4 research outputs found
Salivary Mucocele in a Laboratory Beagle
The histologic characteristics of a salivary mucocele in a beagle used in a toxicity
study are described in this report. A pale yellowish cyst under the mandibular skin
containing frothy mucus was observed at necropsy. Microscopically, numerous villous
projections arose from the internal surface of the cyst and were lined by stratified
epithelial-like macrophages, which were immunopositive for macrophage scavenger receptor
A. A ruptured sublingual interlobar duct connected to the lumen was observed near the
cyst. Luminal amorphous material showed a positive reaction with Alcian blue and periodic
acid-Schiff staining as did mucin in the sublingual gland. Ultrastructurally, the
epithelial-like macrophages had numerous vacuoles containing electron-lucent material,
which was presumed to be lysosomal in origin, and had pseudopods on their cell surfaces
interdigitating with those on the adjacent cells. This case report helps to understand the
diversity of the background findings in beagles used in toxicity studies
Polygenic architecture informs potential vulnerability to drug-induced liver injury
Drug-Induced-Liver-Injury (DILI) is a leading cause of termination in drug development programs and removal of drugs from the market, and this is partially due to the inability to identify patients who are at risk1. Here, we developed a polygenic risk score (PRS) for DILI by aggregating effects of numerous genome-wide loci identified from previous large-scale genome-wide association studies (GWAS)2. The PRS predicted the susceptibility to DILI in patients treated with fasiglifam, amoxicillin-clavulanate or flucloxacillin, and in primary hepatocytes and stem cell-derived organoids from multiple donors treated with over 10 different drugs. Pathway analysis highlighted processes previously implicated in DILI, including unfolded protein responses and oxidative stress. In silico screening identified compounds that elicit transcriptomic signatures present in hepatocytes from individuals with elevated PRS, supporting mechanistic links and suggesting a novel screen for safety of new drug candidates. This genetic-, cellular-, organoid- and human-scale evidence underscored the polygenic architecture underlying DILI vulnerability at the level of hepatocytes, thus facilitating future mechanistic studies. Moreover, the proposed “polygenicity-in-a-dish” strategy might potentially inform designs of safer, more efficient, and robust clinical trials