@article{HuettenDhanasinghHessleretal.2014, author = {H{\"u}tten, Mareike and Dhanasingh, Anandhan and Hessler, Roland and St{\"o}ver, Timo and Esser, Karl-Heinz and M{\"o}ller, Martin and Lenarz, Thomas and Jolly, Claude and Groll, J{\"u}rgen and Scheper, Verena}, title = {In Vitro and In Vivo Evaluation of a Hydrogel Reservoir as a Continuous Drug Delivery System for Inner Ear Treatment}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0104564}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119375}, pages = {e104564}, year = {2014}, abstract = {Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear.}, language = {en} } @article{KastenNaserBruellhoffetal.2014, author = {Kasten, Annika and Naser, Tamara and Br{\"u}llhoff, Kristina and Fiedler, J{\"o}rg and M{\"u}ller, Petra and M{\"o}ller, Martin and Rychly, Joachim and Groll, J{\"u}rgen and Brenner, Rolf E.}, title = {Guidance of Mesenchymal Stem Cells on Fibronectin Structured Hydrogel Films}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {10}, doi = {10.1371/journal.pone.0109411}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114897}, pages = {e109411}, year = {2014}, abstract = {Designing of implant surfaces using a suitable ligand for cell adhesion to stimulate specific biological responses of stem cells will boost the application of regenerative implants. For example, materials that facilitate rapid and guided migration of stem cells would promote tissue regeneration. When seeded on fibronectin (FN) that was homogeneously immmobilized to NCO-sP(EO-stat-PO), which otherwise prevents protein binding and cell adhesion, human mesenchymal stem cells (MSC) revealed a faster migration, increased spreading and a more rapid organization of different cellular components for cell adhesion on fibronectin than on a glass surface. To further explore, how a structural organization of FN controls the behavior of MSC, adhesive lines of FN with varying width between 10 mu m and 80 mu m and spacings between 5 mu m and 20 mu m that did not allow cell adhesion were generated. In dependance on both line width and gaps, cells formed adjacent cell contacts, were individually organized in lines, or bridged the lines. With decreasing sizes of FN lines, speed and directionality of cell migration increased, which correlated with organization of the actin cytoskeleton, size and shape of the nuclei as well as of focal adhesions. Together, defined FN lines and gaps enabled a fine tuning of the structural organization of cellular components and migration. Microstructured adhesive substrates can mimic the extracellular matrix in vivo and stimulate cellular mechanisms which play a role in tissue regeneration.}, language = {en} } @article{EpeHaeringRamaiahetal.1993, author = {Epe, Bernd and H{\"a}ring, Martin and Ramaiah, Danaboyina and Stopper, Helga and Abou-Elzahab, Mohamed M. and Adam, Waldemar and Saha-M{\"o}ller, Chantu R.}, title = {DNA damage induced by furocoumarin hydroperoxides plus UV (360 nm)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86870}, year = {1993}, abstract = {Wben irradiated at 360 nm, furocoumarins with a hydroperoxide group in a side chain effciently give rise to a type of DNA damage that can best be explained by a photoinduced generation of hydroxyl radicals from the excited pbotosensitizers. The observed DNA damage profiles, i.e. the ratios of single-strand breaks, sites of base loss (AP sites) and base modifications sensitive to fonnamidopyrimidine-DNA glycosylase (FPG protein) and endonuclease m, are similar to the DNA damage profile produced by hydroxyl radicals generated by lonizing radiation or by xanthine and xanthine oxidase in the presence of Fe(III)-EDTA. No such damage is observed with the corresponding furocoumarin alcohols or in the absence of near-UV radiation. The damage caused by the photo-excited hydroperoxides is not influenced by superoxide dismutase (SOD) or catalase or by D2O as solvent. The presence of t-butanol, however, reduces both the formation of single-strand breaks and of base odifications sensitive to FPG protein. The cytotoxicity caused by one of the hydroperoxides in L5178Y mome lymphoma cells is found to be dependent on the near-UV irradiation and to be much higher than that of the corresponding alcohol. Therefore the new type of photoinduced damage occurs inside cells. Intercalating photosensitizers with an attached hydroperoxide group might represent a novel and versatile class of DNA damaging agents, e.g. for phototherapy.}, subject = {DNS-Sch{\"a}digung}, language = {en} } @article{LoefflerWirthKreuzHoppetal.2019, author = {Loeffler-Wirth, Henry and Kreuz, Markus and Hopp, Lydia and Arakelyan, Arsen and Haake, Andrea and Cogliatti, Sergio B. and Feller, Alfred C. and Hansmann, Martin-Leo and Lenze, Dido and M{\"o}ller, Peter and M{\"u}ller-Hermelink, Hans Konrad and Fortenbacher, Erik and Willscher, Edith and Ott, German and Rosenwald, Andreas and Pott, Christiane and Schwaenen, Carsten and Trautmann, Heiko and Wessendorf, Swen and Stein, Harald and Szczepanowski, Monika and Tr{\"u}mper, Lorenz and Hummel, Michael and Klapper, Wolfram and Siebert, Reiner and Loeffler, Markus and Binder, Hans}, title = {A modular transcriptome map of mature B cell lymphomas}, series = {Genome Medicine}, volume = {11}, journal = {Genome Medicine}, doi = {10.1186/s13073-019-0637-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237262}, year = {2019}, abstract = {Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.}, language = {en} } @article{SimsekyilmazLiehnWeinandyetal.2016, author = {Simsekyilmaz, Sakine and Liehn, Elisa A. and Weinandy, Stefan and Schreiber, Fabian and Megens, Remco T. A. and Theelen, Wendy and Smeets, Ralf and Jockenh{\"o}vel, Stefan and Gries, Thomas and M{\"o}ller, Martin and Klee, Doris and Weber, Christian and Zernecke, Alma}, title = {Targeting In-Stent-Stenosis with RGD- and CXCL1-Coated Mini-Stents in Mice}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0155829}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-179745}, year = {2016}, abstract = {Atherosclerotic lesions that critically narrow the artery can necessitate an angioplasty and stent implantation. Long-term therapeutic effects, however, are limited by excessive arterial remodeling. We here employed a miniaturized nitinol-stent coated with star-shaped polyethylenglycole (star-PEG), and evaluated its bio-functionalization with RGD and CXCL1 for improving in-stent stenosis after implantation into carotid arteries of mice. Nitinol foils or stents (bare metal) were coated with star-PEG, and bio-functionalized with RGD, or RGD/CXCL1. Cell adhesion to star-PEG-coated nitinol foils was unaltered or reduced, whereas bio-functionalization with RGD but foremost RGD/CXCL1 increased adhesion of early angiogenic outgrowth cells (EOCs) and endothelial cells but not smooth muscle cells when compared with bare metal foils. Stimulation of cells with RGD/CXCL1 furthermore increased the proliferation of EOCs. In vivo, bio-functionalization with RGD/CXCL1 significantly reduced neointima formation and thrombus formation, and increased re-endothelialization in apoE\(^{-/-}\) carotid arteries compared with bare-metal nitinol stents, star-PEG-coated stents, and stents bio-functionalized with RGD only. Bio-functionalization of star-PEG-coated nitinol-stents with RGD/CXCL1 reduced in-stent neointima formation. By supporting the adhesion and proliferation of endothelial progenitor cells, RGD/CXCL1 coating of stents may help to accelerate endothelial repair after stent implantation, and thus may harbor the potential to limit the complication of in-stent restenosis in clinical approaches.}, language = {en} } @article{RichterHuettmannRekowskietal.2019, author = {Richter, Julia and H{\"u}ttmann, Andreas and Rekowski, Jan and Schmitz, Christine and G{\"a}rtner, Selina and Rosenwald, Andreas and Hansmann, Martin-Leo and Hartmann, Sylvia and M{\"o}ller, Peter and Wacker, Hans-Heinrich and Feller, Alfred and Thorns, Christoph and M{\"u}ller, Stefan and D{\"u}hrsen, Ulrich and Klapper, Wolfram}, title = {Molecular characteristics of diffuse large B-cell lymphoma in the Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin lymphomas (PETAL) trial: correlation with interim PET and outcome}, series = {Blood Cancer Journal}, volume = {9}, journal = {Blood Cancer Journal}, doi = {10.1038/s41408-019-0230-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226185}, pages = {67}, year = {2019}, abstract = {No abstract available}, language = {en} } @article{HartmannPluetschowMottoketal.2019, author = {Hartmann, Sylvia and Pl{\"u}tschow, Annette and Mottok, Anja and Bernd, Heinz-Wolfram and Feller, Alfred C. and Ott, German and Cogliatti, Sergio and Fend, Falko and Quintanilla-Martinez, Leticia and Stein, Harald and Klapper, Wolfram and M{\"o}ller, Peter and Rosenwald, Andreas and Engert, Andreas and Hansmann, Martin-Leo and Eichenauer, Dennis A.}, title = {The time to relapse correlates with the histopathological growth pattern in nodular lymphocyte predominant Hodgkin lymphoma}, series = {American Journal of Hematology}, volume = {94}, journal = {American Journal of Hematology}, number = {11}, doi = {10.1002/ajh.25607}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212594}, pages = {1208 -- 1213}, year = {2019}, abstract = {Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first-line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67\% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.}, language = {en} } @article{HeidrichCordesKlinkeretal.2015, author = {Heidrich, Benjamin and Cordes, Hans-J{\"o}rg and Klinker, Hartwig and M{\"o}ller, Bernd and Naumann, Uwe and R{\"o}ssle, Martin and Kraus, Michael R. and B{\"o}ker, Klaus H. and Roggel, Christoph and Schuchmann, Marcus and Stoehr, Albrecht and Trein, Andreas and Hardtke, Svenja and Gonnermann, Andrea and Koch, Armin and Wedemeyer, Heiner and Manns, Michael P. and Cornberg, Markus}, title = {Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0128069}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151811}, pages = {e0128069}, year = {2015}, abstract = {Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80\%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 \(\mu\)g/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68\% [55\%; 81\%] in Group A and 57\% [43\%; 71\%] in Group B achieved SVR (p=0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70\%) was not met. In conclusion, approximately 23\% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group.}, language = {en} }