Novel in vitro and mathematical models for the prediction of chemical toxicity

Williams, Dominic P.; Shipley, Rebecca J.; Ellis, Marianne; Webb, S. David; Ward, J. P.; Gardner, Iain; Creton, Stuart

doi:10.1039/c2tx20031g

Cited by 25 publications

(32 citation statements)

References 130 publications

(195 reference statements)

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“…This technology can be used for a high‐throughput screening of functional cardiotoxicity . However, many in vitro models may lack or incompletely recapitulate important aspects of human biology in vivo, allowing certain toxicities to escape detection. Cardiac performance is the result of an entire functioning organ, including electrophysiological function (rhythms or heartbeats), pump function (cardiac output, stroke volume, stroke work, ejection fraction) and mechanical muscle function (force velocity curve, maximum velocity of shortening (Vmax), LVEF, ventricular contractility (dP/dt)).…”

Section: Research Gaps Challenges Perspectives and Opportunities Tmentioning

confidence: 99%

“…Multi‐organ toxicity resulting from ICIs and CART may reflect the complex scenarios of the immune system in vivo. These problems may be minimized by combining in vitro data with mechanistic mathematical models, which describe intracellular metabolism, fluid‐flow, substrate, hormone, and nutrient distribution and provide the opportunity to mimic the in vivo scenario …”

Section: Cardiotoxicity Induced By Icis and T‐cell Therapymentioning

confidence: 99%

“…This technology can be used for a high-throughput screening of functional cardiotoxicity. 391 However, many in vitro models may lack or incompletely recapitulate important aspects of human biology in vivo, 8,394 allowing certain toxicities to escape detection.…”

Section: Overview Of Living Modeling Systemsmentioning

confidence: 99%

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Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

Zheng

Kros

2017

Medicinal Research Reviews

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To date, five cancer treatment modalities have been defined. The three traditional modalities of cancer treatment are surgery, radiotherapy, and conventional chemotherapy, and the two modern modalities include molecularly targeted therapy (the fourth modality) and immunotherapy (the fifth modality). The cardiotoxicity associated with conventional chemotherapy and radiotherapy is well known. Similar adverse cardiac events are resurging with the fourth modality. Aside from the conventional and newer targeted agents, even the most newly developed, immune‐based therapeutic modalities of anticancer treatment (the fifth modality), e.g., immune checkpoint inhibitors and chimeric antigen receptor (CAR) T‐cell therapy, have unfortunately led to potentially lethal cardiotoxicity in patients. Cardiac complications represent unresolved and potentially life‐threatening conditions in cancer survivors, while effective clinical management remains quite challenging. As a consequence, morbidity and mortality related to cardiac complications now threaten to offset some favorable benefits of modern cancer treatments in cancer‐related survival, regardless of the oncologic prognosis. This review focuses on identifying critical research‐practice gaps, addressing real‐world challenges and pinpointing real‐time insights in general terms under the context of clinical cardiotoxicity induced by the fourth and fifth modalities of cancer treatment. The information ranges from basic science to clinical management in the field of cardio‐oncology and crosses the interface between oncology and onco‐pharmacology. The complexity of the ongoing clinical problem is addressed at different levels. A better understanding of these research‐practice gaps may advance research initiatives on the development of mechanism‐based diagnoses and treatments for the effective clinical management of cardiotoxicity.

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Section: Research Gaps Challenges Perspectives and Opportunities Tmentioning

confidence: 99%

Section: Cardiotoxicity Induced By Icis and T‐cell Therapymentioning

confidence: 99%

See 1 more Smart Citation

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

Zheng

Kros

2017

Medicinal Research Reviews

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“…It will be important in the future to properly integrate mathematical modelling into such an interdisciplinary workflow, although it is likely that this 'true' interdisciplinary approach would require a significant overhaul in the structuring and funding of research, enabling greater flexibility to facilitate this kind of cross-departmental collaboration. However, despite the issues raised in this section, work published thus far has certainly built a convincing case for the utility of interdisciplinary methods in the field of tissue engineering (Byrne et al, 2007;Lawrence et al, 2009;Sanz-Herrera et al, 2009;Shipley and Waters, 2011;Williams et al, 2013).…”

Section: Mathematical Modelling Approaches To Tissue-engineering Chalmentioning

confidence: 99%

An integrated theoretical-experimental approach to accelerate translational tissue engineering

Coy

Evans

Phillips

et al. 2017

J Tissue Eng Regen Med

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Implantable devices utilizing bioengineered tissue are increasingly showing promise as viable clinical solutions. The design of bioengineered constructs is currently directed according to the results of experiments that are used to test a wide range of different combinations and spatial arrangements of biomaterials, cells and chemical factors. There is an outstanding need to accelerate the design process and reduce financial costs, whilst minimizing the required number of animal‐based experiments. These aims could be achieved through the incorporation of mathematical modelling as a preliminary design tool. Here we focus on tissue‐engineered constructs for peripheral nerve repair, which are designed to aid nerve and blood vessel growth and repair after peripheral nerve injury. We offer insight into the role that mathematical modelling can play within tissue engineering, and motivate the use of modelling as a tool capable of improving and accelerating the design of nerve repair constructs in particular. Specific case studies are presented in order to illustrate the potential of mathematical modelling to direct construct design. Copyright © 2016 The Authors Journal of Tissue Engineering and Regenerative Medicine Published by John Wiley & Sons Ltd.

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“…For example, our understanding of the mechanisms involved in the occurrence of adverse drug reactions (ADRs) and druginduced liver injury (DILI) in humans is also an area that remains limited [6]. ADRs currently represent a major encumbrance to the development of new therapeutics with ~21% of drug attrition attributed to toxicity during the development process [7]. Despite a wealth of research utilising a variety of model systems in the field of xenobiotic safety, our comprehensive understanding of the mechanisms underpinning the impact of xenobiotics either on human health or on the environment is not fully established partly owing to the complexity of understanding exposure scenarios [8].…”

Section: Introductionmentioning

confidence: 99%

Impact of cell types and culture methods on the functionality of in vitro liver systems – A review of cell systems for hepatotoxicity assessment

Kyffin

Sharma

Leedale

et al. 2018

Toxicology in Vitro

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Xenobiotic safety assessment is an area that impacts a multitude of different industry sectors such as medicinal drugs, agrochemicals, industrial chemicals, cosmetics and environmental contaminants. As such there are a number of well-developed in vitro, in vivo and in silico approaches to evaluate their properties and potential impact on the environment and to humans. Additionally, there is the continual investment in multidisciplinary scientists to explore non-animal surrogate technologies to predict specific toxicological outcomes and to improve our understanding of the biological processes regarding the toxic potential of xenobiotics. Here we provide a concise, critical evaluation of a number of in vitro systems utilised to assess the hepatotoxic potential of xenobiotics.

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Novel in vitro and mathematical models for the prediction of chemical toxicity

Abstract: Reproduction of centrilobular and periportal hepatocyte phenotypes in vitro is crucial for sensitive detection of cellular stress, combined with mathematical modelling, is a novel tool for drug safety research.

Cited by 25 publications

References 130 publications

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

An integrated theoretical-experimental approach to accelerate translational tissue engineering

Impact of cell types and culture methods on the functionality of in vitro liver systems – A review of cell systems for hepatotoxicity assessment

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