Chromosome-wide mapping of DNA methylation patterns in normal and malignant prostate cells reveals pervasive methylation of gene-associated and conserved intergenic sequences

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.Abstract Background DNA methylation has been linked to genome regulation and dysregulation in health and disease respectively, and methods for characterizing genomic DNA methylation patterns are rapidly emerging. We have developed/refined methods for enrichment of methylated genomic fragments using the methyl-binding domain of the human MBD2 protein (MBD2-MBD) followed by analysis with high-density tiling microarrays. This MBD-chip approach was used to characterize DNA methylation patterns across all non-repetitive sequences of human chromosomes 21 and 22 at high-resolution in normal and malignant prostate cells. Results Examining this data using computational methods that were designed specifically for DNA methylation tiling array data revealed widespread methylation of both gene promoter and non-promoter regions in cancer and normal cells. In addition to identifying several novel cancer hypermethylated 5' gene upstream regions that mediated epigenetic gene silencing, we also found several hypermethylated 3' gene downstream, intragenic and intergenic regions. The hypermethylated intragenic regions were highly enriched for overlap with intron-exon boundaries, suggesting a possible role in regulation of alternative transcriptional start sites, exon usage and/or splicing. The hypermethylated intergenic regions showed significant enrichment for conservation across vertebrate species. A sampling of these newly identified promoter (ADAMTS1 and SCARF2 genes) and non-promoter (downstream or within DSCR9, C21orf57 and HLCS genes) hypermethylated regions were effective in distinguishing malignant from normal prostate tissues and/or cell lines. Conclusions Comparison of chromosome-wide DNA methylation patterns in normal and malignant prostate cells revealed significant methylation of gene-proximal and conserved intergenic sequences. Such analyses can be easily extended for genome-wide methylation analysis in health and disease.Published versio

Modulation of the Proteostasis Network Promotes Tumor Resistance to Oncogenic KRAS Inhibitors

Despite substantial advances in targeting mutant KRAS, tumor resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report proteostasis reprogramming as a key convergence point of multiple KRASi-resistance mechanisms. Inactivation of oncogenic KRAS down-regulated both the heat shock response and the inositol-requiring enzyme 1α (IRE1α) branch of the unfolded protein response, causing severe proteostasis disturbances. However, IRE1α was selectively reactivated in an ER stress-independent manner in acquired KRASi-resistant tumors, restoring proteostasis. Oncogenic KRAS promoted IRE1α protein stability through extracellular signal-regulated kinase (ERK)-dependent phosphorylation of IRE1α, leading to IRE1α disassociation from 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) E3-ligase. In KRASi-resistant tumors, both reactivated ERK and hyperactivated AKT restored IRE1α phosphorylation and stability. Suppression of IRE1α overcame resistance to KRASi. This study reveals a druggable mechanism that leads to proteostasis reprogramming and facilitates KRASi resistance

Genetic programming based structure optimisation

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Anisotropic Elastoplastic Damage Mechanics Method to Predict Fatigue Life of the Structure

New damage mechanics method is proposed to predict the low-cycle fatigue life of metallic structures under multiaxial loading. The microstructure mechanical model is proposed to simulate anisotropic elastoplastic damage evolution. As the micromodel depends on few material parameters, the present method is very concise and suitable for engineering application. The material parameters in damage evolution equation are determined by fatigue experimental data of standard specimens. By employing further development on the ANSYS platform, the anisotropic elastoplastic damage mechanics-finite element method is developed. The fatigue crack propagation life of satellite structure is predicted using the present method and the computational results comply with the experimental data very well

A detached helix of pacemaker pacing lead

Key Clinical Message Permanent pacemaker implantation is the main treatment of symptomatic bradyarrhythmia, which has been widely used. Lead implantation is a critical step. When the lead malfunctions and needs to be replaced, extraction or abandonment of the primary lead (in whole or in part) should be determined according to the situation

Analysis of influencing factors for conversion of laparoscopic cholecystectomy to open surgery

ObjectiveTo analyze the influencing factors for conversion of laparoscopic cholecystectomy to open surgery, and to provide a clinical reference for developing surgical procedures. MethodsA total of 278 patients receiving laparoscopic cholecystectomy in our hospital from January 2009 to December 2013 were analyzed. Among them, 31 patients were converted to open surgery during laparoscopic cholecystectomy, while the remaining 274 patients were not. The influencing factors for conversion to open surgery were investigated. The t test was applied in the comparison of continuous data, whereas the χ2 test was used for categorical data. The univariate logistic regression analysis was performed to investigate significant influencing factors, and the independent influencing factors were determined by multivariate logistic regression analysis. ResultsThe univariate analysis showed that sex (P=0.022), arteriosclerosis (P＜0.001), diabetes (P＜0.001), heart failure (P=0.002), previous upper abdominal surgery (P＜0.001), age (P＜0.001), body mass index (BMI) (P=0.003), gallbladder wall thickness (P＜0.001), the count of white blood cells (P＜0.001), and serum total bilirubin level (P=0.046) were significantly different between groups. The multivariate logistic regression analysis further showed that previous upper abdominal surgery (P＜0.001), sex (P=0.001), BMI (P=0.002), and the count of white blood cells (P=0.019) were independent influencing factors, among which previous upper abdominal surgery was the most significant one (OR=4.646， 95%CI: 2.012-10.729). ConclusionPrevious upper abdominal surgery, sex, BMI, and the count of white blood cells were independent influencing factors for conversion of laparoscopic cholecystectomy to open surgery. Careful evaluation of these factors before surgery would help to increase the operation efficacy, possessing an important clinical value

Autonomous cruise method of unmanned surface vessles cluster based on bacterial obstacle avoidance strategy

A dynamic obstacle avoidance algorithm is proposed for the obstacle avoidance problem in the cruise task of unmanned boat cluster. Firstly, the square grid trajectory cell (SGTC) situation matrix of the waters around the unmanned surface vessle is obtained. Then, based on the principle of bacterial walking foraging, the optimal obstacle avoidance path is dynamically matched in the SGTC set. Finally, on the basis of dynamic obstacle avoidance, the autonomous cruise process of unmanned surface vessle is divided into stages of moving towards the target, dynamic obstacle avoidance, and return replenishment, so as to realize the normal cruise of unmanned surface vessle to the designated waters. The simulation results show that the proposed method has efficient avoidance ability for static point, surface obstacle and moving obstacle. Based on the algorithm, it can realize the normalized unmanned cruise of unmanned boat cluster. The algorithm is not only suitable for obstacle avoidance of unmanned surface vessle, but also has broad application prospects in other heterogeneous unmanned equipment

Experimental Study on the Mechanical Properties and Seepage Characteristics of Red Sandstone with a Single Persistent Joint under Triaxial Compression

In this research, the conventional triaxial compression experiments for intact red sandstone specimens and the specimens with a single persistent joint at different inclination angles, i.e., 0°, 30°, 45°, and 90°, were conducted at first. Based on the results of the conventional tests, the effects of the confining pressure and the joint inclination angle on the mechanical properties including deformation behavior and strength parameters were summarized and analyzed, respectively. We find that the strength and deformation of jointed red sandstone are enlarged due to the increment of confining pressure, and the mechanical parameters of specimens show a U-shaped development with the rise of the joint angle. Besides, to investigate the effects of the pore pressure on seepage characteristics of rocks with joint angles at 0°, 45°, and 90°, a series of triaxial compression drainage tests on the jointed red sandstone were performed. The results show that the pore pressure has a weakening effect on the strength of jointed specimens, which can reduce the strengthening effect induced by confining pressure. Meanwhile, the tested specimens mostly present shear failure modes. As a result, the mechanical responses, seepage characteristics, and cracking modes in red sandstone containing a single persistent joint under triaxial compression are revealed