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G Cox

Publications and source records attributed to G Cox.

At least 19 recordsLinked to original sources
PubMed2005

Identifying optimal agricultural countermeasure strategies for a hypothetical contamination scenario using the strategy model.

A spatially implemented model designed to assist the identification of optimal countermeasure strategies for radioactively contaminated regions is described. Collective and individual ingestion doses for people within the affected area are estimated together with collective exported ingestion dose. A range of countermeasures are incorporated within the model, and environmental restrictions have been included as appropriate. The model evaluates the effectiveness of a given combination of countermeasures through a cost function which balances the benefit obtained through the reduction in dose with the cost of implementation. The optimal countermeasure strategy is the combination of individual countermeasures (and when and where they are implemented) which gives the lowest value of the cost function. The model outputs should not be considered as definitive solutions, rather as interactive inputs to the decision making process. As a demonstration the model has been applied to a hypothetical scenario in Cumbria (UK). This scenario considered a published nuclear power plant accident scenario with a total deposition of 1.7x10(14), 1.2x10(13), 2.8x10(10) and 5.3x10(9)Bq for Cs-137, Sr-90, Pu-239/240 and Am-241, respectively. The model predicts that if no remediation measures were implemented the resulting collective dose would be approximately 36 000 person-Sv (predominantly from 137Cs) over a 10-year period post-deposition. The optimal countermeasure strategy is predicted to avert approximately 33 000 person-Sv at a cost of approximately 160 million pounds. The optimal strategy comprises a mixture of ploughing, AFCF (ammonium-ferric hexacyano-ferrate) administration, potassium fertiliser application, clean feeding of livestock and food restrictions. The model recommends specific areas within the contaminated area and time periods where these measures should be implemented.

Agriculture↗
PubMed2005

The STRATEGY project: decision tools to aid sustainable restoration and long-term management of contaminated agricultural ecosystems.

The STRATEGY project (Sustainable Restoration and Long-Term Management of Contaminated Rural, Urban and Industrial Ecosystems) aimed to provide a holistic decision framework for the selection of optimal restoration strategies for the long-term sustainable management of contaminated areas in Western Europe. A critical evaluation was carried out of countermeasures and waste disposal options, from which compendia of state-of-the-art restoration methods were compiled. A decision support system capable of optimising spatially varying restoration strategies, that considered the level of averted dose, costs (including those of waste disposal) and environmental side effects was developed. Appropriate methods of estimating indirect costs associated with side effects and of communicating with stakeholders were identified. The importance of stakeholder consultation at a local level and of ensuring that any response is site and scenario specific were emphasised. A value matrix approach was suggested as a method of addressing social and ethical issues within the decision-making process, and was designed to be compatible with both the countermeasure compendia and the decision support system. The applicability and usefulness of STRATEGY outputs for food production systems in the medium to long term is assessed.

Agriculture↗
PubMed2005

Cyclooxygenase-2 protein levels are independent of epidermal growth factor receptor expression or activation in operable non-small cell lung cancer.

UNLABELLED: Both cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR) are thought to play important roles in the pathogenesis of non-small cell lung cancer (NSCLC). A number of in vitro studies have postulated a link between EGFR activation and subsequent COX-2 upregulation. The relationship between these factors has not been established in patients with NSCLC. COX-2 and EGFR expression were studied in 172 NSCLC specimens using standard immunohistochemical techniques. Western blotting was used to determine COX-2 and EGFR levels in five NSCLC cell lines. The effect of treatment with EGF on COX-2 expression in A549 cells was assessed. RESULTS: Both EGFR and COX-2 are overexpressed in NSCLC. The predominant pattern of COX-2 and EGFR staining was cytoplasmic. Membranous EGFR staining was seen in 23.3% of cases. There was no relationship between COX-2 and EGFR expression and survival or any clinicopathological features. No correlation was seen between EGFR expression and COX-2 expression in the immunohistochemical series or in the cell lines. Treatment with EGF did not upregulate COX-2 levels in A549 cells, either in serum free or serum-supplemented conditions. CONCLUSIONS: Although COX-2 and EGFR are over-expressed in NSCLC neither was of prognostic significance in this series of cases. There is no correlation between these two factors in either tumour samples or cell lines. Although these factors show no correlation in NSCLC, they remain potential, though independent targets for treatment.

Aged↗
PubMed2004

Coexpression of epidermal growth factor receptor with related factors is associated with a poor prognosis in non-small-cell lung cancer.

The epidermal growth factor receptor (EGFR) is commonly expressed in non-small-cell lung cancer (NSCLC) and promotes a host of mechanisms involved in tumorigenesis. However, EGFR expression does not reliably predict prognosis or response to EGFR-targeted therapies. The data from two previous studies of a series of 181 consecutive surgically resected stage I-IIIA NSCLC patients who had survived in excess of 60 days were explored. Of these patients, tissue was available for evaluation of EGFR in 179 patients, carbonic anhydrase (CA) IX in 177 patients and matrix metalloproteinase-9 (MMP-9) in 169 patients. We have previously reported an association between EGFR expression and MMP-9 expression. We have also reported that MMP-9 (P=0.001) and perinuclear (p)CA IX (P=0.03) but not EGFR expression were associated with a poor prognosis. Perinuclear CA IX expression was also associated with EGFR expression (P<0.001). Multivariate analysis demonstrated that coexpression of MMP-9 with EGFR conferred a worse prognosis than the expression of MMP-9 alone (P<0.001) and coexpression of EGFR and pCA IX conferred a worse prognosis than pCA IX alone (P=0.05). A model was then developed where the study population was divided into three groups: group 1 had expression of EGFR without coexpression of MMP-9 or pCA IX (number=21); group 2 had no expression of EGFR (number=75); and group 3 had coexpression of EGFR with pCA IX or MMP-9 or both (number=70). Group 3 had a worse prognosis than either groups 1 or 2 (P=0.0003 and 0.027, respectively) and group 1 had a better prognosis than group 2 (P=0.036). These data identify two cohorts of EGFR-positive patients with diametrically opposite prognoses. The group expressing either EGFR and or both MMP-9 and pCA IX may identify a group of patients with activated EGFR, which is of clinical relevance with the advent of EGFR-targeted therapies.

Adult↗
PubMed2004

A critical evaluation of the strategy project.

The STRATEGY project (sustainable restoration and long-term management of contaminated rural, urban and industrial ecosystems; www.strategy-ec.org.uk) addressed the need for a holistic decision framework for the selection of optimal remediation strategies for long-term sustainable management of contaminated areas in Western Europe. The project considered both technical and social aspects of implementing restoration strategies for urban and rural environments. The importance of considering socially relevant objectives in addition to the dose reduction was emphasised. A critical evaluation was carried out on 101 selected countermeasures, (including rural waste disposal options), a model was developed to aid optimising countermeasure strategies and a method of carrying out participatory decision-making suggested. The outputs of the project are described and critically evaluated.

Decision Support Systems, Management↗
PubMed2004

Effect of freezing of sputum samples on flow cytometric analysis of lymphocyte subsets.

Sputum samples should be processed shortly after induction to prevent cell degradation. For intermediate storage, freezing of homogenised samples or immediate fixation have been shown to be suitable for cytospins. The aim of this study was to investigate whether freezing or immediate fixation of sputum affect the analysis of lymphocyte subsets by flow cytometry. Selected plugs from 24 sputum samples were homogenised. One aliquot was processed immediately and analysed by flow cytometry. A second aliquot was homogenised, frozen at -20 C after addition of dimethylsulfoxide and stored for a median time of 6 days. In six samples a third aliquot was fixed in formalin after induction and stored for up to 72 h before further processing. Compared to immediate processing, percentages of total lymphocytes and T-suppressor cells were elevated after being frozen, with a minor decrease in the T4/T8 ratio. Proportions of total lymphocytes, T-helper and T-suppressor cells correlated between native and frozen samples, intra-class correlation coefficients being 0.74, 0.85 and 0.70, respectively. The formalin-fixed aliquots could not be analysed with the antibodies used. In conclusion, freezing seems to be a suitable technique to store sputum samples for flow cytometry of CD3, CD4 and CD8 lymphocyte subsets. Its effects were minor compared to the variation between subjects.

Adult↗
PubMed2003

Prevalence of vertebral fractures among patients with chronic obstructive pulmonary disease in Canada.

PURPOSE: Patients with chronic obstructive pulmonary disease (COPD) may be at higher risk for osteoporosis. The primary objective of this case-control study was to determine the prevalence of vertebral fractures among patients with COPD admitted to acute care compared with a gender- and age-matched control group. SUBJECTS AND METHODS: Subjects were identified by chart reviews from an acute care hospital in Hamilton, Ontario, in 1999, including patients who were over 50 years old. In total, 127 patients with ICD-9 codes specifying COPD were randomly selected and compared with 127 gender- and age-matched controls. Chest radiographs were interpreted by two radiologists who defined and graded vertebral fractures using Genant's method. Medications taken, or prescribed at discharge, were recorded from charts. RESULTS: The overall prevalence of at least one vertebral fracture was found to be 34/127 (26.8%) in the COPD patients compared with 30/127 (23.6%) in the controls ( p=0.556). A significantly greater proportion of COPD patients had at least one severe vertebral fracture (OR=3.75, 95% CI 1.24 to 11.3). Review of hospital chest X-ray reports indicated that only 12 of 64 (18.8%) patients with vertebral fractures identified by the study radiologists actually had a vertebral fracture noted in the report. The proportion of COPD patients with vertebral fractures who were discharged on osteoporosis therapy was 5/27 (18.5%). There was a suggestion of lower lung function, as measured by forced vital capacity (FVC%), in patients with severe vertebral fractures ( p=0.067). CONCLUSIONS: These data indicate that: (1) There is an increased proportion of COPD patients with severe vertebral fracture, and (2) Documentation and treatment of osteoporosis in acute care COPD patients is low. Therefore, there is a need to target this high-risk group for osteoporosis screening and potential clinical management.

Aged↗
PubMed2003

Whole-mount sections displaying microvascular and glandular structures in human uterus using multiphoton excitation microscopy.

There has been considerable interest over many years in the precise structural relationships between microvessels and secretory glands in human endometrium. However, microcirculatory networks have rarely been studied in three-dimensions (3D) using modern computerised technologies, this has been partly due to the late arrival of suitable endothelial cell markers. This study was designed to develop a technique to visualize and to reveal the relationships between microvessels, their glandular environment and epithelial boundaries in 3D, using endometrium from human hysterectomy biopsies. Specimens were carefully selected from women with conditions unlikely to affect the microvascular networks. Monoclonal antibodies (mouse anti-human CD 34 and goat anti-mouse fluorescein (FITC)) were used to visualize the microvessels, and polyclonal antibodies (rabbit anti-human keratin and goat anti-rabbit tetramethylrhodamine (TRITC)) were used to visualize the glandular structures. The samples were studied with a Leica multiphoton system using a titanium-sapphire laser (excitation 800 nm with pulses in the 200 fs range) to obtain a stack of two-dimensional (2D) images to a minimal focus depth of 120 microm. The initial data sets acquired were volume rendered using the integrated software of the Leica system to produce 3D images. This software allowed for the acquisition of data sets from the microscope and for an observational morphological assessment to be made, but was limited in preparing the data for any quantitative analysis. The additional use of ImarisBasic 3.1 visualization software allowed for an observational morphological assessment but also included numerous tools for data manipulation.

Animals↗
PubMed2003

Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: potential targets for chemoprevention and systemic therapy.

The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from growth and proliferation to cell death. Cyclooxygenase (COX)-2 is an enzyme which catalyses the conversion of arachidonic acid to prostagladins and thromboxane. It is induced by various inflammatory stimuli, including the pro-inflammatory cytokines, Interleukin (IL)-1beta, Tumour Necrosis Factor (TNF)-alpha and IL-2. Both EGFR and COX-2 are over-expressed in non-small cell lung cancer (NSCLC) and have been implicated in the early stages of tumourigenesis. This paper considers their roles in the development and progression of lung cancer, their potential interactions, and reviews the recent progress in cancer therapies that are directed toward these targets. An increasing body of evidence suggests that selective inhibitors of both EGFR and COX-2 are potential therapeutic agents for the treatment of NSCLC, in the adjuvant, metastatic and chemopreventative settings.

Carcinoma, Non-Small-Cell Lung↗
PubMed2003

A method to preserve sputum for delayed examination.

Examination of sputum cell counts is limited by the need to process samples within hours of expectoration. The validity and repeatability of a method to preserve sputum for delayed processing and examination were investigated in this study. Portions of selected sputum from 39 subjects were dispersed with dithiothreitol (routine method), or were fixed in a dithiothreitol-formaldehyde mixture for 48-72 h before dispersal with trypsin (preservation method). Total and differential cell counts using the two methods were compared; within-method repeatability of the preservation method was also examined. The intraclass correlation coefficient (ICC) for total cell counts and percentage of eosinophils, neutrophils and macrophages in sputum processed by the two methods was 0.89, 0.86, 0.91 and 0.90, respectively. Within-method repeatability (ICC) of the preservation method for the same cellular indices was 0.99, 0.94, 0.97 and 0.97, respectively. The interobserver repeatability for eosinophils, neutrophils and macrophages was 0.96, 0.97 and 0.97 using the preservation method, and 0.96, 0.99 and 0.99 using the routine method, respectively. This method of sputum preservation and dispersal is valid, reliable and convenient, and may be used for delayed processing and examination.

Cell Count↗
PubMed2001

Angiogenesis is an independent prognostic factor in malignant mesothelioma.

Angiogenesis is essential for tumour growth beyond 1 to 2 mm in diameter. The clinical relevance of angiogenesis, as assessed by microvessel density (MVD), is unclear in malignant mesothelioma (MM). Immunohistochemistry was performed on 104 archival, paraffin-embedded, surgically resected MM samples with an anti-CD34 monoclonal antibody, using the Streptavidin-biotin complex immunoperoxidase technique. 93 cases were suitable for microvessel quantification. MVD was obtained from 3 intratumoural hotspots, using a Chalkley eyepiece graticule at x 250 power. MVD was correlated with survival by Kaplan-Meier and log-rank analysis. A stepwise, multivariate Cox model was used to compare MVD with known prognostic factors and the EORTC and CALGB prognostic scoring systems. Overall median survival from the date of diagnosis was 5.0 months. Increasing MVD was a poor prognostic factor in univariate analysis (P = 0.02). Independent indicators of poor prognosis in multivariate analysis were non-epithelial cell type (P = 0.002), performance status > 0 (P = 0.003) and increasing MVD (P = 0.01). In multivariate Cox analysis, MVD contributed independently to the EORTC (P = 0.006), but not to the CALGB (P = 0.1), prognostic groups. Angiogenesis, as assessed by MVD, is a poor prognostic factor in MM, independent of other clinicopathological variables and the EORTC prognostic scoring system. Further work is required to assess the prognostic importance of angiogenic regulatory factors in this disease.

Age Factors↗
PubMed2001

Herceptest: HER2 expression and gene amplification in non-small cell lung cancer.

HER2 is an erbB/HER type 1 tyrosine kinase receptor that is frequently over-expressed in malignant epithelial tumours. Herceptin, a humanised mouse monoclonal antibody to HER2, is proven therapeutically in the management of metastatic breast cancer, significantly prolonging survival when combined with cytotoxic chemotherapeutic agents. Immunohistochemical studies suggest that non-small-cell lung cancer (NSCLC) tumours may over-express HER2. Our aim was to evaluate HER2 gene amplification and semi-quantitative immuno-expression in NSCLC. A total of 344 NSCLC cases were immunostained for HER2 expression in 2 centres using the HercepTest. Fluorescence in situ hybridisation (FISH) analysis for HER2 gene amplification was performed on most positive cases and a subset of negative cases. Fifteen cases (4.3%) demonstrated 2+ or 3+ membranous HER2 immuno-expression. There was no correlation between immuno-expression and tumour histology or grade. Tumours from higher-stage disease were more often HercepTest-positive (p < 0.001). All 4 HercepTest 3+ cases demonstrated gene amplification. One of the 5 2+ cases tested for gene amplification showed areas of borderline amplification and areas of polyploidy. None of the 19 HercepTest-negative cases demonstrated gene amplification or polyploidy (p < 0.001). Gene amplification was demonstrated in all HercepTest 3+ scoring NSCLC cases. Unlike breast cancer, gene amplification and HER2 protein over-expression assessed by the HercepTest appeared to be uncommon in NSCLC. Herceptin may therefore target only a small proportion of NSCLC tumours and be of limited clinical value in this disease, particularly in the adjuvant setting.

Adenocarcinoma↗
PubMed2001

Crystallization and preliminary X-ray analysis of the complex of the epsilon-subunit and the central domain of the gamma-subunit from the Escherichia coli ATP synthase.

A complex of the epsilon-subunit and the central domain of the gamma-subunit from the ATP synthase of Escherichia coli has been purified and crystallized and preliminary X-ray analysis has been carried out. The crystals belong to space group C222(1), with unit-cell parameters a = 76.7, b = 176.1, c = 67.1 A (at 100 K). Determination of the structure of this protein complex promises to greatly improve the understanding of energy coupling between the F(0) and F(1) sectors within the enzyme complex.

Base Sequence↗
PubMed2001

Comparison of control of Listeria by nitric oxide redox chemistry from murine macrophages and NO donors: insights into listeriocidal activity of oxidative and nitrosative stress.

The physiological function of nitric oxide (NO) in the defense against pathogens is multifaceted. The exact chemistry by which NO combats intracellular pathogens such as Listeria monocytogenes is yet unresolved. We examined the effects of NO exposure, either delivered by NO donors or generated in situ within ANA-1 murine macrophages, on L. monocytogenes growth. Production of NO by the two NONOate compounds PAPA/NO (NH2(C3H6)(N[N(O)NO]C3H7) and DEA/NO (Na(C2H5)2N[N(O)NO]) resulted in L. monocytogenes cytostasis with minimal cytotoxicity. Reactive oxygen species generated from xanthine oxidase/hypoxanthine were neither bactericidal nor cytostatic and did not alter the action of NO. L. monocytogenes growth was also suppressed upon internalization into ANA-1 murine macrophages primed with interferon-gamma (INF-gamma) + tumor necrosis factor-alpha (TNF-alpha or INF-gamma + lipid polysaccharide (LPS). Growth suppression correlated with nitrite formation and nitrosation of 2,3-diaminonaphthalene elicited by stimulated murine macrophages. This nitrosative chemistry was not dependent upon nor mediated by interaction with reactive oxygen species (ROS), but resulted solely from NO and intermediates related to nitrosative stress. The role of nitrosation in controlling L. monocytogenes was further examined by monitoring the effects of exposure to NO on an important virulence factor, Listeriolysin O, which was inhibited under nitrosative conditions. These results suggest that nitrosative stress mediated by macrophages is an important component of the immunological arsenal in controlling L. monocytogenes infections.

2-Naphthylamine↗
PubMed2001

Determining isotopic life history trajectories using bone density fractionation and stable isotope measurements: a new approach.

A number of recent studies have attempted to trace diet at different stages of an individual's life by comparing isotope ratios of bone from different gross anatomical sites within the skeleton. In this study we develop this approach further by separating bone of differing mineral densities within one skeletal element, where each density fraction represents a different period of time. Isotope ratios are measured for these fractions. Each density fraction represents a period of bone formation and maturation, where younger (more recently formed) bone is less well-mineralized and therefore less dense than relatively older packets of bone. In an adult, bone is therefore able to partition approximately the last 15 years of life. Bone fractions were recovered by stepped ultracentrifugation in a series of organic solvents of increasing density, and then collagen was recovered by decalcification in dilute acid, and stable carbon isotope ratios ((13)C/(12)C) were measured. Bone density microstructure was checked for bacterial remodelling using backscattered electron imaging in a scanning electron microscope. Our results indicate that the bone density fractionation method is applicable to archaeological material, here extending to a maximum of 5,000 years BP, and that collagen can successfully be extracted from such fractions. The carbon isotope values for bone fractions of different densities patterned out as expected in one modern control bone and in specimens from five archaeological human skeletons, including three precolonial hunter-gatherers and two 18th/19th century individuals. The latter two are known (from previous assessments) to have undergone marked changes in diet during their lifetimes. Postmortem alteration was evident in some of the specimens examined. The bone density fractionation approach has allowed greater resolution of diet than has hitherto been possible and has provided access to the elusive last years and months of an individual's life.

Adult↗
PubMed2001

Bcl-2 is an independent prognostic factor and adds to a biological model for predicting outcome in operable non-small cell lung cancer.

INTRODUCTION: The underlying biology of a tumour may hold the key to predicting the outcome for an individual patient as well as identifying potential therapeutic targets. Using epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP)-9 immunoexpression combined with microvessel counts we have developed a prognostic model for operable non-small cell lung cancer (NSCLC) which predicts outcome independent of stage (Thorax, 56 (2001) 561-566). The aim of this study was to evaluate the impact of bcl-2 expression upon survival in this model. METHODS: This was a retrospective analysis of 167 patients with resected stage I-IIIa NSCLC and >60 days post-operative survival. Minimum follow-up was 2 years. Immunohistochemistry was performed on paraffin-embedded tissue sections for bcl-2, EGFR, MMP-9 and the microvessel marker CD34 to evaluate the relationships between, and impact on survival of these biological markers. RESULTS: Tumour cell MMP-9 (P=0.002), microvessel count > median (P=0.01), bcl-2 (P=0.02) and stage (P=0.02) were independent prognostic factors. Bcl-2 expression was associated with an improved survival in all sub-groups of our prognostic model. CONCLUSION: bcl-2, EGFR and MMP-9 expression and angiogenesis provide prognostic information independent of TNM stage. Prognostic models offer the potential of tailoring the therapeutic management for an individual patient.

Adult↗
PubMed2001

Towards a biological staging model for operable non-small cell lung cancer.

Non-small cell lung cancer is the most common cause of cancer-related death in North America and Europe. Despite improvements in the diagnosis and treatment of the disease the prognosis remains poor, the overall 5-year survival being 4-14%. An increased understanding of the molecular biology of the disease may identify novel targets for drug development. We evaluated epidermal growth factor receptor (EGFR), HER-2/neu, matrix metalloproteinase (MMP)-2, MMP-9, p53 and bcl-2 expression and microvessel density (MVD) in patients who underwent surgery with curative intent in our department between 1991 and 1996. Co-expression of EGFR/MMP-9, MVD and bcl-2 were found to be independent prognostic variables, which allowed prediction of patient outcome independent of surgical stage. Other prognostic factors identified in our series were gender, surgical stage, platelet count, extent of necrosis, the hypoxia marker carbonic anhydrase-9 and beta-catenin. In collaboration with groups in Oxford and Greece, we were also able to establish the angiogenic growth factors vascular endothelial growth factor and platelet-derived endothelial growth factor as prognostic variables. The inter-relationships between these factors are currently being examined in an expanded patient series. Through this work we hope to be able to construct an integrated biological prognostic model which can be tested in prospective studies. This work has identified several potential targets for novel therapeutic agents currently in development.

Adult↗