Potential role for oral tolerance in gene therapy.

Oral immunotherapies are being developed for various autoimmune diseases and allergies to suppress immune responses in an antigen-specific manner. Previous studies have shown that anti-drug antibody (inhibitor) formation in protein replacement therapy for the inherited bleeding disorder hemophilia can be prevented by repeated oral delivery of coagulation factor antigens bioencapsulated in transplastomic lettuce cells. Here, we find that this approach substantially reduces antibody development against factor VIII in hemophilia A mice treated with adeno-associated viral gene transfer.

Prognostic Factors and Treatment Impact on Overall Survival in Adult Craniopharyngioma.

Objective: To examine the demographics, tumor characteristics, treatments, and clinical outcomes of a large adult craniopharyngioma population.

Methods: The 2004-2018 National Cancer Database was queried to investigate adult patients with craniopharyngioma. Univariable and multivariable Cox hazard ratio analysis was conducted to analyze the overall survival (OS) impact of demographic and clinical variables.

Racial disparities in recommendations for surgical resection of primary brain tumours: a registry-based cohort analysis.

Background: Disparities in treatment and outcomes disproportionately affect minority ethnic and racial populations in many surgical fields. Although substantial research in racial disparities has focused on outcomes, little is known about how surgeon recommendations can be influenced by patient race. The aim of this study was to investigate racial and socioeconomic disparities in the surgical management of primary brain tumors.

Modern Management of Complex Tympanojugular Paragangliomas: Systematic Review and Meta-Analysis.

Objective: Tympanojugular paragangliomas (TJPs) are slow-growing tumors arising within the middle ear or jugular foramen. The development of modified skull base approaches and the increasing use of stereotactic radiosurgery have provided more modern techniques in the management of TJPs. Several factors dictating approach selection, and resulting clinical outcomes have been inconsistently described.

IL-15 blockade and rapamycin rescue multifactorial loss of factor VIII from AAV-transduced hepatocytes in hemophilia A mice.

Hepatic adeno-associated viral (AAV) gene transfer has the potential to cure the X-linked bleeding disorder hemophilia A. However, declining therapeutic coagulation factor VIII (FVIII) expression has plagued clinical trials. To assess the mechanistic underpinnings of this loss of FVIII expression, we developed a hemophilia A mouse model that shares key features observed in clinical trials.

B cell-activating factor modulates the factor VIII immune response in hemophilia A.

Inhibitors of factor VIII (FVIII) remain the most challenging complication of FVIII protein replacement therapy in hemophilia A (HA). Understanding the mechanisms that guide FVIII-specific B cell development could help identify therapeutic targets. The B cell-activating factor (BAFF) cytokine family is a key regulator of B cell differentiation in normal homeostasis and immune disorders.

Estimating Risk of Pituitary Apoplexy after Resection of Giant Pituitary Adenomas.

 Pituitary apoplexy after resection of giant pituitary adenomas is a rare but often cited morbidity associated with devastating outcomes. It presents as hemorrhage and/or infarction of residual tumor in the postoperative period. Because of its rarity, its incidence and consequences remain ill defined.

Factors Associated With Morbidity Following Total Pancreatectomy and Islet Autotransplantation: A NSQIP Analysis.

Background: Total pancreatectomy with islet autotransplantation is a therapeutic surgical option for patients with chronic pancreatitis leading to significant reduction in pain, improvement in quality of life, and potential for preservation of partial to full endocrine function. Data on the factors associated with short-term morbidities are limited.

Methods: We queried the American College of Surgeons National Surgery Quality Improvement Project for patients undergoing total pancreatectomy with islet autotransplantation from 2005 to 2015.

The Rate of Symptomatic Ischemic Events after Passing Balloon Test Occlusion of the Major Intracranial Arteries: Meta-Analysis.

Background: Balloon test occlusion is a widely used method for predicting tolerance of vessel occlusion in the treatment of aneurysms, fistulae, and head and neck neoplasms. However, the false-negative rate is variably reported due in part to the diversity of perfusion monitoring methods.

Objective: To evaluate the rate of symptomatic ischemic events after a negative balloon test occlusion and determine whether perfusion monitoring methods contribute to differences in these rates.

An Erythritol-Sweetened Beverage Induces Satiety and Suppresses Ghrelin Compared to Aspartame in Healthy Non-Obese Subjects: A Pilot Study.

Despite the reduced caloric content of artificially sweetened beverages (ASBs) relative to those sweetened with sucrose, consumption of ASBs fail to consistently decrease the risk of obesity and associated diseases. This failure may be due to the inability of ASBs to effectively reduce appetite and hence overall caloric intake. A variety of non-nutritive sweeteners (NNS), however, remain to be screened for effectiveness in promoting satiety and reducing calorie consumption.

Engineering and Selection of a Novel AAV3B Variant with High Hepatocyte Tropism and Reduced Seroreactivity.

Limitations to successful gene therapy with adeno-associated virus (AAV) can comprise pre-existing neutralizing antibodies to the vector capsid that can block cellular entry, or inefficient transduction of target cells that can lead to sub-optimal expression of the therapeutic transgene. Recombinant serotype 3 AAV (AAV3) is an emerging candidate for liver-directed gene therapy. In this study, we integrated rational design by using a combinatorial library derived from AAV3B capsids with directed evolution by selection for liver-targeted AAV variants.

Pancreatic Islets and Gestalt Principles.

The human brain has inherent methodology to efficiently interpret complex environmental stimuli into understanding. This visual perception is governed by the law of simplicity, which is fundamental to Gestalt theory. First introduced in a seminal article by Wertheimer in 1923, the theory explains how the mind groups similar images and fills in gaps in order to perceive an amenable version of reality.

A Molecular Revolution in the Treatment of Hemophilia.

For decades, the monogenetic bleeding disorders hemophilia A and B (coagulation factor VIII and IX deficiency) have been treated with systemic protein replacement therapy. Now, diverse molecular medicines, ranging from antibody to gene to RNA therapy, are transforming treatment. Traditional replacement therapy requires twice to thrice weekly intravenous infusions of factor.

TLR9-Activating CpG-B ODN but Not TLR7 Agonists Triggers Antibody Formation to Factor IX in Muscle Gene Transfer.

Innate immune signals that promote B cell responses in gene transfer are generally ill-defined. In this study, we evaluate the effect of activating endosomal Toll-like receptors 7, 8, and 9 (TLR7, TLR7/8, and TLR9) on antibody formation during muscle-directed gene therapy with adeno-associated virus (AAV) vectors. We examined whether activation of endosomal TLRs, by adenine analog CL264 (TLR7 agonist), imidazolquinolone compound R848 (TLR7/8 agonist), or class B CpG oligodeoxynucleotides ODN1826 (TLR9 agonist), could augment antibody formation upon intramuscular administration of AAV1 expressing human clotting factor IX (AAV1-hFIX) in mice.

Cytonuclear discordance in the Florida Everglades invasive Burmese python (s) population reveals possible hybridization with the Indian python ().

The invasive Burmese python () has been reproducing in the Florida Everglades since the 1980s. These giant constrictor snakes have caused a precipitous decline in small mammal populations in southern Florida following escapes or releases from the commercial pet trade. To better understand the invasion pathway and genetic composition of the population, two mitochondrial (mtDNA) loci across 1,398 base pairs were sequenced on 426 snakes and 22 microsatellites were assessed on 389 snakes.

CD206-positive myeloid cells bind galectin-9 and promote a tumor-supportive microenvironment.

In patients with metastatic melanoma, high blood levels of galectin-9 are correlated with worse overall survival and a bias towards a Th2 inflammatory state supportive of tumor growth. Although galectin-9 signaling through TIM3 on T cells has been described, less is known about the interaction of galectin-9 with macrophages. We aimed to determine whether galectin-9 is a binding partner of CD206 on macrophages and whether the result of this interaction is tumor-supportive.

Identification of a peptide-peptide binding motif in the coating of nab-paclitaxel nanoparticles with clinical antibodies: bevacizumab, rituximab, and trastuzumab.

Antibody directed chemotherapy (ADC) takes advantage of the selectivity of the monoclonal antibody to increase the efficacy of the chemotherapeutic agent, while reducing toxicity. Previously we described three nab-paclitaxel (Abraxane) nanoparticles coated with commercial monoclonal antibodies. Identifying the binding sites responsible for these particles could allow reverse engineering of nab-paclitaxel binding antibodies, creating a modular platform for antibody directed chemotherapeutic nanoparticles.

Antibody-targeted paclitaxel loaded nanoparticles for the treatment of CD20 B-cell lymphoma.

We developed a nano-antibody targeted chemotherapy (nATC) delivery strategy in which tumor specific and clinically relevant antibodies (rituximab, anti-CD20) are non-covalently bound to the albumin scaffold of nab-paclitaxel (ABX). We define the nanoparticle formed when the 2 drugs are bound (AR160). The newly created nATC retains the cytotoxicity of ABX and CD20 affinity of rituximab in vitro.

Detection limits of quantitative and digital PCR assays and their influence in presence-absence surveys of environmental DNA.

A set of universal guidelines is needed to determine the limit of detection (LOD) in PCR-based analyses of low-concentration DNA. In particular, environmental DNA (eDNA) studies require sensitive and reliable methods to detect rare and cryptic species through shed genetic material in environmental samples. Current strategies for assessing detection limits of eDNA are either too stringent or subjective, possibly resulting in biased estimates of species' presence.

Chimney stent technique for treatment of severe abdominal aortic atherosclerotic stenosis.

Application of the "chimney" stent technique is described in a case of complex multilevel atherosclerotic disease involving the juxtarenal aorta. A patient with significant comorbidities was unsuitable for major open reconstructive surgery. He was treated with a combined procedure consisting of chimney stent placement in the juxtarenal aorta, iliac "kissing" stent placement, and right-sided common femoral artery (CFA) replacement.

Endovascular aortic aneurysm repair with the talent stent-graft: outcomes in patients with large iliac arteries.

The purpose of this study is to report outcomes following endovascular aneurysm repair (EVAR) of abdominal aortic aneurysm (AAA) in patients with ectatic common iliac arteries (CIAs). Of 117 AAA patients treated by EVAR between 1998 and 2005, 87 (74%) had CIAs diameters <18 mm and 30 (26%) patients had one or more CIA diameters >18 but <25 mm. All patients were treated with Talent stent-grafts, 114 bifurcated and 3 AUI devices.

Exercise training in patients with stable chronic heart failure: effects on thoracic impedance cardiography and B-type natriuretic peptide.

Purpose: Recent evidence has suggested that patients with stable chronic heart failure (CHF) may respond favorably to a progressive exercise program. The use of noninvasive hemodynamic monitoring and B-type natriuretic peptide (BNP) measurement in these patients is not well reported. This study investigated the utility of noninvasive hemodynamic monitoring and point-of-care BNP in a cardiac rehabilitation outpatient setting.

Successful endovascular repair of a ruptured abdominal aortic aneurysm in a patient with unfavorable anatomy.

Endovascular repair of an abdominal aortic aneurysm (AAA) offers hope of improved outcomes in patients presenting with acute rupture. However, a high proportion of such patients have unfavorable proximal neck anatomy and are not suitable for treatment with conventional endografts. Fenestrated endografts overcome the problem of a short proximal neck, but at present their deployment is time consuming and therefore not easily applicable to a ruptured AAA.

Device migration after endovascular abdominal aortic aneurysm repair: experience with a talent stent-graft.

Purpose: Device migration (DM) may cause late failure after endovascular aortic aneurysm repair (EVAR). Computed tomography (CT) scans following EVAR were reviewed to establish the frequency of DM and whether it can be predicted.

Materials And Methods: Fifty-five patients underwent EVAR with a Talent stent-graft with suprarenal fixation.