Search Results (6,164)

Cancer immunoprevention leverages the immune system’s surveillance mechanisms to mitigate tumor development. Vaccines that constitute a tumor antigen and an immune adjuvant are perceived as immunoprevention modalities. However, relevant tumor antigens are unknown for non-viral cancers, which constitute most human cancers. Our group has recently shown that SA–4–1BBL, a novel agonist of CD137 receptor, but not antibodies, shows immunoprevention efficacy against various tumors. Advanced bioinformatics analyses of bulk RNA-seq data were conducted to elucidate mechanisms underlying cancer immunoprevention. Mice received subcutaneous injections of SA–4–1BBL or agonistic 3H3 antibody, and the injection-site tissue (IS) and draining lymph nodes (LN) were analyzed for differential gene expression. SA–4–1BBL induced a compartmentalized and temporally dynamic immune program characterized by early effector activation at IS and sustained immune regulation in draining LN. K-means clustering of 4564 DEGs identified eight functionally distinct clusters. IS-enriched clusters contained activation genes for CD4⁺ T and NK cells, including Cd28, Klra1, Cd4, Cd40, and Cd40l, while LN clusters were enriched for regulatory genes (Tnfaip3, Irf5, Col1a2) that ensure immune priming and homeostatic restraint for a balanced response. SA–4–1BBL generated a more selective and durable activation of adaptive immunity, TCR signaling, Th1/Th2 differentiation, and NK cytotoxicity. 3H3 activated broader innate inflammatory programs, including Toll-like receptor and neurodegeneration-linked pathways. IMPRes analysis showed that SA–4–1BBL activates sequential immune-regulatory circuits centered on Stat1, Cd247, and Ifng and modulates the CD151–TGF-β axis. These findings demonstrate that SA–4–1BBL elicits a balanced immune response, ensuring both safety and efficacy in preventing cancer development. Full article

Background/Objectives: Upper respiratory tract infections (URTIs) and exercise-induced immune perturbations are common in adults and may adversely affect quality of life, productivity, and physical performance. Immunoglobulin Y (IgY), a food-derived antibody with broad antimicrobial activity, has demonstrated immunomodulatory potential in preclinical and limited clinical studies. This study evaluated the effects of a multi-pathogen-specific IgY supplement (Muno-IgY) on respiratory health, immune and inflammatory markers, exercise-induced physiological stress, and gut microbiome composition in healthy adults. Methods: In this 12-week, double-blind, placebo-controlled trial, 28 healthy adults with a history of URTI were randomly allocated to receive Muno-IgY or placebo and URTI incidence, duration, and severity were recorded daily. Serum immune and inflammatory biomarkers were assessed longitudinally and in response to a standardized exercise challenge. Gut microbiome composition was analyzed using shotgun metagenomic sequencing at baseline and week 12. Safety and tolerability were assessed throughout the study. Results: URTI incidence was lower in the Muno-IgY group compared with placebo (14.3% vs. 35.7%), with shorter average duration and fewer missed workdays, though differences were not statistically significant (p > 0.05). Following an acute exercise challenge, Muno-IgY supplementation resulted in a significant increase in serum IgA at 24 h post-exercise (p = 0.022) and a significantly greater reduction in lactate dehydrogenase at 1 h post-exercise compared with placebo (p < 0.0001). Exploratory gut microbiome analyses suggested favorable directional shifts, though these changes were not statistically tested. Conclusions: In this exploratory pilot study, Muno-IgY supplementation was safe and associated with significant improvements in selected markers of exercise-induced immune response and muscle damage. Numerical trends in URTI incidence and gut microbiome composition were observed but were not statistically significant. These findings are hypothesis-generating and support further evaluation of Muno-IgY in larger, adequately powered clinical trials. Full article

Background/Objectives: The mechanisms leading to oxidative stress and cellular dysfunction during stroke are not well understood. Methods: We tested if transient cerebral artery occlusion (MCAo) in mice results in the generation of oxidized phospholipids (OxPLs) that contribute to neuronal cell death and glial activation. Results: Both in vitro and in vivo cerebral ischemia and reperfusion injury (IRI) resulted in the elevation of specific OxPLs. Neuronal cell death was determined in the presence of OxPLs and the natural OxPL E06 antibody (antioxidized phospholipid antibody) protected the cells from the toxic effects. IRI in mice gave rise to increased immunoreactivity of OxPLs in the brain. E06 reduced inflammatory markers in the brain following IRI, including iba-1, GFAP and inflammatory cytokines. In addition, OxPLs gave rise to M1 and Mox microglial phenotypes which was reversed in the presence of E06 and elicited a more M2 phenotype. Nrf2-deficient mice showed increased infarct volumes and microglia from Nrf2^−/− mice showed a reduction in Mox gene expression, and E06 protects both mice and cells from the Nrf2-deficit. Finally, AB1-2 Ab which recognizes the E06 Ab, ameliorates the impact of E06 Ab on infarct volume in the mouse model. Conclusions: Taken together, the data indicate that OxPLs play an important role in inflammation and neuronal cell loss in cerebral IRI and inactivation of OxPLs may provide novel targets for potential drug targets in the treatment of stroke. Full article

Transcriptomic analyses of public datasets (TCGA and GTEx) revealed that both CD74 and Cathepsin L (CTSL) are significantly overexpressed in diffuse large B-cell lymphoma (DLBCL) compared to normal tissues, and that their expression levels are highly correlated to each other (Spearman R = 0.64, p = 3 × 10⁻⁴⁶). Kaplan–Meier analysis showed that elevated expression of both genes is associated with reduced overall survival (OS), defining a high-risk CD74+/CTSL+ DLBCL subgroup. This is the first study demonstrating coordinated overexpression of CD74 and CTSL and proposing their dual targeting via antibody–drug conjugates (ADCs) to improve outcomes in relapsed or refractory DLBCL. Cysteine cathepsins, a family of proteases, are upregulated in many cancers, facilitating tumor invasion and metastasis. Cathepsins are overexpressed and play key roles in DLBCL progression. GB111-NH₂, a potent broad-spectrum cathepsin inhibitor, significantly reduced cathepsin activity in lymphoma cell lines and patient samples. GB111-NH₂ treatment increased apoptosis and caspase-3 activation in DLBCL patient cells and chronic lymphocytic leukemia (CLL) mononuclear cells. Here, we developed a modified cathepsin inhibitor, M-GB, containing a maleimide linker for site-specific antibody conjugation. While M-GB alone has poor cell permeability, when conjugated to an antibody, it forms an ADC (M-GB–ADC) that selectively induces lymphoma cell death. One M-GB–ADC demonstrated high specificity for CD74-expressing lymphoma cells while exhibiting minimal toxicity to non-target cells in vitro. Our findings highlight the potential of another M-GB–ADC as a targeted therapy for overcoming rituximab resistance and treatment failure in DLBCL. This strategy enhances therapeutic efficacy and represents a preclinical proof-of-concept treatment option by directing a cathepsin-inhibitor payload specifically to malignant B cells. Full article

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005–May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21^CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1–dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers. Full article

Background/Objectives: Porcine epidemic diarrhea virus (PEDV), particularly the emerging GII genotype, poses a severe threat to the swine industry in affected regions, primarily in Asia. Current vaccines based on classical strains often provide limited cross-protection against these heterogeneous variants, though it should be noted that these vaccines are primarily designed to induce maternal immunity in sows. The objective of this study was to develop a novel inactivated vaccine using an emerging PEDV GIIc variant and evaluate its immunogenicity and cross-protective efficacy against heterologous strains. Methods: A novel PEDV strain, designated PEDV-HeN2024, was isolated from clinical samples and identified through cell culture, immunofluorescence assay (IFA), genetic sequencing, and phylogenetic analysis. An inactivated vaccine was prepared by emulsifying the purified virus with ISA 201 VG adjuvant (1:1, v/v). Immunogenicity was assessed in piglets by measuring virus-neutralizing antibody titers and PEDV-specific IgG levels. Cross-protective efficacy was evaluated through in vitro neutralization assays and in vivo challenge studies with homologous GIIc and heterologous GIIa and GIIb strains. Results: The isolated PEDV-HeN2024 strain demonstrated pathogenicity, causing severe diarrhea and 100% mortality in PEDV-naïve neonatal piglets. Sera from vaccinated animals showed potent cross-neutralizing activity against homologous GIIc, as well as heterologous GIIa and GIIb strains. In challenge studies, vaccinated piglets were significantly protected against clinical disease, showing no diarrhea or viral shedding, and maintained normal intestinal architecture. Conclusions: The inactivated vaccine developed from the emerging PEDV GIIc variant elicits robust humoral immunity and provides cross-protection against prevalent heterologous GII strains. These findings highlight its potential as a promising spectrum vaccine candidate for controlling PEDV outbreaks. This study underscores the importance of using recently circulating strains for vaccine development to overcome the limitations of current vaccines. Full article

A Group A Streptococcus (GAS, Streptococcus pyogenes) is an exclusively human pathogen whose virulence is driven by a diverse array of surface structures, secreted toxins, and immune evasion mechanisms. Central to its pathogenicity is the M protein, a surface-anchored molecule that inhibits phagocytosis by interfering with complement deposition and binding host factors such as fibrinogen. GAS also secretes a wide range of toxins and enzymes that damage tissues and disrupt host defences. Streptolysin O and streptolysin S are potent cytolysins that lyse immune cells and contribute to tissue necrosis. Pyrogenic exotoxins (such as SpeA and SpeC) act as superantigens, triggering massive, dysregulated T cell activation and cytokine release, an underlying mechanism in streptococcal toxic shock syndrome. Additional factors like DNases and streptokinase facilitate bacterial spread by breaking down host tissue and counteracting neutrophil extracellular traps (NETs). Immune evasion is further supported by the production of enzymes that interfere with complement functions, like the cleavage of chemokines and the targeting of antibodies. Together, these virulence determinants allow GAS to cause a wide spectrum of diseases, ranging from uncomplicated pharyngitis and impetigo to invasive conditions like necrotising fasciitis and sepsis. This review provides a timely overview of the important GAS virulence factors and an update on the current vaccine landscape. Full article

Background/Objectives: In clinical practice today, platelet concentrates are often used for topical surgical applications. They are biomaterials that can accelerate healing processes associated with oral and maxillofacial surgery as well as in several other clinical applications through the action of growth factors released by platelets at the surgical site. However, in most cases, the exact quantification of the released growth factors is challenging in both the short and long term. The aim of this study was to determine if early platelet activation and degranulation occur during the collection and utilization of platelet-rich plasma (PRP) in the surgical room, where, before its application, PRP undergoes a procedure of gelification via reactions with procoagulant agents. Methods: PRP was prepared from the blood samples of 39 patients following the modified Whitman protocol. The samples were then analyzed at four different time points (1, 6, and 24 h during preparation and clinical application in the surgery room) using flow cytometry and enzyme-linked immunosorbent assays (ELISAs) to investigate the platelet activation/degranulation and TGFβ release in the supernatant (SN) during storage and clinical application. The mean platelet count in the whole blood was 267.5 ± 48.58 × 10³/mL (range: 189–334 × 10³/mL), and the mean concentration was 2925.5 ± 833.37 × 10³/mL (range: 748–3453 × 10³/mL). Results: The activation and degranulation of platelet cells (measured via monoclonal antibodies: CD62p and CD63, respectively) demonstrated a progressive increase at 1 h, 6 h, 24 h, and after gelification. The TGFβ dosage in the supernatant (SN) at different times exhibited a similar trend, with a mean release of 18.36 ng/mL at 1 h, 21.96 ng/mL at 6 h, and 29.45 ng/mL at 24 h. After the gelification of the PRP, a significant reduction was observed, with a value of 15.52 ng/mL. Conclusions: The results reveal that the protocol used for the preparation, storage, and application of the PRP ensures a good-quality hemoderivative and that the platelet concentrate must be applied with the correct timing to support tissue healing processes. Full article

SLAMF7, also known as CD319, a SLAM (signaling lymphocytic activation molecule) family receptor, is relatively weakly expressed on chronic lymphocytic leukemia (CLL) B cells. This study evaluated the ability of elotuzumab (E), an anti-SLAMF7/CD319 antibody, to induce antibody-dependent cellular cytotoxicity (ADCC) against CLL cell lines (MEC-1, MEC-2, CI, HG-3, PGA-1, WA-OSEL). ADCC was assessed by flow cytometry using E (100 μg/mL), rituximab (R, 100 μg/mL), and their combination (E + R). CLL lines served as targets (T), while peripheral blood mononuclear cells (PBMCs) or NK cells from healthy donors served as effectors (E) at an 8:1 E:T ratio for 4 h. With PBMCs, E-induced ADCC ranged from 1.3 ± 1.2% (PGA-1) to 14.6 ± 8.1% (MEC-1); R-induced ADCC ranged from 9.2 ± 4.6% (PGA-1) to 16.6 ± 9.4% (WA-OSEL). With NK cells, E-induced ADCC ranged from 1.8 ± 3.7% (PGA-1) to 27.3 ± 4.7% (MEC-1); R-induced ADCC ranged from 5.1 ± 4.3% (PGA-1) to 27.5 ± 13.6% (CI). E outperformed R in MEC-1, while R was superior elsewhere. Cell lines with higher SLAMF7/CD319 expression displayed increased sensitivity to E. Cell lines with del17p showed higher SLAMF7/CD319 expression. The combination of E + R showed no significant synergy over monotherapies. In conclusion, elotuzumab induced significant ADCC in CLL cells, warranting further therapeutic evaluation. Full article

Porcine epidemic diarrhea virus (PEDV) is a highly infectious virus that leads to severe diarrhea and high death rates in neonatal piglets. Because PEDV primarily infects the intestinal mucosa, the induction of effective mucosal immunity through oral vaccination represents a promising strategy for disease prevention. In this study, a recombinant Lactobacillus paracasei (L. paracasei) strain expressing a multicomponent fusion antigen composed of the PEDV S1 protein, M cell- and dendritic cell-targeting peptides, and the mucosal adjuvant LTB was constructed as a candidate oral vaccine. Pregnant mice orally immunized with the recombinant strain exhibited significantly increased levels of PEDV-specific serum IgG as well as secretory IgA (SIgA) in intestinal mucus and feces, both of which showed in vitro neutralizing activity. In addition, oral immunization markedly enhanced cellular immune responses, as indicated by elevated serum levels of IFN-γ, IL-2, IL-4, and IL-10. Notably, newborn mice delivered by immunized dams displayed significantly higher levels of PEDV-specific SIgA, demonstrating effective maternal antibody transfer. These results indicate that the recombinant L. paracasei strain can robustly induce humoral, cellular, and mucosal immune responses and confer maternal immune protection. This study emphasizes the possibility of oral vaccinations based on L. paracasei as a viable approach to the prevention and management of epidemic diarrhea in piglets. Full article

Thoracic aortic aneurysm (TAA) results from dysregulated remodeling of the extracellular matrix mediated by matrix metalloproteinase (MMP) activity. Previous studies identified elevated membrane type-1 MMP (MT1-MMP) abundance and activity during TAA development and suggested aortic fibroblasts as a potential key source. Herein, we extended our understanding of the role of MT1-MMP during TAA development using various MT1-MMP transgenic mouse strains. MT1-MMP deficient (MT1-MMP^+/−) mice exhibited reduced MT1-MMP abundance, activity, and collagen volume fraction following TAA induction, concomitant with reduced aortic dilatation. TAA tissue from wild-type and MT1-MMP^+/− mice showed a similar reduction in thin collagen fibers, while the MT1-MMP^+/− mice displayed no change in thick collagen fibers. The role of fibroblast-derived MT1-MMP was examined using a conditional fibroblast-specific tamoxifen-inducible MT1-MMP knockout strain (FbMT1KO). TAA-induced changes in aortic diameter and MT1-MMP abundance were attenuated in FbMT1KO mice. Using aortic fibroblasts isolated from multiple mouse strains expressing different levels of MT1-MMP, a significant correlation between MT1-MMP abundance and TGF-β activation was observed. Importantly, treatment with MT1-MMP activity-neutralizing antibody or TGF-β neutralizing antibody resulted in the attenuation aortic dilatation. Together, these findings suggest that fibroblast-derived MT1-MMP is required for TAA development, in part through its ability to induce TGF-β signaling. Full article

Background: Osteosarcoma remains largely refractory to immune checkpoint inhibitor (ICI) monotherapy, and strategies to modulate the tumor immune microenvironment are being actively explored. Mild hyperthermia has been reported to influence antitumor immune responses; however, its impact in combination with PD-1 blockade in osteosarcoma has not been well characterized. Methods: Murine LM8 osteosarcoma cells were subjected to mild thermal stimulation, and changes in PD-L1 expression were evaluated. LM8-bearing mice were treated with mild hyperthermia, anti-PD-1 antibody, or their combination. Tumor growth, lung metastasis, and survival were assessed. Tumor-infiltrating immune cells were profiled using single-cell RNA sequencing to descriptively characterize immune-associated transcriptional features under each treatment condition. Results: Mild thermal stimulation (42 °C, 30 min) increased PD-L1 expression in LM8 cells in vitro. In vivo, combination therapy significantly suppressed primary tumor growth compared with control (χ² = 29.75, p = 1.6 × 10⁻⁶) and reduced lung metastasis burden, with a significant decrease in metastatic nodules (p < 0.01). Kaplan–Meier analysis demonstrated a significant survival benefit in the combination group (log-rank p < 0.001). Single-cell RNA sequencing revealed an increased proportion of CD8⁺ T cells with reduced exhaustion-associated gene expression and a shift toward pro-inflammatory (M1-like) macrophage transcriptional profiles. Conclusions: PD-1 blockade combined with mild hyperthermia was associated with enhanced antitumor efficacy and immune-associated transcriptional remodeling in a murine osteosarcoma model, supporting further preclinical evaluation of this combination strategy. Full article

Background/Objectives: IgA nephropathy (IgAN) is the most common primary glomerulopathy worldwide; it is characterized by a complex pathophysiology involving several inflammatory pathways. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may be critical in this process. This study aimed to investigate the role of this pathway in IgAN and examine related tissue inflammatory markers. Methods: We analyzed 63 biopsy-confirmed patients with IgAN and performed immunohistochemical analysis on renal samples. A panel of antibodies targeting the JAK/STAT pathway, including JAK2, JAK3, p-STAT, STAT3, and MAPK/ERK, was used for this analysis. Six kidney tumor border samples were used as controls. Additionally, CD68 staining was used to evaluate tissue inflammation in the kidney biopsies. Results: Patients with IgAN showed a significantly higher cellular density of JAK3 staining at the glomerular level compared to controls, indicating JAK3 activation (p < 0.0002). Nevertheless, the correlation between JAK3 positivity in glomeruli and clinical parameters such as the initial and final estimated glomerular filtration rate (eGFR) and proteinuria was not statistically significant. Identical results were obtained with CD68+ macrophage counts in the glomerular compartment, which did not show any correlation with clinical parameters, while CD68+ tubulointerstitial staining demonstrated a significant correlation with both initial (p = 0.002) and final eGFRs (p = 0.0014), proteinuria (p = 0.010), and interstitial fibrosis (p < 0.001), as well as with renal disease progression (p = 0.005). Conclusions: Activation of the JAK/STAT pathway was observed in patients with IgAN relative to controls, notwithstanding the inability to assess the full pathway due to technical limitations. Macrophage CD68 staining in the tubulointerstitial area increased and was associated with clinical and laboratory parameters such as eGFR and proteinuria. Additionally, MEST-C histological parameters, such as segmental glomerulosclerosis (S0/S1), tubular atrophy/interstitial fibrosis (T0/T1/T2), and crescents (C0/C1/C2), were associated with a higher number of CD68+ cells. Full article

The development of next-generation HIV-1 therapeutics, including ultralong-acting antivirals, novel mechanistic classes, and curative immunotherapies, promises to overcome the limitations of lifelong, daily antiretroviral therapy (ART). However, the real-world efficacy of these treatments depends on the complex epidemiological landscapes in which they are used. In South America, HIV-1 epidemics intersect hyperendemic arboviruses, including dengue, Zika, chikungunya, and yellow fever, and regionally isolated pathogens, such as mammarenaviruses. These co-infections cause profound episodic immune activation and organ dysfunction that alter drug pharmacokinetics, disrupting healthcare access and adherence. These factors can compromise ART efficacy, promote resistance, and influence latent reservoir dynamics. This review synthesizes clinical and translational evidence of this intersection. We evaluate how emergent agents, such as capsid inhibitors (lenacapavir), long-acting injectables (cabotegravir/rilpivirine), maturation inhibitors (GSK3640254), and broadly neutralizing antibodies (bNAbs), perform in the context of co-endemic viral challenges. Specifically, we argue that therapeutic development must become “co-infection-aware” to progress toward a cure and achieve durable HIV-1 control. We provide a translational roadmap that explicitly incorporates co-infection endpoints into clinical trials, develops preclinical models that better reflect real-world viral exposures, and prioritizes implementation strategies that remain effective in the case of recurrent outbreaks. Integrating regional viral ecology into HIV-1 therapeutic research is therefore a necessary step toward developing interventions that are durable and effective on a global scale. Full article

Inducible costimulator (ICOS) is a costimulatory immune checkpoint receptor expressed on activated T-cells, while the ICOS ligand (ICOSL) is expressed on antigen-presenting cells. The ICOS–ICOSL axis promotes the survival of memory and effector T-cells and induces several immune responses. In addition, the ICOS–ICOSL interaction induces cell proliferation, cell survival, and cytokine production. The roles of ICOS and ICOSL in cutaneous T-cell lymphoma (CTCL) are unclear. In this study, we examined the roles of ICOS and ICOSL in CTCL. The tumor cells co-expressed ICOS and ICOSL, and the upregulated expression of ICOS and ICOSL reflected disease severity. Anti-ICOS and anti-ICOSL neutralizing antibodies inhibited both the in vitro and in vivo proliferation of CTCL cell lines. The anti-ICOSL neutralizing antibodies induced apoptosis and suppressed CCR4 expression on tumor cells, inhibiting CCR4–CCL17-mediated migration. These results suggest that the ICOS–ICOSL axis plays an essential role in CTCL pathogenesis, and targeting the ICOS–ICOSL axis could be a viable strategy for treating CTCL. Full article