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  • 1
    Keywords: EXPRESSION ; prognosis ; UP-REGULATION ; MUTATION ; COLON-CANCER ; C-MYC ; K-RAS ; VEMURAFENIB ; AGGRESSIVE ADENOCARCINOMA ; FACTOR CDX2
    Abstract: BRAF mutations are associated with aggressive, less-differentiated and therapy-resistant colorectal carcinoma. However, the underlying mechanisms for these correlations remain unknown. To understand how oncogenic B-Raf contributes to carcinogenesis, in particular to aspects other than cellular proliferation and survival, we generated three isogenic human colorectal carcinoma cell line models in which we can dynamically modulate the expression of the B-Raf(V600E) oncoprotein. Doxycyclin-inducible knockdown of endogenous B-Raf(V600E) decreases cellular motility and invasion in conventional and three-dimensional (3D) culture, whereas it promotes cell-cell contacts and induces various hallmarks of differentiated epithelia. Importantly, all these effects are recapitulated by B-Raf (PLX4720, vemurafenib, and dabrafenib) or MEK inhibitors (trametinib). Surprisingly, loss of B-Raf(V600E) in HT29 xenografts does not only stall tumor growth, but also induces glandular structures with marked expression of CDX2, a tumor-suppressor and master transcription factor of intestinal differentiation. By performing the first transcriptome profiles of PLX4720-treated 3D cultures of HT29 and Colo-205 cells, we identify several upregulated genes linked to epithelial differentiation and effector functions, such as claudin-1, a Cdx-2 target gene encoding a critical tight junction component. Thereby, we provide a mechanism for the clinically observed correlation between mutant BRAF and the loss of Cdx-2 and claudin-1. PLX4720 also suppressed several metastasis-associated transcripts that have not been implicated as targets, effectors or potential biomarkers of oncogenic B-Raf signaling so far. Together, we identify a novel facet of clinically applied B-Raf or MEK inhibitors by showing that they promote cellular adhesion and differentiation of colorectal carcinoma cells.
    Type of Publication: Journal article published
    PubMed ID: 25381152
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  • 2
    Abstract: The nerve growth factor NGF has been shown to cause cell fate decisions toward either differentiation or proliferation depending on the relative activity of downstream pERK, pAKT, or pJNK signaling. However, how these protein signals are translated into and fed back from transcriptional activity to complete cellular differentiation over a time span of hours to days is still an open question. Comparing the time-resolved transcriptome response of NGF- or EGF-stimulated PC12 cells over 24 h in combination with protein and phenotype data we inferred a dynamic Boolean model capturing the temporal sequence of protein signaling, transcriptional response and subsequent autocrine feedback. Network topology was optimized by fitting the model to time-resolved transcriptome data under MEK, PI3K, or JNK inhibition. The integrated model confirmed the parallel use of MAPK/ERK, PI3K/AKT, and JNK/JUN for PC12 cell differentiation. Redundancy of cell signaling is demonstrated from the inhibition of the different MAPK pathways. As suggested in silico and confirmed in vitro, differentiation was substantially suppressed under JNK inhibition, yet delayed only under MEK/ERK inhibition. Most importantly, we found that positive transcriptional feedback induces bistability in the cell fate switch. De novo gene expression was necessary to activate autocrine feedback that caused Urokinase-Type Plasminogen Activator (uPA) Receptor signaling to perpetuate the MAPK activity, finally resulting in the expression of late, differentiation related genes. Thus, the cellular decision toward differentiation depends on the establishment of a transcriptome-induced positive feedback between protein signaling and gene expression thereby constituting a robust control between proliferation and differentiation.
    Type of Publication: Journal article published
    PubMed ID: 27148350
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  • 3
    Keywords: INCREASE ; P-VALUES ; E-MU-PIM1 TRANSGENIC MICE
    Abstract: The vast majority of in vitro and in vivo studies did not find cancerogenic effects of exposure to electromagnetic fields (RF-EMF), i.e. emitted by mobile phones and base stations. Previously published results from a pilot study with carcinogen-treated mice, however, suggested tumor-promoting effects of RF-EMF (Tillmann et al., 2010). We have performed a replication study using higher numbers of animals per group and including two additional exposure levels (0 (sham), 0.04, 0.4 and 2 W/kg SAR). We could confirm and extend the originally reported findings. Numbers of tumors of the lungs and livers in exposed animals were significantly higher than in sham-exposed controls. In addition, lymphomas were also found to be significantly elevated by exposure. A clear dose-response effect is absent. We hypothesize that these tumor-promoting effects may be caused by metabolic changes due to exposure. Since many of the tumor-promoting effects in our study were seen at low to moderate exposure levels (0.04 and 0.4 W/kg SAR), thus well below exposure limits for the users of mobile phones, further studies are warranted to investigate the underlying mechanisms. Our findings may help to understand the repeatedly reported increased incidences of brain tumors in heavy users of mobile phones.
    Type of Publication: Journal article published
    PubMed ID: 25749340
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  • 4
    Abstract: The mechanistic target of rapamycin (mTOR) is a central regulatory pathway that integrates a variety of environmental cues to control cellular growth and homeostasis by intricate molecular feedbacks. In spite of extensive knowledge about its components, the molecular understanding of how these function together in space and time remains poor and there is a need for Systems Biology approaches to perform systematic analyses. In this work, we review the recent progress how the combined efforts of mathematical models and quantitative experiments shed new light on our understanding of the mTOR signaling pathway. In particular, we discuss the modeling concepts applied in mTOR signaling, the role of multiple feedbacks and the crosstalk mechanisms of mTOR with other signaling pathways. We also discuss the contribution of principles from information and network theory that have been successfully applied in dissecting design principles of the mTOR signaling network. We finally propose to classify the mTOR models in terms of the time scale and network complexity, and outline the importance of the classification toward the development of highly comprehensive and predictive models. WIREs Syst Biol Med 2017, 9:e1379. doi: 10.1002/wsbm.1379 For further resources related to this article, please visit the WIREs website.
    Type of Publication: Journal article published
    PubMed ID: 28186392
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Colloid & polymer science 256 (1978), S. 175-175 
    ISSN: 1435-1536
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Chichester [u.a.] : Wiley-Blackwell
    Journal of Raman Spectroscopy 7 (1978), S. 311-315 
    ISSN: 0377-0486
    Keywords: Chemistry ; Analytical Chemistry and Spectroscopy
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: Previous vibrational assignments for Me4N+ are examined and in some respects revised. Frequency and intensity changes in the Raman spectra of Me4NCl solutions with variations of concentration and solvent (D2O and CD3OH) were observed mainly in the CH stretching and NC4 bending regions. These are interpreted in terms of cation-anion associations the extent of which is found to be much larger in methanolic than in aqueous solution. The effects of temperature on the Raman bands proved to be much smaller than those of concentration or solvent changes.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1437-9813
    Keywords: Gastroschisis ; Abdominal wall defects ; Amniotic graft
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This article describes the use of amniotic grafts (AG) in the repair of large abdominal wall defects in newborns with gastroschisis. From 1988 to 1995, 22 newborns with gastroschisis underwent surgical repair. In 12 primary closure (PC) was performed; in 10 the abdominal wall defect was covered with an AG. A double layer of AG was used and the graft was additionally covered with a silastic silo in 8 cases. The overall mortality was 14%; 3 children died from necrotizing enterocolitis or sepsis after AG. However, the difference in mortality of newborns with PC versus AG was not statistically significant. Patient characteristics, the postoperative courses, nd the frequency of complications were similar after PC and AG. It is concluded that AG has no negative impact on the postoperative course and yields a low overall mortality. In our opinion there are several advantages in using the AG technique: it is an autoplastic material that is readily available without costs, reefing and removal is unnecessary, and there is a potentially low rate of adhesions.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1618-2650
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Es werden die Ergebnisse massenspektrographischer Untersuchungen (mit Funkenionisierung) der festen Bestandteile einiger Thermalwässer der DDR und ČSSR mitgeteilt. Der Vergleich mit bekannten klassischen Naßanalysen zeigt, daß mit der genannten Methode zahlreiche Elemente — im Falle Johannisbad (Jánske Lázně) über 20 Elemente — zusätzlich nachgewiesen werden konnten. Diese sind in dem Thermalwasser in der Mehrzahl in einer Konzentration ≤ 0,1 mg/l vorhanden. Bisherige Untersuchungen zur Ermittlung von Elementempfindlichkeiten reichen noch nicht aus, um für alle Elemente quantitative Auswertungen vornehmen zu können. Das schmälert jedoch nicht die Anwendbarkeit dieser Methode im Hinblick auf die Überwachung der chemischen Bestandteile der Thermalwässer.
    Notes: Abstract The results of mass-spectrographic analyses (with spark ionization) of the solid constituents of some thermal waters of the DDR and of Czechoslovakia are reported. The comparison with well-known classical wet-analyses shows that numerous additional elements — in the case of Johanisbad (Jánske Lázně) more than 20 — could be detected by means of the method mentioned above. In most cases, these elements are contained in the thermal waters in concentrations of ≤ 0.1 mg/l. The existing investigations into the sensitivity of the elements are still insufficient to allow quantitative interpretations for all the elements. This, however, does not reduce the applicability of this method with regard to the control of the chemical constituents of thermal waters.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1618-2650
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Es werden die Ergebnisse massenspektrographischer Analyseuntersuchungen der pulverförmigen Rückstände einiger Thermal- und Oberflächenwässer sowie deren UV-Absorptionsspektren mitgeteilt. Charakteristisch ist danach für die Thermalwässer ihre vergleichsweise größere Elementeanzahl (bis zu 10 Elemente zusätzlich in unseren Beispielen), die kennzeichnend für den Mineralbestand des thermalwasserführenden Speichergesteins ist. Die parallel dazu gemessene und auf Grund des chemischen Bestandes sich ergebende intensivere UV-Transmission (bei Anwesenheit schwacher Fluorescenz) der untersuchten Thermalwässer macht deren Einsatz in Verbindung mit UV-Strahlentherapie (vgl. [2]) zweckmäßig.
    Notes: Abstract The results of mass-spectrographic analyses of powdered residues of some thermal and surface waters, as well as their U.V. absorption spectra are reported. According to these results, a comparatively higher number of elements (up to 10 additional elements in our examples), which is typical of the minerals existing in the reservoir rock bearing thermal waters, is a characteristic of the thermal waters. Parallel to this, the U.V. transmission of the thermal waters examined was measured which (with the occurrence of weak fluorescence) proved to be more intensive because of their chemical constituents and suggests their application in connexion with U.V. radio-therapy (cf. [2]) as useful.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1662-9779
    Source: Scientific.Net: Materials Science & Technology / Trans Tech Publications Archiv 1984-2008
    Topics: Physics
    Type of Medium: Electronic Resource
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