Search Results (25,580)

Neonatal defense against pathogens relies on maternal antibodies transferred both through the placenta (IgG) and through breast milk (primarily secretory IgA). Maternal IgG antibodies are transferred across the placenta to the fetus mainly via the neonatal Fc receptor (FcRn), which is expressed at high levels in placental syncytiotrophoblasts, and results in the acquisition of maternal-fetal IgG. Transplacental transfer via the FcRn pathway can provide therapeutic proteins and protective antibodies following maternal vaccination. However, maternal IgG antibodies can bind to vaccine antigens such as measles, tetanus, and poliovirus, resulting in rapid clearance through FcgRIIB-mediated inhibition and inadequate B cell activation. In this way, they can inhibit de novo immune responses and significantly reduce vaccine response. On the other hand, the interference that breast milk-derived antibodies may have on vaccine-induced immunity is still largely unknown. Vaccination against influenza, pertussis, and COVID-19 during pregnancy or lactation has been shown to induce the production of protective, pathogen-specific, secretory IgA and IgG antibodies in breast milk. Conversely, studies found that breast milk-derived antibodies of vaccinated mothers reduced vaccine-induced immunity in breastfed infants by accelerating the clearance of vaccine antigen, resulting in reduced antigen availability and reduced plasma cell formation after vaccination. Additional factors in middle- and low-income countries, including environmental (increased microbiome diversity, environmental intestinal dysfunction, malnutrition, co-infections) and breastfeeding practices, may exacerbate the interference effect of maternal antibodies. Current evidence supports that breastfeeding is associated with a reduced immunological response exclusively to the rotavirus vaccine. However, the limited evidence base to date precludes definitive conclusions regarding the role of breast milk-derived antibodies in modulating vaccine-induced immunity. Nevertheless, the evidence suggests that although maternal antibodies may theoretically reduce vaccine immunogenicity, the overall protective benefits of breastfeeding outweigh any potential interference with vaccine responses. Full article

Background/Objectives: Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality worldwide. Despite advances in treatment, outcomes for advanced CRC remain unsatisfactory due to uncontrolled proliferation, metastasis, and recurrence. This study investigated the anti-cancer effects of KMU-11342, an indolin-2-one-based multi-protein kinase inhibitor with previously reported anti-inflammatory properties, in human colorectal cancer models. Methods: The anti-cancer effects of KMU-11342 were evaluated in colorectal cancer cells and further investigated in three-dimensional (3D) spheroid and patient-derived organoid models. Cell proliferation, migration, apoptosis, and cell cycle progression were assessed. Kinase activity profiling and molecular docking analyses were performed to identify potential targets and characterize the underlying signaling pathways. Results: KMU-11342 significantly inhibited the proliferation and migration of CRC cells. It reduced CRC cell density by 58.9% and 83.3% at 0.5 and 1 μM, respectively. These effects were accompanied by G2/M cell cycle arrest and apoptotic cell death. In 3D models, spheroid formation was markedly reduced and stemness-related characteristics were diminished. Patient-derived CRC organoids also showed decreased viability, exhibiting 38.6% and 77.4% reductions at 1 and 2 μM, respectively. These effects were observed in a dose-dependent manner in both two-dimensional (2D) and 3D colorectal cancer models. Kinase activity profiling and molecular docking analyses identified glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase 1 (CDK1) as potential mediators of the anti-cancer effects of KMU-11342 through the p53/nuclear factor kappa B (NF-κB) and FoxO1 signaling axes, respectively. Conclusions: KMU-11342 exhibits potent anti-tumor activity against CRC through suppressing proliferation, migration, and stemness in both 2D and 3D models, including patient-derived organoids. Its effects may be mediated, at least in part, through modulation of GSK3β and CDK1 via the p53/NF-κB and FoxO1 signaling pathways. Full article

High-glucose exposure impairs intestinal metabolic homeostasis and barrier integrity in fish, but the transcriptional responses associated with high-glucose adaptation in fish intestinal epithelial cells remain incompletely understood. This study investigated whether exogenous 5-methylcytosine (5MC) alleviates high-glucose-induced metabolic and epithelial stress in grass carp (Ctenopharyngodon Idella) intestinal epithelial cells and whether these responses are associated with changes in DNA methyltransferase 3 beta (dnmt3b) expression and Caudal type homeobox 1b (cdx1b)/Sodium-glucose cotransporter 1 (sglt1)-related transcriptional responses. As exploratory in silico information, molecular docking predicted candidate complex conformations of DNMT3B with CDX1B and SGLT1, with binding energies of −37.2 and −25.9 kcal/mol, respectively. Functionally, dnmt3b knockdown significantly reduced dnmt3b, Interleukin 6 (il6), and Nuclear factor kappa B (nfκb) expression, while increasing cdx1b, sglt1, Solute carrier family 2 member 3a (slc2a3a), 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4a (pfkfb4a), and Amine oxidase copper containing 1 (aoc1) expression (p < 0.05). CDX2/CDX1B-like immunoreactive protein and SGLT1 protein levels were also increased after dnmt3b knockdown (p < 0.05). Under high-glucose stress, exogenous 5MC exerted concentration-dependent effects. Specifically, 6 mM 5MC significantly reduced residual extracellular glucose, lactate dehydrogenase and diamine oxidase activities, and malondialdehyde content, while increasing glutathione content, cell viability, and cell migration (p < 0.05). These effects remained detectable after replacement with high-glucose medium for an additional 12 h. By contrast, 24 mM 5MC markedly increased lactate dehydrogenase activity and reduced cell viability, suggesting potential cytotoxicity (p < 0.05). S-adenosylmethionine (SAM) levels were significantly lower in the NC and 6 mM groups than in the HG, 12 mM, and 24 mM groups, suggesting changes in SAM-related one-carbon metabolic status rather than direct evidence of altered DNA methylation (p < 0.05). Exogenous 5MC, particularly at 6 mM, alleviated high-glucose-induced metabolic and epithelial stress in grass carp intestinal epithelial cells. These effects were accompanied by changes in several glucose metabolism- and inflammation-related genes. However, the cellular uptake, metabolic fate, DNA incorporation, methylation consequences, and causal roles of these gene-expression changes remain to be further verified. Full article

Endothelial dysfunction is an early event in the development of cardiovascular diseases and is characterized by impaired barrier function, inflammatory activation of endothelial cells (ECs), and alterations in lipid metabolism. In addition to typical (mononuclear) endothelial cells (TECs), multinucleated variant endothelial cells (MVECs) are present within the vascular wall; however, their functional role remains poorly understood. The aim of the present study was to investigate the molecular and functional characteristics of MVECs and their potential contribution to the development of endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVECs) were used, and multinucleated cells were generated by polyethylene glycol-induced fusion. Cells were incubated under control conditions or exposed to low-density lipoproteins (LDL; 100 µg/mL, 24 h). A comprehensive analysis was performed, including transcriptomic and proteomic (secretome) profiling using gene set enrichment analysis (GSEA), as well as functional assays assessing transendothelial LDL transport, intracellular cholesterol accumulation, macrophage migration, and the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8). MVECs exhibited pronounced differences compared to TECs. GSEA revealed reduced enrichment of pathways related to canonical nuclear factor kappa B (NF-κB) signaling and negative regulation of NF-κB transcription factor activity, actin cytoskeleton organization, focal adhesion assembly, basement membrane organization, and vesicle-mediated transport in MVECs relative to TECs, indicating impaired cytoskeletal integrity, altered cell–matrix interactions, dysregulated inflammatory signaling, and reduced vesicular trafficking activity. Functionally, MVECs demonstrated an increased capacity for cholesterol accumulation and enhanced transendothelial migration of macrophages. Notably, transendothelial LDL transport across the MVEC monolayer was not increased, suggesting a predominance of intracellular lipid accumulation. MVECs also exhibited a pronounced pro-inflammatory phenotype, characterized by elevated expression and secretion of IL-6 and IL-8. Taken together, these findings indicate that MVECs represent a functionally altered endothelial phenotype with impaired barrier function, dysregulated lipid metabolism, and enhanced inflammatory activity. Local accumulation of MVECs within the vascular wall may contribute to the formation of pro-atherogenic regions and play a role in the initiation and progression of endothelial dysfunction. Full article

Fish are an important criterion for evaluating the quality of river ecosystems, and water flow characteristics may be the main factor affecting the living environment of fish. As the main component of a river, the topography of the bank slope has a significant impact on the characteristics of nearshore water flow. At the same time, eco-revetment structure has the functions of smoothing water flow, maintaining stable bank slopes, and improving river ecology. It can reset the distribution of nearshore water flow and provide a stable living environment for fish. This study focuses on the middle and lower reaches of the Yangtze River as the research area, with the main research object being grass carp. We construct a generalized model based on river morphology and flow characteristics. A new eco-revetment structure is proposed with the main research area of nearshore waters, aiming to improve the flow state of nearshore water and enhance its ecology. A suitability evaluation model for grass carp habitat was constructed based on Large Eddy Simulation and fuzzy mathematics theory, with water flow as the main habitat influencing factor. We study the distribution pattern of suitability for grass carp habitats near nearshore waters. The results indicate that the nitrogen phosphorus ratio near the top of the revetment structure is close to the Redfield value and can be used as a stable foraging area for fish. The flow rate is the dominant factor for the habitat of juvenile grass carp. When there is no vegetation, the suitability of region A is 0–0.4, the suitability of region B is 0.2–0.6, and the area proportion of the high suitability area (0.4–0.6) is maintained at 10–30% with the increase in the flow rate. Region C is not suitable for the long-term survival of juvenile grass carp. When there is vegetation, the suitability of region A ranges from 0 to 0.6, and the proportion of low-suitability areas decreases. The suitability of region B ranges from 0.4 to 0.6, and the proportion of suitable areas is positively correlated with flow velocity. The suitability of region C is consistent with the absence of vegetation. The dominant factors for fish spawning habitat are flow velocity, vorticity, and kinetic energy gradient. The spawning suitability zone (HSI ≥ 0.6) is located between the spanwise structures, with a proportion positively correlated with flow velocity and higher suitability on the deep-water side. The existence of fish has little impact on the habitat. In the juvenile fish habitat area, the proportion of areas suitable for juvenile fish in region A has slightly decreased, and the suitability of region B has increased. In spawning grounds, an HSI ≥ 0.6 accounts for about 5% of the decrease compared to no-fish conditions, and overall can meet the needs of fish habitat, foraging, and spawning. This article provides ideas and foundations for the design of future new eco-revetment structures and a suitability analysis of living environments for fish. Full article

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has fundamentally transformed the treatment landscape for relapsed and refractory B-cell malignancies, yet antigen escape remains a persistent therapeutic challenge that limits long-term remission durability. While antigen loss is typically considered a somatic event acquired during tumor evolution under therapeutic selective pressure, germline CD19 polymorphisms could theoretically influence CAR-binding kinetics, alter epitope presentation, and modulate therapeutic outcomes in ways that remain largely not characterized. Unfortunately, Middle Eastern populations are underrepresented in pharmacogenomic databases and CAR-T clinical trials, creating a knowledge gap that may perpetuate global health disparities in access to precision immunotherapy. We analyzed publicly available whole-exome sequencing data from 1196 individuals of Arab origin to comprehensively characterize CD19 variants with potential relevance to CAR T-cell immunotherapy. The L174V (rs2904880) variant stood out, and showed the Valine/Valine (V/V) genotype frequency was 65.3%, corresponding to a V174 allelic frequency of 76.6%, while the minor allele, L174, has a frequency of 23.4%. The missense mutation (c.520C > G) responsible for this variant results in a leucine-to-valine (L174V) substitution at position 174 of the CD19 protein, relative to the reference genome. The cohort genotypes (CC, CG, and GG) exhibited a significant deviation from Hardy–Weinberg equilibrium (p < 0.00001). While this deviation is consistent with the high consanguinity rates (25–60%) amongst Arab populations, it remains not fully explained, and may be attributed to population structure, relatedness, or technical factors. We further emphasize that our computational analysis cannot establish any direct clinical or functional impact due to this variant, and therefore we refrain from suggesting any specific actions at the current time. In light of these findings, we hypothesize that the distinctive genetic architecture of consanguineous populations should not be viewed as a confounding variable. Instead, it presents a unique opportunity to investigate the clinical relevance of germline variation in the context of precision oncology, particularly at therapy-relevant loci, pending functional validation. Full article

Background/Objectives: Y chromosome microdeletions in the azoospermia factor (AZF) regions are a major genetic cause of severe male infertility, yet their relationship with hormonal profiles in azoospermic men remains unclear. This study aimed to investigate AZF microdeletions and associated hormonal parameters in azoospermic patients. Methods: Azoospermic patients were screened for AZFa, AZFb, and AZFc microdeletions using multiplex real-time PCR targeting sequence-tagged site (STS) markers (sY84, sY127, and sY254). Patients were categorized into AZF-negative and AZF-positive groups, with the latter further stratified according to their deletion subtype. Serum follicle-stimulating hormone (FSH), testosterone, and inhibin B levels were measured. Hormonal parameters were compared between groups using the Mann–Whitney U test, and a logistic regression analysis was performed to evaluate associations between hormonal variables and AZF deletion status. Results: AZF microdeletions were detected in 18.7% (17/91) of patients. Patients without AZF deletions showed a median FSH level of 17.40 (7.12–31.27) IU/L. In contrast, AZFc deletion carriers exhibited an intermediate median FSH level of 21.10 (16.11–26.10) IU/L and lower median inhibin B concentrations (25.50 [25.25–26.00] pg/mL) compared with AZF-negative patients (56.00 [33.50–106.50] pg/mL). Median testosterone levels in AZFc patients (3.61 [2.87–4.35] ng/mL) remained within the expected physiological range. However, no statistically significant differences were observed between the AZF subgroups for age (p = 0.262), FSH (p = 0.506), testosterone (p = 0.615), or inhibin B (p = 0.524). The logistic regression analysis also showed no significant association between hormonal parameters and AZF deletion status. Conclusions: Hormonal parameters alone are insufficient to predict the presence of AZF microdeletions in azoospermic men. These findings highlight the importance of routine genetic screening for accurate diagnosis, clinical management, and reproductive counseling in male infertility. Full article

Background: Para-aortic lymph node involvement is present in approximately 17–24% of women with locally advanced cervical cancer (LACC) and is one of the strongest adverse prognostic factors in this population. Current international guidelines recommend two alternative staging techniques: the International Federation of Gynecology and Obstetrics (FIGO) and European Society of Gynecologic Oncology (ESGO) endorse imaging-based staging as the primary method to define radiation fields, whereas the National Comprehensive Cancer Network (NCCN) lists pre-treatment minimally invasive para-aortic lymphadenectomy as a Category 2B recommendation. Objective: We aimed to review and critically appraise the available evidence on the oncologic impact (progression-free and overall survival) of pre-treatment surgical para-aortic staging compared with clinical imaging-based staging in women with LACC. Methods: We searched MEDLINE (Ovid), Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.gov, and Scopus from inception to January 2026, complemented by manually searching the reference lists for relevant articles and prior reviews. The review focused on comparative studies of women with LACC of squamous, adenocarcinoma, or adenosquamous histology—operationally defined as FIGO 2009 stages IB2–IVA with pelvic nodal involvement or FIGO 2018 stages IB3–IVA who received definitive-intent radiotherapy with or without concurrent chemotherapy and brachytherapy, and for whom comparative survival outcomes between a surgical-staging arm and an imaging-staging arm were reported. For this manuscript, a narrative review style was planned and reported in line with SANRA (Scale for the Assessment of Narrative Review Articles) quality criteria. Results: Twelve studies were included: two randomized controlled trials and ten observational studies (nine retrospective cohorts and one population-based analysis). Surgical staging consistently increased detection of occult para-aortic disease and led to more frequent use of extended-field radiotherapy (18–44%), but it did not yield a reproducible advantage in terms of progression-free or overall survival over imaging-guided chemoradiation. Conclusions: In LACC, pre-treatment surgical para-aortic staging improves anatomic and prognostic information but has not shown a consistent survival advantage over imaging-based staging combined with contemporary chemoradiation. Current comparative evidence does not support routine surgical staging, and its use still warrants further prospective evaluation in large clinical trials. Until results from ongoing phase III trials are available, surgical staging should be considered an individualized option in highly selected cases within multidisciplinary decision-making at experienced clinical centers. Full article

Background: The kidney is an organ rich in peroxisomes, which play a pivotal role in fatty acid oxidation and ROS decomposition. Importantly, peroxisomal dysfunction contributes to the development and progression of various renal diseases. Therefore, we aimed to elucidate whether peroxisomes affect renal damage and fibrosis over time using a unilateral ureteral obstruction (UUO) mouse model. Methods: Expression levels of peroxisome-related factors and ROS- and hypoxia-related genes in UUO mice were measured in a time-dependent manner. Results: UUO led to renal damage and fibrosis progression over time; it significantly increased the protein expression levels of ATG5 and ATG7, while it decreased PMP70 and PEX14 protein expression. In particular, UUO increased the protein expression level of pexophagy receptor NBR1. Although the number of peroxisomes decreased, the protein expression levels of peroxisomal biogenesis-related proteins such as PEX11b, PEX16, and PEX19 remained constant. Decreased lipid metabolism due to reductions in ACOX1, DBP, and catalase caused by UUO and increased ROS production through peroxisomal degradation and mitochondrial antioxidant enzyme dysfunction were observed. Additionally, HIF-1α protein levels gradually increased in the UUO mice, whereas those of HIF-2α initially increased and then decreased. Conclusions: UUO is characterized by a progressive, chronological reduction in peroxisomal markers. Our findings indicate that peroxisomal degradation and associated metabolic dysfunction are tightly correlated with the progression of kidney injury and fibrosis, suggesting a potential involvement of compromised peroxisomal homeostasis in renal pathogenesis rather than proving a direct causal mechanism. Maintaining peroxisomal quality control may nevertheless represent a potential therapeutic avenue for chronic kidney disease. Full article

Acute liver failure (ALF) is characterized by a rapid decline in liver function, leading to metabolic and organ failure. This study employed liver metabolomics, Nuclear Factor kappa-B (NF-κB) signaling pathway analysis, and inflammatory factor profiling to investigate the therapeutic mechanisms of xanthoxylin in ALF. Xanthoxylin administration led to increased antioxidant levels and reduced markers of inflammation and tissue damage. Xanthoxylin downregulated the messenger RNA (mRNA) expression of Nitric Oxide Synthase (NOS), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-α (TNF-α), NF-κB, Inhibitor of NF-κB α (IκBα), and Toll-like receptor 4 (TLR4), and inhibited the protein expression of p-p38 and p-p65 while upregulating B-cell CLL/Lymphoma 2 (Bcl-2) and B-cell Lymphoma-x (Bcl-xl). Metabolomic analysis identified 41 differentially expressed metabolites, 20 of which showed strong correlations with pharmacodynamic parameters. These 20 candidate metabolite signatures are involved in amino acid and carboxylic acid metabolic pathways, with potential links to glycolysis and the tricarboxylic acid (TCA) cycle. Together, these findings suggest that xanthoxylin exerts therapeutic effects against ALF by modulating the IκBα/NF-κB signaling pathway and related metabolic pathways, providing a scientific basis for understanding its multi-target mechanism. Full article

Traditional air conditioning consumes substantial electricity, exacerbates the urban heat island effect, and creates a maladaptive feedback loop, necessitating a shift toward passive-first net-zero pathways. This study takes a typical six-story residential building in Nanjing’s hot summer and cold winter climate zone as a case study. Using EnergyPlus hourly simulations, three progressive passive strategy packages are designed to quantify the impact of building envelope heat exchange on cooling loads, grid stress, and heat resilience. Package A includes external shading and natural ventilation. Package B adds reflective coating and a green roof. Package C further adds night ventilation precooling and high-performance windows. The results show that Package C achieves a 62.5% reduction in peak cooling load and a 63.0% reduction in seasonal cooling load. Daytime peak inward heat gain decreases from 68 W/m² to 22 W/m², while nighttime outward heat dissipation increases from 12 W/m² to 38 W/m². Under an extreme heat day of 41.2 °C with no active cooling, indoor peak temperature drops from 36.8 °C to 29.4 °C, and heat risk hours decrease by 73.6%. Peak-hour power demand is reduced by 70.4%, with a systemic leverage factor of 1.08. Innovations include achieving over 60% load reduction using only mature passive strategies, introducing the systemic leverage factor to quantify urban heat island mitigation benefits, and establishing a vulnerability-to-resilience transformation framework. The passive-first pathway validates building envelope as the first line of defense for net-zero futures. However, the findings are based on a typical six-story residential building in Nanjing and require validation through field measurements or broader application across different climate zones and building typologies before generalization. Full article

Candidozyma auris (formerly known as Candida auris) has emerged as a formidable clinical fungal pathogen as a result of its multidrug resistance and persistent colonization capabilities. In this study, three clinical C. auris strains (namely C. auris strain 01, C. auris strain 03, and C. auris strain 13) with distinct origins were characterized to investigate their phenotypic variations and mechanisms of azole resistance. Comprehensive profiling revealed significant inter-strain differences in biofilm formation, cell surface hydrophobicity, adhesion capacity, and phospholipase activity. Testing for antifungal susceptibility showed that the three clinical strains exhibited different minimum inhibitory concentrations for multiple azoles (fluconazole, voriconazole, and itraconazole) and echinocandins (anidulafungin and micafungin). Sequencing identified Y132F mutations in the ERG11 gene of the three clinical strains. Mechanistic investigations demonstrated that fluconazole exposure significantly upregulated the expression of efflux pump genes (CDR1 and CDR2) and the genes encoding their transcriptional regulators (MDR1 and TAC1b). In a murine skin colonization model, comparing data from the standard strain C. auris strain CBS12766 and clinical strains of C. auris strain 03 and C. auris strain 13 exhibited a significantly higher fungal burden of tissue, whereas strain C. auris strain 01 showed an intermediate level. Host immunity response analysis revealed that expression of the IL-1β gene was significantly elevated in C. auris strain CBS12766-infected mice, while expression of IL-6 and CXCL-1 genes was predominantly increased in the C. auris strain 01, with TNF-α gene expression levels being comparable across all strains. Histopathological examination confirmed local infiltration of inflammatory cells and mild epidermal edema, indicating active host immune engagement. Overall, our findings highlighted substantial phenotypic heterogeneity, different colonization capacities, and differences in expression of inflammatory cytokines among the C. auris strains. Further investigations into fluconazole-response mechanisms identified enhanced efflux pump activity, along with ERG11 gene Y132F mutations and transcription factor modulation among these clinical strains. Full article

Background/Objectives: Small quantities of gastric parietal cell-derived Intrinsic Factor (IF) are present in circulation. Here, we explore circulating concentrations of IF in different medical conditions affecting the stomach, anticipating finding both low and high concentrations depending on the state of the parietal cells. Methods: We measured serum IF in (I) patients before and after bariatric surgery; (II) patients diagnosed with portal hypertension; and (III) patients with suspected pernicious anemia referred for measurement of IF autoantibodies. Results: Patients undergoing bariatric surgery (n = 25) showed a significant drop in serum IF following surgery. Their median serum IF declined from 5.1 pmol/L (pre-surgery) to 3.3 pmol/L (two months post-surgery), and nine out of 25 patients showed serum IF concentrations below reference interval (1.7–11.6 pmol/L). Most patients with portal hypertension (n = 18) showed normal serum IF concentrations, but with unexpectedly high concentrations up to 30 pmol/L in a few patients. Out of 120 patients referred for measurement of IF autoantibodies, 10 patients showed IF concentrations below the reference interval. Three out of four patients with IF autoantibodies showed low concentrations of circulating IF. Conclusions: Our study shows a decline in circulating IF following bariatric surgery consistent with the known decline in vitamin B12 uptake in these patients. Both high and low concentrations were observed in the other two groups. Future longitudinal studies are needed to illuminate possible usefulness for measurement of circulating IF. Full article

Nectin-4 has emerged as a clinically relevant target in muscle-invasive bladder cancer (MIBC), primarily because of its role in antibody–drug conjugate-based therapies. However, the broader biological context of Nectin-4 expression and its association with tumor-promoting signaling pathways in MIBC remain insufficiently characterized. In this single-institution study, Nectin-4 expression (H-score 0–300) was assessed by immunohistochemistry in two independent MIBC cohorts. Associations between Nectin-4 expression and key markers related to growth signaling, metabolic regulation, and inflammation were analyzed alongside clinicopathological characteristics. Nectin-4 expression was significantly higher in malignant tissue than in non-malignant tissue (p = 0.0016 and p = 0.0302, respectively). Nectin-4 expression was not associated with demographic or clinicopathological parameters; however, a trend toward lower expression in more advanced disease stages was observed. Significant positive correlations were identified between Nectin-4 expression and protein kinase B (p = 0.0004), cytoplasmic (p = 0.0115) and membranous somatostatin receptor 2 (p = 0.0125), insulin receptor substrate 1 (p = 0.03), and interleukin-1 receptor antagonist (IL-1RA; p = 0.0045). In contrast, a negative correlation was observed with the IL-1β/IL-1RA ratio (p = 0.0246). Although Nectin-4 expression was not significantly associated with cancer-specific or overall survival, a trend toward shorter relapse-free survival was observed in patients with lower Nectin-4 expression (p = 0.0531). In multivariate analysis, patient age, but not Nectin-4 expression, emerged as an independent prognostic factor. Although Nectin-4 expression does not appear to have independent prognostic value, its biological associations suggest that it reflects an integrated tumor-related signaling context. These findings support further investigation of Nectin-4 as part of rational, biology-driven therapeutic strategies in bladder cancer. Full article

Glioblastoma (GBM), a highly aggressive brain tumor, is characterized by poor treatment outcomes and a strong tendency to recur after therapy. Therapy-induced senescence (TIS) of GBM cells has emerged as a key driver of GBM progression and relapse. Temozolomide (TMZ), which serves as the standard chemotherapeutic agent for GBM, is known to induce senescence; however, the molecular mechanisms underlying this process remain largely unknown. In this work, we found that interferon regulatory factor-1 (IRF1) was downregulated in TMZ-induced senescent GBM cells. Functionally, knockdown of IRF1 increased the activity of senescence-associated β-galactosidase (SA-β-gal), reduced protein expression of Lamin B1, inhibited cell division, and enhanced senescence-associated secretory phenotype (SASP) of GBM cells, indicating that downregulation of IRF1 promotes senescence of GBM cells. Conversely, overexpression of IRF1 partially reversed TMZ-induced senescence. Further exploration revealed that downregulation of IRF1 reduced the expression of 2′,5′-oligoadenylate synthetase 2 (OAS2), and overexpression of IRF1 increased the expression of OAS2. OAS2 was also downregulated in TMZ-induced senescent GBM cells, and knockdown of OAS2 induced senescence of GBM cells as well. Taken together, our study reveals that IRF1 inhibits TMZ-induced senescence of GBM cells through OAS2, highlighting a novel regulatory axis that may offer potential therapeutic targets for improving GBM treatment. Full article