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Laurent C.,Institut Universitaire de France | Laurent C.,French Institute of Health and Medical Research | Laurent C.,University Paul Sabatier | Laurent C.,Laboratoire dExcellence TOUCAN | And 9 more authors.
Medicine (United States) | Year: 2015

Non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) represent a heterogeneous group of malignant lymphoid tumors, which have distinct histological and/or biological characteristics with preferential nodal involvement. However, none of the previous studies have assessed the prevalence of common NHL and HL subtypes at each nodal site of involvement. The aim of our study was to determine the prevalence of HL and NHL subtypes depending on their nodal sites of involvement. We conducted a single-center retrospective study of 938 lymphoma cases diagnosed in the Pathology Department of Toulouse Purpan Hospital in France between 2001 and 2008, taking into account the site that corresponded to the diagnostic biopsy. The most frequent sites were cervical lymph nodes (36.8% of all cases), inguinal lymph nodes (16.4%), axillary lymph nodes (11.9%), and supraclavicular lymph nodes (11%). We found an unexpected association between intraparotid nodes and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and between inguinal nodes and follicular lymphoma. The risk of having classical Hodgkin lymphoma (CHL) was 15 times greater in patients with mediastinal lymphoma compared to those with other sites of involvement. Regarding HL, nodal and extranodal mediastinal sites and supraclavicular nodes were more likely to be involved by nodular sclerosis Hodgkin lymphoma (NSCHL). In addition, intra-abdominal lymph nodes were more frequently involved by lymphocyte depleted Hodgkin lymphoma compared to inguinal nodes where NLPHL predominated. Our study shows that some lymph node sites have a disproportionate prevalence of specific subtypes of lymphoma. Identifying these sites may aid to diagnose and better elucidate the pathogenesis of these tumors. © 2015 Wolters Kluwer Health, Inc.

Ycart B.,Joseph Fourier University | Ycart B.,CNRS Jean Kuntzmann Laboratory | Ycart B.,Laboratoire dExcellence TOUCAN | Pont F.,Laboratoire dExcellence TOUCAN | And 7 more authors.
Journal of Biomedical Informatics | Year: 2014

Fisher's exact test is widely used in biomedical research, particularly in genomic profile analysis. Since in most databases, the frequency distribution of genes is right skewed, we show here that its use can lead to excessive false-positive discoveries. We propose to apply Zelen's exact test on a stratification of the gene set; this solves the false discovery problem, and should avoid misleading interpretations of lists of genes produced by various genome-wide analysis technologies. © 2013 Elsevier Inc.

Tosolini M.,French Institute of Health and Medical Research | Tosolini M.,University Paul Sabatier | Tosolini M.,French National Center for Scientific Research | Tosolini M.,Laboratoire dExcellence TOUCAN | And 29 more authors.
Molecular and Cellular Biology | Year: 2015

Cyclic dinucleotides are important messengers for bacteria and protozoa and are well-characterized immunity alarmins for infected mammalian cells through intracellular binding to STING receptors. We sought to investigate their unknown extracellular effects by adding cyclic dinucleotides to the culture medium of freshly isolated human blood cells in vitro. Here we report that adenosine-containing cyclic dinucleotides induce the selective apoptosis of monocytes through a novel apoptotic pathway. We demonstrate that these compounds are inverse agonist ligands of A2a, a Gαs-coupled adenosine receptor selectively expressed by monocytes. Inhibition of monocyte A2a by these ligands induces apoptosis through a mechanism independent of that of the STING receptors. The blockade of basal (adenosine-free) signaling from A2a inhibits protein kinase A (PKA) activity, thereby recruiting cytosolic p53, which opens the mitochondrial permeability transition pore and impairs mitochondrial respiration, resulting in apoptosis. A2a antagonists and inverse agonist ligands induce apoptosis of human monocytes, while A2a agonists are antiapoptotic. In vivo, we used a mock developing human hematopoietic system through NSG mice transplanted with human CD34+ cells. Treatment with cyclic di-AMP selectively depleted A2a-expressing monocytes and their precursors via apoptosis. Thus, monocyte recognition of cyclic dinucleotides unravels a novel proapoptotic pathway: the A2a Gαs protein-coupled receptor (GPCR)-driven tonic inhibitory signaling of mitochondrion-induced cell death. © 2015, American Society for Microbiology.

Tosolini M.,French Institute of Health and Medical Research | Tosolini M.,University Paul Sabatier | Tosolini M.,French National Center for Scientific Research | Tosolini M.,Laboratoire dExcellence TOUCAN | And 10 more authors.
European Journal of Immunology | Year: 2015

Cyclic dinucleotides, a class of microbial messengers, have been recently identified in bacteria, but their activity in humans remains largely unknown. Here, we have studied the function of cyclic dinucleotides in humans. We found that c-di-AMP and cGAMP, two adenosine-based cyclic dinucleotides, activated T lymphocytes in an unusual manner through monocyte cell death. c-di-AMP and cGAMP induced the selective apoptosis of human monocytes, and T lymphocytes were activated by the direct contact with these dying monocytes. The ensuing T-cell response comprised cell-cycle exit, phenotypic maturation into effector memory cells and proliferation arrest, but not cell death. This quiescence was transient since T cells remained fully responsive to further restimulation. Together, our results depict a novel activation pattern for human T lymphocytes: a transient quiescence induced by c-di-AMP- or cGAMP-primed apoptotic monocytes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Laurent C.,Institut Universitaire de France | Charmpi K.,Laboratoire dExcellence TOUCAN | Charmpi K.,Laboratoire Jean Kuntzmann | Gravelle P.,Institut Universitaire de France | And 6 more authors.
OncoImmunology | Year: 2015

Follicular Lymphomas (FL) and diffuse large B cell lymphomas (DLBCL) must evolve some immune escape strategy to develop from lymphoid organs, but their immune evasion pathways remain poorly characterized. We investigated this issue by transcriptome data mining and immunohistochemistry (IHC) of FL and DLBCL lymphoma biopsies. A set of genes involved in cancer immune-evasion pathways (Immune Escape Gene Set, IEGS) was defined and the distribution of the expression levels of these genes was compared in FL, DLBCL and normal B cell transcriptomes downloaded from the GEO database. The whole IEGS was significantly upregulated in all the lymphoma samples but not in B cells or other control tissues, as shown by the overexpression of the PD-1, PD-L1, PD-L2 and LAG3 genes. Tissue microarray immunostainings for PD-1, PD-L1, PD-L2 and LAG3 proteins on additional biopsies from 27 FL and 27 DLBCL patients confirmed the expression of these proteins. The immune infiltrates were more abundant in FL than DLBCL samples, and the microenvironment of FL comprised higher rates of PD-1+ lymphocytes. Further, DLBCL tumor cells comprised a higher proportion of PD-1+, PD-L1+, PD-L2+ and LAG3+ lymphoma cells than the FL tumor cells, confirming that DLBCL mount immune escape strategies distinct from FL. In addition, some cases of DLBCL had tumor cells co-expressing both PD-1, PD-L1 and PD-L2. Among the DLBCLs, the activated B cell (ABC) subtype comprised more PD-L1+ and PD-L2+ lymphoma cells than the GC subtype. Thus, we infer that FL and DLBCL evolved several pathways of immune escape. © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC.

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