Search Results (4,569)

Background: The CD163+ macrophage is considered a key component of the tumor immune microenvironment (TIME) in osteosarcoma (OS) in relation to tumor progression and chemotherapy resistance. However, the relationship between CD163+ macrophage infiltration and the efficacy of neoadjuvant chemotherapy (NACT) in OS remains unexplored. Methods: This study collected a total of 195 biopsy samples from newly diagnosed, pretreated OS patients. The infiltration of CD163+ macrophages was evaluated using immunohistochemical (IHC) staining with anti-CD163 antibody. Additionally, multiplex fluorescence staining (CD8, CD68, CD163, and PDL1) was employed to further characterize the TIME profiles associated with different levels of CD163+ macrophage infiltration. The relationships between various clinical characteristics, survival outcomes, and CD163+ macrophage infiltration levels were also assessed. Results: CD163+ macrophages in biopsy tissues ranged from 2.25 cells/mm² to 3974.79 cells/mm² and 1.37 cells/mm² to 3027.20 cells/mm² in the training and validation cohorts respectively. Multivariate analysis identified that CD163+ macrophage density was an independent predictor for NACT response. Importantly, patients with high CD163+ macrophage infiltration exhibited poorer DFS, DMFS, and RFS than their counterparts. Conclusions: CD163+ macrophage infiltration was an independent predictor for NACT response. Patients with high CD163+ macrophage density benefited less from NACT and exhibited a more immunosuppressive TIME than low-density patients. Full article

Background/Objectives: Clear cell renal cell carcinoma (ccRCC) involves complex interactions between immune evasion and metabolic reprogramming. This study aimed to characterize ccRCC through integrated immunometabolic profiling, develop a prognostic signature, and investigate the functional role of the key driver gene UCN using in vitro and in vivo approaches. Methods: Integrated immunometabolic profiling was performed to identify molecular subtypes and establish a prognostic gene signature. Two distinct molecular subtypes were identified, and a 9-gene Immune Metabolic Index (IMI) was constructed. The functional role of the key driver gene UCN was investigated through in vitro functional assays and in vivo xenograft models in BALB/c mice, including combination with PD-1 blockade. Results: Two molecular subtypes with significant survival differences (p < 0.001) were identified. The established IMI demonstrated high prognostic accuracy, with Area Under the Curve (AUC) values of 0.813, 0.751, and 0.779 at 1-, 3-, and 5-year intervals, respectively. UCN was identified as the highest-risk gene in the signature. Functional assays showed that UCN silencing significantly inhibited cell proliferation and migration (p < 0.05). In BALB/c mouse xenograft models, UCN silencing remodeled the tumor microenvironment by increasing CD8+ T cell infiltration and reducing regulatory T cells (p < 0.01). Furthermore, UCN knockdown significantly suppressed tumor growth and synergized with PD-1 blockade to enhance antitumor efficacy (p < 0.001). Conclusions: The IMI is a robust tool for risk stratification in ccRCC. Targeting the UCN-driven immunometabolic axis represents a promising therapeutic strategy to overcome immune resistance in ccRCC. Full article

Background/Objectives: Zebrafish fin regeneration serves as a classic model for investigating vertebrate tissue regeneration, yet the core regulatory networks and their crosstalk with the immune microenvironment remain incompletely characterized. This study aimed to identify hub genes, and elucidate the underlying molecular mechanisms and immune microenvironment dynamics during zebrafish fin regeneration. Methods: We integrated multiple bulk RNA-seq datasets of zebrafish fin regeneration from the GEO database, followed by data standardization with batch effect removal. Hub genes were screened via differential expression analysis, weighted gene co-expression network analysis (WGCNA), and predictive models constructed with 13 classic machine learning algorithms. Functional enrichment, time-ordered gene co-expression network (TO-GCN) method, immune infiltration analyses and RT-qPCR validation were further performed. Results: We identified upregulated differentially expressed genes, regeneration-correlated gene modules and their overlapping genes, including 82 candidate genes and 10 hub genes enriched in cytoskeleton remodeling, extracellular matrix organization, and focal adhesion. Temporal analysis uncovered hierarchical gene regulation and functional switching during regeneration. Hub gene expression was significantly correlated with the infiltration of B cells, M1/M2 macrophages and CD8+ T cells, revealing a stage-specific immune microenvironment. RT-qPCR validation showed high consistency with the multi-omics data. Conclusions: This study provides potential gene targets for understanding zebrafish fin regeneration, and offers a valuable reference for investigating the crosstalk between regulatory networks and the immune microenvironment in vertebrate tissue regeneration. Full article

Background/Objectives: Extraintestinal pathogenic Escherichia coli (ExPEC) is a major pathogen that causes septicemia, meningitis, and polyserositis in pigs. The increasing prevalence of antimicrobial resistance and the diverse serotypes of ExPEC highlight the urgent need for broadly protective vaccines. Methods and Results: In this study, an OmpC epitope vaccine based on the T4 phage display system was developed and evaluated. Two B-cell epitopes (OmpC-1 and OmpC-2) were identified by bioinformatic analysis and displayed on recombinant T4 phages. Immunization induced strong antigen-specific IgG responses, with the OmpC-1-T4 group showing significantly higher antibody titers than the OmpC protein group. In the O11 serotype PCN033 challenge model, survival rates reached 100% in the OmpC-1-T4 group, 60% in the OmpC-2-T4 group, and approximately 80% in the OmpC protein group. In the O18 serotype 2103 challenge model, both recombinant phage groups had survival rates of approximately 60%, whereas all the mice in the OmpC protein group died within three days. OmpC-1-T4 immunization also significantly reduced bacterial loads in lung and brain tissues after PCN033 infection and decreased TNF-α and IL-6 expression in lung tissues, accompanied by reduced inflammatory infiltration and tissue damage. Conclusions: Overall, the T4 phage-displayed OmpC epitope vaccine induced strong humoral immunity and provided protection against different ExPEC serotypes. Among the candidates, OmpC-1-T4 showed superior immune protection, bacterial clearance, and inflammation control, supporting its potential as a vaccine candidate against porcine ExPEC infection. Full article

Hyaluronic acid (HA), a major extracellular matrix component, is used therapeutically to aid healing and deliver drugs to injury sites. Burns create serious clinical and aesthetic problems needing fast skin repair to prevent complications. This study compared 1.8% pharmaceutical-grade HA with panthenol-containing gel (PCG) in deep-burn healing in rats against spontaneous healing. HA slightly accelerated wound closure from day 3 compared to PCG; both induced granulation by day 7 and epithelialization by day 28. HA caused early collagen drop (day 3), later matched PCG levels with abnormal distribution, and both exceeded control by day 28. HA normalized systemic leukocyte counts by day 14 while strongly increasing local leukocyte infiltration in the wound area. HA dual immune effect depends on source and properties; further research is required for clinical use in wound healing. Full article

Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor characterized by an intrinsic resistance to immunotherapy, primarily due to its low immunogenicity and immune-cold tumor microenvironment. The mechanisms underlying this resistance remain poorly understood. Methods: A systematic screen of 796 epigenetic regulators was performed to identify candidate genes associated with effector CD8⁺ T cell infiltration and clinical outcomes following chemoimmunotherapy in SCLC. This analysis integrated several public SCLC datasets, including single-cell RNA sequencing (scRNA-seq) data from 20 SCLC tumors, bulk RNA-seq data from the IMpower133 cohort, proteomic profiles from the TU-SCLC cohort, and an independent scRNA-seq dataset of 39 SCLC tumors. In vitro and in vivo functional experiments were conducted to investigate the role of the candidate genes in SCLC. Results: The epigenetic regulator TAF1 emerged as a key candidate, with its expression negatively correlating with effector CD8⁺ T cell infiltration in SCLC. Clinically, patients with low TAF1 expression in tumors showed better outcomes following atezolizumab-based chemoimmunotherapy, particularly in ASCL1-high tumors. Additionally, TAF1 expression was inversely correlated with MHC-I expression. Knockdown of TAF1 in SCLC cells restored MHC-I expression, suppressed tumor growth in immunocompetent mice, and increased CD8⁺ T cell infiltration. Conclusions: TAF1 functions as a potential epigenetic suppressor of MHC-I expression in SCLC. Targeting TAF1 may represent a promising therapeutic strategy to enhance immunotherapy efficacy in SCLC. Full article

Increasing evidence suggests pancreatic cancer develops within a host–microbe ecosystem in which microbial communities across anatomical niches interact with tumour biology, immune regulation, metabolism, and therapeutic response. This review examines pancreatic cancer through the lens of humans as holobionts, integrating evidence from the oral, gut, biliary, and intratumoural microbiomes. Epidemiological and sequencing studies demonstrate consistent microbial alterations across these niches in pancreatic cancer, including oral dysbiosis associated with periodontal pathogens, gut microbial shifts toward pro-inflammatory taxa, disease-specific biliary microbial signatures, and the presence of distinct intratumoural microbial communities. Mechanistic studies indicate that intestinal barrier disruption, microbial translocation, immune and metabolite signalling can influence tumour immune architecture, macrophage polarisation, T-cell infiltration, oncogenic signalling pathways, and chemotherapeutic metabolism, particularly inactivation by tumour-associated bacteria. Microbiome-driven shifts in immunometabolism can reprogramme immune-cell metabolic pathways, impairing effective T-cell activation, promoting tumour-supportive macrophage phenotypes. Emerging therapeutic strategies aim to modulate the microbiome–tumour axis, including dietary interventions, probiotics and immunonutrition, faecal microbiota transplantation, engineered microbial therapies, and microbiome-informed antibiotic strategies. While pre-clinical findings are compelling and early-phase clinical studies suggest feasibility, most evidence remains associative and heterogeneous across cohorts and methodologies. Understanding pancreatic cancer as a multi-site ecological system may help explain inter-patient variability in disease progression and treatment response. This could usher in a new era for therapeutic manipulation where future progress will depend on longitudinal, multi-omic, and interventional studies to determine whether microbiome-targeted strategies can produce clinically meaningful improvements in pancreatic cancer outcomes. Full article

Background: Kinkeliba (Combretum micranthum G. Don), commonly used in West African traditional pharmacopeia for its anti-inflammatory and gastrointestinal properties, remains poorly studied regarding its potential role in the prevention or treatment of ulcerative colitis. Objective: This study evaluated the therapeutic potential of the ethanolic extract of Combretum micranthum (EECM) in a murine model of chronic DSS-induced colitis. Methods: Male C57BL/6 mice were subjected to three cycles of 1.5% DSS administration over nine weeks to induce chronic colitis. EECM was administered orally at 50, 100, or 200 mg/kg during the final week. Disease severity was evaluated using the Disease Activity Index (DAI), colon length, biochemical and hematological markers, along with histopathological and immunohistochemical assessment of colonic tissue. Results: EECM treatment significantly improved clinical parameters and prevented colon shortening in chronic DSS-induced colitis. These improvements were associated with the restoration of serum biochemical and hematological profiles, along with reduced histopathological damage and preservation of colonic tissue architecture. Immunohistochemical analysis further demonstrated decreased CD3-positive T-lymphocyte infiltration in colonic tissue, suggesting modulation of local immune cell responses. Conclusions: These findings highlight the therapeutic potential EECM in ulcerative colitis and support further investigations to elucidate its mechanisms of action and evaluate its efficacy in future translational studies. Full article

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease linked to epidermal barrier dysfunction, Th2-skewed immune polarization, and disrupted gut microbiota homeostasis. While probiotic interventions show promise in managing AD, the mechanisms governing strain-specific efficacy—particularly systemic modulation via the “gut–skin axis”—remaining to be fully elucidated. Methods: This study systematically compared the oral therapeutic effects of three Lacticaseibacillus rhamnosus strains (MG-A047, MG-A054, and LGG) in a 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse model. Results: By integrating behavioral, histopathological, and serological assessments with 16S rRNA-based gut microbiota profiling and in vitro functional assays, this study offers a multidimensional evaluation of the strain-specific advantages and potential therapeutic mechanisms of three L. rhamnosus strains. The results demonstrate that MG-A054 most effectively alleviated cutaneous inflammation and pruritus, significantly reduced serum IgE and IL-4 levels, and attenuated epidermal hyperplasia and inflammatory cell infiltration (including mast cells and eosinophils). Mechanistically, this strain may directly inhibit hyaluronidase activity and mast cell degranulation, and specifically remodel the gut microbiota structure, thereby promoting a shift toward a healthier functional profile. Conclusions: These findings suggest that the superior efficacy of MG-A054 may be achieved through coordinated modulation of the gut–skin axis and related pathways. This study offers new mechanistic clues for understanding the strain-specific actions of probiotics and lays a preclinical foundation for the further development of MG-A054 as a potential targeted microecological therapy for AD. Full article

Background/Objectives: Immune aging has been associated with survival outcomes in patients with lung adenocarcinoma (LUAD), but its relevance within the tumor microenvironment (TME) remains unclear. Methods: Clinical, RNA-sequencing, and somatic mutation data from the TCGA LUAD cohort were analyzed. Immune aging score within the TME was quantified using a predefined blood-driven 121-gene immune aging signature (IAS-121), and patients were categorized into the lowest versus the highest IAS-121 tertiles. Immune cell composition in the TME was inferred using xCell. Overall survival (OS) was evaluated using Kaplan–Meier analysis, Cox proportional hazards models adjusted for age, sex, tumor stage, smoking status, and EGFR mutation status, and restricted cubic spline analysis to examine the dose–response relationship between IAS-121 and mortality risk. Sensitivity analyses comparing the highest versus lowest quartiles or higher than median versus lower than median of IAS-121 were performed. Two independent LUAD cohorts (GSE68465 and GSE50081) were employed for validation. Results: A total of 518 patients with LUAD from the TCGA cohort were analyzed. Restricted cubic spline analysis showed a linear association between IAS-121 and OS. Patients in the highest IAS-121 tertile showed significantly better survival than those in the lowest tertile in both the TCGA cohort (p < 0.001) and the external validation cohorts (p = 0.003). In multivariable-adjusted Cox models, the lowest IAS-121 tertile was associated with worse survival in TCGA (adjusted HR 1.87, 95% CI 1.20–2.92) and in the pooled external cohorts (adjusted HR 1.57, 95% CI 1.02–2.43). Subgroup analyses showed generally consistent associations across clinical strata. Tumors with higher IAS-121 exhibited lower CD8⁺ and CD4⁺ naïve T-cell enrichment but higher neutrophil infiltration. Conclusions: Immune aging within TME is associated with poorer survival in LUAD. Given this study is hypothesis-generating, further investigations integrating tissue- and blood-based measures of immune aging are warranted to clarify its clinical and biological implications. Full article

Background: Aberrant protein O-fucosylation mediated by protein O-fucosyltransferase 1 (POFUT1), has emerged as a hallmark of tumorigenesis that regulates key signaling pathways, including Notch, which is frequently dysregulated in cancers. Protein O-fucosylation, catalyzed by POFUT1, regulates Notch signaling and has been implicated in individual cancers, but its pan-cancer expression patterns, clinical significance, and relationship to tumor immunity remain incompletely characterized. Methodology: We conducted a multi-omics bioinformatics analysis using TCGA and other public datasets to evaluate POFUT1 expression across 33 cancer types (n > 10,000). Differential expressions, tumor stage correlations, and survival outcomes were assessed. Immune cell infiltration was estimated using SangerBox and TIMER algorithms, while promoter methylation patterns were analyzed through UALCAN. Functional enrichment and protein–protein interaction networks were constructed to elucidate functional mechanism. Western blot validation in prostate and ovarian cancer cell lines confirmed our computational analysis. Results: POFUT1 showed significant overexpression in 16 of 33 cancer types (FDR-adjusted p < 0.05), with the highest elevation in BRCA (breast invasive carcinoma; log2FC = 2.31) and LUAD (lung adenocarcinoma; log2FC = 2.1). A high POFUT1 expression correlated with poor overall survival in eight cancer types (HR range: 1.8–3.2, p < 0.01) and disease-free survival in seven cancers. POFUT1 levels positively correlated with myeloid-derived suppressor cells (MDSCs) infiltrating in 15 cancer types, while inversely correlated with natural killer T (NKT) cells presence in 15 cancers (mean R = −0.34, p < 0.05), indicating an association with immunosuppressive microenvironments. Promoter hypomethylation in tumors suggested epigenetic dysregulation as a potential driver of its overexpression. Western blot analysis confirmed POFUT1 protein upregulations in prostate and ovarian cancer cell lines (1.7–2.1-fold. p < 0.01), corroborating transcriptomic findings. Conclusion: This pan-cancer study establishes POFUT1 as a critical oncogenic factor linked to aggressive disease, immune evasion, and poor prognosis. Its consistent overexpression and functional impact highlight its potential as a biomarker and target for anticancer therapy. While these computational findings require experimental validation, POFUT1 emerges as a candidate biomarker warranting functional studies and potential therapeutic targeting. Full article

Diabetic kidney disease (DKD) affects approximately 40% of patients with diabetes mellitus and remains a leading cause of end-stage renal disease worldwide. Early diagnosis and identification of therapeutic targets are critical for improving patient outcomes, yet reliable biomarkers are lacking. This study integrated transcriptomic data from the Gene Expression Omnibus (GEO) database (GSE96804, GSE30528, and GSE142025) with machine learning algorithms and Mendelian randomization (MR) to identify diagnostic biomarkers for DKD. Differentially expressed genes (DEGs) were identified and intersected with key modules from weighted gene co-expression network analysis (WGCNA). Four machine learning methods—least absolute shrinkage and selection operator (LASSO), random forest (RF), support vector machine-recursive feature elimination (SVM-RFE), and extreme gradient boosting (XGBoost)—were applied for feature selection. Five hub genes (SPP1, CD44, VCAM1, C3, and TIMP1) were identified at the intersection of these approaches. Two-sample MR analysis using eQTL data from the eQTLGen Consortium and kidney function GWAS from the CKDGen Consortium provided evidence supporting potential causal associations between SPP1, C3, and TIMP1 expression and estimated glomerular filtration rate decline. Immune infiltration analysis via CIBERSORT estimated elevated proportions of M1 macrophages and activated CD4${}^{+}$ memory T cells in DKD samples, with all five hub genes showing correlations with macrophage infiltration. A diagnostic model based on these five genes achieved a cross-validated area under the receiver operating characteristic curve (CV-AUC) of 0.938 in the discovery dataset and AUC values of 0.917 and 0.889 in two independent external validation cohorts. Drug–gene interaction analysis identified 10 candidate compounds targeting the hub genes. These findings provide a computational framework for identifying candidate diagnostic biomarkers and generating hypotheses regarding potential therapeutic targets for DKD; however, all results are derived from in silico analyses and require experimental validation—including qPCR, immunohistochemistry, and prospective clinical cohort studies—before clinical applicability can be established. Full article

Background: Cellular senescence is a key regulatory mechanism in tumor initiation and progression, influencing cancer development through modulation of the cell cycle, the immune microenvironment, and inflammatory responses. However, the molecular characteristics and potential clinical value of senescence-related genes in lung adenocarcinoma (LUAD) have not been systematically elucidated. This study aimed to comprehensively characterize the expression patterns, molecular subtypes, and prognostic significance of cellular senescence-related genes in LUAD, and to identify key regulatory determinants. Methods: Transcriptomic data of cellular senescence-related genes were obtained from The Cancer Genome Atlas (TCGA) cohort, and integrated analyses were performed to characterize their mutational landscape, copy number variations, and differential expression profiles. Senescence-related molecular subtypes were established using consensus clustering, followed by gene set variation analysis (GSVA) for pathway enrichment and immune infiltration analyses. A prognostic risk model was subsequently constructed using LASSO-penalized Cox regression, and its predictive performance was systematically evaluated. Candidate key regulators were further prioritized through bioinformatic screening, identifying FOLR1 as a hub gene. The biological function of FOLR1 was validated by qRT–PCR, Western blotting, assessment in clinical specimens, and a subcutaneous xenograft tumor model in mice. Results: Cellular senescence-related genes in LUAD exhibited a high frequency of somatic mutations and copy number alterations, accompanied by marked transcriptional dysregulation. Based on the expression profiles of these genes, LUAD patients could be stratified into three distinct molecular subtypes with significantly different clinical outcomes. These subtypes displayed pronounced heterogeneity in pathway enrichment patterns and immune cell infiltration. The subsequently developed prognostic signature demonstrated robust predictive performance in both the training and validation cohorts. Functional assays showed that FOLR1 was significantly downregulated in LUAD tissues and cell lines; FOLR1 knockdown promoted tumor cell proliferation, whereas restoration of its expression or pharmacological intervention markedly suppressed tumor progression. Consistently, in vivo xenograft experiments further corroborated the tumor-suppressive role of FOLR1 in lung adenocarcinoma. Conclusions: This study systematically delineated the molecular landscape of cellular senescence-related genes in LUAD and elucidated their associations with the tumor immune microenvironment and patient prognosis. Moreover, FOLR1 was identified as a potential tumor suppressor and therapeutic target. These findings provide a theoretical basis for senescence-informed molecular stratification and the development of precision treatment strategies in lung adenocarcinoma. Full article

Multiple studies have demonstrated that the conjugation of various metal cores to a modified tamoxifen vector amplifies its antitumor activity, rendering such engineered structures effective even in triple-negative breast cancer (TNBC), a tumor subtype traditionally considered irrelevant for endocrine therapy. With a focus on TNBC cell line, this study shows that hybrids with Pd- and Cu- in comparison to Pt-based counterparts exerted an advanced cytotoxic profile in terms of sustained cytotoxicity throughout all tested periods, well synchronized with an intensive and prolonged oxidative burst measured by 4-amino-5-methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM), dihydroethidium (DHE), and dihydrorhodamine 123 (DHR-123) in the background. Translation to the orthotopic syngeneic mouse in vivo model confirmed their superiority toward Pt-based conjugates, as well as tamoxifen alone, with a more profound tumor-reducing potential of Cu-tamoxifen, which was finally restricted by its toxicity. Surprisingly, the tamoxifen vector per se, with an approx. 2-fold lower cytotoxic potential than Pt- and Cu-hybrids in vitro, showed exceptional tumor-reducing potential in vivo, profiled in the last days of the treatment period. Intensive infiltration of immune cells, preferentially lymphocytes, was observed in tumor samples from animals exposed to the tamoxifen vector, underscoring the ligand’s immune potential and again suggesting that cytotoxicity is not a measure of successful treatment. Full article

Glioblastoma (GBM) is characterized by hypoxia-driven metabolic adaptation and profound therapeutic resistance. Ferroptosis, an iron-dependent lipid peroxidation-related cell death process, has emerged as a potential vulnerability; however, its relationship with hypoxia signaling remains incompletely defined. In this study, we performed integrative transcriptomic and single-cell RNA sequencing analyses to investigate the relationship between hypoxia signaling and ferroptosis-related gene signatures in GBM. Intersection analysis of hypoxia-associated differentially expressed genes and curated ferroptosis-related gene sets identified 29 core candidate genes. FerroScore stratification revealed that tumors with higher ferroptosis-related transcriptional signatures were significantly associated with poor overall survival. Among these genes, HILPDA emerged as a hypoxia-associated gene consistently linked to ferroptosis-related gene expression patterns and immune-related transcriptional programs. HILPDA expression showed significant correlations with iron-ROS axis components, including HMOX1, NOX4, and STEAP3, and was associated with immune microenvironment changes characterized by T cell depletion and inflammatory infiltration. Single-cell RNA-seq analysis further supported the cellular-level association between HILPDA expression and hypoxia-related transcriptional states. Structural equation modeling suggested that the relationship between HILPDA expression and ferroptosis-related gene signatures may be mediated through hypoxia-related pathways. Collectively, these findings indicate a transcriptomic association between hypoxia signaling and ferroptosis-related gene signatures in GBM and identify HILPDA as a candidate gene associated with this axis. Full article