ALTEX最新文献

{"title":"3D fluid-dynamic ovarian cancer model resembling systemic drug administration for efficacy assay.","authors":"Alessandra Marrella,&nbsp;Gabriele Varani,&nbsp;Maurizio Aiello,&nbsp;Ivan Vaccari,&nbsp;Chiara Vitale,&nbsp;Martin Mojzisek,&nbsp;Cristina Degrassi,&nbsp;Silvia Scaglione","doi":"10.14573/altex.2003131","DOIUrl":"https://doi.org/10.14573/altex.2003131","url":null,"abstract":"<p><p>Recently, 3D in vitro cancer models have become important alternatives to animal tests for establishing the efficacy of anticancer treatments. In this work, 3D SKOV-3 cell-laden alginate hydrogels were established as ovarian tumor models and cultured within a fluid-dynamic bioreactor (MIVO®) device able to mimic the capillary flow dynamics feeding the tumor. Cisplatin efficacy tests were performed within the device over time and compared with (i) the in vitro culture under static conditions and (ii) a xenograft mouse model with SKOV-3 cells, by monitoring and measuring cell proliferation or tumor regression, respectively, over time. After one week of treatment with 10 μM cisplatin, viability of cells within the 3D hydrogels cultured under static conditions remained above 80%. In contrast, the viability of cells within the 3D hydrogels cultured within dynamic MIVO® decreased by up to 50%, and very few proliferating Ki67-positive cells were observed through immunostaining. Analysis of drug diffusion, confirmed by computational analysis, explained that these results are due to different cisplatin diffusion mechanisms in the two culture conditions. Interestingly, the outcome of the drug efficacy test in the xenograft model was about 44% of tumor regression after 5 weeks, as predicted in a shorter time in the fluid-dynamic in vitro tests carried out in the MIVO® device. These results indicate that the in vivo-like dynamic environment provided by the MIVO® device allows to better model the 3D tumor environment and predict in vivo drug efficacy than a static in vitro model.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"82-94"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38230960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NAM-supported read-across: From case studies to regulatory guidance in safety assessment.","authors":"Costanza Rovida,&nbsp;Sylvia E Escher,&nbsp;Matthias Herzler,&nbsp;Susanne H Bennekou,&nbsp;Hennicke Kamp,&nbsp;Dinant E Kroese,&nbsp;Lidka Maslankiewicz,&nbsp;Martijn J Moné,&nbsp;Grace Patlewicz,&nbsp;Nisha Sipes,&nbsp;Leon Van Aerts,&nbsp;Andrew White,&nbsp;Takashi Yamada,&nbsp;Bob Van de Water","doi":"10.14573/altex.2010062","DOIUrl":"https://doi.org/10.14573/altex.2010062","url":null,"abstract":"<p><p>The use of new approach methodologies (NAMs) in support of read-across (RAx) approaches for regulatory purposes is a main goal of the EU-ToxRisk project. To bring this forward, EU-ToxRisk partners convened a workshop in close collaboration with regulatory representatives from key organizations including European regulatory agencies, such as the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA), as well as the Scientific Committee on Consumer Safety (SCCS), national agencies from several European countries, Japan, Canada and the USA, as well as the Organisation for Economic Cooperation and Development (OECD). More than a hundred people actively participated in the discussions, bringing together diverse viewpoints across academia, regulators and industry. The discussion was organized starting from five practical cases of RAx applied to specific problems that offered the oppor-tunity to consider real examples. There was general consensus that NAMs can improve confidence in RAx, in particular in defining category boundaries as well as characterizing the similarities/dissimilarities between source and target substances. In addition to describing dynamics, NAMs can be helpful in terms of kinetics and metabolism that may play an important role in the demonstration of similarity or dissimilarity among the members of a category. NAMs were also noted as effective in providing quanti-tative data correlated with traditional no observed adverse effect levels (NOAELs) used in risk assessment, while reducing the uncertainty on the final conclusion. An interesting point of view was the advice on calibrating the number of new tests that should be carefully selected, avoiding the allure of \"the more, the better\". Unfortunately, yet unsurprisingly, there was no single approach befitting every case, requiring careful analysis delineating the optimal approach. Expert analysis and assessment of each specific case is still an important step in the process.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"140-150"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38824549","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using the monocyte activation test as a stand-alone release test for medical devices.","authors":"Jeffrey Brown,&nbsp;Amy J Clippinger,&nbsp;Claire Fritz Briglia,&nbsp;Warren Casey,&nbsp;Kelly Coleman,&nbsp;Anja Fritsch,&nbsp;Thomas Hartung,&nbsp;Djik Maouyo,&nbsp;Thierry Muller,&nbsp;Johannes Reich,&nbsp;Laure Robert,&nbsp;Ruth Roeder,&nbsp;Guillermo Sanchez,&nbsp;Anita Y Sawyer,&nbsp;Shabnam Solati,&nbsp;Radhakrishna Tirumalai,&nbsp;Walter Zwisler,&nbsp;David Allen","doi":"10.14573/altex.2012021","DOIUrl":"https://doi.org/10.14573/altex.2012021","url":null,"abstract":"<p><p>Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this issue, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods and the PETA International Science Consortium Ltd. convened a workshop at the National Institutes of Health on September 18-19, 2018. Participants included representatives from MAT testing laboratories, medical device manufacturers, the U.S. Food and Drug Administration's Center for Devices and Radiologic Health (CDRH), the U.S. Pharmacopeia, the International Organization for Standardization, and experts in the development of MAT protocols. Discussions covered industry experiences with the MAT, remaining challenges, and how CDRH's Medical Device Development Tools (MDDT) Program, which qualifies tools for use in evaluating medical devices to streamline device development and regulatory evaluation, could be a pathway to qualify the use of MAT in place of the rabbit pyrogen test and the limulus amebocyte lysate test for medical device testing. Workshop outcomes and follow-up activities are discussed.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"151-156"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38824550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extending the applicability domain of the human cell line activation test (h-CLAT).","authors":"Karsten R Mewes,&nbsp;Ursula Engels,&nbsp;Birgit Eicker,&nbsp;Dirk Petersohn","doi":"10.14573/altex.2001242","DOIUrl":"https://doi.org/10.14573/altex.2001242","url":null,"abstract":"<p><p>Cosmetic ingredients must be toxicologically assessed to determine their skin sensitizing potential. The in vitro human cell line activation test (h-CLAT; OECD TG 442E) addresses the activation of dermal dendritic cells by analyzing specific protein expression after exposure of THP-1 cells to the test chemical. According to the protocol, FITC-labeled antibodies are used for protein detection. However, some chemicals show strong autofluorescence at FITC-specific wavelengths so that antibody-specific signals cannot be distinguished appropriately from autofluorescence background. This leads to inconclusive or false-negative predictions. Alternative fluorochromes can be used if their equivalence with the FITC-labeled antibodies is proven. In the current paper we describe the results of a proficiency exercise, based on the proficiency chemicals listed in the guideline, with FITC-labeled antibodies as the benchmark and APC-labeled anti­bodies as an alternative detection system. APC emits fluorescence at longer wavelengths, thus avoiding interference in the FITC spectrum. Irrespective of the employed fluorochrome, all chemicals were classified correctly, and the EC150 and 200 values were in the same order of magnitude. Hence, the equivalence in performance of FITC- and APC-labeled antibodies was demonstrated, and the respective demand of the guideline was fulfilled. In a case study, we then tested a proprietary oxidative hair dye using both fluorochromes. Using APC-labeled antibodies, the hair dye was unambiguously identified as a sensitizer, whereas no classification could be made with the FITC-labeled antibodies. With APC, fluorescence interference can be circumvented and the applicability domain of the h-CLAT extended to include autofluorescent chemicals.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"95-110"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38230959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Limitations and uncertainties of acute fish toxicity assessments can be reduced using alternative methods.","authors":"Martin Paparella,&nbsp;Stefan Scholz,&nbsp;Scott Belanger,&nbsp;Thomas Braunbeck,&nbsp;Pascal Bicherel,&nbsp;Kristin Connors,&nbsp;Christopher Faßbender,&nbsp;Marlies Halder,&nbsp;Adam Lillicrap,&nbsp;Roman Liska,&nbsp;Kristin Schirmer,&nbsp;Gilly Stoddart,&nbsp;Paul Thomas,&nbsp;Susanne Walter-Rohde","doi":"10.14573/altex.2006051","DOIUrl":"https://doi.org/10.14573/altex.2006051","url":null,"abstract":"<p><p>Information about acute fish toxicity is routinely required in many jurisdictions for environmental risk assessment of chem­icals. This information is typically obtained using a 96-hour juvenile fish test for lethality according to OECD test guideline (TG) 203 or equivalent regional guidelines. However, TG 203 has never been validated using the criteria currently required for new test methods including alternative methods. Characterization of the practicality and validity of TG 203 is important to provide a benchmark for alternative methods. This contribution systematically summarizes the available knowledge on limitations and uncertainties of TG 203, based on methodological, statistical, and biological consider­ations. Uncertainties stem from the historic flexibility (e.g., use of a broad range of species) and constraints of the basic test design (e.g., no replication). Other sources of uncertainty arise from environmental safety extrapolation based on TG 203 data. Environmental extrapolation models, combined with data from alternative methods, including mechanistic indicators of toxicity, may provide at least the same level of environmental protection. Yet, most importantly, the 3R advan­tages of alternative methods allow a better standardization, characterization, and an improved basic study design. This can enhance data reliability and thus facilitate the comparison of chemical toxicity, as well as the environmental classifi­cations and prediction of no-effect concentrations of chemicals. Combined with the 3R gains and the potential for higher throughput, a reliable assessment of more chemicals can be achieved, leading to improved environmental protection.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"20-32"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38417800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrogen testing revisited on occasion of the 25th anniversary of the whole blood monocyte activation test.","authors":"Thomas Hartung","doi":"10.14573/altex.2101051","DOIUrl":"https://doi.org/10.14573/altex.2101051","url":null,"abstract":"<p><p>The whole blood pyrogen test invented 25 years ago, and its variant based on cryo-preserved blood one year later, brought momentum into the field of pyrogen testing, which, despite the broad application of the Limulus amebocyte lysate (LAL) assay, aka bacterial endotoxin test (BET), consumed several hundred thousand rabbits per year world-wide. The resulting international validation and lengthy acceptance and implementation process of what are called now monocyte activation tests (MATs) finally is impacting on animal numbers - at least in Europe - reducing them by more than 70% and counting. The author sees no reason for continuing any regulatory rabbit testing for pyrogens except the lack of acceptance of MATs in some regions of the world. The availability of MATs has opened also the discussion about the shortcomings of LAL/BET, namely its restriction to Gram-negative pyrogens, non-reflection of the potency of these in humans, interference and masking by many products, and animal welfare concerns for horseshoe crabs. The obvious advantages of MATs in all these respects should lead to a shift from LAL/BET to MATs. We are starting to see this for vac-cines and medical devices, but other areas like safety testing of blood transfusions, cell therapies and nanomaterials, and the assessment of air-borne pyrogens still need to grasp the opportunity provided by MATs. While the different MATs can jointly serve these needs, the whole blood MAT has some advantages as discussed here.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"3-19"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38824548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identifying, naming and documenting of test and tool compound stocks.","authors":"Marcel Leist","doi":"10.14573/altex.2012311","DOIUrl":"https://doi.org/10.14573/altex.2012311","url":null,"abstract":"<p><p>Handling of chemicals is an often-neglected area of test descriptions. Some important aspects are highlighted here, using methyl-phenyl-tetrahydropyridine (MPTP), ferrous sulfate (FeSO4·xH2O) and ciguatoxin as example compounds. These are used to provide some background on aspects of acid-base equilibria, redox state, crystal water, natural compound mixtures, and chemical naming systems. Also, solvents and impurities are addressed, for instance concerning their often high (millimolar range) concentrations in assay buffers and cell culture media. The discussion of these aspects calls for a more standardized preparation of test solutions and a more extensive disclosure of the procedure in publications; it also suggests more flexibility in data mining, as compounds with clearly different identifiers may have been used to produce highly similar or fully identical test conditions. While this short overview is not intended as definitive guidance, it does demand more active involvement of all test developers and performers with these issues, and it calls for more transparent information disclosure concerning the preparation and use of test and control chemical solutions.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"177-182"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38824552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tradition, not science, is the basis of animal model selection in translational and applied research.","authors":"Désirée H Veening-Griffioen,&nbsp;Guilherme S Ferreira,&nbsp;Wouter P C Boon,&nbsp;Christine C Gispen-de Wied,&nbsp;Huub Schellekens,&nbsp;Ellen H M Moors,&nbsp;Peter J K Van Meer","doi":"10.14573/altex.2003301","DOIUrl":"https://doi.org/10.14573/altex.2003301","url":null,"abstract":"<p><p>National and international laws and regulations exist to protect animals used for scientific purposes in translational and applied research, which includes drug development. However, multiple animal models are available for each disease. We evaluated the argumentation behind the selection of a specific animal model using thematic content analysis in project applications issued in 2017-2019 in the Netherlands. In total, 125 animal models for translational and applied research from 110 project applications were assessed. Explanations to select a specific model included: the model’s availability (79%); the availability of expertise (62%); and the model showing similar disease pathology/symptoms (59%) to humans. Therefore, current selection of a specific animal model seems to be based on tradition rather than its potential predictive value for clinical outcome. The applicants’ explanations for the implementation of the 3R prin­ciples (replacement, reduction and refinement) as to the animal model were unspecific. Replacement was achieved by using data from prior in vitro studies, reduction by optimal experimental design and statistics, and refinement by reducing discomfort. Additionally, due to the stated need for a test model with high complexity (47%) and intactness (30%), the full replacement of animal models with alternative (non-live animal) approaches was thought unachievable. Without a clear, systematic and transparent justification for the selection of a specific animal model, the likelihood of poorly trans­latable research remains. It is not only up to the researcher to demonstrate this, as ethical committees and funding bodies can provide positive stimuli to drive this change.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"49-62"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38090500","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Grouping of UVCB substances with new approach methodologies (NAMs) data.","authors":"John S House,&nbsp;Fabian A Grimm,&nbsp;William D Klaren,&nbsp;Abigail Dalzell,&nbsp;Srikeerthana Kuchi,&nbsp;Shu-Dong Zhang,&nbsp;Klaus Lenz,&nbsp;Peter J Boogaard,&nbsp;Hans B Ketelslegers,&nbsp;Timothy W Gant,&nbsp;Fred A Wright,&nbsp;Ivan Rusyn","doi":"10.14573/altex.2006262","DOIUrl":"https://doi.org/10.14573/altex.2006262","url":null,"abstract":"<p><p>One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (unknown or variable composition, complex reaction products and biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, could be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data were used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of repre­sentative substances in each group for testing when needed, and to fill data gaps by read-across.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"123-137"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38513857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated screening for oxidative or methylation-induced DNA damage in human cells.","authors":"Matthias Mack,&nbsp;Katharina Schweinlin,&nbsp;Nicola Mirsberger,&nbsp;Tabea Zubel,&nbsp;Alexander Bürkle","doi":"10.14573/altex.2001221","DOIUrl":"https://doi.org/10.14573/altex.2001221","url":null,"abstract":"<p><p>The assessment of genotoxicity upon exposure to chemical and environmental agents plays an important role in basic research as well as in pharmaceutical, chemical, cosmetic and food industry. Low sensitivity and lack of inter-laboratory comparability are considered problematic issues in genotoxicity testing. Moreover, commonly used mutagenicity assays lack information about early and specific genotoxic events.\u0000Previously, we developed an automated version of the “Fluorimetric detection of Alkaline DNA Unwinding” (FADU) assay as a high-throughput screening method for the detection of DNA strand breaks in living cells. Here, we report an enzyme-modified version of the cell-based FADU assay (emFADU) for the determination of oxidative and methylation lesions in cellular DNA. Our method is based on the use of formamidopyrimidine DNA glycosylase or human alkylad­enine DNA glycosylase for the detection of chemically-induced nucleobase modifications in lysates of immortalized cell lines, growing in suspension or as adherent cells, and in peripheral blood mononuclear cells. We could show that upon treatment with sub-cytotoxic doses of known genotoxins, oxidative and methylation lesions are readily detectable.\u0000This fast, inexpensive, and convenient method could be useful as a high-content screening approach for the sensitive and specific assessment of genotoxicity in human cells. Thus, when implemented in the early compound development in an industrial setting, the emFADU assay could help reduce the number of animals used for toxicity testing. Furthermore, as we established the method for different cell types, this new assay may provide an opportunity for population studies and/or mechanistic research into DNA repair pathways.</p>","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"63-72"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38153532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}