Papers - TAKADA Kouichi

C型肝炎からの肝発癌における酸化的DNA損傷修復系遺伝子群の検討

宮西 浩嗣, 加藤 淳二, 小船 雅義, 河野 豊, 高橋 祥, 高田 弘一, 石渡 裕俊, 林 毅, 佐藤 康史, 新津 洋司郎

肝臓 ( (一社)日本肝臓学会 )  48 ( Suppl.1 ) A68 - A68  2007.04  [Refereed]

[A case of primary carcinoma of the cystic duct with limy bile].

Sho Takahashi, Hisato Homma, Takehide Akiyama, Shinichi Mesawa, Kazuhiko Koike, Kenichiro Hirata, Katsuhisa Kogawa, Yutaka Kawano, Kohichi Takada, Tsutomu Sato, Yoshiro Niitsu

Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology ( 3 )  104 ( 3 ) 394 - 400  2007.03  [Refereed]  [Domestic journal]

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A 78-year-old man had been admitted to a previous hospital because of epigastralgia and a diagnosis of cholecystolithiasis had been made. He had been transferred to our institution for further examination. CT scan and US revealed chronic cholecystitis and gallstone, however, ERC revealed severe obstruction of the cystic duct and EUS revealed dilation of that duct and a solitary mass there. Carcinoma of the cystic duct was diagnosed, and we performed cholecystectomy and resection of the extrahepatic duct with two-field lymphadenectomy. The pathological specimen showed a round flat elevated mass localized in the cystic duct. Histopathologically, the diagnosis was well differentiated tubular adenocarcinoma of the cystic duct with limy bile and tiny gallstone.

DOI PubMed

Hepatitis C virus core protein promotes proliferation of human hepatoma cells through enhancement of transforming growth factor alpha expression via activation of nuclear factor-kappa B

Y. Sato, J. Kato, R. Takimoto, K. Takada, Y. Kawano, K. Miyanishi, M. Kobune, Y. Sato, T. Takayama, T. Matunaga, Y. Niitsu

GUT ( B M J PUBLISHING GROUP )  55 ( 12 ) 1801 - 1808  2006.12  [Refereed]

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Background: Hepatitis C virus (HCV) infection is a major cause of human hepatocellular carcinoma (HCC). The precise mechanism of hepatocarcinogenesis in humans by HCV is currently unclear. It was recently shown, however, that transgenic mice with the HCV core gene often develop HCC, suggesting tumorigenic activity of the HCV core protein. Further, the HCV core protein expressed in HepG2 cells transfected with the core gene was shown to stimulate proliferation of transfectants through activation of nuclear factor-kappa B (NF-kappa B). The downstream target molecule(s) of NF-kappa B activated by the HCV core protein to evoke cell proliferation is not yet identified. Transforming growth factor (TGF)alpha, which is often overexpressed in various tumour tissues such as HCC, has been shown to stimulate hepatocyte proliferation through activation of the mitogen-activated protein kinase or extracellular signal-related protein kinase (MAPK/ERK) cascade. Aims: To explore the possibility that TGF alpha might be a target molecule for NF-kB activated by the HCV core, and that TGFa participates in the growth promotion of the core transfectants in an autocrine manner, activating the MAPK/ERK pathway. Methods: A HCV core expression vector was transfected into human hepatoma Huh-7, HepG2 and Hep3B cells. NF-kappa B activity was examined by an electrophoretic mobility shift assay. TGFa transcription was assessed by a luciferase reporter assay. TGF alpha protein was determined by immunoblot and ELISA. MAPK/ERK activity was examined by an in vitro kinase assay. Cell proliferation was assessed by a water-soluble tetrazolium salt-1 assay. Results: In the HCV core transfectants, NF-kappa B bound to the kappa B site in the TGFa proximal promoter region, resulting in an increase in TGF alpha transcription. Immunoblot as well as ELISA showed increased TGF alpha expression in the HCV core transfectants. SN50, a specific inhibitory peptide for NF-kappa B, cancelled HCV core-induced TGF alpha expression. HCV core protein increased cell proliferation as well as ERK activity of the HCV core transfectants as compared with the mock transfectants. The growth-promoting activity and activation of ERK by the HCV core protein were negated by treatment with anti-TGF alpha antibodies. Conclusions: These results suggest that the HCV core protein promotes proliferation of human hepatoma cells by activation of the MAPK/ERK pathway through up regulation of TGF alpha transcription via activation of NF-kappa B. Our finding provides a new insight into the mechanism of hepatocarcinogenesis by HCV infection.

DOI

多血性胆管細胞癌の2例

高田 弘一, 高橋 究, 高山 哲治, 山口 正人, 早坂 亨子, 太田 由紀子, 鎌形 千夏, 高橋 祥, 河野 豊, 石渡 裕俊, 加藤 淳二, 名取 博, 新津 洋司郎, 水口 徹, 桂巻 正, 尾松 睦子, 長谷川 匡

超音波医学 ( (公社)日本超音波医学会 )  33 ( 6 ) 699 - 700  2006.11  [Refereed]

硬変肝に発生しFNH様の画像所見を呈した多血性結節の1例

高橋 祥, 宮西 浩嗣, 河野 豊, 高田 弘一, 庵原 秀之, 石渡 裕俊, 林 毅, 佐藤 康史, 加藤 淳二, 新津 洋司郎, 尾松 睦子, 長谷川 匡

肝臓 ( (一社)日本肝臓学会 )  47 ( Suppl.3 ) 614 - 614  2006.11  [Refereed]

アルコール性および非アルコール性脂肪性肝炎における鉄代謝異常の解析および酸化的DNA障害の検討

高田 弘一, 加藤 淳二, 河野 豊, 高橋 祥, 奥田 敏徳, 小船 雅義, 瀧本 理修, 宮西 浩嗣, 新津 洋司郎

アルコールと医学生物学 ( (株)響文社 )  26   91 - 95  2006.09  [Refereed]

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アルコール性脂肪性肝炎(ASH)および非アルコール性脂肪性肝炎(NASH)患者の鉄吸収動態や肝への鉄沈着の程度、さらに酸化的DNA傷害について解析した。肝生検を施行し、組織学的に診断したASH 5例、NASH 23例を対象とした。ASHおよびNASHでは正常人に比べ血清フェリチンおよび%トランスフェリン飽和度が高値であった。肝への鉄沈着はASHおよびNASH両者で確認し、NASHの症例において肝への鉄沈着が高い傾向を認めた。8-OH-dGレベルもASHおよびNASHで増加し、ASHと比較してNASHの方が有意に増加した。除鉄療法により、血清フェリチンおよびHbは有意に低下し、ALTも低下した。IV型コラーゲンも低下した。除鉄療法を48週間施行した後、肝生検を行い組織学的にも治療効果判定を行った。Necro-Inflammationの改善が得られたが、Fibrosisの改善は得られなかった。

酸化ストレスと肝疾患 C型慢性肝炎おける鉄代謝異常の発生機序の検討

宮西 浩嗣, 加藤 淳二, 河野 豊, 小船 雅義, 高田 弘一, 藤川 幸司, 奥田 敏徳, 石渡 裕俊, 林 毅, 佐藤 康史, 新津 洋司郎

肝臓 ( (一社)日本肝臓学会 )  47 ( Suppl.1 ) A45 - A45  2006.04  [Refereed]

肝線維化の分子機構と治療 肝星細胞のコラーゲン特異シャペロンHSP47を標的とした肝線維化抑制療法

村瀬 和幸, 加藤 淳二, 佐藤 康史, 小船 雅義, 瀧本 理修, 高田 弘一, 河野 豊, 佐藤 勉, 宮西 浩嗣, 荒木 啓伸, 新津 洋司郎

肝臓 ( (一社)日本肝臓学会 )  47 ( Suppl.1 ) A38 - A38  2006.04  [Refereed]

高度進行肝細胞癌に対する5-FUとCDDPを用いた肝動注化学療法の成績

奥田 敏徳, 宮西 浩嗣, 高田 弘一, 河野 豊, 石渡 裕俊, 林 毅, 佐藤 康史, 高橋 稔, 加藤 淳二, 新津 洋司郎

肝臓 ( (一社)日本肝臓学会 )  47 ( Suppl.1 ) A184 - A184  2006.04  [Refereed]

StageIV膵癌に対するGemcitabineを中心とした多剤併用動注化学療法の治療成績

石渡 裕俊, 林 毅, 宮西 浩嗣, 奥田 敏徳, 河野 豊, 高田 弘一, 新津 洋司郎

日本消化器病学会雑誌 ( (一財)日本消化器病学会 )  103 ( 臨増総会 ) A193 - A193  2006.03  [Refereed]

Ex vivo expansion of G-CSF-mobilized peripheral blood CD133(+) progenitor cells on coculture with human stromal cells

Y Kawano, M Kobune, H Chiba, K Nakamura, R Takimoto, K Takada, Y Ito, J Kato, H Hamada, Y Niitsu

EXPERIMENTAL HEMATOLOGY ( ELSEVIER SCIENCE INC )  34 ( 2 ) 150 - 158  2006.02  [Refereed]

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Objective. The pentaspan molecule CD133 has been shown to be a marker of more primitive hematopoietic progenitors in mobilized peripheral blood (PB). Our objective was to assess the efficacy of PB CD133(+) cells in our coculture system using human telomerized stromal (HTS) cells. Methods. Five thousand PB CD133(+) cells or conventional cord blood (CB) CD34(+) cells were expanded with or without HTS cells in the presence or absence of stem cell factor, thrombopoietin, and Flk-2/Flt-3 ligand. Results. The coculture was significantly superior in expanding PB clonogenic cells as compared with the stroma-free culture (CFU-C, 2 +/- 0 vs 111 +/- 15-fold of initial cell number p < 0.01), and the fold increase of PB clonogenic cells was comparable to that for CB cells after two weeks of coculture (BFU-E, 54 +/- 3 vs 56 +/- 4-fold; CFU-GM, 156 +/- 26 vs 83 +/- 9-fold; CFU-Mix, 30 +/- 11 vs 80 +/- 36-fold). However, proliferation of CFU-Mk from PB on coculture with HTS cells was modest as compared with stroma-free culture. Concomitantly, multiple hematopoietic cells transmigrated below the stromal layer and formed cobblestone areas (CAs). The production of hematopoietic progenitor cells from CAs after coculture with PB was significantly lower than that seen in cells cocultured with CB for four weeks (CFU-Mix, 0 +/- 0 vs 9 +/- 5-fold on day 28, p < 0.01), although a similar number of CAs derived from PB and CB were observed. Conclusion. PB CD133(+) cells proliferated efficiently above the stromal layer, while the characteristics of PB CD133(+) cells underneath the human stromal layer were likely to be maintained, even after long-term hematopoietic-stromal interaction. (C) 2006 International Society for Experimental Hematology. Published by Elsevier Inc.

DOI PubMed

Stage IV膵癌に対する動注化学療法の治療成績

林 毅, 石渡 裕俊, 奥田 敏徳, 河野 豊, 高田 弘一, 宮西 浩嗣, 加藤 淳二, 新津 洋司郎

日本内科学会雑誌 ( (一社)日本内科学会 )  95 ( Suppl. ) 128 - 128  2006.02  [Refereed]

Human Herpesvirus-6 Hepatitis Associated with Cyclosporine-A Encephalitis after Bone Marrow Transplantation for Chronic Myeloid Leukemia

Kuribayashi Kageaki, Matsunaga Takuya, Iyama Satoshi, Takada Koichi, Sato Tsutomu, Murase Kazuyuki, Fujimi Akihito, Takimoto Rishu, Kawanishi Johji, Niitsu Yoshiro

Japanese Journal of Medicine ( The Japanese Society of Internal Medicine )  45 ( 7 ) 475 - 478  2006

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A 31-year-old man referred to our hospital for treatment of his chronic myeloid leukemia (CML) in the first chronic phase by bone marrow transplantation. We pretreated him with cyclophosphamide and total body irradiation and bone marrow transplantation (BMT) was carried out. On day 31, the engraftment was confirmed and on day 52, acute graft versus host disease (GVHD) was observed. On day 189, he lost consciousness due to cyclosporine A-induced leukoencephalopathy and 375 mg cyclosporine A was changed to 100 mg prednisolone. On day 199, liver dysfunction (AST 410 IU/L, ALT 557 IU/L, γGTP 385 IU/L, ALP 363 IU/L, D-Bil 0.3 mg/dl) developed and a liver biopsy was performed. PCR analysis of DNA from the liver biopsy specimen was positive for HHV-6 and immunostaining using anti-HHV-6 and anti-HHV-6b antibodies showed positive staining in the cytosol of hepatocytes. No other viruses were found to induce hepatitis. From these results, he was diagnosed as having HHV-6 hepatitis and it was successfully treated with gancyclovir (GCV) administration.


DOI CiNii

NASHにおける鉄代謝異常の解析と除鉄療法の有用性の検討

高田 弘一, 加藤 淳二, 宮西 浩嗣, 奥田 敏徳, 河野 豊, 高梨 訓博, 石渡 裕俊, 新津 洋司郎, 池田 健

肝臓 ( (一社)日本肝臓学会 )  46 ( Suppl.1 ) A45 - A45  2005.05  [Refereed]

A case of signet ring cell carcinoma of the stomach discovered by abdominal wall metastasis

Kunihiro Takanashi, Yoshimitsu Onodera, Shigeyuki Fujii, Yoshiki Nishibori, Norihiro Takayanagi, Shinya Minami, Takahiro Kogawa, Hiroyuki Nagashima, Seiichiro Abe, Yasuhiro Nagaoka, Masayoshi Horimoto, Kohichi Takada, Yasushi Sato, Yoshiro Niitsu

Japanese Journal of Gastroenterology ( 4 )  102 ( 4 ) 459 - 465  2005.04  [Refereed]

PubMed

Augmentation of antitumor effects of p53 gene therapy by combination with HDAC inhibitor

R Takimoto, J Kato, T Terui, K Takada, G Kuroiwa, J Wu, H Ohnuma, D Takahari, M Kobune, Y Sato, T Takayama, T Matsunaga, Y Niitsu

CANCER BIOLOGY & THERAPY ( LANDES BIOSCIENCE )  4 ( 4 ) 421 - 428  2005.04  [Refereed]

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We have previously shown that the HDAC inhibitors (HDACl) activate the p53 molecule through acetylation of 320 and 373 lysine residues, upregulate PIG3 and NOXA and induce apoptosis in cancer cells expressing wild and pseudo-wild type p53 genes (Terui T, et al. Cancer Res 2003; 63:8948-54). It has also been reported that expression of the Coxackie adenovirus receptor and subsequent transfection efficiency of the adenovirus in cancer cells were enhanced by HDACl treatment. In this study, we extended these observations to explore the combination effect of adenoviral vector carrying wild type p53 (Ad-p53) gene therapy with a HDACl, sodium butyrate (SIB), on xenografted human gastric cancer cells (KATO-III) and hepatocellular carcinoma cells (HuH7) in nude mice. We first confirmed an increased expression of Coxackie adenovirus receptors with an associated increment of transgene (X-gal) expression by SB treatment in KATO-III cells. We then injected Ad-p53 into subcutaneous tumors of KATO-III and HuH7 combined with intraperitoneal administration of SB and found a significantly higher growth suppressive effect than single treatments of each. Even a complete regression of tumors was observed in three of five mice treated with this combination while with single treatment no tumor regression was observed. Tumors treated with the combination showed higher numbers of TUNEL positive cells than those treated with a single modality. Moreover, necrotic changes were more evident in tumors treated with the combination than separately, a compatible finding to the observation that vascularity revealed by CD34 staining was poorer in tumors treated with the combination than those treated with p53 gene or SB alone. This was further supported by the finding that BAI-1 (brain specific angiogenesis inihibitor-1), an inhibitor of vascularization, was induced by SB treatment in KATO-III and HuH7 cells transfected with Ad-p53. Thus SB was shown to be an efficient potentiator of p53 gene therapy for cancer.

PubMed

[A case of metastatic liver tumor from colorectal carcinoma--continued arterial infusion chemotherapy through a microcatheter located in replaced right hepatic artery].

Takanashi K, Takahashi M, Miyanishi K, Hayashi T, Takada K, Oku T, Ishiwatari H, Kogawa T, Takayama T, Kato J, Niitsu Y

Gan to kagaku ryoho. Cancer & chemotherapy ( 9 )  31   1415 - 1417  2004.09  [Refereed]

PubMed

Interleukin-11 as an osteoprotegerin-inducing factor in culture medium of blastic cells from a patient with acute megakaryocytic leukemia complicated with osteosclerosis

T Sato, T Matsunaga, M Kida, K Morii, T Machida, Y Kawano, K Nakamura, K Kuribayashi, K Takada, S Iyama, Y Sato, T Takayama, M Takahashi, J Kato, M Chokki, Y Niitsu

AMERICAN JOURNAL OF HEMATOLOGY ( WILEY-LISS )  77 ( 1 ) 62 - 66  2004.09  [Refereed]

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We came across a rare case of acute megalkaryocytic leukemia, the clinical course of which was relatively chronic and nonaggressive. This case was complicated with generalized severe osteosclerosis (OS). The medium in which blastic cells from the patient were cultured showed a strong activity to enhance the expression of an osteosclerotic cytokine, osteoprotegerin (OPG), as revealed by real-time quantitative RT-PCR and Western blot analysis. The OPG-inducing activity of the culture medium was neutralized by the anti-interieukin-11 (IL-11) antibody. These results indicate that IL-11 produced by the blasts was a causative factor of the OS observed in this patient. (C) 2004 Wiley-Liss, Inc.

DOI PubMed

A comparative randomized trial of intermittent intrahepatic arterial carboplatin- versus doxorubicin-lipiodol emulsion in advanced hepatocellular carcinoma (stage IV)

H Homma, S Mezawa, T Doi, K Miyanishi, K Takada, T Kukitsu, T Oku, E Masuko, S Nojiri, Y Niitsu

HEPATO-GASTROENTEROLOGY ( H G E UPDATE MEDICAL PUBLISHING S A )  51 ( 58 ) 1135 - 1139  2004.07  [Refereed]

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Background/Aims: The study was performed to investigate the anti-tumor effect, survival rate, and toxicity of intermittent intrahepatic infusion chemotherapy with carboplatin suspended in lipiodol. Methodology: We conducted a randomized controlled study containing either doxorubicin or carboplatin in 65 patients with advanced hepatocellular carcinoma. Results: The results observed in the carboplatin- and doxorubicin-lipiodol groups included: response rates, 29.0 and 20.6% respectively, 1-year survival rates of, 60.4% and 40.4%, respectively, and the difference achieved statistical significance (p=0.025). The median survival of 31 patients who received carboplatin emulsified with lipiodol was 16.9 months, 34 patients who received doxorubicin was 12.1 months. The difference achieved statistical significance. Conclusions: Compared with doxorubicin, carboplatin caused neither cardiotoxicity nor nephrotoxicity, and side effects of nausea and vomiting were less severe. Therefore, carboplatin is effective and preferable for repeated intrahepatic arterial administration to treat advanced hepatocellular carcinoma over a relatively long period.

PubMed

Fas-mediated apoptosome formation is dependent on reactive oxygen species derived from mitochondrial permeability transition in Jurkat cells

T Sato, T Machida, S Takahashi, S Iyama, Y Sato, K Kuribayashi, K Takada, T Oku, Y Kawano, T Okamoto, R Takimoto, T Matsunaga, T Takayama, M Takahashi, J Kato, Y Niitsu

JOURNAL OF IMMUNOLOGY ( AMER ASSOC IMMUNOLOGISTS )  173 ( 1 ) 285 - 296  2004.07  [Refereed]

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Generation of reactive oxygen species (ROS) and activation of caspase cascade are both indispensable in Fas-mediated apoptotic signaling. Although ROS was presumed to affect the activity of the caspase cascade on the basis of findings that antioxidants inhibited the activation of caspases and that the stimulation of ROS by itself activated caspases, the mechanism by which these cellular events are integrated in Fas signaling is presently unclear. In this study, using human T cell leukemia Jurkat cells as well as an in vitro reconstitution system, we demonstrate that ROS are required for the formation of apoptosome. We first showed that ROS derived from mitochondrial permeability transition positively regulated the apoptotic events downstream of mitochondrial permeability transition. Then, we revealed that apoptosome formation in Fas-stimulated Jurkat cells was clearly inhibited by N-acetyl-L-cysteine and manganese superoxide dismutase by using both the immunoprecipitation and size-exclusion chromatography methods. To confirm these in vivo findings, we next used an in vitro reconstitution system in which in vitro-translated apoptotic protease-activating factor 1 (Apaf-1), procaspase-9, and cytochrome c purified from human placenta were activated by dATP to form apoptosome; the formation of apoptosome was markedly inhibited by reducing reagents such as DTT or reduced glutathione (GSH), whereas hydrogen peroxide prevented this inhibition. We also found that apoptosome formation was substantially impaired by GSH-pretreated Apaf-1, but not GSH-pretreated procaspase-9 or GSH-pretreated cytochrome c. Collectively, these results suggest that ROS plays an essential role in apoptosome formation by oxidizing Apaf-1 and the subsequent activation of caspase-9 and -3.

PubMed