Uveitis associated with immune checkpoint inhibitors or BRAF/MEK inhibitors in patients with malignant melanoma.

The objective of this study was to evaluate the frequency and characteristics of uveitis associated with immune checkpoint inhibitors (ICIs) or BRAF/MEK inhibitors (B/MIs) in patients with malignant melanoma. Patients diagnosed with malignant melanoma who underwent radical or local resection for malignant melanoma, regardless of clinical stage or postoperative adjuvant therapy, at Hiroshima University Hospital from January 2015 to June 2021 were enrolled in a retrospective cohort. The medical records of patients were collected to estimate the prevalence of ocular adverse events. The clinical characteristics of patients who developed uveitis were reviewed. Among 152 patients, 54 and 12 were treated with ICIs and B/MIs, respectively. Four patients developed uveitis; 1 in the ICI group and 3 in the B/MI group, while there were no uveitis cases among patients who did not receive ICIs or B/MIs. Three patients had Vogt-Koyanagi-Harada disease-like findings. Uveitis was improved by steroid therapy with or without oncological treatment interruption. Oncological treatment could be resumed. Patients with melanoma treated with ICIs or B/MIs had a higher risk of uveitis compared with those who did not receive them. Oncological treatment could be resumed in all patients who developed uveitis.

Irreversible intraocular pressure elevation as a complication of MIRAgel scleral buckling.

Purpose: To report a case of ocular hypertension due to swelling and degeneration of hydrogel explant (MIRAgel) after retinal detachment surgery. Observations: The patient who had a history of left retinal detachment 23 years prior had been regularly followed up for epiretinal membrane in the left eye at the Department of Ophthalmology, Hiroshima University Hospital. Two years after the first presentation, the patient had symptoms of foreign body sensation and hyperemia, with elevation of the intraocular pressure (IOP) of the left eye to 24 mmHg. Two months later, the patient noticed omnidirectional oculomotor disturbances in the left eye, and magnetic resonance imaging (MRI) revealed swelling of the buckle material, presumably hydrogel explant, surrounding his left eye. His oculomotor disturbances worsened, and the left eye IOP remained high at 40 mmHg, despite the administration of antihypertensive eye drops. Subsequently, the swollen hydrogel explant was surgically removed. After the surgery, there was improvement of the diplopia and foreign body sensation. However, IOP in the left eye remained at 34 mmHg, and a trabeculectomy was performed to normalize the IOP. Conclusions and Importance: As far as we know, there have been no reported cases of irreversible ocular hypertension due to hydrogel explant. Stenosis of the trabecular outflow pathway secondary to compression of the superior scleral vein by long-term swollen hydrogel explant and inflammation around the hydrogel explant may be the cause of irreversible IOP elevation. Trabeculectomy may be effective for treating the intraocular hypertension caused by hydrogel explant.

Wnt14 inhibits death of retinal precursor cells.

An earlier proteomics study from our laboratory showed that Wnt14, a member of the Wnt family that regulates the development of vertebrates, was one of the proteins expressed transiently during the development of the chick retina. The purpose of this study was to determine in more detail the changes in the expression of Wnt14 during the development of the chick retina, and to investigate the biological function of Wnt14. Endogenous Wnt14 is located in the retinal ganglion cell layer, and is expressed in the chick retina on embryonic days (ED) 7, ED11, and ED15. The level of Wnt14 is transiently decreased on ED11. In vitro analysis showed that an over-expression of Wnt14 reduced the activation of caspase-3 and inhibited the death of R28 cells induced by serum deprivation or exposure to glutamate. An interferon-induced protein was identified as the protein that was bound to Wnt14. These results suggest that a stable expression of Wnt14 inhibits cell death by inactivating caspase-3 in the developing retina.

GABA A receptors are associated with retinal ganglion cell death induced by oxidative stress.

A previously proteomic study from our laboratory showed that the expression of the protein of the GABA A receptor beta1 subunit was significantly increased in the retina of EAAC1-deficient (EAAC1-/-) mice, a mouse model of glaucoma. The purpose of this study was to investigate the role played by GABA A receptor beta1 subunit in the death of retinal ganglion cells (RGCs) caused by oxidative stress. The retinal sites and expression pattern of GABA A receptor beta1 subunit were determined by immunohistochemistry in the retina of ICR mice. A RGC line, RGC-5, was exposed to GABA A receptor agonist and antagonist, and the cell viability was determined by the MTS assay. The effect of GABA A receptor antagonist on the death of RGCs, and the activation of oxidative stress signaling induced by hydrogen peroxide was investigated. Our results showed that the GABA A receptor beta1 subunit was expressed on the RGCs of ICR mice. GABA A receptor agonist induced RGCs death, and this death was inhibited by bicuculline, a GABA A receptor antagonist. The hydrogen peroxide-induced death of RGCs was reduced by GABA A receptor antagonist, and the oxidative stress signaling activated by hydrogen peroxide was also inhibited. These results indicate that GABA A receptors are expressed on RGCs and may play a role in the death of RGCs induced by oxidative stress.

Proteome profiling of embryo chick retina.

BACKGROUND: Little is known regarding the molecular pathways that underlie the process of retinal development. The purpose of this study was to identify proteins which may be involved in development of retina. We used a proteomics-based approach to identify proteins that are up- or down-regulated during the development of the embryo chick retina. RESULTS: Two-dimensional gel electrophoresis was performed with the retina of embryo chicken, which was obtained from embryos of day 7 (ED7) and of day 11 (ED11). The protein spots showing significant differences were selected for identification by MALDI mass spectrometry. Thirteen proteins were differentially expressed; seven proteins were up-regulated in embryo retina of chicken at ED 11 and six proteins were down-regulated. Significant proteins were also evaluated in embryo day 15 (ED15). Some of identified proteins were known to regulate cell proliferation, cell death, transport, metabolism, organization and extracellular matrix, and others also included novel proteins. CONCLUSION: We identified thirteen proteins which differentially expressed in embryonal retina of chicken at day 7, as compared to the retina of embryo of day 11. They were various regulatory proteins for cellular signaling.

Pigment epithelium-derived factor promotes neurite outgrowth of retinal cells.

The ability of pigment epithelium-derived factor (PEDF) to promote neurite outgrowth of retinal cells through mitogen-activated protein kinase (MAPK) pathways was examined. Neurite outgrowth effects of PEDF were determined by quantifying the neurite length extending from cultured chick embryo retinal explants, and neurite outgrowth ratio of R28 cells (a neural cell line derived from the neonatal rat retina). MAPK activity levels were determined by inhibition assays. The contribution of signaling pathway was quantified with a specific inhibitor for MAPK: PD98059. PEDF (50 ng/ml) promoted chick retinal neurite elongation and increased the extent of R28 cell neurite outgrowth. PD98059 decreased neurite elongation of chicken retinal explants and the extent of R28 cell neurite outgrowth. PEDF possibly promotes neurite outgrowth for retinal cells by activating MAPK pathways. These data suggest that PEDF provides a useful support for retinal cells through the MAPK pathway and leads to the progress of therapy for many retinal diseases.