dataesr/scientific-paragraphs-categorization huggingface dataset:
antigen ELISA is  acceptable for detecting exposure to Toxocara spp. 57  Moreover, we based our definition of exposure on elevated levels of Toxocara spp. IgG4 which lends greater specificity  59  to our findings and therefore greater confidence that our measurements genuinely reflect exposure to the parasite. Furthermore, sera were pre-incubated on A. lumbricoides-coated plates and then transferred to T. canis-coated plates. By applying this method, we limited the possibility that Toxocara spp. positivity is a marker for Ascaris spp. exposure. There is little data on cross-reactivity between Toxocara and environmental allergens. In our study, no association was observed for T. canis IgG4 and allergic sensitization towards HDM. In our study, the RHINESSA offspring were tested for SPT towards cockroach allergen.
ACKNOWLEDGEMENTS This project was funded by a  World Universities Network (WUN) Research Development Fund  award for the project " Helminths and allergy in South-Africa  and  Northern Europe. "RJ Bertelsen  is supported by the  Research Council of Norway , grant number  230827. The Bergen RHINESSA study is funded by the  Research Council of Norway  (Grants No. 214123  and  228174 ), the  Bergen Medical Research Foundation , the  Western Norwegian Regional Health.
Acknowledgements We thank the  Tejero  family for their assistance during fieldwork, especially the field assistant (Lolo, deceased). We thank landowners ( Doña Chona , deceased,  Doña Tila  and  Don Polo ) for allowing us to work on their private properties. We thank my committee members  Dr Luis Manuel Garcia Feria  and  Dr Martha Bonilla Moheno  (INECOL). We thank  Julio García Hernández  for their collaboration providing the photographs of the eggs of the parasites. Finally, we appreciate the invaluable help of the  Medicine Conservation Laboratory of the Instituto Politécnico Nacional, México  ( Don Mario , Omar,  Dr Polo ,  Dr Nogueda ). Funding JCSS supported most of the costs of this work including travel and lab analysis expenses and MAAV was supported by a master degree grant ( CONACYT , scholarship number  280637 ).
Data analysis Individual values noted during the first series of investigations for snail density, egg-mass density and the number of eggs per mass were averaged and standard deviations were established taking into account soil geology (marl or granite) and the length of the egg-laying period. A similar protocol was used for shell growth during the second series of investigations taking into account soil geology, snail generation and the date of sampling. Normality of these values was analyzed using a Shapiro-Wilk normality test  (Shapiro and Wilk, 1965). As their distribution was not normal, the Kruskal-Wallis test was used to establish levels of significance. All the statistical analyses were done using Statview 5. 0 software (SAS Institute Inc. , Cary, NC, USA). In the first series of investigations, week 2 values noted in the habitats on marl for snail density, egg mass density, or the number of eggs per mass were compared with those found in the sites on granite, as they were the highest among values noted during the egg-laying period.
Characteristics of egg-deposits In the four snail habitats, egg-laying occurred over 7 weeks: the first egg-masses were noted at the end of April and the last at mid-June. On week 7, the shell heights of adults on marl ranged from 19. 5¡ 1. 7 mm to 20. 6 ¡ 0. 9 mm. The respective values on granite varied from 16. 3 ¡ 1. 4 mm to 17. 2 ¡ 0. 8 mm. A significant difference (H = 14. 67, P < 0. 001) between these shell heights on marl and granite was noted. In contrast, the shell heights in the two habitats on marl did not significantly differ from each other. A similar finding was also noted in the two sites on granite (data not shown). Figure  2  shows snail density and egg-mass production in the two types of habitats (marl or granite) during the 7 weeks of the egg-laying period. The number of adult snails per m 2 of habitat peaked on week 2 and decreased thereafter until the end of egg-laying.
Adult snails were significantly more numerous (H = 7. 58, P < 0. 01) on week 2 in the habitats on marl than in the other two sites. From week 3, the decrease in snail density was significantly greater (H= 7. 79, P< 0. 01) in the habitats on granite than in the two others (Fig. 2 (a) and (b)). Similar findings were also noted for egg-mass density. On week 2, egg-masses were significantly more numerous (H= 9. 01, P < 0. 01) in the habitats on marl. In contrast, the decrease noted from week 3 was significantly greater (H= 10. 54, P < 0. 01) on granite (Fig. 2(c)  and (d) ). This last finding is strengthened by the ratio between snail density and egg-mass density: from 1. 27 to 0. 52 mass throughout the 7 weeks on marl instead of 1. 29-0. 34 mass on granite (data not shown). If the numbers of egg-masses noted during the 7 weeks are added, each snail laid a total of 6.
The feasibility of this approach has been demonstrated in recent retrospective evaluations of carcinogenicity study results with pharmaceuticals  (ICH, 2016; Sistare et al. , 2011). A group of scientists from the pharmaceutical industry has published an analysis of a database consisting of 2-year carcinogenicity studies and chronic (6-months) toxicity studies in rats with 182 human pharmaceuticals  (Sistare et al. , 2011). The authors concluded that a lack of specific histopathological risk factors for neoplasia such as hyperplasia, foci of cellular alterations or chronic inflammation in a 26week toxicity study in adult rats, together with lack of evidence for genotoxicity and for hormonal perturbation, can predict with 80% accuracy a negative outcome of the 2-year rat carcinogenicity study for these compounds.
The approach is termed the "Negative for Endocrine, Genotoxicity, and Chronic study Associated histopathological Risk factors for Carcinogenicity in the Rat" (NEG CARC Rat) testing paradigm. Applying this prediction paradigm to new pharmaceuticals has the capacity to significantly reduce the number of 2-year rat carcinogenicity studies (40-50%), animals and costs without risk to human safety  (Sistare et al. , 2011). Using the same dataset complemented with study results from an additional 73 pharmaceuticals (255 compounds in total) the relationship of the carcinogenicity study outcome with the pharmacological properties of the compounds was analysed (van der  Laan et al. , 2016). The outcome of this analysis supports the notion that certain pharmacological drug classes are associated with tumour patterns in specific tissues in rats indicating that the pharmacological properties are a frequent key factor for the carcinogenic mode of action of many pharmaceuticals.
In the meantime (September 2016), additional 11 CADs and 7 reports of completed 2-year rat carcinogenicity studies have been submitted to the DRAs for review. For a successful completion of the prospective evaluation study it has been agreed that a dataset of at least 20 cases for category 3 (i. e. , CAD + study report) should be available which is expected to occur by the end of 2019 (ICH Status Report, 2016) (Table  2 ). Based on the degree of accuracy of predictions and of concordance among all parties conditions will be defined under which a weight-of-evidence evaluation to predict human cancer risk is an appropriate alternative to a 2-year rat carcinogenicity study. If this is the case then ICH guideline modifications involving waivers for the conduct of the 2-year rat study can be considered.
is electrophilic or can be metabolically activated; 2. is genotoxic; 3. alters DNA repair or cause genomic instability; 4. induces epigenetic alterations; 5. induces oxidative stress; 6. induces chronic inflammation; 7. is immunosuppressive; 8. modulates receptor-mediated effects; 9. causes immortalization; and 10. alters cell proliferation, cell death, or nutrient supply. These characteristics provide the basis for an objective approach to identifying and evaluating evidence from pertinent mechanistic studies  (Smith et al. , 2016). The 10 key characteristics are used to systematically search the literature for evidence on relevant endpoints, and support objective evaluation of the overall strength of mechanistic information. Additionally, mapping of high-throughput assays to the 10 key characteristics can facilitate systematic evaluation as an additional mechanistic data stream.
This resulted in prediction of accuracies that were even higher when combining gene expression profiles with results from the classical Ames mutagenicity test  (Magkoufopoulou et al. , 2012). These and other studies demonstrated that gene expression patterns consisting of several tenths of genes can be developed which may outperform the existing in vitro/in vivo test battery for predicting genotoxicity/carcinogenicity. MicroRNAs are small non-coding RNA sequences capable of silencing mRNAs thereby down-regulating gene expression. A single microRNA may target multiple different mRNAs. Hypothetically, predictive profiles may thus be generated which consist of only a few microRNAs. This was investigated by retrieving global microRNA data from primary mouse hepatocytes treated with 21 prototypical carcinogens.
Beluga habitat in the St. Lawrence estuary is highly contaminated by polycyclic aromatic hydrocarbons produced by the local aluminum smelters, strongly suggesting that polycyclic aromatic hydrocarbons are a major cause of the high cancer prevalence recorded in this population  (Martineau et al. , 2002). High cancer prevalence has also been recorded in other marine mammals, such as Pacific walrus (Odobenus rosmarus divergens) and Baltic gray seal (Halichoerus grypus). In the former, 18 neoplasms were found during examination of tissues collected from 107 carcasses (17%) from Alaskan subsistence hunting over a 10-year period  (Fleetwood et al. , 2005). However, no data regarding cancer etiology or pathogenesis of the walrus examined are presented. Between 1975 and 1997, 53  female Baltic gray seals aged between 15 and 40 years were found dead along the Baltic coast of Sweden, of which 34 (64%) where diagnosed having developed uterine leiomyomas  (Bäcklin et al.
Materials and Methods The study was conducted from September 2013 to February 2015. Thirty zoological parks were contacted through a partnership with two French animal histopathology laboratories (ONIRIS in Nantes, VetDiagnostic in Lyon) and the French Association of Zoological Park Veterinarians (AFVPZ). Data collection consisted of (1) consultation of veterinarian archives in the zoological parks and (2) analysis of centralized data by veterinarian histopathology laboratories. As accurate cancer diagnosis relies on histopathological examination of samples from biopsies, resection, or autopsy/necropsy  (Martineau et al. , 2002) , we therefore only entered tumor type (benign or malignant) into our database when they had been confirmed by histological analyses. We also recorded the organs affected, and, if any, the presence and the location of metastases.
As our data on tumor prevalence in reptiles are based on fairly small number of individuals we therefore suggest that our results should be interpreted with caution. Although many of the results from the present study are similar to that observed by  Effron et al. (1977)  and  Lombard and Witte (1959)  we do emphasize that the cancer etiology and prevalence were all obtained from animals kept in captivity. Cancer in captive animals has been shown to develop predominantly in older age cohorts. For example, although cancer prevalence in captive black-footed ferrets (Mustela nigripes) has been shown to affect 55% of the ferrets, the cancer almost exclusively affected postreproductive animals  (Lair et al. , 2002). The age-specific increase in cancer prevalence recorded in captive animals suggests that the significance of cancers recorded, similar to that recorded in black-footed ferrets, may therefore have limited or in some cases even no fitness effect in the wild.
Acknowledgments We acknowledge the French zoological parks who welcomed us into their premises and provided data on their animals:  Safari de Peaugres ,  Réserve Africaine de Sigean ,  Zoo de la Barben ,  Zoo La Palmyre ,  Montpellier Parc Zoologique ,  Réserve de la Haute-Touche, ZooParc de Beauval, Zoo de La Boissière-du-Doré, Planète sauvage ,  Bioparc Zoo de Doué ,  Zoo de Lyon ,  La Ménagerie , le zoo du  Jardin des Plantes, Zoo/Fauverie du Mont Faron. This work was supported by the  ANR  ( Blanc  project  EVOCAN ), the  CNRS (INEE) , the  Australian Academy of Science's French-Australian Science Innovation Collaboration Program Early Career Fellowship , and an  International Associated Laboratory Project France/Australia.
Acknowledgements We thank  Philippe Loubry  ( Muséum nationale d'Histoire naturelle, Paris, France ) for the photos, and  Oscar Sanisidro  ( Biodiversity Institute, University of Kansas, Lawrence, USA ) for the Fig. 3. We thank  Alexis Licht  ( University of Washington, Seattle, USA ),  Faruk Ocakoğlu  ( Eskişehir Osmangazi University, Eskişehir, Turkey ),  Mike Taylor  ( Geology Department, University of Kansas, Lawrence, USA ), and  Pauline Coster  ( Biodiversity Institute, University of Kansas, Lawrence, USA ) for helpful discussions regarding the geology and age of the  UCF ,  John Kappelman  and  Mary Maas  (both  University of Texas, Austin, USA ) for information on the UCF fauna, and  Sevket Sen  ( Muséum nationale d'Histoire naturelle, Paris ),  Thierry Smith  ( Royal Belgian Institute of Natural Science, Bruxelles, Belgium ), and  Hans Thewissen  ( Northeast Ohio Medical University, USA ) for their constructive comments on a previous version of the manuscript.
Dose escalation design The aim of the dose escalation study was to assess the safety and tolerability of etoposide phosphate in order to determine the recommended dose in dogs. A traditional 3+3 phase I design was used for the dose escalation study  [27]. In each cohort, a minimum of 3 dogs were included and received the same dose during the protocol. The first cohort was treated at a starting dose that was considered to be safe based on extrapolation from toxicological data  [21]  and the next cohorts were treated at increasing dose levels according to the following criteria: if no Dose Limiting Toxicity (DLT) was observed in the 3 dogs treated in a cohort, another three dogs could be treated at the next higher dose level. If one of the three dogs experienced a DLT, three more dogs were treated at the same dose level.
Search Criteria A systematic literature review was performed using a rigorous search strategy in the PubMed database for English language literature published up to October 2016, based on the following MeSH terms: [("Aspergillus fumigatus"[Mesh]) OR ((("Aspergillosis"  [Mesh] ) OR ("Invasive Pulmonary Aspergillosis"  [Mesh] ) OR ("Pulmonary Aspergillosis"  [Mesh] )) NOT ("Aspergillosis, Allergic Bronchopulmonary"[Mesh])) AND (("Models, Animal"  [Mesh] ) OR (("Rodentia"[Mesh]) OR ("Mice"[Mesh]) OR ("Rats"  [Mesh] ) OR ("Guinea Pigs"  [Mesh] )) OR ("Cricetinae"  [Mesh] )) NOT ("Rabbits"[Mesh]) NOT ("Birds"  [Mesh] )]. Then, the authors exhaustively reviewed the retained articles. For each, they thoroughly focused on the pivotal experimental parameters and the major technical features that are assumed to likely influence the results  (Schmidt, 2002; Clemons and Stevens, 2005; Lewis and Wiederhold, 2005; Patterson, 2005; Capilla et al.
, 2016). Additional information were also provided by Panepinto et al. when they explained how histopathological lesion areas were measured by using ScionImage R analysis software  (Panepinto et al. , 2003). Among the unusual miscellaneous methods for monitoring the course of infection, some investigators reported how useful could be in vivo imaging techniques based on bioluminescent A. fumigatus strain  (Brock et al. , 2008; Ibrahim-Granet et al. , 2010; Fekkar et al. , 2012; Jouvion et al. , 2012) , or antibody-guided positron emission tomography and magnetic resonance imaging  (Rolle et al. , 2016). The former requires luciferin as exogenous substrate, while the latter needs particular caution for radiation protection. Recently, the expanding availability of immunological reagents to monitor the recruitment and functional activation of immune cells informs immune-pathophysiology studies aiming to identify the molecular and cellular basis of antifungal immunity.
When possible, primary alveolar epithelial type II cells (AECII) were derived from the tissues. Seventeen primary AECII cultures were obtained from lung cancers and sixteen from normal lungs (Table  1 ). The lung-derived ovine AECII have been phenotypically characterized for the expression of pro-SP-C and cytokeratin and cultured as previously described  [22]. We studied the mRNA and protein expression in lungs and lung-derived AECII from the same animals when possible; unfortunately, due to the limited number of primary cells directly derived from cancer or normal lungs, this was not possible in all cases. When necessary, we used AECII cultures from other animals from our biobank. Human lung specimens from 18 patients (13 lepidic and five papillary adenocarcinomas) and their associated data were obtained from Cardiobiotec Biobank (CRB-HCL Hospices Civils de Lyon BB-0033-00046), a center for biological resources authorized by the French Ministry of Social Affairs and Health.
Correlating with the decrease of mRNA expression, VEGFR2 proteins were undetectable in cancers but present in 80% of normal lungs (Figures  2A  and C ). VEGFR2 protein expression was null in primary AECIIs derived from normal lungs or cancers (Figure  2B ). These results highlight the loss of expression of VEGFA and of its main receptor VEGFR2 in JSRV-induced pulmonary adenocarcinomas. We measured mRNA expression of VEGFB, VEGFC, VEGFD ligands, of their receptors VEGFR1, VEGFR3 and of their coreceptors NRP1 and NRP2. Except for the expression of VEGFD, which was significantly reduced in JSRV-induced adenocarcinomas, none of the other genes were differentially expressed in cancers (Figure  3 ). Expression of VEGFB and VEGFC was low to undetectable in most tested tissues (Figure  3A ). Expression of the VEGFR1 and VEGFR3 receptors (Figure  3B ) and NRP1 and NRP2 (data not shown) was not modified in JSRV-induced cancers when compared to normal lungs.
Animals Forty-nine client-owned male cats undergoing elective castration were included in the study. The number of participants was established on the basis of a sample size calculation using a commercial software program (SigmStat and SigmaPlot 12). It was performed by setting the power at 80%, the level of significance at 5% and the end point as a postoperative Visual Analogue Scale (VAS) pain score difference between groups of 10 mm with a standard deviation of 5 mm. Cats underwent a routine preanaesthetic physical examination in order to assess the health status. Exclusion criteria were: presence of systemic disease, impaired cardiovascular function, and age above 8 years. Food, but not water, was withdrawn 12 hours prior to surgery. The study was performed under approval of the ethical committee of the Faculty of Veterinary Medicine of Alfort, France, and informed owner consent.
The European Union's ban on animal testing for cosmetic ingredients and products has generated a strong momentum for the development of in silico and in vitro alternative methods. One of the focus of the COSMOS project was ab initio prediction of kinetics and toxic effects through multiscale pharmacokinetic modeling and in vitro data integration. In our experience, mathematical or computer modeling and in vitro experiments are complementary. We present here a summary of the main models and results obtained within the framework of the project on these topics. A first section presents our work at the organelle and cellular level. We then go toward modeling cell levels effects (monitored continuously), multiscale physiologically based pharmacokinetic and effect models, and route to route extrapolation.
Introduction The European decision to ban animal testing for cosmetic ingredients has generated a strong momentum for the development of in silico and in vitro alternative methods. One of the aims of the COSMOS project (funded by the European Commission and by Cosmetics Europe under the 7th Framework Programme) was to develop approaches for the ab initio prediction of kinetics and toxic effects through multiscale pharmacokinetic modeling and in vitro data integration. We present here a summary of the relevant models and results obtained by the COSMOS team. Our major activities were focused on modeling toxicokinetics and toxicodynamics (effects) in vitro and in vivo, which are required to perform quantitative in vitro to in vivo extrapolation (QIVIVE)  (Adler et al. , 2011; Bessems et al. , 2014; Coecke et al.
, 2015 for details). The data were obtained using HepaRG cells  (Guillouzo et al. , 2007) , exposed to the selected chemicals either once (at concentrations ranging from 0. 008 to 8 mM with a 48 h followup) or during repeated exposures (at concentrations ranging from 0. 128 to 8 mM, with a follow-up of 4 weeks). Cellular viability was monitored by impedance measurements with an in vitro label-free cell-based monitoring system (xCELLigence TM , ACEA Biosciences, Roche Diagnostics). The impedance of HepaRG cells was converted to a normalized cell index (NCI). A decrease in NCI is indicative of cell detachment or death  (Xing et al. , 2006). We modeled the in vitro dynamic decrease in concentration for the substance of interest by an apparent linear process (lumping unspecific physico-chemical reactions, plastic binding, evaporation and linear metabolism) or by a Michaelis-Menten equation when saturable cellular metabolism was observed.
A number of QSAR models and software tools are available for the prediction of ADME related properties (Mostrag-Szlichtyng and  Worth, 2010; Worth et al. , 2011). In the context of the COSMOS project we used the ACD/Labs Percepta software (ACD/Labs Percepta, release 2014. Advanced Chemistry Development Inc. , Toronto, Canada. www. acdlabs. com) to predict several physico-chemical parameters (e. g. , Log K ow , pK a , F up ) and ADME properties (e. g. , passive oral absorption, oral bioavailability, total body clearance) that were used for the calibration of PBPK models.
From in silico models to automated workflows Future human safety assessments are likely to rely strongly on the use of multi-scale models, implemented through a combination of computational tools, in order to perform extrapolations such as QIVIVE. The development of automated software tools is now seen as an important step for harmonizing and expediting chemical safety assessments. The KNIME workbench  (Berthold et al. , 2007)  provides a user-friendly graphical workflow interface for data processing and analysis. Most of the mathematical models developed within the framework of COSMOSmostly written in R (R Development Core Team, 2013)have been implemented in the KNIME platform. They already are or will soon be publicly available through the COSMOS KNIME WebPortal (http://knimewebportal. cosmostox.
Materials and Methods Twenty tie-stall housed Holstein dairy cows were randomly selected from the McGill University Macdonald Campus Dairy Complex (Ste-Anne-de-Bellevue, QC, Canada) for use in the study. Cows ranged in parity (mean ± SD and range: 2. 75 ± 0. 99, 1-5) and stage of lactation (DIM (days in milk) mean ± SD and range; 123. 6 ± 115. 45, 2-432). Prior to the start of the validation process, leg mounted 3D accelerometers (HOBO Pendant G Acceleration Data Logger, Onset Computer Corp. , Pocasset, MA, USA), set to record at 1-min intervals, were attached to the rear leg of eight randomly selected cows for a period of seven days to identify three 2-h periods of time where long bouts of standing were common and activity was likely to be high. The three selected 2-h periods were 10:00 to 12:00, 14:30 to 16:30, and 19:00 to 21:00.