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Pappa A.,Medac GmbH | Guerini D.,Novartis
Current Signal Transduction Therapy | Year: 2010

The posttranslational modification of proteins by a single O-linked N-acetylglucosamine (O-GlcNAc) is an intracellular biochemical reaction which is ubiquitous in eukaryotic cells. Two enzymes regulate the process: O-linked Nacetylglucosaminyltransferase (OGT), which attaches O-GlcNAc to serine/threonine residues of proteins, and a β-Nacetylglucosaminidase (O-GlcNAcase), that removes the O-GlcNAc group. The serine or threonine targeted by OGlcNAc can occur at sites modified by other enzymes such as protein kinases. There have been many indications that OGlcNAc modifications are actively involved in the regulation of the immune system and recent results have begun to shed light on possible mechanisms. This review summarizes recent advances in the field of O-GlcNAc modification, with a special attention to its role in the activation of lymphocytes. © 2010 Bentham Science Publishers Ltd.

Gyurkocza B.,Fred Hutchinson Cancer Research Center | Gutman J.,University of Colorado at Denver | Nemecek E.R.,Oregon Health And Science University | Bar M.,Fred Hutchinson Cancer Research Center | And 14 more authors.
Biology of Blood and Marrow Transplantation | Year: 2014

Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial, we assessed the efficacy and toxicity of treosulfan, fludarabine, and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36: 15 refractory cytopenia with multilineage dysplasia, 10 refractory anemia with excess blasts type 1, 10 refractory anemia with excess blasts type 2, 1 chronic myelomonocytic leukemia type 1) or AML (n=60: 35 first complete remission [CR], 18second CR, 3 advanced CR, 4 refractory relapse) were enrolled; median age was 51 (range, 1 to 60) years. Twelve patients had undergone a prior HCT with high-intensity conditioning. Patients received 14g/m2/day treosulfan i.v. on days-6 to-4, 30mg/m2/day fludarabine i.v. on days-6 to-2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30months, the 2-year overall survival (OS), relapse incidence, and nonrelapse mortality were 73%, 27%, and 8%, respectively. The incidences of grades II to IV (III to IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor-risk and good/intermediate-risk cytogenetics (69% and 85%, respectively) or between AML patients with unfavorable and favorable/intermediate-risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% versus 18%) and lower OS (41% versus 79%) at 2years, when compared with patients without MRD. In conclusion, treosulfan, fludarabine, and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse. © 2014 American Society for Blood and Marrow Transplantation.

Neumann L.,German Cancer Research Center | Neumann L.,University of Heidelberg | Pforr C.,German Cancer Research Center | Beaudouin J.,German Cancer Research Center | And 8 more authors.
Molecular Systems Biology | Year: 2010

This study explores the dilemma in cellular signaling that triggering of CD95 (Fas/APO-1) in some situations results in cell death and in others leads to the activation of NF-κB. We established an integrated kinetic mathematical model for CD95-mediated apoptotic and NF-κB signaling. Systematic model reduction resulted in a surprisingly simple model well approximating experimentally observed dynamics. The model postulates a new link between c-FLIP(L) cleavage in the death-inducing signaling complex (DISC) and the NF-κB pathway. We validated experimentally that CD95 stimulation resulted in an interaction of p43-FLIP with the IKK complex followed by its activation. Furthermore, we showed that the apoptotic and NF-κB pathways diverge already at the DISC. Model and experimental analysis of DISC formation showed that a subtle balance of c-FLIP(L) and procaspase-8 determines life/death decisions in a nonlinear manner. We present an integrated model describing the complex dynamics of CD95-mediated apoptosis and NF-κB signaling. © 2010 EMBO and Macmillan Publishers Limited All rights reserved.

Shatnyeva O.M.,German Cancer Research Center | Kubarenko A.V.,German Cancer Research Center | Kubarenko A.V.,University of Bonn | Weber C.E.M.,German Cancer Research Center | And 6 more authors.
PLoS ONE | Year: 2011

Protein modifications of death receptor pathways play a central role in the regulation of apoptosis. It has been demonstrated that O-glycosylation of TRAIL-receptor (R) is essential for sensitivity and resistance towards TRAIL-mediated apoptosis. In this study we ask whether and how glycosylation of CD95 (Fas/APO-1), another death receptor, influences DISC formation and procaspase-8 activation at the CD95 DISC and thereby the onset of apoptosis. We concentrated on N-glycostructure since O-glycosylation of CD95 was not found. We applied different approaches to analyze the role of CD95 N-glycosylation on the signal transduction: in silico modeling of CD95 DISC, generation of CD95 glycosylation mutants (at N136 and N118), modulation of N-glycosylation by deoxymannojirimycin (DMM) and sialidase from Vibrio cholerae (VCN). We demonstrate that N-deglycosylation of CD95 does not block DISC formation and results only in the reduction of the procaspase-8 activation at the DISC. These findings are important for the better understanding of CD95 apoptosis regulation and reveal differences between apoptotic signaling pathways of the TRAIL and CD95 systems. © 2011 Shatnyeva et al.

Hahn S.U.,Scratch Pharmacovigilance GmbH | Stoffers K.L.,Medac GmbH
Zeitschrift fur Allgemeinmedizin | Year: 2014

All active ingredients can also cause adverse events. As clinical trials are performed on a relatively small and strictly selected group of subjects, adverse drug reactions (ADR) are frequently detected after the active substance or drug has been approved. For drug monitoring authorities it is crucial that physicians report suspected ADR and/or ineffective drugs. As an example the Federal Institute for Drugs and Medical Devices (BfArM), the Paul-Ehrlich-lnstitut (PEI) and the Drug Commission of the German Medical Association (AKdÄ) have ADR reporting forms available on their homepages. In fact, physicians are obliged to report ADR by their professional code. As physicians are the first contact person for patients they are the most important source of information for drug monitoring. For reporting a suspected ADR a causality assessment is not required; it is sufficient, if the physician recognizes that a temporal relationship to the suspected drug exists or no other possible causes are known. It is of particular importance to report ADR of drugs which have the black triangle ▼ in their product information. ADR from all over the European Economic Area (EEA) - EU member states and Island, Liechtenstein and Norway - are recorded and evaluated centrally in the EudraVigilance database. Based on the collected data, the risk-benefit profile and therefore the prerequisite for the approval of drugs, is constantly monitored. The success of this system depends essentially on the effective cooperation of pharmaceutical companies, physicians, health professionals and authorities. © Deutscher Ärzte-Verlag.

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