Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

腹腔镜胆囊切除术对胆道结石合并糖尿病患者肠屏障功能的影响

目的观察胆道结石合并糖尿病患者腹腔镜胆囊切除术(LC)后肠屏障功能的变化。方法将择期行LC的126例患者分为糖尿病组41例和非糖尿病组85例。术前及术后第1、3天,采用高效液相色谱法检测尿乳果糖与甘露醇比值(L/M),并采用酶联免疫吸附法(ELISA)检测尿脂肪酸结合蛋白(IFABP)及血清D-乳酸水平。结果2组患者均成功完成手术,无中转开放手术者。糖尿病组术后肛门排气时间长于非糖尿病组,差异有统计学意义(P<0.05)。糖尿病组术后第1、3天尿L/M、血清D-乳酸、尿IFABP均高于术前及非糖尿病组,差异均有统计学意义(P<0.05)。结论合并糖尿病的胆道结石患者行LC后会加重肠屏障功能障碍程度,术前控制好血糖水平或可降低肠道功能损伤的严重程度。     

Does a high Mandard score really define a poor response to chemotherapy in oesophageal adenocarcinoma?

Background A high Mandard score implies a non-response to chemotherapy in oesophageal adenocarcinoma. However, some patients exhibit tumour volume reduction and a nodal response despite a high score. This study examines survival and recurrence patterns in these patients.Methods Clinicopathological factors were analysed using multivariable Cox regression assessing time to death and recurrence. Computed tomography-estimated tumour volume change was examined in a subgroup of consecutive patients.Results Five hundred and fifty-five patients were included. Median survival was 55 months (Mandard 1–3) and 21 months (Mandard 4 and 5). In the Mandard 4 and 5 group (332 patients), comparison between complete nodal responders and persistent nodal disease showed improved survival (90 vs 18 months), recurrence rates (locoregional 14.75 vs 28.74%, systemic 24.59 vs 48.42%) and circumferential resection margin positivity (22.95 vs 68.11%). Complete nodal response independently predicted improved survival (hazard ratio 0.34 (0.16–0.74). Post-chemotherapy tumour volume reduction was greater in patients with a complete nodal response (−16.3 vs −7.7 cm³, p = 0.033) with no significant difference between Mandard groups.Conclusion Patients with a complete nodal response to chemotherapy have significantly improved outcomes despite a poor Mandard score. High Mandard score does not correspond with a non-response to chemotherapy in all cases and patients with nodal downstaging may still benefit from adjuvant chemotherapy.Subject terms: Oesophageal cancer, Surgical oncology     

氨溴特罗片辅助治疗小儿支原体肺炎的疗效及对机体免疫功能、炎症因子的影响

目的 观察氨溴特罗片辅助治疗小儿支原体肺炎的疗效,探讨其对机体免疫功能、炎症因子的影响.方法 纳入2018年2月至2019年3月西北大学附属神木医院收治的支原体肺炎患儿158例,按照随机数字表法随机分为对照组和观察组,各79例.对照组给予阿奇霉素及对症支持治疗,观察组在对照组基础上加用氨溴特罗片治疗.观察两组总有效率,分析、比较两组治疗前后免疫功能(CD3+、CD4+、CD8+水平)、炎症因子[白细胞介素(IL)-17、单核细胞趋化蛋白-4(MCP-4)、巨噬细胞衍生趋化因子(MDC)]水平,以及核因子-κB(NF-κB)、可溶性髓系细胞触发受体1(sTREM-1)水平变化情况,对比两组不良反应发生情况.结果 观察组总有效率为96.20％,显著高于对照组的86.07％(P<0.05).治疗后两组患儿NF-κB、sTREM-1水平均低于治疗前(P<0.05),治疗后观察组患儿NF-κB、sTREM-1水平低于对照组(P<0.05).治疗后两组IL-17、MCP-4、MDC水平均低于治疗前(P<0.05),治疗后观察组患儿IL-17、MCP-4、MDC水平低于对照组(P<0.05).治疗后两组患儿CD3+、CD4+水平均高于治疗前(P<0.05),CD8+水平均低于治疗前(P<0.05),治疗后观察组患儿CD3+、CD4+水平高于对照组(P<0.05),CD8+水平低于对照组(P<0.05).两组均未发生明显药物相关不良反应.结论 氨溴特罗片辅助治疗小儿支原体肺炎疗效确切,可降低患儿NF-κB、sTREM-1水平,能通过减轻炎性反应、提高免疫功能而发挥作用,安全性良好.     

The Using of Concrete Wash Water from Ready Mixed Concrete Plants in Cement Systems

Concrete plants accumulate large amounts of concrete wash water. This water, which pH is highly alkaline, has a negative impact on the environment. Its reuse in fresh concrete slightly reduces its mechanical properties. The combination of concrete wash water and zeolitic by-product led to an increase of 4.6% in the compressive strength at 7 days hydration and up to 30% at 28 days hydration. The same combination led to the denser microstructure compared to the samples made with concrete wash water. This could be explained by the pozzolanic reaction of the zeolitic by-product. The complex chemical reactions of cement, zeolitic by-product, and fines presented in the concrete wash water occurred. Therefore, it was suggested the reusing method of concrete wash water together with zeolitic by-product in the fresh concrete mixtures by substituting some amount of tap water with concrete wash water. In this way, the consumption of tap water is possible to reduce in cement systems.     

TGFβ promotes YAP‐dependent AXL induction in mesenchymal‐type lung cancer cells

The acquisition of chemoresistance remains a major cause of cancer mortality due to the limited accessibility of targeted or immune therapies. However, given that severe alterations of molecular features during epithelial‐to‐mesenchymal transition (EMT) lead to acquired chemoresistance, emerging studies have focused on identifying targetable drivers associated with acquired chemoresistance. Particularly, AXL, a key receptor tyrosine kinase that confers resistance against targets and chemotherapeutics, is highly expressed in mesenchymal cancer cells. However, the underlying mechanism of AXL induction in mesenchymal cancer cells is poorly understood. Our study revealed that the YAP signature, which was highly enriched in mesenchymal‐type lung cancer, was closely correlated to AXL expression in 181 lung cancer cell lines. Moreover, using isogenic lung cancer cell pairs, we also found that doxorubicin treatment induced YAP nuclear translocation in mesenchymal‐type lung cancer cells to induce AXL expression. Additionally, the concurrent activation of TGFβ signaling coordinated YAP‐dependent AXL expression through SMAD4. These data suggest that crosstalk between YAP and the TGFβ/SMAD axis upon treatment with chemotherapeutics might be a promising target to improve chemosensitivity in mesenchymal‐type lung cancer.

Abbreviations

AUC

area under the curve

AXL

AXL receptor tyrosine kinase

BCL2

B‐cell lymphoma 2

CTD2

cancer target discovery and development

CTGF

connective tissue growth factor

DEG

differentially expressed genes

DOXO

doxorubicin

EMT

epithelial–mesenchymal transition

Eto

etoposide

FDA

Food and Drug Administration

ITGB3

integrin beta‐3

MAPK

mitogen‐activated protein kinase

MMP2

matrix metalloproteinase‐2

MMP9

matrix metalloproteinase‐9

mRNA

messenger RNA

NF‐κB

nuclear factor kappa‐light‐chain‐enhancer of activated B cells

SBE

SMAD binding element

SERPINE1

serpin family E member 1

siRNA

small interfering RNA

ssGSEA

single‐sample gene set enrichment analysis

TCGA

The Cancer Genome Atlas

TGFβ

transforming growth factor beta

YAP

Yes‐associated protein

YAP8SA

mutants of inhibitory phosphorylation site at eight serine to Alanine of YAP

ZEB1

zinc finger E‐box binding homeobox 1

ZEB2

zinc finger E‐box‐binding homeobox 2

     

Myeloid-derived suppressor cell (MDSC) key genes analysis in rat anti-CD28-induced immune tolerance kidney transplantation

BackgroundIn the field of transplantation, inducing immune tolerance in recipients is of great importance. Blocking co-stimulatory molecule using anti-CD28 antibody could induce tolerance in a rat kidney transplantation model. Myeloid-derived suppressor cells (MDSCs) reveals strong immune suppressive abilities in kidney transplantation. Here we analyzed key genes of MDSCs leading to transplant tolerance in this model.MethodsMicroarray data of rat gene expression profiles under accession number {"type":"entrez-geo","attrs":{"text":"GSE28545","term_id":"28545"}}GSE28545 in the Gene Expression Omnibus (GEO) database were analyzed. Running the LIMMA package in R language, the differentially expressed genes (DEGs) were found. Enrichment analysis of the DEGs was conducted in the Database for Annotation, Visualization and Integrated Discovery (DAVID) database to explore gene ontology (GO) annotation and their Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Their protein-protein interactions (PPIs) were provided by STRING database and was visualized in Cytoscape. Hub genes were carried out by CytoHubba.ResultsThree hundred and thirty-eight DEGs were exported, including 27 upregulated and 311 downregulated genes. The functions and KEGG pathways of the DEGs were assessed and the PPI network was constructed based on the string interactions of the DEGs. The network was visualized in Cytoscape; the entire PPI network consisted of 192 nodes and 469 edges. Zap70, Cdc42, Stat1, Stat4, Ccl5 and Cxcr3 were among the hub genes.ConclusionsThese key genes, corresponding proteins and their functions may provide valuable background for both basic and clinical research and could be the direction of future studies in immune tolerance, especially those examining immunocyte-induced tolerance.