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Volumn 10, Issue , 2010, Pages

Effect of troglitazone on tumor growth and pulmonary metastasis development of the mouse osteosarcoma cell line LM8

Author keywords

[No Author keywords available]

Indexed keywords

ALCOHOL; BROXURIDINE; CD34 ANTIGEN; DNA; GELATINASE A; MATRIGEL; PROTEIN KINASE B; TROGLITAZONE; 2,4 THIAZOLIDINEDIONE DERIVATIVE; ANTIDIABETIC AGENT; CHROMAN DERIVATIVE;

EID: 77649290013     PISSN: None     EISSN: 14712407     Source Type: Journal    
DOI: 10.1186/1471-2407-10-51     Document Type: Article
Times cited : (9)

References (38)
  • 2
    • 0029731662 scopus 로고    scopus 로고
    • Peroxisome prolifarator-activated receptors: a nuclear receptor signaling pathway in lipid physiology
    • 10.1146/annurev.cellbio.12.1.335, 8970730
    • Lemberger T, Desvergne B, Wahli W. Peroxisome prolifarator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annu Rev Cell Dev Biol 1996, 12:335-363. 10.1146/annurev.cellbio.12.1.335, 8970730.
    • (1996) Annu Rev Cell Dev Biol , vol.12 , pp. 335-363
    • Lemberger, T.1    Desvergne, B.2    Wahli, W.3
  • 3
    • 0030297919 scopus 로고    scopus 로고
    • Adipogenesis and obesity: rounding out the big picture
    • 10.1016/S0092-8674(00)81359-8, 8898192
    • Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell 1996, 87:377-389. 10.1016/S0092-8674(00)81359-8, 8898192.
    • (1996) Cell , vol.87 , pp. 377-389
    • Spiegelman, B.M.1    Flier, J.S.2
  • 6
    • 0032555196 scopus 로고    scopus 로고
    • Ligands for peroxisome proliferator-activated receptor γ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice
    • 10.1073/pnas.95.15.8806, 21158, 9671760
    • Elstner E, Müller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP. Ligands for peroxisome proliferator-activated receptor γ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci USA 1998, 95:8806-8811. 10.1073/pnas.95.15.8806, 21158, 9671760.
    • (1998) Proc Natl Acad Sci USA , vol.95 , pp. 8806-8811
    • Elstner, E.1    Müller, C.2    Koshizuka, K.3    Williamson, E.A.4    Park, D.5    Asou, H.6    Shintaku, P.7    Said, J.W.8    Heber, D.9    Koeffler, H.P.10
  • 7
    • 0037235020 scopus 로고    scopus 로고
    • Peroxisome proliferator-activated receptor γ and cancers
    • Koeffler HP. Peroxisome proliferator-activated receptor γ and cancers. Clin Cancer Res 2003, 9:1-9.
    • (2003) Clin Cancer Res , vol.9 , pp. 1-9
    • Koeffler, H.P.1
  • 8
    • 33847106393 scopus 로고    scopus 로고
    • PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma
    • 10.1186/1471-2407-6-53, 1450298, 16519808
    • Chaffer CL, Thomas DM, Thompson EW, Williams ED. PPARγ-independent induction of growth arrest and apoptosis in prostate and bladder carcinoma. BMC Cancer 2006, 6:53. 10.1186/1471-2407-6-53, 1450298, 16519808.
    • (2006) BMC Cancer , vol.6 , pp. 53
    • Chaffer, C.L.1    Thomas, D.M.2    Thompson, E.W.3    Williams, E.D.4
  • 9
    • 41149138254 scopus 로고    scopus 로고
    • Rosiglitazone inhibits metastasis development of a murine mammary tumor cell line LMM3
    • 10.1186/1471-2407-8-47, 2268944, 18261208
    • Magenta G, Borenstein X, Rolando R, Jasnis MA. Rosiglitazone inhibits metastasis development of a murine mammary tumor cell line LMM3. BMC Cancer 2008, 8:47. 10.1186/1471-2407-8-47, 2268944, 18261208.
    • (2008) BMC Cancer , vol.8 , pp. 47
    • Magenta, G.1    Borenstein, X.2    Rolando, R.3    Jasnis, M.A.4
  • 10
    • 0032727659 scopus 로고    scopus 로고
    • Thiazolidinediones: a new class of antidiabetic drugs
    • 10.1046/j.1464-5491.1999.00023.x, 10227562
    • Day C. Thiazolidinediones: a new class of antidiabetic drugs. Diabet Med 1999, 16:179-192. 10.1046/j.1464-5491.1999.00023.x, 10227562.
    • (1999) Diabet Med , vol.16 , pp. 179-192
    • Day, C.1
  • 11
    • 0035033404 scopus 로고    scopus 로고
    • Current treatment of osteosarcoma
    • 10.1081/CNV-100102557, 11338887
    • Ferguson WS, Goorin AM. Current treatment of osteosarcoma. Cancer Invest 2001, 19:292-315. 10.1081/CNV-100102557, 11338887.
    • (2001) Cancer Invest , vol.19 , pp. 292-315
    • Ferguson, W.S.1    Goorin, A.M.2
  • 12
    • 0033592538 scopus 로고    scopus 로고
    • Cancer Biology: extracellular proteinases in malignancy
    • 10.1016/S0960-9822(00)80011-1, 10531025
    • Matrisian LM. Cancer Biology: extracellular proteinases in malignancy. Curr Biol 1999, 9:R776-R778. 10.1016/S0960-9822(00)80011-1, 10531025.
    • (1999) Curr Biol , vol.9
    • Matrisian, L.M.1
  • 13
    • 0033021566 scopus 로고    scopus 로고
    • Matrix metalloproteinases and metastasis
    • 10.1007/s002800051097, 10357558
    • Kleiner DE, Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 1999, 43(Suppl):S42-S51. 10.1007/s002800051097, 10357558.
    • (1999) Cancer Chemother Pharmacol , vol.43 , Issue.SUPPL.
    • Kleiner, D.E.1    Stetler-Stevenson, W.G.2
  • 15
    • 36949011202 scopus 로고    scopus 로고
    • High VEGF with rapid growth and early metastasis in a mouse osteosarcoma model
    • 10.1155/2007/95628, 2225469, 18274612
    • Yang S-Y, Yu H, Krygier JE, Wooley PH, Mott MP. High VEGF with rapid growth and early metastasis in a mouse osteosarcoma model. Sarcoma 2007, 2007:95628. 10.1155/2007/95628, 2225469, 18274612.
    • (2007) Sarcoma , vol.2007 , pp. 95628
    • Yang, S.-.Y.1    Yu, H.2    Krygier, J.E.3    Wooley, P.H.4    Mott, M.P.5
  • 16
    • 0031776414 scopus 로고    scopus 로고
    • Establishment and characterization of a murine osteosarcoma cell line (LM8) with high metastatic potential to the lung
    • 10.1002/(SICI)1097-0215(19980504)76:3<418::AID-IJC21>3.0.CO;2-5, 9579581
    • Asai T, Ueda T, Itoh K, Yoshioka K, Aoki Y, Mori S, Yoshikawa H. Establishment and characterization of a murine osteosarcoma cell line (LM8) with high metastatic potential to the lung. Int J Cancer 1998, 76:418-422. 10.1002/(SICI)1097-0215(19980504)76:3<418::AID-IJC21>3.0.CO;2-5, 9579581.
    • (1998) Int J Cancer , vol.76 , pp. 418-422
    • Asai, T.1    Ueda, T.2    Itoh, K.3    Yoshioka, K.4    Aoki, Y.5    Mori, S.6    Yoshikawa, H.7
  • 17
    • 67649600831 scopus 로고    scopus 로고
    • Ketoprofen in topical formulation decreases the matrix metalloproteinase-2 expression and pulmonary metastatic incidence in nude mice with osteosarcoma
    • 10.1002/jor.20832, 19105229
    • Kamei S, Sakayama K, Tamashiro S, Aizawa J, Miyawaki J, Miyazaki T, Yamamoto H, Norimatsu Y, Masuno H. Ketoprofen in topical formulation decreases the matrix metalloproteinase-2 expression and pulmonary metastatic incidence in nude mice with osteosarcoma. J Orthop Res 2009, 27:909-915. 10.1002/jor.20832, 19105229.
    • (2009) J Orthop Res , vol.27 , pp. 909-915
    • Kamei, S.1    Sakayama, K.2    Tamashiro, S.3    Aizawa, J.4    Miyawaki, J.5    Miyazaki, T.6    Yamamoto, H.7    Norimatsu, Y.8    Masuno, H.9
  • 19
    • 0014978068 scopus 로고
    • An improved fluorometric assay for DNA
    • 10.1016/0003-2697(71)90476-3, 5544593
    • Hinegardner RT. An improved fluorometric assay for DNA. Anal Biochem 1971, 39:197-201. 10.1016/0003-2697(71)90476-3, 5544593.
    • (1971) Anal Biochem , vol.39 , pp. 197-201
    • Hinegardner, R.T.1
  • 20
    • 0141618461 scopus 로고    scopus 로고
    • Effect of 4-nonylphenol on cell proliferation and adipocyte formation in cultures of fully differentiated 3T3-L1 cells
    • 10.1093/toxsci/kfg203, 12883076
    • Masuno H, Okamoto S, Iwanami J, Honda K, Shiosaka T, Kidani T, Sakayama K, Yamamoto H. Effect of 4-nonylphenol on cell proliferation and adipocyte formation in cultures of fully differentiated 3T3-L1 cells. Toxicol Sci 2003, 75:314-320. 10.1093/toxsci/kfg203, 12883076.
    • (2003) Toxicol Sci , vol.75 , pp. 314-320
    • Masuno, H.1    Okamoto, S.2    Iwanami, J.3    Honda, K.4    Shiosaka, T.5    Kidani, T.6    Sakayama, K.7    Yamamoto, H.8
  • 21
    • 17444394007 scopus 로고    scopus 로고
    • Bisphenol A accelerates terminal differentiation of 3T3-L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway
    • 10.1093/toxsci/kfi088, 15659569
    • Masuno H, Iwanami J, Kidani T, Sakayama K, Honda K. Bisphenol A accelerates terminal differentiation of 3T3-L1 cells into adipocytes through the phosphatidylinositol 3-kinase pathway. Toxicol Sci 2005, 84:319-327. 10.1093/toxsci/kfi088, 15659569.
    • (2005) Toxicol Sci , vol.84 , pp. 319-327
    • Masuno, H.1    Iwanami, J.2    Kidani, T.3    Sakayama, K.4    Honda, K.5
  • 22
    • 33845711007 scopus 로고    scopus 로고
    • PPARγ inhibitors reduce tubulin protein levels by a PPARγ, PPARδ and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells
    • 10.1002/ijc.22361, 17096328
    • Schaefer KL, Takahashi H, Morales VM, Harris G, Barton S, Osawa E, Nakajima A, Saubermann LJ. PPARγ inhibitors reduce tubulin protein levels by a PPARγ, PPARδ and proteasome-independent mechanism, resulting in cell cycle arrest, apoptosis and reduced metastasis of colorectal carcinoma cells. Int J Cancer 2007, 120:702-713. 10.1002/ijc.22361, 17096328.
    • (2007) Int J Cancer , vol.120 , pp. 702-713
    • Schaefer, K.L.1    Takahashi, H.2    Morales, V.M.3    Harris, G.4    Barton, S.5    Osawa, E.6    Nakajima, A.7    Saubermann, L.J.8
  • 23
    • 0010697057 scopus 로고
    • Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase
    • 10.1073/pnas.82.10.3262, 397755, 2860667
    • Celis JE, Celis A. Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. Proc Natl Acad Sci USA 1985, 82:3262-3266. 10.1073/pnas.82.10.3262, 397755, 2860667.
    • (1985) Proc Natl Acad Sci USA , vol.82 , pp. 3262-3266
    • Celis, J.E.1    Celis, A.2
  • 24
    • 0023272510 scopus 로고
    • Immunohistochemical detection of proliferating cell nuclear antigen in solid human malignancies
    • Robbins BA, de la Vega D, Ogata K, Tan EM, Nakamura RM. Immunohistochemical detection of proliferating cell nuclear antigen in solid human malignancies. Arch Pathol Lab Med 1987, 111:841-845.
    • (1987) Arch Pathol Lab Med , vol.111 , pp. 841-845
    • Robbins, B.A.1    de la Vega, D.2    Ogata, K.3    Tan, E.M.4    Nakamura, R.M.5
  • 25
    • 4844231455 scopus 로고    scopus 로고
    • Effect of ketoprofen in topical formulation on vascular endothelial growth factor expression and tumor growth in nude mice with osteosarcoma
    • 10.1016/j.orthres.2004.03.015, 15475193
    • Sakayama K, Kidani T, Miyazaki T, Shirakata H, Kimura Y, Kamogawa J, Masuno H, Yamamoto H. Effect of ketoprofen in topical formulation on vascular endothelial growth factor expression and tumor growth in nude mice with osteosarcoma. J Orthop Res 2004, 22:1168-1174. 10.1016/j.orthres.2004.03.015, 15475193.
    • (2004) J Orthop Res , vol.22 , pp. 1168-1174
    • Sakayama, K.1    Kidani, T.2    Miyazaki, T.3    Shirakata, H.4    Kimura, Y.5    Kamogawa, J.6    Masuno, H.7    Yamamoto, H.8
  • 26
    • 0036500250 scopus 로고    scopus 로고
    • Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion
    • 10.1002/cncr.10355, 11920503
    • Di Nezza LA, Misajon A, Zhang J, Jobling T, Quinn MA, Östör AG, Nie G, Lopata A, Salamonsen LA. Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion. Cancer 2002, 94:1466-1475. 10.1002/cncr.10355, 11920503.
    • (2002) Cancer , vol.94 , pp. 1466-1475
    • Di Nezza, L.A.1    Misajon, A.2    Zhang, J.3    Jobling, T.4    Quinn, M.A.5    Östör, A.G.6    Nie, G.7    Lopata, A.8    Salamonsen, L.A.9
  • 27
    • 0027197245 scopus 로고
    • Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo
    • 10.1038/362841a0, 7683111
    • Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993, 362:841-844. 10.1038/362841a0, 7683111.
    • (1993) Nature , vol.362 , pp. 841-844
    • Kim, K.J.1    Li, B.2    Winer, J.3    Armanini, M.4    Gillett, N.5    Phillips, H.S.6    Ferrara, N.7
  • 28
    • 6044243631 scopus 로고    scopus 로고
    • Troglitazone acts on cellular pH and DNA synthesis through a peroxisome proliferators-activated receptor gamma-independent mechanism in breast cancer-derived cell line
    • 10.1158/1078-0432.CCR-04-0879, 15501982
    • Turturro F, Friday E, Fowler R, Surie D, Welbourne T. Troglitazone acts on cellular pH and DNA synthesis through a peroxisome proliferators-activated receptor gamma-independent mechanism in breast cancer-derived cell line. Clin Cancer Res 2004, 10:7022-7030. 10.1158/1078-0432.CCR-04-0879, 15501982.
    • (2004) Clin Cancer Res , vol.10 , pp. 7022-7030
    • Turturro, F.1    Friday, E.2    Fowler, R.3    Surie, D.4    Welbourne, T.5
  • 29
    • 11244253710 scopus 로고    scopus 로고
    • GW9662, a potent antagonist of PPARγ, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARγ agonist rosiglitazone, independently of PPARγ activation
    • 10.1038/sj.bjp.0705973, 1575954, 15533890
    • Seargent JM, Yates EA, Gill JH. GW9662, a potent antagonist of PPARγ, inhibits growth of breast tumour cells and promotes the anticancer effects of the PPARγ agonist rosiglitazone, independently of PPARγ activation. Br J Pharmacol 2004, 143:933-937. 10.1038/sj.bjp.0705973, 1575954, 15533890.
    • (2004) Br J Pharmacol , vol.143 , pp. 933-937
    • Seargent, J.M.1    Yates, E.A.2    Gill, J.H.3
  • 30
    • 0037728809 scopus 로고    scopus 로고
    • The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines
    • Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, Donowitz M, Tsichlis PN, Larue L. The protein kinase Akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res 2003, 63:2172-2178.
    • (2003) Cancer Res , vol.63 , pp. 2172-2178
    • Grille, S.J.1    Bellacosa, A.2    Upson, J.3    Klein-Szanto, A.J.4    van Roy, F.5    Lee-Kwon, W.6    Donowitz, M.7    Tsichlis, P.N.8    Larue, L.9
  • 31
    • 0035863411 scopus 로고    scopus 로고
    • AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells
    • Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR. AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res 2001, 61:589-593.
    • (2001) Cancer Res , vol.61 , pp. 589-593
    • Tanno, S.1    Mitsuuchi, Y.2    Altomare, D.A.3    Xiao, G.H.4    Testa, J.R.5
  • 32
    • 41649101085 scopus 로고    scopus 로고
    • Inhibition of cell motility by troglitazone in human ovarian carcinoma cell line
    • 10.1186/1471-2407-7-216, 2233635, 18021457
    • Yang Y-C, Ho T-C, Chen S-L, Lai H-Y, Wu J-Y, Tsao Y-P. Inhibition of cell motility by troglitazone in human ovarian carcinoma cell line. BMC Cancer 2007, 7:216. 10.1186/1471-2407-7-216, 2233635, 18021457.
    • (2007) BMC Cancer , vol.7 , pp. 216
    • Yang, Y.-.C.1    Ho, T.-.C.2    Chen, S.-.L.3    Lai, H.-.Y.4    Wu, J.-.Y.5    Tsao, Y.-.P.6
  • 33
    • 0035887436 scopus 로고    scopus 로고
    • Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells
    • Park BK, Zeng X, Glazer RI. Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer Res 2001, 61:7647-7653.
    • (2001) Cancer Res , vol.61 , pp. 7647-7653
    • Park, B.K.1    Zeng, X.2    Glazer, R.I.3
  • 34
    • 0036296153 scopus 로고    scopus 로고
    • A role for focal adhesion kinase in hyaluronan-dependent MMP-2 secretion in a human small-cell lung carcinoma cell line, QC90
    • 10.1006/bbrc.2001.6321, 11798192
    • Zhang Y, Thant AA, Hiraiwa Y, Naito Y, Sein TT, Sohara Y, Matsuda S, Hamaguchi M. A role for focal adhesion kinase in hyaluronan-dependent MMP-2 secretion in a human small-cell lung carcinoma cell line, QC90. Biochem Biophys Res Commun 2002, 290:1123-1127. 10.1006/bbrc.2001.6321, 11798192.
    • (2002) Biochem Biophys Res Commun , vol.290 , pp. 1123-1127
    • Zhang, Y.1    Thant, A.A.2    Hiraiwa, Y.3    Naito, Y.4    Sein, T.T.5    Sohara, Y.6    Matsuda, S.7    Hamaguchi, M.8
  • 35
    • 0030512898 scopus 로고    scopus 로고
    • Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation
    • 10.1016/S0959-8049(96)00379-6, 9059336
    • Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, Pezzella F, Viale G, Weidner N, Harris AL, Dirix LY. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 1996, 32A:2474-2484. 10.1016/S0959-8049(96)00379-6, 9059336.
    • (1996) Eur J Cancer , vol.32 A , pp. 2474-2484
    • Vermeulen, P.B.1    Gasparini, G.2    Fox, S.B.3    Toi, M.4    Martin, L.5    McCulloch, P.6    Pezzella, F.7    Viale, G.8    Weidner, N.9    Harris, A.L.10    Dirix, L.Y.11
  • 36
    • 70350704818 scopus 로고    scopus 로고
    • Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/Akt signaling pathway
    • 10.1002/ijc.24675, 19551863
    • Li B, Tsao SW, Li YY, Wang X, Ling MT, Wong YC, He QY, Cheung AL. Id-1 promotes tumorigenicity and metastasis of human esophageal cancer cells through activation of PI3K/Akt signaling pathway. Int J Cancer 2009, 125:2576-2585. 10.1002/ijc.24675, 19551863.
    • (2009) Int J Cancer , vol.125 , pp. 2576-2585
    • Li, B.1    Tsao, S.W.2    Li, Y.Y.3    Wang, X.4    Ling, M.T.5    Wong, Y.C.6    He, Q.Y.7    Cheung, A.L.8
  • 37
    • 67449104757 scopus 로고    scopus 로고
    • Phosphoinositide 3-kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo
    • 10.1111/j.1349-7006.2009.01084.x, 19469020
    • Teranishi F, Takahashi N, Gao N, Akamo Y, Takeyama H, Manabe T, Okamoto T. Phosphoinositide 3-kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo. Cancer Sci 2009, 100:770-777. 10.1111/j.1349-7006.2009.01084.x, 19469020.
    • (2009) Cancer Sci , vol.100 , pp. 770-777
    • Teranishi, F.1    Takahashi, N.2    Gao, N.3    Akamo, Y.4    Takeyama, H.5    Manabe, T.6    Okamoto, T.7
  • 38
    • 57049152346 scopus 로고    scopus 로고
    • Id-1: Regulator of EGFR and VEGF and potential target for colorectal cancer therapy
    • 10.1186/1756-9966-27-69, 2588562, 19014499
    • Meteoglu I, Meydan N, Erkus M. Id-1: Regulator of EGFR and VEGF and potential target for colorectal cancer therapy. J Exp Clin Cancer Res 2008, 27:69. 10.1186/1756-9966-27-69, 2588562, 19014499.
    • (2008) J Exp Clin Cancer Res , vol.27 , pp. 69
    • Meteoglu, I.1    Meydan, N.2    Erkus, M.3


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