Crystalline engineering and heterostructure have attracted much attention as effective strategies to improve the electrocatalytic activity for hydrogen evolution reaction(HER).In this study,a new heterostructure catal...Crystalline engineering and heterostructure have attracted much attention as effective strategies to improve the electrocatalytic activity for hydrogen evolution reaction(HER).In this study,a new heterostructure catalyst(Ru/RuS_(2)@N-rGO)with low crystallinity was fabricated by a simple and low-temperature method for HER in alkaline solution,applying the Na_(2)SO_(4)as S source and polypyrrole as N source.Optimizing through the controllable crystalline engineering and composition ratio of Ru and RuS_(2),the Ru/RuS_(2)@N-rGO heterocatalyst at the calcining 500°C revealed highly efficient HER activity with overpotential 18 mV at a current density 10 mA/cm^(2)and remarkable stability for 24 h in 1.0 mol/L KOH.This work provides a facile and effective method in designing advanced electrocatalysts for HER in the alkaline electrolytes by synergistically structural and component modulations.展开更多
Thermal loss of exhaust flue gas accounts for the largest proportion of the total boiler thermal loss. Nowadays in China, the exhaust gas temperature in many thermal power plants is much higher than the designed value...Thermal loss of exhaust flue gas accounts for the largest proportion of the total boiler thermal loss. Nowadays in China, the exhaust gas temperature in many thermal power plants is much higher than the designed value, thus, the recycle and reuse of the waste heat of tail flue gas is necessary. However, lower exhaust gas temperature will aggravate low temperature corrosion of the tail heating surface, which also causes huge economic losses. In order to solve this problem, this paper designs a monitoring experiment platform of flue gas low temperature corrosion, which can measure the corrosion condition of different materials by different flue gas compositions and temperature corrosion speeds. Besides, effects of low temperature corrosion factors are analyzed to find the best exhaust gas temperature and the surface material of tail heating surface.展开更多
Dear editor.The remarkably diversified CRISPR-Cas systems in nature have provided unlimited valuable resources to develop genome editing tools that are revolutionizing the fields of biotechnology and medicine.However,...Dear editor.The remarkably diversified CRISPR-Cas systems in nature have provided unlimited valuable resources to develop genome editing tools that are revolutionizing the fields of biotechnology and medicine.However,due to their microbial origin,the activity of most naturally occurring CRISPR-Cas nucleases is relatively poor in mammalian cells(Ran et al.,2015).Thus,improving the mammalian genome editing efficiency becomes the priority for harnessing more CRISPRCas systems for widespread applications.Rational protein engineering serves as a powerful approach to enhance the catalytic activity of enzymes.Whereas,this approach largely relies on proteinic three-dimension(3D)structure information as guide for design.The fact is that of the large numbers of the CRISPR-Cas systems discovered in recent years,only a small number of them with the 3D structures were reported.To bypass this limitation,here,we report an efficient and simple strategy for rational engineering of Cas nucleases without the need of 3D structure information and successfully optimized nucleases from Cas9 and Cas12 families.展开更多
Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal g...Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC).Metastatic disease in the central nervous system(CNS)remains a challenge in the management of NSCLC.This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.Methods:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion.Patients with asymptomatic,stable CNS metastases were included.Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months,then every 12weeks.CNS responsewas assessed by a neuroradiological blinded,independent central review(neuroradiological-BICR).The primary endpoint for this subgroup analysis was CNS progression-free survival(PFS).Results:Of the 429 patients enrolled and randomized in the ANEAS study,106 patients were found to have CNS metastases(CNS Full Analysis Set,cFAS)at baseline by neuroradiological-BICR,and 60 of them had CNS target lesions(CNS Evaluable for Response,cEFR).Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS(29.0 vs.8.3 months;hazard ratio[HR]=0.31;95%confidence interval[CI],0.17-0.56;P<0.001)and cEFR(29.0 vs.8.3 months;HR=0.26;95%CI,0.11-0.57;P<0.001).The confirmed CNS overall response rate in cEFRwas 85.7%and 75.0%in patients treated with aumolertinib and gefitinib,respectively.Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNSmetastases at baseline.No new safety findings were observed.Conclusions:These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases.展开更多
WX-0593(Iruplinalkib)is a novel,highly selective oral ALK and ROS1 tyrosine kinase inhibitor(TKI).In this study,the safety,antitumor activity,and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell l...WX-0593(Iruplinalkib)is a novel,highly selective oral ALK and ROS1 tyrosine kinase inhibitor(TKI).In this study,the safety,antitumor activity,and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer(NSCLC)patients with ALK or ROS1 rearrangement.In the dose-escalation phase and dose-expansion phase,patients were treated with WX-0593 until disease progression,unacceptable toxicity,or subject withdrawal.In the dose-escalation phase,the primary endpoints were maximum tolerated dose(MTD),dose-limiting toxicity(DLT),and safety assessed by investigators.In the dose-expansion phase,the primary endpoint was objective response rate(ORR)assessed by investigators.Between September 25,2017 and October 15,2018,a total of 153 patients received WX-0593 treatment.Two dose-limiting toxicities(DLTs)including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient.MTD was not reached.Overall,140 of the 152(92%)patients experienced treatment-related adverse events(TRAEs)and 35 of the 152(23%)patients had TRAEs≥grade 3.The overall ORR was 59.3%(32 of 54)for the dose-escalation phase and 56.6%(56 of 99)for the dose-expansion phase.For patients who were ALK-rearranged and ALK TKI naive,the ORR were 81.0%(17 of 21)in the dose-escalation phase and 76.3%(29 of 38)in the dose-expansion phase,and for patients who previously received crizotinib as the only ALK TKI,the ORR were 38.1%(8 of 21)and 45.7%(21 of 46)for the two phases,respectively.For patients who were ROS1-rearranged,the ORR were 30.0%(3 of 10)in the dose-escalation phase and 44.4%(4 of 9)in the dose-expansion phase.WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.展开更多
The naturally occurring prokaryotic CRISPR-Cas systems provide valuable resources for the development of new genome-editing tools.However,the majority of prokaryotic Cas nucleases exhibit poor editing efficiency in ma...The naturally occurring prokaryotic CRISPR-Cas systems provide valuable resources for the development of new genome-editing tools.However,the majority of prokaryotic Cas nucleases exhibit poor editing efficiency in mammalian cells,which significantly limits their utility.Here,we have developed a method termed Improving Editing Activity by Synergistic Engineering(MIDAS).This method exerts a synergistic effect to improve mammalian genome-editing efficiency of a wide range of CRISPR-Cas systems by enhancing the interactions of Cas nuclease with the protospacer adjacent motif(PAM)and the single-stranded DNA(ssDNA)substrate in the catalytic pocket simultaneously.MIDAS robustly and significantly increased the gene-editing efficiency of Cas12i,Cas12b,and CasX in human cells.Notably,a Cas12i variant,Cas12iMax,exhibited robust activity with a very broad PAM range(NTNN,NNTN,NAAN,and NCAN)and higher efficiency than the current widely used Cas nucleases.A high-fidelity version of Cas12iMax(Cas12iHiFi)has been further engineered to minimize off-target effects.Our work provides an expandable and efficacious method for engineering Cas nucleases for robust mammalian genome editing.展开更多
基金supported by National Natural Science Foundation of China(Nos.21773184 and 21671158)Key Science and Technology Project of Henan(No.202102210238)+1 种基金Natural Science Foundation of Henan(No.212300410339)Cultivation Program for Young Backbone Teachers in Henan University of Technology(Nos.21420108 and 21420073).
文摘Crystalline engineering and heterostructure have attracted much attention as effective strategies to improve the electrocatalytic activity for hydrogen evolution reaction(HER).In this study,a new heterostructure catalyst(Ru/RuS_(2)@N-rGO)with low crystallinity was fabricated by a simple and low-temperature method for HER in alkaline solution,applying the Na_(2)SO_(4)as S source and polypyrrole as N source.Optimizing through the controllable crystalline engineering and composition ratio of Ru and RuS_(2),the Ru/RuS_(2)@N-rGO heterocatalyst at the calcining 500°C revealed highly efficient HER activity with overpotential 18 mV at a current density 10 mA/cm^(2)and remarkable stability for 24 h in 1.0 mol/L KOH.This work provides a facile and effective method in designing advanced electrocatalysts for HER in the alkaline electrolytes by synergistically structural and component modulations.
文摘Thermal loss of exhaust flue gas accounts for the largest proportion of the total boiler thermal loss. Nowadays in China, the exhaust gas temperature in many thermal power plants is much higher than the designed value, thus, the recycle and reuse of the waste heat of tail flue gas is necessary. However, lower exhaust gas temperature will aggravate low temperature corrosion of the tail heating surface, which also causes huge economic losses. In order to solve this problem, this paper designs a monitoring experiment platform of flue gas low temperature corrosion, which can measure the corrosion condition of different materials by different flue gas compositions and temperature corrosion speeds. Besides, effects of low temperature corrosion factors are analyzed to find the best exhaust gas temperature and the surface material of tail heating surface.
基金supported by the National Key Research and Development Program(2020YFA0707900,2018YFE0201100,2019YFA0110800 to W.L.,2018YFA0108400,2019YFA0903800 to Q.Z.)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16030403 to W.L.)+1 种基金the National Natural Science Foundation of China(31621004 to Q.Z.and W.L.)the CAS Project for Young Scientists in Basic Research(YSBR-012 to W.L.)。
文摘Dear editor.The remarkably diversified CRISPR-Cas systems in nature have provided unlimited valuable resources to develop genome editing tools that are revolutionizing the fields of biotechnology and medicine.However,due to their microbial origin,the activity of most naturally occurring CRISPR-Cas nucleases is relatively poor in mammalian cells(Ran et al.,2015).Thus,improving the mammalian genome editing efficiency becomes the priority for harnessing more CRISPRCas systems for widespread applications.Rational protein engineering serves as a powerful approach to enhance the catalytic activity of enzymes.Whereas,this approach largely relies on proteinic three-dimension(3D)structure information as guide for design.The fact is that of the large numbers of the CRISPR-Cas systems discovered in recent years,only a small number of them with the 3D structures were reported.To bypass this limitation,here,we report an efficient and simple strategy for rational engineering of Cas nucleases without the need of 3D structure information and successfully optimized nucleases from Cas9 and Cas12 families.
基金Hansoh Pharmaceutical Group Co.LtdNational Natural Science Foundation of China,Grant/Award Numbers:82030045,82241227+3 种基金National Multi-disciplinary Treatment Project for Major Diseases,Grant/Award Number:2020NMDTPCollaborative Innovation Center for Clinical and Translational Science by Ministry of Education&Shanghai,Grant/Award Numbers:CCTS-202204,CCTS-202304Shanghai Chest Hospital Basic Research Project,Grant/Award Number:2023YNKT-1Pujiang Program,Grant/Award Number:22PJ1420700。
文摘Background:The initial randomized,double-blinded,actively controlled,phase III ANEAS study(NCT03849768)demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor(EGFR)-mutated advanced non-small cell lung cancer(NSCLC).Metastatic disease in the central nervous system(CNS)remains a challenge in the management of NSCLC.This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study.Methods:Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion.Patients with asymptomatic,stable CNS metastases were included.Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months,then every 12weeks.CNS responsewas assessed by a neuroradiological blinded,independent central review(neuroradiological-BICR).The primary endpoint for this subgroup analysis was CNS progression-free survival(PFS).Results:Of the 429 patients enrolled and randomized in the ANEAS study,106 patients were found to have CNS metastases(CNS Full Analysis Set,cFAS)at baseline by neuroradiological-BICR,and 60 of them had CNS target lesions(CNS Evaluable for Response,cEFR).Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS(29.0 vs.8.3 months;hazard ratio[HR]=0.31;95%confidence interval[CI],0.17-0.56;P<0.001)and cEFR(29.0 vs.8.3 months;HR=0.26;95%CI,0.11-0.57;P<0.001).The confirmed CNS overall response rate in cEFRwas 85.7%and 75.0%in patients treated with aumolertinib and gefitinib,respectively.Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNSmetastases at baseline.No new safety findings were observed.Conclusions:These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases.
基金This study(NCT03389815)was funded by Qilu Pharmaceutical Co.,Ltd.and also supported in part by China National Major Project for New Drug Innovation(2017ZX09304015)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS)(2016-I2M-1-001).
文摘WX-0593(Iruplinalkib)is a novel,highly selective oral ALK and ROS1 tyrosine kinase inhibitor(TKI).In this study,the safety,antitumor activity,and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer(NSCLC)patients with ALK or ROS1 rearrangement.In the dose-escalation phase and dose-expansion phase,patients were treated with WX-0593 until disease progression,unacceptable toxicity,or subject withdrawal.In the dose-escalation phase,the primary endpoints were maximum tolerated dose(MTD),dose-limiting toxicity(DLT),and safety assessed by investigators.In the dose-expansion phase,the primary endpoint was objective response rate(ORR)assessed by investigators.Between September 25,2017 and October 15,2018,a total of 153 patients received WX-0593 treatment.Two dose-limiting toxicities(DLTs)including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient.MTD was not reached.Overall,140 of the 152(92%)patients experienced treatment-related adverse events(TRAEs)and 35 of the 152(23%)patients had TRAEs≥grade 3.The overall ORR was 59.3%(32 of 54)for the dose-escalation phase and 56.6%(56 of 99)for the dose-expansion phase.For patients who were ALK-rearranged and ALK TKI naive,the ORR were 81.0%(17 of 21)in the dose-escalation phase and 76.3%(29 of 38)in the dose-expansion phase,and for patients who previously received crizotinib as the only ALK TKI,the ORR were 38.1%(8 of 21)and 45.7%(21 of 46)for the two phases,respectively.For patients who were ROS1-rearranged,the ORR were 30.0%(3 of 10)in the dose-escalation phase and 44.4%(4 of 9)in the dose-expansion phase.WX-0593 showed favorable safety and promising antitumor activity in advanced NSCLC patients with ALK or ROS1 rearrangement.
基金supported by the National Key Research and Development Program(2019YFA0110800 and 2020YFA0707900 to W.L.and 2018YFA0108400 and 2019YFA0903800 to Q.Z.)the Strategic Priority Research Programof the Chinese Academy of Sciences(XDA16030403 to W.L.)+1 种基金the National Natural Science Foundation of China(31621004 to Q.Z.and W.L.)and the CAS Project for Young Scientists in Basic Research(YSBR-012 to W.L.).
文摘The naturally occurring prokaryotic CRISPR-Cas systems provide valuable resources for the development of new genome-editing tools.However,the majority of prokaryotic Cas nucleases exhibit poor editing efficiency in mammalian cells,which significantly limits their utility.Here,we have developed a method termed Improving Editing Activity by Synergistic Engineering(MIDAS).This method exerts a synergistic effect to improve mammalian genome-editing efficiency of a wide range of CRISPR-Cas systems by enhancing the interactions of Cas nuclease with the protospacer adjacent motif(PAM)and the single-stranded DNA(ssDNA)substrate in the catalytic pocket simultaneously.MIDAS robustly and significantly increased the gene-editing efficiency of Cas12i,Cas12b,and CasX in human cells.Notably,a Cas12i variant,Cas12iMax,exhibited robust activity with a very broad PAM range(NTNN,NNTN,NAAN,and NCAN)and higher efficiency than the current widely used Cas nucleases.A high-fidelity version of Cas12iMax(Cas12iHiFi)has been further engineered to minimize off-target effects.Our work provides an expandable and efficacious method for engineering Cas nucleases for robust mammalian genome editing.
