Lung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of... Show moreLung cancer is the leading cause of cancer death in the Netherlands. For years chemotherapy was the only (palliative) treatment, with a short survival of only months. Since the introduction of immunotherapy in 2015, this survival has increased significantly, with the first results showing a survival of even a few years. However, the response rate is relatively low, the treatment is expensive and the (low percentage of) side effects are severe. Therefore a biomarker is needed to predict which patients would benefit of immunotherapy.This thesis is about the search for a new biomarker. With the use of the RNA of platelets, proteins, tumor markers in blood and a an electronic nose for exhaled breath, we tried to find a non-invasive biomarker for the prediction of response on immunotherapy and for the (future) use in clinical practice, some of which are promising. Show less
Cucurachi, S.; Blanco Rocha, C.F.; Steubing, B.R.P.; Heijungs, R. 2021
Life cycle assessment (LCA) models and databases have increased in size, resolution, and complexity, requiring analysts to rely on an ever-increasing number of uncertain model inputs. Such... Show moreLife cycle assessment (LCA) models and databases have increased in size, resolution, and complexity, requiring analysts to rely on an ever-increasing number of uncertain model inputs. Such increased complexity calls for systematic approaches to assessing the uncertainty of the output results of LCA models and the sensitivity of LCA model outputs to the model's uncertain inputs. In this contribution, we provide a theoretical basis and present a practical software implementation that combines uncertainty analysis and moment-independent global sensitivity analysis, which can be readily applied to full-scale LCA models. We implemented our approach in the Activity-Browser open source LCA software and it is made available for use in LCA studies. We demonstrate the approach and software implementation with a case study of crystalline silicon photovoltaics. Show less
Drug-target binding kinetics determine the time course of the central event in pharmacotherapy: Drug-target interaction. However, the time course of a drug effect is also influenced by many... Show moreDrug-target binding kinetics determine the time course of the central event in pharmacotherapy: Drug-target interaction. However, the time course of a drug effect is also influenced by many other physiological processes such as the metabolism and excretion of a drug and the transduction of the relevant biological signals. In this study, we investigate when target binding kinetics are determining the time course of drug effect and generate understanding into the relation between the parameter values and the rate-limiting step in the duration of a drug effect. Show less
Our study emphasizes the importance of two toxicity-modifying factors (the composition of the surrounding exposure media and mixture effects) in the assessment of toxic effects of metals and... Show more Our study emphasizes the importance of two toxicity-modifying factors (the composition of the surrounding exposure media and mixture effects) in the assessment of toxic effects of metals and metal-based NPs on higher plants. Based on the affinity of metals for binding sites on the biotic ligand at the water-organism interface, the mechanistic models we developed provide better links with the toxicity of metal mixtures. We also recommend that finding a statistically significant deviation from additivity can be the starting point for further mechanistic research concerning toxicologically relevant interactions between substances, instead of the endpoint of research used so far. As an extension of the research discussed in the third chapter of this thesis, the commonly known model for the toxicity of mixtures was proven to be suitable for preliminarily assessing the effects of metal-based NPs on terrestrial organisms. The experimental design of nested combinations helps establish a more realistic exposure scenario for the environment and makes it possible to identify where and how chemical-chemical interactions occur with metal-based NPs. Consequently, our findings enrich the rapidly evolving field of toxicology regarding metals and metal-based NPs. Show less
Koopman, Jacob J.E.; Rozing, Maarten P.; Kramer, Anneke; Abad, José M.; Finne, Patrik; Heaf, James G.; ... ; Westendorp, Rudi G.J. 2015
The rate of senescence can be inferred from the acceleration by which mortality rates increase over age. Such a senescence rate is generally estimated from parameters of a mathematical model fitted... Show moreThe rate of senescence can be inferred from the acceleration by which mortality rates increase over age. Such a senescence rate is generally estimated from parameters of a mathematical model fitted to these mortality rates. However, such models have limitations and underlying assumptions. Notably, they do not fit mortality rates at young and old ages. Therefore, we developed a method to calculate senescence rates from the acceleration of mortality directly without modeling the mortality rates. We applied the different methods to age group–specific mortality data from the European Renal Association—European Dialysis and Transplant Association Registry, including patients with end-stage renal disease on dialysis, who are known to suffer from increased senescence rates (n = 302,455), and patients with a functioning kidney transplant (n = 74,490). From age 20 to 70, senescence rates were comparable when calculated with or without a model. However, when using non-modeled mortality rates, senescence rates were yielded at young and old ages that remained concealed when using modeled mortality rates. At young ages senescence rates were negative, while senescence rates declined at old ages. In conclusion, the rate of senescence can be calculated directly from non-modeled mortality rates, overcoming the disadvantages of an indirect estimation based on modeled mortality rates. Show less
Wu, J.; Chen, Y.; V.J., van Heuven; Schiller, N.O. 2015
Pronunciation dictionaries are usually expensive and time-consuming to prepare for the computational modeling of human languages, especially when the target language is under-resourced. Northern... Show morePronunciation dictionaries are usually expensive and time-consuming to prepare for the computational modeling of human languages, especially when the target language is under-resourced. Northern Chinese dialects are often under-resourced but used by a significant number of speakers. They share the basic sound inventories with Standard Chinese (SC). Also, their words usually share the segmental realizations and logographic written forms with the SC translation equivalents. Hence the pronunciation dictionaries of northern Chinese dialects could be easily available if we were able to predict the tonal realizations of the dialect words from the tonal information of their SC counterparts. This paper applies statistical modeling to investigate the tonal aspect of the related words between a northern dialect, i.e. Jinan Mandarin (JM), and Standard Chinese (SC). Multi-linear regression models were built with between-word pitch distance of JM words as the dependent variable and the following were included as the predictors: SC tonal relations, between-dialect tonal identity, and individual backgrounds. The results showed that tonal relations in SC and between-dialect identity, as predictors featuring the relation between the JM and SC tonal systems, are significant and robust predictors of JM tonal realizations. The speakers’ sociolinguistic and cognitive backgrounds, together with the tonal merge and neutral tone information within JM, are important for the prediction of JM tonal realizations and affect the way that between-language predictors take effect. Show less
For mechanism-based investigations on PK-PD relationships following intranasal administration, the use of advanced animal models and analytical techniques are crucial. As described in this thesis,... Show moreFor mechanism-based investigations on PK-PD relationships following intranasal administration, the use of advanced animal models and analytical techniques are crucial. As described in this thesis, quantitative information on distinction between extent as well as rate of absorption between nose-to-systemic and nose-to-brain distribution can now be obtained. Using plasma prolactin concentrations as a biomarker for dopamine D2 inhibition, a mechanism-based PK-PD model was developed. Most important aspects in this approach were incorporation of target site exposure (brain extracellular fluid) of remoxipride and a biological system response (positive feedback) mechanism on the synthesis of prolactin, thereby increasing the mechanistic insight in modulation of the dopaminergic system in rats. Simulating remoxipride brain extracellular fluid concentrations in humans, allometric scaling and use of independent information on interspecies differences proved that the structural model is applicable in both rats and man. Show less
Dahan, A.; Olofsen, E.; Sigtermans, M.; Noppers, I.; Niesters, M.; Aarts, L.; ... ; Sarton, E. 2011
Environmental life cycle assessment (LCA) is a method for the quantitative assessment of the environmental impacts of products. A number of impact categories are related to toxic effects of... Show moreEnvironmental life cycle assessment (LCA) is a method for the quantitative assessment of the environmental impacts of products. A number of impact categories are related to toxic effects of chemicals. Multimedia models for substance fate, supplemented with models for human exposure, have been developed in the context of human and environmental risk assessment (HERA). Different authors have adapted such models for use in LCA, largely on a continental level. It has sometimes been suggested to merge LCA toxicity assessment and HERA into one common tool. Here, it is demonstrated that LCA and HERA cannot be merged, due to a fundamental difference concerning their respective goals. Subsequently, adaptations to existing multimedia models are proposed to make it possible to extend multimedia models with a module for metals. The core of the thesis is formed by the GLOBOX model: a global, regionally differentiated fate, intake and effect model for LCA toxicity assessment. For emissions of any organic chemical or metal to any compartment in any country or at any sea, this model calculates region-specific characterisation factors. Finally, an updated set of LCA normalisation factors is provided, with which the relative contributions of a product to the different impact categories can be evaluated. Show less
The biological clock regulates daily and seasonal rhythms in mammals. This clock is located in the suprachiasmatic nuclei (SCN), which are two small nuclei each consisting of 10,000 neurons. The... Show moreThe biological clock regulates daily and seasonal rhythms in mammals. This clock is located in the suprachiasmatic nuclei (SCN), which are two small nuclei each consisting of 10,000 neurons. The neurons of the SCN endogenously generate a rhythm of approximately 24 hours. Under the influence of the light-dark cycle, the SCN produce a coordinated output that is subjected to daily environmental changes. The adaptation to the light-dark cycle is a property of the neuronal network of the SCN. This neuronal network also explains the adjustment to long summer days and short winter days, and to shifts in the light-dark cycle caused by transatlantic flights or shift work. In this thesis the neuronal network of the SCN is investigated using computational techniques. The computer simulations were directed by experimental results, while, vice versa, new experiments were guided by results from the simulations. These coordinated efforts of computational science and life sciences show how properties emerge at the neuronal network level, that are not present in individual cells. Show less
It is desirable to model software systems in such a way that analysis of the systems, and tool development for such analysis, is readily possible and feasible in the context of large scientific... Show moreIt is desirable to model software systems in such a way that analysis of the systems, and tool development for such analysis, is readily possible and feasible in the context of large scientific research projects. This thesis emphasizes the methodology that serves as a basis for such developments. I focus on methods for the design of data-languages and their corresponding tools. Show less
Land use change results from the interaction between the human and the natural system and therefore various scientific disciplines have developed paradigms and methods to study land use change.... Show moreLand use change results from the interaction between the human and the natural system and therefore various scientific disciplines have developed paradigms and methods to study land use change. However, these disciplinary approaches can only cover part of the complex system of land use change. The objective of this dissertation is to develop interdisciplinary methodologies to identify and integrate factors that are important in the land use system to describe and model the land use system in a comprehensive manner. The methodological challenges that are addressed in this study include bridging differences in spatial and temporal scales and organisational levels, identification of appropriate units of analysis, combining different disciplinary paradigms and developing new paradigms that unify the disciplines in one concept. The development of these methods is illustrated with a case study in a municipality in the Philippines, where in the past century large land use changes have taken place through commercial logging and expansion of agriculture. To make projections of future land use in the area models were constructed for the case study. In this dissertation it is the combination of approaches that have led to a greater understanding of the land use in the study area. Especially moving between empirical, inductive methods and theoretical, deductive methods has proven to be a useful approach to stimulate theory building. Show less
