Taking college mathematics as an example,a questionnaire was designed for college mathematics teachers and students to fully comprehend the teaching situation.This paper mainly discusses the problems existing in the t...Taking college mathematics as an example,a questionnaire was designed for college mathematics teachers and students to fully comprehend the teaching situation.This paper mainly discusses the problems existing in the teaching of college mathematics and proposes the strategy of integrating PBL with curriculum ideological and political elements in college mathematics,so as to change the teaching process and improve the teaching quality.展开更多
Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T(CAR-T)cells.MEK1/2 inhibitors(MEKIs),widely...Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T(CAR-T)cells.MEK1/2 inhibitors(MEKIs),widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling,have shown potential synergistic effects when combined with immunotherapy.However,the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial.To address this,we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells.Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation,thereby improving CAR-T cell efficacy against hematological and solid tumors.Remarkably,these effects were independent of the specific scFvs and costimulatory domains utilized in CARs.Mechanistically,analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB.Additionally,the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition.Furthermore,our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion,differentiation,anergy,glycolysis,and apoptosis.In summary,our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation.These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.展开更多
基金Innovation Project of Outstanding Talents Training of West Anhui College(Project Number:WXXY2020002)Anhui Province Demonstration Grassroots Teaching Organization Project(Project Number:2020SJSFJX22403)+2 种基金Curriculum Ideological and Political Construction Research Project of Anhui Province(Project Number:2020KCSZYJXM253)Ideological and Political Demonstration Course of Anhui Province(Project Number:2020SZSFKC0940)Ideological and Political Demonstration Course of Anhui Province(Project Number:2020SZSFKC0907)。
文摘Taking college mathematics as an example,a questionnaire was designed for college mathematics teachers and students to fully comprehend the teaching situation.This paper mainly discusses the problems existing in the teaching of college mathematics and proposes the strategy of integrating PBL with curriculum ideological and political elements in college mathematics,so as to change the teaching process and improve the teaching quality.
基金supported by the National Key Research and Development Program of China(2022YFA1103500 to P.Q.)the National Key Nature Science Foundation of China(82130003 to H.H.)+3 种基金the Key Project of Science and Technology Department of Zhejiang Province(2019C03016 and 2020C03G2013586 to H.H.,Z24H080001 to P.Q.)the National Natural Science Foundation of China(82200248 and 82000194 to H.H.,82222003 and 82161138028 to P.Q.)the Key R&D Program of Zhejiang(2024SSYS0023 to H.H.,2024SSYS0024 to P.Q.,2024SSYS0025 to Y.H.)the Fundamental Research Funds for the Central Universities(226-2024-00007 to P.Q.).
文摘Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T(CAR-T)cells.MEK1/2 inhibitors(MEKIs),widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling,have shown potential synergistic effects when combined with immunotherapy.However,the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial.To address this,we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells.Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation,thereby improving CAR-T cell efficacy against hematological and solid tumors.Remarkably,these effects were independent of the specific scFvs and costimulatory domains utilized in CARs.Mechanistically,analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB.Additionally,the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition.Furthermore,our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion,differentiation,anergy,glycolysis,and apoptosis.In summary,our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation.These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.
