L'interleukine-6 (IL-6) exerce des propriétés biologiques multiples telles que l'activation des cellules immunocompétentes, l'activation de la réponse inflammatoire et l'hématopoïèse. Produite également par les cellules tumorales, l'IL-6 impacte la prolifération, la différenciation et la survie de ces dernières. L'IL-6 représente donc depuis plusieurs années une cible thérapeutique pertinente. Dans la première partie de ce travail, nous avons exploré une nouvelle piste potentielle pour bloquer l'activité biologique de l'IL-6, en utilisant un antagoniste naturel que notre équipe a identifié dans plusieurs lignées d'adénocarcinomes du rein, à savoir la molécule tronquée tIL-6. Suite à l'évaluation comparée de deux systèmes d'expression (E. coli versus CHO), nous avons retenu les cellules CHO comme source de production de fractions enrichies en tIL-6 par chromatographie de gel d'exclusion. Disposant d'un panel d'adénocarcinomes de rein (ACHN, Caki1, CLB CHA, CLB VER) et d'une lignée érythroleucémique (TF1), l'activité fonctionnelle de tIL-6 in vitro a été étudiée sur (1) la signalisation IL-6 induite, (2) la prolifération cellulaire IL-6 induite, la survie cellulaire et (4) la modulation de l'expression de protéines relevantes de l'apoptose. La molécule tIL-6 bloque la phosphorylation de la tyrosine Tyr705 de STAT3, qui est un des éléments clés de la voie de signalisation de l'IL-6. Nous rapportons également une autre observation nouvelle indiquant que tIL-6 exerce un effet pro-apoptotique sur certaines lignées RCC. Dans la seconde partie de notre étude, l'impact d'un Ac Mo anti IL-6 dans la réversion de la résistance aux cytotoxiques ou à la radiothérapie a été étudié. Nos résultats démontrent que la voie IL-6 ne constituerait pas un mécanisme majeur de résistance / Interleukin-6 (IL-6) plays numerous physiological roles including haematopoiesis, immune response and inflammation, but also plays a role in modulating cell growth, differentiation and survival of tumors cells. The first goal of the present study was to investigate on the potential role of the truncated protein IL-6 (tIL-6) encoded by the spliced IL-6 mRNA discovered in renal carcinoma cells (RCC). The R&D program was designed based on an industrial approach, aiming at reaching the decision stage to enter or not into preclinical development. Firstly two different expression systems were investigated (E. coli versus CHO cell line). The mammalian expression system was selected as the protein source since a recombinant glycosylated tIL-6 with a molecular weight similar to the predicted natural molecule was obtained from enriched fractions following size exclusion chromatography. Secondly by using a cell line panel including renal carcinoma cells (ACHN, Caki-1, CLB CHA, CLB-VER ) and an erythroleucemic cell line (TF1), in vitro tIL-6 functional activity were analyzed on (1) IL-6 induced signaling, (2) IL-6 induced cell proliferation, (3) on cell survival and also (4) on expression of specific set of proteins involved in apoptosis pathways. The truncated IL-6 was found inhibit IL-6 induced STAT3 Tyr705 and to induce apoptosis in some RCC cell lines which could be depending on IL-6 expression. Understanding more precisely the role of natural truncated IL-6 and its impact in cell tumour growth control will be a major issue in the development of innovative approach to antagonize directly or not IL6. The second goal of the present study was to investigate on reversing resistance of cancer cell lines to cytotoxics or ionizing radiations through the use of a monoclonal antibody directed against IL-6. Our data support the fact that IL-6 is not the preponderant actor of cell resistance to cytotoxics and ionizing radiations, which seems to be regulated by a complex network of proteins

Processen att skapa innehåll till digitala spel för hand är kostsamt och tidskrävande. Allteftersom spelindustrin expanderar ökar behovet av att minska produktionskostnaderna. En lösning på detta problem som det forskas om idag är procedurell generering av spelinnehåll. Kortfattat innebär detta att en algoritm gör det manuella arbetet istället för en designer. I denna uppsats presenterar vi en sådan metod för att automatisera processen att skapa kartor i digitala spel. Vår metod använder kontrollerbara agenter med blandade initiativ (dvs. designern och algoritmen turas om) för att skapa geometri. Vi använder stokastiska agenter för att skapa variation och deterministiska agenter för att garantera spelbarhet. För att kontrollera dessa agenter använder vi en uppsättning parametrar som kan manipuleras. Däröver har designern tillgång till ett antal verktyg inklusive möjligheten att låsa befintlig geometri, konvertera geometri till andra typer, lägga till geometri manuellt, och även möjligheten att använda agenter på specifika områden på kartan. Vi tittar på spelläget Battle i det digitala spelet Mario Kart 64 och visar hur vår metod kan användas för att skapa sådana kartor. Vi utförde en användarstudie på outputen från metoden och resultatet visar att kvaliteten är i allmänhet gynnsam. / The process of creating content for digital games by hand is a costly and time consumingone. As the game industry expands, the need to reduce costs becomes ever more pressing.One solution to this problem being research today is procedural generation of content.In short, this means that an algorithm does the labor rather than a designer. In thisthesis we present such a method for automating the process of creating maps in digitalgames. Our method uses controllable software agents and mixed initiative (i.e. allowingthe designer and algorithm to take turns) to create geometry. We use stochastic agentsto create variation and deterministic agents to ensure playability. To control these agentswe use a set of input parameters which can be manipulated. Furthermore, the designerhas access to a number of tools including the ability to lock existing geometry, convertgeometry to other types, add geometry manually, as well as the ability to use agents onspecific areas of the map. We look at the game mode Battle in the digital game MarioKart 64 and show how our method can be used to create such maps. We conducted auser study on the output of the method and the results show that the quality is generallyfavorable.

Startups within the tech field are incraesingly using proof of concept (POC) customers as a partner when developing new products and services as this enables them to sell the product before building it, ensuring that the product they are developing is aligned with the market needs before making it avaliable to a wider market. Becasue of the positive results that designing and developing new products together with users and customers have shown, the acqusition of POC customers has become a crucial step in the product development process for many startups. The purpose of this study is to understand how the process from business idea to first proof of concept customer evolves and in this process, what are important factors in acquiring the first proof of concept customer. The study is of qualitative nature and leverages a multiple case study based on interviews with eight Swedish tech startups. The findings from the research show that the process is of iterative nature and has seven sub-processes; Defining and scoping proclem, Defining target marker, Finding customers, Defining customer needs, Initial pitch, Persuasion, and finally, Negotiation and signature. Furthermore, five concepts influencing this process were found; Market understanding, Product understanding, Sales tactics, Customer management, and Entrepreneurial attitude. / Startups som verkar inom techindustrin inkluderar allt oftare proof of concept (POC) kunder i utvecklingen av nya produkter och tjänster då det gör det möjligt att säkerställa att produkten är anpassad till marknadens behov. Då utveckling av nya produkter tillsammans med användare och kunder har visat sig effektivt och ha positiva resultat, har förvärvet av POC kunder blivit ett abgörande steg i produktutvecklingsprocessen för många startups. Syftet med denna studie är att förstå hur processen ser ut från affärsidé till signering av första proof of concept kunden, och i denna process även förstå vilka faktorer som är viktiga för att signera första proof of concept-kunden. Studien är av kvalitativ karaktär och använder fallstudier baserad på intervjuer med åtta svenska tech startups. Resultaten visar att processen är av iterativ natur och har sju delprocesser; Definiera problemet, Definiera målgrupp, Hitta kunder, Definiera kundbehov, Inledande pitch, Övertalning och slutligen, Förhandling och signatur. Vidare presenteras fem koncept som påverkar denna proccess; Marknadsförståelse, Produktförståelse, Säljtaktik, Kundhantering och Entreprenöriell attityd.

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In today’s market, digitization and automation are crucial for the survival of most companies due to the high level of software already present. The need to adapt to the demands of the day, forces a big mechanical company to perform a paradigm shift towards becoming a software producing company as well. However, the current systems are limited, they are not developed for such a change. Machines in the construction industry are complicated vehicles that require careful configuration by the operators. Each operator may have their own personal preference of how the settings of a construction machine should be configured in order to get full utilization. The problem for the operators revolves around the current situation of frequently having to configure these settings each time operating a machine, requiring time. Consequently, creating the risk of operators neglecting the configuration. Therefore, the problem of the thesis is that there is no existing system of how to facilitate this reoccurring activity. The purpose of this thesis is to prove the usefulness of introducing a mobile application as the missing system for when operators switch machines, through a proof of concept. The proof of concept suggests a quality approach towards the first steps in automating the work environment of operators for construction machines. The objective is to improve the efficiency of the workflow by saving the operators machine settings in a profile, in order to transfer the settings between the machines. The goal is to investigate and deliver a proof of concept for how to store and transfer the personal settings in a useful manner. Due to the limited time of the thesis, the starting focus is placed on wheel loaders with the research limited to one specific type of machine. The thesis consists of a qualitative study, analysing inductively from details to produce abstractions and hypotheses. The agile design science research method applied to the research, was evaluated continuously in the different phases and iterations of the thesis plan to adjust to improvements reviewed as necessary. The observational research includes an explorative and evaluative aspect, first to form an idea and consequently to prove the idea. A design of an user interface of a mobile application served as a method to support the evaluation. The result for the thesis is the proof of concept of a useful mobile application system to automate the personal settings of the construction machines. The evidence is supported by information gathered during the pre-study and the demonstration of a small prototype tested by engineers as well as the intended users, the operators. The questionnaires prove the prototype to be a useful improvement in the operators daily work environment. The documentation and suggested system construction are approved by the target audience to be viable and of value. / På dagens marknad är digitalisering och automatisering avgörande för de flesta företags överlevnad på grund av den höga nivån av mjukvara som redan finns. Behovet av att anpassa sig till dagens krav tvingar ett stort mekaniskt företag att utföra ett paradigmskifte mot att också bli ett mjukvaruproducerande företag. De nuvarande systemen är dock begränsade, de är inte utvecklade för en sådan förändring. Maskiner inom byggbranschen är komplicerade fordon som kräver noggrann konfiguration av operatörerna. Varje operatör kan ha sina egna personliga preferenser för hur inställningarna för en entreprenadmaskin ska konfigureras för att få fullt utnyttjande. Problemet för operatörerna kretsar kring den nuvarande situationen att ofta behöva konfigurera dessa inställningar varje gång man använder en maskin, vilket kräver tid. Följaktligen skapar risken för att operatorer försummar konfigurationen. Därför är problemet med avhandlingen att det inte finns något befintligt system för hur man kan underlätta denna återkommande aktivitet. Syftet med detta examensarbete är att bevisa användbarheten av att introducera en mobilapplikation som det saknade systemet för när operatörer byter maskin, genom ett proof of concept. proof of concept antyder ett kvalitetstänkande mot de första stegen i att automatisera arbetsmiljön för operatörer för entreprenadmaskiner. Målet är att förbättra effektiviteten i arbetsflödet genom att spara operatörens maskininställningar i en profil, för att överföra inställningarna mellan maskinerna. Målet är att undersöka och leverera ett proof of concept för hur man lagrar och överför de personliga inställningarna på ett användbart sätt. På grund av projektets begränsade tid läggs startfokus på hjullastare med forskningen begränsad till en specifik maskintyp. Projektet består av en kvalitativ studie, som induktivt analyserar från detaljer för att producera abstraktioner och hypoteser. Den agila designvetenskapliga forskningsmetoden som tillämpades på projektet utvärderades kontinuerligt i de olika faserna och iterationerna av projektplanen för att anpassa sig till förbättringar som granskades vid behov. Observationsforskningen innefattar en utforskande och utvärderande aspekt, först för att bilda en idé och följaktligen för att bevisa idén. En design av ett användargränssnitt för en mobilapplikation fungerade som en metod för att stödja utvärderingen. Resultatet för avhandlingen är ett bevis på konceptet för användbarheten av det mobila applikationssystemet för att automatisera entreprenadmaskinernas personliga inställningar. Bevisen stöds av information som samlats in under förstudien och demonstrationen av en liten prototyp som testats av ingenjörer såväl som de tilltänkta användarna, operatörerna. Enkäterna visar att prototypen är en användbar förbättring i operatörens dagliga arbetsmiljö. Dokumentationen och den föreslagna systemkonstruktionen godkänns av målgruppen för att vara lönsam och av värde.

General attrition rates in drug development pipeline have been recognized as a necessity to shift gears towards new methodologies that allow earlier and correct decisions, and the optimal use of all information accrued throughout the process. The quantitative science of pharmacometrics using pharmacokinetic-pharmacodynamic models was identified as one of the strategies core to this renaissance. Coupled with Optimal Design (OD), they constitute together an attractive toolkit to usher more rapidly and successfully new agents to marketing approval. The general aim of this thesis was to investigate how the use of novel pharmacometric methodologies can improve the design and analysis of clinical trials within drug development. The implementation of a Monte-Carlo Mapped power method permitted to rapidly generate multiple hypotheses and to adequately compute the corresponding sample size within 1% of the time usually necessary in more traditional model-based power assessment. Allowing statistical inference across all data available and the integration of mechanistic interpretation of the models, the performance of this new methodology in proof-of-concept and dose-finding trials highlighted the possibility to reduce drastically the number of healthy volunteers and patients exposed to experimental drugs. This thesis furthermore addressed the benefits of OD in planning trials with bio analytical limits and toxicity constraints, through the development of novel optimality criteria that foremost pinpoint information and safety aspects. The use of these methodologies showed better estimation properties and robustness for the ensuing data analysis and reduced the number of patients exposed to severe toxicity by 7-fold.  Finally, predictive tools for maximum tolerated dose selection in Phase I oncology trials were explored for a combination therapy characterized by main dose-limiting hematological toxicity. In this example, Bayesian and model-based approaches provided the incentive to a paradigm change away from the traditional rule-based “3+3” design algorithm. Throughout this thesis several examples have shown the possibility of streamlining clinical trials with more model-based design and analysis supports. Ultimately, efficient use of the data can elevate the probability of a successful trial and increase paramount ethical conduct.

With the digitalization and the ever more computerization of personal vehicles, new attack surfaces are introduced, challenging the security of the in-vehicle network. There is never such a thing as fully securing any computer system, nor learning all the methods of attack in order to prevent a break-in into a system. Instead, with sophisticated methods, we can focus on detecting and preventing attacks from being performed inside a system. The current state of the art of such methods, named intrusion detection systems (IDS), is divided into two main approaches. One approach makes its models very confident of detecting malicious activity, however only on activities that has been previously learned by this model. The second approach is very good at constructing models for detecting any type of malicious activity, even if never studied by the model before, but with less confidence. In this thesis, a new approach is suggested with a redesigned architecture for an intrusion detection system called Multi-mixed IDS. Where we take a middle ground between the two standardized approaches, trying to find a combination of both sides strengths and eliminating its weaknesses. This thesis aims to deliver a proof of concept for a new approach in the current state of the art in the CAN-bus security research field. This thesis also brings up some background knowledge about CAN and intrusion detection systems, discussing their strengths and weaknesses in further detail. Additionally, a brief overview from a handpick of research contributions from the field are discussed. Further, a simple architecture is suggested, three individual detection models are trained and combined to be tested against a CAN-bus dataset. Finally, the results are examined and evaluated. The results from the suggested approach shows somewhat poor results compared to other suggested algorithms within the field. However, it also shows some good potential, if better decision methods between the individual algorithms that constructs the model can be found.

En el futuro, los dispositivos digitales formarán parte del entorno en el que las personas se desenvuelvan, participarán en nuestros objetivos y necesidades y nos ayudarán a "hacer más haciendo menos". A través de los dispositivos portátiles o aquellos que estén embebidos a nuestro alrededor el usuario será capaz de interactuar con el futuro universo de servicios e infraestructuras ubicuas. El principal paradigma que se seguirá se basa en que este universo estará centrado en el usuario ya que éste demandará los servicios que más le convengan en cualquier momento y lugar, todo ello preservando nuestra privacidad y seguridad. Este nuevo concepto no sólo se aplica a un entorno de ocio sino que en el campo profesional las redes inalámbricas de próxima generación permitirán incrementar nuestra productividad, reduciendo el peso de tareas repetitivas, poniendo a nuestra disposición la información relevante en el momento adecuado y según sean las necesidades particulares del usuario en ese momento y permitiéndonos trabajar con otras personas independientemente de donde se encuentren. En particular, se intuye que las redes de próxima generación se diseñen de forma que aglutinen todos los servicios disponibles a través de los diferentes sistemas que existan de forma que las posibles deficiencias de alguno de ellos se vean compensadas por otro. Lo que se pretende conseguir es que el usuario pueda disfrutar en todo momento y lugar de los servicios que desee sin que ello suponga un esfuerzo.Este concepto implica diferentes retos tecnológicos y la integración de múltiples sistemas. Dentro de estos retos tecnológicos esta Tesis aborda los siguientes: soporte de la heterogeneidad en lo referente a las tecnologías de acceso radio que existen y que eventualmente aparecerán en el futuro y que coexistirán en un mismo terminal; desarrollo de técnicas de optimización basadas en la cooperación entre diferentes capas de la pila de protocolos; implementación de estrategias de selección de la red que mejor pueda soportar un determinado servicio ante la posibilidad de utilización de múltiples tecnologías de acceso; optimización del uso de recursos energéticos en las comunicaciones dentro de la red; protección de la privacidad y la seguridad de las comunicaciones personales del usuario.Desde el punto de vista de las aportaciones, en esta Tesis se ha contribuido mediante el diseño, implementación y validación de una serie de técnicas de optimización de las comunicaciones en redes de dispositivos móviles basadas en información intercapa. Para ello, se propone una arquitectura de protocolos novedosa que permite soportar la heterogeneidad en términos de tecnologías de acceso dentro del mismo terminal. El concepto de aislar las capas superiores de la pila de protocolos de las tecnologías de acceso subyacentes se consigue a través de una Capa de Convergencia Universal (UCL, en sus siglas en inglés). El diseño y la especificación esta arquitectura así como de los bloques funcionales que la componen son la primera contribución que se hace en esta Tesis. La UCL supone el marco en el que el resto de técnicas de optimización que se presentan han sido desarrolladas.Igualmente, se desarrollan una serie de técnicas basadas en optimización intercapa que permiten una gestión eficiente de los recursos disponibles así como una mejora en el uso de la energía. Finalmente, se implementan los mecanismos de autenticación y encriptación que permiten asegurar las comunicaciones dentro de la red. El diseño, implementación y validación de estos mecanismos supone la segunda contribución en esta Tesis. El empleo de técnicas de optimización basadas en información procedentes de diferentes capas de la pila de protocolos es la base de los dos mecanismos que se han propuesto. El primero de ellos se basa en la selección dinámica de la tecnología de acceso a utilizar para obtener un rendimiento óptimo del sistema. La segunda estrategia de optimización consiste en el uso simultáneo de varias tecnologías de acceso para conseguir una mejora en las prestaciones de la red. Aparte de la optimización en cuanto al rendimiento en términos de ancho de banda y calidad de servicio, se ha evaluado la mejora de la eficiencia energética conseguida gracias a las soluciones propuestas. Los resultados obtenidos permiten concluir que las propuestas realizadas en el marco de esta Tesis representan una optimización tanto en parámetros de calidad de servicio como en la eficiencia energética del sistema.El mayor avance respecto del estado del arte se centra en habilitar al usuario para que utilice de manera transparente, eficiente y segura los dispositivos que tiene a su alrededor independientemente de la heterogeneidad que presenten y sin requerir de un conocimiento intensivo de la tecnología. El usuario podrá comunicarse haciendo un uso óptimo de los recursos a su alcance sin preocuparse de tener que gestionarlos él mismo. / In the future, computation will be human-centred: it will enter the human world, handling our goals and needs and helping us to do more by doing less. Next generation wireless systems should provide the user access with a broad range of services in a transparent way, independently of user location, by making the technology invisible and embedded in the natural surroundings. New systems will boost our productivity. They will help us automate repetitive human tasks, control a wide range of physical devices in our environment, find the information we need (when we need it, without obliging us to examine thousands of search-engine hits), and enable us to work together with other people through space and time.The achievement of this paradigm led to the identification of a set of optimizations in intra-cluster communications that were needed to fully support it. Firstly, heterogeneity will be a fundamental characteristic of next generation wireless communications since more and more personal devices are equipped with multiple network access technologies so that the user can have access to the different services that the different operational environments provide. However, Next Generation Networks (NGN) will comprise such a diverse number of possibilities that the users cannot be expected to take technical decisions on their own. It is necessary to provide mechanisms that intelligently select the optimal available access network based on context information such as user preferences, power consumption, link quality, etc. Finally, users need to trust the system that supports their personal communications. Within a personal network the most confidential information might be exchanged and the user need to be sure that this will never be disclosed. If the system fails in these features, NGN in general and PNs in particular will never happen.This Thesis has contributed with the development of the mechanisms that tackle the abovementioned challenges. The design and specification of a convergence framework, the so-called Universal Convergence Layer (UCL), has been the first topic addressed. This framework aims to manage all the network access interfaces with which a device is equipped so that they can be transparently used by upper layers as if the node were equipped with a single access technology. On the other hand, the UCL enables the cross-layer optimization paradigm. Its privileged location within the protocol stack gives the UCL the possibility to support both bottom-up and top-down information flow. In this sense, two different solutions based on cross-layer optimization have been proposed to enhance the performance and energy efficiency of the system. The first one deals with the selection at run-time of the most appropriate wireless interface to be used in order to improve the system performance. The second one leverages the striping concept in order to exploit all the network interfaces available. Finally, the UCL also plays a key role in security issues as an enabler for providing link-layer security mechanisms that ensure data confidentiality and integrity, authenticity and non-repudiation. The techniques implemented for node authentication combined with traffic encryption in ad-hoc networks have been thoroughly assessed and have demonstrated their appropriateness.The biggest advance in the state-of-the-art comes from enabling the user to have easy, affordable and seamless control of their devices over heterogeneous communications networks. They are empowered to communicate efficiently and securely with their selected interaction groups, no matter what kind of access is available for them to use.

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