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Cytotoxic responses and cell death mechanisms in adrenocortical carcinoma: Insights into mitotane and cisplatin treatment
No full textAdrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited treatment options, particularly for advanced or metastatic stages. Current therapies primarily involve mitotane, often in combination with cytotoxic agents like cisplatin, yet the mechanisms by which these agents induce cell death in ACC remain poorly understood. A major challenge in elucidating these mechanisms is the reliance on monolayer cultures, which fail to replicate the complex tumour microenvironment (TME) of ACC. To address this, we present a novel three dimensional (3D) cell culture model of ACC using H295R, HAC15, and MUC-1 cell lines cultured in type I collagen matrices. This model more accurately mimics the native TME of ACC compared to 2D cultures and is designed to enhance the understanding of cytotoxic responses and improve therapeutic efficacy.
This thesis demonstrate that this 3D ACC model is viable, steroidogenic, and exhibits tumour like features, including central necrosis. Importantly, resistance to mitotane was observed in the 3D culture system compared to monolayer cultures, with varying degrees of resistance to cisplatin treatment. HAC15 and MUC-1 cells exhibited greater mitotane resistance than H295R cells, and HAC15 cells also displayed resistance to cisplatin. Mitotane treatment in H295R cells predominantly induced classical caspase-3-mediated apoptosis, whereas resistant HAC15 and MUC-1 cells underwent non-apoptotic cell death involving necrosis and necroptosis.
This thesis highlights the heterogeneity of ACC cell responses to treatment and underscores the limitations of apoptosis-based therapies in mitotane resistant cells. The 3D model developed herein represents a significant advancement in preclinical ACC research, providing a more physiologically relevant platform for studying ACC biology and evaluating new therapeutic strategies. By revealing the complex nature of drug-induced cell death in ACC, this work advocates for the inclusion of alternative regulated cell death pathways, such as necroptosis, in therapeutic approaches aimed at improving treatment outcomes in this aggressive malignancy
Exploring farmers’ adoption of greenhouse gas mitigation measures that reduce chemical fertilizer application
No full textGlobal food systems are facing a crisis. They generate a third of the world’s greenhouse gas emissions, contributing to climate change, while at the same time climate change is a major threat to food production. The application of chemical nitrogen (N) fertilizers is of particular concern, as it is a significant source of ammonia and nitrous oxide emissions. In this crisis, the introduction of forage species into grasslands, specifically clover and multi-species swards, has a key role to play. These swards can naturally fix atmospheric N into soils, thereby reducing chemical N fertilizer application needs. Beyond their environmental benefits, they stand out for their potential to increase productivity while reducing production costs. Despite these benefits, adoption rates remain low.
This article-based thesis explores this transition from chemical N fertilizers to the adoption of clover and multi-species swards. It presents three original papers, each employing a different dataset and methodology. First, the factors driving the demand for chemical N fertilizers are examined. Results indicate that dairy farmers’ demand is sensitive to weather variability, inelastic to price changes, chemical N fertilizer is considered a necessity, and dairy farmers exhibit path dependence. Second, the determinants of adoption of clover and multi-species sward are analysed. Main findings show that psychological factors have a key influence on the adoption of clover and multi-species swards. Specifically, farmers’ perceptions of usefulness of adoption significantly drive adoption decisions, while perceptions of complexity constrain them. Additionally, testers of clover are more likely to adopt multi-species swards. Third, the role of information provision to improve adoption rates is explored. Results indicate that farmers underestimate the reduction in chemical N fertilizer that is possible with clover and information interventions can reduce this misperception. Furthermore, farmers show increased consideration of adoption benefits in their beliefs after receiving information.
Findings can contribute to policy development, as they offer avenues to reduce chemical fertilizer application, which is needed to accomplish Ireland’s Climate Action Plan. Additionally, they inform farmers about their peers’ experiences and opinions on the adoption of clover and multi-species swards. Lastly, they offer important contributions to the literature through a variety of methodologies employed, including panel data modelling, focus group discussions, and surveys (one involving a randomized economic experiment)
Exploring the potential for digital tools in cancer care: A patient-centric approach
No full textDigital health tools have potential to empower patients to actively participate in decision-making related to their treatment options, appointment scheduling, medication adherence, and lifestyle management by giving them timely access to personalised information and care tools. Despite demonstrated benefits, the sustainable implementation and adoption of digital tools remain limited in cancer care. Patient needs, trust, interest and willingness to adopt digital tools vary across their cancer journey. Despite the varying needs there is limited evidence on how digital tools can designed to be patient centric.
This thesis explores different aspects of digitisation and how it can contribute to improving the patient experience of cancer care. This research further seeks to understand how techniques as design thinking can guide development of digital tools to improve the experience and outcomes for cancer patients and survivors by integrating patient-centric digital solutions into healthcare practices.
A two-phase mixed-methods approach was adopted. First, a systematic literature review examined applications of design thinking in cancer care. Second, a national cross-sectional survey (n=159) of cancer patients and survivors in Ireland gathered both quantitative and qualitative data on information needs, current information sources, preferred information sources and feature preferences for digital tools to aid cancer care.
Participants had strong digital skills and interest in using digital tools but reported moderate levels of trust. Healthcare professionals were preferred source of information, but patients also increasingly relied on digital medium as mobile apps. Information needs vary according to cancer journey. Key barriers to digital engagement included emotional distress, information overload, and lack of trust in online sources.
Digital tools in cancer care should stage-sensitive and co-designed with patients to address evolving informational needs. Trust in digital tools is critical to adoption. Future research has potential in prototyping and longitudinal testing with iterative process
My Life, My Choice: A critical analysis of whether persons with high support needs living in Ireland can live an independent life within their communities
No full text[No abstract available
Microbial protein production from sulfide-rich biogas through methane- and sulfur-oxidizing consortia
No full textMicrobial protein (MP) represent a potentially powerful solution to help relieve the pressure on the agri-food sector by addressing the expanding protein gap at the global level. Particularly, MP production from waste and residues paves the way towards their valorization into high value products. Biogas from anaerobic digestion of organic waste has been widely investigated as a potential substrate to support gas-based fermentation towards MP production using methane oxidizing bacteria (MOB). The latter, nevertheless, may be potentially inhibited by the presence of H2S in biogas (0-10000 ppm), thereby posing the need for dedicated and expensive pretreatments. Therefore, the overarching aim of this study was to enable an improved H2S-rich biogas-to-MP conversion by combining MOB with sulfur oxidizing bacteria (SOB), capable of oxidizing sulfide and reducing its toxicity.
A MOB-SOB mixed culture was selected and enriched from an inoculum grown on methane in the presence of sulfide and several operating conditions were investigated through batch tests (Chapter 3). The most optimal operating conditions for biomass growth and protein production identified were a CH4:O2 ratio of 2:3, a starting pH of 7.0 and an equivalent H2S concentration in the biogas of 1500 ppm. The enriched MOB-SOB culture, dominated by Methylocystis spp. (MOB) and Chryseobacterium spp. (SOB), could withstand H2S concentrations in the gas phase as high as 4000 ppm, with inhibition occurring at 6000 ppm, thereby suggesting its suitability for direct conversion of sulfide-rich biogas into MP.
Thereafter, the extent of H2S inhibition on MP production from biogas was evaluated under different operating conditions and bioreactor configurations. The enriched MOB-SOB mixed culture was utilized for the continuous production of MP from H2S-rich biogas through bubble column reactors (Chapter 4) and hollow fiber membrane reactors (Chapters 5-6). The continuous operation in the bubble column reactors (Chapter 4) showed promising results in terms of biomass growth (up to 559.9 ± 13.3 mg volatile suspended solids (VSS) per liter in the presence of 1500 ppm of equivalent H2S), being it affected by higher H2S levels as the biomass concentration
decreased up to 40% when fed a biogas with 4000 ppm of H2S.
The utilization of hollow fiber membrane bioreactors (Chapter 5), aiming at more efficient supply of the gaseous substrates, promoted both higher biomass growth (720.3 ± 19.8 mg VSS/L in the presence of 1500 ppm of equivalent H2S) and improved tolerance to higher H2S levels, with biomass concentrations decreasing only by 11% under 4000 ppm of H2S with respect to the presence of 1500 ppm. This higher resistance to sulfide inhibition could be attributed to the beneficial effects of the presence of attached biomass on the membranes, rich in sulfur oxidizing species, which favored overall better process performance in this bioreactor configuration.
Moreover, the potential of the sulfide in biogas to act as source of sulfur, as well as the recovery and the concomitant valorization of nitrogen from anaerobic digestate during MP production, were evaluated (Chapter 6). Particularly, the feasibility of direct nitrogen stripping from digestate performed using the recirculating biogas/oxygen-containing gas stream of the reactor was demonstrated, with encouraging stripping efficiencies when stripping was carried out at 45 °C.
The biomass produced and harvested during continuous MP production from biogas showed an overall high protein content (up to more than 65%), and an amino acid profile rich in essential amino acids, comparable to those of conventional animal- or plant-based protein sources. Moreover, increasing sulfide concentrations in biogas promoted the accumulation (up to 2.5 times more than in the absence of sulfide) of nutritionally-relevant sulfur- containing amino acids, such as methionine and cysteine (up to 61.3 and 58.3 mg/g biomass, respectively)
Behaviour change maintenance in type 2 diabetes self management: Developing the evidence base for optimising education and support programmes
No full textBackground: Attendance at structured diabetes self-management education and support (DSMES) programmes is recommended to support type 2 diabetes (T2DM) management. Evidence indicates that DSMES programmes improve clinical and psychosocial outcomes in the short term, but difficulties maintaining behavioural changes post-programme appear to attenuate their long-term impact. Sustained changes in diabetes self-management, such as diet and physical activity, are critical to achieving and maintaining improvements in glycaemic levels (HbA1c) and minimising the risk of complications. However, little is known about the factors influencing the maintenance of behavioural changes post-programme and the support needs of people with T2DM after attending these programmes. Moreover, the components and ‘active ingredients’ of these programmes remain poorly understood, including whether included content is relevant to maintenance of behaviour change.
Aim: This PhD thesis aimed to develop an evidence base on behaviour change maintenance after attendance at DSMES programmes for T2DM to facilitate the development and optimisation of programmes that better support behaviour change maintenance.
Methods: A multimethod approach was adopted, informed by a modified four-step version of the Behaviour Change Wheel (BCW) approach for refining behavioural interventions. Three studies were conducted. First, a systematic review and qualitative evidence synthesis was conducted to identify and synthesise qualitative research on barriers and enablers to maintaining T2DM self-management behaviours after attending a self-management intervention. Barriers and enablers were synthesised using the best-fit framework synthesis approach guided by the themes and constructs identified by Kwasnicka et al. (2016) in their review of theoretical explanations for behaviour change maintenance.
Second, a documentary analysis of the materials of two DSMES programmes delivered in the Republic of Ireland, the Community-Oriented Diabetes Education (CODE) and the Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) programmes, was conducted to identify their behaviour change content and key features using multiple behavioural science tools, including the Behaviour Change Techniques (BCTs) Taxonomy v1, the Mode of Delivery Ontology v1 and the Intervention Source Ontology v1.
Third, a longitudinal multi-methods qualitative study, comprising four semistructured interviews and optional experience sampling (written notes and photographs), was conducted to explore behaviour change maintenance experiences and post-programme support needs of adults with T2DM over 15 months following attendance at one of two DSMES programmes (CODE and DESMOND) offered in
the Republic of Ireland. Data from this study were analysed following a two-stage process: 1) cross-sectional analysis of data from each interview time point using a combined deductive framework analysis, guided by the framework generated in the systematic review, and inductive thematic analysis, and 2) a longitudinal thematic analysis inspired by trajectory analysis principles. A patient and public involvement panel informed all three studies.
Findings: In study one, the systematic review and qualitative evidence synthesis identified 28 barriers and enablers (13 barriers, five enablers, 10 barriers/enablers) to maintaining self-management behaviours following self-management interventions across 10 studies. Using the best-fit framework approach, an adapted framework was developed, combining constructs from the a priori framework with inductively developed constructs (N = 3) and sub-constructs (N =12). Social support, habit formation, lapse, relapse and coping with behavioural barriers, access to appropriate support and material resources, enjoyment of behaviour and satisfaction with outcomes, self-determination, knowledge, self-regulation skill, fear of negative health consequences, concurrent health problems, competing life demands, weather conditions and sociocultural norms were amongst the most frequently identified theoretical constructs. The review also identified the need for longitudinal studies with a duration of more than nine months and a better understanding of people’s preferences and needs regarding post-intervention support.
In study two, findings from the documentary analysis revealed that the programmes include a relatively low number of BCTs (27-28) from a limited number of BCT groups, with some BCT groups rarely or never included. The BCTs included in the programmes were most frequently related to ‘goals and planning’, ‘feedback and monitoring’ and ‘natural consequences’. These were linked with several mechanisms of action, most frequently reflective motivation (‘beliefs about capabilities’ and ‘beliefs about consequences’) and psychological capability (‘knowledge’), and served different intervention functions, most commonly, ‘education’, ‘enablement’ and ‘persuasion’.
In study three, twenty-one adults (67% female, aged 39–74) participated, seventeen of whom completed all four interviews. The cross-sectional analysis of the data resulted in an adapted framework, the Supporting Understanding and Strategies for Type 2 Diabetes Maintenance Self-Management (SUSTAIN) framework. Three themes, each comprising two to three sub-themes, were developed based on the longitudinal analysis of the data: (1) ‘Integrating the changes amidst the constant ebb and flow of life’; (2) ‘Consolidating the changes: Moving towards independent maintenance’; and (3) ‘Building bridges to self-maintenance: The role of support post-programme’. Theme one represents people’s struggles to maintain behavioural changes post-programme due to the challenges and tensions of integrating changes into their lives and maintaining them amidst the complexities of everyday life, and their strategies to deal with challenges and maintain these changes. Theme two represents two key pathways towards independent behaviour change maintenance: a) behavioural autonomy and intrinsic motivation, and b) behavioural automaticity. Theme three represents people’s experiences of, views about, and additional needs for post-programme support to better maintain behavioural changes.
Conclusions: The findings of this research have advanced the evidence base regarding behaviour change maintenance following DSMES programmes for T2DM, laying the foundation for the development and refinement of programmes for better behaviour change maintenance support. Using multiple methods, including a unique 15-month multi-methods longitudinal qualitative study, this research has extended the international knowledge base in multiple ways. First, it has extended the current understanding of factors influencing behaviour change maintenance following this type of programme. Second, it advanced understanding of these programmes’ features and behaviour change content, thus facilitating the identification of missed opportunities to support behaviour change maintenance. Third, it identified participants’ needs and preferences for support post-programme. Fourth, it identified several research, practice and policy avenues to better understand and promote long term behaviour change maintenance in this context.University of Galway (Hardiman Scholarship
Dissecting enhancer-genes regulatory network in single cells to characterize immune cells’ response to solid tumours
No full textThe characterization of epigenetic heterogeneity at the population level is a critical problem in genomics. In particular, tumour infiltrating T cells are a heterogeneous set of cells for which a comprehensive description of epigenetics regulation is still missing. The advent of single cell ATAC-seq (scATAC-seq) opens the opportunity to identify putative enhancers at the granularity of single cells. However, the prediction of potential enhancer-promoter regulatory interactions over a wide breadth of tumour infiltrating T cell states is missing and remains a gap, because methods to reconstruct cis-regulatory interactions are still lacking. Relying on the understanding that distal non-coding regulatory elements (e.g., enhancers) play a pivotal role in orchestrating the molecular and genetic mechanisms underlying cell identity, we hypothesized that identifying distinct subpopulations within immune cells infiltrating solid tumours could significantly improve patient stratification strategies. Based on these hypotheses we integrated Single- cell RNA sequencing (scRNA-seq) and scATAC-seq data performed on lymph nodes to characterize tumour-infiltrated lymphocytes (TILs) subpopulations in breast cancer. We studied CD8+ T cell differentiation by trajectory analysis, and identified key transcriptional regulatory networks. We also developed a novel epigenomic-based machine learning method, the 3D-SC-EG Profiler, for reconstructing the enhancer-target gene (ETG) regulatory network by integrating multi-omics data and 3D chromatin architecture using Hi-C data. We identified distinct CD8+ T cell subpopulations, including TSTEM and TPEX, critical to T cell exhaustion and stemness. Trajectory analysis revealed key branching points in CD8+ T cell differentiation, with markers like TOX and PDCD1 associated with terminal exhaustion. The 3D-SC-EG Profiler method successfully predicted enhancer-promoter interactions, outperforming existing methods with an AUC of 0.85, providing novel insights into the epigenetic regulation of immune cells. Our study uncovers crucial regulatory networks governing CD8+ T cell differentiation, with implications for improving immunotherapy by targeting transcriptional and epigenetic pathways. Future research should focus on experimentally validating predicted enhancer-gene interactions and refining the 3D-SC-EG Profiler method. Applying this approach to broader datasets, particularly from metastatic breast cancer, could further elucidate disease progression and resistance mechanisms.Additionally, developing the 3D-SC-EG profiler method as an accessible R package would accelerate its adoption by the research community.This work was supported by Ministero della Salute, and one-year AIRC pre-doc fellowship, Ref. 2970
The assessment of the therapeutic potential of induced pluripotent stem cell-derived mesenchymal stromal cells
No full textOsteoarthritis (OA) is a chronic disease that affects synovial joints. OA progression leads to loss of articular cartilage and inflammation. OA is the leading cause of adult disability worldwide. Currently, there are limited regenerative treatments for OA, and the modern standard of care focuses on reducing pain and improving mobility. Mesenchymal stromal cells (MSC) are the most widely studied cell in the cell therapy field. In vitro and in vivo data suggest that MSC are a promising treatment for several disorders, including OA. MSC mediate disease progression by modulating the immune system via cell-to-cell contact, secreted factors, and apoptosis. Although pre-clinical studies show MSC to be a promising candidate for cell therapy, progression to the clinic has failed to meet the pre-clinical hype. The heterogeneity of MSC from different sources and donors is a plausible rationale for MSC failing to gain widespread regulatory approval. Secondly, many clinical trials report minimal efficacy of MSC treatment groups compared to placebo. Induced pluripotent stem cell (ISPC) technologies have revolutionised the field of cell therapies and offer an alternative method for cell production. iPSC-MSC or iMSC might offer an alternative source of MSC with improved expandability and reduced heterogeneity. Subsequently, licensing or the in vitro priming of MSC was shown to be a viable method to attempt to improve MSC therapeutic capacity. iMSC and MSC were compared for their ability to undergo tri-lineage differentiation, secrete antiinflammatory factors and modulate the activation of immune cells, T lymphocytes and monocytes. Also, the response of both cell types to licensing with tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) was examined using these methods. As apoptosis of implanted MSC as a mode of action of MSC has gained more interest in recent literature, the role of apoptosis derived and secreted apoptotic bodies was assessed. The apoptotic bodies from naïve and licensed MSC or iMSC were first isolated and characterised. Next, the apoptotic bodies’ ability to repair OA cartilage, reduce T lymphocyte proliferation, polarise M1 macrophages to their M2 phenotype and miRNA cargo was investigated. Here, we show that the MSC and iMSC, although not identical, are similar in their ability to differentiate, secrete anti-inflammatory factors and modulate the immune system. Likewise, the apoptotic bodies from untreated MSC and iMSC shared similar but not identical characteristics. Also, we demonstrated that licensing with inflammatory factors does improve the immunomodulatory capacity of MSC, iMSC and their apoptotic bodies. Further analysis and in vivo studies will be required to validate these findings. Still, in vitro iMSC behave similarly to MSC, with variations similar to that seen for MSC from alternative sources. iMSC offer greater expandability, reduced cost, and reduced heterogeneity. Additionally, licencing is a realistic alternative approach to improve MSC efficacy. iMSC and licensing may improve the clinical outcome of MSC trials and, therefore, bridge the gaps from clinical trials to the market for MSC cell therapy
Advanced telehealth for chronic heart failure management
No full textHeart Failure (HF), a chronic and progressive clinical syndrome characterized by symptoms like dyspnoea, oedema, and fatigue, affects millions worldwide, leading to high rates of hospitalization and mortality. Traditional management relies on in-person diagnostics and hospital-based care, often resulting in delayed intervention and increased burden on healthcare systems. Remote monitoring (RM) via telehealth represents a pivotal shift towards proactive HF management, allowing for continuous, real-time data collection, early detection of decompensation, and prompt interventions. This thesis explores an innovative approach to HF management through the design, development and validation of a novel implantable sensor for central venous pressure (CVP) monitoring in the inferior vena cava (IVC), and compares its clinical relevance to the existing pulmonary artery pressure (PAP) sensors currently used in clinical practice.
Recent clinical trials utilizing PAP monitoring technologies (e.g., CardioMEMSTM, Abbott, Atlanta, GA, United States, and CordellaTM, Endotronix Inc., Lisle, IL, United States) demonstrate the clinical benefits of RM for HF, including reduced hospitalizations and optimized therapy for high-risk patients with multiple comorbidities. However, these technologies are constrained by their invasiveness, requiring right heart catheterizations, extended procedure times, prolonged exposure to contrast media, and complex target anatomy, which limits their suitability for many patients. The IVC presents a promising alternative site for assessing congestive HF, using CVP as a potential haemodynamic marker in HF monitoring. Unlike PAP, however, the full diagnostic potential of CVP remains underexplored. This thesis addresses this gap by assessing the clinical relevance of CVP in HF diagnostics, designing an anchoring system for an implantable CVP sensor optimized for IVC placement, and evaluating its feasibility within a preclinical context.
A literature review on existing RM technologies and telehealth platforms established the need for improved diagnostic capabilities for HF patients, especially for those ineligible for PAP monitoring. Key research questions included the clinical significance of CVP, benefits and limitations of IVC implantation, and practical challenges in implementing solutions that combine invasive and non-invasive monitoring. Based on these questions, research objectives focused on CVP diagnostics, sensor design, development, and validation, as well as the implementation of a telehealth platform combining both RM approaches.
The first part of this thesis investigated the design and development of a CVP sensor to address unique anatomical challenges in the IVC. A novel anchoring system was engineered to ensure stable sensor positioning, prevent migration, and maintain accurate CVP measurements. Bench testing using custom-made silicone IVC model evaluated device performance under physiological conditions. Computational fluid dynamics (CFD) modelling assessed the implant’s impact on blood flow, validating safety and feasibility for in-vivo testing. An animal study involving simultaneous CVP and PAP measurements established baseline data for haemodynamic trends, with results confirming the sensor’s accuracy and reliability. This study provided foundational data to support the potential of CVP as a valuable marker for HF management and demonstrated a safe, efficient IVC implantation technique.
The second part of this thesis investigated a clinical, observational telehealth study assessing outcomes in three patient cohorts over 12 months: a non-invasive group using commercial devices and a tablet for vital sign monitoring (Croga); an invasive cohort using PAP monitoring along with the same devices and a tablet; and a Control group under routine standard of care. Findings indicated that the Implant group demonstrated the highest compliance (99%) and significant improvements in functional status (P<0.001), aligning with previous studies using similar technology for PAP monitoring. The telehealth intervention successfully reduced HF hospitalizations and improved medication management, underscoring the benefits of remote monitoring in HF patients. Despite these successes, limitations such as small sample size and uneven NYHA class distribution suggests a need for larger-scale studies to validate these findings both clinically and statistically.
This thesis advances HF management by introducing a CVP sensor with potential to address gaps in current RM strategies and by establishing a telehealth platform that accommodates diverse patient needs. The novel integration of CVP and PAP monitoring expands clinical insights into HF progression and treatment efficacy. Future research should focus on refining the bench methods by redesigning sensor technologies and anchoring mechanisms to optimize their placement and use within the cardiovascular system, enhance bedside monitoring by expanding the scope of RM for diverse HF populations, while assessing their long-term relevance and efficacy. The results of this thesis support a more individualised and proactive approach to HF management, offering a significant step forward in the adoption and maintenance of telehealth solutions tailored to the complex and evolving needs of HF patients