Adaptive radiotherapy for virally mediated head and neck cancer

Purpose: Virally mediated head and neck cancers (VMHNC) often present with nodal involvement, and are generally considered radioresponsive, resulting in the need for plan adaptation during radiotherapy in a subset of patients. We sought to identify a high-risk group based on pre-treatment nodal size to be evaluated in a future prospective adaptive radiotherapy trial. Methodology: Between 2005-2010, 121 patients with virally-mediated, node positive nasopharyngeal or oropharyngeal cancers, receiving definitive radiotherapy were reviewed. Patients were analysed based on maximum size of the dominant node at diagnosis with a view to grouping them in varying risk categories for the need of re-planning. The frequency and timing of the re-planning scans were also evaluated. Results: Sixteen nasopharyngeal and 105 oropharyngeal tumours were reviewed. Twenty-five (21%) patients underwent a re-planning CT at a median of 22 (range, 0-29) fractions with 1 patient requiring re-planning prior to the commencement of treatment. Based on the analysis, patients were subsequently placed into 3 groups defined by pre-treatment nodal size; ≤ 35mm (Group 1), 36-45mm (Group 2), ≥ 46mm (Group 3). Applying these groups to the patient cohort, re-planning CT’s were performed in Group 1- 8/68 (11.8%), Group 2- 4/28 (14.3%), Group 3- 13/25 (52%). Conclusion: In this series, patients with VMHNC and nodal size > 46mm appear to be a high-risk group for the need of plan adaptation during a course of definitive radiotherapy. This finding will now be tested in a prospective adaptive radiotherapy study.

The role of randomly mixed-layered chlorite/smectite in the transformation of smectite to chlorite

Vesicular and groundmass phyllosilicates in a hydrothermally altered basalt from the Point Sal ophiolite, California, have been studied using transmission electron microscopy (TEM). Pore-filling phyllosilicates are texturally characterized as having coherent, relatively thick and defect-free crystals of chlorite (14 Å) with occasional 24-Å periodicities. Groundmass phyllosilicates are texturally characterized as 1) randomly oriented crystals up to 200 Å in width and 2) larger, more coherent crystals up to 1000 Å in width. Small crystallites contain predominantly 14-Å layers with some 24-Å units. Large crystals show randomly interlayered chlorite/smectite (C/S), with approximately 50% chlorite on average. Adjacent smectite-like layers are not uncommon in the groundmass phyllosilicates. Electron microprobe analyses show that Fe/Mg ratios of both groundmass and vesicular phyllosilicates are fairly constant. Termination of brucite-like interlayers has been identified in some of the TEM images. The transformation mechanisms represented by these layer terminations are 1) growth of a brucite-like interlayer within smectite interlayer regions and 2) the dissolution and reprecipitation of elements to form chlorite layers. Both mechanisms require an increase in volume as smectite transforms to chlorite. The data, combined with that from previously published reports, suggest that randomly interlayered C/S is a metastable phase formed in microenvironments with low water/rock ratios. Chlorite forms in microenvironments in the same sample dominated by higher water/rock ratios. The relatively constant number of Mg's in the structure (Mg#) of both structures indicates that in both microenvironments the bulk rock composition has influence over the composition of phyllosilicates.

The digital transformation of 21st century news journalism

This paper deals with the transformations that have occurred in news journalism worldwide in the early 21st century. I argue that they havebeen the most significant changes to the profession for 100 years, and the challenges facing the news media industry in responding to them are substantial, as are those facing journalism education. This argument is developed in relation to the crisis of the newspaper business model, and why social media, blogging and citizen journalism have not filled the gap left by the withdrawal of resources from traditional journalism. It also draws upon Wikileaks as a case study in debates about computational and data-driven journalism, and whether large-scale "leaks" of electronic documents may be the future of investigative journalism.

One-stop government portals : transformation or navigation?

E-government is seen as a promising approach for governments to improve their service towards citizens and become more cost-efficient in service delivery. This is often combined with one-stop government, which is a citizen-oriented approach stressing integrated provision of services from multiple departments via a single access point, the one-stop government portal. While the portal concept is gaining prominence in practice, there is little know about its status in academic literature. This hinders academics in building an accumulated body of knowledge around the concept and makes it hard for practitioners to access relevant academic insights on the topic. The objective of this study is to identify and understand the key themes of the one-stop government portal concept in academic, e-government research. A holistic analysis is provided by addressing different viewpoints: social-political, legal, organizational, user, security, service, data & information, and technical. As overall finding we conclude that there are two different approaches: a more pragmatic approach focuses on quick wins in particular related to usability and navigation and a more ambitious, transformational approach having far reaching social-political, legal, organizational implications.

Influencing the experience of people in urban public places through mobile mediated interactions

This study presents research findings to informthe design and development of innovativemobile services aiming to enable collocated people to interact with each other in public urban places. The main goal of this research is to provide applications and deliver guidelines to positively influence the user experience of different public urban places during everyday urban life. This study describes the design and evaluation of mobile content and services enabling mobile mediated interactions in an anonymous way. The research described in this thesis is threefold. First, this study investigates how Information and Communication Technology (ICT) can be utilised in particular urban public places to influence the experience of urban dwellers during everyday life. The research into urban residents and public places guides the design of three different technologies that form case studies to investigate and discover possibilities to digitally augment the public urban space and make the invisible data of our interactions in the urban environment visible. • Capital Music enables urban dwellers to listen to their music on their mobile devices as usual but also visualises the artworks of songs currently being played and listened to by other users in ones’ vicinity. • PlaceTagz uses QR codes printed on stickers that link to a digital message board enabling collocated users to interact with each other over time resulting in a place-based digital memory. • Sapporo World Window, Brisbane Hot Spots, and YourScreen are interactive content applications allowing people to share data with their mobile phones on public urban screens. The applications employ mobile phones to mediate interactions in form of location and video sharing. Second, this study sets out to explore the quality and nature of the experiences created through the developed and deployed case study applications. The development of a user experience framework for evaluating mobile mediated interactions in urban public places is described and applied within each case. Third, drawing on research from urban sociology, psychology, urban design, and the findings from this study, this thesis discusses how such interactions can have an impact on the urban experience.

Identifying the triggers for management services in business transformation management

Business transformations are complex organisational change endeavours that result in a business performing current work differently, or performing different work. Information Technology (IT) is a key enabler of such initiatives, but comes with its challenges, as revamping the IT infrastructure in large-scale organisations implies high complexity, high risk, and often high failure rates. We view business transformations as a collection of management services that are demanded and enacted at a program level, defined as abstract resources that provide the managerial capabilities necessary for business transformations. In this research-in-progress, we explore what triggers the need for management services in response to the challenges in business transformation management. We analyse data from two exploratory case studies using the critical incident technique as our qualitative analysis method. Early findings indicate that management service triggers reside on either the strategic level, which may be internally or externally driven, or at the program management level, which may be situational, influential or reactional. We detail implications for our on-going research.

Vacancy mediated desorption of hydrogen from a sodium alanate surface : An ab initio spin-polarized study

Ab initio spin-polarized density functional theory calculations are performed to explore the effect of single Na vacancy on NaAlH4(001) surface on the initial dehydrogenation kinetics. The authors found that two Al–H bond lengths become elongated and weakened due to the presence of a Na vacancy on the NaAlH4(001) surface. Spontaneous recombination from the surface to form molecular hydrogen is observed in the spin-polarized ab initio molecular dynamics simulation. The authors’ results indicate that surface Na vacancies play a critical role in accelerating the dehydrogenation kinetics in sodium alanate. The understanding gained here will aid in the rational design and development of complex hydride materials for hydrogen storage

Thermal treatment of natural goethite : thermal transformation and physical properties

XRD (X-ray diffraction), XRF (X-ray fluorescence), TG (thermogravimetry), FT-IES (Fourier transform infrared emission spectroscopy), FESEM (field emission scanning electron microscope), TEM (transmission electron microscope) and nitrogen–adsorption–desorption analysis were used to characterize the composition and thermal evolution of the structure of natural goethite. The in situ FT-IES demonstrated the start temperature (250 °C) of the transformation of natural goethite to hematite and the thermodynamic stability of protohematite between 250 and 600 °C. The heated products showed a topotactic relationship to the original mineral based on SEM analysis. Finally, the nitrogen–adsorption–desorption isotherm provided the variation of surface area and pore size distribution as a function of temperature. The surface area displayed a remarkable increase up to 350 °C, and then decreased above this temperature. The significant increase in surface area was attributed to the formation of regularly arranged slit-shaped micropores running parallel to elongated direction of hematite microcrystal. The main pore size varied from 0.99 nm to 3.5 nm when heating temperature increases from 300 to 400 °C. The hematite derived from heating goethite possesses high surface area and favors the possible application of hematite as an adsorbent as well as catalyst carrier.

An investigation into painting's transformation and regeneration through post-photographic intervention in the digital archive

This PhD practice-led research inquiry sets out to examine and describe how the fluid interactions between memory and time can be rendered via the remediation of my painting and the construction of a digital image archive. My abstract digital art and handcrafted practice is informed by Deleuze and Guattari’s rhizomics of becoming. I aim to show that the technological mobility of my creative strategies produce new conditions of artistic possibility through the mobile principles of rhizomic interconnection, multiplicity and diversity. Subsequently through the ongoing modification of past painting I map how emergent forms and ideas open up new and incisive engagements with the experience of a ‘continual present’. The deployment of new media and cross media processes in my art also deterritorialises the modernist notion of painting as a static and two dimensional spatial object. Instead, it shows painting in a postmodern field of dynamic and transformative intermediality through digital formats of still and moving images that re-imagines the relationship between memory, time and creative practice.

In vitro functional characterisation of IGF-I : VN-induced breast cancer progression

Members of the insulin-like growth factor (IGF) family have been shown to play critical roles in normal growth and development, as well as in tumour biology. The IGF system is complex and the biological effects of the IGFs are determined by their diverse interactions between many molecules, including their interactions with extracellular matrix (ECM) proteins. Recent studies have demonstrated that IGFs associate with the ECM protein vitronectin (VN) through IGF-binding proteins (IGFBP) and that this interaction modulates IGF-stimulated biological functions, namely cell migration and cell survival through the cooperative involvement of the type-I IGF receptor (IGF-1R) and VN-binding integrins. Since IGFs play important roles in the transformation and progression of breast cancer and VN has been found to be over-expressed at the leading edge of breast tumours, this project aimed to describe the effects of IGF-I:VN interactions on breast cell function. This was undertaken to dissect the molecular mechanisms underlying IGF-I:VN-induced responses and to design inhibitors to block the effects of such interactions. The studies described herein demonstrate that the increase in migration of MCF-7 breast cancer cells in response to the IGF-I:IGFBP-5:VN complex is accompanied by differential expression of genes known to be involved in migration, invasion and/or survival, including Tissue-factor (TF), Stratifin (SFN), Ephrin-B2, Sharp-2 and PAI-1. This „migration gene signature‟ was confirmed using real-time PCR analysis. Substitution of the native IGF-I within the IGF-I:IGFBP:VN complex with the IGF-I analogue, \[L24]\[A31]-IGF-I, which has a reduced affinity for the IGF-1R, failed to stimulate cell migration and interestingly, also failed to induce the differential gene expression. This supports the involvement of the IGF-1R in mediating these changes in gene expression. Furthermore, lentiviral shRNA-mediated stable knockdown of TF and SFN completely abrogated the increased cell migration induced by IGF-I:IGFBP:VN complexes in MCF-7 cells. Indeed, when these cells were grown in 3D Matrigel™ cultures a decrease in the overall size of the 3D spheroids in response to the IGF-I:IGFBP:VN complexes was observed compared to the parental MCF-7 cells. This suggests that TF and SFN have a role in complex-stimulated cell survival. Moreover, signalling studies performed on cells with the reduced expression of either TF or SFN had a decreased IGF-1R activation, suggesting the involvement of signalling pathways downstream of IGF-1R in TF- and/or SFN-mediated cell migration and cell survival. Taken together, these studies provide evidence for a common mechanism activated downstream of the IGF-1R that induces the expression of the „migration gene signature‟ in response to the IGF-I:IGFBP:VN complex that confers breast cancer cells the propensity to migrate and survive. Given the functional significance of the interdependence of ECM and growth factor (GF) interactions in stimulating processes key to breast cancer progression, this project aimed at developing strategies to prevent such growth factor:ECM interactions in an effort to inhibit the downstream functional effects. This may result in the reduction in the levels of ECM-bound IGF-I present in close proximity to the cells, thereby leading to a reduction in the stimulation of IGF-1R present on the cell surface. Indeed, the inhibition of IGF-I-mediated effects through the disruption of its association with ECM would not alter the physiological levels of IGF-I and potentially only exert effects in situations where abnormal over expression of ECM proteins are found; namely carcinomas and hyperproliferative diseases. In summary, this PhD project has identified novel, innovative and realistic strategies that can be used in vitro to inhibit the functions exerted by the IGF-I:IGFBP:VN multiprotein complexes critical for cancer progression, with a potential to be translated into in vivo investigations. Furthermore, TF and SFN were found to mediate IGF-I:IGFBP:VN-induced effects, thereby revealing their potential to be used as therapeutic targets or as predictive biomarkers for the efficacy of IGF-1R targeting therapies in breast cancer patients. In addition to its therapeutic and clinical scope, this PhD project has significantly contributed to the understanding of the role of the IGF system in breast tumour biology by providing valuable new information on the mechanistic events underpinning IGF-I:VN-mediated effects on breast cell functions. Furthermore, this is the first instance where favourable binding sites for IGF-II, IGFBP-3 and IGFBP-5 on VN have been identified. Taken together, this study has functionally characterised the interactions between IGF-I and VN and through innovative strategies has provided a platform for the development of novel therapies targeting these interactions and their downstream effects.

Building the computer mediated distance learning community: Issues and observations drawn from teaching and learning

This paper discusses computer mediated distance learning on a Master's level course in the UK and student perceptions of this as a quality learning environment.

Developing an adaptive radiotherapy technique for virally mediated head and neck cancer

Purpose Virally mediated head and neck cancers (VMHNC) often present with nodal involvement and are highly radioresponsive, meaning that treatment plan adaptation during radiotherapy (RT) in a subset of patients is required. We sought to determine potential risk profiles and a corresponding adaptive treatment strategy for these patients. Methodology 121 patients with virally mediated, node positive nasopharyngeal (Epstein Barr Virus positive) or oropharyngeal (Human Papillomavirus positive) cancers, receiving curative intent RT were reviewed. The type, frequency and timing of adaptive interventions, including source-to-skin distance (SSD) corrections, re-scanning and re-planning, were evaluated. Patients were reviewed based on the maximum size of the dominant node to assess the need for plan adaptation. Results Forty-six patients (38%) required plan adaptation during treatment. The median fraction at which the adaptive intervention occurred was 26 for SSD corrections and 22 for re-planning CTs. A trend toward 3 risk profile groupings was discovered: 1) Low risk with minimal need (< 10%) for adaptive intervention (dominant pre-treatment nodal size of ≤ 35 mm), 2) Intermediate risk with possible need (< 20%) for adaptive intervention (dominant pre-treatment nodal size of 36 mm – 45 mm) and 3) High-risk with increased likelihood (> 50%) for adaptive intervention (dominant pre-treatment nodal size of ≥ 46 mm). Conclusion In this study, patients with VMHNC and a maximum dominant nodal size of > 46 mm were identified at a higher risk of requiring re-planning during a course of definitive RT. Findings will be tested in a future prospective adaptive RT study.

Proteolytic activation of Chlamydia trachomatis HTRA is mediated by PDZ1 domain interactions with protease domain loops L3 and LC and beta strand β5

Chlamydia trachomatis is a bacterial pathogen responsible for one of the most prevalent sexually transmitted infections worldwide. Its unique development cycle has limited our understanding of its pathogenic mechanisms. However, CtHtrA has recently been identified as a potential C. trachomatis virulence factor. CtHtrA is a tightly regulated quality control protein with a monomeric structural unit comprised of a chymotrypsin-like protease domain and two PDZ domains. Activation of proteolytic activity relies on the C-terminus of the substrate allosterically binding to the PDZ1 domain, which triggers subsequent conformational change and oligomerization of the protein into 24-mers enabling proteolysis. This activation is mediated by a cascade of precise structural arrangements, but the specific CtHtrA residues and structural elements required to facilitate activation are unknown. Using in vitro analysis guided by homology modeling, we show that the mutation of residues Arg362 and Arg224, predicted to disrupt the interaction between the CtHtrA PDZ1 domain and loop L3, and between loop L3 and loop LD, respectively, are critical for the activation of proteolytic activity. We also demonstrate that mutation to residues Arg299 and Lys160, predicted to disrupt PDZ1 domain interactions with protease loop LC and strand β5, are also able to influence proteolysis, implying their involvement in the CtHtrA mechanism of activation. This is the first investigation of protease loop LC and strand β5 with respect to their potential interactions with the PDZ1 domain. Given their high level of conservation in bacterial HtrA, these structural elements may be equally significant in the activation mechanism of DegP and other HtrA family members.

Culture in global business transformation projects : the discovery of a grounded theory

Presently organisations engage in what is termed as Global Business Transformation Projects [GBTPs], for consolidating, innovating, transforming and restructuring their processes and business strategies while undergoing fundamental change. Culture plays an important role in global business transformation projects as these involve people of different cultural backgrounds and span across countries, industries and disciplinary boundaries. Nevertheless, there is scant empirical research on how culture is conceptualised beyond national and organisational cultures but also on how culture is to be taken into account and dealt with within global business transformation projects. This research is situated in a business context and discovers a theory that aids in describing and dealing with culture. It draws on the lived experiences of thirty-two senior management practitioners, reporting on more than sixty-one global business transformation projects in which they were actively involved. The research method used is a qualitative and interpretive one and applies a grounded theory approach, with rich data generated through interviews. In addition, vignettes were developed to illustrate the derived theoretical models. The findings from this study contribute to knowledge in multiple ways. First, it provides a holistic account of global business transformation projects that describe the construct of culture by the elements of culture types, cultural differences and cultural diversity. A typology of culture types has been developed which enlarges the view of culture beyond national and organisational culture including an industry culture, professional service firm culture and 'theme' culture. The amalgamation of the culture types instantiated in a global business transformation project compromises its project culture. Second, the empirically grounded process for managing culture in global business transformation projects integrates the stages of recognition, understanding and management as well as the enablement providing a roadmap for dealing with culture in global business transformation projects. Third, this study identified contextual variables to global business transformation projects, which provide the means of describing the environment global business transformation projects are situated, influence the construct of culture and inform the process for managing culture. Fourth, the contribution to the research method is the positioning of interview research as a strategy for data generation and the detailed documentation applying grounded theory to discover theory.

Open and networked initiatives and the digital transformation of academic publishing in China

Many aspects of China's academic publishing system differ from the systems found in liberal market based economies of the United States, Western Europe and Australia. A high level of government intervention in both the publishing industry and academia and the challenges associated with attempting to make a transition from a centrally controlled towards a more market based publishing industry are two notable differences; however, as in other countries, academic communities and publishers are being transformed by digital technologies. This research explores the complex yet dynamic digital transformation of academic publishing in China, with a specific focus of the open and networked initiatives inspired by Web 2.0 and social media. The thesis draws on two case studies: Science Paper Online, a government-operated online preprint platform and open access mandate; and New Science, a social reference management website operated by a group of young PhD students. Its analysis of the innovations, business models, operating strategies, influences, and difficulties faced by these two initiatives highlights important characteristics and trends in digital publishing experiments in China. The central argument of this thesis is that the open and collaborative possibilities of Web 2.0 inspired initiatives are emerging outside the established journal and monograph publishing system in China, introducing innovative and somewhat disruptive approaches to the certification, communication and commercial exploitation of knowledge. Moreover, emerging publishing models are enabling and encouraging a new system of practising and communicating science in China, putting into practice some elements of the Open Science ethos. There is evidence of both disruptive change to old publishing structures and the adaptive modification of emergent replacements in the Chinese practice. As such, the transformation from traditional to digital and interactive modes of publishing, involves both competition and convergence between new and old publishers, as well as dynamics of co-evolution involving new technologies, business models, social norms, and government reform agendas. One key concern driving this work is whether there are new opportunities and new models for academic publishing in the Web 2.0 age and social media environment, which might allow the basic functions of communication and certification to be achieved more effectively. This thesis enriches existing knowledge of open and networked transformations of scholarly publishing by adding a Chinese story. Although the development of open and networked publishing platforms in China remains in its infancy, the lessons provided by this research are relevant to practitioners and stakeholders interested in understanding the transformative dynamics of networked technologies for publishing and advocating open access in practice, not only in China, but also internationally.