Les réseaux de chambres de culture de sphéroïdes : un outil pour la recherche de traitements combinatoires en oncologie

Le traitement du cancer requiert fréquemment la combinaison de plusieurs traitements tels la chimiothérapie et la radiothérapie afin d’accroitre les chances de survie des patients. L’efficacité de ces combinaisons repose sur les synergies entre les traitements et varie grandement en fonction de la nature du cancer ciblé et des traitements utilisés. Or, il n’existe peu ou pas d’outils spécialisés compatibles à la radiothérapie permettant de tester rapidement ces combinaisons en laboratoire. Nous avons donc développé un dispositif microfluidique composé d’un réseau de valves permettant la réalisation de 12 combinaisons et la culture de sphéroïdes, des agrégats cellulaires tridimensionnels formés d’un ou de plusieurs types de cellules. Le dispositif est composé d’un assemblage d’étages de PDMS, un matériau flexible, transparent et perméable à l’oxygène, et est réalisé à partir de moules fabriqués par impression 3D, permettant la réalisation de plusieurs itérations du dispositif rapidement et à moindre cout. Le dispositif devant être simple à utiliser, compatible aux techniques de culture cellulaire conventionnelles, nous avons conçu des valves magnétiques manuelles afin de pouvoir contrôler le flux des liquides dans le système. Chacune de ces valves peut être contrôlée manuellement et individuellement, conférant un haut degré de flexibilité au dispositif. Elles résistent aussi à des pressions élevées (> 10 kPa), même après une exposition à une dose de radiothérapie de 8 Gy et une incubation de 7 jours à 37°C. Le dispositif final, le réseau de chambres de culture de sphéroïdes (RCCS), est composé de 12 chambres de cultures contenant chacune 25 puits où peuvent se former les sphéroïdes. Chaque chambre de culture est entourée de quatre valves, ce qui permet de contrôler précisément le trajet emprunté par les solutions à l’intérieur du dispositif. En ajustant les valves, il est possible de remplir le RCCS en entier à partir d’une entrée et d’une sortie ou de faire circuler les solutions en empruntant seulement les canaux horizontaux ou verticaux. Les chambres de culture sont aussi séparées les unes des autres de plusieurs millimètres, ce qui permet d’exposer les différentes chambres d’un même dispositif à différentes doses de radiothérapie. Les RCCS ont permis la formation et l’imagerie des sphéroïdes provenant de trois lignées cellulaires différentes directement sur le dispositif. Il reste encore à évaluer leur potentiel dans un contexte réel de recherche de traitements combinatoires en oncologie, mais il ne fait aucun doute qu’une fois ces résultats obtenus, les RCCS pourraient devenir un outil clé pour la recherche en oncologie.----------ABSTRACT Cancer treatment frequently needs a combination of several treatments such as chemotherapy and radiotherapy in order to increase patients’ survival rates. Efficacy of these combinations relies on synergies between treatments and varies greatly in function of the nature of the targeted cancer and the treatments used. However, very few specialized tools exist that allow rapid testing of these combinations in laboratory, while being compatible to radiotherapy. Hence, we developed a microfluidic device composed of an array of valves allowing simultaneous testing of twelve combinations of treatments and culture of spheroids, tridimensional cell aggregates composed of one or more type of cells. The device is composed of an assembly of layers of PDMS, a flexible, transparent and oxygen permeable material. The layers were made from 3D printed molds, allowing cheap and adaptable fabrication of the device according to the different needs. In order for the device to be simple to use and compatible to day to day cell culture techniques, we designed manual magnetic valves to route liquids within the system. Each of these valves can be opened and closed manually, resulting in a high degree of flexibility. They also resist high pressures (> 10 kPa), even after being exposed to 8 Gy radiotherapy and incubated 7 days at 37°C. The final device, the spheroid culture chamber array (SCCA), is composed of 12 culture chambers each containing 25 wells where spheroids can form. Four valves, allowing precise control of solutions pathways within the device, surround each culture chamber. By adjusting the valves configuration, it’s possible to fill the entire device from a single inlet and outlet or to fill only the vertical or horizontal channels. The culture chambers are also separated by several millimeters, which allows exposure of the different chambers to different radiotherapy doses on a single device. SCCA allowed formation and imaging of spheroids from three different cell lines directly on-chip. The potential of the device in a real oncology combinatorial experiment still remains to evaluate, but there is no doubt that, once there experiments will be done, SCCAs could become a key tool in oncology research

Reconfigurable microfluidic magnetic valve arrays: Towards a radiotherapy-compatible spheroid culture platform for the combinatorial screening of cancer therapies

We introduce here a microfluidic cell culture platform or spheroid culture chamber array (SCCA) that can synthesize, culture, and enable fluorescence imaging of 3D cell aggregates (typically spheroids) directly on-chip while specifying the flow of reagents in each chamber via the use of an array of passive magnetic valves. The SCCA valves demonstrated sufficient resistance to burst (above 100 mBar), including after receiving radiotherapy (RT) doses of up to 8 Gy combined with standard 37 degrees C incubation for up to 7 days, enabling the simultaneous synthesis of multiple spheroids from different cell lines on the same array. Our results suggest that SCCA would be an asset in drug discovery processes, seeking to identify combinatorial treatments

Taking the steps toward sustainable livestock: our multidisciplinary global farm platform journey

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Measurement of χ c1 and χ c2 production with s√ = 7 TeV pp collisions at ATLAS

The prompt and non-prompt production cross-sections for the χ c1 and χ c2 charmonium states are measured in pp collisions at s√ = 7 TeV with the ATLAS detector at the LHC using 4.5 fb−1 of integrated luminosity. The χ c states are reconstructed through the radiative decay χ c → J/ψγ (with J/ψ → μ + μ −) where photons are reconstructed from γ → e + e − conversions. The production rate of the χ c2 state relative to the χ c1 state is measured for prompt and non-prompt χ c as a function of J/ψ transverse momentum. The prompt χ c cross-sections are combined with existing measurements of prompt J/ψ production to derive the fraction of prompt J/ψ produced in feed-down from χ c decays. The fractions of χ c1 and χ c2 produced in b-hadron decays are also measured

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Single hadron response measurement and calorimeter jet energy scale uncertainty with the ATLAS detector at the LHC

The uncertainty on the calorimeter energy response to jets of particles is derived for the ATLAS experiment at the Large Hadron Collider (LHC). First, the calorimeter response to single isolated charged hadrons is measured and compared to the Monte Carlo simulation using proton-proton collisions at centre-of-mass energies of sqrt(s) = 900 GeV and 7 TeV collected during 2009 and 2010. Then, using the decay of K_s and Lambda particles, the calorimeter response to specific types of particles (positively and negatively charged pions, protons, and anti-protons) is measured and compared to the Monte Carlo predictions. Finally, the jet energy scale uncertainty is determined by propagating the response uncertainty for single charged and neutral particles to jets. The response uncertainty is 2-5% for central isolated hadrons and 1-3% for the final calorimeter jet energy scale.Comment: 24 pages plus author list (36 pages total), 23 figures, 1 table, submitted to European Physical Journal

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction