Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 tr...Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 trial)showed no additional advantage.The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment(TME)to aid in optimizing sequencing of combination therapies.Methods:The PD-RAD trial(ClinicalTrials.gov identifier:NCT03258788)aimed to enroll thirty NSCLC patients receiving radical-intent RT.Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry(mIHC)and high-dimensional mass cytometry(CyTOF),respectively.Results:Paired biopsies were collected from only three patients(Pts 1,3&4)and blood from four patients(Pts 1-4)before the study was closed early during the COVID-19 pandemic.Programmed Death-Ligand 1(PD-L1)expression in the TME was raised in Patient 1,who responded well to treatment,and unaltered in two patients with progressive disease.CyTOF analysis revealed elevated circulating classical monocytes,highest in the patient with a good response.Conclusions:This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint.The hypothesis-generating findings highlight PD-L1+macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response,but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.展开更多
Aqueous zinc metal batteries(AZMBs)face significant challenges in achieving reversibility and cycling stability,primarily due to hydrogen evolution reactions(HER)and zinc dendrite growth.In this study,by employing car...Aqueous zinc metal batteries(AZMBs)face significant challenges in achieving reversibility and cycling stability,primarily due to hydrogen evolution reactions(HER)and zinc dendrite growth.In this study,by employing carefully designed cells that approximate the structural characteristics of practical batteries,we revisit this widely held view through in-operando X-ray radiography to examine zinc dendrite formation and HER under nearpractical operating conditions.While conventional understanding emphasizes the severity of these processes,our findings suggest that zinc dendrites and HER are noticeably less pronounced in dense,real-operation configurations compared to modified cells,possibly due to a more uniform electric field and the suppression of triple-phase boundaries.This study indicates that other components,such as degradation at the cathode current collector interface and configuration mismatches within the full cell,may also represent important barriers to the practical application of AZMBs,particularly during the early stages of electrodeposition.展开更多
BACKGROUND The incidence of diabetic atherosclerosis(DMA)is increasing worldwide,but its pathogenesis remains incompletely understood.In addition to cardiovascular complications,bladder dysfunction is one of the commo...BACKGROUND The incidence of diabetic atherosclerosis(DMA)is increasing worldwide,but its pathogenesis remains incompletely understood.In addition to cardiovascular complications,bladder dysfunction is one of the common comorbidities associated with DMA but is often refractory to current treatments.AIM To investigate the therapeutic effect of human amniotic fluid stem cell-derived extracellular vesicles(hAFSC-EVs)on the recovery of bladder dysfunction in DMA rats.METHODS Eighty rats were divided into normal control,streptozotocin-induced diabetic rats,diabetic rats subjected to arterial balloon endothelial injury of common iliac artery(DMA),and DMA rats treated with hAFSC-EVs(DMA+hAFSC-EVs).At 4 weeks and 12 weeks after DMA induction,levels of blood glucose,total cholesterol,triglyceride,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,homeostasis model assessment(HOMA)-insulin resistance,and HOMA-βwere measured.Cystometry,common iliac artery wall thickness,and bladder tumor necrosis factor(TNF)-α,interleukin(IL)-6,transforming growth factor(TGF)-β1,Smad3,connective tissue growth factor(CTGF)and fibronectin were also evaluated.RESULTS Bladder weight and blood glucose,triglyceride,HOMA-insulin resistance,common iliac artery intima thickness,voided volume,intercontraction interval,bladder capacity,and mRNA expression of TNF-α,IL-6,TGF-β1,Smad3,CTGF and fibronectin were significantly increased at 4 weeks and 12 weeks after induction,while the HOMA-βlevel decreased at 4 weeks and 12 weeks,and the high-density lipoprotein cholesterol level decreased at 12 weeks.hAFSC-EVs treatment in DMA rats significantly reduced bladder weight and blood glucose,thickness of common iliac arterial intima,voided volume,intercontraction interval and bladder capacity at 4 weeks.The mRNA expression of TNF-α,TGF-β1,and CTGF in DMA rats treated with hAFSC-EVs were significantly decreased at 4 weeks,while the mRNA expressions of IL-6 and Smad3 were significantly decreased 12 weeks.CONCLUSION hAFSC-EVs treatment can help restore DMA-induced bladder dysfunction,which is associated with lowered blood glucose levels,reduced arterial wall thickness,and decreased TNF-α,IL-6,TGF-β1,Smad3,and CTGF expression.展开更多
Objective:Sepsis exhibits remarkable heterogeneity in disease progression trajectories,and accurate identificationof distinct trajectory-based phenotypes is critical for implementing personalized therapeutic strategie...Objective:Sepsis exhibits remarkable heterogeneity in disease progression trajectories,and accurate identificationof distinct trajectory-based phenotypes is critical for implementing personalized therapeutic strategies and prognostic assessment.However,trajectory clustering analysis of time-series clinical data poses substantial methodological challenges for researchers.This study provides a comprehensive tutorial framework demonstrating six trajectory modeling approaches integrated with proteomic analysis to guide researchers in identifying sepsis subtypes after laparoscopic surgery.Methods:This study employs simulated longitudinal data from 300 septic patients after laparoscopic surgery to demonstrate six trajectory modeling methods(group-based trajectory modeling,latent growth mixture modeling,latent transition analysis,time-varying effect modeling,K-means for longitudinal data,agglomerative hierarchical clustering)for identifying associations between predefinedsequential organ failure assessment trajectories and 25 proteomic biomarkers.Clustering performance was evaluated via multiple metrics,and a biomarker discovery pipeline integrating principal component analysis,random forests,feature selection,and receiver operating characteristic analysis was developed.Results:The six methods demonstrated varying performance in identifying trajectory structures,with each approach exhibiting distinct analytical characteristics.The performance metrics revealed differences across methods,which may inform context-specificmethod selection and interpretation strategies.Conclusion:This study illustrates practical implementations of trajectory modeling approaches under controlled conditions,facilitating informed method selection for clinical researchers.The inclusion of complete R code and integrated proteomics workflows offers a reproducible analytical framework connecting temporal pattern recognition to biomarker discovery.Beyond sepsis,this pipeline-oriented approach may be adapted to diverse clinical scenarios requiring longitudinal disease characterization and precision medicine applications.The comparative analysis reveals that each method has distinct strengths,providing a practical guide for clinical researchers in selecting appropriate methods based on their specificstudy goals and data characteristics.展开更多
Recent advancements in Zn-halogen batteries have focused on enhancing the adsorptive or catalytic capability of host materials and stabilizing complex intermediates with electrolyte additives,while the halogen-ion ele...Recent advancements in Zn-halogen batteries have focused on enhancing the adsorptive or catalytic capability of host materials and stabilizing complex intermediates with electrolyte additives,while the halogen-ion electrolyte modifications exhibit strong potential for integrated interfacial regulation.Herein,we design an electrically insulating rigid electrolyte container to immobilize a liquid halogen-ion electrolyte for separator-free Zn-halogen batteries with customizable electron transfer.Robust hydrogen bonding of hydroxyl groups in SiO_(2)with fluorinated moieties in PVDF-hfp regulates Zn^(2+)solvation and suppresses H_(2)O activity,while multi-channels formed by microcracks and interparticle gaps not only enhance mass transfer but also buffer interfacial electric field,jointly enabling a durable Zn plating/stripping.Effective confinement of intermediates also ensures the high reversibility across single-(I^(-)/I0),double-(I^(-)/I0/I^(-)),and triple-(I^(-)/I0/I^(-),Cl-/Cl0)electron transfer mechanisms at cathode,as evidenced by the double-electron transfer systems exhibiting a low capacity decay rate of 0.02‰over 4500 cycles at 10 mA cm^(-2)and a high areal capacity of 11.9 mAh cm^(-2)at 2 mA cm^(-2).This work presents a novel“container engineering”approach to halogen-ion electrolyte design and provides fundamental insights into the relationships between redox reversibility and reaction kinetics.展开更多
The sustainable sourcing of novel bioactive compounds from natural sources is crucial to the success of the pharmaceutical,food,and cosmetics industries.Iris bucharica Foster(syn.Juno bucharica(Foster)Vved.)is a promi...The sustainable sourcing of novel bioactive compounds from natural sources is crucial to the success of the pharmaceutical,food,and cosmetics industries.Iris bucharica Foster(syn.Juno bucharica(Foster)Vved.)is a promising source of novel bioactive molecules,particularly phenolic compounds,which are renowned for their antioxidant properties.In this study,we developed a reliable HPLC-UV-DAD method to identify and quantify phenolic compounds in the leaves and bulbs of I.bucharica,establishing the first set of quality control markers for this species.A total of 21 phenolic compounds were identified in the leaves,with flavonoids isoorientin,guaijaverin,hyperoside,and cosmosiin,the isoflavonoid biochanin A,and the simple phenolic ferulic acid being the most prominent.In comparison,14 compounds were identified in the bulbs,primarily isoflavonoids,including tectoridin and germanaism B,and flavonoid apigenin.The leaves extracts exhibited significant antioxidant activity,whereas the anti-allergic and anti-inflammatory effects were mild.These findings highlight I.bucharica as a sustainable source of bioactive compounds with potential industrial applications.However,further studies are needed to evaluate bioavailability and in vivo efficacy,as well as to optimise extraction methods to realize its industrial potential fully.展开更多
基金the National Institute for Health and Care Research(NHR)Manchester Biomedical Research Centre(BRC)(NIHR203308,NIHR-BRC-1215-20007)Astra-Zeneca(ESR-14-10711)+2 种基金CRUK RadNet(C19941/A27801)TMI and CFF are the recipient of an NIHR Senior Investigator Award(NIHR205054 and NIHR205061)CTH is supported by the NIHR University College London Hospitals NHS Foundation Trust BRC,the City of London CRUK RadNet and the CRUK Lung Cancer Centre of Excellence.
文摘Objectives:The PACIFIC trial established the benefit of durvalumab following chemo-radiotherapy for stage III non-small cell lung cancer(NSCLC).However,the concurrent use of radiotherapy(RT)and durvalumab(PACIFIC-2 trial)showed no additional advantage.The PD-RAD study was set up to understand the immunological effects of RT on the tumor microenvironment(TME)to aid in optimizing sequencing of combination therapies.Methods:The PD-RAD trial(ClinicalTrials.gov identifier:NCT03258788)aimed to enroll thirty NSCLC patients receiving radical-intent RT.Tumor biopsies and blood samples were collected pre-RT and at week 2 during RT and analyzed using multiplex immunohistochemistry(mIHC)and high-dimensional mass cytometry(CyTOF),respectively.Results:Paired biopsies were collected from only three patients(Pts 1,3&4)and blood from four patients(Pts 1-4)before the study was closed early during the COVID-19 pandemic.Programmed Death-Ligand 1(PD-L1)expression in the TME was raised in Patient 1,who responded well to treatment,and unaltered in two patients with progressive disease.CyTOF analysis revealed elevated circulating classical monocytes,highest in the patient with a good response.Conclusions:This study underscores the challenges of integrating advanced immune monitoring during RT delivery and did not meet its primary endpoint.The hypothesis-generating findings highlight PD-L1+macrophages in the TME and classical monocytes in the blood as potential immune biomarkers of RT response,but larger studies are needed to validate these observations and characterize the immune changes following curative-intent RT in patients with NSCLC.
基金the fundamental Research Funds for the central Universities(x2wjD2240360)for the funding supportMeanwhile,Engineering and Physical Sciences Research Council(EPSRC,EP/V027433/3)+2 种基金UK Research and Innovation(UKRI)under the UK government’s Horizon Europe funding(101077226,EP/Y008707/1)Faraday Institution(EP/S003053/1)Degradation project(FIRG001),Royal Society(IEC\NSFC\233361),QUB Agility Fund and Wright Technology and Research Centre(W-Tech,R5240MEE)Funding from UK aid from the UK Government through the Faraday Institution and the Transforming Energy Access Programme(Grant number FIRG050-Device engineering of Zn-based hybrid micro-flow batteries and by-product H2 collection for Emerging Economies)。
文摘Aqueous zinc metal batteries(AZMBs)face significant challenges in achieving reversibility and cycling stability,primarily due to hydrogen evolution reactions(HER)and zinc dendrite growth.In this study,by employing carefully designed cells that approximate the structural characteristics of practical batteries,we revisit this widely held view through in-operando X-ray radiography to examine zinc dendrite formation and HER under nearpractical operating conditions.While conventional understanding emphasizes the severity of these processes,our findings suggest that zinc dendrites and HER are noticeably less pronounced in dense,real-operation configurations compared to modified cells,possibly due to a more uniform electric field and the suppression of triple-phase boundaries.This study indicates that other components,such as degradation at the cathode current collector interface and configuration mismatches within the full cell,may also represent important barriers to the practical application of AZMBs,particularly during the early stages of electrodeposition.
基金the Ministry of Science and Technology Taiwan,No.MOST 109-2314-B-182A-091,No.NSTC 112-2314-B-182A-062, No.NSTC 113-2314-B-182A-125.
文摘BACKGROUND The incidence of diabetic atherosclerosis(DMA)is increasing worldwide,but its pathogenesis remains incompletely understood.In addition to cardiovascular complications,bladder dysfunction is one of the common comorbidities associated with DMA but is often refractory to current treatments.AIM To investigate the therapeutic effect of human amniotic fluid stem cell-derived extracellular vesicles(hAFSC-EVs)on the recovery of bladder dysfunction in DMA rats.METHODS Eighty rats were divided into normal control,streptozotocin-induced diabetic rats,diabetic rats subjected to arterial balloon endothelial injury of common iliac artery(DMA),and DMA rats treated with hAFSC-EVs(DMA+hAFSC-EVs).At 4 weeks and 12 weeks after DMA induction,levels of blood glucose,total cholesterol,triglyceride,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,homeostasis model assessment(HOMA)-insulin resistance,and HOMA-βwere measured.Cystometry,common iliac artery wall thickness,and bladder tumor necrosis factor(TNF)-α,interleukin(IL)-6,transforming growth factor(TGF)-β1,Smad3,connective tissue growth factor(CTGF)and fibronectin were also evaluated.RESULTS Bladder weight and blood glucose,triglyceride,HOMA-insulin resistance,common iliac artery intima thickness,voided volume,intercontraction interval,bladder capacity,and mRNA expression of TNF-α,IL-6,TGF-β1,Smad3,CTGF and fibronectin were significantly increased at 4 weeks and 12 weeks after induction,while the HOMA-βlevel decreased at 4 weeks and 12 weeks,and the high-density lipoprotein cholesterol level decreased at 12 weeks.hAFSC-EVs treatment in DMA rats significantly reduced bladder weight and blood glucose,thickness of common iliac arterial intima,voided volume,intercontraction interval and bladder capacity at 4 weeks.The mRNA expression of TNF-α,TGF-β1,and CTGF in DMA rats treated with hAFSC-EVs were significantly decreased at 4 weeks,while the mRNA expressions of IL-6 and Smad3 were significantly decreased 12 weeks.CONCLUSION hAFSC-EVs treatment can help restore DMA-induced bladder dysfunction,which is associated with lowered blood glucose levels,reduced arterial wall thickness,and decreased TNF-α,IL-6,TGF-β1,Smad3,and CTGF expression.
基金funding from the China National Key Research and Development Program(No.2023YFC3603104)the National Natural Science Foundation of China(Nos.82472243 and 82272180)+6 种基金the Fundamental Research Funds for the Central Universities(No.226-2025-00024)the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LHDMD24H150001)the Key Research&Development Project of Zhejiang Province(No.2024C03240)a collaborative scientific project co-established by the Science and Technology Department of the National Administration of Traditional Chinese Medicine and the Zhejiang Provincial Administration of Traditional Chinese Medicine(No.GZY-ZJ-KJ-24082)he General Health Science and Technology Program of Zhejiang Province(No.2024KY1099)the Project of Zhejiang University Longquan Innovation Center(No.ZJDXLQCXZCJBGS2024016)Wu Jieping Medical Foundation Special Research Grant(No.320.6750.2024-23-07).
文摘Objective:Sepsis exhibits remarkable heterogeneity in disease progression trajectories,and accurate identificationof distinct trajectory-based phenotypes is critical for implementing personalized therapeutic strategies and prognostic assessment.However,trajectory clustering analysis of time-series clinical data poses substantial methodological challenges for researchers.This study provides a comprehensive tutorial framework demonstrating six trajectory modeling approaches integrated with proteomic analysis to guide researchers in identifying sepsis subtypes after laparoscopic surgery.Methods:This study employs simulated longitudinal data from 300 septic patients after laparoscopic surgery to demonstrate six trajectory modeling methods(group-based trajectory modeling,latent growth mixture modeling,latent transition analysis,time-varying effect modeling,K-means for longitudinal data,agglomerative hierarchical clustering)for identifying associations between predefinedsequential organ failure assessment trajectories and 25 proteomic biomarkers.Clustering performance was evaluated via multiple metrics,and a biomarker discovery pipeline integrating principal component analysis,random forests,feature selection,and receiver operating characteristic analysis was developed.Results:The six methods demonstrated varying performance in identifying trajectory structures,with each approach exhibiting distinct analytical characteristics.The performance metrics revealed differences across methods,which may inform context-specificmethod selection and interpretation strategies.Conclusion:This study illustrates practical implementations of trajectory modeling approaches under controlled conditions,facilitating informed method selection for clinical researchers.The inclusion of complete R code and integrated proteomics workflows offers a reproducible analytical framework connecting temporal pattern recognition to biomarker discovery.Beyond sepsis,this pipeline-oriented approach may be adapted to diverse clinical scenarios requiring longitudinal disease characterization and precision medicine applications.The comparative analysis reveals that each method has distinct strengths,providing a practical guide for clinical researchers in selecting appropriate methods based on their specificstudy goals and data characteristics.
基金supported by the Science Fund for Distinguished Young Scholars of Hunan Province(2023JJ10060)the National Natural Science Foundation of China(22575269)Young Elite Scientists Sponsorship Program by CAST(2023QNRC001)。
文摘Recent advancements in Zn-halogen batteries have focused on enhancing the adsorptive or catalytic capability of host materials and stabilizing complex intermediates with electrolyte additives,while the halogen-ion electrolyte modifications exhibit strong potential for integrated interfacial regulation.Herein,we design an electrically insulating rigid electrolyte container to immobilize a liquid halogen-ion electrolyte for separator-free Zn-halogen batteries with customizable electron transfer.Robust hydrogen bonding of hydroxyl groups in SiO_(2)with fluorinated moieties in PVDF-hfp regulates Zn^(2+)solvation and suppresses H_(2)O activity,while multi-channels formed by microcracks and interparticle gaps not only enhance mass transfer but also buffer interfacial electric field,jointly enabling a durable Zn plating/stripping.Effective confinement of intermediates also ensures the high reversibility across single-(I^(-)/I0),double-(I^(-)/I0/I^(-)),and triple-(I^(-)/I0/I^(-),Cl-/Cl0)electron transfer mechanisms at cathode,as evidenced by the double-electron transfer systems exhibiting a low capacity decay rate of 0.02‰over 4500 cycles at 10 mA cm^(-2)and a high areal capacity of 11.9 mAh cm^(-2)at 2 mA cm^(-2).This work presents a novel“container engineering”approach to halogen-ion electrolyte design and provides fundamental insights into the relationships between redox reversibility and reaction kinetics.
基金supported by grants from the National Science and Technology Council(NSTC),Taiwan(NSTC 114-2320-B-037-020-MY3,113-2320-B-037-023,and 112-2320-B-037-012 granted to M.K.,113-2321-B-255-001,113-2321-B-182-003,112-2321-B-182-003,112-2321-B-255-001,111-2320-B-255-006-MY3,and 111-2321-B-255-001 granted to T.L.H.)Kaohsiung Medical University Research Foundation[KMU-Q113011 awarded to M.K.and KMU-M114020 awarded to B.H.C.]NSYSU-KMU joint research project(NSYSU-KMU-114-P16)awarded to M.K.
文摘The sustainable sourcing of novel bioactive compounds from natural sources is crucial to the success of the pharmaceutical,food,and cosmetics industries.Iris bucharica Foster(syn.Juno bucharica(Foster)Vved.)is a promising source of novel bioactive molecules,particularly phenolic compounds,which are renowned for their antioxidant properties.In this study,we developed a reliable HPLC-UV-DAD method to identify and quantify phenolic compounds in the leaves and bulbs of I.bucharica,establishing the first set of quality control markers for this species.A total of 21 phenolic compounds were identified in the leaves,with flavonoids isoorientin,guaijaverin,hyperoside,and cosmosiin,the isoflavonoid biochanin A,and the simple phenolic ferulic acid being the most prominent.In comparison,14 compounds were identified in the bulbs,primarily isoflavonoids,including tectoridin and germanaism B,and flavonoid apigenin.The leaves extracts exhibited significant antioxidant activity,whereas the anti-allergic and anti-inflammatory effects were mild.These findings highlight I.bucharica as a sustainable source of bioactive compounds with potential industrial applications.However,further studies are needed to evaluate bioavailability and in vivo efficacy,as well as to optimise extraction methods to realize its industrial potential fully.
