Autoimmune diseases are a group of disorders with multiple etiologies that disrupt normal immunological function, leading to the immune system mistakenly attacking the body's own tissues. The Notch signaling pathway is a conserved pathway that is in part responsible for multiple cellular behaviors, including proliferation, differentiation, development, and death, through direct cell-to-cell communication. The expression and activation of Notch signaling pathway proteins are aberrantly regulated in autoimmune diseases in a manner that is closely related to their onset and development. We reviewed the functioning of the Notch signaling pathway in several autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), juvenile idiopathic arthritis (JIA), idiopathic thrombocytopenic purpura (ITP), multiple sclerosis (MS), autoimmune vasculitis, autoimmune hepatitis (AIH), autoimmune thyroid disease (AITD), autoimmune kidney diseases and type 1 diabetes mellitus (T1DM). We specifically sought to explore the involvement of the Notch signaling pathway in the occurrence and progression of RA to provide ideas and approaches for developing new therapeutic strategies for this autoimmune disease.

The comorbidity of cardiometabolic diseases, such as hypertension and diabetes, is increasingly prevalent worldwide, particularly among middle-aged and elderly populations. The cardiometabolic index (CMI), a novel composite biomarker integrating features of dyslipidemia and abdominal obesity, has emerged as a potential indicator. However, its association with prevalent hypertension-diabetes comorbidity and its risk discrimination utility across Chinese and American populations remain insufficiently investigated. This investigation utilized data from CHARLS and NHANES, encompassing 12,261 Chinese and 1,329 American participants. Multivariable logistic regression models and restricted cubic spline (RCS) analyses were employed to evaluate the association and dose-response relationship between CMI and prevalent hypertension-diabetes comorbidity. Machine learning models were constructed to evaluate risk discrimination performance, including LightGBM, GBM, and CatBoost. Mediation analysis was further conducted to assess the potential mediating role of body mass index (BMI) in the association between CMI and the outcome. Elevated CMI was significantly associated with an increased risk of hypertension-diabetes comorbidity (CHARLS: OR = 2.16, 95% CI: 2.00-2.34; NHANES: OR = 1.99, 95% CI: 1.48-2.69). RCS analysis revealed a marked nonlinear association within the Chinese cohort (threshold effect, P-nonlinear < 0.001), contrasting with a more linear relationship in the American population (P-nonlinear = 0.764). Among the machine learning models, LightGBM and GBM demonstrated superior risk discrimination performance (CHARLS AUC = 0.841; NHANES AUC = 0.948). Mediation analysis indicated that BMI exerted a significant partial mediating effect, accounting for 32.90% and 43.32% of the total association in the Chinese and American cohorts, respectively. CMI was independently associated with prevalent hypertension-diabetes comorbidity, with notable population-specific differences in association patterns. Machine learning models incorporating CMI showed favorable risk discrimination performance. The partial mediation effect of BMI underscores the critical importance of adiposity management in mitigating cardiometabolic risk. This study provides a novel theoretical framework and methodological support for cross-population cardiometabolic health assessment.

Peripheral T-cell lymphoma (PTCL) is an aggressive malignancy with poor prognosis that requires intensive systemic therapy, highlighting the potential impact of psychosocial factors on disease management and clinical outcomes. In this population-based study using SEER data from 2013 to 2022, we identified 5,919 patients newly diagnosed with PTCL. Propensity score matching (PSM) was applied to control for baseline differences, and survival outcomes were evaluated using Kaplan-Meier analysis and Cox proportional hazards models. Unmarried patients were more likely to be female, younger, and of non-White race. Survival analysis demonstrated that unmarried patients had significantly lower 5-year overall survival (OS: 40.7% vs. 45.7%; P < 0.001) and cause-specific survival (CSS: 49.9% vs. 53.8%; P = 0.0018). This survival disparity persisted after PSM (n = 4,481), with significantly lower 5-year OS (40.0% vs. 47.9%, P < 0.001) and CSS (49.1% vs. 55.3%, P < 0.001) in unmarried patients. On multivariable Cox regression, unmarried status was still associated with worse OS (HR, 1.28; 95% CI, 1.19-1.38; P < 0.001) and CSS (HR, 1.25; 95% CI, 1.15-1.36; P < 0.001). In summary, unmarried status is associated with poorer survival in PTCL, underscoring the need to incorporate psychosocial support into personalized care strategies for socially vulnerable populations.

Osteoporosis is a significant global health challenge, and low bone mineral density (Low-BMD) is a major clinical feature and risk indicator of osteoporosis. Fatty acid metabolism has been increasingly implicated in bone remodeling and inflammatory regulation, but the transcriptomic links between fatty acid metabolism and immune-inflammatory alterations in Low-BMD remain unclear. We integrated three GEO datasets, including 60 High-BMD controls and 59 Low-BMD subjects. Differential expression analysis, immune infiltration analysis, NMF clustering, WGCNA, pseudotime analysis, and machine learning were performed to identify fatty acid metabolism-related genes associated with Low-BMD. AKT1 knockdown was used to evaluate its potential role in regulating inflammatory mediators. Eighteen fatty acid metabolism-related differentially expressed genes were identified between High-BMD and Low-BMD samples and were enriched in inflammatory, immune, and osteoclast-related pathways. NMF clustering revealed two Low-BMD molecular subtypes with distinct metabolic and immune-inflammatory features. Machine learning identified an AKT1-containing diagnostic signature with good predictive performance, and AKT1 was positively correlated with inflammatory response scores and inflammatory markers. Quantitative Real-time PCR confirmed Akt1 knockdown, and ELISA showed reduced IL-6, TNF-α, and IL-1β secretion in MC3T3-E1 cells. AKT1 may serve as a fatty acid metabolism-related candidate gene associated with immune-inflammatory remodeling and inflammatory mediator regulation in Low-BMD. These findings suggest a potential AKT1-associated metabolic-inflammatory regulatory relationship and provide candidate biomarkers for future validation in osteoporosis-related bone loss.

Liver hepatocellular carcinoma (LIHC) continues to present a serious global health burden, with high mortality driven by late-stage detection and poor therapeutic responses. While fumarate has emerged as a key oncometabolite driving tumor progression through metabolic reprogramming and epigenetic regulation, its specific role in LIHC prognosis warrants further investigation to develop novel therapeutic strategies. We constructed and validated a prognostic signature for LIHC based on fumarate metabolism-associated genes (FAMRGs) using data from TCGA and GEO. After screening prognosis-related FAMRGs using differential expression and univariate Cox regression, we built a four-gene model via LASSO and multivariate Cox regression. Model performance was assessed by survival analysis and ROC curves. Immune infiltration was characterized by ssGSEA, CIBERSORT, and ESTIMATE; immunotherapy response was predicted using TIDE scores and the IMvigor210 cohort. Drug sensitivity was estimated with pRRophetic and CellMiner, and molecular subtypes were identified by consensus clustering. This study constructed and validated a prognostic model for LIHC comprising four FAMRGs. The model effectively distinguished between high- and low-risk patients, with the low-risk group demonstrating longer overall survival, more active CD8⁺ T cell infiltration, and lower TIDE scores, suggesting potential heightened sensitivity to immunotherapy. Moreover, distinct risk-group patterns were found in immune features, mutational load, drug responses, and molecular classifications, thereby advancing our understanding of precision medicine for LIHC. The FAMRGs-based prognostic model presented here not only deciphers immune heterogeneity and immunotherapy sensitivity in LIHC but also furnishes a theoretical scaffold for precision medicine approaches.

Acute non-traumatic subarachnoid hemorrhage (SAH) is complicated by systemic inflammation and cardiac dysfunction that contribute to the high rates of morbidity and mortality. To better define the mechanistic relationship between immune response and cardiac complications, we evaluated subpopulations of circulating immune cells and their associations with abnormalities of cardiac rhythm, injury biomarkers, and mechanical function after hemorrhage. In this single-site prospective observational study, we screened all adult patients presenting to our neurocritical care unit with non-traumatic SAH who required external ventricular drain (EVD) placement for treatment of hydrocephalus. Following informed consent, peripheral blood samples were obtained at post-bleed days (PBDs) 1, 3, 5, 7, and 10. Subjects were separated into groups based on evidence of cardiac abnormalities (cAbn(+))" versus "no cardiac abnormalities (cAbn(-))," and flow cytometric analysis was used to identify and quantify immune cell subpopulations. Circulating neutrophil-secreted factors, including myeloperoxidase (MPO), were measured in plasma using ELISA. We measured associations between these immune factors and cardiac abnormalities. Sixty patients were enrolled between January 2018 and August 2023. Our patient cohort was 65% female with a median age of 58 (IQR 51-68). Poor grade SAH (Hunt Hess = 4-5) occurred in 52% (n = 31) of patients. In the overall cohort 47 (78%) required prolonged mechanical ventilation (> 24-hours), and 52 (87%) underwent coil embolization/clipping of their aneurysm. The average ICU and hospital lengths of stay (LOS) were 18.5 (IQR 12.2-22) and 23 (IQR 18.2-33.8) days, respectively. In-hospital mortality for enrolled patients was 11.8% and overall mortality 6 months after discharge was 25% (n = 15). 40% (n = 24) of patients were discharged home, 37% (n = 22) to acute rehabilitation, 8% (n = 5) to SNF, and 3% (n = 2) to hospice. Cardiac abnormalities after SAH were associated with increased circulating neutrophil counts but not monocyte or lymphocyte levels. Circulating neutrophils in patients with cardiac abnormalities also had reduced cell-surface expression of maturation markers CD10, CD14, and CD16 in patients with cardiac abnormalities. Elevated levels of immature neutrophils and circulating levels of lipocalin-2, and myeloperoxidase (MPO) correlated with increased Hunt-Hess score, ICU, and hospital length of stay. Higher grade SAH was associated with increased immature neutrophil response, which was associated with cardiac abnormalities. These cardiac abnormalities tracked with increased levels of pro-inflammatory lipocalin-2 and MPO, and worse outcomes.

Cardiovascular-kidney-metabolic (CKM) syndrome represents the interconnection of metabolic dysfunction, chronic kidney disease, and cardiovascular disease, with advanced stages associated with high mortality. However, the associations of leisure-time physical activity (PA) and sedentary time with mortality in participants with advanced CKM syndrome remain unclear. This study conducted a prospective cohort study using data from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. Multivariate Cox proportional hazards models, restricted cubic spline (RCS) analyses, and subgroup analyses were applied to examine the independent and joint associations of leisure-time PA and sedentary time with all-cause and cardiovascular mortality among participants with advanced CKM syndrome. Among advanced CKM participants, physical inactivity was associated with higher risks of all-cause (HR = 2.43, 95% CI: 1.98-2.97, P < 0.001) and cardiovascular mortality (HR = 2.62, 95% CI: 1.79-3.82, P < 0.001). Compared with < 4 h/day, sedentary time > 8 h/day was independently linked to elevated risks of all-cause (HR = 1.71, 95% CI: 1.33-2.19, P < 0.001) and cardiovascular mortality (HR = 2.12, 95% CI: 1.34-3.38, P = 0.005). Joint analyses showed that the group characterized by physical inactivity combined with ≥ 6 h/day sedentary time was associated with the highest risk of all-cause (HR = 2.77, 95% CI: 2.16-3.56, P < 0.001) and cardiovascular mortality (HR = 3.39, 95% CI: 2.13-5.40, P < 0.001). These associations were further supported by RCS analyses and sensitivity analyses. The findings underscore the potential survival advantages associated with enhancing physical activity and reducing sedentary behavior in this high-risk population.

Oncolytic virotherapy has emerged as a promising cancer treatment that combines selective tumor destruction with potent stimulation of antitumor immunity. Unlike conventional therapies, oncolytic viruses (OVs) preferentially infect and replicate within malignant cells while sparing normal tissues, leading to direct tumor lysis and the release of tumor-associated antigens, pathogen-associated molecular patterns, and damage-associated molecular patterns that activate both innate and adaptive immune responses. Advances in molecular virology and genetic engineering have transformed naturally occurring viruses into programmable therapeutic platforms capable of delivering immunomodulatory payloads that enhance antitumor efficacy and remodel the tumor microenvironment. Multiple DNA- and RNA-based viral platforms, including herpes simplex virus, adenovirus, vaccinia virus, reovirus, measles virus, Newcastle disease virus, vesicular stomatitis virus, and coxsackievirus, are currently under clinical investigation, with regulatory approval of talimogene laherparepvec (T-VEC) and G47Δ providing important proof of clinical feasibility. Increasing evidence indicates that OVs can convert immunologically "cold" tumors into "hot" tumors, thereby improving responsiveness to immune checkpoint inhibitors and other therapeutic modalities. Consequently, oncolytic virotherapy has become an attractive component of combination strategies involving immunotherapy, chemotherapy, radiotherapy, targeted therapies, and cellular therapies. Nevertheless, several challenges continue to limit its broader clinical application, including antiviral immune clearance, inefficient systemic delivery, restricted intratumoral spread, tumor heterogeneity, manufacturing complexity, and the lack of robust predictive biomarkers. This review provides a comprehensive overview of the biological foundations of oncolytic virotherapy, viral engineering strategies, mechanisms of tumor selectivity, direct oncolysis, immunogenic cell death, and immune remodeling of the tumor microenvironment. It further summarizes the major oncolytic virus platforms, recent preclinical and clinical advances, emerging combination strategies, current translational challenges, and future directions expected to advance precision oncolytic virotherapy and expand its role in modern cancer treatment.

El-Sehrawy and colleagues recently proposed a model of clonal thrombo-inflammation in myeloproliferative neoplasms organised around the inflammasome, clonal stability and a multi-compartmental thrombotic niche. Each of these elements was addressed in two reviews published by our group in 2021, neither of which is cited. The first set out the pathogenetic role of the NLRP3 and AIM2 inflammasomes and their link to hypercoagulable states; the second formalised the vascular consequence as the Circulating Wound, a self-sustaining lesion in which tissue-factor-rich clonal platelets, thrombin generation, protease-activated receptor signalling and TGF-β crosstalk reinforce one another. This coagulative arm is absent from the more recent model. We summarise experimental findings from 53 therapy-naive patients that support the earlier formulation, and set out where the two accounts diverge and why the difference bears on the therapeutic reading.

The relationship between body mass index (BMI) and laboratory parameters in Sjögren's disease (SjD) remains unclear. We evaluated associations of BMI with selected serological and haematological parameters and explored its relationship with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). This single-centre retrospective cross-sectional study included 554 unique hospitalised patients with SjD. Multivariable linear regression models were adjusted for age, sex and disease duration. Effect estimates were expressed per 5 kg/m[2] higher BMI, and Benjamini-Hochberg false discovery rate correction was applied across all estimable laboratory outcomes. Generalised additive and segmented regression models examined nonlinear relationships. Natural-log-transformed CRP and TNF-α analyses and an ESSDAI score excluding both biological and haematological domains were used as sensitivity analyses. After adjustment for age, sex and disease duration, each 5 kg/m[2] higher BMI was associated with lower IgG and higher C3, HGB, WBC and RBC after false discovery rate correction. CRP showed a nominal inverse association (P = 0.038, q = 0.076). TNF-α showed no linear association, but U-shaped patterns were observed in raw and log-transformed analyses. BMI was weakly inversely correlated with ESSDAI (ρ=-0.160, P < 0.001) and very weakly with ESSDAI excluding the biological and haematological domains (ρ=-0.085, P = 0.044). BMI was associated with several laboratory parameters and weakly with ESSDAI in this hypothesis-generating cross-sectional study. The underlying mechanisms remain uncertain.

Preserved ratio impaired spirometry (PRISm), an abnormal spirometry condition characterized by a decreased forced expiratory volume at the first second (FEV1), is recognized as a precursor of chronic obstructive pulmonary disease (COPD). Growing studies demonstrate that PRISm is associated with an increased risk of the development of fixed airflow obstruction (FAO) and cardiovascular mortality. However, there is still a lack of comprehensive understanding of the patterns and predictors of lung function trajectories in PRISm. Furthermore, standardized interventions that can prevent the deterioration of lung function in PRISm remain unclear. The purpose of this narrative review is to examine the natural history of PRISm by summarizing current evidence on its progression over time, key determinants, and modifiable factors, thereby identifying opportunities for early intervention. In this review, three main patterns of PRISm trajectories were reported, including PRISm to normal spirometry, persistent PRISm, and PRISm to FAO. In accordance, several important factors, such as body mass index (BMI), smoking status, baseline lung function values, comorbid respiratory symptoms and various diseases, and PRISm subtypes, were identified as predictors for the transition of PRISm to other lung function status. Additionally, several potential intervention strategies were developed to slow down the decline of lung function in PRISm and reduce PRISm-related mortality, including early screening and regular monitoring, non-pharmacological interventions, pharmacological interventions, and hierarchical management.

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are major causes of cancer-related mortality, yet responses to immune checkpoint inhibitors (ICIs) remain heterogeneous. Although programmed death-ligand 1 (PD-L1) is a key component of immune checkpoint biology, antitumor immunity is shaped by multiple tumor-intrinsic and microenvironmental factors, and the contribution of the long non-coding RNA H19 to these processes remains incompletely defined. This narrative review synthesizes experimental and clinical evidence linking H19 to immune regulation in HCC and CRC, with particular emphasis on its potential intersection with PD-L1-mediated immune checkpoint signaling. Evidence was classified as experimentally demonstrated, indirectly supported, contextual, or hypothetical according to the strength, mechanistic resolution, and disease specificity of the available data. Current evidence indicates that H19 perturbation can influence PD-L1-associated phenotypes in selected experimental HCC models; however, a complete, mechanistically resolved H19-dependent PD-L1 regulatory axis, including validated intermediate mechanisms and causal rescue, has not been established in HCC or CRC. Proposed ceRNA and signaling mechanisms remain incompletely validated, while several mechanistic links are supported primarily by indirect or cross-cancer evidence. Beyond direct checkpoint regulation, H19-associated extracellular vesicles and H19-dependent signaling have been implicated in macrophage remodeling, intercellular communication, and T-cell dysfunction, although direct convergence of these processes on H19-mediated PD-L1 regulation remains unproven. Circulating H19 has also shown preliminary associations with tumor presence or burden, but its clinical utility as a diagnostic, prognostic, or predictive biomarker remains insufficiently validated, particularly for ICI response. Overall, H19 represents a biologically plausible interface between non-coding RNA regulation, tumor-intrinsic signaling, and the tumor immune microenvironment rather than an established central regulator of PD-L1. Disease-specific mechanistic studies incorporating H19 perturbation, PD-L1 measurement, pathway-specific rescue, and immune-functional assays are required to determine whether H19 can serve as a clinically actionable component of immune checkpoint regulation.

Targeted therapies significantly extend the survival of patients with myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDS). This prolonged lifespan introduces an unintended clinical hazard. These patients face an elevated risk of developing primary central nervous system (CNS) tumors. The internal relationship between them remains to be explored. We integrated the Global Burden of Disease (GBD) and the Cancer Incidence in Five Continents (CI5) datasets to conduct spatial clustering mapping using Moran's I. Vector autoregression and Granger causality analysis were employed to examine the longitudinal incidence of these diseases in Sweden from 1990 to 2021. Bibliometric profiling was utilized to identify research frontiers, and two-sample Mendelian randomization (MR) was used to determine genetic correlation. Geospatial mapping indicated a dually dominant burden of MPN + MDS (MPN and MDS, not MPN/MDS) and CNS tumors in developed regions. Longitudinal data from Sweden exposed a strictly unidirectional predictive trajectory exclusive to females. Myeloid malignancies reliably preceded CNS tumors. Bibliometric analysis demonstrated a remarkable interdecadal convergence on neuroinflammation and the tumor microenvironment. Significantly, MR confirmed that MPN (odds ratio [OR] = 1.84, 95% confidence interval [CI]: 1.22-2.76) and MDS (OR = 2.54, 95% CI: 1.62-3.96) have definite positive effects on GBM susceptibility. We established the possible comorbidity relationship between MPN + MDS and GBM, and raised the myeloid-neuro-immune crosstalk theory. It lays a reliable foundation on the interactions between MPN + MDS and GBM for future research, and offers insights for building multidisciplinary team collaboration.

Familial Mediterranean fever (FMF), an autoinflammatory disease caused by MEFV mutations, frequently coexists with immune-mediated conditions such as spondyloarthritis (SpA). However, the contribution of innate lymphoid cells (ILCs) to FMF-associated SpA remains poorly defined. Our objective was to characterize the phenotype and functional activity of ILCs in pediatric patients with FMF, SpA, and overlap FMF/SpA. Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from FMF (n = 15), SpA (n = 11), FMF/SpA (n = 13), and age-matched healthy controls (n = 14) were analyzed by flow cytometry to quantify ILC subsets. Plasma and synovial cytokines were measured by ELISA, and expression of ILC-associated cytokines in PBMCs and sorted ILCs was assessed by quantitative PCR. Total ILC frequencies and subset distributions in PBMCs and SFMCs were comparable across groups (p > 0.05). However, FMF/SpA patients demonstrated increased IL4 and IL5 expression in sorted ILCs (p < 0.05), consistent with a type 2-skewed ILC activation profile. PBMC thymic stromal lymphopoietin (TSLP) expression was elevated in SpA (p < 0.01). Plasma IL-6, IL-8 and IP-10 concentrations were higher in the full cohort of FMF/SpA patients; however, these differences were sensitive to outlier exclusion and indicate substantial inter-individual heterogeneity. Synovial fluid from SpA patients showed higher IP-10 and IL-17 levels (p < 0.05). Pediatric FMF/SpA is characterized by altered ILC functional polarization rather than numerical expansion, with a prominent type 2 ILC signature. In contrast, SpA displays synovial IP-10 and IL-17 enrichment and increased PBMC TSLP expression. These findings suggest distinct innate immune activation axes in overlap versus isolated SpA and support further investigation of ILC-mediated pathways in FMF-associated spondyloarthritis in larger cohorts.

We developed and externally validated an interpretable machine-learning model for observed continuous renal replacement therapy (CRRT) initiation in sepsis-associated acute kidney injury (SA-AKI) using a strict 24-hour landmark framework. This multicenter retrospective study used MIMIC-IV and eICU-CRD data. Predictors were restricted to the period from sepsis diagnosis to 24 h, and the outcome was first observed CRRT initiation after the landmark and within 7 days. Patients who died, initiated CRRT, or were no longer under observation by 24 h were excluded. Eight algorithms were evaluated, and a seven-predictor Gradient Boosting model was selected. Discrimination, calibration, incremental value, SHAP-based interpretation, and exploratory prediction-subgroup outcomes were assessed. The final MIMIC-IV cohort included 5,238 patients, with 239 CRRT events; 3,666 were assigned to training and 1,572 to internal validation. The eICU-CRD cohort included 4,683 patients and 157 events. The model retained serum creatinine, AKI stage, SOFA score, urine output, lactate, red blood cell distribution width, and peripheral oxygen saturation. AUCs were 0.905 internally and 0.816 externally, with an external calibration slope of 0.567. In an exploratory age- and sex-matched eICU analysis, the high predicted-risk/no observed CRRT subgroup had higher ICU, 7-day, and 28-day mortality than the true-negative subgroup. The model provided interpretable risk estimates for observed CRRT initiation, but external calibration and incremental value were limited. Findings should not be interpreted as evidence of CRRT indication, undertreatment, or treatment benefit. Prospective validation and local recalibration are required.