dataesr/scientific-paragraphs-categorization huggingface dataset:
The libraries' qualification consists of continuously updating the databases with emerging knowledge from the literature or provided by (pharmaceutical) companies. Additional elements presented by the companies included: version stamp for model output, training datasets with tutorials available to users, validation datasets that remain with the software to allow verification of continued system model reliability, and transparency regarding source of data and assumptions within the system. Overall it was concluded that each software provider has developed internal systems to evaluate and track the reliability of their system models and associated libraries. Further discussion focused on the framework proposed for assessment of systems pharmacology models  7  and referred to the US National Academies framework on Validation, Verification, and Uncertainty Quantitation.
8 In summary, the framework recommends that the software should be open access, "bug-free," with no copying errors. In addition, two types of data should be clearly differentiated: training data published with the model and novel and varied validation data. It was acknowledged that in the field of PBPK, open source software published with training datasets presents a challenge for software providers wishing to protect their intellectual property. Other solutions, such as open source validation datasets (for a specific condition of use), could potentially serve the same purpose. Importantly, there is some mismatch between the terminology used within PBPK and computational science communities: "qualification" or "verification" vs. "validation. " Also acknowledged was that system model qualification is an area that has not been extensively discussed within the PBPK community and that standards are not currently agreed, and that progress to establish best practice is needed.
Acknowledgments. The authors thank the organizers and presenters:  Eva Gil Berglund  (MPA),  Michael Bolger  ( Simulations Plus), Liberty Dixon (ABPI) ,  Rob Hemmings  (MHRA),  Hannah Jones  (Pfizer),  Patrice Larger  (Novartis),  Louise Leong  (ABPI),  Christoph Niederalt  ( Bayer Technology Services ),  Munir Pirmohamed  (meeting chair),  Malcolm Rowland  ( University of Manchester ),  Masanobu Sato  (PMDA),  Vikram Sinha  (FDA),  Jan Snoeys (Janssen) , and  Karen Yeo  (Certara). The views expressed in this article are the personal views of the authors (SC, AN, and TS) and may not be understood or quoted as being made on behalf of or reflecting the position of the  European Medicines Agency  or any National Competent Authority.
Pain in cancer therapy is a common condition and there is a need for new options in therapeutic management. While phytochemicals have been proposed as one pain management solution, knowledge of their utility is limited. The objective of this study was to perform a systematic review of the biomedical literature for the use of phytochemicals for management of cancer therapy pain in human subjects. Of an initial database search of 1,603 abstracts, 32 full-text articles were eligible for further assessment. Only 7 of these articles met all inclusion criteria for this systematic review. The average relative risk of phytochemical versus control was 1. 03 [95% CI 0. 59 to 2. 06]. In other words (although not statistically significant), patients treated with phytochemicals were slightly more likely than patients treated with control to obtain successful management of pain in cancer therapy.
Data Sources and Searches. The internationally accepted Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standard was used for this systematic review  [17, 18]. A comprehensive search of 4 databases was conducted: PubMed (the National Library of Medicine), Ovid/MEDLINE (Wolters Kluwer), Scopus (Elsevier), and Web of Science (Thomson Reuters). English abstracts were searched from each database's inception through July 01, 2015. The search strategy was designed and conducted with a controlled vocabulary supplemented with keywords to search for studies of phytochemicals ("phytotherap*", "phytochemical*", "plant", and "plants"), fungochemicals (mushr*), pain ("pain" and "nociception"), and cancer ("cancer" and "neoplas*"). Case reports, case series, case studies, controlled trials, and comparative studies were included in this search strategy.
Data Synthesis and Analysis. Data abstraction was coordinated and performed using the online systematic review software Covidence (Alfred Health, Monash University, Melbourne, Australia)  [20]. For each study, relative risk was calculated by extracting the number of patients with dichotomous (binary) pain outcomes and comparing between the control and exposure groups. Statistical analysis, as well as forest plot and stacked bar chart generation, was performed using JMP (SAS, Cary, North Carolina). All confidence intervals (CIs) are reported at the 95% level. Final full-text article review was performed by 3 reviewers (Mikhail A. Dziadzko, Fabrice Heritier, and Bennett G. Childs). (Figure  1 ). After removal of duplicate records ( = 516) and record screening against title ( = 985), a total of 102 abstracts remained for screening.
Discussion In this systematic review of the use of phytochemicals for management of pain in cancer therapy, we identified a lack of quality research literature on this subject ( = 7). While we were able to demonstrate a slight therapeutic benefit use of phytochemicals in the management of cancer pain, this benefit did not achieve statistical significance, which is a function of both the quality and marginal number of the studies that were acceptable for inclusion in a systematic review. The average relative risk of phytochemical compared to control for the included studies (total  = 800) was 1. 03 [95% CI 0. 59 to 2. 06]. None of these research studies were performed in the United States and none of these 6 phytochemicals or 1 fungochemical is known to have a psychotropic effect. Over 1,500 research articles were identified potentially examining the use of phytochemicals for management of pain in cancer therapy in initial database screening in this systematic review.
Introduction: the present study conducted in Cameroon from June 2013 to February 2014 aimed to estimating the level of pharmacovigilance knowledge and practice of health professionals in Cameroon. Methods: we conducted a descriptive cross-sectional survey on 149 health professionals in Cameroon from June to September 2013. Data were analyzed using software IBM SPSS 20. 0. We calculated proportions and odd ratio, and confident interval of their values, keeping a threshold of p of 0. 05 to determine the level of significance. Results: ninety percent (90%) of declaration of side effects were made to the medical representatives and 4% to the National Pharmacovigilance Centre. Fifty four percent (54%) of physicians were not aware of the existence of a National Pharmacovigilance system. Ten (10%) of prescribers had never heard of pharmacovigilance, however respondents answered unanimously that they need training on pharmacovigilance.
Methods From June to September 2013, we carried out a study on a sample drawn from a synthetized database of 12526 health professionals composed of physicians, pharmacists and dentists in registered as shown in the national health statistics report of Cameroon in 2010. We asserted that 10% of prescribers have no "knowledge" of pharmacovigilance. We therefore calculated a sample of 138 patients, with an error margin of 5% and a confident level of 95% using Epi Info statcalc. We extended our selection to the four groups as not only physicians prescribe drugs in Cameroon. We sent out to the sample population 200 questionnaires and received 149 exploitable responses. We analyzed data using IBM SPSS 20. 0 software. We applied a 0. 05 threshold for p-value for statistical significance when comparing proportions.
Dynamic Light Scattering (DLS) DLS measurements were performed with a Zetasizer Nano ZS system (Malvern, Herrenberg, Germany) equipped with a 633 nm He-Ne laser. The scattered light was detected by using non-invasive backscatter detection at an angle of 173°. A sample volume of 500 μL was analyzed in single-use polystyrene semi-micro cuvettes with a path length of 10 mm (Brand, Wertheim, Germany). The Dispersion Technology Software version 6. 01 was used for data collection and analysis. If not stated differently, the measurements were made with an automatic attenuator and a controlled temperature of 25°C. The intensity size distribution, Z-average diameter, derived count rate, and polydispersity index were calculated from the autocorrelation function obtained in 'general purpose mode'. Each sample was measured in triplicate.
Nanoparticle Tracking Analysis (NTA) NTA was performed with a NanoSight LM20 (NanoSight, Amesbury, UK). The instrument was equipped with a 405 nm blue laser, a sample chamber and a Viton fluoroelastomer O-ring. If sample dilution was necessary to achieve an optimal concentration for NTA, Milli-Q® water was used as a diluent and all results were calculated back to the original concentration. Samples were loaded into the sample chamber by using a 1-mL syringe and a pre-run volume of 0. 5 mL. Samples were analyzed in triplicate at a stopped flow, while 0. 1 mL was flushed through the chamber between each repetition. The NTA 2. 3 software was used for capturing and analyzing the data. Movements of the particles in the samples were recorded as videos for 60 s, while the shutter and gain settings of the camera were set automatically by the software for an optimal particle resolution.
1b , Table  I ). Furthermore, an increase in concentration of sucrose A in water resulted in a linear increase in nanoparticle concentration determined by NTA, while a water control did not show any particles (Fig. 1c ). Furthermore, the size distribution did not change with increasing sucrose concentration. Additionally, triplicate sample preparations analyzed by DLS and NTA showed high repeatability (data not shown). IgG and lysozyme formulated at various concentrations in 7% sucrose A solutions were analyzed by DLS. At an IgG concentration of 0. 1 mg/mL, the signal from the sucrose molecule (1 nm), the IgG (14 nm) and the 100-200 nm signal were visible (Fig. 1d , upper panel). At 1 mg/mL, the 100-200 nm signal disappeared and at 5 mg/mL also the sucrose signal  (1 nm) vanished, leaving only the signal the IgG.
Only a few examples exist, focusing on one specific approach: the MixLow R package (http://cran. r-project. org/web/packages/mixlow) proposes an implementation of the Loewe Additivity (Boik and Narasimhan 2010); CompuSyn (http://www. combosyn. com) and CalcuSyn (http://www. biosoft. com/w/calcusyn. htm) implements the Median-Effect approach of Chou and Talalay  (Chou and Talalay 1983, 1984; Chou 2006 Chou , 2010)). Publications often mention the use of SAS  (Wang et al. 1997)  or R scripts  (Zhao et al. 2010; Whitehead et al. 2013 ) but do not mention how methods are implemented  (Raffa et al. 2000; Borisy et al. 2003; Leh ar et al. 2007 Leh ar et al. , 2009;; Cokol et al. 2011). Issue 6: combining more than two drugs Drug combination analysis is often presented on drug pairs in order to ease its understanding and because it covers the most common situation in practice.
Acknowledgements We thank  D. Cohen  and  I. Chumakov  for their strong support. We also thank  L. Belo ,  J. Laffaire ,  V. Bertrand ,  A. Boucard ,  R. Hajj ,  Y. Pereira ,  M. De Crignis ,  M. Marcad  e, and  E. Graudens  for their careful reading of our manuscript and their many insightful comments and suggestions.
Orhalquinone demonstrated significant inhibitory activities against both human and yeast farnesyltransferase enzymes, with IC50 values of 0. 4 µM. In our continuing search for bioactive compounds from marine sponges, we have chemically investigated the Indonesian sponge of Xestospongia sp. collected off North Sulawesi, the methanolic crude extract of which showed kinase inhibition, antimicrobial and antioxidant activities. Bio-guided fractionation of the extract led to the isolation of seven new adociaquinone derivatives 1a-4c, together with seven known compounds, adociaquinone A 5 and B 6  [4] , secoadociaquinones A 7 and B 8, 15-chloro-14-hydroxyxestoquinone 9, 14-chloro-15-hydroxyxestoquinone 10  [7]  and xestoquinol sulfate 11  [9]  (Figure  1 ). The known compounds were identified by comparison of their spectroscopic data with those of the literature.
Acknowledgments We acknowledge the financial support of the  European Union   7th Framework Program  ( BlueGenics FP7-KBBE-2012-6 ) under grant agreement n°  311848  (ML. BK, A. L, L. H. M, H. F). The authors are grateful to  J. -C. Braekman  for the gift of the sponge samples, to  R. Van Soest  for sponge identification, to  A. Blond  and  A. Deville  ( MNHN, Paris, France ) for NMR spectra, and to  A. Marie  and  L. Dubost  ( MNHN, Paris, France ) for MS measurements.
Acknowledgments The authors gratefully acknowledge:  Séverine Mahieux  (from the laboratory of bacteriology, Lille 2), the  ARPIA Peru association (Association pour la Recherche sur les Pharmacopées indigenes d' Amazonie ), the  EDF foundation (Electricité De France) , the  Nord Pas de Calais department (SISA: Solidarité Ici Solidarité Ailleurs) , as well as  Clara Mori ,  Corina Güivinsinti  and other Peruvian people who were willing to share with us their knowledge about medicinal plants. The authors declare that they have no conflict of interest.
Acknowledgements The  EPSRC  (grant  EP/K016938/1 ), the  European Community (INTERREG IVa, AI-Chem , project  4494/4196 ), and the  ANR  ( JCJC "ProOFE" grant  ( ANR-13-JS08-0007-01 ) are gratefully acknowledgedf or their financial support. The current work was granted access to the  HPC resources of (CCRT/CINES/IDRIS)  under the allocation c2014085117 made by  GENCI , and  HPC resourcesf rom ArronaxPlus , grant  ANR-11-EQPX-0004  funded by the  ANR. We thank the  CCIPL  for grants of computer time. We are grateful for  EPSRC Core Capability Funding  ( EP/K039466/1 ). Apollo Scientific is gratefully acknowledgedf or the donation of chemicals. Keywords: fluorination • intramolecular interactions • hydrogen bonds • NMR spectroscopy • quantum calculations.
This was correlated to a lack of increase in LDH release in both cell lines. On the other hand, our data suggest that the concentration of 100 mg/ml of DA extract significantly decreased cell viability of both HepG2 and LLC-PK1, and was associated with a significant increase of LDH release. Whether this toxicity could be attributed to the amount of alcohol used in the plant extract remains to be determined. Indeed, alcohol has been shown to increase the number of apoptotic cells  [14, 15]  and lead to the induction of intracellular enzymes like alcohol deshydrogenase and the production reactive oxygen species (ROS)  [16]. Consistent with the observed effect, ethanol cytotoxicity is dose-dependent and occurs within 24 h in vitro  [17]. The effect of ethanol should be assessed as vehicle on our cells.
Acknowledgements The author wishes to thank  Mondher Toumi  for advice and support with recruiting survey participants,  Elisabeth Hoechsmann ,  Karin Steinmann , and  Herb Riband  for our ongoing stimulating discussions, as well as  Heather Connor  for editing and proofreading both the questionnaire and the manuscript. This study was supported by  Interpharma , the association of research-based pharmaceutical companies in Switzerland, and in particular  Heiner Sandmeier 's kind assistance is gratefully acknowledged.
After 96 h, cytotoxicity was evaluated using the WST-1 assay. For each compound tested, the EC50 (effective concentration of drug needed to inhibit cell growth/viability by 50%) was generated from the dose-response curves for each cell line. Seventeen compounds were evaluated on the cell lines and then compared to TBB used as a standard. Among the three best CK2 inhibitors (5a, 5b, 7a), compounds 5a and 5b displayed no marked cytotoxic activity, except for compound 5b on the MEF cell line (EC50 = 4. 4 µM). After 96 h their EC50 values were superior to 10 µM, similar to TBB. No data were obtained with compound 7a due to the lack of solubility. Four compounds, belonging to the sub-series of D-ring paraquinone derivatives (7c, 7d, 7f, 7g), displayed cytotoxic activity (0. 4 < EC50 µM < 8. 8), especially on HEK293T.
In order to understand observed differences in the inhibitory activity of compounds 5a, 7a, 5h (R1 = R2 = H)  [13]  and 7h (R1 = R2 = H)  [14]  (Table  S1  in the supplementary data), the compounds were structurally aligned with the program vROCS  [24]  onto an inhibitor with pyridocarbazolone scaffold cocrystallized with CK2 (PDB code: 3OWJ  [12] ). Subsequently, the compounds were energy minimized in the presence of the enzyme with the program Moloc  [26] , keeping all protein atoms fixed. For this the co-crystallized water molecule 429 was removed, as it clashed with the ligands (distance ≤ 2. 2 Å); in contrast, water molecule 382 was kept as its distance to the ligands was  4 Å. In addition, the minimization was performed with all binding site residues within 5 Å of the ligands (L45-R47, S51, V53, V66, K68, I95, F113-V116, H160-N161, M163, and I174-W176) allowed to move, in order to investigate if the ligand binding would cause conformational changes within the binding site.
Crystallography The structure of compound 4d' has been established by X-ray crystallography (Figure  4 ). Yellow single crystal (0. 76 × 0. 13 × 0. 09 mm 3 ) of 4d' was obtained after 10 days at 17 °C by slow evaporation from a methanol/chloroform (80/20) solution. It crystallized in the monoclinic space group P21/c, a = 13. 103(2) Å, b = 10. 0799(11) Å, c = 16. 411(2) Å, α= 90°, β= 95. 439(13)°, = 90°, V = 2157. 8(5) Å 3 , Z = 4, (calcd) = 1. 310 Mg. m -3 , FW = 425. 44 for C24H24FNO5, F(000) = 896, final R indexes were R1 = 0. 0519 (I > 2σ(I)) and wR2 = 0. 1437 (all data). Crystallographic data were acquired on a Bruker-Nonius Kappa CCD. Full crystallographic results have been deposited at the Cambridge Crystallographic Data Centre (CCDC-977015), UK, as supplementary Material  [30].
Molecular Modeling All four inhibitors 5a, 7a, 5h  [13] , and 7h  [14]  were structurally aligned using the program vROCS  [25]. For this a pharmacophore match based on shape and H-bond donor and acceptor groups with the co-crystallized inhibitor (from PDB code: 3OWJ) was performed. Subsequently, the inhibitors were energy minimized in the binding region of CK2 (from PDB code: 3OWJ) using the program Moloc  [26].
Acknowledgments We acknowledge financial support to FAC by the  "Bonus Qualité Recherche" (BQR)  of the  University Claude Bernard Lyon 1 , by the " Cluster 5 Chimie Durable et Chimie pour la Santé " of the  Region Rhône-Alpes  and by the " ARC 1 Santé " of the  Region Rhône-Alpes. The  "Institut des Sciences Pharmaceutiques et Biologiques" (ISPB)  is also gratefully acknowledged for the funding of an uHPLC/DAD/MS system. M. Le Borgne  thanks " Cancéropôle Lyon Auvergne Rhône-Alpes" (CLARA)  and  "Université France Allemagne" (UFA)  for their funding of ChemBioInteract network. M. Le Borgne  and  Dr. Laurent Ettouati  are grateful to  Christine Ranquet  for her assistance in the stock management of the small molecule library of EA  4446 B2C. We also thank  ChemAxon  for providing us a license to their chemoinformatics software.
5 mg/ml). Three hours later, the plates were centrifuged, the MTT-formazan product was dissolved in 150 l DMSO, and the absorbance was measured using a multiplate reader (Spectra Count, Packard, Ontario, Canada). The drug effect was quantified as the percentage of the control absorbance of the reduced dye at 595 nm. Data are presented as mean ± S. E. M. The IC 50 values and their 95% confidence intervals (CI 95%) were obtained by non-linear regression using the GraphPad Software 4. 0 (Intuitive Software for Science).
Cell density and viability HL-60 cells were seeded in a 24-well plate (3 × 10 5 cells/ml), cultured for 24 h to initiate cell growth and treated, as previously described. Cells were harvested after 3, 6, 12, 24, 28 and 72 h of exposure, centrifuged and resuspended in a 5 g/ml propidium iodide (PI) solution (Sigma-Aldrich). After 5 min incubation in the dark, five thousand events were acquired using the Guava EasyCyte Mini flow cytometer (Guava Technologies) and the Guava Express Plus software on a gated region to exclude debris and doublets from the analysis. Concentration of cells in each treatment and membrane integrity were evaluated and plotted in an XY graph using GraphPad Software 4. 0 (Intuitive Software for Science).
Cell cycle and DNA fragmentation HL-60 cells were seeded in a 24-well plate (3 × 10 5 cells/ml), cultured for 24 h to initiate cell growth and treated, as previously described. After exposure for 3 or 24 h, cells were harvested, centrifuged and resuspended in a solution containing 5 g/ml PI, 0. 1% citrate and 0. 1% Triton X-100. After 30 min incubation in the dark, five thousand events were acquired using the Guava EasyCyte Mini flow cytometer (Guava Technologies) and the Guava Express Plus software on a gated region to exclude debris and doublets from the analysis. Cell cycle histograms were acquired using the FL3 channel (excitation at max 488 nm and emission max 620 nM) to capture the red fluorescence emitted from PI-DNA complexes. The cell cycle profile (G 1 /G 0 -S-G 2 /M) was analyzed in linear scale with the ModFit LT 4.
Trypan blue exclusion HL-60 cells were seeded in a 24-well plate (3 × 10 5 cells/ml), cultured for 24 h to initiate cell growth and pre-treated and treated, as previously described. After exposure for 24 h to all treatment types, cells were harvested, dyed with Trypan blue and differentially counted for viable (not dyed) or non-viable (dyed) counted in a Neubauer chamber. The differences between groups were determined by analysis of variance (ANOVA) followed by Student Newman-Keuls post-test on GraphPad Software 4. 0 (Intuitive Software for Science). The minimal significance level was set at p < 0. 05.
Measurement of reactive oxygen species generation HL-60 cells were seeded in a 24-well plate (3 × 10 5 cells/ml), cultured for 24 h to initiate cell growth and pre-treated and treated, as previously described. After exposure for 1 h to all treatment types, cells were loaded with H 2 -DCF-DA and incubated for 30 min in the dark at 37 • C. Cells were then harvested, washed, resuspended in PBS and immediately analyzed. Five thousand events were acquired using the Guava EasyCyte Mini flow cytometer (Guava Technologies) and the Guava Express Plus software on a gated region to exclude debris and doublets from the analysis, using excitation and emission wave lengths of 490 and 530 nm, respectively. The differences between groups were determined by analysis of variance (ANOVA) followed by Student Newman-Keuls post-test on GraphPad Software 4.
Additionally, a considerable number cells resembling necrosis, were also observed after 24 h treatment. Perezone-treated cells showed volume reduction and some cellular aggregation. Little DNA fragmentation and some membrane rupture were detected. Moreover, picnotic cells were widespread in slides. Such characteristics seamed to retain concentration dependency. Cells pre-treated with l-NAC prior to exposure to 1 showed fewer signs of toxicity, especially those related to apoptosis, at all tested concentrations. Cell viability was assessment by exclusion of trypan blue dye indicated that 1 reduced the number of viable HL-60 cells and Cells were either treated with DMSO 1% (-), 0. 5 M doxorubicin (+), or with 1 at 2, 4 or 8 M, and analyzed by flow cytometry after staining with PI. Data are presented as mean values ± standard error of the mean (S.