CN114134228B - 评估PI3K/Akt/mTOR通路相关基因突变的试剂盒、系统、储存介质及其应用 - Google Patents
评估PI3K/Akt/mTOR通路相关基因突变的试剂盒、系统、储存介质及其应用 Download PDFInfo
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Abstract
本发明提供一种评估PI3K/Akt/mTOR通路相关基因突变的试剂盒、系统、计算机可读储存介质及其应用,涉及医疗诊断技术领域。所述试剂盒包括检测KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因表达量或基因表达相关物质及其产物含量的试剂。所述系统包括数据采集模块、突变评估模块和输出模块。所述计算机可读储存介质包括完成上述系统的程序。本发明所述采用临床已有检测项目的基因作为检测对象,能够在较低检测成本的基础上对PI3K/Akt/mTOR通路相关基因突变进行较高准确度的预测。
Description
技术领域
本发明涉及医疗诊断技术领域,尤其涉及一种评估PI3K/Akt/mTOR通路相关基因突变的试剂盒、系统、计算机可读储存介质及其应用。
背景技术
PI3K/Akt/mTOR通路整合细胞外多种信号刺激,参与体内多条信号通路,影响转增殖分化和凋亡,在对mTOR的研究中发现,其与细胞凋亡、自噬、生长等均有重要联系,该通路对肿瘤的进展有重大意义。肺鳞癌中,PTEN、PIK3CA、STK11、AKT1、AKT2、AKT3、AMPK、TSC1、TSC2和MTOR等基因突变率较高且与PI3K/Akt/mTOR通路高度相关。上述基因的突变会导致PI3K/Akt/mTOR通路改变,进而影响肺鳞癌的增殖、迁移等,进而影响患者的预后。
目前主要研究的是抑制PI3K/Akt/mTOR通路药物,如中国专利CN201210379418.9公开的PRCP拮抗剂以及PRCP、PREP双重拮抗剂,日本专利JP2011533419公开的杂芳基化合物等。但临床上尚未有针对PI3K/Akt/mTOR通路相关基因突变的检测,对于肺鳞癌等PI3K/Akt/mTOR通路相关基因突变几率较高的疾病来说缺少有效的预测方式。
发明内容
本发明为了解决上述问题,提供了一种预测准确率高、成本低的评估PI3K/Akt/mTOR通路相关基因突变的试剂盒、系统、计算机可读储存介质及其应用,采用临床已有检测项目的基因作为检测对象,能够在较低检测成本的基础上对PI3K/Akt/mTOR通路相关基因突变进行较高准确度的预测。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了一种评估PI3K/Akt/mTOR通路相关基因突变的试剂盒,包括检测KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因表达量或基因表达相关物质及其产物含量的试剂。
优选的,所述试剂盒包括检测KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因RNA表达量的试剂。
优选的,所述试剂盒还包括说明书,所述说明书记载有按照如下方法确定的评估公式:
收集已知PI3K/Akt/mTOR通路相关基因突变及未突变的样本,采集上述样本中的目标基因表达量或基因表达相关物质及其产物含量数据,通过二分类Logistic回归法构建相应的评估公式;
优选的,所述当所述试剂盒由检测KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因RNA表达量的试剂组成时,说明书中记载如下评估公式:
Score=(-0.0496×KRT5)+(-0.1734×RPL21)+(0.4230×NDUFB4)+(0.4866×TK1)+(-0.2746×AQP1)+(0.2708×NCLN)+(0.4185×PGM1)+(0.3108×SMARCA4)+(-0.4329×INPPL1)+(-0.4681×TIMM9)+(-0.8354×SMYD5)+(-0.3528×NDUFAF2)+(-0.1590×STMN3)+(-0.3205×FRAT2)+(-0.2556×P3H3)+(-0.4301×MORC4)+(0.0825×TFAP2A)+(0.0163×IRX2)+(-0.2035×RASL11A)+(0.1230×SPINK5)+(-0.3018×PRR4)+(-0.2492×IRS4)+(-0.2400×CLDN6)+3.9460。
本发明还提供了一种评估PI3K/Akt/mTOR通路相关基因突变的系统,包括数据采集模块、突变评估模块和输出模块;
所述数据采集模块采集包括KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6的目标基因在样本中的基因表达量或基因表达相关物质及其产物含量;
所述突变评估模块包括可按照以下方法确定的评估公式对数据采集模块的数据计算的程序,
收集已知PI3K/Akt/mTOR通路相关基因突变及未突变的样本,采集上述样本中的目标基因表达量或基因表达相关物质及其产物含量数据,通过二分类Logistic回归法构建相应的评估公式;
所述输出模块根据突变评估模块的计算结果进行判断并输出评估结果。
优选的,所述输出模块包括可比较突变评估模块计算结果与预设值大小的程序,若计算结果≥预设值,则输出PI3K/Akt/mTOR通路相关基因突变可能性高及其类似结果;若计算结果<预设值,则输出PI3K/Akt/mTOR通路相关基因突变可能性低及其类似结果。
优选的,所述样本为肿瘤组织样本。
优选的,当针对肺鳞癌组织样本进行评估时,评估公式为:
Score=(-0.0496×KRT5)+(-0.1734×RPL21)+(0.4230×NDUFB4)+(0.4866×TK1)+(-0.2746×AQP1)+(0.2708×NCLN)+(0.4185×PGM1)+(0.3108×SMARCA4)+(-0.4329×INPPL1)+(-0.4681×TIMM9)+(-0.8354×SMYD5)+(-0.3528×NDUFAF2)+(-0.1590×STMN3)+(-0.3205×FRAT2)+(-0.2556×P3H3)+(-0.4301×MORC4)+(0.0825×TFAP2A)+(0.0163×IRX2)+(-0.2035×RASL11A)+(0.1230×SPINK5)+(-0.3018×PRR4)+(-0.2492×IRS4)+(-0.2400×CLDN6)+3.9460;
所述预设值为3.111。
本发明还提供了一种包含计算机指令的计算机可读储存介质,所述计算机指令被处理器执行时,完成权利要求上述技术方案所述的系统。
本发明还提供了前述方案所述试剂盒、前述方案所述系统或上述方案所述计算机可读储存介质在制备诊断肺鳞癌进展或预测肺鳞癌预后效果的试剂盒中的应用。
与现有技术相比,本发明的有益效果:
1、本发明提供的评估PI3K/Akt/mTOR通路相关基因突变的试剂盒、系统或计算机可读储存介质,评估PI3K/Akt/mTOR通路相关基因突变可能性的灵敏度在0.723以上,特异度在0.727以上,预测准确度高。有助于提前预测肺鳞癌等PI3K/Akt/mTOR通路相关基因突变相关的患者个性化治疗方案的制定,还可有效预测相关疾病的预后等情况的预测。
2、本发明用于评估PI3K/Akt/mTOR通路相关基因突变的检测对象(KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6等)均是临床上已有检测项目的基因,实际检测中可使用同一样本其他检测项目的相关数据,降低检测成本,有利于临床推广,降低患者负担。
附图说明
图1是本发明实施例1中筛选的187个差异基因分布图;
图2是基于本发明实施例1构建的评分公式的受试者工作特性曲线(ROC)。
具体实施方式
本发明所述的PI3K/Akt/mTOR通路的相关基因至少包括PTEN、PIK3CA、STK11、AKT1、AKT2、AKT3、AMPK、TSC1、TSC2和MTOR基因或其中部分基因片段及与其同源性在90%以上的基因或基因片段。
本发明所述的基因表达相关物质及其产物包括基因表达相关物质和基因表达产物。其中,基因表达相关物质是指直接或间接参加或影响目标基因表达的物质,可以是目标基因表达所需的信号、催化剂、生物酶、引物序列、某些核糖核酸或脱氧核糖核酸、某些氨基酸等,也可以是目标基因表达的前体物质或基因等;基因表达产物包括目标基因表达产生的氨基酸片段、多肽或蛋白及与其同源性在90%以上的氨基酸片段、多肽或蛋白。
本发明提供了一种评估PI3K/Akt/mTOR通路相关基因突变的试剂盒,包括检测KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因表达量或基因表达相关物质及其产物含量的试剂。本发明所述的试剂可以任何适用于本领域已知的基因表达量或基因表达相关物质及其产物含量检测方法的试剂,例如通过PCR、qRT-PCT、RNA-seq等方法检测相应基因在DNA水平、RNA水平上的基因表达量等。在本发明的一个具体实施方式中,所述试剂可以是RNA表达量检测试剂,包括KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因的RNA-Seq分析试剂。
本发明优选的,所述试剂盒还包括说明书,说明书中的记载用于指导使用者对试剂盒的定量检测结果进行评估分析,所述说明书按照如下方法确定所需记载的公式:
收集已知PI3K/Akt/mTOR通路相关基因突变及未突变的样本,采集上述样本中的目标基因表达量或基因表达相关物质及其产物含量数据,通过二分类Logistic回归法构建相应的Score公式。
在本发明的一些具体实施例中,当试剂盒仅包含23个目标基因的RNA表达量检测试剂时,说明书可以记载如下公式:
Score=(-0.0496×KRT5)+(-0.1734×RPL21)+(0.4230×NDUFB4)+(0.4866×TK1)+(-0.2746×AQP1)+(0.2708×NCLN)+(0.4185×PGM1)+(0.3108×SMARCA4)+(-0.4329×INPPL1)+(-0.4681×TIMM9)+(-0.8354×SMYD5)+(-0.3528×NDUFAF2)+(-0.1590×STMN3)+(-0.3205×FRAT2)+(-0.2556×P3H3)+(-0.4301×MORC4)+(0.0825×TFAP2A)+(0.0163×IRX2)+(-0.2035×RASL11A)+(0.1230×SPINK5)+(-0.3018×PRR4)+(-0.2492×IRS4)+(-0.2400×CLDN6)+3.9460。
本发明还提供了一种评估PI3K/Akt/mTOR通路相关基因突变的系统,包括数据采集模块、突变评估模块和输出模块。数据采集模块用于收集评估所需的数据,该数据可以是经有关试剂盒检测得到的数据,也可以包含其他检测项目中调取的全部或部分数据。数据采集模块将所得数据传输至突变评估模块进行评估,突变评估模块包含可运算评估公式的程序。突变评估模块将基于评估公式计算的结果输出至输出模块,由输出模块对该计算结果进行判断,得出评估结果并输出。本发明所述系统能够快速、准确的评估PI3K/Akt/mTOR通路相关基因突变可能性,进而为临床诊断、用药指导以及预后评估等方面提供参考依据。
在本发明中,所述数据采集模块优选的包括数据接收装置和/储存装置,数据接收装置可以是能够输入外来数据的计算机等,也可以是包含有调用医院系统或相关系统数据指令的电子元件;储存装置主要用于存储所采集的数据。在本发明中,所述输出模块优选的包括液晶显示屏。
本发明还提供了一种包含计算机指令的计算机可读储存介质,所述计算机指令被处理器执行时,完成上述技术方案所述的系统。
本发明还提供了一种前述技术方案所述试剂盒、前述技术方案所述系统或上述技术方案所述计算机可读储存介质在制备诊断肺鳞癌进展或预测肺鳞癌预后效果的试剂盒中的应用。
下面结合实施例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实施例1一种评估肺鳞癌PI3K/Akt/mTOR通路相关基因突变的试剂盒、系统及计算机可读储存介质的构建
1、从TCGA数据库中获得496个肺鳞癌样本的基因表达数据,根据是否存在PI3K/Akt/mTOR通路相关基因(PTEN、PIK3CA、STK11、AKT1、AKT2、AKT3、AMPK、TSC1、TSC2和MTOR)突变将样本分为突变组(n=148)和野生组(n=348),对突变组和野生组PI3K/Akt/mTOR通路相关基因进行计算并筛选出187个差异基因。
2、获取469个肺鳞癌样本的187个差异基因RNA表达量数据,以[log2(FPKM+1)形式]进行LASSO回归分析,得到与PI3K/Akt/mTOR通路相关基因突变状态显著相关的基因(如图1所示),从上述与PI3K/Akt/mTOR通路相关基因突变状态显著相关的基因中挑选临床已有检测项目的基因,最终确认23个目标基因,即:
KRT5,RPL21,NDUFB4,TK1,AQP1,NCLN,PGM1,SMARCA4,INPPL1,TIMM9,SMYD5,NDUFAF2,STMN3,FRAT2,P3H3,MORC4,TFAP2A,IRX2,RASL11A,SPINK5,PRR4,IRS4和CLDN6。
3、对步骤2确认的23个目标基因及其在样本中的RNA表达量数据,通过二分类Logistic回归构建如下评估公式:
Score=(-0.0496×KRT5)+(-0.1734×RPL21)+(0.4230×NDUFB4)+(0.4866×TK1)+(-0.2746×AQP1)+(0.2708×NCLN)+(0.4185×PGM1)+(0.3108×SMARCA4)+(-0.4329×INPPL1)+(-0.4681×TIMM9)+(-0.8354×SMYD5)+(-0.3528×NDUFAF2)+(-0.1590×STMN3)+(-0.3205×FRAT2)+(-0.2556×P3H3)+(-0.4301×MORC4)+(0.0825×TFAP2A)+(0.0163×IRX2)+(-0.2035×RASL11A)+(0.1230×SPINK5)+(-0.3018×PRR4)+(-0.2492×IRS4)+(-0.2400×CLDN6)+3.9460。
4、基于步骤3构建的评估公式计算每个样本的得分,通过ROC曲线获取最佳阈值点(如图2所示),即截断值,截断值为3.111。
5、根据截断值将已知的469个TCGA样本分为两组,即:
样本得分≥3.111的,记为突变组’;
样本得分<3.111的,记为野生组’。
将评估公式评估的结果与已知分组结果进行比较,可知该评估公式的灵敏度为0.723,特异度为0.727。
实施例2
一种评估肺鳞癌PI3K/Akt/mTOR通路相关基因突变的试剂盒,包括检测KRT5,RPL21,NDUFB4,TK1,AQP1,NCLN,PGM1,SMARCA4,INPPL1,TIMM9,SMYD5,NDUFAF2,STMN3,FRAT2,P3H3,MORC4,TFAP2A,IRX2,RASL11A,SPINK5,PRR4,IRS4和CLDN6基因的RNA表达量的RNA-Seq分析试剂。
实施例3
一种评估肺鳞癌PI3K/Akt/mTOR通路相关基因突变的系统,包括数据采集模块、突变评估模块和输出模块;
数据采集模块采集KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6的目标基因在样本中的RNA表达量;
突变评估模块包括可运算如下评估公式的程序:
Score=(-0.0496×KRT5)+(-0.1734×RPL21)+(0.4230×NDUFB4)+(0.4866×TK1)+(-0.2746×AQP1)+(0.2708×NCLN)+(0.4185×PGM1)+(0.3108×SMARCA4)+(-0.4329×INPPL1)+(-0.4681×TIMM9)+(-0.8354×SMYD5)+(-0.3528×NDUFAF2)+(-0.1590×STMN3)+(-0.3205×FRAT2)+(-0.2556×P3H3)+(-0.4301×MORC4)+(0.0825×TFAP2A)+(0.0163×IRX2)+(-0.2035×RASL11A)+(0.1230×SPINK5)+(-0.3018×PRR4)+(-0.2492×IRS4)+(-0.2400×CLDN6)+3.9460;
输出模块包括可对比突变评估模块计算结果与预设值3.111的程序,以及用于输出评估结果的液晶屏。
运行上述系统时,将KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因在样本中的RNA表达量输入至数据采集模块。数据采集模块将数据传送至突变评估模块,突变评估模块对数据按照评估公式进行预算并将计算结果输出至输出模块。输出模块将接收到的计算结果与预设值3.111进行比较,若计算结果≥3.111,则判断为PI3K/Akt/mTOR通路相关基因突变可能性大;若计算结果<3.111,则判断为PI3K/Akt/mTOR通路相关基因突变可能性小。输出模块通过液晶屏显示判断结果。
实施例4
一种包含可完成实施例3所述公式的计算机指令的计算机可读储存介质,所述计算机指令被处理器执行时,完成实施例3所述的系统。
实施例5评估效果验证
1、组织样本收集:样本来自于复旦大学中山医院接受手术切除的肺鳞状细胞癌患者。在距肿瘤边缘至少3cm处切除正常肺标本,再从肿瘤中心仅出肿瘤样本后在液氮中快速冷冻后于-80℃储存。取每个样本的一部分进行石蜡包埋,HE染色,然后由有经验的病理学家检查以确保取样的正确。按照步骤1收集了44个肺鳞癌样本。
2、以实施例2的试剂盒对步骤1获得的44个肺鳞癌组织进行RNA-Seq分析,得到KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3,FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因在每个样本中的RNA表达量。
(1)RNA测序:根据制造商的指南,使用RNA样品制备试剂盒v2(Illumina,SanDiego,USA)将总RNA中的mRNA转化为适合后续测序的模板文库。具体步骤包括mRNA的纯化、cDNA合成、末端修复、3'-末端腺苷酸化、cDNA文库PCR扩增等。然后根据制造商的推荐使用的Genome Analyzer II(Illumina)进行测序。使用软件Galaxy(http://galaxyproject.org)进行序列分析以计算每个转录本的RPKM。将给定基因的所有转录本的RPKM值相加以生成该基因表达的量度。每个样品测序两次,取每个目标基因的RPKM值的平均值以反映其实际表达水平。
(2)RNA制备:使用Trizol(Invitrogen,Carlsbad,美国)从每个样本中提取总RNA,然后重新溶解在经过二氢焦碳酸盐处理的水中,使用NanoVue Plus分光光度法(GEHealthcare,Fairfield,USA)定量,并使用琼脂糖凝胶电泳进行完整性评估。根据制造商的指南,使用gDNA Eraser(TaKaRa,Tokyo,Japan)以消除DNA污染。
(3)统计分析:使用IBM SPSS,version 20(Armonk,USA)分析来自RNA-Seq的RPKM数据。平均RPKM值用于评估基因的表达水平,同时RPKM的方差系数用于评估其表达的稳定性。
3、将步骤2获得的RNA表达量输入至实施例3所述系统的数据采集模块,并运行所述系统的突变评估模块,即按照下述公式计算每个样本的评估分数:
Score=(-0.0496×KRT5)+(-0.1734×RPL21)+(0.4230×NDUFB4)+(0.4866×TK1)+(-0.2746×AQP1)+(0.2708×NCLN)+(0.4185×PGM1)+(0.3108×SMARCA4)+(-0.4329×INPPL1)+(-0.4681×TIMM9)+(-0.8354×SMYD5)+(-0.3528×NDUFAF2)+(-0.1590×STMN3)+(-0.3205×FRAT2)+(-0.2556×P3H3)+(-0.4301×MORC4)+(0.0825×TFAP2A)+(0.0163×IRX2)+(-0.2035×RASL11A)+(0.1230×SPINK5)+(-0.3018×PRR4)+(-0.2492×IRS4)+(-0.2400×CLDN6)+3.9460;
4、将所述系统突变评估模块计算的计算结果传输至输出模块,输出模块对比计算结果与预设值3.111的大小,计算结果大于等于截断值3.111的为突变组,低于截断值3.111的为野生组。
5、实验结果分析
使用RNA变异分析来检测PI3K/Akt/mTOR通路相关基因(PTEN、PIK3CA、STK11、AKT1、AKT2、AKT3、AMPK、TSC1、TSC2和MTOR)突变情况,并用以对比,具体流程按照业界金标准GATK(The Genome Analysis Toolkit)流程,具体如下:STAR比对、去重、Split’N’Trim处理、Indel重比对、BQSR以及变异检测等步骤。
将本实施例评估PI3K/Akt/mTOR通路相关基因的结果中突变可能性高的记为“阳性”,突变可能性低的记为“阴性”。对比GATK检测结果与本实施例评估结果(如表1所示),可计算得到本实施例评估的试剂盒/系统灵敏度为0.750,特异度为0.821。
表1 PI3K/Akt/mTOR通路相关基因突变评估结果对比
综上所述,可以看出本发明提供的评估PI3K/Akt/mTOR通路相关基因的试剂盒、系统或计算机可读存储介质能够较为准确的评估评估PI3K/Akt/mTOR通路相关基因的突变可能性,并且检测对象以目前临床已有检测项目的基因为主,检测成本较低,对于肺鳞癌患者的用药指导、预后评估等方面具有重要参考意义。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (1)
1.一种检测试剂在制备评估PI3K/Akt/mTOR通路相关基因突变的试剂盒中的应用,其特征在于,所述检测试剂由检测KRT5、RPL21、NDUFB4、TK1、AQP1、NCLN、PGM1、SMARCA4、INPPL1、TIMM9、SMYD5、NDUFAF2、STMN3、FRAT2、P3H3、MORC4、TFAP2A、IRX2、RASL11A、SPINK5、PRR4、IRS4和CLDN6基因RNA表达量的试剂组成;
PI3K/Akt/mTOR通路的相关基因为PTEN、PIK3CA、STK11、AKT1、AKT2、AKT3、AMPK、TSC1、TSC2和MTOR基因。
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