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2019 Fiscal Year Annual Research Report

熱応答性経路活性化による糖尿病及び合併症改善効果の解明と臨床応用への基盤構築

Research Project

Project/Area Number 17H04201
Research InstitutionKumamoto University

Principal Investigator

荒木 栄一  熊本大学, 大学院生命科学研究部(医), 教授 (10253733)

Co-Investigator(Kenkyū-buntansha) 近藤 龍也  熊本大学, 病院, 講師 (70398204)
Project Period (FY) 2017-04-01 – 2020-03-31
Keywords糖尿病 / 細胞内ストレス / 熱ストレス応答経路 / 慢性炎症
Outline of Annual Research Achievements

(1)膵β細胞特異的HSP72過剰発現糖尿病マウス:HSP72のインスリン分泌能やβ細胞の再生能等に関する解析を目的とする。体重、空腹時血糖値、インスリン値、糖負荷試験におけるインスリン分泌反応、膵島における組織学的検討(インスリン・グルカゴン・PDX-1・MafA・Ngn3発現など)を実施しデータ解析中である。今後はSTZ投与による膵島障害モデルにおいて膵β細胞のストレス抵抗性や再生能を検討する。(2)肝臓・筋肉・脂肪特異的HSP72過剰発現糖尿病マウス:肝臓、筋肉、脂肪細胞におけるHSP72のインスリン作用に関する解析を目的とする。肝臓と脂肪特異的HSP72過剰発現糖尿病マウスの作成に時間を要したが、同ラインは完成し現在高脂肪食負荷継続中である。体重、空腹時血糖値、インスリン値、糖負荷試験、インスリン負荷試験 、解剖時に下大静脈よりインスリンを静注し、各組織を摘出後インスリンシグナル伝達経路を解析予定。さらに諸臓器における酸化ストレスマーカーや小胞体ストレスマーカーなどを検討する。(3)血管内皮特異的/マクロファージ特異的HSP72過剰発現糖尿病マウス:Tgコンストラクト作成中である。(4)全身HSP72ノックアウトマウスと上記Tgの交配マウスの解析。耐糖能異常を呈する全身HSP72ノックアウトマウスに上記Tgを交配し、耐糖能改善程度や臓器特異的表現型・機能を評価することでHSP72の臓器毎における機能を検討する。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

  • Research Products

    (50 results)

All 2020 2019 Other

All Journal Article (18 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 18 results,  Open Access: 18 results) Presentation (26 results) (of which Int'l Joint Research: 10 results,  Invited: 5 results) Book (5 results) Remarks (1 results)

  • [Journal Article] Pharmacokinetics and pharmacodynamics of dapagliflozin in combination with insulin in Japanese patients with type 1 diabetes2020

    • Author(s)
      Watada Hirotaka、Shiramoto Masanari、Ueda Shinya、Tang Weifeng、Asano Michiko、Thor?n Fredrik、Kim Hyosung、Yajima Toshitaka、Boulton David W.、Araki Eiichi
    • Journal Title

      Diabetes, Obesity and Metabolism

      Volume: 21 Pages: 876~882

    • DOI

      10.1111/dom.13593

    • Peer Reviewed / Open Access
  • [Journal Article] Clinical Features of Patients with Acute Aortic Dissection After an Earthquake ~Experience from The Kumamoto Earthquake 2016~2020

    • Author(s)
      Komorita Takashi、Fujisue Koichiro、Sueta Daisuke、Sakamoto Kenji、Yamamoto Eiichiro、Hashimoto Yoichiro、Sakamoto Tomohiro、Tsunoda Ryusuke、Uesugi Hideyuki、Suzuki Ryusuke、Naito Hisaki、Hanzawa Kazuhiko、Araki Eiichi、Nakayama Hideki、Kasaoka Shunji、Hokimoto Seiji、Fukui Toshihiro、Tsujita Kenichi
    • Journal Title

      American Journal of Hypertension

      Volume: 33 (3) Pages: 261-268

    • DOI

      10.1093/ajh/hpz183

    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of inflammation-mediated DPP-4 expression by linagliptin increases M2 macrophages in atherosclerotic lesions2020

    • Author(s)
      Nishida Shuhei、Matsumura Takeshi、Senokuchi Takafumi、Murakami-Nishida Saiko、Ishii Norio、Morita Yutaro、Yagi Yoshitaka、Motoshima Hiroyuki、Kondo Tatsuya、Araki Eiichi
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 524 Pages: 8~15

    • DOI

      10.1016/j.bbrc.2020.01.027

    • Peer Reviewed / Open Access
  • [Journal Article] Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in Dyslipidemic Patients with Renal Impairment2019

    • Author(s)
      Yokote Koutaro、Yamashita Shizuya、Arai Hidenori、Araki Eiichi、Suganami Hideki、Ishibashi Shun
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Pages: 706~706

    • DOI

      10.3390/ijms20030706

    • Peer Reviewed / Open Access
  • [Journal Article] Hyperemesis gravidarum followed by refeeding syndrome causes electrolyte abnormalities induced rhabdomyolysis and diabetes insipidus2019

    • Author(s)
      Kondo Tatsuya、Nakamura Miwa、Kawashima Junji、Matsumura Takeshi、Ohba Takashi、Yamaguchi Munekage、Katabuchi Hidetaka、Araki Eiichi
    • Journal Title

      Endocrine Journal

      Volume: 66 Pages: 253~258

    • DOI

      10.1507/endocrj.EJ18-0496

    • Peer Reviewed / Open Access
  • [Journal Article] Impact of hepatic HSP72 on insulin signaling2019

    • Author(s)
      Kitano Sayaka、Kondo Tatsuya、Matsuyama Rina、Ono Kaoru、Goto Rieko、Takaki Yuki、Hanatani Satoko、Sakaguchi Masaji、Igata Motoyuki、Kawashima Junji、Motoshima Hiroyuki、Matsumura Takeshi、Kai Hirofumi、Araki Eiichi
    • Journal Title

      American Journal of Physiology-Endocrinology and Metabolism

      Volume: 316 Pages: E305~E318

    • DOI

      10.1152/ajpendo.00215.2018

    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52‐week data from the PROVIDE study2019

    • Author(s)
      Araki Eiichi、Yamashita Shizuya、Arai Hidenori、Yokote Koutaro、Satoh Jo、Inoguchi Toyoshi、Nakamura Jiro、Maegawa Hiroshi、Yoshioka Narihito、Tanizawa Yukio、Watada Hirotaka、Suganami Hideki、Ishibashi Shun
    • Journal Title

      Diabetes, Obesity and Metabolism

      Volume: 21 Pages: 1737~1744

    • DOI

      10.1111/dom.13686

    • Peer Reviewed / Open Access
  • [Journal Article] Mineralocorticoid Receptor May Regulate Glucose Homeostasis through the Induction of Interleukin-6 and Glucagon-Like peptide-1 in Pancreatic Islets2019

    • Author(s)
      Goto Rieko、Kondo Tatsuya、Ono Kaoru、Kitano Sayaka、Miyakawa Nobukazu、Watanabe Takuro、Sakaguchi Masaji、Sato Miki、Igata Motoyuki、Kawashima Junji、Motoshima Hiroyuki、Matsumura Takeshi、Shimoda Seiya、Araki Eiichi
    • Journal Title

      Journal of Clinical Medicine

      Volume: 8 Pages: 674~674

    • DOI

      10.3390/jcm8050674

    • Peer Reviewed / Open Access
  • [Journal Article] Pioglitazone suppresses macrophage proliferation in apolipoprotein-E deficient mice by activating PPARγ2019

    • Author(s)
      Murakami-Nishida Saiko、Matsumura Takeshi、Senokuchi Takafumi、Ishii Norio、Kinoshita Hiroyuki、Yamada Sarie、Morita Yutaro、Nishida Shuhei、Motoshima Hiroyuki、Kondo Tatsuya、Komohara Yoshihiro、Araki Eiichi
    • Journal Title

      Atherosclerosis

      Volume: 286 Pages: 30~39

    • DOI

      10.1016/j.atherosclerosis.2019.04.229

    • Peer Reviewed / Open Access
  • [Journal Article] Comparison of the efficacy and safety of once-daily insulin degludec/insulin aspart (IDegAsp) and long-acting second-generation basal insulin (insulin degludec and insulin glargine 300 units/mL) in insulin-na?ve Japanese adults with type 2 diabetes: a pilot, randomized, controlled study2019

    • Author(s)
      Shimoda Seiya、Sakamoto Wakana、Hokamura Ayaka、Matsuo Yasuto、Sekigami Taiji、Ichimori Shinji、Iwashita Shinsuke、Ishii Norio、Otsu Kae、Yoshimura Ryohei、Nishiyama Toshihiko、Sakaguchi Masaji、Nishida Kenro、Araki Eiichi
    • Journal Title

      Endocrine Journal

      Volume: 66 Pages: 745~752

    • DOI

      10.1507/endocrj.EJ19-0179

    • Peer Reviewed / Open Access
  • [Journal Article] Short-Term Cost-Effectiveness of Switching to Insulin Degludec in Japanese Patients with Type 2 Diabetes Receiving Basal-Bolus Therapy.2019

    • Author(s)
      Jakob Langer, Michael L Wolden, Seiya Shimoda, Miki Sato, Eiichi Araki.
    • Journal Title

      Diabetes Therapy

      Volume: 10 (4) Pages: 1347-1356

    • DOI

      10.1007/s13300-019-0635-1

    • Peer Reviewed / Open Access
  • [Journal Article] Superior efficacy with a fixed‐ratio combination of insulin degludec and liraglutide (IDegLira) compared with insulin degludec and liraglutide in insulin‐na?ve Japanese patients with type 2 diabetes in a phase 3, open‐label, randomized trial2019

    • Author(s)
      Kaku Kohei、Araki Eiichi、Tanizawa Yukio、Ross Agner Bue、Nishida Tomoyuki、Ranthe Mattis、Inagaki Nobuya
    • Journal Title

      Diabetes, Obesity and Metabolism

      Volume: 21 Pages: 2674~2683

    • DOI

      10.1111/dom.13856

    • Peer Reviewed / Open Access
  • [Journal Article] Impacts of the 2016 Kumamoto Earthquake on glycemic control in patients with diabetes2019

    • Author(s)
      Kondo Tatsuya、Miyakawa Nobukazu、Motoshima Hiroyuki、Hanatani Satoko、Ishii Norio、Igata Motoyuki、Yoshinaga Kayo、Kukidome Daisuke、Senokuchi Takafumi、Kawashima Junji、Furukawa Noboru、Matsumura Takeshi、Araki Eiichi
    • Journal Title

      Journal of Diabetes Investigation

      Volume: 10 Pages: 521~530

    • DOI

      10.1111/jdi.12891

    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy, Safety, and Tolerability of Oral Semaglutide Versus Placebo Added to Insulin With or Without Metformin in Patients With Type 2 Diabetes: The PIONEER 8 Trial2019

    • Author(s)
      Zinman Bernard、Aroda Vanita R.、Buse John B.、Cariou Bertrand、Harris Stewart B.、Hoff S?ren Tetens、Pedersen Karen Boje、Tarp-Johansen Mads Jeppe、Araki Eiichi
    • Journal Title

      Diabetes Care

      Volume: 42 Pages: 2262~2271

    • DOI

      10.2337/dc19-0898

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Differential predictive factors for cardiovascular events in patients with or without cancer history2019

    • Author(s)
      Sueta Daisuke、Tabata Noriaki、Ikeda Satoshi、Yoshida Naoya、Kamba Tomomi、Araki Eiichi、Iwase Hirotaka、Fujii Kazuhiko、Ihn Hironobu、Kobayashi Yoshio、Minamino Tohru、Yamagishi Masakazu、Maemura Koji、Baba Hideo、Matsui Kunihiko、Tsujita Kenichi
    • Journal Title

      Medicine

      Volume: 98 Pages: e17602~e17602

    • DOI

      10.1097/MD.0000000000017602

    • Peer Reviewed / Open Access
  • [Journal Article] Long-Term Efficacy and Safety of Linagliptin in a Japanese Population With Type 2 Diabetes Aged over 60 Years Treated With Basal Insulin: A Randomised Trial2019

    • Author(s)
      Eiichi Araki, Yuriko Unno, Yuko Tanaka, Wataru Sakamot, Yuki Miyamoto.
    • Journal Title

      Advances in Therapy

      Volume: 36 (10) Pages: 2697-2711

    • DOI

      10.1007/s12325-019-01065-7

    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα): Pooled Analysis of Phase 2 and 3 Studies in Dyslipidemic Patients with or without Statin Combination2019

    • Author(s)
      Yamashita、Arai、Yokote、Araki、Matsushita、Nojima、Suganami、Ishibashi
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Pages: 5537~5537

    • DOI

      10.3390/ijms20225537

    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and safety of dapagliflozin in Japanese patients with inadequately controlled type 1 diabetes (DEPICT‐5): 52‐week results from a randomized, open‐label, phase III clinical trial2019

    • Author(s)
      Araki Eiichi、Watada Hirotaka、Uchigata Yasuko、Tomonaga Osamu、Fujii Hitomi、Ohashi Hiroshi、Okabe Tadashi、Asano Michiko、Thoren Fredrik、Kim Hyosung、Yajima Toshitaka、Langkilde Anna Maria
    • Journal Title

      Diabetes, Obesity and Metabolism

      Volume: 22 Pages: 540~548

    • DOI

      10.1111/dom.13922

    • Peer Reviewed / Open Access
  • [Presentation] Effects of linagliptin on macrophages and on progression of atherosclerosis in high fat-fed apoE-deficient mice2019

    • Author(s)
      Nishida S, Matsumura T, Senokuchi T, Ishii N, Murakami-Nishida S, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E.
    • Organizer
      The 11th Scientific Meeting of the Asian Association for the Study of Diabetes.
    • Int'l Joint Research
  • [Presentation] Unique role of the α4 component for S6-kinase activity in Metabolic Regulation and anti- Apoptotic effect in Brown Adipose Tissue2019

    • Author(s)
      Sakaguchi M, Okagawa S, Kitano S, Kondo T, Araki E
    • Organizer
      The 79th ADA scientific meeting
    • Int'l Joint Research
  • [Presentation] Oral semaglutide as add-on to insulin in T2D: PIONEER 8.2019

    • Author(s)
      Zinman B, Aroda VR, Buse JB, Cariou B, Harris SB, Hoff ST, Pedersen KB, Tarp-Johansen MJ, Araki E
    • Organizer
      The 79th ADA scientific meeting
    • Int'l Joint Research
  • [Presentation] The Hepatic Role of Heat Shock Protein 72 in the Pathogenesis of Type 2 Diabetes2019

    • Author(s)
      Kondo T, Kitano S, Miyakawa N, Watanabe T, Goto R, Ono K, Igata M, Kawashima J, Motoshima H, Matsumura T, Araki E
    • Organizer
      The 79th ADA scientific meeting
    • Int'l Joint Research
  • [Presentation] Pioglitazone Suppresses Macrophage Proliferation in Apolipoprotein-e Deficient Mice by Activating PPARγ2019

    • Author(s)
      Murakami-Nishida S, Matsumura T, Nishida S, Senokuchi T, Ishi N, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
    • Organizer
      The 79th ADA scientific meeting
    • Int'l Joint Research
  • [Presentation] Linagliptin induces M2 macrophage polarization and suppresses progression of atherosclerosis in high fat-fed apoE-deficient mice2019

    • Author(s)
      Nishida S, Matsumura T, Senokuchi T, Ishii N, Murakami-Nishida S, Yamada S, Morita Y, Wada T, Motoshima H, Kondo T, Araki E
    • Organizer
      The 79th ADA scientific meeting
    • Int'l Joint Research
  • [Presentation] FoxK1 and FoxK2 are positive regulators for IR and IGF1R signalling in cell proliferation and metabolism.2019

    • Author(s)
      Sakaguchi M, Araki E, Mann M, Enerbra S, Kahn CR
    • Organizer
      55th Annual Meetng of the European Association of the Study of Diabetes.
    • Int'l Joint Research
  • [Presentation] The organ cross talk in the regulation of glucose homeostasis through heat shock protein 72 expression.2019

    • Author(s)
      Kondo T, Kitano S, Miyakawa N, Watanabe T, Goto R, Igata M, Kawashima J, Motoshima H, Matsumura T, Araki E
    • Organizer
      55th Annual Meetng of the European Association of the Study of Diabetes.
    • Int'l Joint Research
  • [Presentation] Pioglitazone suppresses macrophage proliferation in apolipoprotein-E deficient mice by activating PPARγ.2019

    • Author(s)
      Matsumura T, Nishida S.M, Nishida S, Senokuchi T, Ishii N, Morita Y, Wada T, Motoshima H, Kondo T, Arak E
    • Organizer
      55th Annual Meetng of the European Association of the Study of Diabetes.
    • Int'l Joint Research
  • [Presentation] Role of Tissue Macrophages Proliferation in Insulin Resistance in the Liver and Adipose tissue.2019

    • Author(s)
      Wada T, Senokuchi T, Yamada S, Morita Y, Furusho T, Motoshima H, Ishi N, Matsumura T, Araki E
    • Organizer
      International Diabetes Federation Congress 2019
    • Int'l Joint Research
  • [Presentation] 糖尿病患者における肝細胞癌発生の実態調査.2019

    • Author(s)
      松村剛,瀬ノ口隆文,建石良介,窪田直人,小池和彦,荒木栄一
    • Organizer
      第62回日本糖尿病学会年次学術集会
  • [Presentation] 熊本発ブルーサークルメニューの開発とその効用.2019

    • Author(s)
      近藤龍也
    • Organizer
      第7回アフリカ開発会議 ポストフォーラム in 熊本.
    • Invited
  • [Presentation] 災害時の糖尿病患者支援~学会・協会の取り組みより2019

    • Author(s)
      瀬ノ口隆文,本島 寛之,近藤龍也,荒木 栄一
    • Organizer
      第57回日本糖尿病学会 九州地方会
    • Invited
  • [Presentation] 糖尿病治療薬の心/腎保護効果.2019

    • Author(s)
      荒木栄一
    • Organizer
      日本内科学会学術集会第47回内科学の展望
    • Invited
  • [Presentation] physical medicineによる2型糖尿病新規治療法の開発.2019

    • Author(s)
      近藤龍也
    • Organizer
      第38回日本認知症学会学術集会.
    • Invited
  • [Presentation] 糖尿病診療の Update;合併症の発症・進展阻止のために2019

    • Author(s)
      荒木栄一
    • Organizer
      第66回九州支部生涯教育講演会
    • Invited
  • [Presentation] ピオグリタゾンによるマクロファージ増殖抑制効果を介した糖尿病大血管合併症進展抑制効果.2019

    • Author(s)
      松村剛,西田彩子,瀬ノ口隆文,石井規夫,山田沙梨恵,守田雄太郎,西田周平,和田敏明, 佐藤美希,本島寛之,近藤龍也,荒木栄一
    • Organizer
      第62回日本糖尿病学会年次学術集会
  • [Presentation] 褐色脂肪組織におけるインスリンシグナル新規標的分子FoxK1/2の研究2019

    • Author(s)
      阪口雅司, C Ronald Kahn, 荒木栄一
    • Organizer
      第62回日本糖尿病学会年次学術集会
  • [Presentation] SGLT2阻害薬によるマクロファージ活性制御の機序解明.2019

    • Author(s)
      西田彩子,松村 剛,瀬ノ口隆文,石井規夫,山田沙梨恵,守田雄太郎,西田周平,和田敏明,佐藤美希,本島寛之,近藤龍也,荒木栄一
    • Organizer
      第62回日本糖尿病学会年次学術集会
  • [Presentation] Heat Shock Protein 72 ノックアウトマウスにおける糖代謝異常発生機序の解明.2019

    • Author(s)
      北野さやか,近藤龍也,渡邊拓郎,宮川展和,小野薫,花谷聡子,阪口雅司,後藤理英子,井形元維,河島淳司,本島寛之,荒木栄一
    • Organizer
      第62回日本糖尿病学会年次学術集会
  • [Presentation] 膵α細胞の鉱質コルチコイドレセプタ―は膵島におけるIL-6とGLP-1分泌を制御する2019

    • Author(s)
      後藤理英子, 近藤龍也, 荒木栄一
    • Organizer
      第62回日本糖尿病学会年次学術集会
  • [Presentation] ピオグリタゾンの抗動脈硬化作用としてのマクロファージ増殖抑制効果の解析.2019

    • Author(s)
      西田彩子,松村剛,西田周平,瀬ノ口隆文,石井規夫,山田沙梨恵,守田雄太郎,和田敏明,荒木栄一
    • Organizer
      第51回日本動脈硬化学会総会・学術集会
  • [Presentation] DPP-4阻害薬リナグリプチンによるM2マクロファージ誘導効果の解析,2019

    • Author(s)
      西田周平,松村剛,西田彩子,瀬ノ口隆文,石井規夫,山田沙梨恵,守田雄太郎,和田敏明,荒木栄一
    • Organizer
      第51回日本動脈硬化学会総会・学術集会
  • [Presentation] DPP-4阻害薬によるマクロファージの極性変化を介した抗動脈硬化作用機序の解明2019

    • Author(s)
      西田周平,松村 剛,西田彩子,瀬ノ口隆文,荒木栄一
    • Organizer
      第69回日本体質医学会総会
  • [Presentation] 全大腸切除後の高血糖にGLP-1製剤が有効であった症例の病態解明.2019

    • Author(s)
      近藤龍也、井形元維, 河島淳司、瀬ノ口隆文、松村剛、本島寛之、荒木栄一
    • Organizer
      第57回日本糖尿病学会九州地方会
  • [Presentation] Linagliptinによる糖尿病大血管症進展抑制効果とマクロファージへの影響.2019

    • Author(s)
      西田周平,松村 剛,西田彩子,瀬ノ口隆文,石井規夫,山田沙梨恵,守田雄太郎,和田敏明,荒木栄一
    • Organizer
      第57回日本糖尿病学会九州地方会
  • [Book] 阪口雅司, 荒木栄一2019

    • Author(s)
      日本臨牀 別冊「内分泌症候群(第3版)Ⅳ-その他の内分泌疾患を含めて-」Ⅷ.糖代謝9.インスリン受容体異常症(A型,B型)日本臨床 2019.
    • Total Pages
      376
    • Publisher
      日本臨床社
  • [Book] 糖尿病最新の治療2019-20212019

    • Author(s)
      門脇 孝、荒木 栄一、綿田 裕孝
    • Total Pages
      348
    • Publisher
      南江堂
    • ISBN
      978-4-524-24556-7
  • [Book] 万病のもと!糖尿病徹底対策 これが原因!NHKテキストきょうの健康(3)90-97, 2019.2019

    • Author(s)
      荒木栄一
    • Total Pages
      126
    • Publisher
      NHK出版
  • [Book] 臨床研究から日常診療応用の実際と限界. 糖尿病UP DATE賢島セミナー2018 35 臨床研究から日常診療へのシームレスな活用2019

    • Author(s)
      荒木栄一
    • Total Pages
      101
    • Publisher
      メディカルジャーナル社
    • ISBN
      4908437203
  • [Book] インスリン受容体と共に核内に移行する新規標的経路2019

    • Author(s)
      阪口 雅司、大久保 侑馬、岡川 章太、荒木 栄一
    • Total Pages
      68
    • Publisher
      ニュー・サイエンス社
    • ISBN
      08651-01
  • [Remarks] 熊本大学大学院生命科学研究部 代謝内科学分野

    • URL

      http://www2.kuh.kumamoto-u.ac.jp/met/

URL: 

Published: 2021-01-27  

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