Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in ter...Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in terms of their safety,efficacy,and protection.Methods Mice were vaccinated according to different immunization schedules,and blood was collected for detection of rabies virus neutralizing antibodies(RVNAs)on days 14,21,28,35,and 120after the first immunization.Additionally,different groups of mice were injected with lethal doses of the CVS-11 virus on day 0,subjected to different rabies immunization schedules,and assessed for morbidity and death status.In a clinical trial,185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule,and blood was collected for RVNAs detection on days 28and 42 after the first immunization.Results A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day(P<0.05).The groups 0-3-7-14,0-3-7-21,and 0-3-7-28 showed no statistically significant difference(P>0.05)in RVNAs levels at any time point.The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%,whereas that in the immunization groups was 40%.In the clinical trial,the RVNAs positive conversion rates on days 28(14 days after 4 doses)and 42(14 days after 5 doses)were both 100%,and no significant difference in RVNAs levels was observed(P>0.05).Conclusion The simple 4-dose schedule can produce sufficient RVNAs levels,with no significant effect of a delayed fourth vaccine dose(14–28 d)on the immunization potential.展开更多
Porcine epidemic diarrhea virus(PEDV),an enteric coronavirus,is widely spread worldwide and causes huge economic losses.The effective measure to control the viral infection is to develop ideal vaccines.Here,the collag...Porcine epidemic diarrhea virus(PEDV),an enteric coronavirus,is widely spread worldwide and causes huge economic losses.The effective measure to control the viral infection is to develop ideal vaccines.Here,the collagenase equivalent domain(COE)of PEDV was displayed on the surface of nanoparticles(NPs)in order to develop a newer,safer and more effective subunit vaccine against PEDV.The monomeric COE was displayed on the mi3 protein,which self-assembles into nanoparticles composed of 60 subunits,using the SpyTag/SpyCatcher system.The size,zeta potential,microstructure of the COE-mi3 virus-like particles(VLPs)were investigated.The COE-mi3 VLPs that possessed good security,stability and better retention can be more efficiently taken up by antigen-presenting cells(APCs)and help promote dendritic cells(DCs)maturation.Moreover,COE-mi3 VLPs could prominently improve specifc antibody levels including neutralizing antibodies(NAbs),and serum IgG,mucosal IgA.Moreover,COE-mi3 VLPs elicited more activation of CD4^(+)and CD8^(+)T cells and production of IFN-γand IL-4 cytokines.In particular,COE-mi3 VLPs is an effectual antigen-delivery platform to enhance germinal center(GC)B cell responses.This structure-based self-assembly of NP gives great potential to be developed as a new subunit vaccines attractive platform,and may also provide new ideas for the development of other enteric coronavirus vaccines.展开更多
Dengue fever remains a significant public health challenge in Malaysia,with its incidence continuing to rise despite existing control measures.Dengue,a disease caused by the dengue virus and transmitted by Aedes mosqu...Dengue fever remains a significant public health challenge in Malaysia,with its incidence continuing to rise despite existing control measures.Dengue,a disease caused by the dengue virus and transmitted by Aedes mosquitoes,places a substantial burden on healthcare systems and economic productivity.Despite efforts by the Malaysian government,including the release of Wolbachia-carrying Aedes aegypti mosquitoes in dengue hotspot areas since 2017,the problem persists.In 2023,Malaysia reported 123133 dengue cases,an 86.3%increase compared to 2022[1].This highlights the urgent need for more effective interventions,including the potential integration of dengue vaccines into routine immunization programs.Currently,two dengue vaccines have been licensed:Dengvaxia(CYD-TDV)by Sanofi Pasteur and Qdenga(TAK-003)by Takeda.Dengvaxia,the first licensed dengue vaccine,has significant limitations,as it increases the risk of hospitalization in dengue-naïve individuals due to antibody-dependent enhancement[2,3].As a result,it is only licensed for individuals with prior dengue infections,necessitating pre-vaccination screening.These constraints make it unsuitable for inclusion in Malaysia’s routine immunization programs.展开更多
[Objectives]This study was conducted to evaluate the immunization efficacy and infection status of classical swine fever(CSF),foot-and-mouth disease(FMD),porcine reproductive and respiratory syndrome(PRRS),pseudorabie...[Objectives]This study was conducted to evaluate the immunization efficacy and infection status of classical swine fever(CSF),foot-and-mouth disease(FMD),porcine reproductive and respiratory syndrome(PRRS),pseudorabies(PR),and porcine circovirus type 2(PCV2)in large-scale pig farms.[Methods]Antibody and pathogen detection was performed on 56 serum samples collected in March 2025.[Results]The antibody qualification rates for CSF,FMD,and PRRS were 76.8%,73.2%,and 76.8%,respectively,all meeting the national standards.However,nursery pigs exhibited an immunity gap,indicating a need for timely booster vaccinations.No PRV gE antibodies or PCV2 antibodies were detected,reflecting the absence of vaccination against these diseases and suggesting significant effectiveness of comprehensive biosecurity measures.The low antibody qualification rate for PRRS in the nursery stage highlights the need for improved immunization management.[Conclusions]This study provides data support and practical insights for integrated disease prevention and control in large-scale pig farms.展开更多
Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Method...Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Methods We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital,Southern Medical University from June 1,2020,to February 1,2022.An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels,with the primary outcome being the 7-day mortality rate post-ICU admission.Cox proportional hazards and Restricted Mean Survival Time(RMST)analyses were utilized to explore survival outcomes.Results A total of 321 sepsis patients were included.IL-6(HR 1.69,95%CI:1.22,2.34)and IL-10(HR 1.81,95%CI:1.37,2.40)emerged as independent predictors of 7-day mortality.Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups:Cluster 1(n=166,low inflammatory response),Cluster 2(n=99,moderate inflammatory response with immune suppression),and Cluster 3(n=56,strong inflammatory and immune suppression).Compared to Cluster 1,Clusters 2 and 3 had higher 7-day mortality risks(14.4%vs 23.2%,HR=4.30,95%CI:1.51-12.26;14.4%vs 35.7%,HR=7.32,95%CI:2.57-20.79).Conclusion Septic patients in a protective immune response state(Cluster 1)exhibit better short-term prognoses,suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.展开更多
Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune check...Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.展开更多
Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immun...Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.展开更多
The red imported fire ant,Solenopsis invicta Buren,is a highly invasive eusocial insect pest that threatens native biodiversity,agriculture,and human health.The innate immune system and intricate social immune respons...The red imported fire ant,Solenopsis invicta Buren,is a highly invasive eusocial insect pest that threatens native biodiversity,agriculture,and human health.The innate immune system and intricate social immune responses of S.invicta pose challenges to the development of effective control strategies.Micro RNAs(mi RNAs)play critical roles in the post-transcriptional regulation of gene expression,which influences various biological processes,including immunity and host-pathogen interactions.While the mi RNA-mediated response of insects to pathogens has been extensively studied in solitary insects,little is known about the innate immune responses of individual members within a colony.To address this gap,we constructed small RNA libraries from Metarhizium anisopliae-infected S.invicta workers and investigated the temporal dynamics of mi RNA-mediated immune responses to the entomopathogen.Several differentially expressed mi RNAs were identified,and they were found to regulate genes involved in the Toll,IMD,and melanization immune pathways.Quantitative real-time PCR(q RT-PCR)was employed to analyze the spatiotemporal dynamics of key mi RNAs/target genes,specifically mi R-71/Mod SP1-Relish and mi R-7/Lysozyme2-Serine protease7.A dual luciferase assay(in vitro)was performed to validate the interactions between mi RNAs and their target genes.Overexpression of mi R-71 and mi R-7(via mi RNA mimics)efficiently suppressed their target genes,impaired the antifungal immune response of S.invicta and increased the susceptibility to M.anisopliae infection compared to controls.Furthermore,RNA interference-based gene silencing elucidated the roles of these immune genes in regulating fungal susceptibility,thus providing vital clues for developing virulent and effective mycoinsecticides using modern genetic engineering tools.展开更多
Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growi...Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growing evidence highlights the immune system’s role in PF,with various immune components participating in inflammatory and fibrotic processes.Different immune cells,including neutrophils,lymphocytes,and macrophages,demonstrate distinct effects on PF progression and development.Furthermore,key immune system cytokines,including the interleukin(IL)family,tumor necrosis factor(TNF)-α,interferon(IFN)-γ,transforming growth factor(TGF)-β,and connective tissue growth factor(CTGF),contribute to PF initiation and progression through independent mechanisms and mutual regulation.Currently,limited effective treatments exist for PF,with several treatments causing severe adverse reactions.Natural products,characterized by multi-target effects,holistic regulation,and low toxicity,have emerged as a research focus.This review compiles the mechanisms,therapeutic potential,and active components of various natural products.These compounds can ameliorate pulmonary inflammation,epithelial-mesenchymal transition,and collagen deposition through diverse immune mechanisms,acting at specific stages or throughout the fibrotic process,thereby supporting PF management.This review examines current scientific understanding of natural products’immunological effects in PF,which is crucial for developing future anti-PF therapeutics.展开更多
Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical applicati...Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical application of multi-omics parameters is still restricted by the expensive and less accessible assays,although they accurately reflect immune status.A comprehensive evaluation framework based on“easy-to-obtain”multi-model clinical parameters is urgently required,incorporating clinical features to establish baseline patient profiles and disease staging;routine blood tests assessing systemic metabolic and functional status;immune cell subsets quantifying subcluster dynamics;imaging features delineating tumor morphology,spatial configuration,and perilesional anatomical relationships;immunohistochemical markers positioning qualitative and quantitative detection of tumor antigens from the cellular and molecular level.This integrated phenomic approach aims to improve prognostic stratification and clinical decision-making in hepatocellular carcinoma management conveniently and practically.展开更多
The interplay between gut microbiota and host health has attracted significant interest in the animal science community.Maintaining gut microbiota homeostasis by supplementing probiotics to treat clinical conditions l...The interplay between gut microbiota and host health has attracted significant interest in the animal science community.Maintaining gut microbiota homeostasis by supplementing probiotics to treat clinical conditions like calf diarrhea is an emerging area of research nowadays because of increased concerns regarding antimicrobial resistance(AMR)and drug residues in animal products.Probiotics reduce the incidence of calf diarrhea by increasing the gut microbiota diversity and richness with more commensal bacteria such as Lactobacillus and Bifidobacterium that produce antimicrobial compounds,as well as modulating the immune response by increasing cytokines,Interleukin-2(IL-2),IL-4,IL-6,IL-10,and reducing tumor necrosis factor-α(TNF-α),by increasing production of antibodies,especially immunoglobulin E(Ig E),also Ig G,differentiating naive Th lymphocytes(Tho)into Th1,hence stimulate innate immunity and prime the adaptive immune response.Specific probiotic strains of bacteria and yeast(Saccharomyces cerevisiae)derived probiotics maintain the integrity of the intestinal barrier.In this review,data are being organized to address the role of probiotics in treating calf diarrhea by modulating gut microbiota and stimulating an immune response against notorious pathogens,to present animal and veterinary scientists and nutritionists with a new concept to treat infectious diseases from the perspective of the gut microbiota,increasing animal health,performance,and welfare.In conclusion,health status and gut microbiome are strongly interlinked.Research data indicated a significant reduction in the incidence of diarrhea after probiotic administration.If interrelations between probiotics and existing gut microbiota are explored more quantitatively,novel antibiotic substitutes can emerge in the future.展开更多
Polyfluoroalkyl substances(PFAS)have emerged as persistent environmental contaminants because of their chemical stability,degradation-resistance and bioaccumulation potential.However,current studies mainly focus on th...Polyfluoroalkyl substances(PFAS)have emerged as persistent environmental contaminants because of their chemical stability,degradation-resistance and bioaccumulation potential.However,current studies mainly focus on the toxicity of single PFAS such as perfluorooctanoic acid(PFOA)and perfluorobutanoic acid(PFBA),the knowledge of their combined effects is relatively limited.In this study,we explored the immune response of the gut in large yellow croaker(Larimichthys crocea)under the combined stress of PFOA and PFBA.Histologicalanalyses revealed that the combined effect induced intestinal vacuolization and decreased the length of intestinal villi.And it significantly activated pro-inflammatory pathways with marked upregulation of tnfα,il1β,il6 and myd88 expressions,particularly after 14 days of exposure.Gut microbiota analysis revealed substantial dysbiosis,including 1)reduced alpha diversity,2)increased abundance of potential pathogenic taxa(Proteobacteria and Spirochaetota),and 3)depletion of beneficial Firmicutes.PICRUSt-based functional prediction indicated temporal metabolic shifts,with upregulation of DNA repair pathways at day 3 and enhanced bacterial motility protein activity at days 7 and 14 of post-exposure.The Pearson correlation analysis further indicated that these immune genes had significant positive correlations with Vibrio and Brevinema,and negative correlations with Streptococcus.Our present study will provide novel insights into the microbiome-mediated immunomodulation in the larger yellow croaker exposed to combined PFAS,which will be helpful for healthy farming of economically important marine species.展开更多
Objective:To investigate the correlation between the expression of glucose-6-phosphate dehydrogenase(G6PD)and the clinicopathological characteristics,prognosis and immune cell infiltration of hepatocellular carcinoma(...Objective:To investigate the correlation between the expression of glucose-6-phosphate dehydrogenase(G6PD)and the clinicopathological characteristics,prognosis and immune cell infiltration of hepatocellular carcinoma(HCC).Methods:The expression of G6PD in liver cancer tissues and normal tissues is extracted from TCGA and GEO databases,validated by immunohistochemistry,and the correlation between G6PD expression and clinical features is analyzed.The clinical significance of G6PD in liver cancer is assessed by Kaplan-Meier,Cox regression,and prognostic line graph models.Functional enrichment analysis is performed by protein-protein interaction(PPI)network,GO/KEGG,GSEA and for G6PD-associated differentially expressed genes(DEGs).TIMER and ssGSEA packages are used to assess the correlation between expression and the level of immune cell infiltration.Results:Analysis of TCGA and GEO datasets revealed that G6PD expression is significantly upregulated in hepatocellular carcinoma tissues(P<0.001).G6PD expression is associated with histological grade,pathological stage,T-stage,vascular infiltration,and AFP level(P<0.05);HCC patients in the low G6PD expression group had longer overall survival and better prognosis compared with the high G6PD expression group(P<0.05).The level of G6PD expression affects the levels of macrophages,dendritic cells,B cells,and follicular helper T cells in the tumor microenvironment.Conclusion:High expression of G6PD is a potential biomarker for poor prognosis of hepatocellular carcinoma,and G6PD may be a target for immunotherapy of HCC.展开更多
AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM...AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.展开更多
Background The objective of this study was to investigate the impacts of different dietary soybean meal(SBM)levels on jejunal immunity in nursery pigs at different days post-weaning.Methods Forty-eight pigs(6.2±0...Background The objective of this study was to investigate the impacts of different dietary soybean meal(SBM)levels on jejunal immunity in nursery pigs at different days post-weaning.Methods Forty-eight pigs(6.2±0.3 kg),weaned at 21 days of age,were assigned to 2 dietary treatments(n=12)in a randomized complete block design and fed for 20 or 42 d in 3 phases(10,10,and 22 d,respectively).The dietary treatments consisted of low and high SBM diets.On d 20 and 42,jejunal mucosa and tissue samples were collected.Treatments were arranged in 2×2 factors with dietary SBM levels(low and high SBM diets)and days post-weaning(20 d and 42 d post-weaning).Results Pigs fed high SBM diets had greater(P<0.05)relative abundance(RA)of jejunal Prevotella,tended to have greater(P=0.091)jejunal IgA,had greater(P<0.05)crypt depth,and tended to have lower(P=0.064)villus height to crypt depth ratio(VH:CD)than pigs fed low SBM diets.Pigs at 20 d post-weaning had greater(P<0.05)RA of jejunal Lactobacillus and had greater(P<0.05)jejunal IL-8 and protein carbonyl than pigs at 42 d post-weaning.Pigs at 20 d post-weaning tended to have greater(P=0.090)jejunal IgG,tended to have lower(P=0.059)jejunal IgA,and had greater(P<0.05)proportion(%)of Ki-67+cells in the jejunal crypt than pigs at 42 d post-weaning.Conclusion Pigs fed high SBM diets showed greater RA of Staphylococcus,a greater immune response,and a decreased VH:CD in the jejunum than pigs fed low SBM diets.Pigs at 20 d post-weaning were more susceptible to jejunal inflammation and intestinal damage than pigs at 42 d post-weaning,but the negative impacts of high SBM diets on jejunal inflammation and intestinal damage were consistent compared to low SBM diets at 20 d and 42 d post-weaning.展开更多
Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop met...Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.展开更多
Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regula...Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.展开更多
Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic releva...Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic relevance of exerkines across cancer types remains unclear,and the molecular determinants of exercise responsiveness are poorly defined.Methods:We systematically profiled 183 curated exerkine-related genes across 33 cancer types from The Cancer Genome Atlas(TCGA)using non-negative matrix factorization(NMF)to define molecular subtypes.Prognostic significance was evaluated via Kaplan-Meier analysis.For five cancers with consistent survival divergence(LGG,KIRC,LUAD,PAAD,ACC),we developed an Exerkine Prognostic Index(EPI)using LASSO Cox regression and validated its predictive performance through time-dependent ROC analysis.Immune cell infiltration(CIBERSORT),stromal/immune scores(ESTIMATE),and immune checkpoint expression were assessed to characterize immune landscape differences between EPI subgroups.Results:Exerkine-based NMF clustering identified prognostically distinct subtypes in 25 cancers.The EPI robustly stratified patients into high-and low-risk groups with significant differences in overall survival(p<0.001).High-EPI subgroups were associated with elevated infiltration of immunosuppressive cells(e.g.,Tregs,M0 macrophages),altered immune/stromal scores,and differential expression of immune checkpoints such as PD-L1 and CTLA4 in a cancer-type-specific manner.Discussion:Our findings reveal that exerkine expression patterns capture biologically and clinically relevant heterogeneity across cancers.The EPI provides a robust molecular tool to stratify patients by prognosis and immune contexture,offering insights into differential exercise responsiveness.Conclusions:Exerkines represent promising biomarkers for risk stratification and precision-guided exercise interventions in oncology.展开更多
Radiotherapy(RT)is considered a standard cancer treatment that directly kills tumor cells and promotes a systemic immune response.However,RT may also lead to tumor hypoxia,which further inhibits the antigen-presenting...Radiotherapy(RT)is considered a standard cancer treatment that directly kills tumor cells and promotes a systemic immune response.However,RT may also lead to tumor hypoxia,which further inhibits the antigen-presenting function of dendritic cells(DCs)and thereby weakens the systemic anti-tumor immune response induced by radiotherapy.In this study,the oxygen-loaded in situ gels carrying bacterial outer membrane(MOGel)were synthesized.As the gels slowly degraded,oxygen was gradually released to alleviate tumor hypoxia.The released bacterial outer membrane(OM)continuously activated DCs,enhancing their antigenpresenting capability.The results demonstrated that MOGel combined with RT induced the strongest tumor cell apoptosis in vitro and achieved a 80%tumor suppression rate in a colon cancer orthotopic model.Importantly,MOGel+RT induced an enhanced abscopal effect,and hypoxia and enhanced DCs activation contributed to the systemic immune response.Thus,OM-based oxygen gels may offer a novel strategy for enhancing the systemic immune response to RT.展开更多
Botrytis cinerea is a major necrotrophic pathogen responsible for significant crop losses worldwide.Alternative strategies to control B.cinerea are urgently needed to reduce dependence on chemical fungicides,which are...Botrytis cinerea is a major necrotrophic pathogen responsible for significant crop losses worldwide.Alternative strategies to control B.cinerea are urgently needed to reduce dependence on chemical fungicides,which are increasingly ineffective due to resistance and pose environmental risks.In this study,we identified two immunogenic epitopes derived from the B.cinerea cell death-inducing protein BcCrh1 and used them to engineer disease-resistant plants through a novel,spatially compartmentalized dual-epitope immune activation strategy.The first epitope is derived from a 35-amino acid intracellular peptide that exhibits both immunogenicity and cell death-inducing activity,which was mutated to separate these two properties.The second peptide represents an immunogenic portion of the protein that activates extracellular plant immunity.Transcriptomic and metabolomic analyses revealed that these epitopes trigger complementary defense pathways,and their co-expression integrates these responses into a robust,multilayered immunity,providing significantly enhanced protection compared with individual expression.Although constitutive expression of two epitopes conferred resistance,it also led to growth penalties.In contrast,pathogen-inducible expression of two epitopes preserved normal plant development while maintaining strong resistance to both B.cinerea and Pseudomonas syringae in Arabidopsis and tomato.This inducible strategy offers a major advantage by minimizing fitness costs while maximizing protection,highlighting the potential of spatially and temporally targeted epitope-based immune activation for durable and sustainable crop protection.展开更多
文摘Objective This study aimed to compare the current Essen rabies post-exposure immunization schedule(0-3-7-14-28)in China and the simple 4-dose schedule(0-3-7-14)newly recommended by the World Health Organization in terms of their safety,efficacy,and protection.Methods Mice were vaccinated according to different immunization schedules,and blood was collected for detection of rabies virus neutralizing antibodies(RVNAs)on days 14,21,28,35,and 120after the first immunization.Additionally,different groups of mice were injected with lethal doses of the CVS-11 virus on day 0,subjected to different rabies immunization schedules,and assessed for morbidity and death status.In a clinical trial,185 rabies-exposed individuals were selected for post-exposure vaccination according to the Essen schedule,and blood was collected for RVNAs detection on days 28and 42 after the first immunization.Results A statistically significant difference in RVNAs between mice in the Essen and 0-3-7-14 schedule groups was observed on the 35th day(P<0.05).The groups 0-3-7-14,0-3-7-21,and 0-3-7-28 showed no statistically significant difference(P>0.05)in RVNAs levels at any time point.The post-exposure immune protective test showed that the survival rate of mice in the control group was 20%,whereas that in the immunization groups was 40%.In the clinical trial,the RVNAs positive conversion rates on days 28(14 days after 4 doses)and 42(14 days after 5 doses)were both 100%,and no significant difference in RVNAs levels was observed(P>0.05).Conclusion The simple 4-dose schedule can produce sufficient RVNAs levels,with no significant effect of a delayed fourth vaccine dose(14–28 d)on the immunization potential.
基金supported by the Major Scientific and Technological Project of the Henan Province,China(221100110600)the Beijing Life Science Academy,China(2024500CA0010)+1 种基金the Major Program of National Natural Science Foundation of China(32192452)the Chinese Postdoctoral Science Foundation(2023M743209)。
文摘Porcine epidemic diarrhea virus(PEDV),an enteric coronavirus,is widely spread worldwide and causes huge economic losses.The effective measure to control the viral infection is to develop ideal vaccines.Here,the collagenase equivalent domain(COE)of PEDV was displayed on the surface of nanoparticles(NPs)in order to develop a newer,safer and more effective subunit vaccine against PEDV.The monomeric COE was displayed on the mi3 protein,which self-assembles into nanoparticles composed of 60 subunits,using the SpyTag/SpyCatcher system.The size,zeta potential,microstructure of the COE-mi3 virus-like particles(VLPs)were investigated.The COE-mi3 VLPs that possessed good security,stability and better retention can be more efficiently taken up by antigen-presenting cells(APCs)and help promote dendritic cells(DCs)maturation.Moreover,COE-mi3 VLPs could prominently improve specifc antibody levels including neutralizing antibodies(NAbs),and serum IgG,mucosal IgA.Moreover,COE-mi3 VLPs elicited more activation of CD4^(+)and CD8^(+)T cells and production of IFN-γand IL-4 cytokines.In particular,COE-mi3 VLPs is an effectual antigen-delivery platform to enhance germinal center(GC)B cell responses.This structure-based self-assembly of NP gives great potential to be developed as a new subunit vaccines attractive platform,and may also provide new ideas for the development of other enteric coronavirus vaccines.
文摘Dengue fever remains a significant public health challenge in Malaysia,with its incidence continuing to rise despite existing control measures.Dengue,a disease caused by the dengue virus and transmitted by Aedes mosquitoes,places a substantial burden on healthcare systems and economic productivity.Despite efforts by the Malaysian government,including the release of Wolbachia-carrying Aedes aegypti mosquitoes in dengue hotspot areas since 2017,the problem persists.In 2023,Malaysia reported 123133 dengue cases,an 86.3%increase compared to 2022[1].This highlights the urgent need for more effective interventions,including the potential integration of dengue vaccines into routine immunization programs.Currently,two dengue vaccines have been licensed:Dengvaxia(CYD-TDV)by Sanofi Pasteur and Qdenga(TAK-003)by Takeda.Dengvaxia,the first licensed dengue vaccine,has significant limitations,as it increases the risk of hospitalization in dengue-naïve individuals due to antibody-dependent enhancement[2,3].As a result,it is only licensed for individuals with prior dengue infections,necessitating pre-vaccination screening.These constraints make it unsuitable for inclusion in Malaysia’s routine immunization programs.
基金Supported by Guizhou Provincial Department of Agriculture and Rural Affairs Project(QNYZZZ[2017]No.12,GZSZCYJSTX-04)2025 Quality Supervision and Sampling Project of Normal Temperature Semen for Breeding Pigs(2025-1-10).
文摘[Objectives]This study was conducted to evaluate the immunization efficacy and infection status of classical swine fever(CSF),foot-and-mouth disease(FMD),porcine reproductive and respiratory syndrome(PRRS),pseudorabies(PR),and porcine circovirus type 2(PCV2)in large-scale pig farms.[Methods]Antibody and pathogen detection was performed on 56 serum samples collected in March 2025.[Results]The antibody qualification rates for CSF,FMD,and PRRS were 76.8%,73.2%,and 76.8%,respectively,all meeting the national standards.However,nursery pigs exhibited an immunity gap,indicating a need for timely booster vaccinations.No PRV gE antibodies or PCV2 antibodies were detected,reflecting the absence of vaccination against these diseases and suggesting significant effectiveness of comprehensive biosecurity measures.The low antibody qualification rate for PRRS in the nursery stage highlights the need for improved immunization management.[Conclusions]This study provides data support and practical insights for integrated disease prevention and control in large-scale pig farms.
文摘Objective Sepsis patients exhibit diverse immune states,making it crucial to identify subtypes with distinct inflammatory profiles through Th1/Th2 cytokine data for personalized treatment and improved prognosis.Methods We retrieved data from sepsis patients who underwent Th1/Th2 cytokine testing in Nanfang Hospital,Southern Medical University from June 1,2020,to February 1,2022.An unsupervised K-means clustering method classified participants based on Th1/Th2 cytokine levels,with the primary outcome being the 7-day mortality rate post-ICU admission.Cox proportional hazards and Restricted Mean Survival Time(RMST)analyses were utilized to explore survival outcomes.Results A total of 321 sepsis patients were included.IL-6(HR 1.69,95%CI:1.22,2.34)and IL-10(HR 1.81,95%CI:1.37,2.40)emerged as independent predictors of 7-day mortality.Unsupervised K-means clustering revealed 3 inflammatory/immune subgroups:Cluster 1(n=166,low inflammatory response),Cluster 2(n=99,moderate inflammatory response with immune suppression),and Cluster 3(n=56,strong inflammatory and immune suppression).Compared to Cluster 1,Clusters 2 and 3 had higher 7-day mortality risks(14.4%vs 23.2%,HR=4.30,95%CI:1.51-12.26;14.4%vs 35.7%,HR=7.32,95%CI:2.57-20.79).Conclusion Septic patients in a protective immune response state(Cluster 1)exhibit better short-term prognoses,suggesting the importance of understanding inflammatory/immune states for precise treatment and improved outcomes.
基金supported by the National Natural Science Foundation of China(82472842 and 82473350)and Wuxi Double-Hundred Talent Fund Project(BJ2023075).
文摘Immunotherapy has brought unprecedented breakthroughs to advanced malignant tumors,yet the immune microenvironment shaped by the tumor stroma has often been underestimated in the traditional focus on the“immune checkpoint-T cell”axis.Collagen not only constitutes a mechanical barrier that distinguishes between the periphery and core of solid tumors but also systematically remodels the orientation of metabolism,vasculature,and immune cell phenotypic plasticity through its spatial density,fiber arrangement,and crosslinking patterns(F igure 1)[1,2].Abundant evidence suggests that over-accumulated types I and III collagen drive CD8+T cell exhaustion,NK cell functional inhibition,and tumor-associated macrophage polarization through ligand-receptor networks involving LAIR-1,DDR2,andβ1/β3 integrins[3-6].Mechanistically,collagen engagement of LAIR-1 delivers inhibitory signals in effector lymphocytes,promoting dysfunctional or exhausted states[7-9].In parallel,collagen-β1/β3 integrin signaling activates mechanotransduction pathways(e.g.,FAK/SRC),reducing T-cell motility and immune-tumor contact,while DDR2 activation supports matrix-remodeling programs that limit lymphocyte trafficking.
基金supported by the National Natural Science Foundation of China(Nos.82573045,82460602,82560459)the Hainan Provincial Graduate Student Innovative Research Project(No.Qhys2024-440).
文摘Post-translational modifications(PTMs)regulate the occurrence and development of cancer,and lactylation modification is a new form of PTMs.Recent studies have found that lactic acid modification can regulate the immune tolerance of cancer cells.The classical theory holds that prostate apoptosis response-4(PAR-4)is a tumor suppressor protein.However,our recent research has found that PAR-4 has a biological function of promoting cancer in hepatocellular carcinoma(HCC),and our analysis shows that PAR-4 can be modified of lactic acid.These research evidences suggest that PAR-4 lactylation modification may drive immune tolerance in HCC.Therefore,inhibiting PAR-4 lactylation modification is very likely to increase the sensitivity of HCC to immunotherapy.
基金supported by grants from the National Natural Science Foundation of China(32172498 and W2433052)the National Key R&D Program of China(2021YFD1000500)the Natural Science Foundation of Guangdong,China(2023A1515010305)。
文摘The red imported fire ant,Solenopsis invicta Buren,is a highly invasive eusocial insect pest that threatens native biodiversity,agriculture,and human health.The innate immune system and intricate social immune responses of S.invicta pose challenges to the development of effective control strategies.Micro RNAs(mi RNAs)play critical roles in the post-transcriptional regulation of gene expression,which influences various biological processes,including immunity and host-pathogen interactions.While the mi RNA-mediated response of insects to pathogens has been extensively studied in solitary insects,little is known about the innate immune responses of individual members within a colony.To address this gap,we constructed small RNA libraries from Metarhizium anisopliae-infected S.invicta workers and investigated the temporal dynamics of mi RNA-mediated immune responses to the entomopathogen.Several differentially expressed mi RNAs were identified,and they were found to regulate genes involved in the Toll,IMD,and melanization immune pathways.Quantitative real-time PCR(q RT-PCR)was employed to analyze the spatiotemporal dynamics of key mi RNAs/target genes,specifically mi R-71/Mod SP1-Relish and mi R-7/Lysozyme2-Serine protease7.A dual luciferase assay(in vitro)was performed to validate the interactions between mi RNAs and their target genes.Overexpression of mi R-71 and mi R-7(via mi RNA mimics)efficiently suppressed their target genes,impaired the antifungal immune response of S.invicta and increased the susceptibility to M.anisopliae infection compared to controls.Furthermore,RNA interference-based gene silencing elucidated the roles of these immune genes in regulating fungal susceptibility,thus providing vital clues for developing virulent and effective mycoinsecticides using modern genetic engineering tools.
基金supported by the National Natural Science Foundation of China(No.82260820)the Natural Science Foundation of Jilin Province,Jilin,China(No.YDZJ202201ZYTS155).
文摘Pulmonary fibrosis(PF)is a progressive,fatal fibrotic disease caused by respiratory conditions.The condition can ultimately lead to severe organ failure and mortality,and is associated with multiple risk factors.Growing evidence highlights the immune system’s role in PF,with various immune components participating in inflammatory and fibrotic processes.Different immune cells,including neutrophils,lymphocytes,and macrophages,demonstrate distinct effects on PF progression and development.Furthermore,key immune system cytokines,including the interleukin(IL)family,tumor necrosis factor(TNF)-α,interferon(IFN)-γ,transforming growth factor(TGF)-β,and connective tissue growth factor(CTGF),contribute to PF initiation and progression through independent mechanisms and mutual regulation.Currently,limited effective treatments exist for PF,with several treatments causing severe adverse reactions.Natural products,characterized by multi-target effects,holistic regulation,and low toxicity,have emerged as a research focus.This review compiles the mechanisms,therapeutic potential,and active components of various natural products.These compounds can ameliorate pulmonary inflammation,epithelial-mesenchymal transition,and collagen deposition through diverse immune mechanisms,acting at specific stages or throughout the fibrotic process,thereby supporting PF management.This review examines current scientific understanding of natural products’immunological effects in PF,which is crucial for developing future anti-PF therapeutics.
文摘Hepatocellular carcinoma presents with three distinct immune phenotypes,including immune-desert,immune-excluded,and immune-inflamed,indicating various treatment responses and prognostic outcomes.The clinical application of multi-omics parameters is still restricted by the expensive and less accessible assays,although they accurately reflect immune status.A comprehensive evaluation framework based on“easy-to-obtain”multi-model clinical parameters is urgently required,incorporating clinical features to establish baseline patient profiles and disease staging;routine blood tests assessing systemic metabolic and functional status;immune cell subsets quantifying subcluster dynamics;imaging features delineating tumor morphology,spatial configuration,and perilesional anatomical relationships;immunohistochemical markers positioning qualitative and quantitative detection of tumor antigens from the cellular and molecular level.This integrated phenomic approach aims to improve prognostic stratification and clinical decision-making in hepatocellular carcinoma management conveniently and practically.
基金financial support from the Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20230718)。
文摘The interplay between gut microbiota and host health has attracted significant interest in the animal science community.Maintaining gut microbiota homeostasis by supplementing probiotics to treat clinical conditions like calf diarrhea is an emerging area of research nowadays because of increased concerns regarding antimicrobial resistance(AMR)and drug residues in animal products.Probiotics reduce the incidence of calf diarrhea by increasing the gut microbiota diversity and richness with more commensal bacteria such as Lactobacillus and Bifidobacterium that produce antimicrobial compounds,as well as modulating the immune response by increasing cytokines,Interleukin-2(IL-2),IL-4,IL-6,IL-10,and reducing tumor necrosis factor-α(TNF-α),by increasing production of antibodies,especially immunoglobulin E(Ig E),also Ig G,differentiating naive Th lymphocytes(Tho)into Th1,hence stimulate innate immunity and prime the adaptive immune response.Specific probiotic strains of bacteria and yeast(Saccharomyces cerevisiae)derived probiotics maintain the integrity of the intestinal barrier.In this review,data are being organized to address the role of probiotics in treating calf diarrhea by modulating gut microbiota and stimulating an immune response against notorious pathogens,to present animal and veterinary scientists and nutritionists with a new concept to treat infectious diseases from the perspective of the gut microbiota,increasing animal health,performance,and welfare.In conclusion,health status and gut microbiome are strongly interlinked.Research data indicated a significant reduction in the incidence of diarrhea after probiotic administration.If interrelations between probiotics and existing gut microbiota are explored more quantitatively,novel antibiotic substitutes can emerge in the future.
基金supported by the Ningbo Natural Science Foundation(Youth Foundation,No.2024J449)the Scientific Research Foundation for Introduced Talents of Ningbo University(Nos.ZX2022000602 and ZX2024000043)。
文摘Polyfluoroalkyl substances(PFAS)have emerged as persistent environmental contaminants because of their chemical stability,degradation-resistance and bioaccumulation potential.However,current studies mainly focus on the toxicity of single PFAS such as perfluorooctanoic acid(PFOA)and perfluorobutanoic acid(PFBA),the knowledge of their combined effects is relatively limited.In this study,we explored the immune response of the gut in large yellow croaker(Larimichthys crocea)under the combined stress of PFOA and PFBA.Histologicalanalyses revealed that the combined effect induced intestinal vacuolization and decreased the length of intestinal villi.And it significantly activated pro-inflammatory pathways with marked upregulation of tnfα,il1β,il6 and myd88 expressions,particularly after 14 days of exposure.Gut microbiota analysis revealed substantial dysbiosis,including 1)reduced alpha diversity,2)increased abundance of potential pathogenic taxa(Proteobacteria and Spirochaetota),and 3)depletion of beneficial Firmicutes.PICRUSt-based functional prediction indicated temporal metabolic shifts,with upregulation of DNA repair pathways at day 3 and enhanced bacterial motility protein activity at days 7 and 14 of post-exposure.The Pearson correlation analysis further indicated that these immune genes had significant positive correlations with Vibrio and Brevinema,and negative correlations with Streptococcus.Our present study will provide novel insights into the microbiome-mediated immunomodulation in the larger yellow croaker exposed to combined PFAS,which will be helpful for healthy farming of economically important marine species.
文摘Objective:To investigate the correlation between the expression of glucose-6-phosphate dehydrogenase(G6PD)and the clinicopathological characteristics,prognosis and immune cell infiltration of hepatocellular carcinoma(HCC).Methods:The expression of G6PD in liver cancer tissues and normal tissues is extracted from TCGA and GEO databases,validated by immunohistochemistry,and the correlation between G6PD expression and clinical features is analyzed.The clinical significance of G6PD in liver cancer is assessed by Kaplan-Meier,Cox regression,and prognostic line graph models.Functional enrichment analysis is performed by protein-protein interaction(PPI)network,GO/KEGG,GSEA and for G6PD-associated differentially expressed genes(DEGs).TIMER and ssGSEA packages are used to assess the correlation between expression and the level of immune cell infiltration.Results:Analysis of TCGA and GEO datasets revealed that G6PD expression is significantly upregulated in hepatocellular carcinoma tissues(P<0.001).G6PD expression is associated with histological grade,pathological stage,T-stage,vascular infiltration,and AFP level(P<0.05);HCC patients in the low G6PD expression group had longer overall survival and better prognosis compared with the high G6PD expression group(P<0.05).The level of G6PD expression affects the levels of macrophages,dendritic cells,B cells,and follicular helper T cells in the tumor microenvironment.Conclusion:High expression of G6PD is a potential biomarker for poor prognosis of hepatocellular carcinoma,and G6PD may be a target for immunotherapy of HCC.
基金Supported by the National Natural Science Foundation of China(No.82460215)National Natural Science Foundation of China Pre-experimental Project(No.2025GZRYSY006)+4 种基金2025 Youth Training Project of the Xi’an Municipal Health Commission(No.2025qn05)Xi’an Medical Research-Discipline Capacity Building Project(No.23YXYJ0002)Key R&D Plan of Shaanxi Province:Key Industrial Innovation Chain(Cluster)-Social Development Field(No.2022ZDLSF03-10)Research Incubation Fund of Xi’an People’s Hospital(Xi’an Fourth HospitalNo.LH-13).
文摘AIM:To identify metastasis-associated prognostic genes and construct a robust molecular signature for survival prediction in uveal melanoma(UVM)patients.METHODS:Transcriptomic data and clinical information from 80 UVM patients in the Cancer Genome Atlas(TCGA)-UVM cohort and an external Gene Expression Omnibus(GEO)microarray dataset(GSE73652;8 non-metastatic vs 5 metastatic cases)were analyzed to identify differentially expressed genes(DEGs).Functional enrichment,proteinprotein interaction(PPI)network construction,and survival analyses identified seven metastasis-and prognosisrelated genes.Their expression was further examined using public single-cell RNA-seq data(GSE139829;11 tumors).Experimental validation was performed in UVM cell lines(92.1,OMM1,MEL270)and adult retinal pigment epithelial(ARPE-19)cells using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blotting to confirm transcriptomic trends.A LASSO Cox model was applied to construct a metastasis-related risk Score signature.Tumor immune microenvironment characteristics were evaluated via single-sample gene set enrichment analysis(ssGSEA)and ESTIMATE.Somatic mutation and copy number variation(CNV)profiles were also examined.RESULTS:Seven key genes(UBE2T,KIF20A,DLGAP5,KLC3,TPX2,UBE2C,AURKA)were significantly associated with overall survival and used to construct a metastasisrelated riskScore signature,which effectively stratified patients into high-and low-risk groups and served as an independent prognostic factor.qRT-PCR and Western blot results confirmed that the expression levels of selected key genes in UVM cell lines showed significant differences compared to ARPE-19 cells,which were largely consistent with the transcriptomic findings.The high-risk group exhibited reduced immune infiltration and stromal activity.Single-cell analysis revealed these genes were predominantly expressed in a tumor cell cluster characterized by BAP1 loss and high metastatic potential.Mutation and CNV analyses further supported the relevance of these genes to UVM progression.CONCLUSION:This study establishes and validates a seven-gene signature associated with metastasis and prognosis in UVM.The findings provide a framework for understanding molecular determinants of tumor progression and immune microenvironment alterations,and may offer guidance for future mechanistic studies and therapeutic exploration.
文摘Background The objective of this study was to investigate the impacts of different dietary soybean meal(SBM)levels on jejunal immunity in nursery pigs at different days post-weaning.Methods Forty-eight pigs(6.2±0.3 kg),weaned at 21 days of age,were assigned to 2 dietary treatments(n=12)in a randomized complete block design and fed for 20 or 42 d in 3 phases(10,10,and 22 d,respectively).The dietary treatments consisted of low and high SBM diets.On d 20 and 42,jejunal mucosa and tissue samples were collected.Treatments were arranged in 2×2 factors with dietary SBM levels(low and high SBM diets)and days post-weaning(20 d and 42 d post-weaning).Results Pigs fed high SBM diets had greater(P<0.05)relative abundance(RA)of jejunal Prevotella,tended to have greater(P=0.091)jejunal IgA,had greater(P<0.05)crypt depth,and tended to have lower(P=0.064)villus height to crypt depth ratio(VH:CD)than pigs fed low SBM diets.Pigs at 20 d post-weaning had greater(P<0.05)RA of jejunal Lactobacillus and had greater(P<0.05)jejunal IL-8 and protein carbonyl than pigs at 42 d post-weaning.Pigs at 20 d post-weaning tended to have greater(P=0.090)jejunal IgG,tended to have lower(P=0.059)jejunal IgA,and had greater(P<0.05)proportion(%)of Ki-67+cells in the jejunal crypt than pigs at 42 d post-weaning.Conclusion Pigs fed high SBM diets showed greater RA of Staphylococcus,a greater immune response,and a decreased VH:CD in the jejunum than pigs fed low SBM diets.Pigs at 20 d post-weaning were more susceptible to jejunal inflammation and intestinal damage than pigs at 42 d post-weaning,but the negative impacts of high SBM diets on jejunal inflammation and intestinal damage were consistent compared to low SBM diets at 20 d and 42 d post-weaning.
文摘Objectives:Immunotherapy based on immune checkpoint blockade(ICB)has become a key treatment for melanoma.However,the increasing number of cases of melanoma resistant to immunotherapy highlights the need to develop methods to overcome this resistance.This study aims to collect the most recent information on melanoma immunotherapy,discuss potential strategies to overcome resistance to immunotherapy,and identify areas that require further analysis.Methods:To achieve this goal,scientific publications from 2021-2024 available in PubMed and Google Scholar databases were analyzed.The databases were searched using the following terms:“melanoma”,“immunotherapy”,“Immune Checkpoint Blockade”,and“immunoresistance”.Results:The results of preclinical and early-stage clinical research indicate the potential application of tank-binding kinase 1(TBK-1),fecal microbiota transplant(FMT),Toll-like Receptor 9(TLR9),lipid nanoparticles(LNPs)containing a stimulator of an interferon gene agonist(STING),BRAF inhibitors,Lymphocyte Activation Gene(LAG-3),T-Cell Immunoglobulin and ITIM Domain(TIGIT),and oncolytic viruses(OVs)as potential methods to enhance melanoma sensitivity to ICB.Discussion:To optimize immunotherapy,further research is needed to determine the detailed mechanisms of action,safety profiles,tolerability,and precise patient selection criteria for methods capable of overcoming melanoma’s immunoresistance.
基金funded by the National Natural Science Foundation of China(Grant Nos.82204517 to T.Z.and 82404756 to J.Z.)the Science and Technology Program in Medicine and Health of Zhejiang Province(Grant No.2023KY726 to T.Z.).
文摘Background:Aberrant expression of transcription factors(TFs)is a key mechanism mediating tumor immune escape and therapeutic resistance.The involvement of E26 transformation-specific(ETS)family of TFs in immune regulation is not fully understood.The study aimed to elucidate the function of E-twenty-six variant 4(ETV4)in tumor immune evasion and its potential as a predictive biomarker for immunotherapy in melanoma.Methods:The expression patterns of ETS family TFs were analyzed in melanoma and hepatocellular carcinoma(HCC).Single-cell RNA sequencing(scRNA-seq)was used to dissect the cellular expression and function of ETV4 in the tumor microenvironment.Functional studies and murine models were employed to investigate the role of ETV4 in T cell-mediated tumor killing and tumor growth.The correlation between ETV4 expression level and patient responsiveness to programmed cell death protein 1(PD-1)blockade therapy was evaluated.Results:TFs in the ETS family were found to effectively stratify melanoma and HCC patients into prognostic subgroups.In melanoma,the polyoma enhancer activator 3(PEA3)subfamily,particularly ETV4 and ETV5,showed a negative correlation with immune infiltration.scRNA-seq analysis showed that ETV4 is preferentially expressed in melanoma cells and involves in mediating tumor-immunocyte interactions.Functional studies demonstrated that ETV4 impairs T cell-mediated tumor killing by transcriptionally upregulating programmed death-ligand 1(PD-L1).In immunocompetent murine models,ETV4 downregulation significantly suppressed tumor growth.Furthermore,high ETV4 expression correlated with poor responses to anti-PD-1 therapy.Conclusion:Our findings identify ETV4 as a key transcriptional regulator of immune evasion in melanoma by controlling PD-L1 expression.ETV4 may act as a predictive biomarker for immunotherapy outcomes.
基金supported by Beijing Sport University Graduate Innovation Programme(2024013).
文摘Background:Exercise exerts tumor-suppressive effects across multiple malignancies,partly through exerkines—exercise-induced secreted factors with immunomodulatory and metabolic functions.However,the prognostic relevance of exerkines across cancer types remains unclear,and the molecular determinants of exercise responsiveness are poorly defined.Methods:We systematically profiled 183 curated exerkine-related genes across 33 cancer types from The Cancer Genome Atlas(TCGA)using non-negative matrix factorization(NMF)to define molecular subtypes.Prognostic significance was evaluated via Kaplan-Meier analysis.For five cancers with consistent survival divergence(LGG,KIRC,LUAD,PAAD,ACC),we developed an Exerkine Prognostic Index(EPI)using LASSO Cox regression and validated its predictive performance through time-dependent ROC analysis.Immune cell infiltration(CIBERSORT),stromal/immune scores(ESTIMATE),and immune checkpoint expression were assessed to characterize immune landscape differences between EPI subgroups.Results:Exerkine-based NMF clustering identified prognostically distinct subtypes in 25 cancers.The EPI robustly stratified patients into high-and low-risk groups with significant differences in overall survival(p<0.001).High-EPI subgroups were associated with elevated infiltration of immunosuppressive cells(e.g.,Tregs,M0 macrophages),altered immune/stromal scores,and differential expression of immune checkpoints such as PD-L1 and CTLA4 in a cancer-type-specific manner.Discussion:Our findings reveal that exerkine expression patterns capture biologically and clinically relevant heterogeneity across cancers.The EPI provides a robust molecular tool to stratify patients by prognosis and immune contexture,offering insights into differential exercise responsiveness.Conclusions:Exerkines represent promising biomarkers for risk stratification and precision-guided exercise interventions in oncology.
基金supported by the National Key R&D Program of China(2022YFC3401600)the National Natural Science Foun-dation of China(32530061 and 32171372)+1 种基金the Science and Technology Projects of Xizang Autonomous Region,China(XZ202202YD0029C)the Fundamental Research Funds for the Central Universities(KG202511)。
文摘Radiotherapy(RT)is considered a standard cancer treatment that directly kills tumor cells and promotes a systemic immune response.However,RT may also lead to tumor hypoxia,which further inhibits the antigen-presenting function of dendritic cells(DCs)and thereby weakens the systemic anti-tumor immune response induced by radiotherapy.In this study,the oxygen-loaded in situ gels carrying bacterial outer membrane(MOGel)were synthesized.As the gels slowly degraded,oxygen was gradually released to alleviate tumor hypoxia.The released bacterial outer membrane(OM)continuously activated DCs,enhancing their antigenpresenting capability.The results demonstrated that MOGel combined with RT induced the strongest tumor cell apoptosis in vitro and achieved a 80%tumor suppression rate in a colon cancer orthotopic model.Importantly,MOGel+RT induced an enhanced abscopal effect,and hypoxia and enhanced DCs activation contributed to the systemic immune response.Thus,OM-based oxygen gels may offer a novel strategy for enhancing the systemic immune response to RT.
基金supported by the National Natural Science Foundation of China(grant no.32372514)the Research and Innovation Initiatives of WHPU(grant no.2024J02)+1 种基金Y.L.(202108280009)was funded by the China Scholarship Councilsupported by BARD(grant no.5261-20C)to A.S and T.M.
文摘Botrytis cinerea is a major necrotrophic pathogen responsible for significant crop losses worldwide.Alternative strategies to control B.cinerea are urgently needed to reduce dependence on chemical fungicides,which are increasingly ineffective due to resistance and pose environmental risks.In this study,we identified two immunogenic epitopes derived from the B.cinerea cell death-inducing protein BcCrh1 and used them to engineer disease-resistant plants through a novel,spatially compartmentalized dual-epitope immune activation strategy.The first epitope is derived from a 35-amino acid intracellular peptide that exhibits both immunogenicity and cell death-inducing activity,which was mutated to separate these two properties.The second peptide represents an immunogenic portion of the protein that activates extracellular plant immunity.Transcriptomic and metabolomic analyses revealed that these epitopes trigger complementary defense pathways,and their co-expression integrates these responses into a robust,multilayered immunity,providing significantly enhanced protection compared with individual expression.Although constitutive expression of two epitopes conferred resistance,it also led to growth penalties.In contrast,pathogen-inducible expression of two epitopes preserved normal plant development while maintaining strong resistance to both B.cinerea and Pseudomonas syringae in Arabidopsis and tomato.This inducible strategy offers a major advantage by minimizing fitness costs while maximizing protection,highlighting the potential of spatially and temporally targeted epitope-based immune activation for durable and sustainable crop protection.
