Modélisation Pharmacocinétique – Pharmacodynamique et nouvelles stratégies thérapeutiques en immuno-oncologie

L’immunothérapie représente un grand espoir dans la lutte contre le cancer dont les résultats très prometteurs ont pu être observés ces vingt dernières années. Une meilleure compréhension de la biologie tumorale et immunitaire, ainsi que des mécanismes d’échappement des cellules cancéreuses au système immunitaire a permis de développer de nouvelles stratégies thérapeutiques capables de stimuler efficacement le système immunitaire du patient afin de cibler et d’éliminer les cellules tumorales. Cependant certaines limites subsistent à l’utilisation de ces thérapies, telles que l’accessibilité des traitements aux patients, les capacités actuelles de prédiction de la sécurité, de l’efficacité et de la durabilité à long terme, ainsi que la détermination des doses et les schémas d’administration à étudier en clinique. Dans ce contexte, la modélisation mathématique s’impose comme un outil indispensable qui contribue à l’amélioration de la compréhension des facteurs influençant la variabilité interindividuelle et intra-individuelle observée lors de l’administration des médicaments. La modélisation constitue une aide précieuse à l’optimisation des doses et des schémas d’administration thérapeutiques, permettant de maximiser l’efficacité du médicament tout en limitant la survenue d’effet indésirables. De nos jours, la modélisation mathématique devient un allié du processus du développement des médicaments, qui contribue à la sécurité des patients, à une meilleure évaluation de la réponse médicamenteuse, à l’augmentation de la rapidité de prise de décision go-no go, ainsi qu’à la réduction les coûts de développement des médicaments

Perfusion characterization of liver metastases from endocrine tumors: Computed tomography perfusion

AIM: To assess prospectively parameters of computed tomography perfusion (CT p) for evaluation of vascularity of liver metastases from neuroendocrine tumors

Surface LSP-1 Is a Phenotypic Marker Distinguishing Human Classical versus Monocyte-Derived Dendritic Cells

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Pharmacokinetics and Pharmacodynamics-Based Mathematical Modeling Identifies an Optimal Protocol for Metronomic Chemotherapy

International audienceMetronomic chemotherapy is usually associated with better tolerance than conventional chemotherapy, and encouraging response rates have been reported in various settings. However, clinical development of metronomic chemotherapy has been hampered by a number of limitations, including the vagueness of its definition and the resulting empiricism in protocol design. In this study, we developed a pharmacokinetic/pharmacodynam-ic mathematical model that identifies in silico the most effective administration schedule for gemcitabine monotherapy. This model is based upon four biological assumptions regarding the mechanisms of action of metronomic chemotherapy, resulting in a set of 6 minimally parameterized differential equations. Simulations identified daily 0.5–1 mg/kg gemcitabine as an optimal protocol to maximize antitumor efficacy. Both metronomic protocols (0.5 and 1 mg/kg/day for 28 days) were evaluated in chemoresistant neuroblastoma-bearing mice and compared with the standard MTD protocol (100 mg/kg once a week for 4 weeks). Systemic exposure to gemcitabine was 14 times lower in the metronomic groups compared with the standard group. Despite this, metronomic gemcitabine significantly inhibited tumor angiogenesis and reduced tumor perfusion and inflammation in vivo, while standard gemcitabine did not. Furthermore, met-ronomic gemcitabine yielded a 40%–50% decrease in tumor mass at the end of treatment as compared with control mice (P ¼ 0.002; ANOVA on ranks with Dunn test), while standard gemcitabine failed to significantly reduce tumor growth. Stable disease was maintained in the metronomic groups for up to 2 months after treatment completion (67%–72% reduction in tumor growth at study conclusion, P < 0.001; ANOVA on ranks with Dunn test). Collectively, our results confirmed the superiority of metronomic protocols in chemoresistant tumors in vivo

Genefish: an alternate metagenomic approach for capturing targeted bacterial diversity in an engineered recipient <em>E. coli</em> strain

International audienceThe metagenomic approach, defined as the direct recovery and cloning of bacterial DNA from the environment in domesticated bacterial hosts has been widely used to study bacterial populations and their functional genes in numerous environments. The advantage of this approach over conventional culture based techniques is that it encompasses a wider range of bacteria by bypassing the bias of uncultivability of more than 99% of the bacteria in soil. However, in complex and rich environments such as soils, the huge level of bacterial diversity requires construction, handling and screening of several million clones in order to cover a significant proportion of bacterial genes in the indigenous community. These methods are time and money consuming, and require access to specialized robots that are unavailable to most microbial ecology laboratories. Our objectives were to develop an alternative metagenomic approach in which only bacterial recombinant clones harbouring inserts with sequence based selected genes could develop on growth media. This positive screening technology, called “Genefish” is based on homeologous recombination to extract specific genes from the metagenome into the specifically engineered recipient E. coli strain. The key characteristic of this approach is the use of two inducible lethal genes to kill non recombinant bacteria. We will present molecular details of this “Genefish” recipient E. coli strain and our first results of its in vitro and in situ use to extract denitrification related genes from the soil metagenome

GENEFISHING: AN ALTERNATE METAGENOMIC APPROACH FOR CAPTURING TARGETED BACTERIAL DIVERSITY IN AN ENGINEERED RECIPIENT E. COLI STRAIN

International audienceThe metagenomic approach, defined as the direct recovery and cloning of bacterial DNA from the environment in domesticated bacterial hosts has been widely used to study bacterial populations and their functional genes in numerous environments. The advantage of this approach over conventional culture based techniques is that it encompasses a wider range of bacteria by bypassing the bias of uncultivability of more than 99% of the bacteria in soil. However, in complex and rich environments such as soils, the huge level of bacterial diversity requires construction, handling and screening of several million clones in order to cover a significant proportion of bacterial genes in the indigenous community. These methods are time and money consuming, and require access to specialized robots that are unavailable to most microbial ecology laboratories. Our objectives were to develop an alternative metagenomic approach in which only bacterial recombinant clones harbouring inserts with sequence based selected genes could develop on growth media. This positive screening technology, called “Genefish” is based on homeologous recombination to extract specific genes from the metagenome into the specifically engineered recipient E. coli strain. The key characteristic of this approach is the use of two inducible lethal genes to kill non recombinant bacteria. We will present molecular details of this “Genefish” recipient E. coli strain and our first results of its in vitro and in situ use to extract denitrification related genes from the soil metagenome