Faculty Profiles - TAKAKI Akinobu

PubMed

Multiple hits, including oxidative stress, as pathogenesis and treatment target in non-alcoholic steatohepatitis (NASH)

Akinobu Takaki, Daisuke Kawai, Kazuhide Yamamoto

International Journal of Molecular Sciences 14 ( 10 ) 20704 - 20728 2013.10

Language：English Publishing type：Book review, literature introduction, etc.

Multiple parallel hits, including genetic differences, insulin resistance and intestinal microbiota, account for the progression of non-alcoholic steatohepatitis (NASH). Multiple hits induce adipokine secretion, endoplasmic reticulum (ER) and oxidative stress at the cellular level that subsequently induce hepatic steatosis, inflammation and fibrosis, among which oxidative stress is considered a key contributor to progression from simple fatty liver to NASH. Although several clinical trials have shown that anti-oxidative therapy can effectively control hepatitis activities in the short term, the long-term effect remains obscure. Several trials of long-term anti-oxidant protocols aimed at treating cerebrovascular diseases or cancer development have failed to produce a benefit. This might be explained by the non-selective anti-oxidative properties of these drugs. Molecular hydrogen is an effective antioxidant that reduces only cytotoxic reactive oxygen species (ROS) and several diseases associated with oxidative stress are sensitive to hydrogen. The progress of NASH to hepatocellular carcinoma can be controlled using hydrogen-rich water. Thus, targeting mitochondrial oxidative stress might be a good candidate for NASH treatment. Long term clinical intervention is needed to control this complex lifestyle-related disease. © 2013 by the authors
licensee MDPI, Basel, Switzerland.

DOI： 10.3390/ijms141020704

PubMed

Serum Glycan Markers for Evaluation of Disease Activity and Prediction of Clinical Course in Patients with Ulcerative Colitis

Koji Miyahara, Kazuhiro Nouso, Shunsuke Saito, Sakiko Hiraoka, Keita Harada, Sakuma Takahashi, Yuki Morimoto, Sayo Kobayashi, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Hiroyuki Okada, Maho Amano, Kazuko Hirose, Shin-Ichiro Nishimura, Kazuhide Yamamoto

PLoS ONE 8 ( 10 ) e74861-e74861 2013.10

Language：English

Background:The aims of this study were to determine the change of whole-serum N-glycan profile in ulcerative colitis (UC) patients and to investigate its clinical utility.Methods:We collected serum from 75 UC patients at the time of admission and the same number of age/sex-matched healthy volunteers. Serum glycan profile was measured by comprehensive quantitative high-throughput glycome analysis and was compared with disease activity and prognosis.Results:Out of 61 glycans detected, 24 were differentially expressed in UC patients. Pathway analysis demonstrated that highly sialylated multi-branched glycans and agalactosyl bi-antennary glycans were elevated in UC patients
in addition, the glycan ratio m/z 2378/1914, which also increased in UC, showed the highest Area under Receiver Operating Characteristic curve (0.923) for the diagnosis of UC. Highly sialylated multi-branched glycans and the glycan ratio m/z 2378/1914 were higher in the patients with total colitis, Clinical Activity Index &gt
10, Mayo endoscopic score 3, or a steroid-refractory status. In particular, the glycan ratio m/z 2378/1914 (above median) was an independent prognostic factor for the need for an operation (hazard ratio, 2.67
95% confidence interval, 1.04-7.84).Conclusions:Whole-serum glycan profiles revealed that the glycan ratio m/z 2378/1914 and highly sialylated multi-branched glycans increase in UC patients, and are correlated with disease activity. The glycan ratio m/z 2378/1914 was an independent predictive factor of the prognosis of UC. © 2013 Miyahara et al.

DOI： 10.1371/journal.pone.0074861

PubMed

Pro-angiogenic cytokines for prediction of outcomes in patients with advanced hepatocellular carcinoma

K. Miyahara, K. Nouso, Y. Morimoto, Y. Takeuchi, H. Hagihara, K. Kuwaki, H. Onishi, F. Ikeda, Y. Miyake, S. Nakamura, H. Shiraha, A. Takaki, M. Honda, S. Kaneko, T. Sato, S. Sato, S. Obi, S. Iwadou, Y. Kobayashi, K. Takaguchi, K. Kariyama, Y. Takuma, H. Takabatake, K. Yamamoto

BRITISH JOURNAL OF CANCER 109 ( 8 ) 2072 - 2078 2013.10

Language：English Publisher：NATURE PUBLISHING GROUP

Background: We previously reported that expressions of the pro-angiogenic cytokines angiopoietin-2 (Ang-2), follistatin, granulocyte colony-stimulating factor, hepatocyte growth factor, leptin, platelet-derived growth factor-BB, platelet endothelial cell adhesion molecule-1, and vascular endothelial growth factor were associated with the response to sorafenib in patients with advanced hepatocellular carcinoma (HCC). The aim of the present study is to examine the same relationship in a larger cohort.Methods: In the current retrospective cohort study, we measured serum levels of the eightcytokines in 120 consecutive HCC patients who were treated with sorafenib. We evaluated the effects of increased expression of serum cytokines on progression-free survival (PFS) and overall survival (OS).Results: Elevated expression of Ang-2 correlated both with significantly shorter PFS (hazard ratio (HR), 1.84; 95% confidence interval (CI), 1.21-2.81), and OS (HR, 1.95; 95% CI, 1.21-3.17). Patients with more than three cytokines expressed above the median similarly had significantly shorter PFS (HR, 1.98; 95% CI, 1.30-3.06) and OS (HR, 1.94; 95% CI, 1.19-3.22). Differences in OS were evident in cases with the evidence of macroscopic vascular invasion or extrahepatic metastasis.Conclusion: High expression of Ang-2 or more than cytokines in serum is associated with poor PFS and OS in HCC patients treated with sorafenib.

DOI： 10.1038/bjc.2013.554

Clinical utility of high-throughput glycome analysis in patients with pancreatic cancer

Kazuhiro Nouso, Maho Amano, Yoichi M. Ito, Koji Miyahara, Yuki Morimoto, Hironari Kato, Koichiro Tsutsumi, Takeshi Tomoda, Naoki Yamamoto, Shinichiro Nakamura, Sayo Kobayashi, Kenji Kuwaki, Hiroaki Hagihara, Hideki Onishi, Yasuhiro Miyake, Fusao Ikeda, Hidenori Shiraha, Akinobu Takaki, Taku Nakahara, Shin-Ichiro Nishimura, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY 48 ( 10 ) 1171 - 1179 2013.10

Language：English Publisher：SPRINGER JAPAN KK

Most of the glycan changes reported in cancers were based on the examinations of a small number of patients or particular proteins. The aim of this study was to determine the changes of the serum N-glycan profile comprehensively in a large number of pancreatic cancer patients and investigate its clinical utility.
Glycan levels in the serum of 92 pancreatic cancer patients and 243 healthy volunteers (HLT) were examined by comprehensive quantitative high-throughput glycome analysis and were compared with clinical parameters.
Out of 66 glycans detected, 15 were differentially expressed in pancreatic cancer, and 10 out of the 15 glycans were significantly up-regulated in cases with distant metastasis. There was a clear increase in overall expression of serum glycans, especially highly-branched glycans with fucose moieties, in pancreatic cancer. Among these 15 glycans, a tri-antennary complex type glycan (m/z 3195) showed the highest area under the receiver operating characteristic curve (AUROC = 0.799) for the diagnosis of pancreatic cancer. The ratio of pairs of glycans on the same path of the biosynthesis pathway (m/z 3195/1914) was found to be significantly higher in pancreatic cancer than in HLT (median = 1.11 and 0.41, respectively; p < 0.0001, AUROC = 0.831). For this pair ratio, the hazard ratio for survival (2.60, 95 % CI = 1.44-4.79) was higher than that of any single glycan and 1-year survival of patients with a high and low ratio was 36.9 and 69.2 %, respectively, (p = 0.001).
Comprehensive glycome analysis can be used to know the presence of pancreatic cancer, distant metastasis, and patient prognosis, simultaneously.

DOI： 10.1007/s00535-012-0732-7

Serial Changes of Serum Growth Factor Levels and Liver Regeneration after Partial Hepatectomy in Healthy Humans

Kazuyuki Matsumoto, Yasuhiro Miyake, Yuzo Umeda, Hiroshi Matsushita, Hiroaki Matsuda, Akinobu Takaki, Hiroshi Sadamori, Kazuhiro Nouso, Takahito Yagi, Toshiyoshi Fujiwara, Kazuhide Yamamoto

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 14 ( 10 ) 20877 - 20889 2013.10

Language：English Publisher：MDPI AG

This study aimed to investigate the associations of the serial changes of serum levels of various growth factors with liver regeneration after hepatectomy in healthy liver donors. Sixteen healthy liver donors who underwent conventional liver resection were included. Serum levels of various growth factors before hepatectomy and on postoperative day (POD) 1, 3, 5 and 7 were measured. Liver volume data calculated by multi-detector computed tomography using workstation. The ratio of remnant liver volume on POD 0 to liver volume before the operation was 51% +/- 20%. The ratio of liver volume on POD 14 to liver volume on POD 0 were inversely correlated with remnant liver volume on POD 0 (r = -0.91). The ratio of liver volume on POD 14 to liver volume on POD 0 were significantly correlated with serum hepatocyte growth factor (HGF) levels on POD 1 (r = 0.54), serum leptin levels on POD 1 (r = 0.54), and serum macrophage colony-stimulating factor (M-CSF) levels on POD 5 (r = 0.76) and POD 7 (r = 0.80). These results suggest that early-phase elevation of serum levels of HGF, leptin and M-CSF may be associated with the acceleration of liver regeneration after hepatectomy in humans.

DOI： 10.3390/ijms141020877

Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma

Mamoru Nishimura, Akinobu Takaki, Naofumi Tamaki, Takayuki Maruyama, Hideki Onishi, Sayo Kobayashi, Kazuhiro Nouso, Tetsuya Yasunaka, Kazuko Koike, Hiroaki Hagihara, Kenji Kuwaki, Shinichiro Nakamura, Fusao Ikeda, Yoshiaki Iwasaki, Takaaki Tomofuji, Manabu Morita, Kazuhide Yamamoto

Hepatology Research 43 ( 10 ) 1078 - 1092 2013.10

Language：English

Aim: Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. Methods: We recruited a study population of 208 patients, including healthy volunteers (HV
n=15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n=25, and HBV-HCC, n=50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n=49, and HCV-HCC, n=69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test
OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. Results: Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. Conclusion: HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication. © 2012 The Japan Society of Hepatology.

DOI： 10.1111/hepr.12048

Evaluation of the effect of sorafenib using serum NX-des-gamma-carboxyprothrombin in patients with hepatocellular carcinoma

Koji Miyahara, Kazuhiro Nouso, Yuki Morimoto, Takeshi Tomoda, Sayo Kobayashi, Yasuto Takeuchi, Hiroaki Hagihara, Kenji Kuwaki, Hideki Ohnishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

HEPATOLOGY RESEARCH 43 ( 10 ) 1064 - 1070 2013.10

Language：English Publisher：WILEY-BLACKWELL

AimDes--carboxyprothrombin (DCP) is known to be increased by the use of sorafenib for the treatment of hepatocellular carcinoma (HCC), despite its therapeutic efficacy. In addition to the tumor progression, hypoxia that impairs vitamin K uptake is known to induce DCP and this mechanism may explain DCP elevation by sorafenib. In this study, we tried to evaluate the effect of sorafenib treatment using a new marker, NX-DCP, which is specific to vitamin K absence.
MethodsSerum DCP and NX-DCP were measured in 50 consecutive HCC patients before and 1 week after starting sorafenib, and compared with the treatment effect using the modified Response Evaluation Criteria in Solid Tumors guidelines.
ResultsDCP and NX-DCP increased 1.58- (median, range 0.21-28.7) and 1.20-fold (median, range 0.41-14.2) after the administration of sorafenib, respectively. The increases of both markers were less than twofold in approximately half of the patients (low-elevation group). However, 12 patients showed over twofold increase of both DCP and NX-DCP (double-elevation group), and eight patients showed over twofold increase of DCP alone (DCP-elevation group). The disease control rate (DCR) of the DCP-elevation group (12.5%) was significantly lower than those of the double-elevation group (75.0%, P=0.020) and the low-elevation group (60.0%, P=0.042). Progression-free survival (PFS) was significantly shorter in the DCP-elevation group than in the double-elevation group (P=0.006) and the low-elevation group (P=0.001).
ConclusionNX-DCP in combination with DCP could be a useful biomarker of sorafenib treatment for advanced HCC.

DOI： 10.1111/hepr.12055

Strong hepatitis C virus-specific T-cell immune responses correlate with lower hepatitis activities and donor IL28B major genotype in the early period after living donor liver transplantation

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

HEPATOLOGY 58 1048A - 1048A 2013.10

Nucleoside analogue treatment can not reduce the incidence of hepatocellular carcinoma in patients with chronic hepatitis B

Tetsuya Yasunaka, Fusao Ikeda, Nozomu Wada, Yuuki Morimoto, Kenji Kuwaki, Akinobu Takaki, Kazuhide Yamamoto

HEPATOLOGY 58 671A - 671A 2013.10

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

Akinobu Takaki, Masashi Utsumi, Kazuko Koike, Takahito Yagi, Nobukazu Watanabe, Ryuichiro Tsuzaki, Hirsohi Sadamori, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Tetsuya Yasunaka, Hidenori Shiraha, Kazuhide Yamamoto

HEPATOLOGY 58 1178A - 1178A 2013.10

Prediction of Survival in Patients with Hepatocellular Carcinoma Treated with Sorafenib by Comprehensive Serum Glycan Analysis

Kazuhiro Nouso, Koji Miyahara, Yuuki Morimoto, Yasuto Takeuchi, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Fusao Ikeda, Yasuhiro Miyake, Shinichiro Nakamura, Hidenori Shiraha, Akinobu Takaki, Koichi Takaguchi, Takahisa Sato, Shinpei Sato, Shuntaro Obi, Kazuko Hirose, Maho Amano, Shin-Ichiro Nishimura, Kazuhide Yamamoto

HEPATOLOGY 58 1242A - 1242A 2013.10

Predictive impacts of alpha-fetoprotein levels on development of hepatocellular carcinoma during interferon therapy for chronic hepatitis C

Yasuto Takeuchi, Fusao Ikeda, Tetsuya Yasunaka, Yasuhiro Miyake, Akinobu Takaki, Kazuhiro Nouso, Yoshiaki Iwasaki, Kazuhide Yamamoto

HEPATOLOGY 58 1128A - 1129A 2013.10

肝細胞癌遠隔転移と血小板の関係

森元裕貴, 能祖一裕, 和田望, 竹内康人, 宮原孝治, 萩原宏明, 桑木健志, 安中哲也, 大西秀樹, 三宅康広, 中村進一郎, 白羽英則, 高木章乃夫, 山本和秀

肝臓 54 ( Suppl.2 ) A638 - A638 2013.9

TACE不応症例への治療戦略の検討

和田望, 能祖一裕, 中村進一郎, 森元裕貴, 竹内康人, 安中哲也, 萩原宏明, 桑木健志, 大西秀樹, 白羽英則, 高木章乃夫, 山本和秀

肝臓 54 ( Suppl.2 ) A641 - A641 2013.9

肝細胞におけるCK7の発現はPBCの予後予測に有用である

関博之, 池田房雄, 竹内康人, 森藤由記, 難波真太郎, 安中哲也, 三宅康広, 高木章乃夫, 岩崎良章, 山本和秀

肝臓 54 ( Suppl.2 ) A646 - A646 2013.9

Prognotic impact of serum follistatin in patients with hepatocellular carcinoma

Takeshi Tomoda, Kazuhiro Nouso, Koji Miyahara, Sayo Kobayashi, Hideaki Kinugasa, Junki Toyosawa, Hiroaki Hagihara, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Akinobu Takaki, Kazuhide Yamamoto

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 28 ( 8 ) 1391 - 1396 2013.8

Language：English Publisher：WILEY-BLACKWELL

Background and Aim: Follistatin (FST) is a glycoprotein expressed in most organs, which interacts with activins or other members of the transforming growth factor beta family. Recently, several reports have shown that FST regulates a variety of processes during tumor progression. Here, serum FST in patients with liver diseases was measured, and its clinical utility as a biomarker was assessed.
Methods: Serum was collected from 162 patients (91 hepatocellular carcinoma [HCC], 43 liver cirrhosis, and 28 chronic hepatitis) as well as from 16 healthy volunteers. FST was quantified by enzyme-linked immunosorbent assays, and levels were compared with clinical parameters including survival of the HCC patients.
Results: Median serum FST levels in HCC, liver cirrhosis, chronic hepatitis, and healthy volunteers were 1168, 1606, 1324, and 1661 pg/mL, respectively, not significantly different. In HCC patients, higher serum FST was associated with greater age, hepatitis C virus antibody-negativity, large tumor size, g-glutamyl transpeptidase, des-gamma carboxyprothrombin and presence of portal vein tumor thrombus. Survival of HCC patients with high FST levels was significantly shorter than for those with low levels (P = 0.004). Multivariate analysis revealed that in addition to large tumor size and presence of portal vein thrombus, high FST levels were independently correlated with poor prognosis (hazard ratio = 2.41, 95% confidence interval = 1.16-5.00, P = 0.02).
Conclusions: Serum FST levels are significantly associated with HCC prognosis and could represent a predictive biomarker in this disease.

DOI： 10.1111/jgh.12167