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Haen S.P.,Medizinische Universitatsklinik Tubingen | Haen S.P.,Interfakultares Institute For Zellbiologie | Schumm M.,Klinik fur Kinder und Jugendmedizin | Faul C.,Medizinische Universitatsklinik Tubingen | And 3 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2015

Purpose: Insufficient production of leukocytes, thrombocytes and erythrocytes after allogeneic peripheral blood stem cell transplantation (PBSCT) represents a life-threatening complication. Methods: In 20 adult patients with poor graft function (PGF defined as transfusion-dependent platelet counts <20,000/µl, or leukocytes <1500/µl, or transfusion-dependent anemia) and variable causes of PGF after allogeneic PBSCT, immunomagnetically selected CD34+ stem cell boosts (SCB) from matched unrelated (n = 8), mismatched unrelated (n = 11) or haploidentical (n = 1) donors were applied without prior conditioning. Results: Patients received a median of 4.6 × 106 CD34+ cells per kilogram bodyweight (1.9–9.1 × 106) and low T cell numbers (median 0.2 × 104, range 0.04–0.6 × 104). All patients showed responses in at least one hematopoietic lineage. Engraftment for platelets, leukocytes and hemoglobin was 88, 88 and 100 % after a median of 14, 13 and 18 days, respectively. With regard to the complete cohort, 90 % (n = 18) showed an increase in platelets (median 76,500/µl, range −7000 to 223,000/µl), 95 % (n = 19) had an increase in leukocytes (median 3110/µl, range 150–13,740/µl) and 90 % (n = 18) improved with regard to hemoglobin (median 1.9 g/dl, range −0.9 to 5.1 g/dl). Due to effective T cell depletion, only one patient developed graft versus host disease (GvHD, grade III) after SCB. Patients were followed for a median of 7.5 months (1–74 months) with 11 patients being alive and disease free with normalized peripheral blood counts at the end of follow-up. Conclusions: CD34+-selected SCB are safe and effective and can durably improve PGF even in patients receiving grafts from unrelated matched or mismatched donors with low incidence of GvHD. © 2015, Springer-Verlag Berlin Heidelberg. Source


Menssen R.,University of Stuttgart | Schweiggert J.,University of Stuttgart | Schweiggert J.,University of Heidelberg | Schreiner J.,University of Stuttgart | And 6 more authors.
Journal of Biological Chemistry | Year: 2012

In the yeast Saccharomyces cerevisiae, key regulatory enzymes of gluconeogenesis such as fructose-1,6-bisphosphatase are degraded via the ubiquitin proteasome system when cells are replenished with glucose. Polyubiquitination is carried out by the Gid complex, a multisubunit ubiquitin ligase that consists of seven different Gid (glucose-induced degradation-deficient) proteins. Under gluconeogenic conditions the E3 ligase is composed of six subunits (Gid1/Vid30, Gid2/Rmd5, Gid5/Vid28, Gid7, Gid8, and Gid9/Fyv10). Upon the addition of glucose the regulatory subunit Gid4/Vid24 appears, binds to the Gid complex, and triggers ubiquitination of fructose-1,6-bisphosphatase. All seven proteins are essential for this process; however, nothing is known about the arrangement of the subunits in the complex. Interestingly, each Gid protein possesses several remarkable motifs (e.g. SPRY, LisH, CTLH domains) that may play a role in protein-protein interaction. We, therefore, generated altered versions of individual Gid proteins by deleting or mutating these domains and performed co-immunoprecipitation experiments to analyze the interaction between distinct subunits. Thus, we were able to create an initial model of the topology of this unusual E3 ubiquitin ligase. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Begum T.,University of Tubingen | Reuter R.,Interfakultares Institute For Zellbiologie | Schoffl F.,University of Tubingen
Mechanisms of Development | Year: 2013

The functions of plant class B-heat shock factors (Hsfs) are not well understood. Hsfs belonging to this group differ from class A-Hsfs in structural features of the oligomerization domain and by the absence of a typical AHA motif for transcriptional activation. AtHsfB4 is expressed in different parts of the plants with highest levels in root tissue. Transgenic Arabidopsis plants overexpressing (OE) HsfB4 by CaMV-35S-promoter showed massively enhanced levels of Hsf mRNAs. The root surface of OE-plants was rough and cells became detached. Crossings with cell type specific root marker lines and confocal laser scanning microscopy provided clear evidence for a duplication of cells in the ground tissue and ectopic layers of lateral root cap (LRC) cells in HsfB4-OE plants. A duplication of endodermis cells occurs already during embryonic development, while the ectopic LRC cells are only detected during postembryonic growth. The mutant phenotypes of Hsf-OE plants are without precedence and indicate that class B-Hsfs may play an important role in root development. © 2012 Elsevier Ireland Ltd. Source


Haen S.P.,Medizinische Universitatsklinik Tubingen | Haen S.P.,Interfakultares Institute For Zellbiologie | Brossart P.,Medizinische Universitatsklinik Iii For Hamatologie Und Onkologie | Rammensee H.-G.,Interfakultares Institute For Zellbiologie
Onkologe | Year: 2012

Major breakthroughs in recent years have been made in the active immunization against cancer. Newly identified tumor-antigens have successfully been employed in clinical trials. Even more, ipilimumab and sipuleucel-T have been legally approved, thus, representing the first active substances for the immunotherapy of cancer. Both substances utilize individual properties of the patient's tumor and immune system, leading to improvement of clinical outcomes. In addition, vaccine studies have evaluated individualized approaches in order to specifically target cancer while sparing normal tissue. This article provides an overview of recent therapeutic approaches like vaccination with autologous dendritic cells, autologous or allogeneic whole cell vaccines or application of defined tumor-associated antigens. © Springer-Verlag 2012. Source


Beermann A.,University of Rostock | Beermann A.,Interfakultares Institute For Zellbiologie | Pruhs R.,University of Rostock | Lutz R.,University of Rostock | And 2 more authors.
Development | Year: 2011

Short germ embryos elongate their primary body axis by consecutively adding segments from a posteriorly located growth zone. Wnt signalling is required for axis elongation in short germ arthropods, including Tribolium castaneum, but the precise functions of the different Wnt receptors involved in this process are unclear. We analysed the individual and combinatorial functions of the three Wnt receptors, Frizzled-1 (Tc-Fz1), Frizzled-2 (Tc-Fz2) and Frizzled-4 (Tc-Fz4), and their co-receptor Arrow (Tc-Arr) in the beetle Tribolium. Knockdown of gene function and expression analyses revealed that Frizzled-dependent Wnt signalling occurs anteriorly in the growth zone in the presegmental region (PSR). We show that simultaneous functional knockdown of the Wnt receptors Tc-fz1 and Tc-fz2 via RNAi resulted in collapse of the growth zone and impairment of embryonic axis elongation. Although posterior cells of the growth zone were not completely abolished, Wnt signalling within the PSR controls axial elongation at the level of pair-rule patterning, Wnt5 signalling and FGF signalling. These results identify the PSR in Tribolium as an integral tissue required for the axial elongation process, reminiscent of the presomitic mesoderm in vertebrates. Knockdown of Tc-fz1 alone interfered with the formation of the proximo-distal and the dorso-ventral axes during leg development, whereas no effect was observed with single Tc-fz2 or Tc-fz4 RNAi knockdowns. We identify Tc-Arr as an obligatory Wnt co-receptor for axis elongation, leg distalisation and segmentation. We discuss how Wnt signalling is regulated at the receptor and co-receptor levels in a dose-dependent fashion. © 2011. Published by The Company of Biologists Ltd. Source

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