The therapeutic efficacy of metformin in prostate cancer(PCa)appears uncertain based on various clinical trials.Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation,whic...The therapeutic efficacy of metformin in prostate cancer(PCa)appears uncertain based on various clinical trials.Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation,which leads to drug resistance.However,the underlying mechanism is still unclear.In this study,we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation.Super-enhancers(SEs),crucial regulatory elements,have been shown to be associated with drug resistance in various cancers.Our analysis of SEs in metformin-resistant(MetR)PCa cells revealed a correlation with Prostaglandin Reductase 1(PTGR1)expression,which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing.Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases,resulting in reduced sensitivity to metformin.Additionally,we identified key transcription factors that significantly increase PTGR1 expression,such as SRF and RUNX3,providing potential new targets to address metformin resistance in PCa.In conclusion,our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis,offering potential avenues to enhance metformin’s therapeutic efficacy in PCa.展开更多
In this study we successfully intercalated potassium(K) atoms into single ZrTe_5 crystals by liquid ammonia method, and found a semimetal-to-semiconductor transition at low temperatures in K-intercalated ZrTe_5. As th...In this study we successfully intercalated potassium(K) atoms into single ZrTe_5 crystals by liquid ammonia method, and found a semimetal-to-semiconductor transition at low temperatures in K-intercalated ZrTe_5. As the K concentration increased, the resistance anomalous peak was gradually suppressed until finally disappearing. Whilst, the corresponding Hall resistance measurements consistently showed a sign reversal. The semimetal-to-semiconductor transition can be attributed to a lattice expansion induced by atom intercalation, leading to a larger energy band gap.展开更多
文摘目的探讨高敏肌钙蛋白T(high-sensitivity cardiac troponin T,hs-cTnT)动态变化与晚时间窗内接受机械取栓治疗的前循环大血管闭塞型急性缺血性脑卒中患者不良预后的相关性。方法共纳入161例患者,分别于入院时和24 h测量血清hs-cTnT。hs-cTnT升高定义为大于14 ng/L;hs-cTnT动态变化定义为两次测量值上升或下降超过20%且至少有一次大于14 ng/L。评价hs-cTnT动态变化与3个月时不良预后的相关性;比较入院时hs-cTnT升高与hs-cTnT动态变化预测3个月时不良预后的接收者操作特征(receiver-operating characteristic,ROC)曲线下面积(areas under the ROC curve,AUC)。结果67(41.6%)例患者发生hs-cTnT动态变化。多因素分析显示,hs-cTnT升高(P=0.014,P=0.038)和hs-cTnT动态变化(P<0.001,P<0.001)分别是不良预后和死亡的独立预测因素。AUC比较显示hs-cTnT动态变化对不良预后(AUC 0.765 vs 0.689,P=0.043)和死亡(AUC 0.818 vs 0.687,P=0.008)的预测价值要显著优于入院时hs-cTnT升高。结论hs-cTnT动态变化是晚时间窗进行血管内治疗的急性颅内大血管闭塞性脑卒中患者3个月时不良预后和死亡的独立预测因素。hs-cTnT动态变化对不良预后的预测价值要显著优于入院时hs-cTnT升高。
基金This study was supported by the National Natural Science Foundation of China(82072813,82203557,82103358)The Science and Technology Development Fund,Macao SAR(File no.0031/2021/A,0090/2022/A)+1 种基金GuangDong Basic and Applied Basic Research Foundation(2020A1515110792,2022A1515010342,2020A1515110640,2020A1515011290)Guangzhou Municipal Science and Technology Project(202201010053).We thank Mr.Yuanqi Feng for bioinformatic support and discussion,Mr.Zuqing Deng for technical assistance and discussion.
文摘The therapeutic efficacy of metformin in prostate cancer(PCa)appears uncertain based on various clinical trials.Metformin treatment failure may be attributed to the high frequency of transcriptional dysregulation,which leads to drug resistance.However,the underlying mechanism is still unclear.In this study,we found evidences that metformin resistance in PCa cells may be linked to cell cycle reactivation.Super-enhancers(SEs),crucial regulatory elements,have been shown to be associated with drug resistance in various cancers.Our analysis of SEs in metformin-resistant(MetR)PCa cells revealed a correlation with Prostaglandin Reductase 1(PTGR1)expression,which was identified as significantly increased in a cluster of cells with metformin resistance through single-cell transcriptome sequencing.Our functional experiments showed that PTGR1 overexpression accelerated cell cycle progression by promoting progression from the G0/G1 to the S and G2/M phases,resulting in reduced sensitivity to metformin.Additionally,we identified key transcription factors that significantly increase PTGR1 expression,such as SRF and RUNX3,providing potential new targets to address metformin resistance in PCa.In conclusion,our study sheds new light on the cellular mechanism underlying metformin resistance and the regulation of the SE-TFs-PTGR1 axis,offering potential avenues to enhance metformin’s therapeutic efficacy in PCa.
基金supported by the Ministry of Science and Technology of China(Grant Nos.2014CB921103,and 2015CB921203)the National Natural Science Foundation of China(Grant Nos.11774149,11790311,11674157,11674154,51032003,1171101156,11374149,and 11374140)
文摘In this study we successfully intercalated potassium(K) atoms into single ZrTe_5 crystals by liquid ammonia method, and found a semimetal-to-semiconductor transition at low temperatures in K-intercalated ZrTe_5. As the K concentration increased, the resistance anomalous peak was gradually suppressed until finally disappearing. Whilst, the corresponding Hall resistance measurements consistently showed a sign reversal. The semimetal-to-semiconductor transition can be attributed to a lattice expansion induced by atom intercalation, leading to a larger energy band gap.
