TY - JOUR A1 - Schilbach, Karin A1 - Alkhaled, Mohammed A1 - Welker, Christian A1 - Eckert, Franziska A1 - Blank, Gregor A1 - Ziegler, Hendrik A1 - Sterk, Marco A1 - Müller, Friederike A1 - Sonntag, Katja A1 - Wieder, Thomas A1 - Braumüller, Heidi A1 - Schmitt, Julia A1 - Eyrich, Matthias A1 - Schleicher, Sabine A1 - Seitz, Christian A1 - Erbacher, Annika A1 - Pichler, Bernd J. A1 - Müller, Hartmut A1 - Tighe, Robert A1 - Lim, Annick A1 - Gillies, Stephen D. A1 - Strittmatter, Wolfgang A1 - Röcken, Martin A1 - Handgretinger, Rupert T1 - Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation JF - OncoImmunology N2 - Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo. KW - TH17 cells KW - cancer-targeted IL-12 KW - differentiation KW - humanized mice KW - immunocytokine KW - immunotherapy KW - M1/M2 macrophages KW - rhabdomyosarcoma KW - TH1-induced senescence KW - tumor-infiltrating lymphocytes Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154579 VL - 4 IS - 7 ER - TY - JOUR A1 - Welker, Armin A1 - Kersten, Christian A1 - Müller, Christin A1 - Madhugiri, Ramakanth A1 - Zimmer, Collin A1 - Müller, Patrick A1 - Zimmermann, Robert A1 - Hammerschmidt, Stefan A1 - Maus, Hannah A1 - Ziebuhr, John A1 - Sotriffer, Christoph A1 - Schirmeister, Tanja T1 - Structure‐Activity Relationships of Benzamides and Isoindolines Designed as SARS‐CoV Protease Inhibitors Effective against SARS‐CoV‐2 JF - ChemMedChem N2 - Inhibition of coronavirus (CoV)‐encoded papain‐like cysteine proteases (PL\(^{pro}\)) represents an attractive strategy to treat infections by these important human pathogens. Herein we report on structure‐activity relationships (SAR) of the noncovalent active‐site directed inhibitor (R)‐5‐amino‐2‐methyl‐N‐(1‐(naphthalen‐1‐yl)ethyl) benzamide (2 b), which is known to bind into the S3 and S4 pockets of the SARS‐CoV PL\(^{pro}\). Moreover, we report the discovery of isoindolines as a new class of potent PL\(^{pro}\) inhibitors. The studies also provide a deeper understanding of the binding modes of this inhibitor class. Importantly, the inhibitors were also confirmed to inhibit SARS‐CoV‐2 replication in cell culture suggesting that, due to the high structural similarities of the target proteases, inhibitors identified against SARS‐CoV PL\(^{pro}\) are valuable starting points for the development of new pan‐coronaviral inhibitors. KW - antiviral agents KW - computational chemistry KW - drug design KW - protease inhibitors KW - structure-activity relationships Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225700 VL - 16 IS - 2 SP - 340 EP - 354 ER - TY - THES A1 - Müller, Christian Robert T1 - Nanoelektronische Feldeffekt-Transistoren und Quantenpunktspeicher auf der Basis von modulationsdotierten GaAs/AlGaAs Heterostrukturen T1 - Nanoelectronic field-effect transistors and quantum-dot-flash memories based on modulation-doped GaAs/AlGaAs heterostructures N2 - Diese Arbeit beschäftigt sich mit Elektronentransport in nanostrukturierten Bauelementen auf Halbleiterbasis, wobei im Speziellen deren Transistor- und Speichereigenschaften untersucht werden. Grundlage für die Bauelemente stellt eine modulationsdotierte GaAs/AlGaAs Heterostruktur dar, die mittels Elektronenstrahllithographie und nasschemischen Ätzverfahren strukturiert wird. Auf Grund der Bandverbiegung bildet sich in der Nähe des Heteroübergangs ein zweidimensionales Elektronengas (2DEG) aus, das als leitfähige Schicht in den Strukturen dient. Im Rahmen der Arbeit werden die Transporteigenschaften für unterschiedliche Bauelementdesigns untersucht, wobei die laterale Ausdehnung der Bauelemente wenige 10 nm beträgt. Die Charakterisierung des Elektronentransports erfolgt sowohl im linearen als auch nichtlinearen Transportregime für tiefe Temperaturen (T = 4.2 K) bis hin zu Raumtemperatur. Das erste experimentelle Kapitel beschäftigt sich mit dem Entwurf und der Charakterisierung von statischen Speicherzellen mit integriertem Floating Gate. Bei den hierfür hergestellten Bauelementen befindet sich eine Schicht selbstorganisierter Quantenpunkte (QDs) in direkter Nähe zum 2DEG. Der Abstand zwischen 2DEG und QDs ist kleiner als die Abschirmlänge im Halbleitermaterial, wodurch die QDs als Floating Gate dienen und Informationen elektrisch gespeichert werden können. Die Speicherzellen wurden in Form von Quantendraht-Transistoren (QWTs) und Y-Schaltern (YBSs) realisiert und bezüglich der Speicherfähigkeit der QDs sowohl bei tiefen Temperaturen als auch bei Raumtemperatur untersucht. Im zweiten experimentellen Kapitel dieser Arbeit wird ein neues, auf dem Feldeffekt beruhendes, Transistordesign vorgestellt. Die hierfür hergestellten Heterostrukturen besitzen ein 2DEG, das sich zwischen 33 nm und 80 nm unterhalb der Oberfläche der Heterostruktur befindet. Mittels in die Oberfläche der Heterostruktur geätzter Gräben wird eine Isolation zwischen den leitfähigen Regionen der Bauelemente geschaffen. Das einfache Design der sogenannten Three-Terminal Junctions (TTJs), in Verbindung mit dem oberflächennahen 2DEG, ermöglicht die monolithische Realisierung von integrierten logischen Gattern. Durch eine ausführliche Betrachtung des Transistorverhaltens der TTJs können sowohl Subthreshold Swings kleiner als das thermische Limit klassischer Feldeffekt-Transistoren als auch Hochfrequenzfunktionalität demonstriert werden. N2 - In this thesis, electron transport in nano-structured, semiconductor devices is investigated with focus on transistor characteristics and memory effects. The investigated devices are based on a modulation-doped GaAs/AlGaAs heterostructure and are structured by electron-beam lithography and wet-chemical etching. Close to the heterointerface, a two-dimensional electron gas (2DEG) is formed and serves as conducting layer for the electron transport. Different devices with lateral dimensions of a few 10 nm are fabricated and are characterized in the linear and nonlinear transport regime at low temperatures, i.e. T = 4.2 K, as well as at room temperature. The first chapter is dedicated to the experimental results on the design and characterization of memory devices with a floating gate. The devices are based on a modulation-doped heterostructure with a layer of self-assembled quantum dots (QDs) in close vicinity to the conducting layer. The distance between QDs and 2DEG is less than the screening length and, therefore, the QDs serve as floating gate on the 2DEG. Hence, information can be stored electrically. For the memory devices, quantum-wire transistors (QWTs) and electron Y-branch switches (YBSs) are used and characterized, with respect to the floating-gate function of the QDs, at low temperatures and up to room temperature. In the second chapter of this thesis, a novel transistor design based on the field effect is presented. For this purpose, the 2DEG is situated between 33 and 80 nm below the surface of the heterostructure. The conducting parts of the devices are insulated from each other by etched insulation trenches. Due to the monolithic design of the three-terminal junctions (TTJs) with a shallow 2DEG, an integrated logic gate is realized. By analyzing the switching properties of the TTJs in detail, subthreshold swings below the thermal limit and high frequency functionality are demonstrated. KW - Galliumarsenid KW - Aluminiumarsenid KW - Heterostruktur-Bauelement KW - HEMT KW - SET-Transistor KW - Quantenpunkt KW - Nanodot-Speicher KW - Flash-Speicher KW - HEMT KW - field-effect transistor KW - quantum dot KW - flash memory KW - rectification Y1 - 2009 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-39948 ER - TY - JOUR A1 - Rinaldetti, Sébastien A1 - Pfirrmann, Markus A1 - Manz, Kirsi A1 - Guilhot, Joelle A1 - Dietz, Christian A1 - Panagiotidis, Panayiotidis A1 - Spiess, Birgit A1 - Seifarth, Wolfgang A1 - Fabarius, Alice A1 - Müller, Martin A1 - Pagoni, Maria A1 - Dimou, Maria A1 - Dengler, Jolanta A1 - Waller, Cornelius F. A1 - Brümmendorf, Tim H. A1 - Herbst, Regina A1 - Burchert, Andreas A1 - Janßen, Carsten A1 - Goebeler, Maria Elisabeth A1 - Jost, Philipp J. A1 - Hanzel, Stefan A1 - Schafhausen, Philippe A1 - Prange-Krex, Gabriele A1 - Illmer, Thomas A1 - Janzen, Viktor A1 - Klausmann, Martine A1 - Eckert, Robert A1 - Büschel, Gerd A1 - Kiani, Alexander A1 - Hofmann, Wolf-Karsten A1 - Mahon, François-Xavier A1 - Saussele, Susanne T1 - Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial JF - Clinical Lymphoma, Myeloma & Leukemia N2 - Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc. KW - ABCG2 KW - Biomarker KW - CML KW - Imatinib KW - Prediction Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226281 VL - 18 IS - 4 ER - TY - JOUR A1 - Müller, Konstantin A1 - Leppich, Robert A1 - Geiß, Christian A1 - Borst, Vanessa A1 - Pelizari, Patrick Aravena A1 - Kounev, Samuel A1 - Taubenböck, Hannes T1 - Deep neural network regression for normalized digital surface model generation with Sentinel-2 imagery JF - IEEE Journal of Selected Topics in Applied Earth Observations and Remote Sensing N2 - In recent history, normalized digital surface models (nDSMs) have been constantly gaining importance as a means to solve large-scale geographic problems. High-resolution surface models are precious, as they can provide detailed information for a specific area. However, measurements with a high resolution are time consuming and costly. Only a few approaches exist to create high-resolution nDSMs for extensive areas. This article explores approaches to extract high-resolution nDSMs from low-resolution Sentinel-2 data, allowing us to derive large-scale models. We thereby utilize the advantages of Sentinel 2 being open access, having global coverage, and providing steady updates through a high repetition rate. Several deep learning models are trained to overcome the gap in producing high-resolution surface maps from low-resolution input data. With U-Net as a base architecture, we extend the capabilities of our model by integrating tailored multiscale encoders with differently sized kernels in the convolution as well as conformed self-attention inside the skip connection gates. Using pixelwise regression, our U-Net base models can achieve a mean height error of approximately 2 m. Moreover, through our enhancements to the model architecture, we reduce the model error by more than 7%. KW - Deep learning KW - multiscale encoder KW - sentinel KW - surface model Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349424 SN - 1939-1404 VL - 16 ER -