Iron, Inflammation, and Early Death in Adults With Sickle Cell DiseaseNovelty and Significance by Eduard J. van Beers, Yanqin Yang, Nalini Raghavachari,

Slides:

Advertisements

Similar presentations

Transcriptomic Analysis of Peripheral Blood Mononuclear Cells in Rapid Progressors in Early HIV Infection Identifies a Signature Closely Correlated with.

Advertisements

Date of download: 6/24/2016 Copyright © 2016 American Medical Association. All rights reserved. From: Interleukin 6 and Interleukin 8 as Potential Biomarkers.

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

Sympathetic Stimulation of Thiazide-Sensitive Sodium Chloride Cotransport in the Generation of Salt-Sensitive HypertensionNovelty and Significance by Andrew.

Volume 141, Issue 3, Pages (March 2012)

CYB561 mutations. CYB561 mutations. The upper part shows the structure of the CYB561 gene, with the positions of the identified mutations indicated. Gray.

CYB561 homology modeling. CYB561 homology modeling.A, Close-up of mutation G88R in CYB561. The protein is shown in ribbon presentation in gray, the heme.

Evaluation of Left Ventricular Enlargement as a Marker of Early Disease in Familial Dilated CardiomyopathyClinical Perspective by Diane Fatkin, Thomas.

Volume 143, Issue 2, Pages (February 2013)

M. Fu, G. Huang, Z. Zhang, J. Liu, Z. Zhang, Z. Huang, B. Yu, F. Meng

Bart Tummers, Renske Goedemans, Veena Jha, Craig Meyers, Cornelis J. M

Microarray-Based Prediction of Tumor Response to Neoadjuvant Radiochemotherapy of Patients With Locally Advanced Rectal Cancer Caroline Rimkus, Jan Friederichs,

Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling by.

High Expression of Lymphocyte-Activation Gene 3 (LAG3) in Chronic Lymphocytic Leukemia Cells Is Associated with Unmutated Immunoglobulin Variable Heavy.

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

Potential role of circulating microRNAs as a biomarker for unexplained recurrent spontaneous abortion Weibing Qin, M.D., Ph.D., Yunge Tang, M.D., Ning.

M. Jacobsen, D. Repsilber, K. Kleinsteuber, A. Gutschmidt, S

Systemic inflammation as a predictor of clinical outcomes after lower extremity angioplasty/stenting Kenneth DeSart, MD, Kerri O'Malley, PhD, Bradley.

Expression profiling of snoRNAs in normal hematopoiesis and AML

A Proteome-Derived Longitudinal Pharmacodynamic Biomarker for Diffuse Systemic Sclerosis Skin Lisa M. Rice, Julio C. Mantero, Giuseppina Stifano, Jessica.

Microarray Analysis of B-Cell Lymphoma Cell Lines with the t(14;18)

Microvascular oxygen consumption during sickle cell pain crisis

Volume 129, Issue 3, Pages (September 2005)

Integrated analysis of miRNA and mRNA during differentiation of human CD34+ cells delineates the regulatory roles of microRNA in hematopoiesis Nalini.

by Gregory H. Underhill, David George, Eric G. Bremer, and Geoffrey S

Volume 17, Issue 1, Pages (January 2010)

Volume 20, Issue 1, Pages (January 2012)

Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease by Namita Kumari, Tatiana Ammosova, Sharmin Diaz, Xionghao.

Volume 140, Issue 3, Pages e8 (March 2011)

Molecular Classification of Renal Tumors by Gene Expression Profiling

Volume 124, Issue 3, Pages (March 2003)

Volume 85, Issue 2, Pages (January 2014)

Leon Raskin, Douglas R. Fullen, Thomas J. Giordano, Dafydd G

Bone Marrow–Derived Mesenchymal Stromal Cells from Patients with Sickle Cell Disease Display Intact Functionality Elizabeth O. Stenger, Raghavan Chinnadurai,

Patterns of Somatically Acquired Amplifications and Deletions in Apparently Normal Tissues of Ovarian Cancer Patients Leila Aghili, Jasmine Foo, James.

Distinctive pro-inflammatory gene signatures induced in articular chondrocytes by oncostatin M and IL-6 are regulated by Suppressor of Cytokine Signaling-3

Kaplan–Meier survival curves of all-cause mortality in patients with idiopathic pulmonary fibrosis (IPF). Kaplan–Meier survival curves of all-cause mortality.

p75NTR, TrkA and sortilin expression levels in patients with JIA

Volume 65, Issue 2, Pages (February 2004)

IL-27 Suppresses Antimicrobial Activity in Human Leprosy

Autocrine IL-21 Stimulation Is Involved in the Maintenance of Constitutive STAT3 Activation in Sézary Syndrome Leslie van der Fits, Jacoba J. Out-Luiting,

WNT ligands contribute to the immune response during septic shock and amplify endotoxemia-driven inflammation in mice by Marcela Gatica-Andrades, Dimitrios.

Protective effect of vitamin C on 8-hydroxy-2′-deoxyguanosine level in peripheral blood lymphocytes of chronic hemodialysis patients Der-Cherng Tarng,

Gene expression profiles of cumulus cells obtained from women treated with recombinant human luteinizing hormone + recombinant human follicle-stimulating.

Volume 118, Issue 2, Pages (July 2004)

Significant differences in translational efficiencies of DNA damage repair pathway genes between patient clusters. Significant differences in translational.

AZA treatment induces a distinct gene-expression pattern in stromal cells. AZA treatment induces a distinct gene-expression pattern in stromal cells. (A-C)

A.K.I. Kuroki, Masayuki Iyoda, Takanori Shibata, Tetsuzo Sugisaki

Long Noncoding RNA BC as a Novel Therapeutic Target for Colorectal Cancer that Suppresses Metastasis by Upregulating TIMP3 Jiaxin Lin, Xin Tan,

Volume 1, Issue 3, Pages (September 2007)

Patterns of Somatically Acquired Amplifications and Deletions in Apparently Normal Tissues of Ovarian Cancer Patients Leila Aghili, Jasmine Foo, James.

by Rodrigo Abreu, Frederick Quinn, and Pramod K. Giri

Monitoring the induction of pro-inflammatory mediators and toll-like receptors (TLRs) following inhalation of AZD8848. Monitoring the induction of pro-inflammatory.

Figure 1. Identification of three tumour molecular subtypes in CIT and TCGA cohorts. We used CIT multi-omics data ( Figure 1. Identification of.

CD4+CLA+CD103+ T cells from human blood and skin share a transcriptional profile. CD4+CLA+CD103+ T cells from human blood and skin share a transcriptional.

Insights into Gene Modulation by Therapeutic TNF and IFNγ Antibodies: TNF Regulates IFNγ Production by T Cells and TNF-Regulated Genes Linked to Psoriasis.

Genome-wide expression profiling of B lymphocytes reveals IL4R increase in allergic asthma Marien Pascual, PhD, Sergio Roa, PhD, Asunción García-Sánchez,

Fig. 5. Vitamin B12 supplementation in the host altered the transcriptome of P. acnes in the skin microbiota. Vitamin B12 supplementation in the host altered.

Volume 7, Issue 6, Pages e3 (December 2018)

Survival based on V gene mutation status and CD38 expression among B-CLL patients who stratify to the Rai intermediate risk category. Survival based on.

Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti–IL-6 receptor.

Unsupervised clustering heat map of genome-wide mRNA expression profiles, using skin samples from 49 MF/SS patients and 3 healthy individuals. Unsupervised.

Association between RB pathway alterations and poor prognosis in early-stage lung adenocarcinoma patients. Association between RB pathway alterations and.

Partial alteration of the Treg gene signature by the p.A384T mutation.

by Dezhi Kang, Baochen Shi, Marie C. Erfe, Noah Craft, and Huiying Li

Activation of Wnt signaling pathway in trastuzumab-resistant cell lines. Activation of Wnt signaling pathway in trastuzumab-resistant cell lines. A, bar.

ICOS+ and activated CD4+ T cells are dominant, tumour tissue-specific T cell populations in both mismatch repair-deficient and repair-proficient colorectal.

Volume 25, Issue 5, Pages e4 (May 2017)

Construction of TME signatures and functional annotation.

Cxxc1-deficient TH17 cells exhibit a Treg cell–like expression profile

Presentation transcript:

Iron, Inflammation, and Early Death in Adults With Sickle Cell DiseaseNovelty and Significance by Eduard J. van Beers, Yanqin Yang, Nalini Raghavachari, Xin Tian, Darlene T. Allen, James S. Nichols, Laurel Mendelsohn, Sergei Nekhai, Victor R. Gordeuk, James G. Taylor, and Gregory J. Kato Circulation Research Volume 116(2):298-306 January 16, 2015 Copyright © American Heart Association, Inc. All rights reserved.

A subgroup of sickle cell disease (SCD) patients cluster together in a group with high expression of iron-regulated genes. A subgroup of sickle cell disease (SCD) patients cluster together in a group with high expression of iron-regulated genes. Peripheral blood mononuclear cells (PBMC) transcriptome profiling in 24 SCD patients and 10 healthy controls identified 3 clusters of subjects with high, low, and intermediate expression of iron-regulated genes. Patients (ClinicalTrials.gov identifiers: NCT00072826). The Heat map shows unsupervised 2-way hierarchical clustering of the predefined set of iron-regulated genes on the y axis (for a tabular version of this list, see Online Data Supplement) and the clustering of study participants on the x axis. None of the controls was found to be in the high iron cluster. C indicates control; and S, SCD patient. Eduard J. van Beers et al. Circ Res. 2015;116:298-306 Copyright © American Heart Association, Inc. All rights reserved.

Quantitative polymerase chain reaction (Q-PCR) results confirm the relation between iron-regulated genes and genes involved in inflammatory and anti-inflammatory pathways. Quantitative polymerase chain reaction (Q-PCR) results confirm the relation between iron-regulated genes and genes involved in inflammatory and anti-inflammatory pathways. To validate the microaray results, we performed quantitative polymerase chain reaction (Q-PCR) normalized to the housekeeping gene RNA18S5 on the same samples. (ClinicalTrials.gov identifiers: NCT00072826). A, This diagram shows a good correlation (R=0.72, P=0.023) between the fold change as found by microarray and Q-PCR. B, Bars show the fold change in expression of the group of patients with highly expressed iron-regulated genes over the other groups. C, The number of PCR cycles to reach threshold compared with the housekeeping gene RNA18S5 (ΔCT) of FTL was highly correlated to TLR4 in both patients (R=0.930, P<0.001) as controls (R=0.943, P=0.026), although mean expression of both genes was much higher in patients than in controls (P<0.001). TLR4 was also highly correlated to ALDH1A1, GAPDH, SAT2, and HMOX expression (data not shown). To get a better impression of actual gene expression, x and y axis are reversed and originate 20 ΔCT. D, Bars show the fold change in expression of selected genes in sickle cell disease (SCD) patients compared with healthy controls. Black bars represent genes that were included in the predefined set of iron-regulated genes (see Online Table I). White bars represent genes that were identified as signifcantly differentially expressed between the 3 iron clusters or were included to validate the microarray data. ALDH1A1 indicates aldehyde dehydrogenase 1A1; ECE1, endothelin converting enzyme 1; FTL1, ferritin light chain 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HMOX, heme oxygenase-1; IL6, interleukin-6; SAT2, spermidine/spermine N1-acetyltransferase family member 2; ST13, suppression of tumorigenicity 13; and TLR4, toll-like receptor 4. Eduard J. van Beers et al. Circ Res. 2015;116:298-306 Copyright © American Heart Association, Inc. All rights reserved.

Patients with the ferroportin Q248H mutation which is associated with high retention of intracellular iron have higher levels of C-reactive protein (CRP) and interleukin-6. Patients with the ferroportin Q248H mutation which is associated with high retention of intracellular iron have higher levels of C-reactive protein (CRP) and interleukin-6. To assess relationship between intracellular iron and inflammation, we used available ferroportin Q248H mutation status. Patients were analyzed previously for ferroportin mutation status.29A and B, In the gene-expression part of the study (ClinicalTrials.gov identifier: NCT00072826), the 5 patients with a ferroportin Q248H mutation (GT and TT genotype) had a significant (P<0.05) higher plasma level of CRP, and log 10 interleukin-6 (IL-6) trended (P=0.08) to be higher compared with 19 patients with wild-type ferroportin (GG genotype). C and D, As a sensitivity analysis, we repeated this in a case–control study in selection of patients of the National Institutes of Health (NIH) sickle cell disease (SCD) cohort (ClinicalTrials.gov identifier: NCT00011648). Fourteen patients with Q248H mutation were matched on genotype and ferritin level. We found that the 14 patients with the mutation had a significant higher CRP and log10 il6 than the matched controls. Because the ferroportin Q248H is also associated with less sensitivity for hepcidin and hepcidin levels are strongly associated with ferritin levels in SCD, we decided to perform this last analysis only in patients with a ferritin level <1000 mg/dL. *P<0.05. Eduard J. van Beers et al. Circ Res. 2015;116:298-306 Copyright © American Heart Association, Inc. All rights reserved.

Kaplan–Meier curve showing a significant difference in survival between patients with low and high C-reactive protein (CRP). Kaplan–Meier curve showing a significant difference in survival between patients with low and high C-reactive protein (CRP). Sickle cell disease (SCD) patients (n=412) of the National Institutes of Health (NIH) pulmonary hypertension screening cohort (ClinicalTrials.gov identifier: NCT00011648) were divided in a low, intermediate, and high CRP group at the 50th and 75th percentile. Median follow-up time was 47 months (interquartile range, 24–82; range 2–132). After 100 months, patients were censored. Log-rank test showed that survival of patients between CRP groups was significantly different (P=0.0017). Five-year mortality percentages for the low, intermediate, and high CRP groups were, respectively, 12.4%, 20.5%, and 25.8%. In a multivariate analysis, CRP was an independent predictor of mortality (see Table 2). Eduard J. van Beers et al. Circ Res. 2015;116:298-306 Copyright © American Heart Association, Inc. All rights reserved.