Search Results (735)

Transarterial chemoembolization (TACE) is the standard treatment for patients with intermediate-stage hepatocellular carcinoma (HCC), yet nearly half of treated patients fail to achieve durable benefit, and reliable biomarkers enabling early therapeutic stratification are still lacking. Treatment response is typically assessed by imaging one month after TACE and at three-month intervals, potentially delaying timely access to alternative therapies in non-responding patients. Circulating microRNAs (miRNAs) represent promising biomarkers due to their stability in body fluids and ease of detection. Here, we evaluated circulating miR-22 as an early predictor of TACE non-responder status and as a mechanistically relevant therapeutic target. Circulating miR-22 levels were measured by microarray and quantitative RT–PCR in three independent cohorts of early-to-intermediate-stage HCC patients undergoing TACE. Circulating miR-22 increased significantly in non-responders as early as 48 h after treatment, and fold changes consistently predicted treatment failure across two independent validation cohorts. Mechanistically, we identified the G2/M checkpoint kinase WEE1 as a direct functional target of miR-22. Modulation of the miR-22/WEE1 axis affected cell-cycle progression, proliferation, apoptosis, and DNA damage response in HCC cell lines and xenograft models. Under hypoxia-mimicking conditions combined with doxorubicin exposure, pharmacological inhibition of WEE1 induced mitotic catastrophe in highly proliferative miR-22-silenced cells. Collectively, these findings identify early post-TACE elevation of circulating miR-22 as a biomarker of non-response and highlight the miR-22/WEE1 axis as a potential target for precision treatment strategies in HCC. Full article

Understanding host cell response to viral infection could lead to the identification of molecular targets that can be used for the development of diagnostics and therapeutics. In this study, we investigated human dendritic cell (DC) response to infections with Vaccinia (VAC) virus, a highly immunogenic poxvirus, and Venezuelan Equine Encephalitis (VEE) virus, a single-stranded positive-strand RNA alphavirus, using human gene expression microarrays. Comparative changes in DC mRNA expression resulting from infection by the two viruses at 1, 8, and 12 h post-infection (hpi) revealed distinct temporal dynamics. VAC infection triggered early and robust activation of pathways related to chromatin organization, DNA damage, and antigen presentation, while VEE infection exhibited delayed activation of immune signaling pathways, including interferon signaling and cytokine production. Shared pathways, such as interferon signaling and inflammasome activation, highlight universal antiviral responses and potential therapeutic targets. These findings provide a molecular framework affected by VAC and VEE that need to be validated with additional experiments, such as functional assays or in vivo studies. The specific up- or downregulation of these pathways at different time points likely dictates the overall outcome of the viral infection and could potentially lead to better understanding of the temporal regulatory dynamics of virus host response. Full article

Background/Objectives: Methicillin-resistant Staphylococcus aureus (MRSA) causes hospital- and community-acquired infections. MRSA is a highly diverse strain that includes several epidemic clones, including CC45. A previous study conducted among MRSA isolates in Kuwait identified CC45 in two isolates in the early 2000s. This study provides an update on the prevalence and molecular characteristics of CC45 among MRSA isolates in Kuwait hospitals, during 2016–2022. Methods: A total of 13,276 MRSA isolates were collected during 2016–2022 and typed using antibiogram, DNA microarray, Staphylococcal protein A (spa) typing, pulsed-field gel electrophoresis (PFGE), and multi-locus sequence typing (MLST). Results: CC45 was detected in 87 (0.65%) of the 13,276 MRSA isolates. The isolates were resistant to fusidic acid (n = 71), erythromycin (n = 16), and inducible clindamycin resistance (n = 15). Twenty-one isolates were resistant to multiple antibiotics. Spa typing identified 19 types, with t362 (n = 35) and t132 (n = 27) as the dominant types. DNA microarray identified seven genotypes with CC45-MRSA-[IV + fus] (n = 36) and CC45-MRSA-[VI + fus] (n = 30) as the dominant types. MLST identified six sequence types (STs): ST7119, ST508, ST45, ST46, ST9548, and ST10699. PFGE clustered the isolates into two major types, A and B, with type A being the major type (n = 83), mostly consisting of CC45-MRSA-[IV + fus] isolates. The CC45-MRSA-[IV + fus] and CC45-MRSA-[VI + fus] genotypes were detected throughout the study period (2016–2022), whereas the other genotypes were detected less frequently. Conclusions: The CC45-MRSA circulating in Kuwait hospitals comprises genetically diverse isolates that may have originated from different sources. The emergence of multidrug resistance among the isolates poses challenges for therapy and infection prevention. Full article

Low-dose ionizing radiation exposure remains a major challenge for long-term health risk assessment, particularly in retrospective cohorts with heterogeneous exposure scenarios and limited biological material. Although next-generation sequencing (NGS) technologies dominate contemporary molecular research, DNA microarrays remain relevant in radiation biology due to their standardization, reproducibility, cost-effectiveness, and compatibility with archived biospecimens. This narrative review examines the contribution of microarray-based transcriptomic and epigenomic profiling to the study of low-dose radiation effects (≤100 mSv, millisievert), with emphasis on human observational studies, radiation epidemiology, and biodosimetric applications. The literature was identified through targeted searches in PubMed and Web of Science (2000–2025). Evidence from experimental models and exposed populations is synthesized to identify recurrent molecular pathways, major sources of variability, and challenges affecting reproducibility and cross-cohort comparability. Based on this evidence, a conceptual framework is proposed to define conditions under which microarray-based analyses remain interpretable and translationally informative. Machine learning approaches are discussed in a supportive role, with emphasis on interpretability and biological plausibility. Overall, DNA microarrays are positioned as a mature, niche technology that complements next-generation sequencing platforms and remains particularly suited for retrospective cohort studies and long-term molecular monitoring in radiation research. Full article

Background: Polyploid and chromosomal copy number gains (CNGs) cells may serve as key mediators of tumor plasticity, therapeutic resistance, and clonal evolution. Despite growing interest, their biological and clinical relevance in colorectal cancer, particularly in the metastatic setting, remains poorly defined. Methods: We performed an integrated morphological, cytogenetic, and genomic analysis of metastatic colon cancer. A tissue microarray comprising 100 tumors was evaluated, of which 47 cases were fully assessable for morphology and fluorescence in situ hybridization (FISH). Polyploid nuclei and chromosomal CNGs were assessed morphologically and cytogenetically. High-resolution targeted sequencing (TruSight Oncology 500) was conducted to characterize genomic alterations. Bioinformatic analyses included Gene Ontology enrichment and Phenolyzer network modeling. Associations with clinicopathological variables and survival outcomes were explored. Results: Polyploid nuclei and/or chromosomal CNGs were identified in approximately 25% of evaluable cases. These alterations were enriched in right-sided CRCs and in older patients, suggesting a link with age-related genomic instability. Polyploid/CNG tumors did not show significant enrichment for canonical CRC driver mutations (RAS, TP53, SMAD4), although trends toward co-occurrence with BRAF mutation and mutual exclusivity with HER2 amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. Conclusions: In metastatic colon cancer, the presence of genome-wide copy number gain may delineate a tumor subset with distinctive clinicopathological and molecular characteristics. Further studies are warranted to elucidate the biological significance of these features and to explore their potential implications for tumor evolution, treatment response, and clinical stratification. Full article

Vertical jump performance is known to be a moderately heritable trait. However, previous studies on sport genetics have largely relied on candidate-gene approaches, which do not adequately reflect the polygenic nature of explosive performance, particularly among elite badminton players. Therefore, the aim of the present study was to identify genetic variants associated with lower-limb explosive performance, assessed via vertical jump measures, among elite Turkish badminton players using a genome-wide association study (GWAS) approach. The present study included 90 elite male (n = 47) and female (n = 43) badminton players, and 557 non-athletic controls sourced from a public database. Performance-related traits were evaluated through countermovement jump (CMJ), squat jump (SJ), and their differential. Genome-wide genotyping was performed using DNA microarrays, and associations were examined using linear mixed models fixed for sex/gender, body mass index, and sport experience. Although no variants reached genome-wide significance (p < 1.00 × 10⁻⁷), 13 single-nucleotide polymorphisms (SNPs) exceeded the suggestive threshold (p < 1.00 × 10⁻⁵). CMJ-associated variants were rs4905767, rs2911702, rs10246591, and rs9842454; SJ-associated variants were rs55817650, rs62318127, rs115197840, rs78317172, and rs35930589; and CMJ–SJ-associated variants were rs34638064, rs6679342, rs4931233, and rs9442615. The present study provides preliminary evidence that lower-limb explosive performance among elite badminton players is polygenic, involving regulatory and signaling pathways rather than single performance genes. Full article

Understanding the molecular mechanisms of carcinogenesis, including disruptions in the homologous recombination system, is fundamental to understanding malignant transformation. Dysfunction of homologous recombination genes, such as BRCA1 and BRCA2, contributes to genomic instability and the development of more aggressive tumor clones. The use of chemical carcinogens enables the modeling of tumor formation and the monitoring of changes in molecular genetic parameters. This approach is important for understanding how tumor cells adapt to genotoxic stress and for advancing the development of personalized cancer therapies. The objective of this study was to evaluate the expression of key homologous recombination system genes in a model of chemically induced carcinogenesis in mice. Materials and Methods: Male outbred ICR (CD-1) laboratory mice (n = 40) were used to study chemically induced carcinogenesis. The animals were divided into four groups: two control groups and two experimental groups, which received 3-methylcholanthrene (MC) or trichloroacetic acid (TCA). Tumor cells were identified by histological analysis of autopsy material using light microscopy after standard hematoxylin and eosin staining. RNA and DNA were extracted from cell suspensions using the RNeasy Plus Mini Kit and QIAamp DNA Mini Kit (Qiagen, Hilden, Germany), respectively. The expression levels of homologous recombination genes were assessed by RT-PCR and microarray analysis. Digital PCR was performed to assess chromosomal aberrations in the Brca1 gene. Results: Tumor formations were identified in laboratory animals two months after 3-methylcholanthrene. Histological analysis revealed morphological changes in a pleomorphic cell tumor, forming diverse, multidirectional fascicular and swirling structures, as well as large solid foci composed of markedly polymorphic spindle-shaped and epithelioid cells. Analysis of copy number aberrations in the examined samples showed that the frequency of Brca1 deletions was 60%, while 40% of animals had normal gene copy number. To further characterize the molecular changes, we assessed gene expression levels through expression microarray analysis. A total of 14 genes were hypoexpressed in the tumor compared to the normal tissue, with p < 0.05. A high level of differential expression was characteristic for Rad50, Rad51, Brca1, Brca2, and Pold4. Two genes, Rad52 and Bard1, exhibited increased expression levels. It was shown that as the tumor mass increased, so did the frequency of homologous recombination genes with hypoexpression. Conclusions: Our findings confirm that MC and TCA influence tumor formation and reveal that suppression of homologous recombination genes may contribute to this process. In addition, it has been established that as tumors progress, the expression of DNA repair genes declines and aberrant gene states accumulate. These data emphasize the importance of studying the state of DNA repair genes for the development of more effective strategies for cancer diagnosis and therapy. Full article

Background: Recent findings underscore the importance of ribosome biogenesis, a complex molecular machinery, in cancer biology, highlighting opportunities for targeted treatment strategies. Here, we revealed that dysregulation of ribosome biogenesis is a distinctive feature of non-small lung cancer (NSCLC). However, further investigation is required to pinpoint which specific processes within this complex pathway are aberrant in this malignancy. Methods: The expression levels and clinical significance of NOP56 in NSCLC were investigated by microarray analysis, qPCR, TCGA and GEO datasets. Function assays were conducted to explore the biological role of NOP56 in NSCLC cells. The mechanisms that mediate the upregulation of NOP56 were investigated by bisulfite DNA sequencing, luciferase reporter assay, chromatin immunoprecipitation and TCGA datasets. The downstream pathway of NOP56 was explored by RNA sequencing, qPCR, Western blot and luciferase reporter assay. Results: High expression of NOP56 was detected in NSCLC tissues and was associated with poor prognosis. Functional assays revealed that overexpression of NOP56 promoted NSCLC cellular proliferation, metastasis and ribosome biogenesis in vitro, and further accelerated tumorigenesis in vivo. Mechanistically, NOP56 activates MYC signaling by regulating IRES-dependent translation, which in turn transcriptionally upregulated NOP56 expression, creating a positive feedback loop. Additionally, hypomethylation also contributed to the upregulation of NOP56 in NSCLC. Conclusions: Our study demonstrated that NOP56/MYC forms a positive feedback loop that enhances ribosome biogenesis and drives the progression of NSLSC, positioning NOP56 a promising therapeutic target for this malignancy. Full article

Lavender essential oil (LEO) is commonly used in aromatherapy for stress reduction, relaxation and recovery from (muscle) fatigue. However, molecular mechanisms underlying its potential physiological effects on the skeletal muscle remain unclear. This study investigates whether LEO affects the intracellular signaling pathways in skeletal muscle cells that respond to physical activity. Prior to the experiment, GC-MS analysis confirmed linalyl acetate and linalool as the main components of LEO used in this study. Transdermal permeability was assessed using a reconstructed human epidermis model, which showed that linalool permeated the epidermal layer, while linalyl acetate showed minimal permeation. Following this confirmation, the differentiated C2C12 myotubes were treated with LEO in an in vitro muscle contraction model using electrical pulse stimulation (EPS). LEO significantly increased Interleukin 6 (IL-6) mRNA expression under EPS, and DNA whole-genome microarray analysis showed that LEO induced different gene expression profiles depending on the contraction state of the muscle cells. These results provide the first molecular evidence that LEO modulates skeletal muscle gene networks in a stimulation-dependent manner and may indicate its potential use as an aid to recovery (from fatigue) after exercise. Notably, the skin permeation of LEO components showed a saturation trend at concentrations above 5%, suggesting the presence of an optimal concentration range for topical application in sports aromatherapy. Full article

Introduction: Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive, heterogeneous, and lethal malignancies in humans. Mismatch repair (MMR) proteins constitute a fundamental component of the DNA mismatch repair pathway, which is responsible for correcting replication-associated errors, including incorrect base pairings and small insertions or deletions. This study aims to evaluate the immunohistochemical expression of MSH2, MSH6, MLH1, and PMS2 in resected PDAC and to analyze their association with pTNM stage, perineural and lymphovascular invasion, HER2 and HER3 expression, and tumor volume. Methods: A cohort of 106 patients with currative intent Whipple procedure was evaluated, their corresponding paraffin blocks and slides were analyzed using tissue microarray. Immunohistochemical analysis of MLH1, PMS2, MSH2, and MSH6 was performed. Patients were grouped based on MMR expression profiles: isolated MutS loss (MSH2/MSH6), and isolated MutL loss (MLH1/PMS2). Results: Among the 106 subjects evaluated, 13 (12.3%) exhibited isolated MutS complex loss and 16 (15.1%) showed MutL complex loss. A total of 7 patients (6.6%) demonstrated concurrent loss of all four MMR proteins, representing a pattern suggestive of MMR deficiency MSI-H. These ones were significantly younger (median 56 vs. 64 years, p = 0.0492) and had distinct T-stage distribution (p = 0.0237). Two intermediate subgroups were identified: five patients with isolated MutL loss and one patient with isolated MutS loss. HER3 positivity was observed in 3/5 of the intermediate MutL cases and HER2 positivity in only one. Conclusions: MMR deficiency and potential MSI-H status were identified to be relevant prognostic biomarkers for pancreatic cancer patients, with MSI-H patients displaying a younger age and distinct tumor features. Full article

Background: Advances in genome-wide DNA-based technologies have fundamentally transformed prenatal genetic diagnostics, enabling detection of clinically significant submicroscopic chromosomal abnormalities that are not identifiable by conventional cytogenetic methods. These developments have important implications for the diagnosis and management of pregnancies complicated by fetal structural abnormalities, as they enable more accurate etiological diagnosis, improved prognostic assessment, and more informed clinical decision-making and reproductive counselling. Methods: This narrative review synthesizes contemporary international evidence on prenatal genetic diagnostic approaches, including conventional karyotyping, chromosomal microarray analysis (CMA), and genome-wide sequencing technologies. The review focuses on diagnostic performance, clinical utility, ethical considerations, and implementation within diverse healthcare systems. Results: Accumulating evidence demonstrates that genome-wide approaches—particularly CMA and sequencing-based methods—provide a higher diagnostic yield in fetuses with structural anomalies, with an incremental yield of approximately 3–5% over conventional karyotyping. This is mainly due to their ability to detect pathogenic copy number variants below the cytogenetic resolution of karyotyping. These technologies improve etiological insight, enhance genotype–phenotype correlation, and support more precise prognostication and reproductive counselling, especially in pregnancies with fetal structural anomalies. Emerging sequencing platforms further expand the diagnostic spectrum by integrating copy number and sequence-level variant detection. Conclusions: Genome-wide Copy Number Variation (CNV) analysis represents a critical component of contemporary prenatal diagnostics and should be integrated into invasive prenatal testing pathways in accordance with international recommendations. Genome-wide approaches need robust counselling frameworks and equitable health policy implementation to spread. The expense, lack of required experience, and variation in healthcare infrastructure across locations make widespread deployment difficult. Full article

Objectives: The overall objective of this study is to examine prenatal patients ascertained without an abnormal ultrasound (US) or an abnormal cell-free DNA (cfDNA) finding to provide a unique understanding of pathogenic copy number variants, identity by descent (IBD) and variants of uncertain significance (VUSs) in a normal population. Methods: This study retrospectively provides an analysis of over 28,362 prenatal specimens ascertained without an abnormal US or abnormal cfDNA finding utilizing an SNP microarray. These specimens include at least 10 different ascertainment groups, including advanced maternal age (AMA), anxiety, abnormal maternal serum screen (MSS) with/without AMA, and a previous or familial child/pregnancy with a chromosome abnormality or a genetic disorder. Results: This study provides a basic understanding of pathogenic copy number variants (CNVs), homozygosity and VUSs in an essentially normal population. This low-risk population has a frequency of pathogenic CNVs of ~1.26%; however, ~52% were associated with neurodevelopmental microdeletions/microduplications and ~13% were associated with incidental findings. Overall, ~1.32% of these patients showed an increase in homozygosity, the majority due to consanguinity. Lastly, VUSs were seen in 1.41% of this group, of which ~90% were familial. Conclusions: Overall, these findings provide a better estimate of the baseline frequencies and types of pathogenic CNVs and homozygosity in a low-risk population. It provides insight into the distribution of stretches of homozygosity associated with identity by descent in this population and gives a better understanding of the extent of variants of uncertain significance in phenotypically unaffected individuals. Full article

Background: The present study set out to identify key miRNAs, TFs and signaling pathways associated with bladder cancer, with a view to elucidating the networks of miRNA-TF-gene interactions that may serve as potential molecular biomarkers for disease diagnosis. Methods: An integrative analysis was conducted using the publicly available microarray dataset GSE130598. Expression profanalyzede analyzed from 42 muscle-invasive bladder cancer (MIBC) tissues and 42 matched adjacent normal bladder tissues. After data preprocessing and normalization, differentially expressed genes (DEGs) were identified. To identify the associated biological processes and signaling pathways, functional enrichment analyses were conducted using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Protein–protein interaction (PPI) network analysis was then employed to identify hub genes and key molecular interaction modules associated with bladder cancer. Results: MYC, TP53, SP1, E2F1, E2F3, NFKB1, and TWIST1 were identified as central transcriptional regulators, indicating their roles in controlling genes involved in cell cycle regulation, DNA damage response, and tumor progression. Several miRNA families, including miR-200, miR-17, miR-29, miR-141, and miR-548, have been identified as key post-transcriptional regulators, suggesting their involvement in oncogenic signaling and cellular differentiation. PPI network analysis revealed MAPK3, AKT1, CHEK1, CDK1, AURKA, and AURKB as hub genes associated with cell proliferation, mitotic control, and intracellular signaling. Conclusions: Fundamental molecular processes underlying bladder cancer pathogenesis include cell cycle control, signal transduction, and genomic stability. These findings provide insight into the molecular regulatory landscape of MIBC and highlight potential targets for diagnostic and prognostic applications. Full article

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors primarily involving the adrenal medulla and its associated paraganglia, with heterogeneous clinical behavior and complex molecular drivers. This study aimed to characterize DNA methylation and gene expression patterns in PPGLs to understand the molecular differences between tumor subtypes and malignancy. We performed an integrative analysis of DNA methylation (Illumina EPIC 850K) and gene expression profiles (Affymetrix microarrays) in 24 PPGLs, comparing these with The Cancer Genome Atlas (TCGA) data, to delineate cluster- and malignancy-specific epigenetic patterns. Comparison between pseudohypoxic Cluster I and kinase-signaling Cluster II tumors revealed 13 differentially methylated CpG sites, with a specific CpG within DSCAML1 showing hypermethylation in Cluster II accompanied by increased expression, suggesting context-dependent gene body methylation effects. Benign versus malignant comparisons identified 101 differentially methylated CpGs, including hypermethylated CpG in BAIAP2L1 and hypomethylated CpG in SHANK1 in malignant tumors. Pathway enrichment of differentially methylated genes revealed alterations in Notch signaling, adherens junctions, cytoskeletal regulation, and intracellular transport. Gene expression analysis demonstrated partial overlap between clusters, with malignant tumors exhibiting distinct transcriptional profiles involving RNA processing, metabolism, and adhesion pathways. Correlation between methylation and expression was generally limited, emphasizing that methylation-dependent gene regulation is a locus-specific and context-dependent regulation. These findings illustrate a complex interplay between epigenetic modifications and transcriptional programs in PPGLs, enhancing our understanding of molecular heterogeneity and tumor classification, and identifying candidate biomarkers and therapeutic targets for malignant progression. Full article

Malformations of cortical development (MCD) are a group of neurodevelopmental disorders caused by abnormalities in cerebral cortex development, leading to conditions such as intellectual disability and refractory epilepsy. The prenatal phenotypes of MCD are complex and non-specific, complicating accurate diagnosis and prognosis assessment. Genetic testing, particularly chromosomal microarray analysis (CMA) and whole-exome sequencing (WES), has become an important tool for prenatal diagnosis. This review synthesizes current research on prenatal MCD, focusing on the integration of imaging and genetic diagnostic strategies based on the biological foundation of cortical development and the classification system of MCD. Prenatal MCD phenotypes show significant developmental stage clustering, with proliferation-phase abnormalities (62.9%) being the most common and microcephaly as the core phenotype. Genetic studies have revealed a high degree of genetic heterogeneity in MCD, with etiologies encompassing chromosomal abnormalities and a wide range of single-gene mutations. These mutations are clustered by phenotype: microcephaly is associated with neuronal proliferation/DNA repair genes; macrocephaly is driven by genes in the PI3K-AKT-mTOR and RAS-MAPK signaling pathways; and gyral and sulcal abnormalities are closely linked to microtubule-associated genes and migration pathways. De novo mutations account for the majority of pathogenic genetic alterations identified in MCD (50.6%); up to 75.1% of pathogenic mutations cannot be detected by routine prenatal screening. Based on this, the review emphasizes that for fetuses with suspected MCD, NGS, with WES at its core, plays an increasingly important role in achieving early and accurate prenatal diagnosis. Future research should prioritize the advancement of integrated diagnostic methods and large-scale cohort studies to further elucidate genotype–phenotype associations. Full article