Mechanisms responsible for resistance of sublines derived from leukemia cell lines to an antitumor agent 9-beta-D-arabinofuranosyl-2-fluoroadenine

An agent 9-beta-D-arabinofuranosyl-2-fluoroadenine (2-F-Ara-A) is a main metabolite of fludarabine, a fluorinated purine analogue with antitumor activity in lymphoproliferative malignancies. In this study, the mechanism responsible for the resistance of cancer cells to fludarabine was examined using the 2-F-Ara-A-resistant sublines JOK-1/F-Ara-A and L1210/F-Ara-A from a human hairy leukemic cell line (JOK-1) and a mouse leukemic cell line (L1210) respectively, which were established by continuous treatment of the parental cell lines with 2-F-AraA. JOK-1/F-Ara-A and L1210/F-Ara-A cells were more than 55 and 29 times more resistant to 2-F-Ara-A than were their parent cell lines, and showed a high cross-resistance to 1-beta-D-arabinofuranosylcytosine but not to doxorubicin or vincristine. These resistant sublines intracellularly accumulated almost the same amount of 2-F-Ara-A as did their parent cell lines. However, the amount of 2-F-Ara-ATP, a cytotoxic metabolite of 2-F-Ara-A, decreased by 2.6% (JOK-1/F-Ara-A C3), 6% (L1210/F-Ara-A C1) and 3.7% (L1210/F-Ara-A C7) relative to the levels in the parent cell lines. Enzymatically, these resistant cells hardly activated deoxycytidine (dCyd) and 2-F-Ara-A. In addition, the abilities to phosphorylate deoxyadenosine and deoxyguanosine were also decreased in the resistant cells in comparison with the parent cells. These findings suggest that the deficiency in activity of dCyd kinase may contribute to the resistance of 2-F-Ara-A.     

Paxillin isoforms in mouse. Lack of the gamma isoform and developmentally specific beta isoform expression

Paxillin, a focal adhesion protein, exists as multiple isoforms in humans (alpha, beta, and gamma). To understand more about the physiological role of each isoform, we have employed the mouse system. We found that although the alpha and beta isoforms are present in the mouse, the gamma isoform is not. The alpha isoform protein was detected clearly in most adult tissues, whereas the beta isoform protein was almost undetectable except in spleen, testis, thymus, and lung. On the other hand, mRNAs of both isoforms were detectable in all tissues we examined. High levels of the beta isoform protein was detected in peritoneal exudate macrophage cells in adult mouse as well as in cultured fibroblasts, together with the alpha isoform. The alpha isoform was expressed at a constant level throughout the embryonic stages we examined, whereas the beta isoform protein was detected at the mid-stages of development and increased to levels almost equal to those of the alpha isoform during the late stages of embryogenesis. Therefore, unlike the alpha isoform, expression of the beta isoform protein is restricted in adult tissues. Moreover, we showed that alpha and beta isoforms were colocalized within the same focal adhesion plaques, and cytoplasmic pools of both isoforms exist in the perinuclear area, colocalized with the Golgi apparatus.     

A mesenteric liposarcoma with production of granulocyte colony-stimulating factor

A 77-year-old female was admitted to our hospital because of pyrexia and a right retroperitoneal mass. Leukocytosis and other inflammatory findings were noted. Bone-marrow aspiration revealed hypercellularity with no malignant cells. An additional mass was detected sonographically in the pelvis. The serum concentration of granulocyte colony-stimulating factor (G-CSF) was highly elevated (299 pg/ml). The tumors were removed at laparotomy, and the pelvic mass was found to arise from the ileocecal mesentery. Postoperatively, white blood cell count and serum G-CSF concentrations decreased to normal levels. The mesenteric tumor showed weakly positive immunostaining for human G-CSF, and Northern and polymerase chain reaction (PCR) analyses detected CSF and its mRNA in the mesenteric tumor.     

Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: influence of substituents at the phthaloyl moiety on the activity and stereoselectivity

The synthesis and tumor necrosis factor (TNF)-alpha production enhancing activity of substituted 3'-methylthalidomides on human leukemia cell line HL-60 stimulated with 12-O-tetradecanoyl-phorbol 13-acetate (TPA) are described. Though the introduction of an electron-donating amino group at the phthaloyl moiety of alpha-methylthalidomides enhanced the activity, substituted alpha-methylthalidomides showed decreased stereoselectivity as compared to that of non-substituted alpha-methylthalidomide. The data indicates that the TNF-alpha production enhancing activity of thalidomide derivatives depends on both the electronic-state of substituents at the fused benzene ring and the stereochemistry of the glutarimide moiety.     

Some characteristics of a cellular receptor for virulent infectious bursal disease virus by using flow cytometry

A flow cytometric virus binding assay that directly visualizes the binding of infectious bursal disease virus (IBDV) to its target cells was established. The chicken B lymphoblastoid cell line, LSCC-BK3, which is permissive for IBDV infection, bound high levels of the virus. Another B lymphoblastoid cell line, LSCC-1104-B1, bound low levels of the virus, although it was nonpermissive. No virus binding was detected in nonpermissive T lymphoblastoid cell lines. In the binding assay to heterogeneous cell populations of chicken lymphocytes, IBDV (a highly virulent OKYM strain) bound to 94% cells in the lymphocytes prepared from the bursa of Fabricius, 37% cells in those prepared from the spleen, 3% cells in those prepared from the thymus, and 21% cells in those prepared from the blood. Most of the cells, which bound the virus, were surface immunoglobulin M (SIgM)-positive, but a small number of them were SIgM-negative. Additionally, the binding of IBDV to the LSCC-BK3 cells was affected by treatment of the cells with proteases and N-glycosylation inhibitors. These findings may indicate that the IBDV host range is mainly controlled by the presence of a virus receptor composed of N-glycosylated protein associated with the subtle differentiation stage of B-lymphocytes represented mostly by SIgM-bearing cells.     

Development of next generation PWR in Japan

The demand for energy in Japan is expected to increase steadily into the future, and it seems that the importance of nuclear power generation will be heightened more when the situation of our country which is not rich in energy resources is taken into account.

Furthermore, when we consider the present situation that the light water reactors have become common, recent outlook for the supply and demand for uranium resources, trends in the development of the fast breeder reactor technology, etc., the light water reactors are expected to remain dominant in the nuclear power generation of our country until at least the second half of the 21st century.

Based on such a background five PWR utilities in Japan (Hokkaido, Kansai, Shikoku, Kyushu, and the Japan Atomic Power), and Mitsubishi Heavy Industries, Ltd. have jointly started researching the Next Generation PWR which is expected to be the leading nuclear power plant taking place of APWR.     

Effects of computers on Japanese schools

In this paper I consider how the computer can or should be accepted in Japanese schools. The concept of teaching in Japan stresses learning from a long-term perspective. Whereas in the instructional technology, on which the CAI or the Tutoring System depends, step-by-step attainments in relatively short time are emphasized. The former is reluctant in using the computer, but both share the Platonic perspective which are goal-oriented. However, The Socratic teacher, who intends to activate students' innate disposition to be better, would find another way of teaching and use of the computer.