CCN2 (connective tissue growth factor (CTGF/CCN2)) is a matricellular protein that utilizes integrins to regulate cell proliferation, migration and survival. The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of Ccn2 mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival. Ccn2 mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in Ccn2 mutants, with reduced stress observed in Ccn2 overexpressing transgenic mice. In vitro studies revealed that Ccn2 is a stress responsive gene in chondrocytes. The elevated stress observed in Ccn2−/− chondrocytes is direct and mediated in part through integrin α5. The expression of the survival marker NFκB and components of the autophagy pathway were decreased in Ccn2 mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. These data demonstrate that absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor κB (NFκB) as part of a CCN2/integrin/NFκB signaling cascade.Electronic supplementary materialThe online version of this article (doi:10.1007/s12079-013-0201-y) contains supplementary material, which is available to authorized users.
The quality-adjusted life year (QALY) gained of 0.5646 results in an ICUR of $22,345 for sacubitril /valsartan vs. enalapril. The most influential parameter in univariate sensitivity analysis is the constant term in the statistical model of CV mortality. ConClusions: Sacubitril/valsartan compared with ACEi for HFrEF patients is cost-effective given on a ceiling ratio of $23,000 per LYG in Taiwan.
PCV94Cost-EffECtiVEnEss AnAlysis of iVAbrAdinE in thE trEAtmEnt of PAtiEnts With ChroniC hEArt fAilurE in irAn
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