Altex-Alternatives To Animal Experimentation最新文献_第7页

Applications of microphysiological systems to disease models in the biopharmaceutical industry: Opportunities and challenges. 微生理系统在生物制药业疾病模型中的应用:机遇与挑战。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2204071

Onyi Irrechukwu, Ronnie Yeager, Rhiannon David, Jason Ekert, Anitha Saravanakumar, Colin K Choi

{"title":"Applications of microphysiological systems to disease models in the biopharmaceutical industry: Opportunities and challenges.","authors":"Onyi Irrechukwu, Ronnie Yeager, Rhiannon David, Jason Ekert, Anitha Saravanakumar, Colin K Choi","doi":"10.14573/altex.2204071","DOIUrl":"https://doi.org/10.14573/altex.2204071","url":null,"abstract":"Disease models enable researchers to investigate, test, and identify therapeutic targets that would alter the patients’ disease condition and improve quality of life. Advances in genetic alteration and analytical techniques have enabled rapid development of disease models using preclinical animals and cell cultures. However, success rates of drug development remain low due to limited recapitulation of clinical pathophysiology by these models. To resolve this challenge, the pharmaceutical industry has explored microphysiological system (MPS) disease models, which are complex in vitro systems that include but are not limited to organ-on-a-chip, organoids, spheroids, and 3D bioengineered tissues (e.g., 3D printing, hydrogels). Capable of integrating key in vivo properties, such as disease-relevant human cells, multi-cellularity/dimensionality of organs, and/or well-controlled physical and molecular cues, MPS disease models are being developed for a variety of indications. With on-going qualifications or validations for wide adoption within the pharmaceutical industry, MPS disease models hold exciting potential to enable in-depth investigation of in vivo pathophysiology and enhance drug discovery and development processes. To introduce the present status of MPS disease models, this paper describes notable examples in six disease areas: cancer, liver/kidney diseases, respiratory diseases/COVID-19, neurodegenerative diseases, gastrointestinal diseases, and select rare diseases. Additionally, we describe current technical limitations and provide recommendations for future development that would expand application opportunities within the pharmaceutical industry.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 3","pages":"485-518"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9843669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Intestinal in vitro transport assay combined with physiologically based kinetic modeling as a tool to predict bile acid levels in vivo_suppl2 肠道体外转运试验结合基于生理的动力学模型作为预测体内胆汁酸水平的工具2

2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2302011s2

Véronique de Bruijn

引用次数: 0

Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes_suppl2 利用人诱导多能干细胞衍生心肌细胞的高通量体外硅模型评估环境化学物质的促心律失常电位

2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2306231s2

Hsing-Chieh Lin

{"title":"Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes_suppl2","authors":"Hsing-Chieh Lin","doi":"10.14573/altex.2306231s2","DOIUrl":"https://doi.org/10.14573/altex.2306231s2","url":null,"abstract":"QT prolongation and the potentially fatal arrhythmia Torsades de Pointes are common causes for withdrawing or restricting drugs; however, little is known if environmental chemicals may have similar liabilities. Current in vitro-in silico models for testing proarrhythmic liabilities, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), provide an opportunity to address this data gap. These methods are still low- to medium-throughput and not suitable for testing the tens of thousands of chemicals in commerce. We hypothesized that combining high-throughput population-based in vitro testing in hiPSC-CMs with a fully in silico data analysis workflow can offer sensitive and specific predictions of proarrhythmic potential. We calibrated the model with a published hiPSC-CM dataset of drugs known to be positive or negative for proarrhythmia and tested its performance using internal cross-validation and external validation. Additionally, we used computational down-sampling to examine three study designs for hiPSC-CM data: one replicate of one donor, five replicates of one donor, and one replicate of a population of five donors. We found that the population of five donors had the best performance for predicting proarrhythmic potential. The resulting model was then applied to predict the proarrhythmic potential of environmental chemicals, additionally characterizing risk through margin of exposure (MOE) calculations. Out of over 900 environmental chemicals tested, over 150 were predicted to have proarrhythmic potential, but only seven chemicals have MOE < 1. We conclude that a high throughput in vitro-in silico approach using population-based hiPSC-CM testing provides a reasonable approach to screening environmental chemicals for proarrhythmic potential.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"8 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135445347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Women in Alternatives. 女性的选择。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2303211

Francesca Caloni, Isabella De Angelis, Laura Gribaldo, Tuula Heinonen, Helena Kandarova, Vivian Kral, Silvia Letasiova, Fenna Sillé, Lena Smirnova, Maria Pilar Vinardell, Thomas Hartung

引用次数: 0

Evaluation of 147 perfluoroalkyl substances for immunotoxic and other (patho)physiological activities through phenotypic screening of human primary cells. 通过对人类原代细胞进行表型筛选，评估 147 种全氟烷基物质的免疫毒性和其他（病理）生理活性。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 Epub Date: 2022-09-15 DOI: 10.14573/altex.2203041

Keith A Houck, Katie Paul Friedman, Madison Feshuk, Grace Patlewicz, Marci Smeltz, M Scott Clifton, Barbara A Wetmore, Sharlene Velichko, Antal Berenyi, Ellen L Berg

{"title":"Evaluation of 147 perfluoroalkyl substances for immunotoxic and other (patho)physiological activities through phenotypic screening of human primary cells.","authors":"Keith A Houck, Katie Paul Friedman, Madison Feshuk, Grace Patlewicz, Marci Smeltz, M Scott Clifton, Barbara A Wetmore, Sharlene Velichko, Antal Berenyi, Ellen L Berg","doi":"10.14573/altex.2203041","DOIUrl":"10.14573/altex.2203041","url":null,"abstract":"A structurally diverse set of 147 per- and polyfluoroalkyl substances (PFAS) was screened in a panel of 12 human primary cell systems by measuring 148 biomarkers relevant to (patho)physiological pathways to inform hypotheses about potential mechanistic effects of data-poor PFAS in human model systems. This analysis focused on immunosuppressive activity, which was previously reported as an in vivo effect of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS), by comparing PFAS responses to four pharmacological immunosuppressants. The PFOS response profile had little correlation with reference immunosuppressants, suggesting in vivo activity does not occur by similar mechanisms. The PFOA response profile did share features with the profile of dexamethasone, although some distinct features were lacking. Other PFAS, including 2,2,3,3-tetrafluoropropyl acrylate, demonstrated more similarity to the reference immunosuppressants but with additional activities not found in the reference immunosuppressive drugs. Correlation of PFAS profiles with a database of environmental chemical responses and pharmacological probes identified potential mechanisms of bioactivity for some PFAS, including responses similar to ubiquitin ligase inhibitors, deubiquitylating enzyme (DUB) inhibitors, and thioredoxin reductase inhibitors. Approximately 21% of the 147 PFAS with confirmed sample quality were bioactive at nominal testing concentrations in the 1-60 micromolar range in these human primary cell systems. These data provide new hypotheses for mechanisms of action for a subset of PFAS and may further aid in development of a PFAS categorization strategy useful in safety assessment.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 2","pages":"248–270"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10331698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10142207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Beyond Animal Testing Index: Benchmarking tool for a world beyond animal testing_suppl3 超越动物测试指数:超越动物测试世界的基准工具

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2304161s3

C. Krul

引用次数: 0

Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes_suppl1 利用人诱导多能干细胞衍生心肌细胞的高通量体外硅模型评估环境化学物质的促心律失常电位

2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2306231s1

Hsing-Chieh Lin

{"title":"Assessing proarrhythmic potential of environmental chemicals using a high throughput in vitro-in silico model with human induced pluripotent stem cell-derived cardiomyocytes_suppl1","authors":"Hsing-Chieh Lin","doi":"10.14573/altex.2306231s1","DOIUrl":"https://doi.org/10.14573/altex.2306231s1","url":null,"abstract":"QT prolongation and the potentially fatal arrhythmia Torsades de Pointes are common causes for withdrawing or restricting drugs; however, little is known if environmental chemicals may have similar liabilities. Current in vitro-in silico models for testing proarrhythmic liabilities, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), provide an opportunity to address this data gap. These methods are still low- to medium-throughput and not suitable for testing the tens of thousands of chemicals in commerce. We hypothesized that combining high-throughput population-based in vitro testing in hiPSC-CMs with a fully in silico data analysis workflow can offer sensitive and specific predictions of proarrhythmic potential. We calibrated the model with a published hiPSC-CM dataset of drugs known to be positive or negative for proarrhythmia and tested its performance using internal cross-validation and external validation. Additionally, we used computational down-sampling to examine three study designs for hiPSC-CM data: one replicate of one donor, five replicates of one donor, and one replicate of a population of five donors. We found that the population of five donors had the best performance for predicting proarrhythmic potential. The resulting model was then applied to predict the proarrhythmic potential of environmental chemicals, additionally characterizing risk through margin of exposure (MOE) calculations. Out of over 900 environmental chemicals tested, over 150 were predicted to have proarrhythmic potential, but only seven chemicals have MOE < 1. We conclude that a high throughput in vitro-in silico approach using population-based hiPSC-CM testing provides a reasonable approach to screening environmental chemicals for proarrhythmic potential.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135445354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Organoid intelligence (OI) - The ultimate functionality of a brain microphysiological system. 类器官智能(OI)——大脑微生理系统的终极功能。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2303261

Lena Smirnova, Itzy E Morales Pantoja, Thomas Hartung

{"title":"Organoid intelligence (OI) - The ultimate functionality of a brain microphysiological system.","authors":"Lena Smirnova, Itzy E Morales Pantoja, Thomas Hartung","doi":"10.14573/altex.2303261","DOIUrl":"https://doi.org/10.14573/altex.2303261","url":null,"abstract":"Understanding brain function remains challenging as work with human and animal models is complicated by compensatory mechanisms, while in vitro models have been too simple until now. With the advent of human stem cells and the bioengineering of brain microphysiological systems (MPS), understanding how both cognition and long-term memory arise is now coming into reach. We suggest combining cutting-edge AI with MPS research to spearhead organoid intelligence (OI) as synthetic biological intelligence. The vision is to realize cognitive functions in brain MPS and scale them to achieve relevant short- and long-term memory capabilities and basic information processing as the ultimate functional experimental models for neurodevelopment and neurological function and as cell-based assays for drug and chemical testing. By advancing the frontiers of biological computing, we aim to (a) create models of intelligence-in-a-dish to study the basis of human cognitive functions, (b) provide models to advance the search for toxicants contributing to neurological diseases and identify remedies for neurological maladies, and (c) achieve relevant biological computational capacities to complement traditional computing. Increased understanding of brain functionality, in some respects still superior to today's supercomputers, may allow to imitate this in neuromorphic computer architectures or might even open up biological computing to complement silicon computers. At the same time, this raises ethical questions such as where sentience and consciousness start and what the relationship between a stem cell donor and the respective OI system is. Such ethical discussions will be critical for the socially acceptable advance of brain organoid models of cognition.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 2","pages":"191-203"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9297063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Comparing translational success rates across medical research fields - A combined analysis of literature and clinical trial data. 比较医学研究领域的转化成功率——文献和临床试验数据的综合分析。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 Epub Date: 2023-05-05 DOI: 10.14573/altex.2208261

Gwen Van de Wall, Astrid Van Hattem, Joy Timmermans, Merel Ritskes-Hoitinga, André Bleich, Cathalijn Leenaars

{"title":"Comparing translational success rates across medical research fields - A combined analysis of literature and clinical trial data.","authors":"Gwen Van de Wall, Astrid Van Hattem, Joy Timmermans, Merel Ritskes-Hoitinga, André Bleich, Cathalijn Leenaars","doi":"10.14573/altex.2208261","DOIUrl":"10.14573/altex.2208261","url":null,"abstract":"Many interventions that show promising results in preclinical development do not pass clinical tests. Part of this may be explained by poor animal-to-human translation. Using animal models with low predictability for humans is neither ethical nor efficient. If translational success shows variation between medical research fields, analyses of common practices in these fields could identify factors contributing to successful translation. We assessed translational success rates in medical research fields using two approaches: through literature and clinical trial registers.\u0000Literature: We comprehensively searched PubMed for pharmacology, neuroscience, cancer research, animal models, clinical trials, and translation. After screening, 117 review papers were included in this scoping review. Translational success rates were not different within pharmacology (72%), neuroscience (62%), and cancer research (69%).\u0000Clinical trials: The fraction of phase-2 clinical trials with a positive outcome was used as a proxy (i.e., an indirect resemblance measure) for translational success. Trials were retrieved from the WHO trial register and categorized into medical research fields following the international classification of disease (ICD-10). Of the phase-2 trials analyzed, 65.2% were successful. Fields with the highest success rates were disorders of lipoprotein metabolism (86.0%) and epilepsy (85.0%). Fields with the lowest success rates were schizophrenia (45.4%) and pancreatic cancer (46.0%).\u0000Our combined analyses suggest relevant differences in success rates between medical research fields. Based on the clinical trials, comparisons of practice, e.g., between epilepsy and schizophrenia, might identify factors that influence translational success.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":" ","pages":"584-594"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9432821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 2

Comparison of piecewise structural equation modeling and Bayesian network for de novo construction of a quantitative adverse outcome pathway network. 分段结构方程模型与贝叶斯网络重新构建定量不良后果路径网络的比较。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2207113

Yang Cao, S Jannicke Moe, Riccardo De Bin, Knut Erik Tollefsen, You Song

{"title":"Comparison of piecewise structural equation modeling and Bayesian network for de novo construction of a quantitative adverse outcome pathway network.","authors":"Yang Cao, S Jannicke Moe, Riccardo De Bin, Knut Erik Tollefsen, You Song","doi":"10.14573/altex.2207113","DOIUrl":"https://doi.org/10.14573/altex.2207113","url":null,"abstract":"Quantitative adverse outcome pathway network (qAOPN) is gaining momentum due to its predictive nature, alignment with quantitative risk assessment, and great potential as a computational new approach methodology (NAM) to reduce laboratory animal tests. The present work aimed to demonstrate two advanced modeling approaches, piecewise structural equation modeling (PSEM) and Bayesian network (BN), for de novo qAOPN model construction based on routine ecotoxicological data. A previously published AOP network comprised of four linear AOPs linking excessive reactive oxygen species production to mortality in aquatic organisms was employed as a case study. The demonstrative case study intended to answer: Which linear AOP in the network contributed the most to the AO? Can any of the upstream KEs accurately predict the AO? What are the advantages and limitations of PSEM or BN in qAOPN development? The outcomes from the two approaches showed that both PSEM and BN are suitable for constructing a complex qAOPN based on limited experimental data. Besides quantification of response-response relationships, both approaches could identify the most influencing linear AOP in a complex network and evaluate the predictive ability of the AOP, albeit some discrepancies in predictive ability were identified for the two approaches using this specific dataset. The advantages and limitations of the two approaches for qAOPN construction are discussed in detail, and suggestions on optimal workflows of PSEM and BN are provided to guide future qAOPN development.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":"40 2","pages":"287-298"},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9255553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0