Search Results (2,834)

Glioblastoma (GBM) is a highly aggressive brain tumor marked by invasive growth and therapy resistance. Tumor cells adapt to hostile conditions, such as hypoxia and nutrient deprivation, by activating survival mechanisms including autophagy and metabolic reprogramming. Among GBM-associated changes, hypersialylation, particularly, the aberrant expression of polysialic acid (PSA), has been linked to increased plasticity, motility, and immune evasion. PSA, a long α2,8-linked sialic acid polymer typically attached to the NCAM, is abundant in the embryonic brain and re-expressed in cancers, correlating with poor prognosis. Here, we investigated how PSA expression was regulated in GBM cells under nutrient-limiting conditions. Serum starvation induced a marked increase in PSA-NCAM, driven by upregulation of the polysialyltransferase ST8SiaIV and an autophagy-dependent recycling of sialic acids from degraded glycoproteins. Inhibition of autophagy or sialidases impaired PSA induction, and PSA regulation appeared dependent on p53 function. Immunohistochemical analysis of GBM tissues revealed co-localization of PSA and LC3, particularly around necrotic regions. In conclusion, we identified a novel mechanism by which GBM cells sustain PSA-NCAM expression via autophagy-mediated sialic acid recycling under nutrient stress. This pathway may enhance cell migration, immune escape, and stem-like properties, offering a potential therapeutic target in GBM. Full article

Although PD-1/PD-L1 inhibitors have transformed cancer immunotherapy, a substantial proportion of patients derive no clinical benefit due to resistance driven by the tumour microenvironment (TME). Transforming growth factor-β (TGF-β) is a key immunosuppressive cytokine implicated in this resistance. Several bifunctional antibodies that co-target PD-1 and TGF-β signalling have entered clinical trials and shown encouraging efficacy, but the mechanistic basis of their synergy is not fully understood. Here, we engineered 015s, a bifunctional fusion antibody that simultaneously targets murine PD-1 and TGF-β and evaluated its antitumour efficacy and mechanistic impact in pre-clinical models. Antibody 015s exhibited high affinity, dual target binding, and the effective inhibition of PD-1 and TGF-β signalling. In vivo, 015s significantly suppressed tumour growth compared with anti-mPD-1 or TGF-β receptor II (TGF-βRII) monotherapy. When combined with the CD24-targeted ADC, 015s produced even greater antitumour activity and achieved complete tumour regression. Mechanistic studies demonstrated that 015s significantly reduced tumour cell migration and invasion, reversed epithelial–mesenchymal transition (EMT), decreased microvascular density, and attenuated collagen deposition within the TME. Antibody 015s also decreased bioactive TGF-β1 and increased intratumoural IFN-γ, creating a more immunostimulatory milieu. These findings support further development of PD-1/TGF-β bifunctional antibodies for cancers with high TGF-β activity or limited response to immune checkpoint blockade. Full article

Gastrointestinal (GI) cancers represent a significant global health burden, with high morbidity and mortality often linked to late-stage detection and metastatic disease. The progression of these malignancies is critically driven by angiogenesis, the formation of new blood vessels, and the surrounding dynamic tumor microenvironment (TME), a complex ecosystem comprising various cell types and non-cellular components. This comprehensive review, based on a systematic search of the PubMed database, synthesizes the existing literature to define the intertwined roles of angiogenesis and the TME in GI tumorigenesis. The TME’s influence creates conditions favorable for tumor growth, invasion, and metastasis, but sometimes induces resistance to current therapies. Available therapeutic strategies for inhibiting angiogenesis involve antibodies and oral tyrosine kinase inhibitors, while immune modulation within the tumor microenvironment is mainly achieved through checkpoint inhibitor antibodies and chemotherapy. Creative emerging strategies encompassing cellular therapies, bispecific antibodies, and new targets such as CD40, DLL4, and Ang2, amongst others, are focused on inhibiting proangiogenic pathways more profoundly, reversing resistance to prior drugs, and modulating the TME to enhance therapeutic efficacy. A deeper understanding of the complex interactions between components of the TME is crucial for addressing the unmet need for novel and effective therapeutic interventions against aggressive GI cancers. Full article

Staphylococcus aureus is a Gram-positive bacterium that causes significant human morbidity and mortality. The capacity of S. aureus to cause disease is primarily attributed to an array of virulence factors produced by this pathogen that collectively overcome immune defenses and promote survival in a variety of host tissues. These include an arsenal of different cytotoxins that compromise plasma membrane integrity, with the specificity of each dependent upon the host organism and cell type. S. aureus encounters a variety of peripheral blood cell types during infection that play important roles in maintaining homeostasis and defending against microbial invasion, namely erythrocytes, thrombocytes, and leukocytes. S. aureus targets each of these cell types with specific cytotoxins to successfully establish disease. This review summarizes our current understanding of the susceptibility of different human peripheral blood cell types to each of these cytotoxins. Full article

Breast milk can provide passive immunity to infants, serving as a valuable source of maternal antibodies while remaining a non-invasive sample for investigating maternal immune responses. To date, no studies have evaluated SARS-CoV-2 and potentially cross-reactive HCoV antibodies in breast milk following bamlanivimab administration. A 36-year-old postpartum female was PCR-positive for SARS-CoV-2 four days post-delivery. Bamlanivimab was administered intravenously two days later. Breast milk was collected before bamlanivimab infusion, daily for two weeks post-infusion, then weekly until 102 days post-infusion. Mother and infant sera were collected only at 102 days post-infusion. All milk and serum samples were tested for IgG antibodies against SARS-CoV-2 and HCoV. We observed two distinct SARS-CoV-2 antibody peaks at days 3 and 29 post-infusion, likely representing bamlanivimab transfer and the post-infection antibody response. Beta-HCoV antibodies showed two peaks at days 6 and 29, potentially representing backboosted beta-HCoV responses and/or antibody cross-reactivity with SARS-CoV-2. Infant seropositivity for SARS-CoV-2 102 days post-infusion may represent antibodies from passive transfer via breastfeeding or a subclinical infection. This case highlights the value of breast milk as a non-invasive and repeatable sample to help understand maternal immune responses post-infection, exogenous antibody infusion, and passive antibody transfer during breastfeeding, which can provide insights into maternal–infant health research. Full article

Mitomycin C (MMC) is a widely employed chemotherapeutic agent, particularly in non-muscle invasive bladder cancer (NMIBC), where it functions by inducing DNA cross-linking and promoting tumor cell apoptosis. However, the tumor microenvironment (TME) significantly influences the therapeutic efficacy of MMC. Among the key regulators within the TME, the complement system and the coagulation pathway play a crucial role in modulating immune responses to cancer therapies, including MMC. This article explores the interaction between platinum nanoparticles (PtNPs) with human serum (HS) of NMIBC patients (T1 and Ta subtypes) at three different points: before the chemotherapy instillation of MMC (t₀) and three (t₃) and six months (t₆) after the treatment with MMC. This novel nanoproteomic strategy allowed the identification of a TME proteomic signature associated with the response to MMC treatment. Importantly, two proteins involved in the immune response were found to be deregulated across all patients (T1 and Ta subtypes) during MMC treatment: prothrombin (F2) downregulated and complement component C7 (C7) upregulated. By understanding how these biomarker proteins interact with MMC treatment, novel therapeutic strategies can be developed to enhance treatment outcomes and overcome resistance in NMIBC. Full article

Background/Objectives: Mucosal vaccines, delivered intranasally or via inhalation, are being studied for respiratory infectious diseases like COVID-19 and influenza. These vaccines aim to provide non-invasive administration and strong immune responses at infection sites, making them a promising area of research. This systematic review and meta-analysis assessed their immunogenicity, safety, and protective efficacy. Methods: The study design was a systematic review and meta-analysis, searching PubMed and Cochrane databases up to 30 May 2025. Inclusion criteria followed the PICOS framework, focusing on mucosal vaccines for COVID-19, influenza, RSV, pertussis, and tuberculosis. Results: A total of 65 studies with 229,614 participants were included in the final analysis. Mucosal COVID-19 vaccines elicited higher neutralizing antibodies compared to intramuscular vaccines (SMD = 2.48, 95% CI: 2.17–2.78 for wild-type; SMD = 1.95, 95% CI: 1.32–2.58 for Omicron), with varying efficacy by route (inhaled VE = 47%, 95% CI: 22–74%; intranasal vaccine VE = 17%, 95% CI: 0–31%). Mucosal influenza vaccines protected children well (VE = 62%, 95% CI: 30–46%, I² = 17.1%), but seroconversion rates were lower than those of intramuscular vaccines. RSV and pertussis vaccines had high seroconversion rates (73% and 52%, respectively). Tuberculosis vaccines were reviewed systemically, exhibiting robust cellular immunogenicity. Safety was comparable to intramuscular vaccines or placebo, with no publication bias detected. Conclusions: Current evidence suggests mucosal vaccines are immunogenic, safe, and protective, particularly for respiratory diseases. This review provides insights for future research and vaccination strategies, though limitations include varying efficacy by route and study heterogeneity. Full article

T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion. Full article

Background: Pneumococcal disease is a significant health burden, particularly among older adults and individuals with chronic conditions. Sequential pneumococcal vaccination (PCV13 followed by PPSV23) has been recommended in Italy since 2017 for its demonstrated efficacy, safety, and cost-effectiveness in preventing invasive pneumococcal disease (IPD). Nevertheless, limited data are available on the sequential pneumococcal vaccination coverage in Italy. This study aimed to evaluate the coverage and trends of sequential pneumococcal vaccination among individuals who turned 65 years old within the Viterbo Local Health Authority between 2018 and 2023. Methods: A retrospective cohort study was conducted using data from the Regional Vaccination Registry (AVR), a comprehensive digital vaccination dataset. Vaccination coverage was calculated based on individuals completing the sequential pneumococcal vaccination within two years after turning 65 years old. Trends as well as subgroup variations based on sex, citizenship, district of residence, and municipality size were analyzed. Results: Among 27,657 individuals who turned 65 years of age during the study period, only 2.32% completed the sequential pneumococcal vaccination. Coverage increased steadily from 2018 (0.60%) to a peak in 2020 (3.27%), followed by a plateau and a decline in 2023 (2.53%). Coverage varied across demographic and geographic subgroups: females (2.58%) had higher coverage than males (2.04%), Italian citizens (2.45%) exceeded foreign residents (0.64%), and residents in District C (3.03%) led over District A (1.08%). Smaller municipalities (≤10,000 inhabitants) showed higher coverage (2.52%) than larger ones (1.98%). Conclusions: Adherence to sequential pneumococcal vaccination has been very low throughout the considered study period. This is highly relevant information to consider in the view of new available pneumococcal vaccines for immunization of the elderly. Furthermore, geographic and demographic differences highlight the need for targeted public health interventions. Full article

Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management. Full article

The interleukin-20 (IL-20) cytokine subfamily, a subset of the IL-10 superfamily, includes IL-19, IL-20, IL-22, IL-24, and IL-26. Recently, their involvement in cancer biology has gained attention, particularly due to their impact on the tumor microenvironment (TME). Notably, IL-20 subfamily cytokines can exert both pro-tumorigenic and anti-tumorigenic effects, depending on the context. For example, IL-22 promotes tumor growth by enhancing cancer cell proliferation and protecting against apoptosis, whereas IL-24 demonstrates anti-tumor activity by inducing cancer cell death and inhibiting metastasis. Additionally, these cytokines influence macrophage polarization—an essential factor in the immune landscape of tumors—thereby modulating the inflammatory environment and immune evasion strategies. Understanding the dual role of IL-20 subfamily cytokines within the TME and their interactions with cancer cell hallmarks presents a promising avenue for therapeutic development. Interleukin-20 receptor antagonists are being researched for their role in cancer therapy, since they potentially inhibit tumor growth and progression. This review explores the relationship between IL-20 cytokines and key cancer-related processes, including growth and proliferative advantages, angiogenesis, invasion, metastasis, and TME support. Further research is necessary to unravel the specific mechanisms underlying their contributions to tumor progression and to determine their potential for targeted therapeutic strategies. Full article

Hemolin has been identified as a crucial immune gene in insect immune defense. The silkworm is susceptible to infections by pathogenic microorganisms when reared on artificial diets. In this study, through comparative analysis of the expression patterns of BmHemolin in silkworms fed on mulberry leaves and artificial diets, we found that the expression of BmHemolin was significantly upregulated in silkworms reared on artificial diets, and this upregulation was highly likely induced by pathogenic microorganisms. Further interaction analysis revealed that BmHemolin could bind to pathogenic microorganisms and form aggregates. Meanwhile, BmHemolin enhanced the melanization and aggregation of hemocytes. Subsequent in vitro antibacterial experiments showed that BmHemolin had the ability to inhibit the growth of Escherichia coli. In vivo clearance experiments demonstrated that BmHemolin facilitated the clearance of pathogens in the body. Moreover, CRISPR/Cas9-mediated knockout of the BmHemolin gene led to the downregulation of antimicrobial peptides and phagocytosis-related factors, while an excess of BmHemolin could enhance the expression of these genes, thereby improving the silkworm’s immune resistance to Enterococcus mundtii and increasing survival rates. In summary, our research demonstrates that BmHemolin played a pivotal role in both humoral and cellular immunity in the silkworm, thereby defending against pathogen invasion. Full article

Background/Objectives: The number needed to vaccinate (NNV) is a metric commonly used to evaluate the public health impact of a vaccine as it represents the number of individuals that must be vaccinated to prevent one case of disease. Traditional calculations may underestimate vaccine benefits by neglecting indirect effects and duration of protection (DOP), resulting in NNV overestimation. This study evaluated the NNV for the pediatric 20-valent pneumococcal conjugate (PCV20) US immunization program, as compared to PCV13, with a unique approach to NNV. Methods: A multi-cohort, population-based Markov model accounting for indirect effects was employed to calculate the NNV of PCV20 to avert a case of pneumococcal disease, invasive pneumococcal disease (IPD), hospitalized non-bacteremic pneumonia (NBP), ambulatory NBP, and otitis media (OM), as well as to prevent antibiotic-resistant cases and antibiotic prescriptions. Results: The mean NNV over a 25-year time horizon to prevent one case of pneumococcal disease was 6, with NNVs of 854 for IPD, 106 for hospitalized NBP, 25 for outpatient NBP, and 9 for OM, 11 for a course of antibiotic, and 4 for resistant disease. The mean NNV per year decreased over time, reflecting the DOP and increasing indirect effects over time. Conclusions: This study presents a novel approach to NNVs and shows that relatively few vaccinations are required to prevent disease. The decrease in NNV over time highlights the necessity of including DOP and indirect effects in NNV calculations, ensuring a more realistic assessment of a vaccine’s impact. Full article

The transfer of passive immunity (TPI) is vital for newborn calf health and is typically assessed through blood sampling to measure serum or plasma IgG or total protein levels. Saliva offers a less invasive alternative. This study evaluated the potential of saliva for assessing TPI. Saliva and serum samples were collected from 20 calves at birth and on days 1, 2, and 7 of life to measure IgG, IgA, IgM, and total protein concentrations. Colostrum fed to the calves was also analyzed for gross composition and immunoglobulin content. Colostrum intake and composition were associated with saliva IgG (R² = 0.48; p = 0.019), saliva IgM (R² = 0.73; p = 0.02), and saliva total protein (R² = 0.41; p = 0.043). Serum IgG and IgA levels were predicted by saliva IgG (p < 0.001; R² = 0.33) and IgA (p < 0.001; R² = 0.13), respectively, though predictive accuracy varied by calf age (IgG: p < 0.001; R² = 0.40; IgA: p < 0.001; R² = 0.91). In conclusion, the results suggest that both saliva IgG and IgA concentrations could be used to predict IgG and IgA serum concentrations. Nevertheless, further studies are still needed to clarify the best time for sample collection. Full article

Background and Objectives: Flexible ureteroscopic surgery is a common minimally invasive procedure utilized for the management of various urological conditions. While effective, postoperative complications such as fever can occur, necessitating the identification of reliable biomarkers for early detection and management. In this study, we specifically evaluated the predictive performance of three preoperative hematologic indices: the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune–inflammation index (SII). Materials and Methods: By systematically comparing these biomarkers through receiver operating characteristic (ROC) curve analysis and logistic regression modeling, we aimed to identify the most accurate predictor of postoperative fever development. Our cohort included patients who developed postoperative fever, many of whom exhibited normal WBC counts, allowing us to evaluate the discriminatory power of alternative inflammatory biomarkers. Results: Among the 150 patients, 32 developed postoperative fever. Conventional WBC counts did not predict fever, with 91% of feverish individuals having normal WBC values. In the ROC curve analysis, NLR outperformed SII (AUC 0.847, cutoff 796) and PLR (AUC 0.743, cutoff 106), with an AUC of 0.996 at 2.96. A combined logistic model achieved 100% sensitivity and 91% specificity (AUC = 0.996). Conclusions: This study addresses a critical gap in perioperative monitoring by validating readily available complete blood count-derived ratios as clinically meaningful predictors of postoperative inflammatory responses. Full article