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Takeshita, Yumie ; Takamura, Toshinari ; Kita, Yuki ; Ando, Hitoshi ; Ueda, Teruyuki ; Kato, Kenichiro ; Misu, Hirofumi ; Sunagozaka, Hajime ; Sakai, Yoshio ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi
出版情報: Metabolism: Clinical and Experimental.  61  pp.1388-1394,  2012-10-01.  Elsevier
URL: http://hdl.handle.net/2297/32870
概要: Branched-chain amino acids (BCAAs) improve disorders of albumin metabolism, quality of life, subjective symptoms, and prognosis in patients with chronic hepatitis. However, it remains unclear whether they improve insulin resistance. We examined the effects of BCAAs on glucose tolerance and insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Individuals with a definitive diagnosis of chronic hepatitis C and insulin resistance were eligible for participation. Eligible participants were randomly assigned to the BCAA group or a control group. Participants were then crossed over to the other treatment for a further 12 weeks. Baseline clinical features, laboratory markers, fatty acid levels, and insulin sensitivity, assessed with oral glucose tolerance tests and a hyperinsulinemic euglycemic clamp, were also examined before and 12 and 24 weeks after the beginning of the study. Of the 27 patients who completed the study, 14 began in the BCAA group and 13 began as controls. There were no significant differences in glucose metabolism parameters or lipid profiles between the groups. HbA1c values were improved in 10 patients and worsened or remained unchanged in 17 patients. The only predictive variable for change in HbA1c was the baseline Matsuda index: the lower the index, the greater the improvement in HbA1c values. BCAA therapy did not have adverse effects on glucose tolerance or insulin sensitivity in patients with chronic hepatitis C and insulin resistance. Moreover, it had a therapeutic effect on HbA1c values in patients with marked peripheral (primarily muscle) insulin resistance. © 2012 Elsevier Inc. 続きを見る
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Terashima, Takeshi ; Yamashita, Tatsuya ; Arai, Kuniaki ; Kawaguchi, Kazunori ; Kitamura, Kazuya ; Yamashita, Taro ; Sakai, Yoshio ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi
出版情報: Cancer Science.  107  pp.1263-1269,  2016-09-01.  Japanese Cancer Association / Blackwell Publishing Ltd
URL: http://hdl.handle.net/2297/46176
概要: There is no established treatment for patients with advanced hepatocellular carcinoma (HCC) with Child–Pugh class B cirrhosis. The aim of the present study was to assess the efficacy of hepatic arterial infusion chemotherapy (HAIC) according to Child–Pugh score (CPS) and to evaluate the correlation of a patient's response to HAIC with hepatic reserve and outcome. We retrospectively reviewed the medical records of 377 patients treated with HAIC between March 2003 and February 2015. Subjects included 179 with Child–Pugh class B. Median overall survival was 12.1 months for patients with CPS = 7 (n = 75) and 11.9 months for patients with CPS = 8 (n = 58), which were significantly longer compared with those of patients with CPS = 9 (n = 46, 6.3 months). The objective response rates of patients with CPS = 7, 8 and 9 were 26.7%, 27.6% and 6.5%, respectively. The CPS of responders improved significantly after HAIC, whereas those of nonresponders did not. A multivariate analysis demonstrated that improved CPS, responses to HAIC and absence of extrahepatic lesions were independent favorable prognostic factors. Patients with CPS = 7 or 8 tolerated HAIC, but nine (19.6%) of patients with CPS = 9 were unable to complete one course. HAIC is effective and safe for patients with a CPS = 7 or 8 and improved hepatic reserve of responders significantly. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 続きを見る
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Zeng, Sha Sha ; Yamashita, Taro ; Kondo, Mitsumasa ; Nio, Kouki ; Hayashi, Takehiro ; Hara, Yasumasa ; Nomura, Yoshimoto ; Yoshida, Mariko ; Hayashi, Tomoyuki ; Oishi, Naoki ; Ikeda, Hiroko ; Honda, Masao ; Kaneko, Shuichi
出版情報: Journal of Hepatology.  60  pp.127-134,  2014-01-01.  Elsevier
URL: http://hdl.handle.net/2297/36257
概要: Background & Aims: Recent evidence suggests that hepatocellular carcinoma can be classified into certain molecular subtypes with distinct prognoses based on the stem/maturational status of the tumor. We investigated the transcription program deregulated in hepatocellular carcinomas with stem cell features. Methods: Gene and protein expression profiles were obtained from 238 (analyzed by microarray), 144 (analyzed by immunohistochemistry), and 61 (analyzed by qRT-PCR) hepatocellular carcinoma cases. Activation/suppression of an identified transcription factor was used to evaluate its role in cell lines. The relationship of the transcription factor and prognosis was statistically examined. Results: The transcription factor SALL4, known to regulate stemness in embryonic and hematopoietic stem cells, was found to be activated in a hepatocellular carcinoma subtype with stem cell features. SALL4-positive hepatocellular carcinoma patients were associated with high values of serum alpha fetoprotein, high frequency of hepatitis B virus infection, and poor prognosis after surgery compared with SALL4-negative patients. Activation of SALL4 enhanced spheroid formation and invasion capacities, key characteristics of cancer stem cells, and up-regulated the hepatic stem cell markers KRT19, EPCAM, and CD44 in cell lines. Knockdown of SALL4 resulted in the down-regulation of these stem cell markers, together with attenuation of the invasion capacity. The SALL4 expression status was associated with histone deacetylase activity in cell lines, and the histone deacetylase inhibitor successfully suppressed proliferation of SALL4-positive hepatocellular carcinoma cells. Conclusions: SALL4 is a valuable biomarker and therapeutic target for the diagnosis and treatment of hepatocellular carcinoma with stem cell features. © 2013 European Association for the Study of the Liver. 続きを見る
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Yamashita, Taro ; Honda, Masao ; Nio, Kouki ; Nakamoto, Yasunari ; Yamashita, Tatsuya ; Takamura, Hiroyuki ; Tani, Takashi ; Zen, Yoh ; Kaneko, Shuichi
出版情報: Cancer Research.  70  pp.4687-4697,  2010-06-01.  American Association for Cancer Research
URL: http://hdl.handle.net/2297/24560
概要: 金沢大学附属病院消化器内科<br />Recent evidence suggests that a certain type of hepatocellular carcinoma (HCC) is hierarchicall y organized by a subset of cells with stem cell features (cancer stem cells; CSC). Although normal stem cells and CSCs are considered to share similar self-renewal programs, it remains unclear whether differentiation programs are also maintained in CSCs and effectively used for tumor eradication. In this study, we investigated the effect of oncostatin M (OSM), an interleukin 6-related cytokine known to induce the differentiation of hepatoblasts into hepatocytes, on liver CSCs. OSM receptor expression was detected in the majority of epithelial cell adhesion molecule-positive (EpCAM+) HCC with stem/progenitor cell features. OSM treatment resulted in the induction of hepatocytic differentiation of EpCAM+ HCC cells by inducing signal transducer and activator of transcription 3 activation, as determined by a decrease in stemness-related gene expression, a decrease in EpCAM, α-fetoprotein and cytokeratin 19 protein expressions, and an increase in albumin protein expression. OSM-treated EpCAM+ HCC cells showed enhanced cell proliferation with expansion of the EpCAM-negative non-CSC population. Noticeably, combination of OSM treatment with the chemotherapeutic agent 5-fluorouracil (5-FU), which eradicates EpCAM-negative non-CSCs, dramatically increased the number of apoptotic cells in vitro and suppressed tumor growth in vivo compared with either saline control, OSM, or 5-FU treatment alone. Taken together, our data suggest that OSM could be effectively used for the differentiation and active cell division of dormant EpCAM+ liver CSCs, and the combination of OSM and conventional chemotherapy with 5-FU efficiently eliminates HCC by targeting both CSCs and non-CSCs. ©2010 AACR. 続きを見る
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Honda, Masao ; Sakai, Yoshio ; Yamashita, Taro ; Yamashita, Tatsuya ; Sakai, Akito ; Mizukoshi, Eishiro ; Nakamoto, Yasunari ; Tatsumi, Isamu ; Miyazaki, Yoshitaka ; Tanno, Hiroshi ; Kaneko, Shuichi ; Hokuriku Liver Study Group
出版情報: Biochemical and Biophysical Research Communications.  400  pp.7-15,  2010-09-01.  Elsevier
URL: http://hdl.handle.net/2297/25265
概要: 金沢大学医薬保健研究域医学系<br />To develop a non-invasive and sensitive diagnostic test for cancer using peripheral blood, we evaluated gene expression profiling of blood obtained from patients with cancer of the digestive system and normal subjects. The expression profiles of blood-derived total RNA obtained from 39 cancer patients (11 colon cancer, 14 gastric cancer, and 14 pancreatic cancer) was clearly different from those obtained from 15 normal subjects. By comparing the gene expression profiles of cancer patients and normal subjects, 25 cancer-differentiating genes (p<5.0×10-6 and fold differences >3) were identified and an " expression index" deduced from the expression values of these genes differentiated the validation cohort (11 colon cancer, 8 gastric cancer, 18 pancreatic cancer, and 15 normal subjects) into cancer patients and normal subjects with 100% (37/37) and 87% (13/15) accuracy, respectively. Although, the expression profiles were not clearly different between the cancer patients, some characteristic genes were identified according to the stage and species of the cancer. Interestingly, many immune-related genes such as antigen presenting, cell cycle accelerating, and apoptosis- and stress-inducing genes were up-regulated in cancer patients, reflecting the active turnover of immune regulatory cells in cancer patients. These results showed the potential relevance of peripheral blood gene expression profiling for the development of new diagnostic examination tools for cancer patients. © 2010 Elsevier Inc. 続きを見る
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Komura, Takuya ; Sakai, Yoshio ; Honda, Masao ; Takamura, Toshinari ; Matsushima, Kouji ; Kaneko, Shuichi
出版情報: Diabetes.  59  pp.634-643,  2010-03-01.  American Diabetes Association
URL: http://hdl.handle.net/2297/23966
概要: 金沢大学医薬保健研究域医学系<br />OBJECTIVE - Although patients with diabetes suffer from increased infections and a higher inci dence of cancer due to impaired immune function, details on diabetes-induced decrease in immunity are lacking. We assessed how immune-mediating peripheral blood mononuclear cells (PBMCs) are affected in diabetes. RESEARCH DESIGN AND METHODS - From 33 patients with type 2 diabetes and 28 healthy volunteers, we obtained PBMCs and investigated their susceptibility to apoptosis and functional alteration. RESULTS - In a subpopulation of PBMCs, monocytes derived from patients with diabetes were more susceptible to apoptosis than monocytes from healthy volunteers. Monocytes from patients with diabetes had decreased phagocytotic activity and were less responsive to Toll-like receptor (TLR) ligands, although the expression of TLRs did not differ significantly between the two groups. Furthermore, monocytes from patients with diabetes had a distinctly different gene expression profile compared with monocytes from normal volunteers as assessed with DNA microarray analysis. Specifically, quantitative real-time detection PCR measurements showed an elevated expression of the markers of endoplasmic reticulum (ER) stress in diabetic monocytes, and electron microscopic examination of monocytes revealed morphologic alterations in the ER of cells derived from patients with diabetes. Consistently, the ER stress inducer tunicamycin increased apoptosis of otherwise healthy monocytes and attenuated the proinflammatory responses to TLR ligands. CONCLUSIONS - These data suggest that monocytes comprise a substantially impaired subpopulation of PBMCs in patients with diabetes and that ER stress is involved in these pathologic changes mechanistically. This implies that the affected monocytes should be investigated further to better understand diabetic immunity. © 2010 by the American Diabetes Association. 続きを見る
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Honda, Masao ; Sakai, Akito ; Yamashita, Tatsuya ; Nakamotoa, Yasunari ; Mizukoshi, Eishiro ; Sakai, Yoshio ; Yamashita, Taro ; Nakamura, Mikiko ; Shirasaki, Takayoshi ; Horimoto, Katsuhisa ; Tanaka, Yasuhito ; Tokunaga, Katsushi ; Mizokami, Masashi ; Kaneko, Shuichi ; Hokuriku Liver Study Group
出版情報: Gastroenterology.  139  pp.499-509,  2010-08-01.  Elsevier
URL: http://hdl.handle.net/2297/25264
概要: 金沢大学医薬保健研究域医学系<br />Background & Aims: Multiple viral and host factors are related to the treatment response t o pegylated-interferon and ribavirin combination therapy; however, the clinical relevance and relationship of these factors have not yet been fully evaluated. Methods: We studied 168 patients with chronic hepatitis C who received pegylated-interferon and ribavirin combination therapy. Gene expression profiles in the livers of 91 patients were analyzed using an Affymetrix genechip (Affymetrix, Santa Clara, CA). The expression of interferon-stimulated genes (ISGs) was evaluated in all samples by real-time polymerase chain reaction. Genetic variation in interleukin 28B (IL28B; rs8099917) was determined in 91 patients. Results: Gene expression profiling of the liver differentiated patients into 2 groups: patients with up-regulated ISGs and patients with down-regulated ISGs. A high proportion of patients with no response to treatment was found in the up-regulated ISGs group (P = .002). Multivariate logistic regression analysis showed that ISGs (<3.5) (odds ratio [OR], 16.2; P < .001), fibrosis stage (F1-F2) (OR, 4.18; P = .003), and ISDR mutation (<2) (OR, 5.09; P = .003) were strongly associated with the viral response. The IL28B polymorphism of 91 patients showed that 66% were major homozygotes (TT), 30% were heterozygotes (TG), and 4% were minor homozygotes (GG). Interestingly, hepatic ISGs were associated with the IL28B polymorphism (OR, 18.1; P < .001), and its expression was significantly higher in patients with the minor genotype (TG or GG) than in those with the major genotype (TT). Conclusions: The expression of hepatic ISGs is strongly associated with treatment response and genetic variation of IL28B. The differential role of host and viral factors as predicting factors may also be present. © 2010 AGA Institute. 続きを見る
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Hodo, Yuji ; Hashimoto, Shin-ichi ; Honda, Masao ; Yamashita, Taro ; Suzuki, Yutaka ; Sugano, Sumio ; Kaneko, Shuichi ; Matsushima, Kouji
出版情報: Genomics.  95  pp.217-223,  2010-04-01.  Elsevier
URL: http://hdl.handle.net/2297/23897
概要: 金沢大学医薬保健研究域医学系<br />To elucidate the molecular feature of human hepatocellular carcinoma (HCC), we performed 5 9;-end serial analysis of gene expression (5'SAGE), which allows genome-wide identification of transcription start sites in addition to quantification of mRNA transcripts. Three 5'SAGE libraries were generated from normal human liver (NL), non-B, non-C HCC tumor (T), and background non-tumor tissues (NT). We obtained 226,834 tags from these libraries and mapped them to the genomic sequences of a total of 8,410 genes using RefSeq database. We identified several novel transcripts specifically expressed in HCC including those mapped to the intronic regions. Among them, we confirmed the transcripts initiated from the introns of a gene encoding acyl-coenzyme A oxidase 2 (. ACOX2). The expression of these transcript variants were up-regulated in HCC and showed a different pattern compared with that of ordinary ACOX2 mRNA. The present results indicate that the transcription initiation of a subset of genes may be distinctively altered in HCC, which may suggest the utility of intronic RNAs as surrogate tumor markers. © 2010 Elsevier Inc. 続きを見る
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Matsuzawa-Nagata, Naoto ; Takamura, Toshinari ; Ando, Hitoshi ; Nakamura, Seiji ; Kurita, Seiichiro ; Misu, Hirofumi ; Ota, Tsuguhito ; Yokoyama, Masayoshi ; Honda, Masao ; Miyamoto, Ken-ichi ; Kaneko, Shuichi
出版情報: Metabolism: Clinical and Experimental.  57  pp.1071-1077,  2008-08-01.  Elsevier
URL: http://hdl.handle.net/2297/11570
概要: 金沢大学医薬保健研究域医学系<br />Insulin resistance is a key pathophysiological feature of metabolic syndrome. However, the ini tial events triggering the development of insulin resistance and its causal relations with dysregulation of glucose and fatty acids metabolism remain unclear. We investigated biological pathways that have the potential to induce insulin resistance in mice fed a high-fat diet (HFD). We demonstrate that the pathways for reactive oxygen species (ROS) production and oxidative stress are coordinately up-regulated in both the liver and adipose tissue of mice fed an HFD before the onset of insulin resistance through discrete mechanism. In the liver, an HFD up-regulated genes involved in sterol regulatory element binding protein 1c-related fatty acid synthesis and peroxisome proliferator-activated receptor α-related fatty acid oxidation. In the adipose tissue, however, the HFD down-regulated genes involved in fatty acid synthesis and up-regulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Furthermore, increased ROS production preceded the elevation of tumor necrosis factor-α and free fatty acids in the plasma and liver. The ROS may be an initial key event triggering HFD-induced insulin resistance. © 2008 Elsevier Inc. All rights reserved. 続きを見る
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Sunagozaka, Hajime ; Honda, Masao ; Yamashita, Taro ; Nishino, Ryuhei ; Takatori, Hajime ; Arai, Kuniaki ; Yamashita, Tatsuya ; Sakai, Yoshio ; Kaneko, Shuichi
出版情報: International Journal of Cancer.  129  pp.1576-1585,  2011-11-01.  Wiley-Blackwell
URL: http://hdl.handle.net/2297/29268
概要: The identification of genes involved in tumor growth is crucial for the development of inventive anticancer treatments. Here, we have cloned a 17-kDa secretory protein encoded by c19orf10 from hepatocellular carcinoma (HCC) serial analysis of gene expression libraries. Gene expression analysis indicated that c19orf10 was overexpressed in approximately two-thirds of HCC tissues compared to the adjacent noncancerous liver tissues, and its expression was significantly positively correlated with that of alpha-fetoprotein (AFP). Overexpression of c19orf10 enhanced cell proliferation of AFP-negative HLE cells, whereas knockdown of c19orf10 inhibited cell proliferation of AFP-positive Hep3B and HuH7 cells along with G1 cell cycle arrest. Supplementation of recombinant c19orf10 protein in culture media enhanced cell proliferation in HLE cells, and this effect was abolished by the addition of antibodies developed against c19orf10. Intriguingly, c19orf10 could regulate cell proliferation through the activation of Akt/mitogen-activated protein kinase pathways. Taken together, these data suggest that c19orf10 might be one of the growth factors and potential molecular targets activated in HCC. Copyright © 2010 UICC. 続きを見る