@article{RichterKruppaMunzetal.2019, author = {Richter, Gesa M. and Kruppa, Jochen and Munz, Matthias and Wiehe, Ricarda and H{\"a}sler, Robert and Franke, Andre and Martins, Orlando and Jockel-Schneider, Yvonne and Bruckmann, Corinna and Dommisch, Henrik and Schaefer, Arne S.}, title = {A combined epigenome- and transcriptome-wide association study of the oral masticatory mucosa assigns CYP1B1 a central role for epithelial health in smokers}, series = {Clinical Epigenetics}, volume = {11}, journal = {Clinical Epigenetics}, doi = {10.1186/s13148-019-0697-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226175}, pages = {1-18}, year = {2019}, abstract = {Background The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking. Results Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1. Conclusion This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.}, subject = {AHRR}, language = {en} } @article{SailerWiedemannStraussetal.2019, author = {Sailer, Clara Odilia and Wiedemann, Sophia Julia and Strauss, Konrad and Schnyder, Ingeborg and Fenske, Wiebke Kristin and Christ-Crain, Mirjam}, title = {Markers of systemic inflammation in response to osmotic stimulus in healthy volunteers}, series = {Endocrine Connections}, volume = {8}, journal = {Endocrine Connections}, number = {9}, doi = {10.1530/EC-19-0280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227204}, pages = {1282-1287}, year = {2019}, abstract = {Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interle ukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium >= 150 mmol/L) by hypertonic saline infusion. Copeptin - a marker indicating vasopressin activity - serum sodium and osmolality, plasma IL-8 and TNF-alpha were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-alpha levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.1 2, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.}, subject = {Hyperosmotic Stress}, language = {en} } @article{ReinholdSchwabeLuxetal.2018, author = {Reinhold, Ann Kristin and Schwabe, Joachim and Lux, Thomas J. and Salvador, Ellaine and Rittner, Heike L.}, title = {Quantitative and Microstructural Changes of the Blood-Nerve Barrier in Peripheral Neuropathy}, series = {Frontiers in Neuroscience}, volume = {12}, journal = {Frontiers in Neuroscience}, doi = {10.3389/fnins.2018.00936}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225179}, pages = {936, 1-9}, year = {2018}, abstract = {Peripheral neuropathy is accompanied by changes in the neuronal environment. The blood-nerve barrier (BNB) is crucial in protecting the neural homeostasis: Tight junctions (TJ) seal paracellular spaces and thus prevent external stimuli from entering. In different models of neuropathic pain, the BNB is impaired, thus contributing to local damage, immune cell invasion and, ultimately, the development of neuropathy with its symptoms. In this study, we examined changes in expression and microstructural localization of two key tight junction proteins (TJP), claudin-1 and the cytoplasmic anchoring ZO-1, in the sciatic nerve of mice subjected to chronic constriction injury (CCI). Via qPCR and analysis of fluorescence immunohistochemistry, a marked downregulation of mRNA as well as decreased fluorescence intensity were observed in the nerve for both proteins. Moreover, a distinct zig-zag structure for both proteins located at cell-cell contacts, indicative of the localization of TJs, was observed in the perineurial compartment of sham-operated animals. This microstructural location in cell-cell-contacts was lost in neuropathy as semiquantified via computational analysis, based on a novel algorithm. In summary, we provide evidence that peripheral neuropathy is not only associated with decrease in relevant TJPs but also exhibits alterations in TJP arrangement and loss in barrier tightness, presumably due to internalization. Specifically, semiquantification of TJP in cell-cell-contacts of microcompartments could be used in the future for routine clinical samples of patients with neuropathy.}, language = {en} } @article{ChopraBiehlSteinfattetal.2016, author = {Chopra, Martin and Biehl, Marlene and Steinfatt, Tim and Brandl, Andreas and Kums, Juliane and Amich, Jorge and Vaeth, Martin and Kuen, Janina and Holtappels, Rafaela and Podlech, J{\"u}rgen and Mottok, Anja and Kraus, Sabrina and Jord{\´a}n-Garotte, Ana-Laura and B{\"a}uerlein, Carina A. and Brede, Christian and Ribechini, Eliana and Fick, Andrea and Seher, Axel and Polz, Johannes and Ottmueller, Katja J. and Baker, Jeannette and Nishikii, Hidekazu and Ritz, Miriam and Mattenheimer, Katharina and Schwinn, Stefanie and Winter, Thorsten and Sch{\"a}fer, Viktoria and Krappmann, Sven and Einsele, Hermann and M{\"u}ller, Thomas D. and Reddehase, Matthias J. and Lutz, Manfred B. and M{\"a}nnel, Daniela N. and Berberich-Siebelt, Friederike and Wajant, Harald and Beilhack, Andreas}, title = {Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion}, series = {Journal of Experimental Medicine}, volume = {213}, journal = {Journal of Experimental Medicine}, number = {9}, doi = {10.1084/jem.20151563}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187640}, pages = {1881-1900}, year = {2016}, abstract = {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.}, language = {en} } @article{ReynoldsHofmeisterCliffeetal.2016, author = {Reynolds, David L. and Hofmeister, Brigitte T. and Cliffe, Laura and Siegel, T. Nicolai and Andersson, Britta A. and Beverley, Stephen M. and Schmitz, Robert J. and Sabatini, Robert}, title = {Base J represses genes at the end of polycistronic gene clusters in Leishmania major by promoting RNAP II termination}, series = {Molecular Microbiology}, volume = {101}, journal = {Molecular Microbiology}, number = {4}, doi = {10.1111/mmi.13408}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187727}, pages = {559-574}, year = {2016}, abstract = {The genomes of kinetoplastids are organized into polycistronic gene clusters that are flanked by the modified DNA base J. Previous work has established a role of base J in promoting RNA polymerase II termination in Leishmania spp. where the loss of J leads to termination defects and transcription into adjacent gene clusters. It remains unclear whether these termination defects affect gene expression and whether read through transcription is detrimental to cell growth, thus explaining the essential nature of J. We now demonstrate that reduction of base J at specific sites within polycistronic gene clusters in L. major leads to read through transcription and increased expression of downstream genes in the cluster. Interestingly, subsequent transcription into the opposing polycistronic gene cluster does not lead to downregulation of sense mRNAs. These findings indicate a conserved role for J regulating transcription termination and expression of genes within polycistronic gene clusters in trypanosomatids. In contrast to the expectations often attributed to opposing transcription, the essential nature of J in Leishmania spp. is related to its role in gene repression rather than preventing transcriptional interference resulting from read through and dual strand transcription.}, language = {en} } @article{HagemannKesslerWiesneretal.2014, author = {Hagemann, Carsten and Kessler, Almuth Friederike and Wiesner, Miriam and Denner, Joachim and K{\"a}mmerer, Ulrike and Vince, Giles Hamilton and Linsenmann, Thomas and L{\"o}hr, Mario and Ernestus, Ralf-Ingo}, title = {Expression-analysis of the human endogenous retrovirus HERV-K in human astrocytic tumors}, doi = {10.1186/1756-0500-7-159}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110211}, year = {2014}, abstract = {Background The human endogenous retrovirus K (HERV-K) has been acquired by the genome of human ancestors million years ago. It is the most complete of the HERVs with transcriptionally active gag, pol and env genes. Splice variants of env, which are rec, 1.5 kb transcript and Np9 have been suggested to be tumorigenic. Transcripts of HERV-K have been detected in a multitude of human cancers. However, no such reports are available concerning glioblastomas (GBM), the most common malignant brain tumor in adults. Patients have a limited prognosis of 14.6 months in median, despite standard treatment. Therefore, we elucidated whether HERV-K transcripts could be detected in these tumors and serve as new molecular target for treatment. Findings We analyzed human GBM cell lines, tissue samples from patients and primary cell cultures of different passages for HERV-K full length mRNA and env, rec and 1.5 kb transcripts. While the GBM cell lines U138, U251, U343 and GaMG displayed weak and U87 strong expression of the full length HERV-K, the splice products could not be detected, despite a weak expression of env mRNA in U87 cells. Very few tissue samples from patients showed weak expression of env mRNA, but none of the rec or 1.5 kb transcripts. Primary cells expressed the 1.5 kb transcript weakly in early passages, but lost HERV-K expression with extended culture time. Conclusions These data suggest that HERV-K splice products do not play a role in human malignant gliomas and therefore, are not suitable as targets for new therapy regimen.}, language = {en} } @article{BergmillerPenaMillerBoehmetal.2011, author = {Bergmiller, Tobias and Pena-Miller, Rafael and Boehm, Alexander and Ackermann, Martin}, title = {Single-cell time-lapse analysis of depletion of the universally conserved essential protein YgjD}, series = {BMC Microbiology}, volume = {11}, journal = {BMC Microbiology}, number = {118}, doi = {10.1186/1471-2180-11-118}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142324}, pages = {1-12}, year = {2011}, abstract = {Background: The essential Escherichia coli gene ygjD belongs to a universally conserved group of genes whose function has been the focus of a number of recent studies. Here, we put ygjD under control of an inducible promoter, and used time-lapse microscopy and single cell analysis to investigate the phenotypic consequences of the depletion of YgjD protein from growing cells. Results: We show that loss of YgjD leads to a marked decrease in cell size and termination of cell division. The transition towards smaller size occurs in a controlled manner: cell elongation and cell division remain coupled, but cell size at division decreases. We also find evidence that depletion of YgjD leads to the synthesis of the intracellular signaling molecule (p) ppGpp, inducing a cellular reaction resembling the stringent response. Concomitant deletion of the relA and spoT genes - leading to a strain that is uncapable of synthesizing (p) ppGpp abrogates the decrease in cell size, but does not prevent termination of cell division upon YgjD depletion. Conclusions: Depletion of YgjD protein from growing cells leads to a decrease in cell size that is contingent on (p) ppGpp, and to a termination of cell division. The combination of single-cell time-lapse microscopy and statistical analysis can give detailed insights into the phenotypic consequences of the loss of essential genes, and can thus serve as a new tool to study the function of essential genes.}, language = {en} } @article{WedelHudakSeibeletal.2011, author = {Wedel, Steffen and Hudak, Lukasz and Seibel, Jens-Michael and Makarevic, Jasmina and Juengel, Eva and Tsaur, Igor and Waaga-Gasser, Ana and Haferkamp, Axel and Blaheta, Roman A.}, title = {Molecular targeting of prostate cancer cells by a triple drug combination down-regulates integrin driven adhesion processes, delays cell cycle progression and interferes with the cdk-cyclin axis}, series = {BMC Cancer}, volume = {11}, journal = {BMC Cancer}, number = {375}, doi = {10.1186/1471-2407-11-375}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141075}, pages = {1-14}, year = {2011}, abstract = {Background: Single drug use has not achieved satisfactory results in the treatment of prostate cancer, despite application of increasingly widespread targeted therapeutics. In the present study, the combined impact of the mammalian target of rapamycin (mTOR)-inhibitor RAD001, the dual EGFr and VGEFr tyrosine kinase inhibitor AEE788 and the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on prostate cancer growth and adhesion in vitro was investigated. Methods: PC-3, DU-145 and LNCaP cells were treated with RAD001, AEE788 or VPA or with a RAD-AEE-VPA combination. Tumor cell growth, cell cycle progression and cell cycle regulating proteins were then investigated by MTT-assay, flow cytometry and western blotting, respectively. Furthermore, tumor cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins as well as migratory properties of the cells was evaluated, and integrin alpha and beta subtypes were analyzed. Finally, effects of drug treatment on cell signaling pathways were determined. Results: All drugs, separately applied, reduced tumor cell adhesion, migration and growth. A much stronger anticancer effect was evoked by the triple drug combination. Particularly, cdk1, 2 and 4 and cyclin B were reduced, whereas p27 was elevated. In addition, simultaneous application of RAD001, AEE788 and VPA altered the membranous, cytoplasmic and gene expression pattern of various integrin alpha and beta subtypes, reduced integrin-linked kinase (ILK) and deactivated focal adhesion kinase (FAK). Signaling analysis revealed that EGFr and the downstream target Akt, as well as p70S6k was distinctly modified in the presence of the drug combination. Conclusions: Simultaneous targeting of several key proteins in prostate cancer cells provides an advantage over targeting a single pathway. Since strong anti-tumor properties became evident with respect to cell growth and adhesion dynamics, the triple drug combination might provide progress in the treatment of advanced prostate cancer.}, language = {en} } @article{YinBrocherFischeretal.2011, author = {Yin, Jun and Brocher, Jan and Fischer, Utz and Winkler, Christoph}, title = {Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa}, series = {Molecular neurodegeneration}, volume = {6}, journal = {Molecular neurodegeneration}, number = {56}, doi = {10.1186/1750-1326-6-56}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141090}, pages = {1-17}, year = {2011}, abstract = {Background: Retinitis pigmentosa (RP) is an inherited eye disease characterized by the progressive degeneration of rod photoreceptor cells. Mutations in pre-mRNA splicing factors including PRPF31 have been identified as cause for RP, raising the question how mutations in general factors lead to tissue specific defects. Results: We have recently shown that the zebrafish serves as an excellent model allowing the recapitulation of key events of RP. Here we use this model to investigate two pathogenic mutations in PRPF31, SP117 and AD5, causing the autosomal dominant form of RP. We show that SP117 leads to an unstable protein that is mislocalized to the rod cytoplasm. Importantly, its overexpression does not result in photoreceptor degeneration suggesting haploinsufficiency as the underlying cause in human RP patients carrying SP117. In contrast, overexpression of AD5 results in embryonic lethality, which can be rescued by wild-type Prpf31. Transgenic retina-specific expression of AD5 reveals that stable AD5 protein is initially localized in the nucleus but later found in the cytoplasm concurrent with progressing rod outer segment degeneration and apoptosis. Importantly, we show for the first time in vivo that retinal transcripts are wrongly spliced in adult transgenic retinas expressing AD5 and exhibiting increased apoptosis in rod photoreceptors. Conclusion: Our data suggest that distinct mutations in Prpf31 can lead to photoreceptor degeneration through different mechanisms, by haploinsufficiency or dominant-negative effects. Analyzing the AD5 effects in our animal model in vivo, our data imply that aberrant splicing of distinct retinal transcripts contributes to the observed retina defects.}, language = {en} } @article{BinderMayBaronetal.2011, author = {Binder, Andreas and May, Denisa and Baron, Ralf and Maier, Christoph and T{\"o}lle, Thomas R. and Treede, Rolf-Detlef and Berthele, Achim and Faltraco, Frank and Flor, Herta and Gierthm{\"u}hlen, Janne and Haenisch, Sierk and Huge, Volker and Magerl, Walter and Maih{\"o}fner, Christian and Richter, Helmut and Rolke, Roman and Scherens, Andrea and {\"U}{\c{c}}eyler, Nurcan and Ufer, Mike and Wasner, Gunnar and Zhu, Jihong and Cascorbi, Ingolf}, title = {Transient Receptor Potential Channel Polymorphisms Are Associated with the Somatosensory Function in Neuropathic Pain Patients}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {3}, doi = {10.1371/journal.pone.0017387}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142782}, pages = {e17387}, year = {2011}, abstract = {Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p=0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p=0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p=0.006, p=0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p=0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.}, language = {en} } @article{HaddadChenZhangetal.2011, author = {Haddad, Dana and Chen, Nanhai G. and Zhang, Qian and Chen, Chun-Hao and Yu, Yong A. and Gonzalez, Lorena and Carpenter, Susanne G. and Carson, Joshua and Au, Joyce and Mittra, Arjun and Gonen, Mithat and Zanzonico, Pat B. and Fong, Yuman and Szalay, Aladar A.}, title = {Insertion of the human sodium iodide symporter to facilitate deep tissue imaging does not alter oncolytic or replication capability of a novel vaccinia virus}, series = {Journal of Translational Medicine}, volume = {9}, journal = {Journal of Translational Medicine}, number = {36}, doi = {10.1186/1479-5876-9-36}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140847}, pages = {1-14}, year = {2011}, abstract = {Introduction: Oncolytic viruses show promise for treating cancer. However, to assess therapeutic efficacy and potential toxicity, a noninvasive imaging modality is needed. This study aimed to determine if insertion of the human sodium iodide symporter (hNIS) cDNA as a marker for non-invasive imaging of virotherapy alters the replication and oncolytic capability of a novel vaccinia virus, GLV-1h153. Methods: GLV-1h153 was modified from parental vaccinia virus GLV-1h68 to carry hNIS via homologous recombination. GLV-1h153 was tested against human pancreatic cancer cell line PANC-1 for replication via viral plaque assays and flow cytometry. Expression and transportation of hNIS in infected cells was evaluated using Westernblot and immunofluorescence. Intracellular uptake of radioiodide was assessed using radiouptake assays. Viral cytotoxicity and tumor regression of treated PANC-1tumor xenografts in nude mice was also determined. Finally, tumor radiouptake in xenografts was assessed via positron emission tomography (PET) utilizing carrier-free (124)I radiotracer. Results: GLV-1h153 infected, replicated within, and killed PANC-1 cells as efficiently as GLV-1h68. GLV-1h153 provided dose-dependent levels of hNIS expression in infected cells. Immunofluorescence detected transport of the protein to the cell membrane prior to cell lysis, enhancing hNIS-specific radiouptake (P < 0.001). In vivo, GLV-1h153 was as safe and effective as GLV-1h68 in regressing pancreatic cancer xenografts (P < 0.001). Finally, intratumoral injection of GLV-1h153 facilitated imaging of virus replication in tumors via (124)I-PET. Conclusion: Insertion of the hNIS gene does not hinder replication or oncolytic capability of GLV-1h153, rendering this novel virus a promising new candidate for the noninvasive imaging and tracking of oncolytic viral therapy.}, language = {en} } @article{EnjuanesFernandezHernandezetal.2011, author = {Enjuanes, Anna and Fernandez, Veronica and Hernandez, Luis and Navarro, Alba and Bea, Silvia and Pinyol, Magda and Lopez-Guillermo, Armando and Rosenwald, Andreas and Ott, German and Campo, Elias and Jares, Pedro}, title = {Identification of Methylated Genes Associated with Aggressive Clinicopathological Features in Mantle Cell Lymphoma}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {5}, doi = {10.1371/journal.pone.0019736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140632}, pages = {e19736}, year = {2011}, abstract = {Background: Mantle cell lymphoma (MCL) is genetically characterized by the t(11; 14)(q13; q32) translocation and a high number of secondary chromosomal alterations. The contribution of DNA methylation to MCL lymphomagenesis is not well known. We sought to identify epigenetically silenced genes in these tumours that might have clinical relevance. Methodology/Principal Findings: To identify potential methylated genes in MCL we initially investigated seven MCL cell lines treated with epigenetic drugs and gene expression microarray profiling. The methylation status of selected candidate genes was validated by a quantitative assay and subsequently analyzed in a series of primary MCL (n = 38). After pharmacological reversion we identified 252 potentially methylated genes. The methylation analysis of a subset of these genes (n = 25) in the MCL cell lines and normal B lymphocytes confirmed that 80\% of them were methylated in the cell lines but not in normal lymphocytes. The subsequent analysis in primary MCL identified five genes (SOX9, HOXA9, AHR, NR2F2, and ROBO1) frequently methylated in these tumours. The gene methylation events tended to occur in the same primary neoplasms and correlated with higher proliferation, increased number of chromosomal abnormalities, and shorter survival of the patients. Conclusions: We have identified a set of genes whose methylation degree and gene expression levels correlate with aggressive clinicopathological features of MCL. Our findings also suggest that a subset of MCL might show a CpG island methylator phenotype (CIMP) that may influence the behaviour of the tumours.}, language = {en} } @article{RauertStuehmerBargouetal.2011, author = {Rauert, H. and St{\"u}hmer, T. and Bargou, R. and Wajant, H. and Siegmund, D.}, title = {TNFR1 and TNFR2 regulate the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms}, series = {Cell Death and Disease}, volume = {2}, journal = {Cell Death and Disease}, doi = {10.1038/cddis.2011.78}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133486}, pages = {e194}, year = {2011}, abstract = {The huge majority of myeloma cell lines express TNFR2 while a substantial subset of them failed to show TNFR1 expression. Stimulation of TNFR1 in the TNFR1-expressing subset of MM cell lines had no or only a very mild effect on cellular viability. Surprisingly, however, TNF stimulation enhanced cell death induction by CD95L and attenuated the apoptotic effect of TRAIL. The contrasting regulation of TRAIL- and CD95L-induced cell death by TNF could be traced back to the concomitant NFjBmediated upregulation of CD95 and the antiapoptotic FLIP protein. It appeared that CD95 induction, due to its strength, overcompensated a rather moderate upregulation of FLIP so that the net effect of TNF-induced NFjB activation in the context of CD95 signaling is pro-apoptotic. TRAIL-induced cell death, however, was antagonized in response to TNF because in this context only the induction of FLIP is relevant. Stimulation of TNFR2 in myeloma cells leads to TRAF2 depletion. In line with this, we observed cell death induction in TNFR1-TNFR2-costimulated JJN3 cells. Our studies revealed that the TNF-TNF receptor system adjusts the responsiveness of the extrinsic apoptotic pathway in myeloma cells by multiple mechanisms that generate a highly context-dependent net effect on myeloma cell survival}, language = {en} } @article{SongXiuHuangetal.2011, author = {Song, Ning-Ning and Xiu, Jian-Bo and Huang, Ying and Chen, Jia-Yin and Zhang, Lei and Gutknecht, Lise and Lesch, Klaus Peter and Li, He and Ding, Yu-Qiang}, title = {Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0015998}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133581}, pages = {e15998}, year = {2011}, abstract = {The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreER(T2) mice were generated and crossed with Lmx1b(flox/flox) mice to obtain Pet1-CreER(T2); Lmx1b(flox/flox) mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60\% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2.}, language = {en} } @article{SchierackKletaTedinetal.2011, author = {Schierack, Peter and Kleta, Sylvia and Tedin, Karsten and Babila, Julius Tachu and Oswald, Sibylle and Oelschlaeger, Tobias A. and Hiemann, Rico and Paetzold, Susanne and Wieler, Lothar H.}, title = {E. coli Nissle 1917 Affects Salmonella Adhesion to Porcine Intestinal Epithelial Cells}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {2}, doi = {10.1371/journal.pone.0014712}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135298}, pages = {e14712}, year = {2011}, abstract = {Background: The probiotic Escherichia coli strain Nissle 1917 (EcN) has been shown to interfere in a human in vitro model with the invasion of several bacterial pathogens into epithelial cells, but the underlying molecular mechanisms are not known. Methodology/Principal Findings: In this study, we investigated the inhibitory effects of EcN on Salmonella Typhimurium invasion of porcine intestinal epithelial cells, focusing on EcN effects on the various stages of Salmonella infection including intracellular and extracellular Salmonella growth rates, virulence gene regulation, and adhesion. We show that EcN affects the initial Salmonella invasion steps by modulating Salmonella virulence gene regulation and Salmonella SiiE-mediated adhesion, but not extra-and intracellular Salmonella growth. However, the inhibitory activity of EcN against Salmonella invasion always correlated with EcN adhesion capacities. EcN mutants defective in the expression of F1C fimbriae and flagellae were less adherent and less inhibitory toward Salmonella invasion. Another E. coli strain expressing F1C fimbriae was also adherent to IPEC-J2 cells, and was similarly inhibitory against Salmonella invasion like EcN. Conclusions: We propose that EcN affects Salmonella adhesion through secretory components. This mechanism appears to be common to many E. coli strains, with strong adherence being a prerequisite for an effective reduction of SiiE-mediated Salmonella adhesion.}, language = {en} } @article{OttHacker1991, author = {Ott, M. and Hacker, J{\"o}rg}, title = {Analysis of the variability of S fimbriae expression in an Escherichia coli pathogen.}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-59695}, year = {1991}, abstract = {The uropathogenic Escherichia coli wiJd..:type strain 536 produces S-fimbriae, P-related fimbriae and type I fimbriae. Using immuno-colony dot and ELISA techniques, variants were detected showing an increased degree of S-fimbrial production. It was demonstrated by itrtmunofluorescence microscopy that in noimal (wild-type) and hyperS- fimbriated E. coli populaiions non-fimbriated cells also · exist, and that the percentage of Sfinibrlated and non-fimbriated bacteria was roughly identica1 in either population. Hyper-Sfimbriated variants could be stably maintained. The transition from wild-type to hyper-S-fimbriation, which occurs spontaneously, is markedly higher than vice versa. Southern blot analysis of the S fimbrial adhesin (sfa) determinants of normal and hyper-fimbriated strains revealed no marked difference in the gene structure.}, subject = {Infektionsbiologie}, language = {en} } @article{HaertleinSchiesslWagneretal.1983, author = {H{\"a}rtlein, Michael and Schiessl, Sigrid and Wagner, Wilma and Rdest, Ursula and Kreft, J{\"u}rgen and Goebel, Werner}, title = {Transport of hemolysin by Escherichia coli}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-60619}, year = {1983}, abstract = {No abstract available}, subject = {Biologie}, language = {en} }