Predicting oncology drug-induced cardiotoxicity with donor-specific iPSC-CMs-a proof-of-concept study with doxorubicin.

Many oncology drugs have been found to induce cardiotoxicity in a subset of patients, which significantly limits their clinical use and impedes the benefit of lifesaving anticancer treatments. Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carry donor-specific genetic information and have been proposed for exploring the interindividual difference in oncology drug-induced cardiotoxicity. Herein, we evaluated the inter- and intraindividual variability of iPSC-CM-related assays and presented a proof of concept to prospectively predict doxorubicin (DOX)-induced cardiotoxicity (DIC) using donor-specific iPSC-CMs.

US FDA public meeting: identification of concepts and terminology for multicomponent biomarkers.

The US FDA convened a virtual public workshop with the goals of obtaining feedback on the terminology needed for effective communication of multicomponent biomarkers and discussing the diverse use of biomarkers observed across the FDA and identifying common issues. The workshop included keynote and background presentations addressing the stated goals, followed by a series of case studies highlighting FDA-wide and external experience regarding the use of multicomponent biomarkers, which provided context for panel discussions focused on common themes, challenges and preferred terminology. The final panel discussion integrated the main concepts from the keynote, background presentations and case studies, laying a preliminary foundation to build consensus around the use and terminology of multicomponent biomarkers.

Nitrosative Stress and Lipid Homeostasis as a Mechanism for Zileuton Hepatotoxicity and Resistance in Genetically Sensitive Mice.

Zileuton is an orally active inhibitor of leukotriene synthesis for maintenance treatment of asthma, for which clinical usage has been associated with idiosyncratic liver injury. Mechanistic understanding of zileuton toxicity is hampered by the rarity of the cases and lack of an animal model. A promising model for mechanistic study of rare liver injury is the Diversity Outbred (J:DO) mouse population, with genetic variation similar to that found in humans.

Recent advances in understanding the hepatotoxicity associated with protein kinase inhibitors.

: As of October 2019, the U.S. Food and Drug Administration (FDA) has approved 53 small molecule kinase inhibitors (KI), which account for about 10% of all FDA-approved new molecular entities and new biologics in the past two decades.

Comprehensive Identification and Characterization of Human Secretome Based on Integrative Proteomic and Transcriptomic Data.

Secreted proteins (SPs) play important roles in diverse important biological processes; however, a comprehensive and high-quality list of human SPs is still lacking. Here we identified 6,943 high-confidence human SPs (3,522 of them are novel) based on 330,427 human proteins derived from databases of UniProt, Ensembl, AceView, and RefSeq. Notably, 6,267 of 6,943 (90.

Dr. Daniel Acosta and In Vitro toxicology at the U.S. Food and Drug Administration's National Center for Toxicological Research.

For the past five years, Dr. Daniel Acosta has served as the Deputy Director of Research at the National Center for Toxicological Research (NCTR), a principle research laboratory of the U.S.

Computational identification of structural factors affecting the mutagenic potential of aromatic amines: study design and experimental validation.

A grid-based, alignment-independent 3D-SDAR (three-dimensional spectral data-activity relationship) approach based on simulated C and N NMR chemical shifts augmented with through-space interatomic distances was used to model the mutagenicity of 554 primary and 419 secondary aromatic amines. A robust modeling strategy supported by extensive validation including randomized training/hold-out test set pairs, validation sets, "blind" external test sets as well as experimental validation was applied to avoid over-parameterization and build Organization for Economic Cooperation and Development (OECD 2004) compliant models. Based on an experimental validation set of 23 chemicals tested in a two-strain Salmonella typhimurium Ames assay, 3D-SDAR was able to achieve performance comparable to 5-strain (Ames) predictions by Lhasa Limited's Derek and Sarah Nexus for the same set.

Cytotoxicity of 34 FDA approved small-molecule kinase inhibitors in primary rat and human hepatocytes.

Of the 34 FDA approved oral small-molecule kinase inhibitors (KI), 23 (68%) have warnings for hepatotoxicity in product labeling. To better understand the mechanisms of KI hepatotoxicity and whether such effects can be predicted, we examined 34 KIs for cytotoxicity in primary rat and human hepatocytes. The hepatocytes were treated with KIs at ten concentrations normalized to maximal therapeutic blood levels (Cmax).

Spatial and Ontogenetic Variation in Mercury in Lake Superior Basin Sea Lamprey (Petromyzon marinus).

Mercury concentrations were measured in eggs, larvae, and adult spawning-phase sea lampreys (Petromyzon marinus) collected in tributaries of Lake Superior to investigate spatial and ontogenetic variation. There were significant differences in mercury concentrations between all three life stages, with levels highest in adults (mean = 3.01 µg/g), followed by eggs (mean = 0.

Regulatory landscapes for biomarkers and diagnostic tests: Qualification, approval, and role in clinical practice.

While the term 'biomarker' is relatively new, the concept is millennia old. However, with the introduction of new technologies to discover potential biomarkers comes the need to assess their utility and veracity for any given use. This is particularly true for the use of biomarkers to support regulatory decisions in medical product development.

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans.

Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine.

The Promise of New Technologies to Reduce, Refine, or Replace Animal Use while Reducing Risks of Drug Induced Liver Injury in Pharmaceutical Development.

Drug induced liver injury (DILI) has contributed more to marketed pharmaceutical withdrawals and clinical development failures than any other human organ toxicity. DILI seen in animal studies also frequently leads to the discontinuation of promising drug candidates very early in the pipeline. This manuscript reviews and critically assesses the current regulatory expectations; the current drug development approaches, strategies, and gaps; and the numerous exciting opportunities becoming available to address these gaps through technological advances.

Effects of 31 FDA approved small-molecule kinase inhibitors on isolated rat liver mitochondria.

The FDA has approved 31 small-molecule kinase inhibitors (KIs) for human use as of November 2016, with six having black box warnings for hepatotoxicity (BBW-H) in product labeling. The precise mechanisms and risk factors for KI-induced hepatotoxicity are poorly understood. Here, the 31 KIs were tested in isolated rat liver mitochondria, an in vitro system recently proposed to be a useful tool to predict drug-induced hepatotoxicity in humans.

Molecular Docking for Identification of Potential Targets for Drug Repurposing.

Using existing drugs for new indications (drug repurposing) is an effective method not only to reduce drug development time and costs but also to develop treatments for new disease including those that are rare. In order to discover novel indications, potential target identification is a necessary step. One widely used method to identify potential targets is through molecule docking.

Circulating mitochondrial biomarkers for drug-induced liver injury.

Liver mitochondria affected by drugs can be released into circulation and serve as biomarkers for drug-induced liver injury (DILI). The tissue specificity of ALT was improved by differentiating cytosolic ALT1 and mitochondrial ALT2 isoforms released in circulation. Prior to ALT elevation, mitochondrial cytochrome c, OCT, GLDH, CPS1 and DNA were increased in circulation following DILI.

microRNAs as pharmacogenomic biomarkers for drug efficacy and drug safety assessment.

Much evidence has documented that microRNAs (miRNAs) play an important role in the modulation of interindividual variability in the production of drug metabolizing enzymes and transporters (DMETs) and nuclear receptors (NRs) through multidirectional interactions involving environmental stimuli/stressors, the expression of miRNA molecules and genetic polymorphisms. MiRNA expression has been reported to be affected by drugs and miRNAs themselves may affect drug metabolism and toxicity. In cancer research, miRNA biomarkers have been identified to mediate intrinsic and acquired resistance to cancer therapies.

Understanding and predicting binding between human leukocyte antigens (HLAs) and peptides by network analysis.

Background: As the major histocompatibility complex (MHC), human leukocyte antigens (HLAs) are one of the most polymorphic genes in humans. Patients carrying certain HLA alleles may develop adverse drug reactions (ADRs) after taking specific drugs. Peptides play an important role in HLA related ADRs as they are the necessary co-binders of HLAs with drugs.

Potential of extracellular microRNAs as biomarkers of acetaminophen toxicity in children.

Unlabelled: Developing biomarkers for detecting acetaminophen (APAP) toxicity has been widely investigated. Recent studies of adults with APAP-induced liver injury have reported human serum microRNA-122 (miR-122) as a novel biomarker of APAP-induced liver injury. The goal of this study was to examine extracellular microRNAs (miRNAs) as potential biomarkers for APAP liver injury in children.

Regorafenib impairs mitochondrial functions, activates AMP-activated protein kinase, induces autophagy, and causes rat hepatocyte necrosis.

The tyrosine kinase inhibitor regorafenib was approved by regulatory agencies for cancer treatment, albeit with strong warnings of severe hepatotoxicity included in the product label. The basis of this toxicity is unknown; one possible mechanism, that of mitochondrial damage, was tested. In isolated rat liver mitochondria, regorafenib directly uncoupled oxidative phosphorylation (OXPHOS) and promoted calcium overload-induced swelling, which were respectively prevented by the recoupler 6-ketocholestanol (KC) and the mitochondrial permeability transition (MPT) pore blocker cyclosporine A (CsA).

An integrated flow cytometry-based system for real-time, high sensitivity bacterial detection and identification.

Foodborne illnesses occur in both industrialized and developing countries, and may be increasing due to rapidly evolving food production practices. Yet some primary tools used to assess food safety are decades, if not centuries, old. To improve the time to result for food safety assessment a sensitive flow cytometer based system to detect microbial contamination was developed.

Green tea epigallocatechin gallate binds to and inhibits respiratory complexes in swelling but not normal rat hepatic mitochondria.

Epigallocatechin gallate (EGCG), the major flavonoid in green tea, is consumed via tea products and dietary supplements, and has been tested in clinical trials. However, EGCG can cause hepatotoxicity in humans and animals by unknown mechanisms. Here EGCG effects on rat liver mitochondria were examined.

Biomarkers of tobacco smoke exposure.

Diseases and death caused by exposure to tobacco smoke have become the single most serious preventable public health concern. Thus, biomarkers that can monitor tobacco exposure and health effects can play a critical role in tobacco product regulation and public health policy. Biomarkers of exposure to tobacco toxicants are well established and have been used in population studies to establish public policy regarding exposure to second-hand smoke, an example being the nicotine metabolite cotinine, which can be measured in urine.