Antiangiogenic role of somatostatin receptor 2 in a model of hypoxia-induced neovascularization in the retina: Results from transgenic mice

PURPOSE. To determine whether the somatostatin receptor 2 (sst2) influences angiogenesis and its associated factors in a model of hypoxia-induced retinal neovascularization. METHODS. sst1-knockout (KO) mice, in which sst2 is overexpressed and overfunctional, and sst2-KO mice were used. Angiogenesis was evaluated in fluorescein-perfused retinas. Angiogenesis- associated factors were determined by RT-PCR and immunohistochemistry. RESULTS. Retinal neovascularization was increased in sst2-KO mice, but remained unchanged in sst1-KO compared with wild-type (WT) mice. Retinal levels of sst2 mRNA were not affected by hypoxia. Normoxic levels of angiogenesis regulators were similar in WT and KO retinas except for mRNA levels of IGF-1, Ang-2, and its receptor Tie-2. In WT, hypoxia induced an increase in mRNA levels of (1) VEGF and its receptors, (2) IGF-1R, and (3) Ang-2 and Tie-2. The increase in VEGF and IGF-1R mRNAs was more pronounced after sst2 loss, but was less pronounced when sst2 was overexpressed. In addition, in hypoxic retinas, sst2 loss increased IGF-1 mRNA, whereas it decreased Ang-1, Tie-1, and Tie-2 mRNA levels. Moreover, Tie-1 mRNA increased when sst2 was overexpressed. Immunohistochemistry confirmed the results in hypoxic retinas on increased expression of VEGF, IGF-1, and their receptors after sst2 loss. It also allowed the localization of these factors to specific retinal cells. In this respect, VEGFR-2, IGF-1, and IGF-1R were localized to Mu¨ller cells. CONCLUSIONS. These results suggest that sst2 may be protective against angiogenesis. The immediate clinical importance lies in the establishment of a potential pharmacological target based on sst2 pharmacology.L'articolo è disponibile sul sito dell'editore http://www.arvo.org/eweb/StartPage.aspx?Site=arvo

SerpinB3 and Yap Interplay Increases Myc Oncogenic Activity

SerpinB3 has been recently described as an early marker of liver carcinogenesis, but the potential mechanistic role of this serpin in tumor development is still poorly understood. Overexpression of Myc often correlates with more aggressive tumour forms, supporting its involvement in carcinogenesis. Yes-associated protein (Yap), the main effector of the Hippo pathway, is a central regulator of proliferation and it has been found up-regulated in hepatocellular carcinomas. The study has been designed to investigate and characterize the interplay and functional modulation of Myc by SerpinB3 in liver cancer. Results from this study indicate that Myc was up-regulated by SerpinB3 through calpain and Hippo-dependent molecular mechanisms in transgenic mice and hepatoma cells overexpressing human SerpinB3, and also in human hepatocellular carcinomas. Human recombinant SerpinB3 was capable to inhibit the activity of Calpain in vitro, likely reducing its ability to cleave Myc in its non oncogenic Myc-nick cytoplasmic form. SerpinB3 indirectly increased the transcription of Myc through the induction of Yap pathway. These findings provide for the first time evidence that SerpinB3 can improve the production of Myc through direct and indirect mechanisms that include the inhibition of generation of its cytoplasmic form and the activation of Yap pathway

Plexiform architecture in gastrointestinal stromal tumors is not restricted to succinate dehydrogenase-deficient cases

Accumulating evidence reveals the heterogeneous features of gastrointestinal stromal tumors (GISTs), primarily distinguished by their various molecular triggers defining well characterized subgroups. The identification of the pathogenetic group a given GIST belongs to, in combination with the currently adopted GIST prognosticators, is pivotal for the correct management of GIST patients. Epidemiological, anatomical and morphological features are more or less strictly associated with the various possible GIST molecular pathogenesis; therefore, they can concur to addressing molecular analysis or even influence the identification of GIST subsets by themselves. This is particularly true in a cost/benefit perspective aimed at cutting the expenses of pathology labs. Under these circumstances, a correct classical pathological analysis still appears a fundamental step to achieve an optimal GIST characterization.We herein report a gastric epithelioid PDGFRA-mutant GIST displaying the multinodular/plexiform architecture distinctive of succinate dehydrogenase (SDH)-deficient GISTs. Immunohistochemistry and molecular analysis led to the correct tumor characterization. The reported case constitutes a valuable contribution to GIST pathology in that it demonstrates that multinodular/plexiform architecture is not restricted to SDH-deficient GISTs, but can be found also in PDGFRA-mutant ones; this is an event to be aware of, given the predilection for gastric location and epithelioid morphology shared by these two GIST subgroups, only the latter of which includes imatinib-sensitive cases. Keywords: Gastrointestinal stromal tumor, Platelet-derived growth factor receptor alpha, Multinodular architecture, Plexiform architecture, Succinate dehydrogenas

Tecniche integrate di Remote Sensing e GIS a supporto della stima del potenziale fotovoltaico su tetti in aree urbane

Le ultime linee guida approvate dal Governo Italiano per sostenere finanziariamente il fotovoltaico (PV) e lo sviluppo della produzione di energia solare (Quarto e Quinto Conto Energia, Gennaio 2012 e succ.), al fine di evitare il consumo di suolo in aree agricole o naturali, comprendono indicazioni specifiche che rendono più vantaggiosa l’installazione d’impianti su tetti o superfici di copertura di edifici. In questo contesto diventa importante, per una adeguata attività di pianificazione e monitoraggio del PV, la mappatura estensiva delle superfici a disposizione, coincidenti con i tetti e l’accurata valutazione del loro potenziale fotovoltaico. Dal momento che tali coperture si trovano soprattutto nelle aree urbane o industriali, in cui fattori come eterogeneità tridimensionale, albedo, torbidità atmosferica ed ombreggiamenti reciproci influenzano in modo significativo l’irraggiamento solare locale, è necessario tenere conto adeguatamente di questi elementi mediante una mappatura GIS tridimensionale ed avanzati strumenti di modellazione, in modo da stimare efficacemente la radianza solare disponibile a livello dei tetti. La metodologia implementata, basata su tecniche di telerilevamento e GIS, ha permesso di valutare e mappare la radiazione solare globale su tutti i tetti presenti nel territorio del Comune di Avellino. Partendo da dati di tipo LIDAR, è stato ottenuto in primo luogo il DSM di tutta l’area di interesse (~ 42 Km2), quindi il modello tridimensionale di ogni edificio da cui sono stati derivati i parametri geometrici di tutte le coperture. Per tenere conto della trasparenza atmosferica e della percentuale di radiazione solare (diffusa/diretta) sulle superfici di interesse, sono stati utilizzati i dati e gli strumenti applicativi presenti sul sito web PVGIS, sviluppato dalla UE. L’elaborazione finale, basata sull’utilizzo di strumenti GIS anche di tipo open source, ha permesso di ottenere le mappe di radianza solare e di potenziale PV per tutti i tetti presenti nell’area di studio.The last guidelines approved by Italian government to financially support the solar Photovoltaic (PV) Energy production development (Fourth and Fifth feed-in-scheme, January 2012 and later), in order to avoid soil consumption in agricultural or naturals areas, include specific indications for more advantageously funding the installations exploiting roofs or covers surfaces. In this context it becomes important, for a suitable PV planning and monitoring, the extensive mapping of the available surfaces extent, usually corresponding to covers and properly assessing their quality in term of PV potential. Since the covers are mainly located in urban or industrial areas, whose 3D heterogeneity, albedo, atmospheric turbidity and casting shadows significantly influence the local solar irradiance, it is necessary to suitably account for these distributed factors by means of GIS mapping and advanced modeling tools in order to provide realistic estimates of solar available radiance at roofs level. The implemented methodology, based on remote sensing techniques, has allowed to estimate and map the global solar radiance over all the roofs within Avellino municipality. Starting from LIDAR data, DSM of the entire area of interest (~42 Km2) has been firstly obtained; then the 3D model of each building and related cover has been derived. To account for the atmospheric transparency and the related time-dependent diffuse/direct radiation percentage on the area, data and tools from EU PVGIS web application have been also used. The final processing to obtain the solar radiance maps has been carried out using specific software modules available within commercial and open-source GIS packages

Conjugation of different immunogenic enterococcal vaccine target antigens leads to extended strain coverage

[Abstract] Enterococci have emerged as important nosocomial pathogens due to their resistance to the most commonly used antibiotics. Alternative treatments or prevention options are aimed at polysaccharides and surface-related proteins that play important roles in pathogenesis. Previously, we have shown that 2 Enterococcus faecium proteins, the secreted antigen A and the peptidyl-prolyl cis-trans isomerase, as well as the Enterococcus faecalis polysaccharide diheteroglycan, are able to induce opsonic and cross-protective antibodies. Here, we evaluate the use of glycoconjugates consisting of these proteins and an enterococcal polysaccharide to develop a vaccine with broader strain coverage. Diheteroglycan was conjugated to these 2 enterococcal proteins. Rabbit sera raised against these glycoconjugates showed Immunoglobulin G titers against the corresponding conjugate, as well as against the respective protein and carbohydrate antigens. Effective opsonophagocytic killing for the 2 sera was observed against different E. faecalis and E. faecium strains. Enzyme-linked immunosorbent assays against whole bacterial cells showed immune recognition of 22 enterococcal strains by the sera. Moreover, the sera conferred protection against E. faecalis and E. faecium strains in a mouse infection model. Our results suggest that these glycoconjugates are promising candidates for vaccine formulations with a broader coverage against these nosocomial pathogens and that the evaluated proteins are potential carrier proteins

Role of the Adrenergic System in a Mouse Model of Oxygen-induced Retinopathy: Antiangiogenic Effects of Beta-adrenoreceptor Blockade

METHODS. Propranolol was administered subcutaneously and picropodophyllin (PPP) intraperitoneally. Intravitreal injections of vascular endothelial growth factor (VEGF) were performed. Messengers of -ARs, VEGF, its receptors, IGF-1 and IGF-1R were measured with quantitative RT-PCR. VEGF content was determined with ELISA. -ARs, hypoxia-inducible factor (HIF)-1 , occludin, and albumin were measured with Western blot. Retinal localization of 3-ARs was determined by immunohistochemistry. Retinopathy was assessed by scoring fluorescein-perfused retinas, and plasma extravasation was visualized by Evans blue dye

Tuberculosis in childhood: a systematic review of national and international guidelines

BACKGROUND: Paediatric tuberculosis (TB) represents a major public health concern worldwide. About 1 million children aged less than 15 years develop TB each year, contributing to 3-25% of the total TB caseload. The aim of this review is to evaluate national and international guidelines concerning tuberculosis in childhood and compare them in terms of diagnosis and treatment strategies. METHODS: A literature search of the Pubmed database was performed from January 2000 to August 2013, using the terms “tuberculosis” and “children”. The search was limited to guidelines and consensus conferences, human species and full text availability, with no language restrictions. RESULTS: Twenty-seven national and international guidelines are identified. Several discrepancies on the diagnosis workup of TB are underlined. The main points of disagreement are represented by the interpretation of tuberculin skin test (TST) result and the recommendations on the use of TST and/or interferon-gamma release assay (IGRA) for the diagnosis of TB infection. Otherwise, all guidelines are in agreement that a microbiological confirmation should always be sought. Similarly, susceptibility drug testing and genotyping should be performed whenever it is possible on the basis of resources availability. On the contrary, the use of nucleic acid amplification tests (NAATs) for the M. tuberculosis detection is still controversial. A general consensus exists, otherwise, on TB treatment and only minor discrepancies are evidenced, such as the recommendations on daily or intermittent treatment regimens. CONCLUSIONS: Despite advances in TB diagnostic tools have been reached during the last decade, a lack of uniformity in their availability, indication and interpretation has relevant consequences for clinical practice. Further studies need to be performed to clarify this issue and identify a reliable and reproducible diagnostic workup. Moreover, future studies should analyze the drug metabolism and the efficacy of intermittent dosing regimes in childhood, as well as new treatment regimens in order to improve the therapy compliance