TY - JOUR A1 - Almajhdi, Fahad N. A1 - Senger, Tilo A1 - Amer, Haitham M. A1 - Gissmann, Lutz A1 - Öhlschläger, Peter T1 - Design of a highly effective therapeutic HPV16 E6/E7-specific DNA vaccine: optimization by different ways of sequence rearrangements (Shuffling) JF - PLOS one N2 - Persistent infection with the high-risk Human Papillomavirus type 16 (HPV 16) is the causative event for the development of cervical cancer and other malignant tumors of the anogenital tract and of the head and neck. Despite many attempts to develop therapeutic vaccines no candidate has entered late clinical trials. An interesting approach is a DNA based vaccine encompassing the nucleotide sequence of the E6 and E7 viral oncoproteins. Because both proteins are consistently expressed in HPV infected cells they represent excellent targets for immune therapy. Here we report the development of 8 DNA vaccine candidates consisting of differently rearranged HPV-16 E6 and E7 sequences within one molecule providing all naturally occurring epitopes but supposedly lacking transforming activity. The HPV sequences were fused to the J-domain and the SV40 enhancer in order to increase immune responses. We demonstrate that one out of the 8 vaccine candidates induces very strong cellular E6- and E7- specific cellular immune responses in mice and, as shown in regression experiments, efficiently controls growth of HPV 16 positive syngeneic tumors. This data demonstrates the potential of this vaccine candidate to control persistent HPV 16 infection that may lead to malignant disease. It also suggests that different sequence rearrangements influence the immunogenecity by an as yet unknown mechanism. Y1 - 2014 U6 - https://doi.org/10.1371/journal.pone.0113461 SN - 1932-6203 VL - 11 IS - 9 PB - PLOS CY - San Francisco ER - TY - JOUR A1 - Henken, F. E. A1 - Oosterhuis, K. A1 - Öhlschläger, Peter A1 - Bosch, L. A1 - Hooijberg, E. A1 - Haanen, J. B. A. G. A1 - Steenbergen, R. D. M. T1 - Preclinical safety evaluation of DNA vaccines encoding modified HPV16 E6 and E7 JF - Vaccine N2 - Persistent infection with high-risk human papillomaviruses (hrHPV) can result in the formation of anogenital cancers. As hrHPV proteins E6 and E7 are required for cancer initiation and maintenance, they are ideal targets for immunotherapeutic interventions. Previously, we have described the development of DNA vaccines for the induction of HPV16 E6 and E7 specific T cell immunity. These vaccines consist of ‘gene-shuffled’ (SH) versions of HPV16 E6 and E7 that were fused to Tetanus Toxin Fragment C domain 1 (TTFC) and were named TTFC-E6SH and TTFC-E7SH. Gene-shuffling was performed to avoid the risk of inducing malignant transformation at the vaccination site. Here, we describe the preclinical safety evaluation of these candidate vaccines by analysis of their transforming capacity in vitro using established murine fibroblasts (NIH 3T3 cells) and primary human foreskin keratinocytes (HFKs). We demonstrate that neither ectopic expression of TTFC-E6SH and TTFC-E7SH alone or in combination enabled NIH 3T3 cells to form colonies in soft agar. In contrast, expression of HPV16 E6WT and E7WT alone or in combination resulted in effective transformation. Similarly, retroviral transduction of HFKs from three independent donors with both TTFC-E6SH and TTFC-E7SH alone or in combination did not show any signs of immortalization. In contrast, the combined expression of E6WT and E7WT induced immortalization in HFKs from all donors. Based on these results we consider it justified to proceed to clinical evaluation of DNA vaccines encoding TTFC-E6SH and TTFC-E7SH in patients with HPV16 associated (pre)malignancies. Y1 - 2012 U6 - https://doi.org/10.1016/j.vaccine.2012.04.013 SN - 0264-410X VL - 30 IS - 28 SP - 4259 EP - 4266 PB - Elsevier CY - Amsterdam ER - TY - JOUR A1 - Engelmann, Ulrich M. A1 - Roeth, Anjali A.J. A1 - Eberbeck, Dietmar A1 - Buhl, Eva Miriam A1 - Neumann, Ulf Peter A1 - Schmitz-Rode, Thomas A1 - Slabu, Ioana T1 - Combining Bulk Temperature and Nanoheating Enables Advanced Magnetic Fluid Hyperthermia Efficacy on Pancreatic Tumor Cells JF - Scientific Reports N2 - Many efforts are made worldwide to establish magnetic fluid hyperthermia (MFH) as a treatment for organ-confined tumors. However, translation to clinical application hardly succeeds as it still lacks of understanding the mechanisms determining MFH cytotoxic effects. Here, we investigate the intracellular MFH efficacy with respect to different parameters and assess the intracellular cytotoxic effects in detail. For this, MiaPaCa-2 human pancreatic tumor cells and L929 murine fibroblasts were loaded with iron-oxide magnetic nanoparticles (MNP) and exposed to MFH for either 30 min or 90 min. The resulting cytotoxic effects were assessed via clonogenic assay. Our results demonstrate that cell damage depends not only on the obvious parameters bulk temperature and duration of treatment, but most importantly on cell type and thermal energy deposited per cell during MFH treatment. Tumor cell death of 95% was achieved by depositing an intracellular total thermal energy with about 50% margin to damage of healthy cells. This is attributed to combined intracellular nanoheating and extracellular bulk heating. Tumor cell damage of up to 86% was observed for MFH treatment without perceptible bulk temperature rise. Effective heating decreased by up to 65% after MNP were internalized inside cells. Y1 - 2018 U6 - https://doi.org/10.1038/s41598-018-31553-9 SN - 2045-2322 VL - 8 IS - 1 SP - Article number 13210 PB - Springer Nature CY - Cham ER - TY - CHAP A1 - Müller, Tim M. A1 - Altherr, Lena A1 - Ahola, Marja A1 - Schabel, Samuel A1 - Pelz, Peter F. T1 - Optimizing pressure screen systems in paper recycling: optimal system layout, component selection and operation N2 - Around 60% of the paper worldwide is made from recovered paper. Especially adhesive contaminants, so called stickies, reduce paper quality. To remove stickies but at the same time keep as many valuable fibers as possible, multi-stage screening systems with several interconnected pressure screens are used. When planning such systems, suitable screens have to be selected and their interconnection as well as operational parameters have to be defined considering multiple conflicting objectives. In this contribution, we present a Mixed-Integer Nonlinear Program to optimize system layout, component selection and operation to find a suitable trade-off between output quality and yield. KW - Mixed-integer nonlinear problem KW - MINLP KW - Process engineering KW - Paper recycling KW - Multi-criteria optimization Y1 - 2018 SN - 978-3-030-18499-5 U6 - https://doi.org/10.1007/978-3-030-18500-8_44 SP - 355 EP - 361 PB - Springer CY - Cham ER - TY - CHAP A1 - Müller, Tim M. A1 - Altherr, Lena A1 - Ahola, Marja A1 - Schabel, Samuel A1 - Pelz, Peter F. ED - Rodrigues, H. C. T1 - Multi-Criteria optimization of pressure screen systems in paper recycling – balancing quality, yield, energy consumption and system complexity T2 - EngOpt 2018 Proceedings of the 6th International Conference on Engineering Optimization N2 - The paper industry is the industry with the third highest energy consumption in the European Union. Using recycled paper instead of fresh fibers for papermaking is less energy consuming and saves resources. However, adhesive contaminants in recycled paper are particularly problematic since they reduce the quality of the resulting paper-product. To remove as many contaminants and at the same time obtain as many valuable fibres as possible, fine screening systems, consisting of multiple interconnected pressure screens, are used. Choosing the best configuration is a non-trivial task: The screens can be interconnected in several ways, and suitable screen designs as well as operational parameters have to be selected. Additionally, one has to face conflicting objectives. In this paper, we present an approach for the multi-criteria optimization of pressure screen systems based on Mixed-Integer Nonlinear Programming. We specifically focus on a clear representation of the trade-off between different objectives. Y1 - 2019 SN - 978-3-319-97773-7 U6 - https://doi.org/10.1007/978-3-319-97773-7_105 N1 - EngOpt 2018 Proceedings of the 6th International Conference on Engineering Optimization. 17-19 September 2018. Lisboa, Portugal PB - Springer International Publishing CY - Basel ER - TY - CHAP A1 - Müller, Tim M. A1 - Schmitt, Andreas A1 - Leise, Philipp A1 - Meck, Tobias A1 - Altherr, Lena A1 - Pelz, Peter F. A1 - Pfetsch, Marc E. T1 - Validation of an optimized resilient water supply system T2 - Uncertainty in Mechanical Engineering N2 - Component failures within water supply systems can lead to significant performance losses. One way to address these losses is the explicit anticipation of failures within the design process. We consider a water supply system for high-rise buildings, where pump failures are the most likely failure scenarios. We explicitly consider these failures within an early design stage which leads to a more resilient system, i.e., a system which is able to operate under a predefined number of arbitrary pump failures. We use a mathematical optimization approach to compute such a resilient design. This is based on a multi-stage model for topology optimization, which can be described by a system of nonlinear inequalities and integrality constraints. Such a model has to be both computationally tractable and to represent the real-world system accurately. We therefore validate the algorithmic solutions using experiments on a scaled test rig for high-rise buildings. The test rig allows for an arbitrary connection of pumps to reproduce scaled versions of booster station designs for high-rise buildings. We experimentally verify the applicability of the presented optimization model and that the proposed resilience properties are also fulfilled in real systems. KW - Optimization KW - Mixed-integer nonlinear programming KW - Water distribution system KW - Resilience KW - Validation Y1 - 2021 SN - 978-3-030-77255-0 SN - 978-3-030-77256-7 U6 - https://doi.org/10.1007/978-3-030-77256-7_7 N1 - Proceedings of the 4th International Conference on Uncertainty in Mechanical Engineering (ICUME 2021), June 7–8, 2021 SP - 70 EP - 80 PB - Springer CY - Cham ER - TY - JOUR A1 - Müller, Tim M. A1 - Leise, Philipp A1 - Lorenz, Imke-Sophie A1 - Altherr, Lena A1 - Pelz, Peter F. T1 - Optimization and validation of pumping system design and operation for water supply in high-rise buildings JF - Optimization and Engineering N2 - The application of mathematical optimization methods for water supply system design and operation provides the capacity to increase the energy efficiency and to lower the investment costs considerably. We present a system approach for the optimal design and operation of pumping systems in real-world high-rise buildings that is based on the usage of mixed-integer nonlinear and mixed-integer linear modeling approaches. In addition, we consider different booster station topologies, i.e. parallel and series-parallel central booster stations as well as decentral booster stations. To confirm the validity of the underlying optimization models with real-world system behavior, we additionally present validation results based on experiments conducted on a modularly constructed pumping test rig. Within the models we consider layout and control decisions for different load scenarios, leading to a Deterministic Equivalent of a two-stage stochastic optimization program. We use a piecewise linearization as well as a piecewise relaxation of the pumps’ characteristics to derive mixed-integer linear models. Besides the solution with off-the-shelf solvers, we present a problem specific exact solving algorithm to improve the computation time. Focusing on the efficient exploration of the solution space, we divide the problem into smaller subproblems, which partly can be cut off in the solution process. Furthermore, we discuss the performance and applicability of the solution approaches for real buildings and analyze the technical aspects of the solutions from an engineer’s point of view, keeping in mind the economically important trade-off between investment and operation costs. KW - Technical Operations Research KW - MINLP KW - MILP KW - Experimental validation KW - Pumping systems Y1 - 2020 U6 - https://doi.org/10.1007/s11081-020-09553-4 SN - 1573-2924 VL - 2021 IS - 22 SP - 643 EP - 686 PB - Springer ER - TY - CHAP A1 - Müller, Tim M. A1 - Altherr, Lena A1 - Leise, Philipp A1 - Pelz, Peter F. T1 - Optimization of pumping systems for buildings: Experimental validation of different degrees of model detail on a modular test rig T2 - Operations Research Proceedings 2019 N2 - Successful optimization requires an appropriate model of the system under consideration. When selecting a suitable level of detail, one has to consider solution quality as well as the computational and implementation effort. In this paper, we present a MINLP for a pumping system for the drinking water supply of high-rise buildings. We investigate the influence of the granularity of the underlying physical models on the solution quality. Therefore, we model the system with a varying level of detail regarding the friction losses, and conduct an experimental validation of our model on a modular test rig. Furthermore, we investigate the computational effort and show that it can be reduced by the integration of domain-specific knowledge. KW - Experimental validation KW - MINLP KW - Engineering optimization KW - Water supply system KW - Network design Y1 - 2020 SN - 978-3-030-48438-5 U6 - https://doi.org/10.1007/978-3-030-48439-2_58 N1 - Annual International Conference of the German Operations Research Society (GOR), Dresden, Germany, September 4-6, 2019 SP - 481 EP - 488 PB - Springer CY - Cham ER - TY - CHAP A1 - Butenweg, Christoph A1 - Marinković, Marko A1 - Pavese, Alberto A1 - Lanese, Igor A1 - Hoffmeister, Benno A1 - Pinkawa, Marius A1 - Vulcu, Mihai-Cristian A1 - Bursi, Oreste A1 - Nardin, Chiara A1 - Paolacci, Fabrizio A1 - Quinci, Gianluca A1 - Fragiadakis, Michalis A1 - Weber, Felix A1 - Huber, Peter A1 - Renault, Philippe A1 - Gündel, Max A1 - Dyke, Shirley A1 - Ciucci, M. A1 - Marino, A. T1 - Seismic performance of multi-component systems in special risk industrial facilities T2 - Proceedings of the seventeenth world conference on earthquake engineering N2 - Past earthquakes demonstrated the high vulnerability of industrial facilities equipped with complex process technologies leading to serious damage of the process equipment and multiple and simultaneous release of hazardous substances in industrial facilities. Nevertheless, the design of industrial plants is inadequately described in recent codes and guidelines, as they do not consider the dynamic interaction between the structure and the installations and thus the effect of seismic response of the installations on the response of the structure and vice versa. The current code-based approach for the seismic design of industrial facilities is considered not enough for ensure proper safety conditions against exceptional event entailing loss of content and related consequences. Accordingly, SPIF project (Seismic Performance of Multi- Component Systems in Special Risk Industrial Facilities) was proposed within the framework of the European H2020 - SERA funding scheme (Seismology and Earthquake Engineering Research Infrastructure Alliance for Europe). The objective of the SPIF project is the investigation of the seismic behavior of a representative industrial structure equipped with complex process technology by means of shaking table tests. The test structure is a three-story moment resisting steel frame with vertical and horizontal vessels and cabinets, arranged on the three levels and connected by pipes. The dynamic behavior of the test structure and installations is investigated with and without base isolation. Furthermore, both firmly anchored and isolated components are taken into account to compare their dynamic behavior and interactions with each other. Artificial and synthetic ground motions are applied to study the seismic response at different PGA levels. After each test, dynamic identification measurements are carried out to characterize the system condition. The contribution presents the numerical simulations to calibrate the tests on the prototype, the experimental setup of the investigated structure and installations, selected measurement data and finally describes preliminary experimental results. KW - industrial facilities KW - piping KW - installations KW - seismic loading KW - earthquakes Y1 - 2021 N1 - 17. World Conference on Earthquake Engineering, 17WCEE, Sendai, Japan, 2021-09-27 - 2021-10-02 ER - TY - GEN A1 - Eccleston, Paul A1 - Drummond, Rachel A1 - Middleton, Kevin A1 - Bishop, Georgia A1 - Caldwell, Andrew A1 - Desjonqueres, Lucile A1 - Tosh, Ian A1 - Cann, Nick A1 - Crook, Martin A1 - Hills, Matthew A1 - Pearson, Chris A1 - Simpson, Caroline A1 - Stamper, Richard A1 - Tinetti, Giovanna A1 - Pascale, Enzo A1 - Swain, Mark A1 - Holmes, Warren A. A1 - Wong, Andre A1 - Puig, Ludovic A1 - Pilbratt, Göran A1 - Linder, Martin A1 - Boudin, Nathalie A1 - Ertel, Hanno A1 - Gambicorti, Lisa A1 - Halain, Jean-Philippe A1 - Pace, Emanuele A1 - Vilardell, Francesc A1 - Gómez, José M. A1 - Colomé, Josep A1 - Amiaux, Jérôme A1 - Cara, Christophe A1 - Berthe, Michel A1 - Moreau, Vincent A1 - Morgante, Gianluca A1 - Malaguti, Giuseppe A1 - Alonso, Gustavo A1 - Álvarez, Javier P. A1 - Ollivier, Marc A1 - Philippon, Anne A1 - Hellin, Marie-Laure A1 - Roose, Steve A1 - Frericks, Martin A1 - Krijger, Matthijs A1 - Rataj, Miroslaw A1 - Wawer, Piotr A1 - Skup, Konrad A1 - Sobiecki, Mateusz A1 - Christian Jessen, Niels A1 - Møller Pedersen, Søren A1 - Hargrave, Peter A1 - Griffin, Matt A1 - Ottensamer, Roland A1 - Hunt, Thomas A1 - Rust, Duncan A1 - Saleh, Aymen A1 - Winter, Berend A1 - Focardi, Mauro A1 - Da Deppo, Vania A1 - Zuppella, Paola A1 - Czupalla, Markus ED - Lystrup, Makenzie ED - Perrin, Marshall D. ED - Batalha, Natalie ED - Siegler, Nicholas ED - Tong, Edward C. T1 - The ARIEL payload: A technical overview T2 - Space Telescopes and Instrumentation 2020: Optical, Infrared, and Millimeter Wave N2 - The Atmospheric Remote-Sensing Infrared Exoplanet Large-survey, ARIEL, has been selected to be the next (M4) medium class space mission in the ESA Cosmic Vision programme. From launch in 2028, and during the following 4 years of operation, ARIEL will perform precise spectroscopy of the atmospheres of ~1000 known transiting exoplanets using its metre-class telescope. A three-band photometer and three spectrometers cover the 0.5 µm to 7.8 µm region of the electromagnetic spectrum. This paper gives an overview of the mission payload, including the telescope assembly, the FGS (Fine Guidance System) - which provides both pointing information to the spacecraft and scientific photometry and low-resolution spectrometer data, the ARIEL InfraRed Spectrometer (AIRS), and other payload infrastructure such as the warm electronics, structures and cryogenic cooling systems. KW - Exoplanet KW - Spectroscopy KW - Transit KW - Atmospheres KW - Payload Y1 - 2020 U6 - https://doi.org/10.1117/12.2561478 N1 - Space Telescopes and Instrumentation 2020: Optical, Infrared, and Millimeter Wave, 14–22 December 2020, Online Only, United States VL - 11443 SP - 114430Z PB - SPIE CY - Washington ER -