1.

その他

その他
佐藤, 保則 ; Sato, Yasunori
出版情報: 博士学位論文要旨 論文内容の要旨および論文審査結果の要旨/金沢大学大学院医学研究科.  平成12年7月  2000-07-01.  金沢大学
URL: http://hdl.handle.net/2297/15541
概要: 取得学位:博士(医学), 学位授与番号:医博甲第1395号,学位授与年月日:平成12年3月22日,学位授与年:2000
2.

論文

論文
佐藤, 保則 ; Sato, Yasunori
出版情報: 平成25(2013)年度 科学研究費補助金 基盤研究(C) 研究成果報告書 = 2013 Fiscal Year Final Research Report.  2011-2013  pp.4p.-,  2014-05-28.  金沢大学医薬保健研究域医学系
URL: http://hdl.handle.net/2297/00050996
概要: 金沢大学医薬保健研究域医学系<br />カロリ病+先天性肝線維症の動物モデルとして確立されたPCKラットを用い、肝胆管病変の形成におけるPI3K/Akt/mTORを介した細胞内シグナル伝達の関与、ならびにその阻害剤の治療への応用 性を検討した.PCKラット培養胆管細胞を用いた検討で、NVP-BEZ235(PI3K + mTOR阻害剤)は細胞増殖と嚢胞形成を抑制し、これは培養胆管細胞のアポトーシス抑制とオートファジー誘導を伴っていた.In vivoでPCKラットにNVP-BEZ235を投与すると、PCKラットの胆管拡張と肝線維化を有意に軽減させることが可能であった.<br />Using the PCK rat, an animal model of Caroli's disease with congenital hepatic fibrosis, the involvement of the PI3K/Akt/mTOR pathway in biliary dysgenesis was examined in terms of therapeutic application. NVP-BEZ235 (an inhibitor of PI3K and mTOR) significantly inhibited cell proliferative activity and cystic growth of the cultured PCK cholangiocytes, which was accompanied by inhibition of apoptosis and induction of autophagy in the cells. In vivo, administration of NVP-BEZ235 significantly improved dilatation of intrahepatic bile ducts and liver fibrosis of the PCK rat.<br />研究課題/領域番号:23590392, 研究期間(年度):2011-2013 続きを見る
3.

論文

論文
佐藤, 保則 ; Sato, Yasunori
出版情報: 平成22(2010)年度 科学研究費補助金 若手研究(B) 研究成果報告書 = 2010 Fiscal Year Final Research Report.  2009-2010  pp.4p.-,  2011-04-12.  金沢大学医薬保健研究域医学系
URL: http://hdl.handle.net/2297/00050997
概要: 上皮・間葉変換機構(epithelial-mesenchymal transition,EMT)は癌の浸潤・転移に深く関与している。本研究は胆管癌の浸潤・転移におけるEMTの関与を明らかにすることを目的とした。培養胆管癌細胞と胆管癌の外科的 切除材料を用いた検討により、胆管癌の浸潤・転移にはtransforming growth factor-・1とSnailを介した癌細胞のEMTが深く関与しており、予後不良の難治性癌である胆管癌の増悪因子であることが示された。<br />Epithelial-mesenchymal transition (EMT) is an important mechanism behind the initiation of cancer invasion and metastasis. This study was performed to clarify the involvement of EMT in the progression of cholangiocarcinoma. Studies using cholangiocarcinoma cell lines and surgically resected specimens of cholangiocarcinoma demonstrated that EMT induced by transforming growth factor-β1/Snail activation was closely associated with the aggressive growth of cholangiocarcinoma, resulting in a poor prognosis. 続きを見る
4.

論文

論文
佐藤, 保則 ; Sato, Yasunori
出版情報: 金沢大学十全医学会雑誌 = Journal of the Juzen Medical Society.  128  pp.2-6,  2019-03.  金沢大学十全医学会 — The Juzen Medical Society Kanazawa University
URL: http://hdl.handle.net/2297/00054896
5.

論文

論文
佐藤, 保則 ; Sato, Yasunori
出版情報: 平成29(2017)年度 科学研究費補助金 基盤研究(C) 研究成果報告書.  2015-04-01 - 2018-03-31  pp.4p.-,  2018-05-25.  金沢大学医薬保健研究域医学系
URL: http://hdl.handle.net/2297/00050995
概要: カロリ病+先天性肝線維症の動物モデルであるPCKラットを用いた検討で,PCKラット培養胆管細胞ではmiR-125b-1-3pの発現低下とこれに関連したSmoothenedの発現亢進があり,Hedgehogシグナル伝達系の活性化による胆管細胞 の過剰な増殖があることをin vitroで見出した.PCKラットにSmoothendedアンタゴニスト(cyclopamine)を投与することで,肝内胆管の拡張と腎嚢胞の形成をin vivoで有意に抑制することに成功した.以上の結果から,Hedgehogシグナル伝達系の阻害はカロリ病+先天性肝線維症の新たな治療標的となる可能性が示された.<br />研究課題/領域番号:15K08342, 研究期間(年度):2015-04-01 - 2018-03-31 続きを見る
6.

論文

論文
Kakuda, Yuko ; Harada, Kenichi ; Sawada-Kitamura, Seiko ; Ikeda, Hiroko ; Sato, Yasunori ; Sasaki, Motoko ; Okafuji, Hirofumi ; Mizukoshi, Eishiro ; Terasaki, Shuichi ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Kaizaki, Yasuharu ; Kaneko, Shuichi ; Nakanuma, Yasuni
出版情報: Human Pathology.  44  pp.1107-1117,  2013-06-01.  Elsevier
URL: http://hdl.handle.net/2297/33483
概要: Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions. © 2013 Elsevier Inc. All rights reserved. 続きを見る
7.

論文

論文
Sasaki, Motoko ; Miyakoshi, Masami ; Sato, Yasunori ; Nakanuma, Yasuni
出版情報: Digestive Diseases and Sciences.  57  pp.660-666,  2012-03-01.  Springer Science+Business Media, LLC
URL: http://hdl.handle.net/2297/29481
概要: Background and Aim: Recent studies disclosed that autophagy facilitates the process of senescence. Given that cellular senescence is involved in the pathophysiology of ductular reaction (DR) in primary biliary cirrhosis (PBC), we examined an involvement of autophagy in DRs in PBC and control livers. Methods: We examined immunohistochemically the expression of microtubule-associated proteins light chain 3β (LC3) as autophagy marker, p62/sequestosome-1 (p62) as autophagy-related marker in bile ductular cells in livers taken from the patients with PBC (n = 42), and control livers (n = 100). The expression of senescent markers (p16INK4a and p21WAF1/Cip1) in bile ductular cells and their correlation with autophagy was also evaluated. Results: The expression of LC3 was seen in coarse vesicles in the cytoplasm of bile ductular cells and significantly more frequently in PBC of both early and advanced stages when compared to control livers (p < 0.01). The expression of p62 was seen as intracytoplasmic aggregates and significantly more frequently in PBC when compared to control livers (p < 0.05). The expression of LC3 and p62 significantly correlated with each other (p < 0.01). The expression of LC3 and p62 significantly correlated with the expression of p16INK4a, p21WAF1/Cip1 (p < 0.05). Conclusions: Autophagy is frequently seen in bile ductular cells in DRs in PBC. Since cellular senescence of bile ductular cells is rather frequent in the advanced stage of PBC, autophagy may precede cellular senescence of bile ductular cells in DRs in PBC. © 2011 Springer Science+Business Media, LLC. 続きを見る
8.

論文

論文
Harada, Kenichi ; Sato, Yasunori ; Ikeda, Hiroko ; Maylee, Hsu ; Igarashi, Saya ; Okamura, Atsushi ; Masuda, Shinji ; Nakanuma, Yasuni
出版情報: Virchows Archiv : an international journal of pathology.  460  pp.281-289,  2012-03-01.  Springer Verlag (Germany)
URL: http://hdl.handle.net/2297/31405
概要: Neuroendocrine neoplasms in hepatobiliary organs are very rare, but several cases of mixed adenoneuroendocrine carcinoma (MANEC) have been reported. In this study, we characterized the neuroendocrine component of biliary MANEC. A total of 274 cases of biliary cancer including 17 intrahepatic cholangiocarcinomas (CCs), 15 hepatic hilar CCs without preceding hepatobiliary disease, 55 hepatic hilar CCs with hepatolithiasis, 49 gallbladder cancers, 53 extrahepatic CCs, and 85 hepatocellular carcinomas were examined for a neuroendocrine component using immunohistochemistry with neuroendocrine markers (chromogranin A and synaptophysin). In the MANEC cases, in addition to a close histological examination, the proliferative activity and the expression of somatostatin receptor 2A were also evaluated. In addition to an ordinary adenocarcinoma, a neuroendocrine component occupying more than 30% of the entire tumor was also found in 4% (2/55 cases) of hepatic hilar cholangiocarcinomas with hepatolithiasis, 10% (5/49 cases) of gallbladder cancers, and 4% (2/53 cases) of extrahepatic cholangiocarcinomas, but not in the intrahepatic cholangiocarcinomas, hilar cholangiocarcinomas without preceding hepatobiliary disease, and hepatocellular carcinomas. Two cases were positive for somatostatin receptor 2A. The adenocarcinoma components were predominately located at the surface of the tumors, and the majority of stromal and vascular invasion and lymph node metastasis involved neuroendocrine components, showing the features of neuroendocrine tumor G2 or neuroendocrine carcinomas (NECs). NEC components showed higher proliferative activity on Ki67 immunostaining, compared to the adenocarcinoma components. Biliary MANECs are found in hepatic hilar cholangiocarcinomas with hepatolithiasis, gallbladder cancers, and extrahepatic cholangiocarcinomas and show a characteristic histology. Since the neuroendocrine component in biliary MANEC defines the prognosis, it is important to identify it and consider the indications for adjunctive therapy with somatostatin analogues. 続きを見る
9.

論文

論文
Nakanuma, Yasuni ; Harada, Kenichi ; Sato, Yasunori ; Ikeda, Hiroko
出版情報: Histology and Histopathology.  25  pp.223-235,  2010-02-01.  Histology and Histopathology
URL: http://hdl.handle.net/2297/31474
概要: Recent progress in elucidating the etiopathogenesis of pediatric biliary diseases, particularly Caroli's disease with congenital hepatic fibrosis (CHF) and biliary atresia (BA), is reviewed. The former is characterized by multiple saccular dilatations of the intrahepatic bile ducts. An animal model of this disease, the PCK rat, is being extensively studied. PCK rats and Calori's disease with CHF belong to autosomal recessive polycystic kidney disease (ARPKD) with ductal plate malformation. Mutations of PKHD1 have been identified in ARPKD, and fibrocystin, a product of PKHD1 located in the cilia of bile ducts is lacking in the pathologic intrahepatic bile ducts of ARPKD. Disordered cell kinetics, including apoptosis of biliary epithelial cells (BECs), may be significantly related to ductal plate malformation, and laminin and type IV collagen were immunohistochemically reduced in the basement membrane of intrahepatic bile ducts of ARPKD, and such a reduction is an additional factor for the dilatation of bile ducts. Abundant connective tissue growth factor retained diffusely in heparan sulfate proteoglycan in the fibrous portal tracts are responsible for non-resolving hepatic fibrosis. In addition, pathologic BECs of ARPKD may acquire mesenchymal features and participate in progressive hepatic fibrosis by producing extracellular matrix molecules. In an animal model of BA, an initial virus-induced, T-cell mediated autoimmune-mediated cholangiopathy has been reported. In human BA, virus-induced apoptosis of BECs by a TNF-related apoptosis-inducing ligand followed by the progressive obliteration of bile ducts is also suggested, and epithelial mesenchymal transition of BECs induced by viral infection may be involved in the fibrotic process in sclerosing cholangitis. However, the role of viral infections in the affected tissues is controversial. Comprehensive and analytical studies of ARPKD and BA using human materials and animal models may lead to the clarification of their etiopathogenesis and open the way for new therapeutic strategies. 続きを見る
10.

論文

論文
Sato, Yasunori ; Ren, Xiang Shan ; Nakanuma, Yasuni
出版情報: International Journal of Hepatology.  2012  pp.107945-,  2012-01-01.  Hindawi Publishing Corporation
URL: http://hdl.handle.net/2297/31481
概要: Caroli's disease belongs to a group of hepatic fibropolycystic diseases and is a hepatic manifestation of autosomal recessive polycystic kidney disease (ARPKD). It is a congenital disorder characterized by segmental saccular dilatations of the large intrahepatic bile duct and is frequently associated with congenital hepatic fibrosis (CHF). The most viable theory explaining its pathogenesis suggests that it is related to ductal plate malformation. The development of the polycystic kidney (PCK) rat, an orthologous rodent model of Caroli's disease with CHF as well as ARPKD, has allowed the molecular pathogenesis of the disease and the therapeutic options for its treatment to be examined. The relevance of the findings of studies using PCK rats and/or the cholangiocyte cell line derived from them to the pathogenesis of human Caroli's disease is currently being analyzed. Fibrocystin/polyductin, the gene product responsible for ARPKD, is normally localized to primary cilia, and defects in the fibrocystin from primary cilia are observed in PCK cholangiocytes. Ciliopathies involving PCK cholangiocytes (cholangiociliopathies) appear to be associated with decreased intracellular calcium levels and increased cAMP concentrations, causing cholangiocyte hyperproliferation, abnormal cell matrix interactions, and altered fluid secretion, which ultimately result in bile duct dilatation. This article reviews the current knowledge about the pathogenesis of Caroli's disease with CHF, particularly focusing on studies of the mechanism responsible for the biliary dysgenesis observed in PCK rats. 続きを見る