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Search Results: 1 - 10 of 194621 matches for " Ulrich Dührsen "
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Epigenetic Silencing of the Circadian Clock Gene CRY1 is Associated with an Indolent Clinical Course in Chronic Lymphocytic Leukemia
Maher Hanoun, Lewin Eisele, Masako Suzuki, John M. Greally, Andreas Hüttmann, Semra Aydin, René Scholtysik, Ludger Klein-Hitpass, Ulrich Dührsen, Jan Dürig
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034347
Abstract: Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1) is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL). Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR) CD38+/immunoglobulin variable heavy chain gene (IgVH) unmutated patients as compared to low-risk (LR) CD38?/IgVH mutated patients can be attributed to down-modulation of CRY1 in LR CLL cases. Analysis of the DNA methylation profile of the CRY1 promoter in a subgroup of 57 patients revealed that CRY1 expression in LR CLL cells is silenced by aberrant promoter CpG island hypermethylation. The methylation pattern of the CRY1 promoter proved to have high prognostic impact in CLL where aberrant promoter methylation predicted a favourable outcome. CRY1 mRNA transcript levels did not change over time in the majority of patients where sequential samples were available for analysis. We also compared the CRY1 expression in CLL with other lymphoid malignancies and observed epigenetic silencing of CRY1 in a patient with B cell acute lymphoblastic leukemia (B-ALL).
Progranulin Is a Novel Independent Predictor of Disease Progression and Overall Survival in Chronic Lymphocytic Leukemia
Maria G?bel, Lewin Eisele, Michael M?llmann, Andreas Hüttmann, Patricia Johansson, René Scholtysik, Manuela Bergmann, Raymonde Busch, Hartmut D?hner, Michael Hallek, Till Seiler, Stephan Stilgenbauer, Ludger Klein-Hitpass, Ulrich Dührsen, Jan Dürig
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072107
Abstract: Progranulin (Pgrn) is a 88 kDa secreted protein with pleiotropic functions including regulation of cell cycle progression, cell motility, wound repair and tumorigenesis. Using microarray based gene expression profiling we have recently demonstrated that the gene for Pgrn, granulin (GRN), is significantly higher expressed in aggressive CD38+ZAP-70+ as compared to indolent CD38?ZAP-70? chronic lymphocytic leukemia (CLL) cases. Here, we measured Pgrn plasma concentrations by enzyme-linked immunosorbent assay (ELISA) in the Essen CLL cohort of 131 patients and examined Pgrn for association with established prognostic markers and clinical outcome. We found that high Pgrn plasma levels were strongly associated with adverse risk factors including unmutated IGHV status, expression of CD38 and ZAP-70, poor risk cytogenetics (11q-, 17p-) as detected by flourescence in situ hybridization (FISH) and high Binet stage. Pgrn as well as the aforementioned risk factors were prognostic for time to first treatment and overall survival in this series. Importantly, these results could be confirmed in the independent multicentric CLL1 cohort of untreated Binet stage A patients (n = 163). Here, multivariate analysis of time to first treatment revealed that high risk Pgrn (HR = 2.06, 95%-CI = 1.13–3.76, p = 0.018), unmutated IGHV status (HR = 5.63, 95%-CI = 3.05–10.38, p<0.001), high risk as defined by the study protocol (HR = 2.06, 95%-CI = 1.09–3.89, p = 0.026) but not poor risk cytogenetics were independent prognostic markers. In summary our results suggest that Pgrn is a novel, robust and independent prognostic marker in CLL that can be easily measured by ELISA.
FLT3 Mutations in Early T-Cell Precursor ALL Characterize a Stem Cell Like Leukemia and Imply the Clinical Use of Tyrosine Kinase Inhibitors
Martin Neumann, Ebru Coskun, Lars Fransecky, Liliana H. Mochmann, Isabelle Bartram, Nasrin Farhadi Sartangi, Sandra Heesch, Nicola G?kbuget, Stefan Schwartz, Christian Brandts, Cornelia Schlee, Rainer Haas, Ulrich Dührsen, Martin Griesshammer, Hartmut D?hner, Gerhard Ehninger, Thomas Burmeister, Olga Blau, Eckhard Thiel, Dieter Hoelzer, Wolf-Karsten Hofmann, Claudia D. Baldus
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053190
Abstract: Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) has been identified as high-risk subgroup of acute T-lymphoblastic leukemia (T-ALL) with a high rate of FLT3-mutations in adults. To unravel the underlying pathomechanisms and the clinical course we assessed molecular alterations and clinical characteristics in a large cohort of ETP-ALL (n = 68) in comparison to non-ETP T-ALL adult patients. Interestingly, we found a high rate of FLT3-mutations in ETP-ALL samples (n = 24, 35%). Furthermore, FLT3 mutated ETP-ALL was characterized by a specific immunophenotype (CD2+/CD5-/CD13+/CD33-), a distinct gene expression pattern (aberrant expression of IGFBP7, WT1, GATA3) and mutational status (absence of NOTCH1 mutations and a low frequency, 21%, of clonal TCR rearrangements). The observed low GATA3 expression and high WT1 expression in combination with lack of NOTCH1 mutations and a low rate of TCR rearrangements point to a leukemic transformation at the pluripotent prothymocyte stage in FLT3 mutated ETP-ALL. The clinical outcome in ETP-ALL patients was poor, but encouraging in those patients with allogeneic stem cell transplantation (3-year OS: 74%). To further explore the efficacy of targeted therapies, we demonstrate that T-ALL cell lines transfected with FLT3 expression constructs were particularly sensitive to tyrosine kinase inhibitors. In conclusion, FLT3 mutated ETP-ALL defines a molecular distinct stem cell like leukemic subtype. These data warrant clinical studies with the implementation of FLT3 inhibitors in addition to early allogeneic stem cell transplantation for this high risk subgroup.
Feasibility of Azacitidine Added to Standard Chemotherapy in Older Patients with Acute Myeloid Leukemia — A Randomised SAL Pilot Study
Utz Krug, Anja Koschmieder, Daniela Schwammbach, Joachim Gerss, Nicola Tidow, Bj?rn Steffen, Gesine Bug, Christian H. Brandts, Markus Schaich, Christoph R?llig, Christian Thiede, Richard Noppeney, Matthias Stelljes, Thomas Büchner, Steffen Koschmieder, Ulrich Dührsen, Hubert Serve, Gerhard Ehninger, Wolfgang E. Berdel, Carsten Müller-Tidow
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0052695
Abstract: Introduction Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. Trial Design Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. Patients and Methods Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/μl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. Results Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. Conclusions The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm. Trial Registration This trial is registered at clinical trials.gov (identifier: NCT00915252).
Dirac Hamiltonian with Imaginary Mass and Induced Helicity—Dependence by Indefinite Metric  [PDF]
Ulrich D. Jentschura
Journal of Modern Physics (JMP) , 2012, DOI: 10.4236/jmp.2012.39116
Abstract: It is of general theoretical interest to investigate the properties of superluminal matter wave equations for spin one-half particles. One can either enforce superluminal propagation by an explicit substitution of the real mass term for an imaginary mass, or one can use a matrix representation of the imaginary unit that multiplies the mass term. The latter leads to the tachyonic Dirac equation, while the equation obtained by the substitution m im in the Dirac equation is naturally referred to as the imaginary-mass Dirac equation. Both the tachyonic as well as the imaginary-mass Dirac Hamiltonians commute with the helicity operator. Both Hamiltonians are pseudo-Hermitian and also possess additional modified pseudo-Hermitian properties, leading to constraints on the resonance eigenvalues. Here, by an explicit calculation, we show that specific sum rules over the The spectrum is found to consist of well-defined real energy eigenvalues and complex resonance and anti-resonance energies. In the quantized imaginary-mass Dirac field, one-particle states of right-handed helicity acquire a negative norm (“indefinite metric”) and can be excluded from the physical spectrum by a Gupta-Bleuler type condition.
Enzyme-Supported Immunotherapy: Case Study and Possible Generalizations  [PDF]
Ulrich D. Jentschura
Journal of Cancer Therapy (JCT) , 2018, DOI: 10.4236/jct.2018.92016
Abstract: A combination therapy is discussed for the treatment of cancer, which has recently been applied successfully in a case study. The general approach is based on a combination of immune boosters, digestive enzymes and natural interferones. The idea is to stage a three-prong “pincer attack” on the tumor: while the immune boosters stimulate the immune system to attack cancer cells, the cytostatic properties of the interferones inhibit cancer growth, and the digestive enzymes accelerate the transport mechanism to remove the killed cancer cells from the body. The rationale of the therapy is explained, results of the case study are presented, and possible generalizations are mentioned.
Non-uniform convergence of two-photon decay rates for excited atomic states
Ulrich D. Jentschura
Physics , 2007, DOI: 10.1088/1751-8113/40/9/F02
Abstract: Two-photon decay rates in simple atoms such as hydrogenlike systems represent rather interesting fundamental problems in atomic physics. The sum of the energies of the two emitted photons has to fulfill an energy conservation condition, the decay takes place via intermediate virtual states, and the total decay rate is obtained after an integration over the energy of one of the emitted photons. Here, we investigate cases with a virtual state having an energy intermediate between the initial and the final state of the decay process, and we show that due to non-uniform convergence, only a careful treatment of the singularities infinitesimally displaced from the photon integration contour leads to consistent and convergent results.
Two-Photon Decays Reexamined: Cascade Contributions and Gauge Invariance
Ulrich D. Jentschura
Physics , 2008, DOI: 10.1088/1751-8113/41/15/155307
Abstract: The purpose of this paper is to calculate the two-photon decay rate corresponding to the two-photon transitions nS->1S and nD->1S in hydrogenlike ions with a low nuclear charge number Z (for principal quantum numbers n = 2,...,8. Numerical results are obtained within a nonrelativistic framework, and the results are found to scale approximately as (Z alpha)^6/n^3, where alpha is the fine-structure constant. We also attempt to clarify a number of subtle issues regarding the treatment of the coherent, quasi-simultaneous emission of the two photons as opposed to one-photon cascades. In particular, the gauge invariance of the decay rate is shown explicitly.
Virtual Resonant States in Two-Photon Decay Processes: Lower-Order Terms, Subtractions, and Physical Interpretations
Ulrich D. Jentschura
Physics , 2008, DOI: 10.1103/PhysRevA.79.022510
Abstract: We investigate the two-photon decay rate of a highly excited atomic state which can decay to bound states of lower energy via cascade processes. We show that a naive treatment of the process, based on the introduction of phenomenological decay rates for the intermediate, resonant states, leads to lower-order terms which need to be subtracted in order to obtain the coherent two-photon correction to the decay rate. The sum of the lower-order terms is exactly equal to the one-photon decay rate of the initial state, provided the naive two-photon decay rates are summed over all available two-photon channels. A quantum electrodynamics (QED) treatment of the problem leads to an "automatic" subtraction of the lower-order terms.
Quantifying the Impact of Human Immunodeficiency Virus-1 Escape From Cytotoxic T-Lymphocytes
Ulrich D. Kadolsky ,Becca Asquith
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000981
Abstract: HIV-1 escape from the cytotoxic T-lymphocyte (CTL) response leads to a weakening of viral control and is likely to be detrimental to the patient. To date, the impact of escape on viral load and CD4+ T cell count has not been quantified, primarily because of sparse longitudinal data and the difficulty of separating cause and effect in cross-sectional studies. We use two independent methods to quantify the impact of HIV-1 escape from CTLs in chronic infection: mathematical modelling of escape and statistical analysis of a cross-sectional cohort. Mathematical modelling revealed a modest increase in log viral load of 0.051 copies ml?1 per escape event. Analysis of the cross-sectional cohort revealed a significant positive association between viral load and the number of “escape events”, after correcting for length of infection and rate of replication. We estimate that a single CTL escape event leads to a viral load increase of 0.11 log copies ml?1 (95% confidence interval: 0.040–0.18), consistent with the predictions from the mathematical modelling. Overall, the number of escape events could only account for approximately 6% of the viral load variation in the cohort. Our findings indicate that although the loss of the CTL response for a single epitope results in a highly statistically significant increase in viral load, the biological impact is modest. We suggest that this small increase in viral load is explained by the small growth advantage of the variant relative to the wildtype virus. Escape from CTLs had a measurable, but unexpectedly low, impact on viral load in chronic infection.
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