Cancer therapy using viral- and bacterial proteins, as vectors for vaccines or as carriers of cytostatics

New cancer therapies are urgently needed, since available treatment options today have negative side effects, and cure only about half of the patients with invasive cancer. One, relatively new, option is to vaccinate against cancer, by introducing an antigen that is present on the tumor cells into the patient to stimulate specific immunity against the tumor. For this purpose viral capsid proteins, which can self-assemble into so called virus-like particles (VLPs), can be engineered to contain tumor antigens in the form of DNA, whole protein or peptides and be used as vaccines. Here, VLPs based on murine polyomavirus (MPyV) and murine pneumotropic virus (MPtV) containing the extracellular and transmembrane part of the breast cancer antigen Her2/neu, or the whole prostate cancer antigen PSA, have been produced. As mentioned above there are side effects with cancer treatment, and the use of the common cytostatic anti-cancer drug Cisplatin has a number of side effects, including; nephrotoxicity (kidney damage); neurotoxicity (nerve damage); and ototoxicity (hearing loss). To possibly inhibit some of this toxicity we attempted to make use of the “enhanced permeability and retention” (EPR) effect that causes macromolecules to accumulate more in tumor tissue than in normal tissue, since tumor blood vessels are leaky, and tumors lack effective lymphatic drainage. The use of a macromolecule as a carrier for Cisplatin would therefore hold the potential to reduce some of its negative side effects. For this purpose it was investigated whether the macromolecule right-handed coiled coil “RHCC” protein from bacterium Staphylothermus marinus, that can incorporate heavy metals, would also incorporate cisplatin containing the metal platinum. The overall aim of the first three papers in this thesis was to develop and determine preclinical efficacy of MPyV- and MPtV-VLPs carrying Her2/neu or PSA against tumors expressing these tumor antigens. The overall aim of paper IV was to investigate RHCC’s potential to carry cisplatin efficiently to tumors, while retaining the cytotoxic effect of the drug. In paper I we demonstrated that homologous vaccination with human Her2/neu-VLPs was more efficient against outgrowth of human Her2/neu-expressing tumors than heterologous vaccination with rat Her2/neu-VLPs, while against rat Her2/neu-tumors, rat Her2/neu-VLPs were more efficient. Furthermore, we observed that vaccination with MPtVLPs was more efficient than vaccination with MPyVLPs, and that Her2MPtVLPs could be used for therapeutic vaccination. In paper II we demonstrated that both CD4+ and CD8+T cells are involved in the tumor protective response after Her2MPtVLP vaccination. In paper III immunization with PSA-MPyVLPs, given together with CpG and loaded onto dendritic cells, was shown to protect against outgrowth of PSA-expressing tumor cells. In paper IV RHCC was shown to incorporate cisplatin, and the complex entered human tumor cells, while retaining the cytotoxic potential of the drug both in vitro and in vivo. In conclusion, in this thesis it is shown that VLPs based on MPyV and MPtV were efficient vectors for tumor antigens in cancer vaccination, evoking both CD4+ and CD8+ cell responses. In addition, we show that RHCC can function as a carrier for cisplatin, and that it could potentially reduce some of the negative side effects with cisplatin treatmen

Skräck, kärlek och heuristiker; Ett evolutionärt samband mellan stimuli och heuristiker vid värdering av utilitaristiska köperbjudanden

Uppsatsens syfte är att ge djupare insikt och bredda teorin om sambandet mellan stimuli och heuristiker genom att undersöka hur skräck och romantik kan influera social proof och scarcity vid värdering av utilitaristiska köperbjudanden. Studien baseras på en kvantitativ experimentundersökning där vi studerar hur stimuli påverkar effekten av heuristiker vid val av utilitaristiska köperbjudanden. Genom hypotesprövning avser vi ge svar på problemformuleringen för att uppfylla studiens syfte. Uppsatsens teoretiska referensram utgörs av teorier kring beteendeekonomi, heuristiker och dess evolutionära koppling till känslostimuli samt teori om hedonistiska och utilitaristiska produkter/tjänster. Teorierna ligger sedan till grund för de hypoteser uppsatsen ämnar testa. Empirisk data baseras på två experiment; ett laboratorieexperiment med 121 deltagare där två olika filmklipp används för att framkalla känslorna skräck och romantik samt en online enkätundersökning med 119 deltagare där respondenterna utsattes för känslostimuli genom att läsa två olika texter. Respondenterna bestod av studenter i Lund. Skräckstimuli leder till att effekten av social proof ökar och vid romantisk stimuli ökar effekten av scarcity. Således finns det ett evolutionärt samband mellan stimuli och heuristiker vid värdering av en utilitaristisk produkt när stimulin är framkallad via text. Vår undersökning gav inga signifikanta resultat vid när stimuli framkallades via filmklipp

Murine Polyomavirus Virus-Like Particles Carrying Full-Length Human PSA Protect BALB/c Mice from Outgrowth of a PSA Expressing Tumor

Virus-like particles (VLPs) consist of capsid proteins from viruses and have been shown to be usable as carriers of protein and peptide antigens for immune therapy. In this study, we have produced and assayed murine polyomavirus (MPyV) VLPs carrying the entire human Prostate Specific Antigen (PSA) (PSA-MPyVLPs) for their potential use for immune therapy in a mouse model system. BALB/c mice immunized with PSA-MPyVLPs were only marginally protected against outgrowth of a PSA-expressing tumor. To improve protection, PSA-MPyVLPs were co-injected with adjuvant CpG, either alone or loaded onto murine dendritic cells (DCs). Immunization with PSA-MPyVLPs loaded onto DCs in the presence of CpG was shown to efficiently protect mice from tumor outgrowth. In addition, cellular and humoral immune responses after immunization were examined. PSA-specific CD4+ and CD8+ cells were demonstrated, but no PSA-specific IgG antibodies. Vaccination with DCs loaded with PSA-MPyVLPs induced an eight-fold lower titre of anti-VLP antibodies than vaccination with PSA-MPyVLPs alone. In conclusion, immunization of BALB/c mice with PSA-MPyVLPs, loaded onto DCs and co-injected with CpG, induces an efficient PSA-specific tumor protective immune response, including both CD4+ and CD8+ cells with a low induction of anti-VLP antibodies

CD4+ and CD8+ T Cells Can Act Separately in Tumour Rejection after Immunization with Murine Pneumotropic Virus Chimeric Her2/neu Virus-Like Particles

BACKGROUND: Immunization with murine pneumotropic virus virus-like particles carrying Her2/neu (Her2MPtVLPs) prevents tumour outgrowth in mice when given prophylactically, and therapeutically if combined with the adjuvant CpG. We investigated which components of the immune system are involved in tumour rejection, and whether long-term immunological memory can be obtained. METHODOLOGY AND RESULTS: During the effector phase in BALB/c mice, only depletion of CD4+ and CD8+ in combination, with or without NK cells, completely abrogated tumour protection. Depletion of single CD4+, CD8+ or NK cell populations only had minor effects. During the immunization/induction phase, combined depletion of CD4+ and CD8+ cells abolished protection, while depletion of each individual subset had no or negligible effect. When tumour rejection was studied in knock-out mice with a C57Bl/6 background, protection was lost in CD4-/-CD8-/- and CD4-/-, but not in CD8-/- mice. In contrast, when normal C57Bl/6 mice were depleted of different cell types, protection was lost irrespective of whether only CD4+, only CD8+, or CD4+ and CD8+ cells in combination were eradicated. No anti-Her2/neu antibodies were detected but a Her2/neu-specific IFNgamma response was seen. Studies of long-term memory showed that BALB/c mice could be protected against tumour development when immunized together with CpG as long as ten weeks before challenge. CONCLUSION: Her2MPtVLP immunization is efficient in stimulating several compartments of the immune system, and induces an efficient immune response including long-term memory. In addition, when depleting mice of isolated cellular compartments, tumour protection is not as efficiently abolished as when depleting several immune compartments together

The Role of the Forest in Climate Policy

Abstract In Paper [I], I develop the FOR-DICE model to analyze optimal global forest carbon management. The FOR-DICE is a simple framework for assessing the role of the boreal, tropical, and temperate forests as both a source of renewable energy and a resource to sequester and store carbon. I find that forests play an important role in reducing global emissions, especially under ambitious climate targets. At the global level, efforts should focus on increasing the stock of forest biomass rather than increasing the use of the forest for bioenergy production. The results also highlight the important role of reducing tropical deforestation to reduce climate change. In Paper [II], I develop the FRICE to investigate the role of two key efforts to increase the stock of forest biomass, namely, afforestation and avoided deforestation. FRICE is a multi-regional integrated assessment model that captures the dynamics of forest carbon sequestration in a transparent way and allows me to investigate the allocation of these actions across space and time. I find that global climate policy can benefit considerably from afforestation and avoided deforestation in tropical regions, and in particular in Africa. Avoided deforestation is particularly effective in the short run while afforestation provides the largest emissions reductions in the medium run. This paper also highlights the importance of not solely relying on avoided deforestation as its capacity to reduce emissions is more limited than afforestation, especially under more stringent temperature targets. In Paper [III], we investigate how uncertainties linked to the forest affect the optimal climate policy. We incorporate parameter uncertainty on the intrinsic growth rate and climate effects on the forest by using the state-contingent approach. Our results show that forest uncertainty matters. We find that the importance of including forest in climate policy increases when the forest is subject to uncertainty. This occurs because optimal forest response allows us to reduce the costs associated with uncertainty. In Paper [IV], we explore the implications of asymmetries in climate policy arising from not recognizing forest carbon emissions and sequestration in the decision-making process. We show that not fully including carbon values associated with the forest will have large effects on different forest controls and lead to an increase in emissions, higher carbon prices, and lower welfare.  We further find, by investigating the relative importance of forest emissions compared to sequestration, that recognizing forest emissions from bioenergy and deforestation is especially important for climate policy

Value in Consulting assisted projects : A consultant perspective on value co-creation capabilities and activities

Consultant and client collaborations seek to create value for both parties. This thesis builds on service-dominant logic and examines how value is perceived and co-created by consultants in their client projects. The findings of this qualitative interview study advance a model of value co-creation in consultant assisted projects, which outlines what operant resources embrace the activities in the value co-creation process. The thesis supports the notion of value co-creation as a function of interaction in consulting projects and further contributes to the understanding of value from a professional service suppliers' perspective. The results contribute to the value creation literature and provide insights for consultants, clients and practitioners within the consulting domain.Konsult och kundsamarbeten strävar för att skapa mervärde för båda organisationerna. Denna uppsats bygger på tjänstedominanta logiken och utforskar hur mervärde är uppfattat och skapat av konsulter i deras kundprojekt. Forskningen tar fram en modell som bygger på empirisk kvalitativ intervjudata. Uppsatsen stöder föreställningen av samskapat mervärde som en funktion av interaktion i kontexten av konsultprojekt och ger en insikt i hur konsulter uppfattar mervärde. Resultaten bidrar till mervärde litteraturen och ger insikter för konsultkunder och praktiker inom konsultdomänen

Value in Consulting assisted projects : A consultant perspective on value co-creation capabilities and activities

Consultant and client collaborations seek to create value for both parties. This thesis builds on service-dominant logic and examines how value is perceived and co-created by consultants in their client projects. The findings of this qualitative interview study advance a model of value co-creation in consultant assisted projects, which outlines what operant resources embrace the activities in the value co-creation process. The thesis supports the notion of value co-creation as a function of interaction in consulting projects and further contributes to the understanding of value from a professional service suppliers' perspective. The results contribute to the value creation literature and provide insights for consultants, clients and practitioners within the consulting domain.Konsult och kundsamarbeten strävar för att skapa mervärde för båda organisationerna. Denna uppsats bygger på tjänstedominanta logiken och utforskar hur mervärde är uppfattat och skapat av konsulter i deras kundprojekt. Forskningen tar fram en modell som bygger på empirisk kvalitativ intervjudata. Uppsatsen stöder föreställningen av samskapat mervärde som en funktion av interaktion i kontexten av konsultprojekt och ger en insikt i hur konsulter uppfattar mervärde. Resultaten bidrar till mervärde litteraturen och ger insikter för konsultkunder och praktiker inom konsultdomänen

Så minns vi vågen : En studie av hur journalister i form av en återspeglande rapportering gestaltat Tsunamikatastrofen 2004.

Syftet med vår studie var att undersöka hur journalister väljer att efter tio år återspegla den tsunami som inträffade i Sydostasien 2004. Vi har tittat på hur journalister berättar om katastrofen, vad de rapporterar om och vilka aktörer som yttrar sig i rapporteringen. Vi har även tittat på hur den återspeglande rapporteringen skiljer sig från den som florerade under Tsunamikatastrofen. 2004 verkade journalister under en pågående katastrof, vilket gör att katastrofen inte blir lika känslomässigt påtaglig 2014. Metoden vi använt är en kvantitativ innehållsanalys, där vi tittat på det manifesta innehållet i 233 tidningsartiklar från 42 svenska tidningar. Resultatet analyserade vi med hjälp av tidigare forskning och teorier kring bland annat journalistens arbetsrutiner under både vardagliga och extraordinära förhållanden. Våra resultat visar att rapporteringen 2014 främst handlar om bearbetning, sorg och livet efter tsunamin och att majoriteten av de aktörer som yttrar sig i artiklarna är drabbade/anhöriga och från Sverige. De bilder som florerar föreställer i de allra flesta fall människor. Resultatet visar även att journalister använder en berättarteknik där han eller hon skildrar personliga berättelser. Många gånger skildrar journalisten sina egna upplevelser av katastrofen. När vi tittade på rapporteringen 2004, såg vi att samma aktörer florerade. Dock skiljde sig rapporteringen angående berättarteknik och ämnesval. Av resultatet kan vi konstatera att journalister gestaltat den återspeglande rapporteringen i form av att vara subjektiv och emotionell, då personliga berättelser angående bearbetning och saknad dominerat

Vaccinmotstånd i Europa : Faktorer som kännetecknar tveksamhet eller motstånd till vaccinering mot COVID-19

BakgrundUnder den rådande COVID-19-pandemin som startade år 2020 har vaccinationsfrågan blivit mer aktuell. För att bekämpa COVID-19 behöver en flockimmunitet uppnås, samtidigt som vaccinationsmotstånd är ett komplext problem. Faktorer som ligger bakom beslutet om att tveka inför, eller helt avvisa, vaccinering kan vara många och dessa är viktiga för sjukvårdspersonal att uppmärksamma. Detta för att få en starkare förståelse i vårdmötet med patienter som upplever motvillighet att vaccinera sig. Om sjuksköterskan blir mer insatt skapas förutsättningar för ett tryggt möte med korrekt informationsutbyte till de osäkra patienterna, vilket i sin tur kan leda till en ökad vaccinacceptans. Syfte Att belysa faktorer som kännetecknar tveksamhet eller motstånd till vaccinering mot COVID-19.Metod En allmän litteraturstudie av elva originalartiklar med kvantitativ metod. Sökningar efter artiklar har gjorts i databaserna PubMed och Cinahl. Kvalitetsgranskning har gjorts med hjälp av en bedömningsmall för kvantitativa artiklar och i resultatanalysen identifierades faktorer som sedan delades in i kategorier. Resultat Faktorerna som framkom i studierna kunde delas in i fem olika kategorier. Faktorer som framkom gällande vaccinmotstånd var kvinnligt kön, yngre ålderskategorier, högersympatiserande, lägre inkomst, lägre utbildningsnivå och oro kring vaccinsäkerhet. Slutsats Resultatet belyser faktorer som både kan och inte kan påverkas. En etnisk bakgrund går inte att påverka, men oron som kan finnas hos en del patienter kan påverkas av sjuksköterskan genom information och utbildning. Sjuksköterskan har också en viktig roll i att bemöta den kunskap som patienten redan besitter och utgå ifrån den