Our findings that PlGF is a cancer target and anti-PlGF is useful for anticancer treatment have been challenged by Bais et al. Here we take advantage of carcinogen-induced and transgenic tumor models as well as ocular neovascularization to report further evidence in support of our original findings of PlGF as a promising target for anticancer therapies. We present evidence for the efficacy of additional anti-PlGF antibodies and their ability to phenocopy genetic deficiency or silencing of PlGF in cancer and ocular disease but also show that not all anti-PlGF antibodies are effective. We also provide additional evidence for the specificity of our anti-PlGF antibody and experiments to suggest that anti-PlGF treatment will not be effective for all tumors and why. Further, we show that PlGF blockage inhibits vessel abnormalization rather than density in certain tumors while enhancing VEGF-targeted inhibition in ocular disease. Our findings warrant further testing of anti-PlGF therapies.

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Hypoxia causes increased expression of several proteins that have the potential to promote neovascularization. Vascular endothelial growth factor (VEGF) is up-regulated by hypoxia in the retina and plays a central role in the development of several types of ocular neovascularization, but the effects of other hypoxia-regulated proteins are less clear. Stromal-derived factor-1 (SDF-1) and its receptor, CXCR4, have hypoxia response elements in the promoter regions of their genes and are increased in hypoxic liver and heart. In this study, we found that SDF-1 and CXCR4 are increased in hypoxic retina, with SDF-1 localized in glial cells primarily near the surface of the retina and CXCR4 localized in bone marrow-derived cells. Glial cells also expressed CXCR4, which suggested the possibility of autocrine stimulation, but influx of bone marrow-derived cells is the major source of increased levels of CXCR4. High levels of VEGF in the retina in the absence of hypoxia also increased levels of Cxcr4 and Sdf1 mRNA. CXCR4 antagonists reduced influx of bone marrow-derived cells into ischemic retina and strongly suppressed retinal neovascularization, VEGF-induced subretinal neovascularization, and choroidal neovascularization. These data suggest that SDF-1 and CXCR4 contribute to the involvement of bone marrow-derived cells and collaborate with VEGF in the development of several types of ocular neovascularization. They provide new targets for therapeutic intervention that may help to bolster and supplement effects obtained with VEGF antagonists.

The aim of this study was to evaluate the efficacy and safety of femtosecond laser-assisted cataract surgery (FLACS) versus conventional phacoemulsification cataract surgery (CPCS) in the treatment of cataract. Randomized controlled trials (RCTs) were searched in PubMed, Embase and the Cochrane Central Register of Controlled Trials. Nine qualified studies with a total of 989 eyes were included. Compared with CPCS, FLACS significantly reduced mean phaco energy and effective phacoemulsification time (EPT) required in the surgery. Central corneal thickness (CCT) was significantly lower in FLACS at 1 day of follow-up, but CCT and corneal endothelial cells count was comparable at 1 week of follow-up or longer. FLACS achieved a better visual outcome at postoperative 1 week and 6 months, but the difference was not significant at postoperative 1–3 months. Regard to surgical complications, the incidences of intraoperative anterior capsule tear, postoperative macular edema and elevated intraocular pressure were similar. In conclusion, femtosecond laser pretreatment can reduce phaco energy and EPT, which may reduce the heat damage to ocular tissues by ultrasound. This novel technique might be beneficial for patients with dense cataract and/or low preoperative endothelial cell values. Well-designed RCTs with longer follow-up are still necessary to provide more reliable evidence.

ObjectiveThis study was to aggregate the prevalence and risks of epiretinal membranes (ERMs) and determine the possible causes of the varied estimates.DesignSystematic review and meta-analysis.Data sourcesThe search strategy was designed prospectively. We searched PubMed, Embase and Web of Science databases from inception to July 2016. Reference lists of the included literatures were reviewed as well.Study selectionSurveys published in English language from any population were included if they had a population-based design and reported the prevalence of ERM from retinal photography with or without optical coherence tomography. Eligibility and quality evaluation was conducted independently by two investigators.Data extractionThe literature search generated 2144 records, and 13 population-based studies comprising 49 697 subjects were finally included. The prevalence of ERM and the ORs of potential risk factors (age, sex, myopia, hypertension and so on) were extracted.ResultsThe pooled age-standardised prevalence estimates of earlier ERM (cellophane macular reflex (CMR)), advanced ERM (preretinal macular fibrosis (PMF)) and any ERM were 6.5% (95% CI 4.2% to 8.9%), 2.6% (95% CI 1.8% to 3.4%) and 9.1% (95% CI 6.0% to 12.2%), respectively. In the subgroup analysis, race and photography modality contributed to the variation in the prevalence estimates of PMF, while the WHO regions and image reading methods were associated with the varied prevalence of CMR and any ERM. Meta-analysis showed that only greater age and female significantly conferred a higher risk of ERMs.ConclusionsOur findings suggest that ERMs are relatively common among aged population. Race, image taking and reading methodology may play important roles in influencing the large variability of ERM prevalence estimates.

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Proliferation and epithelial–mesenchymal transition (EMT) of lens epithelium cells (LECs) may contribute to anterior subcapsular cataract (ASC) and posterior capsule opacification (PCO), which are important causes of visual impairment. Histone deacetylases (HDACs)-mediated epigenetic mechanism has a central role in controlling cell cycle regulation, cell proliferation and differentiation in a variety of cells and the pathogenesis of some diseases. However, whether HDACs are involved in the regulation of proliferation and EMT in LECs remain unknown. In this study, we evaluated the expression profile of HDAC family (18 genes) and found that class I and II HDACs were upregulated in transforming growth factor β2 (TGFβ2)-induced EMT in human LEC lines SRA01/04 and HLEB3. Tricostatin A (TSA), a class I and II HDAC inhibitor, suppressed the proliferation of LECs by G1 phase cell cycle arrest not only through inhibition of cyclin/CDK complexes and induction of p21 and p27, but also inactivation of the phosphatidylinositol-3-kinase/Akt, p38MAPK and ERK1/2 pathways. Meanwhile, TSA strongly prevented TGFβ2-induced upregulation of fibronectin, collagen type I, collagen type IV, N-cadherin, Snail and Slug. We also demonstrated that the underlying mechanism of TSA affects EMT in LECs through inhibiting the canonical TGFβ/Smad2 and the Jagged/Notch signaling pathways. Finally, we found that TSA completely prevented TGFβ2-induced ASC in the whole lens culture semi-in vivo model. Therefore, this study may provide a new insight into the pathogenesis of ASC and PCO, and suggests that epigenetic treatment with HDAC inhibitors may be a novel therapeutic approach for the prevention and treatment of ASC, PCO and other fibrotic diseases.

Vasohibin is a recently identified protein that is up-regulated in cultured vascular endothelial cells by vascular endothelial growth factor and fibroblast growth factor 2. It inhibits endothelial cell migration, proliferation, and tube formation, and suppresses angiogenesis in chick chorioallantoic membrane, after subcutaneous implantation of matrigel, and in a tumor xenograft model. This has led to the hypothesis that vasohibin functions as a negative feedback inhibitor of angiogenesis. In this study, we tested that hypothesis in a well-characterized model of retinal neovascularization. In ischemic retina, increased expression of VEGF was accompanied by elevation of vasohibin mRNA and blocking of the increase in vegf mRNA with vegf siRNA significantly attenuated the rise in vasohibin mRNA. In transgenic mice in which the rhodopsin promoter drives expression of VEGF in the retina, there was also a significant increase in vasohibin mRNA. In mice with ischemic retinopathy, there was increased expression of vasohibin in vascular endothelial cells, and vasohibin knockdown caused an increase in neovascularization. Conversely, intraocular injection of recombinant vasohibin or an adenoviral vector containing a vasohibin expression cassette strongly suppressed retinal neovascularization in mice with ischemic retinopathy. Knockdown of vasohibin mRNA in ischemic retina had no significant effect on vegf or vegf receptor 1 mRNA levels but caused a significant elevation in the level of vegf receptor 2 mRNA. These data support the hypothesis that vasohibin acts as a negative feedback regulator of neovascularization in the retina and suggest that suppression of VEGF receptor 2 may play some role in mediating its activity.