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In vivo Study of siRNA Silencing XIAP Gene to Reverse Taxol-resistance in Human Ovarian Cancer Cells

  • Objective To study the relationship between down-regulated expression of X linked inhibitor of apoptosis protein (XIAP) gene and the reversal effect of taxol-resistance by using siRNA interference technology in the taxol-resistant ovarian cancer. Methods Randomly assigned the nude mice into six groups (6 in each group) . Group A: normal saline; Group B: taxol; Group C: siRNA-NC+normal saline; Group D: siRNA-NC+taxol; Group E: siRNA XIAP+normal saline; Group F: siRNA XIAP+taxol. Each group was dealt with the corresponding processing depending on the agreed protocol and the transplanted tumors had a multi-point injection with reagents related siRNA, one time every 3 days, 9 times (27 d) in total. Taxol (2 mg/kg) was used in the intraperitoneal injection, 0.2 mL every time, once a week, for four weeks. After 27 d of siRNA treatment, xenograft volumes and qualities were measured and the inhibitory rate was calculated; RNA expression levels and protein levels of XIAP gene in xenografts were detected respectively by real-time fluorescent quantitative PCR and Western blot. Apoptosis of the transplanted tumor cells was examined by TUNEL method. Results Among the six groups, the proliferation of transplanted tumor in Group F was the slowest, and the tumor inhibition rate was the highest compared with control Group A, followed by Group E, and the tumor inhibition rate was the lowest in Group C. Group F and E expressed the lowest XIAP mRNA and protein expressions (P<0.05, vs. the other 4 groups) .The apoptosis rate was highest in Group F, followed by Group E, and lowest in Group A and C (P<0.05). Conclusion XIAP siRNA has synergy with taxol in taxol-resistant ovarian cancer cells.
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  • [1] ZHAO W J, DENG B Y, WANG X M, et al. XIAP associated factor 1 (XAF1) represses expression of X-linked inhibitor of apoptosis protein (XIAP) and regulates invasion, cell cycle, apoptosis, and cisplatin sensitivity of ovarian carcinoma cells. Asian Pac J Cancer Prev,2015,16(6): 2453–2458. doi: 10.7314/APJCP.2015.16.6.2453
    [2] LI X, CHEN W, ZENG W, et al. microRNA-137 promotes apoptosis in ovarian cancer cells via the regulation of XIAP. Br J Cancer,2017,116(1): 66–76. doi: 10.1038/bjc.2016.379
    [3] LEUNG D T H, NGUYEN T, OLIVER E M, et al. Combined PPARgamma activation and XIAP Inhibition as a potential therapeutic strategy for ovarian granulosa cell tumors. Mol Cancer Ther,2019,18(2): 364–375. doi: 10.1158/1535-7163.MCT-18-0078
    [4] THIBAULT B, GENRE L, LE N A, et al. DEBIO 1143, an IAP inhibitor, reverses carboplatin resistance in ovarian cancer cells and triggers apoptotic or necroptotic cell death. Sci Rep,2018,8(1): 17862. doi: 10.1038/s41598-018-35860-z
    [5] QU Y, XIA P, ZHANG S, et al. Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin. Oncol Rep,2015,33(3): 1177–1184. doi: 10.3892/or.2014.3698
    [6] LIU X G, XU J, LI F, et al. Down-regulation of miR-377 contributes to cisplatin resistance by targeting XIAP in osteosarcoma. Eur Rev Med Pharmacol Sci,2018,22(5): 1249–1257.
    [7] BAO W, ZHU F, DUAN Y, et al. HtrA1 resensitizes multidrug-resistant hepatocellular carcinoma cells by targeting XIAP. Biomed Pharmacother,2015,70: 97–102. doi: 10.1016/j.biopha.2014.12.044
    [8] ZHEN M C, WANG F Q, WU S F, et al. Identification of mTOR as a primary resistance factor of the IAP antagonist AT406 in hepatocellular carcinoma cells. Oncotarget,2017,8(6): 9466–9475.
    [9] CAO L P, SONG J L, YI X P, et al. Double inhibition of NF-kappaB and XIAP via RNAi enhances the sensitivity of pancreatic cancer cells to gemcitabine. Oncol Rep,2013,29(4): 1659–1665. doi: 10.3892/or.2013.2246
    [10] AUGERI D J, LANGENFELD E, CASTLE M, et al. Inhibition of BMP and of TGFbeta receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death. Mol Cancer,2016,15: 27[2019-04-07].https://doi.org/10.1186/s12943-016-0511-9. doi: 10.1186/s12943-016-0511-9
    [11] NESTAL DE MORAES G, DELBUE D, SILVA K L, et al. FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance. Cell Signal,2015,27(12): 2496–2505. doi: 10.1016/j.cellsig.2015.09.013
    [12] HUA Y, ZHU Y, ZHANG J, et al. miR-122 Targets X-linked inhibitor of apoptosis protein to sensitize oxaliplatin-resistant colorectal cancer cells to oxaliplatin-mediated cytotoxicity. Cell Physiol Biochem,2018,51(5): 2148–2159. doi: 10.1159/000495832
    [13] XIONG Z, FU Z, SHI J, et al. HtrA1 Down-regulation induces cisplatin resistance in colon cancer by increasing XIAP and activating PI3K/Akt pathway. Ann Clin Lab Sci,2017,47(3): 264–270.
    [14] SARAEI R, SOLEIMANI M, MOVASSAGHPOUR A A, et al. The role of XIAP in resistance to TNF-related apoptosis-inducing ligand (TRAIL) in leukemia. Biomed Pharmacother,2018,107: 1010–1019. doi: 10.1016/j.biopha.2018.08.065
    [15] LI S, CHEN D, PEI R, et al. L-Tetrahydropalmatine induces apoptosis in EU-4 leukemia cells by down-regulating X-linked inhibitor of apoptosis protein and increases the sensitivity towards doxorubicin. Curr Mol Med,2017,17(3): 236–245.
    [16] ZHANG X, HUANG L, ZHAO Y, et al. Downregulation of miR-130a contributes to cisplatin resistance in ovarian cancer cells by targeting X-linked inhibitor of apoptosis (XIAP) directly. Acta Biochim Biophys Sin (Shanghai),2013,45(12): 995–1001. doi: 10.1093/abbs/gmt113
    [17] FLANAGAN L, KEHOE J, FAY J, et al. High levels of X-linked Inhibitor-of-apoptosis protein (XIAP) are indicative of radio chemotherapy resistance in rectal cancer. Radiat Oncol,2015,10: 131[2019-04-07].https://doi.org/10.1186/s13014-015-0437-1. doi: 10.1186/s13014-015-0437-1
    [18] HE X, KHURANA A, MAGUIRE J L, et al. HtrA1 sensitizes ovarian cancer cells to cisplatin-induced cytotoxicity by targeting XIAP for degradation. Int J Cancer,2012,130(5): 1029–1035. doi: 10.1002/ijc.26044
    [19] MIYAMOTO M, TAKANO M, IWAYA K, et al. X-chromosome-linked inhibitor of apoptosis as a key factor for chemoresistance in clear cell carcinoma of the ovary. Brit J Cancer,2014,110: 2881–2886. doi: 10.1038/bjc.2014.255
    [20] CHAUDHARY A K, YADAV N, BHAT T A, et al. A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy. Drug Discov Today,2016,21(1): 38–47. doi: 10.1016/j.drudis.2015.07.014
    [21] SCHIMMER A D, DALILI S, BATEY RA, et al. Targeting XIAP for the treatment of malignancy. Cell Death Differ,2006,13(2): 179–188. doi: 10.1038/sj.cdd.4401826
    [22] 岳驰, 李冉红, 刘辉. XIAP基因与耐紫杉醇卵巢癌细胞A2780/Taxol耐药关系的研究. 四川大学学报(医学版),2018,49(3): 337–341.
    [23] GE G, ZHANG W, NIU L, et al. miR-215 functions as a tumor suppressor in epithelial ovarian cancer through regulation of the X-chromosome-linked inhibitor of apoptosis. Oncol Rep,2016,35(3): 1816–1822. doi: 10.3892/or.2015.4482
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In vivo Study of siRNA Silencing XIAP Gene to Reverse Taxol-resistance in Human Ovarian Cancer Cells

    Corresponding author: LIU Hui, lh666888@163.com
  • 1. Department of Obstetrics and Gynecology, Henan Provincial People's Hospital, Zhengzhou 450003, China
  • 2. Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu 610041, China
  • 3. Key Laboratory of Obstetric and Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education (Sichuan University), Chengdu 610041, China

doi: 10.12182/20200560203

Abstract:  Objective To study the relationship between down-regulated expression of X linked inhibitor of apoptosis protein (XIAP) gene and the reversal effect of taxol-resistance by using siRNA interference technology in the taxol-resistant ovarian cancer. Methods Randomly assigned the nude mice into six groups (6 in each group) . Group A: normal saline; Group B: taxol; Group C: siRNA-NC+normal saline; Group D: siRNA-NC+taxol; Group E: siRNA XIAP+normal saline; Group F: siRNA XIAP+taxol. Each group was dealt with the corresponding processing depending on the agreed protocol and the transplanted tumors had a multi-point injection with reagents related siRNA, one time every 3 days, 9 times (27 d) in total. Taxol (2 mg/kg) was used in the intraperitoneal injection, 0.2 mL every time, once a week, for four weeks. After 27 d of siRNA treatment, xenograft volumes and qualities were measured and the inhibitory rate was calculated; RNA expression levels and protein levels of XIAP gene in xenografts were detected respectively by real-time fluorescent quantitative PCR and Western blot. Apoptosis of the transplanted tumor cells was examined by TUNEL method. Results Among the six groups, the proliferation of transplanted tumor in Group F was the slowest, and the tumor inhibition rate was the highest compared with control Group A, followed by Group E, and the tumor inhibition rate was the lowest in Group C. Group F and E expressed the lowest XIAP mRNA and protein expressions (P<0.05, vs. the other 4 groups) .The apoptosis rate was highest in Group F, followed by Group E, and lowest in Group A and C (P<0.05). Conclusion XIAP siRNA has synergy with taxol in taxol-resistant ovarian cancer cells.

  • X连锁凋亡抑制蛋白(X linked inhibitor of apoptosis protein,XIAP)目前被一致认为是凋亡抑制蛋白家族中抗凋亡能力最强的内源性凋亡抑制因子,在人类卵巢癌[1-4]、骨肉瘤[5-6]、肝癌[7-8]、胰腺癌[9]、肺癌[10]、乳腺癌[11]、结肠癌[12-13]、白血病[14-15]等多种肿瘤中都有高表达。XIAP的高表达可能是肿瘤发生、化学耐药[16]、放疗[17]和细胞调控失衡[18]的关键,其N端的杆状病毒重复序列区和C端的E3泛素连接酶活性均是其发挥抗凋亡作用必不可少的结构[19-20]。XIAP可直接作用于执行凋亡的半胱天冬蛋白酶(caspase),分别从初始相和执行相抑制其活性,进而实现抗细胞凋亡的作用,引发肿瘤对化疗药物的耐药,故XIAP的高表达可能是卵巢癌耐药的直接原因[21]。目前,国内外对XIAP在铂类耐药卵巢癌方面的研究较多[4, 16],而在紫杉醇耐药性卵巢癌方面的研究甚少,我们前期研究[12]在细胞水平上证实了卵巢癌对紫杉醇耐药与XIAP的高表达有关,特异性的siRNA可通过降低XIAP的表达,促进细胞凋亡,增加耐药癌细胞对紫杉醇的敏感性。本研究拟在前期研究结果的基础上进行动物体内实验,观察XIAP在体内对卵巢癌的紫杉醇耐药的逆转,旨在为紫杉醇耐药性卵巢癌的基因治疗提供实验依据。

    • 紫杉醇由四川大学华西第二医院惠赠,siRNA-阴性对照序列(NC)、siRNA-XIAP由上海吉玛制药技术有限公司合成,EntransterTM-in vivo购于北京英格恩生物科技有限公司;XIAP一抗(兔抗人XIAP抗体、鼠抗人β-actin抗体)购自Abcam;TUNEL试剂盒购自Promega公司。人耐紫杉醇卵巢癌细胞株(A2780/T)引种于上海美轩生物科技有限公司,BALB/C-nu雌性裸小鼠40只,4~6周龄,体质量16~20 g,购于成都达硕实验动物有限公司,动物质量合格证号:SCXK(川)2013-24。动物实验过程严格按照《实验动物福利伦理审查指南(GB/T 35892 2018)》要求执行。

    • 取裸鼠40只,接种前测体质量,在超净工作台内收集对数生长期A2780/T细胞,用含EDTA(质量分数为0.01%)的胰酶消化后悬浮于无血清培养基中,调整细胞密度为2.5×107 mL-1。于裸鼠左上肢背部皮肤接种,每只皮下注入0.2 mL A2780/T细胞培养悬液(约含5×106个细胞)。每3 d测裸鼠的质量和皮下移植瘤的最长径(a,mm)和最短径(b,mm)进行体积(V,mm3)估算,V=1/2(a×b2),用于评估造模是否成功。

    • 待接种处形成粟粒大小(直径0.3~0.5 cm)的皮下移植瘤时,取其中瘤体大小相近的36只裸鼠随机分成6组,每组6只,A组:生理盐水组;B组:紫杉醇组;C组:siRNA-NC+生理盐水组;D组:siRNA-NC+紫杉醇组;E组:siRNA-XIAP+生理盐水组;F组:siRNA-XIAP+紫杉醇组;由同一实验员按照各组不同方案局部瘤体多点注射,C~F组每次每只瘤体内注射剂量为10 μg siRNA(C、D组注射siRNA-NC,E、F组注射siRNA- XIAP)+10 μL DEPC水+5 μL转染试剂,每3 d注射1次,共注射9次(27 d)。紫杉醇(20 mg/kg)溶于生理盐水中,在D、F组第1次给予siRNA干扰后开始给药(C、E组注射生理盐水),每周1次,0.2 mL/次,腹腔内注射,共注射4次(第1 天,第8 天,第15 天,第23天)。A、B组不给予siRNA干扰,只进行紫杉醇或者生理盐水腹腔注射。siRNA干预27 d后处死裸鼠,取出瘤体,测各组移植瘤质量、体积(V),以此次体积测量值计算各组相对于对照组(A组)的抑瘤率(%)=〔(V对照组V实验组)/V对照组〕×100%。比较各组的移植瘤质量和抑瘤率。每个组中有6个样本,6个样本混合后每组分别取等质量的瘤体用于检测。检测前将瘤体组织置于−70 ℃冰箱备用。

    • 将各组移植瘤瘤体剪碎消化后用有机溶剂抽提各组中XIAP的RNA,依次进行cDNA的制备、PCR扩增,XIAP基因DNA序列查询于NCBI人类基因组数据库,引物由上海吉玛制药技术有限公司设计,由Invitrogen公司合成。引物序列,XIAP,F: 5′-CGAGCTGGGTTTCTTTATACCG-3′;R: 5′-GCAATTTGGGGATATTCTCCTGT-3′,扩增产物长度292 bp;β-actin,F:5′-CGTGACATTAAGGAGAAGCTG-3′,R:5′-CTAGAAGCATTTGCGGTGGAC-3′,扩增产物长度188 bp;扩增反应条件:94 ℃ 4 min, 94 ℃ 30 s、56 ℃ 30 s、72 ℃ 30 s 40个循环,72 ℃继续延伸7 min,4 ℃维持至结束。以 2-ΔΔCt法计算基因的相对表达量。然后以A组基因的表达量为1,计算各组移植瘤组织中XIAP的mRNA相对A组的表达量。

    • 取各组瘤体组织(均100 mg)充分剪碎, 每组6个样本混合后裂解提取蛋白质,将蛋白样品与5×上样缓冲液(含β-巯基乙醇)混合后,煮沸变性、冰浴,进行SDS变性10%聚丙烯酰胺凝胶电泳(SDS-PAGE)。分离后电转至硝酸纤维素膜上(100 mA,90 min),封闭;一抗(兔抗人XIAP抗体、鼠抗人β-tublin抗体)稀释至1∶1 000,TBST 洗涤,二抗孵育 (稀释至1∶3 000),TBST洗涤后曝光,采用自动电泳凝胶定量图像分析系统分析结果判定,以相应条带与内参条带积分光密度(IOD)值的比值为目的蛋白的相对表达量。以A组蛋白的表达量为标准值1,计算其它组XIAP条带亮度的相对值。

    • 取各组瘤块组织,多聚甲醛固定,石蜡包埋切片,每组选择两个样切片,按TUNEL试剂盒说明书操作。光学显微镜下进行结果观察。结果判定:每张切片在400倍镜下读取分析,以凋亡细胞数占细胞总数的百分比为凋亡指数(AI)。

    • 所有数据均用$\bar x \pm {\rm{s}}$表示。多组间比较采用单因素方差分析,组间两两比较采用LSD法,P<0.05为差异有统计学意义。

    2.   结果
    • 接种后1周左右,裸鼠接种部位长出直径约0.3~0.5 cm的结节并逐渐长大,周围有新生血管形成,表明造模成功。40只成瘤38只,成瘤率95.0%。成瘤后各组裸鼠及离体移植瘤见图1。接种前后裸鼠精神、活动、饮食、排便及对外界刺激的反应等无明显变化,随瘤体增大,裸鼠精神、饮食及对外界反应均降低。

      Figure 1.  Nude mice and xenograft in each group

    • 表1。移植瘤质量比较:A组和C组移植瘤质量最高,使用紫杉醇治疗(B组和D组)或者仅沉默XIAP(E组)移植瘤质量相当,沉默XIAP且使用紫杉醇治疗(F组)可使移植瘤质量降到最低。抑瘤率比较:C组抑瘤率最低、治疗效果最差,仅使用紫杉醇治疗(B组)、转染阴性对照序列的紫杉醇治疗(D组)、仅沉默XIAP而不使用紫杉醇治疗(E组)三者抑瘤率相当,沉默XIAP且使用紫杉醇治疗(F组)抑瘤率最高,治疗效果最好。抑瘤率比较:C组抑瘤率最低、治疗效果最差,仅使用紫杉醇治疗(B组)、转染阴性对照序列的紫杉醇治疗(D组)、仅沉默XIAP而不使用紫杉醇治疗(E组)三者抑瘤率相当,沉默XIAP且使用紫杉醇治疗(F组)抑瘤率最高,治疗效果最好。

      GroupnTumor mass/gInhibitory rate/%
      A60.50±0.06
      B60.28±0.0157.269
      C60.42±0.13#25.717#
      D60.26±0.07*66.792*
      E60.25±0.06*72.782*
      F60.17±0.03*, #84.574*, #
       *P<0.05, vs. Group A; #P<0.05, vs. Group B . A-F denote the same as fig 1

      Table 1.  Tumor mass and inhibitory rate in each group

    • 图2。经过siRNA-XIAP处理的E组和F组,XIAPmRNA表达降低,E组和F组差异无统计学意义。未沉默XIAP的A~D组XIAP mRNA表达差异均无统计学意义,这4组与E、F组差异有统计学意义(P<0.05),证明XIAP正确沉默。

      Figure 2.  The mRNA expression of XIAP in different groups (n=6)

    • 图3图4。Western blot 结果显示:与mRNA结果一致,沉默XIAPE组和F组XIAP蛋白最低,低于A~D组(P<0.05);E组和F组XIAP蛋白差异无统计学意义,A~D组XIAP蛋白差异无统计学意义。

      Figure 3.  The XIAP protein expression in different groups

      Figure 4.  The relative expression of XIAP protein in different groups detected by Western blot (n=6)

    • 表2。F组AI最高,E组次之,高于B组与D组,而A组与C组AI最低(P<0.05)。B组与D组差异无统计学意义,A组与C组差异无统计学意义。沉默XIAP对AI的影响大于紫杉醇治疗。

      GroupnAI
      A612.70%±0.87%
      B626.70%±0.58%
      C615.30%±2.84%#
      D629.20%±5.24%
      E632.80%±2.31%#
      F645.90%±7.03%
       △ P <0.05 , vs. other groups; #P<0.05, vs. Group B. A-F denote the same as fig 1

      Table 2.  Apoptosis index (AI) of each group

    3.   讨论
    • 国内外许多研究证实XIAP的高表达与多种肿瘤的耐药性相关,下调其表达可促进肿瘤细胞的凋亡,增强癌细胞对化疗药物的敏感性,这亦被我们之前的研究证实[22]。但是国内外有关XIAP与耐紫杉醇的卵巢癌的研究甚少,本研究建立裸鼠移植瘤模型,模拟人体内环境,采用siRNA干扰技术下调XIAP基因的表达,明确XIAP在卵巢癌紫杉醇耐药发生及对逆转紫杉醇耐药的作用,结果提示siRNA-XIAP可抑制癌细胞的增殖,促进癌细胞的凋亡,其效果可能与紫杉醇相当,两者共同作用可明显抑制耐紫杉醇卵巢癌细胞的增殖,明显促进癌细胞的凋亡,证实了抑制XIAP的高表达可增强卵巢癌细胞对紫杉醇的敏感性这一推论。另外,ZHANG等[16]在研究耐顺铂卵巢癌细胞系A2780/DDP的研究中同样发现耐药性卵巢癌细胞中存在XIAP的过表达,下调XIAP基因的表达可增强卵巢癌细胞对化疗药物顺铂的敏感性,促进癌细胞的凋亡,XIAP基因的过表达与卵巢癌细胞的耐药性密切相关。本研究结果显示:经siRNA-XIAP处理的两组,XIAP的表达量均较其他组降低,表明利用针对XIAP的特异siRNA干扰技术,成功实现了裸鼠耐紫杉醇卵巢癌移植瘤细胞中XIAP基因表达的下调。

      另外,耐紫杉醇卵巢癌移植瘤细胞的凋亡结果显示:siRNA-XIAP联合紫杉醇的凋亡率最高,其次为单用siRNA-XIAP和紫杉醇组,结合各组移植瘤细胞中的XIAP在mRNA及蛋白水平的表达结果,可知XIAP基因的高表达很可能为卵巢癌对紫杉醇耐药的关键发生机制之一,通过特异性的siRNA干扰技术有可能逆转这一化疗耐药性。另外,GE等[23]在XIAP与上皮性卵巢癌的研究中同样发现下调XIAP基因的表达可抑制肿瘤细胞的增生,促进肿瘤细胞的凋亡,增强耐药性卵巢癌细胞对化疗药物的敏感性,这与我们的结果相一致。

      综上,本研究认为:XIAP的高表达与卵巢癌细胞对紫杉醇的耐药性相关,利用特异性的siRNA下调耐紫杉醇卵巢癌细胞的XIAP的表达,可抑制癌细胞的生长,促进癌细胞的凋亡,增强耐药性卵巢癌细胞对紫杉醇的敏感性,siRNA-XIAP与紫杉醇联合应用可显著增强紫杉醇对耐药性卵巢癌细胞的杀伤作用,该研究有望为耐药性卵巢癌的靶向治疗的临床应用及卵巢癌诊疗方案的完善提供理论与实验依据。

      本实验课题为随机对照动物实验,模拟了耐药性卵巢癌在人体内发生发展的内环境,但存在一些局限:实验中每组动物数量还不成规模,仍需要更大规模的实验研究进行证实;本实验直接采用化学合成的siRNA-XIAP对耐药性卵巢癌移植瘤进行瘤内多点注射进行干扰,在处理过程中有可能存在siRNA在瘤体内干扰效果分布不均或干扰效率的不稳定,对最终凋亡率可能存在一定的影响,结果可能不十分稳定。另外,卵巢癌耐药的发生是一个内、外环境相互作用的复杂过程,多种基因如细胞凋亡基因、癌基因、抑癌基因等参与耐药性卵巢癌的发生发展,siRNA-XIAP与紫杉醇联合应用可显著增强紫杉醇对耐药性卵巢癌细胞的杀伤作用,具体发生机制尚待我们进一步研究证实,目前研究尚不能排除siRNA-XIAP与紫杉醇在抗肿瘤方面具有协同作用,这亦是我们下一步的工作重心与目标。

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