The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Ignacio I Wistuba - One of the best experts on this subject based on the ideXlab platform.
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biological activity of celecoxib in the Bronchial Epithelium of current and former smokers
Cancer Prevention Research, 2010Co-Authors: Waun Ki Hong, Ignacio I Wistuba, Rodolfo C Morice, Carlos A Jimenez, Georgie A Eapen, Reuben Lotan, Ximing Tang, Robert A Newman, Jonathan M KurieAbstract:Non–small cell lung cancer is the primary cause of cancer-related death in Western countries. One important approach taken to address this problem is the development of effective chemoprevention strategies. In this study, we examined whether the cyclooxygenase-2 inhibitor celecoxib, as evidenced by decreased cell proliferation, is biologically active in the Bronchial Epithelium of current and former smokers. Current or former smokers with at least a 20 pack-year (pack-year = number of packs of cigarettes per day times number of years smoked) smoking history were randomized into one of four treatment arms (3-month intervals of celecoxib then placebo, celecoxib then celecoxib, placebo then celecoxib, or placebo then placebo) and underwent bronchoscopies with biopsies at baseline, 3 months, and 6 months. The 204 patients were primarily (79.4%) current smokers: 81 received either low-dose celecoxib or placebo and 123 received either high-dose celecoxib or placebo. Celecoxib was originally administered orally at 200 mg twice daily and the protocol subsequently increased the dose to 400 mg twice daily. The primary end point was change in Ki-67 labeling (from baseline to 3 months) in Bronchial Epithelium. No cardiac toxicities were observed in the participants. Although the effect of lowdose treatment was not significant, high-dose celecoxib decreased Ki-67 labeling by 3.85% in former smokers and by 1.10% in current smokers—a significantly greater reduction (P = 0.02) than that seen with placebo after adjusting for metaplasia and smoking status. A 3- to 6-month celecoxib regimen proved safe to administer. Celecoxib (400 mg twice daily) was biologically active in the Bronchial Epithelium of current and former smokers; additional studies on the efficacy of celecoxib in non–small cell lung cancer chemoprevention may be warranted. Cancer Prev Res; 3(2); 148–59. ©2010 AACR.
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smoking molecular damage in Bronchial Epithelium
Oncogene, 2002Co-Authors: Ignacio I Wistuba, Adi F GazdarAbstract:Our understanding of the molecular pathology of lung cancer is advancing rapidly with several specific genes and chromosomal regions being identified. Lung cancer appears to require many mutations in both dominant and recessive oncogenes to possess malignant phenotypes. Several genetic and epigenetic changes are common to all lung cancer histologic types, while others appear to be cell type specific. However, specific roles of the genes undergoing mutations and the order of cumulative molecular changes that lead to the development of each lung tumor histologic type remain to be fully elucidated. Recent findings of molecular abnormalities in normal appearing and preneoplastic Bronchial Epithelium from patients with lung cancer and chronic smokers suggest that genetic changes may serve as biomarkers for early diagnosis, risk assessment and monitoring response to chemoprevention.
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molecular changes in the Bronchial Epithelium of patients with small cell lung cancer
Clinical Cancer Research, 2000Co-Authors: Ignacio I Wistuba, Anirban Maitra, Sara Milchgrub, Jarett Berry, Carmen Behrens, Narayan Shivapurkar, Bruce Mackay, John D MinnaAbstract:To better understand the pathways involved in the pathogenesis of small cell lung carcinoma (SCLC), we compared the patterns of molecular changes present in these tumors and their accompanying Bronchial Epithelium with those present in the other two major types of lung cancer [squamous cell carcinoma (SQC) and adenocarcinoma (ADC)]. We obtained DNA from 68 microdissected invasive lung tumors (22 SCLCs, 21 ADCs, and, 25 SQCs) and 119 noncontiguous foci of histologically normal or hyperplastic epithelia from 10 tumors of each histological type. We determined loss of heterozygosity and microsatellite alterations at 12 chromosomal regions frequently deleted in lung cancers using 19 polymorphic microsatellite markers. Our major findings are as follows: (a) the mean index of allelic loss in SCLC (0.85) and SQC (0.71) tumors was higher than that in ADC (0.39) tumors; (b) although there was considerable overlap, each tumor type had a characteristic pattern of allelic loss; (c) most samples of Bronchial Epithelium accompanying SCLC (90%) had allelic loss at one or more loci compared with samples accompanying SQC (54%) or ADC (10%); (d) the mean index of allelic loss was much higher in Bronchial epithelial samples from SCLC (0.27) than in those from SQC (0.08) or ADC (0.01); and (e) although the mean indices of microsatellite alterations in the tumor types were similar, the Bronchial epithelial samples accompanying SCLC had a 10-fold higher mean index (0.063) than those accompanying SQC (0.006) or ADC (0.006). Our findings indicate that extensive genetic damage in the accompanying normal and hyperplastic Bronchial Epithelium is characteristic of SCLC tumors and suggest major differences in the pathogenesis of the three major lung cancer types.
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multiple clonal abnormalities in the Bronchial Epithelium of patients with lung cancer
Journal of the National Cancer Institute, 1999Co-Authors: In Won Park, Ignacio I Wistuba, Anirban Maitra, Sara Milchgrub, Arvind K Virmani, John D Minna, Adi F GazdarAbstract:BACKGROUND: Several molecular changes, including loss of heterozygosity (i.e., deletion of one copy of allelic DNA sequences) and alterations in microsatellite DNA, have been detected early in the pathogenesis of lung cancer, even in histologically normal Epithelium. In the Bronchial Epithelium of patients with lung cancer, we have determined the frequency, size, and patterns of molecularly abnormal clonal patches. METHODS: We studied formalin-fixed, paraffin-embedded samples from 16 surgically resected lung carcinomas (five squamous cell carcinomas, four small-cell carcinomas, six adenocarcinomas, and one large-cell carcinoma). From each carcinoma, we microdissected foci (each containing about 200 cells) of tumor tissue and equivalent samples of histologically normal and abnormal Epithelium. Furthermore, multiple discontinuous foci of Bronchial Epithelium were analyzed from methanol-fixed samples from three additional patients with lung cancer (two with squamous cell carcinoma and one with adenocarcinoma). We used two-step polymerase chain reaction-based assays involving 12 microsatellite markers at seven chromosomal regions frequently deleted in lung cancer. RESULTS: Two hundred eighteen foci of nonmalignant Bronchial Epithelium (195 of histologically normal or slightly abnormal Epithelium and 23 of dysplastic Epithelium) were studied from the 19 surgically resected lobectomy specimens. Thirteen (68%) of the 19 specimens had at least one focus of Bronchial Epithelium with molecular changes. At least one molecular abnormality was detected in 32% of the 195 histologically normal or slightly abnormal foci and in 52% of the 23 dysplastic foci. Extrapolating from our two-dimensional analyses, we estimate that most clonal patches contain approximately 90 000 cells. Although, in a given individual, tumors appeared homogeneous with respect to molecular changes, the clonally altered patches of mildly abnormal Epithelium were heterogeneous. CONCLUSIONS: Our findings indicate that multiple small clonal or subclonal patches containing molecular abnormalities are present in normal or slightly abnormal Bronchial Epithelium of patients with lung cancer.
Arndt Hartmann - One of the best experts on this subject based on the ideXlab platform.
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smoking and cancer related gene expression in Bronchial Epithelium and non small cell lung cancers
The Journal of Pathology, 2006Co-Authors: M Woenckhaus, Ludger Kleinhitpass, U Grepmeier, Johannes Merk, Michael Pfeifer, Peter J Wild, Marcus Bettstetter, Peter H Wuensch, Hagen Blaszyk, Arndt HartmannAbstract:Tobacco smoking is the leading cause of lung cancer worldwide. Gene expression in surgically resected and microdissected samples of non-small-cell lung cancers (18 squamous cell carcinomas and nine adenocarcinomas), matched normal Bronchial Epithelium, and peripheral lung tissue from both smokers (n = 22) and non-smokers (n = 5) was studied using the Affymetrix U133A array. A subset of 15 differentially regulated genes was validated by real-time PCR or immunohistochemistry. Hierarchical cluster analysis clearly distinguished between benign and malignant tissue and between squamous cell carcinomas and adenocarcinomas. The Bronchial Epithelium and adenocarcinomas could be divided into the two subgroups of smokers and non-smokers. By comparison of the gene expression profiles in the Bronchial Epithelium of non-smokers, smokers, and matched cancer tissues, it was possible to identify a signature of 23 differentially expressed genes, which might reflect early cigarette smoke-induced and cancer-relevant molecular lesions in the central Bronchial Epithelium of smokers. Ten of these genes are involved in xenobiotic metabolism and redox stress (eg AKR1B10, AKR1C1, and MT1K). One gene is a tumour suppressor gene (HLF); two genes act as oncogenes (FGFR3 and LMO3); two genes are involved in matrix degradation (MMP12 and PTHLH); three genes are related to cell differentiation (SPRR1B, RTN1, and MUC7); and five genes have not been well characterized to date. By comparison of the tobacco-exposed peripheral alveolar lung tissue of smokers with non-smokers and with adenocarcinomas from smokers, it was possible to identify a signature of 27 other differentially expressed genes. These genes are involved in the metabolism of xenobiotics (eg GPX2 and FMO3) and may represent cigarette smoke-induced, cancer-related molecular targets that may be utilized to identify smokers with increased risk for lung cancer.
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Deletions at chromosome 2q and 12p are early and frequent molecular alterations in Bronchial Epithelium and NSCLC of long-term smokers
International Journal of Oncology, 2005Co-Authors: U Grepmeier, Johannes Merk, Michael Pfeifer, Peter J Wild, Arndt Hartmann, Ferdinand Hofstaedter, Wolfgang Dietmaier, Ellen C. Obermann, Matthias WoenckhausAbstract:Most lung cancer is attributed to long-term smoking. In order to define chromosomal regions with an accumulation of smoking-related early molecular damage, we applied 15 microsatellite markers at 8 chromosomal regions (2q35-q36, 3p21.3, 3p14.2, 3p25, 10q11.2, 11p14-15, 12p13.1-p12.3 and 12q14) in an allelotyping study. We studied samples of 42 patients with primary non-small cell lung cancer (NSCLC) (25 squamous cell carcinomas, 13 adenocarcinomas, 2 large cell and 2 bronchioalveolar carcinomas) to compare the frequency of allelic loss in cancer tissue of smokers with matched Bronchial Epithelium. As a control group we used 11 samples of non-smokers. In NSCLC we found significantly higher frequencies of loss of heterozygosity (LOH) than in matched tumor free Bronchial Epithelium (p = 0.007). Most frequently, allelic loss was detected in NSCLC at chromosome 3p [3p25 (46%), 3p21.3 (45%), 3p14 (40%)], at 2q35 (24%), 12p12 (29%) and 12q14 (13%), but infrequently at 10q11 (7%) and 11p14-15 (5%). In corresponding histological normal Bronchial Epithelium, the highest percentage of LOH was found at chromosome 3p [3p21 (17%), 3p25 (12%), 3p14 (9%)] and chromosome 2q (2q35-q36) (17%) and 12p (12p12-p13) (12%). LOH in histologically normal Bronchial Epithelium was significantly associated with long-term smoking (p = 0.048), especially at chromosome 12p12 (p = 0.018). Our results demonstrate two further deletion hot spots at the chromosomal region 2q35-q36 and 12p12-p13 in tumor tissue of NSCLC and matched histological normal Bronchial Epithelium of long-term smokers, reflecting a phenomenon referred to as 'field cancerization'. These chromosomal regions represent interesting loci for potential NSCLC associated tumor suppressor genes and could be useful as screening markers for molecular risk assessment of smokers.
Xiaoling Zhang - One of the best experts on this subject based on the ideXlab platform.
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similarities and differences between smoking related gene expression in nasal and Bronchial Epithelium
Physiological Genomics, 2010Co-Authors: Xiaoling Zhang, Paola Sebastiani, Frank Schembri, Xiaohui Zhang, Yvesmartine Dumas, Erika M Langer, Yuriy O Alekseyev, George T Oconnor, Daniel R BrooksAbstract:Previous studies have shown that physiological responses to cigarette smoke can be detected via Bronchial airway Epithelium gene expression profiling and that heterogeneity in this gene expression response to smoking is associated with lung cancer. In this study, we sought to determine the similarity of the effects of tobacco smoke throughout the respiratory tract by determining patterns of smoking-related gene expression in paired nasal and Bronchial epithelial brushings collected from 14 healthy nonsmokers and 13 healthy current smokers. Using whole genome expression arrays, we identified 119 genes whose expression was affected by smoking similarly in both Bronchial and nasal Epithelium, including genes related to detoxification, oxidative stress, and wound healing. While the vast majority of smoking-related gene expression changes occur in both Bronchial and nasal Epithelium, we also identified 27 genes whose expression was affected by smoking more dramatically in Bronchial Epithelium than nasal Epithelium. Both common and site-specific smoking-related gene expression profiles were validated using independent microarray datasets. Differential expression of select genes was also confirmed by RT-PCR. That smoking induces largely similar gene expression changes in both nasal and Bronchial Epithelium suggests that the consequences of cigarette smoke exposure can be measured in tissues throughout the respiratory tract. Our findings suggest that nasal epithelial gene expression may serve as a relatively noninvasive surrogate to measure physiological responses to cigarette smoke and/or other inhaled exposures in large-scale epidemiological studies.
Frans C S Ramaekers - One of the best experts on this subject based on the ideXlab platform.
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identification of proteomic differences between squamous cell carcinoma of the lung and Bronchial Epithelium
Molecular & Cellular Proteomics, 2009Co-Authors: Gereon Poschmann, Barbara Sitek, Bence Sipos, Anna Ulrich, Sebastian Wiese, Christian Stephan, Bettina Warscheid, Gunter Kloppel, Ann Vander Borght, Frans C S RamaekersAbstract:Proteins that exhibit different expression levels in normal and malignant lung cells are good candidate biomarkers to improve early diagnosis and intervention. We used a quantitative approach and compared the proteome of microdissected cells from normal human Bronchial Epithelium and squamous cell carcinoma tumors of histopathological grades G2 and G3. DIGE analysis and subsequent MS-based protein identification revealed that 32 non-redundant proteins were differentially regulated between the respective tissue types. These proteins are mainly involved in energy pathways, cell growth or maintenance mechanisms, protein metabolism, and the regulation of DNA and RNA metabolism. The expression of some of these proteins was analyzed by immunohistochemistry using tissue microarrays containing tissue specimen of 55 patients, including normal Bronchial Epithelium, squamous cell carcinomas, adenocarcinomas, and large cell carcinomas. The results of the immunohistochemical studies correlated with the proteome study data and revealed that particularly HSP47 and a group of cytokeratins (i.e. cytokeratins 6a, 16, and 17) are significantly co-regulated in squamous cell carcinoma. Furthermore cytokeratin 17 showed significantly higher abundance in G2 grade compared with G3 grade squamous cell carcinomas in both the gel-based and the immunohistochemical analysis. Therefore this protein might be used as a marker for stratification between different tumor grades.
John D Minna - One of the best experts on this subject based on the ideXlab platform.
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molecular changes in the Bronchial Epithelium of patients with small cell lung cancer
Clinical Cancer Research, 2000Co-Authors: Ignacio I Wistuba, Anirban Maitra, Sara Milchgrub, Jarett Berry, Carmen Behrens, Narayan Shivapurkar, Bruce Mackay, John D MinnaAbstract:To better understand the pathways involved in the pathogenesis of small cell lung carcinoma (SCLC), we compared the patterns of molecular changes present in these tumors and their accompanying Bronchial Epithelium with those present in the other two major types of lung cancer [squamous cell carcinoma (SQC) and adenocarcinoma (ADC)]. We obtained DNA from 68 microdissected invasive lung tumors (22 SCLCs, 21 ADCs, and, 25 SQCs) and 119 noncontiguous foci of histologically normal or hyperplastic epithelia from 10 tumors of each histological type. We determined loss of heterozygosity and microsatellite alterations at 12 chromosomal regions frequently deleted in lung cancers using 19 polymorphic microsatellite markers. Our major findings are as follows: (a) the mean index of allelic loss in SCLC (0.85) and SQC (0.71) tumors was higher than that in ADC (0.39) tumors; (b) although there was considerable overlap, each tumor type had a characteristic pattern of allelic loss; (c) most samples of Bronchial Epithelium accompanying SCLC (90%) had allelic loss at one or more loci compared with samples accompanying SQC (54%) or ADC (10%); (d) the mean index of allelic loss was much higher in Bronchial epithelial samples from SCLC (0.27) than in those from SQC (0.08) or ADC (0.01); and (e) although the mean indices of microsatellite alterations in the tumor types were similar, the Bronchial epithelial samples accompanying SCLC had a 10-fold higher mean index (0.063) than those accompanying SQC (0.006) or ADC (0.006). Our findings indicate that extensive genetic damage in the accompanying normal and hyperplastic Bronchial Epithelium is characteristic of SCLC tumors and suggest major differences in the pathogenesis of the three major lung cancer types.
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multiple clonal abnormalities in the Bronchial Epithelium of patients with lung cancer
Journal of the National Cancer Institute, 1999Co-Authors: In Won Park, Ignacio I Wistuba, Anirban Maitra, Sara Milchgrub, Arvind K Virmani, John D Minna, Adi F GazdarAbstract:BACKGROUND: Several molecular changes, including loss of heterozygosity (i.e., deletion of one copy of allelic DNA sequences) and alterations in microsatellite DNA, have been detected early in the pathogenesis of lung cancer, even in histologically normal Epithelium. In the Bronchial Epithelium of patients with lung cancer, we have determined the frequency, size, and patterns of molecularly abnormal clonal patches. METHODS: We studied formalin-fixed, paraffin-embedded samples from 16 surgically resected lung carcinomas (five squamous cell carcinomas, four small-cell carcinomas, six adenocarcinomas, and one large-cell carcinoma). From each carcinoma, we microdissected foci (each containing about 200 cells) of tumor tissue and equivalent samples of histologically normal and abnormal Epithelium. Furthermore, multiple discontinuous foci of Bronchial Epithelium were analyzed from methanol-fixed samples from three additional patients with lung cancer (two with squamous cell carcinoma and one with adenocarcinoma). We used two-step polymerase chain reaction-based assays involving 12 microsatellite markers at seven chromosomal regions frequently deleted in lung cancer. RESULTS: Two hundred eighteen foci of nonmalignant Bronchial Epithelium (195 of histologically normal or slightly abnormal Epithelium and 23 of dysplastic Epithelium) were studied from the 19 surgically resected lobectomy specimens. Thirteen (68%) of the 19 specimens had at least one focus of Bronchial Epithelium with molecular changes. At least one molecular abnormality was detected in 32% of the 195 histologically normal or slightly abnormal foci and in 52% of the 23 dysplastic foci. Extrapolating from our two-dimensional analyses, we estimate that most clonal patches contain approximately 90 000 cells. Although, in a given individual, tumors appeared homogeneous with respect to molecular changes, the clonally altered patches of mildly abnormal Epithelium were heterogeneous. CONCLUSIONS: Our findings indicate that multiple small clonal or subclonal patches containing molecular abnormalities are present in normal or slightly abnormal Bronchial Epithelium of patients with lung cancer.
