Search Results (20,780)

Human leukocyte antigen (HLA) loci are highly polymorphic genome regions, with allele frequencies varying significantly across different populations. Population HLA frequency databases may contain biases and make cross-study comparison complicated due to varying data curation protocols, genotyping methodologies, resolution, and inconsistencies in the selection criteria for population samples. This study presents HLA allele frequencies of class I (HLA-A, -B, -C) and class II (HLA-DRB1, -DQB1, -DQA1), as well as their combined haplotypes obtained from over 18,000 whole genome sequencing samples of the Russian population. The cohort was stratified based on PCA and admixture components, providing frequencies for 14 different ethnic groups. For 12 groups cohort size allowed us to reach average saturation of 96% of allele frequencies in groups. Moreover, we demonstrated the utility of composed statistics for disease population study using type 1 diabetes (T1D) as an example. Genetically defined population clusters with similar aggregated genetic risk for T1D demonstrated substantial differences in frequencies of risk and protective HLA alleles. Obtained frequency data were made publicly available through the Allele Frequency Net Database improving previously sparse coverage in HLA frequencies data for the East Europe and North Asia regions. Full article

Clear cell renal cell carcinoma (ccRCC) is characterized by a complex molecular landscape driven by recurrent genetic alterations. While genomic and transcriptomic profiling have identified core drivers, they often fail to provide robust biomarkers due to the significant decoupling of mRNA and protein levels, as well as the critical role of post-translational modifications in tumor biology. This review synthesizes current evidence from landmark proteogenomic initiatives, such as the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and independent multi-omic studies. It evaluates the integration of genomic, transcriptomic, and proteomic data to map metabolic reprogramming, signalling pathway activity, and chromatin-level alterations in ccRCC. Proteogenomic analyses reveal that protein-level data provide a functional perspective that is missing from sequencing alone, specifically identifying suppressed oxidative phosphorylation, enhanced glycolysis, and the activation of the PI3K/AKT/mTOR cascade, independent of genetic mutations. Furthermore, proteogenomics has defined novel molecular subtypes and individual protein biomarkers, such as UCHL1 and p-mTOR, which correlate more accurately with clinical outcomes and therapeutic responses than their transcriptomic counterparts. Proteogenomics is a crucial tool for refining disease taxonomy and identifying novel therapeutic vulnerabilities in ccRCC. By bridging the gap between genotype and functional phenotype, this integrated approach facilitates more precise risk stratification and accelerates the development of personalized medicine through better-informed selection of targeted and immune-based therapies. Full article

Purpose: Male breast cancer (maleBC) is an orphan disease. Aside from age, risk factors include genetic mutations and conditions like Klinefelter syndrome or other reasons of hypogonadism. Treatment is based on standards in women, but biological differences may exist, with maleBC exhibiting higher rates of hormone-receptor expression. Limiting data exists regarding the rate of low/ultralow HER2 expression, a predictive biomarker for the antibody–drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in HER2-negative disease in women. Materials and Methods: We conducted a retrospective single-center analysis of clinicopathological features of maleBC at a tertiary cancer center. We identified a cohort of 57 maleBC patients, described demographic, pathological, prognostic and surgical and systemic treatment data and evaluated frequencies of low and ultralow HER2 expression. Results: The mean age was 64.3 (SE ± 1.79) years; 94.7% (n = 54) of patients presented with early/nonmetastatic breast cancer and 40.7% (22 of 54) of patients exhibited nodal involvement. Most patients (92.6%, 50 of 54 patients) had luminal disease and approximately one third of patients received chemotherapy. Endocrine therapy was administered in 87.7% (n = 50/57) of cases. For 52 of the patients included, full receptor status data including HER2 IHC scoring and/or histological specimens were available. IHC slides of tumor specimens from 24 patients with either historically reported “HER2 negative” or “HER2 0” expression were available for reassessment; 79.2% (n = 19 of 24) of these tumors exhibited either HER2-low or -ultralow expression. In the whole cohort, rates of HER2-low and -ultralow expression were 75.0% (39 of 52) and 5.8% (3 of 52 patients), respectively. The median follow-up was 7 years. Six deaths occurred in the total population (n = 57). The median event-free survival (EFS) was 8.39 years (95% CI 7.36–11.35). No statistically significant associations were observed between HER2 expression categories and clinicopathological variables including grade, ER status, nodal status, genetic variant status, age, Ki67 index, or overall survival events. Conclusions: In this cohort of maleBC patients, high rates of combined HER2-low and -ultralow expression were observed upon reassessment of tumors with historically negative HER2 status, shedding light on potential ADC eligibility in male breast cancer. Full article

Folate (vitamin B9) is central to one-carbon metabolism, supporting nucleotide biosynthesis, methylation homeostasis, and epigenetic regulation. The gut microbiome both produces and consumes folate, creating a bidirectional axis influencing host health and disease. We systematically reviewed 159 original studies from MEDLINE, Google Scholar, Embase, and Scopus (inception through January 2026) examining enteric microbiota–folate interactions, with intervention evidence graded using the Oxford Centre for Evidence-Based Medicine 2011 framework. Only a minority of gut bacteria possess complete folate biosynthetic pathways; most depend on cross-feeding from prototrophic taxa including Bifidobacterium, Lactobacillus, and Streptococcus. Altered microbial folate metabolism was associated with metabolic, gastrointestinal, oncologic, neuropsychiatric, cardiovascular, immunologic, and reproductive disorders through convergent mechanisms of disrupted methylation, genomic instability, and immune dysregulation. Probiotic interventions achieved the strongest evidence, supported by multiple human controlled and observational trials and animal models. The evidence for prebiotic, dietary, and folate supplementation interventions was moderate due to the predominant animal models and in vitro data. Overall, the predominant associational and observational evidence base is insufficient to establish causal relationships, underscoring the need for adequately powered human randomized controlled trials with folate-specific endpoints, multi-omics integration, and precision approaches matching folate form and dose to individual microbiome and host genetic profiles. Full article

Wooden Breast (WB) and White Striping (WS) are prevalent myopathies affecting the Pectoralis major (PM) muscle of modern broiler chickens, with significant implications for animal welfare and meat quality. This pilot study aimed to characterize proteomic alterations associated with increasing severity of WB and WS in the PM of Hubbard × Ross 708 broilers. Muscle samples (n = 12) were previously categorized into four severity ranks based on established macroscopic criteria. Presently, proteins were extracted and analyzed using LC-MS/MS-based shotgun proteomics. Statistical comparisons between groups were performed using Generalized Linear Models. Fibronectin 1, fibrinogen alpha chain, musculoskeletal embryonic nuclear protein 1, glutathione S-transferase 2, calsequestrin-2, and endoplasmin emerged as potential biological markers and their prospective roles in the pathogenesis of these myopathies are discussed. Our findings suggest a progressive alteration of the muscle proteome with increasing disease severity, highlighting pathways related to muscle structure, metabolism, and stress response. These results aid in providing new insights into the molecular mechanisms underlying WB and WS and may inform future research on genetic and management strategies. As a pilot study, these findings warrant further investigation in larger cohorts and different commercial lines. Full article

Studies employing animal models play a pivotal role in advancing our understanding of the pathophysiology of retinal diseases. These models enable the investigation of molecular and cellular mechanisms underlying retinal structural damage, as well as the assessment of genetic and environmental factors contributing to disease development. The application of appropriate experimental models provides essential insights into the progression of degenerative processes and tissue responses to therapeutic interventions. The advancement of modern molecular biology and genetic engineering techniques has facilitated the development of increasingly precise animal models, which have proven crucial for identifying pathological alterations occurring in the course of retinal diseases. In recent years, research has demonstrated that, depending on the model employed, the observed changes may involve inflammatory processes, oxidative stress, photoreceptor dysfunction, extracellular matrix remodeling, and aberrant glial cell responses. It has also been shown that the nature and dynamics of these alterations vary according to the specific disease entity and the animal species used. The aim of this review is to compile and systematize current knowledge regarding the most commonly used animal models in retinal disease research and to discuss their utility in analyzing potential pathogenetic mechanisms and therapeutic targets. The review also highlights emerging complementary research strategies associated with New Approach Methodologies (NAMs), including retinal progenitor and iPSC-derived cell-based approaches, advanced retinal imaging techniques, and alternative experimental platforms such as the chorioallantoic membrane (CAM) assay, which may support translational retinal research and reduce reliance on traditional animal models. The authors hope that this work will contribute to the refinement of preclinical research methodologies and, through an improved understanding of the processes underlying the development of retinal diseases, facilitate the advancement of more effective diagnostic and therapeutic strategies in the future. Full article

Inborn errors of metabolism (IEMs) are a group of inherited genetic conditions that, in general, result from a specific enzyme defect. Clinical consequences caused by abnormal enzyme levels often disrupt affected metabolic pathways and their intermediary metabolites. Because diagnostic outcomes depend on early intervention, a timely and accurate diagnosis is essential. Quantitative targeted metabolomics (QTM) is an analytical approach that quantifies predefined metabolites and generates interpretable biochemical phenotypes. Instead of focusing solely on screening, expanded QTM methods enable higher coverage with multi-analyte profiling that can provide more comprehensive characterization of disease-associated metabolic perturbations, particularly in IEMs with overlapping biochemical profiles. This review summarizes diagnostic techniques for IEMs, outlines the principles and advantages of QTM, and evaluates its established role and emerging opportunities and limitations in advancing method development and deep metabolic phenotyping to support precision medicine. Full article

Chronic inflammation mediated by cytokines is central to the pathogenesis of coronary artery disease (CAD). This exploratory study aimed to investigate potential associations between functional gene variations of the cytokines interleukin 18 (IL-18) and interleukin 8 (IL-8) and the CAD susceptibility within a specific regional cohort, while accounting for common clinical comorbidities. Genotype distributions of IL-18 (−607 C/A, −137 G/C) and IL-8 (+781 C/T) were analyzed in a cohort of 102 patients with angiographically confirmed CAD and 102 healthy controls. Genotyping was performed using PCR, allele-specific PCR, and RFLP techniques. Multivariate logistic regression was utilized to assess potential independent associations, adjusting for age and traditional clinical risk factors. In this specific cohort, after adjusting for age, hypertension, diabetes, cholesterol, family history, and smoking, the IL-18 (−137 G/C) CC genotype was observed more frequently in CAD patients (adjusted odds ratio [AOR] = 6.15, 95% CI = 2.10–18.05, p = 0.001). An exploratory analysis of genotype combinations suggested that the IL-18 (−607/−137) CA-CC profile may be linked to an increased risk (AOR = 3.65, p = 0.028), while tentative protective trends were noted for certain IL-18/IL-8 combinations. Notably, a significant deviation from a Hardy–Weinberg equilibrium (HWE) was observed in the control group for the IL-18 loci, which represents a substantial methodological limitation that may influence these risk estimates. Our preliminary findings suggest that specific IL-18 and IL-8 variations may contribute to CAD susceptibility independently of traditional risk factors in the studied population. However, given the modest sample size and the observed HWE deviation, these associations should be regarded as suggestive rather than definitive. While these genetic variations underscore the importance of cytokine pathways in cardiovascular research, they do not currently support clinical implementation for risk stratification. Large-scale, multi-center prospective studies are necessary to validate these preliminary signals and evaluate their long-term scientific utility. Full article

Fusarium spp. are active producers of mycotoxins that enter the food chain and pose risks to human health. Identifying pathogenic agents is a key step in developing disease management strategies. For the first time in Bulgaria, we identified eight Fusarium species in wheat, harvest 2024–2025, through the application of DNA barcoding. For a genetic marker and construction of phylogenetic tree, the protein-coding gene β-tub was chosen. Among 26 identified isolates, F. sporotrichioides (42.3%) dominated, followed by F. proliferatum 23.1%), F. avenaceum (7.7%), F. armeniacum (7.7%), аnd F. poae (7.7%). F. tricinctum (3.8%), F. oxysporum (3.8%), and F. equiaseti (3.9%) were weakly expressed. Phylogenetic analysis classified the isolates into five species complexes: FSAMSC, FFSC, FTSC, FIESC, and FOSC and highlighted the genetic distances between them. Molecular genetic analysis showed that 84.6% of the wheat samples contained only one species of Fusarium, and in 15.4% the co-presence of two species was established. The largest share was in samples with a low infestation of 2–4%, which represented 35% (n = 32) of all positives. No statistically significant difference was found between varieties and contamination level, but a statistically significant positive correlation was demonstrated by the preceding crop (rapeseed, sunflower, and maize). Full article

Hematological malignancies encompass a broad spectrum of relatively rare cancers with diverse biological and clinical characteristics that are capable of affecting individuals across all age groups, though certain subtypes show a predilection for specific age ranges. Advances in next-generation sequencing have greatly enhanced our understanding of the molecular and genetic basis of these diseases, while epigenetic, transcriptional, and proteomic analyses have further clarified their pathogenesis. These developments have shaped the classification and treatment of lymphoma. Updated classification frameworks which include the identification of clinically relevant molecular targets have opened the door to a number of targeted agents, each designed to exploit specific vulnerabilities within malignant cells, while stem cell transplantation continues to offer curative potential for eligible patients, with improving safety profiles over time. CAR-T-cell therapy has been extended to multiple blood cancer indications, achieving lasting remissions in patients with previously exhausted treatment options. Bispecific antibodies have further broadened the immunotherapy landscape by redirecting the body’s own T cells against tumor cells, offering a readily available alternative that overcomes many of the practical limitations associated with CAR-T-cell production. The ability to combine these strategies has fundamentally changed what is achievable in blood cancer treatment, with long-term remission now a realistic goal for many patients. This review seeks to outline the core molecular mechanisms underlying lymphoma and leukemia, evaluate currently approved treatment options, discuss significant ongoing clinical trials with practice-changing potential, and explore the prospect of chemotherapy-free approaches in carefully selected patient groups. Full article

Oxidative stress occurs when reactive oxygen species exceed the capacity of antioxidant defenses, causing molecular damage and alterations in cellular signaling. This process is characterized by interindividual variability, particularly based on biological sex. Hormones such as estrogens, which exert antioxidant effects, and androgens, which can act as pro-oxidants in certain contexts, along with genetic and epigenetic factors linked to sex chromosomes, contribute to the sex-specific regulation of redox homeostasis. Nutraceuticals, including polyphenols, vitamins, carotenoids, and omega-3 fatty acids, influence oxidative processes through both direct and indirect mechanisms. This review evaluates the impact of biological sex on oxidative stress mechanisms and responses to nutraceutical antioxidants, synthesizing the results of molecular, metabolic, and clinical studies published over the past decade. The current literature indicates that biological sex influences both basal redox balance and individual responses to antioxidant mechanisms. Generally, males have a higher oxidative load and may benefit more from supplementation, while females typically possess greater antioxidant capacity, primarily due to hormonal influences. Greater consideration of sex as a biological variable is essential to optimize nutraceutical strategies and develop personalized interventions for oxidative stress-related diseases. Full article

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) and chronic neuroinflammation, with microglia playing a central role in its pathogenesis. Alterations in microglial metabolism have been proposed to contribute to AD-related inflammatory responses and reduced Aβ clearance, suggesting that thiamine-dependent pathways may be relevant in this context. Thiamine pyrophosphate (TPP), the active form of vitamin B1, is essential for glucose metabolism and mitochondrial function; however, its association with microglial changes in AD remains unclear. In this study, 9-month-old female triple-transgenic AD (3xTg-AD) mice and non-transgenic controls (NoTg) received TPP (2.0 mg/mL) or saline as a vehicle for six weeks via osmotic pumps. Nesting, a hippocampus-dependent behavioral test, as well analyses of Aβ burden, microglial morphology, and the expression of genes related to metabolic and immune pathways were evaluated. Differences in nesting behavior between experimental groups were observed, but TPP treatment was not associated with an evident change in 3xTg-AD mice. In the subiculum and CA1 regions of the hippocampus of female 3xTg-AD mice exposed to TPP, a lower Aβ burden was observed, and morphological variations in microglia were detected in both groups (3xTg-AD and NoTg). Additionally, in the brain of the TPP-treated group, some changes in mRNA gene expression were recorded. Together, these findings describe hippocampal microglial and amyloid profiles following TPP treatment in 3xTg-AD mice and provide a basis for further investigation of thiamine-dependent pathways in AD-related neuroinflammatory contexts. Full article

Background/Objectives: The advent of disease modifying therapies (DMTs) for Spinal Muscular Atrophy (SMA) has highlighted the need for reliable tools to assess bulbar function in type I individuals. The Oral and Swallowing Abilities Tool (OrSAT) was originally developed to evaluate swallowing and feeding abilities in infants with SMA type I during the first two years of life. This study aimed to assess the applicability of the OrSAT in a cohort of children with SMA type I older than 2 years. Methods: Fifty-two children with genetically confirmed SMA type I, aged 2 to 12.6 years, were included. All participants had received at least one DMT, administered either soon after diagnosis or when treatment became available. Bulbar and feeding abilities were assessed using the OrSAT and results were grouped according to clinical subtype and feeding modality. Given the small sample size of the subgroups and the ordinal nature of OrSAT scores, comparisons between groups were performed using the non-parametric Kruskal–Wallis test. Results: At follow-up, 27 children were orally fed, 19 were exclusively tube-fed, and 6 were tube-fed but were also able to eat some food by mouth. The OrSAT scores reflect a wide spectrum of bulbar function from severe to no impairment. Most children who required exclusive tube-feeding at follow-up had already been tube-fed at treatment initiation, while a small number showed improvement in swallowing abilities and the partial recovery of oral feeding during follow-up. Conclusions: Our results suggest that the OrSAT, previously used only in the first two years of life, may also be applicable in older children to describe bulbar involvement and monitor changes over time. However, further studies are needed to refine the tool for this age group and to formally validate its use in older children with SMA type I. Its use may contribute to the longitudinal assessment of swallowing abilities and support rehabilitative management. Full article

Background: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a global health priority affecting approximately 30% of the population. It represents the hepatic manifestation of metabolic syndrome, potentially progressing from simple steatosis to Metabolic Dysfunction-Associated Steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. This review aims to compare current knowledge of MASLD in mouse models and humans, focusing on pathophysiology, histological phenotypes, and the role of preclinical imaging as a non-invasive translational screening tool. Methods: A literature search was conducted in PubMed and Web of Science to identify English-language publications from January 2020 to March 2026 on murine models and imaging techniques for MASLD, using pertinent keywords. Attention was given to highlighting similarities and differences between human and murine approaches. Results: MASLD arises from complex interactions between genetics, sedentary lifestyles, and imbalanced diets. While mouse models have been refined to capture the multifactorial interplay driving disease progression and are still essential for drug development, no single model fully mirrors the human condition. Histological assessment remains an essential tool for MASLD staging, in both humans and mouse models. However, imaging is increasingly emerging as an important complementary technique to non-invasively investigate MASLD. Conclusions: Mouse models are essential to address specific mechanistic and therapeutic questions, but understanding of their limitations and strengths is crucial for translational research. Integrating phenotype-driven approaches in both humans and mice, combining traditional histology, quantitative imaging, and metabolic profiling, as well as longitudinal, combined, and humanized preclinical models, will enhance translational alignment and accelerate the development of therapies for MASLD. Full article

Objective: To investigate the association between genetic polymorphisms of the vitamin D receptor (VDR: rs1544410, rs2228570, rs731236), methylenetetrahydrofolate reductase (MTHFR: rs1801131), and DNA methyltransferase (DNMT1: rs2228611, DNMT3A: rs7590760, DNMT3B: rs6087990) genes and the coexistence of periodontitis and systemic lupus erythematosus (SLE). Methods: Systematically healthy individuals and patients with SLE of both sexes, aged over 20 years, were recruited and divided into four groups: healthy, periodontitis, SLE, and SLE with periodontitis. Seven polymorphisms in the VDR, MTHFR, DNMT1, DNMT3A, and DNMT3B genes were analyzed. Results: The frequency of the rs1801131 (MTHFR) AA genotype was higher in the healthy group than in the periodontitis group. The B allele of rs1544410 (VDR) was more frequent in patients with SLE, regardless of the presence of periodontitis. The t allele of rs731236 (VDR) was more frequent in patients with SLE without periodontitis. Conclusions: The polymorphisms studied do not show an exclusive association with the coexistence of periodontitis and SLE. However, the MTHFR rs1801131 polymorphism may be a protective factor against periodontitis, but not when it coexists with SLE. VDR rs1544410 is associated with SLE regardless of the presence of periodontitis, and rs731236 is associated with SLE, but not in coexistence with periodontitis. These data provide insights into the genetics of periodontitis and lupus; however, they are currently exploratory, as they were obtained from a single-center study in which it was not possible to adjust for demographic variables (age and sex) between groups due to the modest sample size. Full article