m6A结合蛋白IGF2BP1在肝细胞癌中的基因调控网络分析

目的 分析m6A阅读器胰岛素样生长因子2-mRNA结合蛋白1（insulin-like growth factor 2 mRNA-binding protein 1，IGF2BP1）在肝细胞癌（hepatocellular carcinoma，HCC）中的表达水平及其对HCC患者预后的影响，并探讨IGF2BP1在HCC发生发展中的作用及其潜在机制。方法 基于5对HCC癌及相应癌旁组织mRNA-seq数据和TCGA数据库LIHC的mRNA-seq数据综合分析IGF2BP1在HCC中的表达情况，同时利用TCGA数据库中343例HCC患者的临床随访资料分析IGF2BP1表达水平对HCC患者总生存期的影响。基于TCGA数据库筛选IGF2BP1的共表达mRNA，并利用m6Avar在线网站预测mRNA的m6A位点及其RNA结合蛋白等信息，最终构建IGF2BP1的基因调控网络。结果 IGF2BP1基因在HCC中表达上调（log2FC HCC转录组数据=10.684，P<0.001；log2FC TCGA-LIHC数据集=7.032，P<0.001）。生存分析显示IGF2BP1低表达的HCC患者中位生存时间为5.84年，IGF2BP1高表达患者为4.44年，高表达患者总生存期缩短（P=0.011）。22个差异表达的mRNA与IGF2BP1存在靶向结合关系，并与其表达水平呈正相关。其中，HMGA2等15个高表达mRNA的HCC患者总生存期缩短。HMGA2、PEG10、CEP55、RHO、CDC6和KIF23基因中的潜在m6A甲基化位点位于mRNA 3'UTR端的miRNA结合区域。结论 IGF2BP1在HCC中高表达且导致患者总生存期缩短。IGF2BP1可能通过m6A甲基化及miRNA抑制作用的方式上调mRNA的表达，促进HCC发生并导致不良预后。     

滋阴清热方治疗对甲状腺功能亢进症阴虚火旺证患者疗效、血浆内皮素-1、炎症因子和免疫功能的影响

目的:研究滋阴清热方治疗对甲状腺功能亢进症阴虚火旺证患者疗效、血浆内皮素-1、炎症因子和免疫功能的影响。方法:将广州市花都区妇幼保健院收治的100例甲状腺功能亢进症阴虚火旺证患者分成观察组和对照组。对照组:给患者使用常规药物治疗;观察组:在对照组的基础上,给予滋阴清热方治疗。干预后,比较两组患者的临床疗效、血浆内皮素-1(Endothelin,ET)、炎症因子[白介素-2(Interleukin-2,IL-2)、白介素-8(Interleukin-8,IL-8)]及肿瘤坏死因子(Tumour Necrosis Factor-α,TNF-α)和免疫功能(CD3^+、CD4^+、CD8^+及CD4^+/CD8^+)。结果:干预前,两组患者IL-2、IL-8及TNF-α无变化,差异无统计学意义(P>0.05);干预后,观察组患者的IL-2比对照组高,且对照组的IL-8及TNF-α比观察组的高,P<0.05,差异有统计学意义;干预前,两组患者的CD3^+、CD4^+、CD8^+及CD4^+/CD8^+与ET无变化;干预后,观察组的CD3^+、CD4^+、CD8+及CD4^+/CD8^+比对照组高,P <0.05,差异有统计学意义,且观察组的ET低于对照组且观察组总有效率明显高于对照组。结论:滋阴清热方治疗降低了血浆内皮素-1,减少炎症的出现,提高免疫功能。     

Association between de novo lipogenesis susceptibility genes and coronary artery disease

Background and aimsCoronary artery disease (CAD) is the principal cause of death in individuals with non-alcoholic fatty liver disease (NAFLD). The aim of this study was to use genetic epidemiology to study the association between de novo lipogenesis (DNL), one of the major pathways leading to NAFLD, and CAD risk.Methods and resultsDNL susceptibility genes were used as instruments and selected using three approaches: 1) genes that are associated with both high serum triglycerides and low sex hormone-binding globulin, both downstream consequences of DNL (unbiased approach), 2) genes that have a known role in DNL (biased approach), and 3) genes that have been associated with serum fatty acids, used as a proxy of DNL. Gene-CAD effect estimates were retrieved from the meta-analysis of CARDIoGRAM and the UK Biobank (～76014 cases and ～264785 controls). Effect estimates were clustered using a fixed-effects meta-analysis. Twenty-two DNL susceptibility genes were identified by the unbiased approach, nine genes by the biased approach and seven genes were associated with plasma fatty acids. Clustering of genes selected in the unbiased and biased approach showed a statistically significant association with CAD (OR:1.016, 95%CI:1.012; 1.020 and OR:1.013, 95%CI:1.007; 1.020, respectively), while clustering of fatty acid genes did not (OR:1.004, 95%CI:0.996–1.011). Subsequent exclusion of potential influential outliers did reveal a statistically significant association (OR:1.009, 95%CI:1.000; 1.018).ConclusionsDNL susceptibility genes are associated with an increased risk of CAD. These findings suggest that DNL may be involved in the pathogenesis of CAD and favor further development of strategies that target NAFLD through DNL.     

Loss of function,missense, and intronic variants in NOTCH1 confer different risks for left ventricular outflow tract obstructive heart defects in two European cohorts

Loss of function variants in NOTCH1 cause left ventricular outflow tract obstructive defects (LVOTO). However, the risk conferred by rare and noncoding variants in NOTCH1 for LVOTO remains largely uncharacterized. In a cohort of 49 families affected by hypoplastic left heart syndrome, a severe form of LVOTO, we discovered predicted loss of function NOTCH1 variants in 6% of individuals. Rare or low-frequency missense variants were found in 16% of families. To make a quantitative estimate of the genetic risk posed by variants in NOTCH1 for LVOTO, we studied associations of 400 coding and noncoding variants in NOTCH1 in 1,085 cases and 332,788 controls from the UK Biobank. Two rare intronic variants in strong linkage disequilibrium displayed significant association with risk for LVOTO amongst European-ancestry individuals. This result was replicated in an independent analysis of 210 cases and 68,762 controls of non-European and mixed ancestry. In conclusion, carrying rare predicted loss of function variants in NOTCH1 confer significant risk for LVOTO. In addition, the two intronic variants seem to be associated with an increased risk for these defects. Our approach demonstrates the utility of population-based data sets in quantifying the specific risk of individual variants for disease-related phenotypes.     

脂蛋白相关磷脂酶A2、胰岛素样生长因子-1与老年VD患者认知功能的关系及预测价值研究

目的 探讨脂蛋白相关磷脂酶A2（Lp-PLA2）、胰岛素样生长因子-1（IGF-1）与老年血管性痴呆（VD）患者认知功能的关系及预测价值。方法 选择2019 年3～6 月在我院接受治疗的VD 患者60 例为研究对象，同时选取同期在我院接受检查的健康者60 例为对照组，比较两组患者的Lp-PLA2、IGF-1、简易智力状态检查量表评分（MMSE）水平；采用Pearson 相关性分析法对Lp-PLA2、IGF-1 与MMSE 评分的相关性进行分析；采用受试者工作曲线（ROC）下面积（AUC）比较Lp-PLA2、IGF-1 对VD 的预测价值。结果 观察组患者的Lp-PLA2 水平明显高于对照组（P＜0.05），观察组患者的IGF-1、MMSE 评分明显低于对照组（P＜0.05）；Lp-PLA2 与MMSE 评分呈负相关性，IGF-1 与MMSE 评分呈正相关性；Lp-PLA2 与IGF-1 诊断VD 的AUC 值分别为0.940、0.954。结论Lp-PLA2 水平越低，IGF-1 水平越高，患者的认知功能越好，且Lp-PLA2、IGF-1 对老年VD 患者均具有较高的预测价值。     

Endoplasmic reticulum stress is involved in ventilator-induced lung injury in mice via the IRE1α-TRAF2-NF-κB pathway

Inflammation plays a critical role in the development of ventilator-induced lung injury (VILI). Endoplasmic reticulum (ER) stress is associated with a variety of diseases through the modulation of inflammatory responses. However, little is known about how ER stress is implicated in VILI. In this study, murine mechanical ventilation models were constructed. Total protein and inflammatory cytokines were measured in bronchoalveolar lavage fluid (BALF), and lung tissue injury was assessed by histology. Our data revealed that mice subjected to high tidal ventilation (TV) for 4 h showed more severe pulmonary edema and inflammation than those of mice with spontaneous breathing and low TV-treatment. In addition, the high TV-treated animals upregulated the ER stress markers GRP78, CHOP, p-IRE1α, TRAF2, and p-NF-κB expression at both the mRNA and protein levels in lung tissue. Administration of thapsigargin exacerbated the histological changes, inflammation and expression of GRP78 and CHOP after high TV, but treatment with ER stress and IRE1α kinase inhibitors attenuated the pathological damage and downregulated the high expression of GRP78, CHOP, p-IRE1α, TRAF2, and p-NF-κB, suggesting that ER stress is involved in VILI though the IRE1α/TRAF2/NF-κB signaling pathway in mice.     

Sensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review

ObjectiveSystematically review the abnormalities in event related potential (ERP) recorded in Rett Syndrome (RTT) patients and animals in search of translational biomarkers of deficits related to the particular neurophysiological processes of known genetic origin (MECP2 mutations).MethodsPubmed, ISI Web of Knowledge and BIORXIV were searched for the relevant articles according to PRISMA standards.ResultsERP components are generally delayed across all sensory modalities both in RTT patients and its animal model, while findings on ERPs amplitude strongly depend on stimulus properties and presentation rate. Studies on RTT animal models uncovered the abnormalities in the excitatory and inhibitory transmission as critical mechanisms underlying the ERPs changes, but showed that even similar ERP alterations in auditory and visual domains have a diverse neural basis. A range of novel approaches has been developed in animal studies bringing along the meaningful neurophysiological interpretation of ERP measures in RTT patients.ConclusionsWhile there is a clear evidence for sensory ERPs abnormalities in RTT, to further advance the field there is a need in a large-scale ERP studies with the functionally-relevant experimental paradigms.SignificanceThe review provides insights into domain-specific neural basis of the ERP abnormalities and promotes clinical application of the ERP measures as the non-invasive functional biomarkers of RTT pathophysiology.     

附加钢板技术治疗股骨干髓内钉术后骨不连的现状和研究进展

目的对附加钢板技术治疗股骨干髓内钉术后骨不连的历史、现状和进展进行综述。方法广泛查阅国内外关于附加钢板技术治疗股骨干髓内钉术后骨不连的临床研究文献，并进行综合分析。结果自 1997 年附加钢板技术已成功用于治疗股骨干髓内钉术后骨不连，根据原髓内钉是否失效，可分为保留原髓内钉和更换原髓内钉两类。该技术不仅适用于简单骨不连，还可用于合并严重畸形的复杂性骨不连。相比更换髓内钉、更换外侧钢板和双钢板技术，附加钢板技术手术创伤更小，骨折愈合时间更短，骨折愈合率更高，患者能更早重返社会和工作。然而，该技术也存在一些问题有待解决，包括双皮质螺钉固定困难、缺乏适合股骨干解剖型附加钢板以及缺乏术后功能和生活质量的评估研究。结论相比其他翻修固定方式，附加钢板技术能够获得更高的骨折愈合率和更好的临床预后。然而，术后患者能否在功能和生活质量方面进一步获益还有待证实。此外，还需要更高质量的临床对照研究深入证明其是否确实优于其他翻修固定方式。