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Article ; Online: Characterization of a long-term mouse primary liver 3D tissue model recapitulating innate-immune responses and drug-induced liver toxicity.

Nudischer, Ramona / Renggli, Kasper / Hierlemann, Andreas / Roth, Adrian B / Bertinetti-Lapatki, Cristina

PloS one

2020 Volume 15, Issue 7, Page(s) e0235745

Abstract: Three-dimensional liver in vitro systems have recently attracted a lot of attention in drug development. These systems help to gain unprecedented insights into drug-induced liver injury (DILI), as they more closely reproduce liver biology, and as drug ... ...

Abstract	Three-dimensional liver in vitro systems have recently attracted a lot of attention in drug development. These systems help to gain unprecedented insights into drug-induced liver injury (DILI), as they more closely reproduce liver biology, and as drug effects can be studied in isolated and controllable microenvironments. Many groups established human-based in vitro models but so far neglected the animal equivalent, although the availability of both models would be desirable. Animal in vitro models enable back- and forward translation of in vitro and in vivo findings, bridge the gap between rodent in vivo and human in vitro scenarios, and ultimately support the interpretation of data generated with preclinical species and humans. Since mice are often used in drug development and physiologically relevant in vitro systems are lacking, we established, for the first time, a mouse liver model that encompasses primary parenchymal and non-parenchymal cells with preserved viability and functionality over three weeks. Using our three-dimensional liver spheroids, we were able to predict the toxicity of known DILI compounds, demonstrated the interaction cascades between the different cell types and showed evidence of drug-induced steatosis and cholestasis. In summary, our mouse liver spheroids represent a valuable in vitro model that can be applied to study DILI findings, reported from mouse studies, and offers the potential to detect immune-mediated drug-induced liver toxicity.
MeSH term(s)	Animals ; Anti-Bacterial Agents/toxicity ; Anti-Inflammatory Agents, Non-Steroidal/toxicity ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/immunology ; Chemical and Drug Induced Liver Injury/metabolism ; Hepatocytes/metabolism ; Immunity, Innate ; Liver/drug effects ; Liver/pathology ; Mice ; Models, Biological ; Primary Cell Culture/methods ; Spheroids, Cellular/cytology ; Spheroids, Cellular/immunology ; Spheroids, Cellular/metabolism
Chemical Substances	Anti-Bacterial Agents ; Anti-Inflammatory Agents, Non-Steroidal
Language	English
Publishing date	2020-07-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0235745
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Article ; Online: Neutrophilic infiltration in organ-on-a-chip model of tissue inflammation.

Gjorevski, Nikolce / Avignon, Blandine / Gérard, Régine / Cabon, Lauriane / Roth, Adrian B / Bscheider, Michael / Moisan, Annie

Lab on a chip

2020 Volume 20, Issue 18, Page(s) 3365–3374

Abstract: The multiphasic etiology of tissue inflammation and the fundamental immunological differences between species render inflammatory pathologies difficult to recapitulate in animal models, and account for the paucity of therapies that are successfully ... ...

Abstract	The multiphasic etiology of tissue inflammation and the fundamental immunological differences between species render inflammatory pathologies difficult to recapitulate in animal models, and account for the paucity of therapies that are successfully translated from rodents to humans. Here, we present a human-relevant organ-on-a-chip platform for experimental inflammatory diseases. We created an immunocompetent in vitro gut model by incorporating intestinal epithelial and immune cells into microfluidic chambers that permit cell movement across an extracellular matrix (ECM) and fluidic channels. This is the first model that integrates a mucosal barrier, a three-dimensional ECM, resident and infiltrating immune cells, and simulates a functional crosstalk that ultimately triggers cellular processes representative of inflammation. Under homeostatic conditions, enterocytes form a tight epithelium and subepithelial macrophages are non-activated. Introduction of pro-inflammatory mediators triggers macrophage activation and inflammation-induced intestinal barrier leakiness. Neutrophils in a parallel, matrix-separated non-epithelial channel are attracted by such a pro-inflammatory microenvironment and migrate through the extracellular matrix, further exacerbating tissue inflammation and damage. With this model, we provide the foundations to recapitulate and investigate the onset of tissue inflammation in a controlled, human-relevant system.
MeSH term(s)	Animals ; Extracellular Matrix ; Homeostasis ; Inflammation ; Lab-On-A-Chip Devices ; Macrophages
Language	English
Publishing date	2020-08-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2056646-3
ISSN	1473-0189 ; 1473-0197
ISSN (online)	1473-0189
ISSN	1473-0197
DOI	10.1039/d0lc00417k
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Article ; Online: Concurrent isolation of hepatic stem cells and hepatocytes from the human liver.

Lee, Serene M L / Bertinetti-Lapatki, Cristina / Schiergens, Tobias S / Jauch, Karl-Walter / Roth, Adrian B / Thasler, Wolfgang E

In vitro cellular & developmental biology. Animal

2020 Volume 56, Issue 3, Page(s) 253–260

Abstract: Hepatocytes differentiated from induced pluripotent stem cells or stem cells have the potential to be representative in vitro models of the human liver for research as well as early safety assessment programs. However, up until now, there has been no ... ...

Abstract	Hepatocytes differentiated from induced pluripotent stem cells or stem cells have the potential to be representative in vitro models of the human liver for research as well as early safety assessment programs. However, up until now, there has been no definitive proof that differentiated hepatocytes recapitulate the phenotype and functional characteristics of primary hepatocytes from the same individual. Thus, a method for the concurrent isolation of hepatocytes and hepatic stem cells is presented here to provide the cells necessary for the evaluation of the required benchmarking. The method presented here generated high-quality hepatocytes with a purity of 94 ± 1% and a high percentage viability of 79 ± 2%. Furthermore, the hepatic stem cells isolated were found to be actively proliferating and have a purity of 98 ± 1%. Thus, these isolated cells can be used as a powerful tool for the validation of differentiated hepatocyte in vitro models.
MeSH term(s)	Cell Separation/methods ; Epithelial Cell Adhesion Molecule/metabolism ; Hepatocytes/cytology ; Humans ; Keratin-19/metabolism ; Liver/cytology ; Liver Cirrhosis/pathology ; Stem Cells/cytology ; Stem Cells/metabolism
Chemical Substances	Epithelial Cell Adhesion Molecule ; Keratin-19
Language	English
Publishing date	2020-03-27
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1077810-x
ISSN	1543-706X ; 0883-8364 ; 1071-2690
ISSN (online)	1543-706X
ISSN	0883-8364 ; 1071-2690
DOI	10.1007/s11626-020-00433-w
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Article: Concurrent isolation of hepatic stem cells and hepatocytes from the human liver

Lee, Serene M. L / Bertinetti-Lapatki, Cristina / Schiergens, Tobias S / Jauch, Karl-Walter / Roth, Adrian B / Thasler, Wolfgang E

In vitro cellular & developmental biology. 2020 Mar., v. 56, no. 3

2020

Abstract	Hepatocytes differentiated from induced pluripotent stem cells or stem cells have the potential to be representative in vitro models of the human liver for research as well as early safety assessment programs. However, up until now, there has been no definitive proof that differentiated hepatocytes recapitulate the phenotype and functional characteristics of primary hepatocytes from the same individual. Thus, a method for the concurrent isolation of hepatocytes and hepatic stem cells is presented here to provide the cells necessary for the evaluation of the required benchmarking. The method presented here generated high-quality hepatocytes with a purity of 94 ± 1% and a high percentage viability of 79 ± 2%. Furthermore, the hepatic stem cells isolated were found to be actively proliferating and have a purity of 98 ± 1%. Thus, these isolated cells can be used as a powerful tool for the validation of differentiated hepatocyte in vitro models.
Keywords	functional properties ; hepatocytes ; humans ; induced pluripotent stem cells ; liver ; models ; phenotype ; safety assessment ; viability
Language	English
Dates of publication	2020-03
Size	p. 253-260.
Publishing place	Springer US
Document type	Article
ISSN	1071-2690
DOI	10.1007/s11626-020-00433-w
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Article ; Online: Use of early phenotypic in vivo markers to assess human relevance of an unusual rodent non-genotoxic carcinogen in vitro.

Boess, Franziska / Lenz, Barbara / Funk, Juergen / Niederhauser, Urs / Bassett, Simon / Zhang, Jitao David / Singer, Thomas / Roth, Adrian B

Toxicology

2017 Volume 379, Page(s) 48–61

Abstract: Foci of altered hepatocytes (FAH) are considered putative, pre-neoplastic lesions that can occur spontaneously in aging rodents, but can also be induced by chemicals or drugs. Progression of FAH to hepatocellular neoplasms has been reported repeatedly ... ...

Abstract	Foci of altered hepatocytes (FAH) are considered putative, pre-neoplastic lesions that can occur spontaneously in aging rodents, but can also be induced by chemicals or drugs. Progression of FAH to hepatocellular neoplasms has been reported repeatedly but increases in foci in rodents do not necessarily lead to tumors in carcinogenicity studies and the relevance for humans often remains unclear. Here we present the case of RG3487, a molecule which induced FAH and, later on, tumors in rats. Because the molecule was negative in genotoxicity assays it was classified as a non-genotoxic carcinogen. In order to assess the potential for liver tumor formation in humans, we analyzed treatment-induced changes in vivo to establish a possible mode of action (MoA). In vivo and in vitro gene expression analysis revealed that nuclear receptor signaling was unlikely to be the relevant MoA and no other known mechanism could be established. We therefore took an approach comparing phenotypic markers, including mRNA changes, proliferation and glycogen accumulation, in vitro using cells of different species to assess the human relevance of this finding. Since the alterations observed in rats were not seen in the liver of mice or dogs in vivo, we could validate the relevance of the cell models chosen by use of hepatocytes from these species in vitro. This ultimately allowed for a cross-species comparison, which suggested that the formation of FAH and liver tumors was rat specific and unlikely to translate to human. Our work showed that phenotypic species comparison in vitro is a useful approach for assessment of the human relevance of pre-clinical findings where no known mechanism can be established.
MeSH term(s)	Animals ; Biomarkers ; Bridged Bicyclo Compounds/toxicity ; Carcinogens/toxicity ; Cells, Cultured ; DNA Replication/drug effects ; Dogs ; Gene Expression Regulation/drug effects ; Hepatocytes/drug effects ; Humans ; Indazoles/toxicity ; Male ; Mice ; Phenotype ; Rats ; Species Specificity
Chemical Substances	Biomarkers ; Bridged Bicyclo Compounds ; Carcinogens ; Indazoles ; N-((3S)-1-azabicyclo(2.2.2)oct-3-yl)-1H-indazole-3-carboxamide hydrochloride (O6J463N18M)
Language	English
Publishing date	2017-02-05
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	184557-3
ISSN	1879-3185 ; 0300-483X
ISSN (online)	1879-3185
ISSN	0300-483X
DOI	10.1016/j.tox.2017.01.018
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Article ; Online: Are Biotransformation Studies of Therapeutic Proteins Needed? Scientific Considerations and Technical Challenges.

Schadt, Simone / Hauri, Simon / Lopes, Filipe / Edelmann, Martin R / Staack, Roland F / Villaseñor, Roberto / Kettenberger, Hubert / Roth, Adrian B / Schuler, Franz / Richter, Wolfgang F / Funk, Christoph

Drug metabolism and disposition: the biological fate of chemicals

2019 Volume 47, Issue 12, Page(s) 1443–1456

Abstract: For therapeutic proteins, the currently established standard development path generally does not foresee biotransformation studies by default because it is well known that the clearance of therapeutic proteins proceeds via degradation to small peptides ... ...

Abstract	For therapeutic proteins, the currently established standard development path generally does not foresee biotransformation studies by default because it is well known that the clearance of therapeutic proteins proceeds via degradation to small peptides and individual amino acids. In contrast to small molecules, there is no general need to identify enzymes involved in biotransformation because this information is not relevant for drug-drug interaction assessment and for understanding the clearance of a therapeutic protein. Nevertheless, there are good reasons to embark on biotransformation studies, especially for complex therapeutic proteins. Typical triggers are unexpected rapid clearance, species differences in clearance not following the typical allometric relationship, a mismatch in the pharmacokinetics/pharmacodynamics (PK/PD) relationship, and the need to understand observed differences between the results of multiple bioanalytical methods (e.g., total vs. target-binding competent antibody concentrations). Early on during compound optimization, knowledge on protein biotransformation may help to design more stable drug candidates with favorable in vivo PK properties. Understanding the biotransformation of a therapeutic protein may also support designing and understanding the bioanalytical assay and ultimately the PK/PD assessment. Especially in cases where biotransformation products are pharmacologically active, quantification and assessment of their contribution to the overall pharmacological effect can be important for establishing a PK/PD relationship and extrapolation to humans. With the increasing number of complex therapeutic protein formats, the need for understanding the biotransformation of therapeutic proteins becomes more urgent. This article provides an overview on biotransformation processes, proteases involved, strategic considerations, regulatory guidelines, literature examples for in vitro and in vivo biotransformation, and technical approaches to study protein biotransformation. SIGNIFICANCE STATEMENT: Understanding the biotransformation of complex therapeutic proteins can be crucial for establishing a pharmacokinetic/pharmacodynamic relationship. This article will highlight scientific, strategic, regulatory, and technological features of protein biotransformation.
MeSH term(s)	Animals ; Biotransformation ; Drug Interactions ; Humans ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/metabolism ; Proteins/administration & dosage ; Proteins/pharmacokinetics ; Proteins/pharmacology ; Small Molecule Libraries/administration & dosage ; Small Molecule Libraries/pharmacokinetics ; Small Molecule Libraries/pharmacology
Chemical Substances	Pharmaceutical Preparations ; Proteins ; Small Molecule Libraries
Language	English
Publishing date	2019-12-02
Publishing country	United States
Document type	Journal Article
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.119.088997
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Article ; Online: Combining In Vivo and Organotypic In Vitro Approaches to Assess the Human Relevance of Basimglurant (RG7090), a Potential CAR Activator.

Nudischer, Ramona / Renggli, Kasper / Bertinetti-Lapatki, Cristina / Hoflack, Jean-Christophe / Flint, Nicholas / Sewing, Sabine / Pedersen, Lykke / Schadt, Simone / Higgins, Larry G / Vardy, Audrey / Lenz, Barbara / Gand, Laurent / Boess, Franziska / Elcombe, Barbara M / Hierlemann, Andreas / Roth, Adrian B

Toxicological sciences : an official journal of the Society of Toxicology

2020 Volume 176, Issue 2, Page(s) 329–342

Abstract: Basimglurant (RG7090), a small molecule under development to treat certain forms of depression, demonstrated foci of altered hepatocytes in a long-term rodent-toxicity study. Additional evidence pointed toward the activation of the constitutive ... ...

Abstract	Basimglurant (RG7090), a small molecule under development to treat certain forms of depression, demonstrated foci of altered hepatocytes in a long-term rodent-toxicity study. Additional evidence pointed toward the activation of the constitutive androstane receptor (CAR), an established promoter of nongenotoxic and rodent-specific hepatic tumors. This mode of action and the potential human relevance was explored in vivo using rodent and cynomolgus monkey models and in vitro using murine and human liver spheroids. Wild type (WT) and CAR/pregnane X receptor (PXR) knockout mice (CAR/PXR KO) were exposed to RG7090 for 8 consecutive days. Analysis of liver lysates revealed induction of Cyp2b mRNA and enzyme activity, a known activation marker of CAR, in WT but not in CAR/PXR KO animals. A series of proliferative genes were upregulated in WT mice only, and immunohistochemistry data showed increased cell proliferation exclusively in WT mice. In addition, primary mouse liver spheroids were challenged with RG7090 in the presence or absence of modified antisense oligonucleotides inhibiting CAR and/or PXR mRNA, showing a concentration-dependent Cyp2b mRNA induction only if CAR was not repressed. On the contrary, neither human liver spheroids nor cynomolgus monkeys exposed to RG7090 triggered CYP2B mRNA upregulation. Our data suggested RG7090 to be a rodent-specific CAR activator, and that CAR activation and its downstream processes were involved in the foci of altered hepatocytes formation detected in vivo. Furthermore, we demonstrated the potential of a new in vitro approach using liver spheroids and antisense oligonucleotides for CAR knockdown experiments, which could eventually replace in vivo investigations using CAR/PXR KO mice.
MeSH term(s)	Animals ; Hepatocytes ; Humans ; Imidazoles/pharmacology ; Liver ; Macaca fascicularis ; Mice ; Mice, Inbred C57BL ; Organoids ; Pyridines/pharmacology ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Steroid
Chemical Substances	2-chloro-4-(1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl)pyridine ; Imidazoles ; Pyridines ; Receptors, Cytoplasmic and Nuclear ; Receptors, Steroid ; constitutive androstane receptor (438XLITDI3)
Language	English
Publishing date	2020-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfaa076
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Article ; Online: Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro.

Nguyen, Deborah G / Funk, Juergen / Robbins, Justin B / Crogan-Grundy, Candace / Presnell, Sharon C / Singer, Thomas / Roth, Adrian B

PloS one

2016 Volume 11, Issue 7, Page(s) e0158674

Abstract: Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level ... ...

Abstract	Modeling clinically relevant tissue responses using cell models poses a significant challenge for drug development, in particular for drug induced liver injury (DILI). This is mainly because existing liver models lack longevity and tissue-level complexity which limits their utility in predictive toxicology. In this study, we established and characterized novel bioprinted human liver tissue mimetics comprised of patient-derived hepatocytes and non-parenchymal cells in a defined architecture. Scaffold-free assembly of different cell types in an in vivo-relevant architecture allowed for histologic analysis that revealed distinct intercellular hepatocyte junctions, CD31+ endothelial networks, and desmin positive, smooth muscle actin negative quiescent stellates. Unlike what was seen in 2D hepatocyte cultures, the tissues maintained levels of ATP, Albumin as well as expression and drug-induced enzyme activity of Cytochrome P450s over 4 weeks in culture. To assess the ability of the 3D liver cultures to model tissue-level DILI, dose responses of Trovafloxacin, a drug whose hepatotoxic potential could not be assessed by standard pre-clinical models, were compared to the structurally related non-toxic drug Levofloxacin. Trovafloxacin induced significant, dose-dependent toxicity at clinically relevant doses (≤ 4uM). Interestingly, Trovafloxacin toxicity was observed without lipopolysaccharide stimulation and in the absence of resident macrophages in contrast to earlier reports. Together, these results demonstrate that 3D bioprinted liver tissues can both effectively model DILI and distinguish between highly related compounds with differential profile. Thus, the combination of patient-derived primary cells with bioprinting technology here for the first time demonstrates superior performance in terms of mimicking human drug response in a known target organ at the tissue level.
MeSH term(s)	Albumins/metabolism ; Bioprinting ; Cell Culture Techniques ; Cell Proliferation ; Cells, Cultured ; Chemical and Drug Induced Liver Injury/diagnosis ; Cytochrome P-450 CYP3A/metabolism ; Drug-Related Side Effects and Adverse Reactions ; Fluoroquinolones/administration & dosage ; Hepatocytes/cytology ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Humans ; Image Processing, Computer-Assisted ; Imaging, Three-Dimensional ; Levofloxacin/administration & dosage ; Lipopolysaccharides/metabolism ; Liver/drug effects ; Liver/metabolism ; Naphthyridines/administration & dosage ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism
Chemical Substances	Albumins ; Fluoroquinolones ; Lipopolysaccharides ; Naphthyridines ; Platelet Endothelial Cell Adhesion Molecule-1 ; Levofloxacin (6GNT3Y5LMF) ; trovafloxacin (9F388J00UK) ; Cytochrome P-450 CYP3A (EC 1.14.14.1) ; CYP3A4 protein, human (EC 1.14.14.55)
Language	English
Publishing date	2016-07-07
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0158674
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Article ; Online: Temporal Patterns of Novel Circulating Biomarkers in IL-2-mediated Vascular Injury in the Rat.

Keirstead, Natalie D / Bertinetti-Lapatki, Cristina / Knapp, Denise / Albassam, Mudher / Hughes, Valerie / Hong, Feng / Roth, Adrian B / Mikaelian, Igor

Toxicologic pathology

2015 Volume 43, Issue 7, Page(s) 984–994

Abstract: Recombinant interleukin-2 (rIL-2) administration in oncology indications is hampered by vascular toxicity, which presents as a vascular leak syndrome. We used this aspect of the toxicity of rIL-2 to evaluate candidate biomarkers of drug-induced vascular ... ...

Abstract	Recombinant interleukin-2 (rIL-2) administration in oncology indications is hampered by vascular toxicity, which presents as a vascular leak syndrome. We used this aspect of the toxicity of rIL-2 to evaluate candidate biomarkers of drug-induced vascular injury (DIVI) in rats given 0.36 mg/kg rIL-2 daily. Groups of rats were given either 2 or 5 doses of rIL-2 or 5 doses of rIL-2 followed by a 7-day recovery. The histomorphologic lexicon and grading scheme developed by the Vascular Injury Working Group of the Predictive Safety Testing Consortium of the Critical Path Institute were utilized to enable semiquantitative integration with circulating biomarker levels. The administration of rIL-2 was associated with time-dependent endothelial cell hyperplasia and hypertrophy and perivascular inflammation that correlated with increases in circulating angiopoietin-2, lipocalin-2, monocyte chemotactic protein-1, tissue inhibitor of metalloproteinase-1, vascular endothelial growth factor A, E-selectin, and chemokine (C-X-C motif) ligand-1, and the microRNAs miR-21, miR-132, and miR-155. The dose groups were differentially identified by panels comprising novel candidate biomarkers and traditional hematologic parameters. These results identify biomarkers of the early stages of DIVI prior to the onset of vascular smooth muscle necrosis.
MeSH term(s)	Animals ; Biomarkers/blood ; Immunohistochemistry ; In Situ Hybridization ; Interleukin-2/toxicity ; Male ; Rats ; Rats, Wistar ; Real-Time Polymerase Chain Reaction ; Recombinant Proteins/toxicity ; Vascular System Injuries/blood ; Vascular System Injuries/chemically induced
Chemical Substances	Biomarkers ; Interleukin-2 ; Recombinant Proteins
Language	English
Publishing date	2015-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	841009-4
ISSN	1533-1601 ; 0192-6233
ISSN (online)	1533-1601
ISSN	0192-6233
DOI	10.1177/0192623315601245
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Zs.A 1975: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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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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