Glycoconjugates (a carbohydrate connected to a lipid, protein or other carbohydrate) play a key role in great variety of biological processes. The synthesis of these constructs is tightly regulated... Show moreGlycoconjugates (a carbohydrate connected to a lipid, protein or other carbohydrate) play a key role in great variety of biological processes. The synthesis of these constructs is tightly regulated by enzymes. Defects in these enzymes may result in an impaired degradation of the glycoconjugate. Consequently, the levels of glycoconjugates are increased and this may eventually lead to storage disorders such as Gaucher disease. The research described in this thesis focuses on the synthesis of chemical tools (activity-based probes, ABPs) to study the enzymes involved in the degradation of glycoconjugates. Using these probes, it was demonstrated that the activity of peptide N-glycanase (the enzyme that is responsible for the hydrolysis of N-linked glycoproteins)inhibitors is determined by its reactive group. Furthermore, the activity-based protein profiling strategy was used to study degradation of glycosy lated proteins. It appeared that deglycosylation of O-GlcNAclated proteins is not a prerequisite for proteasomal degradation. To study beta-glucosidases (enzymes that catalyze the hydrolysis of O-glycosidic linkages), ABPs based on cyclophellitol have been developed. Especially fluorescently labeled probes bind efficiently and selectively to beta-glucosidases. These probes have been used to investigate Gaucher disease. Both wild-type and mutant forms of the enzyme could be labeled in vitro and in living cells which allowed rapid identification activity of this glucosidase. Show less
This Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to... Show moreThis Thesis deals with the design, synthesis and biological evaluation of peptide-based drugs. In chapters 1-4, the development of peptides derived from natural gluten which can serve as drugs to combat the symptoms of celiac disease is described. These symptoms are caused by a misdirected immune response towards dietary gluten in genetically predisposed individuals. Peptides which can inhibit this immune response possibly can be used as an addition to the gluten-free diet, which is the only therapy available today. In Chapters 5 and 6, the synthesis and biological evaluation analogs of the antibiotic peptide Gramicidin S is described. Gramicidin S is a naturally occurring antibiotic peptide. It is very effective against bacteria, but also exhibits toxicity towards human red blood cells which limits its use to topical applications. Analogs of this natural peptide may lead to efficient antibiotics which are broadly applicable. Show less
Because of the disappointing progress that has been made in the last decades in survival in patients with head and neck cancer, existing therapy needs to be improved and/or new treatment needs to... Show moreBecause of the disappointing progress that has been made in the last decades in survival in patients with head and neck cancer, existing therapy needs to be improved and/or new treatment needs to be introduced. This thesis describes a new promising treatment, apoptin gene therapy. The scope of this study was to investigate the applicability of apoptin in head and neck squamous cell carcinoma (HNSCC). First, we assessed its potential in-vitro. Next, a suitable animal model was established, which was used for in-vivo experiments with apoptin. In chapter 2 we describe the results of apoptin treatment in a HNSCC cell line with a mutated p53 and the effect of over-expression of Bcl-xL on the outcome. Chapter 3 describes the synergistic effect of apoptin and irradiation in HNSCC both in radiation sensitive and in more radioresistant HNSCC cell lines. The applicability of an immune competent animal model for in-vivo research is described in chapter 4. The time needed to establish a useful oral squamous cell carcinoma in mice is assessed and immunological comparisons are made with human counterparts. In chapter 5 the tumorigenesis of the same carcinogenic immune competent model is investigated and characteristics are analyzed. The efficacy of the apoptin therapy in-vivo is described in chapter 6. This is done by looking into the effect of intratumoral injection of a constructed adenovirus expressing the apoptin protein. Finally, the data are critically discussed in chapter 7 in view of apoptin as a potential new anti-cancer therapy. Show less
The general aim of this thesis is to determine and compare disease and voice outcome for T1 glottic carcinoma treated with radiotherapy or laser surgery. The findings show similar oncological and... Show moreThe general aim of this thesis is to determine and compare disease and voice outcome for T1 glottic carcinoma treated with radiotherapy or laser surgery. The findings show similar oncological and functional results for radiotherapy and laser surgery in __superficial midcord T1a glottic carcinoma__. This outcome supports the Dutch national guideline __Treatment of Laryngeal Carcinoma__ which was published during the life-time of this thesis. In this guideline laser surgery is labeled treatment of choice in these lesions because of the shorter treatment duration, lower costs and the possibility for repeated treatments and/or additional radiotherapy. For larger T1 lesions, our literature review concludes that more comparative data, especially on functional results, are needed before definite conclusions can be drawn as to the role of laser surgery in these lesions. These studies are now being perform ed in a collaboration between the Leiden University Medical Center and the Eramus Medical Center, Rotterdam. Show less
A catalyst is a compound that speeds up a chemical reaction without being consumed itself. The proces of catalysis is one of the most important technologies in the modern world. Approximately 90%... Show moreA catalyst is a compound that speeds up a chemical reaction without being consumed itself. The proces of catalysis is one of the most important technologies in the modern world. Approximately 90% of all chemicals and materials around us is produced using catalysis. To get a better understanding of these industrial processes, it is important to investigate the exact role of the catalyst in the process, and the factors that can influence the outcome of the reaction. Therefore, it is necessary to first comprehend simple processes, such as the dissociation of hydrogen, the smallest molecule on Earth, on metal surfaces. In addition, this reaction is an elementary step in many industrial processes. My thesis describes the dissociation of hydrogen on bare and CO-precovered ruthenium, and on stepped platinum. These metals are important catalysts in e.g. ammonia synthesis (ruthenium) and fuel cells (platinum). I have discovered that ruthenium is a very good catalyst for hydrogen dissociation. The presence of CO, however, poisons the catalyst, and less hydrogen is able to dissociate. The presence of steps on a platinum surface increases the catalytic activity of the metal significantly. Show less
The first half of this thesis describes the synthesis of several conformationally restricted alkylated and bicyclic sugar amino acids (SAAs). The second half of the thesis describes the application... Show moreThe first half of this thesis describes the synthesis of several conformationally restricted alkylated and bicyclic sugar amino acids (SAAs). The second half of the thesis describes the application of the SAAs and their intermediates presented in the first half, as components of tools applied for the probing of biological systems. Show less
Het onderzoek in het proefschrift heeft betrekking op het opzetten van een theoretisch kader voor het modeleren van ziekteprogressie op een mechanistische grondslag. De nadruk ligt op de uitwerking... Show moreHet onderzoek in het proefschrift heeft betrekking op het opzetten van een theoretisch kader voor het modeleren van ziekteprogressie op een mechanistische grondslag. De nadruk ligt op de uitwerking van dit concept voor een chronisch progressieve ziekte; postmenopausale osteoporose. De onderliggende aanname is dat een betere, samenhangende, beschrijving van dit soort ziektes wordt verkregen door de combinatie van 1) een wiskundige structuur gebaseerd op het onderliggende biologische mechanisme met 2) fysiologische data die de ziekteprogressie en de behandelingseffecten weergeven. Het onderzoek heeft aangetoond dat het modeleren van postmenopausale osteoporose op basis van een ziektesysteem analyse (__disease system analysis__) leidt tot waardevolle inzichten in zowel symptomatische als beschermende (ziekte modificerende) effecten op verschillende biologische markers. Er kan gesteld worden dat deze mechanistische ziektesystemen een __kennisbank__ kunnen en moeten vormen om een beter ge_nformeerd besluitvormingsproces tijdens de ontwikkeling (farmaceutische industrie), de beoordeling (overheden) en uiteindelijk het klinische gebruik van geneesmiddelen. Ziekteprogressie modellen maken het steeds beter mogelijk om informatie vanuit meerdere bronnen samen te voegen op basis van de kennis over het geneesmiddel en de ziekte. Met toenemende kennis over het systeem en de behandelingseffecten van bestaande en nieuwe geneesmiddelen kunnen deze modellen continue worden verbeterd en ingezet in het onderzoek en gebruik van deze middelen. Uiteindelijk leidt dit tot een meer effici_nte en kosteneffectieve benadering van geneesmiddelontwikkeling en het klinisch gebruik van geneesmiddelen. Het is van groot belang dat de farmaceutische industrie, academische instellingen en de overheid verder samenwerken aan het onderzoeken en vergroten van de mogelijkheden van een dergelijke gestructureerde aanpak (www.tipharma.nl). Show less
Koptische muziek, de muziek van de christelijke bevolking van Egypte, is in de Westerse Wereld een onbekend en weinig onderzocht gebied. Alleen van liturgische Koptische muziek zijn ongeveer 300... Show moreKoptische muziek, de muziek van de christelijke bevolking van Egypte, is in de Westerse Wereld een onbekend en weinig onderzocht gebied. Alleen van liturgische Koptische muziek zijn ongeveer 300 melodieën uit een eeuwenlange mondelinge traditie bewaard gebleven. De eenstemmige muziek wordt als wisselgezang door zowel solisten als koren voorgedragen. Om meer over de structuur van deze onbekende muziek te weten te komen heeft de auteur deels opnames verzameld, deels rituelen zelf opgenomen in verschillende Koptische kloosters en kerken. Als onderwerp van onderzoek werden de nachtelijke gezangen tussen zonsondergang- en opgang gekozen, Psalmodia genaamd. Met meer dan 100 muzikale transcripties zijn deze melodieën voor volgende generaties vastgelegd. De gezangen van beroemde kerkzangers uit verschillende delen van Egypte werden met elkaar vergeleken. Uit de analyses van deze melodieën bleek dat de improvisatorisch lijkende, lange cadensen een duidelijke basismelodie hebben, die in alle interpretaties terug te vinden is. Daarnaast bestaan melodische formules die de zangers in staat stellen de basismelodieën aan de verschillende feestelijke situaties aan te passen. De keuze van deze formules is gedeeltelijk door de traditie vastgelegd, gedeeltelijk past iedere cantor ze aan zijn eigen zangkunst aan. De traditionele Koptische liturgische melodieën worden op deze manier als levendige muziekcultuur bewaard Show less
In het digitale tijdperk gaan multimedia een steeds belangrijkere rol spelen en de Universiteit Leiden onderzoekt de toegevoegde waarde van multimediale materialen in voorbereidend leesonderwijs.... Show moreIn het digitale tijdperk gaan multimedia een steeds belangrijkere rol spelen en de Universiteit Leiden onderzoekt de toegevoegde waarde van multimediale materialen in voorbereidend leesonderwijs. In dit dissertatieonderzoek lag het accent op multimediale toevoegingen aan prentenboeken . Naast of in plaats van gedrukte tekst is er gesproken tekst waardoor kleuters de boeken “zelfstandig” kunnen lezen. Voorts zijn de statische prenten vervangen door filmbeelden en aangevuld met welgekozen geluiden en muziek. Traditionele prentenboeken zijn een belangrijke voorbereiding op het latere lezen van teksten. Boeken met multimediale toevoegingen zouden deze functie wellicht in mindere mate vervullen. Filmbeelden die bijna voor zichzelf spreken zouden de motivatie verminderen om goed naar tekst te luisteren, vooral als kinderen veel hiaten hebben in verhaalbegrip zoals de Marokkaanse en Turkse kleuters in dit onderzoek. Voor deze veronderstelling is echter weinig empirische evidentie gevonden. Integendeel, prentenboeken met multimediale toevoegingen zijn zowel voor verhaalbegrip als voor woordenschat een extra stimulans. Dit onderzoek toont aan dat de verklaring moet worden gezocht in de match van beelden met taal. In vergelijking met traditionele prentenboeken maken prentenboeken met multimedia de kans op een goede match groter door met diverse technieken de aandacht te trekken naar details die op dat moment in de tekst genoemd worden. Show less
This thesis starts with a general introduction and a description of the development of a detection and genotyping method for Betapapillomavirus types. This genotyping method is used in three... Show moreThis thesis starts with a general introduction and a description of the development of a detection and genotyping method for Betapapillomavirus types. This genotyping method is used in three chapters to acquire more knowledge on the natural history of Betapapillomavirus infection. Very little is known about this subject and more knowledge could support future studies into the clinical relevance of these viruses. Furthermore, three subsequent chapters focus on possible associations of betaPV infection with three different (pre)malignant diseases. A final chapter includes general discussion and conclusions. Show less
In this thesis the assessment of ultrasonography (US) and Computed Tomography (CT) in the diagnostic strategy of suspected appendicitis is presented. The first study showed that focused single... Show moreIn this thesis the assessment of ultrasonography (US) and Computed Tomography (CT) in the diagnostic strategy of suspected appendicitis is presented. The first study showed that focused single-detector helical CT as well as graded compression US performed in a general community teaching hospital by both body imaging radiologists and general radiology staff members have a similar accuracy for the diagnosis of acute appendicitis. A second study showed that in interpreting CT images the expertise of the attending radiologist should be considered. A third study showed that gender seems to affect the accuracy of US and CT in patients suspected of acute appendicitis. A fourth study showed that US as a sole imaging tool is of limited value both in women with unequivocal and in women with equivocal signs of appendicitis. A fifth study showed that US and CT implemented in a diagnostic pathway yields a high diagnostic accuracy for acute appendicitis without adverse events due to delay in treatment. A sixth study showed that for a majority of the surgeons, the diagnosis of acute appendicitis is based on clinical signs and symptoms. US and CT can be valuable in diagnosing appendicitis but further cooperation between surgeons and radiologists is required. Show less
In this thesis new fluorescent platinum(II) compounds are presented. All these new compounds were designed to overcome the cisplatin-resistance, using bulky ligands surrounding the platinum(II) ion... Show moreIn this thesis new fluorescent platinum(II) compounds are presented. All these new compounds were designed to overcome the cisplatin-resistance, using bulky ligands surrounding the platinum(II) ion. To study their biological activity two cell lines were chosen, the human ovarian carcinoma sensitive to cisplatin (A2780), and its resistant counterpart (A2780R). This thesis is divided in two parts: Part I: New fluorescent platinum(II) compounds containing 9-anthryl pyridyl enone as carrier ligand (chapters 2,3 and 4), and Part II: A new fluorescent platinum(II) compound containing N,N__-bis-(anthracen-9-ylmethyl)propane-1,3-diamine as a carrier ligand (chapter 5, 6 and 7). Show less
In the Netherlands around 10.000 patients are diagnosed with colorectal carcinoma every year, of who about 2500 have rectal carcinoma (www.oncoline.nl). It is the third most common cancer in men ... Show moreIn the Netherlands around 10.000 patients are diagnosed with colorectal carcinoma every year, of who about 2500 have rectal carcinoma (www.oncoline.nl). It is the third most common cancer in men (after prostate and lung cancer) and the second most common in women (after breast cancer). In the treatment of rectal cancer a multi-disciplinary approach is the best way to achieve optimal outcomes. Imaging, (neo)adjuvant therapy, surgery and pathology will be discussed separately to define their role in the treatment of rectal cancer. The principle investigation method of this thesis is the analysis of the patterns of local recurrence of rectal cancer. By determination of the location of locally recurrent rectal cancer on imaging and relating these to patient, treatment and tumor variables, the mechanism of local relapse genesis is reconstructed. By doing this the effect of neoadjuvant treatment, surgery, intra-operative radiotherapy and adjuvant treatment on local control can be quantified. First patterns of local recurrence are described for rectal cancer in general (Chapters 3-5) and then only for locally advanced rectal cancer (Chapters 6-7). Subsequently, the effect of preoperative evaluation of local recurrent rectal cancer on results of the multimodality treatment of local relapse is analyzed (Chapters 8-9). Show less
For the successful application of immunotherapy for leukemia significant numbers of viable T cells with the right antigen specificity have to be available within a limited period of time. TCR gene... Show moreFor the successful application of immunotherapy for leukemia significant numbers of viable T cells with the right antigen specificity have to be available within a limited period of time. TCR gene transfer is a promising strategy enabling the generation of large numbers of T cells with a selective antigen specificity, while reducing the time required for in vitro culture. Future clinical application of TCR engineered T cells may result in an off-the-shelf therapy with TCRs suitable for large numbers of patients. Acquisition of more insight into the possibilities and restrictions of TCR gene transfer and assessment of the efficacy of the therapeutic cells may provide a solid basis for clinical application in the near future. However, the application of immunotherapy for hematological malignancies is currently limited by the restricted number of hematopoiesis specific mHags that can be used as target antigens. Furthermore, an important issue for clinical implementation of TCR gene therapy is the prevention of the formation of mixed TCR dimers, which have recently been shown to induce autoreactivity. In addition, the future development of TCR gene therapy strategies will benefit from increased knowledge about both the T cells that serve as host cell for TCR gene transfer and other T cells present in the patient that may manipulate the immunotherapeutic responses of the TCR engineered T cells. Unfortunately, function analysis of T cell populations using biologically relevant antigens is hampered by the large number of different T cell specificities present and the difficulty to identify the specificity of T cells. The aim of this thesis was to characterize novel T cell populations that may serve as host cells for TCR gene transfer and to determine their possibilities and restrictions as TCR engineered immunotherapeutic effector cells for the treatment of hematological malignancies. Show less
This thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis... Show moreThis thesis describes clinical, cytological, immunological and pharmacological aspects of acute childhood leukaemia and allogeneic stem cell transplantation(SCT), with the emphasis on the analysis of potential improvements in risk stratification and possible treatment adaptation, in order to decrease relapse frequency and disease-related death. Firstly, to study the role of chemokine receptor/ligand interactions in the context of extramedullary leukaemia, we analyzed the homing receptor expression on leukemic blast cells in skin or intestine, peripheral blood and bone marrow of patients with T-ALL en AML, respectively. Secondly, the treatment results of 132 children, who received an allogeneic HLA-identical SCT for acute leukaemia was evaluated, showing the effect of biologically effective TBI dose on relapse risk. Thirdly, to optimize the use of Cyclosporin A(CsA) for adequate Graft-versus-host disease(GVHD) prophylaxis and to avoid drug toxicity, we investigated the pharmacokinetics of CsA in children after SCT, and showed that monitoring CsA exposure early after SCT may provide a tool to influence outcome. Finally, to gain a better understanding of the mechanism of chimerism induction of endothelial and epithelial cells following allogeneic SCT, the occurrence of chimerism in relation to the conditioning regimen, time interval after SCT and development of GVHD was studied. Show less
The Wende results in two opposite effects: the university maintains its continuity and quickly starts to thrive in the newly unified German state, while the professional practice of most professors... Show moreThe Wende results in two opposite effects: the university maintains its continuity and quickly starts to thrive in the newly unified German state, while the professional practice of most professors suffers from discontinuity and a lack of connection to the new social circumstances. This antithesis, continuity for the university versus discontinuity for professorial practice, is the central theme. Relatively minor differences between biographies that had developed in the GDR op untill the Wende can be used to explain why the unification of Germany has widely divergent effects for the five hunderd professors of the Humboldt-Universit_t Show less
The aim of this thesis was to study cardiovascular risk management in old age, in order to facilitate the development of age specific guidelines. In part one the current status of cardiovascular... Show moreThe aim of this thesis was to study cardiovascular risk management in old age, in order to facilitate the development of age specific guidelines. In part one the current status of cardiovascular prevention in old age is described, including a study into general practitioners__ attitudes and perceived barriers in this respect. The second part explores the incremental value of routine-ECGs for cardiovascular risk management in older persons from the general population, beyond existing information from medical records. The third part focuses on primary prevention, exploring the performance of classic risk factors, and some new biomarkers, in predicting cardiovascular mortality in very old people from the general population. It was concluded that a homocysteine level alone accurately identifies those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. Next, in various age strata from age 55 years onwards, the association between blood pressure and mortality was studied. Finally, a systematic review into the diagnostic accuracy of natriuretic peptides for the diagnosis of chronic heart failure in older persons from the general population was performed, followed by a study in a cohort of nonagenarians into the prognostic value of NT-proBNP. A general discussion is provided, including directions for future research. Show less
The thesis deals with the history of terrorism and counter-terrorism legislation, focussing on the legislation in the UK, Spain, Germany and France, in the last 30 years, and analysing its... Show moreThe thesis deals with the history of terrorism and counter-terrorism legislation, focussing on the legislation in the UK, Spain, Germany and France, in the last 30 years, and analysing its compatibility with national and European human rights standards. 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
Venous thrombosis results from blood coagulation in veins, most frequently in the deep veins of the leg. Risk factors for venous thrombosis may be environmental or genetic; in most cases venous... Show moreVenous thrombosis results from blood coagulation in veins, most frequently in the deep veins of the leg. Risk factors for venous thrombosis may be environmental or genetic; in most cases venous thrombosis occurs after an environmental trigger on a background of increased susceptibility. This thesis describes research into the genetic variability that determines why some are more prone to develop venous thrombosis than others. Known genetic variants and the family history of venous thrombosis were evaluated as risk factors, and new variants were identified in a large association study of thousands of single nucleotide polymorphisms. Finally, the possibility of genetic profiling was explored, making use of known and newly identified genetic variants. Show less
