BackgroundValosin-containing protein (VCP)/p97 is an AAA ATPase molecular chaperone that regulates vital cellular functions and protein-processing. A recent study indicated that VCP expression levels are correlated with prognosis and progression of non-small cell lung carcinoma (NSCLC). We not only verified these findings but also identified the specific role of VCP in NSCLC pathogenesis and progression.Methodology/Principal FindingsOur results show that VCP is significantly overexpressed in non-small cell lung carcinoma (NSCLC) as compared to normal tissues and cell lines (p<0.001). Moreover, we observed the corresponding accumulation of ubiquitinated-proteins in NSCLC cell lines and tissues as compared to the normal controls. VCP inhibition by si/shRNA or small-molecule (Eeyarestatin I, EerI) significantly (p<0.05, p<0.00007) suppressed H1299 proliferation and migration but induced (p<0.00001) apoptosis. Cell cycle analysis by flow cytometry verified this data and shows that VCP inhibition significantly (p<0.001, p<0.003) induced cell cycle arrest in the G0/G1 phases. We also found that VCP directly regulates p53 and NFκB protein levels as a potential mechanism to control tumor cell proliferation and progression. Finally, we evaluated the therapeutic potential of VCP inhibition and observed significantly reduced NSCLC tumor growth in both in vitro and xenograft murine (athymic-nude) models after EerI treatment (p<0.05).Conclusions/SignificanceThus, targeting VCP in NSCLC may provide a novel strategy to restore p53 and NFκB levels and ameliorate the growth and tumorigenicity, leading to improved clinical outcomes.

Objectives To determine adherence to the 2011 National Heart, Lung, and Blood Institute lipid screening guidelines and identify patient factors promoting screening. Methods Records of children who received well-child care at age 11 years and turned 12 in 2013 were reviewed. Subjects were stratified by guideline-defined dyslipidemia risk based on documented medical or family history risk factors. We defined adherence as the order of a lipid profile when age 11 years or completed lipid screening at 9 to 10 years. Results Of 298 subjects, 42% were assigned to the dyslipidemia high-risk subgroup. Records of 27.2% demonstrated adherence. Fifty-six percent of high-risk subjects versus 6% of their non-high-risk counterparts received lipid screening by age 12 (P < .001). Among screened subjects, history of obesity and parental history of dyslipidemia were significantly associated with lipid testing. Conclusions Lipid screening rates were low. Strategies to increase lipid screening in the primary care setting are needed.

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This review provides needed perspective on statin efficacy and safety in individuals under 40, 40-75, and > 75 years of age. Starting with the 2013 ACC-AHA cholesterol guidelines extensive evidence base on randomized controlled trials (RCTs) we added references in the past 5 years that discussed statin efficacy and safety over the life span. In those under 40, statins are primarily used for treatment of severe hypercholesterolemia, often familial, and they are well tolerated. In middle-aged adults, statins have strong evidence for benefit in primary and secondary prevention trials; however, in primary prevention, a clinician-patient risk discussion should precede statin prescription in order to determine appropriate treatment. In those over 75, issues of statin intensity and net benefit loom large as associated comorbidity, polypharmacy, and potential for adverse effects impact the decision to use statins with RCT data strongest in support of use in secondary prevention. Statin drugs have been studied by RCTs in a large number of individuals. In those groups shown to benefit, statins have reduced the risk of atherosclerotic cardiovascular disease with few side effects as compared to controls. This review has detailed considerations that should occur when statins are given to individuals in different age groups.

Protein homeostasis (proteostasis) generates and maintains individual proteins in their folded and functional-competent states. The components of the cellular proteostasis machinery also dictate the functional lifetime of a protein by constantly regulating its conformation, concentration and subcellular location. The autosomal recessive disease cystic fibrosis (CF) is caused by a proteostasis-defect in CF transmembrane conductance regulator (CFTR). The most common CF mutation leading to this proteostasis-defect is the deletion of a phenylalanine residue at position 508 (ΔF508) of the CFTR protein. This ΔF508-CFTR protein is prone to aberrant folding, increased ER-associated degradation, atypical intracellular trafficking and reduced stability at the apical membrane. This ΔF508-CF proteostasis-defect leads to an obstructive lung disease characterized by impaired ion transport in airway epithelial cells, mucus buildup in air space and chronic airway inflammation. We assess here whether correcting the underlying defect in ΔF508-CFTR protein processing using therapeutic proteostasis regulators can treat chronic CF lung disease. As a proof of concept, recent studies support that the selective modulation of mutant-CFTR proteostasis may offer promising therapies to reverse chronic CF lung disease.