Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer.

OBJECTIVE: Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. METHODS: High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. RESULTS: Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. CONCLUSION: Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types.

Detection of Respiratory Pathogens Does Not Predict Risks After Outpatient Adenotonsillectomy.

OBJECTIVES/HYPOTHESIS: To determine whether the presence of detectable upper respiratory infections (URIs) at the time of adenoidectomy/adenotonsillectomy is associated with increased morbidity, complications, and unexpected admissions. STUDY DESIGN: Prospective double-blinded cohort. METHODS: In this prospective cohort study, nasopharyngeal swabs were obtained intraoperatively from 164 pediatric patients undergoing outpatient adenoidectomy/tonsillectomy with or without pressure equalization tubes (PETs) and were analyzed with PCR for the presence of 22 known URIs, including SARS-CoV-2. Surgeons and families were blinded to the results. At the conclusion of the study, rates of detectable infection were determined and intraoperative and postoperative events (unexpected admissions, length of PACU stay, rates of laryngospasm/bronchospasm, oxygen desaturation, bradycardia, and postoperative presentation to an emergency department) were compared between infected and uninfected patients. RESULTS: Of the 164 patients (50% male, 50% female, ages 8 mo-18 y), 136 patients (82.9%) tested positive for one or more URI at the time of surgery. Forty one patients (25.0%) tested positive for three or more URIs concurrently, and 11 (6.7%) tested positive for five or more URIs concurrently. There were no significant differences in admission rates, length of PACU stay, rates of laryngospasm/bronchospasm, oxygen desaturation, bradycardia, or postoperative presentation to an emergency department between positive and negative patients. No patients tested positive for SARS-CoV-2. CONCLUSIONS: A recent positive URI test does not confer any additional intraoperative or postoperative risk in the setting of outpatient adenoidectomy/tonsillectomy in healthy patients. There is no utility in preoperative URI testing, and delaying surgery due to a recent positive URI test is not warranted in this population. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:E2074-E2079, 2021.

Development of contact lenses and their worldwide use.

The concept of applying a lens to the cornea as a refractive appliance was first proposed in the early 19th century. By 1888, glass scleral lenses for the correction of optical defects and irregularities were manufactured and used. New materials, especially soft hydrogel lenses and rigid gas-permeable lenses, became available in the 20th century and allowed comfortable contact lenses to be made in any design needed. By the 21st century, the increasing use of silicone hydrogel lenses to address the oxygen need of the cornea has led to increased worldwide use. Of the 125 million global contact lens wearers, most are female and relatively young. Soft lenses are by far the dominant modality used, with silicone hydrogel lenses taking an increasing share of new fittings, particularly for overnight wear. Microbial keratitis, although relatively uncommon, remains the most serious potential complication for these lens wearers. Ongoing basic research, more powerful antimicrobial agents, and the development of safer lens materials are helping to alleviate this problem.