Publications by authors named "Matthew C Kuhls"
Fialuridine (FIAU) is a nucleoside-based drug that caused liver failure and deaths in a human clinical trial that were not predicted by nonclinical safety studies. A recent report concluded that a TK-NOG humanized liver (hu-liver) mouse model detected human-specific FIAU liver toxicity, and broader use of that model could improve drug safety testing. We further evaluated this model at similar dose levels to assess FIAU sensitivity and potential mechanistic biomarkers.
View Article and Find Full Text PDFArticle Synopsis
- Early risk assessment of drug-induced liver injury (DILI) is crucial in pharmaceutical development, and researchers have created rat liver biomarkers to predict the potential for high-risk reactive metabolites.
- A new in vitro assay using advanced micropatterned coculture (HEPATOPAC) with rat hepatocytes has been developed to identify drugs with lower DILI risk, achieving 81% sensitivity and 90% specificity for detecting hepatotoxicants.
- This approach allows for early drug discovery screening, guiding the selection of safer drug candidates while utilizing rat models routinely and human models when needed.
The forces that drive conversion of nascent protein to major histocompatibility complex (MHC) class I-restricted peptides remain unknown. We explored the fundamental property of overt hydrophobicity as such a driver. Relocation of a membrane glycoprotein to the cytosol via signal sequence ablation resulted in rapid processing of nascent protein not because of the misfolded luminal domain but because of the unembedded transmembrane (TM) domain, which serves as a dose-dependent degradation motif.
View Article and Find Full Text PDF