目的BRCA1/2基因胚系变异按照风险等级分为5类,其中3类意义未明位点(variants of the uncertain significance,VUS)需要定期复核。探索变异证据的更新对变异分类的影响并指导携带有害VUS位点的患者进行临床诊疗。方法收集971例进行了BRC...目的BRCA1/2基因胚系变异按照风险等级分为5类,其中3类意义未明位点(variants of the uncertain significance,VUS)需要定期复核。探索变异证据的更新对变异分类的影响并指导携带有害VUS位点的患者进行临床诊疗。方法收集971例进行了BRCA1/2基因胚系检测的患者(乳腺或卵巢癌),筛选出VUS位点128个。整合人群频率数据库、疾病数据库、计算机软件预测、共分离证据、等位基因证据及人群队列研究等证据,重新分析这些VUS位点,明确变异分类是否发生改变。结果142例肿瘤患者携带BRCA1/2基因VUS位点,占14.6%(142/971),变异位点数为128个,其中错义突变、同义突变、框内非移码突变和非编码区突变的比例分别为70.3%、4.7%、3.1%、21.9%。重新复核分析发现11.7%(15/128)的VUS位点可降级为2类,疑似良性。结论随着胚系变异相关证据的不断更新,VUS位点经再次复核后变异分类可能会有所改变。展开更多
Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-asso...Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.展开更多
Chronic enteropathy associated with the SLCO2A1 gene(CEAS)is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss.This review explores ...Chronic enteropathy associated with the SLCO2A1 gene(CEAS)is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss.This review explores the potential mechanisms underlying the pathogenesis of CEAS,focusing on the role of SLCO2A1-encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2(PGE2)levels.Studies have suggested that elevated PGE2 levels contribute to mucosal damage,inflammation,and disruption of the intestinal barrier.The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality,as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS.Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel,targeted therapies.展开更多
目的:评估BRCA1/2基因突变状态与卵巢癌患者临床特征的相关性及对预后的影响。方法:选取2017年11月—2022年6月在兰州大学第一医院进行治疗的51例接受BRCA1/2基因检测的卵巢癌患者作为研究对象,根据检测结果分为BRCA1/2突变组(30例)和BR...目的:评估BRCA1/2基因突变状态与卵巢癌患者临床特征的相关性及对预后的影响。方法:选取2017年11月—2022年6月在兰州大学第一医院进行治疗的51例接受BRCA1/2基因检测的卵巢癌患者作为研究对象,根据检测结果分为BRCA1/2突变组(30例)和BRCA1/2正常组(21例)。比较2组患者的临床基线资料、临床病理特征和预后,分析影响BRCA1/2基因突变的卵巢癌患者预后的相关因素。结果:BRCA1/2突变组与BRCA1/2正常组相比,发病年龄、体质量指数(body mass index,BMI)、恶性肿瘤家族史、治疗前糖类抗原125(carbohydrate antigen 125,CA125)及人附睾蛋白4(human epididymis protein 4,HE4)差异均无统计学意义(均P>0.05)。BRCA1/2突变组与BRCA1/2正常组肿瘤分期及淋巴结转移情况比较,差异有统计学意义(P<0.05)。多因素Cox回归分析显示BRCA1/2基因突变不是卵巢癌生存率及无进展生存期的独立预后因素(HR=0.752,95%CI:0.394~1.435,P=0.329)。结论:BRCA1/2基因突变是决定卵巢癌患者临床治疗的重要因素,与肿瘤分期及淋巴结转移情况显著相关,但仍不能确定BRCA1/2基因突变是卵巢癌的独立危险因素。展开更多
文摘目的BRCA1/2基因胚系变异按照风险等级分为5类,其中3类意义未明位点(variants of the uncertain significance,VUS)需要定期复核。探索变异证据的更新对变异分类的影响并指导携带有害VUS位点的患者进行临床诊疗。方法收集971例进行了BRCA1/2基因胚系检测的患者(乳腺或卵巢癌),筛选出VUS位点128个。整合人群频率数据库、疾病数据库、计算机软件预测、共分离证据、等位基因证据及人群队列研究等证据,重新分析这些VUS位点,明确变异分类是否发生改变。结果142例肿瘤患者携带BRCA1/2基因VUS位点,占14.6%(142/971),变异位点数为128个,其中错义突变、同义突变、框内非移码突变和非编码区突变的比例分别为70.3%、4.7%、3.1%、21.9%。重新复核分析发现11.7%(15/128)的VUS位点可降级为2类,疑似良性。结论随着胚系变异相关证据的不断更新,VUS位点经再次复核后变异分类可能会有所改变。
基金supported by the National Natural Science Foundation of China,Nos.82071008(to BL)and 82004001(to XJ)Medical Science and Technology Program of Health Commission of Henan Province,No.LHGJ20210072(to RQ)Science and Technology Department of Henan Province,No.212102310307(to XJ)。
文摘Retinitis pigmentosa is a group of inherited diseases that lead to retinal degeneration and photoreceptor cell death.However,there is no effective treatment for retinitis pigmentosa caused by PDE6B mutation.Adeno-associated virus(AAV)-mediated gene therapy is a promising strategy for treating retinitis pigmentosa.The aim of this study was to explore the molecular mechanisms by which AAV2-PDE6B rescues retinal function.To do this,we injected retinal degeneration 10(rd10)mice subretinally with AAV2-PDE6B and assessed the therapeutic effects on retinal function and structure using dark-and light-adapted electroretinogram,optical coherence tomography,and immunofluorescence.Data-independent acquisition-mass spectrometry-based proteomic analysis was conducted to investigate protein expression levels and pathway enrichment,and the results from this analysis were verified by real-time polymerase chain reaction and western blotting.AAV2-PDE6B injection significantly upregulated PDE6βexpression,preserved electroretinogram responses,and preserved outer nuclear layer thickness in rd10 mice.Differentially expressed proteins between wild-type and rd10 mice were closely related to visual perception,and treating rd10 mice with AAV2-PDE6B restored differentially expressed protein expression to levels similar to those seen in wild-type mice.Kyoto Encyclopedia of Genes and Genome analysis showed that the differentially expressed proteins whose expression was most significantly altered by AAV2-PDE6B injection were enriched in phototransduction pathways.Furthermore,the phototransductionrelated proteins Pde6α,Rom1,Rho,Aldh1a1,and Rbp1 exhibited opposite expression patterns in rd10 mice with or without AAV2-PDE6B treatment.Finally,Bax/Bcl-2,p-ERK/ERK,and p-c-Fos/c-Fos expression levels decreased in rd10 mice following AAV2-PDE6B treatment.Our data suggest that AAV2-PDE6B-mediated gene therapy promotes phototransduction and inhibits apoptosis by inhibiting the ERK signaling pathway and upregulating Bcl-2/Bax expression in retinitis pigmentosa.
基金Supported by the National High-Level Hospital Clinical Research Fund,No.2022-PUMCH-A-020the Undergraduate Teaching Reform and Innovation Project,No.2022zlgc0108.
文摘Chronic enteropathy associated with the SLCO2A1 gene(CEAS)is a complex gastroenterological condition characterized by multiple ulcers in the small intestine with chronic bleeding and protein loss.This review explores the potential mechanisms underlying the pathogenesis of CEAS,focusing on the role of SLCO2A1-encoded prostaglandin transporter OATP2A1 and its impact on prostaglandin E2(PGE2)levels.Studies have suggested that elevated PGE2 levels contribute to mucosal damage,inflammation,and disruption of the intestinal barrier.The effects of PGE2 on macrophage activation and Maxi-Cl channel functionality,as well as its interaction with nonsteroidal anti-inflammatory drugs play crucial roles in the progression of CEAS.Understanding the balance between its protective and pro-inflammatory effects and the complex interactions within the gastrointestinal tract can shed light on potential therapeutic targets for CEAS and guide the development of novel,targeted therapies.
文摘目的:评估BRCA1/2基因突变状态与卵巢癌患者临床特征的相关性及对预后的影响。方法:选取2017年11月—2022年6月在兰州大学第一医院进行治疗的51例接受BRCA1/2基因检测的卵巢癌患者作为研究对象,根据检测结果分为BRCA1/2突变组(30例)和BRCA1/2正常组(21例)。比较2组患者的临床基线资料、临床病理特征和预后,分析影响BRCA1/2基因突变的卵巢癌患者预后的相关因素。结果:BRCA1/2突变组与BRCA1/2正常组相比,发病年龄、体质量指数(body mass index,BMI)、恶性肿瘤家族史、治疗前糖类抗原125(carbohydrate antigen 125,CA125)及人附睾蛋白4(human epididymis protein 4,HE4)差异均无统计学意义(均P>0.05)。BRCA1/2突变组与BRCA1/2正常组肿瘤分期及淋巴结转移情况比较,差异有统计学意义(P<0.05)。多因素Cox回归分析显示BRCA1/2基因突变不是卵巢癌生存率及无进展生存期的独立预后因素(HR=0.752,95%CI:0.394~1.435,P=0.329)。结论:BRCA1/2基因突变是决定卵巢癌患者临床治疗的重要因素,与肿瘤分期及淋巴结转移情况显著相关,但仍不能确定BRCA1/2基因突变是卵巢癌的独立危险因素。
