Iron-Sulfur Clusters and Iron Responsive Element Binding Proteins Mediate Iron Accumulation in Corneal Endothelial Cells in Fuchs Dystrophy.

Purpose: Evidence suggests that corneal endothelial cell (CEC) death in Fuchs endothelial corneal dystrophy (FECD) is due to ferroptosis, an iron-mediated cell death. Iron-sulfur cluster (ISC)-containing aconitases and the iron responsive element binding proteins IREBP1 and IREBP2 are known mediators of iron homeostasis. This study investigates mechanisms underlying iron dysregulation in CECs and proposes a role for ISCs and IREBPs in the context of FECD pathogenesis.

TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss.

Retrospective Optimization of the Hawkeye Orbital Fracture Prioritization and Evaluation Algorithms for Triaging Ophthalmic Care.

Objectives: Many orbital fracture patients are transferred to tertiary care centers for immediate ophthalmology consultation, though few require urgent ophthalmic evaluation or intervention. This overutilizes limited resources and overburdens patients and the health care system with travel and emergency department (ED) expenses. A simple, easy-to-use, clinical decision-making tool is needed to aid local EDs and triage services in effectively identifying orbital fracture patients who need urgent ophthalmic evaluation.

Traumatic cataract induced by improper use of a percussion massage gun.

Purpose: We describe a case of traumatic cataract after improper use of a percussion massage gun over the periorbital area.

Observations: A 38-year-old female with a history of high myopia and fibromyalgia presented to the emergency department with painless monocular vision loss OS, noticed two days prior and described as a "white film" over her eye. BCVA was 20/20 OD and 20/600 OS.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells.

PRAME induces genomic instability in uveal melanoma.

PRAME is a CUL2 ubiquitin ligase subunit that is normally expressed in the testis but becomes aberrantly overexpressed in many cancer types in association with aneuploidy and metastasis. Here, we show that PRAME is expressed predominantly in spermatogonia around the time of meiotic crossing-over in coordination with genes mediating DNA double strand break repair. Expression of PRAME in somatic cells upregulates pathways involved in meiosis, chromosome segregation and DNA repair, and it leads to increased DNA double strand breaks, telomere dysfunction and aneuploidy in neoplastic and non-neoplastic cells.

RB1 loss triggers dependence on ESRRG in retinoblastoma.

Retinoblastoma (Rb) is a deadly childhood eye cancer that is classically initiated by inactivation of the RB1 tumor suppressor. Clinical management continues to rely on nonspecific chemotherapeutic agents that are associated with treatment resistance and toxicity. Here, we analyzed 103 whole exomes, 20 whole transcriptomes, 5 single-cell transcriptomes, and 4 whole genomes from primary Rb tumors to identify previously unknown Rb dependencies.

Successful response to first-line treatment with osimertinib for choroidal metastasis from EGFR-mutated non-small-cell lung cancer.

Purpose: Describe the use of osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, as the first-line treatment in a patient with choroidal and central nervous system metastases from EGFR-mutated non-small cell lung cancer.

Observations: A 68-year-old man presented with an amelanotic choroidal lesion in the left eye concerning for choroidal metastasis. Systemic evaluation identified widely metastatic adenocarcinoma of the lung with EGFR exon 19 mutation.

Intrafamilial Variability of Ocular Manifestations of von Hippel-Lindau Disease.

In this retrospective cohort study, we describe intrafamilial phenotypic variability of retinal hemangioblastoma (RH) in families with von Hippel-Lindau (VHL) disease. Patients with molecularly confirmed VHL evaluated at our institution were identified, and records were reviewed. For individuals with sufficient follow-up and imaging (n=27), the number and location of RHs at the initial and most recent follow-up visits were recorded along with treatment method and systemic manifestations.

Impact of reduced elective ophthalmic surgical volume on U.S. hospitals during the early coronavirus disease 2019 pandemic.

Purpose: To estimate the financial impact of coronavirus disease 2019 (COVID-19)-related shutdowns on ophthalmic surgery performed at hospital outpatient departments (HOPDs) in the United States.

Setting: Nationally representative sample of U.S.

Whole exome profiling and mutational analysis of Ocular Surface Squamous Neoplasia.

Purpose: To determine genetic mutational profiles in patients with Ocular Surface Squamous Neoplasia (OSSN) using whole exome sequencing.

Methods: Prospective, case-series study. Patient recruitment was conducted in a single tertiary referral center from April to September 2017.

BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers.

The BAP1 tumor suppressor is mutated in many human cancers such as uveal melanoma, leading to poor patient outcome. It remains unclear how BAP1 functions in normal biology or how its loss promotes cancer progression. Here, we show that Bap1 is critical for commitment to ectoderm, mesoderm, and neural crest lineages during development.

BAP1 Loss Is Associated with DNA Methylomic Repatterning in Highly Aggressive Class 2 Uveal Melanomas.

Purpose: The strong association between mutations and metastasizing Class 2 uveal melanoma (UM) suggests that epigenetic alterations may play a significant role in tumor progression. Thus, we characterized the impact of loss on the DNA methylome in UM. Global DNA methylation was analyzed in 47 Class 1 and 45 Class 2 primary UMs and in UM cells engineered to inducibly deplete BAP1.

Genomic evolution of uveal melanoma arising in ocular melanocytosis.

Ocular melanocytosis is the most important predisposing condition for the eye cancer uveal melanoma (UM). Here, we present a patient who developed UM arising within ocular melanocytosis who was treated with enucleation (eye removal), which provided an invaluable opportunity to interrogate both the UM and adjacent uveal tissue containing the melanocytosis using whole-exome and deep-targeted sequencing. This analysis revealed a clonal mutation in the melanocytosis, confirming that this is indeed a neoplastic condition and explaining why it predisposes to UM.

Flavoprotein Fluorescence Correlation with Visual Acuity Response in Patients Receiving Anti-VEGF Injection for Diabetic Macular Edema.

Anti-VEGF treatment of diabetic macular edema (DME) complicating diabetic retinopathy (DR) has greatly improved structural and visual outcomes for patients with diabetes mellitus. However, up to 50% of patients are either nonresponsive or refractory to anti-VEGF treatment (no improvement in BCVA or central macular thickness (CMT)). It is believed that factors such as mitochondrial structural and functional damage, due to oxidative stress, are partially responsible for this lack of improvement.

Noninvasive Detection of Mitochondrial Dysfunction in Ocular Hypertension and Primary Open-angle Glaucoma.

Purpose: To assess mitochondrial dysfunction in vivo in ocular hypertension (OHT) and primary open-angle glaucoma (POAG) using retinal metabolic analysis.

Patients And Methods: This was an observational, cross-sectional study performed from November 2015 to October 2016 at the New York Eye and Ear Infirmary of Mount Sinai. Thirty-eight eyes with varying stages of POAG, 16 eyes with OHT, and 32 control eyes were imaged on a custom fundus camera modified to measure full retinal thickness fluorescence at a wavelength optimized to detect flavoprotein fluorescence (FPF).

Expression and regulation of alarmin cytokine IL-1α in human retinal pigment epithelial cells.

Human retinal pigment epithelial (hRPE) cells play important immune-regulatory roles in a variety of retinal pathologic processes, including the production of inflammatory cytokines that are essential mediators of the innate immune response within the ocular microenvironment. The pro-inflammatory "alarmin" cytokine IL-1α has been implicated in both infectious and non-infectious retinal diseases, but its regulation in the retina is poorly understood. The purpose of this study was to elucidate the expression and regulation of IL-1α within hRPE cells.

Distinct CD40L receptors mediate inflammasome activation and secretion of IL-1β and MCP-1 in cultured human retinal pigment epithelial cells.

CD40L signaling occurs in several diseases with inflammatory components, including ocular and retinal diseases. However, it has never been evaluated as a pathogenic mechanism in age-related macular degeneration (AMD) or as an inducer of inflammasome formation in any cell type. mRNA and protein levels of CD40, IL-1β, NALP1, NALP3, caspase-1, and caspase-5 were determined by RT-PCR, qPCR, and Western blot.

RNA-Sequencing Gene Expression Profiling of Orbital Adipose-Derived Stem Cell Population Implicate HOX Genes and WNT Signaling Dysregulation in the Pathogenesis of Thyroid-Associated Orbitopathy.

Purpose: The purpose of this study was to characterize the intrinsic cellular properties of orbital adipose-derived stem cells (OASC) from patients with thyroid-associated orbitopathy (TAO) and healthy controls.

Methods: Orbital adipose tissue was collected from a total of nine patients: four controls and five patients with TAO. Isolated OASC were characterized with mesenchymal stem cell-specific markers.

Molecular Characteristics of Conjunctival Melanoma Using Whole-Exome Sequencing.

Importance: Conjunctival melanoma (CM) is a highly aggressive ocular cancer for which treatment options are limited; the molecular pathogenesis is poorly understood.

Objective: To identify the molecular characteristics of CM using next-generation whole-exome sequencing (WES).

Design, Setting, And Participants: Whole-exome sequencing was performed on tumor DNA extracted from the archived specimens of 5 patients with CM who had been treated with surgical excision between 2006 and 2011.

Gain of function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies.

Additional Sex Combs-Like 1 () is mutated at a high frequency in all forms of myeloid malignancies associated with poor prognosis. We generated a promoter-driven transgenic mouse model, Tg, to express a truncated FLAG-ASXL1 protein in the hematopoietic system. The Tg mice had an enlarged hematopoietic stem cell (HSC) pool, shortened survival, and predisposition to a spectrum of myeloid malignancies, thereby recapitulating the characteristics of myeloid malignancy patients with mutations.

Whole Exome Sequencing of Lacrimal Gland Adenoid Cystic Carcinoma.

Purpose: To identify genomic mutations in lacrimal gland adenoid cystic carcinoma (LGACC) samples from patients.

Methods: Genomic DNA was extracted from LGACC specimens. Whole exome sequencing (exome-seq) was conducted to screen for mutations.

PRAME as a Potential Target for Immunotherapy in Metastatic Uveal Melanoma.

Importance: Uveal melanoma (UM) is an intraocular primary malignant neoplasm that often gives rise to metastatic disease for which there are no effective therapies. A substantial proportion of UMs express the cancer-testis antigen PRAME (preferentially expressed antigen in melanoma), which can potentially be targeted by adoptive T-cell therapy.

Objective: To determine whether there may be a rationale for PRAME-directed T-cell therapy for metastatic UM.