986 resultados para Xenograft Model Antitumor Assays


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In 2004 Prahalad made managers aware of the great economic opportunity that the population at the BoP (Base of the Pyramid) represents for business in the form of new potential consumers. However, MNCs (Multi-National Corporations) generally continue to penetrate low income markets with the same strategies used at the top of the pyramid or choose not to invest at all in these regions because intimidated by having to re-envision their business models. The introduction of not re-arranged business models and products into developing countries has done nothing more over the years than induce new needs and develop new dependencies. By conducting a critical review of the literature this paper investigates and compares innovative approaches to operate in developing markets, which depart from the usual Corporate Social Responsibility marketing rhetoric, and rather consider the potential consumer at the BoP as a ring of continuity in the value chain − a resource that can itself produce value. Based on the concept of social embeddedness (London & Hart, 2004) and the principle that an open system contemplates different provisions (i.e. MNCs bring processes and technology, NGOs cultural mediating skills, governments laws and regulations, native people know-how and traditions), this paper concludes with a new business model reference that empowers all actors to contribute to value creation, while allowing MNCs to support local growth by turning what Prahalad called ‘inclusive capitalism’ into a more sustainable ‘inclusive entrepreneurial development’.

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Protease-activated receptor-2 (PAR2) is a G protein coupled receptor (GPCR) that is activated by proteolytic cleavage of its amino terminal domain by trypsin-like serine proteases. Cleavage of this receptor exposes a neoepitope, termed the tethered ligand (TL), which binds intramolecularly within the receptor to stimulate signal transduction via coupled G proteins. PAR2-mediated signal transduction is also experimentally stimulated by hexapeptides (agonist peptides; APs) that are homologous to the TL sequence. Due to the irreversible nature of PAR2 proteolysis, downstream signal transduction is tightly regulated. Following activation, PAR2 is rapidly uncoupled from downstream signalling by the post-translational modifications phosphorylation and ubiquination which facilitate interactions with â- arrestin. This scaffolding protein couples PAR2 to the internalisation machinery initiating its desensitisation and trafficking through the early and late endosomes followed by receptor degradation. PAR2 is widely expressed in mammalian tissues with key roles for this receptor in cardiovascular, respiratory, nervous and musculoskeletal systems. This receptor has also been linked to pathological states with aberrant expression and signalling noted in several cancers. In prostate cancer, PAR2 signalling induces migration and proliferation of tumour derived cell lines, while elevated receptor expression has been noted in malignant tissues. Importantly, a role for this receptor has also been suggested in prostate cancer bone metastasis as coexpression of PAR2 and a proteolytic activator has been demonstrated by immunohistochemical analysis. Based on these data, the primary focus of this project has been on two aspects of PAR2 biology. The first is characterisation of cellular mechanisms that regulate PAR2 signalling and trafficking. The second aspect is the role of this receptor in prostate cancer bone metastasis. In addition, to permit these studies, it was first necessary to evaluate the specificity of the commercially available anti-PAR2 antibodies SAM11, C17, N19 and H99. The evaluation of the four commercially available antibodies was assessed using four techniques: immunoprecipitation; Western blot analysis; immunofluorescence; and flow cytometry. These approaches demonstrated that three of the antibodies efficiently detect ectopically expressed PAR2 by each of these techniques. A significant finding from this study was that N19 was the only antibody able to specifically detect N-glycosylated endogenous PAR2 by Western blot analysis. This analysis was performed on lysates from prostate cancer derived cell lines and tissue derived from wildtype and PAR2 knockout mice. Importantly, further evaluation demonstrated that this antibody also efficiently detects endogenous PAR2 at the cell surface by flow cytometry. The anti-PAR2 antibody N19 was used to explore the in vitro role of palmitoylation, the post-translational addition of palmitate, in PAR2 signalling, trafficking, cell surface expression and desensitization. Significantly, use of the palmitoylation inhibitor 2-bromopalmitate indicated that palmitate addition is important in trafficking of PAR2 endogenously expressed by prostate cancer cell lines. This was supported by palmitate labelling experiments using two approaches which showed that PAR2 stably expressed by CHO cells is palmitoylated and that palmitoylation occurs on cysteine 361. Another key finding from this study is that palmitoylation is required for optimal PAR2 signalling as Ca2+ flux assays indicated that in response to trypsin agonism, palmitoylation deficient PAR2 is ~9 fold less potent than wildtype receptor with a reduction of about 33% in the maximum signal induced via the mutant receptor. Confocal microscopy, flow cytometry and cell surface biotinylation analyses demonstrated that palmitoylation is required for efficient cell surface expression of PAR2. Importantly, this study also identified that palmitoylation of this receptor within the Golgi apparatus is required for efficient agonist-induced rab11amediated trafficking of PAR2 to the cell surface. Interestingly, palmitoylation is also required for receptor desensitization, as agonist-induced â-arrestin recruitment and receptor degradation were markedly reduced in CHO-PAR2-C361A cells compared with CHO-PAR2 cells. Collectively, these data provide new insights on the life cycle of PAR2 and demonstrate that palmitoylation is critical for efficient signalling, trafficking, cell surface localization and degradation of this receptor. This project also evaluated PAR2 residues involved in ligand docking. Although the extracellular loop (ECL)2 of PAR2 is known to be required for agonist-induced signal transduction, the binding pocket for receptor agonists remains to be determined. In silico homology modelling, based on a crystal structure for the prototypical GPCR rhodopsin, and ligand docking were performed to identify PAR2 transmembrane (TM) amino acids potentially involved in agonist binding. These methods identified 12 candidate residues that were mutated to examine the binding site of the PAR2 TL, revealed by trypsin cleavage, as well as of the soluble ligands 2f-LIGRLO-NH2 and GB110, which are both structurally based on the AP SLIGRLNH2. Ligand binding was evaluated from the impact of the mutated residues on PAR2-mediated calcium mobilisation. An important finding from these experiments was that mutation of residues Y156 and Y326 significantly reduced 2f-LIGRLO-NH2 and GB110 agonist activity. L307 was also important for GB110 activity. Intriguingly, mutation of PAR2 residues did not alter trypsin-induced signalling to the same extent as for the soluble agonists. The reason for this difference remains to be further examined by in silico and in vitro experimentation and, potentially, crystal structure studies. However, these findings identified the importance of TM domains in PAR2 ligand docking and will enhance the design of both PAR2 agonists and potentially agents to inhibit signalling (antagonists). The potential importance of PAR2 in prostate cancer bone metastasis was examined using a mouse model. In patients, prostate cancer bone metastases cause bone growth by disrupting bone homeostasis. In an attempt to mimic prostate cancer growth in bone, PAR2 responsive 22Rv1 prostate cancer cells, which form mixed osteoblastic and osteolytic lesions, were injected into the proximal aspect of mouse tibiae. A role for PAR2 was assessed by treating these mice with the recently developed PAR2 antagonist GB88. As controls, animals bearing intra-tibial tumours were also treated with vehicle (olive oil) or the prostate cancer chemotherapeutic docetaxel. The effect of these treatments on bone was examined radiographically and by micro-CT. Consistent with previous studies, 22Rv1 tumours caused osteoblastic periosteal spicule formation and concurrent osteolytic bone loss. Significantly, blockade of PAR2 signalling reduced the osteoblastic and osteolytic phenotype of 22Rv1 tumours in bone. No bone defects were detected in mice treated with docetaxel. These qualitative data will be followed in the future by quantitative micro-CT analysis as well as histology and histomorphometry analysis of already collected tissues. Nonetheless, these preliminary experiments highlight a potential role for PAR2 in prostate cancer growth in bone. In summary, in vitro studies have defined mechanisms regulating PAR2 activation, downstream signalling and trafficking and in vivo studies point to a potential role for this receptor in prostate cancer bone metastasis. The outcomes of this project are that a greater understanding of the biology of PAR2 may lead to the development of strategies to modulate the function of this receptor in disease.

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Targeting students’ learning is at the centre of education. In addition, education is promoted as a solution on various issues; consequently educators seek ways for teachers to address societal needs, students’ learning needs, and the overcrowded curriculum. There are definition debates and issues around integrating curricula. However, the rationale for primary students undertaking curricula integrated learning can provide motivation for primary teachers to devise and implement curricula integrated lessons in the classroom. More exploration is required to present models for the practical implementation of curricula integration. This paper provides practical ideas for curricula integration that focus on combining achievement standards from the Australian Curriculum: Science and other key learning areas.

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The productivity of the construction industry worldwide has been declining over the past forty years. One approach to improving the situation is by the introduction of lean construction. The IKEA model has also been shown to be beneficial when used in the construction context. A framework is developed in which the lean construction concept is embodied within the IKEA model by integrating Virtual Prototyping (VP) technology and its implementation is described and evaluated through a real-life case implementing the lean production philosophy. The operational flows of the IKEA model and lean construction are then compared to analyze the feasibility of IKEA-based lean construction. It is concluded that the successful application of the IKEA model in this context will promote the implementation of lean construction and improve the efficiency of the industry.

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Sustainable urban development and the liveability of a city are increasingly important issues in the context of land use planning and infrastructure management. In recent years, the promotion of sustainable urban development in Australia and overseas is facing various physical, socioeconomic and environmental challenges. These challenges and problems arise from the lack of capability of local governments to accommodate the needs of the population and economy in a relatively short timeframe. The planning of economic growth and development is often dealt with separately and not included in the conventional land use planning process. There is also a sharp rise in the responsibilities and roles of local government for infrastructure planning and management. This increase in responsibilities means that local elected officials and urban planners have less time to prepare background information and make decisions. The Brisbane Urban Growth Model has proven initially successful in providing a dynamic platform to ensure timely and coordinated delivery of urban infrastructure. Most importantly, this model is the first step for local governments in moving toward a systematic approach to pursuing sustainable and effective urban infrastructure management.

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In recent years, local government infrastructure management practices have evolved from conventional land use planning to more wide ranging and integrated urban growth and infrastructure management approaches. The roles and responsibilities of local government are no longer simply to manage daily operational functions of a city and provide basic infrastructure. Local governments are now required to undertake economic planning, manage urban growth; be involved in major infrastructure planning; and even engage in achieving sustainable development objectives. The Brisbane Urban Growth model has proven initially successful to ensure timely and coordinated delivery of urban infrastructure. This model may be the first step for many local governments to move toward an integrated, sustainable and effective infrastructure management.

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Broad, early definitions of sustainable development have caused confusion and hesitation among local authorities and planning professionals. This confusion has arisen because loosely defined principles of sustainable development have been employed when setting policies and planning projects, and when gauging the efficiencies of these policies in the light of designated sustainability goals. The question of how this theory-rhetoric-practice gap can be filled is the main focus of this chapter. It examines the triple bottom line approach–one of the sustainability accounting approaches widely employed by governmental organisations–and the applicability of this approach to sustainable urban development. The chapter introduces the ‘Integrated Land Use and Transportation Indexing Model’ that incorporates triple bottom line considerations with environmental impact assessment techniques via a geographic, information systemsbased decision support system. This model helps decision-makers in selecting policy options according to their economic, environmental and social impacts. Its main purpose is to provide valuable knowledge about the spatial dimensions of sustainable development, and to provide fine detail outputs on the possible impacts of urban development proposals on sustainability levels. In order to embrace sustainable urban development policy considerations, the model is sensitive to the relationship between urban form, travel patterns and socio-economic attributes. Finally, the model is useful in picturing the holistic state of urban settings in terms of their sustainability levels, and in assessing the degree of compatibility of selected scenarios with the desired sustainable urban future.

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Recent management research has evidenced the significance of organizational social networks, and communication is believed to impact the interpersonal relationships. However, we have little knowledge on how communication affects organizational social networks. This paper studies the dynamics between organizational communication patterns and the growth of organizational social networks. We propose an organizational social network growth model, and then collect empirical data to test model validity. The simulation results agree well with the empirical data. The results of simulation experiments enrich our knowledge on communication with the findings that organizational management practices that discourage employees from communicating within and across group boundaries have disparate and significant negative effect on the social network’s density, scalar assortativity and discrete assortativity, each of which correlates with the organization’s performance. These findings also suggest concrete measures for management to construct and develop the organizational social network.

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This work-in-progress paper presents an ensemble-based model for detecting and mitigating Distributed Denial-of-Service (DDoS) attacks, and its partial implementation. The model utilises network traffic analysis and MIB (Management Information Base) server load analysis features for detecting a wide range of network and application layer DDoS attacks and distinguishing them from Flash Events. The proposed model will be evaluated against realistic synthetic network traffic generated using a software-based traffic generator that we have developed as part of this research. In this paper, we summarise our previous work, highlight the current work being undertaken along with preliminary results obtained and outline the future directions of our work.

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This paper will present program developers and institutional administrators with a program delivery model suitable for cross cultural international delivery developing students from industry through to master’s level tertiary qualifications. The model was designed to meet the needs of property professionals from an industry where technical qualifications are the norm and tertiary qualifications are emerging. A further need was to develop and deliver a program that enhanced the University’s current program profile in both the domestic and international arenas. Early identification of international educational partners, industry need and the ability to service the program were vital to the successful development of Master of Property program. The educational foundations of the program rest in educational partners, local tutorial support, international course management, cultural awareness of and in content, online communication fora, with a delivery focus on problem-based learning, self-directed study, teamwork and the development of a global understanding and awareness of the international property markets. In enrolling students from a diverse cultural background with technical qualifications and/or extensive work experience there are a number of educational barriers to be overcome for all students to successfully progress and complete the program. These barriers disappear when the following mechanisms are employed: individual student pathways, tutorial support by qualified peers, enculturation into tertiary practice, assessment tasks that recognise cultural norms and values, and finally that value is placed on the experiential knowledge, cultural practices and belief systems of the students.

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Owing to the successful use of non-invasive vibration analysis to monitor the progression of dental implant healing and stabilization, it is now being considered as a method to monitor femoral implants in transfemoral amputees. This study uses composite femur-implant physical models to investigate the ability of modal analysis to detect changes at the interface between the implant and bone simulating those that occur during osseointegration. Using electromagnetic shaker excitation, differences were detected in the resonant frequencies and mode shapes of the model when the implant fit in the bone was altered to simulate the two interface cases considered: firm and loose fixation. The study showed that it is beneficial to examine higher resonant frequencies and their mode shapes (rather than the fundamental frequency only) when assessing fixation. The influence of the model boundary conditions on the modal parameters was also demonstrated. Further work is required to more accurately model the mechanical changes occurring at the bone-implant interface in vivo, as well as further refinement of the model boundary conditions to appropriately represent the in vivo conditions. Nevertheless, the ability to detect changes in the model dynamic properties demonstrates the potential of modal analysis in this application and warrants further investigation.

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Approximate clone detection is the process of identifying similar process fragments in business process model collections. The tool presented in this paper can efficiently cluster approximate clones in large process model repositories. Once a repository is clustered, users can filter and browse the clusters using different filtering parameters. Our tool can also visualize clusters in the 2D space, allowing a better understanding of clusters and their member fragments. This demonstration will be useful for researchers and practitioners working on large process model repositories, where process standardization is a critical task for increasing the consistency and reducing the complexity of the repository.

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Bananas are one of the world�fs most important crops, serving as a staple food and an important source of income for millions of people in the subtropics. Pests and diseases are a major constraint to banana production. To prevent the spread of pests and disease, farmers are encouraged to use disease�] and insect�]free planting material obtained by micropropagation. This option, however, does not always exclude viruses and concern remains on the quality of planting material. Therefore, there is a demand for effective and reliable virus indexing procedures for tissue culture (TC) material. Reliable diagnostic tests are currently available for all of the economically important viruses of bananas with the exception of Banana streak viruses (BSV, Caulimoviridae, Badnavirus). Development of a reliable diagnostic test for BSV is complicated by the significant serological and genetic variation reported for BSV isolates, and the presence of endogenous BSV (eBSV). Current PCR�] and serological�]based diagnostic methods for BSV may not detect all species of BSV, and PCR�]based methods may give false positives because of the presence of eBSV. Rolling circle amplification (RCA) has been reported as a technique to detect BSV which can also discriminate between episomal and endogenous BSV sequences. However, the method is too expensive for large scale screening of samples in developing countries, and little information is available regarding its sensitivity. Therefore the development of reliable PCR�]based assays is still considered the most appropriate option for large scale screening of banana plants for BSV. This MSc project aimed to refine and optimise the protocols for BSV detection, with a particular focus on developing reliable PCR�]based diagnostics Initially, the appropriateness and reliability of PCR and RCA as diagnostic tests for BSV detection were assessed by testing 45 field samples of banana collected from nine districts in the Eastern region of Uganda in February 2010. This research was also aimed at investigating the diversity of BSV in eastern Uganda, identifying the BSV species present and characterising any new BSV species. Out of the 45 samples tested, 38 and 40 samples were considered positive by PCR and RCA, respectively. Six different species of BSV, namely Banana streak IM virus (BSIMV), Banana streak MY virus (BSMYV), Banana streak OL virus (BSOLV), Banana streak UA virus (BSUAV), Banana streak UL virus (BSULV), Banana streak UM virus (BSUMV), were detected by PCR and confirmed by RCA and sequencing. No new species were detected, but this was the first report of BSMYV in Uganda. Although RCA was demonstrated to be suitable for broad�]range detection of BSV, it proved time�]consuming and laborious for identification in field samples. Due to the disadvantages associated with RCA, attempts were made to develop a reliable PCR�]based assay for the specific detection of episomal BSOLV, Banana streak GF virus (BSGFV), BSMYV and BSIMV. For BSOLV and BSGFV, the integrated sequences exist in rearranged, repeated and partially inverted portions at their site of integration. Therefore, for these two viruses, primers sets were designed by mapping previously published sequences of their endogenous counterparts onto published sequences of the episomal genomes. For BSOLV, two primer sets were designed while, for BSGFV, a single primer set was designed. The episomalspecificity of these primer sets was assessed by testing 106 plant samples collected during surveys in Kenya and Uganda, and 33 leaf samples from a wide range of banana cultivars maintained in TC at the Maroochy Research Station of the Department of Employment, Economic Development and Innovation (DEEDI), Queensland. All of these samples had previously been tested for episomal BSV by RCA and for both BSOLV and BSGFV by PCR using published primer sets. The outcome from these analyses was that the newly designed primer sets for BSOLV and BSGFV were able to distinguish between episomal BSV and eBSV in most cultivars with some B�]genome component. In some samples, however, amplification was observed using the putative episomal�]specific primer sets where episomal BSV was not identified using RCA. This may reflect a difference in the sensitivity of PCR compared to RCA, or possibly the presence of an eBSV sequence of different conformation. Since the sequences of the respective eBSV for BSMYV and BSIMV in the M. balbisiana genome are not available, a series of random primer combinations were tested in an attempt to find potential episomal�]specific primer sets for BSMYV and BSIMV. Of an initial 20 primer combinations screened for BSMYV detection on a small number of control samples, 11 primers sets appeared to be episomal�]specific. However, subsequent testing of two of these primer combinations on a larger number of control samples resulted in some inconsistent results which will require further investigation. Testing of the 25 primer combinations for episomal�]specific detection of BSIMV on a number of control samples showed that none were able to discriminate between episomal and endogenous BSIMV. The final component of this research project was the development of an infectious clone of a BSV endemic in Australia, namely BSMYV. This was considered important to enable the generation of large amounts of diseased plant material needed for further research. A terminally redundant fragment (.1.3 �~ BSMYV genome) was cloned and transformed into Agrobacterium tumefaciens strain AGL1, and used to inoculate 12 healthy banana plants of the cultivars Cavendish (Williams) by three different methods. At 12 weeks post�]inoculation, (i) four of the five banana plants inoculated by corm injection showed characteristic BSV symptoms while the remaining plant was wilting/dying, (ii) three of the five banana plants inoculated by needle�]pricking of the stem showed BSV symptoms, one plant was symptomless while the remaining had died and (iii) both banana plants inoculated by leaf infiltration were symptomless. When banana leaf samples were tested for BSMYV by PCR and RCA, BSMYV was confirmed in all banana plants showing symptoms including those were wilting and/or dying. The results from this research have provided several avenues for further research. By completely sequencing all variants of eBSOLV and eBSGFV and fully sequencing the eBSIMV and eBSMYV regions, episomal BSV�]specific primer sets for all eBSVs could potentially be designed that could avoid all integrants of that particular BSV species. Furthermore, the development of an infectious BSV clone will enable large numbers of BSVinfected plants to be generated for the further testing of the sensitivity of RCA compared to other more established assays such as PCR. The development of infectious clones also opens the possibility for virus induced gene silencing studies in banana.

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This paper outlines a novel approach for modelling semantic relationships within medical documents. Medical terminologies contain a rich source of semantic information critical to a number of techniques in medical informatics, including medical information retrieval. Recent research suggests that corpus-driven approaches are effective at automatically capturing semantic similarities between medical concepts, thus making them an attractive option for accessing semantic information. Most previous corpus-driven methods only considered syntagmatic associations. In this paper, we adapt a recent approach that explicitly models both syntagmatic and paradigmatic associations. We show that the implicit similarity between certain medical concepts can only be modelled using paradigmatic associations. In addition, the inclusion of both types of associations overcomes the sensitivity to the training corpus experienced by previous approaches, making our method both more effective and more robust. This finding may have implications for researchers in the area of medical information retrieval.

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Purpose: There is a lack of theory relating to destination brand performance measurement in the destination branding literature, which emerged in the late 1990s (see for example Dosen, Vransevic, & Prebezac, 1998). Additionally, there is a lack of research about the importance of travel context in consumers’ destination decision making (Hu & Ritchie, 1993). This study develops a structural model to measure destination brand performance across different travel situations. The theory of planned behaviour (TpB) was utilised as a framework to underpin the consumer-based brand equity (CBBE) hierarchy to develop a model of destination brand performance. Research approach: A proposed model of destination brand performance was developed through a review of the literature. The first study was used to identify destination image attributes (the core construct) using an analysis of the literature, a document analysis, and personal interviews using the Repertory Test qualitative technique. Underpinned by Personal Construct Theory (PCT), the Repertory Test enables the elicitation of attributes consumers use to evaluate destinations when considering travel. Data was examined in the first study to i) identify any attribute differences in travel contexts and ii) create a scale for use in a questionnaire. A second study was conducted to test the proposed model using a questionnaire with eight groups of participants to assess four destinations across two travel contexts. The model was tested utilising structural equation modelling. Findings: The first study resulted in a list of 29 destination image attributes for use in a scale index. Attributes were assessed across travel contexts and few differences were identified. The second study assessed the congruence of destination brand identity (the destination marketing organisation’s desired image) and destination brand image (the actual perceptions held by consumers) using importance-performance analyses. Finally, the proposed model of destination brand performance was tested. Overall the data supported the model of destination brand performance across travel contexts and destinations. Additionally, this was compared to consumers’ decision sets, further supporting the model. Value: This research provides a contribution to the destination marketing literature through the development of a measurement of destination brand performance underpinned by TpB. Practically; it will provide destination marketing organisations with a tool to track destination brand performance, relative to key competing places, over time. This is important given the development of a destination brand is a long term endeavour.