The role of cancer related inflammation, Src family kinases and matrix metalloproteinase 9 in colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the UK with 41,000 new cases diagnosed in 2011. Despite undergoing potentially curative resection, a significant amount of patients develop recurrence. Biomarkers that aid prognostication or identify patients who are suitable for adjuvant treatments are needed. The TNM staging system does a reasonably good job at offering prognostic information to the treating clinician, but it could be better and identifying methods of improving its accuracy are needed. Tumour progression is based on a complex relationship between tumour behaviour and the hosts’ inflammatory responses. Sustained tumour cell proliferation, evading growth suppressors, resisting apoptosis, replicative immortality, sustained angiogenesis, invasion & metastasis, avoiding immune destruction, deregulated cellular energetics, tumour promoting inflammation and genomic instability & mutation have been identified as hallmarks. These hallmarks are malignant behaviors are what makes the cell cancerous and the more extreme the behaviour the more aggressive the cancer the more likely the risk of a poor outcome. There are two primary genomic instability pathways: Microsatellite Instability (MSI) and Chromosomal Instability (CI) also referred to as Microsatellite Stability (MSS). Tumours arising by these pathways have a predilection for specific anatomical, histological and molecular biological features. It is possible that aberrant molecular expression of genes/proteins that promote malignant behaviors may also act as prognostic and predictive biomarkers, which may offer superior prognostic information to classical prognostic features. Cancer related inflammation has been described as a 7th hallmark of cancer. Despite the systemic inflammatory response (SIR) being associated with more aggressive malignant disease, infiltration by immune cells, particularly CD8+ lymphocytes, at the advancing edge of the tumour have been associated with improved outcome and tumour MSI. It remains unknown if the SIR is associated with tumour MSI and this requires further study. The mechanisms by which colorectal cancer cells locally invade through the bowel remain uncertain, but connective tissue degradation by matrix metalloproteinases (MMPs) such as MMP-9 have been implicated. MMP-9 has been found in the cancer cells, stromal cells and patient circulation. Although tumoural MMP-9 has been associated with poor survival, reports are conflicting and contain relatively small sample sizes. Furthermore, the influence of high serum MMP-9 on survival remains unknown. Src family kinases (SFKs) have been implicated in many adverse cancer cell behaviors. SFKs comprise 9 family members BLK, C-SRC, FGR, FYN, HCK, LCK, LYN, YES, YRK. C-SRC has been the most investigated of all SFKs, but the role of other SFKs in cellular behaviors and their prognostic value remains largely unknown. The development of Src inhibitors, such as Dasatinib, has identified SFKs as a potential therapeutic target for patients at higher risk of poor survival. Unfortunately, clinical trials so far have not been promising but this may reflect inadequate patient selection and SFKs may act as useful prognostic and predictive biomarkers. In chapter 3, the association between cancer related inflammation, tumour MSI, clinicopathological factors and survival was tested in two independent cohorts. A training cohort consisting of n=182 patients and a validation cohort of n=677 patients. MSI tumours were associated with a raised CRP (p=0.003). Hypoalbuminaemia was independently associated with poor overall survival in TNM stage II cancer (HR 3.04 (95% CI 1.44 – 6.43);p=0.004), poor recurrence free survival in TNM stage III cancer (HR 1.86 (95% 1.03 – 3.36);p=0.040) and poor overall survival in CI colorectal cancer (HR 1.49 (95% CI 1.06 – 2.10);p=0.022). Interestingly, MSI tumours were associated with poor overall survival in TNM stage III cancer (HR 2.20 (95% CI 1.10 – 4.37);p=0.025). In chapter 4, the role of MMP-9 in colorectal cancer progression and survival was examined. MMP-9 in the tissue was assessed using IHC and serum expression quantified using ELISA. Serum MMP-9 was associated with cancer cell expression (Spearman’s Correlation Coefficient (SCC) 0.393, p<0.001)) and stromal expression (SCC 0.319, p=0.002). Serum MMP-9 was associated with poor recurrence-free (HR 3.37 (95% CI 1.20 – 9.48);p=0.021) and overall survival (HR 3.16 (95% CI 1.22 – 8.15);p=0.018), but tumour MMP-9 was not survival or MSI status. In chapter 5, the role of SFK expression and activation in colorectal cancer progression and survival was studied. On PCR analysis, although LYN, C-SRC and YES were the most highly expressed, FGR and HCK had higher expression profiles as tumours progressed. Using IHC, raised cytoplasmic FAK (tyr 861) was independently associated with poor recurrence free survival in all cancers (HR 1.48 (95% CI 1.02 – 2.16);p=0.040) and CI cancers (HR 1.50 (95% CI 1.02 – 2.21);p=0.040). However, raised cytoplasmic HCK (HR 2.04 (95% CI 1.11 – 3.76);p=0.022) was independently associated with poor recurrence-free survival in TNM stage II cancers. T84 and HT29 cell lines were used to examine the cellular effects of Dasatinib. Cell viability was assessed using WST-1 assay and apoptosis assessed using an ELISA cell death detection assay. Dasatinib increased T84 tumour cell apoptosis in a dose dependent manner and resulted in reduced expression of nuclear (p=0.008) and cytoplasmic (p=0.016) FAK (tyr 861) expression and increased nuclear FGR expression (p=0.004). The results of this thesis confirm that colorectal cancer is a complex disease that represents several subtypes of cancer based on molecular biological behaviors. This thesis concentrated on features of the disease related to inflammation in terms of genetic and molecular characterisation. MSI cancers are closely associated with systemic inflammation but despite this observation, they retain their relatively improved survival. MMP-9 is a feature of tissue remodeling during inflammation and is also associated with degradation of connective tissue, advanced T-stage and poor outcome when measured in the serum. The lack of stromal quantification due to TMA use rather than full sections makes the value of tumoural MMP-9 immunoreactivity in the prognostication and its association with MSI unknown and requires further study. Finally, SFK activation was also associated with SIR, however, only cytoplasmic HCK was independently associated with poor survival in patients with TNM stage II disease, the group of patients where identifying a novel biomarker is most needed. There is still some way to go before these biomarkers are translated into clinical practice and future work needs to focus on obtaining a reliable and robust scientific technique with validation in an adequately powered independent cohort.

Retos en la implementación de las normas internacionales al interior de los estados. estudio de caso: la región del Mekong y el protocolo de Palermo contra la trata de personas. (2007-2014)

El presente estudio de caso tiene como principal objetivo el de analizar la manera como las características sociopolíticas de los Estados del Mekong, específicamente en el caso de Camboya y Myanmar, dificultan la implementación de las normas enunciadas en el Protocolo de las Naciones Unidas para Prevenir, Reprimir y Sancionar la Trata de Personas, Especialmente Mujeres y Niños, también conocido como el Protocolo de Palermo. En este sentido, se parte de las características principales del Protocolo y de la manera como el tráfico de personas se presenta en el Mekong para posteriormente analizar la forma como la corrupción, la impunidad y la desigualdad de género representan retos sociopolíticos que obstruyen la implementación de los mandatos internacionales enmarcados en este instrumento

Calcium sulfate fillers and binders in Portuguese 15th and 16th centuries: Ground layers from a family painting workshop — Study by multianalytical spectroscopic techniques

This study presents results on a developed methodology to characterize ground layers in Portuguese workshops. In this work a set of altarpieces of the 15th and 16th centuries, assigned to Coimbra painting workshop was studied, overall the masters Vicente Gil (doc. Coimbra 1498–1525), Manuel Vicente (doc. Coimbra 1521–1530) and Bernardo Manuel (act. c. 1559–94), father, son and grandson, encompassing from late gothic to mannerist periods. The aim of the study is to compare ground layers, fillers and binders of Coimbra workshop, and to correlate their characteristics to understand the technical evolution of this family of painters, using complementary microscopic techniques. The cross-sections from the groups of paintings were examined by optical microscopy and the results were integrated through the analysis obtained by μ-X–ray diffraction, scanning electron microscopy with energy dispersive X–ray Spectrometry, μ-confocal Raman and occasionally with μ-Fourier transform infrared spectroscopy imaging. Ground layers are of calcium sulfate, present as gesso grosso (mainly anhydrite with small amounts of gypsum) in the first and last phases of the workshop and gesso mate (mainly gypsum with small amounts of anhydrite) in an intermediate period. Binders have protein and oleic characteristics.

Historical landmarks of decent work

Structured Abstract Purpose: this article systemizes the main historical milestones which led to the current concept of decent work and presents some implications for business. Approach: after presenting the scenario which gives a special meaning and importance to decent work, the historical landmarks are systematized until the definition of the Decent Work Agenda. Findings: Decent work is a concept that has evolved since the ILO Foundation in 1919 and had several important steps throughout its development: Philadelphia Declaration in 1944, ILO constitution update in 1946, Universal Declaration of Human Rights in 1948, Human Development Report, first edition in 1990, World Summit for Social Development in 1995, ILO Declaration on Fundamental Principles and Rights at Work in 1998, World Economic Forum in 1999, Global Compact in 2000, United Nations Millennium Declaration in 2000, ILO Declaration on Social Justice for a Fair Globalization in 2008, Global Jobs Compact in 2009, and inclusion in the 2030 Agenda for Sustainable Development. Throughout this development we can witness the refinement and operationalization of the concept, its institutionalization and its spread at political level, at least as an intention. Practical implications: the business area is a privileged forum to turn policies into practices and some examples are provided. Value: although decent work emerged in a very different social and economic scenario from the present time, it is claimed to be even more topical and relevant for the development of business and society today.

Components of learning and assessment in linear algebra

Linear algebra provides theory and technology that are the cornerstones of a range of cutting edge mathematical applications, from designing computer games to complex industrial problems, as well as more traditional applications in statistics and mathematical modelling. Once past introductions to matrices and vectors, the challenges of balancing theory, applications and computational work across mathematical and statistical topics and problems are considerable, particularly given the diversity of abilities and interests in typical cohorts. This paper considers two such cohorts in a second level linear algebra course in different years. The course objectives and materials were almost the same, but some changes were made in the assessment package. In addition to considering effects of these changes, the links with achievement in first year courses are analysed, together with achievement in a following computational mathematics course. Some results that may initially appear surprising provide insight into the components of student learning in linear algebra.

Cooperation using a robotic ad hoc network made from Bluetooth, JXTA, OSGi and other commercial off the shelf (COTS) products

Abstract - Mobile devices in the near future will need to collaborate to fulfill their function. Collaboration will be done by communication. We use a real world example of robotic soccer to come up with the necessary structures required for robotic communication. A review of related work is done and it is found no examples come close to providing a RANET. The robotic ad hoc network (RANET) we suggest uses existing structures pulled from the areas of wireless networks, peer to peer and software life-cycle management. Gaps are found in the existing structures so we describe how to extend some structures to satisfy the design. The RANET design supports robot cooperation by exchanging messages, discovering needed skills that other robots on the network may possess and the transfer of these skills. The network is built on top of a Bluetooth wireless network and uses JXTA to communicate and transfer skills. OSGi bundles form the skills that can be transferred. To test the nal design a reference implementation is done. Deficiencies in some third party software is found, specifically JXTA and JamVM and GNU Classpath. Lastly we look at how to fix the deciencies by porting the JXTA C implementation to the target robotic platform and potentially eliminating the TCP/IP layer, using UDP instead of TCP or using an adaptive TCP/IP stack. We also propose a future areas of investigation; how to seed the configuration for the Personal area network (PAN) Bluetooth protocol extension so a Bluetooth TCP/IP link is more quickly formed and using the STP to allow multi-hop messaging and transfer of skills.

Media Studies: "Media, History and Society", and "Thinking Popular Culture".

“When cultural life is re-defined as a perpetual round of entertainments, when serious public conversation becomes a form of baby talk, when, in short, a people become an audience and their public business a vaudeville act, then a nation finds itself at risk.” (Postman) The dire tones of Postman quoted in Janet Cramer’s Media, History, Society: A Cultural History of US Media introduce one view that she canvasses, in the debate of the moment, as to where popular culture is heading in the digital age. This is canvassed, less systematically, in Thinking Popular Culture: War Terrorism and Writing by Tara Brabazon, who for example refers to concerns about a “crisis of critical language” that is bothering professionals—journalists and academics or elsewhere—and deplores the advent of the Internet, as a “flattening of expertise in digital environments”.

Esophageal and head and neck cancer

Clinical Nutrition for Oncology Patients provides clinicians with the information they need to help cancer survivors and patients make informed choices about their nutrition and improve their short-term and long-term health. This comprehensive resource outlines nutritional management recommendations for care prior to, during, and after treatment and addresses specific nutritional needs and complementary therapies that may be of help to a patient. This book is written by a variety of clinicians who not only care for cancer survivors and their caregivers but are also experts in the field of nutritional oncology.

Sleeper [for laptop computer and live performer]

Sleeper is an 18'00" musical work for live performer and laptop computer which exists as both a live performance work and a recorded work for audio CD. The work has been presented at a range of international performance events and survey exhibitions. These include the 2003 International Computer Music Conference (Singapore) where it was selected for CD publication, Variable Resistance (San Francisco Museum of Modern Art, USA), and i.audio, a survey of experimental sound at the Performance Space, Sydney. The source sound materials are drawn from field recordings made in acoustically resonant spaces in the Australian urban environment, amplified and acoustic instruments, radio signals, and sound synthesis procedures. The processing techniques blur the boundaries between, and exploit, the perceptual ambiguities of de-contextualised and processed sound. The work thus challenges the arbitrary distinctions between sound, noise and music and attempts to reveal the inherent musicality in so-called non-musical materials via digitally re-processed location audio. Thematically the work investigates Paul Virilio’s theory that technology ‘collapses space’ via the relationship of technology to speed. Technically this is explored through the design of a music composition process that draws upon spatially and temporally dispersed sound materials treated using digital audio processing technologies. One of the contributions to knowledge in this work is a demonstration of how disparate materials may be employed within a compositional process to produce music through the establishment of musically meaningful morphological, spectral and pitch relationships. This is achieved through the design of novel digital audio processing networks and a software performance interface. The work explores, tests and extends the music perception theories of ‘reduced listening’ (Schaeffer, 1967) and ‘surrogacy’ (Smalley, 1997), by demonstrating how, through specific audio processing techniques, sounds may shifted away from ‘causal’ listening contexts towards abstract aesthetic listening contexts. In doing so, it demonstrates how various time and frequency domain processing techniques may be used to achieve this shift.

Enforcing minimum labour standards in Australia from 2010 : correcting or compounding problems

Fair Work Australia is to provide the institutional framework for the Australian industrial relations system from January 2010. Its creation provides the opportunity to improve minimum labour standards’ enforcement in Australia. However, the experience of the past must be appreciated and traditional assumptions about the operation of the Australian enforcement system discarded if the new institution is to be effective in its role. This paper focuses on the role of unions in enforcement as well as institutional location issues to expose a number of central enforcement problems that those seeking to establish new systems and processes should consider. A number of recommendations in respect of the structure of Fair Work Australia and the continuing role of unions are suggested.

Value creation and value capture fro open source software publisher : a new business model based on mutualisation

Key topics: Since the birth of the Open Source movement in the mid-80's, open source software has become more and more widespread. Amongst others, the Linux operating system, the Apache web server and the Firefox internet explorer have taken substantial market shares to their proprietary competitors. Open source software is governed by particular types of licenses. As proprietary licenses only allow the software's use in exchange for a fee, open source licenses grant users more rights like the free use, free copy, free modification and free distribution of the software, as well as free access to the source code. This new phenomenon has raised many managerial questions: organizational issues related to the system of governance that underlie such open source communities (Raymond, 1999a; Lerner and Tirole, 2002; Lee and Cole 2003; Mockus et al. 2000; Tuomi, 2000; Demil and Lecocq, 2006; O'Mahony and Ferraro, 2007;Fleming and Waguespack, 2007), collaborative innovation issues (Von Hippel, 2003; Von Krogh et al., 2003; Von Hippel and Von Krogh, 2003; Dahlander, 2005; Osterloh, 2007; David, 2008), issues related to the nature as well as the motivations of developers (Lerner and Tirole, 2002; Hertel, 2003; Dahlander and McKelvey, 2005; Jeppesen and Frederiksen, 2006), public policy and innovation issues (Jullien and Zimmermann, 2005; Lee, 2006), technological competitions issues related to standard battles between proprietary and open source software (Bonaccorsi and Rossi, 2003; Bonaccorsi et al. 2004, Economides and Katsamakas, 2005; Chen, 2007), intellectual property rights and licensing issues (Laat 2005; Lerner and Tirole, 2005; Gambardella, 2006; Determann et al., 2007). A major unresolved issue concerns open source business models and revenue capture, given that open source licenses imply no fee for users. On this topic, articles show that a commercial activity based on open source software is possible, as they describe different possible ways of doing business around open source (Raymond, 1999; Dahlander, 2004; Daffara, 2007; Bonaccorsi and Merito, 2007). These studies usually look at open source-based companies. Open source-based companies encompass a wide range of firms with different categories of activities: providers of packaged open source solutions, IT Services&Software Engineering firms and open source software publishers. However, business models implications are different for each of these categories: providers of packaged solutions and IT Services&Software Engineering firms' activities are based on software developed outside their boundaries, whereas commercial software publishers sponsor the development of the open source software. This paper focuses on open source software publishers' business models as this issue is even more crucial for this category of firms which take the risk of investing in the development of the software. Literature at last identifies and depicts only two generic types of business models for open source software publishers: the business models of ''bundling'' (Pal and Madanmohan, 2002; Dahlander 2004) and the dual licensing business models (Välimäki, 2003; Comino and Manenti, 2007). Nevertheless, these business models are not applicable in all circumstances. Methodology: The objectives of this paper are: (1) to explore in which contexts the two generic business models described in literature can be implemented successfully and (2) to depict an additional business model for open source software publishers which can be used in a different context. To do so, this paper draws upon an explorative case study of IdealX, a French open source security software publisher. This case study consists in a series of 3 interviews conducted between February 2005 and April 2006 with the co-founder and the business manager. It aims at depicting the process of IdealX's search for the appropriate business model between its creation in 2000 and 2006. This software publisher has tried both generic types of open source software publishers' business models before designing its own. Consequently, through IdealX's trials and errors, I investigate the conditions under which such generic business models can be effective. Moreover, this study describes the business model finally designed and adopted by IdealX: an additional open source software publisher's business model based on the principle of ''mutualisation'', which is applicable in a different context. Results and implications: Finally, this article contributes to ongoing empirical work within entrepreneurship and strategic management on open source software publishers' business models: it provides the characteristics of three generic business models (the business model of bundling, the dual licensing business model and the business model of mutualisation) as well as conditions under which they can be successfully implemented (regarding the type of product developed and the competencies of the firm). This paper also goes further into the traditional concept of business model used by scholars in the open source related literature. In this article, a business model is not only considered as a way of generating incomes (''revenue model'' (Amit and Zott, 2001)), but rather as the necessary conjunction of value creation and value capture, according to the recent literature about business models (Amit and Zott, 2001; Chresbrough and Rosenblum, 2002; Teece, 2007). Consequently, this paper analyses the business models from these two components' point of view.

A review of non-traditional occupational therapy practice placement education : a focus on role-emerging and project placements

Practice placement education has been recognised as an integral and critical component of the training of occupational therapy students. Although there is an extensive body of literature on clinical education and traditional practice placement education models, there has been limited research on alternative placements.-------- This paper reviews the literature on various practice placement education models and presents a contemporary view on how it is currently delivered. The literature is examined with a particular focus on the increasing range of practice placement education opportunities, such as project and role-emerging placements. The drivers for non-traditional practice placement education include shortages of traditional placement options, health reform and changing work practices, potential for role development and influence on practice choice. The benefits and challenges of non-traditional practice placement education are discussed, including supervision issues, student evaluation, professional and personal development and the opportunity to practise clinical skills.--------- Further research is recommended to investigate occupational therapy graduates' perceptions of role-emerging and project placements in order to identify the benefits or otherwise of these placements and to contribute to the limited body of knowledge of emerging education opportunities.

'We just make the pictures...?' How work is portrayed in children's feature length films

This article explores how adult paid work is portrayed in 'family' feature length films. The study extends previous critical media literature which has overwhelmingly focused on depictions of gender and violence, exploring the visual content of films that is relevant to adult employment. Forty-two G/PG films were analyzed for relevant themes. Consistent with the exploratory nature of the research, themes emerged inductively from the films' content. Results reveal six major themes: males are more visible in adult work roles than women; the division of labour remains gendered; work and home are not mutually exclusive domains; organizational authority and power is wielded in punitive ways; there are avenues to better employment prospects; and status/money is paramount. The findings of the study reflect a range of subject matters related to occupational characteristics and work-related communication and interactions which are typically viewed by children in contemporary society.

Why cybersafety tips don’t work for cyberbullying

Research into cyberbullying in Australia has been slow. This is partly because rigorous research takes time, both to conduct, to analyse and to publish. In addition, Australian governments and other decision makers did not realise that cyberbullying was happening until there was greater media attention to the problem in the last few years. This meant that there was no serious research money allocated to cyberbullying research in Australia until about two years ago. In addition, initial research has mainly looked at how many students have been cyberbullied and what were the consequences. As far as I know there is only one large research project which is looking at what programs actually work to prevent and/or intervene in cyberbullying in Australia and that will take time to ascertain. However, our society wants quick fixes and they want a quick fix for cyberbullying.

Union strategies in representing ‘new’ workers : the comparative case of UK and Australian retail unions

This paper is a comparative exploratory study of the changing nature of employee voice through trade union representation in the retail industry in the UK and Australia. In both countries, the retail industry is a major employer and is one of the few private sector service industries with significant union membership (Griffin et al 2003). The relevant unions, the Distributive and Allied Workers Union (USDAW) and the Shop, Distributive and Allied Union (SDA), are the fourth largest and largest unions in the UK and Australia respectively. However, despite this seeming numerical strength in membership, the characteristics of the industry provide unique challenges for employee voice and representation. The significance of the study is that any extension of representation and organisation by unions in the retail sector is valuable socially and politically, given that retail workers are often categorised a s vulnerable, due to their low pay, the predominance of disadvantaged labour market groups such a s women and young people, workers’ atypical employment arrangements and, in the case of the UK, variable levels of union recognition which inhibit representation (Broadbridge 2002; Henley 2006; Lynch 2005; Roan & Diamond 2003; Reynolds et al 2005). In addition, specifically comparative projects have value in that they allow some variables relating to the ‘industry’ to be held constant, thus reducing the range of potential explanations of differences in union strategy. They also have value in that the research partners may be more likely to notice and problematise taken-for-granted aspects of practices in another country, thus bringing to the fore key features and potentially leading to theoretical innovation. Finally, such projects may assist in transnational diffusion of union strategy.