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Development and mechanistic analysis of new PKC ligands as anti-cancer agents

Planned Research

Project AreaChemical Biology using bioactive natural products as specific ligands: identification of molecular targets and regulation of bioactivity
Project/Area Number 23102011
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Science and Engineering
Research InstitutionKyoto University

Principal Investigator

IRIE Kazuhiro  京都大学, (連合)農学研究科(研究院), 教授 (00168535)

Co-Investigator(Kenkyū-buntansha) YANAGITA Ryo C.  香川大学, 農学部, 助教 (10598121)
Project Period (FY) 2011-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥34,580,000 (Direct Cost: ¥26,600,000、Indirect Cost: ¥7,980,000)
Fiscal Year 2015: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2014: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Fiscal Year 2013: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Fiscal Year 2012: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
Fiscal Year 2011: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Keywordsアプリシアトキシン / アプログ / ブリオスタチン / がん細胞増殖抑制 / プロテインキナーゼC / ホルボールエステル / 発がんプロモーター / 抗がん剤 / シグナル伝達 / debromoaplysiatoxin / bryostatin / phorbol ester / 発がん促進 / ヒトがん細胞 / 増殖抑制 / がん細胞 / aplysiatoxin / 発がん促進物質 / 細胞増殖抑制活性 / プロテインキナーゼC / 発がん2段階試験 / TPA
Outline of Final Research Achievements

Protein kinase C (PKC) isozymes play central roles in the signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer and Alzheimer's disease. Although natural PKC ligands like phorbol esters have the potential to become therapeutic leads, most of them are potent tumor promoters and proinflammatory on mouse skin. We focused on the skeleton of aplysiatoxin (ATX), a natural PKC ligand isolated from sea hare. We found 10-methyl-aplog-1, a simplified analog of ATX, to have strong anti-proliferative activity against several cancer cell lines with little tumor-promoting and inflammatory activities. In order to examine the anti-cancer activity in vivo and mechanism of action, several hundred milligrams of 10-methyl-aplog-1 was synthesized. 10-Methyl-aplog-1 exhibited significant anti-cancer activity against mouse xenograft models, and its anti-proliferative activity derived in part from activation of protein kinase C α.

Report

(7 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Products Report
  • Research Products

    (48 results)

All 2016 2015 2014 2013 2012 2011 Other

All Journal Article (13 results) (of which Peer Reviewed: 13 results,  Acknowledgement Compliant: 3 results,  Open Access: 1 results) Presentation (28 results) (of which Int'l Joint Research: 4 results,  Invited: 7 results) Book (1 results) Remarks (4 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Structural optimization of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, as an anticancer lead2016

    • Author(s)
      M. Kikumori, R. C. Yanagita, H. Tokuda, K. Suenaga, H. Nagai, and *K. Irie
    • Journal Title

      Biosci. Biotechnol. Biochem.

      Volume: 80 Issue: 2 Pages: 888-895

    • DOI

      10.1080/09168451.2015.1091718

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Binding mode prediction of aplysiatoxin, a potent agonist of protein kinase C, through moleculer simulation and structure-activity study on simplified analogs of the receptor-recognition domain2016

    • Author(s)
      Y Ashida, R. C. Yanagita*, C Takahashi, Y Kawanami, K Irie
    • Journal Title

      Bioorg. Med. Chem

      Volume: 24 Issue: 18 Pages: 4218-4227

    • DOI

      10.1016/j.bmc.2016.07.011

    • Related Report
      Products Report
    • Peer Reviewed
  • [Journal Article] Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activity2015

    • Author(s)
      Yusuke Hanaki, Ryo C. Yanagita, Takahiro Sugahara, Misako Aida, Harukuni Tokuda, Nobutaka Suzuki, Kazuhiro Irie
    • Journal Title

      Biosci. Biotechnol. Biochem.

      Volume: 印刷中 Issue: 6 Pages: 888-895

    • DOI

      10.1080/09168451.2014.1002452

    • NAID

      120005676639

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Synthesis and biological activities of simplified analogs of the natural PKC ligands, bryostatin-1 and aplysiatoxin2014

    • Author(s)
      Kazuhiro Irie, Ryo C. Yanagita
    • Journal Title

      Chem. Rec.

      Volume: 14 Issue: 2 Pages: 251-267

    • DOI

      10.1002/tcr.201300036

    • NAID

      120005651918

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Improved and Large-Scale Synthesis of 10-Methyl-Aplog-1, a Potential Lead for an Anticancer Drug.2014

    • Author(s)
      Masayuki Kikumori, Ryo C. Yanagita, and Kazuhiro Irie
    • Journal Title

      Tetrahedron

      Volume: 70 Issue: 52 Pages: 9776-9782

    • DOI

      10.1016/j.tet.2014.11.026

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structure-activity studies at position 27 of aplog-1, a simplified analog of debromoaplysiatoxin with anti-proliferative activity.2013

    • Author(s)
      Yusuke Hanaki, Masayuki Kikumori, Sayo Ueno, Harukuni Tokuda, Nobutaka Suzuki and Kazuhiro Irie
    • Journal Title

      Tetrahedron

      Volume: 69 Issue: 36 Pages: 7936-7645

    • DOI

      10.1016/j.tet.2013.02.008

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structure-activity studies on the side chain of a simplified analog of aplysiatoxin (aplog-1) with anti-proliferative activit2013

    • Author(s)
      Kamachi, H., Tanaka, K., Yanagita, R. C., Murakami, A., Murakami, K., Tokuda, H., Suzuki, N., Nakagawa, Y., Irie, K.
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 21 Issue: 10 Pages: 2695-2702

    • DOI

      10.1016/j.bmc.2013.03.013

    • Related Report
      2013 Annual Research Report 2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of the methoxy group in the side chain of dehromoaplysiatoxin on its tumor-promoting and anti-proliferative activities2013

    • Author(s)
      Ryo C. Yanagita, Hiroaki Kamachi, Masayuki Kikumori, Harukuni Tokuda, Nobutaka Suzuki, Kiyotake Suenaga, Hiroshi Nagai and Kazuhiro Irie
    • Journal Title

      Bioorganic and Medicinal Chemistry Letters

      Volume: 23 Issue: 15 Pages: 4319-4323

    • DOI

      10.1016/j.bmcl.2013.05.096

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of new anticancer drugs based on the activation mechanism of protein kinase Cδ2012

    • Author(s)
      Kazuhiro Irie, 他2名
    • Journal Title

      Med.Res.Rev.

      Volume: (印刷中) Issue: 3 Pages: 518-535

    • DOI

      10.1002/med.20220

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis and structure-activity studies of simplified analogs of aplysiatoxin with antiproliferative activity like brvostatin-12012

    • Author(s)
      Kazuhiro Irie, 他9名
    • Journal Title

      Pure Appl.Chem.

      Volume: (印刷中) Issue: 6 Pages: 1341-1351

    • DOI

      10.1351/pac-con-11-08-22

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Structure-Activity Studies on the Spiroketal Moiety of a Simplified Analog of Debromoaplysiatoxin with Antiproliferative Activity2012

    • Author(s)
      M. Kikumori, R. Yanagita, H. Tokuda, N.Suzuki, H.Nagai, K. Suenaga, K. Irie
    • Journal Title

      J. Med. Chem.

      Volume: 55 Issue: 11 Pages: 5614-5626

    • DOI

      10.1021/jm300566h

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of antineoplastic analogs of aplysiatoxin with various side chain structures2012

    • Author(s)
      Yuki Shu
    • Journal Title

      Heterocycles

      Volume: 86 Issue: 1 Pages: 281-303

    • DOI

      10.3987/com-12-s(n)8

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Solid-state NMR analysis of interaction sites of curcumin and 42-residue amyloid β-protein fibrils2011

    • Author(s)
      Masuda, Y., Fukuchi, M., Yatagawa, T., Tada, M., Takeda, K., Irie, K., Akagi, K., Monobe, Y., Imazawa, T., Takegoshi, K.
    • Journal Title

      Bioorganic and Medicinal Chemistry

      Volume: 19 Issue: 20 Pages: 5967-5974

    • DOI

      10.1016/j.bmc.2011.08.052

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] 分子モデリングによるAplysiatoxinとプロテインキナーゼC C1ドメインとの結合様式の予測2016

    • Author(s)
      芦田能基 他
    • Organizer
      2016年度日本農芸化学会大会
    • Place of Presentation
      札幌コンベンションセンター(札幌市)
    • Year and Date
      2016-03-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] 新規抗がん剤シード・10-Me-aplog-1のがん細胞増殖抑制機構2016

    • Author(s)
      花木祐輔 他
    • Organizer
      2016年度日本農芸化学会大会,札幌コンベンションセンター(札幌市)
    • Place of Presentation
      札幌コンベンションセンター(札幌市)
    • Year and Date
      2016-03-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] 新規抗がん剤シード・aplog類のがん細胞増殖抑制機構の解析2016

    • Author(s)
      花木祐輔 他
    • Organizer
      新学術領域研究「天然物ケミカルバイオロジー ~分子標的と活性制御~」地区ミニシンポジウム
    • Place of Presentation
      京都大学楽友会館(京都市)
    • Year and Date
      2016-02-23
    • Related Report
      2015 Annual Research Report
  • [Presentation] Large-scale synthesis, anti-cancer activity in vivo, and mechanism of anti-proliferative activity of 10-methyl-aplog-1, a simplified analog of aplysiatoxin, as an anti-cancer lead2016

    • Author(s)
      Y. Hanaki et al.
    • Organizer
      The 8th Takeda Science Foundation Symposium on PharmaSciences “Biomolecule-based Medicinal Science: Featuring Mid-Size Drugs”
    • Place of Presentation
      Takeda Pharmaceutical Company, Ltd. (Suita, Japan)
    • Year and Date
      2016-01-21
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthesis and biological activities of the amide derivative of aplog-1, a simplified analog of aplysiatoxin with anti-proliferative and cytotoxic activities2015

    • Author(s)
      Y. Hanaki et al.
    • Organizer
      2015 International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2015)
    • Place of Presentation
      Hilton Hawaiian Village (Hawaii, USA)
    • Year and Date
      2015-12-17
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Structure–activity studies on the PKC-recognition domain of aplysiatoxin, a potent tumor-promoter isolated from a sea hare2015

    • Author(s)
      Y. Ashida et al.
    • Organizer
      2015 International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2015)
    • Place of Presentation
      Hilton Hawaiian Village (Hawaii, USA)
    • Year and Date
      2015-12-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Extraction of anti-proliferative activity from pleiotropic debromoaplysiatoxin, a potent tumor promoter and a highly inflammatory principle isolated from sea hare2015

    • Author(s)
      K. Irie et al.
    • Organizer
      2015 International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2015)
    • Place of Presentation
      Hilton Hawaiian Village (Hawaii, USA)
    • Year and Date
      2015-12-15
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] アプリシアトキシンの構造単純化による抗がん剤シーズの開発研究2015

    • Author(s)
      入江一浩
    • Organizer
      第33回メディシナルケミストリーシンポジウム
    • Place of Presentation
      幕張国際研修センター(千葉市)
    • Year and Date
      2015-11-26
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] 天然のプロテインキナーゼCリガンドの単純化による抗がん剤シーズの開発研究2015

    • Author(s)
      入江一浩
    • Organizer
      日本農芸化学会2015年度中四国・西日本支部合同大会
    • Place of Presentation
      愛媛大学農学部(樽味キャンパス,松山市)
    • Year and Date
      2015-09-17
    • Related Report
      2015 Annual Research Report
    • Invited
  • [Presentation] Aplysiatoxin 単純化アナログの アミド誘導体の合成と活性2015

    • Author(s)
      花木祐輔、柳田 亮、菅原貴弘、相田美砂子、徳田春邦、鈴木信孝、入江一浩
    • Organizer
      2015年度日本農芸化学会大会
    • Place of Presentation
      岡山大学津島キャンパス(岡山市)
    • Year and Date
      2015-03-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] AplysiatoxinのPKC C1ドメイン認識部位の構造活性相関研究2015

    • Author(s)
      芦田能基、柳田 亮、川浪康弘、入江一浩
    • Organizer
      2015年度日本農芸化学会大会
    • Place of Presentation
      岡山大学津島キャンパス(岡山市)
    • Year and Date
      2015-03-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] 抗がん剤開発を指向した新規プロテインキナーゼCリガンドの創製2014

    • Author(s)
      入江一浩
    • Organizer
      京都大学学際融合教育研究推進センター・生理化学研究ユニット第4回公開シンポジウム
    • Place of Presentation
      京都大学益川記念館(京都市)
    • Year and Date
      2014-06-24
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] アプリシアトキシン単純化アナログ(Aplog-1)の抗がん剤シーズとしての構造最適化2014

    • Author(s)
      菊森将之、柳田 亮、中川 優、蒲池弘明、徳田春邦、鈴木信孝、入江一浩
    • Organizer
      新学術領域研究・がん支援「化学療法基盤支援活動」第3回シンポジウム
    • Place of Presentation
      万国津梁館(沖縄県、名護市)
    • Year and Date
      2014-05-12
    • Related Report
      2014 Annual Research Report
  • [Presentation] Debromoaplysiatoxin単純化アナログの10位メチル体の発がん促進活性2013

    • Author(s)
      菊森 将之
    • Organizer
      2013年度日本農芸化学会大会
    • Place of Presentation
      東北大学川内キャンパス(仙台市)
    • Year and Date
      2013-03-26
    • Related Report
      2012 Annual Research Report
  • [Presentation] Debromoaplysiatoxin単純化アナログの27位における構造活性相関2013

    • Author(s)
      花木祐輔
    • Organizer
      2013年度日本農芸化学会大会
    • Place of Presentation
      東北大学川内キャンパス(仙台市)
    • Year and Date
      2013-03-26
    • Related Report
      2012 Annual Research Report
  • [Presentation] Structure-activity studies on the spiroketal moiety of aplog-1, a simplified analogue of debromoaplysiatoxin with anti-proliferative activities2012

    • Author(s)
      Masayuki Kikumori
    • Organizer
      The 12th International Kyoto Conference on New Aspects of Organic Chemistry
    • Place of Presentation
      Rega Royal Hotel (Kyoto)
    • Year and Date
      2012-11-15
    • Related Report
      2012 Annual Research Report
  • [Presentation] Structure-activity studies of the simplified analogue of aplysiatoxin with antiproliferative activity like bryostatins2012

    • Author(s)
      Kazuhiro Irie
    • Organizer
      3rd International Symposium on Innovative Areas “Chemical Biology of Natural Products”
    • Place of Presentation
      Kyoto Century Hotel (Kyoto)
    • Year and Date
      2012-10-31
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Debromoaplysiatoxin単純化アナログの10位メチル体の合成と細胞増殖抑制活性2012

    • Author(s)
      菊森 将之
    • Organizer
      2012年度日本農芸化学会関西支部大会
    • Place of Presentation
      京都学園大学(亀岡市)
    • Year and Date
      2012-09-29
    • Related Report
      2012 Annual Research Report
  • [Presentation] プロテインキナーゼCを標的とした新規抗がん剤シーズ2012

    • Author(s)
      入江 一浩
    • Organizer
      京都大学新技術説明会
    • Place of Presentation
      JST東京別館ホール(東京、市ヶ谷)
    • Year and Date
      2012-08-24
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 天然発がんプロモーターの骨格を利用した新規抗がん剤リードの開発2012

    • Author(s)
      入江一浩
    • Organizer
      2012年度日本農芸化学会大会
    • Place of Presentation
      京都女子大学(京都市)(招待講演)
    • Year and Date
      2012-03-25
    • Related Report
      2011 Annual Research Report
  • [Presentation] 抗腫瘍性Aplysiatoxin単純化アナログの側鎖の構造活性相関を目的とした合成経路の確立2012

    • Author(s)
      朱裕姫
    • Organizer
      2012年度日本農芸化学会大会
    • Place of Presentation
      京都女子大学(京都市)
    • Year and Date
      2012-03-23
    • Related Report
      2011 Annual Research Report
  • [Presentation] 抗がん剤開発を指向した新規PKCリガンドの創製と作用機構解析2012

    • Author(s)
      入江一浩
    • Organizer
      新学術領域研究「天然物ケミカルバイオロジー」第一回公開シンポジウム
    • Place of Presentation
      大阪市立大学(大阪市)(招待講演)
    • Year and Date
      2012-01-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] 天然発がんプロモーターの骨格を利用した新規ツール分子と抗がん剤シーズの開発2011

    • Author(s)
      入江一浩
    • Organizer
      日本農芸化学会関西支部例会(第472回講演会)
    • Place of Presentation
      神戸大学(神戸市)(招待講演)
    • Year and Date
      2011-12-10
    • Related Report
      2011 Annual Research Report
  • [Presentation] Development of new molecular probes and therapeutic seeds having skeletons of naturallyoccumng tumor promoters2011

    • Author(s)
      Kazuhiro Irie
    • Organizer
      22nd French-Japanese Symposium of Medicinal and Fine Chemistry
    • Place of Presentation
      Convention Center (Rouen, France)(招待講演)
    • Year and Date
      2011-09-13
    • Related Report
      2011 Annual Research Report
  • [Presentation] Synthesis and structure-activity studies of the simplified analogue of aplysiatoxin with antiproliferative activity like bryostatin 12011

    • Author(s)
      Kazuhiro Irie
    • Organizer
      27th International Symposium on the Chemistry of Natural Products, 7th International Conference on Biodiversity
    • Place of Presentation
      Convention Center (Brisbane, Australia)(招待講演)
    • Year and Date
      2011-07-11
    • Related Report
      2011 Annual Research Report
  • [Presentation] Synthesis and biological activities of the simplified analogs of a natural PKC ligand aplysiatoxin

    • Author(s)
      Kazuhiro Irie
    • Organizer
      International Symposium on Natural Products Chemistry and Chemical Biology 2013
    • Place of Presentation
      Hotel Rubura Ohzan (Nagoya)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Role of methyl groups on the spiroketal moiety of aplog-1, a simplified analogue of debromoaplysiatoxin with anti-proliferative activity

    • Author(s)
      Kikumori, M. et al.
    • Organizer
      23rd French-Japanese Symposium of Medicinal and Fine Chemistry
    • Place of Presentation
      Crowne Plaza ANA Nagasaki Gloverhill (Nagasaki)
    • Related Report
      2013 Annual Research Report
  • [Presentation] Debromoaplysiatoxinの4位不斉メチル基の生物活性おける役割

    • Author(s)
      菊森将之ら
    • Organizer
      2014年度日本農芸化学会大会
    • Place of Presentation
      明治大学生田キャンパス(川崎市)
    • Related Report
      2013 Annual Research Report
  • [Book] CSJ Current Review 生物活性分子のケミカルバイオロジー 標的同定と作用機構2015

    • Author(s)
      入江一浩 他30名
    • Publisher
      化学同人
    • Related Report
      2014 Annual Research Report
  • [Remarks] 生命有機化学研究室 京都大学農学研究科食品生物科学専攻

    • URL

      http://www.orgchem.kais.kyoto-u.ac.jp/

    • Related Report
      2015 Annual Research Report
  • [Remarks] 生命有機化学研究室 食品生物科学専攻

    • URL

      http://www.orgchem.kais.kyoto-u.ac.jp/research.php?id=1

    • Related Report
      2014 Annual Research Report
  • [Remarks] 京都大学 農学研究科 食品生物科学専攻 生命有機化学分野

    • URL

      http://www.orgchem.kais.kyoto-u.ac.jp/

    • Related Report
      2013 Annual Research Report
  • [Remarks]

    • URL

      http://kyouindb.iimc.kyoto-u.ac.jp/j/lZ1hV

    • Related Report
      2011 Annual Research Report
  • [Patent(Industrial Property Rights)] 新規アプリシアトキシン誘導体及びそれを含有する抗がん剤2013

    • Inventor(s)
      入江 一浩, 菊森 将之, 蒲池 弘明, 柳田 亮, 中川 優
    • Industrial Property Rights Holder
      国立大学法人京都大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2013-04-16
    • Acquisition Date
      2017-07-07
    • Related Report
      Products Report
  • [Patent(Industrial Property Rights)] 新規アプリシアトキシン誘導体及びそれを含有する抗がん剤2012

    • Inventor(s)
      入江一浩,菊森将之,蒲池弘明,柳田 亮,中川 優
    • Industrial Property Rights Holder
      入江一浩,菊森将之,蒲池弘明,柳田 亮,中川 優
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2012-092842
    • Filing Date
      2012-04-16
    • Related Report
      2012 Annual Research Report

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Published: 2011-08-01   Modified: 2019-07-29  

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