TY - JOUR A1 - Fiedler, David A1 - Hirsch, Daniela A1 - El Hajj, Nady A1 - Yang, Howard H. A1 - Hu, Yue A1 - Sticht, Carsten A1 - Nanda, Indrajit A1 - Belle, Sebastian A1 - Rueschoff, Josef A1 - Lee, Maxwell P. A1 - Ried, Thomas A1 - Haaf, Thomas A1 - Gaiser, Timo T1 - Genome‐wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine‐phosphate‐guanine methylation and histological subtypes JF - Genes, Chromosomes and Cancer N2 - Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin‐fixed paraffin‐embedded colorectal low‐grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine‐phosphate‐guanine (CpG) islands were frequently hypermethylated, whereas open sea‐ and shelf‐regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines. KW - adenoma KW - DNA methylation KW - epigenetics KW - histological subtype KW - recurrence Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212676 VL - 58 IS - 11 SP - 783 EP - 797 ER - TY - JOUR A1 - Wu, Hao A1 - Reimann, Sabine A1 - Siddiqui, Sophiya A1 - Haag, Rainer A1 - Siegmund, Britta A1 - Dernedde, Jens A1 - Glauben, Rainer T1 - dPGS Regulates the Phenotype of Macrophages via Metabolic Switching JF - Macromolecular Bioscience N2 - The synthetic compound dendritic polyglycerol sulfate (dPGS) is a pleiotropic acting molecule but shows a high binding affinity to immunological active molecules as L‐/P‐selectin or complement proteins leading to well described anti‐inflammatory properties in various mouse models. In order to make a comprehensive evaluation of the direct effect on the innate immune system, macrophage polarization is analyzed in the presence of dPGS on a phenotypic but also metabolic level. dPGS administered macrophages show a significant increase of MCP1 production paralleled by a reduction of IL‐10 secretion. Metabolic analysis reveals that dPGS could potently enhance the glycolysis and mitochondrial respiration in M0 macrophages as well as decrease the mitochondrial respiration of M2 macrophages. In summary the data indicate that dPGS polarizes macrophages into a pro‐inflammatory phenotype in a metabolic pathway‐dependent manner. KW - infection KW - macrophage polarization KW - MCP1 KW - metabolic switch KW - polyglycerol sulfates Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212711 VL - 19 IS - 12 ER - TY - JOUR A1 - Jochmann, Svenja A1 - Elkenani, Manar A1 - Mohamed, Belal A. A1 - Buchholz, Eric A1 - Lbik, Dawid A1 - Binder, Lutz A1 - Lorenz, Kristina A1 - Shah, Ajay M. A1 - Hasenfuß, Gerd A1 - Toischer, Karl A1 - Schnelle, Moritz T1 - Assessing the role of extracellular signal‐regulated kinases 1 and 2 in volume overload‐induced cardiac remodelling JF - ESC Heart Failure N2 - Aims Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal‐regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen‐activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO‐induced cardiac remodelling as this was unknown. Methods and results Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr‐Glu‐Tyr) motif (−28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte‐specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6‐fold, P < 0.05) and protein level (3.1‐fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice. Conclusions VO‐induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte‐specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO. KW - ERK1/2 KW - volume overload KW - aortocaval fistula model KW - cardiac remodelling KW - eccentric hypertrophy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212735 VL - 6 IS - 5 SP - 1015 EP - 1026 ER - TY - JOUR A1 - Gonzalez‐Escamilla, Gabriel A1 - Muthuraman, Muthuraman A1 - Reich, Martin M. A1 - Koirala, Nabin A1 - Riedel, Christian A1 - Glaser, Martin A1 - Lange, Florian A1 - Deuschl, Günther A1 - Volkmann, Jens A1 - Groppa, Sergiu T1 - Cortical network fingerprints predict deep brain stimulation outcome in dystonia JF - Movement Disorders N2 - Background Deep brain stimulation (DBS) is an effective evidence‐based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns. Methods From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior‐outcome group or moderate‐outcome group, depending on whether they had above or below 70% motor improvement, respectively. Fifty‐one patients met MRI‐quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray‐matter fingerprints. Results The moderate‐outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88% of accuracy using individual gray‐matter atrophy patterns to predict DBS outcomes. Conclusions The analysis of cortical integrity, informed by group‐level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS. KW - brain networks KW - clinical outcome KW - deep brain stimulation KW - dystonia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213532 VL - 34 IS - 10 SP - 1536 EP - 1545 ER - TY - JOUR A1 - Wintzheimer, Susanne A1 - Oppmann, Maximilian A1 - Dold, Martin A1 - Pannek, Carolin A1 - Bauersfeld, Marie‐Luise A1 - Henfling, Michael A1 - Trupp, Sabine A1 - Schug, Benedikt A1 - Mandel, Karl T1 - Indicator Supraparticles for Smart Gasochromic Sensor Surfaces Reacting Ultrafast and Highly Sensitive JF - Particle & Particle Systems Characterization N2 - The detection of toxic gases, such as NH\(_{3}\) and CO, in the environment is of high interest in chemical, electronic, and automotive industry as even small amounts can display a health risk for workers. Sensors for the real‐time monitoring of these gases should be simple, robust, reversible, highly sensitive, inexpensive and show a fast response. The indicator supraparticles presented herein can fulfill all of these requirements. They consist of silica nanoparticles, which are assembled to supraparticles upon spray‐drying. Sensing molecules such as Reichardt's dye and a binuclear rhodium complex are loaded onto the microparticles to target NH\(_{3}\) and CO detection, respectively. The spray‐drying technique affords high flexibility in primary nanoparticle size selection and thus, easy adjustment of the porosity and specific surface area of the obtained micrometer‐sized supraparticles. This ultimately enables the fine‐tuning of the sensor sensitivity and response. For the application of the indicator supraparticles in a gas detection device, they can be immobilized on a coating. Due to their microscale size, they are large enough to poke out of thin coating layers, thus guaranteeing their gas accessibility, while being small enough to be applicable to flexible substrates. KW - CO sensing KW - NH\(_{3}\) KW - sensor supports KW - silica supraparticles KW - smart surfaces Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213671 VL - 36 IS - 10 ER - TY - JOUR A1 - Bélanger‐Chabot, Guillaume A1 - Braunschweig, Holger T1 - Hexahalodiborate Dianions: A New Family of Binary Boron Halides JF - Angewandte Chemie International Edition N2 - The electron‐precise binary boron subhalide species [B\(_2\)X\(_6\)]\(^{2−}\) X=F, Br, I) were synthesized and their structures confirmed by X‐ray crystallography. The existence of the previously claimed [B\(_2\)Cl\(_6\)]\(^{2−}\), which had been questioned, was also confirmed by X‐ray crystallography. The dianions are isoelectronic to hexahaloethanes, are subhalide analogues of the well‐known tetrahaloborate anions (BX\(_4\)\(^−\)), and are rare examples of molecular electron‐precise binary boron species beyond B\(_2\)X\(_4\), BX\(_3\), and [BX\(_4\)]\(^−\). KW - binary species KW - boron KW - electron-precise diborates KW - halogens Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219688 VL - 58 IS - 40 ER - TY - JOUR A1 - Mietrach, Nicole A1 - Schlosser, Andreas A1 - Geibel, Sebastian T1 - An extracellular domain of the EsaA membrane component of the type VIIb secretion system: expression, purification and crystallization JF - Acta Crystallographica Section F N2 - The membrane protein EsaA is a conserved component of the type VIIb secretion system. Limited proteolysis of purified EsaA from Staphylococcus aureus USA300 identified a stable 48 kDa fragment, which was mapped by fingerprint mass spectrometry to an uncharacterized extracellular segment of EsaA. Analysis by circular dichroism spectroscopy showed that this fragment folds into a single stable domain made of mostly α‐helices with a melting point of 34.5°C. Size‐exclusion chromatography combined with multi‐angle light scattering indicated the formation of a dimer of the purified extracellular domain. Octahedral crystals were grown in 0.2 M ammonium citrate tribasic pH 7.0, 16% PEG 3350 using the hanging‐drop vapor‐diffusion method. Diffraction data were analyzed to 4.0 Å resolution, showing that the crystals belonged to the enantiomorphic tetragonal space groups P41212 or P43212, with unit‐cell parameters a = 197.5, b = 197.5, c = 368.3 Å, α = β = γ = 90°. KW - ESAT‐6‐like secretion system KW - ESS KW - type VII secretion system KW - EsaA KW - extracellular domain KW - Staphylococcus aureus USA300 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213681 VL - 75 IS - 12 ER - TY - JOUR A1 - Luber, Verena A1 - Lutz, Mathias A1 - Abele-Horn, Marianne A1 - Einsele, Hermann A1 - Grigoleit, Götz Ulrich A1 - Mielke, Stephan T1 - Excretion of Ascaris lumbricoides following reduced‐intensity allogeneic hematopoietic stem cell transplantation and consecutive treatment with mebendazole JF - Transplant Infectious Disease N2 - Here, we present the unique case of a 51‐year‐old German patient with multiple myeloma excreting Ascaris lumbricoides in his stool five weeks after allogeneic hematopoietic stem cell transplantation. Stool analysis remained negative for the presence of eggs, and there was no eosinophilia in the peripheral blood at any time around stem cell transplantation. The patient was commenced on a three‐day treatment with mebendazole, which was well tolerated. No serious interactions with the concomitant post‐transplant medication or negative effects on the hematopoiesis were observed, and the myeloma still is in complete remission. To our knowledge, this is the first report on excretion of A lumbricoides in the context of allogeneic stem cell transplantation. The case is remarkable with view to the fact that the parasite has supposedly survived all courses of myeloma treatment including autologous and allogeneic conditioning. Parasitosis with A lumbricoides has a worldwide prevalence of about a billion and is extremely rare in northern Europe. Possibly the patient got infected during a trip to Egypt years before multiple myeloma was diagnosed. KW - sirolimus KW - mycophenolic acid KW - multiple myeloma KW - mebendazole KW - hematopoietic stem cell transplantation KW - Ascaris lumbricoides Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219608 SN - 1399-3062 VL - 22 IS - 1 ER - TY - JOUR A1 - Da Vià, Matteo Claudio A1 - Solimando, Antonio Giovanni A1 - Garitano-Trojaola, Andoni A1 - Barrio, Santiago A1 - Munawar, Umair A1 - Strifler, Susanne A1 - Haertle, Larissa A1 - Rhodes, Nadine A1 - Vogt, Cornelia A1 - Lapa, Constantin A1 - Beilhack, Andreas A1 - Rasche, Leo A1 - Einsele, Hermann A1 - Kortüm, K. Martin T1 - CIC Mutation as a Molecular Mechanism of Acquired Resistance to Combined BRAF‐MEK Inhibition in Extramedullary Multiple Myeloma with Central Nervous System Involvement JF - The Oncologist N2 - Combined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable. Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient. KW - Multiple myeloma KW - Extramedullary disease KW - Capicua transcriptional repressor KW - Drug resistance KW - BRAF mutation Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219549 VL - 25 IS - 2 ER - TY - JOUR A1 - Lenczyk, Carsten A1 - Roy, Dipak Kumar A1 - Nitsch, Jörn A1 - Radacki, Krzysztof A1 - Rauch, Florian A1 - Dewhurst, Rian D. A1 - Bickelhaupt, F. Matthias A1 - Marder, Todd B. A1 - Braunschweig, Holger T1 - Steric Effects Dictate the Formation of Terminal Arylborylene Complexes of Ruthenium from Dihydroboranes JF - Chemistry - A European Journal N2 - The steric and electronic properties of aryl substituents in monoaryl borohydrides (Li[ArBH\(_3\)]) and dihydroboranes were systematically varied and their reactions with [Ru(PCy\(_3\))\(_2\)HCl(H\(_2\))] (Cy: cyclohexyl) were studied, resulting in bis(σ)‐borane or terminal borylene complexes of ruthenium. These variations allowed for the investigation of the factors involved in the activation of dihydroboranes in the synthesis of terminal borylene complexes. The complexes were studied by multinuclear NMR spectroscopy, mass spectrometry, X‐ray diffraction analysis, and density functional theory (DFT) calculations. The experimental and computational results suggest that the ortho‐substitution of the aryl groups is necessary for the formation of terminal borylene complexes. KW - Arylborylene Complexes KW - Ruthenium KW - Dihydroboranes KW - boranes KW - borohydrides KW - borylenes KW - steric effects KW - sigma boranes Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219537 SN - 1521-3765 VL - 25 IS - 59 ER -