Although anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the... Show moreAlthough anti-cancer treatments have significantly advanced over the past decades, obstacles to accomplishing successful treatment still exist. The occurrence of treatment resistance is one of the major factors that limit the long-lasting efficacy of anti-cancer treatment. Additionally, substantial variability in pharmacokinetics (PK) / pharmacodynamics (PD) of anti-cancer drugs also challenges successful oncology treatment. Therefore, gaining knowledge of and ultimately better suppressing evolutionary resistance development during treatment, and applying personalized treatment are desired to improve anti-cancer treatment. In this thesis, we have applied quantitative modeling approaches to address these needs, aiming for improved treatment for oncology patients. Our work demonstrated that with the quantitative models, the evolutionary progression of tumors could be characterized and predicted, accounting for interactions among heterogeneous tumor cells and supported by mutant gene variants detected in circulating tumor DNA (ctDNA). In addition, we developed population PK /PD models which enabled quantitative description of the PK and PD of anti-cancer drugs and corresponding variabilities in real-world patients. The developed models have been further applied to support the identification of optimal treatment strategies and guide individualized treatment for oncology patients. Show less
Contesting the nature of right to resist continues to be of concern to those in power, for it poses the fundamental question about their legitimacy. From to Antigone to the Occupy Wall Street... Show moreContesting the nature of right to resist continues to be of concern to those in power, for it poses the fundamental question about their legitimacy. From to Antigone to the Occupy Wall Street movement, individuals and communities have expressed their grievances and resisted oppression through a myriad of strategies. And although those taking the streets use the language of rights and appeal to a higher law to vindicate their claims, resistance has usually been considered a political, or rather, a security affair. The thesis vindicates the place of the ius resistendi in the normative order and uses legal probe to evince that there are no reasons why it could not be considered a legal right, except for political opportunity. The thesis challenges some basic postulates of liberal legal theories and develops a broader conception of rights, one in which reserved rights are part of a democratic normative system that performs in a manner consistent with its fundamental values. A primary, indeterminate right, the ius resistendi, I contend, embodies the Arendtian right to have rights. Show less
Egypt became a province of the Persian or Achaemenid Empire in 526 BC. In the decades thereafter, some inhabitants of the Delta and Nile Valley rebelled against their Persian overlords. Though... Show moreEgypt became a province of the Persian or Achaemenid Empire in 526 BC. In the decades thereafter, some inhabitants of the Delta and Nile Valley rebelled against their Persian overlords. Though these rebellions are well known, they have been little studied. The present thesis provides an in-depth study of the first two rebellions of Persian-Period Egypt: the rebellion that began in ca. 521 BC, and which may have lasted until 519/18 BC, and the rebellion that began in ca. 487/86 BC, and which may have lasted until 485/84 BC. Show less
Recently, the recommendations for the treatment of Clostridioides difficile infection (CDI) have been up-dated. However, in addition to the clinical efficacy data, the drug of choice should ideally... Show moreRecently, the recommendations for the treatment of Clostridioides difficile infection (CDI) have been up-dated. However, in addition to the clinical efficacy data, the drug of choice should ideally represent op-timal antimicrobial stewardship, with an emphasis on rapid restoration of the gut microbiota to mini-mize the risk of infection relapses. Oral administration of metronidazole results in low concentration in stool, and interaction with fecal microbiota reduces its antimicrobial bioactivity. Reported elevated min-imum inhibitory concentrations of metronidazole in epidemic C. difficile ribotypes and the emergence of plasmid-mediated resistance to metronidazole represent additional potential risks for clinical failure. If metronidazole is the only CDI treatment option, antimicrobial susceptibility testing on agar contain-ing heme should be performed in C. difficile isolate. Compared with metronidazole, oral vancomycin and fidaxomicin reach very high concentrations in the stool, and therefore can quickly reduce C. difficile shed-ding. Health care facilities with higher CDI incidence and/or occurrence of epidemic ribotypes should not use metronidazole because prolonged C. difficile shedding can increase the risk for further C. difficile transmission. Only fidaxomicin has a narrow spectrum of antimicrobial activity, which might be, together with persistence on spores, the main contributing factor to reduce the recurrent CDI rates.(c) 2022 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ) Show less
We have examined sequences from the ligand-binding domain of the nicotinic acetyl choline receptor (nAChR) in 148 vertebrate species. We are in interested in this receptor because the α-neurotoxins... Show moreWe have examined sequences from the ligand-binding domain of the nicotinic acetyl choline receptor (nAChR) in 148 vertebrate species. We are in interested in this receptor because the α-neurotoxins of many venomous snakes binds to this receptor in its location at the neuromuscular junction in all vertebrates. Furthermore, some animals have evolved resistance to snake venoms and show modifications in the ligand binding domain of the nAChR which inhibit the binding of snake α-neurotoxins. Our analysis has shown that numerous vertebrate species, most of which were not previously known to possess α-neurotoxin resistance, do actually contain resistance-related modifications. These modifications are present in most of the taxa in our dataset, with the unexpected exclusion of the birds. It was particularly surprising to us that the snake-specialist predatory birds Circaetus pectoralis (black-chested snake eagle) and Sagittarius serpentarius (secretary bird) did not possess resistance modifications. There were also relatively few resistance-related mutations within the mammals. By contrast, there were multiple convergent evolutions of the well-characterised N-glycosylation motif within the squamate reptiles—particularly the snakes. We also identified a number of sites under positive selection, such as mutations to the proline subsite. Future functional testing will be needed to validate that these modifications do indeed confer resistance. To provide functional confirmation that resistance-related modifications do indeed reduce susceptibility to toxins, we used developmental bioassays. These assays showed that two species possessing resistance-related modifications of the nAChR (stickleback and bearded dragon) were less susceptible to the toxic effects of cobra venom than two species that lacked such modifications (zebrafish and chicken). In summary, we demonstrate that the range of mechanisms along with the phylogenetic distribution of resistance to snake α-neurotoxin appears to be more extensive than was previously appreciated. It also shows strong evidence of the convergent evolution of the same resistance mutations in independent linages. Our findings also support the notion that the mutations we have identified in this thesis may represent adaptive change in response to selective pressures exerted by α-neurotoxic snake venoms in an evolutionary arms race. Thus, we conclude that the evolutionary arms race between predator and prey appears to be a pervasive feature of the trophic interactions surrounding venomous snakes, which is shaping the molecular evolution of the nAChR in the vertebrates. Show less
The making of sacrifices seems part and parcel of any elite sportsperson’s life. Remarkably, the insights that we find in the current literature in social sport studies are not able to make sense... Show moreThe making of sacrifices seems part and parcel of any elite sportsperson’s life. Remarkably, the insights that we find in the current literature in social sport studies are not able to make sense of the references to sacrifice in the data that emerged in the context of this study on the social significance of elite women’s football. The thesis that I put forward is that the existing Marxist, cultural studies and Foucauldian poststructuralist frameworks that we find in the field of social sport studies must be supplemented by the theory of play inherited from Johan Huizinga, Eugen Fink and Hans-Georg Gadamer for both conceptual and ethical reasons. I argue that the theory of play allows us first of all to make sense of the player’s experience of sacrifice. More precisely, understood as an independent, irreducible structure of experience, play allow us to make sense of the women’s football players’ experiences of sacrifice in a way that is compatible and complimentary to those insights of Marxism, cultural studies and Foucauldian poststructuralism, which remain indispensable. Secondly, the theory of play makes visible that the existing frameworks miss important insights in theorizing the subject, and, by extension, brings forth a notion of freedom and resistance that is currently lacking in the field of social sport studies. ‘Lacking’, as we cannot find these notions in the field of social sport studies, but also ‘lacking’ because the field of study is in need of alternative ways to think about freedom and resistance. This thesis thus contains a systematic point, namely our discovery that “players play”, that their experience cannot be understood without an account of play as such, alongside an analysis of what that means; and a methodological point, namely that in order to take into consideration that players play, we need a new method, which I describe as a feminist playology. The prefix feminist refers to the commitment of this method to understand sport as a gendered activity. Show less
Background: Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi... Show moreBackground: Gastrointestinal stromal tumour (GIST) is commonly treated with tyrosine kinase inhibitors (TKIs), but most patients ultimately develop secondary resistance. Cabozantinib, a multi-targeted TKI inhibitor, has activity in patient-derived GIST mouse xenograft models and can overcome compensatory MET signalling occurring on TKI treatment. European Organisation for Treatment of Cancer (EORTC) 1317 'CaboGIST' assessed the safety and activity of cabozantinib in patients with GIST who had progressed on imatinib and sunitinib.Methods: In this multi-center, open label, single arm phase II study, eligible GIST patients received oral cabozantinib (60 mg) once daily. Primary end-point was the progression-free survival rate at 12 weeks assessed by the local investigator per Response Evaluation Criteria in Solid Tumours 1.1. If at least 21 of the first 41 eligible and evaluable patients were progression-free at week 12, the activity of cabozantinib was sufficient to warrant further exploration according to the A'Hern one-stage study design.Findings: A total of 50 eligible patients started treatment between 02/2017 and 08/2018, including four (8%) still continuing cabozantinib at clinical cut-off (09/2019). The number of 3-weekly treatment cycles ranged from 1 to 30. Among the first 41 eligible and evaluable patients, 24 were progression-free at week 12 (58.5%, 95% confidence interval [CI] 42.0 -74.0%). Among all 50 patients, 30 were progression-free at week 12 (60%, 95% CI 45 -74%). Seven patients achieved a partial response (14%, 95% CI 6-27%), and 34 had stable disease (68%, 95% CI 53-80%) as best response. Progression was seen in eight patients (16%, 95% CI 7-29%), and one was not evaluable. Disease control was achieved in 41 patients (82%, 95% CI 69-91%). Median progression-free survival was 5.5 months (95% CI 3.6-6.9). The most common adverse events were diarrhoea (76%), palmar-plantar erythrodysesthesia syndrome (60%), fatigue (50%), hypertension (42%), weight loss (40%) and oral mucositis (30%), with 32 (64%) patients requiring dose reductions, 27 (54%) having treatment interruptions and no cabozantinib-related deaths observed.Interpretation: EORTC 1317 met its primary end-point, with 24/41 patients being progression free at week 12 of treatment. The objective response was 14% with an encouraging disease control rate of 82%. Results of this trial confirm preclinical findings and warrant further exploration of cabozantinib in GIST. (C) 2020 Elsevier Ltd. All rights reserved. Show less
Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB... Show moreSince several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies.Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations.Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC. Show less
Archaeological research on the Gallina (AD 1100–1300) inhabitants of the region west of the Rio Chama and centered on the Llaves valley has focused on constructing a culture history and examining... Show moreArchaeological research on the Gallina (AD 1100–1300) inhabitants of the region west of the Rio Chama and centered on the Llaves valley has focused on constructing a culture history and examining functional characteristics of artifacts and architecture. Limited research has attempted to understand who the residents of the Gallina heartland were. In this article, using new findings and historical contexts, we argue that the Gallina people had a complicated identity forged around resistance and a deep connection to their past. To better understand them we need to move past previous binary categories used to describe them and perceive them not as isolated or connected, aggressors or victims, traditionalists or innovators, but as an intersectional mix of these axes of identity.La investigación arqueológica sobre los habitantes Gallina (1100–1300 d. C.) de la región oeste del Río Chama, focalizada en el valle de Llaves, se orientó en la construcción de una historia cultural y el análisis de las características funcionales de los artefactos y la arquitectura. De hecho, han sido escasas las investigaciones que han intentado entender quiénes eran los residentes del Gallina. En este artículo, utilizando nuevos hallazgos y contextos históricos, argumentamos que los grupos Gallina tuvieron una identidad compleja, forjada en torno a la resistencia y a una profunda conexión con su historia. Asimismo, para entenderlas necesitamos movernos más allá de las tradicionales categorías binarias usadas para interpretarlos y percibirlos como aislados o conectados, violentos o víctimas, tradicionalistas o inventores, y en cambio, como una mezcla que abarca todos estos ejes de identidad. Show less
In this book, research was conducted into the downfall of Gijs van Hall (1904-1977) as mayor of Amsterdam in the spring of 1967, when he was removed from office by the government. A unique... Show moreIn this book, research was conducted into the downfall of Gijs van Hall (1904-1977) as mayor of Amsterdam in the spring of 1967, when he was removed from office by the government. A unique political and historical event! But is also raised many questions afterwards about both the person Gijs van Hall and his life history, as well as the context in which he should have operated as mayor between 1957 and 1967. The social democrat and war hero Van Hall believed that his removal had something to do with being a descendant of the distinguished 19th century family of public administrators Van Hall. He believed that he had become a symbol of the objectionable regent class and its paternalistic regent mentality, and the victim of opposition to this from a new generation. In his eyes, all the criticism he received was ‘only because I am a Van Hall’. This book tries to shed new light on Van Hall’s forced removal. It is concluded that his downfall was due to his lack of vision on the duties of a mayor, his difficulty to cope with a new media culture and the tragic loss of his brother Walraven during the war. Show less
In this dissertation we present the results of our research on Helicobacter pylori infections in childhood, focusing on the prevalence, diagnosis and treatment of the infection. Our studies were... Show moreIn this dissertation we present the results of our research on Helicobacter pylori infections in childhood, focusing on the prevalence, diagnosis and treatment of the infection. Our studies were conducted in the Netherlands, Europe and Indonesia. We discuss diagnostic tests, therapeutic regimens, resistance and preventive measurements. We highlight clinical and pathophysiological aspects of the infection and describe which particular strains are prevalent and how transmission occurs. Presently, there are no established correlations between a Helicobacter pylori infection and recurrent abdominal pain, gastroesophageal reflux disease or growth retardation. We present data on the prevalence of Helicobacter pylori in young infants in the Netherlands and observe that children with at least one non-Dutch parent form a risk group. We assess risk factors in a Europe-wide study on gastroduodenal erosions and ulcers in childhood. In our study, Helicobacter pylori infection and gastrotoxic medications were relatively little implicated as etiology of that pathology. The prevalence of Helicobacter pylori infection in Indonesian young children is relatively high and points at an early acquisition of the infection. Finally, the resistance of Helicobacter pylori to clarithromycin and metronidazole was assessed for adults and children in the Netherlands. Low resistance rates were found, but the resistance in adults is increasing. We conclude that a test-and-treat regimen is justified for the Netherlands. Show less
Meijer, A.; Jonges, M.; Abbink, F.; Ang, W.; Beek, J. van; Beersma, M.; ... ; Koopmans, M. 2011
Undoubtedly, grapes and wine are globally the most important fruit and food commodities, respectively. The first objective of this research is to optimize an extraction protocol suitable for grape... Show moreUndoubtedly, grapes and wine are globally the most important fruit and food commodities, respectively. The first objective of this research is to optimize an extraction protocol suitable for grape metabolic profiling followed by the application of that protocol to perform metabolic characterization of grape cultivar, wine types, and vintage using NMR spectroscopy in combination with chemometrics methods. This approach was also used to study different physiological processes in grapevine like ripening of berry and resistance against fungal pathogen. Metabolic characterization of different white wines to highlight the metabolites responsible for sensory attributes was also carried out. Another task of this research was to correlate the metabolic profiling data from grapes and wine with the bioactivity data using various multivariate regression models. Show less
Dit proefschrift behandeld allerlei klinische vragen waarmee de arts geconfronteerd wordt als een volwassene zich presenteert met een gecompliceerde urineweginfectie. In verschillende hoofdstukken... Show moreDit proefschrift behandeld allerlei klinische vragen waarmee de arts geconfronteerd wordt als een volwassene zich presenteert met een gecompliceerde urineweginfectie. In verschillende hoofdstukken wordt ingegaan op de volgende vragen: Wanneer moet de pati_nt worden opgenomen? Wanneer dient rekening te worden gehouden met een resistent oorzakelijk micro-organisme? Wanneer is radiologisch onderzoek van de urinewegen nuttig? Wanneer heeft een bloedkweek toegevoegde waarde naast een urinekweek? Hoe lang dient te worden behandeld met antibiotica? Daarnaast wordt de relatie tussen urineweginfecties en de functie van de bekkenbodem beschreven. Show less
Antimicrobial resistance of bacteria is a worldwide and ever-growing problem, directly linked to the use of antimicrobial drugs. Resistant bacteria emerge under the selective pressure of... Show moreAntimicrobial resistance of bacteria is a worldwide and ever-growing problem, directly linked to the use of antimicrobial drugs. Resistant bacteria emerge under the selective pressure of antibiotics. In hospitals, where large-scale usage of antibiotics is common, bacteria frequently become resistant to several antibiotics which causes serious problems for the treatment of patients with infections by these microorganisms. Well-known (multi)-resistant bacteria causing problems in many countries all over the world are methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, penicillin-resistant pneumococci, extended-spectrum betalactamase-producing Klebsiella pneumoniae, carbapenem-resistant Acinetobacter baumannii, and multiresistant Mycobacterium tuberculosis Show less
