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1.
論文 |
Kobayashi, Mio ; Kakuda, Yuko ; Harada, Kenichi ; Sato, Yasunori ; Sasaki, Motoko ; Ikeda, Hiroko ; Terada, Mitsuhiro ; Mukai, Munenori ; Kaneko, Shuichi ; Nakanuma, Yasuni ; 小林, 水緒 ; 原田, 憲一 ; 佐藤, 保則 ; 佐々木, 素子 ; 池田, 博子 ; 金子, 周一 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />AIM: To investigate histological and immunohistochemical differences in hepatitis between autoimmune
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hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. METHODS: Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions. RESULTS: Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgGequal, and IgG-predominant types, with the latter sharing several features with AIH. CONCLUSION: These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.
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2.
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Onishi, Ichiro ; Kitagawa, Hirohisa ; Harada, Kenichi ; Maruzen, Syogo ; Sakai, Seisyo ; Makino, Isamu ; Hayashi, Hironori ; Nakagawara, Hisatoshi ; Tajima, Hidehiro ; Takamura, Hiroyuki ; Fujimura, Takashi ; Kayahara, Masato ; Ikeda, Hiroko ; Ohta, Tetsuo ; Nakanuma, Yasuni ; 北川, 裕久 ; 原田, 憲一 ; 牧野, 勇 ; 林, 泰寛 ; 中川原, 寿俊 ; 田島, 秀浩 ; 高村, 博之 ; 藤村, 隆 ; 萱原, 正都 ; 池田, 博子 ; 太田, 哲生 ; 中沼, 安二
概要:
金沢大学医薬保健研究域医学系<br />We present the first case of an intraductal papillary neoplasm of the bile duct (IPNB) accompanying
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a mixed adenoneuroendocrine carcinoma (MANEC). A 74-yearold woman presented with fever of unknown cause. Laboratory data revealed jaundice and liver injury. Contrast-enhanced computed tomography revealed a 20 mm polypoid tumor in the dilated distal bile duct, which exhibited early enhancement and papillary growth. Upper gastrointestinal endoscopy revealed mucus production from the papilla of Vater, characterized by its protruding and dilated orifice. Endoscopic ultrasonography visualized the polypoid tumor in the distal bile duct, but no invasive region was suggested by diagnostic imaging. Therefore, the initial diagnosis was IPNB. After endoscopic nasobiliary drainage, a pylorus-preserving pancreaticoduodenectomy was performed. Pathological examination of the resected bile duct revealed papillary proliferation of biliary-type cells with nuclear atypia, indicating pancreaticobiliary-type IPNB. In addition, solid portions comprised of tumor cells with characteristic salt-and-pepper nuclei were evident. Immunohistochemistry revealed expression of the neuroendocrine marker synaptophysin in this solid component, diagnosing it as a neuroendocrine tumor (NET). Furthermore, the MIB-1 proliferation index of NET was higher than that of IPNB, and microinvasion of the NET component was found, indicating neuroendocrine carcinoma (NET G3). This unique case of MANEC, comprising IPNB and NET, provides insight into the pathogenesis of biliary NET. © 2013 Baishideng. All rights reserved.
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3.
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Sasaki, Motoko ; Ikeda, Hiroko ; Sawada, Seiko ; Sato, Yasunori ; Nakanuma, Yasuni
概要:
金沢大学医薬保健研究域医学系<br />Background: Primary biliary cirrhosis (PBC) is an autoimmune liver disease targeting the intrahepati
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c small bile ducts showing chronic non-suppurative destructive cholangitis (CNSDC). Recent studies suggest that naturally-occurring CD4+CD25high regulatory T cells (Tregs) expressing Forkhead box P3 (Foxp3) play an active role in immunological self-tolerance. Aims: To investigate whether Foxp3+Tregs are involved in the pathogenesis of PBC. Methods: Foxp3+Tregs was detected immunohistochemically in livers from patients with PBC (n = 27), chronic viral hepatitis (CVH) (n = 15), and normal subjects (n = 10). The distribution of Tregs in portal tracts was semi-quantitatively evaluated in each groups. Levels of Foxp3, IL-10, TGFβ, IFNγ and TNFα mRNA was evaluated in PBC (n= 15) and control livers (n = 21) using semi-quantitative reverse transcriptase-PCR. Results: In PBC and CVH livers, the amounts of infiltrating Foxp3+Tregs in portal tracts were in parallel with the degree of portal inflammation irrespective of disease. The infiltration of Foxp3+Tregs into portal tracts with CNSDC in PBC was foremost in comparison with inflamed portal tracts in CVH or those without CNSDC in PBC (p<0.05). Focally, Tregs infiltrated into the biliary epithelial layer at the site of CNSDC. The level of Foxp3, IL-10 and TGFβ mRNA expression was high in PBC compared with normal livers (p<0.05). IFNγ and TNFα mRNA was high in early PBC and CVH livers. Conclusion: Results of this evaluation of Foxp3+Tregs do not suggest that the reduced regulatory function accounts for the development of CNSDC in PBC.
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4.
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Harada, Kenichi ; Chiba, Mayumi ; Okamura, Atsushi ; Hsu, Maylee ; Sato, Yasunori ; Igarashi, Saya ; Ren, Xiang Shan ; Ikeda, Hiroko ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Nakanuma, Yasuni
概要:
金沢大学医薬保健研究域医学系<br />Aims: Monocyte chemoattractant protein-1 (MCP-1) is a major chemotactic factor for hepatic stellate
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cells (HSCs) associated with hepatic fibrosis. In this study, among several fibrogenetic factors derived from biliary epithelial cells (BECs), MCP-1 produced by the biliary innate immune system was found to be most critical in the histogenesis of hepatic fibrogenesis. Methods: Using cultured human BECs, the expression of five fibrogenetic factors including MCP-1 on stimulation with Toll-like receptor ligands, inflammatory cytokines or bile acids was examined. Moreover, in situ detection of MCP-1 and α-smooth muscle actin proteins was performed using sections from normal and diseased livers by immunohistochemistry. Results: All fibrogenetic factors were detected in BECs, but only MCP-1 expression was upregulated, by all the Toll-like receptor ligands, IL-1β, and tumour necrosis factor-alpha. Proliferating bile ductules in interface areas expressed MCP-1 in diseased livers accompanying α-smooth muscle actin-positive activated HSCs. Conclusions: Bile ductules proliferate in various hepatobiliary diseases, and its significance is still unknown. This study demonstrated that BECs in bile ductules could produce MCP-1, particularly, via biliary innate immunity, suggesting that MCP-1 derived from BECs plays an important role in the recruitment of HSCs to interface areas and the activation of HSCs resulting in the progression of periportal fibrosis. Copyright Article author (or their employer) 2011.
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5.
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Sasaki, Motoko ; Ikeda, Hiroko ; Kataoka, Hiroaki ; Nakanuma, Yasuni
概要:
金沢大学大学院医学系研究科<br />The repair system of damaged biliary mucosa was not fully clarified so far in primary biliary cirrhos
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is (PBC). Given that related factors of the hepatocyte growth factor (HGF) such as HGF activator (HGFA) and HGFA inhibitor type 1 (HAI-1) participate in the repair of injured gastrointestinal mucosa, we investigated the involvement of the HGF/HGFA/HAI-1 system in PBC and control livers. The expression of HGFA, HAI-1, and c-Met was examined in PBC livers (n=24), diseased livers (control, n=30), and normal livers (n=15) by immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction. We examined the expression of HGFA, HAI-1, and c-Met, and the effect of HGF administration on cell proliferation and wound healing, and HAI expression in cultured mouse biliary epithelial cells (BECs). HAI-1 expression was faint in control livers, whereas it was significantly augmented in damaged small bile ducts, bile ductules, and periportal hepatocytes in PBC (p<0.05). HGFA and c-Met were homogeneously expressed in BECs in PBC and control livers. HAI-1 expression was increased at the front of wound healing and the treatment with HGF-enhanced HAI-1 expression, cell proliferation, and wound healing in cultured BECs. HGF/HGFA/HAI-1 system may participate in biliary mucosal repair as reported in gastrointestinal mucosal repair. © Springer-Verlag 2006.
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6.
論文 |
Sasaki, Motoko ; Ikeda, Hiroko ; Nakanuma, Yasuni ; 佐々木, 素子 ; 中沼, 安二
概要:
金沢大学大学院医学系研究科がん細胞学<br />Mucin secreted by mucosal epithelial cells plays a role in the protection of the mucosal surface
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and also is involved in pathological processes. So far, MUC1-4, 5AC, 5B, 6-8, 11-13 and 15-17 genes coding the backbone mucin core protein have been identified in humans. Their diverse physiological distribution and pathological alterations have been reported. We have studied the expression profiles of MUC genes in the intrahepatic biliary system in developmental, normal and diseased livers using immunohistochemistry and in situ hybridization. Fetal intrahepatic bile ducts and ductal plates frequently express MUC1, while intrahepatic large bile ducts after birth express mainly MUC3 mucin. In hepatolithiasis, MUC5AC (gastric foveolar epithelial type) and MUC6 (pyloric gland type) mucins are newly expressed in surface epithelial cells and proliferated peribiliary glands, respectively, and the expression of gel-forming mucin may play a role in lithogenesis. Most biliary epithelial dysplasias and cholangiocarcinomas associated with hepatolithiasis expressed MUC5AC, suggesting that intrahepatic bile ducts express the gastric foveolar phenotype during carcinogenesis. In addition, intestinal metaplasia, intraductal papillary tumor and mucinous carcinoma, characterized by MUC2 expression, are occasionally associated with hepatolithiasis in a CDX2 homeobox gene-dependent manner. These findings may suggest the presence of intestinal metaplasia-related carcinogenesis in the intrahepatic biliary system as in the stomach.
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7.
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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
概要:
Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) tha
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t 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.
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8.
論文 |
Harada, Kenichi ; Sato, Yasunori ; Ikeda, Hiroko ; Maylee, Hsu ; Igarashi, Saya ; Okamura, Atsushi ; Masuda, Shinji ; Nakanuma, Yasuni
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
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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.
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9.
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Funada, Akira ; Masuta, Eiichi ; Fujino, Noboru ; Hayashi, Kenshi ; Ino, Hidekazu ; Kita, Yoshihito ; Ikeda, Hiroko ; Fujii, Takahiko ; Nakanuma, Yasuni ; Yamagishi, Masakazu
概要:
Hypertrophic cardiomyopathy (HCM) is associated with gene mutations that encode sarcomeric proteins. However, the relationship between genotype and histopathologic fndings is unclear. We report on two autopsy cases with advanced
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HCM associated with deletion of lysine 183 mutation in the cardiac troponin I gene. One case, a 74-year-old female exhibited dilated cardiomyopathy-like features. Transmural scarring was diffuse and circumferential, involving the whole left ventricle, especially the ventricular septum which was replaced with extensive fbrosis and showed marked wall thinning. The other case, a 92-year-old male revealed typical HCM fndings. Patchy scars which corresponded to replacement fbrosis were found extending from the septum to the anterior wall. These two autopsy cases indicate the clinical heterogeneity of HCM even within the same disease-causing mutation and suggest that the degree and extent of fbrosis determine differences in the clinical manifestations of HCM. This is the frst autopsy report that demonstrates identical sarcomeric gene mutations causing different clinical manifestations and histologic fndings. The fndings suggest that additional genetic or environmental factors infuence the phenotypic expressions and clinical courses of HCM caused by genetic mutation of sarcomeric proteins.
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10.
論文 |
Nakanuma, Yasuni ; Harada, Kenichi ; Sato, Yasunori ; Ikeda, Hiroko
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
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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.
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