TY  - JOUR
A1  - Wohlfarth, Carolin
A1  - Schmitteckert, Stefanie
A1  - Härtle, Janina D.
A1  - Houghton, Lesley A.
A1  - Dweep, Harsh
A1  - Fortea, Marina
A1  - Assadi, Ghazaleh
A1  - Braun, Alexander
A1  - Mederer, Tanja
A1  - Pöhner, Sarina
A1  - Becker, Philip P.
A1  - Fischer, Christine
A1  - Granzow, Martin
A1  - Mönnikes, Hubert
A1  - Mayer, Emeran A.
A1  - Sayuk, Gregory
A1  - Boeckxstaens, Guy
A1  - Wouters, Mira M.
A1  - Simrén, Magnus
A1  - Lindberg, Greger
A1  - Ohlsson, Bodil
A1  - Schmidt, Peter Thelin
A1  - Dlugosz, Aldona
A1  - Agreus, Lars
A1  - Andreasson, Anna
A1  - D'Amato, Mauro
A1  - Burwinkel, Barbara
A1  - Bermejo, Justo Lorenzo
A1  - Röth, Ralph
A1  - Lasitschka, Felix
A1  - Vicario, Maria
A1  - Metzger, Marco
A1  - Santos, Javier
A1  - Rappold, Gudrun A.
A1  - Martinez, Cristina
A1  - Niesler, Beate
T1  - miR-16 and miR-103 impact 5-HT4 receptor signalling and correlate with symptom profile in irritable bowel syndrome
JF  - Scientific Reports
N2  - Irritable bowel syndrome (IBS) is a gut-brain disorder involving alterations in intestinal sensitivity and motility. Serotonin 5-HT4 receptors are promising candidates in IBS pathophysiology since they regulate gut motor function and stool consistency, and targeted 5-HT4R selective drug intervention has been proven beneficial in subgroups of patients. We identified a single nucleotide polymorphism (SNP) (rs201253747) c.*61 T > C within the 5-HT4 receptor gene \(HTR4\) to be predominantly present in diarrhoea-IBS patients (IBS-D). It affects a binding site for the miR-16 family and miR-103/miR-107 within the isoforms \({HTR4b/i}\) and putatively impairs \(HTR4\) expression. Subsequent miRNA profiling revealed downregulation of miR-16 and miR-103 in the jejunum of IBS-D patients correlating with symptoms. \(In\) \(vitro\) assays confirmed expression regulation via three 3′UTR binding sites. The novel isoform \(HTR4b\_2\) lacking two of the three miRNA binding sites escapes miR-16/103/107 regulationin SNP carriers. We provide the first evidence that \(HTR4\) expression is fine-tuned by miRNAs, and that this regulation is impaired either by the SNP c.*61 T > C or bydiminished levels of miR-16 and miR-103 suggesting that \(HTR4\) might be involved in the development of IBS-D.
KW  - Medicine
KW  - Gene regulation
KW  - Irritable bowel syndrome
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173478
VL  - 7
ER  - 
TY  - JOUR
A1  - Taubenböck, H
A1  - Wurm, M
A1  - Netzband, M
A1  - Zwenzner, H
A1  - Roth, A
A1  - Rahman, A
A1  - Dech, S
T1  - Flood risks in urbanized areas - multi-sensoral approaches using remotely sensed data for risk assessment
JF  - NATURAL HAZARDS AND EARTH SYSTEM SCIENCES
N2  - Estimating flood risks and managing disasters combines knowledge in climatology, meteorology, hydrology, hydraulic engineering, statistics, planning and geography - thus a complex multi-faceted problem. This study focuses on the capabilities of multi-source remote sensing data to support decision-making before, during and after a flood event. With our focus on urbanized areas, sample methods and applications show multi-scale products from the hazard and vulnerability perspective of the risk framework. From the hazard side, we present capabilities with which to assess flood-prone areas before an expected disaster. Then we map the spatial impact during or after a flood and finally, we analyze damage grades after a flood disaster. From the vulnerability side, we monitor urbanization over time on an urban footprint level, classify urban structures on an individual building level, assess building stability and quantify probably affected people. The results show a large database for sustainable development and for developing mitigation strategies, ad-hoc coordination of relief measures and organizing rehabilitation.
KW  - damage assessment disaster
KW  - satellite data
KW  - management
KW  - radar
KW  - inundation
KW  - disaster
KW  - sar
KW  - gis
KW  - integration
KW  - earthquake
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139605
VL  - 11
IS  - 2
ER  - 
TY  - JOUR
A1  - Maurus, K.
A1  - Kosnopfel, C.
A1  - Kneitz, H.
A1  - Appenzeller, S.
A1  - Schrama, D.
A1  - Glutsch, V.
A1  - Roth, S.
A1  - Gerhard-Hartmann, E.
A1  - Rosenfeldt, M.
A1  - Möhrmann, L.
A1  - Fröhlich, M.
A1  - Hübschmann, D.
A1  - Stenzinger, A.
A1  - Glimm, H.
A1  - Fröhling, S.
A1  - Goebeler, M.
A1  - Rosenwald, A.
A1  - Kutzner, H.
A1  - Schilling, B.
T1  - Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen-activated protein kinase pathway
JF  - British Journal of Dermatology
N2  - Background
Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive.

Objectives
To identify genetic alterations by next-generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH.

Methods
DNA and RNA from an EH lesion of an index patient were subjected to whole-genome and RNA sequencing. Multiplex PCR-based panel sequencing of genomic DNA isolated from archival formalin-fixed paraffin-embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations.

Results
We identified somatic mutations in genes of the mitogen-activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low-frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells.

Conclusions
Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour.
KW  - protein kinase pathway
KW  - Background Epithelioid haemangioma
KW  - somatic mutations
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258333
VL  - 186
IS  - 3
ER  - 
TY  - JOUR
A1  - Mainz, Laura
A1  - Sarhan, Mohamed A. F. E.
A1  - Roth, Sabine
A1  - Sauer, Ursula
A1  - Maurus, Katja
A1  - Hartmann, Elena M.
A1  - Seibert, Helen-Desiree
A1  - Rosenwald, Andreas
A1  - Diefenbacher, Markus E.
A1  - Rosenfeldt, Mathias T.
T1  - Autophagy blockage reduces the incidence of pancreatic ductal adenocarcinoma in the context of mutant Trp53
JF  - Frontiers in Cell and Developmental Biology
N2  - Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53\(^{R172H}\)) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.
KW  - pancreatic cancer
KW  - autophagy
KW  - p53
KW  - metastasis
KW  - ATG7
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266005
SN  - 2296-634X
VL  - 10
ER  - 
TY  - JOUR
A1  - Guth, Sabine
A1  - Hüser, Stephanie
A1  - Roth, Angelika
A1  - Degen, Gisela
A1  - Diel, Patrick
A1  - Edlund, Karolina
A1  - Eisenbrand, Gerhard
A1  - Engel, Karl-Heinz
A1  - Epe, Bernd
A1  - Grune, Tilman
A1  - Heinz, Volker
A1  - Henle, Thomas
A1  - Humpf, Hans-Ulrich
A1  - Jäger, Henry
A1  - Joost, Hans-Georg
A1  - Kulling, Sabine E.
A1  - Lampen, Alfonso
A1  - Mally, Angela
A1  - Marchan, Rosemarie
A1  - Marko, Doris
A1  - Mühle, Eva
A1  - Nitsche, Michael A.
A1  - Röhrdanz, Elke
A1  - Stadler, Richard
A1  - van Thriel, Christoph
A1  - Vieths, Stefan
A1  - Vogel, Rudi F.
A1  - Wascher, Edmund
A1  - Watzl, Carsten
A1  - Nöthlings, Ute
A1  - Hengstler, Jan G.
T1  - Contribution to the ongoing discussion on fluoride toxicity
JF  - Archives of Toxicology
N2  - Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.
KW  - pharmacology/toxicology
KW  - occupational medicine/industrial medicine
KW  - environmental health
KW  - biomedicine, general
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-307161
SN  - 0340-5761
SN  - 1432-0738
VL  - 95
IS  - 7
ER  -