Anaplastic lymphoma kinase (ALK) inhibitor response in neuroblastoma is highly correlated with ALK mutation status, ALK mRNA and protein levels

Background In pediatric neuroblastoma (NBL), high anaplastic lymphoma kinase (ALK) levels appear to be correlated with an unfavorable prognosis, regardless of ALK mutation status. This suggests a therapeutic role for ALK inhibitors in NBL patients. We examined the correlation between levels of ALK, phosphorylated ALK (pALK) and downstream signaling proteins and response to ALK inhibition in a large panel of both ALK mutated and wild type (WT) NBL cell lines. Methods We measured protein levels by western blot and ALK inhibitor sensitivity (TAE684) by viability assays in 19 NBL cell lines of which 6 had a point mutation and 4 an amplification of the ALK gene. Results ALK 220 kDa (p=0.01) and ALK 140 kDa (p= 0.03) protein levels were higher in ALK mutant than WT cell lines. Response to ALK inhibition was significantly correlated with ALK protein levels (p<0.01). ALK mutant cell lines (n=4) were 14,9 fold (p<0,01) more sensitive to ALK inhibition than eight WT cell lines. Conclusion NBL cell lines often express ALK at high levels and are responsive to ALK inhibitors. Mutated cell lines express ALK at higher levels, which may define their superior response to ALK inhibition

Anaplastic Lymphoma Kinase Is Required for Neurogenesis in the Developing Central Nervous System of Zebrafish

10.1371/journal.pone.0063757PLoS ONE85

The Receptor Tyrosine Kinase Alk Controls Neurofibromin Functions in Drosophila Growth and Learning

Anaplastic Lymphoma Kinase (Alk) is a Receptor Tyrosine Kinase (RTK) activated in several cancers, but with largely unknown physiological functions. We report two unexpected roles for the Drosophila ortholog dAlk, in body size determination and associative learning. Remarkably, reducing neuronal dAlk activity increased body size and enhanced associative learning, suggesting that its activation is inhibitory in both processes. Consistently, dAlk activation reduced body size and caused learning deficits resembling phenotypes of null mutations in dNf1, the Ras GTPase Activating Protein-encoding conserved ortholog of the Neurofibromatosis type 1 (NF1) disease gene. We show that dAlk and dNf1 co-localize extensively and interact functionally in the nervous system. Importantly, genetic or pharmacological inhibition of dAlk rescued the reduced body size, adult learning deficits, and Extracellular-Regulated-Kinase (ERK) overactivation dNf1 mutant phenotypes. These results identify dAlk as an upstream activator of dNf1-regulated Ras signaling responsible for several dNf1 defects, and they implicate human Alk as a potential therapeutic target in NF1

Society as Cloud

Ce livre se déroule, comme une peinture de paysage chinois que le regard parcourt lentement. J’utilise cette forme car je décris un panorama. Il n’est pas fait de montagnes dans la brume ou de buissons balayés par le vent, mais de centres de traitement de données, d’entrepôts de livraison, de flux de réseaux sociaux…J’explore l’hypothèse qu’Internet s’inscrit dans un mouvement général de réduction de la société à des composants de petite échelle, ce qui permet une fluidification de ses mécanismes. Une idée de chimiste – la décomposition en poudre de la matière permettant de faciliter sa recomposition – est également appliquée aux relations sociales, à la mémoire, à l’humain en général.Tout comme la réduction en poudre de la matière permet d’accélérer les réactions chimiques, la réduction en poudre de la société permet une décomposition et une recomposition accélérée de la matière dont est faite l’humain. Elle permet de multiplier les réactions au sein de la société, les productions de l’humanité, la chimie sociale : combinatoire des passions (Charles Fourier), hyperfragmentation du travail (Mechanical Turk), décomposition du savoir (Paul Otlet), Internet des neurones (Michael Chorost), société par agrégation des micro affects (Facebook). C’est ce que j’appelle la « société-nuage »This book unfolds, like a Chinese landscape painting through which the viewer’s gaze wanders slowly. I describe a panorama. It is not made of mountains in the mist or bushes swept by the wind, but of data centers, automated warehouses, social network feeds...I explore the hypothesis that the Internet is part of a general process that reduces society and materials to small-scale components, which allow its mechanisms to become more fluid. A chemist’s idea – the decomposition of matter into powder to facilitate its recomposition – is also applied to social relations, memory and humans in general.Just as the reduction of matter accelerates chemical reactions, the reduction of society to powder allows for an accelerated decomposition and recomposition of all from which humans are made. It allows to multiply the reactions within society, to accelerate the productions of humanity and the social chemistry : combination of human passions (Charles Fourier), hyperfragmentation of work (Mechanical Turk), decomposition of knowledge (Paul Otlet), Internet of neurons (Michael Chorost), agregation of micro affects (Facebook). This is what I call the « society as cloud 

Le slogan « gated community »

Gated communities are often referred to for what they seem to represent rather than for what they are – in fiction as well as in the theoretical discourse. They seem to embody the America Dream or the suburban nightmare at its climax. The distance between the ordinariness of the phenomenon and the vast imaginary it generates is obvious. This paper questions the nature of this distance: what happens between imaginary and reality? Beyond the analysis of the stories which depict gated communities, another way to address their connections with fiction is to question the expression "gated community" itself

Corrélation entre risque carieux et charge bactérienne : outil potentiel de décision thérapeutique

Many Oral infectious diseases such as dental caries or periodontitis are the result of an organised biofilm. Biofilm’s formation is a multifactorial event involving for example diet (sugar consumption), oral hygiene and oral microbiote composition. The risk to develop the disease is then specific to each individual. The clinician should be able to assess the patient risk in order to use a specific therapeutic in accordance. A simple to use, fast and low cost diagnostic tool doesn’t exist today. Rather than identifying specific species involved in carie development, we aim to measure the activity/quantity of microorganisms at specific sites. In doing so we are trying to find a link between these measurement and carie progression. We used the “2 MIN UNIT-ORAL® " from Clinident institute in our pilot experiment and found interesting results that will lead us to develop an exhaustive clinic study.La maladie carieuse ou les maladies parodontales sont des pathologies plurifactorielles liées aux microorganismes qui s’organisent en biofilm sur les surfaces dentaires. La virulence de ce biofilm dépend de divers facteurs tels que l’alimentation (quantité de sucre), l’hygiène dentaire, ainsi que la composition de la flore buccale. Le risque de développer ces maladies est donc propre à chaque patient. Afin d’individualiser au mieux sa prise en charge, le clinicien devrait posséder dans sa palette diagnostique un outil lui permettant d’évaluer ce risque de manière fiable, rapide et à bas coût. Malheureusement, la composition très hétérogène du microbiote oral, les techniques complexes d’identification des espèces microbiennes et notre incompréhension actuelle des interactions/coopérations inter-espèces au sein du biofilm rendent les différents tests existants inutilisables pour les praticiens. Nous avons donc cherché à savoir si en mesurant la quantité/activité globale de bactéries sur certains sites à risque (espaces interdentaires, poches parodontales), une prédiction du risque carieux du patient pouvait être faite. Pour cela nous avons utilisé le « 2 MIN UNIT-ORAL® » de l’institut Clinident. Nos premiers résultats semblent concluants et encouragent la mise en place d’une étude clinique

Modélisation par contraintes et heuristiques pour l'évaluation de la capacité d'infrastructures ferroviaires

In comparison with others transportation system, the railway transport has many advantages in terms of cost and sustainable development. Nonetheless, transportation is a highly competitive field and the benefits of rail are not sufficient to enable it to prevail. Thus, the SNCF (French National Railway Society) must improve the efficiency of rail transport and the quality of services to clients. Punctuality, train frequency and prices are a central concern. A important work resource on planning is necessary. The problem of assessing the capacity of rail infrastructure sets limits on the network and the impact of modification in the infrastructure. In order to provide solutions to the SNCF, this problem has been modelled in a Constraint Satisfaction Problem. The exact resolution of this problem, with the ILOG SOLVER libraries, shows limits, so improvements are proposed for both the model and the resolution. The improvements focus on reducing the number of constraints, the rewriting of the temporal constraints, suppression of symmetries, cuts and an upper bound. An approached resolution algorithm is proposed, it uses the principles of the meta-heuristics Large and Variables Neighbourhood Search, and the Depth-bounded Discrepancy Search algorithms. The different algorithms and each improvement are validated on a set of random instance and on real data from the railway junction of Pierrefite-Gonesse. The results are the best knownComparativement aux autres moyens de transport, le transport ferroviaire présente de nombreux avantages tant du point de vue coût que développement durable. Malgré cela, le transport est un domaine fortement concurrentiel et les avantages du ferroviaire ne sont pas suffisant pour lui permettre de s'imposer. Ainsi, la SNCF (Société Nationale des Chemins de fer Français) se doit d'améliorer l'efficacité du transport ferroviaire et la qualité des services aux clients. La ponctualité, la fréquence des trains et le prix sont au centre des préoccupations. Un travail conséquent de planification des ressources est nécessaire. Le problème d'évaluation de la capacité d'infrastructures ferroviaires permet de situer les limites du réseau et d'étudier l'impact de modification d'infrastructure. Afin de proposer des solutions à la SNCF, ce problème a été modélisé en un problème de satisfaction de contraintes. La résolution exacte de ce problème par les bibliothèques d'ILOG SOLVER montre des limites, aussi des améliorations sont proposées tant au niveau du modèle que de la résolution. Les améliorations portent sur la réduction du nombre de contraintes, la réécriture des contraintes temporelles, la suppression de symétries, des coupes et une borne supérieure. Un algorithme de résolution approchée est proposé, il utilise les principes de recherche à voisinage large et variables ainsi que de la recherche à arborescence tronquée. Les différents algorithmes et améliorations sont validés sur des instances réelles provenant du nœud ferroviaire de Pierrefite-Gonesse ainsi que sur un ensemble d'instance aléatoires. Les résultats obtenus sont les meilleurs connus à ce jour