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Volumn 10, Issue 4, 2010, Pages 540-545

Mitf silencing cooperates with IL-12 gene transfer to inhibit melanoma in mice

Author keywords

Electroporation; Immunotherapy; Interleukin 12; Melanoma; RNA interference

Indexed keywords

INTERLEUKIN 12; MELANIN; MICROPHTHALMIA ASSOCIATED TRANSCRIPTION FACTOR; SMALL INTERFERING RNA;

EID: 77949488331     PISSN: 15675769     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.intimp.2009.12.015     Document Type: Article
Times cited : (10)

References (46)
  • 1
    • 66149090765 scopus 로고    scopus 로고
    • Molecular pathogenesis of cutaneous melanocytic neoplasms
    • Ibrahim N., and Haluska F.G. Molecular pathogenesis of cutaneous melanocytic neoplasms. Annu Rev Pathol 4 (2009) 551-579
    • (2009) Annu Rev Pathol , vol.4 , pp. 551-579
    • Ibrahim, N.1    Haluska, F.G.2
  • 2
    • 33847615238 scopus 로고    scopus 로고
    • Dendritic cell-based immunotherapy of malignant melanoma: success and limitations
    • Tuettenberg A., Schmitt E., Knop J., and Jonuleit H. Dendritic cell-based immunotherapy of malignant melanoma: success and limitations. J Dtsch Dermatol Ges 5 (2007) 190-196
    • (2007) J Dtsch Dermatol Ges , vol.5 , pp. 190-196
    • Tuettenberg, A.1    Schmitt, E.2    Knop, J.3    Jonuleit, H.4
  • 3
    • 58149183897 scopus 로고    scopus 로고
    • Evaluation of survival in Japanese stage IV melanoma patients treated with melanoma antigen-pulsed mature monocyte-derived dendritic cells
    • Nakai N., Katoh N., Kitagawa T., Ueda E., Takenaka H., and Kishimoto S. Evaluation of survival in Japanese stage IV melanoma patients treated with melanoma antigen-pulsed mature monocyte-derived dendritic cells. J Dermatol 35 (2008) 801-803
    • (2008) J Dermatol , vol.35 , pp. 801-803
    • Nakai, N.1    Katoh, N.2    Kitagawa, T.3    Ueda, E.4    Takenaka, H.5    Kishimoto, S.6
  • 5
    • 34548212430 scopus 로고    scopus 로고
    • MiT transcription factor associated malignancies in man
    • Davis I., and Fisher D.E. MiT transcription factor associated malignancies in man. Cell Cycle 6 (2007) 1724-1729
    • (2007) Cell Cycle , vol.6 , pp. 1724-1729
    • Davis, I.1    Fisher, D.E.2
  • 6
    • 65749085328 scopus 로고    scopus 로고
    • Transcriptional regulation in melanoma
    • viii
    • Mitra D., and Fisher D.E. Transcriptional regulation in melanoma. Hematol Oncol Clin North Am 23 (2009) 447-465 viii
    • (2009) Hematol Oncol Clin North Am , vol.23 , pp. 447-465
    • Mitra, D.1    Fisher, D.E.2
  • 7
    • 18444418797 scopus 로고    scopus 로고
    • Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability
    • McGill G.G., Horstmann M., Widlund H.R., Du J., Motyckova G., Nishimura E.K., et al. Bcl2 regulation by the melanocyte master regulator Mitf modulates lineage survival and melanoma cell viability. Cell 109 (2002) 707-718
    • (2002) Cell , vol.109 , pp. 707-718
    • McGill, G.G.1    Horstmann, M.2    Widlund, H.R.3    Du, J.4    Motyckova, G.5    Nishimura, E.K.6
  • 8
    • 33744531154 scopus 로고    scopus 로고
    • c-Met expression is regulated by Mitf in the melanocyte lineage
    • McGill G.G., Haq R., Nishimura E.K., and Fisher D.E. c-Met expression is regulated by Mitf in the melanocyte lineage. J Biol Chem 281 (2006) 10365-10373
    • (2006) J Biol Chem , vol.281 , pp. 10365-10373
    • McGill, G.G.1    Haq, R.2    Nishimura, E.K.3    Fisher, D.E.4
  • 9
    • 10944228764 scopus 로고    scopus 로고
    • Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF
    • Du J., Widlund H.R., Horstmann M.A., Ramaswamy S., Ross K., Huber W.E., et al. Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF. Cancer Cell 6 (2004) 565-576
    • (2004) Cancer Cell , vol.6 , pp. 565-576
    • Du, J.1    Widlund, H.R.2    Horstmann, M.A.3    Ramaswamy, S.4    Ross, K.5    Huber, W.E.6
  • 10
    • 21844478747 scopus 로고    scopus 로고
    • Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma
    • Garraway L.A., Widlund H.R., Rubin M.A., Getz G., Berger A.J., Ramaswamy S., et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436 (2005) 117-122
    • (2005) Nature , vol.436 , pp. 117-122
    • Garraway, L.A.1    Widlund, H.R.2    Rubin, M.A.3    Getz, G.4    Berger, A.J.5    Ramaswamy, S.6
  • 11
    • 22244467409 scopus 로고    scopus 로고
    • Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells
    • Busca R., Berra E., Gaggioli C., Khaled M., Bille K., Marchetti B., et al. Hypoxia-inducible factor 1{alpha} is a new target of microphthalmia-associated transcription factor (MITF) in melanoma cells. J Cell Biol 170 (2005) 49-59
    • (2005) J Cell Biol , vol.170 , pp. 49-59
    • Busca, R.1    Berra, E.2    Gaggioli, C.3    Khaled, M.4    Bille, K.5    Marchetti, B.6
  • 12
    • 16844387097 scopus 로고    scopus 로고
    • Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas
    • Vance K.W., Carreira S., Brosch G., and Goding C.R. Tbx2 is overexpressed and plays an important role in maintaining proliferation and suppression of senescence in melanomas. Cancer Res 65 (2005) 2260-2268
    • (2005) Cancer Res , vol.65 , pp. 2260-2268
    • Vance, K.W.1    Carreira, S.2    Brosch, G.3    Goding, C.R.4
  • 13
    • 13944273767 scopus 로고    scopus 로고
    • Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression
    • Carreira S., Goodall J., Aksan I., La Rocca S.A., Galibert M.D., Denat L., et al. Mitf cooperates with Rb1 and activates p21Cip1 expression to regulate cell cycle progression. Nature 433 (2005) 764-769
    • (2005) Nature , vol.433 , pp. 764-769
    • Carreira, S.1    Goodall, J.2    Aksan, I.3    La Rocca, S.A.4    Galibert, M.D.5    Denat, L.6
  • 14
    • 12144254034 scopus 로고    scopus 로고
    • MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A
    • Loercher A.E., Tank E.M., Delston R.B., and Harbour J.W. MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A. J Cell Biol 168 (2005) 35-40
    • (2005) J Cell Biol , vol.168 , pp. 35-40
    • Loercher, A.E.1    Tank, E.M.2    Delston, R.B.3    Harbour, J.W.4
  • 15
    • 0036531955 scopus 로고    scopus 로고
    • The melanocyte-specific isoform of the microphthalmia transcription factor affects the phenotype of human melanoma
    • Selzer E., Wacheck V., Lucas T., Heere-Ress E., Wu M., Weilbaecher K.N., et al. The melanocyte-specific isoform of the microphthalmia transcription factor affects the phenotype of human melanoma. Cancer Res 62 (2002) 2098-2103
    • (2002) Cancer Res , vol.62 , pp. 2098-2103
    • Selzer, E.1    Wacheck, V.2    Lucas, T.3    Heere-Ress, E.4    Wu, M.5    Weilbaecher, K.N.6
  • 16
    • 24144477947 scopus 로고    scopus 로고
    • Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation
    • Wellbrock C., and Marais R. Elevated expression of MITF counteracts B-RAF-stimulated melanocyte and melanoma cell proliferation. J Cell Biol 170 (2005) 703-708
    • (2005) J Cell Biol , vol.170 , pp. 703-708
    • Wellbrock, C.1    Marais, R.2
  • 17
    • 24344443229 scopus 로고    scopus 로고
    • The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis
    • Larribere L., Hilmi C., Khaled M., Gaggioli C., Bille K., Auberger P., et al. The cleavage of microphthalmia-associated transcription factor, MITF, by caspases plays an essential role in melanocyte and melanoma cell apoptosis. Genes Dev 19 (2005) 1980-1985
    • (2005) Genes Dev , vol.19 , pp. 1980-1985
    • Larribere, L.1    Hilmi, C.2    Khaled, M.3    Gaggioli, C.4    Bille, K.5    Auberger, P.6
  • 18
    • 33846929162 scopus 로고    scopus 로고
    • Therapeutic RNA interference of malignant melanoma by electrotransfer of small interfering RNA targeting Mitf
    • Nakai N., Kishida T., Shin-Ya M., Imanishi J., Ueda Y., Kishimoto S., et al. Therapeutic RNA interference of malignant melanoma by electrotransfer of small interfering RNA targeting Mitf. Gene Ther 14 (2007) 357-365
    • (2007) Gene Ther , vol.14 , pp. 357-365
    • Nakai, N.1    Kishida, T.2    Shin-Ya, M.3    Imanishi, J.4    Ueda, Y.5    Kishimoto, S.6
  • 20
    • 45449098667 scopus 로고    scopus 로고
    • Antitumor mechanism of intratumoral injection with IL-12-expressing adenoviral vector against IL-12-unresponsive tumor
    • Kanagawa N., Gao J.Q., Motomura Y., Yanagawa T., Mukai Y., Yoshioka Y., et al. Antitumor mechanism of intratumoral injection with IL-12-expressing adenoviral vector against IL-12-unresponsive tumor. Biochem Biophys Res Commun 372 (2008) 821-825
    • (2008) Biochem Biophys Res Commun , vol.372 , pp. 821-825
    • Kanagawa, N.1    Gao, J.Q.2    Motomura, Y.3    Yanagawa, T.4    Mukai, Y.5    Yoshioka, Y.6
  • 22
    • 0035869599 scopus 로고    scopus 로고
    • IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk
    • Strasly M., Cavallo F., Geuna M., Mitola S., Colombo M.P., Forni G., et al. IL-12 inhibition of endothelial cell functions and angiogenesis depends on lymphocyte-endothelial cell cross-talk. J Immunol 166 (2001) 3890-3899
    • (2001) J Immunol , vol.166 , pp. 3890-3899
    • Strasly, M.1    Cavallo, F.2    Geuna, M.3    Mitola, S.4    Colombo, M.P.5    Forni, G.6
  • 23
    • 0033104852 scopus 로고    scopus 로고
    • Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12
    • Yao L., Sgadari C., Furuke K., Bloom E.T., Teruya-Feldstein J., and Tosato G. Contribution of natural killer cells to inhibition of angiogenesis by interleukin-12. Blood 93 (1999) 1612-1621
    • (1999) Blood , vol.93 , pp. 1612-1621
    • Yao, L.1    Sgadari, C.2    Furuke, K.3    Bloom, E.T.4    Teruya-Feldstein, J.5    Tosato, G.6
  • 24
    • 17944369209 scopus 로고    scopus 로고
    • In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice
    • Kishida T., Asada H., Satoh E., Tanaka S., Shinya M., Hirai H., et al. In vivo electroporation-mediated transfer of interleukin-12 and interleukin-18 genes induces significant antitumor effects against melanoma in mice. Gene Ther 8 (2001) 1234-1240
    • (2001) Gene Ther , vol.8 , pp. 1234-1240
    • Kishida, T.1    Asada, H.2    Satoh, E.3    Tanaka, S.4    Shinya, M.5    Hirai, H.6
  • 25
    • 0035870252 scopus 로고    scopus 로고
    • Effective tumor therapy with plasmid-encoded cytokines combined with in vivo electroporation
    • Lohr F., Lo D.Y., D.A. Z., Hu K., Zhang X., Li Y., et al. Effective tumor therapy with plasmid-encoded cytokines combined with in vivo electroporation. Cancer Res 61 (2001) 3281-3284
    • (2001) Cancer Res , vol.61 , pp. 3281-3284
    • Lohr, F.1    Lo, D.Y.2    D.A., Z.3    Hu, K.4    Zhang, X.5    Li, Y.6
  • 26
    • 0036594813 scopus 로고    scopus 로고
    • IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma
    • Lucas M.L., Heller L., Coppola D., and Heller R. IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma. Mol Ther 5 (2002) 668-6675
    • (2002) Mol Ther , vol.5 , pp. 668-6675
    • Lucas, M.L.1    Heller, L.2    Coppola, D.3    Heller, R.4
  • 27
    • 0035110705 scopus 로고    scopus 로고
    • Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model
    • Yamashita Y.I., Shimada M., Hasegawa H., Minagawa R., Rikimaru T., Hamatsu T., et al. Electroporation-mediated interleukin-12 gene therapy for hepatocellular carcinoma in the mice model. Cancer Res 61 (2001) 1005-1012
    • (2001) Cancer Res , vol.61 , pp. 1005-1012
    • Yamashita, Y.I.1    Shimada, M.2    Hasegawa, H.3    Minagawa, R.4    Rikimaru, T.5    Hamatsu, T.6
  • 28
    • 0034926533 scopus 로고    scopus 로고
    • Intratumoral delivery of interleukin 12 expression plasmids with in vivo electroporation is effective for colon and renal cancer
    • Tamura T., Nishi T., Goto T., Takeshima H., Dev S.B., Ushio Y., et al. Intratumoral delivery of interleukin 12 expression plasmids with in vivo electroporation is effective for colon and renal cancer. Hum Gene Ther 12 (2001) 1265-1276
    • (2001) Hum Gene Ther , vol.12 , pp. 1265-1276
    • Tamura, T.1    Nishi, T.2    Goto, T.3    Takeshima, H.4    Dev, S.B.5    Ushio, Y.6
  • 29
    • 0346732375 scopus 로고    scopus 로고
    • IL-12 gene therapy using an electrically mediated nonviral approach reduces metastatic growth of melanoma
    • Lucas M.L., and Heller R. IL-12 gene therapy using an electrically mediated nonviral approach reduces metastatic growth of melanoma. DNA Cell Biol 22 (2003) 755-763
    • (2003) DNA Cell Biol , vol.22 , pp. 755-763
    • Lucas, M.L.1    Heller, R.2
  • 30
    • 77949490670 scopus 로고    scopus 로고
    • Etoposide plus cisplatin followed by concurrent chemo-radiotherapy and irinotecan plus cisplatin for patients with limited-stage small cell lung cancer. A multicenter phase II study
    • Xenidis N., Kotsakis A., Kalykaki A., Christophyllakis C., Giassas S., Kentepozidis N., et al. Etoposide plus cisplatin followed by concurrent chemo-radiotherapy and irinotecan plus cisplatin for patients with limited-stage small cell lung cancer. A multicenter phase II study. Lung Cancer (2009)
    • (2009) Lung Cancer
    • Xenidis, N.1    Kotsakis, A.2    Kalykaki, A.3    Christophyllakis, C.4    Giassas, S.5    Kentepozidis, N.6
  • 31
    • 2942683157 scopus 로고    scopus 로고
    • Combined local bladder hyperthermia and intravesical chemotherapy for the treatment of high-grade superficial bladder cancer
    • Gofrit O.N., Shapiro A., Pode D., Sidi A., Nativ O., Leib Z., et al. Combined local bladder hyperthermia and intravesical chemotherapy for the treatment of high-grade superficial bladder cancer. Urology 63 (2004) 466-471
    • (2004) Urology , vol.63 , pp. 466-471
    • Gofrit, O.N.1    Shapiro, A.2    Pode, D.3    Sidi, A.4    Nativ, O.5    Leib, Z.6
  • 32
    • 1942494048 scopus 로고    scopus 로고
    • Sequence-specific gene silencing in murine muscle induced by electroporation-mediated transfer of short interfering RNA
    • Kishida T., Asada H., Gojo S., Ohashi S., Shin-Ya M., Yasutomi K., et al. Sequence-specific gene silencing in murine muscle induced by electroporation-mediated transfer of short interfering RNA. J Gene Med 6 (2004) 105-110
    • (2004) J Gene Med , vol.6 , pp. 105-110
    • Kishida, T.1    Asada, H.2    Gojo, S.3    Ohashi, S.4    Shin-Ya, M.5    Yasutomi, K.6
  • 33
    • 0033019078 scopus 로고    scopus 로고
    • Potent antitumor effects mediated by local expression of the mature form of the interferon-gamma inducing factor, interleukin-18 (IL-18)
    • Osaki T., Hashimoto W., Gambotto A., Okamura H., Robbins P.D., Kurimoto M., et al. Potent antitumor effects mediated by local expression of the mature form of the interferon-gamma inducing factor, interleukin-18 (IL-18). Gene Ther 6 (1999) 808-815
    • (1999) Gene Ther , vol.6 , pp. 808-815
    • Osaki, T.1    Hashimoto, W.2    Gambotto, A.3    Okamura, H.4    Robbins, P.D.5    Kurimoto, M.6
  • 34
    • 0025884056 scopus 로고
    • Efficient selection for high-expression transfectants with a novel eukaryotic vector
    • Niwa H., Yamamura K., and Miyazaki J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108 (1991) 193-199
    • (1991) Gene , vol.108 , pp. 193-199
    • Niwa, H.1    Yamamura, K.2    Miyazaki, J.3
  • 35
    • 0021988550 scopus 로고
    • Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells
    • Yates J.L., Waren N., and Sugden B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature 313 (1985) 812-815
    • (1985) Nature , vol.313 , pp. 812-815
    • Yates, J.L.1    Waren, N.2    Sugden, B.3
  • 36
    • 0036099019 scopus 로고    scopus 로고
    • Significant antitumor effects obtained by autologous tumor cell vaccine engineered to secrete interleukin (IL)-12 and IL-18 by means of the EBV/lipoplex
    • Asada H., Kishida T., Hirai H., Satoh E., Ohashi S., Takeuchi M., et al. Significant antitumor effects obtained by autologous tumor cell vaccine engineered to secrete interleukin (IL)-12 and IL-18 by means of the EBV/lipoplex. Mol Ther 5 (2002) 609-616
    • (2002) Mol Ther , vol.5 , pp. 609-616
    • Asada, H.1    Kishida, T.2    Hirai, H.3    Satoh, E.4    Ohashi, S.5    Takeuchi, M.6
  • 37
    • 33745870451 scopus 로고    scopus 로고
    • Combination vaccine of dendritic cells (DCs) and T cells effectively suppressed preestablished malignant melanoma in mice
    • Asada H., Kishida T., Hirai H., Shin-Ya M., Imanishi J., Takeuchi M., et al. Combination vaccine of dendritic cells (DCs) and T cells effectively suppressed preestablished malignant melanoma in mice. Cancer Lett 240 (2006) 83-93
    • (2006) Cancer Lett , vol.240 , pp. 83-93
    • Asada, H.1    Kishida, T.2    Hirai, H.3    Shin-Ya, M.4    Imanishi, J.5    Takeuchi, M.6
  • 38
    • 33747882661 scopus 로고    scopus 로고
    • MITF: master regulator of melanocyte development and melanoma oncogene
    • Levy C., Khaled M., and Fisher D.E. MITF: master regulator of melanocyte development and melanoma oncogene. Trends Mol Med 12 (2006) 406-414
    • (2006) Trends Mol Med , vol.12 , pp. 406-414
    • Levy, C.1    Khaled, M.2    Fisher, D.E.3
  • 39
    • 58749104364 scopus 로고    scopus 로고
    • The promises and pitfalls of RNA-interference-based therapeutics
    • Castanotto D., and Rossi J.J. The promises and pitfalls of RNA-interference-based therapeutics. Nature 457 (2009) 426-433
    • (2009) Nature , vol.457 , pp. 426-433
    • Castanotto, D.1    Rossi, J.J.2
  • 40
    • 5444270495 scopus 로고    scopus 로고
    • DNA electrotransfer: its principles and an updated review of its therapeutic applications
    • Andre F., and Mir L.M. DNA electrotransfer: its principles and an updated review of its therapeutic applications. Gene Ther 11 Suppl 1 (2004) S33-S42
    • (2004) Gene Ther , vol.11 , Issue.SUPPL. 1
    • Andre, F.1    Mir, L.M.2
  • 42
    • 10744223089 scopus 로고    scopus 로고
    • Electrochemo-gene therapy of cancer: intratumoral delivery of interleukin-12 gene and bleomycin synergistically induced therapeutic immunity and suppressed subcutaneous and metastatic melanomas in mice
    • Kishida T., Asada H., Itokawa Y., Yasutomi K., Shin-Ya M., Gojo S., et al. Electrochemo-gene therapy of cancer: intratumoral delivery of interleukin-12 gene and bleomycin synergistically induced therapeutic immunity and suppressed subcutaneous and metastatic melanomas in mice. Mol Ther 8 (2003) 738-745
    • (2003) Mol Ther , vol.8 , pp. 738-745
    • Kishida, T.1    Asada, H.2    Itokawa, Y.3    Yasutomi, K.4    Shin-Ya, M.5    Gojo, S.6
  • 44
    • 64449085111 scopus 로고    scopus 로고
    • Comparison of anti-rheumatic effects of local RNAi-based therapy in collagen induced arthritis rats using various cytokine genes as molecular targets
    • Inoue A., Takahashi K.A., Mazda O., Arai Y., Saito M., Kishida T., et al. Comparison of anti-rheumatic effects of local RNAi-based therapy in collagen induced arthritis rats using various cytokine genes as molecular targets. Mod Rheumatol 19 (2009) 125-133
    • (2009) Mod Rheumatol , vol.19 , pp. 125-133
    • Inoue, A.1    Takahashi, K.A.2    Mazda, O.3    Arai, Y.4    Saito, M.5    Kishida, T.6
  • 45
    • 70349650031 scopus 로고    scopus 로고
    • Electrochemotherapy of tumours
    • Sersa G., Cemazar M., and Snoj M. Electrochemotherapy of tumours. Curr Oncol 16 (2009) 34-35
    • (2009) Curr Oncol , vol.16 , pp. 34-35
    • Sersa, G.1    Cemazar, M.2    Snoj, M.3
  • 46
    • 58049200809 scopus 로고    scopus 로고
    • Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma
    • Daud A.I., DeConti R.C., Andrews S., Urbas P., Riker A.I., Sondak V.K., et al. Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Oncol 26 (2008) 5896-5903
    • (2008) J Clin Oncol , vol.26 , pp. 5896-5903
    • Daud, A.I.1    DeConti, R.C.2    Andrews, S.3    Urbas, P.4    Riker, A.I.5    Sondak, V.K.6


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