The increase of obesity that we have experienced during the last decades and its association with insulin resistance, type 2 diabetes and other metabolic diseases has resulted in an enormous interest for understanding the mechanisms underlying these disorders. Tissue inflammation triggered by food with a high glycemic index has been suggested to be an important mediator in the development of insulin resistance. Despite great research efforts lately, more research is needed in order to understand how nutrients interact with the genetic factors that control and triggers the inflammatory responses. The composition of macronutrients in a diet influences the levels of insulin secretion in the body. Besides controlling the blood glucose concentration, insulin also regulates a range of inflammatory processes. Inflammation is largely dependent on some small cell-signaling molecules called cytokines, as these activate a wide range of inflammatory-related genes. The objective of this study is to explore the regulatory effects of insulin and cytokines on the transcription of the following selected genes related to inflammation; D5D, D6D, SCD and FOXO3A. In addition, expression of TRAIL, BTG1 and TWIST1 is studied as they all are target genes for FOXO3A, and related to inflammatory processes and/or glucose metabolism. Quantitative-PCR was used to study mRNA expression of relevant genes in THP-1 cells treated with insulin and cytokines. As the investigation was performed on THP-1 monocytes, it was necessary to optimize the in vitro conditions in order to obtain a maximal response from the insulin and cytokine treatments. The concentration of insulin was an important factor in this study, because the regulation of FOXO3A and desaturases (D5D, D6D and SCD) mRNA expression seemed to be dose-dependent. The treatment period was also critical, as a set of time-course experiments revealed that FOXO3A and the desaturases were regulated by insulin and cytokines at different time-points. In this study, THP-1 cells treated with insulin and/or cytokines revealed significant regulations of the relevant genes. Gene expression of D5D, D6D and SCD was significantly up-regulated in response to insulin. Furthermore, mRNA expression of the transcription factor FOXO3A was significantly down-regulated by insulin, IL-1β and TNF-α. However, neither FOXO3A nor the desaturases were cooperatively regulated by these stimulating factors. TRAIL, TWIST and BTG1 on the other hand, were significantly up-regulated in a synergistic manner when cells were treated with a combination of insulin, IL-1β and TNF-α. The observed regulation of gene expressions in THP-1 monocytes treated with insulin and cytokines suggests that insulin may affect the regulation of inflammatory related genes in circulating human monocytes. As insulin is secreted in the bloodstream followed by elevated levels of glucose after a meal, these results may reflect possible diet-induced changes in gene expression.

Slender well drilling is a method that drills smaller holes and is more economical than conventional drilling due to the use of smaller equipment and rigs. Using the different tools for drilling slender wells, such as expandable reamers and expandable liners means that very deep wells can be drilled. If unexpected problems such as lost circulation or over pressured zones are faced, an expandable liner can be set. This type of solution imply very little or non- loss in diameter of the section. Reducing the amount of drill cuttings, steel, mud and cement means that less storage space is needed on the rig. Less storage needs means that a smaller and lower cost rig can be used. Using smaller equipment will also reduce the risk of the operations because the equipment is easier to handle during drilling and lifting operations. Avoiding the largest hole sizes and drilling more holes in the optimum range for ROP will reduce drilling time. There can also be some disadvantages with drilling slender wells. The equipment will be weaker if small holes are drilled, this is due to the small size of the equipment. In addition to this, hole cleaning can be a problem if mostly liners are used in the well and the well thereby have an upper sections with diameter that is significantly larger than the lower sections, since this will cause a large difference in the annular velocity of mud. The main objective with the thesis is to investigate the potential of using slender wells for exploration and production, as well as giving an overview of slender wells and how they are drilled. The work includes well construction, casing design and hydraulic calculations. The slender well designs are then to be compared with the conventional well design by looking at material savings. Pressure data from a high pressure and high temperature (HPHT) field in the North Sea was used. One of the objectives was to design a slender exploration well for 15 000 psi pressure rating. In addition to this a slender exploration well and a slender production well were designed using a water depth of 360 m. Based in the investigation slender well designs are feasible. The slender exploration wells are drilled in 5 sections, using a riser with an ID of 8 5/8” and an 11” wellhead (WH) and BOP. A 20” conductor casing is set, followed by an 11 3/4” surface casing with an 8 5/8” PIL. Then a 7” liner is set, before the well is drilled through the reservoir using a 5 7/8” drill bit. In the slender production well, an extra casing point is added to the well compared to the conventional well design, this allows more complicated wells to be drilled, or to cope with unexpected drilling problems. For drilling the slender exploration well, a riser with an ID of 12 1/2" is used together with an 11” WH and BOP. The surface casing has a diameter of 20”, followed by a 14” surface casing with a 10 3/4” PIL. An 8 5/8” liner is set below the 10 3/4" PIL. To maintain pressure integrity we install an 8 5/8 x 6 5/8” casing in the next section to isolate the liners, before the well is drilled to target depth (TD) where a 4 1/2" liner is set. The volume of drill cuttings from drilling the slender exploration well was reduced by 61,1 % compared to the conventional well. For the slender production well, the reduction was 53,5 %. The volume of steel for casings and liners in the well was reduced by 59,1 % for the exploration well and 20,1 % for the production compared to conventional well design. The mud volume needed in the well was reduced by 53,2 % for the slender exploration well compared to the conventional well, for the slender exploration well, the reduction in mud volume was 45,2 %. Further focus should be on well completion equipment for 15K pressure rating. This include expandable liner hanger, wellhead, BOP etc. A comparison of equipment for 10K versus 15K would have been of interest. Another important aspect is the time and cost saving from drilling slender wells.

Doxorubicin is a topoisomerase-targeting anthracycline that is one of the most effective anticancer drugs currently known. However, its clinical use is restricted by cardiotoxicity and the development of drug resistance. The main goal of this thesis has been to increase the knowledge of doxorubicin mechanism in addition to evaluate if predictive biomarkers for doxorubicin response could be identified. A total of 128 tumor samples collected from breast cancer patients before and after neoadjuvant treatment with doxorubicin were studied. mRNA expression level in tumor tissue was assessed using whole-genome mRNA microarray analysis (Agilent Human GE 4x44K microarray).More than 5000 genes were found to be up- and down regulated following doxorubicin treatment. The molecular and cellular functions as well as canonical pathways found to be enriched in the list of genes up regulated after doxorubicin exposure were involved in among other cardiovascular system development and function, cellular movement and immune responses. p53 was found to be the transcription factor regulating the highest number of target molecules within the list of up regulated genes. RNA processing, splicing and translation were shown to be overrepresented in the list of down regulated genes. The association between doxorubicin response and changes in gene expression revealed several genes such as CTGF, ITGB4 and IGF1 to be up regulated in the samples collected from patients characterized with a partial response to doxorubicin compared to those with minimal change and/or stable disease following treatment. In addition, the gene expression profiles between samples having wild type compared to mutated TP53 were studied, and a lower induction of expression were found for several genes such as FGF9 and COL11A2 in the samples having a mutated p53. This study showed that the gene expression profile in breast cancer tumors is altered as a response to doxorubicin exposure. Identifying genes significantly altered after therapy and associate their change with response to treatment may help identify the subgroup of patients benefitting from doxorubicin treatment. Patients with little or no effect of treatment could receive alternative therapy and be spared unnecessary treatment and risk of side effects.

Breast cancer is the most common cancer type amongst women, and closer to 3000 women in Norway will be diagnosed with this disease in 2012. Although major improvements have been achieved in the treatment, and thus the outcome, of breast cancer patients in the past years, little has been accomplished for those with an advanced disease. B7-H3 is an immunoregulatory protein, and its overexpression has been associated with advanced disease and poor prognosis in breast cancer. A previous study has shown that B7-H3 silencing increased Paclitaxel sensitivity in B7-H3 expressing breast cancer cell lines. Resistance to treatment is a general challenge in systemic management of advanced breast cancer, and increased knowledge about the molecules and pathways involved in this process is important in order to improve the outcome for these patients.To further study the function of B7-H3 and its putative involvement in lack of treatment response in breast cancer, we compared the efficacy of 22 different anti-cancer drugs in two B7-H3 expressing triple negative metastatic breast cancer cell lines, MDA-MB-435 and MDA-MB-231, and their B7-H3 silenced counterparts. In particular two drugs targeting the PI3K/Akt pathway, API-2 and Everolimus, showed a significantly better efficacy in the B7-H3 silenced cells. To elucidate the cellular mechanisms involved in the observed sensitization in the B7-H3 knockdown cells, we performed Western blot analysis on several proteins in the PI3K/Akt/mTOR pathway. The cells that did not express B7-H3 had lower levels of both phospho-Akt and the downstream signaling molecule phospho-p70S6K following drug exposure, indicating B7-H3 associated the regulation of proteins in this pathway. This, together with the previously observed relationships between B7-H3 expression in metastasis and chemoresistance, suggest that this protein might be a therapeutic marker to increase the effect of current anti-cancer treatment, although the specific roles of B7-H3 in this context need to be investigated further.

Recombinant protein production in Escherichia coli provides a cheap and efficient way of producing medically and industrially relevant proteins. Sequence features of individual genes and especially their 5’ terminal coding sequences act on the efficiency of gene expression by complex regulatory mechanisms which are still not fully understood. This study aimed to investigate the features of the 5’ coding region of recombinant mRNAs, and to optimize them for increased expression in E. coli. A previous study had found that a synonymous change of the bla reporter gene 2nd codon leads to an increased expression, and accordingly a synonymous library in the 5’ bla coding sequence was created by a directed evolution approach building on this feature. Variants conferring up to three-fold increases in active enzyme amounts were identified, and the increased expression was shown to stem from increased transcriptional efficiency. The effect of changing the 2nd codon synonymously was further investigated by synonymous substitutions of the 2nd codons of the bla and two other reporter genes, phoA and celB. These experiments showed that the effect of 2nd codon changes on the gene expression is determined by the sequence context, as changes in expression levels appeared to be gene specific. All the coding sequences of the study were also analysed in silico, and an application for calculating the tRNA adaptation index was programmed in Python and made freely available online.As the synonymous codon changes did not lead to a great improvement in protein amounts and any sequence features affecting the expression were hard to pinpoint, an alternative strategy involving 5’ terminal gene fusions was investigated. Combinatorial mutagenesis coupled to an effective screening technique was applied to further optimize a 5’ terminal fusion partner, previously shown to improve expression of several eukaryotic genes. The application of the best identified fusion partner candidate yielded a 3.8-fold improvement in IFN-α2b protein amounts over the original fusion, and showed twice as high protein amounts than a pelB-IFN-α2b fusion previously proven to give industrial expression amounts. The developed peptide fusion is thus an eligible candidate for further development for use in heterologous protein production.

Oral delivery is considered a convenient route for administration of pharmaceuticals. Great effort has been made to optimize oral delivery vehicles to increase the bioavailability of the pharmaceutical, and enhance patient compliance to ease swallowing. Emulsion-based gelled matrices have shown promising features as delivery systems. They are soft chewable matrices that are easy to swallow, and have the ability to entrap the pharmaceutical, providing prolonged, and controlled release to avoid fast dissolution in the stomach. The purpose of this study was divided into two main objectives. The first aim was to study emulsion-based gelatin matrices intended for oral drug delivery by investigation of the influence of gelatin type and/or oil content on the matrix properties. The second aim was to investigate the properties of multiple emulsions, regarding their potential as oral drug delivery systems for water-soluble pharmaceuticals, and controlled drug delivery. Emulsion-based matrices stabilized by 160g Bloom gelatins, either type A or B, and containing various amounts of corn oil (0, 10, 30 and 50 wt %) were subjected to rheological characterization and in vitro dissolution studies at simulated gastric conditions. The results showed an increase in viscosity, storage modulus and gelling and melting temperatures in line with increased oil content in the matrix, and to a larger extend for matrices with type A gelatin compared to type B. Longitudinal deformations of the gelled matrices did show a trend of slightly increasing Young’s modulus when oil was added to the matrix, but no clear trend was observed for force and strain at break. A correlation between rheological matrix properties and dissolution time was observed: An increase in dissolution time with higher fractions of oil and prolonged dissolution time for matrices with type A gelatin compared to type B. Overall the results showed that different oil contents and gelatin types changed the physical properties of the matrices, providing a possibility to tailor matrices to obtain suitable delivery systems for various pharmaceuticals. Water-in-oil-in-water double emulsions, stabilized by either 226g Bloom gelatin type B or tween80 was examined by long time stability studies, and by in vitro lipolysis studies simulating small intestinal conditions. The water-soluble marker tartrazine, was entrapped in the inner water phase of the emulsions. The release of tartrazine was measured during a period of 78 days and both double emulsions with gelatin and tween80 were found to possess long-term stability at room temperature. In vitro lipolysis of gastric stable double emulsions stabilized by gelatin was conducted in a dissolution medium containing bile extracts, with or without lipases. A complete release of tartrazine was obtained; both in the presence and absence of lipases, while a faster release was observed when lipases were present. Although the release mechanism was not completely determined, the results indicate that release of drugs can occur in the small intestines due to lipolysis. The double emulsions thus offer great potential in delivery of gastric unstable pharmaceuticals.

The work presented in this thesis examines several aspects of Nonlinear ModelPredictive Control (NMPC) that display and confirm its promising potentials as apowerful reconfigurable control scheme. The effects of significant nonlinearities andthe intrinsically unstable nature of high performance fighter aircraft, among otherchallenges, have been shown to be well handled in the NMPC framework. Thiswork illustrates how complex control and stability augmentation measures (whichare normally realized through ad hoc mode switching strategies) can be formulatedand implemented as NMPC objectives and constraints. Further suggestions onrobustness strategies for model/plant mismatch and compensation for couplingeffects which are not properly accounted for, have been presented and examined inthis work. Results on fault tolerance of NMPC are also presented and discussed inthis thesis. In this direction, NMPC has been shown to have unique inherent faultdetection capabilities due to its effective utilization of feedback and its internalmodel predictions. Different types of actuator/control surface failures, includingextreme cases of total actuator failure are examined as test cases for the NMPCreconfigurable fault tolerant control scheme developed in this work. The NMPCautopilots are designed for an F-16 fighter aircraft, and the implementation andsimulations were done using ACADO nonlinear optimization solver, interfaced withthe MATLAB/Simulink environment.

In the last years the cost for rig rental has become very high. To reduce total cost it has been necessary to increase the cost efficiency when drilling to improve profit. One way to improve profit is to reduce the nonproductive time related to faults and failures which could occur during drilling. In addition many of the oil fields in the north sea are starting tail production where the pressure window are small which means that managed pressure drilling or under balanced drilling must be used. This thesis combines fault tolerant control and managed pressure drilling to see if it is feasible to continue drilling with fault in the system. The fault tolerant control system is based on model matching. Simulation is done of choke blocked in closed position such that back pressure pump is used to control the bottom hole pressure. Simulation is done with MATLAB. This to see if it is possible to use back pressure pump if the choke is blocked to such that drilling can proceed even if there is a choke failure which normally would result drilling stop. A simple hydraulic model is used in the simulation. The model does not apply actuator dynamics.The results where positive, back pressure can be used to control bottom hole pressure during managed pressure drilling. The results also showed that the transient between normal and fault system causes controller initiation problem which introduced bumps into the system.

Dette prosjektet har omhandlet videreutvikling av en modernisert rullator for SINTEF, som har vært arbeidsgiveren. Rullatoren startet som en bachelorprosjekt ved Høgskolen i Sør-Trøndelag (HiST), avdeling for automasjon våren 2011, og høsten 2011 ble det gjennomført et prosjekt hvor det ble utviklet et nytt brukergrensesnitt. I denne masteroppgaven har man videreutviklet rullatoren da den hadde funksjoner som ikke fungerte optimalt. Rullatorløsningen SINTEF overtok fra HiST bestod av en rullator med elektromotorer, en instrumentkasse med et batteri og en mikrokontroller samt noe elektronikk til sensorer og motorer og to sensorer i håndtakene som var input for systemet. Systemet fungerte slik at man trykket på to sensorer som var lagt under gummihåndtakene for å få rullatoren til å kjøre fremover i lineær hastighet med kraftinputen. Tanken var at brukeren skulle bruke kroppsvekten for å generere fremdrift når man støttet seg på rullatoren. Dette viste seg ikke å fungere optimalt da man måtte bruke ganske stor kraft med tomlene for å trykke ned disse sensorene. Dette ble endret i høstprosjektet til håndtak som måler kraften brukeren dytter rullatoren fremover med. På den måten fikk man en mer naturlig brukeropplevelse og rullatoren ble enklere å betjene. Mer om løsningen kan leses om i prosjektrapporten «Nye sensorer for en mer brukervennlig rullator» (Skarra, 2011)xvii.Rullatoren skal være et intelligent hjelpemiddel som bidrar med aktiv fremdrift når brukeren trenger det, uten at brukeren selv trenger å gjøre noe for at denne hjelpen kobler inn. For å få til dette ble det gjennom en Use case-analyse avdekket hvilke funksjoner og krav vi måtte sette til rullatorsystemet for å få dette til å fungere. Dette resulterte i forslag til endringer både i det mekaniske og i reguleringsalgoritmen. I den gamle løsningen satt hjulene på faste aksler på motorene. Da vi ville at systemet kun skulle hjelpe til når brukeren trang det måtte flere ting løses. Hjulene ble byttet ut med hjul med frinav slik at rullatoren nå kan rulle fritt uten at motorene trenger å være koblet inn. Det måtte også endres i algoritmen for å få rullatoren til å virke slik vi ville. Vi ville at den skulle hjelpe til i bakker, når den var tungt lastet og når den møtte hindringer som krevde stor kraft for å bevege den fremover. Vi var altså ikke interessert i at den skulle bidra unødig og belaste batteriet når det var lett å dytte den fremover. Algoritmen ble derfor endret slik at man måtte over en viss innkoblingsgrense før motorene hjalp til. Kommer kraften over denne grensen kobler motorene inn og hastigheten er lineær ettersom kraften øker. Det ble så sett på hvordan inngangssignalet ble behandlet i algoritmen da det viste seg at motorpådraget var noe ustabilt. Regulatoren var en ren P-regulator hvor inngangssignalet ble regnet ut som et gjennomsnitt av 5 målinger. Programmeringsfeil gjorde at deler av disse målingene ble lagret etter at rullatorsystemet ble slått av slik at rullatoren beveget seg litt når man skrudde den på igjen. Et nytt filter med glemmefaktor ble designet etter inspirasjon fra faget TTK4195 Systemidentifikasjon og adaptiv regulering, og programmert i mikrokontrolleren. Etter en del testing og justering førte dette frem til at regulatoren nå gir et stabilt og forutsigbart pådrag til motorene slik at den går med en jevn hastighet.  Håndtakene som ble laget i høstprosjektet, ble også modifisert, da de ikke hadde en stopperfunksjon som hindret dem i å bli demontert ved å dra holkene bakover. De er laget slik at holkene man holder i er montert på en ytre hylse som kan beveges frem og tilbake med fjærretur. Dette er gjort for å unngå en eventuell offset. Dette gjorde at man kunne ved et uhell dra holkene av rullatorrammen og ledningen til trykksensorene falt av. Holkene kunne også roteres så brukeropplevelsen virket litt lite robust når man håndterte rullatoren. En skrue ble skrudd gjennom den ytre hylsen og inn i et avlangt hull i den indre. Dette gjorde at man nå kan håndtere rullatoren som en vanlig rullator og trenger ikke være redd for at ledningene faller ut. Skruen kan enkelt skrus ut igjen med en standard stjernetrekker ved eventuelle endringer.Alle disse endringene har gjort rullatoren nærmere et produkt som eventuelt kan settes i serieproduksjon. Det gjenstår fortsatt oppgaver med tanke på å få på plass en mekanisk brems, vektreduksjon, plassering av komponenter og å heve IP-graden til motorløsningen.Rullatoren har nå den styringsstrategien vi ønsker, og resultatene som er presentert i denne rapporten underbygger dette. Arbeidet har vært utfordrende, og spesielt det å jobbe alene i en utviklingsperiode har vært krevende. Prosjektet har krevd at man har måttet ta avgjørelser under tidspress for å komme videre, og dette har vært både utfordrende og lærerikt. Dette er erfaringer som er nyttig å ha med seg inn i arbeidslivet.

Offshore crane operation is a complex task that demands the operator to control the position of the load, predict vessel motion and compensate for load sway, all at the same time. In this thesis an anti-sway, boom tip positioning and a wave following system is presented which purpose is to facilitate not automate the crane operation. Introducing such systems the operator has an extra set of tools to reduce risk of cargo damage and personnel injuries during operation. This is done by suppressing the sway angles and positioning the boom tip to a desired position with the anti-sway and boom tip positioning system, and be able to make the hook follow the heave motion of the vessel by using the wave following system.This thesis contains modeling, visualization, simulation and control of a rotary crane with spherical pendulum. Also models for a trolley with pendant load, vessel motion, and angular deflection of the wire and a wind model is presented. Lagrangian describes the dynamics of the crane models and the equation of motion is derived with Euler-Lagrange equations.The effect of measurement noise in the sensor signals has been reduced through the implementation of an adaptive Kalman-filter. Parameter estimation has been used to find unknown model parameters such as damping, frequency and bias in vessel heave motion model. Several suggestions of sensors to measure the swing angles of the hoist winch wire is presented. The 3D visualization is developed using the V-Realm 3D editor included in Simulink 3D Animation toolbox.Results of the closed loop system shows that it is possible to control the load swing angles and boom tip position and still let the crane operator have the superior control of the crane. In case of stability it can be seen that since all friction terms is neglected in the mathematical model there is no dissipation of energy in the pendulum dynamics, meaning that the anti-sway controller causes any observed damping in the sway dynamics.