Neuroblastom är en barncancer som uppstår ur det sympatiska nervsystemet och drabbar omkring 15 barn i Sverige varje år. Högriskvarianten är associerad med mycket hög dödlighet och risk för återfall, vilket tros ha att göra med att tumörernas ovanligt heterogena sammansättning tillåter resistenta subpopulationer att motstå konventionella behandlingsmetoder. Tidigare forskning har identifierat rubbade mekanismer för celldelning som ett tillvägagångssätt för tumörcellerna att överleva DNA-skador som kemoterapeutiska droger orsakar. I detta masterprojekt analyserades fem ultra-högrisk neuroblastomcellinjer i syfte att belysa deras progression genom celldelningen efter behandling med doxorubicin och/eller gemcitabin. Vidare identifierades ataxia telangesia mutated (ATM) serine/threonine kinase som ett essentiellt protein vid inhibering av celldelningen och i samband med reparation av DNA-skador, vilket bekräftades av förhöjt uttryck av fosforylerat ATM i alla fem cellinjer efter behandling med doxorubicin, gemcitabin, och/eller en kombination av båda. Återväxt av tumörcellerna efter inhibering av fosforylerat ATM i kombination med doxorubicin och gemcitabin analyserades sedan, och fördröjd återväxt noterades i en av cellinjerna efter kombinationsbehandling. Sammantaget har nya mekanismer för behandlingsresistens hos tumörceller identifierats och alternativa kombinationsbehandlingar har visat effekt på en av fem testade neuroblastomcellinjer. / Neuroblastoma is a pediatric cancer of the sympathetic nervous system that afflicts around 15 children annually in Sweden. Despite aggressive treatment, high-risk neuroblastoma is associated with a mortality of 50% and relapse rate of up to 60%, emphasizing the need for novel treatment options. In this study, fluoresce activated cell sorting was used to analyze cell cycle progression in five ultra-high-risk neuroblastoma cell lines: BE(2)-C, Kelly, SK-N-AS, SK-N-DZ, and SK-N-FI, post-treatment with doxorubicin and gemcitabine. In line with previous research, doxorubicin primarily induced cell cycle arrest in G2/M-phase and gemcitabine in the S-phase. Combined, the compounds induced varied effects, with accumulation primarily in the G1-and S-phase. Immunoblotting revealed elevated levels of phosphorylated ATM (pATM), a key regulator of cell cycle arrest and DNA damage signaling, across all five cell lines post-treatment to doxorubicin, gemcitabine, and/or the combination, indicating its vital role in their survival. Kelly stood out in both cell cycle progression and ATM phosphorylation, exhibiting minimal to no changes in cell cycle accumulation or pATM expression when exposed to the combined treatment, despite reacting to both monotherapies. These results may indicate that Kelly might implement an alternative mechanism of regulation compared to the remaining cell lines. To explore targeted inhibition of pATM, we employed the ATM kinase inhibitor KU-55933, which in BE(2)-C cells reduced expression levels of pATM when combined with doxorubicin, but not gemcitabine or the combination. Regrowth assays showed increased efficacy of doxorubicin and gemcitabine upon addition of the ATM kinase inhibitor KU-55933 in one of the tested cell lines in comparison to doxorubicin alone. However, longer incubation time is needed before the effect can be fully evaluated. These findings shed light on the differential cell cycle behavior in high-risk neuroblastoma cell lines exposed to combination therapy and suggest a vital role of ATM in the DNA damage response following doxorubicin and gemcitabine treatment. Further investigations are warranted to explore alternative strategies for enhancing the effectiveness of doxorubicin and gemcitabine in the treatment of this aggressive cancer subtype.

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Indiana University-Purdue University Indianapolis (IUPUI) / Apolipoprotein M (apoM) is necessary for the formation of lipid-poor preβ-HDL particles, the initial precursor of HDL and acceptors of cholesterol efflux from peripheral cells. An assay to quantify apoM in serum is not widely-available, hampering the efforts to further understand apoM and to develop therapeutic methods to increase circulating levels of apoM. An antibody-free, high throughput mass spectrometry (MS)-based assay was developed to quantitatively measure apoM from a variety of species including human, mouse, and rat. Apolipoproteins were enriched by selectively binding to Liposorb, an affinity resin, followed by enzymatic digestion. This peptide mixture was separated by HPLC coupled in-line with tandem MS/ MS. Signal intensities from the MS/ MS fragmentation of apoM-specific peptides were measured simultaneously in a targeted method spanning many commonly used species. The same amount of purified human apolipoprotein A-IV uniformly labeled with 15N was spiked into all samples and was used as an internal standard to correct for any variation in sample handling and recovery. Assay variability and accuracy was statistically validated in a three-day spike recovery experiment to determine the working range of the assay. The concentration range for quantification of apoM using this assay was 11.2-500 nM, whereas average concentration of human apoM measured from a large sampling (n>100) was 370 nM. This assay was used to measure changes in apoM in mouse serum from a pre-clinical study that was designed to evaluate the effects of a microsomal triglyceride transfer protein (MTTP) inhibitor. All measured lipoproteins and apolipoproteins showed a dose-dependent decrease in concentration and the response of apoM closely followed the response of HDL. In a clinical application of the assay, apoM was measured in human serum to evaluate the effects of two cholesterol-lowering compounds, a statin drug and an experimental PPAR-α agonist. ApoM levels did not change with PPAR-α agonist or combination treatments, but significantly decreased with atorvastatin. The measurement of apoM provided additional information on the effects of these drug treatments that previously could not be measured. The availability of a quantitative assay for apoM provides a valuable tool in the development of cardio-protective therapeutics and understanding the mechanisms of these drugs. / Monarch LifeSciences, Eli Lilly and Company

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Júlia Jurčáková Supervisor: RNDr. Jakub Hofman PhD. Title of diploma thesis: The assessment of inhibitory effects of selected targeted anticancer drugs on the activity of ABC drug eflux trasporters. Lung cancer is the leading cause of death within oncological diseases. Non-small cell lung carcinoma (NSCLC) accounts for about 85% of all lung cancer, and its major subtypes include adenocarcinoma and squamous cell carcinoma. In addition to surgery, radiotherapy and chemotherapy, the use of targeted low-molecular substances, which target tumor cells with higher specificity, has recently been used in treatment. The two main causes of death in cancer patients are the formation of metastases and the development of multidrug resistance (MDR). This may also be caused by overexpression of the efflux transporters. ATP-binding cassette (ABC) transporters are groups of transmembrane pumps that use energy in the form of ATP to transfer a wide range of substrates. In particular, P-glycoprotein (ABCB1), breast cancer-resistance protein (ABCG2) and multidrug resistance-associated protein 1 (ABCC1) are associated with MDR. Inhibition of these transporters increases the amount of cytostatic substrate within the...

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Title: Is sharing really caring? Subject: Bachelor thesis in International Marketing, 15hp Authors: Mattias Andersson & Eric Gummesson Keywords: consumer behavior, targeted ads, advertising, privacy, consumer intrusiveness Problem statement: This study looks to provide clarity about consumers' perception of the intrusiveness of a targeted advertisement and their overall behavior in regard to targeted ads. The authors of this look to find out what different factors play a role in a consumer’s mind when they see a perfectly tailored ad made just for them. Have targeting ads possibly become too specific and intrude on consumer privacy? Could this cause a negative reaction because of the huge amount of data consumers are sharing on the web? In what way does the consumer react or behave? Purpose: This study investigates a consumer perspective of targeted advertisement and will provide relevancy of consumers’ behavior regarding targeted ads Method: A qualitative approach has been used in order to gain insight of consumers’ behaviors regarding targeted advertisement. This has been achieved via semi-structured interviews which showed great value and provided detailed information on the matter. Conclusion: The results have led to an increased understanding of what marketers should take into consideration when targeting consumers with tailored advertisements. A big factor as to whether people are more accepting towards the practice of targeting ads was based on the level of awareness and control over their personal data sharing. The study leans towards seeing customized advertising as a more viable option than personalized advertising based on the intrusiveness and the management of consumers personal data. / Titel: Is sharing really caring? Ämne: Kandidatuppsats i Internationell Marknadsföring, 15hp Författare: Mattias Andersson & Eric Gummesson Nyckelord: konsumentbeteende, riktade annonser, marknadsföring, integritet, privatintrång Problemformulering: Denna studie syftar till att ge klarhet i konsumenters uppfattning kring privatintrång och deras övergripande beteende när det gäller riktade annonser. Författarna letar efter vilka olika faktorer som spelar roll hos en konsument när de ser en perfekt skräddarsydd annons som är tillverkade enbart till dem. Har riktade annonser möjligtvis blivit för specifika och inkräktar på konsumentens integritet? Skulle detta kunna leda till en negativ reaktion på grund av den enorma mängd data som konsumenter delar med sig av på webben? På vilket sätt reagerar eller beter sig konsumenten? Syfte: Syftet med studien är att undersöka konsumentperspektivet och ge relevans för konsumentbeteendet gällande riktade annonser. Metod: En kvalitativ studie valdes för att få insikt om konsumenterna beteende kring riktade annonser. Studien genomfördes med hjälp av semistrukturerade intervjuer som gav detaljerad information om ämnet. Slutsats: Resultaten har lett till en djupare kunskap om vad konsumenter känner och om användarnas beteende när de ställs inför skräddarsydda annonser. Dessutom har studien bidragit till en ökad förståelse för vad marknadsförare bör ta hänsyn till när de riktar sig till konsumenter med skräddarsydda annonser. En viktig faktor för konsumenternas uppfattning om riktade annonser berodde på deras medvetenhet och kontroll över personliga datadelning. Studien lutar åt anpassad annonsering som ett mer tillämpligt alternativ än personlig annonsering baserat på privatintrång och hanteringen av konsumenternas personliga data.

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As a consequence of the exposure of scandals involving targeted advertising and data collection, privacy concerns have arisen among users of social media, in particular Facebook. Previous research studies demonstrate that consumers have little knowledge about online behavioural advertising and hold misconceptions about it. According to a recent study by Internetstiftelsen (2021), 85% of Swedish internet users are concerned about big companies collecting data about them, and most people are unaware of the extent to which their online behaviour and activities are monitored. This study aims to examine how Swedish users on Facebook experience the platform's advertisements that are tailored to them. Moreover, this study also explores users’ privacy concerns in relation to advertising on the platform. To implement this study, qualitative interviews have been carried out with eight respondents in the age group 30-50 years of age. The interviews were transcribed and analysed using thematic analysis to answer the study’s research questions. The theoretical frameworks that have been implemented in this study are the “Big brother effect”, the panopticon effect and the digital panopticon. These concepts about surveillance have been complemented by previous research on algorithmic decision-making technologies, privacy concerns, perceptions about targeted advertising and personalisation. Based on the conducted interviews in this study, the results show that Swedish people between the ages of 30-50 years feel that they are being monitored on the platform and this, in turn, raised concerns about a violation of privacy among some of the users, in particular when they feel that Facebook monitors private conversations or intercept them. Participants in this study are more concerned about how much and what data Facebook collects rather than data being utilised for commercial purposes. The result further showed that most of the respondents do not read Facebook's terms and policies even though they claim that they do not trust Facebook with their personal information. Users in this study experience that there is too much advertising on Facebook, while also finding it more pleasant and preferable to get ads that are based on their interests and behaviour rather than receiving randomised ads. / Som en följd av att skandaler med riktad reklam och datainsamling avslöjats har det uppstått oro kring integriteten bland användare på sociala medier, särskilt på Facebook. Tidigare forskningsstudier visar att konsumenterna har lite kunskap om beteendestyrd reklam på nätet och har felaktiga uppfattningar om den. Enligt en nyligen genomförd undersökning från Internetstiftelsen (2021), är 85% av svenska internetanvändare oroliga över att stora företag samlar in uppgifter om de och de flesta är omedvetna om i vilken utsträckning deras beteende och aktiviteter på nätet övervakas. Den här studien syftar till att undersöka hur svenska användare på Facebook upplever plattformens annonser som är skräddarsydda för dem. Vidare undersöker denna studie även användarnas oro för integritet i relation till reklam på plattformen. För att genomföra denna studie har kvalitativa intervjuer genomförts med åtta respondenter i åldersgruppen 30-50 år. Intervjuerna transkriberades och analyserades med hjälp av tematisk analys för att besvara studiens forskningsfrågor. De teoretiska ramverk som har implementerats i denna studie är "Big brother-effekten", panoptikon-effekten och det digitala panoptikonet. Dessa begrepp om övervakning har kompletterats med tidigare forskning om algoritmiskt beslutsfattande teknologier, oro för integritet, uppfattningar om riktad reklam och personlig marknadsföring. Baserat på de genomförda intervjuerna i den här studien visar resultaten att svenskar i åldrarna 30-50 år känner att de övervakas på plattformen och detta i sin tur väckte oro för kränkning av integriteten hos vissa av användarna, särskilt när de känner att Facebook övervakar privata samtal eller avlyssnar dem. Respondenterna i denna studie är mer oroade över hur mycket och vilka uppgifter Facebook samlar in snarare än att uppgifterna används i kommersiella syften. Vidare visade resultatet att de flesta av de tillfrågade inte läser Facebooks villkor och policyer trots att de hävdar att de inte litar på Facebook när det gäller deras personliga information. Användarna i denna studie upplever att det ibland blir för mycket reklam på Facebook, samtidigt som de tycker att det är bättre att få annonser som är baserade på deras intresse och beteende snarare än att få slumpmässiga annonser.

Livsstilsrelaterade sjukdomar ökar idag i världen samt i Sverige och genom hälsofrämjande arbete kan riskfaktorer och ohälsosamma levnadsvanor identifieras. Det har föranlett införandet av riktade hälsosamtal till specifika åldersgrupper i flera regioner i Sverige och nu i Region Halland. Det är inte kartlagt hur hälsosamtalsledare upplever att leda riktade hälsosamtal utefter den regionövergripande rutinen i Halland. Syftet med studien var att undersöka samtalsledarnas upplevelser och erfarenheter av att leda riktade hälsosamtal med 40-åringar under pilotinförandet i Region Halland 2023. Metoden som användes var kvalitativ intervjustudie med induktiv ansats. Resultatet ledde till fyra huvudkategorier: Riktade hälsosamtal upplevs meningsfulla, Arbetsredskap som stöd i hälsosamtalet, Betydelsen av samverkan i team samt Påverkansfaktorer i arbetet med riktade hälsosamtal. Slutsats: Hälsosamtalsledarna upplevde riktade hälsosamtal som ett meningsfullt arbete. Den regionsövergripande rutinen med metodstöd upplevdes strukturerad och lätt att arbeta efter, det digitala verktyget webbstöd behöver förbättras för att underlätta arbetet samt öka patientsäkerheten. Kontinuerlig handledning och återkoppling i motiverande samtal (MI) skulle kunna bidra till ökad trygghet i metoden. Tydligt ledarskap, stöd från kollegor och tillräckligt med tid var viktiga påverkansfaktorer vid implementeringen av riktade hälsosamtal. Framtida studier bör fokusera på att utforska deltagarnas upplevelser av hälsosamtalen samt utvärdera om implementeringen lyckats. / Lifestyle-related diseases are increasing in the world and in Sweden. Through health promotion work, risk factors and unhealthy lifestyle habits can be identified. This has led to the introduction of targeted health dialogues to specific age groups in several regions in Sweden and now in Region Halland. It has not yet been mapped how healthcare worker's experience leading targeted health dialogues according to the region-wide routine in Halland. The purpose of the study was to investigate the healthcare worker's experiences of leading targeted health dialogues with 40-year-olds during the pilot phase in Region Halland in 2023. The method used was a qualitative interview study with an inductive approach. The results led to four main categories: Targeted health dialogues are experienced as meaningful, Supporting tools in the health dialogues, The importance of cooperation in teams and Influence factors in the work with targeted health dialogues. Conclusion: The healthcare worker's experiencedtargeted health dialogues as meaningful. The region-wide routine with the method was perceived as structured and easy to use, the digital tool “Webbstöd” needs to be improved to facilitate the work and increase patient safety. Continuous supervision and feedback in the Motivational interviewing (MI) method could contribute to increased security in the method. Clear leadership, supportive colleagues and sufficient time wereimportant influencing factors in the implementation of targeted health dialogues. Future studies should focus on exploring the participant's experiences of the health dialogues as well as an evaluation of whether the implementation was successful.