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Taking the next steps in unravelling TC-NER
No full textTranscription-coupled nucleotide excision repair (TC-NER) is a specialized DNA repair pathway that removes transcription-blocking lesions from active genes, thereby preventing cellular toxicity and maintaining transcription. TC-NER is initiated by RNA polymerase II stalling, which recruits proteins such as CSB, CSA, and UVSSA to orchestrate repair. While the molecular functions of these proteins have been studied, the precise mechanisms of initiation and regulation remained unclear. Recent advances, including structural insights and the discovery of new repair factors, have provided a more detailed understanding of TC-NER.Using a combination of live cell imaging, functional assays and proteomics approaches, this work uncovered new aspects of TC-NER dynamics, such as regulated chromatin association of CSB and its dependency on the CRL4CSA ubiquitin ligase complex. Novel protein interactors, including proteins involved in chromatin folding, were identified to be important for the removal of endogenous and UV damage, linking chromatin architecture to repair processes. Furthermore, the small protein DDA1 was characterized as a new component of the CRL4CSA complex, where it plays a crucial role in ubiquitylation events and lesion removal.Proximity-labeling experiments expanded the TC-NER interactome, identifying proteins that modulate CSB dynamics and transcription-coupled repair efficiency. Collectively, these findings broaden the understanding of TC-NER regulation, its connections to genome organization, and its implications for aging and disease, while opening new directions for future research.<br/
Noninvasive perioperative monitoring and gas exchange in pediatric anesthesia
No full textThis thesis explores the advancement of non-invasive monitoring in pediatric anesthesia, with a focus on improving gas exchange monitoring to enhance perioperative safety. It begins with a historical overview of anesthesiology, tracing its evolution from fundamental practices to a modern specialty emphasizing safety and monitoring. Technological milestones like pulse oximetry and capnography, along with global safety standards, have shaped current practices.Chapters 2 and 3 focus on non-invasive monitoring modalities. The thesis highlights the challenges of pediatric monitoring, including accuracy and applicability of current technologies. It validates transcutaneous CO₂ sensors as reliable during pediatric anesthesia, though oxygen sensors (tcPO₂) are only dependable for infants under six months.In Chapter 4, a clinical study on transcutaneous CO₂ monitoring during rigid bronchoscopies and microlaryngeal surgeries found no significant differences in ventilation outcomes, but spontaneous breathing led to lower CO₂ levels. These findings show clinical potential, though further refinement is needed.Chapters 5 and 6 critique oxygen management practices. An international survey revealed wide variability in oxygen use, with common intraoperative hyperoxemia. A retrospective analysis confirmed that 89% of pediatric patients experienced excessive oxygen levels, highlighting the need for structured oxygen protocols.Lastly, Chapter 7 introduces hyperspectral imaging as a tool for assessing bowel viability during neonatal surgery, demonstrating feasibility and potential for enhancing tissue perfusion assessment.Overall, the thesis underscores the importance of accurate, continuous, and non-invasive monitoring, and calls for standardized guidelines to improve pediatric anesthesia safety.<br/
A battle on two fronts:Pancreatic cancer during the Covid-19 pandemic
No full textPart I of this thesis focused on improving outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) and those undergoing pancreatic surgery.Chapter II introduced the Multi-Omics DEep Learning Prognosis correlated subtyping model (MODEL-P), designed to identify PDAC subtypes associated with survival outcomes. MODEL-P predicted prognosis more accurately than existing methods, such as the tumor marker Ca19.9, and may guide personalized treatment based on prognosis-related subtypes.Chapter III presented a nationwide retrospective study which investigated the value of extending mortality reporting after pancreatic surgery from the traditional 30-day period to 90 days. This study found that 90-day mortality more reliably captured complication-related deaths compared to the 30-day standard, which missed 30% of complication-related deaths. The findings suggested that adopting a 90-day mortality reporting timeframe would improve the accuracy and reliability of surgical audits and clinical trials.Chapters IV-VI examined postoperative complications, particularly pancreatic fistula (POPF), in relation to preoperative therapies. Chapter IV showed that preoperative chemoradiotherapy reduced the risk of POPF in patients undergoing pancreatoduodenectomy. Chapter V confirmed, through a systematic review and meta-analysis, that preoperative chemoradiotherapy was associated with a lower rate of grade B/C POPF compared to immediate surgery. Chapter VI, presented the FIBROPANC trial, in which high-dose stereotactic body radiotherapy (SBRT) was investigated in high-risk patients. While SBRT increased pancreatic tissue firmness, it did not reduce the POPF rate, suggesting that other interventions may be needed.Part II of this thesis focused on the challenges faced by PDAC patients during the coronavirus disease 2019 (COVID-19) pandemic. Chapter VIII assessed the immunogenicity and safety of COVID-19 vaccines in PDAC patients. The study found that PDAC patients had similar antibody responses to healthy controls after both priming and booster vaccinations. Chapter IX explored the immune transcriptome in postmortem lung biopsies, and found that mast cells contributed to the pathophysiology of COVID-19 pneumonitis. Chapter X identified immune changes in COVID-19 patients with pulmonary arterial thrombosis, suggesting that targeting IL-1 and IL-6 may reduce the risk of thrombosis in these patients.Chapter XI evaluated the antiviral effects of Rintatolimod in pancreatic cancer cells. The study found that Rintatolimod activated innate immune pathways and increased the expression of cytokines and angiogenesis-related genes. Chapter XII assessed infection control measures in a professional sports team, showing that regular testing and preventive protocols may prevent COVID-19 outbreaks. Finally, Chapter XIII discussed the risks of preventive SARS-CoV-2 testing, and underscored that early detection could lead to improper isolation periods for asymptomatic carriers.<br/
From population to individual:A data-driven approach for enhancing patient-centered decision-making in hand and wrist care
No full textCovid-19 vaccine induced immune responses in patients with kidney disease:a cellular perspective
No full textThis thesis investigates humoral and cellular immune responses to COVID-19 vaccination in patients with chronic kidney disease, dialysis patients, and kidney transplant recipients, who show reduced vaccine responsiveness due to immune impairment. The results highlight the critical role of T-cell immunity, particularly IL-2 and IL-21 responses and memory B cells, when antibody responses are weak, and demonstrate that repeated booster vaccinations can substantially enhance immune protection. These findings support personalized vaccination strategies to optimize protection in immunocompromised populations.<br/
Plague in progression:Natural course of Atherosclerosis among women and men
No full textAtherosclerosis is a slowly developing condition, and the rupture of unstable plaques is a major cause of clinical cardiovascular events. Whether a plaque is stable largely depends on its internal tissue composition. Using data from the Rotterdam Study, this thesis describes the natural progression of subclinical atherosclerosis in community-dwelling adults, identifies its risk factors and clinical outcomes.The findings show clear interactions among different plaque components. Stable features such as calcification may promote the development of unstable features, including intraplaque hemorrhage, thereby driving plaques toward a higher risk state. Lifestyle factors, including dietary fat intake, physical activity, and long-term blood pressure trajectory, were also found to influence the evolution of plaque components. In addition, this research demonstrates that silent manifestations of atherosclerosis, such as unrecognized myocardial infarction, are closely linked to underlying cardiovascular disease and show marked differences between women and men.Overall, this thesis deepens our understanding of the natural course of atherosclerosis and highlights the importance of early identification of high-risk plaque features and prevention of cardiovascular disease in the general population.<br/
“We’re in this Together”:Trauma-focused inpatient family treatment: An evaluation of the KINGS program
No full textFamilies affected by chronic adversity, trauma, and cumulative stressors often face problems that extend across generations. For these families, standard trauma-focused or parenting-focused interventions frequently prove insufficient, as safety concerns, complex symptom profiles, and unstable living conditions hinder sustained engagement and improvement. This dissertation examines KINGS (a Dutch acronym for Child IN Healhy System), an intensive inpatient trauma-focused family program designed to address such intertwined difficulties at the level of the whole family system.Using five complementary studies, the dissertation (1) maps international models of Shared Family Care, (2) describes the characteristics and histories of families entering KINGS, (3) documents the intervention elements applied in daily practice, and (4–5) analyses patterns of short-term individual change and longer-term family outcomes as reported across multiple time points.This dissertation contributes to the limited empirical literature on inpatient, trauma-informed family interventions and offers insights into how change unfolds in families with complex and multiple problems. The results underscore the importance of integrated, family-centered approaches and highlight the need for tailored post-program support to help families sustain progress in their home environments