MET: a promising anticancer therapeutic target.

The MET pathway is dysregulated in many human cancers and promotes tumour growth, invasion and dissemination. Abnormalities in MET signalling have been reported to correlate with poor clinical outcomes and drug resistance in patients with cancer. Thus, MET has emerged as an attractive target for cancer therapy. Several MET inhibitors have been introduced into the clinic, and are currently in all phases of clinical trials. In general, initial results from these studies indicate only a modest benefit in unselected populations. In this Review, we discuss current challenges in developing MET inhibitors--including identification of predictive biomarkers--as well as the most-efficient ways to combine these drugs with other targeted agents or with classic chemotherapy or radiotherapy.

Relations intergroupes : attribution à la discrimination et perception d'hostilité chez autrui

Résumé: La thèse que nous présentons s'intéresse aux phénomènes d'attribution d'intentions hostiles. Dodge (1980) observe que les individus agressifs ont tendance, en situation ambiguë, à sur-attribuer des intentions hostiles à leurs pairs, ce qui induit des réponses agressives. Pour l'auteur, l'attribution d'intentions hostiles est un médiateur entre certaines caractéristiques personnelles (l'agressivité) des individus, et le type de réponses qu'ils apportent aux situations. Cependant, les informations concernant l'appartenance groupale des "pairs" ne sont jamais prises en compte dans leurs études. Si ce processus est perméable à l'influence des normes et croyances (Bègue et Muller, 2006), aucune étude ne met en évidence quel serait l'impact d'informations groupales sur l'élaboration des réponses aux situations, dans le cadre de ce modèle. L'objectif de cette thèse est de montrer que l'attribution d'intentions hostiles peut être envisagée comme un processus agissant également à un niveau intergroupes et donc prenant en compte des informations groupales sur les individus. En s'inspirant du modèle de Dodge, nous avons émis l'hypothèse que les logiques intergroupes intervenaient dans l'interprétation des intentions des acteurs impliqués dans les interactions, afin de produire une réponse adaptée aux logiques intergroupes. Afin de tester cette hypothèse, nous avons suivi trois axes de recherches: Dans le premier de ces axes, nous avons introduit, dans le paradigme de Dodge, des informations .sur l'appartenance groupale des protagonistes de l'interaction (endogroupe vs exogroupe). Nous avons montré que le type de situation (ambiguë vs hostile) est moins important que l'information groupale dans la production d'une réponse à la situation (Étude 1). En outre, nous avons mis en évidence des processus différents selon la position des individus dans leur groupe (Étude 2). Dans le second axe, nous avons montré que si les différences de statut entre groupes n'influençaient pas directement le modèle de Dodge, elles interagissaient avec l'appartenance groupale et la clarté de la situation au niveau de l'attribution d'intentions hostiles (étude 3) et des intentions comportementales (Ettide 4). Dans le troisième et deriúer axe, nous avons introduit l'attribution d'intentions hostiles dans un processus de dévalorisation d'une cible expliquant un échec par la discrimination (Kaiser et Miller, 2001; 2003). Nous avons alors montré que l'attribution d'intentions hostiles médiatisait le lien entre l'attribution mobilisée pour expliquer l'événement et l'évaluation de la cible (Étude 5), et que ce type d'attribution était spécifique, aux intentions comportementales agressives (Études 6). Nous avons alors conclu sur la dimension sociale de l'attribution d'intentions hostiles et sur le fait qu'il s'agissait d'un élément permettant la construction d'une représentation des interactions sociales. Abstract The present thesis focuses on the phenomena of hostile intents attribution. Dodge (1980) observes that in ambiguous situations, aggressive people tend to over attribute hostile intents to others. This attribution leads them to respond aggressively. According to the author, hostile intents attribution mediates the link between some personal characteristics (aggressiveness for example) of individuals and their responses to the situation. However information related to participants group membership is always neglected in these studies. Begue and Muller (2006) showed that some beliefs could moderate the interaction between aggressiveness and hostile intents attribution on behaviors, but no study exhibited evidence of a similar effect with social information. The aim of this thesis is to show that hostile intents attribution needs to be considered at an intergroup level by taking into account people's group ineinbership. Based on the Dodge model, we formulated the hypothesis that intergroup strategies had an impact on actors' intents interpretations which in return should lead to different but adapted reactions to the situation. To test this hypothesis, three lines of research were developed. In the first line, we introduced, in the Dodge's paradigm, some information about the participants group membership (ingroup vs outgroup). We showed that when elaborating a response to a specific situation its nature (ambiguous vs hostile) had less impact than group membership information (Study 1). In addition, we highlighted some different processes according to the position of individuals in their group (Study 2). In the second line, we showed that if the differences between groups status didn't influence the Dodge model, they interacted with group membership and situation nature to influence hostile intents attribution (Study 3) and behaviors intents (Study 4). In the last line of research, we introduced hostile intents attribution within the process of derogation of a target explaining its failure by discrimination (Kaiser and Miller, 2001; 2003). We showed that hostile intents attribution mediated the link between the attibution mobilized to explain the failure and the derogation of the target (Study 5), and that this attribution type was specifically linked to aggressive behavior intents (Study 6). We finally concluded that hostile intents attribution imply an important social dimension which needs to be taken into account because involved in the construction of a representation of social interactions.

A Soft Edge Target Zone Model: Theory And Application To Hong Kong

Hong Kong’s currency is pegged to the US dollar in a currency board arrangement. In autumn 2003, the Hong Kong dollar appreciated from close to 7.80 per US dollar to 7.70, as investors feared that the currency board would be abandoned. In the wake of this appreciation, the monetary authorities revamped the one-sided currency board mechanism into a symmetric two-sided system with a narrow exchange rate band. This paper reviews the characteristics of the new currency board arrangement and embeds a theoretical soft edge target zone model typifying many intermediate regimes, to explain the notable achievement of speculative peace and credibility since May 2005.

The Export Base Model with a Supply-Side Stimulus to the Export Sector

Paper delivered at the Western Regional Science Association Annual Conference, Sedona, Arizona, February, 2010.

Off-the-Record Target Zones: Theory with an Application to Hong Kongs Currency Board

This paper provides a modelling framework for evaluating the exchange rate dynamics of a target zone regime with undisclosed bands. We generalize the literature to allow for asymmetric one-sided regimes. Market participants' beliefs concerning an undisclosed band change as they learn more about central bank intervention policy. We apply the model to Hong Kong's one-sided currency board mechanism. In autumn 2003, the Hong Kong dollar appreciated from close to 7.80 per US dollar to 7.70, as investors feared that the currency board would be abandoned. In the wake of this appreciation, the monetary authorities finally revamped the regime as a symmetric two-sided system with a narrow exchange rate band.

Time is Running Out: The 2°C Target and Optimal Climate Policies

The quintessence of recent natural science studies is that the 2 degrees C target can only be achieved with massive emission reductions in the next few years. The central twist of this paper is the addition of this limited time to act into a non-perpetual real options framework analysing optimal climate policy under uncertainty. The window-of-opportunity modelling setup shows that the limited time to act may spark a trend reversal in the direction of low-carbon alternatives. However, the implementation of a climate policy is evaded by high uncertainty about possible climate pathways.

Stress au travail et santé : situation chez les indépendants

Dans le cadre de l'activité professionnelle, des facteurs de stress d'ordre psychologique, social, et liés à l'organisation du travail, peuvent induire des réponses physiologiques et comportementales impliquées dans la survenue de pathologies comme les maladies cardiovasculaires, les troubles de la santé mentale et les troubles musculosquelettiques.Le Régime social des indépendants (RSI) a sollicité l'Inserm afin de disposer d'un bilan des connaissances sur le stress d'origine professionnelle chez les travailleurs indépendants et ses répercussions sur la santé.Regroupant à la fois des compétences en biologie, psychologie, sociologie et économie de la santé, cette expertise collective présente les modèles et les mécanismes explicatifs mettant en relation le stress au travail et les principales pathologies.Les stratégies de prévention individuelle et collective qui se développent dans le milieu des travailleurs salariés peuvent-elles être adaptées aux travailleurs indépendants ? [Ed.]

Pragmatic approach to nutrition in the ICU: Expert opinion regarding which calorie protein target.

BACKGROUND & AIMS: Since the publications of the ESPEN guidelines on enteral and parenteral nutrition in ICU, numerous studies have added information to assist the nutritional management of critically ill patients regarding the recognition of the right population to feed, the energy-protein targeting, the route and the timing to start. METHODS: We reviewed and discussed the literature related to nutrition in the ICU from 2006 until October 2013. RESULTS: To identify safe, minimal and maximal amounts for the different nutrients and at the different stages of the acute illness is necessary. These amounts might be specific for different phases in the time course of the patient's illness. The best approach is to target the energy goal defined by indirect calorimetry. High protein intake (1.5 g/kg/d) is recommended during the early phase of the ICU stay, regardless of the simultaneous calorie intake. This recommendation can reduce catabolism. Later on, high protein intake remains recommended, likely combined with a sufficient amount of energy to avoid proteolysis. CONCLUSIONS: Pragmatic recommendations are proposed to practically optimize nutritional therapy based on recent publications. However, on some issues, there is insufficient evidence to make expert recommendations.

The reasons for discrepancies in target volume delineation : a SASRO study on head-and-neck and prostate cancers.

PURPOSE: To understand the reasons for differences in the delineation of target volumes between physicians. MATERIAL AND METHODS: 18 Swiss radiooncology centers were invited to delineate volumes for one prostate and one head-and-neck case. In addition, a questionnaire was sent to evaluate the differences in the volume definition (GTV [gross tumor volume], CTV [clinical target volume], PTV [planning target volume]), the various estimated margins, and the nodes at risk. Coherence between drawn and stated margins by centers was calculated. The questionnaire also included a nonspecific series of questions regarding planning methods in each institution. RESULTS: Fairly large differences in the drawn volumes were seen between the centers in both cases and also in the definition of volumes. Correlation between drawn and stated margins was fair in the prostate case and poor in the head-and-neck case. The questionnaire revealed important differences in the planning methods between centers. CONCLUSION: These large differences could be explained by (1) a variable knowledge/interpretation of ICRU definitions, (2) variable interpretations of the potential microscopic extent, (3) difficulties in GTV identification, (4) differences in the concept, and (5) incoherence between theory (i.e., stated margins) and practice (i.e., drawn margins).

Onchocerciasis in Ecuador: the situation in 1989

Details are given of the prevalence rates of onchocerciasis from the most recent surveys (1989) conducted in northern Ecuador. The disease has intensified and dispersed considerably due to migration of infected individuals and the presence of a highly efficient vector. Comparison of these data with those from two previous surveys carried out in 1982/83 and 1986 and correlated with entomological findings highly the danger of the formation of new foci of onchocerciasis in areas currently free of the disease. Recommendations are made for further entomological studies in areas either recently or likely to be affected by the disease where potential vectors are unknown or different to those registred in the Santiago focus. Invermectin treatment with local vector control in specific areas is advocated to reduce the disease to a low level of public health importance.

Is the thymus a target organ in infectious diseases?

The thymus is a central lymphoid organ, in wich T cell precursors differentiale and generate most of the so-called T cell reprtoire. Along with a variety of acute infectious diseases, we and others determined important changes in both microenvironmental and lymphoid compartments of the organ. For example, one major and common feature observed in acute viral, bacterial and parasitic diseases, is a depletion of cortical thymocytes, mostly those bearing the CD4-CD8 double positive phenotype. This occurs simmultaneously to the relative enrichment in medullary CD4 or CD8 single positive cells, expressing high densities of the CD3 complex. Additionally we noticed a variety of changes in the thymic microenvironment (and particularly is epithelial component), comprising abnormal location of thymic epithelial cell subsets as well has a denser Ia-bearing cellular network. Moreover, the extracellular matrix network was altered with an intralobular increase of basement membrane proteins that positively correlated with the degree of thymocyte death. Lastly, anti-thymic cell antibodies were detected in both human and animal models of infectious diseases, and in some of them a phenomenon of molecular mimicry could be evidenced. Taken together, the data receiwed herein clearly show that the thymus should be regarded as a target in infectious diseases.

Endothelial Cell-Derived Nitric Oxide Enhances Aerobic Glycolysis in Astrocytes via HIF-1α-Mediated Target Gene Activation.

Astrocytes exhibit a prominent glycolytic activity, but whether such a metabolic profile is influenced by intercellular communication is unknown. Treatment of primary cultures of mouse cortical astrocytes with the nitric oxide (NO) donor DetaNONOate induced a time-dependent enhancement in the expression of genes encoding various glycolytic enzymes as well as transporters for glucose and lactate. Such an effect was shown to be dependent on the hypoxia-inducible factor HIF-1α, which is stabilized and translocated to the nucleus to exert its transcriptional regulation. NO action was dependent on both the PI3K/Akt/mTOR and MEK signaling pathways and required the activation of COX, but was independent of the soluble guanylate cyclase pathway. Furthermore, as a consequence of NO treatment, an enhanced lactate production and release by astrocytes was evidenced, which was prevented by downregulating HIF-1α. Several brain cell types represent possible sources of NO. It was found that endothelial cells, which express the endothelial NO synthase (eNOS) isoform, constitutively produced the largest amount of NO in culture. When astrocytes were cocultured with primary cultures of brain vascular endothelial cells, stabilization of HIF-1α and an enhancement in glucose transporter-1, hexokinase-2, and monocarboxylate transporter-4 expression as well as increased lactate production was found in astrocytes. This effect was inhibited by the NOS inhibitor l-NAME and was not seen when astrocytes were cocultured with primary cultures of cortical neurons. Our findings suggest that endothelial cell-derived NO participates to the maintenance of a high glycolytic activity in astrocytes mediated by astrocytic HIF-1α activation.

Sobolev mappings: Lipschitz density is not an isometric invariant of the target

"Vegeu el resum a l'inici del document del fitxer adjunt."

Dengue in Brazil - situation, transmission and control: a proposal for ecological control

This article discusses dengue in terms of its conceptual and historical aspects, epidemiological and clinical/pathological nature, and evolution up to the present situation in Brazil. The author discusses the ecological relationship in both the production of dengue and its control. Comparison is made between traditional dengue-control programs and a proposed socially-controlled program of an ecological nature without the use of insecticides. Stress is placed on interdisciplinary technical and scientific activity, broadbased participation by communities in discussing methodological aspects involving them, and prospective evaluation comparing the communities selected for intervention and control communities with regard to clinical and subclinical dengue cases and vector infestation rates in relation to climatic, socio-economic, and behavioural factors.