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  • 1
    Keywords: APOPTOSIS ; TUMOR-CELLS ; IN-VIVO ; COMPLEX ; MOLECULE ; IMMUNOTHERAPY ; YOUNG-ADULTS ; childhood tumors ; KILLER-CELLS ; SIGNALING RECEPTOR
    Abstract: Cellular immunotherapy may provide a strategy to overcome the poor prognosis of metastatic and recurrent rhabdomyosarcoma (RMS) under the current regimen of polychemotherapy. Because little is known about resistance mechanisms of RMS to cytotoxic T cells, we investigated RMS cell lines and biopsy specimens for expression and function of immune costimulatory receptors and anti-apoptotic molecules by RT-PCR, Western blot analysis, IHC, and cytotoxicity assays using siRNA or transfection-modified RMS cell lines, together with engineered RMS-directed cytotoxic T cells specific for the fetal acetylcholine receptor. We found that costimulatory CD80 and CD86 were consistently absent from all RMSs tested, whereas inducible T-cell co-stimulator ligand (ICOS-L; alias B7H2) was expressed by a subset of RMSs and was inducible by tumor necrosis factor alpha in two of five RMS cell lines. Anti-apoptotic survivin, along with other inhibitor of apoptosis (IAP) family members (cIAP1, cIAP2, and X-linked inhibitor of apoptosis protein), was overexpressed by RMS cell lines and biopsy specimens. Down-regulation of survivin by siRNA or pharmacologically in RMS cells increased their susceptibility toward a T-cell attack, whereas induction of ICOS-L did not. Treatment of RMS-bearing Rag(-/-) mice with fetal acetylcholine receptor-specific chimeric T cells delayed xenograft growth; however, this happened without definitive tumor eradication. Combined blockade of survivin and application of chimeric T cells in vivo suppressed tumor proliferation during survivin inhibition. In conclusion, survivin blockade provides a strategy to sensitize RMS cells for T-cell-based therapy.
    Type of Publication: Journal article published
    PubMed ID: 23562272
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  • 2
    Abstract: AIMS: To improve survival of patients with advanced rhabdomyosarcomas (RMS), we aimed to adoptively transfer T-cells with redirected specificity for the fetal acetylcholine receptor (AChR), an RMS-specific cell surface antigen. METHODS: A "second generation" chimeric antigen receptor (CAR) with a combined CD28-CD3zeta signaling domain was derived from our previously described chimeric antigen receptor composed of an extracellular human anti-fAChR antibody fragment, an Fc hinge region, and the intracellular T-cell receptor zeta chain. Lymphocytes from the peripheral blood were modified by retroviral transduction and monitored by FACS analysis. Cytotoxicity of modified T-cells towards RMS cells was recorded by MTT-based viability tests; expression of co-stimulatory molecules and anti-apoptotic genes was studied by FACS and qRT-PCR analysis. RESULTS: Co-stimulatory molecules were expressed in low levels on RMS cells giving the rationale to generate a CD28-CD3zeta signalling CAR (chimeric antigen receptor) for redirecting T-cells. T-cells were successfully engineered with the "second generation" AChR-specific chimeric antigen receptor. Despite of high CAR expression engineered T-cells showed low killing efficiency towards RMS compared to redirected killing of CD20+ lymphoma or CEA-expressing adenocarcinoma cell lines when redirected by CD20- and/or CEA-specific CAR. CONCLUSIONS: Data suggest that RMS cells exhibit resistance to a T-cell attack redirected by a fAChR-specific CAR. Inhibition of anti-apoptotic pathways in those cells may improve sensitivity to conventional as well as T-cell-based therapeutics.
    Type of Publication: Journal article published
    PubMed ID: 20730458
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  • 3
    Keywords: GENE ; COMPARATIVE GENOMIC HYBRIDIZATION ; RISK GROUP ; MYCN ; ARM 17Q ; outcome prediction ; 11Q ; 4S NEUROBLASTOMA ; EXPRESSION-BASED CLASSIFICATION ; 17Q TRANSLOCATION BREAKPOINTS
    Abstract: The prognostic relevance of chromosome 17 gain in neuroblastoma is still discussed. This investigation specifies the frequency, type, size, and transcriptional relevance in a large patient cohort. Primary tumor material of 202 patients was analyzed using high-resolution oligonucleotide array-based comparative genomic hybridization (aCGH) and correlated with clinical and survival data. A subset (n = 145) was correlated for differentially expressed genes (DEG) by microarray analysis. Chromosome 17 aCGH analysis showed numerical gain in 94/202 patients (47%), partial gain in 93/202 patients (46%), and no gain in 15/202 patients (7%). The frequency of partial gain was higher in stage 4 neuroblastoma (stage 1 15%; stage 2 12%; stage 3 16%; stage 4S 7%; and stage 4 50%). Overall survival (OS) was superior in patients with numerical gain compared with patients with partial gain or no gain (5-y-OS: 0.95 +/- 0.02 vs. 0.63 +/- 0.05 vs. 0.60 +/- 0.13; P 〈 0.001). Gene expression analysis demonstrated 95/130 DEGs between tumors with numerical or partial chromosome/no gain. Only one DEG (CCKBR) was detected comparing tumors with partial gain and those with no gain. In patients with partial gain, the distribution of breakpoints did not correlate with stage and 11q status, but with MYCN amplification and 1p status. The "best" breakpoints in cases with partial 17q gain were at 42.5 Mb for event-free and 26.6 Mb for OS. Numerical gain of chromosome 17 is associated with a better prognosis than partial and no gain. The group of tumors with partial gain was similar to the group without gain with respect to stage distribution, outcome, and gene expression profile. (c) 2014 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 24737690
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  • 4
    ISSN: 1432-1041
    Keywords: carvedilol ; multiple-action compounds ; hemodynamics ; coronary heart disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Several so-called multiple-action compounds have been developed, such as medroxalol (alpha and beta blockade, and beta-2 stimulation), celiprolol (alpha-2 and beta-1 blockade, and beta-2 stimulation) and carvedilol (beta blockade and vasodilatation) for the treatment of patients with arterial hypertension and with coronary heart disease. Carvedilol exerts relatively uniform peripheral effects, i. e. a reduction of both systolic and diastolic blood pressure at rest and during exercise, and a decrease in the resting and exercise heart rate. Blood pressure fall due to carvedilol may be induced by its vasodilating effect, as documented by measurements of forearm blood flow and peripheral vascular resistance. Moreover, renal hemodynamics does not seem to be significantly altered by carvedilol. Carvedilol may also produce an improvement of the LV contractile status in patients with CHD and impaired LV function, mainly due to afterload reduction, in addition to its antianginal effect, which is due mainly to the beta-blocking properties of this substance. From the studies mentioned it may be concluded that carvedilol is a useful and promising drug for treating patients with both arterial hypertension and with coronary artery disease.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-1041
    Keywords: Crossover study ; Felodipine ER ; hydrochlorothiazide hypertension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The efficacy of extended release felodipine 10 mg (ER) o.d., a new dihydropyridine calcium antagonist, and 25 mg hydrochlorothiazide (HCTZ) o.d. have been compared in a randomized, double-blind, crossover trial in 28 mildly to moderately hypertensive subjects (supine diastolic blood pressure, BP, ≥95 mm Hg and ≤110 mm Hg on three separate occasions). Both drugs significantly reduced systolic and diastolic BP in the sitting position felodipine from 157.1/93.8 mm Hg at baseline to 133/78.9 mm Hg 2.5 h after medication and to 138/82.7 mm Hg after 2 weeks of treatment, and HCTZ from 156/95.6 mm Hg to 147/88.4 mm Hg 2.5 h after medication and to 149/89.5 mm Hg also after 2 weeks. A decrease of the same magnitude in standing systolic and diastolic BP was observed after both treatment regimens with the exception of diastolic BP 2.5 h after dosing with HCTZ, which was not significantly lower. At all times (2.5 h and 2 weeks), the reduction in systolic and diastolic BP was greater after felodipine compared to HCTZ. Heart rate was significantly increased after felodipine in both the sitting and standing positions, and both 2.5 h following medication and after 2 weeks of treatment. The difference between the regimens was significant only 2.5 h after dosing. Overall, felodipine 10 mg ER o.d. was superior to 25 mg HCTZ o.d. in lowering BP.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Horizontal cells are interneurons of the vertebrate retina that exhibit strong electrical and tracer coupling but the identity of the channel-forming connexins has remained elusive. Here we show that horizontal cells of the mouse retina express connexin57 (Cx57). We have generated Cx57-deficient mice by replacing the Cx57 coding region with a lacZ reporter gene, expressed under control of the endogenous Cx57 promoter. These mice were fertile and showed no obvious anatomical or behavioural abnormalities. Cx57 mRNA was expressed in the retina of wild-type littermates but was absent from the retina of Cx57-deficient mice. Previously reported results that the Cx57 gene was very weakly expressed in several other mouse tissues turned out to be unspecific. Cx57 mRNA is abundantly expressed in the retina and weakly in the thymus of adult mice but absent in all other adult tissues tested, including brain. Furthermore, Cx57 is expressed in embryonic kidney at E16.5 to E18.5 days post-conception, as indicated by the pattern of lacZ expression. Within the retina, lacZ signals were assigned exclusively to horizontal cells based on co-localization with cell-type-specific marker proteins. Microinjection of Neurobiotin into horizontal cells of isolated retinae revealed less than 1% of tracer coupling in Cx57-deficient retinae compared with wild-type controls. Cx57 is the first connexin identified in mammalian horizontal cells and the first connexin whose expression is apparently restricted to only one type of neuron.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1434-601X
    Keywords: PACS:25.75.+r Relativistic heavy-ion collisions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract: We study the mixing and the kinetic equilibration of projectile and target nucleons in relativistic heavy-ion collisions in the energy regime between 150 AMeV and 2 AGeV in a coupled-channel BUU (CBUU) approach. We find that equilibrium in the projectile-target degrees of freedom is in general not reached even for large systems at low energy where elastic nucleon-nucleon collisions dominate. Inelastic nucleon excitations are more favorable for equilibration and their relative abundance increases both with energy and mass. Experimentally, the projectile/target admixture can be determined by measuring the degree of isospin equilibration in isospin asymmetric nuclear collisions. For one of the most promising systems currently under investigation, 96 44Ru +96 40Zr, we investigate the influence of the equation of state and the inelastic in-medium cross section.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    The European physical journal 352 (1995), S. 223-230 
    ISSN: 1434-601X
    Keywords: 25.20
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract We calculate the quasifree photoproduction of pions and eta mesons on nuclei from12C to208Pb. Assuming that for the quasifree process the cross sections forπ/η photoproduction on a nucleon in medium are — besides a lowering due to Pauli blocking — identical to those on a free nucleon, we use these as an input. The produced mesons or resonances then propagate through the nucleus where they can undergo several scattering and absorption processes. This final state interaction, which leads to a lowering of the initial meson yield up to 70%, we simulate in a coupled channel Boltzmann-Uehling-Uhlenbeck transport model. It allows us to study in detail the influence of Fermi motion, Pauli blocking and of the additional decay channels for nucleon resonances in medium on the photoproduction cross section. The calculated total and differential cross sections are compared to experimental data and the influence of the different medium effects on the cross sections is discussed in detail.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1434-601X
    Keywords: PACS: 25.75.-q Relativistic heavy-ion collisions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Physics
    Notes: Abstract: We study flow phenomena in relativistic heavy-ion collisions, both in transverse and radial direction, in comparison to experimental data. The collective dynamics of the nucleus-nucleus collision is described within a transport model of the coupled channel BUU type (CBUU). This recently developed version includes all nucleonic resonances up to 1.95 GeV in mass and mean-field potentials both of the Skyrme and momentum dependent MDYI type. We find that heavy resonances play an important role in the description of transverse flow above 1 AGeV incident energy. For radial flow we analyse reaction times and equilibration and extract the parameters T and β for temperature and collective flow velocity within different prescriptions. Furthermore, we apply a coalescence model for fragment production and check the mass dependence of the flow signals.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1619-7089
    Keywords: Technetium 99m hexakis-2-methoxyisobutylisonitrile (99mTc-Sestamibi) ; Quantitative single photon emission tomography (SPET) ; Inter-observer reproducibility ; Coronary disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The quantification of myocardial perfusion abnormalities is necessary to allow comparison of repeated studies, especially in the evaluation of the success of medical, interventional or combined treatment in stable coronary artery disease or in evolving myocardial infarction. The purpose of this study was to assess inter-observer reproducibility of tomographic study processing using a semi-automatic quantitative programme. Technetium 99m hexakis-2-methoxyisobutylisonitrile (99mTc-Sestamibi) was chosen for tomographic imaging of repeated rest-stress studies in patients with stable coronary artery disease. The quantification was performed using a modification of the Cedars polar coding and comparison with the normal data base. The perfusion defects were quantified separately for each standard perfusion area [left anterior descending (LAD), right coronary (RCA) and left circumflex (LCX) arteries] and total area of hypoperfused myocardium. The inter-observer variability for 40 tomographic studies was accomplished. The defects were the largest in the LAD perfusion area (average 19.7% of the normalized LAD supply area) with an inter-observer correlation of 0.84 for this region. The greatest variability was found for the LCX region (r=0.55) and is attributed to a small average perfusion defect (7.1%), only 18 studies having abnormal perfusion in this area. In total, an average 14.3% of the left ventricular myocardium was significantly hypoperfused, and the inter-observer correlation was 0.87. These results show good inter-observer reproducibility using semi-automatic quantitation of perfusion defects. Careful interpretation of smaller defects in the evaluation of treatment results is advised when repeated 99mTc-Sestamibi single photon emission tomography studies are processed by more than one observer.
    Type of Medium: Electronic Resource
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