※一部利用できない機能があります
| 1.
論文 |
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
…
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.
続きを見る
|
||||
| 2.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 3.
論文 |
論文
|
Wakisaka, Naohiro ; Endo, Kazuhira ; Kitazawa, Tomohiro ; Shimode, Yuzo ; Kato, Koroku ; Moriyama-Kita, Makiko ; Koda, Wataru ; Ikeda, Hiroko ; Ishikawa, Kazuya ; Ueno, Takayoshi ; Nakanishi, Yosuke ; Kondo, Satoru ; Sugimoto, Hisashi ; Yoshimura, Kenichi ; Tsujii, Hiroyuki ; Kawashiri, Shuichi ; Omoto, Kiyoshi ; Yoshizaki, Tomokazu ; 脇坂, 尚宏 ; 遠藤, 一平 ; 加藤, 広禄 ; 喜多, 万紀子 ; 香田, 渉 ; 池田, 博子 ; 石川, 和也 ; 上野, 貴雄 ; 中西, 庸介 ; 近藤, 悟 ; 杉本, 寿史 ; 吉村, 健一 ; 川尻, 秀一 ; 吉崎, 智一
概要:
金沢大学医薬保健研究域医学系<br />Background: In sentinel lymph node (SLN) biopsy for head and neck cancers, the radioisotope method h
…
as been the gold standard. However, this method has several problems, such as unavoidable radiation exposure and requirements of expensive equipment. Aims/Objectives: To overcome these problems, we evaluated the contrast-enhanced ultrasonography (CEUS)-guided SLN-detection method, and predicted the SLN metastatic status using novel ultrasound technology, superb microvascular imaging (SMI). Methods: Ten patients (6 with oral and 4 with oropharyngeal cancers) without neck lymph node metastasis were enrolled in this study. Ultrasound contrast agent, Sonazoid ™ , was infiltrated into the mucosa at the primary site to observe the lymphatic ducts and SLNs in the neck field. The detected SLNs were examined for blood flow using SMI to categorize the SLNs metastases-positive or negative. Results: SLNs were successfully detected in 8 out of 10 cases. In 7 out of the 8 cases, in whom SLNs were successfully detected, the metastatic status of SLNs was correctly diagnosed with SMI. Conclusions and significance: Although more clinical data are needed based on a larger cohort, establishing the CEUS-guided SLN-detection and criteria for the accurate diagnosis of SLN-metastases using SMI would be valuable as an alternative to radioisotope method, in oral and oropharyngeal cancers. © 2019, © 2019 Acta Oto-Laryngologica AB (Ltd).<br />Embargo Period 12 months<br /># This study was approved by the Bioethics Committee of Kanazawa University (Nos.2016-037 and 2017-015). The clinical study protocol was explained in detail to patients eligible for the study. Written consent was obtained from all patients who agreed to participate.# This work was supported by a grant-in-aid from The Public Trust Fund For Clinical Cancer Research.
続きを見る
|
||||
| 4.
論文 |
論文
|
池田, 博子 ; Ikeda, Hiroko
概要:
近年，日本国民の約2人に1人は生涯のうちにがんに罹患すると推計されている．日本ではがん対策基本法に基づき，癌に対する取り組みが進められている．1990年に始まったヒトゲノム計画ではヒト1人分の全ゲノム解析に，13年の歳月と30億ドルの費用を
…
要していたが，目覚ましい技術進歩により，2016年には解析期間は1週間以下にまで短縮し，費用は約1000ドルにまで低廉化してきた．こうした技術革新により，次世代シークエンシング法 (next-generation sequencing; NGS) を用いたゲノム解析が，研究のみならず，患者の診断･治療といった診療にも拡がってきている．政府はがんゲノム医療の計画的な推進を提唱し，2017年には厚生労働省主導のがんゲノム医療推進コンソーシアム懇談会が立ち上げられ，当該医療の推進に必要な薬事承認や保険適用の制度設計などが議論されている1)． 悪性腫瘍の病理組織・細胞検体を用いた体細胞遺伝子検査は急増しており，今後は次世代シークエンシング法 (NGS) などの新規技術を用いたゲノム診断 (遺伝子パネル検査) の臨床導入が見込まれている．日常の病理組織診断では，生検もしくは手術などにより採取･切除された組織のホルマリン固定パラフィン包埋 (formalin-fixed, paraffin-embedded; FFPE) 検体が主として用いられ，形態診断に加え，核酸やタンパクなどの検索を目的とした分子診断に供される．ゲノム解析では生体内環境に近い新鮮検体の利用が望ましいが，現況では治療法選択などにおいて腫瘍の病理診断は必須である．今後は形態診断，免疫組織化学法を用いた分子診断，ゲノム診断，いずれの利用にも耐えうる一定水準以上の病理検体の品質が求められるようになり，病理検査室ではその対応が急務となっている． 本稿では，がんゲノム医療の国内動向と遺伝子パネル検査の現状を概説し，ゲノム診療，研究のための病理組織検体取扱い規定を紹介する．
続きを見る
|
||||
| 5.
その他 |
その他
|
池田, 博子 ; Ikeda, Hiroko
|
||||
| 6.
その他 |
その他
|
池田, 博子 ; Ikeda, Hiroko ; イケダ, ヒロコ
概要:
取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1878号 , 学位授与年月日 : 平成19年6月30日, 学位授与大学 : 金沢大学, 主査教授 : 大井 章史, 副査教授 : 金子 周一 , 清水 徹
|
||||
| 7.
論文 |
論文
|
Tajima, Hidehiro ; Takamura, Hiroyuki ; Kitagawa, Hirohisa ; Nakayama, Akira ; Shoji, Masatoshi ; Watanabe, Toshifumi ; Tsukada, Tomoya ; Nakanuma, Shinichi ; Okamoto, Koichi ; Sakai, Seisho ; Kinoshita, Jun ; Makino, Isamu ; Nakamura, Keishi ; Hayashi, Hironori ; Oyama, Katsunobu ; Inokuchi, Masafumi ; Nakagawara, Hisatoshi ; Miyashita, Tomoharu ; Ninomiya, Itasu ; Fushida, Sachio ; Fujimura, Takashi ; Wakayama, Tomohiko ; Iseki, Shoichi ; Ikeda, Hiroko ; Ohta, Tetsuo ; 田島, 秀浩 ; 高村, 博之 ; 北川, 裕久 ; 中村, 信一 ; 岡本, 浩一 ; 木下, 淳 ; 牧野, 勇 ; 中村, 慶史 ; 林, 泰寛 ; 尾山, 勝信 ; 井口, 雅史 ; 中川原, 寿俊 ; 宮下, 知治 ; 二宮, 致 ; 若山, 友彦 ; 藤村, 隆 ; 井関, 尚一 ; 池田, 博子 ; 太田, 哲生
概要:
金沢大学医薬保健研究域医学系<br />A 33-year-old female was diagnosed with a solid pseudopapillary tumor (SPT) of the pancreas and mult
…
iple liver metastases at the Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital (Kanazawa, Japan). Distal pancreatectomy and postoperative systemic chemotherapy with gemcitabine (GEM) and S-1, an oral fluoropyrimidine derivative, was administered, however, liver metastases became enlarged and local recurrence occurred. Therefore, the patient was referred to the Department of Gastroenterologic Surgery at the Graduate School of Medicine (Kanazawa, Japan) for hepatic arterial infusion (HAI) chemotherapy. Oral S-1 (80 mg/m2) was administered as well as HAI chemotherapy with GEM (1,000 mg/standard liver volume). Following 18 cycles, tumor sizes were reduced and 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) examination revealed obvious reduction of tumor FDG uptake. Transarterial tumor embolization (TAE) was performed for the previously unresectable right subphrenic liver tumor, and the other tumors were surgically resected. The resected tumors were diagnosed as liver metastases and a local recurrence of SPT in the postoperative pathological examination, which revealed that the resected tumors were composed of sheets of bland cells, which were positive for CD10, CD56, vimentin, neuron-specific enolase and α-antitrypsin. The postoperative course was uneventful, and the patient is currently under observation at an outpatient clinic; postoperative adjuvant chemotherapy with oral S-1 has continued, and additional TAE is planned. In the future, if the middle segment of the liver becomes enlarged, surgery for the residual right lobe tumor may be possible. This case demonstrates one method of SPT treatment: Preoperative HAI chemotherapy with GEM, plus oral S-1 and TAE. If complete resection can be achieved, the majority of patients with SPT have a favorable prognosis. In patients with unresectable metastases from SPT, it is crucial to conduct systematic multimodal treatment to maximize treatment success. © 2015, Spandidos Publications. All Rights Reserved.<br />Embargo Period 6 months
続きを見る
|
||||
| 8.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 9.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 10.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 11.
論文 |
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
…
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.
続きを見る
|
||||
| 12.
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
概要:
Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) tha
…
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.
続きを見る
|
||||
| 13.
論文 |
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
…
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
|
||||
| 14.
論文 |
論文
|
Ooi, Akishi ; Inokuchi, Masafumi ; Harada, Shinichi ; Inazawa, Johji ; Tajiri, Ryousuke ; Sawada-Kitamura, Seiko ; Ikeda, Hiroko ; Kawashima, Hiroko ; Dobashi, Yoh
概要:
Oestrogen receptor-alpha (ERα), encoded by the ESR1 gene located on 6q25, is a nuclear transcription factor. Since it wa
…
s reported in 2007 that more than 20% of breast cancers show ESR1 gene amplification, there has been considerable controversy about its frequency and clinical significance. We set out to assess the frequency and levels of ESR1 amplification in breast cancers. In a total of 106 breast needle biopsy specimens examined by immunohistochemistry, 78 tumours contained more than 10% ERα-positive cancer cells. In fluorescence in situ hybridization (FISH) analysis with an ESR1-specific probe, variously extended ESR1 signals were found in ERα-expressing cells. Some of these were indistinguishable from large clustered signals generally accepted to mean high-level gene amplification in homogeneously staining regions (HSRs), and could be considered to represent gene amplification. However, with RNase treatment, the 'HSR-like' signals changed to small compact signals, and are thus thought to represent concentrated RNA. FISH using two differently labelled probes corresponding to the non-overlapping 5'- and 3'-end portions of the ESR1 gene on touch smears showed a preserved spatial relationship of the 3' to 5' sequence of ESR1, therefore strongly suggesting that the RNA consisted of primary transcripts. Using touch smears obtained from 51 fresh tumours, precise enumeration of ESR1 signals with a correction by the number of centromere 6 on FISH after RNase A treatment revealed that three tumours (5.9%) had tumour cells with one to three additional copies of ESR1 as predominant subpopulations. This infrequent and low level of gene amplification of ESR1 was also detected as a 'gain' of the gene by analysis with multiplex ligation-dependent probe amplification (MLPA). The consistent results from immunohistochemistry, FISH, and MLPA in the present study settle the long-standing debate concerning gene amplification of ESR1 in breast carcinoma. © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
続きを見る
|
||||
| 15.
論文 |
論文
|
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
…
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.
続きを見る
|
||||
| 16.
論文 |
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
…
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
|
||||
| 17.
論文 |
論文
|
Harada, Kenichi ; Shimoda, Shinji ; Kimura, Yasushi ; Sato, Yasunori ; Ikeda, Hiroko ; Igarashi, Saya ; Ren, Xiang-Shan ; Sato, Hirohide ; Nakanuma, Yasuni
概要:
IgG4 reactions consisting of marked infiltration by immunoglobulin G4 (IgG4)-positive plasma cells in affected organs is
…
found in cancer patients as well as patients with IgG4-related diseases. Notably, extrahepatic cholangiocarcinomas accompanying marked IgG4 reactions clinicopathologically mimic IgG4-related sclerosing cholangitis. The regulatory cytokine interleukin (IL)-10 is thought to induce the differentiation of IgG4-positive cells. In this study, to clarify the mechanism of the IgG4 reaction in extrahepatic cholangiocarcinoma, we investigated nonprofessional antigen-presenting cells (APCs) generating IL-10-producing regulatory T cells (anergy T cells) and Foxp3-positive regulatory cells producing IL-10. Immunohistochemistry targeting IgG4, HLA-DR, CD80, CD86, and Foxp3 was performed using 54 cholangiocarcinoma specimens from 24 patients with gallbladder cancer, 22 patients with common bile duct cancer, and eight patients with cancer of the Papilla of Vater. Moreover, a molecular analysis of Foxp3 and IL-10 was performed using a cultured human cholangiocarcinoma cell line. Consequently, 43% of the cholangiocarcinomas were found to be abundant in IgG4. Those expressing HLA-DR but lacking costimulatory molecules (CD80 and CD86) and those expressing Foxp3 detected by an antibody recognizing the N terminus accounted for 54% and 39% of cases, respectively. Moreover, the number of IgG4-positive cells was larger in these cases than in other groups. In cultured cells, the presence of a splicing variant of Foxp3 messenger RNA and the expression of IL-10 were demonstrated. Conclusion: Extrahepatic cholangiocarcinoma is often accompanied by significant infiltration of IgG4-positive cells. Cholangiocarcinoma cells could play the role of nonprofessional APCs and Foxp3-positive regulatory cells, inducing IgG4 reactions via the production of IL-10 indirectly and directly, respectively. © 2012 American Association for the Study of Liver Diseases.
続きを見る
|
||||
| 18.
論文 |
論文
|
Takeshita, Yumie ; Takamura, Toshinari ; Minato, Hiroshi ; Misu, Hirofumi ; Ando, Hitoshi ; Yamashita, Tatsuya ; Ikeda, Hiroko ; Nakanuma, Yasuni ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />金沢大学医薬保健研究域医学系恒常性制御学<br />Multiple liver metastases were incidentally detected in the lobe of the li
…
ver of an 81-year-old woman following total thyroidectomy and ablative radioactive iodine administration for the treatment of papillary thyroid carcinoma. A biopsy specimen taken from the metastatic liver tumor was histologically diagnosed as anaplastic carcinoma. Immunohistochemical staining for p53 was positive in both the primary tumor and liver biopsy specimens. We considered this to have been caused by anaplastic transformation from papillary thyroid carcinoma during treatment. We report a rare case of multiple liver metastases from a papillary thyroid carcinoma, which we believe to be the result of anaplastic transformation during postoperative radioactive iodine-131 therapy. © 2008 The Japanese Society of Internal Medicine.
続きを見る
|
||||
| 19.
論文 |
論文
|
Harada, Kenichi ; Hsu, Maylee ; Ikeda, Hiroko ; Zeniya, Mikio ; Nakanuma, Yasuni
概要:
BACKGROUND: We proposed a new grading and staging system for primary biliary cirrhosis (PBC), which takes into account t
…
he degree of both chronic cholangitis activity (CA) and hepatitic activity (HA) for grading disease activity and that of fibrosis, bile duct loss, and chronic cholestasis for staging. In this study, we validated our new system. METHODS: Using liver biopsy specimens from 166 cases of PBC, chronic cholangitis with mild periductal lymphoplasmacytic infiltration, including chronic nonsuppurative destructive cholangitis, and the combined activity of interface hepatitis and lobular hepatitis were categorized into 4 grades on the basis of their degree and distribution (CA0-3 and HA0-3, respectively). For staging, because orcein staining was not available in this study, 2 criteria (fibrosis and bile duct loss) were independently scored from 0 to 3 on the basis of their degrees, and a final stage score was created from the sum. RESULTS: Although there was a relatively uniform distribution of CA0/1/2/3 cases, the cases of HA0/1/2/3 were distributed as 21%, 64%, 13%, and 3%, respectively, with a prominent number of cases categorized as having none or mild HA. The distribution of stages 1 to 4 using our system was considerably different from that using the classic system and, importantly, showed a correlation with patient outcome. CONCLUSIONS: Our system revealed that the activities of chronic cholangitis and hepatitis did not correlate with each other in terms of degree and that our staging system properly reflected the outcome of PBC patients. The present study could validate the effectiveness of this new system for characterizing the pathologic condition of PBC. Copyright © 2013 by Lippincott Williams &Wilkins.
続きを見る
|
||||
| 20.
論文 |
論文
|
Tajiri, Ryosuke ; Ooi, Akishi ; Fujimura, Takashi ; Dobashi, Yoh ; Oyama, Takeru ; Nakamura, Ritsuko ; Ikeda, Hiroko
概要:
A humanized monoclonal antibody against ERBB2 is used in neoadjuvant therapy for patients with gastric cancer. A critica
…
l factor in determining patient eligibility and predicting outcomes of this therapy is the intratumoral heterogeneity of ERBB2 amplification in gastric adenocarcinomas. The aims of this study are to assess the underlying mechanisms of intratumoral heterogeneity of ERBB2 amplification; to characterize the diversity of coamplified oncogenes such as EGFR, FGFR2, MET, MYC, CCND1, and MDM2; and to examine the usefulness of multiple ligation-dependent probe amplification (MLPA) in the semicomprehensive detection of these gene amplifications. A combined analysis of immunohistochemistry and fluorescence in situ hybridization revealed ERBB2-amplified cancer cells in 51 of 475 formalin-fixed, paraffin-embedded gastric adenocarcinomas. The fraction of amplification-positive cells in each tumor ranged from less than 10% to almost 100%. Intratumoral heterogeneity of ERBB2 amplification, defined as less than 50% of cancer cells positive for ERBB2 amplification, was found in 41% (21/51) of ERBB2-amplified tumors. The combined analysis of MLPA and fluorescence in situ hybridization revealed that ERBB2 was coamplified with EGFR in 7 tumors, FGFR2 in 1 tumor, and FGFR2 and MET in 1 tumor; however, the respective genes were amplified in mutually exclusive cells. Coamplified ERBB2 and MYC coexisted within single nuclei in 4 tumors, and one of these cases had suspected coamplification in the same amplicon of ERBB2 with MYC. In conclusion, the amplification status of ERBB2 and other genes can be obtained semicomprehensively by MLPA and could be useful to plan individualized molecularly targeted therapy against gastric cancers. © 2014 Elsevier Inc.
続きを見る
|
||||
| 21.
論文 |
論文
|
Harada, Kenichi ; Sato, Yasunori ; Ikeda, Hiroko ; Hsu, Maylee ; Igarashi, Saya ; Nakanuma, Yasuni
概要:
Aims Biliary neuroendocrine tumours (NETs) are rare and mostly exist as a component of mixed adenoneuroendocrine carcinomas (MANECs). Although the NET component in biliary MANECs is generally more malignant and clinically more
…
important to the prognosis than the ordinary adenocarcinomatous component, the histogenesis of biliary NET has not been clarified. In this study, the role of the Notch1-Hes1 signalling axis in the histogenesis of biliary NETs was examined. Methods Immunohistochemistry for Notch1, its ligand Jagged1 and Hes1 was performed using surgical specimens from 11 patients with biliary MANEC. Moreover, after the knock-down of Notch1 mRNA expression in a cholangiocarcinoma cell line, the expression of chromogranin A (a neuroendocrine marker) and Ascl1 (a neuroendocrine-inducing molecule inhibited by activated Hes1) was examined by quantitative PCR. Results Histological examination revealed that the adenocarcinomatous components were predominately located at the luminal surface of the MANEC and the majority of stromal invasion involved NET components. Ordinary adenocarcinomas and non-neoplastic biliary epithelium constantly expressed Notch1, Jagged1 and Hes1, but the expression of Notch1 and Hes1 was decreased or absent in NET components, suggesting interference with the Notch1-Hes1 signalling axis in biliary NET. Moreover, in the cholangiocarcinoma cell line in which the expression of Notch1 mRNA was knocked down, the mRNA expression of Ascl1 and chromogranin A was increased. Conclusions The Notch1-Hes1 signalling axis suppresses neuroendocrine differentiation and maintains tubular/acinar features in adenocarcinoma and nonneoplastic epithelium in the biliary tree. Moreover, a disruption of this signalling axis may be associated with the tumourigenesis of NETs in biliary MANEC.
続きを見る
|
||||
| 22.
論文 |
論文
|
Ikeda, Hiroko ; Katayanagi, Kazuyoshi ; Kurumaya, Hiroshi ; Harada, Kenichi ; Sato, Yasunori ; Sasaki, Motoko ; Nakanuma, Yasuni
概要:
Hypereosinophilic syndrome (HES) is defi ned by elevation more than 1.5×109/L of presence of a peripheral blood count, e
…
vidence of organ involvement, and exclusion of secondary eosinophilia such as allergic, vasculitis, drugs, or parasite infection and also clonal eosinophilia. We present the HES case with hepatic involvement. The patient is 70-year-old male. He complained fever and back pain. Blood examination showed marked peripheral eosinophilia, elevation of transaminase and biliary enzymes. Multiple irregular mass lesions of the liver were pointed out by CT and MRI. The liver biopsy was done for differentiation from malignancy. In parenchyma, hepatic necrotic lesion was observed accompanying severe eosinophilic infi ltration with Charcot-Leyden’s crystals. There was granulomatous reaction. He was diagnosed as HES and got recovery due to steroid therapy. From the review of HES article, the hepatic histology is categorized into four types as below: 1) cholangitis type; 2) chronic active hepatitis type; 3) vasculopathic type, 4) hepatic necrosis type. Our case is classifi ed in hepatic necrosis type. This type seems to be important to distinguish malignant tumor and also visceral larva migrans by liver biopsy.
続きを見る
|
||||
| 23.
論文 |
論文
|
Oyama, Takeru ; Okamoto, Koichi ; Nakamura, Ritsuko ; Tajiri, Ryosuke ; Ikeda, Hiroko ; Ninomiya, Itasu ; Ooi, Akishi
概要:
EGFR and ERBB2 belong to the EGFR gene family. In esophageal squamous cell carcinomas (SCCs), amplification of EGFR or E
…
RBB2 is usually mutually exclusive. EGFR amplification occurs in approximately 15% of SCCs, ERBB2 occurs in less than 5%. Here, we report the co-amplification of EGFR and ERBB2 in an ulcerative and infiltrating-type SCC that measured approximately 4.2 × 2.7 × 1.2cm with a superficial lesion occurring in the thoracic esophagus of a 72-year-old man. Multiplex ligation-dependent probe amplification using representative tumor sections showed gain of CCND1 and coincident amplification of ERBB2 or EGFR or neither. Immunohistochemistry and fluorescence in situ hybridization revealed that the tumor comprised three cancer-cell populations: well-differentiated SCC with high-level ERBB2 amplification and ERBB2 overexpression, more infiltrative poorly-differentiated SCC with high-level EGFR amplification and EGFR overexpression, and poorly-differentiated SCC lacking any ERBB2 or EGFR abnormality. These three populations each had low-level CCND1 amplification and nuclear cyclin D1 overexpression. This histological topology and gene amplification combinations suggested that genetic instability first produced CCND1 amplification, and then ERBB2 or EGFR gene amplification occurred. It is further speculated that during cancer progression and clonal selection indecisive predominance of either clone caused the rare co-amplification of ERBB2 and EGFR in a single chimeric tumor. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.<br />発行後1年より全文公開
続きを見る
|
||||
| 24.
論文 |
論文
|
Ooi, Akishi ; Oyama, Takeru ; Nakamura, Ritsuko ; Tajiri, Ryousuke ; Ikeda, Hiroko ; Fushida, Sachio ; Nakamura, Hiroyuki ; Dobashi, Yoh
概要:
The prognosis of patients with gastric carcinomas at an advanced stage still remains dismal, and therefore novel therape
…
utic modalities are urgently needed. Since the successful targeting of amplified ERBB2 with a humanized monoclonal antibody, the amplified genes of other receptor tyrosine kinases such as EGFR, FGFR2, and MET, as well as those of other cell regulator genes, are being considered as candidate targets of molecular therapy. The aim of the present study was to determine the amplification status of 26 genes, which are frequently amplified in solid cancers, in advanced gastric cancers. A total of 93 formalin-fixed and paraffin-embedded advanced gastric cancer tissues were examined by multiple ligation-dependent probe amplification, and 32 cases with ‘gain’ or ‘amplified’ status of 16 genes were further examined for the respective gene amplification by fluorescence in situ hybridization (FISH) and for the respective protein overexpression by immunohistochemistry. The frequencies of gene amplifications in advanced gastric cancers were as follows: ERBB2 (13 cases, 14%), FGFR2 (7 cases, 8%), MYC (7 cases, 8%), TOP2A (7 cases, 8%), MET (4 cases, 4%), MDM2 (4 cases, 4%), CCND1 (3 cases, 3%), FGF10 (2 cases, 3%), and EGFR (1 case, 1%). Amplification of the receptor tyrosine kinases genes occurred in a mutually exclusive manner except for one tumor in which ERBB2 and FGFR2 were both amplified but in different cancer cells. Co-amplification of ERBB2 and MYC, and EGFR and CCND1, in single nuclei but on different amplicons, was confirmed in one case each. Attempts at correlating the FISH status with the immunohistochemical staining pattern showed variable results from complete concordance to no correlation. In conclusion, combination of multiple ligation-dependent probe amplification and FISH analysis is a feasible approach for obtaining the semi-comprehensive genetic information that is necessary for personalized molecular targeted therapy.Modern Pathology advance online publication, 6 March 2015; doi:10.1038/modpathol.2015.33.
続きを見る
|
||||
| 25.
論文 |
論文
|
Ooi, Akishi ; Oyama, Takeru ; Nakamura, Ritsuko ; Tajiri, Ryousuke ; Ikeda, Hiroko ; Fushida, Sachio ; Dobashi, Yoh
概要:
New and effective treatments for advanced gastric cancer are urgently needed. Cyclins E and D1 form a complex with cycli
…
n-dependent kinase 2, 4, or 6 to regulate G1-S transition. The G1-S regulatory genes encoding cyclin E (CCNE1), cyclin D1 (CCND1), and CDK6 (CDK6) are frequently amplified in gastric cancer and may therefore influence molecularly targeted therapies against ERBB2 or EGFR when coamplified. A total of 179 formalin-fixed and paraffin-embedded gastric cancer specimens were examined for these gene amplifications by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization. Amplification of at least 1 G1-S regulatory gene was found in 35 tumors (CCNE1 amplification, 15% of samples; CCND1, 6%; CDK6, 1%). In 13 of the 35 tumors, dual-color fluorescence in situ hybridization identified coamplification of the G1-S regulatory genes with ERBB2, EGFR, and/or KRAS in single cancer nuclei. The observation that cells with G1-S regulatory gene amplification contained clonal subpopulations with coamplification of ERBB2, EGFR, or KRAS in 5 early and 3 advanced cancers suggests that amplification of the G1-S regulatory genes represents an early event, which precedes ERBB2, EGFR, or KRAS amplification. Amplified CCNE1, CCND1, and CDK6 in advanced gastric cancer may be potentially useful as direct targets for molecular therapy or for combination therapy with ERBB2 or EGFR inhibitors. Multiplex ligation-dependent probe amplification could be a useful tool for identification of patients who would benefit from such therapies. © 2016 Elsevier Inc.<br />Embargo Period 12 months
続きを見る
|
||||
| 26.
論文 |
論文
|
Yamaguchi, Junpei ; Sasaki, Motoko ; Sato, Yasunori ; Itatsu, Keita ; Harada, Kenichi ; Zen, Yoh ; Ikeda, Hiroko ; Nimura, Yuji ; Nagino, Masato ; Nakanuma, Yasuni
概要:
医薬保健研究域医学系<br />Polycomb group protein EZH2, frequently overexpressed in malignant tumors, is the catalytic subunit of p
…
olycomb repressive complex 2 (PRC2). PRC2 interacts with HDACs in transcriptional silencing and relates to tumor suppressor loss. We examined the expression of HDAC isoforms (HDAC 1 and 2) and EZH2, and evaluated the possible use of HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and EZH2 repressor for gallbladder carcinoma. We used 48 surgically resected gallbladders and cultures of human gallbladder epithelial cells (HGECs), gallbladder carcinoma (TGBC2TKB), and cholangiocarcinoma (HuCCT-1 and TFK-1) cell lines for examination. Immunohistochemically, EZH2 was overexpressed in gallbladder carcinoma, especially poorly differentiated carcinoma, but not in normal epithelium. In contrast, HDAC1/2 were expressed in both carcinoma and normal epithelium in vivo. This pattern was verified in cultured cells; EZH2 was highly expressed only in TGBC2TKB, whereas HDAC1/2 were expressed in HGECs and TGBC2TKB. Interestingly, SAHA treatment caused significant cell number decline in three carcinoma cells, and this effect was synergized with EZH2 siRNA treatment; however, HGECs were resistant to SAHA. In TGBC2TKB cells, the expression of EZH2 and HDAC1/2 were decreased by SAHA treatment, and p16INK4a, E-cadherin, and p21were simultaneously activated; however, no such findings were obtained in HGECs, suggesting that the effect of SAHA depends on the EZH2-mediated tumor suppressor loss. In conclusion, this study suggests a possible mechanism by which carcinoma cells but not normal cells are sensitive to SAHA and indicates the efficacy of this new anticancer agent in combination with EZH2 repression in gallbladder carcinoma. © 2009 Japanese Cancer Association.
続きを見る
|
||||
| 27.
論文 |
論文
|
Harada, Kenichi ; Kakuda, Yuko ; Sato, Yasunori ; Ikeda, Hiroko ; Nakanuma, Yasuni
概要:
Aims Oestrogen has been speculated to play an important role in the pathogenesis of primary biliary cirrhosis (PBC), whi
…
ch mainly affects middle-aged and old-aged females because biliary epithelial cells (BECs) are known to express oestrogen receptors (ERs). Oestrogen-related receptors (ERRs) are constitutively active without oestrogen and competitively inhibit the ER-dependent effects of oestrogen. We clarified the effects of oestrogen and the significance of ERRs along with their association with the pathogenesis of cholangiopathy in PBC. Methods We investigated the expression of ERs and ERRs and the apoptosis-related cell kinetics in BECs using cultured human BECs and human liver specimens. Results Although cultured human BECs and the interlobular bile ducts in the liver expressed ERβ, in cultured BECs, oestrogen treatment did not induce significant cell proliferation but increased the expression of a negative cell proliferation regulator (14-3-3σ protein). The cultured BECs constantly expressed ERRα and ERβ, and oestrogen downregulated the ERRγ expression. Furthermore, the ERβ expression was determined in the intrahepatic bile ducts and was stronger in the middle-aged and old-aged females, particularly those with PBC, than in the younger females. The ERβ ligand activated a transcription factor, SP1, and enhanced the expression of the pro-apoptotic Bcl-2 family molecules and Bcl-2 inhibitor-induced apoptosis in cultured BECs. Conclusions Although oestrogen downregulates the ERRγ expression, the increased ERRγ expression under oestrogen-deficient conditions increases the susceptibility to Bcl-2 family-mediated apoptosis in cultured human BECs of females, particularly those with PBC. Understanding the oestrogen-mediated cell kinetics is important for elucidating the pathogenesis of cholangiopathy in PBC. © 2014 by the BMJ Publishing Group Ltd & Association of Clinical Pathologists.
続きを見る
|
||||
| 28.
論文 |
論文
|
Harada, Kenichi ; Kakuda, Yuko ; Sato, Yasunori ; Ikeda, Hiroko ; Shimoda, Shinji ; Yamamoto, Yasuhiko ; Inoue, Hiroshi ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Nakanuma, Yasuni
概要:
Aim: Primary biliary cirrhosis (PBC) is characterised by antimitochondrial antibody against the pyruvate dehydrogenase c
…
omplex (PDC) and chronic nonsuppurative destructive cholangitis (CNSDC). Pyruvate oxidation to acetyl-CoA by PDC is a key step in the glycolytic system. Oestrogen-related receptor-α (ERRa) is functionally activated by inducible coactivators such as peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and Bcl-3. Moreover, the PGC-1α-ERRa axis interrupts glycolytic metabolism through the upregulation of pyruvate dehydrogenase kinase, isozyme 4 (PDK4), which functionally inhibits PDC-E1α and stimulates fatty acid oxidation. In this study, we investigated the PGC-1α-ERRa axis to clarify PDC dysfunction in CNSDC of PBC. Methods: The expression of PGC-1α, Bcl-3, ERRa, PDK4 and PDC-E1α was examined by immunohistochemistry in liver sections from patients with PBC and controls. The expression of these molecules, the activity of mitochondrial dehydrogenase and PDC, and their alterations by starvation, a treatment used to induce PGC-1α expression, were examined in cultured human biliary epithelial cells (BECs). Results: The nuclear expression of PGC-1α, Bcl-3 and ERRa was exclusively observed in CNSDC of PBC. Moreover, the expression of PDK4 and PDC-E1α was enhanced in CNSDC of PBC. In cultured BECs, the amplification of Bcl-3 and PDK4 mRNAs by reversetranscription-PCR and mitochondrial dehydrogenase activity were markedly increased but PDC activity was decreased according to the upregulation of PGC-1α. Conclusions: In CNSDC of PBC, the activation of the ERRa-PGC-1α axis was exclusively observed, suggesting the interference of PDC-related glycolytic function and the induction of the fatty acid degradation system. The switching of the cellular energy system is possibly associated with the pathogenesis of CNSDC in PBC.
続きを見る
|
||||
| 29.
論文 |
論文
|
Matsumoto, Isao ; Oda, Makoto ; Takizawa, Masaya ; Waseda, Ryuichi ; Nakajima, Kenichi ; Kawano, Masaya ; Mochizuki, Takafumi ; Ikeda, Hiroko ; Watanabe, Go
概要:
Background: This study investigated the usefulness of fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-P
…
ET) during the treatment of thymic epithelial tumors in combination with Ki-67 evaluation based on surgical cases in our department. Methods: Between November 2003 and May 2011, 39 patients with thymic epithelial tumor underwent preoperative FDG-PET. The maximum standardized uptake value (SUVmax) of each category within Masaoka stage, World Health Organization classification, tumor diameter, myasthenia gravis, and Ki-67 label index were compared. To examine risk factors for relapse, SUVmax, age, sex, and surgical radicality were investigated in addition to those items. Results: The mean SUVmax was 4.5 (range, 1.2 to 14.6) and was significantly higher for Masaoka stage IV than for I and II (all p < 0.008) and for World Health Organization classified thymic cancer compared with all other types (all p < 0.0001). Mean SUVmax revealed significantly higher values for large tumors than for small tumors (p = 0.02). Mean SUVmax was significantly higher for high Ki-67-positive samples (p = 0.0004), indicating a strong correlation between SUVmax and the Ki-67 label index (ρ = 0.77, p = 0.0001). SUVmax accurately reflected therapeutic efficacy in patients with induction therapy. Univariate analysis revealed Masaoka stages III and IV and pathologically incomplete resection as risk factors for relapse. On multivariate analysis, independent risk factors for relapse comprised only Masaoka stages III and IV. Conclusions: FDG-PET SUVmax does reflect proliferation and invasiveness of thymic epithelial tumors and can provide an index for diagnosis and treatment, although it is not a risk factor for relapse. FDG-PET is also useful for evaluating induction therapy efficacy and detecting relapse. © 2013 The Society of Thoracic Surgeons.
続きを見る
|
||||
| 30.
論文 |
論文
|
Ohtsubo, Koushiro ; Watanabe, Hiroyuki ; Yamada, Tadaaki ; Tsuchiyama, Tomoya ; Mouri, Hisatsugu ; Yamashita, Kaname ; Yasumoto, Kazuo ; Ikeda, Hiroko ; Nakanuma, Yasuni ; Yano, Seiji
概要:
金沢大学医学部附属病院がん高度先進治療センター<br />We report a 47-year-old man with cancer of unknown primary site in whom pancreatic cancer w
…
as confirmed at autopsy. Although a primary lesion was not confirmed, we planned to perform tumor marker-oriented chemotherapy because pancreatic cancer was suspected as the primary lesion based on tumor markers and pathological findings from metastatic lymph node. Neither S-1 nor gemcitabine was effective. However, gemcitabine combined with low-dose cisplatin therapy resulted in a marked decrease in the size of tumors. Microscopic examination at autopsy revealed poorly differentiated adenocarcinoma in the pancreatic head, although a pancreatic mass was not clear macroscopically. © 2009 The Japanese Society of Internal Medicine.
続きを見る
|
||||
| 31.
論文 |
論文
|
Zeng, Sha Sha ; Yamashita, Taro ; Kondo, Mitsumasa ; Nio, Kouki ; Hayashi, Takehiro ; Hara, Yasumasa ; Nomura, Yoshimoto ; Yoshida, Mariko ; Hayashi, Tomoyuki ; Oishi, Naoki ; Ikeda, Hiroko ; Honda, Masao ; Kaneko, Shuichi
概要:
Background & Aims: Recent evidence suggests that hepatocellular carcinoma can be classified into certain molecular subty
…
pes with distinct prognoses based on the stem/maturational status of the tumor. We investigated the transcription program deregulated in hepatocellular carcinomas with stem cell features. Methods: Gene and protein expression profiles were obtained from 238 (analyzed by microarray), 144 (analyzed by immunohistochemistry), and 61 (analyzed by qRT-PCR) hepatocellular carcinoma cases. Activation/suppression of an identified transcription factor was used to evaluate its role in cell lines. The relationship of the transcription factor and prognosis was statistically examined. Results: The transcription factor SALL4, known to regulate stemness in embryonic and hematopoietic stem cells, was found to be activated in a hepatocellular carcinoma subtype with stem cell features. SALL4-positive hepatocellular carcinoma patients were associated with high values of serum alpha fetoprotein, high frequency of hepatitis B virus infection, and poor prognosis after surgery compared with SALL4-negative patients. Activation of SALL4 enhanced spheroid formation and invasion capacities, key characteristics of cancer stem cells, and up-regulated the hepatic stem cell markers KRT19, EPCAM, and CD44 in cell lines. Knockdown of SALL4 resulted in the down-regulation of these stem cell markers, together with attenuation of the invasion capacity. The SALL4 expression status was associated with histone deacetylase activity in cell lines, and the histone deacetylase inhibitor successfully suppressed proliferation of SALL4-positive hepatocellular carcinoma cells. Conclusions: SALL4 is a valuable biomarker and therapeutic target for the diagnosis and treatment of hepatocellular carcinoma with stem cell features. © 2013 European Association for the Study of the Liver.
続きを見る
|
||||
| 32.
論文 |
論文
|
池田, 博子 ; Ikeda, Hiroko
概要:
ラットやマウスなどの動物研究ではDelta-like protein(DLK)-1が肝プロジェニター/ステム細胞に発現していると報告されており,一方で肝線維化に関連することが知られている肝星細胞でのDLK1発現が文献的に報告されている.ヒト
…
肝組織におけるDLK1発現を分子病理学的に解析した.その結果, DLK1はステム細胞関連と推察される腫瘍で発現しており, DLK1が肝癌ステム細胞のマーカーとなりうる分子であることを解明した.<br />The expression of Delta-like protein(DLK)-1 in hepatic progenitor/stem cell has been known in animal experiments, whereas the upregulation of DLK1 in hepatic stellate cells has been reported and implied relation to fibrosis. I examined the expression of DLK1 in human tissue. As results, The expression of DLK1 was demonstrated in liver cancer associated with stem-cell origin. It was suggested that DLK1 could be cancer stem-cell marker of the liver.<br />研究課題/領域番号:22790341, 研究期間(年度):2010-2011
続きを見る
|
||||
| 33.
論文 |
論文
|
池田, 博子 ; Ikeda, Hiroko
概要:
細胞老化は不可逆的な細胞周期の停止として定義されており、前癌病変におけるセネッセンス細胞の出現およびセネッセンスからの回避機序は腫瘍発生初期段階での重要なステップであると考えられている。分子病理学的に検討の結果、ヒト肝組織では肝硬変でセネッ
…
センス関連マーカー発現細胞が出現し、肝ディスプラジア結節では消失していた。肝硬変は肝細胞癌の前癌病変である可能性が示唆された。<br />Cellular senescence is defined as the irreversible arrest of cell cycle. Senescence in premalignant lesion and escape from senescence are thought to be important the early stage of tumoriogenesis. Senescence-associated markers are observed in cirrhotic liver and the markers disappear in dysplastic nodules. The results imply that the cirrhotic state already might to be premalignancy.
続きを見る
|
