Drug induced organ toxicity is the main problem of the drug development and drug usage in the clinic. The liver and kidneys are the most sensitive organs towards drug induced toxicity. The liver... Show moreDrug induced organ toxicity is the main problem of the drug development and drug usage in the clinic. The liver and kidneys are the most sensitive organs towards drug induced toxicity. The liver neutralizes xenobiotic to which human are exposed to while the kidneys remove waste products from the blood. Due to their detoxification function, these organs are continuously exposed to high amount of toxicants leading to potential injury. Investigating the molecular and cellular mechanisms contributing to drug-induced liver injury (DILI) and drug-induced kidney injury (DIKI) will open new avenues that can help in the prediction of induced organ injury caused by drugs as well as other xenobiotics.In this thesis, we mapped the dynamics of cellular stress responses in the liver and kidneys upon the exposure of a set of model compounds in order to gain a more holistic insight in DILI and DIKI. We conducted multiple extensive in vitro and in vivo studies to understand the dynamics of these cellular responses and determined the translation of our findings from in vitro to in vivo. Transcriptomics analysis was central in the research which was complemented with other methodologies, such as reporter cell assay, immunohistochemistry, to unravel the mechanisms of drug-induced organ toxicity in both liver and kidney. Show less
Background Robotic surgery may improve surgical performance during minimally invasive pancreatoduodenectomy as compared to 3D- and 2D-laparoscopy but comparative studies are lacking. This study... Show moreBackground Robotic surgery may improve surgical performance during minimally invasive pancreatoduodenectomy as compared to 3D- and 2D-laparoscopy but comparative studies are lacking. This study assessed the impact of robotic surgery versus 3D- and 2D-laparoscopy on surgical performance and operative time using a standardized biotissue model for pancreatico- and hepatico-jejunostomy using pooled data from two randomized controlled crossover trials (RCTs). Methods Pooled analysis of data from two RCTs with 60 participants (36 surgeons, 24 residents) from 11 countries (December 2017-July 2019) was conducted. Each included participant completed two pancreatico- and two hepatico-jejunostomies in biotissue using 3D-robotic surgery, 3D-laparoscopy, or 2D-laparoscopy. Primary outcomes were the objective structured assessment of technical skills (OSATS: 12-60) rating, scored by observers blinded for 3D/2D and the operative time required to complete both anastomoses. Sensitivity analysis excluded participants with excess experience compared to others. Results A total of 220 anastomoses were completed (robotic 80, 3D-laparoscopy 70, 2D-laparoscopy 70). Participants in the robotic group had less surgical experience [median 1 (0-2) versus 6 years (4-12), p < 0.001], as compared to the laparoscopic group. Robotic surgery resulted in higher OSATS ratings (50, 43, 39 points, p = .021 and p < .001) and shorter operative time (56.5, 65.0, 81.5 min, p = .055 and p < .001), as compared to 3D- and 2D-laparoscopy, respectively, which remained in the sensitivity analysis. Conclusion In a pooled analysis of two RCTs in a biotissue model, robotic surgery resulted in better surgical performance scores and shorter operative time for biotissue pancreatic and biliary anastomoses, as compared to 3D- and 2D-laparoscopy. Show less
This thesis describes the possible applicability of mesenchymal stromal cells (MSCs) in the treatment of liver fibrosis. In CCL4 induced animal models for liver fibrosis, we showed that local... Show moreThis thesis describes the possible applicability of mesenchymal stromal cells (MSCs) in the treatment of liver fibrosis. In CCL4 induced animal models for liver fibrosis, we showed that local administration of MSCs after partial hepatectomy, results in a dose‐dependent on‐site amelioration of fibrosis. Furthermore, we compared the pro-regenerative and anti-fibrotic effects of four different subpopulations of MSCs, categorized on Endoglin (CD105) and VCAM (CD106) membrane expression. Our results showed that VCAM-positive subpopulations of MSCs are superior compared to VCAM-negative subpopulations in relation to their anti-fibrotic and pro-regenerative properties. In another study we showed that TAA induce liver fibrogenesis in zebrafish embryos through mechanisms similar to man and mice. In addition, we found that MSCs ameliorate fibrogenesis in this model.CRIPTO-1 is an (onco)foetal protein and is correlated to poor prognosis in HCC. The observations of our HCC study are suggestive for the existence of a more aggressive subgroup of HCCs recognized by their high CRIPTO-1 expression which also seems to be resistant to Sorafenib treatment. Cell survival and cell proliferation are some of the processes stimulated by CRIPTO-1, which are also known to be important during liver regeneration and fibrogenesis. We identified that multiple species show enhanced CRIPTO-1 during fibrogenesis and that elevated CRIPTO-1 plasma levels in humans with cirrhosis normalize after liver transplantation. Show less
Autologous platelet sequestration pattern is associated with post-splenectomy platelet response in patients with immune thrombocytopenia (ITP). However, published results are contradictory, and... Show moreAutologous platelet sequestration pattern is associated with post-splenectomy platelet response in patients with immune thrombocytopenia (ITP). However, published results are contradictory, and have not been systematically reviewed. Our aim is to systematically review and meta-analyse the association between sequestration pattern and post-splenectomy platelet response. Articles were selected from MEDLINE when they a) included ITP patients, b) performed scintigraphy, and c) included post-splenectomy platelet response. The 23 included studies (published between 1969-2018) represented 2966 ITP-patients. Response to splenectomy occurred most frequently in patients with a splenic pattern (87.1 % in splenic versus 47.1 % in mixed and 25.5 % in hepatic patterns). A pooled analysis of 8 studies showed an odds ratio of 14.21 (95 % CI: 3.65-55.37) for platelet response in the splenic versus the hepatic group. Our findings indicate that a splenic sequestration pattern is associated with better response after splenectomy. Platelet sequestration patterns may be useful in the clinical decision-making regarding splenectomy. Show less
This thesis describes the role of the brain in the regulation of peripheral triglyceride metabolism, in the context of the metabolic syndrome. Based on various pharmacological studies we described... Show moreThis thesis describes the role of the brain in the regulation of peripheral triglyceride metabolism, in the context of the metabolic syndrome. Based on various pharmacological studies we described the role of two hormones, insulin and glucagon-like peptide-1, in the production and clearance of triglycerides. We showed that insulin stimulates the uptake of (triglyceride-derived) fatty acids and that the brain plays an essential role in this process. Additionally, we showed that the glucagon-like peptide-1 receptor analogue exendin-4 decreases triglyceride production by the liver, albeit that the brain does not seem to be involved in this effect. Furthermore, we unraveled the mechanism underlying the effects of metformin, the first-line drug used to treat Type 2 Diabetes, on triglyceride metabolism. We showed that metformin lowers plasma triglyceride levels by stimulating the uptake and subsequent oxidation of triglycerides by the brown adipose tissue, and herewith provided new therapeutical opportunities for this drug. Finally, we showed that apolipoprotein A5, a stimulator of triglyceride hydrolysis and subsequent clearance from the plasma, plays a role in the central regulation of food intake, and herewith described a novel function for this apolipoprotein. Show less
In this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved... Show moreIn this thesis, the role of the liver and lungs in atherosclerosis development were studied. The liver plays an important role in lipid metabolism and inflammation, the two main processes involved in atherogenesis. We show that continuous enhanced inflammation in hepatocytes increased the hepatic production of VLDL and aggravated atherosclerosis development in hyperlipidemic APOE*3-Leiden (E3L) mice as compared to control E3L mice. Poor lung function, most commonly caused by chronic obstructive pulmonary disease (COPD), is a risk factor for atherosclerosis development. To this end, we investigated whether elastase-induced alveolar wall destruction, a model for COPD, would worsen atherosclerosis development in E3L mice. No difference in atherosclerotic lesion size was observed between mice after elastase or vehicle instillation, indicating that alveolar destruction per se is not responsible for the increased risk for atherosclerosis in COPD patients. Furthermore, we studied the anti-atherosclerotic effects of resveratrol which can be found in red wine and Asian medicinal herbs. Hyperlipidemic E3L.CETP mice were fed a diet without (control) or with resveratrol, atorvastatin, or both. Resveratrol protected against atherosclerosis development, but did not add to the anti-atherogenic effects of atorvastatin. Finally, the clinical implications and future perspectives of these results are discussed. Show less
Drug-induced organ toxicity is a major concern for pharmaceutical industry, due to removal of a high number of drugs from the market, as well as for public health, due to numerous hospitalizations... Show moreDrug-induced organ toxicity is a major concern for pharmaceutical industry, due to removal of a high number of drugs from the market, as well as for public health, due to numerous hospitalizations and patient death. The organs that are the primary target for such toxicities are the liver and the kidneys since both organs are continuously exposed to high concentrations of drugs and have high metabolic capacities. The immune system has been shown to be involved in the toxicity of several drugs- inducing liver and kidney injury. In particular, the cytokine tumor necrosis factor _ (TNF-_) has been shown to be the main constituent of the inflammatory processes responsible for the aggravation of drug-induced liver and kidney injuries. In this thesis, the role of TNF-_ in drug-induced organ injury was investigated. The main question was to assess the possible synergy between TNF-_ and druginduced cytotoxicities, and to unravel the underlying molecular mechanisms of such a synergy. Show less
Karkampouna, S.; Dijke, P. ten; Dooley, S.; Kruithof-de Julio, M. 2012
Atherosclerosis is the underlying cause of most cardiovascular diseases. The evidence to support a cholesterol-atherosclerosis link has been revealed in the past three decades. There is a growing... Show moreAtherosclerosis is the underlying cause of most cardiovascular diseases. The evidence to support a cholesterol-atherosclerosis link has been revealed in the past three decades. There is a growing consensus that therapeutic lowering of plasma VLDL- and LDL-cholesterol levels and raising of HDL-cholesterol level will reduce the risk of cardiovascular incidence. This dissertation is dedicated to the regulation of lipid metabolism pathways, both in plasma and liver, and its subsequent effects on atherosclerotic lesion progression and regression. The first part of the thesis focuses on the hepatic lipid metabolism and the pharmaceutical interventions in the liver. The second part of the thesis focuses on the concept of atherosclerotic lesion regression, shedding insights in the role of LXR activation and application of mouse models in regression studies. In Chapter 8, the results obtained from all the experiments mentioned above are summarized and discussed with respect to the implications of these studies for future investigations. Show less
The aim of the thesis was to provide more insight into the influence of myocardial steatosis on left ventricular function in healthy volunteers and in patients with type 2 diabetes mellitus.... Show moreThe aim of the thesis was to provide more insight into the influence of myocardial steatosis on left ventricular function in healthy volunteers and in patients with type 2 diabetes mellitus. Therefore we developed a reproducible proton magnetic resonance (MR) spectroscopic technique with respiratory motion compensation to study myocardial steatosis. Using these technique, combined with MR imaging to study myocardial function, correlations between myocardial steatosis and left ventricular function were shown in several (patho)physiological conditions. Furthermore, we showed that myocardial triglyceride content is increased in patients with type 2 diabetes mellitus and is an independent predictor of left ventricular diastolic dysfunction. In addition, differential, tissue-specific partitioning of triglycerides and/or fatty acids among non-adipose organs during various diets was shown. Given the obesity and type 2 diabetes mellitus pandemic and the increasing evidence indicating that lipid oversupply to cardiomyocytes plays a role in the development of diabetic cardiomyopathy, therapeutic strategies that target reduction of cardiac lipid overexposure might be beneficial to prevent diabetic cardiomyopathy. Show less
Hyperlipidemie is een belangrijk gezondheidsrisico in de westerse samenleving en direct gerelateerd aan diabetes en overgewicht. Zowel eetgewoontes als genetische afwijkingen kunnen zorgen voor een... Show moreHyperlipidemie is een belangrijk gezondheidsrisico in de westerse samenleving en direct gerelateerd aan diabetes en overgewicht. Zowel eetgewoontes als genetische afwijkingen kunnen zorgen voor een verstoord vetmetabolisme en ophoping van cholesterol en triglyceriden in het bloed. Pati_nten die lijden aan Familiaire Dysbetalipoproteinemie hebben een genetisch defect in apolipoproteine E (apoE). ApoE is een eiwit dat een centrale rol speelt in het vetmetabolisme. ApoE bevindt zich op lipoproteine deeltjes die cholesterol en triglyceriden door het bloed vervoeren en zorgt voor interactie met enzymen en receptoren. Een genetisch defect in apoE zal resulteren in verhoogde niveaus van "very-low density lipoprotein" (VLDL) deeltjes in de bloedbaan. In dit proefschrift zijn de positieve en negatieve effecten van apoE in VLDL metabolisme besproken. Negatieve effecten zijn een klaringsdefect dat is geassocieerd met APOE2, maar ook een toename van productie snelheid en verminderde lipolyse van VLDL door overexpressie van APOE4. We vonden dat wanneer het C-terminale domein van APOE4 wordt verwijderd, dit eiwit de APOE2-geassocieerde hyperlipidemie verlaagt. Deze getrunceerde variant van APOE4 heeft niet het lipiden verhogende effect van apoE. Verder hebben we nieuwe inzichten verkregen in de rol van LPL-gemedieerde VLDL-TG hydrolyse in APOE-geassocieerde hyperlipidemie en de interactie tussen LPL, apoE en de back-up lever receptor LRP Show less
This thesis centers on the mechanisms of estrogen action and the effects on the development of atherosclerosis. We have focused on the liver as central organ in lipid and glucose metabolism and the... Show moreThis thesis centers on the mechanisms of estrogen action and the effects on the development of atherosclerosis. We have focused on the liver as central organ in lipid and glucose metabolism and the vessel wall as the actual site where the injury occurs. To gain insight in tissue-specific actions of estrogens, we have spent considerable effort to develop tools for liver and blood vessel specific modulation of the estrogen receptor (ER) signaling cascade. The generation, characterization and application of these tools in vitro and in vivo will be described in the different chapters of this thesis. Show less
