Objectives:While programmed cell death 1(PD-1)inhibitors have improved cancer treatment,the function and mechanisms of programmed cell death ligand 1(PD-L1),particularly when expressed by cancer cells,remain unclear.T...Objectives:While programmed cell death 1(PD-1)inhibitors have improved cancer treatment,the function and mechanisms of programmed cell death ligand 1(PD-L1),particularly when expressed by cancer cells,remain unclear.This study aims to explore the role of PD-L1 within breast cancer cells and identify key targets for future immunotherapy.Methods:RNA-seq was performed on breast cancer cells with silenced PD-L1 to screen for differentially expressed genes,followed by bioinformatics analysis.Clinical specimens from breast cancer patients undergoing primary surgery without preoperative treatment were collected,along with in vitro analysis to validate the potential mechanism.Results:RNA-seq data revealed a significant positive correlation between Ecto-5′-nucleotidase(NT5E)expression and PD-L1.Bioinformatics analysis corroborated this positive correlation.Immunohistochemistry staining demonstrated higher NT5E expression associated with increased lymph node metastasis.High expression of the NT5E gene was associated with poor overall survival(OS)in breast cancer patients,as determined by KM plotter analysis.Following PD-L1 gene silencing by siRNA in breast cancer cells,NT5E mRNA and protein expression significantly decreased.Conversely,no significant changes were observed in PD-L1 expression after NT5E gene silencing.In vitro experiments confirmed that cancer cell proliferation and metastasis abilities were significantly reduced by either PD-L1 or NT5E gene down-regulation.Western blotting demonstrated that PD-L1 expressed by cancer cells regulates NT5E expression through the MAPK/ERK signaling pathway.Conclusion:This study proposes a potential mechanism wherein tumor-expressing PD-L1 regulates NT5E through the MAPK/ERK pathway.Downregulation of PD-L1 or NT5E can significantly inhibit the proliferation and metastatic ability of cancer cells,potentially providing practical therapeutic targets and prognostic markers for combined PD-L1 immunotherapy in breast cancer.展开更多
Designing highly efficient acidic oxygen evolution reaction(OER)electrocatalysts that combine high activity,long-term stability,and low cost has become crucial for proton exchange membrane water electrolyzers.RuO_(2) ...Designing highly efficient acidic oxygen evolution reaction(OER)electrocatalysts that combine high activity,long-term stability,and low cost has become crucial for proton exchange membrane water electrolyzers.RuO_(2) catalysts,following a kinetically favorable lattice oxygen mechanism,exhibit superior intrinsic activity but suffer from inferior stability for acidic OER.Current research predominantly focuses on sacrificing the intrinsic activity of RuO_(2) to enhance stability.The activitystability trade-off in RuO_(2) -based catalysts remains a central research focus.Here,we propose a grain boundary engineering strategy to boost the OER activity and stability of RuO_(2) in acidic media.Grain boundaries in RuO_(2) catalysts do not alter the Ru valence state and Ru-O covalency,thus enabling grain boundary-rich RuO_(2) catalysts(GB-RuO_(2) )to follow the lattice oxygen mechanism pathway.We discover that grain boundaries can increase the content of coordinatively unsaturated Ru6+species and promote the deprotonation kinetics of adsorbed oxygen species,thus balancing acidic OER activity and stability.The optimal GB-RuO_(2) catalysts achieve an exceptionally low acidic OER overpotential of 159 m V at 10 m A cm^(-2)and a minor potential increase of 44 m V after 24 h at 50 m A cm^(-2),significantly surpassing RuO_(2) catalysts with a low grain boundary.展开更多
This study considers an optimal investment and reinsurance problem involving a defaultable security for an insurer in an ambiguous environment.In other words,the insurer is ambiguous about the insurance claim that is ...This study considers an optimal investment and reinsurance problem involving a defaultable security for an insurer in an ambiguous environment.In other words,the insurer is ambiguous about the insurance claim that is exponentially distributed with an uncertain rate parameter.The insurer can purchase proportional reinsurance and invest its wealth in three assets:a risk-free asset,a risky asset,the price process of which satisfies the Heston local-stochastic volatility model,and a defaultable corporate bond.For the optimal investment–reinsurance objective with a smooth ambiguity utility proposed by Klibanoff,P.,Marinacci,M.,and Mukerji,S.[A smooth model of decision making under ambiguity,Econometrica,2005,73(6):1849-1892],the equilibrium strategy is introduced and the extended Hamilton–Jacobi–Bellman equation is established through a stochastic control approach.However,the analytical solution of the strategy under the Heston local-stochastic volatility model cannot be obtained because of the complicated nonlinearity of the partial differential equation.In this study,we employ a perturbation method to derive an asymptotic solution for the post-and pre-default cases.In addition,we present a sensitivity analysis to explain the impact of model parameters on the equilibrium investment–reinsurance strategy.展开更多
基金Provincial Natural Science Foundation J230016Provincial Natural Science Foundation H2023206441Hebei Province Major Science and Technology Support Program Project S&T Program of Hebei 242W7701Z.
文摘Objectives:While programmed cell death 1(PD-1)inhibitors have improved cancer treatment,the function and mechanisms of programmed cell death ligand 1(PD-L1),particularly when expressed by cancer cells,remain unclear.This study aims to explore the role of PD-L1 within breast cancer cells and identify key targets for future immunotherapy.Methods:RNA-seq was performed on breast cancer cells with silenced PD-L1 to screen for differentially expressed genes,followed by bioinformatics analysis.Clinical specimens from breast cancer patients undergoing primary surgery without preoperative treatment were collected,along with in vitro analysis to validate the potential mechanism.Results:RNA-seq data revealed a significant positive correlation between Ecto-5′-nucleotidase(NT5E)expression and PD-L1.Bioinformatics analysis corroborated this positive correlation.Immunohistochemistry staining demonstrated higher NT5E expression associated with increased lymph node metastasis.High expression of the NT5E gene was associated with poor overall survival(OS)in breast cancer patients,as determined by KM plotter analysis.Following PD-L1 gene silencing by siRNA in breast cancer cells,NT5E mRNA and protein expression significantly decreased.Conversely,no significant changes were observed in PD-L1 expression after NT5E gene silencing.In vitro experiments confirmed that cancer cell proliferation and metastasis abilities were significantly reduced by either PD-L1 or NT5E gene down-regulation.Western blotting demonstrated that PD-L1 expressed by cancer cells regulates NT5E expression through the MAPK/ERK signaling pathway.Conclusion:This study proposes a potential mechanism wherein tumor-expressing PD-L1 regulates NT5E through the MAPK/ERK pathway.Downregulation of PD-L1 or NT5E can significantly inhibit the proliferation and metastatic ability of cancer cells,potentially providing practical therapeutic targets and prognostic markers for combined PD-L1 immunotherapy in breast cancer.
基金the financial support from the Excellent Young Scientist Fund(Hong Kong and Macao)from the National Natural Science Foundation of China(22222208)the Research Grants Council of the Hong Kong Special Administrative Region(14307322)+2 种基金the support of the National Natural Science Foundation of China(52402268)the Natural Science Foundation of Jiangsu Province of China(BK20230426)the support of the Poly U Distinguished Postdoctoral Fellowship Schemes(YWEE)。
文摘Designing highly efficient acidic oxygen evolution reaction(OER)electrocatalysts that combine high activity,long-term stability,and low cost has become crucial for proton exchange membrane water electrolyzers.RuO_(2) catalysts,following a kinetically favorable lattice oxygen mechanism,exhibit superior intrinsic activity but suffer from inferior stability for acidic OER.Current research predominantly focuses on sacrificing the intrinsic activity of RuO_(2) to enhance stability.The activitystability trade-off in RuO_(2) -based catalysts remains a central research focus.Here,we propose a grain boundary engineering strategy to boost the OER activity and stability of RuO_(2) in acidic media.Grain boundaries in RuO_(2) catalysts do not alter the Ru valence state and Ru-O covalency,thus enabling grain boundary-rich RuO_(2) catalysts(GB-RuO_(2) )to follow the lattice oxygen mechanism pathway.We discover that grain boundaries can increase the content of coordinatively unsaturated Ru6+species and promote the deprotonation kinetics of adsorbed oxygen species,thus balancing acidic OER activity and stability.The optimal GB-RuO_(2) catalysts achieve an exceptionally low acidic OER overpotential of 159 m V at 10 m A cm^(-2)and a minor potential increase of 44 m V after 24 h at 50 m A cm^(-2),significantly surpassing RuO_(2) catalysts with a low grain boundary.
基金isupported by the National Natural Science Foundation of China(Grant Nos.11871010 and 11971040)the Fundamental Research Funds for the Central Universities(Grant No.2019XD-A11)The work of Weilin Xiao is supported by the Humanities and Social Sciences of Ministry of Education Planning Fund of China(Grant No.23YJA630102).
文摘This study considers an optimal investment and reinsurance problem involving a defaultable security for an insurer in an ambiguous environment.In other words,the insurer is ambiguous about the insurance claim that is exponentially distributed with an uncertain rate parameter.The insurer can purchase proportional reinsurance and invest its wealth in three assets:a risk-free asset,a risky asset,the price process of which satisfies the Heston local-stochastic volatility model,and a defaultable corporate bond.For the optimal investment–reinsurance objective with a smooth ambiguity utility proposed by Klibanoff,P.,Marinacci,M.,and Mukerji,S.[A smooth model of decision making under ambiguity,Econometrica,2005,73(6):1849-1892],the equilibrium strategy is introduced and the extended Hamilton–Jacobi–Bellman equation is established through a stochastic control approach.However,the analytical solution of the strategy under the Heston local-stochastic volatility model cannot be obtained because of the complicated nonlinearity of the partial differential equation.In this study,we employ a perturbation method to derive an asymptotic solution for the post-and pre-default cases.In addition,we present a sensitivity analysis to explain the impact of model parameters on the equilibrium investment–reinsurance strategy.
