Ce travail s'inscrit dans le cadre d'études de structures nucléaires réalisées en utilisant des réactions de fission induites par neutrons froids. Il décrit successivement les résultats d'une étude sur des noyaux ayant un nombre de neutrons N=50-60, sur le développement d'un marqueur d'événements de fission et enfin sur la production de l'isomère Pt-195m. Chacun des différents sous-thèmes trouve son origine dans la campagne EXILL qui s'est déroulée en 2012-2013 et durant laquelle un spectromètre de grande efficacité pour la détection des rayonnements γ (EXOGAM) a été utilisé auprès du réacteur à haut flux de neutrons de l'Institut Laue-Langevin (ILL). Dans la première partie de cette thèse, les noyaux d'intérêt ont été produits par fission induites par des neutrons sur les cibles fissiles U-235 et Pu-241. Des méthodes de spectroscopie γ ont été appliquées pour l'identification des fragments de fission, l'attribution des transitions γ à un noyau et l'analyse des durées de vie moyenne des états excités. L'analyse des durées de vie moyenne des états excités dans la plage de quelques picosecondes à quelques nanosecondes a été réalisée en utilisant deux méthodes complémentaires. Dans les deux cas, il s'agit de réaliser un spectre en temps construit à partir de la coincidence entre une transition qui alimente le niveau mesuré et une transition qui le désexcite. Les durées de vie moyenne pour les noyaux Kr-92, Kr-93 et Zr-101 sont présentées. Dans la seconde partie, les premiers résultats du développement d'un nouveau détecteur pour la discrimination des fragments de fission sont présentés. Ce marqueur d'événements de fission est destiné à être utilisé sur le spectromètre FIssion Prompt Product γ-ray Spectrometer (FIPPS) de l'ILL. Dans le cadre de cette étude, deux conceptions de détecteurs différentes, basées sur un scintillateur en plastique solide et un scintillateur liquide organique, ont été testées. Dans la troisième partie, la possibilité de la population spécifique de l'isomère de spin dans Pt-195 est examinée au regard particulièrement de son utilisation en tant que radio-isotope en médecine nucléaire. Une telle activation spécifique pourrait être réalisée grâce à l'existence d'états excités dont la structure permettrait une population ciblée dans le cas de l'utilisation de réactions de photo-excitation. La recherche de tels états a été initiée lors d'une expérience de capture de neutrons à EXILL dans laquelle des états potentiels ont été identifiés. L'activation de l'isomère par ces états a ensuite été testée avec des réactions photonucléaires à l'aide du faisceau haute intensité disponible auprès de l'installation γ HIGS de TUNL (Triangle Universities Nuclear Laboratory, Duke, USA). / Within the scope of atomic nuclear structure studies with neutron-induced reactions, this work presents the results of a fission fragment study in the N=50-60 region, the development of a fission event tagger, and the production of the isomer Pt-195m. Each of the different sub-topics has its origin in the 2012/13 EXILL campaign, where nuclear structure studies were carried out with neutron-induced reactions, and explored with a γ-efficient detector array. In the first part of this thesis, the neutron-rich region around neutron number N=50-60 was investigated with neutron-induced fission reactions on the fissile targets U-235 and Pu-241. Gamma spectroscopy methods were applied for the identification of the respective fission fragments, the assignment of γ transitions, and the analysis of lifetimes of excited states. The slope fit method as well as the recently developed generalized centroid difference method were used for the analysis of lifetimes in the low picoseconds to sub-nanoseconds range. Lifetimes for the nuclei Kr-92, Kr-93 and Zr-101 are presented. In the second part, first results of the development of a new detector for the discrimination of fission fragments are presented. This fission event tagger is intended to be used at the FIssion Product Prompt γ-ray Spectrometer (FIPPS) at the Institut Laue-Langevin. Within the scope of this study, two different detector designs, based on a solid plastic scintillator and an organic liquid scintillator, respectively, were tested. In the third part the possibility of the specific population of the spin-isomer in Pt-195 is discussed with special regard to its use as radioisotope in nuclear medicine. Such a specific activation could be realized via certain “doorway states” in photo-excitation reactions. The search for these doorway states was initiated within a neutron capture experiment at EXILL where potential states were found. The activation of the isomer via these states was tested afterwards with photonuclear reactions using the high intense γ-beam HIGS of the TUNL facility.

This thesis deals with marketing activities of the Baby Agency, a babysitting company. The aim of this thesis is to map current marketing strategies of the company and to recommend improvements. The thesis itself is divided into two parts. The first theoretical part describes specific sections of marketing, such as marketing strategies, marketing mix of services, communication targeting at children and teenagers, market research techniques or new trends in marketing. The second part analyzes current marketing activities of the company and maps the competition. In the conclusion the thesis suggests the steps to be undertaken to improve the current marketing strategy of the Baby Agency are suggested, based on theoretical findings, analyses and surveys.

This thesis deals with a load testing of web applications. The text is introduced with a definition of the load testing, reasons for its execution and a description of its types. Recommended procedures are provided for preparation, execution and evaluation of the testing. Several commercial and open-source load testing tools are described. Cloud testing -- the contemporary phenomenon -- is also included. The entire process of load testing depicted in this text is demonstrated on a selected application. A following chapter briefly deals with a profiling of web applications. It, again, covers its definition and its purpose, accompanied with a practical example. The aim of this thesis is to introduce the reader to the world of load testing, which is primarily accomplished by describing an example, which provides an in-depth explanation for every step necessary in order to perform the web application testing successfully.

Les immunothérapies de type immune checkpoint blockade (ICB) ont révolutionné les approches thérapeutiques en oncologie médicale et ont largement contribué au fait que l’immunothérapie est maintenant considérée comme le quatrième pilier des traitements anticancer, aux côtés d’approches traditionnelles telles que la chirurgie, la radiothérapie et la chimiothérapie. Malgré les résultats encourageants des études cliniques évaluant ce type d’immunothérapie, la majorité des patients décèderont des suites de leur maladie. Conséquemment, le domaine de recherche visant à comprendre les mécanismes de résistance aux immunothérapies est en expansion constante. Plusieurs stratégies visant à améliorer les issues cliniques ont été proposées, parmi lesquelles figurent: 1) la recherche de nouvelles cibles thérapeutiques dans le microenvironnement immun tumoral et; 2) les études de combinaisons thérapeutiques où une immunothérapie est jumelée à d’autres types de modalités thérapeutiques potentiellement synergiques. Chacune des études présentées dans cette thèse de recherche s’apparente à l’une ou l’autre de ces stratégies. Dans le cadre de notre première étude, nous démontrons que la protéine WISP1 représente une cible prometteuse à l’intérieur du microenvironnement de plusieurs types de tumeurs solides étant donné son association avec différentes variables pronostiques et proinflammatoires, ainsi qu’avec un programme épigénétique complexe, la transition épithélialemésenchymateuse (Epithelial-Mesenchymal Transition; EMT). De plus, nous démontrons que les niveaux d’expression de WISP1 sont significativement plus élevés au sein des tumeurs démontrant une résistance primaire aux immunothérapies de type ICB, particulièrement lorsque qu’une signature reliée à l’EMT peut être retrouvée de façon concomitante. Pour notre deuxième étude, nous avons utilisé des modèles murins in vivo de cancer pulmonaire non à petites cellules KRAS-mutés afin de tester différentes combinaisons thérapeutiques jumelant une thérapie dite ciblée (i.e., un inhibiteur de MEK) a différentes immunothérapies de type ICB. Nos résultats démontrent que l’ajout d’une immunothérapie anti-CTLA-4 à l’inhibiteur de MEK AZD6244 (selumetinib) et une immunothérapie anti-PD-L1 augmente significativement la survie, et que ces bénéfices sont associés à une diminution de marqueurs reliés à l’EMT. Il existe donc un lien commun entre ces deux études qui repose sur l’importance de l’EMT comme facteur favorisant la résistance thérapeutique aux immunothérapies. De plus, nous démontrons pour la première fois que les bénéfices associés à la triple combinaison thérapeutique susmentionnée peuvent être corrélés à une diminution d’expression de marqueurs liés à l’EMT. Par conséquent, nos résultats sont discutés en tant que base potentielle pour de futures études visant à réduire la résistance thérapeutique reliée à l’EMT. Nous discutons également de la valeur translationnelle de nos résultats à travers le développement d’une étude clinique. / Immune checkpoint blockade (ICB) has revolutionized therapeutic approaches in the field of medical oncology and has largely contributed to the fact that immunotherapy is now being regarded as the fourth pillar of cancer treatment alongside surgery, radiotherapy and chemotherapy. Despite encouraging results from clinical trials using ICB, most patients ultimately relapse or succumb to their disease. Therefore, the field of immunotherapeutic resistance research is rapidly expanding. Many strategies to improve ICB responses have been undertaken, including: 1) the search for novel, actionable targets in the immune tumor microenvironment (TME) and; 2) therapeutic combination studies where an ICB backbone is combined with different, synergistic treatment modalities. Each of the studies presented in this research thesis embraces one of these strategies. In our first study, we show that WISP1 represents a promising TME target in multiple solid tumor types by demonstrating its association with prognostic and pro-inflammatory variables, as well as to a complex epigenetic program termed Epithelial-Mesenchymal Transition (EMT). Furthermore, we show that increased WISP1 expression is associated to primary resistance to ICB, particularly when EMT-related signatures are found concomitantly. In our second study, we used in vivo mouse models of KRAS-mutant Non-Small Cell Lung Cancer (NSCLC) to test different therapeutic combinations of targeted therapies (i.e., MEK inhibitor) and ICB. We found that the addition of anti-CTLA-4 ICB to MEK inhibitor AZD6244 (selumetinib) and anti-PD-L1 ICB increases survival, and that these benefits are associated with the downregulation of EMT-related markers. Therefore, there exists a common link between these studies, which relies on the significance of EMT as a detrimental factor within the TME and its association with ICB resistance. Moreover, we show for the first time that the benefits of ICB combination therapy can be associated to the downregulation of EMT markers in vivo. Consequently, we discuss how our results may constitute the basis for future work aiming at reducing EMT-mediated therapeutic resistance, as well as the translational relevance of our pre-clinical results through the development of a clinical trial.

Quatorze femmes canadiennes meurent chaque jour du cancer du sein. Le cancer du sein triple-négatif (CSTN) détient un mauvais pronostic De nombreux efforts sont fournis afin d'offrir à ces patientes des traitements ciblés, comme les inhibiteurs de poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) afin d’améliorer leur survie et de minimiser la toxicité liée à la chimiothérapie. Le sous-groupe de CSTN qui pourrait bénéficier des PARPi reste à être identifié. De plus, différentes stratégies d'administration des PARPi et de la chimiothérapie pourraient améliorer leur efficacité thérapeutique tout en diminuant la toxicité. Nous avons précédemment dérivé une signature génétique de 63 gènes prédisant la réponse aux PARPi avec une précision globale élevée. Nos objectifs sont 1) d'évaluer les implications cliniques de la signature génétique; et 2) de déterminer la séquence optimale d'administration du talazoparib et du carboplatin in vivo en cancer du sein triple-négatif BRCAWT. D'abord, nous avons évalué la fréquence mutationnelle des 63 gènes dans différents contextes cliniques. Deux bases de données publiques furent utilisées. Puis, nous avons comparé trois cohortes de xénogreffes orthotopiques: A) talazoparib en premier, combiné au carboplatin le jour 3; carboplatin en premier suivi du talazoparib B) un jour après; et C) sept jours après. La fréquence mutationnelle des 63 gènes était élevée chez les tumeurs luminales B et celles de mauvais pronostic. Les patientes luminales B mutées avaient une moindre survie que les patientes non mutées. Aussi, l'inhibition tumorale et métastatique était similaire pour les cohortes A et B, cependant la cohorte B avait moins de toxicité. Les PARPi pourraient avoir un rôle chez les tumeurs luminales B et celles de mauvais pronostic. Deuxièmement, le prétraitement avec le carboplatin semble améliorer la sensibilité au talazoparib et diminuer la toxicité. / Fourteen Canadian women die every day from breast cancer. Triple-negative breast cancer (TNBC) has a poor prognosis. Numerous efforts are made to offer these patients targeted therapies such as poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) to improve survival and minimize chemotherapy-related toxicity. It is not well understood which subset of TNBC patients will benefit from PARPi; and if different sequencing strategies of PARPi and chemotherapy can improve therapeutic efficacy and decrease toxicity. We previously derived a 63-gene signature predicting response to PARPi with a high overall accuracy. Our objectives are 1) to evaluate the clinical implications of the 63-gene signature; and 2) to determine the optimal sequence of administration of talazoparib and carboplatin in vivo in BRCAWT TNBC. First, we evaluated the mutational frequency of the 63 genes in different clinical settings using two publically-available datatsets. Second, we compared three cohorts of orthotopic xenografts: A) talazoparib first, combined with carboplatin on day 3; carboplatin first, followed by talazoparib B) one day later; and C) seven days later. We found that the mutational frequency was high in breast cancer subtypes of poor prognosis. Mutated luminal B patients had a lower survival than non-mutated patients. We also found that tumoral and metastatic inhibition were similar between cohorts A and B, but cohort B had less toxicity. In conclusion, there is potential for PARPi efficacy in luminal B and poor prognosis tumors. Second, pretreatment with carboplatin may be an effective approach with less toxicity.

Title: No thanks to unnecessary advertising! -A study on targeted marketing via Big Data in a consumer perspective Authors: Ricky Carlsson and Alexander Vilhelmsson Supervisor: Anders Parment Key words: Targeted marketing, Big Data, Customer segmentation, Buying process, Integrity concern, Customer relationship management, Marketing communication, Strategic management, Big Data management, Online Behavioural Targeting Introduction: In a world that is globalizing and where digital development is advancing, companies have had to adapt. In recent times with the increasingly more digital world, technology has become an increasingly more relevant factor, not least in marketing. A digital method that has emerged is Big Data, whichmakes it possible forcompanies tocollect large amounts of information about consumers. By analysing the information extracted from Big Data, it is easier to find and understand consumers' needs and what motivates their buying process. It is important that companies analyse the information correctly so that they do not run the risk of creating negative effects from targeted marketing via Big Data. Purpose: To investigate Swedish consumers' attitudestowards targeted marketing via Big Data and to find out how companies that sell goods and services to consumers can improve their use of Big Data in targeted marketing from a consumer perspective. Method: The study is a cross-sectional study of a qualitative and quantitative nature. The qualitative empirical data consists of 11 semi-structured interviews with students in Sweden. The quantitative empirical data consists of 203 survey answers collected from consumers around Sweden. The study is based on an abductive approach and has a hermeneutic approach. Conclusion: The result of the study shows that there are both opportunities and challenges for companies when using Big Data in targeted marketing. Targeted marketing with the help of Big Data that is performed correctly should only have a positive impact on the targeted marketing and something that creates value for both the consumers and the companies, but this is not the case today. The population of the study perceives that marketing often does not match their needs; this shows that companies must become better at analysing the data. If the data extracted from Big Data is analysed in a better way, the segmentation of consumers will also be better. / Titel: Nej tack till onödig reklam! - En studie om riktad marknadsföring via Big Data i ett konsumentperspektiv. Författare: Ricky Carlsson och Alexander Vilhelmsson Handledare: Anders Parment Bakgrund: I en värld som globaliseras och där den digitala utvecklingen går framåt har företag varit tvungna att anpassa sig. På senare tid i takt med den ständigt mer digitaliserade världen har teknologi blivit en alltmer relevant faktor, inte minst inom marknadsföring. En digital metod som har vuxit fram är Big Data genom vilken företag har möjlighet att samla in stora mängder information om konsumenter. Genom att analysera informationen som utvinns från Big Data går det att lättare finna och förstå konsumenters behov och vad som motiverar deras köpprocess. Det är viktigt att företag analyserar informationen på rätt sätt för att inte löpa risken att skapa negativa effekter av den riktade marknadsföringen via Big Data. Syfte: Att undersöka svenska konsumenters attityder till riktad marknadsföring via Big Data samt ta reda på hur företag som säljer varor eller tjänster till konsumenter kan förbättra användningen av Big Data inom riktad marknadsföring utifrån ett konsumentperspektiv. Metod: Studien är en tvärsnittsstudie av kvalitativ och kvantitativ karaktär. Den kvalitativa empirin består av 11 semi-strukturerade intervjuer med studenter i Sverige. Den kvantitativa empirin består av 203 insamlade enkätsvar från konsumenter runt om i Sverige. Studien grundas i en abduktiv ansats och har ett hermeneutiskt synsätt. Slutsatser: Resultatet i studien visar på att det finns möjligheter och utmaningar för företag vid användning av Big Data inom riktad marknadsföring. En riktad marknadsföring medhjälp av Big Data som utförs på rätt sätt borde enbart ha en positiv påverkan på den riktade marknadsföringen och något som skapar värde för konsumenter och företag, men så är inte fallet idag. Då studiens population uppfattar att den riktade marknadsföringen ofta inte matchar deras behov bör företag bli bättre på att analysera data. Om data som utvinns från Big Data analyseras på ett bättre sätt kommer även segmenteringen av konsumenter att bli bättre.

This paper considers the issue of social housing and possibilities of cooperation between organized civil society, the municipality, and private landlords regarding social housing in the 5th district of Prague. I focused on the potential hidden in the possible involvement of private landlords and non profit organizations in the system of social housing. In the qualitative research I dealt with the role individual actors play in social housing, as well as possible parallels with social entrepreneurship. I made eleven interviews and one focus group with representatives of the target group households. The paper includes also a description of foreign trends in social housing, and closely considers the German and Dutch cases. It brings forth an analysis of the housing situation in Prague 5, and a proposition of an innovative model of social housing in this particular district.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Colon rectal cancer (CRC) is one of the most common cancers worldwide. It is characterized by the successive accumulation of mutations in genes controlling epithelial cell growth and differentiation leading to genomic in-stability. This results in the activation of proto-oncogene(K-ras), loss of tumor suppressor gene activity and ab-normality in DNA repair genes. Targeted therapy is a new generation of cancer treatment in which drugs attack targets which are specific for the cancer cell and are critical for its survival or for its malignant behavior. Survival of metastatic CRC patients has approximately doubled due to the development of new combinations of stan-dard chemotherapy, and the innovative targeted therapies, such as monoclonal antibodies against epidermal growth factor receptor (EGFR) or monoclonal antibodies against vascular endothelial growth factor (VEGFR).The study is to exhibit the need for right drug-right target and provides a proof of principle for potent efficacy of molecular targeted therapy for CRC. We have performed the weighted gene co-expression network analysis for three different patient cohort treated with different targeted therapy drugs. The results demonstrates the variation across different treatment regime in context of transcription factor networks. New significant tran-scription factors have been identified as potential biomarker for CRC cancer including EP300, STAT6, ATF3, ELK1, HNF4A, JUN, TAF1, IRF1, TP53, ELF1 and YY1. The results provides guidance for future omic study on CRC and additional validation work for potent biomarker for CRC.

Inledning Skolattacker är ett ovanligt och komplext fenomen som ökar i det svenska samhället. Skolattacker kan ha omfattande implikationer för lokalsamhället, men även för uppfattningen om skolan som en trygg och säker plats. Flera instanser i samhället behöver vara förberedda och samverka för att förebygga och minimera risken för att en skolattack ska ske, och för att minimera skadebilden vid en skolattack. Kommuner har en särställning i det samordnande och förebyggande arbetet mot allvarliga olyckor och skador, samt för skola och utbildning i kommunal regi. Styrningen i Sverige är komplex, och omfattar flera olika lagar, förordningar, direktiv, riktlinjer och råd, varför organiseringen för att förebygga skolattacker kan variera mellan olika kommuner mot bakgrund av det kommunala självstyret. Syfte Syftet med studien är att undersöka skillnader och likheter i de policys, handlings- och åtgärdsplaner som finns för att förebygga och hantera skolattacker i ett urval av kommuner. Metod Datainsamling har skett genom att begära ut offentliga handlingar som rör pågående dödligt våld i skolor/skolattacker från ett urval av kommuner. Studien genomförs genom policyanalys genom kvalitativ innehållsanalys av kommuners handlings- och åtgärdsplaner avseende pågående dödligt våld i skolor/skolattacker. Även den information som framkommit i samband med datainsamlingen har tillförts studien. Resultat I studien framkom det att begäran om utlämnande av handling tolkades mycket olika mellan kommunerna. Det fanns organisatoriska skillnader mellan flera av kommunerna om vem som besvarade frågeställningen, samt vilken roll som ansvarade för upprättandet och uppdaterandet av handlings- och åtgärdsplaner. Både utformning och innehåll i handlings- och åtgärdsplanerna varierade mellan kommunerna. Trots detta fanns det indikationer på att det föreligger ett intresse att arbeta förebyggande mot skolattacker, med särskild tonvikt på en pågående skolattack och det efterföljande arbetet. Samtliga kommuner har åtminstone delvis anpassning till Skolverkets riktlinjer, medan enskilda kommuner även inkorporerade information kopplad till tidigare (huvudsakligen amerikansk) forskning.  Slutsatser Det finns stora skillnader i såväl organisation, ansvarsfördelning och upprättande av handlingsplaner, men samtliga kommuner har inkorporerat viss styrning. Samtliga kommuner hade någon typ av arbete avseende våld i skolan, men inte alla hade enskilda dokument eller delar av dokument tillägnat specifikt fenomenet skolattacker. / Introduction School attacks are a rare and complex phenomena, the occurrence of which is increasing in Sweden. School attacks may have extensive implications for the local community, but also for the perception of school as a safe and secure place. Cooperation between many organisations is necessary to prevent and prepare for a school attack, as well as minimise the effects during and after one occurs. Municipalities have a special role in the coordination and preventative work regarding serious accidents and injuries, along with the responisbility for school and education in the municipality. The governance of Sweden is complex, and encompasses many laws, regulations, directives, guidelines and advice. Due to the municipal self-governance, the organisation surrounding the prevention of school attacks may vary between differing municipalities. Purpose The purpose of the study is to examine the similarities and differences in the policies and action plans that exist to prevent and handle school attacks in a sample of municipalities.  Method Data has been collected through requesting public documents regarding ongoing deadly violence in schools (school attacks) from a sample of municipalities. Policy analysis was performed through use of qualitative content analysis of said documents. The information revealed during the data gathering has also been added to the study.  Result This study shows that the request of documentation was treated very differently by the municipalities. There were organisational differences between the municipalities regarding who answered the request, as well as the title and role of the person responsible for the creation and upkeep of the action plans. Both the design and the contents of the action plans varied between the municipalities. Despite this, there were indications of an interest to work preventative against school attacks, with special attention on the ongoing act and the events following an attack. All municipalities have at least partially conformed to the guidelines of Skolverket, though some municipalities also used previous research, most of which was American.  Conclusions All municipalities had some type of governance and action plan regarding violence in schools, though not all had specified school attacks as a phenomena. At the same time, there were large differences in how the action plans were created, who was responsible for the creation and maintenance thereof, as well as the organisations behind them.