dataesr/scientific-paragraphs-categorization huggingface dataset:
Selection of Genes and SNPs from TCPTP pathway. Genotyping in these GWAS studies was performed by one of Illumina HumanHap 317, 317 + 240 S, 370Duo, 550, 610 or 1 M arrays. IMPUTE2 v2. 1. 1 or MaCH v1. 0 software was used for imputation. Genes in the TCPTP pathway were identified from the Molecular Signatures Database (http://www. broadinstitute. org/gsea/index. jsp)  37 and Genecards (http://www. genecards. org/). Overall, 43 genes located on autosomal chromosomes were selected (detailed in Supplementary Table  S1 ). The final meta-analysis contained 5,162 SNPs with the following inclusion criteria: genotyping rate >95%, minor allele frequency (MAF) ≥ 5%, and Hardy-Weinberg Equilibrium (HWE) exact P value ≥ 10 -5. The detailed workflow is shown in Fig. 4. In silico functional prediction and validation.
Statistical analysis. Odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated using Stata (v10, State College, Texas, USA) and PLINK (v1. 06) software. A meta-analysis with the inverse variance method was employed on the 5,162 SNPs. We used Cochran's Q statistic to test for heterogeneity and I 2 statistic for the proportion of the total variation  43. The fixed-effects model was used when there was no heterogeneity among GWAS studies (Q-test P > 0. 100 and I2 < 25%); otherwise, the random-effects model was used. The false discovery rate (FDR) was performed to control for multiple testing with a threshold <0. 20  44. The genes mRNA expression levels in lung cancer and adjacent tissues from TCGA database were performed by paired t-test. Regional association plots were performed by LocusZoom 45.
Acknowledgements As Duke Cancer Institute members, QW, KO, and NR acknowledge support from the  Duke Cancer Institute  as part of the  P30 Cancer Center Support Grant  (Grant ID:  NIH CA014236 ). QW was also supported by the start-up funds from  Duke Cancer Institute, Duke University Medical Center. This work was supported by the  Transdisciplinary Research in Cancer of the Lung (TRICL) Study  and,  U19-CA148127  on behalf of the  Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. The Toronto study was supported by  Canadian Cancer Society Research Institute  ( 020214 ),  Ontario Institute of Cancer and Cancer Care Ontario Chair Award  to RH The ICR study was supported by  Cancer Research UK  ( C1298/A8780 andC1298/A8362 - Bobby Moore Fund for Cancer Research UK ) and NCRN, HEAL and  Sanofi-Aventis.
Additional funding was obtained from  NIH  grants ( 5R01CA055769 ,  5R01CA127219 ,  5R01CA133996 , and  5R01CA121197 ). The Liverpool Lung Project (LLP) was supported by  The Roy Castle Lung Cancer Foundation, UK. The ICR and LLP studies made use of genotyping data from the  Wellcome Trust   Case Control Consortium 2  ( WTCCC2 ); a full list of the investigators who contributed to the generation of the data is available from www. wtccc. org. uk. Sample collection for the Heidelberg lung cancer study was in part supported by a grant ( 70-2919 ) from the  Deutsche Krebshilfe. The work was additionally supported by a  Helmholtz-DAAD fellowship  ( A/07/97379  to MNT) and by the  NIH  ( U19CA148127 ). The  KORA Surveys  were financed by the  GSF , which is funded by the  German Federal Ministry of Education, Science, Research and Technology and the State of Bavaria.
1. 05/2. 1. 00/03. 0101 ). Support for the CARET genome-wide study was also provided by grants from the  US National Cancer Institute ,  NIH  ( R01 CA111703  and  UO1 CA63673 ), and by funds from the  Fred Hutchinson Cancer Research Center. Additional funding for study coordination, genotyping of replication studies and statistical analysis was provided by the  US National Cancer Institute  ( R01 CA092039 ). The lung cancer GWAS from Estonia was partly supported by a  FP7 grant  ( REGPOT245536 ), by the  Estonian Government  ( SF0180142s08 ), by  EU RDF in the frame of Centre of Excellence in Genomics and Estoinian Research Infrastructure 's Roadmap and by  University of Tartu  ( SP1GVARENG ). The work reported in this paper was partly undertaken during the tenure of a Postdoctoral Fellowship from the  IARC  (for MNT).
Study design This was an open-label, dose-escalation, multicenter, phase I study (NCT01140607) of cabazitaxel in patients with non-hematologic cancers and varying degrees of hepatic function. This study was designed to evaluate the maximum tolerated dose (MTD) and safety, and assess the PK properties and relationship between PK and safety parameters, of cabazitaxel in patients with varying degrees of hepatic impairment. A similar design was employed in the study of irinotecan in patients with hepatic dysfunction  [11]. This study was approved by ethics committees/review boards at all participating institutions, and all patients provided written informed consent prior to participation. According to the cabazitaxel dose-escalation schedule and dose-escalation decision rules defined in the protocol, which specified different starting dose levels for each cohort and were based on the number of dose-limiting toxicities (DLTs) observed at the different dose levels, a total of 39-75 patients were expected to be enrolled.
Pharmacokinetic assessments Heparinized blood samples were collected from all patients in Cycle 1, on Day 1 immediately prior to the start of infusion, 5 min before the end of infusion, and then at 5, 15, and 30 min and 1, 2, 3, 5, 7, and 10 h after the end of infusion. Samples were also collected on Days 2, 3, 4, 5, 8, and 10 after cabazitaxel infusion. Cabazitaxel plasma concentrations were analyzed using a validated liquid chromatography with tandem mass spectrometry method (LC-MS/MS; lower limit of quantitation [LLOQ] = 1 ng/ mL). Cabazitaxel PK parameters were calculated using non-compartmental analysis with validated software (PKDMS Version 2. 0 with WinNonlin Professional, Version 5. 2. 1, Pharsight). PK parameters included maximum observed concentration (C max ), area under the concentration versus time curve extrapolated to infinity (AUC inf ), area under the concentration versus time curve calculated using the trapezoidal method from time 0 to real-time t last (AUC last ), terminal half-life (t 1/2z ), total body clearance (CL), and volume of distribution at steady state (V ss ).
Safety data Of the 43 treated patients, 38 were evaluable for DLTs with five excluded due to concomitant G-CSF administration during Cycle 1 in the absence of a DLT. In Cycle 1, 13 patients (34%) across all cohorts experienced a DLT (Table  3 ). Hematologic and non-hematologic DLTs were each reported in eight patients (21%) with three patients experiencing both. No liver-related DLTs were reported. In Cohort 2 (mild hepatic impairment), three of five patients receiving 25 mg/m 2 experienced DLTs (grade 4 febrile neutropenia, grade 3 hypophosphatemia, and grade 4 neutropenia without fever), and the MTD was established as 20 mg/m 2. In Cohort 3 (moderate impairment), the first two patients treated at 20 mg/m 2 experienced DLTs (grade 4 neutropenic sepsis, and grade 3 febrile neutropenia and stoma site infection), and the MTD was established as 15 mg/m 2.
Acknowledgements The authors would like to thank participating patients and their families, in addition to the staff at participating sites. This study was supported by Sanofi. The authors received editorial support in the form of medical writing services provided by Danielle Lindley of MediTech Media, funded by Sanofi. The authors were responsible for all content and editorial decisions and received no honoraria related to the development of this manuscript. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. The authors would like to thank the Institute for Drug Development at the Cancer Therapy and Research Center, University of Texas Health Science Centre, San Antonio, Texas, for the Cancer Center Support Grant (P30CA054174).
Microscopy and image analysis. Strains were inoculated in lysogeny broth (LB) from glycerol stocks and shaken overnight at 37 °C. The next day, cultures were diluted and seeded on a gel pad (1% agarose in LB). The preparation was sealed on a glass coverslip with double-sided tape (Gene Frame, Fischer Scientific). A duct was previously cut through the center of the pad to allow for oxygen diffusion into the gel. Temperature was maintained at 34 or 28 °C using a custom-made temperature controller  68. Bacteria were imaged on a custom microscope using a 100×/ NA 1. 4 objective lens (Apo-ph3, Olympus) and an Orca-Flash4. 0 CMOS camera (Hamamatsu). Image acquisition and microscope control were actuated with a LabView interface (National Instruments). Segmentation  69  and cell lineage were computed using a MatLab code developed in the Elowitz lab (Caltech)  70.
Acknowledgements We thank  Paul Rainey ,  Roberto Kolter ,  Oskar Hallatscheck , and  Jean-Baptiste Boulé  for their comments on the manuscript. We thank  Irene Wang  for her help with force microscopy calculations. We thank  Michael Elowitz  for Schnitzcell. We thank  José Quintas Da-Silva  and  Carlos Gonzales  for design and construction of the mechanical parts. We thank  Mathieu Coppey ,  Manuel Thery ,  Frederic Lechenault , and  Sebastien Moulinet  for stimulating discussions. This work was supported by the  Agence Nationale pour la Recherche   ANR-12-JSV5-0007-01  (to M. B. ),  ANR-10-LABX-62-IBEID  (to C. B. and J. -M. G. ), and  ANR-11-JSV5-005-01  (to N. D. ) and by the  Fondation pour la Recherche Médicale  grant Equipe FRM  DEQ20140329508  (to C. B. and J. -M. G. ).
Relative receptor or Gα subunit expression levels were quantified in each sucrose fractions by recording of the total luminescence. Results are expressed as the percentage of the maximal luminescence measured from all fractions in each experiment. Grey boxes highlight raft nano-domains enriched fractions, identified by detection of the GM1 protein (upper dot plot). Data represent the mean ± s. e. m. of at least three independent experiments. The statistical significance of the difference in membrane distribution in low versus high conditions (*) or versus receptor alone (¤) was assessed using two-way ANOVA followed by a Bonferroni posttest (*P < 0. 05, **P < 0. 01, ***P < 0. 001). adenylyl cyclase activity promoted by Gs (Supplementary Fig. 4 ), most probably due to the amplification and saturation of the second messenger production.
11 (Biolegend, Germany), dilution 1:1000). After incubation for 2 hrs at room temperature, membranes were washed four times with TBS-T (20 mM Tris, 150 mM NaCl, 1% Tween, pH 7. 5) and the secondary antibody donkey anti-rabbit IgG-HRP or goat-anti-mouse IgG HRP (Santa Cruz Biotechnology, Heidelberg, Germany) applied for 1 hr. After washing, bound antibodies were detected using an enhanced chemiluminescence assay (GE Healthcare) and a LAS-3000 documentation system (Fujifilm, Du ¨sseldorf). Quantification of bands was performed using the MultiGauge System V3. 1 (Fujifilm). Cell lysates corresponding to the total protein amount were set to 100%. Only data with recovery values of 100 ± 20% were included in the analysis. Three biological and three technical replicas were performed for each experiment.
1 mM ouabain, +/-10 μM bumetanide, 2 μCi/ml 86 Rb + , pH 7. 4) for 7 min. Afterwards, cells were washed 3 times with 1 ml of ice-cold termination buffer (135 mM Na-gluconate, 7,5 mM NaCl, 15 mM HEPES, pH 7,4). Cells were subsequently lysed in 500 μl 0. 25 M NaOH for 1 hr and neutralized with 250 μl pure acetic acid. 86 Rb + uptake was assayed by Cerenkov radiation, and the protein amount was determined by BCA (Thermo Fisher Scientific, Bonn, Germany). For statistical analysis, data groups were compared using a Student's t-test and p < 0. 05 was considered as statistically significant. Measurement using Cl --sensitive probe Cell culture. For recordings of the fluorescence of the Cl --sensitive probe, neuroblastoma N2a cells were transiently transfected with a mixture of three cDNA constructs encoding: i) ClopHensorN  [49, 50]  ii) human α1 subunit of the glycine receptor-channel (GlyR) and iii) hvKCC, rnKCC2 (KCC2 of rattus norvegicus), or empty pcDNA3.
The fluorescence signal was sampled at 0. 05 Hz using a CoolSNAPHQ Monochrome CCD camera and Metamorph software (Roper Scientific SAS, Evry, France). Excitation lasted 60 and 20 ms for F 436 and F 577 , respectively. All recordings were performed using a LUCPlanFLN 20x Objective, NA 0. 45 (Olympus, Rungis, France) that allowed simultaneous recording of 30-50 transfected cells. The ratiometric signal (R 577/436 ) reflecting changes of [Cl] i was obtained after off line arithmetic division of F 577 and F 436 images. 6 mm coverslips with N2A cells, which were transfected with ChlopHensorN, GlyR and hvKCC or rnKCC2, were placed onto an inverted microscope and were perfused with different solutions using an experimental paradigm described previously  [51]. The perfusion started with the physiologically relevant S1 solution (150 mM NaCl, 2.
The 5' and 3' ends were obtained by rapid amplification of cDNA ends (RACE). The open reading frame of Hydra vulgaris KCC (hvKCC) encodes a 1,032 amino-acid protein (GenBank accession number: XP_012555566. 1) and is composed of 24 exons that spans a total of 44. 1 kb on the genomic level. Exon length varies from 51 bp to 206 bp and introns range from 88 bp to 7. 3 kb (Fig  1A ). The open reading frame of hvN(K)CC encodes a 965 amino-acid protein (GenBank accession number: KY646162). HvN(K)CC comprises 9 exons within a genomic region of 87. 9 kb. Exon length varies from 44 bp to 664 bp and introns range from 62 bp to 29. 2 kb (Fig  1B ). To clarify the phylogenetical relation of hvKCC and hvN(K)CC to the different CCC subfamily members, a multi-sequence alignment of hvKCC, hvN(K)CC, and human CCC isoforms was generated and a phylogenetical tree constructed using the Maximum-Likelihood approach (S1 and S2 Figs).
Library preparation, sequencing and data processing High throughput sequencing was performed on two LF and two LF-SO libraries. The RNA from two cows were pooled to generate each library. The pools were obtained using equal amounts (10 μg) of RNA extracted from the mammary tissues of two cows chosen randomly. The library preparation and sequencing techniques are described in Le Guillou et al. [13]. Briefly, libraries were prepared using the Illumina small RNA kit with RNA isolated from mammary gland, followed by sequencing on an Illumina HiSeq 2000 by GATC biotech Company (Next Gen Lab) according to the Solexa sequencing method. The RNA-seq data were then analysed mainly using miRDeep2 software  [49]  and described in Le Guillou et al. [13].
Statistical analysis Statistical analysis to compare the miRNomes was performed using R version 3. 0. 1 (R Development Core Team, 2013) with the Bioconductor package DESeq2  [51] , as described by Le Guillou et al. [13]. Data were filtered using the Bioconductor package HTSFilter  [47]. This method aims to identify the threshold that maximizes the filtering similarity among biological replicates, or in other words that where most genes tend to have either normalized counts lower than or equal to the cut-off point in all samples (i. e. filtered genes) or higher than the cut-off point in at least one sample (i. e. non-filtered genes). This threshold value was found to be equal to 199. The p-values were adjusted for multiple testing using the Benjamini-Hochberg method  [52] , and those with an adjusted p-value <0.
HTSFilter package  [54]  was applied to remove miRNA that appeared to generate an uninformative signal by identifying a filtering threshold that maximizes so-called filtering similarity among replicates. After this filter, the number of miRNAs was reduced to 272 (Supplementary S1 Table). Among these, 18 were predicted miRNAs which were not identified in any species and thus may be considered as potential novel miRNA  [13].
Variations in the bovine mammary gland miRNome as a function of sunflower oil supplementation This analysis enabled the ranking of miRNAs by their expression level and thus the ranking of their abundance under the two dietary conditions. Eight miRNAs (miR-15a-5p, miR-17-5p, miR-20a-5p, miR-33a-3p, miR-126-3p, miR-181a-5p, miR-142-5p and miR-223-3p; Supplementary S1 Table ) were chosen for further study on the basis of their ranking and their function highlighted in the literature. Their expressions were analysed using qPCR on RNA samples used for sequencing analyses. The profiles obtained using the NGS and qPCR approaches agreed for all the miRNAs tested (Fig  1 ) despite different amplitude responses. However, with  both techniques, the ranking of the expression of the eight selected miRNAs was conserved (data not shown).
Discussion In order to better understand the regulation mechanisms underlying mammary gene expression in response to dietary factors, miRNomes from the mammary glands of cows receiving an LF-SO diet or LF diet were compared. The comparison of these miRNomes enabled identification of several miRNAs that displayed a trend to being up-or down-regulated in the miRNome from cows receiving the LF and LF-SO diets. Among these, eight miRNAs, chosen due to their ranking and their functions, were analysed using qPCR on the same RNA pools. In the same way as several other authors, we show a good correlation between the data obtained using the two different approaches  [55, 56] , an agreement which reinforced the value of our findings. Then among the eight candidate miRNAs highlighted by the RNA sequencing study, it was confirmed, by RT-qPCR on samples from 11 cows (each cow receiving each diet), that the expression of miR-20a-5p and miR-142-5p was decreased by sunflower oil supplementation.
The functions of miR-20a-5p and miR-142-5p have never been investigated in the mammary gland. Due to the nutritional influences of milk fat composition, in order to determine the effects of sunflower oil supplementation on lipid metabolism which was one of the biological process altered by sunflower oil supplementation  [46] , our attention focused on the predicted targets involved in this pathway. Among them, twenty-three predicted targets for miR-20a-5p and miR-142-5p have been identified, using DIANA software, which three were targeted by the two miRNAs. MiR-20a-5p may act i) on lipoprotein metabolism (by targeting APOBEC4 (apolipoprotein B mRNA editing enzyme catalytic polypeptide like 4), LDLR (low density lipoprotein receptor) and VLDLR (very low density lipoprotein receptor)), ii) on fatty acid desaturation (by targeting SCD5 (stearoyl-CoA desaturase 5)), and iii) on lipid secretion (by targeting BTN1A1 (butyrophilin subfamily 1 member A1), a major constituent of the milk fat globule membrane).
Acknowledgments The authors are grateful to  L. Bernard ,  Y. Chilliard  and  J. Rouel  for their assistance with animal experiments and tissue isolation, staff in the animal experimentation unit (UERT), and  F. Dessauge  for providing the BME-UV1 cell lines. The authors also thank  D. Durand  for performing mammary gland biopsies. Their particular thanks also go to  A. de la Foye  for her help with statistical analyses, to  E. Honvo Houeto  for her technical help. This work received support from  INRA ,  AIP BioRessources and ApisGène.
Patients registered in the UMBRELLA protocol will continue to be stratified for postoperative treatment according to tumour stage and histological risk group, as was the protocol in SIOP-2001 (TABLE  1 ). Prospective data from patients who are stratified and treated based on standardized recommendations will be collected and analysed. This data collection, in combination with the results of planned integrated biomarker and imaging studies (which will assess the relative contribution of gain of 1q and assessment of residual blastemal volume), might be used to guide stratification in future protocols. The therapeutic regimen of the experimental arm of the SIOP-2001 trial has been adopted as the new standard management regimen for most patients in the UMBRELLA protocol with stage II-III intermediate-risk Wilms tumours.
Data on the use of this regimen and outcomes will be prospectively captured in the SIOP database and can, therefore, be evaluated in a descriptive study. Bilateral disease (stage V). Synchronous bilateral Wilms tumour (stage V) accounts for ~5-8% of instances of Wilms tumour and long-term overall survival is currently ~80%  [31] [32] [33] [34] [35]. End-stage renal disease (ESRD) is the most clinically significant morbidity for patients with bilateral Wilms tumours and can be caused by underlying germline genetic aberrations as well as treatmentrelated loss of functional renal tissue. Aronson et al. 35  observed that functional renal outcome was considerably better after bilateral nephron sparing surgery (NSS) than when other types of surgery were used  35. Independently of the type of treatment, children with Wilms tumour, aniridia, genitourinary anomalies, and retardation (WAGR), Denys-Drash or other syndromes associated with WT1 mutations, are at increased risk of ESRD  36.
Conclusions As well as providing a useful guideline for routine clinical practice, the UMBRELLA protocol should stimulate international collaboration and research. By standardizing the treatment for all Wilms tumour types, prospectively collected data from a large, homogenous cohort of patients will be available for future vali dation of biomarkers, treatment stratification, and thera peutic targets. Moreover, the UMBRELLA protocol can serve as the SIOP-RTSG best-available treatment standard. It will be the backbone for new treatment approaches in future phase I/II and randomized trials, in which collaboration with the COG will continue to be sought. Global collaboration is still necessary for finding effective treatments for the most unfavourable Wilms tumours, such as refractory metastatic, bilateral, and relapsed high-risk disease, and the UMBRELLA protocol will contribute to this aim.
Acknowledgements The  SIOP-RTSG  wishes to acknowledge the outstanding contribution of  Prof. Dr Ivo Leuschner , a SIOP Pathology Panel member and cochair who was dedicated to improving the outcomes of children with cancer. In this respect, he served as a reference pathologist for many countries. His sudden death is a great loss for us and our society. We will miss him as a friend and colleague and we will keep him in our lasting memories. We further acknowledge all members of the  SIOP-RTSG  for their dedicated contribution to development of the UMBRELLA protocol.
Additional purification was performed with Agencourt AMPure XP Beads (Beckman Coulter, Krefeld, Germany) as recommended in the 454 instructions for amplicon library preparation (Roche, Mannheim, Germany). Sequencing of the 16S rRNA gene amplicon library was performed on a Roche 454 GS FLX Titanium system Pyrosequencer as recommended in the manufacturer's instructions (Roche, Mannheim, Germany). Resulting sequences were processed using the amplicon signal processing pipeline of the Roche software for base calling, trimming of adaptors and quality trimming with one modification in the quality filtering section, where "vfScanAllFlows" was changed from "tionly" to "false" such that 3' trimming for the Amplicon pipeline is activated leading to fewer rejected reads. Sequence data have been submitted to Sequence Read Archive (SRA) of NCBI (BioProject ID: PRJNA296567).