In current clinical practice, histology-based grading of diffuse infiltrative gliomas is the best predictor of patient survival time. Yet histology provides little insight into the underlying biology of gliomas and is limited in its ability to identify and guide new molecularly targeted therapies. We have performed large-scale gene expression analysis using the Affymetrix HG U133 oligonucleotide arrays on 85 diffuse infiltrating gliomas of all histologic types to assess whether a gene expression-based, histologyindependent classifier is predictive of survival and to determine whether gene expression signatures provide insight into the biology of gliomas. We found that gene expression-based grouping of tumors is a more powerful survival predictor than histologic grade or age. The poor prognosis samples could be grouped into three different poor prognosis groups, each with distinct molecular signatures. We further describe a list of 44 genes whose expression patterns reliably classify gliomas into previously unrecognized biological and prognostic groups: these genes are outstanding candidates for use in histology-independent classification of high-grade gliomas. The ability of the large scale and 44 gene set expression signatures to group tumors into strong survival groups was validated with an additional external and independent data set from another institution composed of 50 additional gliomas. This demonstrates that large-scale gene expression analysis and subset analysis of gliomas reveals unrecognized heterogeneity of tumors and is efficient at selecting prognosisrelated gene expression differences which are able to be applied across institutions.

Background: Genes and proteins are organized into functional modular networks in which the network context of a gene or protein has implications for cellular function. Highly connected hub proteins, largely responsible for maintaining network connectivity, have been found to be much more likely to be essential for yeast survival.

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Background-Oxidized low-density lipoprotein reduces endothelial nitric oxide production (an important mediator of vasoregulation) and activates p38 mitogen-activated protein kinase (MAPK), a mediator of vascular inflammation. Animal models of vascular stress have previously predicted improvements in vascular function after p38 MAPK inhibition. We hypothesized that a selective p38␣/␤ MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia. Methods and Results-Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol Ͼ4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (nϭ27) or placebo (nϭ29) twice daily for 28 days. Patients with known vascular disorders (eg, diabetes mellitus, coronary heart disease) were excluded. Forearm blood flow was measured by venous occlusion plethysmography in response to serial intra-arterial infusion of acetylcholine, sodium nitroprusside, and N G -monomethyl-L-arginine (L-NMMA). Acetylcholine and L-NMMA responses were significantly impaired (Pϭ0.01 and Pϭ0.03) compared with responses in control subjects (nϭ12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; Pϭ0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; Pϭ0.02), and to L-NMMA by 10% (95% confidence interval, Ϫ1 to 23; Pϭ0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, Ϫ81 to Ϫ6%; PϽ0.05) in patients treated with losmapimod compared with placebo. Conclusions-Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity. This suggests p38 MAPK as a novel target for patients with cardiovascular disease. Clinical Trial Registration-URL: http://clinicaltrials.gov. Unique identifier: NCT00474864. (Circulation. 2011;123:515-523.) Key Words: endothelial function Ⅲ hypercholesterolemia Ⅲ nitric oxide Ⅲ p38 MAPK Ⅲ vasodilation A therosclerosis is regarded as a complex condition in which inflammation plays a pivotal role, involving low-density lipoprotein (LDL) deposition and oxidation, recruitment of inflammatory cells, and release of cytokines and endothelial dysfunction. 1,2 Reduced nitric oxide (NO) bioavailability accompanies all stages of atherosclerosis and is associated with increased cardiovascular risk. 3 Clinical Perspective on p 523The release of NO is a complex process that can be affected by a number of physiological and pathophysiological factors, 4 including serum levels of LDL, which, when oxidized, have increased atherogenic potential. 5 Oxidized LDL reduces NO bioavailability, destabilizes endothelial NO synthase mRNA, 6 Received February 26, 2010; accepted November 19, 2010 Several p38 MAPK inhibitors are effective in a variety o...