A5077350810- Carcinogens and Genotoxicity Assessment
- Computational Drug Discovery Methods
- Cardiac electrophysiology and arrhythmias
- Pharmacogenetics and Drug Metabolism
- 3D Printing in Biomedical Research
- Pluripotent Stem Cells Research
- Gene expression and cancer classification
- Drug Transport and Resistance Mechanisms
- Neuroscience and Neural Engineering
- Drug-Induced Hepatotoxicity and Protection
- Melanoma and MAPK Pathways
- Protein Degradation and Inhibitors
- Biomedical Ethics and Regulation
- Animal testing and alternatives
- CRISPR and Genetic Engineering
- Bioinformatics and Genomic Networks
- Ion channel regulation and function
- Antioxidant Activity and Oxidative Stress
- Thyroid Disorders and Treatments
- Genomics, phytochemicals, and oxidative stress
- Chemotherapy-induced cardiotoxicity and mitigation
- Toxic Organic Pollutants Impact
- Estrogen and related hormone effects
- Statistical Methods in Clinical Trials
- Growth Hormone and Insulin-like Growth Factors
Bristol-Myers Squibb (United States)
2020-2023
Bristol-Myers Squibb (Germany)
2021
Summit School
2020
Cellular Dynamics International (United States)
2013-2015
La Roche College
2010-2013
Roche (Switzerland)
2007-2013
Roche (United States)
2008-2009
Tonix Pharmaceuticals (United States)
2005-2006
Epix Pharmaceuticals (United States)
2006
Pfizer (United States)
2004
Human-induced pluripotent stem cells (hiPSCs) can differentiate into functional cardiomyocytes; however, the electrophysiological properties of hiPSC-derived cardiomyocytes have yet to be fully characterized. We performed detailed characterization highly pure cardiomyocytes. Action potentials (APs) were recorded from spontaneously beating using a perforated patch method and had atrial-, nodal-, ventricular-like properties. Ventricular-like APs more common maximum diastolic close those human...
Improved in vitro systems for predicting drug-induced toxicity are needed the pharmaceutical and biotechnology industries to decrease late-stage drug attrition. One unmet need is an early screen cardiotoxicity, which accounts about one third of safety-based withdrawn pharmaceuticals. Herein, first published report a high-throughput functional assay employing monolayer beating human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) described, detailing model that accurately...
Diabetic cardiomyopathy is a complication of type 2 diabetes, with known contributions lifestyle and genetics. We develop environmentally genetically driven in vitro models the condition using human-induced-pluripotent-stem-cell-derived cardiomyocytes. First, we mimic diabetic clinical chemistry to induce phenotypic surrogate cardiomyopathy, observing structural functional disarray. Next, consider genetic effects by deriving cardiomyocytes from two patients variable disease progression. The...
Expression of Cyp1a1 and its related enzyme activity have long been used as a biomarker for aryl hydrocarbon receptor (AhR) activation warning dioxin-like toxicity. As result, induction by pharmaceutical drug candidates or environmental contaminants raises significant concern in risk assessment. The current study evaluates the specificity marker AhR affinity provides context to assess relevancy In vivo experiments examined expression other AhR-regulated genes liver, kidney, heart response...
Human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs) are capable of detecting drug-induced clinical arrhythmia, Torsade de Pointes (TdP), and QT prolongation. Efforts herein employ a broad set structurally diverse drugs to optimize the predictive algorithm for applications in discovery toxicology cardiac safety screening. The changes beat rhythm rate confluent monolayer hiPS-CMs by 88 marketed 30 internal compounds were detected with real-time cellular impedance measurement...
To gain insight into the molecular regulation of human heart development, a detailed comparison mRNA and miRNA transcriptomes across differentiating human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes biopsies from fetal, adult, hypertensive hearts was performed. Gene ontology analysis expression levels hiPSCs revealed 3 distinct groups genes: specific, transitional cardiac specification, mature cardiomyocyte specific. Hierarchical clustering data that transcriptome hiPSC...
One application of genomics in drug safety assessment is the identification biomarkers to predict compound toxicity before it detected using traditional approaches, such as histopathology. However, many genomic approaches have failed demonstrate superiority methods, not been appropriately validated on external samples, or derived small data sets, thus raising concerns their general applicability. Using kidney gene expression profiles from male SD rats treated with 64 nephrotoxic...
Oxidative stress results when the balance between production of reactive oxygen species (ROS) overrides antioxidant capability target cell; oxidative damage from interaction with critical cellular macromolecules may occur.ROS interact and modify protein, lipid, DNA, which in altered cell function.The accumulation has been implicated both acute chronic injury including possible participation formation cancer.Acute produce selective death a compensatory increase proliferation.This stimulus...
There is need in the pharmaceutical and chemical industries for high-throughput human cell-based assays identifying hazardous chemicals, thereby reducing overall reliance on animal studies predicting risk of toxic responses humans. Despite instances human-specific teratogens such as thalidomide, use cell-teratogenicity has just started to be explored. Herein, a pluripotent stem cell test (hPST) described, benchmarking vitro findings traditional preclinical toxicology teratogenicity when...
Currently, the only way to identify nongenotoxic hepatocarcinogens is through long-term repeat dose studies such as 2 year rodent carcinogenicity assay. Such assays are both time consuming and expensive require large amounts of active pharmaceutical or chemical ingredients. Thus, results assay not known until very late in discovery development process for new entities. Although many cases rodents considered be irrelevant humans, a positive finding may increase number demonstrate lack...
Background/aims: Monitoring changes in the field potential (FP) of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) following compound administration has been proposed as a novel screening tool to evaluate cardiac ion channel interactions and QT liability. Here we extended use FP pharmacological toxicological properties glycosides. Methods: FPs were recorded using microelectrode arrays (MEAs) spontaneously beating hiPSC-CMs. The vitro effects ouabain digoxin on compared...
Drug-induced gastrointestinal toxicity (GIT) is a common treatment-emergent adverse event that can negatively impact dosing, thereby limiting efficacy and treatment options for patients. An in vitro assay of GIT needed to address patient variability, mimic the microphysiology gut, accurately predict drug-induced GIT. Primary human ileal organoids (termed 'enteroids') have proven useful stimulating intestinal stem cell proliferation differentiation multiple types present gut epithelium....
Exposure to thalidomide during a critical window of development results in limb defects humans and non-human primates while mice rats are refractory these effects. Thalidomide-induced teratogenicity is dependent on its binding cereblon (CRBN), the substrate receptor Cul4A-DDB1-CRBN-RBX1 E3 ubiquitin ligase complex. Thalidomide CRBN elicits subsequent ubiquitination proteasomal degradation neosubstrates including SALL4, transcription factor which polymorphisms phenocopy thalidomide-induced...
Kinases are heavily pursued pharmaceutical targets because of their mechanistic role in many diseases. Small molecule kinase inhibitors (SMKIs) a compound class that includes marketed drugs and compounds various stages drug development. While effective, SMKIs have been associated with toxicity including chromosomal damage. Screening for kinase-mediated as early possible is crucial, better understanding how off-target inhibition may give rise to To end, we employed competitive binding assay...