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Article ; Online: A functional long-term 2D serum-free human hepatic in vitro system for drug evaluation.

Oleaga, Carlota / Bridges, L Richard / Persaud, Keisha / McAleer, Christopher W / Long, Christopher J / Hickman, James J

Biotechnology progress

2020 Volume 37, Issue 1, Page(s) e3069

Abstract: Human in vitro hepatic models generate faster drug toxicity data with higher human predictability compared to animal models. However, for long-term studies, current models require the use of serum and 3D architecture, limiting their utility. Maintaining ... ...

Abstract	Human in vitro hepatic models generate faster drug toxicity data with higher human predictability compared to animal models. However, for long-term studies, current models require the use of serum and 3D architecture, limiting their utility. Maintaining a functional long-term human in vitro hepatic culture that avoids complex structures and serum would improve the value of such systems for preclinical studies. This would also enable a more straightforward integration with current multi-organ devices to study human systemic toxicity to generate an alternative model to chronic animal evaluations. A human primary hepatocyte culture system was characterized for 28 days in 2D and serum-free defined conditions. Under the studied conditions, human primary hepatocytes maintained their characteristic morphology, hepatic markers and functions for 28 days. The acute and chronic administration of known drugs validated the sensitivity of the system for drug testing. This human 2D model represents a realistic system to evaluate hepatic function for long-term drug studies, without the need of animal serum, confounding variable in most models, and with less complexity and resultant cost compared to most 3D models. The defined culture conditions can easily be integrated into complex multi-organ in vitro models for studying systemic effects driven by the liver function for long-term evaluations.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Culture Media, Serum-Free/pharmacology ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP3A/metabolism ; Drug Evaluation, Preclinical ; Hepatocytes/drug effects ; Hepatocytes/enzymology ; Humans ; In Vitro Techniques
Chemical Substances	Antineoplastic Agents ; Culture Media, Serum-Free ; CYP1A1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP3A (EC 1.14.14.1)
Language	English
Publishing date	2020-10-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	165657-0
ISSN	1520-6033 ; 8756-7938
ISSN (online)	1520-6033
ISSN	8756-7938
DOI	10.1002/btpr.3069
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Heterozygous inactivation of tsc2 enhances tumorigenesis in p53 mutant zebrafish.

Kim, Seok-Hyung / Kowalski, Marie L / Carson, Robert P / Bridges, L Richard / Ess, Kevin C

Disease models & mechanisms

2013 Volume 6, Issue 4, Page(s) 925–933

Abstract: Tuberous sclerosis complex (TSC) is a multi-organ disorder caused by mutations of the TSC1 or TSC2 genes. A key function of these genes is to inhibit mTORC1 (mechanistic target of rapamycin complex 1) kinase signaling. Cells deficient for TSC1 or TSC2 ... ...

Abstract	Tuberous sclerosis complex (TSC) is a multi-organ disorder caused by mutations of the TSC1 or TSC2 genes. A key function of these genes is to inhibit mTORC1 (mechanistic target of rapamycin complex 1) kinase signaling. Cells deficient for TSC1 or TSC2 have increased mTORC1 signaling and give rise to benign tumors, although, as a rule, true malignancies are rarely seen. In contrast, other disorders with increased mTOR signaling typically have overt malignancies. A better understanding of genetic mechanisms that govern the transformation of benign cells to malignant ones is crucial to understand cancer pathogenesis. We generated a zebrafish model of TSC and cancer progression by placing a heterozygous mutation of the tsc2 gene in a p53 mutant background. Unlike tsc2 heterozygous mutant zebrafish, which never exhibited cancers, compound tsc2;p53 mutants had malignant tumors in multiple organs. Tumorigenesis was enhanced compared with p53 mutant zebrafish. p53 mutants also had increased mTORC1 signaling that was further enhanced in tsc2;p53 compound mutants. We found increased expression of Hif1-α, Hif2-α and Vegf-c in tsc2;p53 compound mutant zebrafish compared with p53 mutant zebrafish. Expression of these proteins probably underlies the increased angiogenesis seen in compound mutant zebrafish compared with p53 mutants and might further drive cancer progression. Treatment of p53 and compound mutant zebrafish with the mTORC1 inhibitor rapamycin caused rapid shrinkage of tumor size and decreased caliber of tumor-associated blood vessels. This is the first report using an animal model to show interactions between tsc2, mTORC1 and p53 during tumorigenesis. These results might explain why individuals with TSC rarely have malignant tumors, but also suggest that cancer arising in individuals without TSC might be influenced by the status of TSC1 and/or TSC2 mutations and be potentially treatable with mTORC1 inhibitors.
MeSH term(s)	Abdominal Neoplasms/blood supply ; Abdominal Neoplasms/enzymology ; Abdominal Neoplasms/pathology ; Alleles ; Animals ; Blood Vessels/drug effects ; Blood Vessels/metabolism ; Blood Vessels/pathology ; Cell Transformation, Neoplastic/drug effects ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/pathology ; Gene Silencing/drug effects ; Heterozygote ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Mechanistic Target of Rapamycin Complex 1 ; Mechanistic Target of Rapamycin Complex 2 ; Multiprotein Complexes/antagonists & inhibitors ; Multiprotein Complexes/metabolism ; Mutation/genetics ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects ; Sirolimus/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism ; Up-Regulation/drug effects ; Vascular Endothelial Growth Factor A/metabolism ; Zebrafish/genetics ; Zebrafish Proteins/genetics ; Zebrafish Proteins/metabolism
Chemical Substances	Intracellular Signaling Peptides and Proteins ; Multiprotein Complexes ; TSC2 protein, human ; Tsc2 protein, zebrafish ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Protein p53 ; Tumor Suppressor Proteins ; Vascular Endothelial Growth Factor A ; Zebrafish Proteins ; tp53 protein, zebrafish ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Sirolimus (W36ZG6FT64)
Language	English
Publishing date	2013-03-27
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.011494
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Article ; Online: Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics.

McAleer, Christopher W / Long, Christopher J / Elbrecht, Daniel / Sasserath, Trevor / Bridges, L Richard / Rumsey, John W / Martin, Candace / Schnepper, Mark / Wang, Ying / Schuler, Franz / Roth, Adrian B / Funk, Christoph / Shuler, Michael L / Hickman, James J

Science translational medicine

2019 Volume 11, Issue 497

Abstract: A pumpless, reconfigurable, multi-organ-on-a-chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological ... ...

Abstract	A pumpless, reconfigurable, multi-organ-on-a-chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological microelectromechanical systems. In the first configuration of the system, primary human hepatocytes were cultured with two cancer-derived human bone marrow cell lines for antileukemia drug analysis in which diclofenac and imatinib demonstrated a cytostatic effect on bone marrow cancer proliferation. Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%. The second configuration housed a multidrug-resistant vulva cancer line, a non-multidrug-resistant breast cancer line, primary hepatocytes, and induced pluripotent stem cell-derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. Both tamoxifen alone and coadministration with verapamil produced off-target cardiac effects as indicated by a reduction of contractile force, beat frequency, and conduction velocity but did not affect viability. These systems demonstrate the utility of a human cell-based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites; these systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Proliferation/drug effects ; Cells, Cultured ; Diclofenac/pharmacology ; Drug Evaluation, Preclinical/methods ; Humans ; Imatinib Mesylate/pharmacology ; Lab-On-A-Chip Devices ; Tamoxifen/pharmacology ; Verapamil/pharmacology
Chemical Substances	Antineoplastic Agents ; Tamoxifen (094ZI81Y45) ; Diclofenac (144O8QL0L1) ; Imatinib Mesylate (8A1O1M485B) ; Verapamil (CJ0O37KU29)
Language	English
Publishing date	2019-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aav1386
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Article ; Online: On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships.

McAleer, Christopher W / Pointon, Amy / Long, Christopher J / Brighton, Rocky L / Wilkin, Benjamin D / Bridges, L Richard / Narasimhan Sriram, Narasimham / Fabre, Kristin / McDougall, Robin / Muse, Victorine P / Mettetal, Jerome T / Srivastava, Abhishek / Williams, Dominic / Schnepper, Mark T / Roles, Jeff L / Shuler, Michael L / Hickman, James J / Ewart, Lorna

Scientific reports

2019 Volume 9, Issue 1, Page(s) 9619

Abstract: Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) ...

Abstract	Functional human-on-a-chip systems hold great promise to enable quantitative translation to in vivo outcomes. Here, we explored this concept using a pumpless heart only and heart:liver system to evaluate the temporal pharmacokinetic/pharmacodynamic (PKPD) relationship for terfenadine. There was a time dependent drug-induced increase in field potential duration in the cardiac compartment in response to terfenadine and that response was modulated using a metabolically competent liver module that converted terfenadine to fexofenadine. Using this data, a mathematical model was developed to predict the effect of terfenadine in preclinical species. Developing confidence that microphysiological models could have a transformative effect on drug discovery, we also tested a previously discovered proprietary AstraZeneca small molecule and correctly determined the cardiotoxic response to its metabolite in the heart:liver system. Overall our findings serve as a guiding principle to future investigations of temporal concentration response relationships in these innovative in vitro models, especially, if validated across multiple time frames, with additional pharmacological mechanisms and molecules representing a broad chemical diversity.
MeSH term(s)	Drug Discovery/methods ; Humans ; Lab-On-A-Chip Devices ; Microchip Analytical Procedures/methods ; Models, Biological ; Models, Theoretical ; Organ Specificity ; Pharmacokinetics ; Translational Research, Biomedical/methods
Language	English
Publishing date	2019-07-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-45656-4
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system

Oleaga, Carlota / Riu, Anne / Rothemund, Sandra / Lavado, Andrea / McAleer, Christopher W / Long, Christopher J / Persaud, Keisha / Narasimhan, Narasimhan Sriram / Tran, My / Roles, Jeffry / Carmona-Moran, Carlos A / Sasserath, Trevor / Elbrecht, Daniel H / Kumanchik, Lee / Bridges, L. Richard / Martin, Candace / Schnepper, Mark T / Ekman, Gail / Jackson, Max /

Wang, Ying I / Note, Reine / Langer, Jessica / Teissier, Silvia / Hickman, James J

Biomaterials. 2018 Nov., v. 182

2018

Abstract: Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional ... ...

Abstract	Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium. The functional readouts for contractile force and electrical conductivity enabled the non-invasive study of cardiac function. The presence of the hepatocytes in the system induced cardiotoxic effects from cyclophosphamide and reduced them for terfenadine due to drug metabolism, as expected from each compound's pharmacology. A computational fluid dynamics simulation enabled the prediction of terfenadine-fexofenadine pharmacokinetics, which was validated by HPLC-MS. This in vitro platform recapitulates primary aspects of the in vivo crosstalk between heart and liver and enables pharmacological studies, involving both organs in a single in vitro platform. The system enables non-invasive readouts of cardiotoxicity of drugs and their metabolites. Hepatotoxicity can also be evaluated by biomarker analysis and change in metabolic function. Integration of metabolic function in toxicology models can improve adverse effects prediction in preclinical studies and this system could also be used for chronic studies as well.
Keywords	adverse effects ; biochemical pathways ; biomarkers ; cardiac output ; cardiomyocytes ; cosmetics testing ; cyclophosphamide ; electrical conductivity ; fluid mechanics ; hepatocytes ; hepatotoxicity ; high performance liquid chromatography ; humans ; in vitro studies ; liver ; mass spectrometry ; metabolites ; models ; organ-on-a-chip ; pharmacokinetics ; prediction ; toxicology ; xenobiotics
Language	English
Dates of publication	2018-11
Size	p. 176-190.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	603079-8
ISSN	0142-9612
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2018.07.062
Database	NAL-Catalogue (AGRICOLA)

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Article: Long-Term Electrical and Mechanical Function Monitoring of a Human-on-a-Chip System.

Advanced functional materials

2018 Volume 29, Issue 8

Abstract: The goal of human-on-a-chip systems is to capture multi-organ complexity and predict the human response to compounds within physiologically relevant platforms. The generation and characterization of such systems is currently a focal point of research ... ...

Abstract	The goal of human-on-a-chip systems is to capture multi-organ complexity and predict the human response to compounds within physiologically relevant platforms. The generation and characterization of such systems is currently a focal point of research given the long-standing inadequacies of conventional techniques for predicting human outcome. Functional systems can measure and quantify key cellular mechanisms that correlate with the physiological status of a tissue, and can be used to evaluate therapeutic challenges utilizing many of the same endpoints used in animal experiments or clinical trials. Culturing multiple organ compartments in a platform creates a more physiologic environment (organ-organ communication). Here is reported a human 4-organ system composed of heart, liver, skeletal muscle and nervous system modules that maintains cellular viability and function over 28 days in serum-free conditions using a pumpless system. The integration of non-invasive electrical evaluation of neurons and cardiac cells and mechanical determination of cardiac and skeletal muscle contraction allows the monitoring of cellular function especially for chronic toxicity studies
Language	English
Publishing date	2018-12-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2039420-2
ISSN	1616-3028 ; 1616-301X
ISSN (online)	1616-3028
ISSN	1616-301X
DOI	10.1002/adfm.201805792
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Article ; Online: Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system.

Oleaga, Carlota / Riu, Anne / Rothemund, Sandra / Lavado, Andrea / McAleer, Christopher W / Long, Christopher J / Persaud, Keisha / Narasimhan, Narasimhan Sriram / Tran, My / Roles, Jeffry / Carmona-Moran, Carlos A / Sasserath, Trevor / Elbrecht, Daniel H / Kumanchik, Lee / Bridges, L Richard / Martin, Candace / Schnepper, Mark T / Ekman, Gail / Jackson, Max /

Wang, Ying I / Note, Reine / Langer, Jessica / Teissier, Silvia / Hickman, James J

Biomaterials

2018 Volume 182, Page(s) 176–190

Abstract	Regulation of cosmetic testing and poor predictivity of preclinical drug studies has spurred efforts to develop new methods for systemic toxicity. Current in vitro assays do not fully represent physiology, often lacking xenobiotic metabolism. Functional human multi-organ systems containing iPSC derived cardiomyocytes and primary hepatocytes were maintained under flow using a low-volume pumpless system in a serum-free medium. The functional readouts for contractile force and electrical conductivity enabled the non-invasive study of cardiac function. The presence of the hepatocytes in the system induced cardiotoxic effects from cyclophosphamide and reduced them for terfenadine due to drug metabolism, as expected from each compound's pharmacology. A computational fluid dynamics simulation enabled the prediction of terfenadine-fexofenadine pharmacokinetics, which was validated by HPLC-MS. This in vitro platform recapitulates primary aspects of the in vivo crosstalk between heart and liver and enables pharmacological studies, involving both organs in a single in vitro platform. The system enables non-invasive readouts of cardiotoxicity of drugs and their metabolites. Hepatotoxicity can also be evaluated by biomarker analysis and change in metabolic function. Integration of metabolic function in toxicology models can improve adverse effects prediction in preclinical studies and this system could also be used for chronic studies as well.
MeSH term(s)	Cardiotoxicity/etiology ; Cell Line ; Cells, Cultured ; Coculture Techniques/instrumentation ; Cyclophosphamide/metabolism ; Cyclophosphamide/toxicity ; Drug Evaluation, Preclinical/instrumentation ; Equipment Design ; Hepatocytes/cytology ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Histamine H1 Antagonists, Non-Sedating/metabolism ; Histamine H1 Antagonists, Non-Sedating/toxicity ; Humans ; Immunosuppressive Agents/metabolism ; Immunosuppressive Agents/toxicity ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/metabolism ; Lab-On-A-Chip Devices ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Terfenadine/metabolism ; Terfenadine/toxicity
Chemical Substances	Histamine H1 Antagonists, Non-Sedating ; Immunosuppressive Agents ; Terfenadine (7BA5G9Y06Q) ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2018-08-04
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603079-8
ISSN	1878-5905 ; 0142-9612
ISSN (online)	1878-5905
ISSN	0142-9612
DOI	10.1016/j.biomaterials.2018.07.062
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Article ; Online: A functional long-term 2D serum-free human hepatic in vitro system for drug evaluation.

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Article ; Online: Heterozygous inactivation of tsc2 enhances tumorigenesis in p53 mutant zebrafish.

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Article ; Online: Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics.

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Article ; Online: On the potential of in vitro organ-chip models to define temporal pharmacokinetic-pharmacodynamic relationships.

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Article: Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system

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Article: Long-Term Electrical and Mechanical Function Monitoring of a Human-on-a-Chip System.

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Article ; Online: Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system.

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