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Roles of leukemogenic oncogenes in the regulation of metabolism, growth, and differentiation of hematopoietic stem cells

Research Project

Project/Area Number 20390269
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionOsaka University

Principal Investigator

MATSUMURA Itaru  Osaka University, 医学部, 教授 (00294083)

Co-Investigator(Kenkyū-buntansha) KANAKURA Yuzuru  大阪大学, 大学院・医学系研究科, 教授 (20177489)
MIZUKI Masao  大阪大学, 附属病院, 准教授 (80283761)
ORITANI Kenji  大阪大学, 大学院・医学系研究科, 准教授 (70324762)
SHIBAYAMA Hirohiko  大阪大学, 大学院・医学系研究科, 講師 (60346202)
ASHIDA Takashi  近畿大学, 医学部附属病院, 准教授 (30211006)
TATSUMI Yoichi  近畿大学, 医学部附属病院, 准教授 (60236552)
SHIMADA Takahiro  近畿大学, 医学部, 講師 (90319674)
Project Period (FY) 2008 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
Fiscal Year 2010: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2009: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2008: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywords造血幹細胞 / 遺伝子変異 / 慢性骨髄性白血病 / 活性型チロシンキナーゼ / 増殖シグナル / 自己複製 / 白血病 / エネルギー代謝 / SIRT1
Research Abstract

1. The C-terminal deletion mutant of RUNX1, RUNX1dC, attenuates DNA-damage repair responses to UV irradiation in murine c-KIT^+Sca-1^+Lin^- cells by suppressing the expression of Gadd45a.
2. FIP1L1-PDGFRalpha not only enhanced the development of eosinophil progenitors (EoPs) from KSL cells but also aberrantly developed EoPs from progenitors in other lineages.
3.BCR-ABL inhibited erythropoiesis through the induction of p21^<WAF1> via Ras/MAPK, while it promoted granulopoiesis.

Report

(4 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (74 results)

All 2011 2010 2009 2008

All Journal Article (50 results) (of which Peer Reviewed: 33 results) Presentation (19 results) Book (5 results)

  • [Journal Article] Frequency of intravascular large B-cell lymphoma in Japan : Study of the Osaka Lymphoma Study Group.2011

    • Author(s)
      Chihara T, Wada N, Matsumura I, et al., 他
    • Journal Title

      J Hematol Oncol. (online publication.)

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Predictability of the response to tyrosine kinase inhibitors via in vitro analysis of Bcr-Abl phosphorylation.2011

    • Author(s)
      Shibata M, Ezoe S, Matsumura I, et al., 他
    • Journal Title

      Leuk Res. (online publication.)

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Myeloid neoplasm-related gene abnormalities differentially affect dendritic cell differentiation from murine hematopoietic stem/progenitor cells.2011

    • Author(s)
      Fujita J, Mizuki M, Matsumura I, et al., 他
    • Journal Title

      Immunol Lett. 136

      Pages: 61-73

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Senescence induction therapy for the treatment of adult T-cell leukemia.2011

    • Author(s)
      Maeda Y, Sasakawa A, Matsumura I, et al., 他
    • Journal Title

      Leuk Lymphoma. 52

      Pages: 150-152

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Myeloid neoplasm-related gene abnormalities differentially affect dendritic cell differentiation from murine hematopoietic stem/progenitor cells.2011

    • Author(s)
      Fujita J, et al.
    • Journal Title

      Immunol Lett.

      Volume: in press

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Senescence induction therapy for the treatment of adult T-cell leukemia.2011

    • Author(s)
      Maeda Y, et al.
    • Journal Title

      Leuk Lymphoma.2011

      Volume: 52 Pages: 150-152

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] preferentially induces apoptosis in normal hematopoietic cells : a possible mechanism involved in the expansion of MDS cells.2011

    • Author(s)
      Tanaka H, et.al
    • Journal Title

      Exp Hematol

      Volume: in press

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Predictability of response to tyrosine kinase inhibitors via in vitro analysis of Bcr-Abl phosphorylation2011

    • Author(s)
      Masaru Shibata, et al.
    • Journal Title

      Leukemia Research

      Volume: in press

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 新規キナーゼ阻害薬の白血病治療への導入と展望2011

    • Author(s)
      森田泰慶、松村到
    • Journal Title

      血液内科

      Volume: 62 Pages: 63-70

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1.2010

    • Author(s)
      Tokunaga M, Ezoe S, Matsumura I, et al., 他
    • Journal Title

      J Biol Chem. 285

      Pages: 31774-31782

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] BCR-ABL but not JAK2 V617F inhibits erythropoiesis through the Ras signal by inducing p21CIP1/WAF1.2010

    • Author(s)
      Tokunaga M, et al.
    • Journal Title

      J Biol Chem.

      Volume: 41 Pages: 31774-31782

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Therapeutic choice for the chronic myeloid leukemia patients in chronic phase showing late suboptimal response to imatinib.2010

    • Author(s)
      Matsumura I, et al.
    • Journal Title

      臨床血液

      Volume: 51 Pages: 1762-1768

    • NAID

      10027751519

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The 2nd generation of TKIs for chronic myeloid leukemia2010

    • Author(s)
      Matsumura I.
    • Journal Title

      臨床血液

      Volume: 51 Pages: 1386-1394

    • NAID

      10026727759

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CML治療の現状と展望2010

    • Author(s)
      松村到
    • Journal Title

      細胞 The CELL

      Volume: 42 Pages: 14-17

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 白血病治療における最近の薬物療法の進歩2010

    • Author(s)
      森田泰慶、松村到
    • Journal Title

      Medical Science Digest

      Volume: 36 Pages: 868-871

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 慢性骨髄性白血病の治療戦略2010

    • Author(s)
      松村到
    • Journal Title

      Bio Clinica

      Volume: 25 Pages: 18-23

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Improvement of recurrent urticaria in a patient with Schnitzler syndrome associated with B-cell lymphoma with combination rituximab and radiotherapy2010

    • Author(s)
      Murota H, et al.
    • Journal Title

      J of Amer Acad of Dermatol 61

      Pages: 1070-1075

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Effects of iron overload on hematopoiesis2010

    • Author(s)
      Matsumura I, et al.
    • Journal Title

      Porphilins (in press)

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 白血病-「治癒」あるいは「維持」に向けて2010

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      Medical Practice 27

      Pages: 196-202

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2010

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      WHO血液腫瘍分類造血組織編「慢性骨髄性白血病」(医薬ジャーナル社)

      Pages: 47-55

    • Related Report
      2009 Annual Research Report
  • [Journal Article] FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells.2009

    • Author(s)
      Fukushima K, Matsumura I, Ezoe S, et al., 他
    • Journal Title

      J Biol Chem. 284

      Pages: 7719-7732

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] FIP1L1-PDGFRa imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells2009

    • Author(s)
      Fukushima K, et al.
    • Journal Title

      J Biol Chem 284

      Pages: 7719-7732

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Antifungal activity of micafungin in serum2009

    • Author(s)
      Ishikawa J, et al.
    • Journal Title

      Antimicrob Agents Chemother 53

      Pages: 4559-4562

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 急性骨髄性白血病の治療2009

    • Author(s)
      松村到
    • Journal Title

      臨床血液 50

      Pages: 65-76

    • NAID

      10025633845

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 肥満細胞症2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      血液フロンティア 19

      Pages: 37-46

    • Related Report
      2009 Annual Research Report
  • [Journal Article] 慢性骨髄匪白血病治療の現状と病態に基づいた今後の治療2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      血液フロンティア 1

      Pages: 8-17

    • Related Report
      2009 Annual Research Report
  • [Journal Article] CMLに対する新規チロシンキナーゼ阻害薬2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      総合臨床 58

      Pages: 1708-1712

    • Related Report
      2009 Annual Research Report
  • [Journal Article] 血液製剤の種類と適応2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      総合臨床 58

      Pages: 385-389

    • Related Report
      2009 Annual Research Report
  • [Journal Article] MPDに対する新たな治療戦略2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      細胞 41

      Pages: 20-23

    • Related Report
      2009 Annual Research Report
  • [Journal Article] 過剰鉄と造血-生体内自由鉄とのかかわりをさぐる2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      分子細胞治療 6

      Pages: 26-31

    • Related Report
      2009 Annual Research Report
  • [Journal Article] 慢性好酸球性白血病/好酸球増加症候群における染色体・遺伝子異常2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      血液・腫瘍科 58

      Pages: 146-151

    • Related Report
      2009 Annual Research Report
  • [Journal Article] 遺伝子発現からみた急性白血病の予後2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      血液・腫瘍科 58

      Pages: 8-13

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      血液疾患エキスパート「Imatinib耐性・不耐容の慢性骨髄性白血病に対する治療」(中外医学社)

      Pages: 214-228

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      Annual Review血液2009「造血器腫瘍におけるmiRNAの異常とその役割」(中外医学社)

      Pages: 110-116

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      EBM血液疾患の治療2010-2011「分子遺伝学的完全寛解が得られた時点でイマチニブを減量・中止することは可能か? 」(中外医学社)

      Pages: 191-195

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      内科学書「造血の分子機構」(中山書店)

      Pages: 8-9

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      今日の治療指針2010年版「顆粒球減少症(無顆粒球症)」(医学書院)

      Pages: 561-562

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2009

    • Author(s)
      松村到, 金倉譲
    • Journal Title

      Annual Review血液2010「骨髄由来細胞による癌転移の促進」(中外医学社)

      Pages: 107-113

    • Related Report
      2009 Annual Research Report
  • [Journal Article]2009

    • Author(s)
      松村到
    • Journal Title

      慢性骨髄性白血病治療の実践マニュアル(エルセビアジヤパン)

      Pages: 156-175

    • Related Report
      2009 Annual Research Report
  • [Journal Article] Effects of iron overload on hematopoiesis.2009

    • Author(s)
      Matsumura I, et al.
    • Journal Title

      Porphilins (In press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FIPlLl-PDGFRa imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells.2009

    • Author(s)
      Fukush ima K, et al.
    • Journal Title

      J Biol Chem (in press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] AML1/RUNX1 works as a negative regulator of c-Mpl in hematopoietic stem cells.2008

    • Author(s)
      Satoh Y, Matsumura I, Tanaka H, et al., 他
    • Journal Title

      J Biol Chem. 283

      Pages: 30045-30056

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] The expression of anamorsin in diffuse large B cell lymphoma : possible prognostic biomarker for low IPI patients.2008

    • Author(s)
      Shizusawa T, Shibayama H, Matsumura I, et al., 他
    • Journal Title

      Leuk Lymphoma. 49

      Pages: 113-121

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines.2008

    • Author(s)
      Sasaki H, Hayakawa J, Matsumura I, et al., 他
    • Journal Title

      Oncogene. 272

      Pages: 737-2745

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies.2008

    • Author(s)
      Matsumura I, Mizuki M, Kanakura Y.
    • Journal Title

      Cancer Sci. 99

      Pages: 479-485

    • NAID

      10024003430

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] AMLl/runxl works as a negative regulator of C-MPL in hematopoietic stem cells.2008

    • Author(s)
      Satoh Y, et al.
    • Journal Title

      J Biol Chem 283

      Pages: 30045-30056

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Difference between genomic actions of estrogen versus raloxifene in human ovarian cancer cell lines.2008

    • Author(s)
      Sasaki H, et al.
    • Journal Title

      Oncogene 27

      Pages: 2737-2745

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The expression of anamorsin in diffuse large B cell lymphoma : possible prognostic bioraarker for low IPI patients.2008

    • Author(s)
      Shizusawa T, et al.
    • Journal Title

      Leukemia Lymphoma 49

      Pages: 113-121

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Japanese epidemiological survey with consensus statement on Japaneseguidelines for treatment of iron overload in bone marrow failuresyndromes.2008

    • Author(s)
      Suzuki T, et al.
    • Journal Title

      Int J Hematol 88

      Pages: 30-35

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies2008

    • Author(s)
      Matsumura I, et al.
    • Journal Title

      Cancer Science 99

      Pages: 479-485

    • NAID

      10024003430

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Presentation] BCR-ABL suppresses erythropoiesis thruogh Ras signaling by the Induction of P21clp1/waf12010

    • Author(s)
      Tokunaga M, Matsumura I, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Year and Date
      2010-09-24
    • Related Report
      2010 Final Research Report
  • [Presentation] Iron-overload impairs normal hematopoiesis and would conntribute to disease progression of MDS2010

    • Author(s)
      Tanaka H, Matsumura I, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Year and Date
      2010-09-24
    • Related Report
      2010 Final Research Report
  • [Presentation] 慢性骨髄性白血病と第二世代ABLチロシンキナーゼ阻害剤2010

    • Author(s)
      松村到
    • Organizer
      第72回 日本血液学会学術集会
    • Year and Date
      2010-09-24
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] AML幹細胞の特性解析2010

    • Author(s)
      松村到、田中宏和
    • Organizer
      第69回 日本癌学会学術集会
    • Year and Date
      2010-09-22
    • Related Report
      2010 Final Research Report
  • [Presentation] BCR-ABL suppresses erythropoiesis thruogh Ras signaling by the Induction of P21 clp1/waf12010

    • Author(s)
      Masahiro Tokunaga, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report
  • [Presentation] Iron-overload impairs normal hematopoiesis and would conntribute to disease progression of MDS2010

    • Author(s)
      Hirokazu Tanaka, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report
  • [Presentation] EBM-negative nasal-type natural killer/T cell lymphoma of the testis with a long-term survival2010

    • Author(s)
      Masakatsu Emoto, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report
  • [Presentation] A young case diagnosed concomitantly as B-cell and B-cell lymphoma2010

    • Author(s)
      Shinya Rai, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report
  • [Presentation] Efficacy and safety of radioimmunotherapy in patients with relapsed or refractory B-cell lymphoma2010

    • Author(s)
      Yoichi Tatsumi, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report
  • [Presentation] Cellular senescene induction therapy bu retinoid for adult T-cell leukemia2010

    • Author(s)
      Yasuhiro Maeda, et al.
    • Organizer
      第72回 日本血液学会学術集会
    • Place of Presentation
      横浜
    • Related Report
      2010 Annual Research Report
  • [Presentation] C-terminal mutation of RUNX1 deteriorates DNA damage-repair response and promotes the development of aculte myeloid leukemia2009

    • Author(s)
      Satoh S, et al.
    • Organizer
      American Society of Hematology 51th Annual meeting
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2009-12-06
    • Related Report
      2009 Annual Research Report
  • [Presentation] Runxl controls nucleotide excision repair (NER) through transcriotional regulation of Gadd45a2009

    • Author(s)
      Satoh S, et al.
    • Organizer
      第71回日本血液学会総会
    • Place of Presentation
      京都
    • Year and Date
      2009-10-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] 抗アポトーシス分子Anamorsinの造血幹細胞における発現と機能解析2009

    • Author(s)
      谷村朗, 他
    • Organizer
      第71回日本血液学会総会
    • Place of Presentation
      京都
    • Year and Date
      2009-10-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] CMLに対するlmatinib療法の分子遺伝学効果に関する研究2009

    • Author(s)
      石川淳, 他
    • Organizer
      第71回日本血液学会総会
    • Place of Presentation
      京都
    • Year and Date
      2009-10-24
    • Related Report
      2009 Annual Research Report
  • [Presentation] 急性骨髄性白血病の治療2009

    • Author(s)
      松村到
    • Organizer
      第71回日本血液学会総会
    • Place of Presentation
      教育講演
    • Year and Date
      2009-10-23
    • Related Report
      2010 Final Research Report
  • [Presentation] 急性骨髄性白血病の治療2009

    • Author(s)
      松村到
    • Organizer
      第71回日本血液学会総会
    • Place of Presentation
      京都
    • Year and Date
      2009-10-23
    • Related Report
      2009 Annual Research Report
  • [Presentation] RunxlはGadd45aの転写調節を介してヌクレオチド除去修復を制御する2009

    • Author(s)
      佐藤友亮, 松村到, 原田宏徳, 金倉譲
    • Organizer
      第67回日本癌学会総会
    • Place of Presentation
      神奈川
    • Year and Date
      2009-10-02
    • Related Report
      2009 Annual Research Report
  • [Presentation] 組織鉄の功罪:骨髄における過剰鉄がもたらす毒性2009

    • Author(s)
      松村到, 田中宏和, 金倉譲
    • Organizer
      第33回日本鉄バイオサイエンス学会学術集会シンポジウム
    • Place of Presentation
      倉敷
    • Year and Date
      2009-09-12
    • Related Report
      2009 Annual Research Report
  • [Presentation] Effects of iron overload on hematopoiesis2008

    • Author(s)
      松村到
    • Organizer
      The 8th International Porphyrin-Heme Symposium
    • Year and Date
      2008-10-16
    • Related Report
      2010 Final Research Report
  • [Book] WH血液腫瘍分類(WHO分類2008をうまく活用するため)2010

    • Author(s)
      松村到
    • Total Pages
      587
    • Publisher
      医薬ジャーナル社
    • Related Report
      2010 Final Research Report
  • [Book] Annual Review血液2010

    • Author(s)
      松村到
    • Total Pages
      229
    • Publisher
      中外医学社
    • Related Report
      2010 Final Research Report
  • [Book] WHO血液腫瘍分類~WHO分類2008をうまく活用するため~2010

    • Author(s)
      直江知樹, 他
    • Total Pages
      587
    • Publisher
      医薬ジャーナル社
    • Related Report
      2010 Annual Research Report
  • [Book] 造血器腫瘍治療 2版2010

    • Author(s)
      松村到, 他
    • Total Pages
      361
    • Publisher
      中外医学社
    • Related Report
      2010 Annual Research Report
  • [Book] Anuual Review 2010 血液2010

    • Author(s)
      高久史麿, 他
    • Total Pages
      229
    • Publisher
      中外医学社
    • Related Report
      2010 Annual Research Report

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Published: 2008-04-01   Modified: 2016-04-21  

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