Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug r...Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.展开更多
Refractory and relapsed multiple myeloma (RRMM) with plasma-cell leukemia (PCL) transformation is highly aggressive and resistant to conventional therapy. Novel therapeutics are needed for RRMM-transformed PCL. Seline...Refractory and relapsed multiple myeloma (RRMM) with plasma-cell leukemia (PCL) transformation is highly aggressive and resistant to conventional therapy. Novel therapeutics are needed for RRMM-transformed PCL. Selinexor [an oral exportin 1 (XPO1) inhibitor], carfilzomib (a second-in-class proteasome inhibitor), pomalidomide (third generation of immunomodulatory drug) are usually used for RRMM, but there are no reports on their application in PCL transformation. We describe a 62-year-old male initially diagnosed with MM IgD-lambda type with complex karyotype and extramedullary plasmacytoma in 2020, and relapsed after five months of autologous stem cell transplantation. Despite the use of various therapies, the patient rapidly developed into PCL over a 4-month period. The patient was started on selinexor, carfilzomib, pomalidomide, and dexamethasone (XKPd) combination as a salvage regimen in July 2021. He achieved fast response in first cycle. Then, he fulfilled third cycle of consolidation treatment and got four-month remission. The success of XKPd therapy in achieving a good response suggests its utility in RRMM transformed-PCL patients, who have exhausted various combinations of drug regimens and have historically poor survival outcomes.展开更多
目的:探讨蛋白酶体抑制剂(PI)相关血栓性微血管病(TMA)的发生规律和临床特点,为临床安全用药提供参考。方法:检索中国知网、万方数据库、维普数据库、PubMed、Web of Science等数据库中收录的PI相关TMA的案例报道,检索时间为建库至2023...目的:探讨蛋白酶体抑制剂(PI)相关血栓性微血管病(TMA)的发生规律和临床特点,为临床安全用药提供参考。方法:检索中国知网、万方数据库、维普数据库、PubMed、Web of Science等数据库中收录的PI相关TMA的案例报道,检索时间为建库至2023年4月30日。对患者基本信息、用药情况、TMA的临床表现、实验室检查、治疗及预后进行汇总分析。结果:纳入文献37篇,涉及患者92例,其中男性46例(占50.00%),女性29例(占31.52%),性别不详17例(占18.48%);平均年龄为(61±13)岁。TMA的中位发病时间为64 d,临床表现以发热、乏力、恶心/呕吐、少尿/无尿为主。因1例患者出现2次TMA,则合计93例次TMA,患者血小板计数明显降低,中位值为19.5×10^(9)/L,其中0~50×10^(9)/L的患者最多(52例次,占55.91%);64例次患者(占68.82%)的血清肌酐水平升高,其中>177~445μmol/L的患者最多(32例次,占34.41%)。停药和支持治疗后(共93例次),76例次患者(占81.72%)痊愈/好转,6例次(占6.45%)有后遗症,5例次(占5.38%)死亡。PI相关TMA中,主要涉及的药物为卡非佐米(67例次,占72.04%)。结论:应重视PI所致TMA,应用PI时应考虑患者性别、药物种类等因素;根据临床表现及实验室检查结果,尽早识别不良反应,保障患者用药安全。展开更多
We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone(tert-butyl((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermedia...We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone(tert-butyl((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H_2O_2 as oxidant in the presence of carboxylic acid(e.g., acetic acid).展开更多
基金Research Projects-Joint Fund for Applied Basic Research of Kunming Medical University,Yunnan Provincial Department of Science and Technology(No.2018FE001(-113),No.202301AY070001-098)Open project of Yunnan Clinical Medical Center(Nos.2020LCZXKF-XY02,XY06,XY16+1 种基金2022LCZXKF-XY02)Yunnan Health Training Project of High Level Talents(No.D–2018018).
文摘Multiple myeloma(MM)is a hematological tumor with high mortality and recurrence rate.Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM.However,the development of drug resistance is a pervasive obstacle to treating MM.Therefore,elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies.To elucidate the mechanisms of carfilzomib resistance,we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells.Differential gene expression analyses revealed major alterations in the major histocompatibility complex(MHC)and cell adhesion molecules.The upregulation of the tumor necrosis factor(TNF)receptor superfamily member 1A(TNFRSF1A)gene was accompanied by the downregulation of MHC genes and cell adhesion molecules.Furthermore,to investigate the roles of these genes,we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules.Furthermore,TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice,indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity.Furthermore,our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules.The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity.Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells.
文摘Refractory and relapsed multiple myeloma (RRMM) with plasma-cell leukemia (PCL) transformation is highly aggressive and resistant to conventional therapy. Novel therapeutics are needed for RRMM-transformed PCL. Selinexor [an oral exportin 1 (XPO1) inhibitor], carfilzomib (a second-in-class proteasome inhibitor), pomalidomide (third generation of immunomodulatory drug) are usually used for RRMM, but there are no reports on their application in PCL transformation. We describe a 62-year-old male initially diagnosed with MM IgD-lambda type with complex karyotype and extramedullary plasmacytoma in 2020, and relapsed after five months of autologous stem cell transplantation. Despite the use of various therapies, the patient rapidly developed into PCL over a 4-month period. The patient was started on selinexor, carfilzomib, pomalidomide, and dexamethasone (XKPd) combination as a salvage regimen in July 2021. He achieved fast response in first cycle. Then, he fulfilled third cycle of consolidation treatment and got four-month remission. The success of XKPd therapy in achieving a good response suggests its utility in RRMM transformed-PCL patients, who have exhausted various combinations of drug regimens and have historically poor survival outcomes.
文摘目的:探讨蛋白酶体抑制剂(PI)相关血栓性微血管病(TMA)的发生规律和临床特点,为临床安全用药提供参考。方法:检索中国知网、万方数据库、维普数据库、PubMed、Web of Science等数据库中收录的PI相关TMA的案例报道,检索时间为建库至2023年4月30日。对患者基本信息、用药情况、TMA的临床表现、实验室检查、治疗及预后进行汇总分析。结果:纳入文献37篇,涉及患者92例,其中男性46例(占50.00%),女性29例(占31.52%),性别不详17例(占18.48%);平均年龄为(61±13)岁。TMA的中位发病时间为64 d,临床表现以发热、乏力、恶心/呕吐、少尿/无尿为主。因1例患者出现2次TMA,则合计93例次TMA,患者血小板计数明显降低,中位值为19.5×10^(9)/L,其中0~50×10^(9)/L的患者最多(52例次,占55.91%);64例次患者(占68.82%)的血清肌酐水平升高,其中>177~445μmol/L的患者最多(32例次,占34.41%)。停药和支持治疗后(共93例次),76例次患者(占81.72%)痊愈/好转,6例次(占6.45%)有后遗症,5例次(占5.38%)死亡。PI相关TMA中,主要涉及的药物为卡非佐米(67例次,占72.04%)。结论:应重视PI所致TMA,应用PI时应考虑患者性别、药物种类等因素;根据临床表现及实验室检查结果,尽早识别不良反应,保障患者用药安全。
基金Project supported by the National Natural Science Foundation of China(Nos.81601992,81802986,and 81601029)the Natural Science Foundation of Zhejiang Province(No.LQ16H160008)the Medical and Health Program of Zhejiang Province(No.2019338991),China
基金financial support of this work from the National Natural Science Foundation of China (No. 21473226)Key Research Program of Frontier Sciences, CAS(No. QYZDJ-SSWSLH051)Natural Science Foundation of Jiangsu Province (Nos. BK20161261 and BK20170420)
文摘We report herein an efficient catalytic epoxidation reaction for the synthesis of epoxyketone(tert-butyl((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)carbamate), which is an important synthetic intermediate of carfilzomib. A series of bioinspired manganese complexes bearing N4 ligands are carefully investigated in the epoxidation of enone precursor with H_2O_2 as oxidant in the presence of carboxylic acid(e.g., acetic acid).
