Artificial intelligence(AI)processes data-centric applications with minimal effort.However,it poses new challenges to system design in terms of computational speed and energy efficiency.The traditional von Neumann arc...Artificial intelligence(AI)processes data-centric applications with minimal effort.However,it poses new challenges to system design in terms of computational speed and energy efficiency.The traditional von Neumann architecture cannot meet the requirements of heavily datacentric applications due to the separation of computation and storage.The emergence of computing inmemory(CIM)is significant in circumventing the von Neumann bottleneck.A commercialized memory architecture,static random-access memory(SRAM),is fast and robust,consumes less power,and is compatible with state-of-the-art technology.This study investigates the research progress of SRAM-based CIM technology in three levels:circuit,function,and application.It also outlines the problems,challenges,and prospects of SRAM-based CIM macros.展开更多
With the development and introduction of immune checkpoint inhibitors(ICIs)in cancer patients,immune-related side effects have increasingly attracted attention.However,the risks of immune-related renal toxicity are po...With the development and introduction of immune checkpoint inhibitors(ICIs)in cancer patients,immune-related side effects have increasingly attracted attention.However,the risks of immune-related renal toxicity are poorly characterized.In this study,we performed a network meta-analysis(NMA)of ICI-related randomized clinical trials(RCTs)to elucidate the comparative risk of acute kidney injury(AKI)in cancer patients receiving different ICIs.We also sought to identify other factors potentially affecting the risk of AKI.PubMed and EMBASE were searched for peer-reviewed trial reports published between January 2000 and May 2021.Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data.We performed a frequentist NMA to evaluate the risk ratios for grade 1-5 and grade 3-5 AKI between the treatment groups.We also assessed the absolute incidence of AKI in the ICI-containing arm using traditional direct meta-analysis.Once significant heterogeneity was detected in a traditional direct meta-analysis,multivariable meta-regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI.A total of 85 RCTs were included in this study.In the NMA for the risk of grade 1-5 and 3-5 AKI,ipilimumab showed a significantly higher risk than avelumab and durvalumab,whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab(N1I3)showed a significantly higher risk than other groups.In terms of treatment ranking,durvalumab±low-dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1-5 or 3-5 AKI,whereas N1I3,ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1-5 or 3-5 AKI.Compared with other cancers,renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI.The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy.In this NMA involving largescale up-to-date ICI trials,we demonstrated the comparative safety of existing ICI drugs for grade 1-5 and grade 3-5 AKI.Based on data from the ICI arms of these trials,we also revealed several potential risk factors for immune-related AKI,including tumor type and treatment paradigm.展开更多
Rare-earth(RE)elements,known as“industrial vitamins”,have permeated modern lives,especially in high-tech applications.Although the RE elements possess close chemical similarities and have been treated as“one elemen...Rare-earth(RE)elements,known as“industrial vitamins”,have permeated modern lives,especially in high-tech applications.Although the RE elements possess close chemical similarities and have been treated as“one element”in the periodic table,their characteristics differ from each other.The RE microalloying effect is the crux to ameliorate the physicomechanical and thermochemical properties of materials,thereby the study of RE-related phase diagrams becomes indispensable to the design and optimization of RE-containing materials.However,in reality,the knowledge base in this area is considerably scarce compared with that of other commonly-used elements.In this work,the phase equilibria,phase diagrams,phase transformations,and some recent examples of RE-containing materials design are summarized,with which one can predict the RE solubilities,the RE precipitates,as well as the corresponding service behaviors.The attainment of enhanced materials’properties suggests that the thermodynamic rules extracted from the phase diagrams could serve as fundamental criteria for the successful development of novel RE-containing materials.展开更多
Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed ...Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed to design a novel CAR-natural killer(NK)cells with a clinically significant tumoricidal effect on CRPC.Methods:We constructed novel CAR-NK92MI cells with a CD244-based recombinant lentiviral vector.Different intracellular segments(CD244,NKG2D,or CD3ζ)were screened to identify the best candidate according to cell lysis assay and CD107a expression levels.To enhance the affinity of the CAR to the tumor antigen,we compared an antibody specific for prostate-specific membrane antigen(anti-PSMA)with PSMA-targeted polypeptide(p-PSMA),which was screened by phage display combinatorial library.Then,CAR-NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated.In addition,we verified their tumor-killing effect in vitro and in vivo.The release of cytokine by NK92MI cells was compared with that by CAR-NK92MI cells through flow cytometry and enzyme-linked immunosorbent assay.Moreover,ferroptosis-related cell death was explored as a possible underlying mechanism.Results:Three different CAR intracellular regions CAR1(CD244),CAR2(CD244,NKG2D)and CAR3(CD244,NKG2D,and CD3ζ)were constructed.CAR2 was chosen to confer a stronger tumoricidal ability on CAR-NK92MI cells.Compared with anti-PSMA,p-PSMA exhibited enhanced affinity for the tumor antigen.Thus,p-PSMA-CAR-NK92MI cells,which expressed CAR with a polypeptide-based antigen-binding region,an intracellular CD244 and a NKG2D costimulatory domain,were generated.They could selectively and successfully kill PSMA+target cells and exhibited specific lysis rate of 73.19%for PSMA-positive C4-2 cells and 33.04%for PSMA-negative PC3 cells.Additionally,p-PSMA-CAR-NK92MI cells had significantly higher concentrations of IFN-γ,TNF-αand granzyme B than NK92MI cells.In a CRPC cancer xenograft model,p-PSMA-CAR-NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells.Moreover,ferroptosis is a potential mechanism through which CAR-NK92MI cells attack cancer cells,and is triggered by IFN-γ.Conclusions:p-PSMA-CAR-NK92MI cells can effectively kill CRPCPSMA+cells in vitro and in vivo.This strategy may provide additional treatment options for patients with CRPC.展开更多
基金the National Key Research and Development Program of China(2018YFB2202602)The State Key Program of the National Natural Science Foundation of China(NO.61934005)+1 种基金The National Natural Science Foundation of China(NO.62074001)Joint Funds of the National Natural Science Foundation of China under Grant U19A2074.
文摘Artificial intelligence(AI)processes data-centric applications with minimal effort.However,it poses new challenges to system design in terms of computational speed and energy efficiency.The traditional von Neumann architecture cannot meet the requirements of heavily datacentric applications due to the separation of computation and storage.The emergence of computing inmemory(CIM)is significant in circumventing the von Neumann bottleneck.A commercialized memory architecture,static random-access memory(SRAM),is fast and robust,consumes less power,and is compatible with state-of-the-art technology.This study investigates the research progress of SRAM-based CIM technology in three levels:circuit,function,and application.It also outlines the problems,challenges,and prospects of SRAM-based CIM macros.
基金National Key R&D Program of China,Grant/Award Number:2020AAA0109500National Natural Science Foundation of China,Grant/Award Numbers:82030025,32100631,82003269,82122053+3 种基金Young Elite Scientists Sponsorship Program by the China Association for Science and Technology,Grant/Award Number:YESS20210056CAMS Innovation Fund for Medical Sciences,Grant/Award Number:2021-I2M-1-067Central Research Institute Fund of Chinese Academy of Medical Sciences,Grant/Award Number:2021-PT310-001Key-Area Research and Development Program of Guangdong Province,Grant/Award Number:2021B0101420005。
文摘With the development and introduction of immune checkpoint inhibitors(ICIs)in cancer patients,immune-related side effects have increasingly attracted attention.However,the risks of immune-related renal toxicity are poorly characterized.In this study,we performed a network meta-analysis(NMA)of ICI-related randomized clinical trials(RCTs)to elucidate the comparative risk of acute kidney injury(AKI)in cancer patients receiving different ICIs.We also sought to identify other factors potentially affecting the risk of AKI.PubMed and EMBASE were searched for peer-reviewed trial reports published between January 2000 and May 2021.Eligible studies were RCTs studying ICIs in cancer patients and reporting AKI data.We performed a frequentist NMA to evaluate the risk ratios for grade 1-5 and grade 3-5 AKI between the treatment groups.We also assessed the absolute incidence of AKI in the ICI-containing arm using traditional direct meta-analysis.Once significant heterogeneity was detected in a traditional direct meta-analysis,multivariable meta-regression analysis was applied to identify factors that significantly affected the absolute incidence of AKI.A total of 85 RCTs were included in this study.In the NMA for the risk of grade 1-5 and 3-5 AKI,ipilimumab showed a significantly higher risk than avelumab and durvalumab,whereas 1 mg/kg nivolumab plus 3 mg/kg ipilimumab(N1I3)showed a significantly higher risk than other groups.In terms of treatment ranking,durvalumab±low-dose tremelimumab and avelumab were consistently among the top three safest treatments for grade 1-5 or 3-5 AKI,whereas N1I3,ipilimumab and tremelimumab were consistently among the top three treatments with the highest risk for grade 1-5 or 3-5 AKI.Compared with other cancers,renal cell carcinoma and urothelial carcinoma showed a significantly higher risk of AKI.The incidence of AKI was significantly higher with ICI+chemotherapy than with ICI monotherapy.In this NMA involving largescale up-to-date ICI trials,we demonstrated the comparative safety of existing ICI drugs for grade 1-5 and grade 3-5 AKI.Based on data from the ICI arms of these trials,we also revealed several potential risk factors for immune-related AKI,including tumor type and treatment paradigm.
基金the National Natural Science Foundation of China(Nos.52101026 and 52222507)the Natural Science Foundation of Zhejiang Province(No.LQ20E010004)+2 种基金the“Pioneer”and“Leading Goose”R&D Program of Zhejiang(No.2022C01017)the National Natural Science Foundation of China(52101108)the Ningbo 3315 Innovation Team(Nos.2019A-18-C and 2020A-03-C)is gratefully acknowledged.
文摘Rare-earth(RE)elements,known as“industrial vitamins”,have permeated modern lives,especially in high-tech applications.Although the RE elements possess close chemical similarities and have been treated as“one element”in the periodic table,their characteristics differ from each other.The RE microalloying effect is the crux to ameliorate the physicomechanical and thermochemical properties of materials,thereby the study of RE-related phase diagrams becomes indispensable to the design and optimization of RE-containing materials.However,in reality,the knowledge base in this area is considerably scarce compared with that of other commonly-used elements.In this work,the phase equilibria,phase diagrams,phase transformations,and some recent examples of RE-containing materials design are summarized,with which one can predict the RE solubilities,the RE precipitates,as well as the corresponding service behaviors.The attainment of enhanced materials’properties suggests that the thermodynamic rules extracted from the phase diagrams could serve as fundamental criteria for the successful development of novel RE-containing materials.
基金Capital Science and Technology LeadingTalent Project, Grant/Award Number:Z181100006318007National NaturalScience Foundation of China,Grant/Award Numbers: 81972400,32100631+2 种基金Beijing Excellent TalentsProgram-Youth Backbone Project,Grant/Award Number:2018000032600G393Young EliteScientists Sponsorship Program by ChinaAssociation for Science and Technology,Grant/Award Number: YESS20210056Beijing Hope Run Special Fund of CancerFoundation of China, Grant/AwardNumber: LC2019B02。
文摘Background:The mortality of castration-resistant prostate cancer(CRPC)is high due to lack of an effective treatment.Chimeric antigen receptor(CAR)-based therapy is a promising immunotherapeutic strategy.Here,we aimed to design a novel CAR-natural killer(NK)cells with a clinically significant tumoricidal effect on CRPC.Methods:We constructed novel CAR-NK92MI cells with a CD244-based recombinant lentiviral vector.Different intracellular segments(CD244,NKG2D,or CD3ζ)were screened to identify the best candidate according to cell lysis assay and CD107a expression levels.To enhance the affinity of the CAR to the tumor antigen,we compared an antibody specific for prostate-specific membrane antigen(anti-PSMA)with PSMA-targeted polypeptide(p-PSMA),which was screened by phage display combinatorial library.Then,CAR-NK92MI cells with both a high affinity for PSMA and a strong tumoricidal capacity were generated.In addition,we verified their tumor-killing effect in vitro and in vivo.The release of cytokine by NK92MI cells was compared with that by CAR-NK92MI cells through flow cytometry and enzyme-linked immunosorbent assay.Moreover,ferroptosis-related cell death was explored as a possible underlying mechanism.Results:Three different CAR intracellular regions CAR1(CD244),CAR2(CD244,NKG2D)and CAR3(CD244,NKG2D,and CD3ζ)were constructed.CAR2 was chosen to confer a stronger tumoricidal ability on CAR-NK92MI cells.Compared with anti-PSMA,p-PSMA exhibited enhanced affinity for the tumor antigen.Thus,p-PSMA-CAR-NK92MI cells,which expressed CAR with a polypeptide-based antigen-binding region,an intracellular CD244 and a NKG2D costimulatory domain,were generated.They could selectively and successfully kill PSMA+target cells and exhibited specific lysis rate of 73.19%for PSMA-positive C4-2 cells and 33.04%for PSMA-negative PC3 cells.Additionally,p-PSMA-CAR-NK92MI cells had significantly higher concentrations of IFN-γ,TNF-αand granzyme B than NK92MI cells.In a CRPC cancer xenograft model,p-PSMA-CAR-NK92MI cells significantly inhibited tumor growth and exerted a more consistent killing effect than NK92MI cells.Moreover,ferroptosis is a potential mechanism through which CAR-NK92MI cells attack cancer cells,and is triggered by IFN-γ.Conclusions:p-PSMA-CAR-NK92MI cells can effectively kill CRPCPSMA+cells in vitro and in vivo.This strategy may provide additional treatment options for patients with CRPC.