Research Theses Submission

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    Regulation of intracellular trafficking of the insulin-like growth factor I receptor
    (University College Cork, 2023) Godsmark, Grant; O'Connor, Rosemary; Science Foundation Ireland; Swiss Forum for International Agricultural Research
    Insulin-like Growth Factor 1 and its receptor (IGF-1R) are required for normal cellular growth, but aberrant expression is linked to the progression and development of many malignancies. Despite IGF-1R being a promising cancer therapeutic target, clinical targeting has not been generally successful. This has also highlighted gaps in our knowledge on IGF-1 signalling and how the IGF-1R and its regulatory regions function. Two tyrosine residues Tyr1250/1251 located within the 1248SFYYS1252 signalling motif of the IGF-1R are required for receptor internalisation, transformation and Golgi localisation. This thesis aimed to further investigate how this region and the C-terminal tail contribute to IGF-1R trafficking, sub-cellular localisation and regulation by using a range of cell lines and IGF-1R receptor mutants. Phosphorylation of Tyr1250/1251 was shown to be required for IGF-1R localisation to the Golgi and that a phosphomimetic EE (Y1250E/Y1251E) IGF-1R mutant is less stable, is more ubiquitinated and undergoes more rapid proteasomal degradation than wild type IGF-1R. Three lysine residues (Lys1256, Lys1294, Lys1324) were identified within the IGF-1R C-terminal tail as putative ubiquitin binding sites, but mutation of these to arginine in mutational studies established that all of these sites have a minor function in receptor ubiquitination. Peptides encompassing the hydrophobic Tyr1250/1251 site in the IGF-1R were recently proposed as a cargo-sorting motif that binds to the protein trafficking ESCPE-1 (SNX5/SNX6) complex, which rescues the IGF-1R from lysosomal degradation. This was tested this using full-length receptors expressed in different cell models and using siRNA-mediated suppression of SNX5/SNX6. However, our data did not replicate the published observations on SNX5/SNX6 knockout causing reduced IGF-1R protein expression. Furthermore, no effect of SNX5/SNX6 suppression on IGF-1R protein levels or location at different sub-cellular compartments including the Golgi was observed. Interestingly, SNX5/SNX6 suppression induced lysosomal accumulation at the leading edge of cells as well as decreased cellular migration. SNX5/SNX6 was observed to interact with the IGF-1R, but the hydrophilic Y1250E/Y1251E mutant exhibited a stronger interaction, than the hydrophobic Y1250F/Y1251F mutant, which suggest that this interaction may be modulated by phosphorylation in the full-length receptor. In summary, the findings confirm the importance of the IGF-1R C-terminal tail, in particular, Tyr1250/1251, in IGF-1R signalling and regulation. These tyrosines facilitate ubiquitin binding, SNX5/SNX6 interaction and Golgi localisation of the IGF-1R which all contribute to the transformed phenotype. Further research on the associated mechanisms should assist in tailoring future cancer therapy treatments to improve clinical efficacy.
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    Statistical modeling strategies for estimation of the arterial input function in dynamic positron emission tomography data analysis
    (University College Cork, 2023-03) Xiu, Zhaoyan; Huang, Jian; Wolsztynski, Eric; Science Foundation Ireland; European Regional Development Fund; National Cancer Institute; National Institute of Aging
    Kinetic modelling of dynamic PET data requires knowledge of tracer concentration in blood plasma, described by the arterial input function (AIF). Arterial blood sampling is the gold standard for AIF measurement, but is invasive and labour intensive. A number of methods have been proposed to accurately estimate the AIF directly from blood sampling and/or imaging data. In this work, we review some of the main methodologies for AIF estimation, and present two alternatives that aim at addressing some of their major limitations. We developed a tracer travel rate projection model as an early AIF modelling attempt based on tracer travel history in the circulatory system. A penalty was considered for model parameter estimation and we used arterially sampled data for evaluation. To improve on this first model, we developed a population-based projection model that exploits historical data to estimate individual AIFs. We represent the history of a tracer atom at a sampling site by its travel time, modeled as a sum of the time for the atom to initially progress from the injection site to the right ventricle of the heart, and the time it spends in circulation before being sampled. The former is modeled as a realization from a gamma distribution, whose parameters are common to all subjects in the population, and estimated from a collection of arterial sampling data for the given tracer. The latter is represented by a subject-specific linear mixture of these population pro- files. This approach can be seen as a projection of individual AIF characteristics onto a basis of population profile components. It also incorporates knowledge of injection duration into the model fit, allowing for varying injection protocols. Analyses of arterial sampling data from 18F-FDG, 15O-H2O and 18F-FLT clinical studies show that the proposed model can outperform reference techniques. The statistically significant gain offered by using population data to train the basis components, as opposed to fitting these from the single individual sampling data, is measured on the FDG cohort. Kinetic analyses demonstrate the reliability and potential benefit of this approach in estimating physiological parameters. These results are further supported by numerical simulations that demonstrate convergence of the proposed technique with decreasing noise levels, and stable levels of performance under varying training population sizes and noise levels.
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    Mutual fund performance: timing and persistence
    (University College Cork, 2023-04-24) Yin, Zhengnan; O'Sullivan, Niall; Sherman, Meadhbh; University College Cork; China Scholarship Council
    We apply the nonparametric methodology of Jiang (2003) to examine whether bond mutual funds can time the bond market by adjusting their portfolios' market exposure based on anticipated market movement. This approach has several advantages over the widely used regression-based tests such as Treynor-Mazuy(1966) and Henrikkson and Merton (1981). Using a large sample free of survivorship bias from the US, UK, and China, we find some evidence of positive market timing of bond funds at the individual fund level. On average, bond funds show neutral to slightly negative market timing ability. After controlling for public information, we find that a number of bond funds successfully time the market based on private timing signals. In terms of categories, we find strong evidence of positive market timing for Government bond funds as a group, consistent with the findings of Huang and Wang(2014). We apply a nonparametric methodology to test the liquidity timing skills across individual equity mutual funds in three countries(the US, UK, and China). We calculate the monthly stock market liquidity using simple averages and the asymptotic principle analysis(APCA) method based on six stock liquidity measures. Using an across-measure of market liquidity from APCA, we find a relatively small number of funds demonstrate statistically positive liquidity timing skills at a 5% significance level for the period of 2000-2021. After controlling the lagged market liquidity information, we still find a small number of mutual funds that have conditional liquidity timing ability using the nonparametric method. We analyze the performance of asset allocation funds based on the best-fit multifactor model, including both stock and bond market factors. Using US and UK data, we find asset allocation funds do not outperform their benchmarks on average. We use both Treynor and Mazuy(1966) and Henrikkson and Merton (1981) methods to test the stock and bond market timing ability of allocation funds. As groups, US and UK asset allocation funds have neutral to perverse stock market timing ability. However, UK allocation funds have positive bond market timing ability. At the individual fund level, there is a range of funds that demonstrate positive stock market timing as well as bond market timing ability for both markets. We then test the performance persistence of these funds using an innovative bootstrap method to control for the non-normality issue in fund returns. We find little evidence of performance persistence for US funds for both decile portfolios and small-size portfolios. There is some evidence of performance persistence for UK funds using decile and small-size portfolios.
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    Real-time surveillance for evidence-based responses to suicide contagion and clustering
    (University College Cork, 2022-04-01) Benson, Ruth; Arensman, Ella; Rigby, Jan; Brunsdon, Chris; Health Research Board
    Background: Although a rare phenomenon, suicide clusters are a cause for great community concern. In recent years, strong emphasis has been placed on the importance of detection and real-time surveillance of suicide clusters. Cluster detection increases understanding on the aetiology of a suicide cluster and provides the basis for targeted intervention to mitigate further contagion through the identification of linked cases and socioecological factors associated with the increased risk of clustering in the affected area or population. Policy makers and public health officials benefit from detection of suicide clusters by means of implementing targeted evidence-based interventions in identified vulnerable populations and high-risk areas in a timely manner. To date, suicide cluster detection has been largely restricted to retrospective investigations, limiting its capacity as a tool for intervention. Aim: The aim of this research was to provide a comprehensive understanding of the real-time surveillance, detection, and responses to suicide contagion and clustering. Methods: The thesis is comprised of five interrelated studies, based on both primary and secondary research. Primary data collection was conducted on coronial records of post-inquest cases of confirmed suicide or open verdicts meeting the criteria for probably suicide, as well as pre-inquest cases of suspected suicide. This research also involved quantitative Census data from the Central Statistics Office (CSO). The retrospective and prospective space-time scan statistics based on a discrete Poisson model was employed via the R software environment using the ‘rsatscan’ and ‘shiny’ packages to conduct the space-time cluster analysis and deliver the mapping and graphic components of the dashboard interface in study 3. Evidence synthesis was conducted by means of narrative review of existing literature in studies 1 and 4, and by comparative review of response to a structured questionnaire in study 2. Study 5 employs a secondary research approach to report on policy and practice implications of real-time suicide surveillance. Results: Study 1 synthesised the existing evidence on quantitative techniques to detect suicide and self-harm clusters detection, revealing that a Poisson-based scan statistical model is most effective in accurately detecting point and echo suicide clusters, while mass clusters are typically detected by a time-series regression model, albeit that limitations exist. Study 2 demonstrated more commonalities than differences in a comparison of the components and practices of real-time suicide surveillance systems internationally. Commonalities included rapid, routine surveillance based on minimal, provisional data to facilitate timely intervention and postvention efforts. Identified differences include timeliness of case submission and system infrastructure. Study 3 tested the validity of the scan statistic as a cluster detection approach inbuilt in a dashboard prototype developed to visually display real-time suicide surveillance data. Study 4 identified consistency in both increased quantity of media reports and portrayal of specific details of suicide cases to be significantly associated with suicide contagion and increased suicide rates or mass clusters. An elevated period of risk of suicide contagion has been found to take place between the first days up to the first three months following the media coverage of suicide. Study 5 demonstrated the importance of real-time suicide surveillance in the context of policy and practice, with a particular reference to public health emergencies and humanitarian crises. Conclusions: The findings of this thesis are of relevance in furthering our knowledge of monitoring, detecting, and responding to suicide clusters. Collectively, the findings from this thesis indicate that we can work more efficiently and collectively to mitigate further suicidal behaviour by utilising real-time, provisional suicide data to guide quicker action. The outcomes of this research have methodological implications in terms of suicide and self-harm cluster detection and real-time suicide surveillance. The implications of this research further extend to suicide prevention and mental health policy, clinical practice, means restriction, crisis planning and response, and media reporting of suicide.
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    IGF-1 signalling controls mitochondrial morphology and basal mitophagy in cancer
    (University College Cork, 2023-01-06) Murray, Joss; O'Connor, Rosemary; Science Foundation Ireland
    Insulin-Like Growth Factor 1 (IGF-1) signalling is known to support oncogenic transformation and the promotion of cancer development. A growing body of evidence has outlined the protective effect IGF-1 signalling has on the mitochondria, however this has been relatively underexplored in cancer. Therefore, this thesis aims to elucidate the mechanisms by which IGF-1 promotes mitochondrial protection in cancer. Previously, we determined that the mitophagy receptor BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is induced by IGF-1 to support mitochondrial turnover and protection. Here, we analysed a publicly available gene expression dataset of breast cancer cells stimulated by IGF-1. Gene ontology classification revealed a signature of genes induced and repressed by IGF-1 involved with mitochondrial functions. Further analysis to classify genes by biological process suggested that genes involved with apoptosis and suppression of mitochondrial metabolism were most enriched in the gene groups regulated by IGF-1. To further interrogate mitochondrial dynamics downstream of IGF-1 signalling, we assessed mitochondrial morphology. Lack of IGF-1R promoted mitochondrial fusion, while IGF-1 stimulation promoted mitochondrial fragmentation. Mitochondrial fragmentation was associated with increased mitochondrial transport to the leading edge of invasive breast cancer cells. Pharmacological inhibition of mitochondrial fission inhibited the migration of cells expressing the IGF-1R but was ineffective at moderating migration of cells lacking the IGF-1R. Finally, we interrogated the function of BNIP3 downstream of IGF-1 stimulation. While BNIP3 is induced, IGF-1 stimulation suppressed mitophagy. However, BNIP3 turnover was higher in basal cell culture conditions than in nutrient deprived conditions, suggesting that BNIP3-mediates basal mitophagy in cancer cells. Indeed, IGF-1R knockout reduced the basal turnover of BNIP3 implying that IGF-1 regulates basal mitophagy via BNIP3. In totality, this thesis presents evidence that IGF-1 signalling promotes mitochondrial protection by regulating genes involved with redox homeostasis while tempering mitochondrial metabolism. Mitochondrial fragmentation is induced by IGF-1 and can also regulate cancer cell migration, while also supporting basal mitophagy mediated by BNIP3. These findings demonstrate that targeting IGF-1 signalling in cancer could impair mitochondrial protection mechanisms, which offers an avenue for novel therapeutic opportunities.