Associations Between Retinal Vascular Occlusions and Dementia.

Background/objectives: Retinal vascular occlusions, such as retinal vein occlusion (RVO) and retinal artery occlusion (RAO), are associated with cognitive impairment, including dementia. Our objective was to examine the odds of dementia among patients with retinal vascular occlusion.

Methods: This cross-sectional study included 474 patients with retinal vascular occlusion and 948 patients without retinal vascular occlusion (comparison group).

Risk factors for fellow eye treatment in protocol T.

Purpose: To identify risk factors for fellow eye treatment of diabetic retinopathy with Vascular Endothelial Growth Factor (VEGF) injections during the Diabetic Retinopathy Clinical Research Network (DRCR.Net) Protocol T trial METHODS: In this post-hoc analysis of randomized clinical trial data, Cox regression analysis was performed at 52 and 104 weeks to determine risk factors for treatment in 360 fellow eyes. Survival analysis was performed to determine mean time to treatment based upon medication used.

Implantation and Extraction of Penetrating Electrode Arrays in Minipig Retinas.

Purpose: This work was motivated by the goals of demonstrating methods to fabricate and implant large numbers of penetrating arrays into the retina and the feasibility of extraction.

Methods: Arrays of inactive, three-dimensional (3D) SU-8 structures were microfabricated onto 13-µm polyimide substrates. Standard vitreoretinal surgical techniques were used with an approach for subretinal implantation of arrays in 12 mini-pigs.

Bilateral Macular Choroidal Infarction as a Manifestation of Giant Cell Arteritis.

The authors present an unusual case of bilateral macular choroidal infarction as a manifestation of giant cell arteritis (GCA). Due to sequential bilateral presentation, multimodal imaging with spectral-domain optical coherence tomography allows for simultaneous evaluation of progressive stages of outer retinal damage caused by choroidal hypoperfusion seen on fluorescein and indocyanine green angiography. This case report demonstrates that GCA should be considered in the differential diagnosis of placoid maculopathies.

ICG-001 Exerts Potent Anticancer Activity Against Uveal Melanoma Cells.

Purpose: Uveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/β-catenin-mediated transcriptional program.

Methods: We used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression.

Teleretinal imaging for detection of referable macular degeneration.

Purpose: The purpose of this study was to determine the sensitivity and specificity for detection of referable age-related macular degeneration (AMD) using an existing nonmydriatic telemedicine pathway for diabetic retinopathy screening with comparison to same-day face-to-face examination by a retina specialist.

Methods: Subjects in this study underwent nonmydriatic and mydriatic digital retinal imaging on the same day as stereoscopic dilated examination of the macula by a retina specialist and the level of AMD was recorded for each eye. Images were graded by two trained readers as nonreferable or referable (AREDS [Age-Related Eye Disease Study] grading of level 3 or greater).

Protein kinase C inhibitors sensitize GNAQ mutant uveal melanoma cells to ionizing radiation.

Purpose: Uveal melanoma (UM) tumors require large doses of radiation therapy (RT) to achieve tumor ablation, which frequently results in damage to adjacent normal tissues, leading to vision-threatening complications. Approximately 50% of UM patients present with activating somatic mutations in the gene encoding for G protein αq-subunit (GNAQ), which lead to constitutive activation of downstream pathways, including protein kinase C (PKC). In this study, we investigated the impact of small-molecule PKC inhibitors bisindolylmaleimide I (BIM) and sotrastaurin (AEB071), combined with ionizing radiation (IR), on survival in melanoma cell lines.

Genotype-dependent sensitivity of uveal melanoma cell lines to inhibition of B-Raf, MEK, and Akt kinases: rationale for personalized therapy.

Purpose: Inhibitors of B-Raf and MEK kinases hold promise for the management of cutaneous melanomas harboring BRAF mutations. BRAF mutations are rare in uveal melanomas (UMs), but somatic mutations in the G protein α subunits Gαq and Gα11 (encoded by GNAQ and GNA11, respectively) occur in a mutually exclusive pattern in ∼80% of UMs. The impact of B-Raf and MEK inhibitors on Gα-mutant UMs remains unknown.

Angiogenesis assays.

The angiogenic process is central in the pathogenesis of various diseases. The in vitro and in vivo monitoring of the neovascular process is essential for the development and evaluation of angiogenesis inhibitors or stimulators. Since no single method exists that can assess angiogenesis in a robust, reliable, and reproducible fashion, researchers often use a combination of assays to circumvent this problem.

TNF-alpha mediated apoptosis plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations.

Purpose: The pathophysiology of diabetic retinopathy involves leukocyte adhesion to retinal vasculature, early blood-retinal barrier breakdown, capillary nonperfusion, and endothelial cell death. We investigated the involvement of tumor necrosis factor alpha (TNF-alpha) in diabetes-related histopathological changes in two relevant rodent models.

Methods: In short-term studies, Long-Evans rats with streptozotocin-induced diabetes were treated with or without the TNF-alpha inhibitor, etanercept.

Role of alpha 4 integrin (CD49d) in the pathogenesis of diabetic retinopathy.

Purpose: The pathophysiology of diabetic retinopathy is mediated by leukocyte adhesion to the vascular endothelium of the diabetic retina, which results in endothelial injury, blood-retina barrier breakdown, and capillary nonperfusion. Leukocyte adhesion is triggered by the interaction of vascular endothelium adhesion molecules, such as ICAM-1, with leukocyte integrins, such as CD18. Inhibition of ICAM-1/CD18 signaling suppresses but does not completely abolish the cardinal manifestations of diabetic retinopathy, suggesting a role for additional adhesion molecules.

Molecular sequelae of histone deacetylase inhibition in human retinoblastoma cell lines: clinical implications.

Purpose: To characterize the molecular sequelae induced in retinoblastoma (Rb) cells by histone deacetylase inhibitors (HDACIs). Hydroxamic acid-based HDACIs such as vorinostat (suberoylanilide hydroxamic acid) induce the differentiation and apoptosis of transformed cells. Vorinostat has demonstrated significant anticancer activity against hematologic and solid tumors at doses well tolerated by patients and has been approved for the treatment of patients with cutaneous T-cell lymphoma.

Genetics of anterior and stromal corneal dystrophies.

Corneal dystrophies are a group of heterogenous conditions that are characterized by the progressive loss of corneal transparency that results from the accumulation of deposits within the different corneal layers. Up until recently, corneal dystrophies were classified according to their slit lamp appearance, the morphology of the deposits, the depth of the corneal involvement and their histopathological features. This classification has been challenged because of the significant inter-and intra- familial variability in phenotypic expression of the corneal dystrophies and the overlapping characteristics between the different types.

The proteasome inhibitor bortezomib induces apoptosis in human retinoblastoma cell lines in vitro.

Purpose: To evaluate the potential of proteasome inhibitors, a novel class of antitumor agents, for the treatment of retinoblastoma. The proteasome inhibitor bortezomib (PS-341, Velcade; Millennium Pharmaceuticals, Cambridge, MA), approved by the US Food and Drug Administration for the treatment of multiple myeloma, is being studied for the treatment of several other malignancies. Among other effects, it inactivates the transcription factor nuclear factor-kappaB (NF-kappaB) by blocking the degradation of its inhibitor, IkappaB.

Bcl-2 overexpression in thyroid carcinoma cells increases sensitivity to Bcl-2 homology 3 domain inhibition.

Context: The Bcl-2 family of proteins regulates apoptosis in various models and may represent a promising therapeutic target in human malignancies.

Objective/methods: We evaluated the sensitivity of thyroid carcinoma cell lines (two papillary, one follicular, two anaplastic, three medullary) in vitro to BH3I-1 and BH3I-2', two cell-permeable inhibitors of the Bcl-2 homology (BH)-3 domain-mediated interaction between proapoptotic and antiapoptotic Bcl-2 family members. The thyroid carcinoma cell line FRO was stably transfected with cDNA for Bcl-2 or constitutively active Akt and evaluated for sensitivity to BH3-domain inhibition.

Inhibition of Hsp90 attenuates inflammation in endotoxin-induced uveitis.

Heat shock protein (Hsp) 90 inhibitors, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), constitute promising novel therapeutic agents. We investigated the anti-inflammatory activity of 17-AAG in endotoxin-induced uveitis (EIU) in rats. After the induction of EIU with a footpad injection of lipopolysaccharide (LPS), female Lewis rats received a single intraperitoneal.

Targeting BRAFV600E in thyroid carcinoma: therapeutic implications.

B-Raf is an important mediator of cell proliferation and survival signals transduced via the Ras-Raf-MEK-ERK cascade. BRAF mutations have been detected in several tumors, including papillary thyroid carcinoma, but the precise role of B-Raf as a therapeutic target for thyroid carcinoma is still under investigation. We analyzed a panel of 93 specimens and 14 thyroid carcinoma cell lines for the presence of BRAF mutations and activation of the mitogen-activated protein/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway.

VLA-4 blockade suppresses endotoxin-induced uveitis: in vivo evidence for functional integrin up-regulation.

Leukocyte adhesion to the vascular wall is a critical early step in the pathogenesis of inflammatory diseases and is mediated in part by the leukocyte integrin, VLA-4, which binds to endothelial vascular cell adhesion molecule (VCAM) -1. Here, we investigate VLA-4's role in endotoxin-induced uveitis (EIU). At various time points (6-48 h) after EIU induction, the severity of the inflammation was evaluated by quantifying cell and protein content in the aqueous fluid, firm leukocyte adhesion in the retinal vessels, and the number of extravasated leukocytes into the vitreous.

Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro.

Context: The ubiquitin-proteasome pathway is a major pathway for degradation of intracellular proteins. Proteasome inhibitors constitute a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. The proteasome inhibitor bortezomib (PS-341, Velcade) has been approved by the Food and Drug Administration for the treatment of multiple myeloma and is being studied intensely in several other malignancies.

Epidermal growth factor receptor as a therapeutic target in human thyroid carcinoma: mutational and functional analysis.

Context: The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small-cell lung carcinomas harboring activating EGFR TK domain somatic mutations.

Objective And Methods: Because the EGFR pathway has been reported to be important for the pathophysiology of thyroid carcinoma, we investigated the expression and mutational status of EGFR in 14 thyroid carcinoma cell lines as well as its functional role by evaluating their in vitro sensitivity to AEE788, a new dual-family EGFR/ErbB2 and vascular endothelial growth factor receptor TK inhibitor.

Overexpression of FasL in retinal pigment epithelial cells reduces choroidal neovascularization.

Choroidal neovascularization (CNV) is responsible for the severe visual loss in age-related macular degeneration. CNV formation is considered to be due to an imbalance between pro- and antiangiogenic factors that lead to neovascular growth from the choriocapillaris into the subretinal space. To define whether FasL overexpression in retinal pigment epithelial cells (RPE) can inhibit choroidal neovascularization through Fas-FasL-mediated apoptosis, we examined the role of this pathway in a mouse model of laser-induced choroidal neovascularization.