The ubiquitin-proteasome system of Saccharomyces cerevisiae.

Protein modifications provide cells with exquisite temporal and spatial control of protein function. Ubiquitin is among the most important modifiers, serving both to target hundreds of proteins for rapid degradation by the proteasome, and as a dynamic signaling agent that regulates the function of covalently bound proteins. The diverse effects of ubiquitylation reflect the assembly of structurally distinct ubiquitin chains on target proteins.

Balancing risk in ophthalmic prescribing: assessing the safety of anti-VEGF therapies and the risks associated with unlicensed medicines.

Vascular endothelial growth factor (VEGF) inhibitor medications such as ranibizumab, pegaptanib and bevacizumab are in use for the treatment of neovascular age-related macular degeneration (AMD) and other retinal conditions, although only ranibizumab and pegaptanib are approved for these conditions. In contrast, bevacizumab was developed for the intravenous systemic treatment of colorectal cancer and is not formulated for intravitreal use, but is commonly used off-label in ophthalmology. European Union legislation permits the use of drugs outside the terms of their licence ('off-label') only under certain circumstances, such as during clinical trials, compassionate/named patient use in the absence of a licensed alternative, emergency scenarios (e.

Signal-induced disassembly of the SCF ubiquitin ligase complex by Cdc48/p97.

A large group of E3 ubiquitin ligases is formed by the multisubunit SCF complex, whose core complex (Rbx1/Cul1-Cdc53/Skp1) binds one of many substrate recruiting F-box proteins to form an array of SCF ligases with diverse substrate specificities. It has long been thought that ubiquitylation by SCF ligases is regulated at the level of substrate binding. Here we describe an alternative mechanism of SCF regulation by active dissociation of the F-box subunit.

Evaluation of fluocinolone acetonide sustained release implant (Retisert) dissociation during implant removal and exchange surgery.

Purpose: To characterize the phenomenon of dissociation of the 2 components of the sustained-release fluocinolone acetonide implant (Retisert; Bausch & Lomb) during removal or exchange procedures, or both, and to evaluate outcomes after these events.

Design: Retrospective, observational case series.

Methods: Retrospective review of 27 consecutive sustained-release fluocinolone acetonide implant (Retisert) exchanges or removals between 2001 and 2010 at the Cole Eye Institute.

16 Gy low-voltage x-ray irradiation followed by as needed ranibizumab therapy for age-related macular degeneration: 12 month outcomes of a 'radiation-first' strategy.

Background And Objective: To describe 'radiation-first' combination treatment with a non-invasive, low-voltage x-ray irradiation system followed by as needed ranibizumab for neovascular age-related macular degeneration (AMD).

Study Design And Methods: Phase I study of non-invasive, low-voltage 16 Gy x-ray irradiation delivered in three beams via the inferior pars plana in patients with active neovascular AMD. Ranibizumab was administered as needed per protocol.

Aflibercept for age-related macular degeneration: a game-changer or quiet addition?

Purpose: To describe the pharmacokinetics, preclinical studies, and clinical trials of the newly approved anti-vascular endothelial growth factor (VEGF) drug aflibercept (Eylea (VEGF Trap-Eye); Regeneron; and Bayer).

Design: Review with editorial commentary.

Methods: A review of the medical literature and pertinent Internet postings combined with analysis of key studies with expert opinion regarding the use of aflibercept for the treatment of exudative age-related macular degeneration.

Evaluation of very high- and very low-dose intravitreal aflibercept in patients with neovascular age-related macular degeneration.

Purpose: To determine bioactivity and duration of effect of intravitreal aflibercept injection (also known as vascular endothelial growth factor Trap-Eye) for neovascular age-related macular degeneration (AMD).

Methods: In this double-masked, phase 1 study, 28 patients with lesions ≤12 disc areas, ≥50% active choroidal neovascularization (CNV), and best corrected visual acuity (BCVA) ≤20/40 were randomized 1:1 to a single intravitreal injection of aflibercept 0.15 or 4 mg.

Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study.

Purpose: To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD).

Design: Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial.

Participants: Three hundred twenty-one patients randomized to receive either ranibizumab 0.

Protein degradation and the stress response.

Environmental stresses are manifold and so are the responses they elicit. This is particularly true for higher eukaryotes where various tissues and cell types are differentially affected by the insult. Type and scope of the stress response can therefore differ greatly among cell types.

Accuracy of navigation in hip resurfacing with different surgeons and varying anatomy.

The accuracy of a commercial imageless navigation system for hip resurfacing and its reproducibility among different surgeons and for varying femoral anatomy was tested by comparing conventional and navigated implantation of the femoral component on different sawbones in a hip simulator. The position of the component was measured on postoperative radiographs. Variance for varus/valgus alignment and anteversion was higher for conventional implantation.

Ranibizumab for age-related macular degeneration.

Introduction: Age-related macular degeneration (AMD) is the leading cause of blindness in patients over 50 years in the developed world. The wet form of AMD is responsible for the majority of severe vision loss. VEGF-A is a key component in the development of wet AMD.

Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration.

Introduction: Age-related macular degeneration (AMD) continues to be a leading cause of blindness worldwide. The neovascular form of the disease can lead to rapid and progressive vision loss. Vascular endothelial growth factor (VEGF) has emerged as a key target of treatment, with inhibitors of VEGF being shown to arrest the angiogenic process and avoid the visual damage typically associated with its presence.

24-Gy low-voltage x-ray irradiation with ranibizumab therapy for neovascular AMD: 6-month safety and functional outcomes.

Background And Objective: To describe the 6-month safety and preliminary efficacy outcomes of the use of 24-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD).

Patients And Methods: A single treatment of a non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 24 Gy was administered in one session through three locations in the inferior pars plana in a consecutive series of patients with neo-vascular AMD (treatment naïve and previously treated). Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity examinations were performed at 1 week, 1 month, and monthly thereafter with quarterly fluorescein angiography.

In vitro observation of dynamic ordering processes in the extracellular matrix of living, adherent cells.

Collecting information at the interface between living cells and artificial substrates is exceedingly difficult. The extracellular matrix (ECM) mediates all cell-substrate interactions, and its ordered, fibrillar constituents are organized with nanometer precision. The proceedings at this interface are highly dynamic and delicate.

Ensemble-based computational approach discriminates functional activity of p53 cancer and rescue mutants.

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain ("cancer mutants"). Activity can be restored by second-site suppressor mutations ("rescue mutants"). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details.

Panretinal photocoagulation for proliferative diabetic retinopathy: pattern scan laser versus argon laser.

Purpose: To evaluate the efficacy of the pattern scan laser (PASCAL) in treating newly diagnosed high-risk proliferative diabetic retinopathy (PDR).

Design: Retrospective comparative case series.

Setting: Institutional.

16-Gy low-voltage x-ray irradiation with ranibizumab therapy for AMD: 6-month safety and functional outcomes.

Background And Objective: To describe the 6-month safety and preliminary efficacy outcomes of the use of 16-Gy radiation with intravitreal ranibizumab for patients with neovascular age-related macular degeneration (AMD).

Patients And Methods: A single treatment of a non-invasive, externally delivered low-voltage 16-Gy x-ray irradiation was administered in one session through three locations in the inferior pars plana. Optical coherence tomography (OCT) and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) examinations were performed at 1 week, 1 month, and monthly thereafter, with quarterly fluorescein angiography (FA).

16-Gy low-voltage x-ray irradiation followed by as-needed ranibizumab therapy for AMD: 6-month outcomes of a "radiation-first" strategy.

Background And Objective: To describe the effect of a "radiation-first" combination treatment strategy for neovascular age-related macular degeneration (AMD) with ranibizumab rescue therapy.

Patients And Methods: Non-invasive, externally delivered low-voltage x-ray irradiation at a dose of 16 Gy was given in a single session through three locations in the inferior pars plana in a consecutive series of patients with neovascular AMD. Ranibizumab was administered according to prospectively determined criteria.

Ubiquitin and transcription: The SCF/Met4 pathway, a (protein-) complex issue.

Ubiquitylation has emerged as an omnipresent factor at all levels of transcriptional regulation. A recent study that describes the yeast transcriptional activator Met4 as a functional component of the very same ubiquitin ligase that regulates its own activity highlights the close relation between transcription and the ubiquitin proteasome system.

Intraocular pressure outcome of patients with fluocinolone acetonide intravitreal implant for noninfectious uveitis.

Purpose: To evaluate the intraocular pressure (IOP) outcomes of patients with noninfectious posterior uveitis treated with a fluocinolone acetonide (FA) intravitreal implant over an 8-year period.

Design: Retrospective clinical case series.

Participants: Forty-seven eyes of 35 patients.

Emerging therapies for the treatment of neovascular age related macular degeneration.

Numerous drugs that show promise in the treatment of neovascular age related macular degeneration are currently being evaluated in early clinical trials. Some of these drugs target the vascular endothelial growth factor pathway while others act on different targets along the angiogenesis cascade. The mechanism of action of these novel therapeutics and the results of early clinical trials will be discussed along with a review of angiogenesis.

Radiation treatment for age-related macular degeneration.

Age-related macular degeneration (AMD) remains a devastating cause of visual loss among elderly individuals. While considerable progress has been made towards combating the disease, most recently with intravitreal anti-VEGF agents, visual outcomes are still limited by continued retinal pigment epithelium (RPE) degeneration and subsequent neurosensory retinal atrophy. Among the promising new treatment options being explored, radiotherapy appears apt to address the multifactorial etiology of AMD.

Up regulation of the maternal immune response in the placenta of cattle naturally infected with Neospora caninum.

Neospora caninum is an intracellular protozoan parasite which is a major cause of abortion in cattle worldwide. It forms persistent infections which recrudesce during pregnancy leading to foetal infection and in a proportion of cases, abortion. The mechanisms underlying abortion are not understood.

Optical coherence tomography enhanced depth imaging of choroidal tumors.

Purpose: To describe the spectral-domain optical coherence tomography (SD-OCT) features of choroidal tumors imaged using enhanced depth imaging (EDI) technique.

Design: Prospective observational case series.

Methods: One tumor each from 23 eyes of 23 patients was included.

A transcriptional activator is part of an SCF ubiquitin ligase to control degradation of its cofactors.

Multisubunit protein complexes pose a challenge to the coordinated regulation of individual components. We show how the yeast transactivating factor Met4 functions as a component of the SCF(Met30) ubiquitin ligase to synchronize its own activity with cofactor assembly. Cells maintain Met4 in a dormant state by a regulatory ubiquitin chain assembled by SCF(Met30).