1.

論文

論文
Iwata, Yasunori ; Wada, Takashi ; Yokoyama, Hitoshi ; Toyama, Tadashi ; Kitajima, Shinji ; Okumura, Toshiya ; Hara, Akinori ; Yamahana, Junya ; Nakaya, Izaya ; Kobayashi, Motoo ; Kitagawa, Kiyoki ; Kokubo, Satoshi ; Yoshimoto, Keiichi ; Shimizu, Kazuaki ; Sakai, Norihiko ; Furuichi, Kengo ; Koshino, Yoshitaka ; Takaeda, Chikako ; Takeda, Shinichi ; Takasawa, Kazuya ; Ohta, Satoshi ; Takaeda, Masayoshi ; Kaneko, Shuichi
出版情報: Internal Medicine.  46  pp.447-452,  2007-04-08.  日本内科学会
URL: http://hdl.handle.net/2297/6249
概要: 金沢大学保健管理センター<br />金沢大学大学院医学系研究科<br />金沢大学附属病院<br />Background: In hemodialysis patients, adynamic bone disease has been reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. Methods: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). Results: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31±18 pg/mL to 95±96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. Conclusion: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes. © 2007 The Japanese Society of Internal Medicine. 続きを見る
2.

論文

論文
金子, 周一 ; Kaneko, Shuichi
出版情報: 平成25(2013)年度 科学研究費補助金 基盤研究(A) 研究成果報告書.  2011-05-31 – 2014-03-31  pp.4p.-,  2014-05-16.  金沢大学医学系
URL: http://hdl.handle.net/2297/00049427
概要: 肝臓が産生する新規のタンパク(ヘパトカイン)と糖尿病を中心とする生活習慣病との関連を解析した。我々は、ヘパトカインとしてセレノプロテインPを同定したが(Cell Metabolism 2010)、このヘパトカインが脂肪組織および筋組織と関連 してインスリン抵抗性を引き起こすこと(Pros one 2012, 2014)、このヘパトカインに対する薬剤のひとつがメトフォルミンであることを明らかにした(J Biol Chem 2014)。新規のヘパトカインとしてleukocyte cell-derived chemotaxin 2 (LECT2)を同定し(Diabetes 2014)研究を行った。<br />研究課題/領域番号:23249042, 研究期間(年度):2011-05-31 – 2014-03-31 続きを見る
3.

論文

論文
金子, 周一 ; Kaneko, Shuichi
出版情報: 平成22(2010)年度 科学研究費補助金 基盤研究(S) 研究成果報告書.  2006-2010  pp.6p.-,  2011-05-18.  金沢大学医学系
URL: http://hdl.handle.net/2297/00049428
概要: 肝臓は、糖・タンパク・脂質の代謝や薬物および異物の解毒を専門とする巨大な臓器である。大量の物質を血液から取り込んで代謝し、全身の臓器に代謝物を供給する。21世紀の最大の課題である動脈硬化、糖尿病、癌、炎症といった栄養状態が関与する症候群に、 肝臓の機能破綻が大きく関与している可能性を示した。本研究は、過栄養状態における肝臓の変化を明らかにすることによって新たな肝臓病の疾病概念を確立するとともに、肝臓機能の破綻によって生じる肝代謝異常の診断および治療法開発の基盤となるべき研究を行った。<br />研究課題/領域番号:18109008, 研究期間(年度):2006-2010 続きを見る
4.

論文

論文
金子, 周一 ; Kaneko, Shuichi
出版情報: 平成17(2005)年度 科学研究費補助金 基盤研究(S) 研究成果報告書.  2001-2005  pp.15p.-,  2006-04.  金沢大学大学院医学系研究科
URL: http://hdl.handle.net/2297/00049429
概要: 研究成果は目的に応じて、1.肝臓病における包括的発現遺伝子データベース作成、2.従来から知られている肝臓病の解析、3.新たな解析法、診断・治療法の開発、4.従来は肝臓病と考えられていなかった肝臓異常の検出、の4点に分類し以下に簡潔に記入した 。1.肝臓病における包括的発現遺伝子データベース作成肝臓における包括的発現遺伝子情報と臨床情報をデータベース化した。世界最大となる正確で系統的な各種肝臓病のヒト肝臓における発現遺伝子データベースを構築した。2.従来から知られている肝臓病の解析解析情報を用いて慢性肝炎など従来から肝臓病として知られる疾患の研究を行った。B型およびC型慢性肝炎、自己免疫性肝炎および原発性胆汁性肝硬変、肝癌を解析し発現遺伝子情報を用いることによって包括的発現遺伝子情報からみた疾病の診断および病態解析だけでなく、従来の研究手法で解決できなかった重要な問題点を解決した。3.新たな解析法、診断・治療法の開発#1を用いることによってヒトにおいても染色体に臓器特異的な発現遺伝子の集積領域があること、これを用いることによって新規肝臓発現遺伝子の探索が可能であることを示した。病態解析だけでなく肝臓疾患の治療方針の決定にもgenomics技術が有用であることを示し、この業績によって平成16年度の産学官連携功労者文部科学大臣賞を受賞した。4.従来は肝臓病と考えられなかった肝臓異常の検出軽度の異常あるいは従来は正常と診断されていた肝臓の解析を行った。糖尿病および肥満を有する症例の肝臓における包括的発現遺伝子は対照群と大きくことなること、それらの異常が各種の代謝異常と密接に関連し、さらには全身の動脈硬化病変の進行にも密接に関係する可能性を示した。<br />研究課題/領域番号:13854015, 研究期間(年度):2001-2005 続きを見る
5.

論文

論文
金子, 周一 ; Kaneko, Shuichi
出版情報: 平成13(2001)年度 科学研究費補助金 地域連携推進研究費 研究成果報告書.  1999-2001  pp.10p.-,  2002-03.  金沢大学大学院医学系研究科
URL: http://hdl.handle.net/2297/00049430
概要: 癌に対するバイオセンサー型DNAチップを作製するため、初年度は1)肝癌に関連する肝臓内の遺伝子の発現のパターンを明らかにすると同時に、その情報を用いてDNAチップを作製すること、2)このチップの情報を微少電極集積型バイオセンサーにて読みとる 技術を開発することを目的とした。2年目以降はチップの開発をさらにすすめ臨床応用をめざすことを目的とした。肝細胞癌等を用いて、DNAチップにおける解析を行った。100例におよぶ臨床材料の解析から、従来の生化学所見や病理組織では得られなかった情報が得られ、DNAチップが新たな診断法のひとつになりうる可能性を示すことが出来た(Gastroenterology 2001)。また肝癌由来培養細胞および肝癌を用いて、新たな腫瘍マーカーの可能性、および分化度を推定する診断法になる可能性を示した(Hepatology 2001a, 2001b)。serial gene expression analysis(SAGE)法を行い、包括的な遺伝子発現のプロファイルを作製し(BBRC 2000, 2001)、世界最大の肝臓発現遺伝子データベースを有することが出来た。一連の成果から、C型慢性肝炎の薬剤反応性をDNAチップで検査する方法を開発し、臨床検査試薬として平成14年に発売した。微小電極を用いて、液層における反応系を考案し、目的とする核酸の測定を可能とした(平成13年特許出願)。微小電極測定に導入するため小型のサーマルサイクラーを開発し、特許出願した(平成12年)。基盤上の微小な金属電極にDNAをスポットする装置を開発した(特許出願準備中)。これらの研究をもとに微小電極を用いた核酸測定系を開発した(特許出願準備中)。このバイオセンサー型DNA測定系は、臨床の現場で使用することを目的とし、小型で安価、かつ迅速に試料を測定できるものが作製された。<br />研究課題/領域番号:11794017, 研究期間(年度):1999-2001 続きを見る
6.

論文

論文
金子, 周一 ; Kaneko, Shuichi
出版情報: 平成11(1999)年度 科学研究費補助金 基盤研究(B) 研究成果報告書.  1998-1999  pp.8p.-,  2000-03.  金沢大学医学部
URL: http://hdl.handle.net/2297/00049431
概要: C型慢性肝炎の患者血清中に存在するC型肝炎ウイルス(HCV)は、血清中では抗体が結合して比重の重いHCV画分とfreeのウイルス粒子として存在する比重の軽い画分に分類できること、それらの存在様式とインターフェロンによる効果には関連があること を報告した。とりわけ抗体と結合して存在するウイルス画分が少ない症例が、抗ウイルス効果が高かった。このように血液中に存在するこのウイルス画分を除去することによって抗ウイルス効果が得られる可能性が得られ、今回の研究の有効性を示唆した結果であった。また肝臓においてのHCVの存在様式を検討した。肝疾患が進行するに従い、HCVの変異も増加していること、また進行した肝疾患ではHCVの増殖が限られた範囲(compartment)で限られておきるようになることを報告した。肝臓には流血中のウイルスと異なる種類のウイルスが存在する可能性が示され、血液浄化療法を用いたウイルス除去を検討するうえで重要な知見が得られた。こうして存在する抗体と結合しているウイルス画分をのぞくことを目的としてカラムによる血液委浄化療法の可能性を検討した。バッチ法、ミニカラム法にて基礎検討を行った。除去に必要な吸着体量や流量が検討され、またHCVと結合している抗体の吸着率に優れた吸着体を得た。もっとも適した吸着剤を用いてC型肝炎ウイルス量の多い2匹のチンパンジーを用いて、三和化学(株)のチンパンジー飼育施設において血液浄化療法を行った。2匹とも循環・呼吸動態や腎機能に変動なく、血液生化学の変化も一過性であり安全に血液浄化療法を行うことができた。また術後も感染症等の副作用の発現はみられなかった。抗凝固療剤を大量に用いたため、カテーテル刺入部における止血が問題となった。血液および肝におけるC型肝炎ウイルスおよびその複合体の変動に関して解析した。<br />研究課題/領域番号:10557054, 研究期間(年度):1998-1999 続きを見る
7.

論文

論文
金子, 周一 ; Kaneko, Shuichi
出版情報: 平成11(1999)年度 科学研究費補助金 基盤研究(B) 研究成果報告書.  1998-1999  pp.8p.-,  2000-03.  金沢大学医学部
URL: http://hdl.handle.net/2297/00049432
概要: 肝内および肝外移転を有する進行肝細胞癌に対する遺伝子治療法を確立するため、Transcriptional targetingを利用した新たなベクターの開発を検討した。肝癌ら特異的に発現しているalfafetoprotein(AFP)のプロモ ーター領域を改変し、肝癌細胞における発現および移植肝癌における発現を検討した。また治療遺伝子として自殺遺伝子であるherpes simplex virus thymidine kinase遺伝子を用いて担癌マウスにおける抗腫瘍効果を検討した。これらの実験ではtranscriptional tartgetingによる効果が示されたもののAFPプロモーター活性が弱いために十分な治療遺伝子を発現することが出来なかった。そこでCre-loxPシステムを用いて、肝癌に特異的で強力に発現するベクターを作製した。これによって培養細胞およびマウス腫瘍において高い遺伝子発現が得られ、とりわけ肝内および肝外の転移病巣においても十分な発現が得られた。しかしこのCre-loxPの系では2種類のウイルスが同時に感染する必要があり、十分な発現のためにはMOI25以上の力価を要することも示された。こうしたことから投与ベクター量が大量となるため、アデノウイルス投与では問題が生じること示唆され、今後の問題点とされた。これに対し、さらにHVJリポソームといった安全性の高いベクターを用いた検討を行って検討したところ、複数回のベクター投与によって肝内に転移した肝癌を治療することが可能であった。このようにAFP遺伝子を用いたtranscriptional targetingによって肝内および肝外に転移した進行肝癌の治療が可能であることが示唆された。<br />研究課題/領域番号:10470132, 研究期間(年度):1998-1999 続きを見る
8.

論文

論文
Wang, H. ; Sasaki, Y. ; Nemoto-Sasaki, Y. ; Nakamura, Y ; Nakamoto, Yasunari ; Kaneko, Shuichi ; Inoue, M. ; Kobayashi, Kenichi ; Mukaida, Naofumi
出版情報: Cancer Research Institute report.  2000-2002  pp.29-,  2003-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2674
9.

論文

論文
Nakatsu, F. ; Kakiuchi, M. ; Watanabe, M. ; Okada, M. ; Iwasa, H. ; Mori, F. ; Zhu, G. ; Kasagi, Y. ; Kamiya, H. ; Harada, A. ; Takeuchi, A. ; Nakamura, N. ; Nishimura, K. ; Manabe, T. ; Yuasa, S. ; Wakabayashi, Keiji ; Kaneko, Shuichi ; Saito, T. ; Ohno, H.
出版情報: Cancer Research Institute report.  2000-2002  pp.69-,  2003-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2694
10.

論文

論文
Department of Internal Medicine ; Sawabu, Norio ; Okai, Takashi ; Takemori, Yasuhiro ; Kaneko, Shuichi ; Ohmizo, Ryoyo ; Satomura, Yoshitake ; Watanabe, Hiroyuki ; Kawakami, Hiroyasu ; Yamakawa, Osamu ; Sakashita, Mutsuko
出版情報: 金沢大学がん研究所年報 = Cancer Research Institute Report.  pp.87-98,  1988-03-25.  金沢大学がん研究所 Cancer Research Institute, Kanazawa University / 金沢大学
URL: http://hdl.handle.net/2297/34470
11.

論文

論文
Oishi, T. ; Masutomi, Kenichi ; Khurts, S. ; Nakamoto, T. ; Kaneko, Shuichi ; Murakami, Seishi
出版情報: Cancer Research Institute report.  2003-2005  pp.4-,  2006-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2587
12.

論文

論文
Hirano, M. ; Kaneko, Shuichi ; Yamashita, Tatsuya ; Luo, H. ; Qin, W. ; Shirota, Yukihiro ; Nomura, T. ; Kobayashi, Kenichi ; Murakami, Seishi
出版情報: Cancer Research Institute report.  2003-2005  pp.8-,  2006-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2591
13.

論文

論文
Shimakami, Tetsuro ; Hijikata, M. ; Luo, H. ; Ma, Y. ; Kaneko, Shuichi ; Shimotohno, K. ; Murakami, Seishi
出版情報: Cancer Research Institute report.  2003-2005  pp.9-,  2006-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2592
14.

論文

論文
Masutomi, Kenichi ; Yu, E.Y. ; Khurts, S. ; Ben-Porath, I. ; Currier, J.L. ; Mets, G.B. ; Brooks, M.W. ; Kaneko, Shuichi ; Murakami, Seishi ; DeCaprio, J.A. ; Weinberg, R.A. ; Stewart, S.A. ; Hahn, W.C.
出版情報: Cancer Research Institute report.  2003-2005  pp.11-,  2006-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2594
15.

論文

論文
Tsuchiyama, T. ; Nakamoto, Yasunari ; Sakai, Y. ; Mukaida, Naofumi ; Sawabu, Norio ; Kaneko, Shuichi
出版情報: Cancer Research Institute report.  2003-2005  pp.82-,  2006-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2630
16.

論文

論文
Shirota, Yukihiro ; Luo, Hong ; Qin, Weiping ; Kaneko, Shuichi ; Yamashita, Tatsuya ; Kobayashi, Kenichi ; Murakami, Seishi
出版情報: Cancer Research Institute report.  2000-2002  pp.7-,  2003-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2659
17.

論文

論文
Hirano, Masaaki ; Kaneko, Shuichi ; Yamashita, Tatsuya ; Luo, Hong ; Qin, Weiping ; Shirota, Yukihiro ; Nomura, Takahiro ; Kobayashi, Kenichi ; Murakami, Seishi
出版情報: Cancer Research Institute report.  2000-2002  pp.8-,  2003-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2660
18.

論文

論文
Masutomi, Kenichi ; Kaneko, Shuichi ; Hayashi, Naoyuki ; Yamashita, Tatsuya ; Shirota, Yukihiro ; Kobayashi, Kenichi ; Murakami, Seishi
出版情報: Cancer Research Institute report.  2000-2003  pp.9-,  2003-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2661
19.

論文

論文
Arai, Kuniaki ; Masutomi, Kenichi ; Khurts, Shilagardy ; Kaneko, Shuichi ; Kobayashi, Kenichi ; Murakami, Seishi
出版情報: Cancer Research Institute report.  2000-2002  pp.10-,  2003-03-01.  金沢大学がん研究所
URL: http://hdl.handle.net/2297/2662
20.

論文

論文
Otowa, Kanichi ; Takamura, Masayuki ; Murai, Hisayoshi ; Maruyama, Michiro ; Nakano, Manabu ; Ikeda, Tatsunori ; Kobayashi, Daisuke ; Ootsuji, Hiroshi ; Okajima, Masaki ; Furusho, Hiroshi ; Yuasa, Toyoshi ; Takata, Shigeo ; Kaneko, Shuichi
出版情報: Circulation journal.  72  pp.458-462,  2008-03-01. 
URL: http://hdl.handle.net/2297/9608
概要: 金沢大学大学院医学系研究科
21.

論文

論文
Takeshita, Yumie ; Takamura, Toshinari ; Hamaguchi, Erika ; Shimizu, Akiko ; Ota, Tsuguhito ; Sakurai, Masaru ; Kaneko, Shuichi
出版情報: Metabolism: Clinical and Experimental.  55  pp.1464-1472,  2006-11-01.  Elsevier BV
URL: http://hdl.handle.net/2297/2870
概要: 金沢大学大学院医学系研究科環境社会医学<br />Plasminogen activator inhibitor 1 (PAI-1) is an important mediator of atherosclerosis and liver fibrosis in insulin resistance. Circulating levels of PAI-1 are elevated in obese individuals, and PAI-1 messenger RNA is significantly higher in the livers of obese type 2 diabetic individuals than in nonobese type 2 diabetic individuals. To address the mechanism underlying the up-regulation of hepatic PAI-1 in obesity, we tested the effects of tumor necrosis factor α (TNF-α), an important link between obesity and insulin resistance, on PAI-1 production in the nonmalignant human hepatocyte cell line, THLE-5b. Incubation of THLE-5b cells with TNF-α stimulated PAI-1 production via protein kinase C-, mitogen-activated protein kinase-, protein tyrosine kinase-, and nuclear factor-κB-dependent pathways. A thiazolidinedione, pioglitazone, reduced TNF-α-induced PAI-1 production by 32%, via protein kinase C- and nuclear factor-κB-dependent pathways. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin inhibited TNF-α-induced PAI-1 production by 59%, which was reversed by coincubation with mevalonic acid. In conclusion, obesity and TNF-α up-regulation of PAI-1 expression in human hepatocytes may contribute to the impairment of the fibrinolytic system, leading to the development of atherosclerosis and liver fibrosis in insulin-resistant individuals. A thiazolidinedione and a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor may thus be candidate drugs to inhibit obesity-associated hepatic PAI-1 production. © 2006 続きを見る
22.

論文

論文
Ando, Hitoshi ; Oshima, Yasuo ; Yanagihara, Hayato ; Hayashi, Yohei ; Takamura, Toshinari ; Kaneko, Shuichi ; Fujimura, Akio
出版情報: Biochemical and Biophysical Research Communications.  346  pp.1297-1302,  2006-08-01.  Elsevier
URL: http://hdl.handle.net/2297/2868
概要: 金沢大学大学院医学系研究科環境社会医学<br />Although a number of genes expressed in most tissues, including the liver, exhibit circad ian regulation, gene expression profiles are usually examined only at one scheduled time each day. In this study, we investigated the effects of obese diabetes on the hepatic mRNA levels of various genes at 6-h intervals over a single 24-h period. Microarray analysis revealed that many genes are expressed rhythmically, not only in control KK mice but also in obese diabetic KK-Ay mice. Real-time quantitative PCR verified that 19 of 23 putative circadianly expressed genes showed significant 24-h rhythmicity in both strains. However, obese diabetes attenuated these expression rhythms in 10 of 19 genes. More importantly, the effects of obese diabetes were observed throughout the day in only two genes. These results suggest that observation time influences the results of gene expression analyses of genes expressed circadianly. © 2006 Elsevier Inc. All rights reserved. 続きを見る
23.

論文

論文
Hayakawa, Tetsuo ; Takamura, Toshinari ; Abe, Toshio ; Kaneko, Shuichi
出版情報: Metabolism: Clinical and Experimental.  56  pp.44-48,  2007-01-01.  Elsevier BV
URL: http://hdl.handle.net/2297/3469
概要: 金沢大学大学院医学系研究科環境社会医学<br />A C825T polymorphism of the gene encoding the G-protein β3 subunit (GNB3) is associa ted with increased intracellular signal transduction. We know that this C825T polymorphism may influence hypertension and obesity. In whites, the C825T polymorphism has been reported to induce hypertension, obesity, and diabetic nephropathy. Thus, we investigated how genetic variation in the GNB3 gene is associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, and diabetic therapies in 427 Japanese subjects with type 2 diabetes mellitus and in 368 Japanese subjects who underwent general health examinations. The frequency of the GNB3 gene polymorphism was 0.48 and 0.47 in subjects with diabetes and in those who had general health examinations, respectively. The amount of hyperlipidemia of the CT allele was significantly lower than the amount in the CC allele in the Japanese subjects with diabetes. Our results suggest that the C825T polymorphism influences lipid metabolism and is not associated with hypertension, obesity, insulin resistance, diabetes, diabetic complications, or diabetic therapies. © 2007. 続きを見る
24.

論文

論文
Terasaki, Shuichi ; Nakanuma, Yasuni ; Unoura, Masashi ; Kaneko, Shuichi ; Kobayashi, Kenichi
出版情報: Internal Medicine.  36  pp.766-770,  1997-01-01.  日本内科学会 = Japanese Society of Internal Medicine
URL: http://hdl.handle.net/2297/16757
概要: 金沢大学医薬保健研究域医学系<br />We examined the histological changes of the peribiliary glands (PBGs), a hitherto pooly recogn ized anatomical element around the biliary tree, in 7 cases of primary sclerosing cholangitis (PSC). These glands showed proliferation, and nonspecific inflammation with lymphoplasmacy ticinfiltration, fibrosis. and destruction. In addition, there were cystic lesions around the bile ducts, and they were considered to reflect dilatation of the PBGs. These changes were found around the intrahepatic and extrahepatic bile ducts in the cases examined. It is of interest that changes in the PBGs tended to correlate with the inflammatory changes of the bile duct wall itself, though 2 cases showed changes in the duct walls and PBGs unrelated to their distribution along the biliary tree. These findings suggest that the PBGs are also a target structure in addition to the bile ducts themselves in PSC. 続きを見る
25.

論文

論文
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
26.

論文

論文
Tatsumi, Yasuaki ; Hattori, Ai ; Hayashi, Hisao ; Ikoma, Jiro ; Kaito, Masahiko ; Imoto, Masami ; Wakusawa, Shinya ; Yano, Motoyoshi ; Hayashi, Kazuhiko ; Katano, Yoshiaki ; Goto, Hidemi ; Okada, Toshihide ; Kaneko, Shuichi
出版情報: Internal Medicine.  49  pp.809-815,  2010-04-30.  Japanese Society of Internal Medicine = 日本内科学会
URL: http://hdl.handle.net/2297/24280
概要: 金沢大学医薬保健研究域医学系<br />Objective This study evaluated the current state of patients with Wilson disease in central Ja pan. Patients and Methods Between 1999 and 2007, 30 patients were diagnosed as having Wilson disease withan International Diagnostic Score of 4 or more. The phenotypes, genotypes and post-diagnostic courses of these patients were analyzed. Results Twenty-six patients had ATP7B mutations responsible for Wilson disease. Four patients had a single mutant chromosome. There were 2 major mutations of 2333 G>T and 2871 delC (40%), and 6 novel mutations (13%) in our patients. The first clinical manifestation was the hepatic form in 22, neurological form in 5, and hemolysis in 3 patients. The hepatic form was diagnosed around the age of 13 years, followed by neurological complication with a time lag of 9 years. Thus, some patients, especially patients with the neurological form, did not undergo early diagnostic tests including ATP7B analysis. During the post-diagnosis period, 3 patients were hospitalized for recurrent liver disease, and 2 patients committed suicide. One female patient died from acute hepatic failure associated with encephalopathy after fertilization therapy, while 2 male patients recovered from encephalopathy-free, prolonged hepatic failure after noncompliance with drug therapy. The King's Scores for liver transplantation were below the cut-off in both cases. Conclusion To minimize delayed diagnosis, ceruloplasmin determination and ATP7B analysis may be recommended to patients showing hepatic damage of unknown etiology. At gene diagnosis, appropriate management of patients including compliance education and emotional care to prevent suicide might be important. 2010 The Japanese Society of Internal Medicine. © 2010 The Japanese Society of Internal Medicine. 続きを見る
27.

論文

論文
Sakurai, Masaru ; Takamura, Toshinari ; Miura, Katsuyuki ; Kaneko, Shuichi ; Nakagawa, Hideaki
出版情報: Internal Medicine.  48  pp.1573-1574,  2009-01-01.  Japanese Society of Internal Medicine = 日本内科学会
URL: http://hdl.handle.net/2297/19772
概要: 金沢大学医薬保健研究域医学系
28.

論文

論文
Kurita, Seiichiro ; Takamura, Toshinari ; Ota, Tsuguhito ; Matsuzawa-Nagata, Naoto ; Kita, Yuki ; Uno, Masafumi ; Nabemoto, Satoko ; Ishikura, Kazuhide ; Misu, Hirofumi ; Ando, Hitoshi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi
出版情報: European Journal of Pharmacology.  588  2008-07-07.  Elsevier
URL: http://hdl.handle.net/2297/10979
概要: 金沢大学大学院医学系研究科<br />金沢大学医薬保健研究域医学系<br />Insulin resistance is a major pathological condition associated with obesity and metabolic syndrome. Insulin resistance and the renin-angiotensin system are intimately linked. We evaluated the role of the renin-angiotensin system in the pathogenesis of insulin resistance-associated, non-alcoholic steatohepatitis by using the angiotensin II type 1 receptor blocker olmesartan medoxomil in a diabetic rat model. The effects of olmesartan on methionine- and choline-deficient (MCD) diet-induced steatohepatitis were investigated in obese, diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and control Long-Evans Tokushima Otsuka (LETO) rats. Components of the renin-angiotensin system were up-regulated in the livers of OLETF rats, compared with LETO rats. In OLETF, but not LETO, rats, oral administration of olmesartan for 8 weeks ameliorated insulin resistance. Moreover, olmesartan suppressed MCD diet-induced hepatic steatosis and the hepatic expression of lipogenic genes (sterol regulatory element-binding protein-1c and fatty acid synthase) in OLETF, but not LETO, rats. In both OLETF and LETO rats, olmesartan inhibited hepatic oxidative stress (4-hydroxy-2-nonenal-modified protein) and expression of NADPH oxidase. Olmesartan also inhibited hepatic fibrosis, stellate cell activation, and expression of fibrogenic genes (transforming growth factor-β, α1 [I] procollagen, plasminogen activator inhibitor-1) in both OLETF and LETO rats. In conclusion, pharmacological blockade of the angiotensin II type 1 receptor slows the development of steatohepatitis in the OLETF rat model. This angiotensin II type 1 receptor blocker may exert insulin resistance-associated effects against hepatic steatosis and inflammation as well as direct effects against the generation of reactive oxygen species and fibrogenesis. © 2008 Elsevier B.V. All rights reserved. 続きを見る
29.

論文

論文
Takashima, Shinichiro ; Sugimoto, Naotoshi ; Takuwa, Noriko ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Takamura, Masayuki ; Takata, Shigeo ; Kaneko, Shuichi ; Takuwa, Yoh
出版情報: Cardiovascular Research.  79  pp.689-697,  2008-09-01.  Elsevier
URL: http://hdl.handle.net/2297/12043
概要: 金沢大学医薬保健研究域医学系<br />Aims: The lysophospholipid mediator sphingosine-1-phosphate (S1P) activates G protein-coupled receptors (GPCRs) to induce potent inhibition of platelet-derived growth factor (PDGF)-induced Rac activation and, thereby, chemotaxis in rat vascular smooth muscle cells (VSMCs). We explored the heterotrimeric G protein and the downstream mechanism that mediated S1P inhibition of Rac and cell migration in VSMCs. Methods and results: S1P inhibition of PDGF-induced cell migration and Rac activation in VSMCs was abolished by the selective S1P2 receptor antagonist JTE-013. The C-terminal peptides of Gα subunits (Gα-CTs) act as specific inhibitors of respective G protein-GPCR coupling. Adenovirus-mediated expression of Gα12-CT, Gα13-CT, and Gα q-CT, but not that of Gαs-CT or LacZ or pertussis toxin treatment, abrogated S1P inhibition of PDGF-induced Rac activation and migration, indicating that both G12/13 and Gq classes are necessary for the S1P inhibition. The expression of Gαq-CT as well as Gα12-CT and Gα13-CT also abolished S1P-induced Rho stimulation. C3 toxin, but not a Rho kinase inhibitor or a dominant negative form of Rho kinase, abolished S1P inhibition of PDGF-induced Rac activation and cell migration. The angiotensin II receptor AT1, which robustly couples to Gq, did not mediate either Rho activation or inhibition of PDGF-induced Rac activation or migration, suggesting that activation of Gq alone was not sufficient for Rho activation and resultant Rac inhibition. However, the AT1 receptor fused to Gα12 was able to induce not only Rho stimulation but also inhibition of PDGF-induced Rac activation and migration. Phospholipase C inhibition did not affect S1P-induced Rho activation, and protein kinase C activation by a phorbol ester did not mimic S1P action, suggesting that S1P inhibition of migration or Rac was not dependent on the phospholipase C pathway. Conclusion: These observations together suggest that S1P2 mediates inhibition of Rac and migration through the coordinated action of G 12/13 and Gq for Rho activation in VSMCs. © The Author 2008.. 続きを見る
30.

論文

論文
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
31.

論文

論文
Hamaguchi, Erika ; Takamura, Toshinari ; Sakurai, Masaru ; Mizukoshi, Eishiro ; Zen, Yoh ; Takeshita, Yumie ; Kurita, Seiichiro ; Arai, Kuniaki ; Yamashita, Tatsuya ; Sasaki, Motoko ; Nakanuma, Yasuni ; Kaneko, Shuichi
出版情報: Diabetes Care.  33  pp.284-286,  2010-02-01.  American Diabetes Association
URL: http://hdl.handle.net/2297/21173
概要: 金沢大学医薬保健研究域医学系<br />OBJECTIVE - The goal of this study was to examine whether metabolic abnormalities are responsi ble for the histological changes observed in Japanese patients with nonalcoholic fatty liver disease (NAFLD) who have undergone serial liver biopsies. RESEARCH DESIGN AND METHODS - In total, 39 patients had undergone consecutive liver biopsies. Changes in their clinical data were analyzed, and biopsy specimens were scored histologically for stage. RESULTS - The median follow-up time was 2.4 years (range 1.0-8.5). Liver fibrosis had improved in 12 patients (30.7%), progressed in 11 patients (28.2%), and remained unchanged in 16 patients (41%). In a Cox proportional hazard model, decrease in A1C and use of insulin were associated with improvement of liver fibrosis independent of age, sex, and BMI. However, ΔA1C was more strongly associated with the improvement of liver fibrosis than use of insulin after adjustment for each other (χ2; 7.97 vs. 4.58, respectively). CONCLUSIONS - Tight glycemic control may prevent histological progression in Japanese patients with NAFLD. © 2010 by the American Diabetes Association. 続きを見る
32.

論文

論文
Sakurai, Masaru ; Takamura, Toshinari ; Miura, Katsuyuki ; Kaneko, Shuichi ; Nakagawa, Hideaki
出版情報: Metabolism: Clinical and Experimental.  58  pp.456-459,  2009-04-01.  Elsevier
URL: http://hdl.handle.net/2297/17359
概要: 金沢大学医薬保健研究域医学系<br />We attempted to determine sex differences in obesity-related metabolic abnormalities in a rela tively large middle-aged Japanese population. The study population consisted of 2935 men and 1622 women who were 35 to 59 years old. Metabolic abnormalities were determined using the Japanese criteria for metabolic syndrome, and we evaluated the number of metabolic abnormalities discriminated by waist circumference. In men, the mean number of metabolic abnormalities increased as the waist circumference increased. In women, although the mean number of metabolic abnormalities increased as the waist circumference increased, the mean number was less than 1 even in those with a waist circumference of at least 95 cm. According to the receiver operating characteristic curve, the cutoff levels yielding the maximal sensitivity plus specificity for predicting the prevalence of one or more obesity-related metabolic abnormalities were 80 cm in men and 73 cm in women. However, the positive predictive value was as low as 28.8% in men and 7.1% in women, which may not be suitable for a screening test, especially in women. Middle-aged Japanese women seem to be resistant to obesity-induced metabolic abnormalities, and waist circumference would not effectively predict the existence of metabolic syndrome. In setting the cutoff points in guidelines, a greater emphasis should be placed on the absolute risk of having abnormalities or diseases. © 2009 Elsevier Inc. All rights reserved. 続きを見る
33.

論文

論文
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
34.

論文

論文
Sakurai, Sho ; Miura, K. ; Takamura, Toshinari ; Ishizaki, Masao ; Morikawa, Y. ; Nakamura, K. ; Yoshita, Katsushi ; Kido, Teruhiko ; Naruse, Yuchi ; Kaneko, Shuichi ; Nakagawa, H.
出版情報: Diabetic Medicine.  26  pp.753-759,  2009-08-01.  Blackwell Publishing
URL: http://hdl.handle.net/2297/19144
概要: 金沢大学医薬保健研究域医学系<br />金沢医科大学健康増進予防医学(公衆衛生学)<br />Aims This study investigated the relationship between waist c ircumference and the subsequent incidence of Type 2 diabetes and the association with insulin resistance and pancreatic B-cell function in relatively lean Japanese individuals. Methods The study participants were 3992 employees (2533 men and 1459 women, aged 35-55 years) of a metal-products factory in Japan. The incidence of diabetes was determined in annual medical examinations during an 8-year follow-up. We calculated age- and sex-adjusted hazard ratios (HRs) according to the sex-specific quintile of waist circumference at baseline. Differences in baseline insulin resistance [homeostatis model assessment (HOMA)-IR] and pancreatic B-cell function (HOMA-B) were compared between participants who developed diabetes and those who did not. Results During the follow-up, 218 participants developed diabetes. Age- and sex-adjusted HRs across the quintiles of waist circumference were 1.78, 1.00 (reference), 1.59, 3.11 and 3.30, respectively (P for trend, < 0.0001). The HR for the lowest quintile was significantly higher than that for the second quintile. Among participants with waist circumference of the lowest quintile, HOMA-B was lower in those who developed diabetes than in those who did not [33.1 (24.1-45.0) vs. 54.3 (37.9-74.6) median (interquartile range), P < 0.0001], but HOMA-IR did not differ between these groups. Conclusions There was a J-shaped relationship between waist circumference and subsequent risk for Type 2 diabetes in relatively lean Japanese individuals; lower pancreatic B-cell function may also increase the risk of diabetes in very lean Japanese people. © 2009 Diabetes UK. 続きを見る
35.

論文

論文
Takuwa, Noriko ; Ohkura, Sei-Ichiro ; Takashima, Shin-ichiro ; Ohtani, Keisuke ; Okamoto, Yasuo ; Tanaka, Tamotsu ; Hirano, Kaoru ; Usui, Soichiro ; Wang, Fei ; Du, Wa ; Yoshioka, Kazuaki ; Banno, Yoshiko ; Sasaki, Motoko ; Ichi, Ikuyo ; Okamura, Miwa ; Sugimoto, Naotoshi ; Mizugishi, Kiyomi ; Nakanuma, Yasuni ; Ishii, Isao ; Takamura, Masayuki ; Kaneko, Shuichi ; Kojo, Shosuke ; Satouchi, Kiyoshi ; Mitumori, Kunitoshi ; Chun, Jerold ; Takuwa, Yoh
出版情報: Cardiovascular Research.  85  pp.484-493,  2010-02-01.  Oxford University Press (OUP)
URL: http://hdl.handle.net/2297/21766
概要: 金沢大学医薬保健研究域医学系<br />Aims Sphingosine kinase 1 (SPHK1), its product sphingosine-1-phosphate (S1P), and S1P receptor subtypes have been suggested to play protective roles for cardiomyocytes in animal models of ischaemic preconditioning and cardiac ischaemia/reperfusion injury. To get more insight into roles for SPHK1 in vivo, we have generated SPHK1-transgenic (TG) mice and analysed the cardiac phenotype.Methods and results SPHK1-TG mice overexpressed SPHK1 in diverse tissues, with a nearly 20-fold increase in enzymatic activity. The TG mice grew normally with normal blood chemistry, cell counts, heart rate, and blood pressure. Unexpectedly, TG mice with high but not low expression levels of SPHK1 developed progressive myocardial degeneration and fibrosis, with upregulation of embryonic genes, elevated RhoA and Rac1 activity, stimulation of Smad3 phosphorylation, and increased levels of oxidative stress markers. Treatment of juvenile TG mice with pitavastatin, an established inhibitor of the Rho family G proteins, or deletion of S1P3, a major myocardial S1P receptor subtype that couples to Rho GTPases and transactivates Smad signalling, both inhibited cardiac fibrosis with concomitant inhibition of SPHK1-dependent Smad-3 phosphorylation. In addition, the anti-oxidant N-2-mercaptopropyonylglycine, which reduces reactive oxygen species (ROS), also inhibited cardiac fibrosis. In in vivo ischaemia/reperfusion injury, the size of myocardial infarct was 30 decreased in SPHK1-TG mice compared with wild-type mice.Conclusion These results suggest that chronic activation of SPHK1-S1P signalling results in both pathological cardiac remodelling through ROS mediated by S1P3 and favourable cardioprotective effects. 続きを見る
36.

論文

論文
Nakamoto, Yasunari ; Mizukoshi, Eishiro ; Kitahara, Masaaki ; Arihara, Fumitaka ; Sakai, Yoshio ; Kakinoki, Kaheita ; Fujita, Yui ; Marukawa, Yohei ; Arai, Kuniaki ; Yamashita, Tatsuya ; Mukaida, Naofumi ; Matsushima, Kouji ; Matsui, Osamu ; Kaneko, Shuichi
出版情報: Clinical and Experimental Immunology.  163  pp.165-177,  2011-02-01.  Blackwell Publishing
URL: http://hdl.handle.net/2297/26396
概要: 金沢大学医薬保健研究域医学系<br />Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology. 続きを見る
37.

論文

論文
Wada, Takashi ; Sakai, Norihiko ; Sakai, Yoshio ; Matsushima, Kouji ; Kaneko, Shuichi ; Furuichi, Kengo
出版情報: Clinical and Experimental Nephrology.  15  pp.8-13,  2011-02-01.  Japanese Society of Nephrology / Springer Verlag (Germany)
URL: http://hdl.handle.net/2297/26306
概要: 金沢大学医薬保健研究域医学系<br />Cellular mechanisms have been proposed in the pathogenesis of fibrotic processes in the kidney . In this setting, cell sources underlying the generation of matrix-producing cells in diseased kidneys have been categorized as activated resident stromal cells (e.g., fibroblasts, pericytes), infiltrating bone-marrow-derived cells (e.g., fibrocytes, T cells, macrophages), and cells derived from epithelial-mesenchymal transition/endothelial-mesenchymal transition. Among these cell sources, accumulating evidence has shed light on the involvement of bone-marrow-derived cells, including monocytes/macrophages, and a circulating mesenchymal progenitor cell, fibrocyte, in the progression of fibrosis in kidney. Bone-marrow-derived cells positive for CD45 or CD34, and type 1 (pro)collagen dependent on the chemokine and renin-angiotensin systems migrate into diseased kidneys and enhance synthesis matrix protein, cytokines/chemokines, and profibrotic growth factors, which may promote and escalate chronic inflammatory processes and possible interaction with resident stromal cells, thereby perpetuating kidney fibrosis. © 2010 Japanese Society of Nephrology. 続きを見る
38.

論文

論文
Kakinoki, Kaheita ; Nakamoto, Yasunari ; Kagaya, Takashi ; Tsuchiyama, Tomoya ; Sakai, Yoshio ; Nakahama, Tohru ; Mukaida, Naofumi ; Kaneko, Shuichi
出版情報: Journal of Gene Medicine.  12  pp.1002-1013,  2010-12-01.  Wiley-Blackwell
URL: http://hdl.handle.net/2297/26395
概要: 金沢大学医薬保健研究域医学系<br />The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a resul t of intrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system.Methods: Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV-tk, CCL2/MCP-1 and LacZ at multiplicities of infection of Ad-tk/Ad-MCP1 = 3/0.03 (T/MLow), 3/3 (T/MHigh) and Ad-tk/Ad-LacZ = 3/3 (T/L) were injected into BALB/c mice.Results: Intrahepatic tumor growth was significantly lower in T/MLow mice. By contrast, no tumor suppression was observed in T/MHigh mice. The tumor-specific cytolytic activities of splenocytes from T/MLow and T/MHigh mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac-1+ and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/MLow mice. In addition, interleukin-12 production was elevated in these tissues. Vascular endothelial growth factor-A expression and CD31+ microvessels were increased in T/MHigh mice.Conclusions: Collectively, these results demonstrate that an adequate amount of CCL2/MCP-1, together with the HSV-tk/GCV system, may induce T helper 1-polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression. © 2010 John Wiley & Sons, Ltd. 続きを見る
39.

論文

論文
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
40.

論文

論文
Iwata, Yasunori ; Furuichi, Kengo ; Kitagawa, Kiyoki ; Hara, Akinori ; Okumura, Toshiya ; Kokubo, Satoshi ; Shimizu, Kazuaki ; Sakai, Norihiko ; Sagara, Akihiro ; Kurokawa, Yukie ; Ueha, Satoshi ; Matsushima, Satoshi ; Kaneko, Shuichi ; Wada, Takashi
出版情報: Clinical and Experimental Nephrology.  14  pp.411-417,  2010-10-01.  Springer Verlag (Germany) / the Japanese Society of Nephrology = 日本腎臓学会
URL: http://hdl.handle.net/2297/24818
概要: 金沢大学医薬保健研究域医学系<br />Objective: Myeloid-derived suppressor cells (MDSCs) have been identified as immunosuppressive cells in tumor-related inflammation. However, the pathogenesis of MDSCs for autoimmune disease has not been investigated as yet. The aim of this study was to address whether MDSCs contribute to autoimmune organ injury in lupus-prone mice. Methods: MDSCs were analyzed by flow cytometric staining of CD11b+ GR-1+ in MRL-Faslpr mice. CD4+ T-cell proliferation assay was performed by coculture with CD11b+ GR-1+ splenocytes. The percentage of immunosuppressive cells was examined during disease progression. Expression of chemokine receptor on immunosuppressive cells was analyzed, and chemotaxis assay was performed. Results: CD11b+ GR-1low cells had a suppressive effect on CD4+ T-cell proliferation, which was restored by an arginase-1 inhibitor. CD11b+ GR-1low cells increased in percentage during disease progression in kidney and blood. The number of migrated CD11b+ GR-1low cells increased in the presence of monocyte chemoattractant protein-1/CCL2. Conclusion: We assessed the involvement of CD11b+ GR-1low cells in autoimmune disorder in MRL-Faslpr mice. These cells regulate immunological responses via CCL2/CCR2 signaling. The regulation of immunosuppressive monocytes may provide novel therapeutic strategy for organ damage in autoimmune diseases. © 2010 Japanese Society of Nephrology.. 続きを見る
41.

論文

論文
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
42.

論文

論文
Wada, Takashi ; Shimizu, Miho ; Toyama, Tadashi ; Hara, Akinori ; Kaneko, Shuichi ; Furuichi, Kengo
出版情報: Clinical and Experimental Nephrology.  16  pp.96-101,  2012-02-01.  Springer Verlag (Germany) / Japanese Society of Nephrology
URL: http://hdl.handle.net/2297/29219
概要: 金沢大学医薬保健研究域医学系<br />Patients suffering from diabetic nephropathy, resulting in end-stage renal failure, are increa sing in number. The pathophysiology of diabetic nephropathy remains to be fully investigated. In the clinical setting, the presence of albuminuria/overt proteinuria and a low glomerular filtration rate may predict poor renal prognosis, but the prognosis of the normoalbuminuric renally insufficient diabetic patient remains controversial. In addition to the measurement of urinary albumin excretion, biomarker studies to detect diabetic nephropathy more specifically at the early stage have been performed worldwide. There is a growing body of evidence for remission and/or regression of diabetic nephropathy, which may be an indicator for cardiovascular and renal risk reduction. Deeper insights into the pathological characteristics as well as the clinical impact of albuminuria on renal and cardiovascular outcome are required. © 2011 Japanese Society of Nephrology. 続きを見る
43.

論文

論文
Kakuda, Yuko ; Harada, Kenichi ; Sawada-Kitamura, Seiko ; Ikeda, Hiroko ; Sato, Yasunori ; Sasaki, Motoko ; Okafuji, Hirofumi ; Mizukoshi, Eishiro ; Terasaki, Shuichi ; Ohta, Hajime ; Kasashima, Satomi ; Kawashima, Atsuhiro ; Kaizaki, Yasuharu ; Kaneko, Shuichi ; Nakanuma, Yasuni
出版情報: Human Pathology.  44  pp.1107-1117,  2013-06-01.  Elsevier
URL: http://hdl.handle.net/2297/33483
概要: Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions. © 2013 Elsevier Inc. All rights reserved. 続きを見る
44.

論文

論文
Kitajima, Shinji ; Sakai, Norihiko ; Furuichi, Kengo ; Tomokage, Miki ; Hara, Akinori ; Kitagawa, Kiyoki ; Sawada-Kitamura, Seiko ; Zen, Yoh ; Nakada, Mitsutoshi ; Kaneko, Shuichi ; Wada, Takashi
出版情報: Modern Rheumatology.  20  pp.506-510,  2010-10-01.  Japan College of Rheumatology = 日本リウマチ学会
URL: http://hdl.handle.net/2297/25880
概要: 金沢大学医薬保健研究域医学系<br />We described a case of neurosarcoidosis with necrotizing sarcoid granulomatosis in a 22-year-o ld man. Contrast-enhanced brain computed tomography scan and magnetic resonance imaging showed intracerebral multiple nodular lesions. Noncaseating and partial necrotizing granulomas were detected in the specimen resected by neurosurgery. In addition, immunohistochemical examination revealed the expression of angiotensin-converting enzyme in necrotizing granuloma. Thus, these findings were consistent with neurosarcoidosis. Clinical and pathological presentation, immunological features, and treatment modalities of neurosarcoidosis are discussed. © 2010 Japan College of Rheumatology.<br />This is the pre-peer reviewed version of the following article: [Full cite], which has been published in final form at [link to final article]. 続きを見る
45.

論文

論文
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
46.

論文

論文
Oshima, Megumi ; Kitajima, Shinji ; Toyama, Tadashi ; Hara, Akinori ; Kitagawa, Kiyoki ; Iwata, Yasunori ; Shimizu, Miho ; Nishio, Saori ; Imura, Junko ; Yokoyama, Hitoshi ; Furuichi, Kengo ; Kaneko, Shuichi ; Wada, Takashi
出版情報: Internal Medicine.  52  pp.1605-1609,  2013-01-01.  The Japanese Society of Internal Medicine = 日本内科学会
URL: http://hdl.handle.net/2297/36216
概要: We herein report a case of spontaneous pregnancy and preterm delivery in a 29-year-old patient with myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. Her basal serum creatinine level before pregnancy was 1.4 mg/dL and her urinary protein level was approximately 2 g/day. The proteinuria and hematuria increased during pregnancy, and the patient was admitted to our hospital and treated with prednisolone (PSL). At 27 weeks of gestation, she delivered a live infant weighing 848 g via cesarean section. No relapse of ANCA-associated glomerulonephritis occurred. © 2013 The Japanese Society of Internal Medicine. 続きを見る
47.

論文

論文
Yamashita, Tatsuya ; Arai, Kuniaki ; Sunagozaka, Hajime ; Ueda, Teruyuki ; Terashima, Takeshi ; Yamashita, Taro ; Mizukoshi, Eishiro ; Sakai, Akito ; Nakamoto, Yasunari ; Honda, Masao ; Kaneko, Shuichi
出版情報: Oncology.  81  pp.281-290,  2011-11-30.  Karger
URL: http://hdl.handle.net/2297/29835
概要: Objective: This randomized phase II trial compared the response rates to treatment with interferon (IFN) combined with hepatic arterial infusion of fluorouracil (FU) plus cisplatin (CDDP) or FU alone in patients with advanced hepatocellular carcinoma (HCC). Methods: A total of 114 patients with measurable advanced HCC were enrolled and randomized into 2 groups. FU (300 mg/m2, days 1–5, days 8–12) with or without CDDP (20 mg/m2, days 1 and 8) was administered via the hepatic artery. IFNα-2b was administered 3 times per week for 4 weeks. Results: The response rates were 45.6% for the IFN/FU + CDDP group and 24.6% for the IFN/FU group. The response rate was significantly higher in the IFN/FU + CDDP group (p = 0.030). The median overall survival period was 17.6 months in the IFN/FU + CDDP group versus 10.5 months in the IFN/FU group (p = 0.522). The median progression-free survival period was 6.5 months in the IFN/FU + CDDP group versus 3.3 months in the IFN/FU group (p = 0.0048). Hematological toxicity was common, but no toxicity-related deaths were observed. Conclusion: These results show the clinical efficacy of adding CDDP to the hepatic arterial infusion of FU in combined chemotherapy regimens with IFN. 続きを見る
48.

論文

論文
Iwata, Yasunori ; Furuichi, Kengo ; Kaneko, Shuichi ; Wada, Takashi
出版情報: Journal of Biomedicine and Biotechnology.  2011  pp.594809-,  2011-01-01.  Hindawi Publishing Corporation
URL: http://hdl.handle.net/2297/30189
概要: Lupus nephritis (LN) is a major clinical manifestation of systemic lupus erythematosus (SLE). Although numerous abnormalities of immune system have been proposed, cytokine overexpression plays an essential role in the pathogenesis of LN. In the initial phase of the disease, the immune deposits and/or autoantibodies induce cytokine production in renal resident cells, leading to further inflammatory cytokine/chemokine expression and leukocyte infiltration and activation. Then, infiltrate leukocytes, such as macrophages (Mψ) and dendritic cells (DCs), secrete a variety of cytokines and activate nave T cells, leading the cytokine profile towards T helper (Th)1, Th2, and/or Th17. Recent studies revealed these inflammatory processes in experimental animal models as well as human LN. The cytokine targeted intervention may have the therapeutic potentials for LN. This paper focuses on the expression of cytokine and its functional role in the pathogenesis of LN. © 2011 Yasunori Iwata et al. 続きを見る
49.

論文

論文
Takeshita, Yumie ; Takamura, Toshinari ; Inoue, Oto ; Okumura, Miki ; Kato, Kenichiro ; Sunagozaka, Hajime ; Arai, Kuniaki ; Misu, Hirofumi ; Nakamura, Minoru ; Nakanuma, Yasuni ; Kaneko, Shuichi
出版情報: Internal Medicine.  51  pp.79-82,  2012-01-01.  日本内科学会 = The Japanese Society of Internal Medicine
URL: http://hdl.handle.net/2297/30114
概要: A 73-year-old woman had previously been diagnosed with CREST syndrome, PBC and diabetes. Hepatic fibrosis was not evident, in spite of the transudative ascites and active esophageal varices. ACA were positive, whereas AMA and anti-gp210 antibodies were negative. She showed low urinary excretion of C-peptide and was weakly positive for anti-GAD antibody. She was diagnosed with a form of PBC that progresses via portal hypertension rather than liver failure and with SPIDDM. Her HLA type did not contain risk allele for IDDM or PBC. SPIDDM should be considered when patients with PBC with portal hypertension-type progression develop diabetes. © 2012 The Japanese Society of Internal Medicine. 続きを見る
50.

論文

論文
Sakurai, Masaru ; Nakamura, Koshi ; Miura, Katsuyuki ; Takamura, Toshinari ; Yoshita, Katsushi ; Morikawa, Yuko ; Ishizaki, Masao ; Kido, Teruhiko ; Naruse, Yuchi ; Suwazono, Yasushi ; Kaneko, Shuichi ; Sasaki, Satoshi ; Nakagawa, Hideaki
出版情報: Metabolism: Clinical and Experimental.  61  pp.47-55,  2012-01-01.  Elsevier
URL: http://hdl.handle.net/2297/30113
概要: This cohort study investigated the association between dietary glycemic index (GI), glycemic load (GL), and the incidence of type 2 diabetes mellitus in middle-aged Japanese men, and the effect of insulin resistance and pancreatic B-cell function on the association. Participants were 1995 male employees of a metal products factory in Japan. Dietary GI and GL were assessed using a self-administered diet history questionnaire. The incidence of diabetes was detected in annual medical examinations over a 6-year period. The association between GI, GL, and the incidence of diabetes was evaluated using Cox proportional hazards models. During the study, 133 participants developed diabetes. Age- and body mass index-adjusted hazard ratios across the GI quintiles were 1.00 (reference), 1.62, 1.50, 1.68, and 1.80; and those of GL were 1.00 (reference), 1.07, 1.48, 0.95, and 0.98. The hazard ratio for the highest GI quintile was significantly greater than that for the lowest quintile. The influence of GI was more pronounced in the lowest insulin resistance subgroups. GI and pancreatic B-cell function were independently associated with the incidence of type 2 diabetes mellitus; participants with low B-cell function and the highest tertile of GI had the highest risk of diabetes. Dietary GI is associated with the incidence of diabetes in middle-aged Japanese men. GI and B-cell function were independently associated with incidence of diabetes. © 2012 Elsevier Inc. All rights reserved. 続きを見る
51.

論文

論文
Nakagawa, Hidetoshi ; Mizukoshi, Eishiro ; Iida, Noriho ; Terashima, Takeshi ; Kitahara, Masaaki ; Marukawa, Yohei ; Kitamura, Kazuya ; Nakamoto, Yasunari ; Hiroishi, Kazumasa ; Imawari, Michio ; Kaneko, Shuichi
出版情報: Cancer Immunology, Immunotherapy.  63  pp.347-356,  2014-04-01.  Springer-Verlag
URL: http://hdl.handle.net/2297/36504
概要: Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy. © 2013 Springer-Verlag Berlin Heidelberg. 続きを見る
52.

論文

論文
Misu, Hirofumi ; Ishikura, Kazuhide ; Kurita, Seiichiro ; Takeshita, Yumie ; Ota, Tsuguhito ; Saito, Yoshiro ; Takahashi, Kazuhiko ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: PLoS ONE.  7  pp.e34952-,  2012-04-04.  PLoS ONE
URL: http://hdl.handle.net/2297/31364
概要: Background: We recently identified selenoprotein P (SeP) as a liver-derived secretory protein that causes insulin resistance in the liver and skeletal muscle; however, it is unknown whether and, if so, how SeP acts on adipose tissue. The present study tested the hypothesis that SeP is related to hypoadiponectinemia in patients with type 2 diabetes. Methodology/Principal Findings: We compared serum levels of SeP with those of adiponectin and other clinical parameters in 36 patients with type 2 diabetes. We also measured levels of blood adiponectin in SeP knockout mice. Circulating SeP levels were positively correlated with fasting plasma glucose (r = 0.35, P = 0.037) and negatively associated with both total and high-molecular adiponectin in patients with type 2 diabetes (r = -0.355, P = 0.034; r = -0.367, P = 0.028). SeP was a predictor of both total and high-molecular adiponectin, independently of age, body weight, and quantitative insulin sensitivity index (β = -0.343, P = 0.022; β = -0.357, P = 0.017). SeP knockout mice exhibited an increase in blood adiponectin levels when fed regular chow or a high sucrose, high fat diet. Conclusions/Significance: These results suggest that overproduction of liver-derived secretory protein SeP is connected with hypoadiponectinemia in patients with type 2 diabetes. © 2012 Misu et al. 続きを見る
53.

論文

論文
Nakade, Yusuke ; Takamura, Toshinari ; Sakurai, Masaru ; Misu, Hirofumi ; Nagata, Mitsuko ; Nanbu, Yuko ; Oe, Hiroyasu ; Takamura, Toshiji ; Sakai, Yoshio ; Kaneko, Shuichi ; Wada, Takashi
出版情報: Journal of Diabetes Investigation.  2  pp.324-327,  2011-08-01.  Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd. / Wiley Open Access
URL: http://hdl.handle.net/2297/36514
概要: The aim of the present study was to examine whether there is a relationship between autonomic function and post-challenge hyperglycemia in patients with type 2 diabetes. Subjects included 122 Japanese patients newly diagnosed with type 2 diabetes. Autonomic nerve function was assessed using coefficients of variation of the R-R intervals on electrocardiograms (CVRR). Unlike anthropometry, insulin secretion and insulin resistance, age (r =)0.209, P < 0.021) and post-challenge plasma glucose at 120 min (PG120; r =)0.219, P < 0.015) were the only variables significantly correlated with CVRR. Age was not significantly correlated with PG120. In multiple regression analyses, CVRR Z-score, but not age, was significantly correlated with PG120. The present results suggest that autonomic function affects post-challenge blood glucose levels independently of age. © 2011 Asian Association for the Study of Diabetes and Blackwell Publishing Asia Pty Ltd. 続きを見る
54.

論文

論文
Kaneko, Shuichi ; Furuse, Junji ; Kudo, Masatoshi ; Ikeda, Kenji ; Honda, Masao ; Nakamoto, Yasunari ; Onchi, Morikazu ; Shiota, Goshi ; Yokosuka, Osamu ; Sakaida, Isao ; Takehara, Tetsuo ; Ueno, Yoshiyuki ; Hiroishi, Kazumasa ; Nishiguchi, Shuhei ; Moriwaki, Hisataka ; Yamamoto, Kazuhide ; Sata, Michio ; Obi, Shuntaro ; Miyayama, Shiro ; Imai, Yukinori
出版情報: Hepatology Research.  42  pp.523-542,  2012-06-01.  Wiley-Blackwell
URL: http://hdl.handle.net/2297/31395
概要: The "Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma" was prepared by the Study Group on New Liver Cancer Therapies established by the "Research Project on Emergency Measures to Overcome Hepatitis" under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents "clinical questions" on issues pertaining to medical care, makes "recommendations" on diagnosis and treatment in response to each of these clinical questions, and provides a rationale for these recommendations in the form of "scientific statements". © 2012 The Japan Society of Hepatology. 続きを見る
55.

論文

論文
Marukawa, Yohei ; Nakamoto, Yasunari ; Kakinoki, Kaheita ; Tsuchiyama, Tomoya ; Iida, Noriho ; Kagaya, Takashi ; Sakai, Yoshio ; Naito, Makoto ; Mukaida, Naofumi ; Kaneko, Shuichi
出版情報: Cancer Gene Therapy.  19  pp.312-319,  2012-05-01.  Nature Publishing Group
URL: http://hdl.handle.net/2297/31396
概要: Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monocyte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P<0.01). The numbers of Mac-1-, CD4-and CD8a-positive cells were significantly higher in tumor tissues (P<0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC. © 2012 Macmillan Publishers Limited All rights reserved. 続きを見る
56.

論文

論文
Marukawa, Yohei ; Nakamoto, Yasunari ; Kakinoki, Kaheita ; Tsuchiyama, Tomoya ; Iida, Noriho ; Kagaya, Takashi ; Sakai, Yoshio ; Naito, Makoto ; Mukaida, Naofumi ; Kaneko, Shuichi
出版情報: Cancer Gene Therapy.  19  pp.312-319,  2012-05-01.  Nature Publishing Group
URL: http://hdl.handle.net/2297/30373
概要: Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system combined with monocyte chemoattractant protein-1 (MCP-1) provides significant antitumor efficacy. The current study was designed to evaluate the antitumor immunity of a newly developed membrane-bound form of MCP-1 (mMCP-1) in an immunocompetent mouse model of hepatocellular carcinoma (HCC). A recombinant adenovirus vector (rAd) harboring the human MCP-1 gene and the membrane-spanning domain of the CX3CL1 gene was used. Large amounts of MCP-1 protein were expressed and accumulated on the tumor cell surface. The growth of subcutaneous tumors was markedly suppressed when tumors were treated with mMCP-1, as compared with soluble MCP-1, in combination with the HSV-tk/GCV system (P<0.01). The numbers of Mac-1-, CD4- and CD8a-positive cells were significantly higher in tumor tissues (P<0.05), and tumor necrosis factor (TNF) mRNA expression levels with mMCP-1 were almost five-fold higher than those with soluble MCP-1. These results indicate that the delivery of the mMCP-1 gene greatly enhanced antitumor effects following the apoptotic stimuli by promoting the recruitment and activation of macrophages and T lymphocytes, suggesting a novel strategy of immune-based gene therapy in the treatment of patients with HCC.Cancer Gene Therapy advance online publication, 9 March 2012; doi:10.1038/cgt.2012.3. 続きを見る
57.

論文

論文
Sakai, Yoshio ; Kaneko, Shuichi
出版情報: Methods in Molecular Biology.  826  pp.217-223,  2012-01-01.  Springer Science+Business Media, LLC
URL: http://hdl.handle.net/2297/30374
概要: A severely malfunctioning liver, due to acute liver injury or chronic liver disease, can lead to hepatic failure. The ultimate treatment for hepatic failure is liver transplantation; however, the availability of donors is a critical issue. Therefore, regenerative therapy is an anticipated novel approach for restoring liver function. Mesenchymal stem cells are pluripotent somatic cells that can differentiate into several cell types, including hepatocytes. Moreover, they are obtainable from easily accessible autologous adipose tissue, making them ideal for regenerative therapy. This chapter describes experimental methods for isolating mesenchymal stem cells from murine adipose tissues and expanding them, and also describes murine chronic liver disease, steatohepatitis, for the study of experimental regenerative treatments of chronic liver disease. © 2012 Springer Science+Business Media, LLC. 続きを見る
58.

論文

論文
Ohtani, Keisuke ; Usui, Soichiro ; Kaneko, Shuichi ; Takashima, Shin-ichiro ; Kitano, Katsunori ; Yamamoto, Kanako ; Okajima, Masaki ; Furusho, Hiroshi ; Takamura, Masayuki
出版情報: Hypertension Research.  35  pp.287-294,  2012-03-01.  Nature Publishing Group / Japanese Society of Hypertension
URL: http://hdl.handle.net/2297/30372
概要: Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T-and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30 min of left ascending coronary I/R. Benidipine was administered orally at 3 mg kg -1 daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2′ deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels. © 2012 The Japanese Society of Hypertension All rights reserved. 続きを見る
59.

論文

論文
Ikeda, Tatsunori ; Murai, Hisayoshi ; Kaneko, Shuichi ; Usui, Soichiro ; Kobayashi, Daisuke ; Nakano, Manabu ; Ikeda, Keiko ; Takashima, Shin-ichiro ; Kato, Takeshi ; Okajima, Masaki ; Furusho, Hiroshi ; Takamura, Masayuki
出版情報: Journal of Physiology.  590  pp.509-518,  2012-02-01.  The Physiological Society / Wiley-Blackwell
URL: http://hdl.handle.net/2297/30371
概要: Atrial fibrillation (AF) is a common complication in heart failure (HF) patients. However, it remains unclear whether irregular ventricular response patterns induced by AF increase sympathetic nerve activity. We measured resting multi- and single-unit muscle sympathetic nerve activity (MSNA) in 21 age-matched HF patients with chronic AF (n= 11) rhythm or sinus rhythm (SR, n= 10). The multi-unit MSNA, which was expressed as total activity, was similar between HF + AF patients and HF + SR patients. However, the single-unit MSNA in HF + AF patients was significantly greater than that in HF + SR patients (62 ± 9 spikes min -1vs. 42 ± 4 spikes min -1, P < 0.05). Moreover, the incidence of multiple firing of single-unit MSNA within a given burst was augmented in HF + AF patients as compared with HF + SR patients (48 ± 8%vs. 26 ± 3%, P < 0.01). A significant negative relationship was observed between the reduced diastolic pressure induced by a prolonged cardiac interval in AF subjects and single-unit MSNA frequency within one cardiac interval in each HF + AF subject. The firing characteristics of single-unit MSNA were different between HF patients with AF and HF patients with SR; particularly, those with a prolonged long RR interval showed multiple firings of single-unit MSNA. These findings suggest that AF per se leads to the instantaneous augmentation of single-unit MSNA induced by decreased diastolic pressure, which might partially contribute to disease progression in HF patients. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society. 続きを見る
60.

論文

論文
Honda, Masao ; Shirasaki, Takayoshi ; Shimakami, Tetsuro ; Sakai, Akito ; Horii, Rika ; Arai, Kuniaki ; Yamashita, Tatsuya ; Sakai, Yoshio ; Yamashita, Taro ; Okada, Hikari ; Nakamura, Mikiko ; Mizukoshi, Eishiro ; Kaneko, Shuichi
出版情報: Hepatology.  59  pp.828-838,  2014-03-01.  Wiley
URL: http://hdl.handle.net/2297/37866
概要: Pretreatment up-regulation of hepatic interferon (IFN)-stimulated genes (ISGs) has a stronger association with the treatment-resistant interleukin (IL)28B minor genotype (MI; TG/GG at rs8099917) than with the treatment-sensitive IL28B major genotype (MA; TT at rs8099917). We compared the expression of ISGs in the liver and blood of 146 patients with chronic hepatitis C who received pegylated IFN and ribavirin combination therapy. Gene expression profiles in the liver and blood of 85 patients were analyzed using an Affymetrix GeneChip (Affymetrix, Santa Clara, CA). ISG expression was correlated between the liver and blood of the MA patients, whereas no correlation was observed in the MI patients. This loss of correlation was the result of the impaired infiltration of immune cells into the liver lobules of MI patients, as demonstrated by regional gene expression analysis in liver lobules and portal areas using laser capture microdissection and immunohistochemical staining. Despite having lower levels of immune cells, hepatic ISGs were up-regulated in the liver of MI patients and they were found to be regulated by multiple factors, namely, IL28A/B, IFN-λ4, and wingless-related MMTV integration site 5A (WNT5A). Interestingly, WNT5A induced the expression of ISGs, but also increased hepatitis C virus replication by inducing the expression of the stress granule protein, GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1), in the Huh-7 cell line. In the liver, the expression of WNT5A and its receptor, frizzled family receptor 5, was significantly correlated with G3BP1. Conclusions: Immune cells were lost and induced the expression of other inflammatory mediators, such as WNT5A, in the liver of IL28B minor genotype patients. This might be related to the high level of hepatic ISG expression in these patients and the treatment-resistant phenotype of the IL28B minor genotype. © 2014 by the American Association for the Study of Liver Diseases.<br />This article has Supplemental materrial and methods. 続きを見る
61.

論文

論文
Ando, Hitoshi ; Kurita, Seiichiro ; Shimizu, Akiko ; Kato, Ken-ichiro ; Ishikura, Kazuhide ; Taji, Koumei ; Uno, Masafumi ; Takeshita, Yumie ; Misu, Hirofumi ; Fujimura, Akio ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Clinical and Experimental Pharmacology and Physiology.  39  pp.528-534,  2012-06-01.  Blackwell
URL: http://hdl.handle.net/2297/31973
概要: Few studies have evaluated the pharmacokinetics of rapid-acting insulin analogues in patients with Type 2 diabetes, especially under clinical conditions. The aim of the present study was to assess both the pharmacokinetics and pharmacodynamics of insulin aspart in Type 2 diabetic patients who were being treated with the analogue alone. Meal tolerance tests with and without self-injection of a customary dose of insulin aspart (0.05-0.22 U/kg) were conducted in 20 patients in a randomized cross-over study. The dose of insulin aspart (per bodyweight) was significantly correlated with both the maximum concentration (r 2 = 0.59; P < 0.01) and area under the concentration-time curve for insulin aspart (r 2 = 0.53; P < 0.01). However, the time to maximum concentration (T max), which varied widely from < 60 to ≥ 120 min, was not associated with either dosage (r 2 = 0.02; P = 0.51) or body mass index (r 2 = 0.02; P = 0.57). Injection of insulin aspart exacerbated delayed hyperinsulinaemia after meal loading, mainly in patients with T max ≥ 120 min. With regard to pharmacodynamics, insulin aspart had favourable effects on postprandial hyperglycaemia, hyperglucagonaemia and hyperlipidaemia. The T max for this insulin analogue differed greatly between individuals and delayed hyperinsulinaemia was particularly exacerbated in patients with higher T max values. Identification of the factors contributing to interindividual variation in the absorption lag time is essential for improving the efficacy and safety of insulin aspart. © 2012 The Authors. Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd. 続きを見る
62.

論文

論文
Ohtani, Keisuke ; Usui, Soichiro ; Kaneko, Shuichi ; Takashima, Shin-ichiro ; Kitano, Katsunori ; Yamamoto, Kanako ; Okajima, Masaki ; Furusho, Hiroshi ; Takamura, Masayuki
出版情報: Hypertension Research.  35  pp.287-294,  2012-03-01.  Japanese Society of Hypertension 日本高血圧学会 / Nature Publishing Group
URL: http://hdl.handle.net/2297/32000
概要: Aldosterone is implicated in the pathogenesis of several cardiovascular diseases, including ischemia reperfusion (I/R) and myocardial infarction, and also causes oxidative stress and inflammation in cardiovascular systems. Benidipine, a long-acting T-and L-type calcium channel blocker, reduces infarct size following myocardial I/R in rabbits. Benidipine also inhibits the production of aldosterone in vitro. However, the precise mechanism of this phenomenon in vivo remains unknown. We therefore evaluated whether benedipine has a beneficial role through the regulation of oxidative stress in myocardial I/R. C57BL/6J mice were subjected to 30 min of left ascending coronary I/R. Benidipine was administered orally at 3 mg kg -1daily for 3 weeks without any changes in hemodynamic variables. Benidipine significantly reduced infarction size (13.4±2.5%) compared with controls (25.5±3.6%). Urinary 8-hydroxy-2′ deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, increased significantly after I/R. I/R induced increases in 8-OHdG were significantly lower with benidipine. Local myocardial 8-OHdG was also elevated in I/R, but this augmentation was significantly suppressed with benidipine. The plasma aldosterone concentration (PAC) significantly increased 2 days after I/R and remained elevated at least 7 days after I/R. Treatment with benidipine significantly decreased I/R-induced elevation of the PAC. I/R-induced markers of fibrosis in hearts also reduced in benidipine. These results suggest that the administration of benidipine reduces myocardial infarct size as well as systemic oxidative stress after I/R. These phenomena are partially linked to reduced plasma aldosterone levels. © 2012 The Japanese Society of Hypertension All rights reserved. 続きを見る
63.

論文

論文
Takeshita, Yumie ; Takamura, Toshinari ; Minato, Hiroshi ; Misu, Hirofumi ; Ando, Hitoshi ; Yamashita, Tatsuya ; Ikeda, Hiroko ; Nakanuma, Yasuni ; Kaneko, Shuichi
出版情報: Internal Medicine.  47  pp.1709-1712,  2008-01-01.  日本内科学会 = the Japanese Society of Internal Medicine
URL: http://hdl.handle.net/2297/14444
概要: 金沢大学医薬保健研究域医学系<br />金沢大学医薬保健研究域医学系恒常性制御学<br />Multiple liver metastases were incidentally detected in the lo be of the liver of an 81-year-old woman following total thyroidectomy and ablative radioactive iodine administration for the treatment of papillary thyroid carcinoma. A biopsy specimen taken from the metastatic liver tumor was histologically diagnosed as anaplastic carcinoma. Immunohistochemical staining for p53 was positive in both the primary tumor and liver biopsy specimens. We considered this to have been caused by anaplastic transformation from papillary thyroid carcinoma during treatment. We report a rare case of multiple liver metastases from a papillary thyroid carcinoma, which we believe to be the result of anaplastic transformation during postoperative radioactive iodine-131 therapy. © 2008 The Japanese Society of Internal Medicine. 続きを見る
64.

論文

論文
Hara, Akinori ; Wada, Takashi ; Kitajima, Shinji ; Toyama, Tadashi ; Okumura, Toshiya ; Kitagawa, Kiyoki ; Iwata, Yasunori ; Sakai, Norihiko ; Furuichi, Kengo ; Higuchi, Masato ; Kaneko, Shuichi
出版情報: American Journal of Hematology.  83  pp.750-752,  2008-09-01.  John Wiley & Sons
URL: http://hdl.handle.net/2297/11836
概要: 金沢大学医薬保健研究域医学系<br />A 42-year-old woman with systemic lupus erythematosus was admitted to our hospital because of severe anemia. Her bone marrow was almost normocellular and erythroblasts were nearly absent. Laboratory data showed elevated levels of lactate dehydrogenase and positive findings on Coombs' tests. On the basis of these findings, her anemia was diagnosed as the overlap of pure red cell aplasia with autoimmune hemolytic anemia. Radioimmunoprecipitation assay revealed that her serum was positive for anti-erythropoietin antibodies before therapy. Furthermore, the autoantibodies inhibited proliferation of an erythropoietin-dependent cell line in a dose-dependent manner. Immunosuppressive treatment improved the anemia accompanied with disappearance of the autoantibodies. © 2008 Wiley-Liss, Inc. 続きを見る
65.

論文

論文
Kita, Yuki ; Takamura, Toshinari ; Misu, Hirofumi ; Ota, Tsuguhito ; Kurita, Seiichiro ; Takeshita, Yumie ; Uno, Masafumi ; Matsuzawa-Nagata, Naoto ; Kato, Ken-ichiro ; Ando, Hitoshi ; Fujimura, Akio ; Hayashi, Koji ; Kimura, Toru ; Ni, Yinhua ; Otoda, Toshiki ; Miyamoto, Ken-ichi ; Zen, Yoh ; Nakanuma, Yasuni ; Kaneko, Shuichi
出版情報: PLoS ONE.  7  pp.e43056-,  2012-09-18.  Public Library of Science
URL: http://hdl.handle.net/2297/32834
概要: Background: Optimal treatment for nonalcoholic steatohepatitis (NASH) has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. Methodology/Principal Findings: Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF) diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH. Conclusions/Significance: These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance. © 2012 Kita et al. 続きを見る
66.

論文

論文
Mizukoshi, Eishiro ; Fushimi, Kazumi ; Arai, Kuniaki ; Yamashita, Tatsuya ; Honda, Masao ; Kaneko, Shuichi
出版情報: Liver International.  32  pp.1516-1526,  2012-11-01.  John Wiley and Sons
URL: http://hdl.handle.net/2297/32865
概要: Background & Aims: Chondroitin-glucuronate C5-epimerase is an enzyme that converts D-glucuronic acid to L-iduronic acid residues in dermatan sulphate biosynthesis. It is also identified to be a tumour-associated antigen recognized by cytotoxic T cells (CTLs) and its enhanced expression in many cancers has been reported. In the present study, we investigated the usefulness of this molecule as an immunotherapeutic target in hepatocellular carcinoma (HCC). Methods: The expression of chondroitin-glucuronate C5-epimerase in hepatoma cell lines and HCC tissues was confirmed by immunofluorescence and immunohistochemical analysis. CTL responses were investigated by several immunological techniques using peripheral blood mononuclear cells (PBMCs) or tumour-infiltrating lymphocytes. To determine the safety of immunotherapy using chondroitin-glucuronate C5-epimerase-derived peptide, 12 patients with HCC were administered s.c. vaccinations of the peptides and analysed. Results: Chondroitin-glucuronate C5-epimerase was expressed in HCC cell lines and human tissues including alpha-foetoprotein (AFP)-negative individuals. Chondroitin-glucuronate C5-epimerase-specific CTLs could be generated by stimulating PBMCs of HCC patients with peptides and they showed cytotoxicity against HCC cells expressing the protein. The frequency of CTL precursors investigated by enzyme-linked immunospot (ELISPOT) assay was 0-34 cells/3 × 10 5 PBMCs and the infiltration of interferon-gamma-producing CTLs into the tumour site was confirmed. In the vaccination study, no severe adverse events were observed and the peptide-specific CTLs were induced in 4 of 12 patients tested. Conclusions: Chondroitin-glucuronate C5-epimerase is a potential candidate for tumour antigen with immunogenicity and the peptides derived from this antigen could be useful in HCC immunotherapy. © 2012 John Wiley & Sons A/S. 続きを見る
67.

論文

論文
Kato, Ken-ichiro ; Takamura, Toshinari ; Takeshita, Yumie ; Ryu, Yasuji ; Misu, Hirofumi ; Ota, Tsuguhito ; Tokuyama, Kumpei ; Nagasaka, Shoichiro ; Matsuhisa, Munehide ; Matsui, Osamu ; Kaneko, Shuichi
出版情報: PLoS ONE.  9  pp.e92170-,  2014-03-20.  Public Library of Science
URL: http://hdl.handle.net/2297/37643
概要: Objective: The aim of this study was to examine the association between ectopic fat and organ-specific insulin resistance (IR) in insulin-target organs in patients with nonalcoholic fatty liver disease (NAFLD). Methods: Organ-specific IR in the liver (hepatic glucose production (HGP)6fasting plasma insulin (FPI) and suppression of HGP by insulin [%HGP]), skeletal muscle (insulin-stimulated glucose disposal [Rd]), and adipose tissue (suppression of FFA by insulin [%FFA]) was measured in 69 patients with NAFLD using a euglycemic hyperinsulinemic clamp with tracer infusion ([6,6-2H 2]glucose). Liver fat, intramyocellular lipid (IMCL), and body composition were measured by liver biopsy, proton magnetic resonance spectroscopy, and bioelectrical impedance analysis, respectively. Results: HGPxFPI was significantly correlated with Rd (r = -0.57, P<0.001), %HGP with %FFA (r = 0.38, P<0.01), and Rd with %FFA (r = 0.27, P<0.05). Liver steatosis score was negatively associated with Rd (r = -0.47, P<0.001) as well as with HGPxFPI ( r = 0.43, P<0.001). Similarly, intrahepatic lipid was negatively associated with Rd (r = -0.32, P<0.05). IMCL was not associated with Rd (r = -0.16, P = 0.26). Fat mass and its percentage were associated with HGPxFPI (r = 0.50, P<0.001; r = 0.48, P<0.001, respectively) and Rd (r = -0.59, P<0.001; r = -0.52, P<0.001, respectively), but not with %FFA (r = -0.21, P = 0.10; r = -0.001, P = 0.99, respectively). Conclusion: Unexpectedly, fat accumulation in the skeletal muscle and adipose tissue was not associated with organ-specific IR. Instead, liver fat was associated not only with hepatic IR but also with skeletal muscle IR, suggesting a central role of fatty liver in systemic IR and that a network exists between liver and skeletal muscle. © 2014 Kato et al. 続きを見る
68.

論文

論文
Lan, Fei ; Misu, Hirofumi ; Chikamoto, Keita ; Takayama, Hiroaki ; Kikuchi, Akihiro ; Mohri, Kensuke ; Takata, Noboru ; Hayashi, Hiroto ; Matsuzawa-Nagata, Naoto ; Takeshita, Yumie ; Noda, Hiroyo ; Matsumoto, Yukako ; Ota, Tsuguhito ; Nagano, Toru ; Nakagen, Masatoshi ; Miyamoto, Ken-ichi ; Takatsuki, Kanako ; Seo, Toru ; Iwayama, Kaito ; Tokuyama, Kunpei ; Matsugo, Seiichi ; Tang, Hong ; Saito, Yoshiro ; Yamagoe, Satoshi ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Diabetes.  63  pp.1649-1664,  2014-05-01.  American Diabetes Association
URL: http://hdl.handle.net/2297/37595
概要: Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell-derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance. © 2014 by the American Diabetes Association. 続きを見る
69.

論文

論文
Toyama, Tadashi ; Shimizu, Miho ; Furuichi, Kengo ; Kaneko, Shuichi ; Wada, Takashi
出版情報: Clinical and Experimental Nephrology.  18  pp.201-205,  2014-01-01.  Japanese Society of Nephrology (JSN) 日本腎臓学会 / Springer Verlag (Germany)
URL: http://hdl.handle.net/2297/36272
概要: Recent epidemiological research revealed that dyslipidemia is a risk factor for development and progression of diabetic nephropathy. Results from interventional studies revealed the possibility that anti-hyperlipidemic agents have a better effect on diabetic nephropathy through improvement of albuminuria and loss of renal function. In addition, dyslipidemia may be a consequence of albuminuria and renal dysfunction, thereby perpetuating kidney damage. Today, the proportion of diabetic patients receiving statins is increasing due to their beneficial effect on cardiovascular mortality. However, treatment for patients should be determined based on consideration of the risk and benefit of the treatment. More insight into the pathogenesis of diabetic nephropathy and the effects of life-style changes is required. © 2013 Japanese Society of Nephrology. 続きを見る
70.

論文

論文
Kawaguchi, Kazunori ; Honda, Masao ; Yamashita, Taro ; Okada, Hikari ; Shirasaki, Takayoshi ; Nishikawa, Masashi ; Nio, Kouki ; Arai, Kuniaki ; Sakai, Yoshio ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Kaneko, Shuichi
出版情報: American Journal of Pathology.  186  pp.2055-2067,  2016-08-01.  Elsevier
URL: http://hdl.handle.net/2297/46535
概要: Notch signaling abnormalities are reported to be involved in the acceleration of malignancy in solid tumors and stem cell formation or regeneration in various organs. We analyzed specific genes for DNA copy number variations in liver cancer cells and investigated whether these factors relate to clinical outcome. Chromosome 20p, which includes the ligand for Notch pathways, Jagged1, was found to be amplified in several types of hepatoma cells, and its mRNA was up-regulated according to α-fetoprotein gene expression levels. Notch inhibition using Jagged1 shRNA and γ-secretase inhibitors produced significant suppression of cell growth in α-fetoprotein–producing cells with suppression of downstream genes. Using in vivo hepatoma models, the administration of γ-secretase inhibitors resulted in reduced tumor sizes and effective Notch inhibition with widespread apoptosis and necrosis of viable tumor cells. The γ-secretase inhibitors suppressed cell growth of the epithelial cell adhesion molecule–positive fraction in hepatoma cells, indicating that Notch inhibitors could suppress the stem cell features of liver cancer cells. Even in clinical liver cancer samples, the expression of α-fetoprotein and Jagged1 showed significant correlation, and amplification of the copy number of Jagged1 was associated with Jagged1 mRNA expression and poor survival after liver cancer surgical resection. In conclusion, amplification of Jagged1 contributed to mRNA expression that activates the Jagged1-Notch signaling pathway in liver cancer and led to poor outcome. © 2016 American Society for Investigative Pathology<br />Embargo Period 12 months 続きを見る
71.

論文

論文
Terashima, Takeshi ; Yamashita, Tatsuya ; Arai, Kuniaki ; Sunagozaka, Hajime ; Kitahara, Masaaki ; Nakagawa, Hidetoshi ; Kagaya, Takashi ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi
出版情報: Hepatology Research.  44  pp.1179-1185,  2014-11-01.  Blackwell Publishing / 日本肝臓学会 Japan Society of Hepatology
URL: http://hdl.handle.net/2297/40612
概要: Aim: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, although there is no proven therapeutic procedure following the termination of sorafenib, hepatic arterial infusion chemotherapy (HAIC) may be a treatment option in advanced HCC. The aim of this study was to evaluate feasibility and efficacy of HAIC for patients with advanced HCC as subsequent therapy. Methods: We retrospectively evaluated 27 consecutive patients with advanced HCC who were treated with HAIC following sorafenib between June 2009 and December 2012 at our hospital. Cisplatin (20 mg/m2 per day) was administered via the hepatic artery for 10 min, prior to the continuous administration of 5-fluorouracil (330 mg/m2 per day) over 24 h from days 1-5 and 8-12 and the s.c. administration of pegylated interferon α-2b (1 μg/kg) on days 1, 8, 15, and 22. A treatment cycle consisted of 28 days of drug administration followed by 14 days of rest. Results: The toxicity profile showed that hematological toxicities were common, and grade 3/4 neutropenia and thrombocytopenia were observed (51.9% and 48.1%, respectively). Five patients (18.5%) experienced device-related complications. No unexpected adverse reactions and no treatmentrelated deaths were observed. Partial response was obtained in eight patients (29.6%), and stable disease was noted in nine patients (33.3%). Median progression-free survival and median survival time from initiation of HAIC were 4.0 and 7.6 months, respectively. Conclusions: Because HAIC was well tolerated and exhibited moderate antitumor activity, it is a potentially useful treatment procedure in patients with advanced HCC even after failure of sorafenib. 続きを見る
72.

論文

論文
Ishikura, Kazuhide ; Misu, Hirofumi ; Kumazaki, Masafumi ; Takayama, Hiroaki ; Matsuzawa-Nagata, Naoto ; Tajima, Natsumi ; Chikamoto, Keita ; Lan, Fei ; Ando, Hitoshi ; Ota, Tsuguhito ; Sakurai, Masaru ; Takeshita, Yumie ; Kato, Kenichiro ; Fujimura, Akio ; Miyamoto, Ken-ichi ; Saito, Yoshiro ; Kameo, Satomi ; Okamoto, Yasuo ; Takuwa, Yoh ; Takahashi, Kazuhiko ; Kidoya, Hiroyasu ; Takakura, Nobuyuki ; Kaneko, Shuichi ; Takamaura, Toshinari
出版情報: Diabetologia.  57  pp.1968-1976,  2014-09-01.  Springer Verlag
URL: http://hdl.handle.net/2297/39052
概要: Aims/hypothesis Impaired angiogenesis induced by vascular endothelial growth factor (VEGF) resistance is a hallmark of vascular complications in type 2 diabetes; however, its molecular mechanism is not fully understood. We have previously identified selenoprotein P (SeP, encoded by the SEPP1 gene in humans) as a liver-derived secretory protein that induces insulin resistance. Levels of serum SeP and hepatic expression of SEPP1 are elevated in type 2 diabetes. Here, we investigated the effects of SeP on VEGF signalling and angiogenesis. Methods We assessed the action of glucose on Sepp1 expression in cultured hepatocytes. We examined the actions of SeP on VEGF signalling and VEGF-induced angiogenesis in HUVECs. We assessed wound healing in mice with hepatic SeP overexpression or SeP deletion. The blood flow recovery after ischaemia was also examined by using hindlimb ischaemia model with Sepp1-heterozygous-knockout mice. Results Treatment with glucose increased gene expression and transcriptional activity for Sepp1 in H4IIEC hepatocytes. Physiological concentrations of SeP inhibited VEGF-stimulated cell proliferation, tubule formation and migration in HUVECs. SeP suppressed VEGF-induced reactive oxygen species (ROS) generation and phosphorylation of VEGF receptor 2 (VEGFR2) and extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs. Wound closure was impaired in the mice overexpressing Sepp1, whereas it was improved in SeP-/-mice. SeP+/-mice showed an increase in blood flow recovery and vascular endothelial cells after hindlimb ischaemia. Conclusions/interpretation The hepatokine SeP may be a novel therapeutic target for impaired angiogenesis in type 2 diabetes. © 2014 Springer-Verlag Berlin Heidelberg. 続きを見る
73.

論文

論文
Yaegashi, Takanori ; Furusho, Hiroshi ; Chikata, Akio ; Usui, Soichiro ; Kaneko, Shuichi ; Yamagishi, Masakazu ; Takamura, Masayuki
出版情報: Journal of Medical Case Reports.  8  pp.158-,  2014-05-01.  BioMed Central
URL: http://hdl.handle.net/2297/39039
概要: Introduction. Right ventricular septal pacing is thought to be better than right ventricular apical pacing for shortening the QRS duration and for preserving left ventricular function. However, right ventricular septal pacing may not be effective in all cases. In this case report, we present a rare case in which right ventricular septal pacing induced thoroughly separated right and left ventricular excitation despite the presence of a relatively narrow QRS wave during atrium-only pacing. Case presentation. We report a case of 63-year-old Japanese man with cardiomyopathy with an implantable cardioverter defibrillator placement for ventricular tachycardia. Three years after implantation, he developed second-degree atrio-ventricular block. Therefore, atrio-ventricular sequential pacing was started; then his heart failure was much worsened. His electrocardiogram showed a dissociated biphasic QRS wave during right ventricular high-septal pacing, despite the presence of a non-fragmented QRS morphology during atrium-only pacing. An activation map during right ventricular high-septal pacing showed that right ventricular conduction started at the pacing site and ended at the right ventricular basal inferior site. Subsequently after a 10ms interval, left ventricular conduction started at the left ventricular posteroseptum and ended at the left ventricular lateral wall. These data indicate that during right ventricular high-septal pacing, the first component of the QRS wave supposedly reflects only right ventricular excitation and the second component only left ventricular excitation. Also due to the intracardiac electrograms, it was assumed that this phenomenon was caused by transversely limited severe transseptal conduction disturbance. Conclusion: It should be noted that even ventricular septal pacing could evoke harmful interventricular dyssynchrony due to transversely limited severe septal conduction disturbance, despite the presence of a relatively narrow QRS wave. © 2014 Yaegashi et al.; licensee BioMed Central Ltd. 続きを見る
74.

論文

論文
Kitahara, Masaaki ; Mizukoshi, Eishiro ; Nakamoto, Yasunari ; Mukaida, Naofumi ; Matsushima, Kouji ; Kaneko, Shuichi
出版情報: International Immunopharmacology.  21  pp.346-353,  2014-08-01.  Elsevier
URL: http://hdl.handle.net/2297/39073
概要: Background & aims Immunotherapy using dendritic cells (DCs) is a promising cancer therapy. The success of this therapy depends on the function of induced DCs. However, there has been no consensus on optimal conditions for DC preparation in vitro for immunotherapy of hepatocellular carcinoma (HCC) patients. To address relevant issues, we evaluated the procedures to induce DCs that efficiently function in hepatitis C virus (HCV)-related HCC. Methods We studied immunological data from 14 HCC patients. The DC preparation and the surface markers were assessed by flow cytometric analysis. Four different additional activation stimuli (Method I, medium alone; Method II, with OK-432; Method III, with IL-1β + IL-6 + TNF-α; Method IV, with IL-1β + IL-6 + TNF-α + PGE2) were tested and the functions of DCs were confirmed by examination of the ability of phagocytosis, cytokine production and allogeneic mixed lymphocyte reaction (MLR). Results The numbers of DCs induced and their cytokine production ability were not different between healthy controls and HCC patients. T-cell stimulatory activity of DCs in MLR was significantly lower in HCC patients than in healthy controls. The maturation of DCs with OK-432 boosted production of cytokines and chemokines, such as IL-2, IL-12p70, IFN-γ, TNF-α, IL-13 and MIP1α, and restored T-cell stimulatory activity of DCs in MLR. Conclusions The clinically approved compound OK-432 is a candidate for highly immunocompetent DC preparation and may be considered as a key drug for immunotherapy of HCV-related HCC patients. © 2014 Published by Elsevier B.V. 続きを見る
75.

論文

論文
Terashima, Takeshi ; Mizukoshi, Eishiro ; Arai, Kuniaki ; Yamashita, Tatsuya ; Yoshida, Mariko ; Ota, Hajime ; Onishi, Ichiro ; Kayahara, Masato ; Ohtsubo, Koushiro ; Kagaya, Takashi ; Honda, Masao ; Kaneko, Shuichi
出版情報: Cancer Immunology, Immunotherapy.  63  pp.479-489,  2014-05-01.  Springer Science and Business Media Deutschland GmbH
URL: http://hdl.handle.net/2297/39095
概要: Cancer vaccine therapy is one of the most attractive therapies as a new treatment procedure for pancreatic adenocarcinoma. Recent technical advances have enabled the identification of cytotoxic T lymphocyte (CTL) epitopes in various tumor-associated antigens (TAAs). However, little is known about which TAA and its epitope are the most immunogenic and useful for a cancer vaccine for pancreatic adenocarcinoma. We examined the expression of 17 kinds of TAA in 9 pancreatic cancer cell lines and 12 pancreatic cancer tissues. CTL responses to 23 epitopes derived from these TAAs were analyzed using enzyme-linked immunospot (ELISPOT), CTL, and tetramer assays in 41 patients, and factors affecting the immune responses were investigated. All TAAs were frequently expressed in pancreatic adenocarcinoma cells, except for adenocarcinoma antigens recognized by T cells 1, melanoma-associated antigen (MAGE)-A1, and MAGE-A3. Among the epitopes recognized by CTLs in more than two patients in the ELISPOT assay, 6 epitopes derived from 5 TAAs, namely, MAGE-A3, p53, human telomerase reverse transcriptase (hTERT), Wilms tumor (WT)-1, and vascular endothelial growth factor receptor (VEGFR)2, could induce specific CTLs that showed cytotoxicity against pancreatic cancer cell lines. The frequency of lymphocyte subsets correlated well with TAA-specific immune response. Overall survival was significantly longer in patients with TAA-specific CTL responses than in those without. P53, hTERT, WT-1, and VEGFR2 were shown to be attractive targets for immunotherapy in patients with pancreatic adenocarcinoma, and the induction of TAA-specific CTLs may improve the prognosis of these patients. © 2014 Springer-Verlag Berlin Heidelberg. 続きを見る
76.

論文

論文
Kato, Takeshi ; Sekiguchi, Akiko ; Sagara, Koichi ; Tanabe, Hiroaki ; Takamura, Masayuki ; Kaneko, Shuichi ; Aizawa, Tadanori ; Fu, Long-Tai ; Yamashita, Takeshi
出版情報: Journal of Cardiology.  69  pp.706-711,  2017-05-01.  Japanese College of Cardiology = 日本心臓病学会
URL: http://hdl.handle.net/2297/46765
概要: Background: Atrial fibrosis is a hallmark of atrial structural remodeling leading to the persistence of atrial fibrillation. Although fibroblasts play a major role in atrial fibrosis, their source in the adult atrium is unclear. We tested the hypothesis that endothelial cells contribute to fibroblast accumulation through an endothelial-mesenchymal transition in the atrium of patients with atrial fibrillation. Methods and results: The study group consisted of patients with atrial fibrillation and valvular disease or atrial septal defect who underwent left atrial appendectomy during cardiac surgery (n =38). The amount of fibrotic depositions in the left atrium positively correlated with left atrial dimension. Furthermore, snail and S100A4, indicative of endothelial-mesenchymal transition, were quantified in the left atrium using western blot analysis, which showed statistically significant correlations with left atrial dimension. Immunofluorescence assay of the left atrial tissue identified snail and S100A4 being expressed within the endocardium which is composed of CD31+ cells. The snail-positive endocardium also showed the expression of membrane type 1-matrix metalloproteinase. Immunofluorescence multi-labeling experiments identified that heat shock protein 47, prolyl-4-hydroxylase, and procollagen type 1 co-localized with snail and S100A4 within the endothelial cells of the left atrium, indicating the mesenchymal phenotype to produce collagen. Conclusions: In this study, we showed that the endothelial-mesenchymal transition occurs in the atrium of patients with atrial fibrillation. This observation should help in constructing a novel therapeutic approach for preventing atrial structural remodeling. © 2016 Japanese College of Cardiology. 続きを見る
77.

論文

論文
Kato, Ken-ichiro ; Takeshita, Yumie ; Misu, Hirofumi ; Zen, Yoh ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Journal of Diabetes Investigation.  6  pp.158-163,  2015-03-01.  Blackwell Publishing
URL: http://hdl.handle.net/2297/41400
概要: Aims/Introduction: To examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease. Materials and Methods: Liver biopsy specimens were obtained from 72 patients with non-alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method. Results: The degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = -0.45, P < 0.001; grade r = -0.54, P < 0.001; stage r = -0.37, P < 0.01), but not with hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = -0.22, P < 0.05) and grade (coefficient = -0.40, P < 0.01) were associated with Matsuda index, whereas the association between stage and Matsuda index (coefficient = -0.07, P = 0.593) was no longer significant. A similar trend was observed for the association between steatosis and metabolic clearance rate (coefficient = -0.62, P = 0.059). Conclusions: Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle. 続きを見る
78.

論文

論文
Oishi, Naoki ; Shilagardi, Khurts ; Nakamoto, Yasunari ; Honda, Masao ; Kaneko, Shuichi ; Murakami, Seishi
出版情報: Cancer Science.  98  pp.1540-1548,  2007-01-01.  Japanese Cancer Association / Blackwell Publishing Ltd
URL: http://hdl.handle.net/2297/45958
概要: 医薬保健研究域医学系<br />Chronic infection with hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma . The HBV X protein (HBx) is thought to have oncogenic potential, although the molecular mechanism remains obscure. Pathological roles of HBx in the carcinogenic process have been examined using rodent systems and no report is available on the oncogenic roles of HBx in human cells in vitro. We therefore examined the effect of HBx on immortalization and transformation in human primary cells. We found that HBx could overcome active RAS-induced senescence in human immortalized cells and that these cells could form colonies in soft agar and tumors in nude mice. HBx alone, however, could contribute to neither immortalization nor transformation of these cells. In a population doubling analysis, an N-terminal truncated mutant of HBx, HBx-D1 (amino acids 51-154), which harbors the coactivation domain, could overcome active RAS-induced cellular senescence, but these cells failed to exhibit colonigenic and tumorigenic abilities, probably due to the low expression level of the protein. By scanning a HBx expression library of the clustered-alanine substitution mutants, the N-terminal domain was found to be critical for overcoming active RAS-induced senescence by stabilizing full-length HBx. These results strongly suggest that HBx can contribute to carcinogenesis by overcoming active oncogene-induced senescence. © 2007 Japanese Cancer Association. 続きを見る
79.

論文

論文
Mizukoshi, Eishiro ; Yamashita, Tatsuya ; Arai, Kuniaki ; Terashima, Takeshi ; Kitahara, Masaaki ; Nakagawa, Hidetoshi ; Iida, Noriho ; Fushimi, Kazumi ; Kaneko, Shuichi
出版情報: Cancer Immunology, Immunotherapy.  65  pp.715-725,  2016-06-01.  Springer Science and Business Media Deutschland GmbH
URL: http://hdl.handle.net/2297/45591
概要: Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (<3.0 cm), absence of major portal vein invasion, absence of distant metastasis, Union Internationale Contre Le Cancer tumor lymph node metastasis stage (I or II), neutrophil lymphocytic ratio (<2.1) and the frequency of MDSCs (<30.5 %) as factors that prolonged overall survival time after HAIC. Even in the group adjusted with progressive levels of tumors, patients with a low frequency of MDSCs had a significantly longer overall survival time. In conclusion, the frequency of MDSCs before the treatment is a prognostic factor in HAIC against HCC. © 2016 Springer-Verlag Berlin Heidelberg 続きを見る
80.

論文

論文
Katsuki, Tomonori ; Furusho, Hiroshi ; Kusayama, Takashi ; Takashima, Shinichiro ; Kato, Takeshi ; Murai, Hisayoshi ; Usui, Soichiro ; Kaneko, Shuichi ; Takamura, Masayuki
出版情報: Journal of Cardiology Cases.  15  pp.3-5,  2017-01-01.  日本心臓病学会 = Japanese College of Cardiology / Elsevier
URL: http://hdl.handle.net/2297/46782
概要: Many Riata (St. Jude Medical, St. Paul, MN, USA) implantable cardioverter defibrillator (ICD) leads have reportedly developed cable externalization. The most likely cause of cable externalization is insulation abrasion, which often occurs at the can or between the right ventricular coil and superior vena cava (SVC) coil. We report a rare case of an adult male whose ICD lead cable was externalized at the proximal portion of the SVC coil. This lead became fixed to the wall at the subclavian vein and SVC and became bent between these adhesions. Furthermore, the motion of this lead was affected by pulsation of the aortic arch. The ICD lead might develop inside-out abrasion due to mechanical stress evoked by pulsation of the aortic arch at this site.<. Learning objective: Cable externalization of the implantable cardioverter defibrillator lead at the proximal portion of the superior vena cava (SVC) coil has rarely been reported. Externalization might be the result of deformation of the left brachiocephalic vein and the anatomical relationship with the aortic arch. The anatomical pathway of the lead should be carefully considered during the procedure, especially when a dual-coil lead is selected. Moreover, possible cable externalization at both the proximal and distal portions of the SVC coil should be kept in mind during follow-up>. © 2016 Japanese College of Cardiology.<br />Embargo Period 12 months 続きを見る
81.

論文

論文
Ni, Yinhua ; Nagashimada, Mayumi ; Zhuge, Fen ; Zhan, Lili ; Nagata, Naoto ; Tsutsui, Akemi ; Nakanuma, Yasuni ; Kaneko, Shuichi ; Ota, Tsuguhito
出版情報: Scientific Reports.  5  pp.17192-,  2015-11-25.  Nature Publishing Group
URL: http://hdl.handle.net/2297/43909
概要: Hepatic insulin resistance and nonalcoholic steatohepatitis (NASH) could be caused by excessive hepatic lipid accumulation and peroxidation. Vitamin E has become a standard treatment for NASH. However, astaxanthin, an antioxidant carotenoid, inhibits lipid peroxidation more potently than Vitamin E. Here, we compared the effects of astaxanthin and Vitamin E in NASH. We first demonstrated that astaxanthin ameliorated hepatic steatosis in both genetically (ob/ob) and high-fat-diet-induced obese mice. In a lipotoxic model of NASH: mice fed a high-cholesterol and high-fat diet, astaxanthin alleviated excessive hepatic lipid accumulation and peroxidation, increased the proportion of M1-type macrophages/Kupffer cells, and activated stellate cells to improve hepatic inflammation and fibrosis. Moreover, astaxanthin caused an M2-dominant shift in macrophages/Kupffer cells and a subsequent reduction in CD4+ and CD8+ T cell recruitment in the liver, which contributed to improved insulin resistance and hepatic inflammation. Importantly, astaxanthin reversed insulin resistance, as well as hepatic inflammation and fibrosis, in pre-existing NASH. Overall, astaxanthin was more effective at both preventing and treating NASH compared with Vitamin E in mice. Furthermore, astaxanthin improved hepatic steatosis and tended to ameliorate the progression of NASH in biopsy-proven human subjects. These results suggest that astaxanthin might be a novel and promising treatment for NASH. 続きを見る
82.

論文

論文
Mizukoshi, Eishiro ; Nakagawa, Hidetoshi ; Kitahara, Masaaki ; Yamashita, Tatsuya ; Arai, Kuniaki ; Sunagozaka, Hajime ; Iida, Noriho ; Fushimi, Kazumi ; Kaneko, Shuichi
出版情報: Cancer Letters.  369  pp.242-249,  2015-12-01.  Elsevier
URL: http://hdl.handle.net/2297/43914
概要: Multidrug resistance-associated protein 3 (MRP3) is a carrier-type transport protein belonging to the ABC transporters. In this study, we investigated the safety and immunogenicity of a MRP3-derived peptide (MRP3765) as a vaccine and characterized the MRP3-specific T cell responses induced. Twelve hepatocellular carcinoma (HCC) patients treated with hepatic arterial infusion chemotherapy (HAIC) were enrolled. The MRP3-derived peptide was emulsified in incomplete Freund's adjuvant and administered via subcutaneous immunization three times weekly. No serious adverse drug reactions to the peptide vaccine were observed, and the vaccination was well tolerated. The vaccination induced MRP3-specific immunity in 72.7% of the patients. In a phenotypic analysis, the largest post-vaccinated increase in MRP3-specific T cells was due to an increase in cells with the effector memory phenotype. Among the 12 patients, one patient showed a partial response, nine showed a stable disease, and two showed a progressive disease. The median overall survival time was 14.0 months. In conclusion, the safety, effects of immune boosting, and possible prolongation of overall survival by the MRP3-derived peptide demonstrate the potential of the peptide to provide clinical benefit in HCC patients. © 2015. 続きを見る
83.

論文

論文
Kuroda, Kaori ; Takeshita, Yumie ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Journal of Diabetes Investigation.  6  pp.739-740,  2015-11-01.  Wiley Open Access
URL: http://hdl.handle.net/2297/43940
84.

論文

論文
Toyama, Tadashi ; Furuichi, Kengo ; Shimizu, Miho ; Hara, Akinori ; Iwata, Yasunori ; Sakai, Norihiko ; Perkovic, Vlado ; Kobayashi, Makoto ; Mano, Toshiki ; Kaneko, Shuichi ; Wada, Takashi
出版情報: PLoS ONE.  10  pp.e0137449-,  2015-09-10.  Public Library of Science
URL: http://hdl.handle.net/2297/43896
概要: Background: Some observational studies have shown the relationships between hyperuricemia and chronic kidney disease (CKD); however, the threshold of serum uric acid (SUA) for deterioration of kidney function and the association between SUA and kidney injury by baseline kidney function remains unclear. This study aimed to clarify the relationships between SUA and reduced kidney function. Methods: We analyzed a historical cohort of male Japanese individuals who underwent medical checkup between 1998 and 2007. Participants with baseline data and who were followed up for at least one year were included and stratified according to baseline kidney function. Kidney function was classified as normal [estimated glomerular filtration rate (eGFR) ≥ 90 ml/min/1.73 m2] or mildly reduced (eGFR 60-89 ml/min/1.73 m2). The outcome measured was kidney impairment defined as a decrease in eGFR to < 60 ml/min/1.73 m2. Associations between SUA and risk for outcome and eGFR slopes were assessed. Results: A total of 41632 subjects with mean age 45.4 years were included. During a mean follow-up of four years, 3186 (7.6%) subjects developed kidney dysfunction. Subjects with SUA ≥ 6.0 mg/dL had a significantly increased risk for kidney impairment compared with subjects with SUA of 4-4.9 mg/dL. SUA threshold levels were different according to baseline kidney function; SUA ≤ 7.0 and ≤ 6.0 mg/dL for normal and mildly reduced kidney function, respectively. Approximately the same trends were observed for eGFR slopes. Conclusion: In the general population, hyperuricemia appears to be a risk factor for kidney impairment in males. For participants with mild kidney dysfunction, even a slight elevation of SUA can be a risk factor. Copyright: © 2015 Toyama et al.<br />This article has a supplementary figure. Please see the last page of the text. 続きを見る
85.

論文

論文
Terashima, Takeshi ; Yamashita, Tatsuya ; Takata, Noboru ; Nakagawa, Hidetoshi ; Toyama, Tadashi ; Arai, Kuniaki ; Kitamura, Kazuya ; Yamashita, Taro ; Sakai, Yoshio ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi
出版情報: Hepatology Research.  46  pp.650-656,  2016-06-01.  Blackwell Publishing Ltd.
URL: http://hdl.handle.net/2297/44240
概要: Aim: Although sorafenib is a standard drug for advanced hepatocellular carcinoma (HCC), little is known about a patient's clinical course after treatment. We investigated the effect of post-progression survival (PPS) and progression-free survival (PFS) on overall survival (OS) in patients whose advanced HCC was treated by sorafenib. Methods: We searched in the PubMed database for reports with survival data of patients with HCC treated with sorafenib monotherapy, and selected reports with 20 or more patients each that provided data for both OS and PFS or time to progression (TTP). Median PPS (mPPS) was defined as the period obtained by subtracting median PFS or TTP (mPFS/TTP) from median OS (mOS). We identified 56 reports with 5803 patients. We investigated the correlation of mOS and either mPPS or mPFS/TTP using weighted linear regression. Results: Median PPS correlated with mOS (r=0.834) very strongly, whereas mPFS/TTP did not correlate with mOS as highly as PPS did (r=0.546). When we stratified survival data by Child-Pugh classification, a significantly greater average percentage of mPPS to mOS was seen in Child-Pugh class A (54.4±17.6%) than in Child-Pugh class B (32.0±11.6%) (P=0.015). Conclusion: PPS highly correlated with OS, and its importance should be more emphasized for advanced HCC patients treated after sorafenib therapy, whereas we need to take more care in interpreting the results of PFS to evaluate treatment efficacy in clinical trials of advanced HCC. © 2015 The Japan Society of Hepatology.<br />Embargo Period 12 months 続きを見る
86.

論文

論文
Mizukoshi, Eishiro ; Kaneko, Shuichi
出版情報: Inflammation and Immunity in Cancer.  pp.123-132,  2015-01-01.  Springer Japan
URL: http://hdl.handle.net/2297/43915
概要: Hepatocellular carcinoma (HCC) is the sixth most common type of cancer globally. Although many different kinds of treatment are performed for HCC according to the practical guidelines, the prognosis of patients is not still satisfactory because the effects of treatments are limited for advanced tumors and the recurrence rate of HCC, even in early stages, is very high. Therefore, immunotherapy is highly anticipated as a new treatment method for HCC. For the development of a new HCC therapy, we attempted to establish immunotherapy using dendritic cells (DCs) and peptide vaccine. In several clinical trials that we performed, we confirmed that the immunotherapy was safe and well-tolerated by HCC patients. We observed that DC therapy prolonged the recurrence-free survival of patients compared with that of patients without DC infusion, as well as observing the radiological anti-tumor effect in HCC patients with peptide vaccine. In this chapter, we summarize the results of previous studies using DC and peptide vaccine, including our own data, and describe the prospects of immunotherapy for HCC. © 2015, Springer Japan. All rights reserved.<br />[Book Chapter] 続きを見る
87.

論文

論文
Isobe, Yuki ; Sakurai, Masaru ; Kita, Yuki ; Takeshita, Yumie ; Misu, Hirofumi ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Journal of Diabetes Investigation.  7  pp.352-358,  2016-05-01.  Wiley
URL: http://hdl.handle.net/2297/43921
概要: Aims/Introduction: To investigate the clinical and anthropometrical parameters that are associated with non-exercise activity thermogenesis that is composed of basal energy expenditure (BEE) and diet-induced thermogenesis (DIT) in patients with diabetes. Materials and Methods: Body composition was assessed using bioelectrical impedance, and BEE and DIT were measured using indirect calorimetry in 40 Japanese patients with diabetes. Results: BEE correlated positively with bodyweight, body mass index, fat mass, and fat-free mass, and correlated negatively with age in both men and women. In multivariate logistic regression analysis, BEE correlated positively with both fat mass and fat-free mass independently of sex and age. In addition, DIT correlated positively with bodyweight, body mass index, fat mass and fat-free mass, and correlated negatively with age in women, but not men. Fat-free mass contributed to DIT at least partly, and an aging-related decrease in DIT was observed. The best anthropometric parameter that reflected fat mass and fat-free mass was hip circumference (HC) and calf circumference (CC), respectively, in both men and women. Indeed, both HC (men β = 0.600, P < 0.001; women β = 0.752, P < 0.001) and CC (men β = 0.810, P = 0.012; women β = 0.821, P = 0.002) were correlated with BEE independently of age and sex. In addition, CC (β = 0.653, P = 0.009), but not HC was correlated with DIT significantly only in females, independently of age. Conclusions: HC reflects fat mass and was positively associated with BEE, but not with DIT. In contrast, CC reflects fat-free mass, and was positively associated with BEE in both men and women, and with DIT in women. © 2015 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd. 続きを見る
88.

論文

論文
Shimakami, Tetsuro ; Honda, Masao ; Shirasaki, Takayoshi ; Takabatake, Riuta ; Liu, Fanwei ; Murai, Kazuhisa ; Shiomoto, Takayuki ; Funaki, Masaya ; Yamane, Daisuke ; Murakami, Seishi ; Lemon, Stanley M. ; Kaneko, Shuichi
出版情報: Scientific Reports.  4  pp.4688-,  2014-04-15.  Nature Publishing Group
URL: http://hdl.handle.net/2297/45592
概要: Clinical studies suggest that the oral acyclic retinoid Peretinoin may reduce the recurrence of hepatocellular carcinoma (HCC) following surgical ablation of primary tumours. Since hepatitis C virus (HCV) infection is a major cause of HCC, we assessed whether Peretinoin and other retinoids have any effect on HCV infection. For this purpose, we measured the effects of several retinoids on the replication of genotype 1a, 1b, and 2a HCV in vitro. Peretinoin inhibited RNA replication for all genotypes and showed the strongest antiviral effect among the retinoids tested. Furthermore, it reduced infectious virus release by 80-90% without affecting virus assembly. These effects could be due to reduced signalling from lipid droplets, triglyceride abundance, and the expression of mature sterol regulatory element-binding protein 1c and fatty acid synthase. These negative effects of Peretinoin on HCV infection may be beneficial in addition to its potential for HCC chemoprevention in HCV-infected patients. 続きを見る
89.

論文

論文
Takazakura, Akiko ; Sakurai, Masaru ; Bando, Yukihiro ; Misu, Hirofumi ; Takeshita, Yumie ; Kita, Yuki ; Shimizu, Akiko ; Hayakawa, Tetsuo ; Kato, Ken-ichiro ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Journal of Diabetes Investigation.  6  pp.346-353,  2015-05-01.  Blackwell Publishing
URL: http://hdl.handle.net/2297/45713
概要: Introduction: Several studies have shown that statins suppress the progression of diabetic nephropathy. However, few reports have directly compared the renoprotective effects between potent and conventional statins. Materials and Methods: Patients with diabetic nephropathy, selected as those with a serum creatinine level of 0.9-1.5 mg/dL and simultaneously having either microalbuminuria or positive proteinuria, were randomly assigned to one of three groups: a conventional diet therapy group, a group given 10 mg of pravastatin and a group given 10 mg of atorvastatin. Renal function was evaluated before and after a 12-month period of therapy. Results: The atorvastatin group had a significant decrease in low-density lipoprotein cholesterol at 3 months and thereafter compared with the other groups. The urinary albumin-to-creatinine ratio significantly decreased in the atorvastatin group; the degree of this decrease was significantly greater than that in the diet therapy group. The kidney function estimated with cystatin C (CysC) and the estimated glomerular filtration rate calculated from CysC were significantly preserved in the atorvastatin group compared with the pravastatin group. In a multivariate regression analysis, the use of atorvastatin was the only explanatory variable for the changes in CysC; this was independent of changes in low-density lipoprotein cholesterol. Conclusions: Atorvastatin is more effective than pravastatin for the prevention of increase in CysC, and this renoprotective effect was considered to a result of the pleiotropic effect of atorvastatin independent of its lipid-lowering effect. This study was registered with UMIN (no. UMIN 000001774). © 2014 The Authors. 続きを見る
90.

論文

論文
Nagata, Naoto ; Xu, Liang ; Kohno, Susumu ; Ushida, Yusuke ; Aoki, Yudai ; Umeda, Ryohei ; Fuke, Nobuo ; Zhuge, Fen ; Ni, Yinhua ; Nagashimada, Mayumi ; Takahashi, Chiaki ; Suganuma, Hiroyuki ; Kaneko, Shuichi ; Ota, Tsuguhito
出版情報: Diabetes = Diabetes.  66  pp.1222-1236,  2017-05-01.  American Diabetes Association = American Diabetes Association
URL: http://hdl.handle.net/2297/47169
概要: Low-grade sustained inflammation links obesity to insulin resistance and nonalcoholic fatty liver disease (NAFLD). However, therapeutic approaches to improve systemic energy balance and chronic inflammation in obesity are limited. Pharmacological activation of nuclear factor (erythroid-derived 2)–like 2 (Nrf2) alleviates obesity and insulin resistance in mice; however, Nrf2 inducers are not clinically available owing to safety concerns. Thus, we examined whether dietary glucoraphanin, a stable precursor of the Nrf2 inducer sulforaphane, ameliorates systemic energy balance, chronic inflammation, insulin resistance, and NAFLD in high-fat diet (HFD)–fed mice. Glucoraphanin supplementation attenuated weight gain, decreased hepatic steatosis, and improved glucose tolerance and insulin sensitivity in HFD-fed wild-type mice but not in HFD-fed Nrf2 knockout mice. Compared with vehicle-treated controls, glucoraphanin-treated HFD-fed mice had lower plasma lipopolysaccharide levels and decreased relative abundance of the gram-negative bacteria family Desulfovibrionaceae in their gut microbiomes. In HFD-fed mice, glucoraphanin increased energy expenditure and the protein expression of uncoupling protein 1 (Ucp1) in inguinal and epididymal adipose depots. Additionally, in this group, glucoraphanin attenuated hepatic lipogenic gene expression, lipid peroxidation, classically activated M1-like macrophage accumulation, and inflammatory signaling pathways. By promoting fat browning, limiting metabolic endotoxemia-related chronic inflammation, and modulating redox stress, glucoraphanin may mitigate obesity, insulin resistance, and NAFLD. 続きを見る
91.

論文

論文
Takashima, Shin-ichiro ; Usui, Soichiro ; Kurokawa, Keisuke ; Kitano, Teppei ; Kato, Takeshi ; Murai, Hisayoshi ; Furusho, Hiroshi ; Oda, Hiroyuki ; Maruyama, Michiro ; Nagata, Yoshiki ; Usuda, Kazuo ; Kubota, Koji ; Takeshita, Yumie ; Sakai, Yoshio ; Honda, Masao ; Kaneko, Shuichi ; Takamura, Masayuki
出版情報: Open Heart.  3  pp.e000400-,  2016-06-01.  BMJ Publishing Group
URL: http://hdl.handle.net/2297/45929
概要: Objective: Comprehensive profiling of gene expression in peripheral blood leucocytes (PBLs) in patients with acute coronary syndrome (ACS) as a prognosticator is needed. We explored the specific profile of gene expression in PBLs in ACS for long-term risk stratification. Methods: 30 patients with ACS who underwent primary percutaneous coronary intervention (PCI) and 15 age-matched adults who participated in medical check-ups were enrolled from three centres. Peripheral blood samples were collected to extract RNA for microarray analyses. Results: During the 5-year follow-up, 36% of this cohort developed the expected non-fatal coronary events (NFEs) of target lesion revascularisation (TLR) and PCI for a de novo lesion. Class comparison analysis (p<0.005) demonstrated that 83 genes among 7785 prefiltered genes (41 upregulated vs 42 downregulated genes) were extracted to classify the patients according to the occurrence of NFE. Pathway analysis based on gene ontology revealed that the NFEs were associated with altered gene expression regarding the T-cell receptor signalling pathway in ACS. Univariate t test showed that the expression level of death-associated protein kinase1 (DAPK1), known to regulate inflammation, was the most significantly negatively regulated gene in the event group (0.61-fold, p<0.0005). Kaplan-Meier curve analysis and multivariate analysis adjusted for baseline characteristics or clinical biomarkers demonstrated that lower DAPK1 expression in PBL emerged as an independent risk factor for the NFEs (HR: 8.73; CI 1.05 to 72.8, p=0.045). Conclusions: Altered gene expression in T-cell receptor signalling in PBL in ACS could be a prognosticator for secondary coronary events. © Published by the BMJ Publishing Group Limited. 続きを見る
92.

論文

論文
Okada, Hikari ; Honda, Masao ; Campbell, Jean S. ; Takegoshi, Kai ; Sakai, Yoshio ; Yamashita, Taro ; Shirasaki, Takayoshi ; Takabatake, Riuta ; Nakamura, Mikiko ; Tanaka, Takuji ; Kaneko, Shuichi
出版情報: Cancer Science.  106  pp.1143-1152,  2015-09-01.  Japanese Cancer Association / Blackwell Publishing Ltd
URL: http://hdl.handle.net/2297/45964
概要: 医薬保健研究域保健学系<br />Differentially regulated microRNA (miRNA) are associated with hepatic fibrosis; however, their po tential usefulness for blocking hepatic fibrosis has not been exploited fully. We examined the expression of miRNA in the liver of a transgenic mouse model in which platelet-derived growth factor C (PDGF-C) is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis and steatosis and the eventual development of hepatocellular carcinoma (HCC). Robust induction of miR-214 correlated with fibrogenesis in the liver of Pdgf-c Tg mice, atherogenic high-fat diet-induced NASH mice, and patients with chronic hepatitis B or C. Pdgf-c Tg mice were injected with locked nucleic acid (LNA)-antimiR-214 via the tail vein using Invivofectamine 2.0 and the degree of hepatic fibrosis and tumor incidence were evaluated. Pdgf-c Tg mice treated with LNA-antimiR-214 showed a marked reduction in fibrosis and tumor incidence compared with saline or LNA-miR-control-injected control mice. In vitro, LNA-antimiR-214 significantly ameliorated TGF-β1-induced pro-fibrotic gene expression in Lx-2 cells. MiR-214 targets a negative regulator of EGFR signaling, Mig-6. Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF-mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) in Huh-7 cells. Conversely, LNA-antimiR-214 repressed the expression of these genes. In conclusion, miR-214 appears to participate in the development of hepatic fibrosis by modulating the EGFR and TGF-β signaling pathways. LNA-antimiR-214 is a potential therapy for the prevention of hepatic fibrosis. MiR-214 appears to participate in the development of hepatic fibrosis by modulating EGFR and TGF-β signaling pathways. LNA-anti-miR-214 may be a potentially therapy in the prevention of hepatic fibrosis. © 2015 Japanese Cancer Association. 続きを見る
93.

論文

論文
Hayashi, Tomoyuki ; Miura, Miyabi ; Takatori, Hajime ; Kitamura, Kazuya ; Yamashita, Tatsuya ; Kaneko, Shuichi
出版情報: VideoGIE.  1  pp.55-56,  2016-11-01.  American Society for Gastrointestinal Endoscopy / Elsevier
URL: http://hdl.handle.net/2297/47925
94.

論文

論文
Yamashita, Taro ; Honda, Masao ; Kaneko, Shuichi
出版情報: Journal of Gastroenterology and Hepatology.  26  pp.960-964,  2011-06-01.  Blackwell Publishing Asia Pty
URL: http://hdl.handle.net/2297/28344
概要: 金沢大学医薬保健研究域医学系<br />Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) and chron ic liver disease worldwide. Recent developments and advances in HCV replication systems in vitro and in vivo, transgenic animal models, and gene expression profiling approaches have provided novel insights into the mechanisms of HCV replication. They have also helped elucidate host cellular responses, including activated/inactivated signaling pathways, and the relationship between innate immune responses by HCV infection and host genetic traits. However, the mechanisms of hepatocyte malignant transformation induced by HCV infection are still largely unclear, most likely due to the heterogeneity of molecular paths leading to HCC development in each individual. In this review, we summarize recent advances in knowledge about the mechanisms of hepatocarcinogenesis induced by HCV infection. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd. 続きを見る
95.

論文

論文
Takata, Yoshiko ; Nakamoto, Yasunari ; Nakada, Akiko ; Terashima, Takeshi ; Arihara, Fumitaka ; Kitahara, Masaaki ; Kakinoki, Kaheita ; Arai, Kuniaki ; Yamashita, Taro ; Sakai, Yoshio ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Kaneko, Shuichi
出版情報: Cancer Letters.  307  pp.165-173,  2011-08-28.  Elsevier
URL: http://hdl.handle.net/2297/28165
概要: 金沢大学医薬保健研究域医学系<br />The purpose of this study was to assess the properties of CD4+CD25high/low/negative T cell sub sets and analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25high T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25high Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer. © 2011. 続きを見る
96.

論文

論文
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,  2011-10-01.  Wiley-Blackwell
URL: http://hdl.handle.net/2297/28230
概要: 金沢大学医薬保健研究域医学系<br />The identification of genes involved in tumor growth is crucial for the development of inventi ve 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. © 2010 UICC. 続きを見る
97.

論文

論文
Misu, Hirofumi ; Takamura, Toshinari ; Takayama, Hiroaki ; Hayashi, Hiroto ; Matsuzawa-Nagata, Naoto ; Kurita, Seiichiro ; Ishikura, Kazuhide ; Ando, Hitoshi ; Takeshita, Yumie ; Ota, Tsuguhito ; Sakurai, Masaru ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Yamashita, Taro ; Honda, Masao ; Miyamoto, Kenichi ; Kubota, Tetsuya ; Kubota, Naoto ; Kadowaki, Takashi ; Kim, Han-Jong ; Lee, In-kyu ; Minokoshi, Yasuhiko ; Saito, Yoshiro ; Takahashi, Kazuhiko ; Yamada, Yoshihiro ; Takakura, Nobuyuki ; Kaneko, Shuichi
出版情報: Cell Metabolism.  12  pp.483-495,  2010-11-03.  Elsevier
URL: http://hdl.handle.net/2297/25782
概要: 金沢大学医薬保健研究域医学系<br />The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of periphe ral tissues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes. © 2010 Elsevier Inc. 続きを見る
98.

論文

論文
Nakamura, Seiji ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Takayama, Hiroaki ; Misu, Hirofumi ; Noda, Hiroyo ; Nabemoto, Satoko ; Kurita, Seiichiro ; Ota, Tsuguhito ; Ando, Hitoshi ; Miyamoto, Kenichi ; Kaneko, Shuichi
出版情報: The Journal of biological chemistry.  284  pp.14809-14818,  2009-05-29.  American Society for Biochemistry and Molecular Biology
URL: http://hdl.handle.net/2297/18986
概要: Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cause fatty liver disease and hepatic insulin resistance. However, because animal models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH2-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. 続きを見る
99.

論文

論文
Saito, Shigeru ; Honda, Masao ; Kaneko, Shuichi ; Horimoto, Katsuhisa
出版情報: Proceedings of the IEEE Conference on Decision and Control.  pp.5624-5630,  2009-01-01.  IEEE = Institute of Electrical and Electronics Engineers
URL: http://hdl.handle.net/2297/24279
概要: One of the most characteristic features of biological molecular networks is that the network structure itself changes, depending on the cellular environment. Indeed, activated molecules show a variety of responses to distinctive cell conditions, and subsequently the network structures of active molecules also change. Here we present an approach to trace the network structure changes by using the graphical chain model developed from the gene expression data. The previous procedure for applying the graphical chain model to the expression profiles of a limited number of genes has been improved to analyze the entire set of genes. Furthermore, the chain model has been rearranged according to the association strength, and was scrutinized to identify the candidates of essential gene-gene relationships for the network changes, by using the path consistency algorithm. The improved procedure was applied to the expression profiles of 8,427 genes, which were measured in two distinctive stages of liver cancer progression. As a result, the chain model of the 18 gene cluster relationships with strong associations was inferred, in which the coordination of clusters was described in the cell stage progression, and the gene-gene relationships between known cancer-related genes causing the progression were further refined. Thus, the present procedure is a useful method to model the network structure changes in the cell stage progression, and to clarify the gene candidates for the progression. ©2009 IEEE. 続きを見る
100.

論文

論文
Kurita, Seiichiro ; Ando, Hitoshi ; Kaneko, Shuichi ; Takamura, Toshinari
出版情報: Internal medicine (Tokyo, Japan).  47  pp.1065-1066,  2008-01-01.  日本内科学会
URL: http://hdl.handle.net/2297/11571
概要: 金沢大学医薬保健研究域医学系