Search Results (8,077)

Glioblastoma (GBM) is a highly aggressive malignant brain tumor accounting for 15% of all brain tumors and 50% of all gliomas. The exact cause of GBM is not fully understood but risk factors include age, genetic mutations, exposure to ionizing radiation, and certain genetic disorders. Symptoms of GBM include headaches, seizures, cognitive impairment, and weaknesses on one side of the body. Myeloid cells account for 30–50% of the tumor mass and are instrumental in shaping the complex tumor microenvironment (TME). Inflammation in the TME is an important driver of tumor growth and invasion; however, as the environment evolves, the immunosuppressive TME poses a significant hurdle as it hinders the immune-mediated killing of tumor cells. Our work utilizes neuroimmune organoids containing neurons, astrocytes, microglia, and vascular-like cells, to which we add patient-derived GBM cells and/or iPSC-derived macrophages to model the GBM TME. Model characterization was performed using single-cell RNA sequencing and supernatant proteomics to determine cell-specific changes during coculturing. Our findings are consistent with this 7-day coculture model recapitulating key aspects of GBM early tumor establishment and immune activation, with transcriptomic and secretome signatures suggestive of an emerging immune evasion phenotype. Full article

The human immune system executes immune defense against foreign antigens, immune surveillance against mutant cells, and immune homeostasis to maintain bodily physiological equilibrium. Transfer RNA (tRNA) is an important part of gene expression regulation. Recent studies have found that aberrant tRNA modifications can disturb the function of the immune system by altering translation efficiency, including regulating immune recognition and signal transduction, as well as influencing apoptosis and autophagy. tRNA modifications are also closely related to the development and occurrence of immune-related disorders such as infections, tumors, and autoimmune diseases. By integrating current research on immune-related tRNA modifications, this review systematically summarizes the mechanisms of tRNA modifications involved in three major immune functions and their relationship with related diseases, encompassing the direct regulation of immune cells and the indirect immune effects mediated through tissue or tumor cells. In addition, some tRNA modifications can also modulate immune responses by affecting tRNA cleavage and the consequent generation of tRNA-derived small RNAs (tsRNAs). Accordingly, this review outlines promising intervention targets and unresolved research bottlenecks, facilitating follow-up investigations into tRNA modification-dependent immune regulation and translational therapeutic research. Full article

Excessive cyanobacterial proliferation and toxin production increasingly threaten freshwater ecosystems, drinking water systems, and public health. Among cyanotoxins, microcystin-LR (MC-LR) is one of the most prevalent variants and is recognized for its hepatotoxicity, with evidence showing it can also alter gut microbiota composition. Previous studies, including our own, demonstrate that MC exposure can induce inflammation, oxidative stress, and changes in gene expression associated with immune responses, even at concentrations below guideline limits. This study investigated the protective effect of an MC-degrading bacterium, Sphingopyxis sp. IM1 (IM1) with a known enzymatic MC degradation pathway, against MC-LR-induced hepatotoxicity under in vitro conditions. Human Hep3B hepatocytes were pretreated with varying ratios of IM1 bacteria and subsequently exposed to 9.95 ppm of MC-LR for 24 h. RT-qPCR analysis demonstrated that MC-LR exposure strongly increased the expression of the inflammatory markers TNFα and TGF-β1, whereas pretreatment with IM1 significantly attenuated these responses. Mass spectrometric analysis of cell pellets and spent culture media demonstrated reduced concentrations of intact MC-LR in IM1-pretreated samples compared to MC-LR-only controls, accompanied by increased detection of tetrapeptide degradation products generated during mlr-mediated MC degradation. These results demonstrate that IM1-mediated degradation of MC-LR attenuates toxin-induced hepatotoxic and inflammatory responses, highlighting the potential of a novel microbial-based therapeutic approach to mitigate MC-induced toxicity. Full article

Lung cancer ranks first in both incidence and mortality among all malignancies, and tumor microenvironment (TME)-induced CD8⁺ T cell exhaustion is a critical factor driving immune evasion and compromising the efficacy of immunotherapy. MicroRNAs (miRNAs), as key post-transcriptional regulators, shuttle between lung cancer cells and CD8⁺ T cells via extracellular vesicles (EVs), serving as critical communication hubs that reshape the TME. This review systematically synthesizes recent literature to summarize the regulatory patterns of miRNAs on functions of lung cancer cells and CD8⁺ T cells, and dissect the molecular mechanisms underlying miRNA-mediated bidirectional crosstalk between these two cell types. This review focuses on the dual-pronged immune evasion strategy employed by lung cancer cells to counteract CD8⁺ T cells. On the one hand, lung cancer cells aberrantly express endogenous miRNAs, such as miR-20a, miR-149-5p, and miR-326, to remodel their surface ligands and establish immune camouflage. On the other hand, they actively secrete EVs enriched in specific miRNAs, including miR-7108-3p, miR-651-5p, and miR-24-3p, which directly suppress CD8⁺ T cell function. Furthermore, lung cancer cells secrete additional miRNAs, notably miR-6794-5p, miR-708-5p, and miR-1234-3p, to reprogram other TME components, namely tumor-associated macrophages (TAMs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs). These reprogrammed cells, in turn, indirectly attenuate CD8⁺ T cells through a relay-like mechanism via immunosuppressive cytokines or surface checkpoint molecules produced by these cells. In addition, competing endogenous RNA (ceRNA) networks formed by long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) in lung cancer cells regulate miRNA activity at multiple levels, further impairing the immune effector functions of CD8⁺ T cells. Conversely, activated CD8⁺ T cells also secrete miRNA-containing EVs, which deliver these miRNAs to tumor cells, thereby inhibiting tumor progression. Elucidation of this miRNA-based bidirectional communication network will not only advance our understanding of immune evasion mechanisms in lung cancer but also provide novel insights into cell-free immunotherapeutic approaches based on CD8⁺ T cell-derived vesicles. Full article

African swine fever virus (ASFV) causes African swine fever (ASF), a highly lethal disease in pigs. Vietnam has approved two ASF live-attenuated vaccines (LAVs), but their efficacy and safety remain controversial, and no reliable, highly effective commercial ASF vaccine is available yet. Humoral immunity plays an important role in protection against ASFV infection. However, there is still controversy regarding whether ASFV infection can induce antibodies with neutralizing activity. Antibody-dependent cellular cytotoxicity (ADCC), as an antibody-mediated protective mechanism, offers a novel perspective for screening protective ASFV antigens. This study evaluated five structural proteins (pCP312R, pA104R, pA151R, p17, and pF317L) as subunit vaccine candidates based on their ability to induce antibodies that inhibit viral replication and mediate ADCC. The recombinant proteins were expressed in Escherichia coli, purified, and used to immunize pigs. Immune sera collected two weeks after the third immunization were tested for their ability to inhibit ASFV replication in porcine alveolar macrophages (PAMs) using rASFV-Gluc/EGFP. ADCC activity was assessed using a stable HEK293T-p17 cell line as target cells and porcine peripheral blood mononuclear cells (PBMCs) as effectors, with cytotoxicity measured by lactate dehydrogenase release. All five recombinant proteins were successfully expressed and purified. Immunization with pCP312R, pA104R, p17, and pF317L induced the production of specific antibodies in pigs, but only anti-p17 antibodies significantly inhibited ASFV replication in PAMs. The p17 is highly conserved across different ASFV genotypes and is predicted to contain a transmembrane domain. Anti-p17 antibodies effectively mediated PBMCs to specifically kill target cells, demonstrating significant ADCC activity. Moreover, the HEK293T-p17 cell line was specifically recognized by anti-ASFV sera. These findings indicate that p17 is a dual-functional antigen capable of eliciting antibodies that both inhibit viral replication and mediate ADCC in vitro. Furthermore, we have developed an in vitro platform for screening protective ASFV antibodies based on viral inhibition and ADCC, providing candidate targets for the development of next-generation ASF subunit vaccines. Full article

Sustained neurohormonal stress, adverse myocardial remodeling, and inflammation are major components of heart failure (HF) progression. Alterations in circulating neurohormonal signaling are directly sensed by the β-adrenergic receptor (βAR), a system mainly responsible for chronotropic and inotropic cardiac responses. βARs are regulated by G-protein-coupled receptor (GPCR) kinase 2 (GRK2). Within this context, decades of study have unraveled mechanistic details on how GRK2 canonically imposes a “brake” on βARs and other GPCR-mediated signaling. Notably, an expanding body of evidence demonstrates that GRK2 functions in a highly compartment- and cell-dependent manner, with roles extending far beyond GPCR regulation. These noncanonical activities span metabolic control, maintenance of organelle integrity, and regulation of inter-cellular signaling networks, particularly those governing immune–vascular interactions. In this review, we will discuss recent advances in our understanding of the cell-specific functions of GRK2, its emerging biological roles in cardiac diseases, and the opportunities these findings present for advancing mechanistic insights in cardio-oncology. We propose that the therapeutic value of GRK2 is directly dependent on a deeper understanding of its noncanonical functions in a compartment- and cell-specific manner within a disease-specific context. Full article

Myhre syndrome is a rare autosomal-dominant disorder caused by gain-of-function (GOF) variants in SMAD4. Although it is primarily recognized as a fibrotic disease, we and others have identified respiratory infection-associated morbidity as a major clinical burden. Regardless, the epithelial-intrinsic mechanisms underlying increased viral susceptibility in Myhre syndrome remain poorly understood. Here, using patient-derived nasal airway epithelial cells (NECs) and respiratory syncytial virus (RSV) infection as a model, we demonstrate that infection is markedly exacerbated in Myhre syndrome epithelium relative to matched healthy controls. We further show that activation of TGF-β1–SMAD4 signaling in healthy donor NECs phenocopies augmented RSV susceptibility, identifying SMAD4 signaling as a bona fide pro-viral pathway in airway epithelium. Mechanistically, we identify a significant reduction in BPIFA1 expression in Myhre syndrome NECs. BPIFA1 is a key secreted innate defense protein with antimicrobial, immunomodulatory, and emerging antiviral functions. SMAD signaling suppresses BPIFA1 expression, and its knockdown in healthy cells mimics the increased viral susceptibility, linking SMAD4 gain-of-function to impaired epithelial immunity. Therapeutically, we evaluated novel, stabilized 24-amino acid BPIFA1-derived peptides as a potential intervention. Treatment with active peptides (A4-153 and A4-X7) significantly reduced RSV infectivity and epithelial damage in both healthy and Myhre syndrome airway epithelial cultures, whereas a scrambled control peptide (A4-198) showed no significant effect. Collectively, our findings establish that GOF SMAD4 signaling enhances viral vulnerability in airway epithelium through suppression of BPIFA1-mediated antiviral defense and demonstrate that BPIFA1-derived peptide therapeutics represent a promising strategy to restore innate antiviral protection. Full article

Refractory celiac disease (RCeD) is a rare but severe complication of celiac disease characterized by persistent or recurrent malabsorptive symptoms and villous atrophy despite a strict gluten-free diet, after exclusion of ongoing gluten exposure, alternative enteropathies, and overt lymphoma. RCeD comprises two biologically distinct entities. RCeD-I is associated with phenotypically normal, polyclonal intraepithelial lymphocytes and generally reflects persistent gluten-independent mucosal inflammation with a relatively favorable prognosis. RCeD-II is defined by expansion of aberrant clonal intraepithelial lymphocytes lacking normal surface T-cell markers and is increasingly regarded as a low-grade intraepithelial lymphoma or in situ lymphomatous disorder, with substantial risk of progression to enteropathy-associated T-cell lymphoma (EATL). Mechanistic studies identify epithelial stress, IL-15-driven IEL survival, stromal and innate immune amplification, and cytotoxic epithelial injury as central drivers of refractory mucosal damage. In RCeD-II, aberrant IELs acquire a hybrid T/NK-like phenotype, persist through anti-apoptotic IL-15/JAK–STAT signaling, and induce enterocyte killing, while molecular alterations involving JAK1, STAT3, JAK/STAT regulators, NF-κB signaling, epigenetic regulators, and chromosomal abnormalities support stepwise lymphomagenesis. Recent single-cell multiomic studies further reveal genetically altered intestinal lymphocyte clones and intratumoral heterogeneity across the RCeD-II–EATL continuum. From a nutritional immunology perspective, RCeD illustrates a setting in which removal of the initiating dietary antigen is insufficient to restore mucosal immune homeostasis. This review summarizes the pathogenic processes that distinguish RCeD-I from RCeD-II and link failed mucosal recovery after gluten withdrawal to persistent immune-mediated epithelial injury, aberrant IEL expansion, clonal evolution, and lymphoma progression. Full article

Background/Objectives: Amb a 1 is the major allergenic component of Ambrosia artemisiifolia pollen and a clinically relevant marker of genuine ragweed sensitization. Heart failure is increasingly recognized as a systemic syndrome shaped by immune activation, endothelial dysfunction, fibrosis, neurohormonal imbalance, pulmonary comorbidity, and environmental exposures. This narrative review aims to synthesize the translational evidence linking Amb a 1-specific IgE, IgE-mediated inflammation, allergic airway disease, and cardiovascular remodeling in heart failure. Methods: A targeted narrative review was performed, integrating evidence on component-resolved ragweed diagnosis, IgE-FcεRI signaling, mast cell and eosinophil biology, pollen exposure, cardiovascular inflammation, and heart failure pathophysiology. Results: No dedicated clinical studies have validated Amb a 1-specific IgE as a diagnostic, prognostic, or therapeutic biomarker in heart failure. However, adjacent evidence supports biologically plausible links between allergen-specific IgE responses and cardiovascular dysfunction, including mast cell activation, cytokine release, endothelial perturbation, oxidative stress, microvascular dysfunction, pulmonary-cardiac interaction, and myocardial fibrosis. Amb a 1-specific IgE may therefore identify a seasonally vulnerable heart failure phenotype, particularly in patients with allergic rhinitis, asthma, eosinophilic inflammation, or recurrent symptom worsening during ragweed season. A systemic/indirect pathway operating through allergic airway disease is distinguished from a postulated direct cardiac pathway; the latter remains strictly speculative, as no direct evidence demonstrates that inhaled Amb a 1 reaches or activates cardiac mast cells in vivo. Conclusions: Amb a 1-specific IgE should not currently be used to infer cardiac causality or modify heart failure therapy. Prospective, phenotype-rich, exposure-informed studies are needed to determine whether ragweed sensitization has clinically meaningful implications for heart failure endotyping, seasonal risk assessment, and cardio-allergology care. These findings may inform patient-centered heart failure management by improving the interpretation of seasonal dyspnea, allergic comorbidity, and symptom fluctuations in ragweed-endemic regions. Full article

Immune checkpoint inhibitor-related pneumonitis (CIP) is an uncommon but clinically relevant toxicity in renal cell carcinoma (RCC), where immune checkpoint inhibitors are frequently used either as dual immunotherapy or in combination with VEGF-targeted tyrosine kinase inhibitors. In RCC, CIP poses specific diagnostic challenges because respiratory symptoms and computed tomography findings may overlap with pulmonary metastases, infections, thromboembolic events, heart failure, and TKI-related lung toxicity. This review summarizes the incidence of CIP across pivotal RCC trials and real-world cohorts, compares its epidemiology with non-small cell lung cancer, and discusses clinical presentation, radiological patterns, differential diagnosis, and current management strategies. Particular attention is given to RCC-specific mechanisms, including immune-mediated alveolar injury, T cell activation, cytokine dysregulation, macrophage activation, GSDME-mediated pyroptosis, and the potential contribution of VEGF pathway inhibition to pulmonary inflammation. We also review risk factors, steroid-refractory disease, second-line immunosuppression, and the unresolved issue of ICI rechallenge after pneumonitis. A better understanding of these mechanisms and clinical features may improve early recognition, guide multidisciplinary management, and support safer use of immunotherapy-based combinations in patients with RCC. Full article

We report the first documented case of extreme, intact parathyroid hormone (PTH)-independent hypercalcemia mediated by a rare non-osteoclastic bone remodeling mechanism in a 65-year-old Puerto Rican woman, detected within 24 h of the second dose of the Moderna mRNA-1273 COVID-19 vaccine and leading to the diagnosis of high-risk biclonal IgA plasma cell myeloma (R-ISS Stage III). Peak serum calcium reached 17.4 mg/dL with concurrent hyperphosphatemia, normal lactate dehydrogenase (LDH), and without marrow osteoclasts or osteolytic lesions, findings inconsistent with classical cancer-associated hypercalcemia. Hypercalcemia resolved within eight days with supportive treatment alone, remaining durably normal nine months later. The temporal proximity to vaccination, together with the biochemical–histopathological profile, generates the hypothesis, without implying causation, that a vaccine-induced innate immune response triggered a rare inflammatory osteocytic perilacunar/canalicular remodeling. The biclonal gammopathy, Clone-1 (normal karyotype, CD33⁺, OCT-2⁺, MYC⁻, CD19⁺, PAX5⁻) and Clone-2 (complex high-risk karyotype, OCT-2⁻, MYC⁺low, CD19⁻), suggests epigenetic rather than genomic drivers in the predominant clone. This case proposes a novel mechanistic hypothesis for vaccine-associated hypercalcemia and generates testable questions that warrant prospective investigation. Full article

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipids, immune cells, and fibrotic tissue within the arterial wall. Among the immune cells that drive this process, macrophages play a central role by mediating both inflammatory activation and tissue repair. Their polarization into either pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes determines whether plaque progression or stabilization occurs. S100 proteins, particularly S100A8, S100A9, and S100A12, are critical regulators of macrophage function in atherosclerosis. Acting as damage-associated molecular patterns, these calcium-binding proteins interact with receptors such as receptor for advanced glycation end products (RAGE) and toll-like receptor (TLR)-4 to sustain inflammatory signaling, promote oxidative stress, and amplify cytokine production within atherosclerotic plaques. Elevated S100 protein levels correlate with increased macrophage infiltration, plaque instability, and heightened cardiovascular risk. Understanding how S100 proteins influence macrophage polarization offers new insights into the mechanisms underlying chronic vascular inflammation. Targeting the S100A8/A9 and S100A12 pathways represents a promising therapeutic strategy to mitigate macrophage-driven inflammation and improve plaque stability. Approaches such as inhibition of S100 protein-receptor interactions, suppression of downstream reactive oxygen species production, and modulation of macrophage polarization toward the M2 phenotype have shown potential in experimental models. This narrative review explores the roles of macrophages in atherosclerosis, the involvement of S100 proteins in both disease progression and macrophage polarization, and the therapeutic implications of targeting S100 protein–mediated immune responses. Together, these findings highlight S100 proteins as a therapeutic target modulating macrophage polarization to attenuate atherosclerotic plaque vulnerability. Full article

Background: Cancer cells live in a dynamic and favorable ecosystem conducive to their growth and survival, known as the tumor microenvironment (TME). The TME is replete with various proinflammatory cell types that mediate crosstalk via the secretion of cytokines and chemokines to facilitate tumor growth and development. One cardinal proinflammatory cytokine that is present in the TME is interleukin-1 (IL-1). IL-1 promotes tumor angiogenesis and cancer cell metastasis; thus IL-1 receptor antagonist (IL-1Ra) is of clinical interest. Our lab previously reported that chronic exposure to exogenous IL-1 can select for cancer cells that evolve insensitivity to IL-1 signaling, thus rendering IL-1-targeting therapies, like IL-1Ra, irrelevant. While immune cells are the primary source of TME IL-1, cancer cells can also produce and secrete IL-1 to engage in autocrine and/or paracrine signaling. In this context, cancer cell exposure to multiple other sources of exogenous IL-1 beyond autocrine production might also amplify extrinsic IL-1 signaling in these cells, but the consequences of sustained amplified IL-1 signaling on the regulation, function, and therapeutic response of these cancer cells need to be explored. Methods: Using the IL-1-secreting 5637 bladder cancer (BlCa) cell line, we generated chronic IL-1 sublines by spiking the growth medium with additional IL-1α or IL-1β chronically for 6 months. Once established, we assessed subline acute IL-1 sensitivity, paracrine signaling and response to IL-1Ra. Results: Following chronic exposure to elevated exogenous IL-1 levels, the 5637 BlCa cell line retains sensitivity to acute IL-1 and IL-1Ra and maintains the ability to induce IL-1-dependent endothelial cell activation, which is reversed with IL-1Ra. These data suggest that for cancer cells that engage in cell autonomous IL-1 signaling, sustained extrinsic IL-1 exposure does not dampen IL-1 or IL-1Ra sensitivity, supporting the context-dependent use of IL-1 antagonists as rational therapeutics in both acute and chronic inflammatory TMEs. Full article

Coronavirus disease 2019 (COVID-19) and influenza share key pathogenic mechanisms, including viral invasion, dysregulated innate immune activation, and the development of severe systemic complications. A central mediator of disease progression in both infections is the hyperactivation of the NLRP3 inflammasome, which drives excessive production of pro-inflammatory cytokines, immunothrombosis, multiorgan injury, and increased mortality. Colchicine possesses a unique pharmacokinetic property of preferential accumulation within myeloid cells, where sufficiently high intracellular concentrations inhibit NLRP3 inflammasome activation. This mechanism provides a biological rationale for preventing the cytokine storm and its downstream consequences when colchicine is administered early during infection. Available pharmacokinetic, toxicological, and clinical evidence suggests that loading doses of colchicine up to approximately 0.05 mg/kg body weight can be administered safely in appropriately selected patients, provided that clinically significant drug–drug interactions and hepatic or renal impairment are carefully excluded. The widely accepted belief that total doses of 7–7.5 mg are inherently lethal appears to reflect historical cases complicated by drug interactions and/or hepatic or renal impairment, rather than toxicity attributable to colchicine dose alone. These observations support reconsideration of current guideline recommendations regarding colchicine dosing. In particular, cumulative doses below 0.1 mg/kg appear to be consistently safe, whereas doses between 0.1 and 0.2 mg/kg are associated with only a low risk of toxicity and rarely with severe intoxication. Reassessment of colchicine dosing strategies may therefore be warranted to optimize NLRP3 inflammasome inhibition and improve outcomes in patients with COVID-19 and influenza. Full article

Background: Prostate cancer (PCa) exhibits strong multidimensional heterogeneity. The dynamic evolution of Luminal subsets and their crosstalk with the tumor microenvironment (TME) during malignant progression remain poorly understood. Conventional single-cell transcriptomics lacks spatial context, while low-resolution spatial technologies cannot resolve single-cell and subcellular interactions. This study aimed to map a high-resolution spatial transcriptomic atlas to characterize Luminal subset heterogeneity and stromal crosstalk across progressive PCa lesions. Methods: We used high-resolution CosMx spatial molecular imaging (SMI) to profile 6 treatment-naive PCa patients and constructed a single-cell spatial transcriptomic atlas covering 385 fields of view and 154,168 high-quality cells. Unsupervised clustering, functional enrichment, cell–cell communication analysis, and flow cytometry were performed. Results: We identified 28 cell clusters, including 8 Luminal subsets (0–7) and 9 Fibroblast subsets (0–8). Pathological microregion-specific spatial distribution was observed: Luminal 0–2 dominated in BPH/PIN, while Luminal 3–7 were enriched in poorly differentiated PCa and vacuolated adenocarcinoma. These subsets were functionally linked to androgen resistance, EMT, and immune regulation. COLLAGEN, FN1, and LAMININ were identified as key pathways mediating pathological-specific tumor–stromal crosstalk. Flow cytometry verified T-cell exhaustion and immunosuppression in the TME. Conclusions: This study delineated pathological microregion-specific Luminal subset plasticity and dynamic epithelial–stromal communication across the full spectrum of PCa lesions. The uncovered molecular signatures offered mechanistic clues linking EMT, hormone resistance, and local immune status during lesion evolution. Our spatial atlas provided preliminary molecular evidence to support pathological stratification and targeted precision therapeutic strategies for PCa. Full article