Dans cette étude, nous décrivons pour la première fois les propriétés anti-tumorales de composés de type thiomorpholine sulfonamide hydroxamate dans le cancer du sein. Nous avons montré que le TMI-1, un inhibiteur à spécificité double MMPs/ADAM-17, est un puissant inhibiteur de la croissance tumoral in vitro et in vivo. Cette activité anti-tumorale est indépendante de l’inhibition d’ADAM-17 et des MMPs. En effet, le TMI-1 inhibe la croissance tumorale in vitro de 89% des lignées tumorales mammaires à des IC50 de l’ordre du micromolaire, par sa double capacité d’induire l’arrêt du cycle cellulaire en G0/G1 et l’apoptose dépendante de la voie extrinsèque. TMI-1 n’a aucun effet sur les cellules normales. In vivo, le TMI-1 inhibe le développement tumoral et l’apparition de nouvelles tumeurs dans les souris transgéniques MMTV-ERBB2/neu. A la différence des drogues cytotoxiques conventionnelles, TMI-1 à une activité sélective sur les cellules tumorales en affectant le pool de cellules souches cancéreuses mammaires. De plus, le TMI-1 agit en synergie en association avec les drogues de chimiothérapie et de thérapies ciblées. TMI-1 a déjà été utilisé en clinique, est une molécule candidate au repositionnement clinique en cancérologie. D’une manière intéressante, une corrélation marquée a pu être mise en évidence entre TMI-1 et le statut mutationnel de P53. Finalement, TMI-1 représente une alternative thérapeutique prometteuse dans le traitement des cancers, d’autant que la sélectivité semble associée à un marqueur « compagnon » P53, muté dans environ 50% des cancers. Le lien existant entre ces composés et P53 passe par l’identification de la ou les cibles. Ce travail est actuellement en cours, utilisant des approches de protéomique inverse. / In this study, we focused on breast cancer and reported for the first time in vitro and in vivo antitumor properties of thiomorpholin sulfonamide hydroxamate compounds. We found that TMI-1, a dual ADAM-17 and MMP inhibitor is a strong anti-cancer agent. TMI-1 exerts its antitumor activity at micromolar range by induction of cell cycle arrest in G0/G1 and extrinsic apoptosis pathway. TMI-1 is not cytotoxic for normal cells. 89% of breast tumor cells are sensitive to TMI-1 in vitro. TMI-1 is also efficient in vivo, inhibits tumor growth and prevents the formation of additional tumors in MMTV-ERBB2/neu transgenic mice. Unlike conventional cytotoxic drugs, TMI-1 has a selective activity on tumor cells by affecting the pool of cancer stem cells. Interestingly TMI-1 is a potent synergistic drug for breast cancer therapy. TMI-1, already used to treat inflammatory disease, is a candidate for drug repositioning in oncology. Interestingly, a marked correlation was found between TMI-1 and the mutational status of P53. Finally, TMI-1 is of outstanding interest, as efficiency may be related to the surrogate marker P53 mutated in approximately 50% of cancers. The relationship between these compounds and P53 is currently in progress. This is done by a reverse proteomic approaches attempting to identify direct target(s).

The South African higher education sector is currently facing many challenges. Factors such as a decrease in government funding, mergers and student unrest compel higher education institutions to apply effective strategies for funding and recruitment of quality students. Higher education institutions are forced to focus on restructuring and repositioning themselves, build a strong brand, communicate their image and to sustain their position in order to ensure a competitive advantage. In order to be locally relevant and globally competitive, higher education institutions need to become more marketing-oriented. In a restricted financial environment, higher education institutions will have to assess and reassess marketing strategies aimed at attracting quality first year students. A proper assessment of the importance of the choice factors students consider when selecting a higher education institution as well as the usefulness of the information sources they consider, will enable institutions to allocate funds, time and resources more efficiently and effectively. A quantitative study with a self-administrated questionnaire was used to allow students to complete the questionnaire during class lectures. Non-probability convenience sampling was used and a sample of 1241 students responded from six higher education institutions: the University of Pretoria, Tshwane University of Technology, University of Johannesburg, University of the Free State, University of Kwa–Zulu Natal and the North-West University. The sample consisted of 64 percent females and 36 percent male students. The ethnic orientation distribution was as follows: 46 percent Caucasian, 41 percent Black African, 9 percent Indian, 3 percent Coloured and 1 percent students of other ethnic groups. The main goal of this study was to investigate the relevant importance of the choice factors, as well as the usefulness of the information sources, that first year Economic and Management Sciences students at selected higher education institutions in South Africa considered when they decided to enrol at a specific higher education institution. The findings indicated that some choice factors were more important to students than others, as well as the fact that students from different gender groups, ethnic groups, language groups and institutions differed in the importance they attached to the choice factors. The top ten choice factors respondents regarded as important in the selection of a higher education institution are: quality of teaching, employment prospects (possible job opportunities), campus safety and security, academic facilities (libraries and laboratories), international links (study and job opportunities), language policy, image of higher education institution, flexible study mode (evening classes and use of computers), academic reputation (prestige), and a wide choice of subjects/courses. The findings also revealed that information sources directly from a higher education institution, such as open days and campus visits, university publications and websites are the most useful to students, while information from mass media such as radio, television, magazines and newspaper advertisements are not as useful. The findings give marketing educators an indication of the importance of choice factors considered by prospective students in selecting a higher education institution, and enable higher education institutions to use their limited funds more efficiently to attract quality students, create a unique position and gain a competitive advantage. Based on the usefulness of information sources and the importance of choice factors considered, student focused marketing communication can be developed. This should aid students to make more informed decisions about the higher education institution they wish to attend. The study also add to existing theory in the fields of services marketing, higher education marketing and consumer behaviour, especially the field of outlet selection, as the institution can be viewed as the outlet for buying education. Information obtained from this study also contributes to the available research and literature on this topic and could be used by other researchers as a basis for future research. / Thesis (PhD)--University of Pretoria, 2008. / Marketing Management / PhD / Unrestricted

Drug repositioning is the discovery of new indications for approved or failed drugs. This practice is commonly done within the drug discovery process in order to adjust or expand the application line of an active molecule. Nowadays, an increasing number of computational methodologies aim at predicting repositioning opportunities in an automated fashion. Some approaches rely on the direct physical interaction between molecules and protein targets (docking) and some methods consider more abstract descriptors, such as a gene expression signature, in order to characterise the potential pharmacological action of a drug (Chapter 1). On a fundamental level, repositioning opportunities exist because drugs perturb multiple biological entities, (on and off-targets) themselves involved in multiple biological processes. Therefore, a drug can play multiple roles or exhibit various mode of actions responsible for its pharmacology. The work done for my thesis aims at characterising these various modes and mechanisms of action for approved drugs, using a mathematical framework called description logics. In this regard, I first specify how living organisms can be compared to complex black box machines and how this analogy can help to capture biomedical knowledge using description logics (Chapter 2). Secondly, the theory is implemented in the Functional Therapeutic Chemical Classification System (FTC - https://www.ebi.ac.uk/chembl/ftc/), a resource defining over 20,000 new categories representing the modes and mechanisms of action of approved drugs. The FTC also indexes over 1,000 approved drugs, which have been classified into the mode of action categories using automated reasoning. The FTC is evaluated against a gold standard, the Anatomical Therapeutic Chemical Classification System (ATC), in order to characterise its quality and content (Chapter 3). Finally, from the information available in the FTC, a series of drug repositioning hypotheses were generated and made publicly available via a web application (https://www.ebi.ac.uk/chembl/research/ftc-hypotheses). A subset of the hypotheses related to the cardiovascular hypertension as well as for Alzheimer’s disease are further discussed in more details, as an example of an application (Chapter 4). The work performed illustrates how new valuable biomedical knowledge can be automatically generated by integrating and leveraging the content of publicly available resources using description logics and automated reasoning. The newly created classification (FTC) is a first attempt to formally and systematically characterise the function or role of approved drugs using the concept of mode of action. The open hypotheses derived from the resource are available to the community to analyse and design further experiments.

The master thesis named "Corporate identity and corporate image of PRIM" analyses the current position of brand PRIM on the watch market in the Czech Republic whereas the main focus is on the description of its corporate identity elements and the brand management strategy. The thesis consists of two main parts - theoretical and practical. The theoretical part defines the concept of corporate identity, corporate image, as well as strategic planning and strategic brand management. The practical part comprises of the ELTON firm's presentation and analysis of the Czech watch market including the description of typical Czech customer. The major attention is paid to the evaluation of PRIM's corporate identity elements and its strategic brand management. At the end of the practical part, there is a presentation of my own proposals for possible improvements of the current brand strategy and consideration of the possibility of expansion into the foreign market.

The aim of the thesis is to characterize the folding containers as one of the potential solutions to the problem of the repositioning of empty containers and to evaluate the possibility of their practical use in intermodal transport. The theoretical part characterizes contemporary development in international trade, intermodal transportation, the issue of empty containers and also characterizes foldable containers together with the assumptions of their successful introduction to the market. The practical part deals with current concepts of foldable containers, there is also an example for comparing the costs of transport when using standard or foldable containers and the opinion of a representative of one of the leading shipping companies on use foldable containers in practice. To obtain information used in the practical part of the thesis a secondary research was carried out, where most information comes from research papers and websites, and also primary research was done in the form of an interview with a representative of the shipping company. In conclusion is the evaluation of the possibility of using foldable containers in practice which is based on the information obtained through research.

Positioning is a key element of brand's strategic management and it is often a driver for success on given market. In every brand's life cycle there can be a moment, where current positioning simply doesn't work anymore, so there is need to reposition the brand to modify the current one or develop a new one. The main goal of this master thesis is to give readers full detail of the whole process of repositioning and to create ideal scenario for this process in FMCG market. I describe all most important parts of the brand and its strategic management related to positioning in the theoretical part. In the practical part I use a method of case study of Birell brand to describe real example of repositioning. This case study also includes reasons and consequences of the repositioning. In conclusion of the thesis, there is compiled ideal scenario of the whole process, that can serve as a basis for further research or as a instruction for future projects.

No description available.

京都大学 / 新制・課程博士 / 博士(薬学) / 甲第23147号 / 薬博第847号 / 新制||薬||242(附属図書館) / 京都大学大学院薬学研究科薬学専攻 / (主査)教授 中山 和久, 教授 土居 雅夫, 准教授 中川 貴之 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Pharmaceutical industry is today struggling with its productivity as products keep failing after long and expensive development programs. The protability is further threatened by erce competition from cheaper product copies. As an attempt to increase the pipeline output, pharmaceutical companies have lately turned to the strategy of drug repositioning. By applying an already developed drug in new disease areas the lifetime of the product is prolonged and return time on already made investments elongated.  Such development is imbued by less risk than a de novo development and has proven to be a faster and cheaper way to meet the medical demand. With limited company budgets and the often many repositioning possibilities, an informed repositioning selection must be made. As such theoretical model is not publicly available this thesis takes on the task to determine which parameters to take into consideration and how these should be weighted in relation to each other in order to evaluate di erent drug repositioning possibilities. Six main topics are identied to a ect the repositioning success, these are: medical need, economic return, scientic support, timing, life cycle extenders and external relations. These ndings are derived from empirics collected during interviews with employees from ve di erent competence areas involved in repositioning initiatives, na mely: research & development, clinical studies, regulatory a airs, pricing, and commercial. By further support from literature within the elds of drug repositioning and R&D project selection a three-step repositioning model was developed. The first step in the three-step repositioning model consists of primary parameters, these are essential parameters that have to be fullled in order to perform a repositioning strategy. If any of the primary parameters are not fullled, the repositioning opportunity should be killed in a go/no-go decision. In a second step, the secondary parameters are evaluated in a scoring model in order to determine the economical outlook of each repositioning opportunity. The opportunities showing greatest economical outlook should further be evaluated in the third and nal step in the three-step repositioning model. In this nal step the di erent repositioning opportunities are evaluated by their coherence with an overall corporate strategy. By applying this repositioning model to a repositioning selection scarce company resources  ay be focused on the repositioning opportunities showing best future prospect. Evaluating the potential of repositioning opportunities in a structured way should also increase chances to succeed. If successful, a repositioning initiative may a ect both company and society as the company improves return on earlier investments, while more patients in need of treatment will receive access to it. However, the three-step repositioning model presented in this thesis should be tested for more cases and perhaps be complemented with additional parameters or di erent gradings in order to optimize the selection.

No description available.