Extracting spectral density function of a binary composite without a-priori assumption

The spectral representation separates the contributions of geometrical arrangement (topology) and intrinsic constituent properties in a composite. The aim of paper is to present a numerical algorithm based on the Monte Carlo integration and contrainted-least-squares methods to resolve the spectral density function for a given system. The numerical method is verified by comparing the results with those of Maxwell-Garnett effective permittivity expression. Later, it is applied to a well-studied rock-and-brine system to instruct its utility. The presented method yields significant microstructural information in improving our understanding how microstructure influences the macroscopic behaviour of composites without any intricate mathematics.Comment: 4 pages, 5 figures and 1 tabl

Associations of grip strength with cardiovascular, respiratory, and cancer outcomes and all cause mortality: prospective cohort study of half a million UK Biobank participants

Objective: To investigate the association of grip strength with disease specific incidence and mortality and whether grip strength enhances the prediction ability of an established office based risk score. Design: Prospective population based study. Setting: UK Biobank. Participants: 502 293 participants (54% women) aged 40-69 years. Main outcome measures: All cause mortality as well as incidence of and mortality from cardiovascular disease, respiratory disease, chronic obstructive pulmonary disease, and cancer (all cancer, colorectal, lung, breast, and prostate). Results: Of the participants included in analyses, 13 322 (2.7%) died over a mean of 7.1 (range 5.3-9.9) years’ follow-up. In women and men, respectively, hazard ratios per 5 kg lower grip strength were higher (all at P<0.05) for all cause mortality (1.20, 95% confidence interval 1.17 to 1.23, and 1.16, 1.15 to 1.17) and cause specific mortality from cardiovascular disease (1.19, 1.13 to 1.25, and 1.22, 1.18 to 1.26), all respiratory disease (1.31, 1.22 to 1.40, and 1.24, 1.20 to 1.28), chronic obstructive pulmonary disease (1.24, 1.05 to 1.47, and 1.19, 1.09 to 1.30), all cancer (1.17, 1.13 to 1.21, 1.10, 1.07 to 1.13), colorectal cancer (1.17, 1.04 to 1.32, and 1.18, 1.09 to 1.27), lung cancer (1.17, 1.07 to 1.27, and 1.08, 1.03 to 1.13), and breast cancer (1.24, 1.10 to 1.39) but not prostate cancer (1.05, 0.96 to 1.15). Several of these relations had higher hazard ratios in the younger age group. Muscle weakness (defined as grip strength <26 kg for men and <16 kg for women) was associated with a higher hazard for all health outcomes, except colon cancer in women and prostate cancer and lung cancer in both men and women. The addition of handgrip strength improved the prediction ability, based on C index change, of an office based risk score (age, sex, diabetes diagnosed, body mass index, systolic blood pressure, and smoking) for all cause (0.013) and cardiovascular mortality (0.012) and incidence of cardiovascular disease (0.009). Conclusion: Higher grip strength was associated with a range of health outcomes and improved prediction of an office based risk score. Further work on the use of grip strength in risk scores or risk screening is needed to establish its potential clinical utility

Signs of low frequency dispersions in disordered binary dielectric mixtures (50-50)

Dielectric relaxation in disordered dielectric mixtures are presented by emphasizing the interfacial polarization. The obtained results coincide with and cause confusion with those of the low frequency dispersion behavior. The considered systems are composed of two phases on two-dimensional square and triangular topological networks. We use the finite element method to calculate the effective dielectric permittivities of randomly generated structures. The dielectric relaxation phenomena together with the dielectric permittivity values at constant frequencies are investigated, and significant differences of the square and triangular topologies are observed. The frequency dependent properties of some of the generated structures are examined. We conclude that the topological disorder may lead to the normal or anomalous low frequency dispersion if the electrical properties of the phases are chosen properly, such that for ``slightly'' {\em reciprocal mixture}--when $\sigma_1\gg\sigma_2$, and $\epsilon_1<\epsilon_2$--normal, and while for ``extreme'' {\em reciprocal mixture}--when $\sigma_1\gg\sigma_2$, and $\epsilon_1\ll\epsilon_2$--anomalous low frequency dispersions are obtained. Finally, comparison with experimental data indicates that one can obtain valuable information from simulations when the material properties of the constituents are not available and of importance.Comment: 13 pages, 7 figure

On micro-structural effects in dielectric mixtures

The paper presents numerical simulations performed on dielectric properties of two-dimensional binary composites on eleven regular space filling tessellations. First, significant contributions of different parameters, which play an important role in the electrical properties of the composite, are introduced both for designing and analyzing material mixtures. Later, influence of structural differences and intrinsic electrical properties of constituents on the composite's over all electrical properties are investigated. The structural differences are resolved by the spectral density representation approach. The numerical technique, without any {\em a-priori} assumptions, for extracting the spectral density function is also presented.Comment: 24 pages, 8 figure and 7 tables. It is submitted to IEEE Transactions on Dielectrics and Electrical Insulatio

Dose-response associations of cardiorespiratory fitness with all-cause mortality and incidence and mortality of cancer and cardiovascular and respiratory diseases: the UK Biobank cohort study

Objective: To investigate the association of cardiorespiratory fitness with all-cause mortality, and cardiovascular, respiratory, COPD and cancer mortality and incidence. Design: Prospective population based study. Setting: UK Biobank. Participants: Of the 502,628 (5.5% response rate) participants recruited by UK Biobank, we included 73,259 (14.6%) participants with available data in this analysis. Of these, 1,374 participants died and 4,210 developed circulatory diseases, 1,293 respiratory diseases and 4,281 cancer, over a median of 5.0 years [IQR 4.3–5.7] follow-up. Main outcome measures - All-cause mortality and circulatory disease, respiratory disease, chronic obstructive e pulmonary disease (COPD) and cancer (any-type, colorectal, lung, breast and prostate) mortality/incidence. Fitness was estimated with a submaximal cycle ergometer test. Results: The hazard ratio for all-cause mortality for each MET higher fitness was 0.96 ([95% CI 0.93–0.98]). Similar results were observed for incident circulatory (HR 0.96 [0.95–0.97]), respiratory disease (HR 0.96 [0.94–0.98]), COPD (HR 0.90 [0.86–0.95]), and colorectal cancer (HR 0.96 [0.92–1.00]). Nonlinear analysis revealed that a high level of fitness (&gt;10 METs) was associated with a greater incidence of atrial fibrillation (HR 1.24 [1.07–1.44]) and prostate cancer (HR 1.16 [1.02–1.32]) compared with average fitness. All results were adjusted for sociodemographic, lifestyle, and dietary factors, body composition, and morbidity at baseline and excluded events in the first 2 years of follow up. Conclusions: Higher cardiorespiratory fitness was associated with lower risk of premature mortality and incidence of cardiovascular, respiratory disease and colorectal cancer

The inflammatory microenvironment in colorectal neoplasia

Peer reviewedPublisher PD

Identification of key genes for carcinogenic pathways associated with colorectal adenoma-to-carcinoma progression

Colorectal adenomas form a biologically and clinically distinct intermediate stage in development of colorectal cancer (CRC) from normal colon epithelium. Only 5% of adenomas progress into adenocarcinomas, indicating that malignant transformation requires other biological alterations than those involved in adenoma formation. The present study aimed to explore which cancer-related biological processes are affected during colorectal adenoma-to-carcinoma progression and to identify key genes within these pathways that can serve as tumor markers for malignant transformation. The activity of 12 cancer-related biological processes was compared between 37 colorectal adenomas and 31 adenocarcinomas, using the pathway analysis tool Gene Set Enrichment Analysis. Expression of six gene sets was significantly increased in CRCs compared to adenomas, representing chromosomal instability, proliferation, differentiation, invasion, stroma activation, and angiogenesis. In addition, 18 key genes were identified for these processes based on their significantly increased expression levels. For AURKA and PDGFRB, increased mRNA expression levels were verified at the protein level by immunohistochemical analysis of a series of adenomas and CRCs. This study revealed cancer-related biological processes whose activities are increased during malignant transformation and identified key genes which may be used as tumor markers to improve molecular characterization of colorectal tumors

Phospholipase C Isozymes Are Deregulated in Colorectal Cancer – Insights Gained from Gene Set Enrichment Analysis of the Transcriptome

Colorectal cancer (CRC) is one of the most common cancer types in developed countries. To identify molecular networks and biological processes that are deregulated in CRC compared to normal colonic mucosa, we applied Gene Set Enrichment Analysis to two independent transcriptome datasets, including a total of 137 CRC and ten normal colonic mucosa samples. Eighty-two gene sets as described by the Kyoto Encyclopedia of Genes and Genomes database had significantly altered gene expression in both datasets. These included networks associated with cell division, DNA maintenance, and metabolism. Among signaling pathways with known changes in key genes, the “Phosphatidylinositol signaling network”, comprising part of the PI3K pathway, was found deregulated. The downregulated genes in this pathway included several members of the Phospholipase C protein family, and the reduced expression of two of these, PLCD1 and PLCE1, were successfully validated in CRC biopsies (n = 70) and cell lines (n = 19) by quantitative analyses. The repression of both genes was found associated with KRAS mutations (P = 0.005 and 0.006, respectively), and we observed that microsatellite stable carcinomas with reduced PLCD1 expression more frequently had TP53 mutations (P = 0.002). Promoter methylation analyses of PLCD1 and PLCE1 performed in cell lines and tumor biopsies revealed that methylation of PLCD1 can contribute to reduced expression in 40% of the microsatellite instable carcinomas. In conclusion, we have identified significantly deregulated pathways in CRC, and validated repression of PLCD1 and PLCE1 expression. This illustrates that the GSEA approach may guide discovery of novel biomarkers in cancer

Consensus Pathways Implicated in Prognosis of Colorectal Cancer Identified Through Systematic Enrichment Analysis of Gene Expression Profiling Studies

Background: A large number of gene expression profiling (GEP) studies on prognosis of colorectal cancer (CRC) has been performed, but no reliable gene signature for prediction of CRC prognosis has been found. Bioinformatic enrichment tools are a powerful approach to identify biological processes in high-throughput data analysis. Principal Findings: We have for the first time collected the results from the 23 so far published independent GEP studies on CRC prognosis. In these 23 studies, 1475 unique, mapped genes were identified, from which 124 (8.4%) were reported in at least two studies, with 54 of them showing consisting direction in expression change between the single studies. Using these data, we attempted to overcome the lack of reproducibility observed in the genes reported in individual GEP studies by carrying out a pathway-based enrichment analysis. We used up to ten tools for overrepresentation analysis of Gene Ontology (GO) categories or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways in each of the three gene lists (1475, 124 and 54 genes). This strategy, based on testing multiple tools, allowed us to identify the oxidative phosphorylation chain and the extracellular matrix receptor interaction categories, as well as a general category related to cell proliferation and apoptosis, as the only significantly and consistently overrepresented pathways in the three gene lists, which were reported by several enrichment tools. Conclusions: Our pathway-based enrichment analysis of 23 independent gene expression profiling studies on prognosis of CRC identified significantly and consistently overrepresented prognostic categories for CRC. These overrepresented categories have been functionally clearly related with cancer progression, and deserve further investigation

A Genome-Wide Study of Cytogenetic Changes in Colorectal Cancer Using SNP Microarrays: Opportunities for Future Personalized Treatment

In colorectal cancer (CRC), chromosomal instability (CIN) is typically studied using comparative-genomic hybridization (CGH) arrays. We studied paired (tumor and surrounding healthy) fresh frozen tissue from 86 CRC patients using Illumina's Infinium-based SNP array. This method allowed us to study CIN in CRC, with simultaneous analysis of copy number (CN) and B-allele frequency (BAF) - a representation of allelic composition. These data helped us to detect mono-allelic and bi-allelic amplifications/deletion, copy neutral loss of heterozygosity, and levels of mosaicism for mixed cell populations, some of which can not be assessed with other methods that do not measure BAF. We identified associations between CN abnormalities and different CRC phenotypes (histological diagnosis, location, tumor grade, stage, MSI and presence of lymph node metastasis). We showed commonalities between regions of CN change observed in CRC and the regions reported in previous studies of other solid cancers (e.g. amplifications of 20q, 13q, 8q, 5p and deletions of 18q, 17p and 8p). From Therapeutic Target Database, we identified relevant drugs, targeted to the genes located in these regions with CN changes, approved or in trials for other cancers and common diseases. These drugs may be considered for future therapeutic trials in CRC, based on personalized cytogenetic diagnosis. We also found many regions, harboring genes, which are not currently targeted by any relevant drugs that may be considered for future drug discovery studies. Our study shows the application of high density SNP arrays for cytogenetic study in CRC and its potential utility for personalized treatment