Enterovirus 71(EV71)poses a serious threat to human health,with scattered outbreaks worldwide.There are several vaccines against a few EV71 strains but no efficient drug for the treatment of EV71 infection.Therefore,i...Enterovirus 71(EV71)poses a serious threat to human health,with scattered outbreaks worldwide.There are several vaccines against a few EV71 strains but no efficient drug for the treatment of EV71 infection.Therefore,it is urgent and of significance to develop anti-EV71 drugs.Here,we found that PLX8394,a RAF inhibitor,possesses high antiviral activity against EV71 in vitro,being superior to the traditional clinical drug ribavirin.Moreover,PLX8394 exhibits broad-spectrum antiviral activity against enteroviruses.Notably,in a suckling mouse model,PLX8394 provided a 70%protection rate for EV71-infected mice,reduced the viral load in liver and heart tissues,and relieved the inflammatory response.A mechanistic study showed that PLX8394 inhibited EV71 by suppressing the RAF/MEK/ERK signaling pathway.Thus,PLX8394 lays a foundation for the development of new drugs against EV71.展开更多
Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology.Targeting this pathway results in complete or partial regression of most cancers.In recent years,cancer genomic studies have revealed tha...Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology.Targeting this pathway results in complete or partial regression of most cancers.In recent years,cancer genomic studies have revealed that genetic alterations that aberrantly activate the RAS/RAF/MEK/ERK signaling mainly occur on RAF or upstream,which motivated the extensive development of RAF inhibitors for cancer therapy.Currently,the first-generation RAF inhibitors have been approved for treating late-stage cancers with BRAF(V600E)mutations.Although these inhibitors have achieved promising outcomes in clinical treatments,their efficacy is abolished by quick-rising drug resistance.Moreover,cancers with hyperactive RAS exhibit intrinsic resistance to these drugs.To resolve these problems,the second-generation RAF inhibitors have been designed and are undergoing clinical evaluations.Here,we summarize the recent findings from mechanistic studies on RAF inhibitor resistance and discuss the critical issues in the development of next-generation RAF inhibitors with better therapeutic index,which may provide insights for improving targeted cancer therapy with RAF inhibitors.展开更多
Objective： The purpose of the study is to investigate the effects of up-regulation of Raf kinase inhibitor protein （RKIP） on the chemosensitivity of cervical cancer Hela cells. Methods： Eukaryotic expression plasm...Objective： The purpose of the study is to investigate the effects of up-regulation of Raf kinase inhibitor protein （RKIP） on the chemosensitivity of cervical cancer Hela cells. Methods： Eukaryotic expression plasmid pcDNA3.1（±）-ssRKIP containing human overall length RKIPcDNA was transfected into cervical cancer Hela cell by lipofectin assay, establishing a stable cell line containing a target gene by G418. Expression of RKIP in Hela cells was measured by Western blot analysis. After treatment with cisplatin of different concentrations and intervals of time, the effect of RKIP on the proliferation of Hela cells was evaluated by MTT method. The flow cytometry was used to investigate whether the RKIP could inhibit apoptosis in Hela cells induced by cisplatin. Results： The expression of RKIP in Hela cells transfected with pcDNA3.1-ssRKIP was increased obviously. After different concentrations of cisplatin treatment cells for 24, 48 and 72 h, the growth inhibition rate in Hela cells transfected with pcDNA3.1-ssRKIP was significantly higher than in control cells （P 〈 0.05）. With 5 pg/mL cisplatin treatment for 24 h, pcDNA3.1-ssRKIP-transfected Hela cells had an obviously higher percentage of apoptosis （23.2 ± 0.24）% than non-transfected cells （12.4 ± 0.31）% and empty vector-transfected cells （13.4 ± 0.47）%. Without treatment of cisplatin, the percentage of apoptosis for Hela cells transfected with pcDNA3.1-ssRKIP was （5.7 ± 0.12）%, which was still higher than those of the non-transfected cells （2.9 ± 0.21）% and empty vector-transfected cells （3 ± 0.08）%. Conclusion： Higher expres- sion of RKIP gene can improve chemosensitivitv of cervical cancer Hela cells to cisplatin.展开更多
目的:探讨RKIP在Ⅱ期结直肠癌中的表达及其与患者预后的关系。方法:收集130例Ⅱ期结直肠癌患者的术后组织标本,采用免疫组织化学SP法检测RKIP在原发肿瘤组织及癌旁组织中的表达,结合患者临床病理特征分析RKIP的表达水平与Ⅱ期结直肠癌...目的:探讨RKIP在Ⅱ期结直肠癌中的表达及其与患者预后的关系。方法:收集130例Ⅱ期结直肠癌患者的术后组织标本,采用免疫组织化学SP法检测RKIP在原发肿瘤组织及癌旁组织中的表达,结合患者临床病理特征分析RKIP的表达水平与Ⅱ期结直肠癌患者预后的关系。结果:结直肠癌组织中RKIP的表达水平显著低于相应癌旁组织(P<0.001)。与无复发转移患者相比,复发转移患者癌组织中RKIP的表达明显降低(P=0.034)。RKIP高表达组的10年无疾病进展生存率明显优于RKIP低/中表达组(89% vs 75%,P=0.032);与RKIP低/中表达组相比,RKIP高表达组的10年总生存期有延长趋势,但无统计学意义(71%vs88%,P=0.058)。RKIP表达下降(HR 0.37;95%CI:0.13～0.99;P=0.040)和术前CEA水平升高(HR 3.50;95%CI:1.30～9.37;P=0.013)是Ⅱ期结直肠癌患者术后复发转移的危险因素。结论:RKIP在Ⅱ期结直肠癌原发肿瘤组织中表达下调,高表达患者无疾病进展生存期明显延长,提示RKIP表达水平是Ⅱ期结直肠癌患者术后复发转移的重要预后因素。展开更多
基金supported by grants from the National Key Research and Development Plan of China(Grant No.2021YFC2300700)the China Postdoctoral Science Foundation(No.2021M693363)the grants from Hubei Health Commission(No.WJ2021M027).
文摘Enterovirus 71(EV71)poses a serious threat to human health,with scattered outbreaks worldwide.There are several vaccines against a few EV71 strains but no efficient drug for the treatment of EV71 infection.Therefore,it is urgent and of significance to develop anti-EV71 drugs.Here,we found that PLX8394,a RAF inhibitor,possesses high antiviral activity against EV71 in vitro,being superior to the traditional clinical drug ribavirin.Moreover,PLX8394 exhibits broad-spectrum antiviral activity against enteroviruses.Notably,in a suckling mouse model,PLX8394 provided a 70%protection rate for EV71-infected mice,reduced the viral load in liver and heart tissues,and relieved the inflammatory response.A mechanistic study showed that PLX8394 inhibited EV71 by suppressing the RAF/MEK/ERK signaling pathway.Thus,PLX8394 lays a foundation for the development of new drugs against EV71.
基金This study was funded by Asia Fund for Cancer Research(AFCR-2017/2019-JH)SingHealth Foundation(AM/TP011/2018)+1 种基金National Medical Research Council(OFIRG18nov-0078)Duke-NUS Medical School Khoo Foundation(Duke-NUS-KBrFA/2020/0036)to Jiancheng Hu.
文摘Hyperactive RAS/RAF/MEK/ERK signaling has a well-defined role in cancer biology.Targeting this pathway results in complete or partial regression of most cancers.In recent years,cancer genomic studies have revealed that genetic alterations that aberrantly activate the RAS/RAF/MEK/ERK signaling mainly occur on RAF or upstream,which motivated the extensive development of RAF inhibitors for cancer therapy.Currently,the first-generation RAF inhibitors have been approved for treating late-stage cancers with BRAF(V600E)mutations.Although these inhibitors have achieved promising outcomes in clinical treatments,their efficacy is abolished by quick-rising drug resistance.Moreover,cancers with hyperactive RAS exhibit intrinsic resistance to these drugs.To resolve these problems,the second-generation RAF inhibitors have been designed and are undergoing clinical evaluations.Here,we summarize the recent findings from mechanistic studies on RAF inhibitor resistance and discuss the critical issues in the development of next-generation RAF inhibitors with better therapeutic index,which may provide insights for improving targeted cancer therapy with RAF inhibitors.
基金Supported by a grant from the Qingdao Public Sphere Sci-technical Support Project(No.09-1-1-13-nsh)
文摘Objective： The purpose of the study is to investigate the effects of up-regulation of Raf kinase inhibitor protein （RKIP） on the chemosensitivity of cervical cancer Hela cells. Methods： Eukaryotic expression plasmid pcDNA3.1（±）-ssRKIP containing human overall length RKIPcDNA was transfected into cervical cancer Hela cell by lipofectin assay, establishing a stable cell line containing a target gene by G418. Expression of RKIP in Hela cells was measured by Western blot analysis. After treatment with cisplatin of different concentrations and intervals of time, the effect of RKIP on the proliferation of Hela cells was evaluated by MTT method. The flow cytometry was used to investigate whether the RKIP could inhibit apoptosis in Hela cells induced by cisplatin. Results： The expression of RKIP in Hela cells transfected with pcDNA3.1-ssRKIP was increased obviously. After different concentrations of cisplatin treatment cells for 24, 48 and 72 h, the growth inhibition rate in Hela cells transfected with pcDNA3.1-ssRKIP was significantly higher than in control cells （P 〈 0.05）. With 5 pg/mL cisplatin treatment for 24 h, pcDNA3.1-ssRKIP-transfected Hela cells had an obviously higher percentage of apoptosis （23.2 ± 0.24）% than non-transfected cells （12.4 ± 0.31）% and empty vector-transfected cells （13.4 ± 0.47）%. Without treatment of cisplatin, the percentage of apoptosis for Hela cells transfected with pcDNA3.1-ssRKIP was （5.7 ± 0.12）%, which was still higher than those of the non-transfected cells （2.9 ± 0.21）% and empty vector-transfected cells （3 ± 0.08）%. Conclusion： Higher expres- sion of RKIP gene can improve chemosensitivitv of cervical cancer Hela cells to cisplatin.
文摘目的:探讨RKIP在Ⅱ期结直肠癌中的表达及其与患者预后的关系。方法:收集130例Ⅱ期结直肠癌患者的术后组织标本,采用免疫组织化学SP法检测RKIP在原发肿瘤组织及癌旁组织中的表达,结合患者临床病理特征分析RKIP的表达水平与Ⅱ期结直肠癌患者预后的关系。结果:结直肠癌组织中RKIP的表达水平显著低于相应癌旁组织(P<0.001)。与无复发转移患者相比,复发转移患者癌组织中RKIP的表达明显降低(P=0.034)。RKIP高表达组的10年无疾病进展生存率明显优于RKIP低/中表达组(89% vs 75%,P=0.032);与RKIP低/中表达组相比,RKIP高表达组的10年总生存期有延长趋势,但无统计学意义(71%vs88%,P=0.058)。RKIP表达下降(HR 0.37;95%CI:0.13～0.99;P=0.040)和术前CEA水平升高(HR 3.50;95%CI:1.30～9.37;P=0.013)是Ⅱ期结直肠癌患者术后复发转移的危险因素。结论:RKIP在Ⅱ期结直肠癌原发肿瘤组织中表达下调,高表达患者无疾病进展生存期明显延长,提示RKIP表达水平是Ⅱ期结直肠癌患者术后复发转移的重要预后因素。
