Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p= 4.89 x 10 - 57) , high mitotic index (p= 5.25 x 10 - 28), pleomorphism (p= 6.31 x 10-19), ER negative (p= 9.02 x 10-35 ), PR negative (p= 9.24 x 10-24 ), triple negative phenotype (p= 6.67 x 10-21) , PAM50.Her2 (p=5.19 x 10-13 ), PAM50.Basal (p=2.7 x 10-41), PAM50.LumB (p=1.56 x 10-26), integrative molecular cluster 1 (intClust.1) ( p=7.47 x 10-12), intClust.5 (p=4.05 x 10-12) and intClust. 10 (p=7.59 x 10-38 ) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p=4.4 x 10-16) and multivariate analysis (p=9.19 x 10-7). At the protein level, in ER positive tumours , FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps< 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps<0.05). In ER positive as well as in ER negative tumours, FEN1 protein over expression is associated with poor survival in univariate and multivariate analysis (ps<0.01). In ovarian epithelial cancers , similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps<0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer

Identification of floR Variants Associated With a Novel Tn4371-Like Integrative and Conjugative Element in Clinical Pseudomonas aeruginosa Isolates

Florfenicol is widely used to control respiratory diseases and intestinal infections in food animals. However, there are increasing reports about florfenicol resistance of various clinical pathogens. floR is a key resistance gene that mediates resistance to florfenicol and could spread among different bacteria. Here, we investigated the prevalence of floR in 430 Pseudomonas aeruginosa isolates from human clinical samples and identified three types of floR genes (designated floR, floR-T1 and floR-T2) in these isolates, with floR-T1 the most prevalent (5.3%, 23/430). FloR-T2 was a novel floR variant identified in this study, and exhibited less identity with other FloR proteins than FloRv. Moreover, floR-T1 and floR-T2 identified in P. aeruginosa strain TL1285 were functionally active and located on multi-drug resistance region of a novel incomplete Tn4371-like integrative and conjugative elements (ICE) in the chromosome. The expression of the two floR variants could be induced by florfenicol or chloramphenicol. These results indicated that the two floR variants played an essential role in the host’s resistance to amphenicol and the spreading of these floR variants might be related with the Tn4371 family ICE

Development of Quantitative Structure - Property Relationship Models for Early ADME Evaluation in Drug Discovery. 2. Blood-Brain Barrier Penetration

A new molecular lipoaffinity descriptor was introduced in this paper to account for the effect of molecular hydrophobicity on blood-brain barrier penetration. The descriptor was defined based on Kier and Hall\u27s atom-type electrotopological state indices. Its evaluation requires 2-D molecular bonding information only. A multiple linear regression equation using this descriptor and molecular weight reproduces the experimental logBB values of 55 training set compounds and 11 test set compounds satisfactorily with statistical parameters nearly identical to the best models based on polar surface area and ClogP. The results indicate that the lipoaffinity descriptor defined in this paper may be a significant descriptor for molecular transport properties across lipid bilayers

An Integrated Flood Risk Assessment Model for Cities Located in the Transitional Zone between Taihang Mountains and North China Plain: A Case Study in Shijiazhuang, Hebei, China

Cities located in the transitional zone between Taihang Mountains and North China plain run high flood risk in recent years, especially urban waterlogging risk. In this paper, we take Shijiazhuang, which is located in this transitional zone, as the study area and proposed a new flood risk assessment model for this specific geographical environment. Flood risk assessment indicator factors are established by using the digital elevation model (DEM), along with land cover, economic, population, and precipitation data. A min-max normalization method is used to normalize the indices. An analytic hierarchy process (AHP) method is used to determine the weight of each normalized index and the geographic information system (GIS) spatial analysis tool is adopted for calculating the risk map of flood disaster in Shijiazhuang. This risk map is consistent with the reports released by Hebei Provincial Water Conservancy Bureau and can provide reference for flood risk management

The influence of amino and hydroxyl of chitosan on hydroxyl radical scavenging activity

In order to determine the effect of the amido and hydroxyl of chitosan on antioxidant activity, a series of N-deacetylated chitosan with a degree of deacetylation (D.D.) ranging from 45% to 95% were prepared using region selective N-acetylation of chitosan. Their carboxymethyl derivatives (CMC) were also synthesized according to previous method. The antioxidant activity was evaluated on the basis of their abilities to scavenge hydroxyl radical. The results indicated that the hydroxyl radical scavenging ability depended on the degree of deacetylation and concentration. It also showed that the 2-NH 2 had a closer relation than 6-OH in hydroxyl radical scavenging activities. &copy;2009 Crown

Assessment of Genetic Diversity and Discovery of Molecular Markers in Durian (Durio zibethinus L.) in China

Durian (Durio zibethinus L.) is a crop of economic and health importance globally. Efforts are being made to revamp China&rsquo;s only successful commercial-scale durian plantations in Hainan; however, their genetic base is unknown. Therefore, the present study was undertaken to assess the genetic base and population structure of 32 genotypes in durian plantation sites in Hainan, China, and develop simple sequence repeat (SSR) markers by whole genome sequencing through restriction site-associated DNA sequencing technology to facilitate germplasm conservation and breeding. The results from identity by state (IBS), phylogenetic tree, population structure, and principal component analysis grouped the 32 genotypes into two clusters/sub-populations. Based on IBS, genotypes in Cluster I are largely duplicated genotypes; however, results from the model-based population structure demonstrated that most of the genotypes in Sub-population II shared a common genetic background with those in Sub-population I/Cluster I. The results revealed that the core durian collection in the plantation sites in Hainan include D24, D101, MSW, JH, D163, HFH, and NLX-5. In addition, we developed a total of 79,178 SSR markers with varied lengths and amplicon sizes. The genetic diversity and population structure reported in this study will be useful for durian conservation and utilization. In addition, the discovered and developed SSR markers will lay the foundation for molecular breeding via marker-assisted selection, quantitative trait loci mapping, and candidate gene discovery and validation

The β-Lactamase Gene Profile and a Plasmid-Carrying Multiple Heavy Metal Resistance Genes of Enterobacter cloacae

In this work, by high-throughput sequencing, antibiotic resistance genes, including class A (blaCTX-M, blaZ, blaTEM, blaVEB, blaKLUC, and blaSFO), class C (blaSHV, blaDHA, blaMIR, blaAZECL-29, and blaACT), and class D (blaOXA) β-lactamase genes, were identified among the pooled genomic DNA from 212 clinical Enterobacter cloacae isolates. Six blaMIR-positive E. cloacae strains were identified, and pulsed-field gel electrophoresis (PFGE) showed that these strains were not clonally related. The complete genome of the blaMIR-positive strain (Y546) consisted of both a chromosome (4.78 Mb) and a large plasmid pY546 (208.74 kb). The extended-spectrum β-lactamases (ESBLs) (blaSHV-12 and blaCTX-M-9a) and AmpC (blaMIR) were encoded on the chromosome, and the pY546 plasmid contained several clusters of genes conferring resistance to metals, such as copper (pco), arsenic (ars), tellurite (ter), and tetrathionate (ttr), and genes encoding many divalent cation transporter proteins. The comparative genomic analyses of the whole plasmid sequence and of the heavy metal resistance gene-encoding regions revealed that the plasmid sequences of Klebsiella pneumoniae (such as pKPN-332, pKPN-3967, and pKPN-262) shared the highest similarity with those of pY546. It may be concluded that a variety of β-lactamase genes present in E. cloacae which confer resistance to β-lactam antibiotics and the emergence of plasmids carrying heavy metal resistance genes in clinical isolates are alarming and need further surveillance

Characterization of an IncR Plasmid with Two Copies of ISCR-Linked qnrB6 from ST968 Klebsiella pneumoniae

To characterize the molecular structure of IncR plasmid-related sequences, comparative genomic analysis was conducted using 261 IncR plasmid backbone-related sequences. Among the sequences, 257 were IncR plasmids including the multidrug-resistance IncR plasmid pR50-74 from Klebsiella pneumoniae strain R50 of this work, and the other four were from bacterial chromosomes. The IncR plasmids were derived from different bacterial genera or species, mainly Klebsiella pneumoniae (70.82%, 182/257), Escherichia coli (11.28%, 29/257), Enterobacter cloacae (7.00%, 18/257), and Citrobacter freundii (3.50%, 9/257). The bacterial chromosomes carrying IncR plasmid backbone sequences were derived from Proteus mirabilis AOUC-001 and Klebsiella pneumoniae KPN1344, among others. The IncR backbone sequence of P. mirabilis AOUC-001 chromosome shows the highest identity with that of pR50-74. Complex class 1 integrons carrying various copies of ISCR1-sdr-qnrB6-△qacE/sul1 (ISCR1-linked qnrB6 unit) were identified in IncR plasmids. In addition to two consecutive copies of qnrB6-qacE-sul1, the other resistance genes encoded on pR50-74 are all related to mobile genetic elements, such as IS1006, IS26, and the class 1 integron. This study provides a clear understanding of the mobility and plasticity of the IncR plasmid backbone sequence and emphasizes the important role of ISCR in the recruitment of multicopy resistance genes