Toxicology and applied pharmacology最新文献

{"title":"On the relationship between hERG inhibition and the magnitude of QTc prolongation: An in vitro to clinical translational analysis","authors":"","doi":"10.1016/j.taap.2024.117135","DOIUrl":"10.1016/j.taap.2024.117135","url":null,"abstract":"<div><div>Assessing the magnitude of QTc prolongation is crucial in drug development due to its association with Torsades de Pointes. Inhibition of the hERG channel, pivotal in cardiac repolarization, is a key factor in evaluating this risk. In this study, the relationship between hERG inhibition and QTc prolongation magnitude was investigated, with the aim to derive simple guidance on the required hERG margin to avoid a large (&gt;20 ms) QTc prolongation.</div></div><div><h3>Methods</h3><div>Data from literature and FDA sources were searched for compounds with hERG IC₅₀ values alongside clinical QTc data with paired plasma concentrations, or compounds demonstrating a clinical concentration-QTc relationship. Relationships between hERG inhibition, hERG IC₅₀ margin to unbound plasma C_max, and QTc prolongation magnitude were calculated.</div></div><div><h3>Results</h3><div>Analysis of 148 clinical QTc observations from 98 compounds revealed that compounds associated with QTc prolongation &gt;10 ms typically exhibited hERG margins of ≤33-fold, while those exceeding 20 ms were generally associated with margins of ≤24-fold. QTc increases above 10 ms were not observed at hERG margins &gt;100-fold. Based on 53 clinical concentration-QTc datasets, modest hERG inhibition levels of <strong>∼</strong>4–6 % correlated with a 10 ms QTc prolongation, while <strong>∼</strong>10–13 % inhibition corresponded to a 20 ms prolongation.</div></div><div><h3>Conclusions</h3><div>This study enhances understanding of the relationship between hERG inhibition and QTc prolongation magnitude, by conducting analysis across a wide range of 98 compounds. This information can be used to determine the optimal hERG margin, particularly for drug discovery projects with limited scope to completely design-out hERG activity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142561202","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":"Hepatotoxicity of N-nitrosodin-propylamine in larval zebrafish by upregulating the Wnt pathway","authors":"","doi":"10.1016/j.taap.2024.117132","DOIUrl":"10.1016/j.taap.2024.117132","url":null,"abstract":"<div><div>N-nitrosodin-propylamine is an organic compound mainly used in organic synthesis. As a typical pollutant, the accidental release of N-nitrosodin-propylamine may cause environmental pollution, especially water environment pollution. In the present study, we used the zebrafish model for the first time to evaluate the developmental toxicity of this drug in the liver. Zebrafish larvae fertilized at 72hpf showed a range of toxic responses after 72hpf exposure to the drug. These include increased mortality, delayed absorption of yolk sac nutrients, shorter body length, abnormal liver morphology, gene disruption, and altered expression of various indicators with increasing dose. Studies on the mechanism of toxicity showed that N-nitrosodin-propylamine exposure increased the level of oxidative stress, increased the level of apoptosis in hepatocytes, and up-regulated the transcriptional expression level of Wnt signaling pathway genes. Astaxanthin and IWR-1 can effectively save the liver toxicity in zebrafish caused by N-nitrosodin-propylamine. Our study showed that the drug exposure induced hepatotoxicity in zebrafish larvae through the up-regulation of Wnt signaling pathway, oxidative stress and apoptosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558867","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":"Ferritinophagy is involved in hexavalent chromium-induced ferroptosis in Sertoli cells","authors":"","doi":"10.1016/j.taap.2024.117139","DOIUrl":"10.1016/j.taap.2024.117139","url":null,"abstract":"<div><div>Hexavalent chromium [Cr(VI)] has significant adverse effects on the environment and human health, particularly on the male reproductive system. Previously, we observed ferroptosis and autophagy in rat testicular injury induced by Cr(VI). In the present study, we focused on the association between ferroptosis and autophagy in mouse Sertoli cells (TM4) exposed to concentrations of 2.5 μМ, 5 μМ, and 10 μМ Cr(VI). Cr(VI) exposure altered mitochondrial ultrastructure; increased intracellular iron, malondialdehyde, and reactive oxygen species (ROS) levels; decreased glutathione content; increased TfR1 protein expression; and decreased GPX4, FPN1, and SLC7A11 protein expression, ultimately resulting in ferroptosis. Additionally, we observed ferritinophagy, increased expression of BECLIN1, LC3B, and NCOA4, and decreased expression of FTH1 and P62. Inhibition of autophagy and ferritinophagy via 3-MA and small interfering RNA (siRNA)-mediated silencing of NCOA4 ameliorated changes in ferritinophagy- and ferroptosis-associated protein expression, and reduced ROS levels. Rats exposed to Cr(VI) exhibited atrophy of testicular seminiferous tubules, a reduction in germ and Sertoli cells, and the occurrence of ferritinophagy and ferroptosis in cells of the rat testes. These results indicate that ferroptosis, triggered by NCOA4-mediated ferritinophagy, is one of the mechanisms that contribute to Cr(VI)-induced damage in Sertoli cells.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565248","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":"Acute ammonia stress affects the immune response, oxidative stress, ammonia transport and detoxication in the hepatopancreas of freshwater mollusk Solenaia oleivora.","authors":"Ting Zhang, Dongpo Xu, Yanfeng Zhou, Xueyan Ma, Haibo Wen","doi":"10.1016/j.taap.2024.117138","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117138","url":null,"abstract":"<p><p>Ammonia is a common and major pollutant in aquatic systems. Excessive ammonia has toxic effects on hepatopancreas in aquatic animals. In this study, we investigated the toxic effects of acute ammonia (concentration: 10 mg/L; test duration: 48 h) stress on the hepatopancreas of a freshwater mollusk, Solenaia oleivora. Transcriptome analysis identified 3355 differentially expressed genes (DEGs), including 1432 up-regulated and 1923 down-regulated genes. Many DEGs were associated with immune and stress responses, including heat shock proteins, pattern recognition receptors, and lysozyme. In addition, some DEGs were related to ammonia transport and detoxification, such as aquaporins, K⁺channel, V-ATPase, cytochrome p450, glutathione transferase, and glutamine synthetase. Physiological analysis showed that ammonia stress increased the activities of antioxidant enzymes (superoxide dismutase and catalase) and non-specific immune enzymes (acid phosphatase) and the levels of liver injury markers (malonaldehyde, aspartate aminotransferase, and alanine transaminase). TdT-mediated dUTP nick-end labeling assay revealed that ammonia stress induced apoptosis in the hepatopancreas. These results indicated the toxic effects of ammonia on hepatopancreas in the immune response, oxidative stress, ammonia transport and detoxification of S. oleivora. Our findings will accumulate data on the toxic effects of ammonia on the hepatopancreas of aquatic animals.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558866","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":"Lonicerin protects pancreatic acinar cells from caerulein-induced apoptosis, inflammation, and ferroptosis by activating the SIRT1/GPX4 signaling pathway.","authors":"Dahuan Li, Chunyan Li, Simin Jiang, Tianzhong Wang, Chong Zhang, Zhao Zhu, Guoxiu Zhang, Bangjiang Fang","doi":"10.1016/j.taap.2024.117136","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117136","url":null,"abstract":"<p><p>Acute pancreatitis (AP) is a familiar emergency of digestive system characterized by pancreatic inflammation. Lonicerin (LCR) has been reported to exert anti-inflammatory and immunomodulatory characteristics in several inflammatory diseases. Nevertheless, its role and mechanism involved in AP are still unknown. This study was designed to explore the protective effect and potential mechanism of LCR in AP. In this study, LCR and ferrostatin-1 alleviated, but erastin aggravated caerulein (CAE) exposure-induced cytotoxicity and reduction of cell viability in AR42J cells. LCR exhibited a protective role in CAE-treated AR42J cells, as evidenced by alleviation of apoptosis, inflammation, and ferroptosis. Mechanistically, LCR decreased the phosphorylation level of nuclear factor-kappa B p65 and increased the levels of silent information regulator 1 (SIRT1) and glutathione peroxidase 4 (GPX4) in CAE-treated AR42J cells. Furthermore, functional rescue experiments manifested that knockdown of SIRT1 partially negated the inhibitory action of LCR against CAE-induced apoptosis, inflammation, and ferroptosis in AR42J cells. Overall, LCR mitigates apoptosis, inflammation, and ferroptosis in CAE-exposed AR42J cells, which is related to the activation of the SIRT1/GPX4 signaling pathway.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547640","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":"Synergistic polytherapy for the broad-spectrum treatment of chemically-induced seizures in rats.","authors":"Alex S Cornelissen, Roland M van den Berg, Steven D Klaassen, Jelle C de Koning, Jan P Langenberg, Liesbeth C M de Lange, Marloes J A Joosen","doi":"10.1016/j.taap.2024.117137","DOIUrl":"https://doi.org/10.1016/j.taap.2024.117137","url":null,"abstract":"<p><p>Chemically-induced seizures, as a result of exposure to a neurotoxic compound, present a serious health concern. Compounds can elicit seizure activity through disruption of neuronal signaling by neurotransmitters, either by mimicking, modulating or antagonizing their action at the receptor or interfering with their metabolism. Benzodiazepines, such as diazepam and midazolam, and barbiturates are the mainstay of treatment of seizures. However, chemically-induced seizures are often persistent, requiring repeated treatment and increased doses of anticonvulsants, which in turn may lead to severe adverse effects such as respiratory depression. Here, we investigated the potential of rational polytherapy consisting of the benzodiazepine midazolam and the selective a2-adrenergic agonist dexmedetomidine as an improved, generically applicable anticonvulsant treatment regimen. Therapeutic efficacy was evaluated against two experimental paradigm compounds that induce persistent seizures in rats, the rodenticide TETS and the nerve agent soman. Following exposure, both TETS and soman elicited profound seizure activity and convulsions, associated with substantial mortality. Treatment with midazolam or dexmedetomidine alone provided no or limited suppression of seizure activity and improvement of survival at 4 h. Polytherapy consisting of midazolam and dexmedetomidine showed excellent anticonvulsant efficacy. Even at low doses, polytherapy showed a profound effect that lasted for the duration of the experiment. Analysis of the dose-response relationships confirmed presence of synergy. Administration of polytherapy in non-exposed animals did not indicate aggravation of adverse effects on respiration or heart rate. Even though more research is needed for the translation to clinical use, polytherapy consisting of midazolam and dexmedetomidine shows promise for the broad-spectrum treatment of (chemically-induced) seizures in emergency situations.</p>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547641","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 mitigates vincristine-induced peripheral neuropathy by inhibiting TNF-α/astrocytes/microglial cells activation in the spinal cord of rats, while preserving vincristine's chemotherapeutic efficacy in lymphoma cells","authors":"","doi":"10.1016/j.taap.2024.117134","DOIUrl":"10.1016/j.taap.2024.117134","url":null,"abstract":"<div><div>Vincristine (VCR), an anti-tubulin chemotherapy agent, is known to cause peripheral and central nerve damage, inducing severe chemotherapy-induced peripheral neuropathy (CIPN). Although melatonin has been recently recognized for its potential anti-neuropathic effects, its efficacy in countering VCR-induced neuropathy remains unclear. This study examines the neuroprotective potential of melatonin against VCR-induced neuropathy using a rat model. Neuropathic pain was induced through 10 VCR injections (0.1 mg/kg/day i.p.), administered in two five-day cycles with a two-day break. Melatonin treatment started two days before VCR administration and continued daily throughout the experiment. Rats were assigned to five groups: control, VCR, and three melatonin-treated groups receiving VCR with melatonin (5, 10, or 20 mg/kg/day i.p.). We assessed mechanical (<em>von-Frey</em> and <em>Randall-Selitto tests</em>) and thermal (<em>hot-plate</em> and <em>tail-flick tests</em>) hyperalgesia, motor coordination (<em>rotarod test</em>), and sciatic nerve conduction velocity (NCV). Changes in body weight, spinal cord histopathology (H&amp;E), and proinflammatory markers (TNF-α, IL-1β, and IL-6), reactive astrocytes (GFAP) and microglial cells (IBA-1) were also assessed, as well as spinal cord degeneration (Nissl stain) and demyelination (LFB stain and MBP). Finally, the effect of melatonin on the cytotoxic activity of VCR against EL4 lymphoma cells was assessed using an MTT assay. Our results indicated that melatonin coadministration with VCR preserved spinal cord architecture, elevated nociceptive thresholds, improved motor coordination, enhanced NCV, and maintained normal body weight gain. Melatonin also reduced inflammation, decreased reactive astrocytes and microglia, and prevented neurodegeneration and demyelination in the spinal cord. Importantly, melatonin did not affect VCR's cytotoxic activity in cancer cells.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508637","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":"Structural determinants of parabens in inhibiting human and rat gonadal 3β-hydroxysteroid dehydrogenase","authors":"","doi":"10.1016/j.taap.2024.117133","DOIUrl":"10.1016/j.taap.2024.117133","url":null,"abstract":"<div><div>This study delved into the impacts of 10 parabens on the activity of human and rat gonadal 3β-hydroxysteroid dehydrogenase (3β-HSD) within human KGN cell and rat testicular microsomes, as well as on the secretion of progesterone in KGN cells and the inhibitory potency was compared between human and rats. Intriguingly, the outcomes revealed that ethyl, propyl, butyl, hexyl, heptyl, nonyl, phenyl, and benzyl parabens displayed varying IC₅₀ values for human 3β-HSD2, from 4.15 to 139.96 μM, demonstrating characteristics of mixed inhibitors. Notably, within KGN cells, all examined parabens, excluding nonyl and phenyl parabens, significantly inhibited progesterone secretion at 5–50 μM. In the case of rats, the IC₅₀ values for these parabens on gonadal 3β-HSD1 fluctuated between 7.15 and 110.76 μM, likewise functioning as mixed inhibitors. Through docking analysis, it was proposed that most parabens effectively bind to NAD⁺ and/or steroid binding site. Moreover, bivariate correlation analysis unveiled an inverse correlation between IC₅₀ values and structural characteristics such as LogP, molecular weight, heavy atom number, and carbon number within the alcohol moiety of parabens. 3D-QSAR elucidated pivotal regions, comprising hydrogen bond donor, hydrogen bond acceptor, and hydrophobic region, with the most potent inhibitor nonyl paraben engaging with all regions, while the weakest inhibitor ethyl paraben interacted with the regions except for the hydrophobic region. In conclusion, this investigation underscored the inhibitory effects imparted by several parabens on both human and rat gonadal 3β-HSD activity, with their inhibitory potency being modulated by aspects of hydrophobicity and carbon chain length.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508638","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":"In vitro pharmacologic profiling aids systemic toxicity assessment of chemicals","authors":"","doi":"10.1016/j.taap.2024.117131","DOIUrl":"10.1016/j.taap.2024.117131","url":null,"abstract":"<div><div>An adapted <em>in vitro</em> pharmacology profiling panel (APPP) was developed that included targets used in the pharmaceutical industry alongside additional targets whose cellular functions have been linked to systemic toxicities. This panel of 83 target assays was used to profile the activities of 129 cosmetic relevant chemicals with diverse chemical structures, physiochemical properties and cosmetic use types. Internal data consistency was proved robust, as evidenced by the reproducibility between single concentration and concentration-response data and showed good concordance with data reported in the ToxCast and drug excipient datasets. We discuss how the data can be analyzed and multiple potential contexts of use illustrated by case studies, alongside other new approach methodologies, to support cosmetic chemical risk assessments that do not require data from new animal studies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508639","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":"Intestinal ABC transporters: Influence on the metronomic cyclophosphamide-induced toxic effect in an obese mouse mammary cancer model","authors":"","doi":"10.1016/j.taap.2024.117130","DOIUrl":"10.1016/j.taap.2024.117130","url":null,"abstract":"<div><div>Metronomic chemotherapy (MCT) is a cancer therapeutic approach characterized by low dose drug chronic administration and limited or null toxicity. Obesity-induced metabolic alterations worsen cancer prognosis and influence the intestinal biochemical barrier, altering the Multidrug resistance-associated protein 2 (Mrp2) and Multidrug resistance protein-1 (Mdr-1), efflux pumps that transport chemotherapeutic drugs. Obesity and cancer are frequent co-morbidities; thus, our aim was to evaluate the effectiveness and toxicity of MCT with cyclophosphamide (Cy) in obese mice with metabolic alterations bearing a mammary adenocarcinoma. Simultaneously, the expression and activities of intestinal Mrp2 and Mdr-1 were assessed. CBi male mice, were fed with chow diet (C) or diet with 40 % of fat (HFD). After 16 weeks, metabolic alterations were confirmed by biochemical and morphological parameters. At that time-point, HFD group showed decreased expressions of <em>Mrp2</em> mRNA (53 %) as well as <em>Mdr-1a</em> and <em>Mdr-1b</em> (42 % and 59 %, respectively), compared to C (<em>P</em> &lt; 0.05). This result correlated with decreased intestinal Mrp2 and Mdr-1 efflux activities (64 % and 45 %, respectively), compared to C (P &lt; 0.05). Ultimately, mice were challenged with M-406 mammary adenocarcinoma; when the tumor was palpable, mice were distributed into 4 groups. The % inhibition of tumor growth with Cy (30 mg/kg/day) in C + Cy was higher than that of HFD + Cy (<em>P</em> = 0.052). Besides, it was observed a 21 % diminution in body weight and leukopenia in the HFD + Cy group. Conclusion: Obesity-induced metabolic alterations impair intestinal Mrp2 and Mdr-1 functions, bringing about increments in Cy absorption, leading to toxicity; in addition, the antitumor effectiveness of MCT decreased in obese animals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475441","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}