RepoMed (Medizinische Hochschule Hannover)
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Leukämogenes Potential CRISPR-Cas9 induzierter KMT2A-Translokationen in humanen hämatopoetischen Stammzellen in vitro und in vivo
No full textTödliche Verkehrsunfälle im Sektionsgut des Instituts für Rechtsmedizin der Medizinischen Hochschule Hannover im Untersuchungszeitraum 2006–2010
Get PDFEinblicke in das Programm 2017-2019: Ina-Pichlmayr-Mentoring für Nachwuchswissenschaftlerinnen an der MHH
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Stable depletion of RUNX1-ETO in Kasumi-1 cells induces expression and enhanced proteolytic activity of Cathepsin G and Neutrophil Elastase.
No full textThe oncogenic fusion protein RUNX1-ETO is a product of the t(8;21) translocation and consists of the hematopoietic transcriptional master regulator RUNX1 and the repressor ETO. RUNX1-ETO is found in 10-15% of acute myeloid leukemia and interferes with the expression of genes that are essential for myeloid differentiation. The neutrophil serine protease Cathepsin G is one of the genes suppressed by RUNX1-ETO, but little is known about its impact on the regulation of other lysosomal proteases. By lentiviral transduction of the t(8;21) positive cell line Kasumi-1 with an RUNX1-ETO specific shRNA, we analyzed long-term effects of stable RUNX1-ETO silencing on cellular phenotypes and target gene expression. Stable anti RUNX1-ETO RNAi reduces both proliferation and apoptosis in Kasumi-1 cells. In addition, long-term knockdown of RUNX1-ETO leads to an upregulation of proteolytic activity in Kasumi-1 cells, which may be released in vitro upon cell lysis leading to massive degradation of cellular proteins. We therefore propose that protein expression data of RUNX1-ETO-silenced Kasumi-1 cells must be analyzed with caution, as cell lysis conditions can heavily influence the results of studies on protein expression. Next, a mass spectrometry-based approach was used to identify protease cleavage patterns in RUNX1-ETO-depleted Kasumi-1 cells and Neutrophil Elastase has been identified as a RUNX1-ETO candidate target. Finally, proteolytic activity of Neutrophil Elastase and Cathepsin G was functionally confirmed by si/shRNA-mediated knockdown in Kasumi-1 cells
Brief Sensory Training Narrows the Temporal Binding Window and Enhances Long-Term Multimodal Speech Perception.
No full textOur ability to integrate multiple sensory-based representations of our surrounding supplies us with a more holistic view of our world. There are many complex algorithms our nervous system uses to construct a coherent perception. An indicator to solve this 'binding problem' are the temporal characteristics with the specificity that environmental information has different propagation speeds (e.g., sound and electromagnetic waves) and sensory processing time and thus the temporal relationship of a stimulus pair derived from the same event must be flexibly adjusted by our brain. This tolerance can be conceptualized in the form of the cross-modal temporal binding window (TBW). Several studies showed the plasticity of the TBW and its importance concerning audio-visual illusions, synesthesia, as well as psychiatric disturbances. Using three audio-visual paradigms, we investigated the importance of length (short vs. long) as well as modality (uni- vs. multimodal) of a perceptual training aiming at reducing the TBW in a healthy population. We also investigated the influence of the TBW on speech intelligibility, where participants had to integrate auditory and visual speech information from a videotaped speaker. We showed that simple sensory trainings can change the TBW and are capable of optimizing speech perception at a very naturalistic level. While the training-length had no different effect on the malleability of the TBW, the multisensory trainings induced a significantly stronger narrowing of the TBW than their unisensory counterparts. Furthermore, a narrowing of the TBW was associated with a better performance in speech perception, meaning that participants showed a greater capacity for integrating informations from different sensory modalities in situations with one modality impaired. All effects persisted at least seven days. Our findings show the significance of multisensory temporal processing regarding ecologically valid measures and have important clinical implications for interventions that may be used to alleviate debilitating conditions (e.g., autism, schizophrenia), in which multisensory temporal function is shown to be impaired
Psychiatriereform braucht gute Planung – Bund, Länder und Kommunen tragen dafür Verantwortung
No full textÜber die Bedeutung humaner Papillomaviren und möglicher Kofaktoren bei der Genese des Adenokarzinoms der Zervix uteri und seiner Vorstufen: eine detaillierte monozentrische Kohortenanalyse mit 102 Patientinnen
No full textHepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition: Implications for Immunotherapy.
Get PDFT cell immunotherapy is a concept developed for the treatment of cancer and infectious diseases, based on cytotoxic T lymphocytes to target tumor- or pathogen-specific antigens. Antigen-specificity of the T cell receptors (TCRs) is an important selection criterion in the developmental design of immunotherapy. However, off-target specificity is a possible autoimmunity concern if the engineered antigen-specific T cells are cross-reacting to self-peptides in-vivo. In our recent work, we identified several hepatitis E virus (HEV)-specific TCRs as potential candidates to be developed into T cell therapy to treat chronic hepatitis E. One of the identified TCRs, targeting a HLA-A2-restricted epitope at the RNA-dependent RNA polymerase (HEV-1527: LLWNTVWNM), possessed a unique multiple glycine motif in the TCR-β CDR3, which might be a factor inducing cross-reactivity. The aim of our study was to explore if this TCR could cross-recognize self-peptides to underlay autoimmunity. Indeed, we found that this HEV-1527-specific TCR could also cross-recognize an apoptosis-related epitope, Nonmuscle Myosin Heavy Chain 9 (MYH9-478: QLFNHTMFI). While this TCR had dual specificities to both viral epitope and a self-antigen by double Dextramer binding, it was selectively functional against HEV-1527 but not activated against MYH9-478. The consecutive glycine motif in β chain may be the reason promoting TCR binding promiscuity to recognize a secondary target, thereby facilitating cross-recognition. In conclusion, candidate TCRs for immunotherapy development should be screened for autoimmune potential, especially when the TCRs exhibit unique sequence pattern
Umbilical cord as a long-term source of activatable mesenchymal stromal cells for immunomodulation.
Get PDFBACKGROUND:Mesenchymal stromal cells (MSCs) are used in over 800 clinical trials mainly due to their immune inhibitory activity. Umbilical cord (UC), the second leading source of clinically used MSCs, is usually cut in small tissue pieces. Subsequent cultivation leads to a continuous outgrowth of MSC explant monolayers (MSC-EMs) for months. Currently, the first MSC-EM culture takes approximately 2 weeks to grow out, which is then expanded and applied to patients. The initiating tissue pieces are then discarded. However, when UC pieces are transferred to new culture dishes, MSC-EMs continue to grow out. In case the functional integrity of these cells is maintained, later induced cultures could also be expanded and used for cell therapy. This would drastically increase the number of available cells for each patient. To test the functionality of MSC-EMs from early and late induction time points, we compared the first cultures to those initiated after 2 months by investigating their clonality and immunomodulatory capacity. METHODS:We analyzed the clonal composition of MSC-EM cultures by umbilical cord piece transduction using integrating lentiviral vectors harboring genetic barcodes assessed by high-throughput sequencing. We investigated the transcriptome of these cultures by microarrays. Finally, the secretome was analyzed by multiplexed ELISAs, in vitro assays, and in vivo in mice. RESULTS:DNA barcode analysis showed polyclonal MSC-EMs even after months of induction cycles. A transcriptome and secretome analyses of early and late MSC cultures showed only minor changes over time. However, upon activation with TNF-α and IFN-γ, cells from both induction time points produced a multitude of immunomodulatory cytokines. Interestingly, the later induced MSC-EMs produced higher amounts of cytokines. To test whether the different cytokine levels were in a therapeutically relevant range, we used conditioned medium (CM) in an in vitro MLR and an in vivo killing assay. CM from late induced MSC-EMs was at least as immune inhibitory as CM from early induced MSC-EMs. CONCLUSION:Human umbilical cord maintains a microenvironment for the long-term induction of polyclonal and immune inhibitory active MSCs for months. Thus, our results would offer the possibility to drastically increase the number of therapeutically applicable MSCs for a substantial amount of patients