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Development of mature cardiomyocytes from human iPS cells

Research Project

Project/Area Number 26293056
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field General pharmacology
Research InstitutionNational Institute of Health Sciences

Principal Investigator

Kanda Yasunari  国立医薬品食品衛生研究所, 薬理部, 室長 (70510387)

Co-Investigator(Kenkyū-buntansha) 大島 英揮  名古屋大学, 医学部附属病院, 講師 (40378188)
Co-Investigator(Renkei-kenkyūsha) Kurokawa Junko  静岡県立大学, 薬学部, 教授 (40396982)
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,120,000 (Direct Cost: ¥12,400,000、Indirect Cost: ¥3,720,000)
Fiscal Year 2016: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2015: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2014: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
KeywordsiPS細胞 / 心筋細胞 / 成熟化 / インシリコ / イオンチャネル / 安全性薬理 / 不整脈 / 安全性評価 / 創薬 / ヒトiPS細胞 / 多点電極 / 興奮伝播 / 液性因子 / 心筋 / 幹細胞 / 再生医療
Outline of Final Research Achievements

Drug-induced cardiac arrhythmias have been a major reason for drug withdrawal at late stage of clinical trials. Human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) are expected to be applicable to cardiac drug safety testing as research tools. In the present study, our patch-clamp recordings and imaging with voltage-sensitive dye revealed that iPS-CMs exhibited relatively depolarized maximum diastolic potential and lower conduction velocity, suggesting an immature differentiation state of the iPS-CMs. We next established our mathematical simulation in iPS-CMs and found that low expression of the inward-rectifier potassium (IK1) channel is a determinant of spontaneous activity. We also fond that transduction of KCNJ2, which encodes the IK1 channel, induced electrophysiological maturation of iPS-CMs. Thus, our novel approach would provide new insights into the evaluation of drug-induced caridiac toxicities in iPS-CMs.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report

Research Products

(47 results)

All 2017 2016 2015 2014 Other

All Journal Article (13 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 6 results,  Acknowledgement Compliant: 6 results) Presentation (30 results) (of which Int'l Joint Research: 8 results,  Invited: 3 results) Book (1 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes.2017

    • Author(s)
      Ando H, Yoshinaga T, Yamamoto W, Asakura K, Uda T, Taniguchi T, Ojima A, Shinkyo R, Kikuchi K, Osada T, Hayashi S, Kasai C, Miyamoto N, Tashibu H, Yamazaki D, Sugiyama A, Kanda Y, Sawada K, Sekino Y.
    • Journal Title

      J Pharmacol Toxicol Methods

      Volume: 84 Pages: 111-127

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Development of new pharmacological test methods using human iPS cell-derived cardiomyocytes2017

    • Author(s)
      Kanda Y, Yamazaki D, Sekino Y.
    • Journal Title

      Folia Pharmacol. Jpn.

      Volume: 149 Issue: 3 Pages: 110-114

    • DOI

      10.1254/fpj.149.110

    • NAID

      130005403860

    • ISSN
      0015-5691, 1347-8397
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance2017

    • Author(s)
      Izumi-Nakaseko H, Nakamura Y, Wada T, Ando K, Kanda Y, Sekino Y, Sugiyama A.
    • Journal Title

      J. Toxicol. Sci.

      Volume: 42 Issue: 2 Pages: 183-192

    • DOI

      10.2131/jts.42.183

    • NAID

      130005450518

    • ISSN
      0388-1350, 1880-3989
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Points to consider for a validation study of iPS cell-derived cardiomyocytes using a multi-electrode array system.2016

    • Author(s)
      Kanda Y, Yamazaki D, Kurokawa J, Inutsuka T and Sekino Y
    • Journal Title

      J Pharmacol Toxicol Methods

      Volume: 81 Pages: 196-200

    • DOI

      10.1016/j.vascn.2016.06.007

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Good Cell Culture Practice for stem cells and stem-cell-derived models.2016

    • Author(s)
      Pamies D, Bal-Price A, Simeonov A, Tagle D, Allen D, Gerhold D, Yin D, Pistollato F, Inutsuka T, Sullivan K, Stacey G, Salem H, Leist M, Daneshian M, Vemuri MC, McFarland R, Coecke S, Fitzpatrick SC, Lakshmipathy U, Mack A, Wang WB, Yamazaki D, Sekino Y, Kanda Y, Smirnova L, Hartung T.
    • Journal Title

      ALTEX

      Volume: 34 Pages: 95-132

    • DOI

      10.14573/altex.1607121

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Electrophysiological Characteristics of Human iPSC-Derived Cardiomyocytes for the Assessment of Drug-Induced Proarrhythmic Potential.2016

    • Author(s)
      Yamamoto W, Asakura K, Ando H, Taniguchi T, Ojima A, Uda T, Osada T, Hayashi S, Kasai C, Miyamoto N, Tashibu H, Yoshinaga T, Yamazaki D, Sugiyama A, Kanda Y, Sawada K, Sekino Y.
    • Journal Title

      PLoS One

      Volume: 11

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ヒトiPS細胞を利用した心臓安全性評価の開発と国際標準化2016

    • Author(s)
      諫田泰成,山崎大樹,関野祐子
    • Journal Title

      レギュラトリーサイエンス学会誌

      Volume: 6 Pages: 367-74

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] ヒトiPS細胞由来心筋細胞の活動電位イメージングの測定装置と実験プロトコールの開発2016

    • Author(s)
      井出吉紀,山崎大樹,諫田泰成,関野祐子
    • Journal Title

      国立医薬品食品衛生研究所報告

      Volume: 134 Pages: 9-16

    • NAID

      40021073113

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] ヒトiPS細胞から成熟した心筋細胞の 開発と安全性評価への応用2016

    • Author(s)
      諫田泰成、芦原貴司、黒川洵子
    • Journal Title

      日薬理誌

      Volume: 147 Pages: 1-5

    • NAID

      130005156509

    • Related Report
      2015 Annual Research Report
    • Acknowledgement Compliant
  • [Journal Article] ヒトiPS細胞由来心筋細胞シートの不整脈研究への応用可能性:in silico不整脈学の観点から2015

    • Author(s)
      芦原貴司、黒川洵子、諫田泰成、原口亮、稲田慎、中沢一雄、堀江稔
    • Journal Title

      生体医工学

      Volume: 53 Pages: 100-105

    • NAID

      130005106893

    • Related Report
      2015 Annual Research Report
    • Open Access
  • [Journal Article] ヒトiPS細胞を用いた成熟心筋細胞の開発2014

    • Author(s)
      諫田泰成
    • Journal Title

      心電図

      Volume: 34 Pages: 306-309

    • NAID

      130005090839

    • Related Report
      2014 Annual Research Report
  • [Journal Article] 霧島会議Stem Cell Safety Pharmacology Working Groupまとめ-ヒトES/iPS細胞由来心筋細胞を用いた催不整脈作用検出とその課題-2014

    • Author(s)
      澤田光平、松尾純子、長田智治、吉田善紀、白尾智明、佐藤薫、諫田泰成、関野祐子
    • Journal Title

      心電図

      Volume: 34 Pages: 306-309

    • Related Report
      2014 Annual Research Report
  • [Journal Article] ヒトiPS細胞を用いた心毒性試験の現状と課題2014

    • Author(s)
      諫田泰成
    • Journal Title

      毒性質問箱

      Volume: 16 Pages: 91-94

    • Related Report
      2014 Annual Research Report
  • [Presentation] Electrophysiology Studies of iPS-derived Cardiomyocytes as a Surrogate of QT Prolongation2016

    • Author(s)
      Yasunari Kanda
    • Organizer
      Safety Pharmacology Society 16th annual meeting
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2016-09-18
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Electrophysiological and Pharmacological Characterization of Human iPS Cell-Derived Cardiomyocytes As a Model for Predicting the Drug-Induced Arrhythmic Events in Human Hearts2016

    • Author(s)
      Wataru Yamamoto, Keiichi Asakura, Hiroyuki Ando, Tomohiko Taniguchi, Atsuko Ojima, Takaaki Uda, Tomoharu Osada, Seiji Hayashi, Chieko Kasai, Norimasa Miyamoto, Hiroyuki Tashibu, Takashi Yoshinaga, Daiju Yamazaki, Atsushi Sugiyama, Yasunari Kanda, Kohei Sawada, Yuko Sekino
    • Organizer
      Safety Pharmacology Society 16th annual meeting
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2016-09-18
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Drug-Induced Torsadogenic Risk Prediction Using Human iPS Cell-Derived Cardiomyocytes and MEA System (I)2016

    • Author(s)
      Hiroyuki Ando, Takashi Yoshinaga, Wataru Yamamoto, Keiichi Asakura, Tomohiko Taniguchi, Atsuko Ojima, Takaaki Uda, Raku Shinkyo, Kiyomi Kikuchi, Tomoharu Osada, Seiji Hayashi, Chieko Kasai, Norimasa Miyamoto, Hiroyuki Tashibu, Daiju Yamazaki, Atsushi Sugiyama, Yasunari Kanda, Kohei Sawada, Yuko Sekino,
    • Organizer
      Safety Pharmacology Society 16th annual meeting
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2016-09-18
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Drug-Induced Torsadogenic Risk Prediction Using Human iPS Cell-Derived Cardiomyocytes and MEA System (II)2016

    • Author(s)
      Takashi Yoshinaga, Hiroyuki Ando, Tomohiko Taniguchi, Takaaki Uda, Wataru Yamamoto, Keiichi Asakura, Atsuko Ojima, Raku Shinkyo, Kiyomi Kikuchi, Tomoharu Osada, Seiji Hayashi, Chieko Kasai, Hiroyuki Tashibu, Norimasa Miyamoto, Daiju Yamazaki, Yasunari Kanda, Atsushi Sugiyama, Kohei Sawada, Yuko Sekino,
    • Organizer
      Safety Pharmacology Society 16th annual meeting
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2016-09-18
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Drug-Induced Proarrhymic Testing Methods Using VSD and Calcium lndicator in FDSS/uCell2016

    • Author(s)
      DaiiuYamazaki, Yoshinori lde, Yasunari Kanda, Yuko Sekino,
    • Organizer
      Safety Pharmacology Society 16th annual meeting
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2016-09-18
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cardiac Safety Assessment Methods for Human iPSC-Derived Cardiomyocytes: A Voltage Sensitive Dye Imaging with a High-speed CMOS Sensor and a Non-staining Imaging with Polarizers2016

    • Author(s)
      Yoshinori Ide, Michinori Ichikawa, Mariko Kobayashi, Kenji Tsubokura, Daiju Yamazaki, Yasunari Kanda, Yuko Sekino,
    • Organizer
      Safety Pharmacology Society 16th annual meeting
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2016-09-18
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Evaluation of Multi-electrode Array in Combination with Cor.4U Human iPS Cell-Derived Cardiomyocytes to Predict Drug-Induced QT Prolongation and Arrhythmia -Collaboration between CSAHi and JiCSA2016

    • Author(s)
      Takashi Kitaguchi, Yuta Moriyama, Sanae Maeda, Tomohiko Taniguchi, Masakazu Ishimura, Hiroyuki Tashibu, Masao Oguchi, Atsuhiro Yamanishi, Etsushi Takahashi, Kaori Miyamoto, Kaoru Morimura, Daisuke Saji, Hiroki Ohnaka, Daiju Yamazaki, Yasunari Kanda, Yuko Sekino, Norimasa Miyamoto
    • Organizer
      Safety Pharmacology Society 16th annual meeting
    • Place of Presentation
      Vancouver, Canada
    • Year and Date
      2016-09-18
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Toward a proposal of the revised ICH S7B: Update of the activities of Japan iPS cardiac safety assessment (JiCSA) and CiPA2016

    • Author(s)
      Yasunari Kanda, Yuko Sekino
    • Organizer
      5th Chinese Safety Pharmacology Society
    • Place of Presentation
      Jinan, China
    • Year and Date
      2016-05-26
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ヒトiPS細胞技術を用いた次世代心臓安全性評価: JiCSAの取り組み2016

    • Author(s)
      諫田泰成
    • Organizer
      第89回日本薬理学会年会シンポジウム
    • Place of Presentation
      バシフィコ横浜
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] 内向き整流性カリウムチャネルを過剰発現させたヒト iPS 由来心筋細胞を用いた薬理作用解析2016

    • Author(s)
      Erina Hayashi, Reiko Kimura, Min Li, Tomoko Ando,Takashi Ashihara, Yuko Sekino, Tetsushi Furukawa, Yasunari Kanda, Junko Kurokawa.
    • Organizer
      第89回日本薬理学会年会
    • Place of Presentation
      バシフィコ横浜
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒトiPS細胞由来心筋の活動電位形成に関連する遺伝子の定量的発現解析におけるリファレンス遺伝子の選定2016

    • Author(s)
      Reiko Kimura, Masami Kodama, Kazuharu Furutani, Yasunari Kanda, Yoshihisa Kurachi , Yuko Sekino, Tetsushi Furukawa, Junko Kurokawa
    • Organizer
      第89回日本薬理学会年会
    • Place of Presentation
      バシフィコ横浜
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒト iPS 細胞由来の成熟心筋細胞の作製と標準化に向けた次世代評価法の開発2016

    • Author(s)
      諫田泰成
    • Organizer
      第3回心臓安全性に関するシンクタンクミーティング2016合同公開シンポジウム
    • Place of Presentation
      東京
    • Year and Date
      2016-02-18
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒトiPS心筋とMEAシステムによる新規薬剤誘発性TdPリスク評価2016

    • Author(s)
      山崎大樹、諫田泰成、関野祐子
    • Organizer
      筋生理の集い
    • Place of Presentation
      慈恵医大
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒトiPS心筋細胞を利用した催不整脈性リスク評価とICHS7B改訂に関する国際動向について2016

    • Author(s)
      関野祐子, 諫田泰成
    • Organizer
      第43回日本毒性学会学術年会
    • Place of Presentation
      金沢
    • Related Report
      2016 Annual Research Report
  • [Presentation] ヒトカリウムチャネル遺伝子導入によるヒトiPS細胞由来心筋細胞の成熟化のメカニズム-発現レベルからの考察2015

    • Author(s)
      児玉昌美、李敏、芦原貴司、諫田泰成、関野祐子、古川 哲史、黒川洵子
    • Organizer
      生体機能と創薬シンポジウム2015
    • Place of Presentation
      千葉
    • Year and Date
      2015-08-27
    • Related Report
      2015 Annual Research Report
  • [Presentation] ペーシング可能なヒトiPS細胞由来心筋細胞を用いたQT延長薬剤の作用解析2015

    • Author(s)
      黒川洵子、芦原貴司、諫田泰成、古川哲史
    • Organizer
      第10回トランスポーター研究会年会
    • Place of Presentation
      東京
    • Year and Date
      2015-06-21
    • Related Report
      2015 Annual Research Report
  • [Presentation] ヒトiPS細胞由来心筋細胞を用いたQT延長薬剤の頻度依存性の解析2015

    • Author(s)
      黒川洵子、林英里奈、芦原貴司、諫田泰成、関野祐子、古川哲史
    • Organizer
      第92回日本生理学会大会
    • Place of Presentation
      神戸
    • Year and Date
      2015-03-22
    • Related Report
      2014 Annual Research Report
  • [Presentation] 膜輸送体を標的としたiPS細胞由来心筋の創薬応用2015

    • Author(s)
      黒川洵子, 芦原貴司, 諫田泰成, 古川哲史
    • Organizer
      第88回日本薬理学会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-20
    • Related Report
      2014 Annual Research Report
  • [Presentation] ヒトiPS細胞由来心筋細胞シートでの評価2015

    • Author(s)
      松尾純子,宮本 憲優,小島敦子,諫田泰成,澤田光平,有村由貴子,鈴木晶子,吉福智子,関野祐子
    • Organizer
      第88回日本薬理学会
    • Place of Presentation
      名古屋
    • Year and Date
      2015-03-19
    • Related Report
      2014 Annual Research Report
  • [Presentation] A novel approach for evaluation of drug-induced QT prolongation using human induced pluripotent stem cell-derived cardiomyocytes2015

    • Author(s)
      Junko Kurokawa, Jun-ichi Okada, Erina Hayashi, Takashi Ashihara, Takashi Yoshinaga, Seiryo Sugiura, Li Min, Yasunari Kanda, Yuko Sekino, Kohei Sawada, Toshiaki Hisada, Tetsushi Furukawa
    • Organizer
      59th Biophysics meeting
    • Place of Presentation
      Baltimore
    • Year and Date
      2015-02-19
    • Related Report
      2014 Annual Research Report
  • [Presentation] ヒトiPS細胞を用いた安全性薬理試験の開発2015

    • Author(s)
      諫田泰成
    • Organizer
      東京理科大学トランスレーショナルリサーチセンター第1回公開セミナー
    • Place of Presentation
      千葉
    • Year and Date
      2015-01-10
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 安全性薬理試験へのヒト iPS 細胞由来神経細胞の応用―催不整脈評価は可能か?2014

    • Author(s)
      諫田泰成
    • Organizer
      第 11 回医薬品レギュラトリーサイエンスフォーラム
    • Place of Presentation
      東京
    • Year and Date
      2014-12-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] ヒトiPS細胞を用いた新たな安全性薬理試験の開発2014

    • Author(s)
      諫田泰成
    • Organizer
      日本実験動物代替法学会第27回大会
    • Place of Presentation
      横浜
    • Year and Date
      2014-12-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] Effects of substrate elasticity on gene expression profiles of human iPS-derived cardiomyocytes2014

    • Author(s)
      藤塚美紀、中井雄治、諫田泰成、永森收志、金井好克、古川哲史、黒川洵子
    • Organizer
      CBI学会2014年大会
    • Place of Presentation
      東京
    • Year and Date
      2014-10-28
    • Related Report
      2014 Annual Research Report
  • [Presentation] in vitro cardiac safety testing using iPS cells2014

    • Author(s)
      諫田泰成、関野祐子
    • Organizer
      第5回DIA cardiac safety workshop
    • Place of Presentation
      東京
    • Year and Date
      2014-10-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Role of substrate rigidity on function in human iPS cell-derived cardiomyocytes2014

    • Author(s)
      諫田泰成
    • Organizer
      第87回日本生化学会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-15
    • Related Report
      2014 Annual Research Report
  • [Presentation] Evaluation of drug-induced QT-prolongation in human iPS-derived cardiomyocytes2014

    • Author(s)
      黒川洵子、芦原貴司、諫田泰成
    • Organizer
      第87回日本生化学会
    • Place of Presentation
      京都
    • Year and Date
      2014-10-15
    • Related Report
      2014 Annual Research Report
  • [Presentation] ペーシング可能なヒトiPS細胞由来心筋標本の開発2014

    • Author(s)
      李敏、林英里奈、諫田泰成、関野祐子、古川哲史、黒川洵子
    • Organizer
      第130回日本薬理学会関東部会
    • Place of Presentation
      東京
    • Year and Date
      2014-07-05
    • Related Report
      2014 Annual Research Report
  • [Presentation] ヒトiPS細胞由来心筋細胞を用いた安全性評価法の現状と将来の展望2014

    • Author(s)
      諫田泰成
    • Organizer
      第41回日本毒性学会
    • Place of Presentation
      神戸
    • Year and Date
      2014-07-02
    • Related Report
      2014 Annual Research Report
  • [Presentation] ヒトiPS細胞由来心筋細胞を用いた新規心毒性評価系2014

    • Author(s)
      黒川洵子,古川哲史,関野祐子,諫田泰成
    • Organizer
      第41回日本毒性学会
    • Place of Presentation
      神戸
    • Year and Date
      2014-07-02
    • Related Report
      2014 Annual Research Report
  • [Book] 谷本学校毒性質問箱第18号2016

    • Author(s)
      諫田泰成,関野祐子
    • Total Pages
      6
    • Publisher
      サイエンティスト社
    • Related Report
      2016 Annual Research Report
  • [Remarks] 国立衛研・薬理・第二室

    • URL

      http://www.nihs.go.jp/phar/lab/lab2.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 薬理部 各室の紹介 第二室

    • URL

      http://www.nihs.go.jp/phar/lab/lab2.html

    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] 正常な内向きのカリウム電流特性を有するiPS細胞由来心筋モデル細胞2014

    • Inventor(s)
      黒川洵子、古川哲史、諫田泰成、関野祐子
    • Industrial Property Rights Holder
      黒川洵子、古川哲史、諫田泰成、関野祐子
    • Industrial Property Rights Type
      特許
    • Filing Date
      2014-05-30
    • Related Report
      2014 Annual Research Report
    • Overseas

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Published: 2014-04-04   Modified: 2018-03-22  

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