dataesr/scientific-paragraphs-categorization huggingface dataset:
Outcome data were up-dated in June 2012, after a median follow up of 2. 9 years. Between July 2007 and November 2012, 200 patients with newly diagnosed CBF-AML were included in the CBF-2006 trial. 8 mong the 198 eligible patients, 196 achieved complete remission and 176 were evaluated for MRD2 just before the second HiDAC consolidation course (Figure  1 ). Among these 176 patients, 54 presented with a less than 3-log MRD2 reduction: 2 of them experienced early relapse during consolidation therapy, 9 proceeded to ASCT, 18 were included in the DasaCBF study (dasa+ cohort) after consolidation completion and 25 received only consolidation courses without any maintenance therapy nor an SCT (dasacohort); these latter 25 patients were used as a control cohort. Characteristics between dasa+ and dasa-cohort patients were compared using Mann-Whitney test for continuous variables and Fisher exact test for binary variables.
Outcome data were estimated by the Mantel-Byar method, considering dasatinib therapy onset as a time-dependent covariate. 11 Briefly, all patients were considered in the dasa-cohort until the time of dasatinib therapy initiation. Impact of dasatinib therapy on DFS was assessed by univariate Cox proportional hazard regression model. 12 Statistical analyses were performed on the STATA/SE 11. 0 (StataCorp, College Station, TX, USA) software package.
13 Reported IC50 for dasatinib autophosphorylation inhibition ranged from 1-10 nmol/L in wild-type KIT to 10-100 nmol/L in D816 KIT mutants. In comparison, IC50 for BCR-ABL inhibition is around 1 nmol/L. 14 Since targeted IC50 were significantly more elevated for KIT inhibition in CBF-AML than for BCR-ABL in chronic myeloid leukemia, a dosage of 140 mg daily was chosen in this study. Administration was once daily to improve tolerance. 15 his phase II study is the first experience of dasatinib monotherapy in CBF-AML patients. Both the German-Austrian AML Study Group (AMLSG; clinicaltrials. gov identifier: 00850382) and Cancer and Leukemia Group B (CALGB; clinicaltrials. gov identifier: 01238211) have conducted phase II trials combining dasatinib with conventional induction and consolidation therapy, followed by a 1-year dasatinib maintenance therapy in patients with CBF-AML.
The results of these combined studies have not yet been published but the AMLSG group will go on with a randomized phase III study (clinicaltrials. gov identifier: 00850382). Unfortunately, the present phase II study was not able to detect any benefit of dasatinib as single-agent in CBF-AML patients with high risk of relapse. While we assumed a 1-year DFS of 30% in this population of patient without any treatment, the observed post dasatinib 1-year DFS was 31. 5%. All patients with molecular recurrence (n=8) experienced a hematologic relapse within a short median time of 1. 8 months despite dasatinib administration. These patients had relatively high MRD levels prior to dasatinib initiation. In the CBF-2006, 3-year DFS was estimated at 73% in patients who achieved a 3-log MRD2 reduction versus 44% in those who did not (P<0.
ESPOIR cohort This work is derived from a large national, multicentre, longitudinal, prospective cohort of 813 French patients with early arthritis, the ESPOIR (Etude et Suivi des POlyarthrites Indifférentiées Récentes) cohort. The characteristics of the cohort have been described previously elsewhere. 14 Briefly, 813 patients with early arthritis recruited in 14 centres in France with arthritis duration <6 months and no prior treatment with disease-modifying antirheumatic drugs were included between 2002 and 2005. Patients underwent clinical, biological and radiological assessments at baseline and at each subsequent visit. For the present study, we selected individuals who fulfilled the 2010 American College of Rheumatology (ACR)/ European League Against Rheumatisms (EULAR) criteria  15  for RA at baseline with available genotyping data for the HLA-DRB1.
EAC cohort The Leiden Early Arthritis cohort had 597 early Dutch patients with RA who were included from 1993 to 2009 as they had fulfilled the 1987 ACR criteria; 416 of these patients had X-ray at baseline and 1 year. The details of this cohort has already been described elsewhere. 4 adiographs of hand and feet were made at baseline and during the yearly follow-up visits and were chronologically scored by one experienced reader who was blinded to any clinical or genetic data using the SHS (within reader correlation coefficient (ICC) 0. 91). Patients in EAC cohort had higher rate of progression within the first year; thus, we considered a progression of at least five points of mTSS to be clinically significant and this could be regarded in the EAC cohort as the threshold of progression.
RESULTS Characteristics of patients with RA Among the 813 patients with early arthritis included in the ESPOIR cohort, 641 fulfilled the 2010 ACR/EULAR criteria for RA at baseline; genotyping data for HLA-DRB1 were available in 612 patients with RA who constituted the sample of patients used to assess the association between HLA-DRB1 and ACPA presence. Among these patients, 516 had sets of hand and foot radiographs at baseline and at 1 year follow-up available. This sample of 516 patients was used to assess the association between HLA-DRB1 and structural progression within 1 year in the ESPOIR cohort. Among EAC patients, 597 fulfilled the 1987 ACR criteria for RA and among these, 416 had radiographs. The characteristics of the patients of ESPOIR and EAC are summarised in table 1.
Acknowledgements The authors thank  Nathalie Rincheval  for expert monitoring and data management;  S Martin  who did all the central dosages of CRP, IgA and IgM rheumatoid factor, and anti-CCP antibodies; the  Biological Resources Centre (Paris-Bichat ,  J Benessiano ) which was in charge of centralising and managing biological data collection; and all the investigators who recruited and followed the patients ( F Berenbaum ,  Paris-Saint Antoine ;  M C Boissier ,  Paris-Bobigny ;  A Cantagrel , Toulouse;  B Combe , Montpellier;  M Dougados ,  Paris-Cochin ;  P Fardelonne  and  P Boumier , Amiens;  B Fautrel  and  P Bourgeois ,  Paris-La Pitié ;  R M Flipo , Lille;  Ph Goupille , Tours;  F Liote ,  Paris-Lariboisière ;×Le Loet and  O Vittecoq ,  Rouen ;×Mariette,  Paris Bicêtre ;  O Meyer ,  Paris Bichat ;  A Saraux , Brest;  Th Schaeverbeke, Bordeaux ;  J Sibilia , Strasbourg).
Contributors The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf of all authors, an exclusive licence (or non-exclusive for government employees) on a worldwide basis to the  BMJ Publishing Group Ltd  to permit this article (if accepted) to be published in RMD Open and any other BMJPGL products and to sublicense such use and exploit all subsidiary rights, as set out in our licence. Funding An unrestricted grant from  Merck Sharp and Dohme (MSD)  was allocated for the first 5 years of the ESPOIR cohort. Two additional grants from  INSERM  were obtained to support part of the biological database. The  French Society of Rheumatology ,  Pfizer ,  Abbvie and Roche-Chugai  also supported the ESPOIR cohort study.
Analysis of PXR after incubation with the binary cocktail showed a large predominance of a ternary complex corresponding to PXR interacting with EE2 and TNC in a 1:1:1 molar ratio; the global range of affinity of the two compounds binding to PXR was sub-micromolar (Fig. 4d ). Together, these data showed that PXR can accommodate EE2 and TNC simultaneously and suggested greater binding affinity of the binary mixture compared to individual compounds. EE2 and TNC bind cooperatively to PXR. We next assessed the binding characteristics of EE2 and TNC, alone or in mixture, to PXR. Competitive binding assays using time resolved fluorescence resonance energy transfer between a fluorescent PXR ligand and purified human PXR-LBD (LanthaScreen TR-FRET PXR Competitive Binding Assay) showed that the binary mixture binds 10-to 30-fold more avidly to PXR than TNC and EE2 alone (Fig.
At the end of the incubation period, culture medium was replaced with medium containing 3. 10 À 4 M luciferin. Luciferase activity was measured for 2 s in intact living cells using a plate reader (PerkinElmer Luminometer). EC 50 values were measured using GraphPad Prism (GraphPad Software Inc. ). Preparation of primary human hepatocytes. Liver samples were obtained from liver resections performed in adult patients for medical reasons unrelated to our research program or from donors when the liver was considered unsuitable for organ transplantation. The use of human specimens for scientific purposes was approved by the French National Ethics Committee. Written or oral informed consent was obtained from each patient or family prior to surgery. The clinical characteristics of the liver donors are presented in Supplementary Table  2.
Steady-state fluorescence anisotropy. Measure of the binding affinities of the coactivator fragment for the PXR/RXR heterodimer in the absence and presence of various ligands was performed using a Safire2 microplate reader (TECAN). The excitation wavelength was set at 470 nm and emission measured at 530 nm for the fluorescein-tagged fragment. Assays were carried out in the following buffer solution 20 mM Tris-HCl, pH 7. 5, 150 mM NaCl, 1 mM TCEP and 5% (v/v) glycerol. We initiated the measurements at the highest concentration of protein (20 mM) and diluted the protein sample twofold successively with the buffer solution. For each point of the titration curve, the protein sample was mixed with 5 nM of fluorescent fragment and a 3 molar excess of ligand (60 mM final concentrations). Binding data were fitted using a sigmoidal dose-response model using GraphPad Prism (GraphPad Software Inc.
GST-hPXR-LBD (10 nM) was incubated with different concentrations (10-30 mM) of TNC, EE2, TNC and EE2, and SR12813 in the presence of Fluormone PXR ligand (40 nM) and Lanthascreen terbium-anti-GST antibody (10 nM). To read a LanthaScreen TR-FRET assay, the fluorimeter (PHERAstar FS; BMG LABTECH) is configured to excite the terbium donor around 340 nm, and to separately read the terbium emission peak that is centred at B490 nm, and the fluorescein emission that is centred at B520 nm. Results are expressed as the signal from the fluorescein emission divided by the terbium signal to provide a TR-FRET emission ratio. Fluorescence ratio data were fitted using a sigmoidal dose-response model using GraphPad Prism (GraphPad Software Inc. ). Isothermal titration calorimetry. Purified PXR(130-434)-SRC-1 was dialysed overnight against Tris-HCl 20 mM, pH 8.
Heat exchanges were monitored throughout titrations consisting of 19 injections (one time 0. 5 ml followed by 18 times 2 ml) of compound solutions into the cell containing PXR solution. Data analysis and thermodynamic parameter fitting used Microcal Origin software (Malvern). Protein production and purification for structural studies. The human PXR-LBD (130-434) was co-produced with a fragment of the steroid receptor coactivator-1 (SRC-1, 623-710) to enhance PXR stability. The PXR-LBD gene was cloned into pRSET-A with a His 6 tag at the N-terminus (gift from Matthew Redinbo, University of North Carolina at Chapel Hill, USA), and the SRC-1 fragment gene has been inserted into the pACYC184 vector. Proteins were overproduced in E. coli BL21(DE3) cells overnight at 20 °C in LB medium without any ligand.
Acknowledgements We thank  Matthew Redinbo  for providing the expression plasmid used for crystallographic studies. We acknowledge the experimental assistance from the staff of the  European Synchrotron Radiation Facility (ESRF, Grenoble, France ) during data collection. We thank  Diego Tosi  for calculation of the theoretical additive activity curves and  Catherine Teyssier  for preparation of fluorescein-labelled SRC-1  NID. We acknowledge the financial support from the  Agence Nationale de la Recherche , project  TOXSYN ANR-13-CESA-0017-03  (P. B. and W. B. ), and  Plan Cancer Inserm , project  SYNERPXR A12156FS  (J. M. P. , P. B. and W. B. ).
Clinical inputs Search for relevant clinical, cost and utility inputs was performed in the Medline database using key words "functional mitral regurgitation", "prognosis", "mortality", "cost", "NYHA class" in April 2012 and repeated in August 2014. Monthly transition probabilities across NYHA classes for the Carillon and optimal medical therapy arms (Table  1 ) were derived from the TITAN trial  [13]. The TITAN trial enrolled fifty-three patients with dilated ischemic or non-ischemic cardiomyopathy from seven European centers. The inclusion criteria were 1) at least moderate (2+) FMR, 2) a left ventricular ejection fraction (LVEF) <40 %, 3) NYHA class II-IV, 4) a 6 min walk Fig. 1  Decision tree and Markov model structure. NYHA, New York Heart Association; OMT, optimal medical treatment; PMVR, percutaneous mitral valve repair distance between 150 and 450 m and 5) a stable heart failure medication regimen.
Resource utilization and cost data All resource use and cost data were derived from German sources (Table  2 ). The cost of PMVR was calculated from relevant German diagnosis-related group (DRG) (F19C) with the subtracted cost of implant and the added cost of the Carillon device. Peri-operative myocardial infarction was reported among the 20 most prevalent secondary diagnoses for the DRG, and it was assumed that no additional cost was incurred to manage this event. Based on clinical opinions, 14 additional days of hospital stay would be needed to treat a coronary sinus perforation. The basic DRG tariff covers the treatment for 2 to 10 days of hospital stay (average of 5. 2 days). Therefore, incremental costs were applied only for the extra days of hospital stay necessary to treat a vessel perforation.
In our study, a similar level of clinical benefits (incremental QALYs of 1. 15) and cost-effectiveness (ICER of €15,533/QALY) were demonstrated. Our study has several limitations. First, the transition probabilities between the different NYHA functional classes were based on a limited sample from the TITAN trial. Due to the limited sample size, not all transitions were possible in the base-case analysis. This limitation was addressed in the probabilistic sensitivity analysis. Second, the model utilized clinical and surrogate (mitral regurgitation) outcomes to predict mortality and hospitalization. Ideally, data on the impact of PMVR on mortality and hospitalizations as well as the utility data should be obtained directly from prospective randomized controlled trials rather than extrapolated from multiple sources.
Evidence in the field of FMR is increasing and a more precise assessment may be possible in the future. A third limitation relates to the nature of the comparative effectiveness data for PMVR. Data about change of level of mitral regurgitation were obtained from the TITAN trial  [13] , in which the control group consisted of patients who underwent unsuccessful device placement, with explant of Carillon occurring during the procedure. Ideally, the effectiveness data should be obtained from a randomized controlled trial with an intention-to-treat analysis to allow the assessment of outcomes despite the real treatment received in groups with balanced observed and unobserved baseline characteristics. Nevertheless, in TITAN trial both groups had similar baseline demographic and clinical characteristics.
Acknowledgements The study was sponsored by  Cardiac Dimensions Inc. (Kirkland, WA, USA). The authors thank  Laura Geissler, MSc  for the help with the collection of the cost data,  Elisabeth Burdukova, MD, MSc  for help with data analysis, and  Natalia Stelmaszuk, MSc  for editing support. Authors also thanks Journal's reviewers,  Simone Huygens  and  Laura Burgers , for valuable comments, which helped to improve the manuscript.
Acknowledgments The European Code against Cancer project was co-funded by the  European Union  (grant agreement numbers:  2011 53 05 ,  2010 53 04  and  2007IARC01 ) and the  International Agency for Research on Cancer. The authors alone are responsible for the views expressed in this manuscript. We would like to thank  Dr Lawrence von Karsa  (formerly at the  International Agency for Research on Cancer)  for his leadership as co-principal investigator of the update of the European Code against Cancer who, due to his retirement, decided not to coauthor this manuscript.
Results The two sisters of family 1 harbored two compound heterozygous mutations: p. Tyr453Cys (published) and deletion of the entire exon 7 (novel). We identified a new variant in family 2: p. Arg49Glyfs*4 (c. 144del), and p. Thr360Ala, a published mutation. In family 3, we found a homozygous substitution, p. Gly25Cys in both siblings. This new variant was predicted to be benign by different algorithms but was absent from general databases (allele frequency <10 -4 in ExAC). Exome analysis was performed and this variant was the only one to be retained after the various filters. However, this variant remains controversial until extensive family investigation is performed. We confirmed that each parental allele carried a mutation in the 3 families.
Statistical methods. Statistical analyses were performed using the StatView v5. 0 software (Abacus Concepts, Berkeley, CA, USA). Significance between groups in the in vitro and xenograft studies were done using a Student's t-test. For the DLBCL patient samples, mean comparisons were based on Mann-Whitney U test, and correlations between quantitative variables were assessed using the Spearman rank correlation coefficient r. Po0. 05 was considered statistically significant.
This effect could be prevented in ABC cell lines that continue to secrete VEGF even after rituximab exposure, by the constitutive activation of NF-kB pathway known also to be involved in HIF-1a activation  (Karar and Maity, 2011). Finally, inhibition of endogenous Trk signalling by K252a was evaluated with a GCB-DLBCL xenograft model. Data show a statistical reduction of tumour growth which was associated with a cytotoxic effect on tumour cells, as we demonstrated in the in vitro study. This effect was however lower than rituximab monotherapy. Blocking BDNF/TrkB signalling by K252a was recently shown to suppress tumour growth also in gastric cancer, but it did not affect 5-fluorouracil sensitivity  (Okugawa et al, 2013). Interestingly, consistent with our in vitro studies, we demonstrate here for the first time that in combination regimen, pharmacological Trk inhibition potentiates the effects of rituximab monotherapy on established DLBCL xenografts.
ACKNOWLEDGEMENTS We thank  Brigitte Fournier  ( Laboratoire d'Anatomie-Pathologique CHU Limoges, France ) and  Maud Branchaud  for technical supports and  Dr Cornelia Wilson  for reviewing the English version of this manuscript. This work was supported by  Ligue Nationale Contre le Cancer  ( ComiteDepartemental de La Haute-Vienne ) and  CORC (Comited'Orientation Recherche Cancer en Limousin). This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4. 0 Unported License.
The expression of CD27 and CD184 was significantly downregulated (7. 2-and 9. 6-fold, respectively), whereas the expression of HLADR was significantly upregulated (1. 6-fold). The expression of CD38 was not significantly upregulated (2-fold). However, significant upregulation of surface and cytoplasmic IgM expression was observed on D7 (6. 4-and 2. 6-fold, respectively) (Figure  2A ). Furthermore, the cells showed significantly upregulated transcription of the plasma cell marker genes  [43]  Gas6 (800-fold) and CD138 (5. 2fold) on D7 (Figure  2B ). CD138 expression was also studied by flow cytometry. However, CD138 was not detected on the cell surface (data not shown). Nevertheless, there were no statistically significant differences between mutated and unmutated CLL samples in terms of morphological features, IgM secretion, immunophenotype and Gas6 and CD138 gene expression changes.
Immunophenotypic analysis Cells were stained with the appropriate combi nations of fluorochrome-conjugated Abs, in a three-to five-color direct immunofluorescence staining protocol. All antibodies were purchased from BD Biosciences (Le Pont de Claix, France). The Cytofix/Cytoperm kit (BD Biosciences) was used for the intracellular staining of immunoglobulin M (IgM) and Ki67, according to the manufacturer's recommendations. Flow cytometry analysis was performed with a FACSCantoII flow cytometer (BD Biosciences). FlowJo software (Tree Star, Ashland, OR, USA) was used for data analysis.
Immunoblotting Western blotting was performed as previously described  [34] , with antibodies against CD229, c-MYC, HSP90 and actin (from Santa Cruz Biotechnology Inc. ), LEF1, ROR1, p27, PI3K, BTK, BCL2, BLIMP1, IRF4, survivin, TYK2, STAT3, XIAP, MCL1, PUMA and BCLxL (from Cell Signaling Technology, Danvers, MA, USA) and FMOD (from Sigma-Aldrich, France). The antisurvivin antibody used in our work does not detect survivin splicing forms. The results were visualized on a ChemiDocTM MP Imaging System (Bio-Rad, Marnesla-Coquette, France). Densitometric quantification was performed with ImageJ analysis software (NIH) (http:// rsbweb. nih. gov/ij/).
Cell viability and cell cycle analysis Cell viability was measured by flow cytometry using annexin-V-phycoerythrin (PE) and 7-amino-actinomycin (7AAD) staining kit (BD Biosciences) according to the manufacturer's recommendations. Cell cycle status was assessed using Vybrant DyeCycle Violet stain (Invitrogen, Courtaboeuf, France), according to the manufacturer's instructions. Briefly, 3 × 10 5 cells were suspended in complete medium containing 0. 5 μl of Vybrant DyeCycle Violet stain for 30 minutes at 37°C. Cells were analyzed with a FACSCanto flow cytometer (BD Biosciences) and data analysis was performed by FlowJo software (Tree Star).
ACKNOWLEDGMENTS We thank  Dr. Paulo Marcelo  ( ICAP, flow cytometry facility ) for assistance with flow cytometry experiments,  Dr. Vincent Fuentes  for valuable discussions and the  Centre Hospitalier Universitaire d'Amiens ,  Conseil Régional de Picardie ,  Le Réseau d'Hématologie de Picardie (RHEPI)  and the  Comité de l'Oise de la Ligue contre le cancer  for financial support.
Results Combining both spectroscopic probes and chemometrics data analysis, we were able to follow on-line three key parameters: viable cells density (VCD), dead cells density (DCD) and indirectly lysed cells density (LCD) via LDH (lactate dehydrogenase) activity. The parameters employed to build the different models of calibration and the statistic quality of these models are summarized in Table  1. NIR spectroscopy calibration models were generated for LCD through on-line monitoring of extracellularly released LDH upon cell membrane disruption. NIR spectrometry can successfully monitor LDH activity in culture medium online. Knowing that there are 110 units of LDH x10 -9 cells (data not shown), the total density of dead cells (TDCD) having released their pool of LDH in the culture medium, can be estimated.
Real-time reverse transcription PCR (RT-PCR). Total RNA was isolated from NOP ϩ/ϩ , NOP ϩ/eGFP , and NOP eGFP/eGFP mice (n ϭ 4 of each genotype) using RNAeasy Mini kit (Qiagen). To measure mRNA levels, real-time quantitative RT-PCR was performed with the iCycler IQ5 multicolor Real-Time PCR detection system (Bio-Rad Laboratories) using QuantiFast Probe PCR Kit (Qiagen). Gene-specific primers and duallabeled probes for NOP/NOP-eGFP and GAPDH were designed using the NCBI primer-BLAST software and synthesized by Qiagen). The following real-time RT-PCR protocol was used for all genes: cDNA was synthesized using QuantiTect Reverse transcription kit (Qiagen) and cDNA corresponding to 50 ng total RNA was used as a DNA template for real-time PCRs: 95°C for 3 min to activate the HotStart enzyme followed by 45 cycles of amplification and quantification (10 s at 95°C; 30 s at 60°C) each with a single FAM fluorescence measurement.