dataesr/scientific-paragraphs-categorization huggingface dataset:
Although norfloxacin and placebo were purchased from Arrow Génériques SAS (Lyon, France) this company did not participate in any part of the study, including study design, data analysis, or manuscript preparation. The steering committee designed the study, made the decision to submit the manuscript for publication, and vouches for the fidelity of the study to the protocol. Research assistants regularly monitored all centers on site to check adherence to the protocol and the accuracy of recorded data. An investigator was responsible for enrolling patients in the study at each center, ensuring adherence to the protocol, and completing the electronic case-report form. All analyses were performed by the study statistician (BP) and reviewed with the senior epidemiologist (NG) in accordance with the International Conference on Harmonization and Good Clinical Practice guidelines.
Trial Measurements Patients were seen monthly for the first 6 months and at 9 months and 12 months thereafter. Demographic data were collected at baseline. Clinical and laboratory data were obtained at baseline and at each follow-up visit. The value of ascitic fluid protein levels was collected at baseline. Clinical data included heart rate, mean arterial pressure, temperature, respiratory rate, body weight, the presence of ascites, the presence of encephalopathy and ongoing therapies. At each follow-up visit the investigator collected information on prespecified liver-related complications that may have occurred since the previous visit (eg, infections, including the site of infection, presence of Gramnegative or Gram-positive bacteria, and the presence of septic shock; kidney dysfunction; hepatic encephalopathy; or gastrointestinal hemorrhage; details on the definitions of liver-related complications are provided in Supplementary Table  4 ).
Patients' adherence was assessed as follows: At each visit of the study protocol, the patient was asked to bring back their remaining study treatment. In each center, a clinical research assistant mandated by the sponsor (Assistance Publique-Hôpitaux de Paris) was in charge of counting the number of remaining pills. In addition, treatment adherence was assessed by the investigators at each visit by interviewing the patient. A new box of the study study treatment then was provided to the patient. In each center, the research assistant was also in charge of scheduling visits and calling back patients who did not present for a scheduled visit. Finally, research assistants regularly monitored all centers on site to check the following: existence of the patient, written signed consent, inclusion criteria, occurrence of adverse events and severe adverse events, primary end point, and data quality.
Previous trials have been selectively performed in patients with low baseline ascitic fluid protein levels (ie, <15 g/L). 3, 4, 7, 8 In our trial, the results of ascitic fluid proteins levels were available in 66. 8% but not 100% of patients with ascites, in part, probably because paracentesis was not used in some patients with small-volume ascites. In any case, we enrolled patients regardless of baseline ascitic fluid protein levels. Our subgroup analysis in patients with low baseline ascitic fluid protein levels showed that 6-month mortality was lower in patients in the norfloxacin group than those in the placebo group. Lower mortality was not observed with norfloxacin in the subgroup of our patients with high ascitic fluid protein levels (ie, !15 g/L). Although these results should be interpreted with caution, in particular because of missing data regarding ascitic fluid protein levels in some patients, they strongly suggest, along with previous findings obtained in an independent study,  8  that patients with advanced cirrhosis and low ascitic fluid protein levels are good candidates for prolonged norfloxacin administration to decrease mortality.
Acknowledgment The following centers and investigators participated in the NORFLOCIR trial. Angers:  Drs Lannes ,  Oberti ,  Fouchard-Hubert , Bousier, Calès; Besançon:  Drs Thévenot ,  di Martino , Weil; Caen:  Drs Ollivier-Hourmand , Dao, Le Toux; Foch:  Dr Hillaire ; Gonesse:  Dr Pauwels ; Lille:  Dr Louvet ; Montpellier:  Dr Ripault ; Nancy:  Dr Bronowicki ; Nice:  Dr Anty ;  Paris Beaujon :  Drs Moreau ,  Elkrief, Payancé ,  Rautou, Valla , Lebrec; Paris Lariboisière:  Dr Ozenne ;  Paris Paul Brousse :  Dr Saliba ;  Paris Jean Verdier :  Dr Nahon ;  Paris Pitié-Salpêtrière :  Dr Rudler ;  Paris Saint-Antoine :  Dr Carbonell ;  Paris Tenon :  Dr Grangé ; Toulouse:  Drs Bureau ,  Robic ; Tours:  Drs Perarnau ,  d'Alteroche. The authors would like to thank  Ray Kim  and  Jean-François Bergmann  for their critical reading of the manuscript and  Estelle Marcault ,  Isabelle Vivaldo ,  Syana Fausta , and the entire staff of the  Unité de Recherche Clinique Paris Nord Val De Seine  for assistance in monitoring and study management.
Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients' outcome.
Datasets Normalized Reads Per Kilobase Million (RPKM) Illumina GA-IIX RNA-seq profiles were downloaded from the TCGA AML data portal. One hundred and sixty-one patients in the TCGA AML cohort had both RNA-seq and clinical data. RPKM values were log-transformed to the base two after adding a value of 1. Expression levels were extracted from the log-transformed data. A representative probe set with the highest average intensity was selected for each gene in each dataset. The median of expression of each gene was used for patients' stratification (high vs. low score).
The best cut-off value for NANOG expression that discriminates the most death events during time was 13 at 24 months of follow-up (AUC = 0. 77, sensitivity = 0. 61/specificity = 0. 85). The level of significance was set at 5%. OS analysis and graph were performed with the R program (version 3. 2. 3) using the "survival" and "ggplot2" packages.
5a ). Combining the three markers led to an increase in the clinical predictability for AML patient outcome at diagnosis, by identifying patients with a higher risk of relapse (from 33 to 86% risk of relapse; Fig. 5b ). In order to evaluate the importance of NANOG, we performed a Kaplan-Meyer analysis on a larger number of patients and observed that high NANOG transcript levels are associated with poor survival (Fig. 5c ). We performed a multivariate parameter analysis and, as expected, identified a significant correlation only between NANOG and ΔNp73 or Sox2 or Oct4 expression. No correlation with any other parameters appeared significant, as indicated in Supplemental Table  S5. Lastly, a similar analysis using the independent TCGA dataset  36  , this time restricted to patients within the intermediate risk group (n = 92), showed again the association between high expression level of NANOG and shorter survival (P = 0,054).
see figure on previous page) Fig. 5 BMPR1A, ΔNp73, and NANOG expression at diagnosis are correlated with patient outcome. Percentage of AML patients in remission or relapse 3 years after diagnosis, according to BMPR1A, ΔNp73 or NANOG expression levels separately (n = 19) (a) or in combination (n = 13) (b). c Overall survival (OS) curve of AML patients from the date of sampling onwards, by using the Kaplan-Meier method. The level of significance was determined by the log-rank test (n = 52; 23 high and 29 low NANOG level). d Overall survival (OS) curve of AML patients from the date of sampling onwards, by using the Kaplan-Meier method. TCGA dataset from AML patients of the intermediate group. e Schematic representation of the role played by BMPs on homeostasis under healthy conditions (top) and the cascade of dysregulations associated with increased concentration of BMP4 in the microenvironment of leukemic immature cells (bottom).
Acknowledgements We thank  I. Durand  from the  CRCL cytometry platform ,  G. Clapisson  and  S. Tabone-Eglinger , managers of  Plateforme de Gestion des Echantillons Biologiques of Centre Léon Bérard ,  Prof. E. Delabesse  ( Institut de Cancérologie de Toulouse, France ) for access to samples from HIMIP collection and  Prof. O. Herault  for helpful discussions. We greatly thank  Mr. S. Morisset  for expert statistical analyses,  Dr. Janet Hall  for improving the quality of the manuscript and  Dr. S. Gobert  for administrative support. We thank the association  Anim' Montbernier ,  Ruy Montceau  and its president  Mr. Armand Glasson  for support. This work was supported by the  French Ligue Nationale Contre le Cancer: Comité de la Loire and Comité de Saône et Loire, Fondation de France  ( 20140047501 ),  Association Laurette Fugain  ( ALF2014/03 ) and the association " Cent pour Sang la Vie ".
( see figure on previous page) Fig. 5 BMPR1A, ΔNp73, and NANOG expression at diagnosis are correlated with patient outcome. Percentage of AML patients in remission or relapse 3 years after diagnosis, according to BMPR1A, ΔNp73 or NANOG expression levels separately (n = 19) (a) or in combination (n = 13) (b). c Overall survival (OS) curve of AML patients from the date of sampling onwards, by using the Kaplan-Meier method. The level of significance was determined by the log-rank test (n = 52; 23 high and 29 low NANOG level). d Overall survival (OS) curve of AML patients from the date of sampling onwards, by using the Kaplan-Meier method. TCGA dataset from AML patients of the intermediate group. e Schematic representation of the role played by BMPs on homeostasis under healthy conditions (top) and the cascade of dysregulations associated with increased concentration of BMP4 in the microenvironment of leukemic immature cells (bottom).
Background. The proportion of treatment success among patients with multidrug-resistant tuberculosis (MDR-TB) enrolled between 1992 and 1996 was 51. 2%, and that among patients enrolled between 2000 and April 2007 was 61%. To address the challenge of MDR-TB, the Taiwan MDR-TB Consortium (TMTC) was established in May 2007. To assess the performance of the TMTC, we analyzed the data of patients enrolled in its first 5 years. Methods. Comprehensive care was provided at no cost to patients, who were usually hospitalized for 1 month initially. Treatment regimens consisted of 4-5 drugs and the duration of treatment was 18-24 months. A case manager and a directly observed therapy provider were assigned to each patient. Psychosocial support was provided to address emotional stress and stigma. Financial support was offered to avoid the financial hardship faced by patients and their families.
Study Population Our study population includes all MDR-TB patients who were referred to the TMTC between 1 May 2007 and 30 April 2012. However, patients treated in the health facilities that were not part of the TMTC may have been managed in a conventional manner that was less satisfactory; therefore, those who had been treated for 3 or more months for their current episode of MDR-TB before being referred to the TMTC were excluded from the analysis. Furthermore, patients who were <20 years old, patients treated with only first-line drugs, and patient with only extrapulmonary TB were also excluded. The data collected included age, sex, body mass index, smear, cavitary lesions on the chest radiograph, alcohol use, comorbidity (diabetes, cancer, chronic liver disease, hepatitis B surface antigen positive, anti-hepatitis C antibody positive, hypertension, and cardiovascular disease), a history of treatment with anti-TB drugs, type of case registration, the results of first-line and second-line DST, anti-TB drugs used for the current episode of treatment, surgical intervention, and the outcome of treatment (cured, treatment completed, treatment failure, died, lost to follow-up).
Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods: The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics.
Study design and patients GeNeSIS was a prospective, open-label, observational research program conducted in 30 countries at N800 study sites (Clinical Trial Registry Number: NCT01088412) between 1999 and 2015. It was set up as a Core Study on safety and effectiveness of GH treatment for growth, with topic-focused sub-studies that included a DNA Analysis Sub-study for investigating mutations in genes involved in pituitary development or GH secretion (Supplementary Table  S1 ). Patients with severe GHD according to the discretion of the investigator were invited to provide a blood sample for DNA analysis. Patients were classified as having IGHD or CPHD based on clinical and biochemical information reported by the site. The algorithms for diagnosing deficiencies of TSH, gonadotropins, ACTH, PRL or ADH have been previously described in detail  [9].
Data collection Data were collected by investigators according to their common practices and entered on case report forms. They included aetiology of GHD, demographic, auxologic and biochemical data, status of other pituitary hormones, and information on abnormal brain imaging  [10]. Baseline data were collected before initiation of GH treatment and follow-up data were typically collected at 6-month intervals. The diagnosis of GHD in an individual patient was accepted as provided by the investigator irrespective of results of GH testing. If several GH stimulation tests were reported, the highest GH peak value was used in statistical analyses. Serum IGF-I and IGFBP-3 concentrations were determined either centrally (University Children's Hospital, Giessen, Germany) or at local laboratories and converted to central laboratory equivalent values using previously published algorithms  [10].
The sensitivity of the methodology was approximately 85% for SSCP and 96% for dHPLC  [13]. PCR products of 52 patients were directly sequenced. Sequences were compared to the human genomic reference (GRCh37/hg19) obtained from the UCSC Genome Browser and variant positions were annotated according to gene-specific transcript and protein references given in Supplementary Tables  S1  and S2. Variants with a minor allele frequency (MAF) of b1% in at least two of the three large-scale variant databases accessible at the time of evaluation (Supplementary Table  S2 ) were pre-selected followed by classification as pathogenic, likely pathogenic, uncertain significance, likely benign, or benign according to the recommendations of the American College of Medical Genetics and Genomics (ACMG)  [14]. All in silico analyses were performed in April 2017.
Patients with variants classified as pathogenic or likely pathogenic constitute the cohort of "patients with mutations" or "carriers", whereas patients without variants or with variants classified as likely benign, benign or uncertain significance constitute the cohort of "patients without mutations" or "non-carriers". A mutation was annotated as "novel", if all of the following criteria were met: no record in the disease-related variant databases ClinVar and HGMD, no relevant result in a text search using the three-and oneletter codes for amino acids in PubMed, Google and Google Scholar (Supplementary Table  S2 ), no relevant findings on inspection of recent reviews  [2, 3, 5, 15]. All surveys were performed in July 2017.
The latter differed in its breakpoints from the PROP1 deletion found frequently in Kurdish populations  [18, 19]. The most prevalent mutations in our cohort were GH1:c. 291 + 1G N A (n = 10), PROP1:c. 150del (n = 11), and PROP1:c. 301_302del (n = 51). Although the majority of the remaining mutations occurred once (n = 19), only 11 were presumably private; 8 were published elsewhere and/or are listed in the large variant databases. Twelve DNA variants classified as "uncertain significance or benign" are listed in Supplementary Table  S5  and further details are described in the text which follows that table. These patients were considered as non-carriers in statistical analyses.
Pituitary enlargement in patients with PROP1 mutations may be singled out because of its clinical relevance; it regresses spontaneously with time and neurosurgical intervention should not be undertaken  [42]. Additional   2 ) while IGHD type IB with a less severe phenotype was due to GHRHR mutations (#11-17 in Table  2 ). IGHD type II resulted from GH1 mutations #3-8 in Table  2 , and IGHD type III from a SOX3 mutation (#33). The difference between IGHD type I vs. types II and III was significant by ANOVA (P b. 001). (B) Height SDS versus log2(maximum GH peak) in patients (n = 19) and relatives (n = 6) with IGHD types I, II, and III. Pearson correlation (r = 0. 51, P =. 0099) and non-linear regression fitting the log2 presentation of the X-axis (hatched line) were calculated using GraphPad Prism 5 software (GraphPad Software, La Jolla, CA).
GH treatment beyond four years aims primarily at maintaining achieved height gain and avoiding catch-down growth that may occur after discontinuation of GH resulting in loss of investment (cost, daily injections, and exposure to potential risks). While height gain in this study cohort, especially in mutation carriers, was significantly greater than in cohorts with less severe GHD or non-GH deficient forms of short stature, the necessity for GH treatment in patients with severe GHD reaches beyond growth. The majority of such patients, especially those with mutations, require life-long GH replacement for its metabolic effects  [44]. The current study had some limitations: Clinical data were collected as provided by the investigators with limited data monitoring as is common in observational studies.
Acknowledgements The authors thank the patients, their families and the contributing physicians and site study coordinators for their participation and engagement in this study. Special thanks are due to  Johannes Weigel  and  Gunter Flemming  for their assistance in targeted sequencing. The authors thank also the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http:// gnomad. broadinstitute. org/about. The authors thank the  NHLBI GO Exome Sequencing Project  and its ongoing studies which produced and provided exome variant calls for comparison: the  Lung GO Sequencing Project  ( HL-102923 ), the  WHI Sequencing Project  ( HL-102924 ), the  Broad GO Sequencing Project  ( HL-102925 ), the  Seattle GO Sequencing Project  ( HL-102926 ) and the  Heart GO Sequencing Project  ( HL-103010 ).
4 kb sequence (construct referred to as 0. 4Δ) and examined the impact of this deletion on p53-dependent PINK1 promoter activity. This deletion significantly reduced the p53-dependent decrease of PINK1 promoter activity observed with wild-type 0. 4 construct (compare black bars in Fig. 4b, lower ). This data validates the -167/ -154 sequence as a functional p53 responsive element and confirms the ability of p53 to directly repress PINK1 transcription. However, this deletion did not fully abolish p53-associated inhibitory effect (Fig. 4b, lower ). This could indicate a potential participation of the less conserved responsive element located at -296/-285. To validate the physical interaction of p53 with the -167/-154 PINK1 promoter region in physiological conditions, we have performed chromatin immunoprecipitation assay (ChIP).
, Germany), anti-optineurin (sc-166576, Santa Cruz Biotechnology Inc. , Germany), anti-NDP52 (sc-376540, Santa Cruz Biotechnology Inc. , Germany) and anti-actin (clone AC-74, A5316, Sigma) antibodies. Immunological complexes were revealed with either anti-rabbit or anti-mouse IgG-coupled peroxidase antibodies (Jackson ImmunoResearch, UK) by the electrochemiluminescence detection method (Roche Diagnostics S. A. S, France). Chemiluminescence was recorded using a luminescence image analyzer LAS-4000 (Raytest, Fuji, France) and quantifications of non-saturated images were performed with the FUJI Film Multi Gauge image analyzer software.
RNA extraction, reverse transcription and real-time PCR analysis RNA from cells and RNA later (Qiagen, Germany) stabilized mouse brains were extracted and treated with DNAse using RNeasy or RNeasy Plus Universal Mini kits respectively following manufacturer's instructions (Qiagen). Two µg of total RNA were reverse transcribed (GoScript Reverse Transcriptase, Promega) using Oligo-dT priming. Then, samples were subjected to real-time PCR by means of a Rotor-Gene 6000 apparatus (Qiagen), using the SYBR Green detection protocol. Gene-specific primers were designed with the Universal Probe Library Assay Design Center software (Roche Applied Science, France). Relative expression levels of human PINK-1 (forward 5′-CGA GGA ACT CGT TTG AAG GG-3′; reverse 5′-CCA GGT GGC AAA TCA GAC ATG-3′), mouse PINK-1 (forward 5′-CGC CTA TGA AAT CTT TGG GC-3′; reverse 5′-GCA CTG CCT TGG CCA TAG AA-3′), amplification products were normalized for RNA concentrations with human Topoisomerase 1 (forward 5′-CCC TGT ACT TCA TCG ACA AGG-3′; reverse 5′-CCA CAG TGT CCG CTG TTT C-3′), mouse Topoisomerase 1 (forward 5′-TGC CTC CAT CAC ACT ACA GC-3′; reverse 5′-CGC TGG TAC ATT CTC ATC AGG-3′) and human GAPDH (forward 5′-AGC CAC ATC GCT CAG ACA C-3′; reverse 5′-GCC CAA TAC GAC CAA ATC C-3′) and mouse GAPDH (forward 5′-TGT CCG TCG TGG ATC TGA C-3′; reverse 5′-CGT GCT TCA CCA CCT TCT TG-3′) housekeeping genes.
Statistical analysis Statistical analyses were performed with GraphPad Prism software (www. graphpad. com for Windows, CA, USA). No statistical test was used to determine sample size in ex vivo and in vivo studies. No randomization and blindness were used in animal studies. Analysis of two groups of variables was used for samples analyzed by unpaired Student's t-test after having passed a normality test (D'Agostino-Pearse omnibus Normality test) to assure Gaussian distribution of values. All tests are two-sided; the mean was defined as the center value and errors bars correspond to SEM. Analysis of more than two groups of variables (normality test passed) was performed by One-way ANOVA with Newman-Keuls's post-hoc test without any adjustment. The number of samples, replication of experiments and the P value are provided in figures legends.
Acknowledgements The authors deeply thank  Drs. JC. Bourdon ,  M. Oren ,  B. Vogelstein ,  M. Roussel  and  M. Serrano  for providing us either valuable constructs or cellular and animal models. This work was supported by the  "Conseil Départemental des Alpes Maritimes ", by the  Foundation Claude Pompidou  and by the  University Hospital Federation (FHU) OncoAge. This work has been developed and supported through the  LABEX (excellence laboratory, program  investment for the future)  DISTALZ (Development of Innovative Strategies  for a Transdisciplinary approach to ALZheimer's disease). Thomas Goiran is funded by the  "Ligue contre le Cancer ".