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  • 1
    Abstract: Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD(+) leukemia cells. This synergized with the allogeneic CD8(+) T cell response, leading to long-term survival in six mouse models of FLT3-ITD(+) AML. Sorafenib-related IL-15 production caused an increase in CD8(+)CD107a(+)IFN-gamma(+) T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD(+) AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8(+) T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT.
    Type of Publication: Journal article published
    PubMed ID: 29431743
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  • 2
    ISSN: 0942-0940
    Keywords: Computer tomography ; brain radiation therapy ; image processing ; histographic analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Using the EMI computer tomographic (CT) system, EMI-1010, a series of new programmes were developed for the digital analysis of the CT images in order to make a more objective and quantitative assessment possible of two nonsurgical methods of treatment of brain tumours such as irradiation and chemotherapy. Amongst the various therapeutic effects demonstrable from the CT data, a reduction of the mass effect was found to lower the average CT number, with a dilatation of the cisterns and ventricles. In contrast, an improvement in the amount of perifocal oedema increased the average CT number of the region, however the changes in CT number of the tumour itself may be variable. The separate evaluation of these factors, therefore, gives more information about the results of the treatment than a simple analysis of the histogram of the region. Circumscribed tumours are fairly well evaluated with our programme for the statistical analysis of the volume and the CT weight of tumours and the degree of contrast enhancement using histograms and subtraction scans. For the digital analysis of the ventricular system, the subarachnoid space, perifocal oedema, and irregularly shaped infiltrating tumours, our programmes for the character-image print-out and edge correction for the partial-volume effect of skull and air are much more useful than the CRT display for data extraction and geographic-pattern recognition.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1435-1536
    Keywords: Electrostatic interaction ; Ion-penetrablemembranes ; Ionic solubility
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract An analytic, approximate expression for the electrostatic interaction between two membranes immersed in an electrolyte solution is derived on the basis of a simple membrane model. This model assumes that the membrane has a surface layer in which charged groups are uniformly distributed and that electrolyte ions can penetrate into the surface layer. The partition coefficients of cations and anions between the solution and the surface layer, which are related to their solubilities in the surface layer, may be different from unity. The electrostatic interaction depends on the ionic partition coefficients between the solution and the surface layer, and the relative permittivity of the surface layer, as well as on the membrane-fixed charges, the electrolyte concentration in the solution, and the surface layer thickness. It is shown, in particular, that even where the charge layer has no fixed charges, the electrostatic interaction force can be produced if the solubilities of cations and anions are different in the surface layer.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1435-1536
    Keywords: Potentialdistribution ; ionicsolubility ; surface-charge layer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract A model is presented for the potential distribution across a charged membrane. The membrane-fixed charges are assumed to be distributed through a surface layer of non-zero thickness on the membrane. We treat the surface layer as a different phase from the surrounding solution phase. The potential arises from the membrane-fixed charges and from different solubilities of positive and negative electrolyte ions in the two phases. Equations are presented for the potential distribution, which involve the partition coefficients of electrolyte ions and the relative permittivity of the surface layer.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1435-1536
    Keywords: Electrostatic interaction ; ion-penetrable sphere ; rigid sphere
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract The exact expression for the electrostatic interaction between an ionpenetrable sphere and an ion-impenetrable rigid sphere is derived on the basis of the linearized Poisson-Boltzmann equation without recourse to Derjaguin's approximation.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1435-1536
    Keywords: Photochromism ; spirobenzopyran ; surfactant ; vesicle ; cyclodextrin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Notes: Abstract Photochromic reaction of water insoluble 1′,3′,3′-trimethyl-6-nitrospiro[2H-1-benzopyran-2,2′-indoline] (SP) was studied in water with the aid of vesicles and γ-cyclodextrin (γ-CD). In both systems, the photochromic reaction of SP was observable in spite of the low solubility of SP in water. In order to examine the microenvironment around the SP and the reaction product, photomerocyanin (MC), in those systems, the spectrum of MC was measured in various organic solvent of various polarity. Decreasing the polarity of the solvent decreased the peak absorbance and shifted the peak wavelength to the long wavelengths. When the vesicles were used, the reactant, SP, and the product, MC, were solubilized in different regions of different polarity. The reaction substrate was then supposed to have moved from the hydrophobic region of the membrane to the hydrophilic one after the photoisomerzation. The photochromic reaction of SP in the presence of γ-CD was slower than in the vesicles and faster than that in methanol. The polarity in the vesicular membrane and the limited rotation of the reactant in the cavity of γ-CD may have influenced the reaction rate. The prolonged light irradiation period resulted in a simultaneous photoreaction and polymerization, producing some unknown side reaction.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1435-702X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A new method of measuring pupil-blocking force in the human eye is reported. The anterior segment of the eye was photographed using a slit-lamp apparatus and the color photographs then analyzed with a digitizer for converting the optical image of the anterior eye segment into the true image using a computer. This technique permits precise estimation of the relative positions of the anterior chamber, such as pupil margins, iris root insertions, and central anteroposterior pupillary axis. Pupil-blocking force was calculated from these data according to Hook's law. There was a statistically significant difference in pupil-blocking force between normal subjects (mean ± SD, − 0.027 ± 0.029λ; λ = Young's module) and patients with primary angle-closure glaucoma (mean ± SD, + 0.134 ± 0.068λ) (P 〈 0.001). In patients with primary angle-closure glaucoma, during an acute attack the pupil-blocking force was markedly high. This technique for measuring pupil-blocking force will provide valuable data for the analysis of the mechanism of primary angle-closure glaucoma.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1437-1596
    Keywords: Key words Physical examination ; Postinfliction ; interval ; Skin reddening ; Petechial hemorrhages ; Microcirculation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Law
    Notes: Abstract Skin reddening with or without additional changes such as pinpoint intracutaneous hemorrhages and/or minute superficial scratches was observed in 165 out of 739 physical examinations (reddening with additional changes: n = 81; reddening only: n = 84). The most common site where reddening was observed was the neck region (reddening with additional changes: n = 30; reddening only: n = 34). In over 85% of the cases, the postinfliction interval (Pi) was ≤ 1 day, and there were 12 and 10 cases with 1 〈 Pi≤ 3 days, respectively. Among these 22 cases, there were 5 cases with 2 〈 Pi≤ 3 days, (reddening with additional changes: n = 4; reddening only: n = 1). The maximum Pis were almost 3 days, and 2 days and 13 h, respectively. These results demonstrate that reddening of the skin with and that without additional changes (in particular petechiae) were detectable up to approximately 3 and 2 days after the event, respectively. Furthermore, in 17 out of 64 cases with reddening in the neck, petechial hemorrhages were seen in the eyelids and/or conjunctivae (reddening with additional changes: n = 10; reddening only: n = 7). The maximum Pi in which petechial hemorrhages were detectable in the eyelids and/or the palpebral conjunctivae was 1 day and 21 h. The present study indicates that physical examinations within 2 or 3 days after the event seem to be more suitable to find skin reddening and/or petechiae in the eye lids and/or the conjunctivae.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Polymer bulletin 8 (1982), S. 485-485 
    ISSN: 1436-2449
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1435-1463
    Keywords: Parkinson's disease ; tyrosine hydroxylase ; homospecific activity ; compensatory mechanisms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Tyrosine hydroxylase (TH) contents in the caudate nucleus, putamen, and substantia nigra from control and parkinsonism brains were measured for the first time by a sandwich enzyme immunoassay. Both the TH protein content and TH activity (Vmax) were decreased in parallel in the parkinsonian brains as compared with those of the control brains. In contrast, TH “homospecific activity” (activity per enzyme protein) was significantly increased in the parkinsonian brains. The results indicate that the decrease of TH activity in parkinsonian brains is due to the decrease of TH protein content as a result of cell death. The increase in the “homospecific activity” of residual TH in parkinsonian brain suggests such molecular changes in TH molecules as result in a compensatory increase in TH activity.
    Type of Medium: Electronic Resource
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