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Repurposing Alzheimer’s disease medications in a drug combination for the study of the crosstalk between cell apoptosis and autophagy in the modulation of cell death in chronic myeloid leukaemia
Get PDFThe world population is ageing and with this shift is a concurrent rise in comorbidities such as Alzheimer’s disease (AD) and cancer. Interestingly, an increasing number of studies have reported certain AD drugs to possess anti-cancer properties. This raises the possibility of repurposing these AD drugs for the treatment of cancers such as chronic myeloid leukaemia (CML). This requires the understanding of the possible interconnection between CML and AD at the molecular level. The overall aim of this research was to study the crosstalk between cell apoptosis and autophagy in the modulation of cell death and to determine if AD medications, singly and in combination with a CML drug, have the potential to be repurposed for the treatment of CML
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HEK293T (cell model of AD) and K-562 (cell model of CML) cells were individually treated with the test drugs for 24 and 48 h, depending on the assay. Cell viability was assessed by overlaying the treated cells with CyQUANT® Direct assay dye for 40 min before fluorescence signal detection at a wavelength of 485/520 nm excitation/emission. Cell death assay was also conducted using BD FACSCalibur flow cytometer to detect fluorescent emission at 530 nm (FL1), 575 nm (FL3) and excitation wavelength of 488 nm, in Annexin V/PI-stained treated cells. To examine the autophagic and apoptotic effects modulated by the drug treatments, Western blot analyses were carried out and the proteins of interest were quantified using Image Studio software on the Odyssey® Fc LI-COR Imaging System.
The results demonstrated that the chemotherapy drug, Doxorubicin, caused death in both HEK293T and K-562 cells by modulating the apoptotic pathway. In 48 h Doxorubicin (1 μM)-treated K-562 cells, the autophagic proteins, Beclin-1 (p < 0.05) and LC3 (p < 0.001), were also upregulated. With the addition of Chloroquine (10 μM), a known autophagy inhibitor, these autophagic activities were verified as being involved in the induction of cell death in the CML cells. When Imatinib (1 μM), a known tyrosine kinase inhibitor, was used in the treatment of CML K562 cells, it was shown to also induce apoptotic cell death effect but without the involvement of the Beclin-1-induced autophagy pathway. Therapeutically relevant but low concentrations (1, 5 and 10 μM) of Memantine and Donepezil (AD drugs) were shown to be non-toxic in this study, as they induced no measurable cell death in both cell lines tested, with Memantine (1 μM) increasing the viability of HEK293T (the AD cell model) by 41% (p < 0.05). Following the results of the preliminary study, further investigations were carried out employing the combination of Doxorubicin (1 μM) and Memantine (1 μM) to determine if the Doxorubicin-killing effect in the CML cells can be enhanced while mitigating its adverse effects in HEK293T non-cancer cells. For the first time, we report herein the apoptotic and autophagic effects of Doxorubicin and Memantine as a combination drug in K-562 and HEK293T cells. The presence of Memantine in the combination induced an increase in the levels of anti-apoptotic Bcl-2 proteins in the non-cancerous HEK293T cells (p = 0.001), but not in K-562 cells. Also, the autophagy-mediated cell death pathway initially induced by Doxorubicin in K-562 cells was maintained in the Doxorubicin/Memantine (1 μM)-treated CML cells.
The findings from this study indicated that the AD drug, Memantine, could modulate the apoptotic pathway to reduce the Doxorubicin-induced death effect in the non-cancerous HEK293T cells without suppressing its killing effect in the K-562 CML cells. Further studies (in vitro and in vivo) are warranted to help develop this therapeutic strategy that offers non-cancer cell protection while simultaneously providing therapeutic benefits against the cancer cell population in AD and CML co-morbidity
Enactive Agnosis: The playful use of form as a bodily activity of (not) knowing
Get PDFThis is an action research inquiry that takes place within the National Health Service in the UK. I am an NHS consultant, working primarily clinically, who has been involved and interested in change and improvement since 2010. I embarked on this doctorate with the intention of knowing how to do change better, to enhance the impact of conversations about change, and to undertake second-person action research that would impact on how we improve care in the NHS.
Early in the doctorate a move of cities and organisations revealed the challenge of context and how it shapes and constrains any possible inquiry. COVID-19 was then added into the mix a couple of years later and what emerged in response was first-person inquiry into my own epistemology. An exploration that resulted in a markedly altered understanding of ‘knowing’ and ‘not-knowing’ or perhaps more appropriately ‘not-knowledging’ and a focus on methodology.
This thesis is about coming to recognise the challenge and importance of ‘not-knowing’ in the context of change and healthcare, the importance of physicality and metaphor, of knowing versus knowledge, of playfulness as a mindset and of a pragmatic, realistic ‘ish’ positioning. About weaving these ideas into the overarching concept of enactive agnosis.
Enactive agnosis is offered as a methodology and a mindset in the realms of action research, arts-based research and healthcare change. A pragmatic, realistic, playful approach that recognises, enables and enacts ‘not-knowing’ and ‘good enough’ within the context of inquiry and change. A process of bodily active metaphorical knowing that holds and values the space of not-knowledging long enough to make sense differently, to know, to change
Ethical conflicts among physicians and nurses during the COVID‐19 pandemic: a qualitative study
Get PDFRationale, Aims and Objectives
The healthcare system and professionals working in the sector have experienced a high caseload during the coronavirus disease 2019 (COVID-19) pandemic. This has increased the potential for morally harmful events that violate professionals' moral codes and values. The aim of this study was to understand and explore experiences of new moral challenges emerging among physicians and nurses caring for individuals during the COVID-19 pandemic.
Method
The consolidated criteria for reporting qualitative research (COREQ) checklist was used in this qualitative study based on Gadamer's phenomenology. Participants were selected using a convenience sampling method. Thirteen medicine and nursing graduates were interviewed in depth. The participants all worked on the frontline at the start of the COVID-19 pandemic. Data were gathered in two basic healthcare districts in Spain, encompassing both primary care and hospital care.
Results
Four main themes emerged from the data analysis: (1) Betrayal of moral and ethical values as a key source of suffering; (2) Ethical and moral sense of failure accompanying loss of meaning; (3) Lack of confidence in performance; (4) Self-demand and self-punishment as personal condemnation among healthcare workers.
Conclusions
Health institutions must implement interventions for health professionals to help mitigate the consequences of experiencing complex ethical scenarios during the pandemic. In addition, they should promote training in moral and ethical deliberation and prepare them to make decisions of great ethical significance
The role of subsidiaries in Global Value Chains (GVCs): an institutional voids perspective on LVC upgrading and integration
Get PDFWe explore the process through which MNE subsidiaries engage and retain a critical mass of small suppliers in Global Value Chains (GVCs) while addressing institutional voids in emerging markets. Using evidence from an interpretive inductive longitudinal case study in agribusiness, we draw on the GVC and institutional voids literatures to: (1) extend the GVC literature by offering a subsidiary-focused view of GVCs; and (2) demonstrate the dynamic process of void engagement through complementary institutional bridging activities. Our temporal sequencing of subsidiary institutional agency in response to different modalities of voids demonstrates a constellation of bridging activities that results from a dynamic interplay between voids and practice
A novel technology of solarization and phytoremediation enhanced with biosurfactant for the sustainable treatment of PAH‑contaminated soil
Get PDFHydrocarbon-contaminated land has been a significant issue throughout Nigeria’s Niger Delta since the discovery of crude oil in 1956. This paper proposes a novel and sustainable technique involving soil solarization, phytoremediation and biosurfactant to treat polycyclic aromatic hydrocarbon (PAH) contamination. The treatment effect on PAH reduction, plant growth, rhizosphere microorganisms and their enzymatic activities were evaluated. Twenty-eight days of solarization was carried out before the introduction of Chromolaena odorata seedlings for an 84-day phytoremediation period using a 4 x 4 (vegetated) and 2 x 4 (non-vegetated) cell microcosms to simulate the Niger Delta’s sub-tropical conditions. Soil solarization resulted in significant PAH reduction (p≤0.01) of phenanthrene, fluoranthene and benzo(a)pyrene with means reduction of 60.0 %, 38.7 % and 36.1 % compared to their non-solarized counterparts with 18.0 %, 18.0 % and 18.8 % at 95 % CI (32.7, 51.3), (15.4, 26.1) and (8.0, 26.6) respectively. In post-solarization, all solarized and vegetated treatment groups significantly reduced (p≤0.01) PAHs compared to their respective counterparts, whilst biosurfactant contribution in this combination was negligible (p≥0.05). The growth parameters of C. odorata, total soil/rhizosphere heterotrophic microorganisms and their enzymatic activities of dehydrogenase and urease increased in all solarized treatments indicating essential biochemical processes. The novel and successful integration of soil solarization and phytoremediation using indigenous C. odorata as a combined technique to treat even the most recalcitrant form of hydrocarbons (PAHs) brings up new opportunities for a sustainable method of cleaning up contaminated land in Nigeria's oil-rich Niger Delta
Beyond the stomp: the Nobbs Suzuki Praxis as an Australian variant of the Suzuki method of actor training
Get PDFThis article provides a brief overview of the Nobbs Suzuki Praxis (NSP), an Australian variant of the Suzuki Method of Actor Training (SMAT) developed by John Nobbs in collaboration with Jacqui Carroll from the mid-1990s onwards. After a brief introduction to SMAT and the context in which NSP evolved from it, the article outlines NSP’s key differences in exercise practice and design, particularly in the use of signature physical and vocal tools, and the increased use of structured improvisation within NSP formats. It goes on to examine two concepts specific to NSP—‘feeling’ and ‘opposites and paradox’—and outlines how these enable advanced engagement with the training, especially the cultivation of a heightened awareness of self and the performance environment. The article concludes (with reference to Crothers [2021]) by suggesting that NSP adds softness to and is a more playful version of SMAT. By providing room for invention and creativity, NSP embeds creative application of SMAT’s principles within the training itself, rather than seeing it as part of a separate rehearsal process
Exploring British and Finnish preregistration nursing students’ experiences of learning emergency and acute care nursing through a collaborative online international (COIL) classroom
Get PDFBackground: This case study describes the development and evaluation of a collaborative online international learning (COIL) nursing collaboration between Finland and UK in ‘Care of the Acutely Ill Patient’. Aim: The aim was to plan and deliver an online programme of learning experiences on a shared rofessional subject with mixedinternational students, then evaluate this learning experience with a view to expanding or extending it in future as a core element of our nursing programmes. Method: A steering group led the design format of this short course, aligning it to each university’s curriculum and professional goals. Then, a teaching team devised the learning materials and learning sessions. Finally, the steering group evaluated the course. In total there were 38 student participants (Finland n=21, UK n=17). Results: 80 per cent (n= 20) of students felt that their understanding of the subject had increased as a result of taking the course. In total 64 per cent (n=16) felt that the course had enabled them to gain skills to help their future career development. Perceptions of working in mixed international groups was diverse, with challenges of communication, time and perceptions of what constituted ‘group work’ between UK and Finnish students. Learning new nursing aspects from teachers and peers as well as sharing ideas from another country in a novel way was perceived as beneficial and overall ‘uplifting’. Conclusion: This COIL has significant strengths but also some challenges. The outcomes of this case study point to its potential and value within nursing and other professional programmes
Fusion of colour contrasted images for early detection of oesophageal squamous cell dysplasia from endoscopic videos in real time
Get PDFStandard white light (WL) endoscopy often misses precancerous oesophageal changes due to their only subtle differences to the surrounding normal mucosa. While deep learning (DL) based decision support systems benefit to a large extent, they face two challenges, which are limited annotated data sets and insufficient generalisation. This paper aims to fuse a DL system with human perception by exploiting computational enhancement of colour contrast. Instead of employing conventional data augmentation techniques by alternating RGB values of an image, this study employs a human colour appearance model, CIECAM, to enhance the colours of an image. When testing on a frame of endoscopic videos, the developed system firstly generates its contrast-enhanced image, then processes both original and enhanced images one after another to create initial segmentation masks. Finally, fusion takes place on the assembled list of masks obtained from both images to determine the finishing bounding boxes, segments and class labels that are rendered on the original video frame, through the application of non-maxima suppression technique (NMS). This deep learning system is built upon real-time instance segmentation network Yolact. In comparison with the same system without fusion, the sensitivity and specificity for detecting early stage of oesophagus cancer, i.e. low-grade dysplasia (LGD) increased from 75% and 88% to 83% and 97%, respectively. The video processing/play back speed is 33.46 frames per second. The main contribution includes alleviation of data source dependency of existing deep learning systems and the fusion of human perception for data augmentation
Enhancing depositor protection in the mobile money banking sector in sub-Saharan African developing economies – a case for ring-fencing?
Get PDFThis paper analyses the need for enhanced statutory depositor protection in the mobile money/mobile banking sectors, upon banking and corporate insolvency in Sub-Saharan African (SSA) developing economies. The universal banking model, and the concepts of deposit insurance schemes, or deposit guarantee (as is commonly known in the UK/EU) are analysed, their advantages in streamlining depositor protection, and the would be impact in Sub-Saharan African developing economies’ mobile banking sectors are explored. The concepts of ring-fencing and structural separation as conceptual tools that could enhance depositor protection on banking and corporate insolvency in SSA developing economies are examined
International competitiveness readiness, home country institutions, and early internationalisation
Get PDFPurpose (limit 100 words) Synthesising an individual-opportunity nexus model, this research aims to develop a model of early internationalisation by integrating international competitiveness readiness, entrepreneurial motives, and home-country institutions, and empirically assesse this model using a multilevel estimate design. Design/methodology/approach (limit 100 words) Drawing upon a global context comprising 79,402 entrepreneurs from 87 countries, this research applies a Heckman two-step model together with a multilevel approach that allow us to deal with self-selection bias and to take the hierarchical nature of the data into account. Findings (limit 100 words) The findings show that early internationalisation is significantly affected by entrepreneurs' international competitiveness readiness and this association is moderated by entrepreneurial motives. In addition, the findings demonstrate that the individual-level effects are further modified by the quality of country-level governance. Practical implications (limit 100 words) The research findings have significant implications and value for policy-makers who are aiming to stimulate the rate of early internationalisation by influencing the quality of governance. Originality/value (limit 100 words) The results contribute to the development of knowledge and theoretical bases in international entrepreneurship. It provides a multi-level view on the relationships between entrepreneurs and the internationalisation of their firms from an integrative perspective, thereby complementing the perspective of international competitiveness readiness that primarily focuses on the effects of inherent resources and capabilities