Background:In our previous study,we observed a synergistic effect of 2,3,5,4’-Tetrahydroxystilbene-2-O-b-D-glucoside combined with adriamycin to induce apoptosis in MCF-7 breast cancer cells.However,the underlying me...Background:In our previous study,we observed a synergistic effect of 2,3,5,4’-Tetrahydroxystilbene-2-O-b-D-glucoside combined with adriamycin to induce apoptosis in MCF-7 breast cancer cells.However,the underlying mechanisms of epigenetic modifications,such as alternative splicing,have not been explored.In this study,we aimed to investigate the mechanism by which THSG inhibits MCF-7 cell proliferation using full-length transcriptome sequencing.Methods:First,cell viability was examined using the methyl thiazolyl tetrazolium method and full-length transcriptome sequencing was performed to identify genes and pathways.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to identify the principal pathways and targets of THSG.Flow cytometry analysis of cell cycle distribution was performed.Meanwhile,the analysis of alternative splicing and domains of the key proteins was conducted.Quantitative polymerase chain reaction and western blotting were performed for verification.Results:THSG showed significant cytotoxic activity in MCF-7 cells.Full-length transcriptome sequencing revealed differential alternative splicing with 173 upregulated and 263 downregulated genes.Further analysis identified distinct differential expression of genes(CHEK2-211 and CCND1-201)involved in the cell cycle in the THSG-treated group.Subsequently,alternative splicing types of CHEK2(mutually exclusive exon)and CCND1(intron retention).We found that THSG downregulated mRNA expression,as confirmed by quantitative polymerase chain reaction analysis.Interestingly,protein structural analysis revealed that THSG treatment led to the generation of CHK2-211,which was the result of a mutation in the amino acid residues(GLU-150,ASN-151)of the CHEK2 domain(VAL-150,GLY-151).and CyclinD1-201 were obtained when an amino acid(ASP-267)in the domain was lost in CyclinD1.Moreover,molecular docking analysis demonstrated that the domains of key proteins could bind THSG more effectively,with no difference in affinity.Western blotting confirmed that THSG inhibited the expression of CHK2 and CyclinD1.Conclusion:THSG modulated the alternative splicing of CHEK2 and CCND1 by inducing G0/G1 cell cycle arrest,consequently suppressing MCF-7 cell proliferation.展开更多
目的:观察重组人血管内皮抑制素(恩度)窗口期联合化疗治疗晚期大肠癌的临床疗效。方法:选取2014年6月至2018年6月于贵州省肿瘤医院就诊的不可手术的晚期大肠癌患者120例,随机分为重组人血管内皮抑制素窗口期联合化疗组(试验组)及重组人...目的:观察重组人血管内皮抑制素(恩度)窗口期联合化疗治疗晚期大肠癌的临床疗效。方法:选取2014年6月至2018年6月于贵州省肿瘤医院就诊的不可手术的晚期大肠癌患者120例,随机分为重组人血管内皮抑制素窗口期联合化疗组(试验组)及重组人血管内皮抑制素常规方案联合化疗组(对照组)各60例。试验组方案:重组人血管内皮抑制素15 mg/d,d1~d7,间歇7天重复,用药14天为1个周期,化疗于每周期使用重组人血管内皮抑制素第5天(窗口期)开始;对照组方案:重组人血管内皮抑制素15 mg/d,d1~d14,间歇7天重复,21天为1个周期,化疗于重组人血管内皮抑制素治疗第1天开始;两组均采用m FOLFOX6或FOLFIRI方案化疗。对比分析两组的临床疗效。结果:1)试验组与对照组客观有效率(objective response rate,ORR)分别为25.0%和18.3%,疾病控制率(disease control rate,DCR)分别为80.0%和73.3%,差异均无统计学意义(P=0.375,P=0.388);2)试验组与对照组1、2、3年生存率分别为(69.6%vs.62.5%)(39.7%vs.21.3%)(26.8%vs.13.3%),中位生存时间为22个月(95%CI:16.817~27.183)vs.16个月(95%CI:11.890~20.110),试验组较对照组生存率提高、生存时间延长,差异具有统计学意义(P=0.033)。3)试验组与对照组中位疾病进展时间(time to progression,TTP)分别为9、8个月,差异无统计学意义(P>0.05)。结论:重组人血管内皮抑制素窗口期联合化疗较常规应用方案联合化疗提高晚期大肠癌患者的1、2、3年生存率,延长中位生存时间。展开更多
This paper investigates the leader-following consensus problem of multi-agent systems where the leader is static and the controlling effect of each follower depends on its own state. The control protocols are proposed...This paper investigates the leader-following consensus problem of multi-agent systems where the leader is static and the controlling effect of each follower depends on its own state. The control protocols are proposed for two cases： i） for network with switching topologies and undirected information flow; ii） for network with directed information flow and communication time-delays. With the aid of several tools from algebraic graph, matrix theory and stability the- ory, the sufficient conditions guaranteeing leader-following consensus are obtained by constructing appropriate Lyapunov functions. Simulations are presented to demonstrate the effectiveness of our theoretical results.展开更多
基金This research was funded by the Science and Technology Project of Jiaxing City(2019AD32251,2020AY30010)Scientific Research Foundation of Traditional Chinese Medicine of Zhejiang Province(2021ZB291)+2 种基金Medical Scientific Research Foundation of Zhejiang Province(2020KY9482019)the 2023 Jiaxing Key Discipline of Medicine-Clinical Diagnostics(Supporting Subject 2023-ZC-002)Project of Education Commission of Hubei Province(D20202802,B2022192).
文摘Background:In our previous study,we observed a synergistic effect of 2,3,5,4’-Tetrahydroxystilbene-2-O-b-D-glucoside combined with adriamycin to induce apoptosis in MCF-7 breast cancer cells.However,the underlying mechanisms of epigenetic modifications,such as alternative splicing,have not been explored.In this study,we aimed to investigate the mechanism by which THSG inhibits MCF-7 cell proliferation using full-length transcriptome sequencing.Methods:First,cell viability was examined using the methyl thiazolyl tetrazolium method and full-length transcriptome sequencing was performed to identify genes and pathways.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to identify the principal pathways and targets of THSG.Flow cytometry analysis of cell cycle distribution was performed.Meanwhile,the analysis of alternative splicing and domains of the key proteins was conducted.Quantitative polymerase chain reaction and western blotting were performed for verification.Results:THSG showed significant cytotoxic activity in MCF-7 cells.Full-length transcriptome sequencing revealed differential alternative splicing with 173 upregulated and 263 downregulated genes.Further analysis identified distinct differential expression of genes(CHEK2-211 and CCND1-201)involved in the cell cycle in the THSG-treated group.Subsequently,alternative splicing types of CHEK2(mutually exclusive exon)and CCND1(intron retention).We found that THSG downregulated mRNA expression,as confirmed by quantitative polymerase chain reaction analysis.Interestingly,protein structural analysis revealed that THSG treatment led to the generation of CHK2-211,which was the result of a mutation in the amino acid residues(GLU-150,ASN-151)of the CHEK2 domain(VAL-150,GLY-151).and CyclinD1-201 were obtained when an amino acid(ASP-267)in the domain was lost in CyclinD1.Moreover,molecular docking analysis demonstrated that the domains of key proteins could bind THSG more effectively,with no difference in affinity.Western blotting confirmed that THSG inhibited the expression of CHK2 and CyclinD1.Conclusion:THSG modulated the alternative splicing of CHEK2 and CCND1 by inducing G0/G1 cell cycle arrest,consequently suppressing MCF-7 cell proliferation.
文摘目的:观察重组人血管内皮抑制素(恩度)窗口期联合化疗治疗晚期大肠癌的临床疗效。方法:选取2014年6月至2018年6月于贵州省肿瘤医院就诊的不可手术的晚期大肠癌患者120例,随机分为重组人血管内皮抑制素窗口期联合化疗组(试验组)及重组人血管内皮抑制素常规方案联合化疗组(对照组)各60例。试验组方案:重组人血管内皮抑制素15 mg/d,d1~d7,间歇7天重复,用药14天为1个周期,化疗于每周期使用重组人血管内皮抑制素第5天(窗口期)开始;对照组方案:重组人血管内皮抑制素15 mg/d,d1~d14,间歇7天重复,21天为1个周期,化疗于重组人血管内皮抑制素治疗第1天开始;两组均采用m FOLFOX6或FOLFIRI方案化疗。对比分析两组的临床疗效。结果:1)试验组与对照组客观有效率(objective response rate,ORR)分别为25.0%和18.3%,疾病控制率(disease control rate,DCR)分别为80.0%和73.3%,差异均无统计学意义(P=0.375,P=0.388);2)试验组与对照组1、2、3年生存率分别为(69.6%vs.62.5%)(39.7%vs.21.3%)(26.8%vs.13.3%),中位生存时间为22个月(95%CI:16.817~27.183)vs.16个月(95%CI:11.890~20.110),试验组较对照组生存率提高、生存时间延长,差异具有统计学意义(P=0.033)。3)试验组与对照组中位疾病进展时间(time to progression,TTP)分别为9、8个月,差异无统计学意义(P>0.05)。结论:重组人血管内皮抑制素窗口期联合化疗较常规应用方案联合化疗提高晚期大肠癌患者的1、2、3年生存率,延长中位生存时间。
基金supported by the National Natural Science Foundation of China(Nos.61075065,60774045,U1134108)the Ph.D.Programs Foundation of Ministry of Education of China(No.20110162110041)Hunan Provincial Innovation Foundation For Postgraduate(No.CX2011B086)
文摘This paper investigates the leader-following consensus problem of multi-agent systems where the leader is static and the controlling effect of each follower depends on its own state. The control protocols are proposed for two cases： i） for network with switching topologies and undirected information flow; ii） for network with directed information flow and communication time-delays. With the aid of several tools from algebraic graph, matrix theory and stability the- ory, the sufficient conditions guaranteeing leader-following consensus are obtained by constructing appropriate Lyapunov functions. Simulations are presented to demonstrate the effectiveness of our theoretical results.
