Search Results (10,283)

Store-operated calcium entry (SOCE), mediated by the endoplasmic reticulum (ER) Ca²⁺ sensors stromal interaction molecule (STIM) proteins and the plasma membrane (PM) Orai channels, is essential for calcium signaling and a wide range of physiological processes. Precise regulation of SOCE is critical for maintaining tissue homeostasis, whereas its dysregulation contributes to diverse pathological conditions, particularly organ fibrosis. In this review, we outline the molecular basis of SOCE and discuss how its dysregulation is implicated in human disease. We further emphasize the pivotal role of SOCE in driving fibrotic progression across major organ systems. Finally, we summarize current therapeutic strategies targeting SOCE and highlight their potential for the treatment of fibrosis. Full article

Background/Objectives: Response to TNF inhibitors in RA remains heterogeneous and reliable predictors of treatment response are still lacking. Biomarker-based stratification may improve therapeutic decision-making and aligns with the emerging paradigm of precision medicine. Methods: We conducted a prospective observational study including 64 biologic-naïve patients with active RA being inadequately controlled by csDMARDs. All patients initiated anti-TNF therapy and were followed for 12 months. Clinical response was assessed at 6 and 12 months using EULAR response criteria based on DAS28-CRP. Baseline serum levels of classical biomarkers (RF type IgM, RF type IgA, anti-CCP) and additional biomarkers (anti-MCV,14-3-3η protein, COMP) were evaluated. Logistic regression analyses were performed to identify predictors of treatment response. Results: At 6 months, 7 patients were classified as non-responders, 38 as moderate responders, and 19 as good responders Lower baseline levels of RF isotypes, anti-CCP antibodies, 14-3-3η protein, and COMP were associated with favorable clinical response at 6 months. Baseline anti-CCP and 14-3-3η protein levels emerged as significant predictors in univariate analysis. Multivariate logistic regression yielded a predictive model incorporating anti-CCP, 14-3-3η protein, and COMP, achieving an overall prediction accuracy of 89.1%. At 12 months, baseline RF isotypes remained associated with treatment response, whereas the predictive value of other biomarkers diminished. Longitudinal analysis demonstrated significant reductions mainly for classical autoantibody levels under anti-TNF α inhibitors. Conclusions: A combined serum biomarker panel may support early prediction of response to anti-TNF therapy in RA. These findings highlight the potential of integrated biomarker-based stratification to optimize therapeutic decisions and support the implementation of precision medicine approaches in RA. Full article

Copper (Cu) is an essential trace mineral additive in weaned pig diets. Copper citrate (CuCit) and copper sulfate (CuSO₄) are common feed additives, yet their tissue-specific effects at different inclusion levels remain unclear. In this study, ninety pigs (six pens per treatment, three pigs per pen) with an initial body weight of 7.71 ± 0.15 kg were randomly assigned to five treatments for 28 d: a basal diet, and the basal diet supplemented with CuCit or CuSO₄ at 20 or 100 mg/kg. The results show that CuCit increased slow-twitch fiber proportion in longissimus dorsi muscle (p = 0.009), whereas CuSO₄ more markedly upregulated the expression of MyHC I (p = 0.005) and downregulated MyHC IIx (p = 0.006) and MyHC IIb (p = 0.033). Compared with the control group, CuCit and CuSO₄ supplementation increased villus height and decreased crypt depth in ileum (p < 0.05). CuCit at 20 mg/kg showed higher ZO-1 expression than CuSO₄ at 100 mg/kg (p < 0.05). Furthermore, CuCit showed greater T-SOD (p = 0.018) and CAT activities (p = 0.002) than CuSO₄ in muscle, as well as greater T-SOD activity (p = 0.011) and lower MDA content (p = 0.001) in ileal mucosa. These results suggest that CuCit and CuSO₄ exhibit different tissue-specific effects in weaned pigs, providing novel insights for precision Cu supplementation. Full article

Breast cancer remains a leading cause of cancer-related mortality worldwide, with treatment resistance, recurrence, and metastasis significantly limiting the effectiveness of conventional therapies. Photodynamic therapy (PDT) has emerged as a minimally invasive and highly selective approach, utilizing photosensitizer-generated reactive oxygen species (ROS) to achieve precise tumor cytotoxicity while preserving surrounding healthy tissue. However, clinical translation of PDT remains constrained by critical biological barriers within the tumor microenvironment, including tumor hypoxia, limited light penetration, poor photosensitizer stability, and inefficient cellular uptake. Antigen-targeted liposomal nanocarriers offer a compelling solution by enabling targeted drug delivery and tumor-specific photosensitizer accumulation, prolonged systemic circulation, and enhanced cellular internalization. Their multifunctional architecture uniquely supports combinational therapeutic strategies, integrating PDT with chemotherapy, photothermal therapy, gene therapy, X-ray-induced photodynamic therapy (X-PDT) and immune checkpoint blockade, thereby amplifying antitumor efficacy and overcoming drug resistance mechanisms. This review comprehensively summarizes recent advances in liposome-based PDT for breast cancer, highlighting multimodal therapeutic integration. Special emphasis is placed on preclinical and emerging clinical outcomes, pilot-scale manufacturing considerations, and strategies to minimize immune clearance. Full article

Background: This study aimed to develop a fully nested, information leakage-free machine-learning workflow to predict the volumetric response of meningioma to Gamma Knife radiosurgery (GKRS) from pre-treatment MRI and to compare the predictive value of radiomic, fractal, lacunarity and clinical/radiosurgical features. GKRS is widely used for treating meningiomas because of its high precision and efficacy. Variability in tumor volumetric response highlights the need for reliable predictors of treatment outcome. Methods: This retrospective cohort study included 204 patients treated with GKRS for grade I meningioma. Radiomic, fractal and lacunarity features were extracted from pre-treatment CE-T1w 3-Tesla MRIs. Feature signatures were generated using a machine-learning workflow incorporating five feature selectors based on a consensus principle to reduce spurious feature selection, followed by five classifiers to predict binary outcome. Results: The models demonstrated consistent predictive performance in the test folds, with AUC values from 0.77 to 0.84. Supplementing radiomic features with clinical, fractal or lacunarity features did not improve predictive performance. Conclusions: Radiomic features showed the strongest predictive value for meningioma volumetric response to GKRS. Darker intratumoral intensity values were associated with a favorable volumetric response, possibly reflecting biologically less active tumor regions. The supplied code enables individual-level prediction for newly encountered patients. Full article

Background: Nasopharyngeal carcinoma (NPC) presents significant diagnostic and therapeutic challenges, often due to late-stage detection and its complex anatomical location. The increasing integration of artificial intelligence (AI) into oncology offers potential opportunities to enhance the precision of NPC management. This systematic review aims to synthesise the current evidence of AI applications in NPC diagnosis, prognostication, and treatment planning. Methods: A systematic literature search was conducted following PRISMA guidelines across multiple databases (PubMed, Scopus, Embase, Google Scholar, IEEE Xplore) for studies published up to June 2025. From an initial pool of 2549 articles, 55 studies meeting the inclusion criteria were selected for qualitative analysis. The review focuses on AI models applied to key diagnostic modalities: computed tomography (CT), magnetic resonance imaging (MRI), and histopathological whole-slide images (WSI). Results: AI, particularly deep learning (DL), shows promising performance in automating critical tasks across all modalities. For CT and MRI, models have been reported to achieve accurate tumor and organ-at-risk segmentation, potentially supporting radiotherapy planning, and show strong performance in predicting survival outcomes and treatment toxicity. In digital pathology, AI enables automated diagnosis and facilitates the extraction of prognostic “pathomic” features from WSIs, with some studies suggesting performance comparable to or exceeding traditional radiomics. The most significant advances are seen in multimodal AI systems that integrate radiological, pathological, and clinical data, which, in some studies, show modest improvements in prognostic performance compared to single-modality approaches. However, these findings are preliminary, as none of the reviewed multimodal models underwent rigorous external validation in large, multi-center cohorts. Reported performance varies considerably across studies, and claims of superiority should be interpreted with caution. Full article

Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 × 10⁻¹⁷] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 × 10⁻⁸]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients. Full article

Asthma is the most prevalent chronic respiratory disease in childhood, and the objective assessment of airway inflammation remains a major challenge, particularly in younger children in whom conventional lung function testing is often not feasible. The aim of this narrative review is to evaluate the clinical role of fractional exhaled nitric oxide (FeNO) in pediatric asthma, focusing on its diagnostic utility, role in treatment guidance, and value in disease monitoring. A structured literature search was conducted in PubMed for studies published between January 2015 and October 2025, using predefined keywords related to FeNO, asthma, and pediatric populations. After applying the eligibility criteria, 47 studies were included in the final synthesis. Evidence from systematic reviews and clinical studies indicates that FeNO has moderate-to-good diagnostic accuracy for childhood asthma, with a pooled sensitivity of 0.79 and specificity of 0.81, and is most useful as an adjunct to clinical assessment and lung function testing. FeNO-guided therapy may reduce exacerbation rates in selected pediatric populations, although its effects on symptom control and corticosteroid use remain inconsistent. In the monitoring setting, serial FeNO measurements may provide additional information on inflammatory control, treatment adherence, and risk of future exacerbations. However, interpretation is influenced by multiple confounding factors, including atopy, allergic rhinitis, corticosteroid therapy, and asthma phenotype. In conclusion, FeNO is a valuable complementary biomarker in pediatric asthma, with particular utility in improving diagnostic and therapeutic precision. Its optimal use requires careful integration within a multimodal clinical framework rather than reliance as a standalone tool. Full article

Major depressive disorder (MDD) is a mental illness with high mortality, suicide, and relapse rates that could become the leading cause of health problems worldwide by 2030. The microbiota–gut–brain axis involves bidirectional communication between the human gut microbiota and the central nervous system (CNS). The gut microbiome is a complex ecosystem of approximately 100 trillion microorganisms, including viruses, bacteria, and fungi. The gut microbiota has recently been recognized for its impact on various diseases and health concerns. Several factors influence the composition and structure of gut microbes, ultimately affecting human physiology, with the nervous system being particularly vulnerable. The gut–brain–microbiota axis influences several important brain functions through numerous pathways, including vagus nerve signaling, gut microbial synthesis of metabolites, and immune-related chemicals. These factors can influence neurotransmitter activity, neuroinflammation, behavior, and mental health. Despite increased interest, the possibility of modifying the gut microbiota as a therapeutic approach remains unclear. Although numerous studies suggest that microbiota play an important role in many illnesses, the precise mechanisms are yet to be elucidated, and there are currently no evidence-based, microbiota-focused treatments for these illnesses. Recent research indicates that gut dysbiosis (GD) causes increased intestinal permeability (leaky gut), initiates systemic inflammation, and contaminates the blood. Opportunistic microbial metabolites cross the blood–brain barrier, triggering a neuroinflammatory cascade and apoptotic pathways while affecting neurogenesis and neurotransmitters, ultimately resulting in the development of MDD and anxiety. This review examined the factors influencing normal gut microbiota and GD-mediated MDD, as well as possible therapeutic options. The study outlines its objectives and methodological approaches, including the screening and filtering of research on GD-induced depression. Furthermore, it explored the daily use of dietary supplements, revealing new paths for clinical and preclinical research. Full article

Asthma is a chronic inflammatory disease with limited therapeutic options, highlighting the urgent need to explore alternative mechanisms and agents. Chlorogenic acid (CGA), a dietary polyphenol, exhibits anti-asthmatic properties, but its precise molecular mechanisms remain poorly understood. This study aimed to elucidate the mechanistic basis of CGA’s anti-asthmatic effects, hypothesizing a central role in regulating polyunsaturated fatty acid metabolism and ferroptosis. An ovalbumin-induced murine asthma model was established in female BALB/c mice to evaluate the therapeutic efficacy of CGA through inflammatory cell counts, cytokine levels (ELISA), and lung histopathology. Integrated lung lipidomics (LC-MS/MS) was employed to profile lipid mediators and phospholipids. The underlying mechanism was investigated in erastin-induced ferroptosis in BEAS-2B cells and validated in mouse lung tissue using qPCR, immunofluorescence, and assays for reactive oxygen species (ROS) and Fe²⁺. CGA treatment significantly attenuated airway inflammation, reduced Th2 cytokine (IL-4, IL-5) and IgE levels, and ameliorated lung pathology in a dose-dependent manner. Lipidomics revealed that asthma was associated with dysregulated docosahexaenoic acid (DHA) metabolism, characterized by elevated pro-inflammatory lipid peroxidation products (e.g., 11-HDoHE, 14-HDoHE), a profile reversed by CGA intervention. Mechanistically, molecular docking and subsequent validation identified CGA as an activator of the Nrf2 antioxidant pathway, leading to upregulation of the key ferroptosis defense genes SLC7A11 and GPX4 both in vitro and in vivo. Consequently, CGA treatment suppressed erastin-induced ROS production and Fe²⁺ accumulation in BEAS-2B cells. In conclusion, this study demonstrates that CGA exerts anti-asthmatic effects by reprogramming DHA metabolism to suppress ferroptosis while enhancing antioxidant pathways. These findings reveal a novel mechanistic axis for CGA and establish that targeting lipid peroxidation-driven ferroptosis represents a promising therapeutic strategy for asthma. Full article

Background: Effective topical anesthesia is essential to patient comfort and adherence during minimally invasive esthetic procedures. We retrospectively reviewed pain scores recorded after microneedling in a single private clinic where two topical anesthetic formulations—lidocaine 7%/tetracaine 7% (Pliaglis) and lidocaine 2.5%/prilocaine 2.5% (Anesderm)—were used as part of standard clinical practice on different anatomical sites and under different application protocols. Methods: Records were reviewed from 26 healthy female patients (mean age 42 ± 4 years; range 34–48) who underwent microneedling on the face and neck during 2024 in a single private clinic. According to the established clinic protocol, which was not modified for research purposes, Pliaglis was applied to the face without additional occlusion (self-occlusive peel-off film, in accordance with the manufacturer’s recommendation) and Anesderm was applied to the neck under plastic-film occlusion (also in accordance with the manufacturer’s recommendation), both for 45 min prior to microneedling at a fixed depth of 1.25 mm. Treatment allocation was determined by clinic workflow; patients and the operator were not blinded, and the order of the two products within each session was not randomized. Post-procedural pain was recorded using a Visual Analog Scale (VAS, 0–10), with one decimal precision, separately for each anatomical site. Within-patient differences were analyzed using a paired-sample t-test, with a Wilcoxon signed-rank test as a non-parametric sensitivity analysis. Results: Pain scores were lower at the facial site (Pliaglis, no occlusion) than at the cervical site (Anesderm, occlusion): mean VAS 3.00 ± 0.63 vs. 5.38 ± 0.75; mean within-patient difference 2.38 points, 95% CI 1.97–2.80; paired t(25) = 11.87, p < 0.0001; Cohen’s d = 2.33. The Wilcoxon signed-rank test produced a concordant result (p < 0.0001). A within-patient pain reduction of at least 30% on the facial site relative to the cervical site was observed in 81% of patients (21/26). Both products were well tolerated, with only mild transient erythema reported. Conclusions: In this retrospective, non-randomized, non-blinded single-center analysis, lower pain scores were observed at the facial site (treated with lidocaine-tetracaine 7%/7% without additional occlusion, per manufacturer instructions) than at the cervical site (treated with lidocaine-prilocaine 2.5%/2.5% under occlusion, per manufacturer instructions) within the same patients. Because formulation, active-drug concentration, anatomical site, and the manufacturer-mandated occlusion technique co-varied between the two conditions, the observed difference cannot be attributed to formulation alone. These findings should be regarded as hypothesis-generating and require confirmation in prospective, randomized, split-region or split-face studies that disentangle formulation effects from site- and protocol-related factors. Full article

Sarcopenia is increasingly invoked as a determinant of treatment-related toxicity, perioperative morbidity, treatment intolerance, and survival in oncology; however, contemporary international consensus frameworks define sarcopenia as a multidimensional neuromuscular syndrome centered on impaired muscle strength, physical performance, and muscle quality, whereas most oncologic studies operationalize sarcopenia using computed tomography (CT)-derived skeletal muscle mass alone. In this context, muscle quantity is effectively employed as a diagnostic surrogate for a function-centered syndrome. CT-defined skeletal muscle depletion—more precisely described as myopenia—remains a reproducible and clinically informative structural biomarker, yet defining sarcopenia by muscle mass alone aggregates biologically heterogeneous phenotypes, including neuromuscular dysfunction, inflammation-driven cachexia, and substrate-related malnutrition. Such surrogate-based definitions contribute to variable prevalence estimates, inconsistent prognostic associations, and interpretive instability across studies. Clinically, reliance on CT-based muscle mass as a surrogate for sarcopenia may influence chemotherapy dosing, perioperative risk stratification, and supportive care allocation without direct assessment of neuromuscular function; in research settings, mass-based definitions may dilute treatment effects in exercise or nutritional trials and complicate meta-analytic synthesis by conflating structural and functional constructs. This analysis does not question the value of radiologic muscle assessment but argues that CT-derived muscle mass should be recognized as a structural biomarker within a multidimensional framework rather than as a standalone diagnostic surrogate for sarcopenia. A tiered, oncology-adapted approach integrating functional assessment, muscle quality, and relevant metabolic context may enhance risk discrimination, improve trial design, and strengthen translational precision in supportive oncology. Full article

Tracer techniques have emerged as pivotal tools in ophthalmology, offering unprecedented capabilities for visualizing and quantifying complex biological processes within the eye. These techniques—spanning optical, isotopic, and metal-based tracers—have significantly enhanced our ability to detect and monitor ocular diseases, from early-stage pathologies to therapeutic responses. By providing molecular-level specificity, improved signal sensitivity, and real-time dynamic imaging, tracers enable precise analysis of ocular fluid dynamics, retinal and vascular abnormalities, and neural connections between the eye and brain. Furthermore, these technologies are advancing our understanding of the systemic connections between the eye and other organs, such as the brain, thyroid, and lymphatic systems. Tracers are helping to uncover new pathways for understanding these relationships and their impact on both ocular and systemic diseases. Despite challenges in clinical translation, biosafety, and specificity, advances in tracer design, particularly at the nanoscale, are driving the development of multimodal imaging platforms. As these technologies continue to evolve, they will increasingly support the development of tailored treatment regimens, improve early detection, and facilitate the monitoring of therapeutic outcomes. Full article

Efficient nutrient management through fertigation is essential for sustaining table grape production under water-limited Mediterranean environments. This study evaluated the effects of graded potassium (K) fertigation rates on yield and berry quality of grapevines under semi-arid conditions in northern Jordan. Field experiments were conducted over three consecutive seasons at three locations using four potassium application rates (0, 100, 200, and 300 kg K₂O ha⁻¹) applied through drip fertigation and synchronized with key vine phenological stages. Yield and fruit-quality parameters were analyzed using linear mixed-effects models accounting for treatment, year, location, and their interactions. Potassium fertigation significantly increased total yield, cluster weight, and berry physical attributes, including firmness, volume, weight, and diameter, whereas total soluble solids (TSS) and juice pH were largely unaffected. Relative to the control, potassium fertigation progressively increased total yield per vine by approximately 21%, 47%, and 72% under the 100, 200, and 300 kg K₂O ha⁻¹ treatments, respectively, although the magnitude of response differed among locations and growing seasons. Significant treatment × location interactions indicated that site-specific soil conditions influenced potassium response. These results demonstrate that synchronizing potassium supply with vine phenological demand through fertigation enhances productivity and berry physical quality without compromising fruit chemical composition. The observed improvements are consistent with the established physiological roles of potassium in osmotic regulation, assimilate transport, and berry development, supporting optimized potassium fertigation as a key component of precision nutrient management for sustainable viticulture in semi-arid Mediterranean regions. Full article

Preterm birth is a major cause of neonatal morbidity and mortality, and many spontaneous cases remain idiopathic. Increasing evidence suggests that intrauterine inflammation may occur in the absence of detectable infection, leading to the recognition of sterile intrauterine inflammation as an important mechanism contributing to threatened preterm labor and spontaneous preterm birth. This review summarizes current knowledge regarding the role of damage-associated molecular patterns (DAMPs), alarmins, pattern recognition receptors, inflammasome activation, cellular senescence, and pyroptosis in the initiation of sterile inflammatory pathways associated with labor. Key mediators including HMGB1, IL-1α, fetal cell-free DNA, platelet-activating factor, and S100 proteins appear to promote inflammatory activation within fetal membranes and the amniotic cavity. The review also discusses the emerging contribution of fetal immune activation, maternal–fetal immune dysregulation, maternal microchimerism, and epigenetic mechanisms to idiopathic preterm birth. Current diagnostic and therapeutic options remain limited, and no targeted treatment for sterile intrauterine inflammation has yet been established. Future approaches may include precision biomarkers, multiomics-based risk stratification, targeted immunomodulatory therapies, and modulation of maternal–fetal immune interactions. Improved understanding of sterile inflammatory mechanisms may ultimately support development of personalized strategies to prevent preterm birth and improve perinatal outcomes. Full article