TY - JOUR A1 - Verma, Nidhi A1 - Rai, Amit Kumar A1 - Kaushik, Vibha A1 - Brünnert, Daniela A1 - Chahar, Kirti Raj A1 - Pandey, Janmejay A1 - Goyal, Pankaj T1 - Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining JF - Scientific Reports N2 - Gefitinib, an EGFR tyrosine kinase inhibitor, is used as FDA approved drug in breast cancer and non-small cell lung cancer treatment. However, this drug has certain side effects and complications for which the underlying molecular mechanisms are not well understood. By systems biology based in silico analysis, we identified off-targets of gefitinib that might explain side effects of this drugs. The crystal structure of EGFR-gefitinib complex was used for binding pocket similarity searches on a druggable proteome database (Sc-PDB) by using IsoMIF Finder. The top 128 hits of putative off-targets were validated by reverse docking approach. The results showed that identified off-targets have efficient binding with gefitinib. The identified human specific off-targets were confirmed and further analyzed for their links with biological process and clinical disease pathways using retrospective studies and literature mining, respectively. Noticeably, many of the identified off-targets in this study were reported in previous high-throughput screenings. Interestingly, the present study reveals that gefitinib may have positive effects in reducing brain and bone metastasis, and may be useful in defining novel gefitinib based treatment regime. We propose that a system wide approach could be useful during new drug development and to minimize side effect of the prospective drug. KW - gefitinib KW - side effects KW - drug KW - off-targets Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167621 VL - 6 IS - 33949 ER - TY - JOUR A1 - Buttmann, Mathias A1 - Seuffert, Linda A1 - Mäder, Uwe A1 - Toyka, Klaus V. T1 - Malignancies after mitoxantrone for multiple sclerosis: a retrospective cohort study JF - Neurology N2 - Objective: To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis. Methods: This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence. Results: Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95% confidence interval CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs 75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes. Conclusions: While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable. KW - multiple sclerosis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188300 VL - 86 ER - TY - JOUR A1 - Hommers, Wilfried A1 - Görs, Marijke T1 - Information integration of Kohlbergian thoughts about consensual sex JF - Universitas Psychologica N2 - The unification of two major approaches to moral judgment is the purpose of the present approach. Kohlberg's well-known stage theory assumes a sequence of discrete stages that underlie all moral judgment. Stage theory recognizes the problem of integrating considerations but gives no way to solve such integration, even with information from any one stage. And, of course, the stage concept denies any significant integration from different stages. Thus, research on moral judgment needs to study the integration problem which can be tested within Anderson's theory of information integration. The main purpose of the present study was to extend this unificationist approach to the issue of sexual morality. A novel task presents information from two very different stages. The results showed that in contrast to discreteness the stage informers were positively correlated in punishment judgments of both genders about consensual sex of juveniles. Furthermore, the subjects integrated considerations from those very different stages also in contrast to the hypothesis that only a single stage was operative at any time. KW - Information Integration Theory KW - Kohlberg KW - moral judgment KW - cognition development Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168487 VL - 15 IS - 3 ER - TY - JOUR A1 - Schwarz, Roland F. A1 - Tamuri, Asif U. A1 - Kultys, Marek A1 - King, James A1 - Godwin, James A1 - Florescu, Ana M. A1 - Schultz, Jörg A1 - Goldman, Nick T1 - ALVIS: interactive non-aggregative visualization and explorative analysis of multiple sequence alignments JF - Nucleic Acids Research N2 - Sequence Logos and its variants are the most commonly used method for visualization of multiple sequence alignments (MSAs) and sequence motifs. They provide consensus-based summaries of the sequences in the alignment. Consequently, individual sequences cannot be identified in the visualization and covariant sites are not easily discernible. We recently proposed Sequence Bundles, a motif visualization technique that maintains a one-to-one relationship between sequences and their graphical representation and visualizes covariant sites. We here present Alvis, an open-source platform for the joint explorative analysis of MSAs and phylogenetic trees, employing Sequence Bundles as its main visualization method. Alvis combines the power of the visualization method with an interactive toolkit allowing detection of covariant sites, annotation of trees with synapomorphies and homoplasies, and motif detection. It also offers numerical analysis functionality, such as dimension reduction and classification. Alvis is user-friendly, highly customizable and can export results in publication-quality figures. It is available as a full-featured standalone version (http://www.bitbucket.org/rfs/alvis) and its Sequence Bundles visualization module is further available as a web application (http://science-practice.com/projects/sequence-bundles). KW - visualization KW - multiple sequence alignments KW - phylogenetic trees KW - Alvis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166374 VL - 44 IS - 8 ER - TY - JOUR A1 - Weisschuh, Nicole A1 - Mayer, Anja K. A1 - Strom, Tim M. A1 - Kohl, Susanne A1 - Glöckle, Nicola A1 - Schubach, Max A1 - Andreasson, Sten A1 - Bernd, Antje A1 - Birch, David G. A1 - Hamel, Christian P. A1 - Heckenlively, John R. A1 - Jacobson, Samuel G. A1 - Kamme, Christina A1 - Kellner, Ulrich A1 - Kunstmann, Erdmute A1 - Maffei, Pietro A1 - Reiff, Charlotte M. A1 - Rohrschneider, Klaus A1 - Rosenberg, Thomas A1 - Rudolph, Günther A1 - Vámos, Rita A1 - Varsányi, Balázs A1 - Weleber, Richard G. A1 - Wissinger, Bernd T1 - Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing JF - PLoS ONE N2 - Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes. KW - mutation detection KW - retinal dystrophies KW - next generation sequencing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167398 VL - 11 IS - 1 ER - TY - JOUR A1 - Heise, Ruth A1 - Amann, Philipp M. A1 - Ensslen, Silke A1 - Marquardt, Yvonne A1 - Czaja, Katharina A1 - Joussen, Sylvia A1 - Beer, Daniel A1 - Abele, Rupert A1 - Plewnia, Gabriele A1 - Tampé, Robert A1 - Merk, Hans F. A1 - Hermanns, Heike M. A1 - Baron, Jens M. T1 - Interferon Alpha Signalling and Its Relevance for the Upregulatory Effect of Transporter Proteins Associated with Antigen Processing (TAP) in Patients with Malignant Melanoma JF - PLoS ONE N2 - Introduction Interferon alpha (IFNα) is routinely used in the clinical practice for adjuvant systemic melanoma therapy. Understanding the molecular mechanism of IFNα effects and prediction of response in the IFNα therapy regime allows initiation and continuation of IFNα treatment for responder and exclusion of non-responder to avoid therapy inefficacy and side-effects. The transporter protein associated with antigen processing-1 (TAP1) is part of the MHC class I peptide-loading complex, and important for antigen presentation in tumor and antigen presenting cells. In the context of personalized medicine, we address this potential biomarker TAP1 as a target of IFNα signalling. Results We could show that IFNα upregulates TAP1 expression in peripheral blood mononuclear cells (PBMCs) of patients with malignant melanoma receiving adjuvant high-dose immunotherapy. IFNα also induced expression of TAP1 in mouse blood and tumor tissue and suppressed the formation of melanoma metastasis in an in vivo B16 tumor model. Besides its expression, TAP binding affinity and transport activity is induced by IFNα in human monocytic THP1 cells. Furthermore, our data revealed that IFNα clearly activates phosphorylation of STAT1 and STAT3 in THP1 and A375 melanoma cells. Inhibition of Janus kinases abrogates the IFNα-induced TAP1 expression. These results suggest that the JAK/STAT pathway is a crucial mediator for TAP1 expression elicited by IFNα treatment. Conclusion We suppose that silencing of TAP1 expression provides tumor cells with a mechanism to escape cytotoxic T-lymphocyte recognition. The observed benefit of IFNα treatment could be mediated by the shown dual effect of TAP1 upregulation in antigen presenting cells on the one hand, and of TAP1 upregulation in ‘silent’ metastatic melanoma cells on the other hand. In conclusion, this work contributes to a better understanding of the mode of action of IFNα which is essential to identify markers to predict, assess and monitor therapeutic response of IFNα treatment in the future. KW - interferon alpha signalling KW - interferon alpha (IFNα) KW - transporter protein associated with antigen processing-1 (TAP1) KW - melanoma therapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167409 VL - 11 IS - 1 ER - TY - JOUR A1 - Heurich, Marco A1 - Zeis, Klara A1 - Küchenhoff, Helmut A1 - Müller, Jörg A1 - Belotti, Elisa A1 - Bufka, Luděk A1 - Woelfing, Benno T1 - Selective Predation of a Stalking Predator on Ungulate Prey JF - PLoS ONE N2 - Prey selection is a key factor shaping animal populations and evolutionary dynamics. An optimal forager should target prey that offers the highest benefits in terms of energy content at the lowest costs. Predators are therefore expected to select for prey of optimal size. Stalking predators do not pursue their prey long, which may lead to a more random choice of prey individuals. Due to difficulties in assessing the composition of available prey populations, data on prey selection of stalking carnivores are still scarce. We show how the stalking predator Eurasian lynx (Lynx lynx) selects prey individuals based on species identity, age, sex and individual behaviour. To address the difficulties in assessing prey population structure, we confirm inferred selection patterns by using two independent data sets: (1) data of 387 documented kills of radio-collared lynx were compared to the prey population structure retrieved from systematic camera trapping using Manly’s standardized selection ratio alpha and (2) data on 120 radio-collared roe deer were analysed using a Cox proportional hazards model. Among the larger red deer prey, lynx selected against adult males—the largest and potentially most dangerous prey individuals. In roe deer lynx preyed selectively on males and did not select for a specific age class. Activity during high risk periods reduced the risk of falling victim to a lynx attack. Our results suggest that the stalking predator lynx actively selects for size, while prey behaviour induces selection by encounter and stalking success rates. KW - stalking predators KW - prey selection KW - Lynx lynx Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166827 VL - 11 IS - 8 ER - TY - JOUR A1 - Read, Hannah M. A1 - Mills, Grant A1 - Johnson, Sarah A1 - Tsai, Peter A1 - Dalton, James A1 - Barquist, Lars A1 - Print, Cristin G. A1 - Patrick, Wayne M. A1 - Wiles, Siouxsie T1 - The in vitro and in vivo effects of constitutive light expression on a bioluminescent strain of the mouse enteropathogen Citrobacter rodentium JF - PeerJ N2 - Bioluminescent reporter genes, such as those from fireflies and bacteria, let researchers use light production as a non-invasive and non-destructive surrogate measure of microbial numbers in a wide variety of environments. As bioluminescence needs microbial metabolites, tagging microorganisms with luciferases means only live metabolically active cells are detected. Despite the wide use of bioluminescent reporter genes, very little is known about the impact of continuous (also called constitutive) light expression on tagged bacteria. We have previously made a bioluminescent strain of Citrobacter rodentium, a bacterium which infects laboratory mice in a similar way to how enteropathogenic Escherichia coli (EPEC) and enterohaemorrhagic E. coli (EHEC) infect humans. In this study, we compared the growth of the bioluminescent C. rodentium strain ICC180 with its non-bioluminescent parent (strain ICC169) in a wide variety of environments. To understand more about the metabolic burden of expressing light, we also compared the growth profiles of the two strains under approximately 2,000 different conditions. We found that constitutive light expression in ICC180 was near-neutral in almost every non-toxic environment tested. However, we also found that the non-bioluminescent parent strain has a competitive advantage over ICC180 during infection of adult mice, although this was not enough for ICC180 to be completely outcompeted. In conclusion, our data suggest that constitutive light expression is not metabolically costly to C. rodentium and supports the view that bioluminescent versions of microbes can be used as a substitute for their non-bioluminescent parents to study bacterial behaviour in a wide variety of environments. KW - bioluminescence KW - lux KW - luciferase KW - biophotonic imaging KW - bioluminescence imaging KW - enteric pathogens KW - animal model KW - reporter genes KW - phenotypic microarray KW - biolog Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166576 VL - 4 IS - e2130 ER - TY - JOUR A1 - Scherer, Sandra D. A1 - Bauer, Jochen A1 - Schmaus, Anja A1 - Neumaier, Christian A1 - Herskind, Carsten A1 - Veldwijk, Marlon R. A1 - Wenz, Frederik A1 - Sleeman, Jonathan P. T1 - TGF-β1 Is Present at High Levels in Wound Fluid from Breast Cancer Patients Immediately Post-Surgery, and Is Not Increased by Intraoperative Radiation Therapy (IORT) JF - PLoS ONE N2 - In patients with low-risk breast cancer, intraoperative radiotherapy (IORT) during breast-conserving surgery is a novel and convenient treatment option for delivering a single high dose of irradiation directly to the tumour bed. However, edema and fibrosis can develop after surgery and radiotherapy, which can subsequently impair quality of life. TGF-β is a strong inducer of the extracellular matrix component hyaluronan (HA). TGF-β expression and HA metabolism can be modulated by irradiation experimentally, and are involved in edema and fibrosis. We therefore hypothesized that IORT may regulate these factors.Wound fluid (WF) draining from breast lumpectomy sites was collected and levels of TGF-β1 and HA were determined by ELISA. Proliferation and marker expression was analyzed in primary lymphatic endothelial cells (LECs) treated with recombinant TGF-β or WF. Our results show that IORT does not change TGF-β1 or HA levels in wound fluid draining from breast lumpectomy sites, and does not lead to accumulation of sHA oligosaccharides. Nevertheless, concentrations of TGF-β1 were high in WF from patients regardless of IORT, at concentrations well above those associated with fibrosis and the suppression of LEC identity. Consistently, we found that TGF-β in WF is active and inhibits LEC proliferation. Furthermore, all three TGF-β isoforms inhibited LEC proliferation and suppressed LEC marker expression at pathophysiologically relevant concentrations. Given that TGF-β contributes to edema and plays a role in the regulation of LEC identity, we suggest that inhibition of TGF-β directly after surgery might prevent the development of side effects such as edema and fibrosis. KW - TGF-β1 KW - breast cancer KW - intraoperative radiotherapy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166811 VL - 11 IS - 9 ER - TY - JOUR A1 - Hennighausen, Christine A1 - Hudders, Liselot A1 - Lange, Benjamin P. A1 - Fink, Hanna T1 - What If the Rival Drives a Porsche? Luxury Car Spending as a Costly Signal in Male Intrasexual Competition JF - Evolutionary Psychology N2 - Previous research found that men conspicuously consume luxury products to attract a mate and to signal their mate value. However, these studies have yet neglected to investigate the function of male conspicuous consumption in same-sex competition. Given that intersexual selection and intrasexual selection are closely related processes, it stands to reason that a further function of male conspicuous consumption could be to impress and deter same-sex rivals. An 2 (intrasexual competition context vs. control) × 2 (conspicuous luxury vs. inconspicuous nonluxury) between-subjects experimental study conducted with an Amazon Mechanical Turk sample (N = 160) revealed that men reported both higher liking of and an intent to purchase a conspicuous luxury car compared to an inconspicuous nonluxury car due to increased feelings of social status. This effect was stronger in the intrasexual competition than in the control context. An additional perception study using a single-factor between-subjects design (conspicuous luxury vs. inconspicuous nonluxury car) among German men (N = 405) indicated that male participants rated a man who displayed a conspicuous luxury car more as a rival and mate poacher and less as a friend. They further perceived him to be superior on various mate value characteristics (i.e., attractiveness, intelligence, ambition, and status) and rated him as more oriented toward short-term mating. In sum, our findings add to previous research in the field of evolutionary consumer psychology by suggesting that male conspicuous consumption of luxuries may also serve a function in male–male competition. KW - costly KW - dual function KW - intrasexual competition KW - men KW - luxury brands KW - conspicuous consumption KW - signaling KW - evolutionary consumer psychology Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-163481 VL - 14 IS - 4 ER - TY - JOUR A1 - Fornari, C. I. A1 - Rappl, P. H. O. A1 - Morelhao, S. L. A1 - Peixoto, T. R. F. A1 - Bentmann, H. A1 - Reinert, F. A1 - Abramof, E. T1 - Preservation of pristine Bi\(_2\)Te\(_3\) thin film topological insulator surface after ex situ mechanical removal of Te capping layer JF - APL Materials N2 - Ex situ analyses on topological insulator films require protection against surface contamination during air exposure. This work reports on a technique that combines deposition of protective capping just after epitaxial growth and its mechanical removal inside ultra-high vacuum systems. This method was applied to Bi2Te3 films with thickness varying from 8 to 170 nm. Contrarily to other methods, this technique does not require any sputtering or thermal annealing setups installed inside the analyzing system and preserves both film thickness and surface characteristics. These results suggest that the technique presented here can be expanded to other topological insulator materials. KW - Insulator surfaces KW - Atomic force microscopy KW - Insulating thin films KW - Molecular beam epitaxy KW - Surface states KW - Vacuum chambers KW - Thin film growth KW - Sputter deposition KW - Epitaxy Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164468 VL - 4 ER - TY - JOUR A1 - Stoeckel, M. Cornelia A1 - Esser, Roland W. A1 - Gamer, Matthias A1 - Büchel, Christian A1 - von Leupoldt, Andreas T1 - Brain Responses during the Anticipation of Dyspnea JF - Neural Plasticity N2 - Dyspnea is common in many cardiorespiratory diseases. Already the anticipation of this aversive symptom elicits fear in many patients resulting in unfavorable health behaviors such as activity avoidance and sedentary lifestyle. This study investigated brain mechanisms underlying these anticipatory processes. We induced dyspnea using resistive-load breathing in healthy subjects during functional magnetic resonance imaging. Blocks of severe and mild dyspnea alternated, each preceded by anticipation periods. Severe dyspnea activated a network of sensorimotor, cerebellar, and limbic areas. The left insular, parietal opercular, and cerebellar cortices showed increased activation already during dyspnea anticipation. Left insular and parietal opercular cortex showed increased connectivity with right insular and anterior cingulate cortex when severe dyspnea was anticipated, while the cerebellum showed increased connectivity with the amygdala. Notably, insular activation during dyspnea perception was positively correlated with midbrain activation during anticipation. Moreover, anticipatory fear was positively correlated with anticipatory activation in right insular and anterior cingulate cortex. The results demonstrate that dyspnea anticipation activates brain areas involved in dyspnea perception. The involvement of emotion-related areas such as insula, anterior cingulate cortex, and amygdala during dyspnea anticipation most likely reflects anticipatory fear and might underlie the development of unfavorable health behaviors in patients suffering from dyspnea. KW - brain response KW - dyspnea KW - cardiorespiratory disease KW - anticipation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166238 VL - 2016 IS - 6434987 ER - TY - JOUR A1 - Nietzer, Sarah A1 - Baur, Florentin A1 - Sieber, Stefan A1 - Hansmann, Jan A1 - Schwarz, Thomas A1 - Stoffer, Carolin A1 - Häfner, Heide A1 - Gasser, Martin A1 - Waaga-Gasser, Ana Maria A1 - Walles, Heike A1 - Dandekar, Gudrun T1 - Mimicking metastases including tumor stroma: a new technique to generate a three-dimensional colorectal cancer model based on a biological decellularized intestinal scaffold JF - Tissue Engineering Part C-Methods N2 - Tumor models based on cancer cell lines cultured two-dimensionally (2D) on plastic lack histological complexity and functionality compared to the native microenvironment. Xenogenic mouse tumor models display higher complexity but often do not predict human drug responses accurately due to species-specific differences. We present here a three-dimensional (3D) in vitro colon cancer model based on a biological scaffold derived from decellularized porcine jejunum (small intestine submucosa+mucosa, SISmuc). Two different cell lines were used in monoculture or in coculture with primary fibroblasts. After 14 days of culture, we demonstrated a close contact of human Caco2 colon cancer cells with the preserved basement membrane on an ultrastructural level as well as morphological characteristics of a well-differentiated epithelium. To generate a tissue-engineered tumor model, we chose human SW480 colon cancer cells, a reportedly malignant cell line. Malignant characteristics were confirmed in 2D cell culture: SW480 cells showed higher vimentin and lower E-cadherin expression than Caco2 cells. In contrast to Caco2, SW480 cells displayed cancerous characteristics such as delocalized E-cadherin and nuclear location of beta-catenin in a subset of cells. One central drawback of 2D cultures-especially in consideration of drug testing-is their artificially high proliferation. In our 3D tissue-engineered tumor model, both cell lines showed decreased numbers of proliferating cells, thus correlating more precisely with observations of primary colon cancer in all stages (UICC I-IV). Moreover, vimentin decreased in SW480 colon cancer cells, indicating a mesenchymal to epithelial transition process, attributed to metastasis formation. Only SW480 cells cocultured with fibroblasts induced the formation of tumor-like aggregates surrounded by fibroblasts, whereas in Caco2 cocultures, a separate Caco2 cell layer was formed separated from the fibroblast compartment beneath. To foster tissue generation, a bioreactor was constructed for dynamic culture approaches. This induced a close tissue-like association of cultured tumor cells with fibroblasts reflecting tumor biopsies. Therapy with 5-fluorouracil (5-FU) was effective only in 3D coculture. In conclusion, our 3D tumor model reflects human tissue-related tumor characteristics, including lower tumor cell proliferation. It is now available for drug testing in metastatic context-especially for substances targeting tumor-stroma interactions. KW - Multicenter randomized-trial KW - Carcinoma cells KW - Tissue KW - Fluorouracil KW - Matrix KW - 1st-line treatment KW - Beta-catenin KW - Invasion KW - 5-Fluorouracil KW - Fibroblasts Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188202 VL - 22 IS - 7 ER - TY - JOUR A1 - Denner, Ansgar A1 - Jenniches, Laura A1 - Lang, Jean-Nicolas A1 - Sturm, Christian T1 - Gauge-independent (MS)over-bar renormalization in the 2HDM JF - Journal of High Energy Physics N2 - We present a consistent renormalization scheme for the CP-conserving Two-Higgs-Doublet Model based on (MS)over-bar renormalization of the mixing angles and the soft-Z 2-symmetry-breaking scale M sb in the Higgs sector. This scheme requires to treat tadpoles fully consistently in all steps of the calculation in order to provide gauge-independent S-matrix elements. We show how bare physical parameters have to be defined and verify the gauge independence of physical quantities by explicit calculations in a general R ξ -gauge. The procedure is straightforward and applicable to other models with extended Higgs sectors. In contrast to the proposed scheme, the (MS)over-bar renormalization of the mixing angles combined with popular on-shell renormalization schemes gives rise to gauge-dependent results already at the one-loop level. We present explicit results for electroweak NLO corrections to selected processes in the appropriately renormalized Two-Higgs-Doublet Model and in particular discuss their scale dependence. KW - NLO Computations Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166402 VL - 09 IS - 115 ER - TY - JOUR A1 - Wente, Sarah A1 - Schröder, Simone A1 - Buckard, Johannes A1 - Büttel, Hans-Martin A1 - von Deimling, Florian A1 - Diener, Wilfried A1 - Häussler, Martin A1 - Hübschle, Susanne A1 - Kinder, Silvia A1 - Kurlemann, Gerhard A1 - Kretzschmar, Christoph A1 - Lingen, Michael A1 - Maroske, Wiebke A1 - Mundt, Dirk A1 - Sánchez-Albisua, Iciar A1 - Seeger, Jürgen A1 - Toelle, Sandra P. A1 - Boltshauser, Eugen A1 - Brockmann, Knut T1 - Nosological delineation of congenital ocular motor apraxia type Cogan: an observational study JF - Orphanet Journal of Rare Diseases N2 - Background The nosological assignment of congenital ocular motor apraxia type Cogan (COMA) is still controversial. While regarded as a distinct entity by some authorities including the Online Mendelian Inheritance in Man catalog of genetic disorders, others consider COMA merely a clinical symptom. Methods We performed a retrospective multicenter data collection study with re-evaluation of clinical and neuroimaging data of 21 previously unreported patients (8 female, 13 male, ages ranging from 2 to 24 years) diagnosed as having COMA. Results Ocular motor apraxia (OMA) was recognized during the first year of life and confined to horizontal pursuit in all patients. OMA attenuated over the years in most cases, regressed completely in two siblings, and persisted unimproved in one individual. Accompanying clinical features included early onset ataxia in most patients and cognitive impairment with learning disability (n = 6) or intellectual disability (n = 4). Re-evaluation of MRI data sets revealed a hitherto unrecognized molar tooth sign diagnostic for Joubert syndrome in 11 patients, neuroimaging features of Poretti-Boltshauser syndrome in one case and cerebral malformation suspicious of a tubulinopathy in another subject. In the remainder, MRI showed vermian hypo-/dysplasia in 4 and no abnormalities in another 4 patients. There was a strong trend to more severe cognitive impairment in patients with Joubert syndrome compared to those with inconclusive MRI, but otherwise no significant difference in clinical phenotypes between these two groups. Conclusions Systematical renewed analysis of neuroimaging data resulted in a diagnostic reappraisal in the majority of patients with early-onset OMA in the cohort reported here. This finding poses a further challenge to the notion of COMA constituting a separate entity and underlines the need for an expert assessment of neuroimaging in children with COMA, especially if they show cognitive impairment. KW - congenital ocular motor apraxia KW - molar tooth sign KW - Joubert syndrome Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166534 VL - 11 IS - 104 ER - TY - JOUR A1 - Buck, Andreas A1 - Decristoforo, Clemens T1 - Highlights lecture EANM 2015: the search for nuclear medicine's superheroes JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - The EANM 2015 Annual Congress, held from October 10th to 14th in Hamburg, Germany, was outstanding in many respects. With 5550 participants, this was by far the largest European congress concerning nuclear medicine. More than 1750 scientific presentations were submitted, with more than 250 abstracts from young scientists, indicating that the future success of our discipline is fuelled by a high number of young individuals becoming involved in a multitude of scientific activities. Significant improvements have been made in molecular imaging of cancer, particularly in prostate cancer. PSMA-directed PET/CT appears to become a new gold standard for staging and restaging purposes. Novel tumour specific compounds have shown their potential for target identification also in other solid neoplasms and further our understanding of tumour biology and heterogeneity. In addition, a variety of nuclear imaging techniques guiding surgical interventions have been introduced. A particular focus of the congress was put on targeted, radionuclide based therapies. Novel theranostic concepts addressing also tumour entities with high incidence rates such as prostate cancer, melanoma, and lymphoma, have shown effective anti-tumour activity. Strategies have been presented to improve further already established therapeutic regimens such as somatostatin receptor based radio receptor therapy for treating advanced neuroendocrine tumours. Significant contributions were presented also in the neurosciences track. An increasing number of target structures of high interest in neurology and psychiatry are now available for PET and SPECT imaging, facilitating specific imaging of different subtypes of dementia and movement disorders as well as neuroinflammation. Major contributions in the cardiovascular track focused on further optimization of cardiac perfusion imaging by reducing radiation exposure, reducing scanning time, and improving motion correction. Besides coronary artery disease, many contributions focused on cardiac inflammation, cardiac sarcoidosis, and specific imaging of large vessel vasculitis. The physics and instrumentation track included many highlights such as novel, high resolution scanners. The most noteworthy news and developments of this meeting were summarized in the highlights lecture. Only 55 scientific contributions were mentioned, and hence they represent only a brief summary, which is outlined in this article. For a more detailed view, all presentations can be accessed by the online version of the European Journal of Nuclear Medicine and Molecular Imaging (Volume 42, Supplement 1). KW - Conjugate arc therapy KW - Phase-II KW - 18F-FDG PET/CT KW - Highlights Lecture KW - Molecular Imaging KW - Prostate-cancer KW - Radionuclide therapy KW - Myocardial perfusion KW - Preclinical evaluation KW - Targeted therapy KW - Thyroid cancer KW - SPECT KW - 2015 KW - EANM KW - Hamburg KW - Physics and instrumentation KW - Radiopharmacy KW - Oncology KW - Radionuclide Therapy KW - Cardiology KW - Neurosciences Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187613 VL - 43 IS - 10 ER - TY - JOUR A1 - Weidemann, Frank A1 - Maier, Sebastian K. G. A1 - Störk, Stefan A1 - Brunner, Thomas A1 - Liu, Dan A1 - Hu, Kai A1 - Seydelmann, Nora A1 - Schneider, Andreas A1 - Becher, Jan A1 - Canan-Kühl, Sima A1 - Blaschke, Daniela A1 - Bijnens, Bart A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Usefulness of an implantable loop recorder to detect clinically relevant arrhythmias in patients with advanced fabry cardiomyopathy JF - The American Journal of Cardiology N2 - Patients with genetic cardiomyopathy that involves myocardial hypertrophy often develop clinically relevant arrhythmias that increase the risk of sudden death. Consequently, guidelines for medical device therapy were established for hypertrophic cardiomyopathy, but not for conditions with only anecdotal evidence of arrhythmias, like Fabry cardiomyopathy. Patients with Fabry cardiomyopathy progressively develop myocardial fibrosis, and sudden cardiac death occurs regularly. Because 24-hour Holier electrocardiograms (ECGs) might not detect clinically important arrhythmias, we tested an implanted loop recorder for continuous heart rhythm surveillance and determined its impact on therapy. This prospective study included 16 patients (12 men) with advanced Fabry cardiomyopathy, relevant hypertrophy, and replacement fibrosis in "loco typico." No patients previously exhibited clinically relevant arrhythmias on Holier ECGs. Patients received an implantable loop recorder and were prospectively followed with telemedicine for a median of 1.2 years (range 0.3 to 2.0 years). The primary end point was a clinically meaningful event, which required a therapy change, captured with the loop recorder. Patients submitted data regularly (14 +/- 11 times per month). During follow-up, 21 events were detected (including 4 asystole, i.e., ECG pauses >= 3 seconds) and 7 bradycardia events; 5 episodes of intermittent atrial fibrillation (>3 minutes) and 5 episodes of ventricular tachycardia (3 sustained and 2 nonsustained). Subsequently, as defined in the primary end point, 15 events leaded to a change of therapy. These patients required therapy with a pacemaker or cardioverter defibrillator implantation and/or anticoagulation therapy for atrial fibrillation. In conclusion, clinically relevant arrhythmias that require further device and/or medical therapy are often missed with Holier ECGs in patients with advanced stage Fabry cardiomyopathy, but they can be detected by telemonitoring with an implantable loop recorder. KW - Cardiovascular magnetic-resonance KW - Coronary artery disease KW - Ventricular-arrhythmias KW - Task force KW - Management KW - Enzyme replacement therapy KW - Hypertrophic cardiomyopathy KW - Myocardial fibrosis KW - Guidelines KW - Manifestation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188093 VL - 118 IS - 2 ER - TY - JOUR A1 - Weidner, Christopher A1 - Rousseau, Morten A1 - Plauth, Annabell A1 - Wowro, Sylvia J. A1 - Fischer, Cornelius A1 - Abdel-Aziz, Heba A1 - Sauer, Sascha T1 - Iberis amara Extract Induces Intracellular Formation of Reactive Oxygen Species and Inhibits Colon Cancer JF - PLoS ONE N2 - Massively increasing global incidences of colorectal cancer require efficient treatment and prevention strategies. Here, we report unexpected anticancerogenic effects of hydroethanolic Iberis amara extract (IAE), which is known as a widely used phytomedical product for treating gastrointestinal complaints. IAE significantly inhibited the proliferation of HT-29 and T84 colon carcinoma cells with an inhibitory concentration (IC\(_{50}\)) of 6 and 9 μg/ml, respectively, and further generated inhibitory effects in PC-3 prostate and MCF7 breast cancer cells. Inhibition of proliferation in HT-29 cells was associated with a G2/M phase cell cycle arrest including reduced expression of various regulatory marker proteins. Notably, in HT-29 cells IAE further induced apoptosis by intracellular formation of reactive oxygen species (ROS). Consistent with predictions derived from our in vitro experiments, bidaily oral gavage of 50 mg/kg of IAE over 4 weeks resulted in significant inhibition of tumor growth in a mouse HT-29 tumor xenograft model. Taken together, Iberis amara extracts could become useful alternatives for preventing and treating the progression of colon cancer. KW - iberis amara extract KW - colorectal cancer KW - treatment KW - prevention Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167044 VL - 11 IS - 4 ER - TY - JOUR A1 - Vaze, Koustubh M. A1 - Helfrich-Förster, Charlotte T1 - Drosophila ezoana uses an hour-glass or highly damped circadian clock for measuring night length and inducing diapause JF - Physiological Entomology N2 - Insects inhabiting the temperate zones measure seasonal changes in day or night length to enter the overwintering diapause. Diapause induction occurs after the duration of the night exceeds a critical night length (CNL). Our understanding of the time measurement mechanisms is continuously evolving subsequent to Bünning’s proposal that circadian systems play the clock role in photoperiodic time measurement (Bünning, 1936). Initially, the photoperiodic clocks were considered to be either based on circadian oscillators or on simple hour-glasses, depending on ‘positive’ or ‘negative’ responses in Nanda–Hamner and Bünsow experiments (Nanda & Hammer, 1958; Bünsow, 1960). However, there are also species whose responses can be regarded as neither ‘positive’, nor as ‘negative’, such as the Northern Drosophila species Drosophila ezoana, which is investigated in the present study. In addition, modelling efforts show that the ‘positive’ and ‘negative’ Nanda–Hamner responses can also be provoked by circadian oscillators that are damped to different degrees: animals with highly sustained circadian clocks will respond ‘positive’ and those with heavily damped circadian clocks will respond ‘negative’. In the present study, an experimental assay is proposed that characterizes the photoperiodic oscillators by determining the effects of non-24-h light/dark cycles (T-cycles) on critical night length. It is predicted that there is (i) a change in the critical night length as a function of T-cycle period in sustained-oscillator-based clocks and (ii) a fxed night-length measurement (i.e. no change in critical night length) in damped-oscillator-based clocks. Drosophila ezoana flies show a critical night length of approximately 7 h irrespective of T-cycle period, suggesting a damped-oscillator-based photoperiodic clock. The conclusion is strengthened by activity recordings revealing that the activity rhythm of D. ezoana flies also dampens in constant darkness. KW - photoperiodic time mesurement KW - wyeomyia smithii KW - protophormia terraenovae KW - immunoreactive neurons KW - geographical variation KW - reproductive diapause KW - rhythmic components KW - locomotor activity KW - circadian clock KW - damped-oscillator-model of photoperiodic clock KW - diapause KW - Drosophila KW - hour-glass KW - pitcher-plant mosquito KW - bug riptortus-pedestris KW - Nanda-Hamner KW - photoperiodism Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-204278 VL - 41 IS - 4 ER - TY - JOUR A1 - Beer, Katharina A1 - Steffan-Dewenter, Ingolf A1 - Härtel, Stephan A1 - Helfrich-Förster, Charlotte T1 - A new device for monitoring individual activity rhythms of honey bees reveals critical effects of the social environment on behavior JF - Journal of Comparative Physiology A N2 - Chronobiological studies of individual activity rhythms in social insects can be constrained by the artificial isolation of individuals from their social context. We present a new experimental set-up that simultaneously measures the temperature rhythm in a queen-less but brood raising mini colony and the walking activity rhythms of singly kept honey bees that have indirect social contact with it. Our approach enables monitoring of individual bees in the social context of a mini colony under controlled laboratory conditions. In a pilot experiment, we show that social contact with the mini colony improves the survival of monitored young individuals and affects locomotor activity patterns of young and old bees. When exposed to conflicting Zeitgebers consisting of a light-dark (LD) cycle that is phase-delayed with respect to the mini colony rhythm, rhythms of young and old bees are socially synchronized with the mini colony rhythm, whereas isolated bees synchronize to the LD cycle. We conclude that the social environment is a stronger Zeitgeber than the LD cycle and that our new experimental set-up is well suited for studying the mechanisms of social entrainment in honey bees. KW - Social entrainment KW - Foragers KW - Nurses KW - Locomotor activity KW - Temperature rhythms Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188030 VL - 202 IS - 8 ER -