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    "Completed life": Older adults who have a death wish without being severely ill

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    This dissertation is about older adults who have a death wish without being severely ill. Some older adults may come to the conclusion that even though they are not severely ill, the quality and the meaning of their life has deteriorated to such extent that they do no longer see a future for themselves and prefer death over life, leading to a death wish and sometimes also to a wish for a self-directed death. One commonly used expression for this experience is “completed life”. In the beginning of 2019 when the work for this dissertation started, there was an ongoing public and political debate about “completed life”. The debate centered around the question whether older adults with “completed life” who are not eligible for EAS but wish for a self-directed death should have legal options for assisted dying. At the same time, due to the limited empirical knowledge that was available, arguments for and against offering such legal options were mainly ideological and theoretical in nature. For well-informed policymaking on how the death wish of older adults with “completed life” can be appropriately responded to, more empirical knowledge was required. There was insufficient empirical knowledge on how many older adults have a death wish without being severely ill, who these older adults are, what the background of their death wishes is, and how their requests for EAS are handled by medical professionals. This dissertation aimed to address this knowledge gap by answering the following research questions: 1. What is the prevalence of older adults with a death wish without severe illness? 2. How can older adults with a death wish without severe illness be described in terms of characteristics and circumstances? 3. What is the background of the death wish of older adults without severe illness considering the nature of the death wish, motivations and needs behind the death wish, and communication about the death wish? 4. How are requests for euthanasia and assisted suicide (EAS) of older adults with a death wish without severe illness decided upon by Euthanasia Expertise Center (EEC) and assessed by the Regional Euthanasia Review Committees (RTEs)? 5. In what ways can be appropriately responded to the death wish of older adults without severe illness in light of empirical findings

    Towards Unraveling the Puzzle of KMT2A-rearranged Infant Acute Lymphoblastic Leukemia: novel insights into the relapse mechanisms, pathobiology, and therapeutic vulnerabilities

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    Despite centuries of research progress, cancer remains challenging to understand and treat, persisting as a prominent contributor to global mortality. Childhood cancer is rare, however it remains a leading cause of death from illness in children. Pediatric cancer requires special attention due to differences from adult cancer, with fewer genetic mutations and less association with lifestyle factors. A distinct approach is needed, considering the long-term effects on children. Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer, accounting for 20% of cases. Although overall pediatric ALL treatment has improved, infants (under 1 year) with ALL, constituting 5% of cases, still face a lower survival rate. Infant ALL is marked by an 80% occurrence of chromosomal abnormalities in the KMT2A gene, leading to a highly aggressive form with a unique biology. Current treatment protocols yield a 40% survival rate for infants with KMT2A-rearranged ALL. As demonstrated previously, KMT2A-rearranged infant ALL is characterized by aberrant DNA methylation patterns, which led to the evaluation of DNA methyltransferase inhibitors. While in vitro cytotoxicity has been observed, data on the in vivo efficacy of demethylating agents were lacking. Therefore, the in vivo anti-leukemic potential of low and clinically relevant decitabine doses in a human KMT2A-rearranged ALL xenograft mouse model was assessed. Additionally, a prolonged low-dose decitabine exposure was evaluated for sensitization of ALL cells to conventional chemotherapy and other epigenetic-based and anti-neoplastic compounds. Acquired resistance to DOT1L inhibition, a class of epigenetic drugs targeting KMT2A-rearranged acute leukemias, was investigated. KMT2A-rearranged leukemias arise from a fusion between the KMT2A gene and another gene, forming abnormal KMT2A fusion proteins that attract DOT1L, leading to abnormal gene regulation and leukemia development. An extensively characterized cell line model of acquired resistance to the primary DOT1L inhibitor, pinometostat, offered insights into the adaptive capacity of KMT2A-rearranged ALL cells. These cells evade the effects of DOT1L inhibitors by adopting myeloid-associated characteristics and/or exhibiting cellular plasticity. The observation that KMT2A-rearranged ALL cells can overcome their dependency on DOT1L, a crucial oncogenic property of this type of leukemia, raises the question whether there are other specific epigenetic vulnerabilities in these cells. Additional epigenetic regulators and essential kinases for KMT2A-rearranged ALL cells were identified utilizing CRISPR-Cas9 technology, revealing new molecular dependencies and potential therapeutic targets, including ARID4B, MBD3, and BMPR2. Ongoing investigations focus on understanding the roles of these targets in the context of KMT2A-rearranged ALL and exploring their treatment potential Understanding how KMT2A-rearranged ALL cells drive leukemogenesis and identifying therapeutic strategies is crucial. Equally imperative is comprehending mechanisms underlying leukemia relapse within current treatment regimens. Therefore, single-cell RNA sequencing was utilized to analyze gene expression in individual leukemia cells from diagnostic samples of infants with KMT2A-rearranged ALL providing. By categorizing cells as 'resistant' or 'sensitive' to treatment, we identified subpopulations predicting future relapses in individual patients. This insight into therapy-resistant cells at diagnosis is pivotal for understanding recurrence mechanisms and developing preventive measures, shedding light on the complex biology of leukemia relapse


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    Exploring Molecular Mechanisms and Biomarkers in Psoriasis: Insights from Omics Technologies and Single-Cell Analyses

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    The skin, the body's largest external organ, serves as the primary interface with the outside world. Psoriasis, a chronic skin condition, involves a complex interplay of immunological and environmental factors, initially affecting the skin but eventually leading to systemic immune dysregulation, rendering it a multifaceted systemic disease. Over the past decade, the introduction of biologics has revolutionized psoriasis treatment by modulating the immune environment. However, it's important to recognize that not all psoriasis patients respond favorably to these biologics. This underscores the intricate and heterogeneous nature of psoriasis, which involves multiple immune pathways and genetic elements. Biologics targeting specific cytokines or cell types may not be universally effective in controlling the disease. Furthermore, the skin's immune response is intricately linked with the broader immune system, necessitating continuous interactions for immune regulation. In Chapter 1, we explored the utility of omics technologies in the context of psoriasis, emphasizing the need for ongoing exploration of omics data to gain a comprehensive understanding of the intricate biological processes at play. Subsequent chapters (2-5) delved into the application of various omics techniques to investigate the transcriptomic, proteomic, and microbiomic aspects of both skin tissue and blood samples from patients with psoriasis and other autoimmune conditions like psoriatic arthritis, ankylosing spondylitis, and atopic dermatitis. Chapter 2 employed a tree-based machine learning approach to uncover the gene regulatory networks underlying psoriasis, identifying key regulators that could serve as potential drug targets and disease severity markers. Notably, the interferon signaling pathway emerged as a central component of psoriatic inflammation. In Chapter 3, we examined the associations between the transcriptome and microbiome in different skin samples, revealing significant differences in the transcriptome profiles between lesion and non-lesion skin. Functional annotation highlighted a strong emphasis on neutrophil activation. A core gene network emerged, intricately linked to inflammation and hyper-keratinization, with microbiome analysis shedding light on correlations with specific microbial species. Chapter 4 focused on identifying psoriasis biomarkers through proteome profiling of patient serum and transcriptome sequencing of skin samples. Peptidase inhibitor 3 (PI3) emerged as a significant biomarker, correlating with local skin gene expression and disease severity. Single-cell analysis confirmed PI3's high expression in psoriatic keratinocytes, suggesting its utility as a psoriasis-specific biomarker. In Chapter 5, single-cell RNA sequencing and T cell repertoire profiling were employed to understand the immune response in psoriasis, both in peripheral blood and skin samples. Immune signatures of various myeloid and lymphocyte subsets were revealed, highlighting significant alterations in immune cell subsets in psoriasis patients. Specific characteristics, such as the CD8+ TRM cells producing high levels of IFN-γ or IL-17, were identified as unique to psoriasis. These findings provide valuable insights into the pathophysiology of psoriasis. Based on our findings, it is increasingly likely that environmental microbial triggers activate and recruit neutrophils and pDCs to the skin. This stimulation leads to the secretion of antimicrobial peptides like PI3 by keratinocytes, which can enter the circulation. Circulating monocytes and effector memory T cells may respond to these processes and migrate to the skin, forming monocyte-derived macrophages and resident memory T cells cells, thus contributing to the pro-inflammatory loop driving the development of psoriatic lesions. Finally, it is important to note that our observations might be the consequences of the transcriptional state rather than having been conclusively proven


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    Treatment optimization of fluoropyrimidine-based chemotherapy

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    This thesis is focused on a group of anticancer agents known as fluoropyrimidines, vital in the treatment of several solid tumors. Although the extensive experience with fluoropyrimidines severe toxicity remains a major clinical problem. Only recently has attention turned to the influence of inter-individual variability in activity of the DPD enzyme – encoded by the DPYD gene – on the safety of fluoropyrimidines. Pre-therapeutic screening of the DPYD gene for relevant single nucleotide polymorphisms (DPYD*2A, c.1236G>A, c.2846A>T, and c.1679T>G) and subsequent dose-individualizations have shown to significantly reduced severe toxicity. However, despite the reproducible link between the four DPYD variants and toxicity, ~23% of patients who do not carry any of these variants still experience severe toxicity. The first part of this thesis focuses on the dose-individualization strategies enhance fluoropyrimidine safety. We have sought to identify potential biomarkers inside of severe toxicity in- and outside of the DPYD gene to explain the remaining toxicity. We have shown that it is unlikely that at a population level, testing for single markers in addition to the four established DPYD variants, currently has limited value in improving fluoropyrimidine toxicity prediction. Measurement of uracil as a DPD phenotyping method as an alternative to DPYD-genotyping was studied, revealed that uracil is highly susceptible to pre-analytical factors. In a large prospective clinical trial, we demonstrated that uracil-based dose-individualization reduces severe fluoropyrimidine-related toxicity. However, this approach led to inadequate exposure to the primary metabolite 5-fluorouracil. Therefore, this strategy is currently not recommended for dose-individualization of fluoropyrimidines. Additionally, we developed a predictive model based on patient-related and treatment-related factors aimed at estimating the risk of developing severe capecitabine-related toxicity. This model includes readily available parameters and demonstrates a good discriminative ability of prediction of severe toxicity and may be a helpful tool for clinicians to assess the risk of developing severe toxicity. In the second part we explored the clinical outcomes of DPYD variant carriers treated with a reduced dose. Our findings indicate that DPYD-guided dosing does not negatively impact PFS and OS in DPYD variant carriers. However, in the individual group of c.1236G>A carriers a shorter PFS was found when treated with a 25% reduced dose. Therefore, close monitoring with early dose-modifications based on toxicity is recommended, especially for c.1236G>A carriers receiving a reduced starting dose. Furthermore, predictors of severe toxicity in elderly treated with fluoropyrimidines were studied and showed that polychemotherapy, reduced starting dose of polychemotherapy and low BMI trended towards increased risk of severe toxicity. In addition, multiple deficits across multiple geriatric domains and combination chemotherapy were predictors of poor treatment tolerability. In the third part, the focus is on bioanalysis supporting fluoropyrimidine-based chemotherapy. We developed a bioanalytical assay for the quantification of capecitabine and its metabolites in a single assay. Additionally, we studied the stability of uracil and dihydrouracil. This study revealed that uracil is highly instable at room temperature and should be processed within 1 hour after blood sampling, when stored at room temperature, to ensure stable and reliable results

    Pharmaceutical formulations for poorly water-soluble drugs: From technology to solutions for clinical use

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    The thesis, titled 'Pharmaceutical formulations for poorly water-soluble drugs - From technology to solutions for clinical use' explores various formulation strategies to improve the water solubility of poorly water-soluble drugs. Such drugs are often associated with poor drug absorption, which can compromise their therapeutic efficacy and necessitate innovative formulation strategies to enhance their solubility, dissolution, and ultimately, their bioavailability in the human body. While the challenges tied with poorly water-soluble drugs are longstanding, so are the established strategies employed to address them. The formulator’s toolbox, though limited, still contains overlooked possibilities to overcome these challenges. Some of these options are often, but not exclusively, linked with parenteral applications. Two of these strategies are detailed in this thesis and include mixed micelles (of bile salts and phospholipids) and lipid nanoemulsions. Additionally, it explores the more established technique of self-emulsifying drug delivery systems. The (re-)formulation of three existing poorly-water soluble drugs, known for issues related to their (bio)availability, are described using the aforementioned strategies. This includes vitamin K, propofol and idebenone, respectively. Special emphasis is giving to vitamin K. Despite our understanding of the function of vitamin K for nearly a century, the availability of various formulations since the nineteen fifties, and the global awareness for many years that current oral formulations are ineffective in preventing vitamin K deficiency bleedings (VKDBs) in infancy, progress towards a solution has been slow and is primarily driven by academic research. In thesis, for the first time, we present an oral solution which protects newborns against life-threatening bleedings. Furthermore, we provide a physicochemical explanation how the long known, but unexplained, incidence difference of VKDBs in formula-fed versus breastfed can be explained. This thesis further increases our fundamental understanding of why vitamin K deficiency bleedings still occurs, details the extemporaneous preparation of a propofol emulsion without specialized manufacturing equipment and describes how the oral bioavailability of idebenone can be improved by targeting lymphatic uptake. This thesis brings us one step closer to various technological solutions

    Geriatric impairments, medication and interventions in older persons: With focus on patients with cardiovascular disease

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    The number of patients with cardiovascular disease (CVD) is increasing worldwide. Many patients with CVD are 75 years of age or older. Frailty and geriatric impairments such as problems with thinking (cognitive impairment), concomitant use of several medications (polypharmacy), falls and reduced self-reliance are particularly common in the older patient. In recent years, frailty and geriatric impairments have been demonstrated to play a role in recognizing patients at increased risk of adverse outcomes from treatments. In this thesis, we investigated the occurrence of geriatric impairments in different patient groups with CVD, by means of a geriatric investigation (known as comprehensive geriatric assessment). We concluded that geriatric impairments and frailty are common in patients with CVD, especially in those screened for an implanted mechanical heart pump (left ventricular assist device), heart transplantation or aortic valve implantation through the groin (transcatheter aortic valve implantation). Geriatric impairments (including cognitive impairment and hyperpolypharmacy (≥10 medications)) and frailty were associated with adverse outcomes in patients with CVD. Knowledge of the predictive value of these conditions provides a better understanding of the potential risks of a treatment and may therefore improve shared decision-making. Several recommendations for treatments to reduce the risk of geriatric impairments and complications follow from the geriatric assessment which includes a medication review. Geriatric impairments often have several causes. In line with this, two literature reviews we conducted showed that treatments with multiple components in particular are effective in preventing falls and hospital readmissions

    Immunomodulation by specific HMOS and the relevance in allergy management: Towards advanced human in vitro mucosal immune models

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    Early life is considered an essential period in life for the maturation of the immune system. Flawed immune maturation predisposes for immunological abnormalities later in life such as the development of disorders including autoimmunity and allergic diseases. In light of the increasing prevalence and incidence of allergic diseases observed in the past decades, an urgent need for preventive strategies is identified. The development of immune homeostasis and therefore potential prevention of allergic sensitization in infants is supported by breastfeeding. Human milk contains many biological active components, which may contribute to the allergy preventive effects. Using several in vitro and in vivo approaches, this thesis aims to investigate the immunomodulatory effects of a unique group of human milk components: the human milk oligosaccharides. The development of novel advanced in vitro human mucosal immune models to improve our understanding of allergic sensitization upon allergen exposure and predict sensitizing allergenicity risk is described in this thesis. These models were used to reveal the ability of specific fucosylated and sialylated human milk oligosaccharides to affect crosstalk between epithelial and immune cells during allergic inflammation in intestinal and airway mucosal settings. Specific human milk oligosaccharides were found to differentially support mucosal immune responses during allergic inflammation in vitro, these findings were supported by preclinical models for food allergy and allergic asthma. This thesis provides building blocks, novel insights and potential options for interventions to understand and build preventive strategies for allergy development in early life

    Explaining Lupus Anticoagulant in Thrombotic Antiphospholipid Syndrome

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    The acquired thrombotic risk factor known as lupus anticoagulant (LA) is detected as a phospholipid-dependent prolongation of the clotting time and is the most clinically relevant antiphospholipid antibody within the antiphospholipid syndrome (APS). LA can be caused by autoantibodies against β2-glycoprotein I (β2GPI) or prothrombin. The association of LA with thrombosis represents a paradox, as prolonged clotting times are normally indicative for a bleeding tendency. The aim of this thesis was to gain more insight into the thrombotic mechanism of LA-causing antiphospholipid antibodies and to investigate how these antibodies interfere with coagulation assays. In Chapter 2, we described how anti-β2GPI and anti-prothrombin antibodies interfere in coagulation assays leading to the LA phenomenon. We showed that anti-β2GPI and anti-prothrombin antibodies cause LA through different mechanisms of action: while anti-β2GPI antibodies interfere with Factor V activation by Factor Xa through a direct interaction with FV, anti-prothrombin antibodies compete with FXa for phospholipid binding sites. In Chapter 3, we focused on the other part of the LA paradox by looking into the effect of anti-β2GPI and anti-prothrombin antibodies on the pro-thrombotic mechanism of activated protein C (APC) resistance. We showed that anti-β2GPI antibodies with LA-activity cause APC resistance via interference with the cofactor function of FV during Factor VIIIa inactivation. LA-causing anti-prothrombin antibodies interfere with the anticoagulant function of APC by preventing FV(a) cleavage. In Chapter 4, we further elaborated on the prothrombotic mechanisms of anti-β2GPI antibodies. We showed that these antibodies interfere with the anticoagulant function of tissue factor pathway inhibitor (TFPI) resulting in increased thrombin formation. In Chapter 5, we focused on LA in clinical settings. During the COVID-19 pandemic many patients with COVID-19 who were submitted to intensive care units (ICU) developed thrombosis. LA was frequently observed in these patients. We studied the association of LA with thrombosis in a cohort of COVID-19 patients admitted to ICU. We found high prevalence of LA and other antiphospholipid antibodies in these patients. And importantly, LA, as measured on admission to ICU, was strongly associated with thrombosis in critically ill COVID-19 patients, especially in patients <65 years of age. In Chapter 6, we discussed the interference of LA with international normalized ratio (INR). APS patients receive anticoagulant therapy with vitamin K antagonists (VKA) to prevent recurrent thrombosis. As the use of VKA imposes considerable bleeding risks, it requires strict monitoring with INR. It is known that LA can lead to elevated INR values with point-of-care-testing (POCT) devices which could result in inadequate adaptation of anticoagulant therapy. We found discrepancies between the standard POCT device used in the Netherlands (Coaguchek XS) and two laboratory-INR methods (Owren and Quick). We showed that elevated anti-β2GPI IgG antibodies are more frequently observed in patients with deviating POCT-INR results. In conclusion, we gained more insight into how anti-β2GPI and anti-prothrombin antibodies influence both procoagulant and anticoagulant pathways. The coming years will hopefully show more progress into the complete understanding of the thrombotic mechanism underlying APS together with the development of targeted therapy for patients with thrombotic APS


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