dataesr/scientific-paragraphs-categorization huggingface dataset:
The most frequently identified primary sites (~55%) are biliary, urothelial, colorectal and pulmonary. The primary origin is identified with a probability superior to 80% in 48% of cases. When the test predicts a more treatment-sensitive type of cancer, the median survival is improved significantly compared to other tumour types (13. 4 versus 7. 6 months, respectively; p = 0. 04)  [11]. However, this prospective trial did not answer the question as to whether a treatment adapted to the primary tumour identified by molecular analysis influences the outcome of patients. The currently ongoing European randomized, phase III, multi-centric trial GEFCAPI04 aims to answer this question (Clinicaltrials. gov/NCT01540058) [72, 73]. This study compared a diagnostic and therapeutic strategy based on molecular analysis followed by tailored specific therapy for a suspected primary cancer, to an empiric strategy in patients with CUPs.
Acknowledgments: The authors thank the  Cancéropole PACA , the  "Fondation ARC pour la Recherche sur le Cancer " ( ARC SL220110603478 ), the  CANC ' AIR Genexposomic  project, the  "Conseil Départemental des Alpes-Maritimes", the "Région Provence Alpes-Côte d'Azur"  for their financial support. The authors would like to thank  Peggy Dartigues ,  Zahira Merabet  and  Jean-Yves Scoazec  ( Institut Gustave Roussy, Villejuif, France ),  Isabelle Birtwisle-Peyrottes  ( Centre Antoine Lacassagne, Nice, France), Françoise Tanguy (Medipath, Mougins, France ),  Maxime Benchetrit  ( DIAG, Nice, France ) for their advice and support for this work.
Moreover, the gap width was evaluated using Image J software (National Institutes of Health, Bethesda, MD). EndoActivator ® did not result in a significantly higher circumferential percentage of sealer penetration than conventional irrigation (p > 0. 05). However, the gap width was significantly lower with EndoActivator ® , compared to conventional needles at both 1 mm (p = 0. 035) and 5 mm (p = 0. 038). The EndoActivator ® irrigation system did not significantly improve the NTS penetration, as compared to the conventional endodontic needle irrigation. Activation of the irrigation reduced the gap width significantly.
Confocal Laser Scanning Microscopic Analysis of the Roots Root canal segments were examined with a Zeiss confocal laser scanning microscope (Carl Zeiss, LSM 780, Jena, Germany) at five magnifications and set in fluorescent mode (at a wavelength of 514 nm), as shown in Figure  1. Digital images were imported into Image J software (National Institutes of Health, Bethesda, MD, USA). To determine the circumferential percentage of sealer penetration, we first outlined and measured the circumference of the root canal wall with the software measuring tool (Figure  2 ). Next, we outlined and measured the canal walls into which the sealer penetrated the dentinal tubules with any distance. Finally, to calculate the circumferential percentage of sealer penetration, we divided the outlined distances by the canal circumference  [25].
Statistical Analysis The statistical software SPSS for Windows (Version 22. 0, Chicago, IL, USA) was used for statistical analysis of the data. The level of significance was set at 0. 05. The normality distribution of continuous variables was assessed with Kolmogorov-Smirnov tests. The percentage of penetration, maximum and average depth penetration of the sealer into the dentinal tubules, and the gap width were compared between the two groups (CN and EA) at 1 and 5 mm from the apex. A two-way analysis of variance was conducted, followed by a univariate analysis and multiple comparisons tests of Tukey (HSD). The Mann-Whitney tests were conducted to compare the gap width between different groups.
RNA-seq and data analysis For each NPC sample, 200 ng of input RNA was prepared using the Ribo-Zero Gold rRNA Removal Kit (Illumina, San Diego, CA, USA), followed by library preparation using the TruSeq Stranded Total RNA Sample Prep Kit (Illumina). Libraries were sequenced to >100 million paired-end 100 bp reads on the Illumina HiSeq 2000. The reads were then aligned using STAR  65  (v2. 4. 2a), and the expression values were summarized using RSEM  66 (v1. 2. 21).
Micro-computed tomography Micro-computed tomography (microCT) was used to determine the three-dimensional microstructure of the scaffolds. The samples were scanned with SkyScan 1172 mi-croCT imaging system (Bruker microCT, Kontich, Belgium) at 6 µm voxel resolution using source voltage of 40 kV and current of 167 µA without source filter. The samples were rotated 180 ∘ around their vertical axis and three absorption images were recorded every 0. 4 ∘ rotation. The absorption images were then reconstructed with the standard SkyScan reconstruction software (NRecon) to serial coronal-oriented tomograms using 3D cone beam reconstruction algorithm. For the reconstruction, beam hardening was set to 5% and ring artefact reduction to 10. The image analysis of the reconstructed axial bitmap images was performed using the standard SkyScan software (CTan and CTvox) and included thresholding and despeckling (removing objects smaller than 1000 voxels and not connected to the 3D body).
Samples were also analysed with PIXE (Particle-Induced X-ray Emission) nuclear microprobe, a technique that is very similar to SEM-EDS or an electron microprobe, but shows increased sensitivity by 100 times. Reacted scaffolds were embedded in Agar resin and cut into slices of about 150 µm thickness with a low speed diamond saw. Quantitative chemical imaging of the obtained crosssections was carried out at the AIFIRA platform (CENBG, France) using a 3 MeV incident proton beam (beam diameter of 1 µm). An 80 mm 2 Si (Li) detector equipped with a 12 µm-thick beryllium window and an aluminium funny filter (a 100 µm thick filter with a 2 mm hole drilled at its centre, placed in front of the detector window) orientated at 135 ∘ with respect to the incident beam axis was used for X-ray detection. Concentrations in Ca, P and Si were determined using the Gupixwin software after calibration against the NIST 620 (soda-lime glass) standard reference material.
Mechanical testing Mechanical properties of BG-PCL hybrid scaffolds were assessed using a TA Instruments 2980 Dynamic Mechanical Analyser. Cylindrical scaffolds with a 5 mm height and a 10 mm diameter were compressed at a constant force rate of 1 N•min -1 and their deformation was measured over time. The Young's modulus was determined from the slope of the linear elastic regime using the TA Universal Analysis software. The yield strength was determined at the transition from the elastic regime to the stress plateau.
1 mm under copious saline irrigation. The bone cavity was washed with saline solution and filled with the material, then the wound was closed with resorbable inner sutures and cutaneous surgical fastener. The sacrifice was carried out after 9 or 15 weeks by CO 2 asphyxiation. The specimens were immediately fixed in 4% formalin at 4 ∘ C for 9 days and then kept in phosphate-buffered saline. Because BG-PCL hybrid is sensitive to temperature, the explants were embedded in the cold-curing resin Technovit 9100 (Kulzer). The obtained blocks were cut into slices of 7 µm using a RM2255 microtome (Leica) and stained following the Goldner's trichrome method or with von Kossa/MacNeal. Histological sections were eventually observed with a light microscope (Nikon) and analysed using the NIS Elements D software.
Here the release of Ca ions is followed by a rapid decrease of Ca and P concentrations in the medium (Figure  3a ), which is in accordance with the precipitation of calcium phosphates on the samples (Figure  3b ). Moreover, quantitative analysis on the scaffolds immersed for 7 days in SBF shows a Ca/P atomic ratio of 1. 6 in the most reacted areas (data not shown) corresponding to that of biological apatites found in bone  [39]. SEM on this sample further confirms these observations, as Figure  3c  and Figure  3d  reveal the formation of an apatite-like layer on its surface. The cross-sections of scaffolds were also observed by quantitative chemical mapping using the PIXE nuclear microprobe. After 3 days of soaking in SBF (Figure  3e g), phosphorus is found on the surface as well as in the walls of the hybrid scaffolds.
The project was supported by the "Fonds Européens de Développement Régional" (FEDER). The Conseil Régional d'Auvergne is acknowledged for funding. The SATT Grand-Centre is acknowledged for financial support. Dr Mhammed Benbakkar and the Laboratoire Magma et Volcans (UMR 6524, CNRS/Université Blaise Pascal) are acknowledged for ICP-AES measurements. The Centre d'Études Nucléaires de Bordeaux-Gradignan and the AIFIRA staff are acknowledged for Brought to you by | University of Oslo Norway Authenticated Download Date | 12/15/18 6:14 PM allowing the PIXE experiments. Dr Brigitte Gaillard-Martinie, the Plateau Technique de Microscopie du Centre INRA ARA (UMR 454, MEDIS) and the Centre Imagerie Cellulaire Santé (Faculté de Médecine de Clermont-Ferrand) are acknowledged for SEM imaging on biomaterials with cells.
Acknowledgement: The project was supported by the "Fonds Européens de Développement Régional" (FEDER). The Conseil Régional d'Auvergne is acknowledged for funding. The SATT Grand-Centre is acknowledged for financial support. Dr Mhammed Benbakkar and the Laboratoire Magma et Volcans (UMR 6524, CNRS/Université Blaise Pascal) are acknowledged for ICP-AES measurements. The Centre d'Études Nucléaires de Bordeaux-Gradignan and the AIFIRA staff are acknowledged for Brought to you by | University of Oslo Norway Authenticated Download Date | 12/15/18 6:14 PM allowing the PIXE experiments. Dr Brigitte Gaillard-Martinie, the Plateau Technique de Microscopie du Centre INRA ARA (UMR 454, MEDIS) and the Centre Imagerie Cellulaire Santé (Faculté de Médecine de Clermont-Ferrand) are acknowledged for SEM imaging on biomaterials with cells.
Reactive Oxygen Species (ROS) Production Analysis Quantitative measurements of ROS, namely superoxide radicals in THP-1 cells undergoing oxidative stress, were performed using the Muse Oxidative Stress kit (Millipore, Bedford, MA, USA) in accordance with the manufacturer protocol. Briefly, after 24 h of contact with CaP-CHI-HA and controls, adhered and non-adhered THP-1 were re-suspended at a concentration of 1 × 106 cells/mL in 1× assay buffer and incubated in oxidative stress working solution for 30 min at 37 • C. ROS positive cells, determined as median fluorescence intensities (MFI), were assessed by flow cytometry using BD LSRFortessa flow (BD Biosciences, San Jose, CA, USA) cell analyzer and BD FACSDiva (BD Biosciences, San Jose, CA, USA) and FlowLogic (Inivai Technologies, Melbourne, Australia) software.
CD44 Quantification Adhered and non-adhered THP-1 on CaP-CHI-HA and on controls were re-suspended at a concentration of 1 × 10 6 cells/mL, labelled and analyzed by flow cytometry (BD LSRFortessa, BD Biosciences, San Jose, CA, USA) through the expression of cluster of differentiation CD44 using FITC-conjugated mouse anti-human CD44-(C26), for 1 h at room temperature, and appropriate isotype controls. Stained cells were immediately analyzed (10,000 events) and performed with the BD FACSDiva (BD Biosciences, San Jose, CA, USA) and FlowLogic (Inivai Technologies, Melbourne, Australia) software.
Statistical Analysis All results were obtained with six independent spray experiments. Results were represented on histograms as mean ± standard error of the mean using GraphPad ® Prism 5 software. ELISA results, performed on 10 conditioned media samples, are presented as median. All statistical analysis were performed using GraphPad ® Prism 5 software. For Mann Whitney test, a value of p < 0. 05 was accepted as statistically significant p (rejection level of the null-hypothesis of equal medians).
L. rhamnosus GG (LGG) (ATCC® 53103 ™ ) was included as a positive control (Laparra and Sanz 2009) and was grown as previously described by  Kebouchi et al. (2016). Bacterial cultures were grown for 13 h (stationary phase) before storage and use for auto-aggregation assay or adhesion experiments. Escherichia coli strains (Table  1 ) used for plasmid propagation were routinely grown in Luria-Bertani (LB) medium  (Sambrook and Russell 2006)  at 37 °C with shaking, supplemented with erythromycin (100 μg mL -1 ) or spectinomycin (50 μg mL -1 ). The F6-1 strain characterized further in this study has been deposited at the CIRM (Centre International de Ressources Microbiennes, Nouzilly, France) under the accession number CIRMBP-1193.
DNA sequencing and sequence analysis Genomes of 12 S. salivarius strains used in this work were sequenced using an Illumina HiSeq2000 sequencer by Beckman Coulter Genomics (2 × 100 bp after paired-end library construction, at least 60× coverage). De novo assemblies w ere performed using C LC Genomics Workbench (CLC Bio) using default parameters. Scaffold of the genomes was built by using the Genome Finishing m o dule of C LC G en om i c s Wo r kb en ch w i t h t h e S. salivarius JIM8777 genome as reference. Some assembly gaps were filled by doing PCR and sequencing. Multifasta files (one per genome) representing all translated CDSs of the studied genomes were generated. Among proteins, the ones being putatively secreted proteins were identified by their peptide signal sequence using the software Signal P 4.
Nucleotide sequence accession numbers The sequences of the complete putative surface proteins have been deposited in the GenBank database under accession numbers MF497539 to MF497549 for F6-1 SALIVA_1475 homologs, MF497550 to MF497560 for F6-1 SALIVA_1473 homologs, MF497561 to MF497571 for F6-1 SALIVA_1472 homologs, and MF497572 to MF497580 for F6-1 SALIVA_1457 homologs. The F6-1 genome has been deposited at DDBJ/ENA/GenBank under the accession NPDJ00000000.
Identification of F6-1 LPxTG adhesins In order to test the involvement of all the putative surface proteins containing an LPxTG motif in the adhesion to HT29MTX cells, the gene encoding the sortase A was replaced by an erythromycin resistance gene to generate the F6-1 ΔsrtA mutant. Its adhesion capacity to HT29-MTX cells (13. 4 ± 0. 9 CFU per HT29-MTX cell) is 7. 5 times lower than that of F6-1 wild type (Fig. 3 ). This result suggests that at least some if not all the F6-1 surface proteins with an LPxTG motif are involved in the adhesion of F6-1 to HT29-MTX cells. ACT at 5 h The 10 putative surface proteins with an LPxTG motif were analyzed to identify domains that are known to be involved in bacterial adhesion in other bacterial species (Table  2 ). Only the MucBP domain (PF06458) is known to be directly involved in bacterial adhesion to human intestinal epithelium.
It is present as one copy in the F6-1 SALIVA_1472 protein of S. salivarius F6-1 (Table  2 ), whereas it is present as four copies in the MBF (mucus-binding factor) protein of L. rhamnosus GG, which is involved in its adhesion to the human intestinal mucus  (von Ossowski et al. 2011). Seven other putative surface proteins contain domains which are not directly involved in adhesion to human intestinal epithelium but in adhesion to constituents of human body. For example, a collagen-binding domain (PF05737) is present as one copy in the F6-1 Big_3-4 protein of S. salivarius F6-1 (Table  2 ). It is known to be involved in the adhesion to collagen of Staphylococcus aureus strains  (Symersky et al. 1997 ). The CshA-type fibril repeat (CshA_fibril_rpt, TIGR04225) is present as 27 copies in the F6-1 SALIVA_0893 protein of S.
salivarius F6-1 (Table  2 ). It is involved in the adhesion to fibronectin of S. gordonii but only in the presence of another protein with a Hsa domain  (Jakubovics et al. 2009 ). The serine-rich repeat adhesion glycoprotein AST domain (ser_adhes_Nterm, TIGR04224) is present as one copy in the F6-1 SALIVA_1456 and F6-1 SALIVA_1457 proteins of S. salivarius F6-1 (Table  2 ). It is known to be also involved in fibronectin linkage which allows adhesion to extracellular matrix and so to epithelium in streptococci  (Handley et al. 2005). Other domains could be important for adhesion. For example, the glucan-binding protein C domain (GbpC; PF08363) is present as one copy in the F6-1 CDS_812 and F6-1 CDS_813 proteins of S. salivarius F6-1 (Table  2 ) and is known to be involved in adhesion to glucans  (Sato et al.
1997). The G5 domain (PF07501) is present as two copies in the F6-1 SALIVA_1473 protein of S. salivarius F6-1 (Table  2 ). This domain is known to be involved in biofilm formation which involves adhesion as first step, as it has been demonstrated for the IgA1 peptidase of Streptococcus pneumoniae  (Bateman et al. 2005). The sequence of the F6-1 SALIVA_1473 protein also shows 31% of identity with ZmpC from S. pneumoniae (data not shown), suggesting that it is a zinc metalloprotease. Streptococcus zinc metalloproteases are less described but  Novak et al. (2000)  showed their role in S. pneumoniae adhesion to the nasopharyngeal epithelium. Furthermore, ZmpC is known to be involved in S. pneumoniae adhesion to the eye mucins (Muc16) and to act as a virulence factor in this bacterium  (Govindarajan et al.
2007 ). The collagen-binding domain (PF05737) present as one copy in the F6-1 SALIVA_0576 protein of S. salivarius F6-1 (Table  2 ) is known to be involved in the adhesion to collagen of some S. aureus strains  (Symersky et al. 1997). Other domains could participate to human colonization. For example, the Antigen_C domain (PF16364) is present as 10 copies in the F6-1 SALIVA_1475 protein of S. salivarius F6-1 (Table  2 ). It is present as two copies in SspB of S. gordonii, an antigen I/II family protein that is involved in host adhesion  (Demuth et al. 1996). The GBS-Bsp-like domain (PF08481) is present in the F6-1 CDS_800, F6-1 SALIVA_0442, and F6-1 SALIVA_0518 proteins as 2, 2, and 4 copies, respectively (Table  2 ). It is present in Bsp of Streptococcus agalactiae that is involved in cellular morphology that impacts adhesion  (Reinscheid et al.
2002). The SH3_5 domain (PF08460) is also present in the F6-1 SALIVA_0442 (6 copies) and F6-1 SALIVA_0518 (9 copies) proteins of S. salivarius F6-1 (Table  2 ). It is known to be involved in the interactions between proteins with proline-rich sequences, in cell-cell adhesion and in cell aggregation  (Machiyama et al. 2015; Morton and Campbell 1994; Pawson and Schlessingert 1993). Three of these F6-1 surface proteins were selected in order to test their involvement in the F6-1 adhesion to HT29-MTX cells. The genes encoding the F6-1 SALIVA_0442 (GBS_Bsp-like and SH3_5 domains), F6-1 SALIVA_0576 (FctA and collagen_bind domains), and F6-1 SALIVA_1475 (Antigen_C and FctA domains) proteins were separately replaced by a spectinomycin resistance gene to generate the F6-1 Δ0442, F6-1 Δ0576, and F6-1 Δ1475 mutants.
Identification of homologs of putative adhesins in Streptococci genomes Thus, our results show the involvement of four putative adhesins in the attachment of F6-1 to HT29-MTX cells, the three LPxTG proteins F6-1 SALIVA_1457, F6-1 SALIVA_1472, and F6-1 SALIVA_1473 and a protein devoid of LPxTG motif, F6-1 SALIVA_1475. Therefore, homologs of these F6-1 proteins were searched in all the translated CDSs of 33 S. salivarius sequenced genomes. These include 22 genomes already available in the NCBI database and 11 newly sequenced ones corresponding to S. salivarius strains tested in our aggregation/adhesion study. The sequence of the F6-1 SALIVA_1457 gene has two internal assembly gaps, which cannot be filled because of sequence repetitions. Such problem was also observed for 14 other sequences of F6-1 SALIVA_1457 homologs which are partial (data not shown).
Acknowledgements Fanny Chaffanel is recipient of a PhD fellowship from the  Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche. This work received financial support from the  Région Lorraine and Université de Lorraine  and from the  Fédération de recherche EFABA (Écosystèmes Forestiers, Agroressources, Bioprocédés et Alimentation). Compliance with ethical standards.
Objectives: Voriconazole, amphotericin B (AmB) formulations, and isavuconazole are all included in guideline recommendations for treatment of patients with invasive aspergillosis (IA) but the relative efficacy of isavuconazole versus AmB formulations has not been directly compared. We aimed to estimate the relative efficacy of isavuconazole compared with AmB deoxycholate (AmB-D), liposomal AmB (L-AmB), and voriconazole for the treatment of patients with proven/probable IA. Methods: Nine literature databases were screened for randomized controlled trials comparing treatments with any of voriconazole, AmB-D, L-AmB and isavuconazole for treatment of proven/probable IA. Articles meeting the criteria were included in a meta-analysis to determine the efficacy of AmB-D, L-AmB and voriconazole relative to isavuconazole based on all-cause mortality (ACM) and overall response using a fixed-effects model.
Systematic review: database searches and study selection Search strategies were designed and performed for each database screened (Supplementary Material), which included Embase, MEDLINE, CDSR, DARE, NHS EED, HTA, CENTRAL, ICTRP and NGC, and searches were supplemented by hand searching reference lists. The initial search was conducted on 6 January 2015; criteria are summarized in Table  1. Strategies were designed to identify RCTs that had used isavuconazole or any of the comparators as monotherapy for the treatment of probable or proven IA. Inclusion criteria were RCTs with human subjects published in English since 1995, treatment of patients with invasive fungal disease (IFD) caused by Aspergillus spp. , and measures of clinical effectiveness of isavuconazole or any of the comparators (mortality, overall response, rate of hospitalization, discontinuation [due to adverse events or any reason], adverse events or serious adverse events).
Network meta-analysis Data extracted from RCTs were subjected to network analysis within a Bayesian framework using Markov-chain Monte Carlo methods as per Lu and Ades  15  and Dias et al. (2011  16  and 2013  17  ). The models were run with OpenBUGS version 3. 2. 3 (http://www. openbugs. net/w/FrontPage). Where possible, outcome data was obtained from patients with proven or probable IFDs as defined using the 2008 criteria of the European Organisation for Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG)  18. For studies performed and published prior to the publication of the 2008 EORTC/MSG guidelines, IFDs were categorized using the 2002 EORTC/MSG guidelines  19. For studies that had been reanalyzed and republished after the publication of the 2008 guidelines, data was extracted from the parental study when not available from the re-analysis.
0-1. 5 mg/kg) in patients with IA and for which three articles were found  [23] [24] [25]. Outcomes for patients with proven and probable IA using 2008 EORTC/MSG criteria were published in a re-analysis of the original study data  25. Study 4 was a clinical trial of isavuconazole (200 mg QD maintenance dose) versus voriconazole (4 mg/kg BID maintenance dose) in patients with IFD and for which two articles were found  4, 26. In the primary publication, most patients with proven or probable IFD (determined by an independent data review committee) had documented IA or positive serum galactomannan test results (isavuconazole group, 86. 7%; voriconazole group, 83. 7%)  4. For the purposes of this analysis, all patients from Study 1 (AmB-D vs. L-AmB) were included, whereas for Studies 2-4, only patients with probable or proven IFD or IA who received at least one dose of study drug (modified intent-to-treat [mITT] populations) were included.