Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia.

Background Immune-checkpoint (IC) inhibitors have revolutionized the treatment of multiple solid tumors and defined lymphomas, but they are largely ineffective in acute myeloid leukemia (AML). The reason why especially PD1/PD-L1 blocking agents are not efficacious is not well-understood but it may be due to the contribution of different IC ligand/receptor interactions that determine the function of T cells in AML. Methods To analyze the interactions of IC ligands and receptors in AML, we performed a comprehensive transcriptomic analysis of FACS-purified leukemia stem/progenitor cells and paired bone marrow (BM)-infiltrating CD4+ and CD8+ T cells from 30 patients with AML. The gene expression profiles of activating and inhibiting IC ligands and receptors were correlated with the clinical data. Epigenetic mechanisms were studied by inhibiting the histone deacetylase with valproic acid or by gene silencing of PAC1. Results We observed that IC ligands and receptors were mainly upregulated in leukemia stem cells. The gene expression of activating IC ligands and receptors correlated with improved prognosis and vice versa. In contrast, the majority of IC receptor genes were downregulated in BM-infiltrating CD8+ T cells and partially in CD4+ T cells, due to pathological chromatin remodeling via histone deacetylation. Therefore, treatment with histone deacetylase inhibitor (HDACi) or silencing of PAC1, as a T cell-specific epigenetic modulator, significantly increased the expression of IC receptors and defined effector molecules in CD8+ T cells. Conclusions Our results suggest that CD8+ T cells in AML are dysfunctional mainly due to pathological epigenetic silencing of activating IC receptors rather than due to signaling by immune inhibitory IC receptors, which may explain the limited efficacy of antibodies that block immune-inhibitory ICs in AML

Elimination of chronic viral infection by blocking CD27 signaling

Neutralizing antibody (nAb) responses to lymphocytic choriomeningitis virus (LCMV) in mice and immunodeficiency virus and hepatitis C virus in humans are usually weak and slow to develop. This may be the result of structural properties of the surface glycoprotein, a low frequency of B cells with neutralizing specificity, and the necessity of prolonged affinity maturation of specific nAbs. In this study, we show that during LCMV infection, CD27 signaling on CD4+ T cells enhances the secretion of interferon-γ and tumor necrosis factor-α. These inflammatory cytokines lead to the destruction of splenic architecture and immunodeficiency with reduced and delayed virus-specific nAb responses. Consequently, infection with the otherwise persistent LCMV strain Docile was eliminated after CD27 signaling was blocked. Our data provide a novel mechanism by which LCMV avoids nAb responses and suggest that blocking the CD27–CD70 interaction may be an attractive strategy to prevent chronic viral infection

II.5 Where to find the CoRoT data?

This book is dedicated to all the people interested in the CoRoT mission and the beautiful data that were delivered during its six year duration. Either amateurs, professional, young or senior researchers, they will find treasures not only at the time of this publication but also in the future twenty or thirty years. It presents the data in their final version, explains how they have been obtained, how to handle them, describes the tools necessary to understand them, and where to find them. It also highlights the most striking first results obtained up to now. CoRoT has opened several unexpected directions of research and certainly new ones still to be discovered

Estimating Be Star Disk Radii using H-alpha Emission Equivalent Widths

We present numerical models of the circumstellar disks of Be stars, and we describe the resulting synthetic H-alpha emission lines and maps of the wavelength-integrated emission flux projected onto the sky. We demonstrate that there are monotonic relationships between the emission line equivalent width and the ratio of the angular half-width at half maximum of the projected disk major axis to the radius of the star. These relationships depend mainly upon the temperatures of the disk and star, the inclination of the disk normal to the line of sight, and the adopted outer boundary for the disk radius. We show that the predicted H-alpha disk radii are consistent with those observed directly through long baseline interferometry of nearby Be stars (especially once allowance is made for disk truncation in binaries and for dilution of the observed H-alpha equivalent width by continuum disk flux in the V-band).Comment: 12 pages, 2 figures, ApJL in pres

The CDS information hub

The Centre de Donnees astronomiques de Strasbourg (CDS) provides homogeneousaccess to heterogeneous information of various origins: information aboutastronomical objects in Simbad; catalogs and observation logs in VizieR and inthe catalogue service; reference images and overlays in Aladin; nomenclature inthe Dictionary of Nomenclature; Yellow Page services; the AstroGLU resourcediscovery tool; mirror copies of other reference services; and documentation.With the implementation of links between the CDS services, and with otheron--line reference information, CDS has become a major hub in the rapidlyevolving world of information retrieval in astronomy, developing efficienttools to help astronomers to navigate in the world-wide `Virtual Observatory'under construction, from data in the observatory archives to results publishedin journals. The WWW interface to the CDS services is available at:http://cdsweb.u-strasbg.fr

Near and mid-IR sub-arcsecond structure of the dusty symbiotic star R Aqr

The results of a high-resolution interferometric campaign targeting the symbiotic long-period variable (LPV) R~Aqr are reported. With both near-infrared measurements on baselines out to 10m and mid-infrared data extending to 32m, we have been able to measure the characteristic sizes of regions from the photosphere of the LPV and its extended molecular atmosphere, out to the cooler circumstellar dust shell. The near-infrared data were taken using aperture masking interferometry on the Keck-I telescope and show R~Aqr to be partially resolved for wavelengths out to 2.2 microns but with a marked enlargement, possibly due to molecular opacity, at 3.1 microns. Mid-infrared interferometric measurements were obtained with the U.C. Berkeley Infrared Spatial Interferometer (ISI) operating at 11.15 microns from 1992 to 1999. Although this dataset is somewhat heterogeneous with incomplete coverage of the Fourier plane and sampling of the pulsation cycle, clear changes in the mid-infrared brightness distribution were observed, both as a function of position angle on the sky and as a function of pulsation phase. Spherically symmetric radiative transfer calculations of uniform-outflow dust shell models produce brightness distributions and spectra which partially explain the data, however limitations to this approximation are noted. Evidence for significant deviation from circular symmetry was found in the mid-infrared and more tentatively at 3.08 microns in the near-infrared, however no clear detection of binarity or of non-LPV elements in the symbiotic system is reported.Comment: Accepted to Astrophysical Journal. To appear in volume 534. 14 pages; 3 postscript figure

MOST observations of the roAp stars HD 9289, HD 99563, and HD 134214

We report on the analysis of high-precision space-based photometry of the roAp (rapidly oscillating Ap) stars HD 9289, HD 99563, and HD134214. All three stars were observed by the MOST satellite for more than 25 days, allowing unprecedented views of their pulsation. We find previously unknown candidate frequencies in all three stars. We establish the rotation period of HD 9289 (8.5 d) for the first time and show that the star is pulsating in two modes that show different mode geometries. We present a detailed analysis of HD 99563's mode multiplet and find a new candidate frequency which appears independent of the previously known mode. Finally, we report on 11 detected pulsation frequencies in HD 134214, 9 of which were never before detected in photometry, and 3 of which are completely new detections. Thanks to the unprecedentedly small frequency uncertainties, the p-mode spectrum of HD 134214 can be seen to have a well-defined large frequency spacing similar to the well-studied roAp star HD 24712 (HR 1217).Comment: 11 pages, 12 figures, accepted for publication in A&

CD27 Expression Promotes Long-Term Survival of Functional Effector–Memory CD8+Cytotoxic T Lymphocytes in HIV-infected Patients

Human immunodeficiency virus (HIV)-specific CD8+ T cells persist in high frequencies in HIV-infected patients despite impaired CD4+ T helper response to the virus, but, unlike other differentiated effector cytotoxic T lymphocytes, most continue to express the tumor necrosis factor receptor family member CD27. Because the ligand for CD27 (CD70) is also overexpressed in HIV-infected hosts, we examined the nature of expression and potential functional consequences of CD27 expression on HIV-specific CD8+ T cells. Analysis of CD27+ and CD27− T cells derived from the same HIV-specific clone revealed that retention of CD27 did not interfere with acquisition of effector functions, and that after T cell receptor stimulation, CD27+ cells that concurrently were triggered via CD27 exhibited more resistance to apoptosis, interleukin 2 production, and proliferation than CD27− T cells. After transfer back into an HIV-infected patient, autologous HIV-specific CD27− T cells rapidly disappeared, but CD27+ T cells derived from the same clone persisted at high frequency. Our findings suggest that the CD27–CD70 interaction in HIV infection may provide CD27+ CD8+ T cells with a survival advantage and compensate for limiting or absent CD4+ T help to maintain the CD8 response