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1.
DNA损伤是衰老相关疾病领域的研究热点, 可引起细胞周期停滞、凋亡, 加快个体衰老速度、增加衰老相关疾病的患病风险。本文将从细胞衰老和个体衰老两个层面阐述其与衰老之间的研究进展, 并综述其与衰老常见相关疾病(肿瘤、心血管疾病、阿尔茨海默病)及早衰综合征的关系, 为抗衰老研究和临床干预衰老相关疾病提供理论依据。  相似文献   
2.
目的:探讨长链非编码RNA肝癌高表达转录本(long non-coding RNA highly up-regulated in liver cancer,LncRNA HULC)降低PTEN启动子甲基化以及组蛋白乙酰化促进胶质母细胞瘤细胞增殖和侵袭的作用。方法:稳转HULC的胶质母细胞瘤细胞株U251,分为LncRNA HULC过表达组(HULC组)及空白对照组(vec组)。实时荧光定量PCR(qRT-PCR)检测各组HULC、PTEN表达水平。亚硫酸氢盐处理后测序(Bisulfite Sequencing PCR,BSP)检测PTEN启动子甲基化水平。蛋白免疫印迹(Western Blotting,WB)检测PTEN、组蛋白H3/H4、乙酰化组蛋白H3/H4表达水平。细胞增殖实验、平板克隆形成实验、划痕-愈合实验和Transwell实验分别检测各组细胞增殖、迁移和侵袭能力。结果:与vec组相比,HULC组PTEN启动子甲基化水平及组蛋白乙酰化水平较低(P<0.05),细胞的增殖、迁移和侵袭能力显著增高(P<0.05)。结论:LncRNA HULC降低PTEN启动子甲基化和组蛋白乙酰化水平,促进胶质母细胞瘤细胞的增殖和侵袭。  相似文献   
3.
Objective: Nucleolar organizer regions (NORs) are DNA coils that transcribe to ribosomal RNA. The NOR-associated protein, termed argyrophilic NOR (AgNOR), was visible within the nucleus by staining with silver nitrate examination via the light microscope. AgNOR counting is a proliferation marker and may help in the diagnosis and prognosis of various neoplastic lesions. Aneuploidy (abnormal DNA content) can predict the progression, survival and prognosis of the tumors. The aim of this study was to evaluate the role of AgNORs, DNA ploidy status, and total S-phase fraction (TSPF) as prognostic parameters in malignant salivary gland tumors (MSGTs). Methods: The current study is a retrospective study on a cohort of MSGTs (N=47), to assess AgNORs using Silver Nitrate stain, DNA index (DI), and TSPF using flow cytometry (FCM). Data including tumor size and site, lymphovascular invasion (LVI), lymph node metastasis (LNM) were collected. Results: The AgNORs count was statistically significant with MSGT type. DI was found to have a significant association with tumor site, tumor size and MSGT type. In addition, TSPF was found to be significantly associated with LVI. A moderate positive correlation was noted between AgNORs count and TSPF. LNM, tumor site, high AgNORs and low DI were all associated with short disease-free survival (DFS) and poor overall survival (OS). Conclusion: The present study revealed that high AgNORs count, DNA aneuploidy and TSPF had a poor influence on MSGTs prognosis.  相似文献   
4.
We propose a Deep learning-based weak label learning method for analyzing whole slide images (WSIs) of Hematoxylin and Eosin (H&E) stained tumor tissue not requiring pixel-level or tile-level annotations using Self-supervised pre-training and heterogeneity-aware deep Multiple Instance LEarning (DeepSMILE). We apply DeepSMILE to the task of Homologous recombination deficiency (HRD) and microsatellite instability (MSI) prediction. We utilize contrastive self-supervised learning to pre-train a feature extractor on histopathology tiles of cancer tissue. Additionally, we use variability-aware deep multiple instance learning to learn the tile feature aggregation function while modeling tumor heterogeneity. For MSI prediction in a tumor-annotated and color normalized subset of TCGA-CRC (n=360 patients), contrastive self-supervised learning improves the tile supervision baseline from 0.77 to 0.87 AUROC, on par with our proposed DeepSMILE method. On TCGA-BC (n=1041 patients) without any manual annotations, DeepSMILE improves HRD classification performance from 0.77 to 0.81 AUROC compared to tile supervision with either a self-supervised or ImageNet pre-trained feature extractor. Our proposed methods reach the baseline performance using only 40% of the labeled data on both datasets. These improvements suggest we can use standard self-supervised learning techniques combined with multiple instance learning in the histopathology domain to improve genomic label classification performance with fewer labeled data.  相似文献   
5.
目的 探究N6-甲基腺苷(m6A)去甲基化酶ALKBH5对紫外线诱导的晶状体上皮细胞(LEC)氧化损伤模型中DNA损伤修复的影响。方法 运用qRT-PCR和免疫印迹实验检测年龄相关性白内障(ARC)患者和对照组晶状体前囊膜上皮细胞中ALKBH5的mRNA和蛋白的表达。通过紫外线B(UVB)构建晶状体上皮细胞株SRA01/04细胞氧化损伤模型和靶向ALKBH5设计小干扰RNA(siRNA)转染构建敲降模型,运用qRT-PCR和免疫印迹实验检测氧化损伤模型和敲降模型中ALKBH5的mRNA和蛋白表达。运用CCK-8法检测Control组、UVB组、UVB+siNC组和UVB+siALKBH5#3组中SRA01/04细胞活力变化。免疫荧光染色检测UVB+siNC组和UVB+siALKBH5#3组中15A3的荧光强度变化。运用qRT-PCR检测转染对照siNC组和转染siALKBH5#3组中11个DNA氧化损伤修复基因(ODRGs)的mRNA表达变化。结果 在ARC患者的晶状体前囊膜上皮细胞中,ALKBH5的mRNA和蛋白表达水平均显著升高。在UVB以时间梯度诱导SRA01/04的细胞氧化损伤模型中,ALKBH5的mRNA和蛋白表达水平均呈上升后下降趋势,其中UVB照射10 min后ALKBH5 mRNA和蛋白表达升高最为显著。ALKBH5敲降效率结果显示,与转染对照siNC组相比,转染靶向ALKBH5的siRNA后,ALKBH5的mRNA和蛋白表达均显著下降。CCK-8法检测结果显示,与UVB+siNC组相比,UVB+siALKBH5#3组SRA01/04细胞活力明显降低。免疫荧光染色检测结果显示,与UVB+siNC组相比,UVB+siALKBH5#3组SRA01/04细胞内DNA氧化损伤指标15A3染色显著增加。同时,与转染对照siNC组相比,转染ALKBH5#3组SRA01/04细胞的ODRGs中,TREX1、FANCD2、LIG1、MSH2、MSH3、RPA2、SMUG1、XRCC6 mRNA的表达均显著上升,DCLRE1A mRNA的表达显著下降,MGMT和MRE11A mRNA的表达则未见明显差异。结论 m6A去甲基化酶ALKBH5在UVB诱导的LEC氧化损伤模型中诱导性表达上升,敲降ALKBH5可促进LEC内大部分ODRGs表达升高,参与调控LEC内损伤DNA的修复,阻止ARC的发生。  相似文献   
6.
Background and aimChildhood obesity is an emerging problem often leading to earlier onset of non-communicable diseases in later life. Biomarkers to identify individual risk scores are insufficient in routine clinical practice, which is related to the need for easily sampled, non-invasive survey methods in children. We aimed to investigate and strengthen possible pro-inflammatory markers and epigenetic risk factors in saliva of obese children compared to lean controls.Methods and results19 overweight/obese (OC, 10.1 ± 1.9 years, BMI 27.7 ± 3.2 kg/m2) and 19 lean control children (CC, 9.7 ± 2.5 years, BMI 16.4 ± 1.8 kg/m2) participated in this explorative pilot study. Anthropometric measures, saliva and cheek swab samples were taken. Saliva profiles were examined for acute phase proteins (CRP and neopterin) and pro-inflammatory cytokines (IL-17a/IL-1β/IL-6). Cheek swabs were analyzed to investigate DNA methylation differences with subsequent hierarchical cluster and principal component analyses (PCA). Saliva analysis showed significant increased CRP concentrations in OC compared to CC (p < 0.001). There were no significant differences, but high intra-individual values in neopterin, IL-17a, IL-1β and IL-6. An unsupervised PCA of CpG loci with high variance (σ/σmax > 0.2) clearly separated OC and CC according to their methylation pattern. Furthermore, a supervised approach revealed 7125 significantly differentially methylated loci, whose corresponding genes were significantly enriched for genes playing roles in e.g., cellular signalling, cytoskeleton organization and cell motility.ConclusionsCRP and methylation status determinations in saliva are suitable as non-invasive methods for early detection of risks for non-communicable diseases in children/adolescents and might be a useful supplementary approach in the routine clinical practice/monitoring.  相似文献   
7.
Objective: The main aim of the present study was to determine the clinical significance of the DNA methyltransferase 3B (DNMT3B) gene –579 G>T polymorphism in colorectal cancer (CRC) patients. Methods: A total of 140 patients with CRC and 164 healthy individuals were included in the study. According to the manufacturer’s instructions, DNA was isolated from blood, and genotypes were determined on agarose gel by the PCR-RFLP method. Genotype confirmation was performed using Sanger sequencing in randomly selected samples. Results: When comparing the case and control groups, heterozygous GT (OR=0.53; 95% CI=0.32–0.88), under the dominant model (OR=0.53; 95% CI=0.33–0.87), and the mutant T allele (OR=0.71; 95% CI=0.51–0.98) were statistically associated with a reduced risk of CRC. However, when the age, pathological tumor grade and stage, smoking habit, and alcohol consumption were compared, no significant relationship was determined (P>0.05). Furthermore, among males, heterozygous GT was associated with a reduced risk of CRC (OR=0.40; 95% CI=0.19–0.84). Conclusion: Our study highlighted that the –579 G>T polymorphism of the DNMT3B gene plays a protective role against CRC development.  相似文献   
8.
9.
Microhaplotypes have been highly regarded for forensic mixture DNA deconvolution because they do not experience interference from stutters in the same way as short tandem repeat markers, and they tend to be more polymorphic than single nucleotide polymorphism markers. However, forensic microhaplotype kits have not been reported. The MHSeqTyper47 kit genotypes 47 microhaplotype loci. In this study, MiSeq FGx sequencing metrics for MHSeqTyper47 were presented, and the genotyping accuracy of this kit was examined. The sensitivity of MHSeqTyper47 reached 62.5 pg, and full genotyping results were obtained from degraded DNA samples with degradation indexes ≤ 3.00. Full genotypes were obtained in the presence of 100 ng/μL tannin, 50 μM heme, 25 ng/μL humic acid, and 1.25 μg/μL indigo dye. In DNA mixture studies, a minimum of 31 loci of the minor contributor were correctly genotyped at 1:99 or 99:1 mixing ratios, with the cumulative random matching probability of these loci reaching 4.54 × 10−25. Mixing ratios could be reliably predicted from two-donor DNA mixtures based on the loci with four called alleles. Taken together, these data showed that the MHSeqTyper47 kit was effective for forensically challenging DNA analysis.  相似文献   
10.
KDM5C encodes a demethylase of the histone H3 lysine 4 residue, involved in chromatin regulation and gene expression. Hemizygous KDM5C pathogenic variants cause X-linked intellectual disability of Claes-Jensen type. Because of its mode of inheritance and the low specificity of the clinical phenotype, interpretation of variants can be difficult, hence the need for functional studies and biomarkers specific to this disorder. We present the case of a male patient with intellectual disability, behavioral abnormalities and subtle dysmorphic features, in which genetic investigation identified a hemizygous novel missense KDM5C variant of uncertain significance (VUS), inherited from his asymptomatic mother and present in his paucisymptomatic sister. We assessed the global genomic DNA methylation status from a whole blood sample of the proband. Global DNA methylation profiling specifically identified the recently discovered epi-signature of Claes-Jensen syndrome. This result served as a biomarker which independently highlighted KDM5C as the cause of the disorder in this patient. Because of the X-linked mode of inheritance, variant reclassification had a high impact on genetic counseling in this family. This example highlights the value of global methylome profiling in situations of variants of uncertain significance in genes with a known specific epi-signature.  相似文献   
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