Neovascularization and vascular remodeling are functionally important for brain repair after stroke. We show that neutrophils accumulate in the peri-infarct cortex during all stages of ischemic stroke. Neutrophils producing intravascular and intraparenchymal neutrophil extracellular traps (NETs) peak at 3-5 days. Neutrophil depletion reduces blood-brain barrier (BBB) breakdown and enhances neovascularization at 14 days. Peptidylarginine deiminase 4 (PAD4), an enzyme essential for NET formation, is upregulated in peri-ischemic brains. Overexpression of PAD4 induces an increase in NET formation that is accompanied by reduced neovascularization and increased BBB damage. Disruption of NETs by DNase 1 and inhibition of NET formation by genetic ablation or pharmacologic inhibition of PAD increases neovascularization and vascular repair and improves functional recovery. Furthermore, PAD inhibition reduces stroke-induced STING-mediated production of IFN-β, and STING knockdown and IFN receptor-neutralizing antibody treatment reduces BBB breakdown and increases vascular plasticity. Collectively, our results indicate that NET release impairs vascular remodeling during stroke recovery.

Intracerebral hemorrhage associated with thrombolytic therapy with tissue plasminogen activator (tPA) in acute ischemic stroke continues to present a major clinical problem. Here, we report that infusion of tPA resulted in a significant increase in markers of neutrophil extracellular traps (NETs) in the ischemic cortex and plasma of mice subjected to photothrombotic middle cerebral artery occlusion. Peptidylarginine deiminase 4 (PAD4), a critical enzyme for NET formation, is also significantly upregulated in the ischemic brains in tPA-treated mice. Blood-brain barrier (BBB) disruption following ischemic challenge in an in vitro model of BBB was exacerbated after exposure to NETs. Importantly, disruption of NETs by DNase 1 or inhibition of NET production by PAD4 deficiency restored tPA-induced loss of BBB integrity and consequently decreased tPA-associated brain hemorrhage after ischemic stroke. Furthermore, either DNase 1 or PAD4 deficiency reversed tPA-mediated upregulation of the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS). Administration of cGAMP after stroke abolished DNase 1-mediated downregulation of the STING pathway and type I interferon (IFN) production, and blocked the antihemorrhagic effect of DNase 1 in tPA-treated mice. We also show that tPA-associated brain hemorrhage after ischemic stroke was significantly reduced in cGas-/- mice. Collectively, these findings demonstrate that NETs significantly contribute to tPA-induced BBB breakdown in ischemic brain, and suggest that targeting NETs or cGAS may ameliorate thrombolytic therapy for ischemic stroke by reducing tPA-associated hemorrhage.

BackgroundTransnasal endoscopic nasopharyngectomy (TEN) has become increasingly used for recurrent nasopharyngeal carcinoma (rNPC); however, there is no report on the definitive resectable contour for TEN according to the latest staging system for nasopharyngeal carcinoma. The aim of this study was to establish the types of TEN for rNPC.Materials and MethodsA total of 101 rNPC patients underwent TEN from January 2016 to April 2019 at the authors’ institution. TEN was categorized into four types, which included type I (n=40) with resection of the nasopharynx and sinuses; type II (n=10) with lateral extension to the parapharyngeal space; type III (n=40) with lateral extension to the floor of the middle cranial fossa and the infratemporal fossa and superior extension to the orbital apex and the cavernous sinus back to the prevertebral region; and type IV (n=11) with the resection of the involved internal carotid artery following type III. The 2-year overall survival rate (OS) and local recurrence-free survival rate (LRFS) were assessed.ResultsThe median time of follow-up was 20 months. Twenty-five patients reoccurred. Nineteen patients died. Independent predictors of outcome on multivariate analysis were recurrent T stage (P = 0.039), types of TEN (P = 0.002) and surgical margin (P = 0.003). The 2-year OS and LRFS was 76.2% and 53.6%, respectively.ConclusionsThe result of TEN in the treatment of rNPC is promising. The types of TEN will provide effective guideline for surgical treatment of rNPC.

Background Allergen‐specific immunotherapy (AIT) is the only available treatment that can induce specific immune tolerance to allergens. However, the treatment course lasts >3 years, and there is no reliable method to predict treatment response. Therefore, in this study we aimed to establish a method that can predict treatment response to AIT in the second year. Methods This prospective study enrolled 119 patients who had undergone 2‐years of standard‐quality house dust mite subcutaneous immunotherapy. Clinical characteristics, skin‐prick test response, and treatment response were evaluated at months 4, 6, 12, and 18. Effective AIT was defined as a 25% reduction in average adjusted symptom score (AAdSS) from baseline at the end of the second year of immunotherapy. Results The overall efficacy rate at the end of year 2 of the AIT was 67.4%. Age, sex, asthma, body mass index, smoking history, and aeroallergen categories were not associated with efficacy of AIT. Meanwhile, efficacy data at month 4 (odds ratio [OR], 4.250; p = 0.004), month 6 (OR, 10.476; p < 0.000), month 12 (OR, 18.000; p < 0.000), and month 18 (OR, 9.716; p < 0.000) were associated with month 24 efficacy. The area under the curve for improvement at 4, 6, 12, and 18 months was 0.805, 0.834, 0.837, and 0.854, respectively. Conclusion Efficacy of AIT at months 4, 6, 12, and 18 is strongly associated with efficacy at month 24. Efficacy as early as month 4 can predict efficacy at the second year, and this may help to determine the need for long‐term treatment. Our findings may be useful for identifying novel treatment strategies for AIT.

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Our study indicates that the treatment of fibrous dysplasia patients should be tailored according to patient and disease characteristics. The main surgical procedure is the endoscopic approach, and the effect is good. Although the recurrence rate is low, follow-up is necessary.

Blood–brain barrier (BBB) breakdown and inflammation occurring at the BBB have a key, mainly a deleterious role in the pathophysiology of ischemic stroke. Neddylation is a ubiquitylation-like pathway that is critical in various cellular functions by conjugating neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) to target proteins. However, the roles of neddylation pathway in ischemic stroke remain elusive. Here, we report that NEDD8 conjugation increased during acute phase after ischemic stroke and was present in intravascular and intraparenchymal neutrophils. Inhibition of neddylation by MLN4924, also known as pevonedistat, inactivated cullin-RING E3 ligase (CRL), and reduced brain infarction and improved functional outcomes. MLN4924 treatment induced the accumulation of the CRL substrate neurofibromatosis 1 (NF1). By using virus-mediated NF1 silencing, we show that NF1 knockdown abolished MLN4924-dependent inhibition of neutrophil trafficking. These effects were mediated through activation of endothelial P-selectin and intercellular adhesion molecule-1 (ICAM-1), and blocking antibodies against P-selectin or anti–ICAM-1 antibodies reversed NF1 silencing-induced increase in neutrophil infiltration in MLN4924-treated mice. Furthermore, we found that NF1 silencing blocked MLN4924-afforded BBB protection and neuroprotection through activation of protein kinase C δ (PKCδ), myristoylated alanine-rich C-kinase substrate (MARCKS), and myosin light chain (MLC) in cerebral microvessels after ischemic stroke, and treatment of mice with the PKCδ inhibitor rottlerin reduced this increased BBB permeability. Our study demonstrated that increased neddylation promoted neutrophil trafficking and thus exacerbated injury of the BBB and stroke outcomes. We suggest that the neddylation inhibition may be beneficial in ischemic stroke.