Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)...Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.展开更多
Objective:The plastic role of regulatory factor X1(RFX1)in colon cancer progression and its impact on the tumor microenvironment remain poorly understood.The study aimed to clarify the molecular and clinical role of R...Objective:The plastic role of regulatory factor X1(RFX1)in colon cancer progression and its impact on the tumor microenvironment remain poorly understood.The study aimed to clarify the molecular and clinical role of RFX1 in colon cancer.Methods:We classified colon cancers into subgroups with high and low RFX1 expression and characterized their immune profiles,mutational profiles,cancer immunotherapy and drug sensitivity.By combining RFX1 expression with persistent tumor mutational burden,we proposed a novel nomogram clinical prediction model and validated its predictive performance,and the correlation between high expression and poor prognosis.Results:Compared to tumor mutational burden(TMB),persistent tumor mutational burden(pTMB)is an independent predictor of prognosis in patients with colon cancer.The predictive efficacy of the combination of RFX1 expression and pTMB was superior to and sensitive than the combination of RFX1 expression with TMB.Among them,patients in the RFX1^(high)/pTMB^(high) subgroup had the worst quality of survival and prognosis,whereas those in the RFX1low/pTMBlow subgroup had a relatively better prognosis(p<0.0001).Univariate Cox regression revealed a significant association between high RFX1 expression and increased risk in colon cancer patients(Hazard Ratio[HR]=1.58,95%Confidence Interval[CI]:1.10–2.25,p=0.012),which remained independently predictive in multivariate analysis after covariate adjustment(HR=1.52,95%CI:1.04–2.22,p=0.031).Conclusion:A nomogram model based on RFX1 combined with pTMB provides an alternative approach for the diagnosis and treatment of colon cancer.展开更多
以草酸与氨基胍碳酸氢盐为原料,经脱水成环、重氮化取代、氧化、中和反应合成了不敏感含能材料1,1′-二羟基-3,3′-二硝基-5,5′-联-1,2,4-三唑二羟胺盐(MAD-X1),总收率为41.2%,采用红外光谱、1 H NMR、13 C NMR及元素分析对产物的结构...以草酸与氨基胍碳酸氢盐为原料,经脱水成环、重氮化取代、氧化、中和反应合成了不敏感含能材料1,1′-二羟基-3,3′-二硝基-5,5′-联-1,2,4-三唑二羟胺盐(MAD-X1),总收率为41.2%,采用红外光谱、1 H NMR、13 C NMR及元素分析对产物的结构进行了表征。探讨了一锅法合成中间体5,5′-二氨基-3,3′-联-1,2,4-三唑(DABT)的机理及亚硝酸钠与硫酸摩尔比对重氮化取代反应收率的影响,对MAD-X1的热性能进行了分析,用NASA-CEA程序计算了MAD-X1-CMDB推进剂的能量特性。结果表明,采用一锅法合成DABT,周期短、收率高(75.1%),亚硝酸钠与硫酸的最佳摩尔比为2.4∶1,酸化试剂为浓盐酸,MAD-X1的热分解峰温度为248.7℃;MAD-X1-CMDB推进剂的理论比冲和特征速度分别为2 449.6N·s/kg和1 540.7m/s。展开更多
基金supported by Guangdong Province Basic and Applied Basic Research Fund Project(2023A1515220104)Open Fund of Key Laboratory of Hepatoaplenic Surgery,Ministry of Education(Award Number:GPKF202407).
文摘Objectives:Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and Philadelphia-like B-cell acute lymphoblastic leukemia(Ph+/Ph-like ALL)constitute the majority of relapsed/refractory B-ALL(R/R B-ALL)cases,highlighting an urgent need to discover new therapeutic targets.This study aims to elucidate the mechanisms underlying poor prognosis in Ph+/Ph-like ALL through transcriptome sequencing and functional cytological assays,with the goal of informing new clinical treatment strategies.Results:Transcriptomic analysis of Ph+/Ph-like ALL patients revealed that low expression of P2X Purinoceptor 1(P2RX1)was associated with unfavorable outcomes.Specifically,patients with poor prognosis and low P2RX1 expression exhibited downregulation of genes involved in energy and calcium metabolism pathways,along with upregulation of genes governing key cellular processes such as cell proliferation(e.g.,MYC),cell cycle progression(e.g.,CCND2),and apoptosis inhibition(e.g.,DASP6).Cellular experiments demonstrated that SUP-B15 cells overexpressing P2RX1 displayed elevated intracellular levels of ATP,calcium,and glucose,together with enhanced glycolytic capacity,compared to empty vector controls.Treatment of SUP-B15 cells with dexamethasone(Dex),Imatinib,or their combination significantly suppressed proliferation and promoted apoptosis,which was accompanied by increases in intracellular ATP,calcium,and glucose.Moreover,exogenous ATP administration(a P2RX1 agonist)enhanced apoptosis and inhibited proliferation in control cells.Conversely,treatment with NF449(a P2RX1 inhibitor)increased proliferation in both P2RX1-overexpressing and control SUP-B15 cells.Conclusion:Our findings indicate that P2RX1 may exert this function through modulating energy metabolism and calcium homeostasis,resulting in elevated intracellular calcium levels.Sustained elevation of calcium promotes apoptosis,whereas exogenous ATP activates P2RX1,enhances calcium influx,and attenuates the suppression of apoptosis associated with P2RX1 underexpression,ultimately correlating with improved treatment response.
基金sponsored by the National Natural Science Foundation of China(82002507)Shanghai Sailing Program(20YF1430100)Shanghai Hospital Development Center(SHDC2023CRT004).
文摘Objective:The plastic role of regulatory factor X1(RFX1)in colon cancer progression and its impact on the tumor microenvironment remain poorly understood.The study aimed to clarify the molecular and clinical role of RFX1 in colon cancer.Methods:We classified colon cancers into subgroups with high and low RFX1 expression and characterized their immune profiles,mutational profiles,cancer immunotherapy and drug sensitivity.By combining RFX1 expression with persistent tumor mutational burden,we proposed a novel nomogram clinical prediction model and validated its predictive performance,and the correlation between high expression and poor prognosis.Results:Compared to tumor mutational burden(TMB),persistent tumor mutational burden(pTMB)is an independent predictor of prognosis in patients with colon cancer.The predictive efficacy of the combination of RFX1 expression and pTMB was superior to and sensitive than the combination of RFX1 expression with TMB.Among them,patients in the RFX1^(high)/pTMB^(high) subgroup had the worst quality of survival and prognosis,whereas those in the RFX1low/pTMBlow subgroup had a relatively better prognosis(p<0.0001).Univariate Cox regression revealed a significant association between high RFX1 expression and increased risk in colon cancer patients(Hazard Ratio[HR]=1.58,95%Confidence Interval[CI]:1.10–2.25,p=0.012),which remained independently predictive in multivariate analysis after covariate adjustment(HR=1.52,95%CI:1.04–2.22,p=0.031).Conclusion:A nomogram model based on RFX1 combined with pTMB provides an alternative approach for the diagnosis and treatment of colon cancer.
文摘以草酸与氨基胍碳酸氢盐为原料,经脱水成环、重氮化取代、氧化、中和反应合成了不敏感含能材料1,1′-二羟基-3,3′-二硝基-5,5′-联-1,2,4-三唑二羟胺盐(MAD-X1),总收率为41.2%,采用红外光谱、1 H NMR、13 C NMR及元素分析对产物的结构进行了表征。探讨了一锅法合成中间体5,5′-二氨基-3,3′-联-1,2,4-三唑(DABT)的机理及亚硝酸钠与硫酸摩尔比对重氮化取代反应收率的影响,对MAD-X1的热性能进行了分析,用NASA-CEA程序计算了MAD-X1-CMDB推进剂的能量特性。结果表明,采用一锅法合成DABT,周期短、收率高(75.1%),亚硝酸钠与硫酸的最佳摩尔比为2.4∶1,酸化试剂为浓盐酸,MAD-X1的热分解峰温度为248.7℃;MAD-X1-CMDB推进剂的理论比冲和特征速度分别为2 449.6N·s/kg和1 540.7m/s。
