Introduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases,... Show moreIntroduction Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1.Materials and methods This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies.Results 169 irAEs were experienced by 86/143 patients (137 grades 1–2, 32 grades 3–4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597).Conclusion The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction. Show less
De volledige titel van de scriptie is "Positie verkenner, functie regels: De haalbaarheid, vorm en inhoud van een regeling van de verkenningsfase in de kabinetsformatie". De scriptie is te... Show moreDe volledige titel van de scriptie is "Positie verkenner, functie regels: De haalbaarheid, vorm en inhoud van een regeling van de verkenningsfase in de kabinetsformatie". De scriptie is te raadplegen via NJB Blog: https://www.njb.nl/blogs/positie-van-de-verkenner/ Show less
Retinopathy of prematurity (ROP) is the most important cause of vision loss premature infants. With a continuous growth in this vulnerable population, the number of newborns at risk for severe,... Show moreRetinopathy of prematurity (ROP) is the most important cause of vision loss premature infants. With a continuous growth in this vulnerable population, the number of newborns at risk for severe, sight threatening ROP increases. In this thesis the results of the national Dutch inventory on risk factors, screening, treatment and sequelae of ROP are presented. The principal aims of the study were to determine characteristics of newborns who are at highest risk to develop severe ROP to assess quality of screening and treatment and to evaluate the national ROP guideline. Following these studies together with extensive cost-effectiveness analyses, the current Dutch ROP screening and treatment guideline was adapted and implemented in November 2023. The NEDROP 2 allowed for more stringent screening inclusion criteria, lowering the number of infants that need to undergo burdensome screening under the precondition that no severe ROP would be missed. Annually, this will lower the screening costs by nearly 60,000 euros. Show less
Protein posttranslational modifications by small ubiquitin-like modifiers (SUMOs) are critical for regulating a variety of cellular processes. Dysregulation of SUMOylation is increasingly... Show moreProtein posttranslational modifications by small ubiquitin-like modifiers (SUMOs) are critical for regulating a variety of cellular processes. Dysregulation of SUMOylation is increasingly associated with cancer and inhibitors that block SUMOylation are currently being explored as cancer treatment. We aimed to gain a better understanding of how the SUMO system governs the integrated network of nuclear signaling pathways, with a specific focus on genome maintenance. For this, we combined unbiased global mass spectrometry-based proteomics approaches with mechanistic follow-up studies. We found that the SUMO protease SENP6 maintains genome stability by ensuring the timely removal of SUMO chains on proteins involved in the response to DNA damage, affecting their localization, kinetics and nuclear condensation state. In addition, we found that noncovalent protein interactions with SUMOs mediated by SUMO-interaction motifs (SIMs) are also critical in maintaining genome stability, by facilitating the recruitment of DNA damage response proteins to the sites of damage. Lastly, we offer valuable new insights on noncovalent SUMO interactions by providing a comprehensive dataset of proteins that bind SUMO independently of the classical SUMO-SIM interaction. This suggests that the relevance of alternate modes of SUMO interactions is currently underestimated by the field and opens up new avenues for future research. Show less
Posttraumatic stress disorder (PTSD) is a psychological disorder that develops following exposure to perceived life-threatening trauma. Characteristic features include behavioral changes caused by... Show morePosttraumatic stress disorder (PTSD) is a psychological disorder that develops following exposure to perceived life-threatening trauma. Characteristic features include behavioral changes caused by heightened arousal, including fear and anxiety. Glucocorticoid receptor (GR) hypersensitivity, as defined by strong negative feedback, has been one of the most robust findings of altered HPA axis function in PTSD. In this thesis, we evaluated GR-related changes that were exposed to the three consecutive stressors of the single prolonged stress (SPS) animal model for PTSD. We tested the potential of the GR antagonist RU486 treatment in reversing these stress-induced effects. We found that GR antagonism can normalize some stress-induced parameters. We demonstrated that varying the timing of RU486 administration and evaluation gave different behavioral results and dynamics of gene expression, that revealed complex interactions between stress and RU486 over time. We also tested the GR sensitivity after administered the exogenous corticosterone. Our data suggest the enhanced stress responsiveness after SPS to moderate but not mild stressors and a sensitization of brain GR signaling that extends beyond direct negative feedback regulation. Lastly, we provide evidence for a role of β-arrestin-2 as a modulator of regulating amygdala activity in response to fear/anxious memory of PTSD. Show less
In this thesis, we have studied cell images from two types of cells, including pollen grains and the immune cells, neutrophils. These images are captured using a bright field microscope and a... Show moreIn this thesis, we have studied cell images from two types of cells, including pollen grains and the immune cells, neutrophils. These images are captured using a bright field microscope and a confocal microscope. We aim to analyze the insight in the understanding of the content of these images. In order to do these analyses, we need computational methods. The two main tasks are the classification of pollen images and the dynamic analysis of neutrophils through tracking in time-lapse sequences. In this study, we have demonstrated the use of deep learning methods for different kinds of cell imagery and shown the potential for future use while illustrating pitfalls, but also presenting efficient new algorithmic approaches. Show less
The circadian system has evolved to benefit the fitness of the organism. A properly functioning clock improves overall performance and promotes health. By gaining more knowledge about how the... Show moreThe circadian system has evolved to benefit the fitness of the organism. A properly functioning clock improves overall performance and promotes health. By gaining more knowledge about how the system works and responds to changes, therapies can be developed to promote the functioning of the circadian system. In this thesis, the response of the circadian system to changes in daylength (e.g. long summer days and short winter days was investigated. In addition the functioning of the circadian system with aging was investigated. This is relevant since aging is known to be accompanied by a weakening of the circadian system in humans, which has been associated with deterioration of a number of age-related conditions such as arteriosclerosis, type 2 diabetes and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In addition, a large proportion of the elderly will experience fragmentation of sleep, meaning that people have difficulty sleeping at night, while during the day they are very sleepy. Promoting the circadian rhythm with relatively simple interventions, such as correctly timed exposure to (day) light, physical activity and food intake can support the circadian system and promote general health. Show less
The thesis explores Ghanaian Sign Language (GSL), the national sign language of Ghana within urban deaf communities. Using historical, linguistic and ideological data, the research discovered GSL... Show moreThe thesis explores Ghanaian Sign Language (GSL), the national sign language of Ghana within urban deaf communities. Using historical, linguistic and ideological data, the research discovered GSL is a cover term for various signing forms (e.g., ENGLISH, BROKEN, LOCAL). Tracing GSL roots back to the introduction of American Sign Language (ASL) in 1957 by an American missionary, this research unveils a lasting connection between ASL signs and GSL. The thesis presents GSL's historical journey amidst significant challenges such as discrimination and sign language bans (oralism). It sheds light on signers' resilience and contributions to GSL's evolution. This exploration also highlights the emergence of local signing varieties (e.g., school-lects) alongside foreign-based signing forms within a triglossic framework that resembles the distribution and use of spoken languages in Ghana and other African countries. The thesis unearths lexical relationships, examining variants of GSL’s connections not only with ASL but also with locally evolved village sign languages like Adamorobe SL and Nanabin SL. Moreover, the study investigates the expression of Size and Shape Specifiers (SASS) within GSL and Ghanaian gestural communication, offering valuable insights into the susceptibility of sign languages to their gestural environment throughout their life spans. Beyond linguistics, the book explores social landscapes and language ideologies of sign languages in the Ghanaian urban deaf communities. It reveals a pluridimensional continuum of GSL usage and the interplay between high- and low-prestige variants. As an invaluable resource, this thesis enhances the understanding of African national sign languages, providing essential insights for researchers, teachers, and learners Show less
Silva, A.B. da; Ramiro, S.; Boel, A.; Lunteren, M. van; Marques, M.L.; Sande, M. van de; ... ; Gaalen, F. van 2024
Objective: The objective of this study was to compare health-related quality of life (HRQoL) and work productivity in axial SpA (axSpA) and nonaxSpA patients with chronic back pain of <2 years.... Show moreObjective: The objective of this study was to compare health-related quality of life (HRQoL) and work productivity in axial SpA (axSpA) and nonaxSpA patients with chronic back pain of <2 years. Methods: Baseline and 2-year data for patients included in the SPondyloArthritis Caught Early cohort were analysed. HRQoL was assessed by the physical (PCS) and mental component summary (MCS) scores of the 36-Item Short-Form Health Survey, and presenteeism, absenteeism, work productivity loss (WPL) and activity impairment (AI) by the Work Productivity and Activity Impairment questionnaire. Linear or zero-inflated negative binomial regression was conducted to compare 2-year outcomes between groups (axSpA and non-axSpA), adjusting for the baseline value, sex, age and use of NSAIDs. Results: There were 265 axSpA and 108 non-axSpA patients: males 52% vs 26%, mean age 29 vs 31 years, respectively. At baseline, nonaxSpA patients showed worse PCS (mean 28.6 axSpA vs 26.6 non-axSpA), presenteeism (31.1% vs 37.3%), absenteeism (8.2% vs 10.3%), WPL (34.7% vs 44.1%) and AI (39.6% vs 48.5%). MCS was not impaired in either group. After 2 years, PCS, presenteeism, WPL and AI significantly improved in both groups; absenteeism only improved in axSpA. In multivariable analysis, axSpA (vs non-axSpA) was associated with 22% less WPL [incidence rate ratio (95% CI): 0.78 (0.62; 0.98)] and 18% less AI [0.82 (0.69; 0.97)]. Conclusion: HRQoL and work productivity are more impaired in non-axSpA (vs axSpA) at baseline and also after 2 years. Although most outcomes improve in both groups, axSpA is associated with larger reductions in WPL and AI. Show less
Both underuse as well as overuse of medical services is associated with poor outcomes in healthcare. Underuse includes the failure to use effective medical interventions, where overuse refers to... Show moreBoth underuse as well as overuse of medical services is associated with poor outcomes in healthcare. Underuse includes the failure to use effective medical interventions, where overuse refers to providing low value medical services. This could be described as services that are more likely to cause harm, waste resources or could lead to unnecessary healthcare costs. To improve quality of care and to create a sustainable healthcare system, it is essential to prevent underuse of effective medical care and to reduce the use of low value care by implementation and de-implementation initiatives. Implementation can be described as the planned process to introduce or to improve the use of medical interventions with the aim that those medical interventions are given a structural place within care practice. In de-implementation, the use of low value medical interventions is reduced or stopped on a structural basis in a planned process. The aim of this thesis was to extend the knowledge on effective strategies for de-implementation of low value care and the implementation of underused medical services in orthopedic surgery as well as in nursing practice. Show less
In this thesis, we identified several novel modulators of TGF-β/SMAD signaling. We studied the role of these modulators in TGF-β-induced EMT and migration in breast and lung cancer cells, and... Show moreIn this thesis, we identified several novel modulators of TGF-β/SMAD signaling. We studied the role of these modulators in TGF-β-induced EMT and migration in breast and lung cancer cells, and elucidated the mechanisms by which they fine-tune TGF-β/SMAD signaling transduction. These studies contribute to a better understanding of the regulatory networks of TGF-β signaling and may offer new therapeutic potentials to target TGF-β signaling in patients with breast or lung cancer. Show less
This dissertation is a call to place the health of adults with autistic traits and autism-caregivers higher on the agenda of clinicians, researchers, policymakers, and autistic adults and autism... Show moreThis dissertation is a call to place the health of adults with autistic traits and autism-caregivers higher on the agenda of clinicians, researchers, policymakers, and autistic adults and autism-caregivers themselves. Primarily, clinicians should be educated about the increased health risks in autistic adults and autism-caregivers, in order to be able to prevent or recognize these comorbidities timely. This is relevant because of the higher prevalence of both metabolic syndrome and gastrointestinal symptoms in adults from the general population with higher levels of autistic traits, as shown in this dissertation. The associations we found between biopsychosocial factors and respectively metabolic syndrome and gastrointestinal symptoms ask for more psychiatric and somatic integrated care for autistic adults. Future research could use the associations we found between the biopsychosocial model and autistic traits to develop preventive interventions specifically targeted for adults with autism (or higher levels of autistic traits). To make sure future preventive measures and the treatment of physical health problems are effective for this target population to improve their health, barriers in the healthcare for autistic people should be reduced. Therefore, this dissertation also offers recommendations for improvement of primary care, the gatekeeper of adequate healthcare for autistic adults. Show less
Rapid technological breakthroughs originating from fundamental microbiology research have yielded novel genome engineering tools that greatly facilitate our ability to modify specific genomic... Show moreRapid technological breakthroughs originating from fundamental microbiology research have yielded novel genome engineering tools that greatly facilitate our ability to modify specific genomic sequences in living cells and organisms. As a corollary, these technologies are also starting to permeate the realm of medicine when applied as a form of “genomic surgery”. These genetic therapies aim at tacking the root cause of human pathologies, inherited or acquired, by correcting or modulating the genetic content or expression, respectively, present in target cells, tissues and organs. To this end, delivery vehicles capable of introducing, in an efficient and safe manner, the increasingly sophisticated (epi)genome editing reagents are in demand, especially when considering in vivo genetic therapies. The research presented in this thesis reveals the feasibility and utility of using regular and high-specificity nicking RGNs for achieving efficient and accurate genetic modification of human cells involving targeted gene knockouts and knock-ins. Moreover, it establishes the suitability of the HC-AdV platform for the versatile investigation of prime editing systems. Finally, this thesis establishes causal relationships between specific chromatin states and the activities and fidelities attained by base editing and prime editing complexes in human cells, which has consequences for their further development and optimal deployment. Show less
Vascular diseases pose a significant burden on society, mainly due to the lack of effective treatment methods. A major reason for this is the shortcomings of current preclinical model systems. In... Show moreVascular diseases pose a significant burden on society, mainly due to the lack of effective treatment methods. A major reason for this is the shortcomings of current preclinical model systems. In this study, we have taken steps toward developing a more complex and relevant model system for (brain) blood vessels to address this issue. We used human induced pluripotent stem cells (hiPSCs) in the lab as a cellular source to generate the different types of cells needed for stable blood vessels. These cells were then combined in 3D microscopic culture environments (so-called vessel-on-chip systems) to closely mimic physiological conditions. Using this model, we were able to demonstrate specific abnormalities in a hereditary vascular disease, which was not possible with more 'traditional' culture methods. Additionally, we included brain cells to better investigate brain-specific disorders in the future. This work lays the essential foundation for a better understanding and treatment of complex vascular diseases, while potentially reducing the number of animal models needed. Show less
Identifying, targeting, and evaluating the consequences of Acquired Brain Injury (ABI) in young individuals (4-25 years old) are essential elements of medical specialist rehabilitation care for... Show moreIdentifying, targeting, and evaluating the consequences of Acquired Brain Injury (ABI) in young individuals (4-25 years old) are essential elements of medical specialist rehabilitation care for this group. Several knowledge gaps regarding the occurrence and severity of consequences and the delivery of rehabilitation existed.This thesis enhanced the understanding of ABI-related consequences and aimed to optimize rehabilitation care provided to young Dutch individuals with ABI.Section 1 of this thesis investigated the severity and course over 2 years of persisting ABI-related problems in young people with ABI and their families. In this cohort, many problems were found in the domains of Health-related Quality of Life (HRQoL), fatigue, participation, and family impact at time of referral to rehabilitation and these problems tended to persist over time.In section 2, the structure and process of rehabilitation for young patients with ABI across Dutch rehabilitation centers and the development of a national consensus-based framework for clinical practice, including preferred assessments, interventions, and psychoeducation, for young people with ABI was described.This thesis emphasizes the importance of a holistic approach to rehabilitation and lays the foundation for future initiatives aiming to further optimize rehabilitation treatment for young individuals with ABI and their families. Show less
A crucial step of the radiotherapy workflow is the segmentation of the tumors. Currently, this is done manually, which is very time-consuming and therefore puts a lot of burden in the clinical... Show moreA crucial step of the radiotherapy workflow is the segmentation of the tumors. Currently, this is done manually, which is very time-consuming and therefore puts a lot of burden in the clinical workflow. Deep learning techniques, currently state of the art for computer vision tasks, are a potential solution to speed up the process. Even though they have been applied to segment other structures of interest for the RT workflow, they still underperform for the case of tumors. Furthermore, there is limited research in automatic segmentation of tumors for the particular case of MRI, even though this imaging modality presents better soft tissue contrast and it is therefore ideal to visualize tumors. The goal of this thesis was to develop automatic segmentation techniques for tumors on MRI images that deliver clinically acceptable segmentations. The different automatic segmentation methods were applied in two different tasks: the automatic segmentation of the oropharyngeal primary tumor in multiparametric diagnostic MRI images and the automatic segmentation of the cervical cancer gross tumor volume in the MRI images of the brachytherapy treatment images. Show less
One of the key discoveries in exoplanet research over the past decade is the abundance of small planets in our Milky Way. Despite their high numbers, our understanding of their atmospheres remains... Show moreOne of the key discoveries in exoplanet research over the past decade is the abundance of small planets in our Milky Way. Despite their high numbers, our understanding of their atmospheres remains limited, and it is unknown if they possess atmospheres at all. Predicting the presence of an atmosphere on small planets is challenging due to factors like atmospheric escape and volcanism. Reliable determination requires direct study of thermal emission, reflected light, or transmission spectrum. With the launch of the JWST in late 2021, we gained unprecedented access to detailed observations of rocky exoplanets, enabling the search for atmospheres composed of carbon dioxide, oxygen, and nitrogen on temperate rocky worlds. My thesis summarizes my work on atmospheric characterization of small, rocky exoplanets using space-based telescopes such as Spitzer, Hubble, and JWST. I have studied a wide temperature range, from lava worlds with atmospheres of outgassed rock vapor at over 2000 Kelvin, to terrestrial planets with temperatures around 400 Kelvin, similar to our inner solar system. I characterized the surfaces and atmospheres of exoplanets like K2-141 b and TRAPPIST-1 c to ultimately learn about their surfaces and the conditions under which rocky planets can retain atmospheres. Show less
