Search Results (18,302)

Microglia are central regulators of Alzheimer’s disease pathogenesis, but their roles cannot be reduced to a simple protective-versus-harmful dichotomy. Genetic, single-cell, and spatial studies have shown that Alzheimer ’s-associated microglia occupy diverse disease-linked states shaped by amyloid plaques, tau pathology, lipid stress, complement activation, astrocyte signaling, aging, and immune genetic risk. Among the regulatory nodes controlling these states, SPI1, which encodes the myeloid transcription factor PU.1, has emerged as a key determinant of microglial identity and disease responsiveness. Human genetic studies suggest that reduced SPI1 expression may be protective, whereas experimental data indicate that excessive PU.1 suppression can impair essential microglial functions. This review examines the emerging concept that partial, plaque-associated reduction in PU.1 may enable a distinct lymphoid-like immunoregulatory microglial program marked by CD28 expression. Recent evidence suggests that PU.1-low CD28-positive microglia may restrain neuroinflammation and amyloid pathology, raising the possibility that Alzheimer’s plaques induce not only inflammatory and phagocytic microglial responses, but also endogenous suppressive programs that limit tissue damage. We discuss this proposed PU.1/CD28 regulatory axis in relation to disease-associated microglia, TREM2–APOE signaling, complement-mediated synapse loss, antigen-presentation pathways, plaque-niche biology, and therapeutic microglial reprogramming. We also highlight major unresolved questions, including whether PU.1-low CD28-positive microglia are present and functional in human Alzheimer’s disease, whether they are specific to amyloid-rich niches or extend to tau and mixed pathologies, and how such states could be safely manipulated without disrupting essential immune surveillance. We propose that lymphoid-like suppressive microglia represent a promising but still unproven framework for understanding protective neuroimmune regulation in Alzheimer’s disease and for developing state-specific microglial therapies. Full article

Background/Objectives: Immune surveillance is increasingly recognized as a modifier of myeloproliferative neoplasm (MPN) initiation and evolution, yet the contribution of the NKG2D receptor and its ligands MICA/MICB to CALR-mutated disease remains unclear. Methods: We performed high-resolution next-generation sequencing genotyping of MICA and MICB in 43 patients with CALR-mutated MPN (WHO 2022 criteria) and compared the allele and haplotype distributions with those of 156 healthy Bulgarian controls and 85 patients with JAK2 V617F-positive MPN. Associations were tested using age- and sex-adjusted additive generalized linear models; bi-locus haplotypes were evaluated using haplotype score methods. In a genotyped subgroup (35 CALR-mutated MPN patients and 105 controls), functional KLRK1 (NKG2D) polymorphisms were analyzed for haplotype-level associations. We also performed 700 ns molecular dynamics simulations of selected MICA variants in complex with NKG2D and reanalyzed publicly available single-cell RNA-sequencing data (GSE117826) and RNA-sequencing data from CRISPR/Cas9-edited CALR-mutant iPSC-derived megakaryocytes to evaluate MICA/MICB expression. Results: MICA*004:001 was significantly associated with CALR-mutated MPN versus controls (p = 0.004; Bonferroni-adjusted p = 0.047), while MICB*008:001 showed only nominal association. Exploratory haplotype analyses identified a MICA*009:01-MICB*004:001 haplotype associated with CALR-mutated status (p = 0.008) and a KLRK1 G-A-G-T haplotype (rs1049174-rs2617160-rs2246809-rs2617170) associated with increased CALR-mutated MPN risk (OR = 3.61; p = 0.029). Transcriptomic reanalysis indicated a higher fraction of CALR-mutant stem and progenitor cells expressing detectable MICA/MICB transcripts, and heterozygous CALR-mutant megakaryocytes exhibited higher MICA expression than the wild type. Conclusions: Together, these data support an exploratory immunogenetic and transcriptomic link between the NKG2D-MICA/MICB axis and CALR-mutated MPN, but direct protein-level and functional studies are required before mechanistic or therapeutic conclusions can be drawn. Full article

Background: Portal hypertension can lead to complications such as ascites, hepatic encephalopathy, esophageal varices, and gastrointestinal (GI) bleeding, all of which are associated with significant morbidity and mortality. Variceal bleeding is the most severe complication, with an estimated mortality of up to 30%. In children, evidence-based guidelines for the management of GI bleeding secondary to portal hypertension are lacking. In this con-text, octreotide, a synthetic somatostatin analog approved for other indications, has been increasingly used off-label and represents a paradigmatic example of drug re-purposing in pediatrics. Methods: Following the 2020 PRISMA guidelines, this systematic review evaluated the efficacy and safety of octreotide for the treatment of portal hyperten-sion-related GI bleeding in children. A comprehensive search of six sources, including five bibliographic databases (PubMed, Embase, Web of Science, Cochrane Library, and EBSCOhost) and the ClinicalTrials.gov registry, was conducted to identify studies in-cluding pediatric patients with GI bleeding secondary to portal hypertension. Results: Three non-randomized observational studies were included, assessing bleeding recurrence, packed red blood cell requirements, and adverse events following octreotide admin-istration. Overall, 33 patients were analyzed, with a mean age of 6.3 years. One study reported a reduction in rebleeding episodes and transfusion requirements after oc-treotide treatment. Across all included studies, no serious adverse events were ob-served; mild and reversible hyperglycemia was the only reported drug-related effect. Quantitative synthesis was not feasible due to substantial heterogeneity, missing data, and a serious risk of bias, resulting in very low certainty of evidence. Conclusions: Octreotide may represent a feasible therapeutic option for portal hypertension-related GI bleeding in children; however, further prospective and standardized studies are needed to establish its long-term safety and efficacy. Full article

Aim: Retinopathy of prematurity (ROP) is the leading cause of blindness in preterm infants. In this study, we evaluated the potential role of anemia and packed red blood cell (RBC) transfusions as risk factors in ROP development. Methods: A retrospective cohort study was conducted on premature infants who met the following inclusion criteria: infants with gestational age (GA) ≤ 32 weeks and very low birth weight (VLBW) who were admitted to the Neonatology-Preterm Department of Emergency Pediatric Hospital Cluj-Napoca during a two-year period (from 1 January 2023 to 31 December 2024). We investigated differences in the following perinatal characteristics between the two groups, those with ROP and those without: GA, birth weight (BW), severe respiratory distress syndrome, early-onset and late-onset sepsis, hemoglobin (Hb) levels, and RBC transfusions. We used the statistically significant variables to perform binary logistic regression. Results: A total of 124 newborns were recruited, with the following inclusion criteria: GA ≤ 32 weeks and BW ≤ 1500 g, of whom 79 received at least one RBC transfusion prior to 36 weeks corrected GA. Of them, 48 developed ROP with an incidence of 38.7%. In 20 cases, ROP required treatment. To adjust for clinical illness, a binary logistic regression model was created, including known risk factors for ROP and illness severity (GA, severe respiratory distress syndrome, and early- and late-onset sepsis) that were closely related to the risk of ROP development. For this regression model, Nagelkerke R-squared = 0.358, p < 0.001, and the AOR was 4.812 (95% CI: 1.374–16.847). Conclusions: RBC transfusions increased the risk of ROP. Full article

Immunosenescence is a critical driver of tumor initiation and progression. In this study, we systematically characterized immune cell senescence by integrating transcriptomic profiles from 17 physiologically aged tissues with pan-cancer single-cell datasets, encompassing 206 samples across nine cancer types. Cross-tissue comparison of senescence-associated alterations, integrated with spatial transcriptomics, revealed that malignant cells triggered senescence in the core myeloid subpopulation designated Mac_DAB2 via a conserved MIF-CD74 signaling axis. By integrating shared myeloid differentiation programs across normal tissues and the tumor microenvironment (TME) with their transcriptional regulatory networks, we defined a myeloid senescence-associated gene (MSAG) signature. This signature successfully distinguishes a senescence-associated, immunosuppressive subtype linked to poor prognosis in pan-cancer cohorts. Finally, we established the MSAG.SIG prognostic model using an ensemble framework of 117 machine learning algorithms, which demonstrated robust and consistent predictive performance across multiple independent cohorts. Overall, this study elucidates the mechanisms underlying TME-driven myeloid senescence, establishes MSAG as a conceptual framework for characterizing myeloid immunosenescence, and provides a clinically relevant pan-cancer prognostic tool with translational potential. Full article

Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are systemic inflammatory diseases deeply rooted in age-related immunosenescence and inflammaging. Conventional long-term glucocorticoid (GC) therapy poses significant metabolic and infectious risks for older adults, necessitating safer alternatives. This review critically evaluates the pathophysiological rationale and clinical efficacy of small-molecule drugs, including Janus kinase inhibitors (JAKi) and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), as steroid-sparing treatments for PMR and GCA. By selectively inhibiting intracellular networks like the JAK-STAT pathway and nucleotide biosynthesis, these agents aim to attenuate maladaptive inflammation. Clinical evidence highlights that JAK inhibitors, particularly upadacitinib for GCA and tofacitinib or baricitinib for PMR, demonstrate the potential to induce remission and significantly reduce the required GC burden in a subset of patients. Although methotrexate remains the primary csDMARD, its modest overall efficacy suggests it should be reserved for patients with definitive contraindications or restricted access to JAK inhibitors. Furthermore, novel therapies like clofutriben demonstrate potential in reversing GC-induced morbidities without compromising disease control. Ultimately, integrating targeted small-molecule immunomodulators establishes a crucial therapeutic paradigm that attempts to maximize clinical remission while safeguarding the physiological integrity of geriatric patients against severe GC toxicities. Full article

Introduction: A major health issue in individuals living at high-altitude regions is an increase in the number of red blood cells (RBCs). This condition generates a series of physiological alterations including the nervous system, where damage can occur due to increased blood viscosity. This increased viscosity, in turn, could compromise oxygen uptake, potentially linked to a degree of cognitive impairment. Objective: To determine the association between exposure to chronic hypoxia and sleep quality with the degree of cognitive impairment in a young adult population residing at different altitude levels. Methodology: A cross-sectional study was conducted with 200 apparently healthy subjects (aged 21–26 years) permanently residing in four Peruvian cities: Lima (154 m), Arequipa (2335 m), Puno (3820 m), and La Rinconada (5100 m) (n = 50 per location). Physiological profiles (SpO₂, blood pressure, heart rate, hemoglobin, and hematocrit) were measured. Cognitive impairment and sleep quality were evaluated using the Montreal Cognitive Assessment (MoCA) and the Pittsburgh Sleep Quality Index (PSQI). Sex-stratified hierarchical multiple linear regression models with bootstrapping were utilized for independent correlation analysis. Results: Hemoglobin levels gradually increased with altitude, peaking at 19.47 ± 3.01 g/dL in La Rinconada, while SpO₂ decreased to 81.64%. Moderate-to-severe cognitive impairment was exclusively restricted to the extreme altitude population of La Rinconada, where only 10% of subjects remained unaffected. In the sex-stratified multivariate regression, residency in La Rinconada initially served as a robust negative predictor of MoCA scores among women (β = −5.52, p < 0.001); however, this geographical effect lost statistical significance after adjusting for biological variables in Model 2 (β = −4.72, p = 0.178). In the fully adjusted models, neither individual hemoglobin levels nor SpO₂ fluctuations displayed an independent linear association with cognitive performance in either sex (p > 0.05). Sleep quality was poor across cohorts but showed no significant association with cognitive impairment (p = 0.174). Conclusions: Chronic exposure to severe hypoxia (>5000 m) is associated with a greater presence of cognitive impairment, which is largely accounted for by individual physiological adaptations rather than isolated, linear effects of independent hematological or subjective sleep parameters. Full article

Human papillomavirus type 53 (HPV53) is one of the most prevalent HPV genotypes in China, frequently detected in cervical intraepithelial neoplasia and cervical cancer, yet remains outside the coverage of all currently available prophylactic vaccines and is relatively understudied. This study performed a comprehensive analysis of HPV53 clinical infection profiles, genomic diversity, and T-cell epitopes to inform therapeutic vaccine development. Clinical analysis of 158 HPV53-positive patients showed that infections were most prevalent in women aged 40–59 years, with persistent infection identified in 13.3% participants and a subset of cases associated with cervical lesions. Genomic analysis of 134 HPV53 isolates identified four lineages (A-D, with lineage D further subdivided into four sublineages, and an overall nucleotide variability of 4.4%. E2 was the most variable protein while E7 was the most conserved. Immunoinformatic prediction identified 176 HLA class I-restricted T-cell epitopes across E6, E7, E1, and E2, from which 20 candidates were selected for experimental validation. Ten demonstrated strong HLA binding affinity in vitro, and murine immunization identified a E6 peptide VYNFAYTDL as an immunodominant epitope. Three validated epitopes exhibited sequence overlap with 12 to 13 of other 13 high-risk HPV genotypes, suggesting their potential as broadly cross-reactive targets. These findings clarify the genomic diversity and immunogenic epitope landscape of HPV53, providing a foundation for the rational design of therapeutic vaccines. Full article

Weaning stress and immune challenges can negatively affect the health and performance of young pigs by inducing inflammatory responses. Functional protein sources, such as enzymatically hydrolyzed whole blood (EHB), may help alleviate inflammation and improve immune status during stressful conditions. A total of 20 late-weaned pigs [Landrace × Yorkshire × Duroc], 42 days of age, with an initial body weight of 15.34 ± 1.17 kg, were used in a 2-week experiment. Pigs were allotted to a 2 × 2 factorial arrangement with two dietary protein sources [plasma protein (PP) and/or EHB] and two immune challenges (saline or LPS). The four experimental groups were as follows: (1) Plasma-Sal, PP diet + saline injection; (2) Plasma-LPS, PP diet + LPS injection (100 μg/kg BW); (3) EHB-Sal, EHB diet + saline injection; and (4) EHB-LPS, EHB diet + LPS injection (100 μg/kg BW). Each treatment consisted of five replicate pens with one pig/pen. Pigs fed either protein diet with and without LPS showed no (p > 0.05) difference in their nutrient digestibility and microbial population. However, pigs challenged with LPS exhibited a higher (p < 0.05) rectal temperature, with significant differences observed at 6 h and 12 h post-injection (p < 0.001). Dietary effects (p < 0.05) were observed for IL-6 and TNF-α concentrations, with pigs fed EHB exhibiting lower values compared with those fed the PP diet following LPS challenge. Consistent with an inflammatory response, pigs challenged with LPS showed elevated (p < 0.05) IL-6 and TNF-α concentrations, together with increased white blood cell and lymphocyte counts, at 12 h post-challenge. Moreover, significant (p < 0.05) diet × LPS interactions were detected for IL-6 and TNF-α concentrations at 6 h post-challenge, indicating that dietary EHB attenuated the inflammatory response induced by LPS. In summary, a diet formulated with EHB showed a reduced effect of LPS challenge in pigs, making it promising as a functional dietary protein source for improving immune resilience in weaned piglets. Full article

Background/Objectives: Blood-based biomarkers may improve risk stratification of indeterminate pulmonary nodules detected on low-dose computed tomography (LDCT). We evaluated the diagnostic performance and independent predictive value of an aptamer-based blood assay, AptoDetect™-Lung, in a high-risk Korean screening population. Methods: This multicenter prospective cohort study enrolled adults with Lung Imaging Reporting and Data System (Lung-RADS) category 3 or 4 pulmonary nodules identified on LDCT across ten tertiary hospitals in South Korea between June 2023 and December 2024. Analyses focused on a predefined high-risk subgroup meeting Korean screening criteria (age 54–74 years and ≥30 pack-years of smoking). Baseline serum AptoDetect™-Lung scores were measured. Associations with lung cancer diagnosis were assessed using univariate and multivariable logistic regression, adjusting for clinical and radiologic variables. Diagnostic performance was evaluated using receiver operating characteristic analysis. Results: Among 1084 participants with histopathologic confirmation, 319 met high-risk criteria, of whom 260 (81.5%) were diagnosed with lung cancer. In this subgroup, the AptoDetect™-Lung score was independently associated with malignancy after adjustment (adjusted odds ratio of 1.14 per unit; 95% confidence interval of 1.02–1.27; p = 0.020). Discriminative performance was higher in the high-risk subgroup than in the overall cohort (area under the curve [AUC] of 0.639 vs. 0.570; p = 0.025). Performance was higher for squamous cell carcinoma and small-cell lung cancer than for adenocarcinoma. A multivariable model incorporating biomarker score, Lung-RADS category, age, and family history achieved an AUC of 0.710. Conclusions: An aptamer-based blood biomarker may provide modest adjunctive value for risk stratification in high-risk individuals. Full article

Aging is a systemic degenerative process that can lead to functional decline in multiple organs, such as skeletal muscles and the heart, and accelerates the overall aging process through organ-to-organ interactions mediated by metabolites such as short-chain fatty acids (SCFAs). SCFAs serve as a crucial link connecting intestinal health and anti-aging, and their levels and functions undergo significant changes with aging. However, current research lacks understanding of the downstream molecular mechanisms of SCFAs, and intervention methods are mostly limited to simple regulation. This article clarifies the intrinsic relationship between SCFAs and aging from a systemic perspective, analyzes their regulatory mechanisms through key signaling pathways, examines their roles in tissue barrier protection, the improvement of metabolic disorders, and immune regulation, and summarizes their therapeutic potential and diversified intervention strategies in aging-related diseases. The detailed molecular mechanisms by which SCFAs regulate aging are still unclear, and there are no precise intervention plans for different aging stages and organ damage. In the future, we need to utilize techniques such as single-cell sequencing and organ models to explore the regulation of aging cell fates, providing support for the development of metabolite-mediated personalized anti-aging intervention measures. Full article

Purpose/Objective: To evaluate the safety and failure patterns of consolidative hypofractionated thoracic radiotherapy (RT) following induction chemoimmunotherapy in patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC). Materials/Methods: This retrospective study included 34 patients treated between 2019 and 2025. All patients received induction chemoimmunotherapy followed by consolidative hypofractionated RT based on multidisciplinary tumor board recommendations. The primary endpoint was local recurrence (LR); secondary endpoints were regional recurrence (RR), distant metastasis (DM), overall survival (OS), progression-free survival (PFS), and treatment-related toxicity. Results: Median age was 64 years, and median PD-L1 expression was 20%. Most patients had stage III disease; squamous cell carcinoma (56%) and adenocarcinoma (38%) were the predominant histologies. The most common systemic regimen was carboplatin/paclitaxel plus nivolumab, with a median of four induction cycles. Post-induction response was complete in 21%, partial in 62%, stable in 12%, and progressive in 6%. Median RT dose was 52.5 Gy in 15 fractions, and maintenance immunotherapy was administered in 79%. At a median follow-up of 16.7 months, using cumulative incidence functions with death treated as a competing event, the 1- and 2-year cumulative incidences of local failure were 6.9% and 14.7%, respectively. The corresponding cumulative incidences of regional failure were 10.2% and 18.8%, while distant metastasis incidences were 15.9% and 39.2%. No isolated local or regional recurrences occurred. One- and two-year OS rates were 86% and 81%, and corresponding PFS rates were 76% and 54%. No grade 4–5 RT-related toxicity occurred; one grade 5 immune-related pneumonitis was observed. Conclusions: Consolidative hypofractionated RT following chemoimmunotherapy appears feasible and associated with favorable outcomes, supporting further prospective investigation. Full article

Background/Objectives: Autophagy is a key degradative pathway involved in orthodontic tooth movement. DNA damage-regulated autophagy modulator 1 (DRAM1), a protein that plays a central role in the degradation of autophagic cargo, exhibits differential regulation in human periodontal ligament (hPDL) fibroblasts under compressive force. Single-nucleotide polymorphisms (SNPs) may influence force-induced gene expression. Therefore, this study investigated the impact of DRAM1 SNPs on its expression in hPDL fibroblasts under compression force. Methods: The hPDL sample comprised cells of 59 patients. A physiological compressive strain of 2 g/cm³ was used to simulate orthodontic tooth movement. Total RNA from hPDL fibroblasts was isolated to determine DRAM1 relative gene expression under loaded conditions and in a physiological control. Furthermore, a genotyping analysis of six SNPs within the DRAM1 gene (rs756534 (G/T), rs2138257 (C/T), rs2176092 (C/T), rs4622329 (A/G), rs10860812 (A/G), and rs4764657 (A/G)) was performed using real-time polymerase chain reaction. DRAM1 expression was com-pared among genotypes of each SNP using an alpha of 5%. Linear regression analysis was then employed to evaluate SNP-SNP interaction. Results: The relative DRAM1 gene expression was not statistically significantly different (p > 0.05) according to the geno-types. The SNP-SNP interaction did not demonstrate any statistically significant associ-ation either. Conclusions: DRAM1 gene expression in hPDL fibroblasts under orthodontic compression may not be regulated by the studied intronic SNPs in the gene encoding DRAM1. Full article

Background/Objectives: To explore potential associations between pediatric obesity and retinal and anterior segment ocular structures using OCT and ocular biometry. This study was designed as an exploratory, hypothesis-generating analysis without a pre-specified primary endpoint; all findings should be interpreted accordingly. Methods: This retrospective cross-sectional study included 52 children (104 eyes): 27 obese children (body mass index (BMI) percentile ≥95%) and 25 healthy controls (BMI percentile 5–85%). Optical coherence tomography (OCT) and ocular biometry were used to assess retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), focal loss volume (FLV), global loss volume (GLV), Early Treatment Macular Map 5 (EMM5), corneal parameters, axial length (AL), anterior chamber depth (ACD), and white-to-white corneal diameter (WTOW). Group comparisons and cluster-robust bootstrap regression adjusted for inter-eye dependency, age, and sex; Bonferroni correction was applied. Results: Obese children showed nominally higher GCC average thickness, RNFL, and EMM5 values and shallower ACD; however, no parameter survived Bonferroni correction. ACD showed the most internally consistent exploratory pattern (unadjusted p = 0.006; adjusted p = 0.018; Bonferroni p = 0.249); however, this finding did not survive Bonferroni correction and should not be interpreted as a confirmed association. Other corneal and biometric parameters were not significantly different. Conclusions: Pediatric obesity may be associated with subtle ocular structural variations, but all findings are exploratory and hypothesis-generating. Larger prospective, pre-registered studies are needed to determine whether pediatric obesity is associated with structural ocular changes. Full article

Inhalational anesthesia, which includes anesthetics such as sevoflurane, isoflurane, and desflurane, is widely used in clinical settings for surgical interventions across all age groups. Nonetheless, recent findings from preclinical research raise important questions regarding their potential neurotoxic effects, especially within the developing brain, though clinical implications remain to be fully established. This narrative review was conducted through a literature search of the PubMed database and synthesizes preclinical investigations into gene modifications associated with neurotoxicity following exposure to inhalation anesthetics. Emphasis was placed on anesthetic exposure in human and animal-derived cell lines, neurodevelopmental animal models, as well as adult and aged animals. In various models, the neurotoxic mechanisms of inhalational anesthesia involve a complex interaction of apoptosis, oxidative stress, mitochondrial dysfunction, neuroinflammation, and epigenetic remodeling. Developmental studies indicate additional susceptibilities, including impaired neuronal migration, myelination deficits, and transgenerational epigenetic effects, whereas aging models exhibit oxidative stress injury, microglial activation, and heightened perioperative neurocognitive sensitivity. Understanding these neurotoxic mechanisms is essential for identifying risk factors, formulating age-specific neuroprotective strategies, and enhancing the overall safety of anesthetic use, particularly in vulnerable populations. Full article