36 results on '"Peter W. Hamilton"'
Search Results
2. Delivering a research-enabled multistakeholder partnership for enhanced patient care at a population level: The Northern Ireland Comprehensive Cancer Program
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Margaret Grayson, Anna Gavin, Tracy Robson, Jacqueline James, Manuel Salto-Tellez, Kevin M. Prise, Robert D. Ladner, Liam J. Murray, David Waugh, Peter W. Hamilton, Patrick G. Johnston, Richard D. Kennedy, Darragh G. McArt, Ruth Boyd, Richard H. Wilson, Sandra Van Schaeybroeck, Tim Harrison, Mark Lawler, Joe M. O'Sullivan, and Denis Paul Harkin
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0301 basic medicine ,Cancer Research ,Government ,Population level ,business.industry ,Northern ireland ,Precision medicine ,Ethos ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Transformative learning ,Oncology ,Nursing ,030220 oncology & carcinogenesis ,General partnership ,Health care ,Medicine ,business ,health care economics and organizations - Abstract
The last 20 years have seen significant advances in cancer care in Northern Ireland, leading to measureable improvements in patient outcomes. Crucial to this transformation has been an ethos that recognizes the primacy role of research in effecting heath care change. The authors' model of a cross‐sectoral partnership that unites patients, scientists, health care professionals, hospital trusts, bioindustry, and government agencies can be truly transformative, empowering tripartite clinical‐academic‐industry efforts that have already yielded significant benefit and will continue to inform strategy and its implementation going forward.
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- 2015
3. Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with potential for clinical utility
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Richard C. Turkington, Maurice B. Loughrey, Perry Maxwell, Richard H. Wilson, Claire McGready, Victoria Bingham, Stephen McQuaid, Peter W. Hamilton, Darragh G. McArt, Jacqueline James, Paul J Kelly, Manuel Salto-Tellez, Muhammad A Alvi, Frank Emmert-Streib, Matthew Alderdice, Marc-Aurel Fuchs, Shailesh Tripathi, and Clare M. McCabe
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p53 ,Male ,Pathology ,DNA Mutational Analysis ,Epigenesis, Genetic ,Intestine, Small ,Gene expression ,Pathology, Molecular ,Oligonucleotide Array Sequence Analysis ,Aged, 80 and over ,Kazald1 ,CHN2 ,biology ,Molecular pathology ,High-Throughput Nucleotide Sequencing ,Middle Aged ,Gene Expression Regulation, Neoplastic ,Treatment Outcome ,Oncology ,CpG site ,DNA methylation ,Adenocarcinoma ,Female ,Nucleophosmin ,Small intestine cancer ,Adult ,medicine.medical_specialty ,SDG 3 - Good Health and Well-being ,Pathology Section ,Intestinal Neoplasms ,Biomarkers, Tumor ,medicine ,Humans ,PTEN ,Aged ,Retrospective Studies ,Gene Expression Profiling ,small intestine cancer ,Chimerin Proteins ,DNA Methylation ,Genes, p53 ,medicine.disease ,Research Paper: Pathology ,Gene expression profiling ,Mutation ,Cancer research ,biology.protein ,CpG Islands - Abstract
Small bowel accounts for only 0.5% of cancer cases in the US but incidence rates have been rising at 2.4% per year over the past decade. One-third of these are adenocarcinomas but little is known about their molecular pathology and no molecular markers are available for clinical use. Using a retrospective 28 patient matched normal-tumor cohort, next-generation sequencing, gene expression arrays and CpG methylation arrays were used for molecular profiling. Next-generation sequencing identified novel mutations in IDH1, CDH1, KIT, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p < 0.01). Merging gene expression and DNA methylation data revealed CHN2 as consistently hypermethylated and downregulated in this disease (Spearman -0.71, p < 0.001). Mutations in TP53 which were found in more than half of the cohort (15/28) and Kazald1 hypomethylation were both were indicative of poor survival (p = 0.03, HR = 3.2 and p = 0.01, HR = 4.9 respectively). By integrating high-throughput mutational, gene expression and DNA methylation data, this study reveals for the first time the distinct molecular profile of small bowel adenocarcinoma and highlights potential clinically exploitable markers.
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- 2015
4. IHC-based subcellular quantification provides new insights into prognostic relevance of FLIP and procaspase-8 in non-small-cell lung cancer
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Philip D Dunne, Ryan Hutchinson, Elaine W. Kay, Darragh G. McArt, Daniel B. Longley, Kathy Gately, Robert Cummins, Seedevi Senevirathne, Vincent Young, Peter W. Hamilton, Helen G. Coleman, Siobhan Nicholson, and Sean O. Hynes
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0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,Immunology ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Stroma ,Journal Article ,Medicine ,Lung cancer ,business.industry ,Proportional hazards model ,Cell Biology ,medicine.disease ,030104 developmental biology ,Flip ,030220 oncology & carcinogenesis ,Immunohistochemistry ,Adenocarcinoma ,Biomarker (medicine) ,business - Abstract
In this study, we developed an image analysis algorithm for quantification of two potential apoptotic biomarkers in non-small-cell lung cancer (NSCLC): FLIP and procaspase-8. Immunohistochemical expression of FLIP and procaspase-8 in 184 NSCLC tumors were assessed. Individual patient cores were segmented and classified as tumor and stroma using the Definiens Tissue Studio. Subsequently, chromogenic expression of each biomarker was measured separately in the nucleus and cytoplasm and reported as a quantitative histological score. The software package pROC was applied to define biomarker thresholds. Cox proportional hazards analysis was applied to generate hazard ratios (HRs) and associated 95% CI for survival. High cytoplasmic expression of tumoral (but not stromal) FLIP was associated with a 2.5-fold increased risk of death in lung adenocarcinoma patients, even when adjusted for known confounders (HR 2.47, 95% CI 1.14–5.35). Neither nuclear nor cytoplasmic tumoral procaspase-8 expression was associated with overall survival in lung adenocarcinoma patients; however, there was a significant trend (P for trend=0.03) for patients with adenocarcinomas with both high cytoplasmic FLIP and high cytoplasmic procaspase-8 to have a multiplicative increased risk of death. Notably, high stromal nuclear procaspase-8 expression was associated with a reduced risk of death in lung adenocarcinoma patients (adjusted HR 0.31, 95% CI 0.15–0.66). On further examination, the cells with high nuclear procaspase-8 were found to be of lymphoid origin, suggesting that the better prognosis of patients with tumors with high stromal nuclear procaspase-8 is related to immune infiltration, a known favorable prognostic factor. No significant associations were detected in analysis of lung squamous cell carcinoma patients. Our results suggest that cytoplasmic expression of FLIP in the tumor and nuclear expression of procaspase-8 in the stroma are prognostically relevant in non-small-cell adenocarcinomas but not in squamous cell carcinomas of the lung.
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- 2017
5. Statin use, Candidate Mevalonate Pathway Biomarkers, and Colon Cancer Survival in a Population-Based Cohort Study
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Helen G. Coleman, Liam J. Murray, Roisin O'Neill, Maurice B Loughrey, Peter Bankhead, Anna Gavin, Christopher Cardwell, Jacqueline James, Claire McGready, Kenneth Arthur, Ronan T. Gray, Victoria Bingham, Peter W. Hamilton, Manuel Salto-Tellez, and Stephen McQuaid
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0301 basic medicine ,Oncology ,Colonic Neoplasms/chemistry ,Male ,Cancer Research ,Epidemiology ,Colorectal cancer ,Pharmacology ,medicine.disease_cause ,Cohort Studies ,0302 clinical medicine ,HMGCR protein ,Aged, 80 and over ,education.field_of_study ,Tissue microarray ,Hazard ratio ,Gastroenterology ,colonic neoplasms ,Middle Aged ,tumour suppressor protein p53 ,Survival Rate ,030220 oncology & carcinogenesis ,Cohort ,lipids (amino acids, peptides, and proteins) ,Female ,KRAS ,Mevalonic Acid/metabolism ,Metabolic Networks and Pathways ,Cohort study ,medicine.medical_specialty ,Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ,Population ,Mevalonic Acid ,Biology ,survival ,Proto-Oncogene Proteins p21(ras) ,Biomarkers, Tumor/analysis ,Proto-Oncogene Proteins p21(ras)/genetics ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,education ,Survival rate ,Aged ,Hepatology ,Proportional hazards model ,business.industry ,Hydroxymethylglutaryl CoA Reductases/analysis ,medicine.disease ,Tumor Suppressor Protein p53/analysis ,030104 developmental biology ,Hydroxymethylglutaryl CoA Reductases ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Tumor Suppressor Protein p53 ,business - Abstract
BACKGROUND: Statin use after colorectal cancer diagnosis may improve survival but evidence from observational studies is conflicting. The anti-cancer effect of statins may be restricted to certain molecular subgroups. In this population-based cohort study, the interaction between p53 and 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) expression, KRAS mutations, and the association between statin use and colon cancer survival was assessed.METHODS: The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Statin use was determined through clinical note review. Tissue blocks were retrieved to determine immunohistochemical expression of p53 and HMGCR in tissue microarrays and the presence of KRAS mutations in extracted DNA. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer-specific and overall survival.RESULTS: Statin use was not associated with improved cancer-specific survival in this cohort (HR=0.91, 95% CI 0.64-1.28). Statin use was also not associated with improved survival when the analyses were stratified by tumour p53 (wild-type HR=1.31, 95% CI 0.67-2.56 vs aberrant HR=0.80, 95% CI 0.52-1.24), HMGCR (HMGCR-high HR=0.69, 95% CI 0.40-1.18 vs HMGCR-low HR=1.10, 95% CI 0.66-1.84), and KRAS (wild-type HR=0.73, 95% CI 0.44-1.19 vs mutant HR=1.21, 95% CI 0.70-2.21) status.CONCLUSIONS: Statin use was not associated with improved survival either independently or when stratified by potential mevalonate pathway biomarkers in this population-based cohort of colon cancer patients.
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- 2017
6. Molecular pathology - The value of an integrative approach
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Manuel Salto-Tellez, Peter W. Hamilton, and Jacqueline James
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Cancer Research ,business.industry ,Molecular pathology ,Computational Biology ,Translational research ,Tissue Banks ,Review ,General Medicine ,Molecular diagnostics ,Bioinformatics ,Data science ,Translational Research, Biomedical ,Oncology ,Neoplasms diagnosis ,Neoplasms ,Biomarkers, Tumor ,Genetics ,Animals ,Humans ,Molecular Medicine ,Medicine ,Pathology, Molecular ,Biomarker discovery ,business - Abstract
Molecular Pathology (MP) is at the heart of modern diagnostics and translational research, but the controversy on how MP is best developed has not abated. The lack of a proper model or trained pathologists to support the diagnostic and research missions makes MP a rare commodity overall. Here we analyse the scientific and technology areas, in research and diagnostics, which are encompassed by MP of solid tumours; we highlight the broad overlap of technologies and analytical capabilities in tissue research and diagnostics; and we describe an integrated model that rationalizes technical know-how and pathology talent for both. The model is based on a single, accredited laboratory providing a single standard of high-quality for biomarker discovery, biomarker validation and molecular diagnostics.
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- 2014
7. Challenging the cancer molecular stratification dogma: Intratumoral heterogeneity undermines consensus molecular subtypes and potential diagnostic value in colorectal cancer
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Maurice B. Loughrey, Tony O'Grady, Helen L. Barrett, Daniel B. Longley, Elaine W. Kay, Robert Cummins, Paul G. O’Reilly, David Waugh, Peter W. Hamilton, Ken Arthur, Simon S. McDade, Manuel Salto-Tellez, Wendy L. Allen, Sandra Van Schaeybroeck, Mark Lawler, Philip D Dunne, Darragh G. McArt, Conor A Bradley, Patrick G. Johnston, Dunne, Philip D, McArt, Darragh G, Bradley, Conor A, O'Reilly, Paul G, Barrett, Helen L., Cummins, Robert, O'Grady, Tony, Arthur, Ken, Loughrey, Maurice B, Allen, Wendy L., McDade, Simon S, Waugh, David J, Hamilton, Peter W, Longley, Daniel B, Kay, Elaine W, Johnston, Patrick G, Lawler, Mark, Salto Tellez, Manuel, and Van Schaeybroeck, Sandra
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Stromal cell ,Colorectal cancer ,Biology ,Bioinformatics ,Transcriptome ,03 medical and health sciences ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Internal medicine ,Gene expression ,medicine ,Biomarkers, Tumor ,gene expression profiling ,Humans ,cancer ,Gene ,Neoplasm Staging ,Regulation of gene expression ,Gene Expression Profiling ,medicine.disease ,molecular subtype ,Gene expression profiling ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Organ Specificity ,030220 oncology & carcinogenesis ,Lymphatic Metastasis ,RNA extraction ,Stromal Cells ,Colorectal Neoplasms - Abstract
Purpose: A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled. Experimental Design: We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients. Results: We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR = 2.914 (confidence interval 0.9286–9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stem-like biology have undergone a widespread epithelial–mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed. Conclusions: Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer. Clin Cancer Res; 22(16); 4095–104. ©2016 AACR. See related commentary by Morris and Kopetz, p. 3989
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- 2016
8. Building a 'Repository of Science': The importance of integrating biobanks within molecular pathology programmes
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Stephen McQuaid, Darragh G. McArt, Claire Lewis, Jacqueline James, Peter W. Hamilton, and Manuel Salto-Tellez
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0301 basic medicine ,Cancer Research ,Biomedical Research ,Informatics ,Sample (statistics) ,Northern Ireland ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Databases, Genetic ,Biomarkers, Tumor ,Medicine ,Humans ,Cooperative Behavior ,Pathology, Molecular ,Precision Medicine ,Biological Specimen Banks ,business.industry ,Molecular pathology ,Digital pathology ,Precision medicine ,Data science ,Biobank ,Metadata ,030104 developmental biology ,Oncology ,Molecular Diagnostic Techniques ,030220 oncology & carcinogenesis ,Tissue bank ,business ,Databases, Chemical - Abstract
Repositories containing high quality human biospecimens linked with robust and relevant clinical and pathological information are required for the discovery and validation of biomarkers for disease diagnosis, progression and response to treatment. Current molecular based discovery projects using either low or high throughput technologies rely heavily on ready access to such sample collections. It is imperative that modern biobanks align with molecular diagnostic pathology practices not only to provide the type of samples needed for discovery projects but also to ensure requirements for ongoing sample collections and the future needs of researchers are adequately addressed. Biobanks within comprehensive molecular pathology programmes are perfectly positioned to offer more than just tumour derived biospecimens; for example, they have the ability to facilitate researchers gaining access to sample metadata such as digitised scans of tissue samples annotated prior to macrodissection for molecular diagnostics or pseudoanonymised clinical outcome data or research results retrieved from other users utilising the same or overlapping cohorts of samples. Furthermore, biobanks can work with molecular diagnostic laboratories to develop standardised methodologies for the acquisition and storage of samples required for new approaches to research such as 'liquid biopsies' which will ultimately feed into the test validations required in large prospective clinical studies in order to implement liquid biopsy approaches for routine clinical practice. We draw on our experience in Northern Ireland to discuss how this harmonised approach of biobanks working synergistically with molecular pathology programmes is a key for the future success of precision medicine.
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- 2016
9. The impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria
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Cherith N. Reid, Peter W. Hamilton, Thiagarajan Nambirajan, Kate E. Williamson, Mark W. Ruddock, Michael Stevenson, Funso Abogunrin, Joe M. O'Sullivan, Brian Duggan, Ruth Boyd, Hugh F. O'Kane, John Victor Lamont, Declan O'Rourke, and Neil H. Anderson
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Cancer Research ,Multivariate statistics ,Univariate analysis ,Bladder cancer ,biology ,business.industry ,Confounding ,Cancer ,Hyperplasia ,medicine.disease ,Logistic regression ,Carcinoembryonic antigen ,Oncology ,medicine ,biology.protein ,business ,Algorithm - Abstract
BACKGROUND: We appraised 23 biomarkers previously associated with urothelial cancer in a case-control study. Our aim was to determine whether single biomarkers and/or multivariate algorithms significantly improved on the predictive power of an algorithm based on demographics for prediction of urothelial cancer in patients presenting with hematuria. METHODS: Twenty-two biomarkers in urine and carcinoembryonic antigen (CEA) in serum were evaluated using enzyme-linked immunosorbent assays (ELISAs) and biochip array technology in 2 patient cohorts: 80 patients with urothelial cancer, and 77 controls with confounding pathologies. We used Forward Wald binary logistic regression analyses to create algorithms based on demographic variables designated prior predicted probability (PPP) and multivariate algorithms, which included PPP as a single variable. Areas under the curve (AUC) were determined after receiver-operator characteristic (ROC) analysis for single biomarkers and algorithms. RESULTS: After univariate analysis, 9 biomarkers were differentially expressed (t test; P < .05). CEA AUC 0.74; bladder tumor antigen (BTA) AUC 0.74; and nuclear matrix protein (NMP22) 0.79. PPP included age and smoking years; AUC 0.76. An algorithm including PPP, NMP22, and epidermal growth factor (EGF) significantly improved AUC to 0.90 when compared with PPP. The algorithm including PPP, BTA, CEA, and thrombomodulin (TM) increased AUC to 0.86. Sensitivities = 91%, 91%; and specificities = 80%, 71%, respectively, for the algorithms. CONCLUSIONS: Addition of biomarkers representing diverse carcinogenic pathways can significantly impact on the ROC statistic based on demographics. Benign prostate hyperplasia was a significant confounding pathology and identification of nonmuscle invasive urothelial cancer remains a challenge. Cancer 2011. © 2011 American Cancer Society.
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- 2011
10. PARP inhibition induces BAX/BAK-independent synthetic lethality of BRCA1-deficient non-small cell lung cancer
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Kathy Gately, Peter W. Hamilton, Keith M. Kerr, Kenneth J. O'Byrne, Jennifer E. Quinn, Jacqueline James, Jaine K. Blayney, E Lamers, Kienan I. Savage, D. Paul Harkin, Michael Sheaff, Dean A. Fennell, Kenneth Arthur, Derek J. Richard, and Ian M. Paul
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Cisplatin ,Programmed cell death ,endocrine system diseases ,biology ,Tumor suppressor gene ,Synthetic lethality ,Pathology and Forensic Medicine ,Bcl-2-associated X protein ,Apoptosis ,PARP inhibitor ,biology.protein ,Cancer research ,medicine ,skin and connective tissue diseases ,Bcl-2 Homologous Antagonist-Killer Protein ,medicine.drug - Abstract
Evasion of apoptosis contributes to both tumourigenesis and drug resistance in non-small cell lung carcinoma (NSCLC). The pro-apoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis. New strategies for targeting NSCLC in a mitochondria-independent manner should bypass this common mechanism of apoptosis block. BRCA1 mutation frequency in lung cancer is low; however, decreased BRCA1 mRNA and protein expression levels have been reported in a significant proportion of lung adenocarcinomas. BRCA1 mutation/deficiency confers a defect in homologous recombination DNA repair that has been exploited by synthetic lethality through inhibition of PARP (PARPi) in breast and ovarian cells; however, it is not known whether this same synthetic lethal mechanism exists in NSCLC cells. Additionally, it is unknown whether the mitochondrial apoptotic pathway is required for BRCA1/PARPi-mediated synthetic lethality. Here we demonstrate that silencing of BRCA1 expression by RNA interference sensitizes NSCLC cells to PARP inhibition. Importantly, this sensitivity was not attenuated in cells harbouring mitochondrial apoptosis block induced by co-depletion of BAX and BAK. Furthermore, we demonstrate that BRCA1 inhibition cannot override platinum resistance, which is often mediated by loss of mitochondrial apoptosis signalling, but can still sensitize to PARP inhibition. Finally we demonstrate the existence of a BRCA1-deficient subgroup (11-19%) of NSCLC patients by analysing BRCA1 protein levels using immunohistochemistry in two independent primary NSCLC cohorts. Taken together, the existence of BRCA1-immunodeficient NSCLC suggests that this molecular subgroup could be effectively targeted by PARP inhibitors in the clinic and that PARP inhibitors could be used for the treatment of BRCA1-immunodeficient, platinum-resistant tumours.
- Published
- 2011
11. pcDNA3.1tdTomato Is Superior to pDsRed2-N1 for Optical Fluorescence Imaging in the F344/AY-27 Rat Model of Bladder Cancer
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Vincent Koo, Kate E. Williamson, Peter W. Hamilton, Osama Sharaf Eldin, Chris J Watson, and A Lee
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Cancer Research ,Pathology ,medicine.medical_specialty ,DNA, Plant ,Transgene ,Biology ,Fluorescence ,Solanum lycopersicum ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Bladder cancer ,Transfection ,medicine.disease ,Rats, Inbred F344 ,In vitro ,Rats ,Disease Models, Animal ,Urinary Bladder Neoplasms ,Oncology ,Cell culture ,Rats, Transgenic ,Preclinical imaging - Abstract
Animal models are important for pre-clinical assessment of novel therapies in metastatic bladder cancer. The F344/AY-27 model involves orthotopic colonisation with AY-27 tumour cells which are syngeneic to F344 rats. One disadvantage of the model is the unknown status of colonisation between instillation and sacrifice. Non-invasive optical imaging using red fluorescence reporters could potentially detect tumours in situ and would also reduce the number of animals required for each experiment. AY-27 cells were stably transfected with either pDsRed2-N1 or pcDNA3.1tdTomato. The intensity and stability of fluorescence in the resultant AY-27/DsRed2-N1 and AY-27/tdTomato stable cell lines were compared using Xenogen IVIS®200 and Olympus IX51 systems. AY-27/tdTomato fluorescence intensity was 60-fold brighter than AY27/DsRed2-N1 and was sustained in AY-27/tdTomato cells following freezing and six subsequent sub-cultures. After sub-cutaneous injection, fluorescence intensity from AY-27/tdTomato cells was threefold stronger than that detected from AY-27/DsRed2-N1 cells. IVIS®200 detected fluorescence from AY-27/tdTomato and AY-27/DsRed2-N1 cells colonising resected and exteriorised bladders, respectively. However, the deep-seated position of the bladder precluded in vivo imaging. Characteristics of AY-27/tdTomato cells in vitro and in tumours colonising F344 rats resembled those of parental AY-27 cells. Tumour transformation was observed in the bladders colonised with AY-27/DsRed2-N1 cells. In vivo whole-body imaging of internal red fluorescent animal tumours should use pcDNA3.1tdTomato rather than pDsRed2-N1. Optical imaging of deep-seated organs in larger animals remains a challenge which may require proteins with brighter red or far-red fluorescence and/or alternative approaches.
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- 2009
12. Hyperacetylation in prostate cancer induces cell cycle aberrations, chromatin reorganization and altered gene expression profiles
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Ken Arthur, Peter W. Hamilton, James Diamond, Perry Maxwell, Jenny Watson, Declan J. McKenna, and Valerie J. McKelvey-Martin
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Male ,Hydroxamic Acids ,trichostatin A ,Chromatin remodeling ,Histones ,image analysis ,Cell Line, Tumor ,LNCaP ,medicine ,Humans ,Epigenetics ,Cell Proliferation ,Regulation of gene expression ,Dose-Response Relationship, Drug ,epigenetics ,biology ,Gene Expression Profiling ,Lysine ,Cell Cycle ,G1 Phase ,histone acetylation ,Prostatic Neoplasms ,Acetylation ,Original Articles ,Cell Biology ,Cell cycle ,Flow Cytometry ,prostate cancer ,Chromatin ,Gene Expression Regulation, Neoplastic ,Histone ,Trichostatin A ,biology.protein ,Cancer research ,Molecular Medicine ,medicine.drug - Abstract
Histone acetylation is a fundamental mechanism in the regulation of local chromatin conformation and gene expression. Research has focused on the impact of altered epigenetic environments on the expression of specific genes and their pathways. However, changes in histone acetylation also have a global impact on the cell. In this study we used digital texture analysis to assess global chromatin patterns following treatment with trichostatin A (TSA) and have observed significant alterations in the condensation and distribution of higher-order chromatin, which were associated with altered gene expression profiles in both immortalised normal PNT1A prostate cell line and androgen-dependent prostate cancer cell line LNCaP. Furthermore, the extent of TSA-induced disruption was both cell cycle and cell line dependent. This was illustrated by the identification of sub-populations of prostate cancer cells expressing high levels of H3K9 acetylation in the G2/M phase of the cell cycle that were absent in normal cell populations. In addition, the analysis of enriched populations of G1 cells showed a global decondensation of chromatin exclusively in normal cells.
- Published
- 2009
13. Chromatin Phenotype Karyometry Can Predict Recurrence in Papillary Urothelial Neoplasms of Low Malignant Potential
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Marina Scarpelli, Rodolfo Montironi, Janine G. Einspahr, James Ranger-Moore, Peter W. Hamilton, David S. Alberts, Hubert G. Bartels, Roberta Mazzucchelli, Antonio Lopez-Beltran, and Peter H. Bartels
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Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Urologic Neoplasms ,papillary urothelial neoplasm of low malignant potential ,recurrence ,Karyometry ,lcsh:RC254-282 ,Pathology and Forensic Medicine ,Text mining ,Discriminant function analysis ,medicine ,Humans ,lcsh:QH573-671 ,Papillary urothelial neoplasm of low malignant potential ,Cell Nucleus ,business.industry ,lcsh:Cytology ,Reproducibility of Results ,Cell Biology ,General Medicine ,Middle Aged ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,Phenotype ,Carcinoma, Papillary ,Chromatin ,Sample size determination ,Test set ,Molecular Medicine ,Biomarker (medicine) ,Female ,Radiology ,Other ,Urothelium ,Neoplasm Recurrence, Local ,business - Abstract
Background: A preceding exploratory study (J. Clin. Pathol. 57(2004), 1201–1207) had shown that a karyometric assessment of nuclei from papillary urothelial neoplasms of low malignant potential (PUNLMP) revealed subtle differences in phenotype which correlated with recurrence of disease. Aim of the Study: To validate the results from the exploratory study on a larger sample size. Materials: 93 karyometric features were analyzed on haematoxylin and eosin-stained sections from 85 cases of PUNLMP. 45 cases were from patients who had a solitary PUNLMP lesion and were disease-free during a follow-up period of at least 8 years. The other 40 were from patients with a unifocal PUNLMP, with one or more recurrences in the follow-up. A combination of the previously defined classification functions together with a new P-index derived classification method was used in an attempt to classify cases and identify a biomarker of recurrence in PUNLMP lesions. Results: Validation was pursued by a number of separate approaches. First, the exact procedure from the exploratory study was applied to the large validation set. Second, since the discriminant function 2 of the exploratory study had been based on a small sample size, a new discriminant function was derived. The case classification showed a correct classification of 61% for non-recurrent and 74% for recurrent cases, respectively. Greater success was obtained by applying unsupervised learning technologies to take advantage of phenotypical composition (correct classification of 92%). This approach was validated by dividing the data into training and test sets with 2/3 of the cases assigned to the training sets, and 1/3 to the test sets, on a rotating basis, and validation of the classification rate was thus tested on three separate data sets by a leave-k-out process. The average correct classification was 92.8% (training set) and 84.6% (test set). Conclusions: Our validation study detected subvisual differences in chromatin organization state between non-recurrent and recurrent PUNLMP, thus allowing a very stable method of predicting recurrence of papillary urothelial neoplasms of low malignant potential by karyometry.
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- 2007
14. Epidermal growth factor receptor immunohistochemistry: new opportunities in metastatic colorectal cancer
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Darragh G. McArt, Peter W. Hamilton, Bharat Jasani, Richard Adams, Ryan Hutchinson, and Manuel Salto-Tellez
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Pathology ,medicine.medical_specialty ,medicine.drug_class ,Colorectal cancer ,Review ,Monoclonal antibody ,General Biochemistry, Genetics and Molecular Biology ,Image analysis ,03 medical and health sciences ,0302 clinical medicine ,Biomarkers, Tumor ,Image Processing, Computer-Assisted ,medicine ,Humans ,Panitumumab ,Epidermal growth factor receptor ,Neoplasm Metastasis ,030304 developmental biology ,Medicine(all) ,0303 health sciences ,integumentary system ,Cetuximab ,biology ,Biochemistry, Genetics and Molecular Biology(all) ,Metastatic colorectal cancer ,business.industry ,Cancer ,General Medicine ,Localisation ,medicine.disease ,Immunohistochemistry ,3. Good health ,ErbB Receptors ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Personalised medicine ,Heterogeneity ,Colorectal Neoplasms ,business ,medicine.drug ,Companion diagnostic - Abstract
The treatment of cancer is becoming more precise, targeting specific oncogenic drivers with targeted molecular therapies. The epidermal growth factor receptor has been found to be over-expressed in a multitude of solid tumours. Immunohistochemistry is widely used in the fields of diagnostic and personalised medicine to localise and visualise disease specific proteins. To date the clinical utility of epidermal growth factor receptor immunohistochemistry in determining monoclonal antibody efficacy has remained somewhat inconclusive. The lack of an agreed reproducible scoring criteria for epidermal growth factor receptor immunohistochemistry has, in various clinical trials yielded conflicting results as to the use of epidermal growth factor receptor immunohistochemistry assay as a companion diagnostic. This has resulted in this test being removed from the licence for the drug panitumumab and not performed in clinical practice for cetuximab. In this review we explore the reasons behind this with a particular emphasis on colorectal cancer, and to suggest a way of resolving the situation through improving the precision of epidermal growth factor receptor immunohistochemistry with quantitative image analysis of digitised images complemented with companion molecular morphological techniques such as in situ hybridisation and section based gene mutation analysis.
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- 2015
15. PICan: An integromics framework for dynamic cancer biomarker discovery
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Ryan Hutchinson, Paul B. Mullan, Manuel Salto-Tellez, Jacqueline James, Peter W. Hamilton, Declan Kieran, Yinhai Wang, David P Boyle, Michael Moran, Philip D Dunne, Darragh G. McArt, Peter Bankhead, Richard D. Kennedy, Jaine K. Blayney, Mark Catherwood, D. Paul Harkin, and Gareth Irwin
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Cancer Research ,business.industry ,Cancer ,Digital pathology ,Genomics ,General Medicine ,medicine.disease ,Bioinformatics ,3. Good health ,Oncology ,Neoplasms ,Databases, Genetic ,Genetics ,medicine ,Technical Note ,Biomarkers, Tumor ,Molecular Medicine ,Biomarker (medicine) ,Humans ,Clinical significance ,Biomarker discovery ,business ,Patient stratification ,Predictive biomarker - Abstract
Modern cancer research on prognostic and predictive biomarkers demands the integration of established and emerging high-throughput technologies. However, these data are meaningless unless carefully integrated with patient clinical outcome and epidemiological information. Integrated datasets hold the key to discovering new biomarkers and therapeutic targets in cancer. We have developed a novel approach and set of methods for integrating and interrogating phenomic, genomic and clinical data sets to facilitate cancer biomarker discovery and patient stratification. Applied to a known paradigm, the biological and clinical relevance of TP53, PICan was able to recapitulate the known biomarker status and prognostic significance at a DNA, RNA and protein levels.
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- 2015
16. Non-Invasive in vivo Imaging in Small Animal Research
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Vincent Koo, Peter W. Hamilton, and Kathleen Williamson
- Subjects
Diagnostic Imaging ,Cancer Research ,Fluorescence-lifetime imaging microscopy ,medicine.medical_specialty ,non-invasive ,Review ,lcsh:RC254-282 ,Pathology and Forensic Medicine ,Medical imaging ,medicine ,Bioluminescence imaging ,Animals ,Medical physics ,Animal model ,lcsh:QH573-671 ,Fluorescent Dyes ,Tomography, Emission-Computed, Single-Photon ,medicine.diagnostic_test ,business.industry ,lcsh:Cytology ,imaging ,Magnetic resonance imaging ,Cell Biology ,General Medicine ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,bioluminescence ,Magnetic Resonance Imaging ,in vivo ,PET ,Positron emission tomography ,Positron-Emission Tomography ,Models, Animal ,Imaging technology ,Molecular Medicine ,fluorescence ,Molecular imaging ,business ,Preclinical imaging ,CT ,MRI - Abstract
Non-invasive real time in vivo molecular imaging in small animal models has become the essential bridge between in vitro data and their translation into clinical applications. The tremendous development and technological progress, such as tumour modelling, monitoring of tumour growth and detection of metastasis, has facilitated translational drug development. This has added to our knowledge on carcinogenesis. The modalities that are commonly used include Magnetic Resonance Imaging (MRI), Computed Tomography (CT), Positron Emission Tomography (PET), bioluminescence imaging, fluorescence imaging and multi-modality imaging systems. The ability to obtain multiple images longitudinally provides reliable information whilst reducing animal numbers. As yet there is no one modality that is ideal for all experimental studies. This review outlines the instrumentation available together with corresponding applications reported in the literature with particular emphasis on cancer research. Advantages and limitations to current imaging technology are discussed and the issues concerning small animal care during imaging are highlighted.
- Published
- 2006
17. Cathepsin S expression: An independent prognostic factor in glioblastoma tumours—a pilot study
- Author
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Clare Nicholson, Peter W. Hamilton, Meenakshi Mirakhur, David W. Ellison, James Diamond, Patrick G. Johnston, Christopher J. Scott, Chirag Patel, D. McCormick, Caroline McGoohan, Brian Walker, Gordon McGregor, Gordon Cran, Thomas Flannery, David Mendelow, Lorraine Martin, Rob McConnell, and Stephen McQuaid
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Pilot Projects ,Central nervous system disease ,Biomarkers, Tumor ,medicine ,Humans ,neoplasms ,Survival rate ,Cathepsin S ,Regulation of gene expression ,CATS ,business.industry ,Astrocytoma ,Middle Aged ,Prognosis ,medicine.disease ,Cathepsins ,Recombinant Proteins ,nervous system diseases ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Oncology ,Immunohistochemistry ,Glioblastoma ,business - Abstract
Cysteine proteinases have been implicated in astrocytoma invasion. We recently demonstrated that cathepsin S (CatS) expression is up-regulated in astrocytomas and provided evidence for a potential role in astrocytoma invasion (Flannery et al., Am J Path 2003;163(1):175-82). We aimed to evaluate the significance of CatS in human astrocytoma progression and as a prognostic marker. Frozen tissue homogenates from 71 patients with astrocytomas and 3 normal brain specimens were subjected to ELISA analyses. Immunohistochemical analysis of CatS expression was performed on 126 paraffin-embedded tumour samples. Fifty-one astrocytoma cases were suitable for both frozen tissue and paraffin tissue analysis. ELISA revealed minimal expression of CatS in normal brain homogenates. CatS expression was increased in grade IV tumours whereas astrocytoma grades I-III exhibited lower values. Immunohistochemical analysis revealed a similar pattern of expression. Moreover, high-CatS immunohistochemical scores in glioblastomas were associated with significantly shorter survival (10 vs. 5 months, p = 0.014). With forced inclusion of patient age, radiation dose and Karnofsky score in the Cox multivariate model, CatS score was found to be an independent predictor of survival. CatS expression in astrocytomas is associated with tumour progression and poor outcome in glioblastomas. CatS may serve as a useful prognostic indicator and potential target for anti-invasive therapy.
- Published
- 2006
18. Scientific Poster Presentations April 6–8
- Author
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Peter W. Hamilton, Kate E. Williamson, Valerie J. McKelvey-Martin, Nor Fadilah Rajab, Declan J. McKenna, and James Diamond
- Subjects
Cancer Research ,Cell Biology ,General Medicine ,Cell cycle ,Biology ,Molecular biology ,Cell Cycle Gene ,Pathology and Forensic Medicine ,Chromatin ,Trichostatin A ,Gene expression ,LNCaP ,medicine ,Molecular Medicine ,Histone deacetylase ,Epigenetics ,Other ,medicine.drug - Abstract
Introduction. Chromatin reorganisation associated withreversible epigenetic modifications is consideredresponsible for changes in gene expression observedduring prostate cancer progression. Histone acetylationis an important epigenetic modification promoting an‘open’ chromatin configuration and transcriptionalactivation. Trichostatin A (TSA), an inhibitor of HDACactivity, has been associated with a globalhyperacetylation that may lead to the disruption ofchromatin phenotype and the transcription of a selectionof genes that inhibit tumour growth. We have alreadyshown that at concentrations of >50ng/ml, TSA inducesapoptosis and G2M cell cycle arrest in these cell lines.However, even at low doses of TSA, which have noobvious impact on the cell cycle or apoptosis (sub-lethaldoses), subtle changes in chromatin phenotype areinduced. The aim of this study was to establish theunderlying alterations in gene expression in normalprostate cell line (PNT1A) and lymph node metastaticcell line (LNCaP) induced by Trichostatin A.Materials and Methods. Following treatment of PNT1Aand LNCaP cell lines with sublethal (12ng/ml) and lethal(100ng/ml) doses of TSA, total cellular RNA wasisolated from cell samples. cDNA was synthesised fromextracted RNA, and control and test samples weredifferentially labelled with fluorescent Cy3 and Cy5 dyesin situ for direct comparison. Dye swaps wereincorporated into the study design to ensure preciseinterpretation of expression profiles. Hybridisation ofappropriately labelled cDNA to MWG Human 30K arrayA containing 9,984 oligonucleotide probes, wasperformed under optimum binding conditions. Scanningand analysis of the microarray slide was completed usingGenePix and Acuity (Axon Instruments) software.Results. Gene expression was clearly disrupted in bothPNT1A and LNCaP in response to TSA inducedhyperacetylation. A significant trend for up-regulation ingene expression was identified in PNT1A following highconcentrations of TSA. This includes the increasedexpression of cell cycle genes such as a 2.27 foldincrease in cyclin g2, as well as a selection of genesrelated to the onset of apoptosis. This is likely to beassociated with increased apoptosis and cell cycle arrestseen at these concentrations. Interestingly, altered geneexpression was also evident in cells treated with sublethaldoses of TSA, where no cytotoxic effects of the treatmentare visible. Several functional gene groups were found tobe down-regulated across both cell lines in response toTSA, including a range of general transcription factors,along with genes involved in the MAP Kinase pathway.A consistent up-regulation can also be reported in both asubset of homeobox genes, and cytochrome c oxidasegenes. Also important is the observation that theKallikrein (prostate specific antigen) gene has beenfound to be down-regulated in both normal prostate andmetastatic cell lines in response to TSA treatment.Conclusions. Histone hyperacetylation and subsequentchromatin redistribution are associated with thedisruption of gene expression profiles in prostate cancer.Disruption in gene expression occurs in the absence ofcytotoxic effects which may be due to subtle chromatinphenotypic changes observed at sublethal doses of TSA,and may therefore be indicative of those genes directly orindirectly regulated by histone acetylation.
- Published
- 2005
19. Induction of apoptosis by mitomycin-C in an ex vivo model of bladder cancer
- Author
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S. R. Johnston, John D. Kelly, Patrick F. Keane, Peter W. Hamilton, Kate E. Williamson, H.P. Weir, and D.T. McManus
- Subjects
Cisplatin ,Pathology ,medicine.medical_specialty ,Programmed cell death ,Chemotherapy ,Bladder cancer ,business.industry ,Urology ,medicine.medical_treatment ,Mitomycin C ,medicine.disease ,In vivo ,Apoptosis ,Cancer research ,medicine ,business ,Ex vivo ,medicine.drug - Abstract
Objective To examine mitomycin-C (MMC)-induced apoptosis in an ex vivo model of superficial TCC, and relate it to the in vivo response to chemotherapy.Materials and methods Dose- and time-response curves were constructed to determine the optimal conditions for the induction of apoptosis by MMC in an ex vivo model of superficial bladder cancer. Subsequently, 41 individual tumours were exposed to MMC in the model and the effects assessed by measuring of apoptosis before and after chemotherapy. The relationships between tumour grade and stage and the intrinsic and induced apoptotic counts were determined. In tandem, in a clinical study, the relationship between in vivo response of a marker tumour to MMC and the ex vivo induction of apoptosis was determined.Results In the ex vivo model, apoptosis was induced at a MMC concentration of 0.5 mg/mL after an incubation time of 8 h. In 41 tumours the intrinsic apoptotic index (AI) was higher with increased grade and stage of tumour (P = 0.048). There was no correlation between the intrinsic AI and the AI after treatment with MMC (induced AI). In 21 tumours (51%) the induced AI did not increase above a predetermined response threshold and these tumours were considered resistant to MMC. Resistance to MMC was related to tumour grade (P = 0.037) with a trend for G3 pT1 tumours to be resistant to the therapy. There was a significant association between ex vivo sensitivity and in vivo marker tumour response (P = 0.02).Conclusions Apoptosis is differentially induced in an ex vivo incubation model of superficial TCC by MMC and evidence suggests that this response matches that seen in vivo. The measurement of apoptosis before therapy does not predict the apoptotic response of a tumour to chemotherapy. The ability to undergo apoptosis correlates with clinical outcome.
- Published
- 2001
20. Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer
- Author
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Joel S. Riley, Ryan Hutchinson, Nyree Crawford, Manuel Salto-Tellez, Caitriona Holohan, Kenneth J. O'Byrne, Darragh G. McArt, Patrick G. Johnston, Ian M. Paul, Elaine W. Kay, Daniel B. Longley, Kathy Gately, Robert Cummins, Dean A. Fennell, Peter W. Hamilton, S. Van Schaeybroeck, and Izabela Stasik
- Subjects
Cancer Research ,C131 ,Cell Survival ,FLIP ,Blotting, Western ,Immunology ,Cell ,CASP8 and FADD-Like Apoptosis Regulating Protein ,TRAIL ,In Vitro Techniques ,Biology ,Caspase 8 ,Q1 ,caspase-8 ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,SDG 3 - Good Health and Well-being ,HDAC inhibitor ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Lung cancer ,non-small cell lung cancer ,Retrospective Studies ,Cisplatin ,Entinostat ,B131 ,B132 ,A100 ,Cell Biology ,Flow Cytometry ,medicine.disease ,Molecular biology ,respiratory tract diseases ,medicine.anatomical_structure ,chemistry ,Flip ,Cell culture ,Apoptosis ,Cancer research ,Original Article ,medicine.drug - Abstract
Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents.
- Published
- 2013
21. Recent Advances in the Quantitative Morphological Evaluation of Prostate Neoplasia
- Author
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Peter W. Hamilton, Roberta Mazzucchelli, Rodolfo Montironi, Peter H. Bartels, Wael Sakr, David G. Bostwick, and Deborah Thompson
- Subjects
PROSTATE NEOPLASIA ,business.industry ,Cancer research ,Medicine ,business - Published
- 2000
22. p53 MUTATION, ALLELE LOSS ON CHROMOSOME 17p, AND DNA CONTENT IN OVARIAN CARCINOMA
- Author
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Peter W. Hamilton, Kenneth Arthur, P. G. Toner, S. E. H. Russell, Damian T. McManus, and M. Murphy
- Subjects
medicine.medical_specialty ,Cytogenetics ,Aneuploidy ,Locus (genetics) ,Biology ,medicine.disease ,Molecular biology ,Pathology and Forensic Medicine ,law.invention ,Chromosome 17 (human) ,Loss of heterozygosity ,chemistry.chemical_compound ,chemistry ,law ,Cancer research ,medicine ,Microsatellite ,Polymerase chain reaction ,DNA - Abstract
The aim of this investigation was to explore the relationships between p53 mutation, DNA aneuploidy, 17p deletions, and clinical stage in ovarian cancer. Nuclear suspensions were obtained by tissue disaggregation, stained with propidium iodide, and analysed on a Coulter EPICS Elite flow cytometer. DNA cell cycle analysis was performed using Multicycle software (Phoenix Flow Systems). DNA extracted from paraffin-embedded archival carcinomas/non-tumour tissue was used as template for PCR amplification of the microsatellite dinucleotide repeat polymorphism D17S513, a locus telomeric to p53 on 17p13.1. Allele loss at D17S513 was detected in 64.5 per cent of carcinomas (20 of 31 informative cases). DNA aneuploidy was detected in 20 of 54 (37 per cent) carcinomas. Eight of ten cases previously shown to harbour p53 mutations showed aneuploid DNA content. Although ten other DNA aneuploid cases had shown no p53 mutations, the results show a statistically significant association between p53 mutation and DNA aneuploidy (P < 0.01). Furthermore, the mean DNA index of the DNA aneuploid cases was significantly higher in p53 mutant cases compared with those showing no p53 mutation (P = 0.02). There was also a significant association between p53 mutations and stage, between ploidy and stage, and between allelic deletions at D17S513 or p53 and stage, but not between these allelic deletions and ploidy. p53 mutations appear to be associated with DNA aneuploidy in ovarian cancer independently of 17p deletions. p53 mutations, DNA aneuploidy, and 17p deletions are associated with late stage.
- Published
- 1996
23. Colorectal cell kinetics
- Author
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Neil H. Anderson, Peter W. Hamilton, Kate E. Williamson, R. Gilliland, and R. H. Wilson
- Subjects
Pathology ,medicine.medical_specialty ,Colon ,medicine.drug_class ,Cell ,Endogeny ,Monoclonal antibody ,S Phase ,Flow cytometry ,Proliferating Cell Nuclear Antigen ,Mitotic Index ,Carcinoma ,Humans ,Medicine ,Mitosis ,Ploidies ,medicine.diagnostic_test ,business.industry ,Cell growth ,Cell Cycle ,Rectum ,Nuclear Proteins ,medicine.disease ,Neoplasm Proteins ,Ki-67 Antigen ,medicine.anatomical_structure ,Cancer research ,Immunohistochemistry ,Surgery ,business ,Biomarkers ,Cell Division ,Thymidine - Abstract
The assessment of cell proliferation in colorectal tissue may provide information with both prognostic and therapeutic implications. A variety of methods are available, including flow cytometric estimations of S phase fraction, immunohistochemical and autoradiographic visualization of exogenous and endogenous proliferation proteins, and morphological and stathmokinetic techniques. There is some correlation between Dukes stage and proliferation state features, and there is increased proliferative activity throughout the adenoma–carcinoma sequence. Data on cell proliferation rates are difficult to obtain. When correctly applied, the metaphase arrest technique remains the ‘gold standard’ of measuring proliferation, but its usefulness in clinical practice is limited. Recent studies have employed dual measurement flow cytometry and double labelling techniques to produce rate data.
- Published
- 1996
24. Ultra-fast processing of gigapixel Tissue MicroArray images using high performance computing
- Author
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Yinhai Wang, David McCleary, Ching-Wei Wang, Paul Kelly, Jackie James, Dean A. Fennell, and Peter W. Hamilton
- Subjects
Cancer Research ,Lung Neoplasms ,parallel processing ,virtual slide ,Computing Methodologies ,Pathology and Forensic Medicine ,Time ,Tissue MicroArray ,Carcinoma, Non-Small-Cell Lung ,Image Interpretation, Computer-Assisted ,Biomarkers, Tumor ,Humans ,natural sciences ,TMA ,dynamic load balancing ,RC254-282 ,QH573-671 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell Biology ,General Medicine ,Immunohistochemistry ,high performance computing ,ComputingMethodologies_PATTERNRECOGNITION ,Oncology ,Cluster ,Tissue Array Analysis ,Molecular Medicine ,Other ,Cytology ,Software - Abstract
Background: Tissue MicroArrays (TMAs) are a valuable platform for tissue based translational research and the discovery of tissue biomarkers. The digitised TMA slides or TMA Virtual Slides, are ultra-large digital images, and can contain several hundred samples. The processing of such slides is time-consuming, bottlenecking a potentially high throughput platform.Methods: A High Performance Computing (HPC) platform for the rapid analysis of TMA virtual slides is presented in this study. Using an HP high performance cluster and a centralised dynamic load balancing approach, the simultaneous analysis of multiple tissue-cores were established. This was evaluated on Non-Small Cell Lung Cancer TMAs for complex analysis of tissue pattern and immunohistochemical positivity.Results: The automated processing of a single TMA virtual slide containing 230 patient samples can be significantly speeded up by a factor of circa 22, bringing the analysis time to one minute. Over 90 TMAs could also be analysed simultaneously, speeding up multiplex biomarker experiments enormously.Conclusion: The methodologies developed in this paper provide for the first time a genuine high throughput analysis platform for TMA biomarker discovery that will significantly enhance the reliability and speed for biomarker research. This will have widespread implications in translational tissue based research.
- Published
- 2010
25. Abstract 4792: Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with clinical utility
- Author
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Richard H. Wilson, Clare M. McCabe, Darragh G. McArt, Matthew Alderdice, Jacqueline James, Paul J Kelly, Peter W. Hamilton, Marc-Aurel Fuchs, Victoria Bingham, Claire McGready, Stephen McQuaid, Muhammad A Alvi, Manuel Salto-Tellez, and Perry Maxwell
- Subjects
Neuroblastoma RAS viral oncogene homolog ,Oncology ,Cancer Research ,medicine.medical_specialty ,IDH1 ,biology ,business.industry ,Molecular pathology ,Microsatellite instability ,Disease ,medicine.disease_cause ,Bioinformatics ,medicine.disease ,Internal medicine ,DNA methylation ,medicine ,biology.protein ,PTEN ,KRAS ,business - Abstract
Small bowel accounts for only 0.5% of cancer cases in the US; a third of which are adenocarcinomas. But incidence rates have been rising at a rate of 2.4% per year over the last decade. Because of the rarity of this cancer, little is known about its molecular pathology and there are no molecular markers for diagnosis, predicting prognosis or therapeutic intervention. The aim of this study was therefore to look into this disease at a molecular level to better understand its biology and identify biomarkers and potential points of therapeutic intervention. Using a retrospective 28 patient matched normal-tumor cohort next generation sequencing (NGS) was performed using a 50 gene cancer hotspot panel, gene expression arrays were used to profile ∼29,000 RNA transcripts and 450k CpG methylation arrays were used to carry out DNA methylation analysis. We also looked at microsatellite instability (MSI), HER2 and p53 expression. NGS identified novel mutations in IDH1, CDH1, KIT, NRAS, FGFR2, FLT3, NPM1, PTEN, MET, AKT1, RET, NOTCH1 and ERBB4. Previously known mutations such as high-frequency KRAS and TP53 and low-frequency HER2 were also confirmed in our cohort. The average patient had 2.6 mutations with eight patients having only a single mutation to one having seven. Array data revealed 17% of CpGs and 5% of RNA transcripts assayed to be differentially methylated and expressed respectively (p This study has for the first time highlighted the extent of molecular changes taking place in SBA. The clinical potential of TP53 mutations and Kazald1 hypomethylation as prognostic biomarkers and CHN2 as a diagnostic biomarker are focus areas for further research by our group. Citation Format: Muhammad A. Alvi, Darragh G. McArt, Paul Kelly, Marc-Aurel Fuchs, Matthew Alderdice, Clare M. McCabe, Victoria Bingham, Claire McGready, Stephen McQuaid, Perry Maxwell, Peter Hamilton, Jacqueline A. James, Richard Wilson, Manuel Salto-Tellez. Comprehensive molecular pathology analysis of small bowel adenocarcinoma reveals novel targets with clinical utility. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4792. doi:10.1158/1538-7445.AM2015-4792
- Published
- 2015
26. Molecular classification of the invasive front in colorectal cancer
- Author
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Elaine W. Kay, Daniel B. Longley, Peter W. Hamilton, Sandra Van Schaeybroeck, Patrick G. Johnston, Mark Lawler, David Waugh, Ken Arthur, Philip D Dunne, Manuel Salto-Tellez, Darragh G. McArt, Helen Barrett, and Anthony O'Grady
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,medicine.medical_treatment ,Locally advanced ,Disease ,medicine.disease ,Bioinformatics ,Molecular classification ,Internal medicine ,medicine ,Stage (cooking) ,business ,Adjuvant - Abstract
3573 Background: Despite the use of 5-FU-based adjuvant therapies, a large proportion of stage III (locally advanced) colorectal cancer (CRC) patients will relapse and die of metastatic disease. Re...
- Published
- 2015
27. Abstract 1905: Defining a therapeutic classification of breast cancer by actionable targets
- Author
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Martha Minter, T Lioe, Richard D. Kennedy, Paul B. Mullan, Peter W. Hamilton, Charlotte Charlotte Wilhelm-Benartzi, David P Boyle, Stephen McQuaid, Manuel Salto-Tellez, Darragh G. McArt, Denis Paul Harkin, and Gareth Irwin
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,medicine.medical_treatment ,Cancer ,medicine.disease ,Targeted therapy ,Breast cancer ,Trastuzumab ,Internal medicine ,Immunology ,Cohort ,biology.protein ,Medicine ,Hormonal therapy ,Biomarker (medicine) ,PTEN ,business ,medicine.drug - Abstract
Breast cancer remains a frequent cause of female cancer death despite the great strides in elucidation of biological subtypes and their reported clinical and prognostic significance. We have defined a general cohort of breast cancers in terms of putative actionable targets, involving growth and proliferative factors, the cell cycle, and apoptotic pathways, both as single biomarkers across a general cohort and within intrinsic molecular subtypes. We identified 293 patients treated with adjuvant chemotherapy. Additional hormonal therapy and trastuzumab was administered depending on hormonal and HER2 status respectively. We performed immunohistochemistry for ER, PR, HER2, MM1, CK5/6, p53, TOP2A, EGFR, IGF1R, PTEN, p-mTOR and e-cadherin. The cohort was classified into luminal (62%) and non-luminal (38%) tumors as well as luminal A (27%), luminal B HER2 negative (22%) and positive (12%), HER2 enriched (14%) and triple negative (25%). Patients with luminal tumors and co-overexpression of TOP2A or IGF1R loss displayed worse overall survival (p=0.0251 and p=0.0008 respectively). Non-luminal tumors had much greater heterogeneous expression profiles with no individual markers of prognostic significance. Non-luminal tumors were characterised by EGFR and TOP2A overexpression, IGF1R, PTEN and p-mTOR negativity and extreme p53 expression. Our results indicate that only a minority of intrinsic subtype tumors purely express single novel actionable targets. This lack of pure biomarker expression is particular prevalent in the triple negative subgroup and may allude to the mechanism of targeted therapy inaction and myriad disappointing trial results. Utilising a combinatorial biomarker approach may enhance studies of targeted therapies providing additional information during design and patient selection while also helping decipher negative trial results. Citation Format: Manuel Salto-Tellez, David P. Boyle, Darragh McArt, Gareth Irwin, Charlotte Charlotte Wilhelm-Benartzi, Tong G. LIoe, Martha Minter, Stephen McQuaid, Paul Mullan, Richard D. Kennedy, Peter Hamilton, D P. Harkin. Defining a therapeutic classification of breast cancer by actionable targets. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1905. doi:10.1158/1538-7445.AM2014-1905
- Published
- 2014
28. Phenotypic changes in mitochondrial membrane potential (Delta psi(m)) during valinomycin-induced depolarisation and apoptosis
- Author
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Perry Maxwell, Ken Arthur, M.L. Morrison, G.J. Price, Kathleen Williamson, and Peter W. Hamilton
- Subjects
Cancer Research ,Programmed cell death ,Time Factors ,Context (language use) ,Mitochondrion ,Biology ,lcsh:RC254-282 ,Pathology and Forensic Medicine ,Valinomycin ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,lcsh:QH573-671 ,Inner mitochondrial membrane ,Membrane potential ,Membrane Potential, Mitochondrial ,lcsh:Cytology ,G1 Phase ,apoptosis ,Depolarization ,Cell Biology ,General Medicine ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cell biology ,Mitochondria ,Phenotype ,chemistry ,colon cancer ,Apoptosis ,Molecular Medicine ,Other ,Mitochondrial membrane potential - Abstract
A large body of evidence has implicated mitochondria in control of cell death, where key apoptotic mechanisms involve change in mitochondrial membrane permeability and depolarisation of mitochondrial membrane potential (Δψm). Assessment of Δψm is traditionally conducted using the lipophilic cation JC-1 on the flow cytometer or by fluorescent microscopy. Here we assess JC-1 aggregation using the novel tool of digital texture analysis to establish mitochondrial phenotypic changes induced by the K+ ionophore, valinomycin in a unique model comprising SW480 and SW620 cell lines. This provides an opportunity to study these phenomena in the context of colorectal cancer. Valinomycin-induced apoptosis was detected using morphology and analysis of DNA content. Cells were treated with valinomycin, images digitally recorded on a calibrated video photometer and subjected to high resolution digital texture analysis. This demonstrated that the HARAM texture features (Mean of the Haralick texture features) were highly valuable in describing the transition of Δψm as the cell undergoes apoptosis. In Conclusion this study illustrates the potential of texture analysis as a novel and additional technique for quantifying JC-1 aggregation and revealing the spectrum of collapse of Δψm during apoptosis.
- Published
- 2005
29. Apoptosis and cell-cycle regulatory proteins in colorectal carcinoma: relationship to tumour stage and patient survival
- Author
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Neil Anderson, Peter W. Hamilton, Mohamed A. Elkablawy, Kate E. Williamson, and Perry Maxwell
- Subjects
Adult ,Male ,medicine.medical_specialty ,Mitotic index ,Colorectal cancer ,Rectum ,Apoptosis ,Cell Cycle Proteins ,Biology ,Adenocarcinoma ,Gastroenterology ,Pathology and Forensic Medicine ,Immunophenotyping ,Immunoenzyme Techniques ,Internal medicine ,medicine ,Carcinoma ,Rectal Adenocarcinoma ,Biomarkers, Tumor ,Mitotic Index ,Humans ,Stage (cooking) ,Survival analysis ,Aged ,Neoplasm Staging ,Aged, 80 and over ,Analysis of Variance ,Middle Aged ,medicine.disease ,Prognosis ,Neoplasm Proteins ,Survival Rate ,medicine.anatomical_structure ,Cancer research ,Immunohistochemistry ,Female ,Colorectal Neoplasms ,Follow-Up Studies - Abstract
The quantitative assessment of apoptotic index (AI) and mitotic index (MI) and the immunoreactivity of p53, bcl-2, p21, and mdm2 were examined in tumour and adjacent normal tissue samples from 30 patients with colonic and 22 with rectal adenocarcinoma. Individual features and combined profiles were correlated with clinicopathological parameters and patient survival data to assess their prognostic value. Increased AI was significantly associated with increased bcl-2 expression (p
- Published
- 2001
30. 483 POSTER Kinetic modelling of R8BH3BID induced BAX/BAK activation dynamics in Non-Small Cell Lung Cancer cells
- Author
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S.F.C. C'Rourke, Claire Grills, E. Hopkins, J. Diamond, A. Chacko, Peter W. Hamilton, P. Harriott, N. Crawford, Dean A. Fennell, and B. Greer
- Subjects
Cancer Research ,Oncology ,Chemistry ,Dynamics (mechanics) ,medicine ,Non small cell ,Lung cancer ,medicine.disease ,Cell biology - Published
- 2006
31. Three-dimensional computerised analysis of epithelial cell proliferation in the gastrointestinal tract
- Author
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J. Grimes, Peter W. Hamilton, Kenneth Arthur, Kate E. Williamson, and Richard H. Wilson
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Colon ,Crypt ,Biology ,Epithelium ,chemistry.chemical_compound ,Intestinal mucosa ,Reference Values ,Risk Factors ,Biopsy ,medicine ,Mitotic Index ,Humans ,Computer Simulation ,Intestinal Mucosa ,Gastrointestinal tract ,medicine.diagnostic_test ,Glandular Cell ,medicine.anatomical_structure ,Oncology ,chemistry ,Bromodeoxyuridine ,Immunohistochemistry ,Colorectal Neoplasms ,Cell Division ,Software ,Research Article - Abstract
This study describes a new technique for the visualisation and quantitation of glandular epithelial cell proliferation in gastrointestinal mucosa using computerised three-dimensional reconstruction. The tissue used in this study was colorectal biopsy tissue infiltrated in vitro with bromodeoxyuridine (BrdU), although the method could be applied to any gastrointestinal site labelled with any specific marker for cell proliferation. The method is as follows. Five-micron-thick serial sections (> 100) were cut from colorectal biopsies infiltrated in vitro with BrdU. After labelling all the sections for BrdU-positive cells using standard immunohistochemistry, colorectal glands were identified which were completely sectioned within the series. Each microscopic image of the sectioned gland was orientated, digitised and stored using a Kontron image analyser. On each of the stored images, the crypt profile, the positive cells and the negative cells were interactively marked and digitally stored. Using three-dimensional (3-D) reconstruction software, the outer surface of the crypt, the total positive and the total negative fractions could be viewed in three dimensions. The total BrdU-positive cell number could be automatically calculated for the complete crypt or, alternatively, compartmental analysis of the labelling pattern within the crypt could be obtained. This represents a powerful technique: it does not require orientation, it can be carried out on complex glandular structures and is not affected by the biases involved in measuring labelling indices from single tissue sections. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 6
- Published
- 1994
32. The effect of PARP inhibition on BAX/BAK independent synthetic lethality of BRCA1-deficient non-small cell lung cancer
- Author
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Derek J. Richard, Kenneth J. O'Byrne, Kienan Savage, Michael Sheaff, Jacqueline James, Jennifer E. Quinn, Kathy Gately, Jaine K. Blayney, Dean A. Fennell, Ian M. Paul, Peter W. Hamilton, E Lamers, and Keith M. Kerr
- Subjects
Cancer Research ,Poly ADP ribose polymerase ,Drug resistance ,Synthetic lethality ,Biology ,medicine.disease_cause ,Evasion (ethics) ,medicine.disease ,Cell biology ,Oncology ,Apoptosis ,Cancer research ,medicine ,Non small cell ,biological phenomena, cell phenomena, and immunity ,Carcinogenesis ,Lung cancer - Abstract
e13519 Background: Evasion of apoptosis contributes to both tumorigenesis and drug resistance. The proapoptotic BCL-2 family proteins BAX and BAK are critical regulators of mitochondrial apoptosis....
- Published
- 2011
33. SELDI-TOF analysis of induced sputum from patients with lung cancer, ‘at risk’ control subjects and healthy control subjects
- Author
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Robert D. Gray, Peter W. Hamilton, R. Shepherd, Joseph Elborn, Andrew P. Greening, Nicholas David Magee, T.J. Warke, M. Imrie, and M. Ennis
- Subjects
Pulmonary and Respiratory Medicine ,Cancer Research ,medicine.medical_specialty ,business.industry ,Induced sputum ,Control subjects ,medicine.disease ,Gastroenterology ,Oncology ,Internal medicine ,Seldi tof ,Healthy control ,medicine ,Lung cancer ,business - Published
- 2008
34. International Society for Cellular Oncology
- Author
-
Peter W. Hamilton
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Article Subject ,business.industry ,lcsh:Cytology ,Foreword ,Cell Biology ,General Medicine ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Pathology and Forensic Medicine ,Cellular Oncology ,Internal medicine ,medicine ,Molecular Medicine ,lcsh:QH573-671 ,business - Published
- 2005
35. Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance
- Author
-
D.T. McManus, Peter W. Hamilton, Kate E. Williamson, John D. Kelly, and Johnston
- Subjects
Cancer Research ,Lymphocytic leukaemia ,biology ,business.industry ,Bcl 2 bax ,Drug resistance ,medicine.disease ,In vitro ,Leukemia ,Bcl-2-associated X protein ,Oncology ,Apoptosis ,hemic and lymphatic diseases ,Immunology ,Cancer research ,medicine ,biology.protein ,Neoplasm ,business - Abstract
Bcl-2/Bax ratios in chronic lymphocytic leukaemia and their correlation with in vitro apoptosis and clinical resistance
- Published
- 1998
36. The role of morphometry in predicting prognosis in pancreatic islet cell tumors
- Author
-
Colin F. Johnston, Peter W. Hamilton, P. C. H. Watt, B. D. Kenny, K.D. Buchanan, and James M. Sloan
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Text mining ,Oncology ,Pleomorphism (cytology) ,business.industry ,Pancreatic islet cell tumors ,Medicine ,business ,Malignancy ,medicine.disease ,Pancreatic islet cell - Abstract
Morphometry of 31 pancreatic islet cell tumors was examined to determine the value of this technique in assessing tumor behavior. Patients were followed for a mean period of 5.1 years (range, 1 month-14 years) after diagnosis. Initially 17 localized and nine metastatic tumors were studied. Discriminant analysis was carried out on these cases and identified nuclear/cytoplasmic ratio and number of nuclei/mm2 as the significant discriminatory features. These were combined to derive a classification rule which was capable of correctly identifying localized and metastatic tumors in 92% of cases. The classification rule was applied subsequently to an additional five test cases, all of which were classified successfully. The failure of increased nuclear size and pleomorphism to correlate with malignancy in these tumors was confirmed. Tumors which metastasized had significantly greater gross diameters than localized lesions, but overlap existed. Mitotic counts were not a helpful discriminatory feature. Morphometry may be useful in improving histologic assessment of pancreatic islet cell tumor behavior.
- Published
- 1989
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