IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta-Analysis

Background

Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.

Methodology and Principal Findings

An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.

Conclusion

Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.     

A Comparison of Methods for Clustering 16S rRNA Sequences into OTUs

Recent studies of 16S rRNA sequences through next-generation sequencing have revolutionized our understanding of the microbial community composition and structure. One common approach in using these data to explore the genetic diversity in a microbial community is to cluster the 16S rRNA sequences into Operational Taxonomic Units (OTUs) based on sequence similarities. The inferred OTUs can then be used to estimate species, diversity, composition, and richness. Although a number of methods have been developed and commonly used to cluster the sequences into OTUs, relatively little guidance is available on their relative performance and the choice of key parameters for each method. In this study, we conducted a comprehensive evaluation of ten existing OTU inference methods. We found that the appropriate dissimilarity value for defining distinct OTUs is not only related with a specific method but also related with the sample complexity. For data sets with low complexity, all the algorithms need a higher dissimilarity threshold to define OTUs. Some methods, such as, CROP and SLP, are more robust to the specific choice of the threshold than other methods, especially for shorter reads. For high-complexity data sets, hierarchical cluster methods need a more strict dissimilarity threshold to define OTUs because the commonly used dissimilarity threshold of 3% often leads to an under-estimation of the number of OTUs. In general, hierarchical clustering methods perform better at lower dissimilarity thresholds. Our results show that sequence abundance plays an important role in OTU inference. We conclude that care is needed to choose both a threshold for dissimilarity and abundance for OTU inference.     

Splicing Factor Transformer-2β (Tra2β) Regulates the Expression of Regulator of G Protein Signaling 4 (RGS4) Gene and Is Induced by Morphine

Regulator of G protein signaling 4 (RGS4) is a critical modulator of G protein-coupled receptor (GPCR)-mediated signaling and plays important roles in many neural process and diseases. Particularly, drug-induced alteration in RGS4 protein levels is associated with acute and chronic effects of drugs of abuse. However, the precise mechanism underlying the regulation of RGS4 expression is largely unknown. Here, we demonstrated that the expression of RGS4 gene was subject to regulation by alternative splicing of the exon 6. Transformer-2β (Tra2β), an important splicing factor, bound to RGS4 mRNA and increased the relative level of RGS4-1 mRNA isoform by enhancing the inclusion of exon 6. Meanwhile, Tra2β increased the expression of full-length RGS4 protein. In rat brain, Tra2β was co-localized with RGS4 in multiple opioid action-related brain regions. In addition, the acute and chronic morphine treatment induced alteration in the expression level of Tra2β in rat locus coerulus (LC) in parallel to that of RGS4 proteins. It suggests that induction of this splicing factor may contribute to the change of RGS4 level elicited by morphine. Taken together, the results provide the evidence demonstrating the function of Tra2β as a new mediator in opioid-induced signaling pathway via regulating RGS4 expression.     

Localized Retinal Nerve Fiber Layer Defects Detected by Optical Coherence Tomography: The Beijing Eye Study

Objective

To assess the prevalence of localized retinal nerve fiber layer defects (LRNFLD) and associated factors in adult Chinese.

Methods

The population-based Beijing Eye Study 2011 included 3468 individuals (mean age: 64.6±9.8 years (range: 50–93 years)). The study participants underwent a detailed ophthalmological examination including spectral-domain optical coherence tomography (Spectralis^R-OCT) assisted measurement of the RNFL. A LRNFLD was defined as a sector in which the RNFL contour line dipped into the red zone for a length of <180°.

Results

Readable OCT images were available for 3242 (93.5%) subjects. LRNFLDs were detected in 640 eyes (9.9±0.4%) of 479 subjects (14.8±0.6%). In the age groups of 50–59 years, 60–69 years, 70–79 years, and 80+ years, the prevalence of LRNFLD per person increased from 9.9±0.9%, 11.6±1.0% and 20.6±1.4% to 33.0±3.2%, respectively. In multivariate analysis, prevalence of LRNFLDs was significantly associated with older age (P = 0.001; Odds Ratio (OR): 1.03; 95% Confidence Interval (CI): 1.01,1.05), myopic refractive error (P<0.001;OR:0.79;95%CI:0.74,0.85), larger beta zone of parapapillary atrophy (P<0.001; OR:1.34;95%CI:1.20,1.50), presence of glaucomatous optic neuropathy (P<0.001;OR:7.02;95%CI:3.87,12.7), presence of non-glaucomatous optic nerve damage (P = 0.001;OR:43.3;95%CI:8.24,227.1), and presence of diabetic retinopathy (P = 0.003;OR:2.79;95%CI:1.43,5.44).

Conclusions

OCT-defined LRNFLDs were present in a prevalence of 14.8±0.6% in a population-based study sample of subjects aged 50+ years. Prevalence of LRNFLDs increased with higher age, myopic refractive error, and larger parapapillary beta zone. Major ocular diseases associated with LRNFLs were glaucoma, non-glaucomatous optic nerve damage and diabetic retinopathy. These data may be helpful for a semiautomatic assessment of the RNFL.     

Association between Telomere Length and Type 2 Diabetes Mellitus: A Meta-Analysis

Background

Several epidemiological studies have examined the association between shortened telomere length and type 2 diabetes mellitus (T2DM), while the results remained conflicting. We conducted a meta-analysis to derive a more precise estimation of the relationship between them.

Methods

We systematically reviewed the databases of PubMed, EMBASE, and Web of Science for all studies on the association between telomere length and T2DM. We conducted this study assessed by STATA 11.0. Data were summarized using random-effects or fixed-effects meta-analysis. The heterogeneity and publication bias among studies were examined by using χ²-based Q statistic test and Egger’s test, respectively.

Results

Nine cohorts consisting of 5759 cases and 6518 controls were selected into the meta-analysis. The results indicated that shortened telomere length was significantly associated with T2DM risk (OR: 1.291; 95% CI: 1.112, 1.498; P<0.001) with heterogeneity (I² = 71.6%). When three cohorts responsible for the heterogeneity were excluded, the pooled OR for the remaining cohorts indicated a significant association between shortened telomere length and T2DM (OR: 1.117; 95% CI: 1.002, 1.246; P = 0.045) without heterogeneity.

Conclusion

We found a statistically significant association between shortened telomere length and T2DM.     

MicroRNA-221 Mediates the Effects of PDGF-BB on Migration,Proliferation, and the Epithelial-Mesenchymal Transition in Pancreatic Cancer Cells

The platelet-derived growth factor (PDGF) signaling pathway has been found to play important roles in the development and progression of human cancers by regulating the processes of cell proliferation, apoptosis, migration, invasion, metastasis, and the acquisition of the epithelial-mesenchymal transition (EMT) phenotype. Moreover, PDGF signaling has also been found to alter the expression profile of miRNAs, leading to the reversal of EMT phenotype. Although the role of miRNAs in cancer has been documented, there are very few studies documenting the cellular consequences of targeted re-expression of specific miRNAs. Therefore, we investigated whether the treatment of human pancreatic cancer cells with PDGF could alter the expression profile of miRNAs, and we also assessed the cellular consequences. Our study demonstrates that miR-221 is essential for the PDGF-mediated EMT phenotype, migration, and growth of pancreatic cancer cells. Down-regulation of TRPS1 by miR-221 is critical for PDGF-mediated acquisition of the EMT phenotype. Additionally, the PDGF-dependent increase in cell proliferation appears to be mediated by inhibition of a specific target of miR-221 and down-regulation of p27Kip1.     

Ursolic Acid Inhibits Adipogenesis in 3T3-L1 Adipocytes through LKB1/AMPK Pathway

Background

Ursolic acid (UA) is a triterpenoid compound with multiple biological functions. This compound has recently been reported to possess an anti-obesity effect; however, the mechanisms are less understood.

Objective

As adipogenesis plays a critical role in obesity, the present study was conducted to investigate the effect of UA on adipogenesis and mechanisms of action in 3T3-L1 preadipocytes.

Methods and Results

The 3T3-L1 preadipocytes were induced to differentiate in the presence or absence of UA for 6 days. The cells were determined for proliferation, differentiation, fat accumulation as well as the protein expressions of molecular targets that regulate or are involved in fatty acid synthesis and oxidation. The results demonstrated that ursolic acid at concentrations ranging from 2.5 µM to 10 µM dose-dependently attenuated adipogenesis, accompanied by reduced protein expression of CCAAT element binding protein β (C/EBP_β), peroxisome proliferator-activated receptor γ (PPAR_γ), CCAAT element binding protein α (C/EBP_α) and sterol regulatory element binding protein 1c (SREBP-1c), respectively. Ursolic acid increased the phosphorylation of acetyl-CoA carboxylase (ACC) and protein expression of carnitine palmitoyltransferase 1 (CPT1), but decreased protein expression of fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4). Ursolic acid increased the phosphorylation of AMP-activated protein kinase (AMPK) and protein expression of (silent mating type information regulation 2, homolog) 1 (Sirt1). Further studies demonstrated that the anti-adipogenic effect of UA was reversed by the AMPK siRNA, but not by the Sirt1 inhibitor nicotinamide. Liver kinase B1 (LKB1), the upstream kinase of AMPK, was upregulated by UA. When LKB1 was silenced with siRNA or the inhibitor radicicol, the effect of UA on AMPK activation was diminished.

Conclusions

Ursolic acid inhibited 3T3-L1 preadipocyte differentiation and adipogenesis through the LKB1/AMPK pathway. There is potential to develop UA into a therapeutic agent for the prevention or treatment of obesity.     

Salt-Restriction-Spoon Improved the Salt Intake among Residents in China

Objective

To evaluate the effect of an improved salt-restriction spoon on the attitude of salt-restriction, the using rate of salt-restriction-spoon, the actual salt intake, and 24-hour urinary sodium excretion (24HUNa).

Design

A community intervention study.

Setting

Two villages in Beijing.

Participants

403 local adult residents being responsible for home cooking.

Intervention

Participants were randomly assigned to the intervention group or the control group. Those in the intervention group were provided with an improved salt-restriction-spoon and health education, and were informed of their actual salt intake and 24HUNa. Not any intervention was given to those in the control group.

Main Outcome Measures

The scores on the variables of Health Belief Model, the using rate of salt-restriction-spoon, the actual salt intake, and 24HUNa.

Analysis

Covariance analyses, Chi-square tests, Student’s t tests, and repeated measures analyses of variance.

Results

After 6 months of intervention, the intervention group felt significantly less objective barriers, and got access to significantly more cues to action as compared to the control group. The using rate and the correctly using rate of salt-restriction-spoon were significantly higher in the intervention group. The daily salt intake decreased by 1.42 g in the intervention group and by 0.28 g in the control group, and repeated measures analysis of variance showed significant change over time (F = 7.044, P<0.001) and significant difference between groups by time (F = 2.589, P = 0.041). The 24HUNa decreased by 34.84 mmol in the intervention group and by 33.65 mmol in the control group, and repeated measures analysis of variance showed significant change over time (F = 14.648, P<0.001) without significant difference between groups by time (F = 0.222, P = 0.870).

Conclusions

The intervention effect was acceptable, therefore, the improved salt-restriction-spoon and corresponding health education could be considered as an alternative for salt reduction strategy in China and other countries where salt intake comes mainly from home cooking.     

Effects of Tidal Action on Pollination and Reproductive Allocation in an Estuarine Emergent Wetland Plant–Sagittaria graminea (Alismataceae)

In estuarine wetlands, the daily periodic tidal activity has a profound effect on plant growth and reproduction. We studied the effects of tidal action on pollination and reproductive allocation of Sagittaria graminea. Results showed that the species had very different reproductive allocation in tidal and non-tidal habitats. In the tidal area, seed production was only 9.7% of that in non-tidal habitat, however, plants produced more male flowers and nearly twice the corms compared to those in non-tidal habitat. An experiment showed that the time available for effective pollination determined the pollination rate and pollen deposition in the tidal area. A control experiment suggested that low pollen deposition from low visitation frequency is not the main cause of very low seed sets or seed production in this plant in tidal habitat. The negative effects of tides (water) on pollen germination may surpass the influence of low pollen deposition from low visitation frequency. The length of time from pollen deposition to flower being submerged by water affected pollen germination rate on stigmas; more than three hours is necessary to allow pollen germination and complete fertilization to eliminate the risk of pollen grains being washed away by tidal water.