Development of an outcomes management program at an academic medical center

Donor CD4+ and CD8+ T cells mediate graft-vs.-leukemia (GVL) responses in the allogeneic bone marrow transplantation (alloBMT) setting. To evaluate the role of functional T cell subsets in the mediation of GVL, alloreactive donor CD4+ (Th1/Th2) and CD8+ (Tc1/Tc2) T cells of defined cytokine phenotype were generated by in vitro culture. A leukemia/transplantation model (B6 into B6C3F1; 1050 cGy host irradiation) was established using the bcr/abl-transfected myeloid leukemia line, 32Dp210 (P210; H-2k). Leukemia control mice (1X10(4) P210 cells per recipient) died at day 12.0 post-BMT. Recipients of the CD4+, Th1-type or CD8+, Tc1-type populations were conferred a survival advantage (death at 20.7 and 23.5 days post-BMT, respectively). In contrast, the CD4+, Th2-type population did not mediate GVL (death at 12.3 days). Furthermore, cell mixing experiments demonstrated that the Th2 subset abrogated both Th1- and Tc1-mediated GVL. The CD8+, Tc2 population, which secreted type II cytokines and lysed the P210 leukemia target in vitro, mediated GVL in some experiments; interestingly, the magnitude of Tc2-mediated GVL was inversely related to the level of interleukin-10 (IL-10) secreted in vitro by the Tc2 population. These studies therefore indicate that alloreactive T cells of type I phenotype maximally generate GVL, and that type I/type II interactions are an important consideration for allogeneic transplantation in the setting of leukemic hosts.     

Deformation of Mesoporous Titania Nanostructures in Contact with D2O Vapor

For many applications, mesoporous titania nanostructures are exposed to water or need to be backfilled via infiltration with an aqueous solution, which can cause deformations of the nanostructure by capillary forces. In this work, the degree of deformation caused by water infiltration in two types of mesoporous, nanostructured titania films exposed to water vapor is compared. The different types of nanostructured titania films are prepared via a polymer template assisted sol–gel synthesis in conjunction with a polymer‐template removal at high‐temperatures under ambient conditions versus nitrogen atmosphere. Information about surface and inner morphology is extracted by scanning electron microscopy and grazing incidence small‐angle neutron scattering (GISANS) measurements, respectively. Furthermore, complementary information on thin film composition and porosity are probed via X‐ray reflectivity. The backfilling induced deformation of near surface structures and structures inside the mesoporous titania films is determined by GISANS before and after D₂O infiltration. The respective atmosphere used for template removal influences the details of the titania nanostructure and strongly impacts the degree of water induced deformation. Drying of the films shows reversibility of the deformation.     

A scaled 0.25-μm bipolar technology using full e-beamlithography

The full leverage offered by electron-beam lithography has been exploited in a scaled 0.25-μm double polysilicon bipolar technology. Devices and circuits were fabricated using e-beam lithography for all mask levels with level-to-level overlays tighter than 0.06 μm. Ion implantation was used to form a sub-100-nm intrinsic base profile, and a novel in-situ doped polysilicon emitter process was used to minimize narrow emitter effects. Transistors with 0.25-μm emitter width have current gains above 80 and cutoff frequencies as high as 40 GHz. A record ECL gate delay of 20.8 ps at 4.82 mW has been measured together with a minimum power-delay product of 47 fJ (42.1 ps at 1.12 mW). These results demonstrate the feasibility and resultant performance leverage of aggressive scaling of conventional bipolar technologies     

Advanced pebble bed high temperature reactor with central graphite column for future applications

Design evaluations of the advanced pebble bed high temperature reactor, AHTR, with central graphite column are given. This reactor, as a nuclear heat source, is suitable for coal refinement as well as for electricity generation with closed gas turbine primary helium circuit. With this design of the central graphite column, it is possible to limit the core temperatures under the required value of about 1600°C in case of accident conditions, even with higher thermal power and higher core inlet and outlet temperatures. The designs of core internals are described. The after heat removal system is integrated in the prestressed concrete reactor pressure vessel, which is based on the principals of natural convection.Research work is being carried out, whereby the spherical fuel elements are coated with a layer of silicon carbide, to improve the corrosion resistance as well as the effectiveness of the fission products barrier.     

Inline‐Beschichtung von optischen Substraten. Inline coating of optical substrates

Applications of optical technologies like vision care, digital imaging or data communication play a decisive role in our daily life. Manipulation of light is mainly done using optical lenses. Beside mineral lenses, transparent plastic materials become more and more important. The optical and mechanical properties of lenses are crucially improved by high‐quality coatings. These includes primarily anti‐reflective coatings to enhance light transmission, hard coats to improve scratch resistance of the sensitive plastic substrates and finally clean coats to inhibit dusting of the lenses and to ease cleaning. In the following we present modern vacuum coating technologies for industrial refinement of optical substrates. The focal point is set to the coating of plastic eyeglass lenses using a revolutionary inline technology. On one hand the technology merges all coating steps in a fully automated system and enables on the other hand the flexible combination of different layer stacks necessary for RX‐production of ophthalmic lenses. This inline technology is available by the coating system OPTICUS. The design of the OPTICUS is described in the last chapter.     

Homologous recombination in plant cells is enhanced by in vivo induction of double strand breaks into DNA by a site-specific endonuclease

Induction of double strand breaks (DSBs) is coupled to meiotic and mitotic recombination in yeast. We show that also in a higher eukaryote induction of DSBs is directly correlated with a strong enhancement of recombination frequencies. We cotransfected Nicotiana plumbaginifolia protoplasts with a plasmid carrying a synthetic I-SceI gene, coding for a highly sequence specific endonuclease, together with recombination substrates carrying an I-SceI-site adjacent to their homologous sequences. We measured efficiencies of extrachromosomal recombination, using a well established transient beta-glucuronidase (GUS) assay. GUS enzyme activities were strongly increased when a plasmid carrying the I-SceI gene in sense but not in antisense orientation with respect to the promoter was included in the transfections. The in vivo induced DSBs were detected in the recombination substrates by Southern blotting, demonstrating that the yeast enzyme is functional in plant cells. At high ratios of transfected I-SceI-genes to I-SceI-sites the majority of the I-SceI-sites in the recombination substrates are cleaved, indicating that the induction of the DSBs is the rate limiting step in the described recombination reaction. These results imply that in vivo induction of transient breaks at specific sites in the plant genome could allow foreign DNA to be targeted to these sites via homologous recombination.     

Cellular proteins bind to multiple sites of the leader region of cauliflower mosaic virus 35S RNA

Recently, several studies have proposed models describing the mechanisms of Alzheimer's beta-amyloid fibril formation in vitro. However, these models are somewhat controversial and no exact kinetic analyses measuring the polymerization velocity as an indicator of the reaction, have thus far been available. We first formed beta-amyloid fibrils from a synthetic peptide, beta-amyloid(1-40), and determined the optimum conditions for quantitative fluorometry of these beta-amyloid fibrils with thioflavine T. Optimum fluorescence measurements of beta-amyloid fibrils were obtained at the excitation and emission wavelengths of 446 and 490 nm, respectively, with the reaction mixture containing 5 microM thioflavine T and 50 mM of glycine-NaOH buffer, pH 8.5. We then focused our study on the extension phase of beta-amyloid fibril formation in vitro. When beta-amyloid fibrils were incubated with monomeric beta-amyloid(1-40) in conditions where de novo seed formation does not occur, the extension of beta-amyloid fibrils was observed with electron microscopy. Quantitative fluorometry revealed that: (a) extension of amyloid fibrils proceeded by a pseudo-first-order exponential increase as measured by the fluorescence of thioflavine T; (b) the rate of extension was maximum around pH 7.5, and was dependent on the incubation temperature. Between 20 and 37 degrees C, good linearity was observed between the common logarithm of the initial rate and the reciprocal of the absolute temperature; (c) the rate of polymerization was found to be proportional to the product of beta-amyloid fibrils number concentration and the beta-amyloid(1-40) concentration; (d) the net rate of extension was the sum of the rates of polymerization and depolymerization. These results show that beta-amyloid fibril formation can be explained by a first-order kinetic model: i.e., the extension of beta-amyloid fibrils proceeds via the consecutive association of beta-amyloid(1-40) onto the ends of existing fibrils.     

Synthesis and Characterization of Telmisartan-Derived Cell Death Modulators to Circumvent Imatinib Resistance in Chronic Myeloid Leukemia

New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core on the cell death-modulating effects of the telmisartan-derived lead 4′-((2-propyl-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid ( 3 b ) was investigated. Inspired by the pharmacodynamics of HYL-6d and the selective PPARγ ligand VSP-51, the benzimidazole was replaced by a carbazole or an indole core. The results indicate no correlation between PPARγ activation and sensitization of resistant CML cells to imatinib. The 2-COOH derivatives of the carbazoles or indoles achieved low activity at PPARγ, while the benzimidazoles showed 60-100 % activation. Among the 2-CO₂CH₃ derivatives, only the ester of the lead ( 2 b ) slightly activated PPARγ. Sensitizing effects were further observed for this non-cytotoxic 2 b (80 % cell death), and to a lesser extent for the lead 3 b or the 5-Br-substituted ester of the benzimidazoles ( 5 b ).