Endothelial cell sphingosine 1-phosphate receptor 1 restrains VE-cadherin cleavage and attenuates experimental inflammatory arthritis.

In rheumatoid arthritis, inflammatory mediators extravasate from blood into joints via gaps between endothelial cells (ECs), but the contribution of ECs is not known. Sphingosine 1-phosphate receptor 1 (S1PR1), widely expressed on ECs, maintains the vascular barrier. Here, we assessed the contribution of vascular integrity and EC S1PR1 signaling to joint damage in mice exposed to serum-induced arthritis (SIA). EC-specific deletion of S1PR1 or pharmacological blockade of S1PR1 promoted vascular leak and amplified SIA, whereas overexpression of EC S1PR1 or treatment with an S1PR1 agonist delayed SIA. Blockade of EC S1PR1 induced membrane metalloproteinase-dependent cleavage of vascular endothelial cadherin (VE-cadherin), a principal adhesion molecule that maintains EC junctional integrity. We identified a disintegrin and a metalloproteinase domain 10 (ADAM10) as the principal VE-cadherin "sheddase." Mice expressing a stabilized VE-cadherin construct had decreased extravascular VE-cadherin and vascular leakage in response to S1PR1 blockade, and they were protected from SIA. Importantly, patients with active rheumatoid arthritis had decreased circulating S1P and microvascular expression of S1PR1, suggesting a dysregulated S1P/S1PR1 axis favoring vascular permeability and vulnerability. We present a model in which EC S1PR1 signaling maintains homeostatic vascular barrier function by limiting VE-cadherin shedding mediated by ADAM10 and suggest this signaling axis as a therapeutic target in inflammatory arthritis.

Marital Status Independently Predicts Mortality in Adult Patients with Craniopharyngioma: A SEER-Based Study.

BACKGROUND: The relationship between marital status and overall survival (OS) in adult patients with craniopharyngioma has not been explored in depth. We aimed to elucidate the impact of marital status on the prognosis of craniopharyngioma patients excluding bias from baseline demographics and treatment. METHODS: We extracted 1539 patients diagnosed with craniopharyngioma between 2000 and 2019 from the Surveillance, Epidemiology, and End Results database and divided patients into 4 marital subgroups: married, single, divorced/separated, and widowed. Kaplan-Meier curves with a log-rank test were used to discern differences in OS between marital subgroups. Univariate and multivariate Cox regression were used to identify independent prognostic factors of mortality. RESULTS: There were 1539 eligible patients: 863 (56.1%) were married, 466 (30.3%) were single, 135 (8.8%) were divorced/separated, and 75 (4.9%) were widowed. Widowed patients had the worst mean OS, 5-year OS and 10-year OS at 84.2 months, 58.0% and 26.9%, respectively. After stratifying patients by age, our multivariate analysis showed that marital status was an independent predictor of mortality in middle-aged craniopharyngioma patients (40-60 years, P < 0.001), but not in young adults (18-39 years, P = 0.646) or elderly patients (>60 years, P = 0.076). Among middle-aged patients, single (hazard ratio 1.72, confidence interval 1.19-2.47, P = 0.004) and divorced/separated patients (hazard ratio = 2.29, confidence interval = 1.49-3.54, P < 0.001) showed a higher risk of mortality compared to married patients (reference). CONCLUSIONS: Marital status is an independent prognostic factor predicting OS for middle-aged patients with craniopharyngioma. Providing additional social and psychological support for single and divorced/separated patients may improve outcomes for this vulnerable population.

Tissue-specific activation of gene expression by the Synergistic Activation Mediator (SAM) CRISPRa system in mice.

CRISPR-based transcriptional activation is a powerful tool for functional gene interrogation; however, delivery difficulties have limited its applications in vivo. Here, we created a mouse model expressing all components of the CRISPR-Cas9 guide RNA-directed Synergistic Activation Mediator (SAM) from a single transcript that is capable of activating target genes in a tissue-specific manner. We optimized Lipid Nanoparticles and Adeno-Associated Virus guide RNA delivery approaches to achieve expression modulation of one or more genes in vivo. We utilized the SAM mouse model to generate a hypercholesteremia disease state that we could bidirectionally modulate with various guide RNAs. Additionally, we applied SAM to optimize gene expression in a humanized Transthyretin mouse model to recapitulate human expression levels. These results demonstrate that the SAM gene activation platform can facilitate in vivo research and drug discovery.