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Elucidation of molecular mechanism of cytokie receptor activation by mutant CALR

Research Project

Project/Area Number 16K09859
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionJuntendo University

Principal Investigator

ARAKI MARITO  順天堂大学, 医学(系)研究科(研究院), 准教授 (80613843)

Co-Investigator(Kenkyū-buntansha) 森下 総司  順天堂大学, 医学部, 助教 (10635866)
小松 則夫  順天堂大学, 医学部, 教授 (50186798)
Research Collaborator ITO akihiro  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords骨髄増殖性腫瘍 / サイトカイン受容体 / 分子シャペロン / シグナル伝達 / トロンボポエチン / JAK2 / CALR / MPL / calreticulin / thrombopoietin / Calreticulin
Outline of Final Research Achievements

By studying the mechanism for the development of myeloproliferative neoplasms (MPN) by calreticulin mutation, this study uncovered that mutant CALR preferentially interacted with MPL, induced activation of MPL like cytokine, constitutively activated its downstream molecules such as JAK2, ERK1/2, and STAT5, and thus promoted the cellular transformation.

Academic Significance and Societal Importance of the Research Achievements

本研究により、CALR変異遺伝子による骨髄増殖性腫瘍(MPN)の発症メカニズムが明らかになったことから、CALR遺伝子変異を有するMPN患者に対する有効な治療薬の開発が大いに期待される。さらに、『分子シャペロンの変異による受容体活性化が引き起こす細胞腫瘍化』という新しい腫瘍生物学の概念が明らかになったことから、他の疾患や生命現象の解明に結びつくことが大いに期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (52 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (3 results) Journal Article (12 results) (of which Peer Reviewed: 10 results,  Open Access: 4 results) Presentation (34 results) (of which Int'l Joint Research: 13 results,  Invited: 6 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Ludwig Cancer Research(ベルギー)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] CeMM(オーストリア)

    • Related Report
      2018 Annual Research Report
  • [Int'l Joint Research] INSERM(フランス)

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Homomultimerization of mutant calreticulin is a prerequisite for MPL binding and activation2018

    • Author(s)
      Araki Marito、Yang Yinjie、Imai Misa、Mizukami Yoshihisa、Kihara Yoshihiko、Sunami Yoshitaka、Masubuchi Nami、Edahiro Yoko、Hironaka Yumi、Osaga Satoshi、Ohsaka Akimichi、Komatsu Norio
    • Journal Title

      Leukemia

      Volume: 33 Issue: 1 Pages: 122-131

    • DOI

      10.1038/s41375-018-0181-2

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Skewed megakaryopoiesis in human induced pluripotent stem cell-derived haematopoietic progenitor cells harbouring calreticulin mutations2018

    • Author(s)
      Hiraku Takei, Yoko Edahiro, Shuichi Mano, Nami Masubuchi, Yoshihsa Mizukami, Misa Imai, Soji Morishita, Kyohei Misawa, Tomonori Ochiai, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
    • Journal Title

      British Journal of Haematology

      Volume: 印刷中 Issue: 6 Pages: 791-802

    • DOI

      10.1111/bjh.15266

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutant molecular chaperone activates cytokine receptor as a homomultimer2018

    • Author(s)
      Araki Marito、Komatsu Norio
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 81 Pages: 35201-35202

    • DOI

      10.18632/oncotarget.26221

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of myeloproliferative neoplasms by mutant calreticulin: underlying mechanisms2018

    • Author(s)
      荒木 真理人
    • Journal Title

      Rinsho Ketsueki

      Volume: 59 Issue: 8 Pages: 1072-1077

    • DOI

      10.11406/rinketsu.59.1072

    • NAID

      130007472202

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms.2018

    • Author(s)
      Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
    • Journal Title

      Int J Hematol

      Volume: 印刷中 Issue: 6 Pages: 673-680

    • DOI

      10.1007/s12185-018-2421-7

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] The 2014 BCSH criteria and the 2016 WHO criteria for essential thrombocythemia: A comparison in a large-scale cohort.2018

    • Author(s)
      Ochiai T, Yasuda H, Araki M, Misawa K, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
    • Journal Title

      Eur J Haematol

      Volume: 印刷中 Issue: 6 Pages: 544-549

    • DOI

      10.1111/ejh.13041

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Novel molecular mechanism of cellular transformation by a mutant molecular chaperone in myeloproliferative neoplasms2017

    • Author(s)
      Araki Marito、Komatsu Norio
    • Journal Title

      Cancer Sci

      Volume: 108 Issue: 10 Pages: 1907-1912

    • DOI

      10.1111/cas.13327

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Somatic mutations of calreticulin in myeloproliferative neoplasms2017

    • Author(s)
      Imai Misa、Araki Marito、Komatsu Norio
    • Journal Title

      Int J Hematol

      Volume: 105 Issue: 6 Pages: 743-747

    • DOI

      10.1007/s12185-017-2246-9

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The 2016 WHO diagnostic criteria for polycythemia vera renders an accurate diagnosis to a broader range of patients including masked polycythemia vera: Comparison with the 2008 WHO diagnostic criteria.2017

    • Author(s)
      Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
    • Journal Title

      Am J Hematol

      Volume: 92 Issue: 7

    • DOI

      10.1002/ajh.24752

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] 骨髄増殖性腫瘍におけるドライバー遺伝子変異による腫瘍化の分子メカニズム2017

    • Author(s)
      荒木真理人
    • Journal Title

      最新醫學

      Volume: 72 Pages: 1522-1528

    • Related Report
      2017 Research-status Report
  • [Journal Article] 骨髄増殖性腫瘍を引き起こす変異型calreticulinによるTPO受容体の活性化.2016

    • Author(s)
      今井美沙, 荒木真理人, 森下総司, 小松則夫.
    • Journal Title

      血液内科

      Volume: 73 Pages: 789-793

    • Related Report
      2016 Research-status Report
  • [Journal Article] 骨髄増殖性腫瘍の遺伝子変異 最近の知見.2016

    • Author(s)
      荒木真理人, 森下総司, 小松則夫.
    • Journal Title

      臨床血液.

      Volume: 57 Pages: 2526-2534

    • Related Report
      2016 Research-status Report
    • Peer Reviewed
  • [Presentation] The molecular mechanism of oncogenic activation of thrombopoietin receptor by mutant calreticulin2018

    • Author(s)
      Marito Araki
    • Organizer
      The 1st MPN Summit
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Boarding on the secretary pathway is required for the oncogenic property of mutant calreticulin2018

    • Author(s)
      Araki M, Masubuchi N, Hayashi E, Yang Y, Imai M, Kihara Y, Mizukami Y, Hironaka Y, Edahiro Y, Ohsaka A, Komatsu N.
    • Organizer
      23rd Congress of the European Hematology Association
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Copy number of JAK2V617F modulates human hematopoietic cell differentiation2018

    • Author(s)
      Edahiro Y, Mano S, Takei H, Morishita S, Tsuneda S, Ohsaka A, Araki M, Komatsu N.
    • Organizer
      8th International Conference on Myeloproliferative Neoplasms
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 変異型分子シャペロンによるサイトカイン受容体活性化の分子メカニズム2018

    • Author(s)
      荒木真理人, 小松則夫
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 変異型CALRの多量体化はMPLとの結合と活性化に必須である2018

    • Author(s)
      荒木真理人, 楊印杰, 今井美沙, 水上喜久, 木原慶彦, 角南義孝, 増渕菜弥, 枝廣陽子, 弘中由美, 大佐賀智, 大坂顯通, 小松則夫
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Wild-type JAK2 may suppress mutant JAK2 activity in cytokine receptor activation.2018

    • Author(s)
      Kitazawa S, Araki M, Morishita S, Yang Y, Imai M, Ohsaka A, Komatsu N.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] APL細胞の分化誘導におけるATRA標的遺伝子の同定.2018

    • Author(s)
      角南義孝, 荒木真理人, 山本誠司, 堀内祥行, 辻岡一也, 薫 茂, 今井美沙, 森下総司, 大坂顯通, 小松則夫.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] トリプルネガティブ本態性血小板血症症例の臨床像と遺伝子変異.2018

    • Author(s)
      稲野資明, 荒木真理人, 福田泰隆, 森下総司, 落合友則, 三澤恭平, 伊藤雅文, 山本紘司, 楊印杰, 田口鉄平, 枝廣陽子, 今井美沙, 後藤明彦, 大坂顯通, 小松則夫.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 細胞減少療法はPMF患者における腎機能の悪化を防止する.2018

    • Author(s)
      福田泰隆, 荒木真理人, 山本紘司, 森下総司, 稲野資明, 三澤恭平, 落合友則, 枝廣陽子, 今井美沙, 後藤明彦, 大坂顯通, 小松則夫.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Introduction of CALR and JAK2 V617F mutations to UT-7/Epo and K562 by the CRISPR/Cas9 system.2018

    • Author(s)
      Yasuda S, Aoyama S, Watanabe D, Araki M, Komatsu N, Miura O, Kawamata N.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] JAK2V617F変異アレル数はヒト血球分化を変化させる.2018

    • Author(s)
      竹井拓, 枝廣陽子, 李麗華, 水上喜久, 森下総司, 大坂顯通, 荒木真理人, 小松則夫.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 骨髄線維化を伴う骨髄異形成症候群の臨床病態および分子発症機序の解明.2018

    • Author(s)
      新谷直樹, 原田浩徳, 原田結花, 飯塚弘子, 森下総司, 荒木真理人, 大坂顯通, 土岐典子, 大橋一輝, 萩原政夫, 小松則夫.
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] The Zygosity of JAK2V617F Determines the Disease Entities of Myeloproliferative Neoplasms By Modulating Erythropoiesis but Not Megakaryopoiesis2018

    • Author(s)
      Takei H, Edahiro Y, Li L, Mizukami Y, Imai M, Morishita S, Ohsaka A, Araki M, Komatsu N.
    • Organizer
      60th Annual Meeting & Exposition of American Society of Hematology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Secreted Mutant Calreticulins As Rogue Cytokines Trigger Thrombopoietin Receptor Activation Specifically in CALR Mutated Cells: Perspectives for MPN Therapy2018

    • Author(s)
      Pecquet C, Araki M, et al.
    • Organizer
      60th Annual Meeting & Exposition of American Society of Hematology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] SLAMF7high CD16negative Monocytes Increase in Peripheral Blood of Patients with Myelofibrosis in Correlation with JAK2V617F Mutation2018

    • Author(s)
      Maekawa T, Kato S, Okada Y, Tachi N, Teramoto M, Kawamura T, Osawa Y, Kobayashi S, Sato K, Hashimoto M, Suzu S, Usuki K, Morishita S, Araki M, Komatsu N, Kimura F.
    • Organizer
      60th Annual Meeting & Exposition of American Society of Hematology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The molecular mechanism of oncogenic activation of thrombopoietin receptor by mutant calreticulin2018

    • Author(s)
      Marito Araki
    • Organizer
      The 3rd MPN Conference in Asia
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Activation of the Thrombopoietin Receptor by Mutant Calreticulin in CALR-Mutant Myeloproliferative Neoplasms.2017

    • Author(s)
      Araki M
    • Organizer
      The Gordon Research Conference on Cell Biology of Megakaryocytes & Platelets.
    • Place of Presentation
      Lucca, Italy
    • Year and Date
      2017-02-26
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] Skewed megakaryopoiesis by mutant calreticulin is associated with increased GATA2 expression2017

    • Author(s)
      Hiraku Takei, Shuichi Mano, Nami Masubuchi, Yoshihisa Mizukami, Misa Imai, Soji Morishita, Yoko Edahiro Yumi Hironaka Mai Nudejima Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 骨髄増殖性腫瘍に見出される変異型 CALR 蛋白質の細胞内局在2017

    • Author(s)
      林英里奈, 荒木真理人, 増渕菜弥, 水上喜久, 楊印杰, 今井美沙 , 弘中由美, 竹井拓, 木原慶彦, 枝廣陽子, 大坂顯通, 小松則夫
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Engagement of mutant calreticulin and MPL in a cellular compartment is required for MPL activation2017

    • Author(s)
      Nami Masubuchi, Marito Araki, Erina Hayashi, Yinjie Yang, Misa Imai Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Soji Morishita, Yoshihiko Kihara, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Mechanisms governing the accumulation of mutant calreticulin2017

    • Author(s)
      Yoshihiko Kihara, Marito Araki, Yinjie Yang, Misa Imai, Nami Masubuchi, Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Localization of mutant calreticulin in the Golgi apparatus is required for its oncogenic capacity2017

    • Author(s)
      Nami Masubuchi, Marito Araki, Erina Hayashi, Yinjie Yang, Misa Imai Yoshihiko Kihara, Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
    • Organizer
      59th Annual Meeting & Exposition of American Society of Hematology
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Establishment of an in vitro model for the skewed megakaryopoiesis by calreticulin mutation in human cells2017

    • Author(s)
      Hiraku Takei, Shuichi Mano, Nami Masubuchi, Yoshihisa Mizukami, Soji Morishita, Misa Imai, Yoko Edahiro, Yumi Hironaka, Mai Nudejima, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
    • Organizer
      22nd Congress of the European Hematology Association
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 変異型CALRの細胞内コンパートメントへの局在がトロンボポエチン受容体の活性化に必要である2017

    • Author(s)
      荒木真理人, 小松則夫
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] The mechanism of the development of myeloproliferative neoplasms by mutant molecular chaperone2017

    • Author(s)
      Marito Araki
    • Organizer
      The 26th KOGO Annual Conference 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research / Invited
  • [Presentation] The mechanism of the development of myeloproliferative neoplasms by mutant molecular chaperone2017

    • Author(s)
      Marito Araki
    • Organizer
      第79回日本血液学会学術集会シンポジウム「骨髄系腫瘍とクリニカルシーケンス」
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] A novel molecular mechanism of cellular transformation via a mutant molecular chaperone2017

    • Author(s)
      Marito Araki
    • Organizer
      MD Anderson Cancer Center - Tokyo Oncology Consortium Sister Institute Memorial Symposium
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Mutant Calreticulin activates the thrombopoietin receptor in myeloproliferative neoplasms.2017

    • Author(s)
      Marito Araki, Yinjie Yang, Nami Masubuchi, Yoshihisa Mizukami, Misa Imai, Erina Hayashi, Yumi Hironaka, Soji Morishita, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
    • Organizer
      The annual GAP Conference
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 骨髄増殖生腫瘍を引き起こす変異型Calreticulinの細胞内局在2016

    • Author(s)
      増渕 菜弥, 荒木 真理人, Yinjie Yang, 弘中 由美, 竹井 拓, 森下 総司, 今井 美沙, 水上 喜久, Kan Shin、大坂 顯通, 小松 則夫.
    • Organizer
      第39回日本分子生物学会
    • Place of Presentation
      横浜
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] Mutant Calreticulin activates the thrombopoietin receptor in myeloproliferative neoplasms.2016

    • Author(s)
      Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Ohsaka A, Komatsu N.
    • Organizer
      第78回日本血液学会学術集会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] Modeling MPN phenotypes in vitro by using iPSC harboring CALR ins5 mutation.2016

    • Author(s)
      Takei H, Masubuchi N, Mano S, Araki M, Morishita S, Mizukami Y, Kan S, Edahiro Y, Sunami Y, Hironaka Y, Endo H, Nakamura S, Eto K, Ohsaka A, Komatsu N.
    • Organizer
      第78回日本血液学会学術集会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] Cell surface localization of mutant Calreticulin that induces myeloproliferative neoplasms (MPNs).2016

    • Author(s)
      Masubuchi N, Araki M, Yang Y, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Ohsaka A, Komatsu N.
    • Organizer
      第78回日本血液学会学術集会
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] Mutant Calreticulin activates JAK2 by an interaction with thrombopoietin receptor in myeloproliferative neoplasm cells.2016

    • Author(s)
      Araki M, Komatsu N.
    • Organizer
      第75回日本癌学会学術総会.
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-06
    • Related Report
      2016 Research-status Report
  • [Presentation] Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms.2016

    • Author(s)
      Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Ohsaka A, Komatsu N.
    • Organizer
      21st Congress of the European Hematology Association.
    • Place of Presentation
      Copenhagen, Denmark
    • Year and Date
      2016-06-09
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Remarks] 研究室ホームページ

    • URL

      http://www.juntendo.ac.jp/graduate/laboratory/labo/ketsueki_naika/

    • Related Report
      2017 Research-status Report
  • [Remarks] 研究室ホームページ

    • URL

      http://www.juntendo.ac.jp/graduate/laboratory/labo/ketsueki_naika/k4.html

    • Related Report
      2016 Research-status Report
  • [Patent(Industrial Property Rights)] 非公開2019

    • Inventor(s)
      荒木真理人、小松則夫、木原慶彦
    • Industrial Property Rights Holder
      荒木真理人、小松則夫、木原慶彦
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2019-036119
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report

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Published: 2016-04-21   Modified: 2020-03-30  

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