@article{SchmidtSkafGavriletal.2017,
  author    = {Schmidt, Marianne and Skaf, Josef and Gavril, Georgiana and Polednik, Christine and Roller, Jeanette and Kessler, Michael and Holzgrabe, Ulrike},
  title     = {The influence of Osmunda regalis root extract on head and neck cancer cell proliferation, invasion and gene expression},
  series = {BMC Complementary and Alternative Medicine},
  volume    = {17},
  journal   = {BMC Complementary and Alternative Medicine},
  number    = {518},
  doi       = {10.1186/s12906-017-2009-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158704},
  year      = {2017},
  abstract  = {Background: According to only a handful of historical sources, Osmunda regalis, the royal fern, has been used already in the middle age as an anti-cancer remedy. To examine this ancient cancer cure, an ethanolic extract of the roots was prepared and analysed in vitro on its effectiveness against head and neck cancer cell lines. Methods: Proliferation inhibition was measured with the MTT assay. Invasion inhibition was tested in a spheroid-based 3-D migration assay on different extracellular matrix surfaces. Corresponding changes in gene expression were analysed by qRT-PCR array. Induction of apoptosis was measured by fluorescence activated cell sorting (FACS) with the Annexin V binding method. The plant extract was analysed by preliminary phytochemical tests, liquid chromatography/mass spectroscopy (LC-MS) and thin layer chromatography (TLC). Anti-angiogenetic activity was determined by the tube formation assay. Results: O. regalis extract revealed a growth inhibiting effect on the head and neck carcinoma cell lines HLaC78 and FaDu. The toxic effect seems to be partially modulated by p-glycoprotein, as the MDR-1 expressing HLaC79-Tax cells were less sensitive. O. regalis extract inhibited the invasion of cell lines on diverse extracellular matrix substrates significantly. Especially the dispersion of the highly motile cell line HlaC78 on laminin was almost completely abrogated. Motility inhibition on laminin was accompanied by differential gene regulation of a variety of genes involved in cell adhesion and metastasis. Furthermore, O. regalis extract triggered apoptosis in HNSCC cell lines and inhibited tube formation of endothelial cells. Preliminary phytochemical analysis proved the presence of tannins, glycosides, steroids and saponins. Liquid chromatography/mass spectroscopy (LC-MS) revealed a major peak of an unknown substance with a molecular mass of 864.15 Da, comprising about 50\% of the total extract. Thin layer chromatography identified ferulic acid to be present in the extract. Conclusion: The presented results justify the use of royal fern extracts as an anti-cancer remedy in history and imply a further analysis of ingredients.},
  language  = {en}
}
@article{LaglerElMeseryKuebleretal.2017,
  author    = {Lagler, Charlotte and El-Mesery, Mohamed and K{\"u}bler, Alexander Christian and M{\"u}ller-Richter, Urs Dietmar Achim and St{\"u}hmer, Thorsten and Nickel, Joachim and M{\"u}ller, Thomas Dieter and Wajant, Harald and Seher, Axel},
  title     = {The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {10},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158993},
  pages     = {e0185720},
  year      = {2017},
  abstract  = {Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48-72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.},
  language  = {en}
}
@article{SeherLaglerStuehmeretal.2017,
  author    = {Seher, Axel and Lagler, Charlotte and St{\"u}hmer, Thorsten and M{\"u}ller-Richter, Urs Dietmar Achim and K{\"u}bler, Alexander Christian and Sebald, Walter and M{\"u}ller, Thomas Dieter and Nickel, Joachim},
  title     = {Utilizing BMP-2 muteins for treatment of multiple myeloma},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {5},
  doi       = {10.1371/journal.pone.0174884},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158144},
  pages     = {e0174884},
  year      = {2017},
  abstract  = {Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.},
  language  = {en}
}
@article{FehrholzSeidenspinnerKunzmann2017,
  author    = {Fehrholz, Markus and Seidenspinner, Silvia and Kunzmann, Steffen},
  title     = {Expression of surfactant protein B is dependent on cell density in H441 lung epithelial cells},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {9},
  doi       = {10.1371/journal.pone.0184556},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158291},
  pages     = {e0184556},
  year      = {2017},
  abstract  = {Background Expression of surfactant protein (SP)-B, which assures the structural stability of the pulmonary surfactant film, is influenced by various stimuli, including glucocorticoids; however, the role that cell-cell contact plays in SP-B transcription remains unknown. The aim of the current study was to investigate the impact of cell-cell contact on SP-B mRNA and mature SP-B expression in the lung epithelial cell line H441. Methods Different quantities of H441 cells per growth area were either left untreated or incubated with dexamethasone. The expression of SP-B, SP-B transcription factors, and tight junction proteins were determined by qPCR and immunoblotting. The influence of cell density on SP-B mRNA stability was investigated using the transcription inhibitor actinomycin D. Results SP-B mRNA and mature SP-B expression levels were significantly elevated in untreated and dexamethasone-treated H441 cells with increasing cell density. High cell density as a sole stimulus was found to barely have an impact on SP-B transcription factor and tight junction mRNA levels, while its stimulatory ability on SP-B mRNA expression could be mimicked using SP-B-negative cells. SP-B mRNA stability was significantly increased in high-density cells, but not by dexamethasone alone. Conclusion SP-B expression in H441 cells is dependent on cell-cell contact, which increases mRNA stability and thereby potentiates the glucocorticoid-mediated induction of transcription. Loss of cell integrity might contribute to reduced SP-B secretion in damaged lung cells via downregulation of SP-B transcription. Cell density-mediated effects should thus receive greater attention in future cell culture-based research.},
  language  = {en}
}
@article{SchulzRuppertHermsetal.2017,
  author    = {Schulz, Herbert and Ruppert, Ann-Kathrin and Herms, Stefan and Wolf, Christiane and Mirza-Schreiber, Nazanin and Stegle, Oliver and Czamara, Darina and Forstner, Andreas J. and Sivalingam, Sugirthan and Schoch, Susanne and Moebus, Susanne and P{\"u}tz, Benno and Hillmer, Axel and Fricker, Nadine and Vatter, Hartmut and M{\"u}ller-Myhsok, Bertram and N{\"o}then, Markus M. and Becker, Albert J. and Hoffmann, Per and Sander, Thomas and Cichon, Sven},
  title     = {Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus},
  series = {Nature Communications},
  volume    = {8},
  journal   = {Nature Communications},
  doi       = {10.1038/s41467-017-01818-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173168},
  year      = {2017},
  abstract  = {Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the \(cis\)-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify \(cis\)-meQTLs at 14,118 CpG methylation sites and \(cis\)-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal \(cis\)-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. \(Cis\)-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of \(cis\)-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.},
  language  = {en}
}
@article{BocukWolffKrauseetal.2017,
  author    = {Bocuk, Derya and Wolff, Alexander and Krause, Petra and Salinas, Gabriela and Bleckmann, Annalen and Hackl, Christina and Beissbarth, Tim and Koenig, Sarah},
  title     = {The adaptation of colorectal cancer cells when forming metastases in the liver: expression of associated genes and pathways in a mouse model},
  series = {BMC Cancer},
  volume    = {17},
  journal   = {BMC Cancer},
  number    = {342},
  doi       = {10.1186/s12885-017-3342-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170853},
  year      = {2017},
  abstract  = {Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in men and women. Systemic disease with metastatic spread to distant sites such as the liver reduces the survival rate considerably. The aim of this study was to investigate the changes in gene expression that occur on invasion and expansion of CRC cells when forming metastases in the liver. Methods: The livers of syngeneic C57BL/6NCrl mice were inoculated with 1 million CRC cells (CMT-93) via the portal vein, leading to the stable formation of metastases within 4 weeks. RNA sequencing performed on the Illumina platform was employed to evaluate the expression profiles of more than 14,000 genes, utilizing the RNA of the cell line cells and liver metastases as well as from corresponding tumour-free liver. Results: A total of 3329 differentially expressed genes (DEGs) were identified when cultured CMT-93 cells propagated as metastases in the liver. Hierarchical clustering on heat maps demonstrated the clear changes in gene expression of CMT-93 cells on propagation in the liver. Gene ontology analysis determined inflammation, angiogenesis, and signal transduction as the top three relevant biological processes involved. Using a selection list, matrix metallopeptidases 2, 7, and 9, wnt inhibitory factor, and chemokine receptor 4 were the top five significantly dysregulated genes. Conclusion: Bioinformatics assists in elucidating the factors and processes involved in CRC liver metastasis. Our results support the notion of an invasion-metastasis cascade involving CRC cells forming metastases on successful invasion and expansion within the liver. Furthermore, we identified a gene expression signature correlating strongly with invasiveness and migration. Our findings may guide future research on novel therapeutic targets in the treatment of CRC liver metastasis.},
  language  = {en}
}
@article{WeistePedrottiSelvanayagametal.2017,
  author    = {Weiste, Christoph and Pedrotti, Lorenzo and Selvanayagam, Jebasingh and Muralidhara, Prathibha and Fr{\"o}schel, Christian and Nov{\´a}k, Ondřej and Ljung, Karin and Hanson, Johannes and Dr{\"o}ge-Laser, Wolfgang},
  title     = {The Arabidopsis bZIP11 transcription factor links low-energy signalling to auxin-mediated control of primary root growth},
  series = {PLoS Genetics},
  volume    = {13},
  journal   = {PLoS Genetics},
  number    = {2},
  doi       = {10.1371/journal.pgen.1006607},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157742},
  pages     = {e1006607},
  year      = {2017},
  abstract  = {Plants have to tightly control their energy homeostasis to ensure survival and fitness under constantly changing environmental conditions. Thus, it is stringently required that energy-consuming stress-adaptation and growth-related processes are dynamically tuned according to the prevailing energy availability. The evolutionary conserved SUCROSE NON-FERMENTING1 RELATED KINASES1 (SnRK1) and the downstream group C/S\(_{1}\) basic leucine zipper (bZIP) transcription factors (TFs) are well-characterised central players in plants' low-energy management. Nevertheless, mechanistic insights into plant growth control under energy deprived conditions remains largely elusive. In this work, we disclose the novel function of the low-energy activated group S\(_{1}\) bZIP11-related TFs as regulators of auxin-mediated primary root growth. Whereas transgenic gain-of-function approaches of these bZIPs interfere with the activity of the root apical meristem and result in root growth repression, root growth of loss-of-function plants show a pronounced insensitivity to low-energy conditions. Based on ensuing molecular and biochemical analyses, we propose a mechanistic model, in which bZIP11-related TFs gain control over the root meristem by directly activating IAA3/SHY2 transcription. IAA3/SHY2 is a pivotal negative regulator of root growth, which has been demonstrated to efficiently repress transcription of major auxin transport facilitators of the PIN-FORMED (PIN) gene family, thereby restricting polar auxin transport to the root tip and in consequence auxin-driven primary root growth. Taken together, our results disclose the central low-energy activated SnRK1-C/S\(_{1}\)-bZIP signalling module as gateway to integrate information on the plant's energy status into root meristem control, thereby balancing plant growth and cellular energy resources.},
  language  = {en}
}
@article{BrodehlBelkeGarnettetal.2017,
  author    = {Brodehl, Andreas and Belke, Darrell D. and Garnett, Lauren and Martens, Kristina and Abdelfatah, Nelly and Rodriguez, Marcela and Diao, Catherine and Chen, Yong-Xiang and Gordon, Paul M. K. and Nygren, Anders and Gerull, Brenda},
  title     = {Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling},
  series = {PLoS ONE},
  volume    = {12},
  journal   = {PLoS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0174019},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171084},
  pages     = {e0174019},
  year      = {2017},
  abstract  = {Background Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology. Methods and results We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age. Conclusion Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.},
  language  = {en}
}