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Articles by T Kosaka
Total Records ( 3 ) for T Kosaka
  T Mishima , Y Tajima , T Kuroki , T Kosaka , T Adachi , A Kitasato , N Tsuneoka , T Kitajima and T. Kanematsu

The present study was designed to investigate whether an inducible nitric oxide synthase (iNOS)-specific inhibitor, ONO-1714 [(1S, 5S, 6R, 7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0] heptane], could prevent inflammation-associated biliary carcinogenesis in bilioenterostomized hamsters. Syrian golden hamsters underwent choledochojejunostomy and then received subcutaneous injections of the chemical carcinogen N-nitrosobis(2-oxopropyl)amine every 2 weeks at a dose of 10 mg/kg body wt, starting 4 weeks after surgery and continuing for 18 weeks. The hamsters were divided into two groups according to their oral intake of either a standard pelleted diet containing ONO-1714 at 100 p.p.m. for 18 weeks (ONO group, n = 15) or an ordinary diet alone (control group, n = 15). The animals were killed 22 weeks after surgery, and the development of biliary tumors was examined histologically. The presence and degree of cholangitis, cell kinetic status of the biliary epithelium and iNOS expression were evaluated. Intrahepatic biliary adenomas developed in all control animals, whereas they developed in only seven (47%) hamsters treated with ONO-1714 (P < 0.05). Intrahepatic biliary carcinomas were present in 13 (87%) hamsters in the control group and in only 6 (40%) hamsters in the ONO groups (P < 0.05). Histological and immunohistochemical examinations demonstrated a significant decrease in the degree of cholangitis, biliary epithelial cell kinetics and the expression of iNOS in the biliary epithelium in the ONO group in comparison with the control (P < 0.05). These results indicate that ONO-1714 represses N-nitrosobis(2-oxopropyl)amine-induced biliary carcinogenesis in bilioenterostomized hamsters and inhibits iNOS expression in the biliary epithelium. ONO-1714 may therefore be a promising agent for the prevention of biliary carcinoma in various inflammation-associated biliary disorders.

  M Ishida , S Mikami , E Kikuchi , T Kosaka , A Miyajima , K Nakagawa , M Mukai , Y Okada and M. Oya

Aryl hydrocarbon receptor (AhR) and the activation of the AhR pathway are involved in xenobiotic-induced toxicity and carcinogenesis. Although xenobiotics, such as cigarette smoke, contribute to the development of urothelial carcinoma (UC), the relationship between AhR and UC is unclear. In the present study, we investigated AhR expression in 209 patients with upper urinary tract UC. The nuclear expression of AhR was significantly associated with histological grade, pathological T stage, lymphovascular invasion and lymph node involvement. A multivariate Cox analysis revealed that nuclear AhR expression was a significant and independent predictor for disease-specific survival (hazard ratio = 2.469, P = 0.013). To determine whether the AhR pathway can be activated in the T24 UC cell line, we examined the expression of cytochrome P450 (CYP) 1A1 and CYP1B1, which are target genes of the AhR pathway, following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a ligand of AhR. TCDD treatment upregulated the expression levels of AhR, CYP1A1 and CYP1B1. TCDD enhanced T24 cell invasion associated with the upregulation of matrix metalloproteinase (MMP)-1 and MMP-9. Furthermore, targeting AhR messenger RNA (mRNA) expression in T24 cells with small interfering RNA (siRNA) downregulated the mRNA expression of AhR, CYP1A1, CYP1B1, MMP-1, MMP-2 and MMP-9; furthermore, the cells transfected with siRNA for AhR showed decreased invasion activity in comparison with the cells transfected with a non-targeting siRNA. Our results therefore suggest that AhR plays a role in the invasiveness of UC cells and can serve as a marker for the prognosis of upper urinary tract UC.

  S Shirotake , E Kikuchi , K Matsumoto , S Yazawa , T Kosaka , A Miyajima , K Nakagawa and M. Oya

The role of pelvic lymphadenectomy in patients with lymph node-negative bladder cancer at radical cystectomy (RC) has not yet been examined in detail. We retrospectively reviewed patients who underwent RC with pelvic lymphadenectomy for bladder cancer from January 1987 to March 2008.


We identified consecutive data on 169 patients who underwent RC for bladder cancer. The mean follow-up was 64 months (range: 1–253 months). Node-positive status (pN(+)) was seen in 16 patients and 91 were diagnosed as node-negative (pN(–)). The lymph node status of the remaining 62 patients was unclear (pN(x)). We analysed the association between lymph node status and cancer-specific survival (CSS), and examined the role of the number of retrieved lymph nodes, particularly in pN(–).


The median number of retrieved nodes was 12.9 and 10.2 for stage pN(+) and stage pN(–), respectively. In 91 patients with pN(–), multivariate analysis revealed that pathological T3-4 (P = 0.0276) and less than nine retrieved lymph nodes (P = 0.0108) were independent risk factors for CSS. In a subgroup of 83 patients with pT3-4, Kaplan–Meier curves showed that the 5-year CSS rate in pN(–) patients with less than nine retrieved lymph nodes was 38.8%, which was extremely similar to the 40.8% in pN(+) and 45.1% in pN(x).


Our results demonstrate that at least nine lymph nodes should be removed to improve the survival of pN(–) patients at RC and lymphadenectomy, and would provide information not only on prognosis but also on the therapeutic impact on pT3-4 invasive bladder cancer.

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