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Search Results: 1 - 10 of 5568 matches for " Markus Loeffler "
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Effectiveness of cytopenia prophylaxis for different filgrastim and pegfilgrastim schedules in a chemotherapy mouse model
Markus Scholz, Manuela Ackermann, Frank Emmrich, Markus Loeffler, Manja Kamprad
Biologics: Targets and Therapy , 2009, DOI: http://dx.doi.org/10.2147/BTT.S4426
Abstract: tiveness of cytopenia prophylaxis for different filgrastim and pegfilgrastim schedules in a chemotherapy mouse model Original Research (4703) Total Article Views Authors: Markus Scholz, Manuela Ackermann, Frank Emmrich, Markus Loeffler, Manja Kamprad Published Date December 2008 Volume 2009:3 Pages 27 - 37 DOI: http://dx.doi.org/10.2147/BTT.S4426 Markus Scholz1, Manuela Ackermann2, Frank Emmrich2, Markus Loeffler1, Manja Kamprad2 1Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Haertelstrasse 16–18, 04107 Leipzig, Germany; 2Institute for Clinical Immunology and Transfusion Medicine, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany Objectives: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to treat neutropenia during cytotoxic chemotherapy. The optimal scheduling of rhG-CSF is unknown and can hardly be tested in clinical studies due to numerous therapy parameters affecting outcome (chemotherapeutic regimen, rhG-CSF schedules, individual covariables). Motivated by biomathematical model simulations, we aim to investigate different rhG-CSF schedules in a preclinical chemotherapy mouse model. Methods: The time course of hematotoxicity was studied in CD-1 mice after cyclophosphamide (CP) administration. Filgrastim was applied concomitantly in a 2 × 3-factorial design of two dosing options (2 × 20 μg and 4 × 10 μg) and three timing options (directly, one, and two days after CP). Alternatively, a single dose of 40 μg pegfilgrastim was applied at the three timing options. The resulting cytopenia was compared among the schedules. Results: Dosing and timing had a significant influence on the effectiveness of filgrastim schedules whereas for pegfilgrastim the timing effect was irrelevant. The best filgrastim and pegfilgrastim schedules exhibited equivalent toxicity. Monocytes dynamics performed analogously to granulocytes. All schedules showed roughly the same lymphotoxicity. Conclusion: We conclude that effectiveness of filgrastim application depends heavily on its scheduling during chemotherapy. There is an optimum of timing. Dose splitting is better than concentrated applications. Effectiveness of pegfilgrastim is less dependent on timing.
Effectiveness of cytopenia prophylaxis for different filgrastim and pegfilgrastim schedules in a chemotherapy mouse model
Markus Scholz,Manuela Ackermann,Frank Emmrich,Markus Loeffler
Biologics: Targets and Therapy , 2008,
Abstract: Markus Scholz1, Manuela Ackermann2, Frank Emmrich2, Markus Loeffler1, Manja Kamprad21Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Haertelstrasse 16–18, 04107 Leipzig, Germany; 2Institute for Clinical Immunology and Transfusion Medicine, University of Leipzig, Johannisallee 30, 04103 Leipzig, GermanyObjectives: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to treat neutropenia during cytotoxic chemotherapy. The optimal scheduling of rhG-CSF is unknown and can hardly be tested in clinical studies due to numerous therapy parameters affecting outcome (chemotherapeutic regimen, rhG-CSF schedules, individual covariables). Motivated by biomathematical model simulations, we aim to investigate different rhG-CSF schedules in a preclinical chemotherapy mouse model.Methods: The time course of hematotoxicity was studied in CD-1 mice after cyclophosphamide (CP) administration. Filgrastim was applied concomitantly in a 2 × 3-factorial design of two dosing options (2 × 20 μg and 4 × 10 μg) and three timing options (directly, one, and two days after CP). Alternatively, a single dose of 40 μg pegfilgrastim was applied at the three timing options. The resulting cytopenia was compared among the schedules.Results: Dosing and timing had a significant influence on the effectiveness of filgrastim schedules whereas for pegfilgrastim the timing effect was irrelevant. The best filgrastim and pegfilgrastim schedules exhibited equivalent toxicity. Monocytes dynamics performed analogously to granulocytes. All schedules showed roughly the same lymphotoxicity.Conclusion: We conclude that effectiveness of filgrastim application depends heavily on its scheduling during chemotherapy. There is an optimum of timing. Dose splitting is better than concentrated applications. Effectiveness of pegfilgrastim is less dependent on timing.Keywords: rhG-CSF, chemotherapy toxicity, mice, cyclophosphamide, cytopenia, neutropenia
A Biomathematical Model of Human Erythropoiesis under Erythropoietin and Chemotherapy Administration
Sibylle Schirm, Christoph Engel, Markus Loeffler, Markus Scholz
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065630
Abstract: Anaemia is a common haematologic side effect of dose-dense multi-cycle cytotoxic polychemotherapy requiring erythrocyte transfusions or erythropoietin (EPO) administration. To simulate the effectiveness of different EPO application schedules, we performed both modelling of erythropoiesis under chemotherapy and pharmacokinetic and dynamic modelling of EPO applications in the framework of a single comprehensive biomathematical model. For this purpose, a cell kinetic model of bone marrow erythropoiesis was developed that is based on a set of differential compartment equations describing proliferation and maturation of erythropoietic cell stages. The system is regulated by several feedback loops comprising those mediated by EPO. We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications. Chemotherapy is modelled by a transient depletion of bone marrow cell stages. Unknown model parameters were determined by fitting the predictions of the model to data sets of circulating erythrocytes, haemoglobin, haematocrit, percentage of reticulocytes or EPO serum concentrations derived from the literature or cooperating clinical study groups. Parameter fittings resulted in a good agreement of model and data. Depending on site of injection and derivative (Alfa, Beta, Delta, Darbepoetin), nine groups of EPO applications were distinguished differing in either absorption kinetics or pharmacokinetics. Finally, eight different chemotherapy protocols were modelled. The model was validated on the basis of scenarios not used for parameter fitting. Simulations were performed to analyze the impact of EPO applications on the risk of anaemia during chemotherapy. We conclude that we established a model of erythropoiesis under chemotherapy that explains a large set of time series data under EPO and chemotherapy applications. It allows predictions regarding yet untested EPO schedules. Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules.
Stem Cell Fate Analysis Revisited: Interpretation of Individual Clone Dynamics in the Light of a New\newline Paradigm of Stem Cell Organization
Ingo Roeder,Katrin Braesel,Ronny Lorenz,Markus Loeffler
Journal of Biomedicine and Biotechnology , 2007, DOI: 10.1155/2007/84656
Abstract: Many experimental findings on heterogeneity, flexibility, and plasticity of tissue stem cells are currently challenging stem cell concepts that assume a cell intrinsically predefined, unidirectional differentiation program. In contrast to these classical concepts, nonhierarchical self-organizing systems provide an elegant and comprehensive alternative to explain the experimental data. Here we present the application of such a self-organizing concept to quantitatively describe the hematopoietic stem cell system. Focusing on the analysis of individual-stem-cell fates and clonal dynamics, we particularly discuss implications of the theoretical results on the interpretation of experimental findings. We demonstrate that it is possible to understand hematopoietic stem cell organization without assumptions on unidirectional developmental hierarchies, preprogrammed asymmetric division events or other assumptions implying the existence of a predetermined stem cell entity. The proposed perspective, therefore, changes the general paradigm of thinking about stem cells.
Individual fates of mesenchymal stem cells in vitro
Axel Krinner, Martin Hoffmann, Markus Loeffler, Dirk Drasdo, Joerg Galle
BMC Systems Biology , 2010, DOI: 10.1186/1752-0509-4-73
Abstract: By simulation studies, we provide detailed insight into the kinetics of MSC organisation. Monitoring the fates of individual cells in high and low oxygen culture, we calculated the average transition times of individual cells into stem cell and differentiated states. We predict that at low oxygen the heterogeneity of a MSC population with respect to differentiation regenerates from any selected subpopulation in about two days. At high oxygen, regeneration becomes substantially slowed down. Simulation results on the composition of the functional stem cell pool of MSC populations suggest that most of the cells that constitute this pool originate from more differentiated cells.Individual cell-based models are well-suited to provide quantitative predictions on essential features of the spatio-temporal organisation of MSC in vitro. Our predictions on MSC plasticity and its dependence on the environment motivate a number of in vitro experiments for validation. They may contribute to a better understanding of MSC organisation in vitro, including features of clonal expansion, environmental adaptation and stem cell ageing.The generation and maintenance of replenishing tissues relies on an appropriately regulated balance between self-renewal and differentiation within a relatively small population of adult stem cells. According to the common stem cell paradigm this balance can be explained assuming a strict differentiation hierarchy and irreversible fate decisions [1,2]. However, the organisation of stem cell populations is strongly influenced by environmental factors such as specific cell-cell interactions, growth factor and oxygen supply, as well as the geometry and mechanical properties of the local environment [3,4]. Accordingly, it has been suggested that stemness represents a particular regulatory cell state rather than an entity and that this state may be approached in principle by any cell [5,6]. Supporting these ideas, recent experimental results in hematopoietic sys
A Comprehensive Model of the Spatio-Temporal Stem Cell and Tissue Organisation in the Intestinal Crypt
Peter Buske ,J?rg Galle ,Nick Barker,Gabriela Aust,Hans Clevers,Markus Loeffler
PLOS Computational Biology , 2011, DOI: 10.1371/journal.pcbi.1001045
Abstract: We introduce a novel dynamic model of stem cell and tissue organisation in murine intestinal crypts. Integrating the molecular, cellular and tissue level of description, this model links a broad spectrum of experimental observations encompassing spatially confined cell proliferation, directed cell migration, multiple cell lineage decisions and clonal competition. Using computational simulations we demonstrate that the model is capable of quantitatively describing and predicting the dynamic behaviour of the intestinal tissue during steady state as well as after cell damage and following selective gain or loss of gene function manipulations affecting Wnt- and Notch-signalling. Our simulation results suggest that reversibility and flexibility of cellular decisions are key elements of robust tissue organisation of the intestine. We predict that the tissue should be able to fully recover after complete elimination of cellular subpopulations including subpopulations deemed to be functional stem cells. This challenges current views of tissue stem cell organisation.
Stem Cell Proliferation and Quiescence—Two Sides of the Same Coin
Ingmar Glauche ,Kateri Moore,Lars Thielecke,Katrin Horn,Markus Loeffler,Ingo Roeder
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000447
Abstract: The kinetics of label uptake and dilution in dividing stem cells, e.g., using Bromodeoxyuridine (BrdU) as a labeling substance, are a common way to assess the cellular turnover of all hematopoietic stem cells (HSCs) in vivo. The assumption that HSCs form a homogeneous population of cells which regularly undergo cell division has recently been challenged by new experimental results. For a consistent functional explanation of heterogeneity among HSCs, we propose a concept in which stem cells flexibly and reversibly adapt their cycling state according to systemic needs. Applying a mathematical model analysis, we demonstrate that different experimentally observed label dilution kinetics are consistently explained by the proposed model. The dynamically stabilized equilibrium between quiescent and activated cells leads to a biphasic label dilution kinetic in which an initial and pronounced decline of label retaining cells is attributed to faster turnover of activated cells, whereas a secondary, decelerated decline results from the slow turnover of quiescent cells. These results, which support our previous model prediction of a reversible activation/deactivation of HSCs, are also consistent with recent findings that use GFP-conjugated histones as a label instead of BrdU. Based on our findings we interpret HSC organization as an adaptive and regulated process in which the slow activation of quiescent cells and their possible return into quiescence after division are sufficient to explain the simultaneous occurrence of self-renewal and differentiation. Furthermore, we suggest an experimental strategy which is suited to demonstrate that the repopulation ability among the population of label retaining cells changes during the course of dilution.
Noise-Driven Stem Cell and Progenitor Population Dynamics
Martin Hoffmann, Hannah H. Chang, Sui Huang, Donald E. Ingber, Markus Loeffler, Joerg Galle
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0002922
Abstract: Background The balance between maintenance of the stem cell state and terminal differentiation is influenced by the cellular environment. The switching between these states has long been understood as a transition between attractor states of a molecular network. Herein, stochastic fluctuations are either suppressed or can trigger the transition, but they do not actually determine the attractor states. Methodology/Principal Findings We present a novel mathematical concept in which stem cell and progenitor population dynamics are described as a probabilistic process that arises from cell proliferation and small fluctuations in the state of differentiation. These state fluctuations reflect random transitions between different activation patterns of the underlying regulatory network. Importantly, the associated noise amplitudes are state-dependent and set by the environment. Their variability determines the attractor states, and thus actually governs population dynamics. This model quantitatively reproduces the observed dynamics of differentiation and dedifferentiation in promyelocytic precursor cells. Conclusions/Significance Consequently, state-specific noise modulation by external signals can be instrumental in controlling stem cell and progenitor population dynamics. We propose follow-up experiments for quantifying the imprinting influence of the environment on cellular noise regulation.
Spatial Organization of Mesenchymal Stem Cells In Vitro—Results from a New Individual Cell-Based Model with Podia
Martin Hoffmann,Jens-Peer Kuska,Matthias Zscharnack,Markus Loeffler,Joerg Galle
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0021960
Abstract: Therapeutic application of mesenchymal stem cells (MSC) requires their extensive in vitro expansion. MSC in culture typically grow to confluence within a few weeks. They show spindle-shaped fibroblastoid morphology and align to each other in characteristic spatial patterns at high cell density. We present an individual cell-based model (IBM) that is able to quantitatively describe the spatio-temporal organization of MSC in culture. Our model substantially improves on previous models by explicitly representing cell podia and their dynamics. It employs podia-generated forces for cell movement and adjusts cell behavior in response to cell density. At the same time, it is simple enough to simulate thousands of cells with reasonable computational effort. Experimental sheep MSC cultures were monitored under standard conditions. Automated image analysis was used to determine the location and orientation of individual cells. Our simulations quantitatively reproduced the observed growth dynamics and cell-cell alignment assuming cell density-dependent proliferation, migration, and morphology. In addition to cell growth on plain substrates our model captured cell alignment on micro-structured surfaces. We propose a specific surface micro-structure that according to our simulations can substantially enlarge cell culture harvest. The ‘tool box’ of cell migratory behavior newly introduced in this study significantly enhances the bandwidth of IBM. Our approach is capable of accommodating individual cell behavior and collective cell dynamics of a variety of cell types and tissues in computational systems biology.
Indistinguishable photons from the resonance fluorescence of a single quantum dot in a microcavity
Serkan Ates,Sven Markus Ulrich,Stephan Reitzenstein,Andreas Loeffler,Alfred Forchel,Peter Michler
Physics , 2009, DOI: 10.1103/PhysRevLett.103.167402
Abstract: We demonstrate purely resonant continuous-wave optical laser excitation to coherently prepare an excitonic state of a single semiconductor quantum dot (QDs) inside a high quality pillar microcavity. As a direct proof of QD resonance fluorescence, the evolution from a single emission line to the characteristic Mollow triplet10 is observed under increasing pump power. By controlled utilization of weak coupling between the emitter and the fundamental cavity mode through Purcell-enhancement of the radiative decay, a strong suppression of pure dephasing is achieved, which reflects in close to Fourier transform-limited and highly indistinguishable photons with a visibility contrast of 90%. Our experiments reveal the model-like character of the coupled QD-microcavity system as a promising source for the generation of ideal photons at the quantum limit. From a technological perspective, the vertical cavity symmetry -- with optional dynamic tunability -- provides strongly directed light emission which appears very desirable for future integrated emitter devices.
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