Triple Negative Breast Cancer (TNBC), an aggressive type of Breast Cancer (BC) characterized by the loss of expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal growth factor Receptor 2 (HER2) protein. TNBC is quite heterogenous in nature with limited available therapeutic options due to the lack of defined molecular targets. Epigenetic abnormalities have been implicated in the onset, progression, immune escape, and resistance to treatment in TNBC. Important epigenetic modulations, include DNA methylation, histone lactylation, histone modifications, and chromatin remodeling. Global hypomethylation contributes to genomic instability, while promoter hypermethylation inhibits tumor suppressor genes, by dysregulating their expression, thereby promoting uncontrolled proliferation, EMT, metastasis, and immune evasion in TNBC. Targeting epigenetic modulators, have the potential to develop novel therapeutic interventions have been developed and being explored. These epidrugs have proven to be effective in preclinical and clinical trials when used in combination with chemotherapy, immunotherapy, or targeted therapy, reducing drug resistance and aberrant proliferation. Despite of the advancements, challenges like target specificity, precise biomarkers and treatment related toxicity are the major hurdles. The review comprehensively summarized the important epigenetic alterations as well as novel treatment strategies with potential clinical applications in TNBC.
Neurodevelopmental disorder with spasticity, epilepsy and brain atrophy (NEDESBA) is a rare autosomal recessive condition, first described in 2020. It has been associated with biallelic pathogenic variants in the Trafficking Protein Particle Complex Subunit 4 (TRAPPC4) gene. This disorder belongs to the expanding group of TRAPPopathies, caused by mutations in genes encoding components of the transport protein particle (TRAPP) complex, which are essential for intracellular trafficking, autophagy and dendritic spine morphogenesis. Variants in these genes typically result in overlapping clinical features, including microcephaly, early‐onset epilepsy, intellectual disability, neurodevelopmental regression, spasticity and abnormal brain MRI findings. Here, we report a 13‐month‐old affected male born to consanguineous parents, presenting with epileptic spasms and progressive neurodevelopmental delay. Importantly, proband also exhibits hair loss and skin rashes in early infancy. Initial metabolic screening suggested biotinidase deficiency, based on low biotin levels (0.6 nmol/min/mL; normal > 5) and overlapping clinical symptoms. However, confirmatory biochemical and enzymatic studies ruled out classic biotinidase deficiency. Whole exome sequencing revealed a homozygous splice‐site variant (c.454+3A>G) in the TRAPPC4 gene, confirming the diagnosis of NEDESBA. This variant has been reported in multiple previous reports, mainly born out of consanguineous marriages. The phenotypic overlap between metabolic and genetic neurodevelopmental disorders in these cases emphasizes the critical role of early molecular testing in achieving a precise diagnosis.
Anil Kumar, Ajay Kumar, Arvinder Wander et al.· International Journal of Dev...· 0 citations
