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Spleen cells from C57BL/6 beige mouse showed significantly lower cytotoxic T lymphocyte (CTL) generation in vitro against allogeneic target cells as compared with spleen cells from the wild type, whereas the heterozygous littermate showed a response similar to that of the wild type. In contrast, the responsiveness of beige spleen cells in the mixed lymphocyte reaction against allogeneic stimulator cells was in the normal range, suggesting that beige spleen cells recognize allogeneic stimulator cells to the same extent as spleen cells from normal mouse, resulting in a significant proliferation. The addition of interleukin 1 (IL-1)-containing supernatant from lipopolysaccharide-stimulated J774.1 cells to the culture of spleen cells from beige mouse stimulated with allogeneic cells restored the impaired CTL generation in a dose-dependent manner. The molecules responsible for restoration of the impaired CTL response co-migrated with IL-1 on gel filtration. The addition of purified interleukin 2(IL-2) also augmented the induction of CTL from beige spleen cells. However, the magnitude of augmentation by IL-2 was appreciably lower than that of augmentation by IL-1. These results suggest that the role of IL-1 in the induction of CTL is not only to provide a signal for activated amplifier T cells to release IL-2, but also to magnify otherwise low responsiveness of CTL-precursors and/or CTL-helpers. Moreover, intraperitoneal injection of IL-1 without allo-antigenic stimulation was able to restore the in vitro CTL responsitivity to allo-antigen but not the natural killer cell activity, indicating that IL-1 has a therapeutic potential in vivo for preferentially correcting impaired CTL generation associated with beige mutation.

Amplified c-myc oncogene was found in the DNAs of 2 of 11 human stomach cancers transplanted into nude mice; the amplification was 8- to 10-fold in one tumor and 13- to 15-fold in the other. Both tumors in which the c-myc oncogene was amplified were poorly differentiated adenocarcinomas, but there was no clear-cut correlation between the histological types or growth rates of the tumors and amplification of the c-myc oncogene. No amplification of the c-myc gene was detected in DNAs from 4 cultured stomach cancer cell lines, 19 primary stomach cancers or 11 metastases to lymph nodes from human stomach cancers.

A protein p40x was identified as a product encoded by frame IV in the pX region of human T-cell leukemia virus type I. Sera from patients with adult T-cell leukemia contained antibodies against p40x, indicating its expression in vivo. The occurrence of splicing to form pX mRNA is proposed and the possible significance of p40x is discussed.

A newly synthesized fluorescent TPA derivative, O-(N-dansylamino-3-tetradecanoyl)-12,O-acetyl-13-phorbol (Dansyl-TPA), inhibited metabolic cooperation of Chinese hamster V79 cells in culture and also the specific binding of [3H]phorbol dibutyrate to V79 cells. Dansyl-TPA should be a valuable tool for studying the cellular targets of TPA.

The clonal origin of spontaneous multiple mammary tumors in mice was examined. For this purpose, hybrid female mice (Pgk-1b/Pgk-1a), F1[SHN(Pgk-1b) X C3H/He (Pgk-1a)], with X-chromosome inactivation mosaicism with regard to the phosphoglycerate kinase (PGK)-1 isozyme together with a high incidence of spontaneous mammary tumors were constructed. Thirty-seven of 45 mammary tumors (82%) in mosaic mice had a single phenotype of PGK, indicating monoclonal origin. The multiple mammary tumors formed in these mice varied in PGK type, indicating independent cellular origins.

Plasmids containing v-rasH and Ecogpt were constructed, and used to transfect two established cell lines of mouse origin, NIH3T3 cells and m5S cells. After transfection, most NIH3T3 cells, which are resistant to mycophenolic acid, showed phenotypes characteristic of neoplastic transformation, whereas no mycophenolic acid-resistant m5S cells showed these phenotypes; integration of functionally intact v-rasH in immortalized murine cells is not sufficient for neoplastic transformation in m5S cells. The resistance to the transformation was probably due to a lower level of the v-rasH gene transcripts in m5S cells.

The mode of interaction of deoxycholate (DOC) or lithocholate (LC) with F344 rat colon was examined by measurements of uptake, 31P nuclear magnetic resonance (NMR) spectroscopy and observation of morphological changes. DOC as well as LC was taken up by the colon in a nonsaturable manner with respect to concentration and time, up to 30 min. None of several metabolic inhibitors reduced the uptake of the bile acids, nor did pretreatment of colon segments with chloroform-methanol (2:1, (v/v), heat or trypsin. Further, the bile acids were not transported by the colon against concentration gradients, and they were bound to both the mucosa and serosa equally. From these findings, it is concluded that the bile acids are transported in a passive manner, and no specific receptor for them is contained in colonic mucosa. The uptake of the bile acids by the colon varied with temperature and was related to the fluidity of the colonic membranes. The extent of uptake of dehydrocholate and taurocholate, which do not induce ornithine decarboxylase (ODC) activity, was almost the same as that of LC. The 31P NMR spectra of the colonic mucosal cells indicated that the proportion of the bilayer structure is increased by 0.5 mM DOC. Among a variety of bile acids examined, the extent of membrane alteration was in parallel with the extent of ODC induction. Treatment of the colonic mucosa with 0.5 mM DOC caused marked degeneration of the surface but not the deeper layers of the mucosa. Thus, physiological concentrations of bile acids influence the membrane organization of the colonic mucosa in a nonspecific manner that is possibly related to the tumor-promoting activity.

The intracellular structure and expression of integrated hepatitis B virus (HBV) DNA in the hepatoma tissue #1707 obtained from an 11-year-old boy were studied. It was found that most of the HBV genome was present in the #1707 DNA. Virus-specific 21S mRNA was also demonstrated by blot hybridization. This is the first direct evidence for the expression of the integrated viral genome in human hepatoma tissue.

The activities of ribonucleotide reductase and thymidine kinase, and the thymidine incorporation rate were measured in 16 cultured human hematologic malignant cell lines with different cell proliferation rates. Thymidine kinase activity was significantly higher in myeloid and monocytoid cell lines than in other cell lines, but ribonucleotide reductase activity presented as CDP reductase activity was similar in the different cell lines. The ratio of thymidine kinase to CDP reductase activity was high in monocytoid cell lines. A close correlation was found between the cell proliferation rate and CDP reductase activity, but not thymidine kinase activity or the thymidine incorporation rate. The ratio of thymidine kinase to CDP reductase activity was high in slowly growing cell lines and low in rapidly growing cell lines. These results indicate that in cultured human malignant cells a high potential for proliferation may depend mainly on the de novo pyrimidine pathway of DNA biosynthesis.

12-O-Tetradecanoylphorbol-13-acetate (TPA), a potent promoter of mouse skin carcinogenesis, was tested for possible tumor-enhancing effects on urinary bladder carcinogenesis using the heterotopically transplanted bladder (HTB) model. Weekly administration of TPA at 1.0 microgram/week to N-methyl-N-nitrosourea-initiated HTBs did not increase tumor incidence, but instead, resulted in a significantly high incidence of nodulopapillary hyperplasia, an early neoplastic lesion, suggesting possible tumor enhancement by TPA. In addition, administration of a high dose of TPA with or without a carcinogen treatment led to the development of numerous finger-like epithelial projections on the luminal surface of the HTBs. Evidence indicates that epithelial projections are formed as a result of proliferation of intermediate cells. Whether these structures evolve into true neoplastic lesions is at present unknown.