Population Pharmacokinetics of Palbociclib and Its Correlation with Clinical Efficacy and Safety in Patients with Advanced Breast Cancer.

Neutropenia is the most frequent dose-limiting toxicity reported in patients with metastatic breast cancer receiving palbociclib. The objective of this study was to investigate the pharmacokinetic-pharmacodynamic (PK/PD) relationships for toxicity (i.e., absolute neutrophil count, ANC) and efficacy (i.e., progression-free survival, PFS). A semi-mechanistic PK/PD model was used to predict neutrophils' time course using a population approach (NONMEM). Influence of demographic and clinical characteristics was evaluated. Cox proportional hazards models were developed to evaluate the influence of palbociclib PK on PFS. A two-compartment model with first-order absorption and a lag time adequately described the 255 palbociclib concentrations provided by 44 patients. The effect of the co-administration of proton-pump inhibitors in fasting conditions increased palbociclib clearance by 56%. None of the tested covariates affected the PD parameters. Model-based simulations confirmed the concentration-dependent and non-cumulative properties of palbociclib-induced neutropenia, reversible after treatment withdrawal. The ANC nadir occurred approximately at day 24 of each cycle. Cox analyses revealed a trend for better PFS with increasing palbociclib exposure in older patients. By characterizing palbociclib-induced neutropenia, this model offers support to clinicians to rationally optimize treatment management through patient-individualized strategies

Conduire le changement en bibliothèque

Comment conduire le changement de manière efficace dans le contexte très particulier introduit par les révolutions du numérique et des réseaux dans les bibliothèques ? Comment assurer le bon fonctionnement d’un équipement lorsque le rythme des changements à conduire s’accélère ? Ce volume apporte des éléments de réponses pratiques, tirées de réalisations concrètes et propose une réflexion plus générale sur les modalités du management en bibliothèque, centrée sur la notion émergente, dans les institutions publiques, d’organisation apprenante

Engineering of Three-Finger Fold Toxins Creates Ligands with Original Pharmacological Profiles for Muscarinic and Adrenergic Receptors

Protein engineering approaches are often a combination of rational design and directed evolution using display technologies. Here, we test “loop grafting,” a rational design method, on three-finger fold proteins. These small reticulated proteins have exceptional affinity and specificity for their diverse molecular targets, display protease-resistance, and are highly stable and poorly immunogenic. The wealth of structural knowledge makes them good candidates for protein engineering of new functionality. Our goal is to enhance the efficacy of these mini-proteins by modifying their pharmacological properties in order to extend their use in imaging, diagnostics and therapeutic applications. Using the interaction of three-finger fold toxins with muscarinic and adrenergic receptors as a model, chimeric toxins have been engineered by substituting loops on toxin MT7 by those from toxin MT1. The pharmacological impact of these grafts was examined using binding experiments on muscarinic receptors M1 and M4 and on the α1A-adrenoceptor. Some of the designed chimeric proteins have impressive gain of function on certain receptor subtypes achieving an original selectivity profile with high affinity for muscarinic receptor M1 and α1A-adrenoceptor. Structure-function analysis supported by crystallographic data for MT1 and two chimeras permits a molecular based interpretation of these gains and details the merits of this protein engineering technique. The results obtained shed light on how loop permutation can be used to design new three-finger proteins with original pharmacological profiles

Laser, préparations cavitaires et dentisterie adhésive

CLERMONT FD-BCIU Odontol. (631132226) / SudocCLERMONT FD-BCIU-Santé (631132104) / SudocSudocFranceF

Metabolomics analysis of postphotosynthetic effects of gaseous O-2 on primary metabolism in illuminated leaves

International audienceThe response of underground plant tissues to O-2 limitation is currently an important topic in crop plants since adverse environmental conditions (e.g. waterlogging) may cause root hypoxia and thus compromise plant growth. However, little is known on the effect of low O-2 conditions in leaves, probably because O-2 limitation is improbable in these tissues under natural conditions, unless under complete submersion. Nevertheless, an O-2-depleted atmosphere is commonly used in gas exchange experiments to suppress photorespiration and estimate gross photosynthesis. However, the nonphotosynthetic effects of gaseous O, depletion, particularly on respiratory metabolism, are not well documented. liere, we used metabolomics obtained under contrasting O, and CO, conditions to examine the specific effect of a changing O-2 mole fraction from ambient (21%) to 0%, 2% or 100%. In addition to the typical decrease in photorespiratory intermediates (glycolate, glycine and serine) and a build-up in photosynthates (sucrose), low O, (0% or 2%) was found to trigger an accumulation of alanine and change succinate metabolism. In 100% O-2, the synthesis of threonine and methionine from aspartate appeared to be stimulated. These responses were observed in two species, sunflower (Helianthus annuus L.) and Arahidopsis thaliana (L.) Heynh. Our results show that O-2 causes a change in the oxygenation : carboxylation ratio and also alters postphotosynthetic metabolism: (i) a hypoxic response at low O, mole fractions and (ii) a stimulation of S metabolism at high O, mole fractions. The latter effect is an important piece of information to better understand how photorespiration may control S assimilation

Moving Toward Indigenous-Centred Perinatal Care in Urban Quebec

This article explores Abinodjic, an initiative of the Native Friendship Centre in Val-d’Or, Quebec, Canada, which aims to move toward Indigenous-centred perinatal care for Indigenous mothers and families. Drawing on the findings of a three-year collaborative developmental evaluation, this article describes the emergence and relevance of a model of perinatal care in which Mino Pimatisi8in (a wholistic view of well-being) is the overarching goal, and where parental experiences, healthy lifestyles, support networks, and cultural knowledges are four interdependent areas of intervention that support children’s well-being, in the context of culturally safe services and approaches. We discuss three key elements significant to the initiative: (a) valuing Indigenous ways of being, (b) centring relationships and supporting the social networks, and (c) being advocates, both directly for community members as well as for Indigenous Peoples generally within the health and social services system. Findings demonstrate the importance of situating perinatal care within a continuum of Indigenous-led social and health services, and providing specific outreach, support, and guidance that are relational, strengths-based, and empowering for Indigenous families

Muscarinic toxins

International audienceMuscarinic toxins isolated from the venom of Dendroaspis snakes may interact with a high affinity, large selectivity and various functional properties with muscarinic receptors. Therefore, these toxins are invaluable tools for studying the physiological role, molecular functioning and structural organization of the five subtypes of these G-Protein Coupled Receptors. We review the data on the most relevant results dealing with the isolation/identification, mode of action, structure/function and exploitation of these toxins and finally highlight the unresolved issues related to their pharmacological studies

L’action collective des femmes à travers le mouvement social des centres d’amitié autochtones au Québec

Avec une population autochtone urbaine désormais plus nombreuse que la population résidente des communautés territoriales, on assiste à une transformation de la présence citoyenne autochtone dans les villes du Québec. Une partie importante de cette présence collective, dans laquelle les femmes sont grandement majoritaires, est canalisée à travers l’action et le leadership du mouvement québécois des centres d’amitié autochtones. Cet article vise à retracer le parcours des femmes qui ont donné naissance à ce mouvement et qui en ont continuellement révisé les fondements jusqu’à devenir aujourd’hui un acteur institutionnel incontournable de la scène sociopolitique québécoise et autochtone.With the rise of the Native urban population, that now even surpasses the resident population on reserves, we are currently witnessing a transformation with regard to the presence of Indigenous citizens in Quebec cities. A major part of this collective presence, composed of a majority of women, is spurred by the actions and leadership of the Quebec Native friendship centre movement. This article aims to recount the history of the women behind the creation of this movement: their continued effort to revise its founding principles has now turned it into a key institutional actor on the Quebec and Native socio-political scenes.Con una población indígena urbana que ahora supera a la población residente de las comunidades territoriales, estamos asistiendo a una transformación de la presencia cívica indígena en las ciudades de Quebec. Una parte importante de esta presencia colectiva, en la que las mujeres son una gran mayoría, se canaliza a través de la acción y el liderazgo del movimiento quebequés de los Centros de Amistad Indígena. Este artículo pretende trazar la trayectoria de las mujeres que dieron origen a este movimiento y que han revisado continuamente sus fundamentos hasta convertirlo en un actor institucional clave en la escena sociopolítica quebequense e indígena

Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain metastatic BRAF-V600 mutated melanoma

International audienc