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Melichar Prof. B.,Palacky University | Matveev V.,Blokhin Cancer Research Center | Alekseev B.,Research Oncology Institute | Zyryanov A.,Region Hospital and 1 Oncology | And 11 more authors.
Annals of Oncology | Year: 2013

Background: Avastin and Roferon in Renal Cell Carcinoma (AVOREN) demonstrated efficacy for bevacizumab plus interferon-α2a (IFN; 9 MIU tiw) in first-line metastatic renal cell carcinoma (mRCC). We evaluated bevacizumab with lowdose IFN in mRCC to determine whether clinical benefit could be maintained with reduced toxicity. Methods: BEVLiN was an open-label, single-arm, multinational, phase II trial. Nephrectomized patients with treatmentnaive, clear cell mRCC and favourable/intermediate Memorial Sloan-Kettering Cancer Center scores received bevacizumab (10 mg/kg every 2 weeks) and IFN (3 MIU thrice weekly) until disease progression. Descriptive comparisons with AVOREN patients having favourable/intermediate MSKCC scores treated with bevacizumab plus IFN (9 MIU) were made. Primary end points were grade =3 IFN-associated adverse events (AEs) and progression-free survival (PFS). All grade =3 AEs and bevacizumab/IFN-related grade 1-2 AEs occurring from first administration until 28 days after last treatment were reported. Results: A total of 146 patients were treated; the median follow-up was 29.4 months. Any-grade and grade =3 IFNassociated AEs occurred in 53.4% and 10.3% of patients, respectively. The median PFS and overall survival were 15.3 [95% confidence interval (CI): 11.7-18.0] and 30.7 months (95% CI: 25.7-not reached), respectively. The ORR was 28.8%. Conclusions: Compared with a historical control AVOREN subgroup, low-dose IFN with bevacizumab resulted in a reduction in incidence rates of IFN-related AEs, without compromising efficacy [NCT00796757]. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Woudenberg J.,University of Groningen | Woudenberg J.,Radbound University Nijmegen Medical Center | Rembacz K.P.,University of Groningen | Hoekstra M.,University of Groningen | And 9 more authors.
Hepatology | Year: 2010

Peroxisomes are particularly abundant in the liver and are involved in bile salt synthesis and fatty acid metabolism. Peroxisomal membrane proteins (PMPs) are required for peroxisome biogenesis [e.g., the interacting peroxisomal biogenesis factors Pex13p and Pex14p] and its metabolic function [e.g., the adenosine triphosphate-binding cassette transporters adrenoleukodystrophy protein (ALDP) and PMP70]. Impaired function of PMPs is the underlying cause of Zellweger syndrome and X-linked adrenoleukodystrophy. Here we studied for the first time the putative association of PMPs with cholesterol-enriched lipid rafts and their function in peroxisome biogenesis. Lipid rafts were isolated from Triton X-100-lysed or Lubrol WX-lysed HepG2 cells and analyzed for the presence of various PMPs by western blotting. Lovastatin and methyl-β-cyclodextrin were used to deplete cholesterol and disrupt lipid rafts in HepG2 cells, and this was followed by immunofluorescence microscopy to determine the subcellular location of catalase and PMPs. Cycloheximide was used to inhibit protein synthesis. Green fluorescent protein-tagged fragments of PMP70 and ALDP were analyzed for their lipid raft association. PMP70 and Pex14p were associated with Triton X-100-resistant rafts, ALDP was associated with Lubrol WX-resistant rafts, and Pex13p was not lipid raft-associated in HepG2 cells. The minimal peroxisomal targeting signals in ALDP and PMP70 were not sufficient for lipid raft association. Cholesterol depletion led to dissociation of PMPs from lipid rafts and impaired sorting of newly synthesized catalase and ALDP but not Pex14p and PMP70. Repletion of cholesterol to these cells efficiently reestablished the peroxisomal sorting of catalase but not ALDP. Conclusion: Human PMPs are differentially associated with lipid rafts independently of the protein homology and/or their functional interaction. Cholesterol is required for peroxisomal lipid raft assembly and peroxisome biogenesis. Copyright © 2010 by the American Association for the Study of Liver Diseases.


Oschlies I.,University of Kiel | Lisfeld J.,Justus Liebig University | Lamant L.,Center Hospitalier University Purpan | Nakazawa A.,National Center for Child Health and Development | And 14 more authors.
Haematologica | Year: 2013

Anaplastic large cell lymphomas are peripheral T-cell lymphomas that are characterized by a proliferation of large anaplastic blasts expressing CD30. In children, systemic anaplastic large cell lymphomas often present at advanced clinical stage and harbor translocations involving the anaplastic lymphoma kinase (ALK) gene leading to the expression of chimeric anaplastic lymphoma kinase (ALK)-fusion proteins. Primary cutaneous anaplastic large cell lymphoma is regarded as an ALK-negative variant confined to the skin and is part of the spectrum of primary cutaneous CD30-positive T-cell lymphoproliferative disorders. Thirty-three of 487 pediatric patients registered within the Anaplastic Large Cell Lymphoma-99 trial (1999 to 2006) presented with a skin limited CD30-positive lymphoproliferative disorder. In 23 of the 33 patients, material for international histopathological review was available, and the cases were studied for histopathological, immunophenotypical and clinical features as well as for breaks within the ALK gene. Five of 23 cases and one additional case (identified after closure of the trial) expressed ALKprotein. Complete staging excluded any other organ involvement in all children. Expression of ALK proteins was demonstrated by immunohistochemistry in all cases and the presence of breaks of the ALK gene was genetically confirmed in 5 evaluable cases. The histopathological and clinical picture of these skin-restricted ALK-positive lymphomas was indistinguishable from that of cutaneous anaplastic large cell lymphoma. Five children presented with a single skin lesion that was completely resected in 4 and incompletely resected in one. Three of these patients received no further therapy, 2 additional local radiotherapy, and one chemotherapy. All children remain in complete remission with a median follow up of seven years (range 1-8 years). We present 6 pediatric cases of ALK-positive primary cutaneous anaplastic large cell lymphomas. After thorough exclusion of systemic involvement, therapy confined to local measures seems to be sufficient to induce cure. ©2013 Ferrata Storti Foundation.


Quizhpe P A.,Radboud University Nijmegen | Quizhpe P A.,University of Cuenca | Gassowski M.,Radboud University Nijmegen | Encalada T L.,University of Cuenca | Barten F.,Radbound University Nijmegen Medical Center
F1000Research | Year: 2013

Objectives: To investigate the differences in antibiotic use and knowledge between adolescent and adult mothers of children under the age of 5 years in Ecuador. Methods: A cross sectional study was performed in four health centers and hospitals. Mothers of children under five years, seeking medical attention their child's upper respiratory tract infection (URI), were included. The data was collected through interviews, using a structured questionnaire. The questionnaire covered the topics knowledge of antibiotic treatment, risk and resistance. Results: 777 mothers were included in the study, of which 15.8% were adolescent and 84.1% adult mothers. There were significant differences in the social and economic characteristics of the mothers (p ≤ 0.05), with adolescent mothers being more likely to have an incomplete high school education and lack of basic services in their home. Significant differences between these groups were found in adherence to treatment, knowledge about risks associated with antibiotic use, and having heard of antibiotic resistance. Among the adult mothers, 83.5% reported correct adherence, 28.5% were knowledgeable about risks associated with antibiotic use, and 29.3% had heard of antibiotic resistance. Among the adolescent mothers, these numbers were 75.4%, 15.0%, and 19.8%, respectively. Conclusions: To develop successful interventions, it is crucial to understand the factors causing differences in antibiotic use and knowledge between mothers. © 2013 Quizhpe P A et al.


PubMed | University of Turku, University of Leipzig, Radbound University Nijmegen Medical Center, Aalto University and 3 more.
Type: Journal Article | Journal: International journal of computer assisted radiology and surgery | Year: 2016

Radiofrequency ablation (RFA) is one of the most popular and well-standardized minimally invasive cancer treatments (MICT) for liver tumours, employed where surgical resection has been contraindicated. Less-experienced interventional radiologists (IRs) require an appropriate planning tool for the treatment to help avoid incomplete treatment and so reduce the tumour recurrence risk. Although a few tools are available to predict the ablation lesion geometry, the process is computationally expensive. Also, in our implementation, a few patient-specific parameters are used to improve the accuracy of the lesion prediction.Advanced heterogeneous computing using personal computers, incorporating the graphics processing unit (GPU) and the central processing unit (CPU), is proposed to predict the ablation lesion geometry. The most recent GPU technology is used to accelerate the finite element approximation of Pennes bioheat equation and a three state cell model. Patient-specific input parameters are used in the bioheat model to improve accuracy of the predicted lesion.A fast GPU-based RFA solver is developed to predict the lesion by doing most of the computational tasks in the GPU, while reserving the CPU for concurrent tasks such as lesion extraction based on the heat deposition at each finite element node. The solver takes less than 3 min for a treatment duration of 26 min. When the model receives patient-specific input parameters, the deviation between real and predicted lesion is below 3 mm.A multi-centre retrospective study indicates that the fast RFA solver is capable of providing the IR with the predicted lesion in the short time period before the intervention begins when the patient has been clinically prepared for the treatment.


PubMed | Radbound University Nijmegen Medical Center, University of Cuenca and Radboud University Nijmegen
Type: | Journal: F1000Research | Year: 2014

To investigate the differences in antibiotic use and knowledge between adolescent and adult mothers of children under the age of 5 years in Ecuador.A cross sectional study was performed in four health centers and hospitals. Mothers of children under five years, seeking medical attention their childs upper respiratory tract infection (URI), were included. The data was collected through interviews, using a structured questionnaire. The questionnaire covered the topics knowledge of antibiotic treatment, risk and resistance.777 mothers were included in the study, of which 15.8% were adolescent and 84.1% adult mothers. There were significant differences in the social and economic characteristics of the mothers (p 0.05), with adolescent mothers being more likely to have an incomplete high school education and lack of basic services in their home. Significant differences between these groups were found in adherence to treatment, knowledge about risks associated with antibiotic use, and having heard of antibiotic resistance. Among the adult mothers, 83.5% reported correct adherence, 28.5% were knowledgeable about risks associated with antibiotic use, and 29.3% had heard of antibiotic resistance. Among the adolescent mothers, these numbers were 75.4%, 15.0%, and 19.8%, respectively.To develop successful interventions, it is crucial to understand the factors causing differences in antibiotic use and knowledge between mothers.


Azaiez H.,University of Iowa | Booth K.T.,University of Iowa | Bu F.,University of Iowa | Huygen P.,Radbound University Nijmegen Medical Center | And 6 more authors.
Human Mutation | Year: 2014

Hereditary hearing loss is extremely heterogeneous. Over 70 genes have been identified to date, and with the advent of massively parallel sequencing, the pace of novel gene discovery has accelerated. In a family segregating progressive autosomal-dominant nonsyndromic hearing loss (NSHL), we used OtoSCOPE® to exclude mutations in known deafness genes and then performed segregation mapping and whole-exome sequencing to identify a unique variant, p.Ser178Leu, in TBC1D24 that segregates with the hearing loss phenotype. TBC1D24 encodes a GTPase-activating protein expressed in the cochlea. Ser178 is highly conserved across vertebrates and its change is predicted to be damaging. Other variants in TBC1D24 have been associated with a panoply of clinical symptoms including autosomal recessive NSHL, syndromic hearing impairment associated with onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS syndrome), and a wide range of epileptic disorders. © 2014 WILEY PERIODICALS, INC.


Shalom-Feuerstein R.,French Institute of Health and Medical Research | Shalom-Feuerstein R.,University of Nice Sophia Antipolis | Shalom-Feuerstein R.,Bruce Rappaport Institute | Lena A.M.,University of Rome Tor Vergata | And 9 more authors.
Cell Death and Differentiation | Year: 2011

p63, a member of p53 family, has a significant role in the development and maintenance of stratified epithelia. However, a persistent dispute remained over the last decade concerning the interpretation of the severe failure of p63-null embryos to develop stratified epithelia. In this study, by investigating both p63-deficient strains, we demonstrated that p63-deficient epithelia failed to develop beyond ectodermal stage as they remained a monolayer of non-proliferating cells expressing K8/K18. Importantly, in the absence of p63, corneal-epithelial commitment (which occurs at embryonic day 12.5 of mouse embryogenesis) was hampered 3 weeks before corneal stem cell renewal (that begins at P14). Taken together, these data illustrate the significant role of p63 in epithelial embryogenesis, before and independently of other functions of p63 in adult stem cells regulation. Transcriptome analysis of laser captured-embryonic tissues confirmed the latter hypothesis, demonstrating that a battery of epidermal genes that were activated in wild-type epidermis remained silent in p63-null tissues. Furthermore, we defined a subset of novel bona fide p63-induced genes orchestrating first epidermal stratification and a subset of p63-repressed mesodermal-specific genes. These data highlight the earliest recognized action of ΔNp63 in the induction epidermal morphogenesis at E11.5. In the absence of p63, a mesodermal program is activated while epidermal morphogenesis does not initiate. © 2011 Macmillan Publishers Limited All rights reserved.


PubMed | Radbound University Nijmegen Medical Center
Type: Journal Article | Journal: Rhinology | Year: 2011

The aim of this study was to evaluate symmetry of the lip and nose in patients with CUCLP after primary cheiloseptoplasty (Afroze technique), in comparison to non-cleft controls.In this prospective study, forty-four patients with operated non-syndromic CUCLP were included. The control group consisted of 44 volunteers without cleft defects of approximately the same age and sex. Primary septoplasty was performed in conjunction with the cleft lip (CL) repair using the Afroze incision. 3D facial images were acquired using 3D stereophotogrammetry. After a 3D cephalometric analysis of the lip and nose was performed in both groups, linear and volumetric data were acquired. Lip and nose symmetry were calculated and compared using Student`s t-tests as well as the Chi square test.For all measurements, the control group was up to 36% closer to perfect symmetry compared to the CUCLP group after primary surgery. This difference was statistically significant.After primary cheiloseptoplasty according to the Afroze technique in patients with CUCLP, asymmetry in the nose and lip area still exists as compared to non-cleft controls. Although non-cleft individuals also show some degree of asymmetry, the results of this study stress the difficulty in obtaining near normal symmetrical relations.


PubMed | Radbound University Nijmegen Medical Center and Radboud University Nijmegen
Type: Journal Article | Journal: Pain practice : the official journal of World Institute of Pain | Year: 2016

Pain and neuropathic symptoms impact quality of life of patients with cancer. To obtain more insight in the prevalence, severity, and treatment of neuropathic symptoms in patients with cancer and their interference with daily activities, we conducted a cross-sectional study at the outpatient clinic of a Dutch university hospital.A cross-sectional study among outpatients with cancer. To identify pain, its intensity, quality, and interference with daily activities, the Brief Pain Inventory (BPI) was used. Neuropathic symptoms were identified with the Douleur Neuropathique (DN4) interview and pain characteristics with the McGill Pain Questionnaire (MPQ). Pain medication and adjuvant analgesics were also collected with a prestructured questionnaire. Descriptives, chi-squared tests, t-tests, and a logistic regression analysis were conducted.892 patients completed the questionnaires. Twenty-three percent (n=204) reported moderate to severe pain, and 19% (n=170) scored positive on neuropathic symptoms (DN43). Particularly in patients with a rating on a numeric rating scale (NRS)<5, existence of neuropathic symptoms significantly increased interference with daily activities. Of patients with neuropathic symptoms, 8% received adjuvant pain treatment. Receiving curative treatment, using a systemic drug with neurotoxicity, having had an operation, and having had a lymph node dissection independently contributed to having neuropathic symptoms.This study shows that over 40% of the patients with moderate to severe pain also have neuropathic symptoms, causing increased interference with daily activities. Most of these patients do not receive adjuvant analgesics. There is a need to improve management of neuropathic symptoms in patients with cancer.

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