Treatment of Experimental Choroidal Neovascularization via RUNX1 Inhibition.

Choroidal neovascularization (CNV) is a prevalent cause of vision loss in patients with age-related macular degeneration. Runt-related transcription factor 1 (RUNX1) has been identified as an important mediator of aberrant retinal angiogenesis in proliferative diabetic retinopathy and its modulation has proven to be effective in curbing pathologic angiogenesis in experimental oxygen-induced retinopathy. However, its role in CNV remains to be elucidated. This study demonstrates RUNX1 expression in critical cell types involved in a laser-induced model of CNV in mice. Furthermore, the preclinical efficacy of Ro5-3335, a small molecule inhibitor of RUNX1, in experimental CNV is reported. RUNX1 inhibitor Ro5-3335, aflibercept-an FDA-approved vascular endothelial growth factor (VEGF) inhibitor, or a combination of both, were administered by intravitreal injection immediately after laser injury. The CNV area of choroidal flatmounts was evaluated by immunostaining with isolectin B4, and vascular permeability was analyzed by fluorescein angiography. A single intravitreal injection of Ro5-3335 significantly decreased the CNV area 7 days after laser injury, and when combined with aflibercept, reduced vascular leakage more effectively than aflibercept alone. These data suggest that RUNX1 inhibition alone or in combination with anti-VEGF drugs may be a new therapy upon further clinical validation for patients with neovascular age-related macular degeneration.

Targeting Runt-Related Transcription Factor 1 Prevents Pulmonary Fibrosis and Reduces Expression of Severe Acute Respiratory Syndrome Coronavirus 2 Host Mediators.

Pulmonary fibrosis (PF) can arise from unknown causes, as in idiopathic PF, or as a consequence of infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Current treatments for PF slow, but do not stop, disease progression. We report that treatment with a runt-related transcription factor 1 (RUNX1) inhibitor (Ro24-7429), previously found to be safe, although ineffective, as a Tat inhibitor in patients with HIV, robustly ameliorates lung fibrosis and inflammation in the bleomycin-induced PF mouse model. RUNX1 inhibition blunted fundamental mechanisms downstream pathologic mediators of fibrosis and inflammation, including transforming growth factor-ß1 and tumor necrosis factor-α, in cultured lung epithelial cells, fibroblasts, and vascular endothelial cells, indicating pleiotropic effects. RUNX1 inhibition also reduced the expression of angiotensin-converting enzyme 2 and FES Upstream Region (FURIN), host proteins critical for SARS-CoV-2 infection, in mice and in vitro. A subset of human lungs with SARS-CoV-2 infection overexpress RUNX1. These data suggest that RUNX1 inhibition via repurposing of Ro24-7429 may be beneficial for PF and to battle SARS-CoV-2, by reducing expression of viral mediators and by preventing respiratory complications.

TNF-α signaling regulates RUNX1 function in endothelial cells.

Runt-related transcription factor 1 (RUNX1) acts as a mediator of aberrant retinal angiogenesis and has been implicated in the progression of proliferative diabetic retinopathy (PDR). Patients with PDR, retinopathy of prematurity (ROP), and wet age-related macular degeneration (wet AMD) have been found to have elevated levels of Tumor Necrosis Factor-alpha (TNF-α) in the eye. In fibrovascular membranes (FVMs) taken from patients with PDR RUNX1 expression was increased in the vasculature, while in human retinal microvascular endothelial cells (HRMECs), TNF-α stimulation causes increased RUNX1 expression, which can be modulated by RUNX1 inhibitors. Using TNF-α pathway inhibitors, we determined that in HRMECs, TNF-α-induced RUNX1 expression occurs via JNK activation, while NF-κB and p38/MAPK inhibition did not affect RUNX1 expression. JNK inhibitors were also effective at stopping high D-glucose-stimulated RUNX1 expression. We further linked JNK to RUNX1 through Activator Protein 1 (AP-1) and investigated the JNK-AP-1-RUNX1 regulatory feedback loop, which can be modulated by VEGF. Additionally, stimulation with TNF-α and D-glucose had an additive effect on RUNX1 expression, which was downregulated by VEGF modulation. These data suggest that the downregulation of RUNX1 in conjunction with anti-VEGF agents may be important in future treatments for the management of diseases of pathologic ocular angiogenesis.

Incidence and Reimbursement Trends for Facial Fracture Repair in the Elderly: A Medicare Analysis.

OBJECTIVES: The aim was to describe incidence and reimbursement trends of surgical repair of facial fractures among the Medicare population. METHODS: The annual procedure data from the Centers for Medicare and Medicaid Service National Part B Data File from 2000 to 2019 were queried. RESULTS: The total number of surgically corrected facial fractures increased from 10,148 in 2000 to 19,631 in 2019 in a linear pattern (r = 0.924). Specifically, nasal bone/septum fracture repairs increased the most by 200.6% (n = 4682 to n = 14,075), whereas operations for TMJ dislocations, malar/zygoma fractures, and alveolar ridge/mandibular fractures decreased by 27.9%, 12.3%, and 3.2%, respectively, between 2000 and 2019. Correspondingly, the total Medicare reimbursement rose from $2,574,317 in 2000 to $4,129,448 in 2019 (r = 0.895). However, the mean reimbursement for all procedures decreased from $376.63 to $210.35 (44.1% fall) over the same time after adjusting for inflation, with this trend holding for individual fracture types as well. CONCLUSIONS: Given the population's increasing age, there has been a significant increase in the number of surgical repairs of facial fractures in Medicare patients between 2000 and 2019. However, this is largely driven by an increase in nasal bone/septum closed reductions, with stagnant and, in some cases, declining incidence among other fracture repairs. The reason is unclear and may be related to an increase in nonoperative management or poor outcomes. Nevertheless, like other subfields within otolaryngology and medicine at large, payments have lagged far behind, which may play some role. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:659-665, 2024.

Effective low-cost pediatric vision screening by naive nonophthalmic examiners using the 'Arclight' device.

PURPOSE: To explore whether a low-cost ophthalmoscope (Arclight) can be used by naive nonophthalmic examiners to effectively screen for pediatric eye disease. METHODS: Fifty-four children (108 eyes) were examined by five medical students using an Arclight. Gold standard examination was performed by an ophthalmologist using a slit lamp and indirect ophthalmoscope. Examinations performed included ophthalmoscopy of the optic disc, estimation of the cup-to-disc ratio (CDR), corneal light reflex test (CRT), Bruckner's reflex test (BRT), and evaluation of refractive error. We determined the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the nonophthalmologist's Arclight exam compared to the gold standard findings of comprehensive evaluation by pediatric ophthalmologists. RESULTS: Using the Arclight, the optic nerve exam was successfully completed in 65% of patients. CDRs above and below 0.5 could be determined with 66.7% sensitivity and 84.4% specificity. Arclight CRT measurements were significant (P < .00001) predictors of strabismus, with 80% sensitivity, 95.1%, specificity, 80% PPV, and 95.1% NPV. BRT was not a significant predictor of amblyopia, with a 34.6% sensitivity, 85.7% specificity, 69.2% PPV, and 58.5% NPV. Refractive error was estimated with a success rate of 81% for emmetropia, 38% for myopia, and 21% for hyperopia. The Arclight ease-of-use was rated on average as 4.4 (SD = 0.9) on a scale of 1 to 5, with 1 being the hardest and 5 being the easiest. CONCLUSIONS: Our study shows the Arclight as an affordable and effective alternative to the traditional ophthalmoscope for assessing eye disease in children. This device can improve eye health services in under-resourced regions.

Topical Nanoemulsion of a Runt-related Transcription Factor 1 Inhibitor for the Treatment of Pathologic Ocular Angiogenesis.

Purpose: To test the efficacy of runt-related transcription factor 1 (RUNX1) inhibition with topical nanoemulsion containing Ro5-3335 (eNano-Ro5) in experimental ocular neovascularization. Design: Preclinical experimental study. Participants: In vitro primary culture human retinal endothelial cell (HREC) culture. C57BL/6J 6- to 10-week-old male and female mice. Methods: We evaluated the effect of eNano-Ro5 in cell proliferation, cell toxicity, and migration of HRECs. We used an alkali burn model of corneal neovascularization and a laser-induced model of choroidal neovascularization to test in vivo efficacy of eNano-Ro5 in pathologic angiogenesis in mice. We used mass spectrometry to measure penetration of Ro5-3335 released from the nanoemulsion in ocular tissues. Main Outcome Measures: Neovascular area. Results: RUNX1 inhibition reduced cell proliferation and migration in vitro. Mass spectrometry analysis revealed detectable levels of the active RUNX1 small-molecule inhibitor Ro5-3335 in the anterior and posterior segment of the mice eyes. Topical treatment with eNano-Ro5 significantly reduced corneal neovascularization and improved corneal wound healing after alkali burn. Choroidal neovascularization lesion size and leakage were significantly reduced after treatment with topical eNano-Ro5. Conclusions: Topical treatment with eNano-Ro5 is an effective and viable platform to deliver a small-molecule RUNX1 inhibitor. This route of administration offers advantages that could improve the management and outcomes of these sight-threatening conditions. Topical noninvasive delivery of RUNX1 inhibitor could be beneficial for many patients with pathologic ocular neovascularization.