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To develop and validate a practical, in vitro, cell-based model to assess human hepatotoxicity potential of drugs, we used the new technology of high content screening (HCS) and a novel combination of critical model features, including (1) use of live, human hepatocytes with drug metabolism capability, (2) preincubation of cells for 3 days with drugs at a(More)
Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid beta protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence(More)
Biomarkers are increasingly used in drug development to aid scientific and clinical decisions regarding the progress of candidate and marketed therapeutics. Biomarkers can improve the understanding of diseases as well as therapeutic and off-target effects of drugs. Early implementation of biomarker strategies thus promises to reduce costs and time-to-market(More)
Received Revised This paper describes work undertaken in the ADEPT (Advanced Decision Environment for Process Tasks) project towards developing an agent-based infrastructure for managing business processes. We describe how the key technology of negotiating, service providing, autonomous agents was realised and demonstrate how this was applied to the BT(More)
The toxicity and carcinogenicity of formaldehyde (HCHO) has been attributed to its ability to form adducts with DNA and proteins. A marked decrease in mitochondrial membrane potential and inhibition of mitochondrial respiration that was accompanied by reactive oxygen species formation occurred when isolated rat hepatocytes were incubated with low(More)
Malignant hyperthermia (MH) causes neurological, liver, and kidney damage and death in humans and major economic losses in the swine industry. A single point mutation in the porcine gene for the skeletal muscle ryanodine receptor (ryr1) was found to be correlated with MH in five major breeds of lean, heavily muscled swine. Haplotyping suggests that the(More)
Quinones are probably found in all respiring animal and plant cells. They are widely used as anticancer, antibacterial or antimalarial drugs and as fungicides. Toxicity can arise as a result of their use as well as by the metabolism of other drugs and various environmental toxins or dietary constituents. In rapidly dividing cells such as tumor cells,(More)
The Fanconi anemia group C protein (FANCC) plays an important role in hematopoiesis by ensuring the survival of hematopoietic progenitor cells through an unknown mechanism. We investigated the function of FANCC by identifying FANCC-binding proteins in hematopoietic cells. Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and(More)
Treatment of rat liver microsomes with 2,5-di(tert-butyl)-1,4-benzohydroquinone caused a dose-related inhibition (Ki congruent to 1 microM) of ATP-dependent Ca2+ sequestration. This was paralleled by a similar impairment of the microsomal Ca2+-stimulated ATPase activity. In contrast, the hydroquinose failed to induce Ca2+ release from Ca2+-loaded liver(More)
Acute compartment syndrome of the lower extremity is a clinical condition that, although uncommon, is seen fairly regularly in modern orthopedic practice. The pathophysiology of the disorder has been extensively described and is well known to physicians who care for patients with musculoskeletal injuries. The diagnosis, however, is often difficult to make.(More)