Cynthia X. Qian

RasGAP Promotes Autophagy and Thereby Suppresses Platelet-Derived Growth Factor Receptor-Mediated Signaling Events, Cellular Responses, and Pathology

ABSTRACT Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) make profound contributions to both physiology and pathology. While it is widely believed that direct (PDGF-mediated) activation is the primary mode of activating PDGFRs, the discovery that they can also be activated indirectly begs the question of the relevance of the indirect mode of activating PDGFRs. In the context of a blinding eye disease, indirect activation of PDGFRα results in persistent signaling, which suppresses the level of p53 and thereby promotes viability of cells that drive pathogenesis. Under the same conditions, PDGFRβ fails to undergo indirect activation. In this paper, we report that RasGAP (GTPase-activating protein of Ras) prevented indirect activation of PDGFRβ. RasGAP, which associates with PDGFRβ but not PDGFRα, reduced the level of mitochondrion-derived reactive oxygen species, which are required for enduring activation of PDGFRs. Furthermore, preventing PDGFRβ from associating with RasGAP allowed it to signal enduringly and drive pathogenesis of a blinding eye disease. These results indicate a previously unappreciated role of RasGAP in antagonizing indirect activation of PDGFRβ, define the underlying mechanism, and raise the possibility that PDGFRβ-mediated diseases involve indirect activation of PDGFRβ.

The Impact of Cataract Surgery on AMD Development and Progression

Abstract Age-related macular degeneration (AMD) and cataract are two leading causes of visual impairment worldwide which often occur concurrently in the same patient. With more than 1.6 million cataract operations performed per year in the United States, many of which occur in the nearly 1.75 million individuals diagnosed with AMD, there is ample incentive to further explore the interaction between these two conditions. Notably, the role of cataract surgery on AMD development and progression is of particular interest. This review summarizes the major findings from literature focusing on the effect of cataract surgery on AMD.

Prevention of Proliferative Vitreoretinopathy by Suppression of Phosphatidylinositol 5-Phosphate 4-Kinases.

Purpose Previous studies have shown that vitreous stimulates degradation of the tumor suppressor protein p53 and that knockdown of phosphatidylinositol 5-phosphate 4-kinases (PI5P4Kα and -β) abrogates proliferation of p53-deficient cells. The purpose of this study was to determine whether vitreous stimulated expression of PI5P4Kα and -β and whether suppression of PI5P4Kα and -β would inhibit vitreous-induced cellular responses and experimental proliferative vitreoretinopathy (PVR). Methods PI5P4Kα and -β encoded by PIP4K2A and 2B, respectively, in human ARPE-19 cells were knocked down by stably expressing short hairpin (sh)RNA directed at human PIP4K2A and -2B. In addition, we rescued expression of PI5P4Kα and -β by re-expressing mouse PIP4K2A and -2B in the PI5P4Kα and -β knocked-down ARPE-19 cells. Expression of PI5P4Kα and -β was determined by Western blot and immunofluorescence. The following cellular responses were monitored: cell proliferation, survival, migration, and contraction. Moreover, the cell potential of inducing PVR was examined in a rabbit model of PVR effected by intravitreal cell injection. Results We found that vitreous enhanced expression of PI5P4Kα and -β in RPE cells and that knocking down PI5P4Kα and -β abrogated vitreous-stimulated cell proliferation, survival, migration, and contraction. Re-expression of mouse PIP4Kα and -β in the human PI5P4Kα and -β knocked-down cells recovered the loss of vitreous-induced cell contraction. Importantly, suppression of PI5P4Kα and -β abrogated the pathogenesis of PVR induced by intravitreal cell injection in rabbits. Moreover, we revealed that expression of PI5P4Kα and -β was abundant in epiretinal membranes from PVR grade C patients. Conclusions The findings from this study indicate that PI5P4Kα and -β could be novel therapeutic targets for the treatment of PVR.

Fibrovascular ingrowth after 25-gauge transconjunctival vitrectomy in proliferative diabetic retinopathy.

The authors describe two patients with proliferative diabetic retinopathy bilaterally who were treated with transconjunctival 25-gauge pars plana vitrectomy (PPV) for dense vitreous hemorrhage (VH). After 4 and 10 months, respectively, both developed recurrent VH. They were initially managed with in-office gas-fluid exchange and anti-VEGF intravitreal injection. Soon after gas bubble resorption, the VH recurred. Color external photos revealed engorged episcleral vessels superotemporally, and ultrasound biomicroscopy confirmed the presence of fibrovascular ingrowth (FVI) at the sclerotomy site in both patients. They were successfully treated with a slightly modified 25-gauge PPV technique. Although FVI is well-recognized following conventional 20-gauge vitrectomy, this report is the first to detail FVI arising after small-gauge transconjunctival vitrectomy.

Tractional Maculopathies in Age-related Macular Degeneration

loss of visual function that occurs with aging, and is the leading cause of visual loss in the Western Hemisphere in the elderly. Although common, the pathways mediating its onset and progression are complex and multifactorial. While many studies have looked at the pathogenesis and physiological changes that occur at the outer retina during AMD, research on inner retinal changes is less common. More specifically, when AMD is compounded by degenerative tractional changes at the vitreomacular interface and inner retina, the problem becomes greater than the sum of its parts. In this article, we address the different etiologies of vitreomacular interface pathologies found in association with both dry and exudative AMD, their pathogenesis, and how their pharmacological and surgical treatment responses differ from the presentation and treatment of either condition alone.

Confluent Endpoint Subthreshold Argon Laser for Serous Macular Detachment in Tilted Disc Syndrome Refractory to Anti-VEGF

A 70-year-old woman presented with 20/200 visual acuity in the right eye. Multimodal imaging revealed tilted disc syndrome (TDS) with macular serous detachment (MSD) and pigmentary changes at the temporal margin of the optic disc. Subretinal fluid persisted after three monthly intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) injections and threshold focal laser photocoagulation. Subsequently, confluent subthreshold argon laser was applied over the entire area of retinal pigment epithelium (RPE) abnormalities, resulting in the resolution of subretinal fluid without recurrence through 3 years of follow-up. Subthreshold argon laser treatment may serve as a therapeutic option for MSD in TDS. Targeting leakage sites and stimulating RPE cells might help absorb subretinal fluid. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:760-763.].

Surgical Therapy: Retisert Implant

The fluocinolone acetonide (Retisert™) 0.59-mg implant is a device approved by the Food and Drug Administration for the management of non-infectious posterior uveitis. Its intraocular sustained-release design allows it to circumvent the side effects of traditional systemic corticosteroid treatment and avoid the drawbacks of frequent and repeated local drug administration. This chapter will review the current literature regarding efficacy and safety of the implant.

Occult Perforating Globe Injury Caused by Intraocular Foreign Body.

Intraocular foreign bodies (IOFBs) may be associated with occult exit wounds. The authors present a case of a man who sustained a zipper-tooth IOFB through the cornea from a car tire explosion. CT showed an IOFB within the vitreous cavity, but the IOFB was not identified during vitrectomy. Extension of the peritomy revealed an exit wound with the foreign body lodged in the extraocular space. This case demonstrates that IOFBs can rest within the vitreous cavity after creating an exit wound, but may escape detection by being driven back out of the globe during vitrectomy due to the pressurized eye. Coexistent ocular surface and intraocular pathology often limit intraoperative visualization, but a perforating through-and-through injury should be suspected if the IOFB cannot be identified during vitrectomy. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1162-1163.].