CD8^(+)T cell-based immune-therapeutics,including immune checkpoint inhibitors and adoptive cell therapies(tumor-infiltrating lymphocytes(TILs),T cell receptor-engineered T cells(TCR-T),chimeric antigen receptor T cel...CD8^(+)T cell-based immune-therapeutics,including immune checkpoint inhibitors and adoptive cell therapies(tumor-infiltrating lymphocytes(TILs),T cell receptor-engineered T cells(TCR-T),chimeric antigen receptor T cells(CAR-T)),have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases.However,immunotherapy resistance and tumor insusceptibility frequently occur,leading to treatment failure.Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites,immune-inhibitory cytokines,and alteration of gene expression,which suppress the activity of immune cells,particularly CD8^(+)T cells to evade immune surveillance.Therefore,targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy.Here,we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming,focusing on the regulatory mechanisms underlying tumor cell glucose metabolism,amino acid metabolism,and lipid metabolism in influencing CD8^(+)T cells to provide promising metabolic targets or combinational strategies for immunotherapy.展开更多
Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising ap...Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising approach for addressing these urgent clinical requirements.This review provides a thorough analysis of the application of 3D cell-based approaches to liver regeneration and their potential impact on patients with end-stage liver failure.Here,we discuss various 3D culture models that incorporate hepatocytes and stem cells to restore liver function and ameliorate the consequences of liver failure.Furthermore,we explored the challenges in transitioning these innovative strategies from preclinical studies to clinical applications.The collective insights presented herein highlight the significance of 3D cell-based strategies as a transformative paradigm for liver regeneration and improved patient care.展开更多
The structural and molecular organization of the cell surface plays a pivotal role in governing cell-extracellular environment interactions.While glycosylated transmembrane proteins have long been considered the prima...The structural and molecular organization of the cell surface plays a pivotal role in governing cell-extracellular environment interactions.While glycosylated transmembrane proteins have long been considered the primary components of plasma membranes,emerging evidence highlights the critical contributions of RNA-binding proteins(RBPs)and glycosylated RNAs(glycoRNAs)to cell surface functions.展开更多
Polyglutamine(poly Q)expansion underlies neurodegenerative disorders such as Huntington's disease(Ross,2002).In these conditions,CAG repeats beyond a threshold(typically>35 glutamines)drive protein misfolding,a...Polyglutamine(poly Q)expansion underlies neurodegenerative disorders such as Huntington's disease(Ross,2002).In these conditions,CAG repeats beyond a threshold(typically>35 glutamines)drive protein misfolding,aggregation,and cellular toxicity(Mirkin,2007).Paradoxically,many transcription factors(TFs),including FOXP2,a key regulator of speech and language development,harbor native poly Q tracts as long as or longer than those in disease contexts,yet remain soluble in healthy cells(Enard et al.,2002).展开更多
T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments,severely compromising the effectiveness of antitumor and antiviral immunity.In recent years,there has been significant prog...T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments,severely compromising the effectiveness of antitumor and antiviral immunity.In recent years,there has been significant progress in understanding the underlying mechanisms of T cell exhaustion,including external factors and intrinsic cellular changes that drive this dysfunctional state.Key external factors such as persistent antigen exposure,immune checkpoint signaling,and the cytokine milieu,as well as intrinsic changes such as altered metabolic processes,epigenetic modifications,and transcriptional reprogramming,contribute to T cell dysfunction.Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity.These therapeutic strategies include immune checkpoint inhibition,cytokine therapies,metabolic reprogramming,and cell-based therapies.Despite these advancements,reversing T cell exhaustion presents several challenges,such as individual variability,resistance,and potential side effects.Furthermore,accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas.This review provides an overview of the history and milestones in T cell exhaustion research;summarizes the mechanisms of T cell exhaustion and its implications in cancer,chronic infections,and autoimmune diseases;discusses advancements and challenges in emerging therapies;and explores future research directions aimed at improving T cell function and enhancing immune responses.展开更多
Foot ulcerations in patients with diabetes are common and severe,typically caused by infection and chronic inflammation.Poor blood circulation and neuropathy impair the body's ability to heal wounds effectively,cr...Foot ulcerations in patients with diabetes are common and severe,typically caused by infection and chronic inflammation.Poor blood circulation and neuropathy impair the body's ability to heal wounds effectively,creating a conducive environment for ulcers.Excessive reactive oxygen species contribute to ulcer development by damaging cellular structures and hindering wound healing.The administration of antioxidants can protect cells from oxidative damage and promote wound recovery.Antioxidants such as epidermal growth factors,flavonoid hesperidin,alphalipoic acid,and N-acetylcysteine effectively reduce oxidative stress.Encapsulating various drugs into nanoparticles and targeting carriers such as hydrogels,metal-organic frameworks,and nanohydrogels can improve their therapeutic effects.Nanotechnologies have been shown to boost tissue regeneration by modifying biomaterial properties,modulating signal release,and targeting key factors.Here,we describe the occurrence and development of diabetic foot ulcers(DFUs),emphasizing the role of oxidative damage in these processes.This review summarizes the strategy for targeting oxidative damage in DFUs using nanotechnology-loaded antioxidant drugs.This review advocates for the use of personalized biomaterials in treating DFUs and provides a theoretical basis for their potential clinical and translational applications.展开更多
Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop n...Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop new tools for decision-making of lung cancer.In this study,we proposed the China Protocol,a complete workflow of lung cancer tailored to the Chinese population,which is implemented by steps including early screening by evaluation of risk factors and three-dimensional thin-layer image reconstruction technique for low-dose computed tomography(Tre-LDCT),accurate diagnosis via artificial intelligence(Al)and novel biomarkers,and individualized treatment through non-invasive molecule visualization strategies.The application of this protocol has improved the early diagnosis and 5-year survival rates of lung cancer in China.The proportion of early-stage(stage I)lung cancer has increased from 46.3%to 65.6%,along with a 5-year survival rate of 90.4%.Moreover,especially for stage IA1 lung cancer,the diagnosis rate has improved from 16%to 27.9%;meanwhile,the 5-year survival rate of this group achieved 97.5%.Thus,here we defined stage IA1 lung cancer,which cohort benefits significantly from early diagnosis and treatment,as the"ultra-early stage lung cancer",aiming to provide an intuitive description for more precise management and survival improvement.In the future,we will promote our findings to multicenter remote areas through medical alliances and mobile health services with the desire to move forward the diagnosis and treatment of lung cancer.展开更多
Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment,profoundly influencing both the onset and progression of various diseases.Under physiological co...Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment,profoundly influencing both the onset and progression of various diseases.Under physiological conditions,oxidative free radicals generated by the mitochondrial oxidative respiratory chain,endoplasmic reticulum,and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses.These responses elevate the synthesis of superoxide dismutase(SOD),catalase,as well as key molecules like nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH),thereby maintaining cellular redox homeostasis.Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases.Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation,highlighting the pivotal roles of genomic instability,epigenetic modifications,protein degradation,and metabolic reprogramming.These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies.While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role,their effcacy in diseases characterized by complex,multifactorial etiologies remains controversial.A deeper,context-specific understanding of redox signaling,particularly the roles of redox-sensitive proteins,is critical for designing targeted therapies aimed at re-establishing redox balance.Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes,setting the stage for forthcoming clinical trials.In this review,we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.展开更多
Uncontrolled hemorrhage remains the leading cause of death in clinical and emergency care,posing a major threat to human life.To achieve effective bleeding control,many hemostatic materials have emerged.Among them,nat...Uncontrolled hemorrhage remains the leading cause of death in clinical and emergency care,posing a major threat to human life.To achieve effective bleeding control,many hemostatic materials have emerged.Among them,nature-derived biopolymers occupy an important position due to the excellent inherent biocompatibility,biodegradability and bioactivity.Additionally,sponges have been widely used in clinical and daily life because of their rapid blood absorption.Therefore,we provide the overview focusing on the latest advances and smart designs of biopolymer-based hemostatic sponge.Starting from the component,the applications of polysaccharide and polypeptide in hemostasis are systematically introduced,and the unique bioactivities such as antibacterial,antioxidant and immunomodulation are also concerned.From the perspective of sponge structure,different preparation processes can obtain unique physical properties and structures,which will affect the material properties such as hemostasis,antibacterial and tissue repair.Notably,as development frontier,the multifunctions of hemostatic materials is summarized,mainly including enhanced coagulation,antibacterial,avoiding tumor recurrence,promoting tissue repair,and hemorrhage monitoring.Finally,the challenges facing the development of biopolymer-based hemostatic sponges are emphasized,and future directions for in vivo biosafety,emerging materials,multiple application scenarios and translational research are proposed.展开更多
Retinoblastoma(RB)is the most common primary ocular malignancy in children,arising from the developing retina.While higher doses of local chemotherapy have improved tumor control,concerns regarding retinal toxicity an...Retinoblastoma(RB)is the most common primary ocular malignancy in children,arising from the developing retina.While higher doses of local chemotherapy have improved tumor control,concerns regarding retinal toxicity and the development of chemoresistance remain significant.Oncolytic adenovirus(OA)presents a promising therapeutic approach for RB,but rapid clearance often limits its therapeutic effects.In this study,we engineered a genetically modified OA derived from human adenovirus 5(Ad5),designed to selectively target and lyse RB cells.The combination of OA with low-dose melphalan demonstrates an enhanced antitumor effect,while minimizing retinal toxicity.In vitro and in vivo experiments demonstrated that melphalan significantly enhanced the antitumor effect of OA and extended ocular survival.More importantly,we developed a biocompatible injectable hydrogel delivery system based on the covalent coupling of collagen and aldehyde-modified cyclodextrin,which effectively enhances the loading efficiency of melphalan and enables sustained co-delivery of OA and melphalan.The mouse RB tumor model confirmed that this hydrogel system(OA-Mel@CCA)achieved localized and sustained delivery of both therapeutics,effectively controlling tumor growth and preventing brain metastasis.Additionally,retinal structure and function were notably preserved in mice treated with OA-Mel@CCA,with no observed retinal toxicity.These findings suggest that the injectable hydrogel-based co-delivery of melphalan and oncolytic adenovirus could represent a promising strategy for RB treatment.展开更多
Neoantigens exhibit high immunogenic potential and confer a uniqueness to tumor cells,making them ideal targets for personalized cancer immunotherapy.Neoantigens originate from tumor-specific genetic alterations,abnor...Neoantigens exhibit high immunogenic potential and confer a uniqueness to tumor cells,making them ideal targets for personalized cancer immunotherapy.Neoantigens originate from tumor-specific genetic alterations,abnormal viral infections,or other biological mechanisms,including atypical RNA splicing events and post-translational modifications(PTMs).These neoantigens are recognized as foreign by the immune system,eliciting an immune response that largely bypasses conventional mechanisms of central and peripheral tolerance.Advances in next-generation sequencing(NGS),mass spectrometry(MS),and artificial intelligence(AI)have greatly expedited the rapid detection and forecasting of neoantigens,markedly propelling the development of diverse immunotherapeutic strategies,including cancer vaccines,adoptive cell therapy,and antibody treatment.In this review,we comprehensively explore the discovery and characterization of neoantigens and their clinical use within promising immunotherapeutic frameworks.Additionally,we address the current landscape of neoantigen research,the intrinsic challenges of the field,and potential pathways for clinical application in cancer treatment.展开更多
Outer membrane(OM)lipoproteins serve vital roles in Gram-negative bacteria,contributing to their pathogenicity and drug resistance.For these lipoproteins to function,they must be transported from the inner membrane(IM...Outer membrane(OM)lipoproteins serve vital roles in Gram-negative bacteria,contributing to their pathogenicity and drug resistance.For these lipoproteins to function,they must be transported from the inner membrane(IM),where they are assembled,to the OM by the ABC transporter LolCDE.We have previously captured structural snapshots of LolCDE in multiple states,revealing its dynamic conformational changes.However,the exact mechanism by which LolCDE recognizes and transfers lipoprotein between domains remains unclear.Here,we characterized the E.coli LolCDE complex bound with endogenous lipoprotein or ATP to explore the molecular features governing its substrate binding and transport functions.We found that the N-terminal unstructured linker of lipoprotein is critical for efficient binding by LolCDE;it must be sufficiently long to keep the lipoprotein’s main body outside the complex while allowing the triacyl chains to bind within the central cavity.Mutagenic assays identified key residues that mediate allosteric communication between the cytoplasmic and transmembrane domains and in the periplasmic domain to form a lipoprotein transport pathway at the LolC-LolE interface.This study provides insights into the OM lipoprotein relocation process mediated by LolCDE,with significant implications for antimicrobial drug development.展开更多
Short-term stress positively affects homeostasis recovery;however,long-term stress leads to various diseases.Accumulating evidence shows that cancer processes are not only related to genetics and environment but also ...Short-term stress positively affects homeostasis recovery;however,long-term stress leads to various diseases.Accumulating evidence shows that cancer processes are not only related to genetics and environment but also to chronic stress.For patients with cancer,the disease process induces prolonged psychological and physical stress,including fear and pain,which makes chronic stress common in patients.Chronic stress,in turn,regulates different components of the primary tumor and tumor microenvironment through a wide variety of stress mediators.Furthermore,studies indicate that chronic stress increases tumor burden and mortality in patients with different types of cancer,while the management of chronic stress can alleviate disease burden and extend patient survival.Therefore,a deeper understanding of the role and mechanism of chronic stress in cancer is necessary for developing new strategies for cancer treatment beyond traditional treatment approaches.Herein,we explored the different sources of chronic stress,the molecular mechanisms through which chronic stress affects cancer development and progression,and the stress mediators involved.We discussed the multiple impacts of chronic stress on cancer,as well as the currently available intervention strategies.We also highlighted the prospects and challenges of chronic stress management in the clinical treatment of cancer.展开更多
Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting again...Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine.By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, includingfree SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cysredox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteinsmodified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved inimmunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasingwith age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cysmodifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signalingpathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidativestress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. Thiswork decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulatorsof oxidative stress and redox signaling.展开更多
Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC a...Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.展开更多
Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role ...Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.展开更多
Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applicat...Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applications.Hydrogels,possessing commendable biocompatibility,degradability,adjustability,and physical properties akin to biological tissues,have also found extensive utility in tissue engineering and regenerative repair.The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process.This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin,bone,cartilage,nerves and tendons,with a focus on the methods for encapsulating and releasing exosomes within the hydrogels.It has also critically examined the gaps and limitations in current research,whilst proposed future directions and potential applications of this innovative approach.展开更多
Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artifici...Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artificial intelligence(AI)has the capability to mine imaging features specific to different pathogens and fuse multimodal features to reach a synergistic diagnosis,enabling more precise investigation and individualized clinical management.In this study,we successfully developed a multimodal integration(MMI)pipeline to differentiate among bacterial,fungal,and viral pneumonia and pulmonary tuberculosis based on a real-world dataset of 24,107 patients.The area under the curve(AUC)of the MMI system comprising clinical text and computed tomography(CT)image scans yielded 0.910(95%confidence interval[CI]:0.904–0.916)and 0.887(95%CI:0.867–0.909)in the internal and external testing datasets respectively,which were comparable to those of experienced physicians.Furthermore,the MMI system was utilized to rapidly differentiate between viral subtypes with a mean AUC of 0.822(95%CI:0.805–0.837)and bacterial subtypes with a mean AUC of 0.803(95%CI:0.775–0.830).Here,the MMI system harbors the potential to guide tailored medication recommendations,thus mitigating the risk of antibiotic misuse.Additionally,the integration of multimodal factors in the AI-driven system also provided an evident advantage in predicting risks of developing critical illness,contributing to more informed clinical decision-making.To revolutionize medical care,embracing multimodal AI tools in pulmonary infections will pave the way to further facilitate early intervention and precise management in the foreseeable future.展开更多
Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic vir...Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.展开更多
Hydroxycarboxylic acid receptor 2(HCAR2),a member of Class A G-protein-coupled receptor(GPCR)family,plays a pivotal role in anti-lipolytic and anti-inflammatory effects,establishing it as a significant therapeutic tar...Hydroxycarboxylic acid receptor 2(HCAR2),a member of Class A G-protein-coupled receptor(GPCR)family,plays a pivotal role in anti-lipolytic and anti-inflammatory effects,establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases.展开更多
基金funded by National Natural Science Foundation of China(Grant Nos.:82373336,and 82303238,Sichuan Science and Technology Department,China(Grant Nos.:2024NSFSC1945,and 2023NSFSC0667)The Third People's Hospital of Chengdu Clinical Research Program,China(Program Nos.:CSY-YN-01-2023-013,CSY-YN-01-2023-005,and CSY-YN-03-2024-003)+1 种基金Sichuan University“From 0 to 1”Innovative Research Project,China(Project No.:2023SCUH0024)Health Commission of Chengdu,China(Grant No.:2024291).
文摘CD8^(+)T cell-based immune-therapeutics,including immune checkpoint inhibitors and adoptive cell therapies(tumor-infiltrating lymphocytes(TILs),T cell receptor-engineered T cells(TCR-T),chimeric antigen receptor T cells(CAR-T)),have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases.However,immunotherapy resistance and tumor insusceptibility frequently occur,leading to treatment failure.Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites,immune-inhibitory cytokines,and alteration of gene expression,which suppress the activity of immune cells,particularly CD8^(+)T cells to evade immune surveillance.Therefore,targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy.Here,we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming,focusing on the regulatory mechanisms underlying tumor cell glucose metabolism,amino acid metabolism,and lipid metabolism in influencing CD8^(+)T cells to provide promising metabolic targets or combinational strategies for immunotherapy.
基金This work was supported by grants fromthe Sichuan Science and Technology Program(2023NSFSC1877).
文摘Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising approach for addressing these urgent clinical requirements.This review provides a thorough analysis of the application of 3D cell-based approaches to liver regeneration and their potential impact on patients with end-stage liver failure.Here,we discuss various 3D culture models that incorporate hepatocytes and stem cells to restore liver function and ameliorate the consequences of liver failure.Furthermore,we explored the challenges in transitioning these innovative strategies from preclinical studies to clinical applications.The collective insights presented herein highlight the significance of 3D cell-based strategies as a transformative paradigm for liver regeneration and improved patient care.
基金supported by the National Natural Science Foundation of China(82203474)the Natural Science Foundation of Sichuan,China(2023NSFSC0719)the 1·3·5 Project for Disciplines of Excellence,West China Hospital(ZYGD23017)。
文摘The structural and molecular organization of the cell surface plays a pivotal role in governing cell-extracellular environment interactions.While glycosylated transmembrane proteins have long been considered the primary components of plasma membranes,emerging evidence highlights the critical contributions of RNA-binding proteins(RBPs)and glycosylated RNAs(glycoRNAs)to cell surface functions.
基金supported by the National Key Research and Development Program of China(2022YFA1303102,2022YFA1105203)the National Natural Science Foundation of China(32025011,32270772,32061160470)+1 种基金the Natural Science Foundation of Zhejiang Province(LZ24C070001)the Central Guidance for Local Scientific and Technological Development Funding Project(2025ZY01106)。
文摘Polyglutamine(poly Q)expansion underlies neurodegenerative disorders such as Huntington's disease(Ross,2002).In these conditions,CAG repeats beyond a threshold(typically>35 glutamines)drive protein misfolding,aggregation,and cellular toxicity(Mirkin,2007).Paradoxically,many transcription factors(TFs),including FOXP2,a key regulator of speech and language development,harbor native poly Q tracts as long as or longer than those in disease contexts,yet remain soluble in healthy cells(Enard et al.,2002).
基金supported by Chinese National Natural Science Funds(32125016,32525002,U24A20371,and W2411011)a special program from the Ministry of Science and Technology of China(2021YFA1101000,2022YFA1105200,2022YFF0608400,and 2023YFA1800200,2024YFC2707400)+6 种基金a Key R&D Program of Zhejiang Province(2023C03044 and 2024C03142)the Suzhou Innovation and Entrepreneurship Leading Talent Program(ZXL2022505,ZXL2022442)the Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2303027,YXY2302017)the Joint Proiect of Pinnacle Disciplinary Group,the Second Affiliated Hospital of Chongqing Medical,Bo Xi Clinical Research Project of the First Affiliated Hospital of Soochow University(BXLC007)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)the Zhejiang Provincial Natural Science Foundation of China(LMS25H050002)the National Traditional Chinese Medicine Comprehensive Reform Demonstration Zone Science and Technology Construction Project(GZY-KJS-ZJ-2025-092).
文摘T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments,severely compromising the effectiveness of antitumor and antiviral immunity.In recent years,there has been significant progress in understanding the underlying mechanisms of T cell exhaustion,including external factors and intrinsic cellular changes that drive this dysfunctional state.Key external factors such as persistent antigen exposure,immune checkpoint signaling,and the cytokine milieu,as well as intrinsic changes such as altered metabolic processes,epigenetic modifications,and transcriptional reprogramming,contribute to T cell dysfunction.Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity.These therapeutic strategies include immune checkpoint inhibition,cytokine therapies,metabolic reprogramming,and cell-based therapies.Despite these advancements,reversing T cell exhaustion presents several challenges,such as individual variability,resistance,and potential side effects.Furthermore,accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas.This review provides an overview of the history and milestones in T cell exhaustion research;summarizes the mechanisms of T cell exhaustion and its implications in cancer,chronic infections,and autoimmune diseases;discusses advancements and challenges in emerging therapies;and explores future research directions aimed at improving T cell function and enhancing immune responses.
基金partly supported by the National Natural Science Foundation of China(grant numbers 32060184,81760149,and 82303506)Joint Special Funds for the Department of Science and Technology of Yunnan Province-Kunming Medical University(grant number 202401AY070001-029)+4 种基金the Scientific and Technological Innovation Team of Kunming Medical University(grant number CXTD202101)Yunnan Fundamental Research Projects(grant number 202401CF070184)Achievement Transformation Funding of Frontiers Medical Center,Tianfu Jincheng Laboratory(grant number 2025ZH048)First-Class Discipline Team of Kunming Medical University(2024XKT DTS11)Yunnan Revitalization Talent Support Program.
文摘Foot ulcerations in patients with diabetes are common and severe,typically caused by infection and chronic inflammation.Poor blood circulation and neuropathy impair the body's ability to heal wounds effectively,creating a conducive environment for ulcers.Excessive reactive oxygen species contribute to ulcer development by damaging cellular structures and hindering wound healing.The administration of antioxidants can protect cells from oxidative damage and promote wound recovery.Antioxidants such as epidermal growth factors,flavonoid hesperidin,alphalipoic acid,and N-acetylcysteine effectively reduce oxidative stress.Encapsulating various drugs into nanoparticles and targeting carriers such as hydrogels,metal-organic frameworks,and nanohydrogels can improve their therapeutic effects.Nanotechnologies have been shown to boost tissue regeneration by modifying biomaterial properties,modulating signal release,and targeting key factors.Here,we describe the occurrence and development of diabetic foot ulcers(DFUs),emphasizing the role of oxidative damage in these processes.This review summarizes the strategy for targeting oxidative damage in DFUs using nanotechnology-loaded antioxidant drugs.This review advocates for the use of personalized biomaterials in treating DFUs and provides a theoretical basis for their potential clinical and translational applications.
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project of China(2024ZD0529500/2024ZD0529504,2024ZD0529500/2024ZD0529505)National Natural Science Foundation of China(82470109,92159302)+3 种基金Science and Technology Project of Sichuan(2022ZDZX0018)1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYYC23027)1.3.5 projects for Artificial Intelligence,West China Hospital,Sichuan University(ZYAI24016)1.3.5 Project of State Key Laboratory of Respiratory Health and Multimorbidity,West China Hospital,Sichuan University(RHM24208).
文摘Early screening,diagnosis,and treatment of lung cancer are pivotal in clinical practice since the tumor stage remains the most dominant factor that affects patient survival.Previous initiatives have tried to develop new tools for decision-making of lung cancer.In this study,we proposed the China Protocol,a complete workflow of lung cancer tailored to the Chinese population,which is implemented by steps including early screening by evaluation of risk factors and three-dimensional thin-layer image reconstruction technique for low-dose computed tomography(Tre-LDCT),accurate diagnosis via artificial intelligence(Al)and novel biomarkers,and individualized treatment through non-invasive molecule visualization strategies.The application of this protocol has improved the early diagnosis and 5-year survival rates of lung cancer in China.The proportion of early-stage(stage I)lung cancer has increased from 46.3%to 65.6%,along with a 5-year survival rate of 90.4%.Moreover,especially for stage IA1 lung cancer,the diagnosis rate has improved from 16%to 27.9%;meanwhile,the 5-year survival rate of this group achieved 97.5%.Thus,here we defined stage IA1 lung cancer,which cohort benefits significantly from early diagnosis and treatment,as the"ultra-early stage lung cancer",aiming to provide an intuitive description for more precise management and survival improvement.In the future,we will promote our findings to multicenter remote areas through medical alliances and mobile health services with the desire to move forward the diagnosis and treatment of lung cancer.
基金supported by the National Key Research and Development Project of China(2023YFC3402100)the National Natural Science Foundation of China(81821002 and 82130082,82341004)1:3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD22007).
文摘Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment,profoundly influencing both the onset and progression of various diseases.Under physiological conditions,oxidative free radicals generated by the mitochondrial oxidative respiratory chain,endoplasmic reticulum,and NADPH oxidases can be effectively neutralized by NRF2-mediated antioxidant responses.These responses elevate the synthesis of superoxide dismutase(SOD),catalase,as well as key molecules like nicotinamide adenine dinucleotide phosphate(NADPH)and glutathione(GSH),thereby maintaining cellular redox homeostasis.Disruption of this finely tuned equilibrium is closely linked to the pathogenesis of a wide range of diseases.Recent advances have broadened our understanding of the molecular mechanisms underpinning this dysregulation,highlighting the pivotal roles of genomic instability,epigenetic modifications,protein degradation,and metabolic reprogramming.These findings provide a foundation for exploring redox regulation as a mechanistic basis for improving therapeutic strategies.While antioxidant-based therapies have shown early promise in conditions where oxidative stress plays a primary pathological role,their effcacy in diseases characterized by complex,multifactorial etiologies remains controversial.A deeper,context-specific understanding of redox signaling,particularly the roles of redox-sensitive proteins,is critical for designing targeted therapies aimed at re-establishing redox balance.Emerging small molecule inhibitors that target specific cysteine residues in redox-sensitive proteins have demonstrated promising preclinical outcomes,setting the stage for forthcoming clinical trials.In this review,we summarize our current understanding of the intricate relationship between oxidative stress and disease pathogenesis and also discuss how these insights can be leveraged to optimize therapeutic strategies in clinical practice.
基金jointly sponsored by Sichuan Science and Tech-nology Program(2024NSFSC0002 and MZGC20240011)“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23037)+1 种基金the Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC2023010002)the National Natural Science Foundation of China(Grant No.32171351).
文摘Uncontrolled hemorrhage remains the leading cause of death in clinical and emergency care,posing a major threat to human life.To achieve effective bleeding control,many hemostatic materials have emerged.Among them,nature-derived biopolymers occupy an important position due to the excellent inherent biocompatibility,biodegradability and bioactivity.Additionally,sponges have been widely used in clinical and daily life because of their rapid blood absorption.Therefore,we provide the overview focusing on the latest advances and smart designs of biopolymer-based hemostatic sponge.Starting from the component,the applications of polysaccharide and polypeptide in hemostasis are systematically introduced,and the unique bioactivities such as antibacterial,antioxidant and immunomodulation are also concerned.From the perspective of sponge structure,different preparation processes can obtain unique physical properties and structures,which will affect the material properties such as hemostasis,antibacterial and tissue repair.Notably,as development frontier,the multifunctions of hemostatic materials is summarized,mainly including enhanced coagulation,antibacterial,avoiding tumor recurrence,promoting tissue repair,and hemorrhage monitoring.Finally,the challenges facing the development of biopolymer-based hemostatic sponges are emphasized,and future directions for in vivo biosafety,emerging materials,multiple application scenarios and translational research are proposed.
基金supported by the National Natural Science Foundation of China(No.82403838)the Natural Science Foundation of Sichuan Province(No.2025ZNSFSC1711 and 2023NSFSC1666,China)+2 种基金the China Postdoctoral Science Foundation(No.2024M752253,China)the Postdoctoral Fellowship Program of CPSF(No.GZB20240489 and GZB20240497,China)the Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(No.TFJC2023010006,China).
文摘Retinoblastoma(RB)is the most common primary ocular malignancy in children,arising from the developing retina.While higher doses of local chemotherapy have improved tumor control,concerns regarding retinal toxicity and the development of chemoresistance remain significant.Oncolytic adenovirus(OA)presents a promising therapeutic approach for RB,but rapid clearance often limits its therapeutic effects.In this study,we engineered a genetically modified OA derived from human adenovirus 5(Ad5),designed to selectively target and lyse RB cells.The combination of OA with low-dose melphalan demonstrates an enhanced antitumor effect,while minimizing retinal toxicity.In vitro and in vivo experiments demonstrated that melphalan significantly enhanced the antitumor effect of OA and extended ocular survival.More importantly,we developed a biocompatible injectable hydrogel delivery system based on the covalent coupling of collagen and aldehyde-modified cyclodextrin,which effectively enhances the loading efficiency of melphalan and enables sustained co-delivery of OA and melphalan.The mouse RB tumor model confirmed that this hydrogel system(OA-Mel@CCA)achieved localized and sustained delivery of both therapeutics,effectively controlling tumor growth and preventing brain metastasis.Additionally,retinal structure and function were notably preserved in mice treated with OA-Mel@CCA,with no observed retinal toxicity.These findings suggest that the injectable hydrogel-based co-delivery of melphalan and oncolytic adenovirus could represent a promising strategy for RB treatment.
基金supported by grants from National Key Research & Development Program of China(Nos.2023YFC3402100,2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(No.2019B030302012)+2 种基金National Natural Science Foundation of China(Nos.81821002,82130082,and 81790251)1·3·5 projects for disciplines of excellence,West China Hospital,Sichuan University(Nos.ZYGD22007 and ZYJC21004)Sichuan Science and Technology Program(No.2023YFS0073).
文摘Neoantigens exhibit high immunogenic potential and confer a uniqueness to tumor cells,making them ideal targets for personalized cancer immunotherapy.Neoantigens originate from tumor-specific genetic alterations,abnormal viral infections,or other biological mechanisms,including atypical RNA splicing events and post-translational modifications(PTMs).These neoantigens are recognized as foreign by the immune system,eliciting an immune response that largely bypasses conventional mechanisms of central and peripheral tolerance.Advances in next-generation sequencing(NGS),mass spectrometry(MS),and artificial intelligence(AI)have greatly expedited the rapid detection and forecasting of neoantigens,markedly propelling the development of diverse immunotherapeutic strategies,including cancer vaccines,adoptive cell therapy,and antibody treatment.In this review,we comprehensively explore the discovery and characterization of neoantigens and their clinical use within promising immunotherapeutic frameworks.Additionally,we address the current landscape of neoantigen research,the intrinsic challenges of the field,and potential pathways for clinical application in cancer treatment.
基金supported by the National Key Research and Development Program of China(2021YFA1301900 to H.D.)the National Natural Science Foundation of China(31900039 and 32170029 to X.T.,32000844 to S.C.,81971974 and 82372297 to H.D.)+1 种基金the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYYC23014 to H.D.)the Sichuan Provincial Natural Science Foundation Outstanding Young Scientist Fund Project(2024NSFJQ0002 to H.D.).
文摘Outer membrane(OM)lipoproteins serve vital roles in Gram-negative bacteria,contributing to their pathogenicity and drug resistance.For these lipoproteins to function,they must be transported from the inner membrane(IM),where they are assembled,to the OM by the ABC transporter LolCDE.We have previously captured structural snapshots of LolCDE in multiple states,revealing its dynamic conformational changes.However,the exact mechanism by which LolCDE recognizes and transfers lipoprotein between domains remains unclear.Here,we characterized the E.coli LolCDE complex bound with endogenous lipoprotein or ATP to explore the molecular features governing its substrate binding and transport functions.We found that the N-terminal unstructured linker of lipoprotein is critical for efficient binding by LolCDE;it must be sufficiently long to keep the lipoprotein’s main body outside the complex while allowing the triacyl chains to bind within the central cavity.Mutagenic assays identified key residues that mediate allosteric communication between the cytoplasmic and transmembrane domains and in the periplasmic domain to form a lipoprotein transport pathway at the LolC-LolE interface.This study provides insights into the OM lipoprotein relocation process mediated by LolCDE,with significant implications for antimicrobial drug development.
基金supported by the National Natural Science Fundation of China(32125016,32525002,32025011,W2411011,T2321005,and U24A20371)programs from the Ministry of Science and Technology of China(2024YFC2707400,2021YFA1101000,2022YFA1105200,and 2023YFA1800200)+6 种基金a Key R&D Program of Zhejiang Province(2024C03142)a project funded by Basic Research Program of Jiangsu(BK20250359)Jiangsu Funding Program for Excellent Postdoctoral Talent,the China Postdoctoral Science Foundation(2025M772706)the Suzhou Medical College Basic Frontier Innovation Cross Project(YXY2303027)the Suzhou Medical College-Qilu Medical Research Program of Soochow University(24QL101301)the Joint Project of Pinnacle Disciplinary Group,the Second Affiliated Hospital of Chongqing Medical,Principal Investigator Foundation of Tianfu Jincheng Laboratory(TFJCPI20250022)a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions,and the Postdoctoral Research Fund of The First Affiliated Hospital of Soochow University(09020320250001).
文摘Short-term stress positively affects homeostasis recovery;however,long-term stress leads to various diseases.Accumulating evidence shows that cancer processes are not only related to genetics and environment but also to chronic stress.For patients with cancer,the disease process induces prolonged psychological and physical stress,including fear and pain,which makes chronic stress common in patients.Chronic stress,in turn,regulates different components of the primary tumor and tumor microenvironment through a wide variety of stress mediators.Furthermore,studies indicate that chronic stress increases tumor burden and mortality in patients with different types of cancer,while the management of chronic stress can alleviate disease burden and extend patient survival.Therefore,a deeper understanding of the role and mechanism of chronic stress in cancer is necessary for developing new strategies for cancer treatment beyond traditional treatment approaches.Herein,we explored the different sources of chronic stress,the molecular mechanisms through which chronic stress affects cancer development and progression,and the stress mediators involved.We discussed the multiple impacts of chronic stress on cancer,as well as the currently available intervention strategies.We also highlighted the prospects and challenges of chronic stress management in the clinical treatment of cancer.
基金supported by the National Key R&D Program of China(no.2022YFA1303200)the National Natural Science Foundation of China(nos.82073221,32201216,and 31870826)+2 种基金the Science and Technology Project of Sichuan Province(nos.2024YFFK0099,2023NSFSC1525,and 2021YFS0134)the National Clinical Research Center for Geriatrics at West China Hospital(no.Z2024JC002)the West China Hospital 135 project(nos.ZYYC23013 and ZYYC23025).
文摘Oxidative stress plays a crucial role in organ aging and related diseases, yet the endogenous regulators involved remain largelyunknown. This work highlights the importance of metabolic homeostasis in protecting against oxidative stress in the large intestine.By developing a low-input and user-friendly pipeline for the simultaneous profiling of five distinct cysteine (Cys) states, includingfree SH, total Cys oxidation (Sto), sulfenic acid (SOH), S-nitrosylation (SNO), and S-glutathionylation (SSG), we shed light on Cysredox modification stoichiometries and signaling with regional resolution in the aging gut of monkeys. Notably, the proteinsmodified by SOH and SSG were associated primarily with cell adhesion. In contrast, SNO-modified proteins were involved inimmunity. Interestingly, we observed that the Sto levels ranged from 0.97% to 99.88%, exhibiting two distinct peaks and increasingwith age. Crosstalk analysis revealed numerous age-related metabolites potentially involved in modulating oxidative stress and Cysmodifications. Notably, we elucidated the role of fumarate in alleviating intestinal oxidative stress in a dextran sulfate sodium (DSS)-induced colitis mouse model. Our findings showed that fumarate treatment promotes the recovery of several cell types, signalingpathways, and genes involved in oxidative stress regulation. Calorie restriction (CR) is a known strategy for alleviating oxidativestress. Two-month CR intervention led to the recovery of many antioxidative metabolites and reshaped the Cys redoxome. Thiswork decodes the complexities of redoxomics during the gut aging of non-human primates and identifies key metabolic regulatorsof oxidative stress and redox signaling.
基金This review was supported by the National Natural Science Foundation of China(82073318)Sichuan Science and Technology Program(2019YFS0003,China)the Support Program of Science&Technology Department of Sichuan Provincial(2023YFSY0046 and 2022NSFSC1365,China).
文摘Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.
基金provided by the National Natural Science Foundation of China(82073318)the Fundamental Research Funds for the Central Universities(SCU2022D025,0082604151345,China)+1 种基金Sichuan Science and Technology Program Projects(2019YFS0003,China)to Yuxi Wangprovided by the University of Tennessee College of Pharmacy Drug Discovery Center to Wei Li。
文摘Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.
基金supported by Natural Science Foundation of Sichuan Province,Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC2023010002)“1.3.5”Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYGD23037).
文摘Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applications.Hydrogels,possessing commendable biocompatibility,degradability,adjustability,and physical properties akin to biological tissues,have also found extensive utility in tissue engineering and regenerative repair.The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process.This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin,bone,cartilage,nerves and tendons,with a focus on the methods for encapsulating and releasing exosomes within the hydrogels.It has also critically examined the gaps and limitations in current research,whilst proposed future directions and potential applications of this innovative approach.
基金supported by the National Natural Science Foundation of China(82341083,82100119)the Science and Technology Project of Sichuan(2020YFG0473,2022ZDZX0018)+3 种基金the Beijing Municipal Science and Technology Planning Project(Z211100003521009)Hong Kong Research Grants Council through General Research Fund(Grant 17207722)the Sichuan University from“0”to“1”Innovation Project(2023SCUH0051)the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(ZYYC23027)。
文摘Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artificial intelligence(AI)has the capability to mine imaging features specific to different pathogens and fuse multimodal features to reach a synergistic diagnosis,enabling more precise investigation and individualized clinical management.In this study,we successfully developed a multimodal integration(MMI)pipeline to differentiate among bacterial,fungal,and viral pneumonia and pulmonary tuberculosis based on a real-world dataset of 24,107 patients.The area under the curve(AUC)of the MMI system comprising clinical text and computed tomography(CT)image scans yielded 0.910(95%confidence interval[CI]:0.904–0.916)and 0.887(95%CI:0.867–0.909)in the internal and external testing datasets respectively,which were comparable to those of experienced physicians.Furthermore,the MMI system was utilized to rapidly differentiate between viral subtypes with a mean AUC of 0.822(95%CI:0.805–0.837)and bacterial subtypes with a mean AUC of 0.803(95%CI:0.775–0.830).Here,the MMI system harbors the potential to guide tailored medication recommendations,thus mitigating the risk of antibiotic misuse.Additionally,the integration of multimodal factors in the AI-driven system also provided an evident advantage in predicting risks of developing critical illness,contributing to more informed clinical decision-making.To revolutionize medical care,embracing multimodal AI tools in pulmonary infections will pave the way to further facilitate early intervention and precise management in the foreseeable future.
基金funded by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09201018-013)by Natural Science Foundation Project of Sichuan(No.2022NSFSC0848)+1 种基金as well as supported by the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYGD18007)The Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC202310005).
文摘Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.
基金This work was supported by the National Natural Science Foundation of China(32100988 to W.Y.,31972916 to Z.S,82271190 and 32100965 to L.C.)Science and Technology Department of Sichuan Province(2020YFQ0055 to P.F.and 2022ZYD0085 to Z.S.)+1 种基金Ministry of Technology Department of China grant(2019YFA0508800 to Z.S)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD18027 to P.F,ZYYC20023 to Z.S).
文摘Hydroxycarboxylic acid receptor 2(HCAR2),a member of Class A G-protein-coupled receptor(GPCR)family,plays a pivotal role in anti-lipolytic and anti-inflammatory effects,establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases.
