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Hypoxia-mediated tumour microenvironment in hormone receptor-negative breast cancer
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Breast cancer is the most common malignancy in women, causing approximately 670,000 deaths annually worldwide. Prognostic and predictive markers largely rely on the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). ER/PR-negative subtypes represent a more aggressive form of the disease, with a higher likelihood of relapse compared to ER/PR-positive cases.
Hypoxia is a hallmark of solid tumours, driving cancer aggressiveness and treatment resistance. It is preferentially associated with ER/PR-negative breast cancer. Carbonic anhydrase IX (CAIX) is a well-established hypoxic marker linked to poor survival outcomes in breast cancer, particularly in ER/PR-negative cases. Currently, a CAIX-targeted inhibitor is under investigation in a phase I clinical trial for advanced solid tumours. This study aimed to explore the CAIX-associated gene signature and identify novel hypoxia-related therapeutic targets in breast cancer.
Bulk RNA sequencing (Tempo-Seq) analysis was conducted on 131 ER/PR-negative breast cancer samples with available CAIX immunohistochemistry (IHC) data from the Glasgow Breast Cancer Cohort. Differential gene expression analysis comparing high versus low CAIX expression identified four significantly upregulated genes: NDRG1, CA9, VEGFA, and PPFIA4. Gene Set Enrichment Analysis (GSEA) revealed that hypoxia and glycolysis were the top two enriched pathways. Additionally, protein-protein interaction analysis using the STRING tool showed moderate interactions between the identified genes with the exception of PPFIA4.
The expression of NDRG1, CA9, VEGFA, and PPFIA4 was validated at both the mRNA and protein levels in vitro using MDA-MB-231, SKBR-3, and MCF-7 breast cancer cell lines. Under hypoxic conditions (1% O₂), all four genes exhibited increased mRNA expression. At the protein level, CAIX and NDRG1 were upregulated in hypoxia, thus NDRG1 warranted further investigation.
Immunohistochemistry analysis of NDRG1 was performed on tissue microarrays (TMA) from the full Glasgow Breast Cancer Cohort. High cytoplasmic NDRG1 expression correlated with significantly poorer overall survival (OS) and cancer-specific survival (CSS). However, when stratified by ER/PR status, NDRG1 expression did not significantly impact survival outcomes. Several limitations should be noted: TMAs might not fully represent whole tumour sections, and there is no standardised cutoff for high versus low NDRG1 expression, which may introduce bias. Additionally, the lack of an independent validation cohort highlights the need for further studies.
To explore the functional role of NDRG1 under hypoxic conditions, it was hypothesised that NDRG1 contributes to aerobic glycolysis, similar to CAIX, as suggested by GSEA. Metabolic assessments were performed using Seahorse assays to measure the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Additionally, lactate and ATP assays were conducted to validate the Seahorse findings. Silencing NDRG1 led to decreased lactate production (a glycolysis byproduct) in MDA-MB-231 and MCF-7 cells. However, its impact on ECAR varied: no effect was observed in MDA-MB-231 cells, while ECAR increased in MCF-7 cells. Silencing NDRG1 increased OCR and ATP production in MCF-7 cells but had no effect in MDA-MB-231 cells. These findings suggest that NDRG1 plays a role in glycolytic pathways under hypoxic conditions, but its function may vary depending on the molecular background of the different breast cancer subtypes. Further studies are needed to investigate alternative metabolic pathways, such as fatty acid oxidation and glutamine metabolism, which may be mediated by NDRG1 under hypoxic conditions, particularly in MDA-MB-231 cells.
This study identified NDRG1, CA9, VEGFA, and PPFIA4 as differentially expressed genes associated with CAIX-driven hypoxia in breast cancer. NDRG1 emerged as a potential hypoxic biomarker, as high expression correlated with worse OS and CSS in the Glasgow Breast Cancer Cohort. Additionally, NDRG1 was upregulated in hypoxia and played a role in aerobic glycolysis. Silencing NDRG1 alleviated glycolysis by reducing lactate production and enhanced mitochondrial respiration by increasing OCR. Further studies are warranted to explore the mechanistic role of NDRG1 in hypoxia-driven metabolism and to validate these findings in independent breast cancer cohorts
Unveiling the dynamics of ICO underpricing: an analysis of regulatory changes and female leadership
Get PDFProviding funding for innovative enterprises is a primary focus in entrepreneurial finance. Initial Coin Offering (ICO) constitutes a novel mechanism for raising funds for highly innovative enterprises utilizing Distributed Ledger Technology (DLT). The most common type of DLT is blockchain technology. In an ICO, companies raise funds by issuing tokens and selling them to a group of investors. Typically, these tokens are cryptocurrencies designed to serve as currency within the company's ecosystem. While ICOs share similarities with Initial Public Offerings (IPOs) and crowdfunding, there are distinctions. In contrast to IPOs, investors purchasing stocks gain equity, whereas investors acquiring tokens in ICOs do not obtain equity. Another distinguishing feature from crowdfunding is the use of DLT, which is essential for token issuance and constitutes the core of these enterprises. DLT, especially blockchain technology, represents a revolutionary and disruptive technological innovation. Therefore, providing funds for these enterprises is crucial in the field of entrepreneurial finance.
ICO, being a new financing method, faces incomplete regulatory frameworks across various countries and regions. This preliminary study aims to investigate the impact of ICO regulations on token depreciation and whether the presence of female leaders in companies amplifies or mitigates this impact.
Our multiple regression analysis, conducted on a sample of 377 ICOs from 2016 to 2020, indicates that ICO depreciation is reduced in the presence of ICO regulations. Additionally, when companies have female leaders, ICO depreciation becomes more severe. However, the interaction between regulation and female leadership mitigates ICO depreciation, meaning that female leaders exacerbate the impact of regulations on ICOs.
By integrating regulation, female leadership, and ICO depreciation, this study fills a gap in the research field. Furthermore, we provide relevant recommendations in the conclusion, offering guidance for establishing regulatory systems and ensuring fair pricing
Techno-enablement in school data management: policy practices and inter-agency governance in Malaysia
Get PDFThis study explores the implementation of data-driven decision-making (DDDM) within the Malaysia Education Blueprint (MEB), focusing on why it has not effectively enhanced educational delivery and outcomes as intended. Despite the MEB’s clear key outcomes, the reasons for the shortfall in achieving these goals through DDDM have not been thoroughly examined. This research critically investigates the underlying issues in School Data Management (SDM) practices and proposes a solution through the lens of techno-enablement, a framework that integrates power and potential.
Drawing from Foucault’s relational power, Heidegger’s potentiality, and Valsiner’s enablementism, this study critiques the assumption that empowerment alone ensures effective SDM. It adopts a structural-relational perspective, recognising that governance structures (policy, bureaucracy, and institutional hierarchies) shape but do not fully determine decision-making autonomy. Rather than viewing SDM failures as either technocratic inefficiencies (structural) or human limitations (relational), this study examines how structural constraints and relational agency interact to enable or constrain DDDM practices.
This research used a sequential qualitative methodology and multiple phases of data collection to uncover the disconnect between policy and practice in SDM. The study investigated the experiences of 40 headteachers as school-level data managers, using online questionnaires and consultation sessions. Additionally, it focused on educational officers from District Education Offices (DEO), the Ministry of Education (MOE), and the Malaysian Administrative Modernisation and Management Planning Unit (MAMPU), engaging them through focus groups and interviews to understand the challenges of policy implementation at the district and ministry levels.
The findings revealed a significant disconnect between the policy narratives of the MEB and the lived experiences of educators, highlighting ambivalence in SDM practices. In response, this study introduced techno-enablement, a theoretical framework that explains how governance conditions determine whether SDM empowers institutions or constrains decision-making autonomy. From this foundation, the Techno-Enabler Framework is developed, identifying five interrelated enabling conditions for SDM effectiveness: Techno-Governance (policy coherence), Techno-Competency (data literacy), Techno-Networking (inter-agency collaboration), Techno-Decisioning (institutional autonomy), and Techno-Integration (policy adaptability).
Rather than an empirical test of causality, this study provides a theoretical exploration of SDM governance, aligning with interpretive social science traditions. While informed by empirical findings, its goal is not to prove direct cause-effect relationships but to explore why SDM remains compliance-driven rather than participatory. Instead of isolating variables for causal testing, it examines governance structures, policy translation, and institutional agency to identify enabling conditions for SDM effectiveness.
This study advocates for a new way of thinking about the role of technology and human agency in SDM. Techno-enablement offers a cohesive approach for leveraging data technologies in tandem with human capacities to enhance educational outcomes. The findings and the proposed Techno-Enablement Framework not only aim to improve educational delivery and outcomes within Malaysia but also offer a model for other countries with similar centralised-decentralised educational structures, potentially transforming how data-driven decision-making is approached in global educational contexts. Future research should empirically test the Techno-Enabler Framework through a longitudinal study, assessing how SDM governance evolves over time and whether governance conditions adapt to institutional needs
Youth-championing research-practice collaboration as vehicle for collaborative knowledge discovery and stewardship: insights from an exploratory study with four schools in the Western Cape, South Africa
Get PDFIn educational research, interest in collaborative research strategies including research-practice partnerships (RPPs), research-practice collaborations (RPCs) and related approaches has grown significantly over the past decade, expanding beyond RPPs initial roots in the US to an increasingly global footprint. Yet many questions remain about how to engage in collaborative educational research as well as the benefits, ‘impact’, and relevance of doing so for all parties involved. The South African context is one of many - outside the US, UK, and other emerging hot spots - where the potential of these approaches has only been explored sporadically. The core focus of this proof of principle study is how enabling, hospitable spaces for collaborative knowledge discovery and stewardship (CKD&S) can be fostered through RPCs with schools in the Western Cape, SA. RPC is defined as a concept that is closely related to RPPs yet distinct in potentially valuable ways in terms of key challenges that have been identified around the significant investments such partnerships demand. The thesis narrates and interprets four emergent, youth-championing RPCs with schools that ran in parallel over the first two terms of 2023. These RPCs centred on the collaborative prototyping of a developmental intervention for learners in key transitional grades in the SA education system. Drawing on the perspectives of school leaders, staff as well as over 200 learners, the potential of RPCs as vehicles for fostering enabling, hospitable spaces for CKD&S that are tailored to context, allow for differentiated collaborator engagement as well as flexible, distributed, servant leadership, is considered. The discussion augments broader deliberations in the literature on the formative potential of RPCs for researchers and practitioners, as well how the value and transferability of these collaborative research strategies may be assessed. A proposal for first prototype heuristic to support clearer conversations around CKD&S activities is outlined
Investigation of biomarkers for the detection of pre-cancerous lesions associated with pancreatic ductal adenocarcinoma (PDAC)
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Horace and Iambos: a literary study of the sexual vocabulary, imagery, and metaphors in the Epodes
No full textThis thesis examines the use of sexual language, imagery, and metaphors in Horace's Epodes, highlighting how these elements play a role in his refashioning of the iambic genre. By exploring Horace's incorporation of Archaic iambic traditions from poets like Archilochus and Hipponax, along with his engagement with earlier Latin poets such as Lucilius and Catullus, this study shows that Horace's use of explicit sexual content goes beyond mere vulgarity. Instead, it serves broader literary aims, including critiques of societal norms, explorations of personal vulnerability, and reflections on the poet's literary identity. Horace's originality is evident in how he merges iambic conventions with a distinctly Roman perspective, giving voices to marginalised figures, especially women, while employing self-ridicule as a tool for personal and poetic self-reflection. Through a layered combination of invective, humour, and self-satire, Horace positions himself as both a successor and an innovator within the iambic tradition, adapting its conventions for a Roman audience while preserving its sharp satirical edge. Ultimately, this thesis argues that Horace creates a distinct space for reflecting on sexuality and literary ambition
Industry agglomeration and firm productivity in China: does highway access matter?
Get PDFUsing detailed GIS and firm-level data, this thesis investigates the effect of highway access on within-industry agglomeration, coagglomeration and firm productivity in China during the period 1998-2007. In order to address the potential endogeneity problem and shed light on causality, this study constructs three types of time-variant instruments for the highway access variable, including the historical routes, least cost path network and straight line network.
This study finds that highway access positively affects within-industry agglomeration, and the results are consistent with IV estimations. The improved highway access enhances agglomeration for downstream industries by increasing their flexibility in location choices. Additionally, input-output adjusted highway access promotes within-industry agglomeration by lowering transportation costs for accessing inputs and outputs from other industries.
Regardingtheeffectsofhighwayaccessoncoagglomerationofindustrypairs,thisstudyfinds that better highway access increases coagglomeration at the province and city levels, but the effect is insignificant at the county level. The positive effect of highways on coagglomeration is larger for industry pairs with a lower share of state-owned enterprises, for related industries, and for those with input-output linkages.
The results indicate that highway access has a positive effect on firm productivity, with a 1% change in highway access yielding a 0.018% increase in firm TFP. Four channels are investigated, including within-industry agglomeration, coagglomeration, export, and innovation. This study finds that highway access affects firm productivity through the channels of within-industry agglomeration, coagglomeration, and exports, while the innovation channel is less significant
Improving exploration of tactile graphics by visually impaired people: Theoretical advances and a novel mobile application
Get PDFThe goal of this PhD study is to improve the accessibility of tactile graphics for people with visual impairments. Tactile graphics provide a means for blind individuals to understand nontextual information through touch. However, they often require supplementary audio or Braille text descriptions, which can be time-consuming and create obstacles to learning. For instance, some individuals may find that reading Braille or listening to a screen reader takes longer because they have to go through all the text or audio to locate the necessary information. To address these challenges, this study develops and evaluates TAURIS (Tactile AUdio Responsive Intelligent System), a novel system that provides real-time audio descriptions that accompany tactile graphics. TAURIS is comprised of pre-labelled tactile graphics, an interactive web tool for labelling, and a mobile application. The mobile application relies on a customised deep learning computer vision model to detect the user’s fingertips as they explore the tactile graphics and provides information about what they are touching. Notably, no system simultaneously detecting the fingertips of both hands in real-time and under different lighting conditions has been implemented on a mobile device.
In order to evaluate the efficacy of TAURIS, a mixed-methods approach was employed. This approach consisted of structured interviews, experiments, and post-experimental feedback sessions involving a total of 20 participants, including one pilot participant. The structured interviews were designed to gather information on the participants’ experiences with tactile graphics and mobile devices. In the subsequent experiments, response times and the number of correct answers were recorded during end-user testing of the app. The resulting data was analysed using the Wilcoxon signed-rank test. The analysis revealed three statistically significant findings: TAURIS allowed for faster interaction with tactile graphics and higher accuracy in answering questions compared to both Braille text and screen readers. Additionally, while no significant difference in memory retention was observed between TAURIS and Braille text, TAURIS demonstrated a significant advantage in memory retention over screen readers. Additionally, the participants provided feedback on their impressions, comments, and suggestions for improving the system. Finally, a mixed-methods approach was used to triangulate the data from multiple sources and strengthen the validity of these findings.
Based on these findings, TAURIS has the potential to empower individuals with visual impairments by providing an accessible and efficient tool that supports independent learning and improves knowledge retention. Further research with a larger number of participants in various schools for the blind and countries would be valuable for gaining additional insights, increasing the power of the statistical analysis, and enabling further comparisons
Investigating the role of RNA modifying enzymes in RNA virus infection
Get PDFViruses, as obligate intracellular parasites, rely heavily on their close interactions with host cells to replicate. To have a successful lifecycle, a virus must subvert the host machinery for its own use, while avoiding inducing an immune response in the cell. One mechanism of inducing an immune response is the sensing of foreign nucleic acid, whether that be through unusual nucleic acid structure or specific motifs on viral RNA and DNA. In the resting cell, all post transcriptional modifications of cellular RNA play an important role in the life cycle of RNA, and these modifications in turn act as a signal in the cell to avoid triggering an immune response. In the eternal battle of viruses and their hosts to adapt and counter adapt to overcome each other, viruses have evolved intricate mechanisms to avoid mounting an immune response. One such method is to mimic the cellular landscape of RNA to avoid being sensed by the host. To do this, viruses hijack cellular RNA modifying enzymes to ‘decorate’ their genomes. These modifications also serve a functional purpose in viral RNA and can enhance processes like translation of viral mRNAs. However, in the co-evolution of virus and host trying to counter each other, the host cell can also methylate viral RNA to initiate an innate immune mechanism to restrict viral growth. To understand the dynamicity of RNA modifications in viral infection, I have created a CRISPR-Cas9 knockout platform where I systematically knockout each known human RNA modifying enzyme and observe if the lack of the gene increases or decreases viral infection. This allows us to determine whether the gene of interest inhibits or enhances viral infection. Those genes that are identified as necessary for viral infection are subjected to further analysis to identify the function of these RNA modifications and if the same modifications are shared between viruses. Using this platform, I identified several RNA modifying enzymes and characterised one protein that had an antiviral effect against several viruses – NOP2. In the resting cell NOP2 is involved in ribosome biogenesis and I established that after infection it switches its activity to become an antiviral effector. The data in this thesis demonstrates the utility of arrayed CRISPR/Cas9 screening to identify new proteins involved in virus infection and how it can be used as a discovery-based platform to further characterise the host-virus arms race
Investigating the molecular basis of sexual differentiation and effects of Wolbachia in Aedes aegypti
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