Molecular and immunological mechanisms of clonal evolution in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages

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

Molecular and immunological mechanisms of clonal evolution in multiple myeloma

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages

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

Age and environment affect constitutive immune function in Red Knots (Calidris canutus)

We studied subspecies, age and environmental effects on constitutive immune function (natural antibody and complement titres, haptoglobin activity and leukocyte concentrations) in Red Knots (Calidris canutus). We compared C. c. islandica and C. c. canutus in the Wadden Sea and found no difference in immune function between subspecies. However, C. c. canutus on their wintering grounds in Banc d’Arguin had higher natural antibody and lower complement levels than C. c. canutus or C. c. islandica in the Wadden Sea. This suggests that immune function is determined more by the surrounding environment than by subspecies. We also compared age classes in the Wadden Sea and found that first year birds had significantly lower natural antibody levels than adults, but that second year birds no longer differed from adults. Finally, we examined the interaction of age and environment in Banc d’Arguin. We found that first year birds (but not adults) in a low quality habitat had higher leukocyte concentrations than first year birds or adults in a high quality habitat. Differences in available resources and defence needs between environments, and differences among individuals differentially distributed between sites, are likely important contributors to the variation in immune function we report. Future studies, which examine these factors on wild birds, will be important for our understanding of how animals function in their natural environment.

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