MicroRNA-199b-5p Impairs Cancer Stem Cells through Negative Regulation of HES1 in Medulloblastoma

BACKGROUND: Through negative regulation of gene expression, microRNAs (miRNAs) can function in cancers as oncosuppressors, and they can show altered expression in various tumor types. Here we have investigated medulloblastoma tumors (MBs), which arise from an early impairment of developmental processes in the cerebellum, where Notch signaling is involved in many cell-fate-determining stages. MBs occur bimodally, with the peak incidence seen between 3-4 years and 8-9 years of age, although it can also occur in adults. Notch regulates a subset of the MB cells that have stem-cell-like properties and can promote tumor growth. On the basis of this evidence, we hypothesized that miRNAs targeting the Notch pathway can regulated these phenomena, and can be used in anti-cancer therapies. METHODOLOGY/PRINCIPAL FINDINGS: In a screening of MB cell lines, the miRNA miR-199b-5p was seen to be a regulator of the Notch pathway through its targeting of the transcription factor HES1. Down-regulation of HES1 expression by miR-199b-5p negatively regulates the proliferation rate and anchorage-independent growth of MB cells. MiR-199b-5p over-expression blocks expression of several cancer stem-cell genes, impairs the engrafting potential of MB cells in the cerebellum of athymic/nude mice, and of particular interest, decreases the MB stem-cell-like (CD133+) subpopulation of cells. In our analysis of 61 patients with MB, the expression of miR-199b-5p in the non-metastatic cases was significantly higher than in the metastatic cases (P = 0.001). Correlation with survival for these patients with high levels of miR-199b expression showed a positive trend to better overall survival than for the low-expressing patients. These data showing the down-regulation of miR-199b-5p in metastatic MBs suggest a potential silencing mechanism through epigenetic or genetic alterations. Upon induction of de-methylation using 5-aza-deoxycytidine, lower miR-199b-5p expression was seen in a panel of MB cell lines, supported an epigenetic mechanism of regulation. Furthermore, two cell lines (Med8a and UW228) showed significant up-regulation of miR-199b-5p upon treatment. Infection with MB cells in an induced xenograft model in the mouse cerebellum and the use of an adenovirus carrying miR-199b-5p indicate a clinical benefit through this negative influence of miR-199b-5p on tumor growth and on the subset of MB stem-cell-like cells, providing further proof of concept. CONCLUSIONS/SIGNIFICANCE: Despite advances in our understanding of the pathogenesis of MB, one-third of these patients remain incurable and current treatments can significantly damage long-term survivors. Here we show that miR-199b-5p expression correlates with metastasis spread, identifying a new molecular marker for a poor-risk class in patients with MB. We further show that in a xenograft model, MB tumor burden can be reduced, indicating the use of miR199b-5p as an adjuvant therapy after surgery, in combination with radiation and chemotherapy, for the improvement of anti-cancer MB therapies and patient quality of life. To date, this is the first report that expression of a miRNA can deplete the tumor stem cells, indicating an interesting therapeutic approach for the targeting of these cells in brain tumors

CSAR Benchmark Exercise of 2010: Combined Evaluation Across All Submitted Scoring Functions

As part of the Community Structure-Activity Resource (CSAR) center, a set of 343 high-quality, protein–ligand crystal structures were assembled with experimentally determined <i>K</i>_d or <i>K</i>_i information from the literature. We encouraged the community to score the crystallographic poses of the complexes by any method of their choice. The goal of the exercise was to (1) evaluate the current ability of the field to predict activity from structure and (2) investigate the properties of the complexes and methods that appear to hinder scoring. A total of 19 different methods were submitted with numerous parameter variations for a total of 64 sets of scores from 16 participating groups. Linear regression and nonparametric tests were used to correlate scores to the experimental values. Correlation to experiment for the various methods ranged <i>R</i>² = 0.58–0.12, Spearman ρ = 0.74–0.37, Kendall τ = 0.55–0.25, and median unsigned error = 1.00–1.68 p<i>K</i>_d units. All types of scoring functionsforce field based, knowledge based, and empiricalhad examples with high and low correlation, showing no bias/advantage for any particular approach. The data across all the participants were combined to identify 63 complexes that were poorly scored across the majority of the scoring methods and 123 complexes that were scored well across the majority. The two sets were compared using a Wilcoxon rank-sum test to assess any significant difference in the distributions of >400 physicochemical properties of the ligands and the proteins. Poorly scored complexes were found to have ligands that were the same size as those in well-scored complexes, but hydrogen bonding and torsional strain were significantly different. These comparisons point to a need for CSAR to develop data sets of congeneric series with a range of hydrogen-bonding and hydrophobic characteristics and a range of rotatable bonds

A ring system detected around the Centaur (10199) Chariklo

Hitherto, rings have been found exclusively around the four giant planets in the Solar System. Rings are natural laboratories in which to study dynamical processes analogous to those that take place during the formation of planetary systems and galaxies. Their presence also tells us about the origin and evolution of the body they encircle. Here we report observations of a multichord stellar occultation that revealed the presence of a ring system around (10199) Chariklo, which is a Centaur-that is, one of a class of small objects orbiting primarily between Jupiter and Neptune-with an equivalent radius of 124â â 9â kilometres (ref. 2). There are two dense rings, with respective widths of about 7 and 3 kilometres, optical depths of 0.4 and 0.06, and orbital radii of 391 and 405 kilometres. The present orientation of the ring is consistent with an edge-on geometry in 2008, which provides a simple explanation for the dimming of the Chariklo system between 1997 and 2008, and for the gradual disappearance of ice and other absorption features in its spectrum over the same period. This implies that the rings are partly composed of water ice. They may be the remnants of a debris disk, possibly confined by embedded, kilometre-sized satellites. © 2014 Macmillan Publishers Limited.Fil: Braga Ribas, F.. Observatório Nacional; BrasilFil: Sicardy, B.. Universite Pierre et Marie Curie; FranciaFil: Ortiz, J.L.. Consejo Superior de Investigaciones Científicas; EspañaFil: Snodgrass, C.. Max Planck Institute for Solar System Research; AlemaniaFil: Roques, F.. Universite Pierre et Marie Curie; FranciaFil: Vieira Martins, R.. Centre National de la Recherche Scientifique; Francia. Universidade Federal do Rio de Janeiro; BrasilFil: Camargo, J.I.B.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Assafin, M.. Universidade Federal do Rio de Janeiro; BrasilFil: Duffard, R.. Consejo Superior de Investigaciones Científicas; EspañaFil: Jehin, E.. Université de Liège; BélgicaFil: Pollock, J.. Appalachian State University; Estados UnidosFil: Leiva, R.. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Emilio, M.. Universidade Estadual de Ponta Grossa; BrasilFil: MacHado, D.I.. Universidade Estadual Do Oeste Do Pará; BrasilFil: Colazo, C.. Universidad Nacional de Córdoba; Argentina. Ministerio de Educación de la Provincia de Córdoba; ArgentinaFil: Lellouch, E.. Universite Pierre et Marie Curie; FranciaFil: Skottfelt, J.. University of Copenhagen; Dinamarca. Geological Museum; DinamarcaFil: Gillon, M.. Université de Liège; BélgicaFil: Ligier, N.. Universite Pierre et Marie Curie; FranciaFil: Maquet, L.. Universite Pierre et Marie Curie; FranciaFil: Benedetti Rossi, G.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Gomes, A. Ramos. Universidade Federal do Rio de Janeiro; BrasilFil: Kervella, P.. Universite Pierre et Marie Curie; FranciaFil: Monteiro, H.. Instituto de Física e Química; BrasilFil: Sfair, R.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Moutamid, M. El. Universite Pierre et Marie Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Tancredi, G.. Observatorio Astronómico Los Molinos; Uruguay. Universidad de la República; UruguayFil: Spagnotto, J.. Observatorio El Catalejo la Pampa; ArgentinaFil: Maury, A.. San Pedro de Atacama Celestial Explorations; ChileFil: Morales, N.. Consejo Superior de Investigaciones Científicas; EspañaFil: Gil Hutton, Ricardo Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico ; ArgentinaFil: Roland, S.. Observatorio Astronómico Los Molinos; UruguayFil: Ceretta, A.. Universidad de la República; Uruguay. Observatorio del IPA; UruguayFil: Gu, S.-H.. Chinese Academy of Sciences; República de ChinaFil: Wang, X.-B.. Chinese Academy of Sciences; República de ChinaFil: Harpsøe, K.. University of Copenhagen; Dinamarca. Geological Museum; DinamarcaFil: Rabus, M.. Universidad Católica de Chile; Chile. Pontificia Universidad Católica de Chile; Chile. Max Planck Institute for Astronomy; AlemaniaFil: Manfroid, J.. Université de Liège; BélgicaFil: Opitom, C.. Université de Liège; BélgicaFil: Vanzi, L.. Pontificia Universidad Católica de Chile; Chile. Universidad Católica de Chile; ChileFil: Mehret, L.. Universidade Estadual de Ponta Grossa;Fil: Lorenzini, L.. Polo Astronômico Casimiro Montenegro Filho; BrasilFil: Schneiter, E.M.. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Iate-conicet; ArgentinaFil: Melia, R.. Universidad Nacional de Córdoba; ArgentinaFil: Lecacheux, J.. Universite Pierre et Marie Curie; FranciaFil: Colas, F.. Centre National de la Recherche Scientifique; FranciaFil: Vachier, F.. Centre National de la Recherche Scientifique; FranciaFil: Widemann, T.. Universite Pierre et Marie Curie; FranciaFil: Almenares, L.. Universidad de la República; Uruguay. Observatorio Astronomico Los Molinos; UruguayFil: Sandness, R.G.. San Pedro de Atacama Celestial Explorations; ChileFil: Char, F.. Universidad de Antofagasta; ChileFil: Perez, V.. Universidad de la República; Uruguay. Observatorio Astronomico Los Molinos; UruguayFil: Lemos, P.. Universidad de la República; Uruguay. Observatorio Astronomico Los Molinos; UruguayFil: Martinez, N.. Universidad de la República; Uruguay. Observatorio Astronomico Los Molinos; UruguayFil: Jørgensen, U.G.. Universidad de Copenhagen; DinamarcaFil: Dominik, M.. University of St. Andrews; Reino UnidoFil: Roig, F.. Ministério de Ciencia, Tecnologia e Innovacao. Observatorio Nacional; BrasilFil: Reichart, D.E.. University of North Carolina; Estados UnidosFil: Lacluyze, A.P.. University of North Carolina; Estados UnidosFil: Haislip, J.B.. University of North Carolina; Estados UnidosFil: Ivarsen, K.M.. University of North Carolina; Estados UnidosFil: Moore, J.P.. University of North Carolina; Estados UnidosFil: Frank, N.R.. University of North Carolina; Estados UnidosFil: Garcia Lambas, Diego Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Astronomía Teórica y Experimental. Universidad Nacional de Córdoba. Observatorio Astronómico de Córdoba. Instituto de Astronomía Teórica y Experimental; Argentin