联合TCGA和GEO数据库筛选乳腺癌易感基因

本研究是利用公共基因芯片数据库筛选乳腺癌的预后基因,预测和探索这些基因在乳腺癌进展中的可能机制和临床价值.首先,我们筛选了公共基因芯片数据库(gene expression omnibus,GEO)GSE22820和癌症基因组图谱(the cancer genome atlas,TCGA)乳腺癌数据库的重叠差异表达基因,联合R语言分析乳腺癌组织与癌旁正常组织差异表达的基因;其次,基于STRING数据库及Cytoscape软件构建蛋白质相互作用网络图,分析并识别了中枢基因和前3个模块;之后进行了更多的功能分析,包括基因本体(gene ontology,GO)和京都基因与基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路分析以及基因集富集分析(gene set enrichment analysis,GSEA),以研究这些基因的作用以及潜在的潜在机制;最后进行了Kaplan-Meier分析和Cox比例风险分析,以阐明这些基因的诊断和预后效果.相关数据分析表明15个基因的表达水平与生存预后相关,高表达基因患者的总生存时间短于低表达患者(P＜0.05);Cox比例风险分析表明UBE2T、ER-CC6L和RAD51这3个基因是预后生存的独立因素(P＜0.05);GSEA分析表明在UBE2T、ERCC6L和RAD51基因中细胞周期、基础转录因子和卵母细胞减数分裂明显富集.最终,我们得出结论,这3种基因标志物的高表达是乳腺癌预后不良因素,可作为预测乳腺癌患者转移和预后的有效生物标志物.     

NEDD9 overexpression: Prognostic and guidance value in acute myeloid leukaemia

It has been demonstrated that neural precursor cell expressed developmentally downregulated protein (NEDD) plays crucial roles in tumorigenesis and may serve as potential biomarkers in cancer diagnosis and prognosis. However, few studies systematically investigated the expression of NEDD family members in acute myeloid leukaemia (AML). We systemically determined the expression of NEDD family members in AML and determined their clinical significance. We identified that NEDD9 expression was the only member among NEDD family which was significantly increased in AML. NEDD9 overexpression was more frequently classified as FAB-M4/M5 (p = 0.008 and 0.013, respectively), hardly as FAB-M2/M3. Moreover, NEDD9 overexpression was significantly associated with complex karyotype and TP53 mutation. The significant association between NEDD9 overexpression and survival was also observed in whole-cohort AML and non-M3 AML patients. Notably, AML patients with NEDD9 overexpression may benefit from hematopoietic stem cell transplantation (HSCT), whereas those cases without NEDD9 overexpression did not. Finally, a total of 822 mRNAs and 31 microRNAs were found to be differentially expressed between two groups. Among the microRNAs, miR-381 was also identified as a microRNA that could direct target NEDD9. Taken together, our findings demonstrated that NEDD9 overexpression is associated with genetic abnormalities as well as prognosis and might act as a potential biomarker guiding the choice between HSCT and chemotherapy in patients with AML after achieving complete remission.     

Norcantharidin Induced DU145 Cell Apoptosis through ROS-Mediated Mitochondrial Dysfunction and Energy Depletion

Norcantharidin (NCTD), a demethylated analog of cantharidin derived from blister beetles, has attracted considerable attentions in recent years due to their definitely toxic properties and the noteworthy advantages in stimulating bone marrow and increasing the peripheral leukocytes. Hence, it is worth studying the anti-tumor effect of NCTD on human prostate cancer cells DU145. It was found that after the treatment of NCTD with different concentrations (25-100 μM), the cell proliferation was significantly inhibited, which led to the appearance of micronucleus (MN). Moreover, the cells could be killed in a dose-/ time-dependent manner along with the reduction of PCNA (proliferating cell nuclear antigen) expression, destruction of mitochondrial membrane potential (MMP), down-regulation of MnSOD, induction of ROS, depletion of ATP, and activation of AMPK (Adenosine 5‘-monophosphate -activated protein kinase) . In addition, a remarkable release of cytochrome c was found in the cells exposed to 100 μM NCTD and exogenous SOD-PEG could eliminate the generation of NCTD-induced MN. In conclusion, our studies indicated that NCTD could induce the collapse of MMP and mitochondria dysfunction. Accumulation of intercellular ROS could eventually switch on the apoptotic pathway by causing DNA damage and depleting ATP.     

Phylogenetic Diversity of the Bacillus pumilus Group and the Marine Ecotype Revealed by Multilocus Sequence Analysis

Bacteria closely related to Bacillus pumilus cannot be distinguished from such other species as B. safensis, B. stratosphericus, B. altitudinis and B. aerophilus simply by 16S rRNA gene sequence. In this report, 76 marine strains were subjected to phylogenetic analysis based on 7 housekeeping genes to understand the phylogeny and biogeography in comparison with other origins. A phylogenetic tree based on the 7 housekeeping genes concatenated in the order of gyrB-rpoB-pycA-pyrE-mutL-aroE-trpB was constructed and compared with trees based on the single genes. All these trees exhibited a similar topology structure with small variations. Our 79 strains were divided into 6 groups from A to F; Group A was the largest and contained 49 strains close to B. altitudinis. Additional two large groups were presented by B. safensis and B. pumilus respectively. Among the housekeeping genes, gyrB and pyrE showed comparatively better resolution power and may serve as molecular markers to distinguish these closely related strains. Furthermore, a recombinant phylogenetic tree based on the gyrB gene and containing 73 terrestrial and our isolates was constructed to detect the relationship between marine and other sources. The tree clearly showed that the bacteria of marine origin were clustered together in all the large groups. In contrast, the cluster belonging to B. safensis was mainly composed of bacteria of terrestrial origin. Interestingly, nearly all the marine isolates were at the top of the tree, indicating the possibility of the recent divergence of this bacterial group in marine environments. We conclude that B. altitudinis bacteria are the most widely spread of the B. pumilus group in marine environments. In summary, this report provides the first evidence regarding the systematic evolution of this bacterial group, and knowledge of their phylogenetic diversity will help in the understanding of their ecological role and distribution in marine environments.     

Hsa-miR-34b/c rs4938723 T>C and hsa-miR-423 rs6505162 C>A Polymorphisms Are Associated with the Risk of Esophageal Cancer in a Chinese Population

Esophageal cancer is the eighth most common cancer and sixth leading cause of cancer associated death worldwide. Besides environmental risk factors, genetic factors might play an important role in the esophageal cancer carcinogenesis. We conducted a hospital based case–control study to evaluate the genetic susceptibility of functional single nucleotide polymorphisms (SNPs) in the microRNAs on the development of esophageal cancer. A total of 629 esophageal squamous cell carcinoma (ESCC) cases and 686 controls were recruited for this study. The hsa-miR-34b/c rs4938723 T>C, pri-miR-124-1 rs531564 C>G, pre-miR-125a rs12975333 G>T and hsa-miR-423 rs6505162 C>A genotypes were determined using Ligation Detection Reaction (LDR) method. Our results demonstrated that hsa-miR-34b/c rs4938723 CC genotype had a decreased risk of ESCC. The association was evident among patients who never drinking. Hsa-miR-423 rs6505162 C>A might associated with a significantly increased risk of ESCC in patients who smoking. These findings indicated that functional polymorphisms hsa-miR-34b/c rs4938723 T>C and hsa-miR-423 rs6505162 C>A might alter individual susceptibility to ESCC. However, our results were obtained with a limited sample size. Future larger studies with other ethnic populations are required to confirm current findings.     

Genome-Scale Screening of Drug-Target Associations Relevant to Ki Using a Chemogenomics Approach

The identification of interactions between drugs and target proteins plays a key role in genomic drug discovery. In the present study, the quantitative binding affinities of drug-target pairs are differentiated as a measurement to define whether a drug interacts with a protein or not, and then a chemogenomics framework using an unbiased set of general integrated features and random forest (RF) is employed to construct a predictive model which can accurately classify drug-target pairs. The predictability of the model is further investigated and validated by several independent validation sets. The built model is used to predict drug-target associations, some of which were confirmed by comparing experimental data from public biological resources. A drug-target interaction network with high confidence drug-target pairs was also reconstructed. This network provides further insight for the action of drugs and targets. Finally, a web-based server called PreDPI-K_i was developed to predict drug-target interactions for drug discovery. In addition to providing a high-confidence list of drug-target associations for subsequent experimental investigation guidance, these results also contribute to the understanding of drug-target interactions. We can also see that quantitative information of drug-target associations could greatly promote the development of more accurate models. The PreDPI-K_i server is freely available via: http://sdd.whu.edu.cn/dpiki.     

The Embedding Problem for Markov Models of Nucleotide Substitution

Continuous-time Markov processes are often used to model the complex natural phenomenon of sequence evolution. To make the process of sequence evolution tractable, simplifying assumptions are often made about the sequence properties and the underlying process. The validity of one such assumption, time-homogeneity, has never been explored. Violations of this assumption can be found by identifying non-embeddability. A process is non-embeddable if it can not be embedded in a continuous time-homogeneous Markov process. In this study, non-embeddability was demonstrated to exist when modelling sequence evolution with Markov models. Evidence of non-embeddability was found primarily at the third codon position, possibly resulting from changes in mutation rate over time. Outgroup edges and those with a deeper time depth were found to have an increased probability of the underlying process being non-embeddable. Overall, low levels of non-embeddability were detected when examining individual edges of triads across a diverse set of alignments. Subsequent phylogenetic reconstruction analyses demonstrated that non-embeddability could impact on the correct prediction of phylogenies, but at extremely low levels. Despite the existence of non-embeddability, there is minimal evidence of violations of the local time homogeneity assumption and consequently the impact is likely to be minor.