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      Microarray analysis in pulmonary hypertension

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          Abstract

          Microarrays are a powerful and effective tool that allows the detection of genome-wide gene expression differences between controls and disease conditions. They have been broadly applied to investigate the pathobiology of diverse forms of pulmonary hypertension, namely group 1, including patients with idiopathic pulmonary arterial hypertension, and group 3, including pulmonary hypertension associated with chronic lung diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. To date, numerous human microarray studies have been conducted to analyse global (lung homogenate samples), compartment-specific (laser capture microdissection), cell type-specific (isolated primary cells) and circulating cell (peripheral blood) expression profiles. Combined, they provide important information on development, progression and the end-stage disease. In the future, system biology approaches, expression of noncoding RNAs that regulate coding RNAs, and direct comparison between animal models and human disease might be of importance.

          Abstract

          Comprehensive overview of compartment-specific microarray studies of material from pulmonary hypertension patients http://ow.ly/YEFO2

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          Most cited references70

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          Variance stabilization applied to microarray data calibration and to the quantification of differential expression.

          We introduce a statistical model for microarray gene expression data that comprises data calibration, the quantification of differential expression, and the quantification of measurement error. In particular, we derive a transformation h for intensity measurements, and a difference statistic Deltah whose variance is approximately constant along the whole intensity range. This forms a basis for statistical inference from microarray data, and provides a rational data pre-processing strategy for multivariate analyses. For the transformation h, the parametric form h(x)=arsinh(a+bx) is derived from a model of the variance-versus-mean dependence for microarray intensity data, using the method of variance stabilizing transformations. For large intensities, h coincides with the logarithmic transformation, and Deltah with the log-ratio. The parameters of h together with those of the calibration between experiments are estimated with a robust variant of maximum-likelihood estimation. We demonstrate our approach on data sets from different experimental platforms, including two-colour cDNA arrays and a series of Affymetrix oligonucleotide arrays.
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            Transcriptome Sequencing to Detect Gene Fusions in Cancer

            Recurrent gene fusions, typically associated with hematological malignancies and rare bone and soft tissue tumors1, have been recently described in common solid tumors2–9. Here we employ an integrative analysis of high-throughput long and short read transcriptome sequencing of cancer cells to discover novel gene fusions. As a proof of concept we successfully utilized integrative transcriptome sequencing to “re-discover” the BCR-ABL1 10 gene fusion in a chronic myelogenous leukemia cell line and the TMPRSS2-ERG 2,3 gene fusion in a prostate cancer cell line and tissues. Additionally, we nominated, and experimentally validated, novel gene fusions resulting in chimeric transcripts in cancer cell lines and tumors. Taken together, this study establishes a robust pipeline for the discovery of novel gene chimeras using high throughput sequencing, opening up an important class of cancer-related mutations for comprehensive characterization.
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              Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure.

              At present, six groups of chronic pulmonary hypertension (PH) are described. Among these, group 1 (and 1') comprises a group of diverse diseases termed pulmonary arterial hypertension (PAH) that have several pathophysiological, histological, and prognostic features in common. PAH is a particularly severe and progressive form of PH that frequently leads to right heart failure and premature death. The diagnosis of PAH must include a series of defined clinical parameters, which extend beyond mere elevations in pulmonary arterial pressures and include precapillary PH, pulmonary hypertensive arteriopathy (usually with plexiform lesions), slow clinical onset (months or years), and a chronic time course (years) characterized by progressive deterioration. What appears to distinguish PAH from other forms of PH is the severity of the arteriopathy observed, the defining characteristic of which is "plexogenic arteriopathy." The pathogenesis of this arteriopathy remains unclear despite intense investigation in a variety of animal model systems. The most commonly used animal models ("classic" models) are rodents exposed to either hypoxia or monocrotaline. Newer models, which involve modification of classic approaches, have been developed that exhibit more severe PH and vascular lesions, which include neointimal proliferation and occlusion of small vessels. In addition, genetically manipulated mice have been generated that have provided insight into the role of specific molecules in the pulmonary hypertensive process. Unfortunately, at present, there is no perfect preclinical model that completely recapitulates human PAH. All models, however, have provided and will continue to provide invaluable insight into the numerous pathways that contribute to the development and maintenance of PH. Use of both classic and newly developed animal models will allow continued rigorous testing of new hypotheses regarding pathogenesis and treatment. This review highlights progress that has been made in animal modeling of this important human condition.
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                Author and article information

                Journal
                Eur Respir J
                Eur. Respir. J
                ERJ
                erj
                The European Respiratory Journal
                European Respiratory Society
                0903-1936
                1399-3003
                13 April 2016
                July 2016
                : 48
                : 1
                : 229-241
                Affiliations
                [1 ]Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria
                [2 ]Dept of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany
                [3 ]Dept of Experimental Anaesthesiology, Medical University of Graz, Graz, Austria
                Author notes
                Grazyna Kwapiszewska, Ludwig Boltzmann Institute for Lung Vascular Research c/o ZMF, Stiftingtalstrasse 24, 8010 Graz, Austria. E-mail: Grazyna.Kwapiszewska@ 123456lvr.lbg.ac.at
                Article
                ERJ-02030-2015
                10.1183/13993003.02030-2015
                5009873
                27076594
                2927c36e-f682-45f6-8d57-43212ba8944e
                Copyright ©ERS 2016

                ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.

                History
                : 03 December 2015
                : 15 February 2016
                Categories
                Review
                7

                Respiratory medicine
                Respiratory medicine

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