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| December 2006 | Inside IOVS | Volume 47/12 |
Chromosome 3 Monosomy and Metastatic Potential in Choroidal Melanoma
Choroidal melanoma is usually of mixed cell type, meaning that it is composed of a mixture of spindle-shaped and more rounded epithelioid cells. The behavior of these tumors is difficult to predict but around 15% of tumors metastasize. Cytogenetic studies have shown that loss of one copy of chromosome 3 in tumor cells is an important predictor of metastases. In their study, Sandinha et al. (p. 5177) show that in some choroidal melanomas there is clonal heterogeneity for monosomy 3 and that this corresponds with areas of different cell type. They conclude that the genetic information obtained from small samples of such tumors may not always be representative.
Caspase-1 and Photoreceptor Degeneration
Interference with photoreceptor apoptosis is a promising strategy to treat retinal degeneration. Samardzija et al. (p. 5181) evaluated molecular mechanisms of the degenerative process with special emphasis on caspase-1. A strong upregulation of caspase-1 RNA and protein levels was found in three different animal models. However, no maturation of the proform and no classical enzymatic activity was detected. Ablation of caspase-1 protected photoreceptors only in a model of adRP, suggesting a modulatory role of caspase-1 for photoreceptor apoptosis in some but not all models. This role may involve a caspase-1 function different from the classical activation of interleukin-1b.
Protein Phosphatases and the Modulation of Corneal Epithelial Cell Migration
Epidermal growth factor, EGF, participates in the control of corneal epithelial cell proliferation through stimulation of the ERK and p38 pathways in the mitogen activated protein kinase (MAPK) cascade. Wang et al. (p. 5267) show here that the magnitude of the migratory response to EGF is dependent on the extent of crosstalk between these signaling pathways. PP2A and MKP-1 are two of the protein phosphatases (PP) that elicit such feedback control. This realization suggests that modulation of PP expression and activity could provide a novel therapeutic approach for hastening wound healing in the clinical setting.
Wound Healing in the Pax6+/- Corneal Epithelium
In contrast to wild-type, Pax6+/- corneal epithelial cells in culture take up to two hours to initiate cell migration after wounding. Kucerova et al. (p. 5276) found that blocking the action of some classes of cell surface glycoproteins recapitulates this delay in wild-types, and, intriguingly, the data suggest that these glycoproteins may be mislocalized to the Golgi apparatus in mutant cells. Failure of cellular trafficking, rather than glycoprotein production, may therefore underlie the abnormal Pax6+/- wound healing response.
Mapping the Brittle Cornea Gene
Brittle cornea syndrome (BCS) is an autosomal recessive connective tissue disease characterized by a thin cornea that tends to perforate. In Israel the disease has been described mainly among Tunisian Jews, the vast majority of whom have red hair. Abu et al. (p. 5283) assumed that the gene that causes BCS is located very close to the gene responsible for hair color and used this fact to map the BCS gene to chromosome 16q24. Future cloning of this gene should increase our understanding of the molecular pathways involved in the pathogenesis of corneal and connective tissue disorders and will enable prenatal diagnosis.
Leber's Hereditary Optic Neuropathy with Childhood Onset
Barboni et al. (p. 5303) undertook the first systematic characterization of Leber's hereditary optic neuropathy (LHON) cases with childhood onset. Fourteen patients were enrolled, 11.5 % of LHON affected cases, and an extensive ophthalmologic evaluation, which included retinal nerve fiber layer analysis and optic nerve head analysis by optical coherence tomography, was performed. The results provide some important clues about LHON: a benign course of the disease in its childhood form as opposed to the classic form in young adults, a definition of specific clinical patterns useful for differential diagnosis with other childhood optic neuropathies, and morphological features of the optic nerve head which may be relevant to understanding the disease pathogenesis.
Aldose Reductase in Ocular Inflammation
Aldose reductase (AR), a member of aldo-keto reductase super family, that has earlier been shown to mediate cytotoxic signals induced by high glucose, cytokines, and growth factors, also mediates the inflammatory signals induced by Gram-negative bacterial endotoxin, lipopolysaccharide (LPS) in human lens epithelial cells (HLEC). Pladzyk et al. (p. 5395) found that inhibition or ablation of AR suppressed the LPS-induced cytotoxic signals leading to HLEC apoptosis and expression of NF-kB-dependent inflammatory markers such as TNF-a, MMP2, MMP9, and Cox-2. Inhibition of AR also prevented the production of nitric oxide and prostaglandin E2. These results suggest the therapeutic use of AR inhibitors to prevent ocular inflammation.
Autofluorescence Patterns in Atrophic and Neovascular AMD
The relationships between autofluorescence patterns (lipofuscin accumulations) and clinical age-related macular degeneration (AMD) status suggest new disease models. Smith et al. (p. 5495) found that, in early AMD, focally increased autofluorescence (FIAF) colocalizes with large soft drusen and hyperpigmentation, suggesting linked disease processes, whereas in advanced atrophic AMD, FIAF is found mostly adjacent to drusen and atrophy, suggesting dispersal of drusen-associated lipofuscin. Conversely, lipofuscin does not appear to be a major determinant of choroidal neovascularization (CNV). Instead, reticular hypoautofluorescence, consistent with multifocal damage to the RPE, and photographic reticular pseudodrusen are highly associated with each other and CNV, suggesting an inflammatory basis for some neovascularization, perhaps in genetically susceptible individuals.
Tissue Bioengineering for Filtering Blebs
Chen et al. (p. 5310) describe a biodegradable, porous collagen matrix implanted over the scleral flap after trabeculectomy as an alternative to antifibrotic agents, which predispose to thin-walled blebs, late leakage, and blebitis. Fibroblasts can migrate through thousands of micropores in the matrix to create a spongy bleb. This new means of avoiding early wound contraction and fibrosis may provide a way of maintaining long-term IOP control by creating a loosely structured and functional filtering bleb. If long-term success can be shown in human trials currently in progress, the implant can provide an alternative to antifibrotic agents and reduce long-term complications.
Oxysterol-induced Apoptosis In Human RPE Cells – Implications In AMD
Oxidative stress is believed to be an important contributing factor to the pathogenesis of age-related macular degeneration (AMD). Luthra et al. (p. 5569) show that caspase-8, -12, and -3 but not caspase-9 are activated in ARPE-19 cells treated with 40mg/ml of 7-ketocholesterol (7kCh). This supports the hypothesis that within the eye, cholesterol undergoes oxidation into oxysterols, including 7kCh, which can act as an oxidative stressor and is cytotoxic to RPE cells, macrophages, and vascular cells. Eventually, RPE cells undergo apoptosis leading to regional atrophy, thereby affecting the adjacent retina. Elucidating the specific apoptotic pathways involved may have therapeutic implications for AMD and other retinal disorders.
Rb in the Developing Human Retina
Retinoblastomas form due to the loss of Rb in early retinal cells. Curiously, the tumors occur almost exclusively in humans. To gain insight into the origin of this tumor, Lee et al. (p. 5590) examined Rb expression in the developing human retina. They show that Rb is expressed in a cell cycle-specific manner in retinal progenitor cells, is not detectable in early post-mitotic retinal neurons, and is re-expressed during later stages of neuronal differentiation - particularly in cones. The findings suggest that Rb may have an important role in retinal neurons that have already exited the cell cycle and initiated differentiation.
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