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221 results on '"André B. P. van Kuilenburg"'

201. Darier Disease

Author

Dieter Metze, Tam Nguyen, Birgit Haack, Alexander K. C. Leung, Noriko Miyake, Naomichi Matsumoto, A. J. Larner, Oliver Bartsch, Barbara C. Van Munster, Christine A. F. Von Arnim, Jochen Klucken, Peter Heutink, Chaeyoung Lee, Alexander A. C. Leung, Justine H. S. Fong, Silke Hofmann, Leena Bruckner-Tuderman, Anca Sindrilaru, Cord Sunderkötter, Lev G. Goldfarb, Andreas Barthel, Erwin Schleicher, Andreas Fritsche, Derek LeRoith, Gunter Wolf, Wilgard Hunger-Dathe, John-John B. Schnog, Victor E. A. Gerdes, Michael Benatar, Michael Fromm, Jörg-Dieter Schulzke, Stefan Bröer, André B. P. Van Kuilenburg, Albert H. Van Gennip, André B. P. Kuilenburg, Albert H. Gennip, Michael Straub, Albrecht Hesse, Hugo Ten Cate, Nigel Laing, Frank Mastaglia, Manish Suneja, Christie P. Thomas, Ulrich Müller, Birgit Zirn, Daniela Steinberger, Mary Redmond Hutson, Margaret L. Kirby, Peter L. M. Jansen, Sönke Weihe, Jan Schulte Am Esch, Wolfram Trudo Knoefel, Andrew L. Wong, August H. M. Smelt, Johannes Schumacher, Per Hoffmann, Markus M. Nöthen, Andrea Schuppenies, Markus G. Donner, Dieter Häussinger, Norman Kock, Katja Lohmann, and Christine Klein

Published
2009
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202. Dextroposed Aorta

Author

Dieter Metze, Tam Nguyen, Birgit Haack, Alexander K. C. Leung, Noriko Miyake, Naomichi Matsumoto, A. J. Larner, Oliver Bartsch, Barbara C. Van Munster, Christine A. F. Von Arnim, Jochen Klucken, Peter Heutink, Chaeyoung Lee, Alexander A. C. Leung, Justine H. S. Fong, Silke Hofmann, Leena Bruckner-Tuderman, Anca Sindrilaru, Cord Sunderkötter, Lev G. Goldfarb, Andreas Barthel, Erwin Schleicher, Andreas Fritsche, Derek LeRoith, Gunter Wolf, Wilgard Hunger-Dathe, John-John B. Schnog, Victor E. A. Gerdes, Michael Benatar, Michael Fromm, Jörg-Dieter Schulzke, Stefan Bröer, André B. P. Van Kuilenburg, Albert H. Van Gennip, André B. P. Kuilenburg, Albert H. Gennip, Michael Straub, Albrecht Hesse, Hugo Ten Cate, Nigel Laing, Frank Mastaglia, Manish Suneja, Christie P. Thomas, Ulrich Müller, Birgit Zirn, Daniela Steinberger, Mary Redmond Hutson, Margaret L. Kirby, Peter L. M. Jansen, Sönke Weihe, Jan Schulte Am Esch, Wolfram Trudo Knoefel, Andrew L. Wong, August H. M. Smelt, Johannes Schumacher, Per Hoffmann, Markus M. Nöthen, Andrea Schuppenies, Markus G. Donner, Dieter Häussinger, Norman Kock, Katja Lohmann, and Christine Klein

Published
2009
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203. Diabetes Mellitus Type 1

Author

Dieter Metze, Tam Nguyen, Birgit Haack, Alexander K. C. Leung, Noriko Miyake, Naomichi Matsumoto, A. J. Larner, Oliver Bartsch, Barbara C. Van Munster, Christine A. F. Von Arnim, Jochen Klucken, Peter Heutink, Chaeyoung Lee, Alexander A. C. Leung, Justine H. S. Fong, Silke Hofmann, Leena Bruckner-Tuderman, Anca Sindrilaru, Cord Sunderkötter, Lev G. Goldfarb, Andreas Barthel, Erwin Schleicher, Andreas Fritsche, Derek LeRoith, Gunter Wolf, Wilgard Hunger-Dathe, John-John B. Schnog, Victor E. A. Gerdes, Michael Benatar, Michael Fromm, Jörg-Dieter Schulzke, Stefan Bröer, André B. P. Van Kuilenburg, Albert H. Van Gennip, André B. P. Kuilenburg, Albert H. Gennip, Michael Straub, Albrecht Hesse, Hugo Ten Cate, Nigel Laing, Frank Mastaglia, Manish Suneja, Christie P. Thomas, Ulrich Müller, Birgit Zirn, Daniela Steinberger, Mary Redmond Hutson, Margaret L. Kirby, Peter L. M. Jansen, Sönke Weihe, Jan Schulte Am Esch, Wolfram Trudo Knoefel, Andrew L. Wong, August H. M. Smelt, Johannes Schumacher, Per Hoffmann, Markus M. Nöthen, Andrea Schuppenies, Markus G. Donner, Dieter Häussinger, Norman Kock, Katja Lohmann, and Christine Klein

Published
2009
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204. Dyskeratosis Follicularis

Author

Dieter Metze, Tam Nguyen, Birgit Haack, Alexander K. C. Leung, Noriko Miyake, Naomichi Matsumoto, A. J. Larner, Oliver Bartsch, Barbara C. Van Munster, Christine A. F. Von Arnim, Jochen Klucken, Peter Heutink, Chaeyoung Lee, Alexander A. C. Leung, Justine H. S. Fong, Silke Hofmann, Leena Bruckner-Tuderman, Anca Sindrilaru, Cord Sunderkötter, Lev G. Goldfarb, Andreas Barthel, Erwin Schleicher, Andreas Fritsche, Derek LeRoith, Gunter Wolf, Wilgard Hunger-Dathe, John-John B. Schnog, Victor E. A. Gerdes, Michael Benatar, Michael Fromm, Jörg-Dieter Schulzke, Stefan Bröer, André B. P. Van Kuilenburg, Albert H. Van Gennip, André B. P. Kuilenburg, Albert H. Gennip, Michael Straub, Albrecht Hesse, Hugo Ten Cate, Nigel Laing, Frank Mastaglia, Manish Suneja, Christie P. Thomas, Ulrich Müller, Birgit Zirn, Daniela Steinberger, Mary Redmond Hutson, Margaret L. Kirby, Peter L. M. Jansen, Sönke Weihe, Jan Schulte Am Esch, Wolfram Trudo Knoefel, Andrew L. Wong, August H. M. Smelt, Johannes Schumacher, Per Hoffmann, Markus M. Nöthen, Andrea Schuppenies, Markus G. Donner, Dieter Häussinger, Norman Kock, Katja Lohmann, and Christine Klein

Published
2009
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205. Thyroiditis, Subacute

Author

Satish R. Raj, S. R. Wayne Chen, Robert S. Sheldon, Arti N. Shah, Bharat K. Kantharia, Ulrich Salzer, Bodo Grimbacher, Alexander K. C. Leung, Deepak Kamat, Genovefa D. Kolovou, Katherine K. Anagnostopoulou, Dennis V. Cokkinos, Takahiro Shinkai, Rosaline C. M. Quinlivan, Robert Beynon, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Christophe Nicot, Werner Kempf, Reinhard Dummer, Günter Burg, Urban W. Geisthoff, Deborah Bartholdi, Albert Schinzel, Stefan R. Bornstein, Nenad Blau, Elizabeth Goldmuntz, John-John B. Schnog, Victor E. A. Gerdes, Jacky Bonaventure, Donatus Nohr, Anthony M. Marinaki, Monica Arenas, Robert F. Groff IV, Jason H. Huang, Hugo Ten Cate, Ayalew Tefferi, Han-Mou Tsai, Mofid Ibraheim, Amaj Ikomi, Bob Olsson, Hans Wadenvik, Julian Ilcheff, Henri Bounameaux, Marc Righini, Christopher J. Boos, Gregory Y. H. Lip, Yuval Ramot, Neta Goldschmidt, Abraham Nyska, André B. P. Van Kuilenburg, Albert H. Van Gennip, Christian A. Koch, Nicholas J. Sarlis, Douglas Forrest, Peter Kopp, Seda Sancak, Markus Eszlinger, Ralf Paschke, Antonella Fioravanti, Maria Antonietta Mazzei, Giuseppina Coppola, Luca Volterrani, Hans-Peter Zenner, Ilse Maria Zalaman, Ulrike Schumacher, Ingo B. Autenrieth, Nitin Wadhani, Hari Red, Shah Azmoon, Harpreet Singh, Bramah N. Singh, David W. Brown, Tal Geva, Claudio Guarneri, Francesco Borgia, Mario Vaccaro, Norbert Müller, Jürgen Kohlhase, Andreas Erhardt, Freddy Mboti, Karina Yazdanbakhsh, Millicent Sutton, Jan-Luuk Hillebrands, Roel de Weger, Jan Rozing, Linda Leatherbury, Cecilia Lo, Jutta Engel, Elan D. Louis, Fabrizio Guarneri, Mark Berneburg, Thomas Schwarz, Gabriele A. Krombach, Alfonso Baldi, Koichiro Niwa, Sefik Guran, Trevor J. Pugh, Marco A. Marra, John Wolstenholme, Hardally R. Hegde, Joachim Richter, Hiroyuki Yamagishi, Keiichi Fukuda, Maximilian Ledochowski, Dietmar Fuchs, Pushpa Agrawal, Md. Suhail Alam†, Saurabh K. Garg†, Ralf Wienecke, Giovambattista Capasso, Mauro Bernardi, Franco Trevisani, Kimitoshi Nakamura, Shiro Matsumoto, Hiroshi Mitsubuchi, and Fumio Endo

Published
2009
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206. Dilated Cardiomyopathy, Idiopathic

Author

Dieter Metze, Tam Nguyen, Birgit Haack, Alexander K. C. Leung, Noriko Miyake, Naomichi Matsumoto, A. J. Larner, Oliver Bartsch, Barbara C. Van Munster, Christine A. F. Von Arnim, Jochen Klucken, Peter Heutink, Chaeyoung Lee, Alexander A. C. Leung, Justine H. S. Fong, Silke Hofmann, Leena Bruckner-Tuderman, Anca Sindrilaru, Cord Sunderkötter, Lev G. Goldfarb, Andreas Barthel, Erwin Schleicher, Andreas Fritsche, Derek LeRoith, Gunter Wolf, Wilgard Hunger-Dathe, John-John B. Schnog, Victor E. A. Gerdes, Michael Benatar, Michael Fromm, Jörg-Dieter Schulzke, Stefan Bröer, André B. P. Van Kuilenburg, Albert H. Van Gennip, André B. P. Kuilenburg, Albert H. Gennip, Michael Straub, Albrecht Hesse, Hugo Ten Cate, Nigel Laing, Frank Mastaglia, Manish Suneja, Christie P. Thomas, Ulrich Müller, Birgit Zirn, Daniela Steinberger, Mary Redmond Hutson, Margaret L. Kirby, Peter L. M. Jansen, Sönke Weihe, Jan Schulte Am Esch, Wolfram Trudo Knoefel, Andrew L. Wong, August H. M. Smelt, Johannes Schumacher, Per Hoffmann, Markus M. Nöthen, Andrea Schuppenies, Markus G. Donner, Dieter Häussinger, Norman Kock, Katja Lohmann, and Christine Klein

Published
2009
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207. Thyroid Cancer

Author

Satish R. Raj, S. R. Wayne Chen, Robert S. Sheldon, Arti N. Shah, Bharat K. Kantharia, Ulrich Salzer, Bodo Grimbacher, Alexander K. C. Leung, Deepak Kamat, Genovefa D. Kolovou, Katherine K. Anagnostopoulou, Dennis V. Cokkinos, Takahiro Shinkai, Rosaline C. M. Quinlivan, Robert Beynon, Thomas Kolter, Ute Schepers, Konrad Sandhoff, Christophe Nicot, Werner Kempf, Reinhard Dummer, Günter Burg, Urban W. Geisthoff, Deborah Bartholdi, Albert Schinzel, Stefan R. Bornstein, Nenad Blau, Elizabeth Goldmuntz, John-John B. Schnog, Victor E. A. Gerdes, Jacky Bonaventure, Donatus Nohr, Anthony M. Marinaki, Monica Arenas, Robert F. Groff IV, Jason H. Huang, Hugo Ten Cate, Ayalew Tefferi, Han-Mou Tsai, Mofid Ibraheim, Amaj Ikomi, Bob Olsson, Hans Wadenvik, Julian Ilcheff, Henri Bounameaux, Marc Righini, Christopher J. Boos, Gregory Y. H. Lip, Yuval Ramot, Neta Goldschmidt, Abraham Nyska, André B. P. Van Kuilenburg, Albert H. Van Gennip, Christian A. Koch, Nicholas J. Sarlis, Douglas Forrest, Peter Kopp, Seda Sancak, Markus Eszlinger, Ralf Paschke, Antonella Fioravanti, Maria Antonietta Mazzei, Giuseppina Coppola, Luca Volterrani, Hans-Peter Zenner, Ilse Maria Zalaman, Ulrike Schumacher, Ingo B. Autenrieth, Nitin Wadhani, Hari Red, Shah Azmoon, Harpreet Singh, Bramah N. Singh, David W. Brown, Tal Geva, Claudio Guarneri, Francesco Borgia, Mario Vaccaro, Norbert Müller, Jürgen Kohlhase, Andreas Erhardt, Freddy Mboti, Karina Yazdanbakhsh, Millicent Sutton, Jan-Luuk Hillebrands, Roel de Weger, Jan Rozing, Linda Leatherbury, Cecilia Lo, Jutta Engel, Elan D. Louis, Fabrizio Guarneri, Mark Berneburg, Thomas Schwarz, Gabriele A. Krombach, Alfonso Baldi, Koichiro Niwa, Sefik Guran, Trevor J. Pugh, Marco A. Marra, John Wolstenholme, Hardally R. Hegde, Joachim Richter, Hiroyuki Yamagishi, Keiichi Fukuda, Maximilian Ledochowski, Dietmar Fuchs, Pushpa Agrawal, Md. Suhail Alam†, Saurabh K. Garg†, Ralf Wienecke, Giovambattista Capasso, Mauro Bernardi, Franco Trevisani, Kimitoshi Nakamura, Shiro Matsumoto, Hiroshi Mitsubuchi, and Fumio Endo

Published
2009
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208. Pleiotropic effects of fenretinide in neuroblastoma cell lines and multicellular tumor spheroids

Author

Roos, Cuperus, Godelieve A M, Tytgat, René, Leen, Pedro, Brites, Johannes, Bras, Huib N, Caron, and André B P, Van Kuilenburg

Subjects
Membrane Potential, Mitochondrial, Time Factors, Dose-Response Relationship, Drug, Fenretinide, Cell Survival, Genes, myc, Antineoplastic Agents, Apoptosis, Flow Cytometry, Immunohistochemistry, Antioxidants, Gene Expression Regulation, Neoplastic, Inhibitory Concentration 50, Neuroblastoma, Cell Line, Tumor, Spheroids, Cellular, Animals, Humans, Chromans, Reactive Oxygen Species, Cell Aggregation, Cell Proliferation
Abstract

The efficacy and mechanism of action of fenretinide (4-HPR), a vitamin A analogue, was investigated in a panel of six neuroblastoma cell lines and multicellular tumor spheroids. The latter are three dimensional cell aggregates and as such, a model for micrometastases. In all cell lines, the production of reactive oxygen species (ROS) increased with 163-680% after 1 h of treatment with 4-HPR. In addition, a decrease of the mitochondrial membrane potential of 30-75% was observed after 4 h of incubation with 4-HPR. A 6-12-fold difference was observed between the IC50 values for cell proliferation and viability between the most sensitive (IMR32) and most resistant (NASS) cell line towards 4-HPR. Flow cytometric analysis showed an increased amount of apoptotic bodies and no cell-cycle arrest. The antioxidant Trolox completely inhibited the accumulation of 4HPR-induced ROS and prevented the 4HPR-associated cytotoxicity. In all neuroblastoma spheroids, 4-HPR induced a complete cytostasis at clinical relevant concentrations (3-10 microM). Immunohistochemical analysis of 4-HPR-treated spheroids showed a decreased staining for proliferation marker Ki-67 and an increased staining for cleaved-PARP, a marker of apoptosis. Our results suggest that 4-HPR might be a promising agent for the treatment of micrometastases and high-risk neuroblastoma.

Published
2008

209. Screening for Disorders of Purine and Pyrimidine Metabolism Using HPLC-Electrospray Tandem Mass Spectrometry

Author

Nico G.G.M. Abeling, André B. P. van Kuilenburg, and Arno van Cruchten

Subjects
Purine, chemistry.chemical_compound, Electrospray, Biochemistry, chemistry, Electrospray ionization, Pyrimidine metabolism, Selected reaction monitoring, Purine nucleoside phosphorylase, Tandem mass spectrometry, High-performance liquid chromatography
Abstract

The concentrations of purine and pyrimidine metabolites in urine are useful indicators for the diagnosis of patients suspected of an inborn error of the purine and pyrimidine pathway or a urea-cycle defect. In this paper, we describe a fast and specific method to measure these metabolites in liquid urine samples or urine-soaked filter paper strips. The filter paper strips offer the advantage of easy collection, transport, and storage of the urine samples. Analysis of 23 purine and pyrimidine metabolites is performed using reverse-phase HPLC combined with electrospray ionization (ESI) tandem mass spectrometry (MS/MS). Detection is performed by multiple reaction monitoring and transitions and instrument settings are established for all metabolites. Stable-isotope-labeled reference compounds are used as internal standards. With a total analysis time of 15 min, HPLC-ESI MS/MS proves to be a rapid screening method for disorders of purine and pyrimidine metabolism.

Published
2008
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210. β-Ureidopropionase deficiency: phenotype, genotype and protein structural consequences in 16 patients

Author

Kaoru Eto, Martin Smitka, Tetsuya Ito, André B. P. van Kuilenburg, Kayoko Saito, Mohamed S. Rashed, Birgit Assmann, Chunhua Zhang, Doreen Dobritzsch, Martin Engvall, Laila Selim, Lida Zoetekouw, Judith Meijer, Michael Krumpel, Raoul C.M. Hennekam, Rutger Meinsma, Nico G.G.M. Abeling, Wang Xu, and Bernhard Lohkamp

Subjects
Genetics, Pediatrics, Perinatology and Child Health, Phenotype genotype, Biology
Published
2013
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211. Dihydropyrimidinase deficiency and severe 5-fluorouracil toxicity

Author

André B P, van Kuilenburg, Rutger, Meinsma, Bernard A, Zonnenberg, Lida, Zoetekouw, Frank, Baas, Koichi, Matsuda, Nanaya, Tamaki, and Albert H, van Gennip

Subjects
Antimetabolites, Antineoplastic, Purine-Pyrimidine Metabolism, Inborn Errors, Blotting, Western, DNA Mutational Analysis, Molecular Sequence Data, Mutation, Missense, Breast Neoplasms, Middle Aged, Transfection, Polymerase Chain Reaction, Amidohydrolases, Carcinoma, Ductal, Pharmacogenetics, Escherichia coli, Mutagenesis, Site-Directed, Humans, Female, Amino Acid Sequence, Fluorouracil, Chromatography, High Pressure Liquid
Abstract

Dihydropyrimidinase (DHP) is the second enzyme in the catabolism of 5-fluorouracil (5FU), and it has been suggested that patients with a deficiency of this enzyme are at risk from developing severe 5FU-associated toxicity. In this study, we demonstrated for the first time that in one patient the severe toxicity, after a treatment with 5FU, was attributable to a partial deficiency of DHP. Analysis of the DHP gene showed that the patient was heterozygous for the missense mutation 833GA (G278D) in exon 5. Heterologous expression of the mutant enzyme in Escherichia coli showed that the G278D mutation leads to a mutant DHP enzyme without residual activity. An analysis for the presence of this mutation in 96 unrelated Dutch Caucasians indicates that the allele frequency in the normal population is0.5%. Our results show that a partial DHP deficiency is a novel pharmacogenetic disorder associated with severe 5FU toxicity.

Published
2003

212. Determination of the deoxycytidine kinase activity in cell homogenates with a non-radiochemical assay using reversed-phase high performance liquid chromatography; Identification of a novel metabolite of 2-chlorodeoxyadenosine

Author

Jörgen, Bierau, René, Leen, Albert H van, Gennip, Huib N, Caron, and André B P van, Kuilenburg

Subjects
Cell Line, Tumor, Deoxycytidine Kinase, Cladribine, Humans, Spectrophotometry, Ultraviolet, Chromatography, High Pressure Liquid
Abstract

A non-radioactive procedure to measure the deoxycytidine kinase (dCK) activity in crude cell free homogenates was developed. 2-Chlorodeoxyadenosine (CdA) was used as the substrate for dCK and was separated from its product 2-chlorodeoxyadenosine-5'-monophosphate (CdAMP) by reversed-phase HPLC. A complete separation of CdA and its metabolites was achieved in 30 min. The minimum amount of CdAMP that could be detected was 1 pmol. The assay was linear with reaction times up to at least 3h. With respect to the protein concentration, the reaction was linear with protein concentrations up to 760 microg/ml in the assay. An amount of 8 x 10(3) cells was already sufficient to determine the specific dCK activity in SK-N-BE(2)c cells. CdA was not only converted to CdAMP but also to 2-chloroadenine and, surprisingly, also to 2-chlorodeoxyinosine, in MOLT-3 cells. The deamination of CdA was completely inhibited by deoxycoformycin, which clearly demonstrates that CdA is a substrate for adenosine deaminase.

Published
2003

213. Cyclopentenyl cytosine increases the phosphorylation and incorporation into DNA of 1-beta-D-arabinofuranosyl cytosine in a human T-lymphoblastic cell line

Author

Arnauld C, Verschuur, Albert H, Van Gennip, René, Leen, P A, Voûte, Josanne, Brinkman, and André B P, Van Kuilenburg

Subjects
Time Factors, Dose-Response Relationship, Drug, Cytidine Triphosphate, Cytarabine, Antineoplastic Agents, Apoptosis, Cytidine, DNA, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Drug Resistance, Neoplasm, Deoxycytosine Nucleotides, Tumor Cells, Cultured, Humans, Phosphorylation, Cell Division
Abstract

The cytotoxic effect of 1-beta-D-arabinofuranosyl cytosine (araC) depends on the intracellular phosphorylation into its active compound araCTP, on the degree of degradation of araCTP and on the incorporation of araCTP into DNA. Deoxycytidine triphosphate (dCTP) inhibits the phosphorylation of araC (by feedback inhibition of the enzyme deoxycytidine kinase) and the incorporation of araCTP into DNA (by competition for DNA polymerase). In a T-lymphoblastic cell line, we studied whether the cytotoxicity of araC (2 nM-50 microM) could be enhanced by decreasing the concentration of dCTP, using the nucleoside-analogue cyclopentenyl cytosine (CPEC), an inhibitor of the enzyme CTP synthetase. Preincubation of the cells with CPEC (100-1,600 nM) for 2 hr increased the concentrations of araCMP 1.6-9.5-fold, which was significant for each concentration of CPEC used. The concentration of araCDP remained low, whereas the concentration of araCTP changed depending on the concentration of araC used. With 2-15 microm of araC and a preincubation with 400 nM of CPEC, the araCTP concentration increased by 4-15% (not significant), and the total amount of araC nucleotides increased significantly by 21-45%. When using a concentration of araC of 2 nM after a preincubation with CPEC of 100 nM, the concentration of araCMP increased by 60% (p = 0.015), whereas that of araCTP decreased by 10% (p = 0.008). This was compensated by an increase of 41% (p = 0.005) of araCTP incorporation into DNA, which represented 43% of all araC metabolites. Moreover, by performing pulse/chase experiments with 400 nM of CPEC and 2 microM of araC, the retention of cytosolic araCTP and the incorporated amount of araCTP into DNA were increased by CPEC. The modulation by CPEC of araC metabolism was accompanied by a synergistic increase of araC-induced apoptosis and by an additive effect on the araC-induced growth inhibition.

Published
2002

214. The Roles of Uridine-Cytidine Kinase and CTP Synthetase in the Synthesis of CTP in Malignant Human T-Lymphocytic Cells

Author

Albert H. van Gennip, Henk van Lenthe, A. André van den Berg, and André B. P. van Kuilenburg

Subjects
Pyrimidine, biology, Kinase, Cytidine, medicine.disease, Molecular biology, Uridine, Uridine kinase, chemistry.chemical_compound, Leukemia, chemistry, biology.protein, medicine, heterocyclic compounds, CTP synthetase, Cytosine
Abstract

In human T-lymphocytic cells pyrimidine ribonucleotides are predominantly synthesized via the salvage pathways [1, 2]. Cytosine ribonucleotides can be synthesized by salvage of cytidine or through the salvage of uridine and subsequent conversion of UTP into CTP by the action of CTP synthetase (E.C. 6.3.4.2.). Uridine and cytidine are competing substrates for uridine/cytidine kinase (urd/cyd kinase, EC 2.7.1.48) [3]. Before, we demonstrated increased CTP pools in human lymphocytic leukemia blasts and MOLT-3 T-ALL cell-line cells as well as in proliferating normal human T-lymphocytic cells in comparison with resting human peripheral blood lymphocytes [1, 4]. At physiological concentrations of uridine and cytidine, in the MOLT-3 cells this increase correlates with an increased activity of CTP synthetase [4]. For benign proliferating human T lymphocytes a similar increase in cytosine ribonucleotides as in MOLT-3 cells was found. However, CTP synthetase contributes less to this pool compared to the enzyme in the MOLT-3 cells [4, 5]. Therefore, we hypothesized that cytidine is more avidly converted into CTP in the normal T lymphocytes, compared to the MOLT-3 cells at physiological concentrations of uridine and cytidine.

Published
1995
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215. Dravet syndrome (severe myoclonic epilepsy of infancy)

Author

Erwin Schleicher, Hugo Ten Cate, Albrecht Hesse, A. J. Larner, André B. P. Van Kuilenburg, Nigel Laing, Lev G. Goldfarb, Andrea Schuppenies, Michael Benatar, Wolfram Trudo Knoefel, Frank Mastaglia, Peter L. M. Jansen, Alexander A. C. Leung, Andrew L. Wong, G. Pahlavan, Michael Fromm, Dieter Häussinger, Jochen Klucken, John-John B. Schnog, Christie P. Thomas, Gunter Wolf, Tam Nguyen, Albert H. Van Gennip, Norman Kock, Cord Sunderkötter, Katja Lohmann, Silke Hofmann, Dieter Metze, Alexander K. C. Leung, Derek LeRoith, Naomichi Matsumoto, Christine Klein, Justine H. S. Fong, Stefan Bröer, Leena Bruckner-Tuderman, Andreas Fritsche, Andreas Barthel, Per Hoffmann, Wilgard Hunger-Dathe, Barbara C. Van Munster, Anca Sindrilaru, Peter Heutink, Markus M. Nöthen, Jörg-Dieter Schulzke, Johannes Schumacher, Noriko Miyake, Victor E. A. Gerdes, Manish Suneja, Mary Redmond Hutson, Ulrich Müller, Chaeyoung Lee, Daniela Steinberger, August H. M. Smelt, André B. P. Kuilenburg, Albert H. Gennip, Michael Straub, Birgit Haack, Jan Schulte Am Esch, Sönke Weihe, Birgit Zirn, Markus G. Donner, Oliver Bartsch, Christine A. F. Von Arnim, and Margaret L. Kirby

Subjects
Pharmacology, Pediatrics, medicine.medical_specialty, Dravet syndrome, business.industry, medicine, Myoclonic epilepsy, Pharmacology (medical), medicine.disease, business
Published
2009
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216. Ganciclovir nucleotides accumulate in mitochondria of rat liver cells expressing the herpes simplex virus thymidine kinase gene.

Author

Marjolijn M. van der Eb, Sacha B. Geutskens, André B. P. van Kuilenburg, Henk van Lenthe, Jan-Hein van Dierendonck, Peter J. K. Kuppen, Hans van Ormondt, Cornelis J. H. van de Velde, Ronald J. A. Wanders, Albert H. van Gennip, and Rob C. Hoeben

Subjects
GANCICLOVIR, NUCLEOTIDES, DNA viruses, DNA, MITOCHONDRIA, HERPES simplex virus
Abstract

Ganciclovir exhibits broad-spectrum activity against DNA viruses such as cytomegaloviruses, herpes simplex viruses, varicella-zoster virus, Epstein-Barr virus and human herpes virus-6. Ganciclovir is widely applied for anti-herpetic treatment, cytomegalovirus prophylaxis after organ transplantation, and, more recently, in experimental gene therapy to eradicate cycling cells that express the herpes simplex virus thymidine kinase gene. Although ganciclovir supposedly acts as a chain terminator, there is compelling evidence demonstrating the presence of ganciclovir, but not of acyclovir, incorporated internally into DNA, leaving the precise mechanism by which ganciclovir inhibits DNA synthesis enigmatic. To study the potential involvement of mitochondria in the ganciclovir nucleotide cytotoxicity, we used adenovirus-mediated gene transfer to express herpes simplex virus thymidine kinase in rat liver and administered ganciclovir 2 days post-infection. The integrity and function of mitochondria in the rat liver cells were evaluated by several techniques. In addition, we analyzed the nucleotide pools in cellular extracts and in isolated mitochondria. We show that ganciclovir nucleotides are abundantly present in the mitochondria of rat livers that express the HSVtk gene. Already 48 h after administration, 10–30% of the total mitochondrial nucleotide pool consists of ganciclovir nucleotides. Their presence is correlated with a lower amount of mitochondrial DNA, a reduced mitochondrial-membrane potential, morphological abnormalities, and liver dysfunction. These data provide evidence for the involvement of mitochondria in the hepatotoxicity of the HStk/ganciclovir combination. This may explain the toxicity of the HSVtk/gancilovir combination in some metabolically active but non-proliferating cells, such as liver cells. This toxicity limits the applicability of this enzyme/prodrug combination. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Published
2003
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217. ß-Ureidopropionase deficiency: Phenotype, genotype and protein structural consequences in 16 patients

Author

Lida Zoetekouw, Birgit Assmann, Martin Engvall, Chunhua Zhang, Bernhard Lohkamp, Nico G.G.M. Abeling, Martin Smitka, Kaoru Eto, Kayoko Saito, Mohamed S. Rashed, Doreen Dobritzsch, Rutger Meinsma, Tetsuya Ito, Wang Xu, André B. P. van Kuilenburg, Laila Selim, Judith Meijer, Raoul C.M. Hennekam, Michael Krumpel, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatrics

Subjects
Male, Models, Molecular, Purine-Pyrimidine Metabolism, Inborn Errors, Microcephaly, Aminoisobutyric Acids, Protein Conformation, Mutant, medicine.disease_cause, Neurological abnormalities, Central Nervous System Diseases, Catalytic Domain, Missense mutation, Child, chemistry.chemical_classification, Genetics, Mutation, biology, Homology modeling, Amino acid, Drosophila melanogaster, Child, Preschool, Molecular Medicine, Female, Adult, Genotype, Molecular Sequence Data, Mutation, Missense, Amidohydrolases, Escherichia coli, medicine, Animals, Humans, Point Mutation, Protein Interaction Domains and Motifs, Amino Acid Sequence, Molecular Biology, Functional and structural protein analysis, Point mutation, Racial Groups, Infant, Newborn, Infant, UPB1, biology.organism_classification, medicine.disease, Pyrimidines, Enzyme, Amino Acid Substitution, chemistry, Biocatalysis, Mutagenesis, Site-Directed, beta-Alanine, ß-Ureidopropionase
Abstract

beta-Ureidopropionase is the third enzyme of the pyrimidine degradation pathway and catalyzes the conversion of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid to beta-alanine and beta-aminoisobutyric acid, ammonia and CO2. To date, only five genetically confirmed patients with a complete beta-ureidopropionase deficiency have been reported. Here, we report on the clinical, biochemical and molecular findings of 11 newly identified beta-ureidopropionase deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological abnormalities (intellectual disabilities, seizures, abnormal tonus regulation, microcephaly, and malformations on neuro-imaging) and markedly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in urine and plasma. Analysis of UPB1, encoding beta-ureidopropionase, showed 6 novel missense mutations and one novel splice-site mutation. Heterologous expression of the 6 mutant enzymes in Escherichia coli showed that all mutations yielded mutant beta-ureidopropionase proteins with significantly decreased activity. Analysis of a homology model of human beta-ureidopropionase generated using the crystal structure of the enzyme from Drosophila melanogaster indicated that the point mutations p.G235R, p.R236W and p.S264R lead to amino acid exchanges in the active site and therefore affect substrate binding and catalysis. The mutations L13S, R326Q and T359M resulted most likely in folding defects and oligomer assembly impairment. Two mutations were identified in several unrelated beta-ureidopropionase patients, indicating that beta-ureidopropionase deficiency may be more common than anticipated. (c) 2012 Elsevier B.V. All rights reserved

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218. Dihydropyrimidinase deficiency: Phenotype, genotype and structural consequences in 17 patients

Author

Georg F. Hoffmann, Lawrence Greed, André B. P. van Kuilenburg, Suzanne Lind, Susanne Schubert, Antonia Ribes, Doreen Dobritzsch, Jean-François Benoist, Adrian C. Sewell, K Otfried Schwab, Raoul C.M. Hennekam, John H. Walter, Marinus Duran, Maaike de Vries, Rutger Meinsma, Jörn Oliver Sass, Gerd Kurlemann, Andreas Hahn, François Eyskens, Lida Zoetekouw, Birgit Assmann, Judith Meijer, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, CCA -Cancer Center Amsterdam, Laboratory Genetic Metabolic Diseases, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, and Paediatrics

Subjects
Adult, Male, Models, Molecular, endocrine system, Adolescent, Genotype, Nonsense mutation, Mutant, Biology, medicine.disease_cause, Models, Biological, Protein Structure, Secondary, Amidohydrolases, Structure-Activity Relationship, Young Adult, Dihydropyrimidinase, Metabolic Diseases, medicine, Humans, Missense mutation, Neurological and gastrointestinal abnormalities, Child, Molecular Biology, DPYS, Functional and structural protein analysis, Genetics, Mutation, Protein Stability, Physics, Point mutation, Crystal structure, Infant, Newborn, Infant, Phenotype, Molecular biology, Chemistry, Child, Preschool, Molecular Medicine, Female, Human medicine
Abstract

Dihydropyrimidinase (DHP) is the second enzyme of the pyrimidine degradation pathway and catalyses the ring opening of 5,6-dihydrouracil and 5,6-dihydrothymine. To date, only 11 individuals have been reported suffering from a complete DHP deficiency. Here, we report on the clinical, biochemical and molecular findings of 17 newly identified DHP deficient patients as well as the analysis of the mutations in a three-dimensional framework. Patients presented mainly with neurological and gastrointestinal abnormalities and markedly elevated levels of 5,6-dihydrouracil and 5,6-dihydrothymine in plasma, cerebrospinal fluid and urine. Analysis of DPYS, encoding DHP, showed nine missense mutations, two nonsense mutations, two deletions and one splice-site mutation. Seventy-one percent of the mutations were located at exons 5-8, representing 41% of the coding sequence. Heterologous expression of 11 mutant enzymes in Escherichia coli showed that all but two missense mutations yielded mutant DHP proteins without significant activity. Only DHP enzymes containing the mutations p.R302Q and p.T343A possessed a residual activity of 3.9% and 49%, respectively. The crystal structure of human DHP indicated that the point mutations p.R490C, p.R302Q and p. V364M affect the oligomerization of the enzyme. In contrast, p.M70T, p.D81G, p.L337P and p.T343A affect regions near the di-zinc centre and the substrate binding site. The p.S379R and p.L7V mutations were likely to cause structural destabilization and protein misfolding. Four mutations were identified in multiple unrelated DHP patients, indicating that DHP deficiency may be more common than anticipated. (C) 2010 Elsevier B.V. All rights reserved.

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220. Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors.

Author

Maarten Arends, Marieke Biegstraaten, Derralynn A Hughes, Atul Mehta, Perry M Elliott, Daniel Oder, Oliver T Watkinson, Frédéric M Vaz, André B P van Kuilenburg, Christoph Wanner, and Carla E M Hollak

Subjects
Medicine, Science
Abstract

Despite enzyme replacement therapy, disease progression is observed in patients with Fabry disease. Identification of factors that predict disease progression is needed to refine guidelines on initiation and cessation of enzyme replacement therapy. To study the association of potential biochemical and clinical prognostic factors with the disease course (clinical events, progression of cardiac and renal disease) we retrospectively evaluated 293 treated patients from three international centers of excellence. As expected, age, sex and phenotype were important predictors of event rate. Clinical events before enzyme replacement therapy, cardiac mass and eGFR at baseline predicted an increased event rate. eGFR was the most important predictor: hazard ratios increased from 2 at eGFR 90. In addition, men with classical disease and a baseline eGFR 60. Proteinuria was a further independent risk factor for decline in eGFR. Increased cardiac mass at baseline was associated with the most robust decrease in cardiac mass during treatment, while presence of cardiac fibrosis predicted a stronger increase in cardiac mass (3.36 gram/m2/year). Of other cardiovascular risk factors, hypertension significantly predicted the risk for clinical events. In conclusion, besides increasing age, male sex and classical phenotype, faster disease progression while on enzyme replacement therapy is predicted by renal function, proteinuria and to a lesser extent cardiac fibrosis and hypertension.

Published
2017
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221. Hydrogen sulfide donor NaHS reduces organ injury in a rat model of pneumococcal pneumosepsis, associated with improved bio-energetic status.

Author

Hamid Aslami, Wilco P Pulskens, Maria T Kuipers, Aafkeline P Bos, André B P van Kuilenburg, Ronald J A Wanders, Jeroen Roelofsen, Joris J T H Roelofs, Raphaela P Kerindongo, Charlotte J P Beurskens, Marcus J Schultz, Wim Kulik, Nina C Weber, and Nicole P Juffermans

Subjects
Medicine, Science
Abstract

Sepsis is characterized by a generalized inflammatory response and organ failure, associated with mitochondrial dysfunction. Hydrogen sulfide donor NaHS has anti-inflammatory properties, is able to reduce metabolism and can preserve mitochondrial morphology and function. Rats were challenged with live Streptococcus pneumonia or saline and infused with NaHS (36 µmol/kg/h) or vehicle. Lung and kidney injury markers were measured as well as mitochondrial function, viability and biogenesis. Infusion of NaHS reduced heart rate and body temperature, indicative of a hypo-metabolic state. NaHS infusion reduced sepsis-related lung and kidney injury, while host defense remained intact, as reflected by unchanged bacterial outgrowth. The reduction in organ injury was associated with a reversal of a fall in active oxidative phosphorylation with a concomitant decrease in ATP levels and ATP/ADP ratio. Preservation of mitochondrial respiration was associated with increased mitochondrial expression of α-tubulin and protein kinase C-ε, which acts as regulators of respiration. Mitochondrial damage was decreased by NaHS, as suggested by a reduction in mitochondrial DNA leakage in the lung. Also, NaHS treatment was associated with upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α, with a subsequent increase in transcription of mitochondrial respiratory subunits. These findings indicate that NaHS reduces organ injury in pneumosepsis, possibly via preservation of oxidative phosphorylation and thereby ATP synthesis as well as by promoting mitochondrial biogenesis. Further studies on the involvement of mitochondria in sepsis are required.

Published
2013
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