Objective: To explore the effect of dysregulation of epigenetic regulator EZH1 and EZH2 on the proliferation in MCL and the underlying mechanisms.Methods: In this study, we elucidated the role of EZH1 and EZH2 overexp...Objective: To explore the effect of dysregulation of epigenetic regulator EZH1 and EZH2 on the proliferation in MCL and the underlying mechanisms.Methods: In this study, we elucidated the role of EZH1 and EZH2 overexpression by immunohistochemistry and correlated them to clinical outcome in 41 MCL patients.Quantitative real-time PCR and Western blot were applied to confirm the level of EZH1 and EZH2 in well-characterized MCL cell lines which were compared to those of na?ve B cells.Then we manipulated the expression of EZH1 and EZH2 in MCL cells using CRISPR/Cas9 system to directly investigate their functional roles in MCL.We also evaluated the effect of two small molecule selective inhibitors, EPZ005687 and UNC1999, on MCL cell proliferation, cell cycle distribution and apoptosis in vitro.Finally, we performed RNA-sequencing(RNA-Seq) and Chromatin immunoprecipitation(ChIP) assay to further gain insight into the underlying molecular mechanisms.Results: We found that EZH2 protein is overexpressed in approximately half of this cohort of MCL cases.More importantly, the overexpression of EZH2 is associated with poor OS in the patients.Nevertheless, simple EZH2 depletion in vitro has little impact on the viability of MCL cells, predominantly because of the consequent up-regulation of EZH1.Consistently, UNC1999, a dual EZH1/2 inhibitor, unlike the EZH2 selective inhibitor EPZ005687, exerts a potent inhibitory effect on MCL cells.Furthermore, we discover CDKN1C and TP53 INP1 as the two important cell cycle regulators, the expression of which are repressed by EZH1/2 mediated epigenetic regulation and are restored by EZH1/2 dual inhibition.Conclusions: Our study suggests that EZH2 participates in the pathogenesis of MCL which may serve as a potential biomarker for prognosis prediction.The dual inhibition of EZH1/2 is a promising therapeutic strategy for MCL.展开更多
The dynamic cumulative damage of rigid-flexible coupling model of high-speed train with flexible bogie frame is performed by using the coupled scheme of elastic and multibody dynamics theories.The motion equations of ...The dynamic cumulative damage of rigid-flexible coupling model of high-speed train with flexible bogie frame is performed by using the coupled scheme of elastic and multibody dynamics theories.The motion equations of the present problem are firstly established by integrating the finite element method and floating frame of reference approach based on the virtual power principle and D'Alembert principle.The process of condensing the elastic DOFs of the obtained finite element model involving the incorporation of the substructure technique and sparse approximate inverse method is tentatively carried out.Then,the motion equations are further solved by virtue of the generalized α method and the Jacobian-free Newton-Krylov technologies.And the superiority of coupled scheme is proven by comparing with the traditional approach.Finally,besides the dynamic behaviors of the considered vehicle model,the time-variations of stresses on the elastic bogie frame's dangerous nodes and the distributions of stresses of bogie frame at some specified moments are synchronously calculated and analyzed.More importantly,the real-time and time-varying cumulative damages of some typical nodes on bogie frame are investigated.展开更多
Background:The predictive value of the neutrophil-to-lymphocyte ratio(NLR)for immune checkpoint inhibitors(ICIs)in various tumors remains uncertain despite its use in forecasting the effectiveness of immunotherapy.The...Background:The predictive value of the neutrophil-to-lymphocyte ratio(NLR)for immune checkpoint inhibitors(ICIs)in various tumors remains uncertain despite its use in forecasting the effectiveness of immunotherapy.The purpose of our research was to determine the prognostic significance of NLR for immune checkpoint inhibitor-related myocarditis in non-small-cell lung cancer(NSCLC)patients.Methods:We enrolled and monitored patients with NSCLC who received ICI therapy at the Fifth Medical Center of Chinese PLA General Hospital between January 1,2018,and February 20,2021.NLR was determined before and soon after each cycle of ICIs.All participants in this study were periodically examined for troponin and brain natriuretic peptide(BNP),and an electrocardiogram(ECG)and echocardiography were done.Cox's proportional hazards regression model and receiver operating characteristic(ROC)were used to assess the predictive value for ICI-related myocarditis.Results:A total of 146 patients received ICI treatment and completed a follow-up.Of these,17 patients(11.64%)developed ICIrelated myocarditis that met the diagnostic criteria.The initial cycle revealed that the NLR was a reliable predictor of potential myocarditis related to ICIs,with an area under the curve(AUC)of 0.833 and a 95% confidence interval(CI)of 0.721-0.945.Following the initial round of ICI treatment,an NLR elevation(NLR≥3.25)appeared to be the most significant standalone indicator of ICI-related myocarditis(HR:11.094;95%CI:3.186-38.631;p<0.001).Conclusions:Our study confirmed that NLR elevation in the early phase after ICI treatment of NSCLC is a reliable predictive factor of ICI-related myocarditis.Regular and frequent cardiac monitoring may help to avoid the occurrence of severe and fatal cases.展开更多
基金supported by a grant from the National Natural Science Foundation of China (Grant No.81372539)
文摘Objective: To explore the effect of dysregulation of epigenetic regulator EZH1 and EZH2 on the proliferation in MCL and the underlying mechanisms.Methods: In this study, we elucidated the role of EZH1 and EZH2 overexpression by immunohistochemistry and correlated them to clinical outcome in 41 MCL patients.Quantitative real-time PCR and Western blot were applied to confirm the level of EZH1 and EZH2 in well-characterized MCL cell lines which were compared to those of na?ve B cells.Then we manipulated the expression of EZH1 and EZH2 in MCL cells using CRISPR/Cas9 system to directly investigate their functional roles in MCL.We also evaluated the effect of two small molecule selective inhibitors, EPZ005687 and UNC1999, on MCL cell proliferation, cell cycle distribution and apoptosis in vitro.Finally, we performed RNA-sequencing(RNA-Seq) and Chromatin immunoprecipitation(ChIP) assay to further gain insight into the underlying molecular mechanisms.Results: We found that EZH2 protein is overexpressed in approximately half of this cohort of MCL cases.More importantly, the overexpression of EZH2 is associated with poor OS in the patients.Nevertheless, simple EZH2 depletion in vitro has little impact on the viability of MCL cells, predominantly because of the consequent up-regulation of EZH1.Consistently, UNC1999, a dual EZH1/2 inhibitor, unlike the EZH2 selective inhibitor EPZ005687, exerts a potent inhibitory effect on MCL cells.Furthermore, we discover CDKN1C and TP53 INP1 as the two important cell cycle regulators, the expression of which are repressed by EZH1/2 mediated epigenetic regulation and are restored by EZH1/2 dual inhibition.Conclusions: Our study suggests that EZH2 participates in the pathogenesis of MCL which may serve as a potential biomarker for prognosis prediction.The dual inhibition of EZH1/2 is a promising therapeutic strategy for MCL.
基金support for the research:National Natural Science Foundation of China(Grant No.11872257 and 11572358)Key Project of Natural Science Foundation of Hebei Province(Grant No.A2020210008)Hebei Provincial Department of Education Youth Top Talents Project(Grant No.BJK2023018).
文摘The dynamic cumulative damage of rigid-flexible coupling model of high-speed train with flexible bogie frame is performed by using the coupled scheme of elastic and multibody dynamics theories.The motion equations of the present problem are firstly established by integrating the finite element method and floating frame of reference approach based on the virtual power principle and D'Alembert principle.The process of condensing the elastic DOFs of the obtained finite element model involving the incorporation of the substructure technique and sparse approximate inverse method is tentatively carried out.Then,the motion equations are further solved by virtue of the generalized α method and the Jacobian-free Newton-Krylov technologies.And the superiority of coupled scheme is proven by comparing with the traditional approach.Finally,besides the dynamic behaviors of the considered vehicle model,the time-variations of stresses on the elastic bogie frame's dangerous nodes and the distributions of stresses of bogie frame at some specified moments are synchronously calculated and analyzed.More importantly,the real-time and time-varying cumulative damages of some typical nodes on bogie frame are investigated.
基金supported by the Young Talent Project of Chinese PLA General Hospital(20230433).
文摘Background:The predictive value of the neutrophil-to-lymphocyte ratio(NLR)for immune checkpoint inhibitors(ICIs)in various tumors remains uncertain despite its use in forecasting the effectiveness of immunotherapy.The purpose of our research was to determine the prognostic significance of NLR for immune checkpoint inhibitor-related myocarditis in non-small-cell lung cancer(NSCLC)patients.Methods:We enrolled and monitored patients with NSCLC who received ICI therapy at the Fifth Medical Center of Chinese PLA General Hospital between January 1,2018,and February 20,2021.NLR was determined before and soon after each cycle of ICIs.All participants in this study were periodically examined for troponin and brain natriuretic peptide(BNP),and an electrocardiogram(ECG)and echocardiography were done.Cox's proportional hazards regression model and receiver operating characteristic(ROC)were used to assess the predictive value for ICI-related myocarditis.Results:A total of 146 patients received ICI treatment and completed a follow-up.Of these,17 patients(11.64%)developed ICIrelated myocarditis that met the diagnostic criteria.The initial cycle revealed that the NLR was a reliable predictor of potential myocarditis related to ICIs,with an area under the curve(AUC)of 0.833 and a 95% confidence interval(CI)of 0.721-0.945.Following the initial round of ICI treatment,an NLR elevation(NLR≥3.25)appeared to be the most significant standalone indicator of ICI-related myocarditis(HR:11.094;95%CI:3.186-38.631;p<0.001).Conclusions:Our study confirmed that NLR elevation in the early phase after ICI treatment of NSCLC is a reliable predictive factor of ICI-related myocarditis.Regular and frequent cardiac monitoring may help to avoid the occurrence of severe and fatal cases.
