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Search Results: 1 - 10 of 835 matches for " Achim Temme "
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Chimeric Antigen Receptor-Engineered T Cells for Immunotherapy of Cancer
Marc Cartellieri,Michael Bachmann,Anja Feldmann,Claudia Bippes,Slava Stamova,Rebekka Wehner,Achim Temme,Marc Schmitz
Journal of Biomedicine and Biotechnology , 2010, DOI: 10.1155/2010/956304
Abstract: CD4
SOX2-RNAi attenuates S-phase entry and induces RhoA-dependent switch to protease-independent amoeboid migration in human glioma cells
Felix Oppel, Nadja Müller, Gabriele Schackert, Sandy Hendruschk, Daniel Martin, Kathrin D Geiger, Achim Temme
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-137
Abstract: Retroviral shRNA-vectors were utilized to stably knockdown SOX2 in U343-MG and U373-MG cells. The resulting phenotype was investigated by Western blot, migration/invasion assays, RhoA G-LISA, time lapse video imaging, and orthotopic xenograft experiments.SOX2 depletion results in pleiotropic effects including attenuated cell proliferation caused by decreased levels of cyclinD1. Also an increased TCF/LEF-signaling and concomitant decrease in Oct4 and Nestin expression was noted. Furthermore, down-regulation of focal adhesion kinase (FAK) signaling and of downstream proteins such as HEF1/NEDD9, matrix metalloproteinases pro-MMP-1 and -2 impaired invasive proteolysis-dependent migration. Yet, cells with knockdown of SOX2 switched to a RhoA-dependent amoeboid-like migration mode which could be blocked by the ROCK inhibitor Y27632 downstream of RhoA-signaling. Orthotopic xenograft experiments revealed a higher tumorigenicity of U343-MG glioma cells transduced with shRNA targeting SOX2 which was characterized by increased dissemination of glioma cells.Our findings suggest that SOX2 plays a role in the maintenance of a less differentiated glioma cell phenotype. In addition, the results indicate a critical role of SOX2 in adhesion and migration of malignant gliomas.Despite multimodal treatment the prognosis for glioblastoma (GBM), the most common and most malignant brain tumor remains poor, with the majority of patients dying within 1 year after diagnosis [1]. Glioblastomas, gliomas of WHO grade IV, diffusely spread into the surrounding brain and the invading tumor cells migrate along the white matter tracks and assemble satellites around neuron cell bodies, blood vessels and the subpial region [2,3]. Since glioblastoma cells infiltrate wide areas of the brain every resection of the bulk tumor is usually followed by a tumor re-initiation at the resection site or at another place in the brain [4,5]. The cellular origin of glioblastoma is still under investigation and it is h
Tumor Evasion from T Cell Surveillance
Katrin T pfer,Stefanie Kempe,Nadja Müller,Marc Schmitz,Michael Bachmann,Marc Cartellieri,Gabriele Schackert,Achim Temme
Journal of Biomedicine and Biotechnology , 2011, DOI: 10.1155/2011/918471
Abstract: An intact immune system is essential to prevent the development and progression of neoplastic cells in a process termed immune surveillance. During this process the innate and the adaptive immune systems closely cooperate and especially T cells play an important role to detect and eliminate tumor cells. Due to the mechanism of central tolerance the frequency of T cells displaying appropriate arranged tumor-peptide-specific-T-cell receptors is very low and their activation by professional antigen-presenting cells, such as dendritic cells, is frequently hampered by insufficient costimulation resulting in peripheral tolerance. In addition, inhibitory immune circuits can impair an efficient antitumoral response of reactive T cells. It also has been demonstrated that large tumor burden can promote a state of immunosuppression that in turn can facilitate neoplastic progression. Moreover, tumor cells, which mostly are genetically instable, can gain rescue mechanisms which further impair immune surveillance by T cells. Herein, we summarize the data on how tumor cells evade T-cell immune surveillance with the focus on solid tumors and describe approaches to improve anticancer capacity of T cells.
The Detergent-Soluble Cytoplasmic Pool of Survivin Suppresses Anoikis and Its Expression Is Associated with Metastatic Disease of Human Colon Cancer
Masato Hori, Tomoharu Miki, Mayumi Okamoto, Futoshi Yazama, Hiroaki Konishi, Hiroshi Kaneko, Fumio Shimamoto, Takahide Ota, Achim Temme, Masaaki Tatsuka
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055710
Abstract: Survivin is a component of the chromosomal passenger complex (CPC) that is essential for accurate chromosome segregation. Interfering with the function of Survivin in mitosis leads to chromosome segregation errors and defective cytokinesis. Survivin contains a Baculovirus IAP Repeat (BIR) and therefore was originally classified as inhibitor of apopotosis protein (IAP), yet its role in apoptosis after cellular stress remains largely unknown. We demonstrate here, that Survivin predominantly suppresses anoikis, a form of programmed cell death induced by loss of cellular adhesion to extracellular matrix. Interestingly, cells ectopically overexpressing EGFP-Survivin showed after loss of cell-matrix-interaction a decreased expression of IκB-α. Subsequent subcellular protein fractionation and immunoprecipitation experiments revealed that XIAP interacts with detergent-soluble Survivin which is known to cooperatively activate NF-κB signaling. Examination of the expression levels of detergent soluble Survivin in colorectal cancer cell lines and in colorectal cancerous tissues revealed that detergent soluble cytoplasmic Survivin levels correlated inversely with anoikis susceptibility in colorectal cancer. Therefore, the detergent soluble cytoplasmic Survivin might be a promising predictive biomarker for lymph node and distant metastases of colorectal cancer. We conclude that an anti-apoptotic function of detergent-soluble Survivin in interphase cells experiencing anoikis is mediated at least via XIAP/IκB-α/NF-κB signaling.
tRNA Modifying Enzymes, NSUN2 and METTL1, Determine Sensitivity to 5-Fluorouracil in HeLa Cells
Mayumi Okamoto equal contributor,Mamoru Fujiwara equal contributor,Masato Hori,Kaoru Okada,Futoshi Yazama,Hiroaki Konishi,Yegui Xiao,Guangying Qi,Fumio Shimamoto,Takahide Ota,Achim Temme,Masaaki Tatsuka
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004639
Abstract: Nonessential tRNA modifications by methyltransferases are evolutionarily conserved and have been reported to stabilize mature tRNA molecules and prevent rapid tRNA decay (RTD). The tRNA modifying enzymes, NSUN2 and METTL1, are mammalian orthologs of yeast Trm4 and Trm8, which are required for protecting tRNA against RTD. A simultaneous overexpression of NSUN2 and METTL1 is widely observed among human cancers suggesting that targeting of both proteins provides a novel powerful strategy for cancer chemotherapy. Here, we show that combined knockdown of NSUN2 and METTL1 in HeLa cells drastically potentiate sensitivity of cells to 5-fluorouracil (5-FU) whereas heat stress of cells revealed no effects. Since NSUN2 and METTL1 are phosphorylated by Aurora-B and Akt, respectively, and their tRNA modifying activities are suppressed by phosphorylation, overexpression of constitutively dephosphorylated forms of both methyltransferases is able to suppress 5-FU sensitivity. Thus, NSUN2 and METTL1 are implicated in 5-FU sensitivity in HeLa cells. Interfering with methylation of tRNAs might provide a promising rationale to improve 5-FU chemotherapy of cancer.
Lower bounds to the spectral gap of Davies generators
Kristan Temme
Physics , 2013, DOI: 10.1063/1.4850896
Abstract: We construct lower bounds to the spectral gap of a family of Lindblad generators known as Davies maps. These maps describe the thermalization of quantum systems weakly coupled to a heat bath. The steady state of these systems is given by the Gibbs distribution with respect to the system Hamiltonian. The bounds can be evaluated explicitly, when the eigenbasis and the spectrum of the Hamiltonian is known. A crucial assumption is that the spectrum of the Hamiltonian is non-degenerate. Furthermore, we provide a counterexample to the conjecture, that the convergence rate is always determined by the gap of the associated Pauli master equation. We conclude, that the full dynamics of the Lindblad generator has to be considered. Finally, we present several physical example systems for which the bound to the spectral gap is evaluated.
Thermalization time bounds for Pauli stabilizer Hamiltonians
Kristan Temme
Physics , 2014,
Abstract: We prove a general lower bound to the spectral gap of the Davies generator for Pauli stabilizer Hamiltonians. These Hamiltonians, defined on the Hilbert space of $N$-qubits, serve as one of the most frequently considered candidates for a self-correcting quantum memory. A spectral gap bound on the Davies generator establishes an upper limit on the life time of such a quantum memory and can be used to estimate the time until the system relaxes to thermal equilibrium when brought into contact with a thermal heat bath. The bound can be shown to behave as $\lambda \geq {\cal O}(N^{-1}\exp(-2\beta \, \overline{\epsilon}))$, where $\overline{\epsilon}$ is a generalization of the well known energy barrier for logical operators. Particularly in the low temperature regime we expect this bound to provide the correct asymptotic scaling of the gap with the system size up to a factor of $N^{-1}$.
Power Utility Maximization in Discrete-Time and Continuous-Time Exponential Levy Models
Johannes Temme
Quantitative Finance , 2011, DOI: 10.1007/s00186-012-0388-3
Abstract: Consider power utility maximization of terminal wealth in a 1-dimensional continuous-time exponential Levy model with finite time horizon. We discretize the model by restricting portfolio adjustments to an equidistant discrete time grid. Under minimal assumptions we prove convergence of the optimal discrete-time strategies to the continuous-time counterpart. In addition, we provide and compare qualitative properties of the discrete-time and continuous-time optimizers.
A Novel Modular Antigen Delivery System for Immuno Targeting of Human 6-sulfo LacNAc-Positive Blood Dendritic Cells (SlanDCs)
Claudia C. Bippes,Anja Feldmann,Slava Stamova,Marc Cartellieri,Adrian Schwarzer,Rebekka Wehner,Marc Schmitz,E. Peter Rieber,Senming Zhao,Knut Sch?kel,Achim Temme,R. Hal Scofield,Biji T. Kurien,Holger Bartsch,Michael Bachmann
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0016315
Abstract: Previously, we identified a major myeloid-derived proinflammatory subpopulation of human blood dendritic cells which we termed slanDCs (e.g. Sch?kel et al. (2006) Immunity 24, 767–777). The slan epitope is an O-linked sugar modification (6-sulfo LacNAc, slan) of P-selectin glycoprotein ligand-1 (PSGL-1). As slanDCs can induce neoantigen-specific CD4+ T cells and tumor-reactive CD8+ cytotoxic T cells, they appear as promising targets for an in vivo delivery of antigens for vaccination. However, tools for delivery of antigens to slanDCs were not available until now. Moreover, it is unknown whether or not antigens delivered via the slan epitope can be taken up, properly processed and presented by slanDCs to T cells.
A Novel Ex Vivo Isolation and Expansion Procedure for Chimeric Antigen Receptor Engrafted Human T Cells
Marc Cartellieri, Stefanie Koristka, Claudia Arndt, Anja Feldmann, Slava Stamova, Malte von Bonin, Katrin T?pfer, Thomas Krüger, Mathias Geib, Irene Michalk, Achim Temme, Martin Bornh?user, Dirk Lindemann, Gerhard Ehninger, Michael P. Bachmann
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0093745
Abstract: Genetically engineered T lymphocytes are a promising option for cancer therapy. Prior to adoptive transfer they have to be expanded in vitro to reach therapeutically sufficient numbers. So far, no universal method exists for selective in vitro expansion of engineered T lymphocytes. In order to overcome this problem and for proof of concept we incorporated a novel unique peptide sequence of ten amino acids as epitope (E-Tag) into the binding domains of two novel chimeric antigen receptors (ECARs) directed against either prostate stem cell antigen (PSCA) for the treatment of prostate cancer (PCa) or CD33 for the treatment of acute myeloide leukemia (AML). The epitope tag then was utilized for expanding ECAR engrafted T cells by triggering the modified T cells via a monoclonal antibody directed against the E-Tag (Emab). Moreover, the E-Tag served as an efficient selection epitope for immunomagnetic isolation of modified T cells to high purity. ECAR engrafted T cells were fully functional and mediated profound anti-tumor effects in the respective models of PCa or AML both in vitro and in vivo. The method can be integrated straightforward into clinical protocols to improve therapeutic efficiency of tumor treatment with CAR modified T lymphocytes.
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