Breast cancer has a high mortality in women worldwide. Tumor cells experience hypoxia, which is accompanied by alterations in cell metabolism and can drive metastasis by triggering an epithelial... Show moreBreast cancer has a high mortality in women worldwide. Tumor cells experience hypoxia, which is accompanied by alterations in cell metabolism and can drive metastasis by triggering an epithelial–mesenchymal transition (EMT) in the tumor cells. Yes-associated protein (YAP) and a transcriptional co-activator with PDZ-binding (TAZ) are two transcriptional co-activators involved in growth, metabolism, and metastasis in cancer. Breast cancer can be divided into different subtypes. One criterium underlying such subtypes is based on the levels of Human Epidermal growth factor Receptor 2 (HER-2), Estrogen Receptor (ER) and Progesterone Receptor (PR). The subtypes include luminal-like (luminal A and luminal B), HER-2 enriched and basal-like (often “triple negative”). Triple negative breast cancer (TNBC) has a lower survival rate due to the lack of therapeutic targets. Fundamental research exploring the molecular mechanisms at work in cancer cells and their response to a hypoxic environment may contribute to insights for future clinical treatment. This thesis focused on profiling breast cancer cells belonging to distinct subtypes under acute and chronic hypoxia, investigating the crosstalk between hypoxia regulated pathways and YAP/TAZ signaling in luminal breast cancer versus TNBC cells, and identification of the potential targets of TAZ in breast cancer cells. Show less
Most preterm infants need respiratory support and extra oxygen during their admission to the neonatal intensive care. The amount of oxygen required can fluctuate a lot. Bedside staff frequently... Show moreMost preterm infants need respiratory support and extra oxygen during their admission to the neonatal intensive care. The amount of oxygen required can fluctuate a lot. Bedside staff frequently administer extra oxygen, and when the blood oxygen level is normalised, reduce this extra oxygen carefully. This is a delicate process, a fraction too much or a fraction too little may harm their underdeveloped organs.As one of the first, the LUMC has been titrating oxygen automatically since 2015. In this thesis we investigated the effect of this automatization and how preterm infants can profit from this technology. We found that automated oxygen titration reduced the duration of invasive ventilation, but outcome at two years of age was left unchanged. A new automated oxygen controller from 2018 led to even more improvement. Infants spent more time in the narrow therapeutic range, needed even less intensive respiratory support and developed less retinopathy – a disease of the retina which, when untreated, can lead to blindness.From this thesis we can conclude that there is a short-term benefit from automated oxygen titration and we are moving in the right direction. Further research is needed to make the most out of this technology. Show less
Metabolic reprogramming of cancer cells generates a tumour microenvironment (TME) characterised by nutrient restriction, hypoxia, acidity and oxidative stress. While these conditions are... Show moreMetabolic reprogramming of cancer cells generates a tumour microenvironment (TME) characterised by nutrient restriction, hypoxia, acidity and oxidative stress. While these conditions are unfavourable for infiltrating effector T cells, accumulating evidence suggests that regulatory T cells (Tregs) continue to exert their immune-suppressive functions within the TME. The advantages of Tregs within the TME stem from their metabolic profile. Tregs rely on oxidative phosphorylation for their functions, which can be fuelled by a variety of substrates. Even though Tregs are an attractive target to augment anti-tumour immune responses, it remains a challenge to specifically target intra-tumoral Tregs. We provide a comprehensive review of distinct mechanistic links and pathways involved in regulation of Treg metabolism under the prevailing conditions within the tumour. We also describe how these Tregs differ from the ones in the periphery, and from conventional T cells in the tumour. Targeting pathways responsible for adaptation of Tregs in the tumour microenvironment improves anti-tumour immunity in preclinical models. This may provide alternative therapies aiming at reducing immune suppression in the tumour. Show less
Jasperse, L.; Levin, M.; Rogers, K.; Perkins, C.; Bosker, T.; Griffitt, R.J.; ... ; De Guise, S. 2019
Conventional chemotherapy often suffers from a lack of specificity, affecting both normal and cancer cells. Light-activated drugs provide spatial and temporal control over their activity, providing... Show moreConventional chemotherapy often suffers from a lack of specificity, affecting both normal and cancer cells. Light-activated drugs provide spatial and temporal control over their activity, providing a possible solution for this problem. This dissertation describes the synthesis and biological applications of (blue/green/red) light-activated ruthenium polypyridyl drugs as potential prodrugs against cancer. Show less
Kraus, A.; Grampp, S.; Goppelt-Struebe, M.; Schreiber, R.; Kunzelmann, K.; Peters, D.J.M.; ... ; Buchholz, B. 2016
Vertebrates, especially mammals, have long been used as research models in the study of human diseases. During this research we have demonstrated the usefulness of a relatively new animal model,... Show moreVertebrates, especially mammals, have long been used as research models in the study of human diseases. During this research we have demonstrated the usefulness of a relatively new animal model, the zebrafish, in understanding human disease formation, progression and even treatment. We first analysed the impact that exposure to constant chronic hypoxia has in the zebrafish heart, both at the morphological and genetic levels. On chapters three and four we demonstrated the worth of the zebrafish larvae in understanding metastasis formation and progression. Whereas in chapter three we focused on the use of the zebrafish as a model to rapidly test the metastatic behaviour of human pancreatic cancer cell lines and primary human tumours; on chapter four we researched the role of retinoic acid receptor antagonist, and mir10-a, as a potential new anti-cancer therapy for pancreatic adenocarcinoma. Show less
Air travel has become a well-known risk factor for venous thrombosis with an absolute risk of 1 in 4600 long-haul flights and a dose-response relationship with duration and number of flights. In... Show moreAir travel has become a well-known risk factor for venous thrombosis with an absolute risk of 1 in 4600 long-haul flights and a dose-response relationship with duration and number of flights. In this thesis we studied the pathophysiology that underlies the risk as well as the effect of behaviour of passengers on the risk of thrombosis after air travel. To study the pathophysiology, we conducted a case-crossover study in which we investigated the effect on the coagulation system of 8 hours of air travel, 8 hours of immobilisation in a cinema and 8 hours of daily activities in 71 volunteers. Behaviour of passengers was studied in the MEGA study, a large case-control study on risk factors of venous thrombosis. The main conclusion of this thesis is that immobilisation alone does not explain coagulation activation after air travel. A factor that seems to contribute is hypoxia. The results of this thesis do not support the theories that fluid loss, air pollution, infection or stress play a role in coagulation activation after air travel. Certain kinds of behaviour during air travel affect the risk of venous thrombosis. Lastly, harmless prevention methods possibly counter the effect of immobilisation. Show less
Migraine is a severe headache syndrome, affecting approximately 33% of females and 13% of males. Patients suffer from recurring headache episodes in combination with nausea, vomiting, phono and... Show moreMigraine is a severe headache syndrome, affecting approximately 33% of females and 13% of males. Patients suffer from recurring headache episodes in combination with nausea, vomiting, phono and photophobia. It is a paroxysmal disorder for which several several trigger factors have been identified by patients. This thesis has focused on the relation between i) psychosocial stress, ii) nitroglycerin and iii) hypoxia and the occurrence of a migraine attack, as well as the mechanism of action. The first conclusion is that, in contrast to previous studies, we could not detect a correlation between psychosocial stress and migraine. The second conclusion is that normobaric hypoxia might be a trigger factor for migraine possibly through the development of mild cerebral edema. The third conclusion is that migraine can be triggered by nitroglycerin through a vascular effect without any indication of vasodilation in cerebral or meningeal arteries during the delayed provoked attack. Show less
Head and Neck Paragangliomas (HNP) are hypervascular tumours characterised by a slow growth pattern and a strong hereditary context that originate from the neural crest derived paraganglia, which... Show moreHead and Neck Paragangliomas (HNP) are hypervascular tumours characterised by a slow growth pattern and a strong hereditary context that originate from the neural crest derived paraganglia, which are associated with the autonomous nervous system and are situated at several locations in the head and neck region. Inactivating mutations in subunits of complex II (SDH) of the mitochondrial respiratory chain are responsible for hereditary tumours and have lead to a novel concept of mitochondrial tumoursupressor-genes and further insight in the intricate association of cellular oxygen sensing mechanisms and (pseudo)-hypoxia as environmental risk factors. However, further characterisation of the tumour biology is warranted for better understanding of the natural behaviour of HNP and possible identification clinicopathological parameters that could aid the clinician in his treatment decisions. In this thesis several studies on the molcular pathology of HNP are discussed including genotype-fenotype relations, the role of bFGF in tumourgenisis, the interplay between proliferation, cell cycle activity and apoptosis, and the nature of sustentacular cells in these apparent biphasic tumours. Additionally, in a clincal study the prevalence of synchronic or metachronic pheochromocytomas in patients with SDHD-linked HNP was determined. Show less
Waar mensen zijn vindt nutriënten-verrijking van het water plaats. In de zomer kunnen algen hierdoor goed groeien. Dode algen en andere resten zakken naar de bodem waarna door rottingsprocessen de... Show moreWaar mensen zijn vindt nutriënten-verrijking van het water plaats. In de zomer kunnen algen hierdoor goed groeien. Dode algen en andere resten zakken naar de bodem waarna door rottingsprocessen de zuurstofconcentratie in het water sterk kan dalen. Het water wordt hierdoor onleefbaar voor vissen en andere organismen. In het Victoriameer in Afrika is het altijd zomer en grote gebieden zijn hier de laatste decennia zuurstofarm geworden. Men kan aannemen dat dit zeer slecht is voor de visstand. Toch blijken Victoriameervissen beter te kunnen overleven dan men dacht. In ons laboratorium in Leiden zagen we drie weken oude Victoriameervisjes (cichlidensoorten) zeer snel konden wennen aan zuurstofarme omstandigheden. Zij bleken zelfs met tien keer minder zuurstof (0,8 mg per liter) net zo hard te groeien als nestgenoten die onder normale omstandigheden leefden. Volwassen vissen gaan dood of overleven dit slechts tijdelijk. Jonge visjes kunnen zo goed overleven omdat zij tot 80% grotere kieuwen krijgen en continue een veel hogere ademactiviteit hebben. De aanleg van deze superkieuwen kost zoveel ruimte dat zelfs hun kop van vorm veranderde. Het bloed dat door de kieuwen stroomt bleek meer en beter zuurstof te kunnen binden terwijl een soort meerdere nieuwe typen hemoglobine bleek te produceren. Dit is een unieke eigenschap die bij andere dieren alleen optreedt bij geboorte of bijvoorbeeld transformaties van water naar land bij amfibieën. Het waterpeil in het Victoriameer was 14.000 jaar geleden extreem laag en mogelijkerwijs heeft een voorouder van deze soort deze truc destijds onder de knie gekregen die in het zuurstofarme water van nu weer van pas komt. Show less
