Changes in Gene Expression Profiles in Patients with Pulmonary Arterial Hypertension Associated with Scleroderma Treated with Tadalafil
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75173 | GEO | 2016/08/26
SECONDARY ACCESSION(S): PRJNA302682
REPOSITORIES: GEO
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Project description:RNA expression profiling was carried out for systemic sclerosis (scleroderma) on skin biopsies obtained from both diffuse scleroderma (dcSSc) and limited scleroderma (lcSSc) subjects patients and compared to normal subjects. The patient group comprised of 4 dcSSc and 2 lcSSc subjects, all of whom were Caucasian and belonged to the age range of 42-73 (Mean age = 61.6). Patient sample set consisted of 3 females and 3 males. Race matched female volunteers from the same geographical area were recruited as controls (n = 4) and belonged to the age range of 41-62 (Mean age = 52).
2015-03-25 | E-MEXP-1214 | biostudies-arrayexpress
Project description:This experiment was performed using the following cohorts: 1) healthy controls, 2) patients with scleroderma at low risk for pulmonary hypertension, 3) pateints with scleroderma at high risk for pulmonary hypertension who underwent a catheterization and were found to have normal pressures, borderline elevated pressures or pulmonary arterial hypertensino (PAH). Whole blood was drawn directly into EDTA tubes at rest and again at peak exercise for each human subject. The samples were processed to plasma by MCRU and stored at -80 in the Biorepository.
2017-06-19 | ST000763 | MetabolomicsWorkbench
Project description:Neutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased migration consistent with increased vinculin, identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature in PAH neutrophils and an increase in human endogenous retrovirus (HERV-K) envelope protein. NE and interferon genes are induced by HERV-K envelope and vinculin is increased by HERV-K dUTPase that is elevated in PAH plasma. Neutrophil exosomes from PAH plasma contain increased NE and HERV-K envelope and induce pulmonary hypertension in mice, that is mitigated by the NE inhibitor and antiviral agent, elafin. Thus elevated HERVs explain pathological neutrophils linked to PAH induction and progression.
2023-03-11 | PXD023134 | Pride
Project description:This experiment was performed using the following cohorts: 1) healthy controls, 2) patients with scleroderma at low risk for pulmonary hypertension, 3) pateints with scleroderma at high risk for pulmonary hypertension who underwent a catheterization and were found to have normal pressures, borderline elevated pressures or pulmonary arterial hypertensino (PAH). Whole blood was drawn directly into EDTA tubes at rest and again at peak exercise for each human subject. The samples were processed to plasma by MCRU and stored at -80 in the Biorepository.
2018-08-02 | MSV000082744 | GNPS
Project description:We have analyzed the genome-wide patterns of gene expression with DNA microarrays in skin biopsies from 34 subjects: 17 patients with SSc with diffuse scleroderma (dSSc), 7 patients with SSc with limited scleroderma (lSSc), 3 patients with morphea and 6 healthy controls. In total, 61 skin biopsies were analyzed. The addition of 14 technical replicates resulted in a total of 75 microarray hybridizations. The Intrinsic_scleroderma_genes.txt supplementary file lists the 995 genes with the most consistent expression between each forearm-back pair and technical replicates, but with the highest variance across all samples analyzed. An intrinsic gene identifier algorithm was used to select a set of intrinsic scleroderma genes. A total of 34 experimental groups were defined, each representing the 34 different subjects in our study. Replicate hybridizations for a given patient were assigned to the same experimental group. Each gene was analyzed and assigned a score that is inversely related to how intrinsic the gene's expression is across the samples analyzed. The analysis was repeated on randomized data in order to estimate a False Discovery Rate (FDR). An intrinsic score of 0.3 selected 995 genes with an FDR of 4% (39 ± 7 genes) while retaining reproducible clustering of technical replicates. Keywords: global gene expression profiling using Agilent Whole Human genome oligo arrays
2008-07-15 | GSE9285 | GEO
Project description:BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a progressive condition with no cure. Even with pharmacologic advances, survival remains poor. Lung pathology on PAH therapies still shows impressive occlusive arteriolar remodeling and plexiform lesions. Cardiosphere derived cells (CDCs) are heart derived progenitor cells exhibiting anti inflammatory and immunomodulatory effects, are anti fibrotic, anti oxidative and anti apoptotic to potentially impact several aspects of PAH pathobiology. In preclinical trials CDCs reduced right ventricular (RV) systolic pressure, RV hypertrophy, pulmonary arteriolar wall thickness and inflammation.
METHODS: The ALPHA study was a Phase 1a/b study in which CDCs were infused into patients with Idiopathic (I)PAH, Heritable (H) HPAH, PAH connective tissue disease (CTD ) and PAH human immunodeficiency virus (HIV). The study was IRB approved and DSMB monitored. Phase 1a, was an open label study (n=6). Phase 1b was a double blind placebo controlled study (n=20) in which half received 100 million CDCs (the maximum feasible dose from manufacturing perspective) and half placebo (PLAC) infusions. Right heart catheterization (RHC) and cardiac MR imaging (cMR) were performed at baseline and at 4 months post infusion. Patients were followed over a year.
FINDINGS: No short term clinical safety adverse events (AE) were related to the IP, the primary outcome measure. There were no adverse hemodynamic, gas exchange, rhythm or other clinical events following infusion and in the 1st 23 hours monitored in hospital. There were no long term AEs over 12 months noted, including unrelated limited hospitalizations. No immunologic short or long term AEs were noted. We examined exploratory outcomes across multiple domains to determine encouraging signals to motivate future advanced phase testing. Phase 1a data showed encouraging observations for both 50 and 100 million CDC doses. Several encouraging findings favoring CDCs (n=16) compared to placebo (n=10) were noted. On cMR, the RV end diastolic volume (RVEDV) and index (RVEDVI) decreased with CDCs with a rise in the PLAC group. The 6 minute walk distance was increased 2 months post infusion in the CDC group compared with PLAC. With PLAC, diffusing capacity (DLCO) decreased at 4 months but was unchanged with CDCs. Serum creatinine decreased with CDCs at 4 months. Encouraging observations favoring CDCs were also noted for RV fractional area change on echo and RV ejection fraction (RVEF) on cMR at 4 months. No differences were observed for mean pulmonary artery pressures or pulmonary vascular resistance. Review of long term data to 12 months showed continued decline in DLCO for the PLAC cohort at 6 months with no change through 12 months. By contrast, CDC subjects showed an unchanged DLCO over 12 months. For parameters exhibiting early encouraging exploratory findings in CDC subjects, no further improvement was noted in long term follow up through 12 months.
INTERPRETATION: Intravenous CDCs were safe in both the short and long term in PAH subjects and thus may be safe in larger cohorts, in line with our extensive track record of safety in clinical trials for other conditions. Further, CDCs exhibited encouraging exploratory findings across several domains. Repeat dosing (quarterly, over one year) of intravenous CDCs has been reported to yield highly significant sustained disease modifying bioactivity in subjects with advanced Duchenne muscular dystrophy. Because only single CDC doses were used here, the findings represent a lower limit estimate of CDCs potential in PAH. Upcoming phase 2 studies would logically use a repeat dosing paradigm.
2023-11-06 | MSV000093323 | MassIVE
Project description:We have analyzed the genome-wide patterns of gene expression with DNA microarrays in skin biopsies from 34 subjects: 17 patients with SSc with diffuse scleroderma (dSSc), 7 patients with SSc with limited scleroderma (lSSc), 3 patients with morphea and 6 healthy controls. In total, 61 skin biopsies were analyzed. The addition of 14 technical replicates resulted in a total of 75 microarray hybridizations. The Intrinsic_scleroderma_genes.txt supplementary file lists the 995 genes with the most consistent expression between each forearm-back pair and technical replicates, but with the highest variance across all samples analyzed. An intrinsic gene identifier algorithm was used to select a set of intrinsic scleroderma genes. A total of 34 experimental groups were defined, each representing the 34 different subjects in our study. Replicate hybridizations for a given patient were assigned to the same experimental group. Each gene was analyzed and assigned a score that is inversely related to how intrinsic the gene's expression is across the samples analyzed. The analysis was repeated on randomized data in order to estimate a False Discovery Rate (FDR). An intrinsic score of 0.3 selected 995 genes with an FDR of 4% (39 ± 7 genes) while retaining reproducible clustering of technical replicates. Keywords: global gene expression profiling using Agilent Whole Human genome oligo arrays common reference design; we used Universal Human Reference RNA (Stratagene) as our reference for every array; For every hybridization sample RNA was always labeled with Cy3, and reference RNA was always labeled with Cy5; Microarray hybridizations were performed for 61 RNA samples from 34 subjects resulting 61 hybridizations. Fourteen replicate hybridizations were added, resulting in a total of 75 microarray hybridizations.
2010-05-26 | E-GEOD-9285 | biostudies-arrayexpress
Project description:We hypothesize that transpulmonary metabolomic profiling will demonstrate a PAH-specific metabolic signature. We will examine organ-specific metabolism by measuring blood flowing into (pulmonary artery) and out of (pulmonary artery wedge) the pulmonary circulation at the time of right heart catheterization (RHC). We will compare PAH to patients without PH and to a disease control cohort with PH due to left heart disease (pulmonary ventrical hypertension - PVH).
2016-09-07 | ST000464 | MetabolomicsWorkbench
