Citations

We observe previously unknown interactions between clinically important adenovirus vector capsids, platelet factor 4, and CAR.

Background: Patients with cerebral or spinal cavernous malformations (CM) and a primary headache disorder are often limited in medication options due to concern for bleeding risk. Methods: From a prospective cohort of CM patients (2015–2020), demographics, mode of clinical presentation, and radiographic data were collected. Follow up of patients was performed with electronic medical record review, in person visits and/or written surveys. Select medication use was ascertained from the time of the CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, or death. The influence of non-aspirin NSAID (NA-NSAID), triptan, or OnabotulinumtoxinA on prospective hemorrhage risk was assessed. Results: As of August 20, 2020, 329 patients with spinal or cerebral CM (58% female; 20.1% familial; 42.2% initial presentation due to hemorrhage; 27.4% brainstem) were included. During a follow-up of 1799.9 patient years, 92 prospective hemorrhages occurred. Use of NA-NSAIDs, triptans, and OnabotulinumtoxinA after the diagnosis of CM was unassociated with an increased risk of prospective hemorrhage. Conclusions: Use of triptans and NA-NSAIDs, does not precipitate CM hemorrhage. Similarly, we did not find that OnabotulinumtoxinA precipitated CM hemorrhage in a limited number of patients at doses <200 units per session.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) on immune-modifying therapies may have a lower vaccine response to certain vaccines. The aim of our study was to evaluate humoral immunogenicity of mRNA coronavirus disease 2019 (COVID-19) vaccines among patients with IBD and healthy controls (HCs). METHODS: We performed a prospective study to evaluate humoral immunogenicity among patients with IBD and HCs after completion of mRNA COVID-19 vaccines. RESULTS: One hundred twenty-two patients with IBD and 60 HCs were enrolled. All HCs and 97% of patients with IBD developed antibodies. Antibody concentrations were lower in patients with IBD compared with those in HCs (median 31 vs 118 μg/mL; P < 0.001). Those who received the mRNA-1273 (Moderna) COVID-19 (median 38; interquartile range [IQR] 24–75 vs μg/mL) had higher antibody concentrations compared with those who received the Pfizer-BNT vaccine series (median 22; IQR 11–42 μg/mL; P < 0.001). Patients on immune-modifying therapy (median 26; IQR 13–50 μg/mL) had lower antibody concentrations compared with those who were on no treatment, aminosalicylates, or vedolizumab (median 59; IQR 31–75 μg/mL; P = 0.003). DISCUSSION: Almost all patients with IBD in our study mounted an antibody response. Future studies are needed in evaluating sustained humoral immunity and the impact of booster dosing in patients with IBD.

Background Headache in patients with moyamoya disease is an under-addressed topic in the medical literature. Delay in the diagnosis of moyamoya disease or inappropriate treatment of headache could lead to devastating cerebrovascular outcome. With the evolving understanding of moyamoya disease, migraine pathophysiology, and various migraine-specific medications that have become available, it is crucial to provide an updated overview on this topic. Methods We searched PubMed for keywords including moyamoya disease, moyamoya syndrome, headache in moyamoya, surgical revascularization, surgical bypass, migraine and moyamoya, and calcitonin gene-related peptide (CGRP). We summarized the literature and provide a comprehensive review of the headache presentation, possible mechanisms, the impact of various surgical revascularizations on headache in patients with moyamoya disease, and the medical management of headache incorporating novel migraine-specific treatments. Results and conclusion: The most common headache phenotype is migraine; tension-type headache, hemiplegic migraine, and cluster headache have also been reported. Most patients experience improvement of headache after surgical revascularization, though some patients report worsening, or new-onset headache after surgery. Given the complexity of moyamoya disease, careful consideration of different types of medical therapy for headache is necessary to improve the quality of life while not increasing the risk of adverse cerebrovascular events. More prospective studies are warranted to better understand and manage headache in patients with moyamoya disease.

Background Retinal migraine is defined by fully reversible monocular visual phenomena. We present two cases that were complicated by permanent monocular vision deficits. Cases A 57-year-old man with history of retinal migraine experienced persistent monocular vision loss after one stereotypical retinal migraine, progressing to finger-count vision over 4 days. He developed paracentral acute middle maculopathy that progressed to central retinal artery occlusion. A 27-year-old man with history of retinal migraine presented with persistent right eye superotemporal scotoma after a retinal migraine. Relative afferent pupillary defect and superotemporal visual field defect were noted, consistent with ischemic optic neuropathy. Conclusion Retinal migraine can complicate with permanent monocular visual loss, suggesting potential migrainous infarction of the retina or optic nerve. A thorough cerebrovascular evaluation must be completed, which was unrevealing in our cases. Acute and preventive migraine therapy may be considered in retinal migraine patients, to mitigate rare but potentially permanent visual loss.

TNF ligation of TNF receptor 1 (TNFR1) promotes either inflammation and cell survival by (a) inhibiting RIPK1’s death-signaling function and activating NF- κ B or (b) causing RIPK1 to associate with the death-inducing signaling complex to initiate apoptosis or necroptosis. The cellular source of TNF that results in RIPK1-dependent cell death remains unclear. To address this, we employed in vitro systems and murine models of T cell–dependent transplant or tumor rejection in which target cell susceptibility to RIPK1-dependent cell death could be genetically altered. We show that TNF released by T cells is necessary and sufficient to activate RIPK1-dependent cell death in target cells and thereby mediate target cell cytolysis independently of T cell frequency. Activation of the RIPK1-dependent cell death program in target cells by T cell–derived TNF accelerates murine cardiac allograft rejection and synergizes with anti-PD1 administration to destroy checkpoint blockade–resistant murine melanoma. Together, the findings uncover a distinct immunological role for TNF released by cytotoxic effector T cells following cognate interactions with their antigenic targets. Manipulating T cell TNF and/or target cell susceptibility to RIPK1-dependent cell death can be exploited to either mitigate or augment T cell–dependent destruction of allografts and malignancies to improve outcomes.

Abstract Although the Sonic hedgehog (SHH) signaling pathway has been implicated in promoting malignant phenotypes of prostate cancer, details on how it is activated and exerts its oncogenic role during prostate cancer development and progression is less clear. Here, we show that GLI3, a key SHH pathway effector, is transcriptionally upregulated during androgen deprivation and posttranslationally stabilized in prostate cancer cells by mutation of speckle-type POZ protein (SPOP). GLI3 is a substrate of SPOP-mediated proteasomal degradation in prostate cancer cells and prostate cancer driver mutations in SPOP abrogate GLI3 degradation. Functionally, GLI3 is necessary and sufficient for the growth and migration of androgen receptor (AR)–positive prostate cancer cells, particularly under androgen-depleted conditions. Importantly, we demonstrate that GLI3 physically interacts and functionally cooperates with AR to enrich an AR-dependent gene expression program leading to castration-resistant growth of xenografted prostate tumors. Finally, we identify an AR/GLI3 coregulated gene signature that is highly correlated with castration-resistant metastatic prostate cancer and predictive of disease recurrence. Together, these findings reveal that hyperactivated GLI3 promotes castration-resistant growth of prostate cancer and provide a rationale for therapeutic targeting of GLI3 in patients with castration-resistant prostate cancer (CRPC). Implications: We describe two clinically relevant mechanisms leading to hyperactivated GLI3 signaling and enhanced AR/GLI3 cross-talk, suggesting that GLI3-specific inhibitors might prove effective to block prostate cancer development or delay CRPC.

Structural studies reveal that the V domain of HD-PTP has two tandem binding sites for binding ubiquitin. Like its yeast counterpart Bro1, HD-PTP binds the Vps4 MIT domain, stimulating its activity in a manner that is augmented by ubiquitin binding.

AbstractObjectiveThis study was undertaken to determine whether the vertical parasagittal approach or the lateral peri‐insular/peri‐Sylvian approach to hemispheric surgery is the superior technique in achieving long‐term seizure freedom.MethodsWe conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri‐insular/peri‐Sylvian, or lateral trans‐Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time‐to‐event method and calculated using the Kaplan–Meier survival method.ResultsData for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri‐insular/peri‐Sylvian or trans‐Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%–70.2%) of the entire cohort at 10‐year follow‐up. Seizure freedom was 88.8% (95% CI = 78.9%–94.3%) at 1‐year follow‐up and persisted at 85.5% (95% CI = 74.7%–92.0%) across 5‐ and 10‐year follow‐up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%–91.5%) at 1‐year to 72.1% (95% CI = 66.9%–76.7%) at 5‐year to 57.2% (95% CI = 46.6%–66.4%) at 10‐year follow‐up for the lateral subgroup. Log‐rank test found that vertical hemispherotomy was associated with durable seizure‐free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time‐to‐seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08–6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05–12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique.SignificanceThis pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise‐based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long‐term seizure outcomes.