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k-MED entwickelte sich von einem fachbezogenen Projekt im Jahr 1999 zu einem e-Learning-Dienstleister mit umfangreichen Lehr-Lernangeboten sowie einer technischen und organisatorischen Infrastruktur für Autoren und Nutzer. Es bietet heute – Mitte 2006 – 5000 Studierenden, v.a. der Humanmedizin, ca. 170 Lernkurse aus 16 medizinischen Fächern. Das Projekt umfasst erfahrenes Fachpersonal und nutzt eine eigene Online-Autorenumgebung sowie eine internetbasierte Lernplattform, deren Funktionalitäten in Abstimmung mit evaluierten Lehr- und Lern-Szenarien ständig weiter entwickelt werden. Die wichtigste Aufgabe ist die Vollversorgung von Bildungseinrichtungen, darunter vor allem medizinische Fakultäten, mit Lehr-Lern- und Kommunikationsinstrumenten. Aktuelle Informationen sind zu finden unter http://www.k-med.org.
Objective: Establishment of an immunocompetent mouse model representing the typical progressive stages observed in malignant human gliomas for the in vivo evaluation of novel target-specific regimens.
Methods: Isolated clones from tumours that arose spontaneously in GFAP-v-src transgenic mice were used to develop a transplantable brain tumour model in syngeneic B6C3F1 mice. STAT3 protein was knocked down by infection of tumour cells with replication-defective lentivirus encoding STAT3-siRNA. Apoptosis is designed to be induced by soluble recombinant TRAIL + chemical Bcl-2/Bcl-xL inhibitors.
Results: Striatal implantation of 105 mouse tumour cells resulted in the robust development of microscopically (2 – 3 mm) infiltrating malignant gliomas. Immunohistochemically, the gliomas displayed the astroglial marker GFAP and the oncogenic form of STAT3 (Tyr-705-phosphorylated) which is found in many malignancies including gliomas. Phosphorylated STAT3 was particularly prominent in the nucleus but was also found at the plasma membrane of peripherally infiltrating glioma cells. To evaluate the role of STAT3 in tumour progression, we stably expressed siRNA against STAT3 in several murine glioma cell lines. The effect of STAT3 depletion on proliferation, invasion and survival will be first assessed in vitro and subsequently after transplantation in vivo. Upstream and downstream components of the STAT3 signalling pathway as well as possible non-specific side effects of STAT3-siRNA expression after lentiviral infection will be examined, too.
Conclusions: Its high rate of engraftment, its similarity to the malignant glioma of origin, and its rapid locally invasive growth should make this murine model useful in testing novel therapies for malignant gliomas.
Survivin functions as an apoptosis inhibitor and a regulator of cell division during development and tumorigenesis. Since survivin is a highly relevant target for tumor therapy, we investigated whether interference with it’s dynamic cellular localization represents a novel strategy to inhibit survivin’s cancer promoting functions. We confirmed survivin overexpression in head and neck as well as in colorectal cancers and identified an evolutionary conserved Crm1-dependent nuclear export signal (NES) in survivin. Importantly, nuclear export was required for survivin mediated protection against chemo- and radiotherapy-induced apoptosis by securing efficient interference with cytoplasmic caspases. In dividing cells, the NES was required for tethering of survivin and of the survivin/Aurora-B kinase complex to the mitotic machinery, which was inevitable for proper cell division. The clinical relevance of our findings was supported by showing that preferential nuclear localization of survivin correlated with enhanced survival in a cohort of colorectal cancer patients. Targeting survivin’s nuclear export by the application of NES-specific antibodies promoted its nuclear accumulation and inhibited its cytoprotective function. We here show that nuclear export is essential for the tumor promoting activities of survivin and encourage the identification of chemical inhibitors to specifically interfere with survivin’s nuclear export as a novel class of anticancer therapeutics.
A new technique for precision ion implantation has been developed. A scanning probe has been equipped with a small aperture and incorporated into an ion beamline, so that ions can be implanted through the aperture into a sample. By using a scanning probe the target can be imaged in a non-destructive way prior to implantation and the probe together with the aperture can be placed at the desired location with nanometer precision. In this work first results of a scanning probe integrated into an ion beamline are presented. A placement resolution of about 120 nm is reported. The final placement accuracy is determined by the size of the aperture hole and by the straggle of the implanted ion inside the target material. The limits of this technology are expected to be set by the latter, which is of the order of 10 nm for low energy ions. This research has been carried out in the context of a larger program concerned with the development of quantum computer test structures. For that the placement accuracy needs to be increased and a detector for single ion detection has to be integrated into the setup. Both issues are discussed in this thesis. To achieve single ion detection highly charged ions are used for the implantation, as in addition to their kinetic energy they also deposit their potential energy in the target material, therefore making detection easier. A special ion source for producing these highly charged ions was used and their creation and interactions with solids of are discussed in detail.
Die Entwicklung künstlicher Ribonucleasen bietet das Potential, Werkzeuge für die Biotechnologie und langfristig neuartige Pharmaka bereitzustellen. 2-Aminobenzimidazole haben sich als metallfreie Katalysatoren zur unspezifischen Spaltung von Ribonucleinsäuren bewährt. In der vorliegenden Arbeit sollte das Konzept von künstlichen Ribonucleasen auf Basis dieser Molekülklasse auf seine Tragfähigkeit gerprüft werden. Außerdem sollten weitere mechanistische Erkenntnisse über die Katalyse der RNA-Hydrolyse durch 2-Aminobenzimidazole gewonnen werden. Hierzu wurden kupplungsfähige 2-Aminobenzimidazol-Derivate hergestellt und anschließend an RNA-Liganden gekuppelt. Diese Konjugate wurden auf ihre Spaltaktivität gegenüber RNA bei physiologischen Bedingungen sowie auf ihre Substrat- und Ortsspezifität getestet. Zunächst wurden Tripeptidkonjugate synthetisiert und untersucht. Hierbei konnte eine gegenüber den unkonjugierten Spezies erhöhte Affinität der Konjugate zum Substrat festgestellt werden. Auch wurde gezeigt, dass 2-Aminobenzimidazole, die in wässriger Lösung zur Aggregation neigen, auch als Einzelmoleküle in der Lage sind, die RNA-Hydrolyse zu katalysieren. Die Substrat- und Ortsspezifität der Tripeptidkonjugate ließ jedoch zu wünschen übrig. Durch die Konjugation von 2-Aminobenzimidazol-Derivaten an Antisense-DNA gelang schließlich die sequenz- und ortsspezifische Affinitätsspaltung von RNA mit beachtlicher Aktivität. Damit war die Tragfähigkeit des Konzepts bewiesen. Ferner konnten durch die weitere Untersuchung der Konjugate starke Indizien gewonnen werden, die das Modell, auf dem die Auswahl der 2-Aminobenzimidazole als katalytische Einheit beruht, stützen.
Background: The APOBEC3G protein represents a novel innate defense mechanism against retroviral infection. It facilitates the deamination of the cytosine residues in the single stranded cDNA intermediate during early steps of retroviral infection. Most poxvirus genomes are relatively A/T-rich, which may indicate APOBEC3G-induced mutational pressure. In addition, poxviruses replicate exclusively in the cytoplasm where APOBEC3G is located. It was therefore tempting to analyze whether vaccinia virus replication is affected by APOBEC3G.
Results: The replication of vaccinia virus, a prototype poxvirus, was not, however, inhibited in APOBEC3G-expressing cells, nor did other members of the APOBEC3 family alter vaccinia virus replication. HIV counteracts APOBEC3G by inducing its degradation. However, Western blot analysis showed that the levels of APOBEC3G protein were not affected by vaccinia virus infection.
Conclusion: The data indicate that APOBEC3G is not a restriction factor for vaccinia virus replication nor is vaccinia virus able to degrade APOBEC3G.
Following publication of the data presented by von Minckwitz and colleagues it has been brought to our attention that some patients should be scored differently. Stable disease was seen in three of the eighteen patients instead of two of the eighteen patients: one patient with transitional cell carcinoma treated at 4 µg/kg scFv(FRP5)-ETA per day, and two breast cancer patients treated at 4 and 12.5 µg/kg scFv(FRP5)-ETA per day. Disease progression occured in 9 of the eighteen patients evaluated (see corrected Table 2 overleaf). This does not affect the conclusions of our study. In addition we would like to correct the following errors: patient IDs for patients U01 and U02 in the original Table 2 were interchanged. In addition, patient N03 had a grade 3 elevation of gamma-glutamyl transferase, and not grade 2 (see corrected Table 2 overleaf).
In the present work we applied the Optically read out PArticle track Chamber, OPAC, for the measurement of radial dose distributions, d(r), around tracks of heavy ions passing through the gas-filled sensitive volume of the chamber. The measured data were compared with d(r) functions derived from data calculated with the Monte Carlo particle transport code, TRAX – which is used for the heavy ion therapy planning at GSI. To measure this quantity we have used here an optically read out time projection chamber (OPAC) with a parallel-drift field and one or several electron and light amplification stages. The two dimensional projection of the three dimensional ionization pattern caused by the ionizing particle passing through the chamber is captured by an image intensified CCD camera. The work is motivated by the role the radial dose distribution plays in the estimation of the relative biological effectiveness (RBE) of heavy ions, e.g. in radiation therapy and in radiation protection. The most successful model for high-dose irradiation with ions (applicable e.g. for heavy ion therapy) is found to be the local effect model (LEM). The present work intends to deliver measured data for one of the basic physical parameters which serve as input for the application of the local effect model: the radial dose distribution, d(r). The first goal of our measurement program was the measurement of d(r) distributions around carbon ions of different energies from 400 MeV/u down to the Bragg peak regions. We found an excellent agreement between the measured and simulated distributions at all carbon energies for the r–range in which the measurements deliver useful results. The lower limit of this range is about 100 nm and the upper limit is 6000 nm at a resolution of down to 33 nm - if scaled to water density. Despite the simplifications in the TRAX code (e.g. binary encounter theory for the emission ionization electrons), the discrepancies between the simulated and measured d(r) distributions are found to be lower than the measurement uncertainties at most measured carbon ion energies in almost the whole observed r-range. Hence, within the limitations of our measurements we can conclude that the precision of TRAX is sufficient to simulate the d(r) distributions around carbon ions to serve as input parameter for therapy planning. However, this conclusion is only valid for larger radial distances (r >100 nm). For smaller radial distances the measured data are dominated by the diffusion. Apart from carbon ion tracks, tracks of very heavy ions (40Ar, 84Kr and 238U) were also measured with OPAC. The simulated d(r) values were typically slightly or significantly higher than the measured data in the 100 nm < r < 5000 nm region. The experience has shown: the heavier or the faster the ion, the higher the discrepancies. On the one hand, we found a surprisingly good agreement between measurements and simulations if the ions had energies of around 50 MeV/u (i.e. relatively low energy). On the other hand, at higher energies, simulated data underestimate the measured ones by up to a factor of two in the region of 100 nm < r < 1000 nm for 84Kr (E = 650 MeV/u) or in the region of 100 nm < r < 6000 nm for 238U (E = 1 GeV/u). A possible reason for these discrepancies is that the BEA model, used in TRAX for the production ionization electrons, is not adequate for very heavy projectiles. The energy values of the very heavy ions were selected with the aim of comparing the track structures - and namely the d(r) distributions - of ions with largely different atomic mass but similar LET values. From the Z-dependency of the stopping power we know that for heavier ions a higher specific ion energy (expressed in MeV/u) is required to provide the same LET. For example the common LET of 315 keV/micro-m was achieved at largely different specific energy levels of 4,4 MeV/u for 12C, 65 MeV/u for 40Ar and 650 MeV/u for 84Kr ions. The difference in the track structures was expected mainly due to the different ion velocities and thus e.g. different ranges of d-electrons. This expectation could be confirmed by the measurements. The reason why - in line with the simulations - no strong differences could be observed in the d(r) distributions of the argon and krypton ions is the relatively small difference in the velocities of the both ion types in conjunction with the limited range in r, where the data can be compared. In contrary, the d(r) function of the carbon ion shows a qualitatively different behavior than the heavier ions inside the observable radius-range - in agreement with the simulations.