Search Results (2,437)

Tooth development (odontogenesis) is regulated by interactions between epithelial and mesenchymal tissues through signaling pathways such as Bone Morphogenetic Protein (BMP), Wingless-related integration site (Wnt), Sonic Hedgehog (SHH), and Fibroblast Growth Factor (FGF). Mesenchymal stem cells (MSCs) derived from dental tissues—including dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), and dental follicle progenitor cells (DFPCs)—show promise for regenerative dentistry due to their multilineage differentiation potential. Epigenetic regulation, particularly DNA methylation, is hypothesized to underpin their distinct regenerative capacities. This study reanalyzed publicly available DNA methylation data generated with Illumina Infinium HumanMethylation450 BeadChip arrays (450K arrays) from DPSCs, PDLSCs, and DFPCs. High-confidence CpG sites were selected based on detection p-values, probe variance, and genomic annotation. Principal Component Analysis (PCA) and hierarchical clustering identified distinct methylation profiles. Functional enrichment analyses highlighted biological processes and pathways associated with specific methylation clusters. Noncoding RNA analysis was integrated to construct regulatory networks linking DNA methylation patterns with key developmental genes. Distinct epigenetic signatures were identified for DPSCs, PDLSCs, and DFPCs, characterized by differential methylation across specific genomic contexts. Functional enrichment revealed pathways involved in odontogenesis, osteogenesis, and neurodevelopment. Network analysis identified central regulatory nodes—including genes, such as PAX6, FOXC2, NR2F2, SALL1, BMP7, and JAG1—highlighting their roles in tooth development. Several noncoding RNAs were also identified, sharing promoter methylation patterns with developmental genes and being implicated in regulatory networks associated with stem cell differentiation and tissue-specific function. Altogether, DNA methylation profiling revealed that distinct epigenetic landscapes underlie the developmental identity and differentiation potential of dental-derived mesenchymal stem cells. This integrative analysis highlights the relevance of noncoding RNAs and regulatory networks, suggesting novel biomarkers and potential therapeutic targets in regenerative dentistry and orthodontics. Full article

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical and chemotherapeutic approaches, the presence of metastatic or recurrent disease is still detrimental to the patient’s outcome. Major advances in understanding the molecular mechanisms of OS are needed to substantially improve outcomes for patients being treated for OS. This review integrates new data on the molecular biology, pathophysiology, and immune landscape of OS, as well as introducing salient areas of tumorigenesis underpinning these findings, such as chromothripsis; kataegis; cancer stem cell dynamics; and updated genetic, epigenetic, and glycosylation modifiers. In addition, we review promising biomarkers, diagnostic platforms, and treatments, including immunotherapy, targeted small molecule inhibitors, and nanomedicine. Using genomic techniques, we have defined OS for its significant genomic instability due to TP53 and RB1 mutations, chromosomal rearrangements, and aberrant glycosylation. The TME is also characterized as immunosuppressive and populated by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately inhibiting immune checkpoint inhibitors. Emerging fields such as glycomics and epigenetics, as well as stem cell biology, have defined promising biomarkers and targets. Preclinical studies have identified that glycan-directed CAR therapies could be possible, as well as metabolic inhibitors and 3D tumor models, which presented some preclinical success and could allow for tumoral specificity and enhanced efficacy. OS is a biologically and clinically complex disease; however, advances in exploring the molecular and immunologic landscape of OS present new opportunities in biomarkers and the development of new treatment options with adjunctive care. Successful treatments in the future will require personalized, multi-targeted approaches to account for tumor heterogeneity and immune evasion. This will help us turn the corner in providing improved outcomes for patients with this resilient malignancy. Full article

Prostate cancer (PC) remains a leading cause of malignancy in men worldwide, with current diagnostic methods such as prostate-specific antigen (PSA) testing and tissue biopsies facing limitations in specificity, invasiveness, and ability to capture tumor heterogeneity. Liquid biopsy, especially analysis of circulating tumor DNA (ctDNA), has emerged as a transformative tool for non-invasive detection, real-time monitoring, and treatment selection for PC. This review examines the role of ctDNA in both localized and metastatic PCs, focusing on its utility in early detection, risk stratification, therapy selection, and post-treatment monitoring. In localized PC, ctDNA-based biomarkers, including ctDNA fraction, methylation patterns, fragmentation profiles, and mutations, demonstrate promise in improving diagnostic accuracy and predicting disease recurrence. For metastatic PC, ctDNA analysis provides insights into tumor burden, genomic alterations, and resistance mechanisms, enabling immediate assessment of treatment response and guiding therapeutic decisions. Despite challenges such as the low ctDNA abundance in early-stage disease and the need for standardized protocols, advances in sequencing technologies and multimodal approaches enhance the clinical applicability of ctDNA. Integrating ctDNA with imaging and traditional biomarkers offers a pathway to precision oncology, ultimately improving outcomes. This review underscores the potential of ctDNA to redefine PC management while addressing current limitations and future directions for research and clinical implementation. Full article

Background: RiBi is integral to cell proliferation, and its dysregulation is increasingly recognized as a hallmark of aggressive cancers. We sought to develop and validate a composite “PanRibo-515 score” reflecting RiBi activity across multiple tumor types, assess its prognostic significance, and explore its relationship with immune checkpoint therapy outcomes. Methods: We curated 515 RiBi–associated genes (PanRibo-515) and used a LASSO regression-based strategy on a training dataset (GSE202203) to select the prognostically most relevant subset of 68 genes (OncoRibo-68). Directionality (positive or negative impact on survival) was assigned based on the sign of the LASSO coefficients. We integrated a forward selection approach to identify a refined subset of genes for computing the OncoRibo-68 score. For validation, patients in The Cancer Genome Atlas (TCGA) were stratified into high or low OncoRibo-68 score groups for survival analyses. Additional validation for immunotherapy response was conducted using bioinformatic platforms used for immunotherapy response analysis. Results: A higher OncoRibo-68 score consistently correlated with poorer overall and progression-free survival across multiple cancers. Elevated OncoRibo-68 score was linked to an immunosuppressive tumor microenvironment, but interestingly to increased response to checkpoint inhibitors. Conclusions: Our findings highlight RiBi as an important determinant of tumor aggressiveness and identify the OncoRibo-68 score as a promising biomarker for risk stratification and therapy selection. Future research may evaluate whether targeting RiBi pathways could enhance treatment efficacy, particularly in combination with immunotherapy. Full article

The treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC) has transformed significantly with the advent of triplet therapy involving androgen deprivation therapy (ADT), docetaxel, and androgen receptor signalling inhibitors (ARSIs). While clinical guidelines increasingly support early intensification, real-world practice remains challenged by patient heterogeneity, evolving evidence, and limited consensus on treatment sequencing. This narrative review integrates evidence from landmark trials, clinical guidelines, and expert insights from oncologists managing mHSPC in India. Findings affirm that triplet therapy, particularly with darolutamide, improves survival in high-volume disease and underscores the need for personalized treatment based on disease burden, comorbidities, and genomic profiles. The review also highlights gaps in real-world data, sequencing strategies, and biomarker-driven therapy, reinforcing the need for precision medicine and locally relevant evidence to guide treatment. Ultimately, optimizing mHSPC management requires harmonizing guideline-based approaches with individualized, real-world decision making to improve patient outcomes. Full article

Background/Objectives: Male infertility is a major health concern with a complex etiopathology, yet a substantial proportion of cases remain idiopathic. Mitochondrial dysfunction and non-coding RNA (ncRNA) deregulation have both been implicated in impaired spermatogenesis, but their interplay remains poorly understood. This study aimed to identify infertility-specific variants in ncRNAs that affect mitochondrial dynamics and homeostasis and to explore their roles. Methods: Whole-genome sequencing (WGS) was performed on genomic DNA samples from teratozoospermic, asthenozoospermic, oligozoospermic, and normozoospermic men. Variants uniquely present in infertile individuals and mapped to ncRNAs that affect mitochondrial dynamics were selected and prioritized using bioinformatics tools. An independent transcriptomic validation was conducted using RNA-sequencing data from testicular biopsies of men with non-obstructive azoospermia (NOA) to determine whether the ncRNAs harboring WGS-derived variants were transcriptionally altered. Results: We identified several infertility-specific variants located in lncRNAs known to interact with mitochondrial regulators, including GAS5, HOTAIR, PVT1, MEG3, and CDKN2B-AS1. Transcriptomic analysis confirmed significant deregulation of these lncRNAs in azoospermic testicular samples. Bioinformatic analysis also implicated the disruption of lncRNA–miRNA–mitochondria networks, potentially contributing to mitochondrial membrane potential loss, elevated reactive oxygen species (ROS) production, impaired mitophagy, and germ cell apoptosis. Conclusions: Our integrative genomic and transcriptomic analysis highlights lncRNA–mitochondrial gene interactions as a novel regulatory layer in male infertility, while the identified lncRNAs hold promise as biomarkers and therapeutic targets. However, future functional studies are warranted to elucidate their mechanistic roles and potential for clinical translation in reproductive medicine. Full article

Transcription factors play crucial roles in regulating gene expression, and any dysregulation in their levels could be involved in cancer progression. The role of androgen receptors (AR) and zinc finger (ZNF) proteins in tumors, like prostate cancer (PC), remains poorly understood. Moreover, due to the multifaceted transcriptional behavior of ARs and ZNFs, their biological role in cancer progression may also depend on the interplay with micro-RNAs (miRNAs). Based on The Cancer Genome Atlas (TCGA) database, we analyzed the expression levels of zinc finger transcripts and ARs in PC. Specifically, exploring their involvement in cancer progression and regulation by miRNAs. The analysis relied on several tools to create a multivariate combination of the original biomarkers to improve their diagnostic efficacy. Multidimensional Scaling (MDS) identified two new dimensions that were entered into a regression analysis to determine the best predictors of overall survival (OS) and disease-free interval (DFI). A combination of both dimensions predicted almost 50% (R² = 0.46) of the original variance of OS. Kaplan–Meier survival analysis also confirmed the significance of these two dimensions regarding the clinical output. This study showed preliminary evidence that several transcription factor expression levels belonging to the zinc family and related miRNAs can effectively predict patients’ overall PC survivability. Full article

CNOT2, a central component of the CCR4-NOT transcription complex subunit 2, plays a pivotal role in the regulation of gene expression and metabolism. CNOT2 is involved in various cellular processes, including transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability. CNOT2 specifically contributes to the structural integrity and enzymatic activity of the CCR4-NOT complex with transcription factors and RNA-binding proteins. Recent studies have elucidated its involvement in cellular differentiation, immune response modulation, and the maintenance of genomic stability. Abnormal regulation of CNOT2 has been implicated in a spectrum of pathological conditions, including oncogenesis, neurodegenerative disorders, and metabolic dysfunctions. This review comprehensively examines the interplay between CNOT2 and p53, elucidating their collaborative and antagonistic interactions in various cellular contexts. CNOT2 is primarily involved in transcriptional regulation, mRNA deadenylation, and the modulation of mRNA stability, thereby influencing diverse biological processes such as cell proliferation, apoptosis, and differentiation. Conversely, p53 is renowned for its role in maintaining genomic integrity, inducing cell cycle arrest, apoptosis, and senescence in response to cellular stress and DNA damage. Emerging evidence suggests that CNOT2 can modulate p53 activity through multiple mechanisms, including the regulation of p53 mRNA stability and the modulation of p53 target gene expression. The dysregulation of CNOT2 and p53 interactions has been implicated in the pathogenesis and progression of various cancers, highlighting their potential as therapeutic targets. Additionally, CNOT2 regulates c-Myc, a well-known oncogene, in cancer cells. This review shows the essential roles of CNOT2 in maintaining cancer cellular homeostasis and explores its interactions within the CCR4-NOT complex that influence transcriptional and post-transcriptional regulation. Furthermore, we investigate the potential of CNOT2 as a biomarker and therapeutic target across various disease states, highlighting its significance in disease progression and treatment responsiveness. Full article

Chromosomal microarray analysis (CMA) was performed for 40 patients with B-ALL undergoing treatment according to the ALL-2016 protocol to investigate the copy number alterations (CNAs) and copy neutral loss of heterozygosity (cnLOH) associated with minimal residual disease (MRD)-positive remission. Aberrations involving over 20,000 genes were identified, and a random forest approach was applied to isolate a subset of genes whose CNAs and cnLOH are significantly associated with poor therapeutic response. We have assembled the triple matched healthy population data and used that data as a reference, but not as a matched control. We identified a recurrent cluster of cnLOH in the 19q13.2–19q13.31 region, significantly enriched in MRD-positive patients (70% vs. 47% in the reference group vs. 16% in MRD-negative patients). This region includes the pregnancy-specific glycoprotein (PSG) gene family and the oncogene ERF, suggesting a potential role in leukemic persistence and treatment resistance. Additionally, we observed significant deletions involving 7p22.3 and 16q13, often as part of large-scale losses affecting almost the entire chromosomes 7 and 16, indicative of global chromosomal instability. These findings highlight specific genomic regions potentially involved in therapy resistance and may contribute to improved risk stratification in B-ALL. Our findings emphasize the value of high-resolution CMA in diagnostics and risk stratification and suggest that PSG genes and other candidate genes could serve as biomarkers for predicting treatment outcomes. Full article

Traditional ecotoxicology primarily investigates pollutant toxicity through physiological, biochemical, and single-molecular indicators. However, the limited data obtained through this approach constrain its application in the mechanistic analysis of pollutant toxicity. Omics technologies have emerged as a major research focus in recent years, enabling the comprehensive and accurate analysis of biomolecular-level changes. The integration of multi-omics technologies can holistically reveal the molecular toxicity mechanisms of pollutants, representing a primary emphasis in current toxicological research. This paper introduces the fundamental concepts of genomics, transcriptomics, proteomics, and metabolomics, while reviewing recent advancements in integrated omics approaches within aquatic toxicology. Furthermore, it provides a reference framework for the implementation of multi-omics strategies in ecotoxicological investigations. While multi-omics integration enables the unprecedented reconstruction of pollutant-induced molecular cascades and earlier biomarker discovery (notably through microbiome–metabolome linkages), its full potential requires experimental designs, machine learning-enhanced data integration, and validation against traditional toxicological endpoints within environmentally relevant models. Full article

Legumes are vital sources of protein, dietary fibre and nutrients, making them crucial for global food security and sustainable agriculture. However, their widespread acceptance and consumption are often limited by undesirable sensory characteristics, such as “a beany flavour”, bitterness or variable textures. Addressing these challenges requires a comprehensive understanding of the complex molecular mechanisms governing appearance, aroma, taste, flavour, texture and palatability in legumes, aiming to enhance their sensory appeal. This review highlights the transformative power of multi-omics approaches in dissecting these intricate biological pathways and facilitating the targeted enhancement of legume sensory qualities. By integrating data from genomics, transcriptomics, proteomics and metabolomics, the genetic and biochemical networks that directly dictate sensory perception can be comprehensively unveiled. The insights gained from these integrated multi-omics studies are proving instrumental in developing strategies for sensory enhancement. They enable the identification of key biomarkers for desirable traits, facilitating more efficient marker-assisted selection (MAS) and genomic selection (GS) in breeding programs. Furthermore, a molecular understanding of sensory pathways opens avenues for precise gene editing (e.g., using CRISPR-Cas9) to modify specific genes, reduce off-flavour compounds or optimise texture. Beyond genetic improvements, multi-omics data also inform the optimisation of post-harvest handling and processing methods (e.g., germination and fermentation) to enhance desirable sensory profiles and mitigate undesirable ones. This holistic approach, spanning from the genetic blueprint to the final sensory experience, will accelerate the development of new legume cultivars and products with enhanced palatability, thereby fostering increased consumption and ultimately contributing to healthier diets and more resilient food systems worldwide. Full article

Pancreatic cancer is frequently accompanied by cancer-associated cachexia, a debilitating metabolic syndrome marked by progressive skeletal muscle wasting and systemic metabolic dysfunction. This study presents a systems biology framework to simultaneously identify therapeutic targets for both pancreatic ductal adenocarcinoma (PDAC) and its associated cachexia (PDAC-CX), using cell-specific genome-scale metabolic models (GSMMs). The human metabolic network Recon3D was extended to include protein synthesis, degradation, and recycling pathways for key inflammatory and structural proteins. These enhancements enabled the reconstruction of cell-specific GSMMs for PDAC and PDAC-CX, and their respective healthy counterparts, based on transcriptomic datasets. Medium-independent metabolic biomarkers were identified through Parsimonious Metabolite Flow Variability Analysis and differential expression analysis across five nutritional conditions. A fuzzy multi-objective optimization framework was employed within the anticancer target discovery platform to evaluate cell viability and metabolic deviation as dual criteria for assessing therapeutic efficacy and potential side effects. While single-enzyme targets were found to be context-specific and medium-dependent, eight combinatorial targets demonstrated robust, medium-independent effects in both PDAC and PDAC-CX cells. These include the knockout of SLC29A2, SGMS1, CRLS1, and the RNF20–RNF40 complex, alongside upregulation of CERK and PIKFYVE. The proposed integrative strategy offers novel therapeutic avenues that address both tumor progression and cancer-associated cachexia, with improved specificity and reduced off-target effects, thereby contributing to translational oncology. Full article

Precision neurosurgery is rapidly evolving as a medical specialty by merging genomic medicine, multi-omics technologies, and artificial intelligence (AI) technology, while at the same time, society is shifting away from the traditional, anatomic model of care to consider a more precise, molecular model of care. The general purpose of this review is to contemporaneously reflect on how these advances will impact neurosurgical care by providing us with more precise diagnostic and treatment pathways. We hope to provide a relevant review of the recent advances in genomics and multi-omics in the context of clinical practice and highlight their transformational opportunities in the existing models of care, where improved molecular insights can support improvements in clinical care. More specifically, we will highlight how genomic profiling, CRISPR-Cas9, and multi-omics platforms (genomics, transcriptomics, proteomics, and metabolomics) are increasing our understanding of central nervous system (CNS) disorders. Achievements obtained with transformational technologies such as single-cell RNA sequencing and intraoperative mass spectrometry are exemplary of the molecular diagnostic possibilities in real-time molecular diagnostics to enable a more directed approach in surgical options. We will also explore how identifying specific biomarkers (e.g., IDH mutations and MGMT promoter methylation) became a tipping point in the care of glioblastoma and allowed for the establishment of a new taxonomy of tumors that became applicable for surgeons, where a change in practice enjoined a different surgical resection approach and subsequently stratified the adjuvant therapies undertaken after surgery. Furthermore, we reflect on how the novel genomic characterization of mutations like DEPDC5 and SCN1A transformed the pre-surgery selection of surgical candidates for refractory epilepsy when conventional imaging did not define an epileptogenic zone, thus reducing resective surgery occurring in clinical practice. While we are atop the crest of an exciting wave of advances, we recognize that we also must be diligent about the challenges we must navigate to implement genomic medicine in neurosurgery—including ethical and technical challenges that could arise when genomic mutation-based therapies require the concurrent application of multi-omics data collection to be realized in practice for the benefit of patients, as well as the constraints from the blood–brain barrier. The primary challenges also relate to the possible gene privacy implications around genomic medicine and equitable access to technology-based alternative practice disrupting interventions. We hope the contribution from this review will not just be situational consolidation and integration of knowledge but also a stimulus for new lines of research and clinical practice. We also hope to stimulate mindful discussions about future possibilities for conscientious and sustainable progress in our evolution toward a genomic model of precision neurosurgery. In the spirit of providing a critical perspective, we hope that we are also adding to the larger opportunity to embed molecular precision into neuroscience care, striving to promote better practice and better outcomes for patients in a global sense. Full article

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors, with a five-year overall survival rate below 10%. While the introduction of multi-agent chemotherapy regimens has improved outcomes marginally, most patients with advanced disease continue to have limited therapeutic options. Molecular profiling has uncovered actionable genomic alterations in select subgroups of PDAC, yet the clinical impact of targeted therapies remains modest. This review aims to provide a clinically oriented synthesis of emerging molecular targets in PDAC, their therapeutic relevance, and practical considerations for biomarker testing, including current FDA and EMA indications. Methods: A narrative review was conducted using data from PubMed, Embase, Scopus, and international guidelines (NCCN, ESMO, ASCO). The selection focused on evidence published between 2020 and 2025, highlighting molecularly defined PDAC subsets and the current status of targeted therapies. Results: Actionable genomic alterations in PDAC include KRAS G12C mutations, BRCA1/2 and PALB2-associated homologous recombination deficiency, MSI-H/dMMR status, and rare gene fusions involving NTRK, RET, and NRG1. While only a minority of patients are eligible for targeted treatments, early-phase trials and real-world data have shown promising results in these subgroups. Testing molecular profiling is increasingly standard in advanced PDAC. Conclusions: Despite the rarity of targetable mutations, systematic molecular profiling is critical in advanced PDAC to guide off-label therapy or clinical trial enrollment. A practical framework for identifying and acting on molecular targets is essential to bridge the gap between precision oncology and clinical management. Full article

Genomic instability markers are important hallmarks of aging, as previously evidenced within the European study of biomarkers of human aging, MARK-AGE; however, establishing the specific metabolic determinants of vascular aging is challenging. The objective of the present study was to evaluate the impact of the susceptibility to oxidation of serum LDL particles (LDLox) and the plasma metabolization products of nitric oxide (NOx) on relevant genomic instability markers. The analysis was performed on a MARK-AGE cohort of 1326 subjects (635 men and 691 women, 35–75 years old) randomly recruited from the general population. The Inverse Probability of Treatment Weighting causal inference algorithm was implemented in order to assess the potential causal relationship between the LDLox and NOx octile-based thresholds and three genomic instability markers measured in mononuclear leukocytes: the percentage of telomeres shorter than 3 kb, the initial DNA integrity, and the DNA damage after irradiation with 3.8 Gy. The results showed statistically significant telomere shortening for LDLox, while NOx yielded a significant impact on DNA integrity. Overall, the effect on the genomic instability markers was higher than for the confirmed vascular aging determinants, such as low HDL cholesterol levels, indicating a meaningful impact even for small changes in LDLox and NOx values. Full article