1,25-(OH)2-Vitamin D3, the active metabolite of vitamin D, is a secosteroid hormone with known differentiating activity in leukemic cells. Studies have demonstrated the presence of vitamin D receptors (VDR) in a wide range of tissues and cell types. Antiproliferative activity of 1,25-(OH)2-vitamin D3 has been documented in osteosarcoma, melanoma, colon carcinoma, and breast carcinoma cells. This study was designed to analyze vitamin D receptor level in breast cancer cells as a marker of differentiation and as a predictor of growth inhibition by 1,25-(OH)2-vitamin D3. VDR messenger RNA was found to be present in relatively high levels in well-differentiated cells and in low levels in poorly differentiated cells. All cell lines had detectable VDR mRNA. Radiolabeled ligand binding assay showed a similar pattern. MCF-7 and T47D cells, which express VDR at moderate levels, showed significant growth inhibition by 10(-9) M1,25-(OH)2-vitamin D3 (p < 0.05). MDA-MB-231 cells, which have very low levels of VDR, demonstrated no growth inhibition by 1,25-(OH)2-vitamin D3 at concentrations up to 10(-6) M. Based on these results it can be stated that VDR expression is lost with de-differentiation and that receptor is essential for the antiproliferative response to 1,25-(OH)2-vitamin D3.

BACKGROUND: The COVID-19 pandemic disrupted the delivery of surgical services. The purpose of this communication was to report the impact of the pandemic on surgical training and learner well-being and to document adaptations made by surgery departments. STUDY DESIGN: A 37-item survey was distributed to educational leaders in general surgery and other surgical specialty training programs. It included both closed-and open-ended questions and the self-reported stages of GME during the COVID-19 pandemic, as defined by the ACGME. Statistical associations for items with stage were assessed using categorical analysis. RESULTS: The response rate was 21% (472 of 2,196). US stage distribution (n ¼ 447) was as follows: stage 1, 22%; stage 2, 48%; and stage 3, 30%. Impact on clinical education significantly increased by stage, with severe reductions in nonemergency operations (73% and 86% vs 98%) and emergency operations (8% and 16% vs 34%). Variable effects were reported on minimal expected case numbers across all stages. Reductions were reported in outpatient experience (83%), in-hospital experience (70%), and outside rotations (57%). Increases in ICU rotations were reported with advancing stage (7% and 13% vs 37%). Severity of impact on didactic education increased with stage (14% and 30% vs 46%). Virtual conferences were adopted by 97% across all stages. Severity of impact on learner well-being increased by stagedphysical safety (6% and 9% vs 31%), physical health (0% and 7% vs 17%), and emotional health (11% and 24% vs 42%). Regardless of stage, most but not all made adaptations to support trainees' well-being. CONCLUSIONS: The pandemic adversely impacted surgical training and the well-being of learners across all surgical specialties proportional to increasing ACGME stage. There is a need to develop education disaster plans to support technical competency and learner well-being. Careful Disclosure Information: Nothing to disclose. Disclosure outside the scope of this work: Dr Ellison receives royalty payments for original contributions from McGraw-Hill Medical and Wolters Kluwer. All other authors have nothing to disclose.

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Protein geranylgeranylation (GGylation) is an important biochemical process for many cellular signaling molecules. Previous studies have shown that GGylation is essential for cell survival in many types of cancer. However, the molecular mechanism mediating the cell survival effect remains elusive. In this report, we show that the Hippo pathway mediates GGylation-dependent cell proliferation and migration in breast cancer cells. Blockade of GGylation enhanced phosphorylation of Mst1/2 and Lats1, and inhibited YAP and TAZ activity and the Hippo-YAP/TAZ pathway-dependent transcription. The effect of GGylation blockade on inhibition of breast cancer cell proliferation and migration is dependent on the Hippo-YAP/TAZ signaling, in which YAP appears to regulate cell proliferation and TAZ to regulate cell migration. Furthermore, GGylation-dependent cell proliferation is correlated with the activity of YAP/TAZ in breast cancer cells. Finally, Gγ and RhoA are the GGylated proteins that may transduce GGylation signals to the Hippo-YAP/TAZ pathway. Taken together, our studies have demonstrated that the Hippo-YAP/TAZ pathway is essential for GGylation-dependent cancer cell proliferation and migration.

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Therapeutic study, level IV. Economic study, level III.