Purpose – The purpose of this master thesis is to explore how an e-tailer selling bulky items can use a multiple criteria ABC analysis to make its purchasing process more effective, while balancing richness and reach, with the performance measurements of profitability, total asset turnover and inventory turnover. The purpose will be accomplished through a single case study on an e-tailer active on the Swedish furniture and home furnishing market. Methodology – This thesis applies a multiple criteria ABC-analysis to a single case study. The approach is semi-deductive as theory is combined with interviews on how to match and adapt theory about inventory control and purchasing with the specific requirements of an e-tailer selling bulky items. Findings – This thesis has resulted in a set of recommendations that aim to make the purchasing process of an e-tailer more effective. That is, capital and inventory space will be better allocated to the e-tailer’s more profitable items. Among other things, this thesis shows how dead articles can be identified and how a purchaser can prioritize more profitable articles over less profitable ones when making procurement decisions. The other recommendations are for the e-tailer to investigate the possibilities of decoupling the supply chain by keeping stock at the suppliers’ premises, to match the supplier reliability with their importance in the supply chain, and lastly to explore possibilities of drop shipment. Further, the main finding is that a comparison between the A-, B-, and C-classes and the reliability of the suppliers, highlights a gap and a possible risk. Put differently, the importance of a specific item for the business should be reflected in the choice of supplier and the multiple criteria ABC analysis is the tool to illustrate the importance. Keywords – E-commerce, E-tailer, richness, reach, transaction cost, ABC analysis, multiple criteria ABC, MCABC, inventory turnover ratio, supplier selection, purchasing Paper type – Masters thesis / Syfte – Syftet med detta examensarbete är att undersöka hur en e-handelsdetaljist som säljer skrymmande artiklar kan använda en flerdimensionell ABC-analys för att göra sin inköpsprocess mer effektiv och balansera richness och reach, med mätetal som lönsamhet, kapitalomsättningshastighet och lageromsättningshastighet. Syftet kommer att uppfyllas genom en fallstudie på en e-handelsdetaljist verksam på den svenska möbel- och heminredningsmarknaden. Metod – Denna fallstudie använder sig av en flerdimensionell ABC-analys. Tillvägagångssättet är semi-deduktivt då intervjuer och teori om hur lagerstyrning och inköp kan matchas och anpassas till ett företags specifika behov. Resultat – Den här uppsatsen har resulterat i en rad åtgärder som syftar till att göra en ehandlares inköpsprocess mer effektiv. På så vis att kapital och lageryta bättre allokeras till ehandlarens lönsamma artiklar. Bland annat visar den här uppsatsen hur döda artiklar kan identifieras och hur inköparen kan prioritera mer lönsamma artiklar över olönsamma vid inköp. De andra åtgärdena handlar om att undersöka möjligheter att frikoppla försörjningskedjan genom att lagra produkter hos leverantören, att matcha leverantörernas pålitlighet och deras betydelse i försörjningskedjan, och slutligen att utforska möjligheter att utöka drop shipment. Det främsta bidraget är att eventuella felprioriteringar och risker blir tydliga genom en jämförelse mellan A-, B- och C-klasserna och leverantörernas pålitlighet. Med andra ord bör den affärsmässiga inverkan som respektive artikel har på e-handlarens resultat avspegla sig i valet av leverantör. En flerdimensionell ABC-analys kan användas för att påvisa respektive artikels affärsmässiga inverkan. Publikationstyp – Examensarbete för utbildning till civilingenjör (masteruppsats).

<p>Produktplacering har växt i popularitet över åren och används i allt fler typer av medier. Det har gjorts flera studier om konsumenters attityder till produktplacering men endast ett fåtal av dem har gjort en distinktion mellan konsumenters attityder till produktplacering i olika slags medier. Genom att använda fokusgrupper ska denna studie därmed undersöka studenters attityder till produktplacering i de fyra följande medierna; filmer, musikvideor, datorspel samt bloggar. För att ta reda på detta användes ABC-modellen av attityder och studenternas attityder delades upp under de tre olika kategorierna inverkan, beteende och kognition. Resultaten visar att studenter överlag är positiva till produktplacering i filmer och anser att det ofta är en naturlig del av filmer. Produktplacering i musikvideor anses lämplig så länge det inte är för mycket fokus på produkten. Angående datorspel tycker studenter att datorspel ibland är bättre när de använder produktplacering för att det gör dem mer realistiska. Emellertid är vissa produkter mer passande än andra att produktplacera i datorspel när det handlar om sannolikhet att de påverkar konsumenters till köp i verkligheten. Bloggar ses som den mest trovärdiga typen av medium för produktplacering då studenter anser att de är mer trovärdiga och pålitliga än andra typer av medier. Likväl är det svårt att uppskatta huruvida produkter i bloggar är produktplacering eller inte.</p> / <p>Product placement has grown in popularity over the years and is current in more and more types of media. While there have been several studies made about people’s attitudes towards product placement, only a few of them have made a distinction been people’s attitudes towards product placement in different types of media. Thus, by using focus groups this study seeks to study students’ attitudes towards product placement in the following four types of media; movies, music videos, video games and blogs. In order to achieve this purpose the ABC-model of attitudes was used and the students’ attitudes were divided into the three different categories affect, behavior and cognition. Findings suggest that students overall are positive towards product placement in movies and believe that it is often a natural part of movies. Product placement in music videos is deemed adequate as long as there is not too much focus on the product itself. Regarding video games students find that video games are sometimes better when they use product placement because it makes them more realistic. However, some products that are placed in video games are more suited than others in terms of likelihood of affecting people to buy the products in real life. Blogs are seen as the most realistic media for product placement because students feel that they are more trustworthy and reliable than other forms of media. Nevertheless, it is difficult to estimate whether products in blogs are in fact product placement or not.</p>

ARE subfamily proteins belonging to ABC transporters confers a different degree of resistance to macrolides, linkosamides and streptogramins antibiotics. Among the most clinically ARE subfamily proteins in staphylococci is Vga(A) protein lead to the award resistance to streptogtramins A. In 2006, discovered the new variant called the Vga(A)LC, which in addition to streptogramins A resistance also confers linkosamides. Vga(A) and Vga(A)LC differ in only 7 amino acids, yet confer different resistance phenotypes. In previous experiments it was found that the central role in determining substrate specificity play a 4 amino acid differences that accumulate in the section of 15 amino acids within the linker connecting the two ABC domains (positions 212, 219, 220 and 226). The combination of amino acids LGAG Vga(A) increases resistance to streptogramins A while present in combination SVTS Vga(A)LC increased resistance to linkosamides. Although in this subfamily includes a large number of resistance proteins, the mechanism of resistance has not yet been established with certainty. The aim was to create a new Vga(A) variants that contain specific combinations of amino acids for Vga(A) and Vga(A)LC protein at positions 212, 219, 220 and 226 and compared their ability to grant resistance to linkosamides. We also...

L’efficacité des chimiothérapies est limitée par la surexpression de pompes d’efflux adressées à la membrane plasmique des cellules cibles. En effet, celles-ci réduisent le taux intracellulaire des médicaments anticancéreux, antiviraux, antifongiques et antibactériens. La P-gp/ABCB1 est la plus impliquée dans ce phénomène, suivie de MRP1/ABCC1 et de BCRP/ABCG2. Une approche pour surmonter ce phénomène est de développer des médicaments qui ne soient pas expulsés par ces pompes. Dans ce contexte, nous avons développé une nouvelle classe d’inhibiteurs de la protéase du VIH-1 qui ne sont ni transportés par P-gp ni par BCRP. Ils sont ainsi des candidats intéressants aux trithérapies contre le SIDA. Un point clé pour comprendre comment ces transporteurs font traverser les médicaments à travers la membrane est d’identifier des nouvelles structures. Ainsi, nous avons résolu trois structures de P-gp de souris. Une d’entre-elles est complexée à un nano-anticorps lié au premier NBD («nucleotide-binding domain»), qui fige la P-gp dans une nouvelle conformation ouverte vers l'intérieur. Pour finir, nous avons localisé deux sites de liaison de P-gp en caractérisant les modes d'inhibition de deux inhibiteurs précédemment cocristallises avec la pompe. Ceci permet de mieux comprendre le mécanisme de translocation et offre la possibilité de cibler plus précisément ces sites pour développer des modulateurs de cette pompe / 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. / Resistance to chemotherapy is partly due to efflux pumps expressed in the plasma membrane, which prevent the accumulation of anticancer drugs in tumor cells. Three human ABC transporters are particulary involved in this chemoresistance : P-gp/ABCB1, MRP1-ABCC1 and BCRP/ABCG2. The overexpression of these trnasporters can also be an "Achille heel" for resistant cancer cells by sensitizing them to various drugs. This phenomenom, called collateral sensitivity, could constitute a new chemotherapy to eradicate cancers becoming resistant or cancer which ara resistant prioir to any treatment. Thus, S-verapamil triggers selective apoptosis of MRP1 overexpressing correlated to the massive and rapide extrusion of cellular glutathione by MRP1. We showed that verapamil is able to selectivity deprive H69AR MRP1 positive and resistant lung tumors, as soon as 3 hours of acute exposure. Verapamil being highly cardiotoxic, we have developed new collateral sensitivity drugs, more selective than verapamil, such as xanthone 9, flavonoïdd 36 and flavonoïd dimer 4e. Finally, thanks to the characterization of MRP1/MRP2 chimera, we showed that the MRP1 region including the intracellular loop L0 L1-TM12 might constitute the substrate and the modulator binding sites for GSH.

Pouco se sabe sobre o mecanismo de ação da pentamidina, um composto utilizado no tratamento das leishmanioses. Para uma melhor compreensão do mecanismo de ação assim como o mecanismo de resistência à pentamidina, foi isolado um gene que codifica um membro da família de transportadores ABC, chamado PRP1 capaz de conferir resistência à pentamidina em formas promastigotas e amastigotas de Leishmania spp. O tratamento dos transfectantes que superexpressam a PRP1 com pentamidina em presença de concentrações não tóxicas de verapamil, um inibidor de transportadores ABC, foi capaz de reverter a resistência mediada por esse transportador. Foram ainda isolados nesse estudo duas linhagens de L. amazonensis resistentes à pentamidina. A análise molecular dos parasitos indicou que esses mutantes não apresentaram nenhuma amplificação de DNA, inclusive do gene PRP1 que também não se mostrou superexpresso em ambas as linhagens. As duas linhagens resistentes à pentamidina tiveram sua resistência revertida quando tratadas com verapamil, indicando que o mecanismo de resistência nesses mutantes pode estar associado a um transportador ABC. Os resultados obtidos nesse estudo fornecem dados para uma melhor compreensão do mecanismo de resistência à pentamidina e sugerem um provável potencial da associação pentamidina e verapamil no tratamento da doença. / Little it is known about the mechanism of action of pentamidine, an compound used for leishmaniases chemotherapy. To understand the mechanism of action and resistance of pentamidine, it was isolated a gene that codifies a member of ABC transporter family, named as PRP1 able to confer pentamidine resistance in promastigotes and amastigotes of Leishmania spp. Treatment of transfectants overexpressing PRP1 with pentamidine in presence of non toxic concentration of verapamil, an inhibitor of ABC transporters, was able to reverse the drug resistance mediated by this transporter. Two lines of L. amazonensis resistant to pentamidine were selected. Molecular analysis of parasites indicated that these mutants do not contain amplified DNA, including the PRP1 gene either not associated with overexpression in both lines. The two lines resistant to pentamidine had their resistance reversed when treated with verapamil, indicating that the mechanism of resistance may be associated to an ABC transporter. The results of this work lead to new insights for a better understanding of the mechanism of of resistance suggesting a probably potencial of pentamidine and verapamil association in the chemotherapy.

Este trabalho analisa a criação da Universidade Federal do ABC e seu projeto pedagógico, que pretende trazer importantes inovações para o ensino superior brasileiro, avaliando sua implantação e seu impacto tanto no contexto regional quanto nacional de educação superior. Analisa-se sua capacidade transformadora da realidade, a partir de uma discussão sobre o conceito de desenvolvimento econômico e social contido em seu projeto. Para isso, em primeiro lugar situa-se seu aparecimento, apresentando-se um panorama do ensino superior na região do ABC, bem como o contexto de reestruturação produtiva naqueles municípios, com base na coleta de dados do IBGE e do INEP e na análise de documentos institucionais e na verificação bibliográfica. Em seguida, analisa-se o projeto pedagógico em si, problematizando-o e mostrando as principais visões de universidade e de sociedade atuantes e conflitantes em seu interior. Por fim, resgata-se o debate sobre o conceito de desenvolvimento social e econômico e as relações com a universidade, buscando entender a função social da UFABC. / This study examines the creation of the Federal University of ABC and its project, which aims to bring important innovations to the Brazilian higher education, evaluating its implementation and its impact both on the regional and national higher education. We analyze its capacity to transform reality, from a discussion of social and economic developments concept contained in the project. We present, then, an overview of higher education in the ABC region, and the context of productive restructuring on those municipalities, based on data collection and analysis of institutional documents and bibliographic verification. Next, we analyze the pedagogical project itself, questioning and showing the main visions of the university and society active inside. Finally, it\'s indicated the debate on the concept of economic development and relations with the university, trying to understand the social function of UFABC.

ABC-Transmembrantransporter sind an der Aufnahme, Verteilung und Ausscheidung vieler Arznei- und Fremdstoffe beteiligt. Sie spielen eine Schlüsselrolle in der Pharmakokinetik und in der Ausscheidung toxischer endogener oder exogener Substanzen. Das Ziel der hier präsentierten Untersuchungen war deshalb, den Einfluss genetischer Polymorphismen des bekanntesten Vertreters dieser Proteinfamilie, MDR1 (ABCB1) zu untersuchen. Darüberhinaus sollte der ebenfalls zur ABC-Transporterfamilie gehörende hepatozelluläre Exporter für monoanionische Gallensäuren identifiziert und charakterisiert werden. MDR1 erwies sich als ein hochpolymorphes Gen mit zahlreichen Einzelbasenaustauschen (SNPs). Die meisten SNPs waren intronisch oder stumm. Für den nichtkodierenden SNP im Exon 26 3435C>T ergab sich bei homozygoten Trägern des T-Allels eine im Vergleich zum Wildtyp geringere intestinale P-Glykoprotein Expression mit einer entsprechend höheren und schnelleren Absorption von Digoxin. Die Auswertung pharmakokinetischer Profile von Digoxin in Individuen mit MDR1-Haplotypen der miteinander verbundenen SNPs in Exon 21 2677 und Exon 26 3435 untermauerte die beobachteten pharmakogenetischen Effekte. Nach oraler Einzelgabe von 1 mg Digoxin konnten wahrscheinlich aufgrund der Überschreitung der P-Glykoprotein Transportkapazität keine genotypischen Unterschiede beobachtet werden. Der biliäre Exporter für monoanionische Gallensäuren (Bsep) konnte als ein 160 kDa Glykoprotein aus einer Rattenleber cDNA-Bibliothek identifiziert werden und gehört ebenfalls zur ABC Transporter-Familie. Die transkriptionelle Regulation und Möglichkeiten der Modulation der Expression des Bsep-Gens wurden in vitro und in Tiermodellen der Cholestase untersucht. Dabei zeigte sich, dass Gallensäuren über ein proximales FXRE-Motiv die Bsep Promotoraktivität stimulierten. Arzneistoffe hatten ebenfalls einen Einfluss auf die Transkription des Bsep-Gens. Die adaptive Regulation hepatozellulärer Transporter während der Cholestase ergab eine verminderte Expression der meisten basolateralen Aufnahmetransporter und eine unveränderte oder heraufregulierte Proteinmasse kanalikulärer (apikaler) Efflux-Transporter. Dieses Regulationsmuster dient dem Schutz der Leberzelle, indem eine intrazelluläre Anreicherung toxischer Gallensäuren vermindert und der Gallefluss für eine intakte biliäre Clearance aufrechterhalten wird. / ABC transmembrane transporters are involved in absorption, distribution and excretion of diverse drugs and xenobiotics. They are key factors in pharmacokinetics and in the elimination of toxic endogenous or exogenous compounds. Therefore, the aim of the present study was to investigate the influence of genetic polymorphisms of the best known member of this protein family, MDR1 (ABCB1). In addition, the identity of another ABC transporter assumed to be the major hepatocellular export pump for monoanionic bile acids should be revealed and characterized. MDR1 turned out as a highly polymorphic gene with many single nucleotide polymorphisms (SNPs). Most of the SNPs were intronic or silent. Homozygous carriers of the non-coding SNP in exon 26 3435C>T had lower intestinal P-glycoprotein expression rates and thus enhanced absorption of the model compound digoxin as compared to wildtype controls. The analysis of pharmacokinetic profiles in different MDR1-haplotypes of the linked SNPs in exon 21 2677 and exon 26 3435 supported the above data. An oral single dose of 1 mg digoxin did not result in genotypic differences of tested genotypes, probably because this dose was above the maximal transport capacity of P-glycoprotein. The biliary export pump for monoanionic bile acids (Bsep) was identified as an 160 kDa glycoprotein of the ABC transporter family by screening a rat liver cDNA library. The transcriptional regulation and modulatory factors of Bsep (Abcb11) gene expression were analyzed in vitro and in animal models of cholestasis. The promoter activity of Bsep was stimulated by bile acids via a proximal FXRE motif. Drugs were also able to modify Bsep gene transcription. Adaptive regulation of hepatocellular transporters during cholestasis followed a pattern of diminished expression of most basolateral uptake carrier systems and maintained or even upregulated protein mass of canalicular (apical) exporters. This pattern serves as a protective mechanism of the liver cells preventing intracellular accumulation of toxic bile acids and providing unimpaired biliary flow and clearance.

Multidrug Resistenz (MDR), die simultane Resistenz gegenüber strukturell und funktionell nicht-verwandten Zytostatika, stellt eine wesentliche Ursache für unzureichende Behandlungserfolge maligner Erkrankungen dar. Die inherente Resistenz bzw. Resistenzentwicklung gegenüber chemotherapeutischen Substanzen ist vor allem die Folge der Präsens und Regulation unterschiedlicher Transportproteine wie MDR1, MRP1, BCRP und MVP. In der Konsequenz kommt es zu alteriertem Influx und/oder Efflux von Zytostatika, verminderter Akkumulation und Effektivität von Chemotherapeutika. Sowohl Zytostatika als auch Zytokine zeigten modulierende Einflüsse auf die Expression der MDR-Gene MDR1, MRP1 und MVP (Kapitel 2-9). Zytostatika wie Adriamycin resultierten vorwiegend in induzierten MDR1-Expressionen, dem hauptsächlichen Interventionstarget zur Überwindung des klassischen MDR-Phänotyps. Zytokine wie TNFa führten, extern appliziert als auch durch Gentransfer, zur Chemosensitivierung der Tumorzellen, verbunden mit Down-Regulationen von MDR1 und MVP. Die Zytokin-vermittelte Überwindung des klassischen MDR-Phänotyps weist auf die Inklusion definierter Zytokine in etablierte Chemotherapieprotokolle hin, wie bereits angewendet bei der hyperthermen isolierten Extremitätenperfusion mit TNFa (Kapitel 13). Die Verwendung BCRP-spezifischer Ribozyme demonstrierte deren Potential zur Überwindung des BCRP-bedingten, atypischen MDR-Phänotyps. Darüber hinaus wurde gezeigt, dass die Expression der ABC-Transporter als auch des MVP durch Hyperthermie temperatur- und zeitabhängig induzierbar ist (Kapitel 10-13). Diese Hyperthermie-Induktion wird für MDR1 und MRP1 über den Transkriptionsfaktor YB-1 zeitnah zum Stressereignis vermittelt. In der klinischen Situation konnte anhand verfügbarer Biopsien von Kolonkarzinomen, Sarkomen und Melanomen, jeweils mittels Hyperthermie im Kontext multimodaler Behandlungsregime behandelt, kein direktes, generelles Risiko einer MDR1- oder MRP1-vermittelten, Hyperthermie-bedingten Induktion/Verstärkung einer MDR beobachtet werden. Die Analyse der Promotoren MDR-assoziierter Gene wie MDR1 und MVP zeigte deren Induzierbarkeit durch unterschiedliche Therapie-relevante Faktoren wie Zytostatika und Hyperthermie in verschiedenen in vitro- und in vivo-Modellen (Kapitel 10,14-20). Spezifische Sequenzmotive sind für die Stressfaktor-induzierte Bindung von Transkriptionsfaktoren wie YB-1 verantwortlich; Mutationen in diesen Sequenzbereichen modulierten die Induzierbarkeit (Kapitel 14,15,20). Der Einsatz Therapie-induzierbarer Promotoren unterschiedlicher MDR-Gene wie MDR1 (Kapitel 14-18) und MVP (Kapitel 19,20) erlaubt somit generell die Anpassung an etablierte Behandlungsprotokolle verschiedener Tumorentitäten. In fortführenden Arbeiten bleibt die erfolgreiche Anwendung von Therapie-induzierbaren MDR-Promotorsequenzen zur Expression therapeutisch relevanter Gene im Kontext einer Gentherapie maligner Erkrankungen zu prüfen. / Multidrug resistance, the simultaneous resistance towards structurally and functionally unrelated cytostatic drugs, still represents a major cause of cancer treatment failure. Inherent or acquired resistance against a wide variety of chemotherapeutic drugs depends mainly on the presence and regulation of different transporter proteins, such as MDR1, MRP1, BCRP, and MVP. Thus, decreased uptake and/or increased efflux, lowered net accumulation, and in consequence, less efficiency of anti-cancer drugs is the clinical hurdle to struggle with. Cytostatics as well as cytokines showed modulating effects on the expression of the MDR-associated genes MDR1, MRP1, and MVP (chapter 2-9). Cytostatics such as adriamycin resulted mainly in increased expression of the MDR1 gene, the most prominent intervention target for the reversal of the classical MDR phenotype. Cytokines such as TNFa, externally applied or by gene transfer, led to chemosensitization of tumor cells, and to down regulation of MDR1 and MVP. This cytokine-mediated reversal of the classical MDR phenoype refer to the inclusion of defined cytokines into established chemotherapy protocols, as already realized by the hyperthermic isolated limb perfusion with TNFa (chapter 13). The employment of BCRP-specific ribozymes demonstrated their potential to reverse the BCRP-mediated atypical MDR phenotype. Furthermore it was shown, that the expression of the ABC transporters as well as of MVP was inducible by hyperthermia in a temperature and time-dependet manner (chapter 10-13). This hyperthermia-caused induction of MDR1 and MRP1 is mediated by the transcription factor YB-1 timely close to the stress event. However, no direct, general risk of a MDR1- or MRP1-mediated hyperthermia-caused induction/enhancement of the MDR phenotype was observed in clinical settings, analyzed by using biopsies available from colon carcinomas, sarcomas, and melanomas, which were treated with hyperthermia in the context of multimodal regimes. The analyses of promoters of the MDR-associated genes MDR1 and MVP revealed their inducibility by different therapy-related factors such as cytostatics and hyperthermia in several in vitro- and in vivo models (chapter 10,14-20). Specific sequence motifs were found to be responsible for the stress-induced binding of transcription factors; mutations within these sequence regions modulated their inducibility (chapter 14,15,20). Thus, the employment of therapy-inducible promoters of different MDR genes such as MDR1 (chapter 14-18) and MVP (chapter 19,20) allows the improvement of established treatment protocols for different tumor localizations. Based on this, the succesful use of therapy-inducible MDR promoter sequences for the expression of therapeutically relevant genes in the context of a gene therapy of cancer represents an ambitious goal for the future.

Esta pesquisa estuda as políticas públicas em São Bernardo do Campo, no Pós-Guerra, durante o período 1945 – 1964. São abordados, nesse contexto, aspectos do crescimento econômico e urbano da cidade, que faz parte do chamado “ABC Paulista", região diferenciada no Estado de São Paulo por apresentar intensa industrialização. A ação pública ligada a tais características, tratada como objeto desta pesquisa, revelou-se de tipo bastante tradicional. Ao expressar as convicções políticas da época, fazia com que a política pública não se antecipasse às demandas da população, mas enquadrava-se no ideário otimista que previa um futuro sempre melhor, ao estilo da lógica desenvolvimentista. / This research studies the public policies in São Bernardo do Campo, in the Post-War period (1945 – 1964). Issues from the economic growth and urbanization of the City – which is part of the metropolitan-industrial sub-region of “ABC Paulista" - were studied. The sum of public policies related to these issues, which is the object of this research, revealed itself as being of a traditional kind, not anticipating the real necessities of the people of the countship, besides being always optimistic about the future, incorporating the ideology of Economic Development, under the form of the so called “desenvolvimentismo".