dataesr/scientific-paragraphs-categorization huggingface dataset:
Safety data were summarized for 3 years of tofacitinib exposure. Results Tofacitinib 5 and 10 mg twice daily (BID) showed superiority over placebo for all efficacy end points at week 16, with response maintained for 52 weeks of continued treatment. Tofacitinib improved patients' quality of life and was well tolerated. Rates of safety events of interest (except herpes zoster) were similar to those in the published literature and healthcare databases for other systemic psoriasis therapies. Tofacitinib 10 mg BID demonstrated greater efficacy than 5 mg BID. Conclusions Tofacitinib has a benefit-risk profile in moderate-to-severe psoriasis consistent with that of other systemic treatments. What's already known about this topic? • Psoriasis is a chronic, systemic inflammatory disease, which has a significant impact on patients' health-related quality of life.
Study design These analyses were based on pooled data from one phase II double-blind randomized controlled trial (ClinicalTrials. gov identifier NCT00678210),  18  four phase III double-blind randomized controlled trials (collectively referred to as the index studies) (OPT Pivotal 1, NCT01276639;  15  OPT Pivotal 2, NCT01309737;  15  OPT Compare, NCT01241591;  14  OPT Retreatment, NCT01186744)  13  and one open-label long-term extension study (NCT01163253). 19 Further details of the study designs and treatments are provided in Table  S1  (see Supporting Information).
Efficacy data Data from OPT Pivotal 1 and OPT Pivotal 2, up to week 52, were pooled for the efficacy analyses. The full analysis set included all patients who were randomized and received at least one dose of study drug in either Pivotal study. For dichotomized data, missing observations were set to nonresponders unless otherwise stated. The Cochran-Mantel-Haenszel approach to adjust the study effect was used to estimate the treatment difference among treatment groups at week 16 (before placebo-treated patients advanced to tofacitinib). Statistical testing was based on normal approximation to the binomial proportions. No statistical analyses were applied to data beyond week 16.
Safety data Data from patients who received at least one dose of tofacitinib, including all events through to 4 April 2014 (interim data for the long-term extension study), were considered for the safety analyses. Safety data from the phase II and III studies were summarized for tofacitinib 5 mg and 10 mg twice daily (BID) over 16 weeks (vs. placebo) and over 1 year (no placebo arm; for patients initially receiving placebo then advanced to tofacitinib at week 16, the data after week 16 were included). Safety data were also summarized for combined tofacitinib exposure for up to 3 years in the index and long-term extension studies. Total tofacitinib exposure data are presented for patients who received tofacitinib 10 mg BID for ≥ 80% of their study duration (10-mg BID group) and for pooled tofacitinib doses (tofacitinib all).
For patients who switched from placebo or etanercept to tofacitinib, a new baseline was established, with the first day of tofacitinib treatment considered as day 1. To contextualize IRs for safety events, a systematic review of published randomized clinical trials and observational studies reporting AEs with other psoriasis treatments was undertaken (Appendix S1 and Table  S2 ; see Supporting Information). Additionally, data from the six tofacitinib clinical trials were benchmarked against two Pfizer-commissioned comparison cohorts of patients with moderate-to-severe psoriasis, derived from U. S. Medicare and Kaiser Permanente Northern California (KPNC) databases (Appendix S1). All clinical studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and with the International Council for Harmonisation Good Clinical Practice Guidelines.
19 Improvements in nail psoriasis (reported to be nonresponsive to traditional psoriasis treatments),  24, 25  relief of itch within 2 days of treatment,  14  sustained improvements in quality of life, and improvements in the HADS depression score were seen with both tofacitinib doses. ] [15]  Based on the results of OPT Compare (NCT01241591), tofacitinib 10 mg BID had similar efficacy to etanercept 50 mg twice weekly (PASI 75: 63Á6% and 58Á5%, respectively; PGA response: 68Á2% and 66Á3%, respectively), whereas 5 mg BID did not meet the noninferiority criteria (PASI 75: 39Á5%; PGA response: 47Á1%). 14 A meta-analysis conducted by Pfizer has shown the efficacy of tofacitinib 5 mg BID to be similar to those of oral methotrexate and etanercept 25 mg twice weekly, and numerically higher than with the oral psoriasis therapies acitretin and apremilast.
31 e authors acknowledge some limitations of this study. The study included data from clinical trials, and the selection criteria for the trials were such that the study populations may not fully reflect the characteristics of patients seen in everyday clinical practice. The clinical trials included limited numbers of patients and involved relatively short follow-up periods compared with the time course of a chronic disease like psoriasis, and therefore estimates of rare safety events, such as malignancies, may be less reliable than when long-term data are available. As psoriasis is a chronic disease, often occurring from an early age, over their lifetimes most patients will receive multiple therapies, with some not responding well to any; there is therefore an unmet need for new and effective treatment options with acceptable safety profiles.
Acknowledgments The authors would like to thank  Maryam Asgari  and  Charlie Quesenberry , principal investigators of the KPNC database cohort study, and  Kevin Winthrop  and  Jeffrey Curtis , principal investigators of the Medicare database cohort. This study was supported by  Pfizer Inc. Medical writing support under the guidance of the authors was provided by  Sandrine M. Dupr e, PhD , and  Carole Evans, PhD , at and on behalf of Complete Medical Communications, Manchester, U. K. , and was funded by  Pfizer Inc. , New York, NY, U. S. A. , in accordance with the Good Publication Practice (GPP3) guidelines. 44.
Patients All patients with heterozygous germline GATA2 mutations diagnosed between 2011 and 2016 in France and Belgium were enrolled in this survey, secondary to their identification through the laboratories which performed their genetic diagnosis in France and Belgium (JB, CBC, HC-AC, ED, CP). Fourteen patients with chronic neutropenia, and who were registered in the French Severe Chronic Neutropenia Registry, had been reported previously. 11 This registry has been recognized as a national registry by the French health authorities since 2008, and has contributed to several studies. 15, 16 The database was approved by the French national data protection agency (CNIL, certificate n. 97. 075). This registry was primary established to enrol all the patients with chronic neutropenia in France.
Genetic analysis The patient or his/her parents gave their written informed consent to undergo genetic testing and participate in the study. Genomic DNA was extracted from a blood sample. Genetic analysis included the Sanger sequencing of exons 2 to 6, the intronic regulatory region (intron 4) of the GATA2 gene (NM_032631. 4), and the search for exonic or large genomic deletions by quantitative PCR and/or MLPA. The germline status of the identified GATA2 mutation was confirmed by analyzing non-hematopoietic tissue (cultured skin fibroblasts, hair follicles or nails) in 30 probands. Null mutations (nonsense, frameshift, multi-exon deletion) were considered to be diseasecausing. The pathogenicity of missense mutations and splicesite variants that did not affect the canonical +1 and +2 splice site bases were based on the following criteria: frequency in the general-population database [Exome Aggregation Consortium (ExAC): http://exac.
Statistical analysis Stata® software (v. 13) was used for all the statistical analyses. Lower and upper interquartile and median values express the distribution of quantitative variables. Differences between groups of patients were analyzed using Fisher's exact test if the event was discrete and Wilcoxon's test for quantitative variables. Survival was compared between the groups of subjects using the log-rank test, and Cox's model was used for the multivariate analysis. As we performed repeated tests, P<0. 01 was considered significant, unless otherwise stated. For survival, the end points were death, MDS or AL; the time-period started at birth until an event or the day of last news. We also analyzed survival after onset of a clonal event. The time period started from the first clonal event (MDS or AL) until death or the day of last news.
Early onset of severe infections and/or hematologic diseases in GATA2 deficiency Forty males and 39 females from 53 families with a heterozygous germline GATA2 mutation are herein reported (Table  1  and Online Supplementary Table  S1 ), including 14 previously described patients,  11  whose clinical and biological data have been up-dated. The patients were enrolled in France (n=72) and Belgium (n=7). Median age at the last follow up was 24. 5 years old (range, 3. 9-73). The probability of remaining symptom-free was 38% at the age of 20 (95%CI: 27-48. 7%) and 8% at the age of 40 (95%CI: 3. 3-15%) (Figure  1A ). All patients except 5 were symptomatic at the time of the last follow up. These 5 individuals were first-degree relatives of symptomatic patients with a GATA2 mutation (Online Supplementary Table  S2 ).
Acknowledgments The Authors thank the patients and families for their participation in this study. The French registry is supported by grants from  Amgen SAS, Chugai SA, Novartis , and by a grant from the  Inserm. This project is supported by grants from  Associations Laurette Fugain ,  111 les Arts, Société Française des Cancers de l'Enfant, Enfanfare ,  Association Sportive de Saint Quentin Fallavier , and  Barth France. The Authors thank the association  IRIS  for its support.
Acknowledgement The workshop was organized and supported by the  Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) , the  Swedish Research Council (SRC)  and the  Centre for Antibiotic Resistance Research at University of Gothenburg, Sweden (CARe). This project received funding from the  European Union 's  Horizon 2020 research and innovation programme  under grant agreement  JPI-EC-AMR No 681055. Individual member states of the JPIAMR also covered travel costs for participants.
Acknowledgements The authors thank the patients and their families and caregivers and all investigators and site personnel and  Roger Dansey, MD  ( Merck & Co. , Inc. , Kenilworth, NJ, USA ), for critical manuscript review. Medical writing and/or editorial assistance was provided by  Trisha Stankiewicz, PhD , and  Payal Gandhi, PhD , of the  ApotheCom pembrolizumab team (Yardley, PA, USA ). This assistance was funded by  Merck Sharp & Dohme Corp. , a subsidiary of  Merck & Co. , Inc. , Kenilworth, NJ,  USA.
Black arrows indicate SDF-1 addition. Each trace represents the response of one cell and data are representative of at least three independent experiments. Typical response of unique cell (peak or peak follow by sustained plateau phase) are present as example (Ab). Data were processed using GraphPad prism. (A) Pharmacological characterization of SDF-1-induced Ca 2+ increase. Cells were recorded in extracellular saline solution (HBSS) containing 2 mM Ca 2+ (2 Ca, (Aa)) or in Ca 2+ -free HBSS (0 Ca, (Ac)). Cells were pre-incubated with BTP2 (Ae) or GSK7975A (Af) at 10 µM for 30 min and recorded in 2 mM Ca 2+ HBSS containing inhibitors. (Ad,Ag) Histograms represent areas under curves (AUC) calculated, under various recording conditions, between the application time of SDF-1 and t = 2050 s, and normalized compared to control (2 Ca or shNT).
Data are expressed as mean ± SEM, * p < 0. 05. (B) Effect of Orai1 or STIM1 expression knock-down on SDF-1-induced Ca 2+ response. The stable modified HLY-1 cell line established after lentiviral transduction with plasmid containing non targeting shRNA (shNT), shRNA against Orai1 or STIM1 were recorded in extracellular saline solution (HBSS) containing 2 mM Ca 2+.
Calcium Imaging Single-cell [Ca 2+ ] i imaging was performed, using Fluo2-AM-leak resistant (LR) calcium dye. Cells were loaded with 10 µM Fluo2-AM-LR in the presence of 0. 02% pluronic F127 at room temperature in HBSS for 25 min. The cells were rinsed with HBSS and incubated in the absence of Fluo2-AM-LR for 15 min to allow complete de-esterification of the dye. Fluorescence time-lapse images were captured at 515 nm using a confocal microscope Zeiss LSM 510 (Göttingen, Germany) equipped with a Plan Neofluar 25× 0. 8 NA oil objective. The recording lasted 2050 s and SDF-1 was added at t = 200 s. Images were recorded at constant 10 s intervals under the control of LSM 510 software (Zeiss). Regions of interest corresponding to recorded cells were drawn to analyze fluorescence signal. Data were processed using Prism 6 (GraphPad).
Transwell Assay Transmigration of DLBCL cell lines was assessed in 96-transwell chemotaxis chambers with a pore size of 5 µm (Corning). Cells (5 × 10 5 ) were rinsed and suspended in serum-free media before being loaded in the upper chamber of the transwell culture insert. The bottom chamber was filled with culture medium with or without SDF-1 (100 ng/mL). To test the effect of the pharmacological agents on chemotaxis induced by SDF-1, cells were pre-treated during 20 min in the presence, or not, of the agents before being loaded to upper transwell chambers. After 10 hours of incubation for SU-DHL-4 and 16 hours for HLY-1 cells, the upper chambers were removed and cells that had migrated were counted after adding an internal microsphere counting standard (Precision count beads, Ozyme) by flow cytometry using a FACSCalibur cytometer equipped with an HTS module and Cell Quest software (BD Biosciences).
Tissue Microarrays Tissue Microarrays (TMA) were purchased from US Biomax (Rockville, MD, USA). TMA were composed of 26 spots of normal lymph node and 87 spots of DLBCL tumoral tissue divided into 43 spots of nodal and 44 spots of extranodal DLBCL. Co-immunostainings were performed using Orai1 antibody (HPA016583, Sigma) or STIM1 antibody (HPA012123, Sigma) and mouse anti-human CD20 and anti-human CD19 revealed by Alexa 488-conjugated donkey anti-rabbit and Alexa532-conjugated goat anti-mouse polyclonal antibodies, respectively. Nuclei were stained with DAPI. After acquisition on Icys laser scanning cytometer (Thorlabs, Maison Lafitte, France), a segmentation analysis base on phantoms was done to determine the percentage of CD20/CD19 positive cells expressing protein of interest for each spot as described previously  [44].
Western Blot Cell lysates from various cell lines were prepared using Cell Signaling Technology cell lysis buffer supplemented with protease/phosphatase inhibitor cocktails (Cell Signaling Technology, Ozyme, Saint Quentin en Yvelines, France). Proteins were loaded onto 10% Tris-acrylamide gels, transferred with I-blot system (Thermofisher Scientific, Bordeaux, France) on PVDF membrane and blotted with anti-human Orai1 or STIM1 antibodies overnight at 4 • C. Proteins of interest were visualized using a chemiluminescent HRP substrate kit (Merck-Millipore, Fontenay sous bois, France) revealed with a Fusion system (Vilber Lourmat, Marne-laVallée, France) and analyzed using Bio1D software (Vilber Lourmat). The densitometry values were normalized with those of β-actin (loading control).
Cells were pre-incubated with BTP2 (Ae) or GSK7975A (Af) at 10 µM for 30 min and recorded in 2 mM Ca 2+ HBSS containing inhibitors. (Ad,Ag) Histograms represent areas under curves (AUC) calculated, under various recording conditions, between the application time of SDF-1 and t = 2050 s, and normalized compared to control (2 Ca or shNT). Data are expressed as mean ± SEM, * p < 0. 05. (B) Effect of Orai1 or STIM1 expression knock-down on SDF-1-induced Ca 2+ response. The stable modified HLY-1 cell line established after lentiviral transduction with plasmid containing non targeting shRNA (shNT), shRNA against Orai1 or STIM1 were recorded in extracellular saline solution (HBSS) containing 2 mM Ca 2+.
Acknowledgments: We thank  Richard Iggo  and  Elodie Richard  for their technical support with lentivirus production. We also thank  Ravi Nookala  of  Institut Begonié  for the medical writer service. We thank the  University of Bordeaux 's cytometry platform and  Benoît Rousseau  who greatly facilitated mice experiments at the  A2 Animal facility in Bordeaux (TBM Core ).
Bioinformatic analysis Bioinformatic analysis was performed on RNA sequencing data from European seabass anterior intestine to study their physiological and molecular responses to dietary hydrolysate inclusion in a low fish meal diet. We tested 5 dietary conditions on the transcriptomic response of sea bass intestine: FM5 and FM20 diets as negative and positive control groups, respectively, and the SH, TH and MH hydrolysate-based diets as experimental groups. The whole raw dataset was filtered and trimmed using Trimmomatic v(0. 30)  [55] , using the following parameters: ILLUMINACLIP:adapter. fa:2:30:10, LEADING:5, TRAILING:5, SLIDING WINDOW:4:5, MINLEN:25. Global sequence quality was checked using FastQC (v 0. 11. 3) (https://www. bioinformatics. babraham. ac. uk/projects/fastqc). Global assembly was conducted using Trinity 2.
1. 1. [56] , a dedicated package for de novo transcriptomics. A normalization step was conducted according to kmer coverage (kmer of 25 nt, maximum coverage of 30) proposed by the Trinity package. The inconsistent contigs generated by Trinity were removed after a remapping of reads using Bowtie (v 1. 1. 2) [57] , and estimating relative abundance using RSEM  [58]  to get the FPKM values (v 1. 2. 22) (the two software programs were launched through perl wrappers provided by the Trinity package). Finally, only transcripts with at least an FPKM value above 1 and isoforms corresponding to more than 1% of the total gene count were kept. Annotation of contig sequences was performed using both Blast2Go software  [59]  and the Trinotate pipeline (http://trinotate. github. io), as described in  [60].
Sequences were blasted against the NCBI nr database (release 193) with the following set-up parameters: max BLAST hits 20, min Expect Value 10 -3 , and against the human proteome Ensembl database (release 82) (BLASTX). Only hits with E-values < 0. 001 were kept. Peptide prediction was performed using Transdecoder  [60]. Similarity search (blastp of the Transdecoder-predicted peptides) was performed against the uniprot-swissprot database (release 2015-05). Peptide signal prediction was performed using signalP v4. 1  [61]. Transmembrane peptide detection was performed using TMHMM v2. 0c  [62]. Protein domain search was performed using hmmscan from the hmmer v. 3. 1b1 suite against the Pfam-A database  [63]. Finally, transcriptome functional annotation was performed using the Trinotate pipeline.
Differential expression analysis Differential gene expression between dietary treatments was identified using R software  [64]  and the DESeq2 package  [65]. Multiple testing was accounted for by controlling the false discovery rate (FDR) at 5% using the Benjamini-Hochberg procedure. The RNA targets with adjusted P-values < 0. 2 and absolute fold changes ≥1. 4 were considered as differentially expressed. The relatively low stringency of the cut-off criteria is consistent with other nutrigenomic studies  [48]. The impacts of hydrolysate diets on specific pathways were monitored using Ingenuity Pathway Analysis software (Qiagen, Hilden, Germany) with standard parameters. All annotated regulated genes were used.
Quantitative analysis of differential gene expression Differential gene expression analysis of RNA-seq data was performed to compare diets containing hydrolysates included to low (FM5) and high (FM20) fish meal diets. A total of 383 unique genes were differentially expressed (Table  3 ). Compared to the FM5 diet, 46 and 50 genes were differentially regulated by diets containing TH and SH, respectively, and this number was higher in the FM20 (197) and MH (270) groups. Compared to the FM5 diet again, the distribution of differentially regulated genes between the FM20 diet and diets including hydrolysates indicated that 30. 4% (14/46), 66. 0% (33/50), and 39. 3% (106/270) of regulated genes were shared with the TH, SH and MH diets, respectively. A total of 301 genes were only regulated by diets containing hydrolysates, but not by the FM20 diet, whereas some genes were regulated only by a specific hydrolysate diet.
In particular, 9, 9, and 55 differentially regulated genes participated to metabolic pathways (KO: 01100) in response to the TH, SH, and MH diets, respectively. To be more precise, the metabolic pathways impacted by the TH diet mainly influenced carbohydrate metabolism, whereas the SH diet impacted the nucleotide metabolism and terpenoid backbone biosynthesis. In addition to these metabolic pathways, defense and immunity pathways were also affected by hydrolysate inclusion to the diet. The complete list of impacted pathways and corresponding genes is available in Additional file 5. We also investigated the pathways regulated by dietary treatments using Ingenuity Pathway Analysis Software. Results are summarized in Table  9 , focusing on the top canonical pathways as well as on molecular and cellular functions.
of the soma for the activity of the niche and stem cells, as well as for the maintenance of the testis. Here, we applied genome-wide in vivo mapping of DNA-protein interactions to determine genes active in the Drosophila larval testis soma and germline as well as genes targeted by two transcription factors (TFs) active in the somatic lineage. One of them is the well-described stem cell regulator Zfh-1  (Leatherman and Dinardo, 2008) , and the other one is the Hox TF Abdominal-A (Abd-A), for which we uncovered a stem cell function in the Drosophila testis. Meta-analysis of these datasets recovered a set of genes known to control stem cell development in the Drosophila testis and identified a large number of regulators. To make our dataset accessible and amenable to comparative analysis, we developed an interactive data-mining and analysis tool.
Data cross-comparison using this tool allowed us to identify major processes active in the soma. By comparing our data to published datasets from diverse stem cell systems and organisms, we uncovered a core gene set of adult stem cells conserved across species boundaries. Testing TFs from this category revealed an unusually high frequency of stem cell phenotypes in the Drosophila testis and intestine. Moreover, our analysis identified system specific regulators, which may represent factors that allow individual cell types to respond to and interact with their typical yet diverse microenvironments. Taken together, we elucidate mechanisms used by somatic support cells to control the activity of neighboring germ cells and provide a rich resource to identify important (and conserved) regulators of the proliferation-differentiation balance in a genetically tractable stem cell system.
RESULTS Defining Abd-A as a Regulator in the Drosophila Testis Soma To uncover gene activities in the testis soma, we determined the transcriptome of the somatic and germline lineages by RNA polymerase II Targeted DamID (TaDa)  (Southall et al. , 2013) , followed by the identification of genes bound by two regulators active in somatic subpopulations and controlling their development using regular DNA adenine methyltransferase identification (DamID)  (van Steensel et al. , 2001). By combinatorial analysis of these datasets, we expected to identify genes specifically active in Drosophila testis support cells and contributing to their functions. We focused on Zfh-1, which is highly expressed in CySCs (Figures 1C, 1E, 1F, 2A, and 2A 0 ) and known to block CySCs differentiation as well as to control GSC self-renewal  (Leatherman and Dinardo, 2008).