Chemical Research in Toxicology最新文献

{"title":"Quantitative Structure–Activity Relationship Models to Predict Cardiac Adverse Effects","authors":"Zhongyu Mou,&nbsp;Patra Volarath,&nbsp;Rebecca Racz,&nbsp;Kevin P. Cross,&nbsp;Mounika Girireddy,&nbsp;Suman Chakravarti and Lidiya Stavitskaya*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0018610.1021/acs.chemrestox.4c00186","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00186https://doi.org/10.1021/acs.chemrestox.4c00186","url":null,"abstract":"<p >Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1924–1933 1924–1933"},"PeriodicalIF":3.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.chemrestox.4c00186","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142843355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemical Composition of Aerosols from the E-Cigarette Vaping of Natural and Synthetic Cannabinoids","authors":"Nicholas E. Robertson,&nbsp;Jack Connolly,&nbsp;Nikolay Shevchenko,&nbsp;Mark Mascal,&nbsp;Kent E. Pinkerton,&nbsp;Sascha C. T. Nicklisch and Tran B. Nguyen*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0032610.1021/acs.chemrestox.4c00326","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00326https://doi.org/10.1021/acs.chemrestox.4c00326","url":null,"abstract":"<p >Vaping cannabinoids in electronic (e)-cigarette devices is rapidly increasing in popularity, particularly among adolescents, although the chemistry affecting the composition of the vape aerosol is not well understood. This work investigates the formation of aerosol mass, bioactive hydroxyquinones, and harmful or potentially harmful carbonyls from the e-cigarette vaping of natural and synthetic cannabinoids e-liquids in propylene glycol and vegetable glycerin (PG/VG) solvent at a 50 mg/mL concentration in a commercial fourth-generation vaping device. The following cannabinoids were studied: cannabidiol (CBD), 8,9-dihydrocannabidiol (H2CBD), 1,2,8,9-tetrahydrocannabidiol (H4CBD), cannabigerol (CBG), and cannabidiolic acid (CBDA). Quantification of analytes was performed using liquid chromatography coupled to accurate mass spectrometry. The addition of cannabinoids significantly increased aerosol and carbonyl formation compared with the PG/VG solvent alone. All cannabinoids in the study formed hydroxyquinones during vaping (up to ∼1% mass conversion) except for CBDA, which primarily decarboxylated to CBD. Hydroxyquinone formation increased and carbonyl formation decreased, with a decreasing number of double bonds among CBD and its synthetic analogues (H2CBD and H4CBD). During the vaping process, ∼3–6% of the cannabinoid mass can be observed as carbonyls under the study conditions. Oxidation of the terpene moiety on the cannabinoids is proposed as a major contributor to carbonyl formation. CBD produced significantly higher concentrations of formaldehyde, acetaldehyde, acrolein, diacetyl, and methylglyoxal compared with the other cannabinoid samples. CBG produced significantly higher levels of acetone, methacrolein, and methylglyoxal. Conversion of CBD to tetrahydrocannabinol (THC) was not observed under the study conditions. The chemical mechanism basis for these observations is discussed. Compared with other modalities of use for CBD and other cannabinoids, vaping has the potential to adversely impact human health by producing harmful products during the heated aerosolization process.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1965–1975 1965–1975"},"PeriodicalIF":3.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142843356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Melatonin Vapes Contain Potential Contaminants and Alter the Human Bronchial Epithelial Transcriptome","authors":"Kevin D. Schichlein,&nbsp;Hye-Young H. Kim,&nbsp;Charlotte A. Love,&nbsp;Tara N. Guhr Lee,&nbsp;Charles R. Esther Jr.,&nbsp;Ned A. Porter,&nbsp;Meghan E. Rebuli,&nbsp;Brandie M. Ehrmann,&nbsp;Phillip W. Clapp and Ilona Jaspers*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0029510.1021/acs.chemrestox.4c00295","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00295https://doi.org/10.1021/acs.chemrestox.4c00295","url":null,"abstract":"<p >Melatonin vaping products, touted for their faster absorption than oral melatonin supplements, have been gaining popularity among adolescents as sleep aid. Here, we elucidated the response of human bronchial epithelial cells (hBECs) to high levels of melatonin from vaped aerosols, investigated the uptake of melatonin by hBECs <i>in vitro</i>, and characterized the chemical composition of three commercially available melatonin vapes. Melatonin vape exposure decreased the secretion of chemokines and produced an immunosuppressive gene expression signature. The tested devices contained potential contaminants, including pharmaceuticals and industrial chemicals. Further investigation is needed for melatonin vapes to determine their local and systemic toxicity.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 12","pages":"1919–1923 1919–1923"},"PeriodicalIF":3.7,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142843013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell Painting and Chemical Structure Read-Across Can Complement Each Other for Rat Acute Oral Toxicity Prediction in Chemical Early Derisking","authors":"Fabrice Camilleri,&nbsp;Joanna M. Wenda,&nbsp;Claire Pecoraro-Mercier,&nbsp;Jean-Paul Comet and David Rouquié*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0016910.1021/acs.chemrestox.4c00169","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00169https://doi.org/10.1021/acs.chemrestox.4c00169","url":null,"abstract":"<p >Early derisking decisions in the development of new chemical compounds enable the identification of novel chemical candidates with improved safety profiles. In vivo studies are traditionally conducted in the early assessment of acute oral toxicity of crop protection products to avoid compounds, which are considered “very acutely toxic”, with an in vivo lethal dose of 50% (LD50) ≤ 60 mg/kg body weight. Those studies are lengthy and costly and raise ethical concerns, catalyzing the use of nonanimal alternatives. The objective of our analysis was to assess the predictive efficacy of read-across approaches for acute oral toxicity in rats, comparing the use of chemical structure information, in vitro biological data derived from the Cell Painting profiling assay on U2OS cells, or the combination of both. Our findings indicate that the classification of compounds as very acute oral toxic (LD50 ≤ 60 mg/kg) or not is possible using a read-across approach, with chemical structure information, morphological profiles, or a combination of both. When classifying compounds structurally similar to those in the training set, the chemical structure was more predictive (balanced accuracy of 0.82). Conversely, when the compounds to be classified were structurally different from those in the training set, the morphological profiles were more predictive (balanced accuracy of 0.72). Combining the two models allowed for the classification of compounds structurally similar to those in the training set to slightly improve the predictions (balanced accuracy of 0.85).</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1851–1866 1851–1866"},"PeriodicalIF":3.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Intercalator Ethidium Bromide Generates Covalent Adducts at Apurinic/Apyrimidinic Sites in DNA","authors":"Tanhaul Islam,&nbsp;Saosan Binth Md Amin and Kent S. Gates*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0037810.1021/acs.chemrestox.4c00378","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00378https://doi.org/10.1021/acs.chemrestox.4c00378","url":null,"abstract":"<p >Ethidium bromide was first described as a DNA intercalator 60 years ago and, over the ensuing years, may be the most widely used fluorescent DNA stain in molecular biology, biochemistry, and histology. Noncovalent DNA binding by ethidium has been well characterized, but to date, there have been no reports of covalent DNA adduct formation by ethidium bromide. This report describes the characterization of covalent adducts generated by the reaction of ethidium with apurinic/apyrimidinic (AP) sites in DNA. Adduct formation proceeds via the reaction of the amino group(s) on ethidium with the ring-opened aldehyde residue of the AP site in DNA to yield an imine. Ethidium-AP adducts may form under a variety of circumstances due to the ubiquitous occurrence of AP sites in cellular and synthetic DNA.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1911–1917 1911–1917"},"PeriodicalIF":3.7,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Dysfunction in Environmental Toxicology: Mechanisms, Impacts, and Health Implications","authors":"Mingyang Zuo,&nbsp;Mingqi Ye,&nbsp;Haofeng Lin,&nbsp;Shicheng Liao,&nbsp;Xiumei Xing,&nbsp;Jianjun Liu,&nbsp;Desheng Wu,&nbsp;Zhenlie Huang* and Xiaohu Ren*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0032810.1021/acs.chemrestox.4c00328","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00328https://doi.org/10.1021/acs.chemrestox.4c00328","url":null,"abstract":"<p >Mitochondria, pivotal to cellular metabolism, serve as the primary sources of biological energy and are key regulators of intracellular calcium ion storage, crucial for maintaining cellular calcium homeostasis. Dysfunction in these organelles impairs ATP synthesis, diminishing cellular functionality. Emerging evidence implicates mitochondrial dysfunction in the etiology and progression of diverse diseases. Environmental factors that induce mitochondrial dysregulation raise significant public health concerns, necessitating a nuanced comprehension and classification of mitochondrial-related hazards. This review systematically adopts a toxicological perspective to illuminate the biological functions of mitochondria, offering a comprehensive exploration of how toxicants instigate mitochondrial dysfunction. It delves into the disruption of energy metabolism, the initiation of mitochondrial fragility and autophagy, and the induction of mutations in mitochondrial DNA by mutagens. The overarching objective is to enhance our understanding of the repercussions of mitochondrial damage on human health.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1794–1806 1794–1806"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Practical Aspects of Flavin-Containing Monooxygenase-Mediated Metabolism","authors":"John R. Cashman*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0031610.1021/acs.chemrestox.4c00316","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00316https://doi.org/10.1021/acs.chemrestox.4c00316","url":null,"abstract":"<p >Hepatic flavin-containing monooxygenase 3 (FMO3) is arguably the most important FMO in humans from the standpoint of drug metabolism. Recently, adult hepatic FMO3 has been linked to several conditions including cardiometabolic diseases, aging, obesity, and atherosclerosis in small animals. Despite the importance of FMO3 in drug and chemical metabolism, relative to cytochrome P-450 (CYP), fewer studies have been published describing drug and chemical metabolism. This may be due to the properties of human hepatic FMO3. For example, FMO3 is thermally labile, and often methods reported in the study of human hepatic FMO3 are not optimal. Herein, I describe some practical aspects for studying human hepatic FMO3 and other FMOs.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1776–1793 1776–1793"},"PeriodicalIF":3.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deploying Validated Mass Spectrometry for Frontline Detection and Treatment of Human Poisoning by Long-Acting Anticoagulant Rodenticides","authors":"Richard B. van Breemen*,&nbsp;Bianca Flores,&nbsp;Israel Rubinstein and Douglas L. Feinstein,&nbsp;","doi":"10.1021/acs.chemrestox.4c0034410.1021/acs.chemrestox.4c00344","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00344https://doi.org/10.1021/acs.chemrestox.4c00344","url":null,"abstract":"<p >Derived from the same natural anticoagulant as warfarin (dicoumarol), long-acting anticoagulant rodenticides (LAARs) or superwarfarins have much longer half-lives in human blood than warfarin (weeks instead of hours) and are more potent inhibitors of the same enzyme, vitamin K epoxide reductase component 1. While used effectively worldwide as rodenticides, LAARs can elicit severe, protracted, life-threatening coagulopathy in humans at blood concentrations &gt;10 ng/mL leading to numerous accidental and intentional poisonings annually. To facilitate timely identification and quantitative analysis of LAARs in patients presenting unexplained severe, protracted, life-threatening coagulopathy, several analytical methods have been developed, all of which are based on electrospray liquid chromatography–mass spectrometry (LC–MS). In this perspective, we evaluated and compared these LC–MS methods in terms of validation, simultaneous detection of multiple LAARs, measurement of individual stereoisomers, and clinical applications.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1769–1775 1769–1775"},"PeriodicalIF":3.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142671847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and Enzyme Kinetic Characterization of Novel CYP2D6 Variants","authors":"Yun-shan Zhong,&nbsp;Qi-hui Kong,&nbsp;Jing Wang,&nbsp;Feng Ye,&nbsp;Xin-yue Li,&nbsp;Li-qun Zhang,&nbsp;Da-peng Dai,&nbsp;Guo-xin Hu,&nbsp;Jian-ping Cai*,&nbsp;Jian-chang Qian* and Fu-sui Ji*,&nbsp;","doi":"10.1021/acs.chemrestox.4c0029810.1021/acs.chemrestox.4c00298","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00298https://doi.org/10.1021/acs.chemrestox.4c00298","url":null,"abstract":"<p >Cytochrome P450 2D6 (CYP2D6) exhibits rich genetic polymorphism, and functional changes caused by variations are the key reasons for differences in substrate drug systemic exposure. Discovering novel variants and defining their enzymatic kinetic characteristics can contribute to the personalized application of drugs. In this study, a data chain of variant-function-structure was established through population-based sequencing, baculovirus insect cell expression, <i>in vitro</i> enzymatic incubation, and ultrahigh performance liquid chromatography tandem mass spectrometry. Results revealed nine novel missense mutations in the exonic regions. After the corresponding microsomes were obtained, the kinetics of the variants were investigated using dextromethorphan as a probe substrate. It was found that the activities of CYP2D6.2, 10, 17, 35, 65, R28G, T76M, and E215K were significantly reduced, while D301V almost led to loss of enzyme function. Additionally, the relative clearance rate of R25Q was significantly increased. From the molecular structure perspective, the mutation sites are distributed outside the dextromethorphan binding pocket, suggesting that they primarily influence CYP2D6 activity via allosteric modulation. These research findings provide fundamental data for the precise application of CYP2D6 substrate drugs.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":"37 11","pages":"1903–1910 1903–1910"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142665721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective HLA Class II Allele-Restricted Activation of Atabecestat Metabolite-Specific Human T-Cells.","authors":"Megan Ford, Paul J Thomson, Jan Snoeys, Xiaoli Meng, Dean J Naisbitt","doi":"10.1021/acs.chemrestox.4c00262","DOIUrl":"10.1021/acs.chemrestox.4c00262","url":null,"abstract":"<p><p>Elevations in hepatic enzymes were detected in several trial patients exposed to the Alzheimer's drug atabecestat, which resulted in termination of the drug development program. Characterization of hepatic T-lymphocyte infiltrates and diaminothiazine (DIAT) metabolite-responsive, human leukocyte antigen (HLA)-DR-restricted, CD4+ T-lymphocytes in the blood of patients confirmed an immune pathogenesis. Patients with immune-mediated liver injury expressed a restricted panel of HLA-DRB1 alleles including HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01. Thus, the objectives of this study were to (i) generate DIAT-responsive T-cell clones from HLA-genotyped drug-naive donors, (ii) characterize pathways of DIAT-specific T-cell activation, and (iii) assess HLA allele restriction of the DIAT-specific T-cell response. Sixteen drug-naive donors expressing the HLA-DR molecules outlined above were recruited, and T-cell clones were generated. Cellular phenotype, function, and HLA-allele restriction were assessed using culture assays. Peptides displayed by HLA class II molecules in the presence and absence of atabecestat were analyzed by mass spectrometry. Several DIAT-responsive CD4+ clones, displaying no reactivity toward the parent drug, were successfully generated from donors expressing HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 but not from other donors expressing other HLA-DRB1 alleles. T-cell clones were activated following direct binding of DIAT to HLA-DR proteins expressed on the surface of antigen presenting cells. DIAT binding did not alter the HLA-DRB1 peptide binding repertoire, indicative of a binding interaction with the HLA-associated peptide rather than with the HLA protein itself. DIAT-specific T-cell responses displayed HLA-DRB1*12:01, HLA-DRB1*13:02, and HLA-DRB1*15:01 restriction. These data demonstrate that DIAT displays a degree of selectivity toward HLA protein and associated peptides, with expression of certain alleles increasing and that of others decreasing, the likelihood that a drug-specific T-cell response develops.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1712-1727"},"PeriodicalIF":3.7,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11497358/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142337331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}