A first-in-human phase I, dose-escalation, multicentre study of HSP990 administered orally in adult patients with advanced solid malignancies

Heat-shock protein 990 (HSP990) is a potent and selective synthetic small-molecule HSP90 inhibitor. The primary objectives of this phase I first-in-human study were to determine dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included characterisation of the safety profile, pharmacokinetics (PKs) and pharmacodynamics (PDs). Heat-shock protein 990 was administered orally once or two times weekly on a 28-day cycle schedule in patients with advanced solid tumours. Dose escalation was guided by a Bayesian logistic regression model with overdose control. A total of 64 patients were enrolled. Fifty-three patients received HSP990 once weekly at 2.5, 5, 10, 20, 30, 50 or 60 mg, whereas 11 patients received HSP990 two times weekly at 25 mg. Median duration of exposure was 8 weeks (range 1-116 weeks) and 12 patients remained on treatment for >16 weeks. Dose-limiting toxicities occurred in seven patients and included diarrhoea, QTc prolongation, ALT/AST elevations and central neurological toxicities. The most common drug-related adverse events were diarrhoea, fatigue and decreased appetite. Further dose escalation beyond 60 mg once weekly was not possible owing to neurological toxicity. Rapid absorption, no drug accumulation and large interpatient variability in PK exposures were observed. No objective responses were seen; 25 patients had a best overall response of stable disease. Heat-shock protein 990 is relatively well tolerated, with neurological toxicity being the most relevant DLT. The single agent MTD/RP2D of HSP990 was declared at 50 mg once weekly

Coupled glide-climb diffusion-enhanced crystal plasticity

International audienceThis paper presents a fully coupled glide-climb crystal plasticity model, whereby climb is controlled by the diffusion of vacancies. An extended strain gradient crystal plasticity model is therefore proposed, which incorporates the climbing of dislocations in the governing transport equations. A global-local approach is adopted to separate the scales and assess the influence of local diffusion on the global plasticity problem. The kinematics of the crystal plasticity model is enriched by incorporating the climb kinematics in the crystallographic split of the plastic strain rate tensor. The potential of the fully coupled theory is illustrated by means of two single slip examples that illustrate the interaction between glide and climb in either bypassing a precipitate or destroying a dislocation pile-up

Variabilidad del gen RYR1 y efecto en el pH de la carne en cerdos híbridos argentinos

The RYR1 gene is the principal cause of the porcine stress syndrome (PSS) and the presence of pale, soft and exudative meat (PSE) in swine. In Argentina there are no reports about the variability of RYR1 gene in hybrid swine and its effect on the quality of carcass. \nBy PCR-HRM we analyzed 403 hybrids swines from Argentina and 65.0% were homozygous NN, 30.8% heterozygous Nn and 4,2% homozygous nn. Additionally, a significant effect (p <0.0001) of the RYR1 gene was detected on the pH of carcass at 45 minutes after slaughter. Normal genotypes NN showed the highest pH values at 45 minutes after slaughter (6.27), heterozygous Nn showed intermediate pH values (5.94) and homozygous susceptible nn showed the lowest pH values (5.64). Argentina present high incidence of Nn and nn genotypes for the RYR1 gene in relation to Brazil, the principal pig producer of Latin America. Additionally the RYR1 gene affects the pH of the meat, one of the principal parameters in the determination of the PSE meat.Fil: Marini, S.J. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaFil: Vanzetti, L.S. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaFil: Borelli, V.S. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Las Breñas. Chaco, ArgentinaFil: Villareal, A.O. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Leales, Chañar Pozo Leales. Tucumán, ArgentinaFil: Denegri, G.D. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaFil: Cottura, G.A. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaFil: Panichelli, D. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaFil: Silva, P. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias. Departamento Sistemas de Producción Animal. Cátedra de Nutrición Animal. Santa Fe, ArgentinaFil: Campagna, D. Universidad Nacional de Rosario. Facultad de Ciencias Agrarias. Cátedra de Producción Animal. Santa Fe, ArgentinaFil: Spiner, N. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaFil: Brunori, J.C. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaFil: Franco, R. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria (EEA) Marcos Juárez. Grupo Porcino. Laboratorio de Biotecnología. Córdoba, ArgentinaEl gen RYR1 es la principal causa del síndrome de estrés porcino (PSS) y la presencia de carne pálida, blanda y exudativa (PSE) en los cerdos. En Argentina no existen informes sobre la variabilidad de dicho gen en cerdos híbridos y su efecto sobre la calidad de la canal.\nPor PCR-HRM se analizaron 403 cerdos híbridos de Argentina y el 65,0% eran homocigotos NN, 30.8% heterocigotos Nn y el 4,2% homocigotos nn. Además, se detectó un efecto significativo (p <0,0001) del gen RYR1 en el pH de la canal a los 45 minutos post faena. Los genotipos NN mostraron los mayores valores de pH a los 45 minutos después del sacrificio (6.27), los heterocigotos Nn mostraron valores intermedios de pH (5,94) y los homocigotos nn presentaron los valores más bajos de pH (5,64).\nArgentina presenta alta incidencia de los genotipos Nn y nn del gen RYR1 en relación a Brasil, el principal productor de cerdos de América Latina. Además, el gen RYR1 afecta al pH de la carne, uno de los principales parámetros para la determinación de carnes PSE

Cariprazine add-on in inadequate clozapine response: A report on two cases

Cariprazine is a novel antipsychotic drug that exerts partial agonism of dopamine D2/D3receptors with preferential binding to the D3receptor, antagonism of 5HT2B receptors, and partial agonism of 5HT1A. Currently, cariprazine has shown clinical efficacy in patients with schizophrenia and with bipolar disorder, as well as adjunctive treatment in patients with Major Depressive Disorder (MDD) and drug-resistant MDD. In the present case series, we report on two patients with treatment-resistant schizophrenia and partial response to clozapine who benefit from combination with cariprazine. The effects of cariprazine combination were remarkable also concerning the adverse metabolic effects of clozapine

Generalized continua and phase-field models : application to crystal plasticity

International audienceThree continuum field theories are presented that account for the size-dependent behaviour of materials. The micromorphic medium is endowed with microdeformation degrees of freedom that describe the rotation and distortion of a triad of microstructural directions, like crystallographic lattice directions. It is a very general framework that can be specialized to strain gradient plasticity theory dedicated to the modelling of plastic events in metals and alloys. Both frameworks are developed here in the special case of crystal plasticity as a complete example of transition from micro-physical phenomena to continuum macro-modelling. Finally the phase field method is introduced in this landscape as a continuum modelling approach to the motion of phase boundaries and interfaces driven by thermodynamics and mechanics