Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells

Le cancer colorectal est la 3ème cause de décès liée au cancer dans l'Europe de l'Ouest et nécessite une prise en charge pluridisciplinaire. Les thérapies anticancéreuses récentes développées visent à inhiber les voies de signalisation cellulaires responsables de la prolifération des cellules tumorales. L'inhibition de la voie de signalisation cellulaire mTOR, est une stratégie prometteuse. En effet, mTOR est souvent suractivé dans les cellules du cancer colorectal et régule la croissance, la prolifération et la survie cellulaire. De nombreuses études récentes ont démontrés l'importance de l'activité de mTOR dans le développement du cancer colorectal et l'efficacité anti-tumorale des inhibiteurs allostériques de mTOR, telle que la rapamycine. Récemment, une nouvelle classe d'inhibiteur de mTOR, notamment PP242 et NVP-BEZ235, agissant comme inhibiteur ATP- compétitif a été développée. L'efficacité de ces inhibiteurs n'a pas été démontrée dans le contexte du cancer colorectal. Dans cette étude, nous avons comparé l'effet de PP242, un inhibiteur ATP-compétitif de mTOR et NVP-BEZ235, un inhibiteur dual de PI3K/mTOR par rapport à la rapamycine. Nous avons étudié, in vitro, leur effet sur la croissance, la prolifération et la survie cellulaire sur des lignées cellulaires du cancer du colon (LS174, SW480 et DLD-1) et, in vivo, sur la croissance de xénogreffes dans un modèle murin. Nous avons émis l'hypothèse que l'effet des ces nouveaux inhibiteurs seraient plus importants qu'avec la rapamycine. Nous avons observé que le PP242 et le NVP-BEZ235 réduisent significativement et de façon plus marquée que la rapamycine la croissance, la prolifération et la survie cellulaire des cellules LS174T et DLD-1. Ces inhibiteurs réduisent également la prolifération et la survie cellulaire des cellules SW480 alors que celles-ci étaient résistantes à la rapamycine. Nous avons également observé que les inhibiteurs PP242 et NVP-BEZ235 réduisaient la croissance des xénogreffes avec les lignées cellulaires LS174 et SW480. Finalement, nous avons remarqué que l'effet anti-tumoral des inhibiteurs ATP-compétitifs de mTOR était potentialisé par l'U0126, un inhibiteur de MEK/MAPK, souvent activé dans les voies de signalisation cellulaire du cancer colorectal. En conclusion, nous avons observé que les inhibiteurs ATP-compétitifs de mTOR bloquent la croissance de cellules tumorales du cancer colorectal in vitro et in vivo. Ces résultats démontrent que ces inhibiteurs représentent une option thérapeutique prometteuse dans le traitement du cancer colorectal et méritent d'être évalués dans des études cliniques.

Changes in a Rhodic Hapludox under no-tillage and urban waste compost in the northwest of Rio Grande do Sul, Brazil

The use of urban waste compost as nutrient source in agriculture has been a subject of investigation in Brazil and elsewhere, although the effects on soil physical and chemical properties and processes are still poorly known. The aim of this study was to evaluate the effect of application of urban waste compost and mineral fertilizer on soil aggregate stability and organic carbon and total nitrogen content of a Rhodic Hapludox under no-tillage in the northwestern region of Rio Grande do Sul, Brazil, in the 2009/2010 and 2010/2011 growing seasons. The experiment was arranged in a 2 × 6 (seasons and fertilization) factorial in a randomized complete block design with four replications. The factor time consisted of two growing seasons (sunflower in 2009/10 and maize in 2010/11) and the factor fertilization of five rates of urban waste compost (0, 25, 50, 75 and 100 m³ ha-1), and mineral fertilizer. Soil samples were collected from the 0.0-0.10 m layer to determine aggregate stability (mean weight and geometric diameter), soil organic carbon (SOC) and total nitrogen (TN). Rates of up to 75 m³ ha-1 of urban waste compost, after two years of application to no-tillage maize and sunflower, improved aggregation compared to mineral fertilization in a Rhodic Hapludox. After the second crop, the SOC and TN contents increased linearly with the levels of urban waste compost.

Affaires de patrons, usages de la frontière : géographie des réseaux marchands entre Niger, Bénin et Nigéria

Résumé L'objectif de la thèse est de comprendre le mode d'organisation économique spécifique aux petits centres urbains qui composent les espaces frontaliers sahéliens, en s'interrogeant sur leur concurrence ou leur complémentarité éventuelle à l'intérieur d'un régime de spatialité particulier. En s'appuyant sur l'exemple du carrefour économique de Gaya-Malanville-Kamba situé à la frontière entre le Niger, le Bénin et le Nigeria, il questionne le rôle de la ville-frontière ainsi que le jeu des acteurs marchands localement dominants, à partir de quatre grandes interrogations : Quelles sont les spécificités de l'Afrique sahélienne qui obligent à renouveler les approches géographiques de l'espace marchand? Quels sont les facteurs déterminants de l'activité économique frontalière? Les formes d'organisation de l'espace qui concourent à la structuration de l'économie sont-elles concurrentes ou coopératives? Les logiques économiques frontalières sont-elles compatibles avec l'orientation des programmes de développement adoptés par les pays sahéliens et leurs partenaires bi- ou multilatéraux? Dans une première partie, un modèle territorial de l'Afrique sahélienne permet de rendre compte de la prédominance des logiques circulatoires sur les logiques productives, une propriété essentielle de toute organisation économique confrontée à l'instabilité climatique. Dans une seconde partie, l'étude considère les facteurs déterminants de l'activité économique frontalière que sont le degré d'enclavement des territoires, la libre circulation des biens et des personnes, les relations concurrentielles ou coopératives qui lient les marchés ainsi que les liens clientélistes qui unissent patron et obligés. Une troisième partie est consacrée aux productions agricoles de tente organisées sous forme de coopératives paysannes ou d'initiatives privées. Une quatrième partie s'intéresse aux réseaux de l'import-export et du commerce de détail qui bénéficient de l'augmentation des besoins engendrée par l'urbanisation sahélienne. L'économie spatiale qui résulte de ces flux est organisée selon deux logiques distinctes : d'une part, les opportunités relatives à la production agricole conduisent certains investisseurs à intensifier l'irrigation pour satisfaire la demande des marchés urbains, d'autre part, les acteurs du capitalisme marchand, actifs dans l'import-export et la vente de détail, développent des réseaux informels et mobiles qui se jouent des différentiels nationaux. Les activités commerciales des villes-marchés connaissent alors des fluctuations liées aux entreprises productives et circulatoires de ces patrons, lesquelles concourent à l'organisation territoriale générale de l>Afrique sahélienne. Ces logiques évoluent dans un contexte fortement marqué par les politiques des institutions financières internationales, des agences bilatérales de coopération et des ONGs. Celles-ci se donnent pour ambition de transformer les économies, les systèmes politiques et les organisations sociales sahéliennes, en faisant la promotion du libéralisme, de la bonne gouvernance et de la société civile. Ces axes directeurs, qui constituent le champ de bataille contemporain du développement, forment un ensemble dans lequel la spécificité sahélienne notamment frontalière est rarement prise en compte. C'est pourquoi l'étude conclut en faveur d'un renouvellement des politiques de développement appliquées aux espaces frontaliers. Trois grands axes d'intervention peuvent alors être dégagés, lesquels permettent de réconcilier des acteurs et des logiques longtemps dissociés: ceux des espaces séparés par une limite administrative, ceux de la sphère urbaine et rurale et ceux du capitalisme marchand et de l'investissement agricole, en renforçant la coopération économique transfrontalière, en prenant en considération les interactions croissantes entre villes et campagnes et en appuyant les activités marchandes. Abstract: Urbanisation in West Africa is recent and fast. If only 10 % of the total population was living in urban areas in 1950, this proportion reached 40 % in 2000 and will be estimated to 60 % in 2025. Small and intermediate cities, located between the countryside and large metropolis, are particularly concerned with this process. They are nowadays considered as efficient vectors of local economic development because of fiscal or monetary disparities between states, which enable businessmen to develop particular skills based on local urban networks. The majority of theses networks are informal and extremely flexible, like in the Gaya - Malanville - Kamba region, located between Niger, Benin and Nigeria. Evidence show that this economic space is characterised by high potentialities (climatic and hydrological conditions, location on main economic West African axis) and few constraints (remoteness of some potentially high productive areas). In this context, this PhD deals with the economic relationships between the three market cities. Focusing on the links that unite the businessmen of the local markets - called patron; - it reveals the extreme flexibility of their strategies as well as the deeply informal nature of their activities. Through the analysis of examples taken from the commerce of agricultural products, import and export flows and detail activities, it studies the changes that have taken place in the city centres of Gaya, Malanville and Kamba. Meanwhile, this research shows how these cities represent a border economical area based on rival and complementary connections. In the first Part, it was necessary to reconsider the usual spatial analysis devoted to the question of economic centrality. As a matter of fact, the organisation of West African economic spaces is very flexible and mobile. Centrality is always precarious because of seasonal or temporary reasons. This is why the first chapters are devoted to the study of the specificity of the Sahelian territoriality. Two main elements are relevant: first the population diversity and second, the urban-rural linkages. In the second part, the study considers three main factors on which the cross-border economic networks are dependent: enclosure that prevents goods to reach the markets, administrative constraints that limit free trade between states and cities and the concurrent or complementary relationships between markets. A third part deals with the clientelist ties engaged between the patrons and their clients with the hypothesis that these relationships are based on reciprocity and inequality. A fourth part is devoted to' the study of the spatial organisation of commercial goods across the borders, as far as the agriculture commercial products, the import-export merchandises and the retail products are concerned. This leads to the conclusion that the economic activity is directly linked to urban growth. However, the study notices that there is a lack of efficient policies dealing with strengthening the business sector and improving the cross-border cooperation. This particularity allows us to favour new local development approaches, which would take into account the important potential of private economical actors. In the same time, the commercial flows should be regulated with the help of public policies, as long as they are specifically adapted to the problems that these areas have to deal with.

Psychiatric co-morbidities and cardiovascular risk factors in people with lifetime history of epilepsy of an urban community.

OBJECTIVES: Depression has been consistently reported in people with epilepsy. Several studies also suggest a higher burden of cardiovascular diseases. We therefore analysed psychosocial co-morbidity and cardiovascular risk factors in patients with a lifetime history of epilepsy in the PsyCoLaus study, a Swiss urban population-based assessment of mental health and cardiovascular risk factors in adults aged between 35 and 66 years. PATIENTS AND METHODS: Among 3719 participants in the PsyCoLaus study, we retrospectively identified those reporting at least 2 unprovoked seizures, defined as epilepsy. These subjects were compared to all others regarding psychiatric, social, and cardiovascular risk factors data using uni- and multivariable assessments. RESULTS: A significant higher need for social help (p<0.001) represented the only independent difference between 43 subjects with a history of epilepsy and 3676 controls, while a higher prevalence of psychiatric co-morbidities (p=0.015) and a lower prevalent marital status (p=0.01) were only significant on univariate analyses. Depression and cardio-vascular risk factors, as well as educational level and employment, were similar among the groups. CONCLUSIONS: This analysis confirms an increased prevalence of psychosocial burden in subjects with a lifetime history of epilepsy; conversely, we did not find a higher cardiovascular risk. The specific urban and geographical location of our cohort and the age span of the studied population may account for the differences from previous studies.

Roadway Design Standards for Rural and Suburban Subdivisions Final Report, June 2007

In Iowa, there are currently no uniform design standards for rural and suburban subdivision development roadways. Without uniform design standards, many counties are unable to provide adequate guidance for public facilities, particularly roadways, to be constructed as part of a rural subdivision development. If a developer is not required to install appropriate public improvements or does not do so properly, significant liability and maintenance expenses can be expected, along with the potential for major project costs to correct the situation. Not having uniform design standards for rural and suburban subdivision development improvements in Iowa creates situations where there is potential for inconsistency and confusion. Differences in the way development standards are applied also create incentives or disincentives for developers to initiate subdivision platting in a particular county. With the wide range of standards or lack of standards for local roads in development areas, it is critical that some level of uniformity is created to address equity in development across jurisdictional lines. The standards must be effective in addressing the problem, but they must not be so excessive as to curtail development activities within a local jurisdiction. In order to address the concerns, cities and counties have to work together to identify where growth is going to be focused. Within that long-term growth area, the roadways should be constructed to urban standards to provide an easier transition to traditional urban facilities as the area is developed. Developments outside of the designated growth area should utilize a rural cross section since it is less likely to have concentrated urban development. The developers should be required to develop roadways that are designed for a minimum life of 40 years, and the county should accept dedication of the roadway and be responsible for its maintenance.

Risk Mitigation Strategies for Operations and Maintenance Activities, Final Report, April 2012

The objective of this research was to investigate the application of integrated risk modeling to operations and maintenance activities, specifically moving operations, such as pavement testing, pavement marking, painting, snow removal, shoulder work, mowing, and so forth. The ultimate goal is to reduce the frequency and intensity of loss events (property damage, personal injury, and fatality) during operations and maintenance activities. This report includes a literature review that identifies the current and common practices adopted by different state departments of transportation (DOTs) and other transportation agencies for safe and efficient highway operations and maintenance (O/M) activities. The final appendix to the report includes information for eight innovative O/M risk mitigation technologies/equipment and covers the following for these technologies/equipment: Appropriate conditions for deployment Performance/effectiveness, depending on hazard/activity Cost to purchase Cost to operate and maintain Availability (resources and references)

Assessment of Medicaid and SCHIP Quality Improvement Activities for the State of Iowa, September, 2008

CMS has established the medicaid Quality Improvement which serves to fulfill the objectives of they Medicaid Quality goal established through the Federal Government Performance and Results At. One of the objectives of the goal calls for the Centers foe Medicare and Medicaid Services to work in partnership with State Medicaid Directors to develop a Nation Medicaid Quality Framework that will articulate broad principles and a common vision of quality for the program.

Review of targeted small business procurement activities for the year ended June 30, 2012

Review of targeted small business procurement activities for the year ended June 30, 2012

Activities of amino acid metabolizing enzymes in the stomach and small intestitine of developing rats

The activities of aspartate and alanine transaminase, serine dehydratase, arginase, glutamate dehydrogenase, adenylate deaminase and glutamine synthetase were determined in the stomach and small intestine of developing rats. Despite the common embryonic origin of the intestine and stomach, their enzymes showed quite different activity levels and patterns of development, depending on their roles. Most enzyme activities were low during late intrauterine life and after birth, attaining adult levels with the change of diet at weaning. No arginase activity was found in the stomach and no changes were detected in adenylate deaminase in the stomach or intestine throughout the period studied. Alanine transaminase, serine dehydratase and, to some extent, glutamine synthetase levels, significantly higher in late intrauterine life, decreased after birth, suggesting that the foetal stomach has a transient ability to handle amino acids.

Factors influencing privatization of urban solid waste collection: some evidence from Spain

In this paper we analyse some of the organisational aspects of the urban solid waste collection and, in particular, the privatization modality of contracting out. We start by discussing some of the theoretical aspects of contracting out. We then specify and estimate an explanatory model on a sample of municipalities that we surveyed. Our purpose is twofold: on the one hand, we identify the economic factors at work when deciding to contract out the service and, on the other hand, we analyse the role of ideological factors in choosing between the public production of the service or contracting it out. The results show a significant effect of the demand for waste collection on contracting out. There also appears to be a neighbouring effect as the municipalities close to other cities that contract out are also more prone to do so. Finally, the decisions to contract seem to have been motivated by pragmatic rather than ideological reasons.