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  • 1
    Abstract: Pediatric high-grade gliomas (pedHGG) belong to the most aggressive cancers in children with a poor prognosis due to a lack of efficient therapeutic strategies. The beta-catenin/Wnt-signaling pathway was shown to hold promising potential as a treatment target in adult high-grade gliomas by abrogating tumor cell invasion and the acquisition of stem cell-like characteristics. Since pedHGG differ from their adult counterparts in genetically and biologically we aimed to investigate the effects of beta-catenin/Wnt-signaling pathway-inhibition by the beta-catenin/CBP antagonist ICG-001 in pedHGG cell lines. In contrast to adult HGG, pedHGG cells displayed minimal detectable canonical Wnt-signaling activity. Nevertheless, low doses of ICG-001 inhibited cell migration/invasion, tumorsphere- and colony formation, proliferation in vitro as well as tumor growth in vivo/ovo, suggesting that ICG-001 affects pedHGG tumor cell characteristics independent of beta-catenin/Wnt-signaling. RNA-sequencing analyses support a Wnt/beta-catenin-independent effect of ICG-001 on target gene transcription, revealing strong effects on genes involved in cellular metabolic/biosynthetic processes and cell cycle progression. Among these, high mRNA expression of cell cycle regulator JDP2 was found to confer a better prognosis for pedHGG patients. In conclusion, ICG-001 might offer an effective treatment option for pedHGG patients functioning to regulate cell phenotype and gene expression programs in absence of Wnt/beta-catenin signaling-activity.
    Type of Publication: Journal article published
    PubMed ID: 28460484
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  • 2
    Abstract: The MHC class I chain-related molecule A (MICA) is a highly polymorphic ligand for the activating natural killer (NK)-cell receptor NKG2D. A single nucleotide polymorphism causes a valine to methionine exchange at position 129. Presence of a MICA-129Met allele in patients (n = 452) undergoing hematopoietic stem cell transplantation (HSCT) increased the chance of overall survival (hazard ratio [HR] = 0.77, P = 0.0445) and reduced the risk to die due to acute graft-versus-host disease (aGVHD) (odds ratio [OR] = 0.57, P = 0.0400) although homozygous carriers had an increased risk to experience this complication (OR = 1.92, P = 0.0371). Overall survival of MICA-129Val/Val genotype carriers was improved when treated with anti-thymocyte globulin (HR = 0.54, P = 0.0166). Functionally, the MICA-129Met isoform was characterized by stronger NKG2D signaling, triggering more NK-cell cytotoxicity and interferon-gamma release, and faster co-stimulation of CD8(+) T cells. The MICA-129Met variant also induced a faster and stronger down-regulation of NKG2D on NK and CD8(+) T cells than the MICA-129Val isoform. The reduced cell surface expression of NKG2D in response to engagement by MICA-129Met variants appeared to reduce the severity of aGVHD.
    Type of Publication: Journal article published
    PubMed ID: 26483398
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  • 3
    Keywords: EFFECTOR ; CPG-ISLANDS ; CONSTRUCTS ; RNAi
    Abstract: Use of transcription activator-like effector nucleases (TALENs) is a promising new technique in the field of targeted genome engineering, editing and reverse genetics. Its applications span from introducing knockout mutations to endogenous tagging of proteins and targeted excision repair. Owing to this wide range of possible applications, there is a need for fast and user-friendly TALEN design tools. We developed E-TALEN ( ext-link-type="uri" xlink:href="http://www.e-talen.org" xmlns:xlink="http://www.w3.org/1999/xlink"〉http://www.e-talen.org), a web-based tool to design TALENs for experiments of varying scale. E-TALEN enables the design of TALENs against a single target or a large number of target genes. We significantly extended previously published design concepts to consider genomic context and different applications. E-TALEN guides the user through an end-to-end design process of de novo TALEN pairs, which are specific to a certain sequence or genomic locus. Furthermore, E-TALEN offers a functionality to predict targeting and specificity for existing TALENs. Owing to the computational complexity of many of the steps in the design of TALENs, particular emphasis has been put on the implementation of fast yet accurate algorithms. We implemented a user-friendly interface, from the input parameters to the presentation of results. An additional feature of E-TALEN is the in-built sequence and annotation database available for many organisms, including human, mouse, zebrafish, Drosophila and Arabidopsis, which can be extended in the future.
    Type of Publication: Journal article published
    PubMed ID: 24003033
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  • 4
    ISSN: 1420-9136
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences , Physics
    Notes: Summary Energetic electrons are continually removed from the radiation belts by resonant pitch-angle scattering with ELF turbulence. A realistic simulation of the concomitant precipitation loss of such electrons to the atmosphere shows it to be a significant source for the nocturnal ionospheric D-region. During geomagnetically quiet (non-storm) periods, precipitating electrons are expected to provide the dominant nocturnal ionization source at medium invariant latitudes corresponding to field lines just inside the plasmapause. When the level of scattering turbulence is high the quiet time precipitation can dominate for an extended range of latitudes (Λ∼ 55° to 65°). Observed fluctuations in the level of scattering turbulence should produce modulations in the concentration of nocturnal middle latitude D-region electrons which may be detected using radio probing techniques.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Abdominal imaging 6 (1981), S. 319-323 
    ISSN: 1432-0509
    Keywords: Abdomen, abnormalities ; Gastrointestinal tract, foreign bodies ; Drug smuggling, complications
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Four cases of attempts to smuggle narcotics (marijuana, heroin, and cocaine) by swallowing a large number of drug-filled foreign bodies (condoms and capsules) and hiding them from customs authorities in the gastrointestinal canal during transit are described. This is compared with a psychiatric patient who swallowed 48 Vicks Inhalers®. Drug smuggling by swallowing condoms or capsules containing narcotics is now a worldwide ethical-legal problem. It also is of therapeutic and prognostic importance as this may lead to such emergencies as mechanical obstruction, rupture of the drug-containing foreign bodies, and life-threatening intoxication of the carrier.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Transcriptional activation of the gene coding for the neuropeptide hormone oxytocin by oestrogens does not follow the classical model of oestrogen receptor action. The oxytocin promoter does not contain an oestrogen response element (ERE), but instead a high-affinity binding site for nuclear orphan receptors. In the present study, the oestrogen-dependent up-regulation of the bovine oxytocin promoter is investigated in MDA-MB 231 cells. Control by oestrogen is shown to be dependent on the integrity of the nuclear orphan receptor binding site and the presence of ligand-activated oestrogen receptor, but independent of oestrogen receptor binding to DNA. Partial agonists tamoxifen and raloxifen and the pure antagonist ICI 182 780 all show agonistic activities on transcription, while exhibiting normal binding affinities to oestrogen receptor (ER)α. Nuclear orphan receptors oestrogen receptor-related receptor α (ERRα) and germ cell nuclear factor (GCNF) are expressed to significant levels in MDA-MB 231 cells. Binding of ERRα to the oxytocin promoter binding site can be demonstrated, suggesting the involvement of this nuclear orphan receptor in oestrogen-dependent up-regulation. The oestrogenic stimulation of the oxytocin promoter apparently is dependent on the stimulation of the transcriptional activity of this nuclear orphan receptor by ERK-1/ERK-2 mitogen-activated protein kinases (MAP kinases). This novel nonclassical mechanism of oestrogen action most probably is not restricted to the regulation of neuropeptide hormone expression, but may further contribute to the multitude of tissue-specific effects of oestrogenic substances.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: In vivo there appears to be a marked association between oestrogen levels and the expression of the oxytocin (OT) gene in most tissues. Transfection and DNA-protein binding experiments using high levels of either oestrogen receptor (ER)α or ERβ imply a direct interaction of these transcription factors with the multiple hormone response element (HRE) at approximately −160 from the transcription start site of the OT gene in most species. In an extensive set of experiments, we show, using both transfection and protein-DNA binding, that low to moderate amounts of either oestrogen receptor, while being able to interact directly with a classic oestrogen response element (ERE) fail to interact with the human OT −160 HRE. Instead, this element, similar to its bovine counterpart, has a high affinity for the orphan receptors steroidogenic factor 1 and chicken ovalbumin upstream promoter transcription factor. Second, the human and bovine OT promoter can be made artificially responsive towards oestrogen in a cotransfection system over-expressing ERα or ERβ, but not in cells expressing natural levels of these steroid receptors. Interestingly, nuclear extracts from both ERα-positive MCF7 cells and ERα-negative MDA-MB231 cells both contain a transcription factor which binds specifically to both the hOT-HRE element and to a classic ERE, and which has orphan receptor-like binding properties rather than those of an oestrogen receptor. Together, these and other results suggest that oestrogen action in vivo on the OT gene in all species is more likely to involve a DNA-independent mechanism than classic direct interactions with dimeric oestrogen receptors.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 0167-0115
    Keywords: Aberrant transcript ; COUP transcription factor ; Corpus luteum ; Neurophysin ; Oxytocin ; Testis ; Vasopressin
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Space science reviews 23 (1979), S. 499-538 
    ISSN: 1572-9672
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract This paper reviews major developments in our understanding of the physics of energetic heavy ions in the Earth's plasma environment during the past four years (1974–1977). Emphasis is placed on processes that influence or are influenced by the ion charge states. This has been a period of growing awareness of the important role heavy ions play in space plasmas. Large fluxes of helium ions and even heavier ions have been observed at the geostationary altitude and in the heart of the radiation belts. Such ions have also been observed on low latitude rockets and satellites, and oxygen ion precipitation exceeding that of protons has been reported. In the outer parts of the Earth's plasma envelope there is mounting evidence for significant fluxes of heavy ions: in the magnetotail, the magnetosheath and in the polar cusp regions. In the inner magnetosphere there is a limited theoretical understanding of equatorially mirroring ions, but generally only radial diffusion at one pitch angle and pitch angle diffusion at one L- shell have been studied; for ions the coupled equations are yet unsolved even for the simplest case of only one charge state (protons). Theoretical modeling of the charge state structures of geophysical heavy ion populations is in part frustrated by the lack of adequate laboratory measurements of the pertinent charge exchange cross sections. A first attempt has, however, been made to treat the charge state transformation processes in the radiation belts for equatorially mirroring atomic oxygen ions. Wave-particle interactions in the magnetosphere become much more complex in multi component and multi charge state plasmas where hybrid resonances and wave-particle interaction induced non-linear species-species coupling could be important. Heavy ion plasma physics in the Earth's magnetosphere and in the magnetospheres of other planets should be a field of fruitful study for both experimentalists and theoreticians in the years ahead.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1435-1803
    Keywords: bypass graft ; carotid artery ; ultrastructure ; vasa vasorum ; development ; arterialization ; rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Mit Hilfe elektronenmikroskopischer Methoden wurde versucht, die Funktionsfähigkeit autologer Venentransplantate mit ultrastrukturellen Veränderungen in einem Zeitraum von 5 Tagen bis 6 Monaten p. o. zu korrelieren. Frühe degenerative Veränderungen der Transplantate umfassen Endothelabschilferungen mit anschließender Fibrin- bzw. Plättchenauflagerung, murale Ödeme und ausgedehnte mediale und adventitielle Degenerationen. Die Regeneration der Transplantate wird ermöglicht durch eine frühe adventitielle Kapillarisierung (10 Tage p. o.), die die überlebenden glatten Muskelzellen und Fibrozyten in die Lage versetzt, zu proliferieren und ein arterienähnliches Gefäß zu entwickeln. Der Aufbau der 6 Monate alten Vene ist vergleichbar mit der Arteria carotis communis der Tiere, zeigt aber im Gegensatz dazu überwiegend Merkmale einer Arterie vom muskulären Typ.
    Notes: Summary Electron microscopic techniques were used to correlate the patency of venous autografts in rabbits with ultrastructural changes within a time range from 5 days to 6 months p.o. Early degenerative changes of the grafts include endothelial desquamation followed by fibrin deposition or platelet adhesion, mural edema and extensive medial and adventitial degeneration. The regeneration of the grafts is due to an early adventitial vascularization (10 days p.o.), which enables the surviving smooth muscle cells and fibrocytes to proliferate and to develop an arterial-like vessel. The organization of the 6-month-old graft is comparable to the carotid artery of the animal, but shows, in contrast, many features of a muscular artery.
    Type of Medium: Electronic Resource
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