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Hospital de Órbigo, Spain

Amarasinghe K.C.,University of Melbourne | Li J.,Bioinformatics Core Facility | Halgamuge S.K.,University of Melbourne
BMC Bioinformatics

Background: One of the main types of genetic variations in cancer is Copy Number Variations (CNV). Whole exome sequenicng (WES) is a popular alternative to whole genome sequencing (WGS) to study disease specific genomic variations. However, finding CNV in Cancer samples using WES data has not been fully explored. Results: We present a new method, called CoNVEX, to estimate copy number variation in whole exome sequencing data. It uses ratio of tumour and matched normal average read depths at each exonic region, to predict the copy gain or loss. The useful signal produced by WES data will be hindered by the intrinsic noise present in the data itself. This limits its capacity to be used as a highly reliable CNV detection source. Here, we propose a method that consists of discrete wavelet transform (DWT) to reduce noise. The identification of copy number gains/losses of each targeted region is performed by a Hidden Markov Model (HMM). Conclusion: HMM is frequently used to identify CNV in data produced by various technologies including Array Comparative Genomic Hybridization (aCGH) and WGS. Here, we propose an HMM to detect CNV in cancer exome data. We used modified data from 1000 Genomes project to evaluate the performance of the proposed method. Using these data we have shown that CoNVEX outperforms the existing methods significantly in terms of precision. Overall, CoNVEX achieved a sensitivity of more than 92% and a precision of more than 50%. © 2013 Amarasinghe et al. Source

Balamuth F.,Childrens Hospital of Philadelphia | Balamuth F.,University of Pennsylvania | Zhang Z.,Bioinformatics Core Facility | Rappaport E.,Childrens Hospital of Philadelphia | And 4 more authors.
Pediatric Emergency Care

Background: Adolescents are at high risk for pelvic inflammatory disease (PID). Because accurate diagnosis of PID is difficult, and complications of untreated PID are significant, novel methods to improve diagnosis are essential. Objectives: To determine if patients with PID have unique RNA expression patterns compared to controls. Methods: Peripheral blood was collected from adolescent females with PID in the emergency department, and from control patients in the operating room. RNAwas isolated, and microarray analysis was performed. Initial analysis involved a training set of 18 patients (9 PID patients with either Neisseria gonorrhoeae or Chlamydia trachomatis infection and 9 control patients). Supervised and unsupervised cluster analyses were performed, followed by network analysis. The training set was used to classify a set of 15 additional PID patients and 2 controls. Results: Supervised cluster analysis of the training set revealed 170 genes which were differentially expressed in PID patients versus controls. Network analysis indicated that several differentially expressed genes are involved in immune activation. Analysis of additional PID patients based on the training set findings revealed that patients with positive testing for Trichomonas vaginalis partitioned with the PID group, whereas patients with no organism identified partitioned with both groups. Conclusions: RNA sample collection fromadolescents in the emergency department is feasible. Genes were identified which were differentially expressed in PID patients versus controls, many of which are involved in inflammation. Future studies should confirm the training set findings on a larger sample and may lead to improved accuracy of PID diagnosis. © 2015 Wolters Kluwer Health, Inc. Source

Faner R.,Fundacio Privada Clinic per a la Recerca Biomedica | Faner R.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Faner R.,CIBER ISCIII | Gonzalez N.,Fundacio Privada Clinic per a la Recerca Biomedica | And 7 more authors.

Background: Tobacco smoking is the main risk factor of chronic obstructive pulmonary disease (COPD) but not all smokers develop the disease. An abnormal pulmonary and systemic inflammatory response to smoking is thought to play a major pathogenic role in COPD, but this has never been tested directly. Methods: We studied the systemic biomarker and leukocyte transcriptomic response (Affymetrix microarrays) to smoking exposure in 10 smokers with COPD and 10 smokers with normal spirometry. We also studied 10 healthy never smokers (not exposed to smoking) as controls. Because some aspects of COPD may differ in males and females, and the inflammatory response to other stressors (infection) might be different in man and women, we stratified participant recruitment by sex. Differentially expressed genes were validated by q-PCR. Ontology enrichment was evaluated and interaction networks inferred. Results: Principal component analysis identified sex differences in the leukocyte transcriptomic response to acute smoking. In both genders, we identified genes that were differentially expressed in response to smoking exclusively in COPD patients (COPD related signature) or smokers with normal spirometry (Smoking related signature), their ontologies and interaction networks. Conclusions: The use of an experimental intervention (smoking exposure) to investigate the transcriptomic response of peripheral leukocytes in COPD is a step beyond the standard case-control transcriptomic profiling carried out so far, and has facilitated the identification of novel COPD and Smoking expression related signatures which differ in males and females. © 2014 Faner et al. Source

Montraveta A.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Xargay-Torrent S.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Lopez-Guerra M.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Rosich L.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | And 9 more authors.

Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses.The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients. Source

Jordanovski D.,University of Cologne | Herwartz C.,University of Cologne | Pawlowski A.,University of Cologne | Taute S.,University of Cologne | And 3 more authors.

Activation of the hypoxia inducible transcription factor HIF and the NF-KB pathway promotes inflammation-mediated tumor progression. The cellular transcription factor ZNF395 has repeatedly been found overexpressed in various human cancers, particularly in response to hypoxia, implying a functional relevance. To understand the biological activity of ZNF395, we identified target genes of ZNF395 through a genome-wide expression screen. Induced ZNF395 expression led to the upregulation of genes known to play a role in cancer as well as a subset of interferon (IFN)-stimulated genes (ISG) involved in antiviral responses such as IFIT1/ISG56, IFI44 and IFI16. In cells that lack ZNF395, the IFN-α-mediated stimulation of these factors was impaired, demonstrating that ZNF395 is required for the full induction of these antiviral genes. Transient transfections revealed that ZNF395-mediated activation of the IFIT1/ISG56 promoter depends on the two IFN-stimulated response elements within the promoter and on the DNA-binding domain of ZNF395, a so-called C-clamp. We also show that IK{green}Bα kinase (IKK)-signaling is necessary to allow ZNF395 to activate transcription and simultaneously enhances its proteolytic degradation. Thus, ZNF395 becomes activated at the level of protein modification by IKK. Moreover, we confirm that the expression of ZNF395 is induced by hypoxia. Our results characterize ZNF395 as a novel factor that contributes to the maximal stimulation of a subset of ISGs. This transcriptional activity depends on IKK signaling further supporting a role of ZNF395 in the innate immune response. Given these results it is possible that under hypoxic conditions, elevated levels of ZNF395 may support inflammation and cancer progression by activating the target genes involved in the innate immune response and cancer. © 2013 Steger et al. Source

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