Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin.

Colorectal cancer (CRC) forms one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancement in cancer therapeutics. About 50% of human CRCs are reported to have defective p53 expression resultant of TP53 gene mutation often contributing to drug resistance. The current study was aimed to investigate the response of wild-type TP53 harboring HCT 116 and mutant TP53 harboring HT 29 colon cancer cells to chemotherapeutic drug oxaliplatin (OX) and to elucidate the underlying molecular mechanisms of sensitivity/resistance in correlation to their p53 status. OX inhibited growth of wild-type p53-harboring colon cancer cells via p53/p21-Bax mediated apoptosis. Our study revealed that dysregulated phosphorylation of p53, autophagy as well as cancer stemness attributes the mutant p53-harboring colon cancer cells impaired sensitivity to OX.

Variants of resistin gene and the risk of idiopathic dilated cardiomyopathy in Pakistan.

BACKGROUND: In cardiovascular disease phenotypes, a genetic factor is an important determinant of both familial and non-familial dilated cardiomyopathies. Resistin is a novel adipocyte derived peptide, associated with inflammation and suggested to be involved in contractile abnormalities of cardiomyocytes. METHODS: In this study, we examined the association of the RETN SNPs in - 420 and + 299 in patients with idiopathic dilated cardiomyopathy (IDCM). Patients with IDCM (n = 250) and healthy controls (n = 250) were enrolled in this study. RETN genotyping was performed by using PCR-RFLP method. RESULTS: RETN - 420C > G and + 299G > A polymorphisms were significantly more prevalent in patient group vs. controls (P < 0.0001 and P = 0.0007, respectively). GG genotype at - 420 and AA genotype at + 299 were higher in the patient group compared with healthy controls (OR = 11.4, P < 0.0001, and OR = 2.3, P = 0.030, respectively). We found that the - 420G allele increased the risk of developing IDCM in patients (P < 0.0001). Moreover, there was a significant difference between G and A alleles at RETN + 299 from IDCM cases and controls (P = 0.0032). The RETN - 420G and + 299A haplotypes were more prevalent in the patient vs. control group (P < 0.0001). CONCLUSION: The results suggest that the RETN - 420C > G and + 299G > A polymorphisms may have a role in the pathogenesis of IDCM.

Heritability of IL-1A Gene Promoter Polymorphism in Patients With Coronary Artery Disease: A Trio-Family Study.

OBJECTIVE: To investigate the potential role of IL-1A gene variations in pathogenesis of coronary artery disease (CAD) with familial history. MATERIALS AND METHODS: We investigated the IL-1A-889C>T polymorphism in 335 patients with CAD and 335 healthy individuals for case-control association analysis. In this study, we also investigated the heritability of the susceptible allele from 130 trio families with CAD-affected offspring. We performed genotyping using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The IL-1A-889 C/T polymorphism was significantly associated with CAD in patients compared with healthy controls. The minor allele T at -889 was more prevalent in cases vs controls. The results of a transmission disequilibrium test revealed a significant association between the IL-1A-889 polymorphism and CAD. The mutant genotype CT+TT was significantly associated with high levels of high-sensitivity C-reactive protein (CRP) and other relative markers from patients with CAD. CONCLUSION: For the first time in the literature, to our knowledge, we demonstrate a significant association of the IL-1A-889 functional polymorphism with CAD.

Gender differences in normal left ventricle of adult FVB/N mice due to variation in interleukins and natriuretic peptides expression levels.

This study examined the sex differences for physical, morphological, histological, mRNA, and protein expression levels changes for interleukins and natriuretic peptides in left ventricle (LV) of two groups of adult FVB/N mice; males (WM) and females (WF). LV morphological, histological, reverse transcription and quantitative real-time PCR (RT-PCR), and immunohistochemical (IHC) alterations were determined in FVB/N mice at 34-35 weeks on gender basis. Confirming the gender dimorphism, FVB/N males (WM) illustrated a significant reduction in ANP and IL1-A levels as well as significantly increased body weight (BW (gm)), tibia length (TL (mm)), heart weight (HW (mg)), heart weight-to-body weight (HW/BW (mg/gm)) ratio, heart weight-to-tibia length (HW/TL (mg/mm)) ratio, left ventricle weight (LV (mg)), left ventricle-to-body weight (LV/BW (mg/gm)) ratio, and left ventricle-to-tibia length (LV/TL (mg/mm)) ratio, left ventricular (LV) cardiomyocyte diameter, high BNP, NPRA, IL-1B, and IL1R1 expression in comparison with FVB/N females (WF). Gender differences in relation to left ventricle (LV) may be due to differences in the interleukins and natriuretic peptides levels as an outcome of sex related hormones.