Improved Detection of Drug-Induced Liver Injury by Integrating Predicted and Data.

Drug-induced liver injury (DILI) has been a significant challenge in drug discovery, often leading to clinical trial failures and necessitating drug withdrawals. Over the last decade, the existing suite of proxy-DILI assays has generally improved at identifying compounds with hepatotoxicity. However, there is considerable interest in enhancing the prediction of DILI because it allows for evaluating large sets of compounds more quickly and cost-effectively, particularly in the early stages of projects.

Improved Detection of Drug-Induced Liver Injury by Integrating Predicted and Data.

Drug-induced liver injury (DILI) has been significant challenge in drug discovery, often leading to clinical trial failures and necessitating drug withdrawals. The existing suite of in vitro proxy-DILI assays is generally effective at identifying compounds with hepatotoxicity. However, there is considerable interest in enhancing in silico prediction of DILI because it allows for the evaluation of large sets of compounds more quickly and cost-effectively, particularly in the early stages of projects.

Investigation of the functional impact of CHED- and FECD4-associated SLC4A11 mutations in human corneal endothelial cells.

Mutations in the solute linked carrier family 4 member 11 (SLC4A11) gene are associated with congenital hereditary endothelial dystrophy (CHED) and Fuchs corneal endothelial dystrophy type 4 (FECD4), both characterized by corneal endothelial cell (CEnC) dysfunction and/or cell loss leading to corneal edema and visual impairment. In this study, we characterize the impact of CHED-/FECD4-associated SLC4A11 mutations on CEnC function and SLC4A11 protein localization by generating and comparing human CEnC (hCEnC) lines expressing wild type SLC4A11 (SLC4A11WT) or mutant SLC4A11 harboring CHED-/FECD4-associated SLC4A11 mutations (SLC4A11MU). SLC4A11WT and SLC4A11MU hCEnC lines were generated to express either SLC4A11 variant 2 (V2WT and V2MU) or variant 3 (V3WT and V3MU), the two major variants expressed in ex vivo hCEnC.

Keratitis Fugax Hereditaria Associated With a Novel NLRP3 Mutation in a Non-Finnish Patient.

Purpose: The aim of this study was to report a novel heterozygous variant c.1712G>T (p.Gly571Val) in the nucleotide-binding domain, leucine-rich repeat family, pyrin domain-containing 3 gene ( NLRP3 ) in a previously unreported non-Finnish individual with keratitis fugax hereditaria (KFH).

44-year-old Man with Hemoptysis and Hypoxemic Respiratory Failure: A Case Report.

Introduction: Hemoptysis can be a highly alarming presentation in the emergency department (ED). Even seemingly minor cases may represent potentially lethal underlying pathology. It requires thorough evaluation and careful consideration of a broad differential diagnosis.

Raspberry plant stress detection using hyperspectral imaging.

Monitoring plant responses to stress is an ongoing challenge for crop breeders, growers, and agronomists. The measurement of below-ground stress is particularly challenging as plants do not always show visible signs of stress in the above-ground organs, particularly at early stages. Hyperspectral imaging is a technique that could be used to overcome this challenge if associations between plant spectral data and specific stresses can be determined.

Novel DCN Mutation in Armenian Family With Congenital Stromal Corneal Dystrophy.

Purpose: Congenital stromal corneal dystrophy (CSCD) is a rare congenital, dominantly inherited disorder characterized by diffuse stromal opacification associated with mutations in the decorin gene ( DCN ). As only 5 families with genetically confirmed CSCD have been reported, the identification of a novel pedigree provides the opportunity to better characterize the phenotype and genetic basis.

Methods: An Armenian family with individuals in 4 consecutive generations demonstrated clinical features consistent with CSCD.

approaches in organ toxicity hazard assessment: current status and future needs in predicting liver toxicity.

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed.

Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.

Background: Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear.

The hepatocyte export carrier inhibition assay improves the separation of hepatotoxic from non-hepatotoxic compounds.

An in vitro/in silico method that determines the risk of human drug induced liver injury in relation to oral doses and blood concentrations of drugs was recently introduced. This method utilizes information on the maximal blood concentration (C) for a specific dose of a test compound, which can be estimated using physiologically-based pharmacokinetic modelling, and a cytotoxicity test in cultured human hepatocytes. In the present study, we analyzed if the addition of an assay that measures the inhibition of bile acid export carriers, like BSEP and/or MRP2, to the existing method improves the differentiation of hepatotoxic and non-hepatotoxic compounds.

Transfer of hepatocellular microRNA regulates cytochrome P450 2E1 in renal tubular cells.

Background: Extracellular microRNAs enter kidney cells and modify gene expression. We used a Dicer-hepatocyte-specific microRNA conditional-knock-out (Dicer-CKO) mouse to investigate microRNA transfer from liver to kidney.

Methods: Dicer mice were treated with a Cre recombinase-expressing adenovirus (AAV8) to selectively inhibit hepatocyte microRNA production (Dicer-CKO).

HepG2 (C3A) spheroids show higher sensitivity compared to HepaRG spheroids for drug-induced liver injury (DILI).

High-throughput, automation-friendly and therapeutically-predictive assays are needed in early drug discovery in order to prioritise compounds and reduce the risk of new drugs causing Drug-Induced Liver Injury (DILI). We evaluated the suitability of high-throughput 3D liver spheroid models of HepG2 (C3A clone) and HepaRG cell lines to predict DILI in early drug development. Spheroids were formed in 384-well ultra-low-attachment plates and dosed via direct acoustic droplet ejection at nine half-log spaced concentrations per compound.

"Before the training I just assumed they've done something bad": Reporting on professional training for pharmacy assistants and pharmacy dispensary technicians on medically assisted treatment of opioid dependence.

Background: A study that examined the lived experiences of Medically Assisted Treatment of Opioid Dependence (MATOD) consumers suggested that they had experienced discrimination and stigma in pharmacies in regional Victoria, Australia. To address this, the need for professional training opportunities for Pharmacy Assistants (PAs) and Pharmacy Dispensary Technicians (PTDs) had been emphasised. A research project was undertaken to develop training modules using Social Determinants of Health (SDH) for PAs and PDTs involved in providing MATOD pharmacy services in regional Victoria, and to evaluate their effectiveness.

Morphological and Mechanistic Aspects of Thiourea-Induced Acute Lung Injury and Tolerance in the Rat.

Thiourea-based molecules cause pulmonary edema when administered to rats at relatively low doses. However, rats survive normally lethal doses after prior exposure to a lower, nonlethal dose; this phenomenon is known as tolerance. The present study investigated the morphological and functional aspects of acute lung injury (ALI) induced by methylphenylthiourea (MPTU) in the Wistar rat and the pulmonary response involved in prevention of the injury.

The utility of a differentiated preclinical liver model, HepaRG cells, in investigating delayed toxicity via inhibition of mitochondrial-replication induced by fialuridine.

During its clinical development fialuridine caused liver toxicity and the death of five patients. This case remains relevant due to the continued development of mechanistically-related compounds against a back-drop of simple in vitro models which remain limited for the preclinical detection of such delayed toxicity. Here, proteomic investigation of a differentiated, HepaRG, and proliferating, HepG2 cell model was utilised to confirm the presence of the hENT1 transporter, thymidine kinase-1 and -2 (TK1, TK2) and thymidylate kinase, all essential in order to reproduce the cellular activation and disposition of fialuridine in the clinic.

Differences in Cardiovascular Care Between Adults With and Without Opioid Prescriptions in the United States.

Background Patients prescribed opioids often have chronic conditions that increase their risk of adverse cardiovascular outcomes, but little is known about the primary preventive cardiovascular care these patients receive. Methods and Results We analyzed data from the 2014 to 2016 National Ambulatory Medical Care Survey to evaluate physicians' provision of primary preventive cardiovascular care to adults with and without opioid prescriptions. We included all visits made by adults 40 to 79 years old with at least 1 cardiovascular risk factor but no existing atherosclerotic cardiovascular disease.

Determining organ weight toxicity with Bayesian causal models: Improving on the analysis of relative organ weights.

Regulatory authorities require animal toxicity tests for new chemical entities. Organ weight changes are accepted as a sensitive indicator of chemically induced organ damage, but can be difficult to interpret because changes in organ weight might reflect chemically-induced changes in overall body weight. A common solution is to calculate the relative organ weight (organ to body weight ratio), but this inadequately controls for the dependence on body weight - a point made by statisticians for decades, but which has not been widely adopted.

Multiscale modelling of drug transport and metabolism in liver spheroids.

In early preclinical drug development, potential candidates are tested in the laboratory using isolated cells. These experiments traditionally involve cells cultured in a two-dimensional monolayer environment. However, cells cultured in three-dimensional spheroid systems have been shown to more closely resemble the functionality and morphology of cells .

Functionality of primary hepatic non-parenchymal cells in a 3D spheroid model and contribution to acetaminophen hepatotoxicity.

In addition to hepatocytes, the liver comprises a host of specialised non-parenchymal cells which are important to consider in the development of in vitro models which are both physiologically and toxicologically relevant. We have characterized a 3D co-culture system comprising primary human hepatocytes (PHH) and non-parenchymal cells (NPC) and applied it to the investigation of acetaminophen-induced toxicity. Firstly, we titrated ratios of PHH:NPC and confirmed the presence of functional NPCs via both immunohistochemistry and activation with both LPS and TGF-β.

Expression of Concern to: Diet restriction inhibits apoptosis and HMGB1 oxidation and promotes inflammatory cell recruitment during acetaminophen hepatoxicity.

The Editors-in-Chief would like to alert readers that this article [1] is part of an investigation being conducted by the journal following the conclusions of an institutional enquiry at the University of Liverpool with respect to the quantitative mass spectrometry-generated results regarding acetylated and redox-modified HMGB1.

Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models.

Drug-induced liver injury (DILI) is a patient-specific, temporal, multifactorial pathophysiological process that cannot yet be recapitulated in a single in vitro model. Current preclinical testing regimes for the detection of human DILI thus remain inadequate. A systematic and concerted research effort is required to address the deficiencies in current models and to present a defined approach towards the development of new or adapted model systems for DILI prediction.

Reproducing human and cross-species drug toxicities using a Liver-Chip.

Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds.