Notch and its ligands play critical roles in cell fate determination. Expression of Notch and ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the Notch pathway have suggested a critical role for Notch signaling in vasculogenesis and angiogenesis. However, the angiogenic signaling that controls Notch and ligand gene expression is unknown. We show here that vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor can induce gene expression of Notch1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 and is transmitted via the phosphatidylinositol 3-kinase/Akt pathway but is independent of mitogen-activated protein kinase and Src tyrosine kinase. Constitutive activation of Notch signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model, whereas blocking Notch signaling can partially inhibit network formation. This study provides the first evidence for regulation of Notch/Delta gene expression by an angiogenic growth factor and insight into the critical role of Notch signaling in arteriogenesis and angiogenesis

Abstract-We hypothesized that the dynamic relation between diastolic and systolic blood pressure over 24 hours provides a measure of arterial stiffness and might, therefore, predict cardiovascular mortality over and above pulse pressure. At baseline, while not on antihypertensive medication, 11 291 patients (mean age, 54.6 years; 5965 women) underwent ambulatory blood pressure monitoring. Using all of the blood pressure readings, we plotted diastolic against systolic blood pressure from each individual and calculated the regression slope. The ambulatory arterial stiffness index (AASI) was defined as 1 minus this regression slope. Over a median follow-up of 5.3 years, 566 cardiovascular deaths occurred, including 151 from stroke and 358 from cardiac disorders. Before and after adjustment for other cardiovascular risk factors, AASI and pulse pressure significantly predicted total cardiovascular mortality. AASI was a stronger predictor than pulse pressure for stroke (mutually adjusted relative hazard ratios for 1 SD increase, Key Words: arteries Ⅲ blood pressure monitoring, ambulatory Ⅲ epidemiology Ⅲ mortality C urrent guidelines for the management of hypertension recommend the use of ambulatory blood pressure monitoring to identify white-coat reactors and to establish the need for antihypertensive drug treatment. Although arterial stiffness is a strong predictor of cardiovascular complications, 1-7 it is underused in routine clinical practice for risk stratification. Its measurement, with the exception of pulse pressure, requires special equipment and trained observers. We hypothesized that the dynamic relation between diastolic and systolic blood pressure over 24 hours provides insights into the stiffness of the arterial wall. In this article, we describe the derivation of the ambulatory arterial stiffness index (AASI), and we explore the additional predictive value of AASI, over and above pulse pressure and established risk factors, for fatal cardiovascular outcomes among a large cohort of patients referred to a single center in Dublin, Ireland. In a companion article, 8 we demonstrate that AASI closely correlated with aortic pulse wave velocity and the central and peripheral systolic augmentation indexes, and we propose reference values for AASI based on observations in Chinese and European subjects.

ObjectiveNon-oxidative metabolism of ethanol (NOME) produces fatty acid ethyl esters (FAEEs) via carboxylester lipase (CEL) and other enzyme action implicated in mitochondrial injury and acute pancreatitis (AP). This study investigated the relative importance of oxidative and non-oxidative pathways in mitochondrial dysfunction, pancreatic damage and development of alcoholic AP, and whether deleterious effects of NOME are preventable.DesignIntracellular calcium ([Ca2+]C), NAD(P)H, mitochondrial membrane potential and activation of apoptotic and necrotic cell death pathways were examined in isolated pancreatic acinar cells in response to ethanol and/or palmitoleic acid (POA) in the presence or absence of 4-methylpyrazole (4-MP) to inhibit oxidative metabolism. A novel in vivo model of alcoholic AP induced by intraperitoneal administration of ethanol and POA was developed to assess the effects of manipulating alcohol metabolism.ResultsInhibition of OME with 4-MP converted predominantly transient [Ca2+]C rises induced by low ethanol/POA combination to sustained elevations, with concurrent mitochondrial depolarisation, fall of NAD(P)H and cellular necrosis in vitro. All effects were prevented by 3-benzyl-6-chloro-2-pyrone (3-BCP), a CEL inhibitor. 3-BCP also significantly inhibited rises of pancreatic FAEE in vivo and ameliorated acute pancreatic damage and inflammation induced by administration of ethanol and POA to mice.ConclusionsA combination of low ethanol and fatty acid that did not exert deleterious effects per se became toxic when oxidative metabolism was inhibited. The in vitro and in vivo damage was markedly inhibited by blockade of CEL, indicating the potential for development of specific therapy for treatment of alcoholic AP via inhibition of FAEE generation.

NFTs in the substantia nigra are associated with gait impairment in older persons with and without dementia.

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) 1-3 of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% CI 0.82-0.88; P=7.72x10−20) and rs1642764 at 17p13.1 (per-allele OR= 0.88, 95% CI 0.85-0.91; P=3.10x10−13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR=1.33, 95% CI 1.22-1.46; P=1.99x10−10). Our joint analysis identified new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region.

BackgroundBreast cancer is very common and highly fatal in women. Current non-invasive detection methods like mammograms are unsatisfactory. Lipidomics, a promising detection method, may serve as a novel prognostic approach for breast cancer in high-risk patients.ResultsAccording the predictive model, the combination of 15 lipid species had high diagnostic value. In the training set, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the combination of these 15 lipid species were 83.3%, 92.7%, 89.7%, and 87.9%, respectively. The AUC in the training set was 0.926 (95% CI 0.869-0.982). Similar results were found in the validation set, with the sensitivity, specificity, PPV and NPV at 81.0%, 94.5%, 91.9%, and 86.7%, respectively. The AUC was 0.938 (95% CI 0.889-0.986) in the validation set.MethodsUsing triple quadrupole liquid chromatography electrospray ionization tandem mass spectrometry, this study was to detect global lipid profiling of a total of 194 plasma samples from 84 patients with early-stage breast cancer (stage 0–II) and 110 patients with benign breast disease included in a training set and a validation set. A binary logistic regression was used to build a predictive model for evaluating the lipid species as potential biomarkers in the diagnosis of breast cancer.ConclusionThe combination of these 15 lipid species as a panel could be used as plasma biomarkers for the diagnosis of breast cancer.

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ObjectiveTo explore the transcriptome of epicardial adipose tissue (EAT) as compared to subcutaneous adipose tissue (SAT) and its modifications in a small number of patients with coronary artery disease (CAD) versus valvulopathy.Design and MethodsSAT and EAT samples were obtained during elective cardiothoracic surgeries. The transcriptome of EAT was evaluated using an unbiased, whole-genome approach as compared to SAT in subjects with CAD (n=6) and without CAD (n=5), where the patients without CAD had cardiac valvulopathy.ResultsRelative to SAT, EAT is a highly inflammatory tissue enriched with genes involved in endothelial function, coagulation, immune signaling, potassium transport and apoptosis. EAT is lacking in expression of genes involved in protein metabolism, TGF-beta signaling, and oxidative stress. Although underpowered, in subjects with severe CAD, there is an expression trend suggesting widespread downregulation of EAT encompassing a diverse group of gene sets related to intracellular trafficking, proliferation/transcription regulation, protein catabolism, innate immunity/lectin pathway and ER stress.ConclusionsThe EAT transcriptome is unique when compared to SAT. In the setting of CAD versus valvulopathy, there is possible alteration of the EAT transcriptome with gene suppression. This pilot study explores the transcriptome of EAT in CAD and valvulopathy, providing new insight into its physiologic and pathophysiologic roles.