Faculty Profiles - TAKAKI Akinobu

Papers - TAKAKI Akinobu

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職域での出張肝臓病教室と同時開催の肝炎検診の意義

難波志穂子, 池田房雄, 下村泰之, 犬山奈穂美, 大久保進之介, 槇田崇志, 長谷川祐子, 岩井賢司, 細羽章子, 三浦留美, 藤井洋輔, 安中哲也, 竹内康人, 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, 岡田裕之

肝臓 58 ( 5 ) 304 - 306 2017.5

Language：Japanese Publisher：(一社)日本肝臓学会

出張肝臓病教室では、岡山大学病院の肝疾患サポートチームが職域に出向き、職員全員を対象として肝炎検診受検や肝臓専門機関受診の重要性を説明した。12回の出張肝臓病教室を603人が受講し、アンケート回答に欠損のない565人の回答を分析した。肝臓病で通院中の人は3人(0.5%)、健康診断で今まで肝機能異常を指摘されたことがない人が468人(82.8%)、健康診断で肝臓に関する検査結果を意識してみていない人が263人(46.5%)であった。肝臓病教室を受講して肝炎ウイルス検査を受けようと思った人が300人(53.1%)、既に受けている人が154人(27.3%)で、111人(19.6%)は受けないと回答した。講演が職場の肝臓病に対する偏見や誤解の解消に非常に役立つと思った人が347人(61.4%)、少し役に立つと思った人が208人(36.8%)であった。出張肝臓病教室に参加した306名中288名(94.1%)が肝炎検診を受検し、HBs抗原陽性者3名(1%)、HCV抗体陽性者3名(1%)であった。陽性者6名全員が肝炎専門医療機関を受診した。

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J00263&link_issn=&doc_id=20170601230005&doc_link_id=10.2957%2Fkanzo.58.304&url=https%3A%2F%2Fdoi.org%2F10.2957%2Fkanzo.58.304&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Redox Signaling in NASH Reviewed

A. Takaki, D. Uchida, K. Yamamoto

Liver Pathophysiology: Therapies and Antioxidants 169 - 180 2017.3

Language：English Publishing type：Part of collection (book) Publisher：Elsevier

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) is multifactorial and difficult to unify. The progression of benign nonalcoholic fatty liver (NAFL) to progressive nonalcoholic steatohepatitis (NASH) is acknowledged to be a multiple parallel hit process. Oxidative stress is one of the main factors that drives progression of NAFL to NASH, although it is also essential for vital cellular processes. Overaccumulation of long chain fatty acid results in mitochondrial ?-oxidation pathway activation followed by reactive oxygen species (ROS) production. ROS can mediate the oxidative stress response in hepatocytes, Kupffer cells, or hepatic stellate cells resulting in hepatocyte damage, and in proinflammatory and profibrogenic responses that should be well balanced. ROS detoxification pathway signaling is often damaged in NAFLD following ROS accumulation. Inactivation of pro-oxidant production pathways and activation of detoxifying signaling pathways are the required treatment approach.

DOI： 10.1016/B978-0-12-804274-8.00012-6

The Serum Oxidative/Anti-oxidative Stress Balance Becomes Dysregulated in Patients with Non-alcoholic Steatohepatitis Associated with Hepatocellular Carcinoma. Reviewed

Yasuyuki Shimomura, Akinobu Takaki, Nozomu Wada, Tetsuya Yasunaka, Fusao Ikeda, Takayuki Maruyama, Naofumi Tamaki, Daisuke Uchida, Hideki Onishi, Kenji Kuwaki, Shinichiro Nakamura, Kazuhiro Nouso, Yasuhiro Miyake, Kazuko Koike, Takaaki Tomofuji, Manabu Morita, Kazuhide Yamamoto, Hiroyuki Okada

Internal Medicine Vol.56 ( No.3 ) 243 - 251 2017.2

Language：English Publishing type：Research paper (scientific journal)

Objective Oxidative stress is associated with the progression of chronic liver disease. Non-alcoholic fatty liver disease (NAFLD) is also an oxidative stress-related disease. However, the oxidative/anti-oxidative balance has not been fully characterized in NAFLD. The objective of the present study was to investigate the balance between oxidative stress and the anti-oxidative activity in NAFLD, including non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC). Patients We recruited 69 patients with histologically proven NAFLD without HCC (NAFLD; n=58), and with NASH-related HCC (NASH-HCC; n=11). The 58 NAFLD patients included patients with non-alcoholic fatty liver (NAFL; n=14) and NASH (n=44). Methods The serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY) were determined and then used to calculate the oxidative index. The correlations among such factors as ROM, OXY, oxidative index, and clinical characteristics were investigated. Results In NAFLD, ROM positively correlated with the body mass index (BMI), hemoglobin A1c (HbA1c), C-reactive protein (CRP), and the histological grade or inflammatory scores, while only high HbA1c and CRP levels were significant factors that correlated with a higher ROM according to a multivariate analysis. OXY positively correlated with the platelet counts, albumin, and creatinine levels, while negatively correlating with age. However, it improved after treatment intervention. The oxidative index positively correlated with BMI, CRP, and HbA1c. The NASH-HCC patients exhibited a lower OXY than the NASH patients, probably due to the effects of aging. Conclusion Oxidative stress correlated with the levels of NASH activity markers, while the anti-oxidative function was preserved in younger patients as well as in patients with a well-preserved liver function. The NASH-HCC patients tended to be older and exhibited a diminished anti-oxidative function.

DOI： 10.2169/internalmedicine.56.7002

Oxidative stress in nonalcoholic steatohepatitis

Akinobu Takaki, Daisuke Uchida, Kazuhide Yamamoto

Reactive Oxygen Species in Biology and Human Health 349 - 361 2017.1

Language：English Publishing type：Part of collection (book) Publisher：CRC Press

Nonalcoholic fatty liver disease (NAFLD) is a disease with increasing prevalence that is potentially lethal after decades of persistent fat toxicity on the liver and accompanying organs. The pathogenesis for the progression of benign nonalcoholic fatty liver (NAFL) to progressive nonalcoholic steatohepatitis (NASH) is acknowledged as a multiple parallel hit process, including fat deposition, genetic factors, insulin resistance, and oxidative stress. Oxidative stress is one of the main pathogenic factors driving the progression of NAFL to NASH. Excessive accumulation of long chain fatty acids results in activation of the mitochondrial b-oxidation pathway and consequent reactive oxygen species (ROS) production. ROS can mediate oxidative stress responses in hepatocytes, Kupffer cells and hepatic stellate cells (HSCs), resulting in hepatocyte damage as well as proinflammatory and profibrogenic responses. ROS detoxification pathway signaling is often damaged in NAFLD following ROS accumulation. Inactivation of the prooxidant production pathway is presently the primary treatment strategy. However, as oxidative stress is an essential response in living organisms, a new treatment strategy that activates toxic oxidative stress detoxifying pathways while maintaining essential oxidative stress responses is preferred.

DOI： 10.1201/b20228

Corrigendum to "Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation"

Seiji Kawano, Akinobu Takaki, Masaya Iwamuro, Tetsuya Yasunaka, Yoshiyasu Kono, Kou Miura, Toshihiro Inokuchi, Yoshiro Kawahara, Yuzo Umeda, Takahito Yagi, Hiroyuki Okada

BioMed research international 2017 6418529 2017.1

Safety and Efficacy of Small Bowel Examination by Capsule Endoscopy for Patients before Liver Transplantation Reviewed

Kawano Seiji, Takaki Akinobu, Iwamuro Masaya, Yasunaka Tetsuya, Kono Yoshiyasu, Miura Kou, Inokuchi Toshihiro, Kawahara Yoshiro, Umeda Yuzo, Yagi Takahito, Okada Hiroyuki

BIOMED RESEARCH INTERNATIONAL 2017 2017

Language：English Publishing type：Research paper (scientific journal) Publisher：HINDAWI LTD

Background and Aims. Gastrointestinal surveillance is a requirement prior to liver transplantation (LT), but small intestine examination is not generally undertaken. The aim of the present studywas to evaluate the safety and efficacy of capsule endoscopy (CE) for patients with end-stage liver disease. Methods. 31 patients who needed LT were enrolled, and 139 patients who underwent CE over the same period of time acted as controls. Results. Frequency of successful achievement of evaluation of the full length of the small bowel, the mean gastric transit time, and the mean small bowel transit time were not significantly different between the two groups. Abnormalities in the small bowel were found in 26 patients. Comparative analysis revealed that history of EV rupture, history of EV treatment, red color sign of EV, and presence of PHG or HCC were significantly associated with patients with >2 two such findings (high score group). Conclusions. Small bowel examination by CE in patients before liver transplantation could be performed safely and is justified by the high rate of abnormal lesions detected particularly in patients with history of EV therapy or bleeding, red color sign, and presence of PHG or HCC. This study was registered in the UMIN Clinical Trial Registry (UMIN 000008672).

DOI： 10.1155/2017/8193821

P2-10 慢性腸炎マウスモデルにおけるベルベリンの改善効果と作用機序の検討

高原政宏, 高木章乃夫, 平岡佐規子, 池田愛璃, 足立卓哉, 松下浩志, 小池和子, 岡田裕之

日本臨床免疫学会会誌 40 ( 4 ) 311b - 311b 2017

Language：Japanese Publisher：日本臨床免疫学会

<p>【背景】生薬であるベルベリン（BBR）は下痢止めとして臨床応用されているが，抗炎症など多彩な作用も有することが明らかになっている．BBRは細胞のエネルギーの調節因子であるAMPKを活性化させることが知られており，近年，このAMPKがT細胞を含む免疫細胞の応答に関わっていることが報告されている．【目的，方法】慢性腸炎マウスモデルを用いて，大腸炎粘膜のCD4⁺T細胞（LP CD4⁺T細胞）におけるBBRの抗炎症作用とその機序についての検証をin vitroおよびIn vivoで行う．1）CD4⁺CD45RB^highT細胞移入腸炎マウスのLPCD4⁺T細胞をPMA/Ionomysinで刺激し，IFN-γ産生細胞を誘導，BBRの効果について，AMPKの関与も含めて検討．2）上記腸炎マウスにBBRを含んだ餌を投与し，腸炎の抑制効果について検討．【結果】1）LP CD4⁺T細胞はBBRと共培養すると，IFN-γ産生細胞が優位に低下し，ウェスタンブロッティングでは，AMPKの活性化を認めた．次に，AMPKのagonistとantagonistを用いた培養系でIFN-γの産生を調べたところ，agonistで抑制，antagonistで増加を認めた．以上から，BBRにより活性化されたAMPKがIFN-γを制御していることが示唆された．2）上記腸炎マウスにBBRを経口投与した結果，腸炎は優位に抑制された．【結論】BBRは，慢性腸炎マウスモデルの腸炎を抑制し，その作用機序の一つとしてAMPKを介した機序が示唆された．</p>

DOI： 10.2177/jsci.40.311b

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

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 Vol.54 ( No.22 ) 2815 - 2826 2015.11

Language：English Publishing type：Research paper (scientific journal)

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 alveolar-arterial oxygen gradient (AaDO2) 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 AaDO2, 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

当院における生体肝移植後の胆管狭窄に対する内視鏡治療

友田健, 加藤博也, 内田大輔, 秋元悠, 松本和幸, 山本直樹, 堀口繁, 堤康一郎, 高木章乃夫, 岡田裕之, 八木孝仁

移植 50 ( 4-5 ) 481 - 481 2015.10

Hepatic stellate cells promote upregulation of epithelial cell adhesion molecule and epithelial-mesenchymal transition in hepatic cancer cells. Reviewed International journal

Nagahara T, Shiraha H, Sawahara H, Uchida D, Takeuchi Y, Iwamuro M, Kataoka J, Horiguchi S, Kuwaki T, Onishi H, Nakamura S, Takaki A, Nouso K, Yamamoto K

Oncology reports 34 ( 3 ) 1169 - 1177 2015.9

Language：English Publishing type：Research paper (scientific journal)

Microenvironment plays an important role in epithelial-mesenchymal transition (EMT) and stemness of cells in hepatocellular carcinoma (HCC). Epithelial cell adhesion molecule (EpCAM) is known as a tumor stemness marker of HCC. To investigate the relationship between microenvironment and stemness, we performed an in vitro co-culture assay. Four HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) were co-cultured with the TWNT-1 immortalized hepatic stellate cells (HSCs), which create a microenvironment with HCC. Cell proliferation ability was analyzed by flow cytometry (FCM) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while migration ability was assessed by a wound healing assay. Expression of EpCAM was analyzed by immunoblotting and FCM. HCC cell lines were co-cultured with TWNT-1 treated with small interfering RNA (siRNA) for TGF-β and HB-EGF; we then analyzed proliferation, migration ability and protein expression using the methods described above. Proliferation ability was unchanged in HCC cell lines co-cultured with TWNT-1. Migration ability was increased in HCC cell lines (HepG2, Hep3B, HuH-7 and PLC/PRF/5) directly (216.2±67.0, 61.0±22.0, 124.0±66.2 and 51.5±40.3%) and indirectly (102.5±22.0, 84.6±30.9, 86.1±25.7 and 73.9±29.7%) co-cultured with TWNT-1 compared with the HCC uni-culture. Immunoblot analysis revealed increased EpCAM expression in the HCC cell lines co-cultured with TWNT-1. Flow cytometry revealed that the population of E-cadherin-/N-cadherin+ and EpCAM-positive cells increased and accordingly, EMT and stemness in the HCC cell line were activated. These results were similar in the directly and indirectly co-cultured samples, indicating that humoral factors were at play. Conversely, HCC cell lines co-cultured with siRNA‑treated TWNT-1 showed decreased migration ability, a decreased population of EpCAM-positive and E-cadherin-/N-cadherin+ cells. Taken together, humoral factors secreted from TWNT-1 promote upregulation of EpCAM and EMT in hepatic cancer cells.

DOI： 10.3892/or.2015.4126

Effectiveness of Extending Treatment Duration in Therapy with Pegylated Interferon and Ribavirin for Genotype 2 Hepatitis C Virus Infection Reviewed

Shintarou Nanba, Fusao Ikeda, Shin-ichi Fujioka, Yasuyuki Araki, Kouichi Takaguchi, Noriaki Hashimoto, Hiroyuki Seki, Akinobu Takaki, Yoshiaki Iwasaki, Kazuhide Yamamoto

ACTA MEDICA OKAYAMA 69 ( 4 ) 237 - 244 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

The effectiveness of extending treatment duration as response guided therapy was previously reported for chronic hepatitis C (CHC) genotype 1, but is still controversial for genotype 2. The present study is a retrospective cohort study to investigate the effectiveness of extending treatment duration in therapy with pegylated interferon and ribavirin for patients with CHC genotype 2 by focusing on the timing at which patients obtained undetectable HCV RNA. A total of 306 patients who obtained undetectable HCV RNA by week 24 of treatment and completed 24 weeks of treatment were enrolled. Rapid virological response (RVR) to standard therapy was achieved by 122 patients (51%), and 89% of them obtained sustained virological response (SVR), while 69% of non-RVR patients achieved SVR. Non-RVR patients with undetectable HCV RNA at week 8, and insufficient adherence < 80% pegylated interferon and ribavirin during the first 24 weeks, significantly improved their SVR rate by extended therapy. Among patients receiving extended therapy, drug adherences did not differ between SVR and non-SVR patients, indicating that extending treatment duration might compensate for insufficient antiviral effects due to insufficient drug adherences. This finding might be useful in creating a guideline for extending treatment duration for patients with CHC genotype 2.

Serum N-glycan profiles in patients with intraductal papillary mucinous neoplasms of the pancreas Reviewed

Yutaka Akimoto, Kazuhiro Nouso, Hironari Kato, Koji Miyahara, Chihiro Dohi, Yuki Morimoto, Hideaki Kinugasa, Takeshi Tomoda, Naoki Yamamoto, Koichiro Tsutsumi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

PANCREATOLOGY 15 ( 4 ) 432 - 438 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：KARGER

Background/objectives: Diagnosing the invasiveness of intraductal papillary mucinous neoplasms (IPMNs) is difficult, especially by blood test. Alterations in serum glycan profiles have been reported for several cancers, but changes in serum glycan profiles have not been investigated in patients with IPMNs. The objectives of this study were to determine the serum N-glycan profile and to investigate its clinical utility in patients with IPMNs.
Methods: We measured serum N-glycan profiles in 79 patients with IPMNs, including 13 invasive IPMNs, by performing comprehensive glycome analysis and assessed the relationship between N-glycan changes and clinical parameters.
Results: Seventy glycans were identified and their expression profiles were significantly different depending on the cyst size, the presence of an enhancing solid component, and the histological grade of the IPMN. Nine glycans were highly expressed in patients with invasive IPMNs. The glycan m/z 3195, which is a fucosylated tri-antennary glycan, had the highest diagnostic value for distinguishing invasive IPMNs from non-invasive IPMNs (area under the receiver operating characteristic curve = 0.803). Multivariate analyses revealed high levels of m/z 3195 [odds ratio (OR), 20.5; 95% confidence interval (CI) 2.60-486.4] and the presence of enhancing solid components (OR, 35.8; 95% Cl, 5.39-409.6) were significant risk factors for invasive IPMNs.
Conclusions: We performed a comprehensive evaluation of the changes in serum N-glycan profiles in patients with IPMNs for the first time. We determined that increased expression of fucosylated complex-type glycans, especially m/z 3195, is a potential marker for invasive IPMNs. Copyright (C) 2015, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

DOI： 10.1016/j.pan.2015.05.470

Prognostic Value of Altered N-Glycosylation of Circulating Glycoproteins in Patients With Unresectable Pancreatic Cancer Treated With Gemcitabine Reviewed

Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Hideaki Kinugasa, Hironari Kato, Naoki Yamamoto, Koichiro Tsutsumi, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Taku Nakahara, Yoshiaki Miura, Hidehisa Asada, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

PANCREAS 44 ( 4 ) 551 - 556 2015.5

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Objectives: The objectives of this study were to examine the whole serum N-glycan profile of patients with unresectable pancreatic cancer and to evaluate the ability of glycans to predict gemcitabine treatment efficacy and patient survival.
Methods: We collected serum from 52 patients with advanced pancreatic cancer before they began gemcitabine monotherapy. The serum glycan profile was measured through comprehensive quantitative high-throughput glycome analysis and compared with the treatment efficacy and patient survival.
Results: Of the 61 glycans detected, the serum levels of glycan 4310 (molecular weight [m/z] 1549.566), 6301 (m/z 2032.724), and 9200 (m/z 2010.692) were high in patients with a short time to tumor progression (TTP). Multivariate analysis revealed that a high glycan 9200 concentration was an independent risk factor for shorter TTP (hazard ratio, 2.11; 95% confidence interval, 1.07-4.17) and poor overall survival (hazard ratio, 2.56; 95% confidence interval, 1.08-6.19). The median TTP of patients with up-regulation of 9200 after gemcitabine treatment was shorter than for the remaining patients (91 vs 301 days; P = 0.0005). A similar relationship was observed for overall survival (median, 181 vs 561 days; P = 0.001).
Conclusions: Glycan 9200 is a possible biomarker predicting gemcitabine efficacy survival in patients with unresectable pancreatic cancer.

DOI： 10.1097/MPA.0000000000000321

Randomized Trial of Peginterferon Alpha-2b Plus Low and Escalating Dose of Ribavirin in Patients With Chronic Hepatitis C With High Viral Load Genotype 1 Reviewed

Yoshiaki Iwasaki, Yasuyuki Araki, Hideaki Taniguchi, Ryo-ichi Okamoto, Haruhiko Kobashi, Fusao Ikeda, Yasuhiro Miyake, Akinobu Takaki, Kazuhide Yamamoto

JOURNAL OF MEDICAL VIROLOGY 87 ( 4 ) 625 - 633 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

It has been reported that elderly patients with chronic hepatitis C infection cannot tolerate standard combination therapy. In this randomized, controlled trial, the efficacy and safety of peginterferon alpha-2b plus a low and escalating dose of ribavirin in chronic hepatitis C patients with high viral load genotype 1 were investigated. Sixty-two patients were randomized into combination therapy with standard ribavirin dosing (group 1) or low and escalating ribavirin dosing (group 2). Patients were evaluated for safety and efficacy of treatment. There was no significant difference in the prevalence of virological response between the groups throughout the treatment as well as 24 weeks after treatment. However, the response in patients 60 years of age was higher in group 1 than in group 2 at early treatment phase (P=0.015). The prevalence of completion of therapy in patients 60 years of age tended to be higher in group 2 than in group 1 (50% vs. 0%, P=0.055). There was no significant difference in dose modification of peginterferon alpha-2b between the groups. However, dose modification of ribavirin was significantly more frequent in group 1 than in group 2 (60% vs. 24%, P=0.005). These data suggest that combination therapy with low and escalating dosing of ribavirin may be safer in elderly patients than that with standard dosing of ribavirin without impairing the treatment response. J. Med. Virol. 87:625-633, 2015. (c) 2015 Wiley Periodicals, Inc.

DOI： 10.1002/jmv.24097

Use of non-invasive serum glycan markers to distinguish non-alcoholic steatohepatitis from simple steatosis. Reviewed International journal

Yamasaki Y, Nouso K, Miyahara K, Wada N, Dohi C, Morimoto Y, Kinugasa H, Takeuchi Y, Yasunaka T, Kuwaki K, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Iwasaki Y, Amano M, Nishimura S, Yamamoto K

Journal of gastroenterology and hepatology 30 ( 3 ) 528 - 534 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：3

BACKGROUND AND AIMS: Serum glycans have been reported to be promising diagnostic markers for many inflammatory diseases and cancers. The aims of this study were to investigate whole glycan expression in patients with non-alcoholic fatty liver diseases and to evaluate the potential use of glycan profiles as new clinical biomarkers to distinguish non-alcoholic steatohepatitis (NASH) from simple steatosis (SS). METHODS: We collected sera from 42 histologically proven NASH and 15 SS patients prior to treatment. Serum glycan profiles were measured by comprehensive, quantitative, high-throughput glycome analysis, and diagnostic values of serum glycans for NASH prediction were examined. RESULTS: Among the 41 serum glycans examined, the expression levels of 8 glycans in NASH were significantly higher than those of SS. Out of these eight glycans, three glycans (m/z 1955, 2032, and 2584) showed high areas under the receiver operating characteristic curve (0.833, 0.863, and 0.866, respectively) for distinguishing NASH from SS. In multivariate analyses with clinical parameters and serum glycans, these three glycans were significant predictive factors for distinguishing NASH from SS. The odds ratio of m/z 1955, 2032, and 2584 were 48.5, 6.46, and 11.8, respectively. These glycans also correlated significantly with lobular inflammation, ballooning, and fibrosis, but not with steatosis. CONCLUSION: We clearly demonstrated whole-serum glycan profiles in NASH patients, and the feasibility of serum glycans (m/z 1955, 2032, and 2584) as new noninvasive biomarkers for distinguishing NASH from SS.

DOI： 10.1111/jgh.12726

Local recurrence and complications after percutaneous radiofrequency ablation of hepatocellular carcinoma: a retrospective cohort study focused on tumor location. Reviewed

Toshimori J, Nouso K, Nakamura S, Wada N, Morimoto Y, Takeuchi Y, Yasunaka T, Kuwaki K, Ohnishi H, Ikeda F, Shiraha H, Takaki A, Yamamoto K

Acta medica Okayama 69 ( 4 ) 219 - 226 2015

Alpha-fetoprotein before and after pegylated interferon therapy for predicting hepatocellular carcinoma development Reviewed

Yasuto Takeuchi, Fusao Ikeda, Toshiya Osawa, Yasuyuki Araki, Kouichi Takaguchi, Youichi Morimoto, Noriaki Hashimoto, Kousaku Sakaguchi, Tatsuro Sakata, Masaharu Ando, Yasuhiro Makino, Shuji Matsumura, Hiroki Takayama, Hiroyuki Seki, Shintarou Nanba, Yuki Moritou, Tetsuya Yasunaka, Hideki Ohnishi, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

World Journal of Hepatology 7 ( 19 ) 2220 - 2228 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：Baishideng Publishing Group Co

AIM: To investigate factors that accurately predict hepatocellular carcinoma (HCC) development after antiviral therapy in chronic hepatitis C (CHC) patients. METHODS: CHC patients who received pegylated interferon and ribavirin were enrolled in this cohort study that investigated the ability of alpha-fetoprotein (AFP) to predict HCC development after interferon (IFN) therapy. RESULTS: Of 1255 patients enrolled, 665 developed sustained virological response (SVR) during mean follow-up period of 5.4 years. HCC was occurred in 89 patients, and 20 SVR patients were included. Proportional hazard models showed that HCC occurred in SVR patients showing AFP ≥ 5ng/mL before therapy and in non-SVR patients showing AFP ≥ 5ng/mL before and 1year after therapy besides older age, and low platelet counts. SVR patients showing AFP ≥ 5ng/mL before therapy and no decrease in AFP to &lt
5ng/mL 1year after therapy had significantly higher HCC incidence than non-SVR patients showing AFP ≥ 5ng/ mL before therapy and decreased AFP (P = 0.043). AFP ≥ 5ng/mL before therapy was significantly associated with low platelet counts and high values of alanine aminotransferase (ALT) in stepwise logistic regression analysis. After age, gender, platelet count, and ALT was matched by propensity score, significantly lower HCC incidence was shown in SVR patients showing AFP &lt
5ng/mL before therapy than in those showing AFP ≥ 5ng/mL. CONCLUSION: The criteria of AFP &lt
5ng/mL before and 1year after IFN therapy is a benefical predictor for HCC development in CHC patients.

DOI： 10.4254/wjh.v7.i19.2220

Polycythemia Vera Diagnosed after Esophageal Variceal Rupture.

Yoshiyasu Kono, Akinobu Takaki, Hideo Gobara, Ken-Ichi Matsuoka, Masato Nishino, Hiroyuki Okada, Kazuhide Yamamoto

Internal medicine (Tokyo, Japan) 54 ( 18 ) 2395 - 9 2015

Language：English Publishing type：Research paper (scientific journal)

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that leads to hyperviscosity and the risk of thrombosis. We encountered the case of a young male Filipino patient diagnosed with PV after the rupture of esophageal varices. The complete blood cell count showed a slight increase in white blood cells. An abdominal computed tomography scan disclosed splenomegaly and occlusion of the portal vein and collateral vessels. A blood examination demonstrated an increase in all three blood cell lines within three months. Based on the presence of severe hypercellularity of the bone marrow and positivity for the JAK2V617F mutation, we finally diagnosed the patient with PV.

DOI： 10.2169/internalmedicine.54.4687

Ultrastructural analysis of a gastric persimmon phytobezoar Reviewed

Masaya Iwamuro, Haruo Urata, Masumi Furutani, Yoshinari Kawai, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Kazuhide Yamamoto

CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY 38 ( 4 ) E85 - E87 2014.9

L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway Reviewed

Hisashi Ishikawa, Akinobu Takaki, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Yasuyuki Shimomura, Hiroyuki Seki, Hiroshi Matsushita, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Kazuhiro Nouso, Kazuhide Yamamoto

PLOS ONE 9 ( 7 ) 2014.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% alpha-tocopherol (alpha-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial beta-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although alpha-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion: L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial beta-oxidation and redox system.

DOI： 10.1371/journal.pone.0100627

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