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Search Results: 1 - 10 of 402161 matches for " Kwun M Fong "
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Expression profiling identifies genes involved in emphysema severity
Santiyagu Francis, Jill E Larsen, Sandra J Pavey, Rayleen V Bowman, Nicholas K Hayward, Kwun M Fong, Ian A Yang
Respiratory Research , 2009, DOI: 10.1186/1465-9921-10-81
Abstract: Gene expression profiling was performed on total RNA extracted from non-tumor lung tissue from 30 smokers with emphysema. Class comparison analysis based on gas transfer measurement was performed to identify differentially expressed genes. Genes were then selected for technical validation by quantitative reverse transcriptase-PCR (qRT-PCR) if also represented on microarray platforms used in previously published emphysema studies. Genes technically validated advanced to tests of biological replication by qRT-PCR using an independent test set of 62 lung samples.Class comparison identified 98 differentially expressed genes (p < 0.01). Fifty-one of those genes had been previously evaluated in differentiation between normal and severe emphysema lung. qRT-PCR confirmed the direction of change in expression in 29 of the 51 genes and 11 of those validated, remaining significant at p < 0.05. Biological replication in an independent cohort confirmed the altered expression of eight genes, with seven genes differentially expressed by greater than 1.3 fold, identifying these as candidate determinants of emphysema severity.Gene expression profiling of lung from emphysema patients identified seven candidate genes associated with emphysema severity including COL6A3, SERPINF1, ZNHIT6, NEDD4, CDKN2A, NRN1 and GSTM3.Chronic obstructive pulmonary disease (COPD) is a major health burden worldwide [1]. Smoking is the primary cause of COPD, with up to 50% of smokers developing the disease [2]. It is frequently under-diagnosed and under-treated [3] since its early stages are often asymptomatic. COPD patients are classified into mild, moderate and severe based on the degree of airflow limitation, which is a result of damage in the large airways (bronchitis), small airways (bronchiolitis) and or alveoli (emphysema). Emphysema affects 40% of heavy smokers [4] and causes loss of elastic recoil, leading to abnormal gas exchange and breathlessness. Despite smoking cessation, some individuals con
Genes and Gene Ontologies Common to Airflow Obstruction and Emphysema in the Lungs of Patients with COPD
Santiyagu M. Savarimuthu Francis,Jill E. Larsen,Sandra J. Pavey,Edwina E. Duhig,Belinda E. Clarke,Rayleen V. Bowman,Nick K. Hayward,Kwun M. Fong,Ian A. Yang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017442
Abstract: Chronic obstructive pulmonary disease (COPD) is a major public health problem with increasing prevalence worldwide. The primary aim of this study was to identify genes and gene ontologies associated with COPD severity. Gene expression profiling was performed on total RNA extracted from lung tissue of 18 former smokers with COPD. Class comparison analysis on mild (n = 9, FEV1 80–110% predicted) and moderate (n = 9, FEV1 50–60% predicted) COPD patients identified 46 differentially expressed genes (p<0.01), of which 14 genes were technically confirmed by quantitative real-time-PCR. Biological replication in an independent test set of 58 lung samples confirmed the altered expression of ten genes with increasing COPD severity, with eight of these genes (NNMT, THBS1, HLA-DPB1, IGHD, ETS2, ELF1, PTGDS and CYRBD1) being differentially expressed by greater than 1.8 fold between mild and moderate COPD, identifying these as candidate determinants of COPD severity. These genes belonged to ontologies potentially implicated in COPD including angiogenesis, cell migration, proliferation and apoptosis. Our secondary aim was to identify gene ontologies common to airway obstruction, indicated by impaired FEV1 and KCO. Using gene ontology enrichment analysis we have identified relevant biological and molecular processes including regulation of cell-matrix adhesion, leukocyte activation, cell and substrate adhesion, cell adhesion, angiogenesis, cell activation that are enriched among genes involved in airflow obstruction. Exploring the functional significance of these genes and their gene ontologies will provide clues to molecular changes involved in severity of COPD, which could be developed as targets for therapy or biomarkers for early diagnosis.
MicroRNA-218 Is Deleted and Downregulated in Lung Squamous Cell Carcinoma
Morgan R. Davidson,Jill E. Larsen,Ian A. Yang,Nicholas K. Hayward,Belinda E. Clarke,Edwina E. Duhig,Linda H. Passmore,Rayleen V. Bowman,Kwun M. Fong
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012560
Abstract: MicroRNAs (miRNAs) are a family of small, non-coding RNA species functioning as negative regulators of multiple target genes including tumour suppressor genes and oncogenes. Many miRNA gene loci are located within cancer-associated genomic regions. To identify potential new amplified oncogenic and/or deleted tumour suppressing miRNAs in lung cancer, we inferred miRNA gene dosage from high dimensional arrayCGH data. From miRBase v9.0 (http://microrna.sanger.ac.uk), 474 human miRNA genes were physically mapped to regions of chromosomal loss or gain identified from a high-resolution genome-wide arrayCGH study of 132 primary non-small cell lung cancers (NSCLCs) (a training set of 60 squamous cell carcinomas and 72 adenocarcinomas). MiRNAs were selected as candidates if their immediately flanking probes or host gene were deleted or amplified in at least 25% of primary tumours using both Analysis of Copy Errors algorithm and fold change (≥±1.2) analyses. Using these criteria, 97 miRNAs mapped to regions of aberrant copy number. Analysis of three independent published lung cancer arrayCGH datasets confirmed that 22 of these miRNA loci showed directionally concordant copy number variation. MiR-218, encoded on 4p15.31 and 5q35.1 within two host genes (SLIT2 and SLIT3), in a region of copy number loss, was selected as a priority candidate for follow-up as it is reported as underexpressed in lung cancer. We confirmed decreased expression of mature miR-218 and its host genes by qRT-PCR in 39 NSCLCs relative to normal lung tissue. This downregulation of miR-218 was found to be associated with a history of cigarette smoking, but not human papilloma virus. Thus, we show for the first time that putative lung cancer-associated miRNAs can be identified from genome-wide arrayCGH datasets using a bioinformatics mapping approach, and report that miR-218 is a strong candidate tumour suppressing miRNA potentially involved in lung cancer.
Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD)
Janet G Shaw, Annette G Dent, Linda H Passmore, Darryl J Burstow, Rayleen V Bowman, Paul V Zimmerman, Kwun M Fong, Ian A Yang
BMC Pulmonary Medicine , 2012, DOI: 10.1186/1471-2466-12-25
Abstract: In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia.580 COPD patients were recruited, 341 patients had a transthoracic echocardiogram, with RVSP measurable in 278 patients (mean age 69?years, mean FEV1 50% predicted, mean RVSP 44?mmHg, median history of 50 pack-years). Of the 7 tested SNPs, the NOS3-VNTR polymorphism was significantly associated with RVSP in a dose-dependent fashion for the risk allele: mean RVSP for a/a and a/b genotypes were 52.0 and 46.6?mmHg respectively, compared to 43.2?mmHg for b/b genotypes (P?=?0.032). No associations were found between RVSP and other polymorphisms. ACE II or ID genotypes were associated with a lower FEV1% predicted than the ACE DD genotype (P?=?0.028). The NOS3-298 TT genotype was associated with lower KCO % predicted than the NOS3-298 GG or GT genotype (P?=?0.031).The NOS3-VNTR polymorphism was associated with RVSP in patients with COPD, supporting its involvement in the pathogenesis of PH in COPD. ACE and NOS3 genotypes were associated with COPD disease severity, but not with the presence of PH. Further study of these genes could lead to the development of prognostic and screening tools for PH in COPD.Pulmonary hypertension (PH) is a serious complication of chronic obstructive pulmonary disease (COPD) and develops in 30% to 70% of patients with COPD, increasing their morbidity and mortality [1]. PH is progressive in COPD, with mean pulmonary arterial pressure increasing over time [2,3]. Understanding variations in susceptibility to PH in patients with COPD could significantly enhance diagnosis, risk stratification and therapy for these patients.Vascular remodelling is the main pathological feature in PH and is mediated via vasoactive molecules [4]. Genes encoding these mediators contain genetic polymorphisms that potentially affect their function and
Array-Comparative Genomic Hybridization Reveals Loss of SOCS6 Is Associated with Poor Prognosis in Primary Lung Squamous Cell Carcinoma
Krishna B. Sriram, Jill E. Larsen, Santiyagu M. Savarimuthu Francis, Casey M. Wright, Belinda E. Clarke, Edwina E. Duhig, Kevin M. Brown, Nicholas K. Hayward, Ian A. Yang, Rayleen V. Bowman, Kwun M. Fong
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030398
Abstract: Background Primary tumor recurrence commonly occurs after surgical resection of lung squamous cell carcinoma (SCC). Little is known about the genes driving SCC recurrence. Methods We used array comparative genomic hybridization (aCGH) to identify genes affected by copy number alterations that may be involved in SCC recurrence. Training and test sets of resected primary lung SCC were assembled. aCGH was used to determine genomic copy number in a training set of 62 primary lung SCCs (28 with recurrence and 34 with no evidence of recurrence) and the altered copy number of candidate genes was confirmed by quantitative PCR (qPCR). An independent test set of 72 primary lung SCCs (20 with recurrence and 52 with no evidence of recurrence) was used for biological validation. mRNA expression of candidate genes was studied using qRT-PCR. Candidate gene promoter methylation was evaluated using methylation microarrays and Sequenom EpiTYPER analysis. Results 18q22.3 loss was identified by aCGH as being significantly associated with recurrence (p = 0.038). Seven genes within 18q22.3 had aCGH copy number loss associated with recurrence but only SOCS6 copy number was both technically replicated by qPCR and biologically validated in the test set. SOCS6 copy number loss correlated with reduced mRNA expression in the study samples and in the samples with copy number loss, there was a trend for increased methylation, albeit non-significant. Overall survival was significantly poorer in patients with SOCS6 loss compared to patients without SOCS6 loss in both the training (30 vs. 43 months, p = 0.023) and test set (27 vs. 43 months, p = 0.010). Conclusion Reduced copy number and mRNA expression of SOCS6 are associated with disease recurrence in primary lung SCC and may be useful prognostic biomarkers.
MS4A1 Dysregulation in Asbestos-Related Lung Squamous Cell Carcinoma Is Due to CD20 Stromal Lymphocyte Expression
Casey M. Wright, Santiyagu M. Savarimuthu Francis, Maxine E. Tan, Maria U. Martins, Clay Winterford, Morgan R. Davidson, Edwina E. Duhig, Belinda E. Clarke, Nicholas K. Hayward, Ian A. Yang, Rayleen V. Bowman, Kwun M. Fong
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034943
Abstract: Asbestos-related lung cancer accounts for 4–12% of lung cancers worldwide. We have previously identified ADAM28 as a putative oncogene involved in asbestos-related lung adenocarcinoma (ARLC-AC). We hypothesised that similarly gene expression profiling of asbestos-related lung squamous cell carcinomas (ARLC-SCC) may identify candidate oncogenes for ARLC-SCC. We undertook a microarray gene expression study in 56 subjects; 26 ARLC-SCC (defined as lung asbestos body (AB) counts >20AB/gram wet weight (gww) and 30 non-asbestos related lung squamous cell carcinoma (NARLC-SCC; no detectable lung asbestos bodies; 0AB/gww). Microarray and bioinformatics analysis identified six candidate genes differentially expressed between ARLC-SCC and NARLC-SCC based on statistical significance (p<0.001) and fold change (FC) of >2-fold. Two genes MS4A1 and CARD18, were technically replicated by qRT-PCR and showed consistent directional changes. As we also found MS4A1 to be overexpressed in ARLC-ACs, we selected this gene for biological validation in independent test sets (one internal, and one external dataset (2 primary tumor sets)). MS4A1 RNA expression dysregulation was validated in the external dataset but not in our internal dataset, likely due to the small sample size in the test set as immunohistochemical (IHC) staining for MS4A1 (CD20) showed that protein expression localized predominantly to stromal lymphocytes rather than tumor cells in ARLC-SCC. We conclude that differential expression of MS4A1 in this comparative gene expression study of ARLC-SCC versus NARLC-SCC is a stromal signal of uncertain significance, and an example of the rationale for tumor cell enrichment in preparation for gene expression studies where the aim is to identify markers of particular tumor phenotypes. Finally, our study failed to identify any strong gene candidates whose expression serves as a marker of asbestos etiology. Future research is required to determine the role of stromal lymphocyte MS4A1 dysregulation in pulmonary SCCs caused by asbestos.
A Genome-Wide Screen for Promoter Methylation in Lung Cancer Identifies Novel Methylation Markers for Multiple Malignancies
David S Shames,Luc Girard,Boning Gao,Mitsuo Sato,Cheryl M Lewis,Narayan Shivapurkar,Aixiang Jiang,Charles M Perou,Young H Kim,Jonathan R Pollack,Kwun M Fong,Chi-Leung Lam,Maria Wong,Yu Shyr,Rita Nanda,Olufunmilayo I Olopade,William Gerald,David M Euhus,Jerry W Shay,Adi F Gazdar,John D Minna
PLOS Medicine , 2006, DOI: 10.1371/journal.pmed.0030486
Abstract: Background Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The “rules” governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. Methods and Findings In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5′ CpG islands, are induced from undetectable levels by 5-aza-2′-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. Conclusions By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention.
The Interplay of PPARs with Parasites and Related Intracellular Pathogens
Marion M. Chan,Dunne Fong
PPAR Research , 2012, DOI: 10.1155/2012/624845
Abstract:
The Interplay of PPARs with Parasites and Related Intracellular Pathogens
Marion M. Chan,Dunne Fong
PPAR Research , 2012, DOI: 10.1155/2012/624845
Abstract:
The Chinese ba as a Verb: A Constructional-Cognitive Approach  [PDF]
Ronald Fong
Open Journal of Modern Linguistics (OJML) , 2015, DOI: 10.4236/ojml.2015.51005
Abstract: Although there have been various studies on the Chinese ba-construction, this article presents some unconventional views. Most studies do not treat ba as a verb. This article argues that ba is a verb, although it has some non-typical verbal properties. Firstly, the argument establishes that it is a verb based upon the “gradient” analysis, which has not been applied to ba before. Secondly, having been treated as a verb, ba shows special properties of its own such as marking subordination. Apart from this non-traditional view, ba is shown to be highly transitive, which is also a verbal feature. Different from previous analyses, this article argues that ba is a radial category showing various associated meanings. Finally, ba is shown to produce blending with other verb complements, such as the resultative construction, through its ability to create mental spaces.
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