Jasmine Holail

Background: Warfarin remains a widely used anticoagulant for long-term thromboprophylaxis, but its narrow therapeutic index and substantial interindividual variability increase the risk of bleeding complications. Functional variants in vascular endothelial growth factor A (VEGFA) may therefore influence vascular integrity during anticoagulant therapy. This study investigated the association between functional VEGFA polymorphisms and warfarin-associated bleeding in a Saudi cohort. Methods: In this retrospective cohort study, 161 Saudi patients receiving stable maintenance warfarin therapy were genotyped for five VEGFA single-nucleotide polymorphisms (SNPs): rs699947, rs833069, rs2010963, rs35410204, and rs866236. Clinical characteristics and bleeding events during warfarin therapy were obtained from electronic medical records. Bleeding status was determined from clinically documented bleeding events during warfarin therapy that required medical evaluation, hospitalization, or blood transfusion. Genotype-phenotype associations were assessed using chi-square analysis and a multivariable logistic regression model. Results: Bleeding occurred in 39% of the patients (63/161). Among the five VEGFA variants studied, rs699947 and rs833069 showed associations with bleeding in bivariate analysis. The rs699947 A/A genotype and rs833069 T/T genotype were less frequent in patients with bleeding than in those without bleeding (6.7% vs 25.5%, p = 0.009; and 16.4% vs 37.5%, p = 0.013, respectively). The rs833069 association did not survive Bonferroni correction for multiple testing and is therefore considered exploratory. Following adjustment for age, sex, body mass index, international normalized ratio, systolic blood pressure, and diastolic blood pressure, rs699947 remained significantly associated with bleeding. For rs833069, the overall genotype association remained statistically significant; however, individual genotype comparisons were not statistically significant. For rs699947, the A/A genotype was associated with lower odds of bleeding compared with the C/C genotype (OR 0.249, 95% CI 0.062– 0.999; p = 0.050). No significant associations were observed for rs2010963, rs35410204, or rs866236. Conclusion: In this exploratory retrospective cohort study, VEGFA rs699947 and rs833069 showed possible associations with bleeding during warfarin therapy in Saudi patients. These findings provide preliminary evidence that VEGFA polymorphisms may contribute to bleeding susceptibility during warfarin therapy. Given the modest sample size, these findings should be interpreted cautiously and require validation in larger prospective studies.

Bone metastasis develops within a specialized marrow ecosystem where hematopoiesis, immune regulation, vascular trafficking, and skeletal remodeling intersect. Neutrophil-lineage cells occupy a unique position in this setting because they are generated, retained, mobilized, aged, and reprogrammed within the same bone marrow niches that disseminated tumor cells exploit for homing and survival. This review examines how neutrophils, tumor-associated neutrophils, immature neutrophils, low-density neutrophils, and PMN-MDSCs shape skeletal colonization. We discuss tumor-to-marrow signaling, CXCR2-dependent recruitment, CXCR4/CXCL12-mediated marrow retention, neutrophil–circulating tumor cell interactions, vascular arrest, dormancy escape, NET-mediated matrix remodeling, immune suppression, and effects on osteoclast–osteoblast coupling. Evidence is strongest in breast and prostate cancer models, where pathways such as CXCL5/CXCR2, CTNND1–CXCR4/CXCL12, PR3–RAGE, and DKK1–CKAP4–STAT6–CHI3L3 link neutrophil-lineage cells to skeletal progression and immunotherapy resistance. However, several mechanisms, including CTC–neutrophil clustering and NET-driven dormancy awakening, remain partly extrapolated from non-skeletal models. We therefore emphasize evidence hierarchy, methodological limitations, and therapeutic opportunities, arguing that selective reprogramming or functional inhibition of pro-metastatic neutrophil states may be more promising than indiscriminate neutrophil depletion in metastatic bone disease. A clearer understanding of these context-dependent neutrophil programs may help refine biomarker development and guide combination therapies for patients with skeletal metastases.

Bone metastasis remains a significant cause of morbidity and diminished quality of life in patients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 and RASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases.

Current research demonstrates the expanding therapeutic potential of heparin derivatives in oncology, extending beyond traditional anticoagulation mechanisms. This systematic analysis examines the structural characteristics, molecular mechanisms, and therapeutic applications of heparin-based compounds in malignancy treatment. The essential antithrombin binding pentasaccharide sequence has enabled development of specialized molecular variants, particularly fractionated heparins and their non-anticoagulant counterparts. These agents exert antineoplastic effects via multiple pathways, particularly through modulation of heparanase enzymatic activity and specific protein–glycosaminoglycan interactions. Evidence from pivotal clinical trials (FRAGMATIC, MAGNOLIA, GASTRANOX) confirms efficacy in managing cancer-associated thrombosis while indicating potential enhancement of chemotherapeutic outcomes. The preparation methods utilize enzymatic cleavage reactions and selective chemical derivatization to generate structurally modified heparins exhibiting unique molecular characteristics and biological activities. Analysis of the glycosaminoglycan analog dociparstat sodium reveals significant activity in myeloid malignancies, mediated by specific interference with CXCL12/CXCR4 signaling cascades. Significant challenges remain in manufacturing scale-up, analytical validation, and long-term safety assessment. Future studies must address dose optimization, combination strategies, and controlled clinical trials to determine the full therapeutic potential of these compounds in clinical oncology.

S6 Kinase 2 (S6K2) is a key regulator of cellular signaling and is crucial for cell growth, proliferation, and survival. This review is divided into two parts: the first focuses on the complex network of upstream effectors, downstream modulators, and post-translational modifications (PTMs) that regulate S6K2 activity. We emphasize the dynamic nature of S6K2 regulation, highlighting its critical role in cellular homeostasis and its potential as a therapeutic target in diseases like cancer. The second part utilizes in silico analyses, employing computational tools to model S6K2’s three-dimensional structure and predict its interaction networks. Molecular dynamics simulations and docking studies reveal potential binding sites and interactions with novel known inhibitors. We also examine the effects of environmental contaminants that potentially disrupt S6K2 function and provide insights into the role of external factors that could impact its regulatory mechanisms. These computational findings provide a deeper understanding of the conformational dynamics of S6K2 and its interactions with its inhibitors. Together, this integrated biochemical and computational approach enhances our understanding of S6K2 regulation and identifies potential new therapeutic strategies targeting S6K2 in the oncology setting.

Objectives: Despite its wide usage, warfarin therapy remains challenging due to its narrow therapeutic index, inter-individual response variability, and risk of bleeding. Previous reports have suggested that polymorphisms in VKORC1 and CYP2C9 genes could influence warfarin therapy. Herein, we investigated whether VKORC1 −1173C>T, CYP2C9*2, and CYP2C9*3 gene polymorphisms are associated with warfarin dose adjustment and related bleeding events. Methods: This cross-sectional study was conducted on Saudi adults receiving warfarin for more than 1 month. Their demographics and relevant clinical data were obtained. Genotyping for VKORC1 −1173C>T, CYP2C9*2, and CYP2C9*2 genotypes was performed. Results: Patients who are homozygous for the mutant T allele VKORC1 T/T required the lowest warfarin daily maintenance dose, compared to VKORC1 C/T and VKORC1 C/C. Similarly, there was a significant reduction in warfarin daily maintenance dose among CYP2C9*1/*3 and CYP2C9*1/*2 groups compared to CYP2C9*1/*1. However, we found no significant correlation between the studied polymorphisms and warfarin-associated bleeding. Conclusions: Similar to other populations, the VKORC1 and CYP2C9 gene polymorphisms are significantly associated with warfarin dosage in Saudi patients. The presence of at least one copy of the mutant alleles for VKORC1 −1173C>T, CYP2C9*2, and CYP2C9*3 is associated with a significant reduction in warfarin maintenance dose.