IF 5.6

ALTEX Pub Date : 2021-01-01 DOI: 10.14573/altex.2012311

Marcel Leist

引用次数: 1

Tradition, not science, is the basis of animal model selection in translational and applied research. 在转化和应用研究中，选择动物模型的基础是传统，而不是科学。

IF 5.6

ALTEX Pub Date : 2021-01-01 Epub Date: 2020-06-22 DOI: 10.14573/altex.2003301

Désirée H Veening-Griffioen, Guilherme S Ferreira, Wouter P C Boon, Christine C Gispen-de Wied, Huub Schellekens, Ellen H M Moors, Peter J K Van Meer

{"title":"Tradition, not science, is the basis of animal model selection in translational and applied research.","authors":"Désirée H Veening-Griffioen, Guilherme S Ferreira, Wouter P C Boon, Christine C Gispen-de Wied, Huub Schellekens, Ellen H M Moors, Peter J K Van Meer","doi":"10.14573/altex.2003301","DOIUrl":"https://doi.org/10.14573/altex.2003301","url":null,"abstract":"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.","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}

引用次数: 11

Grouping of UVCB substances with new approach methodologies (NAMs) data. 用新方法方法(NAMs)数据对UVCB物质进行分组。

IF 5.6

ALTEX Pub Date : 2021-01-01 Epub Date: 2020-10-09 DOI: 10.14573/altex.2006262

John S House, Fabian A Grimm, William D Klaren, Abigail Dalzell, Srikeerthana Kuchi, Shu-Dong Zhang, Klaus Lenz, Peter J Boogaard, Hans B Ketelslegers, Timothy W Gant, Fred A Wright, Ivan Rusyn

{"title":"Grouping of UVCB substances with new approach methodologies (NAMs) data.","authors":"John S House, Fabian A Grimm, William D Klaren, Abigail Dalzell, Srikeerthana Kuchi, Shu-Dong Zhang, Klaus Lenz, Peter J Boogaard, Hans B Ketelslegers, Timothy W Gant, Fred A Wright, Ivan Rusyn","doi":"10.14573/altex.2006262","DOIUrl":"https://doi.org/10.14573/altex.2006262","url":null,"abstract":"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.","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}

引用次数: 17

Automated screening for oxidative or methylation-induced DNA damage in human cells. 人类细胞中氧化或甲基化诱导的DNA损伤的自动筛选。

IF 5.6

ALTEX Pub Date : 2021-01-01 Epub Date: 2020-07-13 DOI: 10.14573/altex.2001221

Matthias Mack, Katharina Schweinlin, Nicola Mirsberger, Tabea Zubel, Alexander Bürkle

{"title":"Automated screening for oxidative or methylation-induced DNA damage in human cells.","authors":"Matthias Mack, Katharina Schweinlin, Nicola Mirsberger, Tabea Zubel, Alexander Bürkle","doi":"10.14573/altex.2001221","DOIUrl":"https://doi.org/10.14573/altex.2001221","url":null,"abstract":"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.","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}

引用次数: 5

Examination of microcystin neurotoxicity using central and peripheral human neurons. 微囊藻毒素对人中枢和外周神经元的神经毒性检测。

IF 5.6

ALTEX Pub Date : 2021-01-01 Epub Date: 2020-06-23 DOI: 10.14573/altex.2003182

Stefanie Klima, Ilinca Suciu, Lisa Hoelting, Simon Gutbier, Tanja Waldmann, Daniel R Dietrich, Marcel Leist

{"title":"Examination of microcystin neurotoxicity using central and peripheral human neurons.","authors":"Stefanie Klima, Ilinca Suciu, Lisa Hoelting, Simon Gutbier, Tanja Waldmann, Daniel R Dietrich, Marcel Leist","doi":"10.14573/altex.2003182","DOIUrl":"https://doi.org/10.14573/altex.2003182","url":null,"abstract":"Microcystins (MC) are a group of cyanobacterial toxins that comprises MC-LF and other cyclic heptapeptides, best known as potent hepatotoxicants. Cell culture and epidemiological studies suggest that MC might also affect the nervous system when there is systemic exposure, e.g., via drinking water or food. We asked whether in vitro studies with human neurons could provide estimates on the neurotoxicity hazard of MC-LF. First, we used LUHMES neurons, a well-established test system for neurotoxicants and neuropathological processes. These central nervous system cells express OATP1A2, a presumed carrier of MC-LF, and we observed selective neurite toxicity in the μM range (EC20 = 3.3 μM ≈ 3.3 μg/mL). Transcriptome changes pointed towards attenuated cell maintenance and biosynthetic processes. Prolonged exposure for up to four days did not increase toxicity. As a second model, we used human dorsal root ganglia-like neurons. These peripheral nervous system cells represent parts of the nervous system not protected by the blood-brain barrier in humans. Toxicity was observed in a similar concentration range (EC20 = 7.4 μM). We conclude that MC-LF poses a potential neurotoxic hazard in humans. The adverse effect concentrations observed here were orders of magnitude higher than those presumed to be encountered after normal nutritional or environmental exposure. However, the low μM concentrations found to be toxic are close to levels that may be reached after very excessive algae supplement intake.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"73-81"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38090499","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}

引用次数: 1

Measuring endogenous corticosterone in laboratory mice - a mapping review, meta-analysis, and open source database. 测量实验室小鼠体内的内源性皮质酮——一个图谱回顾、荟萃分析和开源数据库。

IF 5.6

ALTEX Pub Date : 2021-01-01 Epub Date: 2020-10-06 DOI: 10.14573/altex.2004221

Stevie Van der Mierden, Cathalijn H C Leenaars, Erin C Boyle, Florenza L Ripoli, Peter Gass, Mattea Durst, Vivian C Goerlich-Jansson, Paulin Jirkof, Lydia M Keubler, Steven R Talbot, Anne Habedank, Lars Lewejohann, Rene H Tolba, André Bleich

{"title":"Measuring endogenous corticosterone in laboratory mice - a mapping review, meta-analysis, and open source database.","authors":"Stevie Van der Mierden, Cathalijn H C Leenaars, Erin C Boyle, Florenza L Ripoli, Peter Gass, Mattea Durst, Vivian C Goerlich-Jansson, Paulin Jirkof, Lydia M Keubler, Steven R Talbot, Anne Habedank, Lars Lewejohann, Rene H Tolba, André Bleich","doi":"10.14573/altex.2004221","DOIUrl":"https://doi.org/10.14573/altex.2004221","url":null,"abstract":"Evaluating stress in laboratory animals is a key principle in animal welfare. Measuring corticosterone is a common method to assess stress in laboratory mice. There are, however, numerous methods to measure glucocorticoids with differences in sample matrix (e.g., plasma, urine) and quantification techniques (e.g., enzyme immunoassay or radioimmunoassay). Here, the authors present a mapping review and a searchable database, giving a complete overview of all studies measuring endogenous corticosterone in mice up to February 2018. For each study, information was recorded regarding mouse strain and sex; corticosterone sample matrix and quantification technique; and whether the study covered the research theme animal welfare, neuroscience, stress, inflammation, or pain (the themes of specific interest in our consortium). Using all database entries for the year 2012, an exploratory meta-regression was performed to determine the effect of predictors on basal corticosterone concentrations. Seventy-five studies were included using the predictors sex, time-since-lights-on, sample matrix, quantification technique, age of the mice, and type of control. Sex, time-since-lights-on, and type of control significantly affected basal corticosterone concentrations. The resulting database can be used, inter alia, for preventing unnecessary duplication of experiments, identifying knowledge gaps, and standardizing or heterogenizing methodologies. These results will help plan more efficient and valid experiments in the future and can answer new questions in silico using meta-analyses.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"111-122"},"PeriodicalIF":5.6,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38610091","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}

引用次数: 6

Bottom-up physiologically-based biokinetic modelling as an alternative to animal testing. 自下而上的基于生理的生物动力学建模作为动物试验的替代方法。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2019-05-10 DOI: 10.14573/altex.1812051

James C Y Chan, Shawn P F Tan, Zee Upton, Eric C Y Chan

{"title":"Bottom-up physiologically-based biokinetic modelling as an alternative to animal testing.","authors":"James C Y Chan, Shawn P F Tan, Zee Upton, Eric C Y Chan","doi":"10.14573/altex.1812051","DOIUrl":"https://doi.org/10.14573/altex.1812051","url":null,"abstract":"There is a growing need for alternatives to animal testing to derive biokinetic data for evaluating both efficacy and safety of chemicals. One such alternative is bottom-up physiologically-based biokinetic (PBK) modeling which requires only in vitro data. The primary objective of this study is to develop and validate bottom-up PBK models of 3 HMG-CoA reductase inhibitors: rosuvastatin, fluvastatin and pitavastatin. Bottom-up PBK models were built using the Simcyp® Simulator by incorporating in vitro transporter and metabolism data (Vmax, Jmax, Km, CLint) obtained from the literature and proteomics-based scaling factors to account for differences in transporters expression between in vitro systems and in vivo organs. Simulations were performed for single intravenous, single oral and multiple oral dose of these chemicals. The results showed that our bottom-up models predicted systemic exposure (AUC0h-t), maximum plasma concentration (Cmax), plasma clearance and time to reach Cmax (Tmax) within two-fold of the observed data, with the exception of parameters associated with multiple oral pitavastatin dosing and single oral fluvastatin dosing. Additional middle-out simulations were performed using animal distribution data to inform tissue-to-plasma equilibrium distribution ratios for rosuvastatin and pitavastatin. This improved the predicted plasma-concentration time profiles but did not significantly alter the predicted biokinetic parameters. Our study demonstrates that quantitative proteomics-based mechanistic in vitro-to-in vivo extrapolation (IVIVE) could account for downregulation of transporters in culture and predict whole organ clearances without empirical scaling. Hence, bottom-up PBK modeling incorporating mechanistic IVIVE could be a viable alternative to animal testing in predicting human biokinetics.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"597-612"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37230375","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}

引用次数: 14

Retrospective review of anesthetic and analgesic regimens used in animal research proposals. 动物研究方案中使用的麻醉和镇痛方案的回顾性回顾。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-09-14 DOI: 10.14573/altex.1804011

Kathrin Herrmann, Paul Flecknell

{"title":"Retrospective review of anesthetic and analgesic regimens used in animal research proposals.","authors":"Kathrin Herrmann, Paul Flecknell","doi":"10.14573/altex.1804011","DOIUrl":"https://doi.org/10.14573/altex.1804011","url":null,"abstract":"Pain has a profound effect on an animal's wellbeing. In Germany, researchers using animals have been legally required since 1972 to reduce any possible pain, suffering, distress or lasting harm to an absolute minimum. To evaluate how these provisions have been implemented in practice, an assessment of refinements to experimental techniques was conducted by retrospectively reviewing 684 surgical interventions described in 506 animal research applications that were sent to the German competent authorities for approval in 2010. This paper focuses on the efficacy of proposed anesthesia and peri- and postoperative analgesia. Postoperative analgesia was not proposed for 30 % of surgeries. Following 10 % of procedures, animals were to be given pain relieving medication if the investigators decided this was necessary; however, structured assessments to detect pain were absent. Consequences of unalleviated pain and omission of pain assessment techniques are discussed, and some recommendations to improve anesthesia and analgesia are given. The findings of this review highlight the need for improvement, both to fulfil legal requirements and to improve animal welfare. To monitor compliance with animal welfare regulations, and ensure good veterinary and scientific practices, education and training needs to be intensified. Adherence to the items listed in the PREPARE and ARRIVE guidelines and the Gold Standard Publication checklist (GSPC) should become legally binding.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"65-80"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36495038","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}

引用次数: 32

A three-dimensional model to study human synovial pathology. 研究人类滑膜病理的三维模型。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-10-09 DOI: 10.14573/altex.1804161

Mathijs G A Broeren, Claire E J Waterborg, Renske Wiegertjes, Rogier M Thurlings, Marije I Koenders, Peter L E M Van Lent, Peter M Van der Kraan, Fons A J Van de Loo

{"title":"A three-dimensional model to study human synovial pathology.","authors":"Mathijs G A Broeren, Claire E J Waterborg, Renske Wiegertjes, Rogier M Thurlings, Marije I Koenders, Peter L E M Van Lent, Peter M Van der Kraan, Fons A J Van de Loo","doi":"10.14573/altex.1804161","DOIUrl":"https://doi.org/10.14573/altex.1804161","url":null,"abstract":"Therapeutic agents that are used by patients with rheumatic and musculoskeletal diseases were originally developed and tested in animal models, and although retrospective studies show a limited predictive value, it could be explained by the fact that there are no good in vitro alternatives. In this study, we developed a 3-dimensional synovial membrane model made of either human primary synovial cell suspensions or a mix of primary fibroblast-like synoviocytes and CD14+ mononuclear cells. We analyzed the composition of the mature micromasses by immunohistochemical staining and flow cytometry and show that the outer surface forms a lining layer consisting out of fibroblast-like and macrophage-like cells, reflecting the in vivo naïve synovial membrane. To recreate the affected synovial membrane in rheumatoid arthritis (RA), the micromasses were exposed to the pro-inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-α). This led to increased pro-inflammatory cytokine expression and production and to hyperplasia of the membrane. To recreate the synovial membrane in osteoarthritis (OA), the micromasses were exposed to Transforming Growth Factor Beta (TGF-β). This led to fibrosis-like changes of the membrane, including increased Alpha Smooth Muscle Actin and increased expression of fibrosis-related genes PLOD2 and COL1A1. Interestingly, the macrophages in the micromass showed phenotypic plasticity as prolonged TNF-α or TGF-β stimulation strongly reduced the occurrence of Cluster of Differentiation 163-positive M2-like macrophages. We showed the plasticity of the micromasses as a synovial model for studying RA and OA pathology and propose that the synovial lining micromass system can be a good alternative for testing drugs.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"18-28"},"PeriodicalIF":5.6,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36571791","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}

引用次数: 25

Zebrafish embryo and acute fish toxicity test show similar sensitivity for narcotic compounds. 斑马鱼胚胎毒性试验和急性鱼类毒性试验显示对麻醉性化合物具有相似的敏感性。

IF 5.6

ALTEX Pub Date : 2019-01-01 Epub Date: 2018-10-29 DOI: 10.14573/altex.1808101

Anita Birke, Stefan Scholz

引用次数: 8

ALTEX最新文献