Cancer progression is a multi-step process requiring cells to acquire specific properties that aid the neoplastic growth. One such property is the ability to survive in the absence of matrix-attachment, a critical necessity for cells to traverse in circulation and seed metastases. Therefore, understanding the signalling mechanisms that protect cells from undergoing death in matrix-deprived condition, termed as anoikis, is important. We have used two systems to study this, one involving experimental transformation model, and another involving cancer cell lines. In the in vitro transformation model system involving the serial introduction of oncogenes, the ability to survive in anchorage-independent condition and generate spheres/colonies was dependent on the presence of the Simian Virus Small T antigen, SV40 ST. We identified that the viral antigen mediates its effects, at least in part, by activating the master metabolic regulator and cellular stress kinase AMP-activated protein kinase (AMPK) leading to maintenance of energy homeostasis. Consistent with this, our lab has previously identified both activation of AMPK upon matrix-deprivation in breast cells, as well as its requirement for survival under these conditions. However, a pathway often associated with survival under matrix-deprivation is the PI3K/Akt pathway. Surprisingly, we observed an AMPK-dependent decrease in Akt activity under conditions of matrix-detachment. Since this was contrary to the general notion, we probed deeper into a possible crosstalk between these two kinases. Our work revealed that AMPK activation in suspension inhibits Akt via upregulation of a known Akt phosphatase, pleckstrin homology domain leucinrich repeat protein phosphatise (PHLPP). We further show that the AMPK-PHLPP-Akt signalling axis is important for anoikis-resistance and metastasis. In addition, our results point to a yet unidentified protumorigenic role of PHLPP in breast cancer progression. With an aim to identify cellular proteins differentially regulated upon AMPK activation in breast cancer cells, we undertook a proteomics approach. Using 2-dimensional gel electrophoresis followed by mass spectrometric analysis, we identified some candidate proteins. We have validated the increase in levels of one of these proteins, annexin A2, in cancer cells upon AMPK activation. In summary, the present study unveils novel oncogenic functions of AMPK in cancer cells under the stress of matrix-deprivation. Furthermore, our results elucidate a double-negative feedback loop between two critical cellular kinases AMPK and Akt, and also identify a novel pro-tumorigenic role of PHLPP in breast cancer. In addition, we identify PHLPP and annexin A2 as novel proteins upregulated by AMPK in cancer cells. Thus, our results begin to identify pathways utilised by cancer cells to aid anchorage-independent growth, a critical step for cancer metastasis. Based on our results, inhibition of AMPK or perturbation of signalling axes involving AMPK, and PHLPP or annexin A2 might be considered as novel therapeutic approaches to combat cancer progression

Digitalization is an upcoming trend that divides the manufacturing industry of today. As an increasing number of companies chose to implement digitalization as a business strategy, some companies still struggle with implementing digitalization into their businesses. Previous research has developed digital transformation models, but has been admitted as too generic. This thesis used the most comprehensive transformation model as base and aimed to make it practically implementable for a manufacturing company with a process layout. To enable this, a case study was conducted on a steel-processing company with this layout design. This thesis had an inductive approach, where primary data were collected from one selected company through a pilot study and semi structured interviews, and secondary data were collected through a literature review. During the study, it was discovered that a company can benefit from using a customized guidance of how to implement digitalization, to optimally use digital opportunities. This thesis contributed with additional steps and extensions of the previous transformation model. The contribution consisted of the involvement of competency, creation of definition, identified digitalization trends relating to a SWOT analysis, additional phenomenon to take into consideration when analyzing future scenarios, additional questions to consider when analyzing impacted areas, creation of a digital business strategy, a comparison of impacted areas with previous projects, additional identified actions to fill the gap between current state and goals, and five identified criteria’s on how to prioritize these actions. This study extends current research with details and depth regarding a digital transformation model, and hence make it more practical. For future research, a case study testing the potential of the transformation model on a similar company should be conducted, and thereby improve the model further. / Digitalisering är en uppgående trend som delar upp dagens tillverkningsindustri. Medan ett ökande antal företag väljer att implementera digitalisering som en affärsstrategi, så kämpar fortfarande andra företag med att implementera digitalisering i sin verksamhet. Tidigare forskning har utvecklat digitala transformationsmodeller, men de har ansetts för allmänna. Denna uppsats använder den mest omfattande digitala transformationsmodellen som bas med syfte att göra den praktiskt användbar för ett tillverkande företag med en funktionell verkstadslayout. För att möjliggöra detta genomfördes en fallstudie på ett stålföretag med denna fabriksdesign. Uppsatsen genomfördes med ett induktivt tillvägagångssätt där primärdata samlades in genom en pilotstudie och halvstrukturerade intervjuer, och sekundärdata samlades in genom en litteraturstudie. Under studien framkom det att ett företag skulle ha nytta av en anpassad vägledning för hur digitalisering ska implementeras för att optimalt utnyttja digitala möjligheter. Denna studie bidrog med ytterligare steg och utökningar av den tidigare transformationsmodellen. Studiens bidrag involverar kompetenssäkring, identifierade digitaliseringstrender relaterade till en SWOTanalys, fenomen att ta hänsyn till gällande framtida scenarion, frågor att överväga vid analys av de påverkade områdena, skapande av en digital affärsstrategi, en jämförelse av påverkade områden med tidigare genomförda projekt, åtgärder för att fylla gapet mellan företagets nuvarande tillstånd och mål och kriterier för hur man prioriterar dessa åtgärder. Denna studie utökar aktuell forskning med detaljer och djup gällande en digital transformationsmodell, och gör den därav mer praktisk. I framtida forskning bör en fallstudie som testar potentialen hos transformationsmodellen på ett liknande företag genomföras, och därigenom förbättra modellen ytterligare.

Submitted by Aelson Maciera (aelsoncm@terra.com.br) on 2017-05-03T20:33:15Z No. of bitstreams: 1 DissASA.pdf: 6143481 bytes, checksum: ae99305f43474756b358bade1f0bd0c7 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-05-04T13:50:02Z (GMT) No. of bitstreams: 1 DissASA.pdf: 6143481 bytes, checksum: ae99305f43474756b358bade1f0bd0c7 (MD5) / Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-05-04T13:50:10Z (GMT) No. of bitstreams: 1 DissASA.pdf: 6143481 bytes, checksum: ae99305f43474756b358bade1f0bd0c7 (MD5) / Made available in DSpace on 2017-05-04T13:53:49Z (GMT). No. of bitstreams: 1 DissASA.pdf: 6143481 bytes, checksum: ae99305f43474756b358bade1f0bd0c7 (MD5) Previous issue date: 2016-01-05 / Não recebi financiamento / Context: MDD (Model-Driven Development) is a software development paradigm in which the main artefacts are models, from which source code or other artefacts are generated. Even though MDD allows different views of how to decompose a problem and how to design a software to solve it, this paradigm introduces new challenges related to the input models, transformations and output artefacts. Problem Statement: Thus, software testing is a fundamental activity to reveal defects and improve confidence in the software products developed in this context. Several techniques and testing criteria have been proposed and investigated. Among them, functional testing has been extensively explored primarily in the M2M (Model-to-Model) transformations, while structural testing for M2T (Model-to-Text) transformations still poses challenges and lacks appropriate approaches. Objective: This work aims to to present a proposal for the structural testing of M2T transformations through the characterisation of input models as complex data, templates and output artefacts involved in this process. Method: The proposed approach was organised in five phases. Its strategy proposes that the complex data (grammars and metamodels) are represented by directed hypergraphs, allowing that a combinatorial-based traversal algorithm creates subsets of the input models that will be used as test cases for the M2T transformations. In this perspective, we carried out two exploratory studies with the specific purpose of feasibility analysis of the proposed approach. Results and Conclusion: The evaluation of results from the exploratory studies, through the analysis of some testing coverage criteria, demonstrated the relevance and feasibility of the approach for characterizing complex data for M2T transformations testing. Moreover, structuring the testing strategy in phases enables the revision and adjustment of activities, in addition to assisting the replication of the approach within different applications that make use of the MDD paradigm. / Contexto: O MDD (Model-Driven Development ou Desenvolvimento Dirigido por Modelos) e um paradigma de desenvolvimento de software em que os principais artefatos são os modelos, a partir dos quais o código ou outros artefatos são gerados. Esse paradigma, embora possibilite diferentes visões de como decompor um problema e projetar um software para soluciona-lo, introduz novos desafios, qualificados pela complexidade dos modelos de entrada, as transformações e os artefatos de saída. Definição do Problema: Dessa forma, o teste de software e uma atividade fundamental para revelar defeitos e aumentar a confiança nos produtos de software desenvolvidos nesse contexto. Diversas técnicas e critérios de teste vem sendo propostos e investigados. Entre eles, o teste funcional tem sido bastante explorado primordialmente nas transformações M2M (Model-to-Model ou Modelo para Modelo), enquanto que o teste estrutural em transformações M2T (Model-to-Text ou Modelo para Texto) ainda possui alguns desafios e carência de novas abordagens. Objetivos: O objetivo deste trabalho e apresentar uma proposta para o teste estrutural de transformações M2T, por meio da caracterização dos dados complexos dos modelos de entrada, templates e artefatos de saída envolvidos neste processo. Metodologia: A abordagem proposta foi organizada em cinco fases e sua estratégia propõe que os dados complexos (gramáticas e metamodelos) sejam representados por meio de hipergrafos direcionados, permitindo que um algoritmo de percurso em hipergrafos, usando combinatória, crie subconjuntos dos modelos de entrada que serão utilizados como casos de teste para as transformações M2T. Nesta perspectiva, realizou-se dois estudos exploratórios com propósito específico da analise de viabilidade quanto a abordagem proposta. Resultados: A avaliação dos estudos exploratórios proporcionou, por meio da analise dos critérios de cobertura aplicados, um conjunto de dados que demonstram a relevância e viabilidade da abordagem quanto a caracterização de dados complexos para os testes em transformações M2T. A segmentação das estratégias em fases possibilita a revisão e adequação das atividades do processo, além de auxiliar na replicabilidade da abordagem em diferentes aplicações que fazem uso do paradigma MDD.

Entrepreneurial Orientation (EO) is a widely researched construct of corporate entrepreneurship. Despite long-standing research on EO, past studies on this construct have been unable to resolve issues related to its measurement. Innovation Intensity (II) is also a dynamic construct of corporate entrepreneurship but has received relatively less empirical attention. Previous research has reported an absence of an empirically validated quantitative scale of innovation, particularly innovation intensity. This research has addressed these gaps by proposing a refinement and validation of the Entrepreneurial Orientation scale and the development of an Innovation Intensity scale. The research proposes an Entrepreneurial Transformational Model (ETM) positing that EO impacts II. A predominantly quantitative research strategy supported by qualitative inputs, is employed to obtain empirical data from 404 corporate firms in Oman, drawing from a list of corporate firms registered with the Oman Chamber of Commerce and Industry. A mix of questionnaire survey and semi-structured interviews was conducted with senior managers from firms representing various industries of the Omani corporate sector. Utilising exploratory factor analysis (EFA), confirmatory factor analysis (CFA), and structural equation modelling (SEM), a two-stage data analysis approach was adopted. Measurement and structural models were developed for EO and II measures, while a complete SEM model was developed to test the causal relationship between EO and II. The results indicate that EO is a second-order construct consisting of five first-order factors, namely ready to innovate, competitive aggressiveness, autonomy, risk taking and proactiveness, which are its reflective components. Similarly, II is a second-order construct consisting of two first-order factors, namely degree and frequency of incremental and radical innovation, which are its reflective components. The II scale developed through this study allows corporate firms to assess their innovation intensity on a two-dimensional four-celled grid with varying levels of degree and frequency of innovation. Finally, EO is found to influence II and the entire relationship is posited as Entrepreneurial Transformation Model. This study, by addressing the empirical irregularities, has brought clarity to the measurement of EO and II constructs and is an original contribution to the advancement of theoretical knowledge and improvement in professional practice.