Therapeutic Targeting of TGFβ Ligands in Glioblastoma Using Novel Antisense Oligonucleotides Reduces the Growth of Experimental Gliomas

PURPOSE Transforming growth factor (TGF)-β is expressed at high levels by glioma cells and contributes to the malignant phenotype of glioblastoma. However, its therapeutic targeting remains challenging. Here, we examined an alternative therapeutic approach of TGFβ inhibition using two novel phosphorothioate-locked nucleic acid (LNA)-modified antisense oligonucleotide gapmers, ISTH1047 and ISTH0047, which specifically target TGFβ and TGFβ. EXPERIMENTAL DESIGN We characterized the effects of ISTH1047 and ISTH0047 on TGFβ expression, downstream signaling and growth of human LN-308, LN-229, and ZH-161 cells as well as murine SMA-560 glioma cells . Furthermore, we assessed their target inhibition and effects on survival in orthotopic xenogeneic and syngeneic rodent glioma models . RESULTS Both antisense oligonucleotides specifically silenced their corresponding target and abrogated SMAD2 phosphorylation in several glioma cell lines. Moreover, inhibition of TGFβ or TGFβ expression by ISTH1047 or ISTH0047 reduced the migration and invasiveness of LN-308 and SMA-560 glioma cells. Systemic antisense oligonucleotide administration to glioma-bearing mice suppressed or mRNA expression as well as the expression of the downstream target in orthotopic gliomas. Glioma-bearing mice had significantly prolonged survival upon systemic treatment with ISTH1047 or ISTH0047, which was associated with a reduction of intratumoral SMAD2 phosphorylation and, in a fully immunocompetent model, with increased immune cell infiltration. CONCLUSIONS Targeting TGFβ expression with the novel LNA antisense oligonucleotides ISTH1047 or ISTH0047 results in strong antiglioma activity and , which may represent a promising approach to be examined in human patients with glioma

TGF-β1 and TGF-β2 abundance in liver diseases of mice and men

TGF-β1 is a major player in chronic liver diseases promoting fibrogenesis and tumorigenesis through various mechanisms. The expression and function of TGF-β2 have not been investigated thoroughly in liver disease to date. In this paper, we provide evidence that TGF-β2 expression correlates with fibrogenesis and liver cancer development. Using quantitative realtime PCR and ELISA, we show that TGF-β2 mRNA expression and secretion increased in murine HSCs and hepatocytes over time in culture and were found in the human-derived HSC cell line LX-2. TGF-β2 stimulation of the LX-2 cells led to upregulation of the TGF-β receptors 1, 2, and 3, whereas TGF-β1 treatment did not alter or decrease their expression. In liver regeneration and fibrosis upon CCl4 challenge, the transient increase of TGF-β2 expression was accompanied by TGF-β1 and collagen expression. In bile duct ligation-induced fibrosis, TGF-β2 upregulation correlated with fibrotic markers and was more prominent than TGF-β1 expression. Accordingly, MDR2-KO mice showed significant TGF-β2 upregulation within 3 to 15 months but minor TGF-β1 expression changes. In 5 of 8 hepatocellular carcinoma (HCC)/hepatoblastoma cell lines, relatively high TGF-β2 expression and secretion were observed, with some cell lines even secreting more TGF-β2 than TGF-β1. TGF-β2 was also upregulated in tumors of TGFα/cMyc and DEN-treated mice. The analysis of publically available microarray data of 13 human HCC collectives revealed considerable upregulation of TGF-β2 as compared to normal liver. Our study demonstrates upregulation of TGF-β2 in liver disease and suggests TGF-β2 as a promising therapeutic target for tackling fibrosis and HCC

Regional-scale climate-variability synchrony of cholera epidemics in West Africa

BACKGROUND: The relationship between cholera and climate was explored in Africa, the continent with the most reported cases, by analyzing monthly 20-year cholera time series for five coastal adjoining West African countries: Côte d'Ivoire, Ghana, Togo, Benin and Nigeria. METHODS: We used wavelet analyses and derived methods because these are useful mathematical tools to provide information on the evolution of the periodic component over time and allow quantification of non-stationary associations between time series. RESULTS: The temporal variability of cholera incidence exhibits an interannual component, and a significant synchrony in cholera epidemics is highlighted at the end of the 1980's. This observed synchrony across countries, even if transient through time, is also coherent with both the local variability of rainfall and the global climate variability quantified by the Indian Oscillation Index. CONCLUSION: Results of this study suggest that large and regional scale climate variability influence both the temporal dynamics and the spatial synchrony of cholera epidemics in human populations in the Gulf of Guinea, as has been described for two other tropical regions of the world, western South America and Bangladesh

The Wnt-dependent signaling pathways as target in oncology drug discovery

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways

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"Que reste-t-il de la loi du 2 mars 1982 ?"

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"La loi 3DS. Les institutions et les compétences"

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Droit des collectivités territoriales

Le droit des collectivités territoriales est devenu une discipline juridique à part entière et il est enseigné en tant que tel dans tous les établissements d'enseignement supérieur, facultés ou instituts. Il est au programme de la quasi-totalité des concours.La décentralisation qu'il s'agisse de son acte I des années 1980, de son acte II à partir de 2002 ou des réformes entreprises depuis 2010 , a profondément modifié cette branche du droit et a contribué à lui donner une autonomie et une diversité sans précédent. Les collectivités territoriales, dotées d'une existence constitutionnelle renforcée par la révision de 2003, ont acquis à la fois des compétences et des moyens nouveaux. Leurs organes ont vu leur mode de désignation et leur statut profondément renouvelés. Leurs agents sont devenus des fonctionnaires territoriaux et l'autonomie financière des collectivités est consacrée. Malgré les alternances politiques que la France a connues, le législateur a cherché à adapter l'organisation territoriale du pouvoir local, en métropole ou dans la France d'outre-mer. La crise économique a néanmoins conduit les pouvoirs publics nationaux à orienter ces réformes dans le sens d'une meilleure utilisation des deniers publics.Le présent ouvrage vise à répondre à l'attente des étudiants en droit, en science politique et en administration économique et sociale et de tous ceux qui se destinent aux carrières administratives, en leur donnant une vision globale et actualisée de la matière. Il s'adresse aussi à tous ceux qui s'intéressent à la vie locale, qu'il s'agisse des élus, des agents ou des citoyens. Il est à jour des dernières lois de l'année 2015

Droit des collectivités territoriales

2ème éditionInternational audienceLe droit des collectivités territoriales est désormais une discipline juridique à part entière et il est enseigné en tant que tel, dans les établissements d'enseignement supérieur, facultés de droit ou instituts d'études politiques.Les réformes décentralisatrices initiées à partir de 1982 ont profondément modifié son approche, son contenu et ses contentieux.Les collectivités territoriales, dotées d'une existence constitutionnelle renforcée par la révision de 2003, ont acquis des compétences et des moyens nouveaux. Les crises économiques et financières ont amené néanmoins l'État à corriger certaines politiques publiques, quitte, selon certains points de vue, à pratiquer une forme de re-centralisation.À jour des dernières réformes législatives, du projet de révision constitutionnelle, ainsi que des évolutions de la jurisprudence, le présent ouvrage est destiné aux étudiants, aux candidats aux concours administratifs, aux agents des collectivités, aux élus mais aussi à ceux qui travaillent avec et pour les collectivités décentralisées