Search

Your search keyword '"de Witte, P. A. M."' showing total 47 results
Start Over Author "de Witte, P. A. M."
47 results on '"de Witte, P. A. M."'

1. Adjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial

Author

Bol, Kalijn F., Schreibelt, Gerty, Bloemendal, Martine, van Willigen, Wouter W., Hins-de Bree, Simone, de Goede, Anna L., de Boer, Annemiek J., Bos, Kevin J. H., Duiveman-de Boer, Tjitske, Olde Nordkamp, Michel A. M., van Oorschot, Tom G. M., Popelier, Carlijn J., Pots, Jeanne M., Scharenborg, Nicole M., van de Rakt, Mandy W. M. M., de Ruiter, Valeska, van Meeteren, Wilmy S., van Rossum, Michelle M., Croockewit, Sandra J., Koeneman, Bouke J., Creemers, Jeroen H. A., Wortel, Inge M. N., Angerer, Caroline, Brüning, Mareke, Petry, Katja, Dzionek, Andrzej, van der Veldt, Astrid A., van Grünhagen, Dirk J., Werner, Johanna E. M., Bonenkamp, Johannes J., Haanen, John B. A. G., Boers-Sonderen, Marye J., Koornstra, Rutger H. T., Boomsma, Martijn F., Aarntzen, Erik H. J., Gotthardt, Martin, Nagarajah, James, de Witte, Theo J. M., Figdor, Carl G., de Wilt, Johannes H. W., Textor, Johannes, de Groot, Jan Willem B., Gerritsen, Winald R., and de Vries, I. Jolanda M.

Published
2024
Full Text
View/download PDF

10. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: Inhibition of epileptic seizures by the serotonin agonist fenfluramine

Author

Zhang, Yang, Kecskés, A., Copmans, D., Langlois, Melanie, Crawford, Alexander Dettmar, Ceulemans, B., Lagae, L., De Witte, P. A. M., Esguerra, C. V., and Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center]

Subjects
Danio rerio, Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Animalia, Article, Multidisciplinary, general & others [D99] [Human health sciences]
Abstract

Dravet syndrome (DS) is one of the most pharmacoresistant and devastating forms of childhood epilepsy syndromes. Distinct de novo mutations in the SCN1A gene are responsible for over 80% of DS cases. While DS is largely resistant to treatment with existing anti-epileptic drugs, promising results have been obtained in clinical trials with human patients treated with the serotonin agonist fenfluramine as an add-on therapeutic. We developed a zebrafish model of DS using morpholino antisense oligomers (MOs) targeting scn1Lab, the zebrafish ortholog of SCN1A. Zebrafish larvae with an antisense knockdown of scn1Lab (scn1Lab morphants) were characterized by automated behavioral tracking and high-resolution video imaging, in addition to measuring brain activity through local field potential recordings. Our findings reveal that scn1Lab morphants display hyperactivity, convulsive seizure-like behavior, loss of posture, repetitive jerking and a myoclonic seizure-like pattern. The occurrence of spontaneous seizures was confirmed by local field potential recordings of the forebrain, measuring epileptiform discharges. Furthermore, we show that these larvae are remarkably sensitive to hyperthermia, similar to what has been described for mouse models of DS, as well as for human DS patients. Pharmacological evaluation revealed that sodium valproate and fenfluramine significantly reduce epileptiform discharges in scn1Lab morphants. Our findings for this zebrafish model of DS are in accordance with clinical data for human DS patients. To our knowledge, this is the first study demonstrating effective seizure inhibition of fenfluramine in an animal model of Dravet syndrome. Moreover, these results provide a basis for identifying novel analogs with improved activity and significantly milder or no side effects. © 2015 Zhang et al.

Published
2015

11. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Author

Schubert, J., Siekierska, A., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., de Kovel, C. G. F., Thiele, H., Konrad, K., Kawalia, A., Toliat, M. R., Sander, T., Ruschendorf, F., Caliebe, A., Nagel, I., Kohl, B., Kecskes, A., Jacmin, M., Hardies, K., Weckhuysen, S., Riesch, E., Dorn, T., Brilstra, E. H., Baulac, S., Moller, R. S., Hjalgrim, H., Koeleman, B. P. C., Jurkat-Rott, K., Lehman-Horn, F., Roach, J. C., Glusman, G., Hood, L., Galas, D. J., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nurnberg, P., Crawford, A. D., Esguerra, C. V., Weber, Y. G., Lerche, H., Euro, Epinomics R. E. S. Consortium, EuroEPINOMICS RES Consortium, [GIN] Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Institute for Systems Biology [Seattle] (ISB), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurogenetics Group, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Cologne Center for Genomics (CCG), University of Cologne, Department of Molecular and Developmental Genetics (VIB11), Flanders institute of biotechnology, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Laboratory, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratory of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences Lueven Belgium, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Center for Genomics and Transcriptomics (CEGAT), Antwerp University Hospital [Edegem] (UZA), Children’s Hospital of Philadelphia (CHOP ), Cologne Center for Genomics, University of Cologne, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Heidelberg [Heidelberg] = Heidelberg University, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Genetic Linkage, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Syntaxin 1, medicine.disease_cause, Epilepsy/genetics, Cohort Studies, Epilepsy, 0302 clinical medicine, Syntaxin 1/genetics, Missense mutation, Exome, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Zebrafish, Genetics, 0303 health sciences, Mutation, Comparative Genomic Hybridization, Temperature, PAROXYSMAL KINESIGENIC DYSKINESIA SYNAPTIC VESICLE FUSION DE-NOVO MUTATIONS FEBRILE SEIZURES INFANTILE CONVULSIONS GENERALIZED EPILEPSY PRRT2 MUTATIONS GENERATION DISORDERS ZEBRAFISH, Pedigree, Phenotype, Codon, Nonsense, Female, Molecular Sequence Data, Biology, Polymorphism, Single Nucleotide, Seizures, Febrile, 03 medical and health sciences, SCN1B, medicine, Animals, Humans, Amino Acid Sequence, Seizures, Febrile/genetics, Generalized epilepsy, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Sequence Analysis, DNA, Paroxysmal dyskinesia, medicine.disease, Epilepsy syndromes, Human medicine, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Gene Deletion
Abstract

Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B(6), that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees(7,8) identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

Published
2014
Full Text
View/download PDF

12. Optimization and Pharmacological Validation of a Leukocyte Migration Assay in Zebrafish Larvae for the Rapid In Vivo Bioactivity Analysis of Anti-Inflammatory Secondary Metabolites

Author

Cordero-Maldonado, M. L., Siverio-Mota, D., Vicet-Muro, L., Wilches-Arizábala, I. M., Esguerra, C. V., de Witte, P. A. M., and Crawford, Alexander Dettmar

Subjects
Lipopolysaccharides, animal structures, Matricaria, Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Syzygium, Anti-Inflammatory Agents, Syzygium montanum extract, Harpagophytum procumbens extract, Calendula officinalis, Cell Migration Assays, Leukocyte, Arnica montana extract, Harpagophytum, Animals, Matricaria recutita extract, Araliaceae, Zebrafish, Multidisciplinary, general & others [D99] [Human health sciences], Inflammation, Capraria biflora, fungi, Chamaemelum nobile extract, Schefflera chimbuensis, Schefflera chimbuensis extract, Arnica montana, Chamaemelum, Larva, Syzygium montanum, Capraria biflora extract, Scrophulariaceae
Abstract

Over the past decade, zebrafish (Danio rerio) have emerged as an attractive model for in vivo drug discovery. In this study, we explore the suitability of zebrafish larvae to rapidly evaluate the anti-inflammatory activity of natural products (NPs) and medicinal plants used in traditional medicine for the treatment of inflammatory disorders. First, we optimized a zebrafish assay for leukocyte migration. Inflammation was induced in four days post-fertilization (dpf) zebrafish larvae by tail transection and co-incubation with bacterial lipopolysaccharides (LPS), resulting in a robust recruitment of leukocytes to the zone of injury. Migrating zebrafish leukocytes were detected in situ by myeloperoxidase (MPO) staining, and anti-inflammatory activity was semi-quantitatively scored using a standardized scale of relative leukocyte migration (RLM). Pharmacological validation of this optimized assay was performed with a panel of anti-inflammatory drugs, demonstrating a concentration-responsive inhibition of leukocyte migration for both steroidal and non-steroidal anti-inflammatory drugs (SAIDs and NSAIDs). Subsequently, we evaluated the bioactivity of structurally diverse NPs with well-documented anti-inflammatory properties. Finally, we further used this zebrafish-based assay to quantify the anti-inflammatory activity in the aqueous and methanolic extracts of several medicinal plants. Our results indicate the suitability of this LPS-enhanced leukocyte migration assay in zebrafish larvae as a front-line screening platform in NP discovery, including for the bioassay-guided isolation of anti-inflammatory secondary metabolites from complex NP extracts. © 2013 Cordero-Maldonado et al.

Published
2013

13. A phenotypic screen in zebrafish identifies a novel small-molecule inducer of ectopic tail formation suggestive of alterations in non-canonical Wnt/PCP signaling

Author

Gebruers, E., Cordero-Maldonado, M. L., Gray, A. I., Clements, C., Harvey, A. L., Edrada-Ebel, R., De Witte, P. A. M., Crawford, Alexander Dettmar, Esguerra, C. V., and Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center]

Subjects
Tail, animal structures, Embryo, Nonmammalian, Coumaric Acids, Multidisciplinaire, généralités & autres [D99] [Sciences de la santé humaine], Jasminum, Oleaceae, Drug Evaluation, Preclinical, BMP signaling pathway, Zebrafish Proteins, PCP signaling pathway, Wnt signaling pathway, Papua New Guinea, Pyrimidines, Jasminum gilgianum extract, Bone Morphogenetic Proteins, Animals, Pyrazoles, Zebrafish, Multidisciplinary, general & others [D99] [Human health sciences], Jasminum gilgianum
Abstract

Zebrafish have recently emerged as an attractive model for the in vivo bioassay-guided isolation and characterization of pharmacologically active small molecules of natural origin. We carried out a zebrafish-based phenotypic screen of over 3000 plant-derived secondary metabolite extracts with the goal of identifying novel small-molecule modulators of the BMP and Wnt signaling pathways. One of the bioactive plant extracts identified in this screen - Jasminum gilgianum, an Oleaceae species native to Papua New Guinea - induced ectopic tails during zebrafish embryonic development. As ectopic tail formation occurs when BMP or non-canonical Wnt signaling is inhibited during the tail protrusion process, we suspected a constituent of this extract to act as a modulator of these pathways. A bioassay-guided isolation was carried out on the basis of this zebrafish phenotype, identifying para-coumaric acid methyl ester (pCAME) as the active compound. We then performed an in-depth phenotypic analysis of pCAME-treated zebrafish embryos, including a tissue-specific marker analysis of the secondary tails. We found pCAME to synergize with the BMP-inhibitors dorsomorphin and LDN-193189 in inducing ectopic tails, and causing convergence-extension defects in compound-treated embryos. These results indicate that pCAME may interfere with non-canonical Wnt signaling. Inhibition of Jnk, a downstream target of Wnt/PCP signaling (via morpholino antisense knockdown and pharmacological inhibition with the kinase inhibitor SP600125) phenocopied pCAME-treated embryos. However, immunoblotting experiments revealed pCAME to not directly inhibit Jnk-mediated phosphorylation of c-Jun, suggesting additional targets of SP600125, and/or other pathways, as possibly being involved in the ectopic tail formation activity of pCAME. Further investigation of pCAME's mechanism of action will help determine this compound's pharmacological utility. © 2013 Gebruers et al.

Published
2013

14. MODELING OF FEVER-ASSOCIATED EPILEPSY SYNDROMES CAUSED BY MUTATIONS IN STX1B IN ZEBRAFISH

Author

Siekierska, A., Schubert, J., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., De Kovel, C. G. F., Thiele, H., Kecskes, A., Jacmin, M., Koeleman, B., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nuernberg, P., Crawford, A. D., Weber, Y. G., Lerche, H., Esguerra, C. V., Siekierska, A., Schubert, J., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., De Kovel, C. G. F., Thiele, H., Kecskes, A., Jacmin, M., Koeleman, B., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nuernberg, P., Crawford, A. D., Weber, Y. G., Lerche, H., and Esguerra, C. V.

Published
2015

15. Pharmacological characterization of an antisense knockdown zebrafish model of Dravet syndrome: Inhibition of epileptic seizures by the serotonin agonist fenfluramine

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], Zhang, Yang, Kecskés, A., Copmans, D., Langlois, Melanie, Crawford, Alexander Dettmar, Ceulemans, B., Lagae, L., De Witte, P. A. M., Esguerra, C. V., Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], Zhang, Yang, Kecskés, A., Copmans, D., Langlois, Melanie, Crawford, Alexander Dettmar, Ceulemans, B., Lagae, L., De Witte, P. A. M., and Esguerra, C. V.

Abstract

Dravet syndrome (DS) is one of the most pharmacoresistant and devastating forms of childhood epilepsy syndromes. Distinct de novo mutations in the SCN1A gene are responsible for over 80% of DS cases. While DS is largely resistant to treatment with existing anti-epileptic drugs, promising results have been obtained in clinical trials with human patients treated with the serotonin agonist fenfluramine as an add-on therapeutic. We developed a zebrafish model of DS using morpholino antisense oligomers (MOs) targeting scn1Lab, the zebrafish ortholog of SCN1A. Zebrafish larvae with an antisense knockdown of scn1Lab (scn1Lab morphants) were characterized by automated behavioral tracking and high-resolution video imaging, in addition to measuring brain activity through local field potential recordings. Our findings reveal that scn1Lab morphants display hyperactivity, convulsive seizure-like behavior, loss of posture, repetitive jerking and a myoclonic seizure-like pattern. The occurrence of spontaneous seizures was confirmed by local field potential recordings of the forebrain, measuring epileptiform discharges. Furthermore, we show that these larvae are remarkably sensitive to hyperthermia, similar to what has been described for mouse models of DS, as well as for human DS patients. Pharmacological evaluation revealed that sodium valproate and fenfluramine significantly reduce epileptiform discharges in scn1Lab morphants. Our findings for this zebrafish model of DS are in accordance with clinical data for human DS patients. To our knowledge, this is the first study demonstrating effective seizure inhibition of fenfluramine in an animal model of Dravet syndrome. Moreover, these results provide a basis for identifying novel analogs with improved activity and significantly milder or no side effects. © 2015 Zhang et al.

Published
2015

16. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], ESF, European Science Foundation; WT089062, Wellcome Trust; 098051, Wellcome Trust; 261123, EC, European Commission; DFG, Deutsche Forschungsgemeinschaft [sponsor], Suls, A., Jaehn, J. A., Kecskés, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djémie, T., Afrikanova, T., Gormley, P., Von Spiczak, S., Kluger, G., Iliescu, C. M., Talvik, T., Talvik, I., Meral, C., Caglayan, H. S., Giraldez, B. G., Serratosa, J., Lemke, J. R., Hoffman-Zacharska, D., Szczepanik, E., Barisic, N., Komarek, V., Hjalgrim, H., Møller, R. S., Linnankivi, T., Dimova, P., Striano, P., Zara, F., Marini, C., Guerrini, R., Depienne, C., Baulac, S., Kuhlenbäumer, G., Crawford, Alexander Dettmar, Lehesjoki, A.-E., De Witte, P. A. M., Palotie, A., Lerche, H., Esguerra, C. V., De Jonghe, P., Helbig, I., Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], ESF, European Science Foundation; WT089062, Wellcome Trust; 098051, Wellcome Trust; 261123, EC, European Commission; DFG, Deutsche Forschungsgemeinschaft [sponsor], Suls, A., Jaehn, J. A., Kecskés, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djémie, T., Afrikanova, T., Gormley, P., Von Spiczak, S., Kluger, G., Iliescu, C. M., Talvik, T., Talvik, I., Meral, C., Caglayan, H. S., Giraldez, B. G., Serratosa, J., Lemke, J. R., Hoffman-Zacharska, D., Szczepanik, E., Barisic, N., Komarek, V., Hjalgrim, H., Møller, R. S., Linnankivi, T., Dimova, P., Striano, P., Zara, F., Marini, C., Guerrini, R., Depienne, C., Baulac, S., Kuhlenbäumer, G., Crawford, Alexander Dettmar, Lehesjoki, A.-E., De Witte, P. A. M., Palotie, A., Lerche, H., Esguerra, C. V., De Jonghe, P., and Helbig, I.

Abstract

Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and feversensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures. © 2013 by The American Society of Human Genetics. All rights reserved.

Published
2013

17. A phenotypic screen in zebrafish identifies a novel small-molecule inducer of ectopic tail formation suggestive of alterations in non-canonical Wnt/PCP signaling

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], Gebruers, E., Cordero-Maldonado, M. L., Gray, A. I., Clements, C., Harvey, A. L., Edrada-Ebel, R., De Witte, P. A. M., Crawford, Alexander Dettmar, Esguerra, C. V., Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group) [research center], Gebruers, E., Cordero-Maldonado, M. L., Gray, A. I., Clements, C., Harvey, A. L., Edrada-Ebel, R., De Witte, P. A. M., Crawford, Alexander Dettmar, and Esguerra, C. V.

Abstract

Zebrafish have recently emerged as an attractive model for the in vivo bioassay-guided isolation and characterization of pharmacologically active small molecules of natural origin. We carried out a zebrafish-based phenotypic screen of over 3000 plant-derived secondary metabolite extracts with the goal of identifying novel small-molecule modulators of the BMP and Wnt signaling pathways. One of the bioactive plant extracts identified in this screen - Jasminum gilgianum, an Oleaceae species native to Papua New Guinea - induced ectopic tails during zebrafish embryonic development. As ectopic tail formation occurs when BMP or non-canonical Wnt signaling is inhibited during the tail protrusion process, we suspected a constituent of this extract to act as a modulator of these pathways. A bioassay-guided isolation was carried out on the basis of this zebrafish phenotype, identifying para-coumaric acid methyl ester (pCAME) as the active compound. We then performed an in-depth phenotypic analysis of pCAME-treated zebrafish embryos, including a tissue-specific marker analysis of the secondary tails. We found pCAME to synergize with the BMP-inhibitors dorsomorphin and LDN-193189 in inducing ectopic tails, and causing convergence-extension defects in compound-treated embryos. These results indicate that pCAME may interfere with non-canonical Wnt signaling. Inhibition of Jnk, a downstream target of Wnt/PCP signaling (via morpholino antisense knockdown and pharmacological inhibition with the kinase inhibitor SP600125) phenocopied pCAME-treated embryos. However, immunoblotting experiments revealed pCAME to not directly inhibit Jnk-mediated phosphorylation of c-Jun, suggesting additional targets of SP600125, and/or other pathways, as possibly being involved in the ectopic tail formation activity of pCAME. Further investigation of pCAME's mechanism of action will help determine this compound's pharmacological utility. © 2013 Gebruers et al.

Published
2013

19. Anti-Inflammatory Activity and Cheminformatics Analysis of New Poten t 2-Substituted 1-Methyl-5-Nitroindazolinones

Author

Siverio-Mota, Dany, Andujar, Isabel, Marrero-Ponce, Yovani, Giner, Rosa M., Diaz-Mendoza, Claudia, Paba, Ganiveth Manjarrez, Vicet-Muro, Liliana, Cordero-Maldonado, Maria Lorena, de Witte, Peter A. M., Crawford, Alexander D., Veitia, Maite Sylla-Iyarreta, Perez-Jimenez, Facundo, and Aran, Vicente J.

Abstract

After the identification of the anti-inflammatory properties of VA5-13l (2-benzyl-1- methyl-5-nitroindazolinone) in previous investigations, some of its analogous compounds were designed, synthesized and evaluated in two anti-inflammatory methods: LPS-enhanced leukocyte migration assay in zebrafish; and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema. The products evaluated (3, 6, 8, 9 and 10) showed the lower values of relative leukocyte migration at 30 µM (0.14, 0.07, 0.10, 0.13 and 0.07, respectively), while in ear edema and myeloperoxidase activity methods, all the compounds reduced inflammation, only 4 and 16 yielded unsatisfactory results. The relationship linking structure and activity (SAR analysis) was determinate by using SARANEA software. The importance of the 5-Nitro group of the indazole ring for the activity was evident, and showed modest reduction when benzyl (Bn) is changed by alkyl group. A substituted Bn moiety at N2 (R) is the best substituent (5-10); nevertheless, if methylene group of Bn is deleted, the activity is affected. Also, introduction of halogen atoms mainly at positions 3 or 4 of the benzyl moiety (6 and 10) leads in general to strong activities. In fact, compounds 7 and 8 (R = 4-FBn or 4-ClBn, respectively) exhibit satisfactory results in in vivo tests and appear promising. The production of IL-6 at all doses assayed was significantly reduced, except with 16. Nonetheless, the production of TNF-α was significantly inhibited only by this chemical (16) at concentration of 50 μM. On the other hand, compound 2 was the one that mostly inhibited the expression of COX-2 and iNOS. From these results, it can be concluded that the inhibition in the release of cytokines can be one of the mechanisms of action responsible for the anti-inflammatory effect for 2-benzyl derivates while other 2-alkyl derivatives can inhibit production of NO. Therefore, nitroindazolinone chemical prototype could be an interesting structural group with anti-inflammatory purposes in the therapeutic.

Published
2017

26. In vitro and in vivo multidrug resistance reversal activity by a Betti-base derivative of tylosin.

Author

Gy,ém,ánt, N., Engi, H., Schelz, Z., Szatm,ári, I., Tóth, D., Fül,öp, F., Molnár, J., de Witte, P. A. M., Gyémánt, N, Szatmári, I, Tóth, D, Fülöp, F, and Molnár, J

Subjects
MULTIDRUG resistance, TUMOR proteins, MICRODIALYSIS, DRUG therapy, GLYCOPROTEINS
Abstract

Background: The multidrug resistance (MDR) proteins are present in a majority of human tumours. Their activity is important to understand the chemotherapeutic failure. A search for MDR-reversing compounds was conducted among various Betti-base derivatives of tylosin.Methods: Here, we evaluate the in vitro and in vivo P-glycoprotein (P-gp)-modulating activity of the most promising compound N-tylosil-1-alpha-amino-(3-bromophenyl)-methyl-2-naphthol (TBN) using human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines.Results: In vitro experiments showed that TBN dramatically increased the P-gp-mediated cellular uptake of the fluorescent substrate rhodamine 123. Similarly, TBN was found to act as a very potent enhancer of the cytotoxicity of doxorubicin on the resistant cell line. We also provide in vivo evidence using DBA/2 mice in support for an increased tumoural accumulation of doxorubicin, without affecting its tissue distribution, resulting in an enhanced antitumoural effect.Conclusion: Our results suggest that TBN is a potent modulator of the P-gp membrane pump and that the compound could be of clinical relevance to improve the efficacy of chemotherapy in MDR cancers. [ABSTRACT FROM AUTHOR]

Published
2010
Full Text
View/download PDF

27. Photosensitizing activity of hypericin and hypericin acetate after topical application on normal mouse skin.

Author

Boiy, A., Roelandts, R., van den Oord, J., and de Witte, P. A. M.

Subjects
SKIN diseases, HYPERICUM, ANIMAL models in research, PHOTOCHEMOTHERAPY, DERMATOLOGY
Abstract

Background Hypericin, originating from Hypericum perforatum, is a potent photosensitizer known to induce skin phototoxicity when given systemically. Previously, we have examined the penetration and distribution of hypericin and its acetate ester in the skin of hairless mice after topical application. Objectives In this study, we assessed the time course and skin histopathology of the phototoxic response after a single topical application of hypericin and hypericin acetate, and subsequent irradiation. The amount of blood-borne photosensitizer and the skin clearance, as well the remaining photosensitizing capacity as a function of time, were evaluated. Furthermore, elicited phototoxic responses were compared with those after application of methyl aminolaevulinic acid (Me-ALA). Methods At different time points after topical application of hypericin (0·1–1%) and hypericin acetate (0·015–1·5%) onto mouse ears, penetration and retention of hypericin were assessed by fluorescence microscopy. After definite application times, the ears were irradiated (10 J cm−2, 20 mW cm−2). Ear thickness measurements were conducted daily, and frequently ear samples were taken for histological analysis. Results Application of hypericin on mouse ears resulted only in limited phototoxicity, probably due to confined penetration into the epidermal layers. Extended penetration achieved by administration of hypericin acetate did give rise to a more severe and prolonged response after irradiation, characterized by intense erythema and ear swelling. Skin damage induced by 0·15% hypericin acetate application completely healed in 14 days without scar formation. After a single application of hypericin acetate, the residual photosensitizing capacity was found to decline quickly and was hardly detectable after 7 days. Under the experimental conditions used, hypericin acetate induced equal or more severe phototoxic responses compared with Me-ALA, depending on the concentration. Conclusions Our results indicate that hypericin is an effective photosensitizer not only after systemic administration, but also after topical application, especially when applied as its precursor acetate ester. Moreover, our data provide some insights on safety limits and the time course of skin phototoxicity following hypericin and hypericin acetate application. These data will aid in developing protocols for future photodynamic therapy in the dermatological clinic. [ABSTRACT FROM AUTHOR]

Published
2008
Full Text
View/download PDF

28. Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome

Author

Luesink, Maaike, Pennings, Jeroen L. A., Wissink, Willemijn M., Linssen, Peter C. M., Muus, Petra, Pfundt, Rolph, de Witte, Theo J. M., van der Reijden, Bert A., and Jansen, Joop H.

Abstract

In acute promyelocytic leukemia (APL), differentiation therapy with all-trans retinoic acid (ATRA) and/or arsenic trioxide can induce a differentiation syndrome (DS) with massive pulmonary infiltration of differentiating leukemic cells. Because chemokines are implicated in migration and extravasation of leukemic cells, chemokines might play a role in DS. ATRA stimulation of the APL cell line NB4 induced expression of multiple CC-chemokines (CCLs) and their receptors (> 19-fold), resulting in increased chemokine levels and chemotaxis. Induction of CCL2 and CCL24 was directly mediated by ligand-activated retinoic acid receptors. In primary leukemia cells derived from APL patients at diagnosis, ATRA induced chemokine production as well. Furthermore, in plasma of an APL patient with DS, we observed chemokine induction, suggesting that chemokines might be important in DS. Dexamethasone, which efficiently reduces pulmonary chemokine production, did not inhibit chemokine induction in APL cells. Finally, chemokine production was also induced by arsenic trioxide as single agent or in combination with ATRA. We propose that differentiation therapy may induce chemokine production in the lung and in APL cells, which both trigger migration of leukemic cells. Because dexamethasone does not efficiently reduce leukemic chemokine production, pulmonary infiltration of leukemic cells may induce an uncontrollable hyperinflammatory reaction in the lung.

Published
2009
Full Text
View/download PDF

29. Liquidphase synthesis of mixturebased bicyclic βlactam libraries

Author

Gedey, Szilvia, Fülöp, Ferenc, Vainiotalo, Pirjo, De Witte, Peter A. M., and Zupkó, Istvían

Abstract

Five sets of 27membered combinatorial libraries of alicyclic βlactams were prepared vialiquidphase Ugi 4center 3component reactions U4C3CR utilizing 3 different cisβamino acids, 3 different isonitriles and 5×3 sets of aldehydes. Through combinations of the building blocks of one of these libraries, all of the possible sublibraries were also generated. A few azetidinone derivatives were synthesized individually by parallel synthesis.

Published
2003
Full Text
View/download PDF

30. The Impact of Diabetes Mellitus As Comorbid Condition, in Patients with Lower-Risk Myelodysplastic Syndromes (MDS)— a Study of the European Leukemianet-Based MDS (EUMDS) Registry

Author

Symeonidis, Argiris, Yu, Ge, Smith, Alexandra, Fenaux, Pierre, Mittelman, Moshe, Stauder, Reinhard, Sanz, Guillermo, Cermak, Jaroslav, Hellstrom-Lindberg, Eva, Malcovati, Luca, Langemeijer, Saskia, Germing, Ulrich, Madry, Krzysztof, Holm, Mette Skov, Tatic, Aurelia, Almeida, Antonio Medina de, Savic, Aleksandar, Simec, Njetocka Gredelj, Guerci-Bresler, Agnes, Droste, Jackie, de Witte, T. M. M, and Bowen, David T.

Abstract

Background: Myelodysplastic syndrome is mainly a disease of the elderly, while the prevalence of Diabetes Mellitus (DM) in the aged population is about 25%.

Published
2017
Full Text
View/download PDF

31. The Addition of Midostaurin to Standard Chemotherapy Decreases Cumulative Incidence of Relapse (CIR) in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603 / RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3Mutations

Author

Stone, Richard M., Mandrekar, Sumithra J, Sanford, Ben L., Laumann, Kristine, Geyer, Susan M., Bloomfield, Clara D., Dohner, Konstanze, Thiede, Christian, Marcucci, Guido, Lo Coco, Francesco, Klisovic, Rebecca B., Wei, Andrew, Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, T. M. M, Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C, Tallman, Martin S., Krauter, Jurgen, Schlenk, Richard F., Ganser, Arnold, Serve, Hubert, Ehninger, Gerhard, Amadori, Sergio, Dohner, Hartmut, and Larson, Richard A.

Abstract

Background: Midostaurin (M) is an oral, multi-targeted, small molecule FLT3 inhibitor with single agent activity in both internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant (mut) FLT3AML. This global randomized, double-blinded placebo-controlled phase III trial demonstrated a statistically significant overall survival (OS) benefit when M was added to induction and consolidation chemotherapy followed by maintenance compared to standard chemotherapy in patients (pts) with activating FLT3muts (HR=0.78, one sided p=0.0001; Stone et al NEJM, 2017). We now report a detailed comparison of CIR in each arm to determine if M significantly lowered the risk of relapse.

Published
2017
Full Text
View/download PDF

32. Can We Diagnose MDS without Bone Marrow Examination? a Proposed EUMDS-Based Non-Invasive Diagnostic Model

Author

Oster, Howard S., Abu Shrkihe, Bander, Crouch, Simon, Smith, Alexandra, Yu, Ge, Carmi, Gal, Ben-Ezra, Jonathan, Naor, Shachar, Fenaux, Pierre, Symeonidis, Argiris, Stauder, Reinhard, Cermak, Jaroslav, Sanz, Guillermo, Hellstrom-Lindberg, Eva, Malcovati, Luca, Langemeijer, Saskia, Germing, Ulrich, Holm, Mette Skov, Madry, Krzysztof, Tatic, Aurelia, Almeida, Antonio Medina de, Savic, Aleksandar, Gredelj-Šimec, Njetočka, Guerci Bresler, Agnes, van Marrewijk, Corine, Bowen, David T., de Witte, T. M. M, and Mittelman, Moshe

Abstract

Background: Bone marrow examination (BME) is the gold standard for diagnosing myelodysplastic syndromes (MDS). Because it is invasive, many physicians and patients (pts) avoid BME, and the MDS Diagnosis is missed. Recently (Oster et al. Int MDS, Valencia, May 2017), we proposed a non-invasive MDS diagnostic model, using logistic regression (LoR) with a small group of patients (47 BME-proven MDS vs 63 controls with no MDS by BME). The variables gender, age, Hb, MCV, PLT and WBC were found to be the most important. Putting the variables in the formula (Fig 1) yielded a score Y, reflecting the probability of having MDS. The area under the curve (AUC) for the ROC curve was 0.748, indicating a good model, but one insufficient to provide a single Y, above which MDS could be established clearly. We therefore established two cut-off values: Pts with Y≥0.633 were found to have high likelihood for MDS, and those with Y≤0.288, a low likelihood of having MDS. Those pts (about 50%) where Y fell between the two cutoffs were indeterminate. In this study, the large European MDS Registry (EUMDS) database was used to validate and improve the model.

Published
2017
Full Text
View/download PDF

33. Validation of Scores Predicting Non-Relapse Mortality in Patients with Myelodysplastic Syndrome: A Study on 1276 Patients on Behalf the Chronic Malignancies Working Party of the EBMT

Author

Carre, Martin, Porcher, Raphael, Finke, Jürgen, Ehninger, Gerhard, Beelen, Dietrich W, Koster, Linda, Ganser, Arnold, Ayuk, Francis A, Socié, Gérard, Volin, Liisa, Sengeloev, Henrik, Michallet, Mauricette, Tischer, Johanna, Pascual, Maria-Jesús, Yener, Koc, Jindra, Pavel, Arat, Mutlu, de Witte, T. M. M, Kröger, Nicolaus, and Robin, Marie

Abstract

Allogeneic stem cell transplantation (HSCT) is the only potential curative treatment for myelodysplastic syndromes (MDS). Non-relapse mortality (NRM) remains a matter of concern despite the introduction of reduced-intensity conditioning in this disease, occurring mainly in an elderly population. Disease features and status at transplant are cornerstones for the risk of relapse. Different pre-transplant parameters have been analysed in various population without resulting in consensus.

Published
2017
Full Text
View/download PDF

34. The Impact of Cytogenetic Clonality on Outcomes in Younger Acute Myeloid Leukemia Patients: Results on 1290 Patients Included in the EORTC/Gimema AML-10 and AML-12 Trials

Author

Baron, Frederic, Stevens-Kroef, Marian, Kicinski, Michal, Meloni, Giovanna, Muus, Petra, Marie, Jean-Pierre, Halkes, Constantijn J.M., Thomas, Xavier, Vrhovac, Radovan, Pasciolla, Crescenza, Lefrere, Francois, Sica, Simona, Mancini, Marco, Venditti, Adriano, Hagemeijer, Anne, Becker, Heiko, Jansen, Joop H., Amadori, Sergio, de Witte, T. M. M, Willemze, Roelof, and Suciu, Stefan

Abstract

Background.A recent large retrospective study has observed that the presence of cytogenetic clonal heterogeneity, as detected by metaphase karyotyping, was associated with poor prognosis in patients (pts) with AML (Bochtler et al., J Clin Oncol 2013, 31: 3898-905).

Published
2017
Full Text
View/download PDF

35. An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3Mutations

Author

Larson, Richard A., Mandrekar, Sumithra J, Sanford, Ben L., Laumann, Kristine, Geyer, Susan M., Bloomfield, Clara D., Thiede, Christian, Prior, Thomas W, Dohner, Konstanze, Marcucci, Guido, Lo Coco, Francesco, Klisovic, Rebecca B., Wei, Andrew, Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, T. M. M, Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C, Tallman, Martin S., Krauter, Jurgen, Schlenk, Richard F., Ganser, Arnold, Serve, Hubert, Ehninger, Gerhard, Amadori, Sergio, Döhner, Hartmut, and Stone, Richard M.

Published
2017
Full Text
View/download PDF

36. Impact of In VivoT-Cell Depletion in Patients with Myelodysplastic Syndromes Undergoing Allogeneic Hematopoietic Stem Cell Transplant: A Registry Study from the Chronic Malignancies Working Party of the EBMT

Author

Forcade, Edouard, Chevret, Sylvie, Finke, Jürgen, Ehninger, Gerhard, Ayuk, Francis A, Beelen, Dietrich W, Koster, Linda, Ganser, Arnold, Socié, Gérard, Volin, Liisa, Sengeloev, Henrik, Michallet, Mauricette, Tischer, Johanna, Jindra, Pavel, Pascual, Maria-Jesús, Koc, Yener, Arat, Mutlu, de Witte, T. M. M, Kröger, Nicolaus, and Robin, Marie

Abstract

Background: in vivo T-cell depletion (TCD) is frequently used in the setting of allogeneic hematopoietic stem cell in order to decrease acute and chronic GVHD incidence. Several randomized studies, enrolling patients with myeloid disease have concluded to a decreased risk of GVHD without increasing the relapse risk. The present study included only myelodysplastic syndrome patients and evaluated the impact of anti-thymoglobulin (ATG) or alemtuzumab on outcomes.

Published
2017
Full Text
View/download PDF

37. Prognostic Impact of NPM1/FLT3-ITDgenotypes from Randomized Patients with Acute Myeloid Leukemia (AML) Treated within the International Ratify Study

Author

Döhner, Konstanze, Thiede, Christian, Larson, Richard A., Prior, Thomas W, Marcucci, Guido, Jones, Dan, Krauter, Jürgen, Heuser, Michael, Lo Coco, Francesco, Ottone, Tiziana, Nomdedeu, Josep, Mandrekar, Sumithra J, Sanford, Ben L., Laumann, Kristine, Geyer, Susan M., Klisovic, Rebecca B., Wei, Andrew, Sierra, Jorge, Sanz, Miguel A., Brandwein, Joseph M., de Witte, T. M. M, Jansen, Joop H., Niederwieser, Dietger, Appelbaum, Frederick R., Medeiros, Bruno C, Tallman, Martin S., Schlenk, Richard F., Ganser, Arnold, Serve, Hubert, Ehninger, Gerhard, Amadori, Sergio, Cheng, Yuan, Pallaud, Celine, Stone, Richard M., Döhner, Hartmut, and Bloomfield, Clara D.

Abstract

Background:Patients (pts) with AML harboring FLT3-ITD mutations have poor outcomes. The higher relapse rate and inferior overall survival (OS) largely depend on the ITD mutant to wild-type (wt) allelic ratio. Furthermore, there is a strong gene-gene interaction between NPM1mutation (NPM1mut) and FLT3-ITD. Consequently, the 2017 European LeukemiaNet (ELN) has included defined NPM1/FLT3-ITD genotypes for risk categorization. In the recent phase III RATIFY trial [NCT00651261; Stone et al., NEJM 2017] the addition of the multi-targeted kinase inhibitor midostaurin (M) to standard chemotherapy significantly prolonged OS and event-free survival (EFS) in pts with newly diagnosed AML and FLT3mutation. Here, we evaluated the prognostic impact in a post-hoc analysis of the NPM1/FLT3-ITD genotypes as defined by the 2017 ELN from randomized pts treated within the RATIFY trial.

Published
2017
Full Text
View/download PDF

38. The Use of Immunosuppressive Therapy (IST) in Patients with the Myelodysplastic Syndromes (MDS): Clinical Outcomes and Their Predictors in a Large International Patient Cohort

Author

Stahl, Maximilian, Deveaux, Michelle, de Witte, T. M. M, Neukirchen, Judith, Sekeres, Mikkael A., Brunner, Andrew M., Roboz, Gail J., Steensma, David P., Bhatt, Vijaya R., Platzbecker, Uwe, Cluzeau, Thomas, Prata, Pedro H, Fenaux, Pierre, Fathi, Amir T., Smith, Alex, Germing, Ulrich, Ritchie, Ellen K, Verma, Vivek, Podoltsev, Nikolai A., Arenillas, Leonor, Prebet, Thomas, Santini, Valeria, Gore, Steven D., Komrokji, Rami S., and Zeidan, Amer M.

Published
2017
Full Text
View/download PDF

39. Impact of Treatment with Iron Chelation Therapy in Lower-Risk MDS Patients Participating in the European Leukemianet MDS (EUMDS) Registry

Author

Hoeks, Marlijn, Yu, Ge, Langemeijer, Saskia, Crouch, Simon, De Swart, Louise, Fenaux, Pierre, Symeonidis, Argiris, Cermak, Jaroslav, Hellstrom-Lindberg, Eva, Sanz, Guillermo, Stauder, Reinhard, skov-Holm, Mette, Mittelman, Moshe, Madry, Krzysztof, Malcovati, Luca, Tatic, Aurelia, Almeida, Antonio Medina de, Germing, Ulrich, Savic, Aleksandar, Gredelj-Šimec, Njetočka, Culligan, Dominic, Itzykson, Raphael, Guerci-Bresler, Agnes, Slama, Borhane, van Marrewijk, Corine, Droste, Jackie, van Kraaij, Marian, Bowen, David T., de Witte, T. M. M, and Smith, Alex

Abstract

BackgroundIron overload/toxicity due to red blood cell transfusions (RBCT) is associated with morbidity and mortality in various patient groups, including patients with lower-risk myelodysplastic syndrome (LR-MDS). Many studies suggested improved overall survival (OS) after iron chelation therapy (ICT), but most studies suffer from methodological problems. In daily practice, many transfused LR-MDS patients receive ICT according to (inter)national guidelines to counteract the effects of RBCT. The value of ICT in LR-MDS remains unproven. The aim of this study is to assess the effect of ICT on OS in LR-MDS patients.

Published
2017
Full Text
View/download PDF

40. A Prognostic Classifier Based on Early Platelet Drop in Lower-Risk MDS. a Study from the European Leukemianet Lower-Risk MDS (EUMDS) Registry

Author

Itzykson, Raphael, Crouch, Simon, Smith, Alex, Symeonidis, Argiris, Hellstrom-Lindberg, Eva, Sanz, Guillermo, Cermak, Jaroslav, Stauder, Reinhard, Malcovati, Luca, Germing, Ulrich, Mittelman, Moshe, Langemeijer, Saskia, Madry, Krzysztof, Tatic, Aurelia, Holm, Mette Skov, Almeida, Antonio Medina de, Savic, Aleksandar, Gredelj-Šimec, Njetočka, Luño Fernandez, Elisa, Culligan, Dominic, Guerci Bresler, Agnes, van Marrewijk, Corine, Bowen, David T., de Witte, T. M. M, and Fenaux, Pierre

Published
2017
Full Text
View/download PDF

46. Photodynamic therapy using topically applied hypericin: comparative effect with methyl-aminolevulinic acid on UV induced skin tumours.

Author

Boiy A, Roelandts R, and de Witte PA

Subjects
Administration, Topical, Aminolevulinic Acid therapeutic use, Animals, Anthracenes, Antineoplastic Agents administration & dosage, Disease Models, Animal, Female, Keratosis, Actinic drug therapy, Mice, Mice, Hairless, Microscopy, Fluorescence, Perylene administration & dosage, Perylene therapeutic use, Photosensitizing Agents administration & dosage, Skin Neoplasms etiology, Skin Neoplasms pathology, Aminolevulinic Acid analogs & derivatives, Antineoplastic Agents therapeutic use, Perylene analogs & derivatives, Photochemotherapy, Photosensitizing Agents therapeutic use, Skin Neoplasms drug therapy, Ultraviolet Rays
Abstract

Photodynamic therapy (PDT) is a treatment option particularly well-suited for superficial (pre)malignant skin lesions due to the skin's accessibility to light. In the present study, the efficacy of topical hypericin-PDT was evaluated using a mouse model for actinic keratosis. For comparison, similar experiments were conducted with methyl-aminolevulinic acid (Me-ALA). Small skin tumours (1-2 mm) were induced in hairless mice by chronic UV irradiation. After topical application of hypericin (0.1% in gelcream for 24 h) or Me-ALA (Metvix® for 4 h), the lesional/non-lesional skin surface fluorescence ratio was determined and fluorescence microscopy was used to study the skin penetration of the photosensitizers. The antitumour activity of topical PDT (20 mW cm(-2), 40 J cm(-2)) was evaluated by measurement of the lesional diameters. Moreover, biopsies were taken at various time points after PDT for histological evaluation of the therapy. Our results demonstrate that after topical application of hypericin and Me-ALA, tumour selectivity is limited in mouse skin. The microscopic distribution of hypericin fluorescence showed an accumulation in the stratum corneum and low fluorescence levels in the rest of the lesions, whereas the distribution of PpIX in the skin was more homogenous. Topical hypericin-PDT was found to be less efficient (44% total lesional clearance) as compared to Me-ALA-PDT (80% total lesional clearance). Full lesional necrosis was observed in responsive lesions, and the atypical cells of actinic keratosis were replaced by normal keratinocytes 3 weeks later, both after hypericin-PDT and Me-ALA-PDT., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Published
2011
Full Text
View/download PDF

47. Hypericin-based fluorescence diagnosis of bladder carcinoma.

Author

D'Hallewin MA, Kamuhabwa AR, Roskams T, De Witte PA, and Baert L

Subjects
Anthracenes, Cystoscopy methods, Humans, Microscopy, Fluorescence methods, Sensitivity and Specificity, Carcinoma in Situ diagnosis, Carcinoma, Papillary diagnosis, Perylene analogs & derivatives, Radiation-Sensitizing Agents, Urinary Bladder Neoplasms diagnosis
Abstract

Objective: To determine the use of hypericin instillation for the fluorescent detection of papillary bladder cancer and carcinoma in situ., Patients and Methods: Eighty-seven patients with papillary bladder cancer and/or carcinoma in situ received instillations with 40 mL of an 8 micromol/L hypericin solution for at least 2 h. Fluorescent excitation with blue light was effective for up to 16 h, and biopsies were examined by fluorescence microscopy., Results: There were no side-effects reported, no photobleaching and all papillary lesions fluoresced red. The sensitivity and specificity for detecting carcinoma in situ was 94% and 95%, respectively. An interval of 4 months is recommended after BCG instillations before using this test. Fluorescence microscopy showed that hypericin was selectively localized in the epithelium., Conclusions: Hypericin-induced fluorescence has a high sensitivity and specificity for detecting bladder cancer. After 4 months there are few false-positive results in patients treated with BCG.

Published
2002
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results