目的失重环境下成骨细胞增殖能力下降是引起失重性骨丢失的重要原因之一,然而其具体机制仍不清楚。本文在前期研究基础上,研究CDK12参与模拟失重抑制成骨细胞增殖的作用及机制。方法采用RPM模拟失重条件,以CDK12高/低表达成骨细胞与对...目的失重环境下成骨细胞增殖能力下降是引起失重性骨丢失的重要原因之一,然而其具体机制仍不清楚。本文在前期研究基础上,研究CDK12参与模拟失重抑制成骨细胞增殖的作用及机制。方法采用RPM模拟失重条件,以CDK12高/低表达成骨细胞与对照组成骨细胞为研究对象,分别采用Ed U染色、流式细胞术、细胞免疫荧光染色、Real time PCR和Western Blot检测成骨细胞增殖、细胞周期、CDK12分布,以及CDK12介导的信号转导的变化,并检测CDK12高表达对失重抑制成骨细胞增殖的挽救作用。结果(1)模拟失重条件抑制成骨细胞增殖,改变细胞周期,下调成骨细胞中CDK12表达;(2)CDK12低表达抑制成骨细胞增殖,且改变细胞周期;(3)模拟失重条件或CDK12低表达抑制了RNAPⅡ磷酸化水平,并下调了DNA复制相关基因表达;(4)模拟失重条件下,CDK12高表达促进成骨细胞增殖、增加RNAPⅡ磷酸化水平,并上调DNA复制相关基因表达,对模拟失重条件抑制成骨细胞增殖具有挽救作用。结论CDK12在模拟失重条件抑制成骨细胞增殖中起重要作用。模拟失重条件下,CDK12表达受到抑制,RNAPⅡ磷酸化水平降低,进而抑制CDC6等DNA复制相关基因表达,改变细胞周期,导致成骨细胞增殖能力下降,而CDK12高表达对模拟失重抑制成骨细胞增殖具有挽救作用。展开更多
目的:对CDK4/6抑制剂联合氟维司群二线治疗Luminal型乳腺癌进行有效性及安全性评价。方法:根据检索式从Embase、PubMed、Web of Science、中国知网、万方医学网和维普网等数据库中网络检索与CDK4/6抑制剂联合氟维司群治疗Luminal型内分...目的:对CDK4/6抑制剂联合氟维司群二线治疗Luminal型乳腺癌进行有效性及安全性评价。方法:根据检索式从Embase、PubMed、Web of Science、中国知网、万方医学网和维普网等数据库中网络检索与CDK4/6抑制剂联合氟维司群治疗Luminal型内分泌耐药乳腺癌有关的随机对照试验并进行筛选,使用Stata17.0和RevMan5.4软件对纳入的RCT进行评价及Meta分析。结果:纳入8篇文献,共5项RCT,纳入研究对象2466例。Meta分析结果显示,CDK4/6抑制剂联合氟维司群与单纯应用氟维司群相比可延长患者的无进展生存期[HR=0.51,95%CI(0.46,0.56),P<0.00001]及总生存期[HR=0.73,95%CI(0.65,0.83),P<0.00001],两组间差异具有统计学意义(P<0.05)。然而CDK4/6抑制剂联合氟维司群治疗时更容易造成中性粒细胞减少、白细胞计数下降、贫血、血小板下降及疲乏等不良反应,两组间差异具有统计学意义(P<0.05)。结论:与氟维司群加安慰剂相比,CDK4/6抑制剂联合氟维司群显著延长Luminal型乳腺癌患者的PFS和OS。用药过程中常见的不良反应是血液系统的中性粒细胞减少、白细胞计数下降、贫血、血小板下降及疲乏等,且3级及以上不良反应发生率可控,在临床治疗上获益较大。展开更多
Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic ...Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic landscape.Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects.Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)–ABC.Methods:This retrospective study enrolled 82 patients with HR+/HER2–ABC who were treated with cross-line CDK4/6is(abemaciclib,palbociclib,ribociclib,and dalpiciclib)after progression with another CDK4/6i.The primary endpoint was progression-free survival(PFS)according to version 1.1 of the Response Evaluation Criteria in Solid Tumors.Secondary endpoints included toxicity,objective response rate,disease control rate,and overall survival.Adverse events(AEs)were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events,as promulgated by the U.S.Department of Health and Human Services.Results:Eighty-two HR+/HER2–ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled.The median age of the patients was 60 years.The median PFS of all patients was 7.6 months(95%CI,5.9-9.2).Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS.Notably,patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months.The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i,then to a subsequent CDK4/6i merits further investigation.Hematologic toxicity was the most common grade≥3 AEs.No instances of fatal safety events were observed.Conclusions:Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2–ABC,which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.展开更多
Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is ...Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis,and has a single treatment method.As one of the CDK4/6 inhibitors,abemaciclib can effectively inhibit the growth of breast tumors.In this study,we synthesized LA-D-B1,a derivative of Abemaciclib,and investigated its anti-tumor effects in breast cancer.Methods:Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cell cloning and migration abilities were determined by colony formation assay and wound healing assay.Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay.The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting,which quantified the levels of proteins associated with the cyclin-dependent kinase(CDK)4/6-cyclin D-Rb-E2F pathway.The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane(CAM)model.Results:The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation,induced apoptosis,and caused cell cycle arrest.Furthermore,LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway,including CDK4,CDK6 and E2F1.The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model.Conclusion:In this study,LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer.These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.展开更多
Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a cru...Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.展开更多
文摘目的失重环境下成骨细胞增殖能力下降是引起失重性骨丢失的重要原因之一,然而其具体机制仍不清楚。本文在前期研究基础上,研究CDK12参与模拟失重抑制成骨细胞增殖的作用及机制。方法采用RPM模拟失重条件,以CDK12高/低表达成骨细胞与对照组成骨细胞为研究对象,分别采用Ed U染色、流式细胞术、细胞免疫荧光染色、Real time PCR和Western Blot检测成骨细胞增殖、细胞周期、CDK12分布,以及CDK12介导的信号转导的变化,并检测CDK12高表达对失重抑制成骨细胞增殖的挽救作用。结果(1)模拟失重条件抑制成骨细胞增殖,改变细胞周期,下调成骨细胞中CDK12表达;(2)CDK12低表达抑制成骨细胞增殖,且改变细胞周期;(3)模拟失重条件或CDK12低表达抑制了RNAPⅡ磷酸化水平,并下调了DNA复制相关基因表达;(4)模拟失重条件下,CDK12高表达促进成骨细胞增殖、增加RNAPⅡ磷酸化水平,并上调DNA复制相关基因表达,对模拟失重条件抑制成骨细胞增殖具有挽救作用。结论CDK12在模拟失重条件抑制成骨细胞增殖中起重要作用。模拟失重条件下,CDK12表达受到抑制,RNAPⅡ磷酸化水平降低,进而抑制CDC6等DNA复制相关基因表达,改变细胞周期,导致成骨细胞增殖能力下降,而CDK12高表达对模拟失重抑制成骨细胞增殖具有挽救作用。
文摘目的:对CDK4/6抑制剂联合氟维司群二线治疗Luminal型乳腺癌进行有效性及安全性评价。方法:根据检索式从Embase、PubMed、Web of Science、中国知网、万方医学网和维普网等数据库中网络检索与CDK4/6抑制剂联合氟维司群治疗Luminal型内分泌耐药乳腺癌有关的随机对照试验并进行筛选,使用Stata17.0和RevMan5.4软件对纳入的RCT进行评价及Meta分析。结果:纳入8篇文献,共5项RCT,纳入研究对象2466例。Meta分析结果显示,CDK4/6抑制剂联合氟维司群与单纯应用氟维司群相比可延长患者的无进展生存期[HR=0.51,95%CI(0.46,0.56),P<0.00001]及总生存期[HR=0.73,95%CI(0.65,0.83),P<0.00001],两组间差异具有统计学意义(P<0.05)。然而CDK4/6抑制剂联合氟维司群治疗时更容易造成中性粒细胞减少、白细胞计数下降、贫血、血小板下降及疲乏等不良反应,两组间差异具有统计学意义(P<0.05)。结论:与氟维司群加安慰剂相比,CDK4/6抑制剂联合氟维司群显著延长Luminal型乳腺癌患者的PFS和OS。用药过程中常见的不良反应是血液系统的中性粒细胞减少、白细胞计数下降、贫血、血小板下降及疲乏等,且3级及以上不良反应发生率可控,在临床治疗上获益较大。
基金supported by grants from the CAMS Innovation Fund for Medical Sciences[CIFMS](Grant Nos.2021-I2M-1-014 and 2022-I2M-2-002).
文摘Objective:CDK4/6 inhibitors(CDK4/6is)in combination with endocrine therapy have secured a central role in the treatment of hormone receptor(HR)-positive advanced breast cancer(ABC)and have transformed the therapeutic landscape.Cross-line CDK4/6i therapy in which another CDK4/6i is continued after progression on a prior CDK4/6i may still offer advantageous therapeutic effects.Cross-line CDK4/6i therapy is an area of active investigation in the ongoing pursuit to improve outcomes for patients with HR+/human epidermal growth factor receptor 2(HER2)–ABC.Methods:This retrospective study enrolled 82 patients with HR+/HER2–ABC who were treated with cross-line CDK4/6is(abemaciclib,palbociclib,ribociclib,and dalpiciclib)after progression with another CDK4/6i.The primary endpoint was progression-free survival(PFS)according to version 1.1 of the Response Evaluation Criteria in Solid Tumors.Secondary endpoints included toxicity,objective response rate,disease control rate,and overall survival.Adverse events(AEs)were graded according to version 5.0 of the Common Terminology Criteria for Adverse Events,as promulgated by the U.S.Department of Health and Human Services.Results:Eighty-two HR+/HER2–ABC patients who received cross-line CDK4/6i therapy from January 2022 to February 2024 were enrolled.The median age of the patients was 60 years.The median PFS of all patients was 7.6 months(95%CI,5.9-9.2).Cox regression analysis identified lung metastasis and a switch to endocrine therapy following prior CDK4/6i therapy as independent predictive factors for PFS.Notably,patients who previously received abemaciclib and switched to palbociclib upon disease progression had a median PFS of 10.7 months.The strategy of transitioning to chemotherapy after progression on a prior CDK4/6i,then to a subsequent CDK4/6i merits further investigation.Hematologic toxicity was the most common grade≥3 AEs.No instances of fatal safety events were observed.Conclusions:Cross-line CDK4/6i therapy is associated with significant clinical benefits and manageable safety profiles in patients with HR+/HER2–ABC,which underscores cross-line CDK4/6i therapy potential as an effective treatment strategy.
基金supported by the National Natural Science Foundation of China(82273167,82104174,81602626,12271068,82172558 and 82373112)Jiangsu Province Basic Research Program Natural Science Foundation(Outstanding Youth Fund Project,BK20220063)+7 种基金the Key Program of Basic Science(Natural Science)of Jiangsu Province(22KJA350001)“Huaguo Mountain Talent Plan”of Lianyungang City(Innovative Talents Liu Bin)Qing Lan Project of Jiangsu Universities(Outstanding Young Backbone Teachers,Ji Jing)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(No.20KJB350008)Priority Academic Program Development of Jiangsu Higher Education Institutions,College Students’Innovative Entrepreneurial Training Plan Program(Project Nos.SY202211641640011,SY202311641640002 and SZ202311641640002)Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province(Project No.CXPJJH123003-027)the Distinguished Young Scholars of Nanjing(JQX20008)Scientific Research Foundation for Returned Scholars of Tongji Hospital(Project 2022hgry021).
文摘Background:Regulatory proteins involved in human cellular division and proliferation,cyclin-dependent kinases 4 and 6(CDK4/6)are overexpressed in numerous cancers,including triple-negative breast cancer(TNBC).TNBC is a common pathological subtype of breast cancer that is prone to recurrence and metastasis,and has a single treatment method.As one of the CDK4/6 inhibitors,abemaciclib can effectively inhibit the growth of breast tumors.In this study,we synthesized LA-D-B1,a derivative of Abemaciclib,and investigated its anti-tumor effects in breast cancer.Methods:Cellular viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT)assay.Cell cloning and migration abilities were determined by colony formation assay and wound healing assay.Cell invasion abilities and adhesion were determined by cell invasion assay and cell adhesion assay.The impact of compound LA-D-B1 on cell proliferation and the cell cycle was analyzed through Western blotting,which quantified the levels of proteins associated with the cyclin-dependent kinase(CDK)4/6-cyclin D-Rb-E2F pathway.The in vivo anti-tumor activity of compound LA-D-B1 was investigated using a chick chorioallantoic membrane(CAM)model.Results:The study demonstrated that LA-D-B1 effectively suppressed breast cancer cell proliferation,induced apoptosis,and caused cell cycle arrest.Furthermore,LA-D-B1 reduced the expression of key proteins in the CDK4/6-cyclin D-Rb-E2F pathway,including CDK4,CDK6 and E2F1.The results also indicated significant antitumor activity of LA-D-B1 in a transplanted tumor model.Conclusion:In this study,LA-D-B1 demonstrated a potent anti-tumor effect by effectively suppressing cell proliferation and inhibiting cell cycle progression in breast cancer.These findings highlight the potential of LA-D-B1 as a valuable compound for enhancing therapeutic outcomes and controlling the progression of breast cancer.
基金This work was supported by the Major Subject of Science and Technology of Anhui Province(Grant Number:201903a07020030).
文摘Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.
