Search Results (1,979)

Background/Objectives: VEXAS (Vacuoles, E1-Enzyme, X-linked, Autoinflammatory, and Somatic) syndrome is a recently described adult-onset autoinflammatory disorder. It is characterized by somatic mutations in the UBA1 gene, systemic inflammation, macrocytic anemia, cytopenias, and bone marrow vacuolization and frequently overlaps with Sweet’s syndrome, relapsing polychondritis, and myelodysplastic syndrome (MDS). Because treatment options are evolving, we reviewed the current and latest evidence of clinical features and therapeutic methods. Methods: A comprehensive literature review was conducted using PubMed and MEDLINE for studies published between 1 January 2020 and 1 July 2025. Search terms included “VEXAS” and “treatment.” Eligible publications comprised clinical trials, multicenter and observational studies, and case reports containing therapeutic data. Findings were analyzed narratively with emphasis on treatment response, steroid-sparing effects, survival outcomes, and molecular responses. Results: Glucocorticoids remain the first-line therapy for acute management; however, this comes with near-universal steroid dependence. DMARDs and TNF-α inhibitors showed limited benefits. IL-6 inhibitors and JAK inhibitors showed improvement in overall response, with JAK inhibitors demonstrating a superior effect. Ruxolitinib showed a higher complete response rate and transfusion independence compared to other JAK inhibitors. Hypomethylating agents, particularly azacitidine, improved hematologic responses in patients with co-existing MDS and reduced UBA1 variant allele burden. Allogeneic hematopoietic stem cell transplantation may be the only current curative method, though with notable transplant-related mortality. Conclusions: JAK inhibitors and hypomethylating agents offer promising disease-modifying potential, while transplant may provide curative intent in selected patients. Ongoing clinical trials are taking place to dictate the treatment direction of VEXAS syndrome. Full article

Impacted mandibular third-molar surgery commonly causes early postoperative pain, swelling, and trismus. This randomized, controlled, three-arm parallel trial evaluated whether intra-alveolar corticosteroid delivery via an absorbable gelatin sponge improves postoperative recovery compared with a saline control. Fifty-five patients were assessed for eligibility; 37 healthy adults (18–35 years) undergoing standardized mandibular third-molar extraction were randomized to dexamethasone 8 mg (Decort^®), methylprednisolone 40 mg (Prednol^®), or control (saline), all applied intra-alveolarly using a gelatin sponge carrier. Doses were selected using standard systemic glucocorticoid equivalence tables as a pragmatic potency reference, acknowledging unknown intra-alveolar pharmacokinetics/bioavailability. The prespecified primary endpoint (used for sample size planning) was postoperative Day 1 VAS pain; key secondary endpoints were Day 1 analgesic consumption and Day 3 facial swelling. Pain (VAS), analgesic use, trismus, and facial swelling (tragus–pogonion, tragus–labial commissure, and angulus–canthus distances) were assessed on postoperative Days 1, 2, 3, and 7 by a blinded evaluator. Two participants in the methylprednisolone group did not attend postoperative visits. To address potential attrition bias, an Intention-to-Treat (ITT) sensitivity analysis using conservative control-median imputation was performed alongside the available-case analyses. A global False Discovery Rate (FDR) correction was also applied to control for multiplicity. In both analyses, the steroid groups showed lower Day 1 pain scores than the control group. Methylprednisolone was associated with lower Day 3 swelling values than control for the tragus–pogonion and angulus–canthus measurements. These findings should be interpreted as preliminary, given the small sample size, linear swelling measurements, and lack of blinding verification. Full article

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which B-cell dysregulation plays a central pathogenic role beyond autoantibody production. Advances in B-cell biology have led to the development of targeted therapies, including inhibition of the B-cell activating factor (BAFF) pathway. Belimumab, a monoclonal antibody that neutralizes soluble BAFF, modulates B-cell survival signals upstream, promoting progressive immunologic remodeling rather than rapid depletion. This review integrates current knowledge on BAFF-dependent B-cell biology with mechanistic, pharmacokinetic, and clinical data to provide a comprehensive framework for understanding belimumab’s effects in SLE and lupus nephritis (LN). Belimumab preferentially reduces transitional and naïve B cells, while memory B cells show a relative transient increase followed by a gradual return to baseline levels, reflecting redistribution rather than expansion, and long-lived plasma cells are largely unaffected. These effects result in progressive remodeling of B-cell compartment dynamics and contribute to broader modulation of adaptive immune amplification pathways. Pharmacokinetic data support a threshold-based model of BAFF neutralization, with exposure influenced by disease-related factors such as proteinuria in LN. Clinical response is primarily determined by baseline disease biology, with greater benefit observed in patients with serologically active disease and less established organ involvement. Across clinical trials and real-world studies, belimumab reduces disease activity and flares, enables glucocorticoid tapering, and slows organ damage accrual. In LN, it improves renal outcomes and reduces the risk of kidney-related events. Collectively, these findings support belimumab as a disease-modifying therapy in SLE. Further research is needed to refine patient selection and optimize treatment sequencing and combination strategies. Full article

Background: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody (ANCA)-associated necrotizing vasculitis primarily affecting small and medium-sized vessels. The typical presentation commonly includes upper and/or lower respiratory tract and renal involvement. GPA has a particularly strong association with proteinase-3 (PR3) ANCA. Though well defined, GPA may be clinically difficult to recognize, particularly in early disease. Initial presentations may include nonspecific symptoms, including but not limited to fatigue, fever, and sinus congestion or sinusitis, which may be mistaken for infection. Though initial ANCA testing is useful, it is not definitive as early stages of disease may be negative, thus delaying diagnosis; Clinical Significance: This case highlights the importance of including GPA in the differential diagnosis of patients with unremitting upper or lower respiratory and constitutional symptoms despite negative ANCA testing. Though atypical, GPA cases may lack renal involvement and even have negative ANCA serologies, leading to a delay in diagnosis and increased morbidity. ANCA positivity can be as low as 60% in limited GPA cases, and less than 20% of individuals have renal involvement at presentation. If GPA suspicion is high, repeat testing and biopsy are warranted; Case Presentation: A woman in her 50s initially presented to the emergency department with recurrent/persistent fever with nonspecific sinus symptoms that remained unresolved despite multiple outpatient treatments and tests. Infectious work-up was negative. She was found to have multiple pulmonary nodules on various scans. Initial testing on admission was unremarkable or nondiagnostic, including anti-neutrophil cytoplasmic antibody (ANCA) serologies. The patient’s hospital course was complicated by acute hypoxic respiratory failure with distributive shock during bronchoscopy. Repeat serological testing was positive for PR3-ANCA, and lung biopsy demonstrated necrotizing granulomatous vasculitis consistent with a diagnosis of granulomatosis with polyangiitis (GPA). The patient demonstrated clinical improvement with avacopan, glucocorticoids, and rituximab; Conclusions: The diagnosis of GPA should be suspected in all patients with nonspecific constitutional symptoms along with clinical evidence of upper/lower respiratory tract involvement, regardless of renal function. Physicians with a strong suspicion of an autoimmune disease, such as GPA, should utilize a thorough clinical history, physical exam, and other labs in the setting of a negative autoimmune marker and/or negative imaging. Clinical judgment is required to not rule out GPA despite a negative workup when other more serious causes have been excluded, as the diagnosis may be life-threatening. Full article

Canine atopic dermatitis is a hereditary chronic inflammatory and pruritic skin disease, which is mediated by T cells and requires long-term, individualized management. In recent years, numerous studies have described a wide range of therapeutic approaches for canine atopic dermatitis, including fast-acting symptomatic treatments, long-term immune-modulating interventions, and strategies to support skin barrier function and microbial balance. This review summarizes the principal treatment modalities currently available, including glucocorticoids, cyclosporine A, mycophenolate, Janus kinase inhibitors, lokivetmab, and allergen-specific immunotherapy, as well as complementary strategies aimed at restoring skin barrier integrity. Emphasis is placed on the importance of a multimodal and personalized approach to optimize long-term disease control and improve quality of life in affected dogs. Providing an integrated overview of current evidence, this article aims to guide clinicians in making informed, evidence-based decisions and to support the safe and effective management of canine atopic dermatitis. Full article

This case highlights a novel genotype–phenotype correlation in the field of endocrinology. Specific endocrine and imaging assessment, in addition to next-generation sequencing (NGS), was performed on the Illumina MiSeq platform, using a TruSight One Sequencing Panel kit for genomic analysis of coding regions of 4813 genes. A 54-year-old female was confirmed with a papillary thyroid carcinoma after total thyroidectomy and underwent radioiodine ablative therapy. Three years later, a left femoral enchondroma of almost 3 cm was identified at computed tomography (CT) scan and magnetic resonance imaging (MRI). She experienced hypertension (in addition to obesity, dyslipidaemia and impaired glucose tolerance) and was later confirmed with ACTH-independent cortisol excess [lack of cortisol suppression at 1 mg dexamethasone testing of 13.9 (normal < 1.8 µg/dL)], noting bilateral adrenal tumors, of 4.7 cm (right), respectively, and of 1.6 cm (left) at CT. Right laparoscopic adrenalectomy was performed with post-operative adrenal insufficiency, requiring glucocorticoid replacement and stopping the anti-hypertensive medication. Pathology report confirmed an adrenocortical adenoma (a Ki67 proliferation index of 2%). Noting the unusual association of the mentioned conditions, NGS was performed in the peripheral blood and identified a heterozygote missense variant of the APC gene (c.5759G>A, p.Arg1920Gln), a heterozygote missense variant of the MSH6 gene (c.2092C>G, p.Gln698Glu), and an incidental additional finding: a heterozygote stop gain pathogenic variant of the CACNA1S gene (c.2707C>T, p.Arg903*). The first two are currently classified as variants of uncertain significance. Whether the co-presence of a triple mutation may change the clinical picture and the life-long outcomes across reciprocal influence is still an open matter. Further research will point out the clinical implications of this genotype–phenotype association, which, to our best knowledge, has not been previously reported. Full article

In vertebrates, corticosterone and cortisol are glucocorticoid (GC) steroid hormones central to the vertebrate stress response, but their relative contribution depends on context and life history. We used water-borne hormone sampling in lesser sirens, Siren intermedia, to examine whether corticosterone or cortisol predominates in stress responses and evaluated whether dermal secretions reliably track acute corticosterone changes. First, we measured corticosterone via dermal swabbing over a 2 h period following a hand-restraint stressor. Dermal corticosterone did not increase relative to pre-stressor baseline levels during the 2 h sampling period, suggesting that dermal measurements may not reflect acute circulating GC changes. We then measured cortisol and corticosterone across the GC profile (baseline, stressed, and recovery) using water-borne sampling techniques in juveniles. Cortisol release rates were significantly higher than corticosterone and were elevated during the recovery phase relative to baseline (p = 0.08), whereas stressed samples did not differ from baseline. Additionally, cortisol release rates were positively associated with temperature, while no effect of temperature was detected on corticosterone. Although cortisol and corticosterone were strongly correlated, cortisol responded to environmental temperatures and was repeatable, whereas corticosterone was not. Finally, we validated the use of water-borne sampling techniques to measure cortisol and corticosterone in S. intermedia. Cortisol was higher in juvenile sirens, highlighting that each GC may play functionally distinct roles across contexts. Together, these findings indicate that cortisol is the more environmentally responsive GC in juvenile S. intermedia and that water-borne sampling provides a more reliable method for assessing acute stress physiology in this species. Full article

Glucocorticoid-induced hypertension affects over 30% of treated patients, yet its underlying mechanisms remain unclear, particularly how glucocorticoids regulate renin within the renin-angiotensin-aldosterone system (RAAS). Modeling these dynamics is difficult because only four dose-response measurements are available at a single 24-h timepoint (36 observations total), while the system depends on roughly eleven biochemical parameters spanning minutes-long receptor interactions to days-long protein secretion. Classical parameter estimation becomes unreliable in this extremely underdetermined setting, and purely data-driven methods offer limited biological interpretability. In this paper, we introduce a physics-informed neural network (PINN) framework that integrates ELISA measurements from As4.1 juxtaglomerular cells, ordinary differential equations describing glucocorticoid receptor signaling and renin transcription, and automatic differentiation to enforce mechanistic constraints. By systematically tuning synthetic-data weights (SW in {0.2, 0.3, 0.5}), we identify an intermediate value of SW = 0.3 that provides the best overall balance between predictive accuracy, accepted ensemble size, and biologically plausible parameter estimates among the tested configurations. The framework uses adaptive constraint scheduling with a plateau ramp to reduce premature convergence and introduces calibrated plausibility thresholds reflecting experimental noise. The accepted PINN ensemble (n = 5, 50% success rate) achieved R² = 0.803, compared with 0.759 for the SW = 0.5 baseline and −0.220 for the ODE-only baseline, with RMSE = 0.024. Key learned parameters (IC₅₀ = 2.925 ± 0.012 mg/dL, Hill = 1.950 ± 0.009) are biologically plausible within the model assumptions, and the best single accepted model attained R² = 0.891. Information criteria favored the PINN over the ODE model, with improvements of approximately 77× (AIC) and 5.9× (BIC). Despite training on a single timepoint, the PINN also infers full 48-h trajectories and reproduces non-monotonic dose-response behavior. This work presents, to our knowledge, the first PINN framework for glucocorticoid-mediated renin regulation and should be interpreted as a proof-of-concept approach for integrating sparse biomedical data with mechanistic constraints. The inferred parameters and temporal dynamics are best viewed as model-dependent, hypothesis-generating estimates rather than validated biological quantities. Full article

Maternal nutrition during late gestation is critical for fetal development, neonatal resilience, and postnatal adaptation in beef cattle. This study aimed to evaluate the effects of nutritional restriction and supplementation of hydroxytyrosol (HT) in late pregnancy on behavioural, circadian, stress-related, and inflammatory responses in cows and their restricted nursed offspring. Pregnant cows were allocated to a 2 × 2 factorial experimental design (feeding level: T100% vs. T60% of nutrient requirements; HT: 0 vs. 180 mg/kg of diet). Cow behaviours were recorded during meals (from week −12 prepartum to term), and calf activities, body temperature, and mother–offspring interactions were assessed at 5 weeks postpartum. Nutritional restriction accelerated feed intake in cows and increased stress-related behaviours, while HT partially mitigated these effects. Molecular analyses in blood samples revealed dynamic prepartum upregulation of glucocorticoid-receptor NR3C1 in week −6, and downregulation of circadian (BMAL1, PER1, CRY1) gene expression in week 5 after parturition, both in T60%-HT cows. In calves, maternal HT supplementation promoted active exploratory behaviour, and counteracted behavioural and circadian (CRY1 and PER1) and inflammatory markers (IL8) gene expression resulting from prenatal nutrient restriction, leading to behavioural profiles and blood gene expression comparable to those observed in calves born to adequately fed dams. Full article

SUMOylation may be involved in preeclampsia (PE) progression. We aimed to investigate the roles of SUMOylation in PE and its underlying mechanism using animal and cell models. A rat PE model was established by dexamethasone (DEX) treatment from pregnancy day 7.5–17.5. HTR8 and BeWo trophoblasts were used as cell models. Placental RNA-seq analysis coupled with Western blotting showed upregulated SUMOylation in placentas of DEX-treated rats. SUMOylation inhibitor TAK-981 treatment robustly alleviated PE-like features including reduced blood pressure and improved renal injury, fetal weight, spiral artery remodeling and placental blood flow in DEX-treated rats. DEX increased SUMOylation in HTR8 and BeWo cells. TAK-981 reversed DEX-induced dysfunction in HTR8 and BeWo cells, such as migration, invasion and syncytialization. Mass spectrum analysis of SUMO1 immunoprecipitation coupled with functional validation showed that SUMOylated proteins related to oxidative stress caused by DEX were reversed by TAK-981 in cultured trophoblasts. TAK-981 mitigated placental oxidative stress in DEX-treated rats. GEO database combined with Western blotting showed upregulated SUMOylation in human placentas with PE. Our findings indicate that protein SUMOylation is one of the key events in PE, particularly in that associated with high glucocorticoid exposure. Targeting placental SUMOylation might be a promising therapeutic strategy for PE. Full article

Dietary supplementation with functional nutrients is a safe strategy to improve bone health. This study aimed to investigate the ameliorative effects of Berberine (BBR) on dexamethasone-induced bone loss in mice and its potential mechanisms. Micro-CT, histological staining, ELISA and Western blot were employed to evaluate BBR’s skeletal benefits; 16S rRNA sequencing, serum metabolomics and correlation analysis were used to explore its regulatory mechanisms. In vivo experiments showed that BBR improved bone mineral density and trabecular microarchitecture, and upregulated osteogenic markers (COL1 and BMP2). Intestinal bacterial sequencing showed that BBR altered gut bacterial composition, increasing the abundance of Desulfovibrio and Bacteroides while decreasing opportunistic pathogens. BBR also modulated bacterial richness, evenness, and community stability. Serum metabolomics identified 107 BBR-reversed differential metabolites; of these, 33.64% were lipids and lipid-like molecules, which were mainly involved in glycerophospholipid metabolism. Further correlation analysis revealed that BBR-enriched Desulfovibrio was linked to pathway R04864, producing a key glycerophospholipid metabolite positively correlated with bone mass parameters. Overall, these findings suggest that the attenuation of bone loss by BBR may be associated with alterations in the gut microbiota–glycerophospholipid metabolic axis, supporting its potential as a functional food ingredient for bone health. Full article

Adult acute lymphoblastic leukemia (ALL) is a highly heterogeneous hematologic malignancy where treatment response and relapse risk do not exclusively rely on the identification of genetic lesions but also on dynamic biological states sustained by specific transcriptional and epigenetic programs. Although the integrated application of multi-omics approaches has significantly expanded our knowledge of oncogenic dependencies, cellular plasticity, and mechanisms of therapeutic resistance, its systematic translation into the clinical practice of adult ALL is yet to become a reality. The aim of this review is to provide a critical and focused synthesis on how the integration of genomics, transcriptomics, and epigenetics enables the interpretation of disease biological behaviors and may guide personalized therapeutic strategies while simultaneously addressing the major limitations that hinder clinical implementation. Genomics allows for the identification of driver events and pharmacologically actionable vulnerabilities, whereas transcriptomics, including single-cell analyses, reveals functional states associated with clonal persistence, glucocorticoid resistance, and therapeutic adaptation, even in the absence of new mutations. In parallel, epigenetic signatures emerge as key elements in stabilizing oncogenic programs and resistant phenotypes, contributing to the biological plasticity of leukemic cells and representing potentially reversible therapeutic targets. Taken together, multi-omics signatures provide an integrated functional readout of adult ALL and support a dynamic precision-medicine model. However, adaptive therapeutic decisions aimed at relapse prevention require the full integration of these approaches through standardized strategies, longitudinal studies, and a sustainable implementation of molecular profiling and minimal residual disease monitoring. Full article

This study investigated whether tongue motor loss induced by bilateral transection of the hypoglossal nerves (Hx) alters anxiety- and/or depression-like behaviors in rats and examined the associated neuroendocrine changes. Male Sprague–Dawley rats underwent Hx or sham surgery and were evaluated in the ambulatory activity, elevated plus maze, forced swim, and sucrose preference tests at different postoperative time points. Neuroendocrine parameters were assessed by plasma corticosterone assay, quantitative real-time PCR, Western blot analysis, and adrenal histology. At two weeks after surgery, Hx rats exhibited anxiety-like behavioral changes in the elevated plus maze and increased immobility with reduced struggling in the forced swim test, consistent with a depression-like behavior. Reduced sucrose intake was observed at earlier postoperative stages, suggesting early anhedonia-like behavior. Hx rats also showed chronically increased plasma corticosterone levels, adrenocortical hypertrophy, and decreased hippocampal glucocorticoid receptor expression. These findings highlight a potential oral–systemic interaction in which loss of oral motor function alters neuroendocrine homeostasis and emotional regulation. Full article

Chronic stress is defined as a prolonged state of emotional disturbance and psychological strain resulting from an inability to maintain internal homeostasis. It is recognized as a significant risk factor for breast cancer, primarily through the chronic activation of the sympathetic nervous system and the hypothalamic–pituitary–adrenal (HPA) axis. This neuroendocrine activation leads to elevated systemic levels of epinephrine, norepinephrine, and glucocorticoids. By binding to their respective adrenergic and glucocorticoid receptors, these hormones disrupt immune homeostasis and exacerbate oxidative stress within the tumor microenvironment. Such physiological shifts promote critical oncogenic processes, including angiogenesis and tumor cell proliferation, thereby driving the development, progression, and distant metastasis of breast cancer. Mastication, or the act of chewing, serves as a practical and effective behavioral strategy for modulating the deleterious effects of chronic psychological stress. Recent animal studies have provided compelling evidence that chewing can attenuate excessive stress responses. Specifically, it has been shown to mitigate stress-induced breast cancer progression and metastasis by modulating the expression of stress hormones, their corresponding receptors, and key downstream signaling pathways. These findings suggest that the rhythmic activity of chewing may exert a protective effect against stress-related tumor exacerbation. Consequently, further clinical research is warranted to determine whether chewing interventions can serve as a viable complementary strategy alongside conventional breast cancer prevention and treatment protocols. Full article

Background: Tuberculosis (TB) remains a major global health threat, particularly in low- and middle-income countries, with TB infection (TBI) serving as the primary source of TB disease. While HIV infection has long been recognised as a major risk factor for TB progression, the rise of Non-Communicable Diseases (NCDs), which may exert immunosuppressive effects, further compounded by their treatment, contributes to increased TB susceptibility. This scoping review synthesises evidence from systematic reviews on medical and behavioural risk factors for TBI progression to TB disease, for both asymptomatic and symptomatic disease. Methods: A preliminary literature search was conducted on 11 January 2025, in PUBMED using the keywords “tuberculosis,” “asymptomatic or subclinical tuberculosis” “risk factors,” and “systematic review” followed by targeted reviews on the identified medical and behavioural risk factors for TB infection progression to TB disease. Results: A total of 25 systematic reviews were included. Medical risk factors for progression from TB infection to TB disease included diabetes mellitus (DM), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), undernutrition (including iron and vitamin D deficiency), cancer—particularly haematological malignancies—and immunosuppressive therapies (TNF-α inhibitors and glucocorticoids). Iron and vitamin D deficiency, particularly severe deficiency, is linked to increased TB risk, especially among people living with HIV. Behavioural risk factors, including tobacco, drug, and alcohol use, were also highlighted. Geographic variations in TB prevalence, diagnostic practices, and healthcare systems contributed to differences in risk estimates across reviews. No systematic reviews were identified that examined risk factors for asymptomatic TB. Conclusions: The convergence of TB with NCDs, compounded by immunosuppressive therapies, poses a public health challenge in high TB burden settings. Effective TB prevention requires targeted screening, along with enhanced management of these NCDs. Nutritional support, particularly screening and treatment of anaemia and vitamin D deficiency, may benefit individuals with TBI, comorbid NCDs, and HIV. A multidisciplinary approach, integrating behavioural interventions and tailored prevention strategies, is essential to achieving WHO’s End TB targets. Addressing the evidence gap on risk factors for asymptomatic TB is also critical to improve early detection and interrupt transmission. Full article