Mathew Oyelami

Sickle Cell Disease (SCD) is a hereditary hemoglobinopathy arising from a single-nucleotide transversion (GAG → GTG) at codon six of the HBB gene on chromosome 11, substituting glutamic acid with valine in the β-globin chain and producing hemoglobin S (HbS). Under hypoxic conditions, HbS polymerizes and distorts erythrocytes into the characteristic sickle shape, initiating a cascade of vaso-occlusion, chronic hemolytic anemia, and progressive multi-organ damage that defines the clinical burden of this disease. Although SCD has ancient origins in sub-Saharan Africa, the Indian subcontinent, the Middle East, and the Mediterranean, regions where it conferred heterozygous resistance to malaria, the ease of human migration has long since made it a global health concern, affecting an estimated 300,000–400,000 newborns annually. Advances in molecular and genomic research have deepened our understanding of SCD pathophysiology, revealing the central contributions of hemoglobin polymerization, oxidative stress, endothelial inflammation, and nitric oxide depletion to disease progression. Current management rests on supportive pharmacological interventions, including hydroxyurea, chronic transfusion therapy, L-glutamine, and multimodal pain management, complemented by lifestyle modifications. Curative approaches have advanced substantially: hematopoietic stem cell transplantation (HSCT) remains the established standard of cure, while the regulatory approvals in late 2023 of the CRISPR/Cas9-based exagamglogene autotemcel (Casgevy) and the lentiviral vector-based lovotibeglogene autotemcel (Lyfgenia) represent the most transformative development in the history of SCD therapeutics. This review traces the disease from its ancient origins and molecular characterization through to its clinical manifestations, inheritance patterns, screening strategies, and the full spectrum of current and emerging therapies. Persistent challenges, prohibitive treatment costs, healthcare inequities, the ethical dimensions of genome editing, and the urgent need for long-term safety data, are examined critically, with a view to informing the research and policy agenda that must accompany these remarkable scientific advances.

Background: Colorectal cancer (CRC) remains a global health issue with high morbidity and mortality. According to molecular profiling, genetic mutations such as KRAS, NRAS, and BRAF play a significant role in tumor biology, treatment effectiveness, and patient prognosis. The exact effect of these alterations on overall survival (OS) is, however, unclear. This systematic review and meta-analysis estimated the combined effect of KRAS, NRAS, and BRAF mutations on CRC survival relative to wild-type tumors. Methods: This study focused on research conducted in the last decade and was registered on PROSPERO (Reg No: CRD420251003000). Search was done using PubMed, EMBASE, MEDLINE, and Google Scholar. Cohort, case control, and randomized controlled trials reporting Overall Survival Hazard Ratios (HRs) for CRC patients with and without KRAS, NRAS, or BRAF mutations were considered. Multiple reviewers independently extracted and assessed data quality using the Newcastle–Ottawa Scale. For heterogeneity, pooled HRs were computed using a random-effects model. Publication bias was determined by funnel plot asymmetry. Results: Nine trials with 3096 participants qualified. Compared to wild-type CRC, KRAS, NRAS, and BRAF mutations were substantially linked with lower overall survival (pooled HR > 1, P < .05). KRAS mutations were most common and consistently associated with poor survival, while BRAF mutations had the largest impact. Mild funnel plot asymmetry suggested publication bias, but risk-of-bias assessment showed moderate to high methodological quality across trials. Conclusions: This meta-analysis shows that KRAS, NRAS, and BRAF mutations are important for adverse prognostic markers in colorectal cancer, linked to reduced overall survival. Routine molecular testing for these mutations is vital to enable personalized treatment, improve patient stratification, and enhance clinical outcomes in colorectal cancer management.