CpG-ODN-induced sustained expression of BTLA mediating selective inhibition of human B cells.

BTLA (B- and T-lymphocyte attenuator) is a prominent co-receptor that is structurally and functionally related to CTLA-4 and PD-1. In T cells, BTLA inhibits TCR-mediated activation. In B cells, roles and functions of BTLA are still poorly understood and have never been studied in the context of B cells activated by CpG via TLR9. In this study, we evaluated the expression of BTLA depending on activation and differentiation of human B cell subsets in peripheral blood and lymph nodes. Stimulation with CpG upregulated BTLA, but not its ligand: herpes virus entry mediator (HVEM), on B cells in vitro and sustained its expression in vivo in melanoma patients after vaccination. Upon ligation with HVEM, BTLA inhibited CpG-mediated B cell functions (proliferation, cytokine production, and upregulation of co-stimulatory molecules), which was reversed by blocking BTLA/HVEM interactions. Interestingly, chemokine secretion (IL-8 and MIP1β) was not affected by BTLA/HVEM ligation, suggesting that BTLA-mediated inhibition is selective for some but not all B cell functions. We conclude that BTLA is an important immune checkpoint for B cells, as similarly known for T cells

Aging studies of Micromegas prototypes for the HL-LHC

The micromegas technology is a promising candidate to replace the forward muon chambers for the luminosity upgrade of ATLAS. The LHC accelerator luminosity will be five times the nominal one, increasing background and pile-up event probability. This requires detector performances which are currently under study in intensive R&D activities. Aging is one of the key issues for a high-luminosity LHC application. For this reason, we study the properties of resistive micromegas detectors under intense X-ray radiation and under thermal neutrons in different CEA-Saclay facilities. This study is complementary to those already performed using fast neutrons.Comment: Proceedings of the MPGD2011 Conferenc

Immunoregulation of Dendritic Cell Subsets by Inhibitory Receptors in Urothelial Cancer.

Blockade of inhibitory receptors (IRs) overexpressed by T cells can activate antitumor immune responses, resulting in the most promising therapeutic approaches, particularly in bladder cancer, currently able to extend patient survival. Thanks to their ability to cross-present antigens to T cells, dendritic cells (DCs) are an immune cell population that plays a central role in the generation of effective antitumor T-cell responses. While IR function and expression have been investigated in T cells, very few data are available for DCs. Therefore, we analyzed whether DCs express IRs that can decrease their functions. To this end, we investigated several IRs (PD-1, CTLA-4, BTLA, TIM-3, and CD160) in circulating CD1c javax.xml.bind.JAXBElement@4f1331d4 DCs, CD141 javax.xml.bind.JAXBElement@68e4feef DCs, and plasmacytoid DCs from healthy donors and patients with urothelial cancer (UCa). Different DC subsets expressed BTLA and TIM-3 but not other IRs. More importantly, BTLA and TIM-3 were significantly upregulated in DCs from blood of UCa patients. Locally, bladder tumor-infiltrating DCs also overexpressed BTLA and TIM-3 compared to DCs from paired nontumoral tissue. Finally, in vitro functional experiments showed that ligand-mediated engagement of BTLA and TIM-3 receptors significantly reduced the secretion of effector cytokines by DC subpopulations. Our findings demonstrate that UCa induces local and systemic overexpression of BTLA and TIM-3 by DCs that may result in their functional inhibition, highlighting these receptors as potential targets for UCa treatment. We investigated the expression and function of a panel of inhibitory receptors in dendritic cells (DCs), an immune cell subpopulation critical in initiation of protective immune responses, among patients with urothelial carcinoma. We found high expression of BTLA and TIM-3 by blood and tumor DCs, which could potentially mediate decreased DC function. The results suggest that BTLA and TIM-3 might be new targets for urothelial carcinoma treatment

Identification of Urine Biomarkers to Improve Eligibility for Prostate Biopsy and Detect High-Grade Prostate Cancer

PCa screening is based on the measurements of the serum prostate specific antigen (PSA) to select men with higher risks for tumors and, thus, eligible for prostate biopsy. However, PSA testing has a low specificity, leading to unnecessary biopsies in 50–75% of cases. Therefore, more specific screening opportunities are needed to reduce the number of biopsies performed on healthy men and patients with indolent tumors. Urine samples from 45 patients with elevated PSA were collected prior to prostate biopsy, a mass spectrometry (MS) screening was performed to identify novel biomarkers and the best candidates were validated by ELISA. The urine quantification of PEDF, HPX, CD99, CANX, FCER2, HRNR, and KRT13 showed superior performance compared to PSA. Additionally, the combination of two biomarkers and patient age resulted in an AUC of 0.8196 (PSA = 0.6020) and 0.7801 (PSA = 0.5690) in detecting healthy men and high-grade PCa, respectively. In this study, we identified and validated novel urine biomarkers for the screening of PCa, showing that an upfront urine test, based on quantitative biomarkers and patient age, is a feasible method to reduce the number of unnecessary prostate biopsies and detect both healthy men and clinically significant PCa

Single electron response and energy resolution of a Micromegas detector

Micro-Pattern Gaseous Detectors (MPGDs) such as Micromegas or GEM are used in particle physics experiments for their capabilities in particle tracking at high rates. Their excellent position resolutions are well known but their energy characteristics have been less studied. The energy resolution is mainly affected by the ionisation processes and detector gain fluctuations. This paper presents a method to separetely measure those two contributions to the energy resolution of a Micromegas detector. The method relies on the injection of a controlled number of electrons. The Micromegas has a 1.6-mm drift zone and a 160-$\mu$m amplification gap. It is operated in Ne 95%-iC$\mathrm{_4}$H$\mathrm{_{10}}$ 5% at atmospheric pressure. The electrons are generated by non-linear photoelectric emission issued from the photons of a pulsed 337-nm wavelength laser coupled to a focusing system. The single electron response has been measured at different gains (3.7 10$\mathrm{^4}$, 5.0 10$\mathrm{^4}$ and 7.0 10$\mathrm{^4}$) and is fitted with a good agreement by a Polya distribution. From those fits, a relative gain variance of 0.31$\pm$0.02 is deduced. The setup has also been characterised at several voltages by fitting the energy resolution measured as a function of the number of primary electrons, ranging from 5 up to 210. A maximum value of the Fano factor (0.37) has been estimated for a 5.9 keV X-rays interacting in the Ne 95%-iC$\mathrm{_4}$H$\mathrm{_{10}}$ 5% gas mixture.Comment: Preprint submitted to Nuclear Instrumentation and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment; Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment in press (2009

ChPT tests at the NA48 and NA62 experiments at CERN

The NA48/2 Collaboration at CERN has accumulated unprecedented statistics of rare kaon decays in the Ke4 modes: Ke4(+-) ($K^\pm \to \pi^+ \pi^- e^\pm \nu$) and Ke4(00) ($K^\pm \to \pi^0 \pi^0 e^\pm \nu$) with nearly one percent background contamination. The detailed study of form factors and branching rates, based on these data, has been completed recently. The results brings new inputs to low energy strong interactions description and tests of Chiral Perturbation Theory (ChPT) and lattice QCD calculations. In particular, new data support the ChPT prediction for a cusp in the $\pi^0\pi^0$ invariant mass spectrum at the two charged pions threshold for Ke4(00) decay. New final results from an analysis of about 400 $K^\pm \to \pi^\pm \gamma \gamma$ rare decay candidates collected by the NA48/2 and NA62 experiments at CERN during low intensity runs with minimum bias trigger configurations are presented. The results include a model-independent decay rate measurement and fits to ChPT description.Comment: XIIth International Conference on Heavy Quarks and Leptons 2014, Mainz, German

First Observation and Measurement of the Decay K+- -> pi+- e+ e- gamma

Using the full data set of the NA48/2 experiment, the decay K+- -> pi+- e+ e- gamma is observed for the first time, selecting 120 candidates with 7.3 +- 1.7 estimated background events. With K+- -> pi+- pi0D as normalisation channel, the branching ratio is determined in a model-independent way to be Br(K+- -> pi+- e+ e- gamma, m_eegamma > 260 MeV/c^2) = (1.19 +- 0.12_stat +- 0.04_syst) x 10^-8. This measured value and the spectrum of the e+ e- gamma invariant mass allow a comparison with predictions of Chiral Perturbation Theory.Comment: 13 pages, 3 figures. Accepted for publication in Phys.Lett.

Empirical parameterization of the K+- -> pi+- pi0 pi0 decay Dalitz plot

As first observed by the NA48/2 experiment at the CERN SPS, the \p0p0 invariant mass (M00) distribution from \kcnn decay shows a cusp-like anomaly at M00=2m+, where m+ is the charged pion mass. An analysis to extract the pi pi scattering lengths in the isospin I=0 and I=2 states, a0 and a2, respectively, has been recently reported. In the present work the Dalitz plot of this decay is fitted to a new empirical parameterization suitable for practical purposes, such as Monte Carlo simulations of K+- -> pi+- pi0 pi0 decays.Comment: 9 pages, 3 figures