Optic Studies for the T9 Beam Line in the CERN PS East Area Secondary Beam Facility

The CERN PS East Area provides secondary beams in the momentum range from 1 to 15 GeV/c for tests of LHC detector components (e.g. for the LHC experiments) and for physics experiments (such as HARP). This latter experiment requires high quality beams of very small size within tight tolerances. In the framework of the HARP beam commissioning, extensive optic studies have been made. Simultaneous measurements of Twiss parameters and emittance were used to obtain a set of initial parameters at the production target. The measurements were consolidated by detailed tracking simulations. This paper gives an overview of the optics design and beam study activities in the T9 beam line of the PS East Area and compares measurements and simulation result

Inhibition of NF-κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes pro-survival stimuli to induce apoptosis in chronic lymphocytic leukemia cells

Purpose: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. Experimental Design: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry–based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flow cytometry, Western blotting, and quantitative real-time PCR. Results: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of IκBα expression. Conclusions: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL

Multisensory data fusion for localisation in mobile robotics

Mobile robotics is an essential application field for multisensor fusion . This paper presents some works performed in three Frenc h laboratories concerning the localisation of mobile robots . The proposed methods and algorithms combine the relative localisatio n obtained from vehicle referenced sensors (odometers and accelerometers) and measurements from world characteristics (punctua l beacons and landmarks) such as distances or angles . The main discussed formalism is Kalman filtering . Anyway, the method is shown to be adaptable to the use of bounded erro r estimation algorithms . This last technique has been found to be well suited to the treatment of blind zones in (restricted) visio n problems . Sensor fusion yields at the same time an estimation of the robot configuration (position, orientation, . . .) together wit h the uncertainty of this estimation . A generalisation of localisation algorithms in a partially known environment is further discussed . In this case, the position of poorly known beacons is updated in the same time the localisation of the robot is obtained from accurately known references . Additionally, an intelligent management of world referenced measurements is used to select the most useful data in order to limit th e computational burden of the localisation and to speed up the real time execution of the algorithms without significant degradatio n of estimator performances . The different solutions have been validated and are illustrated by simulations and real experiments .La robotique mobile est un champ d'application privilégié de la fusion de données multisensorielles. Cet article est une synthèse de travaux effectués dans trois laboratoires sur la localisation de véhicules mobiles. Après avoir défini le problème, nous présentons les algorithmes proposés combinant la localisation relative - obtenue par exploitation des données fournies par différents capteurs proprioceptifs (odomètre et centrale à inertie) - avec un recalage absolu par rapport à des balises ponctuelles ou des segments de droite - les mesures étant des distances et/ou des angles. Le formalisme retenu est principalement celui du filtrage de Kalman mais, de manière similaire, la localisation des véhicules peut être obtenue en mettant en oeuvre un algorithme d'estimation à erreur bornée. Cette dernière technique est bien adaptée pour la gestion de données manquantes dans des angles morts, point qui est également abordé. La fusion de données fournit non seulement une estimation de la configuration du robot (position, orientation,...) mais également l'incertitude avec laquelle cette grandeur est connue. Une généralisation des algorithmes dans un environnement qui n'est que partiellement connu est également présentée : la position des repères mal connus est recalée et la localisation du robot est effectuée avec des repères bien connus. Une gestion intelligente des données extéroceptives permet de sélectionner ou de prévoir celles qui sont les plus pertinentes, limitant ainsi les traitements et les calculs sans pour autant dégrader de façon significative les performances de l'estimateur de la configuration du véhicule. Les différentes solutions proposées ont été validées en simulation et partiellement testées sur site réel avec différents robots et capteurs

Comparison of large-angle production of charged pions with incident protons on cylindrical long and short targets

The HARP collaboration has presented measurements of the double-differential pi+/pi- production cross-section in the range of momentum 100 MeV/c <= p 800 MeV/c and angle 0.35 rad <= theta <= 2.15 rad with proton beams hitting thin nuclear targets. In many applications the extrapolation to long targets is necessary. In this paper the analysis of data taken with long (one interaction length) solid cylindrical targets made of carbon, tantalum and lead is presented. The data were taken with the large acceptance HARP detector in the T9 beam line of the CERN PS. The secondary pions were produced by beams of protons with momenta 5 GeV/c, 8 GeV/c and 12 GeV/c. The tracking and identification of the produced particles were performed using a small-radius cylindrical time projection chamber (TPC) placed inside a solenoidal magnet. Incident protons were identified by an elaborate system of beam detectors. Results are obtained for the double-differential yields per target nucleon d2 sigma / dp dtheta. The measurements are compared with predictions of the MARS and GEANT4 Monte Carlo simulations.Comment: 43 pages, 20 figure

Feasibility Study of a Neutron Time Of Flight Facility at the CERN-PS

This report summarises the feasibility study of a neutron time-of-flight facility at the CERN-PS as described in Refs. [1] and [2]. The idea is to extract at 24 GeV/cproton bunches (r.m.s. length ~7 ns) on to a target. The neutrons produced by spallation are directed to an experimental area located 230 m downstream throughout a vacuum pipe (diameter ~80 cm) making use of the existing TT2A tunnel about 7 m below the ISR tunne

Exosomes released by EBV-infected nasopharyngeal carcinoma cells convey the viral Latent Membrane Protein 1 and the immunomodulatory protein galectin 9

BACKGROUND: Nasopharyngeal carcinomas (NPC) are consistently associated with the Epstein-Barr virus (EBV). Their malignant epithelial cells contain the viral genome and express several antigenic viral proteins. However, the mechanisms of immune escape in NPCs are still poorly understood. EBV-transformed B-cells have been reported to release exosomes carrying the EBV-encoded latent membrane protein 1 (LMP1) which has T-cell inhibitory activity. Although this report suggested that NPC cells could also produce exosomes carrying immunosuppressive proteins, this hypothesis has remained so far untested. METHODS: Malignant epithelial cells derived from NPC xenografts – LMP1-positive (C15) or negative (C17) – were used to prepare conditioned culture medium. Various microparticles and vesicles released in the culture medium were collected and fractionated by differential centrifugation. Exosomes collected in the last centrifugation step were further purified by immunomagnetic capture on beads carrying antibody directed to HLA class II molecules. Purified exosomes were visualized by electron microscopy and analysed by western blotting. The T-cell inhibitory activities of recombinant LMP1 and galectin 9 were assessed on peripheral blood mononuclear cells activated by CD3/CD28 cross-linking. RESULTS: HLA-class II-positive exosomes purified from C15 and C17 cell supernatants were containing either LMP1 and galectin 9 (C15) or galectin 9 only (C17). Recombinant LMP1 induced a strong inhibition of T-cell proliferation (IC50 = 0.17 nM). In contrast recombinant galectin 9 had a weaker inhibitory effect (IC50 = 46 nM) with no synergy with LMP1. CONCLUSION: This study provides the proof of concept that NPC cells can release HLA class-II positive exosomes containing galectin 9 and/or LMP1. It confirms that the LMP1 molecule has intrinsic T-cell inhibitory activity. These findings will encourage investigations of tumor exosomes in the blood of NPC patients and assessment of their effects on various types of target cells

Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation

Oxazaphosphorines (Oxaza) represented by cyclophosphamide (CPA) and ifosfamide (IFO) are still the corner stone of several polychemotherapy protocols as they are widely indicated in the treatment of numerous cancer from soft tissue sarcomas to lymphomas and immune-related diseases. However, Oxaza are prodrugs requiring cytochrome (CYP) P450 bioactivation responsible of limiting adverse effects. In the case of IFO, bioactivation leads to a low release of 4-OH-IFO (10%), which generates the active nitrogen mustard displaying DNA cross-links. Associated toxicities of IFO due to acrolein, (urotoxicity) and to chloroacetaldehyde (neuro and nephrotoxicity) have been described. Thus, increasing IFO therapeutic index could be of major interest. To circumvent these toxicities, our team has designed new pre-activated IFO analogs to avoid CYP bioactivation (Skarbek et al J Med Chem 2015). Among these analogues some have the ability to self-assemble as nanoassemblies (NAs), the others can be encapsulated within nano-lipid capsules (NLCs). These new drug delivery systems (DDS) can take advantage of passive targeting, as stealthiness of these DDS can be provided by PEGylation by using Cholesterol-polyethylene glycol or the use of surfactant. These DDS can also be functionalized by appropriate monoclonal antibodies leading to multi stage DDS with active targeting properties. Regarding CPA, it has been shown and described in literature that low doses of CPA enhance the immunity by promoting differentiation of CD4⁺ cell toward Th1. As IFO is isomeric form of CPA, it was assumed that IFO could also have such properties. Studies on immunocompetent MCA205 mouse model, an immunogenic fibrosarcoma mouse model, demonstrate a dose-dependent immunomodulation of IFO towards a modulation of the secretion of IFNy, IL-17A and IL-6 cytokines. The ongoing experiments on mouse model depleted in CD4⁺ T cells and CD8⁺ T cells show the antitumor efficacy of IFO 150mg/kg on these immune cells in tumor regression. Both strategies could lead to the design of nano-immuno-conjugates (NICs) which could benefit of the immunomodulatory effects of X-Oxaza combined to their antiproliferative properties targeted through immune checkpoint antibodies. These new functionalized DDS may provide a useful strategy to give specificity to active drugs used for many years in clinical practice. Both DDS could be grafted with mAbs which could lead to a new family of DDS aiming to combine antiproliferative and immunomodulatory properties for a dual antitumoral action Citation Format: Julia Delahousse, Charles Skarbek, Valentine Gauthier, M Desbois, Emilie Roger, C. Pioche-Durieu, M. Rivard, D. Desmaële, T. Martens, E. LeCam, Jean-Pierre Benoit, P. Couvreur, Nathalie Chaput-Gras, Angelo Paci. Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2195. doi:10.1158/1538-7445.AM2017-219