Search Results (848)

Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder frequently associated with ovarian teratomas in young women. Although infectious triggers have been proposed to contribute to immune activation, direct evidence linking viral presence within tumor tissue to disease pathogenesis remains limited. Case Presentation: An 18-year-old woman presented with acute neuropsychiatric symptoms, fever, gastrointestinal prodrome, and rapidly progressive behavioral disturbance progressing to encephalopathy. Cerebrospinal fluid and blood test results, together with clinical features, supported the diagnosis of anti-NMDAR encephalitis. Imaging identified an ovarian mass, and surgical resection was performed. Histopathology confirmed a mature teratoma containing neuroglial elements. Molecular analysis detected parvovirus B19 DNA within the resected teratomatous tissue. No systemic viremia or active central nervous system viral infection was identified. The patient received immunotherapy combined with tumor removal, with subsequent clinical improvement. Discussion: Ovarian teratomas remain a critical etiologic factor in anti-NMDAR encephalitis and mandate prompt surgical management. Detection of B19 viral DNA within teratomatous neuroglial tissue raises the hypothesis that viral persistence could enhance local immune activation and autoantibody generation. However, in this case polymerase chain reaction positivity does not indicate active infection, and the biological significance of this finding remains uncertain. Conclusions: This case documents rare detection of B19V DNA within an ovarian teratomatous tissue in anti-NMDAR encephalitis. The observation is hypothesis-generating rather than causal; established management priorities remain immunotherapy and tumor resection, and viral nucleic acid detection should be interpreted within the broader clinical context. Full article

Atopic dermatitis (AD) is a chronic inflammatory skin disorder that is significantly contributed to by epigenetics. We developed a machine learning-based framework to identify DNA methylation biomarkers associated with AD classification and severity. Genome-wide methylation data from peripheral blood were processed using four feature selection algorithms: coarse approximation linear function (CALF), elastic net (EN), minimum redundancy maximum relevance (mRMR), and recursive feature elimination with cross-validation (RFECV). The integrative framework identified a central panel of 8 CpG sites that achieved an area under the curve (AUC) of 1.00 in the test set. This panel demonstrated high disease specificity, showing poor classification performance for systemic lupus erythematosus (AUC = 0.46), Crohn’s disease (AUC = 0.50), and oral squamous cell carcinoma (AUC = 0.58). Severity prediction using RFECV-selected 63 CpG sites (RFE63) achieved high accuracy across classifiers, with Random Forest (accuracy = 0.94) outperforming the others. The functional enrichment of CpG-associated genes highlighted key immune-related transcriptional regulators, including STAT5A, RUNX1, MEIS1, and PAX4. These genes are linked to chromatin remodeling, T helper cell differentiation, and interleukin-2 regulation, which are critical in AD pathogenesis and severity. Our findings demonstrate the utility of machine learning-integrated epigenomics in identifying robust, disease-specific biomarkers for AD diagnosis and monitoring, offering new insights into the molecular mechanisms underlying childhood AD. However, further validation in large-scale independent cohorts is required to confirm their clinical robustness and generalizability. Full article

Hypoxic pulmonary hypertension (HPH), classified as Group 3 pulmonary hypertension in the current clinical classification system, represents a complex and progressive cardiopulmonary disorder characterized by elevated pulmonary arterial pressure due to chronic alveolar hypoxia. This condition significantly contributes to morbidity and mortality in patients with chronic lung diseases and individuals residing at high altitudes. The pathogenesis of HPH involves a multifactorial interplay between sustained hypoxic pulmonary vasoconstriction, pulmonary vascular remodeling, endothelial dysfunction, and inflammatory responses. This review provides a comprehensive synthesis of recent advances in HPH pathophysiology and their clinical translation, with a focus on integrating molecular mechanisms with emerging therapeutic strategies. The pathogenesis of HPH involves a complex interplay of hypoxia-inducible factor (HIF) signaling, mechanosensitive ion channel dysregulation (particularly TRPC channels), metabolic reprogramming featuring glycolytic shift and mitochondrial dysfunction, immune–inflammatory mechanisms including macrophage-centered immunopathology, and dysregulation of the nitroxidergic system. Recent clinical advances include refined risk stratification using advanced echocardiographic techniques, identification of novel biomarkers such as lactylation-associated proteins, and development of targeted therapies including immunomodulatory approaches, metabolic modulators, and epigenetic interventions. Ongoing clinical trials are investigating innovative strategies ranging from iron supplementation to nanoparticle-based drug delivery systems. Despite these advances, significant translational challenges remain, including limitations of preclinical models, patient heterogeneity, and the need for HPH-specific outcome measures. This review bridges the gap between mechanistic insights and clinical applications, offering an integrated framework that highlights precision medicine approaches, emerging therapeutic targets, and priority research directions for improving outcomes in this challenging condition. Full article

Gastrointestinal indolent B-cell lymphomas (GI-iBCLs) are a group of low-grade, slowly progressive malignancies, accounting for approximately 1–4% of all gastrointestinal tumors. They represent the most common type of extranodal indolent B-cell lymphoma. Their clinical presentation often overlaps with that of benign inflammatory conditions, posing diagnostic challenges. In recent years, the incidence of GI-iBCL has been increasing in Asia and Europe, while advances in molecular pathology have facilitated more precise classification. This review systematically summarizes recent progress in understanding the epidemiology, clinical features, pathogenesis, pathological characteristics, treatment, and prognosis of GI-iBCLs, with a specific focus on mucosa-associated lymphoid tissue (MALT) lymphoma and duodenal-type follicular lymphoma (DTFL). We also discuss critical issues such as the risk of histological transformation, treatment optimization for refractory cases, the potential of molecular markers, and the evolving landscape of precision medicine. Full article

Endometriosis and PCOS are both leading causes of female infertility, each affecting approximately 10% of reproductive-aged women worldwide. Both conditions markedly impair quality of life by affecting physical health, emotional well-being, mental health, and social functioning, and they impose a substantial economic burden through surgical treatments, assisted reproductive technologies, and work absenteeism. Insulin resistance (IR) plays a key role in the pathogenesis of both disorders by promoting chronic low-grade inflammation and disrupting sex hormone homeostasis. Consequently, interventions targeting metabolic dysfunction and inflammatory processes may improve clinical outcomes. In this context, the kynurenine system—the primary metabolic pathway of tryptophan degradation—has emerged as a potential mechanistic link between inflammation, metabolic disturbances, and reproductive disorders. Chronic inflammation and psychological stress can enhance kynurenine pathway activation, leading to immune dysregulation, oxidative stress, altered neuroendocrine signaling, and impaired ovarian function. Dysregulated kynurenine metabolism has also been associated with IR and mood disturbances, which are common features of endometriosis and PCOS. Physical activity (PA) is widely recognized for its anti-inflammatory, metabolic, and stress-reducing effects. Emerging evidence suggests that PA may also modulate the kynurenine system by shifting tryptophan metabolism toward neuroprotective pathways. Various exercise modalities—including aerobic, resistance, and mind–body exercises—have shown beneficial effects; however, well-designed long-term studies are still needed. The aim of this review is to synthesize and critically evaluate the published literature on the effects of PA on IR, inflammation, kynurenine metabolism, and reproductive health in women with endometriosis and PCOS. Full article

Foreign material is an uncommon finding in routine gastrointestinal histopathology, but may occasionally contribute to disease pathogenesis or create diagnostic pitfalls. We report two illustrative cases highlighting the diverse clinical and histologic implications of ingested plant material. The first case involves a 10-year-old boy who presented with clinical features consistent with acute appendicitis and underwent appendectomy. Although gross examination revealed a macroscopically unremarkable appendix, histological evaluation demonstrated mucosal ulceration associated with an impacted plant seed within the appendiceal lumen, supporting a diagnosis of obstructive acute appendicitis. The second case describes a 60-year-old woman undergoing a screening colonoscopy, during which a small sessile lesion in the transverse colon was resected. Histologic examination revealed no colonic mucosa; instead, the specimen consisted entirely of plant material, morphologically consistent with a tomato seed, representing an incidental finding mimicking a colonic polyp. These cases underscore that plant seeds, while rare, may act as obstructive agents in appendicitis or simulate true pathological lesions during endoscopic and histologic evaluation. Awareness of the characteristic microscopic features of plant material is essential to avoid misdiagnosis and to recognise their potential clinical and forensic relevance. Full article

Colitis-associated carcinoma (CAC) represents ~1% of colorectal carcinomas and has important differences from sporadic colorectal carcinoma (sCRC). The precursors and carcinomas that arise in the setting of IBD are uniquely challenging to visualize by endoscopy and diagnose via histology, and the rising prevalence of IBD amplifies the challenges of surveillance to informed management. Although in broad strokes, CAC and sCRC share molecular features (~85% chromosomal instability pathway 15% microsatellite instability high (MSI-H)), CAC has a distinct distribution of molecular abnormalities, including lower frequencies of APC and KRAS mutations, greater prevalence of IDH1R132H, and more frequent copy number alterations (e.g., MYC amplifications), and functional data indicate that most CACs show far less dependence on Wnt signaling than sCRC, suggesting a distinct pathogenesis from the earliest stages. Although there are significant gaps in our knowledge of the pathogenesis of CAC, our understanding is growing. This review summarizes how chronic colitis reshapes epithelial homeostasis and somatic evolution, resulting in the distinctive pathogenesis of CAC, and highlights knowledge gaps that could be addressed by applying multimodal technologies to well-annotated clinical material. The review is structured in two sections, the first introducing the IBDs and the homeostatic mechanisms that preserve integrity and prevent colorectal neoplasia. The second section compares failure modes in sporadic and colitic settings and describes the differences in the resulting neoplasms. Full article

Background: Juvenile Idiopathic Arthritis (JIA) is the most prevalent rheumatological disease in childhood. It is classified into seven subtypes, each with specific clinical features. The pathogenesis of JIA involves an increased inflammatory response. Treatment options include pharmacological therapy, patient education, physical therapy, and rehabilitation. Methods: Patients received IAC injections and were subsequently divided into two groups: one group underwent HKT, while the other did not. The effects of HKT were assessed before treatment and one month after the IAC injections and initiation of HKT, using the Child Health Assessment Questionnaire (CHAQ), Visual Analogue Scale (VAS), and the Child Health Questionnaire—Parent Form 50 (CHQ-PF50). Results: Data were analyzed using the t-test. The HKT group showed non-statistically significant improvements in CHAQ and VAS scores compared to the non-HKT group. However, statistically significant differences were observed in the CHQ-PF50, particularly in the self-esteem and pain subscales. Conclusions: Although global differences between groups were not statistically significant, the group that underwent HKT demonstrated better scores, suggesting that HKT may reduce pain and contribute to improved quality of life in children with JIA. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and remains incurable in approximately 30–40% of patients despite advances in immunochemotherapy. Although gene expression profiling has improved risk stratification, there is an ongoing need for non-invasive, cost-effective, and clinically practical biomarkers to identify patients at high risk of treatment resistance or relapse (R/R). Systemic inflammation plays a pivotal role in DLBCL pathogenesis, impacting both tumor progression and treatment response. The C-reactive protein–albumin–lymphocyte (CALLY) index, integrating markers of inflammation, nutritional status, and immune competence, has demonstrated prognostic relevance in solid tumors; however, its relevance in hematologic malignancies remains unexplored. Methods: We retrospectively analyzed 180 adults with newly diagnosed DLBCL, NOS (not otherwise specified) who received frontline rituximab-based immunochemotherapy (R-CHOP or CHOP-like regimens) between January 2014 and December 2019 at three tertiary centers in Serbia. The median age was 67 years (IQR 59–73), and 56.1% were female. Receiver operating characteristic (ROC) analysis determined 6.5 as the optimal CALLY index cut-off (AUC 0.744, 95% CI 0.670–0.817; p < 0.001). Results: A low CALLY index (<6.5) was significantly associated with adverse clinical features, including anemia, elevated lactate dehydrogenase and β2-microglobulin, poor ECOG performance status, bulky disease, advanced stage, and unfavorable IPI, R-IPI, and NCCN-IPI scores (all p < 0.001). In contrast, no associations were observed with tumor subtype, immunophenotype, or comorbidities. Furthermore, patients with CALLY <6.5 showed lower overall response rates to treatment (59.6% vs. 85.5%, p < 0.001) and higher relapse rates (21.0% vs. 6.2%, p = 0.014). They also experienced reduced 3- and 5-year overall survival (OS) and event-free survival (EFS) (all p < 0.001). In multivariate analysis, a low CALLY index independently predicted poorer OS (HR 2.04, 95% CI 1.13–3.67; p = 0.017) and EFS (HR 1.89, 95% CI 1.13–3.14; p = 0.015). In addition, it independently identified patients at risk of relapsed/refractory (R/R) disease (OR 2.50, 95% CI 1.02–10.10; p = 0.04), outperforming standard prognostic indices. Conclusions: The CALLY index is a simple, low-cost, and widely accessible biomarker that independently predicts prognosis in DLBCL, NOS. It outperforms standard indices in identifying R/R cases. The CALLY index may enhance risk stratification and guide individualized treatment strategies. Full article

Liver cirrhosis represents the end stage of chronic liver disease arising from diverse etiologies and is characterized by persistent hepatic injury, architectural distortion, extensive fibrosis, and nodular regeneration. While decompensated cirrhosis is commonly associated with overt, life-threatening complications such as hepatic encephalopathy, hepatorenal syndrome and gastrointestinal bleeding, less apparent manifestations—including sarcopenia and metabolic disturbances—have emerged as major determinants of prognosis. Sarcopenia, defined by the progressive loss of skeletal muscle mass and function, is highly prevalent in cirrhotic patients and is closely linked to frailty, increased morbidity, mortality, and adverse liver transplantation outcomes. Increasing data support the role of gastrointestinal dysfunction in the pathogenesis of sarcopenia in liver cirrhosis. In chronic liver disease, intestinal dysfunction is exacerbated by portal hypertension, which promotes increased intestinal permeability and bacterial translocation. Furthermore, gut dysbiosis, a key feature of advanced liver disease, contributes to impaired digestion, malabsorption of macro- and micronutrients, increased intestinal permeability, malnutrition and systemic inflammation. These alterations promote negative energy balance, reduce muscle protein synthesis and enhance muscle catabolism, thereby accelerating muscle wasting. Despite increasing recognition of the individual roles of gut dysbiosis, malabsorption, and sarcopenia in cirrhosis, their complex interrelationship has not been comprehensively addressed. This narrative review synthesizes current evidence on the interplay between gut dysbiosis, malabsorption and sarcopenia in patients with liver cirrhosis. We discuss underlying pathophysiological mechanisms, clinical implications and potential therapeutic strategies, while highlighting existing knowledge gaps and future research directions. Improved understanding of the gut-liver-muscle axis may offer novel opportunities for early intervention and optimization of outcomes in this high-risk patient population. Full article

Cerebral small vessel disease (CSVD) is a leading cause of stroke, cognitive impairment, and vascular dementia, yet disease-modifying therapeutic strategies remain limited. Emerging evidence suggests that sleep fragmentation (SF), a common and often under-recognized feature of aging and cardiometabolic disorders, plays a pivotal role in CSVD pathogenesis by disrupting the glymphatic system, the brain’s primary waste clearance pathway. Sleep-dependent glymphatic function facilitates the removal of neurotoxic metabolites and maintains neurovascular homeostasis. In contrast, SF impairs cerebrospinal fluid (CSF)–interstitial fluid (ISF) exchange, promotes perivascular space enlargement, endothelial dysfunction, blood–brain barrier (BBB) breakdown, and chronic neuroinflammation, hallmarks of CSVD. This review synthesizes current mechanistic, preclinical, and clinical evidence linking SF to glymphatic dysfunction and small vessel pathology, framing these interactions as a sleep–glymphatic–vascular continuum underlying CSVD progression and cognitive decline. We further explore the emerging therapeutic potential of tocotrienols (T3), vitamin E isoforms with potent antioxidant, anti-inflammatory, and vasculoprotective properties, as modulators of neurovascular integrity within this continuum. Although direct evidence linking T3 to glymphatic regulation remains limited, converging data support their capacity to preserve endothelial function, attenuate oxidative stress, and stabilize astrocytic and BBB dynamics, mechanisms highly relevant to glymphatic and microvascular health. By integrating sleep biology, glymphatic neuroscience, and nutritional vascular protection, this review highlights hypothesis-generating preventive and therapeutic avenues for CSVD and delineates key knowledge gaps, including the need for longitudinal human studies, standardized glymphatic imaging, objective sleep phenotyping, and interventional trials to establish causal and translational relevance. Full article

Background: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that primarily affects the motor neurons. T cell intracellular antigen 1 (TIA1) is a risk gene for ALS pathogenesis. To elucidate TIA1-mediated disease mechanisms, a mouse model recapitulating clinical and pathological features of ALS is needed. TIA1 mutations are rare in human ALS, and mutations are heterozygous, while this study uses a homozygous TIA1 mutant mouse model to amplify pathogenic effects for experimental tractability. Methods: To explore the mechanisms by which mutant TIA1 causes ALS neurodegeneration, we generated a TIA1 mutant mouse by introducing ALS-causing mutations into the endogenous animal via cytosine base editors. Next, behavioral experiments (open-field and rotarod tests) assessed motor function and analyzed pathologies using morphological assessments. Results: Our TIA1Δ mouse model phenocopies select pivotal features of ALS, including TAR DNA-binding protein 43 (TDP-43) accumulation, motor neuron loss, neuroinflammation in the lumbar spinal cord, and muscle atrophy. Notably, this homozygous mutation design with reduced TIA1 expression differs from human heterozygous TIA1 mutations. Conclusions: This work provides a foundation for understanding the TIA1-ALS relationship and for developing strategies to treat this intractable neurodegenerative disorder. Caution is warranted extrapolating findings to human ALS pathogenesis due to model design differences. Full article

The Mediator complex is a central regulator of eukaryotic transcription, functioning as a dynamic molecular interface between gene-specific transcription factors and RNA polymerase II (Pol II). Although its overall architecture and general role in transcription have been extensively reviewed, accumulating genetic, genomic, and clinical evidence indicates that individual Mediator subunits make distinct and non-redundant contributions to human physiology and disease. In this review, we move beyond a generic description of Mediator function and present a subunit-resolved synthesis of Mediator biology with an emphasis on disease pathogenesis. A key feature of this review is a comprehensive table integrating disease associations and molecular functions of individual human Mediator subunits, enabling rapid assessment of functional specialization across the complex. We further discuss chromatin-based mechanisms of Mediator action, including cooperation with cohesin and architectural factors to regulate enhancer-promoter communication and higher-order genome organization. By organizing recent structural, mechanistic, and pathological findings into a unified framework, this review highlights how disruption of specific Mediator subunits contributes to cancer, developmental disorders, and metabolic disease, and outlines emerging opportunities for therapeutic intervention. Full article

Background/Objectives: An important diagnostic problem is to differentiate between active tuberculosis (TB) and latent TB infection (LTBI). Furthermore, the current biomarkers also offer minimal insight into disease pathogenesis to direct treatment. This triggered us to design a two-mode biomarker signature based on the multicohort analysis using a transcriptomic and stringent machine learning pipeline. Methods: When analyzing active TB, latent TB, and healthy control samples, a rigorous filter (ANOVA, p < 0.001) was used, followed by the selection of features with the help of Boruta-XGBoost and LASSO regression. This determined a small four-gene signature (TAP2, SORT1, WARS, and ANKRD22), which was selectively and highly upregulated in the active TB clinical state (p < 0.001). An ensemble staking classifier based on this signature (Random Forest and XGBoost) had a very high diagnostic performance (ROC-AUC = 0.991 (95% CI: 0.983–0.997)) in the stratification of infection phases, which was strongly confirmed in another cohort (GSE19444). Results: Importantly, the analysis of the functional pathways showed that all the genes are mapped to core dysregulated host pathways in active TB: antigen presentation (TAP2), lipid trafficking (SORT1), interferon response (WARS), and inflammasome signaling (ANKRD22). In such a way, the signature has a dual advantage: (1) high specificity, non-sputum transcriptional diagnostic of active TB, and (2) a mechanistic map of key host pathways, which describes targets of intervention. Conclusions: Thus, the signature provides a two-fold response: a biomarker panel aligned with WHO performance targets for TB triage and a mechanistic plan of therapy, which provides an easy way to implement transcriptomic discovery into clinical action against TB. Full article

Objectives: To characterize the clinical features, corneal topography, and imaging findings of peripheral hypertrophic subepithelial corneal degeneration (PHSCD) in a single-center study and to evaluate potential associations with systemic conditions. Methods: All patients underwent comprehensive ophthalmic examination, anterior segment photography, high-resolution spectral-domain optical coherence tomography (OCT), and corneal topography/tomography. Patient demographics, ocular history, systemic conditions, and corneal parameters were analyzed. Results: Fourteen patients were included in the study (11 females and 3 males). The mean age was 52.6 ± 12.4 years, and the mean best-corrected visual acuity was 0.56 ± 0.23. Five females had Hashimoto’s disease and two had hyperthyroidism. The mean central corneal thickness was 549.4 μm (SD = 71.0 μm), with significant sectoral thickness variations, particularly in the superior-nasal quadrants (SN-IT sector mean difference: 56.4 μm). High-resolution OCT revealed sharply demarcated, hyperreflective fibrosis within the anterior stroma, predominantly in the superior-nasal quadrants, causing corneal flattening with compensatory steepening and astigmatism. Three patients underwent in vivo confocal microscopy, which showed fibrotic acellular tissue adjacent to normal corneal epithelium. Conclusions: PHSCD predominantly affects middle-aged females and presents with characteristic peripheral, subepithelial fibrosis, causing significant corneal thickness variations and astigmatism. The observed association with thyroid disorders, particularly Hashimoto’s disease, suggests a potential immunological component in PHSCD pathogenesis that warrants further investigation. Advanced imaging with OCT and confocal microscopy provides valuable diagnostic information to accurately characterize this rare corneal condition. Full article