Le microenvironnement, composé de différents éléments cellulaires et de la matrice extracellulaire, joue un rôle primordial dans le développement tumoral et la dissémination métastatique. Ainsi, l'étude de ces interactions cellulaires est importante pour que des thérapies ciblées luttent contre la chimiorésistance des cellules tumorales. Ce travail de thèse a pour but d'étudier le rôle du facteur de croissance IGF-I dans la chimiorésistance des cellules du cancer de l'ovaire et des leucémies myéloïdes présente au sein du microenvironnement.Dans un premier temps, nous avons mis en évidence que la chimiorésistance des cellules du cancer de l'ovaire, acquise grâce aux cellules hôtes (hospicells), est liée à la sécrétion de IGF-I par ces cellules. Nous avons également montré que IGF-I est impliqué dans la régulation de certains gènes ABC (MDR-1, MRP1, MRP2, et BCRP) via les voies de STAT3, Jak2, PI3K et ERK.Dans les leucémies myéloïdes, nous avons montré que IGF-I a un effet sur la prolifération des cellules tumorales. Il induit l'expression de la protéine P-gp ainsi que la chimiorésistance des cellules sensibles à la chimiothérapie. Nous avons également déterminé le rôle de IGF-I dans la résistance des cellules leucémiques en présence des hospicells. Ces dernières ont une activité hyperangiogénique in vivo, lié à l'HIF-1 et au VEGF, et inhibent les réponses immunes des lymphocytes T par production de NO.Nous avons déterminé le rôle crucial de MMP-9 dans la migration des cellules résistantes du cancer du sein exprimant la protéine P-gp et dans la formation d'un réseau tubulaire, suggérant un lien existant entre l'expression de P-gp et de MMP-9.

Resistance to chemotherapy is partly due to efflux pumps expressed in the plasma membrane which prevents the accumulation of anticancer, antiviral, antifungal and antibacterial drugs in target cells. Three human ABC transporters are particularly involved in MDR phenotype: P-gp/ABCB1, MRP1/ABCC1 and BCRP/ABCG2. Among the different approaches used to overcome the resistance linked to these transporters, the development of non-substrate drugs MDR-ABC transporters has been described. Here, new class of HIV-1 protease inhibitors not recognized by P-gp/BCRP were identified, promising to be attractive candidates to HAART therapy. Since the determination of the X-ray structures in different conformations is a key point to understand how MDR-ABC transporters translocate drugs across the plasma membrane, the crystal structures of three inward-facing conformations of mouse P-gp were resolved. One structure has a camel nanobody bound to the C-terminal side of the first nucleotide-binding domain, revealing a unique epitope on P-gp and freezing a new open-inward conformation. Finally, the enzymatic characterization of two inhibitors co-crystallized with the mouse P-gp has allowed to localize two main binding sites by which drugs efflux occurs. These results bring new findings of the drug-efflux mechanism and offer the possibility to target more precisely those sites to develop modulators of this pump

La surexpression de pompes d'efflux par les cellules cancéreuses permet l'élimination d'agents cytotoxiques, induisant alors une résistance à la chimiothérapie. Trois transporteurs ABC sont principalement impliqués dans cette résistance : P-gp/ABCB1, MRP1-ABCC1 et BCRP/ABCG2. La surexpression des ces transporteurs peut également être le "talon d'Achille" des cellules cancéreuses résistantes en les sensibilisant à certains composés. Ce phénomène, appelé sensibilité collatérale, pourrait constituer un nouvel outil thérapeutique conter les les cancers intrinséquement ou rendus résistants en éliminant sélectivement les cellules cancéreuse résistances. Ainsi, le S-vérapamil provoque la mort sélective par apoptose des cellules surexprimant suite à l'extrusion rapide et massive du glutathion 5GSH) intracellulaire par MRP1. Nous avons démontré que le vérapamil est capable de dépléter s"lectivement de leur contenu en GSH les tumeurs de cancer du poumon H69AR, MRP1 positives et résistantes, dès 3 heures d'exposition aiguë. Le vérapamil étant fortemnt carditoxique, nous avons développé de nouveaux agents de sensibilité collatérale, plus sélectif que le vérapamil, comme le xanthone 9, le flavonoïde 36 et le dimère de flavonoïde 4e. Enfin, grâce à l'étude de chimères MRP1/MRP2, nous avons démontré que la région comprenant les boucles L0 et L1-TM12 pourrait constituter les sites modualteurs et substrat du GSH sur MRP1.

隨著科技技術的發達，資訊科技的產品生命週期也相對縮短，電子產品製造 商為使能快速生產新產品以獲得市佔率賺取利潤，進而要求新廠建造工期快速完工且品質穩定以掌握市場趨勢，搶先競爭者發表新產品以站穩市場銷售地位。有鑑於此，本研究個案公司為科技廠房建造業者，在面臨超速競爭下之龐大壓力，需以快、狠、準的第一時間掌握顧客需求，同時，在科技廠房建造業之大量同業競爭下，價格之透明化也壓縮利潤空間。因此，本研究個案公司需能精準掌握成本，以最少的成本達到顧客對品質的需求，有鑑於此，擁有企業內部成本絕佳控制能力遂變成本研究個案公司之競爭優勢。 為重新找尋個案公司之競爭優勢，本研究率先透過SWOT 進行企業內部優劣勢與外部機會威脅之分析，探討現存企業之經營問題。本研究發現在外部環境變遷下低成本優勢已不復存，因此，解決此問題重新尋求新競爭優勢變得刻不容 緩之事，而其中個案公司內部「成本控制」就變得極為重要。接著，利用ABC 對個案公司之作業流程進行初步了解，發現個案公司需導入作業成本控制系統以 彌補傳統成本控制系統之不足，使成本資訊更加科學，真實呈現產品間之成本， 讓企業產銷決策更為合理。最後，本研究希冀未來個案公司能發展專屬自己之新 作業成本制度，以精準掌握各分公司間之成本，消滅不增值之作業，改進增值之 作業，以有效充分利用資源，健全公司成本控管系統，用最少成本發揮最大利潤， 獲得獨特競爭優勢，讓管理者能充分瞭解企業內部各產品間之營利狀況，重新定 位其策略方針並調整內部管理。 / The product life cycle in information technology industry has been getting shorter with the development of technology. It is clear to see that semiconductor manufacturing companies which can shorten the construction period in building high-tech construction plants to produce and release new products sooner than ever before are possible to grab more market share than competitors in boosting profits. The company discussed in this paper focuses on building high-tech construction plants. Faced with the price competition from competitors, low cost strategy simply does not offer an advantage. The company in this case study must establish the cost management system to analyze and predict the cost of each project accurately in advance that leads to spend the least expenditure to meet customer need.

Αναμφισβήτητα, τις τελευταίες δεκαετίες έχουν λάβει χώρα σημαντικές αλλαγές στο επιχειρησιακό περιβάλλον σε παγκόσμια κλίμακα, οι οποίες έχουν μεταβάλλει ριζικά τη δομή του. Παραδείγματα τέτοιων αλλαγών αποτελούν η εισαγωγή ευέλικτων συστημάτων παραγωγής, η εντατικοποίηση και η αυτοματοποίηση των παραγωγικών διαδικασιών, η αύξηση των γενικών εξόδων τόσο ως ποσό όσο και ως ποσοστό επί του συνολικού κόστους των προϊόντων, η μείωση του κόστους άμεσης εργασίας (κυρίως στη βιομηχανία ) ως ποσοστό του κόστους παραγωγής, η αύξηση της ποικιλίας προϊόντων που παράγονται σε μικρές ποσότητες και με διαφορετικές προδιαγραφές, η αύξηση του ρυθμού εισαγωγής νέων προϊόντων στην αγορά τα οποία έχουν μικρό κύκλο ζωής, η υιοθέτηση πελατοκεντρικού προσανατολισμού κ.α. Οι παραπάνω αλλαγές σε συνδυασμό με την αύξηση της έντασης του ανταγωνισμού και της συνεπακόλουθης μείωσης των περιθωρίων κέρδους, έχουν ανάγει σε πηγή ανταγωνιστικού πλεονεκτήματος την αποτελεσματική παρακολούθηση και, κυρίως, διοίκηση τους κόστους των ξενοδοχειακών επιχειρήσεων. Για τη λήψη ορθών επιχειρηματικών αποφάσεων απαιτείται ορθή πληροφόρηση, η οποία, σε μεγάλο βαθμό, στηρίζεται στα αριθμητικά μεγέθη που παράγει η κοστολογική οργάνωση των ξενοδοχειακών επιχειρήσεων. Εξάλλου, ο σωστός προγραμματισμός και η άσκηση της οικονομικής πολιτικής από το Κράτος απαιτεί επίσης σωστή και αντικειμενική πληροφόρηση, που στηρίζεται τα μέγιστα στα μεγέθη του κόστους. Η Κοστολόγηση είναι, δηλαδή, η διαδικασία που αριθμοποιεί τη ζωή των οικονομικών μονάδων, συγκεντρώνει, αναλύει, επεξεργάζεται, συσχετίζει τα αριθμητικά μεγέθη τα οποία συνοψίζει και παρουσιάζει καταλλήλως ώστε να είναι αξιοποιήσιμα από τους λήπτες των επιχειρηματικών αποφάσεων. Για να είναι όμως τα μεγέθη του κόστους αξιοποιήσιμα θα πρέπει, εκτός των άλλων, να τυγχάνουν μιας τέτοιας επεξεργασίας, κατάταξης και συσχετισμών ώστε να διασφαλίζεται η μέσω αυτών και δι’ αυτών κατάρτιση ορθών οικονομικών εκθέσεων και γενικά η άσκηση ελέγχου για την ορθότητα κάθε επιχειρηματικής απόφασης. Η σημαντικότητα του εργαλείου της κοστολόγησης για την παροχή αξιόπιστων πληροφοριών στη διοίκηση της ξενοδοχειακής επιχείρησης, για τη λήψη αποφάσεων αποτέλεσε έναυσμα για τη διενέργεια της παρούσας μελέτης η οποία αναφέρεται σε ένα από τα πλέον σύγχρονα πεδία έρευνας και ανάπτυξης της Λογιστικής Επιστήμης που συνδέεται με τη χρησιμοποίηση επιστημονικών μεθόδων, αρχών και κανόνων, στη Διοίκηση των επιχειρήσεων και ιδιαίτερα των ξενοδοχειακών. Όπως είναι γνωστό, η διοίκηση των επιχειρήσεων, πραγματοποιείται μέσω των λαμβανόμενων καθημερινά επιχειρηματικών αποφάσεων από τους υπεύθυνους φορείς εξουσίας – αρμοδιότητας και ευθύνης – που βρίσκονται σε όλα τα επίπεδα της Διοικητικής πυραμίδας. Αναλυτικότερα, οι επιμέρους στόχοι της παρούσας μελέτης είναι οι ακόλουθοι: Μέσα από την ανάλυση και την εμπειρική έρευνα των ξενοδοχείων να προκύψει μια πολιτική λογιστικής και κοστολογικής οργάνωσης αυτών, επισήμανση της σημασίας και του μεγέθους της τουριστικής ανάπτυξης της Ελλάδας, αναφορά στον εγχώριο και διεθνή ανταγωνισμό, παρουσίαση της κοστολογικής οργάνωσης των ξενοδοχείων και ανάλυση των κοστολογικών συστημάτων που χρησιμοποιούνται από αυτά, λαμβάνοντας υπόψη τις ιδιαιτερότητες του κλάδου των ξενοδοχειακών επιχειρήσεων που έχουν αντίκτυπο στην κοστολόγηση (τιμολόγηση, εποχικότητα, κόστος αδράνειας- υπολειτουργίας, value added, non value added δαπάνες, κ.λπ.). Η παρούσα διπλωματική μελέτη αποτελείται από οκτώ (8) κεφάλαια στα οποία πραγματεύονται τα ακόλουθα : Στο Κεφάλαιο 1 αναλύεται η δομή του ξενοδοχειακού συστήματος, στο Κεφάλαιο 2 αναλύεται η δομή του Τουριστικού συστήματος, στο Κεφάλαιο 3 αξιολογείται και παρουσιάζεται η οργάνωση του κόστους ως μεταβλητής που στηρίζει απαραιτήτως κάθε επιχειρηματική απόφαση, στο Κεφάλαιο 4 παρουσιάζεται η κοστολογική οργάνωση των ξενοδοχειακών επιχειρήσεων, στο Κεφάλαιο 5 αναλύεται ένα από τα σημαντικότερα είδη Κοστολόγησης, η Κοστολόγηση ανά δραστηριότητα, στο Κεφάλαιο 6 παρουσιάζονται στατιστικά στοιχεία για την χρηματοοικονομική ανάλυση του κλάδου των ξενοδοχειακών μονάδων, στο Κεφάλαιο 7 παρουσιάζεται η κοστολογική ανάλυση του κλάδου και στο Κεφάλαιο 8 παρουσιάζονται τα βασικά συμπεράσματα της μελέτης καθώς και προτάσεις βελτίωσης της εφαρμογής της κοστολόγησης στην εποχή μας. / Undeniably, the last decades have taken place important changes in the operational environment in world scale, that have alter radically his structure. Examples of such changes constitute the import of flexible systems of production, the intensifying and the automation of productive processes, the increase of general expenses so much as sum what as percentage on the total cost of products, the reduction of cost of direct work (mainly in the industry) as percentage of cost of production, the increase of variety of products that is produced in small quantities and with different specifications, the increase of rhythm of import of new products in the market which have small circle of life, the adoption of orientation to the customers, etc. The above changes in combination with the increase of intensity of competition and subsequent reduction of margins of profit, have reduced in source of competitive advantage the effective follow-up and, mainly, their administration of cost of hotel enterprises. For the decision-making equitable enterprising is required equitable information, which, to a great degree, is supported in the numerical sizes that produces the cost estimating organization of hotel enterprises. Moreover, the correct planning and the exercise of economic policy from the State require also correct and objective information that supports biggest in sizes of cost. The cost accounting is, that is to say, the process that puts in a line the life of economic units, assembles, analyzes, processes, connects the numerical sizes which it summarizes and presents suitably so that they are exploitable from the recipients of enterprising decisions. In order to be the sizes of cost exploitable it will be supposed, except the other, that they enjoy a such treatment, classification and correlations so that is ensured via these and of these training of equitable economic reports and in general the exercise of control on the correctness of each enterprising decision. The importance of tool of cost accounting for the benefit of reliable information in the administration of hotel enterprise, for the decision-making constituted spark for the realization of present study which is reported in one of the most modern fields of research and growth of Accountant Science that is connected with the utilization of scientific methods, values and rules, in the Administration of enterprises and particularly of hotels. As it is known, the administration of enterprises, it is realized via the received daily enterprising decisions by the responsible institutions of power- competence and responsibility - that they are found in all levels of Administrative pyramid. More analytically, the individual objectives of present study are the followings: Through the analysis and the empiric research of hotels result a policy accountant and cost estimating organization of these, pointing out of importance and size of tourist growth of Greece, report in the domestic and international competition, presentation of cost estimating organization of hotels and analysis of cost estimating systems that is used by them, taking into consideration his particularities of branch of hotel enterprises that have impact in the cost accounting (pricing, cost of inactivity, value added, non value added expenses, etc.). The present diplomatic study is constituted from eight (8) capitals in which deal with following: In Capital 1 it is analyzed the structure of hotel system, in Capital 2 it is analyzed the structure of Tourist system, in Capital 3 it is evaluated and presents itself the organization of cost as variable that supports essentially each enterprising decision, in Capital 4 it is presented the cost estimating organization of hotel enterprises, in Capital 5 it is analyzed one of the most important types of Cost accounting, the Cost accounting per activity, in Capital 6 they are presented statistical elements for the financing analysis of branch of hotel units, in Capital 7 it is presented the cost estimating analysis of branch and in Capital 8 they are presented the basic conclusions of study as well as proposals of improvement of application of cost accounting in our period of time.

Devido aos constantes avanços tecnológicos e a grande competitividade no mercado atual, as empresas devem definir de forma mais objetiva possível, suas estratégias e formas de atuação. Para que se coloque um novo produto no mercado, este deve ser muito bem estudado pela empresa, a fim de ter o melhor resultado possível em sua distribuição, de forma que chegue da melhor maneira ao consumidor final. A pesquisa se justifica pela necessidade da empresa Kidde Brasil se adequar às exigências de uma nova resolução, “Resolução 157 do Contran”, de 22 de abril de 2004, onde foram regulamentadas várias mudanças na fabricação e comercialização do “Extintor de Incêndio Veicular”, bem como a substituição do antigo extintor por um novo e mais eficiente. Surgiu o interesse em desenvolver um estudo de modo que pudesse atender as necessidades da empresa Kidde Brasil em colocar o produto no mercado, através do melhor canal de distribuição possível. Esta pesquisa tem como objetivos avaliar a escolha correta por um canal de distribuição, no lançamento de um novo produto, o Extintor Veicular ABC; identificar os diferentes canais de distribuição para o Extintor Veicular ABC; organizar os critérios de escolha destes canais, a fim de utilizar um modelo de decisão; verificar o resultado, comparado com o canal escolhido pela empresa. O método de desenvolvimento é baseado no “Sistema Ranking”, que é um sistema de apoio a decisões multicriteriais que combina a metodologia de modelagem visual e interativa e o método de função de valor, para apoiar no processo de decisão. Sendo assim ,o sistema Ranking auxilia o decisor,para que este tenha um melhor entendimento de todo o processo,fornecendo suporte e sugerindo ações. Os resultados revelam que o melhor canal de distribuição para o novo extintor veicular, são as empresas recarregadoras, que já trabalhavam com produto similar. / Due the constants technological’s advances and the great competitivity in the actual market, the enterprises must define in a most objective way, it’s strategies and action’s ways. To a new product be introduced in the market, the enterprise must study it a lot, to have the best possible result in it’s distribution, to reach the final consumer in a better way. The research is justified by the Kidde Brasil enterprise necessity to be adequated in the demanding of a new resolution, “Contran’s Resolution 157”, by 22 apryl of 2004, on which many changes were registered in law to the fabrication and trading of the “Car’s Fire Extinguisher”, as well the old extinguisher’s fire substitution by a new and more effective one. Appeared the interest in the development of a study to attend the necessities of the Kidde Brasil enterprise in introduce a product in the market, trought a best distribution chanel. guisher, are the reload enterprises, which has already worked with similar product. This research has the objectives to evaluate the correct choice by a best distribution chanel, in the entry of a new product, the Car’s Fire Extnguisher ABC, identify the differents distribution chanels to the Car’s Fire Extinguisher ABC, organize the criterions to choose these chanels, with the purpose of using a decision model, analise the result, compared with the chanel choose by the enterprise. The development way will have the base in the “Ranking System”, which is a system of to the decisions with many criterials which combinate the methods of visual modeling and interactive and the method of value function to support the decision process. So, the Ranking System helps the one who makes the decision, to this one have a better understanding of all the process, giving support and suggesting actions. The results revelate that the best distribution chanel to the new car’s fire extinguisher, are the reload enterprises, which has already worked with similar product.

This piece of work is focused on getting particular logistics management process streamlined and on reasonable recommendations leading to improvement of the current state in any logistics company. In accordance with the thesis objective, respective working hypothesis is defined: "The correct implementation of the replenishment method as far as inventory management in a logistics company is concerned contributes to the reduction of the stock." The application of results is performed on the manufacturing site Honeywell Brno. The first section of the thesis explains logistics and its tools, processes within material and inventory management and other related theoretical issues. Further, methods that have been applied are described. Main part is focused on the streamlining the production process in the company using calculations that respect factors directly influencing a level of the stock. The comparison of Kanban and Kitting system is provided too. Last part is discussing the obtained results, their expected economic consequences and recommendations for potential implementation in logistics chains elsewhere.

Made available in DSpace on 2010-04-20T20:14:37Z (GMT). No. of bitstreams: 0 Previous issue date: 1992-11-27T00:00:00Z / Apresenta um sistema de gerenciamento de custos para o novo ambiente de fabricação, que caracteriza-se pela concorrência acirrada, utilização de medernas tecnologias e filosofias de fabricação e conceitos avançados de gerenciamento. Este sistema tem três dimensões, um modelo contábil, medidas de desempenho e gerenciamento de investimento, integrando estes aspectos. Ilustra estas inovações contábeis e tecnológicas com o enfoque do gerenciamento de custos japoneses. / The proposal of this project is to present a cost management system. We have presented the tradicional cost accounting system and its shortcomings in the new environment of manufacturing consisting of advanced manufacturing technology and philosophies and intense competition leading to its substitution by the cost management approach. This approach provides a wider and more practical vision in considering cost information in strategic decision-making. Cost management systems are based on three points accounting model, performance measures and investment management. The main aim of this system is to help companies to produce competitive goods and services in terms of price, high quality, low cost and delivery deadlines. This system by its characteristics of relevance and timing, helps companies in their search for excellence.

Made available in DSpace on 2010-04-20T20:14:43Z (GMT). No. of bitstreams: 0 Previous issue date: 1999-03-25T00:00:00Z / Este estudo procura estabelecer a adequação da metodologia de Custeio por Atividade como ferramenta de melhoria contínua, num contexto de mudanças sociais, tecnológicas e administrativas ocorridas nas últimas décadas. Aborda questões como Organizações, Qualidade e Estratégia para justificar sua utilização. O estudo fornece informações sobre o Custeio baseado em atividades, utilizando bibliografia anglo-francesa atualizada, procurando definir seus conceitos, e exemplificando sua utilização relacionando-o com o conceito de gestão estratégica de empresa. / This work presents Activity Based Costing as a flexible tool, suitable for our technology era. Concepts as dinamic environment, organisational structure, learning organisation, quality, life-cycle costing and strategy are integrated in this work to support the idea of a system that works as a cata1yst for management continuous improvement . A real-life example ilustrates the use of this powerfull tool from the definition of processes, activities, cost drivers, to the linking to the company strategy and the feedback for a continuous improvement basis.

A quantitative, descriptive and comparative study was conducted to determine the attitudes of young people aged 15-25 years towards the “ABC” strategy in the prevention of HIV/AIDS in Francistown, Botswana. Differences between two age groups and gender were determined. Structured questionnaire was used and 241 young people participated in the study. Data were analysed with SPSS version 13.0, guided by the Health Belief Model. The findings revealed that young people did not perceive the seriousness and severity of the HIV/AIDS when it came to the practice of “ABC” strategy. Young people’s cue to action was very high but their confidence to adopt and practice the “ABC” strategy were low. They had adequate knowledge of the benefits of abstinence and condoms but they perceived barriers towards the use of condom. The differences between the two age groups, 15-19 and 20-25 years and between the males and females were not statistically significant. / Public Health / M.A. (Public Health)