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Decoding Hematopoietic-Stromal Interactions in MPN:The Role of Hedgehog Signaling and Inflammation
No full textThis research highlights the complex, cell type specific roles of hedgehog signaling as well as its links to inflammation in the development of Myeloproliferative Neoplasm (MPN). We show that in hematopoietic cells, the GLI1 transcription factor is activated via non-canonical, inflammation linked pathways, promoting clonal expansion and further inflammatory cytokine secretion driving critical disease phenotype. Additionally, we describe how in non-hematopoietic stromal cells, canonical GLI2 activation drives fibrosis. In both cases, inflammation emerges as a central disease driving mechanism.Targeting GLI1, GLI2, and CXCL4, effectively reduces fibrosis and inflammatory signalling, suggesting a path forward beyond the current first line treatment option of JAK inhibitor monotherapy. Our research also suggests that blocking PDGFRβ-driven inflammation could prevent disease progression and secondary malignancies.Thus, future MPN treatment strategies should take combinatorial strategies into consideration, guided by biomarkers such as GLI1 expression and circulating inflammatory cytokines. Overall, this mechanism-based approach offers new hope for more effective, disease-modifying therapies in MPN patients.<br/
Monodisperse microbubbles for controlled drug delivery
No full textThis thesis investigates the production and therapeutic application of monodispersephospholipid-coated microbubbles for ultrasound-mediated drug delivery. The firstpart (Chapters 2–5) focuses on developing reliable production methods, physical characterization,and acoustic evaluation of monodisperse microbubbles generated throughmicrofluidic techniques. The second part (Chapters 6–8) explores the biological interactionsand underlying mechanisms of microbubble-mediated drug delivery in both invitro and in vivo models
From evidence synthesis to population-based research:Pharmaco-epidemiological studies on Arteriosclerosis
No full textThis thesis aimed to explore how different drugs impact arteriosclerosis, specifically by looking at how they affect arterial calcification. In the first chapter, the research focused on statins, a type of cholesterol-lowering medication, and synthesized prior evidence. A review of 41 studies showed that observational studies linked statin use to higher levels of coronary artery calcification, although these findings were prone to confounding by indication. The effect derived from randomized trials didn’t reach significance, but had a relatively short follow-up period. A second review of 9 cohort studies focused on patients with type 2 diabetes and found that statin use lowered the risk of major cardiovascular events and death, especially in people with higher cholesterol levels, although the modification in effects across cholesterol levels was not statistically significant.In the second part of the thesis, the effects of drugs and biomarkers on arterial calcification were examined using data from the long-term Rotterdam Study cohort of the general population. Prolonged statin use (mean 8 years) was associated with increased calcification in arteries, particularly in the coronary and aortic arteries. Bisphosphonates, commonly used to treat osteoporosis, also have pharmacological potential to affect calcification in arteries. We found that longer use (mean 4.9 years) linked to higher calcification, especially in the coronary arteries, with a dose gradient. Additionally, two biomarkers, VWF and ADAMTS13, were studied for their relationship with arterial calcification as a marker of atherosclerosis. Higher levels of ADAMTS13 were linked to less calcification, suggesting it may have a protective role, while VWF didn’t show a clear effect. The combined effect of these biomarkers appeared to have a synergistic link to higher arterial calcification and, by extension, atherosclerosis.<br/
Voices from a messy practice:Conversation with Jeannette Pols
No full textVoordat we op het Malieveld gaan demonstreren tegen de bezuinigingen in het hoger onderwijs en onderzoek, spreek ik met Jeannette Pols, hoogleraar antropologie van de alledaagse ethiek in de gezondheidszorg aan de Universiteit van Amsterdam en Amsterdam UMC. In haar boek Reinventing the Good Life: An empirical contribution to the philosophy of care betoogt ze dat ideeën over het goede leven en goed bestuur door de opkomst van de sociale en economische wetenschappen zijn getransformeerd tot algemene en rationeel hanteerbare begrippen
Microbial safety in gastrointestinal endoscopy:Risk factors, surveillance, and interventions
No full textEndoscopes are essential for the diagnosis and treatment of gastrointestinal conditions but also pose a potential risk of contamination and infection. This thesis examines the frequency, causes, risks, and potential solutions for endoscope contamination, aiming to improve patient safety.International outbreaks have shown that particularly duodenoscopes, used in endoscopic retrograde cholangiopancreatography (ERCP) procedures, can become contaminated and transmit pathogens. This thesis demonstrates that infections from contaminated duodenoscopes also occur outside of outbreak situations. The risk appears low (<0.9%), but these infections are difficult to recognize, necessitating further research.Additionally, the prevalence of multidrug-resistant organisms (MDROs) among ERCP patients was investigated, which is about 11% in the Netherlands. However, the reliability of rectal swabs as a screening method proved to be limited. The presence of MDROs in the duodenum was therefore overestimated, potentially leading to unnecessary preventive measures.The frequency of duodenoscope contamination with oral or gastrointestinal flora ranged from 14% to 48% in retrospective analyses and was 21% in a prospective study. The biopsy and suction channels were the most frequently contaminated. The duration of manual pre-cleaning was found to be important, with manual cleaning times shorter than five minutes significantly increasing the risk of contamination. Interventions such as the introduction of a new endoscope cleaning brush (Endoss Push and Pull) and an automatic water-based cleaning system (Aquatyphoon) reduced contamination frequency.Finally, this thesis shows that culture methods are not always reliable, and contamination of duodenoscopes sometimes goes unnoticed. Biofilm plays a central role in this process. An innovative mass spectrometric method is described as a potential future technique for biofilm detection in endoscopes.<br/
Historisch besef en koloniaal verleden:Veranderende interpretaties in het onderwijs
No full textIn 2020 zei David Van Reybrouck in een interview naar aanleiding van zijn boek Revolusi: ‘Ik wist niet dat in grote delen van de Nederlandse samenleving zo weinig historisch besef is. Ik hoop dat mijn boek bijdraagt aan inzicht, en ook leerkrachten bereikt.’ Het is scherpe kritiek op het historisch besef van Nederlanders over het kolonialisme en de onafhankelijkheidsstrijd van Indonesië. Maar wat bedoelt Van Reybrouck precies met historisch besef
Exploring vascular aging in ERCC1-deficient mice and progressing toward human vessel-on-a-chip models
No full textCardiovascular diseases are the number one cause of death globally. The most important determinant of cardiovascular health is a person’s age. Aging results in structural changes and functional decline of the cardiovascular system. DNA damage is an important contributor to the aging process, and mice with a DNA repair defect caused by Ercc1 deficiency display hypertension, vascular stiffening, and loss of vasomotor control. In this thesis we investigated RAS alterations by assessing intrarenal renin activity in Ercc1Δ/− mice using the renin-activated, near-infrared fluorescent probe ReninSense680™. Furthermore, we aimed to characterize vascular aging in mice with hampered ERCC1 function. Building on these insights, we further examined the calcification potential of VSMCs with an ERCC1 mutation and investigated the molecular mechanisms underlying the effects of dietary restriction (DR), a well-known anti-aging intervention, on vascular aging.<br/
Self-management in solid organ transplantation:From measurement to nurse-led intervention
No full textOrgan transplantation is the preferred treatment performed in cases of end-stage organ failure. Statistics from the Dutch Transplant Foundation show that in 2023, 1434 patients in the Netherlands received an organ. The majority of these were kidney transplants (71%). Survival rates and graft survival rates have improved in the past decades (1-3). Yet organ transplant recipients can encounter various challenges, such as consistently taking medication to prevent rejection, as well as dietary restrictions or anxiety and depression. Not all people are able to deal with these challenges, which can negatively impact their quality of life. This requires attention from both the healthcare professional and the patient on how to cope with living with an organ, as quality of life is a valuable indicator for the relative success of an organ transplantation (4)
Association of biomarkers with acute ischemic stroke:Clinical and radiological outcomes
No full textIn this thesis, I will describe studies on the association between hemostatic biomarkersin patients included in the MR CLEAN-NOIV trial, and NETs in patients included in theMR CLEAN-MED trial, and clinical and radiological outcomes post-EVT.In chapter 2, we present a review of the studies on the association of hemostasisand NETs with the clinical and radiological outcomes of AIS patients post-treatmentto select the most relevant biomarkers for the CONTRAST trials; in chapter 3, weinvestigated the association of primary and secondary hemostasis biomarkers withAIS outcome in patients undergoing thrombectomy, with or without thrombolytics;in chapter 4, we study the association between coagulation activity and clinical andimaging outcomes in AIS patients undergoing EVT, with or without thrombolytics; inchapter 5, we examine the association of fibrinolysis with AIS outcomes in patientsundergoing thrombectomy and assess whether additional administration of r-tPAmodifies these outcomes; in chapter 6, we study the association of NETs markers withclinical and radiological outcomes in patients with AIS undergoing thrombectomy andevaluate whether heparin treatment modifies these outcomes; and in chapter 7, weinvestigate the level of anticoagulation and its impact on outcomes in patients receivingheparin during EVT treatment
From evidence synthesis to population-based research:Pharmaco-epidemiological studies on Arteriosclerosis
No full textThis thesis aimed to explore how different drugs impact arteriosclerosis, specifically by looking at how they affect arterial calcification. In the first chapter, the research focused on statins, a type of cholesterol-lowering medication, and synthesized prior evidence. A review of 41 studies showed that observational studies linked statin use to higher levels of coronary artery calcification, although these findings were prone to confounding by indication. The effect derived from randomized trials didn’t reach significance, but had a relatively short follow-up period. A second review of 9 cohort studies focused on patients with type 2 diabetes and found that statin use lowered the risk of major cardiovascular events and death, especially in people with higher cholesterol levels, although the modification in effects across cholesterol levels was not statistically significant.In the second part of the thesis, the effects of drugs and biomarkers on arterial calcification were examined using data from the long-term Rotterdam Study cohort of the general population. Prolonged statin use (mean 8 years) was associated with increased calcification in arteries, particularly in the coronary and aortic arteries. Bisphosphonates, commonly used to treat osteoporosis, also have pharmacological potential to affect calcification in arteries. We found that longer use (mean 4.9 years) linked to higher calcification, especially in the coronary arteries, with a dose gradient. Additionally, two biomarkers, VWF and ADAMTS13, were studied for their relationship with arterial calcification as a marker of atherosclerosis. Higher levels of ADAMTS13 were linked to less calcification, suggesting it may have a protective role, while VWF didn’t show a clear effect. The combined effect of these biomarkers appeared to have a synergistic link to higher arterial calcification and, by extension, atherosclerosis.<br/