Search Results (7,250)

Retrotransposons exhibit increased activity in cancer cells. One possible approach to anticancer therapy is to use this activity to influence the energy balance in cells. Abnormal distribution of retrotransposons in the genome requires additional energy consumption, which can lead to a significant decrease in the total amount of free ATP molecules in the cell. A decrease in ATP levels below a certain threshold can in turn trigger a cell death program. To investigate the possibility of such a scenario, we developed a mathematical model of the cellular energy balance that describes the dynamics of energy consumption by the main cellular processes, including costs of retrotransposon activity. The model considers changes in the concentrations of ATP, active retrotransposons (LINE-1 and SINE) in the human genome, as well as mRNAs and proteins that are expression products of retrotransposon and constitutive genes. We estimated the parameter values in the model based on literature data and numerical optimization. We found a single stable stationary solution, characterized by low retrotransposon activity, and used it as the reference steady state for further analysis. Parametric sensitivity analysis revealed the parameters whose changes had the greatest impact on cellular ATP levels. The LINE-1 deactivation rate constant and the maximum LINE-1 transcription rate were the most sensitive among the transposon-related parameters. Perturbation of these parameters led to a decrease in the number of free ATP to 30% of the reference value and below. Transcription of retrotransposons under perturbed parameters became comparable to the translation of constitutive genes in terms of energy costs. The presented results indicate that cancer cell death can be initiated by increasing the load on the energy balance due to the activation of transposons. Full article

Background: Gefitinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) targeting EGFR-mutated non-small cell lung cancer (NSCLC) and is a current first-line treatment for NSCLC. However, acquired resistance leads to the failure of treatment and remains a challenge. Therefore, identifying novel therapeutic approaches to combat EGFR-TKI resistance is crucial. Methods: The Cancer Genome Atlas (TCGA) database analysis and gefitinib-resistant cell lines were used to analyze VDR expression in NSCLC. Cell proliferation and apoptosis were assessed via MTT assay, colony formation assay, and flow cytometry. Immunofluorescence, qPCR, and Western blotting were used to measure mRNA and protein expression levels of VDR and other related molecules. Xenograft tumors in BALB/c nude mice were employed to investigate the effects of VDR and 1,25-dihydroxyvitamin D3 (1,25(OH)₂D₃) on gefitinib-resistant tumors in vivo. Results: We found that VDR was significantly upregulated in EGFR-TKI-resistant NSCLC cells. Patients with high VDR expression exhibited poor prognosis. VDR knockdown significantly inhibited cell proliferation, tumor growth, and reduced gefitinib resistance, whereas VDR overexpression enhanced resistance. VDR knockdown downregulated EGFR and FASN expression. Silencing either EGFR or FASN confirmed the existence of a positive feedback regulatory loop involving VDR, EGFR, and FASN. Treatment with 1,25(OH)₂D₃ increased VDR levels but decreased EGFR and FASN expression. VDR knockdown significantly enhanced the inhibitory effect of 1,25(OH)₂D₃ on gefitinib resistance. The combination of VDR knockdown and 1,25(OH)₂D₃ treatment was more effective than either treatment alone in suppressing EGFR and FASN expression. Conclusions: VDR promotes NSCLC resistance to EGFR-TKIs by regulating EGFR and FASN expression through a positive feedback loop. Knocking down VDR effectively enhances the ability of 1,25(OH)₂D₃ to overcome gefitinib resistance, mediated by the synergistic downregulation of EGFR and FASN expression. Targeting VDR represents a potential strategy to enhance the efficacy of 1,25(OH)₂D₃ in overcoming EGFR-TKI resistance. Full article

Background/Objectives: Human endogenous retroviruses (ERVs) are genomic sequences integrated into the human genome from ancestral exogenous retroviruses and are epigenetically silenced under normal conditions. Growing evidence has shown that they can be reactivated in human diseases such as cancers and autoimmune diseases. However, their clinical implications in colon cancer are yet to be explored. Methods: RNA-seq data were downloaded from RNA Atlas and TCGA for cell lines and tissue samples, respectively. After alignment, ERV expression was quantified against comprehensively compiled ERVs (3220). ERV expression profiles were compared between sequencing protocols, cancer and normal cells, and matched tumor and normal tissue pairs. Unsupervised clustering was used to identify ERV-defined tumor subtypes and their associations with clinical and other molecular features. ERV association with disease-specific survival (DSS) was performed using the Cox regression model. Results: PolyA and total RNA protocols were comparable in ERV expression detection. Cancer cells had significantly increased ERV expression and reactivation. Upregulated ERVs were significantly enriched in viral protein interactions with cytokine and cytokine receptors. ERV expression-defined tumor classes were significantly associated with tumor mutation burden and immuno-phenotypes such as antigen processing and presenting machinery and tumor immune infiltration score. Survival analysis identified 152 ERVs to be independently associated with DSS. Conclusions: ERV abnormal expression is common in colon cancer. The ERV-defined subtypes are associated with tumor immunity, and some ERVs are independently associated with patient outcomes. Full article

Background and Aims: Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy marked by rapid disease progression, limited therapeutic avenues, and high recurrence risk. Ferroptosis an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a promising therapeutic vulnerability in oncology. This study delineates the ferroptosis-associated molecular architecture of TNBC to identify key regulatory genes with prognostic and translational significance. Methods: Transcriptomic profiles from the GSE103091 dataset (130 TNBC and 30 normal breast tissue samples) were analyzed to identify ferroptosis-related differentially expressed genes (DEGs) using GEO2R. Protein–protein interaction (PPI) networks were constructed via STRING and GeneMANIA, with functional enrichment performed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses. Prognostic relevance was evaluated using GEPIA, BC-GenExMiner, and Kaplan–Meier Plotter survival analyses. Results: Six ferroptosis drivers (MAPK1, TLR4, IFNG, ATM, ULK2, and ATF3) and five suppressors (NFS1, GCLC, TP63, CD44, and SRC) were identified alongside HMOX1, a bifunctional regulator with context-dependent pro- and anti-ferroptotic activity. Enrichment analyses revealed significant associations with oxidative stress regulation, autophagy, immune modulation, and tumor progression pathways. Elevated IFNG expression was consistently linked to improve overall, disease-free, and distant metastasis-free survival, underscoring its dual function in antitumor immunity and ferroptosis sensitization. Conclusions: Ferroptosis represents a critical axis in TNBC pathophysiology, with IFNG emerging as both a prognostic biomarker and a viable therapeutic target. These insights provide a mechanistic foundation for integrating ferroptosis-inducing agents with immunotherapeutic modalities to enhance clinical outcomes and overcome therapeutic resistance in TNBC. Full article

Over the past decade, patient-derived organoids (PDOs) have emerged as powerful in vitro models that closely recapitulate the histological, genetic, and functional features of their parental primary tissues, representing a ground-breaking tool for cancer research and precision medicine. This advancement has led to the development of living PDO biobanks, collections of organoids derived from a wide range of tumor types and patient populations, which serve as essential platforms for drug screening, biomarker discovery, and functional genomics. The classification and global distribution of these biobanks reflect a growing international effort to standardize protocols and broaden accessibility, supporting both basic and translational research. While their relevance to personalized medicine is increasingly recognized, the establishment and maintenance of PDO biobanks remain technically demanding, particularly in terms of optimizing long-term culture conditions, preserving sample viability, and mimicking the tumor microenvironment. In this context, this review provides an overview of the classification and worldwide distribution of tumor and paired healthy tissue-specific PDO biobanks, explores their translational applications, highlights recent advances in culture systems and media formulations, and discusses current challenges and future perspectives for their integration into clinical practice. Full article

Background/Objectives: Protocadherin 7 (Pcdh7) belongs to the protocadherin family, the largest subgroup of cell adhesion molecules. Members of this family are highly expressed in the brain, where they serve fundamental roles in many neurodevelopmental processes, including axon guidance, dendrite self-avoidance, and synaptic formation. PCDH7 has been strongly associated with epilepsy in multiple genome-wide association studies (GWAS), as well as with schizophrenia, PTSD, and childhood aggression. Despite these associations, the specific contributions of PCDH7 to epileptogenesis and brain development remain largely unexplored. Most of the existing literature on PCDH7 focuses on its function during cancer progression, with only one study suggesting that PCDH7 regulates dendritic spine morphology and synaptic function via interaction with GluN1. Methods: Here, we generate, validate, and characterize a murine null Pcdh7 allele in which a large deletion was introduced by CRISPR. Results: Analysis of embryonic, postnatal, and adult brain datasets confirmed PCDH7 widespread expression. Pcdh7^+/− and Pcdh7^−/− mice present no gross morphological defects and normal cortical layer formation. However, a seizure susceptibility assay revealed increased latencies in Pcdh7^+/− mice, but not in Pcdh7^+/+ and Pcdh7^−/− mice, potentially explaining the association of PCDH7 with epilepsy. Conclusions: This initial characterization of Pcdh7 null mice suggests that, despite its widespread expression in the CNS and involvement in human epilepsy, PCDH7 is not essential for murine brain development and thus is not a suitable animal model for understanding PCDH7 disruption in humans. However, further detailed analysis of this mouse model may reveal circuit or synaptic abnormalities in Pcdh7 null brains. Full article

Messenger RNA (mRNA) vaccine technology has revolutionized the field of immunization, offering a non-infectious, non-genome-integrating platform that addresses many limitations of traditional vaccine modalities. Recent advancements in chemical modifications, delivery systems, and manufacturing processes have enhanced the stability, efficacy, and safety of RNA-based therapeutics, expanding their application beyond infectious diseases to include genetic disorders, cancer, and rare diseases. Central to the success of RNA vaccines is their ability to orchestrate a finely tuned immune response, leveraging both innate and adaptive immunity to achieve robust and durable protection. This review synthesizes current knowledge on the immunological mechanisms underpinning RNA vaccine efficacy, with a focus on the roles of pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) in sensing exogenous RNA, the impact of RNA modifications and manufacturing impurities on innate immune activation, and the subsequent cytokine and chemokine milieu that shapes adaptive responses. We also discuss the dual role of lipid nanoparticle (LNP) delivery systems as both carriers and adjuvants, highlighting their contribution to the vaccine’s immunogenicity and reactogenicity profile. Understanding these complex immune interactions is critical for optimizing RNA vaccine design, minimizing adverse effects, and expanding their therapeutic potential. This review aims to provide a comprehensive overview of the immune symphony orchestrated by RNA vaccines and to identify key areas for future research to further refine and expand the utility of this transformative technology. Full article

Leishmaniasis is caused by protozoan parasites from the genus Leishmania and remains one of the major threats to global health, impacting millions of people worldwide as well as animals including dogs. Several treatments have been used for managing leishmaniasis; nevertheless, drug resistance has emerged as an important obstacle to disease control. Therefore, there is an urgent need to discover new therapeutic targets. The aim of this work was to study the role played by the breast cancer associated 1 C-terminal (BRCT) domain from LmjPES protein (Pescadillo ribosomal biogenesis factor) in Leishmania major‘s pathogenesis through the construction of novel genomic tools. For this purpose, Leishmania integrative plasmids that were able to express the BRCT domain from LmjPES and a hypothetical defective LmjPES lacking this BRCT domain were constructed. It was observed that the overexpression of the aforementioned BRCT domain in L. major dysregulated the mRNA expression of 152 genes (95 up-regulated and 57 down-regulated) in respect to control parasites. Furthermore, clustering studies of these altered genes revealed an enrichment in genes related to metabolic processes, transporter activity, response to stimuli, and protein folding, which are categories described to be associated with the metacyclogenesis process and parasite survival. Interestingly, these genes reached normal levels of expression in parasites transfected with a defective LmjPES (a mutated gene lacking the coding sequence of the BRCT domain). In addition, it was found that the footpad of mice inoculated with LmjPES BRCT-overexpressing parasites had significantly greater inflammation compared to the size of the footpad of animals infected with the control parasites. Based on all these results, it was suggested that the BRCT domain from LmjPES might play a role in L. major‘s infection process and pathogenesis. Full article

Genome-wide paternal uniparental isodisomy mosaicism (GWpUPIDM) is an extremely rare condition characterized by varying proportions of an androgenetic cell line across different tissues. It is primarily associated with severe congenital hyperinsulinism (CHI), Beckwith–Wiedemann syndrome (BWS) stigmata, a high risk (69–79%) of developing neoplasia and, in some cases, additional manifestations of multilocus paternal imprinting disorders (MPIDs). We herein report the first Mexican/Latin American female patient GWpUPIDM presenting with non-syndromic CHI requiring subtotal pancreatectomy and persistent but unexplained asymptomatic diffuse hepatopathy. When she was 8.5 years old, whole-exome sequencing (WES) in blood revealed an unexpectedly high (~92%) proportion of regions of homozygosity. DNA profiling confirmed a single haploid set of paternal chromosomes in both biparental and androgenetic cell lines, with varying proportions of the androgenetic lineage in leukocytes (84%), resected pancreas (74%), buccal cells (47%), and hair follicles (0.7%). Additional WES trio analysis using gDNA from the patient’s buccal cells and blood samples from both parents revealed an allelic frequency of ~75% for the paternally inherited variant NM_000158.4(GBE1):c.555+1G>T [ClinVar:632422; dbSNP:rs759707498]. At age 8.5, the patient exhibited no clinical features of BWS, MPIDs, or neoplasia. However, she presented persistent hepatic abnormalities that warrant further investigation to rule out an unmasked glycogen storage disease type IV (OMIM#232500). Our findings emphasize the critical need for early diagnosis of GWpUPIDM using SNP-based microarray or WES with further confirmation through DNA profiling in patients presenting with CHI, placental mesenchymal dysplasia, BWS stigmata, or other MPID-related conditions, including neoplasia, to facilitate timely cancer surveillance and management. Full article

Background: The amount of data produced from biological experiments has increased geometrically, posing a challenge for the development of new methodologies that could enable their interpretation. We propose a novel approach for the analysis of transcriptomic data derived from acute lymphoblastic leukemia (ALL) and rhabdomyosarcoma (RMS) cell lines, using bioinformatics, systems biology and geometrical approaches. Methods: The expression profile of each cell line was investigated using microarrays, and identified genes were used to create a systems pathway model, which was then simulated using differential equations. The transcriptomic profile used involved genes with similar expression levels. The simulated results were further analyzed using geometrical approaches to identify common expressional dynamics. Results: We simulated and analyzed the system network using time series, regression analysis and helical functions, detecting predictable structures after iterating the modelled biological network, focusing on TIE1, STAT1, MAPK14 and ADAM17. Our results show that such common attributes in gene expression patterns can lead to more effective treatment options and help in the discovery of universal tumor biomarkers. Discussion: Our approach was able to identify complex structures in gene expression patterns, indicating that such approaches could prove useful towards the understanding of the complex tumor dynamics. Full article

Background: Circulating tumor DNA (ctDNA), shed into bodily fluids by cancer cells through apoptosis, necrosis, or active secretion, is currently used in the field of genomic investigation in clinical settings, primarily for advanced stages of non-small-cell lung cancer (NSCLC). However, its potential role in guiding the multi-omic approach to early-stage NSCLC is emerging as a promising area of investigation. Efforts are being made to integrate the genomics not only in surgery, but also in the definition of long-term prognosis after surgical or radiotherapy and for the prediction of recurrence. Methods: An extensive literature search was conducted on PubMed, covering publications from 2000 to 2024. Using the advanced search tool, titles and abstracts were filtered based on the following keywords: ctDNA, early stage, NSCLC. From this search, 20 studies that fulfilled all inclusion criteria were selected for analysis in this review. Results: This review highlights the growing body of evidence supporting the potential clinical use of ctDNA as a genomic biomarker in managing early-stage NSCLC. Baseline ctDNA levels offer valuable information about tumor molecular biology and histological characteristics. Beyond its prognostic value before treatment, liquid biopsy has proven useful for tracking minimal residual disease and forecasting recurrence following curative interventions such as surgery or radiotherapy. Future adjuvant treatment decisions may increasingly rely on predictive models that incorporate liquid biopsy findings alongside other clinical factors. Conclusions: The potential use of this analyte introduces new opportunities for the integration of genomic data in treatment, as well as relapse monitoring with more accurate and innovative than traditional methods, particularly in patients with early-stage NSCLC Full article

Tumor-initiating cells (TICs) constitute a subpopulation of cancer cells with stem-like properties contributing to tumorigenesis, progression, recurrence, and therapeutic resistance. Despite their biological importance, their molecular signatures that distinguish them from non-TICs remain incompletely characterized. This study aimed to comprehensively analyze transcriptomic differences between TICs and non-TICs, identify TIC-specific gene expression patterns, and construct a machine learning-based classifier that could accurately predict TIC status. RNA sequencing data were obtained from four human cell lines representing TIC (TS10 and TS32) and non-TIC (32A and Epi). Transcriptomic profiles were analyzed via principal component, hierarchical clustering, and differential expression analysis. Gene-Ontology and Kyoto-Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted for functional interpretation. A logistic-regression model was trained on differentially expressed genes to predict TIC status. Model performance was validated using synthetic data and external projection. TICs exhibited distinct transcriptomic signatures, including enrichment of non-coding RNAs (e.g., MIR4737 and SNORD19) and selective upregulation of metabolic transporters (e.g., SLC25A1, SLC16A1, and FASN). Functional pathway analysis revealed TIC-specific activation of oxidative phosphorylation, PI3K-Akt signaling, and ribosome-related processes. The logistic-regression model achieved perfect classification (area under the curve of 1.00), and its key features indicated metabolic and translational reprogramming unique to TICs. Transcriptomic state-space embedding analysis suggested reversible transitions between TIC and non-TIC states driven by transcriptional and epigenetic regulators. This study reveals a unique transcriptomic landscape defining TICs and establishes a highly accurate machine learning-based TIC classifier. These findings enhance our understanding of TIC biology and show promising strategies for TIC-targeted diagnostics and therapeutic interventions. Full article

This narrative review examines the genomic-adjusted radiation dose (GARD), a biologically informed framework developed to personalize radiotherapy by integrating tumor-specific genomic data. GARD combines the radiosensitivity index (RSI), based on gene expression, with the linear quadratic model to estimate patient-specific radiation effect. Since its introduction in 2017, GARD has demonstrated prognostic value across multiple cancer types in retrospective studies. This review summarizes key studies evaluating GARD across various tumor types and clinical contexts. Emerging trials, including a Phase II trial in HPV-positive oropharyngeal cancer, aim to validate GARD-guided dosing in precision radiotherapy. Future efforts may focus on refining RSI, addressing tumor heterogeneity, and validating GARD-guided dosing in prospective settings. Full article

Melanoma is a highly aggressive skin cancer with survival rates varying significantly based on stage and genomic characteristics. While localized melanoma has favorable outcomes, metastatic melanoma is associated with poor prognosis and limited treatment options. Radiotherapy (RT), one of the most commonly used cancer treatments, is less effective in melanoma due to its intrinsic radioresistance. This review discusses the current knowledge about the biological mechanisms contributing to melanoma radioresistance, including the role of cancer stem cells (CSCs), DNA repair mechanisms, hypoxia, altered metabolism, and melanin production. It also examines preclinical and clinical studies on novel therapeutic approaches, such as targeting CSC pathways, inhibiting DNA repair, modulating hypoxia-induced metabolic shifts, and combining RT with immunotherapies or targeted therapies. Promising strategies, such as RT-induced immune responses and advanced RT techniques, show the potential to overcome resistance. However, melanoma’s heterogeneity and the limited clinical validation of these approaches remain significant challenges. Integrated therapeutic strategies targeting the multifaceted mechanisms of melanoma radioresistance are essential to improve treatment outcomes. Further clinical validation and personalized approaches are needed to address the heterogeneity of melanoma and enhance the efficacy of novel interventions. Full article

Pancreatic neuroendocrine tumors (pNETs) are rare malignancies, accounting for 1–2% of pancreatic cancers, with an incidence of ≤1 case per 100,000 individuals annually. Originating from pancreatic endocrine cells, pNETs display significant clinical and biological heterogeneity. Traditional classification based on proliferative grading does not fully capture the complex mechanisms involved, such as oxidative stress, mitochondrial dysfunction, and tumor-associated macrophage infiltration. Recent advances in molecular profiling have revealed key oncogenic drivers, including MEN1 (menin 1), DAXX (death domain–associated protein), ATRX (alpha thalassemia/mental retardation syndrome X-linked), CDKN1B (cyclin-dependent kinase inhibitor 1B) mutations, chromatin remodeling defects, and dysregulation of the mTOR pathway. Somatostatin receptors, particularly SSTR2, play a central role in tumor biology and serve as important prognostic markers, enabling the use of advanced diagnostic imaging (e.g., Gallium-68 DOTATATE PET/CT) and targeted therapies like somatostatin analogs and peptide receptor radionuclide therapy (PRRT). Established biomarkers such as Chromogranin A and the Ki-67 proliferation index remain vital for diagnosis and prognosis, while emerging markers, like circulating tumor DNA and microRNAs, show promise for enhancing disease monitoring and diagnostic accuracy. This review summarizes the molecular landscape of pNETs and highlights genomic, transcriptomic, proteomic, and epigenomic factors that support the identification of novel diagnostic, prognostic, and therapeutic biomarkers, ultimately advancing personalized treatment strategies. Full article