Withaferin A inhibits expression of ataxia telangiectasia and Rad3-related kinase and enhances sensitivity of human breast cancer cells to cisplatin.

Ataxia telangiectasia and Rad3-related (ATR) is a serine/threonine-specific kinase that plays an important role in the maintenance of genomic integrity. In this study, we investigated the role of ATR in cell-cycle arrest by withaferin A (WA), a cancer preventative steroidal lactone derived from Withania somnifera plant abundant in India and surrounding countries. The WA treatment decreased the viability of MCF-7, MDA-MB-231, and SUM159 cells. Exposure of breast cancer cells to WA also resulted in suppression of protein level as well as phosphorylation of ATR and its downstream effector kinase (checkpoint kinase 1; CHK1). Both transcriptional and posttranscriptional mechanisms were involved in the WA-mediated downregulation of ATR protein. Downregulation of ATR protein expression resulting from WA exposure was not attenuated by overexpression of manganese superoxide dismutase. In contrast, the overexpression of CHK1 attenuated WA-mediated G2 /M arrest and augmented S10 phosphorylation of histone H3, a marker of mitotic arrest. The protein level of ATR was lowered by about 50% in breast tumors of WA-treated mouse mammary tumor virus-neu mice when compared with vehicle-treated controls but the difference was not significant due to small sample size. WA treatment sensitized MDA-MB-231 and SUM159 cells to growth inhibition and apoptosis induction by cisplatin. Cisplatin treatment resulted in increased autophosphorylation of ATR (T1989) and CHK1 (S345) phosphorylation that was markedly suppressed in the presence of WA. These results indicate that WA is an inhibitor of ATR in human breast cancer cells.

The Relationship Between Public Interest and Surgical Demand During the COVID-19 Pandemic.

INTRODUCTION: Surgical databases are useful for examining outcomes and case volume to improve care, while public interest data has the potential to track the supply and demand of medical services in specific communities. However, the relationship between public interest data and case volume from surgical databases, specifically during disruptive instances like the coronavirus pandemic, is unknown. Therefore, the purpose of this study is to determine how public interest data is related to the case volume of coronavirus and other surgical procedures performed during the coronavirus pandemic. METHODS: This retrospective study included a review of appendectomy, total hip arthroplasty (THA), and total knee arthroplasty (TKA) cases from the National Surgery Quality Improvement Project and relative search volume (RSV) of hip replacement, knee replacement, appendicitis, and coronavirus from Google Trends from 2019 to 2020. T-tests were used to compare surgical caseload and RSV data before and after the COVID-19 surge in March 2020, while linear models were used to determine relationships between confirmed procedures and relative search volumes. RESULTS: The RSV for knee replacement (p < 0.001, Cohen's D [d] = -5.01, 95% confidence interval [CI]: -7.64 to -2.34) and hip replacement (p < 0.001, d = -7.22, 95% CI: -10.85 to -3.57) had a large dip during the coronavirus pandemic, while the RSV for appendicitis had a smaller dip (p = 0.003, d = -2.37, 95% CI: -3.93 to -0.74). Linear models showed very strong linear relationships between surgical RSV and surgical volume for TKA (R2 = 0.931) and THA (R2 = 0.940). CONCLUSIONS: There was a significant reduction in the number of elective surgeries, which correlated to drops in public interest during COVID-19. The strong correlations between RSV, surgical volume, and coronavirus cases indicate that public interest can be used to track and predict surgical case volume. Our findings allow for greater insight into the use of public interest data to gauge surgical demand.