Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma

BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma

Pig-to-Nonhuman Primates Pancreatic Islet Xenotransplantation: An Overview

The therapy of type 1 diabetes is an open challenging problem. The restoration of normoglycemia and insulin independence in immunosuppressed type 1 diabetic recipients of islet allotransplantation has shown the potential of a cell-based diabetes therapy. Even if successful, this approach poses a problem of scarce tissue supply. Xenotransplantation can be the answer to this limited donor availability and, among possible candidate tissues for xenotransplantation, porcine islets are the closest to a future clinical application. Xenotransplantation, with pigs as donors, offers the possibility of using healthy, living, and genetically modified islets from pathogen-free animals available in unlimited number of islets. Several studies in the pig-to-nonhuman primate model demonstrated the feasibility of successful preclinical islet xenotransplantation and have provided insights into the critical events and possible mechanisms of immune recognition and rejection of xenogeneic islet grafts. Particularly promising results in the achievement of prolonged insulin independence were obtained with newly developed, genetically modified pigs islets able to produce immunoregulatory products, using different implantation sites, and new immunotherapeutic strategies. Nonetheless, further efforts are needed to generate additional safety and efficacy data in nonhuman primate models to safely translate these findings into the clinic

Modeling of air pollutant concentrations in an industrial region of Turkey

The hourly SO2 and PM10 concentrations in ambient air of the Kutahya city located at the western part of Turkey have exceeded the air quality limits in winter months since several years. The region has major industrial plants including lignite-fired power plants and open-cast mining activities, residential areas, and traffic sources. To obtain and quantify the sector-wise anthropogenic emissions and spatial distribution of the major pollutants including SO2, NOx , PM10, and CO, a comprehensive emission inventory with 1-km spatial resolution was prepared for the year of 2014, and the AERMOD dispersion model was used to predict ambient air concentrations in a domain of 140 km by 110 km. Validation of the model results was also done referring to in situ routine measurements at two monitoring stations located in the study area. Total emissions of SO2, PM10, NOx , and CO in the study area were calculated as 64,399, 9770, 24,627, and 29,198 tons/year, respectively. The results showed that industrial plants were the largest sources of SO2, NOx , and PM10 emissions, while residential heating and road traffic were the most contributing sectors for CO emissions. Three major power plants in the region with total annual lignite consumption of 10 million tons per year were main sources of high SO2 concentrations, while high PM10 concentrations mainly originated from two major open-cast lignite mines. Major contributors of high NOx and CO concentrations were traffic including highways and urban streets, and residential heating with high lignite consumption in urban areas. Results of the dispersion model run with the emission inventory resulted in partially high index of agreement (0.75) with SO2 measured in the urban station within the modeled area