P-gp、c-erbB-2/Her2与肿瘤
摘要
化疗药物的耐药导致化疗的失败,肿瘤产生耐药的机制较为复杂,目前认为,肿瘤产生多药耐药最重要的分子机制是跨膜药泵基因的扩增或过表达,这类基因以Mdr1(Mutidrug resistance-1)最为重要,其表达产物为一种膜相关糖蛋白P-糖蛋白(P-glycoprotein,P-gp)。人原癌基因c-erbB-2又称neu或Her2,表达蛋白与表皮生长因子受体(EGFR)同属Ⅰ型生长因子受体家族。c-erbB-2/ Her2编码的酪氨酸激酶可使G2期DNA修复时间延长,并同时增强DNA修复酶的活性,进而产生耐药。本文综述了P-gp及c-erbB-2的发现过程、结构、功能和机制,并详述了它们在多系统肿瘤当中的表达及二者间表达的关系。
The drug resistance leads to the chemotherapy failure. The mechanism of the drug resistance is very complicated,so far, the most important mechanism of the drug resistance is the over expressing of Mdr1,it's production is a glycoprotein (P-gp).Protein c-erbB-2 (neu or her-2) belongs toⅠtype growth factor receptors as epidermal growth factor receptor. Protein tyrosine kinase (PTK) coded by HER-2/neu made reparation DNA of G2 stage prolonged and reinfored repair enzymatic active of DNA, and then drug fast of tumour cell appeared.This article reviews the discovery , structure, function and mechanisms of P-gp and c-erbB-2 .The expressions of P-gp and c-erbB-2 in multisysterm tumors and the corelation between the expressions of P-gp and c-erbB-2 were specified.
The drug resistance leads to the chemotherapy failure. The mechanism of the drug resistance is very complicated,so far, the most important mechanism of the drug resistance is the over expressing of Mdr1,it's production is a glycoprotein (P-gp).Protein c-erbB-2 (neu or her-2) belongs toⅠtype growth factor receptors as epidermal growth factor receptor. Protein tyrosine kinase (PTK) coded by HER-2/neu made reparation DNA of G2 stage prolonged and reinfored repair enzymatic active of DNA, and then drug fast of tumour cell appeared.This article reviews the discovery , structure, function and mechanisms of P-gp and c-erbB-2 .The expressions of P-gp and c-erbB-2 in multisysterm tumors and the corelation between the expressions of P-gp and c-erbB-2 were specified.
引文
1 Ling V. P-glycoprotein and resistance to anticancer drugs[J].Cancer, 1992; 69(10):2603~2612.
2 Lincke CR, Sm it JJ van der Velde- Koerts T, et al Structure of the human MDR3 gene and physicalm apping of the hunam MDR locus[J]. J biol Chem, 1991, 266(8): 1814~1819.
3 Robert J .Resistance to cytotoxic agents[ J].Curr Opin pharm acol 2001, 1(4): 353~357.
4 Li P, Nijhawan D, Budihardjo I, et al. Cytochrome C and dATP-dependent formation of Apaf-1/caspace-9 complexinitiates an apoptotic protease cascade[J]. Cell, 1997, 91(4):479~489.
5 Smyth MJ, Krasovskis E, Sutton VR, et al. The drug efflux Protein , P-glyloprotein , additionally protects drug-Resistant tumor cells from multiple forms of caspase-dependenl apoptosis[J]. Proc Natl Acad sci USA, 1998, 95: 7024.
6 Marzolini C, Paus E, Buclin T, et al .Polymorphisms in human MDR1(P-glycoprotein):recent advances and clinical relevance[J]. Clin Pharm acol Ther , 2004 ,75(1):13~33.
7 Szabo D,Keyzer H, Kaiser HE, et al Reversal of multidrug resistance of tumor cells [J]. Anticancer Res, 2000,20(6B): 4261~4274.
8 阚兵,罗锋,雷松,等.用流式细胞术检测肿瘤组织细胞多药耐药基因表达产物[J].华西医科大学学报,1998,29( 3):269.
9 Orita H, Maehara Y, Anai H, et al. Expression of P-glycoprotein influences against anthracycline in clinical gastric carcinomas[J]. Semin Surg Oncol,1994,10:135.
10 Gurel S,Yerci O,Filiz G,et al. High expression of multidrug resistance-1(MDR-1) and its relationship with multiple prognostic factors in gastric cacinomas in patients in Turkey[J] .J Int Med Res,1999,27(2):79~84.
11 张威,邹寿椿,赵大健,等.多药耐药相关基因在胃癌组织中的表达及意义[J].肿瘤学杂志,2002,8(2):76~78.
12 陈晓耕,王清水,陈新,等.多药耐药基因产物表达和细胞凋亡对胃癌影响的研究[J].中华肿瘤杂志,2000,22(6):487~489
13 于佩瑶,关宏伟,韩辉,等.胃癌黏膜活检组织 P-gp 的检测及意义[J].医师进修杂志,2001,24(14):16~17
14 蔡颖,冯一中,张熔熔,等.胃癌中 P-糖蛋白和 c-erbB-2的表达及其相关性研究[J].苏州大学学报(医学版),2005,25(2):281~283.
15 Kato A, Miyazaki M, Ambiru S, et al. Multidrug resistance gene (MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection . J Surg Oncol, 2001;78:110~115.
16 Potonick U, Ravnik-Glavac M, Golouh R, et al. Naturally occurring mutations and functional polymorphisms in multidrug resistance 1 gene: correlation with microsatellite instability and lymphoid infiltration in colorectal cancers . J Med Genet,2002;39:340~346.
17 Young LC, Campling BG, Voskoglou-Nomikos T, et al. Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response[J].Clin Cancer Res,1999, 5(3):673~680.
18 Oka M,Fukuda M,Sakamoto A, et al.The clinical role of MDR1 gene expression in human lung cancer[J].Anticancer Res,1997,17(1B): 721~724.
19 Zhu L , Lang JH.P-glycoprotein and multidrug resistance[J]Chin J Obstet Gynecol,1998, 33( 6):381~383.
20 Wood L, Palmer M, Hewitt J, et al. Results of a phaseⅢ, double-blind, placebo-controlled trial of megestrol acetate modulation of P-glycoprotein-mediated drug resistance in the first -line management of small-cell lung carcinoma[J].Br J Cancer,1998, 77( 4):627~631.
21 Nakagawa M,Emoto A,Nasu n,et al.Clinical significance of multi-drug resistance associated protein and p-glycoprotein in patients with bladder cancer[J].J Urol,1997,157(4):1260~1264.
22 Holzmayer TA,Hilsenbeck S, et al.Clinical correlates of MDR1(P-glycoprotein) gene expression in ovarian and small-cell lung carcinoma[J]. J Natl Cancer Inst,1992; 84(19):1486~91.
23 Kavallaris M et al. MDR1 and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumors .Cancer Lett,1996;102 :7~16.
24 Joncourt F et al. Multiple Drug Resistance Parameter Expression in Ovarian Cancer Gynecol Onco1 ,1998;70:176~182.
25 应红梅,张有望,许良中.鼻咽癌组织中 P-糖蛋白表达的临床意义.中华放射肿瘤学杂志,2000, 9: 45.
26 Hsu CH,Chen CL, Hong RL, et al. Prognostic value of multidrug resistance 1,glutathione-S-transferase-p1 and p53 in advanced nasopharyngeal carcinoma treated with systemic chemotherapy. Oncology, 2002, 62:305~312.
27 蔡晓岚,王天铎,史丽。喉咽癌患者多药耐药基因多药耐药相关蛋白基因的表达及其临床意义[J]中华耳鼻咽喉科杂志,1999,34(3)173~176.
28 王影,张兵,等。P-糖蛋白在喉癌组织中的表达及意义[J]四川医学,2002,23(11)1198~1199
29 Campos L , et al. Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood , 1992,79(2):473.
30 Yamameto T,Ikawa S ,Akiyama T,et al. Similarity of protein encoded by the human C-erbB-2 gene to epidermal growth factor receptor, Nature 1986;319:230~234.
31 Ullrich A,Schlessinger .Signal transduction by receptors with tyrosine kinase activity.Cell,1990;61:203~212.
32 Bargmano CI , Hung MC.Wernberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 1986;319:226~230.
33 Yu D,Hung M-C. Overexpression of ErbB2 in cancer and erbB2 strategies.Oncogene 2000,19:6115~6121.
34 Yu D,Wolf Jk,Scanlon M , et al. Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by EIA.Cancer Res 1993,53:891~898.
35 Slamon DJ ,Godolphin W, Jones LA,et al. Study of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science ,1989, 244 :707~712.
36 Wen D , Peles E, Cupples R, et al. Neu differentiationFactor:A transmembrane glycoprotein containing an EGF domain and an immunolglubulin homology Unit.Cell,1992,69:559~572.
37 Sliwkowski MX , Schaefer G , Akita RW , et al.Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem, 1994,269:14661~14665.
38 Samanta A, Levea CM,Dougall Wc,et al. Ligand and p185c-neu density govern receptor interactions and tyrosine kinase activation. Proc Natl Acad USA , 1994 ,91:1711~1715.
39 Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol , 2001,12(suppl 1):s3~8.
40 成军.肿瘤相关基因.北京:北京医科大学出版社.1999. 29~37.
41 Knuefermann C. Lu Y. Liu B, et aL Her2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells.Oncogene, 2003,22(21):3205~3212.
42 Oki E, Baba H, Tokunega E, et al.Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer, 2005,117(3):376~380.
43 Wang W, Cassidy J.Constitutive nuclear factor-kappa B mRNA , protein overexpression and enhanced DNA-binding activity in thymidylate synthase inhibitor-resistant tumour cells.Br J cancer , 2003 ,88(4):624~629.
44 Hickey K, Grehan D. Reid IM, et a1. Expression of epidermal growth factor receptor and proliferating cell nuclear antigen predicts response of esophageal squamous cell carcinoma to chemoradiotherapy .Cancer , 1994: 74:1693~1698.
45 Mukaida H, Toi M. Hirai T, et al. Clinical significance of the expression of epidermal growth factor and its receptor in esophageal cancer Cancer.1991;68:142~148.
46 Hollstein MC, Smits AM, Galiana C, et al. Amplification of epidermal growth factor receptor gene but no evidence of ras mutations in primary human esophageal cancers. Cancer Res.1988;48:5119~5123.
47 Duhaylongsod FG, Gottfried MR, Iglehart JD, et al. The significance of c-erb B-2 and p53 immunoreactivity in patients with adenocarcinoma of the esophagus .Ann Surg. 1995;221:677~684.
48 Im SA, Lee KE,Nam E, et al. Potential prognostic significance of p185 ( HER2 ) overexpression with loss of PTEN expression in gastric carcinomas. Tumori,2005,91(6):513~521.
49 Funato T, Kozawa K, Fujimaki S,et aL Increased sensitivity to cisplatin in gastric cancer by antisense inhibition of the her-2/neu ( c-erbB-2) gene. Chemotherapy, 2001,47(4):297~303.
50 Berns EM, Foekens JA, Staveren IL, et al. Oncogene amplification and prognosis in breast cancer: relationshipto a systemic treatment[J].Gene,1995, 159: 11.
51 Slamon DJ. Godolphin W. Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science,1989;244:707~712.
52 Walker RA. Gullick WJ. Varley JM.An evaluation of immnoreactivity for the c-erbB-2 protein as a marker of poor short- term prognosis in breast cancers[J].Br J Cancer, 1989, 60: 426~429.
53 Bieche I, Franc B, Vidaud D, et al. Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction. Thyroid, 2001,11: 147~152.
54 Beckhardt RN. Kiyokawa N. Xi L. Liu TJ. et al. HER-2/neu oncogene characterization in head and neck squamous cell carcinoma Arch Otolaryngol Head Neck Surg ,1995;121:1265.
55 Riviere A. wilckens c, Loning T: Expression of c-erbB2 and c-myc in squamous epithelia and squamous of the head and neck and the lower female genital tract. J Oral Pathol Med 1990,19:408~413.
56 李勇,汤晓飞.C-erbB-2 蛋白在口腔鳞状细胞癌中表达意义的研究.白求恩医科大学学报.2001,27(2):156~157.
57 Wilkman Ts , Hietancn Jp , Malmstrom MJ , et al.Immunohistochemical analysis of the oncoprotein C-erbB-2 expression in oral benign and malignant lesions, Int Oral Maxillofac Surg ,1998, 27 ( 3 ) :209~212.
58 Xia W,lau YK,Zhang HZ,et al. Strong correlation between C-erbB-2 overexpression and overall survival of patients with oral squamouse cell carcinoma.Clin Cancer Res.1997,3(1):3~9.
59 Kallioniemi Op, Holli Kaija, Visakorpi Tapio, et al. Association of c-erbB-2 protein over-expression with high rate of cell proliferation , increased risk of visceral metastasis and poor long-term survival in breast cancer.. Int J Cancer,1991,49;650~655.
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70 陶晓钰,顾学文,肖芹,等.胃腺癌组织中 P-糖蛋白与 P53、c-erbB-2、nm23 表达的关系[J].实用癌症杂志,2002,17(6):605~607.
2 Lincke CR, Sm it JJ van der Velde- Koerts T, et al Structure of the human MDR3 gene and physicalm apping of the hunam MDR locus[J]. J biol Chem, 1991, 266(8): 1814~1819.
3 Robert J .Resistance to cytotoxic agents[ J].Curr Opin pharm acol 2001, 1(4): 353~357.
4 Li P, Nijhawan D, Budihardjo I, et al. Cytochrome C and dATP-dependent formation of Apaf-1/caspace-9 complexinitiates an apoptotic protease cascade[J]. Cell, 1997, 91(4):479~489.
5 Smyth MJ, Krasovskis E, Sutton VR, et al. The drug efflux Protein , P-glyloprotein , additionally protects drug-Resistant tumor cells from multiple forms of caspase-dependenl apoptosis[J]. Proc Natl Acad sci USA, 1998, 95: 7024.
6 Marzolini C, Paus E, Buclin T, et al .Polymorphisms in human MDR1(P-glycoprotein):recent advances and clinical relevance[J]. Clin Pharm acol Ther , 2004 ,75(1):13~33.
7 Szabo D,Keyzer H, Kaiser HE, et al Reversal of multidrug resistance of tumor cells [J]. Anticancer Res, 2000,20(6B): 4261~4274.
8 阚兵,罗锋,雷松,等.用流式细胞术检测肿瘤组织细胞多药耐药基因表达产物[J].华西医科大学学报,1998,29( 3):269.
9 Orita H, Maehara Y, Anai H, et al. Expression of P-glycoprotein influences against anthracycline in clinical gastric carcinomas[J]. Semin Surg Oncol,1994,10:135.
10 Gurel S,Yerci O,Filiz G,et al. High expression of multidrug resistance-1(MDR-1) and its relationship with multiple prognostic factors in gastric cacinomas in patients in Turkey[J] .J Int Med Res,1999,27(2):79~84.
11 张威,邹寿椿,赵大健,等.多药耐药相关基因在胃癌组织中的表达及意义[J].肿瘤学杂志,2002,8(2):76~78.
12 陈晓耕,王清水,陈新,等.多药耐药基因产物表达和细胞凋亡对胃癌影响的研究[J].中华肿瘤杂志,2000,22(6):487~489
13 于佩瑶,关宏伟,韩辉,等.胃癌黏膜活检组织 P-gp 的检测及意义[J].医师进修杂志,2001,24(14):16~17
14 蔡颖,冯一中,张熔熔,等.胃癌中 P-糖蛋白和 c-erbB-2的表达及其相关性研究[J].苏州大学学报(医学版),2005,25(2):281~283.
15 Kato A, Miyazaki M, Ambiru S, et al. Multidrug resistance gene (MDR-1) expression as a useful prognostic factor in patients with human hepatocellular carcinoma after surgical resection . J Surg Oncol, 2001;78:110~115.
16 Potonick U, Ravnik-Glavac M, Golouh R, et al. Naturally occurring mutations and functional polymorphisms in multidrug resistance 1 gene: correlation with microsatellite instability and lymphoid infiltration in colorectal cancers . J Med Genet,2002;39:340~346.
17 Young LC, Campling BG, Voskoglou-Nomikos T, et al. Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response[J].Clin Cancer Res,1999, 5(3):673~680.
18 Oka M,Fukuda M,Sakamoto A, et al.The clinical role of MDR1 gene expression in human lung cancer[J].Anticancer Res,1997,17(1B): 721~724.
19 Zhu L , Lang JH.P-glycoprotein and multidrug resistance[J]Chin J Obstet Gynecol,1998, 33( 6):381~383.
20 Wood L, Palmer M, Hewitt J, et al. Results of a phaseⅢ, double-blind, placebo-controlled trial of megestrol acetate modulation of P-glycoprotein-mediated drug resistance in the first -line management of small-cell lung carcinoma[J].Br J Cancer,1998, 77( 4):627~631.
21 Nakagawa M,Emoto A,Nasu n,et al.Clinical significance of multi-drug resistance associated protein and p-glycoprotein in patients with bladder cancer[J].J Urol,1997,157(4):1260~1264.
22 Holzmayer TA,Hilsenbeck S, et al.Clinical correlates of MDR1(P-glycoprotein) gene expression in ovarian and small-cell lung carcinoma[J]. J Natl Cancer Inst,1992; 84(19):1486~91.
23 Kavallaris M et al. MDR1 and multidrug resistance-associated protein (MRP) gene expression in epithelial ovarian tumors .Cancer Lett,1996;102 :7~16.
24 Joncourt F et al. Multiple Drug Resistance Parameter Expression in Ovarian Cancer Gynecol Onco1 ,1998;70:176~182.
25 应红梅,张有望,许良中.鼻咽癌组织中 P-糖蛋白表达的临床意义.中华放射肿瘤学杂志,2000, 9: 45.
26 Hsu CH,Chen CL, Hong RL, et al. Prognostic value of multidrug resistance 1,glutathione-S-transferase-p1 and p53 in advanced nasopharyngeal carcinoma treated with systemic chemotherapy. Oncology, 2002, 62:305~312.
27 蔡晓岚,王天铎,史丽。喉咽癌患者多药耐药基因多药耐药相关蛋白基因的表达及其临床意义[J]中华耳鼻咽喉科杂志,1999,34(3)173~176.
28 王影,张兵,等。P-糖蛋白在喉癌组织中的表达及意义[J]四川医学,2002,23(11)1198~1199
29 Campos L , et al. Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood , 1992,79(2):473.
30 Yamameto T,Ikawa S ,Akiyama T,et al. Similarity of protein encoded by the human C-erbB-2 gene to epidermal growth factor receptor, Nature 1986;319:230~234.
31 Ullrich A,Schlessinger .Signal transduction by receptors with tyrosine kinase activity.Cell,1990;61:203~212.
32 Bargmano CI , Hung MC.Wernberg RA. The neu oncogene encodes an epidermal growth factor receptor-related protein. Nature 1986;319:226~230.
33 Yu D,Hung M-C. Overexpression of ErbB2 in cancer and erbB2 strategies.Oncogene 2000,19:6115~6121.
34 Yu D,Wolf Jk,Scanlon M , et al. Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by EIA.Cancer Res 1993,53:891~898.
35 Slamon DJ ,Godolphin W, Jones LA,et al. Study of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science ,1989, 244 :707~712.
36 Wen D , Peles E, Cupples R, et al. Neu differentiationFactor:A transmembrane glycoprotein containing an EGF domain and an immunolglubulin homology Unit.Cell,1992,69:559~572.
37 Sliwkowski MX , Schaefer G , Akita RW , et al.Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J Biol Chem, 1994,269:14661~14665.
38 Samanta A, Levea CM,Dougall Wc,et al. Ligand and p185c-neu density govern receptor interactions and tyrosine kinase activation. Proc Natl Acad USA , 1994 ,91:1711~1715.
39 Rubin I, Yarden Y. The basic biology of HER2. Ann Oncol , 2001,12(suppl 1):s3~8.
40 成军.肿瘤相关基因.北京:北京医科大学出版社.1999. 29~37.
41 Knuefermann C. Lu Y. Liu B, et aL Her2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells.Oncogene, 2003,22(21):3205~3212.
42 Oki E, Baba H, Tokunega E, et al.Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer, 2005,117(3):376~380.
43 Wang W, Cassidy J.Constitutive nuclear factor-kappa B mRNA , protein overexpression and enhanced DNA-binding activity in thymidylate synthase inhibitor-resistant tumour cells.Br J cancer , 2003 ,88(4):624~629.
44 Hickey K, Grehan D. Reid IM, et a1. Expression of epidermal growth factor receptor and proliferating cell nuclear antigen predicts response of esophageal squamous cell carcinoma to chemoradiotherapy .Cancer , 1994: 74:1693~1698.
45 Mukaida H, Toi M. Hirai T, et al. Clinical significance of the expression of epidermal growth factor and its receptor in esophageal cancer Cancer.1991;68:142~148.
46 Hollstein MC, Smits AM, Galiana C, et al. Amplification of epidermal growth factor receptor gene but no evidence of ras mutations in primary human esophageal cancers. Cancer Res.1988;48:5119~5123.
47 Duhaylongsod FG, Gottfried MR, Iglehart JD, et al. The significance of c-erb B-2 and p53 immunoreactivity in patients with adenocarcinoma of the esophagus .Ann Surg. 1995;221:677~684.
48 Im SA, Lee KE,Nam E, et al. Potential prognostic significance of p185 ( HER2 ) overexpression with loss of PTEN expression in gastric carcinomas. Tumori,2005,91(6):513~521.
49 Funato T, Kozawa K, Fujimaki S,et aL Increased sensitivity to cisplatin in gastric cancer by antisense inhibition of the her-2/neu ( c-erbB-2) gene. Chemotherapy, 2001,47(4):297~303.
50 Berns EM, Foekens JA, Staveren IL, et al. Oncogene amplification and prognosis in breast cancer: relationshipto a systemic treatment[J].Gene,1995, 159: 11.
51 Slamon DJ. Godolphin W. Jones LA et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science,1989;244:707~712.
52 Walker RA. Gullick WJ. Varley JM.An evaluation of immnoreactivity for the c-erbB-2 protein as a marker of poor short- term prognosis in breast cancers[J].Br J Cancer, 1989, 60: 426~429.
53 Bieche I, Franc B, Vidaud D, et al. Analyses of MYC, ERBB2, and CCND1 genes in benign and malignant thyroid follicular cell tumors by real-time polymerase chain reaction. Thyroid, 2001,11: 147~152.
54 Beckhardt RN. Kiyokawa N. Xi L. Liu TJ. et al. HER-2/neu oncogene characterization in head and neck squamous cell carcinoma Arch Otolaryngol Head Neck Surg ,1995;121:1265.
55 Riviere A. wilckens c, Loning T: Expression of c-erbB2 and c-myc in squamous epithelia and squamous of the head and neck and the lower female genital tract. J Oral Pathol Med 1990,19:408~413.
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