Citations

We clarify that DNA damage triggers autophagy by CHK2-FOXK axis, and misregulation of this pathway leads to chemoresistance.

Drug safety is a severe clinical pharmacology and toxicology problem that has caused immense medical and social burdens every year. Regretfully, a reproducible method to assess drug safety systematically and quantitatively is still missing. In this study, we developed an advanced machine learning model for de novo drug safety assessment by solving the multilayer drug‐gene‐adverse drug reaction (ADR) interaction network. For the first time, the drug safety was assessed in a broad landscape of 1,156 distinct ADRs. We also designed a parameter ToxicityScore to quantify the overall drug safety. Moreover, we determined association strength for every 3,807,631 gene‐ADR interactions, which clues mechanistic exploration of ADRs. For convenience, we deployed the model as a web service ADRAlert‐gene at http://www.bio-add.org/ADRAlert/. In summary, this study offers insights into prioritizing safe drug therapy. It helps reduce the attrition rate of new drug discovery by providing a reliable ADR profile in the early preclinical stage.

Purpose To investigate the biomechanical effects of superior capsule reconstruction with subacromial allograft spacer on superior humeral head translation and subacromial contact pressure. Methods Eight cadaveric shoulder specimens were tested in 4 conditions: (1) intact rotator cuff, (2) supraspinatus tear and superior capsule excision, (3) superior capsule reconstruction with human dermal allograft, and (4) superior capsule reconstruction with subacromial resurfacing using human dermal allograft. In each condition, specimens were tested at 0, 30, 60, and 90° of shoulder abduction in balanced and unbalanced loaded states for subacromial contact pressure and superior humeral head translation. Statistical comparisons were made using a repeated‐measures analysis of variance test, followed by a Tukey post hoc test for pairwise comparisons. A P value <.05 was set as statistically significant. Results Superior humeral head translation and subacromial contact pressure were increased after irreparable rotator cuff tear ( P = .001). There was no significant difference between superior capsule reconstruction and intact cuff in regard to superior humeral head translation and subacromial contact pressure at all abduction angles. Superior capsule reconstruction with subacromial resurfacing decreased superior humeral head translation relative to intact (0°, P = .004; 30°, P = .02; 60°, P = .08; 90°, P = .01), superior capsule reconstruction (0°, P = .001; 30°, P = .003; 60°, P = .019; 90°, P = .001), and cuff‐deficient states ( P = .001). Superior capsule reconstruction with subacromial resurfacing resulted in nonsignificant increases in subacromial contact pressure relative to intact cuff at 0 to 90° abduction angles. Conclusions Superior capsule reconstruction with subacromial resurfacing using human dermal allograft results in decreased superior humeral head translation relative to superior capsule reconstruction with human dermal allograft only, while increasing subacromial contact pressure. Clinical Relevance Superior capsule reconstruction with subacromial resurfacing using human dermal allograft reduces superior humeral head translation while increasing subacromial contact pressure in a cadaveric model.

We previously reported that testis‐specific Y‐encoded‐like protein (TSPYLs) are transcription regulators for CYP3A4, CYP2C9, and CYP2C19. Here, we observed dual roles for TSPYLs in mediating serotonin transport and the metabolism of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD). The widely prescribed SSRIs, citalopram, and escitalopram are metabolized mainly by CYP2C19. The TSPYL1 rs3828743 single nucleotide polymorphism (SNP), which decreases its suppression of CYP2C19 expression, was associated with rapid escitalopram metabolism and worse treatment response in the Mayo PGRN‐AMPS clinical trial. We also found that TSPYLs can regulate expression of the serotonin transporter protein, SLC6A4, and, in turn, serotonin transport into cells. The SNPs in tight linkage disequilibrium with the TSPYL1 rs10223646 SNP were significantly correlated with baseline severity of depression in patients with MDD in the Sequenced Treatment Alternatives to Relieve Depression and International SSRI Pharmacogenomics Consortium clinical trials. Our findings suggest that genetic variation in TSPYL genes may be novel indicators for baseline severity of depression and SSRI poor response.