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Frankfurt am Main, Germany

Giles F.J.,National University of Ireland | Le Coutre P.D.,Humboldt University of Berlin | Pinilla-Ibarz J.,H. Lee Moffitt Cancer Center and Research Institute | Larson R.A.,University of Chicago | And 14 more authors.
Leukemia | Year: 2013

Nilotinib (Tasigna) is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to imatinib. The 48-month follow-up data for patients with CML-CP treated with nilotinib after imatinib resistance or intolerance on an international phase II study were analyzed. Overall, 59% of patients achieved major cytogenetic response; 45% achieved complete cytogenetic response while on study. The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively. Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months. Of the 321 patients initially enrolled in the study, 98 (31%) were treated for at least 48 months. Discontinuations were primarily due to disease progression (30%) or adverse events (21%). Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to imatinib. Further significant improvements in therapy are required for patients who are resistant or intolerant to imatinib. © 2013 Macmillan Publishers Limited All rights reserved. Source

Herold N.,University of Heidelberg | Herold N.,University Hospital of Frankfurt | Anders-Osswein M.,University of Heidelberg | Glass B.,University of Heidelberg | And 4 more authors.
Journal of Virology | Year: 2014

Cytoplasmic entry of HIV-1 requires binding of the viral glycoproteins to the cellular receptor and coreceptor, leading to fusion of viral and cellular membranes. Early studies suggested that productive HIV-1 infection occurs by direct fusion at the plasma membrane. Endocytotic uptake of HIV-1 was frequently observed but was considered to constitute an unspecific dead-end pathway. More recent evidence suggested that endocytosis contributes to productive HIV-1 entry and may even represent the predominant or exclusive route of infection. We have analyzed HIV-1 binding, endocytosis, cytoplasmic entry, and infection in Tcell lines and in primary CD4+ T cells. Efficient cell binding and endocytosis required viral glycoproteins and CD4, but not the coreceptor. The contribution of endocytosis to cytoplasmic entry and infection was assessed by two strategies: (i) expression of dominant negative dynamin-2 was measured and was found to efficiently block HIV-1 endocytosis but to not affect fusion or productive infection. (ii) Making use of the fact that HIV-1 fusion is blocked at temperatures below 23°C, cells were incubated with HIV-1 at 22°C for various times, and endocytosis was quantified by parallel analysis of transferrin and fluorescent HIV-1 uptake. Subsequently, entry at the plasma membrane was blocked by high concentrations of the peptidic fusion inhibitor T-20, which does not reach previously endocytosed particles. HIV-1 infection was scored after cells were shifted to 37°C in the presence of T-20. These experiments revealed that productive HIV-1 entry occurs predominantly at the plasma membrane in SupT1- R5, CEM-ss, and primary CD4+ T cells, with little, if any, contribution coming from endocytosed virions. © 2014, American Society for Microbiology. Source

Schott M.,University of Heidelberg | Grosskinsky S.,University of Heidelberg | Brenner C.,University of Heidelberg | Kraiczy P.,University Hospital of Frankfurt | Wallich R.,University of Heidelberg
Infection and Immunity | Year: 2010

In North America, tick-borne relapsing fever is caused by the species Borrelia hermsii, B. parkeri, and B. turicatae, which are transmitted to humans through the bite of the respective infected tick vectors. Here we describe the identification and functional characterization of a surface lipoprotein of B. parkeri, designated BpcA, that binds the human complement regulators factor H and factor H-related protein 1 and, simultaneously, the host protease plasminogen. In contrast, the homologous B. turicatae protein failed to bind human factor H and factor H-related protein 1 but retained its plasminogen binding capacity. Factor H bound to BpcA maintains its regulatory capacity to control C3b deposition and C3 convertase activity. Ectopic expression of BpcA in a serum-sensitive B. burgdorferi strain protects transformed cells from complement-mediated killing. Furthermore, bound plasminogen/plasmin endows B. parkeri and B. turicatae with the potential to degrade extracellular matrix components. These findings expand our understanding of the putative recent evolutionary separation of Borrelia parkeri and Borrelia turicatae, provide evidence that B. parkeri differs from B. turicatae in its ability to resist complement attack, and may help in understanding the pathological processes underlying tick-borne relapsing fever. Copyright © 2010, American Society for Microbiology. All Rights Reserved. Source

Kraiczy P.,University Hospital of Frankfurt | Hortschansky P.,Leibniz Institute for Natural Product Research and Infection Biology | Wallich R.,University of Heidelberg | Zipfel P.F.,Friedrich - Schiller University of Jena
Journal of Infectious Diseases | Year: 2010

Lyme disease-causing Borrelia burgdorferi spirochetes express up to 5 complement regulator-acquiring surface proteins (CRASPs). To better define how CRASP-1 contributes to infection, we aimed to identify novel CRASP- 1-binding host proteins. Here, we identified a number of novel human CRASP-1-binding proteins, including bone morphogenic protein 2, collagen I, collagen III, collagen IV, fibronectin, laminin, and plasminogen. The plasminogen-binding regions were located in 2 separate regions of CRASP-1. Our results demonstrated that plasminogen-bound CRASP-1 can be converted to plasmin by the urokinase-type plasminogen activator and that proteolytically active plasmin cleaves the synthetic chromogenic substrate S-2251 and the natural substrate fibrinogen. In conclusion, CRASP-1 is a multifunctional protein of B. burgdorferi that binds to several human extracellular matrix proteins and plasminogen. These interactions may contribute to adhesion, bacterial colonization, and organ tropism and may allow dissemination of B. burgdorferi in the host. © 2010 by the Infectious Diseases Society of America. Source

Schutzer S.E.,The New School | Fraser-Liggett C.M.,University of Maryland, Baltimore | Qiu W.-G.,York College - The City University of New York | Kraiczy P.,University Hospital of Frankfurt | And 4 more authors.
Journal of Bacteriology | Year: 2012

It has been known for decades that human Lyme disease is caused by the three spirochete species Borrelia burgdorferi, Borrelia afzelii, and Borrelia garinii. Recently, Borrelia valaisiana, Borrelia spielmanii, and Borrelia bissettii have been associated with Lyme disease. We report the complete genome sequences of B. valaisiana VS116, B. spielmanii A14S, and B. bissettii DN127. © 2012, American Society for Microbiology. All Rights Reserved. Source

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