Genes最新文献

{"title":"The Multifaceted Role of the <i>FLNC</i> Gene in Hereditary Cardiomyopathies and Prognosis.","authors":"Maria D'Apolito, Alessandra Ranaldi, Teresa Gaudiano, Angela Bruna Maffione, Rosa Santacroce, Giovanna D'Andrea, Massimo Iacoviello, Maurizio Margaglione","doi":"10.3390/genes17091136","DOIUrl":"10.3390/genes17091136","url":null,"abstract":"<p><p>Variants in the filamin C (<i>FLNC</i>) gene are increasingly recognized as causes of cardiac and skeletal muscle disease. Cardiomyopathy-associated <i>FLNC</i> variants span dilated cardiomyopathy (DCM), nondilated left ventricular cardiomyopathy (NDLVC), arrhythmogenic cardiomyopathy (ACM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM), but their clinical interpretation depends strongly on variant class and evidence of pathogenicity. <i>FLNC</i> truncating variants (<i>FLNC</i>tv), including nonsense, frameshift, and canonical splice-site variants, usually cause haploinsufficiency through nonsense-mediated decay and are predominantly associated with DCM/NDLVC and left-dominant ACM. These phenotypes frequently show subepicardial or circumferential ring-like fibrosis and clinically important ventricular arrhythmias that may occur despite only mild left ventricular dysfunction. On the other hand, selected pathogenic missense variants, particularly within the actin-binding domain or ROD2 immunoglobulin-like repeats 18-21, may promote protein misfolding and aggregation and have been associated with HCM or RCM, including the distinctive saw-tooth myocardial phenotype. However, most reported <i>FLNC</i> missense variants remain variants of uncertain significance and must not be considered disease-causing on the basis of location alone. This narrative review summarizes FLNC molecular biology, genotype-phenotype relationships, imaging features, arrhythmic risk, and implications for clinical management. It also discusses the limited evidence linking <i>FLNC</i>tv to arrhythmogenic mitral valve prolapse with mitral annular disjunction. Accurate variant classification and phenotype integration are essential for diagnosis and for individualized prevention of sudden cardiac death (SCD).</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers in Clear Cell Renal Cell Carcinoma: From Biological Association to Clinical Decision-Making.","authors":"Hadi Al Etri, Lea Al Zoghby, Mohamad Sadek Zoghbi, Ahmad Karim Morad, Hatem Hassanein, Jad Chahoud","doi":"10.3390/genes17091137","DOIUrl":"10.3390/genes17091137","url":null,"abstract":"<p><p>Therapeutic options in renal cell carcinoma (RCC) have expanded rapidly, including adjuvant pembrolizumab, HIF-2α-directed therapy, and multiple effective first-line combinations for metastatic clear-cell RCC (ccRCC), yet treatment selection remains largely clinicopathologic. This review evaluates biomarkers at three clinical decision points: characterization of an indeterminate renal mass; recurrence-risk assessment and adjuvant treatment selection after nephrectomy; and first-line regimen selection in metastatic ccRCC. DNA-methylation classifiers and carbonic anhydrase IX-targeted [⁸⁹Zr]Zr-girentuximab PET/CT can improve characterization of selected renal tumors, but neither replaces histopathology in routine practice. After nephrectomy, elevated plasma kidney injury molecule-1 (KIM-1) and detectable circulating tumor DNA (ctDNA) identify patients at higher risk of recurrence; however, low tumor shedding limits ctDNA sensitivity, so a negative result does not exclude molecular residual disease or justify adjuvant de-escalation; neither biomarker is validated to direct surveillance, adjuvant therapy, or treatment escalation. In metastatic ccRCC, PD-L1 expression, tumor mutational burden, and individual genomic alterations do not reliably distinguish patients who should receive dual immune-checkpoint blockade from those who should receive an immune-checkpoint inhibitor plus a VEGFR tyrosine kinase inhibitor. Transcriptomic states, myeloid composition, and spatial immune organization provide more detailed treatment-relevant biology, but no prospective comparative trial has shown that biomarker-guided regimen selection improves outcomes. Clinical implementation will require standardized assays, independent multicenter validation, and prospective trials powered to test biomarker-by-treatment interactions.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenomic Remodeling by Lipid Metabolism: A Cross-Disease Perspective on Cancer and Brain Disorders.","authors":"Asma Rafique, Adeel Farooq, Clara E Cho, Marica Bakovic","doi":"10.3390/genes17091134","DOIUrl":"10.3390/genes17091134","url":null,"abstract":"<p><p>Lipid metabolism is no longer viewed simply as a source of membrane biomass or ATP. It is now proposed as a regulatory system that determines which metabolites reach the nucleus, which chromatin-modifying enzymes are engaged, and which transcriptional states become stable during disease progression. This review develops a mechanistic cross-disease framework emphasizing metabolite flux, subcellular compartmentalization, cell-type specificity, and the temporal persistence of chromatin states. We synthesize recent evidence linking lipid metabolism to chromatin remodeling in cancer, Alzheimer's disease, and Parkinson's disease, and we highlight how emerging single-cell multi-omics and spatial lipidomics may shape potential metabolism-targeted epigenetic therapies. In both cancer and brain disorders, lipid flux alters the availability of acetyl-CoA, S-adenosylmethionine, NAD+, and bioactive fatty acid derivatives, thereby reshaping histone acetylation, DNA and histone methylation, chromatin accessibility, and transcription-factor activity. In cancer, de novo lipogenesis, acetate scavenging, fatty acid oxidation, and phospholipid remodeling sustain nuclear acetyl-CoA pools, promote oncogenic super-enhancers, and support survival under hypoxia, acidosis, and therapy stress. In neurodegenerative disease, mitochondrial dysfunction, cholesterol dyshomeostasis, sphingolipid imbalance, oxysterol accumulation, and microglial lipid droplet formation may distort the epigenetic programs required for neuronal maintenance, synaptic plasticity, and inflammatory resolution. However, neurodegenerative disorders are not uniformly hypoacetylated; instead, they exhibit stage-, region- and cell-type-specific chromatin remodeling, with hypoacetylation at some vulnerable loci coexisting with hyperacetylation at others. By comparing lipid-epigenome coupling across proliferative and degenerative conditions, we argue that the same metabolic nodes can yield markedly different pathological outcomes depending on cellular context, providing a basis for more precise therapeutic design.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"G2/M Checkpoint Dependency in High-Grade Serous Tubo-Ovarian Carcinoma: Mechanisms and Therapeutic Implications.","authors":"Zhiyu Tian, Karen McLean","doi":"10.3390/genes17091135","DOIUrl":"10.3390/genes17091135","url":null,"abstract":"<p><p>High-grade serous carcinoma (HGSC) of tubo-ovarian origin is an aggressive malignancy in need of new treatment options. At the molecular level, HGSC is characterized by genomic instability, including nearly universal <i>TP53</i> mutations, copy number alterations, and chromothripsis, which elevate replication stress. These fundamental alterations result in tumor cell dependence on the G2/M checkpoint for survival, thus revealing this checkpoint as a potential therapeutic target. In this review, we discuss the normal cell cycle progression and checkpoints as well as the regulation of DNA replication, and we consider how replication stress in HGSC leads to a dependence on the G2/M checkpoint. We then present information on the current state of targeted therapy development for HGSC including clinical trials and the role of biomarkers in optimal patient selection. Thus, targeting the G2/M checkpoint is driven by sound molecular rationale and may yield clinical benefit in patients with HGSC, but will likely require careful patient selection and consideration of treatment toxicities.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond VO_2max: Integrated Physiological Phenotyping and Candidate-Gene Analysis of Elite Versus Recreational Endurance Runners.","authors":"Hasan Uğur Öncel, Jason Siegler, Alper Özkan, Okan Oğul, Mikail Yalçın, Şahabettin Karabulut, Rıfat Gülmez, Seyed Houtan Shahidi","doi":"10.3390/genes17091133","DOIUrl":"10.3390/genes17091133","url":null,"abstract":"<p><p><b>Background:</b> Endurance performance reflects integrated cardiorespiratory, metabolic and musculoskeletal traits with substantial heritability, yet sex-balanced studies that simultaneously deep-phenotype athletes and genotype candidate loci against trained comparators remain scarce. <b>Objective:</b> We aim to characterize the integrated physiological profile and genotype distributions at five endurance-relevant polymorphisms in elite versus recreationally trained runners. <b>Methods:</b> Eighty runners (20 elite male, 20 elite female, 20 recreational male, 20 recreational female) completed graded treadmill testing with breath-by-breath gas exchange and capillary blood lactate sampling, together with whole-body dual-energy X-ray absorptiometry. A sub-sample of 40 participants (10 per subgroup) underwent next-generation sequencing of <i>ACTN3</i> R577X, <i>VEGFA</i> rs699947, <i>PPARGC1A</i> Gly482Ser, <i>ACE</i> I/D and <i>PPARG</i> Pro12Ala. Physiology was compared using one-way ANOVA with Tukey's HSD and Cohen's d; genotype distributions were compared using Monte Carlo exact tests with Benjamini-Hochberg correction. <b>Results:</b> Elite runners exhibited higher VO2max (elite male 71.8 ± 4.9; elite female 65.3 ± 3.6 mL·kg^-1·min^-1; both vs. same-sex controls, <i>p</i> < 0.001; η² = 0.62), superior running economy (η² = 0.76), lactate thresholds shifted rightward by ~1 km·h^-1, and more favorable body composition (lean mass η² = 0.80; body fat η² = 0.48). Principal component analysis separated elites from recreational runners along PC1 (40.1% variance) in both sexes. Effect-allele frequencies were numerically higher in elites at every locus (odds ratios 1.48-2.03), but no genotype × group association survived correction (all q ≥ 0.82). <b>Conclusions:</b> Elite endurance status was robustly distinguished by an integrated physiological phenotype with large effect sizes. Effect-allele frequencies at five candidate loci were numerically higher in the expected direction but did not reach statistical significance; given the small genotyped sub-sample, these genetic data are purely exploratory and hypothesis-generating and require replication in adequately powered cohorts.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prime Editing for Precision Genetic Medicine: A Systematic Review of Technologies, Delivery, and Therapeutic Applications.","authors":"Douglas M Ruden","doi":"10.3390/genes17091138","DOIUrl":"10.3390/genes17091138","url":null,"abstract":"<p><strong>Background: </strong>Prime editing has rapidly evolved from a CRISPR-based \"search-and-replace\" approach for precise sequence modification into a diverse family of genome editing technologies. This systematic review maps the technological evolution of prime editing, with emphasis on editor architecture, guide RNA engineering, delivery, therapeutic applications, computational approaches, and emerging capabilities.</p><p><strong>Methods: </strong>PubMed and Web of Science were systematically searched for studies in which prime editing constituted a substantive experimental, technological, computational, delivery, or therapeutic component. After deduplication and screening, candidate studies underwent manual re-screening against prespecified eligibility criteria. Reviews, corrections, plant and bacterial studies, conventional CRISPR or base editing studies without a substantive prime editing component, and other non-relevant records were excluded. A total of 294 studies were included in the final systematic evidence synthesis. Because of substantial heterogeneity in editor architectures, targets, experimental models, outcomes, and reporting, the literature was synthesized using systematic mapping and qualitative thematic analysis rather than meta-analysis.</p><p><strong>Results: </strong>The evidence demonstrates rapid diversification from the original Cas9 nickase-reverse transcriptase-prime editing guide RNA architecture through improvements in pegRNA design, Cas and reverse transcriptase engineering, DNA repair modulation, delivery, computational design, and increasingly complex sequence modification. Therapeutic studies span disease modeling, correction of pathogenic variants, ex vivo applications, and direct in vivo editing; however, high editing efficiency does not necessarily translate into functional or therapeutic rescue. Large-sequence insertion and replacement strategies further extend the capabilities of prime editing, although these approaches remain less mature than small-sequence correction and face substantial challenges in efficiency, fidelity, cargo delivery, and genomic safety.</p><p><strong>Conclusions: </strong>Prime editing has developed into a versatile precision genome editing platform, but the evidence base remains heterogeneous and predominantly preclinical. Translation to genetic medicine will require improvements in reproducibility across targets and cell types, delivery to clinically relevant tissues, product purity, genomic safety, and demonstration of meaningful functional benefit. Emerging large-sequence editing approaches broaden the potential scope of prime editing but should be distinguished from technologies with established experimental and therapeutic evidence.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical, Neuroimaging, and Molecular Characterization of a Juvenile PLAN-like Phenotype in Two Siblings Carrying p.Arg645Gln and an Unresolved Exon 4-7 Copy-Number Gain: A Case Report.","authors":"Małgorzata Janeczko-Czarnecka, Maciej Gręda, Dorota Cichosz, Robert Śmigiel, Mateusz Biela","doi":"10.3390/genes17091132","DOIUrl":"10.3390/genes17091132","url":null,"abstract":"<p><p>PLA2G6-associated neurodegeneration (PLAN) is an autosomal recessive neurodegenerative spectrum encompassing infantile, juvenile/atypical and adult-onset phenotypes. Juvenile PLAN may initially resemble autism spectrum disorder or nonspecific developmental regression, delaying diagnosis. We describe a 14-year-old boy and his 9-year-old sister, both with initially normal early development, followed by progressive gait impairment, speech and cognitive regression, epilepsy or paroxysmal events, contractures and loss of independent ambulation. Brain MRI in both siblings demonstrated marked symmetric cerebellar atrophy, susceptibility-weighted hypointensity of the globus pallidus and substantia nigra compatible with iron accumulation and bilateral optic nerve thinning. Electroneurography showed selective motor axonal involvement. Molecular testing identified the same two heterozygous <i>PLA2G6</i> findings in both children: c.1934G>A (p.Arg645Gln), classified as likely pathogenic by the diagnostic laboratory, and a copy-number gain encompassing exons 4-7. Parental testing was unavailable; therefore, the phase of the findings could not be established, and it remains unknown whether they are in trans or in cis. The shared phenotype is highly suggestive of juvenile PLAN. However, unresolved phase and incomplete structural characterization of the copy-number gain preclude confirmation of biallelic <i>PLA2G6</i> involvement and definitive molecular attribution. These related cases provide a descriptive account of a juvenile PLAN-like phenotype, without independently attributing the phenotype to p.Arg645Gln, establishing variant pathogenicity or a specific genotype-phenotype correlation.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dietary <i>Lepidium meyenii</i> Supplementation Is Associated with Hepatic Transcriptomic and Targeted DNA Methylation Changes in Pigs.","authors":"Weronika Loba-Pasternak, Anita Zaworska-Zakrzewska, Joanna Nowacka-Woszuk","doi":"10.3390/genes17091128","DOIUrl":"10.3390/genes17091128","url":null,"abstract":"<p><p><b>Background</b>: <i>Lepidium meyenii</i> Walp. (maca) is a plant-derived feed supplement rich in bioactive compounds such as macamides, macaenes, glucosinolates, and polyphenols. In this study, it was selected as a potential natural functional feed additive based on its bioactive phytochemical composition, reported metabolic properties, and previously observed effects on porcine cells. However, its molecular effects in livestock remain poorly characterised. This study investigated hepatic molecular responses to dietary maca supplementation in pigs using transcriptomic analysis followed by DNA methylation, promoter polymorphism, and protein analyses to explore the mechanisms underlying the observed transcriptional changes. <b>Methods</b>: Female pigs were assigned to two groups fed a diet supplemented with 1% maca powder (E) or a control diet (C). Liver samples were analysed using RNA sequencing and qPCR validation of selected genes. DNA methylation, promoter variants, and TUBA4A protein abundance were assessed using pyrosequencing, Sanger sequencing, and Western blotting, respectively. <b>Results</b>: RNA-seq identified 104 differentially expressed genes (DEGs) after DESeq2 analysis with intensity difference filtering. qPCR validated the differential expression of <i>INHBE</i>, <i>PPP1R3C</i>, <i>PPP1R3B</i>, <i>TUBA4A</i>, and <i>GCK</i>. Gene Ontology enrichment analysis indicated the over-representation of terms related to extracellular matrix organisation, collagen-containing structures, response to transforming growth factor beta, and glycogen biosynthetic processes. Methylation analysis revealed no significant methylation changes in <i>GCK</i>, <i>INHBE</i>, <i>PPP1R3C</i>, or <i>TUBA4A</i> after FDR correction, whereas <i>PPP1R3B</i> showed significant differences at seven CpG sites. Promoter polymorphisms were identified in <i>PPP1R3C</i> and <i>TUBA4A</i>, but genotype frequencies did not differ between groups. Additionally, TUBA4A protein abundance was not altered. <b>Conclusions</b>: Dietary maca supplementation was associated with moderate hepatic molecular changes, including alterations in genes and pathways related to glycogen metabolism and extracellular matrix organisation. Maca may represent a promising natural feed supplement for pigs, although further studies are needed to confirm its efficacy and practical applicability.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Epigenetic Aging-Cancer Continuum: Biomarkers, Metabolism, and Therapy.","authors":"Christos Papaneophytou, Myrtani Pieri, Maria-Eleni Makreli, Evelina Charidemou, Eleni P Andreou","doi":"10.3390/genes17091130","DOIUrl":"10.3390/genes17091130","url":null,"abstract":"<p><p>Aging and cancer form a biological continuum influenced by epigenomic changes, metabolic dysfunction, inflammation, cellular senescence, and loss of tissue homeostasis. Age-related epigenetic alterations can promote cancer, which exploits plasticity for evolution, immune evasion, metastasis, and resistance. Nutrition and metabolism affect this process through one-carbon metabolism, methyl-donor availability, acetyl-CoA and NAD⁺ balance, redox status, microbiome metabolites, and chromatin enzyme activity. Circulating biomarkers such as cell-free DNA methylation, mutation-based ctDNA, fragmentomic features, and non-coding RNAs can detect tumor and host changes linked to aging, inflammation, nutrition, and treatment with minimal invasiveness. This review explores the epigenetic aging-cancer link, how nutrition and metabolism modify pathways, and the potential of circulating biomarkers for diagnosis, prognosis, prediction, and monitoring. The focus is on epigenetic plasticity, drug-tolerant states, resistance, epigenetic drugs, metabolic targeting, and nutritional interventions. New technologies, including single-cell and spatial epigenomics, long-read sequencing, and multimodal computational approaches, aid biomarker discovery and clinical use. Challenges include variability, misclassification, heterogeneity, confounding, reverse causality, overfitting, and limited validation. Clinical applications need standard workflows, representative cohorts, transparent models, and proof that biomarker-guided strategies improve outcomes.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Candidate Stress-Specific microRNA Expression in Pediatric Thrombosis and Healthy Children: A Comparative Analysis of Serum miR-34a-5p in Relation to Stress Levels and Inflammatory Genetic Traits.","authors":"Iphigenia Gintoni, Elissavet Damaskopoulou, Zoi Siouti, Kleoniki Baldouni, Maria Skoufou, Nikolaos Pachis, Athina Dettoraki, Aikaterini Michalopoulou, Helen Pergantou, Dimitrios Vlachakis, George P Chrousos, Christos Yapijakis","doi":"10.3390/genes17091124","DOIUrl":"10.3390/genes17091124","url":null,"abstract":"<p><strong>Background: </strong>Pediatric thrombosis (PT) is a rare clinical entity manifesting from neonatal life to adolescence with possibly severe clinical complications and increasing prevalence in the last decade. Its pathogenesis has been attributed to a multitude of factors, all of which share stress and inflammation as a common denominator. Although stress-induced inflammation, marked by the upregulation of proinflammatory interleukins, such as IL-1β, creates a prothrombotic environment, its relation with thrombosis remains incompletely defined, especially in the context of PT, which differs substantially from adult thrombosis. Here, we aimed to epigenetically explore the potential link between PT and stress-induced inflammation through a combinatorial approach.</p><p><strong>Methods: </strong>Initially, we bioinformatically identified candidate stress-specific miRNAs in childhood, followed by subsequent experimental assessment in serum samples of PT patients and healthy controls in relation to subjectively perceived stress levels and the functional +3953C/T genetic polymorphism of the <i>IL1B</i> gene, which affects the circulating levels of the proinflammatory and stress-induced interleukin 1beta (IL-1β).</p><p><strong>Results: </strong>The bioinformatic analysis identified miR-34a-5p as the most stress-specific candidate microRNA in childhood, exhibiting the highest gene-target coverage (80.6%) of the developed panel of adversity-related genes, but is also known to regulate <i>IL1B</i> expression. The expression of serum miR-34a-5p was not significantly influenced by subjectively perceived stress; however, its expression was significantly reduced in the presence of the T allele of the functional +3953C/T polymorphism of its target gene, <i>IL1B</i>, associated with increased levels of the stress-induced proinflammatory and simultaneously prothrombotic IL-1β cytokine (FC:0.57; <i>p</i> = 0.024).</p><p><strong>Conclusions: </strong>The observed downregulation of miR-34a-5p in the presence of the IL-1β-increasing T allele possibly indicates a dynamic regulatory relationship, which, alongside its previously established long-term downregulation in PT, renders miR-34a-5p a promising candidate molecule for bridging the biological processes of stress-associated inflammation and thrombosis. In addition, its bioinformatically yielded candidate stress-specific role holds great potential for the non-invasive evaluation of adversity-related stress in childhood.</p>","PeriodicalId":12688,"journal":{"name":"Genes","volume":"17 9","pages":""},"PeriodicalIF":3.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13606060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149060188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}