2011 Fiscal Year Annual Research Report
ヒトの肝臓を主座とする遺伝性疾患を有するマウスモデルの創生
Project/Area Number |
22659147
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Research Institution | Hiroshima University |
Principal Investigator |
茶山 一彰 広島大学, 大学院・医歯薬学総合研究科, 教授 (00211376)
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Keywords | 肝臓学 / ノックアウトマウス / トランスジェニックマウス / 不死化肝細胞 |
Research Abstract |
ヒトの遺伝性疾患は、ノックアウトマウスなどを使用して研究されていることが多い。しかし、マウスとヒトの病態は必ずしも同一ではなく、また、マウスで耐性致死であるために良好なモデルが作製できない場合も多い。また、ノックアウトマウスは作製に多大な時間と人手を要するため、わずかの違いを有するマウスを作製するのにも再度全く同じ手間を要する。本研究では、培養ヒト肝細胞に遺伝子導入することにより、ヒトの疾患と同様の状態の肝細胞を作製し、この細胞をuPA-scid mouseに移植することにより、遺伝病状態のヒト肝臓を有するマウスを作製することを目的として研究を行った。このマウスに、遺伝病の遺伝子を導入することは技術的に困難であったが、ヒト肝細胞キメラマウスにB型肝炎ウイルスを感染させ、さらにヒトリンパ球を投与することにより、ヒト肝細胞キメラマウスに劇症肝炎に類似した肝細胞の広範な壊死をもたらすモデルを作製することができた。この肝炎モデルではこれまでに想定されていたcytotoxicTlymphocyteではなく、FAS抗原を提示している肝細胞に対するNatural killer cellと樹状細胞が重要な役割を果たしていることが明らかになった。さらに、アルファインターフェロン、ガンマインターフェロンはこのモデルでは重要な役割を果たしておらず、他のサイトカインが肝炎の発症に必要であることが想定された。B型劇症肝炎は遺伝病ではないが、劇症肝炎も治療がきわめて困難な疾患であり、貴重なモデルを作製することができた。
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Research Products
(56 results)
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[Journal Article] Impact of pegylated interferon therapy on outcomes of patients with hepatitis C virus-related hepatocellular carcinoma after curative hepatic resection2012
Author(s)
Tanimoto Y, Tashiro H, Aikata H, Amano H, Oshita A, Kobayashi T, Kuroda S, Tazawa H, Takahashi S, Itamoto T, Chayama K, Ohdan H
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Journal Title
Ann Surg Oncol
Volume: 19
Pages: 418-425
DOI
Peer Reviewed
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[Journal Article] Severe necroinflammatory reaction caused by natural killer by Fas/FasL interaction and dendritic cells in human hepatocyte chimeric mouse2012
Author(s)
Okazaki A, Hiraga N, Imamura M, Nelson Hayes C, Tsuge M, Takahashi S, Aikata H, Abe H, Miki D, Ochi H, Tateno C, Yoshizato K, Ohdan H, Chayama K
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Journal Title
Hepatology
Volume: (in press)
DOI
Peer Reviewed
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[Journal Article] IL28B polymorphism is associated with fatty change in the liver of chronic hepatitis C patients2012
Author(s)
Ohnishi M, Tsuge M, Kohno T, Zhang Y, Abe H, Hyogo H, Kimura Y, Miki D, Hiraga N, Imamura M, Takahashi S, Ochi H, Hayes CN, Tanaka S, Arihiro K, Chayama K
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Journal Title
J Gastroenterol
Volume: (in press)
DOI
Peer Reviewed
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[Journal Article] Combination of hepatitis B viral antigens and DNA for prediction of relapse after discontinuation of nucleos(t)ide analogs in patients with chronic hepatitis B2012
Author(s)
Matsumoto A, Tanaka E, Suzuki Y, Kobayashi M, Tanaka Y, Shinkai N, Hige S, Yatsuhashi H, Nagaoka S, Chayama K, Tsuge M, Yokosuka O, Imazeki F, Nishiguchi S, Saito M, Fujiwara K, Torii N, Hiramatsu N, Karino Y, Kumada H
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Journal Title
Hepatol Res
Volume: 42
Pages: 139-149
DOI
Peer Reviewed
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[Journal Article] Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population2012
Author(s)
Sumida Y, Yoneda M, Hyogo H, Itoh Y, Ono M, Fujii H, Eguchi Y, Suzuki Y, Aoki N, Kanemasa K, Fujita K, Chayama K, Saibara T, Kawada N, Fujimoto K, Kohgo Y, Yoshikawa T, Okanoue T, Jsg-Nafld JS
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Journal Title
BMC Gastroenterol
Volume: (Epub)
DOI
Peer Reviewed
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[Journal Article] Identification of the Niemann-Piok C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor2012
Author(s)
Sainz B, Jr., Barretto N, Martin DN, Hiraga N, Imamura M, Hussain S, Marsh KA, Yu X, Chayama K, Alrefai WA, Uprichard SL
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Journal Title
Nat Med
Volume: 18
Pages: 281-285
DOI
Peer Reviewed
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[Journal Article] Dual therapy with the nonstructural Protein 5A Inhibitor, BMS-790052, and the Nonstructural Protein 3 Protease Inhibitor, BMS-650032, in Hepatitis C Virus Genotype 1b-Infected Null Responders2012
Author(s)
Chayama K, Takahashi S, Toyota J, Karino Y, Ikeda K, Ishikawa H, Watanabe H, McPhee F, Hughes E, Kumada H
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Journal Title
Hepatology
Volume: 55
Pages: 742-8
DOI
Peer Reviewed
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[Journal Article] Amino Acid Substitution in HCV Core/NS5A Region and Genetic Variation Near IL28B Gene Affect Treatment Efficacy to Interferon plus Ribavirin Combination Therapy2012
Author(s)
Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H
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Journal Title
Intervirology
Volume: 55
Pages: 231-41
DOI
Peer Reviewed
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[Journal Article] Rapid emergence of telaprevir resistant hepatitis C virus strain from wildtype clone in vivo2011
Author(s)
Hiraga N, Imamura M, Abe H, Hayes CN, Kono T, Onishi M, Tsuge M, Takahashi S, Ochi H, Iwao E, Kamiya N, Yamada I, Tateno C, Yoshizato K, Matsui H, Kanai A, Inaba T, Tanaka S, Chayama K.
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Journal Title
Hepatology 2011
Volume: 54
Pages: 781-788
DOI
Peer Reviewed
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[Journal Article] IL28 variation affects expression of interferon stimulated genes and peg-interferon and ribavirin therapy2011
Author(s)
Abe H, Hayes CN, Ochi H, Maekawa T, Tsuge M, Miki D, Mitsui F, Hiraga N, Imamura M, Takahashi S, Kubo M, Nakamura Y, Chayama K.
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Journal Title
Hepatol 2011
Volume: 54
Pages: 1094-1101
DOI
Peer Reviewed
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[Journal Article] A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma2011
Author(s)
Okusaka T, Kasugai H, Ishii H, Kudo M, Sata M, Tanaka K, Shioyama Y, Chayama K, Kumada H, Yoshikawa M, Seki T, Saito H, Hayashi N, Shiratori K, Okita K, Sakaida I, Honda M, Kusumoto Y, Tsutsumi T, Sakata K
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Journal Title
Invest New Drugs
Volume: (Published online : 21 Dec.)(Epub)
DOI
Peer Reviewed
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[Journal Article] Recent trend of clinical features in patients with hepatocellular carcinoma2011
Author(s)
Nagaoki Y, Hyogo H, Aikata H, Tanaka M, Naeshiro N, Nakahara T, Honda Y, Miyaki D, Kawaoka T, Takaki S, Hiramatsu A, Waki K, Imamura M, Kawakami Y, Takahashi S, Chayama K
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Journal Title
Hepatol Res
Volume: (Epub 13 Dec.)(Epub)
DOI
Peer Reviewed
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[Journal Article] Platelet count for predicting fibrosis in nonalcoholic fatty liver disease2011
Author(s)
Yoneda M, Fujii H, Sumida Y, Hyogo H, Itoh Y, Ono M, Eguchi Y, Suzuki Y, Aoki N, Kanemasa K, Imajo K, Chayama K, Saibara T, Kawada N, Fujimoto K, Kohgo Y, Yoshikawa T, Okanoue T, Japan Study Group of Nonalcoholic Fatty Liver D
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Journal Title
J Gastroenterol
Volume: 46
Pages: 1300-1306
DOI
Peer Reviewed
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[Journal Article] Clinical outcome of esophageal varices after hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with major portal vein tumor thrombus2011
Author(s)
Kodama H, Aikata H, Murakami E, Miyaki D, Nagaoki Y, Hashimoto Y, Azakami T, Katamura Y, Kawaoka T, Takaki S, Hiramatsu A, Waki K, Imamura M, Kawakami Y, Takahashi S, Ishikawa M, Kakizawa H, Awai K, Kenjo M, Nagata Y, Chayama K
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Journal Title
Hepatol Res
Volume: 41
Pages: 1046-1056
DOI
Peer Reviewed
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[Journal Article] Eradication of hepatitis C virus genotype 1 after liver transplantation by interferon therapy before surgery : Report of three patients with analysis of interleukin-28 polymorphism, hepatitis C virus core region and in terferon-sensitivity determining region2011
Author(s)
Kawaoka T, Aikata H, Miyaki D, Murakami E, Azakami T, Takaki S, Nagaoki Y, Hashimoto Y, Katamura Y, Hiramatsu A, Waki K, Hiraga N, Miki D, Tsuge M, Imamura M, Kawakami Y, Takahashi S, Ochi H, Tashiro H, Ohdan H, Chayama K
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Journal Title
Hepatol Res
Volume: 41
Pages: 1126-1131
DOI
Peer Reviewed
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[Journal Article] A huge metastatic liver tumor from leiomyosarcoma of the inferior venacava : report of a case2011
Author(s)
Hashimoto M, Kobayashi T, Tashiro H, Amano H, Oshita A, Tanimoto Y, Kuroda S, Tazawa H, Aikata H, Chayama K, Fujii M, Arihiro K, Ohdan H
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Journal Title
Surg Today
Volume: (Epub 11 Nov.)(Epub)
DOI
Peer Reviewed
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[Journal Article] Lymphocyte subset characterization associated with persistent hepatitis C virus infection and subsequent progression of liver fibrosis2011
Author(s)
Yoshida K, Ohishi W, Nakashima E, Fujiwara S, Akahoshi M, Kasagi F, Chayama K, Hakoda M, Kyoizumi S, Nakachi K, Hayashi T, Kusunoki Y
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Journal Title
Hum Immunol
Volume: 72
Pages: 821-826
DOI
Peer Reviewed
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[Journal Article] A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population2011
Author(s)
Mbarek H, Ochi H, Urabe Y, Kumar V, Kubo M, Hosono N, Takahashi A, Kamatani Y, Miki D, Abe H, Tsunoda T, Kamatani N, Chayama K, Nakamura Y, Matsuda K
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Journal Title
Hum Mol Genet
Volume: 20
Pages: 3884-3892
DOI
Peer Reviewed
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[Journal Article] IL28B polymorphism may guide pegylated interferon plus ribavirin therapy even after curative treatment for hepatitis C virus-related hepatocellular carcinoma2011
Author(s)
Kawaoka T, Aikata H, Takaki S, Hiramatsu A, Waki K, Hiraga N, Miki D, Tsuge M, Imamura M, Kawakami Y, Takahashi S, Ochi H, Tashiro H, Ohdan H, Chayama K
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Journal Title
J Viral Hepat
Volume: 18
Pages: e550-560
DOI
Peer Reviewed
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[Journal Article] Hepatitis C virus infection suppresses the interferon response in the liver of the human hepatocyte chimeric mouse2011
Author(s)
Tsuge M, Fujimoto Y, Hiraga N, Zhang Y, Ohnishi M, Kohno T, Abe H, Miki D, Imamura M, Takahashi S, Ochi H, Hayes CN, Miya F, Tsunoda T, Chayama K
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Journal Title
PLoS One
Volume: 6
Pages: e23856
DOI
Peer Reviewed
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[Journal Article] Impact of viral amino acid substitutions and host interleukin-28b polymorphism on replication and susceptibility to interferon of hepatitis C virus2011
Author(s)
Hiraga N, Abe H, Imamura M, Tsuge M, Takahashi S, Hayes CN, Ochi H, Tateno C, Yoshizato K, Nakamura Y, Kamatani N, Chayama K
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Journal Title
Hepatology
Volume: 54
Pages: 764-771
DOI
Peer Reviewed
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[Journal Article] Inverse association of IL28B genotype and liver mRNA expression of genes promoting or suppressing antiviral state2011
Author(s)
Abe H, Hayes CN, Ochi H, Tsuge M, Miki D, Hiraga N, Imamura M, Takahashi S, Kubo M, Nakamura Y, Kamatani N, Chayama K
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Journal Title
J Med Virol
Volume: 83
Pages: 1597-1607
DOI
Peer Reviewed
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[Journal Article] In vivo adaptation of hepatitis C virus in chimpanzees for efficient virus production and evasion of apoptosis2011
Author(s)
Saeed M, Shiina M, Date T, Akazawa D, Watanabe N, Murayama A, Suzuki T, Watanabe H, Hiraga N, Imamura M, Chayama K, Choi Y, Krawczynski K, Liang TJ, Wakita T, Kato T
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Journal Title
Hepatology
Volume: 54
Pages: 425-433
DOI
Peer Reviewed
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[Journal Article] Variation in the DEPDC5 locus is associated with progression to hepatocellular carcinoma in chronic hepatitis C virus carriers2011
Author(s)
Miki D, Ochi H, Hayes CN, Abe H, Yoshima T, Aikata H, Ikeda K, Kumada H, Toyota J, Morizono T, Tsunoda T, Kubo M, Nakamura Y, Kamatani N, Chayama K
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Journal Title
Nat Genet
Volume: 43
Pages: 797-800
DOI
Peer Reviewed
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[Journal Article] Achievement of Sustained Viral Response after Switching Treatment from Pegylated Interferon alpha-2b to alpha-2a and Ribavirin in Patients with Recurrence of Hepatitis C Virus Genotype 1 Infection after Liver Transplantation : A Case Report2011
Author(s)
Kawaoka T, Hiraga N, Takahashi S, Takaki S, Tsuge M, Nagaoki Y, Hashimoto Y, Katamura Y, Miki D, Hiramatsu A, Waki K, Imamura M, Kawakami Y, Aikata H, Ochi H, Tashiro H, Ohdan H, Chayama K
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Journal Title
Intervirology
Volume: (Epub 25 Aug.)(Epub)
DOI
Peer Reviewed
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[Journal Article] Will there be an HCV meeting in 2020? Summary of the 17th international meeting on hepatitis C virus and related viruses2011
Author(s)
Wakita T, Suzuki T, Evans MJ, Shimotohno K, Chayama K, Matsuura Y, Hijikata M, Moriishi K, Seya T, Enomoto N, Koike K, Kato N, Kanto T, Hotta H
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Journal Title
Gastroenterology
Volume: 141
Pages: e1-5
DOI
Peer Reviewed
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[Journal Article] Effects of hepatitis B virus infection on the interferon response in immunodeficient human hepatocyte chimeric mice2011
Author(s)
Tsuge M, Takahashi S, Hiraga N, Fujimoto Y, Zhang Y, Mitsui F, Abe H, Kawaoka T, Imamura M, Ochi H, Hayes CN, Chayama K
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Journal Title
J Infect Dis
Volume: 204
Pages: 224-228
DOI
Peer Reviewed
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[Journal Article] Treatment strategy for early hepatocellular carcinomas : comparison of radiofrequency ablation with or without transcatheter arterial chemoembolization and surgical resection2011
Author(s)
Tashiro H, Aikata H, Waki K, Amano H, Oshita A, Kobayashi T, Tanimoto Y, Kuroda S, Tazawa H, Chayama K, Asahara T, Ohdan H
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Journal Title
J Surg Oncol
Volume: 104
Pages: 3-9
DOI
Peer Reviewed
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[Journal Article] Antiviral effects of peginterferon alpha-2b and ribavirin following 24-week monotherapy of telaprevir in Japanese hepatitis C patients2011
Author(s)
Ozeki I, Akaike J, Karino Y, Arakawa T, Kuwata Y, Ohmura T, Sato T, Kamiya N, Yamada I, Chayama K, Kumada H, Toyota J
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Journal Title
J Gastroenterol
Volume: 46
Pages: 929-937
DOI
Peer Reviewed
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[Journal Article] IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C2011
Author(s)
Chayama K, Hayes CN, Abe H, Miki D, Ochi H, Karino Y, Toyota J, Nakamura Y, Kamatani N, Sezaki H, Kobayashi M, Akuta N, Suzuki F, Kumada H
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Journal Title
J Infect Dis
Volume: 204
Pages: 84-93
DOI
Peer Reviewed
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[Journal Article] ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo2011
Author(s)
Abe H, Imamura M, Hiraga N, Tsuge M, Mitsui F, Kawaoka T, Takahashi S, Ochi H, Maekawa T, Hayes CN, Tateno C, Yoshizato K, Murakami S, Yamashita N, Matsuhira T, Asai K, Chayama K
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Journal Title
J Hepatol
Volume: 55
Pages: 11-18
DOI
Peer Reviewed
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[Journal Article] Clinical features and prognosis in patients with hepatocellular carcinoma that developed after hepatitis C virus eradication with interferon therapy2011
Author(s)
Nagaoki Y, Aikata H, Miyaki D, Murakami E, Hashimoto Y, Katamura Y, Azakami T, Kawaoka T, Takaki S, Hiramatsu A, Waki K, Imamura M, Kawakami Y, Takahashi S, Chayama K
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Journal Title
J Gastroenterol
Volume: 46
Pages: 799-808
DOI
Peer Reviewed
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[Journal Article] Significant regression of a cavernous hepatic hemangioma to a sclerosed hemangioma over 12 years : a case study2011
Author(s)
Mlyaki D, Aikata H, Waki K, Murakami E, Hashimoto Y, Nagaoki Y, Katamura Y, Kawaoka T, Takaki S, Hiramatsu A, Imamura M, Takahashi S, Ohya T, Sakimoto H, Arihiro K, Chayama K
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Journal Title
Nihon Shokakibyo Gakkai Zasshi
Volume: 108
Pages: 954-961
Peer Reviewed
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[Journal Article] Cutaneous complications after transcatheter arterial treatment for hepatocellular carcinoma via the internal mammary artery : how to avoid this complication2011
Author(s)
Kajiwara K, Kakizawa H, Takeuchi N, Toyota N, Hieda M, Ishikawa M, Tanitame K, Tani C, Suzuki T, Fujikawa K, Aikata H, Chayama K, Awai K
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Journal Title
Jpn J Radiol
Volume: 29
Pages: 307-315
DOI
Peer Reviewed
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[Journal Article] Prediction of response to peginterferon-alfa-2b plus ribavirin therapy in Japanese patients infected with hepatitis C virus genotype 1b2011
Author(s)
Hashimoto Y, Ochi H, Abe H, Hayashida Y, Tsuge M, Mitsui F, Hiraga N, Imamura M, Takahashi S, Nelson Hayes C, Ohishi W, Kubo M, Tsunoda T, Kamatani N, Nakamura Y, Chayama K
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Journal Title
J Med Virol
Volume: 83
Pages: 981-988
DOI
Peer Reviewed
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[Journal Article] Common genetic polymorphism of ITPA gene affects ribavirin-induced anemia and effect of peg-interferon plus ribavirin therapy2011
Author(s)
Azakami T, Hayes CN, Sezaki H, Kobayashi M, Akuta N, Suzuki F, Kumada H, Abe H, Miki D, Tsuge M, Imamura M, Kawakami Y, Takahashi S, Ochi H, Nakamura Y, Kamatani N, Chayama K
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Journal Title
J Med Virol
Volume: 83
Pages: 1048-1057
DOI
Peer Reviewed
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[Journal Article] Elimination of hepatitis C virus by short term NS3-4A and NS5B inhibitor combination therapy in human hepatocyte chimeric mice2011
Author(s)
Ohara E, Hiraga N, Imamura M, Iwao E, Kamiya N, Yamada I, Kono T, Onishi M, Hirata D, Mitsui F, Kawaoka T, Tsuge M, Takahashi S, Abe H, Hayes CN, Ochi H, Tateno C, Yoshizato K, Tanaka S, Chayama K
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Journal Title
J Hepatol
Volume: 54
Pages: 872-878
DOI
Peer Reviewed
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[Journal Article] IL-28B predicts response to chronic hepatitis C therapy--fine-mapping and replication study in Asian populations2011
Author(s)
Ochi H, Maekawa T, Abe H, Hayashida Y, Nakano R, Imamura M, Hiraga N, Kawakami Y, Aimitsu S, Kao JH, Kubo M, Tsunoda T, Kumada H, Nakamura Y, Hayes CN, Chayama K
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Journal Title
J Gen Virol
Volume: 92
Pages: 1071-1081
DOI
Peer Reviewed
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[Journal Article] Factors predictive of sustained virological response following 72 weeks of combination therapy for genotype 1b hepatitis C2011
Author(s)
Chayama K, Hayes CN, Yoshioka K, Moriwaki H, Okanoue T, Sakisaka S, Takehara T, Oketani M, Toyota J, Izumi N, Hiasa Y, Matsumoto A, Nomura H, Seike M, Ueno Y, Yotsuyanagi H, Kumada H
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Journal Title
J Gastroenterol
Volume: 46
Pages: 545-555
DOI
Peer Reviewed
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