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  • 1
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    Abstract 9929: Epigenome-Wide-Association-Study Characterizes DNA Methylation Changes Associated With Lung and Right Ventricle Dysfunction in Pulmonary Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy associated with pulmonary arteries remodeling and right ventricle (RV) dysfunction. Epigenetic dysregulation, including altered DNA methylation (DNAm), promotes PAH. However, the DNAm changes associated with PAH remain unexplored in human PAH RV and lungs. We conducted an exploratory study using human lung and RV samples to characterize the DNA methylome and transcriptomic changes associated with PAH. Methods/Results: We observed that PAH is associated with substantial changes in the DNAm landscape in both organs. We identified 88 identical differentially methylated probe (DMP) in both PAH Lungs and RV. Functionally, we observed that 65, and 76 of those DMP correlate with myocardial fibrosis and adverse pulmonary vascular remodeling, respectively. Then we clustered DMP onto functional differentially methylated region (DMR) and reported that 41% and 11.5% of the genes carrying a DMR are differentially expressed in PAH RV and lungs, respectively. Gene ontology analysis suggests that both impaired DNAm (DNA methylome) and genes expression (RNA sequencing) observed in PAH regulate biological functions related to inflammation, fibrosis, cell proliferation and vascular remodeling. Impaired DNAm landscape observed in PAH RV and lung is associated with the disease severity and contributes to 4.1% and 2.7% of the whole transcriptomic reprograming associated with PAH development in RV and lungs samples, respectively. Despite the modest overlap between DNAm and transcriptomic changes, we observed that DNAm affects genes and molecular pathways involved in PAH development. Conclusion: Although exploratory, our study is the first to characterize the DNAm and transcriptomic change associated with PAH in human RV and lung. Our data suggest that impaired DNAm landscape might contribute to the disease development/severity.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.9929
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 1466401-X
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  • 2
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    BET Protein Inhibition for Pulmonary Arterial Hypertension: A Pilot Clinical Trial
    American Thoracic Society ; 2022
    In:  American Journal of Respiratory and Critical Care Medicine Vol. 205, No. 11 ( 2022-06-01), p. 1357-1360
    Details
    In: American Journal of Respiratory and Critical Care Medicine, American Thoracic Society, Vol. 205, No. 11 ( 2022-06-01), p. 1357-1360
    Type of Medium: Online Resource
    ISSN: 1073-449X , 1535-4970
    URL: Article
    DOI: 10.1164/rccm.202109-2182LE
    RVK:
    XA 21200
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 2022
    detail.hit.zdb_id: 1468352-0
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  • 3
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    Identification of Long Noncoding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 142, No. 15 ( 2020-10-13), p. 1464-1484
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 142, No. 15 ( 2020-10-13), p. 1464-1484
    Abstract: Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long noncoding RNAs are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown. Methods: Expression of the long noncoding RNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV or decompensated RV based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in 2 rat models mimicking RV failure, namely the monocrotaline and pulmonary artery banding. Echocardiographic, hemodynamic, histological, and biochemical analyses were conducted. In vitro gain- and loss-of-function experiments were performed in rat cardiomyocytes. Results: We demonstrated that H19 is upregulated in decompensated RV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in monocrotaline and pulmonary artery banding rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in monocrotaline and pulmonary artery banding rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated upregulation of enhancer of zeste homolog 2. In vitro, knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in 2 independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels or the risk score proposed by both REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) and the 2015 European Pulmonary Hypertension Guidelines. Conclusions: Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.120.047626
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
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  • 4
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    Abstract 10900: Implication of the Post-Translational Formation of Hypusine in Eif5a in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Pulmonary Arterial Hypertension (PAH) is characterized by progressive pulmonary arteries (PAs) obstruction leading to heart failure and death. PA smooth muscle cells (PASMCs) of PAH patients display a “cancer-like” phenotype that contributes to PA remodeling. Eukaryotic translation initiation factor 5A (eIF5A) was shown to provide cancer cells with a competitive advantage by increasing translation of mRNAs with oncogenic proprieties, many of them containing proline/glycine-rich patterns. Strikingly, eIF5A is the only protein containing the unique, polyamine-derived amino acid hypusine, which is required for its function. Hypusine formation is catalyzed by the sequential actions of deoxyhypusine synthase (DHPS) and deoxyhypusine hydrolase (DOHH). We hypothesized that increased eiF5A Hyp in PAH-PASMCs is required to promote translational efficiency of a set of factors conferring a higher survival and fibroproliferative capacity, leading to pulmonary vascular remodeling. Data derived from a comparative proteomic analysis (LC-MSMS) between normal and PAH-PASMCs and confirmed by Western blot indicate that DHPS and DOHH are overexpressed in PAH-PASMCs compared to controls (p 〈 0.05). Consistently, both total and hypusinated forms of eIF5A were found up-regulated in dissected PAs and PASMCs from PAH patients and animal models (MCT and Su/Hx rats, p 〈 0.05). In vitro , inhibition of DHPS and DOHH, using GC7 and ciclopirox, respectively, significantly attenuates PAH-PASMCs survival and proliferation, (Annexin V; Ki67 labeling and EdU incorporation, p 〈 0.01). These effects were confirmed by a reduced expression eiF5A Hyp , MCM2, PCNA and Survivin (p 〈 0.01) and a downregulation of BRD4, EP300 and COL1, three factors implicated in PAH containing proline/glycine-rich patterns. In vivo , inhibition of DHPS using GC7 in MCT rats with established PAH improves hemodynamics (RVSP, mPAP, CO, p 〈 0.05) and vascular remodeling (EVG, p 〈 0.05). Furthermore, preliminary data indicate that smooth muscle cells-targeted inactivation of one allele of Dhps tends to confer protection against Su/Hx-induced PAH in mice. We showed for the first time that hypusine signaling is implicated in PAH development and represents a new promising therapeutic target.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.10900
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 5
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    Abstract 150: Targeting The Lipogenic Enzyme ATP Citrate Lyase As A Potential Therapy Against Coronary Artery Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 43, No. Suppl_1 ( 2023-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 43, No. Suppl_1 ( 2023-05)
    Abstract: Introduction: Coronary artery disease (CAD) such as coronary stenosis and intra vein graft stenosis are characterized by a cancer-like pro-proliferative and apoptosis-resistant phenotype of smooth muscle cells (SMCs), fueled by a metabolic shift toward glycolysis and interconnected global changes in the epigenetic landscape. The nucleo-cytoplasmic enzyme ATP Citrate Lyase (ACLY) has recently emerged as a key player and therapeutic target in cancer by favoring Warburg effect, lipid synthesis and chromatin remodeling. However, its role in CAD is still unknown. We hypothesized that ACLY is upregulated in CAD and supports the abnormal phenotype of CAD-CoASMCs. Methods and Results: ACLY expression positively correlates with vascular remodeling (aSMA labeling) in human distal coronary artery (CoAs, p 〈 0,01) as well as in dog saphenous vein (SV) graft from bypass surgery (p 〈 0,05). Increased expression and activation (phosphorylation) of ACLY were also observed in CoASMCs isolated from CAD patients (immunoblot, p 〈 0,01) with preferential localization in the nucleus (immunofluorescence ACLY labelling (p 〈 0,001)). Pharmacological (BMS303141) or molecular (siRNA) ACLY inhibition resulted in decreased survival, proliferation (immunoblot: PCNA, MCM2 and SURVIVIN (p 〈 0,05) & immunofluorescence Ki67 and Annexin V labelling (p 〈 0,001)), histones acetylation (immunoblot: acH3K27 and acH4 (p 〈 0,05)) and reversed Warburg effect (immunoblot: pPDH, LDHA, PFKBP3 (p 〈 0,01) & seahorse assays (p 〈 0,05)) of CAD-CoASMC. RNA sequencing analysis showed that ACLY molecular inhibition in CAD-CoASMC mostly affectes cell cycle and cell proliferation pathways. Ex-vivo, ACLY inhibition attenuates vascular remodeling (EVG staining) in human CoAs and SVs rings denuded of endothelial cells and exposed to growth factors (p 〈 0,05). In vivo, SMS-targeted loss of Acly in mice model of carotid artery denudation injury prevents vascular remodeling (p 〈 0,05). Same results are observed with pharmacological inhibition of ACLY (BMS303141 & bempedoic acid) in carotid artery wire injury rat model (p 〈 0,05). Conclusion: We demonstrated that ACLY is implicated in vascular remodeling in CAD and its Pharmacological inhibition may represent a novel avenue as therapeutic treatment.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.43.suppl_1.150
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 1494427-3
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  • 6
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    Implication of EZH2 in the Pro-Proliferative and Apoptosis-Resistant Phenotype of Pulmonary Artery Smooth Muscle Cells in PAH: A Transcriptomic and Proteomic Approach
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 6 ( 2021-03-15), p. 2957-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 6 ( 2021-03-15), p. 2957-
    Abstract: Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by a sustained elevation of pulmonary artery (PA) pressure, right ventricular failure, and premature death. Enhanced proliferation and resistance to apoptosis (as seen in cancer cells) of PA smooth muscle cells (PASMCs) is a major pathological hallmark contributing to pulmonary vascular remodeling in PAH, for which current therapies have only limited effects. Emerging evidence points toward a critical role for Enhancer of Zeste Homolog 2 (EZH2) in cancer cell proliferation and survival. However, its role in PAH remains largely unknown. The aim of this study was to determine whether EZH2 represents a new factor critically involved in the abnormal phenotype of PAH-PASMCs. We found that EZH2 is overexpressed in human lung tissues and isolated PASMCs from PAH patients compared to controls as well as in two animal models mimicking the disease. Through loss- and gain-of-function approaches, we showed that EZH2 promotes PAH-PASMC proliferation and survival. By combining quantitative transcriptomic and proteomic approaches in PAH-PASMCs subjected or not to EZH2 knockdown, we found that inhibition of EZH2 downregulates many factors involved in cell-cycle progression, including E2F targets, and contributes to maintain energy production. Notably, we found that EZH2 promotes expression of several nuclear-encoded components of the mitochondrial translation machinery and tricarboxylic acid cycle genes. Overall, this study provides evidence that, by overexpressing EZH2, PAH-PASMCs remove the physiological breaks that normally restrain their proliferation and susceptibility to apoptosis and suggests that EZH2 or downstream factors may serve as therapeutic targets to combat pulmonary vascular remodeling.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22062957
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 7
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    R-Crizotinib predisposes to and exacerbates pulmonary arterial hypertension in animal models
    European Respiratory Society (ERS) ; 2021
    In:  European Respiratory Journal Vol. 57, No. 5 ( 2021-05), p. 2003271-
    Details
    In: European Respiratory Journal, European Respiratory Society (ERS), Vol. 57, No. 5 ( 2021-05), p. 2003271-
    Type of Medium: Online Resource
    ISSN: 0903-1936 , 1399-3003
    URL: Article
    URL: Article
    DOI: 10.1183/13993003.03271-2020
    DOI: 10.1183/13993003.03271-2020.Shareable1
    Language: English
    Publisher: European Respiratory Society (ERS)
    Publication Date: 2021
    detail.hit.zdb_id: 2834928-3
    detail.hit.zdb_id: 1499101-9
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  • 8
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    Transcriptional profiling unveils molecular subgroups of adaptive and maladaptive right ventricular remodeling in pulmonary hypertension
    Springer Science and Business Media LLC ; 2023
    In:  Nature Cardiovascular Research Vol. 2, No. 10 ( 2023-09-28), p. 917-936
    Details
    In: Nature Cardiovascular Research, Springer Science and Business Media LLC, Vol. 2, No. 10 ( 2023-09-28), p. 917-936
    Abstract: Right ventricular (RV) function is critical to prognosis in all forms of pulmonary hypertension. Here we perform molecular phenotyping of RV remodeling by transcriptome analysis of RV tissue obtained from 40 individuals, and two animal models of RV dysfunction of both sexes. Our unsupervised clustering analysis identified ‘early’ and ‘late’ subgroups within compensated and decompensated states, characterized by the expression of distinct signaling pathways, while fatty acid metabolism and estrogen response appeared to underlie sex-specific differences in RV adaptation. The circulating levels of several extracellular matrix proteins deregulated in decompensated RV subgroups were assessed in two independent cohorts of individuals with pulmonary arterial hypertension, revealing that NID1, C1QTNF1 and CRTAC1 predicted the development of a maladaptive RV state, as defined by magnetic resonance imaging parameters, and were associated with worse clinical outcomes. Our study provides a resource for subphenotyping RV states, identifying state-specific biomarkers, and potential therapeutic targets for RV dysfunction.
    Type of Medium: Online Resource
    ISSN: 2731-0590
    URL: Article
    DOI: 10.1038/s44161-023-00338-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 3076837-8
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  • 9
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    Abstract 10904: Integrins Signaling Represents an Exciting Therapeutic Avenue to Counter Vascular Remodeling and Right Ventricular Failure in Pulmonary Arterial Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: Pulmonary arterial hypertension (PAH) is characterized by progressive obstruction of pulmonary arteries (PAs), culminating in right ventricular (RV) failure and premature death. Like cancer cells, PA smooth muscle cells (PASMCs) isolated from PAH patients exhibit exaggerated proliferation and resistance to apoptosis in response to extracellular matrix remodeling. Integrins, members of the cell adhesion receptors superfamily, are known to promote cell proliferation, survival, hypertrophic growth and fibrosis, which are key elements contributing to PAs remodeling and RV failure. Therefore, we hypothesized that integrins signaling could promote PAH-PASMC proliferation and resistance to apoptosis contributing to PAs vascular remodeling, and RV maladaptive hypertrophy and fibrosis, leading to RV failure. Using NanoString, we found that members of the fibronectin-binding integrin (FiBI) family were the most abundantly expressed in PASMCs and RV fibroblasts (RVFbs) isolated from PAH patients. By western blot (WB), we showed that FiBIs expression is significantly changed in distal PAs, PASMCs, PA endothelial cells and decompensated RV from PAH patients compared to controls (p 〈 0.05). In vitro , pharmacological inhibition of FiBIs decreases PAH-PASMCs proliferation (WB: PLK1; Ki67 labeling; p 〈 0.05, n=5) and resistance to apoptosis (WB: Survivin; Annexin V labeling; p 〈 0.05, n=5). These effects were associated with a decreased activation of FiBIs downstream signaling, FAK and MAPK pathways. In adult rat cardiomyocytes and human RVFbs, FiBIs inhibition decreases phenylephrine-induced hypertrophy (f-actin labeling; p 〈 0.001) and TGFβ1-induced RVFb activation (WB: αSMA, and Col1; p 〈 0.05). In vivo , in both moncrotaline and sugen/hypoxia rats with established PAH, pharmacological inhibition of FiBIs alone or in combination with macitentan and tadalafil improves hemodynamic (mPAP, CO, TAPSE, RVFAC; p 〈 0.05) and vascular remodeling (EVG; p 〈 0.01). In the PA banding rat model, inhibition of FiBIs attenuates RV failure (CO, TAPSE, RVEDP, RVFAC; p 〈 0.01). Our results suggest that integrins play a key role in the pathophysiology of PAH in both the lungs and the RV. Their inhibition provided significant beneficial effects both in vitro and in vivo .
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.10904
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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  • 10
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    Abstract 15564: Transcriptional Profiling Unveils New Molecular Subgroups of Adaptive and Maladaptive Right Ventricular Remodeling in Pulmonary Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Circulation Vol. 146, No. Suppl_1 ( 2022-11-08)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 146, No. Suppl_1 ( 2022-11-08)
    Abstract: The right ventricle (RV) function plays a crucial role in the prognosis and functional outcome of PAH (Pulmonary Arterial Hypertension) patients. However, RV remodeling and its underlying mechanisms in PAH, and the molecular phenotype of RV in different disease conditions are poorly understood. Therefore, we designed this study to deeply investigate molecular changes underlying right ventricular remodeling and dysfunction in PAH. To this aim, we generated RNA-seq data from 40 patients' RV tissues, clinically classified in adaptive versus maladaptive RV hypertrophy. Using an unsupervised clustering-based analysis, we identified “early” and “late” subgroups in both diseased RV states, associated with patients’ hemodynamic profiles. We then demonstrated that the compensated RV is characterized by an upregulation of cell cycle-associated genes and mitochondrial respiration, whereas excessive levels of extracellular matrix components were central in the decompensation phase. However, dysregulation of fatty acid β-oxidation characterized the early decompensation phase. Furthermore, a comparative analysis from 30 RV samples of monocrotaline (MCT)-induced rat model largely confirmed the stage-specific molecular phenotypes, along with subgroups identification. Finally, we assessed the circulating levels of several dysregulated proteins in two independent cohorts of PAH patients and introduced a panel of five ECM-related proteins that had a significant alteration in patients with compensated vs. decompensated RV in both cohorts. Among those, NID1, C1QTNF1, and CRTAC1 demonstrated higher importance in predicting the development of maladaptive RV hypertrophy in both cohorts, while the correlation of their expression with cardiac functions confirmed their potential biomarker capacity in the prognosis of PAH-associated RV hypertrophy and failure. In conclusion, this comprehensive transcriptome study revealed new subgroups of human RV hypertrophy beyond the clinical measurements, while combination with proteome analysis proposed a panel of potential PAH biomarkers related to patients' RV function. Furthermore, our comparative analysis of two species supports the relevance of current animal models to explore new targets.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.146.suppl_1.15564
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
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