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Toxicological assessment of the pulmonary response to air pollution particles

There is strong epidemiological evidence of association between PMi0 (particulate matter with an aerodynamic diameter less than or equal to 10 microns) and adverse health outcomes including death and increased hospital admissions for cardio-pulmonary conditions. Ambient PMi0 surrogates such as diesel exhaust particles (DEP), a common component of UK PMi0, have been shown to induce lung inflammation in both humans and rodents. To date, few studies have reported on the toxicological response of UK PM 0 in experimental animals. This thesis summarises the characterisation of the pulmonary toxicity of Cardiff urban PM10. Firstly, the pulmonary toxicological responses in male Sprague Dawley rats following the intratracheal instillation of Cardiff urban PM 0 were examined. A mild, but significant, change in lung permeability was observed in the lung post instillation of a high (10 mg) dose of the whole PMi0 as adjudged by increases in lung to body weight ratio and total acellular lavage protein. Such effects were less marked following instillation of a water-soluble fraction (80% of the total mass) but histological examination showed that lung capillaries were swollen in size with this treatment. Secondly, expression profiling of PM exposed lung tissue identified distinct genes differentially expressed as a consequence of exposure to a high dose (10 mg) of whole PM and equivalent dose of water soluble component of PM. Such changes were linked to different histopathological events within the lung. In conclusion, conventional toxicological, histological and toxicogenomic studies have indicated that Cardiff PM10 exhibits low bioreactivity in the form of mild permeability changes. In vitro toxicological assessment of the bio reactivity of the PM sample using primary cultures of epithelial type II and alveolar macrophage cells were used to identify the relative contribution of the different fractions (whole, washed "durable" fraction and water soluble component) to the overall PM toxicity. Correlations with total metal content and particle size were identified in the different cell types. Cellular analysis using advanced fluorescence labelling and microscopy identified the ability of the PM to induce subtle changes in cell and nuclear morphology that may result in increased cell death and apoptosis even at low particulate doses. Expression profiling of the PM exposed cells proved difficult and realised limited information regarding the cellular responses to the toxicant. This approach failed to identify the same gene changes reported in the lung tissue profiling, illustrating the importance of the different cell types within the lung to orchestrate a pulmonary response. In conclusion, the use of toxicogenomics and gene expression arrays in toxicological is still relatively novel approach to the assessment of lung injury. The study addresses initial problems and offers some possible solutions regarding the use of macro arrays and expression profiling in toxicology research. Expression arrays offer considerable scope as a research tool and in future will provide a powerful insight into gene changes on a global scale.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Interpretation bias in preschool children at risk for anxiety: a prospective study.

A story-stem paradigm was used to assess interpretation bias in preschool children. Data were available for 131 children. Interpretation bias, behavioural inhibition (BI) and anxiety were assessed when children were aged between 3 years 2 months and 4 years 5 months. Anxiety was subsequently assessed 12-months, 2-years and 5-years later. A significant difference in interpretation bias was found between participants who met criteria for an anxiety diagnosis at baseline, with clinically anxious participants more likely to complete the ambiguous story-stems in a threat-related way. Threat interpretations significantly predicted anxiety symptoms at 12-month follow-up, after controlling for baseline symptoms, but did not predict anxiety symptoms or diagnoses at either 2-year or 5-year follow-up. There was little evidence for a relationship between BI and interpretation bias. Overall, the pattern of results was not consistent with the hypothesis that interpretation bias plays a role in the development of anxiety. Instead, some evidence for a role in the maintenance of anxiety over relatively short periods of time was found. The use of a story-stem methodology to assess interpretation bias in young children is discussed along with the theoretical and clinical implications of the findings

Toxicological assessment of the pulmonary response to air pollution particles.

There is strong epidemiological evidence of association between PMi0 (particulate matter with an aerodynamic diameter less than or equal to 10 microns) and adverse health outcomes including death and increased hospital admissions for cardio-pulmonary conditions. Ambient PMi0 surrogates such as diesel exhaust particles (DEP), a common component of UK PMi0, have been shown to induce lung inflammation in both humans and rodents. To date, few studies have reported on the toxicological response of UK PM 0 in experimental animals. This thesis summarises the characterisation of the pulmonary toxicity of Cardiff urban PM10. Firstly, the pulmonary toxicological responses in male Sprague Dawley rats following the intratracheal instillation of Cardiff urban PM 0 were examined. A mild, but significant, change in lung permeability was observed in the lung post instillation of a high (10 mg) dose of the whole PMi0 as adjudged by increases in lung to body weight ratio and total acellular lavage protein. Such effects were less marked following instillation of a water-soluble fraction (80% of the total mass) but histological examination showed that lung capillaries were swollen in size with this treatment. Secondly, expression profiling of PM exposed lung tissue identified distinct genes differentially expressed as a consequence of exposure to a high dose (10 mg) of whole PM and equivalent dose of water soluble component of PM. Such changes were linked to different histopathological events within the lung. In conclusion, conventional toxicological, histological and toxicogenomic studies have indicated that Cardiff PM10 exhibits low bioreactivity in the form of mild permeability changes. In vitro toxicological assessment of the bio reactivity of the PM sample using primary cultures of epithelial type II and alveolar macrophage cells were used to identify the relative contribution of the different fractions (whole, washed "durable" fraction and water soluble component) to the overall PM toxicity. Correlations with total metal content and particle size were identified in the different cell types. Cellular analysis using advanced fluorescence labelling and microscopy identified the ability of the PM to induce subtle changes in cell and nuclear morphology that may result in increased cell death and apoptosis even at low particulate doses. Expression profiling of the PM exposed cells proved difficult and realised limited information regarding the cellular responses to the toxicant. This approach failed to identify the same gene changes reported in the lung tissue profiling, illustrating the importance of the different cell types within the lung to orchestrate a pulmonary response. In conclusion, the use of toxicogenomics and gene expression arrays in toxicological is still relatively novel approach to the assessment of lung injury. The study addresses initial problems and offers some possible solutions regarding the use of macro arrays and expression profiling in toxicology research. Expression arrays offer considerable scope as a research tool and in future will provide a powerful insight into gene changes on a global scale

Prostate cancer, PI3K, PTEN and prognosis

Loss of function of the PTEN tumour suppressor, resulting in dysregulated activation of the phosphoinositide 3-kinase (PI3K) signalling network, is recognized as one of the most common driving events in prostate cancer development. The observed mechanisms of PTEN loss are diverse, but both homozygous and heterozygous genomic deletions including PTEN are frequent, and often accompanied by loss of detectable protein as assessed by immunohistochemistry (IHC). The occurrence of PTEN loss is highest in aggressive metastatic disease and this has driven the development of PTEN as a prognostic biomarker, either alone or in combination with other factors, to distinguish indolent tumours from those likely to progress. Here, we discuss these factors and the consequences of PTEN loss, in the context of its role as a lipid phosphatase, as well as current efforts to use available inhibitors of specific components of the PI3K/PTEN/TOR signalling network in prostate cancer treatment.</jats:p

PTEN protein phosphatase activity is not required for tumour suppression in the mouse prostate

Loss PTEN function is one of the most common events driving aggressive prostate cancers and biochemically, PTEN is a lipid phosphatase which opposes the activation of the oncogenic PI3K-AKT signalling network. However, PTEN also has additional potential mechanisms of action, including protein phosphatase activity. Using a mutant enzyme, PTEN Y138L, which selectively lacks protein phosphatase activity, we characterised genetically modified mice lacking either the full function of PTEN in the prostate gland or only lacking protein phosphatase activity. The phenotypes of mice carrying a single allele of either wild-type Pten or Pten(Y138L) in the prostate were similar, with common prostatic intraepithelial neoplasia (PIN) and similar gene expression profiles. However, the latter group, lacking PTEN protein phosphatase activity additionally showed lymphocyte infiltration around PIN and an increased immune cell gene expression signature. Prostate adenocarcinoma, elevated proliferation and AKT activation were only frequently observed when PTEN was fully deleted. We also identify a common gene expression signature of PTEN loss conserved in other studies (including Nkx3.1, Tnf and Cd44). We provide further insight into tumour development in the prostate driven by loss of PTEN function and show that PTEN protein phosphatase activity is not required for tumour suppression