Lucy Q. Shen

PPARγ ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis

Several drugs approved for a variety of indications have been shown to exhibit antiangiogenic effects. Our study focuses on the PPARgamma ligand rosiglitazone, a compound widely used in the treatment of type 2 diabetes. We demonstrate, for the first time to our knowledge, that PPARgamma is highly expressed in tumor endothelium and is activated by rosiglitazone in cultured endothelial cells. Furthermore, we show that rosiglitazone suppresses primary tumor growth and metastasis by both direct and indirect antiangiogenic effects. Rosiglitazone inhibits bovine capillary endothelial cell but not tumor cell proliferation at low doses in vitro and decreases VEGF production by tumor cells. In our in vivo studies, rosiglitazone suppresses angiogenesis in the chick chorioallantoic membrane, in the avascular cornea, and in a variety of primary tumors. These results suggest that PPARgamma ligands may be useful in treating angiogenic diseases such as cancer by inhibiting angiogenesis.

Therapeutic potential of thiazolidinediones as anticancer agents.

Thiazolidinediones (TZDs) are synthetic ligands that activate the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ). These compounds are widely used in the treatment of Type 2 diabetes. TZDs have antitumour activity in a wide variety of experimental cancer models, in vitro and in vivo, by affecting the cell cycle, induction of cell differentiation and apoptosis as well as by inhibiting tumour angiogenesis. These effects are mediated through both PPAR-γ-dependent and -independent pathways depending on concentration and tumour cell type. Angiogenesis inhibition mechanisms of TZDs include directly inhibiting endothelial cell proliferation and migration as well as decreasing tumour cell vascular endothelial growth factor production. Further studies suggest that TZDs may be effective in prevention of certain cancers and in the treatment of cancer as adjuvant therapy.

Rosiglitazone and delayed onset of proliferative diabetic retinopathy.

OBJECTIVE To evaluate whether rosiglitazone maleate, an oral peroxisome-proliferating activated receptor gamma agonist and oral insulin sensitizing agent with potential antiangiogenic activity, delays onset of proliferative diabetic retinopathy (PDR). METHODS Longitudinal medical record review of all patients treated with rosiglitazone receiving both medical and ophthalmic care at the Joslin Diabetes Center from May 1, 2002, to May 31, 2003 (N = 124), and matched control patients not taking a glitazone drug (N = 158). The mean duration of follow-up was 2.8 years (range, 0.3-9.0 years). RESULTS Baseline characteristics and final hemoglobin A(1c) values (7.6% and 7.8%, respectively) were similar in the rosiglitazone and control groups (P = .10). In eyes with severe nonproliferative diabetic retinopathy at baseline (rosiglitazone group, 14 eyes; control group, 24 eyes), progression to PDR over 3 years occurred in 19.2% in the rosiglitazone group and 47.4% in the control group, representing a 59% relative risk reduction (Wilcoxon, P = .045; log-rank, P = .059). Fewer eyes in the rosiglitazone group experienced 3 or more lines of visual acuity loss (P = .03). The incidence of diabetic macular edema was similar in both groups. CONCLUSIONS Rosiglitazone may delay the onset of PDR, possibly because of its antiangiogenic activity. Future clinical investigations should consider analysis of this potential benefit along with ongoing evaluation of potential cardiac risk in studies where the risk-benefit profiles are deemed appropriate.

Glaucoma progression and role of glaucoma surgery in patients with Boston keratoprosthesis.

Purpose: The aim of this study was to evaluate glaucoma onset and progression after implantation of Boston Keratoprostheses (B-KPro) and the role of glaucoma surgery. Methods: Records of patients with B-KPro implantation during 2004 to 2009 were reviewed. Parameters relevant to B-KPro surgery and glaucoma status were recorded. The data were analyzed in 5 groups based on the preoperative diagnosis. Results: One hundred six eyes of 87 patients were included, and the average age was 54 ± 6.7 years. Forty-six percent were female. Eighteen eyes had a B-KPro with a titanium back plate, and the others had a poly(methyl methacrylate) back plate. Thirty-three eyes were pseudophakic, and the rest were left aphakic. The follow-up time was 3.3 ± 1.0 years. Indications for implantation included past infection, congenital glaucoma, trauma, autoimmune diseases, aniridia, burns, and others. Sixty-six percent of the eyes had glaucoma preoperatively, and 26% developed de novo glaucoma afterward. The mean intraocular pressure (by finger palpation) was 16.5 ± 5.7 mm Hg. Reliable visual field tests were only available in 59% of the eyes; hence, the cup-to-disc ratio of the optic nerve head was used as the main outcome measure. In B-KPro–implanted eyes with glaucoma, 65% had undergone glaucoma surgery at some point, and 30% did not show progression. Thirty-one percent of the total cohort had disc pallor with a cup-to-disc ratio of <0.8. Conclusions: Glaucoma in B-KPro remains a challenge, despite aggressive attempts to slow down its progression. Patients with glaucoma before B-KPro implantation should be considered for glaucoma surgery before or simultaneously with B-KPro implantation. The high number of eyes with disc pallor suggests that additional mechanisms other than elevated intraocular pressure may play a role in optic neuropathy.

Macular Imaging for Glaucoma Using Spectral-domain Optical Coherence Tomography: A Review

Since its introduction, optical coherence tomography (OCT) has become widely used and accepted as an imaging modality to detect and follow glaucoma, with measurement of the peripapillary retinal nerve fiber layer (pRNFL) being the most utilized parameter. Up until recently, macular thickness parameters have not been commonly used in glaucoma due to results of earlier studies with time-domain OCT (TD-OCT) that revealed macular imaging to be inferior to pRNFL in the diagnosis of glaucoma. The recent advent of spectral-domain OCT (SD-OCT) has renewed interest in the potential uses of macular imaging in glaucoma due to its ability to better segment and measure individual retinal layers. Multiple studies have been performed in the last few years to investigate the diagnostic ability, reproducibility, and limitations of these new SD-OCT macular parameters. The purpose of this paper is to review the findings of those studies to assess the current utility of macular SD-OCT in glaucoma. Overall, SD-OCT has been shown to have higher reproducibility than TD-OCT, and though there have been some conflicting reports, the majority of studies seem to concur that the diagnostic sensitivity of SD-OCT macular parameters is at least comparable to TD-OCT and other SD-OCT parameters.

A Peptide That Antagonizes TCR-Mediated Reactions with Both Syngeneic and Allogeneic Agonists: Functional and Structural Aspects

We identify and consider some characteristics of a peptide antagonist for the Ag-specific receptor on 2C cells (the 2C TCR). The peptide, GNYSFYAL (called GNY), binds to H-2Kb, and a very high-resolution crystal structure of the GNY-Kb complex at 1.35 Å is described. Although the GNY peptide does not bind to Ld, the potency of GNY-Kb as an antagonist is evident from its ability to specifically inhibit 2C TCR-mediated reactions to an allogenic agonist complex (QLSPFPFDL-Ld), as well as to a syngeneic agonist complex (SIYRYYGL-Kb). The crystal structure and the activities of alanine-substituted peptide variants point to the properties of the peptide P4 side chain and the conformation of the Tyr-P6 side chain as the structural determinants of GNYSFYAL antagonist activity.

Effects of caffeinated coffee consumption on intraocular pressure, ocular perfusion pressure, and ocular pulse amplitude: a randomized controlled trial

PurposeTo examine the effects of caffeinated coffee consumption on intraocular pressure (IOP), ocular perfusion pressure (OPP), and ocular pulse amplitude (OPA) in those with or at risk for primary open-angle glaucoma (POAG).MethodsWe conducted a prospective, double-masked, crossover, randomized controlled trial with 106 subjects: 22 with high tension POAG, 18 with normal tension POAG, 20 with ocular hypertension, 21 POAG suspects, and 25 healthy participants. Subjects ingested either 237 ml of caffeinated (182 mg caffeine) or decaffeinated (4 mg caffeine) coffee for the first visit and the alternate beverage for the second visit. Blood pressure (BP) and pascal dynamic contour tonometer measurements of IOP, OPA, and heart rate were measured before and at 60 and 90 min after coffee ingestion per visit. OPP was calculated from BP and IOP measurements. Results were analysed using paired t-tests. Multivariable models assessed determinants of IOP, OPP, and OPA changes.ResultsThere were no significant differences in baseline IOP, OPP, and OPA between the caffeinated and decaffeinated visits. After caffeinated as compared with decaffeinated coffee ingestion, mean mm Hg changes (±SD) in IOP, OPP, and OPA were as follows: 0.99 (±1.52, P<0.0001), 1.57 (±6.40, P=0.0129), and 0.23 (±0.52, P<0.0001) at 60 min, respectively; and 1.06 (±1.67, P<0.0001), 1.26 (±6.23, P=0.0398), and 0.18 (±0.52, P=0.0006) at 90 min, respectively. Regression analyses revealed sporadic and inconsistent associations with IOP, OPP, and OPA changes.ConclusionConsuming one cup of caffeinated coffee (182 mg caffeine) statistically increases, but likely does not clinically impact, IOP and OPP in those with or at risk for POAG.

Solar Exposure and Residential Geographic History in Relation to Exfoliation Syndrome in the United States and Israel

IMPORTANCE Residential (geographic) history and extent of solar exposure may be important risk factors for exfoliation syndrome (XFS) but, to our knowledge, detailed lifetime solar exposure has not been previously evaluated in XFS. OBJECTIVE To assess the relation between residential history, solar exposure, and XFS. DESIGN, SETTING, AND PARTICIPANTS This clinic-based case-control study was conducted in the United States and Israel. It involved XFS cases and control individuals (all ≥ 60-year-old white individuals) enrolled from 2010 to 2012 (United States: 118 cases and 106 control participants; Israel: 67 cases and 72 control participants). MAIN OUTCOMES AND MEASURES Weighted lifetime average latitude of residence and average number of hours per week spent outdoors as determined by validated questionnaires. RESULTS In multivariable analyses, each degree of weighted lifetime average residential latitude away from the equator was associated with 11% increased odds of XFS (pooled odds ratio [OR], 1.11; 95% CI, 1.05-1.17; P < .001). Furthermore, every hour per week spent outdoors during the summer, averaged over a lifetime, was associated with 4% increased odds of XFS (pooled OR, 1.04; 95% CI, 1.00-1.07; P = .03). For every 1% of average lifetime summer time between 10 am and 4 pm that sunglasses were worn, the odds of XFS decreased by 2% (OR, 0.98; 95% CI, 0.97-0.99; P < .001) in the United States but not in Israel (OR, 1.00; 95% CI, 0.99-1.01; P = .92; P for heterogeneity = .005). In the United States, after controlling for important environmental covariates, history of work over water or snow was associated with increased odds of XFS (OR, 3.86; 95% CI, 1.36-10.9); in Israel, there were too few people with such history for analysis. We did not identify an association between brimmed hat wear and XFS (P > .57). CONCLUSIONS AND RELEVANCE Lifetime outdoor activities may contribute to XFS. The association with work over snow or water and the lack of association with brimmed hat wear suggests that ocular exposure to light from reflective surfaces may be an important type of exposure in XFS etiology.

Patterns of functional vision loss in glaucoma determined with archetypal analysis

Glaucoma is an optic neuropathy accompanied by vision loss which can be mapped by visual field (VF) testing revealing characteristic patterns related to the retinal nerve fibre layer anatomy. While detailed knowledge about these patterns is important to understand the anatomic and genetic aspects of glaucoma, current classification schemes are typically predominantly derived qualitatively. Here, we classify glaucomatous vision loss quantitatively by statistically learning prototypical patterns on the convex hull of the data space. In contrast to component-based approaches, this method emphasizes distinct aspects of the data and provides patterns that are easier to interpret for clinicians. Based on 13 231 reliable Humphrey VFs from a large clinical glaucoma practice, we identify an optimal solution with 17 glaucomatous vision loss prototypes which fit well with previously described qualitative patterns from a large clinical study. We illustrate relations of our patterns to retinal structure by a previously developed mathematical model. In contrast to the qualitative clinical approaches, our results can serve as a framework to quantify the various subtypes of glaucomatous visual field loss.

Infliximab after Boston Keratoprosthesis in Stevens-Johnson Syndrome: An Update.

ABSTRACT Purpose: To report our experience using intravenous infliximab for the treatment of tissue melt after Boston keratoprosthesis (B-KPro) types I and II in patients with autoimmune disease. Methods: Case series. Results: We identified four patients who were treated with intravenous infliximab in the context of tissue melt after B-KPro. Stevens–Johnson syndrome-associated corneal blindness was the primary surgical indication for B-KPro implantation in all patients. Two patients received a B-KPro type I and two patients received a B-KPro type II. The patients received intravenous infliximab for skin retraction around B-KPro type II, melting of the carrier graft or leak. Treatment resulted in a dramatic decrease in inflammation and, in some cases, arrest of the melting process. Cost and patient adherence were limiting factors to pursuing infliximab therapy. In addition, one patient developed infusion reactions. Conclusions: Intravenous infliximab may be considered as globe- and sight-saving therapy for tissue melt after B-KPro.