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Primary open angle glaucoma (POAG) is defined as a "genetically complex trait", where modifying factors act on a genetic predisposing background. For the majority of glaucomatous conditions, DNA variants are not sufficient to explain pathogenesis. Some genes are clearly underlying the more "Mendelian" forms, while a growing number of related polymorphisms in other genes have been identified in recent years. Environmental, dietary, or biological factors are known to influence the development of the condition, but interactions between these factors and the genetic background are poorly understood. Several studies conducted in recent years have led to evidence that epigenetics, that is, changes in the pattern of gene expression without any changes in the DNA sequence, appear to be the missing link. Different epigenetic mechanisms have been proven to lead to glaucomatous changes in the eye, principally DNA methylation, post-translational histone modification, and RNA-associated gene regulation by non-coding RNAs. The aim of this work is to define the principal epigenetic actors in glaucoma pathogenesis. The identification of such mechanisms could potentially lead to new perspectives on therapeutic strategies.

Background and Objectives . Retinitis pigmentosa (RP) is the most common inherited rod-cone dystrophy (RCD), resulting in nyctalopia, progressive visual field, and visual acuity decay in the late stages. The autosomal dominant form (ADRP) accounts for about 20% of RPs. Among the over 30 genes found to date related to ADRP, RP1 pathogenic variants have been identified in 5-10% of cases. In a cohort of RCD patients from the Palermo province on the island of Sicily, we identified a prevalent nonsense variant in RP1 , which was associated with ADRP. The objective of our study was to analyse the clinical and molecular data of this patient cohort and to evaluate the potential presence of a founder effect. Materials and Methods . From 2005 to January 2023, 84 probands originating from Western Sicily (Italy) with a diagnosis of RCD or RP and their relatives underwent deep phenotyping, which was performed in various Italian clinical institutions. Molecular characterisation of patients and familial segregation of pathogenic variants were carried out in different laboratories using Sanger and/or next-generation sequencing (NGS). Results. Among 84 probands with RCD/RP, we found 28 heterozygotes for the RP1 variant c.2219C>G, p.Ser740* ((NM_006269.2)*, which was therefore significantly prevalent in this patient cohort. After a careful interview process, we ascertained that some of these patients shared the same pedigree. Therefore, we were ultimately able to define 20 independent family groups with no traceable consanguinity. Lastly, analysis of clinical data showed, in our patients, that the p.Ser740* nonsense variant was often associated with a late-onset and relatively mild phenotype. Conclusions . The high prevalence of the p.Ser740* variant in ADRP patients from Western Sicily suggests the presence of a founder effect, which has useful implications for the molecular diagnosis of RCD in patients coming from this Italian region. This variant can be primarily searched for in RP-affected subjects displaying compatible modes of transmission and phenotypes, with an advantage in terms of the required costs and time for analysis. Moreover, given its high prevalence, the RP1 p.Ser740* variant could represent a potential candidate for the development of therapeutic strategies based on gene editing or translational read-through therapy for suppression of nonsense variants.

Histopathologically, uveal melanomas (UMs) can be classified as spindle cell, mixed cell and epithelioid cell type, with the latter having a more severe prognosis. The aim of our study was to assess the correlation between the apparent diffusion coefficient (ADC) and the histologic type of UMs in order to verify the role of diffusion-weighted magnetic resonance imaging (DWI) as a noninvasive prognostic marker. A total of 26 patients with UMs who had undergone MRI and subsequent primary enucleation were retrospectively selected. The ADC of the tumor was compared with the histologic type. The data were compared using both one-way analysis of variance (ANOVA) (assessing the three histologic types separately) and the independent t -test (dichotomizing histologic subtypes as epithelioid versus non-epithelioid). Histologic type was present as follows: the epithelioid cell was n = 4, and the spindle cell was n = 11, the mixed cell type was n = 11. The mean ADC was 1.06 ± 0.24 × 10 -3 mm 2 /s in the epithelioid cells, 0.98 ± 0.19 × 10 -3 mm 2 /s in the spindle cells and 0.96 ± 0.26 × 10 -3 mm 2 /s in the mixed cell type. No significant difference in the mean ADC value of the histopathologic subtypes was found, either when assessing the three histologic types separately ( p = 0.76) or after dichotomizing the histologic subtypes as epithelioid and non-epithelioid ( p = 0.82). DWI-ADC is not accurate enough to distinguish histologic types of UMs.

The corneal epithelium, representing the outermost layer of the cornea, acts as a barrier to protect the eye against external insults such as ultraviolet B (UV-B) radiations. The inflammatory response induced by these adverse events can alter the corneal structure, leading to visual impairment. In a previous study, we demonstrated the positive effects of NAP, the active fragment of activity-dependent protein (ADNP), against oxidative stress induced by UV-B radiations. Here, we investigated its role to counteract the inflammatory event triggered by this insult contributing to the disruption of the corneal epithelial barrier. The results indicated that NAP treatment prevents UV-B-induced inflammatory processes by affecting IL-1β cytokine expression and NF-κB activation, as well as maintaining corneal epithelial barrier integrity. These findings may be useful for the future development of an NAP-based therapy for corneal disease.

Necrosis in uveal melanomas can be spontaneous or induced by radiotherapy. The purpose of our study was to compare the histopathologic and MRI findings of radiation-induced necrosis of a group of proton beam-irradiated uveal melanomas with those of spontaneous necrosis of a control group of patients undergoing primary enucleation. 11 uveal melanomas who had undergone proton beam radiotherapy, MRI and secondary enucleation, and a control group of 15 untreated uveal melanomas who had undergone MRI and primary enucleation were retrospectively identified. Within the irradiated and nonirradiated group, 7 and 6 eyes with histological evidence of necrosis respectively, were furtherly selected for the final analysis; the appearance of necrosis was assessed at histopathologic examination and MRI. Irradiated melanomas showed a higher degree of necrosis as compared with nonirradiated tumors. Irradiated and nonirradiated lesions differed based on the appearance and distribution of necrosis. Irradiated tumors showed large necrotic foci, sharply demarcated from the viable neoplastic tissue; nonirradiated tumors demonstrated small, distinct foci of necrosis. Radiation-induced necrosis, more pigmented than surrounding viable tumor, displayed high signal intensity on T1-weighted and low signal intensity on T2-weighted images. The hemorrhagic/coagulative necrosis, more prevalent in nonirradiated tumors (4 out of 6 vs. 1 out of 7 cases), appeared hyperintense on T2-weighted and hypointense on T1-weighted images. Our study boosts the capability to recognize radiation-induced alterations in uveal melanomas at MRI and may improve the accuracy of radiologists in the evaluation of follow-up MR examination after radiotherapy.

Glaucoma is a heterogeneous group of chronic neurodegenerative disorders characterized by a relatively selective, progressive damage to the retinal ganglion cells (RGCs) and their axons, which leads to axon loss and visual field alterations. To date, many studies have shown the role of various elements, mainly metals, in maintaining the balance of prooxidative and antioxidative processes, regulation of fluid and ion flow through cell membranes of the ocular tissues. Based on the earlier and current research results, their relationship with the development and progression of glaucoma seems obvious and is increasingly appreciated. In this review, we aimed to summarize the current evidence on the role of trace elements in the pathogenesis and prevention of glaucomatous diseases. Special attention is also paid to the genetic background associated with glaucoma-related abnormalities of physiological processes that regulate or involve the ions of elements considered as trace elements necessary for the functioning of the cells.

Background: It has been shown that a possible pathogenetic mechanism of neurodegeneration in the mouse model of glaucoma (DBA/2J) may be an alteration of kynurenic acid (KYNA) in the retina. This study aimed to verify the hypothesis that alterations of tryptophan (TRP) metabolism in DBA/2J mice is not limited to the retina., Methods: Samples of the retinal tissue and serum were collected from DBA/2J mice (6 and 10 months old) and control C57Bl/6 mice of the same age. The concentration of TRP, KYNA, kynurenine (KYN), and 3-hydroxykynurenine (3OH-K) was measured by HPLC. The activity of indoleamine 2,3-dioxygenase (IDO) was also determined as a KYN/TRP ratio., Results: TRP, KYNA, L-KYN, and 3OH-K concentration were significantly lower in the retinas of DBA/2J mice than in C57Bl/6 mice. 3OH-K concentration was higher in older mice in both strains. Serum TRP, L-KYN, and KYNA concentrations were lower in DBA/2J than in age-matched controls. However, serum IDO activity did not differ significantly between compared groups and strains., Conclusions: Alterations of the TRP pathway seem not to be limited to the retina in the murine model of hereditary glaucoma.

Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults; little is known about the contribution of non-coding RNAs (ncRNAs) to UM pathogenesis. Competitive endogenous RNA (ceRNA) networks based on RNA-RNA interactions regulate physiological and pathological processes. Through a combined approach of in silico and experimental biology, we investigated the expression of a set of long non-coding RNAs (lncRNAs) in patient biopsies, identifying LINC00518 as a potential oncogene in UM. The detection of LINC00518 dysregulation associated with several in vitro functional assays allowed us to investigate its ceRNA regulatory network and shed light on its potential involvement in cancer-related processes, such as epithelial to mesenchymal transition (EMT) and CoCl 2 -induced hypoxia-like response. In vitro transient silencing of LINC00518 impaired cell proliferation and migration, and affected mRNA expression of LINGO2 , NFIA , OTUD7B , SEC22C , and VAMP3 . A "miRNA sponge" and "miRNA protector" model have been hypothesized for LINC00518 -induced regulation of mRNAs. In vitro inhibition of MITF suggested its role as a potential activator of LINC00518 expression. Comprehensively, LINC00518 may be considered a new oncogene in UM and a potential target for RNA-based therapeutic approaches.

Transforming growth factor β1 (TGFβ1) is a proinflammatory cytokine that has been implicated in the pathogenesis of diabetic retinopathy (DR), particularly in the late phase of disease. The aim of the present study was to validate serum TGFβ1 as a diagnostic and prognostic biomarker of DR stages. Thirty-eight subjects were enrolled and, after diagnosis and evaluation of inclusion and exclusion criteria, were assigned to six groups: (1) healthy age-matched control, (2) diabetic without DR, (3) non-proliferative diabetic retinopathy (NPDR) naïve to treatment, (4) NPDR treated with intravitreal (IVT) aflibercept, (5) proliferative diabetic retinopathy (PDR) naïve to treatment and (6) PDR treated with IVT aflibercept. Serum levels of vascular endothelial growth factor A (VEGF-A), placental growth factor (PlGF) and TGFβ1 were measured by means of enzyme-linked immunosorbent assay (ELISA). Foveal macular thickness (FMT) in enrolled subjects was evaluated by means of structural-optical coherence tomography (S-OCT). VEGF-A serum levels decreased in NPDR and PDR patients treated with aflibercept, compared to naïve DR patients. PlGF serum levels were modulated only in aflibercept-treated NPDR patients. Particularly, TGFβ1 serum levels were predictive of disease progression from NPDR to PDR. A Multivariate ANOVA analysis (M-ANOVA) was also carried out to assess the effects of fixed factors on glycated hemoglobin (HbA1c) levels, TGFβ1, and diabetes duration. In conclusion, our data have strengthened the hypothesis that TGFβ1 would be a biomarker and pharmacological target of diabetic retinopathy.

A large number of preclinical studies suggest the involvement of resveratrol in the prevention and treatment of eye diseases induced by oxidative stress and inflammation. We tested the hypothesis that resveratrol influences many pathways of in vitro and in vivo models of diabetic retinopathy through a systematic literature review of original articles. The review was conducted in accordance with the PRISMA guidelines. A literature search of all original articles published until April 2019 was performed. The terms "resveratrol" in combination with "retina", "retinal pathology", "diabetic retinopathy" and "eye" were searched. Possible biases were identified with the adopted SYRCLE's tool. Eighteen articles met inclusion/exclusion criteria for full-text review. Eleven of them included in vitro experiments, 11 studies reported in vivo data and 3 studies described both in vitro and in vivo experiments. Most of the in vivo studies did not include data that would allow exclusion of bias risks, according to SYRCLE's risk of bias tool. Both in vitro and in vivo data suggest anti-apoptotic, anti-inflammatory and anti-oxidative actions of resveratrol in models of diabetic retinopathy. However, results on its anti-angiogenic effects are contradictory and need more rigorous studies.

Uveal melanoma (UM) represents the most frequent primary intraocular tumor, however, limited therapeutic options are still available. We have previously shown that cluster of differentiation 47 (CD47) is significantly upregulated in UM cells following inflammatory stimuli and that it represents a predictor of disease progression. Here, we aimed to better characterize the pathophysiological role of CD47 in UM. We show that CD47 is not modulated at different cancer stages, although patients with the lowest expression of CD47 show significant better progression-free survival, after correcting for the presence of BAP1, GNAQ, and GNA11 mutations. By stratifying patients based on the expression of CD47 in the tumor, we observed that patients with high levels of CD47 have a significant increase in immune score as compared to patients with low levels of CD47. In particular, deconvolution analysis of infiltrating immune cell populations revealed that a significantly higher number of CD4+ and CD8+ T cells can be found in patients with high CD47 levels, with the most enriched populations being the Th2, Treg, and CD8+ Tcm cells. We also show that a large number of transcripts are significantly modulated between the groups of patients with high and low levels of CD47, with a significant enrichment of interferon IFN-alpha regulated genes. The results from this study may propel the development of anti-CD47 therapies for UM patients.