Mutations of PIK3CA in gastric adenocarcinoma

BACKGROUND: Activation of the phosphatidylinositol 3-kinase (PI3K) through mutational inactivation of PTEN tumour suppressor gene is common in diverse cancer types, but rarely reported in gastric cancer. Recently, mutations in PIK3CA, which encodes the p110α catalytic subunit of PI3K, have been identified in various human cancers, including 3 of 12 gastric cancers. Eighty percent of these reported mutations clustered within 2 regions involving the helical and kinase domains. In vitro study on one of the "hot-spot" mutants has demonstrated it as an activating mutation. METHODS: Based on these data, we initiated PIK3CA mutation screening in 94 human gastric cancers by direct sequencing of the gene regions in which 80% of all the known PIK3CA mutations were found. We also examined PIK3CA expression level by extracting data from the previous large-scale gene expression profiling study. Using Significance Analysis of Microarrays (SAM), we further searched for genes that show correlating expression with PIK3CA. RESULTS: We have identified PIK3CA mutations in 4 cases (4.3%), all involving the previously reported hotspots. Among these 4 cases, 3 tumours demonstrated microsatellite instability and 2 tumours harboured concurrent KRAS mutation. Data extracted from microarray studies showed an increased expression of PIK3CA in gastric cancers when compared with the non-neoplastic gastric mucosae (p < 0.001). SAM further identified 2910 genes whose expression levels were positively associated with that of PIK3CA. CONCLUSION: Our data suggested that activation of the PI3K signalling pathway in gastric cancer may be achieved through up-regulation or mutation of PIK3CA, in which the latter may be a consequence of mismatch repair deficiency

Integration of DNA Copy Number Alterations and Transcriptional Expression Analysis in Human Gastric Cancer

Background: Genomic instability with frequent DNA copy number alterations is one of the key hallmarks of carcinogenesis. The chromosomal regions with frequent DNA copy number gain and loss in human gastric cancer are still poorly defined. It remains unknown how the DNA copy number variations contributes to the changes of gene expression profiles, especially on the global level. Principal Findings: We analyzed DNA copy number alterations in 64 human gastric cancer samples and 8 gastric cancer cell lines using bacterial artificial chromosome (BAC) arrays based comparative genomic hybridization (aCGH). Statistical analysis was applied to correlate previously published gene expression data obtained from cDNA microarrays with corresponding DNA copy number variation data to identify candidate oncogenes and tumor suppressor genes. We found that gastric cancer samples showed recurrent DNA copy number variations, including gains at 5p, 8q, 20p, 20q, and losses at 4q, 9p, 18q, 21q. The most frequent regions of amplification were 20q12 (7/72), 20q12-20q13.1 (12/72), 20q13.1-20q13.2 (11/72) and 20q13.2-20q13.3 (6/72). The most frequent deleted region was 9p21 (8/72). Correlating gene expression array data with aCGH identified 321 candidate oncogenes, which were overexpressed and showed frequent DNA copy number gains; and 12 candidate tumor suppressor genes which were down-regulated and showed frequent DNA copy number losses in human gastric cancers. Three networks of significantly expressed genes in gastric cancer samples were identified by ingenuity pathway analysis. Conclusions: This study provides insight into DNA copy number variations and their contribution to altered gene expression profiles during human gastric cancer development. It provides novel candidate driver oncogenes or tumor suppressor genes for human gastric cancer, useful pathway maps for the future understanding of the molecular pathogenesis of this malignancy, and the construction of new therapeutic targets. © 2012 Fan et al.published_or_final_versio

DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer

Background: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). Results: Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.016 and &lt; 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 (p &lt; 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. Conclusions: The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies

Dominância fiscal : uma investigação empírica sobre o caso brasileiro no período de 2003 a 2014

A estabilização econômica dos anos de 1990 e a adoção do tripé econômico, a partir de 1999, marcam o fim de um capítulo delicado da história brasileira; a partir de então, era necessária a existência de certa sintonia de políticas monetária e fiscal para a manutenção do controle dos diversos indicadores econômicos. Contudo, com essa reciprocidade na política econômica, são incitadas discussões sobre a orientação do governo na hora de definir suas prioridades nesse campo: as variáveis fiscais são priorizadas e, por conseguinte, determinadas, forçando as monetárias a se ajustarem – ou o contrário? A resposta para esse questionamento leva à discussão sobre a dominância fiscal. Assim, esse trabalho visa verificar empiricamente, usando das modelagens econométricas VAR e estudo de eventos, se há dominância fiscal ou monetária na economia brasileira e se a eficácia da política monetária mudou na transição do governo Lula para o governo Dilma. O resultado foi inconclusivo para o governo Lula e indicou dominância fiscal no governo Dilma. Ainda verificou-se não haver modificação na eficácia da política monetária.Economic stabilization, in the 1990s, and utilization of an economic tripod, after 1999, represents the end of a delicate chapter in Brazilian history. Ever since, it was necessary the existence of a certain agreement between monetary and fiscal politic, in order to maintain under control a variety of economic indicators. However, this reciprocity (in economic politic) starts discussions about the real government orientations when it comes to define its priority on this subject: are the fiscal variables priorized, and then, determined, forcing monetary variables to adjust themselves, or the opposite? The answer to these questions emerge from the fiscal dominance discussion. This paper intends to empiric verify, using econometric modeling VAR and event study, if there is fiscal dominance or monetary in Brazilian economy and whether the effectiveness of monetary politic has changed in the transition from Lula's government to the Dilma government. The result was inconclusive for the Lula government and indicated fiscal dominance in the Dilma government. There was still no change in the efficiency of the monetary politic.CAPE

Reply to 'Heritable germline epimutation is not the same as transgenerational epigenetic inheritance'

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Prognostic relevance of DNA copy number changes in colorectal cancer

In a study of 109 colorectal cancers, DNA copy number aberrations were identified by comparative genomic hybridization using a DNA microarray covering the entire genome at an average interval of less than 1 Mbase. Four patterns were revealed by unsupervised clustering analysis, one of them associated with significantly better prognosis than the others. This group contained tumours with short, dispersed, and relatively few regions of copy number gain or loss. The good prognosis of this group was not attributable to the presence of tumours showing microsatellite instability (NISI-H). Supervised methods were employed to determine those genomic regions where copy number alterations correlate significantly with multiple indices of aggressive growth (lymphatic spread, recurrence, and early death). Multivariate analysis identified DNA copy number loss at 18q12.2, harbouring a single gene, BRUNOL4 that encodes the Bruno-like 4 splicing factor, as an independent prognostic indicator. The data show that the different patterns of DNA copy number alterations in primary tumours reveal prognostic information and can aid identification of novel prognosis-associated genes. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.</p

qSOFA is a Poor Predictor of Short-Term Mortality in All Patients: A Systematic Review of 410,000 Patients

Background: To determine the validity of the Quick Sepsis-Related Organ Failure Assessment (qSOFA) in the prediction of outcome (in-hospital and 1-month mortality, intensive care unit (ICU) admission, and hospital and ICU length of stay) in adult patients with or without suspected infections where qSOFA was calculated and reported; Methods: Cochrane Central of Controlled trials, EMBASE, BIOSIS, OVID MEDLINE, OVID Nursing Database, and the Joanna Briggs Institute EBP Database were the main databases searched. All studies published until 12 April 2018 were considered. All studies except case series, case reports, and conference abstracts were considered. Studies that included patients with neutropenic fever exclusively were excluded. Results: The median AUROC for in-hospital mortality (27 studies with 380,920 patients) was 0.68 (a range of 0.55 to 0.82). A meta-analysis of 377,623 subjects showed a polled AUROC of 0.68 (0.65 to 0.71); however, it also confirmed high heterogeneity among studies (I2 = 98.8%, 95%CI 98.6 to 99.0). The median sensitivity and specificity for in-hospital mortality (24 studies with 118,051 patients) was 0.52 (range 0.16 to 0.98) and 0.81 (0.19 to 0.97), respectively. Median positive and negative predictive values were 0.2 (range 0.07 to 0.38) and 0.94 (0.85 to 0.99), respectively