Search Results (1,546)

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

Endometriosis affects approximately 10% of reproductive-age women and is associated with genomic instability; however, the contribution of specific DNA repair deficiencies remains poorly understood. This study investigated the expression and function of GEN1, a Holliday junction resolvase critical for homologous recombination, in patient-derived endometrial epithelial organoids (EEOs). Endometrial tissue was obtained by pipelle biopsy from women with laparoscopically confirmed endometriosis (n = 3, stage III–IV) and controls without endometriosis (n = 3). GEN1 mRNA and protein expression were reduced in primary endometrial cells from endometriosis patients compared with controls (mRNA: 0.52 ± 0.14 vs. 1.00 ± 0.19, p = 0.05; immunofluorescence intensity: 0.54 ± 0.18 vs. 1.00 ± 0.22, p = 0.05). Patient-derived EEOs from the endometriosis group showed trends toward lower formation efficiency (18.4 ± 5.6% vs. 25.2 ± 6.8%, p = 0.10) and reduced mean diameter (124.6 ± 34.2 vs. 155.8 ± 32.6 µm, p = 0.10). RNA interference (RNAi)-mediated GEN1 knockdown reduced proliferation in both groups, with a more pronounced effect in endometriosis-derived EEOs (49.7% vs. 39.5% reduction, p = 0.05). Endometriosis-derived EEOs exhibited elevated baseline γH2AX (phosphorylated histone H2AX) immunofluorescence compared with controls (2.32 ± 0.44 vs. 1.00 ± 0.28, p = 0.05), indicating increased DNA double-strand break accumulation. Furthermore, GEN1 knockdown directly increased γH2AX intensity in both groups, with endometriosis-derived EEOs showing a greater absolute increase (Δ1.26 vs. Δ0.72). To our knowledge, this study provides the first organoid-based evidence that GEN1 is downregulated in endometriosis and functionally linked to impaired proliferation and elevated DNA damage, suggesting a potential contribution of homologous recombination dysregulation to endometriosis pathogenesis. Full article

Obesity-associated carcinogenesis offers a model to explore the transition from metabolic dysregulation to genomic instability and carcinogenesis. Adenosine 5′-monophosphate-activated protein kinase (AMPK), the principal cellular energy sensor, coordinates adenosine triphosphate (ATP) production with metabolic demand; however, in obesity, AMPK activity is impaired, resulting in reduced ATP, elevated Adenosine Monophosphate (AMP), and cellular energy stress. Deoxyribonucleic Acid (DNA) polymerases ε (Pol ε) and δ (Pol δ) maintain replication fidelity via a 3′→5′ exonuclease proofreading activity that removes misincorporated nucleotides. Elevated AMP directly binds and selectively inhibits the exonucleases, conserving energy at the expense of genomic accuracy. As a result, replication errors escape correction and accumulate, some conferring a selective advantage and driving carcinogenic evolution. Therapeutic and lifestyle interventions that activate AMPK—including weight loss, exercise, metformin, and aspirin—restore ATP production, lower AMP, and relieve inhibition of exonuclease proofreading, thereby preserving genomic integrity and slowing mutation-driven carcinogenesis. This framework reveals two core biological principles: 1. Energy metabolism and DNAreplication fidelity are mechanistically coupled at the DNA polymerase active site. 2. The mutation rate is an adaptive metabolic phenotype, modulated by AMP levels. These concepts redefine the metabolic–genetic interface in carcinogenesis and highlight AMPK activation as a rational target for obesity-associated cancer prevention. Full article

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by high metabolic activity, chronic endoplasmic reticulum stress, and persistent redox imbalance. Excessive immunoglobulin synthesis and adaptation to the hypoxic bone marrow microenvironment lead to sustained production of reactive oxygen species (ROS). Their excessive accumulation promotes genomic instability, disease progression, osteolytic bone disease, and resistance to therapy. Paradoxically, MM cells adapt to oxidative stress by activating antioxidant and metabolic defense mechanisms, including Nuclear factor erythroid 2-related factor 2 (NRF2)- and Heme Oxygenase 1 (HMOX1)-dependent pathways, metabolic reprogramming, and overexpression of ROS-scavenging enzymes such as peroxiredoxin 6 (PRDX6), allowing survival at the threshold of oxidative toxicity. Evidence indicates that biomarkers of oxidative stress—such as lipid and protein oxidation products, antioxidant enzyme activity, and the Oxidative Stress Score—correlate with disease stage, prognosis, and treatment response. Redox-modulating therapeutic strategies, including pharmacological ROS induction, inhibition of antioxidant defenses, and the use of natural pro-oxidant compounds, are emerging as promising adjuncts to standard MM therapies. Recent studies also highlight the gut microbiota as an indirect regulator of oxidative balance, immune modulation, and metabolic homeostasis in MM. This review summarizes current knowledge on oxidative stress in multiple myeloma, emphasizing its role in pathogenesis, drug resistance, biomarker development, and emerging therapeutic and supportive strategies. Full article

Background/Objectives: Traditional histopathologic grading of renal cell carcinoma (RCC) is subjective, is poorly reproducible, and fails to predict responses to modern targeted agents or immunotherapies. In the era of precision oncology, molecular pathology offers objective tools for individualized management. We aimed to characterize genomic alterations in clear-cell RCC (ccRCC) with venous tumor thrombus and to develop pathology-driven panels for personalized prognostic stratification, with exploratory assessment of their potential to predict therapeutic response. Methods: Formalin-fixed paraffin-embedded pT1 ccRCC samples with and without thrombus underwent whole-exome sequencing. Distinct somatic mutations and copy number variations were incorporated into multigene panels. External assessment was performed in TCGA and PAWG cohorts, assessing survival outcomes and therapeutic biomarkers including homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI). Results: Thrombus cases showed unique genomic heterogeneity compared with matched controls. Three multigene panels were constructed. Across external datasets, including a 354-patient TCGA-KIRC ccRCC cohort, the panels provided consistent molecular stratification signals for overall, disease-specific, and progression-free survival, complementing established pathological risk factors. They were significantly associated with established therapy-related genomic biomarkers, including HRD, TMB, and MSI, showing high sensitivity and negative predictive value in identifying patients unlikely to harbor these biomarker-positive profiles. These findings support the panels’ prognostic utility, with exploratory evidence for their potential in therapy response prediction. Conclusions: Small ccRCC with thrombus harbors distinct molecular pathological features. The proposed pathology-driven panels, compatible with FFPE tissue, represent pathology-compatible genomic tools that may support modern precision pathology by improving molecular risk stratification and informing exploratory therapeutic biomarker assessment. Full article

Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. Full article

Background/Objectives: Early embryonic arrest during the cleavage stage (days 2–4) accounts for a substantial proportion of developmental failure in in vitro fertilization. This phenomenon remains poorly understood at the molecular level, even in chromosomally normal embryos identified by preimplantation genetic testing. This review aims to redefine cleavage-stage arrest from a passive energy deficit to a checkpoint-regulated endpoint caused by inadequate coordination among metabolism, transcriptome integrity, and stress-response pathways. Methods: We integrate evidence from long-read transcriptomics, metabolomics, epigenetics, and immunobiology relevant to pre-blastocyst development. These data are assembled into a unifying mechanistic framework and a clinically oriented stratification model, together with candidate multimodal readouts for early classification. Results: We propose a three-axis model linking: (i) metabolic–epigenetic insufficiency, including defective histone lactylation and impaired alpha-ketoglutarate-dependent DNA demethylation; (ii) isoform-level abnormalities, including intron retention and retrotransposon activation within a hidden transcriptomic landscape better resolved by long-read sequencing; and (iii) stress-related immune signaling, in which NLRP7 links alternative splicing and DNA-damage-response dysfunction with mitochondrial stress and p53-associated arrest. Within this framework, we distinguish three molecular arrest states: an early transition failure marked by defective maternal-to-embryonic reprogramming and severe splicing disruption; a metabolically quiescent state that may retain a limited rescue window; and a later stress-associated state characterized by senescence-like features, oxidative stress, and broad transcriptomic and genomic instability. Conclusions: Early embryo arrest should no longer be viewed as a nonspecific developmental failure, but as a mechanistically stratifiable condition with distinct metabolic, transcriptomic, and stress-associated trajectories. A diagnostic platform combining fluorescence lifetime imaging microscopy, long-read sequencing, and digital polymerase chain reaction may improve early mechanistic classification, help identify embryos with possible reversibility, and reduce uncertainty in embryo selection during in vitro fertilization. Full article

Cancer remains a significant challenge to global public health. Preliminary studies indicate that the protein Golgi-associated, Gamma-adaptin Ear Containing, ARF Binding Protein 2 (GGA2) may influence various cancers. However, the potential role of GGA2 in oncogenesis remains unknown. We utilized data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) projects to analyze GGA2 expression levels. Genetic variations and protein expression of GGA2 in human tissues were assessed using the cBioPortal. Gene Set Enrichment Analysis (GSEA) provided deeper insights into GGA2’s oncogenic functions. Comprehensive analysis of TCGA datasets combined with ESTIMATE and TIMER tools demonstrated significant correlations between GGA2 expression levels and clinical outcomes, survival metrics, genomic instability markers (microsatellite instability (MSI)/tumor mutational burden (TMB)), and immune microenvironment composition. Functional validation in prostate cancer models employed qRT-PCR quantification, immunoblotting verification, and cellular behavior assessments through colony formation, Transwell migration, and wound closure assays. Our findings suggest GGA2 could serve as a prognostic biomarker in various cancers. Abnormal levels of GGA2 promoter methylation and genetic alterations may contribute to its dysregulated expression in some cancers. Distinctly, GGA2 expression correlates with MSI and TMB across different cancers and is linked to the expression of immune checkpoint genes. Functionally, GGA2 is instrumental in inhibiting oncogenic mechanisms by diminishing the proliferation, colony formation, invasion, and migratory capabilities of prostate cancer cells. Our study shows that the oncogenic role of GGA2 in various cancers and GGA2 could be served as a biomarker of PARD. Full article

Vitamin B6 is an essential micronutrient whose biologically active form, pyridoxal 5′-phosphate (PLP), acts as a cofactor in metabolic reactions linked to tumorigenesis and also functions as an antioxidant. Low plasma PLP levels are consistently associated with cancer, but studies on dietary intake have yielded conflicting results. Overall, evidence suggests that the effects of vitamin B6 deficiency on cancer are context-dependent, varying with cell type and tumor stage. Accordingly, high expression of PDXK and PNPO, two key genes involved in PLP biosynthesis, is associated with tumor progression in some malignancies, whereas it correlates with improved outcomes in others. This review explores Drosophila melanogaster as a useful model to investigate underlying mechanisms, bypassing the limitations of human studies. Research in Drosophila demonstrates that PLP deficiency promotes cancer by triggering genomic instability. Furthermore, a critical PLP-SHMT gene–nutrient interaction impacting oncogenesis has been established in flies, offering significant therapeutic implications. Finally, studies in Drosophila have shown that PLP deficiency can promote tumor development by also triggering the loss of heterozygosity (LOH). These findings highlight Drosophila as a powerful tool to elucidate the molecular pathways linking vitamin B6 deficiency to cancer. 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

The accelerating frequency of emerging infectious diseases (EIDs) in livestock poses a significant threat to global food security, as well as to animal and public health. While wastewater-based surveillance (WBS) has advanced significantly for human health surveillance, its application to livestock production systems remains fragmented and lacks standardization. This review synthesizes current evidence on livestock wastewater-based surveillance (L-WBS) as an early-warning sentinel for emerging viral pathogens, evaluating their dynamics, economic impacts, biosecurity measures, and One Health implications. Existing studies demonstrate that L-WBS effectively detects emerging viral pathogens in agricultural effluent, swine manure, and municipal wastewater systems serving livestock regions, frequently preceding clinical outbreak recognition. We further conceptualized a multifactorial framework linking environmental drivers such as climate and ecological disruption and agricultural intensification to pathogen emergence dynamics. Economic assessments show substantial direct losses (approximately US$ 950 per H5N1-infected dairy cow and US$ 25.9 billion in African swine fever virus (ASFV)-related damages across China) alongside indirect costs from biosecurity implementation, workforce disruption, and supply-chain instability. We recommend prioritizing methodological standardization through unified sampling and extraction protocols, integration of next-generation sequencing for genomic surveillance, and cross-sectoral policy frameworks to operationalize L-WBS as a global early-warning infrastructure for mitigating zoonotic spillover and livestock-dependent community resilience. Full article

Background: Mitochondria are multifunctional organelles that play a central role in maintaining cellular homeostasis by regulating energy metabolism, reactive oxygen species (ROS) generation, ion homeostasis, and apoptotic signaling. Dynamic processes such as mitochondrial fission, fusion, and intracellular trafficking enable cells to adapt to metabolic and environmental stress. Growing evidence indicates that dysregulation of these processes is a hallmark of cancer, contributing to metabolic reprogramming, redox imbalance, evasion of apoptosis, and disease progression. This narrative review aims to discuss the role of mitochondrial alterations in the pathophysiology of chronic myeloid leukemia (CML) and their potential therapeutic implications. Methods: Original research articles published between 2010 and 2025 were considered in this narrative review. The selected studies were critically discussed and categorized into three principal thematic domains: mitochondrial regulation of redox homeostasis, metabolic rewiring, and control of cell death pathways. Evidence was synthesized to elucidate the contribution of mitochondrial dysfunction to CML initiation, progression, and therapeutic resistance. Results: The reviewed studies highlight how mitochondrial abnormalities play a pivotal role in BCR-ABL1-driven leukemogenesis. Alterations in mitochondrial metabolism and ROS signaling support sustained proliferative signaling, promote genomic instability, and facilitate resistance to apoptosis. In addition, mitochondrial adaptations contribute to resistance to tyrosine kinase inhibitors (TKIs) and are essential for the persistence and survival of leukemic stem cells. Conclusions: Mitochondria emerge as central regulators of CML pathobiology. Therapeutic strategies targeting mitochondrial metabolism, redox homeostasis, and apoptotic signaling pathways represent promising approaches to overcoming TKI resistance and may improve clinical outcomes for patients with CML. Full article

Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in cancer and its malignant progression. The nucleus represents a physical barrier for the migration and invasion in dense 3D extracellular matrix (ECM) scaffolds. Therefore, the deformability of the nucleus seems to determine the migration limit in circumstances where the enzymatic remodeling of the surroundings is impaired. There are still significant knowledge gaps regarding effects of nuclear deformation during cancer dissemination. It seems that nuclear deformation can alter gene transcription, induce alternative splicing processes, impact nuclear envelope rupture, nuclear pore complex dilatation, damage the DNA, and increase the genomic instability. These mechanically induced alterations can in turn impact the migratory behavior of the cancer cells. The stiffness of the nucleus relies on the condensation of chromatin, and the nuclear lamina, which consists of a network of intermediate filaments underneath the nuclear envelope. All of this is discussed in the review and it is argued that nuclear deformability is universally found in various cancer types. Another focus is placed on the nuclear envelope proteins like emerin, and the SUN-KASH complex and how they contribute to the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which consequently couples the nucleus and the cytoskeleton. It is argued that this connection is crucial for force transmission, which governs nuclear stiffness dynamically, depending on the force applied. In this review, recent findings are described that couple ECM-induced nuclear mechanosensing and mechanotransduction with the migration and invasion of cancer cells. Moreover, it is suspected that changes in the mechanosensory characteristics of the cell nucleus could play a pivotal part in the malignancy of cancer cells and the heterogeneity of tumors. Finally, it is discussed what impact the individual elements of the nucleus offer to mechanically alter cellular migration and invasion in cancer and its malignant progression. Full article

Soft-tissue sarcomas (STSs) comprise a rare, heterogeneous group of mesenchymal malignancies in which histologic grade remains the strongest determinant of outcome, metastatic risk, and therapeutic strategy. Intermediate/high-grade STSs exhibit a pronounced propensity for early distant relapse, yet growing evidence indicates that metastatic behaviour is not uniform. Within this spectrum, an oligometastatic phenotype, characterised by a limited number of metastases, often confined to the lung, has emerged as a clinically and biologically distinct state associated with more indolent metastatic kinetics and improved survival when treated with aggressive local interventions. However, the criteria that define true oligometastatic STSs remain unsettled, and prospective evidence is lacking. Emerging molecular and immunological correlates provide a potential framework for biological triage. Low genomic complexity (low-risk CINSARC), a B-cell/TLS-rich tumour microenvironment, high immune-cytotoxic signatures, and persistently low or undetectable circulating tumour DNA (ctDNA) are each linked to reduced metastatic competence and may underpin oligometastatic trajectories. Conversely, high chromosomal instability, immunosuppressive microenvironments, and elevated ctDNA levels align with covertly polymetastatic biology despite limited radiographic disease. In this context, artificial intelligence and machinelearning approaches applied to computational genomics, immune profiling, imaging, and liquid-biopsy data offer a powerful strategy to integrate these multi-dimensional features and refine predictions of metastatic behaviour in STS. Oligometastatic STS therefore represents a biologically definable subset amenable to multimodal management integrating local ablative therapies, systemic agents, and immune-based strategies. Prospective, biomarker-stratified trials are needed to validate selection frameworks and optimise treatment sequencing in this evolving therapeutic space. Full article

Glial brain tumours, including astrocytoma IDH (Isocitrate Dehydrogenase) mutant and glioblastoma IDH wild-type, are highly malignant brain tumours with poor clinical outcomes. Genomic instability, encompassing microsatellite (MIN) and chromosomal instability (CIN), drives tumour heterogeneity and evolution. In this study, genomic instability was analysed in 85 patients using AP-PCR (Arbitrarily Primed Polymerase Chain Reaction) by comparing tumour and normal tissue (blood) DNA profiles of the same patient. Both types of alterations were present in all analysed samples, contributing almost equally to the total level of genomic instability. The dominant pattern of genomic instability in our cohort was low overall instability, predominantly manifesting as low-degree microsatellite instability. A general decrease in genomic instability was observed with increasing tumour grade. Glioblastoma IDH wild-type was more prevalent in older patients, whereas astrocytoma IDH mutant predominated in younger individuals. Notably, low genomic instability (both MIN and CIN) was associated with poorer survival in patients over 50 years of age. Females, compared to males, exhibited higher MIN in grade 2 tumours and elevated CIN in grade 4 tumours. Our results confirm that genomic instability contributes to tumour progression, MIN being the pivotal factor, and could serve as a prognostic biomarker in malignant gliomas. Full article