ABSTRACT
BACKGROUND: Acute myeloid leukemia (AML) is a bone marrow malignancy having multiple molecular pathways driving its progress. In recent years, the main causes of AML considered all over the world are genetic variations in cancerous cells. The RUNX1 and FLT3 genes are necessary for the normal hematopoiesis and differentiation process of hematopoietic stem cells into mature blood cells, therefore they are the most common targets for point mutations resulting in AML. METHODS: We screened 32 CN-AML patients for FLT3-ITD (by Allele-specific PCR) and RUNX1 mutations (by Sanger sequencing). The FLT3 mRNA expression was assessed in all AML patients and its subgroups. RESULTS: Eight patients (25%) carried RUNX1 mutation (K83E) while three patients (9.37%) were found to have internal tandem duplications in FLT3 gene. The RUNX1 mutation data were correlated with clinical parameters and FLT3 gene expression profile. The RUNX1 mutations were observed to be significantly prevalent in older males. Moreover, RUNX1 and FLT3-mutated patients had lower complete remission rate, event-free survival rate, and lower overall survival rate than patients with wild-type RUNX1 and FLT3 gene. The RUNX1 and FLT3 mutant patients with up-regulated FLT3 gene expression showed even worse prognosis. Bradford Assay showed that protein concentration was down-regulated in RUNX1 and FLT3 mutants in comparison to RUNX1 and FLT3 wild-type groups. CONCLUSION: This study constitutes the first report from Pakistan reporting significant molecular mutation analysis of RUNX1 and FLT3 genes including FLT3 expression evaluation with follow-up. This provides an insight that aforementioned mutations are markers of poor prognosis but the study with a large AML cohort will be useful to further investigate their role in disease biology of AML.
ABSTRACT
BPA, a ubiquitously used plasticizer, has become one of the contaminants of emerging concern and causes many serious health implications in humans due to multiple exposure pathways. The current study was aimed at investigating the deformities of structures that arise by exposure of the small intestine to BPA through trace elements estimation of tissues as well as the study of serum profile. Two major groups of Wistar rats were established: one control group and the other experimental group, which was further divided into four groups based on dose (10 mg/kg/bodyweight and 25 mg/kg/bodyweight, respectively) and duration of exposure (6 and 12 weeks, respectively). Histological study of the small intestine showed the distorted structures in the experimental groups. The special staining performed illustrated the accumulation of calcium deposits in the small intestinal tissue in treated groups. Trace metals estimation showed a significant increase in the metallic content of sodium and iron and a decrease in the calcium content in the experimental groups (p=0.05). Serum profiling illustrated an increase in total iron-binding capacity and glucose levels and a decrease in the serum total iron level (p=0.05). An increased expression of a proinflammatory cytokine (IFN-α) was observed in the liver. From all these findings, it was inferred that BPA caused many structural alterations in the small intestinal tissue, which further affected its functioning. The calcium deposits seen through special staining affected the motility of the small intestine and caused its dysfunction. It was also induced from serum profiling that BPA affected the homeostasis of iron and glucose and caused its imbalance. Also, as BPA got absorbed from the small intestine and reached the liver via the blood stream, it caused hepatoxicity in the liver and led to increased inflammatory response by IFN-α against the toxicant.
