dataesr/scientific-paragraphs-categorization huggingface dataset:
Figure5. Deciphering rosetting ligands involved in IGFBP7-mediated rosetting. (A) IRBC-trypsin treatments on IGFBP7-mediated rosetting. Dotted lines demonstrate data collected from same isolates. IGFBP7 increased rosetting in the untreated settings (paired t-test Pf (n = 5): p=0. 0171; Pv (n = 4): p=0. 0023) but did not significantly alter rosetting in groups treated with 10 mg/ml trypsin (Pf: p=0. 3739; Pv: p=0. 3910) and 1 mg/ml trypsin (Pf: same values; Pv: p=0. 3910). (B) Rosetting rates (mean and SD from quintuplicate experiment repeats shown) along rhIGFBP7 concentrations for PfCS2-WT and PfSBP1-KO-CS2. Significant CS2-WT rosette-stimulation was noted from rhIGFBP7 of 100 ng/ml (Friedman with Dunn's test: p=0. 0230). No significant changes noted for SBP1-KO-CS2 across the range of IGFBP7 concentrations studied (Friedman with Dunn's test: p>0.
Acknowledgements The authors would like to express gratitude to the staff of  SMRU  who assisted in the management of this study. This study received financial support from the following funds: WCL, SWH, SKB, BM and LR were supported by core funding from  A*STAR  to SIgN. LR was also funded by  A*STAR  grant ( JCO-DP BMSI/15-800006-SIGN ). WCL was also funded by  Open Fund-Young   Individual Research Grant  ( OF-YIRG NMRC/OFYIRG/0070/2018 ) by the  National Medical Research Council, Ministry of Health, Singapore. RMS was supported by Core funding from  IMCB  and  Young Investigator Grant   YIG 2015  (A*STAR). BR was funded by  University of Otago, Dunedin, New Zealand Start-Up  Grant. YL was supported by  University of Malaya High Impact Research (HIR)  Grant ( UM. C/HIR/MOHE/ MED/16 ) from  Ministry of Higher Education, Malaysia.
Specific signal was amplified using the TSA Cyanine 3 (Cy3) detection kit according to the manufacturer's protocols. Appropriate washing steps with PBS containing 0. 05% Tween20 (Sigma-Aldrich, Missouri, USA) were performed during the procedure. For embedding, Prolong Diamond anti-fade mounting medium with or without DAPI was used (Invitrogen/ Thermo Fisher Scientific, P36962 and P36961, Oregon, USA). Finally, slides were scanned at room temperature using the TissueFAXS acquisition software and microscope (TissueGnostics, Vienna, Austria) with the following specifications: Zeiss EC "Plan-Neofluar" 40x/1. 30 Oil, DIC objective, CMOS-color camera PL-B623 Pixelink (3. 1 Megapixels), EXFO Excite 120 PC fluorescence illumination and Chroma ET Dapi (49000), Chroma ET CY3 (49004), Chroma ET Cy5 (49006), and Chroma FITC (49011) filter sets.
Overlay images were produced using Adobe Photoshop software. MHC-I scoring was performed manually by two individuals blinded for clinicopathological data. Cores were categorically scored as low (<1% of CK + cells MHC-I positive), intermediate (>1-<80% of CK + cells MHC-I positive), or high expression (>80% of CK + cells MHC-I positive). Patients were included if at least two cores contained >20% tumor epithelium.
Statistics Heatmaps were constructed in R (version 3. 3. 1) with package pheatmap. Differences in the percentage of immune cell subpopulations between clusters were determined using a nonparametric Kruskal-Wallis test, followed by Dunn's post hoc analysis. Differences in the number of tumor-infiltrating immune cells on FFPE slides were determined by two-tailed Mann Whitney test. Differences in the immune cell density between MHC-I groups were determined using a nonparametric Kruskal-Wallis test, followed by Dunn's post hoc analysis. Differences in disease-specific survival were determined by a logrank test. Variables associated with diseasespecific survival were entered into a multivariate analysis using the Cox proportional hazards model. All statistical analyses were performed using IBM SPDSS 24 (SPDSS inc.
To confirm the observed co-expression in CD8 + T cells, we also analyzed a recently published dataset of CD8 + TIL from ovarian cancer. 19 COS, TNFRSF18 (GITR), as well as in the intracellular signaling adaptor for GITR: TRAF1 were overexpressed in ICOS + vs. ICOS - TILs (Figure  4c ). ICOS and GITR are also often co-expressed with immune checkpoint CTLA4 (cytotoxic T-lymphocyte attenuator 4). 19  Therefore, we investigated the expression levels of CTLA4 within the various ICOS/GITR CD4 + and CD8 + T-cell subpopulations (Figure  4d ) and found that mean fluorescent intensities (MFI) for CTLA-4 were higher in ICOS/GITR double-positive Treg cells when compared to the other subpopulations.
Data sources and variables This analysis covers the period of the initial 10-months of implementation (July 23, 2018 -June 4, 2019) in five clinics located in Bordeaux (n = 3), Bayonne (n = 1), and Périgueux (n = 1). Participants consulting between July 23, 2018 -May 15, 2019 and invited to participate were considered for this analysis if they had provided informed consent and had at least one recorded hospital consultation or hospitalization between the 1st of January 2017 and the 6th of June 2019. All available selfreported data, saved as participants progressed through each stage of the assessment, were considered for analysis, regardless of whether or not they had been submitted. Paper questionnaires, returned prior to the 4th of June 2019, were entered and considered for this analysis.
Participants completed a self-administered questionnaire, reporting their educational attainment (ranging from none to 5 years post-secondary education or higher), net household income (ranging from less than 900€ to more than 4000€ per month), profession, employment status, and whether or not they lived with a partner. They also completed the French version of the WHOQOL-HIV BREF. Participants' self-reported data were merged with those routinely collected from their medical records at either enrolment or at the most recent hospital consultation. We derived the participant's age, transmission route (coded as men who have sex with men (MSM), heterosexuals, intravenous (IV) drug use, or other), place of origin, time in years since HIV diagnosis, time in years since start of first ART, HIV stage according to the Centers for Disease Control and Prevention (CDC) categories, and history of hospitalizations of > 48 h in the past 2 years  [27].
Basic characteristics The WHOQOL-HIV BREF questionnaire was completed by 587 PLWH during the study period. One observation was excluded due to delays in data entry. Five hundred eighty-six participants having completed at least the first item of the WHOQOL-HIV BREF were therefore considered for this analysis; 406 (69. 3%) completed an electronic version of the questionnaire and 180 (30. 7%) an identical paper version. Five hundred seventy-four participants had completed all items for physical health, 569 for psychological health, 560 for level of independence, 557 for social relations, 557 for environmental health and 570 for personal beliefs domains. The study population's characteristics are described in detail in Table  1. Respondents were mostly male (n = 430, 73. 2%) and their median age was 55 years old (IQR 48.
Strengths & Limitations the effort, money and time required to develop a new instrument designed to measure a multi-dimensional construct like (HR)QoL, many have urged researchers to rely on existing instruments and ensure their validity in new populations. We have followed this recommendation. This study has the advantage of drawing on objective and detailed clinical and laboratory data which were prospectively collected within the ANRS CO3 Aquitaine cohort. However, we enrolled PLWH on a voluntary basis in clinic and relied on their willingness and ability to complete a self-administered assessment. This resulted in the exclusion of people who had severe neurocognitive impairment or were not able to understand and/or read French sufficiently well. This recruitment strategy may have resulted in a less representative sample of French-speaking people in care in 2019.
Acknowledgements We would like to acknowledge  Alain Volney-Anne  (European AIDS Treatment Group) who reviewed the content of the battery of PRO measures. We would like to thank  Eugenie Destandau  who provided input on the study's communicatation strategy. We acknowledge the contribution of members of the  IT department  who developed the APREGE® 2. 0 module for the collection of electronic PROs. We would like to thank the  COREVIH Nouvelle Aquitaine 's coordinator (Isabelle Crespel) and its Clinical Research Associates ( Marie-Jose Blaizeau ,  Fatou Diarra ,  Madeleine Decoin ,  Sandrine Delveaux ,  Corinne Hanappier ,  Anne Pougetoux ,  Bellancille Uwamaliya ,  Kateryna Zara ) and investigators, cited below, for their unstinting support in successfully implementing this initial phase of the QuAliV ancillary study.
The randomized, prospective, multicenter, phase III ELAM02 trial (clinicaltrials. gov identifier: NCT00149162) was conducted from March, 2005 to December, 2011 in pediatric patients (aged 0-18 years old) with AML. 10  Children with secondary AML and AML with an underlying known predisposition disorder (Down syndrome, chromosomal breakage diseases, Kostman and Schwachman-Diamond diseases) were excluded. Of note, two patients have been previously reported: one with a germline GATA2 pathogenic variant and the other one with a germline RUNX1 deletion. 9, 11 atients with available amplicon-based high-throughput sequencing data and information from single nucleotide polymorphism (SNP)-array analyses at the time of diagnosis of AML were selected for the present study (385 patients out of the 438 patients included in the ELAM02 trial).
The molecular profiling using a 36-gene panel with a high depth of coverage (>1500×) at AML diagnosis was reported previously 10 (Online Supplementary Table  S1 ). CEBPA mutations were systematically sought by Sanger sequencing because of insufficient coverage by the highthroughput sequencing. Single nucleotide variants were selected based on the absence of a description in public databases of human polymorphisms, and their functional effect was assessed by in silico predictions as previous- 908 haematologica | 2021; 106(3) Letters to the Editor ly described. 10 Cytoscan HD array (ThermoFisher) was used, according to the manufacturer's instructions, to screen for gene deletions. The data were analyzed using Chromosome Analysis Suite (ChAS) 3. 1 software (ThermoFisher). Since germline specimen collection was not planned by the ELAM02 protocol, blood samples taken at the time of complete remission were used to assess the germline status of variants and deletions by direct Sanger sequencing and SNP-array, respectively.
Correspondence: LAURENE FENWARTH -laurene. fenwarth@chru-lille. fr doi:10. 3324/haematol. 2020. 248872 Disclosures: no conflicts of interest to disclose. Contributions: GL was the principal investigator of the ELAM02 trial. AP, GL, TL, VG, WAC, SD, MP, PS, CD, PS and CHD enrolled patients in the study. HL and AP created the patient database. HL centralized all the AML samples in the ELAM02 national tumor bank. LF, AMR and ND performed the genomic analysis. LF performed the research and wrote the manuscript. CP revised the manuscript which was approved by all authors.
Acknowledgments: the authors would like to thank all the patients, their families and the staff of all the centers of the  Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'adolescent (SFCE)  for their involvement in the ELAM02 trial. The authors are grateful to the ELAM02 national bank and the  Tumor Bank at Lille University Hospital  (certification NF  96900-2014/65453-1 ) for handling, conditioning and storing patients' samples. Funding: the ELAM02 trial was supported by a grant from the.
Rats were captured alive using Manufrance live-traps (280 × 100 × 100 mm). Traps were set between 17. 00 and 19. 30, and retrieved the following morning between 6. 00 and 8. 00. The trapping effort per site (# traps set x # nights) was adjusted according to the method described by  Nelson and Clark (1973). Captured animals were transferred alive to the pathology laboratory where they were anesthetised using 5% isoflurane before euthanasia via an intra-peritoneal barbiturate overdose. Rats were identified to species based on morphological characters. For each animal, the following data were recorded: sex, body mass (g), body length (nose to anus, mm), cutaneous wound score, and sexual maturity. Presence of cutaneous wounds was scored into five categories based on  Glass et al. (1988) , i. e.
unwounded animals: score 0; minor tail wounds: score 1; large wounds on the tail and small wounds on the rump, base of the tail or limbs: score 2; larger wounds on the body: score 3; more extensive wounds: score 4. Males were considered sexually mature if they had scrotal (vs. inguinal) testes and developed seminal vesicles. Females were considered mature if their uterus showed distinct blood supply, placental scars, or presence of embryos as defined in  (Vadell et al. 2010). During necropsy, lung and kidney tissues were collected aseptically. A ten mm tail tip was sampled for barcoding purpose. All samples were maintained at -80 °C until DNA extraction. Maps of the capture sites were built using QGIS 3. 4. 5  (QGIS Development Team, 2018) ; the raster data "Orthofoto 2016 Wien" (Open Data Österreich, https://www.
2007). Amplicons were Sanger sequenced on an ABI3130xl capillary electrophoresis analyser (Applied Biosystems). Sequences were aligned using BioEdit  (Hall 1999 ) and compared through Blast-based analysis against the National Center for Biotechnology Information (NCBI) nucleotide collection database (NCBI Resource Coordinators 2017). Molecular detection of Leptospira spp. DNA was extracted from kidney and lung tissues (25 mg) using the DNeasy® Blood & Tissue kit (Qiagen, Hilden, Germany) in accordance with the manufacturer's instructions. Quality and concentration of DNA extracts were estimated via spectrophotometry using a NanoDrop 1000 instrument (Thermo Fisher Scientific, Waltham, Massachusetts). Sample concentrations were then normalised to 15 ng/μl prior to amplification. The DNA was stored at -20 °C until used.
The amplification protocol consisted of an initial denaturation at 95 °C for 3 min followed by 15 cycles of denaturation at 98 °C for 20 s, primer annealing at 56 °C for 30 s, and DNA extension at 72 °C for 45 s before the final extension step at 72 °C for 5 min. The barcoded amplicons were purified as described in  (Rohland and Reich 2012). The amplicon concentrations were estimated using Qubit ds DNA BR Assay Kit (Life Technologies, Eugene, Oregon) in accordance with manufacturer's instructions. The tag-indexed PCR products were pooled in equimolar concentrations and underwent 150 bp pair-end sequencing on an Illumina MiSeq PE 150 system (Illumina, San Diego, California) at the Vienna Biocenter Core Facility (Vienna, Austria). Sequencing data was first de-multiplexed and adaptors removed before quality filtering of reads.
All reads were run through a custom bioinformatics pipeline based on strain identification from the USEARCH program  (Edgar 2010). Briefly, the pipeline discards reads that are sequencing artefacts (including chimeras) and then groups the remainder into operational taxonomic units (OTUs) which are analogous to strains of Leptospira. Due to lack of overlap in the paired-end reads each read was analysed separately and then combined for species annotation through Blast-based analysis against the NCBI nucleotide collection database (NCBI Resource Coordinators 2017).
Land-use data To determine urban environmental features that could affect Leptospira occurrence in rats we extracted land-use data from the Vienna land-use dataset (Realnutzungskartierung ab 2007/ 08 Wien) (Bundesministerium für Digitalisierung und Wirtschaftsstandort 2019) using the software QGIS 3. 4. 5  (QGIS Development Team, 2018). This database contains three levels of land-use classification with 32 land-use classes. First, we approximated the home range of each captured rat by constructing a 200 m-radius  (Gardner-Santana et al. 2009; Heiberg et al. 2012 ) circular buffer zone around each point of capture. Using the Intersection and the Add Geometry Attributes tools, we extracted for each buffer zone (i. e. approximated home range for each captured rat) the surface area covered by four major land-use categories, i.
| Study design We reviewed the clinical research forms (CRF) of 780 patients with newly diagnosed, advanced-stage HL enrolled in the prospective, open-label randomized phase II trial HD0607 which aimed to improve the 3-year PFS of advanced-stage HL patients switching from ABVD to escalated BEACOPP when an early interim PET proved positive. 15 White blood cells differential counts missed in nine cases, thus 771 subjects were eligible for the study. The HD0607 trial (NCT00795613, Eudract code 2007-007168-94 at ClinicalTRials. gov) was conducted in accordance with the International Conference on Harmonization for Good Clinical Practice guidelines and the Declaration of Helsinki. Before enrollment, all patients gave their written informed consent, as per the Italian Pharmacology Agency (AIFA) and the ethics committees of all the participating centers approvals.
| Statistical analysis Descriptive data are presented through median with range for continuous variables and frequency with percentage for categorical variables. Pairwise comparisons were performed using the Mann-Whitney test for continuous variables and the Pearson's chi-squared test or the Fisher's exact test for categorical variables. Receiver operating characteristic (ROC) analysis was performed to assess the utility of NLR and LMR to predict treatment failure (progression, relapse, or death) at diagnosis and to confirm the best thresholds identified by previous retrospective series in the field (2). Survival outcomes were estimated using the Kaplan-Meier method and the log-rank test was applied to test differences between groups. PFS was measured from the date of registration to the date of first appearance of disease progression, relapse, or death for any cause or, whichever came first, to the date of the last follow-up visit; positive status of PET-2 was not considered as an event.
Overall survival (OS) was measured from the date of registration to the date of death for any cause or to the date of the last follow-up visit. Predictive factors of PET-2-positive status were assessed with logistic regression, while Cox proportional hazard models were performed to assess factors that were predictive of PFS and OS. Proportional hazard assumption was verified for all estimated models. All reported p-values were two sided and the conventional 5% significance level was fixed. Statistical analysis was performed using SAS (version 9. 4) and R (version 3. 5. 0).
Statistical analysis Statistical analyses were done using the STATISTICA software package (version 25, Stat-Soft Inc. Tulsa, OK, USA) and GraphPad Prism V. 8. 0 (GraphPad Software Inc, San Diego, CA, USA). Two-way ANOVA and Tukey's multiple comparisons post-hoc tests were used. Each experiment was repeated three times and the data were reported as means AE SD (N ¼ 3) with 95% confidence interval (CI). A p-value less than 0. 05 (p < 0. 05) was considered statistically significant.
Altogether, these results suggest a progressive, outcomedependent accumulation of divergent gene expression signatures starting from more comparable acute phase transcriptional profiles. A topology-based analysis, which relies not only on the assignment of dysregulated genes to a given pathway but also on gene connections derived from pathway annotation, was then applied to the T1 and T2 datasets. Twenty-nine dysregulated pathways (Benjamini-Hochberg corrected q-value ≤ 0. 05) were identified by this analysis in T1/early HCV-specific CD8+ T cells from chronically evolving compared to self-limited acute patients (Fig. 1c  and Supplementary Data 1). By contrast, 277 dysregulated pathways were retrieved by the same analysis from the T2/ late comparison of HCV-specific exhausted and memory CD8+ T cells from chronic and resolved patients, respectively.
1d ). Other genes related to glucose homeostasis, including genes coding for gluconeogenesis enzymes known to be involved in the production of glycolytic intermediates under low glucose conditions  28  (see Supplementary Data 1), also emerged as enriched from topologybased analysis. The entire T1 dataset was then subjected to unsupervised geneset enrichment analysis (GSEA), which allows to reveal sets of differentially regulated, functionally related genes, rather than individual high-scoring genes, above an arbitrarily set cut-off. As shown in Fig. 1e  and Supplementary Fig. 2  (see also the T1 sheets in Supplementary Data 2), all dysregulated pathways and gene ontology categories identified by GSEA were upregulated in HCV-specific CD8+ T cells from T1/early chronic patients. In particular, GSEA confirmed a strong upregulation of multiple DNA damage response, intracellular signaling and cell-cycle control genes, including immune-checkpoint inhibitors, such as PD-1 (also known as PDCD1), CD160, CTLA4 and TIGIT (see the T1 sheets in Supplementary Data 2).
Notably, GSEA also confirmed the upregulation of a large set of genes coding for mitochondrial oxidative phosphorylation (OXPHOS) and electron transport, reactive oxygen species (ROS) detoxification and fatty acid oxidation (FAO) components (see Fig. 1e  and Supplementary Data 2). Further analysis of GSEA data using the KEGG Reactome and GO databases allowed to group T1 upregulated genes into eight distinct functional categories matching the above mentioned dysregulated processes (Supplementary Fig. 2 ). A generalized upregulation thus appears to be the predominant but not exclusive feature of acute-phase dysregulation.
Z-axis the dysregulation of metabolism-related genes and progression toward the exhaustion phenotype, GSEA analysis was applied using the molecular signature identified in the murine model of chronic LCMV infection  25  , obtained by merging the leadingedge genes belonging to the different metabolic KEGG pathways. As shown in Supplementary Fig. 3a , a significant overlap was observed between metabolism-related genes that appear to be dysregulated in early exhausted LCMV-specific lymphocytes and in T1/early exhausted HCV-specific CD8+ T cells. Importantly, in the case of the 'glycolysis and gluconeogenesis' and 'oxidative phosphorylation' pathways, and of the 'glucose deprivation signature  25, 29  , the correlation of the two datasets was confirmed also when all genes (not only those restricted to the leading-edge set) were considered (Supplementary Fig.
self-limited-T1/early-and of late chronic vs. spontaneously resolved patients-T2/late). d List of the 14 T1/early-specific dysregulated pathways, half of which are upregulated (red), while the remaining half is downregulated (blue). e Heat-map of differentially expressed genes derived from GSEA (Molecular Signature Database, C2 canonical pathways and C5 gene ontology sets) at T1/early time-point, related to cell cycle, DNA damage/DNA repair, cell signaling, mitochondrion and metabolism. Upregulated genes in red; downregulated genes in blue. T cells, which are comparable to, or even lower than, the frequencies typically found in our acute HCV patients cohorts (data not shown). p53 drives early metabolic dysregulation in HCV-specific CD8+ T cells. We then sought to elucidate the mechanisms responsible for glycolytic impairment and the functionally ineffective transcriptional upregulation of OXPHOS genes.