Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models

BACKGROUND: The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1α subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers. METHODS: Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1α is known to be active under hypoxic conditions. HIF-1α status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines. RESULTS: Intracellular HIF-1α was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1α in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells. CONCLUSIONS: These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression.

Application of signal detection methods to fisheries management

The abundance of many commercially important fish stocks are declining and this has led to widespread concern on the performance of traditional approach in fisheries management. Quantitative models are used for obtaining estimates of population abundance and the management advice is based on annual harvest levels (TAC), where only a certain amount of catch is allowed from specific fish stocks. However, these models are data intensive and less useful when stocks have limited historical information. This study examined whether empirical stock indicators can be used to manage fisheries. The relationship between indicators and the underlying stock abundance is not direct and hence can be affected by disturbances that may account for both transient and persistent effects. Methods from Statistical Process Control (SPC) theory such as the Cumulative Sum (CUSUM) control charts are useful in classifying these effects and hence they can be used to trigger management response only when a significant impact occurs to the stock biomass. This thesis explores how empirical indicators along with CUSUM can be used for monitoring, assessment and management of fish stocks. I begin my thesis by exploring various age based catch indicators, to identify those which are potentially useful in tracking the state of fish stocks. The sensitivity and response of these indicators towards changes in Spawning Stock Biomass (SSB) showed that indicators based on age groups that are fully selected to the fishing gear or Large Fish Indicators (LFIs) are most useful and robust across the range of scenarios considered. The Decision-Interval (DI-CUSUM) and Self-Starting (SS-CUSUM) forms are the two types of control charts used in this study. In contrast to the DI-CUSUM, the SS-CUSUM can be initiated without specifying a target reference point (‘control mean’) to detect out-of-control (significant impact) situations. The sensitivity and specificity of SS-CUSUM showed that the performances are robust when LFIs are used. Once an out-of-control situation is detected, the next step is to determine how much shift has occurred in the underlying stock biomass. If an estimate of this shift is available, they can be used to update TAC by incorporation into Harvest Control Rules (HCRs). Various methods from Engineering Process Control (EPC) theory were tested to determine which method can measure the shift size in stock biomass with the highest accuracy. Results showed that methods based on Grubb’s harmonic rule gave reliable shift size estimates. The accuracy of these estimates can be improved by monitoring a combined indicator metric of stock-recruitment and LFI because this may account for impacts independent of fishing. The procedure of integrating both SPC and EPC is known as Statistical Process Adjustment (SPA). A HCR based on SPA was designed for DI-CUSUM and the scheme was successful in bringing out-of-control fish stocks back to its in-control state. The HCR was also tested using SS-CUSUM in the context of data poor fish stocks. Results showed that the scheme will be useful for sustaining the initial in-control state of the fish stock until more observations become available for quantitative assessments.

Prostate cancer treatment as an embodied rite of passage: impotence and incontinence as challenges to status reversal and reintegration

Introduction and Rationale: A central argument in the thesis is that performative acts of control, sexual potency and spontaneity are central to the continuous construction of embodied masculine identities. The acts of control, and particularly issues of spontaneity, are central to understandings and addressing the difficulties men face at varying levels of embodied identity. Using Watson’s (2000) ‘Male body schema’, I will explore the challenges and opportunities men face when negotiating normative, pragmatic, and experiential embodiment. I will later then explore the importance of these levels of embodiment to achieving visceral embodiment; or what I would define as a renewed unconscious satisfaction and ability to achieve and maintain normative, pragmatic and experiential forms of embodiment. Purpose and Objectives: Using the concept of liminality, and permanent liminality, the thesis explores how we can interpret and understand men’s experience of prostate cancer diagnosis and treatment, and their struggle to regain power and control in the context of diagnosis, and also the side effects to treatment. The strategies men adopt in seeking out personalised medical programmes of treatment with their doctors are explored in detail. The power and control that can be exercised over medical professionals and treatment options is demonstrated. Method: Collecting responses online from prostate specific discussion boards via gatekeepers, and from interviews on the ‘health talk’ online database, three intersecting conceptual categories - liminality, masculinity and the body/embodiment - are combined in this research. Liminality and ‘time’ are directly linked to notions of ‘success’ and ‘outcome’ during the treatment process, and mark distinct points at which men, and their families, expect measures or limits to have been reached. Exploring liminality within the context of Turner’s ‘rites of passage’, I explore the difficulty men face in concluding the third stage of the rites; reintegration. Results: Prostate cancer diagnosis and treatment, impotence and incontinence, in particular, have profound implications for the continuous construction of embodied masculine identities, and thus identity in general, making the construction of hegemonic ideals in the context of a highly ‘performative’ society highly troublesome. The issue of ‘spontaneity’ in the construction of various forms of embodied identities is of particular concern for men who contributed to this study.

Valuing maternity care: a comparison of stated preference methods with an application to cost-benefit analysis

This research investigates whether a reconfiguration of maternity services, which collocates consultant- and midwifery-led care, reflects demand and value for money in Ireland. Qualitative and quantitative research is undertaken to investigate demand and an economic evaluation is performed to evaluate the costs and benefits of the different models of care. Qualitative research is undertaken to identify women’s motivations when choosing place of delivery. These data are further used to inform two stated preference techniques: a discrete choice experiment (DCE) and contingent valuation method (CVM). These are employed to identify women’s strengths of preferences for different features of care (DCE) and estimate women’s willingness to pay for maternity care (CVM), which is used to inform a cost-benefit analysis (CBA) on consultant- and midwifery-led care. The qualitative research suggests women do not have a clear preference for consultant or midwifery-led care, but rather a hybrid model of care which closely resembles the Domiciliary Care In and Out of Hospital (DOMINO) scheme. Women’s primary concern during care is safety, meaning women would only utilise midwifery-led care when co-located with consultant-led care. The DCE also finds women’s preferred package of care closely mirrors the DOMINO scheme with 39% of women expected to utilise this service. Consultant- and midwifery-led care would then be utilised by 34% and 27% of women, respectively. The CVM supports this hierarchy of preferences where consultant-led care is consistently valued more than midwifery-led care – women are willing to pay €956.03 for consultant-led care and €808.33 for midwifery-led care. A package of care for a woman availing of consultant- and midwifery-led care is estimated to cost €1,102.72 and €682.49, respectively. The CBA suggests both models of care are cost-beneficial and should be pursued in Ireland. This reconfiguration of maternity services would maximise women’s utility, while fulfilling important objectives of key government policy.