Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment

PHARMACOGENETIQUE DES MEDICAMENTS THIOPURINIQUES Implication des enzymes TPMT et IMPDH2 et de la RhoGTPase RAC1

The thiopurine drugs, azathioprine, 6-mercaptopurine and 6-thioguanine, have been used for decades for their cytotoxic and immunosuppressive properties in the treatment of leukemias, chronic inflammatory or autoimmune diseases and in the prevention of allograft rejection. However, some patients treated with conventional doses of these molecules develop very severe side effects. The deficient activity of the thiopurine S-methyltransferase (TPMT), an enzyme involved in thiopurine inactivation, is one of the key factors in the myelotoxicity of these drugs. The determination of the TPMT phenotype by genotyping test is a preventive measure before the initiation of thiopurine therapy and is based on the identification of the most common inactivating mutations of the TPMT gene. First, our study consisted in the functional analysis of four new allelic variants of TPMT, using an heterologous expression system, the yeast S. cerevisiae. The non-functional character of two of those variants was demonstrated. However, TPMT deficiency explain only about 30 % of cases of thiopurine myelotoxicity, suggesting the existence of other genetic abnormalities affecting other genes involved in the response toward thiopurines. Accordingly, we studied the genetic polymorphism of two other proteins, the inosine monophosphate dehydrogenase type 2 (IMPDH2), a key enzyme in the production of the active metabolites of thiopurine, and the RhoGTPase RAC1, which is one of the pharmacological targets of these molecules. Some of the polymorphisms that we identified in those two genes seem to affect in vitro the expression and / or activity of these proteins and, therefore, could contribute to inter-individual variations of the response to thiopurineLes médicaments thiopuriniques que sont l'azathioprine, la 6-mercaptopurine et la 6-thioguanine sont utilisés depuis des décennies pour leurs propriétés cytotoxiques et immunosuppressives dans le traitement de certaines leucémies, de maladies inflammatoires chroniques ou auto-immunes ainsi que dans la prévention du rejet de greffe. Certains patients, traités par des doses conventionnelles de ces molécules, développent cependant des effets indésirables parfois très sévères. Le déficit d'activité, d'origine génétique, de la thiopurine S-méthyltransférase (TPMT), enzyme impliquée dans le métabolisme des thiopurines, constitue l'un des facteurs majeurs de la myélotoxicité de ces médicaments. La détermination du phénotype TPMT par génotypage, qui est une mesure préventive avant l'introduction d'un traitement thiopurinique, repose sur l'identification des mutations inactivatrices les plus fréquentes du gène TPMT. Une partie de ce travail a consisté en l'analyse fonctionnelle de quatre variants alléliques rares du gène TPMT dans un système d'expression hétérologue, la levure S. cerevisiae. Le caractère non-fonctionnel de deux d'entre eux a ainsi été démontré. Cependant, le déficit d'activité de la TPMT ne permet d'expliquer qu'environ 30 % des cas de myélotoxicité sous thiopurines, ce qui laisse supposer l'existence d'autres anomalies génétiques affectant d'autres gènes impliqués dans la réponse de l'organisme à ces molécules. Ainsi, nous avons étudié le polymorphisme génétique de deux autres protéines candidates, celui de l'inosine monophosphate déshydrogénase de type 2 (IMPDH2), enzyme-clé de la formation des métabolites actifs des thiopurines, et celui de la RhoGTPase RAC1, qui est l'une des cibles pharmacologiques de ces molécules. Certains des polymorphismes que nous avons identifiés dans ces deux gènes semblent affecter in vitro l'expression et/ou l'activité de ces protéines et pourraient, par conséquent, contribuer aux variations inter-individuelles de réponse aux thiopurine

Petit éloge du biais. Ou comment la fiction habille l’Histoire par le travers ; exposé illustré de quelques exemples de couture – la photo de famille, l’archive, le document

En faisant référence aux romans Nous nous connaissons déjà (2003), Dans la main du diable (2006), L’Enfant des ténèbres (2008), Pense à demain (2010), et Programme sensible (2013), il s’agira de montrer comment l’on peut tailler un costume à l’Histoire dans le biais le plus subjectif sans négliger le coupon de réalité, à savoir le factuel historique. Mais pour oser aborder l’antériorité sans travailler dans le droit fil de l’Histoire (en particulier dans la trilogie qui couvre la durée d’un siècle environ, quatre générations de la fin du XIXe à aujourd’hui) et réchauffer le discours de la raison historienne, il faut s’appuyer sur l’expérience empirique, sur une archive sensible, une trace, l’héritage de la mémoire familiale : objets en tout genre, images cinématographiques et photographiques, articles de presse, plans et cartes... tel est le carburant dont le roman a besoin

Caractérisation de nouveaux variants alléliques de la Thiopurine S-Méthyltransferase (TPMT)

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Intoxications chez l'enfant et l'animal : (caractéristiques et comparaison : )

LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

Pharmacogénétique des médicaments thiopuriniques (implication des enzymes TPMT et IMPDH2 et de la RhoGTPase RAC1)

The thiopurine drugs, azathioprine, 6-mercaptopurine and 6-thioguanine, have been used for decades for their cytotoxic and immunosuppressive properties in the treatment of leukemias, chronic inflammatory or autoimmune diseases and in the prevention of allograft rejection. However, some patients treated with conventional doses of these molecules develop very severe side effects. The deficient activity of the thiopurine S-methyltransferase (TPMT), an enzyme involved in thiopurine inactivation, is one of the key factors in the myelotoxicity of these drugs. The determination of the TPMT phenotype by genotyping test is a preventive measure before the initiation of thiopurine therapy and is based on the identification of the most common inactivating mutations of the TPMT gene. First, our study consisted in the functional analysis of four new allelic variants of TPMT, using an heterologous expression system, the yeast S. cerevisiae. The non-functional character of two of those variants was demonstrated. However, TPMT deficiency explain only about 30 % of cases of thiopurine myelotoxicity, suggesting the existence of other genetic abnormalities affecting other genes involved in the response toward thiopurines. Accordingly, we studied the genetic polymorphism of two other proteins, the inosine monophosphate dehydrogenase type 2 (IMPDH2), a key enzyme in the production of the active metabolites of thiopurine, and the RhoGTPase RAC1, which is one of the pharmacological targets of these molecules. Some of the polymorphisms that we identified in those two genes seem to affect in vitro the expression and / or activity of these proteins and, therefore, could contribute to inter-individual variations of the response to thiopurine.LILLE2-BU Santé-Recherche (593502101) / SudocSudocFranceF

TRAITEMENT DES DYSKINESIES TARDIVES INDUITES PAR LES NEUROLEPTIQUES (USAGE DE LA TETRABENAZINE DANS UN SERVICE DE NEUROLOGIE (HOPITAL NEUROLOGIQUE DE LYON))

LYON1-BU Santé (693882101) / SudocSudocFranceF

Swelling of natural fibre bundles under hygro- and hydrothermal conditions: determination of hydric expansion coefficients by automated laser scanning

International audienceThe effect of humidity conditions on the moisture content and dimensional variations of natural fibre bundles from several botanical origins with contrasting biochemical and structural characteristics is investigated. Results highlight wide variations in water uptake and swelling behaviour of fibre bundles as a function of plant species. Two main swelling mechanisms are identified: (i) a microscopic swelling due to the sorption of bound water in the cell walls and the middle lamella, and (ii) a macroscopic swelling related to the formation of free water in pores and lumens, which induces anisotropic deformation of bast fibre bundles. Surface hygro- and hydroexpansion coefficients are determined and studied in relation with the structural features of plant fibre bundles. These results constitute key data for the predictive modelling of “in-service” mechanical behaviour of biocomposites