Altex-Alternatives To Animal Experimentation最新文献_第10页

Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals_suppl1 将纳米材料诱导的线粒体功能障碍与现有的不良后果通路联系起来

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2305011s1

S. Murugadoss

引用次数: 0

Alternative Methods in Science: Towards Fluidic Systems. 科学中的替代方法：走向流体系统。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2307101

Francesca Caloni, Alessandra Cazzaniga, Arno C Gutleb, Helena Kandarova, Giulia Ranaldi, Hassan Rashidi, Sonja von Aulock, Doris Wilflingseder

引用次数: 0

Lung tumor microphysiological system with 3D endothelium to evaluate modulators of T-cell migration. 具有3D内皮的肺肿瘤微物理系统，用于评估T细胞迁移的调节剂。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 Epub Date: 2023-06-16 DOI: 10.14573/altex.2208121

Katrina M Wisdom, Johnny Suijker, Lenie Van den Broek, BanuPriya Sridharan, Taraka Sai Pavan Grandhi, Aaron Cheng, Mahdi Lamb, Steven A Titus, Derek Poore, Niyant Shah, Shih-Hsun Cheng, Edward Kim, Suzanne Griffin, Jason Ekert

{"title":"Lung tumor microphysiological system with 3D endothelium to evaluate modulators of T-cell migration.","authors":"Katrina M Wisdom, Johnny Suijker, Lenie Van den Broek, BanuPriya Sridharan, Taraka Sai Pavan Grandhi, Aaron Cheng, Mahdi Lamb, Steven A Titus, Derek Poore, Niyant Shah, Shih-Hsun Cheng, Edward Kim, Suzanne Griffin, Jason Ekert","doi":"10.14573/altex.2208121","DOIUrl":"10.14573/altex.2208121","url":null,"abstract":"Lung cancer is a leading cause of death worldwide, with only a fraction of patients responding to immunotherapy. The correlation between increased T-cell infiltration and positive patient outcomes has motivated the search for therapeutics promoting T-cell infiltration. While transwell and spheroid platforms have been employed, these models lack flow and endothelial barriers, and cannot faithfully model T-cell adhesion, extravasation, and migration through 3D tissue. Presented here is a 3D chemotaxis assay, in a lung tumor-on-chip model with 3D endothelium (LToC-Endo), to address this need. The described assay consists of a HUVEC-derived vascular tubule cultured under rocking flow, through which T-cells are added; a collagenous stromal barrier, through which T-cells migrate; and a chemoattractant/tumor (HCC0827 or NCI-H520) compartment. Here, activated T-cells extravasate and migrate in response to gradients of rhCXCL11 and rhCXCL12. Adopting a T-cell activation protocol with a rest period enables proliferative burst prior to introducing T-cells into chips and enhances assay sensitivity. In addition, incorporating this rest recovers endothelial activation in response to rhCXCL12. As a final control, we show that blocking ICAM-1 interferes with T-cell adhesion and chemotaxis. This microphysiological system, which mimics in vivo stromal and vascular barriers, can be used to evaluate potentiation of immune chemotaxis into tumors while probing for vascular responses to potential therapeutics. Finally, we propose translational strategies by which this assay could be linked to preclinical and clinical models to support human dose prediction, personalized medicine, and the reduction, refinement, and replacement of animal models.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9820151","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

The GARD™skin assay: Investigation of the applicability domain for metals. GARD™皮肤试验:金属适用领域的研究。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2203021

Andy Forreryd, Robin Gradin, Olivia Larne, Nissanka Rajapakse, Eliot Deag, Henrik Johansson

{"title":"The GARD™skin assay: Investigation of the applicability domain for metals.","authors":"Andy Forreryd, Robin Gradin, Olivia Larne, Nissanka Rajapakse, Eliot Deag, Henrik Johansson","doi":"10.14573/altex.2203021","DOIUrl":"https://doi.org/10.14573/altex.2203021","url":null,"abstract":"New approach methodologies (NAMs) for hazard identification of skin sensitizing chemicals were adopted as test guidelines by the OECD during the last decade. These alternatives to animal models align to individual key events (KE) in the adverse outcome pathway (AOP) for skin sensitization for which the molecular initiating event (MIE) is covalent binding to proteins. As it currently stands, the AOP does not include mechanistic events of sensitization by metals, and limited information is available on whether NAMs accurately predict the sensitization potential of such molecules, which have been proposed to act via alternative mechanisms to organic chemicals. Methods for assessing the sensitization potential of metals would be valuable tools to support risk management within, e.g., occupational settings during production of new metal salts or within the medical device industry to evaluate leachables from metal alloys. This paper describes a systematic evaluation of the applicability domain of the GARD™skin assay for the assessment of metals. Hazard classifications were supplemented with an extended analysis of gene expression profiles induced by metal sensitizers to compare the induction of toxicity pathways between metals and organic sensitizers. Based on the results of this study, the accuracy, sensitivity, and specificity of GARD™skin for the prediction of skin sensitizing hazard were 92% (12/13), 100% (7/7), and 83% (5/6), respectively. Thus, the performance of GARD™skin for the assessment of metals was found to be similar to that observed for conventional organic substances, providing support for inclusion of metals within the applicability domain of the test method.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9843211","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

Development of a network of carcinogenicity adverse outcome pathways and its employment as an evidence framework for safety assessment 致癌性不良后果途径网络的建立及其作为安全性评估的证据框架

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2201311

Alex N Cayley, Robert S Foster, Emma Hill, Steven Kane, Grace Kocks, Alun Myden, Daniel Newman, Susanne A Stalford, Jonathan D Vessey, Reza Zarei, Antonio Anax F De Oliveira

{"title":"Development of a network of carcinogenicity adverse outcome pathways and its employment as an evidence framework for safety assessment","authors":"Alex N Cayley, Robert S Foster, Emma Hill, Steven Kane, Grace Kocks, Alun Myden, Daniel Newman, Susanne A Stalford, Jonathan D Vessey, Reza Zarei, Antonio Anax F De Oliveira","doi":"10.14573/altex.2201311","DOIUrl":"https://doi.org/10.14573/altex.2201311","url":null,"abstract":"The traditional paradigm for safety assessment of chemicals for their carcinogenic potential to humans relies heavily on a battery of well-established genotoxicity tests, usually followed up by long-term, high-dose rodent studies. There are a variety of problems with this approach, not least that the rodent may not always be the best model to predict toxicity in humans. Consequently, new approach methodologies (NAMs) are being developed to replace or enhance predictions coming from the existing assays. However, a combination of the data arising from NAMs is likely to be required to improve upon the current paradigm, and consequently a framework is needed to combine evidence in a meaningful way. Adverse outcome pathways (AOPs) represent an ideal construct on which to organize this evidence. In this work, a data structure outlined previously was used to capture AOPs and evidence relating to carcinogenicity. Knowledge held within the predictive system Derek Nexus was extracted, built upon, and arranged into a coherent network containing 37 AOPs. 60 assays and 351 in silico alerts were then associated with KEs in this network, and it was brought to life by associating data and contextualizing evidence and predictions for over 13,400 compounds. Initial investigations into using the network to view knowledge and reason between evidence in different ways were made. Organizing knowledge and evidence in this way provides a flexible framework on which to carry out more consistent and meaningful carcinogenicity safety assessments in many different contexts.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10539877","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: 4

Comparison of pyrogen assays by testing products exhibiting low endotoxin recovery. 内毒素回收率低的产品热原测定的比较。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2202021

Tammy L Thurman, Carol J Lahti, Jeanne M Mateffy, Ren-Yo Forng, Friedrich von Wintzingerode, Lindsey M Silva, Sven M Deutschmann, Ned Mozier

{"title":"Comparison of pyrogen assays by testing products exhibiting low endotoxin recovery.","authors":"Tammy L Thurman, Carol J Lahti, Jeanne M Mateffy, Ren-Yo Forng, Friedrich von Wintzingerode, Lindsey M Silva, Sven M Deutschmann, Ned Mozier","doi":"10.14573/altex.2202021","DOIUrl":"https://doi.org/10.14573/altex.2202021","url":null,"abstract":"The use of pyrogen tests to assess the risk of endotoxin in biological products has increased recently due to concerns of some regulatory authorities about products exhibiting low endotoxin recovery (LER). Manufacturers increasingly seek to reduce the use of animals unless essential to assure patient safety. The current study compares the ability of the monocyte activation test (MAT) and the bacterial endotoxin test (BET) to the rabbit pyrogen test (RPT) to detect endotoxin spikes in samples of products shown to exhibit LER. Product samples or water were spiked with endotoxin and held for three days or tested immediately in the BET, the RPT, and two variations of the MAT at the same time. Results show high sensitivity to endotoxin of both the BET and MAT, and much lower sensitivity of the RPT, indicating that much higher levels of reference standard endotoxin are required to induce pyrogenicity in the RPT than the 5 endotoxin units (EU) per kg common threshold. The results of the BET and MAT correlated well for the detection of endotoxin spike in water. We also show that LER (masking of endotoxin) found in the BET is also seen in the MAT and RPT, suggesting that the products themselves elicit a biological inactivation of spiked endotoxin over time, thereby rendering it less or non-pyrogenic. We conclude that the non-animal MAT option is a suitable replacement for the RPT to measure spiked endotoxin in biopharmaceuticals.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10539887","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

Linking nanomaterial-induced mitochondrial dysfunction to existing adverse outcome pathways for chemicals_suppl2 将纳米材料诱导的线粒体功能障碍与现有的不良后果途径联系起来

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2305011s2

S. Murugadoss

引用次数: 0

Beyond Animal Testing Index: Benchmarking tool for a world beyond animal testing_suppl5 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.2304161s5

C. Krul

引用次数: 0

Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment. 将新方法纳入非临床药物安全性评估监管。

IF 4.5 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 Epub Date: 2023-01-18 DOI: 10.14573/altex.2212081

Jan Turner, Pandora Pound, Carla Owen, Isobel Hutchinson, Marina Hop, David Y S Chau, Lady V Barrios Silva, Mike Coleman, Audrey Dubourg, Lorna W Harries, Victoria Hutter, J Gerry Kenna, Volker M Lauschke, Winfried Neuhaus, Clive Roper, Paul B Watkins, Jonathan Welch, Laura R Alvarez, Katy Taylor

{"title":"Incorporating new approach methodologies into regulatory nonclinical pharmaceutical safety assessment.","authors":"Jan Turner, Pandora Pound, Carla Owen, Isobel Hutchinson, Marina Hop, David Y S Chau, Lady V Barrios Silva, Mike Coleman, Audrey Dubourg, Lorna W Harries, Victoria Hutter, J Gerry Kenna, Volker M Lauschke, Winfried Neuhaus, Clive Roper, Paul B Watkins, Jonathan Welch, Laura R Alvarez, Katy Taylor","doi":"10.14573/altex.2212081","DOIUrl":"10.14573/altex.2212081","url":null,"abstract":"New approach methodologies (NAMs) based on human biology enable the assessment of adverse biological effects of pharmaceuticals and other chemicals. Currently, however, it is unclear how NAMs should be used during drug development to improve human safety evaluation. A series of 5 workshops with 13 international experts (regulators, preclinical scientists, and NAMs developers) was conducted to identify feasible NAMs and to discuss how to exploit them in specific safety assessment contexts. Participants generated four “maps” of how NAMs can be exploited in the safety assessment of the liver, respiratory, cardiovascular, and central nervous systems. Each map shows relevant endpoints measured and tools used (e.g., cells, assays, platforms), and highlights gaps where further development and validation of NAMs remains necessary. Each map addresses the fundamental scientific requirements for the safety assessment of that organ system, providing users with guidance on the selection of appropriate NAMs. In addition to generating the maps, participants offered suggestions for encouraging greater NAM adoption within drug development and their inclusion in regulatory guidelines. A specific recommendation was that pharmaceutical companies should be more transparent about how they use NAMs in-house. As well as giving guidance for the four organ systems, the maps provide a template that could be used for additional organ safety testing contexts. Moreover, their conversion to an interactive format would enable users to drill down to the detail necessary to answer specific scientific and regulatory questions.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":null,"pages":null},"PeriodicalIF":4.5,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9895255","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

Microphysiological endothelial models to characterize subcutaneous drug absorption. 表征皮下药物吸收的微生理内皮模型。

IF 5.6 2区医学

Altex-Alternatives To Animal Experimentation Pub Date : 2023-01-01 DOI: 10.14573/altex.2207131

Giovanni S Offeddu, Jean Carlos Serrano, Zhengpeng Wan, Mark A Bryniarski, Sara C Humphreys, Sophia W Chen, Hamsini Dhoolypala, Kip Conner, Roger D Kamm

{"title":"Microphysiological endothelial models to characterize subcutaneous drug absorption.","authors":"Giovanni S Offeddu, Jean Carlos Serrano, Zhengpeng Wan, Mark A Bryniarski, Sara C Humphreys, Sophia W Chen, Hamsini Dhoolypala, Kip Conner, Roger D Kamm","doi":"10.14573/altex.2207131","DOIUrl":"https://doi.org/10.14573/altex.2207131","url":null,"abstract":"The high variability in subcutaneous bioavailability of protein therapeutics is poorly understood, contributing to critical delays in patient access to new therapies. Preclinical animal and in vitro models fail to provide a physiologically relevant testbed to parse potential contributors to human bioavailability, therefore new strategies are necessary. Here, we present a microphysiological model of the human hypodermal vasculature at the injection site to study the interactions of administered protein therapeutics within the microenvironment that influence subcutaneous bioavailability. Our model combines human dermal endothelial cells, fibroblasts, and adipocytes, self-assembled into three-dimensional, perfusable microvessels that express relevant extracellular matrix. We demonstrate the utility of the model for measurement of biophysical parameters within the hypodermal microenvironment that putatively impact protein kinetics and distribution at the injection site. We propose that microphysiological models of the subcutaneous space have applications in preclinical development of protein therapeutics intended for subcutaneous administration with optimal bioavailability.","PeriodicalId":51231,"journal":{"name":"Altex-Alternatives To Animal Experimentation","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9631203","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