Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personali...Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial.展开更多
Commercial suspension emulsion(SE) of(8% chlorfenapyr + 20% clothianidin), as a pre-registered product in China, was firstly investigated under Chinese open-field conditions. A MWCNTs-based QuEChERS method for simulta...Commercial suspension emulsion(SE) of(8% chlorfenapyr + 20% clothianidin), as a pre-registered product in China, was firstly investigated under Chinese open-field conditions. A MWCNTs-based QuEChERS method for simultaneous determination of chlorfenapyr and clothianidin in leek was established and validated through rapid resolution liquid chromatography triples quadrupole tandem mass spectrometry(RRLC-QqQ-MS/MS). Based on this method, the dissipation behaviors, residue distributions and dietary risk probability of these fungicides in leek from two representative locations in China in 2016, which were previously treated with these insecticides at the doses of 420–630 g a.i./ha twice applications, were further investigated for food safety. Dissipation behavior of chlorfenapyr and clothianidin in leek followed first-order kinetics with the half-lives of 2.9–7.2 days, and the highest residues(HR) of these insecticides in leek were below 0.3811 mg/kg and 0.2989 mg/kg, respectively, at the pre-harvest interval(PHI, 7 days). For dietary risk assessments, the risk quotients(RQs) of chlorfenapyr and clothianidin in leek were evaluated by comparing the value of national estimated daily intake(NEDI) with acceptable daily intake(ADI), based on the trials data under good agricultural practices(GAP) conditions. The results indicated that RQs of chlorfenapyr and clothianidin in leek were21.5% and 0.29%, respectively, which exhibited an acceptably low health risk to leek consumption. The current study could not only guide reasonable usage of the formulation, but also facilitate the setting of maximum residue limits(MRLs) of chlorfenapyr and clothianidin in leek for Chinese展开更多
As an effective non-petroleum based process for producing light olefins, the methanol-to-olefin(MTO) route has become an indispensable alternative to the industrial production of light olefins. The silicoaluminophosph...As an effective non-petroleum based process for producing light olefins, the methanol-to-olefin(MTO) route has become an indispensable alternative to the industrial production of light olefins. The silicoaluminophosphate SAPO-34 zeolite(CHA-type structure) has proven to be an efficient industrial catalyst for the production of ethylene and propylene by the MTO reaction. However, the inherent structure and related diffusion limitations of SAPO-34 limit the mass transport and thus cause rapid deactivation of the catalyst. Fabrication of hierarchical SAPO-34 zeolite is one of the most effective strategies to address the intrinsic diffusion limitation. As simple, inexpensive, and efficient approach, the post-synthetic route has attracted considerable attention and widely used to introduce secondary meso-/macropores into the microporous SAPO-34 material. Significant effort has been dedicated to the development of post-synthesis strategies to prepare hierarchical SAPO-34 zeolite, thereby enhancing its catalytic performance in the MTO process. This mini-review addresses the post-synthesis preparation of hierarchical SAPO-34 catalysts and their MTO performance. Furthermore, some current problems and prospects of the post-synthesis route to hierarchical SAPO-34 catalysts are also revised. We expect this minireview to inspire the more efficient preparation of hierarchical SAPO-34 catalysts for the MTO process.展开更多
With the increasingly stringent standards for limiting sulfide content in liquid fuels,oxidative desulfurization(ODS)has become a promising ultra-deep desulfurization process in fuel desulfurization.TS-1 zeolites show...With the increasingly stringent standards for limiting sulfide content in liquid fuels,oxidative desulfurization(ODS)has become a promising ultra-deep desulfurization process in fuel desulfurization.TS-1 zeolites show great potential as catalysts for ODS reactions,due to its remarkable oxidation activity at low temperatures and pressure.However,the inherent microporous structure of conventional TS-1 zeolites restricts the mass transportation and renders the active sites in the microporous space of TS-1 zeolites inaccessible for bulky aromatic organosulfur compounds.Fabrication of hierarchical TS-1 zeolites by incorporating meso-/macropores into microporous TS-1 zeolites is an effective strategy to improve mass transportability.In recent years,abundant efforts have been dedicated to developing synthetic strategies of hierarchical TS-1 zeolite,thereby improving its catalytic performance in the ODS process.This mini-review addresses the synthetic methods of hierarchical TS-1 catalysts and their catalytic performance in the ODS reactions.In addition,some current problems and prospects of synthesis routes for constructing hierarchical TS-1 catalysts have also been revised.We expect this mini-review to shed light on the more efficient preparation strategies of hierarchical TS-1 zeolites for the ODS process.展开更多
Zeolites and zeo-type materials with nanosized dimensions are of great practical interest owing to their favorable transport properties,faster adsorption kinetics,and large external surface area.This mini-review prese...Zeolites and zeo-type materials with nanosized dimensions are of great practical interest owing to their favorable transport properties,faster adsorption kinetics,and large external surface area.This mini-review presents recent developments in the organic template-free synthesis of nanosized zeolites and related materials.The advantages and challenges of these methods are addressed with particular attention to the green synthesis of nanozeolites.展开更多
A novel decentralized indirect adaptive output feedback fuzzy controller is developed for a class of large-scale uncertain nonlinear systems using error filtering.By the properly filtering of the observation error dyn...A novel decentralized indirect adaptive output feedback fuzzy controller is developed for a class of large-scale uncertain nonlinear systems using error filtering.By the properly filtering of the observation error dynamics,the strictly positive-real condition is guaranteed to hold such that the proposed output feedback and adaptation mechanisms are practicable in practice owing to the fact that its implementation does not require the observation error vector itself any more,which corrects the impracticable schemes in the previous literature involved.The presented control algorithm can ensure that all the signals of the closed-loop large-scale system keep uniformly ultimately bounded and that the tracking error converges to zero asymptotically.The decentralized output feedback fuzzy controller can be applied to address the longitudinal control problem of a string of vehicles within an automated highway system（AHS） and the effectiveness of the design procedure is supported by simulation results.展开更多
Background:Transforming growth factor-β1(TGF-β1)is a pleiotropic cytokine that plays a central role in the pathogenesis of idiopathic pulmonary fibrosis(IPF).While previous studies have revealed a cross-talk between...Background:Transforming growth factor-β1(TGF-β1)is a pleiotropic cytokine that plays a central role in the pathogenesis of idiopathic pulmonary fibrosis(IPF).While previous studies have revealed a cross-talk between vitamin D and TGF-β1 signaling,it is still unclear how they interact with each other to regulate the progression of IPF.Methods:In this work,we searched for a novel mediator of TGF-β1 activity in lung fibroblasts and examined its regulation by vitamin D.In addition,we investigated the mechanism underlying the interaction between vitamin D and TGF-β1 signaling in lung fibroblast activation.Bioinformatic analysis was performed to identify TGF-β1 downstream target genes.Knockdown and overexpression expression experiments were conducted to determine gene function in the regulation of lung fibroblast proliferation and migration.Results:Analysis of publicly available datasets revealed that RAS guanyl releasing protein 3(RasGRP3)was upregulated in TGF-β1-treated lung fibroblasts and lung tissues from IPF patients relative to healthy controls.Our data confirmed the upregulation of RasGRP3 by TGF-β1 in human MRC5 lung fibroblasts.Overexpression of RasGRP3 enhanced MRC5 cell proliferation and migration.Knockdown of RasGRP3 blocked TGF-β1-induced MRC5 proliferation and migration.Vitamin D abolished TGF-β1-induced RasGRP3 upregulation,which was reversed by inhibition of the vitamin D receptor(VDR).Mechanistically,vitamin D promoted VDR enrichment and prevented mothers against decapentaplegic homolog(SMAD)2 and 3 occupancy at the promoter of RasGRP3.Additionally,overexpression of RasGRP3 reversed the suppressive effect of vitamin D on MRC5 cell proliferation and migration.Conclusion:In conclusion,vitamin D antagonizes TGF-β1-induced lung fibroblast activation by repressing RasGRP3 transcription.展开更多
The rational design and construction of inexpensive and highly active electrocatalysts for hydrogen evolution reaction(HER)is of great importance for water splitting.Herein,we develop a facile approach for preparation...The rational design and construction of inexpensive and highly active electrocatalysts for hydrogen evolution reaction(HER)is of great importance for water splitting.Herein,we develop a facile approach for preparation of porous carbon-confined Ru-doped Cu nanoparticles(denoted as Ru-Cu@C)by direct pyrolysis of the Ru-exchanged Cu-BTC metal–organic framework.When served as the electrocatalyst for HER,strikingly,the obtained Ru-Cu@C catalyst exhibits an ultralow overpotential(only 20 mV at 10 mA cm^(-2))with a small Tafel slope of 37 m V dec^(-1)in alkaline electrolyte.The excellent performance is comparable or even superior to that of commercial Pt/C catalyst.Density functional theory(DFT)calculations confirm that introducing Ru atoms into Cu nanocrystals can significantly alter the desorption of H_(2) to achieve a close-to-zero hydrogen adsorption energy and thereby boost the HER process.This strategy gives a fresh impetus to explore low-cost and high-performance catalysts for HER in alkaline media.展开更多
Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinas...Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles.In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.展开更多
A number of CaHfO_(3)modified BiFeO_(3)-0.33BaTiO_(3)(BF-0.33BT-xCH)lead-free piezoceramics were fabri-cated through the solid-state sintering method and comprehensively investigated in this work.Under the optimal sin...A number of CaHfO_(3)modified BiFeO_(3)-0.33BaTiO_(3)(BF-0.33BT-xCH)lead-free piezoceramics were fabri-cated through the solid-state sintering method and comprehensively investigated in this work.Under the optimal sintering temperature,all compositions display a typical perovskite structure in a pseudo-cubic phase with slightly larger lattice parameters as the CH content increases.The electrical resistivity is highly enhanced due to the addition of CH.Microstructures,including the grain morphology,core-shell structure,and chemistry inhomogeneities,are demonstrated upon different BF-0.33BT-xCH composi-tions.In particular,the core-shell structures with non-uniform element distributions in the compositions can be eliminated by adding sufficient CH content(x>0.05).The highest saturation polarization(40.1 mC/cm^(2)),remnant polarization(26.8 mC/cm^(2)),and converse piezoelectric coefficient(290 pm/V)are achieved in the BF-0.33BT-0.01CH piezoceramic,which are significantly enhanced in comparison with the undoped BF-0.33BT piezoceramic.With further increasing the CH content,the piezoelectric properties of BF-0.33BT-xCH ceramics decline rapidly,and they start to exhibit characteristics of relaxor ferroelectrics.展开更多
BiFeO_(3)-BaTiO_(3)is a promising lead-free piezoelectric ceramic,exhibiting high Curie temperature and superior electrochemical characteristics.In this work,e_(1-x)TBiFeO_(3)-xBaTiO_(3)(BF-xBT,x=0.26,0.28,0.30,0.32,0...BiFeO_(3)-BaTiO_(3)is a promising lead-free piezoelectric ceramic,exhibiting high Curie temperature and superior electrochemical characteristics.In this work,e_(1-x)TBiFeO_(3)-xBaTiO_(3)(BF-xBT,x=0.26,0.28,0.30,0.32,0.34,0.36)ceramics were fabricated using the conventional solid-state reaction method through precise composition control.Multiple characterization techniques,including X-ray powder diffraction(XRD),scanning electron microscope(SEM),and electrical property testing systems,were applied to systematically examine the crystallographic structure,microstructure,as well as the dielectric,ferroelectric and piezoelectric properties of the BF-xBT ceramics.The XRD results confirm that all compositions exhibit a typical perovskite structure,transitioning from a single rhombohedral phase to a rhombohedral-cubic phase mixture as the BT content increases.SEM shows apparent core-shell microstructures in the ceramics.Notably,the results demonstrated that the BF-0.30BT ceramic exhibits the maximum piezoelectric constant(d_(33))-217 pC/N,while the BF-0.34BT ceramic displays the maximum converse piezoelectric constant(d_(33)^(*))-323 pm/V,which highlights the suitability of BF-BT ceramics for high-performance piezoelectric applications.展开更多
基金Supported by Grants from Beijing Academic Leaders Program,NO.2009-2-17Beijing Natural Science Foundation,No.7102029+5 种基金Capital Medical Developed Research Fund,No.2007-1023New Scholar Star Program of Ministry of EducationNational Basic Research Program of China,No.2011CB504300Specialized Research Fund for the Doctoral Program of Higher Education,No.20130001110108National Natural Science Foundation for Distinguished Young Scholars,No.81301748Science Fund for Creative Research Groups of the National Natural Science Foundation of China,No.IRT13003 and No.NIH/NCI U54 CA156735
文摘Esophageal squamous cell carcinoma continues to heavily burden clinicians worldwide. Researchers have discovered the genomic landscape of esophageal squamous cell carcinoma, which holds promise for an era of personalized oncology care. One of the most pressing problems facing this issue is to improve the understanding of the newly available genomic data, and identify the driver-gene mutations, pathways, and networks. The emergence of a legion of novel targeted agents has generated much hope and hype regarding more potent treatment regimens, but the accuracy of drug selection is still arguable. Other problems, such as cancer heterogeneity, drug resistance, exceptional responders, and side effects, have to be surmounted. Evolving topics in personalized oncology, such as interpretation of genomics data, issues in targeted therapy, research approaches for targeted therapy, and future perspectives, will be discussed in this editorial.
基金financially supported by the Natural Science Foundation of Beijing (No. 8162029)National Natural Science Foundation of China (No. 21677009)
文摘Commercial suspension emulsion(SE) of(8% chlorfenapyr + 20% clothianidin), as a pre-registered product in China, was firstly investigated under Chinese open-field conditions. A MWCNTs-based QuEChERS method for simultaneous determination of chlorfenapyr and clothianidin in leek was established and validated through rapid resolution liquid chromatography triples quadrupole tandem mass spectrometry(RRLC-QqQ-MS/MS). Based on this method, the dissipation behaviors, residue distributions and dietary risk probability of these fungicides in leek from two representative locations in China in 2016, which were previously treated with these insecticides at the doses of 420–630 g a.i./ha twice applications, were further investigated for food safety. Dissipation behavior of chlorfenapyr and clothianidin in leek followed first-order kinetics with the half-lives of 2.9–7.2 days, and the highest residues(HR) of these insecticides in leek were below 0.3811 mg/kg and 0.2989 mg/kg, respectively, at the pre-harvest interval(PHI, 7 days). For dietary risk assessments, the risk quotients(RQs) of chlorfenapyr and clothianidin in leek were evaluated by comparing the value of national estimated daily intake(NEDI) with acceptable daily intake(ADI), based on the trials data under good agricultural practices(GAP) conditions. The results indicated that RQs of chlorfenapyr and clothianidin in leek were21.5% and 0.29%, respectively, which exhibited an acceptably low health risk to leek consumption. The current study could not only guide reasonable usage of the formulation, but also facilitate the setting of maximum residue limits(MRLs) of chlorfenapyr and clothianidin in leek for Chinese
基金supported by the National Natural Science Foundation of China(21971082)the Jilin Province Science and Technology Development Plan(20190201229JC and 20200201096JC)+1 种基金the China Postdoctoral Science Foundation(2018M640280 and 2019T120235)for supporting this workthe National 111 Project(B17020)。
文摘As an effective non-petroleum based process for producing light olefins, the methanol-to-olefin(MTO) route has become an indispensable alternative to the industrial production of light olefins. The silicoaluminophosphate SAPO-34 zeolite(CHA-type structure) has proven to be an efficient industrial catalyst for the production of ethylene and propylene by the MTO reaction. However, the inherent structure and related diffusion limitations of SAPO-34 limit the mass transport and thus cause rapid deactivation of the catalyst. Fabrication of hierarchical SAPO-34 zeolite is one of the most effective strategies to address the intrinsic diffusion limitation. As simple, inexpensive, and efficient approach, the post-synthetic route has attracted considerable attention and widely used to introduce secondary meso-/macropores into the microporous SAPO-34 material. Significant effort has been dedicated to the development of post-synthesis strategies to prepare hierarchical SAPO-34 zeolite, thereby enhancing its catalytic performance in the MTO process. This mini-review addresses the post-synthesis preparation of hierarchical SAPO-34 catalysts and their MTO performance. Furthermore, some current problems and prospects of the post-synthesis route to hierarchical SAPO-34 catalysts are also revised. We expect this minireview to inspire the more efficient preparation of hierarchical SAPO-34 catalysts for the MTO process.
基金supported by the National Natural Science Foundation of China(21971082)the Jilin Province Science and Technology Development Plan(20200201096JC and 20190201229JC)+1 种基金the China Postdoctoral Science Foundation(2019T120235 and 2018M640280)for supporting this workthe 111 Project(B17020)。
文摘With the increasingly stringent standards for limiting sulfide content in liquid fuels,oxidative desulfurization(ODS)has become a promising ultra-deep desulfurization process in fuel desulfurization.TS-1 zeolites show great potential as catalysts for ODS reactions,due to its remarkable oxidation activity at low temperatures and pressure.However,the inherent microporous structure of conventional TS-1 zeolites restricts the mass transportation and renders the active sites in the microporous space of TS-1 zeolites inaccessible for bulky aromatic organosulfur compounds.Fabrication of hierarchical TS-1 zeolites by incorporating meso-/macropores into microporous TS-1 zeolites is an effective strategy to improve mass transportability.In recent years,abundant efforts have been dedicated to developing synthetic strategies of hierarchical TS-1 zeolite,thereby improving its catalytic performance in the ODS process.This mini-review addresses the synthetic methods of hierarchical TS-1 catalysts and their catalytic performance in the ODS reactions.In addition,some current problems and prospects of synthesis routes for constructing hierarchical TS-1 catalysts have also been revised.We expect this mini-review to shed light on the more efficient preparation strategies of hierarchical TS-1 zeolites for the ODS process.
基金supported by the National Natural Science Foundation of China(Grant 21971082 and 22001090)the Jilin Province Science and Technology Development Plan(Grant 20190201229JC and 20200201096JC)。
文摘Zeolites and zeo-type materials with nanosized dimensions are of great practical interest owing to their favorable transport properties,faster adsorption kinetics,and large external surface area.This mini-review presents recent developments in the organic template-free synthesis of nanosized zeolites and related materials.The advantages and challenges of these methods are addressed with particular attention to the green synthesis of nanozeolites.
基金supported by the National Natural Science Foundation of China (6096400460864004+2 种基金50808025)the Fok Ying Tung Education Foundation (122013)the Scientific Research Fund of Hunan Provincial Education Department (08A003)
文摘A novel decentralized indirect adaptive output feedback fuzzy controller is developed for a class of large-scale uncertain nonlinear systems using error filtering.By the properly filtering of the observation error dynamics,the strictly positive-real condition is guaranteed to hold such that the proposed output feedback and adaptation mechanisms are practicable in practice owing to the fact that its implementation does not require the observation error vector itself any more,which corrects the impracticable schemes in the previous literature involved.The presented control algorithm can ensure that all the signals of the closed-loop large-scale system keep uniformly ultimately bounded and that the tracking error converges to zero asymptotically.The decentralized output feedback fuzzy controller can be applied to address the longitudinal control problem of a string of vehicles within an automated highway system（AHS） and the effectiveness of the design procedure is supported by simulation results.
基金the Basic Scientific Research Project of Wenzhou of China(Y20210068)the Collaborative Education Project of Industry-University Cooperation of the Ministry of Education of China(202101160012).
文摘Background:Transforming growth factor-β1(TGF-β1)is a pleiotropic cytokine that plays a central role in the pathogenesis of idiopathic pulmonary fibrosis(IPF).While previous studies have revealed a cross-talk between vitamin D and TGF-β1 signaling,it is still unclear how they interact with each other to regulate the progression of IPF.Methods:In this work,we searched for a novel mediator of TGF-β1 activity in lung fibroblasts and examined its regulation by vitamin D.In addition,we investigated the mechanism underlying the interaction between vitamin D and TGF-β1 signaling in lung fibroblast activation.Bioinformatic analysis was performed to identify TGF-β1 downstream target genes.Knockdown and overexpression expression experiments were conducted to determine gene function in the regulation of lung fibroblast proliferation and migration.Results:Analysis of publicly available datasets revealed that RAS guanyl releasing protein 3(RasGRP3)was upregulated in TGF-β1-treated lung fibroblasts and lung tissues from IPF patients relative to healthy controls.Our data confirmed the upregulation of RasGRP3 by TGF-β1 in human MRC5 lung fibroblasts.Overexpression of RasGRP3 enhanced MRC5 cell proliferation and migration.Knockdown of RasGRP3 blocked TGF-β1-induced MRC5 proliferation and migration.Vitamin D abolished TGF-β1-induced RasGRP3 upregulation,which was reversed by inhibition of the vitamin D receptor(VDR).Mechanistically,vitamin D promoted VDR enrichment and prevented mothers against decapentaplegic homolog(SMAD)2 and 3 occupancy at the promoter of RasGRP3.Additionally,overexpression of RasGRP3 reversed the suppressive effect of vitamin D on MRC5 cell proliferation and migration.Conclusion:In conclusion,vitamin D antagonizes TGF-β1-induced lung fibroblast activation by repressing RasGRP3 transcription.
基金the National Key R&D Program of China(2018YFB0605700)the National Natural Science Foundation of China(51778570,51879230,21725101,21871244,21521001,and 21703145)+1 种基金China Postdoctoral Science Foundation(2019TQ0298,2019M660151)Fujian Institute of Innovation(CAS)。
文摘The rational design and construction of inexpensive and highly active electrocatalysts for hydrogen evolution reaction(HER)is of great importance for water splitting.Herein,we develop a facile approach for preparation of porous carbon-confined Ru-doped Cu nanoparticles(denoted as Ru-Cu@C)by direct pyrolysis of the Ru-exchanged Cu-BTC metal–organic framework.When served as the electrocatalyst for HER,strikingly,the obtained Ru-Cu@C catalyst exhibits an ultralow overpotential(only 20 mV at 10 mA cm^(-2))with a small Tafel slope of 37 m V dec^(-1)in alkaline electrolyte.The excellent performance is comparable or even superior to that of commercial Pt/C catalyst.Density functional theory(DFT)calculations confirm that introducing Ru atoms into Cu nanocrystals can significantly alter the desorption of H_(2) to achieve a close-to-zero hydrogen adsorption energy and thereby boost the HER process.This strategy gives a fresh impetus to explore low-cost and high-performance catalysts for HER in alkaline media.
基金supported by the National Major Scientific and Technological Special Project(Nos.2018ZX09201002,2018ZX09711001-011 and 2019ZX09201001)the National Natural Science Foundation of China(No.81773375)
文摘Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles.In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.
基金supported by the Science,Technology and Innovation Commission of Shenzhen Municipality,grants No:RCBS20210706092341001 and No:JCYJ20220531095802005.
文摘A number of CaHfO_(3)modified BiFeO_(3)-0.33BaTiO_(3)(BF-0.33BT-xCH)lead-free piezoceramics were fabri-cated through the solid-state sintering method and comprehensively investigated in this work.Under the optimal sintering temperature,all compositions display a typical perovskite structure in a pseudo-cubic phase with slightly larger lattice parameters as the CH content increases.The electrical resistivity is highly enhanced due to the addition of CH.Microstructures,including the grain morphology,core-shell structure,and chemistry inhomogeneities,are demonstrated upon different BF-0.33BT-xCH composi-tions.In particular,the core-shell structures with non-uniform element distributions in the compositions can be eliminated by adding sufficient CH content(x>0.05).The highest saturation polarization(40.1 mC/cm^(2)),remnant polarization(26.8 mC/cm^(2)),and converse piezoelectric coefficient(290 pm/V)are achieved in the BF-0.33BT-0.01CH piezoceramic,which are significantly enhanced in comparison with the undoped BF-0.33BT piezoceramic.With further increasing the CH content,the piezoelectric properties of BF-0.33BT-xCH ceramics decline rapidly,and they start to exhibit characteristics of relaxor ferroelectrics.
基金supported by the Science,Technology and Innovation Committee of Shenzhen Municipality(Grant Nos.:JCYJ20220531095802005 and RCBS20210706092341001).
文摘BiFeO_(3)-BaTiO_(3)is a promising lead-free piezoelectric ceramic,exhibiting high Curie temperature and superior electrochemical characteristics.In this work,e_(1-x)TBiFeO_(3)-xBaTiO_(3)(BF-xBT,x=0.26,0.28,0.30,0.32,0.34,0.36)ceramics were fabricated using the conventional solid-state reaction method through precise composition control.Multiple characterization techniques,including X-ray powder diffraction(XRD),scanning electron microscope(SEM),and electrical property testing systems,were applied to systematically examine the crystallographic structure,microstructure,as well as the dielectric,ferroelectric and piezoelectric properties of the BF-xBT ceramics.The XRD results confirm that all compositions exhibit a typical perovskite structure,transitioning from a single rhombohedral phase to a rhombohedral-cubic phase mixture as the BT content increases.SEM shows apparent core-shell microstructures in the ceramics.Notably,the results demonstrated that the BF-0.30BT ceramic exhibits the maximum piezoelectric constant(d_(33))-217 pC/N,while the BF-0.34BT ceramic displays the maximum converse piezoelectric constant(d_(33)^(*))-323 pm/V,which highlights the suitability of BF-BT ceramics for high-performance piezoelectric applications.
