Novel Dormancy Mechanism of Castration Resistance in Bone Metastatic Prostate Cancer Organoids.

Advanced prostate cancer (PCa) patients with bone metastases are treated with androgen pathway directed therapy (APDT). However, this treatment invariably fails and the cancer becomes castration resistant. To elucidate resistance mechanisms and to provide a more predictive pre-clinical research platform reflecting tumor heterogeneity, we established organoids from a patient-derived xenograft (PDX) model of bone metastatic prostate cancer, PCSD1. APDT-resistant PDX-derived organoids (PDOs) emerged when cultured without androgen or with the anti-androgen, enzalutamide. Transcriptomics revealed up-regulation of neurogenic and steroidogenic genes and down-regulation of DNA repair, cell cycle, circadian pathways and the severe acute respiratory syndrome (SARS)-CoV-2 host viral entry factors, ACE2 and TMPRSS2. Time course analysis of the cell cycle in live cells revealed that enzalutamide induced a gradual transition into a reversible dormant state as shown here for the first time at the single cell level in the context of multi-cellular, 3D living organoids using the Fucci2BL fluorescent live cell cycle tracker system. We show here a new mechanism of castration resistance in which enzalutamide induced dormancy and novel basal-luminal-like cells in bone metastatic prostate cancer organoids. These PDX organoids can be used to develop therapies targeting dormant APDT-resistant cells and host factors required for SARS-CoV-2 viral entry.

Tuning Crystal Structures of Iron-Based Metal-Organic Frameworks for Drug Delivery Applications.

Iron-based metal-organic frameworks (Fe-MOFs) have emerged as promising candidates for drug delivery applications due to their low toxicity, structural flexibility, and safe biodegradation in a physiological environment. Here, we studied two types of Fe-MOFs: MIL-53 and MIL-88B, for in vitro drug loading and releasing of ibuprofen as a model drug. Both Fe-MOFs are based on the same iron clusters and organic ligands but form different crystal structures as a result of two different nucleation pathways. The MIL-53 structure demonstrates one-dimensional channels, while MIL-88B exhibits a three-dimensional cage structure. Our studies show that MIL-53 adsorbs more ibuprofen (37.0 wt %) compared to MIL-88B (19.5 wt %). A controlled drug release was observed in both materials with a slower elution pattern in the case of the ibuprofen-encapsulated MIL-88B. This indicates that a complex cage structure of MIL-88 is beneficial to control the rate of drug release. A linear correlation was found between cumulative drug release and the degree of material degradation, suggesting the biodegradation of Fe-MILs as the main drug elution mechanism. The cytotoxicity of MIL-88B was evaluated in vitro with NIH-3T3 Swiss mouse fibroblasts, and it shows that MIL-88B has no adverse effects on cell viability up to 0.1 mg/mL. This low toxicity was attributed to the morphology of MIL-88B nanocrystals. The very low toxicity and controlled drug release behavior of Fe-MIL-88B suggest that better materials for drug-delivery applications can be created by controlling not only the composition but also the crystal structure and nanoparticle morphology of the material.

Timing of Hospital-acquired Venous Thromboembolism and Its Relationship with Venous Thromboembolism Prevention Measures in Immobile Patients.

BACKGROUND: The aim of this study is to describe the timing of venous thromboembolism (VTE) diagnosis in patients with cerebral or spinal trauma and stroke and describe the relationships between VTE prophylaxis and timing of VTE diagnosis at a community hospital. METHODS: Retrospective cohort observational study over a span of 10 years from 2006 to 2016 was conducted. RESULTS: Lower extremity ultrasound surveillance identified 138 patients who developed VTE during their hospital stay (mean age 62 years, 61.6% males). Mechanical prophylaxis was used in 79.7% and pharmacologic prophylaxis in 78.3% of patients. The average time of admission to administration of mechanical prophylaxis was 1.92 and 7.7 days for pharmacologic prophylaxis. In patients who received pharmacologic prophylaxis within 2 days, 51.5% of all VTE events occurred during the first week, 73.5% by the second week, and 91.2% by the third week of the hospital stay. In patients who started pharmacologic prophylaxis after 2 days in the hospital, 85% of all VTE events occurred within the first week and 90% within 10 days of the hospital stay (P < 0.001). The timing of initiation of mechanical prophylaxis did not influence the timing of VTE events. CONCLUSIONS: In immobilized patients with stroke, traumatic brain injury, or spinal cord injury, VTE screening should be performed at different schedules based on the timing of initiation of pharmacologic prophylaxis. In patients who did not start prophylaxis during the first 2 days of admission to the hospital, the majority of the VTE events occurred during the first 10 days.

Percutaneous Treatment of Superficial Femoral Artery Stenosis Secondary to Radiation Arteritis.

Radiation arteritis is a rare cause of lower extremity peripheral arterial occlusive disease, and has been traditionally treated with open interventions. There have been only a few reported cases of endovascular interventions for this disease. Previous reports described endovascular treatment in the iliac and common femoral regions, but intervention in the superficial femoral artery have not been described. Described here is a case of acute lower extremity ischemia caused by remote radiation arteritis of the superficial femoral artery, which was successfully treated by percutaneous endovascular technique.