Search Results (7,718)

Inconsistent presentation of STAT3 variants in clinical settings makes them challenging to use in diagnostics and the prevention of unfavorable outcomes. Patients harboring the STAT3^R152W variant display a range of autoimmune disorders, including type 1 diabetes, hemolytic anemia, and thrombocytopenia. Because of a complex interplay of genetic and environmental cofactors, it is difficult to discern the direct role STAT3 plays in the development of those conditions. Here, we report a mouse model of the STAT3^R152W variant and describe its hematopoietic populations throughout adulthood. We observed profound changes in both innate and adaptive immunity, including increased splenic Th17 component consistent with a gain-of-function mutation, as described in the literature. At the same time, the mice did not develop obvious symptoms of autoimmunity. R152W mutants show lowered hemoglobin and hematocrit, indicating susceptibility to anemia, but also an increased number of thrombocytes, contradictory to reports of autoimmune thrombocytopenia. We showcase how those changes develop and wane in time, and the differences between male and female animals. Our findings paint the STAT3^R152W variant as a cause of severe immune dysregulation, but only as a cofactor in the development of autoimmunity. Full article

The Middle Meningeal Artery (MMA) occupies a pivotal role in the pathophysiology of migraine, functioning as a vascular and neuroimmune interface that precipitates the characteristic pulsatile pain. The inhibition of this pathophysiological cascade has been investigated as a therapeutic strategy. However, fewer than a dozen centers globally have disseminated procedural or mechanistic data. Given the nascency of this field and the imperative for standardization, the present review synthesizes mechanistic and clinical evidence underpinning intra-arterial pharmacological modulation of the MMA for migraine management. Methods: A focused narrative review was undertaken, drawing upon select but influential studies from pioneering research groups investigating intra-arterial interventions targeting the MMA. The extant literature was thematically categorized and organized according to the loci of cascade interruption and their corresponding clinical outcomes. Results: Since 2009, intra-arterial therapies for severe headache syndromes have evolved, initially utilizing nimodipine for vasospasm-related headaches, progressing to verapamil for reversible cerebral vasoconstriction, and more recently, lidocaine for refractory or status migrainosus, occasionally in conjunction with MMA embolization. Contemporary research uses language that conceptualizes migraine as an immunologically mediated neurovascular disorder, as opposed to a purely vascular or neuronal entity. Recent investigations have identified interleukins such as Interleukin-1β, Tumor Necrosis Factor-α, and Interleukin-6 as critical amplifiers of trigeminovascular activation. Purinergic signaling through the P2X3 receptor and the P2Y13 receptor, in conjunction with pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal peptide pathways, has been implicated in the modulation of MMA excitability and neuropeptide release. The development of novel calcitonin gene-related peptide receptor antagonists, such as zavegepant, further substantiates the artery’s significance as a pharmacological target. Conclusions: These findings support a shift toward immune-modulating intra-arterial therapeutic strategies, with migraine interventions targeting cytokine and neuroimmune signaling within the MMA, rather than relying exclusively on vasodilatory mechanisms. Full article

Chronic pain is a highly prevalent and disabling condition with a well-documented female predominance in incidence, severity and persistence. These sex differences are driven by sexually dimorphic neuroimmune mechanisms rather than psychosocial factors alone. This systematic review was conducted to comprehensively synthesize human clinical and translational evidence on sex-specific neuroimmune and glial cell pathways underlying chronic pain. Scientific literature was systematically searched from database inception to December 2025 across multiple biomedical databases to identify relevant clinical and translational studies. Across pain conditions, convergent evidence demonstrated that chronic pain mechanisms diverge by sex at cellular and molecular levels. Male-predominant pathways were characterized by microglial activation, particularly P2X4 receptor–mediated signaling and brain-derived neurotrophic factor–dependent neuronal disinhibition, supported by neuroimaging, transcriptomic, and pharmacological data. In contrast, female-predominant mechanisms involved adaptive immune processes, including CD4⁺ and CD8⁺ T cell infiltration, pannexin-1–dependent leptin release, chemokine signaling, and astrocyte-mediated neuroimmune crosstalk. Sex-specific cytokine and chemokine profiles, differential glial activation patterns, and divergent neuroimmune–endocrine interactions further distinguished pain pathways between males and females. Despite consistent mechanistic trends, substantial heterogeneity within each sex, limited sex-stratified power in many studies, and variability in outcome measures constrained quantitative synthesis and generalizability. The findings indicate that chronic pain is not a unitary disorder but rather a collection of mechanistically distinct conditions shaped by biological sex. These results highlight the limitations of sex-neutral therapeutic strategies and support the development of precision medicine approaches incorporating sex-informed neuroimmune biomarkers and mechanism-matched interventions. Future studies should prioritize adequately powered sex-stratified analyses, integration of neuroimmune biomarkers and clinical trial designs capable of detecting sex-by-treatment interactions. Full article

Background/Objectives: Adjuvants, added to vaccines to enhance immune responses, are central to shaping the magnitude and durability of immunity, yet their precise mechanisms remain incompletely defined. This study evaluated how diverse adjuvant combinations influence HPV vaccine immunogenicity in non-human primates, with a particular focus on impacts on hematopoietic biology—megakaryocytes and platelets—and broader innate and adaptive pathways. Methods: Eight adjuvanted formulations, each incorporating distinct immunomodulatory components and delivery platforms, were compared against an alum-only control in non-human primates. Longitudinal antibody titers (HPV16-specific) were measured up to 54 weeks, and blood transcriptomes were profiled at Day 1 and Day 7 after both prime and boost doses to assess pathway-level enrichment and gene-expression patterns. Results: Several adjuvant combinations significantly increased antibody titers at 54 weeks compared with alum alone. Formulations containing cationic lipid or monophosphoryl lipid A (MPL) were associated with enhanced antibody responses. Early upregulation of immune-related genes across innate and adaptive pathways was also observed, with some combinations (e.g., inclusion of QS21 or ISCOMs) showing similar trends. Distinct group- and time-dependent transcriptional signatures were observed, with higher-responding formulations exhibiting stronger enrichment in pathogen-influenced signaling and cellular/humoral immune programs. Conclusions: Adjuvant selection and formulation strategy substantially modulate vaccine immunogenicity and early transcriptional programs, including innate, adaptive, and hematopoietic pathways. While individual adjuvants differentially regulate immune and platelet-associated genes, common pathway-level patterns emerge across formulations. These findings suggest candidate mechanisms for prolonged vaccine efficacy and provide actionable insights to guide rational adjuvant design for sustained immune protection. Full article

Background: Septic shock is a leading cause of mortality worldwide, with community-acquired (CA) and hospital-acquired (HA) infections representing distinct clinical entities. The differences in clinical characteristics, immune response profiles, and effects of sepsis treatments between CA and HA septic shock have not been fully elucidated. Methods: This retrospective cohort study included 726 adults with septic shock who were admitted to two ICUs at Modena University Hospital between January 2006 and September 2024. Patients were classified as having CA or HA septic shock based on the origin of the infection. Clinical, microbiological, and immunological data, treatments, and outcomes were analysed. Immune cell dynamics were assessed during the first week after the onset of the shock. Multivariable Cox regression models were used to identify predictors and the effects of treatment on ICU mortality. Results: Among 344 patients with CA and 382 with HA septic shock, those with CA had higher severity scores but lower ICU and in-hospital mortality. Patients with HA exhibited a higher prevalence of multidrug-resistant organisms and more comorbidities. Immunologically, CA survivors showed increasing lymphocyte counts over time, whereas HA survivors mainly demonstrated recovery in T helper cells. Therapeutic strategies were similar between groups; however, continuous renal replacement therapy was more frequent in patients with HA. Neither appropriate empiric antibiotics nor steroids or immunoglobulin therapy independently improved mortality in the multivariate analyses. Conclusions: CA and HA septic shock differ significantly in terms of clinical severity, microbiological aetiology, immune recovery patterns, and outcomes. The lack of mortality benefit from standard treatments highlights the need for personalised management strategies that integrate clinical, immunological, and microbiological data to optimise care in septic shock subpopulations. Full article

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine disease marked by rapid growth, early metastatic spread, and poor outcomes. The addition of immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis to first-line chemotherapy has recently reshaped the treatment landscape for extensive-stage SCLC (ES-SCLC); however, the resulting survival gains remain modest compared with non-small lung cancer (NSCLC). This review explores the molecular features of the SCLC immune landscape that contribute to its predominantly “cold” tumor phenotype, including low MHC class I expression, T-cell exhaustion, and a profoundly immunosuppressive tumor microenvironment (TME). We summarize key clinical findings from landmark trials and examine mechanisms of both primary and acquired resistance against ICIs in SCLC. In addition, we have reviewed the growing role of precision medicine in SCLC, including molecular subtyping (SCLC-A, -N, -P, and -I) and the development of next-generation immunotherapies such as bispecific T-cell engagers (BiTEs), B7-H3, targeted therapy, and antibody–drug conjugates. By combining existing clinical evidence with new molecular insights, this review article presents strategies to overcome the existing therapeutic plateau and enhance personalized immunotherapy approaches in SCLC. Full article

Background: Outcomes after critical illness vary markedly despite similar diagnoses and severity scores, underscoring the limitations of chronological age and conventional Intensive Care Unit (ICU) prognostic tools. Personalization of critical care is increasingly essential to improve not only short-term survival but also long-term post-discharge outcomes. Biological aging clocks provide a quantitative framework to capture physiological reserve, immune competence, and vulnerability to stress. Methods: We conducted a scoping review of original human studies published between January 2015 and October 2025 that evaluated biological aging biomarkers in adult ICU populations. PubMed/MEDLINE, Scopus, Web of Science, and Embase were searched, with backward citation screening. Results: Across epigenetic, telomere-based, cfDNA, proteomic, metabolomic, and phenotypic aging measures, accelerated biological aging was consistently associated with increased mortality, organ dysfunction, and post-ICU vulnerability. Despite substantial methodological heterogeneity, a convergent signal emerged linking inflammation-weighted and stress-responsive deep biological clocks to clinically meaningful outcomes in critically ill patients. Conclusions: Biological aging biomarkers represent a mechanistically grounded approach to personalized prognostication in critical care. From a translational perspective, deep biological clocks hold promise for personalized risk stratification, prognostication, and the identification of high-risk recovery phenotypes, although prospective validation and implementation studies are required. Full article

Aquaculture of molluscs and crustaceans represents an important and expanding sector within global food production. The intensification of these systems has been accompanied by an increased prevalence and severity of infectious diseases, which continue to constrain productivity and sustainability. Current disease management approaches include biosecurity measures, husbandry practices, therapeutics, and selective breeding, which have shown limited efficacy against many emerging pathogens affecting invertebrate species. Unlike finfish, aquatic invertebrates lack adaptive immunity and rely exclusively on innate immune mechanisms, limiting the effectiveness of traditional vaccine strategies. There is growing interest in immunostimulants that enhance innate defenses and support immune priming or trans-generational immune priming (TGIP). This review summarises the current understanding of immune defence mechanisms in molluscs and crustaceans and examines recent progress in the development of immunomodulators and prophylactic interventions aimed at improving health outcomes and disease resilience in invertebrate aquaculture. Full article

As the critical component of the gastrointestinal tract, which lives in trillions of gut microorganisms, in a healthy state, the host interacts with the gut microbiota and is symbiotic. The species Limosilactobacillus reuteri, Ligilactobacillus salivarius, and Lactobacillus johnsonii are indigenous gut commensal bacteria that are mainly found in the digestive tracts. These three bacteria possess a variety of characteristics that reflect their ability to adapt to the gastrointestinal environment. Herein, we summarize the current progress of research on the probiotic properties of these strains in terms of their ability to protect against harmful pathogens, maintain intestinal health, and improve disease outcomes. These bacteria can impact the intestinal barrier function and enhance intestinal immunity through various mechanisms, such as upregulating the tight-junction protein expression and mucin secretion of intestinal epithelial cells, adjusting and balancing the gut microbiota, and blocking pro-inflammatory cytokine production. They have been shown to ameliorate intestinal inflammation in animal models and provide protective effects against various healthy issues in humans, including diarrhea, constipation, colorectal cancer, obesity, and liver diseases. However, the detailed mechanisms of certain strains remain unclear. Full article

Background/Objectives: Postoperative atrial fibrillation (POAF) is a common and serious complication after coronary artery bypass grafting (CABG), leading to increased morbidity and healthcare utilization. Although systemic inflammation is a well-established driver of POAF pathogenesis, no composite preoperative inflammatory biomarker has been validated for risk stratification in this population. This study aimed to evaluate the novel Inflammatory Burden Index (IBI)—the first composite biomarker combining acute-phase (C-reactive protein, CRP) and chronic cellular (neutrophil-to-lymphocyte ratio, NLR) inflammation—as a preoperative predictor of POAF after CABG. Methods: In this large retrospective cohort study, we included 3481 consecutive patients who underwent isolated CABG at a high-volume cardiac center between 2019 and 2024. Preoperative IBI was calculated as CRP (mg/dL) × NLR. The primary outcome was new-onset POAF within the first 7 postoperative days, confirmed by continuous telemetry on 12-lead ECG. Predictive performance was assessed using multivariable logistic regression, receiver operating characteristic (ROC) curve analysis (area under the curve, AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), and internal validation via bootstrapping (1000 resamples). Results: POAF developed in 866 patients (24.9%). Patients with POAF exhibited significantly higher preoperative IBI levels (39.4 ± 18.6 vs. 26.3 ± 16.7, p < 0.01). In multivariable analysis adjusted for age, hypertension, left atrial diameter, and other clinical covariates, IBI emerged as a strong independent predictor of POAF (adjusted OR 1.041, 95% CI 1.036-1.046, p < 0.01). The IBI alone demonstrated moderate-to-good discriminative performance (AUC 0.72, 95% CI 0.70–0.74), significantly outperforming the Systemic Immune/Inflammation Index (SII; AUC 0.61, DeLong test p < 0.001) and providing superior reclassification (NRI 0.150, IDI 0.032) and model fit (lower AIC). Combining IBI with established clinical risk factors further improved predictive accuracy (combined AUC 0.74, specificity 72.4%). Tertile-based stratification revealed a clear graded relationship with POAF incidence (low IBI: 16.6%, medium: 21.3%, high: 35.1%; p = 0.02). Notably, the medium IBI stratum (11.18-25.44) displayed the highest discriminative power (AUC 0.87, 95% CI 0.85-0.88), with bootstrap validation confirming model stability (minimal bias, robust 95% CI). Conclusions: This study establishes the preoperative Inflammatory Burden Index (IBI) as the first validated composite inflammatory biomarker independently associated with POAF following CABG. Its superior performance over existing indices (SII), graded risk stratification, and peak accuracy in the moderate inflammation window highlight its potential for personalized preoperative risk assessment and targeted perioperative intervention strategies. Full article

Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non-small cell lung cancer (NSCLC). The influence of statin use, chemotherapy, PD-L1 expression, and sex on immunotherapy outcomes remains incompletely defined in real-world settings. We performed a multicenter retrospective analysis of patients with advanced NSCLC treated with immunotherapy-based regimens. Patients were stratified by statin exposure, chemotherapy use, PD-L1 expression (<1% vs. ≥1%), and sex. Overall survival (OS) and progression-free survival (PFS) were analyzed using Kaplan–Meier estimates and log-rank tests. Statin use was not associated with a significant OS benefit, while a numerical improvement in PFS was observed in selected subgroups. Among immunotherapy-treated patients, OS did not differ significantly by chemotherapy or statin use (median range, 19–27 months), whereas PFS differed significantly, with the longest PFS observed in patients receiving immunotherapy plus statins (26 months; p = 0.046). PD-L1 expression was the strongest determinant of outcomes, with PD-L1 ≥ 1% tumors demonstrating markedly longer OS and PFS compared with PD-L1 < 1% disease (OS up to 31 vs. 16 months; PFS up to 21 vs. 12 months; p < 0.001). No significant differences in OS or PFS were observed by sex or statin exposure (OS, 23–27 months; PFS, 14–19 months). In this real-world cohort, PD-L1 expression remained the primary predictor of survival outcomes following immunotherapy. Statin use was associated with modest PFS improvements but no consistent OS benefit, while sex did not significantly influence outcomes. These findings support continued reliance on established biomarkers and warrant prospective evaluation of statins as potential adjuncts to immunotherapy. Full article

Endometriosis is a chronic, estrogen-dependent inflammatory disorder that is increasingly recognized as a systemic condition with profound implications for female reproductive potential. In addition to pelvic distortion and impaired folliculogenesis, growing evidence indicates that intrinsic alterations in oocyte morphology, mitochondrial function, and developmental competence contribute to infertility. The disease is driven by a multifactorial interplay of somatic mutations, epigenetic remodeling, immune dysregulation, and aberrant steroid signaling, which together create a pro-inflammatory, oxidative, and fibrotic microenvironment. Elevated cytokines, reactive oxygen species, and disrupted granulosa-cell function within the follicular niche impair meiotic progression, cytoplasmic maturation, and mitochondrial integrity, potentially accelerating oocyte aging and diminishing reproductive longevity. Epigenetic and post-transcriptional disturbances—including altered DNA methylation, histone modifications, and RNA-splicing defects—further reinforce estrogen dominance, progesterone resistance, and impaired decidualization, with downstream consequences for ovarian–endometrial communication. Although morphological abnormalities have been documented in oocytes from women with endometriosis, clinical outcomes remain heterogeneous, highlighting the need for integrative models that connect molecular alterations to functional reproductive endpoints. A deeper understanding of these mechanisms is essential for identifying biomarkers of oocyte competence and modifiable strategies—ranging from nutritional optimization to reduction of environmental risk factors—in clinical care to safeguard the reproductive potential of women with endometriosis. Full article

Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its clinical benefit for OC has been limited, in part due to an extremely immunosuppressive tumor microenvironment (TME) and diverse, overlapping immune evasion mechanisms. In this review, we present a comprehensive and timely synthesis of next-generation immunotherapeutic approaches for ovarian cancer, emphasizing strategies that overcome the immunosuppressive tumor microenvironment and improve clinical responsiveness. We describe the emerging molecular mechanisms of immune evasion in OC, including altered antigen presentation, inhibition of T-cell activation (e.g., via immunological checkpoints, metabolic reprogramming), polarization of tumor-associated macrophages (TAMs), and dysfunction of natural killer (NK) cells. We also critically examine several emerging therapeutic approaches, including combination immune checkpoint blockade (ICB), bispecific T-cell engagers (BiTEs), neoantigen-based vaccines, chimeric antigen receptor (CAR)-T- and CAR-NK-cell therapies, oncolytic viruses (OVs), and nanoparticle-mediated immunomodulation. In addition, we highlight recent advances in tumor microenvironment–targeted therapies for ovarian cancer, focusing on strategies that modulate non-lymphoid components such as cancer-associated fibroblasts (CAFs), hypoxia-driven signaling, and the PI3K/AKT/mTOR axis to enhance antitumor immune responsiveness. Finally, we discuss how predictive biomarkers, multi-omics systems, and patient-derived organoid models are accelerating the development and deployment of precision immunotherapies for OC. We would like to highlight the translational promise of next-generation immunotherapies and identify novel molecular targets that may be leveraged to achieve durable responses in OC. Full article

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency or inborn error of immunity (IEI) encountered in clinical practice. Characterized by a remarkably broad clinical spectrum, CVID presents with phenotypes spanning from “infection only” to significant non-infectious complications. The frequent overlap between these classifications underscores that their distinction is more accurately viewed as a continuous spectrum, rather than a binary categorization. CVID-associated liver disease is a significant source of morbidity, yet often poses diagnostic challenges due to its insidious and clinically silent nature, typically becoming apparent only upon the development of complications. Manifestations range from abnormal liver tests to irreversible organ damage, with reports including granulomas, autoimmune hepatitis, fibrosis, and porto-sinusoidal vascular disorder (PSVD). Regenerative nodular hyperplasia (RNH), commonly associated with PSVD, is a frequent histopathological finding. Management requires a multidisciplinary approach, including cause-directed immunosuppression and supportive treatment for non-cirrhotic portal hypertension. Despite significant advances in comprehending CVID-associated liver involvement, substantial gaps persist concerning its pathogenesis, its optimal management, and the correlation between histological findings and clinical outcomes. A heightened awareness of CVID-associated liver disease is paramount for multidisciplinary teams across IEI centers. Furthermore, given its prevalence, its insidious clinical phenotype until advanced complications, and the significant diagnostic delay and underdiagnosis, such awareness is critical across a broader range of medical specialties. In this paper, we aim to consolidate current knowledge regarding CVID-related liver disease, examining its clinical presentation, recent genetic and pathogenetic advancements along with current diagnostic methodologies, and therapeutic strategies. Full article

Breast cancer remains a leading cause of mortality among women worldwide. The inherent heterogeneity in tumors among patients with breast cancer poses a challenge to effective therapeutic management. The extracellular matrix (ECM) is an important structural component of the tumor microenvironment (TME) that regulates cellular behavior. When the ECM adopts a stiff configuration, this coincides with biochemical remodeling in response to biomechanical cues that drive tumor cell invasion, immune evasion, and metastatic spread in breast cancer. Emerging studies suggest that patient ancestry significantly impacts ECM stiffness to contribute to disparities in breast cancer survival. In this review, we discuss recent advances in our understanding of how the tumor ECM orchestrates breast cancer invasion and metastasis through mechanotransduction signaling to promote breast cancer progression. We also discuss ancestry-associated differences in breast ECM architecture and agents targeting mechanotransduction signaling pathways with potential to treat breast cancer and improve patient outcomes. Collectively, this review will highlight the significance of tumor mechanobiology and present emerging therapies that target stiffness-sensitive mechanotransduction pathways. By integrating mechanistic insights with therapeutic innovation, we aim to support the development of ECM-targeted therapies to enable more efficacious treatment of aggressive breast cancer subtypes. Full article