ABSTRACT
A subset of neovascular age-related macular degeneration (nvAMD) subjects appears to be refractory to the effects of anti-VEGF treatment and require frequent intravitreal injections. Prokineticin-2 (Bv8) expression in CD11b(+) cells has been linked to anti-VEGF response. We have developed a reproducible method to quantify gene expression in circulating CD11b + cells. Utilizing this method we tested the hypothesis that high Bv8 expression in circulating CD11b(+) cells is associated with anti-VEGF refractoriness in nvAMD patients. Two groups of nvAMD subjects undergoing treatment with anti-VEGF agents were recruited and classified as refractory or non-refractory to anti-VEGF treatment (n = 33 for each group). Two blood draws were obtained from each subject 1-9 months apart. Peripheral blood mononuclear cells (PBMCs) were isolated and CD11b(+) cells were purified via magnetic bead separation. RNA was purified, and relative expression of Bv8 among the subjects was compared via quantitative PCR analysis. Utilizing this approach no significant difference was detected in the mean LogRQ values between the first and second blood draws (t-test, p = 0.826) indicating low intra-patient variability and demonstrating good reproducibility of the assay. There was no significant difference in Bv8 expression between nvAMD subjects classified as refractory versus non-refractory. We were unable to find a correlation between Bv8 expression in CD11b + cells and anti-VEGF refractoriness in human nvAMD subjects. Relatively high expression in Bv8 in these subjects did not correlate with clinical treatment history, as measured by the frequency of injections. Utilizing this well characterized technique, studies are underway to examine alternative gene expression profiles in various circulating cell populations that may contribute to anti-VEGF refractoriness.
Subject(s)
Choroidal Neovascularization/metabolism , Gastrointestinal Hormones/metabolism , Leukocytes, Mononuclear/metabolism , Macular Degeneration/metabolism , Neuropeptides/metabolism , Polymerase Chain Reaction/methods , Aged , Aged, 80 and over , Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , CD11b Antigen/metabolism , Choroidal Neovascularization/drug therapy , Female , Gene Expression Profiling/methods , Humans , Intravitreal Injections , Leukocytes, Mononuclear/immunology , Macular Degeneration/drug therapy , Male , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/bloodABSTRACT
BACKGROUND: Topical bevacizumab is a potential treatment modality for corneal neovascularization, and several recent studies have demonstrated its efficacy. No previous study of the pharmacokinetics of topical bevacizumab has been performed in human eyes. The purpose of this study is to investigate the pharmacokinetics of topical administration of bevacizumab in human eyes, and also to compare the pharmacokinetics of intravitreal bevacizumab injections with previously reported data. METHODS: Twenty-two (22 eyes) were included in this study, and divided into four groups: eight patients received topical bevacizumab and aqueous samples were obtained 1 hour later during cataract extraction surgery (group 1), eight patients received topical bevacizumab and vitreous samples were obtained 1 day later during pars-plana vitrectomy (PPV) (group 2), three patients received intravitreal bevacizumab and vitreous samples were obtained during PPV (group 3). Vitreous samples from three patients who received no bevacizumab served as controls (group 4). All samples underwent enzyme-linked immunosorbent assay to detect bevacizumab. RESULTS: No bevacizumab was detected in the aqueous or vitreous of any topically treated eyes. The mean vitreal half-life for intravitreally injected bevacizumab was 4.9 days in four non-vitrectomized eyes and 0.66 days in one previously vitrectomized eye. CONCLUSIONS: Topically administered bevacizumab does not penetrate the cornea into the anterior chamber and vitreous cavity, indicating that topical use for treating corneal neovascularization has minimal risk of intraocular penetration and adverse events related to intraocular vascular endothelial growth factor inhibition. The half-life following intravitreal bevacizumab injection measured in this study is comparable to that of previous reports, and includes the first demonstration of a significantly reduced half-life following intravitreal injection in a previously vitrectomized eye.
Subject(s)
Angiogenesis Inhibitors/pharmacokinetics , Antibodies, Monoclonal, Humanized/pharmacokinetics , Aqueous Humor/metabolism , Vitreous Body/metabolism , Administration, Topical , Aged , Aged, 80 and over , Angiogenesis Inhibitors/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Bevacizumab , Cataract Extraction , Enzyme-Linked Immunosorbent Assay , Female , Half-Life , Humans , Intravitreal Injections , Male , Middle Aged , Tissue Distribution , Vascular Endothelial Growth Factor A/antagonists & inhibitorsABSTRACT
We present the integration of epitaxial graphene with thin film dielectric materials for the purpose of graphene transistor development. The impact on epitaxial graphene structural and electronic properties following deposition of Al(2)O(3), HfO(2), TiO(2), and Ta(2)O(5) varies based on the choice of dielectric and deposition parameters. Each dielectric film requires the use of a nucleation layer to ensure uniform, continuous coverage on the graphene surface. Graphene quality degrades most severely following deposition of Ta(2)O(5), while the deposition if TiO(2) appears to improve the graphene carrier mobility. Finally, we discuss the potential of dielectric stack engineering for improved transistor performance.
