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細胞傷害性リンパ球を応用した炎症性腸疾患新規治療法の開発

Research Project

Project/Area Number 22K07978
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

長堀 正和  東京医科歯科大学, 東京医科歯科大学病院, 准教授 (60420254)

Co-Investigator(Kenkyū-buntansha) 永石 宇司  東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (60447464)
Project Period (FY) 2022-04-01 – 2025-03-31
Project Status Granted (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2024: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2023: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords免疫 / 細胞傷害性リンパ球 / 消化器病学 / 炎症性腸疾患 / 免疫学 / 細胞傷害性 / 腸管免疫
Outline of Research at the Start

我々はこれまでの一貫して腸管粘膜における免疫寛容の誘導機構に注目してきた研究結果から、本研究計画では細胞傷害活性を有するサブセットを応用した炎症性腸疾患(IBD)に対する新規治療法開発を遂行する。本研究は細胞傷害性リンパ球による病原性エフェクターT細胞の制御機構という独自の概念に着目しつつ、細胞傷害性リンパ球サブセットの機能解析法、培養・移植法、生体イメージングなど、我々が独自に樹立している技術を融合し、得られる成果から IBD新規治療法の開発基盤と技術基盤の樹立を目指した先駆的研究になることが期待される。

Outline of Annual Research Achievements

本研究はこれまで申請者らが見出してきた「細胞傷害性リンパ球による病原性CD4+エフェクターT細胞の分化調節機構」という独自の概念や知見を基盤として、こうしたリンパ球分画による細胞傷害活性を応用したIBDに対する新規治療法開発の可能性を追求する研究を展開している。その結果、本研究では当該研究期間に以下のような成果が得られた。
1)野生型C57BL/6マウス (WT)の脾臓をはじめとした二次リンパ組織あるいは腸管組織から単離した各細胞傷害性リンパ球サブセットを様々な刺激法で培養し、複数系統の株化に成功した。その上で、これらの樹立した株のプロファイルをあらためて構築しつつ、細胞傷害活性(サイトカイン産生能、細胞溶解能、細胞死誘導能)が解析可能であることを確認した。2)ところが、こうした株は継代による長期培養は困難であることが判明した。3)上記の株のうち、T細胞との混合培養の結果からT細胞に対する特異的反応を示すクローンに着目して、細胞傷害活性関連遺伝子群の解析を試みた結果、このサブセットが発現している可能性のある分化・活性化マーカーあるいは受容体を複数同定することができた。
これらの研究成果は生理的条件下における上記リンパ球サブセットの免疫学的解析が可能であること、とくにT細胞に影響を与える細胞傷害性リンパ球サブセットの免疫学的解析を通じ、IBDの治療標的となり得る候補遺伝子の抽出が可能であることを示唆している。さらに現在、これらの細胞を用いた生化学的解析や機能的解析を進めている。また実験IBDモデルを用いて、これらの細胞による新規細胞治療の技術開発に向けて、その条件検討を現在準備中である。

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

IBDの病態には過剰に賦活化したCD4 effecter T細胞によって誘導される免疫異常が根幹にあり、腸管粘膜の免疫恒常性維持がeffecter T細胞に対する細胞傷害性リンパ球サブセットの機能によって制御されている可能性に着目しているが、今回我々はマウスから複数の細胞傷害性を持ったリンパ球分画をそれぞれ分取した上で新たな機能を見出し、さらにこれらの細胞の刺激・培養条件を樹立しつつ、新規治療標的の可能性を秘めた遺伝子を複数抽出できたことは大きな成果であるといえる。

Strategy for Future Research Activity

次年度は同定した各リンパ球サブセットによる異なる細胞傷害活性などの機能に引き続き着目し、これをさらに詳細に解析するために、in vitroおよびex vivo実験系では51[Cr]を用いた細胞溶解試験、分子生物学的解析、そして網羅的解析による細胞傷害活性関連遺伝子群のさらなる抽出の準備、またin vivo実験系では遺伝子改変動物におけるIBDモデルの誘導とその臨床および病理学的解析、FACS解析、サイトカイン測定、また免疫組織染色や生体イメージングなどを行う予定である。

Report

(2 results)
  • 2023 Research-status Report
  • 2022 Research-status Report
  • Research Products

    (39 results)

All 2024 2023 2022 Other

All Int'l Joint Research (2 results) Journal Article (23 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 17 results,  Open Access: 8 results) Presentation (14 results) (of which Int'l Joint Research: 7 results)

  • [Int'l Joint Research] Brigham and Women's Hospital/Harvard Medical School(米国)

    • Related Report
      2022 Research-status Report
  • [Int'l Joint Research] University of British Columbia(カナダ)

    • Related Report
      2022 Research-status Report
  • [Journal Article] Single cell analysis revealed that two distinct, unique CD4+ T cell subsets were increased in the small intestinal intraepithelial lymphocytes of aged mice.2024

    • Author(s)
      Yuki Yonemoto, Yasuhiro Nemoto, Ryo Morikawa, Nana Shibayama, Shigeru Oshima, Takashi Nagaishi, Tomohiro Mizutani, Go Ito, Satoru Fujii, Ryuichi Okamoto.
    • Journal Title

      Frontiers in Immunology.

      Volume: 15 Pages: 1340048-1340048

    • DOI

      10.3389/fimmu.2024.1340048

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] IgA による腸内細菌叢調節と腸管粘膜防御の検証.2023

    • Author(s)
      永石宇司.
    • Journal Title

      東京医科歯科大学医科同窓会会報.

      Volume: 301 Pages: 23-23

    • Related Report
      2023 Research-status Report
  • [Journal Article] 炎症性腸疾患モデルにおける炎症性発癌機構の解析.2023

    • Author(s)
      井上忠彦, 永石宇司.
    • Journal Title

      細胞.

      Volume: 55 Pages: 1005-1009

    • Related Report
      2023 Research-status Report
  • [Journal Article] IgAによる回腸免疫恒常性の維持.2023

    • Author(s)
      永石宇司, 井上忠彦, 伏見萌音, 山田大貴, 岡本隆一, 安達貴弘.
    • Journal Title

      消化器病学サイエンス.

      Volume: 7 Pages: 86-89

    • Related Report
      2023 Research-status Report
  • [Journal Article] 慢性下痢の原因となる薬剤.2023

    • Author(s)
      山田大貴, 永石宇司.
    • Journal Title

      IBD Research.

      Volume: 17 Pages: 112-115

    • Related Report
      2023 Research-status Report
  • [Journal Article] Analysis of Clinical Trial Screen Failures in Inflammatory Bowel Diseases [IBD]: Real World Results from the International Organization for the Study of IBD.2023

    • Author(s)
      S. Vieujean, J. O. Lindsay, F. D’Amico, V. Ahuja, M. S. Silverberg, A. Sood, J.K. Yamamoto-Furusho, M.Nagahori, et al.
    • Journal Title

      Journal of Crohn’s and Colitis.

      Volume: 18 Issue: 4 Pages: 548-559

    • DOI

      10.1093/ecco-jcc/jjad180

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Trajectory analyses to identify persistently low responders to COVID-19 vaccination in patients with inflammatory bowel disease: a prospective multicentre controlled study, J-COMBAT2023

    • Author(s)
      Watanabe Kenji、Tsuchiya Kiichiro、et al. on behalf of the J-COMBAT study group
    • Journal Title

      Journal of Gastroenterology

      Volume: 58 Issue: 10 Pages: 1015-1029

    • DOI

      10.1007/s00535-023-02029-z

    • Related Report
      2023 Research-status Report
    • Peer Reviewed
  • [Journal Article] Association of Ulcerative Colitis Symptom Severity and Proctocolectomy with Multidimensional Patient-Reported Outcomes: A Cross-Sectional Study.2023

    • Author(s)
      K. Matsuoka, H. Yamazaki, M. Nagahori, T. Kobayashi, T. Omori, Y. Mikami, T. Fujii, S. Shinzaki, M. Saruta, M. Matsuura, T. Yamamoto, S. Motoya, T. Hibi, M. Watanabe, J. Fernandez, S. Fukuhara, T. Hisamatsu.
    • Journal Title

      J Gastroenterol.

      Volume: 58 Issue: 8 Pages: 751-765

    • DOI

      10.1007/s00535-023-02005-7

    • Related Report
      2023 Research-status Report
    • Peer Reviewed
  • [Journal Article] A Web-Based Survey on Self-Management for Patients with Inflammatory Bowel Disease in Japan.2023

    • Author(s)
      M. Nagahori, T. Imai, M. Nakashoji, A. Tairaka, J.L. Fernandez.
    • Journal Title

      PLOS ONE

      Volume: 18 Issue: 7 Pages: e0287618-e0287618

    • DOI

      10.1371/journal.pone.0287618

    • Related Report
      2023 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Motility Mapping Quantification Using the Classical Optical Flow Algorithm for Small Bowel Crohn’s Disease: Comparison with Balloon-assisted Enteroscopy Findings2023

    • Author(s)
      Kitazume Yoshio、Takenaka Kento、Ohtsuka Kazuo、Ozawa Yasuo、Kimura Koichiro、Watanabe Ryosuke、Tsuchiya Junichi、Fujii Toshimitsu、Nagahori Masakazu、Watanabe Mamoru、Tateishi Ukihide
    • Journal Title

      Magnetic Resonance in Medical Sciences

      Volume: 22 Issue: 3 Pages: 325-334

    • DOI

      10.2463/mrms.mp.2021-0037

    • ISSN
      1347-3182, 1880-2206
    • Related Report
      2023 Research-status Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] IBDの検査と治療: 炎症性腸疾患(IBD)における内視鏡検査の課題と今後に期待すること.2023

    • Author(s)
      長堀正和.
    • Journal Title

      日本大腸検査学会雑誌.

      Volume: 39 Pages: 141-141

    • Related Report
      2023 Research-status Report
  • [Journal Article] 治療法の再整理とアップデートのために: 専門家による私の治療; 直腸粘膜脱症候群.2023

    • Author(s)
      長堀正和.
    • Journal Title

      日本医事新報.

      Volume: 5182 Pages: 46-47

    • Related Report
      2023 Research-status Report
  • [Journal Article] Apelin expression is downregulated in T cells in a murine model of chronic colitis2023

    • Author(s)
      Yamada D、Kojima Yi、Hosoya A、Suzuki、Watabe T、Inoue T、Tsugawa N、Asakawa T、Yonemoto Y、Onizawa M、Nemoto Y、Oshima S、Shimonaka M、Kuba Ki、Ishida J、Fukamizu A、Penninger JM、Watanabe M、Okamoto R、Nagaishi T
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 647 Pages: 72-79

    • DOI

      10.1016/j.bbrc.2023.01.068

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A case of venous stasis colitis possibly caused by eplerenone2023

    • Author(s)
      Eiko Saito, Kazuo Ohtsuka, Ami Kawamoto, Toshimitsu Fujii, Kento Takenaka, Shuji Hibiya, Hiromichi Shimizu, Masakazu Nagahori, Shohei Tomii, Ryuichi Okamoto
    • Journal Title

      Clin J Gastroenterol.

      Volume: 16 Issue: 1 Pages: 69-72

    • DOI

      10.1007/s12328-022-01722-5

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Treatment Escalation and De-Escalation Decisions in Crohn’s Disease: Delphi Consensus Recommendations from Japan, 2021.2023

    • Author(s)
      Hiroshi Nakase, Motohiro Esaki, Fumihito Hirai, Taku Kobayashi, Katsuyoshi Matsuoka, Minoru Matsuura, Makoto Naganuma, Masayuki Saruta, Kiichiro Tsuchiya, Motoi Uchino, Kenji Watanabe, Tadakazu Hisamatsu, Masakazu Nagahori, et al.
    • Journal Title

      Journal of Gastroenterology.

      Volume: - Issue: 4 Pages: 313-345

    • DOI

      10.1007/s00535-023-01958-z

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transmural remission characterized by high biologic concentrations demonstrates better prognosis in Crohn's disease2022

    • Author(s)
      Kento Takenaka, Ami Kawamoto, Yoshio Kitazume, Toshimitsu Fujii, Yumi Udagawa, Hiromichi Shimizu, Shuji Hibiya, Masakazu Nagahori, Kazuo Ohtsuka, Mamoru Watanabe, Ryuichi Okamoto
    • Journal Title

      J Crohns Colitis.

      Volume: - Issue: 6 Pages: 855-862

    • DOI

      10.1093/ecco-jcc/jjac185

    • Related Report
      2023 Research-status Report 2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Serum Leucine-Rich α2 Glycoprotein: A Novel Biomarker for Transmural Inflammation in Crohn's Disease2022

    • Author(s)
      Kento Takenaka, Yoshio Kitazume, Ami Kawamoto, Toshimitsu Fujii, Yumi Udagawa, Ryosuke Wanatabe, Hiromichi Shimizu, Shuji Hibiya, Masakazu Nagahori, Kazuo Ohtsuka, Hiroyuki Sato, Akihiro Hirakawa, Mamoru Watanabe, Ryuichi Okamoto
    • Journal Title

      Am J Gastroenterol.

      Volume: - Issue: 6 Pages: 1028-1035

    • DOI

      10.14309/ajg.0000000000002127

    • Related Report
      2023 Research-status Report 2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hemorrhagic gastric ulcer in a patient with Behcet's disease successfully treated with infliximab2022

    • Author(s)
      Shun Fujiwara, Ami Kawamoto, Maiko Motobayashi, Shuji Hibiya, Kento Takenaka, Hiromichi Shimizu, Eiko Saito, Toshimitsu Fujii, Masakazu Nagahori, Daisuke Kawata, Natsuka Umezawa, Tadashi Hosoya, Shinsuke Yasuda, Kazuo Ohtsuka, Ryuichi Okamoto
    • Journal Title

      DEN Open.

      Volume: 3 Issue: 1

    • DOI

      10.1002/deo2.196

    • Related Report
      2023 Research-status Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis.2022

    • Author(s)
      Tamura A, Ito G, Matsuda H, Nibe-Shirakihara Y, Hiraoka Y, Kitagawa S, Hiraguri Y, Nagata S, Aonuma E, Otsubo K, Nemoto Y, Nagaishi T, Watanabe M, Okamoto R, Oshima S.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 628 Pages: 147-154

    • DOI

      10.1016/j.bbrc.2022.08.046

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Deep neural network for video colonoscopy of ulcerative colitis: a cross-sectional study2022

    • Author(s)
      Kento Takenaka, Toshimitsu Fujii, Ami Kawamoto, Kohei Suzuki, Hiromichi Shimizu, Chiaki Maeyashiki, Osamu Yamaji, Maiko Motobayashi, Akira Igarashi, Ryoichi Hanazawa, Shuji Hibiya, Masakazu Nagahori, Eiko Saito, Ryuichi Okamoto, Kazuo Ohtsuka, Mamoru Watanabe
    • Journal Title

      Lancet Gastroenterol Hepatol

      Volume: 7 Issue: 3 Pages: 230-237

    • DOI

      10.1016/s2468-1253(21)00372-1

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mucosal healing of small intestinal stricture is associated with improved prognosis post-dilation in Crohn's disease2022

    • Author(s)
      Shuji Hibiya, Kazuo Ohtsuka, Kento Takenaka, Ami Kawamoto, Yusuke Matsuyama, Yumi Udagawa, Maiko Motobayashi, Hiromichi Shimizu, Toshimitsu Fujii, Eiko Saito, Masakazu Nagahori, Ryuichi Okamoto, Mamoru Watanabe
    • Journal Title

      BMC Gastroenterol.

      Volume: 22 Issue: 1 Pages: 218-218

    • DOI

      10.1186/s12876-022-02300-2

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Educational programs on drug development are required for medical students and physicians to promote the involvement of medical stakeholders2022

    • Author(s)
      Kanako Takatsuki, Minako Uchino, Toshinari Takamura, Kenichi Ishizawa, Hayato Niiyama, Maiko Jibiki, Hayato Yamazaki, Masakazu Nagahori.
    • Journal Title

      Translational and Regulatory Sciences

      Volume: 4 Issue: 3 Pages: 53-60

    • DOI

      10.33611/trs.2022-009

    • ISSN
      2434-4974
    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Interim analysis of a multicenter registry study of COVID-19 patients with inflammatory bowel disease in Japan (J-COSMOS)2022

    • Author(s)
      Nakase Hiroshi、Hayashi Yuki、Hirayama Daisuke、、Ishihara Shunji、et all、J-COSMOS group
    • Journal Title

      Journal of Gastroenterology

      Volume: 57 Issue: 3 Pages: 174-184

    • DOI

      10.1007/s00535-022-01851-1

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] A pathogenic role of activated mucosal-associated invariant T cells in an animal model of Inflammatory Bowel Disease.2024

    • Author(s)
      Yusuke Yasutomi, Asako Chiba, Keiichi Haga, Goh Murayama, Ayako Makiyama, Akihito Nagahara, Takashi Nagaishi, Sachiko Miyake.
    • Organizer
      Annual meeting of European Crohn's and Colitis Organisation 2024.
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] Downregulated apelin expression in T cells in the setting of chronic colitis.2024

    • Author(s)
      Tadahiko Inoue, Mone Fushimi, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takashi Nagaishi.
    • Organizer
      Annual meeting of European Crohn's and Colitis Organisation 2024.
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] B cell receptor signaling-mediated activation in lymphoid tissues is regulated by the long isoform of CEACAM1.2024

    • Author(s)
      Tadahiko Inoue, Mone Fushimi, Naoya Tsugawa, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takahiro Adachi, Richard S. Blumberg, Takashi Nagaishi.
    • Organizer
      Annual meeting of Japanese Society of Immunology 2024.
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] APL downregulation in T cells in an animal model of chronic colitis.2024

    • Author(s)
      Mone Fushimi, Tadahiko Inoue, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takashi Nagaishi.
    • Organizer
      Annual meeting of Japanese Society of Immunology 2024.
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] 小腸疾患治療の最前線: クローン病の小腸病変モニタリングにおけるバイオマーカーの有用性2024

    • Author(s)
      田村皓子, 河本亜美, 竹中健人, 小林桜子, 森川亮, 日比谷秀爾, 清水寛路, 藤井俊光, 齊藤詠子, 長堀正和, 大塚和朗, 岡本隆一.
    • Organizer
      日本消化管学会
    • Related Report
      2023 Research-status Report
  • [Presentation] APL downregulation in T cells in the setting of chronic colitis.2023

    • Author(s)
      Mone Fushimi, Tadahiko Inoue, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takashi Nagaishi.
    • Organizer
      United European Gastroenterology Week 2024.
    • Related Report
      2023 Research-status Report
    • Int'l Joint Research
  • [Presentation] 難治性潰瘍性大腸炎に対するcarotegrastおよびbiologicsのdual therapyの検討.2023

    • Author(s)
      藤井俊光, 青沼優子, 清水寛路, 日比谷秀爾, 河本亜美, 齊藤詠子, 竹中健人, 長堀正和, 大塚和朗, 岡本隆一.
    • Organizer
      日本消化器病学会
    • Related Report
      2023 Research-status Report
  • [Presentation] クローン病小腸病変部狭窄・吻合部狭窄に対する内視鏡的バルーン拡張術の予後の検討.2023

    • Author(s)
      日比谷秀爾, 大塚和朗, 竹中健人, 河本亜美, 藤井俊光, 清水寛路, 斎藤詠子, 長堀正和, 岡本隆一.
    • Organizer
      日本大腸検査学会
    • Related Report
      2023 Research-status Report
  • [Presentation] IBDの検査と治療: クローン病の小腸病変モニタリングにおける新規バイオマーカーの有効性.2023

    • Author(s)
      河本亜美, 竹中健人, 日比谷秀爾, 藤井俊光, 齊藤詠子, 清水寛路, 長堀正和, 大塚和朗, 渡辺守, 岡本隆一.
    • Organizer
      日本大腸検査学会
    • Related Report
      2023 Research-status Report
  • [Presentation] 炎症性腸疾患の多職種連携について(そのニーズと可能性).2023

    • Author(s)
      長堀正和.
    • Organizer
      医学教育
    • Related Report
      2023 Research-status Report
  • [Presentation] 潰瘍性大腸炎における5-ASA不耐症の臨床的特徴の探索.2023

    • Author(s)
      青沼優子, 日比谷秀爾, 藤井俊光, 河本亜美, 竹中健人, 清水寛路, 齊藤詠子, 長堀正和, 大塚和朗, 岡本隆一.
    • Organizer
      日本消化器病学会
    • Related Report
      2023 Research-status Report
  • [Presentation] Selective IgA deficiency induces spontaneous inflammation in the ileum.2022

    • Author(s)
      Nagaishi T, Yamada D, Inoue T, Blumberg RS, Okamoto R, Adachi T.
    • Organizer
      The 51st Annual meeting of Japanese Society of Immunology.
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research
  • [Presentation] 選択的IgA欠損によって誘発される回腸特異的な免疫異常.2022

    • Author(s)
      永石宇司, 山田大貴, 渡部太郎, 渡辺守, 岡本隆一, 安達貴弘.
    • Organizer
      第59回 日本消化器免疫学会
    • Related Report
      2022 Research-status Report
  • [Presentation] Spontaneous inflammation specifically in the ileum is induced by selective IgA deficiency.2022

    • Author(s)
      Nagaishi T, Yamada D, Adachi T, Watanabe M, Okamoto R, Blumberg RS.
    • Organizer
      Annual meeting of American Gastroenterology Association, Digestive Disease Week
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research

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Published: 2022-04-19   Modified: 2024-12-25  

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