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.

The c-Met Tyrosine Kinase Inhibitor JNJ-38877605 Causes Renal Toxicity through Species-Specific Insoluble Metabolite Formation.

Purpose: The receptor tyrosine kinase c-Met plays an important role in tumorigenesis and is a novel target for anticancer treatment. This phase I, first-in-human trial, explored safety, pharmacokinetics, pharmacodynamics, and initial antitumor activity of JNJ-38877605, a potent and selective c-Met inhibitor.

Experimental Design: We performed a phase I dose-escalation study according to the standard 3+3 design.

IGF-I enhances survival of embryonic chick ciliary ganglion neurons in a calcium-dependent way.

We have shown that neurons from embryonic chick ciliary ganglia in primary culture possess receptors for insulin-like growth factor I (IGF-I). When added to serum- and insulin-free culture medium, the factor potently enhanced neuronal survival as observed after 24 and 48 h of culture. The effect saturated at 5 ng/ml.

Immunohistochemistry for light microscopy in safety evaluation of therapeutic agents: an overview.

The history of immunohistochemistry started in 1941 when Coons identified pneumococci using a direct fluorescent method. Then followed the indirect method, the addition of horseradish peroxidase, the peroxidase anti-peroxidase technique of 1979 and the use of the Avidin and Biotin complex in the early 1980s. This sequence of events can help one appreciate the differences in these various techniques and their increased sophistication and sensitivity.

Immunohistochemical investigation of gamma-aminobutyric acid ontogeny and transient expression in the central nervous system of Xenopus laevis tadpoles.

The ontogeny of the gamma-aminobutyric acid (GABA)-positive neurons in the brain of Xenopus laevis tadpoles was investigated by means of immunohistochemistry, using specific antibodies both against GABA and its biosynthetic enzyme, glutamate decarboxylase (GAD). The results obtained with the two antisera were comparable. The GABA system differentiates very early during development.