Purpose: To investigate the trends and progresses in glaucoma research by searching two major clinical trial registries; clinicaltrials.gov, and Australianclinicaltrials.gov.au.Methods: All clinical trials with glaucoma covered by Clinicaltrials.gov, and Australianclinicaltrials.gov.au starting the study before 1 January 2021 were included. Trials evaluating glaucoma treatment were separated from non-treatment trials and divided into three major categories: “laser treatment,” “surgical treatment,” and “medical treatment.” In the category of “medical treatment,” new compounds and their individual targets were identified and subcategorized according to treatment strategy; intraocular pressure (IOP)-lowering, neuroprotective or vascular. The phase transition success rates were calculated.Results: One-thousand five hundred and thirty-seven trials were identified. Sixty-three percent (n = 971) evaluated glaucoma treatment, of which medical treatment accounted for the largest proportion (53%). The majority of medical trials evaluated IOP-lowering compounds, while trials with neuroprotective or vascular compounds accounted for only 5 and 3%, respectively. Eighty-eight new compounds were identified. Phase I, II, and III transition success rates were 63, 26, and 47%, respectively.Conclusion: The number of clinical trials in glaucoma research has increased significantly over the last 30 years. Among the most recently evaluated compounds, all three main treatment strategies were represented, but clinical trials in neuroprotection and vascular modalities are still sparse. In addition to traditional medicines, dietary supplements and growth factors are assessed for a potential anti-glaucomatous effect. Phase II and III success rates were below previously reported success rates for all diseases and ophthalmology in general. A stricter phenotyping of patients can improve the success rates in glaucoma and ophthalmological research and gain a better understanding of responders and non-responders.

RhoGEF proteins activate the Rho family of small GTPases and thus play a key role in regulating fundamental cellular processes such as cell morphology and polarity, cell cycle progression and gene transcription. We identified a Caenorhabditis elegans RhoGEF protein, RHGF-2, as a binding partner of the C. elegans multi-PDZ domain scaffold protein MPZ-1 (MUPP1 in mammals). RHGF-2 exhibits significant identity to the mammalian RhoGEFs PLEKHG5/Tech/Syx and contains a class I C-terminal PDZ binding motif (SDV) that interacts most strongly to MPZ-1 PDZ domain eight. RHGF-2 RhoGEF activity is specific to the C. elegans RhoA homolog RHO-1 as determined by direct binding, GDP/GTP exchange and serum response element-driven reporter activity. rhgf-2 is an essential gene since rhgf-2 deletion mutants do not elongate during embryogenesis and hatch as short immobile animals that arrest development. Interestingly, the expression of a functional rhgf-2::gfp transgene appears to be exclusively neuronal and rhgf-2 overexpression results in loopy movement with exaggerated body bends. Transient expression of RHGF-2 in N1E-115 neuroblastoma cells prevents neurite outgrowth similar to constitutive RhoA activation in these cells. Together, these observations indicate neuronally expressed RHGF-2 is an essential RHO-1 specific RhoGEF that binds most strongly to MPZ-1 PDZ domain eight and is required for wild-type C. elegans morphology and growth.

ABSTRACT.Purpose: Aquaporins (AQPs) are widely expressed and have diverse distribution patterns in the eye. AQPs 0-5 have been localized at the cellular level in human eyes. We investigated the presence of the more recently discovered AQPs 6-12 in the human eye. Methods: RT-PCR was performed on fresh tissue from two human eyes divided into the cornea, corneal limbus, ciliary body and iris, lens, choroid, optic nerve, retina and sclera. Each structure was examined to detect the mRNA of AQPs 6-12. Twenty-one human eyes were examined using immunohistochemical and immunofluorescence techniques to determine the topographical localization of AQPs 6-12.Results: mRNA transcripts of AQP7, AQP9 and AQP11 were found in the ciliary body, corneo-limbal tissue, optic nerve, retina and sclera. AQP9 and AQP11 mRNA was also detected in the choroid. No mRNA of AQP6, AQP8, AQP10 or AQP12 was detected. Anti-AQP7 immunolabelling was detected in the corneal epithelium, corneal endothelium, trabecular meshwork endothelium, ciliary epithelia, lens epithelium, the inner and outer limiting membrane of the retina, the retinal pigment epithelium and the capillary endothelium of all parts of the eye. AQP9 immunolabelling was detected in the nonpigmented ciliary epithelium and retinal ganglion cells. AQP11 immunolabelling was detected in the corneo-limbal epithelium, nonpigmented ciliary epithelium and inner limiting membrane of the retina. Conclusion: Selective expression of AQP7, AQP9 and AQP11 was found within various structures of the human eye. The detection of these aquaporins in the eye implies a role that may be related not only to water transport but also to the transport of glycerol, lactate and ammonia, with importance for metabolism, especially in the retina.

Aquaporins (AQP) are channels in the cell membrane that mainly facilitate a passive transport of water. In the eye, AQPs are expressed in the ciliary body and retina and may contribute to the pathogenesis of glaucoma and optic neuropathy. We investigated the expression of AQP1, AQP3, AQP4, AQP5, AQP7 and AQP9 in human glaucoma eyes compared with normal eyes. Nine glaucoma eyes were examined. Of these, three eyes were diagnosed with primary open angle glaucoma; three eyes had neovascular glaucoma; and three eyes had chronic angle-closure glaucoma. Six eyes with normal intraocular pressure and without glaucoma were used as control. Immunohistochemistry was performed using antibodies against AQP1, AQP3, AQP4, AQP5, AQP7 and AQP9. For each specimen, optical densities of immunoprecipitates were measured using Photoshop and the staining intensities were calculated. Immunostaining showed labelling of AQP7 and AQP9 in the nonpigmented ciliary epithelium and the staining intensities were significantly decreased in glaucoma eyes (p = 0.003; p = 0.018). AQP7 expression in the Müller cell endfeet was increased (p = 0.046), and AQP9 labelling of the retinal ganglion cells (RGC) showed decreased intensity (p = 0.037). No difference in AQP1, AQP4 and AQP9 expression was found in the optic nerve fibres. This study is the first investigating AQPs in human glaucoma eyes. We found a reduced expression of AQP9 in the retinal ganglion cells of glaucoma eyes. Glaucoma also induced increased AQP7 expression in the Müller cell endfeet. In the ciliary body of glaucoma eyes, the expression of AQP7 and AQP9 was reduced. Therefore, the expression of AQPs seems to play a role in glaucoma.

No abstract

No abstract

No abstract

Two cases of invasive myoepithelial carcinoma arising from the paranasal sinuses and invading the orbit are presented. Patient 1, a 53-year-old man, had a 3-month history of proptosis, pain and epiphora of the right eye. The second patient, a 24-year-old man, had for a week been complaining of protrusion of his left eye and of orbital pain. Computed tomography scan and magnetic resonance imaging revealed tumour masses in the frontal, ethmoidal and maxillary sinuses with invasion of the orbit and the frontal lobe. Biopsies from both cases showed spindle and epithelioid tumour cells. Mitotic figures were frequent. Immunohistochemical staining showed positive reaction for bcl-2, calponin, cytokeratins, CD99, S100, muscle-specific antigen, smooth muscle antigen and vimentin. The Ki-67 index was between 30-50% and 5-25%, respectively. Ultrastructurally, intermediate filaments, perinuclear tonofilaments and desmosomes were present. Based on these findings, a diagnosis of myoepithelial carcinoma of mixed cell type in both cases was evident. Both patients died shortly after the diagnosis was made even though both underwent radical surgery. Myoepithelial carcinoma of the paranasal sinuses is very rare and only six cases have been reported previously. We present the first two cases of myoepithelial carcinoma in the paranasal sinuses with invasion of the orbit. This is also the first report of myoepithelial carcinoma arising in the ethmoidal sinus.