Maternally Expressed Gene 3 (MEG3) is an imprinted gene that encodes a long non-coding RNA (lncRNA) associated with tumorigenesis. Autophagy is activated in cancer cells and contributes to tumor cell survival. However, little is known about whether MEG3 regulates bladder cancer development by controlling autophagy. In the study, we found that MEG3 levels were significantly reduced in bladder cancer tissues compared with normal controls, and autophagy activity was increased in bladder cancer tissues. A significant negative correlation was observed between MEG3 levels and LC3-II (autophagy marker) levels in vivo. We further demonstrated that MEG3 markedly suppressed autophagy activation, whereas MEG3 knockdown activated autophagy in human bladder cancer cell lines. Downregulated expression of MEG3 inhibited cell apoptosis, whereas autophagy inhibition increased MEG3-knockdown cell apoptosis. MEG3 knockdown also increased cell proliferation. More importantly, autophagy inhibition abrogated MEG3 knockdown-induced cell proliferation. These data demonstrated that downregulated MEG3 activates autophagy and increases cell proliferation in bladder cancer.

Introduction Although the new classification of premature ejaculation (PE) has been proposed by Waldinger et al., there have been few studies investigating the four PE syndromes in China. Aims We investigated the prevalence and factors associated with the complaint of PE and the four PE syndromes in Anhui province, China. Methods Between September 2011 and September 2012, subjects were selected from five cities in Anhui province, China. They participated in this survey by completing a detailed verbal questionnaire regarding their demographic data and medical and sexual history. Men with PE complaint were diagnosed as lifelong PE (LPE), acquired PE (APE), natural variable PE (NVPE), or premature-like ejaculatory dysfunction (PLED). Main Outcome Measures PE complaint was divided into four PE syndromes. Anxiety, depression, and erectile dysfunction were independently assessed by the self-rating anxiety/depression scale and the international index of erectile function-5, respectively. Results Of the 3,016 men evaluated, 25.80% complained of PE. The distribution of the four PE syndromes in men with PE complaint was in the order of NVPE (44.09%), PLPE (24.81%), APE (18.77%), and LPE (12.34%). Patients with PE complaint were older and more likely to smoke, had more comorbidities, and a higher body mass index (BMI) than patients without the complaint (P < 0.001 for all). Similar findings were also observed in patients with APE compared with other PE patients (depression P = 0.012, cardiovascular P = 0.003, others P < 0.001). In addition, the rates of counseling by a doctor in men with LPE and APE were higher than those in men with NVPE and PLED (P < 0.001). Conclusion The prevalence of PE complaint in male population of Anhui province, China, was 25.80%, with the highest PE syndromes being NVPE and PLPE. Patients with PE complaint or APE were older and more likely to smoke, had more comorbidities, and a higher BMI.

Cerebral palsy (CP), a neurodevelopmental disorder characterized by irreversible, nonprogressive central motor dysfunction, is commonly associated with prematurity or perinatal brain injury. However, accumulating evidence suggests deleterious genomic variants may contribute to CP in addition to environmental insults. To identify genes contributing to risk for CP, we performed whole-exome sequencing on 250 parent-offspring CP trios. We identified a significant contribution of damaging de novo mutations (DNMs), especially in genes that are intolerant to loss of function mutations. Eight genes had multiple, independently-arising damaging DNMs, including two novel CP-associated genes, FBXO31 and RHOB, and four genes previously implicated in cerebral palsy phenotypes, TUBA1A, CTNNB1, SPAST, and ATL1. Functional experiments, including molecular and biochemical assays and patient fibroblast studies indicate that the recurrent RHOB mutation identified in patients enhances Rho effector binding in the active state and that the FBXO31 mutation leads to elevated levels of cyclin D. Analysis of candidate CP risk genes highlighted genetic overlap with hereditary spastic paraplegia as well as intellectual disability, autism, and epilepsy, converging with epidemiologic findings. Computational network analysis of risk genes identified significant enrichment of Rho GTPase, extracellular matrix, focal adhesions, cytoskeleton, and cell projection pathways. CP risk genes in Rho GTPase, cytoskeleton and cell projection pathways were found to play an important role in neuromotor development via a Drosophila reverse genetics screen. Based on enrichment analysis, we estimate that an excess of damaging de novo and inherited recessive variants collectively account for ~14% of the cases in our cohort, whereas perinatal asphyxia is currently estimated to occur in 8-10% of CP cases. Together, these findings provide evidence for the role of genetically-mediated dysregulation of early brain connectivity in CP.

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ObjectiveTo evaluate the efficacy and safety of repeated low‐dose human recombinant erythropoietin (rhEPO) in the improvement of neurological outcomes in very preterm infants.MethodsA total of 800 infants of ≤32‐week gestational age who had been in an intensive care unit within 72 hours after birth were included in the trial between January 2009 and June 2013. Preterm infants were randomly assigned to receive rhEPO (500IU/kg; n = 366) or placebo (n = 377) intravenously within 72 hours after birth and then once every other day for 2 weeks. The primary outcome was death or moderate to severe neurological disability assessed at 18 months of corrected age.ResultsDeath and moderate/severe neurological disability occurred in 91 of 338 very preterm infants (26.9%) in the placebo group and in 43 of 330 very preterm infants (13.0%) in the rhEPO treatment group (relative risk [RR] = 0.40, 95% confidence interval [CI] = 0.27–0.59, p < 0.001) at 18 months of corrected age. The rate of moderate/severe neurological disability in the rhEPO group (22 of 309, 7.1%) was significantly lower compared to the placebo group (57 of 304, 18.8%; RR = 0.32, 95% CI = 0.19–0.55, p < 0.001), and no excess adverse events were observed.InterpretationRepeated low‐dose rhEPO treatment reduced the risk of long‐term neurological disability in very preterm infants with no obvious adverse effects. Ann Neurol 2016;80:24–34