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Articles by Y Shimizu
Total Records ( 5 ) for Y Shimizu
  N Takatsuka , A Hasegawa , A Takamori , Y Shimizu , H Kato , T Ohashi , T Amagasa , T Masuda and M. Kannagi

Human T-cell leukemia virus type I (HTLV-I) is associated with adult T-cell leukemia, HTLV-I-associated myelopathy/tropical spastic paraparesis and various autoimmune-like disorders. T-cell immune suppression is also associated with HTLV-I infection. Mechanisms of diverse immune dysregulation in HTLV-I infection are obscure. Here, we investigated a potential link between autoimmunity and immune suppression in HTLV-I infection. G14, an IL-2-dependent HTLV-I-negative CD4+CD8+ T-cell line previously established from an HTLV-I-infected rat, constantly proliferated and produced IFN-. IFN- production by G14 cells was dependent on interactions between CD4 and MHC-II, suggesting that G14 cells recognized self-antigens presented by MHC-II on themselves. To examine immune response to G14 cells, we inoculated G14 cells into syngeneic naive rats. Interestingly, T-cells isolated from these rats vigorously proliferated when stimulated with G14-Tax cells that stably expressed HTLV-I Tax, but not with G14 cells. G14-Tax-mediated T-cell proliferation was abrogated by antibodies to CD80 and CD86 that were up-regulated in G14-Tax cells. T-cells propagated by repetitive G14-Tax cell stimulations in culture with IL-2 expressed CD4, CD25 and cytolytic T lymphocyte-associated antigen 4 (CTLA-4), produced abundant amounts of IL-10 and IFN- in response to G14 cells and suppressed growth of G14 cells mainly through supernatant-mediated mechanisms. Similar IL-10- and IFN--producing CD4+CD25+CTLA-4+ T-cells were predominantly induced in culture of splenocytes from HTLV-I-infected rats following stimulation with G14-Tax cells. These results implied that expression of Tax in the otherwise low immunogenic autoreactive T-cells induced IL-10- and IFN--producing T-cell responses with regulatory effects against the autoreactive cells. Our findings provide new insights into the complex immune conditions underlying HTLV-I-associated diseases.

  Y Kanemitsu , T Kato , Y Shimizu , Y Inaba , Y Shimada , K Nakamura , A Sato , Y Moriya and for the Colorectal Cancer Study Group (CCSG) of Japan Clinical Oncology Group

A randomized controlled trial is being conducted in Japan to compare hepatectomy alone with hepatectomy followed by adjuvant chemotherapy as treatment in patients with curatively resected liver metastases from colorectal cancer to improve survival with intensive chemotherapy. Between 42 and 70 days after liver resection, patients are randomly assigned to either hepatectomy alone or hepatectomy followed by 12 cycles of modified FOLFOX6 (mFOLFOX6) regimen. A total of 300 patients (including 78 patients in Phase II) will be accrued from 38 institutions within 3 years. The primary endpoint is treatment compliance at nine courses of mFOLFOX6 regimen in Phase II and disease-free survival in Phase III. The secondary endpoints are overall survival, incidence of adverse events and patterns of recurrence.

  N Nakamura , Y Shimizu , T Shinkawa , M Nakata , B Bammes , J Zhang and W. Chiu

We have developed an automated specimen search algorithm for cryo-electron microscopy imaging of ice-embedded single particles suspended across regularly spaced holes. To maximize the particle visibility under a low electron exposure rate condition, specimen searching is carried out in diffraction mode. However, images in diffraction mode contain significant pincushion distortion, making it difficult to computationally predict the locations of the regularly spaced holes. We have implemented a distortion-correction mechanism to restore the primitive distortion-free image and a correlation-based algorithm to accurately determine the periodicity of the holes. A stage-shift method to optimize positional reproducibility is also implemented. Addition of our algorithms to the JADAS software for automated transmission electron microscopy data acquisition has significantly improved the accuracy of specimen search.

  Y Shimizu , T Takeuchi , S Mita , K Mizuguchi , T Kiyono , M Inoue and S. Kyo

Dienogest is a specific progesterone receptor agonist with potent oral endometrial activity and is used in the treatment of endometriosis. In this study, we examined the direct effects of dienogest on the proliferation of human endometrial epithelial cells using an immortalized cell line. 5-Bromo-2'-deoxyuridine incorporation into the cells was inhibited by dienogest and by progesterone (P4) in dose-dependent fashion at concentrations of 10–8 mol/l or higher. To identify the target genes of dienogest and P4, we screened the expression of 84 genes related to cell cycle regulation by real-time polymerase chain reaction after 6 h of treatment at a concentration of 10–7 mol/l. Results showed that only cyclin D1 expression was significantly down-regulated, although expression of the other genes did not significantly change after dienogest or P4 treatment compared with the control. In a time-course study during the first 24 h after drug treatment, dienogest and P4 each produced a lasting decrease in the expression of cyclin D1 mRNA, followed by a decrease in cyclin E1 mRNA but not an increase in the expression of cell cycle inhibitor genes (p21, p27 and p53). These findings suggest that dienogest directly inhibits the proliferation of human endometrial epithelial cells with suppression of cyclin D1 gene expression.

  T Kobayashi , T Inoue , Y Shimizu , N Terada , A Maeno , Y Kajita , T Yamasaki , T Kamba , Y Toda , Y Mikami , T Yamada , T Kamoto , O Ogawa and E. Nakamura

We and others previously showed that signaling through cSrc or atypical protein kinase C (aPKC) pathway regulates the proliferation of prostate cancer cells and is associated with their progression to castrate-resistance in vivo. However, the interrelation of these two kinases has been largely unexplored. In the present study, we show that androgen-induced activation of cSrc regulates the activity of aPKC through the small molecular weight G protein Rac1 in androgen-dependent LNCaP cells. Knockdown of cSrc in those cells reduces the phosphorylation of aPKC and the abundance of activated form of Rac1. Additionally, the treatment of those cells with Rac1 inhibitor repressed cell cycle progression at G1/S transition. In fact, forced expression of a constitutively active Rac1 mutant in LNCaP cells promoted cell proliferation under androgen-depleted conditions both in vitro and in vivo. Moreover, LNCaP C4-2 and AILNCaP cells, the syngeneic androgen-independent sublines from LNCaP cells, harbored abundant Rac1-GTP. Importantly, the inhibition of Rac1 suppressed cell proliferation and induced apoptotic cell death in all prostate cancer cell lines tested irrespective of their androgen-dependence. In immunohistochemical evaluation of tumor specimens from prostate cancer patients, Rac1 pathway appeared to be activated in the majority of castrate-resistant diseases. Collectively, our present results both in vitro and in vivo highly implicate that Rac1 can be a potential therapeutic target for patients with advanced prostate cancer, especially those with castrate-resistant status.

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