Endothelial cells serve as a barrier between blood and tissues. Maintenance of the endothelial cell barrier depends on the integrity of intercellular junctions, which is regulated by a polarity complex that includes the ζ isoform of atypical protein kinase C (PKCζ) and partitioning defective 3 (PAR3). We revealed that the E3 ubiquitin ligase PDZ domain-containing ring finger 3 (PDZRN3) regulated endothelial intercellular junction integrity. Endothelial cell-specific overexpression of Pdzrn3 led to early embryonic lethality with severe hemorrhaging and altered organization of endothelial intercellular junctions. Conversely, endothelial-specific loss of Pdzrn3 prevented vascular leakage in a mouse model of transient ischemic stroke, an effect that was mimicked by pharmacological inhibition of PKCζ. PDZRN3 regulated Wnt signaling and associated with a complex containing PAR3, PKCζ, and the multi-PDZ domain protein MUPP1 (Discs Lost-multi-PDZ domain protein 1) and targeted MUPP1 for proteasomal degradation in transfected cells. Transient ischemic stroke increased the ubiquitination of MUPP1, and deficiency of MUPP1 in endothelial cells was associated with decreased localization of PKCζ and PAR3 at intercellular junctions. In endothelial cells, Pdzrn3 overexpression increased permeability through a PKCζ-dependent pathway. In contrast, Pdzrn3 depletion enhanced PKCζ accumulation at cell-cell contacts and reinforced the cortical actin cytoskeleton under stress conditions. These findings reveal how PDZRN3 regulates vascular permeability through a PKCζ-containing complex.

BACKGROUND In contrast to benign meningiomas, malignant meningiomas (MM) are rare and associated with an unfavourable prognosis. Reports on MM concern fairly small cohorts, often comprising less than 30 cases. OBJECTIVE To describe the outcome MM and identify factors that may influence survival. METHODS Pathology reports and clinical data of 178 patients treated between 1989 and 2017 for a MM at 6 different international institutions were retrospectively reviewed. Seventy-six patients (42.7%) had a previous history of grade I or grade II meningioma. The patients underwent a total of 380 surgical resections and 72.5% received radiotherapy. Median follow-up was 4.5 yr. RESULTS At data collection, 111 patients were deceased (63.4%) and only 23 patients (13.7%) were alive without any residual tumor on the most recent scan. Median overall survival was 2.9 yr, 95% confidence interval [CI; 2.4, 4.5]. Overall survival rates at 1, 5, and 10 yr, respectively, were: 77.7%, 95% CI [71.6, 84.3], 40%, 95% CI [32.7, 49], and 27.9%, 95% CI [20.9, 37.3]. In the multivariable analysis, age at MM surgery <65 yr (hazard ratio [HR] = 0.44, 95% CI [0.29, 0.67], P < .001), previous benign or atypical meningioma surgery (HR = 1.9, 95% CI [1.23, 2.92], P = .004), completeness of resection (HR = 0.51, 95% CI [0.34, 0.78], P = .002), and adjuvant radiotherapy (HR = 0.64, 95% CI [0.42, 0.98], P = .039) were established as independent prognostic factors for survival. CONCLUSION This large series confirms the poor prognosis associated with MM, the treatment of which remains challenging. Patients under 65-yr-old with primary MM may live longer after complete resection and postoperative radiotherapy. Even with aggressive treatments, local control remains difficult to achieve.

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Objective: To describe and analysed the functional outcome (FO) after spinal meningioma (SM) surgery.Methods: We processed the système national des données de santé (SNDS) i.e. , the French national administrative medical database to retrieve appropriate cases. We analysed the International Classification of Diseases 10 codes to assess the FO. Logistic models were implemented to search for variables associated with a favourable FO i.e. , a patient being independent at home without disabling symptom.Results: A total of 2,844 patients were identified of which 79.1% were female. Median age at surgery was 66 years, interquartile range (IQR) (56–75). Ninety-five point nine percent of the SMs were removed through a posterior ± lateral approach and 0.7% need an associated stabilisation. Benign meningioma represented 92.9% and malignant 2.1%. Median follow-up was 5.5 years, IQR (2.1–8), and at data collection 9% had died. The FO was good and increased along the follow-up: 84.3% of the patients were alive and had not associated symptoms at one year, 85.9% at 2 and 86.8% at 3 years. Nonetheless, 3 years after the surgery 9.8% of the alive patients still presented at least one disabling symptom of which 2.7% motor deficit, 3.3% bladder control problem, and 2.5% gait disturbance. One point seven percent were care-provider dependent and 2.1% chair or bedfast. In the multivariable logistic regression an older age at surgery (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.29–0.47, p < 0.001), a high level of comorbidities (OR, 0.71; 95% CI, 0.66–0.75, p < 0.001), and an aggressive tumor (OR, 0.49; 95% CI, 0.33–0.73; p < 0.001) were associated with a worse FO.Conclusion: FO after meningioma surgery is favourable but, may be impaired for older patients with a high level of comorbidities and aggressive tumor.