TY  - JOUR
A1  - Davis, Lea K.
A1  - Yu, Dongmei
A1  - Keenan, Clare L.
A1  - Gamazon, Eric R.
A1  - Konkashbaev, Anuar I.
A1  - Derks, Eske M.
A1  - Neale, Benjamin M.
A1  - Yang, Jian
A1  - Lee, S. Hong
A1  - Evans, Patrick
A1  - Barr, Cathy L.
A1  - Bellodi, Laura
A1  - Benarroch, Fortu
A1  - Berrio, Gabriel Bedoya
A1  - Bienvenu, Oscar J.
A1  - Bloch, Michael H.
A1  - Blom, Rianne M.
A1  - Bruun, Ruth D.
A1  - Budman, Cathy L.
A1  - Camarena, Beatriz
A1  - Campbell, Desmond
A1  - Cappi, Carolina
A1  - Cardona Silgado, Julio C.
A1  - Cath, Danielle C.
A1  - Cavallini, Maria C.
A1  - Chavira, Denise A.
A1  - Chouinard, Sylvian
A1  - Conti, David V.
A1  - Cook, Edwin H.
A1  - Coric, Vladimir
A1  - Cullen, Bernadette A.
A1  - Deforce, Dieter
A1  - Delorme, Richard
A1  - Dion, Yves
A1  - Edlund, Christopher K.
A1  - Egberts, Karin
A1  - Falkai, Peter
A1  - Fernandez, Thomas V.
A1  - Gallagher, Patience J.
A1  - Garrido, Helena
A1  - Geller, Daniel
A1  - Girard, Simon L.
A1  - Grabe, Hans J.
A1  - Grados, Marco A.
A1  - Greenberg, Benjamin D.
A1  - Gross-Tsur, Varda
A1  - Haddad, Stephen
A1  - Heiman, Gary A.
A1  - Hemmings, Sian M. J.
A1  - Hounie, Ana G.
A1  - Illmann, Cornelia
A1  - Jankovic, Joseph
A1  - Jenike, Micheal A.
A1  - Kennedy, James L.
A1  - King, Robert A.
A1  - Kremeyer, Barbara
A1  - Kurlan, Roger
A1  - Lanzagorta, Nuria
A1  - Leboyer, Marion
A1  - Leckman, James F.
A1  - Lennertz, Leonhard
A1  - Liu, Chunyu
A1  - Lochner, Christine
A1  - Lowe, Thomas L.
A1  - Macciardi, Fabio
A1  - McCracken, James T.
A1  - McGrath, Lauren M.
A1  - Restrepo, Sandra C. Mesa
A1  - Moessner, Rainald
A1  - Morgan, Jubel
A1  - Muller, Heike
A1  - Murphy, Dennis L.
A1  - Naarden, Allan L.
A1  - Ochoa, William Cornejo
A1  - Ophoff, Roel A.
A1  - Osiecki, Lisa
A1  - Pakstis, Andrew J.
A1  - Pato, Michele T.
A1  - Pato, Carlos N.
A1  - Piacentini, John
A1  - Pittenger, Christopher
A1  - Pollak, Yehunda
A1  - Rauch, Scott L.
A1  - Renner, Tobias J.
A1  - Reus, Victor I.
A1  - Richter, Margaret A.
A1  - Riddle, Mark A.
A1  - Robertson, Mary M.
A1  - Romero, Roxana
A1  - Rosàrio, Maria C.
A1  - Rosenberg, David
A1  - Rouleau, Guy A.
A1  - Ruhrmann, Stephan
A1  - Ruiz-Linares, Andreas
A1  - Sampaio, Aline S.
A1  - Samuels, Jack
A1  - Sandor, Paul
A1  - Sheppard, Broke
A1  - Singer, Harvey S.
A1  - Smit, Jan H.
A1  - Stein, Dan J.
A1  - Strengman, E.
A1  - Tischfield, Jay A.
A1  - Valencia Duarte, Ana V.
A1  - Vallada, Homero
A1  - Van Nieuwerburgh, Flip
A1  - Veenstra-VanderWeele, Jeremy
A1  - Walitza, Susanne
A1  - Wang, Ying
A1  - Wendland, Jens R.
A1  - Westenberg, Herman G. M.
A1  - Shugart, Yin Yao
A1  - Miguel, Euripedes C.
A1  - McMahon, William
A1  - Wagner, Michael
A1  - Nicolini, Humberto
A1  - Posthuma, Danielle
A1  - Hanna, Gregory L.
A1  - Heutink, Peter
A1  - Denys, Damiaan
A1  - Arnold, Paul D.
A1  - Oostra, Ben A.
A1  - Nestadt, Gerald
A1  - Freimer, Nelson B.
A1  - Pauls, David L.
A1  - Wray, Naomi R.
A1  - Stewart, S. Evelyn
A1  - Mathews, Carol A.
A1  - Knowles, James A.
A1  - Cox, Nancy J.
A1  - Scharf, Jeremiah M.
T1  - Partitioning the Heritability of Tourette Syndrome and Obsessive Compulsive Disorder Reveals Differences in Genetic Architecture
JF  - PLoS Genetics
N2  - The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.
KW  - TIC disorders
KW  - missing heritability
KW  - complex diseases
KW  - neuropsychiatric disorders
KW  - common SNPS
KW  - gilles
KW  - family
KW  - brain
KW  - expression
KW  - autism
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127377
SN  - 1553-7390
VL  - 9
IS  - 10
ER  - 
TY  - JOUR
A1  - Erhardt, A.
A1  - Akula, N.
A1  - Schumacher, J.
A1  - Czamara, D.
A1  - Karbalai, N.
A1  - Müller-Myhsok, B.
A1  - Mors, O.
A1  - Borglum, A.
A1  - Kristensen, A. S.
A1  - Woldbye, D. P. D.
A1  - Koefoed, P.
A1  - Eriksson, E.
A1  - Maron, E.
A1  - Metspalu, A.
A1  - Nurnberger, J.
A1  - Philibert, R. A.
A1  - Kennedy, J.
A1  - Domschke, K.
A1  - Reif, A.
A1  - Deckert, J.
A1  - Otowa, T.
A1  - Kawamura, Y.
A1  - Kaiya, H.
A1  - Okazaki, Y.
A1  - Tanii, H.
A1  - Tokunaga, K.
A1  - Sasaki, T.
A1  - Ioannidis, J. P. A.
A1  - McMahon, F. J.
A1  - Binder, E. B.
T1  - Replication and meta-analysis of TMEM132D gene variants in panic disorder
JF  - Translational Psychiatry
N2  - A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n 1038 cases and n 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.
KW  - candidate gene
KW  - genome-wide association
KW  - Japanese population
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133324
VL  - 2
IS  - e156
ER  - 
TY  - JOUR
A1  - Müller, Stefanie H.
A1  - Girard, Simon L.
A1  - Hopfner, Franziska
A1  - Merner, Nancy D.
A1  - Bourassa, Cynthia V.
A1  - Lorenz, Delia
A1  - Clark, Lorraine N.
A1  - Tittmann, Lukas
A1  - Soto-Ortolaza, Alexandra I.
A1  - Klebe, Stephan
A1  - Hallett, Mark
A1  - Schneider, Susanne A.
A1  - Hodgkinson, Colin A.
A1  - Lieb, Wolfgang
A1  - Wszolek, Zbigniew K.
A1  - Pendziwiat, Manuela
A1  - Lorenzo-Betancor, Oswaldo
A1  - Poewe, Werner
A1  - Ortega-Cubero, Sara
A1  - Seppi, Klaus
A1  - Rajput, Alex
A1  - Hussl, Anna
A1  - Rajput, Ali H.
A1  - Berg, Daniela
A1  - Dion, Patrick A.
A1  - Wurster, Isabel
A1  - Shulman, Joshua M.
A1  - Srulijes, Karin
A1  - Haubenberger, Dietrich
A1  - Pastor, Pau
A1  - Vilariño-Güell, Carles
A1  - Postuma, Ronald B.
A1  - Bernard, Geneviève
A1  - Ladwig, Karl-Heinz
A1  - Dupré, Nicolas
A1  - Jankovic, Joseph
A1  - Strauch, Konstantin
A1  - Panisset, Michel
A1  - Winkelmann, Juliane
A1  - Testa, Claudia M.
A1  - Reischl, Eva
A1  - Zeuner, Kirsten E.
A1  - Ross, Owen A.
A1  - Arzberger, Thomas
A1  - Chouinard, Sylvain
A1  - Deuschl, Günther
A1  - Louis, Elan D.
A1  - Kuhlenbäumer, Gregor
A1  - Rouleau, Guy A.
T1  - Genome-wide association study in essential tremor identifies three new loci
JF  - Brain
N2  - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
KW  - quality-control
KW  - disease
KW  - tool
KW  - movement disorders
KW  - genome-wide association study
KW  - tremor
KW  - genetics
KW  - essential tremor
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541
VL  - 139
ER  - 
TY  - JOUR
A1  - Tymoshenko, Y. V.
A1  - Onykiienko, Y. A.
A1  - Müller, T.
A1  - Thomale, R.
A1  - Rachel, S.
A1  - Cameron, A. S.
A1  - Portnichenko, P. Y.
A1  - Efremov, D. V.
A1  - Tsurkan, V.
A1  - Abernathy, D. L.
A1  - Ollivier, J.
A1  - Schneidewind, A.
A1  - Piovano, A.
A1  - Felea, V.
A1  - Loidl, A.
A1  - Inosov, D. S.
T1  - Pseudo-Goldstone magnons in the frustrated \(S=3/2\) Heisenberg helimagnet \(ZnCr_2Se_4\) with a pyrochlore magnetic sublattice
JF  - Physical Review X
N2  - Low-energy spin excitations in any long-range ordered magnetic system in the absence of magnetocrystalline anisotropy are gapless Goldstone modes emanating from the ordering wave vectors. In helimagnets, these modes hybridize into the so-called helimagnon excitations. Here we employ neutron spectroscopy supported by theoretical calculations to investigate the magnetic excitation spectrum of the isotropic Heisenberg helimagnet \({ZnCr_2Se_4}\) with a cubic spinel structure, in which spin\(-3/2\) magnetic \({Cr^{3+}}\) ions are arranged in a geometrically frustrated pyrochlore sublattice. Apart from the conventional Goldstone mode emanating from the \((0~ 0~ {q_h})\) ordering vector, low-energy magnetic excitations in the single-domain proper-screw spiral phase show soft helimagnon modes with a small energy gap of \({∼0.17~ meV}\), emerging from two orthogonal wave vectors \(({q_h}~ 0~ 0)\) and \({(0~ {q_h}~ 0)}\) where no magnetic Bragg peaks are present. We term them pseudo-Goldstone magnons, as they appear gapless within linear spinwave theory and only acquire a finite gap due to higher-order quantum-fluctuation corrections. Our results are likely universal for a broad class of symmetric helimagnets, opening up a new way of studying weak magnon-magnon interactions with accessible spectroscopic methods.
KW  - physics
KW  - spin waves
KW  - helimagnets
KW  - inelastic neutron scattering
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172770
VL  - 7
IS  - 4
ER  - 
TY  - JOUR
A1  - Gratwohl, A
A1  - Pfirrmann, M
A1  - Zander, A
A1  - Kröger, N
A1  - Beelen, D
A1  - Novotny, J
A1  - Nerl, C
A1  - Scheid, C
A1  - Spiekermann, K
A1  - Mayer, J
A1  - Sayer, HG
A1  - Falge, C
A1  - Bunjes, D
A1  - Döhner, H
A1  - Ganser, A
A1  - Schmidt-Wolf, I
A1  - Schwerdtfeger, R
A1  - Baurmann, H
A1  - Kuse, R
A1  - Schmitz, N
A1  - Wehmeier, A
A1  - Fischer, J Th
A1  - Ho, AD
A1  - Wilhelm, M
A1  - Goebeler, M-E
A1  - Lindemann, HW
A1  - Bormann, M
A1  - Hertenstein, B
A1  - Schlimok, G
A1  - Baerlocher, GM
A1  - Aul, C
A1  - Pfreundschuh, M
A1  - Fabian, M
A1  - Staib, P
A1  - Edinger, M
A1  - Schatz, M
A1  - Fauser, A
A1  - Arnold, R
A1  - Kindler, T
A1  - Wulf, G
A1  - Rosselet, A
A1  - Hellmann, A
A1  - Schäfer, E
A1  - Prümmer, O
A1  - Schenk, M
A1  - Hasford, J
A1  - Heimpel, H
A1  - Hossfeld, DK
A1  - Kolb, H-J
A1  - Büsche, G
A1  - Haferlach, C
A1  - Schnittger, S
A1  - Müller, MC
A1  - Reiter, A
A1  - Berger, U
A1  - Saußele, S
A1  - Hochhaus, A
A1  - Hehlmann, R
T1  - Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment
JF  - Leukemia
N2  - Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P = 0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.
KW  - chronic myeloid leukemia
KW  - stem cell transplantation
KW  - drug treatment
KW  - CML
KW  - tyrosine kinase inhibitors
KW  - allogeneic hematopoietic stem cell transplantation
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150368
VL  - 30
ER  - 
TY  - JOUR
A1  - Deltz, E.
A1  - Müller-Hermelink, HK
A1  - Ulrichs, Karin
A1  - Thiede, A.
A1  - Müller-Ruchholtz, W.
T1  - Development of graft-versus-host reaction in various target organs after small intestine transplantation
N2  - The GVHRIL foHowing transplantation of small intestine are different from those found after bone marrow transplantation or spleen cell injections in that they show a remarka ble, significant prevalence of lesions within the intestinal mucosa. These findings are consistent with the observation that jntestinal lymphocytes newly formed in mesenteric lymph nodes predominantly home in on the intestine again.& The degree of histologic alteration within different tissues indicates that the graft and the host may survive the lesions of the lymphatic tissues, whereas the severe intestinal lesions following GVHR may easily cause death of the recipient. With regard to clinical sman bowel transplantation two statements can be made: (l) GVHRIL play a significant role in small bowel trans~ plantation. (2) To minimize their biologic importance, a selective elimination of the graft's Jymph nodes by irradiation or surgical resection should be considered in view of the remarkable difference between GVHRIL in lymph nodes and in the graft's intestinal wall itself.
KW  - Chirurgie
Y1  - 1981
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45459
ER  - 
TY  - JOUR
A1  - Müller, J. G.
A1  - Krenn, V.
A1  - Schindler, C.
A1  - Czub, S.
A1  - Stahl-Henning, C.
A1  - Coulibaly, C.
A1  - Hunsmann, G.
A1  - Kneitz, C.
A1  - Kerkau, T.
A1  - Rethwilm, A.
A1  - ter Meulen, V.
A1  - Müller-Hermelink, H. K.
T1  - Alterations of Thymus Cortical Epithelium and Interdigitating Dendritic Cells but No Increase of Thymocyte Cell Death in the Early Course of Simian Immunodeficiency Virus Infection
JF  - American Journal of Pathology
N2  - The role of the thymus in the pathogenesis of simian acquired immunodeficiency syndrome was investigated in 18 juvenile rhesus monkeys (Macaca mulatta). The thymus was infected from the first week post-SIVmac inoculation, but the amount of virus-positive cells was very low « 1 in 1 04 T cells) as demonstrated by polymerase chain reaction and in situ hybridization. First morphological alteration was a narrowing of the cortex at 12 and 24 wpi. Morphometry revealed no increase of pyknotic T cells but a decrease of the proliferation rate andflow cytometry showed a reduction of the immature \(CD4^+/CD8^+\) double-positive T cells. Ultrastructural analysis revealed vacuolization, shrinkage, andfinally cytolysis of the cortical epithelial cells and the interdigitating dendritic cells. Immunofluorescence staining exhibited a widespread loss of cortical epithelial cells. This damage to the thymic microenvironment could explain the breakdown of the intrathymic T cell proliferation. It preceded fully developed simian acquired immunodeficiency syndrome and is therefore considered to play a major role in its pathogenesis.
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128250
VL  - 143
IS  - 3
ER  - 
TY  - JOUR
A1  - Fuchs, A.
A1  - Youssef, A.
A1  - Seher, A.
A1  - Hochleitner, G.
A1  - Dalton, P. D.
A1  - Hartmann, S.
A1  - Brands, R. C.
A1  - Müller-Richter, U. D. A.
A1  - Linz, C,
T1  - Medical-grade polycaprolactone scaffolds made by melt electrospinning writing for oral bone regeneration – a pilot study in vitro
JF  - BMC Oral Health
N2  - Background
The spectrum of indications for the use of membranes and scaffolds in the field of oral and maxillofacial surgery includes, amongst others, guided bone regeneration (GBR). Currently available membrane systems face certain disadvantages such as difficult clinical handling, inconsistent degradation, undirected cell growth and a lack of stability that often complicate their application. Therefore, new membranes which can overcome these issues are of great interest in this field.

Methods
In this pilot study, we investigated polycaprolactone (PCL) scaffolds intended to enhance oral wound healing by means of melt electrospinning writing (MEW), which allowed for three-dimensional (3D) printing of micron scale fibers and very exact fiber placement. A singular set of box-shaped scaffolds of different sizes consisting of medical-grade PCL was examined and the scaffolds’ morphology was evaluated via scanning electron microscopy (SEM). Each prototype sample with box sizes of 225 μm, 300 μm, 375 μm, 450 μm and 500 μm was assessed for cytotoxicity and cell growth by seeding each scaffold with human osteoblast-like cell line MG63.

Results
All scaffolds demonstrated good cytocompatibility according to cell viability, protein concentration, and cell number. SEM analysis revealed an exact fiber placement of the MEW scaffolds and the growth of viable MG63 cells on them. For the examined box-shaped scaffolds with pore sizes between 225 μm and 500 μm, a preferred box size for initial osteoblast attachment could not be found.

Conclusions
These well-defined 3D scaffolds consisting of medical-grade materials optimized for cell attachment and cell growth hold the key to a promising new approach in GBR in oral and maxillofacial surgery.
KW  - melt electrospinning writing
KW  - polycaprolactone
KW  - scaffold
KW  - guided bone regeneration
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200274
VL  - 19
ER  - 
TY  - JOUR
A1  - Gattenloehner, Stefan
A1  - Joerissen, H.
A1  - Huhn, M.
A1  - Vincent, A.
A1  - Beeson, D.
A1  - Tzartos, S.
A1  - Mamalaki, A.
A1  - Etschmann, B.
A1  - Muller-Hermelink, H. K.
A1  - Koscielniak, E.
A1  - Barth, S.
A1  - Marx, A.
T1  - A Human Recombinant Autoantibody-Based Immunotoxin Specific for the Fetal Acetylcholine Receptor Inhibits Rhabdomyosarcoma Growth In Vitro and in a Murine Transplantation Model [Research Article]
N2  - Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) γ-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA).While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms.
KW  - Medizin
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68200
ER  - 
TY  - JOUR
A1  - Merz, H.
A1  - Fliedner, A.
A1  - Lehrnbecher, T.
A1  - Sebald, Walter
A1  - Müller-Hermelink, H. K.
A1  - Feller, A. C.
T1  - Cytokine expression in B-cell non-Hodgkin lymphomas
N2  - No abstract available
KW  - Biochemie
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62539
ER  - 
TY  - JOUR
A1  - Merz, H.
A1  - Fliedner, A.
A1  - Orscheschek, K.
A1  - Binder, T.
A1  - Sebald, Walter
A1  - Müller-Hermelink, H. K.
A1  - Feller, A. C.
T1  - Cytokine expression in T-cell lymphomas and Hodgkin's disease. Its possible implication in autocrine or paracrine production as a potential basis for neoplastic growth
N2  - No abstract available
KW  - Biochemie
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62483
ER  - 
TY  - JOUR
A1  - Gentschev, Ivaylo
A1  - Müller, Meike
A1  - Adelfinger, Marion
A1  - Weibel, Stephanie
A1  - Grummt, Friedrich
A1  - Zimmermann, Martina
A1  - Bitzer, Michael
A1  - Heisig, Martin
A1  - Zhang, Qian
A1  - Yu, Yong A.
A1  - Chen, Nanhai G.
A1  - Stritzker, Jochen
A1  - Lauer, Ulrich M.
A1  - Szalay, Aladar A.
T1  - Efficient Colonization and Therapy of Human Hepatocellular Carcinoma (HCC) Using the Oncolytic Vaccinia Virus Strain GLV-1h68
JF  - PLOS ONE
N2  - Virotherapy using oncolytic vaccinia virus strains is one of the most promising new strategies for cancer therapy. In this study, we analyzed for the first time the therapeutic efficacy of the oncolytic vaccinia virus GLV-1h68 in two human hepatocellular carcinoma cell lines HuH7 and PLC/PRF/5 (PLC) in cell culture and in tumor xenograft models. By viral proliferation assays and cell survival tests, we demonstrated that GLV-1h68 efficiently colonized, replicated in, and did lyse these cancer cells in culture. Experiments with HuH7 and PLC xenografts have revealed that a single intravenous injection (i.v.) of mice with GLV-1h68 resulted in a significant reduction of primary tumor sizes compared to uninjected controls. In addition, replication of GLV-1h68 in tumor cells led to strong inflammatory and oncolytic effects resulting in intense infiltration of MHC class II-positive cells like neutrophils, macrophages, B cells and dendritic cells and in up-regulation of 13 pro-inflammatory cytokines. Furthermore, GLV-1h68 infection of PLC tumors inhibited the formation of hemorrhagic structures which occur naturally in PLC tumors. Interestingly, we found a strongly reduced vascular density in infected PLC tumors only, but not in the non-hemorrhagic HuH7 tumor model. These data demonstrate that the GLV-1h68 vaccinia virus may have an enormous potential for treatment of human hepatocellular carcinoma in man.
KW  - Breast-tumors
KW  - Nude-mice
KW  - In-vivo
KW  - Cancer
KW  - Inhibitor
KW  - Tissue
KW  - Agent
KW  - COX-2
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135319
VL  - 6
IS  - 7
ER  - 
TY  - JOUR
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Winoto-Morbach, S.
A1  - Vanucchi, A.
A1  - Jäger, H.
A1  - Müller-Ruchholtz, W.
T1  - Erste Kieler Erfahrungen mit 45 Isolierungen von Langerhansinseln aus Schweinepankreas
N2  - No abstract available.
KW  - Langerhans-Inseln
KW  - Bauchspeicheldrüse
KW  - Schwein
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-73205
ER  - 
TY  - JOUR
A1  - Ulrichs, Karin
A1  - Eckstein, V.
A1  - Tibell, A.
A1  - Groth, C. G.
A1  - Korsgren, O.
A1  - Müller-Ruchholtz, W.
A1  - Thiede, A.
T1  - Natürliche und induzierte xenoreaktive Antikörper vor und nach klinischer Transplantation fötaler porziner Pankreasinselzellen
N2  - No abstract available.
KW  - Antikörper
KW  - Langerhans-Inseln
KW  - Schwein
KW  - Transplantation
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-72967
ER  - 
TY  - JOUR
A1  - Zeiner, P. S.
A1  - Zinke, J.
A1  - Kowalewski, D. J.
A1  - Bernatz, S.
A1  - Tichy, J.
A1  - Ronellenfitsch, M. W.
A1  - Thorsen, F.
A1  - Berger, A.
A1  - Forster, M. T.
A1  - Muller, A.
A1  - Steinbach, J. P.
A1  - Beschorner, R.
A1  - Wischhusen, J.
A1  - Kvasnicka, H. M.
A1  - Plate, K. H.
A1  - Stefanović, S.
A1  - Weide, B.
A1  - Mittelbronn, M.
A1  - Harter, P. N.
T1  - CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival
JF  - Acta Neuropathologica Communications
N2  - Abstract
Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.

We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.

We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74\(^{high}\) and TIL\(^{high}\) tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.

In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
KW  - CD74
KW  - HLA class II
KW  - brain metastasis
KW  - HLA peptidome
KW  - tumor infiltrating lymphocytes
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233882
VL  - 6
ER  - 
TY  - JOUR
A1  - Fuchs, Andreas
A1  - Hartmann, Stefan
A1  - Ernestus, Karen
A1  - Mutzbauer, Grit
A1  - Linz, Christian
A1  - Brands, Roman C.
A1  - Kübler, Alexander C.
A1  - Müller-Richter, Urs D. A.
T1  - Mandibular intraosseous pseudocarcinomatous hyperplasia: a case report
JF  - Journal of Medical Case Reports
N2  - Background

Mandibular pseudocarcinomatous hyperplasia is a rare and generally benign pathology. We report on one of these rare cases.

Case presentation

The case history of a 73-year-old white man stated that he had a carcinoma of the oropharynx, which was primarily treated with radiotherapy and chemotherapy 4 years prior. As a result of radiotherapy he developed an osteoradionecrosis of his mandible and a consecutive pathological fracture of his left mandibular angle. Subsequent osteosynthesis was performed with a reconstruction plate. When we first saw him, his reconstruction plate was partially exposed with intraoral and extraoral fistulation. The resected bone of his defect-bordering jaw showed the typical pathohistological findings of an intraosseous mandibular pseudocarcinomatous hyperplasia. After a first reconstruction attempt with an iliac crest graft failed, definitive reconstruction of his mandible with a microvascular anastomosed fibula graft was achieved.

Conclusions

Intraosseous pseudocarcinomatous hyperplasia of the mandible is a rare differential diagnosis in maxillofacial surgery. Besides other benign epithelial neoplasms, such as calcifying epithelial odontogenic tumor, squamous odontogenic tumor, or different forms of ameloblastoma, the far more frequent invasive squamous cell carcinoma needs to be excluded. A misinterpretation of pseudocarcinomatous hyperplasia as squamous cell carcinoma must be avoided because it can lead to a massive overtreatment.
KW  - intraosseous
KW  - case report
KW  - pseudocarcinomatous hyperplasia
KW  - mandible
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146873
VL  - 16
IS  - 268
ER  - 
TY  - JOUR
A1  - Walter, T.
A1  - Collenburg, L.
A1  - Japtok, L.
A1  - Kleuser, B.
A1  - Schneider-Schaulies, S.
A1  - Müller, N.
A1  - Becam, J.
A1  - Schubert-Unkmeir, A.
A1  - Kong, J. N.
A1  - Bieberich, E.
A1  - Seibel, J.
T1  - Incorporation and visualization of azido-functionalized N-oleoyl serinol in Jurkat cells, mouse brain astrocytes, 3T3 fibroblasts and human brain microvascular endothelial cells
JF  - Chemical Communications
N2  - The synthesis and biological evaluation of azido-N-oleoyl serinol is reported. It mimicks biofunctional lipid ceramides and has shown to be capable of click reactions for cell membrane imaging in Jurkat and human brain microvascular endothelial cells.
KW  - Ceramide
KW  - Apoptosis
KW  - Golgi
KW  - N-oleoyl serinol
KW  - Jurkat cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191263
VL  - 52
IS  - 55
ER  - 
TY  - JOUR
A1  - Chopra, Martin
A1  - Biehl, Marlene
A1  - Steinfatt, Tim
A1  - Brandl, Andreas
A1  - Kums, Juliane
A1  - Amich, Jorge
A1  - Vaeth, Martin
A1  - Kuen, Janina
A1  - Holtappels, Rafaela
A1  - Podlech, Jürgen
A1  - Mottok, Anja
A1  - Kraus, Sabrina
A1  - Jordán-Garotte, Ana-Laura
A1  - Bäuerlein, Carina A.
A1  - Brede, Christian
A1  - Ribechini, Eliana
A1  - Fick, Andrea
A1  - Seher, Axel
A1  - Polz, Johannes
A1  - Ottmueller, Katja J.
A1  - Baker, Jeannette
A1  - Nishikii, Hidekazu
A1  - Ritz, Miriam
A1  - Mattenheimer, Katharina
A1  - Schwinn, Stefanie
A1  - Winter, Thorsten
A1  - Schäfer, Viktoria
A1  - Krappmann, Sven
A1  - Einsele, Hermann
A1  - Müller, Thomas D.
A1  - Reddehase, Matthias J.
A1  - Lutz, Manfred B.
A1  - Männel, Daniela N.
A1  - Berberich-Siebelt, Friederike
A1  - Wajant, Harald
A1  - Beilhack, Andreas
T1  - Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion
JF  - Journal of Experimental Medicine
N2  - Donor CD4\(^+\)Foxp3\(^+\) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo.
KW  - Tumor-necrosis-factor
KW  - Regulatory-cells
KW  - Bone marrow transplantantation
KW  - Graft-versus-leukemia
KW  - Rheumatoid arthritis
KW  - Autoimmune diseases
KW  - Factor receptor
KW  - Alpha therapy
KW  - Expression
KW  - Suppression
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187640
VL  - 213
IS  - 9
ER  - 
TY  - JOUR
A1  - Beisser, Daniela
A1  - Grohme, Markus A.
A1  - Kopka, Joachim
A1  - Frohme, Marcus
A1  - Schill, Ralph O.
A1  - Hengherr, Steffen
A1  - Dandekar, Thomas
A1  - Klau, Gunnar W.
A1  - Dittrich, Marcus
A1  - Müller, Tobias
T1  - Integrated pathway modules using time-course metabolic profiles and EST data from Milnesium tardigradum
N2  - Background: Tardigrades are multicellular organisms, resistant to extreme environmental changes such as heat, drought, radiation and freezing. They outlast these conditions in an inactive form (tun) to escape damage to cellular structures and cell death. Tardigrades are apparently able to prevent or repair such damage and are therefore a crucial model organism for stress tolerance. Cultures of the tardigrade Milnesium tardigradum were dehydrated by removing the surrounding water to induce tun formation. During this process and the subsequent rehydration, metabolites were measured in a time series by GC-MS. Additionally expressed sequence tags are available, especially libraries generated from the active and inactive state. The aim of this integrated analysis is to trace changes in tardigrade metabolism and identify pathways responsible for their extreme resistance against physical stress. Results: In this study we propose a novel integrative approach for the analysis of metabolic networks to identify modules of joint shifts on the transcriptomic and metabolic levels. We derive a tardigrade-specific metabolic network represented as an undirected graph with 3,658 nodes (metabolites) and 4,378 edges (reactions). Time course metabolite profiles are used to score the network nodes showing a significant change over time. The edges are scored according to information on enzymes from the EST data. Using this combined information, we identify a key subnetwork (functional module) of concerted changes in metabolic pathways, specific for de- and rehydration. The module is enriched in reactions showing significant changes in metabolite levels and enzyme abundance during the transition. It resembles the cessation of a measurablemetabolism (e.g. glycolysis and amino acid anabolism) during the tun formation, the production of storage metabolites and bioprotectants, such as DNA stabilizers, and the generation of amino acids and cellular components from monosaccharides as carbon and energy source during rehydration. Conclusions: The functional module identifies relationships among changed metabolites (e.g. spermidine) and reactions and provides first insights into important altered metabolic pathways. With sparse and diverse data available, the presented integrated metabolite network approach is suitable to integrate all existing data and analyse it in a combined manner.
KW  - Milnesium tardigradum
KW  - Integrated network analysis
KW  - Functional modules
KW  - Metabolic profiles
KW  - Metabolic pathways
KW  - Trend test
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75241
ER  - 
TY  - JOUR
A1  - Gattenlöhner, S.
A1  - Etschmann, B.
A1  - Kunzmann, V.
A1  - Thalheimer, A.
A1  - Hack, M.
A1  - Kleber, G.
A1  - Einsele, H.
A1  - Germer, C.
A1  - Müller-Hermelink, H.-K.
T1  - Concordance of KRAS/BRAF Mutation Status in Metastatic Colorectal Cancer before and after Anti-EGFR Therapy
N2  - Anti-EGFR targeted therapy is a potent strategy in the treatment of metastatic colorectal cancer (mCRC) but activating mutations in the KRAS gene are associated with poor response to this treatment. Therefore, KRAS mutation analysis is employed in the selection of patients for EGFR-targeted therapy and various studies have shown a high concordance between the mutation status in primary CRC and corresponding metastases. However, although development of therapy related resistance occurs also in the context of novel drugs such as tyrosine kinase-inhibitors the effect of the anti-EGFR treatment on the KRAS/BRAF mutation status itself in recurrent mCRC has not yet been clarified. Therefore, we analyzed 21mCRCs before/after anti-EGFR therapy and found a pre-/posttherapeutic concordance of the KRAS/BRAF mutation status in 20 of the 21 cases examined. In the one discordant case, further analyses revealed that a tumor mosaicism or multiple primary tumors were present, indicating that anti-EGFR therapy has no influence on KRAS/BRAF mutation status in mCRC. Moreover, as the preselection of patients with a KRASwt genotype for anti-EGFR therapy has become a standard procedure, sample sets such ours might be the basis for future studies addressing the identification of potential anti-EGFR therapy induced genetic alterations apart from KRAS/BRAF mutations.
KW  - Krebs
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68240
ER  - 
TY  - JOUR
A1  - Adam, W.
A1  - Ahrweiler, M.
A1  - Saha-Möller, C. R.
A1  - Sauter, M.
A1  - Schönberger, A.
A1  - Epe, B.
A1  - Müller, E.
A1  - Schiffmann, D.
A1  - Stopper, Helga
A1  - Wild, D.
T1  - Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells
N2  - 1.2-Dioxetanes, very reactive and high energy molecules. are involved as labile intermediates in dioxygenase- activated aerobic metabolism and in physiological processes. Various toxico1ogica1 tests reveal that dioxetanes are indeed genotoxic. In supercoiled DNA of bacteriophage PM2 they induce endonucleasesensitive sites, most of them are FPG protein-sensitive base modifications (8-hydroxyguanine, fonnamidopyrimidines). Pyrimidinedimersand sites ofbase loss (AP sites) which were probed by UV endonuclease and exonuclease 111 are minor lesions in this system. While the alky1-substituted dioxetanes do not show any significant mutagenic activity in different Salmonella typhimurium strains, heteroarene dioxetanes such as benzofuran and furocoumarin dioxetanes are strongly mutagenic in S. typhimurium strain TA I 00. DNA adducts formed with an intermediary alkyJating agent appear to be responsible for the mutagenic activity of benzofuran dioxetane. We assume that the benzofuran epoxides, generated in situ from benzofuran dioxetanes by deoxygenation are the ultimate mutagens of the latter. since benzofuran epoxides are highly mutagenic in the S. typhimurium strain TAIOO and they form DNA adducts. as detected by the 212Ppostlabelling technique. Our results imply that the type of D NA darnage promoted by dioxetanes is dependent on the structural feature of dioxetanes. Furthermore, the direct photochemical DNA darnage by energy transfer. i.e., pyrimidine dimers, plays a minor role in the genotoxicity of dioxetanes. Instead, photooxidation dominates in isolated DNA. while radical darnage and alkylation prevail in the cellular system.
KW  - Toxikologie
KW  - 1
KW  - 2-Dioxetane
KW  - Benzefuran dioxetane
KW  - Benzefuran epoxide
KW  - DNA damage
KW  - Mutagenicity
KW  - DNA adduct . Repair endonuclease
KW  - FPG protein
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63420
ER  - 
TY  - CHAP
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Müller-Ruchholtz, W.
T1  - Enzyme Kinetics of Commercial Collagenases and their Influence on Porcine Islet Isolation
N2  - No abstract available
KW  - Heterotransplantation
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45488
ER  - 
TY  - CHAP
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Eckstein, V.
A1  - Müller-Ruchholtz, W.
T1  - Xenogeneic Cellular Response of  Human Lymphocytes Against Porcine Lymphocytes and Isolated Pancreatic Islets
N2  - no abstract available
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45479
ER  - 
TY  - JOUR
A1  - Ulrichs, Karin
A1  - Bosse, M.
A1  - Wacker, HH
A1  - Heiser, A.
A1  - Müller-Ruchholtz, W.
T1  - Histologic analysis of the porcine pancreas to improve islet yield and integrity after collagenase digestion
N2  - No abstract available
KW  - Chirurgie
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45166
ER  - 
TY  - JOUR
A1  - Ulrichs, Karin
A1  - Deltz, E.
A1  - Thiede, A.
A1  - Müller-Ruchholtz, W.
T1  - Lymphoid tissue transplantation in rats leads to a GVHR, inducing a specific T-cell mediated autoreactivity against MHC-antigens
N2  - No abstract available
Y1  - 1982
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45420
ER  - 
TY  - JOUR
A1  - Breitkreuz, A.
A1  - Ulrichs, Karin
A1  - Eckstein, V.
A1  - Müller-Ruchholz, W.
T1  - Long-term suppression of natural and graft-induced xenophile antibodies by short-term antigen-cyclophosphamide treatment
N2  - No abstract available
KW  - Chirurgie
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45262
ER  - 
TY  - JOUR
A1  - Engemann, R.
A1  - Ulrichs, Karin
A1  - Thiede, A.
A1  - Müller-Ruchholtz, W.
A1  - Hamelmann, H.
T1  - Value of a physiological liver transplant model in rats. Induction of specific graft tolerance in a fully allogeneic strain combination
N2  - No abstract available
Y1  - 1990
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45622
ER  - 
TY  - JOUR
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Müller-Ruchholtz, W.
T1  - Prophylactic trypsin inhibition during the isolation procedure guarantees reproducible, high porcine islet yields
N2  - Abstract: For isolating islets from the porcine pancreas, we established a semiautomated digestion method. Although the isolation technique was standardized and collagenase of controlled quality was used, until now the reproducibility of high islet yields was unsatisfactory. Our hypothesis was that pancreatic trypsin was responsible for this failure. The aim of this study was to investigate the effect of endogenous trypsin on islet yield. Our results demonstrate that a high trypsin level correlates with poor islet yield, whereas low trypsin activity always correlates with high islet yield. Specific inhibition of trypsin results in low trypsin activity and reproducible, high islet yields.
KW  - islets of Langerhans
KW  - xenogenic transplantation
KW  - swine
KW  - enzyme activation
KW  - enzyme inhibitors
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45531
ER  - 
TY  - CHAP
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Eckstein, V.
A1  - Müller-Ruchholtz, W.
T1  - The Human Cell Mediated Response to Xenogeneic (Porcine) Transplantation Antigen Depends on the Stimulator Cell Compartment
N2  - No abstract available
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45670
ER  - 
TY  - CHAP
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Müller-Ruchholtz, W.
T1  - Enzyme Activities in Commercial Collagenase Preparations and Their Kinetics During Islet Isolation Procedure
N2  - No abstract available
KW  - Transplantation
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45633
ER  - 
TY  - JOUR
A1  - Koch, R.
A1  - Deger, A.
A1  - Klotz, Karl-Norbert
A1  - Schenzle, D.
A1  - Krämer, H.
A1  - Kelm, S.
A1  - Müller, G.
A1  - Rapp, R.
A1  - Weber, U.
T1  - Characterization of solubilized insulin receptors from rat liver microsomes. Existence of two receptor species with  different binding properties
N2  - Insulin receptors were solubilized from rat liver microsomes by the nonionic detergent Triton X-100. After gel filtration of the extract on Sepharose CL-6B, two insulin-binding species (peak I and peak li) were obtained. The structure and binding properties of both peaks were characterized. Gel filtration yielded Stokes radii of 9.2 nm (peak I) and 8.0 nm (peak Il). Both peaks were glycoproteins. At 4°C peak 1 showed optimal insulin binding at pH 8.0 and high ionic strength. In contrast, peak li bad its binding optimum at pH 7.0 and low ionic strength, where peak I bindingwas minimal. For peak I the change in insulin binding under different conditions of pH and ionic strength was due to a change in receptor affinity only. For peak 11 an additional change in receptor number was found. Both peaks yielded non-linear Scatchard plots under most of the buffer conditions examined. At their binding optima at 4 oc the high affinity dissociation constants were 0.50 nM (peak I) and 0.55 nM (peak II). Sodium dodecyl sulfatejpolyacrylamide gel electrophoresis of peak I revealed five receptor bands with Mr 400000, 365000, 320000, 290000, and 245000 under non-reducing conditions. For peak II two major receptor bands with M\(_r\) 210000 and 115000 were found. The peak II receptor bands were also obtained aftermild reduction of peak I. After complete reduction both peaks showed one major receptor band with M\(_r\) 130000. The reductive generation of the peak II receptor together with molecular mass estimations suggest that the peak I receptor is the disulfide-linked dimer of the peak II receptor. Thus, Triton extracts from rat liver microsomes contain two receptor species, which are related, but differ considerably in their size and insulin-binding properties.
KW  - Toxikologie
Y1  - 1986
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60215
ER  - 
TY  - JOUR
A1  - Brinkmann, R.
A1  - Schwinn, A.
A1  - Müller, J.
A1  - Stahl-Hennig, C.
A1  - Coulibaly, C.
A1  - Hunsmann, G.
A1  - Czub, S.
A1  - Rethwilm, Axel
A1  - Dörries, R.
A1  - ter Meulen, Volker
T1  - In vitro and in vivo infection of rhesus monkey microglial cells by simian immunodeficiency virus
N2  - The observation that microglial cells in brain tissue are probably a major target for human immunodeficiency virus (HIV) infection has raised interest in the pathogenic role of this cell population for the development of neuro-AIOS. Since it is very difficult to obtain microglia from normal or diseased human brain we studied microglial cells isolated from fresh brain tissue of uninfected and simian immunodeficiency virus (SIV) infected rhesus monkeys (Macacca mulatta) in comparison to peripheral blood macrophages. Besides the characterization of the phenotypes of these two cell populations, we examined the replication of SIV in the cells in addition to the effect of viral infection on the expression of cell surface molecules. We found that microglia and macrophages support replication of the wild-type SIV\(_{mac25}\), strain as well as the infectious clone (SIV\(_239\)). Infectious viruswas produced and a CPE developed. Isolated microglial cells from SIV-infected monkeys were latently infected independent of the presence of neuropathological lesions and produced infectious virus after 20-25 days in culture. In situ hybridization revealed that only a small percentage of isolated microglial cells are productively infected in vivo, yet the majority of these expressed MHC class II molecules. This indicated a state of activation that is acquired in vivo. These findings indicate that microglia are a prime target cell for SIV infection in CNS tissue.
KW  - Virologie
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61415
ER  - 
TY  - JOUR
A1  - Förster, Frank
A1  - Beisser, Daniela
A1  - Grohme, Markus A.
A1  - Liang, Chunguang
A1  - Mali, Brahim
A1  - Siegl, Alexander Matthias
A1  - Engelmann, Julia C.
A1  - Shkumatov, Alexander V.
A1  - Schokraie, Elham
A1  - Müller, Tobias
A1  - Schnölzer, Martina
A1  - Schill, Ralph O.
A1  - Frohme, Marcus
A1  - Dandekar, Thomas
T1  - Transcriptome analysis in tardigrade species reveals specific molecular pathways for stress adaptations
JF  - Bioinformatics and biology insights
N2  - Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade \(Milnesium\) \(tardigradum\) were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from \(Hypsibius\) \(dujardini\), revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for \(M.\) \(tardigradum\) are different from typical motifs known from higher animals. \(M.\) \(tardigradum\) and \(H.\) \(dujardini\) protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of \(M.\) \(tardigradum\). These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and \(M.\) \(tardigradum\) in particular so highly stress resistant.
KW  - RNA
KW  - expressed sequence tag
KW  - cluster
KW  - protein familiy
KW  - adaption
KW  - tardigrada
KW  - transcriptome
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123089
N1  - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
VL  - 6
ER  - 
TY  - JOUR
A1  - Buder, Kristina
A1  - Müller, Philip A.
A1  - Beekmann, Gabriele
A1  - Ugurel, Selma
A1  - Bröcker, Eva-Bettina
A1  - Becker, Jürgen C.
T1  - Denileukin Diftitox plus Total Skin Electron Beam Radiation in Patients with Treatment-refractory Cutaneous T-cell Lymphoma (Mycosis Fungoides): Report of Four Cases
JF  - Acta Dermato-Venereologica
N2  - Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL) (1). Most patients initially respond well to standard therapy, but advanced MF is often treatment refractory. Thus, a combination of the available treatment options is an important strategy. Total skin electron beam radiation (TSEB) is effective in MF, with a complete remission rate of up to 90% in the early stages. However, in patients with more advanced stages, remission rates are considerably lower (2, 3). Denileukin diftitox (DD) (Ontak®) is a recombinant fusion protein of the receptor-binding domain of interleukin (IL)-2 and the enzymatic and translocation domains of diphtheria toxin (4). It targets the alpha-subunit of the IL-2-receptor (CD25). There are no reports on this combination therapy in MF.
KW  - lymphoma
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120091
N1  - Der Zugang zum Volltext ist aus rechtlichen Gründen gesperrt.
VL  - 94
ER  - 
TY  - JOUR
A1  - Staiger, Christine
A1  - Cadot, Sidney
A1  - Kooter, Raul
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Klau, Gunnar W.
A1  - Wessels, Lodewyk F. A.
T1  - A Critical Evaluation of Network and Pathway-Based Classifiers for Outcome Prediction in Breast Cancer
JF  - PLoS One
N2  - Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single genes classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single genes classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single genes classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single genes sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single genes classifiers for predicting outcome in breast cancer.
KW  - modules
KW  - protein-interaction networks
KW  - expression signature
KW  - classification
KW  - set
KW  - metastasis
KW  - stability
KW  - survival
KW  - database
KW  - markers
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131323
VL  - 7
IS  - 4
ER  - 
TY  - JOUR
A1  - Ludwig, K. U.
A1  - Sämann, P.
A1  - Alexander, M.
A1  - Becker, J.
A1  - Bruder, J.
A1  - Moll, K.
A1  - Spieler, D.
A1  - Czisch, M.
A1  - Warnke, A.
A1  - Docherty, S. J.
A1  - Davis, O. S. P.
A1  - Plomin, R.
A1  - Nöthen, M. M.
A1  - Landerl, K.
A1  - Müller-Myhsok, B.
A1  - Hoffmann, P.
A1  - Schumacher, J.
A1  - Schulte-Körne, G.
A1  - Czamara, D.
T1  - A common variant in Myosin-18B contributes to mathematical abilities in children with dyslexia and intraparietal sulcus variability in adults
JF  - Translational Psychiatry
N2  - The ability to perform mathematical tasks is required in everyday life. Although heritability estimates suggest a genetic contribution, no previous study has conclusively identified a genetic risk variant for mathematical performance. Research has shown that the prevalence of mathematical disabilities is increased in children with dyslexia. We therefore correlated genome-wide data of 200 German children with spelling disability, with available quantitative data on mathematic ability. Replication of the top findings in additional dyslexia samples revealed that rs133885 was a genome-wide significant marker for mathematical abilities\((P_{comb}=7.71 x 10^{-10}, n=699)\), with an effect size of 4.87%. This association was also found in a sample from the general population (P=0.048, n=1080), albeit with a lower effect size. The identified variant encodes an amino-acid substitution in MYO18B, a protein with as yet unknown functions in the brain. As areas of the parietal cortex, in particular the intraparietal sulcus (IPS), are involved in numerical processing in humans, we investigated whether rs133885 was associated with IPS morphology using structural magnetic resonance imaging data from 79 neuropsychiatrically healthy adults. Carriers of the MYO18B risk-genotype displayed a significantly lower depth of the right IPS. This validates the identified association between rs133885 and mathematical disability at the level of a specific intermediate phenotype.
KW  - disability
KW  - sulcal morphology
KW  - prelevance
KW  - identification
KW  - brain
KW  - cancer
KW  - association
KW  - developmental dyscalculia
KW  - tumor-suppressor gene
KW  - correlate
KW  - disorders
KW  - dyscalculia
KW  - dyslexia
KW  - genomic imaging
KW  - mathematics
KW  - quantitative trait
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131513
N1  - Supplementary Information accompanies the paper on the Translational Psychiatry website (http://www.nature.com/tp).
VL  - 3
IS  - e229
ER  - 
TY  - JOUR
A1  - Huang, Bei
A1  - Belharazem, Djeda
A1  - Li, Li
A1  - Kneitz, Susanne
A1  - Schnabel, Philipp A.
A1  - Rieker, Ralf J.
A1  - Körner, Daniel
A1  - Nix, Wilfried
A1  - Schalke, Berthold
A1  - Müller-Hermelink, Hans Konrad
A1  - Ott, German
A1  - Rosenwald, Andreas
A1  - Ströbel, Philipp
A1  - Marx, Alexander
T1  - Anti-apoptotic signature in thymic squamous cell carcinomas – functional relevance of anti-apoptotic BIRC3 expression in the thymic carcinoma cell line 1889c
JF  - Frontiers in Oncology
N2  - The molecular pathogenesis of thymomas and thymic arcinomas (TCs) is poorly understood and results of adjuvant therapy are unsatisfactory in case of metastatic disease and tumor recurrence. For these clinical settings, novel therapeutic strategies are urgently needed. Recently, limited sequencing efforts revealed that a broad spectrum of genes that play key roles in various common cancers are rarely affected in thymomas and TCs, suggesting that other oncogenic principles might be important.This made us re-analyze historic expression data obtained in a spectrumof thymomas and thymic squamous cell carcinomas (TSCCs) with a custom-made cDNA microarray. By cluster analysis, different anti-apoptotic signatures were detected in type B3 thymoma and TSCC, including overexpression of BIRC3 in TSCCs. This was confirmed by qRT-PCR in the original and an independent validation set of tumors. In contrast to several other cancer cell lines, the BIRC3-positive TSCC cell line, 1889c showed spontaneous apoptosis after BIRC3 knock-down. Targeting apoptosis genes is worth testing as therapeutic principle in TSCC.
KW  - gene expression
KW  - MTCH2
KW  - targeted
KW  - myasthenia gravis
KW  - apoptosis
KW  - thymus
KW  - thymoma
KW  - thymic carcinoma
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132214
VL  - 3
IS  - 316
ER  - 
TY  - JOUR
A1  - Schwarz, Tobias
A1  - Remer, Katharina A.
A1  - Nahrendorf, Wiebke
A1  - Masic, Anita
A1  - Siewe, Lisa
A1  - Müller, Werner
A1  - Roers, Axel
A1  - Moll, Heidrun
T1  - T Cell-Derived IL-10 Determines Leishmaniasis Disease Outcome and Is Suppressed by a Dendritic Cell Based Vaccine
JF  - PLoS Pathogens
N2  - Abstract
In the murine model of Leishmania major infection, resistance or susceptibility to the parasite has been associated with the development of a Th1 or Th2 type of immune response. Recently, however, the immunosuppressive effects of IL-10 have been ascribed a crucial role in the development of the different clinical correlates of Leishmania infection in humans. Since T cells and professional APC are important cellular sources of IL-10, we compared leishmaniasis disease progression in T cell-specific, macrophage/neutrophil-specific and complete IL-10-deficient C57BL/6 as well as T cell-specific and complete IL-10-deficient BALB/c mice. As early as two weeks after infection of these mice with L. major, T cell-specific and complete IL-10-deficient animals showed significantly increased lesion development accompanied by a markedly elevated secretion of IFN-γ or IFN-γ and IL-4 in the lymph nodes draining the lesions of the C57BL/6 or BALB/c mutants, respectively. In contrast, macrophage/neutrophil-specific IL-10-deficient C57BL/6 mice did not show any altered phenotype. During the further course of disease, the T cell-specific as well as the complete IL-10-deficient BALB/c mice were able to control the infection. Furthermore, a dendritic cell-based vaccination against leishmaniasis efficiently suppresses the early secretion of IL-10, thus contributing to the control of parasite spread. Taken together, IL-10 secretion by T cells has an influence on immune activation early after infection and is sufficient to render BALB/c mice susceptible to an uncontrolled Leishmania major infection.

Author Summary
The clinical symptoms caused by infections with Leishmania parasites range from self-healing cutaneous to uncontrolled visceral disease and depend not only on the parasite species but also on the type of the host's immune response. It is estimated that 350 million people worldwide are at risk, with a global incidence of 1–1.5 million cases of cutaneous and 500,000 cases of visceral leishmaniasis. Murine leishmaniasis is the best-characterized model to elucidate the mechanisms underlying resistance or susceptibility to Leishmania major parasites in vivo. Using T cell-specific and macrophage-specific mutant mice, we demonstrate that abrogating the secretion of the immunosuppressive cytokine IL-10 by T cells is sufficient to render otherwise susceptible mice resistant to an infection with the pathogen. The healing phenotype is accompanied by an elevated specific inflammatory immune response very early after infection. We further show that dendritic cell-based vaccination against leishmaniasis suppresses the early secretion of IL-10 following challenge infection. Thus, our study unravels a molecular mechanism critical for host immune defense, aiding in the development of an effective vaccine against leishmaniasis.
KW  - cytokines
KW  - mouse models
KW  - T cells
KW  - lymph nodes
KW  - leishmania major
KW  - secretion
KW  - parasitic diseases
KW  - immune response
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130385
VL  - 9
IS  - 6
ER  - 
TY  - JOUR
A1  - Diestel, Uschi
A1  - Resch, Marcus
A1  - Meinhardt, Kathrin
A1  - Weiler, Sigrid
A1  - Hellmann, Tina V.
A1  - Mueller, Thomas D.
A1  - Nickel, Joachim
A1  - Eichler, Jutta
A1  - Muller, Yves A.
T1  - Identification of a Novel TGF-beta-Binding Site in the Zona Pellucida C-terminal (ZP-C) Domain of TGF-\(\beta\)-Receptor-3 (TGFR-3)
JF  - PLoS ONE
N2  - The zona pellucida (ZP) domain is present in extracellular proteins such as the zona pellucida proteins and tectorins and participates in the formation of polymeric protein networks. However, the ZP domain also occurs in the cytokine signaling co-receptor transforming growth factor beta (TGF-\(\beta\)) receptor type 3 (TGFR-3, also known as betaglycan) where it contributes to cytokine ligand recognition. Currently it is unclear how the ZP domain architecture enables this dual functionality. Here, we identify a novel major TGF-beta-binding site in the FG loop of the C-terminal subdomain of the murine TGFR-3 ZP domain (ZP-C) using protein crystallography, limited proteolysis experiments, surface plasmon resonance measurements and synthetic peptides. In the murine 2.7 angstrom crystal structure that we are presenting here, the FG-loop is disordered, however, well-ordered in a recently reported homologous rat ZP-C structure. Surprisingly, the adjacent external hydrophobic patch (EHP) segment is registered differently in the rat and murine structures suggesting that this segment only loosely associates with the remaining ZP-C fold. Such a flexible and temporarily-modulated association of the EHP segment with the ZP domain has been proposed to control the polymerization of ZP domain-containing proteins. Our findings suggest that this flexibility also extends to the ZP domain of TGFR-3 and might facilitate co-receptor ligand interaction and presentation via the adjacent FG-loop. This hints that a similar C-terminal region of the ZP domain architecture possibly regulates both the polymerization of extracellular matrix proteins and cytokine ligand recognition of TGFR-3.
KW  - coreceptor
KW  - receptor type III
KW  - growth factor beta
KW  - ligand binding
KW  - betaglycan
KW  - proteins
KW  - mutagenesis
KW  - polymerization
KW  - glycoprotein
KW  - superfamily
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130904
VL  - 8
IS  - 6
ER  - 
TY  - JOUR
A1  - Hennings, Johannes M.
A1  - Kohli, Martin A.
A1  - Czamara, Darina
A1  - Giese, Maria
A1  - Eckert, Anne
A1  - Wolf, Christiane
A1  - Heck, Angela
A1  - Domschke, Katharina
A1  - Arolt, Volker
A1  - Baune, Bernhard T.
A1  - Horstmann, Sonja
A1  - Brückl, Tanja
A1  - Klengel, Torsten
A1  - Menke, Andreas
A1  - Müller-Myhsok, Bertram
A1  - Ising, Marcus
A1  - Uhr, Manfred
A1  - Lucae, Susanne
T1  - Possible Associations of NTRK2 Polymorphisms with Antidepressant Treatment Outcome: Findings from an Extended Tag SNP Approach
JF  - PLoS ONE
N2  - Background: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment.
Methods: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples.
Results: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (\(P_{corr}\) = .018, \(P_{corr}\) = .015 and \(P_{corr}\) = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients.
Conclusions/Limitations: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies.
KW  - brain
KW  - bipolar disorder
KW  - mood disorder
KW  - treatment response
KW  - genome-wide association
KW  - major depressive disorder
KW  - neurotrophic factor gene
KW  - VAL66MET polymorphism
KW  - sequence variations
KW  - messenger RNA
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130924
VL  - 8
IS  - 6
ER  - 
TY  - JOUR
A1  - Semmler, Anna-Lena
A1  - Sacconi, Sabrina
A1  - Bach, J. Elisa
A1  - Liebe, Claus
A1  - Bürmann, Jan
A1  - Kley, Rudolf A.
A1  - Ferbert, Andreas
A1  - Anderheiden, Roland
A1  - Van den Bergh, Peter
A1  - Martin, Jean-Jacques
A1  - De Jonghe, Peter
A1  - Neuen-Jacob, Eva
A1  - Müller, Oliver
A1  - Deschauer, Marcus
A1  - Bergmann, Markus
A1  - Schröder, J. Michael
A1  - Vorgerd, Matthias
A1  - Schulz, Jörg B.
A1  - Weis, Joachim
A1  - Kress, Wolfram
A1  - Claeys, Kristl G.
T1  - Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies
JF  - Orphanet Journal of Rare Diseases
N2  - Background: Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement. 
Methods: We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms. 
Results: We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p. Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p. Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%). 
Conclusions: We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.
KW  - polyneuropathy
KW  - MFM
KW  - next generation sequencing
KW  - bcl-2 associated athanogene protein 3
KW  - protein aggregation
KW  - hearing impairment
KW  - early respiratory-failure
KW  - myopathy
KW  - muscular-dystrophy
KW  - skeletal myopathy
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115623
SN  - 1750-1172
N1  - Additional files are available here: http://www.ojrd.com/content/9/1/121/additional
VL  - 9
IS  - 121
ER  - 
TY  - JOUR
A1  - Morris, E. Kathryn
A1  - Caruso, Tancredi
A1  - Buscot, Francois
A1  - Fischer, Markus
A1  - Hancock, Christine
A1  - Maier, Tanja S.
A1  - Meiners, Torsten
A1  - Müller, Caroline
A1  - Obermaier, Elisabeth
A1  - Prati, Daniel
A1  - Socher, Stephanie A.
A1  - Sonnemann, Ilja
A1  - Wäschke, Nicola
A1  - Wubet, Tesfaye
A1  - Wurst, Susanne
A1  - Rillig, Matthias C.
T1  - Choosing and using diversity indices: insights for ecological applications from the German Biodiversity Exploratories
JF  - Ecology and Evolution
N2  - Biodiversity, a multidimensional property of natural systems, is difficult to quantify partly because of the multitude of indices proposed for this purpose. Indices aim to describe general properties of communities that allow us to compare different regions, taxa, and trophic levels. Therefore, they are of fundamental importance for environmental monitoring and conservation, although there is no consensus about which indices are more appropriate and informative. We tested several common diversity indices in a range of simple to complex statistical analyses in order to determine whether some were better suited for certain analyses than others. We used data collected around the focal plant Plantago lanceolata on 60 temperate grassland plots embedded in an agricultural landscape to explore relationships between the common diversity indices of species richness (S), Shannon's diversity (H'), Simpson's diversity (D-1), Simpson's dominance (D-2), Simpson's evenness (E), and Berger-Parker dominance (BP). We calculated each of these indices for herbaceous plants, arbuscular mycorrhizal fungi, aboveground arthropods, belowground insect larvae, and P.lanceolata molecular and chemical diversity. Including these trait-based measures of diversity allowed us to test whether or not they behaved similarly to the better studied species diversity. We used path analysis to determine whether compound indices detected more relationships between diversities of different organisms and traits than more basic indices. In the path models, more paths were significant when using H', even though all models except that with E were equally reliable. This demonstrates that while common diversity indices may appear interchangeable in simple analyses, when considering complex interactions, the choice of index can profoundly alter the interpretation of results. Data mining in order to identify the index producing the most significant results should be avoided, but simultaneously considering analyses using multiple indices can provide greater insight into the interactions in a system.
KW  - molecular diversity
KW  - plant diversity
KW  - plantago lanceolata
KW  - shannon index
KW  - simpson's index
KW  - arbuscular mycorrhizal fungi
KW  - Hill's powers
KW  - chemical diversity
KW  - Berger-Parker
KW  - arthropods
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115462
SN  - 2045-7758
VL  - 4
IS  - 18
ER  - 
TY  - JOUR
A1  - Peter, Stefanie
A1  - Bultinck, Jennyfer
A1  - Myant, Kevin
A1  - Jaenicke, Laura A.
A1  - Walz, Susanne
A1  - Müller, Judith
A1  - Gmachl, Michael
A1  - Treu, Matthias
A1  - Boehmelt, Guido
A1  - Ade, Casten P.
A1  - Schmitz, Werner
A1  - Wiegering, Armin
A1  - Otto, Christoph
A1  - Popov, Nikita
A1  - Sansom, Owen
A1  - Kraut, Norbert
A1  - Eilers, Martin
T1  - H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase
JF  - EMBO Molecular Medicine
N2  - Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.
KW  - colorectal cancer
KW  - HUWE1
KW  - MIZ1
KW  - MYC
KW  - ubiquitination
KW  - cancer
KW  - digestive system
KW  - pharmacology
KW  - drug discovery
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118132
SN  - 1757-4684
VL  - 6
IS  - 12
ER  - 
TY  - JOUR
A1  - Boschert, Verena
A1  - Klenk, Nicola
A1  - Abt, Alexander
A1  - Raman, Sudha Janaki
A1  - Fischer, Markus
A1  - Brands, Roman C.
A1  - Seher, Axel
A1  - Linz, Christian
A1  - Müller-Richter, Urs D. A.
A1  - Bischler, Thorsten
A1  - Hartmann, Stefan
T1  - The influence of Met receptor level on HGF-induced glycolytic reprogramming in head and neck squamous cell carcinoma
JF  - International Journal of Molecular Sciences
N2  - Head and neck squamous cell carcinoma (HNSCC) is known to overexpress a variety of receptor tyrosine kinases, such as the HGF receptor Met. Like other malignancies, HNSCC involves a mutual interaction between the tumor cells and surrounding tissues and cells. We hypothesized that activation of HGF/Met signaling in HNSCC influences glucose metabolism and therefore substantially changes the tumor microenvironment. To determine the effect of HGF, we submitted three established HNSCC cell lines to mRNA sequencing. Dynamic changes in glucose metabolism were measured in real time by an extracellular flux analyzer. As expected, the cell lines exhibited different levels of Met and responded differently to HGF stimulation. As confirmed by mRNA sequencing, the level of Met expression was associated with the number of upregulated HGF-dependent genes. Overall, Met stimulation by HGF leads to increased glycolysis, presumably mediated by higher expression of three key enzymes of glycolysis. These effects appear to be stronger in Met\(^{high}\)-expressing HNSCC cells. Collectively, our data support the hypothesized role of HGF/Met signaling in metabolic reprogramming of HNSCC.
KW  - HNSCC
KW  - head and neck cancer
KW  - HGF
KW  - Met
KW  - cancer metabolism
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235995
SN  - 1422-0067
VL  - 21
IS  - 2
ER  - 
TY  - JOUR
A1  - Sweeney, Reinhart A.
A1  - Seubert, Benedikt
A1  - Stark, Silke
A1  - Homann, Vanessa
A1  - Müller, Gerd
A1  - Flentje, Michael
A1  - Guckenbeger, Matthias
T1  - Accuracy and inter-observer variability of 3D versus 4D cone-beam CT based image-guidance in SBRT for lung tumors
N2  - Background: To analyze the accuracy and inter-observer variability of image-guidance (IG) using 3D or 4D cone-beam CT (CBCT) technology in stereotactic body radiotherapy (SBRT) for lung tumors. Materials and methods: Twenty-one consecutive patients treated with image-guided SBRT for primary and secondary lung tumors were basis for this study. A respiration correlated 4D-CT and planning contours served as reference for all IG techniques. Three IG techniques were performed independently by three radiation oncologists (ROs) and three radiotherapy technicians (RTTs). Image-guidance using respiration correlated 4D-CBCT (IG-4D) with automatic registration of the planning 4D-CT and the verification 4D-CBCT was considered gold-standard. Results were compared with two IG techniques using 3D-CBCT: 1) manual registration of the planning internal target volume (ITV) contour and the motion blurred tumor in the 3D-CBCT (IG-ITV); 2) automatic registration of the planning reference CT image and the verification 3D-CBCT (IG-3D). Image quality of 3D-CBCT and 4D-CBCT images was scored on a scale of 1–3, with 1 being best and 3 being worst quality for visual verification of the IGRT results. Results: Image quality was scored significantly worse for 3D-CBCT compared to 4D-CBCT: the worst score of 3 was given in 19 % and 7.1 % observations, respectively. Significant differences in target localization were observed between 4D-CBCT and 3D-CBCT based IG: compared to the reference of IG-4D, tumor positions differed by 1.9 mm± 0.9 mm (3D vector) on average using IG-ITV and by 3.6 mm± 3.2 mm using IG-3D; results of IG-ITV were significantly closer to the reference IG-4D compared to IG-3D. Differences between the 4D-CBCT and 3D-CBCT techniques increased significantly with larger motion amplitude of the tumor; analogously, differences increased with worse 3D-CBCT image quality scores. Inter-observer variability was largest in SI direction and was significantly larger in IG using 3D-CBCT compared to 4D-CBCT: 0.6 mm versus 1.5 mm (one standard deviation). Inter-observer variability was not different between the three ROs compared to the three RTTs. Conclusions: Respiration correlated 4D-CBCT improves the accuracy of image-guidance by more precise target localization in the presence of breathing induced target motion and by reduced inter-observer variability.
KW  - Medizin
KW  - Lung cancer
KW  - Image-guidance
KW  - Cone-beam CT
KW  - Inter-observer variability
KW  - Respiration correlated imaging
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75698
ER  - 
TY  - JOUR
A1  - Krzymanski, M.
A1  - Waaga, A. M.
A1  - Ulrichs, Karin
A1  - Müller-Ruchholtz, Wolfgang
T1  - Long-standing rat kidney graft survival by a combination of organ perfusion with MHC class II monoclonal antibody and immunosuppression with reduced doses of 15-deoxyspergualin.
N2  - No abstract available
KW  - Niere
KW  - Ratte
KW  - MHC Klasse II
KW  - kidney
KW  - rat
Y1  - 1991
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64442
ER  - 
TY  - JOUR
A1  - Hendricks, Anne
A1  - Müller, Sophie
A1  - Fassnacht, Martin
A1  - Germer, Christoph-Thomas
A1  - Wiegering, Verena A.
A1  - Wiegering, Armin
A1  - Reibetanz, Joachim
T1  - Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma — a systematic review and meta-analysis
JF  - Cancers
N2  - (1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I–III) and those including all tumor stages (I–IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001–2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26–0.68). Based on results of studies including patients with ACC stage I–IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70–1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I–III).
KW  - adrenocortical carcinoma
KW  - adrenal cancer
KW  - lymphadenectomy
KW  - lymph node dissection
KW  - LND
KW  - LNE
KW  - review
KW  - meta-analysis
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254798
SN  - 2072-6694
VL  - 14
IS  - 2
ER  - 
TY  - JOUR
A1  - Winoto-Morbach, S.
A1  - Krout, OS
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Müller-Ruchholtz, W.
T1  - Lectin binding to acinar tissue for complete magnetophoretic purification of porcine pancreatic islets depends on the composition and pH of the incubation medium
N2  - No abstract available
KW  - Chirurgie
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45183
ER  - 
TY  - JOUR
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Müller-Ruchholtz, W.
T1  - Influence of porcine strain, age, and pH of the isolation medium on porcine pancreatic islet isolation success
N2  - No abstract available
KW  - Chirurgie
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-45171
ER  - 
TY  - JOUR
A1  - Heiser, A.
A1  - Müller-Ruchholtz, W.
A1  - Ulrichs, Karin
T1  - Isolation of Islets of Langerhans: Improvement of the Isolation Technique Using the Pig Model.
N2  - During the last view years, interest in pancreatic islet transplantation for the cure of type I diabetes has increased markedly. A serious barrier to clinical islet transplantation is the isolation of a sufficient mass of viable and functional islets. We used a porcine islet isolation model to examine various parameters of the isolation procedure and to improve isolation technique.
KW  - Langerhans-Inseln
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-87765
ER  - 
TY  - JOUR
A1  - Ulrichs, Karin
A1  - Eckstein, V.
A1  - Heiser, A.
A1  - Müller-Ruchholtz, W.
T1  - Die zellvermittelte Immunantwort des menschlichen Transplantat Empfängers gegen xenogenes Antigen (Schwein) ist abhängig vom Spenderkompartiment.
N2  - No abstract available.
KW  - Transplantation
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86978
ER  - 
TY  - JOUR
A1  - Breitkreuz, A.
A1  - Ulrichs, Karin
A1  - Eckstein, V.
A1  - Müller-Ruchholtz, W.
T1  - Induktion von Transplantat-Toleranz gegen Xenoantigen durch eine Pharmakon-Antigen-Kombinationsbehandlung
N2  - No abstract available.
KW  - Transplantat
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86969
ER  - 
TY  - JOUR
A1  - Heiser, A.
A1  - Ulrichs, Karin
A1  - Gier, C.
A1  - Müller-Ruchholtz, W.
T1  - Isolierung Langerhans'scher Inseln aus dem Pankreas von Schweinen: Einfluss biologischer und technischer Parameter auf die Inselausbeite und -integrität
N2  - No abstract available.
KW  - Langerhans-Inseln
KW  - Isolierung <Mikrobiologie>
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-73223
ER  - 
TY  - JOUR
A1  - Ulrichs, Karin
A1  - Heiser, A.
A1  - Bosse, M.
A1  - Wacker, H. H.
A1  - Müller-Ruchholtz, W.
T1  - Histologische Untersuchungen des Schweinepankreas zur Verbesserung der Inselausbeute und -integrität nach Kollagenase-Verdauung
N2  - No abstract available.
KW  - Schwein
KW  - Bauchspeicheldrüse
KW  - Histologie
KW  - Kollagenase
Y1  - 1993
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-73237
ER  - 
TY  - JOUR
A1  - Ulrichs, Karin
A1  - Eckstein, V.
A1  - Korsgren, O.
A1  - Tibell, A.
A1  - Groth, C. G.
A1  - Müller-Ruchholtz, W.
T1  - Characterization of natural and induced human xenophile antibodies before and after transplantation of the fetal porcine endocrine pancreas
N2  - No abstract available.
KW  - Bauspeicheldrüse
KW  - Antikörper
KW  - Transplantation
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86985
ER  - 
TY  - JOUR
A1  - Temme, Fabian
A1  - Adam, Jan
A1  - Ahnen, Max L.
A1  - Baack, Dominik
A1  - Balbo, Matteo
A1  - Bergmann, Matthias
A1  - Biland, Adrian
A1  - Blank, Michael
A1  - Bretz, Thomas
A1  - Brügge, Kai A.
A1  - Buss, Jens
A1  - Dmytriiev, Anton
A1  - Dorner, Daniela
A1  - Einecke, Sabrina
A1  - Hempfling, Christina
A1  - Hildebrand, Dorothee
A1  - Hughes, Gareth
A1  - Linhoff, Lena
A1  - Mannheim, Karl
A1  - Müller, Sebastian
A1  - Neise, Dominik
A1  - Neronov, Andrii
A1  - Nöthe, Max
A1  - Paravac, Aleksander
A1  - Pauss, Felicitas
A1  - Rhode, Wolfgang
A1  - Shukla, Amit
A1  - Thaele, Julia
A1  - Walter, Roland
T1  - Long-Term monitoring of bright blazars in the multi-GeV to TeV range with FACT
JF  - Galaxies
N2  - Blazars like Markarian 421 or Markarian 501 are active galactic nuclei (AGN), with their jets orientated towards the observer. They are among the brightest objects in the very high energy (VHE) gamma ray regime (>100 GeV). Their emitted gamma-ray fluxes are extremely variable, with changing activity levels on timescales between minutes, months, and even years. Several questions are part of the current research, such as the question of the emission regions or the engine of the AGN and the particle acceleration. A dedicated longterm monitoring program is necessary to investigate the properties of blazars in detail. A densely sampled and unbiased light curve allows for observation of both high and low states of the sources, and the combination with multi-wavelength observation could contribute to the answer of several questions mentioned above. FACT (First G-APD Cherenkov Telescope) is the first operational telescope using silicon photomultiplier (SiPM, also known as Geigermode—Avalanche Photo Diode, G-APD) as photon detectors. SiPM have a very homogenous and stable longterm performance, and allow operation even during full moon without any filter, leading to a maximal duty cycle for an Imaging Air Cherenkov Telescope (IACT). Hence, FACT is an ideal device for such a longterm monitoring of bright blazars. A small set of sources (e.g., Markarian 421, Markarian 501, 1ES 1959+650, and 1ES 2344+51.4) is currently being monitored. In this contribution, the FACT telescope and the concept of longterm monitoring of bright blazars will be introduced. The results of the monitoring program will be shown, and the advantages of densely sampled and unbiased light curves will be discussed.
KW  - Imaging Air Cherenkov Telescope
KW  - First G-APD Cherenkov Telescope
KW  - very high energy gamma rays
KW  - long-term monitoring
KW  - silicon photo multiplier
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-198088
SN  - 2075-4434
VL  - 5
IS  - 1
PB  - MDPI
ER  - 
TY  - JOUR
A1  - Uhler, Johannes
A1  - Haase, Peter
A1  - Hoffmann, Lara
A1  - Hothorn, Torsten
A1  - Schmidl, Jürgen
A1  - Stoll, Stefan
A1  - Welti, Ellen A. R.
A1  - Buse, Jörn
A1  - Müller, Jörg
T1  - A comparison of different Malaise trap types
JF  - Insect Conservation and Diversity
N2  - Recent reports on insect decline have highlighted the need for long‐term data on insect communities towards identifying their trends and drivers.
With the launch of many new insect monitoring schemes to investigate insect communities over large spatial and temporal scales, Malaise traps have become one of the most important tools due to the broad spectrum of species collected and reduced capture bias through passive sampling of insects day and night. However, Malaise traps can vary in size, shape, and colour, and it is unknown how these differences affect biomass, species richness, and composition of trap catch, making it difficult to compare results between studies.
We compared five Malaise trap types (three variations of the Townes and two variations of the Bartak Malaise trap) to determine their effects on biomass and species richness as identified by metabarcoding.
Insect biomass varied by 20%–55%, not strictly following trap size but varying with trap type. Total species richness was 20%–38% higher in the three Townes trap models compared to the Bartak traps. Bartak traps captured lower richness of highly mobile taxa but increased richness of ground‐dwelling taxa. The white roofed Townes trap captured a higher richness of pollinators.
We find that biomass, total richness, and taxa group specific richness are all sensitive to Malaise trap type. Trap type should be carefully considered and aligned to match monitoring and research questions. Additionally, our estimates of trap type effects can be used to adjust results to facilitate comparisons across studies.
KW  - Bartak
KW  - biodiversity
KW  - insect communities
KW  - insect monitoring
KW  - Malaise trap
KW  - Townes
KW  - trap selectivity
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-293694
VL  - 15
IS  - 6
SP  - 666
EP  - 672
ER  - 
TY  - JOUR
A1  - Graus, Dorothea
A1  - Li, Kunkun
A1  - Rathje, Jan M.
A1  - Ding, Meiqi
A1  - Krischke, Markus
A1  - Müller, Martin J.
A1  - Cuin, Tracey Ann
A1  - Al‐Rasheid, Khaled A. S.
A1  - Scherzer, Sönke
A1  - Marten, Irene
A1  - Konrad, Kai R.
A1  - Hedrich, Rainer
T1  - Tobacco leaf tissue rapidly detoxifies direct salt loads without activation of calcium and SOS signaling
JF  - New Phytologist
N2  - Salt stress is a major abiotic stress, responsible for declining agricultural productivity. Roots are regarded as hubs for salt detoxification, however, leaf salt concentrations may exceed those of roots. How mature leaves manage acute sodium chloride (NaCl) stress is mostly unknown.

To analyze the mechanisms for NaCl redistribution in leaves, salt was infiltrated into intact tobacco leaves. It initiated pronounced osmotically‐driven leaf movements. Leaf downward movement caused by hydro‐passive turgor loss reached a maximum within 2 h.

Salt‐driven cellular water release was accompanied by a transient change in membrane depolarization but not an increase in cytosolic calcium ion (Ca\(^{2+}\)) level. Nonetheless, only half an hour later, the leaves had completely regained turgor. This recovery phase was characterized by an increase in mesophyll cell plasma membrane hydrogen ion (H\(^{+}\)) pumping, a salt uptake‐dependent cytosolic alkalization, and a return of the apoplast osmolality to pre‐stress levels. Although, transcript numbers of abscisic acid‐ and Salt Overly Sensitive pathway elements remained unchanged, salt adaptation depended on the vacuolar H\(^{+}\)/Na\(^{+}\)‐exchanger NHX1.

Altogether, tobacco leaves can detoxify sodium ions (Na\(^{+}\)) rapidly even under massive salt loads, based on pre‐established posttranslational settings and NHX1 cation/H+ antiport activity. Unlike roots, signaling and processing of salt stress in tobacco leaves does not depend on Ca\(^{2+}\) signaling.
KW  - calcium signaling
KW  - cytosolic pH
KW  - leaf response
KW  - NaCl transport
KW  - NHX1
KW  - osmotic effects
KW  - Salt Overly Sensitive pathway
KW  - salt stress
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312152
VL  - 237
IS  - 1
SP  - 217
EP  - 231
ER  - 
TY  - JOUR
A1  - Bazihizina, Nadia
A1  - Böhm, Jennifer
A1  - Messerer, Maxim
A1  - Stigloher, Christian
A1  - Müller, Heike M.
A1  - Cuin, Tracey Ann
A1  - Maierhofer, Tobias
A1  - Cabot, Joan
A1  - Mayer, Klaus F. X.
A1  - Fella, Christian
A1  - Huang, Shouguang
A1  - Al‐Rasheid, Khaled A. S.
A1  - Alquraishi, Saleh
A1  - Breadmore, Michael
A1  - Mancuso, Stefano
A1  - Shabala, Sergey
A1  - Ache, Peter
A1  - Zhang, Heng
A1  - Zhu, Jian‐Kang
A1  - Hedrich, Rainer
A1  - Scherzer, Sönke
T1  - Stalk cell polar ion transport provide for bladder‐based salinity tolerance in Chenopodium quinoa
JF  - New Phytologist
N2  - Chenopodium quinoa uses epidermal bladder cells (EBCs) to sequester excess salt. Each EBC complex consists of a leaf epidermal cell, a stalk cell, and the bladder.

Under salt stress, sodium (Na\(^{+}\)), chloride (Cl\(^{−}\)), potassium (K\(^{+}\)) and various metabolites are shuttled from the leaf lamina to the bladders. Stalk cells operate as both a selectivity filter and a flux controller.

In line with the nature of a transfer cell, advanced transmission electron tomography, electrophysiology, and fluorescent tracer flux studies revealed the stalk cell’s polar organization and bladder‐directed solute flow.

RNA sequencing and cluster analysis revealed the gene expression profiles of the stalk cells. Among the stalk cell enriched genes, ion channels and carriers as well as sugar transporters were most pronounced. Based on their electrophysiological fingerprint and thermodynamic considerations, a model for stalk cell transcellular transport was derived.
KW  - halophyte
KW  - polar ion transport
KW  - quinoa
KW  - salt tolerance
KW  - stalk cell
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287222
VL  - 235
IS  - 5
SP  - 1822
EP  - 1835
ER  - 
TY  - JOUR
A1  - Stein, Kiera
A1  - Maruf, Abdullah Al
A1  - Müller, Daniel J.
A1  - Bishop, Jeffrey R.
A1  - Bousman, Chad A.
T1  - Serotonin transporter genetic variation and antidepressant response and tolerability: a systematic review and meta-analysis
JF  - Journal of Personalized Medicine
N2  - Antidepressants are used to treat several psychiatric disorders; however, a large proportion of patients do not respond to their first antidepressant therapy and often experience adverse drug reactions (ADR). A common insertion–deletion polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (SLC6A4) gene has been frequently investigated for its association with antidepressant outcomes. Here, we performed a systematic review and meta-analysis to assess 5-HTTLPR associations with antidepressants: (1) response in psychiatric disorders other than major depressive disorder (MDD) and (2) tolerability across all psychiatric disorders. Literature searches were performed up to January 2021, yielding 82 studies that met inclusion criteria, and 16 of these studies were included in the meta-analyses. Carriers of the 5-HTTLPR LL or LS genotypes were more likely to respond to antidepressant therapy, compared to the SS carriers in the total and European ancestry-only study populations. Long (L) allele carriers taking selective serotonin reuptake inhibitors (SSRIs) reported fewer ADRs relative to short/short (SS) carriers. European L carriers taking SSRIs had lower ADR rates than S carriers. These results suggest the 5-HTTLPR polymorphism may serve as a marker for antidepressant outcomes in psychiatric disorders and may be particularly relevant to SSRI treatment among individuals of European descent.
KW  - 5-HTTLPR
KW  - genotype
KW  - pharmacogenetics
KW  - antidepressant
KW  - efficacy
KW  - tolerability
KW  - SLC6A4
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252294
SN  - 2075-4426
VL  - 11
IS  - 12
ER  - 
TY  - JOUR
A1  - Bernt, Alexander
A1  - Rangrez, Ashraf Y.
A1  - Eden, Matthias
A1  - Jungmann, Andreas
A1  - Katz, Sylvia
A1  - Rohr, Claudia
A1  - Müller, Oliver J.
A1  - Katus, Hugo A.
A1  - Sossalla, Samuel T.
A1  - Williams, Tatjana
A1  - Ritter, Oliver
A1  - Frank, Derk
A1  - Frey, Norbert
T1  - Sumoylation-independent activation of Calcineurin-NFAT-signaling via SUMO2 mediates cardiomyocyte hypertrophy
JF  - Scientific Reports
N2  - The objective of this study was to identify unknown modulators of Calcineurin (Cn)-NFAT signaling. Measurement of NFAT reporter driven luciferase activity was therefore utilized to screen a human cardiac cDNA-library (~10\(^{7}\) primary clones) in C2C12 cells through serial dilutions until single clones could be identified. This extensive screening strategy culminated in the identification of SUMO2 as a most efficient Cn-NFAT activator. SUMO2-mediated activation of Cn-NFAT signaling in cardiomyocytes translated into a hypertrophic phenotype. Prohypertrophic effects were also observed in mice expressing SUMO2 in the heart using AAV9 (Adeno-associated virus), complementing the in vitro findings. In addition, increased SUMO2-mediated sumoylation in human cardiomyopathy patients and in mouse models of cardiomyopathy were observed. To decipher the underlying mechanism, we generated a sumoylation-deficient SUMO2 mutant (ΔGG). Surprisingly, ΔGG replicated Cn-NFAT-activation and the prohypertrophic effects of native SUMO2, both in vitro and in vivo, suggesting a sumoylation-independent mechanism. Finally, we discerned a direct interaction between SUMO2 and CnA, which promotes CnA nuclear localization. In conclusion, we identified SUMO2 as a novel activator of Cn-NFAT signaling in cardiomyocytes. In broader terms, these findings reveal an unexpected role for SUMO2 in cardiac hypertrophy and cardiomyopathy, which may open the possibility for therapeutic manipulation of this pathway.
KW  - Calcineurin-NFATsignaling
KW  - activation
KW  - SUMO2
KW  - cardiac hypertrophy
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167525
VL  - 6
IS  - 35758
ER  - 
TY  - JOUR
A1  - Hardulak, Laura A.
A1  - Morinière, Jérôme
A1  - Hausmann, Axel
A1  - Hendrich, Lars
A1  - Schmidt, Stefan
A1  - Doczkal, Dieter
A1  - Müller, Jörg
A1  - Hebert, Paul D. N.
A1  - Haszprunar, Gerhard
T1  - DNA metabarcoding for biodiversity monitoring in a national park: Screening for invasive and pest species
JF  - Molecular Ecology Resources
N2  - DNA metabarcoding was utilized for a large‐scale, multiyear assessment of biodiversity in Malaise trap collections from the Bavarian Forest National Park (Germany, Bavaria). Principal component analysis of read count‐based biodiversities revealed clustering in concordance with whether collection sites were located inside or outside of the National Park. Jaccard distance matrices of the presences of barcode index numbers (BINs) at collection sites in the two survey years (2016 and 2018) were significantly correlated. Overall similar patterns in the presence of total arthropod BINs, as well as BINs belonging to four major arthropod orders across the study area, were observed in both survey years, and are also comparable with results of a previous study based on DNA barcoding of Sanger‐sequenced specimens. A custom reference sequence library was assembled from publicly available data to screen for pest or invasive arthropods among the specimens or from the preservative ethanol. A single 98.6% match to the invasive bark beetle Ips duplicatus was detected in an ethanol sample. This species has not previously been detected in the National Park.
KW  - biodiversity
KW  - DNA barcoding
KW  - invasive species
KW  - metabarcoding
KW  - monitoring
KW  - pest species
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217812
VL  - 20
IS  - 6
SP  - 1542
EP  - 1557
ER  - 
TY  - JOUR
A1  - Hofrichter, Michaela A. H.
A1  - Mojarad, Majid
A1  - Doll, Julia
A1  - Grimm, Clemens
A1  - Eslahi, Atiye
A1  - Hosseini, Neda Sadat
A1  - Rajati, Mohsen
A1  - Müller, Tobias
A1  - Dittrich, Marcus
A1  - Maroofian, Reza
A1  - Haaf, Thomas
A1  - Vona, Barbara
T1  - The conserved p.Arg108 residue in S1PR2 (DFNB68) is fundamental for proper hearing: evidence from a consanguineous Iranian family
JF  - BMC Medical Genetics
N2  - Background:
Genetic heterogeneity and consanguineous marriages make recessive inherited hearing loss in Iran the second most common genetic disorder. Only two reported pathogenic variants (c.323G>C, p.Arg108Pro and c.419A>G, p.Tyr140Cys) in the S1PR2 gene have previously been linked to autosomal recessive hearing loss (DFNB68) in two Pakistani families. We describe a segregating novel homozygous c.323G>A, p.Arg108Gln pathogenic variant in S1PR2 that was identified in four affected individuals from a consanguineous five generation Iranian family.

Methods:
Whole exome sequencing and bioinformatics analysis of 116 hearing loss-associated genes was performed in an affected individual from a five generation Iranian family. Segregation analysis and 3D protein modeling of the p.Arg108 exchange was performed.

Results:
The two Pakistani families previously identified with S1PR2 pathogenic variants presented profound hearing loss that is also observed in the affected Iranian individuals described in the current study. Interestingly, we confirmed mixed hearing loss in one affected individual. 3D protein modeling suggests that the p.Arg108 position plays a key role in ligand receptor interaction, which is disturbed by the p.Arg108Gln change.

Conclusion:
In summary, we report the third overall mutation in S1PR2 and the first report outside the Pakistani population. Furthermore, we describe a novel variant that causes an amino acid exchange (p.Arg108Gln) in the same amino acid residue as one of the previously reported Pakistani families (p.Arg108Pro). This finding emphasizes the importance of the p.Arg108 amino acid in normal hearing and confirms and consolidates the role of S1PR2 in autosomal recessive hearing loss.
KW  - 3D modeling
KW  - autosomal recessive non-synstromic hearing loss
KW  - DFNB68
KW  - mixed hearing loss
KW  - whole exome sequencing
KW  - S1PR2
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175755
VL  - 19
IS  - 81
ER  - 
TY  - JOUR
A1  - Doll, Julia
A1  - Vona, Barbara
A1  - Schnapp, Linda
A1  - Rüschendorf, Franz
A1  - Khan, Imran
A1  - Khan, Saadullah
A1  - Muhammad, Noor
A1  - Alam Khan, Sher
A1  - Nawaz, Hamed
A1  - Khan, Ajmal
A1  - Ahmad, Naseer
A1  - Kolb, Susanne M.
A1  - Kühlewein, Laura
A1  - Labonne, Jonathan D. J.
A1  - Layman, Lawrence C.
A1  - Hofrichter, Michaela A. H.
A1  - Röder, Tabea
A1  - Dittrich, Marcus
A1  - Müller, Tobias
A1  - Graves, Tyler D.
A1  - Kong, Il-Keun
A1  - Nanda, Indrajit
A1  - Kim, Hyung-Goo
A1  - Haaf, Thomas
T1  - Genetic Spectrum of Syndromic and Non-Syndromic Hearing Loss in Pakistani Families
JF  - Genes
N2  - The current molecular genetic diagnostic rates for hereditary hearing loss (HL) vary considerably according to the population background. Pakistan and other countries with high rates of consanguineous marriages have served as a unique resource for studying rare and novel forms of recessive HL. A combined exome sequencing, bioinformatics analysis, and gene mapping approach for 21 consanguineous Pakistani families revealed 13 pathogenic or likely pathogenic variants in the genes GJB2, MYO7A, FGF3, CDC14A, SLITRK6, CDH23, and MYO15A, with an overall resolve rate of 61.9%. GJB2 and MYO7A were the most frequently involved genes in this cohort. All the identified variants were either homozygous or compound heterozygous, with two of them not previously described in the literature (15.4%). Overall, seven missense variants (53.8%), three nonsense variants (23.1%), two frameshift variants (15.4%), and one splice-site variant (7.7%) were observed. Syndromic HL was identified in five (23.8%) of the 21 families studied. This study reflects the extreme genetic heterogeneity observed in HL and expands the spectrum of variants in deafness-associated genes.
KW  - genetic diagnosis
KW  - consanguinity
KW  - genome-wide linkage analysis
KW  - hearing loss
KW  - Pakistan
KW  - exome sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219293
SN  - 2073-4425
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Otto, C.
A1  - Schmidt, S.
A1  - Kastner, C.
A1  - Denk, S.
A1  - Kettler, J.
A1  - Müller, N.
A1  - Germer, C.T.
A1  - Wolf, E.
A1  - Gallant, P.
A1  - Wiegering, A.
T1  - Targeting bromodomain-containing protein 4 (BRD4) inhibits MYC expression in colorectal cancer cells
JF  - Neoplasia
N2  - The transcriptional regulator BRD4 has been shown to be important for the expression of several oncogenes including MYC. Inhibiting of BRD4 has broad antiproliferative activity in different cancer cell types. The small molecule JQ1 blocks the interaction of BRD4 with acetylated histones leading to transcriptional modulation. Depleting BRD4 via engineered bifunctional small molecules named PROTACs (proteolysis targeting chimeras) represents the next-generation approach to JQ1-mediated BRD4 inhibition. PROTACs trigger BRD4 for proteasomale degradation by recruiting E3 ligases. The aim of this study was therefore to validate the importance of BRD4 as a relevant target in colorectal cancer (CRC) cells and to compare the efficacy of BRD4 inhibition with BRD4 degradation on downregulating MYC expression. JQ1 induced a downregulation of both MYC mRNA and MYC protein associated with an antiproliferative phenotype in CRC cells. dBET1 and MZ1 induced degradation of BRD4 followed by a reduction in MYC expression and CRC cell proliferation. In SW480 cells, where dBET1 failed, we found significantly lower levels of the E3 ligase cereblon, which is essential for dBET1-induced BRD4 degradation. To gain mechanistic insight into the unresponsiveness to dBET1, we generated dBET1-resistant LS174t cells and found a strong downregulation of cereblon protein. These findings suggest that inhibition of BRD4 by JQ1 and degradation of BRD4 by dBET1 and MZ1 are powerful tools for reducing MYC expression and CRC cell proliferation. In addition, downregulation of cereblon may be an important mechanism for developing dBET1 resistance, which can be evaded by incubating dBET1-resistant cells with JQ1 or MZ1.
KW  - Cancer
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202451
VL  - 21
IS  - 11
ER  - 
TY  - JOUR
A1  - Müller, Anna A.
A1  - Dolowschiak, Tamas
A1  - Sellin, Mikael E.
A1  - Felmy, Boas
A1  - Verbree, Carolin
A1  - Gadient, Sandra
A1  - Westermann, Alexander J.
A1  - Vogel, Jörg
A1  - LeibundGut-Landmann, Salome
A1  - Hardt, Wolf-Dietrich
T1  - An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection
JF  - PLoS Pathogens
N2  - Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and –injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf\(^{-/-}\) ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens.
KW  - NK cells
KW  - Salmonella Typhimurium
KW  - mucosal inflammation
KW  - diarrhea
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167429
VL  - 12
IS  - 6
ER  - 
TY  - JOUR
A1  - Zottnick, Sven H.
A1  - Sprenger, Jan A. P.
A1  - Finze, Maik
A1  - Müller‐Buschbaum, Klaus
T1  - Statistic Replacement of Lanthanide Ions in Bis‐salicylatoborate Coordination Polymers for the Deliberate Control of the Luminescence Chromaticity
JF  - ChemistryOpen
N2  - Based on the strand‐like coordination polymer (CP) type \(^{1}\)\(_{∞}\)[Ln(BSB)\(_{3}\)(py)\(_{2}\)], [BSB]−=bis‐salicylatoborate anion, mixed Eu/Tb‐containing compounds of the constitution \(^{1}\)\(_{∞}\)[Eu\(_{x}\)Tb\(_{1-x}\)(BSB)\(_{3}\)(py)\(_{2}\)] were synthesised ionothermally for a phase width of (x=0.25–0.75) and characterized regarding structure and optical properties. Previously, known only for other lanthanides, the mixed 1D−Eu/Tb‐CPs show excellent options for statistic replacement of the Ln‐cations during synthesis yielding solid solutions. The products are highly luminescent, with the chromaticity being a direct function of the amount of the respective Ln‐ions. Corresponding to an overall addition of emission intensities, the green Tb\(^{3+}\) emission and the red Eu\(^{3+}\) emission allow for a chromaticity control that also includes yellow emission. Control of the luminescence colour renders them suitable examples of the versatility of statistic replacement of metal ions in coordination chemistry. In addition, crystallization of [EMIm]\(_{2}\)[YCl\(_{5}\)(py)] illuminates possible other products of the ionothermal reactions of [EMIm][BSB] with LnCl\(_{3}\) constituted by components not being part of the main CPs.
KW  - borates
KW  - coordination polymers
KW  - ionic liquids
KW  - lanthanides
KW  - luminescence
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239953
VL  - 10
IS  - 2
SP  - 164
EP  - 170
ER  - 
TY  - JOUR
A1  - Boschert, Verena
A1  - Teusch, Jonas
A1  - Aljasem, Anwar
A1  - Schmucker, Philipp
A1  - Klenk, Nicola
A1  - Straub, Anton
A1  - Bittrich, Max
A1  - Seher, Axel
A1  - Linz, Christian
A1  - Müller-Richter, Urs D. A.
A1  - Hartmann, Stefan
T1  - HGF-induced PD-L1 expression in head and neck cancer: preclinical and clinical findings
JF  - International Journal of Molecular Sciences
N2  - Head and neck squamous cell carcinoma (HNSCC) is a widespread disease with a low survival rate and a high risk of recurrence. Nowadays, immune checkpoint inhibitor (ICI) treatment is approved for HNSCC as a first-line treatment in recurrent and metastatic disease. ICI treatment yields a clear survival benefit, but overall response rates are still unsatisfactory. As shown in different cancer models, hepatocyte growth factor/mesenchymal–epithelial transition (HGF/Met) signaling contributes to an immunosuppressive microenvironment. Therefore, we investigated the relationship between HGF and programmed cell death protein 1 (PD-L1) expression in HNSCC cell lines. The preclinical data show a robust PD-L1 induction upon HGF stimulation. Further analysis revealed that the HGF-mediated upregulation of PD-L1 is MAP kinase-dependent. We then hypothesized that serum levels of HGF and soluble programmed cell death protein 1 (sPD-L1) could be potential markers of ICI treatment failure. Thus, we determined serum levels of these proteins in 20 HNSCC patients before ICI treatment and correlated them with treatment outcomes. Importantly, the clinical data showed a positive correlation of both serum proteins (HGF and sPD-L1) in HNSCC patient’s sera. Moreover, the serum concentration of sPD-L1 was significantly higher in ICI non-responsive patients. Our findings indicate a potential role for sPD-L1 as a prognostic marker for ICI treatment in HNSCC.
KW  - HNSCC
KW  - head and neck cancer
KW  - HGF
KW  - Met
KW  - PD-L1
KW  - immune therapy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236220
SN  - 1422-0067
VL  - 21
IS  - 20
ER  - 
TY  - JOUR
A1  - Boschert, Verena
A1  - Teusch, Jonas
A1  - Müller-Richter, Urs D. A.
A1  - Brands, Roman C.
A1  - Hartmann, Stefan
T1  - PKM2 modulation in head and neck squamous cell carcinoma
JF  - International Journal of Molecular Sciences
N2  - The enzyme pyruvate kinase M2 (PKM2) plays a major role in the switch of tumor cells from oxidative phosphorylation to aerobic glycolysis, one of the hallmarks of cancer. Different allosteric inhibitors or activators and several posttranslational modifications regulate its activity. Head and neck squamous cell carcinoma (HNSCC) is a common disease with a high rate of recurrence. To find out more about PKM2 and its modulation in HNSCC, we examined a panel of HNSCC cells using real-time cell metabolic analysis and Western blotting with an emphasis on phosphorylation variant Tyr105 and two reagents known to impair PKM2 activity. Our results show that in HNSCC, PKM2 is commonly phosphorylated at Tyrosine 105. Its levels depended on tyrosine kinase activity, emphasizing the importance of growth factors such as EGF (epidermal growth factor) on HNSCC metabolism. Furthermore, its correlation with the expression of CD44 indicates a role in cancer stemness. Cells generally reacted with higher glycolysis to PKM2 activator DASA-58 and lower glycolysis to PKM2 inhibitor Compound 3k, but some were more susceptible to activation and others to inhibition. Our findings emphasize the need to further investigate the role of PKM2 in HNSCC, as it could aid understanding and treatment of the disease.
KW  - HNSCC
KW  - head and neck cancer
KW  - cancer metabolism
KW  - glycolysis
KW  - PKM2
KW  - Warburg effect
KW  - CD44
KW  - Compound 3k
KW  - DASA-58
KW  - AMPK
KW  - TXNIP
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284458
SN  - 1422-0067
VL  - 23
IS  - 2
ER  - 
TY  - JOUR
A1  - Boehm, Anne
A1  - Meininger, Susanne
A1  - Tesch, Annemarie
A1  - Gbureck, Uwe
A1  - Müller, Frank A.
T1  - The mechanical properties of biocompatible apatite bone cement reinforced with chemically activated carbon fibers
JF  - Materials
N2  - Calcium phosphate cement (CPC) is a well-established bone replacement material in dentistry and orthopedics. CPC mimics the physicochemical properties of natural bone and therefore shows excellent in vivo behavior. However, due to their brittleness, the application of CPC implants is limited to non-load bearing areas. Generally, the fiber-reinforcement of ceramic materials enhances fracture resistance, but simultaneously reduces the strength of the composite. Combining strong C-fiber reinforcement with a hydroxyapatite to form a CPC with a chemical modification of the fiber surface allowed us to adjust the fiber–matrix interface and consequently the fracture behavior. Thus, we could demonstrate enhanced mechanical properties of CPC in terms of bending strength and work of fracture to a strain of 5% (WOF5). Hereby, the strength increased by a factor of four from 9.2 ± 1.7 to 38.4 ± 1.7 MPa. Simultaneously, the WOF5 increased from 0.02 ± 0.004 to 2.0 ± 0.6 kJ∙m−2, when utilizing an aqua regia/CaCl2 pretreatment. The cell proliferation and activity of MG63 osteoblast-like cells as biocompatibility markers were not affected by fiber addition nor by fiber treatment. CPC reinforced with chemically activated C-fibers is a promising bone replacement material for load-bearing applications.
KW  - calcium phosphate cement
KW  - damage tolerant cement
KW  - carbon fiber reinforcement
KW  - interface control
KW  - fiber–matrix interaction
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197808
SN  - 1996-1944
VL  - 11
IS  - 2
ER  - 
TY  - JOUR
A1  - Seifert, Annika
A1  - Groll, Jürgen
A1  - Weichhold, Jan
A1  - Boehm, Anne V.
A1  - Müller, Frank A.
A1  - Gbureck, Uwe
T1  - Phase Conversion of Ice‐Templated α‐Tricalcium Phosphate Scaffolds into Low‐Temperature Calcium Phosphates with Anisotropic Open Porosity
JF  - Advanced Engineering Materials
N2  - The current study aims to extend the material platform for anisotropically structured calcium phosphates to low-temperature phases such as calcium-deficient hydroxyapatite (CDHA) or the secondary phosphates monetite and brushite. This is achieved by the phase conversion of highly porous α-tricalcium phosphate (α-TCP) scaffolds fabricated by ice-templating into the aforementioned phases by hydrothermal treatment or incubation in phosphoric acid. Prior to these steps, α-TCP scaffolds are either sintered for 8 h at 1400 °C or remain in their original state. Both nonsintered and sintered α-TCP specimens are converted into CDHA by hydrothermal treatment, while a transformation into monetite and brushite is achieved by incubation in phosphoric acid. Hydrothermal treatment for 72 h at 175 °C increases the porosity in nonsintered samples from 85% to 88% and from 75% to 88% in the sintered ones. An increase in the specific surface area from (1.102 ± 0.005) to (9.17 ± 0.01) m2 g−1 and from (0.190 ± 0.004) to (2.809 ± 0.002) m2 g−1 due to the phase conversion is visible for both the nonsintered and sintered samples. Compressive strength of the nonsintered samples increases significantly from (0.76 ± 0.11) to (5.29 ± 0.94) MPa due to incubation in phosphoric acid.
KW  - phase conversion
KW  - α-tricalcium phosphate
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256311
VL  - 23
IS  - 5
ER  - 
TY  - JOUR
A1  - Fiedler, Mascha O.
A1  - Muellenbach, Ralf M.
A1  - Rolfes, Caroline
A1  - Lotz, Christopher
A1  - Nickel, Felix
A1  - Müller-Stich, Beat P.
A1  - Supady, Alexander
A1  - Lepper, Philipp M.
A1  - Weigand, Markus A.
A1  - Meybohm, Patrick
A1  - Kalenka, Armin
A1  - Reyher, Christian
T1  - Pumpless extracorporeal hemadsorption technique (pEHAT): a proof-of-concept animal study
JF  - Journal of Clinical Medicine
N2  - Background: Extracorporeal hemadsorption eliminates proinflammatory mediators in critically ill patients with hyperinflammation. The use of a pumpless extracorporeal hemadsorption technique allows its early usage prior to organ failure and the need for an additional medical device. In our animal model, we investigated the feasibility of pumpless extracorporeal hemadsorption over a wide range of mean arterial pressures (MAP). Methods: An arteriovenous shunt between the femoral artery and femoral vein was established in eight pigs. The hemadsorption devices were inserted into the shunt circulation; four pigs received CytoSorb\(^®\) and four Oxiris\(^®\) hemadsorbers. Extracorporeal blood flow was measured in a range between mean arterial pressures of 45–85 mmHg. Mean arterial pressures were preset using intravenous infusions of noradrenaline, urapidil, or increased sedatives. Results: Extracorporeal blood flows remained well above the minimum flows recommended by the manufacturers throughout all MAP steps for both devices. Linear regression resulted in CytoSorb\(^®\) blood flow [mL/min] = 4.226 × MAP [mmHg] − 3.496 (R-square 0.8133) and Oxiris\(^®\) blood flow [mL/min] = 3.267 × MAP [mmHg] + 57.63 (R-square 0.8708), respectively. Conclusion: Arteriovenous pumpless extracorporeal hemadsorption resulted in sufficient blood flows through both the CytoSorb\(^®\) and Oxiris\(^®\) devices over a wide range of mean arterial blood pressures and is likely an intriguing therapeutic option in the early phase of septic shock or hyperinflammatory syndromes.
KW  - blood purification
KW  - extracorporeal hemadsorption
KW  - cytokines
KW  - adsorption
KW  - animal model
KW  - immunosorbents
KW  - septic shock
KW  - endotoxin
KW  - extracorporeal techniques in hemadsorption therapy
KW  - arteriovenous extracorporeal hemadsorption technique
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297347
SN  - 2077-0383
VL  - 11
IS  - 22
ER  - 
TY  - JOUR
A1  - Müller, Jörg
A1  - Mitesser, Oliver
A1  - Schaefer, H. Martin
A1  - Seibold, Sebastian
A1  - Busse, Annika
A1  - Kriegel, Peter
A1  - Rabl, Dominik
A1  - Gelis, Rudy
A1  - Arteaga, Alejandro
A1  - Freile, Juan
A1  - Leite, Gabriel Augusto
A1  - de Melo, Tomaz Nascimento
A1  - LeBien, Jack
A1  - Campos-Cerqueira, Marconi
A1  - Blüthgen, Nico
A1  - Tremlett, Constance J.
A1  - Böttger, Dennis
A1  - Feldhaar, Heike
A1  - Grella, Nina
A1  - Falconí-López, Ana
A1  - Donoso, David A.
A1  - Moriniere, Jerome
A1  - Buřivalová, Zuzana
T1  - Soundscapes and deep learning enable tracking biodiversity recovery in tropical forests
JF  - Nature Communications
N2  - Tropical forest recovery is fundamental to addressing the intertwined climate and biodiversity loss crises. While regenerating trees sequester carbon relatively quickly, the pace of biodiversity recovery remains contentious. Here, we use bioacoustics and metabarcoding to measure forest recovery post-agriculture in a global biodiversity hotspot in Ecuador. We show that the community composition, and not species richness, of vocalizing vertebrates identified by experts reflects the restoration gradient. Two automated measures – an acoustic index model and a bird community composition derived from an independently developed Convolutional Neural Network - correlated well with restoration (adj-R² = 0.62 and 0.69, respectively). Importantly, both measures reflected composition of non-vocalizing nocturnal insects identified via metabarcoding. We show that such automated monitoring tools, based on new technologies, can effectively monitor the success of forest recovery, using robust and reproducible data.
KW  - animal behaviour
KW  - conservation biology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358130
VL  - 14
ER  - 
TY  - JOUR
A1  - Righesso, L. A. R.
A1  - Terekhov, M.
A1  - Götz, H.
A1  - Ackermann, M.
A1  - Emrich, T.
A1  - Schreiber, L. M.
A1  - Müller, W. E. G.
A1  - Jung, J.
A1  - Rojas, J. P.
A1  - Al-Nawas, B.
T1  - Dynamic contrast-enhanced magnetic resonance imaging for monitoring neovascularization during bone regeneration — a randomized in vivo study in rabbits
JF  - Clinical Oral Investigations
N2  - Objectives
Micro-computed tomography (μ-CT) and histology, the current gold standard methods for assessing the formation of new bone and blood vessels, are invasive and/or destructive. With that in mind, a more conservative tool, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), was tested for its accuracy and reproducibility in monitoring neovascularization during bone regeneration. Additionally, the suitability of blood perfusion as a surrogate of the efficacy of osteoplastic materials was evaluated.

Materials and methods
Sixteen rabbits were used and equally divided into four groups, according to the time of euthanasia (2, 3, 4, and 6 weeks after surgery). The animals were submitted to two 8-mm craniotomies that were filled with blood or autogenous bone. Neovascularization was assessed in vivo through DCE-MRI, and bone regeneration, ex vivo, through μ-CT and histology.

Results
The defects could be consistently identified, and their blood perfusion measured through DCE-MRI, there being statistically significant differences within the blood clot group between 3 and 6 weeks (p = 0.029), and between the former and autogenous bone at six weeks (p = 0.017). Nonetheless, no significant correlations between DCE-MRI findings on neovascularization and μ-CT (r =−0.101, 95% CI [−0.445; 0.268]) or histology (r = 0.305, 95% CI [−0.133; 0.644]) findings on bone regeneration were observed.

Conclusions
These results support the hypothesis that DCE-MRI can be used to monitor neovascularization but contradict the premise that it could predict bone regeneration as well.
KW  - animal experimentation
KW  - bone regeneration
KW  - multiparametric magnetic resonance imaging
KW  - neovascularization, physiologic
KW  - tissue engineering
KW  - translational medical research
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307614
SN  - 1432-6981
SN  - 1436-3771
VL  - 25
IS  - 10
ER  - 
TY  - JOUR
A1  - Dindas, Julian
A1  - Scherzer, Sönke
A1  - Roelfsema, M. Rob G.
A1  - Meyer, Katharina von
A1  - Müller, Heike M.
A1  - Al-Rasheid, K. A. S.
A1  - Palme, Klaus
A1  - Dietrich, Petra
A1  - Becker, Dirk
A1  - Bennett, Malcolm J.
A1  - Hedrich, Rainer
T1  - AUX1-mediated root hair auxin influx governs SCFTIR1/AFB-type Ca2+ signaling
JF  - Nature Communications
N2  - Auxin is a key regulator of plant growth and development, but the causal relationship between hormone transport and root responses remains unresolved. Here we describe auxin uptake, together with early steps in signaling, in Arabidopsis root hairs. Using intracellular microelectrodes we show membrane depolarization, in response to IAA in a concentration- and pH-dependent manner. This depolarization is strongly impaired in aux1 mutants, indicating that AUX1 is the major transporter for auxin uptake in root hairs. Local intracellular auxin application triggers Ca2+ signals that propagate as long-distance waves between root cells and modulate their auxin responses. AUX1-mediated IAA transport, as well as IAA- triggered calcium signals, are blocked by treatment with the SCFTIR1/AFB - inhibitor auxinole. Further, they are strongly reduced in the tir1afb2afb3 and the cngc14 mutant. Our study reveals that the AUX1 transporter, the SCFTIR1/AFB receptor and the CNGC14 Ca2+ channel, mediate fast auxin signaling in roots.
KW  - auxin
KW  - permeation and transport
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225368
VL  - 9
ER  - 
TY  - JOUR
A1  - Müller, P.A.
A1  - Bröcker, E.B.
A1  - Klinker, E.
A1  - Stoevesandt, J.
A1  - Benoit, S.
T1  - Adjuvant treatment of recalcitrant Bullous pemphigoid with immunoadsorption
JF  - Dermatology
N2  - Elimination of pathogenic autoantibodies by immunoadsorption (IA) has been described as an effective adjuvant treatment in severe bullous autoimmune diseases, especially in pemphigus. There is much less experience in the treatment of bullous pemphigoid (BP). BP was diagnosed in a 62-year-old Caucasian woman presenting a pruritic rash with multiple tense blisters. Standard treatments with topical and oral corticosteroids, steroid-sparing agents including dapsone, azathioprine, mycophenolate mofetil (MMF) and intravenous immunoglobulins were ineffective or had to be discontinued due to adverse events. An immediate clinical response could be achieved by two treatment cycles of adjuvant protein A immunoadsorption (PA-IA) in addition to continued treatment with MMF (2 g/day) and prednisolone (1 mg/kg/day). Tolerance was excellent. Clinical improvement remained stable after discontinuation of IA and went along with sustained reduction of circulating autoantibodies. Our data demonstrate that PA-IA might be a safe and effective adjuvant treatment in severe and recalcitrant BP.
KW  - Bullous pemphigoid
KW  - Immunoadsorption
KW  - Immunoapheresis
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196620
SN  - 1018-8665
SN  - 1421-9832
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 224
IS  - 3
SP  - 224
EP  - 227
ER  -