Optimisation of immune effector function within the tumour microenvironment

Cancer represents a leading of cause of death in the developed world, inflicting tremendous suffering and plundering billions from health budgets. The traditional treatment approaches of surgery, radiotherapy and chemotherapy have achieved little in terms of cure for this deadly disease. Instead, life is prolonged for many, with dubious quality of life, only for disease to reappear with the inevitable fatal outcome. “Blue sky” thinking is required to tackle this disease and improve outcomes. The realisation and acceptance of the intrinsic role of the immune system in cancer pathogenesis, pathophysiology and treatment represented such a “blue sky” thought. Moreover, the embracement of immunotherapy, the concept of targeting immune cells rather than the tumour cells themselves, represents a paradigm shift in the approach to cancer therapy. The harnessing of immunotherapy demands radical and innovative therapeutic endeavours – endeavours such as gene and cell therapies and RNA interference, which two decades ago existed as mere concepts. This thesis straddles the frontiers of fundamental tumour immunobiology and novel therapeutic discovery, design and delivery. The work undertaken focused on two distinct immune cell populations known to undermine the immune response to cancer – suppressive T cells and macrophages. Novel RNAi mediators were designed, validated and incorporated into clinically relevant gene therapy vectors – involving a traditional lentiviral vector approach, and a novel bacterial vector strategy. Chapter 2 deals with the design of novel RNAi mediators against FOXP3 – a crucial regulator of the immunosuppressive regulatory T cell population. Two mediators were tested and validated. The superior mediator was taken forward as part of work in chapter 3. Chapter 3 deals with transposing the RNA sequence from chapter 2 into a DNA-based construct and subsequent incorporation into a lentiviral-based vector system. The lentiviral vector was shown to mediate gene delivery in vitro and functional RNAi was achieved against FOXP3. Proof of gene delivery was further confirmed in vivo in tumour-bearing animals. Chapter 4 focuses on a different immune cell population – tumour-associated macrophages. Non-invasive bacteria were explored as a specific means of delivering gene therapy to this phagocytic cell type. Proof of delivery was shown in vitro and in vivo. Moreover, in vivo delivery of a gene by this method achieved the desired immune response in terms of cytokine profile. Overall, the data presented here advance exploration within the field of cancer immunotherapy, introduce novel delivery and therapeutic strategies, and demonstrate pre-clinically the potential for such novel anti-cancer therapies.

Designing tools that enhance communication and understanding between multiple stakeholders: the case of mobile payment value networks

The pervasive use of mobile technologies has provided new opportunities for organisations to achieve competitive advantage by using a value network of partners to create value for multiple users. The delivery of a mobile payment (m-payment) system is an example of a value network as it requires the collaboration of multiple partners from diverse industries, each bringing their own expertise, motivations and expectations. Consequently, managing partnerships has been identified as a core competence required by organisations to form viable partnerships in an m-payment value network and an important factor in determining the sustainability of an m-payment business model. However, there is evidence that organisations lack this competence which has been witnessed in the m-payment domain where it has been attributed as an influencing factor in a number of failed m-payment initiatives since 2000. In response to this organisational deficiency, this research project leverages the use of design thinking and visualisation tools to enhance communication and understanding between managers who are responsible for managing partnerships within the m-payment domain. By adopting a design science research approach, which is a problem solving paradigm, the research builds and evaluates a visualisation tool in the form of a Partnership Management Canvas. In doing so, this study demonstrates that when organisations encourage their managers to adopt design thinking, as a way to balance their analytical thinking and intuitive thinking, communication and understanding between the partners increases. This can lead to a shared understanding and a shared commitment between the partners. In addition, the research identifies a number of key business model design issues that need to be considered by researchers and practitioners when designing an m-payment business model. As an applied research project, the study makes valuable contributions to the knowledge base and to the practice of management.

Within the carnal: re-reading Merleau-Ponty through the language of drawing

In order to present visual art as a paradigm for philosophy, Merleau-Ponty investigated the creative processes of artists whose work corresponded closely with his philosophical ideas. His essays on art are widely valued for emphasising process over product, and for challenging the primacy of the written word in all spheres of human expression. While it is clear that he initially favoured painting, Merleau-Ponty began to develop a much deeper understanding of the complexities of how art is made in his late work in parallel with his advancement of a new ontology. Although his ontology remains unfinished and only exists as working notes and a manuscript entitled The Visible and Invisible, Merleau-Ponty had begun to appreciate the fundamental role drawing plays in the making of art and the creation of a language of expression that is as vital as the written or spoken word. Through an examination of Merleau-Ponty’s unfinished manuscript and working notes my thesis will investigate his working methods and use of materials and also explore how he processed his ideas by using my own art practice as the basis of my research. This research will take the form of an inquiry into how the unfinished and incomplete nature of text and artworks, while they are still ‘works in progress’, can often reveal the more human and carnal components of creative processes. Applying my experience as a practitioner and a teacher in an art school, I focus on the significance of drawing practice for Merleau-Ponty’s later work, in order to rebalance an overemphasis on painting in the literature. Understanding the differences between these two art forms, and how they are taught, can offer an alternative engagement with Merleau-Ponty’s later work and his struggle to find a language to express his developing new ontology. In addition, by re-reading his work through the language of drawing, I believe we gain new insights which reaffirm Merleau-Ponty's relevance to contemporary art making and aesthetics.

A review of the methodologies used in the computer simulation of evacuation from the built environment

Computer based analysis of evacuation can be performed using one of three different approaches, namely optimisation, simulation or risk assessment. Furthermore, within each approach different means of representing the enclosure, the population, and the behaviour of the population are possible. The myriad of approaches which are available has led to the development of some 22 different evacuation models. This article attempts to describe each of the modelling approaches adopted and critically review the inherent capabilities of each approach. The review is based on available published literature.

Evacuation modelling analysis within the operational research context: a combined approach for improving enclosure designs

Evacuation models have been playing an important function in the transition process from prescriptive fire safety codes to performance-based ones over the last three decades. In fact, such models became also useful tools in different tasks within fire safety engineering field, such as fire risks assessment and fire investigation. However, there are some difficulties in this process when using these models. For instance, during the evacuation modelling analysis, a common problem faced by fire safety engineers concerns the number of simulations which needs to be performed. In other terms, which fire designs (i.e., scenarios) should be investigated using the evacuation models? This type of question becomes more complex when specific issues such as the optimal positioning of exits within an arbitrarily structure needs to be addressed. Therefore, this paper presents a methodology which combines the use of evacuation models with numerical techniques used in the operational research field, such as Design of Experiments (DoE), Response Surface Models (RSM) and the numerical optimisation techniques. The methodology here presented is restricted to evacuation modelling analysis, nevertheless this same concept can be extended to fire modelling analysis.

Law in the community: the University of Greenwich/Greenwich Association of Disabled People Centre for Independent Living (GAD) research project

The GAD Advocacy Service is funded by the London Borough of Greenwich Directorate of Neighbourhood Services; its remit to support disabled people experiencing Hate Crime, Domestic Violence and Harassment. Run by disabled personnel and giving advice to all disabled people it is unique in London. Since its inception in 2004, the Advocacy Service has been stretched to its limit - there is a need to extend the remit of the Advocacy Service to give specialist legal advice on other issues. In 2003, the CEDRM-UK project was set up in the University of Greenwich Law Department as part of the Disability Rights Promotion International Legal Education and Research Project; its objectives were firstly, to facilitate the collection of data on the effectiveness of legislation in promoting the rights of disabled persons; and secondly, to pilot new methods in teaching and training in Human Rights Law – students acquire an expertise in Human Rights Law through research into the practical application of legislation relating to civil and human rights in the daily life of the community. In July 2007, GAD and CEDRM-UK embarked on a joint project to report on the work of the Advocacy Service and to create a database to support its caseload. The 2008-9 Project team will report on their work and findings relating to facilitating equality in the workplace; the inclusion of cancer, HIV and multiple sclerosis within the legal definition of disability and the implications of the statutory duty to promote disability equality for the provision of extracurricular activities for schoolchildren. [From the Author]

Accelerating innovation in the built environment by research and education

Awareness of climate change and adaptations of building stock play a key role in the UK government’s environmental agenda. While some European countries and countries like Japan move forward by bringing their sustainability agenda to the public sector, the UK seems to be slow in embracing these ideas and long term sustainability in improved products and processes for better performance, efficiency and innovative application of renewable technology is yet to come. While funding remains a major constraint research show that a number of detrimental issues including; organisation, risk, mind sets of the stakeholders, planning constraints, reluctance to accept change and the unexploited markets are major contributing factors. Most of these barriers can be overcome with research, development and information and knowledge transfer techniques. Educating all stakeholders can act as an accelerator for innovation. This paper examines innovation in the built environment and how research and education can stimulate this process. It explores drivers and barriers for innovation and how research and education in construction, design, engineering and project management can enhance this process. It presents and discusses lessons learnt from two action research projects in relation to innovation.

Heterogeneous distribution of plankton within the mixed layer and its implications for bloom formation in tropical seas

Intensive sampling at the coastal waters of the central Red Sea during a period of thermal stratification, prior to the main seasonal bloom during winter, showed that vertical patches of prokaryotes and microplankton developed and persisted for several days within the apparently density uniform upper layer. These vertical structures were most likely the result of in situ growth and mortality (e.g., grazing) rather than physical or behavioural aggregation. Simulating a mixing event by adding nutrient-rich deep water abruptly triggered dense phytoplankton blooms in the nutrient-poor environment of the upper layer. These findings suggest that vertical structures within the mixed layer provide critical seeding stocks that can rapidly exploit nutrient influx during mixing, leading to winter bloom formation.

Discovering keys to explain social policies within the social and democratic rule-of-law sate

There is a collective worldview on social policies that is expressed and understood by university professionals. However, it takes students time to construct this knowledge. Here, we provide fundamental ideas and a dynamic to facilitate learning of social policies. The preparation of a brief dictionary of significant terms is to be constructed as a group, alongside the maieutic work to be carried out by the teacher. The goal is to discover keys to understand the meaning of social policies and the underlying values that sustain a social and democratic rule-of-law state such as the one proposed in the Spanish Constitution of 1978. Attention is focused on the structure of the mixed welfare state. This is an integral proposal and comprises three dimensions. First, it considers the state and its possible welfare agents: business, market, the Church and civil society. The attitudes with which universal and inclusive social action is promoted, breaking radically with the aid-based meaning contained in other systems, are then addressed. Finally, we examine human dignity as a principle and aim of intervention, a basis for understanding other concepts such as human, social, labour and political rights. It is to be hoped that these pages prove useful for both teaching staff and students.

Social Networks Usage Profile: Descriptive study with students in the University of Murcia

Telematic tools are very important for our lives in the present era and moreover this idea is made more evident if we analyse young people behaviours. However, it seems that the possibilities that these tools allow subjects from a professional point of view, beyond the purely playful aspects, are still not fully exploited both by subjects, neither by educational institutions where they learn. Our work studies the uses of social media in the context of university students. In order to this we have designed a research based on quantitative methodology with a survey. We have applied a questionnaire to students in the University of Murcia. The questionnaire was answered by 487 students in the first half of 2014. The survey results confirm our hypothesis that social networks are part of the basic and habitual tools of communication between the youth of our university and eminently used for leisure purposes, and that the tools used for more academic activities are those allowing greater control of privacy.

Approaches of the Action Art in early childhood Education. Some other ways of interrelation within the educational system

This Artistic research project was created in order to test how to put into practice approaches between Contemporary Art and University daily life. In this particular case, between Action Art and the students at the Early Childhood Education University in Alicante. The generalized lack of awareness about changes which took place in Art in the XX century, demonstrates the lack of interest on the part of students about Contemporary Art, and therefore, it is still remarkable, the distance between Art and life. Thus, as artists and teachers, the chance to carry out specific experiments is open within everyday educational life. Therefore, through Action Art a communicative interaction is possible to be achieved as an active learning process and, in such way, change the usual existing relationships in a predetermine context, creating this way, future Contemporary Art consumers and transmitters.

Analyzing the Influence of Gender Upon High Technology Venturing Within the Context of Business Incubation

We explore the influence of sex role attribution and associated gendered ascriptions upon the entrepreneurial experiences of a female high-technology business owner operating within the context of business incubation. Our literature analysis and empirical evidence suggest that stereotypical gendered expectations surrounding incubated high-technology venturing reproduce masculine norms of entrepreneurial behavior. The adoption of a gendered perspective to explore the experience of business incubation responds to contemporary calls to embed feminist analyses within the entrepreneurial field of enquiry. Furthermore, we draw upon evidence from a detailed case study informed by a life history narrative to explore a female entrepreneur's experience of incubated high-technology entrepreneurship. © 2011 Baylor University.

A hybrid metaheuristic approach to the university course timetabling problem

This paper describes the development of a novel metaheuristic that combines an electromagnetic-like mechanism (EM) and the great deluge algorithm (GD) for the University course timetabling problem. This well-known timetabling problem assigns lectures to specific numbers of timeslots and rooms maximizing the overall quality of the timetable while taking various constraints into account. EM is a population-based stochastic global optimization algorithm that is based on the theory of physics, simulating attraction and repulsion of sample points in moving toward optimality. GD is a local search procedure that allows worse solutions to be accepted based on some given upper boundary or ‘level’. In this paper, the dynamic force calculated from the attraction-repulsion mechanism is used as a decreasing rate to update the ‘level’ within the search process. The proposed method has been applied to a range of benchmark university course timetabling test problems from the literature. Moreover, the viability of the method has been tested by comparing its results with other reported results from the literature, demonstrating that the method is able to produce improved solutions to those currently published. We believe this is due to the combination of both approaches and the ability of the resultant algorithm to converge all solutions at every search process.