dataesr/scientific-paragraphs-categorization huggingface dataset:
PDCLs maintain genetic TP53 status heterogeneity observed in human GBM tumors Thirty-six GBM cell lines including 32 PDCLs from two sets (cohort #1 and cohort #2, 4/32 PDCLs were used in both cohorts) and 4 commercially available cell lines were used in the present study. Data acquired from both cohorts were obtained from two independent laboratories. A summary of PDCL genetic status can be seen in supplementary data (S4). MDM2 and MDM4 high level amplifications were detected in 2/32 (BT484 and 3731) and 2/32 (BT112 and BT216) GBM PDCLs respectively, roughly equivalent with the incidence rate reported in patient samples in the TCGA dataset. MDM2 and MDM4 gain was seen in 3/32 and 2/32 PDCLs cell lines, respectively. Forteen out of the total cohort of 36 GBM lines carry TP53 point mutations altering p53 functions.
Finally, RG7112 appeared to be inactive in a TP53 mutant model (4339). Taken together, these observations correlate with the data observed in vitro. The efficacy of RG7112 (100 mg/kg) was then assessed in the MDM2-amplified 3731 orthotopic GBM in vivo model. RG7112 decreased tumor progression rate as shown by bioluminescence imaging curves (Figures  5, Panels A-C ). This decrease of tumor growth was validated on T2-weighted MRI anatomical images (Figure  5 , Panel D). The tumor volume decreased from 4. 91 mm 3 prior to RG7112 treatment to 4. 28 mm 3 at the end of treatment (13% decrease). In contrast, tumor volume increased from 5. 97 to 84. 84 mm 3 in vehicle-treated tumors, representing a 14. 2-fold volume increase in these animals. Finally, RG7112 prolonged survival of tumor-bearing mice treated with RG7112 versus vehicletreated mice (p=0.
In the clinic, RG7112 treatment of MDM2-amplified liposarcoma patients resulted in a stable disease (14 out of 20 patients) or a partial response (1 out of 20 patients)  [11]. The data reported here in the orthotopic model is coherent with this observation, as tumor growth was inhibited by the treatment, but seemed to be reinitiated when the treatment was halted. In this same clinical study, increased p53, p21 and MDM2 protein expression and decreased Ki67 expression were observed in the tumor after the first 6-10 days cycle of daily RG7112 administration  [11]. In our study, increased expression of p53, p21, MDM2 and decreased expression of Ki67 were also measured in subcutaneous treated tumors 48 h after RG7112 dosing. In both orthotopic and subcutaneous models, it appears that inhibition of MDM2 prevented tumor growth.
Acknowledgments Funding information: This work is part of the  GlioTex (i. e. , Glioblastoma and Experimental Therapeutics)  project funded by  La Fondation ARC pour la Recherche sur le Cancer  and supported by  L'Institut Universitaire de Cancérologie (IUC). Additional support for this work was received from the  DFCI Brain Tumor Therapeutics Accelerator Program  (to P. Y. Wen ) and the  National Cancer Institute of the National Institutes of Health  under award numbers  P50CA165962  (to P. Y. Wen  and  K. L. Ligon ),  R01CA170592  (to P. Y. Wen  and  K. L. Ligon ),  R01 CA188228  (to  K. L. Ligon  and  R. Beroukhim ) and  P01CA142536  (to K. L. Ligon). Animal studies were performed with the technical support of staff of the  Pitié-Salpêtrière Functional Experimentation Center  and the  Animal Resource Facility at Dana-Farber Cancer Institute in Boston.
We thank the  Harvard ICCB-Longwood Screening Facility  for assistance with screening. MRI data were acquired by the  Center for Neuroimaging Research (CENIR)  who has received funding from the program " Investissements d'avenir "  ANR-10-IAIHU-06 , from the  Ile-de-France Region  ( DIM Cerveau et Pensée ), and from  IPRIAC  ( Institution de Prévoyance d'Inaptitude à la Conduite ).
In addition, serum 25(OH)D concentrations or HOMA-IR were included in the models, as covariates, according to the dependent variable. The effects of the covariates were assessed by the values of the regression coefficients corresponding to the non-standardized regression coefficients (nSRC). IBM SPSS Statistics, version 21 (SPSS, Chicago, IL) were used for data analyses. A P value < 0. 05 was considered significant.
Acknowledgements We would like to acknowledge all children and parents who participated in the study. Great thanks to the nurses and physicians of the  AGREXAM Health Centre , to the teachers of physical education, to  Mrs L Nesty , the headmaster of the middle school named " College Saint John Perse " located in Guadeloupe and to  Dr M Meissonnier , the head of the  Health Centre. This study was partly supported by grants from the  University Hospital of Guadeloupe.
The jury remains out on the most appropriate ICD, algorithm and programming for ICD patients, including the most appropriate boundaries of the VT zone. In the initially published OPTION trial (ClinicalTrials. gov-NCT00729703, date of registration: August 4, 2008)  7  therapy with DC settings for ICD discrimination combined with algorithms for minimising ventricular pacing was associated with reduced risk for inappropriate shock compared SC settings, with no differences in morbidity or mortality between the two therapies. During a follow-up period of 27 months, the DC setting arm in OPTION showed superior results both on the time to the first inappropriate shock (p = 0. 012, log-rank test for the differences between the groups) and on the percentage of patients who received inappropriate shocks (4.
Methods The design and main results of the OPTION trial have been published  7, 8. In brief, this prospective, randomised (1:1), multicentre, single-blinded (patients), parallel-group trial enrolled 462 patients eligible for ICD therapy for primary or secondary prevention of sudden cardiac death (left ventricular ejection fraction ≤ 40% despite optimal tolerated heart-failure therapy). After enrolment by physicians, random allocation sequence was requested by the investigator to the Sponsor. The 4-block permutation randomization list was generated by the study statistician using the proc plan procedure (SAS ® software v9. 2). Upon each request, the sponsor sent a closed envelope containing the assigned intervention for the patient considered. The envelope was opened by the investigator just before implant.
Rates of patients with appropriate and inappropriate shocks at two years of follow-up were obtained from the OPTION database. All reported shocks in the OPTION trial were validated by a blinded events committee of 5 experts who analysed the electrographic recordings in the device memories  7. Data on shocks were obtained from the device records. For the analysis, the rates of patients with total, inappropriate and appropriate shocks were calculated for shocks triggered at heart rates ≥ 170 bpm and at rates ≥ 200 bpm, respectively in the SC and DC groups. Statistical analyses. Data were analysed using the SAS ® statistical software package version 9. 2. Continuous data are presented as mean ± SD. Proportions are presented as counts and percentages. Proportions were compared with χ 2 test or with Fisher's exact test when unpaired.
Sorin, St. Jude Medical. Dr. D. Babuty has received travel support from Biotronik, Boston Scientific, Medtronic, Sorin and St. Jude Medical; he has performed clinical studies supported by Biotronik, Medtronic, Sorin and St. Jude Medical. Dr. P. Sick has received a research grant from Sorin. Dr. J. M. Davy has received travel support from Biotronik, Boston, Medtronic, Sorin and St. Jude Medical; he is a consultant to Boston Scientific, Medtronic and Sorin and has performed clinical studies supported by Biotronik, Boston, Medtronic, Sorin and St. Jude Medical. Dr. G. Molon has received travel support from Boston Scientific and Medtronic; he is a consultant to Boston Scientific and Medtronic and has performed clinical studies supported by Boston, Medtronic, Sorin and St. Jude Medical. Dr. J. Schwab has received speaker's honorarium and research support by Biotronik, Boston Scientific, Medtronic, Sorin and St.
Method Participants. Fifteen observers (eight female) participated in Experiment 1. 1  Participants were recruited from Utrecht University. All participants were between 18 and 23 years of age and reported normal or corrected-to-normal vision. All participants signed informed consent before participating and received monetary compensation. Apparatus and software. The left eye was recorded with an Eyelink 1,000 (SR Research, Mississauga, Ontario, Canada), a video-based eye tracker sampling at 1,000 Hz. Stimuli were presented on a 24-in. LG 24MB65PM monitor (1,920 ϫ 1,200 px, 60 Hz). Stimulus presentation was controlled with OpenSesame  (Mathôt, Schreij, & Theeuwes, 2012)  and PsychoPy  (Peirce, 2007). A chin rest was used to fixate the participant's head relative to the camera. Procedure and stimuli.
This research was funded by  VIDI  Grant  452-13-008  from the  Netherlands Organization for Scientific Research  to  Stefan Van der Stigchel , by  European Research Council  Consolidator Grant  615423  awarded to CNLO, and by the  People Programme  ( Marie Curie Actions ) of the European Union's  Seventh Framework Programme  (FP7/2007-2013) under  Research Executive Agency  Grant Agreement 622738 awarded to  Sebastiaan Mathôt.
Epidemiological assumptions and data Survival (S) was modeled based upon the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) study  4  and extrapolated to a 5-year time (t) horizon as a constant hazard. 5 No ethical permission was required for this study, as the COHERE study data was previously published and ethical permission was previously retained. Hazard rates were specific to age, sex, and early or late detection, defined as a CD4 cell count of. 350/µL or ,350/µL, respectively. The constant per annum risk of death is r, with the expected survival after 1 year in a population of HIV infected patients being: S (t + 1) = (1 -r)S(t) (1) When expressed more generally, for a population of N patients infected with HIV, survival over time was represented by the hazard function: S (t) = N(1 -r) t (2) Survival in years (S(t)) 1 to 5 is evaluated at the beginning of each year.
Older adults (. = 50 years) diagnosed late were 14 times more likely to die within a first year of diagnosis compared to older adults diagnosed early. 18 he assumptions that 14% of all newly-diagnosed HIV infections occur in individuals aged over 50 years and that 64% of these are males were combined with life expectancy data from a cohort of recently-diagnosed individuals in the Netherlands to generate the survival probabilities in Table  1. 5, 18, 19 IV transmission rates were modeled using scaling parameters and multipliers which reflect population average transmission data on a per infected person basis. Infections in a year are uniquely determined by the number of infected individuals in the year, plus the estimated new infections occurring in the population based upon the transmission coefficient determined by the scaling parameters employed.
Cost impact calculations In order to calculate the total medical care costs incurred for the cohort under the current and future scenarios, each year of survival of an individual was multiplied by the appropriate annual cost. The annual cost is the sum of all categories of HIV clinical care from a payer perspective and includes inpatient, outpatient, and day patient care, test procedures, costs of ART (based upon current BHIVA guidelines) and other drugs. 6 Costs for these resource categories were taken from data collected by the National Prospective Monitoring System from 1996-2006. 8, 9 The costs applied depend on whether each individual is treatment-naïve or treatmentexperienced and, within these categories, whether they are diagnosed early or late. The cost differentials depicted in Table  2  between treatment-naïve and treatment-experienced patients reflect the empirical findings that the direct costs of care in the year following a diagnosis of HIV are driven almost exclusively by the timing of the diagnosis (early versus late), rather than the patient characteristics (age, race, other demographic variables, and even severity of illness).
Results We modeled large-scale resting state brain dynamics using simple linear diffusion of noise over the anatomical structure. This is the well known Ornstein-Uhlenbeck model as described for example in  [35] , where Galán applied this model to investigate micro-scale networks. To test the results against empirical data, we used 20 minutes resting-state fMRI BOLD signal time series for 14 healthy subjects. For the same subjects we also had structural data from DTI and tractography. The parcellation used is a modified version of the Desikan-Killany atlas, as described in  [16] , which comprises 66 areas. The details of the data, model and the analytic treatment can be found in Materials and Methods. Predicting FC from SC Matrix operation. The analytic operation used to compute the covariance from SC is C ¼ À s 2 2 ðÀI þ cWÞ À1 : ð1Þ where W is equal to SC with the diagonal removed if present.
Data collection Structural data from DTI and resting-state BOLD signal time series were acquired for 14 healthy subjects (age between 25 and 33 years old, 6 females). Data can be found in S1 Folder. A detailed description of the generation of SC and FC matrices from those data can be found in  [46]. Empirical data were acquired at Berlin Center for Advanced Imaging, Charité University Medicine, Berlin, Germany. All participants of this study gave written informed consent before the study, which was performed in compliance with the relevant laws and institutional guidelines and approved by the ethics committee of the Charité University Berlin. For functional imaging (EEG-fMRI)  [54, 55] , subjects were asked to keep awake and keep their eyes closedno other controlled task had to be performed.
mgz). 3. WM and subcortical segmentation, cortical tessellation generating GM-WM and GM-pia interface surface-triangulations, probabilistic atlas based cortical parcellation, e. g. , using Desikan-Killany (DK) atlas  [56]. This generates aparc+aseg. mgz volumes that contain all parcellated regions (cortical and subcortical) with corresponding region labels used for fiber-tracking and BOLD time-series extraction. Diffusion-weighted MRI (dwMRI) data are parcellated according to the high-resolution atlases derived from T1-weighted data yielding estimated white matter fiber tracts and SC matrices. The parcellations are used for defining seed-and stop-locations during tractography. Tractography. Tractography requires binary WM masks to restrict tracking to WM voxels. WM masks ensure that none of the tracks extend into GM.
After this step, FSL's FEAT pipeline is used to perform the following operations: deleting the first five images of the series to exclude possible saturation effects in the images, high-pass temporal filtering (100 seconds high-pass filter), motion correction, brain extraction and a 6 DOF linear registration to the MNI space. Functional data is registered to the subject's T1-weighted images and parcellated according to FREESURFER's cortical segmentation. By inverting the mapping rule found by registration, anatomical segmentations are mapped onto the functional space. Finally, average BOLD signal time series for each region are generated by computing the mean over all voxel time-series of each region. From the region wise aggregated BOLD data, FC matrices are computed within MATLAB using pairwise mutual information (on z-transformed data), and Pearson's linear correlation coefficient as FC metrics.
Any pre-processing technique, which implies a normalization of data must be avoided when using our analytic operation, for this reason it is important to stress that we did not perform global signal regression on data. Global regression, in fact, changes the distribution of the eigenvalues of the FC and, in particular, shifts the correlations towards negative values. In resting-state BOLD data, this means that zero and negative correlations are introduced. While the debate on the meaning of these negative correlations and on the appropriateness of the use of global regression is open (see for example  [60] ), this procedure must absolutely be avoided when using the analytical operation here presented as the introduction of zero eigenvalues leads to the impossibility of inverting FC to obtain SC.
Since the first phase was used for identification, this correction was applied to the number of variants tested in the meta-analysis. When several SNPs located on the same gene were significantly associated with ACPA or erosion, haplotypes were built and analysed. Haplotypes were assigned to each individual using PLINK 1. 08 requiring a probability of >0. 8. Analyses of the haplotypes were performed with methods similar to those used to analyse the individual SNPs, by then testing for the presence or absence of a haplotype. The epistatic interactions between the SNPs of the different genes were tested using three methods: the RERI method, a logistic regression with an interaction parameter and PLINK epistasis software. 19 Interactions with the HLA-DRB1*Shared Epitope allele carriage were also tested using the same methods.
Furthermore, an SNP located on RANKL (rs7325635) had a trend for significant association with erosions with a p=0. 06 on the χ 2 test and a p value of 0. 05 on the Cochran-Armitage test. Thus, it was also added to the meta-analysis. Association between the SNPs located on RANK, RANKL and OPG and ACPA or erosions in the three cohorts: results of the meta-analysis The results of the first explanatory genotype analysis conducted us to analyse the effects of the SNPs located on RANK, RANKL and OPG on ACPA presence and erosions in a meta-analysis with an allele dominant effect model. The SNPs located on RANKL were in linkage disequilibrium (r 2 comprising 0. 83-0. 94) and thus haplotypes were built using PLINK software. The association of the protective haplotype GGG was assessed in comparison to non-RANKL-GGG haplotype carriers.
Tan et al 10 further showed that rs7984870 located on the promoter of RANKL modulated the expression of RANKL via activated T cells only in rheumatic factor positive patients with RA. In a recent study, Knevel et al 9 identified an SNP (rs1485305) on OPG associated with radiographic progression in a meta-analysis of 4 independent data sets including 1418 patients with RA. In our study, this SNP was not associated with erosions in the ESPOIR cohort and thus not included in the meta-analysis. rs8086340 located in the intronic region of RANK should have no functional effect on RANK, but could play a role in regulating gene transcription or could be in linkage disequilibrium with another SNP with potential functional effects. rs7325635 and rs7984870 are both located in the intronic region of RANKL while rs1054016 is located after the last exon in a non-coding region of RANKL.
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 Lioté ,  Paris-Lariboisière ;  X Le Loet  and  O Vittecoq ,  Rouen ;  X Mariette ,  Paris Bicêtre ;  O Meyer ,  Paris Bichat ;  A Saraux , Brest;  Th Schaeverbeke, Bordeaux ;  J Sibilia , Strasbourg).
Funding This work received a grant from the  French Society of Rheumatology. 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, Abbott  and Wyeth also supported the ESPOIR cohort study.
e. large nanoparticles while the second component is a priori assigned to slowly relaxing nanoparticles, i. e. with intermediate size. But at this stage, different scenarios can be considered and it remains difficult to model the hyperfine structure from experimental data coming from the measurements obtained at one temperature. Ferritin-M6A reveals hypoxic regions in C6 glioma tumours. The spatial distribution of high relaxivity HA-HFn-M6A cells was evaluated using mice in which C6 glioma cells overexpressing either HA-HFn or HA-HFn-M6A were inoculated subcutaneously above the gluteal muscle on both sides of the mouse. Three weeks after inoculation, when the tumours reached approximately 0. 8 cm in diameter, MRI measurements were acquired from a single axial slice through the centre of both tumours.
Purified ferritin-M6A was crystallised using the sitting-drop vapour-diffusion method at 293 K. 0. 5 mL ferritin-M6A (20 mg mL -1 ) and 0. 5 mL reservoir solution (0. 1 M Na-cacodylate pH 6. 5, 0. 2 M magnesium acetate and 30% MPD) were mixed to form the drop. Crystals were harvested and flash-cooled in liquid nitrogen without addition of cryoprotecting solution. Diffraction data were collected on beamline ID14-4 of the ESRF (Grenoble, France) equipped with an ADSC Q4 CCD detector. Data collection was performed at 100 K. A total of 530 frames were collected with an oscillation range of 0. 25° and an exposure time of 0. 1 s per image. The crystal-to-detector distance was 290. 96 mm. Data were reduced and scaled using the HKL2000 suite  28. Ferritin-M6A phases were obtained using Phaser molecular replacement  29  and PDB code: 1IES 30 as a template.
The final model was built by Coot  31  and refined in REFMAC  32. For Rfree calculation, 5% of the data were excluded. Structural figures were prepared with PyMOL  33. RMS calculations were performed with SwissPDB viewer 34 over all Cα atoms using the domain alternate fit to align structures on the basis of the conserved domain. Small angle X-ray scattering (SAXS) measurements and model fitting. Prior to performing the SAXS experiments all protein samples were subjected to SEC purification to eliminate products of complex formation or aggregation. Ferritin and ferritin-M6A samples were diluted each with 20 mM Tris pH 8, 200 mM NaCl, 5 mM β -mercaptoethanol and 10% glycerol. SAXS measurements were performed at the French national synchrotron facility, SOLEIL, on the SWING beamline. The incident beam energy was 12 keV.
The sample-to-detector (Aviex CCD) distance was set to 1892 mm, covering a q-range of 0. 004-0. 7 Ǻ -1. All experiments were temperature controlled at 25 °C. Typically, 55 successive frames of 0. 5 s each were recorded for both protein solution and its corresponding buffer. Each frame was first angularly averaged and the final spectrum and experimental error were obtained by averaging over all frames and subtracting the pure solvent spectrum from the sample spectrum. Intensities were scaled using the scattering of water  35. Data analysis was based on fitting the scattering curve to an appropriate model by a least-squares method using software provided by NIST  36  (NIST SANS Analysis version 7. 0 on IGOR). The scattering intensity of a monodispersed system of particles of identical shape can be described by the following equation 34 : = I q NP q S q ( ) ( ) ( ) ( 1 ) where N is the number of particles per unit volume, P(q) is the form factor revealing the specific size and shape of the scatterers and S(q) is the structure factor that accounts for the interparticle interactions.