A Role for VEGFR2 Activation in Endothelial Responses Caused by Barrier Disruptive OxPAPC Concentrations

Introduction: Oxidation products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (OxPAPC) differentially modulate endothelial cell (EC) barrier function in a dose-dependent fashion. Vascular endothelial growth factor receptor-2 (VEGFR2) is involved in the OxPAPC-induced EC inflammatory activation. This study examined a role of VEGFR2 in barrier dysfunction caused by high concentrations of OxPAPC and evaluated downstream signaling mechanisms resulting from the effect of OxPAPC in EC from pulmonary and systemic circulation

Vascular Endothelial Growth Factor Receptor-2 Couples Cyclo-Oxygenase-2 with Pro-Angiogenic Actions of Leptin on Human Endothelial Cells

The adipocyte-derived hormone leptin influences the behaviour of a wide range of cell types and is now recognised as a pro-angiogenic and pro-inflammatory factor. In the vasculature, these effects are mediated in part through its direct leptin receptor (ObRb)-driven actions on endothelial cells (ECs) but the mechanisms responsible for these activities have not been established. In this study we sought to more fully define the molecular links between inflammatory and angiogenic responses of leptin-stimulated human ECs../Akt/COX-2 signalling axis is required for leptin's pro-angiogenic actions and that this is regulated upstream by ObRb-dependent activation of VEGFR2. These studies identify a new function for VEGFR2 as a mediator of leptin-stimulated COX-2 expression and angiogenesis and have implications for understanding leptin's regulation of the vasculature in both non-obese and obese individuals

The Iberian Pyrite Belt: a mineralized system dismembered by voluminous high-level sills

The Iberian Pyrite Belt is a world-ranking massive sulphide province in which a reassessment of the palaeovolcanology has dramatically changed understanding of the source of metals and mechanism of ore formation. In the northern sector, the deposits are hosted by a sill-sediment complex in which more than 90% of the sills post-date the sulphide sheets. Because of a very high sill/sediment ratio, these late intrusions dominate the host succession and have severely disrupted the post-mineralization configuration thus obscuring the true genetic relationships. For example, some oxide deposits have been separated by hectometric sills from sulphide deposits they originally capped, creating seemingly totally independent mineralizing systems. In addition, stratiform sulphide sheets without underlying stockworks are not necessarily allochthonous. An early timing for the mineralization with respect to volcanism means that metals had to be predominantly sourced from the sedimentary basin and the continental crust below the volcanogenic sequence

Phosphoproteomic analysis of platelets activated by pro-thrombotic oxidized phospholipids and thrombin.

Specific oxidized phospholipids (oxPCCD36) promote platelet hyper-reactivity and thrombosis in hyperlipidemia via the scavenger receptor CD36, however the signaling pathway(s) induced in platelets by oxPCCD36 are not well defined. We have employed mass spectrometry-based tyrosine, serine, and threonine phosphoproteomics for the unbiased analysis of platelet signaling pathways induced by oxPCCD36 as well as by the strong physiological agonist thrombin. oxPCCD36 and thrombin induced differential phosphorylation of 115 proteins (162 phosphorylation sites) and 181 proteins (334 phosphorylation sites) respectively. Most of the phosphoproteome changes induced by either agonist have never been reported in platelets; thus they provide candidates in the study of platelet signaling. Bioinformatic analyses of protein phosphorylation dependent responses were used to categorize preferential motifs for (de)phosphorylation, predict pathways and kinase activity, and construct a phosphoproteome network regulating integrin activation. A putative signaling pathway involving Src-family kinases, SYK, and PLCγ2 was identified in platelets activated by oxPCCD36. Subsequent ex vivo studies in human platelets demonstrated that this pathway is downstream of the scavenger receptor CD36 and is critical for platelet activation by oxPCCD36. Our results provide multiple insights into the mechanism of platelet activation and specifically in platelet regulation by oxPCCD36

Clinicopathological variables, immunophenotype, chromosome 1p36 loss and tumour recurrence of 247 meningiomas grade I and II

The WHO grading scheme distinguishesbenign (grade I), atypical (grade II) and anaplastic(grade III) meningiomas. Both atypical and anaplasticmeningiomas exhibited an overall increased rate ofrecurrence, but between 15-20% benign meningiomaswill also exhibit an unfavourable clinical course withrecurrence before 10 years despite aggressive surgery.We investigated 247 cases of meningiomas grade I andII. The immunohistochemical expression of 30 differentmolecular biomarkers of cell adhesion molecules, cell-cycle and apoptosis regulators and checkpoints wasanalyzed. We also determined apoptosis by in-situhybridization (APOPDETEK™) and loss ofchromosome 1p36 by FISH. The study revealed astatistically significant co-variation (p<0.05) betweenmeningiomas grade II associated with severalclinicopathological features (Simpson grade of clinicalresection, necrosis, nuclear atypia, macronucleoli,transition to small cell, sheet-like growth, highcellularity), increased expression of several biomarkersof tumour proliferation (Cyclin A, Cyclin E, MIB-1 orMDM2), proteases (Cathepsin D) or cell-adhesion(CD44) and lower expression of progesterone receptorsthan meningiomas grade I. The presence of Psammomabodies or the location at convexity were protectiveprognostic factors for tumour recurrence while highcellularity and early age of onset (<57 year-old) wereindicators of increased recurrence risk. The expressionof COX-2, γ-catenin, Topoisomerase IIa, VEGF andMIB-1 was significantly higher in the cohort of recurrentmeningiomas. Meningiomas with chromosome 1p36 lossshowed a higher recurrence rate (33.3%) than meningiomas with normal chromosome 1p36 (18%).Increased COX-2 expression in recurrent meningiomamay also suggest a putative role of COX-2 inhibitors asa chemopreventive treatment for recurrence

Phosphoproteomic Analysis of Platelets Activated by Pro-Thrombotic Oxidized Phospholipids and Thrombin

<div><p>Specific oxidized phospholipids (oxPC_CD36) promote platelet hyper-reactivity and thrombosis in hyperlipidemia via the scavenger receptor CD36, however the signaling pathway(s) induced in platelets by oxPC_CD36 are not well defined. We have employed mass spectrometry-based tyrosine, serine, and threonine phosphoproteomics for the unbiased analysis of platelet signaling pathways induced by oxPC_CD36 as well as by the strong physiological agonist thrombin. oxPC_CD36 and thrombin induced differential phosphorylation of 115 proteins (162 phosphorylation sites) and 181 proteins (334 phosphorylation sites) respectively. Most of the phosphoproteome changes induced by either agonist have never been reported in platelets; thus they provide candidates in the study of platelet signaling. Bioinformatic analyses of protein phosphorylation dependent responses were used to categorize preferential motifs for (de)phosphorylation, predict pathways and kinase activity, and construct a phosphoproteome network regulating integrin activation. A putative signaling pathway involving Src-family kinases, SYK, and PLCγ2 was identified in platelets activated by oxPC_CD36. Subsequent <i>ex vivo</i> studies in human platelets demonstrated that this pathway is downstream of the scavenger receptor CD36 and is critical for platelet activation by oxPC_CD36. Our results provide multiple insights into the mechanism of platelet activation and specifically in platelet regulation by oxPC_CD36.</p></div