Higher age is accompanied with multimorbidity and is also associated with the presence of geriatricconditions. A geriatric assessment (GA) is used to explore the domains of somatic status, mental... Show moreHigher age is accompanied with multimorbidity and is also associated with the presence of geriatricconditions. A geriatric assessment (GA) is used to explore the domains of somatic status, mental,physical and social functioning. Only few studies have assessed the association of a GA withoutcomes in older patients with severe diseases. We show that the majority of the studies inpatients with head and neck cancer and esophageal cancer, reported a significant association ofimpairment in functional and cognitive performance, mood or social environment with a higher riskof adverse outcomes. Third, we investigated older patients reaching end-stage renal disease andreported that high age, low education, low functional status, frailty, higher burden of WMH and ahistory of vascular disease were associated with impaired cognitive function. Finally, we studied apatient reported outcome measurement (self-rated health; SRH) in older patients visiting theemergency department and show that it is at least partly dependent on factors of functional capacityand functional decline. In conclusion, we report that aspects of the GA are associated with adversehealth outcomes. This endorses the importance of taking geriatric characteristics into account inpatients who possibly need intensive treatment, however more research is needed. Show less
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
Endocytosis is a crucial mechanism for the cell to maintain homeostasis. By vesicular transport the cell is able to take up cargo from the cell surface, send molecules to the plasma membrane for... Show moreEndocytosis is a crucial mechanism for the cell to maintain homeostasis. By vesicular transport the cell is able to take up cargo from the cell surface, send molecules to the plasma membrane for excretion or to regulate positioning of internalized cargo in the cell. This thesis describes the regulation of transport complexes associated to these vesicles that determines their movement in the cell. Through recruitment of RAB7GAP the GTPase Rab7 can be removed from the vesicular membrane, allowing for transport mediated by another GTPase called Arl8b.The second part of this thesis focusses on the bacterium Salmonella which manipulates the endosomal system in order to create a niche that supports its own survival. By excretion of effector molecules Salmonella imodulates the membrane content of vesicles and thereby prevents its own lysosomal degradation. This allows Salmonella to create a Salmonella containing vesicle compartment that benefits its own survival in the host cell. This thesis describes how release of these effector molecules can support transformation of host cells. These results explain the strrong correlation between gallbladder cancer and chronic S. Typhi infections observed in patients from countries like India, where S. Typhi infections are still common. Show less
Huntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT... Show moreHuntington’s disease (HD) is a progressive autosomal dominant neurodegenerative disorder with a broad spectrum of clinical features. The disease is caused by a mutation in the Huntingtin gene (HTT) on the short arm of chromosome 4. In September 2015, the first-in-human study looking into the safety of an intrathecally administered antisense oligonucleotide therapy to reduce mutant HTT (mHTT) protein was launched in HD patients, where the drug proved to be safe and the intended mHTT lowering was demonstrated. The aim of this thesis is to find biomarkers corresponding with disease state and measuring progression in different stages of HD, which in turn can be used as suitable objective surrogate clinical trial endpoints. We put special emphasis on longitudinal study designs, as these provide the most useful clinical progression and parameter change associations. Although previous neuroimaging studies have shown potential markers, findings remain inconsistent or lacking association with disease state. As such, further exploration of neuroimaging techniques is of great relevance. Using different approaches to evaluate the potential usefulness of specific markers, we demonstrate biomarkers that may assist in the objective assessment of a potential disease-modifying intervention. Show less
DNA encodes the genetic instructions for living organisms. However, damage to the DNA is inevitable, because DNA itself is an unstable molecule and environmental factors such as UV-radiation or X... Show moreDNA encodes the genetic instructions for living organisms. However, damage to the DNA is inevitable, because DNA itself is an unstable molecule and environmental factors such as UV-radiation or X-rays cause damage to the DNA. A certain type of DNA damages can block DNA replication, an essential step before cell can divide. The polymerases that normally replicate DNA are incredibly efficient and virtually flawless on undamaged DNA, but they cannot replicate damaged DNA. In multi-celled organisms, the most important defense mechanism against this is Translesion DNA synthesis (TLS). TLS protects against various negative consequences of damage to the DNA. For this, TLS utilizes specialized TLS polymerases that can replicate damaged DNA.My experiments show that the strong evolutionary conservation of TLS is explained by the dual functions of TLS: guarding replication potential and genome stability. TLS suppresses genomic instability, by preventing conversion of replication blocks to double-stranded DNA breaks (DSBs). Without functional TLS, DSBs arise and result in larger and more harmful mutations. TLS is beneficial for organisms because it supports continuous reproduction and growth. Although DNA damage is always present and unavoidable, TLS guards against the formation of mutations that would otherwise lead to cancer, aging and congenital disease. Show less
This thesis gives insight into the patient group that survived an OHCA and gives directions to the development, evaluation and implementation of integrated rehabilitation treated programs, with the... Show moreThis thesis gives insight into the patient group that survived an OHCA and gives directions to the development, evaluation and implementation of integrated rehabilitation treated programs, with the ultimated goal being that all surviors and their spouses regain optimal quality of life and autonomy. Our studies showed that survivors of an OHCA attending a rehabilitation program may experience cognitive problems. A first attempt of identifying cognitive problems with a set of cognitive screening instruments in patients who attend a (cardiac) rehabilitation program appeared to be feasible, although the screening needs further refinement. The finding that cognitive impairments have a negative effect on exercise capacity is important to take into account while further optimising the best rehabilitation program. Finally, the rehabilitation program should not only focus on the patient but also on the spouse or the caregiver. By developing a core outcome set for rehabilitation the effectivenss of cognitive rehabilitation in OHCA patients and their relatives can be better evaluated. Show less
Currently, Forensic DNA research is conducted almost exclusively using capillary electrophoresis to determine the length of fragments containing Short Tandem Repeats (STRs). Over the past decade,... Show moreCurrently, Forensic DNA research is conducted almost exclusively using capillary electrophoresis to determine the length of fragments containing Short Tandem Repeats (STRs). Over the past decade, developments in MPS (Massively Parallel Sequencing techniques, also known as Next Generation Sequencing) offered new possibilities for forensic DNA research. This thesis focusses on the preparation, validation and implementation of MPS and the accompanying data analysis. By MPS, the exact DNA sequence of STRs is determined often revealing additional variation on top of the fragment length resulting in an even more unique DNA profile. Sequence information provides more insight on the DNA molecules comprising a conventional DNA profile. With this information, a software could be developed to make a better distinction between genuine alleles and noise offering possibilities for analysis of unbalanced DNA mixtures which are often encountered in forensic casework.As alternative DNA marker to STRs, research was conducted to select microhaplotypes (multiple variable positions in a small fragment). The statistical power of a profile generated from these microhaplotypes turned out to be almost as strong as that of STRs without suffering from the known STR-artefacts thereby offering possibilities for interpretation of DNA mixtures. Show less
The research described in this thesis aimed focused on CHIKV replication and on the identification of much-needed inhibitors of CHIKV infection. Following the development of an in vitro assay to... Show moreThe research described in this thesis aimed focused on CHIKV replication and on the identification of much-needed inhibitors of CHIKV infection. Following the development of an in vitro assay to study CHIKV replication, this tool was used to characterize the mode of action (MoA) of antiviral compounds and suramin was identified as a potent inhibitor of viral RNA synthesis. However, we discovered that in cell culture, suramin’s antiviral activity was mainly due to inhibition of CHIKV binding/entry, and to a lesser extent of virus release. Suramin was also found to inhibit binding/entry and virion biogenesis of Zika virus (ZIKV), a recently emerged flavivirus. Due to its ability to form electrostatic interactions with positive charges on proteins, suramin may block the contact between virions and their (co)receptors, by interacting with either virus or receptor, or with both. Using radioactively-labelled suramin, it was clearly shown that the compound interacts with CHIKV particles, more specifically with their envelope proteins. Additionally, suramin could interfere with cell attachment and/or the structural changes required for fusion. Suramin-resistant CHIKV variants were selected, which contained mutations in the E2 envelope protein (involved in receptor interactions), supporting the idea that suramin blocks the early steps of the infectious cycle. Show less
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of thrombocytopenia in otherwise healthy newborns. During pregnancy, fetal blood cells enter the maternal circulation... Show moreFetal and neonatal alloimmune thrombocytopenia (FNAIT) is the most common cause of thrombocytopenia in otherwise healthy newborns. During pregnancy, fetal blood cells enter the maternal circulation and might result in alloimmunization, the maternal production of antigen-specific alloantibodies. Once these alloantibodies enter the fetal circulation, they can cause damage. Clinical presentation can vary from an asymptomatic thrombocytopenia or relatively harmless bruises and petechiae to severe life-threatening and invalidating intracranial hemorrhages (ICHs). Once alloimmunization is detected and diagnosed, subsequent pregnancies can be treated to prevent the recurrence of bleeding complications. Unfortunately, in absence of population-based screening, alloimmunization is virtually only known after an affected fetus or newborn. Affected infants that might have been prevented if only the alloimmunization was known and treated prior to the occurrence of bleeding complications. Implementation of population-based screening in order to prevent FNAIT needs to be a carefully weighed decision. The benefits of screening need to outweigh the potential harm. To guide careful consideration and decision-making, Wilson and Jungner (W&J) proposed and published ten screening criteria. With this thesis, important evidence is presented that can be used for the fulfillment of the W&J criteria. Show less
This thesis describes a cross-sectional behavioral and neuroimaging study in a sample of n=85 adolescents with a history of childhood sexual abuse related PTSD (CSA-related PTSD), anxiety and/or... Show moreThis thesis describes a cross-sectional behavioral and neuroimaging study in a sample of n=85 adolescents with a history of childhood sexual abuse related PTSD (CSA-related PTSD), anxiety and/or depressive disorders or no psychiatric symptoms. We assessed attachment representation as well as psychopathological symptoms, attentional bias and emotional face processing among diagnostic groups. We also correlated unresolved-disorganized attachment representation (Ud) and psychopathology using a general psychopathology factor (GPF) to grey matter (volume), white matter (tracts) and resting state functional connectivity (RSFC) of the brain in the entire sample. We found that clinical groups did not significantly differ in psychopathology. The unresolved-disorganized cannot classify category (Ud/CC) was overrepresented in the CSA-related PTSD group. Coherence of mind also differentiated the clinical groups, but Ud did not. The CSA-related PTSD group had a negative attention bias for neutral and fearful faces, the anxiety/depressive disorders group only for fearful faces. No differences were found for emotional face processing among diagnostic groups. We found a differential relationship of Ud and a GPF to grey matter volume, white matter integrity of white matter tracts and RSFC for Ud. Ud was associated with lateralization of the brain to the left with regard to amygdala RSFC and hippocampal volume. Show less
Hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D) is an early onset hereditary form of Cerebral amyloid angiopathy (CAA) caused by a point mutation of the Amyloid Precursor... Show moreHereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D) is an early onset hereditary form of Cerebral amyloid angiopathy (CAA) caused by a point mutation of the Amyloid Precursor protein (APP). CAA refers to the accumulation of Amyloid β (Aβ) peptide, resulting from APP protein cleavage, in intracerebral vessels. CAA pathology is present in the majority of Alzheimer’s Disease (AD) brains and is associated with intracerebral hemorrhages in the elderly. The general aim of this thesis is to decipher the molecular pathogenesis of HCHWA-D. Since no proven therapeutic treatment exists to prevent or even delay the disease onset, the understanding of underlying pathomechanisms in HCHWA-D is important. It may help discovering new therapeutic targets and biomarkers that can be used to assess the efficacy of candidate drugs in treatment trials. The main finding of this thesis is that Transforming growth factor β (TGFβ) deregulation plays a central role in HCHWA-D pathogenesis. In the final chapter, the beneficial and detrimental aspects of TGFβ on the vascular and parenchymal brain components are reviewed and the possible causes of TGFβ activation in HCHWA-D as well as its implication for future studies and therapeutic intervention are discussed. Show less
Hematopoietic stem and progenitor cells (HSPC) reside in specific niches in the bone marrow, where they are part of a complex micro-environment. Several cytokines, chemokines and small molecules... Show moreHematopoietic stem and progenitor cells (HSPC) reside in specific niches in the bone marrow, where they are part of a complex micro-environment. Several cytokines, chemokines and small molecules are involved in mobilization of HSPC from the bone marrow towards peripheral blood. This thesis describes several studies on the mechanisms of HSPC mobilization: the kinetics of HSPC mobilization following the administration of Flt3-ligand in a murine model, the effects of repeated in vivo administration of recombinant human G-CSF and murine recombinant G-CSF in mice, the role of alpha-1-antitrypsin in steady state and during G-CSF-induced mobilization in humans and the effects of mesenchymal stromal cells on the stem cell niche in a murine model of G-CSF-induced HSPC mobilization. Show less
The risk of cutaneous squamous cell carcinoma (cSCC) is highly increased in organ transplant recipients (OTR) and these tumours carry a major health burden for these patients. This thesis dealt... Show moreThe risk of cutaneous squamous cell carcinoma (cSCC) is highly increased in organ transplant recipients (OTR) and these tumours carry a major health burden for these patients. This thesis dealt with several aspects of cSCC in OTR. The chapters 2 and 3 review the role of HPV in cSCC and study HPV as a prognostic factor in the aetiology of cSCC. Subsequently, diagnostic factors were studied. In chapter 4 we intended to identify p16 as a possible histopathological marker for cSCC and in chapter 5 we studied the clinical implication of pain as a symptom to differentiate cSCC from other keratinocyte lesions. In chapter 6 we reviewed the literature on metastasis risk in immunocompetent versus OTR population. We studied in chapter 7 in our own population the risk for metastasis, and subsequently risk factors, of cSCC in OTR compared to immunocompetent patients. Show less
The work presented in this thesis provides novel contributions to advanced quantitative functional assessment of vascular endothelial and smooth muscle cells differentiated from hiPSCs. The... Show moreThe work presented in this thesis provides novel contributions to advanced quantitative functional assessment of vascular endothelial and smooth muscle cells differentiated from hiPSCs. The automated assays described provide an unbiased and quantitative assessment of the functionality of hiPSC derivatives which are extremely needed for disease modeling and drug screening. Also, we have demonstrated the consistency of results obtained from cells differentiated from multiple healthy hiPSC lines which makes them good candidates for realistic in vitro models of human vasculature. Show less
In this thesis the additional value of targeted Next-Generation Sequencing was described in order to optimize the diagnostic process of patients with a suspect pancreatic lesion. Furthermore,... Show moreIn this thesis the additional value of targeted Next-Generation Sequencing was described in order to optimize the diagnostic process of patients with a suspect pancreatic lesion. Furthermore, several imaging techniques are described to visualize pancreatic cancer or colorectal liver metastases prior to surgery and during surgery. By better visualization of the tumor extent optimal treatment plans can be proposed and radical resections can be accomplished. Show less
The aim of the research described in this thesis was to gain a better understanding of the role of the different immune cells and the different FcR on their cell surface, in antibody therapy and... Show moreThe aim of the research described in this thesis was to gain a better understanding of the role of the different immune cells and the different FcR on their cell surface, in antibody therapy and to investigate whether the effectiveness of the tumor-killing mechanisms, activated by the antibodies, can be improved. First, we investigated the role of FcR in various immune responses using a genetically modified mouse, in which all FcR were missing. After defining that role, we studied antibody therapy in a mouse model for melanoma in two different ways: on the one hand, after vaccination using a viral vector that expressed a melanoma antigen, on the other hand, by injecting a melanoma-specific antibody in combination with other substances that activate the immune system. Show less
Using a variety of anti-malaria tools has resulted in a steady decline of malaria in several endemic countries worldwide. An effective vaccine will be critical to halt malaria or even succeed to... Show moreUsing a variety of anti-malaria tools has resulted in a steady decline of malaria in several endemic countries worldwide. An effective vaccine will be critical to halt malaria or even succeed to final eradication. In that perspective, we studied the potential of whole sporozoite immunization by bites of P. falciparum infected mosquitoes under chemoprophylaxis (CPS). In this thesis we further explored this CPS model and assessed different immunizing doses, type of chemoprophylaxis and immunological determinants of disease and protection. We found a clear dose dependent efficacy, independent of type of chemoprophylaxis, found CD107a and CD8 T cells producing granzyme B related to protective immunity. In the field many genetically different strains circulate and a future vaccine should be able to cover multiple strains. We re-challenged volunteers with a different strain and found modest heterologously protection.We retrospectively assessed the parasitological dynamics and adverse events using a positive qPCR rather than thick smear and found reduced the clinical symptoms of malaria for volunteers after challenge.Successful malaria eradication will be more likely to be achieved with a multi-disciplinary approach. Additionally, sufficient and continuous funds will proof to be of tremendous necessity. Show less
Sexual health and fertility does not come naturally for men and women suffering chronic kidney disease (CKD); sexual dysfunction and fertility issues are common throughout all stages of disease,... Show moreSexual health and fertility does not come naturally for men and women suffering chronic kidney disease (CKD); sexual dysfunction and fertility issues are common throughout all stages of disease, including dialysis and transplantation. These issues, alongside with other side-effects of CKD, affect patients social and relation life as well. Besides, their partners often fulfill an important and supportive role during intensive treatments or a lingering sickbed. As a result, the disease and the accompanying burdens affect also their partners’ well-being on several levels.Since CKD patients and their partners face multiple challenges in the area of sexuality, fertility, and relationships one could assume awareness about these difficulties exist among their care providers. Unfortunately, this thesis shows that renal care providers do not routinely discuss sexuality with their patients, underlying reasons varied between the different renal care providers. Whereas the results imply that providing an opportunity to discuss sexuality during is preferred by patients and their partners, especially after renal transplantations.As for fertility, most nephrologists include this subject in their consultation. However nurses of the nephrology department could also play an important role in addressing this part of renal care, however, insufficient knowledge is a retaining factor for them. Show less
Persistent postoperative step-off of the posterior fragment in trimalleolar fractures is the most important predictor for development of posttraumatic osteoarthritis and therefore for worse... Show morePersistent postoperative step-off of the posterior fragment in trimalleolar fractures is the most important predictor for development of posttraumatic osteoarthritis and therefore for worse functional outcome. An anatomical reduction and fixation of posterior fragments is therefore essential and can probably be performed best, and in a safe way, through an open posterolateral approach. Show less
This thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is... Show moreThis thesis on systemic treatment options in soft tissue sarcomas consists of two parts. In part I, the pharmacogenetics of systemic gastro-intestinal stromal tumors (GIST) treatment is investigated. SNPs related to the pharmacokinetics and pharmacodynamics of imatinib and sunitinib have been associated to survival and to toxicity. SNPs in VEGFA and SLCO1B3 have been associated to worse progression free survival during imatinib treatment of advanced GIST. SNPs in ABCG2 and CYP1A2 have been associated with the need for dose reduction in patients receiving imatinib for GIST. A SNP in POR was associated with better progression free survival during sunitinib treatment of advanced GIST . In part II the usage of trabectedin is soft tissue sarcomas (STS) in the Netherlands is studied. Trabectedin as second line treatment of soft tissue sarcoma was compared to ifosfamide monotherapy. The Incremental Cost-Effectiveness Ratio for leiomyosarcomas and liposarcomas was at the top end of what is considered acceptable in the Netherlands. For other soft tissue sarcomas subtypes, ifosfamide dominated trabectedin. The venous access related adverse events of trabectedin have been described. The research in this thesis contributes towards personalised treatment for advanced soft tissue sarcomas. Show less
