Etude experimentale et simulation numerique de l'ecoulement convectif du a la cristallisation d'un sel en milieu confine

SIGLECNRS T 57826 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Radioimmunothérapie alpha du myélome multiple

La radioimmunothérapie alpha permet de vectoriser un radioélément émetteur de particules alpha au contact de cellules tumorales. Nous avons appliqué cette thérapeutique pour le traitement du myélome multiple, dans le but de déterminer les modalités les plus adaptées à un passage vers des études cliniques ultérieures. La première étape a permis de déterminer l'anticorps et le radioélément le mieux adapté pour la radioimmunothérapie et de mieux comprendre les mécanismes de la mort cellulaire radioinduite par l'irradiation alpha. Nous avons mis en évidence des diffe rences de sensibilité des lignées de myélome multiple, ce qui nous a amené dans une deuxième étape à rechercher une majoration de l'efficacité de la radioimmunothérapie alpha par la combinaison de chimiothérapies anti-mitotiques. Nous avons observé un effet supra-additif entre la RIT alpha et le paclitaxel ou la doxorubicine. Enfin, dans une troisième étape, nous avons analysé l'implication de la voie de K-ras afin de comprendre les mécanismes de transduction du signal impliqués dans la réponse à la radioimmunothérapie alpha.Alpha-radioimmunotherapy can vectorize an alpha particle emitter to target cancer cells. We developed this technique for the treatment of multiple myeloma, with the goal of determining the best suited modalities for later clinical studies. A first step determined the antibody and the radionuclide best suited for radioimmunotherapy and to better understand the mechanisms of alpha-radioimmunotherapy induced cell death. We observed some difference in the radiosensitivity of cell lines and decided in a second step to increase the efficacy of alpha-radioimmunotherapy by combining chemotherapeutic drugs. We found a synergistic effect between alpha-RIT and paclitaxel or doxorubicin. In a third and last step, we analysed the K-ras pathway in order to understand signal transduction following alpha-radioimmunotherapy.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Which radionuclide, carrier molecule and clinical indication for alpha-immunotherapy?

International audienc

Fatal overdose after ingestion of a transdermal fentanyl patch in two non-human primates

 Case history and presentation: Two non-human primates (Macaca fascicularis) enrolled in an experimental protocol received a 25 μg hour−1 transdermal fentanyl patch for postoperative analgesia. The following day both animals were clinically normal, but after a new induction of anaesthesia with ketamine, they developed severe and prolonged respiratory distress, profound coma and myosis. Management and follow-up: Attempted reversal with naloxone was ineffective. After several hours of ventilation, both primates eventually died, 7 hours and hours after ketamine injection, respectively. In both cases, the patch was discovered in the animal’s cheek pouch. Subsequent fentanyl serum concentration measurements (8.29 and 80 μg L−1) confirmed fentanyl overdose. Conclusions: This report of two fatal intoxications in non-human primates secondary to ingestion of a transdermal fentanyl patch demonstrates that this method of analgesia is inappropriate for non-human primates, because of their tendency to chew almost anything they can reach

Thermalhydraulics studies in support of the ASTRID reactor design

International audienceA large number of thermal hydraulics studies are conducted while designing a nuclear reactor.For normal operating conditions in a pool type Sodium Fast Reactor, some design options are chosen according to the thermal hydraulic behavior of the primary circuit in order to minimize the thermal loadings on the structures and the components. For example:- thermal hydraulics studies of the hot plenum aim to verify the thermal hydraulic stability of the jet coming from the core (for nominal and partial loads), evaluate the thermal fluctuations on the Above Core Structure grid, verify the position of the thermal stratification in the hot collector and the homogeneity of the intermediate heat exchangers flow supply,- thermal hydraulics studies of the cold plenum aim to verify the lack of thermal stress on pump-diagrid connecting pipes and strongback due to heterogeneities of temperatures at the intermediate heat exchangers outlet and determine temperatures stratification in the upper part of the cold plenum.For dimensioning transients, thermal hydraulics studies provide input data for damage evaluations.For accidental conditions, thermal hydraulics studies aim at checking the respect of safety criteria to ensure tightness or integrity. In particular, the study of transient leading to decay heat removal in natural convection contribute to the components layout design in the reactor block and to the secondary loops design. The study of unprotected transients aim at checking the effectiveness of design options of the core and the reactor.This paper gives an overview of thermal hydraulics studies realized in the framework of the Advanced Sodium Technological Reactor for Industrial Demonstration (ASTRID) project and the evolutions of the design as a result of these studies

Synthesis of C-functionalized TE1PA and comparison with its analogues. An example of bioconjugation on 9E7.4 mAb for multiple myeloma 64 Cu-PET imaging

International audienceIn view of the excellent copper(ii) and 64-copper(ii) complexation of a TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while maintaining its chelating properties. Overcoming the already known drawback of grafting via its carboxyl group, which is essential to the overall properties of the ligand, a TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to an architecture that is comparable to that of other commercially available bifunctional copper(ii) chelators such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno-PET imaging. The C-functionalization of TE1PA on one carbon atom in the β-N position of the cyclam backbone was successfully achieved by adapting our patented methodology to the huge challenge, allowing the regiospecific mono-N-functionalization of the unsymmetrical ligand. The obtained ligand p-SCN-Bn-TE1PA was coupled to a 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was assessed by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity, and in particular by comparing with 9E7.4-p-SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained from commercial and presumably highly efficient chelators NOTA and DOTA, respectively. The results are quite clear, showing that p-SCN-Bn-TE1PA has a coupling rate 5 times higher and an immunoreactivity 1.5 to 2 times greater than those of its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. The first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was performed, confirming the good in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, considering the high clearance even after 24 h and the particularly important tumor-to-liver ratio that was increasing at 48 h

Human alpha-Iduronidase Gene Transfer Mediated by Adeno-Associated Virus Types 1, 2, and 5 in the Brain of Nonhuman Primates: Vector Diffusion and Biodistribution

International audienceWe have previously demonstrated that delivery of a recombinant adeno-associated virus (rAAV) encoding human α-iduronidase (hIDUA) in the putamen and centrum semiovale was feasible and beneficial in a dog model of Hurler's syndrome. In the present study, we investigated the safety and vector diffusion profile of three rAAV serotypes (rAAV2/1, rAAV2/2, and rAAV2/5), encoding hIDUA in the central and peripheral nervous systems of nonhuman primates. Six macaques received the same vector dose injected into the right putamen and the homolateral internal capsule. Neurological examinations were done regularly and showed no detectable clinical consequence of the intracerebral injections. Because transgene IDUA was indistinguishable from endogenous enzymatic activity, we looked for vector diffusion by performing quantitative polymerase chain reaction on serial sections from the brain and spinal cord. We found that global diffusion throughout the brain was not significantly different between the three serotypes. However, rAAV2/1 and rAAV2/5 resulted in higher vector copy numbers per cell than did rAAV2/2, respectively, in the brain and the distal neuronal structures (spinal cord and peripheral nerves)