Search Results (1,097)

Camptothecin (CPT) is a natural alkaloid with potent antiproliferative activity, mediated by the inhibition of Topoisomerase I (Topo I), an essential enzyme for deoxyribonucleic acid (DNA) replication. However, its clinical application has been limited by low solubility and the instability of the lactone ring under physiological conditions, both of which decrease its efficacy. Semi-synthetic analogs such as irinotecan (CPT-11) and topotecan (TPT) have been developed and approved for the treatment of various types of cancer; however, challenges related to drug resistance and side effects continue to arise. Therefore, nanomedicine and nanoparticle-based delivery systems, including nanoemulsions, liposomes, and antibody–drug conjugates (ADCs), emerge as promising strategies to improve the stability, bioavailability, and effectiveness of CPT, despite significant challenges such as scalability, pharmacokinetic variability, and regulatory requirements. This review discusses recent advances in CPT, its analogs, and these delivery platforms, highlighting its potential to optimize cancer therapy and reduce toxicity while outlining translational challenges such as scalability, pharmacokinetic variability, and regulatory requirements. Full article

The Hedgehog (HH) signaling pathway is an evolutionarily conserved, multi-component signaling pathway. Its activation is initiated by the Hh protein, which signals upstream regulators PATCH and SMO to activate the transcription factor GLI. Upon activation, GLI translocates to the nucleus to induce the transcription of Hh/GLI target genes. Under normal conditions, the HH pathway plays a crucial role in embryogenesis, development, tissue patterning, and stem cell maintenance. Deregulation of the HH signaling pathway leads to various diseases, including cancer. However, in many human cancers, GLI1 is upregulated through a non-canonical pathway (independent of the HH pathway). This aberrant regulation of GLI1 via a non-canonical pathway is linked to the increased expression of various oncogenes. Aberrant expression of GLI not only affects the genes of several DNA repair pathways but also cancer stem cell pathways, which can contribute to genome instability and ultimately lead to cancer. The ineffectiveness of current HH pathway inhibitors in clinical trials necessitates the discovery of new HH pathway inhibitors. In this review, we will discuss our current understanding of the aberrant signaling of the HH-GLI pathway and focus on GLI1-mediated HH signaling in cancers, cancer stem cells, and carcinogenesis. We will also discuss the effectiveness of current HH inhibitors/drugs and combination therapies based on recent advances in this field. Furthermore, we will also review the role of HH-GLI in cancer stem cell markers, DNA damage response, gene regulation, tumor initiation, metastasis, cancer pathogenesis, and the role of drugs/inhibitors on this pathway. Full article

Mitochondria play a central role in energy metabolism, redox homeostasis, and signal transduction in the thyroid cells. Increasing evidence indicates that mitochondrial DNA (mtDNA) mutations, copy number variations, and haplogroup-specific polymorphisms are closely associated with metabolic reprogramming and malignant progression of thyroid cancer. This review summarizes recent advances in the understanding of the impact of mitochondrial genome instability and metabolic plasticity on thyroid tumorigenesis. We discuss how mtDNA alterations disrupt oxidative phosphorylation (OXPHOS), trigger adaptive metabolic rewiring, and interact with key oncogenic pathways, such as HIF-1α, BRAFV600E mutations, and TSHR signaling in thyroid cancer. We also highlight the emerging diagnostic and therapeutic potential of mtDNA in thyroid cancer and outline current challenges and future research directions. Gaining deeper insights into the mitochondria–metabolism axis may provide novel biomarkers and metabolic intervention strategies for precision medicine in thyroid oncology. Full article

Inherited Bone Marrow Failure Syndromes (IBMFS) encompass a group of rare genetic disorders characterized by intrinsic hematopoietic stem cell defects, leading to impaired hematopoiesis and increased predisposition to malignancies, particularly hematologic cancers. As advances in supportive care and hematopoietic stem cell transplantation have extended patient survival, there is growing recognition of an elevated risk of solid tumors, including colorectal cancer (CRC), within this population. Epidemiologic data, although limited by small cohort sizes, suggest the need for earlier and more intensive CRC surveillance protocols tailored to IBMFS patients, who tend to develop CRC at younger ages compared to the general population. Among IBMFS, the most robust association with CRC has been reported in Diamond–Blackfan anemia syndrome (DBAS) and Fanconi anemia (FA), while emerging evidence suggests a potential link in dyskeratosis congenita (DC) and Shwachman–Diamond syndrome (SDS). The pathophysiological basis involves defective DNA repair mechanisms, telomere dysfunction, ribosomal protein abnormalities, and impaired cellular stress responses, each contributing to genomic instability and malignant transformation. The understanding of the molecular mechanisms underpinning the association between IBMFS and CRC may provide a foundation for future targeted prevention and surveillance strategies and offer broader insights into colorectal carcinogenesis. Full article

Telomere maintenance enables unlimited cell proliferation by counteracting telomere erosion. While the majority of tumors activate telomerase, a significant subset—approximately 10–15%—utilizes alternative lengthening of telomeres (ALT), a recombination-based mechanism. ALT-positive cancers are classically associated with genomic instability, anaphase bridges, chromosomal rearrangements, and resistance to DNA-damaging therapies. This process is closely associated with genetic instability, which contributes to chromosomal rearrangements and tumor evolution. Consequently, ALT has traditionally been considered an adverse prognostic marker in aggressive malignancies such as osteosarcoma, pancreatic neuroendocrine tumors, and high-grade sarcomas. Paradoxically, recent evidence demonstrates that ALT positivity correlates with improved survival in glioblastoma (GBM) and chondrosarcoma, two tumor types that have historically been regarded as immune-cold and therapeutically intractable. This favorable outcome likely reflects a convergence of factors, including replication stress and DNA damage that impose a fitness cost in slow-growing or metabolically constrained tumors. Loss of ATRX/DAXX, while enabling ALT, further amplifies chromatin fragility, and ALT-mediated instability may paradoxically enhance immunogenicity within immune-quiescent microenvironments. Moreover, ALT-positive cells exhibit unique therapeutic vulnerabilities, particularly to ATR and PARP inhibitors. Together, these observations support a context-dependent model in which ALT functions as a double-edged sword, acting as a driver of malignant aggressiveness in rapidly proliferating cancers while serving as a relative liability in slower-growing, immune-cold tumors. Understanding this duality not only refines prognostic stratification but also opens opportunities for precision oncology. By integrating ALT-specific biomarkers into clinical workflows and exploiting ALT-related DNA repair dependencies, clinicians may transform a once uniformly negative prognostic factor into an actionable therapeutic target. Full article

The maintenance of gene integrity is important for all types of cells, but, in the case of early embryonic cells, it is absolutely essential. This is because it influences not only the further development of the embryo but also, in some respects, the offspring. The occurrence and incorrect repair of cellular abnormalities after DNA damage during this period are the primary causes of fetal developmental disorders. If DNA damage occurs in germ cells or the fertilized oocyte and the DNA lesions are not satisfactorily repaired, this can lead to the occurrence of chromosomal aberrations during early embryogenesis and eventually to genetic instability during embryonic development. This developmental ability is related to the level of the DNA damage. Therefore, examining the events related to DNA damage response at the sub-cellular levels is of the utmost importance. In this context, subcellular diagnostics of such events during the selection of embryos with the highest implantation potential applied in the practice of assisted human reproduction are key to successful outcomes. It is important to apply new relevant knowledge from basic research to clinical practice, as well as considering new technical possibilities or trends in this area. The aim of this review is to provide a general overview of the molecular events associated with DNA damage in the early embryo and to outline the possible use of this basic knowledge in assisted reproduction procedures. Full article

Background/Objectives: Short inverted repeats (SIRs) are abundant DNA motifs capable of forming secondary structures, such as hairpins and cruciforms, that can induce genome instability. However, their mutational consequences in cancer, particularly in osteosarcoma (OS), remain largely unexplored. Methods: In this study, we systematically identified over 5.2 million SIRs in the human genome and analyzed their mutational patterns across six common cancer types. Results: We found that increased small insertion and deletion (INDEL) density within SIR spacer regions represents a consistent feature across cancers, whereas elevated single nucleotide variant (SNV) and structural breakpoint density is cancer-type specific. Integrating whole-genome sequencing data from 13 OS patients, we found that both SNVs and INDELs are significantly enriched within SIR spacer regions in OS. Notably, genomic regions with higher SIR density tend to accumulate more somatic mutations, suggesting a link between SIR abundance and local genome instability. SIR-associated mutations frequently occur in oncogenes and tumor suppressor genes, including TP53, NFATC2, MECOM, LRP1B, RB1, CNTNAP2, and PTPRD, as well as in long non-coding RNAs. Mutational signature analysis further suggests that defective DNA mismatch repair and homologous recombination may act in concert with SIR-induced DNA structural instability to drive OS development. Conclusions: Our findings highlight SIRs as mutational hotspots and potential drivers of osteosarcoma pathogenesis. Full article

Cancer is a multifaceted disease characterized by uncontrolled cell division resulting from substantial disruptions of normal biological processes. Central to its development is cellular transformation, which involves a dynamic sequence of events including chromosomal translocations, genetic mutations, abnormal DNA methylation, post-translational protein modifications, and other genetic and epigenetic alterations. These changes compromise physiological regulatory mechanisms and contribute to accelerated tumor growth. A critical factor in this process is the dysregulation of transcription factors (TFs) which regulate gene expression and DNA transcription. Dysregulation of TFs initiates a cascade of biochemical events, such as abnormal DNA replication, that further enhance cell proliferation and increase genomic instability. This microenvironment not only sustains tumor growth but also promotes the accumulation of somatic mutations, thereby fueling tumor evolution and heterogeneity. In this study, we employed an in silico approach to identify TFs regulating 622 key genes whose mutations are implicated in carcinogenesis. Transcriptional regulatory networks were analyzed through bioinformatics methods to elucidate molecular pathways involved in cancer development. A thorough understanding of these processes may help to clarify the function of dysregulated TFs and facilitate the development of novel therapeutic approaches designed to make cancer treatments personalized and efficacious. Full article

The mitochondrial DNA of trypanosomatid parasites consists of thousands of catenated minicircles and dozens of maxicircles that form a complex network structure, the kinetoplast (kDNA). Although kDNA replication and segregation during mitotic division are well studied, its inheritance during genetic exchange events remains unclear. In Trypanosoma brucei, hybrids inherit minicircles biparentally but retain maxicircles from a single parent. Although biparental inheritance of minicircles has been described in natural Trypanosoma cruzi hybrids, this process has not been explored in laboratory-generated hybrids of this parasite. In the present study, we analyzed kDNA inheritance in T. cruzi experimental hybrids using a comprehensive minicircle hypervariable region (mHVR) database and genome sequencing data. Our findings revealed biparental inheritance of minicircles, with hybrid lines retaining mHVRs from both parents for over 800 generations. In contrast, maxicircles were exclusively inherited from one parent. Unexpectedly, we observed an increase in kDNA content in hybrids, affecting both minicircles and maxicircles, and exhibiting instability over time. To explain these findings, we propose a Replicative Mixing (REMIX) model, where the hybrid inherits one kinetoplast from each parent and they are replicated allowing minicircle mixing. Instead maxicircle networks remain physically separated, leading to uniparental fixation after segregation in the first cell division of the hybrid. This model challenges previous assumptions regarding kDNA inheritance and provides a new framework for understanding kinetoplast dynamics in hybrid trypanosomes. Full article

Multiple sclerosis (MS) is a chronic autoimmune neurodegenerative disorder characterized by progressive demyelination and axonal degeneration within the central nervous system, driven by complex genomic and epigenomic dysregulation. Its pathogenesis involves aberrant DNA methylation patterns at CpG islands of numbers of genes like OLIG1 and OLIG2 disrupting protein expression at myelin with compromised oligodendrocyte differentiation. Furthermore, histone modifications, particularly H3K4me3 and H3K27ac, alter the promoter regions of genes responsible for myelination, affecting myelin synthesis. MS exhibits chromosomal instability and copy number variations in immune-regulatory gene loci, contributing to the elevated expression of genes for pro-inflammatory cytokines (TNF-α, IL-6) and reductions in anti-inflammatory molecules (IL-10, TGF-β1). Vitamin D deficiency correlates with compromised immune regulation through hypermethylation and reduced chromatin accessibility of vitamin D receptor (VDR) dysfunction and is reported to be associated with dopaminergic neuronal loss. Vitamin D supplementation demonstrates therapeutic potential through binding with VDR, which facilitates nuclear translocation and subsequent transcriptional activation of target genes via vitamin D response elements (VDREs), resulting in suppression of NF-κB signalling, enhancement of regulatory T-cell (T_reg) responses due to upregulation of specific genes like FOXP3, downregulation of pro-inflammatory pathways, and potential restoration of the chromatin accessibility of oligodendrocyte-specific gene promoters, which normalizes oligodendrocyte activity. Identification of differentially methylated regions (DMRs) and differentially expressed genes (DEGs) that are in proximity to VDR-mediated gene regulation supports vitamin D supplementation as a promising, economically viable, and sustainable therapeutic strategy for MS. This systematic review integrates clinical evidence and eventual bioinformatical meta-analyses that reference transcriptome and methylome profiling and identify prospective molecular targets that represent potential genetic and epigenetic biomarkers for personalized therapeutic intervention. Full article

Precision medicine approaches rely on accurate somatic variant detection, where the DNA input into genomic workflows is a key variable. However, there are no gold standard methods for total DNA quantification. In this study, a pentaplex reference gene panel using digital PCR (dPCR) was developed as a candidate reference method. The multiplex approach was compared between two assay chemistries, applied to healthy donor genomic DNA and plasma cell-free DNA (cfDNA) to measure the ERBB2 (HER2) copy number variation in cancer cell line DNA. The multiplex approach demonstrated robust performance with the two assay chemistries, demonstrating comparable results and a wide dynamic range. Ratios of reference genes were close to the expected 1:1 in healthy samples; however, some small but significant differences (<1.2-fold) were observed in one of the five targets. Expanded relative measurement uncertainty was 12.1–19.8% for healthy gDNA and 9.2–25.2% for cfDNA. The multiplex approach afforded lower measurement uncertainty compared to the use of a single reference for total DNA quantification, which is an advantage for its potential use as a calibration method. It avoided potential biases in the application to CNV quantification of cancer samples, where cancer genome instability may be prominent. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Iron metabolism and chronic inflammation are two interrelated processes that significantly influence the initiation and progression of CRC. Iron is essential for cell proliferation, but its excess promotes oxidative stress and DNA damage, while inflammation driven by cytokine-regulated pathways accelerates tumourigenesis. We therefore conducted this narrative review to collate the available evidence on the link between iron homeostasis and inflammatory signalling in CRC and highlight potential diagnostic and therapeutic applications. Methods: This narrative review of preclinical and clinical studies explores the molecular and cellular pathways that connect iron regulation and inflammation to CRC. Key regulatory molecules, such as the transferrin receptor (TFRC), ferroportin (SLC40A1), ferritin (FTH/FTL), hepcidin, and IL-6, were reviewed. Additionally, we summarised the findings of transcriptomic, epigenomic, and proteomic studies. Relevant therapeutic approaches, including iron chelation, ferroptosis induction, and anti-inflammatory strategies, were also discussed. Results: Evidence suggests that CRC cells exhibit altered iron metabolism, marked by the upregulation of transferrin receptor (TFRC), downregulation of ferroportin, and dysregulated expression of ferritin. Inflammatory mediators such as IL-6 activate hepcidin and STAT3 signalling, which reinforce intracellular iron retention and oxidative stress. Increased immune evasion, epithelial proliferation, and genomic instability appear to be linked to the interaction between inflammation and iron metabolism. Other promising biomarkers include ferritin, hepcidin, and composite gene expression signatures; however, their clinical application remains limited. Although several preclinical studies support the use of targeted iron therapies and combination approaches with anti-inflammatory agents or immunotherapy, there is a lack of comprehensive clinical validation confirming their efficacy and safety in humans. Conclusion: Although preclinical studies suggest that iron metabolism and inflammatory signalling form an interconnected axis closely linked to CRC, translating this pathway into reliable clinical biomarkers and effective therapeutic strategies remains a significant challenge. Future biomarker-guided clinical trials are essential to determine the clinical relevance and to establish precision medicine strategies targeting the iron–inflammation crosstalk in CRC. Full article

Background/Objectives: Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. While most cases are sporadic, approximately 10% show familial clustering with only a minority explained by known hereditary syndromes. The remaining, termed familial non-hereditary gastric cancer (FNHGC), lack a defined high-penetrance germline mutation. This review aims to summarize current knowledge regarding the diagnosis, risk factors, molecular characteristics and management of FNHGC. Methods: A comprehensive narrative review of the literature was conducted focusing on epidemiologic, molecular and clinical studies addressing families with multiple GC cases but no identified germline mutation. Results: The etiology of FNHGC is multifactorial, and H. pylori, with its related chronic gastritis, is probably the key driver. Familial clustering likely occurs when combined with other elements such as genetic polymorphisms, shared exposures to risk factors or even epigenetic phenomena. Molecular profiling reveals distinct patterns in familial tumors such as more frequent microsatellite instability; somatic CDH1 promoter hypermethylation; and recurrent somatic mutations in TP53, RHOA and DNA repair genes. Current management focuses on genetic testing to rule out hereditary syndromes, endoscopic surveillance and mitigation of risk factors, with eradication of H. pylori paramount. Conclusions: FNHGC represents a distinct subgroup of GC characterized by a multifactorial etiology related to exposure to risk factors and genetic susceptibility although significant gaps remain in fully explaining the condition. Ongoing research holds promise to provide tools for better detection and prevention in order to reduce the burden of GC in familial settings. Full article

The rising global prevalence of inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, is paralleled by an increased risk of colitis-associated colorectal cancer. Persistent intestinal inflammation promotes genetic instability and epigenetic reprogramming within epithelial and immune cells, driving the multistep transition from inflammation to neoplasia. This review integrates human and preclinical model evidence with literature mining and bioinformatic analyses of genetic, epigenetic, and ncRNA data to dissect molecular mechanisms driving colitis-associated colorectal cancer from chronic inflammation. We highlight how pro-inflammatory cytokines (e.g., TNF-α, IL-6), oxidative stress, and microbial dysbiosis converge on key transcriptional regulators such as NF-κB and STAT3, inducing DNA methylation and histone modifications (e.g., H3K27me3); altering chromatin dynamics, gene expression, and non-coding RNA networks (e.g., miR-21, MALAT1, CRNDE); ultimately reshaping pathways involved in proliferation, apoptosis, and immune evasion. This review updates new potential associations of entities with these diseases, in their networks of interaction, summarizing major aspects of genetic and chromatin-level regulatory mechanisms in inflammatory bowel disease and colorectal cancer, and emphasizing how these interactions drive the inflammatory-to-neoplastic transition. By underscoring the reversibility of epigenetic changes, we explore their translational potential in early detection, surveillance, and precision epigenetic therapy. Understanding the interplay between genetic mutations and chromatin remodeling provides a roadmap for improving diagnostics and personalized treatments in inflammatory bowel disease-associated colorectal carcinogenesis. Full article

Background: Oncogenic fusions of MAML2 with CRTC1, CRTC3, YAP1, and NR1D1 retain the MAML2 transactivating domain (TAD) and are believed to drive aberrant gene transcription. While the oncogenic roles of these known fusions have been established, we aimed to identify novel MAML2 fusions across a range of human malignancies. Methods: DNA and RNA sequencing were performed on tumor samples submitted to Caris Life Sciences. MAML2 fusions were identified from RNA transcripts and filtered to include only known pathogenic fusions or recurrent, in-frame fusions containing a C-terminal MAML2 TAD. Fusion burden was defined as the number of unique fusion isoforms per sample. Results: Among 180,124 tumor samples, 143 specimens harbored MAML2 fusions with a MAML2 TAD: >50% of specimens harbored known fusions, but novel fusions with MTMR2 (31/143), SESN3 (11/143), CCDC82 (6/143), FAM76B (4/143), and ATXN3 (3/143) were also identified. Compared to the known fusions, the novel fusions generally had lower expressions (median: 8 vs. 13 junction reads/sample, p = 0.0064), higher fusion burdens (median: 6 vs. 2 unique fusion isoforms/sample, p < 0.0001), more frequent TP53 co-mutations (80% vs. 11.5%, p < 0.0001), and no clear association with the tissue of origin. Excluding ATXN3::MAML2, the novel fusion partners were located near MAML2 in the genome, likely arose from duplications or deletions, and occurred in samples harboring concurrent mutations. In contrast, ATXN3::MAML2 arose via interchromosomal translocation, occurred in samples with a low fusion burden, and was not associated with TP53 mutations. Conclusions: We identified novel MAML2 fusion partners, most of which likely represent passenger alterations, possibly arising from genomic instability or impaired p53 function. However, ATXN3::MAML2 fusions, previously reported in a pre-cancerous pancreatic disease case, may represent a pathogenic alteration warranting further investigation. Full article