Corneal Lymphangiogenesis: Current Pathophysiological Understandings and Its Functional Role in Ocular Surface Disease.

The cornea is a transparent and avascular tissue that plays a central role in light refraction and provides a physical barrier to the external environment. Corneal avascularity is a unique histological feature that distinguishes it from the other parts of the body. Functionally, corneal immune privilege critically relies on corneal avascularity. Corneal lymphangiogenesis is now recognized as a general pathological feature in many pathologies, including dry eye disease (DED), corneal allograft rejection, ocular allergy, bacterial and viral keratitis, and transient corneal edema. Currently, sizable data from clinical and basic research have accumulated on the pathogenesis and functional role of ocular lymphangiogenesis. However, because of the invisibility of lymphatic vessels, ocular lymphangiogenesis has not been studied as much as hemangiogenesis. We reviewed the basic mechanisms of lymphangiogenesis and summarized recent advances in the pathogenesis of ocular lymphangiogenesis, focusing on corneal allograft rejection and DED. In addition, we discuss future directions for lymphangiogenesis research.

Ethical and regulatory guidelines in clinical trials of xenocorneal transplantation in Korea; the Korean xenocorneal transplantation consensus statement.

BACKGROUND: To establish the consensus about the conditions for undertaking clinical trials in xenocorneal transplantation in Korea, specific issues regarding the xenocorneal transplantation on ethical and regulatory aspects are addressed, and the guidelines to conduct clinical trial of the xenocorneal transplantation are proposed. METHOD AND RESULTS: Chapter 1 reviews the key ethical requirements and progress of a Korean regulatory framework for clinical trials of xenocorneal transplantation. Chapters 2-7 provide recommendations on source pigs, quality control of porcine corneal procurement, preclinical efficacy required to justify a clinical trial, strategies to prevent transmission of porcine endogenous retrovirus (PERV), patient selection for clinical trials, and informed consent in xenocorneal transplantation using either cellularized or decellularized porcine graft, which are essentially based on the International Xenotransplantation Association (IXA) islet xenotransplantation consensus statement. The consensus statement of the inclusion criteria for the patients' selection has been made by the executive board members in Korean External Eye Disease Society. CONCLUSIONS: This consensus statement will be a good initiative for Korean Food and Drug Administration to discuss final regulatory guidelines in conducting clinical trials of xenocorneal transplantation in Korea and for International Xenotransplantation Association to develop International Consensus Standards of Xenocorneal Transplantation.

Validation of IL-7R as an Immunological Biomarker for Human Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer for which no early diagnostic method is available. The immune surveillance hypothesis suggests that the immune system plays crucial roles in tumor development and progression. We validated a PDAC-specific biomarker derived from peripheral blood mononuclear cells (PBMCs) to facilitate early PDAC diagnosis. mRNA levels of interleukin-7R (IL-7R), reportedly a potential immunological marker for PDAC, were measured in PBMCs isolated prospectively from healthy controls (n = 100) and patients with PDAC (n = 135), pancreatic cysts (n = 82), chronic pancreatitis (n = 42), acute pancreatitis (n = 47), and other malignancies (n = 116). The IL-7R level was significantly higher in patients with PDAC than in healthy controls, patients with benign pancreatic disease, and patients with other malignancies. As diagnostic parameters, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for IL-7R were 58.5%, 92%, 90.8%, 62.2%, and 72.8%, respectively. The area under the receiver operating characteristic curve (AUROC) was 0.766. IL-7R levels did not differ between resectable and unresectable PDAC cases. The combined measurement of IL-7R and carbohydrate antigen 19-9 (CA19-9) significantly improved the diagnostic parameters and AUROC compared with the use of IL-7R or CA19-9 alone. IL-7R is significantly upregulated in PBMCs in patients with PDAC, and it may be a novel diagnostic marker for PDAC. The combined use of IL-7R and CA19-9 enhanced the diagnostic performance.

Alterations of aqueous humor Aß levels in Aß-infused and transgenic mouse models of Alzheimer disease.

Alzheimer's disease (AD) is an ageing-related neurodegenerative disease characterized and diagnosed by deposition of insoluble amyloid-ß (Aß) plaques in the brain. The plaque accumulation in the brain directly affects reduced levels of Aß in cerebrospinal fluid (CSF) and blood, as Aß can freely transport the blood-brain barrier, and clinical investigations have suggested these two biofluids as promising samples for in vitro diagnosis. Given that the human eye structurally resembles the brain and Aß accumulation often observed in the ocular region of AD patients, in this study, we examined aqueous humor Aß as another possible surrogate biomarker. First, using the acute Aß-infused AD mouse model by injecting Aß to the CSF in intracerebroventricular region of normal ICR mice, we investigated whether Aß concentration in the aqueous humor in AD models is positively correlated with the concentration in the CSF. Then, we examined the correlation of aqueous humor Aß levels with increased plaque deposition in the brain and reduced Aß levels in both CSF and blood in adult and aged 5XFAD Alzheimer transgenic mice. Collectively, the synthetic Aß injected into CSF immediately migrate to the aqueous humor, however, the age-dependently reducing pattern of Aß levels in CSF and blood was not observed in the aqueous humor.

Mass transfer in the absorption of SO2 and NO(x) using aqueous euchlorine scrubbing solution.

Attempts have been made to generate euchlorine gas by chlorate-chloride process and to utilize it further to clean up SO2 and NO(x) from the flue gas in a lab scale bubbling reactor. Preliminary experiments were carried out to determine the gas and liquid phase mass transfer coefficients and their correlation equations have been established. Simultaneous removal of SO2 and NO(x) from the simulated flue gas using aqueous euchlorine scrubbing solution has been investigated. Euchlorine oxidized NO into NO2 completely and the later subsequently absorbed into the scrubbing solution in the form of nitrate. SO2 removal efficiency around 100% and NO(x) removal efficiency around 72% were achieved under optimal conditions. Mass balance has been confirmed by analyzing the sulfate, nitrate, euchlorine and chloride ion using ion chromatograph/auto-titrator and comparing it with their corresponding calculated values.

Simultaneous removal of SO2 and NO by wet scrubbing using aqueous chlorine dioxide solution.

The present study attempts to generate chlorine dioxide (ClO(2)) gas continuously by chlorate-chloride process and to utilize it further to clean up SO(2) and NO(x) gases simultaneously from the flue gas in the lab-scale bubbling reactor. Experiments were carried out to examine the effect of various operating parameters like input SO(2) concentration, input NO concentration, pH of the reaction medium, and ClO(2) feeding rate on the SO(2) and NO(x) removal efficiencies at 45 degrees C. Complete oxidation of NO into NO(2) occurred on passing sufficient ClO(2) gas into the scrubbing solution. SO(2) removal efficiency of about 100% and NO(x) removal efficiency of 66-72% were achieved under optimized conditions. NO(x) removal efficiency decreased slightly with increasing pH and NO concentration. Input SO(2) concentration had marginal catalytic effect on NO(2) absorption. No improvement in the NO(x) removal efficiency was observed on passing excess of chlorine dioxide in the scrubbing solution.

Bioinert membranes prepared from amphiphilic poly(vinyl chloride)-g-poly(oxyethylene methacrylate) graft copolymers.

Poly(vinyl chloride) (PVC) membrane was hydrophilically modified by grafting with poly(oxyethylene methacrylate) (POEM) using atom transfer radical polymerization (ATRP). The successful grafting of PVC main chain by POEM was characterized by Fourier transform infrared spectroscopy (FT-IR). The molecular weight and hydrophilicity of membranes increased with the amount of POEM grafting, as characterized by gel permeation chromatography (GPC) and contact angle measurement, respectively. Transmission electron microscope (TEM) and small angle X-ray scattering (SAXS) analysis revealed the microphase-separated structure of PVC-g-POEM and the domain spacing increased from 59.3 to 86.1 nm with increasing grafting degree. Scanning electron microscopy (SEM) was used for the direct visualization of the mouse embryonic fibroblast (MEF) cell and bacteria adhesion on the membrane surface. Protein adsorption and eukaryotic and prokaryotic cell adhesion tests showed that the bioinert properties of membranes were significantly increased with POEM content.

Vascular endothelial growth factor as an autocrine survival factor for retinal pigment epithelial cells under oxidative stress via the VEGF-R2/PI3K/Akt.

PURPOSE: Vascular endothelial cell growth factor (VEGF) is strongly induced by oxidative stress in retinal pigment epithelial (RPE) cells, and VEGF-A is a survival factor for various cell types. This study was conducted to determine whether the autocrine VEGF signaling pathway in RPE cells is involved in the mechanism of adaptive response to oxidative stress. METHODS: ARPE-19 cells were treated with hydrogen peroxide, and cell death was measured by flow cytometry with annexin V-fluorescein isothiocyanate. Survival analysis was performed with pretreatment of VEGF-A-neutralizing antibodies, VEGF receptor tyrosine kinase inhibitor (SU5416), or VEGF-A receptor-neutralizing antibodies (anti-VEGF-R1 and anti-VEGF-R2). The expression of VEGF-A, -R1, -R2, and soluble VEGF-R1 was determined by semiquantitative RT-PCR or Western blot analysis. Phosphorylation of VEGF-R2 was detected with immunoprecipitation and immunoblot analysis. RESULTS: Hydrogen peroxide-induced cell death was promoted by pretreatment with VEGF-A and anti-VEGF-R2-neutralizing antibodies, but not with anti-VEGF-R1-neutralizing antibody. Phosphorylation of VEGF-R2 in RPE cells was induced by hydrogen peroxide, and pretreatment with anti-VEGF-A-neutralizing antibody inhibited phosphorylation. Phosphorylation of Akt under oxidative stress was abrogated by pretreatment with neutralizing antibodies against either VEGF-A or SU5416. CONCLUSIONS: Autocrine VEGF-A enhanced RPE cell survival under oxidative stress; the autocrine VEGF-A/VEGF-R2/PI3K/Akt pathway is involved. Neutralization of VEGF-A signaling, as in eyes with age-related macular degeneration, may influence RPE cell survival.