International Migration, Integration and Social Cohesion online publications
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Discovery beyond the void:Energizing T cells in chronic lymphocytic leukemia
Full text linkIn the last decade, efficacy of treatment of chronic lymphocytic leukemia (CLL) has improved considerably. Highly effective targeted therapies such as ibrutinib and venetoclax have been developed and replaced chemoimmunotherapy as first-line treatment for CLL. However, these targeted therapies are not curative. CAR-T cell therapy for the treatment of hematological malignancies has curative potential, but CLL patients treated with CAR-T cells show poor responses. The current dogma is that exhaustion of T cells in CLL is to blame for CAR-T cell inefficacy. Since CAR-T cell therapy is a single dose therapy and has the potential to be curative, it is worthwhile to investigate and invent novel methods to increase its efficacy in CLL. Therefore this thesis focused on identifying the mechanism of T-cell exhaustion in CLL, whether this is reversible, and how we use this information to improve existing autologous based immunotherapies such as CAR-T cell therapy. In in this manuscript it is described that T cells in CLL patients are functionally and metabolically impaired. However, T cells in CLL are not terminally exhausted. In the final chapters of this thesis we present multiple methods to reverse T cell dysfunction in CLL, creating new possibilities to improve autologous based therapies in CLL
Animal hunts in late antiquity:Continuities and changes between the 4th and 6th century AD in the east of the Roman empire
Full text linkAnimal hunts (lat. venationes) were a popular form of mass entertainment in the Roman empire, from their origins in the republican period until Late Antiquity. Venationes continued to be presented even after gladiator fights, with which animal hunts were traditionally combined, disappeared from public life. They endured despite facing harsh and persistent opposition by Christian critics from the 2nd century AD onwards. The present thesis seeks to understand the reasons for the persistence and popularity of venationes in the late antique East from the beginning of the 4th century AD onward and for their eventual end in the mid-6th century AD. In previous scholarship, animal hunts have mostly been discussed in general works on Roman spectacles, in which they have often been sidelined next to gladiator fights and chariot racing. Additionally, evidence stemming from later periods and from outside Rome has received little attention. By centring animal hunts, this dissertation fills a lacuna in current research on Roman spectacles and highlights the unique circumstances and developments of venationes in Late Antiquity. The dissertation looks at a variety of sources to bring together local practices, inter-provincial networks, and imperial policies for a comprehensive understanding of the cultural and social significance of animal hunts for late antique society. By studying animal hunts as a historical instance of human-animal interaction, the dissertation acknowledges that animals are central to what venationes looked like, what venues were needed to accommodate them, what was necessary to organise them, and how the spectators and critics saw them
The human cost of development:Situating development-induced displacement in international human rights law
Full text linkDevelopment-induced displacement (DID)—a phenomenon where people are involuntarily moved from their homes or residences to make room for development projects—is one of the prominent causes of internal displacement affecting millions of people every year. DID can be caused by a range of small and large-scale development projects, such as the construction of dams, urban (re)development projects, and extraction of natural resources. While these development projects have significant economic potential, the involuntary displacement they often cause comes with a plethora of risks and consequences including, inter alia, loss of land, a decrease of income sources, lack of access to public services, and disruption of culture and way of life. These adverse consequences further interfere with and potentially violate a range of human rights, such as the right to housing, the right to property, the right to work, and the right to education. Moreover, DID and its adverse consequences often hit the hardest vulnerable and marginalized groups potentially perpetuating existing vulnerabilities and inequalities. Against this background, the current study seeks to situate DID and its adverse consequences in international human rights law. Using the human rights-based approach as a theoretical framework, it seeks to (re)frame the adverse consequences of DID as human rights issues and explore rights-based solutions to address these issues. The study will identify the pertinent human rights norms and assess their application in the context of DID. In doing so, it seeks to explore the human rights safeguards that need to be provided for people(s) affected by DID and the corresponding obligations of states. Overall, the objectives of this research are twofold, i.e. map out the existing international human rights law norms that apply to DID and assess the adequacy of these norms in addressing the adverse consequences and the salient features of DID
Challenging the HIV DNA integration dogma:Integration-independent HIV replication to escape from integrase inhibitors
Full text linkLike other retroviruses, human immunodeficiency virus (HIV) has an RNA genome that is converted into a linear DNA molecule upon infecting host cells. This viral DNA is then integrated into the host’s cellular DNA by the viral integrase and subsequently used for the production of new virus particles. Integrase inhibitors, such as dolutegravir (DTG), effectively block DNA integration and inhibit virus replication, and are therefore widely used in antiretroviral therapy. HIV typically escapes the effects of inhibitors by acquiring mutations in the gene encoding the targeted protein. Accordingly, mutations in the viral integrase have been linked to resistance to DTG. However, this thesis describes an alternative mechanism of DTG resistance involving mutations in the viral 3’-polypurine tract (3’PPT), an RNA sequence element that serves as a primer for the regular reverse transcription of HIV RNA into DNA. These mutations inactivate the 3’PPT element, leading to the production of circular, rather than linear, HIV DNA. This circular HIV DNA does not integrate into the host genome but still allows the production of new virus particles. As a result, the virus can replicate in the presence of integrase inhibitors, thereby reducing the effectiveness of these antivirals. Moreover, this integration-independent replication pathway challenges the prevailing dogma that integration is an essential step in retrovirus replication
The human cost of development:Situating development-induced displacement in international human rights law
Full text linkDevelopment-induced displacement (DID)—a phenomenon where people are involuntarily moved from their homes or residences to make room for development projects—is one of the prominent causes of internal displacement affecting millions of people every year. DID can be caused by a range of small and large-scale development projects, such as the construction of dams, urban (re)development projects, and extraction of natural resources. While these development projects have significant economic potential, the involuntary displacement they often cause comes with a plethora of risks and consequences including, inter alia, loss of land, a decrease of income sources, lack of access to public services, and disruption of culture and way of life. These adverse consequences further interfere with and potentially violate a range of human rights, such as the right to housing, the right to property, the right to work, and the right to education. Moreover, DID and its adverse consequences often hit the hardest vulnerable and marginalized groups potentially perpetuating existing vulnerabilities and inequalities. Against this background, the current study seeks to situate DID and its adverse consequences in international human rights law. Using the human rights-based approach as a theoretical framework, it seeks to (re)frame the adverse consequences of DID as human rights issues and explore rights-based solutions to address these issues. The study will identify the pertinent human rights norms and assess their application in the context of DID. In doing so, it seeks to explore the human rights safeguards that need to be provided for people(s) affected by DID and the corresponding obligations of states. Overall, the objectives of this research are twofold, i.e. map out the existing international human rights law norms that apply to DID and assess the adequacy of these norms in addressing the adverse consequences and the salient features of DID
Biomarkers and diagnostic tests for coagulopathies in the critically ill and injured
Full text linkCoagulopathy is a severe complication of both critical illness and injury, contributing to morbidity and mortality. As such, there is a clear clinical need for improved hemostasis management. However, to date, methods of (early) detection of coagulopathy are limited. Coagulopathy in the critically ill has many phenotypes, ranging from a hyper- to a hypocoagulable state that can give rise to multiple hemostatic complications including thrombosis and bleeding, which can also occur simultaneously. Early clinical suspicion of thrombosis is important to guide timing of imaging tools. Evidently, the assessment of risk of thrombosis and bleeding is important for decisions about timing and dose of anticoagulant therapy. Additionally, a better understanding of the risk of bleeding can help decisions about specific procoagulant interventions. In the critically injured, coagulopathy also frequently occurs, with an inability to clot during bleeding, which may transition to a hypercoagulable state after bleeding has been contained. Rotational thromboelastometry (ROTEM) is used as a point-of-care test to guide bleeding, but knowledge about the coagulation disturbances that underlie the test results is limited. In this thesis, the potential of biomarkers and of ROTEM to estimate risks of hemostatic complications from coagulopathies in the critically ill and injured is explored
Replenishing dopamine in Parkinson’s disease:Tyrosine hydroxylase Ser40 phosphorylation and phosphodiesterase inhibition
Full text linkThis thesis focuses on the biosynthesis machinery of the neurotransmitter dopamine and its therapeutic potential in the treatment of Parkinson's disease, a degenerative disorder caused by a deficiency in dopamine. Although L-DOPA is the current treatment for Parkinson's disease, it can lead to adverse effects and eventually lose effectiveness. As an alternative approach to replenish dopamine levels, this thesis suggests regulating the activity of tyrosine hydroxylase, the rate-limiting enzyme involved in dopamine production. By stimulating tyrosine hydroxylase activity, dopamine production can be increased, activating dopamine cells in the brain. The activity of tyrosine hydroxylase is regulated by Ser40 phosphorylation, a chemical reaction in which a phosphate group is added to an amino acid in the enzyme. This thesis explores the mechanisms that influence Ser40 phosphorylation and how they can be manipulated to increase the dopamine biosynthesis machinery in the dopamine neurons that are affected in Parkinson’s disease, specifically. The research findings indicate that cyclic nucleotide-mediated signaling plays a vital role in promoting Ser40 phosphorylation. Furthermore, the thesis investigates the impact of inhibiting phosphodiesterases, which break down cyclic nucleotides, on Ser40 phosphorylation. The results demonstrate that phosphodiesterase inhibition can upregulate tyrosine hydroxylase Ser40 phosphorylation and, as such, can stimulate the dopamine biosynthesis machinery. Overall, these findings suggest that manipulating tyrosine hydroxylase activity through phosphodiesterase inhibition could be a promising strategy to replenish dopamine levels and improve the quality of life for Parkinson's disease patients
Poetik der Komplizenschaft:Zum kommunikativen Potenzial von Exilautobiographien der NS-Zeit
Full text linkZwischen 1933 und 1945 ergriffen zahlreiche Geflüchtete gegen das NS-Regime das Wort und versuchten anhand ihrer persönlichen Erfahrungen mit dem Dritten Reich eine Weltöffentlichkeit über dessen Verbrechen aufzuklären. Autobiographisches Schreiben wurde als Medium dazu genutzt, der totalitären Vereinnahmung von Identität(en) ein Gegennarrativ entgegenzustellen und Deutungsmacht zu beanspruchen, das durch Zensur und Repression auferlegte Schweigen zu durchbrechen, aber auch direkten Einfluss auf die alliierten Mächte auszuüben. Solche im Modus des Testimonialen operierende Autobiographien zeichnen sich durch eine starke Appellstruktur aus: sie versuchen ihr Publikum von ihrer Sicht der Dinge zu überzeugen und zu mobilisieren, fordern Anerkennung, Empathie, Vertrauen und Parteinahme ein und positionieren ihre Leser:innen auf diese Weise performativ als Kompliz:innen. In der Forschung wurden testimoniale Exilautobiographien zwischen 1933 und 1945 vor allem als zeithistorische und soziokulturelle Quellen behandelt, wobei ihre ästhetischen Qualitäten entweder ausgeblendet oder diese als formkonservativ und anspruchslos etikettiert wurden. Dabei wird das Genre einem an fiktionaler Literatur orientierten Werteraster unterworfen, welches seine sozialkommunikative Funktion und gattungsspezifische Eigenlogik unberücksichtigt lassen. Genau hier setzt der in dieser Arbeit entwickelte Analysebegriff der ‚Komplizenschaft‘ an, indem er das ästhetische Potenzial der testimonialen NS-Exilautobiographik in ihrer intersubjektiv-kommunikativen Dimension verortet. Die These ist, dass die prekären Produktions- und Rezeptionsbedingungen des Exils, die Positionierung der eigenen Lebensgeschichte als Gegendiskurs und spezifische rhetorische und narrative Techniken eine komplizitäre Lektürehaltung generieren, die konstitutiv für die Poetik dieser Texte ist. Zentral stehen drei Fallstudien: Catherine Kleins Escape from Berlin (1944), Sebastian Haffners Geschichte eines Deutschen (1939/2000) und Stefan Zweigs Die Welt von Gestern (1942)
Biomarkers and diagnostic tests for coagulopathies in the critically ill and injured
Full text linkCoagulopathy is a severe complication of both critical illness and injury, contributing to morbidity and mortality. As such, there is a clear clinical need for improved hemostasis management. However, to date, methods of (early) detection of coagulopathy are limited. Coagulopathy in the critically ill has many phenotypes, ranging from a hyper- to a hypocoagulable state that can give rise to multiple hemostatic complications including thrombosis and bleeding, which can also occur simultaneously. Early clinical suspicion of thrombosis is important to guide timing of imaging tools. Evidently, the assessment of risk of thrombosis and bleeding is important for decisions about timing and dose of anticoagulant therapy. Additionally, a better understanding of the risk of bleeding can help decisions about specific procoagulant interventions. In the critically injured, coagulopathy also frequently occurs, with an inability to clot during bleeding, which may transition to a hypercoagulable state after bleeding has been contained. Rotational thromboelastometry (ROTEM) is used as a point-of-care test to guide bleeding, but knowledge about the coagulation disturbances that underlie the test results is limited. In this thesis, the potential of biomarkers and of ROTEM to estimate risks of hemostatic complications from coagulopathies in the critically ill and injured is explored
It takes a village to grow stronger:A socio-ecological model of resilience in refugees
No full textThe present dissertation explores the factors promoting refugees' resilience and complex relationship between these factors and resilience. This dissertation presents a breadth of methodology, using mixed-methods to study refugee resilience. Specifically, we started with an extensive and comprehensive systematic review to scope the literature on risk and protective factors of resilience in refugees. Then, we conducted qualitative interviews to explore refugees’ rich narratives of resilience, and finally, we ended with experimental studies to test causal relations and survey studies to model resilience and its associated factors. Findings from all of the studies conducted for this dissertation offer a multi-layered understanding of the nature of refugee resilience. Refugees’ resilience is determined by internal and external factors across four socio-ecological levels: individual, family, community, and society. This dissertation emphasizes that resilience is not merely an individual capacity, but a context-dependent process influenced by structural conditions and relational resources