Vitamin D Receptor Antagonist MeTC7 Inhibits PD-L1.

Small-molecule inhibitors of PD-L1 are postulated to control immune evasion in tumors similar to antibodies that target the PD-L1/PD-1 immune checkpoint axis. However, the identity of targetable PD-L1 inducers is required to develop small-molecule PD-L1 inhibitors. In this study, using chromatin immunoprecipitation (ChIP) assay and siRNA, we demonstrate that vitamin D/VDR regulates PD-L1 expression in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells. We have examined whether a VDR antagonist, MeTC7, can inhibit PD-L1. To ensure that MeTC7 inhibits VDR/PD-L1 without off-target effects, we examined competitive inhibition of VDR by MeTC7, utilizing ligand-dependent dimerization of VDR-RXR, RXR-RXR, and VDR-coactivators in a mammalian 2-hybrid (M2H) assay. MeTC7 inhibits VDR selectively, suppresses PD-L1 expression sparing PD-L2, and inhibits the cell viability, clonogenicity, and xenograft growth of AML cells. MeTC7 blocks AML/mesenchymal stem cells (MSCs) adhesion and increases the efferocytotic efficiency of THP-1 AML cells. Additionally, utilizing a syngeneic colorectal cancer model in which VDR/PD-L1 co-upregulation occurs in vivo under radiation therapy (RT), MeTC7 inhibits PD-L1 and enhances intra-tumoral CD8+T cells expressing lymphoid activation antigen-CD69. Taken together, MeTC7 is a promising small-molecule inhibitor of PD-L1 with clinical potential.

Calculating surgical readmission rates in gynecologic oncology: The impact of patient factors.

OBJECTIVE: To determine the 30-day surgical readmission rate after major gynecologic oncology surgeries at a high-volume academic institution and correlated risk factors. METHODS: Retrospective cohort study was conducted of surgical admissions from January 2016 - December 2019 at a single institution. Data were extracted from patient charts, including reason for readmission and length of stay. A readmission rate was calculated. Nested case control design was used to identify correlations between readmission and patient specific risk-factors. Multivariable logistic regression models were used to determine risk factors with readmission. RESULTS: A total of 2152 patients were included. The readmission rate was 3.5%, most commonly due to GI disturbance and surgical site infection. Average readmission length was 5 days. Prior to adjusting for covariates, insurance status, primary diagnosis, index admission length, and disposition at discharge differed between patients who were and were not readmitted. After adjusting for co-variates, younger patients, index admission >2 days, and higher Charlson co-morbidity index were associated with readmission. CONCLUSIONS: Our surgical readmission rate was lower than previously reported rates in gynecologic oncology patients. Patient factors associated with readmission included younger age, longer index hospital admission, and higher medical co-morbidity index scores. Provider factors and institutional practice patterns could contribute to the decreased readmission rate. These findings underscore the importance of standardizing how we calculate readmission rate and interpret these data. Varying readmission rates and institutional practice patterns deserve closer scrutiny to inform best practice and future policies.

Effects of amantadine on corneal endothelium.

PURPOSE: An adverse effect of amantadine, a drug used for Parkinson's disease, is corneal edema. While corneal endothelial cell loss is noted with amantadine toxicity, the reversibility of corneal edema suggests that amantadine affects active mechanisms regulating corneal hydration. Although mainly known as a NMDA receptor antagonist, amantadine is also a K+-channel blocker. The purpose of this study was to investigate potential mechanisms of amantadine's toxic effects on corneal endothelium. METHODS: Bovine corneas were used for short-circuit current measurements of corneal endothelial active ion transport to compare the effects of amantadine with an NMDA receptor agonist (NMDA) and antagonist (D-APV), and the K+-channel blockers BaCl2 and clotrimazole. Cell death and changes in cell morphology were observed using annexin V stain, alizarin red S staining of the intercellular junctions, ZO-1 immunolocalization, and phalloidin stain of the actin cytoskeleton. RESULTS: Amantadine caused a transient decrease in the short-circuit current that mimicked the effect of clotrimazole. BaCl2, and the NMDA receptor agonist and antagonist had no effect on the short-circuit current. Tissue incubation with amantadine caused an increase in cell area (measured by ZO-1 localization) and cell height (measured by phalloidin stain) but did not increase apoptotic cell death (annexin V stain). CONCLUSIONS: The similarity of amantadine and clotrimazole effects on the short-circuit current and the effects on cell volume suggest that amantadine's actions on corneal endothelium are mediated via K+ channels. The observed absence of cell death and transient effect on short-circuit current support the reported reversibility of amantadine-induced corneal edema.