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Development of strategies to overcome therapeutic resistance by using induced cancer stem cells (iCSCs)

Planned Research

Project AreaDevelopment of Novel Treatment Strategies Targeting Cancer Stem Cells
Project/Area Number 22130007
Research Category

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

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionKeio University

Principal Investigator

SAYA Hideyuki  慶應義塾大学, 医学部, 教授 (80264282)

Project Period (FY) 2010-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥171,470,000 (Direct Cost: ¥131,900,000、Indirect Cost: ¥39,570,000)
Fiscal Year 2014: ¥31,070,000 (Direct Cost: ¥23,900,000、Indirect Cost: ¥7,170,000)
Fiscal Year 2013: ¥32,500,000 (Direct Cost: ¥25,000,000、Indirect Cost: ¥7,500,000)
Fiscal Year 2012: ¥33,930,000 (Direct Cost: ¥26,100,000、Indirect Cost: ¥7,830,000)
Fiscal Year 2011: ¥33,670,000 (Direct Cost: ¥25,900,000、Indirect Cost: ¥7,770,000)
Fiscal Year 2010: ¥40,300,000 (Direct Cost: ¥31,000,000、Indirect Cost: ¥9,300,000)
Keywords発がん / がん微小環境 / 幹細胞 / 癌幹細胞 / 骨肉腫 / IGF / 脂肪細胞 / 分化 / マクロファージ / 細胞 / 癌 / 増殖 / 抗癌剤 / 代謝
Outline of Final Research Achievements

We previously developed induced cancer stem cells (iCSCs). Based on this technology, we characterized the dynamics of CSCs and analyzed their interaction with non-CSCs. Specific aim of our project was to identify the molecules regulating the functions of CSCs and compounds targeting those molecules, leading to the development of the strategies to overcome therapeutic resistance of CSCs. We have identified: i) Imp3 as a master regulator for tumorigenesis of osteosarcoma CSCs, ii) the IGF signals which promote therapeutic resistance of CSCs and iii) CD44v as a functional molecule to reduce reactive oxygen species and to promote tumor growth and therapeutic resistance.

Report

(6 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • Research Products

    (52 results)

All 2015 2014 2013 2012 2011 2010 Other

All Journal Article (34 results) (of which Peer Reviewed: 34 results,  Open Access: 8 results,  Acknowledgement Compliant: 1 results) Presentation (12 results) (of which Invited: 8 results) Remarks (4 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] TSPAN2 Is Involved in Cell Invasion and Motility during Lung Cancer Progression.2014

    • Author(s)
      Otsubo C, Otomo R, Miyazaki M, Matsushima-Hibiya Y, Kohno T, Iwakawa R, Takeshita F, Okayama H, Ichikawa H, Saya H, Kiyono T, Ochiya T, Tashiro F, Nakagama H, Yokota J and Enari M
    • Journal Title

      Cell Rep

      Volume: 7 Issue: 2 Pages: 527-538

    • DOI

      10.1016/j.celrep.2014.03.027

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression of CD24 is associated with HER2 expression and supports HER2-Akt signaling in HER2-positive breast cancer cells.2014

    • Author(s)
      Hosonaga M, Arima Y, Sugihara E, Kohno N and Saya H
    • Journal Title

      Cancer Sci

      Volume: 105 Issue: 7 Pages: 779-787

    • DOI

      10.1111/cas.12427

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] A human cancer xenograft model utilizing normal pancreatic duct epithelial cells conditionally transformed with defined oncogenes.2014

    • Author(s)
      Inagawa Y, Yamada K, Yugawa T, Ohno SI, Hiraoka N, Esaki M, Shibata T, Aoki K, Saya H and Kiyono T
    • Journal Title

      Carcinogenesis

      Volume: 35 Issue: 8 Pages: 1840-1846

    • DOI

      10.1093/carcin/bgu112

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Integrated analysis identifies different metabolic signatures for tumor-initiating cells in a murine glioblastoma model2014

    • Author(s)
      Saga I, Shibao S, Okubo J, Osuka S, Kobayashi Y, Yamada S, Fujita S, Urakami K, Kusuhara M, Yoshida K, Saya H, Sampetrean O
    • Journal Title

      Neuro Oncol.

      Volume: 16 Issue: 8 Pages: 1048-1056

    • DOI

      10.1093/neuonc/nou096

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional analysis of a novel glioma antigen, EFTUD1.2014

    • Author(s)
      Saito K, Iizuka Y, Ohta S, Takahashi S, Nakamura K, Saya H, Yoshida K, Kawakami Y and Toda M
    • Journal Title

      Neuro-Oncol

      Volume: 16 Pages: 1618-1629

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A stem cell medium containing neural stimulating factor induces a pancreatic cancer stem-like cell-enriched population.2014

    • Author(s)
      Watanabe Y, Yoshimura K, Yoshikawa K, Tsunedomi R, Shindo Y, Matsukuma S, Maeda N, Kanekiyo S, Suzuki N, Kuramasu A, Sonoda K, Tamada K, Kobayashi S, Saya H, Hazama S and Oka M
    • Journal Title

      Int J Oncol

      Volume: 45 Issue: 5 Pages: 1857-1866

    • DOI

      10.3892/ijo.2014.2603

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas.2014

    • Author(s)
      Mikami S, Mizuno R, Kosaka T, Saya H, Oya M and Okada Y
    • Journal Title

      Int J Cancer

      Volume: 136 Issue: 7 Pages: 1504-1514

    • DOI

      10.1002/ijc.29137

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] IGF2 Preserves Osteosarcoma Cell Survival by Creating an Autophagic State of Dormancy That Protects Cells against Chemotherapeutic Stress2014

    • Author(s)
      Shimizu T, Sugihara E, Yamaguchi-Iwai S, Tamaki S, Koyama Y, Kamel W, Ueki A, Ishikawa T, Chiyoda T, Osuka S, Onishi N, Ikeda H, Kamei J, Matsuo K, Fukuchi Y, Nagai T, Toguchida J, Toyama Y, Muto A, Saya H
    • Journal Title

      Cancer Res

      Volume: 74 Issue: 22 Pages: 6531-6541

    • DOI

      10.1158/0008-5472.can-14-0914

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impacts of CD44 knockdown in cancer cells on tumor and host metabolic systems revealed by quantitative imaging mass spectrometry.2014

    • Author(s)
      Ohmura M, Hishiki T, Yamamoto T, Nakanishi T, Kubo A, Tsuchihashi K, Tamada M, Toue S, Kabe Y, Saya H and Suematsu M
    • Journal Title

      Nitric Oxide

      Volume: pii: S1089-8603 Pages: 495-499

    • DOI

      10.1016/j.niox.2014.11.005

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] TNF-a/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells2014

    • Author(s)
      Oshima H, Ishikawa T, Yoshida GJ, et al.
    • Journal Title

      Oncogene

      Volume: 33 Issue: 29 Pages: 3820-3829

    • DOI

      10.1038/onc.2013.356

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD44s signals the acquisition of the mesenchymal phenotype required for anchorage-independent cell survival in hepatocellular carcinoma.2014

    • Author(s)
      Okabe H, Ishimoto T, Mima K, Nakagawa S, Hayashi H, Kuroki H, Imai K, Nitta H, Saito S, Hashimoto D, Chikamoto A, Ishiko T, Watanabe M, Nagano O, Beppu T, Saya H and Baba H
    • Journal Title

      Br J Cancer

      Volume: 印刷中 Issue: 4 Pages: 958-66

    • DOI

      10.1038/bjc.2013.759

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of MKL1 via actin cytoskeleton dynamics drives adipocyte differentiation.2014

    • Author(s)
      Nobusue H
    • Journal Title

      Nat Commun

      Volume: 5 Issue: 1 Pages: 3368-3368

    • DOI

      10.1038/ncomms4368

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inversed relationship between CD44 variant and c-Myc due to oxidative stress-induced canonical Wnt activation.2014

    • Author(s)
      Yoshida GJ and Saya H
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 443 Issue: 2 Pages: 622-627

    • DOI

      10.1016/j.bbrc.2013.12.016

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ink4a/Arf –/– and HRAS(G12V) transform mouse mammary cells into triple-negative breast cancer containing tumorigenic CD49f – quiescent cells.2014

    • Author(s)
      Kai K
    • Journal Title

      Oncogene

      Volume: 33 Issue: 4 Pages: 440-448

    • DOI

      10.1038/onc.2012.609

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia2013

    • Author(s)
      Wada T, Ishimoto T, Seishima R, Tsuchihashi K, Yoshikawa M, et al
    • Journal Title

      Cancer Science

      Volume: 104 Issue: 10 Pages: 1323-9

    • DOI

      10.1111/cas.12236

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] TNFα promotes osteosarcoma progression by maintaining tumor cells in an undifferentiated state.2013

    • Author(s)
      Mori T
    • Journal Title

      Oncogene

      Volume: Epub ahead of print Issue: 33 Pages: 4236-4241

    • DOI

      10.1038/onc.2013.545

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] In vivo pH monitoring using boron doped diamond microelectrode and silver needles: Application to stomach disorder diagnosis.2013

    • Author(s)
      Fierro S, Seishima R, Nagano O, Saya H and Einaga Y
    • Journal Title

      Sci Rep

      Volume: 3 Issue: 1 Pages: 3257-3257

    • DOI

      10.1038/srep03257

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Complexity of cancer stem cells.2013

    • Author(s)
      Sugihara E, Saya H.
    • Journal Title

      Int J Cancer.

      Volume: 132(6): Issue: 6 Pages: 1249-1259

    • DOI

      10.1002/ijc.27961

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Redox regulation in stem-like cancer cells by CD44 variant isoforms.2013

    • Author(s)
      Nagano O, Okazaki S, Saya H.
    • Journal Title

      Oncogene

      Volume: 32 Issue: 44 Pages: 5191-5198

    • DOI

      10.1038/onc.2012.638

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Establishment of HRASG12V Transgenic Medaka as a Stable Tumor Model for In Vivo Screening of Anticancer Drugs.2013

    • Author(s)
      Matsuzaki Y, Hosokai H, Mizuguchi Y, Fukamachi S, Shimizu A, Saya H
    • Journal Title

      PLoS ONE

      Volume: 8 Issue: 1 Pages: e54424-e54424

    • DOI

      10.1371/journal.pone.0054424

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] xCT Inhibition Depletes CD44v-Expressing Tumor Cells That Are Resistant to EGFR-Targeted Therapy in Head and Neck Squamous Cell Carcinoma2013

    • Author(s)
      Yoshikawa M, Tsuchihashi K, Ishimoto T, Yae T, Motohara T, Sugihara E, Onishi N, Masuko T, Yoshizawa K, Kawashiri S, Mukai M, Asoda S, Kawana H, Nakagawa T, Saya H, Nagano O
    • Journal Title

      Cancer Res

      Volume: 73(6) Issue: 6 Pages: 1855-1866

    • DOI

      10.1158/0008-5472.can-12-3609-t

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Twist2 functions as a tumor suppressor in murine osteosarcoma cells.2013

    • Author(s)
      Ishikawa T
    • Journal Title

      Cancer Sci

      Volume: 印刷中

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell.2012

    • Author(s)
      Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T,Mogushi K, Tanaka H, Osawa T, Kanki Y, et al
    • Journal Title

      Nature Communications

      Volume: 6;3 Issue: 1 Pages: 883-883

    • DOI

      10.1038/ncomms1892

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Up-regulation of imp3 confers in vivo tumorigenicity on murine osteosarcoma cells.2012

    • Author(s)
      Ueki A, Shimizu T, Masuda K, Yamaguchi SI, Ishikawa T, Sugihara E, Onishi N, Kuninaka S, Miyoshi K, Muto A, Toyama Y, Banno K, Aoki D, Saya H.
    • Journal Title

      PLoS One

      Volume: 7(11) Issue: 11 Pages: e50621-e50621

    • DOI

      10.1371/journal.pone.0050621

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reactive Oxygen Species-Induced Autophagic Degradation of Helicobacter pylori CagA Is Specifically Suppressed in Cancer Stem-like Cells2012

    • Author(s)
      Tsugawa H, Suzuki H, Saya H, Hatakeyama M, Hirayama T, Hirata K, Nagano 0, Matsuzaki J, et al.
    • Journal Title

      Cell Host & Microbe

      Volume: 12 Issue: 6 Pages: 764-777

    • DOI

      10.1016/j.chom.2012.10.014

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells2012

    • Author(s)
      Mayumi Tamada, et al
    • Journal Title

      Cancer Research

      Volume: 72 Issue: 6 Pages: 1438-1448

    • DOI

      10.1158/0008-5472.can-11-3024

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Fibroblast Growth Factor-2 Is an Important Factor that Maintains Cellular Immaturity and Contributes to Aggressiveness of Osteosarcoma2012

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

      Mol Cancer Res

      Volume: 10(3) Issue: 3 Pages: 454-468

    • DOI

      10.1158/1541-7786.mcr-11-0347

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor2012

    • Author(s)
      Sugihara E, Saya H, et al
    • Journal Title

      Oncogene

      Volume: (印刷中) Issue: 23 Pages: 2849-2861

    • DOI

      10.1038/onc.2011.462

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] NKX2.2 suppresses self renewal of glioma-initiating cells.2011

    • Author(s)
      Muraguchi T, Saya H, et al.
    • Journal Title

      Cancer Res

      Volume: 71 Pages: 1135-1145

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress.2011

    • Author(s)
      Ishizawa J, Saya H, et al.
    • Journal Title

      Cancer Sci

    • NAID

      10029293305

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc- and thereby promotes tumor growth.2011

    • Author(s)
      Ishimoto T, Saya H, et al.
    • Journal Title

      Cancer Cell

      Volume: 19 Pages: 387-400

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis.2010

    • Author(s)
      Shimizu T, Saya H, et al.
    • Journal Title

      Oncogene

      Volume: 29 Pages: 5687-5699

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of CD44 as a cell surface marker for Muller glia precursor cells.2010

    • Author(s)
      Shinoe T, Saya H, et al.
    • Journal Title

      J Neurochem

      Volume: 115 Pages: 1633-1642

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mad2 targets the mitotic kinesin MKlp2 and inhibits its kinesin function required for cytokinesis.2010

    • Author(s)
      Lee SH, Saya H, et al.
    • Journal Title

      J Cell Biol

      Volume: 191 Pages: 1069-1077

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Presentation] Regulation of cell differentiation by actin dynamics and its application in cancer treatment.2015

    • Author(s)
      Hideyuki Saya
    • Organizer
      Aichi Cancer Center 50th Anniversary International Symposium.
    • Place of Presentation
      Aichi Cancer Center, Nagoya
    • Year and Date
      2015-03-13 – 2015-03-14
    • Related Report
      2014 Annual Research Report
  • [Presentation] 骨肉腫幹細胞の性状解析と分化制御による治療戦略の考案2014

    • Author(s)
      佐谷秀行
    • Organizer
      第56回日本小児血液・がん学会学術集会
    • Place of Presentation
      岡山コンベンションセンター、岡山
    • Year and Date
      2014-11-29
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] がん幹細胞を標的とした治療戦略2014

    • Author(s)
      佐谷秀行
    • Organizer
      第18回日本がん分子標的治療学会学術集会
    • Place of Presentation
      ホテルメトロポリタン仙台、仙台
    • Year and Date
      2014-06-25
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Roles of CD44 in cancer stem cells.2013

    • Author(s)
      Hideyuki Saya
    • Organizer
      The American Association for Cancer Research (AACR) Annual Meeting 2013
    • Place of Presentation
      Washington DC, USA
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Novel therapeutic strategies for cancer stem cells.2013

    • Author(s)
      Hideyuki Saya
    • Organizer
      The 39th Annual Meeting of Korean Cancer Association.
    • Place of Presentation
      Seoul, Korea
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] CD44 and gastric epithelial stem cells.2013

    • Author(s)
      Hideyuki Saya
    • Organizer
      6th Annual Scientific Meeting, Singapore Gastric Cancer Consortium.
    • Place of Presentation
      Singapore
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Therapeutic strategies for targeting cancer stem cells.2013

    • Author(s)
      佐谷秀行
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Redox regulation of cancer cells by CD44v, a marker for cancer stem cell.2013

    • Author(s)
      Hideyuki Saya
    • Organizer
      The 86th Annual Meeting of The Japanese Biochemical Society
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Novel strategies for targeting cancer stem cells.2013

    • Author(s)
      Saya H
    • Organizer
      Ninth AACR-Japanes Cancer Association Joint Conference
    • Place of Presentation
      Hawaii,米国
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] A novel therapeutic approach targeting the CD44 variant functions.2012

    • Author(s)
      Saya H
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      札幌
    • Related Report
      2012 Annual Research Report
  • [Presentation] Role of CD44 in cancer stem cells and metastasis2011

    • Author(s)
      Saya H
    • Organizer
      8^<th> International Symposium on Minmal Residual Cancer
    • Place of Presentation
      Osaka International Convention Center, Osaka(招待講演)
    • Year and Date
      2011-09-23
    • Related Report
      2011 Annual Research Report
  • [Presentation] Role of CD44 in Cancer Stem Cells.2011

    • Author(s)
      Saya H
    • Organizer
      The 29^<th> Nagoya International Cancer Treatment Symposium.
    • Place of Presentation
      愛知がんセンター(愛知県)
    • Year and Date
      2011-02-11
    • Related Report
      2010 Annual Research Report
  • [Remarks] 慶應義塾大学医学部先端医科学研究所

    • URL

      http://www.genereg.jp/

    • Related Report
      2014 Annual Research Report
  • [Remarks] 慶應義塾大学 医学部 先端医科学研究所 遺伝子制御研究部門

    • URL

      http://www.genereg.jp/

    • Related Report
      2012 Annual Research Report
  • [Remarks]

    • URL

      http://www.genereg.jp/

    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://www.genereg.jp/

    • Related Report
      2010 Annual Research Report
  • [Patent(Industrial Property Rights)] がん幹細胞の増殖抑制剤および細胞内活性酸素蓄積誘導剤2014

    • Inventor(s)
      永野修、佐谷秀行、岡崎章悟
    • Industrial Property Rights Holder
      永野修、佐谷秀行、岡崎章悟
    • Industrial Property Rights Type
      特許
    • Filing Date
      2014-01-29
    • Related Report
      2013 Annual Research Report
  • [Patent(Industrial Property Rights)] 抗腫瘍剤2011

    • Inventor(s)
      佐谷秀行、永野修、益子高、丹羽眞一郎
    • Industrial Property Rights Holder
      学校法人慶應義塾、学校法人近畿大学、リンク・ジェノミクス(株)
    • Filing Date
      2011-01-13
    • Related Report
      2010 Annual Research Report

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Published: 2010-08-23   Modified: 2019-07-29  

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