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Chen X, Chen Y, Wiggs JL, Pasquale LR, Sun X, Fan BJ. Association of Matrix Metalloproteinase-9 (MMP9) Variants with Primary Angle Closure and Primary Angle Closure Glaucoma. PLoS One 2016;11(6):e0157093.Abstract

Shorter axial length observed in patients with primary angle closure glaucoma (PACG) might be due to altered matrix metalloproteinase-9 (MMP9) activity resulting in ECM remodeling during eye growth and development. This study aimed to evaluate common variants in MMP9 for association with PACG. Six tag SNPs of MMP9 were genotyped in a Chinese sample of 1,030 cases, including 572 PACG and 458 primary angle closure (PAC), and 499 controls. None of 6 SNPs were significantly associated with overall PAC/PACG (P > 0.07) or with PAC/PACG subgroups (Pc > 0.18). Meta-analysis of two non-Chinese studies revealed significant association between rs17576 and PACG (ORs = 0.56, P < 0.0001); however, meta-analysis of our dataset with 4 Chinese datasets did not replicate this association (ORs = 1.23, P = 0.29). Prior significant association for rs3918249 in one Caucasian study (OR = 0.63, P = 0.006) was not replicated in meta-analysis of 3 Chinese studies including this study (ORs = 0.91, P = 0.13). Significant heterogeneity between non-Chinese and Chinese datasets precluded overall meta-analysis for rs17576 and rs3918249 (Q = 0.001 and 0.04 respectively). rs17577 was nominally associated with PACG in one Caucasian study (OR = 1.71, P = 0.02), but not in 3 Chinese studies including our study (ORs = 1.20, P = 0.07). Overall meta-analysis revealed nominal association for rs17577 and PAC/PACG (ORs = 1.26, Pc = 0.05). Meta-analysis did not show significant association between the other SNPs and PAC/PACG (P > 0.47). The largest association study to date did not find significant association between MMP9 and PAC/PACG in Chinese; meta-analysis with other Chinese datasets did not produce significant association. In most instances combination with non-Chinese datasets was not possible except for one variant showing nominally significant association. More work is needed to define the role of MMP9 variants in PACG.

Liu C, Vojnovic D, Kochevar IE, Jurkunas UV. UV-A Irradiation Activates Nrf2-Regulated Antioxidant Defense and Induces p53/Caspase3-Dependent Apoptosis in Corneal Endothelial Cells. Invest Ophthalmol Vis Sci 2016;57(4):2319-27.Abstract

PURPOSE: To examine whether Nrf2-regulated antioxidant defense and p53 are activated in human corneal endothelial cells (CEnCs) by environmental levels of ultraviolet A (UV-A), a known stimulator of oxidative stress. METHODS: Immortalized human CEnCs (HCEnCi) were exposed to UV-A fluences of 2.5, 5, 10, or 25 J/cm2, then allowed to recover for 3 to 24 hours. Control HCEnCi did not receive UV-A. Reactive oxygen species (ROS) were measured using H2DCFDA. Cell cytotoxicity was evaluated by lactate dehydrogenase (LDH) release. Levels of Nrf2, HO-1, NQO-1, p53, and caspase3 were detected by immunnoblotting or real-time PCR. Activated caspase3 was measured by immunoblotting and a fluorescence assay. RESULTS: Exposure of HCEnCi to 5, 10, and 25 J/cm2 UV-A increased ROS levels compared with controls. Nrf2, HO-1, and NQO-1 mRNA increased 1.7- to 3.2-fold at 3 and 6 hours after irradiation with 2.5 and 5 J/cm2 UV-A. At 6 hours post irradiation, UV-A (5 J/cm2) enhanced nuclear Nrf2 translocation. At 24 hours post treatment, UV-A (5, 10, and 25 J/cm2) produced a 1.8- to 2.8-fold increase in phospho-p53 and a 2.6- to 6.0-fold increase in activated caspase3 compared with controls, resulting in 20% to 42% cell death. CONCLUSIONS: Lower fluences of UV-A induce Nrf2-regulated antioxidant defense and higher fluences activate p53 and caspase3, indicating that even near-environmental levels of UV-A may affect normal CEnCs. This data suggest that UV-A may especially damage cells deficient in antioxidant defense, and thus may be involved in the etiology of Fuchs' endothelial corneal dystrophy (FECD).

Pennock S, Kim LA, Kazlauskas A. Vascular Endothelial Cell Growth Factor A Acts via Platelet-Derived Growth Factor Receptor α To Promote Viability of Cells Enduring Hypoxia. Mol Cell Biol 2016;36(18):2314-27.Abstract

Vascular endothelial cell growth factor A (VEGF) is a biologically and therapeutically important growth factor because it promotes angiogenesis in response to hypoxia, which underlies a wide variety of both physiological and pathological settings. We report here that both VEGF receptor 2 (VEGFR2)-positive and -negative cells depended on VEGF to endure hypoxia. VEGF enhanced the viability of platelet-derived growth factor receptor α (PDGFRα)-positive and VEGFR2-negative cells by enabling indirect activation of PDGFRα, thereby reducing the level of p53. We conclude that the breadth of VEGF's influence extends beyond VEGFR-positive cells and propose a plausible mechanistic explanation of this phenomenon.

Ma J, Sun Y, López FJ, Adamson P, Kurali E, Lashkari K. Blockage of PI3K/mTOR Pathways Inhibits Laser-Induced Choroidal Neovascularization and Improves Outcomes Relative to VEGF-A Suppression Alone. Invest Ophthalmol Vis Sci 2016;57(7):3138-44.Abstract

PURPOSE: Choroidal neovascularization (CNV) is a major cause of visual loss with age-related macular degeneration (AMD). We evaluated whether blockade of phosphatidyl-inositol-3-kinase (PI3K) and the mammalian target of rapamycin (mTOR), by impairing VEGF-A and other growth factor receptors like platelet-derived growth factor (PDGF), would reduce laser-induced CNV in mice. METHODS: Choroidal neovascularization lesions were induced in C57BL/6 mice. Two groups of mice received oral GSK2126458 (3 mg/kg) or vehicle for 14 days following laser, whereas three groups were treated with GSK2126458 (6 μg/eye), aflibercept (2 μL/eye), or vehicle intravitreally on days 0 and 7 after laser. Vascular leakage was measured by fluorescein angiography (FA) on day 14. Choroidal neovascularization membranes were evaluated on choroidal flat mounts following FITC-dextran perfusion, as well as ED1 and isolectin B4 (IB4) immunohistochemistry. RESULTS: Oral and intravitreal (IVT) GSK2126458 reduced leakage and area of CNV lesions. Greater probability of leaking lesions (∼60%; P < 0.05) was observed in both vehicle groups. Fluorescein isothiocyanate-dextran-labeled total CNV burden area (total lesion area/eye) was reduced ∼67% (P < 0.05) and 35% (P = 0.0528) after oral and IVT GSK2126458 administration. GSK2126458 treatment reduced lesion size by ∼80% (P < 0.05) and 50% (P < 0.05) for oral and IVT control groups. Aflibercept did not alter lesion size (∼27% reduction). CONCLUSIONS: Phosphatidyl-inositol-3-kinase/mTOR is involved in laser-induced CNV angiogenic processes. GSK2126458 effectively reduces CNV size and leakage. Choroidal neovascularization size following IVT GSK2126458 was smaller than after oral administration. Therefore, inhibition of PI3K/mTOR pathways may be more effective due to blockade of action of multiple growth factors.

Jakobiec FA, Borkar DS, Stagner AM, Lee NG. Intraocular Teratoid Medulloepithelioma Presenting With a Completely Rhabdomyosarcomatous Distant Metastasis. JAMA Ophthalmol 2016;134(8):919-923.Abstract

Importance: Medulloepithelioma is the second most common primary neuroepithelial tumor of the eye. The full range of its morphologic expressions and appearances in metastases have not been fully explored. Observations: A patient in her 50s with glaucoma for decades had undergone multiple filtering surgical procedures, including the placement of a glaucoma drainage device. A paraspinal mass was discovered, and tumor and bone marrow biopsies disclosed rhabdomyosarcoma. This led to the discovery of a multicystic intraocular tumor. A metastatic rhabdomyosarcoma to the eye was considered unlikely because, to our knowledge, this event had never been reported. An enucleation was performed, and an intraocular tumor composed almost entirely of rhabdomyoblasts (desmin- and myogenin-positive) was discovered along with rare clusters of persistent neuroepithelial cells. Conclusions and Relevance: To our knowledge, this is the first case of a medulloepithelioma in which teratoid rhabdomyoblasts effaced all but trace amounts of neuroepithelium and generated a distant metastasis entirely composed of rhabdomyoblasts. The prolonged history and filtering procedures probably led to these 2 phenomena.

Wan MJ, Ullrich NJ, Manley PE, Kieran MW, Goumnerova LC, Heidary G. Long-term visual outcomes of optic pathway gliomas in pediatric patients without neurofibromatosis type 1. J Neurooncol 2016;129(1):173-8.Abstract

Sporadic optic pathway gliomas (OPGs) have been reported to cause more vision loss than OPGs associated with neurofibromatosis type-1, but long-term visual outcome data are limited. The purpose of this study was to report the visual outcomes of a cohort of pediatric patients with sporadic OPGs. This was a retrospective, cohort study at a tertiary care pediatric hospital and cancer institute. The study included all patients with sporadic OPGs evaluated from 1990 to 2014. The primary outcome was visual acuity at final follow-up. Secondary outcomes were risk factors for a poor visual outcome and the rate of progression. There were 59 pediatric patients included in the study. Median age at presentation was 2.5 years old and median follow-up was 5.2 years. In the worse eye at final follow-up, 16 patients (27 %) were 20/30 or better, 9 patients (15 %) were between 20/40 and 20/80, and 34 patients (58 %) were 20/100 or worse. In the better eye at final follow-up, 33 patients (56 %) were 20/30 or better, 11 patients (19 %) were between 20/40 and 20/80, and 15 patients (25 %) were 20/100 or worse. Risk factors for a poor visual outcome included younger age at presentation, optic nerve pallor, and tumor extent. Of the 54 patients (92 %) who received treatment, 40 (74 %) experienced disease progression during or after treatment. A majority of pediatric patients with sporadic OPGs had significant long-term visual impairment. In spite of treatment, tumor progression is common. Serial ophthalmic examinations with quantitative vision measurements are essential in the management of sporadic OPGs.

Hsu JC, Gonzalez-Gonzalez LA, Lu VH, Lu CY. Longitudinal trends in use of targeted therapies for treatment of malignant neoplasms of the eye: a population-based study in Taiwan. BMJ Open 2016;6(5):e010706.Abstract

OBJECTIVES: This study examined the recent trend in use and costs of antineoplastic agents for treatment of eye malignancies in Taiwan from 2009 to 2012. We also forecasted use and costs of targeted therapies up to and including year 2016 based on the current patterns. DESIGN: Retrospective observational study focusing on the usage of targeted therapies for treatment of eye malignancy. SETTING: The monthly claims data for eye malignancy-related antineoplastic agents were retrieved from Taiwan's National Health Insurance Research Database (2009-2012). MAIN OUTCOME MEASURES: We calculated the number of prescriptions and costs for each class of medications, and analysed their time trends. In addition, using a time series design with ARIMA models, we estimated the market share by prescription volume and the proportion of costs for targeted therapies for year 2016. RESULTS: The market share by prescription volume of targeted therapies grew from 1.56% in 2009 to 9.98% in 2012 among all antineoplastic agents, and the proportion of costs for targeted therapies rose from 15.12% in 2009 to 58.88% in 2012. Especially, the proportion of costs for protein kinase inhibitors grew from 25.62% to 45.28% among all antineoplastic agents between 2010 and 2012. The market share by prescription volume and the proportion of costs for targeted therapies for treatment of eye malignancies were predicted to reach 27.33% and 91.39% by the fourth quarter in 2016, respectively. CONCLUSIONS: This is the first study that examined and forecasted use and costs of targeted therapies for treatment of eye malignancies in Taiwan. Our findings indicate that, compared with other classes of drugs, targeted therapies are having a more and more relevant share among all treatment strategies for eye malignancies in Taiwan, and due to their high costs they are likely to cause great economic burden.

Yonekawa Y, Wu W-C, Kusaka S, Robinson J, Tsujioka D, Kang KB, Shapiro MJ, Padhi TR, Jain L, Sears JE, Kuriyan AE, Berrocal AM, Quiram PA, Gerber AE, Paul Chan RV, Jonas KE, Wong SC, Patel CK, Abbey AM, Spencer R, Blair MP, Chang EY, Papakostas TD, Vavvas DG, Sisk RA, Ferrone PJ, Henderson RH, Olsen KR, Hartnett EM, Chau FY, Mukai S, Murray TG, Thomas BJ, Meza AP, Drenser KA, Trese MT, Capone A. Immediate Sequential Bilateral Pediatric Vitreoretinal Surgery: An International Multicenter Study. Ophthalmology 2016;123(8):1802-8.Abstract

PURPOSE: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. DESIGN: International, multicenter, interventional, retrospective case series. PARTICIPANTS: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. METHODS: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. MAIN OUTCOME MEASURES: Ocular and systemic adverse events. RESULTS: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143±59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. CONCLUSIONS: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.

Tang JCY, Drokhlyansky E, Etemad B, Rudolph S, Guo B, Wang S, Ellis EG, Li JZ, Cepko CL. Detection and manipulation of live antigen-expressing cells using conditionally stable nanobodies. Elife 2016;5Abstract

The ability to detect and/or manipulate specific cell populations based upon the presence of intracellular protein epitopes would enable many types of studies and applications. Protein binders such as nanobodies (Nbs) can target untagged proteins (antigens) in the intracellular environment. However, genetically expressed protein binders are stable regardless of antigen expression, complicating their use for applications that require cell-specificity. Here, we created a conditional system in which the stability of an Nb depends upon an antigen of interest. We identified Nb framework mutations that can be used to rapidly create destabilized Nbs. Fusion of destabilized Nbs to various proteins enabled applications in living cells, such as optogenetic control of neural activity in specific cell types in the mouse brain, and detection of HIV-infected human cells by flow cytometry. These approaches are generalizable to other protein binders, and enable the rapid generation of single-polypeptide sensors and effectors active in cells expressing specific intracellular proteins.

Yang L, Li S, Miao L, Huang H, Liang F, Teng X, Xu L, Wang Q, Xiao W, Ridder WH, Ferguson TA, Chen DF, Kaufman RJ, Hu Y. Rescue of Glaucomatous Neurodegeneration by Differentially Modulating Neuronal Endoplasmic Reticulum Stress Molecules. J Neurosci 2016;36(21):5891-903.Abstract

UNLABELLED: Axon injury is an early event in neurodegenerative diseases that often leads to retrograde neuronal cell death and progressive permanent loss of vital neuronal functions. The connection of these two obviously sequential degenerative events, however, is elusive. Deciphering the upstream signals that trigger the neurodegeneration cascades in both neuronal soma and axon would be a key step toward developing the effective neuroprotectants that are greatly needed in the clinic. We showed previously that optic nerve injury-induced neuronal endoplasmic reticulum (ER) stress plays an important role in retinal ganglion cell (RGC) death. Using two in vivo mouse models of optic neuropathies (traumatic optic nerve injury and glaucoma) and adeno-associated virus-mediated RGC-specific gene targeting, we now show that differential manipulation of unfolded protein response pathways in opposite directions-inhibition of eukaryotic translation initiation factor 2α-C/EBP homologous protein and activation of X-box binding protein 1-promotes both RGC axons and somata survival and preserves visual function. Our results indicate that axon injury-induced neuronal ER stress plays an important role in both axon degeneration and neuron soma death. Neuronal ER stress is therefore a promising therapeutic target for glaucoma and potentially other types of neurodegeneration. SIGNIFICANCE STATEMENT: Neuron soma and axon degeneration have distinct molecular mechanisms although they are clearly connected after axon injury. We previously demonstrated that axon injury induces neuronal endoplasmic reticulum (ER) stress and that manipulation of ER stress molecules synergistically promotes neuron cell body survival. Here we investigated the possibility that ER stress also plays a role in axon degeneration and whether ER stress modulation preserves neuronal function in neurodegenerative diseases. Our results suggest that neuronal ER stress is a general mechanism of degeneration for both neuronal cell body and axon, and that therapeutic targeting of ER stress produces significant functional recovery.

Salvador-Culla B, Kolovou PE. Keratoprosthesis: A Review of Recent Advances in the Field. J Funct Biomater 2016;7(2)Abstract

Since its discovery in the years of the French Revolution, the field of keratoprostheses has evolved significantly. However, the path towards its present state has not always been an easy one. Initially discarded for its devastating complications, the introduction of new materials and the discovery of antibiotics in the last century gave new life to the field. Since then, the use of keratoprostheses for severe ocular surface disorders and corneal opacities has increased significantly, to the point that it has become a standard procedure for corneal specialists worldwide. Although the rate of complications has significantly been reduced, these can impede the long-term success, since some of them can be visually devastating. In an attempt to overcome these complications, researchers in the field have been recently working on improving the design of the currently available devices, by introducing the use of new materials that are more biocompatible with the eye. Here we present an update on the most recent research in the field.

Noseda R, Bernstein CA, Nir R-R, Lee AJ, Fulton AB, Bertisch SM, Hovaguimian A, Cestari DM, Saavedra-Walker R, Borsook D, Doran BL, Buettner C, Burstein R. Migraine photophobia originating in cone-driven retinal pathways. Brain 2016;139(Pt 7):1971-86.Abstract

Migraine headache is uniquely exacerbated by light. Using psychophysical assessments in patients with normal eyesight we found that green light exacerbates migraine headache significantly less than white, blue, amber or red lights. To delineate mechanisms, we used electroretinography and visual evoked potential recording in patients, and multi-unit recording of dura- and light-sensitive thalamic neurons in rats to show that green activates cone-driven retinal pathways to a lesser extent than white, blue and red; that thalamic neurons are most responsive to blue and least responsive to green; and that cortical responses to green are significantly smaller than those generated by blue, amber and red lights. These findings suggest that patients' experience with colour and migraine photophobia could originate in cone-driven retinal pathways, fine-tuned in relay thalamic neurons outside the main visual pathway, and preserved by the cortex. Additionally, the findings provide substrate for the soothing effects of green light.

Clermont A, Murugesan N, Zhou Q, Kita T, Robson PA, Rushbrooke LJ, Evans MD, Aiello LP, Feener EP. Plasma Kallikrein Mediates Vascular Endothelial Growth Factor-Induced Retinal Dysfunction and Thickening. Invest Ophthalmol Vis Sci 2016;57(6):2390-9.Abstract

PURPOSE: Plasma kallikrein is a serine protease and circulating component of inflammation, which exerts clinically significant effects on vasogenic edema. This study examines the role of plasma kallikrein in VEGF-induced retinal edema. METHODS: Intravitreal injections of VEGF and saline vehicle were performed in plasma prekallikrein-deficient (KLKB1-/-) and wild-type (WT) mice, and in both rats and mice receiving a selective plasma kallikrein inhibitor, VA999272. Retinal vascular permeability (RVP) and retinal thickness were measured by Evans blue permeation and optical coherence tomography, respectively. The retinal kallikrein kinin system was examined by Western blotting and immunohistochemistry. Retinal neovascularization was investigated in KLKB1-/- and WT mice subjected to oxygen-induced retinopathy. RESULTS: Vascular endothelial growth factor-induced RVP and retinal thickening were reduced in KLKB1-/- mice by 68% and 47%, respectively, compared to VEGF responses in WT mice. Plasma kallikrein also contributes to TNFα-induced retinal thickening, which was reduced by 52% in KLKB1-/- mice. Systemic administration of VA999272 reduced VEGF-induced retinal thickening by 57% (P < 0.001) in mice and 53% (P < 0.001) in rats, compared to vehicle-treated controls. Intravitreal injection of VEGF in WT mice increased plasma prekallikrein in the retina, which was diffusely distributed throughout the inner and outer retinal layers. Avascular and neovascular areas induced by oxygen-induced retinopathy were similar in WT and KLKB1-/- mice. CONCLUSIONS: Vascular endothelial growth factor increases extravasation of plasma kallikrein into the retina, and plasma kallikrein is required for the full effects of VEGF on RVP and retinal thickening in rodents. Systemic plasma kallikrein inhibition may provide a therapeutic opportunity to treat VEGF-induced retina edema.

Primo V, Graham M, Bigger-Allen AA, Chick JM, Ospina C, Quiroz YT, Manent J, Gygi SP, Lopera F, D'Amore PA, Arboleda-Velasquez JF. Blood biomarkers in a mouse model of CADASIL. Brain Res 2016;1644:118-26.Abstract

Mutations in NOTCH 3 are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a neurological disorder characterized by stroke, and vascular cognitive impairment and dementia. Loss of vascular smooth muscle cells (VSMC) and accumulation of granular osmiophilic material (GOM) deposits are hallmarks of CADASIL. There are no therapies for CADASIL and experimental endpoints to examine the preclinical efficacy of potential drugs are lacking. This study aims to use a mouse carrying the C455R mutation in Notch 3 to identify biomarkers associated with CADASIL. Mass spectrometry and antibody arrays were used to explore the aorta and blood proteomes of CADASIL mice, ELISA assays were utilized for biomarker validation, a ligand-dependent assay was applied to examine the relationship between Notch signaling and biomarker expression, and retinal histology was performed for quantification of VSMC loss in arteries. Two-hundred day-old mice with the C455R CADASIL mutation in Notch 3 mice display robust VSMC loss in retinal arteries and had increased plasma levels of collagen18α1/endostatin (col18α1) and high-temperature requirement A serine peptidase 1 (HTRA1) and reduced levels of Notch 3 extracellular domain (N3ECD), compared to control wild type mice. Measurements of plasma endostatin, HTRA1 and N3ECD, along with VSMC quantification in retinal arteries, may serve as surrogate endpoints for assessing efficacy in preclinical therapeutic studies of CADASIL using mice.

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