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Jacksonville Beach, FL, United States

Stewart M.W.,Mayo Clinic Florida
Inflammation and Allergy - Drug Targets | Year: 2011

The inflammatory cytokine, vascular endothelial growth factor (VEGF), plays a central role in human growth and development, and vascular maintenance. VEGF mediated angiogenesis is essential for tumor growth, as well as exudative age-related macular degeneration, proliferative diabetic retinopathy and retinopathy of prematurity, all of which are characterized by abnormal neovascularization. Ischemia and inflammation also lead to VEGF-mediated breakdown of the blood-retinal barrier, which causes vision diminishing macular edema. To combat these effects, anti-VEGF drugs (antibodies, aptamers, and tyrosine kinase inhibitors) have been developed for both systemic and local (intraocular) use. The next drug to receive regulatory approval will probably be aflibercept (VEGF-Trap), a fusion protein with high VEGF affinity attributed to binding sequences from the native receptors VEGFR1 and VEGFR2. Aflibercept monotherapy significantly reduces tumor growth and extends survival in several orthotropic animal models, and has both prevented and reduced the growth of experimental choroidal neovascularization. Ongoing phase III trials are evaluating the effectiveness of aflibercept combined with chemotherapy in patients with advanced carcinomas. The phase III VELOUR trial determined that patients receiving aflibercept with irinotecan/5-FU as second line chemotherapy for metastatic colorectal cancer experienced extended progression free survival and overall survival. Intravitreal aflibercept improved visual acuity in patients with exudative age-related macular degeneration and was non-inferior to standard therapy (ranibizumab). Ongoing phase III trials are investigating the use of aflibercept for retinal vein occlusions and diabetic macular edema. A regulatory approval application for use in exudative macular degeneration has been filed, with a decision expected by late 2011. © 2011 Bentham Science Publishers. Source


Wallace M.B.,Mayo Clinic Florida | Keisslich R.,Johannes Gutenberg University Mainz
Gastroenterology | Year: 2010

Colon cancer screening is arguably the most important activity performed by gastroenterologists. Recent decreases in rates of death from colorectal cancer indicate that screening methods such as colonoscopy have a positive impact. There is still room for improvement, however, particularly in prevention of right-sided colon cancer. Practice issues, such as making colonoscopy more comfortable, safer, and less costly, are keys to continued success in cancer prevention. Colonoscopy techniques, technologies, and quality control measures have advanced to improve detection, classification, and removal of early neoplasias. In particular, slow, careful inspection of the colon by gastroenterologists who have been trained in lesion recognition has improved rates of detection of polypoid and flat neoplasias. Image enhancement methods such as chromoendoscopy have greatly improved neoplasia detection in patients with chronic colitis, but are not widely used because they are perceived as inconvenient. More convenient methods, such as "digital" chromoendoscopy, show promise but have had mixed results. Ultra-high magnification systems, including optical magnification and confocal endomicroscopy, can be used during the colonoscopy examination to evaluate small polyps, allowing physicians to make immediate diagnoses and decisions about whether to remove polyps. In patients with inflammatory bowel disease, improved imaging techniques could eliminate the needs for analysis of randomly selected biopsy samples and resection of all (neoplastic and non-neoplastic) polyps. It is important to maintain high standards of quality for colonoscopy examination, detection, and removal of high-risk lesions, as well as to make colon cancer screening more widely accepted and affordable for the entire at-risk population. © 2010 AGA Institute. Source


Saido T.,RIKEN | Leissring M.A.,Mayo Clinic Florida
Cold Spring Harbor Perspectives in Medicine | Year: 2012

The amyloid β-protein (Aβ) is subject to proteolytic degradation by a diverse array of peptidases and proteinases, known collectively as Aβ-degrading proteases (AβDPs). A growing number of AβDPs have been identified, which, under physiological and/or pathophysiological conditions, contribute significantly to the determination of endogenous cerebral Aβ levels. Despite more than a decade of investigation, the complete set of AβDPs remains to be established, and our understanding of even well-established AβDPs is incomplete. Nevertheless, the study of known AβDPs has contributed importantly to our understanding of the molecular pathogenesis of Alzheimer disease (AD) and has inspired the development of several novel therapeutic approaches to the regulation of cerebral Aβ levels. In this article, we discuss the general features of Aβ degradation and introduce the best-characterized AβDPs, focusing on their diverse properties and the numerous conceptual insights that have emerged from the study of each. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Source


Ertekin-Taner N.,Mayo Clinic Florida
Molecular Neurodegeneration | Year: 2011

Uncovering the underlying genetic component of any disease is key to the understanding of its pathophysiology and may open new avenues for development of therapeutic strategies and biomarkers. In the past several years, there has been an explosion of genome-wide association studies (GWAS) resulting in the discovery of novel candidate genes conferring risk for complex diseases, including neurodegenerative diseases. Despite this success, there still remains a substantial genetic component for many complex traits and conditions that is unexplained by the GWAS findings. Additionally, in many cases, the mechanism of action of the newly discovered disease risk variants is not inherently obvious. Furthermore, a genetic region with multiple genes may be identified via GWAS, making it difficult to discern the true disease risk gene. Several alternative approaches are proposed to overcome these potential shortcomings of GWAS, including the use of quantitative, biologically relevant phenotypes. Gene expression levels represent an important class of endophenotypes. Genetic linkage and association studies that utilize gene expression levels as endophenotypes determined that the expression levels of many genes are under genetic influence. This led to the postulate that there may exist many genetic variants that confer disease risk via modifying gene expression levels. Results from the handful of genetic studies which assess gene expression level endophenotypes in conjunction with disease risk suggest that this combined phenotype approach may both increase the power for gene discovery and lead to an enhanced understanding of their mode of action. This review summarizes the evidence in support of gene expression levels as promising endophenotypes in the discovery and characterization of novel candidate genes for complex diseases, which may also represent a novel approach in the genetic studies of Alzheimer's and other neurodegenerative diseases. © 2011 Ertekin-Taner; licensee BioMed Central Ltd. Source


Stewart M.W.,Mayo Clinic Florida
Current Diabetes Reviews | Year: 2012

Diabetic mellitus is the leading cause of blindness in working aged patients in developing nations. Due to the buildup of abnormal metabolites from several overactive biochemical pathways, chronic hyperglycemia causes oxidative stress in the retina which upregulates vascular endothelial growth factor (VEGF). Together with other growth factors and metabolites, VEGF causes endothelial cell proliferation, vasodilation, recruitment of inflammatory cells, and increased vascular permeability, leading to breakdown of the blood-retinal barrier. This allows trans-cellular exudation into the interstitial space resulting in diabetic macular edema (DME). For over 3 decades the standard treatment for DME has been laser photocoagulation. Though laser reduces the incidence of vision loss by 50%, few eyes with diffuse edema experience improved vision. This has led physicians to use the VEGF-binding drugs pegaptanib, ranibizumab, and aflibercept, each of which has been approved for the treatment of exudative macular degeneration, and bevacizumab which is commonly used off-label for a variety of chorioretinal disorders. Intravitreal administration of each drug frequently causes rapid improvement of DME with sustained improvement in vision through 2 years. Though these drugs significantly outperform laser photocoagulation over treatment periods of 1 year of less, the advantages appear to lessen when trials approach 2 years. Further studies to better determine relative efficacies of anti-VEGF drugs and laser photocoagulation are continuing. © 2012 Bentham Science Publishers. Source

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