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      Differential expression and analysis of extrachromosomal circular DNAs as serum biomarkers in pulmonary arterial hypertension


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          Extrachromosomal circular DNAs (eccDNAs) have been reported to play a key role in the occurrence and development of various diseases. However, the characterization and role of eccDNAs in pulmonary arterial hypertension (PAH) remain unclear.


          In the discovery cohort, we first explored eccDNA expression profiles by Circle-sequencing analysis. The candidate eccDNAs were validated by routine polymerase chain reaction (PCR), TOPO-TA cloning and Sanger sequencing. In the validation cohort, 30 patients with PAH and 10 healthy controls were recruited for qPCR amplification to detect the candidate eccDNAs. Datas at the baseline were collected, including clinical background, biochemical variables, echocardiography and hemodynamic factors. Receiver operating characteristic curve was used to investigate the diagnostic effect of the eccDNA.


          We identified a total of 21,741 eccDNAs in plasma samples of 3 IPAH patients and 3 individuals in good health, and the expression frequency, GC content, length distribution, and genome distribution of the eccDNAs were thoroughly characterized and analyzed. In the validation cohort, 687 eccDNAs were differentially expressed in patients with IPAH compared with healthy controls (screening threshold: |FC|≥2 and P < 0.05). Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the specific eccDNAs in IPAH were significantly enriched in calcium channel activity, the mitogen-activated protein kinase pathway, and the wnt signaling pathway. Verification queue found that the expression of eccDNA-chr2:131208878–131,424,362 in PAH was considerably higher than that in healthy controls and exhibited a high level of accuracy in predicting PAH with a sensitivity of 86.67% and a specificity of 90%. Furthermore, correlation analysis disclosed a significant association between serum eccDNA-chr2:131208878–131,424,362 and mean pulmonary artery pressure (mPAP) ( r = 0.396, P = 0.03), 6 min walking distance (6MWD) ( r = -0.399, P = 0.029), N-terminal pro-B-type natriuretic peptide (NT-proBNP) ( r = 0.685, P < 0.001) and cardiac index (CI) ( r = − 0.419, P = 0.021).


          This is the first study to identify and characterize eccDNAs in patients with PAH. We revealed that serum eccDNA-chr2:131208878–131,424,362 is significantly overexpressed and can be used in the diagnosis of PAH, indicating its potential as a novel non-invasive biomarker.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12931-024-02808-z.

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          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.

            The rapid technological developments of the past decade and the changes in echocardiographic practice brought about by these developments have resulted in the need for updated recommendations to the previously published guidelines for cardiac chamber quantification, which was the goal of the joint writing group assembled by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. This document provides updated normal values for all four cardiac chambers, including three-dimensional echocardiography and myocardial deformation, when possible, on the basis of considerably larger numbers of normal subjects, compiled from multiple databases. In addition, this document attempts to eliminate several minor discrepancies that existed between previously published guidelines.
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                Author and article information

                Respir Res
                Respir Res
                Respiratory Research
                BioMed Central (London )
                25 April 2024
                25 April 2024
                : 25
                : 181
                [1 ]Department of Respiratory Medicine, Zhongda Hospital of Southeast University, ( https://ror.org/01k3hq685) Dingjiaqiao 87, Nanjing City, Jiangsu Province 210000 People’s Republic of China
                [2 ]Center of Pathology and Clinical Laboratory, Sir Run Run Hospital, Nanjing Medical University, ( https://ror.org/059gcgy73) Nanjing, 210000 People’s Republic of China
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                : 29 October 2023
                : 6 April 2024
                Funded by: National Natural Science Foundation of China
                Award ID: grant number 82170063
                Funded by: Science Foundation of Ministry of Health of Jiangsu Province in China
                Award ID: grant number ZDA2020016
                Funded by: 2021 Jiangsu Shuangchuang (Mass Innovation and Entrepreneurship) Talent Program
                Award ID: grant number JSSCBS20210147
                Funded by: the Open Fund of the State Key Laboratory of Medical Biotechnology, Nanjing University
                Award ID: grant number KF-202305
                Custom metadata
                © BioMed Central Ltd., part of Springer Nature 2024

                Respiratory medicine
                eccdna,pulmonary arterial hypertension,high-throughput sequencing,differential expression,biomarker


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