Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.

The development of reliable gene expression profiling technology is having an increasing impact on our understanding of lung cancer biology. Our study aimed to determine any correlation between the phenotypic heterogeneity and genetic diversity of lung cancer. Microarray analysis was performed on a set of 46 tumor samples and 45 paired nontumor samples of nonsmall cell lung cancer (NSCLC) samples to establish gene signatures in primary adenocarcinomas and squamous-cell carcinomas, determine differentially expressed gene sequences at different stages of the disease and identify sequences with biological significance for tumor progression. After the microarray analysis, the expression level of 92 selected genes was validated by qPCR and the robust Bonferroni test in an independent set of 70 samples composed of 48 tumor samples and 22 nontumor samples. Gene sequences were differentially expressed as a function of tumor type, stage and differentiation grade. High upregulation was observed for KRT15 and PKP1, which may be good markers to distinguish squamous-cell carcinoma samples. High downregulation was observed for DSG3 in stage IA adenocarcinomas.Lung cancer is the leading cause of cancer death in the United States 1 and worldwide. The two major forms of lung cancer are nonsmall cell lung cancer (NSCLC %85% of all lung cancers) and small-cell lung cancer (SCLC %15%). NSCLC can be divided into three major histological subtypes: squamous-cell carcinoma, adenocarcinoma and large-cell lung cancer. Smoking causes all types of lung cancer but is most strongly linked with SCLC and squamous-cell carcinoma, while adenocarcinoma is the most frequent type in patients who have never smoked.2-5 Patients with early-stage NSCLC who undergo curative resection still have a substantial risk of developing metastases. The 5-year survival rates for patients with Stage IA and IB NSCLC are only 67 and 57%, respectively.

S ystemic lupus erythematosus (SLE) is a multisystemic chronic autoimmune inflammatory disorder that is associated with a high risk for the development of renal and cardiovascular disease, 1,2 which are major causes of mortality in these patients. 3 It predominantly affects young women of child-bearing age, the same population that is at lowest relative risk of atherosclerotic heart disease. In fact, women with lupus (age, 35-44 years) are >50 times as likely as healthy women without lupus to have a myocardial infarction. 4 Indeed, SLE is characterized by a high incidence of hypertension, 5-7 a wellestablished risk factor for the development and acceleration of atherosclerosis and ischemic heart disease. Oxidative stress and the inactivation of nitric oxide (NO) by vascular superoxide anion (O 2 ·− ) play a critical role in the pathogenesis of endothelial dysfunction, an early event in most cardiovascular diseases, including hypertension. 8,9 Reactive oxygen species (ROS) have been considered as risk and enhancer factors for autoimmune diseases, 10 and oxidation is one of the major factors responsible for atheroma development in this context. Indeed, SLE is a disease characterized by an increased oxidative damage.11-14 Free radical-mediated reactions are implicated in endothelial dysfunction in SLE, 15 and renal oxidative stress plays an important mechanistic role in the development of autoimmune-mediated hypertension. 16Abstract-Hydroxychloroquine has been shown to be efficacious in the treatment of autoimmune diseases, including systemic lupus erythematosus. Hydroxychloroquine-treated lupus patients showed a lower incidence of thromboembolic disease. Endothelial dysfunction, the earliest indicator of the development of cardiovascular disease, is present in lupus.Whether hydroxychloroquine improves endothelial function in lupus is not clear. The aim of this study was to analyze the effects of hydroxychloroquine on hypertension, endothelial dysfunction, and renal injury in a female mouse model of lupus. NZBWF1 (lupus) and NZW/LacJ (control) mice were treated with hydroxychloroquine 10 mg/kg per day by oral gavage, or with tempol and apocynin in the drinking water, for 5 weeks. Hydroxychloroquine treatment did not alter lupus disease activity (assessed by plasma double-stranded DNA autoantibodies) but prevented hypertension, cardiac and renal hypertrophy, proteinuria, and renal injury in lupus mice. Aortae from lupus mice showed reduced endotheliumdependent vasodilator responses to acetylcholine and enhanced contraction to phenylephrine, which were normalized by hydroxychloroquine or antioxidant treatments. No differences among all experimental groups were found in both the relaxant responses to acetylcholine and the contractile responses to phenylephrine in rings incubated with the nitric oxide synthase inhibitor N G -nitro-l-arginine methyl ester. Vascular reactive oxygen species content and mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase subunits NOX-1 and p47 phox were increased in lupus...