Molecular Profiles Associated with Calcineurin Inhibitor Toxicity Post-Kidney Transplant: Input to Chronic Allograft Dysfunction
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Catherine Dumur
PROVIDER: E-GEOD-53605 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The molecular basis of calcineurin inhibitor toxicity (CNIT) in kidney transplantation (KT) and its contribution to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA) were evaluated. Molecular signatures characterizing CNIT samples were identified. The recognized CNIT gene signature was most common in patients with decreased graft function and histological evidence of IF/TA.
2014-06-01 | GSE53605 | GEO
Project description:Histological features of acute rejection can be detected in surveillance biopsies despite stable graft function and can negatively impact graft outcomes. However, routine surveillance biopsies for detection of subclinical rejection are not generally performed due to potential risks and costs associated with repeated biopsies. Noninvasive biomarkers are required to facilitate early detection of acute rejection and borderline changes. We examined the impact of histological abnormalities at 3-month in surveillance biopsies on graft outcomes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study. We then performed RNA sequencing on whole blood collected at the time of biopsy in 88 patients (22 vs. 66) to identify transcripts associated with histological abnormalities. Subjects with subclinical ACR or borderline ACR at 3 month (ACR-3) had higher risk of subsequent clinical acute rejection at 12 and 24 month (P < 0.05), more rapid functional decline (P < 0.05) and a decreased graft survival in adjusted cox analysis (P < 0.01) than patients with no abnormalities on 3-month biopsy. We then identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3.
2019-09-11 | GSE120396 | GEO
Project description:Histological features of acute rejection can be detected in surveillance biopsies despite stable graft function and can negatively impact graft outcomes. However, routine surveillance biopsies for detection of subclinical rejection are not generally performed due to potential risks and costs associated with repeated biopsies. Noninvasive biomarkers are required to facilitate early detection of acute rejection and borderline changes. We examined the impact of histological abnormalities at 3-month in surveillance biopsies on graft outcomes in kidney transplant recipients from the prospective Genomics of Chronic Allograft Rejection (GoCAR) study. We then performed RNA sequencing on whole blood collected at the time of biopsy in 88 patients (22 vs. 66) to identify transcripts associated with histological abnormalities. Subjects with subclinical ACR or borderline ACR at 3 month (ACR-3) had higher risk of subsequent clinical acute rejection at 12 and 24 month (P < 0.05), more rapid functional decline (P < 0.05) and a decreased graft survival in adjusted cox analysis (P < 0.01) than patients with no abnormalities on 3-month biopsy. We then identified a 17-gene signature in peripheral blood that accurately diagnosed ACR-3. The gene set was then validated for diagnosis of ACR-3 using microarray data (N=65; 12 vs. 53; 26 overlapping with the RNAseq cohort).
2019-09-11 | GSE120397 | GEO
Project description:The histological evaluation of liver via biopsy remains as the standard for the diagnosis of both acute cellular rejection (ACR) and recurrent hepatitis C (RHC) after liver transplantation. Nevertheless, it is often difficult to diagnose ACR in HCV-positive recipients because of common co-existing and overlapping morphological changes with RHC. The aim of the study was to identify potential target genes for ACR in recipients with RHC. We analyzed 22 liver biopsy samples obtained from 21 HCV-positive recipients. The clinicopathological diagnoses for the biopsies were ACR-predominant with superimposed RHC in 9 samples (ACR group) and RHC with no ACR (non-ACR group) in the remaining. We compared the transcriptional alterations between the two groups with oligonucleotide microarray and selected 2206 genes which were significantly modulated in ACR. Subsequently we analyzed the regulatory networks in ACR using Ingenuity Pathway Analysis, and focused on 5 genes (IFNAR1, IL-12RB2, NFATC3, BMP2, and CASP8) from the core network as the target genes for ACR. In conclusion, our results demonstrated that novel transcriptome patterns of ACR and concurrent RHC were present and distinct from recipients with only RHC, suggesting that gene expression profiling may have a role in the diagnosis of ACR in recipients with hepatitis C. Keywords: Gene identification in ACR with recurrent HCV infection
2009-08-05 | GSE13440 | GEO
Project description:The histological evaluation of liver via biopsy remains as the standard for the diagnosis of both acute cellular rejection (ACR) and recurrent hepatitis C (RHC) after liver transplantation. Nevertheless, it is often difficult to diagnose ACR in HCV-positive recipients because of common co-existing and overlapping morphological changes with RHC. The aim of the study was to identify potential target genes for ACR in recipients with RHC. We analyzed 22 liver biopsy samples obtained from 21 HCV-positive recipients. The clinicopathological diagnoses for the biopsies were ACR-predominant with superimposed RHC in 9 samples (ACR group) and RHC with no ACR (non-ACR group) in the remaining. We compared the transcriptional alterations between the two groups with oligonucleotide microarray and selected 2206 genes which were significantly modulated in ACR. Subsequently we analyzed the regulatory networks in ACR using Ingenuity Pathway Analysis, and focused on 5 genes (IFNAR1, IL-12RB2, NFATC3, BMP2, and CASP8) from the core network as the target genes for ACR. In conclusion, our results demonstrated that novel transcriptome patterns of ACR and concurrent RHC were present and distinct from recipients with only RHC, suggesting that gene expression profiling may have a role in the diagnosis of ACR in recipients with hepatitis C. Keywords: Gene identification in ACR with recurrent HCV infection Of 22 liver biopsy samples, 9 represented the clinicopathological diagnoses for ACR-predominant with superimposed RHC (ACR group) and 13 represented the clinicopathological diagnoses for RHC with no ACR (non-ACR group) .
2010-05-15 | E-GEOD-13440 | biostudies-arrayexpress
Project description:Aims. Serial invasive endomyocardial biopsies (EMB) remain the gold standard for acute cellular rejection (ACR) diagnosis. However histological grading has several limitations. We aimed to explore the value of myocardial Gene Expression Profiling (GEP) for diagnosing and identifying predictive biomarkers of ACR. Methods. A case-control study nested within a retrospective heart transplant patients cohort included 126 patients with median (IQR) age 50 (41-57) years and 111 (88%) males. Among 1157 EMB performed, 467 were eligible (i.e, corresponding to either ISHLT grade 0 or â¥3A), among which 36 were selected for GEP according to the grading: 0 (CISHLT, n= 13); rejection â¥3A (RISHLT, n=13); 0 one month before ACR (BRISHLT, n=10). Results. We found 294 genes differentially expressed between CISHLT and RISHLT, mainly involved in immune activation, and inflammation. Hierarchical clustering showed a clear segregation of CISHLT and RISHLT groups and heterogeneity of GEP within RISHLT. All EMB presented immune activation, but some RISHLT EMB were strongly subject to inflammation, whereas others, closer to CISHLT, were characterized by structural modifications with lower inflammation level. We identified 15 probes significantly different between BRISHLT and CISHLT, including the gene of the muscular protein TTN. This result suggests that structural alterations precede inflammation in ACR. Linear Discriminant Analysis based on these 15 probes was able to identify the histological status of every 36 samples. Conclusion. Myocardial GEP is a helpful method to accurately diagnose ACR, and predicts rejection one month before its histological occurrence. These results should be considered in cardiac allograft recipientsâ care.
2017-03-07 | E-MTAB-5136 | biostudies-arrayexpress
Project description:Purpose: Chronic allograft dysfunction (CAD) remains a major obstacle in kidney transplantation. However, the molecular pathogenesis of human CAD is unknown. Herein, we tested the hypothesis that single nuclei transcriptomics of human kidney allograft fibrosis will reveal diverse cell types, deconvolve complex fibrosis-driving pathways, and provide deeper insights into the progression of kidney allograft dysfunction.
2023-03-06 | GSE195718 | GEO
Project description:Interstitial fibrosis and tubular atrophy (IF/TA) after kidney transplantation causes chronic deterioration of graft function. IF/TA can be diagnosed by graft biopsy; however, non-invasive diagnostic methods are unavailable. In this study, we identified IF/TA-related differentially expressed genes (DEGs) through next-generation sequencing using peripheral blood mononuclear cells (PBMCs) PBMC samples from kidney transplantation recipients under standard immunosuppressive therapy (tacrolimus/mycophenolate mofetil or mycophenolate sodium/steroid) and diagnosed as IF/TA (n = 41) or normal (controls; n = 41) at their 1-year protocol biopsy were recruited between January 2020 and August 2020.
2023-08-30 | GSE218048 | GEO
Project description:Purpose: To examine and characterize the expression profile of genes expressed at the neuromuscular junctions (NMJs) of extraocular muscles (EOMs) in comparison to the NMJs of tibialis anterior muscle (TA). Methods: Adult rat rectus EOMs and TAs were dissected, flash-frozen, serially sectioned and stained for acetylcholinesterase to identify NMJs. Approximately 6000 NMJs for EOM (EOMsyn) and 6000 NMJs for TA (TAsyn) and equal amounts of NMJ-free fiber regions (EOMfib, TAfib) and underlying myonuclei were captured using laser capture microdissection (LCM). RNA was isolated, processed and used for microarray-based expression profiling. Profiles were generated for genes differentially expressed at synaptic and non-synaptic regions of TA (TAsyn vs TAfib) and EOM (EOMsyn vs EOMfib) using a false discovery rate (FDR) of 5% as well as an 'interaction list' revealing the most significantly differentially expressed genes at an FDR of 1%. We validated the profiles by real-time quantitative reverse transcription-polymerase chain reaction (qPCR). Results: The regional transcriptomes associated with NMJ of EOMs and TAs were identified. We found 275 genes that were preferentially expressed in EOMsyn and 230 known transcripts that were preferentially expressed in TAsyn; 288 of the transcripts were common to both synapses; these included well-known, evolutionarily conserved, synaptic markers (e.g. nicotinic Acetylcholine receptor (ACHR) alpha and epsilon subunits, nestin) as well as a large number of novel genes. Conclusion: Transcriptome level differences exist between EOM synaptic regions and TA synaptic regions. Our definition of the synaptic transcriptome provides insight into the mechanism of formation and functioning of the unique synapses of EOM and their differential involvement in diseases noted in the EOM allotype. Tissue preparation: A total of 4 rats were killed by CO2 inhalation. The bony orbit was removed from the skull and opened at the lamina cribrosa. The globe with the four recti EOMs still attached was carefully dissected from the bony orbit. The eyeball with muscles was placed on cryomolds, covered with OCT tissue embedding medium (Tissue-Tek: Sakura Finetek, Tokyo, Japan) and flash-frozen in isopentane, cooled in liquid nitrogen and stored at -80 degreeC. The tibialis anterior (TA) muscles of all rats were dissected and frozen in the same way. The EOM and TA were then cut transversely into 10 um sections using a Microm HM 500 cryostat (Zeiss, Oberkochen, Germany), mounted on PEN (poly-ethylene-naphthalene) Membrane Slides (Arcturus) and refrozen immediately. Unfixed sections were stored at -80 degreeC until needed. Section staining: Sections for LCM were stained for acetylcholinesterase based on the method of Karnowsky and Roots to visualize NMJ. Palm microdissection: The PALM MicroBeam System was used for microdissection and for catapulting isolated tissue into a microfuge cap containing 80 ul RLT-Lysis Buffer (Quiagen). Approximately 1000 NMJ and equal amount of non-synaptic regions were collected for each muscle.
2010-04-28 | E-GEOD-15737 | biostudies-arrayexpress
Project description:The mammalian FoxO transcription factors - FoxO1, FoxO3, FoxO4 - function in the nucleus to direct transcription of specific gene targets governing cellular survival, proliferation, metabolism, differentiation and oxidative defense. Activation of PI3K by extracellular growth factors leads to AKT-mediated phosphorylation of FoxO1, FoxO3 and FoxO4, resulting in their sequestration in the cytoplasm such that they are unable to regulate their gene targets. Our study identified FoxOs as novel tumor suppressors in kidney cancer (Gan et al, 2010, Cancer Cell). To understand the tumor suppression function of FoxOs in kidney cancer cells, we performed gene expression profiling in human kidney cancer cells upon FoxO1 or FoxO3 reactivation in order to identify the key transcriptomic alterations mediating FoxO tumor suppression function in kidney cancer cells. We generated RCC4 and UMRC2 cell lines (two human kidney cancer cells with low endogenous FoxO1 and FoxO3 expression) with stable expression of FoxO1(TA)ERT2 or FoxO3(TA)ERT2 construct, which expressed a fusion protein consisting of FoxO(TA) (containing three Ser/Thr AKT phosphorylation sites mutated to alanine) fused to the T2-modified estrogen receptor (ERT2) moiety. We documented that the FoxO(TA)ERT2 fusion protein sequestered FoxO(TA) in the cytoplasm and that 4OHT treatment resulted in rapid translocation of FoxO(TA)ERT2 into the nucleus. We also established stable cell lines with ERT2 expression as control cell lines. (For simplicity, ERT2, FoxO1(TA)ERT2 and FoxO3(TA)ERT2 cell lines will be referred to as EV (empty vector), FoxO1 and FoxO3, respectively, hereafter). We then conducted comparative transcriptome analysis (using the Human Genome U133 Plus 2.0 Array) of EV, FoxO1, or FoxO3-expressing RCC4 and UMRC2 cells at 12 hours with or without 100 nm 4OHT treatment (cultured in DMEM+10% FBS with puromycin selection). To enrich for more proximal actions of FoxO, we selected the 12 hour time point as time course studies revealed dramatic transcriptional changes of known FoxO targets (such as Cyclin D1), yet no discernable cellular phenotypes (apoptosis and cell cycle arrest). We generated 4 transcriptome datasets: FoxO1 RCC4, FoxO3 RCC4, FoxO1 UMRC2, and FoxO3 UMRC2 (by comparing transcriptome data with or without 4OHT treatment), and normalized these transcriptome data against 4OHT-treated EV cells, which show modest 4OHT-induced transcriptional changes.
2011-10-20 | E-GEOD-23926 | biostudies-arrayexpress