Measuring clinical utility in the context of genetic testing: a scoping review.

Standardized approaches to measuring clinical utility will enable more robust evaluations of genetic tests. To characterize how clinical utility has been measured, this scoping review examined outcomes used to operationalize this concept in the context of genetic testing, spanning relevant literature (2015-2017). The search strategy and analysis were guided by the Fryback and Thornbury hierarchical model of efficacy (FT Model). Through searches in Ovid MEDLINE, EMBASE and Web of Science, 194 publications were identified for inclusion. Two coders reviewed titles, abstracts, and full texts to determine eligibility. Results were analyzed using thematic and frequency analyses. This review generated a catalog of outcomes mapped to the efficacy domains of the FT Model. The degree of representation observed in each domain varied by the clinical purpose and clinical indication of genetic testing. Diagnostic accuracy (68%), technical (28.4%), and patient outcome (28.4%) efficacy studies were represented at the highest rate. Findings suggest that the FT Model is suitable for the genetics context however domain refinements may be warranted. More diverse clinical settings, robust study designs, and novel strategies for measuring clinical utility are needed.

Celastrol can inhibit proteasome activity and upregulate the expression of heat shock protein genes, hsp30 and hsp70, in Xenopus laevis A6 cells.

In eukaryotes, the ubiquitin-proteasome system (UPS) is responsible for the degradation of most proteins. Proteasome inhibition, which has been associated with various diseases, can cause alterations in various intracellular processes including the expression of heat shock protein (hsp) genes. In this study, we show that celastrol, a quinone methide triterpene and anti-inflammatory agent, inhibited proteasome activity and enhanced HSP accumulation in Xenopus laevis A6 kidney epithelial cells. Treatment of cells with celastrol induced the accumulation of ubiquitinated protein and inhibited chymotrypsin-like activity. This was accompanied by a dose- and time-dependent accumulation of HSP30 and HSP70. Celastrol-induced HSP accumulation was mediated by HSF1-DNA binding activity since this response was inhibited by the HSF1 activation inhibitor, KNK437. Simultaneous exposure of cells with celastrol plus either mild heat shock or the proteasome inhibitor, MG132, produced an enhanced accumulation of HSP30 that was greater than the sum of the individual stressors alone. Immunocytochemical analysis revealed that celastrol-induced HSP30 accumulation occurred in the cytoplasm in a granular pattern supplemented with larger circular HSP30 staining structures. HSP30 was also noted in the nucleus with less staining in the nucleolus. In some cells, celastrol induced the collapse of the actin cytoskeleton and conversion to a rounder morphology. In conclusion, this study has shown that celastrol inhibited proteasome activity and induced HSF1-mediated expression of hsp genes in amphibian cells.