Enhanced Cellular Uptake of Virus by Increased Expression Levels of the Coxsackie-and Adenovirus Receptor

Replication–selective oncolytic adenoviruses have shown great promise as novel anti-cancer agents. These mutant viruses act through different mechanisms than traditional anti-cancer therapies and consequently do not develop cross-resistance with these drugs. A limiting factor for success with cancer treatment using oncolytic adenoviruses is the delivery and entry of virus to the correct target cells. An important step in adenoviral adsorption to host cells is the interaction between cellular CAR and viral fibre domains. Reports have indicated a down-regulation of CAR- levels in various cancer cell lines and clinical specimens. Enhancing the expression of CAR could potentially increase the efficacy of treatment with oncolytic adenoviruses. In this project, prostate cancer cell lines have been evaluated for their sensitivity to adenoviral infection, with and without treatment with the MEK-inhibitors PD98059, U0126 and the histone deacetylase inhibitor Trichostatin A. Trichostatin A was found to be a potent enhancer of sensitivity to viral-induced cytopathic effect in prostate cancer cell lines. Furthermore, prostate cancer cell lines have been evaluated for their surface expression of CAR, uptake of adenovirus and adenoviral replication with and without treatment with Trichostatin A. Trichostatin A was found to enhance CAR- expression and adenoviral uptake in some prostate cancer cell lines but did not have any significant effects on adenoviral replication. In conclusion, Trichostatin A could be used to improve the effects of oncolytic adenoviruses in treatment of prostate cancer through enhanced expression of CAR.Onkolytiska virus är en ny behandlingsmetod för cancer, som utnyttjar helt andra verkningsmekanismer än gängse läkemedel och behandlingsformer. Adenovirus är små DNA-virus som infekterar epitelceller, replikerar, spränger sin värdcell och sprider sig i vävnaden. Onkolytiska adenovirus är modifierade på sådant sätt att de selektivt angriper tumörceller och lämnar friska celler oskadda. För att adherera till värdcellerna binder adenovirus med sitt ”fibre”-protein till CAR (Coxsackie-adenovirus receptor) och tar sig sedan in genom cellmembranet genom att utnyttja integriner på cellytan. Mycket litet är känt om CA-receptorns fysiologiska funktioner, den tros vara en celladhesionsmolekyl, men kan också vara inblandad i kommunikation celler emellan. Mängden CAR varierar mellan olika celltyper och är genomgående nedreglerad i flera typer av avancerade tumörer. Att kunna uppreglera CAR skulle potentiellt kunna förbättra cancerbehandling med onkolytiska adenovirus. I detta projekt har cellinjer från prostatatumörer screenats för känslighet mot adenovirusinfektion, med och utan behandling av MEK-hämmarna PD98059, U0126 och histone deacetylase-hämmaren Trichostatin A. Trichostatin A visades sig kunna förstärka känsligheten mot virus hos de använda cellinjerna. Därefter undersöktes samma cellinjer för att se om deras uttryck av CAR på cellytan, upptag av virus och virusreplikation förändrades efter behandling med Trichostatin A. Efter behandling ökade både uttrycket av CAR och upptaget av virus i de flesta cellinjer, däremot sågs inga förändringar av virusreplikationen. Sammantaget visade denna studie att Trichostatin A skulle kunna användas för att förbättra behandling av prostatacancer med onkolytiska adenovirus genom att öka uttrycket av CAR hos värdcellerna

Inflammatory bowel disease, colorectal neoplasia and treatment with ursodeoxycholic acid in primary sclerosing cholangitis

Background: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease closely associated with inflammatory bowel disease. PSC is progressive and ultimately leads to death or need for liver transplantation. Patients are also at high risk of developing colorectal neoplasia (CRN). Aims: The main aim of this thesis was to study IBD in patients with PSC. We aimed to describe the phenotype of Crohn’s disease (CD) in patients with PSC and to determine the risks of CRN and IBD activity before and after liver transplantation. The secondary aim was to study the drug ursodeoxycholic acid (UDCA) in patients with PSC and UDCAs effect on the development of CRN and survival in PSC. Results: In Paper I we investigated CD in 28 patients with PSC and compared them with a matched control group of 46 patients with CD without PSC. We found that smoking, perianal fistulas, bowel strictures and small bowel involvement were rare in PSC patients. We also found a significantly increased risk for development of CRN in PSC patients (P=0.001, log rank). Papers II and III are multicentre studies of IBD in PSC patients undergoing liver transplantation (OLT), and include all liver-transplanted Nordic PSC patients (n=439). The IBD activity was increased after transplantation and the choice of immunosuppression influenced the activity. A univariate analysis identified age <20 years at diagnosis of IBD, use of tacrolimus, and dual therapy with tacrolimus and mycophenolate mofetil as significant risk factors for worsening of IBD, whereas dual treatment with cyclosporine A and azathioprine showed a significant protective effect. The cumulative risk of any type of neoplasia in the group of patients still at risk after OLT (n=244, 36 cases of neoplasia) was higher than the corresponding number before OLT (353, 52 cases) (HR: 1.9: 95% CI 1.3-2.9, P = 0.002). In Papers IV and V the effect of UDCA at a dose of 17-23 mg/kg in patients with PSC was evaluated using an extended follow-up of a previous randomised controlled trial. In paper IV all patients with concomitant IBD at risk for CRN were included (n=98). There was no detectable difference in dysplasia- and cancer-free survival when the groups were compared using the Kaplan-Meier method (p = 0.73 log-rank test). Paper V evaluated the effect of UDCA on long-term survival without liver transplantation. No difference in endpoint-free survival was detected between UDCA treated and untreated patients. However we found that a reduction in alkaline phosphatase (ALP) by 40% or more was associated to significantly better long-term survival in patients with PSC (P = 0.0001, log rank). Conclusions: Our studies show that patients with IBD and PSC have a high risk of developing CRN regardless of IBD phenotype, and that the risk of CRN and IBD activity increases after OLT and appears correlated to the type of immunosuppression given. In patients undergoing OLT a shift from the present standard maintenance treatment with tacrolimus and mycophenolate mofetil to cyclosporine A and azathioprine should be considered. The evidence that UDCA improves survival in PSC or that it should be used as a chemopreventive agent in PSC-IBD is weak. ALP is a marker for disease progression in PSC and should be used in future clinical trials

BENCHOP - The BENCHmarking project in Option Pricing

The aim of the BENCHOP project is to provide the finance community with a common suite of benchmark problems for option pricing. We provide a detailed description of the six benchmark problems together with methods to compute reference solutions. We have implemented fifteen different numerical methods for these problems, and compare their relative performance. All implementations are available on line and can be used for future development and comparison

Bees increase seed set of wild plants while the proportion of arable land has a variable effect on pollination in European agricultural landscapes

Background and aims - Agricultural intensification and loss of farmland heterogeneity have contributed to population declines of wild bees and other pollinators, which may have caused subsequent declines in insect-pollinated wild plants. Material and methods - Using data from 37 studies on 22 pollinator-dependent wild plant species across Europe, we investigated whether flower visitation and seed set of insect-pollinated plants decline with an increasing proportion of arable land within 1 km. Key results - Seed set increased with increasing flower visitation by bees, most of which were wild bees, but not with increasing flower visitation by other insects. Increasing proportion of arable land had a strongly variable effect on seed set and flower visitation by bees across studies. Conclusion - Factors such as landscape configuration, local habitat quality, and temporally changing resource availability (e.g. due to mass-flowering crops or honey bee hives) could have modified the effect of arable land on pollination. While our results highlight that the persistence of wild bees is crucial to maintain plant diversity, we also show that pollen limitation due to declining bee populations in homogenized agricultural landscapes is not a universal driver causing parallel losses of bees and insect-pollinated plants.Peer reviewe

Increased risk of colorectal cancer in patients diagnosed with breast cancer in women

BackgroundEpidemiological studies have shown a potential association between sex hormones and colorectal cancer. The risk of colorectal cancer in breast cancer patients who may have been exposed to increased levels of endogenous sex hormones and/or exogenous sex hormones (e.g. anti-hormonal therapy) has not been thoroughly evaluated.MethodsUsing the National Swedish Cancer Register we established a population-based prospective cohort of breast cancer patients in women diagnosed in Sweden between 1961 and 2010. Subsequent colorectal cancers were identified from the same register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95%CIs) were used to estimate the risk of colorectal cancer after a diagnosis of breast cancer. The association between breast cancer therapy and risk of colorectal cancer was evaluated in a subcohort of breast cancer patients treated in Stockholm between 1977 and 2007. Hazard ratios (HRs) and 95%CIs were estimated using Cox regression models.ResultsIn a cohort of 179,733 breast cancer patients in Sweden, 2571 incident cases of colorectal cancer (1008 adenocarcinomas in the proximal colon, 590 in the distal colon and 808 in the rectum) were identified during an average follow-up of 9.68 years. An increased risk of colorectal adenocarcinoma was observed in the breast cancer cohort compared with that in the general population (SIR=1.59, 95%CI: 1.53, 1.65). Adenocarcinoma in the proximal colon showed a non-significantly higher SIR (1.72, 95%CI: 1.61, 1.82) compared with the distal colon (1.46, 95%CI: 1.34, 1.58). In the subcohort of 20,171 breast cancers with available treatment data, 299 cases with colorectal cancers were identified. No treatment-dependent risk of colorectal cancer was observed among the breast cancer patients.ConclusionAn increased risk of colorectal adenocarcinoma - especially in the proximal colon - was observed in the breast cancer cohort. Breast cancer treatment did not alter this risk

Non-bee insects are important contributors to global crop pollination

Wild and managed bees are well documented as effective pollinators of global crops of economic importance. However, the contributions by pollinators other than bees have been little explored despite their potential to contribute to crop production and stability in the face of environmental change. Non-bee pollinators include flies, beetles, moths, butterflies, wasps, ants, birds, and bats, among others. Here we focus on non-bee insects and synthesize 39 field studies from five continents that directly measured the crop pollination services provided by non-bees, honey bees, and other bees to compare the relative contributions of these taxa. Non-bees performed 25–50% of the total number of flower visits. Although non-bees were less effective pollinators than bees per flower visit, they made more visits; thus these two factors compensated for each other, resulting in pollination services rendered by non-bees that were similar to those provided by bees. In the subset of studies that measured fruit set, fruit set increased with non-bee insect visits independently of bee visitation rates, indicating that non-bee insects provide a unique benefit that is not provided by bees. We also show that non-bee insects are not as reliant as bees on the presence of remnant natural or seminatural habitat in the surrounding landscape. These results strongly suggest that non-bee insect pollinators play a significant role in global crop production and respond differently than bees to landscape structure, probably making their crop pollination services more robust to changes in land use. Non-bee insects provide a valuable service and provide potential insurance against bee population declines

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Design of top of the range ceramic cooktop with emphasis on usability and interface

This project’s aim is to develop a ceramic cooktop for the premier market suitable to be sold in Europe, America, Asia and Australia. The final concept is a ceramic cooktop that with as high profit margin as possible for Electrolux also appeals the most for high-end consumers from all over the world. Today ceramic cooktops from different producers have aesthetics very similar to each other and it is hard to differentiate one brand from another. Therefore by designing a cooktop that stands out from the rest, Electrolux’s aim to get in to the premier segment of the market and to profile itself there, would be possible to reach. A problem that soon was noticed was that the interface of cooktops often is very hard to understand and that the control panel technique can be experienced as unreliable. So, emphasis was, besides making an original design, also laid on making the cooktop as user friendly as possible. Facts and information about components were thoroughly read to get a good understanding of the product. Theory about how to make a proper benchmarking and also theories about symbols and gestalts were studied. Following and parallel to this, a systematic development work was conducted by further investigating the actual problem and customer needs. Kitchen standards all over the world were mapped to find out what dimensions the cooktop should have. The result of this was the benchmark form and the product specification. The benchmarking was then carried out by comparing cooktops made both by Electrolux and other producers. By following the benchmark form to grade each cooktop, conclusions about the design were made. User tests on the cooktops gave additional information about usability and interface issues. Dividing the design into sub areas in a screening matrix and brainstorming about these led to a wide range of ideas. The solutions to each area were then combined in different ways to create the best concepts. To choose one concept the necessity of desired criteria’s were weighed against each other and then the concepts were scored by how well they fulfilled those. All this led up to the final concept, the Clear Cooktop. The dimensions of Clear are suited to fit the selected markets as good as possible. It has a smooth and easy to clean top surface consisting of two different types of ceramic glass, black above the elements, and a frosted clear glass piece where the control panel is. The control panel and the interface are developed with capacitive touch control technique in mind. This is a more reliable technique than the techniques used in existing cooktops. The interface, the new control panel technique and the unique combination of two different ceramic glasses will for sure make the cooktop stand out on the market.Validerat; 20101217 (root

Data-driven decision support for product change management : Making explainable classifications of product change requests at Scania using machine learning methods

Decision making is a big part of our day-to-day lives, both personal and professional. A good decision support can provide a decision process with high quality, efficiency and consistency. In recent years, machine learning has shown outstanding capacity for making complex processes understandable and provide decision support. But what good is this decision support if it is not trusted? Our work tries to improve the usage of machine learning models by making their results more understandable and trustworthy. In this thesis, we investigate the decisions in the Product Development (PD) process at Scania. Two important steps in the PD process is to prioritize a Product Change Request (PCR) and decide if it should be realized or not. Our main objective is to build machine learning models that can be incorporated in this process and help with the decision making. In order to choose the most suitable model, different machine learning models are trained on historical data. The model with the best performance is chosen and can be used to make predictions on new PCRs. The model that performed best when deciding the priority of a given PCR was Extreme Gradient Boosting (XGB), which achieved a F1 score of 46.6% and an accuracy of 48.0%. However, we found that the data was not suitable for making classifications regarding the priorities. The model that performed the best when deciding if a PCR should be realized or not was the random forest, which achieved a F1 score of 67.4% and an accuracy of 79.4%. We found that better classifications could be made regarding if a PCR should be realized or not when additional data was added to the model, and we therefore recommend changes to the collection and storage of data. The random forest achieved a F1 score of 73.5% and an accuracy of 83.8% with the additional data from attachments. We also explain and visualize how the random forest makes its classification and how each feature from the PCRs affect the classification. This is important in order to improve the trust in the decision support provided by the model. Att ta beslut är en stor del av våra dagliga liv, både personligt och professionellt. Ett bra beslutsstöd kan skapa en beslutsprocess med hög kvalitet, effektivitet och stabilitet. Under de senaste åren har maskininlärning blivit ett viktigt verktyg för att förstå komplexa processer och skapa beslutsstöd. Men vilken nytta gör detta beslutsstöd om människor inte litar på det? Vårt arbete försöker att hantera detta problem och göra resultaten från maskininlärningsmodeller mer förståeliga och tillförlitliga. I den här rapporten undersöker vi besluten som tas i processen för produktutveckling hos Scania. Två viktiga steg i denna process är att prioritera föreslagna produktförändringar och att bestämma ifall dessa ska genomföras eller inte. Vårt huvudmål är att bygga maskininlärningsmodeller som kan användas i denna process och hjälpa till vid beslutstagandet. För att kunna välja den lämpligaste modellen så tränas olika maskininlärningsmodeller på historiska data. Modellen som presterar bäst väljs och kan användas för att förutsäga besluten för nya föreslagna produktförändringar. Den modell som lyckades bäst med att förutsäga vilken prioritet som en föreslagen produktförändring ska ha var Extreme Gradient Boosting (XGB) som uppnådde ett F1-score på 46,6% och en träffsäkerhet på 48,0%. Vi såg däremot att den data som fanns inte var lämplig för att göra klassificeringar gällande prioriteringen. Den modell som lyckades bäst med att bestämma ifall en föreslagen produktförändring borde genomföras eller inte var random forest, som uppnådde ett F1-score på 67,4% och en träffsäkerhet på 79,4%. Vi visar att bättre klassificeringar kan göras gällande om en föreslagen produktförändring ska genomföras eller inte när mer data läggs till i modellen, och vi kan därmed föreslå förändringar av insamlingen och lagringen av data. Random forest uppnådde ett F1-score på 73,5% och en träffsäkerhet på 83,8% med data insamlat från bilagor. Vi förklarar och visar även hur random forest gör sin klassificering och hur varje faktor från den föreslagna produktförändringen påverkar klassificeringen. Detta är viktigt för att kunna öka förtroendet för det beslutsstöd som modellen ger