Anthracycline pharmacodynamics and pharmacokinetics in acute myeloid leukemia

The goal of this thesis has been to study pharmacodynamics and pharmacokinetics of anthracyclines in acute myeloid leukemia (AML) with the ultimate goal to improve chemotherapy- 1. By studying the relation between daunorubicin (DNR) and idarubicin (IDA) uptake in vitro and in vivo and apoptosis in vitro in leukemic cells isolated from patients with AML. We studied the intracellular concentrations of DNR and IDA and apoptosis in leukemic cells after a one hour pulse incubation with increasing concentrations of anthracyclines. A clear concentration-response relationship was found between intracellular anthracycline concentrations and apoptosis although there was a large interindividual variation. Furthermore, the intracellular concentrations of DNR in vivo, directly after DNR infusion, were approximately tenfold lower than the concentrations needed to induce effective apoptosis in vitro. A significant correlation was found between in vivo intracellular concentrations and clinical remission. We also found a significant relation between apoptosis induction by IDA in vitro and clinical remission. The results indicate that the intracellular anthracycline levels in vivo are suboptimal and treatment protocols that increase the intracellular levels of anthracyclines should be considered. 2. By studying DNR metabolism in leukemic cells isolated from patients with AML. The metabolism of DNR in leukemic cell extracts from 25 AML patients was determined and related to the expressions of carbonyl reductase 1 (CR1) and aldo-keto reductase 1A1 (AKR1A1). We found a large interindividual variation (up to 47-fold) in the leukemic cells ability to convert DNR to its main metabolite daunorubicinol (DOL) and the metabolic rate was significantly correlated with CR1 expression. Zeraleone analogue-5, a specific inhibitor of CR1, significantly inhibited reduction of DNR. Our results support that CR1 is the most important enzyme for DNR metabolism in leukemic cells. 3. By studying the effect of the leukemic cell burden on plasma levels of DNR. Plasma and mononuclear cells were isolated from 40 patients with AML at the end of DNR infusion, after 5 h, and 24 h after the start of the DNR infusion. We found a weak and significant inverse correlation between the white blood cell count (WBC) and plasma levels of DNR. By using a population based pharmacokinetic model we found a significant correlation between the WBC count and volume of distribution (Vd). This study suggests that the leukemic cell burden lowers plasma levels of anthracyclines although further studies are needed to investigate if patients with a high WBC would benefit from higher doses of anthracyclines. 4. By comparing the uptake mechanisms of different anthracyclines in leukemic cells. The mechanisms behind anthracycline uptake are not completely understood. In this study we compared the uptake of five anthracyclines; DNR, doxorubicin (DOX), epirubicin (EPI), idarubicin (IDA), and pirarubicin (PIRA) by leukemic cells and investigated the possible involvement of specific carriers. HL-60 cells were incubated for one hour with the anthracyclines under various conditions and then the cellular uptake was determined. DNR, IDA, and PIRA had the highest intracellular accumulation. The uptake of DOX, DNR, and IDA was significantly reduced at 0° C. Suramin, a purinergic-2-receptor inhibitor, strongly inhibited the uptake of all anthracyclines except PIRA and dipyridamole, a nucleoside transport inhibitor, only inhibited the uptake of DNR. The addition of nucleosides reduced the uptake of DNR, IDA and PIRA. The results of this study indicate that anthracyclines may have different uptake mechanisms. Furthermore, our data also suggest that the uptake might be carrier mediated with a possible involvement of the nucleoside transporter family

Combatting long-term unemployment among immigrants beyond the COVID-19 pandemic : Experiences from the Nordic countries

The number of people experiencing long-term unemployment also grew in all Nordic countries during the COVID-19 pandemic. This report documents and compares how immigrants have been affected by long-term unemployment and investigates which policies and initiatives policymakers implemented to support them.The report aims to answer the following research questions:Have immigrants in the Nordic countries been more likely to face long-term unemployment? How has the number of long-term unemployed immigrants developed and is it an ongoing challenge? Which national-level institutions and actors have been involved in supporting long-term unemployed immigrants and which policies and measures have been used? Which initiatives have been implemented to help long-term unemployed immigrants in finding new employment? What can we learn from these initiatives?

State of the Nordic Region 2022

State of the Nordic Region 2022 has its point of departure in the Covid-19 pandemic and examines how it has affected demography, labour market and economy in the Nordic countries, regions, and municipalities. State of the Nordic Region is published every two years and provides a comprehensive account of regional development trends in the Nordic countries based on the latest statistical data. Charts and maps on different geographical scales are accompanied by expert analysis, providing policymakers and practitioners with a solid evidence base for informed decision making. In writing this edition of State of the Nordic Region, it was, of course, vital to acknowledge the impact of the Covid-19 pandemic. Given the magnitude of this crisis, a conscious decision was taken early in the process to make the pandemic the explicit focus of the publication. State of the Nordic Region 2022 is produced and published by Nordregio

SENSE tool deployment: Report on the testing of SENSE-tool and EID scheme in food chains - SENSE Deliverable 4.2

This report is part of the SENSE project (www.senseproject.eu) The aim was to develop a web based tool aimed at facilitating a harmonized sustainability assessment for the life cycle of products for SMEs in the food sector. The SENSE tool is designed with a user-friendly data entry and harmonized life cycle assessment (LCA) methodologies to calculate environmental impacts. The assessment when using the SENSE tool is simplified for SMEs by applying selected input data defined as Key Environmental Performance Indicators (KEPIs). The reporting includes the Phase 3 validation during pilot implementation of the SENSE tool in external companies in the fruit juice, meat and dairy and salmonid aquaculture food sectors.Project co-funded by European Commission within the Seventh Framework Programme, Project no. 288974. SENSE ‘HarmoniSed Environmental Sustainability in the European food and drink chain