Search Results (5,338)

Solute carrier family 25 member 39 (SLC25A39) is a pivotal mitochondrial glutathione transporter and an emerging oncoprotein in hepatocellular carcinoma (HCC). While its cell-intrinsic roles are increasingly recognized, its comprehensive functions in modulating the tumor immune microenvironment (TIME) and epigenetic landscape within HCC remain undefined. To address this, we employed an integrated multi-omics and experimental approach, including TCGA, ssGSEA, CCK-8, Transwell, etc. Our study confirmed SLC25A39 upregulation and its pro-tumorigenic role. Notably, we provide several key novel insights: First, we establish the first link between SLC25A39 promoter hypermethylation at specific CpG sites and poor patient prognosis, revealing an epigenetic regulatory layer in HCC. Second and most importantly, we pioneer the exploration of SLC25A39 in the HCC immune context, demonstrating its association with a distinct immunosuppressive TIME characterized by a Th2-skewed profile, reduced cytotoxic cell infiltration, and elevated immune checkpoint (CTLA-4, PD-1) expression. Furthermore, drug sensitivity analysis linked SLC25A39 to a broader spectrum of pharmacological agents beyond sorafenib. Collectively, our findings not only reinforce SLC25A39 as a therapeutic target but, for the first time, reposition it as a potential modulator at the intersection of tumor metabolism, epigenetics, and immunology in HCC, offering a rationale for its inhibition, particularly combined with immunotherapy. Full article

Background/Objectives: Epigenetic modifications, particularly DNA methylation, contribute to tumor progression and therapy resistance. Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. We evaluated the combination of guadecitabine with carboplatin as a second-line treatment for extensive-stage small-cell lung cancer (SCLC; NCT03913455), one of the deadliest malignancies. Here, we report methylome changes in peripheral blood mononuclear cells (PBMCs) collected at baseline and during treatment from patients on the trial. Methods: PMBC DNA was analyzed using Infinium HumanMethylationEPIC v1.0 bead chips. Data were processed, and differentially methylated positions (DMPs) were identified and analyzed for pathway enrichment using bioinformatic approaches, and immune deconvolution analyses were conducted to investigate the impact on immune cell composition. Results: Direct comparison of PBMCs between cycle 2 day 5 (C2D5; post-treatment) vs. cycle 1 day 1 (C1D1; pre-treatment) revealed a greater number of hypomethylated DMPs (380 DMPs in C2D5 vs. C1D1 PBMCs; p < 0.05, |β| > 20%). Moreover, when first compared with normal PBMCs from cancer-free controls, the number of hypomethylated DMPs was even greater in C2D5 than in C1D1 (1771 vs. 237 DMPs, respectively; p < 0.05, |β| > 20%). Long interspersed nucleotide elements-1 (LINE-1) were significantly hypomethylated in PBMCs after HMA treatment (C2D5 vs. C1D1). Pathway analysis of hypomethylated DMPs revealed significant alterations in key signaling pathways, including NF-κB, Rho GTPase, and pulmonary fibrosis in C1D1 vs. C2D5. Normal PBMCs to C1D1 PBMCs revealed changes in IL-3 signaling, Fcγ receptor-mediated phagocytosis, and molecular mechanisms of cancer. Deconvolution analysis revealed a greater percentage of monocytes in C1D1 vs. normal PBMCs; after HMA treatment, percentages of monocytes and B cells decreased, while the eosinophil percentage increased in C1D1 vs. C2D5. Conclusions: HMA treatment has a global impact on PBMC methylomes in cancer patients. DNA methylation changes were associated with biological pathways related to PBMC function, and shifts in distinct immune cell populations were observed. Full article

Background: Sialylation, a key terminal glycosylation modification, plays a pivotal role in tumor progression and immune evasion. The sialyltransferase ST3GAL4 is implicated in individual cancers, but its pan-cancer landscape and systemic associations remain undefined. Methods: We performed an integrated multi-omics analysis using transcriptomic, proteomic, genomic, DNA methylation, and tumor microenvironment datasets from TCGA, CPTAC, GTEx, and other public resources. Immune associations were evaluated via TIMER2.0 and TISIDB. Experimental validation included immunofluorescence staining for ST3GAL4 protein in human tumor specimens. Results: ST3GAL4 exhibited pervasive, lineage-specific dysregulation across cancers. Elevated expression correlated with adverse prognosis, genomic instability, and specific RNA modification patterns. Tumor microenvironment analyses revealed significant associations: ST3GAL4 expression positively correlated with cancer-associated fibroblast and endothelial cell infiltration but was inversely associated with cytotoxic T-cell abundance. Functional enrichment implicated ST3GAL4 within glycosphingolipid metabolism and glycan biosynthetic pathways. In experimental models, its expression demonstrated context-dependent modulation following cytokine stimulation and immunotherapy. Immunofluorescence confirmed tumor-specific protein expression and its spatial co-occurrence with stromal and immune cell markers. Conclusion: This multi-omics study delineates a comprehensive pan-cancer atlas of ST3GAL4, establishing its association with aggressive tumor behavior, an immunosuppressive microenvironment, and core glycosylation pathways. These findings position ST3GAL4 as a potential cross-tumor node linking sialylation to immune evasion, providing a rationale for future mechanistic and therapeutic exploration. Full article

Lung squamous cell carcinoma (LUSC) tends to arise in the setting of interstitial or emphysematous lung diseases, including idiopathic pulmonary fibrosis (IPF), pulmonary emphysema (PE), and smoking-related interstitial fibrosis (SRIF), where field cancerization may extend. DNA methylation of promoter regions of p16, CDH13, and RASSF1A and p16 exon 2 was assessed by methylation-specific PCR. Tumor, adjacent (<3 cm), and distant (≥3 cm) lung tissues were obtained from 25 patients with LUSC (IPF, n = 7; PE, n = 8; SRIF, n = 10). p16 exon 2 methylation was significantly higher in tumors than in non-tumorous tissues in PE and SRIF cases. In contrast, IPF cases showed p16 exon 2 hypermethylation also in distant tissues. Across tumor samples, p16 promoter hypermethylation was frequently observed in stage II or higher. p16 expression in tumors was generally reduced in IPF and PE cases, compared with SRIF cases. No consistent methylation or expression patterns were observed for CDH13 or RASSF1A. p16-associated molecular alterations exhibited disease- and stage-related differences, suggesting heterogeneity in LUSC carcinogenesis. These findings indicate a broader epigenetic field effect, as reflected by p16 exon 2, in IPF-associated LUSC and suggest that complex, elusive mechanisms underlying p16 aberrations may contribute to this phenomenon. Full article

Temozolomide and dacarbazine are untargeted anticancer prodrugs that have been widely employed in the treatment of melanoma and glioblastoma. These agents decompose into a short-lived monomethyl triazene intermediate, culminating in the release of a methyl diazonium cation that serves as the DNA-alkylating species responsible for tumour destruction. However, due to their high chemical lability, these agents have been associated with chemotherapy resistance, mutagenicity, tumour relapse, and significant off-target toxicity. One promising strategy towards the resolution of these limitations involves the design of arylmethyl triazene prodrugs, which enable targeted tumour-specific drug delivery. This review explores the various approaches used to selectively deliver alkyl aryl triazenes as alternatives to current therapies. It highlights early chemical strategies such as N-acylation and etherification of monomethyl triazenes, along with associated kinetic studies. The selective activation of novel triazenes in murine and human melanoma cells through a tyrosinase-responsive promoiety is discussed. Recent progress in nitroaromatic-based prodrugs designed to exploit the hypoxic microenvironment of glioblastoma is also examined. Additionally, we summarise the development of combi-triazenes and their underlying chemistries, which enable the simultaneous release of two active therapeutic agents. Full article

The rapid expansion of cardiac imaging has substantially increased patient and occupational exposure to low-dose ionizing radiation. Evidence suggests that cumulative exposures below 100 mSv may contribute to long-term risks of cancer and non-cancer diseases, including cardiovascular disease. However, establishing causality at these dose levels is challenging, as epidemiological studies are limited by heterogeneous endpoints, uncertainties in dose reconstruction, and incomplete control of confounding factors. Molecular biomarkers offer a promising strategy to bridge the gap between radiation exposure and clinically manifest disease, enabling more precise individualized risk assessment and targeted preventive strategies. This review summarizes current evidence on genetic and epigenetic biomarkers for evaluating the biological effects of radiation in cardiac imaging and interventional cardiology and examines their potential role in risk stratification and occupational surveillance. Genetic markers—including γ-H2AX foci, micronucleus assays, and telomere length alterations—alongside epigenetic modifications such as DNA methylation changes and microRNA expression profiles provide sensitive indicators of radiation-induced cellular damage. Integrating biomarker profiling with individualized dosimetry and longitudinal follow-up may improve risk prediction, enhance occupational protection, and support safer, more sustainable imaging practices in contemporary cardiovascular care. Full article

Maternal stress during lifetime and pregnancy may influence offspring epigenetic age, impacting long-term health. We conducted a systematic review and meta-analysis of associations between maternal stress and epigenetic aging markers: telomere length (TL) and DNA methylation (DNAm) age acceleration. The systematic search was performed according to PRISMA guidelines and registered on PROSPERO (ref. CRD42023474640). Fixed and random effect meta-analyses were carried out, stratified by stress type and marker type (TL, DNAm). Sixteen studies met inclusion criteria; 12 were meta-analyzed (10 TL, 2 DNAm). Due to high heterogeneity, restricted maximum likelihood meta-analysis suggested significant inverse associations between maternal stress and offspring TL. Perceived stress was associated with shorter TL (p-value = 7 × 10⁻⁴, β = −0.085, 95%CI [−0.135, −0.036]), as was lifetime stress/trauma (p-value = 0.01, β = −0.209, 95%CI [−0.370, −0.049]). In contrast, maternal stress showed no significant associations with DNAm age acceleration (p-value = 0.32). Both perceived maternal stress and maternal stress were associated with shorter offspring TL, suggesting that stress exposure across the maternal lifespan influences offspring biological aging markers. No significant association was observed with DNAm-based aging clocks. Further studies with larger sample sizes and more homogeneous settings are needed to confirm and expand upon our observations. Full article

Gastric cancer (GC) represents one of the most common and lethal cancers worldwide. The lack of early detection methods and wide heterogeneity from both histopathological and molecular points of view contribute to the high mortality associated with GC. Nowadays, the growing interest in the epigenetic landscape appears to represent a promising approach for improving early diagnosis, disease monitoring, therapy selection, and drug response. The knowledge of the epigenetic landscape in cancerous and, especially in precancerous lesions, remain scarce and controversial. The limitations must be identified due to the lack of standardization in experimental settings which introduce bias and lead to discrepancies in final conclusions. This review aims to provide an overview of epigenetics in the diagnostic setting of gastric cancer and in preneoplastic conditions, illustrating the available experimental approaches and therapeutic management in the era of epigenetics. Full article

Background/Objectives: Lifestyle behaviors such as smoking, vaping, and physical activity can induce epigenetic modifications that influence health trajectories and may provide forensic value. DNA methylation signatures linked to these behaviors offer potential for behavioral inference, personalized health assessment, and improved investigative practices. This study aimed to characterize methylation patterns associated with nicotine exposure and exercise using buccal cell DNA profiling, and to evaluate the extent to which these patterns differentiate harmful and protective lifestyle habits. Methods: Buccal epithelial DNA was analyzed using the Illumina Infinium MethylationEPIC v2 BeadChip to assess genome-wide methylation. Participants were categorized by smoking status, vaping behavior, and exercise activity. Differentially methylated regions (DMRs) and CpG sites were identified through pairwise comparisons among smokers, vapers, non-smokers/non-vapers, athletes, and sedentary individuals. A threshold of p < 1 × 10⁻⁴ was applied for significant differentially methylated CpG sites. Results: Distinct epigenetic profiles were associated with smoking/vaping and physical activity. Five DMRs differentiated smokers from non-smokers/non vapers, while 11 DMRs distinguished vapers from the same reference group. Twenty-eight DMRs displayed divergent methylation patterns between smokers and vapers. Exercise also showed measurable epigenetic influence: control athletes exhibited 26 significantly differentially methylated CpG sites relative to non-athletes, and smoker athletes demonstrated 126 suggestive differential sites compared to sedentary smokers. Additionally, 63 sites differentiated smoker athletes from non-smoker/non-vaper non-athletes, indicating interactions between risk-associated and health-promoting behaviors. Conclusions: Buccal cell DNA methylation profiling effectively captured signatures associated with smoking, vaping, and physical activity. These findings underscore the potential of epigenetic markers for lifestyle assessment in both personalized medicine and forensic investigations. Full article

Background: Gene expression and cellular identity are regulated by epigenetics that occurs through chromatin modifications, RNA changes, chromatin accessibility, and three-dimensional genome organization. Although DNA methylation has been the focus of most epigenetics studies in the past, other non-methyl epigenetic processes, including histone post-translational modifications (PTMs), epitranscriptomic marks, and chromatin remodeling, are dynamic, reversible, and context-dependent, and thus are difficult to accurately interrogate using endpoint sequencing-based assays, especially in heterogeneous tissues, developing systems, and therapeutic response environments. Scope and Approach: The present review discusses epigenetic modifications other than DNA methylation regarding sensor-based technologies that can measure live, dynamic, and spatially resolved measurements. Epigenetic sensors include any genetically encoded sensors (GECs) based on resonance energy transfer, CRISPR/dCas-derived sensors, or aptamer-based sensors, and hybrid biochemical/imaging sensors that can be used in live or semi-live settings. It lays emphasis on the technologies, which have been developed recently, that allow real-time kinetic measurements, working in three-dimensional and organoid models, and being applied to disease-relevant perturbations. On these platforms, performance properties such as specificity, sensitivity, spatial and temporal resolution, ability to perform dynamic versus locus-specific interrogation, and perturbed endogenous chromatin states are compared. Key Conclusions and Outlook: Together, these sensing strategies are complementary to the traditional methods of measuring epigenomics in that they show epigenetic dynamics unobservable with static measurements. We list the important technical issues, including specificity, quantitation, multiplexing, and chromatin perturbation, and report the barriers and solutions in development and design. Lastly, we provide a conceptual map of how live epigenetic sensing and multi-omics and translational models can be integrated, and how the two methodologies can be used to develop functional epigenetics and guide disease modeling and drug development. Full article

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

Neonicotinoids are widely used pesticides that have caused a catastrophic decrease in bee and bumblebee populations worldwide. In addition to insects, neonicotinoids induce toxic effects in other species, including lizards, birds, and mammals. Previous studies have shown that gestational exposure to thiacloprid promotes transgenerational effects in the testes and thyroid. In this project, we described the epigenetic effects of thiacloprid on prostate tissue in directly exposed F1 and non-directly exposed F3 outbred Swiss male mice. We used paraffin sections for morphological analysis and frozen tissue for immunofluorescence analysis, RT–qPCR, and protein analysis. We purified histones and analyzed them through Western blot. We used ChIP–qPCR for histone H3K4me3 occupancy analysis. A tendency to increase in epithelial hyperplasia in F1 but not in F3 prostate was detected. Elevated levels of phosphorylated histone H3 at serine 10, a marker of mitosis, in both the F1 and F3 prostates were noted. A significant increase in the level of the Ki-67 marker of proliferation was detected in the F1 but not in the F3 anterior prostate. Hox gene expression was upregulated in the F1 and downregulated in the F3 prostate. The changes in gene expression were positively associated with histone H3K4me3 alterations at the promoters of the Hoxa and Hoxb13 genes. We determined that regions of Hox genes that play important roles in prostate development had altered DNA methylation in the sperm of F1 and F3. These alterations in DNA methylation were negatively related to gene expression. This is an observational study, as it was part of our previous research on the effects of thiacloprid on the testis and thyroid. Our analysis revealed that gestational exposure to thiacloprid induced an increase in cell proliferation in the prostates of directly exposed F1. Some persistent epigenetic alterations in the prostate of F3 males were not associated with phenotypic changes. Full article

Background/Objectives: Chronic lymphocytic leukemia (CLL) is characterized by genetic and epigenetic alterations. This study aimed to assess the methylation status of E-Cadherin and MMP-9 gene promoters and to explore their relationships with disease pathogenesis and hematological parameters in CLL patients. Methods: A case–control study was conducted with 70 newly diagnosed CLL patients and 70 age- and sex-matched healthy controls. Promoter methylation of E-Cadherin and MMP-9 genes was evaluated using methylation-specific PCR (MSP) and methylation-sensitive restriction enzyme PCR (MSRE-PCR), respectively. Results: The median patient age was 62 years, and 68.5% were males. Binet stage A was the most common stage (57.3%). E-Cadherin promoter methylation was detected in 75.7% of CLL patients and 77.1% of controls (p = 0.91), showing no significant association with disease occurrence; however, it showed a significant correlation with higher lymphocyte counts (p = 0.01). In contrast, MMP-9 promoter methylation was significantly less frequent in CLL cases (70.0%) than in controls (100%, p = 0.001). Unmethylated MMP-9 correlated significantly with female gender (p = 0.02), lower hemoglobin (p = 0.031), reduced platelet counts (p = 0.001), and higher lymphocyte counts (p = 0.035). Conclusions: MMP-9 promoter hypomethylation may play a pathogenic role in CLL and is associated with female gender and cytopenia, whereas E-Cadherin methylation appears to be non-specific. MMP-9 methylation status could therefore serve as a potential biomarker for CLL biology and prognosis. Full article

Patients with Liver Hepatocellular carcinoma (LIHC) have a poor prognosis due to late-stage diagnosis and the limited efficacy of drug treatments. Dysregulation of nuclear pore complex (NPC) components, particularly nucleoporins (NUPs), may play a role in tumor progression. However, the specific role of NUP205 in LIHC has not been comprehensively investigated. We evaluated the expression, prognostic significance, epigenetic regulation, microRNA(miRNA) interactions, drug sensitivity, and biological functions of NUP205 in LIHC. Comprehensive bioinformatics analyses were performed using publicly available databases and web-based analysis platforms, including The Cancer Genome Atlas (TCGA), UALCAN, and the Kaplan–Meier Plotter (KM Plotter), among others. In vitro validation was performed using small interfering RNA (siRNA)-mediated knockdown of NUP205 in HepG2 cells, followed by quantitative reverse transcription PCR (RT-qPCR), apoptosis assay and wound-healing assay. NUP205 expression was significantly elevated in patients with LIHC and was associated with advanced clinicopathological features and poor prognosis. Promoter hypomethylation and miRNAs were identified as regulatory mechanisms influencing NUP205 expression. Increased NUP205 levels were associated with resistance to multiple chemotherapeutic agents. NUP205 knockdown significantly reduced messenger RNA (mRNA) expression in HepG2 and PLC/PRF/5 cells, and also reduced the expression of Transmembrane protein 209 (TMEM209) in HepG2 cells and improved sensitivity to doxorubicin. NUP205 expression was consistently associated with adverse clinicopathological features, poor prognosis, and altered drug sensitivity in LIHC. Integrative analyses suggest that NUP205 dysregulation may be linked to epigenetic and miRNA-associated regulatory mechanisms. These findings support NUP205 as a candidate prognostic biomarker and a potential regulatory factor in LIHC, warranting further mechanistic and protein-level validation. Further research is necessary to fully elucidate its underlying mechanisms and potential clinical applications. Full article