A Meta-Analysis of Anti-Vascular Endothelial Growth Factor Remedy for Macular Edema Secondary to Central Retinal Vein Occlusion

Background

Central retinal vein occlusion (CRVO) associates with severe vision outcome and no proven beneficial treatment. Our meta-analysis intended to appraise the efficacy and safety of anti-vascular endothelial growth factor (anti-VEGF) agents in macular edema (ME) following CRVO.

Methods

Data were collected and analyzed by Review Manager 5.2.1. We employed a random-effects model to eliminate between-study heterogeneity. N_fs (called fail-safe number) was calculated to evaluate the publication bias.

Results

We included 5 trials consisting 323 cases and 281 controls. Primary outcomes showed that overall comparison of anti-VEGF agents with placebo control yielded a 374% and 136% increased tendency for a gain of 15 letters or more on Early Treatment Diabetic Retinopathy Study (ETDRS) chart (95% confidence interval [95% CI]: 2.43–9.23; P<0.00001; I² = 59%, 95% CI: 1.60–3.49; P<0.0001; I² = 0%, respectively) at 6 and 12 months. Secondary outcomes showed that a 90% and 77% decreased risk at 6 and 12 months for a loss of 15 letters or more. The overall mean difference showed a statistically significance in best-corrected visual acuity (BCVA) on each time point. However, changes of central retinal thickness (CRT) lost significance at 12 months after 6-month as-needed treatment. The incidence of adverse events (AEs) had no statistical difference between anti-VEGF and placebo groups. Subgroup analyses indicated that patients receiving Aflibercept got the highest tendency to gain 15 letters or more (OR = 9.78; 95% CI: 4.43–21.56; P<0.00001). Age controlled analysis suggested a weaken tendency of BCVA improvement in age over 50 (MD = 12.26; 95% CI: 7.55–16.98; P<0.00001). Subgroup analysis by clinical classification showed a strengthen difference of BCVA changes at 6 months in ischemic type (MD = 19.65 letters, 95% CI: 13.15 to 26.14 letters, P<0.00001).

Conclusions

Our results showed that anti-VEGF agents were superior to placebo in CRVO-ME treatment with no statistically significant AEs, especially in younger people and for ischemic type.     

Molecular Modeling Reveals the Novel Inhibition Mechanism and Binding Mode of Three Natural Compounds to Staphylococcal α-Hemolysin

α-Hemolysin (α-HL) is a self-assembling, channel-forming toxin that is produced as a soluble monomer by Staphylococcus aureus strains. Until now, α-HL has been a significant virulence target for the treatment of S. aureus infection. In our previous report, we demonstrated that some natural compounds could bind to α-HL. Due to the binding of those compounds, the conformational transition of α-HL from the monomer to the oligomer was blocked, which resulted in inhibition of the hemolytic activity of α-HL. However, these results have not indicated how the binding of the α-HL inhibitors influence the conformational transition of the whole protein during the oligomerization process. In this study, we found that three natural compounds, Oroxylin A 7-O-glucuronide (OLG), Oroxin A (ORA), and Oroxin B (ORB), when inhibiting the hemolytic activity of α-HL, could bind to the “stem” region of α-HL. This was completed using conventional Molecular Dynamics (MD) simulations. By interacting with the novel binding sites of α-HL, the ligands could form strong interactions with both sides of the binding cavity. The results of the principal component analysis (PCA) indicated that because of the inhibitors that bind to the “stem” region of α-HL, the conformational transition of α-HL from the monomer to the oligomer was restricted. This caused the inhibition of the hemolytic activity of α-HL. This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay. This study can facilitate the design of new antibacterial drugs against S. aureus.     

LncRNAs Expression in Preeclampsia Placenta Reveals the Potential Role of LncRNAs Contributing to Preeclampsia Pathogenesis

Background

Long non-coding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. They are aberrantly expressed in many types of diseases. In this study, we aimed to investigate the lncRNA profiles in preeclampsia. Preeclampsia has been observed in patients with molar pregnancy where a fetus is absent, which demonstrate that the placenta is sufficient to cause this condition. Thus, we analyzed the lncRNA profiles in preeclampsia placentas.

Methodology/Principal Findings

In this study, we described the lncRNA profiles in six preeclampsia placentas (T) and five normal pregnancy placentas (N) using microarray. With abundant and varied probes accounting for 33,045 LncRNAs in our microarray, 28,443 lncRNAs that were expressed at a specific level were detected. From the data, we found 738 lncRNAs that were differentially expressed (≥1.5-fold-change) among preeclampsia placentas compared with controls. Coding-non-coding gene co-expression networks (CNC network) were constructed based on the correlation analysis between the differentially expressed lncRNAs and mRNAs. According to the CNC network and GO analysis of differentially expressed lncRNAs/mRNAs, we selected three lncRNAs to analyze the relationship between lncRNAs and preeclampsia. LOC391533, LOC284100, and CEACAMP8 were evaluated using qPCR in 40 preeclampsia placentas and 40 controls. These results revealed that three lncRNAs were aberrantly expressed in preeclampsia placentas compared with controls.

Conclusions/Significance

Our study is the first study to determine the genome-wide lncRNAs expression patterns in preeclampsia placenta using microarray. These results revealed that clusters of lncRNAs were aberrantly expressed in preeclampsia placenta compared with controls, which indicated that lncRNAs differentially expressed in preeclampsia placenta might play a partial or key role in preeclampsia development. Misregulation of LOC391533, LOC284100, and CEACAMP8 might contribute to the mechanism underlying preeclampsia. Taken together, this study may provide potential targets for the future treatment of preeclampsia and novel insights into preeclampsia biology.     

Confocal Comparison of Corneal Reinnervation after Small Incision Lenticule Extraction (SMILE) and Femtosecond Laser In Situ Keratomileusis (FS-LASIK)

Purpose

To evaluate corneal reinnervation, and the corresponding corneal sensitivity and keratocyte density after small incision lenticule extraction (SMILE) and femtosecond laser in situ keratomileusis (FS-LASIK).

Methods

In this prospective, non-randomized observational study, 18 patients (32 eyes) received SMILE surgery, and 22 patients (42 eyes) received FS-LASIK surgery to correct myopia. The corneal subbasal nerve density and microscopic morphological changes in corneal architecture were evaluated by confocal microscopy prior to surgery and at 1 week, 1 month, 3 months, and 6 months after surgery. A correlation analysis was performed between subbasal corneal nerve density and the corresponding keratocyte density and corneal sensitivity.

Results

The decrease in subbasal nerve density was less severe in SMILE-treated eyes than in FS-LASIK-treated eyes at 1 week (P = 0.0147), 1 month (P = 0.0243), and 3 months (P = 0.0498), but no difference was detected at the 6-month visit (P = 0.5277). The subbasal nerve density correlated positively with central corneal sensitivity in both groups (r = 0.416, P<0.0001, and r = 0.2567, P = 0.0038 for SMILE group and FS-LASIK group, respectively). The SMILE-treated eyes have a lower risk of developing peripheral empty space with epithelial cells filling in (P = 0.0005).

Conclusions

The decrease in subbasal nerve fiber density was less severe in the SMILE group than the FS-LASIK group in the first 3 months following the surgeries. The subbasal nerve density was correlated with central corneal sensitivity.     

Ab Initio Modeling and Experimental Assessment of Janus Kinase 2 (JAK2) Kinase-Pseudokinase Complex Structure

The Janus Kinase 2 (JAK2) plays essential roles in transmitting signals from multiple cytokine receptors, and constitutive activation of JAK2 results in hematopoietic disorders and oncogenesis. JAK2 kinase activity is negatively regulated by its pseudokinase domain (JH2), where the gain-of-function mutation V617F that causes myeloproliferative neoplasms resides. In the absence of a crystal structure of full-length JAK2, how JH2 inhibits the kinase domain (JH1), and how V617F hyperactivates JAK2 remain elusive. We modeled the JAK2 JH1–JH2 complex structure using a novel informatics-guided protein-protein docking strategy. A detailed JAK2 JH2-mediated auto-inhibition mechanism is proposed, where JH2 traps the activation loop of JH1 in an inactive conformation and blocks the movement of kinase αC helix through critical hydrophobic contacts and extensive electrostatic interactions. These stabilizing interactions are less favorable in JAK2-V617F. Notably, several predicted binding interfacial residues in JH2 were confirmed to hyperactivate JAK2 kinase activity in site-directed mutagenesis and BaF3/EpoR cell transformation studies. Although there may exist other JH2-mediated mechanisms to control JH1, our JH1–JH2 structural model represents a verifiable working hypothesis for further experimental studies to elucidate the role of JH2 in regulating JAK2 in both normal and pathological settings.     

Dexamethasone Inhibits Repair of Human Airway Epithelial Cells Mediated by Glucocorticoid-Induced Leucine Zipper (GILZ)

Background

Glucocorticoids (GCs) are a first-line treatment for asthma for their anti-inflammatory effects, but they also hinder the repair of airway epithelial injury. The anti-inflammatory protein GC-induced leucine zipper (GILZ) is reported to inhibit the activation of the mitogen-activated protein kinase (MAPK)-extracellular-signal-regulated kinase (ERK) signaling pathway, which promotes the repair of airway epithelial cells around the damaged areas. We investigated whether the inhibition of airway epithelial repair imposed by the GC dexamethasone (DEX) is mediated by GILZ.

Methods

We tested the effect of DEX on the expressions of GILZ mRNA and GILZ protein and the MAPK-ERK signaling pathway in human airway epithelial cells, via RT-PCR and Western blot. We further evaluated the role of GILZ in mediating the effect of DEX on the MAPK-ERK signaling pathway and in airway epithelium repair by utilizing small-interfering RNAs, MTT, CFSE labeling, wound-healing and cell migration assays.

Results

DEX increased GILZ mRNA and GILZ protein levels in a human airway epithelial cell line. Furthermore, DEX inhibited the phosphorylation of Raf-1, Mek1/2, Erk1/2 (components of the MAPK-ERK signaling pathway), proliferation and migration. However, the inhibitory effect of DEX was mitigated in cells when the GILZ gene was silenced.

Conclusions

The inhibition of epithelial injury repair by DEX is mediated in part by activation of GILZ, which suppressed activation of the MAPK-ERK signaling pathway, proliferation and migration. Our study implicates the involvement of DEX in this process, and furthers our understanding of the dual role of GCs.     

The Association between Leptin Level and Breast Cancer: A Meta-Analysis

Background

Contradictory results have been reported regarding the association between leptin level and breast cancer. Therefore, a meta-analysis was performed to investigate this issue.

Methods

Published literature from PubMed and the Chinese National Knowledge Infrastructure (CNKI) Database was retrieved. This study was performed based on different cases and control groups. The combined effect () with 95% confidence interval (CI) was calculated using fixed-effects or random-effects model analysis.

Results

Overall, the mean serum leptin level of case groups was significantly higher than that of control groups. A) For 9 studies comparing breast cancer cases and healthy controls the combined effect was 0.58 with 95% CI (0.48, 0.68). B) For 4 studies comparing premenopausal breast cancer cases and healthy controls the was 0.32 (0.12, 0.52). C) For 5 studies comparing postmenopausal cases and healthy controls the was 0.65 (0.46, 0.84). D) For 4 studies comparing breast cancer cases and breast benign controls the was 0.38 (0.17, 0.59). E) For 2 studies comparing premenopausal breast cancer cases and breast benign controls the was 0.33 (-0.25, 0.91). F) For 6 studies comparing postmenopausal breast cancer cases and breast benign controls the was 0.39 (0.19, 0.60). G) For 4 studies comparing lymph node metastasis positive cases and negative controls the was 0.72 (0.45, 1.00). H) For 3 studies comparing breast benign cases and healthy controls the was 0.71 (0.41, 1.01).

Conclusion

This meta-analysis suggests that leptin level plays a role in breast cancer and has potential for development as a diagnostic tool.