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Nijmegen, Netherlands
Nijmegen, Netherlands

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Boots-Sprenger S.H.E.,Radboud University Nijmegen | Sijben A.,Canisius Wilhelmina Hospital | Sijben A.,Spectrum | Rijntjes J.,Radboud University Nijmegen | And 14 more authors.
Modern Pathology | Year: 2013

The histopathological diagnosis of diffuse gliomas often lacks the precision that is needed for tailored treatment of individual patients. Assessment of the molecular aberrations will probably allow more robust and prognostically relevant classification of these tumors. Markers that have gained a lot of interest in this respect are co-deletion of complete chromosome arms 1p and 19q, (hyper)methylation of the MGMT promoter and IDH1 mutations. The aim of this study was to assess the prognostic significance of complete 1p/19q co-deletion, MGMT promoter methylation and IDH1 mutations in patients suffering from diffuse gliomas. The presence of these molecular aberrations was investigated in a series of 561 diffuse astrocytic and oligodendroglial tumors (low grade n=110, anaplastic n=118 and glioblastoma n=333) and correlated with age at diagnosis and overall survival. Complete 1p/19q co-deletion, MGMT promoter methylation and/or IDH1 mutation generally signified a better prognosis for patients with a diffuse glioma including glioblastoma. However, in all 10 patients with a histopathological diagnosis of glioblastoma included in this study complete 1p/19q co-deletion was not associated with improved survival. Furthermore, in glioblastoma patients >50 years of age the favorable prognostic significance of IDH1 mutation and MGMT promoter methylation was absent. In conclusion, molecular diagnostics is a powerful tool to obtain prognostically relevant information for glioma patients. However, for individual patients the molecular information should be interpreted with caution and weighed in the context of parameters such as age and histopathological diagnosis. © 2013 USCAP, Inc.


Dankers A.C.A.,Radboud University Nijmegen | Mutsaers H.A.M.,Radboud University Nijmegen | Dijkman H.B.P.M.,RUNMC | van den Heuvel L.P.,RUNMC | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2013

Hyperuricemia is related to a variety of pathologies, including chronic kidney disease (CKD). However, the pathophysiological mechanisms underlying disease development are not yet fully elucidated. Here, we studied the effect of hyperuricemia on tryptophan metabolism and the potential role herein of two important uric acid efflux transporters, multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Hyperuricemia was induced in mice by treatment with the uricase inhibitor oxonic acid, confirmed by the presence of urate crystals in the urine of treated animals. A transport assay, using membrane vesicles of cells overexpressing the transporters, revealed that uric acid inhibited substrate-specific transport by BCRP at clinically relevant concentrations (calculated IC50 value: 365±13μM), as was previously reported for MRP4. Moreover, we identified kynurenic acid as a novel substrate for MRP4 and BCRP. This finding was corroborated by increased plasma levels of kynurenic acid observed in Mrp4-/- (107±19nM; P=0.145) and Bcrp-/- mice (133±10nM; P=0.0007) compared to wild type animals (71±11nM). Hyperuricemia was associated with >1.5 fold increase in plasma kynurenine levels in all strains. Moreover, hyperuricemia led to elevated plasma kynurenic acid levels (128±13nM, P=0.005) in wild type mice but did not further increase kynurenic acid levels in knockout mice. Based on our results, we postulate that elevated uric acid levels hamper MRP4 and BCRP functioning, thereby promoting the retention of other potentially toxic substrates, including kynurenic acid, which could contribute to the development of CKD. © 2013 Elsevier B.V.


Jacobs B.,Radboud University Nijmegen | Jacobs B.,University of Groningen | Beems T.,Radboud University Nijmegen | Van Der Vliet T.M.,RUNMC | And 11 more authors.
Neurocritical Care | Year: 2013

Background: With this study we aimed to design validated outcome prediction models in moderate and severe traumatic brain injury (TBI) using demographic, clinical, and radiological parameters. Methods: Seven hundred consecutive moderate or severe TBI patients were included in this observational prospective cohort study. After inclusion, clinical data were collected, initial head computed tomography (CT) scans were rated, and at 6 months outcome was determined using the extended Glasgow Outcome Scale. Multivariate binary logistic regression analysis was applied to evaluate the association between potential predictors and three different outcome endpoints. The prognostic models that resulted were externally validated in a national Dutch TBI cohort. Results: In line with previous literature we identified age, pupil responses, Glasgow Coma Scale score and the occurrence of a hypotensive episode post-injury as predictors. Furthermore, several CT characteristics were associated with outcome; the aspect of the ambient cisterns being the most powerful. After external validation using Receiver Operating Characteristic (ROC) analysis our prediction models demonstrated adequate discriminative values, quantified by the area under the ROC curve, of 0.86 for death versus survival and 0.83 for unfavorable versus favorable outcome. Discriminative power was less for unfavorable outcome in survivors: 0.69. Conclusions: Outcome prediction in moderate and severe TBI might be improved using the models that were designed in this study. However, conventional demographic, clinical and CT variables proved insufficient to predict disability in surviving patients. The information that can be derived from our prediction rules is important for the selection and stratification of patients recruited into clinical TBI trials. © 2012 Springer Science+Business Media New York.


van Nimwegen M.,Radboud University Nijmegen | Speelman A.D.,Radboud University Nijmegen | Smulders K.,Donders Institute for Brain | Smulders K.,HAN University of Applied Sciences | And 6 more authors.
BMC Neurology | Year: 2010

Background: Many patients with Parkinson's disease (PD) lead a sedentary lifestyle. Promotion of physical activities may beneficially affect the clinical presentation of PD, and perhaps even modify the course of PD. However, because of physical and cognitive impairments, patients with PD require specific support to increase their level of physical activity.Methods: We developed the ParkFit Program: a PD-specific and multifaceted behavioral program to promote physical activity. The emphasis is on creating a behavioral change, using a combination of accepted behavioral motivation techniques. In addition, we designed a multicentre randomized clinical trial to investigate whether this ParkFit Program increases physical activity levels over two years in sedentary PD patients. We intended to include 700 sedentary patients. Primary endpoint is the time spent on physical activities per week, which will be measured every six months using an interview-based 7-day recall.Results: In total 3453 PD patients were invited to participate. Ultimately, 586 patients - with a mean (SD) age of 64.1 (7.6) years and disease duration of 5.3 (4.5) years - entered the study. Study participants were younger, had a shorter disease duration and were less sedentary compared with eligible PD patients not willing to participate.Discussion: The ParkFit trial is expected to yield important new evidence about behavioral interventions to promote physical activity in sedentary patients with PD. The results of the trial are expected in 2012. © 2010 van Nimwegen et al; licensee BioMed Central Ltd.


News Article | December 12, 2016
Site: www.eurekalert.org

Researchers at the Umeå Center for Molecular Medicine have created the first 3D spatial visualization of an obese mouse pancreas showing the distribution dynamics of insulin producing beta cells. The results show significant amounts of cystic lesions within pancreatic islets. These lesions could be linked to alterations in the mass and function of insulin producing beta cells. "By using the method optical projection tomography (OPT), we created the first 3D-spatial and quantitative account of beta cell mass distribution in an obese and insulin resistant mouse model," says Saba Parween, researcher at the Umeå Center for Molecular Medicine. The 3D-depiction revealed a previously unreported degree of cystic lesions in large islets that were occupied by red blood cells and fibrin mesh. According to Saba Parween, these lesions could be caused by a mechanism involving the leakage of red blood cells and blood plasma due to increased blood flow and vessel instability within the islets. Intra-islet lesions have apparently been overlooked in the past. The pancreatic endocrine cells, most importantly the insulin producing beta cells, play an important role in regulating blood glucose homeostasis. Alterations in the beta cell mass or the function of the insulin producing cells play a major role in the development and progression of diabetes. "Understanding beta cell mass dynamics in disease models is therefore a key aspect for better interpretation of research results. More in depth studies will be required to address the potential effects of these cystic lesions on beta cell function," says Saba Parween. The data also indicated that different lobes of the pancreas have different potential for expanding their beta cell mass. The observed variations in beta cell mass expansion suggest that a careful consideration of these variations is required while performing tissue sampling for studying diabetes disease dynamics. The possibility to monitor beta cell mass in vivo would radically improve researcher's abilities to study the pathogenesis of diabetes and potentially also the effectiveness of therapeutic interventions. Single photon emission computed tomography (SPECT) is a widely used technique that has become a promising approach to monitor changes in beta cell mass in vivo. A key issue for using this approach is to evaluate the beta cell specificity and read out of the utilized radiotracers. This is most commonly performed by conventional stereological approaches, which rely on the extrapolation of 2D data. "Therefore, we developed a new OPT-based multimodal imaging protocol that enables rapid and accurate cross evaluation of radiotracers for SPECT-based beta cell imaging. We propose that this protocol is an accurate and better approach for validating the performance radiotracers for beta cell imaging," concludes Saba Parween. Saba Parween is a molecular biologist from India working on imaging beta cells during diabetes by using optical projection tomography. She has been a Marie Curie research fellow in the BetaTrain consortium, did her secondment at R&D site of Novo Nordisk in Copenhagen for a month and had a collaboration with Radboud Universuity Nijmegen Medical Centre (RUNMC) during her PhD in Molecular Medicine. Before starting her PhD in 2012, she earned her Master's in Biotechnology in 2010 and then worked at National Brain Research Centre in India. For more information, please contact: Saba Parween, Umeå Center for Molecular Medicine Phone: 090-785 4419 Email: saba.parween@umu.se


Wortmann S.B.,Radboud University Nijmegen | Wortmann S.B.,Institute of Genetic and Metabolic Disease IGMD | Vaz F.M.,Metabolic | Gardeitchik T.,Radboud University Nijmegen | And 48 more authors.
Nature Genetics | Year: 2012

Using exome sequencing, we identify SERAC1 mutations as the cause of MEGDEL syndrome, a recessive disorder of dystonia and deafness with Leigh-like syndrome, impaired oxidative phosphorylation and 3-methylglutaconic aciduria. We localized SERAC1 at the interface between the mitochondria and the endoplasmic reticulum in the mitochondria-associated membrane fraction that is essential for phospholipid exchange. A phospholipid analysis in patient fibroblasts showed elevated concentrations of phosphatidylglycerol-34:1 (where the species nomenclature denotes the number of carbon atoms in the two acyl chains:number of double bonds in the two acyl groups) and decreased concentrations of phosphatidylglycerol-36:1 species, resulting in an altered cardiolipin subspecies composition. We also detected low concentrations of bis(monoacyl-glycerol)-phosphate, leading to the accumulation of free cholesterol, as shown by abnormal filipin staining. Complementation of patient fibroblasts with wild-type human SERAC1 by lentiviral infection led to a decrease and partial normalization of the mean ratio of phosphatidylglycerol-34: 1 to phosphatidylglycerol-36:1. Our data identify SERAC1 as a key player in the phosphatidylglycerol remodeling that is essential for both mitochondrial function and intracellular cholesterol trafficking. © 2012 Nature America, Inc. All rights reserved.


Nillesen W.M.,RUNMC | Yntema H.G.,RUNMC | Moscarda M.,Catholic University | Verbeek N.E.,UMC Utrecht | And 12 more authors.
Human Mutation | Year: 2011

The core phenotype of Kleefstra syndrome (KS) is characterized by intellectual disability, childhood hypotonia, and a characteristic facial appearance. This can be caused by either submicroscopic 9q34 deletions or loss of function mutations of the EHMT1 gene. Remarkably, in three patients with a clinical suspicion of KS, molecular cytogenetic analysis revealed an interstitial 9q34 microdeletion proximal to the coding region of the EHMT1 gene based on the NM- 024757.3 transcript. Because we found a mono-allelic EHMT1 transcript suggestive for haploinsufficiency of EHMT1 in two of these patients tested, we hypothesized that a deletion of regulatory elements or so far unknown coding sequences in the 5' region of the EHMT1 gene, might result in a phenotype compatible with KS. We further characterized the molecular content of deletions proximal to the transcript NM- 024757.3 and confirmed presence of a novel predicted open reading frame comprising 27 coding exons (NM- 024757.4). Further analysis showed that all three deletions included the presumed novel first exon of the EHMT1 gene. Subsequent testing of 75 individuals without previously detectable EHMT1 aberrations showed one additional case with a deletion comprising only this 5' part of the gene. These results have important implications for the genetic screening of KS and for studies of the functional significance of EHMT1. © 2011 Wiley-Liss, Inc.


De Goeij M.,Pain and Palliative Medicine | Van Eijk L.T.,RUNMC | Van Eijk L.T.,Nijmegen Institute for Infection | Vanelderen P.,Pain and Palliative Medicine | And 9 more authors.
PLoS ONE | Year: 2013

Background: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods. Methods and Results: Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20±4% and 13±3%, respectively. In controls only a minor decrease in pressure pain thresholds (7±3%) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques. Conclusions and Significance: In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception. © 2013 de Goeij et al.


Cany J.,Radboud University Nijmegen | van der Waart A.B.,Radboud University Nijmegen | Tordoir M.,Radboud University Nijmegen | Franssen G.M.,RUNMC | And 7 more authors.
PLoS ONE | Year: 2013

Natural killer (NK) cell-based adoptive immunotherapy is an attractive adjuvant treatment option for patients with acute myeloid leukemia. Recently, we reported a clinical-grade, cytokine-based culture method for the generation of NK cells from umbilical cord blood (UCB) CD34+ hematopoietic progenitor cells with high yield, purity and in vitro functionality. The present study was designed to evaluate the in vivo anti-leukemic potential of UCB-NK cells generated with our GMP-compliant culture system in terms of biodistribution, survival and cytolytic activity following adoptive transfer in immunodeficient NOD/SCID/IL2Rgnull mice. Using single photon emission computed tomography, we first demonstrated active migration of UCB-NK cells to bone marrow, spleen and liver within 24 h after infusion. Analysis of the chemokine receptor expression profile of UCB-NK cells matched in vivo findings. Particularly, a firm proportion of UCB-NK cells functionally expressed CXCR4, what could trigger BM homing in response to its ligand CXCL12. In addition, high expression of CXCR3 and CCR6 supported the capacity of UCB-NK cells to migrate to inflamed tissues via the CXCR3/CXCL10-11 and CCR6/CCL20 axis. Thereafter, we showed that low dose IL-15 mediates efficient survival, expansion and maturation of UCB-NK cells in vivo. Most importantly, we demonstrate that a single UCB-NK cell infusion combined with supportive IL-15 administration efficiently inhibited growth of human leukemia cells implanted in the femur of mice, resulting in significant prolongation of mice survival. These preclinical studies strongly support the therapeutic potential of ex vivo-generated UCB-NK cells in the treatment of myeloid leukemia after immunosuppressive chemotherapy. © 2013 Cany et al.

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