dataesr/scientific-paragraphs-categorization huggingface dataset:
Tissue and lesions Retrieval of BM tissues and non-tumoral brain tissues (NT) was facilitated by the APIX database of the Department of Pathology, University Hospital of Nice. All specimens were excisions with histology performed. A total of 49 consecutively operated BM without preoperative radiotherapy were selected during the period between June 2011 and September 2012 together with 18 consecutive cases of post-radiotherapy recurrent BM during the period between November 2007 and September 2012. Among the 53 cases of NT, 37 cases corresponded to peri-metastatic gliosis and 16 cases corresponded to peri-abscess (14 cases) or peri-hematoma (1 case) gliosis and radionecrosis (1 case). BM and lesions are detailed in Table  1. All of the samples are the property of the tissue collection of the Pathology department, which is declared annually to the French Health Ministry.
Discussion The differential diagnosis between recurrent BM and radionecrosis remains a clinical challenge in the follow-up of patients with BM because tumor recurrence and post-irradiation changes may be similar on MRI. Positron emission tomography using radiolabeled amino acid (PET-AA) appears to be promising in the management of BM, because AA-uptake appears to be specific for tumor cells. The amino acid transporter LAT1 and its cofactor CD98 which are involved in AA uptake in brain lesions  [18] [19] [20]  are overexpressed in numerous tumors but there is no data concerning their expression in BM. Our study showed that LAT1 expression is almost always seen in BM and that CD98 is expressed by almost two thirds of BM, regardless of the histological type and the origin of the tumor. We selected a cohort of 67 BM of various histological subtypes and from different primary sites, in order to define the status of LAT1 and CD98 expression in metastatic tissues reflecting the epidemiology of BM.
Target verification and distribution To demonstrate the reproducibility in measuring CDH5 and FABP1, the average Pearson correlation taken over the different cohorts was determined as 0. 85 and 0. 95 respectively. For correlation plots between repeated experiments, see Figure  S3. Antibody targeting with HPA030562 and HPA028275 for CDH5 and FABP1, respectively, was confirmed with Western blot of serum samples from the SAFE-T DILI cohort, a recombinant CDH5 standard and FABP1 overexpression lysate. Bands at the predicted molecular mass were detected (Fig. S4 ). Further evidence of ontarget detection was given by the comparison to beadbased sandwich immunoassays (Fig. S5 ). The presence, distribution and abundance of CDH5 and FABP1 in relation to protein and RNA expression were investigated in healthy human tissue.
This study has its main limitation in the difficulty to access DILI samples. DILI is a rare clinical event. A number of international collaborations, such as the Spanish DILI Registry or the Drug-induced Liver Injury Network, have been created to establish large patient databases as well as a standardized case definition of DILI. Still, the access to well-characterized clinical samples from DILI cases is the main limiting factor for the discovery and qualification of new DILI biomarkers. Furthermore, the SAFE-T DILI cohort was based on a large heterogeneity of causative drugs collected during the DILI episode without available baseline samples. Relatively small liver enzyme elevations were observed in the HV APAP cohort. Here, subjects received the therapeutic dose of 4 g APAP per day and responders showed transient elevations lower than in cases of APAP overdose.
Acknowledgements Members of the  SAFE-T DILI work  package are acknowledged as follows:  M Merz ,  G A Kullak-Ublick ,  S Ormarsdottir ,  Joachim Tillner  and  Frances Hackman. Financial support: This work has received support from the  EU/EFPIA Innovative Medicines Initiative Joint Undertaking  ( SAFE-T, grant  no  115003 ),  ProNova VINN Excellence Centre for Protein Technology  and the  KTH Center for Applied Proteomics  funded by the  Erling-Persson Family Foundation.
Patients and HCPs were recruited through various channels. The recorded discussions and interviews were transcribed verbatim. The dataset was analysed using thematic analysis and arranged according to the Unified Theory of Acceptance and Use of Technology. Results Seven focus group discussions and 13 interviews were conducted. In total, 21 HCPs and 50 patients participated. Identified factors that may influence the use of the app were the type of feedback given on reported ADRs, how ADR reports are stored and the type of drug news. Also mentioned were other functions of the app, ease of use, type of language, the source of safety information provided through the app, security of the app, layout, the operating systems on which the app can be used and the costs. Conclusions Further research is needed to assess associations between user characteristics and the direction (positive or negative) of the factors potentially influencing app use.
A semi-structured guide was used during the second and third step (Online Resource 2, see electronic supplementary material). On average, the duration of the focus group discussions and face-to-face interviews was approximately 90 min. Focus group discussions and faceto-face interviews were conducted until theoretical saturation was reached. Theoretical saturation means that no new topics appear and all aspects of a theory are covered  [27]. All data collected from the discussions and interviews across all countries were used in this assessment.
Molecular dynamics calculations The simulation setup included 100 molecules of β-CD and 900 guest molecules. At the beginning of the molecular dynamics calculations all β-CD cavities were empty. The initial geometries of all molecules were taken from quantumchemical calculations (B3LYP/6-31G*). The molecules were distributed on a rectangular three-dimensional lattice. Each molecule was randomly rotated in space. Calculations were performed with the NAMD2 package  [41]  and CHARMM force fields  [42] [43] [44]. The CHARMM general force field and the CHARMM all-atom force field for carbohydrates were used to model guest molecules and β-CD respectively. The applicability of this combination of force fields for modeling inclusion complexes of β-CD was shown in our previous study  [36] , by comparison with Born-Oppenheimer ab initio molecular dynamics.
Acknowledgments This research was supported in part by  PL-Grid infrastructure. Calculations were performed on a computer cluster purchased with financial support from the  European Regional Development Fund  in the framework of the  Polish Innovation Economy Operational Program  (contract no. POIG. 02. 01. 00-12-023/08 ) and on  PL-Grid infrastructure at ACK CYFRONET  with the support of the  HPC Infrastructure for Grand Challenges of Science and Engineering project. AIMAll sofwere  ( Version 13. 11. 04 ,http://aim. tkgristmill. com)was used to perform QTAIM analysis. Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4. 0 International License (http:// creativecommons. org/licenses/by/4. 0/),which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Purity of the peptide was evaluated by integrating the UV chromatogram acquired in LC-E-SI-MS experiments (97%). Furthermore, elemental analysis (Vario Micro Cube, Elementar) was used to determine the net peptide content (NPC), through the measurement of nitrogen mass ratio in the sample (78%). This information, which represents the organic fraction of the sample, allowed to estimate the relative amount of material contaminating the peptides (counter-ions, salts, residual solvents, water,. ). The final purity was calculated by multiplying the UV signal integration with the NPC figure i. e. 76%. Data are given in S2 Protocol.
Acknowledgments We acknowledge  Bernard Mouillac  ( IGF, Montpellier ) for providing transfected CHO V1A cells lines,  Maxime Rossato  for providing the AVP sample,  Didier Gagne  and  Jacky Marie  for supplying specific binding data through conventional radioactive experiments,  Jean-Alain Fehrentz  for HF manipulation (IBMM, Montpellier, France) and Paul Alewood together with  Zoltan Dekan  ( IMB, Brisbane, Australia ) for training E. Cordeau to selenium-containing peptide synthesis.
Agence Nationale de la Recherche  ( ANR , project  ANR-13-BSV5-0003-01 ) (http://www. agencenationale-recherche. fr), Conseil Régional d'Aquitaine  ( 20071303002PFM ) (http://www. aquitaine. fr), and  FEDER  ( 31486/08011464 ) (http://www. europe-enfrance. gouv. fr /Configuration-Generale-Pagessecondaires/FEDER) are also acknowledged for their financial supports. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Methods This was a prospective, multicentre, double-blind, placebo-controlled phase IIa study (EudraCT number 2010-020657-14; Clinical trial. gov: NCT01318525). The protocol was approved by the official agencies (S2 and S3 Text), by the "Comité de Protection des Personnes (CPP)" of the Bicêtre hospital (France) on July 2010 (S4 Text) and by the Essen Ethic Committee (Germany) in April 2011(S5 Text). Patients were recruited in 12 Liver units with transplant facilities located in France and in Germany. Written informed consent was obtained from all participants or their next of kin when they were unable to sign. In addition to ALF-5755 or placebo, patients received the best standard treatment on assessment of investigators. The study was opened on October 2010 in France and July 2011 in Germany and closed on April 2013.
e 72h (mathematical formula: (PRH0-PRH72)/72). PR was measured every twelve hours. The secondary end-points were the transplant-free survival rate, defined as being alive and not transplanted, at Day 21, a variable proposed early by Lee et al  [8] , the length of hospitalization, the safety and the rate of change in MELD  [20]  during 72 hours following treatment initiation. MELD is a scoring system for assessing the severity of chronic liver disease based on the patient's values for serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time (INR). It usually ranges from less than 10 to more than 40; higher is the value, poorer is the survival prognosis. After the unblinding of the study data the time to reach a prothrombin value equal to 50%, a cut-off above which liver transplant is no more considered, was added as a secondary efficacy analyze.
The laser pulse width was 3 ns with a maximum power of 20 Hz. Spectra were recorded in reflector mode with an acceleration voltage of 19 kV and delay of 400 ns. 100 single shot acquisitions were summed to give the spectra and the data were analyzed using Data Explorer software. Samples were prepared by dissolving the matrix 2-(4hydroxyphenylazo)benzoic acid (HABA) in the solvent (acetone, 20 mg mL -1 ), mixing with the polymer (1 mg mL -1 ) and sodium iodide in acetone (15 mg mL -1 ) that was used as a cationising agent.
Samples were placed in a 1 mL syringe, loaded into the system and the NTA syringe pump set to a flow rate of 30 AU. Videos were recorded for 60 seconds. 5 videos were collected per individual sample, and triplicate samples were recorded. Analysis used NTA v3. 0 software. All NTA sizing experiments were performed at room temperature (25 °C) under the constant flow from the syringe pump, to obtain data representative of the dispersions. Experiments to assess surface functionality and polymer loading were carried out with lyophilised nanoparticles. FTIR spectra were recorded using a Spectrum 100 FTIR spectrophotometer (Perkin Elmer, UK). Spectra are the average of 32 scans, between 4000 and 550 cm -1 , at a resolution of 4 cm -1. FT-Raman spectra were recorded on a Nicolet NXR 9650 Raman spectrophotometer (Thermo Scientific, UK) as an average of 1000 scans, between 4000 and 10 cm -1 , at a resolution of 4 cm -1.
All sections were cut using a Bright 5040 cryostat in a Bright Model PTF freezing chamber at -20 °C (Bright Instrument Co. Ltd, UK). Sections were placed under a Leica MZ10F stereomicroscope (Leica Microsystems, UK). All images were taken through an ET-GFP filter (Leica Microsystems, UK) using an exposure time of 0. 8 ms. 10 images were taken for each particle type, at each time point from a separate section of tissue. ImageJ software (National Institute of Health, USA, v1. 43) was used to quantify penetration of the nanoparticles. For each image, the background was subtracted, a line drawn across the mucus barrier, and the "plot profile" measured. A diagrammatical representation of this process can be found in ESI (Fig. S2 † ). This was repeated 5 times at random locations along the mucosal barrier for each image, providing a total of 50 (10 × 5) profiles for each sample.
Penetration into gastric mucosa and tissue histology In order to assess penetration of the functionalised nanoparticles into gastric mucosa, fluorescence microscopy was employed. The summarised data in Fig. 7  illustrates that PMOZ-silica particles are significantly more diffusive than both PEOZ, and PNPOZ functionalised silica ( p > 0. 05) at all time points, a relationship that was found to be linear with time (with R 2 values of 0. 95, 0. 98, and 0. 92, respectively, Fig. S5 † ). The variance in rate of penetration accords with the diffusion coefficients for the particles in the mucin dispersion (Fig. 6 ). As the alkyl chain length increases (from methyl to propyl) there is a significant (P < 0. 05) change in both penetration and diffusion coefficient of PMOZ and PEOZ-silica nanoparticles, again a trend which was found to be linear (R 2 = 0.
Sample Analysis and Data Management Baseline sample and six pooled post-dose samples (0-4 h, 4-8 h, 8-12 h, 12-16 h, 16-20 h, 20-24 h) were analyzed to assess intradermal kinetics. CP-17 was measured after liquid-liquid extraction by LC-MS/MS in selected multiple-reaction monitoring (MRM) positive ion mode. Internal standard (CP-17-d3), 15 mM NH 4 OH (50 μL), and diethylether/hexane 80/20 (400 μL) were added to 50 μL of standards or samples. The samples were vortexed and centrifuged. Then, the organic layer was removed and evaporated to dryness under vacuum. The residue was redissolved in 30% acetonitrile (20 μL) and subsequently analyzed. The measurement was performed on a U300 Ultimate HPLC system (Dionex) coupled to a TSQ Ultra AM triple quadrupole mass spectrometer (Thermo). The separation was carried out on a Zorbax SB-C18 (0.
CONCLUSION In conclusion, the dermal pharmacokinetics of highly lipophilic CP-17 released from a commercial low-strength cream in patients in vivo was successfully assessed by dOFM and time as well as depth (i. e. , spatially) resolved kinetic data were delivered. These data showed that CP-17 does not significantly accumulate in the dermis following repeated topical dosing and revealed a reduced penetration rate of the high-potent glucocorticoid into hyperkeratosed psoriatic skin. Therefore, our data support the assumption that the thickened SC of psoriatic skin acts as trap compartment for lipophilic topical drugs. In terms of methodological advancements our study shows the utility of dOFM to support the clinical development of new drugs by facilitating studies with short treatment duration and low drug amount at early stages with limited preclinical prerequisites.
ACKNOWLEDGMENTS AND DISCLOSURES Open access funding has been provided by the  Medical University of Graz, Austria. The clinical study was sponsored by  Galderma R&D  ( Sophia Antipolis, France ). The authors thank  Stefan Korsatko ,  Sigrid Deller  and  Wolfgang Weger  at the  Medical University Graz  for their medical support,  Phillipe Martel ,  Maurice Guyomar ,  Celine Masson  and  Charbel Azar  for their scientific inputs,  Sophie Narath  for statistical support,  Christian Höfferer  for help with study procedures as well as  Agnes Prasch  and  Maria Ratzer  at  Joanneum Research  for bioanalysis and sample management.
Materials As already described in a previous publication  [18] , a part of the experiments (n¼24 biopsies) were carried out at SOLEIL-Synchrotron (Saint-Aubin, Gif-sur-Yvette, France) on the SMIS beamline. The synchrotron radiation-mFTIR mappings were collected in reflection mode using an Infrared microscope (Thermo/Nicolet Nic-Plan) coupled to a mFTIR spectrometer (Thermo Nicolet MAGNA-IR 550). The IR microscope is equipped with a motorized sample stage (precision 1 mm) and a liquid nitrogen cooled mercury cadmium telluride (MCT e 250 mm) detector. Most of the analysis and maps presented here were achieved with a projected area on the sample of 6 Â 6 mm 2 and a step size of 6 mm, and each spectrum was acquired after 64 accumulations at 8 cm À1 spectral resolution. Data acquisition and processing were performed using OMNIC software (Version 7.
4, Thermo-Scientific). The compounds were identified by comparing them to reference spectra  [19]. IR microspectroscopy was performed on an IN10MX microscope (Thermo Scientific) for recording large maps. All spectra were collected in ultrafast mode using a 50 mmÂ50 mm aperture. The spectra were collected in the 4000e700 cm À1 mid-IR range at a resolution of 8 cm À1 with one spectrum per pixel. Data analysis of IR spectra and chemical images was performed using OMNIC software (Thermo Scientific). Other biopsies were analyzed, in our hospital department in the Service des Explorations Fonctionnelles Multidisciplinaires (Tenon hospital e Paris), with the Spotlight 400 FTIR imaging System in the mid-infrared spectral range to obtain infrared maps of tissue slides at high spatial resolution, down to 10 microns.
Acknowledgements This work was supported by the  Physics and Chemistry Institutes of CNRS  and by contracts  ANR-09-BLAN-0120-02 ,  ANR-12-BS08-0022 ,  ANR-13-JSV-10010-01 , convergence Fig. 6. Kidney biopsy containing atazanavir crystals. A: Optical image; B: IR map; C: IR spectrum of atazanavir with the characteristic peaks (3428, 1722, 1529, 1053 cm À1 ) in a protein matrix (kidney tissue); D: Electronic images of atazanavir crystals obtained by  SEM. Please cite this article in press as:  V. Frochot , et al. , Nephrotoxicity induced by drugs: The case of foscarnet and atazanavirdA SEM and mFTIR investigation, Comptes Rendus Chimie (2016), http://dx. doi. org/10. 1016/j. crci. 2016. 08. 007UPMC CVG1205  and  CORDDIM-2013-COD130042. The authors are grateful to the  Soleil SR Facility  for beam time allocation (proposal numbers, SMIS-20130016, SMIS-20120070, SMIS-20110084, SMIS-20100566, and  SMIS-20100039 ), which allowed them to start this research.
Clinical Trials Registration. NCT01378286. Keywords. Plasmodium vivax; malaria; chloroquine; randomized clinical trial; artesunate-amodiaquine. There were an estimated 214 million malaria episodes and 438 000 related deaths in 2015 [1]. Plasmodium vivax is the malaria-causing parasite species with the widest geographical distribution, resulting in 2. 85 billion people at risk [2]. Studies from all P. vivax endemic areas demonstrate that this infection can progress to have severe and fatal outcomes [3, 4], rendering the long-held belief that P. vivax is benign as no longer valid [5]. Resistance to antimalarials is a major barrier for case-management and control of transmission [6, 7] and requires constant monitoring. For more than 60 years, the mainstay of P. vivax treatment has been a combination of chloroquine (CQ) with primaquine (PQ) as an antirelapse drug  [8, 9].
A limitation of our study was the small number of children included. This population is at higher risk of treatment failure  [53, 54] , for which age-stratified sampling would be important. There was a higher loss to follow-up in the ASAQ arm, which had an impact on the efficacy assessment in the ITT population. An examination of the notification database did not reveal a higher rate of failure among losses. As we were not able to assess the pharmacokinetic profile of amodiaquine, evaluation of the effect of a longer elimination half-life in this population on efficacy against late recurrences was not possible. By not coadministering PQ, we were able to estimate CQR, which at 11. 5%, considering concurrent blood drug levels criterion, is very high. This is important, as patients receiving CQ are at higher risk of recurring episodes from resistant parasites that arise from either recrudescence or relapse.
Acknowledgements. We acknowledge  Director-President of FMT-HVD Professor Maria Alecrim  for the institutional support, all the personnel from the  Malaria Laboratory  for their contribution in running the trial, and the study monitor from  Sanofi. We thank the patients and their families for taking part in the study. C. T. D. R. and M. V. G. L. are recipients of a grant from the  Conselho Nacional de Desenvolvimento Científico e Tecnológico as Bolsistas de Produtividade  and A. M. S. receives a short-term training grant from  WHO's Special Programme for Research and Training in Tropical Diseases.
During the open-label phase (the last 6 months), all patients received CsA CE. Treatment efficacy and safety were assessed at the end of the 6-month randomized period; safety was also assessed at 12 months following the 6-month open-label period. Intermediate visits also occurred at months 1, 3, and 9. All enrolled patients provided written informed consent, and the study was conducted in accordance with the principles of Good Clinical Practice and with the ethical principles set out in the Declaration of Helsinki. This study was registered under the following number in the EudraCT database: 2011-000160-97 with the protocol code number NVG10E117  (20).
Statistical analysis The primary efficacy endpoint of this study was the combined CFS-OSDI responder rate at month 6. A CFS-OSDI responder was defined as a subject displaying an improvement of ≥2 grades in CFS from baseline and an improvement of ≥30% in OSDI from baseline. This endpoint was analyzed on the full analysis set (FAS) using imputed data with a logistic regression model (factors "treatment" and "pooled country"). The FAS comprised all patients randomized into the study who received any amount of the study drug and were analyzed according to randomized treatment (intentionto-treat principle). Missing data were imputed as follows. Patients who discontinued treatment before month 6 were considered nonresponders if discontinuation was due to lack of efficacy, lack of tolerance, or change in dry eye therapy.
Patients who discontinued before month 1, or who did not discontinue before month 6 but for whom month 1, month 3, and month 6 evaluations were missing, were also considered as nonresponders. If the patient discontinued before month 6 due to a reason other than those specified above, a last observation carried forward (LOCF) procedure was used (carrying forward the month 3 or month 1 evaluation). The LOCF was also used if a patient did not discontinue before month 6 but for whom the evaluation was missing. Sensitivity analyses were also performed for the primary efficacy endpoint using the primary logistic model on the perprotocol set (PPS), on the FAS using observed data only, and on the FAS considering the actual treatment received and using a Cochran-Mantel-Haenszel (CMH) test controlling for pooled country.