The subject of the diploma thesis is storage and current storage technology in a business company. The first part of the thesis defines the theoretical basis of logistics, supply, international trade and especially warehousing. The practical part is focused on the current situation in the company and inventory analysis. Based on the analysis and all the findings, two proposals were submitted that could contribute to the company to improve the current storage and storage technology and thus increase customer satisfaction.

The process of strategy purchasing management in multinational companies is described and analysed in this master´s thesis. Both methodology and strategy of purchasing management in the multainational companies have been compiled in this work by means of theoretical knowledge from literature and according to the analysis of the current state of purchasing management in a company.

This thesis focuses on changing the internal supply logistic. The first part provides theoretical knowledge, then is indtroduces the production company and analysis of the current state of current management inventory status. Based on the analysis I have proposed measures which are more efficient inventory management. Conditions needed for the implementation of these proposals are proposed as well. The analysis part offers quantified benefits of each proposal.

This diploma thesis deals with the isssue of packaging management. At the first it explains the general concepts of the logistics, stock and packaging management. Using methods employed in logistics, the analysis will examine the current situation and its related problem areas. In the last part, there will be designed management concept that would prevent and eliminate the problems with packaging management.

Le lymphome diffus à grandes cellules B (DLBCL, Diffuse Large B-Cell Lymphoma) constitue le lymphome non Hodgkinien le plus fréquemment diagnostiqué. Les DLBCL sont composés principalement de deux sous groupes : l’entité nommée ABC (Activated B Cell-like) qui est la plus agressive, avec un taux de survie de 30% après traitement, et l’entité GCB (Germinal-Center B Cell). Contrairement aux GCB DLBCL, les ABC DLBCL se caractérisent par une signature génique similaire aux lymphocytes B activés par leur récepteur antigénique (BCR, B Cell Receptor) à cause de l'accumulation de mutations génétiques. Ceci a pour conséquence une activation constitutive du facteur de transcription NF-κB pour laquelle les lymphomes ABC DLBCL ont développé une profonde addiction. Toutefois, la nature pléiotrope de NF-κB rend son ciblage thérapeutique inenvisageable. Mon projet de thèse visait à caractériser de nouveaux régulateurs de la voie d’activation du facteur NF-κB par les récepteurs antigéniques en condition physiologique et pathologique. Dans un premier temps, grâce à un crible protéomique par spectrométrie de masse, nous avons identifié un complexe ternaire nommé LUBAC (Linear Ubiquitin Chain Assembly Complex) comme un acteur majeur de l’activation de NF-κB par le TCR et le BCR, et de la survie des lymphomes ABC DLBCL. Dans un second temps, le crible d’une librairie de mille deux cents molécules chimiques nous a permis d’isoler un composé sélectivement toxique in vitro pour les lymphomes ABC DLBCL. Nous montrons que ce composé entraine la mort apoptotique des ABC DLBCL sans toutefois affecter la signalisation NF-κB. Un tel composé pourrait, dans le futur, être utilisé comme une nouvelle molécule thérapeutique pour le traitement du lymphome ABC DLBCL. / The diffuse large B cell lymphoma (DLBCL) is the most common non Hodgkinien lymphoma. Two main different entities composed the DLBCL : the Activated B Cell-like subtype (ABC DLBCL) witch is the most aggressive and associated with a poor survival prognostic, and the Germinal-Center B Cell subtype (GCB DLBCL). Unlike the GCB DLBCL, ABC DLBCL are characterized by a genetic signature similar to activated B lymphocytes stimulated by their antigen receptor (BCR, B cell receptor) which results from mutations accumulation. As a consequence, ABC DLBCL survival and proliferation requires the constitutive activation of NF-κB transcription factors. Because NF-κB has pleiotropic effect on different tissues, strategies aiming at targeting NF-κB heterodimers might have deleterious consequences on an organism.My project focuses on identifying new modulators involved in antigen receptor mediated NF-κB activation in physiological and pathological condition.We first performed a mass spectrometry analysis and identified the LUBAC (Linear Ubiquitin Chain Assembly Complex) as a new regulator of antigen receptor mediated a NF-κB ctivation and ABC DLBCL survival. Then, we screened a library of one thousand two hundred chemical compounds on DLBCL viability and identified one compound selectively toxic in vitro for the ABC DLBCL subtype. This compound induced ABC DLBCL apoptosis without affected NF-κB signaling. In the future, this compound could be used as a new therapeutic compound for ABC DLBCL.

Les protéines de chocs thermiques (HSP) sont des protéines très conservées au cours de l’évolution des espèces. Ce sont des chaperons moléculaires impliqués dans le repliement des protéines nouvellement synthétisée ou dénaturées. Les HSP sont fortement exprimées dans les cellules cancéreuses, où elles contribuent à la résistance à l’apoptose et aux chimiothérapies. Parmi les HSP, HSP110 est jusqu’à présent peu étudiée. Cependant, HSP110 a été récemment associée au lymphome diffus à grandes cellules B (DLBCL). Le DLBCL est le syndrome lympho-prolifératif agressif le plus fréquent chez l’adulte (30% des lymphomes non-Hodgkinien). Il existe trois principaux sous-type de DLBCL : le type B activé (ABC-DLBCL), le type centre germinatif (GC-DLBCL) et le type lymphome primaire du médiastin (PMBL). La forme activée est celle associée au plus mauvais pronostic clinique. Bien que les thérapies classiques de chimiothérapies associées aux anti-CD20 aient permis d’augmenter le pronostic de survie des patients souffrant de l’ABC-DLBCL, nombreux sont ceux qui développent des résistances ou qui ne répondent pas aux traitements. L’identification de nouvelles cibles thérapeutiques est donc nécessaire.Mes travaux présentent un rôle de HSP110 dans l’activité d’une voie oncogénique du lymphome ABC-DLBCL. En effet, ces travaux démontrent une forte expression d’HSP110 dans les échantillons patients ABC-DLBCL. De plus, ces travaux in vitro sur des lignées ABC-DLBCL montrent une interconnexion entre HSP110 et Myd88 L265P, protéine mutée responsable de l’activation de la voie NF-kB. HSP110 stabilise l’oncogène Myd88 L265P, et participe à l’amplification de la voie NFkB dans le lymphome ABC, voie responsable de la survie et de la prolifération des cellules ABC-DLBCL.Par le biais d’une collaboration, nous avons pu obtenir récemment des inhibiteurs de HSP110. Ainsi, mon travail à également consisté aux criblages in vitro de ces inhibiteurs pour évaluer leur capacité d’inhibition de HSP110. Deux composés ont alors été identifiés comme candidats inhibiteurs d’HSP110. Je me suis ensuite intéressé à l’utilisation de ces inhibiteurs in vitro dans l’ABC-DLBCL. Mes résultats tendent à montrer que ces inhibiteurs ont une action similaire à ceux observés lors de l’inhibition de HSP110 par siRNA ou shRNA.Mes travaux de thèse présente donc HSP110 comme une cible moléculaire potentielle de l’ABC DLBCL. / Heat shock proteins (HSPs) are highly conserved protein across species, and are expressed in all cell type. HSPs are molecular chaperones involved in the folding of newly synthesized or denaturated proteins. HSPs are overexpressed in cancer cells, where they contribute to cancer resistance to chemotherapies. Among HSPs, roles and functions of HSP110 are less described. Interestingly, HSP110 was recently associated with lymphoma aggressiveness in Diffuse Large B Cell Lymphoma (DLBCL). DLBCL is the most lymphoproliferative disease diagnosed in adult (30% of Non-Hodgkin Lymphoma). Three main subtypes of DLBCL are described: Activated-B-Cell lymphoma (ABC-DLBCL), Germinal Center lymphoma (GC-DLBCL), and Primary Mediastinal B Lymphoma (PMBL). ABC-DLBCL is the most aggressive form associated with a poor prognosis. Even if R-CHOP therapies had improve patient’s survival over the last decades, most of patients experiences relapses or treatment resistances. New molecular target are now necessary to treat efficiently these subtypes.My PhD work has highlighted the role of HSP110 in the NFkB signaling pathway, which is an oncogenic pathway in ABC-DLBCL. First, we show that HSP110 is overexpressed in ABC-DLBCL patient sample. We also show an interaction between HSP110 and Myd88 L265P, that is an oncogenic protein responsible for NFkB pathway activation. Consequently, HSP110 stabilizes Myd88 L265P, leading to a sustain NFkB pathway activation in lymphoma cells, and promoting ABC-DLBCL cell survival and proliferation.Finally, our team recently characterized the first known HSP110 inhibitors. I took the opportunity to test these putative inhibitors in my study. My results suggest that these compounds have similar effects than siRNA or shRNA inhibition of HSP110 on ABC-DLBCL survival. This result provide a ground for future in vivo testing of chemical inhibitors of HSP110.In conclusion, my work highlight HSP110 as a potential therapeutic target in ABC-DLBCL.

The history of populations or species is of fundamental importance in a variety of areas. Gaining details about demographic, cultural, climatic or political aspects of the past may provide insights that improve the understanding of how populations have evolved over time and how they may evolve in future. Different types of resources can be informative about different periods of time. One especially important resource is genetic data, either from a single individual or a group of organisms. Environmental conditions and circumstances can directly affect the existence and success of a group of individuals. Since genetic material gets passed on from generation to generation, traces of past events can still be detected in today\''s genetic data. For many decades scientists have tried to understand the principles of how external influences can directly affect the appearance and features of populations, leading to theoretical models that can interpret modern day genetic variation in the light of past events. Among other influencing factors like migration, natural selection etc., population size changes can have a great impact on the genetic diversity of a group of organisms. For example, in the field of conservation biology, gaining insights into how the size of a population evolves may assist in detecting past or ongoing temporal reductions of population size. This seems crucial since the reduction in size also correlates with a reduction in genetic diversity which in turn might negatively affect the evolutionary potential of a population. Using computational and population genetics methods, sequences from whole genomes can be scanned for traces of such events and therefore assist in new interpretations of historical details of populations or groups of interest. This thesis focuses on the detection and interpretation of past population size changes. Two approaches to infer particular parameters from underlying demographic models are described. The first part of this thesis introduces two summary statistics which were designed to detect fluctuations in size from genome-wide Single Nucleotide Polymorphism (SNP) data. Demographic inferences from such data are inherently complicated due to recombination and ascertainment bias. Hence, two new statistics are introduced: allele frequency-identity by descent (AF-IBD) and allele frequency-identity by state (AF-IBS). Both make use of linkage disequilibrium information and exhibit defined relationships to the time of the underlying mathematical process. A fast and efficient Approximate Bayesian Computation framework based on AF-IBD and AF-IBS is constructed that can accurately estimate demographic parameters. These two statistics were tested for the biasing effects of hidden recombination events, ascertainment bias and phasing errors. The statistics were found to be robust to a variety of these tested biases. The inference approach was then applied to genome-wide SNP data to infer the demographic histories of two human populations: (i) Yoruba from Africa and (ii) French from Europe. Results suggest, that AF-IBD and AF-IBS are able to capture sufficient amounts of information from underlying data sets in order to accurately infer parameters of interest, such as the beginning, end and strength of periods of varying size. Additionally the results from empirical data suggest a rather stable ancestral population size with a mild recent expansion for Yoruba, whereas the French apparently experienced a rather long-lasting strong bottleneck followed by a drastic population growth. The second part of this thesis introduces a new way of summarizing information from the site frequency spectrum. Commonly applied site frequency spectrum based inference methods make use of allele frequency information from individual segregating sites. Our newly developed method, the 2 point spectrum, summarizes allele frequency information from all possible pairs of segregating sites, thereby increasing the number of potentially informative values from the same underlying data set. These additional information are then incorporated into a Markov Chain Monte Carlo framework. This allows for a high degree of flexibility and implements an efficient method to infer population size trajectories over time. We tested the method on a variety of different simulated data sets from underlying demographic models. Furthermore, we compared the performance and accuracy of our method to already established methods like PSMC and diCal. Results indicate that this non-parametric 2 point spectrum method can accurately infer the extent and times of past population size changes and therefore correctly estimates the history of temporal size fluctuations. Furthermore, the initial results suggest that the amount of required data and the accuracy of the final results are comparable with other publicly available non-parametric methods. An easy to use command line program was implemented and will be made publicly available. In summary, we introduced three highly sensitive summary statistics and proposed different approaches to infer parameters from demographic models of interest. Both methods provide powerful frameworks for accurate parameter inference from genome-wide genetic data. They were tested for a variety of demographic models and provide highly accurate results. They may be used in the settings as described above or incorporated into already existing inference frameworks. Nevertheless, the statistics should prove useful for new insights into populations, especially those with complex demographic histories.

Introduction: Colorectal cancer (CRC) is one of the most frequent malignancies and affects approximately 5% of worldwide population. More than 75% of CRC cases represent sporadic forms. Susceptibility to nonhereditary CRC is significantly influenced by polymorphisms and mutations in low-penetrance genes. Variations in biotransformation and DNA repair genes may result in acumulation of toxins and DNA damage in cells leading to the development of cancer. Furthermore, different gene expression profiles of membrane transporters affecting the accumulation of anticancer drugs in tumour cells, e.g. ABC drug transporters, may largely influence inter-individual variability in drug response and chemotherapy outcome. The aim of this study was to evaluate the role of genetic and lifestyle factors in the risk of onset and progression of colorectal cancer. This study followed selected genetic alterations in xenobiotic-metabolizing enzymes (CYP1B1, GSTM1, GSTT1, GSTP1, NQO1 and EPHX1) and genes involved in response to DNA damage (CHEK2 and NBN), as potential CRC susceptibility factors. Another aim of this study was to investigate expression profile of all human ABC transporter genes to follow their prognostic and predictive potential in colorectal carcinoma. Materials and methods: The polymorphisms and other...

Le glioblastome (GBM) est le cancer du cerveau le plus fréquent et grave chez l’adulte. Son pronostic sombre est en partie dû à la résistance de ces tumeurs aux chimiothérapies. L’une des principales causes de ces résistances est l’incapacité des chimiothérapies à pénétrer dans le cerveau depuis le sang à cause de la barrière hémato-encéphalique (BHE), une spécificité des vaisseaux sanguins cérébraux. Par l’injection de microbulles et l’envoi d’ultrasons dans le cerveau, il est possible d’ouvrir cette BHE pour permettre à des chimiothérapies d’entrer dans le cerveau. Nous avons montré quela chimiothérapie carboplatine gagnait en efficacité lorsqu’elle était injectée après ce procédé. Les GBM peuvent aussi montrer une résistance aux chimiothérapies par des mécanismes génétiques intrinsèques à la tumeur. Nous avons étudié l’expression et l’impact sur le pronostique des patients atteints de GBM des gènes de la famille des transporteurs ABC, dont le membre ABCA13 s’est avéré important. / Glioblastoma (GBM) is the most frequent and severe brain cancer for adults. Its dark prognosis in partly due to the resistance of these tumors to chemotherapies. One of the main causes of these resistances is the incapacity of chemotherapies to enter the brain from the blood circulation because of the bloodbrain barrier (BBB), a specificity of cerebral blood vessels. By the injection of microbubbles and the delivery of ultrasound into the brain, it is possible to open this BBB to allow chemotherapies to enter the brain. We have showed that the chemotherapeutic agent carboplatin gained efficacy when it was injectedafter this procedure. GBM can also exhibit resistance to chemotherapies by genetic mechanisms intrinsic to the tumor. We studied the expression and the impact on prognosis for GBM patients of the genes of the ABC transporters family, which member ABCA13 appeared important.

Detta examensarbete har utförts på företaget Hillmers Logistik AB i Katrineholm. Syftet med examensarbetet har varit att utvärdera en ny artikelplacering, baserat på metoden ABCklassificering, som reducerar tiden det tar för företaget att utföra lageraktiviteten orderplockning. Examensarbetet har jämfört och utvärderat den föreslagna artikelplaceringen som företaget använder i nuläget. För att uppfylla syftet med studien användes frågeställningarna: vilka klassificeringskriterier som är lämpliga att använda vid ABC-klassificeringen av artiklarna som lagras hos företaget, hur bör artiklarna placeras med avseende på ABC-klassificeringen och hur mycket tid kan företaget spara genom den föreslagna artikelplaceringen? En fältstudie utfördes för att bidra till den analys som krävs för att svara på frågeställningarna. Under fältstudien utfördes en intervju av låg struktureringsgrad med företagets chef som kvalitativ metod. Examensarbetet använder sig av både kvalitativa och kvantitativa metoder för att skapa en större bredd via triangulering. En ABC-klassificering över företagets samtliga artiklar utfördes. Klassificeringen använder sig av en dubbel ABC-klassificering där kriterierna var uttagningsfrekvensen och lagringskriterium. Resultatet från ABC-klassificeringen visar att: AA-klassen innehåller 0,23% av alla artiklar men står för 22,17% av alla uttag; BA-klassen innehåller 1,39% av artiklarna och står för 18,31% av uttagen; CA-klassen innehåller 4,87% av artiklarna och står för 24,57% av uttagen; DA-klassen innehåller 47,33% av artiklarna och utgör 14,48% av uttagen; och den resterande DB-klassen står för 46,17% av artiklarna och utgör 20,47% av uttagen. Artikelplaceringens princip är att klasserna AA, BA, CA och DA placeras i fallande ordning i lagret. Klass AA placeras lättillgängligast med hänsyn till orderplockningens start- och slutpunkt. DB-klassen placeras i ett hyllsystem vilket skiljer sig från de övriga klasserna som placeras i pallsystem. Den föreslagna lagerplaceringen med hänsyn till ABC-klassificeringen ger företagets orderplockning en total tidsförbättring på 5,6% jämfört med den nuvarande artikelplaceringen. / <p>Examensarbetet är utfört vid Institutionen för teknik och naturvetenskap (ITN) vid Tekniska fakulteten, Linköpings universitet</p>