The Experts below are selected from a list of 72 Experts worldwide ranked by ideXlab platform
N. Ravi - One of the best experts on this subject based on the ideXlab platform.
-
Changes in mitochondrial stability during the progression of the Barrett’s Esophagus Disease sequence
BMC Cancer, 2016Co-Authors: N. J. O’farrell, R. Feighery, S. L. Picardo, N. Lynam-lennon, M. Biniecka, S. A. Mcgarrigle, J. J. Phelan, F. Maccarthy, D. O’toole, N. RaviAbstract:Background Barrett’s Esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett’s Esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this Disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett’s Disease progression is under studied. Methods Using an in-vitro model representing the Barrett’s Esophagus Disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles. Results Barrett’s metaplastic cells demonstrated increased levels of ROS ( p
-
changes in mitochondrial stability during the progression of the barrett s Esophagus Disease sequence
BMC Cancer, 2016Co-Authors: Naoimh J Ofarrell, R. Feighery, S. L. Picardo, M. Biniecka, S. A. Mcgarrigle, J. J. Phelan, F. Maccarthy, Niamh Lynamlennon, Dermot Otoole, N. RaviAbstract:Barrett’s Esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett’s Esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this Disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett’s Disease progression is under studied. Using an in-vitro model representing the Barrett’s Esophagus Disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles. Barrett’s metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett’s Disease sequence in-vitro. Using patient in-vivo samples, Barrett’s metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the Disease sequence. Using ex-vivo Barrett’s metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett’s metaplastic tissue compared with matched normal squamous epithelium. We have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett’s Disease sequence.
Jan Brabender - One of the best experts on this subject based on the ideXlab platform.
-
Quantitative Expressionsanalyse multipler Gene zur molekularen Charakterisierung des Plattenepithels des Ösophagus von gesunden Patienten und Patienten mit Barrett-Ösophagus oder Barrett-Carcinom
Deutsche Gesellschaft für Chirurgie, 2020Co-Authors: Jan Brabender, Ralf Metzger, Peter V Danenberg, Arnulf H. Hölscher, Paul M. SchneiderAbstract:Background: In order to identify genes or combination of genes that have the power to descriminate between patients with premalignant Barrett’s Esophagus and Barrett’s-associated adenocarcinoma based on the molecular profile of the corresponding normal squamous Esophagus tissues, we analyzed a panel of 23 genes using quantitative real-time RT-PCR (qRT-PCR, Taqman®) and bioinformatic tools. Methods: 48 histological normal squamous esophageal tissues collected from 19 patients with Barrett’s Esophagus (BE), 19 patients with Barrett’s - associated esophageal adenocarcinoma (EA), and a healthy control group of 10 patients (CG) were studied. A quantitative real time RT-PCR method (TaqMan®) was used to measure, relative to the internal standard beta actin, the mRNA expression levels of the following 23 genes: c-Myb, ODC, CDX2, DNMT1, DNMT3a, DNMT3b, RXRalpha, RXRbeta, RXRgamma, RARalpha, RARgamma, BFT, GSTPI, COX1, COX2, DPD, SPARC, BCL2, TP. BAX, DAPK, TM4SF3, TSPAN. Triplicate analysis for the full 23 gene of interest panel was performed for all samples for a total of more than 3528 single PCR reactions. Results: Median mRNA gene expression levels were significantly different in normal squamous Esophagus tissues from patients with Barrett’s Esophagus, Barrett’s-associated adenocarcinoma and the healthy control group for the following genes: Bax (P = 0.002), BFT (P = 0.001), CDX2 (P = 0.005), COX2 (P = 0.042), DAPK (P = 0.2), DNMT1 (P< 0.001), GSTPI (P = 0.003), RARalpha (P = 0.042), RARgamma (P< 0.001), RXRalpha (P = 0.002), RXRbeta (P = 0.008), SPARC (P = 0.039), TSPAN (P = 0.041), VEGF (P = 0.006). A blinded linear discriminant analysis was able to distinguish three genetically different groups of normal squamous Esophagus tissues. The three groups consisted solely of normal tissues from patients with EA, BE or CG. A cross-validation study revealed that molecular separation for the three groups could be achieved with an error-rate of 0.1. Conclusion: This study provides the first non-array parallel mRNA quantitation analysis of a panel of genes in normal squamous Esophagus tissues in Barrett’s Esophagus Disease. It shows substantial differences in gene expression levels in normal Esophagus tissues of patients with EA, BE and CG. Our results suggest that mRNA expression quantitation of a panel of genes in combination with a linear discriminant analysis can discriminate between healthy patients, premalignant Barrett’s patients, and malignant Barrett’s cancer based on the molecular profile of corresponding histological normal squamous Esophagus tissues. Further studies are warranted to determine the potential clinical value for the treatment of patients with this Disease.
-
the molecular signature of normal squamous esophageal epithelium identifies the presence of a field effect and can discriminate between patients with barrett s Esophagus and patients with barrett s associated adenocarcinoma
Cancer Epidemiology Biomarkers & Prevention, 2005Co-Authors: Jan Brabender, Paul Marjoram, Reginald V Lord, Ralf Metzger, Dennis Salonga, Daniel Vallbohmer, H Schafer, Kathleen D Danenberg, Peter V Danenberg, Florin M SelaruAbstract:Background and Aim: Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the Esophagus Disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous Esophagus epihelium of patients with Barrett's Esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's Disease. Methods: Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's Esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis. Results: A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RARα, RARγ, RXRα, RXRβ, SPARC, TSPAN , and VEGF . Based on the expression signature of the normal appearing squamous Esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%. Conclusion: This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's Esophagus Disease. Based on the gene expression signature of the normal Esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's Esophagus Disease.
-
Role of Retinoid X receptor mRNA expression in Barrett’s Esophagus
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased ( P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased ( P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues ( P = 0.01; Wilcoxon test) and adenocarinoma tissues ( P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r^2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r^2 = 0.63; P < 0.001), and adenocarcinoma tissues (r^2 = 0.68; P = 0.001). There were significant differences in RXR-α ( P = 0.011) and RXR-β ( P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.
-
Role of retinoid X receptor mRNA expression in Barrett's Esophagus.
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased (P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues (P = 0.01; Wilcoxon test) and adenocarinoma tissues (P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r2 = 0.63; P < 0.001), and adenocarcinoma tissues (r2 = 0.68; P = 0.001). There were significant differences in RXR-α (P = 0.011) and RXR-β (P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.
Paul M. Schneider - One of the best experts on this subject based on the ideXlab platform.
-
Quantitative Expressionsanalyse multipler Gene zur molekularen Charakterisierung des Plattenepithels des Ösophagus von gesunden Patienten und Patienten mit Barrett-Ösophagus oder Barrett-Carcinom
Deutsche Gesellschaft für Chirurgie, 2020Co-Authors: Jan Brabender, Ralf Metzger, Peter V Danenberg, Arnulf H. Hölscher, Paul M. SchneiderAbstract:Background: In order to identify genes or combination of genes that have the power to descriminate between patients with premalignant Barrett’s Esophagus and Barrett’s-associated adenocarcinoma based on the molecular profile of the corresponding normal squamous Esophagus tissues, we analyzed a panel of 23 genes using quantitative real-time RT-PCR (qRT-PCR, Taqman®) and bioinformatic tools. Methods: 48 histological normal squamous esophageal tissues collected from 19 patients with Barrett’s Esophagus (BE), 19 patients with Barrett’s - associated esophageal adenocarcinoma (EA), and a healthy control group of 10 patients (CG) were studied. A quantitative real time RT-PCR method (TaqMan®) was used to measure, relative to the internal standard beta actin, the mRNA expression levels of the following 23 genes: c-Myb, ODC, CDX2, DNMT1, DNMT3a, DNMT3b, RXRalpha, RXRbeta, RXRgamma, RARalpha, RARgamma, BFT, GSTPI, COX1, COX2, DPD, SPARC, BCL2, TP. BAX, DAPK, TM4SF3, TSPAN. Triplicate analysis for the full 23 gene of interest panel was performed for all samples for a total of more than 3528 single PCR reactions. Results: Median mRNA gene expression levels were significantly different in normal squamous Esophagus tissues from patients with Barrett’s Esophagus, Barrett’s-associated adenocarcinoma and the healthy control group for the following genes: Bax (P = 0.002), BFT (P = 0.001), CDX2 (P = 0.005), COX2 (P = 0.042), DAPK (P = 0.2), DNMT1 (P< 0.001), GSTPI (P = 0.003), RARalpha (P = 0.042), RARgamma (P< 0.001), RXRalpha (P = 0.002), RXRbeta (P = 0.008), SPARC (P = 0.039), TSPAN (P = 0.041), VEGF (P = 0.006). A blinded linear discriminant analysis was able to distinguish three genetically different groups of normal squamous Esophagus tissues. The three groups consisted solely of normal tissues from patients with EA, BE or CG. A cross-validation study revealed that molecular separation for the three groups could be achieved with an error-rate of 0.1. Conclusion: This study provides the first non-array parallel mRNA quantitation analysis of a panel of genes in normal squamous Esophagus tissues in Barrett’s Esophagus Disease. It shows substantial differences in gene expression levels in normal Esophagus tissues of patients with EA, BE and CG. Our results suggest that mRNA expression quantitation of a panel of genes in combination with a linear discriminant analysis can discriminate between healthy patients, premalignant Barrett’s patients, and malignant Barrett’s cancer based on the molecular profile of corresponding histological normal squamous Esophagus tissues. Further studies are warranted to determine the potential clinical value for the treatment of patients with this Disease.
-
Role of Retinoid X receptor mRNA expression in Barrett’s Esophagus
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased ( P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased ( P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues ( P = 0.01; Wilcoxon test) and adenocarinoma tissues ( P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r^2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r^2 = 0.63; P < 0.001), and adenocarcinoma tissues (r^2 = 0.68; P = 0.001). There were significant differences in RXR-α ( P = 0.011) and RXR-β ( P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.
-
Role of retinoid X receptor mRNA expression in Barrett's Esophagus.
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased (P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues (P = 0.01; Wilcoxon test) and adenocarinoma tissues (P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r2 = 0.63; P < 0.001), and adenocarcinoma tissues (r2 = 0.68; P = 0.001). There were significant differences in RXR-α (P = 0.011) and RXR-β (P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.
Peter V Danenberg - One of the best experts on this subject based on the ideXlab platform.
-
Quantitative Expressionsanalyse multipler Gene zur molekularen Charakterisierung des Plattenepithels des Ösophagus von gesunden Patienten und Patienten mit Barrett-Ösophagus oder Barrett-Carcinom
Deutsche Gesellschaft für Chirurgie, 2020Co-Authors: Jan Brabender, Ralf Metzger, Peter V Danenberg, Arnulf H. Hölscher, Paul M. SchneiderAbstract:Background: In order to identify genes or combination of genes that have the power to descriminate between patients with premalignant Barrett’s Esophagus and Barrett’s-associated adenocarcinoma based on the molecular profile of the corresponding normal squamous Esophagus tissues, we analyzed a panel of 23 genes using quantitative real-time RT-PCR (qRT-PCR, Taqman®) and bioinformatic tools. Methods: 48 histological normal squamous esophageal tissues collected from 19 patients with Barrett’s Esophagus (BE), 19 patients with Barrett’s - associated esophageal adenocarcinoma (EA), and a healthy control group of 10 patients (CG) were studied. A quantitative real time RT-PCR method (TaqMan®) was used to measure, relative to the internal standard beta actin, the mRNA expression levels of the following 23 genes: c-Myb, ODC, CDX2, DNMT1, DNMT3a, DNMT3b, RXRalpha, RXRbeta, RXRgamma, RARalpha, RARgamma, BFT, GSTPI, COX1, COX2, DPD, SPARC, BCL2, TP. BAX, DAPK, TM4SF3, TSPAN. Triplicate analysis for the full 23 gene of interest panel was performed for all samples for a total of more than 3528 single PCR reactions. Results: Median mRNA gene expression levels were significantly different in normal squamous Esophagus tissues from patients with Barrett’s Esophagus, Barrett’s-associated adenocarcinoma and the healthy control group for the following genes: Bax (P = 0.002), BFT (P = 0.001), CDX2 (P = 0.005), COX2 (P = 0.042), DAPK (P = 0.2), DNMT1 (P< 0.001), GSTPI (P = 0.003), RARalpha (P = 0.042), RARgamma (P< 0.001), RXRalpha (P = 0.002), RXRbeta (P = 0.008), SPARC (P = 0.039), TSPAN (P = 0.041), VEGF (P = 0.006). A blinded linear discriminant analysis was able to distinguish three genetically different groups of normal squamous Esophagus tissues. The three groups consisted solely of normal tissues from patients with EA, BE or CG. A cross-validation study revealed that molecular separation for the three groups could be achieved with an error-rate of 0.1. Conclusion: This study provides the first non-array parallel mRNA quantitation analysis of a panel of genes in normal squamous Esophagus tissues in Barrett’s Esophagus Disease. It shows substantial differences in gene expression levels in normal Esophagus tissues of patients with EA, BE and CG. Our results suggest that mRNA expression quantitation of a panel of genes in combination with a linear discriminant analysis can discriminate between healthy patients, premalignant Barrett’s patients, and malignant Barrett’s cancer based on the molecular profile of corresponding histological normal squamous Esophagus tissues. Further studies are warranted to determine the potential clinical value for the treatment of patients with this Disease.
-
the molecular signature of normal squamous esophageal epithelium identifies the presence of a field effect and can discriminate between patients with barrett s Esophagus and patients with barrett s associated adenocarcinoma
Cancer Epidemiology Biomarkers & Prevention, 2005Co-Authors: Jan Brabender, Paul Marjoram, Reginald V Lord, Ralf Metzger, Dennis Salonga, Daniel Vallbohmer, H Schafer, Kathleen D Danenberg, Peter V Danenberg, Florin M SelaruAbstract:Background and Aim: Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the Esophagus Disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous Esophagus epihelium of patients with Barrett's Esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's Disease. Methods: Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's Esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis. Results: A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RARα, RARγ, RXRα, RXRβ, SPARC, TSPAN , and VEGF . Based on the expression signature of the normal appearing squamous Esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%. Conclusion: This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's Esophagus Disease. Based on the gene expression signature of the normal Esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's Esophagus Disease.
-
Role of Retinoid X receptor mRNA expression in Barrett’s Esophagus
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased ( P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased ( P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues ( P = 0.01; Wilcoxon test) and adenocarinoma tissues ( P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r^2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r^2 = 0.63; P < 0.001), and adenocarcinoma tissues (r^2 = 0.68; P = 0.001). There were significant differences in RXR-α ( P = 0.011) and RXR-β ( P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.
-
Role of retinoid X receptor mRNA expression in Barrett's Esophagus.
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased (P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues (P = 0.01; Wilcoxon test) and adenocarinoma tissues (P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r2 = 0.63; P < 0.001), and adenocarcinoma tissues (r2 = 0.68; P = 0.001). There were significant differences in RXR-α (P = 0.011) and RXR-β (P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.
Ralf Metzger - One of the best experts on this subject based on the ideXlab platform.
-
Quantitative Expressionsanalyse multipler Gene zur molekularen Charakterisierung des Plattenepithels des Ösophagus von gesunden Patienten und Patienten mit Barrett-Ösophagus oder Barrett-Carcinom
Deutsche Gesellschaft für Chirurgie, 2020Co-Authors: Jan Brabender, Ralf Metzger, Peter V Danenberg, Arnulf H. Hölscher, Paul M. SchneiderAbstract:Background: In order to identify genes or combination of genes that have the power to descriminate between patients with premalignant Barrett’s Esophagus and Barrett’s-associated adenocarcinoma based on the molecular profile of the corresponding normal squamous Esophagus tissues, we analyzed a panel of 23 genes using quantitative real-time RT-PCR (qRT-PCR, Taqman®) and bioinformatic tools. Methods: 48 histological normal squamous esophageal tissues collected from 19 patients with Barrett’s Esophagus (BE), 19 patients with Barrett’s - associated esophageal adenocarcinoma (EA), and a healthy control group of 10 patients (CG) were studied. A quantitative real time RT-PCR method (TaqMan®) was used to measure, relative to the internal standard beta actin, the mRNA expression levels of the following 23 genes: c-Myb, ODC, CDX2, DNMT1, DNMT3a, DNMT3b, RXRalpha, RXRbeta, RXRgamma, RARalpha, RARgamma, BFT, GSTPI, COX1, COX2, DPD, SPARC, BCL2, TP. BAX, DAPK, TM4SF3, TSPAN. Triplicate analysis for the full 23 gene of interest panel was performed for all samples for a total of more than 3528 single PCR reactions. Results: Median mRNA gene expression levels were significantly different in normal squamous Esophagus tissues from patients with Barrett’s Esophagus, Barrett’s-associated adenocarcinoma and the healthy control group for the following genes: Bax (P = 0.002), BFT (P = 0.001), CDX2 (P = 0.005), COX2 (P = 0.042), DAPK (P = 0.2), DNMT1 (P< 0.001), GSTPI (P = 0.003), RARalpha (P = 0.042), RARgamma (P< 0.001), RXRalpha (P = 0.002), RXRbeta (P = 0.008), SPARC (P = 0.039), TSPAN (P = 0.041), VEGF (P = 0.006). A blinded linear discriminant analysis was able to distinguish three genetically different groups of normal squamous Esophagus tissues. The three groups consisted solely of normal tissues from patients with EA, BE or CG. A cross-validation study revealed that molecular separation for the three groups could be achieved with an error-rate of 0.1. Conclusion: This study provides the first non-array parallel mRNA quantitation analysis of a panel of genes in normal squamous Esophagus tissues in Barrett’s Esophagus Disease. It shows substantial differences in gene expression levels in normal Esophagus tissues of patients with EA, BE and CG. Our results suggest that mRNA expression quantitation of a panel of genes in combination with a linear discriminant analysis can discriminate between healthy patients, premalignant Barrett’s patients, and malignant Barrett’s cancer based on the molecular profile of corresponding histological normal squamous Esophagus tissues. Further studies are warranted to determine the potential clinical value for the treatment of patients with this Disease.
-
the molecular signature of normal squamous esophageal epithelium identifies the presence of a field effect and can discriminate between patients with barrett s Esophagus and patients with barrett s associated adenocarcinoma
Cancer Epidemiology Biomarkers & Prevention, 2005Co-Authors: Jan Brabender, Paul Marjoram, Reginald V Lord, Ralf Metzger, Dennis Salonga, Daniel Vallbohmer, H Schafer, Kathleen D Danenberg, Peter V Danenberg, Florin M SelaruAbstract:Background and Aim: Genetic alterations in the normal tissues surrounding various cancers have been described, but a comprehensive analysis of this carcinogenic field effect in Barrett's-associated adenocarcinoma of the Esophagus Disease has not been reported. The aim of this study was to analyze the gene expression profile of a panel of highly selected genes in the normal squamous Esophagus epihelium of patients with Barrett's Esophagus, patients with Barrett's-associated adenocarcinoma, and a healthy control group to define the existence of a carcinogenic field effect, and to investigate the clinical importance of such a field effect in the management of Barrett's Disease. Methods: Forty-nine histologic normal squamous esophageal epithelia collected from 19 patients with Barrett's Esophagus, 20 patients with Barrett's-associated esophageal adenocarcinoma, and a healthy control group of 10 patients were studied. A quantitative real-time reverse transcription-PCR method (TaqMan) was used to measure the expression of a panel of genes with known associations with gastrointestinal carcinogenesis. Results: A widespread carcinogenic field effect was detected for more than 50% of the genes analyzed including Bax, BFT, CDX2, COX2, DAPK, DNMT1, GSTP1, RARα, RARγ, RXRα, RXRβ, SPARC, TSPAN , and VEGF . Based on the expression signature of the normal appearing squamous Esophagus, a linear discriminant analysis was able to distinguish between the three groups of patients with an error rate of 0%. Conclusion: This study provides the first comprehensive investigation of a carcinogenic field effect in Barrett's Esophagus Disease. Based on the gene expression signature of the normal Esophagus, patients could be correctly characterized according to their pathologic classification by applying a linear discriminant analysis. Our results provide evidence that a molecular classification might have clinical importance for the diagnosis and treatment of patients with Barrett's Esophagus Disease.
-
Role of Retinoid X receptor mRNA expression in Barrett’s Esophagus
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased ( P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased ( P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues ( P = 0.01; Wilcoxon test) and adenocarinoma tissues ( P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r^2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r^2 = 0.63; P < 0.001), and adenocarcinoma tissues (r^2 = 0.68; P = 0.001). There were significant differences in RXR-α ( P = 0.011) and RXR-β ( P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.
-
Role of retinoid X receptor mRNA expression in Barrett's Esophagus.
Journal of Gastrointestinal Surgery, 2004Co-Authors: Jan Brabender, Reginald V Lord, Ralf Metzger, Dennis Salonga, Kathleen D Danenberg, Peter V Danenberg, Jimin Park, Arnulf H. Hölscher, Paul M. SchneiderAbstract:The Barrett’s multistage process is characterized histopathologically by progression from Barrett’s intestinal metaplasia to Barrett’s Esophagus with dysplasia and ultimately adenocarcinoma. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Retinoid X receptors (RXR) play an important role in regulating the morphogenesis, development, growth, and differentiation of cells. Alterations in RXR expression have been observed in a variety of solid tumors; however, the role in Barrett’s Esophagus Disease has yet to be determined. The aim of this study was to assess the prevalence and timing of RXR messenger RNA expression in the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence and to investigate its role in the development and progression of this Disease. We analyzed the mRNA expression of all three RXR subtypes (RXR-alpha, RXR-beta, and RXR-gamma) by using a quantitative real-time reverse transcription-polymerase chain reaction method in 108 specimens from 19 patients with Barrett’s Esophagus without carcinoma (BE group), 20 patients with Barrett’s-associated adenocarcinoma (EA group), and a control group of 10 patients without evidence of gastroesophageal reflux Disease (CG). RXR-α mRNA expression was significantly decreased (P < 0.001; Kruskal-Wallis test), and RXR-γ was significantly increased (P < 0.001) at higher stages in Barrett’s Esophagus. RXR-β expression was highest in Barrett’s tissues and was significantly increased compared to normal squamous tissues (P = 0.01; Wilcoxon test) and adenocarinoma tissues (P = 0.018, Mann-Whitney test). RXR-α and RXR-β mRNA expression was significantly associated in normal squamous Esophagus tissues (r2 = 0.49; P < 0.001; Spearman test), Barrett’s tissues (r2 = 0.63; P < 0.001), and adenocarcinoma tissues (r2 = 0.68; P = 0.001). There were significant differences in RXR-α (P = 0.011) and RXR-β (P = 0.005) mRNA expression in histopathologically normal squamous Esophagus tissues in patients with cancer and the control group without evidence of gastroesophageal reflux Disease. These findings suggest that alterations in the mRNA expression of all three RXR subtypes are frequent events in the development and progression of Barrett’s Esophagus and associated adenocarcinoma, that RXR mRNA expression levels may be useful biomarkers for this Disease, and that a widespread "field-effect" is present in the normal Esophagus of patients with esophageal adenocarcinoma.