Role of nicotine during diabetic macular edema development

Diabetic macular edema (DME) represents the major cause of visual loss in diabetes patients. It is characterized by retinal thickening in the macular area due to breakdown of the blood-retinal barrier (BRB) [1]. By altering blood vessels supplying retina, hyperglycemia triggers tissue hypoxia. The primary response to latter is mediated by hypoxia-inducible factors (HIFs) which in turn promote vascular endothelial growth factor (VEGF) expression. The most important psychoactive compound in cigarette smoke, nicotine (NT), binds nicotinic cholinergic receptors (nAchRs) which are widely distributed in several human tissues, including retinal pigmented epithelium (RPE) [2]. Until now, little is known about risk factors linked to cigarette smoke inducing DME development. In the present study, we have evaluated NT effect in an in vitro model of outer BRB following exposure to hyperglycemic/hypoxic insult mimicking DME microenvironment. Our results have suggested that NT deeply impacts on outer BRB integrity by increasing its permeability. To investigate the molecular mechanisms involved in negative effect of this compound, we have analyzed HIF/VEGF system in cells exposed to hyperglycemic/hypoxic damage. NT treatment induced upregulation of HIF-1α/HIF-2α, VEGF mediated through activation of MAPK/ERK1/2 pathway. In conclusion, all this data have suggested a unfavorable role of this psychoactive agent in smokers DME affected

Correlation between expression profile of Wilms tumor 1 gene isoforms and neuroblastoma grade malignancy

Wilms tumor 1 gene (WT1) is expressed in neuroblastoma (NB) which represents the most aggressive extracranial pediatric tumor. This latter may transform into a more benign form such as ganglioneuroblastoma and ganglioneuroma or progress into a highly aggressive metastatic cancer with a poor survival rate. WT1 acts as tumor suppressor gene in NB by inducing the maturation in a less invasive mass. To date, it has been identified 13 mRNA WT1 variants encoding 13 proteins, however, most of the studies have focused their attention exclusively on isoform of ~49 kDa molecular weight (1, 2). In the present study, we have analyzed, the expression profile of WT1 isoforms, in undifferentiated and all-trans retinoic acid (RA) differentiated NB cells in order to evaluate their involvement in tumor malignancy. Results have shown that different isoforms are expressed both in untreated and RA treated NB cells. Their expression is significantly increased in RA treated cells, suggesting that WT1 isoforms are inversely related to NB malignancy grade. In accord to this hypothesis, WT1 isoforms and nestin expression are inversely related in undifferentiated and RA treated cells. Furthermore, the inhibition of the two signalling pathways specifically involved in differentiation of NB, PI3K/Akt and MAPK/ERK respectively, trigger an overexpression of all WT1 isoforms. In conclusion, these data suggest that overexpression of WT1 isoforms might promote trans-differentiation of NB into a more benign tumor such as ganglioneuroblastoma or ganglioneuroma

Effect of PACAP on Hypoxia-Induced Angiogenesis and Epithelial–Mesenchymal Transition in Glioblastoma

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts different effects in various human cancer. In glioblastoma (GBM), PACAP has been shown to interfere with the hypoxic micro-environment through the modulation of hypoxia-inducible factors via PI3K/AKT and MAPK/ERK pathways inhibition. Considering that hypoxic tumor micro-environment is strictly linked to angiogenesis and Epithelial–Mesenchymal transition (EMT), in the present study, we have investigated the ability of PACAP to regulate these events. Results have demonstrated that PACAP and its related receptor, PAC1R, are expressed in hypoxic area of human GBM colocalizing either in epithelial or mesenchymal cells. By using an in vitro model of GBM cells, we have observed that PACAP interferes with hypoxic/angiogenic pathway by reducing vascular-endothelial growth factor (VEGF) release and inhibiting formation of vessel-like structures in H5V endothelial cells cultured with GBM-conditioned medium. Moreover, PACAP treatment decreased the expression of mesenchymal markers such as vimentin, matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) as well as CD44 in GBM cells by affecting their invasiveness. In conclusion, our study provides new insights regarding the multimodal role of PACAP in GBM malignancy

Pseudorapidity densities of charged particles with transverse momentum thresholds in pp collisions at √ s = 5.02 and 13 TeV

The pseudorapidity density of charged particles with minimum transverse momentum (pT) thresholds of 0.15, 0.5, 1, and 2 GeV/c is measured in pp collisions at the center of mass energies of √s=5.02 and 13 TeV with the ALICE detector. The study is carried out for inelastic collisions with at least one primary charged particle having a pseudorapidity (η) within 0.8pT larger than the corresponding threshold. In addition, measurements without pT-thresholds are performed for inelastic and nonsingle-diffractive events as well as for inelastic events with at least one charged particle having |η|2GeV/c), highlighting the importance of such measurements for tuning event generators. The new measurements agree within uncertainties with results from the ATLAS and CMS experiments obtained at √s=13TeV.