京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第22752号 / 薬科博第126号 / 新制||薬科||14(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 金子 周司, 教授 土居 雅夫, 教授 竹島 浩 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

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Systems biology is an interdisciplinary field that focuses on elucidating complex biological processes (systems) by investigating the interactions among its components through an iterative cycle composed of data generation, data analysis and mathematical modeling. Our contributions to systems biology revolve around the following two axes: - Data analysis: Two data analysis projects, which were initiated when I was a co-op at GlaxoSmithKline, are discussed in this thesis. First, next generation sequencing data generated for a phase I clinical trial is analyzed to determine the altered microbial community in human gut before and after antibiotic usage (Chapter 2). To our knowledge, there have not been similar comparative studies in humans on the impacts on the gut microbiome of an antibiotic when administered by different modes. Second, publicly available gene expression data is analyzed to investigate human immune response to tuberculosis (TB) infection (Chapter 3). The novel feature of this study is systematic drug repositioning for the prevention, control and treatment of TB using the Connectivity map. - Mathematical modeling: Polynomial dynamical systems, a state- and time- discrete logical modeling framework, is used to model two biological processes. First, a denitrification pathway in Pseudomonas aeruginosa is modeled to shed light on the reason of greenhouse gas nitrous oxide accumulation (Chapter 4). It is the first mathematical model of denitrification that can predict the effect of phosphate on the denitrification performance of this bacterium. Second, an iron homeostasis pathway linked to iron utilization, oxidative stress response and oncogenic pathways is constructed to investigate how normal breast cells become cancerous (Chapter 5). To date, our intracellular model is the only expanded core iron model that can capture a breast cancer phenotype by overexpression and knockout simulations. / Ph. D.

Prior to 1980, the practice in multilevel autorack management was to load the railcars at various origin points, ship them to the destination ramps, unload them, and then return each car to the loading point where it originated. Recognizing the inefficiency of such a practice with respect to the fleet size that had to be maintained, and the associated poor utilization due to the excessive empty miles logged, a consolidation of the railcars was initiated and completed by February 1982. Under this pooling program, a central management was established to control the repositioning of three types of empty railcars for eight principal automobile manufacturers. Today, the practice is to consolidate the fleets of all automobile manufacturers for each equipment type, and to solve the distribution problem of repositioning empty multilevel autoracks of each type from points at which they are unloaded to automobile assembly facilities where they need to be reloaded. Each such problem is referred to in the railroad industry as a repositioning scenario. In this dissertation, we present two tactical models to assist in the task of centrally managing the distribution of empty railcars on a day-to-day basis for each repositioning scenario. These models take into account various practical issues such as uncertainties, priorities with respect to time and demand locations, multiple objectives related to minimizing different types of latenesses in delivery, and blocking issues. It is also of great practical interest to the central management team to have the ability to conduct various sensitivity analyses in its operation. Accordingly, the system provides for the capability to investigate various what-if scenarios such as fixing decisions on running a specified block of cars (control orders) along certain routes as dictated by business needs, and handling changes in supplies, demands, priorities, and transit time characteristics. Moreover, the solution methodology provides a flexible decision-making capability by permitting a series of runs based on a sequential decision-fixing process in a real-time operational mode. A turn-around response of about five minutes per scenario (on a Pentium PC or equivalent) is desired in practice. This dissertation begins by developing several progressive formulations that incorporate many practical considerations in the empty railroad car distribution planning system. We investigate the performance of two principal models in this progression to gain more insights into the implementation aspects of our approach. The first model (TDSS1: Tactical Decision Support System-1) considers all the identified features of the problem except for blocking, and results in a network formulation of the problem. This model examines various practical issues such as time and demand location-based priorities as well as uncertainty in data within a multiple objective framework. In the second model (TDSS2: Tactical Decision Support System-2), we add a substantial degree of complexity by addressing blocking considerations. Enforcement of block formation renders the model as a network flow problem with side-constraints and discrete side-variables. We show how the resulting mixed-integer-programming formulation can be enhanced via some partial convex hull constructions using the Reformulation-Linearization Technique (RLT). This tightening of the underlying linear programming relaxation is shown to permit the solution of larger problem sizes, and enables the exact solution of certain scenarios having 5,000 - 8,000 arcs. However, in order to accommodate the strict run-time limit requirements imposed in practice for larger scenarios having about 150,000 arcs, various heuristics are developed to solve this problem. In using a combination of proposed strategies, 23 principal heuristics, plus other hybrid variants, are composed for testing. By examining the performance of various exact and heuristic procedures with respect to speed of operation and the quality of solutions produced on a test-bed of real problems, we prescribe recommendations for a production code to be used in practice. Besides providing a tool to aid in the decision-making process, a principal utility of the developed system is that it provides the opportunity to conduct various what-if analyses. The effects of many of the practical considerations that have been incorporated in TDSS2 can be studied via such sensitivity analyses. A special graphical user interface has been implemented that permits railcar distributors to investigate the effects of varying supplies, demands, and routes, retrieving railcars from storage, diverting en-route railcars, and exploring various customer or user-driven fixed dispositions. The user has the flexibility, therefore, to sequentially compose a decision to implement on a daily basis by using business judgment to make suggestions and studying the consequent response prompted by the model. This system is currently in use by the TTX company, Chicago, Illinois, in order to make distribution decisions for the railroad and automobile industries. The dissertation concludes by presenting a system flowchart for the overall implemented approach, a summary of our research and provides recommendations for future algorithmic enhancements based on Lagrangian relaxation techniques. NOTE: (03/2011) An updated copy of this ETD was added after there were patron reports of problems with the file. / Ph. D.

Finansbranschen utmärker sig som en bransch med höga krav på tillförlitlighet och trovärdighet. En grundförutsättning för finansföretagens överlevnad är kundens fortsatta förtroende där varumärket har en avgörande roll. När marknaden skiftar kan varumärken indirekt behöva anpassas för att till exempel behålla marknadspositionen eller för att nå ut till en bredare målgrupp. Då kan en rebranding- och repositioningprocess bli aktuell. Denna studie syftar till att undersöka vilka utmaningar ett företag verksamt inom finansbranschen kan möta vid rebranding och repositioning samt vilka olika typer av strategier och modeller som finns för att bemöta dessa eventuella utmaningar. Studiens teoretiska ramverk utgörs av Miller et al. (2014) modell över corporate rebranding, en modell som presenterar en rebrandingprocess som följer en kronologisk ordning genom olika faser. Insamlingen av empirin skedde genom att studera sekundärdata i form av befintlig teori och litteratur kring områdena branding, positioning, rebranding och repositioning. Primärdata samlades in genom intervjuer med personer anställda på en kommunikationsbyrå och på ett företag som var högaktuella med en rebranding- och repositioningprocess. Urvalet av intervjupersoner till studien utgick från ett tvåstegsurval. I studien framkommer flertalet utmaningar som ett företag kan möta vid en rebranding- och repositioningprocess. För företag verksamma inom finansbranschen finns ytterligare utmaningar som behöver hanteras. Av studiens analys framkommer inga specifika modeller och strategier för finansföretag att nyttja vid en rebranding- och repositioningprocess. Modellerna och strategierna specialanpassas utifrån företagens rådande situation. / The financial industry stands out as an industry with high demands for reliability and credibility. A fundamental requirement for the survival of financial companies is the continued trust of the customers, where the brand plays a crucial role. When the market shifts, brands may indirectly need to be adapted, for example, to maintain market position or reach a broader target audience. In such cases, a rebranding and repositioning process may become relevant. This study aims to examine the challenges that a company operating in the finance industry may face during rebranding and repositioning, as well as the different types of strategies and models available to address these potential challenges. The theoretical framework of the study is based on Miller et al. (2014) model of corporate rebranding, which presents a rebranding process following a chronological order through different phases. The empirical data collection was conducted by studying secondary data in the form of existing theories and literature on the topics of branding, positioning, rebranding, and repositioning. Primary data was gathered through interviews with individuals employed at a communication agency and a company actively engaged in a rebranding and repositioning process. The selection of interviewees for the study was based on a two-stage sampling. The study reveals several challenges that a company may encounter during a rebranding and repositioning process. For companies operating in the finance industry, there are additional challenges that need to be addressed. The analysis of the study does not identify specific models and strategies for financial companies to utilize during a rebranding and repositioning process. The models and strategies are custom-tailored based on the companies' specific circumstances.

Les tumeurs gliales et glioneuronales sont les tumeurs cérébrales les plus fréquentes chez l'enfant. Elles sont généralement d'excellent pronostic. En revanche, les astrocytomes pilocytiques (AP) hypothalamo-chiasmatiques, ont un potentiel évolutif plus agressif. Ce travail de thèse propose une nouvelle stratégie thérapeutique pour ce sous-type d'AP selon la méthode du « drug repositioning », en employant la combinaison du celecoxib et de la fluvastatine. Nos travaux ont montré in vitro que cette association de molécules était synergique, capable d'arrêter le cycle cellulaire, de diminuer la prolifération et d'induire l'apoptose des cellules tumorales. Cette combinaison a également été testée avec succès chez une patiente souffrant d'un AP multifocal et réfractaire aux traitements conventionnels dans le cadre d'une thérapie métronomique. Ce manuscrit décrit également l'étude histo-moléculaire de plusieurs séries de tumeurs gliales et glioneuronales pédiatriques menées afin d'améliorer leur caractérisation et leur diagnostic. Nos travaux ont confirmé la présence de la fusion KIAA1549:BRAF dans les AP analysés ainsi que le caractère péjoratif de la topographie hypothalamo-chiasmatique, du variant histologique pilomyxoïde et de l'âge au diagnostic inférieur à 36 mois. Ils ont également montré l'absence de différence moléculaire entre les gliomes corticaux de grade II et des DNT. Enfin, nos travaux ont montré que les DNT, les GG et les PXA partagent la mutation BRAFV600E et l'expression de CD34. Ces travaux confirment l'implication majeure de l'altération de la voie des MAPKinases dans la tumorigenèse de ces tumeurs, constituant ainsi une cible thérapeutique prometteuse. / Glial and glioneuronal tumors are the most frequent brain tumors in children. They are characterized by an excellent prognosis. However, hypothalamic-chiasmatic pilocytic astrocytomas (PA) have a more aggressive outcome. In the first part, we propose a new therapeutic strategy for hypothalamic-chiasmatic PA according to drug repositioning method, by using celecoxib, and fluvastatin. We showed that, in vitro, this combination was synergistic, stopped cell cycle, inhibited cell proliferation and increased apoptosis. In addition, this combination was tested with success, under a metronomic chemotherapy, for a girl suffering from a multifocal PA and refractory to conventional treatment. This new strategy of treatment appears promising for this type of tumor because it is less toxic than conventional chemotherapy and not too expensive. In the second part, this manuscript describes the histo-molecular study of several retrospective series of glial and glioneuronal pediatric tumors conducted to improve their characterization and their diagnosis. We confirmed the presence of the fusion gene KIAA1549: BRAF in PA as well as the pejorative nature of the hypothalamic-chiasmatic topography, pilomyxoïde histology and the age at diagnosis less than 36 months. We also showed no molecular difference between cortical grade II gliomas associated with chronic epilepsy and the DNT group. Finally, we showed that DNT, GG and PXA share BRAFV600E mutation and expression of CD34. These studies confirm the major implication of the MAPKinase altered pathway in tumorigenesis of glial and glioneuronal pediatric tumors, constituting a promising therapeutic target.

The amount of biomedical literature has been increasing rapidly during the last decade. Text mining techniques can harness this large-scale data, shed light onto complex drug mechanisms, and extract relation information that can support computational polypharmacology. In this work, we introduce CASSANDRA, a fully corpus-based and unsupervised algorithm which uses the MEDLINE indexed titles and abstracts to infer drug gene associations and assist drug repositioning. CASSANDRA measures the Pointwise Mutual Information (PMI) between biomedical terms derived from Gene Ontology (GO) and Medical Subject Headings (MeSH). Based on the PMI scores, drug and gene profiles are generated and candidate drug gene associations are inferred when computing the relatedness of their profiles. Results show that an Area Under the Curve (AUC) of up to 0.88 can be achieved. The algorithm can successfully identify direct drug gene associations with high precision and prioritize them over indirect drug gene associations. Validation shows that the statistically derived profiles from literature perform as good as (and at times better than) the manually curated profiles. In addition, we examine CASSANDRA’s potential towards drug repositioning. For all FDA-approved drugs repositioned over the last 5 years, we generate profiles from publications before 2009 and show that the new indications rank high in these profiles. In summary, co-occurrence based profiles derived from the biomedical literature can accurately predict drug gene associations and provide insights onto potential repositioning cases.

Cancer is a leading cause of death worldwide. Development of new cancer drugs is increasingly costly and time-consuming. By exploiting massive amounts of biological data, computational repositioning proposes new uses for old drugs to reduce these development hurdles. A promising approach is the systematic analysis of structural data for identification of shared binding pockets and modes of action. In this thesis, I developed the Protein-Ligand Interaction Profiler (PLIP), which characterizes and indexes protein-ligand interactions to enable comparative analyses and searching in all available structures. Following, I applied PLIP to identify new treatment options in cancer: the heat shock protein Hsp27 confers resistance to drugs in cancer cells and is therefore an attractive target with a postulated drug binding site. Starting from Hsp27, I used PLIP to define an interaction profile to screen all structures from the Protein Data Bank (PDB). The top prediction was experimentally validated in vitro. It inhibits Hsp27 and significantly reduces resistance of multiple myeloma cells against the chemotherapeutic agent bortezomib. Besides computational repositioning, PLIP is used in docking, binding mode analysis, quantification of interactions and many other applications as evidenced by over 12,000 users so far. PLIP is provided to the community online and as open source.

<p>This thesis aims to study brand change, which can be of interest since a brand during its lifetime can be expected to meet a lifecycle consisting of five phases; innovation, introduction, growth, maturity and recession. In order to avoid the recession phase and the sales decline that follows there is a need for a change of the brand.</p><p>In order to study brand change, theoretical framework is compared to two real world cases that have gone through an active change.</p><p>The conceptions of positioning, repositioning and revitalization are clarified. Positioning deals with how brands are located in customer’s minds as well as on the real market. Repositioning implies a change of the current position and is also often a move towards a new market segment. Revitalization deals with giving the brand new associations as well as changes in the product. Revitalization in its simplest form can be just a repetition of old messages and associations mixed, in some cases in combination with new ones. Ongoing revitalization can in the long run be seen as incremental repositioning since the brand is updated with small steps in order to follow the customer’s changes in preferences and after a while end up in a new position. Radical repositioning means that you during a short period of time change the foundation of a brand by creating new associations and an almost new product, all to accomplish a trustworthy message to the new target group.</p><p>The two brands, Festis and Explorer Vodka, have both gone through changes but with different reasons. Festis did not have a large customer group and therefore aimed at finding a new attractive target group. Explorer Vodka already had a large circle of customer, which it could not afford to lose, and therefore just a small image change was the solution.</p><p>Festis performed a radical repositioning and switched target group and thereby recaptured the market leader position in the stilldrinkmarket. Explorer Vodka has with small steps improved its image and at the same time stick to their target group by revitalization.</p> / <p>I denna uppsats studeras förändring av varumärken, vilket kan vara av intresse eftersom det kan förväntas att ett varumärke under sin livstid kan komma att möta en livscykel bestående av fem olika faser, utveckling, introduktion, tillväxt, mognad, och slutligen nedgång. För att undvika nedgångsfasen och en eventuell död krävs en förändring av varumärket.</p><p>För att studera förändring av varumärken tillämpas uppsatsens teorier på två fallstudier av varumärken som genomgått ett aktivt förändringsarbete.</p><p>I uppsatsen behandlas begreppet positionering av varumärken såväl som förändringsbegreppen ompositionering och revitalisering. Positionering beskriver hur ett varumärke är placerat i konsumenternas medvetande såväl som på marknaden. Ompositionering innebär förändringar av befintlig position och är ofta en förflyttning till ett annat marknadssegment. Revitalisering innebär bland annat att skapa nya associationer till varumärket genom direkta åtgärder och/eller förändringar i produkten. Ständig revitalisering kan i längden ses som en inkrementell ompositionering eftersom man i små steg följer förändringarna i kundernas uppfattningar. Radikal ompositionering innebär att man under en kort tid förändrar hela grunden för varumärket och istället skapar nya associationer och även förändrar produkten för att på ett så trovärdigt sätt som möjligt rikta sig till en ny målgrupp.</p><p>De två varumärkena Festis och Explorer Vodka har båda genomgått förändringar. Dessa förändringar har skett med lite olika motiv, Festis hade ingen stark kundbas och behövde hitta ett nytt attraktivt kundsegment. Explorer Vodka hade en stark kundbas med och hög försäljning som man inte fick förlora, dock behövde varumärkets image förbättras.</p><p>Festis genomförde en radikal ompositionering och bytte kundsegment och återtog därmed sin forna position som marknadsledare på stilldrinksmarknaden. Explorer Vodka har med små steg förbättrat sin image och samtidigt stannat kvar i samma kundsegment, vilket kan liknas vid en revitaliseringsstrategi.</p>