Chan, Andrew S.

[["dc.bibliographiccitation.firstpage","2517"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","2530"],["dc.bibliographiccitation.volume","132"],["dc.contributor.author","Cotte, S."],["dc.contributor.author","von Ahsen, Nicolas"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Huber, B."],["dc.contributor.author","Winkelmann, Alexander"],["dc.contributor.author","Zettl, Uwe K."],["dc.contributor.author","Starck, Michaela"],["dc.contributor.author","Koenig, N."],["dc.contributor.author","Tellez, N."],["dc.contributor.author","Doerr, J."],["dc.contributor.author","Paul, Friedemann"],["dc.contributor.author","Zipp, Frauke"],["dc.contributor.author","Luehder, Fred"],["dc.contributor.author","Koepsell, Hermann"],["dc.contributor.author","Pannek, H."],["dc.contributor.author","Montalban, Xavier"],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Chan, A."],["dc.date.accessioned","2018-11-07T11:24:34Z"],["dc.date.available","2018-11-07T11:24:34Z"],["dc.date.issued","2009"],["dc.description.abstract","Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677GT, 3435CT and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2 of patients) was 37.7 lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P 0.05, 14.8 of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(/) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(/) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6), ABCB1/ABCG2-L 28/33 (84.8), exact Cochran-Armitage test P 0.039]. The odds ratio for response was 1.9 (95 CI 1.03.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to I-, and I to L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m(2) MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation."],["dc.description.sponsorship","Merck Serono, Germany"],["dc.identifier.doi","10.1093/brain/awp164"],["dc.identifier.isi","000269963600021"],["dc.identifier.pmid","19605531"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6073"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/56436"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","0006-8950"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","277"],["dc.bibliographiccitation.journal","Journal of Neuroimmunology"],["dc.bibliographiccitation.lastpage","279"],["dc.bibliographiccitation.volume","278"],["dc.contributor.author","Grey (nee Cotte), Steffi"],["dc.contributor.author","Salmen (nee Stroet), Anke"],["dc.contributor.author","von Ahsen, Nico"],["dc.contributor.author","Starck, Michaela"],["dc.contributor.author","Winkelmann, Alexander"],["dc.contributor.author","Zettl, Uwe K."],["dc.contributor.author","Comabella, Manuel"],["dc.contributor.author","Montalban, Xavier"],["dc.contributor.author","Zipp, Frauke"],["dc.contributor.author","Fleischer, Vinzenz"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Chan, Andrew"],["dc.date.accessioned","2018-11-07T10:02:07Z"],["dc.date.available","2018-11-07T10:02:07Z"],["dc.date.issued","2015"],["dc.description.abstract","Background: Mitoxantrone is used on an off-label basis in primary progressive MS (PPMS).ABC-transporter-genotypes are associated with therapeutic response in relapsing/secondary progressive MS (RP/SPMS). Objective: To evaluate potential pharmacogenetic response markers for mitoxantrone in PPMS. Methods: 41 mitoxantrone-treated PPMS-patients, 155 mitoxantrone-treated RP/SPMS-patients and 43 PPMS-controls were retrospectively assessed for clinical therapy-response and in correlation with four single-nucleotide-polymorphisms in ABCB1- and ABCG2-genes. Results: 53.7% PPMS-patients were mitoxantrone-responders, in comparison to 78.1% of RP/SPMS-patients (p = 0.039). There was no association between genotype and treatment response. Conclusion: Our data discourages the use of mitoxantrone in PPMS regardless of pharmacogenetic response markers previously described in RP/SPMS. (C) 2014 Elsevier B.V. All rights reserved."],["dc.identifier.doi","10.1016/j.jneuroim.2014.11.017"],["dc.identifier.isi","000349269300035"],["dc.identifier.pmid","25468777"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/38167"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Bv"],["dc.relation.issn","1872-8421"],["dc.relation.issn","0165-5728"],["dc.title","Lack of efficacy of mitoxantrone in primary progressive Multiple Sclerosis irrespective of pharmacogenetic factors: A multi-center, retrospective analysis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","MULTIPLE SCLEROSIS"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","von Ahsen, Nicolas"],["dc.contributor.author","Cotte, S."],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Chan, A."],["dc.date.accessioned","2018-11-07T09:22:42Z"],["dc.date.available","2018-11-07T09:22:42Z"],["dc.date.issued","2006"],["dc.format.extent","S215"],["dc.identifier.isi","000241921400707"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29413"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Sage Publications Ltd"],["dc.publisher.place","London"],["dc.relation.conference","22nd Congress of the European-Committee-for-the-Treatment-and-Resarch-in-Multiple-Sclerosis"],["dc.relation.eventlocation","Madrid, SPAIN"],["dc.relation.issn","1352-4585"],["dc.title","ABC-transporter gene-polymorphisms as potential predictors of therapeutic efficacy of mitoxantrone in multiple sclerosis"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","293"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","MULTIPLE SCLEROSIS"],["dc.bibliographiccitation.lastpage","302"],["dc.bibliographiccitation.volume","16"],["dc.contributor.author","Blecharz, Kinga G."],["dc.contributor.author","Haghikia, Aiden"],["dc.contributor.author","Stasiolek, Mariusz"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Drenckhahn, Detlev"],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Roewer, Norbert"],["dc.contributor.author","Chan, Andrew"],["dc.contributor.author","Foerster, Carola Y."],["dc.date.accessioned","2018-11-07T08:45:36Z"],["dc.date.available","2018-11-07T08:45:36Z"],["dc.date.issued","2010"],["dc.description.abstract","Compromised blood-brain barrier integrity is a major hallmark of active multiple sclerosis (MS). Alterations in brain endothelial tight junction protein and gene expression occur early during neuroinflammation but there is little known about the underlying mechanisms. In this study, we analysed barrier compromising effects of sera from MS patients and barrier restoring effects of glucocorticoids on blood-brain barrier integrity in vitro. cEND murine brain microvascular endothelial cell monolayers were incubated with sera from patients in active phase of disease or in relapse. Data were compared with effects of the glucocorticoid dexamethasone alone or in combination with MS sera on barrier integrity. Tight junction protein levels and gene expression were evaluated concomitant with barrier integrity. We reveal down-regulation of claudin-5 and occludin protein and mRNA and an accompanying upregulation in expression of matrix metalloproteinase MMP-9 after incubation with serum from active disease and remission and also a minor reconstitution of barrier functions related to dexamethasone treatment. Moreover, we for the first time describe downregulation of claudin-5 and occludin protein after incubation of cEND cells with sera from patients in remission phase of MS. Our findings reveal direct and differential effects of MS sera on blood-brain barrier integrity."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft [SFB688-TPA5, SFB-TPA1 RG]"],["dc.identifier.doi","10.1177/1352458509358189"],["dc.identifier.isi","000275179200004"],["dc.identifier.pmid","20203147"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13047"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/20482"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Sage Publications Ltd"],["dc.relation.issn","1352-4585"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Glucocorticoid effects on endothelial barrier function in the murine brain endothelial cell line cEND incubated with sera from patients with multiple sclerosis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","13"],["dc.bibliographiccitation.issue","1-2"],["dc.bibliographiccitation.journal","Journal of Neuroimmunology"],["dc.bibliographiccitation.lastpage","21"],["dc.bibliographiccitation.volume","182"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Cetin, Seray"],["dc.contributor.author","Chan, Andrew"],["dc.contributor.author","Gold, Ralf"],["dc.contributor.author","Luehder, Fred"],["dc.date.accessioned","2018-11-07T11:06:57Z"],["dc.date.available","2018-11-07T11:06:57Z"],["dc.date.issued","2007"],["dc.description.abstract","For the neurotrophin BDNF several splice variants were recently described. We analyzed the expression of mBDNF mRNA splice variants in cells of the immune system in comparison to the central nervous system (CNS). Whereas all splice variants are expressed in the CNS, only mBDNF 3 mRNA could be detected in primary and secondary lymphoid organs as well as in purified T cells and macrophages. After activation, only mBDNF 3 mRNA expression was upregulated in T cells without the additional appearance of other mBDNF splice variants. Therefore, mBDNF mRNA is differentially regulated in the CNS and the immune system opening the possibility of specific manipulation of mBDNF expression in immune cells without globally affecting mBDNF in the CNS. (c) 2006 Elsevier B.V. All rights reserved."],["dc.identifier.doi","10.1016/j.jneuroim.2006.09.001"],["dc.identifier.isi","000243962200002"],["dc.identifier.pmid","17046071"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/52435"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Bv"],["dc.relation.issn","0165-5728"],["dc.title","Differential expression of BDNF mRNA splice variants in mouse brain and immune cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","MULTIPLE SCLEROSIS"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Chan, A."],["dc.contributor.author","Cotte, S."],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","von Ahsen, N."],["dc.contributor.author","Zettl, Uwe K."],["dc.contributor.author","Tellez, N."],["dc.contributor.author","Montalban, Xavier"],["dc.contributor.author","Gold, Ralf"],["dc.date.accessioned","2018-11-07T10:58:18Z"],["dc.date.available","2018-11-07T10:58:18Z"],["dc.date.issued","2007"],["dc.format.extent","S243"],["dc.identifier.isi","000251423400756"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/50448"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Sage Publications Ltd"],["dc.publisher.place","London"],["dc.relation.conference","23rd Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis/12th Annual Conference of Rehabilitation in MS"],["dc.relation.eventlocation","Prague, CZECH REPUBLIC"],["dc.relation.issn","1352-4585"],["dc.title","ABC-transporter gene-polymorphisms as potential predictors of therapeutic efficacy of mitoxantrone in multiple sclerosis"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]