IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2022-01-17 DOI: 10.14573/altex.2107261

Nanette G Vrijenhoek, Matthias M Wehr, Steven J Kunnen, Lukas S Wijaya, Giulia Callegaro, Martijn J Moné, Sylvia E Escher, Bob Van de Water

{"title":"Application of high-throughput transcriptomics for mechanism-based biological read-across of short-chain carboxylic acid analogues of valproic acid.","authors":"Nanette G Vrijenhoek, Matthias M Wehr, Steven J Kunnen, Lukas S Wijaya, Giulia Callegaro, Martijn J Moné, Sylvia E Escher, Bob Van de Water","doi":"10.14573/altex.2107261","DOIUrl":"https://doi.org/10.14573/altex.2107261","url":null,"abstract":"Chemical read-across is commonly evaluated without specific knowledge of the biological mechanisms leading to observed adverse outcomes in vivo. Integrating data that indicate shared modes of action in humans will strengthen read-across cases. Here we studied transcriptomic responses of primary human hepatocytes (PHH) to a large panel of carboxylic acids to include detailed mode-of-action data as a proof-of-concept for read-across in risk assessment. In rodents, some carboxylic acids, including valproic acid (VPA), are known to cause hepatic steatosis, whereas others do not. We investigated transcriptomics responses of PHHs exposed for 24 h to 18 structurally different VPA analogues in a concentration range to determine biological similarity in relation to in vivo steatotic potential. Using a targeted high-throughput screening assay, we assessed the differential expression of ~3,000 genes covering relevant biological pathways. Differentially expressed gene analysis revealed differences in potency of carboxylic acids, and expression patterns were highly similar for structurally similar compounds. Strong clustering occurred for steatosis-positive versus steatosis-negative carboxylic acids. To quantitatively define biological read-across, we combined pathway analysis and weighted gene co-expression network analysis. Active carboxylic acids displayed high similarity in gene network modulation. Importantly, free fatty acid synthesis modulation and stress pathway responses are affected by active carboxylic acids, providing coherent mechanistic underpinning for our findings. Our work shows that transcriptomic analysis of cultured human hepatocytes can reinforce the prediction of liver injury outcome based on quantitative and mechanistic biological data and support its application in read-across.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"207–220"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39830262","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: 4

The nearest neighbor nuclei method to objectify analysis of pertussis toxin-induced clustering. 用最近邻核法客观分析百日咳毒素致聚类。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2021-10-15 DOI: 10.14573/altex.2012171

Marieke E Hoonakker, Ed Remarque, Jennifer Veth, Arjen Sloots, Jeffrey J Bajramovic

{"title":"The nearest neighbor nuclei method to objectify analysis of pertussis toxin-induced clustering.","authors":"Marieke E Hoonakker, Ed Remarque, Jennifer Veth, Arjen Sloots, Jeffrey J Bajramovic","doi":"10.14573/altex.2012171","DOIUrl":"https://doi.org/10.14573/altex.2012171","url":null,"abstract":"The in vivo histamine sensitization test (HIST) has historically been performed to guarantee the safety of acellular pertussis vaccine batches. Non-compliance of batches is primarily associated with the presence of low levels of pertussis toxin (PTx). Because of ethical, standardization and scientific reasons, a variety of alternative in vitro approaches have been studied to replace the lethal HIST. A broadly applied and partially accepted method is the CHO cell clustering test, which is based on the clustered growth pattern of CHO cells when exposed to minute amounts of PTx. One of the major hurdles for global application of the CHO clustering test is the manual assessment of the clusters, which is associated with suboptimal reproducibility of test outcomes and is time-consuming. Here, various parameters of CHO cell nuclei were evaluated in search for a reliable, objective read-out parameter. We demonstrate that the distance between each nucleus and its nearest neighbor (3N method) is the most suitable parameter to assess clustered cell growth. This method detects 2.8 mIU PTx/mL and thereby complies with the requirement set for the sensitivity of the CHO clustering test based on visual reading. In commercial acellular pertussis vaccines spiked with PTx, the method detects 45 mIU/mL PTx, which is substantially lower than the 181-725 mIU/mL PTx detected by visual interpretation. The 3N method thus allows objective and sensitive assessment of CHO clustering and thereby encourages broad and global implementation of the in vitro test as an alternative to the HIST.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"140-148"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39525187","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

In vitro models of the canine digestive tract as an alternative to in vivo assays: Advances and current challenges. 犬消化道的体外模型作为体内试验的替代:进展和当前的挑战。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2022-01-13 DOI: 10.14573/altex.2109011

Charlotte Deschamps, Sylvain Denis, Delphine Humbert, Jürgen Zentek, Nathalie Priymenko, Emmanuelle Apper, Stéphanie Blanquet-Diot

{"title":"In vitro models of the canine digestive tract as an alternative to in vivo assays: Advances and current challenges.","authors":"Charlotte Deschamps, Sylvain Denis, Delphine Humbert, Jürgen Zentek, Nathalie Priymenko, Emmanuelle Apper, Stéphanie Blanquet-Diot","doi":"10.14573/altex.2109011","DOIUrl":"https://doi.org/10.14573/altex.2109011","url":null,"abstract":"Dogs occupy a full place in the family, and their well-being is of paramount importance to their owners. Digestion, a complex process involving physicochemical, mechanical, and microbial parameters, plays a central role in maintaining canine health. As in vivo studies in dogs are increasingly restricted by ethical, regulatory, societal, and cost pressures, an alternative option is the use of in vitro models simulating the different compartments of the canine gastrointestinal tract. This review introduces digestion and gut microbiota as key factors in dog nutrition and health under both healthy and diseased conditions (obesity and inflammatory bowel disease) and highlights similarities and differences between the human and canine digestive tract and processes. We provide the first in-depth description of currently available models of the canine digestive tract, discuss technical and scientific challenges that need to be addressed, and introduce potential applications of in vitro gut models in the food and veterinary fields. Even if the development of some in vitro models is still limited by a lack of in vivo data in dogs that is necessary for relevant configuration and validation, translation of long-term expertise on human in vitro gut models to dogs opens avenues for model optimization and adaptation to specific canine digestive conditions associated with various dog ages, sizes, breeds and/or diets, in both physiological and diseased states.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"235–257"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39699983","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: 3

A high-throughput and highly automated genotoxicity screening assay. 一种高通量和高度自动化的遗传毒性筛选试验。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2021-09-28 DOI: 10.14573/altex.2102121

Renxiang Chen, Yun-Tien Lin, Albert J Fornace, Heng-Hong Li

{"title":"A high-throughput and highly automated genotoxicity screening assay.","authors":"Renxiang Chen, Yun-Tien Lin, Albert J Fornace, Heng-Hong Li","doi":"10.14573/altex.2102121","DOIUrl":"https://doi.org/10.14573/altex.2102121","url":null,"abstract":"The increasing number of compounds under development and chemicals in commerce that require safety assessments pose a serious challenge for regulatory agencies worldwide. In vitro screening using toxicogenomic biomarkers has been proposed as a first-tier screen in chemical assessment and has been endorsed internationally. We previously developed, evaluated, and validated an in vitro transcriptomic biomarker responsive to DNA damage-inducing (DDI) agents, namely TGx-DDI, for genotoxicity testing in human cells and demonstrated the feasibility of using TGx-DDI in a medium-throughput, cell-based genotoxicity testing system by implementing this biomarker with the Nanostring nCounter system. In this current study, we took advantage of Nanostring nCounter Plexset technology to develop a highly automated, multiplexed, and high-throughput genotoxicity testing assay, designated the TGx-DDI Plexset assay, which can increase the screening efficiency eight-fold compared to standard nCounter technology while decreasing the hands-on time. We demonstrate the high-throughput capability of this assay by eliminating concentration determination and RNA extraction steps without compromising the specificity and sensitivity of TGx-DDI. Thus, we propose that this simple, highly automated, multiplexed high-throughput pipeline can be widely used in chemical screening and assessment.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"71-81"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39491409","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: 3

Animal metrics: Tracking contributions of new approach methods to reduced animal use. 动物指标:追踪新方法对减少动物使用的贡献。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2021-10-22 DOI: 10.14573/altex.2107211

M Sue Marty, Amanda K Andrus, Katherine A Groff

{"title":"Animal metrics: Tracking contributions of new approach methods to reduced animal use.","authors":"M Sue Marty, Amanda K Andrus, Katherine A Groff","doi":"10.14573/altex.2107211","DOIUrl":"https://doi.org/10.14573/altex.2107211","url":null,"abstract":"Many companies and global regulatory programs have expressed the intent to move away from in vivo animal testing to new approach methods (NAMs) as part of product safety assessments. NAMs, which include non-animal approaches for testing and assessment – from computer-based modeling to in chemico or in vitro models – allow faster data generation with potentially greater relevance to humans while avoiding animal use. To monitor progress implementing NAMs, each organization first must define what is in scope, starting with the definition of “animal” (e.g., mammals, vertebrates) and applicable studies (e.g., animals used for “in-house” experiments, at contract research organizations, as part of environmental monitoring). Next, organizations must establish baseline animal use, including defined rules for inclusion/ exclusion of animals that ensure consistency in future assessments. Lastly, organizations must establish metrics for animal savings based on the utility of NAM data. This paper presents one approach to establish “animal use” metrics in a toxicology program at The Dow Chemical Company. The premise of our program is that most NAM information has value for animal savings, but the value depends on how data are used (e.g., research and development, screening, or regulatory requirements) and the level of certainty for internal decision-making. This manuscript provides metrics on the impact of NAMs, allowing a quantitative assessment of animal use numbers over time, accountability for resources spent on NAM development, and identification of areas where NAM development is still needed. This approach can be refined for use at other organizations.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"95-112"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39539641","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: 2

Photomotor response data analysis approach to assess chemical neurotoxicity with the zebrafish embryo. 光度计反应数据分析方法评估斑马鱼胚胎的化学神经毒性。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2021-08-02 DOI: 10.14573/altex.2004021

Julia Ortmann, Rolf Altenburger, Stefan Scholz, Till Luckenbach

{"title":"Photomotor response data analysis approach to assess chemical neurotoxicity with the zebrafish embryo.","authors":"Julia Ortmann, Rolf Altenburger, Stefan Scholz, Till Luckenbach","doi":"10.14573/altex.2004021","DOIUrl":"https://doi.org/10.14573/altex.2004021","url":null,"abstract":"The photomotor response (PMR) of zebrafish embryos, a light pulse-triggered undirected movement, is known to be altered by neuroactive chemicals. Here, we developed an approach for data analysis of the distribution of PMR movement activities along the time axis; differences between treatment and respective controls are expressed by an aggregated value integrating the time-resolved density of the movement parameter as a measure for a chemically elicited PMR effect. Logistic concentration-PMR effect relationships were modeled for neuroactive test compounds with different modes of action (acetylcholinesterase inhibition, activation and inhibition of voltage-gated sodium channels); 50% effect concentrations (EC50) were in the low to medium μM range (EC50 < 10 μM for flucythrinate, esfenvalerate, azinphos-methyl, propoxur; EC50 > 10 μM for tricaine). Modulation of movement activities in different phases of the PMR (i.e., “fingerprint”) by neuroactive test compounds varied across concentrations, showing that mode of action-specific PMR fingerprints are also concentration-dependent. Above concentrations causing 10% lethality (LC10; 48 h), 3,4-dichloroaniline caused movement inhibition. This substance presumably is not neuroactive; its effect on the PMR therefore is considered a secondary toxic effect. Quantitative morphological examinations of chemically exposed embryos showed that malformations occurred only above PMR effect concentrations, indicating that changes in the PMR were not due to such indirect effects. The PMR assay will provide a useful measure in ecotoxicological risk assessment of neuroactive chemicals with zebrafish embryos and could potentially be used to infer acute fish toxicity levels from PMR effect concentrations of neurotoxic compounds.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"82-94"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39288637","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: 4

Cross-industrial applications of organotypic models. 有机型模型的跨行业应用。

IF 5.6

ALTEX Pub Date : 2022-01-01 DOI: 10.14573/altex.2112202

Katarzyna S Kopanska, Markus Rimann

引用次数: 0

Practical workshop on replacing fetal bovine serum (FBS) in life science research: From theory into practice. 生命科学研究中替代胎牛血清的实践研讨会:从理论到实践。

IF 5.6

ALTEX Pub Date : 2022-01-01 DOI: 10.14573/altex.2207071

Sebastian Eggert, Joachim Wiest, Jessica Rosolowski, Tilo Weber

引用次数: 1

Leveraging microphysiological systems to address challenges encountered during development of oligonucleotide therapeutics. 利用微生理系统来解决在寡核苷酸治疗发展过程中遇到的挑战。

IF 5.6

ALTEX Pub Date : 2022-01-01 Epub Date: 2021-11-11 DOI: 10.14573/altex.2108241

Diane Ramsden, David G Belair, Saket Agarwal, Patrik Andersson, Sara Humphreys, Deidre A Dalmas, Simone H Stahl, Chris Maclauchlin, Joseph A Cichocki

{"title":"Leveraging microphysiological systems to address challenges encountered during development of oligonucleotide therapeutics.","authors":"Diane Ramsden, David G Belair, Saket Agarwal, Patrik Andersson, Sara Humphreys, Deidre A Dalmas, Simone H Stahl, Chris Maclauchlin, Joseph A Cichocki","doi":"10.14573/altex.2108241","DOIUrl":"https://doi.org/10.14573/altex.2108241","url":null,"abstract":"Oligonucleotide therapeutics (ONTs) encompass classes of medicines that selectively target and potentially ameliorate previously untreatable and often rare diseases. Several unique classes of ONTs provide versatility, enabling direct modulation of gene expression by virtue of Watson-Crick base pairing or modulation of cell signaling through structural mimicry or interference with protein-receptor interactions. Due to a lack of suitable in vitro models capable of recapitulating or predicting in vivo effects of ONTs, their discovery and optimization has relied heavily on animal studies for predicting efficacy and safety in humans. Since ONTs often lack cross-species activity, animal models with genetic humanization and/or species-specific surrogate ONTs are often required. Human microphysiological systems (MPS) offer an opportunity to reduce the use of animals and may enable evaluation of drug mechanisms, optimization of cell and tissue targeting ligands or delivery vehicles, and characterization of pharmacokinetics (PK), pharmacodynamics (PD), and safety of candidate ONTs. The lack of published examples for MPS applications with ONT demonstrates the need for a focused effort to characterize and build confidence in their utility. The goals of this review are to summarize the current landscape of ONTs and highlight potential opportunities and challenges for application of MPS during ONT discovery and development. In addition, this review aims to raise awareness with ONT drug developers and regulatory authorities on the potential impact of MPS with respect to characterizing pharmacology, ADME, and toxicity and to educate MPS platform developers on unique design attributes needed to fully appreciate MPS advantages in ONT development.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"273–296"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39614168","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: 8

Designing a national strategy to enable human-relevant research in India: A multistakeholder roundtable meeting report. 设计一项国家战略，使印度能够进行与人类有关的研究:一份多利益攸关方圆桌会议报告。

IF 5.6

ALTEX Pub Date : 2022-01-01 DOI: 10.14573/altex.2111151

Surat Parvatam

{"title":"Designing a national strategy to enable human-relevant research in India: A multistakeholder roundtable meeting report.","authors":"Surat Parvatam","doi":"10.14573/altex.2111151","DOIUrl":"https://doi.org/10.14573/altex.2111151","url":null,"abstract":"In the past few years, there has been a substantial increase in research and initiatives towards human-relevant technologies in India, particularly the use and development of microphysiological systems models in India. However, this rise has also been accompanied by significant roadblocks in the availability of infrastructure, training and education programs, supply chain issues, and lack of funding. A recent meeting between technology developers in academia and industry had led to suggestions to address these limitations. To take forward these suggestions, a first-of-its-kind multi-stakeholder meeting was held between participants from the Indian government and regulatory bodies, policy-makers, pharma companies, and academia. Several recommendations were proposed by the government and regulatory bodies to address the current limitations to developing MPS technologies in India. We end with strategies to achieve the proposed recommendations and envision that these initiatives would commence in the coming few months. This would assist in achieving the proposed goal of developing India as a key player in the development and usage of human-relevant technologies.","PeriodicalId":520550,"journal":{"name":"ALTEX","volume":" ","pages":"151-153"},"PeriodicalIF":5.6,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39823746","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

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