Hypermethylation of TUSC5 genes in breast cancer tissue

Aim: Breast cancer (BC) is one of the most common forms of cancer amongst females. Early diagnosis, prognosis and therapy plays crucial role in the survival of patients with breast cancer. The study was aimed on identification of potential markers for early BC diagnostics by means of genome-wide comparative analysis of gene expression in cancer and normal tissue of breast. Methods: The analysis of gene expression in 15 invasive adenocarcinoma specimens and 15 normal breast tissue was conducted using the full-genome microarrays Sentrix HumanWD-6V3 BeadChip (Illumina). Methylation of TP53INK1 and TUSС5 promoters was interrogated by the combined bisulfite restriction analysis (COBRA). Results: Analysis of gene expression in the samples of breast adenocarcinoma revealed abnormal expression of more than 2,300 genes. While genes TFF1, S100P, ERBB2, TOP2A, CDF15, HOOK1, DNAJC12, CORO2A were up-regulated in cancer, decreased expression was found for genes TUSC5, SFRP1, PPPQR1B, NTRK4, TIMP4, BARD1, AKR1C2, TP53INK1 and others. Analysis of DNA methylation of TUSC5 by COBRA revealed higher levels of exon 1 methylation (11/12) in samples of breast cancer, whereas the gene was essentially unmethylated in matched normal appearing tissue of breast (2/12). TP53INK1 gene was methylated neither in cancer nor in normalcy. Conclusion: A total of 149 genes exhibited the highest difference in expression in cancer versus normal appearing tissue of breast. Most prominent down-regulated candidates, TUSC5 and TP53INK1, were reported for the first time in breast cancer and may be considered as potential markers of the disease. Aberrant DNA hypermethylation of TUSC5 suggests epigenetic mechanism of cancer associated down-regulation

Hypermethylation of TUSC5 genes in breast cancer tissue.

Breast cancer (BC) is one of the most common forms of cancer amongst females. Early diagnosis, prognosis and therapy plays crucial role in the survival of patients with breast cancer. The study was aimed on identification of potential markers for early BC diagnostics by means of genome-wide comparative analysis of gene expression in cancer and normal tissue of breast. The analysis of gene expression in 15 invasive adenocarcinoma specimens and 15 normal breast tissue was conducted using the full-genome microarrays Sentrix HumanWD-6V3 BeadChip (Illumina). Methylation of TP53INK1 and TUSС5 promoters was interrogated by the combined bisulfite restriction analysis (COBRA). Results: Analysis of gene expression in the samples of breast adenocarcinoma revealed abnormal expression of more than 2,300 genes. While genes TFF1, S100P, ERBB2, TOP2A, CDF15, HOOK1, DNAJC12, CORO2A were up-regulated in cancer, decreased expression was found for genes TUSC5, SFRP1, PPPQR1B, NTRK4, TIMP4, BARD1, AKR1C2, TP53INK1 and others. Analysis of DNA methylation of TUSC5 by COBRA revealed higher levels of exon 1 methylation (11/12) in samples of breast cancer, whereas the gene was essentially unmethylated in matched normal appearing tissue of breast (2/12). TP53INK1 gene was methylated neither in cancer nor in normalcy. Conclusion: A total of 149 genes exhibited the highest difference in expression in cancer versus normal appearing tissue of breast. Most prominent down-regulated candidates, TUSC5 and TP53INK1, were reported for the first time in breast cancer and may be considered as potential markers of the disease. Aberrant DNA hypermethylation of TUSC5 suggests epigenetic mechanism of cancer associated down-regulation. Key Words: differentially expressed genes, DNA methylation, breast cancer

Process Oriented Collaboration in Grid-Environments: A Case Study in the Construction Industry

This paper addresses the process-oriented collaboration based on a grid-based platform for the support of virtual organizations (VO), illustrated on the example of the construction industry. Distributed, organizational and IT-structures of teams involved in vintage complex projects cannot be managed with conventional methods in an appropriate manner. Both using a grid platform and grid-based services, in conjunction with semantic methods for consistency saving and goal-oriented process management can increase the efficiency of collaboration processes in large-scale projects. A hybrid grid- and web service-based architecture for the next generation of VO service and a gateway solution was developed integrating the process-oriented perspective and prototypically implemented. The problem, as well as the solution on the basis of the hybrid system architecture combing the benefits of the cutting-edge technologies, the methodical concept for modeling VO processes and their automated execution on a grid platform are discussed in detail

Coccinellids, Aphids, and Pollen in Diversified Vegetable Fields with Transgenic and Isoline Cultivars

The influence of concurrent introduction of three transgenic vegetable cultivars on seasonal dynamics of coccinellids and their food, aphids and pollen, was examined within diversified farm systems practicing insect pest management in northeastern US agroecosystems. The transgenic cultivars used included sweet corn, potato, and winter squash, expressing Cry1(A)b, Cry3A, and plant viral coat proteins that target Lepidoptera, Coleoptera, and aphid-transmitted viruses, respectively. Transgenic systems reduced insecticides by 25%. Weekly differences in coccinellid density between transgenic and isoline crops were rare and transitory, governed by timing of at-planting or foliar insecticide use patterns; however cumulative frequencies for three of the six coccinellid species differed between transgenic and isoline crops. At a multicrop, farm systems level, seasonal dynamics of the coccinellids and aphids tracked dynamics in the sweet corn, which far surpassed the other crops in abundance of coccinellids and pollen, and harbored consistently higher aphid densities. Although these results warrant further study, the patterns suggest that diversified transgenic vegetable crops under current commercial management demonstrated transitory conservation of coccinellids, and that integration with selective insecticides or other IPM tactics could increase this potential

Effects of three-body interactions on the structure and thermodynamics of liquid krypton

Large-scale molecular dynamics simulations are performed to predict the structural and thermodynamic properties of liquid krypton using a potential energy function based on the two-body potential of Aziz and Slaman plus the triple-dipole Axilrod-Teller (AT) potential. By varying the strength of the AT potential we study the influence of three-body contribution beyond the triple-dipole dispersion. It is seen that the AT potential gives an overall good description of liquid Kr, though other contributions such as higher order three-body dispersion and exchange terms cannot be ignored.Comment: 11 pages, 3 figures, LaTeX, to appear in J. Chem. Phy

DNA Methylation of the ABO Promoter Underlies Loss of ABO Allelic Expression in a Significant Proportion of Leukemic Patients

Background: Loss of A, B and H antigens from the red blood cells of patients with myeloid malignancies is a frequent occurrence. Previously, we have reported alterations in ABH antigens on the red blood cells of 55% of patients with myeloid malignancies. Methodology/Principal Findings: To determine the underlying molecular mechanisms of this loss, we assessed ABO allelic expression in 21 patients with ABH antigen loss previously identified by flow cytometric analysis as well as an additional 7 patients detected with ABH antigen changes by serology. When assessing ABO mRNA allelic expression, 6/12 (50%) patients with ABH antigen loss detected by flow cytometry and 5/7 (71%) of the patients with ABH antigen loss detected by serology had a corresponding ABO mRNA allelic loss of expression. We examined the ABO locus for copy number and DNA methylation alterations in 21 patients, 11 with loss of expression of one or both ABO alleles, and 10 patients with no detectable allelic loss of ABO mRNA expression. No loss of heterozygosity (LOH) at the ABO locus was observed in these patients. However in 8/11 (73%) patients with loss of ABO allelic expression, the ABO promoter was methylated compared with 2/10 (20%) of patients with no ABO allelic expression loss (P = 0.03). Conclusions/Significance: We have found that loss of ABH antigens in patients with hematological malignancies is associated with a corresponding loss of ABO allelic expression in a significant proportion of patients. Loss of ABO allelic expression was strongly associated with DNA methylation of the ABO promoter.Tina Bianco-Miotto, Damian J. Hussey, Tanya K. Day, Denise S. O'Keefe and Alexander Dobrovi

Sdhd and Sdhd/H19 Knockout Mice Do Not Develop Paraganglioma or Pheochromocytoma

BACKGROUND: Mitochondrial succinate dehydrogenase (SDH) is a component of both the tricarboxylic acid cycle and the electron transport chain. Mutations of SDHD, the first protein of intermediary metabolism shown to be involved in tumorigenesis, lead to the human tumors paraganglioma (PGL) and pheochromocytoma (PC). SDHD is remarkable in showing an 'imprinted' tumor suppressor phenotype. Mutations of SDHD show a very high penetrance in man and we postulated that knockout of Sdhd would lead to the development of PGL/PC, probably in aged mice. METHODOLOGY/PRINCIPAL FINDINGS: We generated a conventional knockout of Sdhd in the mouse, removing the entire third exon. We also crossed this mouse with a knockout of H19, a postulated imprinted modifier gene of Sdhd tumorigenesis, to evaluate if loss of these genes together would lead to the initiation or enhancement of tumor development. Homozygous knockout of Sdhd results in embryonic lethality. No paraganglioma or other tumor development was seen in Sdhd KO mice followed for their entire lifespan, in sharp contrast to the highly penetrant phenotype in humans. Heterozygous Sdhd KO mice did not show hyperplasia of paraganglioma-related tissues such as the carotid body or of the adrenal medulla, or any genotype-related pathology, with similar body and organ weights to wildtype mice. A cohort of Sdhd/H19 KO mice developed several cases of profound cardiac hypertrophy, but showed no evidence of PGL/PC. CONCLUSIONS: Knockout of Sdhd in the mouse does not result in a disease phenotype. H19 may not be an initiator of PGL/PC tumorigenesis

Somatic mutations in exocrine pancreatic tumors: association with patient survival.

KRAS mutations are major factors involved in initiation and maintenance of pancreatic tumors. The impact of different mutations on patient survival has not been clearly defined. We screened tumors from 171 pancreatic cancer patients for mutations in KRAS and CDKN2A genes. Mutations in KRAS were detected in 134 tumors, with 131 in codon 12 and only 3 in codon 61. The GGT>GAT (G12D) was the most frequent mutation and was present in 60% (80/134). Deletions and mutations in CDKN2A were detected in 43 tumors. Analysis showed that KRAS mutations were associated with reduced patient survival in both malignant exocrine and ductal adenocarcinomas (PDAC). Patients with PDACs that had KRAS mutations showed a median survival of 17 months compared to 30 months for those without mutations (log-rank P = 0.07) with a multivariate hazard ratio (HR) of 2.19 (95%CI 1.09-4.42). The patients with G12D mutation showed a median survival of 16 months (log-rank-test P = 0.03) and an associated multivariate HR 2.42 (95%CI 1.14-2.67). Although, the association of survival in PDAC patients with CDKN2A aberrations in tumors was not statistically significant, the sub-group of patients with concomitant KRAS mutations and CDKN2A alterations in tumors were associated with a median survival of 13.5 months compared to 22 months without mutation (log-rank-test P = 0.02) and a corresponding HR of 3.07 (95%CI 1.33-7.10). Our results are indicative of an association between mutational status and survival in PDAC patients, which if confirmed in subsequent studies can have potential clinical application

Deterministic Classifiers Accuracy Optimization for Cancer Microarray Data

The objective of this study was to improve classification accuracy in cancer microarray gene expression data using a collection of machine learning algorithms available in WEKA. State of the art deterministic classification methods, such as: Kernel Logistic Regression, Support Vector Machine, Stochastic Gradient Descent and Logistic Model Trees were applied on publicly available cancer microarray datasets aiming to discover regularities that provide insights to help characterization and diagnosis correctness on each cancer typology. The implemented models, relying on 10-fold cross-validation, parameterized to enhance accuracy, reached accuracy above 90%. Moreover, although the variety of methodologies, no significant statistic differences were registered between them, at significance level 0.05, confirming that all the selected methods are effective for this type of analysis.info:eu-repo/semantics/publishedVersio