研究者詳細 - 高木　章乃夫

MISC - 高木　章乃夫

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Serum Oxidative/anti-oxidative Stress Balance Is Dysregulated in Potentially Pulmonary Hypertensive Patients with Liver Cirrhosis: A Case Control Study

Masako Terao, Akinobu Takaki, Takayuki Maruyama, Hiroki Oe, Tetsuya Yasunaka, Naofumi Tamaki, Kazufumi Nakamura, Takaaki Tomofuji, Takahito Yagi, Hiroshi Sadamori, Yuzo Umeda, Susumu Shinoura, Ryuichi Yoshida, Kazuhiro Nouso, Daisuke Ekuni, Kazuko Koike, Fusao Ikeda, Hidenori Shiraha, Manabu Morita, Hiroshi Ito, Toshiyoshi Fujiwara, Kazuhide Yamamoto

INTERNAL MEDICINE 54 ( 22 ) 2815 - 2826 2015年

記述言語：英語出版者・発行元：JAPAN SOC INTERNAL MEDICINE

Objective Hepatopulmonary syndrome (HPS) is characterized by vascular dilatation and hyperdynamic circulation, while portopulmonary hypertension (POPH) is characterized by vasoconstriction with fibrous obliteration of the vascular bed. Vasoactive molecules such as nitric oxide (NO) are candidate factors for cirrhotic complications associated with these diseases. However, oxidative stress balance is not well characterized in HPS and POPH. The present objective is to investigate the oxidative stress and anti-oxidative stress balance and NO pathway balance in patients with potential HPS and POPH.
Methods We recruited patients with decompensated cirrhosis (n = 69) admitted to our hospital as liver transplantation candidates. Patients exhibiting partial pressure of oxygen lower than 80 mmHg and alveolararterial oxygen gradient (AaDO(2)) >= 15 mmHg were categorized as potentially having HPS (23 of 69 patients). Patients exhibiting a tricuspid regurgitation pressure gradient >= 25 mmHg were categorized as potentially having POPH (29 of 61 patients). Serum reactive oxygen metabolites were measured and anti-oxidative OXY-adsorbent test (OXY) were performed, and the balance of these tests was defined as the oxidative index. The correlation between these values and the clinical characteristics of the patients were assessed in a cross-sectional study.
Results Potential HPS patients exhibited no correlation with oxidative stress markers. Potential POPH patients exhibited lower OXY (p = 0.037) and higher oxidative index values (p = 0.001). Additionally, the vascular NO synthase enzyme inhibiting protein, asymmetric dimethylarginine, was higher in potential POPH patients (p = 0.049). The potential POPH patients exhibited elevated AaDO(2), suggesting the presence of pulmonary shunting.
Conclusion Potential POPH patients exhibited elevated oxidative stress with decreased anti-oxidative function accompanied by inhibited NO production. Anti-oxidants represent a candidate treatment for potential POPH patients.

DOI： 10.2169/internalmedicine.54.4889

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Liver cirrhosis; Advances in research and clinics

2015年

門脈圧亢進症の病態と治療基礎から臨床へ門脈圧亢進症における心肺機能と酸化ストレスについての検討(共著）

高木章乃夫, 寺尾正子, 安中哲也, 白羽英則, 中村進一郎, 麻植浩樹, 中村一文, 岡田裕之

日本門脈圧亢進症学会雑誌 21 ( 3 ) 67 - 67 2015年

A multicenter survey of enteroscopy for the diagnosis of intestinal follicular lymphoma. 国際誌

Iwamuro M, Okada H, Kawano S, Shiode J, Takenaka R, Imagawa A, Inaba T, Suzuki S, Nishimura M, Mizuno M, Araki M, Mannami T, Ueki T, Kobashi H, Fukatsu H, Tanaka S, Omoto A, Kawai Y, Kitagawa T, Toyokawa T, Takata K, Yoshino T, Takaki A, Yamamoto K

Oncol Lett. 10 ( 1 ) 131 - 136 2015年

肝炎ウイルススクリーニング検査陽性患者に対する検査報告システムの構築による肝臓専門医受診率向上への取り組み

下村泰之, 池田房雄, 能祖一裕, 高木章乃夫, 渡邊都貴子, 岩月啓氏, 草野展周, 合地明, 山本和秀

肝臓 56 ( 4 ) 137 - 143 2015年

Prevention of vagotonia and pain during radiofrequency ablation of liver tumors

Shinichiro Nakamura, Kazuhiro Nouso, Hideki Onishi, Kenji Kuwaki, Hiroaki Hagihara, Yasuto Takeuchi, Nozomu Wada, Yuki Morimoto, Koji Miyahara, Tetsuya Yasunaka, Fusao Ikeda, Yasuhiro Miyake, Yoshiyuki Kobayashi, Hidenori Shiraha, Shinichi Ishikawa, Akinobu Takaki, Kazuhide Yamamoto

HEPATOLOGY RESEARCH 44 ( 13 ) 1367 - 1370 2014年12月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

Radiofrequency ablation (RFA) is frequently used to treat early stage hepatocellular carcinoma. Two of the most cumbersome side-effects of the ablation procedure are intractable pain and vagotonia when deep sedation is not used. We describe local injection of anesthetic into Glisson's sheath as a new technique for overcoming these problems. Lidocaine was injected into Glisson's sheath when radiofrequency ablation of hepatocellular carcinomas, which were located adjacent to Glisson's sheath, could not be continued due to severe pain (n=8) or bradycardia (n=3). In all three patients who showed vagotonia with bradycardia during the ablations, injection of lidocaine prevented bradycardia, allowing completion of the radiofrequency ablation. Pain was reduced in all eight patients who experienced pain during ablation. No side-effects were observed during the procedures. Injection of anesthetic into Glisson's sheath is simple and effective for reducing intractable pain and vagotonia associated with RFA.

DOI： 10.1111/hepr.12321

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Involvement of platelets in extrahepatic metastasis of hepatocellular carcinoma

Yuki Morimoto, Kazuhiro Nouso, Nozomu Wada, Yasuto Takeuchi, Hideaki Kinugasa, Koji Miyahara, Tetsuya Yasunaka, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

HEPATOLOGY RESEARCH 44 ( 14 ) E353 - E359 2014年12月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

AimRecently, a relationship between platelets and cancer metastasis has been reported. The aim of this study is to elucidate the risk factors for extrahepatic metastasis (EHM), with emphasis on association with platelets in patients, with hepatocellular carcinoma (HCC).
MethodsWe examined risk factors for EHM in 1613 consecutive, newly diagnosed HCC patients by logistic regression analysis (case-control study). We also examined the factors by Cox proportional hazard model in a retrospective cohort fashion in 803 patients who received non-curative treatment for HCC.
ResultsIn the case-control study, multivariate analysis revealed that high platelet counts (odds ratio [OR]=4.84; 95% confidence interval [CI]=1.29-29.54; P=0.01), high tumor number and the presence of macroscopic vascular invasion were significantly associated with EHM. In the cohort study, EHM was diagnosed in 71 patients during the study period (mean observation time=23.3 months). On multivariate analysis, high tumor number, high des--carboxyprothrombin (DCP) and Child-Pugh class A were significantly correlated with EHM, and the patients with high platelet counts tended to develop EHM (OR=1.73; 95% CI=0.99-3.14; P=0.055).
ConclusionHCC patients with high platelet counts, as well as large numbers of tumors, high serum DCP and Child-Pugh class A, are at risk for EHM.

DOI： 10.1111/hepr.12315

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Nursing Support Increases the Efficacy of Interferon Therapy in Patients with Chronic Hepatitis C

Shihoko Namba, Kayoko Miyake, Fusao Ikeda, Tomoko Hazama, Yu Hitobe, Noriko Yamasaki, Hidenori Shiraha, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 68 ( 5 ) 263 - 268 2014年10月

記述言語：英語出版者・発行元：OKAYAMA UNIV MED SCHOOL

Nursing support might help patients with chronic hepatitis C (CHC) remain in good mental and physical condition during interferon (IFN) therapy. However, the effects of nursing support have not been studied adequately in this context. This case-control study evaluated the effects of nursing support during IFN therapy. Twenty-four CHC patients who received pegylated IFN and ribavirin were enrolled. Nurses advised patients on the maintenance of their mental and physical condition at weekly visits, based on the results of written questionnaires. An additional 24 patients who received IFN therapy without nursing support and who were matched for age, sex, platelet count, viral serogroup and IFN regimen were selected with propensity score matching as controls. The patients with nursing support during IFN therapy achieved higher sustained virological responses (79%) than those without nursing support (58%). Adherence to the IFN and ribavirin regimens at 24 weeks of therapy were slightly higher in the patients with nursing support than those without it, but these differences were not statistically significant. Adherence to ribavirin after 24 weeks of therapy was significantly higher in those with nursing support than those without it (93% and 66%, p = 0.045). These results suggested that nursing support services could contribute to the virological responses of CHC patients by promoting drug-regimen adherence.

DOI： 10.18926/AMO/52894

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Hepatitis C Virus-specific T-cell Response Correlates with Hepatitis Activity and Donor IL28B Genotype Early after Liver Transplantation

Ryuichiro Tsuzaki, Akinobu Takaki, Takahito Yagi, Fusao Ikeda, Kazuko Koike, Yoshiaki Iwasaki, Hidenori Shiraha, Yasuhiro Miyake, Hiroshi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Eiichi Nakayama, Toshiyoshi Fujiwara, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 68 ( 5 ) 291 - 302 2014年10月

記述言語：英語出版者・発行元：OKAYAMA UNIV MED SCHOOL

It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-gamma) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At > 3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.

DOI： 10.18926/AMO/52898

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非B非C肝癌の臨床的特徴

竹内康人, 能祖一裕, 和田望, 桑木健志, 大西秀樹, 中村進一郎, 白羽英則, 高木章乃夫, 山本和秀

肝臓 55 ( Suppl.2 ) A633 - A633 2014年9月

γ-secretase inhibitorによるNotch経路阻害は膵癌幹細胞を阻害し抗癌剤治療効果を増強する可能性がある

堀口繁, 白羽英則, 内田大輔, 永原照也, 片岡淳朗, 岩室雅也, 加藤博也, 高木章乃夫, 能祖一裕, 山本和秀

日本消化器病学会雑誌 111 ( 臨増大会 ) A951 - A951 2014年9月

テラプレビルにおける早期皮疹へのcytokineの関与について

和田望, 池田房雄, 下村泰之, 森元裕貴, 竹内康人, 安中哲也, 三宅康広, 高木章乃夫, 岩崎良章, 白藤宜紀, 山本和秀

肝臓 55 ( Suppl.2 ) A658 - A658 2014年9月

Prevalence and Outcomes of Acute Hepatitis B in Okayama, Japan, 2006-2010

Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Sohji Nishina, Masaaki Korenaga, Keisuke Hino, Shin-ichi Fujioka, Toshiya Osawa, Tatsuya Itoshima, Miwa Kawanaka, Gotaro Yamada, Kazuya Kariyama, Hiroki Takayama, Junichi Kubota, Yoichi Morimoto, Takaaki Mizushima, Haruhiko Yamashita, Hiroaki Tanioka, Yuji Negoro, Junichi Toshimori, Haruhiko Kobashi, Atsushi Hirano, Yasuo Itano, Akinobu Takaki, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 68 ( 4 ) 243 - 247 2014年8月

記述言語：英語出版者・発行元：OKAYAMA UNIV MED SCHOOL

Hepatitis B virus (HBV) is one of the major viruses causing acute hepatitis. Recently, the incidence of acute hepatitis with genotype A has been increasing in Japan. The aim of this study was to investigate acute hepatitis B (AHB) in Okayama prefecture, with special attention to HBV genotype A. AHB patients who visited one of 12 general hospitals in Okayama prefecture between 2006 and 2010 were retrospectively analyzed. Over the course of the study period, 128 patients were diagnosed with AHB. Sexual transmission was supposed in the majority of patients (78 patients, 61%), including 59 (76%) having sex with heterosexual partners. The genotypes of HEY were assessed in 90 patients (70%), of whom 27 patients were infected with genotype A, 5 with genotype B, and 58 with genotype C. The prevalence of genotype A was significantly higher among male patients (28.7%), aged 20-29 (35.6%, p < 0.01), among men who had sex with men (100%, p < 0.005), and among patients having sex with unspecified partners (44.8%, p < 0.005). Genotype A was not a significant factor associated with delayed HBsAg disappearance. Caution should be exercised with regard to sexually transmissible diseases in order to slow the pandemic spread of AHB due to genotype A.

DOI： 10.18926/AMO/52790

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【肝胆膵領域の光学医療;一見に如かず】肝臓領域の腹腔鏡検査代表的な肝疾患腹腔鏡アトラス(後世に残る図譜として)

安中哲也, 池田房雄, 下村泰之, 和田望, 森元裕貴, 三宅康広, 白羽英則, 高木章乃夫, 能祖一裕, 岩崎良章, 山本和秀

肝・胆・膵 69 ( 2 ) 169 - 176 2014年8月

Loss of runt-related transcription factor 3 induces gemcitabine resistance in pancreatic cancer (vol 7, pg 840, 2013)

Shigeru Horiguchi, Hidenori Shiraha, Teruya Nagahara, Jyunnro Kataoka, Masaya Ituamuro, Minoru Matsubara, Shinichi Nishina, Hironari Kato, Akinobu Takaki, Kazuhiro Nouso, Takehiro Tanaka, Koichi Ichimura, Takahito Yagi, Kazuhide Yamamoto

MOLECULAR ONCOLOGY 8 ( 5 ) 1054 - 1054 2014年7月

Frequency of regulatory T-cell and hepatitis C viral antigen-specific immune response in recurrent hepatitis C after liver transplantation

Masashi Utsumi, Akinobu Takaki, Yuzo Umeda, Kazuko Koike, Stephanie C. Napier, Nobukazu Watanabe, Hiroshi Sadamori, Susumu Shinoura, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Eiichi Nakayama, Kazuhide Yamamoto, Toshiyoshi Fujiwara, Takahito Yagi

TRANSPLANT IMMUNOLOGY 31 ( 1 ) 33 - 41 2014年6月

記述言語：英語出版者・発行元：ELSEVIER SCIENCE BV

Introduction: Regulatory T (Treg) and type 1 regulatory T (Tr1) cells facilitate hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT). However, their frequencies and effects on HCV-specific immune responses have not been well investigated.
Methods: We determined Treg and Tr1 frequencies in OLT patients with hepatitis C and assessed their associations with HCV-specific T cell responses. These patients comprised the following groups: an early post-transplantation group (n = 14); an OLT-chronic active hepatitis C group (n = 14) with active hepatitis C (alanine aminotransferase of > upper limit of normal/positive for HCV-RNA); an OLT-persistently normal alanine aminotransferase group (n = 12) without active hepatitis C (not interferon/positive for HCV-RNA); and an OLT-sustained viral response group (n = 6) with sustained viral responses using interferon treatment (negative for HCV-RNA). The frequencies of HCV-specific CD4+ T cells that secreted interferon-gamma were determined by enzyme-linked immunosorbent spot assay (except for the OLT early group).
Results: Treg and Tr1 frequencies were low during the early post-transplantation period. OLT patients with sustained viral responses had lower Treg frequencies than those with chronic hepatitis C, whereas Tr1 frequencies were significantly reduced in OLT patients with persistently normal alanine aminotransferase levels compared to those with chronic hepatitis C (p < 0.05). Treg frequencies positively correlated with HCV NS3 antigen-specific interferon-gamma responses, which corresponded to HCV clearance.
Conclusions: Increased Treg frequencies and reduced HCV-NS3 antigen-specific responses recovered after viral eradication in post-OLT chronic hepatitis C patients. Reduced Tr1 frequencies were associated with hepatitis activity control, which may facilitate controlling chronic hepatitis C in patients after OLT. (C) 2014 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.trim.2014.05.006

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膵癌におけるγセクレターゼ阻害剤を用いた幹細胞抑制による抗癌剤増強効果の検討

堀口繁, 白羽英則, 内田大輔, 永原照也, 片岡淳朗, 岩室雅也, 加藤博也, 高木章乃夫, 能祖一裕, 山本和秀

膵臓 29 ( 3 ) 553 - 553 2014年6月

Molecular Mechanisms and New Treatment Strategies for Non-Alcoholic Steatohepatitis (NASH)

Akinobu Takaki, Daisuke Kawai, Kazuhide Yamamoto

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 15 ( 5 ) 7352 - 7379 2014年5月

記述言語：英語掲載種別：書評論文，書評，文献紹介等出版者・発行元：MDPI AG

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD), in which most patients exhibit non-progressive, non-alcoholic fatty liver (NAFL) attributable to simple steatosis. Multiple hits, including genetic differences, fat accumulation, insulin resistance and intestinal microbiota changes, account for the progression of NASH. NAFLD is strongly associated with obesity, which induces adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level, which in turn induces hepatic steatosis, inflammation and fibrosis. Among these factors, gut microbiota are acknowledged as having an important role in initiating this multifactorial disease. Oxidative stress is considered to be a key contributor in the progression from NAFL to NASH. Macrophage infiltration is apparent in NAFL and NASH, while T-cell infiltration is apparent in NASH. Although several clinical trials have shown that antioxidative therapy with vitamin E can effectively control hepatitis pathology in the short term, the long-term effects remain obscure and have often proved to be ineffective in many other diseases. Several long-term antioxidant protocols have failed to reduce mortality. New treatment modalities that incorporate current understanding of NAFLD molecular pathogenesis must be considered.

DOI： 10.3390/ijms15057352

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Potential of adenovirus-mediated REIC/Dkk-3 gene therapy for use in the treatment of pancreatic cancer

Daisuke Uchida, Hidenori Shiraha, Hironari Kato, Teruya Nagahara, Masaya Iwamuro, Junro Kataoka, Shigeru Horiguchi, Masami Watanabe, Akinobu Takaki, Kazuhiro Nouso, Yasutomo Nasu, Takahito Yagi, Hiromi Kumon, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 29 ( 5 ) 973 - 983 2014年5月

記述言語：英語出版者・発行元：WILEY-BLACKWELL

Background and AimThe reduced expression in immortalized cells REIC/the dickkopf 3 (Dkk-3) gene, tumor suppressor gene, is downregulated in various malignant tumors. In a prostate cancer study, an adenovirus vector carrying the REIC/Dkk-3 gene (Ad-REIC) induces apoptosis. In the current study, we examined the effects of REIC/Dkk-3 gene therapy in pancreatic cancer.
MethodsREIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry in the pancreatic cancer cell lines (ASPC1, MIAPaCa2, Panc1, BxPC3, SUIT-2, KLM1, and T3M4) and pancreatic cancer tissues. The Ad-REIC agent was used to investigate the apoptotic effect in vitro and antitumor effects in vivo. We also assessed the therapeutic effects of Ad-REIC therapy with gemcitabine.
ResultsThe REIC/Dkk-3 expression was lost in the pancreatic cancer cell lines and decreased in pancreatic cancer tissues. Ad-REIC induced apoptosis and inhibited cell growth in the ASPC1 and MIAPaCa2 lines in vitro, and Ad-REIC inhibited tumor growth in the mouse xenograft model using ASPC1 cells. The antitumor effect was further enhanced in combination with gemcitabine. This synergistic effect may be caused by the suppression of autophagy via the enhancement of mammalian target of rapamycin signaling.
ConclusionsAd-REIC induces apoptosis and inhibits tumor growth in pancreatic cancer cell lines. REIC/Dkk-3 gene therapy is an attractive therapeutic tool for pancreatic cancer.

DOI： 10.1111/jgh.12501

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NASH肝硬変における肝移植後の経過

高木章乃夫, 八木孝仁, 池田房雄, 保田裕子, 安中哲也, 貞森裕, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 内海方嗣, 藤原俊義, 山本和秀

移植 49 ( 1 ) 155 - 155 2014年5月

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