In dit proefschrift worden verschillende methodes onderzocht en uitgevoerd om de ovariële functie te sparen bij vrouwen die een behandeling moeten ondergaan als chemotherapie en/ of radiotherapie,... Show moreIn dit proefschrift worden verschillende methodes onderzocht en uitgevoerd om de ovariële functie te sparen bij vrouwen die een behandeling moeten ondergaan als chemotherapie en/ of radiotherapie, die de ovaria kunnen aantasten.Een behandeling is het invriezen van ovariumweefsel en indien een vrouw daadwerkelijk in de overgang is geraakt kan dit weefsel weer in haar eigen lichaam terug geplaatst worden. Het percentage vrouwen dat na ovarium cryopreservatie vervroegd in de overgang komt, is laag. Wij adviseren daarom enkel ovarium cryopreservatie aan te bieden aan vrouwen die door een gonadotoxische behandeling een hoog risico hebben op het ontwikkelen van vervroegde overgang. De autotransplantatie zelf is een effectieve methode met 86% herstel van ovariele functie en 57% levendgeborenen. Het risico van uitzaaiingen van de primaire ziekte in de ovaria bij patiënten met kanker is in onze studie zeer klein gebleken en is deze techniek dus een veilige methode.Ovariumtranspositie voorafgaand aan radiotherapie op het bekken is een veilige en zinvolle behandeling ter preventie van vervroegde overgang en zou standaard aangeboden moeten worden bij vrouwen tot 35 jaar.Met betrekking tot de reeds geaccepteerde techniek van vitrificatie dient men zicht te realiseren, dat alvorens deze techniek te implementeren, er een steile leercurve is. Show less
The clandestine revolutionary politics for women was marked by an environment in which gender roles and expectations were constantly challenged and reproduced as a result of the extraordinary... Show moreThe clandestine revolutionary politics for women was marked by an environment in which gender roles and expectations were constantly challenged and reproduced as a result of the extraordinary conditions under which they had to live and operate. These conditions were not stable but evolved and transformed in a dynamic environment in which not only various political actors were involved and interacted, but also the repercussions of their actions were influential on various levels. This study claims that, what the women involved in the clandestine revolutionary movements in Turkey and Iran in the 1970s experienced at the micro level was directly related to and influenced by both the macro level developments and political settings, and the meso level processes and mechanisms. Instead of holding only certain characteristics of the regimes, societies, or organizations responsible for the character of the women’s experiences, this study argues that causal mechanisms which played a significant role in the radicalization processes of the leftist movements in Turkey and Iran could also help us account for the similarities and differences between the women’s experiences in the two cases. Show less
In 1686, the French Jesuit and writer René Rapin wrote his treatise Du grand ou du sublime, in which he proclaimed French king Louis XIV as being the most sublime person. To do this, he used the... Show moreIn 1686, the French Jesuit and writer René Rapin wrote his treatise Du grand ou du sublime, in which he proclaimed French king Louis XIV as being the most sublime person. To do this, he used the concept of 'le sublime', a notion Rapin derived from the Greek classical writer Longinus. With his book, Rapin actually builds on an older tradition: writers had been using an elevated rhetoric to write about Louis XIV for many decades. In this discourse, architecture played a key factor. Writers recognized the overwhelming potential of the king's buildings and future projects, and also employed architectural metaphors and transcendent fictions to try and elevate the monarch. Ultimately, however, all of these works and projects - like Rapin's claim - proved very problematic. Firstly, the rhetoric of the sublime used to evoke the effect of sublimity has always been problematic, since it relies on an interplay between opposite extremes, which are highly unstable. Secondly, when attempting to establish the king himself as sublime, writers were confronted with the far-reaching implications of this claim. The sublime is not only an extreme notion but also a highly subjective one. It cannot be asserted, nor can it be wielded. Show less
Inactivating mutations in BRCA1 or BRCA2 genes predispose to several types of cancer. Owing to their roles in maintaining genomic stability, lack of BRCA1/2 results in DNA damage repair defects, a... Show moreInactivating mutations in BRCA1 or BRCA2 genes predispose to several types of cancer. Owing to their roles in maintaining genomic stability, lack of BRCA1/2 results in DNA damage repair defects, a vulnerability that can be exploited therapeutically by the inhibition of poly(ADPribose) polymerase 1 (PARP1). Unfortunately, clinical benefit of PARPi therapy is often limited by emerging drug resistance. Identification of PARPi resistance mechanisms is therefore crucial to improve the clinical outcome and design strategies that would ultimately prevent or target resistant tumors.The use of genetically engineered mouse models (GEMMs) of BRCA1/2-associated breastcancer in this work has allowed us to model PARPi resistance in vivo in well-defined genetic contexts. By combining high-throughput genetic screens, multiple omics analyses and functional assays, we identified several factors of PARPi resistance and explained their role in therapy failure. Moreover, we established a new tumor-derived organoid system thatenables robust in vivo validation of putative drug resistance factors. Finally, work described in this thesis has advanced our understanding of basic biological processes involved in DNA damage signaling and repair. Show less
The Open Society and Its Animals is an interdisciplinary study centred on the political and legal position of animals in liberal democracies. With due concern for both animals and the... Show moreThe Open Society and Its Animals is an interdisciplinary study centred on the political and legal position of animals in liberal democracies. With due concern for both animals and the sustainability of liberal democracies, The Open Society and Its Animals seeks to redefine animals’ political-legal position in the most successful political model of our time: the liberal democracy.The dual focus on both animals and the open society is reflected in the book’s main research question: Should the fundamental structures of liberal democracies reflect the fact that many non-human animals are individuals with interests, and is this possible without undermining or destabilizing their institutions? The first, normative, stage of the investigation asks whether the fact that many animals have interests should have consequences for the fundamental structures of liberal democracies, and if so, what criteria the new political-legal position of animals should meet (‘enfranchisement criteria’). The second stage of the investigation involves an inquiry into the current political-legal position of non-human animals in liberal democracies, the extent to which this position meets the just mentioned enfranchisement criteria, and how this position could possibly be improved. Show less
This study explores long-term landscape transformations of the Fort-Liberté region, Haiti. By using a landscaped biography approach, this research aims to understand the substantial developments... Show moreThis study explores long-term landscape transformations of the Fort-Liberté region, Haiti. By using a landscaped biography approach, this research aims to understand the substantial developments of the region, from the Amerindian occupation, through the Spanish colonization, to the French colonial period. The study of the transformation of the landscape in the longue-durée suggests that activities of cultural groups are considered as events that were connected to each other, not just as superposed layers or isolated events. The archaeological sites dispersed in the natural environment express the idea of a complex palimpsest of the region’s history. This study of the Haitian cultural landscape has proposed to take into account the multi-layered nature of the landscape in order to avoid the dichotomy between pre-colonial and colonial in this context of long-term landscape transformation Show less
The subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known... Show moreThe subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness. One of the biggest risk factors for glaucoma is elevated eye pressure. Our study found that glaucoma may in fact be an autoimmune disorder. We found that the body’s own T cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore these T cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria that normally live in our body. This opens a new approach to prevent and treat glaucoma. Currently most treatments focus on lowering eye pressure. However, in many patients, the disease worsens even after intraocular pressure returns to normal. We showed that when we blocked these autoreactive T cells in the eye, not only does it diminish the loss of retinal ganglion cells and axons, but it also preserves retinal function. Show less
Morphometric and morphological differences have been used extensively in the past to study domestication of the wolf and the origin of dogs. Certainly before genetic testing was performed, these... Show moreMorphometric and morphological differences have been used extensively in the past to study domestication of the wolf and the origin of dogs. Certainly before genetic testing was performed, these methods were the only means to diverge both groups. But still now, when aDNA cannot be extracted, morphometry and morphology are still important study methods to discern between wolves and dogs.Many of the historically claimed differences were based on studying rather low numbers of Specimens, and on comparisons with genetically isolated groups of dogs or breeds that had anatomical variants which diverge from the mean. This led to several claimed differences that needed rigorous re-evaluated, by investigating larger groups of specimens, both dogs and wolves, and more importantly, and if possible, Pleistocene wolves and the oldest archaeological dogs.We re-evaluated all important morphological and morphometric criteria published in the literature. Most are related to oral, mandibular and skull differences, but also difference in stature was reported. From all criteria we re-tested very few proved to be valuable. And those that show a difference, can often only be used to a limited extend, as only the extremes of these criteria are non-overlapping between groups. Show less
This dissertation consists of five articles and focuses on five cases of deception, all presented and exposed in early modern London: The Originall of Idolatries (1624), Alexander Bendo’s... Show moreThis dissertation consists of five articles and focuses on five cases of deception, all presented and exposed in early modern London: The Originall of Idolatries (1624), Alexander Bendo’s mountebank handbill (1676), George Psalmanazar’s An Historical and Geographical Description of Formosa (1704), the case of Mary Toft (1726) and the Great Bottle Hoax (1749). These are all examples of creative forgery, fakes without a prototype, that were created to be woven into the fabric of reality. The articles discuss the cases’ dynamics of persuasion and response within their respective cultural contexts but they also explore the wider implications of the five cases and what they can tell us about the perception and role of forgery in early modern culture. Why did early modern illusionist artists and playwrights explicitly compare their work to this kind of deception? How did forgery contribute to the development of the distinction between fiction and scholarship? And what can discussions of newly exposed forgeries tell us about the cultural negotiation of the concepts of reality, authenticity and originality in early modern England? Show less
We developed an easy and semi-automated way to collect large numbers of cluster headache patients for large scale genetic-epidemiologic studies which we called the LUCA program. Cluster headache is... Show moreWe developed an easy and semi-automated way to collect large numbers of cluster headache patients for large scale genetic-epidemiologic studies which we called the LUCA program. Cluster headache is associated with three times higher odds for lifetime depression compared to controls. About one third of cluster headache patients report allodynia during attacks. The term cluster-tic should be avoided as it, incorrectly, suggests a separate clinically entity, with an innate pathophysiological mechanism and treatment. Cluster headache and epilepsy are comorbid disorders which supports the hypothesis that cortical hyperexcitability may play a role in cluster headache. The ICON study will determine if occipital nerve stimulation is an effective preventive treatment for patients suffering medically intractable chronic cluster headache. Show less
When observing star-forming galaxies, we are not only seeing stellar light, but we also see how this interacts with galactic gas and dust. This thesis contains studies of the stellar, nebular and... Show moreWhen observing star-forming galaxies, we are not only seeing stellar light, but we also see how this interacts with galactic gas and dust. This thesis contains studies of the stellar, nebular and dust properties of low mass star-forming galaxies. We analyse data from the first statistical sample of low mass galaxies with stellar masses down to 10^7 solar masses, and investigate the emission from the stellar populations and their impact on and properties of the ionised surrounding gaseous nebulae, in order to understand the amount of ionising photons that are produced and the fraction of these that can escape from the galaxies. Since the stellar masses in low-mass systems may be stochastically sampled, we predict the influence of this on their nebular emission lies, and in particular on the derivation of their gas metallicity (the abundances of elements heavier than hydrogen and helium in the gas). To interpret observations of galaxies correctly, it is important to know the amount of interstellar dust grains, and its impact on the stellar and nebular light. We therefore finalise this thesis with a new method to derive dust properties in star-forming galaxies. Show less
In this thesis, I aimed at decoding the role of SUMO in the DNA damage repair pathway. The SUMO system is believed to be involved in this process at several levels. I focused on the most inevitable... Show moreIn this thesis, I aimed at decoding the role of SUMO in the DNA damage repair pathway. The SUMO system is believed to be involved in this process at several levels. I focused on the most inevitable DNA obstacle causing DNA replication stress, and the cellular roles of SUMOylation in repairing DNA replication stress caused DNA damage. Post-translational modifications are essential regulators of proteins. PTMs do not only play their roles solo but extensively interact with each other. Our knowledge about proteins modified by a combination of SUMO and ubiquitin, SUMO and phosphate and crosstalk between them is quite limited. This thesis also aimed at deciphering the crosstalk between SUMOylation and phosphorylation and ubiquitination during the DNA damage response and searching for indirect and direct targets for the human STUbL RNF4, which mediates the ubiquitination of SUMOylated target proteins. Lastly, we adopted the strategy described for SUMO and introduced His10-tagged UFM-1-K0 to identify UFM-1 acceptor lysines. We identified and confirmed RPL26 as a key UFM1 target and further confirmed that the UFMylated form of RPL26 can efficiently interact with the Signal Recognition Particle Receptor, implicating that UFMylation could regulate protein transfer to the Endoplasmic Reticulum. Show less
Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. Show less
Studies in this thesis were performed in a secondary care cohort of patients with hand osteoarthritis. Several factors were investigated for their association with disease status and disease... Show moreStudies in this thesis were performed in a secondary care cohort of patients with hand osteoarthritis. Several factors were investigated for their association with disease status and disease progression after two years. These factors included comorbidity, illness perceptions and MRI-defined inflammatory features such as bone marrow lesions, synovitis and joint effusion. In the MRI studies we found that these MRI-features have a clinically relevant role for their association with pain (at the same moment and after two years) and progression of radiographic damage after two years. In the second part of this thesis we evaluated the clinimetric properties of two new instruments: self-reported painful joint count and semi-automatic joint space width measurements. Show less
The thesis has been an attempt to make sense of the political discourse in Kashmir from the early 1940s till the emergence of the popular uprising in the Valley towards the late 1980s. The thesis... Show moreThe thesis has been an attempt to make sense of the political discourse in Kashmir from the early 1940s till the emergence of the popular uprising in the Valley towards the late 1980s. The thesis has tried to underscore the fragmented nature of the political in Kashmir, and the implications it has had on the politics of the region, particularly on the politics of rai-shumari (self determination) and aazadi. These inner fragments or contradictions that underline the political life in Kashmir may be attributed, as the thesis has sought to argue, to the multiple political subjectivities that constitute ‘Kashmiri people’ as a community. Show less
Archaic and Classical architectural terracottas constituted an integral part of the architecture of monumental buildings at Akragas. These objects therefore provide unique insights into the... Show moreArchaic and Classical architectural terracottas constituted an integral part of the architecture of monumental buildings at Akragas. These objects therefore provide unique insights into the built environment of sanctuaries at this important Greek colony in Sicily. This research's multi-disciplinary approach to the material allows for the creation of a revised typology, which takes into account stylistic characteristics, fabric, production techniques, material composition, and architectural context. The investigation is based on original analyses and documentation of over 250 fragments, of which a significant number was previously unpublished. By approaching these objects as complex architectural elements, and not just as decorative roof edges, a more nuanced image of local production is revealed. While the terracotta roofs from Akragas demonstrate a proficiency in regional stylistic and technical conventions, a number of adaptations is used in the decoration, profile and production techniques, which changes throughout different time periods. By investigating the required technical knowledge and the use of a local technical style, this research has gained new insights into the organization of local production and the distribution of architectural innovations. Show less
Controlling mobilities in the EU is increasingly depending on information and information technology. Abolishing permanent border control between Schengen Member States has created the dilemma... Show moreControlling mobilities in the EU is increasingly depending on information and information technology. Abolishing permanent border control between Schengen Member States has created the dilemma of economic benefits versus security issues of the freedom of movement. The solution to this issue is often sought in the development and implementation of information technology. While expectations of information and information technologies are high, empirical research on how such border technologies are used in practice is scarce and subsequently little is known about to what extent the envisioned benefits are actually achieved. This dissertation aims to gain more insight in the use of information and information technology in controlling mobilities in intra-Schengen border areas by using a case study of the Mobile Security Monitor as carried out by the Royal Netherlands Marechaussee. Through extensive observations of border checks, focus groups with border patrol officers, interviews with Marechaussee staff members, discourse analysis of political debates and policy documentation and quantitative data, this dissertation aims to gain insight in the decision-making process on the political, organizational and street-level and the role of information and information technology therein. Show less
The central question of this thesis is: What drives late Middle Paleolithic stone artifact variability? In its attempt to answer this question, this thesis is a contribution to understanding... Show moreThe central question of this thesis is: What drives late Middle Paleolithic stone artifact variability? In its attempt to answer this question, this thesis is a contribution to understanding variability within and between late Middle Paleolithic assemblages of the European Plain. The selected research area is rich in late Middle Paleolithic open-air sites but up to now lacking detailed quantitative comparisons between them. This thesis uses standardized, more quantitative methods to analyze stone tool variability across techno-complexes. Stone artifact assemblages where analyzed based on a detailed attribute analysis and compared using multivariate methods, like Principal Component Analysis and Nonmetric Multidimensional Scaling. Additionally, methods from 3D geometric morphometrics where applied for the analysis of some individual tool types. The central finding of the studies presented in this thesis is that most of the variability observed in the record is not related to typo-technological classification, and it is not necessarily site-specific nor geographical. The variability can be related to raw materials, but it can also be related to the varying application of similar methods in blank and tool production. The analyses of individual tools suggest further that certain tool concepts, like the bifacial Keilmesser are not restricted to bifacial tools only. Show less
Most lymphomas and leukemias are neo¬plasms of B cells. Due to the many different B cell development stages from which these neoplasms arise, the resulting diseases are quite heterogeneous, which... Show moreMost lymphomas and leukemias are neo¬plasms of B cells. Due to the many different B cell development stages from which these neoplasms arise, the resulting diseases are quite heterogeneous, which amongst other things is manifested in different tumor growth location, proliferation potential and surface antigen repertoire. Neverthe¬less, some population characteristics are found in almost all B cell malignancies as the cell-of-origin is identical. One of these is the cell surface antigen CD20. Originally used as a marker to distinguishing B cells from other lymphocytes, it quickly became a target for immunotherapy. Immuno-therapy is a treatment that makes use of immune system components to fight cancer, in this case by the injection of a monoclonal antibody specifically targeting one protein: CD20. The addition of CD20-targeting an¬tibodies to an anti-tumor treatment allows your immune system to recognize CD20-ex¬pressing B cells (diseased and healthy), and dispose of them. Overall, after several decades of research and therapeutic experience with antibodies targeting CD20, new functional discoveries as well as therapeutic advances are still being made, and CD20 therefore remains a highly attractive and fruitful target for the therapy of B cell malignancies as well as certain B-cell mediated autoimmune diseases. Show less
