dataesr/scientific-paragraphs-categorization huggingface dataset:
See P, Dutertre CA, Chen J, et al. Mapping the human DC lineage through the integration of highdimensional techniques. Science 2017 ; 56. pii: eaag3009. doi: 10. 1126/science. aag3009. 7. Villani AC, Satija R, Reynolds G, et al. Single-cell RNAseq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science 2017 ; 3. pii: eaah4573. doi: 10. 1126/science. aah4573. 8. Müller-Trutwin M, Hosmalin A. Role for plasmacytoid dendritic cells in anti-HIV innate immunity. Immunol Cell Biol 2005 ; 83 : 578-85. REMERCIEMENTS Ces travaux de recherche ont été soutenus par les subventions suivantes, attribuées à Philippe Benaroch : ANRS (agence nationale de recherche contre le SIDA et les hépatites virales) ECTZ72276, Sidaction (Ensemble contre le SIDA) 2018-1-AEQ-11984, ANR (agence nationale pour la recherche) ANR-10-IDEX-0001-02 PSL et ANR-11-LABX-0043.
Source des données La source des données est le Système national d'information inter-régimes de l'assurance maladie (SNIIRAM). Cette base de données contient des informations individualisées, anonymes et combinables. Ces données sont enregistrées de fac on prospective pour pratiquement chaque patient bénéficiant de l'assurance maladie en France. Elles comprennent des données démographiques, ou concernant les affections de longue durée invalidantes (ALD) permettant le remboursement à 100 % des dépenses médicales, des hospitalisations, les actes médicaux et la délivrance de médicaments hors cadre hospitalier, notamment les vaccins  [17]. Les données relatives à la distribution de médicaments hors du cadre hospitalier comprennent le nom du médicament, son dosage et sa forme galénique, la quantité délivrée et la date de distribution.
Sélection des patients Ce processus a été décrit dans un article précédant  [16]. En bref, les données de tous les patients présentant au moins un code ACG d'ALD (code M31. 5 « Artérite à cellules géantes avec pseudo polyarthrite rhizomélique (PPR) » ou M31. 6 « Autres artérites à cellules géantes » de la Classification internationale des maladies, 10 e version) ont été extraites de la base de données SNIIRAM de la région Midi-Pyrénées, de 2005 à 2008 auxquels nous avons appliqué les critères d'inclusions suivant : • cas incident d'ACG défini par : patients recevant des GC depuis au moins 6 mois, ET n'ayant pas été exposés précédemment à des GC au cours des 6 mois précédents, ET la première prescription correspondant à une dose d'équivalent prednisone comprise entre 5 et 150 mg/j ; • patient de 65 ans ou plus.
Exposition aux vaccins Nous avons évalué la distribution du vaccin anti grippal dans la base de données de remboursement des médicaments hors cadre hospitalier de 2005 à avril 2011. Chaque année, le vaccin anti grippal saisonnier est disponible en pharmacie à partir de la fin de septembre et les campagnes de vaccination se poursuivent jusqu'au 31 janvier de l'année suivante.
par un transporteur du pore nucléaire, la transportine-1, et ont ainsi permis de mieux comprendre les étapes qui contrôlent l'entrée du VIH dans le noyau des cellules cibles. Étonnamment, la transportine-1 a aussi été identifiée comme favorisant le désassemblage et l'import nucléaire de l'adénovirus  [16]  et du virus de la grippe  [17] , ce qui permet d'envisager le développement de médicaments antiviraux à large spectre qui cibleraient l'entrée de virus dans le noyau. ‡ Transportin-1 orchestrates HIV-1 uncoating and nuclear entry REMERCIEMENTS Ce travail a bénéficié d'une aide du Labex EpiGenMed au titre du programme Investissements d'avenir (référence ANR-10-LABX-12-01), du programme ATIP-Avenir, de l'ANRS (Agence nationale de recherche sur le SIDA), et du Sidaction.
Résumé Introduction : Le rhumatisme psoriasique (PsA) est un rhumatisme inflammatoire chronique caractérisé de longue date par un risque cardiovasculaire important. Au cours des dernières années, les données épidémiologiques ont quelque peu changé depuis l'utilisation croissante de biomédicaments efficaces pour réduire cette inflammation. L'objectif de cette revue est d'évaluer les données actuelles sur la morbidité et la mortalité cardiovasculaires dans le PsA et d'évaluer le risque cardiovasculaire en cas de PsA. Méthode : Nous avons effectué une revue de la littérature sur les bases de données Pubmed et Medline en utilisant les mots clés suivants : " Psoriatic Arthritis " AND « Cardiovascular ».
Méthodes Nous avons réalisé une revue de la littérature sur les bases de données Pubmed et Medline comprenant des articles liés au risque cardiovasculaire parus de 2017 à 2019. Les différents mots-clés choisis étaient "Psoriatic Arthritis" and "Cardiovascular Risk", "mortality", "hypertension", diabetes", "dyslipidemia", "obesity", "smoking". Nous avons retenu uniquement les articles rédigés en anglais.
DMARDS biologiques L'impact des biomédicaments sur le risque CV a été largement évalué dans la PR. Dans le PsA, cette question a également fait l'objet de publications récentes. Lee et al  [54]  ont évalué, sur la base de données ARAD incluant 412 patients atteints de PsA, l'incidence des événements cardiovasculaires majeurs (MACE) sur un intervalle minimum de 12 mois. Ils ont ainsi démontré un effet protecteur des inhibiteurs du TNF (HR 0,85 [0,76-0,95]) et des autres bDMARD (HR 0,81 [0,70-0,95]) avec une diminution de la probabilité de survenue des événements CV. Une méta-analyse réalisée en 2016  [59]  comprenant 20 articles et 2261 patients a confirmé la présence d'une altération de la fonction endothéliale et de l'épaisseur intima-média dans le PsA. De plus, ils ont observé une diminution du risque de MACE secondaire à l'utilisation d'inhibiteurs du TNF par rapport à la photothérapie (RR 0,58 ; IC à 95 %, 0,43-0,77 ; P < 0,001) ou au méthotrexate (RR 0,67 ; IC à 95 %, 0,52-0,88 ; P = 0,003).
Transcriptional states of CD3 + tumor-infiltrating lymphocytes in NSCLC We performed scRNA-seq on CD3 + T cells from 11 primary, untreated, early-stage resected NSCLC patients (Fig. 1A ). For six of these patients, matched scTCR-seq information was also collected. Combined analysis of all patient samples identified a large source of variation associated with 3' versus 5'-oriented single cell chemistries (Fig. S1A-C ) that was resolved using computational methods  (18). Rigorous assessment of intra-sample heterogeneity, including TCR, showed that integration did not over correct the sample expression profiles. After removing contaminating cell types, we collected data on 28,936 cells over the 11 patients (Fig. 1 B ). Uniform Manifold Approximation and Projection (UMAP) and unsupervised graph-based clustering partitioned cells into 21 clusters based on their transcriptome (Fig.
(13)  are also highly expressed on the left and right ends of this axis, respectively. Comparison of our dataset with a study on chronic viral infection in mice  (25) , shows progenitor and terminal exhausted signatures with enhanced expression on the left and right ends of this axis, respectively (Fig. S2A  and B ). These results suggest that CD8 + T cell clusters on the left of the UMAP are "memory-like precursors" (clusters CD8-GZMK, CD8-KLF2 and CD8-XCL1) and those on the right part of the UMAP (CD8-GZMH and CD8-LAYN) are more differentiated, and most likely related to late exhausted/dysfunctional cells. Memory-like precursors include 2 main sub-clusters, CD8-GZMK/CD8-KLF2 and CD8-XCL1, expressing high levels of the Guo et al. (13)  GZMK and ZNF683 signatures respectively (Fig. 2A ). Memory-like precursors are enriched in signatures of negative regulation of cell proliferation, while terminally differentiated cells are enriched for lympho cyte activation-related genes and adhesion integrins (Fig.
Two distinct circulating precursor subsets Previous studies have associated precursor CD8 + TILs to favorable prognosis and to better response to ICB-based immunotherapies  (25). To investigate the possible relevance of the different clusters defined here to clinical outcomes, we compared our dataset to a previous single -cell study from Sade-Feldman et al. (17)  and applied signatures from melanoma patients responding (good response) versus not responding (bad response) to ICB. CD8 -KLF2-circulating and CD8-XCL1resident precursor clusters express higher levels of the good response signature (Fig. 2 B  and C ). In contrast, CD8-LAYN and CD8-GZMH late clusters, and a part of CD8-GZMK early clusters, express higher levels of the poor response signature (Fig. 2B  and C ). Differential analysis of genes expressed in the CD8-KLF2 and CD8-GZMK clusters reveals that cells in the latter overexpress genes related to T cell activation (HLA-DR/DP/DQ), effector related genes (KLRG1, GZMB, H, A, in addition to GZMK) and chemokines (CXCR6, CCL5) (Fig.
2D  and E ). The CD8-KLF2 cluster overexpresses genes related to the control of CD8 + T cell differentiation, including NR4A1/2/3 and KLF2 (Fig. 2D  and E ). These two closely related populations of CD8 + TILs are also present in other public datasets  (Sade Feldman et al. 2018 , Guo et al. 2018 , Azizi et al. 2018)   (13, 16, 17)  , including some generated on different technological platforms (SMART-Seq2/Mars-Seq) and in other tumor types, such as melanoma and breast carcinoma (Fig. S2C ).
We quantified robustness of clustering using the silhouette score (Fig. 3  G, Fig. S3E ), which validates consistency by evaluating how close each cell inside a cluster is to its neighboring cells within the same cluster (high score), compared to its neighboring cells in other clusters (low score). As shown in Fig. 3G , the silhouette score is lower for cells in the CD8-GZMH cluster, as compared to cells in all other CD8 + clusters. Consistent with this analysis, label transfer, a method introduced for the integration of multiple single-cell datasets  (18) , of cells from the CD8-GZMH cluster shows even projection to the corresponding neighboring clusters, including CD8 -GZMK (upper left part of the UMAP), CD8-XCL1 (lower left) and CD8-LAYN (to the right) (Fig 3H, Fig. S3F ). These results, as hypothesized earlier, are consistent with early precursor CD8 + populations (CD8-GZMK, CD8-KLF2 and CD8-XCL1) differentiating into terminally dysfunctional CD8-LAYN cells, via a transitional CD8-GZMH state.
Terminally differentiated, not memory-like, CD8 + T cells are in cell cycle The question of the cycling activity of early memory-like vs. late terminally differentiated TILs is still a matter of debate  (34). As T cells require TCR signaling to enter the cell cycle, clones identified to be actively cycling intratumorally strongly suggest a local (intratumor) source of antigen. Because cell cycle-related genes are expressed at high levels, cycling cells cluster independently in scRNA-seq analyses. These clusters, however, may include cells that also bear underlying signatures from other clusters, which are in some way "masked" by highly expressed cell cycle genes. We took two independent approaches to investigate if the cells in the cycling cluster are related to other particular clusters. First, we focused on the transcriptomic dataset.
S5B ). The CD8-LAYN subset has previously been associated with exhausted/dysfunctional CD8 + T cells  (13, 33, 35, 36). Among cycling cells, the ones transcriptionally related to the CD8-LAYN cluster by label transfer also express higher levels of DNA damage repair genes (Fig. S5C ). These cells also express higher levels of gene signatures for DNA damage repair and stress (Fig. 5E ), as well as of the terminal differentiated LAYN signature (13) (Fig. S5D ), as compared to cycling cells reattributed to the CD8-GZMH cluster. Analysis of the Guo et al. dataset  (13)  for the cycling signature shows that the LAYN and the cycling populations also overlap (Fig. S5E ), suggesting that late differentiating cells, and not early progenitors, are the main cycling T cells in NSCLC TILs. Next, we reasoned that if late differentiating cells cycle, clonally amplified TCRs in these clusters should also be found in cycling T cells.
Software versions Data were collected using Cell Ranger software (10X Genomics) v. 2. 2. 032, and analyzed using R v. 3. 5. 1, and the following packages and versions in R for analysis: Seurat v3. 1. 1, ENHANCE v1. 0. 0, DroptletUtils v1. 8, clustree v0. 4. 1, cluster v2. 1. 0 Two-dimensional gene expression maps were generated using coordinates from the UMAP algorithm 39 using the R package uwot v0. 1. 3 implementation. Figures were produced using the following packages and versions in R: RColorBrewer v1. 1-2; pheatmap v1. 0. 12; ggplot v3. 2. 0; ggsignif v0. 6. 0.
Human specimens Eleven patients, who were pathologically diagnosed with NSCLC were enrolled in this study, including 10 adenocarcinoma and one squamous-cell carcinoma patients. All patients were untreated, in early disease stage. Tumor tissue samples were obtained from all 11 NSCLC resected patients. For 4 of them paired peripheral blood was also collected and analyzed. Among those 4, for 2 of the patients, matched adjacent normal lung tissue was collected and analyzed. All samples were collected from the Institute Mutualiste Montsouris, under a dedicated protocol for lung cancer specimens approved by the French Ethics and Informatics Commission (EUdract 2017 -A03081-52). All patients in this study provided written informed consent for sample collection and d ata analysis. Tumor tissue and adjacent normal lung tissue were obtained from surgical specimens, after macroscopic examination of the tissue by a pathologist.
Flow cytometry and antibodies Flow cytometry analysis was performed in a dataset of 10 additional untreated NSCLC patients, in early disease stage. For the isolation of lymphocytes from tumor tissue and normal adjacent lung tissues, as well as of PBMCs, the same steps pre-described above were followed. For negative selection of CD3 + T cells we used the Pan T cell Isolation Kit (Miltenyi), that leads to approximately 80% purity. All cells were then stained in 1X PBS buffer with Zombie NIR fixable viability kit (#B262784, Biolegend) according to the manufacturer instructions, using a combination of monoclonal antibodies from the following: CD3 -AF532 Samples were analyzed using a Cytek®Aurora spectral flow cytometer. Gating was applied by using monocolors and FMO controls. Data analysis was performed using FlowJo v.
Single-cell RNA/TCR seq data processing Single-cell expression was analyzed using the Cell Ranger single-cell Software Suite (v2. 0. 1 and v3. 0. 2 for the last 2 patients, 10X Genomics) to perform quality control, sample de-multiplexing, barcode processing, and single-cell 3′ and 5' gene counting. Sequencing reads were aligned to the GRCh38 human reference genome. We used emptyDrops  (39)  function from R package dropletUtils when analyzing the samples processed with version Cellranger v2. 0. 1. Cells with a p < 0. 01 were considered for further analysis. The emptyDrops function is already implemented in Cellranger v3. Further analysis was performed in R (v3. 5. 1) using the Seurat package (v3. 1. 1) (18). Cells were then filtered out when expressing less than 500 genes or more than 5000 genes, or when expressing more than 10% mitochondrial genes.
Altogether, among the 17 samples (11 from tumors, 6 from blood and 2 from juxta-tumor) 54247 cells were kept for statistical analysis. For each sample, the gene-cell-barcode matrix of the samples was then normalized to a total of 1e4 molecules. The top 2000 variable features were identified using the "vst" method from Seurat where both lowly and highly expressed genes are transformed onto a common scale. For the 11 tumor samples altogether, we then computed the integration anchors using the Seurat v3 integration method. This method is leveraging closely-related cells (termed anchors) between datasets to compute a batch-corrected matrix. Top 30 CCA components were used to find transfer anchors between datasets and used to generated the integrated matrix for the 11 tumors.
Dimension reduction and unsupervised clustering Top 30 Principal Components were computed and UMAP was performed using the top 30 PCs of the integrated matrix. Clusters were identified using the FindNeighbors and FindClusters function in Seurat with a resolution parameter of 1. 2 and using the first 30 principal components. To choose the optimal number of clusters and prevent overclustering, clustree analysis was performed using the clustree package v0. 4. 1  (40). Unique cluster-specific genes were identified by running the Seurat FindAllMarkers function using Wilcoxon test on the uncorrected matrix. Then, three clusters containing contaminating cells were removed from the analysis: A cluster of myeloid cells expressing APOE, B cells expressing CD19, epithelial cells expressing KRT1. Signature scores were computed using the Seurat function AddModuleScore using the gene signature of interest and the integrated matrix.
Pathway enrichment Pathways enrichment tests were performed using Metascape  (41)  with default parameters using differentially expressed genes between early precursors (CD8-KLF2, CD8-GZMK, CD8-XCL1) and terminally differentiated CD8 + T cells (CD8-GZMH, CD8-LAYN). Gene sets from MSigDB, v. 7. 0 were downloaded in GMT format from https://www. gseamsigdb. org/gsea/msigdb/collections. jsp. These gene sets were used as modules for the "module score" function in Seurat.
Label transfer using a reference TCR-seq data for each sample was processed using Cell Ranger software (versions as above), with the command 'cellranger vdj' using the human reference genome GRCh38. Cells with the same TCR receptor can be considered clonally related, however two factors complicate the identification of clonotypes: -One cell can contain up to two alpha chains and one beta chain but they may not all be sequenced in a given cell due to e. g. dropout. This can lead to the artificial split of one clonotype into two or alternatively to the union of two different clonotypes which happen to share one chain by chance. -Two unrelated cells can be barcoded together within the same droplet (a doublet), joining two independent clonotypes. We choose a pragmatic, easily reproducible approach and use the same criteria as 10X: for all the samples collected from a patient, cells that share the exact same set of productive CDR3 nucleotide sequences are considered clones.
Acknowledgments: The authors wish to thank the  Flow Cytometry Platform of Institut Curie  and  Lea Guyonnet  for helpful discussions. We thank all the thoracic surgery, respiratory medicine, pathology, and tissue procurement staff of  Institut Mutualiste Montsouris , as well as all the patients and their families. Funding: C. M received a PhD fellowship from  Servier Laboratories  and funds by the  PhD Program "FIRE -Programme Bettencourt ". P. G. is supported by a PhD fellowship from  Ligue Nationale contre le Cancer at Université Paris Descartes (Paris V). This study was supported by grants from  "Janssen Horizon", "Fondation ARC pour la recherche sur le cancer", "Fondation chercher et trouver -StiftungSchweiz ", "European Research Council   COG 724208 " (T. D, T. M & A. W),  ANR-10-EQPX-03  ( Equipex ),  ANR-10-INBS-09-08  ( France Génomique Consortium ) from the  Agence Nationale de la Recherche  (" Investissements d'Avenir" program ) and the  SiRIC-Curie program -SiRIC Grant INCa-DGOS-4654.
Remerciements La SFGM-TC remercie les partenaires industriels pour leur soutien financier qui ont permis la réussite de cette dixième édition des ateliers d'harmonisation des pratiques : BIOTEST, CELGENE, CHUGAI, GILEAD, INCYTE, JANSSEN, JAZZ PHARMACEUTICALS, KEOCYT, MACOPHARMA, MALLINCKRODT THERAKOS, MSD FRANCE, NOVARTIS, OCTAPHARMA, SANOFI.
Les cytokines IL-2, IL-7 et IL-15 jouent un rôle important dans le développement, la prolifération et la survie des lymphocytes T. L'IL-2 sont associées à la radiothérapie dans un essai clinique chez les patients atteints de mélanome ou de cancer rénal (NCT01884961). L'administration d'IL-7 chez des patients augmente le taux de lymphocytes T CD8+ et T CD4+ et diminue le taux de lymphocytes T reg CD4+ (Rosenberg et al. , 2006). L'administration d'IL-7 et d'IL-15 lors de la radiothérapie pourrait s'avérer une option afin de restaurer une lymphopénie radioinduite. L'injection d'IL-15 pouvant stimuler la prolifération lymphocytaire est actuellement administrée dans un essai clinique de phase I afin de déterminer la toxicité chez des patients atteints de cancer rénal ou de mélanome (53). A notre connaissance, il n'y a pour l'heure pas d'essais d'administration d'IL-15 ou d'IL-7 en concomitant d'une radiothérapie.
Material and methods We reviewed data of all iTTP patients of the French reference Center for thrombotic microangiopathies (CNR-MAT, www. cnr-mat. fr) registry prospectively enrolled through a 10-year period, between 2008 and 2018. iTTP diagnostic criteria and management were based on previous studies. Patients with a suboptimal response to standard TPEbased treatment received a salvage therapy with rituximab  [5]. Informed consent was obtained from all patients. This study was approved by our institutional review board in accordance with the Declaration of Helsinki and the French Data Protection Authority ("Commission Nationale Informatique et Libertés", authorization n°911,539, and "Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé", authorization n°11.
537, Paris). For each patient epidemiologic, clinical and biological data were collected by a research study nurse, as previously reported  [5]. Data were collected retrospectively with particular attention to any thrombophilia risk factors (obesity, oral contraceptive use, presence of antiphospholipid antibodies [anticardiolipin and anti-β2GP1 antibodies]) and a pre-existing history of VTE. Supplemental data were collected to define other conditions during iTTP potentially increasing the risk of VTE: the time to platelet count recovery from the first TPE, the total volume of plasma required to achieve a durable complete remission, the number and the sites of inserted central venous catheter. Venous thrombosis included either thrombosis of central venous catheter, suspected on the basis of clinical symptoms, i.
Acknowledgements Patients were recruited with the help of the members of the Reference Center for Thrombotic Microangiopathies (CNR-MAT) (listed in the appendix). We thank  S. Benghezal ,  S. Savigny ,  S. Capdenat  ( Laboratoire d'Hématologie, Hôpital Lariboisière, AP-HP; Paris ) and  S. Malot  ( Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, AP-HP; Paris ) for technical assistance.
Cette technologie est actuellement développée pour la transfection dans le muscle ciliaire d'un plasmide de grade médical, pEYS606. Celuici est dépourvu de gène de sélection par un antibiotique et code une protéine de fusion, hTNFR-Is, entièrement humanisée (hTNFR-Is / hIgG1)  [48]. Les études de toxicité à dose unique et à doses répétées, menées avec l'électrotransfert de pEYS606 chez le lapin, ne montrent aucun effet négatif, histologique ou fonctionnel. Un essai clinique de phase I/II à doses croissantes, évaluant l'innocuité, la tolérance et l'activité clinique de pEYS606 chez des patients en phase avancée d'uvéite postérieure, intermédiaires et de panuvéite est actuellement en cours en France et au Royaume-Uni (https://clinicaltrials. gov/ct2/show/NCT03308045). Un essai de phase II a également été initié aux États-Unis, afin d'évaluer l'innocuité de l'administration répétée du plasmide pEYS606 chez des patients en phase active d'uvéites non infectieuses (https://clinicaltrials.