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Search Results: 1 - 10 of 168961 matches for " Belinda E. Clarke "
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Pleural fluid cell-free DNA integrity index to identify cytologically negative malignant pleural effusions including mesotheliomas
Sriram Krishna B,Relan Vandana,Clarke Belinda E,Duhig Edwina E
BMC Cancer , 2012, DOI: 10.1186/1471-2407-12-428
Abstract: Background The diagnosis of malignant pleural effusions (MPE) is often clinically challenging, especially if the cytology is negative for malignancy. DNA integrity index has been reported to be a marker of malignancy. The aim of this study was to evaluate the utility of pleural fluid DNA integrity index in the diagnosis of MPE. Methods We studied 75 pleural fluid and matched serum samples from consecutive subjects. Pleural fluid and serum ALU DNA repeats [115bp, 247bp and 247bp/115bp ratio (DNA integrity index)] were assessed by real-time quantitative PCR. Pleural fluid and serum mesothelin levels were quantified using ELISA. Results Based on clinico-pathological evaluation, 52 subjects had MPE (including 16 mesotheliomas) and 23 had benign effusions. Pleural fluid DNA integrity index was higher in MPE compared with benign effusions (1.2 vs. 0.8; p<0.001). Cytology had a sensitivity of 55% in diagnosing MPE. If cytology and pleural fluid DNA integrity index were considered together, they exhibited 81% sensitivity and 87% specificity in distinguishing benign and malignant effusions. In cytology-negative pleural effusions (35 MPE and 28 benign effusions), elevated pleural fluid DNA integrity index had an 81% positive predictive value in detecting MPEs. In the detection of mesothelioma, at a specificity of 90%, pleural fluid DNA integrity index had similar sensitivity to pleural fluid and serum mesothelin (75% each respectively). Conclusion Pleural fluid DNA integrity index is a promising diagnostic biomarker for identification of MPEs, including mesothelioma. This biomarker may be particularly useful in cases of MPE where pleural aspirate cytology is negative, and could guide the decision to undertake more invasive definitive testing. A prospective validation study is being undertaken to validate our findings and test the clinical utility of this biomarker for altering clinical practice.
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.
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.
Synergy between molecular biology and imaging science toward mechanism-based biomarkers associated with prostate cancer  [PDF]
Belinda Seto
Journal of Biomedical Science and Engineering (JBiSE) , 2012, DOI: 10.4236/jbise.2012.512A107

Prostate cancer is a heterogeneous disease with subtypes that are characterized by different molecular profiles as a result of chromosomal rearrangements, epigenetic modifications, and activation of various signaling pathways. The subtype heterogeneity contributes to the challenges with a definitive diagnosis and biomarkers for disease progression. The current diagnostic test based on the detection of prostate specific antigen lacks sensitivity and specificity. Imaging plays an important role in characterizing biomarkers and elucidating the underlying molecular mechanisms. For example, 18F-fluoro-2-deoxy glucose is commonly used to assess cancer cell metabolism. More recently, magnetic resonance spectroscopic observations of the in vivo dynamic conversion of hyperpolarized 13C- pyruvate to lactate demonstrate that imaging enables the visualization of molecular processes. Biomarkers have also been developed that reveal aberrant cell growth and proliferation, both hallmarks of cancer. Androgen dependent and independent signaling path- ways underpin prostate cancer pathogenesis as they lead to downstream effect in cell growth, proliferation, survival, and suppression of apoptosis. Molecular imaging with radiolabeled ligands and positron emission tomography/computed tomography has provided quantitative characterization of the interactions between receptors and testosterone or growth factors. These observations, along with data on genetic alterations of the receptor genes, shed light on signal transduction involved in prostate cancer. This review article highlights advances in the understanding of the molecular mechanisms of prostate cancer and the synergy of this knowledge with imaging in characterizing potential biomarkers of the disease.

Resolving issues concerning Eskdalemuir geomagnetic hourly values
S. Macmillan ,E. Clarke
Annales Geophysicae (ANGEO) , 2011,
Abstract: The hourly values of the geomagnetic field from 1911 to 1931 derived from measurements made at Eskdalemuir observatory in the UK, and available online from the World Data Centre for Geomagnetism at http://www.wdc.bgs.ac.uk/, have now been corrected. Previously they were 2-point averaged and transformed from the original north, east and vertical down values in the tables in the observatory yearbooks. This paper documents the course of events from discovering the post-processing done to the data to the final resolution of the problem. As it was through the development of a new index, the Inter-Hour Variability index, that this post-processing came to light, we provide a revised series of this index for Eskdalemuir and compare it with that from another European observatory. Conclusions of studies concerning long-term magnetic field variability and inferred solar variability, whilst not necessarily consistent with one another, are not obviously invalidated by the incorrect hourly values from Eskdalemuir. This series of events illustrates the challenges that lie ahead in removing any remaining errors and inconsistencies in the data holdings of different World Data Centres.
'Die verswygde storie': ’n gevallestudie oor die manifestasie van bates by ’n kleuter met spina bifida mi lomeningoseel
I. Eloff,E. Clarke
Koers : Bulletin for Christian Scholarship , 2007, DOI: 10.4102/koers.v72i4.220
Abstract: 'The unmentioned story': a case study of the manifestation of assets in a toddler with spina bifida mi lomeningoseel In South Africa a few major discourses with regard to disability can be distinguished. Although these discourses construct disability differently, three of them – the lay, charity and medical discourses – tend to view disability negatively. This article endeavours to challenge the stereotypical “picture” of a person with a disability. By conducting an intrinsic case study the unique intrapersonal assets of a boy (who has a physical disability, spina bifida) is identified. An asset-based approach accompanied the research design as a theoretical framework in order to explore whether positive aspects of this boy’s life-world could be identified. This article identifies and embraces the positive side of living with a physical disability and illustrates ways in which positive constructions of an individual with disabilities can be pursued.
Hepatitis E: a complex and global disease
I Clarke,E Pelosi
Emerging Health Threats Journal , 2008, DOI: 10.3134/ehtj.08.008
Abstract: Thirty years after its discovery, the hepatitis E virus (HEV) continues to represent a major public health problem in developing countries. In developed countries, it has emerged as a significant cause of non-travel-associated acute hepatitis. HEV infects a wide range of mammalian species and a key reservoir worldwide appears to be swine. Genomic sequence similarity between some human HEV genotypes and swine HEV strains has been identified and we know that humans can acquire HEV infection from animals. Although for the most part the clinical course of HEV infection is asymptomatic or mild, significant risk of serious disease exists in pregnant women and those with chronic liver disease. In addition, there are data on the threat of chronic infections in immunocompromised patients. Beyond management of exposure by public health measures, recent data support that active immunisation can prevent hepatitis E, highlighting the need for vaccination programmes. Here we review the current knowledge on HEV, its epidemiology, and the management and prevention of human disease.
Single Session, Multiple Band Ligation for Haemorrhoids  [PDF]
K. Alubaidi, G. Clarke, A. Jamil, E. Ghareeb
Surgical Science (SS) , 2016, DOI: 10.4236/ss.2016.75032
Abstract: Background: Single session, multiple Band Ligations (BL) for haemorrhoids has been practised in the UK for more than 40 years. It has been claimed that multiple BL in a single session can cause pain and discomfort [1]-[3], although this issue has not been formally assessed in the past. Our study was designed to examine this claim. Methods: Patients were randomly chosen for this study from rectal bleeding clinics and endoscopy lists. On diagnosis of haemorrhoids at proctoscopy these patients were offered, and treated with multiple BL. Results: 50 patients were treated with BL for 2nd and (the majority) 3rd degree haemorrhoids. All patients needed 2 - 3 haemorrhoids banded. 76% stated that they had no pain or discomfort, 14% complained of slight pain and 10% complained of very slight discomfort. 90% were successfully treated, and 97% stated that they would be prepared to undergo further treatment if necessary. Conclusion: Single session multiple haemorrhoids band ligations are a safe procedure which can be performed by surgeons in outpatient clinics with minimal discomfort for patients.
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