Tankyrase inhibition interferes with junction remodeling, induces leakiness, and disturbs YAP1/TAZ signaling in the endothelium.

Tankyrase inhibitors are increasingly considered for therapeutic use in malignancies that are characterized by high intrinsic ß-catenin activity. However, how tankyrase inhibition affects the endothelium after systemic application remains poorly understood. In this study, we aimed to investigate how the tankyrase inhibitor XAV939 affects endothelial cell function and the underlying mechanism involved. Endothelial cell function was analyzed using sprouting angiogenesis, endothelial cell migration, junctional dynamics, and permeability using human umbilical vein endothelial cells (HUVEC) and explanted mouse retina. Underlying signaling was studied using western blot, immunofluorescence, and qPCR in HUVEC in addition to luciferase reporter gene assays in human embryonic kidney cells. XAV939 treatment leads to altered junctional dynamics and permeability as well as impaired endothelial migration. Mechanistically, XAV939 increased stability of the angiomotin-like proteins 1 and 2, which impedes the nuclear translocation of YAP1/TAZ and consequently suppresses TEAD-mediated transcription. Intriguingly, XAV939 disrupts adherens junctions by inducing RhoA-Rho dependent kinase (ROCK)-mediated F-actin bundling, whereas disruption of F-actin bundling through the ROCK inhibitor H1152 restores endothelial cell function. Unexpectedly, this was accompanied by an increase in nuclear TAZ and TEAD-mediated transcription, suggesting differential regulation of YAP1 and TAZ by the actin cytoskeleton in endothelial cells. In conclusion, our findings elucidate the complex relationship between the actin cytoskeleton, YAP1/TAZ signaling, and endothelial cell function and how tankyrase inhibition disturbs this well-balanced signaling.

Medical use and combination drug therapy among US adult users of central nervous system stimulants: a cross-sectional analysis.

OBJECTIVE: Examine patterns of adult medical use of amphetamine and methylphenidate stimulant drugs, classified in the USA as Schedule II controlled substances with a high potential for psychological or physical dependence. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: Prescription drug claims for US adults, age 19-64 years, included in a commercial insurance claims database with 9.1 million continuously enrolled adults from 1 October 2019, through 31 December 2020. Stimulant use was defined as adults filling one or more stimulant prescriptions during calendar 2020. OUTCOME MEASURES: The primary outcome was an outpatient prescription claim, service date and days' supply for central nervous system (CNS)-active drugs. Combination-2 was defined as 60 days or more of combination treatment with a Schedule II stimulant and one or more additional CNS-active drugs. Combination-3 therapy was defined as the addition of 2 or more additional CNS-active drugs. Using service date and days' supply, we examined the number of stimulant and other CNS-active drugs for each of the 366 days of 2020. RESULTS: Among 9 141 877 continuously enrolled adults, the study identified 276 223 individuals (3.0%) using Schedule II stimulants during 2020. They filled a median of 8 (IQR, 4-11) prescriptions for these stimulant drugs that provided 227 (IQR, 110-322) treatment days of exposure. Among this group, 125 781 (45.5%) combined use of one or more additional CNS active drugs for a median of 213 (IQR, 126-301) treatment days. Also, 66 996 (24.3%) stimulant users used two or more additional CNS-active drugs for a median of 182 (IQR, 108-276) days. Among stimulants users, 131 485 (47.6%) were exposed to an antidepressant, 85 166 (30.8%) filled prescriptions for anxiety/sedative/hypnotic medications and 54 035 (19.6%) received opioid prescriptions. CONCLUSION: A large proportion of adults using Schedule II stimulants are simultaneously exposed to one or more other CNS-active drugs, many with tolerance, withdrawal effects or potential for non-medical use. There are no approved indications and limited clinical trial testing of these multi-drug combinations, and discontinuation may be challenging.

Changes in medical use of central nervous system stimulants among US adults, 2013 and 2018: a cross-sectional study.

OBJECTIVE: To assess the 5-year changes in the adult medical use of central nervous system (CNS) stimulants with higher risk of dependence and evaluate the population characteristics of users and their medical and/or neurological conditions. DESIGN: Cross-sectional study. SETTING: Annual US Medical Expenditure Panel Survey, a stratified random sample of approximately 30 000 persons designed to produce national population estimates. It focuses on reported medical spending, medical services used, health status and prescription medications. PARTICIPANTS: Adults age 19 years and older who reported obtaining one or more prescriptions for amphetamine or methylphenidate products during two survey years, 2013 and 2018. MAIN OUTCOMES MEASURES: Prescriptions obtained, the specific stimulant product and annual treatment days of drug supplied. RESULTS: In 2018, an estimated 4.1 million US adults (95% CI 3.4 million to 4.8 million) reported prescriptions for CNS stimulants, having filled a mean of 7.3 (95% CI 6.8 to 7.8) prescriptions with a mean of 226 (95% CI 210 to 242) days' supply. Compared with 2013, the estimated number of adults reporting using CNS stimulants in 2018 increased by 1.8 million (95% CI 1.0 million to 2.7 million) or 79.8%. Most 2018 adult stimulant users reported taking psychoactive medication for one or more mental, behavioural or neurodevelopment disorders. Overall, 77.8% (95% CI 72.6% to 83.0%) reported some medication for adult attention deficit disorder, 26.8% (95% CI 22.2% to 31.5%) took medication for anxiety, 25.1% (95% CI 19.9% to 30.3%) for depression and 15.3% (95% CI 9.8% to 20.8%) indicated drug treatment for other mental or neurological disorders. Adult CNS stimulant use was higher in females, in younger age cohorts and among individuals of white race/ethnicity. CONCLUSIONS: Adult medical use of prescription stimulants increased markedly in 5 years and occurred in a population often reporting multiple mental or neurological disorders. Further action is needed to understand and manage this new resurgence in drugs with high risks of dependence.