A Model of Lung Tumor Angiogenesis in a Biomimetic Poly(ethylene glycol)-based Hydrogel System

Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. A major outstanding challenge associated with studying tumor angiogenesis is that existing preclinical models are limited in their recapitulation of in vivo cellular organization in 3D. This disparity highlights the need for better approaches to study the dynamic interplay of relevant cells and signaling molecules as they are organized in the tumor microenvironment. In this thesis, we combined 3D culture of lung adenocarcinoma cells with adjacent 3D microvascular cell culture in 2-layer cell-adhesive, proteolytically-degradable poly(ethylene glycol) (PEG)-based hydrogels to study tumor angiogenesis and the impacts of neovascularization on tumor cell behavior.

In initial studies, 344SQ cells, a highly metastatic, murine lung adenocarcinoma cell line, were characterized alone in 3D in PEG hydrogels. 344SQ cells formed spheroids in 3D culture and secreted proangiogenic growth factors into the conditioned media that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells alone in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, the engineered 2-layer tumor angiogenesis model with 344SQ and vascular cell layers was employed. Large, invasive 344SQ clusters developed at the interface between the layers, and were not evident further from the interface or in control hydrogels without vascular cells. A modified model with spatially restricted 344SQ and vascular cell layers confirmed that observed 344SQ cluster morphological changes required close proximity to vascular cells. Additionally, TGF-β1 inhibition blocked endothelial cell-driven 344SQ migration.

Two other lung adenocarcinoma cell lines were also explored in the tumor angiogenesis model: primary tumor-derived metastasis-incompetent, murine 393P cells and primary tumor-derived metastasis-capable human A549 cells. These lung cancer cells also formed spheroids in 3D culture and secreted proangiogenic growth factors into the conditioned media. Epithelial morphogenesis varied for the primary tumor-derived cell lines compared to 344SQ cells, with far less epithelial organization present in A549 spheroids. Additionally, 344SQ cells secreted the highest concentration of two of the three angiogenic growth factors assessed. This finding correlated to 344SQ exhibiting the most pronounced morphological response in the tumor angiogenesis model compared to the 393P and A549 cell lines.

Overall, this dissertation demonstrates the development of a novel 3D tumor angiogenesis model that was used to study vascular cell-cancer cell interactions in lung adenocarcinoma cell lines with varying metastatic capacities. Findings in this thesis have helped to elucidate the role of vascular cells in tumor progression and have identified differences in cancer cell behavior in vitro that correlate to metastatic capacity, thus highlighting the usefulness of this model platform for future discovery of novel tumor angiogenesis and tumor progression-promoting targets.

Accuracy of computer-aided design/computer-assisted manufacture (CAD/CAM) fabricated dental restorations: a comparative study

Introduction: Computer-Aided-Design (CAD) and Computer-Aided-Manufacture (CAM) has been developed to fabricate fixed dental restorations accurately, faster and improve cost effectiveness of manufacture when compared to the conventional method. Two main methods exist in dental CAD/CAM technology: the subtractive and additive methods. While fitting accuracy of both methods has been explored, no study yet has compared the fabricated restoration (CAM output) to its CAD in terms of accuracy. The aim of this present study was to compare the output of various dental CAM routes to a sole initial CAD and establish the accuracy of fabrication. The internal fit of the various CAM routes were also investigated. The null hypotheses tested were: 1) no significant differences observed between the CAM output to the CAD and 2) no significant differences observed between the various CAM routes. Methods: An aluminium master model of a standard premolar preparation was scanned with a contact dental scanner (Incise, Renishaw, UK). A single CAD was created on the scanned master model (InciseCAD software, V2.5.0.140, UK). Twenty copings were then fabricated by sending the single CAD to a multitude of CAM routes. The copings were grouped (n=5) as: Laser sintered CoCrMo (LS), 5-axis milled CoCrMo (MCoCrMo), 3-axis milled zirconia (ZAx3) and 4-axis milled zirconia (ZAx4). All copings were micro-CT scanned (Phoenix X-Ray, Nanotom-S, Germany, power: 155kV, current: 60µA, 3600 projections) to produce 3-Dimensional (3D) models. A novel methodology was created to superimpose the micro-CT scans with the CAD (GOM Inspect software, V7.5SR2, Germany) to indicate inaccuracies in manufacturing. The accuracy in terms of coping volume was explored. The distances from the surfaces of the micro-CT 3D models to the surfaces of the CAD model (CAD Deviation) were investigated after creating surface colour deviation maps. Localised digital sections of the deviations (Occlusal, Axial and Cervical) and selected focussed areas were then quantitatively measured using software (GOM Inspect software, Germany). A novel methodology was also explored to digitally align (Rhino software, V5, USA) the micro-CT scans with the master model to investigate internal fit. Fifty digital cross sections of the aligned scans were created. Point-to-point distances were measured at 5 levels at each cross section. The five levels were: Vertical Marginal Fit (VF), Absolute Marginal Fit (AM), Axio-margin Fit (AMF), Axial Fit (AF) and Occlusal Fit (OF). Results: The results of the volume measurement were summarised as: VM-CoCrMo (62.8mm3 ) > VZax3 (59.4mm3 ) > VCAD (57mm3 ) > VZax4 (56.1mm3 ) > VLS (52.5mm3 ) and were all significantly different (p presented as areas with different colour. No significant differences were observed at the internal aspect of the cervical aspect between all groups of copings. Significant differences (p< M-CoCrMo Internal Occlusal, Internal Axial and External Axial 2 ZAx3 > ZAx4 External Occlusal, External Cervical 3 ZAx3 < ZAx4 Internal Occlusal 4 M-CoCrMo > ZAx4 Internal Occlusal and Internal Axial The mean values of AMF and AF were significantly (p M-CoCrMo and CAD > ZAx4. Only VF of M-CoCrMo was comparable with the CAD Internal Fit. All VF and AM values were within the clinically acceptable fit (120µm). Conclusion: The investigated CAM methods reproduced the CAD accurately at the internal cervical aspect of the copings. However, localised deviations at axial and occlusal aspects of the copings may suggest the need for modifications in these areas prior to fitting and veneering with porcelain. The CAM groups evaluated also showed different levels of Internal Fit thus rejecting the null hypotheses. The novel non-destructive methodologies for CAD/CAM accuracy and internal fit testing presented in this thesis may be a useful evaluation tool for similar applications.

Nanowires for 3d silicon interconnection – low temperature compliant nanowire-polymer film for z-axis interconnect

Semiconductor chip packaging has evolved from single chip packaging to 3D heterogeneous system integration using multichip stacking in a single module. One of the key challenges in 3D integration is the high density interconnects that need to be formed between the chips with through-silicon-vias (TSVs) and inter-chip interconnects. Anisotropic Conductive Film (ACF) technology is one of the low-temperature, fine-pitch interconnect method, which has been considered as a potential replacement for solder interconnects in line with continuous scaling of the interconnects in the IC industry. However, the conventional ACF materials are facing challenges to accommodate the reduced pad and pitch size due to the micro-size particles and the particle agglomeration issue. A new interconnect material - Nanowire Anisotropic Conductive Film (NW-ACF), composed of high density copper nanowires of ~ 200 nm diameter and 10-30 µm length that are vertically distributed in a polymeric template, is developed in this work to tackle the constrains of the conventional ACFs and serves as an inter-chip interconnect solution for potential three-dimensional (3D) applications.

Drug prescribing patterns in the General Medical Services Scheme in Ireland and projected costs to 2026

The primary objective is to investigate the main factors contributing to GMS expenditure on pharmaceutical prescribing and projecting this expenditure to 2026. This study is located in the area of pharmacoeconomic cost containment and projections literature. The thesis has five main aims: 1. To determine the main factors contributing to GMS expenditure on pharmaceutical prescribing. 2. To develop a model to project GMS prescribing expenditure in five year intervals to 2026, using 2006 Central Statistics Office (CSO) Census data and 2007 Health Service Executive{Primary Care Reimbursement Service (HSE{PCRS) sample data. 3. To develop a model to project GMS prescribing expenditure in five year intervals to 2026, using 2012 HSE{PCRS population data, incorporating cost containment measures, and 2011 CSO Census data. 4. To investigate the impact of demographic factors and the pharmacology of drugs (Anatomical Therapeutic Chemical (ATC)) on GMS expenditure. 5. To explore the consequences of GMS policy changes on prescribing expenditure and behaviour between 2008 and 2014. The thesis is centered around three published articles and is located between the end of a booming Irish economy in 2007, a recession from 2008{2013, to the beginning of a recovery in 2014. The literature identified a number of factors influencing pharmaceutical expenditure, including population growth, population aging, changes in drug utilisation and drug therapies, age, gender and location. The literature identified the methods previously used in predictive modelling and consequently, the Monte Carlo Simulation (MCS) model was used to simulate projected expenditures to 2026. Also, the literature guided the use of Ordinary Least Squares (OLS) regression in determining demographic and pharmacology factors influencing prescribing expenditure. The study commences against a backdrop of growing GMS prescribing costs, which has risen from e250 million in 1998 to over e1 billion by 2007. Using a sample 2007 HSE{PCRS prescribing data (n=192,000) and CSO population data from 2008, (Conway et al., 2014) estimated GMS prescribing expenditure could rise to e2 billion by2026. The cogency of these findings was impacted by the global economic crisis of 2008, which resulted in a sharp contraction in the Irish economy, mounting fiscal deficits resulting in Ireland's entry to a bailout programme. The sustainability of funding community drug schemes, such as the GMS, came under the spotlight of the EU, IMF, ECB (Trioka), who set stringent targets for reducing drug costs, as conditions of the bailout programme. Cost containment measures included: the introduction of income eligibility limits for GP visit cards and medical cards for those aged 70 and over, introduction of co{payments for prescription items, reductions in wholesale mark{up and pharmacy dispensing fees. Projections for GMS expenditure were reevaluated using 2012 HSE{PCRS prescribing population data and CSO population data based on Census 2011. Taking into account both cost containment measures and revised population predictions, GMS expenditure is estimated to increase by 64%, from e1.1 billion in 2016 to e1.8 billion by 2026, (ConwayLenihan and Woods, 2015). In the final paper, a cross{sectional study was carried out on HSE{PCRS population prescribing database (n=1.63 million claimants) to investigate the impact of demographic factors, and the pharmacology of the drugs, on GMS prescribing expenditure. Those aged over 75 (ẞ = 1:195) and cardiovascular prescribing (ẞ = 1:193) were the greatest contributors to annual GMS prescribing costs. Respiratory drugs (Montelukast) recorded the highest proportion and expenditure for GMS claimants under the age of 15. Drugs prescribed for the nervous system (Escitalopram, Olanzapine and Pregabalin) were highest for those between 16 and 64 years with cardiovascular drugs (Statins) were highest for those aged over 65. Females are more expensive than males and are prescribed more items across the four ATC groups, except among children under 11, (ConwayLenihan et al., 2016). This research indicates that growth in the proportion of the elderly claimants and associated levels of cardiovascular prescribing, particularly for statins, will present difficulties for Ireland in terms of cost containment. Whilst policies aimed at cost containment (co{payment charges, generic substitution, reference pricing, adjustments to GMS eligibility) can be used to curtail expenditure, health promotional programs and educational interventions should be given equal emphasis. Also policies intended to affect physicians prescribing behaviour include guidelines, information (about price and less expensive alternatives) and feedback, and the use of budgetary restrictions could yield savings.

Death Threat Letters: Allegories of American Authorship in the Age of Terrorism

This dissertation examines novels that use terrorism to allegorize the threatened position of the literary author in contemporary culture. Allegory is a term that has been differently understood over time, but which has consistently been used by writers to articulate and construct their roles as authors. In the novels I look at, the terrorist challenge to authorship results in multiple deployments of allegory, each differently illustrating the way that allegory is used and authorship constructed in the contemporary American novel. Don DeLillo’s Mao II (1991), first puts terrorists and authors in an oppositional pairing. The terrorist’s ability to traffic in spectacle is presented as indicative of the author’s fading importance in contemporary culture and it is one way that terrorism allegorizes threats to authorship. In Philip Roth’s Operation Shylock (1993), the allegorical pairing is between the text of the novel and outside texts – newspaper reports, legal cases, etc. – that the novel references and adapts in order to bolster its own narrative authority. Richard Powers’s Plowing the Dark (1999) pairs the story of an imprisoned hostage, craving a single book, with employees of a tech firm who are creating interactive, virtual reality artworks. Focusing on the reader’s experience, Powers’s novel posits a form of authorship that the reader can take into consideration, but which does not seek to control the experience of the text. Finally, I look at two of Paul Auster’s twenty-first century novels, Travels in the Scriptorium (2007) and Man in the Dark (2008), to suggest that the relationship between representations of authors and terrorists changed after 9/11. Auster’s author-figures forward an ethics of authorship whereby novels can use narrative to buffer readers against the portrayal of violent acts in a culture that is suffused with traumatizing imagery.

Measuring the Diversity and the Integration of Film Production in Mercosur: A Social Network Analysis

Based on an original and comprehensive database of all feature fiction films produced in Mercosur between 2004 and 2012, the paper analyses whether the Mercosur film industry has evolved towards an integrated and culturally more diverse market. It provides a summary of policy opportunities in terms of integration and diversity, emphasizing the limiter role played by regional policies. It then shows that although the Mercosur film industry remains rather disintegrated, it tends to become more integrated and culturally more diverse. From a methodological point of view, the combination of Social Network Analysis and the Stirling Model opens up interesting research tracks to analyse creative industries in terms of their market integration and their cultural diversity.

Circular migration and the Internet: The role of social networks in the sociocultural context of Mexican residents in Barcelona

This work focuses on the study of the circular migration between America and Europe, particularly in the discussion about knowledge transfer and the way that social networks reconfigure the form of information distribution among people, that due to labor and academic issues have left their own country. The main purpose of this work is to study the impact of social media use in migration flows between Mexico and Spain, more specifically the use by Mexican migrants who have moved for  multiple years principally for educational purposes and then have returned to their respective locations in Mexico seeking to integrate themselves into the labor market. Our data collection concentrated exclusively on a group created on Facebook by Mexicans who mostly reside in Barcelona, Spain or wish to travel to the city for economic, educational or tourist reasons.  The results of this research show that while social networks are spaces for exchange and integration, there is a clear tendency by this group to "narrow lines" and to look back to their homeland, slowing the process of opening socially in their new context.

Non-radial instabilities and progenitor asphericities in core-collapse supernovae

Since core-collapse supernova simulations still struggle to produce robust neutrino-driven explosions in 3D, it has been proposed that asphericities caused by convection in the progenitor might facilitate shock revival by boosting the activity of non-radial hydrodynamic instabilities in the post-shock region. We investigate this scenario in depth using 42 relativistic 2D simulations with multigroup neutrino transport to examine the effects of velocity and density perturbations in the progenitor for different perturbation geometries that obey fundamental physical constraints (like the anelastic condition). As a framework for analysing our results, we introduce semi-empirical scaling laws relating neutrino heating, average turbulent velocities in the gain region, and the shock deformation in the saturation limit of non-radial instabilities. The squared turbulent Mach number, 〈Ma2〉, reflects the violence of aspherical motions in the gain layer, and explosive runaway occurs for 〈Ma2〉 ≳ 0.3, corresponding to a reduction of the critical neutrino luminosity by ∼25∼25 per cent compared to 1D. In the light of this theory, progenitor asphericities aid shock revival mainly by creating anisotropic mass flux on to the shock: differential infall efficiently converts velocity perturbations in the progenitor into density perturbations δρ/ρ at the shock of the order of the initial convective Mach number Maprog. The anisotropic mass flux and ram pressure deform the shock and thereby amplify post-shock turbulence. Large-scale (ℓ = 2, ℓ = 1) modes prove most conducive to shock revival, whereas small-scale perturbations require unrealistically high convective Mach numbers. Initial density perturbations in the progenitor are only of the order of Ma2progMaprog2 and therefore play a subdominant role.

Design and Implementation of a Low Cost Virtual Rugby Decision Making Interactive

The paper describes the design and implementation of a novel low cost virtual rugby decision making interactive for use in a visitor centre. Original laboratory-based experimental work in decision making in rugby, using a virtual reality headset [1] is adapted for use in a public visitor centre, with consideration given to usability, costs, practicality and health and safety. Movement of professional rugby players was captured and animated within a virtually recreated stadium. Users then interact with these virtual representations via use of a lowcost sensor (Microsoft Kinect) to attempt to block them. Retaining the principles of perception and action, egocentric viewpoint, immersion, sense of presence, representative design and game design the system delivers an engaging and effective interactive to illustrate the underlying scientific principles of deceptive movement. User testing highlighted the need for usability, system robustness, fair and accurate scoring, appropriate level of difficulty and enjoyment.

The music video in the new media: music as an integrated experience

"The Music Vidio in the New Media" is an exploration of the past, present and future of the music cullture. After the evaluation of the existing new media chanels I propose Virtual Reality as a potential media to experience the music. The project explores following terms and topics within them: New Media / New Media Channels and Virtual Reality (...)

Realidade aumentada aplicada em bibliotecas: multiplicidade no acesso a informação

Conceitua Realidade Aumentada do ponto de vista histórico de vários autores e como surgiu esse segmento através da evolução tecnológica até os dias atuais. Aborda seu funcionamento, como também, seus sistemas e aplicações em diversos campos de pesquisas e estudos científicos. Diferencia Realidade Aumentada de Realidade Virtual, visando melhor esclarecimento entre ambas na intenção de descaracterizá-las com uma única “realidade”. Apresenta a Realidade Aumentada e sua aplicação dentro de um contexto de uma unidade de informação, promovendo uma melhor interação com os usuários e as adaptações pelas quais as bibliotecas terão que passar futuramente para se adequarem a “explosão” tecnológica. Descreve o funcionamento da biblioteca ARToolKIT, baseada em RA e suas principais etapas de funcionamento para visualização de objetos virtuais em 3D. Exemplifica os benefícios que uma unidade de informação, que utiliza Realidade Aumentada, promove aos usuários portadores de deficiência, além de sua inclusão no meio digital e sua inserção no mercado de trabalho

Real, rubber or virtual: The vision of “one’s own” body as a means for pain modulation. A narrative review

In the last few years a branch of pain research has been focussing on the modulatory effects of the vision of the body on pain perception. So, for instance, the vision of one’s own real body has been proven to induce analgesic effects. On the other hand, bodily illusions such as the rubber hand illusion have provided new tools for the study of perceptual processes during altered body ownership states. Recently, new paradigms of body ownership made use of a technology that is going places both in clinical and in experimental settings, i.e. virtual reality. While the vision of one’s own real body has been proven to yield compelling analgesic effects, slightly more controversial are those attributed to the vision of “owned” dummy bodies. This review will discuss the studies that examined the effects on pain perception of the vision of the own body, with or without body ownership illusions.

Handling Heterogeneity in Collaborative Networked Surgical Simulators

Stand-alone and networked surgical virtual reality based simulators have been proposed as means to train surgical skills with or without a supervisor nearby the student or trainee -- However, surgical skills teaching in medicine schools and hospitals is changing, requiring the development of new tools to focus on: (i) importance of mentors role, (ii) teamwork skills and (iii) remote training support -- For these reasons, a surgical simulator should not only allow the training involving a student and an instructor that are located remotely, but also the collaborative training of users adopting different medical roles during the training sesión -- Collaborative Networked Virtual Surgical Simulators (CNVSS) allow collaborative training of surgical procedures where remotely located users with different surgical roles can take part in the training session -- To provide successful training involving good collaborative performance, CNVSS should handle heterogeneity factors such as users’ machine capabilities and network conditions, among others -- Several systems for collaborative training of surgical procedures have been developed as research projects -- To the best of our knowledge none has focused on handling heterogeneity in CNVSS -- Handling heterogeneity in this type of collaborative sessions is important because not all remotely located users have homogeneous internet connections, nor the same interaction devices and displays, nor the same computational resources, among other factors -- Additionally, if heterogeneity is not handled properly, it will have an adverse impact on the performance of each user during the collaborative sesión -- In this document, the development of a context-aware architecture for collaborative networked virtual surgical simulators, in order to handle the heterogeneity involved in the collaboration session, is proposed -- To achieve this, the following main contributions are accomplished in this thesis: (i) Which and how infrastructure heterogeneity factors affect the collaboration of two users performing a virtual surgical procedure were determined and analyzed through a set of experiments involving users collaborating, (ii) a context-aware software architecture for a CNVSS was proposed and implemented -- The architecture handles heterogeneity factors affecting collaboration, applying various adaptation mechanisms and finally, (iii) A mechanism for handling heterogeneity factors involved in a CNVSS is described, implemented and validated in a set of testing scenarios

Realidade aumentada aplicada em bibliotecas: multiplicidade no acesso a informação

Conceitua Realidade Aumentada do ponto de vista histórico de vários autores e como surgiu esse segmento através da evolução tecnológica até os dias atuais. Aborda seu funcionamento, como também, seus sistemas e aplicações em diversos campos de pesquisas e estudos científicos. Diferencia Realidade Aumentada de Realidade Virtual, visando melhor esclarecimento entre ambas na intenção de descaracterizá-las com uma única “realidade”. Apresenta a Realidade Aumentada e sua aplicação dentro de um contexto de uma unidade de informação, promovendo uma melhor interação com os usuários e as adaptações pelas quais as bibliotecas terão que passar futuramente para se adequarem a “explosão” tecnológica. Descreve o funcionamento da biblioteca ARToolKIT, baseada em RA e suas principais etapas de funcionamento para visualização de objetos virtuais em 3D. Exemplifica os benefícios que uma unidade de informação, que utiliza Realidade Aumentada, promove aos usuários portadores de deficiência, além de sua inclusão no meio digital e sua inserção no mercado de trabalho