First results on ProtoDUNE-SP liquid argon time projection chamber performance from a beam test at the CERN Neutrino Platform

The ProtoDUNE-SP detector is a single-phase liquid argon time projection chamber with an active volume of 7.2× 6.1× 7.0 m3. It is installed at the CERN Neutrino Platform in a specially-constructed beam that delivers charged pions, kaons, protons, muons and electrons with momenta in the range 0.3 GeV/c to 7 GeV/c. Beam line instrumentation provides accurate momentum measurements and particle identification. The ProtoDUNE-SP detector is a prototype for the first far detector module of the Deep Underground Neutrino Experiment, and it incorporates full-size components as designed for that module. This paper describes the beam line, the time projection chamber, the photon detectors, the cosmic-ray tagger, the signal processing and particle reconstruction. It presents the first results on ProtoDUNE-SP\u27s performance, including noise and gain measurements, dE/dx calibration for muons, protons, pions and electrons, drift electron lifetime measurements, and photon detector noise, signal sensitivity and time resolution measurements. The measured values meet or exceed the specifications for the DUNE far detector, in several cases by large margins. ProtoDUNE-SP\u27s successful operation starting in 2018 and its production of large samples of high-quality data demonstrate the effectiveness of the single-phase far detector design

First results on ProtoDUNE-SP liquid argon time projection chamber performance from a beam test at the CERN Neutrino Platform

The ProtoDUNE-SP detector is a single-phase liquid argon time projection chamber with an active volume of 7.2×6.0×6.9 m3. It is installed at the CERN Neutrino Platform in a specially-constructed beam that delivers charged pions, kaons, protons, muons and electrons with momenta in the range 0.3 GeV/c to 7 GeV/c. Beam line instrumentation provides accurate momentum measurements and particle identification. The ProtoDUNE-SP detector is a prototype for the first far detector module of the Deep Underground Neutrino Experiment, and it incorporates full-size components as designed for that module. This paper describes the beam line, the time projection chamber, the photon detectors, the cosmic-ray tagger, the signal processing and particle reconstruction. It presents the first results on ProtoDUNE-SP's performance, including noise and gain measurements, dE/dx calibration for muons, protons, pions and electrons, drift electron lifetime measurements, and photon detector noise, signal sensitivity and time resolution measurements. The measured values meet or exceed the specifications for the DUNE far detector, in several cases by large margins. ProtoDUNE-SP's successful operation starting in 2018 and its production of large samples of high-quality data demonstrate the effectiveness of the single-phase far detector design

Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers

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Population pharmacokinetic analysis of 5-FU and 5-FDHU in colorectal cancer patients: search for biomarkers associated with gastro-intestinal toxicity

Purpose The anticancer drug 5-fluorouracile (5-FU) which is indicated for the treatment of a variety of solid malignancies such as colorectal, breast, head and neck neoplasms is extensively biotransformed to 5- fluoro-5,6-dihydrouracil (5-FDHU) by the dihydropyrimidine deshydrogenase enzyme (DPD). DPD deficiency is recognized as an important risk factor, predisposing patient to undergo severe/lethal toxicities. To date, relationships between 5-FU, 5-FDHU and toxicity following iv bolus administration has not been studied using the population pharmacokinetics approach. Methods Retrospective pharmacokinetic data of 5-FU and 5-FDHU from 127 colorectal cancer patients were used for the population pharmacokinetic analysis. Treatment schedule consisted of an adjuvant therapy with 5-FU plus leucovorin. 5-FU and 5-FDHU complete plasma profiles recorded on day-1 of the first chemotherapy cycle were modeled simultaneously using NONMEM software. Gastro-intestinal adverse events graded according to the WHO criteria were recorded after the first cycle. A population logistic regression model was developed to identify predictive factors of these adverse events. Results A three-compartment pharmacokinetic mixture model best described 5-FU and 5-FDHU kinetics profiles. Linear and saturated elimination from the central compartment of 5-FU and a linear elimination from the 5-FDHU compartment were used. A bimodal distribution of the intercompartmental clearance was observed allowing two subpopulation with high (17 L/h) and low values (3.35 L/h). DPD-phenotype is suspected to explain this mixture. No covariates were introduced in the final model. Also, no relationship was found between maximal metabolism rate and DPD-phenotype. Predictive factors associated with occurrence of high grade gastro-intestinal adverse events were gender, dose and lean body mass suggesting serious cautions with the BSA- weighted dose for women. For the low-grade toxicities, 5-FU area under curve was predictive for woman and 5-FDHU area under curve for men. 3 Conclusion A population pharmacokinetic mixture model was developed to describe kinetic profiles of 5-FU and its major metabolite. This model has significant implications, to identify patients with potentially low DPD phenotype requiring earlier adjustment of the 5-FU dose. Also this analysis highlights the need for developing alternative dosing-scheme for women

EVALUATION OF SACCADIC EYE-MOVEMENTS AS AN OBJECTIVE TEST OF RECOVERY FROM ANESTHESIA

International audienceSaccadic eye movements have been previously used to assess residual effect of anaesthetics, but this test is seldom compared to other psychomotor tests. The aim of the present study was to validate saccades as a recovery index in relation to frequently referred subjective and psychometric tests. Eight healthy subjects were tested before and after intra-muscular injection of either placebo or 0.15 mg . kg(-1) of midazolam. Each session consisted of a saccadic rest (recorded by electro-oculography), a choice-reaction-time test (CRT), a subjective state-of-alertness test (11 visual analogic scales) and blood sampling (to monitor midazolam plasma concentration), before and 30 (t30), 60 (t60), 120 (t120), 180 (t180), 240 (t240) minutes after drug administration In the placebo group, there was no change in subjective assessment, saccade characteristics (latency, peak velocity and duration) or CRT results. In the midazolam group, 6 subjective items changed with different time-courses, when compared to baseline: from t30 to t120 (drowsy, in shape, tired, clumsy strong) and at t120 (woolly). Saccade latency and duration were significantly different from 130 to t120 and until t180 for peak velocity. CRT performance was significantly altered From t30 to t120. Midazolam plasma concentration decreased From 177+/-33 ng . ml(-1) at t30 to 47+/-12 ng . ml(-1) at t240. At this latter time, sensorimotor functions returned to the baseline. All subjects fulfilled the clinical conditions for home discharge 4 hours after administration. These results suggest that a saccadic eye movement test is a sensitive and reliable tool for the assessment of residual effect of anaesthetics. This test was found to be more sensitive than CRT test since peak saccadic velocity was the last psychometric parameter to be returned to baseline after midazolam injection. This study also confirms the poor reliability of subjective assessment, as subjects tended to underestimate the alteration of their performance immediately following drug injection

From 3D spheroids to tumor bearing mice: efficacy and distribution studies of trastuzumab-docetaxel immunoliposome in breast cancer

Anne Rodallec,1 Guillaume Sicard,1 Sarah Giacometti,1 Manon Carré,1 Bertrand Pourroy,2 Fanny Bouquet,3 Ariel Savina,3 Bruno Lacarelle,1 Joseph Ciccolini,1 Raphaelle Fanciullino1 1SMARTc Unit, Laboratory of Pharmacokinetics and Toxicology UFR Pharmacy, Center for Research on Cancer of Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille University, Marseille, France; 2Pharmacy Department, APHM La Conception, Marseille, France; 3Roche Institute, Boulogne Billancourt, France Purpose: Nanoparticles are of rising interest in cancer research, but in vitro canonical cell monolayer models are not suitable to evaluate their efficacy when prototyping candidates. Here, we developed three-dimensional (3D) spheroid models to test the efficacy of trastuzumab-docetaxel immunoliposomes in breast cancer prior to further testing them in vivo. Materials and methods: Immunoliposomes were synthesized using the standard thin film method and maleimide linker. Two human breast cancer cell lines varying in Her2 expression were tested: Her2+ cells derived from metastatic site: mammary breast MDA-MB-453 and triple-negative MDA-MB-231 cells. 3D spheroids were developed and tested with fluorescence detection to evaluate viability. In vivo efficacy and biodistribution studies were performed on xenograft bearing nude mice using fluorescent and bioluminescent imaging. Results: In vitro, antiproliferative efficacy was dependent upon cell type, size of the spheroids, and treatment scheduling, resulting in subsequent changes between tested conditions and in vivo results. Immunoliposomes performed better than free docetaxel + free trastuzumab and ado-trastuzumab emtansine (T-DM1). On MDA-MB-453 and MDA-MB-231 cell growth was reduced by 76% and 25%, when compared to free docetaxel + free trastuzumab and by 85% and 70% when compared to T-DM1, respectively. In vivo studies showed tumor accumulation ranging from 3% up to 15% of the total administered dose in MDA-MB-453 and MDA-MB-231 bearing mice. When compared to free docetaxel + free trastuzumab, tumor growth was reduced by 89% (MDA-MB-453) and 25% (MDA-MB-231) and reduced by 66% (MDA-MB-453) and 29% (MDA-MB-231) when compared to T-DM1, an observation in line with data collected from 3D spheroids experiments. Conclusion: We demonstrated the predictivity of 3D in vitro models when developing and testing nanoparticles in experimental oncology. In vitro and in vivo data showed efficient drug delivery with higher efficacy and prolonged survival with immunoliposomes when compared to current anti-Her2 breast cancer strategies. Keywords: docetaxel, trastuzumab, breast cancer, immunoliposome, spheroids, distribution, tumor xenograf

EVALUATION OF SACCADIC EYE-MOVEMENTS AS AN OBJECTIVE TEST DURING RECOVERY FROM ANESTHESIA

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