Användningen av per oral cancerbehandling har ökat de senaste åren. Per oral cancerbehandling är inte automatiskt förknippat med samma strikta riktlinjer som vid intravenös behandling, däremot så är biverkningsprofilen med allvarliga och ibland livshotande tillstånd i stort sett densamma. Forskning har visat att följsamheten till den per orala cancerbehandlingen varierar, ibland är låg och inte är bättre än andra kroniskt sjuka gruppers följsamhet. Patienten sköter till stor del behandlingen själv. Konsekvenserna av detta kan vara ett försämrat behandlingsresultat, risk för över resp. underdosering och oförutsägbara biverkningar. Mätning av följsamhet är komplext och det finns ingen standardiserad metod.                              Syftet med denna studie var att belysa faktorer som påverkar patienters följsamhet till läkemedelsordinationer med per oral cancerbehandling. Metoden var en en forskningsöversikt. Sökorden som användes var; oral administration, antineoplastic agents, patient compliance, nursing care, medication adherence, treatment compliance och drug administration methods. De databaser som söktes igenom var PubMed, Cinahl och PsykInfo (Ovid). Totalt så inkluderades 15 artiklar i resultatet. Resultatet visade att förekomst av biverkningar och svårighet att hantera dessa kunde hindra följsamhet. Ett samband mellan följsamhet och chansen till att behandlingen var verksam hittades. Andra faktorer som framkom var att yngre patienter kunde löpa högre risk för att inte följa ordinationen, följsamheten var till viss del lägre bland yngre patienter. Enstaka studier fann ett samband mellan var behandlingen gavs (universitetssjukhus eller andra vårdinrättningar) och socioekonomisk status. Utbildning kunde öka följsamheten enligt en studie. En studie visade att psykologisk hälsa hos patienten kunde påverka följsamheten. Slutsatsen var att följsamhet till per oral cancerbehandling beror på flera olika faktorer. Förekomst av biverkningar, patientens uppfattning om prognos och ålder kan påverka följsamheten. Socioekonomisk status, var behandlingen ges och psykologisk hälsa är faktorer som kan påverka följsamheten och behöver studeras vidare. Informationen måste vara individuell och samtal kring följsamhet kan vara av betydelse. Hantering av biverkningar och information kring konsekvenserna av en låg följsamhet behöver utvecklas. Vårdpersonalen behöver utbildas i vad som kan påverka följsamhet och vara lyhörda för eventuella missuppfattningar kring behandlingens effekt. Vikten av följsamhet bör tas upp av både läkare och sjuksköterskor och gärna tillsammans med anhöriga.

No description available.

Intracellular sterol redistribution is an important step in the lipid homeostasis of organisms, a process directly linked to the organizational arrangement in the plasma membrane (PM) of cells. Previous studies in the budding yeast Saccharomyces cerevisiae have demonstrated that the ARV1 (ACAT-related enzyme-2 required for viability 1) protein is a major regulator of sterol transport from the endoplasmic reticulum to the plasma membrane, contributing to the structural organization of the PM, rendering it resistant to anti-fungal compounds as well as maintaining ER integrity. This study assessed the significance of ARV1 in the plant pathogenic fungus Cryphonectria parasitica (Cparv1) and investigated its role in the pathogenesis and virulence of the fungus. C. parasitica is the causative agent of Chestnut blight, which has wreaked havoc on the American chestnut species. Genomic analysis revealed that the Cparv1 gene is very closely linked to another gene that putatively encodes a cyanamide hydratase (Cpcah). An initial gene deletion event resulted in the elimination of both genes and a highly deformed phenotype in C. parasitica that was fully recoverable by complementation. PCR-based expression analysis determined that the lack of Cparv1 was responsible for the debilitated phenotype of the double mutant, with no transcript detectable from Cpcah. Subsequent complementation of the Cparv1 gene was also observed to restore the wildtype phenotype. Mass spectrometry-based (MS) results indicated a decrease in sterol content of the DCparv1 mutant strain compared to wildtype EP155 thus confirming a role for Cparv1 in sterol homeostasis. It has been shown that infection of C. parasitica with virulence-attenuating hypoviruses altered intracellular lipid content and protein secretion. Ultrastructure studies conducted on the Cparv1 strain showed disrupted organelle integrity and the presence of cytoplasmic double membrane stretches. Decreased sterol content in C. parasitica infected with CHV1-EP713 was observed similar to DCparv1 suggesting a connection between the hypovirus-infected phenotype and Cparv1. Furthermore, a non-targeted metabolomic study on all three strains identified 324 metabolites. Through the subsequent pathway analysis, we have investigated the pleiotropic effects in the C. parasitica strains and established a mechanistic linkage between this the activity of the ARV-1 protein and the hypovirus-infected phenotype.

Pollinator conservation has recently become a topic of greater interest and research around the world as native insect pollinator species increasingly face population declines. In the United States, growing concerns regarding food security and decreased biodiversity have led to the creation of programmatic and best management practices (BMPs) promotional efforts among governmental and non-governmental organizations. These efforts seek to support pollinators on public and private lands by addressing the primary causes of decline (e.g., habitat loss and increased chemical use). Although these organizations have worked diligently to increase awareness and applicability of programs to private landholders, there is still a gap in pollinator BMP adoption. The purpose of my dissertation was to address the pollinator BMP adoption gap through empirical research with two primary goals: 1) develop and test a measurement instrument to investigate the current state of adoption in Mississippi, landholder attributes, and attribute influence on adoption intentions, and 2) conduct segmentation analyses to develop preliminary recommendations for future educational and outreach efforts to increase adoption of pollinator BMPs. I used two sociological theories to develop a questionnaire consisting of constructs measuring landholder attributes, including Attitudes, Injunctive Norms, Perceived Behavioral Control, Intentions, Knowledge, and Communication Channel Use. I conducted a selfministered mail survey during summer 2018 and received a 38.5% effective response rate. Relative to the first goal, major findings from the research included evidence of reliability and validity for the measurement constructs, landholders having more favorable than unfavorable Attitudes regarding the use of pollinator BMPs on their properties, and Perceived Behavioral Control as the strongest influence on adoption intentions compared to additional landholder attributes. Relative to the second goal, major findings included the generation of four distinct clusters and three land use type segments that allowed for group comparisons and development of a recommended two-step targeted educational and outreach approach. My dissertation provided theoretical and substantive advances to the fields of adoption research and pollinator conservation from which future research and outreach efforts can grow.

No description available.

Per- and polyfluoroalkyl substances (PFAS) have been manufactured and used in differentapplications for several decades, including food packaging materials. During the last 20 yearsthese compounds have been acknowledged as hazardous for humans and the environment, anddifferent regulations on PFAS have been established on both national and international levels.Companies started to phase-out long-chain PFAS, including both PFOA and PFOS, around 20years ago. Since PFAS are persistent, this cause concerns both for our health and theenvironment, as well as possible PFAS contamination in new products due to the recycling ofmaterials. The aim of this study was to find an effective method to extract PFAS from differentfood packaging materials; analyze the samples for their extractable organofluorine (EOF)content using combustion ion chromatography; as well as analyze targeted PFAS in the samplesusing ultra-high performance liquid chromatography tandem mass spectrometry. The findingsof this study suggest that none of the selected samples had EOF contents above the Danishindicator value of 20 mg/kg dw TOF set to determine whether PFAS has been intentionallyadded to a material, and that only two samples exceeded the limit of detection for EOF. Atakeaway bowl made out of 100% sugarcane contained the highest EOF content while the outerpackaging of a cereal box contained the second highest EOF. Both PFOA and PFOS, alongwith other long-chain PFAS were detected in a majority of the samples. The lowest total PFASconcentrations when analyzing for targeted PFAS was detected in the sugarcane take awaybowl. The highest total PFAS concentration was detected in an egg carton, followed by theouter packaging of a cereal box (same as above) and the outer box of a waffle mix. The targetedPFAS was detected in almost all samples, with PFNA and 6:2 diPAP being the most frequentlydetected PFAS. PFCAs, PFSAs, FTSAs, FOSAAs and PAPs were detected in a majority of thesamples. The highest concentrations were measured for diSAmPAP in a majority of thesamples. Mass balance calculations of the sugarcane bowl showed that the targeted PFAS onlyaccounted for 0.04% of the extractable organofluorine content. In conclusion, none of thesamples displayed EOF contents higher than the Danish indicator value, suggesting that noneof the samples were intentionally treated with PFAS. However, targeted PFAS analysis of thesesamples showed that they still contain PFAS, that could be further recycled along with therecycling of paper and board food packaging materials. Considering the persistence of PFASand that these compounds can remain in the recycling chain, with the risk of also being releasedinto the environment, it is of importance that PFAS is not introduced in any of the stages in apaper or board containers life cycle.

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.

No description available.

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...