Metabolism of the dual FLT-3/Aurora kinase inhibitor CCT241736 in preclinical and human in vitro models: Implication for the choice of toxicology species.

CCT241736 is a dual fms-like tyrosine kinase 3 (FLT3)/Aurora kinase inhibitor in development for the treatment of acute myeloid leukaemia. The successful development of any new drug relies on adequate safety testing including preclinical toxicology studies. Selection of an appropriate preclinical species requires a thorough understanding of the compound's metabolic clearance and pathways, as well as other pharmacokinetic and pharmacodynamic considerations. In addition, elucidation of the metabolising enzymes in human facilitates improved clinical prediction based on population pharmacokinetics and can inform drug-drug interaction studies. Intrinsic clearance (CLint) determination and metabolite profiling of CCT241736 in human and four preclinical species (dog, minipig, rat and mouse) was undertaken in cryopreserved hepatocytes and liver microsomes. Recombinant human cytochrome P450 bactosomes (rCYP) were utilised to provide reaction phenotyping data and support prediction of metabolic pathways. CCT241736 exhibited low CLint in both hepatocytes and liver microsomes of human, dog, minipig and rat, but considerably higher CLint in mouse. CYP3A4 and CYP3A5 were identified as the major enzymes responsible for biotransformation of CCT241736 in human, exclusively forming five out of seven metabolites. Minipig showed greatest similarity to human with regard to both overall metabolic profile and abundance of specific metabolites relative to parent compound, and is therefore proposed as the most appropriate toxicological species. The greatest disparity was observed between human and dog. Based on metabolic profile, either mouse or rat is a suitable rodent species for toxicology studies

Top Management inside Debt and Corporate Social Responsibility? Evidence from the US

This study provides evidence on the relationship between CEO inside debt and corporate social responsibility (hereinafter, CSR). We find that an increase in CEO inside debt leads to high levels of CSR. This finding is robust to controlling for the sensitivity of CEO equity compensation to volatility as well as to alternative measures of CSR. We also find that CEO inside debt is directly related to firms' primary stakeholders (Community, Diversity, Employee Relations, Environment, and Product Characteristics). Our results are in line with the risk mitigation hypothesis and shed more light on CSR as a channel through which managers with more inside debt tend to respond to debtholders' demands as their appetite for risk decreases. © 2019 Board of Trustees of the University of Illinoi

TOWARDS A COLLABORATIVE KNOWLEDGE DISCOVERY SYSTEM FOR ENRICHING SEMANTIC INFORMATION ABOUT RISKS OF GEOSPATIAL DATA

The aim of this research is to design and implement a knowledge discovery system that facilitates, using a web 2.0 collaborative approach, the identification of new risks of geospatial data misuse based on a contributed knowledge repository fed by application domain experts. [Context/Motivation] This research is motivated by the irregularity of risk analysis efforts and the poor semantic of the collected information about risks. In the context of risk analysis during geospatial database design, the knowledge about risks of geospatial data misuse is typically held by domain application experts. The collection and record of that knowledge are usually considered as optional activities. It is usually performed through face-to-face risk assessment meetings and reports. Such techniques end up by restricting the scope of risk analysis to a set of obvious risks usually already identified. Besides, little consideration is devoted to the storage of risk information in an appropriate format for automatic reasoning and new risk information discovery. As a consequence, many foreseeable risky aspects inherent to the data remain overlooked leading to ill-defined specification and faulty decisions. [Principal ideas/results] In this paper, we present a contributed knowledge discovery system that aims at enriching the semantic information about risks of geospatial data misuse in order to identify foreseeable risks. The proposed web-based system relies on a systematic and more active involvement of users in risk analysis. The approach consists of 1) providing an overview of the related work in the domains of risk analysis within the context of geospatial database design, 2) presenting an ontology-based knowledge discovery system that helps experts in risks identification based on an upper-level risk ontology and on a structured representation of the domain-specific knowledge and, 3) presenting the components of the proposed system architecture and how it may be implemented and used in practice, and finally 4) we conclude by discussing the approach. [Contribution] A major outcome is that the proposed platform can help discovering implicit domain knowledge, and facilitating the identification of foreseeable risks of geospatial data misuse in a way to preventively improve the resulting fitness-for-use

Reactivity of Green Leaf Volatiles (GLVs) in the atmosphere: Kinetics, products and secondary organic aerosol formation

International audienceIn nature, plants can undergo many different stress phenomena. In response to biotic or abiotic stress factors, they will emit so called Green Leaf Volatiles (GLVs), which are part of the large group of biogenic volatile organic compounds (BVOC). Among the BVOCs unsaturated aldehydes are emitted in larger quantities from plants during stress periods; however, the understanding of their atmospheric reactivity is still very limited, particularly with respect to their impact on secondary organic aerosol (SOA) formation. Accordingly, the main objective of the present work is to investigate the fate of unsaturated aldehydes in the atmosphere focusing on SOA formation.In a first part, the kinetics of the reactions of trans-2-pentenal (T2P) and trans-2-hexenal (T2H) with O3 and Cl atoms was studied both in a Teflon chamber (0.3 m3) and in a Pyrex laminar flow reactor (O3 only) at the SAGE department.The second part was focused on the investigation of SOA formation during the ozonolysis of T2P and T2H in three different environmental chambers: the Teflon reactor mentioned above, the stainless steel CHARME (CHamber for Atmospheric Reactivity and Metrology of the Environment) at the LPCA (9.2 m3) and the quartz reactor QUAREC at the University of Wuppertal (1.1 m3). Parallel investigation of gaseous products by gas/liquid chromatography and IR spectroscopy was also carried out. Results will be discussed in terms of chemical mechanisms and the effect of the chamber

Automatic image annotation with relevance feedback and latent semantic analysis

The goal of this paper is to study the image-concept relationship as it pertains to image annotation. We demonstrate how automatic annotation of images can be implemented on partially annotated databases by learning image-concept relationships from positive examples via inter-query learning. Latent semantic analysis (LSA), a method originally designed for text retrieval, is applied to an image/session matrix where relevance feedback examples are collected from a large number of artificial queries (sessions). Singular value decomposition (SVD) is exploited during LSA to propagate image annotations using only relevance feedback information. We will show how SVD can be used to filter a noisy image/session matrix and reconstruct missing values

Réactivité de COVB oxygénés avec deux oxydants atmosphériques : O3 et Cl. Cinétiques, formation d’aérosols organiques secondaires et produits de réaction

International audienceLes émissions de composés organiques volatils d’origine biogénique (COVB) sont généralement supérieures d’un facteur dix aux émissions anthropiques. Le changement climatique entraine une augmentation des stress biotiques et abiotiques sur les plantes et induit des modifications dans les flux de COVB. Les aldéhydes insaturés sont des COVB dont les émissions sont renforcées en période de stress ; cependant, les connaissances sur leur réactivité atmosphérique sont encore très limitées, en particulier la formation des aérosols organiques secondaires (AOS). C’est dans ce cadre que ce projet a été réalisé avec l’objectif d’apporter des informations indispensables sur le devenir atmosphérique des aldéhydes insaturés.Ce travail se subdivise en trois parties. Une première partie a été consacrée à la détermination des constantes cinétiques avec O3 et Cl du trans-2-pentenal (T2P) et du trans-2-hexenal (T2H) au moyen d'une chambre de simulation atmosphérique (CSA) souple en Téflon (300 L). Les cinétiques d’ozonolyse ont également été réalisées dans un réacteur à écoulement laminaire en Pyrex.Au cours de la deuxième partie, la formation des AOS à partir de l'ozonolyse des T2P et T2H a été étudiée dans deux réacteurs : la CSA en Téflon et la CSA CHARME (CHamber for Atmospheric Reactivity and Metrology of the Environment) du LPCA (réacteur en inox électropoli de 9,2 m3).La troisième partie a été consacrée à l'étude des produits d’ozonolyse à l'aide d’analyses par chromatographies HPLC et GC-MS, et par spectroscopie IRTF. Dans cette partie, c’est essentiellement la CSA en Téflon qui a été utilisée. Des résultats préliminaires du réacteur cylindrique en quartz QUAREC de l'Université de Wuppertal (Allemagne) seront présentés