental groups including the control, but the rates were not considered to be drug-related. Incidences of individual tumors were not significantly different each other between cholestyramine-fed groups and control group. Thus, it was not recognized that cholestyramine induced any drug-related specific tumors and an accelerated growth of any tumors.
The SHN mouse strain, which has a high incidence of mammary cancer, developed by inbreeding and selection from Swiss stock mice by Dr. H. Nagasawa and co-workers (Meiji University, Tokyo, Japan), harbored an endogenous mammary tumor virus (MTV) responsible for a high frequency of mammary tumors early in life. The locus was called "Mtv-4" and was only comparable with Mtv-2 of the GR mouse strain in its inducing capacity of mammary cancer. Molecular hybridization with 32P-labeled MTV complementary DNA showed that the characteristic Mtv-2 bands of the GR strain were absent in the SHN strain.
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Urethane administrated in the drinking water of breeding female mice of five inbred strains (DDf, KF, C3Hf, ddY and C57BL) leads to a higher incidence of mammary tumors at an extremely early age in four of these strains (DDf, KF, C3Hf and ddY). In the case of the DDf strain the tumors are adenoacanthomas, but in the case of the other strains adenocarcinomas are also observed. The effect of urethane in the drinking water on expression of endogenous retroviral structural proteins of the B and C type (MTV and MuLV) was studied in the milk by an immunodiffusion test and in organ extracts by radioimmunoassays (for MTVp27, MTVgp52 and MuLVp30). Organs tested include salivary glands, thymus and spleen from female and male animals. In addition, prostate and seminal vesicles were tested in male animals and uterus and mammary glands in females. Mammary tumors induced by urethane were also treated. Urethane does not induce or enhance endogenous retroviral antigen expression, either in these organs or in the mammary gland, one of the target organs for tumorigenesis by this agent.