Colorectal cancer cells exhibit limited cytotoxicity towards Tiazofurin, a pro-drug metabolized by cytosolic nicotinamide mononucleotide adenylyltransferase2 (NMNAT2) to thiazole-4-carboxamide adenine dinucleotide, a potent inhibitor of inosine 5'-monophosphate dehydrogenase required for cellular guanylate synthesis. We tested the hypothesis that colorectal cancer cells that exhibit low levels of NMNAT2 and are refractory to Tiazofurin can be rendered sensitive to Tiazofurin by overexpressing NMNAT2. Transfection of hNMNAT2 resulted in a six- and threefold cytoplasmic overexpression in Caco2 and HT29 cell lines correlating with Tiazofurin-induced enhanced cell-kill. Folate receptors expressed on the cell surface of 30-50% colorectal carcinomas were exploited for cellular targeting with Tiazofurin encapsulated in folate-tethered nanoparticles. Our results indicated that in wild-type colorectal cancer cells, free Tiazofurin-induced EC50 cell-kill was 1500-2000 μM, which was reduced to 66-156 μM in hNMNAT2-overexpressed cells treated with Tiazofurin encapsulated in non-targeted nanoparticles. This efficacy was improved threefold by encapsulating Tiazofurin in folate-tethered nanoparticles to obtain an EC(50) cell-kill of 22-59 μM, an equivalent of 100-300 mg m(-2) (one-tenth of the approved dose of Tiazofurin in humans), which will result in minimal toxicity leading to cancer cell-kill. This proof-of-principle study suggests that resistance of colorectal cancer cell-kill to Tiazofurin can be overcome by sequentially overexpressing hNMNAT2 and then facilitating the uptake of Tiazofurin by folate-tethered nanoparticles, which enter cells via folate receptors.
Background The Protocol-guided Rapid Evaluation of Veterans Experiencing New Transient Neurologic Symptoms (PREVENT) program was designed to address systemic barriers to providing timely guideline-concordant care for patients with transient ischemic attack (TIA). Objective We evaluated an implementation bundle used to promote local adaptation and adoption of a multi-component, complex quality improvement (QI) intervention to improve the quality of TIA care Bravata et al. (BMC Neurology 19:294, 2019). Design A stepped-wedge implementation trial with six geographically diverse sites. Participants The six facility QI teams were multi-disciplinary, clinical staff. Interventions PREVENT employed a bundle of key implementation strategies: team activation; external facilitation; and a community of practice. This strategy bundle had direct ties to four constructs from the Consolidated Framework for Implementation Research (CFIR): Champions, Reflecting & Evaluating, Planning, and Goals & Feedback. Main Measures Using a mixed-methods approach guided by the CFIR and data matrix analyses, we evaluated the degree to which implementation success and clinical improvement were associated with implementation strategies. The primary outcomes were the number of completed implementation activities, the level of team organization and > 15 points improvement in the Without Fail Rate (WFR) over 1 year. Key Results Facility QI teams actively engaged in the implementation strategies with high utilization. Facilities with the greatest implementation success were those with central champions whose teams engaged in planning and goal setting, and regularly reflected upon their quality data and evaluated their progress against their QI plan. The strong presence of effective champions acted as a pre-condition for the strong presence of Reflecting & Evaluating, Goals & Feedback, and Planning (rather than the other way around), helping to explain how champions at the +2 level influenced ongoing implementation. Conclusions The CFIR-guided bundle of implementation strategies facilitated the local implementation of the PREVENT QI program and was associated with clinical improvement in the national VA healthcare system. Trial registration: clinicaltrials.gov: NCT02769338
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