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People with type 2 Diabetes have an elevated risk for developing cardiovascular disease (CVD) for which dyslipidemia is the major contributor. Diabetic patients have characteristic pattern of dyslipidemia with decreased level of high density lipoprotein cholesterol (HDL-C) and elevated triglycerides (TG) level. However, in diabetes mellitus, low density lipoprotein cholesterol (LDL-C) which is used as one of the markers for the risk of CVD, is underestimated so in such cases the levels of non-High density lipoprotein cholesterol (non-HDL-C) can be a stronger predictor of CVD as it strongly correlates with atherogenic lipoproteins. Therefore, an attempt has been made to evaluate the level of non-HDL-C as a newer marker for the risk of cardiovascular disease and to fi nd out the pattern of dyslipidemia in diabetes mellitus. The present study comprised of 82 type 2 Diabetic cases and 81 non-diabetic controls. Among the diabetics, the majority of the subjects (61.0%) were HDL-C dyslipidemic. However, among the controls, the maximum numbers of individuals (40.7%) were TG dyslipidemic. Diabetics have signifi cantly elevated ratio of total cholesterol to high density lipoprotein cholesterol (TC/HDL-C) and the signifi cant increased levels of non-high density lipoprotein cholesterol (non-HDL-C) compared to controls which can be used as markers of dyslipidemia and can also be used to predict the risk of cardiovascular disease in type 2 Diabetes Mellitus.
Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.