Faculty Profiles - TAKAKI Akinobu

MISC - TAKAKI Akinobu

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Changes of Immunoglobulin-Bound Glycans in Patients With Gastro-Intestinal Cancers

Chihiro Dohi, Kazuhiro Nouso, Soichiro Ako, Yuuki Morimoto, Koji Miyahara, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

GASTROENTEROLOGY 150 ( 4 ) S614 - S614 2016.4

Association of hepatic oxidative stress and iron dysregulation with HCC development after interferon therapy in chronic hepatitis C

Shintaro Nanba, Fusao Ikeda, Nobuyuki Baba, Koichi Takaguchi, Tomonori Senoh, Takuya Nagano, Hiroyuki Seki, Yasuto Takeuchi, Yuki Moritou, Tetsuya Yasunaka, Hideki Ohnishi, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

JOURNAL OF CLINICAL PATHOLOGY 69 ( 3 ) 226 - 233 2016.3

Language：English Publisher：BMJ PUBLISHING GROUP

Background Oxidative stress may play pathogenic roles in the mechanisms underlying chronic hepatitis C (CHC). The impact of excessive oxidative stress and iron dysregulation on the development of hepatocellular carcinoma (HCC) after interferon therapy has not been established.
Methods We investigated the impact of oxidative stress and iron deposition on HCC development after therapy with pegylated interferon (PegIFN)+ribavirin in CHC patients. Systemic and intracellular iron homeostasis was evaluated in liver tissues, peripheral blood mononuclear cells and sera.
Results Of 203 patients enrolled, 13 developed HCC during the 5.6-year follow-up. High hepatic 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were significantly associated with HCC development in multivariate analysis (p=0.0012) which was also significantly correlated with severity of hepatic iron deposition before therapy (p<0.0001). Systemic and intracellular iron regulators of hepcidin and F-box and leucine-rich repeat protein 5 (FBXL5) expression levels were significantly suppressed in CHC patients (p=0.0032 and p=0.016, respectively) despite their significantly higher levels of serum iron and ferritin compared with controls. However, intracellular iron regulators of FBXL5 and iron regulatory proteins were regulated in balance with hepatic iron deposition. Significant correlations were observed among IL-6, bone morphogenetic protein 6, hepcidin and ferroportin, as regards systemic iron regulation.
Conclusions Measurement of hepatic oxidative stress before antiviral therapy is useful for the prediction of HCC development after interferon therapy. Low baseline levels of the intracellular iron regulators of FBXL5 in addition to a suppressed hepcidin level might be associated with severe hepatic iron deposition in CHC patients.

DOI： 10.1136/jclinpath-2015-203215

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Entecavir Reduces Hepatocarcinogenesis in Chronic Hepatitis B Patients

Tetsuya Yasunaka, Fusao Ikeda, Nozomu Wada, Yuki Morimoto, Shin-ichi Fujioka, Junichi Toshimori, Haruhiko Kobashi, Kazuya Kariyama, Yoichi Morimoto, Hiroki Takayama, Tomonori Seno, Koichi Takaguchi, Akio Moriya, Hirokazu Miyatake, Ryoichi Okamoto, Kazuhisa Yabushita, Akinobu Takaki, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 70 ( 1 ) 1 - 12 2016.2

Language：English Publisher：OKAYAMA UNIV MED SCHOOL

Chronic hepatitis B (CHB) leads to cirrhosis and hepatocellular carcinoma (HCC). With a cohort of 1,206 CHB patients who visited Okayama University Hospital and related hospitals in 2011 and 2012, we compared the incidence rates of HCC among the patients grouped by age, hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg), and treatment. HCCs were observed in 115 patients with the median observation period of 1,687 days. Among the HCC patients aged >= 35 years, HBV DNA >= 4 log copies/mL and positive HBeAg at diagnosis (n = 184), the HCC incidence rate was 8.4% at 5 years in the entecavir (ETV)-treated patients, 21.8% in the lamivudine (LVD)-treated patients, and 26.4% among the patients not treated with drugs. The cumulative HCC incidence was significantly reduced in the ETV-treated patients compared to those treated with LVD or not treated (p = 0.013). Among the patients aged >= 35 years with HBV DNA >= 4 log copies/mL and negative HBeAg (n = 237), the cumulative HCC incidence was 14.6% in 5 years in ETV group and 13.9% among those not treated with a drug (p > 0.05). Only small numbers of HCCs occurred in other patients. In CHB patients aged >= 35 years with HBV DNA >= 4 log copies/mL and positive HBeAg, ETV treatment is recommended for the suppression of HCC development.

DOI： 10.18926/AMO/53996

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Insufficiency of phosphatidylethanolamine N-methyltransferase is risk for lean non-alcoholic steatohepatitis

Atsuko Nakatsuka, Makoto Matsuyama, Satoshi Yamaguchi, Akihiro Katayama, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Daisuke Ogawa, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Eijiro Watanabe, Jun Wada

SCIENTIFIC REPORTS 6 2016.2

Language：English Publisher：NATURE PUBLISHING GROUP

Although obesity is undoubtedly major risk for non-alcoholic steatohepatitis (NASH), the presence of lean NASH patients with normal body mass index has been recognized. Here, we report that the insufficiency of phosphatidylethanolamine N-methyltransferase (PEMT) is a risk for the lean NASH. The Pemt-/-mice fed high fat-high sucrose (HFHS) diet were protected from diet-induced obesity and diabetes, while they demonstrated prominent steatohepatitis and developed multiple liver tumors. Pemt exerted inhibitory effects on p53-driven transcription by forming the complex with clathrin heavy chain and p53, and Pemt-/-mice fed HFHS diet demonstrated prominent apoptosis of hepatocytes. Furthermore, hypermethylation and suppressed mRNA expression of F-box protein 31 and hepatocyte nuclear factor 4 alpha resulted in the prominent activation of cyclin D1. PEMT mRNA expression in liver tissues of NASH patients was significantly lower than those with simple steatosis and we postulated the distinct clinical entity of lean NASH with insufficiency of PEMT activities.

DOI： 10.1038/srep21721

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Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

Daisuke Uchida, Akinobu Takaki, Hisashi Ishikawa, Yasuko Tomono, Hironari Kato, Koichiro Tsutsumi, Naofumi Tamaki, Takayuki Maruyama, Takaaki Tomofuji, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Hiroshi Matsushita, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Kazuhiro Nouso, Ryuichi Yoshida, Yuzo Umeda, Susumu Shinoura, Takahito Yagi, Toshiyoshi Fujiwara, Manabu Morita, Masaki Fukushima, Kazuhide Yamamoto, Hiroyuki Okada

FREE RADICAL RESEARCH 50 ( 7 ) 732 - 743 2016

Language：English Publisher：TAYLOR & FRANCIS LTD

Background: Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
Methods: We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
Results: Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. L-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
Conclusion: Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent L-carnitine is a good candidate to control oxidative stress conditions.

DOI： 10.3109/10715762.2016.1172071

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A case of unresectable combined hepatocellular cholangiocarcinoma showing favorable response to LFP therapy

Sayuri Kato, Yasuto Takeuchi, Nozomu Wada, Yuuki Morimoto, Kenji Kuwaki, Hideki Ohnishi, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada

Journal of Japanese Society of Gastroenterology 113 ( 12 ) 2050 - 2056 2016

Language：Japanese Publisher：Japanese Society of Gastroenterology

A woman in her 50s was admitted to our hospital because of multiple tumors detected in her liver. She was diagnosed with combined hepatocellular cholangiocarcinoma using gadolinium-ethoxybenzyldiethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) and biopsy of the liver tumors. We judged the tumors to be unresectable because they were found in both lobes of the liver, with a tumor thrombus being found in the main left portal vein. The pathological findings showed that the tumors exhibited characteristics of hepatocellular carcinoma Therefore, sorafenib was administered
however, 6 months later, the disease progressed. Consequently, she received second-line chemotherapy with a one-shot intra-arterial injection of cisplatin, but this too was ineffective, and her general condition worsened. As hence, we changed the regimen to 5-fluorouracil continuous infusion and consecutive low dose cisplatin (LFP) therapy. After one cycle of chemotherapy with LFP, Gd-EOB-DTPA-enhanced MRI showed markedly decreased sizes and numbers of tumors. To date, she has completed six cycles of LFP therapy, and almost all her tumors are no longer visible on MRI. She has recovered to a good state and has achieved long-term survival. Thus, this case indicates that although LFP therapy is generally selected for cases of advanced hepatocellular carcinoma, it also appears to be effective for long-term disease control in cases of hepatocellular cholangiocarcinoma.

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Low frequency of drug-resistant virus did not affect the therapeutic efficacy in daclatasvir plus asunaprevir therapy in patients with chronic HCV genotype-1 infection

Hideaki Kinugasa, Fusao Ikeda, Kouichi Takaguchi, Chizuru Mori, Takehiro Matsubara, Hidenori Shiraha, Akinobu Takaki, Yoshiaki Iwasaki, Shinichi Toyooka, Kazuhide Yamamoto

ANTIVIRAL THERAPY 21 ( 1 ) 37 - 44 2016

Language：English Publisher：INT MEDICAL PRESS LTD

Background: The efficacy of a direct-acting antiviral agent (DAA) is compromised by the development of drug resistance. The associations between resistance-associated virus (RAV) and therapeutic outcomes have not been well-understood.
Methods: A total of 30 patients with HCV genotype-1b were enrolled and treated for 24 weeks with asunaprevir (ASV) and daclatasvir (DCV). Viral sequences in non-structural (NS) regions 3 and 5A in serum and liver tissue before treatment were examined with direct sequencing, next-generation sequencing (NGS) and the PCR-invader method to evaluate the importance of drug-resistance in the prediction of the outcomes of ASV plus DCV therapy.
Results: Of 30 patients (22 treatment-naive patients, 2 interferon-intolerant patients and 6 non-responders), 25 patients (83.3%) achieved sustained virological response (SVR) 24 weeks after the treatment. Viral breakthrough occurred in three treatment-naive patients and one non-responder. One treatment-naive patient experienced viral relapse. Among 25 patients without RAV, 24 obtained SVR, whereas 5 patients had RAV with a 1.3 to 88% frequency, resulting in various therapeutic outcomes. As for HCV compartments, similar RAVs were detected in serum and liver tissue for a patient obtaining SVR despite HCV NS5A Y93H and another developed viral breakthrough although no RAV was detected. Direct sequencing could not detect RAVs in low frequency (1.3 to 12%) for three of four patients.
Conclusions: Low frequency of RAVs might not affect the outcomes of ASV plus DCV therapy. Deep sequencing and PCR-invader methods can detect clinically significant RAVs for ASV plus DCV therapy.

DOI： 10.3851/IMP2976

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肝移植医療を地域と大学が一体としてまとめ上げた実績とさらなる発展

八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 渡辺信之, 高木弘誠, 須井健太, 藤原俊義, 高木章乃夫, 吉田真理, 保田裕子, 森松博史

肝胆膵 72 ( 3 ) 481 - 487 2016

Beneficial impact of Gpnmb and its significance as a biomarker in nonalcoholic steatohepatitis

Akihiro Katayama, Atsuko Nakatsuka, Jun Eguchi, Kazutoshi Murakami, Sanae Teshigawara, Motoko Kanzaki, Tomokazu Nunoue, Kazuyuki Hida, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Akinobu Takaki, Kazuhide Yamamoto, Hiroshi Kiyonari, Hirofumi Makino, Jun Wada

SCIENTIFIC REPORTS 5 2015.11

Language：English Publisher：NATURE PUBLISHING GROUP

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. Gpnmb is classified as a type 1 membrane protein and its soluble form is secreted by ADAM10-mediated cleavage. Gpnmb mRNA was found in the Kupffer cells and white adipose tissues (WATs) and its upregulation in obesity was recently found. Here, we generated aP2 promoter-driven Gpnmb transgenic (Tg) mice and the overexpression of Gpnmb ameliorated the fat accumulation and fibrosis of the liver in diet-induced obesity model. Soluble form of Gpnmb in sera was elevated in Gpnmb Tg mice and Gpnmb concentrated in hepatic macrophages and stellate cells interacted with calnexin, which resulted in the reduction of oxidative stress. In the patients with non-alcoholic steatohepatitis, serum soluble GPNMB concentrations were higher compared with the patients with simple steatosis. The GPNMB is a promising biomarker and therapeutic target for the development and progression of NAFLD in obesity.

DOI： 10.1038/srep16920

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異なる経過をたどった多発肝転移合併脾臓原発血管肉腫の2例

脇地一生, 大西秀樹, 能祖一裕, 大山淳史, 足立卓哉, 下村泰之, 和田望, 森元裕貴, 安中幸, 竹内康人, 安中哲也, 桑木健志, 池田房雄, 中村進一郎, 白羽英則, 高木章乃夫, 岡田裕之

肝臓 56 ( Suppl.3 ) A1122 - A1122 2015.11

TACE後RFAまでの腫瘍縮小を目指した至適待機期間の探索

赤穂宗一郎, 中村進一郎, 能祖一裕, 和田望, 森元裕貴, 竹内康人, 安中哲也, 桑木健志, 大西秀樹, 池田房雄, 白羽英則, 高木章乃夫, 岡田裕之

肝臓 56 ( Suppl.3 ) A954 - A954 2015.11

急性肝不全に対する内科的治療と肝移植の現状

楳田祐三, 賀来隆治, 安中哲也, 篠浦先, 吉田龍一, 信岡大輔, 松崎孝, 保田裕子, 高木章乃夫, 藤原俊義, 八木孝仁

移植 50 ( 4-5 ) 477 - 477 2015.10

初回および再肝移植後に脂肪性肝炎を発症した1例

田中健大, 田中顕之, 柳井広之, 篠浦先, 楳田祐三, 吉田龍一, 高木章乃夫, 藤原俊義, 八木孝仁

移植 50 ( 4-5 ) 551 - 551 2015.10

岡山大学病院ICUにおける急性肝不全に対する肝移植までのBridging Therapyについて

賀来隆治, 楳田祐三, 松崎孝, 柴田麻里, 篠浦先, 吉田龍一, 信岡大輔, 保田裕子, 高木章乃夫, 八木孝仁, 森松博史

移植 50 ( 4-5 ) 477 - 478 2015.10

Serum oxidative-anti-oxidative stress balance is dysregulated in patients with non-alcoholic steatohepatitis and related hepatocellular carcinoma

Yasuyuki Shimomura, Akinobu Takaki, Nozomu Wada, Daisuke Uchida, Yasuto Takeuchi, Tetsuya Yasunaka, Fusao Ikeda, Hideki Onishi, Kenji Kuwaki, Shinichiro Nakamura, Kazuhiro Nouso, Yasuhiro Miyake, Kazuko Koike

HEPATOLOGY 62 1297A - 1297A 2015.10

Alteration of N-glycan profiles in patients with chronic hepatitis and hepatocellular carcinoma

Koji Miyahara, Kazuhiro Nouso, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

HEPATOLOGY RESEARCH 45 ( 9 ) 986 - 993 2015.9

Language：English Publisher：WILEY-BLACKWELL

AimMost of the modification of N-glycosylation reported in cancers including hepatocellular carcinoma (HCC) were based on the examinations of a small number of patients or particular proteins. The aim of this study is to reveal changes in whole serum N-glycan profiles systematically during the process of hepatocarcinogenesis and to elucidate their clinical application.
MethodsWe analyzed sera from 105 patients with chronic hepatitis/liver cirrhosis (CH/LC) and age-/sex-matched healthy volunteers (HLT), as well as from 114 patients with HCC. Serum N-glycan profiles were measured comprehensively by a new, quantitative, high-throughput method and compared with clinical parameters.
ResultsThe total amount of N-glycan expression was significantly higher in patients with CH/LC than in HLT; however, no differences were observed between CH/LC and HCC patients. In HCC patients, multi-antennary glycans with fucose residues, particularly m/z 3195, were increased compared with CH/LC patients. The expression of m/z 3195 was high, especially in patients with a high number of intrahepatic lesions (>3), large tumor size (>3cm), macroscopic vascular invasion or metastasis. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) showed a higher area under the receiver-operator curve of 0.810 than any other single glycan to distinguish HCC from CH/LC.
ConclusionWe demonstrate the full spectrum of the alterations of serum N-glycans comprehensively in patients with liver disease, and elucidate the possible use of glycans as novel biomarkers of liver disease progression.

DOI： 10.1111/hepr.12441

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肝臓移植における血管吻合とくに非顕微鏡的肝動脈再建と肝静脈・下大静脈置換の手技

八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 渡辺信之, 高木弘誠, 須井健太, 木村祐司, 藤原俊義, 吉田真理, 保田裕子, 高木章乃夫

移植 50 ( 総会臨時 ) 197 - 197 2015.9

肝移植術前管理と肝移植後の難治性腹水におけるトルバプタンの有効性

楳田祐三, 八木孝仁, 高木章乃夫, 篠浦先, 吉田龍一, 信岡大輔, 安中哲也, 渡辺信之, 杭瀬崇, 高木弘誠, 保田裕子, 藤原俊義

移植 50 ( 総会臨時 ) 336 - 336 2015.9

移植医療におけるHCV治療up-to-date 肝移植後C型肝炎における免疫抑制性T細胞とキメリズムの病態への影響

高木章乃夫, 内海方嗣, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 高木弘誠, 安中哲也, 保田裕子, 八木孝仁

移植 50 ( 総会臨時 ) 207 - 207 2015.9

移植医療人の役割分担と協調はどうあるべきか外科医、内科医、コーディネーターの関係

八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 渡辺信之, 高木弘誠, 須井健太, 木村祐司, 藤原俊義, 吉田真理, 保田裕子, 高木章乃夫

移植 50 ( 総会臨時 ) 219 - 219 2015.9

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