Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treatin...Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and downregulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.展开更多
目的:探讨TP53突变和缺失对弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)患者预后的影响。方法:收集我院2017至2020年94例初发DLBCL患者的石蜡病理组织,应用免疫组化及二代测序检测TP53突变,FISH技术检测TP53缺失,分析TP5...目的:探讨TP53突变和缺失对弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)患者预后的影响。方法:收集我院2017至2020年94例初发DLBCL患者的石蜡病理组织,应用免疫组化及二代测序检测TP53突变,FISH技术检测TP53缺失,分析TP53突变、缺失与临床病理及分子分型的相关性,以及对生存的影响。应用COX回归分析DLBCL的生存影响因素。结果:27.7%(26/94)患者过表达p53,23.5%(19/81)患者存在TP53突变,16.0%(15/94)患者TP53缺失,结外受累(P=0.027)、MUM-1(P=0.04)及p53蛋白(P<0.01)表达在在TP53突变和/或缺失及TP53正常两组中存在明显差异。生存分析显示,“双阳性(TP53突变合并缺失)”组生存最差,“双阴性(无TP53突变及缺失)”组预后最好,TP53突变或缺失则次之,其中单突变与单缺失两组总生存无明显统计学差异(P=0.689),其余各组之间生存有显著差异(P<0.05)。GCB中,TP53突变组预后较差(P=0.046)。多因素分析显示合并B症状、TP53异常及双表达是影响DLBCL生存的独立危险因素。结论:TP53突变或缺失,特别是同时合并突变和缺失是DLBCL的不良预后因素,在新的分子分型中,其预后意义仍值得进一步的深入研究。展开更多
Non-small cell lung cancer(NSCLC)is a malignant tumor with high incidence worldwide.Triptolide(TP),extracted from Tripterygium wilfordii Hook F,exhibits potent broad-spectrum antitumor activity.Although some mechanism...Non-small cell lung cancer(NSCLC)is a malignant tumor with high incidence worldwide.Triptolide(TP),extracted from Tripterygium wilfordii Hook F,exhibits potent broad-spectrum antitumor activity.Although some mechanisms through which TP inhibits NSCLC are well understood,those that involve ribosomal proteins remain yet to be understood.In this study,the transcriptome and proteome were integrated and analyzed.Our data indicated ribosomal protein L4(RPL4)to be a core hub protein in the protein-protein interaction network.RPL4 is overexpressed in NSCLC tissues and cells.Transfection with siRPL4 or TP treatment alone arrested the cell cycle in the G1 phase,induced cell apoptosis,and repressed cell invasion.Compared to treating cells with TP alone or siRPL4,treating them with siRPL4–TP enhanced the inhibition of NSCLC cells.Reduced RPL4 expression reinforced the inhibitory effects of TP on NSCLC cells by disrupting the MDM2-P53 pathway and by altering the expression of PARP1/Snail/cyclin D1.In vivo assays verified that TP induced cell apoptosis and reduced RPL4 expression in xenografts.These findings provide clues to facilitate the development of effective TP-based therapeutic strategies to kill NSCLC cells.展开更多
目的探讨贝伐珠单抗联合TP(紫杉醇+顺铂)化疗方案治疗晚期非小细胞肺癌(NSCLC)的疗效及对预后的影响。方法选取晚期NSCLC患者78例,随机分为A组(39例,予以TP化疗方案)和B组(39例,予以TP化疗方案+贝伐珠单抗)。比较2组的客观缓解率(ORR)...目的探讨贝伐珠单抗联合TP(紫杉醇+顺铂)化疗方案治疗晚期非小细胞肺癌(NSCLC)的疗效及对预后的影响。方法选取晚期NSCLC患者78例,随机分为A组(39例,予以TP化疗方案)和B组(39例,予以TP化疗方案+贝伐珠单抗)。比较2组的客观缓解率(ORR)、疾病控制率(DCR)和血清肿瘤标志物[血管内皮生长因子(VEGF)、细胞角蛋白19片段(CYFRA21-1)、癌胚抗原(CEA)]水平。记录治疗期间肝肾功能损害、白细胞减少、中性粒细胞减少、血小板减少、胃肠道反应等不良反应发生情况。自实施治疗日始对患者进行随访,统计2组患者的5年生存率、无进展生存期(PFS)和总生存期(OS)。结果B组ORR、DCR分别为58.97%、89.74%,分别高于A组的35.90%、71.79%(P<0.05)。治疗后2组血清VEGF、CYFRA21-1、CEA水平均降低,且B组低于A组(P<0.05)。2组肝、肾功能损害,白细胞减少,中性粒细胞减少,血小板减少,胃肠道反应发生率均无明显差异(P>0.05)。B组5年生存率为20.51%,与A组(12.82%)相比无明显差异(P>0.05)。Kaplan-Meier生存曲线显示,B组的中位PFS长于A组(8.9 vs 7.2个月)(P<0.05);B组的中位OS长于A组(25.6 vs 17.9个月)(P<0.05)。结论相比于TP化疗方案治疗晚期NSCLC,联合贝伐珠单抗可提高ORR和DCR,延长PFS和OS,且可降低VEGF、CYFRA21-1、CEA肿瘤标志物水平。展开更多
骨髓增生异常肿瘤(myelodysplastic neoplasms,MDS)患者的预后与其细胞遗传学和分子遗传学特征密切相关,TP53基因作为MDS最常见的突变基因之一,其异常是MDS独立的不良预后因素以及向急性髓系白血病(acute myeloid leuke⁃mia,AML)转化的...骨髓增生异常肿瘤(myelodysplastic neoplasms,MDS)患者的预后与其细胞遗传学和分子遗传学特征密切相关,TP53基因作为MDS最常见的突变基因之一,其异常是MDS独立的不良预后因素以及向急性髓系白血病(acute myeloid leuke⁃mia,AML)转化的危险因素之一。新近更新的第5版世界卫生组织血液淋巴肿瘤分类标准(the 5th edition of the who classifica⁃tion of haematolymphoid tumours,WHO 2022)以及髓系肿瘤和急性白血病的国际共识分类(international consensus classification of myeloid neoplasms and acute leukemia,ICC)将伴有TP53双等位基因失活(biallelic TP53 inactivation,biTP53)的MDS作为独立的亚型列出,该亚型患者预后极差,生存期极短。目前针对伴TP53基因异常的MDS患者的治疗尚未能有效改善该类患者预后,新型靶向药物、免疫治疗等均在探索中,本文就国内外对伴TP53基因异常的MDS的临床研究进展进行综述。展开更多
基金supported by grants from the National Key Research and Development Program of China(Grant Nos.:2020YFA0908000,2022YFC2303600)the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(Grant No.:ZYYCXTD-C-202002)+7 种基金the National Natural Science Foundation of China(Grant Nos.:82201786,82141001,82274182,82074098,82173914)the CACMS Innovation Fund(Grant Nos.:CI2021A05101,CI2021A05104)the Scientific and Technological Innovation Project of China Academy of Chinese Medical Sciences(Grant No.:CI2021B014)the Science and Technology Foundation of Shenzhen(Grant Nos.:JCYJ20220818102613029,JCYJ20210324114014039,JCYJ20210324115800001)Guangdong Basic and Applied Basic Research Foundation(Grant Nos.:2020A1515110549,2021A1515110646)the Science and Technology Foundation of Shenzhen(Shenzhen Clinical Medical Research Center for Geriatric Diseases)the National Key R&D Program of China Key projects for international cooperation on science,technology and innovation(Grant No.:2020YFE0205100)and the Fundamental Research Funds for the Central Public Welfare Research Institutes(Grant Nos.:ZZ14-YQ-050,ZZ14-YQ-051,ZZ14-YQ-052,ZZ14-FL-002,ZZ14-ND-010,ZZ15-ND-10).
文摘Triptolide is a key active component of the widely used traditional Chinese herb medicine Tripterygium wilfordii Hook.F.Although triptolide exerts multiple biological activities and shows promising efficacy in treating inflammatory-related diseases,its well-known safety issues,especially reproductive toxicity has aroused concerns.However,a comprehensive dissection of triptolide-associated testicular toxicity at single cell resolution is still lacking.Here,we observed testicular toxicity after 14 days of triptolide exposure,and then constructed a single-cell transcriptome map of 59,127 cells in mouse testes upon triptolide-treatment.We identified triptolide-associated shared and cell-type specific differentially expressed genes,enriched pathways,and ligand-receptor pairs in different cell types of mouse testes.In addition to the loss of germ cells,our results revealed increased macrophages and the inflammatory response in triptolide-treated mouse testes,suggesting a critical role of inflammation in triptolide-induced testicular injury.We also found increased reactive oxygen species(ROS)signaling and downregulated pathways associated with spermatid development in somatic cells,especially Leydig and Sertoli cells,in triptolide-treated mice,indicating that dysregulation of these signaling pathways may contribute to triptolide-induced testicular toxicity.Overall,our high-resolution single-cell landscape offers comprehensive information regarding triptolide-associated gene expression profiles in major cell types of mouse testes at single cell resolution,providing an invaluable resource for understanding the underlying mechanism of triptolide-associated testicular injury and additional discoveries of therapeutic targets of triptolide-induced male reproductive toxicity.
文摘目的:探讨TP53突变和缺失对弥漫大B细胞淋巴瘤(diffuse large B-cell lymphoma, DLBCL)患者预后的影响。方法:收集我院2017至2020年94例初发DLBCL患者的石蜡病理组织,应用免疫组化及二代测序检测TP53突变,FISH技术检测TP53缺失,分析TP53突变、缺失与临床病理及分子分型的相关性,以及对生存的影响。应用COX回归分析DLBCL的生存影响因素。结果:27.7%(26/94)患者过表达p53,23.5%(19/81)患者存在TP53突变,16.0%(15/94)患者TP53缺失,结外受累(P=0.027)、MUM-1(P=0.04)及p53蛋白(P<0.01)表达在在TP53突变和/或缺失及TP53正常两组中存在明显差异。生存分析显示,“双阳性(TP53突变合并缺失)”组生存最差,“双阴性(无TP53突变及缺失)”组预后最好,TP53突变或缺失则次之,其中单突变与单缺失两组总生存无明显统计学差异(P=0.689),其余各组之间生存有显著差异(P<0.05)。GCB中,TP53突变组预后较差(P=0.046)。多因素分析显示合并B症状、TP53异常及双表达是影响DLBCL生存的独立危险因素。结论:TP53突变或缺失,特别是同时合并突变和缺失是DLBCL的不良预后因素,在新的分子分型中,其预后意义仍值得进一步的深入研究。
基金supported by the National Natural Science Foundation of China(Grant Nos.82004007 and 81774026).
文摘Non-small cell lung cancer(NSCLC)is a malignant tumor with high incidence worldwide.Triptolide(TP),extracted from Tripterygium wilfordii Hook F,exhibits potent broad-spectrum antitumor activity.Although some mechanisms through which TP inhibits NSCLC are well understood,those that involve ribosomal proteins remain yet to be understood.In this study,the transcriptome and proteome were integrated and analyzed.Our data indicated ribosomal protein L4(RPL4)to be a core hub protein in the protein-protein interaction network.RPL4 is overexpressed in NSCLC tissues and cells.Transfection with siRPL4 or TP treatment alone arrested the cell cycle in the G1 phase,induced cell apoptosis,and repressed cell invasion.Compared to treating cells with TP alone or siRPL4,treating them with siRPL4–TP enhanced the inhibition of NSCLC cells.Reduced RPL4 expression reinforced the inhibitory effects of TP on NSCLC cells by disrupting the MDM2-P53 pathway and by altering the expression of PARP1/Snail/cyclin D1.In vivo assays verified that TP induced cell apoptosis and reduced RPL4 expression in xenografts.These findings provide clues to facilitate the development of effective TP-based therapeutic strategies to kill NSCLC cells.
文摘目的探讨贝伐珠单抗联合TP(紫杉醇+顺铂)化疗方案治疗晚期非小细胞肺癌(NSCLC)的疗效及对预后的影响。方法选取晚期NSCLC患者78例,随机分为A组(39例,予以TP化疗方案)和B组(39例,予以TP化疗方案+贝伐珠单抗)。比较2组的客观缓解率(ORR)、疾病控制率(DCR)和血清肿瘤标志物[血管内皮生长因子(VEGF)、细胞角蛋白19片段(CYFRA21-1)、癌胚抗原(CEA)]水平。记录治疗期间肝肾功能损害、白细胞减少、中性粒细胞减少、血小板减少、胃肠道反应等不良反应发生情况。自实施治疗日始对患者进行随访,统计2组患者的5年生存率、无进展生存期(PFS)和总生存期(OS)。结果B组ORR、DCR分别为58.97%、89.74%,分别高于A组的35.90%、71.79%(P<0.05)。治疗后2组血清VEGF、CYFRA21-1、CEA水平均降低,且B组低于A组(P<0.05)。2组肝、肾功能损害,白细胞减少,中性粒细胞减少,血小板减少,胃肠道反应发生率均无明显差异(P>0.05)。B组5年生存率为20.51%,与A组(12.82%)相比无明显差异(P>0.05)。Kaplan-Meier生存曲线显示,B组的中位PFS长于A组(8.9 vs 7.2个月)(P<0.05);B组的中位OS长于A组(25.6 vs 17.9个月)(P<0.05)。结论相比于TP化疗方案治疗晚期NSCLC,联合贝伐珠单抗可提高ORR和DCR,延长PFS和OS,且可降低VEGF、CYFRA21-1、CEA肿瘤标志物水平。
文摘骨髓增生异常肿瘤(myelodysplastic neoplasms,MDS)患者的预后与其细胞遗传学和分子遗传学特征密切相关,TP53基因作为MDS最常见的突变基因之一,其异常是MDS独立的不良预后因素以及向急性髓系白血病(acute myeloid leuke⁃mia,AML)转化的危险因素之一。新近更新的第5版世界卫生组织血液淋巴肿瘤分类标准(the 5th edition of the who classifica⁃tion of haematolymphoid tumours,WHO 2022)以及髓系肿瘤和急性白血病的国际共识分类(international consensus classification of myeloid neoplasms and acute leukemia,ICC)将伴有TP53双等位基因失活(biallelic TP53 inactivation,biTP53)的MDS作为独立的亚型列出,该亚型患者预后极差,生存期极短。目前针对伴TP53基因异常的MDS患者的治疗尚未能有效改善该类患者预后,新型靶向药物、免疫治疗等均在探索中,本文就国内外对伴TP53基因异常的MDS的临床研究进展进行综述。