@article{ChopraLangSalzmannetal.2013, author = {Chopra, Martin and Lang, Isabell and Salzmann, Steffen and Pachel, Christina and Kraus, Sabrina and B{\"a}uerlein, Carina A. and Brede, Christian and Jord{\´a}n Garrote, Ana-Laura and Mattenheimer, Katharina and Ritz, Miriam and Schwinn, Stefanie and Graf, Carolin and Sch{\"a}fer, Viktoria and Frantz, Stefan and Einsele, Hermann and Wajant, Harald and Beilhack, Andreas}, title = {Tumor Necrosis Factor Induces Tumor Promoting and Anti-Tumoral Effects on Pancreatic Cancer via TNFR1}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0075737}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97246}, year = {2013}, abstract = {Multiple activities are ascribed to the cytokine tumor necrosis factor (TNF) in health and disease. In particular, TNF was shown to affect carcinogenesis in multiple ways. This cytokine acts via the activation of two cell surface receptors, TNFR1, which is associated with inflammation, and TNFR2, which was shown to cause anti-inflammatory signaling. We assessed the effects of TNF and its two receptors on the progression of pancreatic cancer by in vivo bioluminescence imaging in a syngeneic orthotopic tumor mouse model with Panc02 cells. Mice deficient for TNFR1 were unable to spontaneously reject Panc02 tumors and furthermore displayed enhanced tumor progression. In contrast, a fraction of wild type (37.5\%), TNF deficient (12.5\%), and TNFR2 deficient mice (22.2\%) were able to fully reject the tumor within two weeks. Pancreatic tumors in TNFR1 deficient mice displayed increased vascular density, enhanced infiltration of CD4+ T cells and CD4+ forkhead box P3 (FoxP3)+ regulatory T cells (Treg) but reduced numbers of CD8+ T cells. These alterations were further accompanied by transcriptional upregulation of IL4. Thus, TNF and TNFR1 are required in pancreatic ductal carcinoma to ensure optimal CD8+ T cell-mediated immunosurveillance and tumor rejection. Exogenous systemic administration of human TNF, however, which only interacts with murine TNFR1, accelerated tumor progression. This suggests that TNFR1 has basically the capability in the Panc02 model to trigger pro-and anti-tumoral effects but the spatiotemporal availability of TNF seems to determine finally the overall outcome.}, language = {en} } @article{ChatterjeeAndrulisStuehmeretal.2013, author = {Chatterjee, Manik and Andrulis, Mindaugas and St{\"u}hmer, Thorsten and M{\"u}ller, Elisabeth and Hofmann, Claudia and Steinbrunn, Torsten and Heimberger, Tanja and Schraud, Heike and Kressmann, Stefanie and Einsele, Hermann and Bargou, Ralf C.}, title = {The PI3K/Akt signaling pathway regulates the expression of Hsp70, which critically contributes to Hsp90-chaperone function and tumor cell survival in multiple myeloma}, series = {Haematologica}, volume = {98}, journal = {Haematologica}, number = {7}, doi = {10.3324/haematol.2012.066175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130574}, pages = {1132-1141}, year = {2013}, abstract = {Despite therapeutic advances multiple myeloma remains largely incurable, and novel therapeutic concepts are needed. The Hsp90-chaperone is a reasonable therapeutic target, because it maintains oncogenic signaling of multiple deregulated pathways. However, in contrast to promising pre-clinical results, only limited clinical efficacy has been achieved through pharmacological Hsp90 inhibition. Because Hsp70 has been described to interact functionally with the Hsp90-complex, we analyzed the suitability of Hsp72 and Hsp73 as potential additional target sites. Expression of Hsp72 and Hsp73 in myeloma cells was analyzed by immunohistochemical staining and western blotting. Short interfering RNA-mediated knockdown or pharmacological inhibition of Hsp72 and Hsp73 was performed to evaluate the role of these proteins in myeloma cell survival and for Hsp90-chaperone function. Furthermore, the role of PI3K-dependent signaling in constitutive and inducible Hsp70 expression was investigated using short interfering RNA-mediated and pharmacological PI3K inhibition. Hsp72 and Hsp73 were frequently overexpressed in multiple myeloma. Knockdown of Hsp72 and/or Hsp73 or treatment with VER-155008 induced apoptosis of myeloma cells. Hsp72/Hsp73 inhibition decreased protein levels of Hsp90-chaperone clients affecting multiple oncogenic signaling pathways, and acted synergistically with the Hsp90 inhibitor NVP-AUY922 in the induction of death of myeloma cells. Inhibition of the PI3K/Akt/GSK3b pathway with short interfering RNA or PI103 decreased expression of the heat shock transcription factor 1 and down-regulated constitutive and inducible Hsp70 expression. Treatment of myeloma cells with a combination of NVP-AUY922 and PI103 resulted in additive to synergistic cytotoxicity. In conclusion, Hsp72 and Hsp73 sustain Hsp90-haperone function and critically contribute to the survival of myeloma cells. Translation of Hsp70 inhibition into the clinic is therefore highly desirable. Treatment with PI3K inhibitors might represent an alternative therapeutic strategy to target Hsp70.}, language = {en} } @article{RascheDuellMorgneretal.2013, author = {Rasche, Leo and Duell, Johannes and Morgner, Charlotte and Chatterjee, Manik and Hensel, Frank and Rosenwald, Andreas and Einsele, Hermann and Topp, Max S. and Br{\"a}ndlein, Stephanie}, title = {The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0063414}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130125}, pages = {e63414}, year = {2013}, abstract = {In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM.}, language = {en} } @article{RauertWunderlichSiegmundMaieretal.2013, author = {Rauert-Wunderlich, Hilka and Siegmund, Daniela and Maier, Eduard and Giner, Tina and Bargou, Ralf C. and Wajant, Harald and St{\"u}hmer, Thorsten}, title = {The IKK Inhibitor Bay 11-7082 Induces Cell Death Independent from Inhibition of Activation of NF kappa B Transcription Factors}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0059292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130140}, pages = {e59292}, year = {2013}, abstract = {Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20\% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells.}, language = {en} } @article{LueckerathLapaSpahmannetal.2013, author = {L{\"u}ckerath, Katharina and Lapa, Constantin and Spahmann, Annika and J{\"o}rg, Gerhard and Samnick, Samuel and Rosenwald, Andreas and Einsele, Herrmann and Knop, Stefan and Buck, Andreas}, title = {Targeting Paraprotein Biosynthesis for Non-Invasive Characterization of Myeloma Biology}, doi = {10.1371/journal.pone.0084840}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111319}, year = {2013}, abstract = {Purpose Multiple myeloma is a hematologic malignancy originating from clonal plasma cells. Despite effective therapies, outcomes are highly variable suggesting marked disease heterogeneity. The role of functional imaging for therapeutic management of myeloma, such as positron emission tomography with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG-PET), remains to be determined. Although some studies already suggested a prognostic value of 18F-FDG-PET, more specific tracers addressing hallmarks of myeloma biology, e.g. paraprotein biosynthesis, are needed. This study evaluated the amino acid tracers L-methyl-[11C]-methionine (11C-MET) and [18F]-fluoroethyl-L-tyrosine (18F-Fet) for their potential to image myeloma and to characterize tumor heterogeneity. Experimental Design To study the utility of 11C-MET, 18F-Fet and 18F-FDG for myeloma imaging, time activity curves were compared in various human myeloma cell lines (INA-6, MM1.S, OPM-2) and correlated to cell-biological characteristics, such as marker gene expression and immunoglobulin levels. Likewise, patient-derived CD138+ plasma cells were characterized regarding uptake and biomedical features. Results Using myeloma cell lines and patient-derived CD138+ plasma cells, we found that the relative uptake of 11C-MET exceeds that of 18F-FDG 1.5- to 5-fold and that of 18F-Fet 7- to 20-fold. Importantly, 11C-MET uptake significantly differed between cell types associated with worse prognosis (e.g. t(4;14) in OPM-2 cells) and indolent ones and correlated with intracellular immunoglobulin light chain and cell surface CD138 and CXCR4 levels. Direct comparison of radiotracer uptake in primary samples further validated the superiority of 11C-MET. Conclusion These data suggest that 11C-MET might be a versatile biomarker for myeloma superior to routine functional imaging with 18F-FDG regarding diagnosis, risk stratification, prognosis and discrimination of tumor subtypes.}, language = {en} } @article{EnckHefnerHerbertetal.2013, author = {Enck, Paul and Hefner, Jochen and Herbert, Beate M. and Mazurak, Nazar and Weimer, Katja and Muth, Eric R. and Zipfel, Stephan and Martens, Ute}, title = {Sensitivity and Specificity of Hypnosis Effects on Gastric Myoelectrical Activity}, series = {PLOS ONE}, volume = {8}, journal = {PLOS ONE}, number = {12}, issn = {1932-6203}, doi = {10.1371/journal.pone.0083486}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127654}, pages = {e83486}, year = {2013}, abstract = {Objectives: The effects of hypnosis on physiological (gastrointestinal) functions are incompletely understood, and it is unknown whether they are hypnosis-specific and gut-specific, or simply unspecific effects of relaxation. Design: Sixty-two healthy female volunteers were randomly assigned to either a single session of hypnotic suggestion of ingesting an appetizing meal and an unappetizing meal, or to relax and concentrate on having an appetizing or unappetizing meal, while the electrogastrogram (EGG) was recorded. At the end of the session, participants drank water until they felt full, in order to detect EGG-signal changes after ingestion of a true gastric load. During both conditions participants reported their subjective well-being, hunger and disgust at several time points. Results: Imagining eating food induced subjective feelings of hunger and disgust as well as changes in the EGG similar to, but more pronounced than those seen with a real gastric water load during both hypnosis and relaxation conditions. These effects were more pronounced when imagining an appetizing meal than with an unappetizing meal. There was no significant difference between the hypnosis and relaxation conditions. Conclusion: Imagination with and without hypnosis exhibits similar changes in subjective and objective measures in response to imagining an appetizing and an unappetizing food, indicating high sensitivity but low specificity.}, language = {en} } @article{BeilhackChopraKrausetal.2013, author = {Beilhack, Andreas and Chopra, Martin and Kraus, Sabrina and Schwinn, Stefanie and Ritz, Miriam and Mattenheimer, Katharina and Mottok, Anja and Rosenwald, Andreas and Einsele, Hermann}, title = {Non-Invasive Bioluminescence Imaging to Monitor the Immunological Control of a Plasmablastic Lymphoma-Like B Cell Neoplasia after Hematopoietic Cell Transplantation}, doi = {10.1371/journal.pone.0081320}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111341}, year = {2013}, abstract = {To promote cancer research and to develop innovative therapies, refined pre-clinical mouse tumor models that mimic the actual disease in humans are of dire need. A number of neoplasms along the B cell lineage are commonly initiated by a translocation recombining c-myc with the immunoglobulin heavy-chain gene locus. The translocation is modeled in the C.129S1-Ighatm1(Myc)Janz/J mouse which has been previously engineered to express c-myc under the control of the endogenous IgH promoter. This transgenic mouse exhibits B cell hyperplasia and develops diverse B cell tumors. We have isolated tumor cells from the spleen of a C.129S1-Ighatm1(Myc)Janz/J mouse that spontaneously developed a plasmablastic lymphoma-like disease. These cells were cultured, transduced to express eGFP and firefly luciferase, and gave rise to a highly aggressive, transplantable B cell lymphoma cell line, termed IM380. This model bears several advantages over other models as it is genetically induced and mimics the translocation that is detectable in a number of human B cell lymphomas. The growth of the tumor cells, their dissemination, and response to treatment within immunocompetent hosts can be imaged non-invasively in vivo due to their expression of firefly luciferase. IM380 cells are radioresistant in vivo and mice with established tumors can be allogeneically transplanted to analyze graft-versus-tumor effects of transplanted T cells. Allogeneic hematopoietic stem cell transplantation of tumor-bearing mice results in prolonged survival. These traits make the IM380 model very valuable for the study of B cell lymphoma pathophysiology and for the development of innovative cancer therapies.}, language = {en} } @article{FujiKappEinsele2013, author = {Fuji, Shigeo and Kapp, Markus and Einsele, Hermann}, title = {Monitoring of Pathogen-Specific T-Cell Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation}, series = {Frontiers in Immunology}, volume = {4}, journal = {Frontiers in Immunology}, number = {276}, doi = {10.3389/fimmu.2013.00276}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129250}, year = {2013}, abstract = {The clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT) has been significantly improved during the last decades with regard to the reduction in organ failure, infection, and severe acute graft-versus-host disease. However, severe complications due to infectious diseases are still one of the major causes of morbidity and mortality after allogeneic HSCT, in particular in patients receiving haploidentical HSCT or cord blood transplant due to a slow and often incomplete immune reconstitution. In order to improve the immune control of pathogens without an increased risk of alloreactivity, adoptive immunotherapy using highly enriched pathogen-specificT cells offers a promising approach. In order to identify patients who are at high risk for infectious diseases, several monitoring assays have been developed with potential for the guidance of immunosuppressive drugs and adoptive immunotherapy in clinical practice. In this article, we aim to give a comprehensive overview regarding current developments of T-cell monitoring techniques focusing on T cells against viruses and fungi. In particular, we will focus on rather simple, fast, non-labor-intensive, cellular assays which could be integrated in routine clinical screening approaches.}, language = {en} } @article{LiuHuNiemannetal.2013, author = {Liu, Dan and Hu, Kai and Niemann, Markus and Herrmann, Sebastian and Cikes, Maja and St{\"o}rk, Stefan and Beer, Meinrad and Gaudron, Philipp Daniel and Morbach, Caroline and Knop, Stefan and Geissinger, Eva and Ertl, Georg and Bijnens, Bart and Weidemann, Frank}, title = {Impact of Regional Left Ventricular Function on Outcome for Patients with AL Amyloidosis}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0056923}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130293}, pages = {e56923}, year = {2013}, abstract = {Objectives The aim of this study was to explore the left ventricular (LV) deformation changes and the potential impact of deformation on outcome in patients with proven light-chain (AL) amyloidosis and LV hypertrophy. Background Cardiac involvement in AL amyloidosis patients is associated with poor outcome. Detecting regional cardiac function by advanced non-invasive techniques might be favorable for predicting outcome. Methods LV longitudinal, circumferential and radial peak systolic strains (Ssys) were assessed by speckle tracking imaging (STI) in 44 biopsy-proven systemic AL amyloidosis patients with LV hypertrophy (CA) and in 30 normal controls. Patients were divided into compensated (n = 18) and decompensated (n = 26) group based on clinical assessment and followed-up for a median period of 345 days. Results Ejection fraction (EF) was preserved while longitudinal Ssys (LSsys) was significantly reduced in both compensated and decompensated groups. Survival was significantly reduced in decompensated group (35\% vs. compensated 78\%, P = 0.001). LSsys were similar in apical segments and significantly reduced in basal segments between two patient groups. LSsys at mid-segments were significantly reduced in all LV walls of decompensated group. Patients were further divided into 4 subgroups according to the presence or absence of reduced LSsys in no (normal), only basal (mild), basal and mid (intermediate) and all segments of the septum (severe). This staging revealed continuously worse prognosis in proportion to increasing number of segments with reduced LSsys (mortality: normal 14\%, mild 27\%, intermediate 67\%, and severe 64\%). Mid-septum LSsys<11\% suggested a 4.8-fold mortality risk than mid-septum LSsys≥11\%. Multivariate regression analysis showed NYHA class and mid-septum LSsys were independent predictors for survival. Conclusions Reduced deformation at mid-septum is associated with worse prognosis in systemic amyloidosis patients with LV hypertrophy.}, language = {en} } @article{MuellerLoebnitzOstermannFranzkeetal.2013, author = {Mueller-Loebnitz, Christoph and Ostermann, Helmut and Franzke, Anke and Loeffler, Juergen and Uharek, Lutz and Topp, Max and Einsele, Hermann}, title = {Immunological Aspects of Candida and Aspergillus Systemic Fungal Infections}, series = {Interdisciplinary Perspectives on Infectious Diseases}, journal = {Interdisciplinary Perspectives on Infectious Diseases}, number = {ID 102934}, doi = {10.1155/2013/102934}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129327}, year = {2013}, abstract = {Patients with allogeneic stem cell transplantation (SCT) have a high risk of invasive fungal infections (IFIs) even after neutrophil regeneration. Immunological aspects might play a very important role in the IFI development in these patients. Some data are available supporting the identification of high-risk patients with IFI for example patients receiving stem cells fromTLR4 haplotype S4 positive donors. Key defense mechanisms against IFI include the activation of neutrophils, the phagocytosis of germinating conidia by dendritic cells, and the fight of the cells of the innate immunity such as monocytes and natural killer cells against germlings and hyphae. Furthermore, immunosuppressive drugs interact with immune effector cells influencing the specific fungal immune defense and antimycotic drugs might interact with immune response. Based on the current knowledge on immunological mechanism in Aspergillus fumigatus, the first approaches of an immunotherapy using human T cells are in development. This might be an option for the future of aspergillosis patients having a poor prognosis with conventional treatment.}, language = {en} }