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2000 Fiscal Year Final Research Report Summary

In vivo gene therapy for hepatocellular carcinoma and colorectal carcinoma using suicide genes and cytokine genes

Research Project

Project/Area Number 10470140
Research Category

Grant-in-Aid for Scientific Research (B).

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionNara Medical University

Principal Investigator

KURIYAMA Shigeki  Nara Medical University, Third Dept.of Internal Medicine, Assistant Professor, 医学部, 講師 (50244710)

Co-Investigator(Kenkyū-buntansha) TOMINAGA Kentaro  Nara Medical University, Third Dept.of Internal Medicine, Research Fellow, 医学部, 医員
KOJIMA Hideyuki  Nara Medical University, Third Dept.of Internal Medicine, Research Associate, 医学部, 助手 (60326345)
YOSHIKAWA Masahide  Nara Medical University, Department of Parasitology, Associate Professor, 医学部, 助教授 (50230701)
TSUJINOUE Hirohisa  Nara Medical University, Third Dept.of Internal Medicine, Research Fellow, 医学部, 医員
YOSHIJI Hitoshi  Nara Medical University, Third Dept.of Internal Medicine, Research Fellow, 医学部, 医員
Project Period (FY) 1998 – 2000
Keywordsgene therapy / retrovirus / adenovirus / hepatocellular carcinoma / colorectal carcinoma / suicide gene / cytokine gene
Research Abstract

(1) We have shown that retroviral packaging cells introduced with the polyoma virus early regions could produce high-titer recombinant retroviruses compared with conventional retroviral packaging cells.
(2) We have shown that intratumoral injections of retroviruses carrying the herpes simplex virus thymidine kinase (HSV-tk) gene under the control of the albumin promoter could induce complete cure of subcutaneously established hepatocellular carcinoma in mice. We have also shown that intraperitoneal injections of retroviruses carrying the HSV-tk gene under the control of the albumin promoter could profoundly prolong the survival periods of mice with carcinomatous peritonitis due to invasion of hepatocellular carcinoma.
(3) We have shown that the addition of the 5' sequences of the α-fetoprotein gene to the retroviral long terminal repeat promoter or the housekeeping phosphoglycerate kinase promoter could induce hepatocellular carcinoma cell-selective expression of suicide genes and cytoki … More ne genes used for a therapeutic purpose.
(4) We have shown that intraperitoneal injections of retroviruses carrying the bacterial cytosine deaminase (CD) gene under the control of the carcinoembryonic antigen promoter could profoundly prolong the survival periods of mice with peritoneal dissemination of colorectal carcinoma. Furthermore, intraperitoneal injections of the retroviruses followed by 5-fluorocytosine (5-FC) treatment did not cause significant bone marrow suppression, while intraperitoneal injections of retroviruses carrying the CD gene under the control of the retroviral long terminal repeat promoter caused severe bone marrow suppression with 5-FC treatment.
(5) We have shown that intravenous infusion of adenoviruses could induce marked expression of a transgene in the liver not only in mice with normal livers but also in mice with severely damaged livers such as fulminant hepatitis and liver cirrhosis. However, transgene expression was transient and reinfusion of the same adenoviruses could not induce re-expression of the transgene. We have demonstrated that administration of immunosuppressive agents such as cyclophosphamide and FK506 around the time of adenoviral re-infusion could successfully induce expression of the original gene construct. Less

  • Research Products

    (76 results)

All Other

All Publications (76 results)

  • [Publications] Korlyama S, et al.: "Inhibitory Effects of Human Sera on Adenovirus-Mediated Gene Transfer into Rat Liver"Anticancer Res. 18. 2345-2352 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cao G, et al: "Comparison of carcinoembryonic antigen promoter regions isolated from human colorectal carcinoma and normal adjacent mucosa to induce strong tumor-selective gene expression"Int J Cancer. 78. 242-247 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cao G, et al.: "Gene therapy for human colorectal carcinoma using human CEA promoter controlled bacterial ADP-ribosylating toxin genes : PEA and DTA gene tranfer"World J Gastroenterol. 4. 388-391 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshikawa M, et al.: "Intragastric administration of ursodeoxycholic acid suppresses immunoglobulin secretion by lymphocytes from liver, but not from peripheral blood, spleen or Peyer's patches in mice"Int J Immunopharmacol. 20. 29-38 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Analysis of Intrahepatic Invasion of Heparocellular Carcinoma Using Fluorescent Dye-Labeled Cells in Mice"Anticancer Res. 18. 4181-4188 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Bysstander Effect Caused by Cytosine Deaminase Gene and 5-Fluorocytosine in Vitro is Substantially Mediated by Generated 5-Fluorouracil"Anticancer Res. 18. 3399-3406 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshimatsu S, et al.: "Improvement of retroviral packaging cell lines by introducing the polyomavirus early region"Hum Gene Ther. 9. 161-172 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Koriyama S, et al: "Expression of a retrovirally transduced gene under control of an internal housekeeping gene promoter does not persist due to methyation and is restored partially by 5-azacytidine treatment"Gene Ther. 5. 1299-1305 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshiji H, et al: "Vascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells"Hepatology. 28. 1489-1496 (1998)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Antitumor effect of electrochemotherapy on colorectal carcinoma in an orthotopic mouse model"Int J Oncol. 14. 321-326 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Cytosine Deaminase/ 5-Fluorocytosine Gene Therapy can Induce Efficient Anti-Tumor Effects and Protective Immunity in Immunocompetent Mice but not in Athymic Nude Mice"Int J Cancer. 81. 592-597 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Comparison of Gene Therapy with the Herpes Simplex Virus Thymidine Kinase Gene and the Bacterial Cytosine Deaminase Gene for the Treatment of Hepatocellular Carcinoma"Soand J Gastroenterol. 34. 1033-1041 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Electrochemotherapy against colorecral carcinoma : comparison or in vitro cytotoxicity of 5-fluorouracil, cisplatin and bleomycin"Int J Oncol. 15. 89-94 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cao G, et al.: "In vivo gene transfer of a suicide gene under the transcriptional control of the carcinoembryonic antigen promoter results in bone marrow transduction but can avoid bone marrow suppression"Int J Oncol. 15. 107-112 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Sonographic Estimation of Liver Tumor Development Induced by Oral Administration of Thioacetamide in Rat"In Vivo. 13. 129-134 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Transient cyclophosphamide treatment before intraportal readministration of an adenoviral vector can induce re-expression of the original gene construct in rat liver"Gene Ther. 6. 749-75 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Complete cure of established murine hepatocellular carcinoma is achievable by repeated injections of retroviruses carrying the herpes simplex virus thymidine kinase gene"Gene Ther. 6. 525-533 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al: "Hepatocellular Carcinome in an Orthotopic Mouse Model Metastasizes Intrahepatically in Cirrhotic but not in Normal Liver"Int J Cancer. 80. 471-476

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cao G, et al.: "Effective and safe gene therapy for colorectal carcinoma using the cytosine deaminase gene derected by the carcinoembryonic antigen promoter"Gene Ther. 6. 83-90 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Cancer Gene Therapy with HSV-tk/ GCV System Depends on T-cell-Mediated Immune Responses and Causes Apoptotic Death of Tumor Cells in vivo"Int J Cancer. 83. 374-380 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshiji H, et al.: "Protein Kinase C Lies on the Signaling Pathway for Vascular Endothelial Growth Factor-mediated Tumor Development and Angiogenesis"Cancer Res. 59. 4413-4418 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshiji H, et al.: "KDR/Flk-1 is a major regulator or vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells"Hepatology. 30. 1179-1186 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cao G, et al: "Analysis of the human carcinoembryonic antigen promoter core region in colorectal carcinoma-selective cytosine deaminase gene therapy"Cancer Gene Ther. 6. 572-580 (1999)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Mitoro A, et al: "Electrochemotherapy with bleomycin against colorectal carcinoma in a mouse model : evaluatiions of the dose and administration route of the drug and the electric field intensity"Int J Oncol. 16. 97-104 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Immunomodulation with FK506 around the time of intravenous re-administration of an adenoviral vector facilitates gene transfer into primed rat liver"Int J Cancer. 85. 839-844 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cao G, et al.: "A Novel Approach for Inducing Enhanced and Selective Transgene Expression in Hepatocellular-Carcinoma Cells"Int J Cancer. 87. 247-252 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakatani T, et al.: "Assessment of efficiency and safety of adenovirus mediated gene transfer into normal and damaged murine livers"Gut. 47. 563-570 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Particle-mediated gene transfer into murine livers using a newly developed gene gun"Gene Ther. 7. 1132-1136 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Toyokawa Y, et al.: "Retrovirus-mediated in Vivo Gene Therapy Using Herpes Simplex Virus Thymidine Kinase Gene against Carcinomatous Peritonitis"Scand J Gastroenterol. 35. 852-860 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al: "Electrochemotherapy can eradicate established colorectal carcinoma and leaves a systemic protective memory in mice"Int J Oncol. 16. 979-985 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al: "Electrochemotherapy for Colorectal Cancer with Commonly Used Chemotherapeutic Agents in a Mouse Model"Dig Dis Sci. 45. 1568-1577 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshiji H, et al: "Tissue Inhibitor of Metalloproteinases-1 Promoters Liver Fibrosis Development in a Transgenic Mouse Model"Hepatology. 32. 1248-1254 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Tsujimoto T, et al: "Augmented hepatocellular carcinoma prgression and depressed Kupffer cell activity in rat cirrhotic liver"Int J Oncol. 18. 41-47 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nagao S, et al: "Adenovirus-mediated gene transfer into tumors : evaluation of direct readministration of an adenoviral vector into subcutaneous tumors of immunocornpetent mice"Int J Oncol. 18. 57-65 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Cao G, et al: "Gene therapy for hepatocellular carcinoma based on tumour-selective suicide gene expression using the alpha-fetoprotein (AFP) enhancer and a housekeeping gene promoter"Eur J Cancer. 37. 140-147 (2001)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuriyama S, et al.: "Molecular Target for Hematological Malignancies and Cancer"Kyushu University Press (Niho Y, ed.). 159 (2000)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Yoshiji H, et al.: "Vascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells."Hepatology. 28. 1489-1496 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Expression of a retrovirally transduced gene under control of an internal housekeeping gene promoter does not persist due to methylation and is restored partially by 5-azacytidine treatment."Gene Ther. 5. 1299-1305 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshimatsu T, et al.: "Improvement of retroviral packaging cell lines by introducing the polyomavirus early region."Hum Gene Ther. 9. 161-172 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Bystander effect caused by cytosine deaminase gene and 5-fluorocytosine in vitro is substantially mediated by generated 5-fluorouracil."Anticancer Res. 18. 3399-3406 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Analysis of intrahepatic invasion of hepatocellular carcinoma using fluorescent dye-labeled cells in mice."Anticancer Res. 18. 4181-4188 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshikawa M, et al.: "Intragastric administration of ursodeoxycholic acid suppresses immunoglobuli secretion by lymphocytes from liver, but not from peripheral blood, spleen or Peyer's patches in mice."Int J Immunopharmacol. 20. 29-38 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cao G, et al.: "Gene therapy for human colorectal carcinoma using human CEA promoter controlled bacterial ADP-ribosylating toxin genes : PEA and DTA gene transfer."World J Gastroentero. 14. 388-391 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cao G, et al.: "Comparison of carcinoembryonic antigen promoter regions isolated from human colorectal carcinoma and normal adjacent mucosa to induce strong tumor-selective gene expression."Int J Cancer. 78. 242-247 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Inhibitory effects of human sera on adenovirus-mediated gene transfer into rat liver."Anticancer Res. 18. 2345-2352 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cao G, et al.: "Analysis of the human carcinoembryonic antigen promoter core region in colorectal carcinoma-selective cytosine deaminase gene therapy."Cancer Gene Ther. 6. 572-580 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshiji H, et al.: "KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells."Hepatology. 30. 1179-1186 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshiji H, et al.: "Protein kinase C lies on the signaling pathway for vascular endothelial growth factor-mediated tumor development and angiogenesis."Cancer Res. 59. 4413-4418 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Cancer gene therapy with HSV-tk/GCV system depends on T-cell-mediated immune responses and causes apoptotic death of tumor cells in vivo."Int J Cancer. 83. 374-380 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cao G, et al.: "Effective and safe gene therapy for colorectal carcinoma using the cytosine deaminase gene directed by the carcinoembryonic antigen promoter."Gene Ther. 6. 83-90 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Hepatocellular carcinoma in an orthotopic mouse model metastasizes intrahepatically in cirrhotic but not in normal"Int J Cancer. 80. 471-476 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Complete cure of established murine hepatocellular carcinoma is achievable by repeated injections of retroviruses carrying the herpes simplex virus thymidine kinase"Gene Ther. 6. 525-533 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Transient cyclophosphamide treatment before intraportal readministration of an adenoviral vector can induce re-expression of the original gene construct in rat liver."Gene Ther. 6. 749-757 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Sonographic estimation of liver tumor developmen induced by oral administration of thioacetamide in rat."In Vivo. 13. 129-134 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cao G, et al.: "In vivo gene transfer of a suicide gene under the transcriptional control of the carcinoembryonic antigen promoter results in bone marrow transduction but can avoid bone marrow suppression."Int J Oncol. 15. 107-112 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Electrochemotherapy against colorectal carcinoma : comparison of in vitro cytotoxicity of 5-fluorouracil, cisplatin and bleomycin."Int J Oncol. 15. 89-94 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Comparison of gene therapy with the herpes simplex virus thymidine kinase gene and the bacterial cytosine"Scand J Gastroenterol. 34. 1033-1041 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Cytosine deaminase/5-fluorocytosine gene therapy can induce efficient anti-tumor effects and protective immunity in immunocompetent mice but not in athymic nude mice."Int J Cancer. 81. 592-597 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Antitumor effect of electrochemotherapy on colorectal carcinoma in an orthotopic mouse model."Int J Oncol. 14. 321-326 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Electrochemotherapy for colorectal cancer with commonly used chemotherapeutic agents in a mouse model."Dig Dis Sci. 45. 1568-1577 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Electrochemotherapy can eradicate established colorectal carcinoma and leaves a systemic protective memory in mice."Int J Oncol. 16. 979-985 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toyokawa Y, et al.: "Retrovirus-mediated in vivo gene therapy using the herpes simplex virus thymidine kinase gene against carcinomatous peritonitis."Scand J Gastroenterol. 35. 852-860 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Particle-mediated gene transfer into murine livers using a newly developedgene gun."Gene Ther. 7. 1132-1136 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakatani T, et al.: "Assessment of efficiency and safety of adenovirus-mediated gene transfer into normal and damaged murine livers."Gut. 47. 563-570 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cao G, et al.: "A novel approach for inducing enhanced and selective transgene expression in hepatocellular carcinoma cells."Int J Cancer. 87. 247-252 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "Immunomodulation with FK506 around the time of intravenous readministration of an adenoviral vector facilitates gene transfer into primed rat liver."Int J Cancer. 85. 839-844 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Mitoro A, et al.: "Electrochemotherapy with bleomycin against colorectal carcinoma in a mouse model : evaluations of the dose and administration route of the drug and the electric field intensity."Int J Oncol. 16. 97-104 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshiji H, et al.: "Tissue inhibitor of metalloproteinase-1 promotes liver fibrosis development in a transgenic mouse model."Hepatology. 32. 1249-1254 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nagao S, et al.: "Adenovirus-mediated gene transfer into tumors : evaluation of direct readministration of an adenoviral vector into subcutaneous tumors of immunocompetent mice."Int J Oncol. 18. 57-65 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsujimoto T, et al.: "Augmented hepatocellular carcinoma progression and depressed Kupffer cell activity in rat cirrhotic liver."Int J Oncol. 18. 41-47 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakatani Y, et al.: "Endotoxin clearance and its relation to hepatic and renal disturbances in rats with liver cirrhosis."Liver. 21. 64-70 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yoshikawa M, et al.: "Hepatic adenomas treated with percutaneous ethanol injection in a patient with glycogen storage disease type Ia."J Gastroenterol. 36. 52-61 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsujinoue H, et al.: "Intravenous readministration of an adenoviral vector performed long after the initial administration failed to induce re-expression of the original transgene in rats."Int J Oncol. 18. 575-580 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tsujinoue H, et al.: "Amelioration of retrovirus-mediated gene transfer into hepatocellular carcinoma cells"Int J Oncol. 18. 801-807 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Cao G, et al.: "Gene therapy for hepatocellular carcinoma based on tumor-selective suicide gene expression using the α-fetoprotein enhancer and housekeeping gene promotoer"Eur J Cancer. 37. 140-147 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuriyama S, et al.: "A potential approach for electrochemotherapy against colorectal carcinoma using a clinically available alternating current system with bipolar snare in a mouse model."Scand J Gastroenterol. (In press).

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2002-03-26  

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