Now showing items 21-40 of 1521

    • Characterisation of Cutaneous Wound Healing Process in Naked Mole Rats

      Botchkarev, Vladimir A.; Mardaryev, Andrei N.; Fessing, Michael Y.; Poterlowicz, Krzysztof; Fatima, Iqra (University of BradfordSchool of Chemistry and Biosciences. Faculty of Life Sciences, 2022)
      Being the longest-lived rodent, naked mole-rats (NMR; Heterocephalus glaber) are an exceptional model for biogerontological research. However, unlike other rodents, not much is known about their wound healing process. To investigate that, full-thickness wounds were created in the back skin of naked mole rats. Our initial data confirmed that wound closure in NMR skin was achieved primarily by reepithelialization and granulation tissue formation, with only ~26% wound contraction, making them an excellent model to study human cutaneous wound healing. Similar to mice and human skin, changes in wound epithelial tongue included progressive enlargement of wound epithelium, increased proliferation and changes in the expression pattern of epidermal markers including K14, K17, integrin α6 and E-cadherin. Further analysis revealed characteristics of reduced scarring in NMR wounds including low collagen I to III ratio, increased HA expression (HMW) and increased fibronectin expression. Transcriptional profiling of TGFβ isoforms and different pro/anti-inflammatory cytokines revealed a balance in the expression and repression of different cytokines, potentially contributing into reduced scarring. Comparison of RNA-seq data from NMR and human fullthickness wounds revealed a delay in the activation of important biological processes and pathways in NMR skin in response to injury. Further analysis based on cultured human and NMR cells revealed differential regulation of TGFβ signalling pathway between both species. 3-D collagen gel contraction assay revealed that NMR fibroblast showed noticeable contraction but independently of TGFβ treatment, while human fibroblast showed marked increased in gel contraction in the presence of TGFβ. In conclusion, NMR can serve as a very useful model to study human cutaneous wound healing. The reduced scarring in NMR could be a result of multiple factors including HMW-HA, balanced cytokine expression and differential regulation of different TGFβ cytokines as observed in the in vitro studies.
    • Designing and Building a Novel Magnetic Heating System to Investigate the Dependence of the Magnetic System and the Optical Emission from Nanoparticles

      Drake, Philip; Swift, Thomas; Abd-Alhameed, Raed; Algaddafi, Ali E. (University of BradfordSchool of Chemistry and Biosciences. Faculty of Life Sciences, 2022)
      A Magnetic Heating Coil (MHC) has been designed, which has the potential to interact with magnetic Nanoparticles (NPs) to produce local temperature changes. The aim is to design a device capable of studying medically targeted magnetic-fluorescent core-shell NPs (with potential applications in cancer therapy via hyperthermia). Very little is known about how the magnetic-fluorescent NPs respond to magnetic fields and the effect this would have on their optical properties, therefore, considerable work is still required in order to understand the detailed interactions. Several modelling and simulations of the MHC were conducted besides developing the MHC that was designed and built for small samples of NPs (1-10ml volumes). Two different heating coil geometries were examined (coil A and coil B), where the former operates at 83 kHz and the latter operates at 125 kHz. Several tests for fluorescent emission, lifetime and anisotropy with several different NPs samples were conducted. We found that as the temperature increased from 5 °C to 45 °C, the fluorescence lifetime dropped from 3.8 ns to 3.6 ns. Also, the correlation time of the fluorescence in dilute solutions with varying temperatures from 20 °C to 40 °C was investigated, and it was found that decreased from 0.9 ns to 0.6 ns showing that the rotational diffusion of the dye increased and the molecules become more mobile. The MNPs were found to quench the fluorescent emission at high concentrations. Also, the MNPs induce only a small change in a lifetime from 3.9 ns to 3.4 ns.
    • A Strategic Public Diplomacy Framework for Enhancing Implementation of Public Diplomacy Practice in the Diplomatic Field of Qatar

      Shahi, Afshin; Alhamar, Nasser A.J. (University of BradfordFaculty of Management, Law and Social Sciences, 2023)
      The role of Public Diplomacy (PD) in conducting foreign relations has emerged as a critical component for modern statecraft, foreign policy and arguably for the state’s global existence. With the world now more interconnected than ever before, public diplomacy has taken on new meaning and new importance. However, despite these marked shifts, public diplomacy remains under-researched and under-utilised both as a concept and as a vital activity. The complexities that underscore the development and evolution of public diplomacy within a dynamic international milieu therefore warrant renewed attention. The benefits and opportunities that accompany public diplomacy are equally complicated by a number of challenges to its practice. This research identifies and advances a critical understanding of public diplomacy through a theoretically rigorous perspective that accounts for the fluid environment in which it operates, the evolving nature of stakeholders and audiences involved in shaping it, the sweeping impact of global information and communications development, the persistence of cultural divides and conflicts of interests and how they contribute to the lack of strategic frameworks in place to advance public diplomacy practice. This thesis investigates Qatar as a case study due to its international stature and influence despite it being a small geographical state. Renowned for its international role as a leading actor in conflict reconciliation and commended for its contributions to international humanitarianism, the ambitious, forward-looking and steadfast foreign policy of Qatar has faced increased pressure in recent years. Qatar has encountered significant challenges in the form of the Nepali workers’ crisis that ensued following its selection as host for FIFA World Cup 2022 and with the diplomatic siege against it by a number of Gulf Cooperation Council (GCC) states. This study critically analyses Qatar’s public diplomacy practice considering these pressing developments and advances an original strategic public diplomacy framework that can assist Qatar in managing and mitigating the effect of these crises on its global image and reputation. This research contributes to enhancing public diplomacy practice within the diplomatic context of statecraft and foreign policy by developing a nuanced and original framework that can be utilised by Qatar and other states to manage and mitigate modern public diplomacy challenges. The thesis utilises a mixed-methods research approach that includes literature reviews, media analyses, interviews and questionnaires. The study contributes to knowledge and practice by advancing research in an understudied field and by developing and implementing an original strategic PD empowerment framework.
    • The development and validation of a brand-building framework for platform-centric startups

      Ismagilova, Elvira; Weerakkody, Vishanth J.P.; Roshanzamir, Amir H. (University of BradfordSchool of Management. Faculty of Management, Law, and Social Sciences, 2022)
      Platform-centric startups that generate value by facilitating interactions between two or more interdependent groups digitally transform and disrupt the business environment, leading to significant changes in how people purchase, sell, communicate, and even live. Some of these, such as Uber and Airbnb, have become among the most beloved and successful brands, though they had serious challenges in building up their brands at the early stages due to lack of resources. The purpose of this dissertation is to develop a framework of branding in platform-centric startups by identifying the pillars of brand‐building and linking the relevant factors. This study employs qualitative method to propose a four-level framework including passion, innovation, co-creation, and moralization for brand-building in startups. The novelty of this framework reveals that the locus of brand-building is gradually expanding from the founders to the company, then to the customers, and finally to a larger societal constituency. The framework can assist founders and stakeholders in monitoring the growth of a new venture in the real business world while guiding branding scholars to investigate the discipline of startup branding.
    • Competence and Professional Advancement in Computed Tomography (ComPACT)

      Hardy, Maryann L.; Scally, Andy J.; Harris, Martine A. (University of BradfordFaculty of Health Studies, 2022)
      Background: Evolving technology, practice boundaries, and models of service provision have changed what the diagnostic radiography workforce in Computed Tomography (CT) need to know and be able to do at different career stages. It is unknown whether existing UK educational and practice frameworks support CT roles, or how organisational role descriptors constitute CT competence. Aims: The study explores multiple stakeholder perspectives of competent practice in diagnostic radiography and CT using this information to generate and gain consensus on novel modality-specific skills for the four-tier radiography structure. Methods: Study 1: Document analysis of published UK educational and practice frameworks using content and framework analysis. Study 2: Document analysis of UK CT role descriptors using a context analytical approach. Study 3: Modified e-Delphi study to gain consensus on novel technical and clinical CT practice competencies. Results: Existing radiography competencies were classified into 3 themes: delivering person-centred care; applying technical principles, quality and efficiency; and ensuring best practice. Generic competencies endorsed by professional and regulatory bodies were not consistently replicated within organisational role descriptors. CT practice expectations are ambiguous and modified from radiographic competencies. Modified e-Delphi panellists provided judgement on 215 practice competencies and advanced capabilities which have been refined and organised into a coherent framework. Conclusions: The ComPACT framework formalises the tacit technical knowledge, clinical competencies and professional capabilities that specifically address the practice area of CT. Further work is required to validate the framework and define educational standards, but there is potential to influence future graduates, workforce development and national standards.
    • The role of CCR7 axis in facilitating chemoresistance, radioresistance and induction of cell proliferation in cancer

      Afarinkia, Kamyar; Vinader, Victoria; Shnyder, Steven; Salem, Anwar S.A.S. (University of BradfordInstitute of Cancer Therapeutics. School of Pharmacy. Faculty of Life Sciences, 2021)
      Chemokines are a family of chemotactic cytokines that play a multifaceted role in human biology. Chemokine receptor CCR7, activated by its ligands CCL19 & CCL21, is known to play a significant role in cancer metastasis. In view of the wider roles that chemokines play in the biology of the cell, we hypothesised that CCR7 could influence cancer progression through other mechanisms in particular increased proliferation and/or increased chemo- and radioresistance, and whether these effects may have a physiological/clinical relevance. Interestingly, CXCR4 involvement in cancer recurrence, metastasis and proliferation is already well established. Thus, it was used as a point of reference to compare whether CCR7 axis effect on cancer proliferation and chemoresistance is similar to that observed in CXCR4 axis. It is proven that hypoxia is a driving factor in increased CCR7 expression. This study shows that CCR7 expression is upregulated as a response to a number of other stress factors, in particular that caused by different chemotherapeutic treatments. In addition, we showed that CCL21, one of the two endogenous ligands for CCR7 is similarly produced under these conditions We used several techniques to establish the expression and functionality of CCR7 and CXCR4 in different cancer cell lines. We then showed that activation of the CCR7 axis by physiologically relevant concentrations of CCL21 induces cancer cell proliferation and chemo- and radio-resistance. Furthermore, these effects are abrogated by small molecule antagonists (ICT13069), neutralizing monoclonal antibody, or CCR7 knockdown. Our findings support the hypothesis that antagonising CCR7 receptor will not only inhibit cancer metastasis, as it is well-illustrated in the literature, but it would also lead to alternative therapeutic approaches as well as potential clinical endpoints.
    • Synthesis and biological evaluation of MMP-activated anti-cancer prodrugs

      Falconer, Robert A.; Loadman, Paul; Banisalman, Katreen A.F. (University of BradfordFaculty of Life Sciences, 2021)
    • Food Waste Reduction through Food Sharing Initiatives: The lived Experiences of Restaurants and Food Bank Employees in Riyadh

      Sharif, Amir M.; Sivarajah, Uthayasankar; Eldabi, Tillal; Abdur-Rahim, Abdulwasih I. (University of BradfordSchool of Management. Faculty of Management, Law, and Social Sciences, 2023)
      Today’s world is characterised by considerable inconsistency. In some parts of the world people are living in starvation and malnutrition, while in some other parts of the same world, about 1.3 billion tons of food is wasted every year. We do not know enough about what contributes to food waste. However, there seems to be an emergent pattern of behaviour around sharing food. This hermeneutic phenomenological research will explore how food sharing might reduce food waste in a cultural and community-based society like Saudi Arabia through the lived experiences of restaurants and food bank employees. Research data were collected through a face-to-face semi-structured interview method from 15 participants from selected restaurants and food bank in Riyadh. Using the theory of planned behaviour (TPB) as the theoretical lens, a conceptual framework was proposed to elicit underlying behavioural and cultural factors impeding food waste reduction and the inefficiency of food sharing. Using Paul Colaizzi’s approach, the collected interview data were reviewed, analysed, and seventeen themes were elicited for further discussion. The findings suggest that culture through an affluent way of life and the show-off lifestyle of hosts continue to contribute to more food wastage. The strictly business nature of restaurants operation leads to edible food fit for human consumption ending up in the garbage. The revised conceptual framework provides insight into the factors hindering food waste reduction and food sharing. With supporting regulations and policies, food leftovers can either be distributed to people in need or put to an alternative use.
    • Application of Hansen Solubility Parameters and Thermomechanical Techniques to the Prediction of Miscibility of Amorphous Solid Dispersion. Investigating the role of cohesive energy and free volume to predict phase separation kinetics in hot-melt extruded amorphous solid dispersion using dynamic mechanical analyser, shear rheometer and solubility parameters data

      Isreb, Mohammad; Gough, Timothy D.; Timmins, Peter; Mousa, Mohamad A.M.R. (University of BradfordSchool of Pharmacy. Faculty of Life Sciences, 2022)
      Hot-melt extruded solid dispersion technique is increasingly employed to improve the solubility of poorly water-soluble drugs. The technique relies on the enhanced solubility of the amorphous form of the drug compared to its crystalline counterpart. These systems however are thermodynamically unstable. This means that the drug crystallises with time. Therefore, efforts to measure the stability of these systems over the life span of the product are crucial. This study focused on investigating the use of Hansen Solubility Parameters to quantify polymer-drug interaction and to predict the stability of solid dispersions. This was achieved through a systematic review of hot-melt extruded solid dispersion literature. The study also investigated the use of a combined mechanical and rheological model to characterise the physicochemical and release behaviour of three solid dispersion immediately after preparation and after storage for one month at 40oC or three months at room temperature. Results revealed that the total solubility parameter |ΔбT| was able to predict the stability of the systems for more than 4 months using a cut-off point of 3 MPa-1 with a negative predictive value of 0.9. This was followed by ΔбD with a cut-off point of 1.5 MPa- 1. Moreover, Dynamic Mechanical Analyser and shear rheometry data were shown to be more sensitive than Differential Scanning Calorimetry, Powder X-Ray Diffraction, Scanning Electron Microscope and Fourier Transform Infrared in detecting crystallisation and the interaction between the drug and the polymer. The Dynamic Mechanical Analyser data were consistent with the dissolution behaviour of the samples when comparing the freshly prepared samples with those after storage. The results highlight the need for a unified characterisation approach and the necessity of verifying the homogeneity of mixing during the extrusion process.
    • Study of the Continuous Intention to use Artificial Intelligence Based Internet of Medical Things (IoMT) During Concurrent Diffusion. The Influence Diffusion of Innovation Factors Has as Determinants of Continuous Intention to Use Ai-Based IoMT

      Weerakkody, Vishanth J.P.; Sivarajah, Uthayasankar; Aldhaen, Fatema S.F.A. (University of BradfordFaculty of Management, Law and Social Sciences, 2022)
      This research was about the continuous intention of healthcare professionals to use internet of medical things (IoMT) embedded with artificial intelligence (AI). IoMT and AI are evolving innovations and diffusing at the same time. It was not known in what way the two complex technologies diffusing concurrently could influence continuous intention to use IoMT. In addition, behavioural aspects namely motivation and training to use IoMT have been argued to intervene in the relationship between an AI based IoMT and continuous intention to use IoMT. Diffusion of Innovation theory was applied to explain the relationship between diffusion factors that aid the diffusion of AI based IoMT and continuous intention to use IoMT. The five factors relative advantage, compatibility, complexity, observability and trialability were chosen as determinants of continuous intention to use IoMT using DoI theory. Self-determination theory and theory of planned behaviour were used to introduce the interventions in the relationship between diffusion factors and continuous intention to use IoMT. UTAUT was used to explain the influence of the moderators artificial intelligence awareness, novelty seeking behaviour and age of healthcare professionals. The central issue investigated was the determinants of continuous intention of healthcare professionals to use IoMT with behavioural attributes of motivation and training conceived as mediators of the relationship between diffusion factors and continuous intention to use IoMT in the presence of moderators. Quantitative research methodology was used to test the research model developed to understand the relationship between the five diffusion of innovation theory factors and continuous intention to use IoMT when AI based IoMT is still diffusing. The concurrent diffusion of two new technologies was investigated using a research model that was developed for studying the healthcare professionals and their intention. The research was conducted in Bahrain in the healthcare sector. A sample of 354 healthcare professionals participated in the research. Structural equation modelling was used to analyse the data and test the hypothesis. The research showed that healthcare professionals will continue to use concurrently diffusing technologies depending on the relative advantage, complexity and compatibility of the innovations that diffuse. In addition, the results show that healthcare professionals will be motivated by the compatibility of AI-based IoMT if they have to continuously use IoMT. Furthermore, training enables both the organization and the healthcare professionals to overcome dilemma in case they have to continue to use an innovation during its diffusion or when new innovation surface in the market. Finally, artificial intelligence awareness is able to moderate the relationship between relative advantage, complexity and training to use IoMT. Thus, this research contributes to the discipline of behavioural intention of healthcare professionals in determining the influence of an artificial intelligence based IoMT on continuous intention to use IoMT when artificial intelligence embedded in IoMT diffuses concurrently with IoMT. Where IoMT diffusion factors can be used as a determine of continuous intention to use IoMT, artificial intelligence could be understood as a moderator of the relationship between diffusion factors and training to use IoMT, thus demonstrating the combined diffusion of the two technologies diffusing concurrently.
    • Self-Congruity Theory: An Investigation of the Pro-Environmental Tourist Behaviours. An Application and Extension of Self-Congruity Theory of the Eco-Tourism Destinations in Pakistan and UK

      Trivedi, Rohit; Waseem, Donia; Amin, Obaidullah (University of BradfordSchool of Management. Faculty of Management, Law and Social Sciences, 2023)
    • Investigation to Identify the Influence of the Surface Energetics of the Dry Powder Formulations of Budesonide and Theophylline on Their Aerodynamic Dose Emission Characteristics.

      Assi, Khaled H.; Vangala, Venu R.; Jamal, Abdullateef J.A.M.A. (University of BradfordSchool of Pharmacy. Faculty of Life Sciences, 2022)
      Surface energetics play a key role in the delivery of a dry powder inhaler formulation into the lungs, as there must be a sufficient balance of adhesive and cohesive forces to allow optimal lung delivery. In this study, measuring the surface energies of a set of single drug and carrier (budesonide or theophylline with either mannitol or lactose) with different levels of surfactant using Inverse Gas Chromatography, and comparing them to their lung deposition performance using a Next Generation Impactor established a relationship between the two. A 1:10 mixing ratio of budesonide with either carrier was found to have the highest FPF. Coating the carriers with 0.05% sodium lauryl sulphate resulted in a further increase in the FPF when using either budesonide or theophylline as the API, and the same results were seen when a sonocrystallised version of the API was substituted for the micronised form. The calculated IGC values then showed that the highest performing formulations had the lowest dispersive energy and total free surface energy. Furthermore, a trend was observed in the work of adhesion (Wa) and work of cohesion (Wc) for each set of formulations depending on which API was chosen, where for the less polar drug (budesonide) a higher Wa/Wc ratio was associated with the highest formulation performance, and for the more polar drug (theophylline) a smaller Wa/Wc ratio was associated with the highest formulation performance, enabling the estimation of lung performance for a set of single drug and carrier using their surface energy data.
    • An Evaluation of Technological, Organizational and Environmental Determinants of Emerging Technologies Adoption Driving SMEs’ Competitive Advantage

      Sivarajah, Uthayasankar; Rana, Nripendra P.; Vincent, Charles; Dobre, Marius (University of BradfordSchool of Management. Faculty of Management, Law, and Social Sciences, 2022)
      This research evaluates the technological, organizational, and environmental determinants of emerging technologies adoption represented by Artificial Intelligence (AI) and Internet of Things (IoT) driving SMEs’ competitive advantage within a resource-based view (RBV) theoretical approach supported by the technological-organizational-environmental (TOE)-framework setting. Current literature on SMEs competitive advantage as outcome of emerging technologies in the technological, organisational, and environmental contexts presents models focused on these contexts individual components. There are no models in the literature to represent the TOE framework as an integrated structure with gradual levels of complexity, allowing for incremental evaluation of the business context in support of decision making towards emerging technologies adoption supporting the firm competitive advantage. This research gap is addressed with the introduction of a new concept, the IT resource-based renewal, underpinned by the RBV, and supported by the TOE framework for providing a holistic understanding of the SMEs strategic renewal decision through information technology. This is achieved through a complex measurement model with four level constructs, leading into a parsimonious structural model that evaluates the relationships between IT resource-based renewal, and emerging technologies adoption driving SMEs competitive advantage. The model confirms the positive association between the IT resource-based renewal and emerging technologies adoption, and between the IT resource-based renewal and SME competitive advantage for the SMEs managers model, with the SME owners model outcomes are found not being supportive towards emerging technologies adoption driving SME competitive advantage. As methodology, PLS-SEM is used for its capabilities of assessing complex paths among model variables. Analysis is done on three models, one for the full sample, with two subsequent ones for owners and managers, respectively, as SME decision makers, with data collected using a web-based survey in Canada, the UK, and the US, that has provided 510 usable answers. This research has a theoretical contribution represented by the introduction of the IT resource-based renewal concept, that integrates the RBV perspective and the TOE framework for supporting organization’s decision on emerging technologies adoption driving SMEs competitive advantage. As practical implications, this thesis provides SMEs with a reference framework on adopting emerging technologies, offering SME managers and owners a comprehensive model of hierarchical factors contributing to SMEs competitive advantage acquired as outcome of AI and IoT adoption. This research makes an original contribution to the enterprise management, information systems adoption, and SME competitive advantage literature, with an empirical approach that verifies a model of emerging technologies adoption determinants driving SMEs competitive advantage.
    • Historic settlement on Unst, Shetland. An holistic study of abandoned settlements on Unst, Shetland utilising historical archaeology and prospection approaches

      Bond, Julie M.; Gaffney, Christopher F.; Heron, Carl P.; Legg, Robert M. (University of BradfordSchool of Archaeological and Forensic Sciences. Faculty of Life Sciences, 2018)
      A holistic study of abandoned house sites on the island of Unst was conducted to address the extent to which perceptions of historic settlement on Shetland are supportable. These perceptions cast long lived nucleated settlement as the normative traditional form of historic settlement, and dispersed settlements as short-lived exceptions to this norm. Historic settlement, in these perceptions are argued to be static, which is not borne out in archaeological evidence. Issues associated with historic Shetland settlement models were identified to parallel traditional views of Scottish highland rural settlement, which cast the highland society as ahistoric and unchanging. Historical, archaeological and geographic evidence for settlement on Unst were used to assess the geographical distribution of historic settlement on the island. Two detailed case studies integrated archaeological prospection techniques with the historical, archaeological and landscape contexts to form new narratives for the field remains around two abandoned house sites. Assessment of the historical settlement of Unst highlighted a much greater degree of variation between the different evidence strands for the perceptions to truly represent the island’s historical settlement. Similarly, findings from the case studies highlighted a much greater degree of alterations to the field systems and enclosures associated with the settlements than would be anticipated. Alternative narratives with several phases were hypothesised for field remains of each case study.
    • The therapeutic/anti-carcinogenic effect of cord blood stem cells-derived exosomes in malignant melanoma

      Najafzadeh, Mojgan; Anderson, Diana; Isreb, Mohammad; Baumgartner, Adolf; Wright, Andrew; Naeem, Parisa (University of BradfordFaculty of Life Sciences, 2022)
      Malignant melanoma is an invasive type of skin cancer with high mortality rates, if not detected promptly. The mortality trends are generally linked to multiple dysplastic nevi, positive family history, genetic susceptibility and phenotypic features including fair skin, freckles, numerous atypical nevi, light coloured hair and eyes, inability to tan and prolonged exposure to ultraviolet radiation B (UVB). To date, the major anti-cancer therapeutics for melanoma include surgery, chemotherapy, radiotherapy, and immunotherapy. Recently, extracellular vesicles, especially exosomes, have been highlighted for their therapeutic benefits in numerous chronic diseases such as cancer. Exosomes display multifunctional properties, including inhibition of cancer cell proliferation and initiation of apoptosis. Hence, this study aimed to evaluate the genotoxicity and cytotoxicity of cord blood stem cell-derived (CBSC) exosomes on 6 samples of peripheral blood lymphocytes taken from healthy individuals and melanoma patients and on 3 samples of melanoma (CHL-1) cells. The limited number of samples was due to the time limitations and restrictions that were in place due to the COVID-19 pandemic. In this in vitro study, the optimal concentration of CBSC-derived exosomes (0, 100, 200, 300, 400 μg/ml protein at 24, 48 and 72h treatments) was confirmed by the CCK-8 assay. CBSC exosomes (300 μg/ml) were used to treat lymphocytes and CHL-1 cells in the Comet assay and evaluated using the real-time polymerase chain reaction (qPCR) and Western blotting (WB). The data of the CCK-8 and Comet assays illustrated that exosomes exerted genotoxic effects on CHL-1 cells (CCK-8 assay, ****p < 0.0001), (Comet assay, *p <0.05, **p < 0.01). However, the data portraying a reduction in the viability of lymphocytes needs further investigation as the number of samples was limited, therefore, further clarification is required. Importantly, no significant adverse effect was observed in healthy lymphocytes when treated with the same exosomes (p = ns). When further challenged with UVA+B radiation, the exosomes did not induce any genoprotective effect on ROS-induced CHL-1 cells, compared to the positive control (p = ns). Our data insinuates that the damage might be caused by inducing apoptosis. The anti-tumourigenic potential of exosomes was observed by activating the p53-mediated apoptotic pathway in CHL-1 cells, up-regulating p53, p21 and caspase 3 and down-regulating BCL-2 at mRNA (**p < 0.01, ***p <0.001, ****p <0.0001) and protein levels (*p < 0.05, **p <0.01). The potency of CBSC exosomes in inhibiting cancer progression in CHL-1 cells whilst causing no harm to the healthy lymphocytes makes it an ideal potential candidate for anti-cancer therapy. More samples are required to evaluate the therapeutic effect of exosomes on lymphocytes from cancer patients to fully understand their mechanism of action.
    • Fabrication Characterisation and Optimisation of Electrospun Scaffolds for Ligament Tissue Reconstruction. The Development of an Anterior Cruciate Ligament (ACL) Analogue using Electrospun PCL, PVA Hydrogel and Polyester Sutures

      Sefat, Farshid; Twigg, Peter C.; Agbabiaka, Oluwadamilola A. (University of BradfordSchool of Biomedical and Electronics Engineering. Faculty of Engineering and Informatics, 2022)
      Year 2019, football, rugby, netball and skiing had most occurring ACL injuries, listed by United Kingdom National Ligament Report (NLR). The standard procedure treatment of complete laceration of the ACL, is performed by tissue autograft implantation designed from a patellar tendon, for replacement of damaged tissue using orthopaedic surgery. The aim of this thesis is to design and fabricate an ACL graft, attempting to mimic the natural ACL, for the purpose of tissue reconstruction. The desired graft analogues exhibited properties imitating native connective tissue, reducing pain through drug delivery with great biocompatibility and enhance suture mechanical strength. Various biomaterials were implemented into this study, utilising strategies; polymer solution fabrication, electrospinning, hydrogel synthesis, mechanical braiding and graft assembly to fabricate an ACL graft. The polymeric material poly (E- caprolactone) (PCL) was researched, utilising its ability to fabricate scaffolds. Results showed, three analogue ACL grafts (Braided PCL-BP, Braided PCL + Hydrogel-BPH & Braided PCL + Sutures-BPS) created utilising the properties of braiding, hydrogels and sutures, ultimately improving the versatility of electrospinning for tissue engineering and reconstruction. Graft analogues were tested and compared against patellar tendons producing similar tensile properties. Poly vinyl alcohol (PVA) hydrogels successfully held ibuprofen, revealing drug delivery characteristics, polyester threads improved mechanical properties of electrospun grafts and dry degradation showed that PCL did not lose significant mass over two months. Conclusion, tensile strength of patella tendon was 395x, 790x & 56x of analogue grafts (BP, BPH & BPS) respectively, having potential for improvement of tensile parameters for ligament reconstruction.
    • Sparse Representation and its Application to Multivariate Time Series Classification

      Lei, Ci; Neagu, Daniel; Sani, Habiba M. (University of BradfordDepartment of Computer Science. Faculty of Engineering and Informatics, 2022)
      In signal processing field, there are various measures that can be employed to analyse and represent the signal in order to obtain meaningful outcome. Sparse representation (SR) has continued to receive great attention as one of the well-known tools in statistical theory which among others, is used to extract specific latent temporal features that can reveal salient primitive and sparsely represented features of complex data signals, including temporal data analysis. Under reasonable conditions, many signals are assumed to be sparse within a domain, such as spatial, time, or timefrequency domain, and this sparse characteristics of such signals can be obtained through the SR. The ECG signal, for instance, is typically a temporal sparse signal, comprises of various periodic activities such as time delay and frequency amplitudes, plus additive noise and possible interference. Particularly challenging in signal processing, especially time series signals is how to reconstruct and extract the various features that characterized the signal. Many problems (e.g., signal components analysis, feature extraction/selection in signals, signal reconstruction, and classification) can be formulated as linear models and solved using the SR technique The reconstruction of signals through SR can offer a rich representation of the sparsified temporal structure of the original signal. Due to its numerous advantages, such as noise tolerance and widespread use in various signal processing tasks, this has motivated many researchers to adopt the use of this technique for various signal representation analysis for a better and richer representation of the original input signal. In line with this, therefore, the goal of this study is to propose a SR-based mathematical framework and a coherence function for reconstruction and feature extraction from signals for subsequent analysis. The time embedding principle was first applied to restructure the signal into tine delay vectors and then the proposed approach, referred to as temporal subsequence SR approach was used to reconstruct the noisy signals and provides a sparsified time dependent input signal representation, and then the coherence function is further used to compute and extract the correlational coefficient quantities between the temporal subsequence signals to form the final feature vectors representing the discriminative features for each of the signal. These final feature vectors representing the signal are further used as inputs to machine learning classifiers. Experiments are carried out to illustrate the usefulness of the proposed methods and to assess their impact on the classification performance of the SVM and MLP classifiers using the popular and widely used ECG time series benchmark dataset. This research study supports the general hypothesis that, signal reconstruction methods (datadriven approach) can be valuable in learning compact features from the original signals for classifications.
    • Towards the development of an integrated case-finding tool to facilitate the review of anticholinergic prescribing for frail older people

      Petty, Duncan R.; Faisal, Muhammad; Johnson, O.A.; Gardner, Peter; Mehdizadeh, David (University of BradfordSchool of Pharmacy and Medical Sciences. Faculty of Life Sciences, 2022)
      Background: The cumulative effect of taking anticholinergic medicines (anticholinergic burden) is associated with adverse outcomes for older people. Prevalence of anticholinergic prescribing is increasing, and there is a need for tools to proactively identify at-risk patients for medication reviews. Aim: To explore the need for, and feasibility of, an integrated case-finding tool that predicts risks using electronic health records (EHRs), facilitating the review of anticholinergic medicines for frail older people. Methods: Mixed methods, adopting a pragmatic approach. A systematic review, prediction modelling of cohort study data, and qualitative interviews were undertaken. Results: The systematic review found anticholinergic exposure was associated with adverse outcomes for the frail; poorer physical function, falls, and mortality, indicating a need for a risk reducing intervention. In the prediction modelling study, predicting risks using composite measures of anticholinergic burden and frailty indicated limited feasibility. Neither enhanced the performance of best subset models using cohort study data. Their predictive utility needs to be investigated using EHR data, to determine their feasibility within primary care. The qualitative study found healthcare professionals needed a proactive tool, supporting risk prediction as a feasible approach. Factors influencing future implementation were; upskilling requirements, deprescribing confidence, patient reluctance, motivation, holistic care, interoperability, trust in risk prediction, remuneration, among other barriers and facilitators. Conclusions: Through identifying a need, and potential feasibility, foundations towards the future developments of a case-finding tool have been provided, informing an early tool prototype (AC-FRAIL). Recommendations for further work suggest a roadmap ahead, to maximise the potential for integrated solutions to proactively reduce anticholinergic risks.
    • Proteomic Investigation of Endocrine Therapy Resistance in Breast Cancer Investigating the Molecular Mechanisms for SERM Resistant Cell Lines Using SILAC-Based Proteomic Approach

      Sutton, Chris W.; Shnyder, Steven; Al-Kabariti, Aya Y. (University of BradfordSchool of Pharmacy. Faculty of Life Sciences, 2022)
      Introduction: Breast cancer is the second highest cause of cancer mortality in women worldwide. Hormonal therapy is considered one of the most effective therapies and is used against luminal-type malignancies. However, 40-50% of tumour cells can develop resistance, thereby limiting the success in breast cancer treatment. In this study, mechanisms of resistance were investigated using a novel multi-stable isotope labelled amino acids (SILAC) proteomics approach in phenotype-specific breast cancer cell lines resistant to endocrine treatment. Method: In vitro chemo-sensitivity (IC50) was determined for MCF7, T47D, MDA-MB-231, MDA-MB-468, MDA-MB-453, BT-20 and MCF-10A breast cell lines using four endocrine-based therapeutic agents (Tamoxifen, 4-Hydroxytamoxifen OHT, Raloxifene, Anastrozole) to select viable strains for resistance studies. MCF7 (luminal-type A) and MDA-MB-231 (triple negative breast cancer, TNBC) were selected and initially subject to OHT or raloxifene exposure with gradual increments for 10 months. WT cells were grown in the absence of drug in parallel as passage controls. Resistant cell lines were assessed by MTT and IF for comparison with parental cell lines. Resistant cell lines, along with the passage control and a SILAC control, were grown in “light” SILAC medium together with WT strains cultured in “heavy” SILAC medium. Proteins were extracted, concentrations determined and analysed by SDS PAGE for quality control. An aliquot of each “light” cell line (resistant, passage control or SILAC control) was combined with an equal amount of “heavy” WT, trypsin digested and analysed by nano-HPLC Orbitrap Fusion mass spectrometry (2D-LC MS/MS). Proteins were identified by database searching using MascotTM. Relative changes (resistant/WT ratio) in protein levels were determined and bioinformatics tools (STRING and UniProt) used to explore significantly changed pathways associated with resistance. Western blotting was used to verify selected target proteins. Results: Four consistently resistant sublines were generated MCF7 OHT Res (2.00-fold more resistant), MCF7 Ralx Res (2.00-fold), MDA-MB-231 OHT Res (1.90-fold change) and MDA-MB-231 Ralx Res (2.00-fold), in addition to two high passage controls. ER expression by IF was decreased in MCF7 OHT Res compared to the WT and MCF7 Ralx Res, whereas CD44 was increased. Proteomic analysis revealed 2247 and 2880 total proteins in MCF7 OHT Res and MCF7 Ralx Res whilst 3471 and 3495 total proteins were identified in MDA-MB-231 OHT Res and MDA-MB-231 Ralx Res, respectively. Bioinformatics tools identified significantly changed pathways included apoptosis, cytoskeleton, cell motility and redox cell homeostasis. Components of the MAPK-signalling cascade were consistently found to be upregulated in resistant cell lines. MAPK1 (ERK2), previously associated with tamoxifen resistance was increased in MDA-MB-231 Ralx Res cell lines by 4.45-fold and confirmed by Western blotting. Sorcin, which contributes to calcium homeostasis and is also linked to multidrug resistance was increased 4.11- and 2.35-fold in MCF7 OHT Res and Ralx Res sub cell lines, respectively. Some results, such as those for c-Jun, were inconsistent between proteomic analysis and Western blotting and require further investigation. Conclusion: The unique resistant cell lines generated here, as well the MCF7 OHT resistant line, provided novel data that give insights into the biological pathways involved in mechanisms of endocrine drug resistance in breast cancer. Proteomics analysis provided extensive data on common functionality and pathways across the resistant cell lines independent of phenotype or SERM. Overall, the results provided interesting targets for re-sensitising resistant breast cancer and the potential to investigate novel combination therapies in the future.
    • Proteomic profiling of matched normal and tumour tongue biopsies from smokers and non-smokers. Oncoproteomic applications for oral tongue squamous cell carcinoma biomarker discovery

      Sutton, Chris W.; Pors, Klaus; Saeed, Sidra (University of BradfordFaculty of Life Sciences. School of Pharmacy, 2021)
      Despite considerable development in the therapeutic repertoire for managing cancer-related malignancies, head and neck cancer mortality has not significantly improved. The burden of HNSCC fluctuates across countries and has been associated with exposure to tobacco-derived carcinogens, excessive alcohol consumption or combinations. Due to late detection, patients often present with oral pre-malignant lesions which have progressed to an advanced stage of HNSCC. In this study, the samples were from a male cohort as generally, men are at two to four-fold higher risk than women with over 90% of HNSCCs arising in the upper aerodigestive tract. Therefore, the purpose of this thesis was to identify HNSCC biomarkers in males associated within defined anatomical region (tongue) and causative agents, specific to smoking. An iTRAQ proteomic approach was used to profile protein changes in matched normal and tumour samples from male non-smoking (n=6) and smoking patients (n=6) with tongue carcinomas revealing identification of potential targets specific to cancer. Samples were subjected to liquid nitrogen cryo-pulverisation and protein determination. Protein extracts from the same category were pooled, trypsin digested and iTRAQ 4-plex labelled. Data was generated by 2D-LC/MS on an Orbitrap Fusion and significantly changed proteins (median ± SD) were subject to bioinformatics appraisal. A total of 3426 proteins were identified and quantified by proteomic analysis. Comparison of non-smoker tumour (NS:T) with smoker tumour (S:T) distinguished 64 proteins that were upregulated and 62 downregulated, S:T vs S:N categorised 349 proteins up- and 395 down-regulated respectively and NS:T vs NS:N identified 469 proteins up- and 431 down-regulated, respectively. Arginase-1 (ARG1), Keratin Type-2 Cytoskeletal 8 (KRT8), Lipocalin-1 (LCN1) and DNA replication licensing factor MCM2 (MCM2) were identified as biologically associated with smoking compared to non-smoking, providing viable targets for verification by immunochemical methods which further supported the proteomic data. Overall, the project demonstrated the importance of using matched biopsies with good clinicopathological data for experimental design and provided a set of unique targets for a more expanded verification study.