Universität Stuttgart
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Item Open Access ROSIE : RObust Sparse ensemble for outlIEr detection and gene selection in cancer omics data(2022) Jensch, Antje; Lopes, Marta B.; Vinga, Susana; Radde, NicoleThe extraction of novel information from omics data is a challenging task, in particular, since the number of features (e.g. genes) often far exceeds the number of samples. In such a setting, conventional parameter estimation leads to ill-posed optimization problems, and regularization may be required. In addition, outliers can largely impact classification accuracy. Here we introduce ROSIE, an ensemble classification approach, which combines three sparse and robust classification methods for outlier detection and feature selection and further performs a bootstrap-based validity check. Outliers of ROSIE are determined by the rank product test using outlier rankings of all three methods, and important features are selected as features commonly selected by all methods. We apply ROSIE to RNA-Seq data from The Cancer Genome Atlas (TCGA) to classify observations into Triple-Negative Breast Cancer (TNBC) and non-TNBC tissue samples. The pre-processed dataset consists of 16,600 genes and more than 1,000 samples. We demonstrate that ROSIE selects important features and outliers in a robust way. Identified outliers are concordant with the distribution of the commonly selected genes by the three methods, and results are in line with other independent studies. Furthermore, we discuss the association of some of the selected genes with the TNBC subtype in other investigations. In summary, ROSIE constitutes a robust and sparse procedure to identify outliers and important genes through binary classification. Our approach is ad hoc applicable to other datasets, fulfilling the overall goal of simultaneously identifying outliers and candidate disease biomarkers to the targeted in therapy research and personalized medicine frameworks.Item Open Access Lernen und üben wir das Richtige? : Kritische Erfolgsfaktoren der Bewältigung des Massenanfalls von Verletzten : Ergebnisse einer FMEA und einer Analyse von MANV-bezogenen Curricula(2021) Drews, Patrick; Berger, Maximilian; Sautter, Johannes; Rohde, AnnikaDer Massenanfall von Verletzten (MANV) ist eine Ausnahmesituation für Rettungsdienst und andere Einsatzkräfte. Trotz niedriger Inzidenz müssen sich die Einsatzkräfte sowohl auf ärztlicher als auch auf nichtärztlicher Seite auf diesen Einsatzfall vorbereiten. In der vorliegenden Pilotstudie wurden anhand einer Fehlermöglichkeits- und -einflussanalyse (FMEA) die kritischen Einsatzfaktoren im MANV ermittelt und mit den Ausbildungscurricula verglichen. Die herangezogenen Curricula waren Notfallsanitäter:in, organisatorische:r Leiter:in, Konzept zur katastrophenmedizinischen Ausbildung im studentischen Unterricht an deutschen Hochschulen, Nationaler Kompetenz-basierter Lernzielkatalog Medizin (NKLM), Zusatz-Weiterbildung Notfallmedizin und Fortbildung zum:zur leitenden Notarzt:ärztin. Die Ergebnisse lassen vermuten, dass in der praktischen Ausbildung der MANV eine eher untergeordnete Rolle spielt. Weitere empirische Untersuchungen sind aus Sicht der Autoren notwendig.Item Open Access Untersuchungen zur Eignung mikrohydraulischer Antriebe für die minimal invasive Chirurgie(Stuttgart : Fraunhofer Verlag, 2016) Cuntz, Timo; Verl, Alexander (Univ.-Prof. Dr.-Ing. Dr. h.c. mult.)Da schonender für den Patienten, werden chirurgische Eingriffe zunehmend minimal invasiv durchgeführt. Dabei führt der Chirurg durch kleine Schnitte in Haut und Gewebe, ein Endoskop zur Sichtbarmachung der Operationsumgebung als auch chirurgische Spezialinstrumente in den Körper ein. Trotz der hohen Zunahme, der minimal invasiven Eingriffe, stagniert die Entwicklung neuer Werkzeuge für diese Operationstechnik. Zwar wurden neuartige Instrumente mit mehreren Bewegungsfreiheitsgraden an der Spitze entwickelt, diese besitzen aber solch große technische Probleme bei ihrer Anwendung, dass sie kaum benutzt werden. Ein Wechsel, weg von der der mechanischen Kraftübertragung mit Seilzügen, hin zu Direktantrieben, mit kompakten Aktoren in der Instrumentenspitze verspricht die Lösung dieser Probleme. So besteht in der minimal invasiven Chirurgie ein großer Bedarf an leichten, kraftvollen aber dennoch kompakten Antrieben, welche lediglich durch Kabel oder Schläuche und somit räumlich unabhängig im Körper versorgt werden. Beim Vergleich existierender Antriebsarten konnte gezeigt werden, dass hydraulische Antriebe die besten Voraussetzungen mitbringen um die zuvor erarbeiteten Anforderungen zu erfüllen. Die in der Konzeptphase in der Theorie angestellten Abschätzungen, vor allem zur Miniaturisierbarkeit hydraulischer Systeme, damit sich diese für den Einsatz in hydraulisch betriebenen Instrumenten für die Chirurgie eignen, konnten in praktischen Versuchsreihen bestätigt werden. In der Arbeit wurden zunächst leistungsstarke Hydraulikzylinder mit Durchmessern von wenigen Millimetern entwickelt, aus denen anschließend hydraulisch betriebene Instrumentenfunktionsmuster entstanden. Durch die Verwendung biokompatibler Materialien bis hin zu den Hydraulikmedien und dem Nachweis der Sterilisierbarkeit der kompletten Systeme wurde gezeigt, dass hydraulisch betriebene Instrumente die grundlegenden Medizinischen Anforderungen erfüllen und somit ein der Chirurgie eingesetzt werden können. Die durchgeführte Verifizierung der Instrumente demonstrierte, dass sie die geforderten Kräfte erreichen und sogar bei weitem übertreffen. Im Rahmen dieser Arbeit wurde der Nachweis für die Eignung hydraulischer betriebener Instrumente in der minimal invasiven Chirurgie erbracht.Item Open Access Nano-in-micro-particles consisting of PLGA nanoparticles embedded in chitosan microparticles via spray-drying enhances their uptake in the olfactory mucosa(2021) Spindler, Lena Marie; Feuerhake, Andreas; Ladel, Simone; Günday, Cemre; Flamm, Johannes; Günday-Türeli, Nazende; Türeli, Emre; Tovar, Günter E. M.; Schindowski, Katharina; Gruber-Traub, CarmenIntranasal delivery has gained prominence since 1990, when the olfactory mucosa was recognized as the window to the brain and the central nervous system (CNS); this has enabled the direct site specific targeting of neurological diseases for the first time. Intranasal delivery is a promising route because general limitations, such as the blood-brain barrier (BBB) are circumvented. In the treatment of multiple sclerosis (MS) or Alzheimer’s disease, for example, future treatment prospects include specialized particles as delivery vehicles. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are well known as promising delivery systems, especially in the area of nose-to-brain (N2B) delivery. Chitosan is also broadly known as a functional additive due to its ability to open tight junctions. In this study, we produced PLGA nanoparticles of different sizes and revealed for the first time their size-time-dependent uptake mechanism into the lamina propria of porcine olfactory mucosa. The intracellular uptake was observed for 80 and 175 nm within only 5 min after application to the epithelium. After 15 min, even 520 nm particles were detected, associated with nuclei. Especially the presence of only 520 nm particles in neuronal fibers is remarkable, implying transcellular and intracellular transport via the olfactory or the trigeminal nerve to the brain and the CNS. Additionally, we developed successfully specialized Nano-in-Micro particles (NiMPs) for the first time via spray drying, consisting of PLGA nanoparticles embedded into chitosan microparticles, characterized by high encapsulation efficiencies up to 51%, reproducible and uniform size distribution, as well as smooth surface. Application of NiMPs accelerated the uptake compared to purely applied PLGA nanoparticles. NiMPs were spread over the whole transverse section of the olfactory mucosa within 15 min. Faster uptake is attributed to additional paracellular transport, which was examined via tight-junction-opening. Furthermore, a separate chitosan penetration gradient of ∼150 µm caused by dissociation from PLGA nanoparticles was observed within 15 min in the lamina propria, which was demonstrated to be proportional to an immunoreactivity gradient of CD14. Due to the beneficial properties of the utilized chitosan-derivative, regarding molecular weight (150-300 kDa), degree of deacetylation (80%), and particle size (0.1-10 µm) we concluded that M2-macrophages herein initiated an anti-inflammatory reaction, which seems to already take place within 15 min following chitosan particle application. In conclusion, we demonstrated the possibility for PLGA nanoparticles, as well as for chitosan NiMPs, to take all three prominent intranasal delivery pathways to the brain and the CNS; namely transcellular, intracellular via neuronal cells, and paracellular transport.Item Open Access Acquisition, but not retrieval of delayed alternation is impaired by ketamine(1990) Hauber, Wolfgang; Schmidt, Werner J.Dissociative anaesthetics as ketamine and related drugs induce marked behavioral changes in rats, in particular behavioral stereotypies and learning impairments. In the resent study the effect of ketamine on acquisition and retrieval of a delayed alternation task was investigated. Results indicate that ketamine (8mg/kg i.p.) impaired specifically acquisition, while retrieval was not affected. Thus, stereotypies competing with ongoing behavior and therefore interfere with learning, appear not to be causative to the acquisition deficit, since retrieval should be affected in the same way. A possible involvement of NMDA receptors in deficient acquisition is discussed.Item Open Access Multiphasic modelling and computation of metastatic lung-cancer cell proliferation and atrophy in brain tissue based on experimental data(2021) Ehlers, Wolfgang; Rehm, Markus; Schröder, Patrick; Stöhr, Daniela; Wagner, ArndtCancer is one of the most serious diseases for human beings, especially when metastases come into play. In the present article, the example of lung-cancer metastases in the brain is used to discuss the basic problem of cancer growth and atrophy as a result of both nutrients and medication. As the brain itself is a soft tissue that is saturated by blood and interstitial fluid, the biomechanical description of the problem is based on the Theory of Porous Media enhanced by the results of medication tests carried out in in-vitro experiments on cancer-cell cultures. Based on theoretical and experimental results, the consideration of proliferation, necrosis and apoptosis of metastatic cancer cells is included in the description by so-called mass-production terms added to the mass balances of the brain skeleton and the interstitial fluid. Furthermore, the mass interaction of nutrients and medical drugs between the solid and the interstitial fluid and its influence on proliferation, necrosis and apoptosis of cancer cells are considered. As a result, the overall model is appropriate for the description of brain tumour treatment combined with stress and deformation induced by cancer growth in the skull.Item Open Access Patterns of autologous and nonautologous interactions between core nuclear egress complex (NEC) proteins of α-, β- and γ-herpesviruses(2020) Häge, Sigrun; Sonntag, Eric; Borst, Eva Maria; Tannig, Pierre; Seyler, Lisa; Bäuerle, Tobias; Bailer, Susanne M.; Lee, Chung-Pei; Müller, Regina; Wangen, Christina; Milbradt, Jens; Marschall, ManfredNuclear egress is a regulated process shared by α-, β- and γ-herpesviruses. The core nuclear egress complex (NEC) is composed of the membrane-anchored protein homologs of human cytomegalovirus (HCMV) pUL50, murine cytomegalovirus (MCMV) pM50, Epstein-Barr virus (EBV) BFRF1 or varicella zoster virus (VZV) Orf24, which interact with the autologous NEC partners pUL53, pM53, BFLF2 or Orf27, respectively. Their recruitment of additional proteins leads to the assembly of a multicomponent NEC, coordinately regulating viral nucleocytoplasmic capsid egress. Here, the functionality of VZV, HCMV, MCMV and EBV core NECs was investigated by coimmunoprecipitation and confocal imaging analyses. Furthermore, a recombinant MCMV, harboring a replacement of ORF M50 by UL50, was analyzed both in vitro and in vivo. In essence, core NEC interactions were strictly limited to autologous NEC pairs and only included one measurable nonautologous interaction between the homologs of HCMV and MCMV. A comparative analysis of MCMV-WT versus MCMV-UL50-infected murine fibroblasts revealed almost identical phenotypes on the levels of protein and genomic replication kinetics. In infected BALB/c mice, virus spread to lung and other organs was found comparable between these viruses, thus stating functional complementarity. In conclusion, our study underlines that herpesviral core NEC proteins are functionally conserved regarding complementarity of core NEC interactions, which were found either virus-specific or restricted within subfamilies.Item Open Access Bericht über die konstituierende Sitzung der Arbeitsgruppe "Unfallchirurgische Laserapplikationen und ihre biologischen und medizinischen Nebenwirkungen" am 29. Oktober 1990 im Laser-Laboratorium Göttingen(1990) Dressel, Martin; Jahn, RenateAnlaß dieser Besprechung stellten die schnellen technischen Fortschritte auf dem Gebiet der biologischen Hartgewebeabtragung mit kurzgepulsten Lasern aus dem UV-Bereich (speziell der Excimerlaser-Wellenlänge 308 nm) dar. Die ungenügend erforscht oder kontrovers in der Literatur diskutierten Nebenwirkungen stellten die grundsätzliche Thematik dieser Tagung dar, die von Herrn Prof. Harder in folgende Gebiete eingegrenzt wurde: - Wechselwirkung von gepulster UV-Strahlung mit biologischem Gewebe - toxische Abfallprodukte und Rückstände - mutagene und kanzerogene Nebeneffekte - Ionisation.Item Open Access Patient motion compensation for renal scintigraphic studies by a fast correlation image registration method(1994) Georgiou, Michalis F.; Sfakianakis, George N.; Nagel, Joachim H.; Cideciyan, Artur V.A computer method has been developed to compensate for patient motion which is a serious problem in real scintigraphic studies. The developed computer method compensates for translational and rotational differences between images acquired while the patient was not moving and images acquired after the occurrence of motion.Item Open Access The effect of pooling on the detection of the nucleocapsid protein of SARS-CoV-2 with rapid antigen tests(2021) Berking, Tim; Lorenz, Sabrina; Ulrich, Alexander; Greiner, Joachim; Kervio, Eric; Bremer, Jennifer; Wege, Christina; Kleinow, Tatjana; Richert, ClemensThe COVID-19 pandemic puts significant stress on the viral testing capabilities of many countries. Rapid point-of-care (PoC) antigen tests are valuable tools but implementing frequent large scale testing is costly. We have developed an inexpensive device for pooling swabs, extracting specimens, and detecting viral antigens with a commercial lateral flow test for the nucleocapsid protein of SARS-CoV-2 as antigen. The holder of the device can be produced locally through 3D printing. The extraction and the elution can be performed with the entire set-up encapsulated in a transparent bag, minimizing the risk of infection for the operator. With 0.35 mL extraction buffer and six swabs, including a positive control swab, 43 ± 6% (n = 8) of the signal for an individual extraction of a positive control standard was obtained. Image analysis still showed a signal-to-noise ratio of approximately 2:1 at 32-fold dilution of the extract from a single positive control swab. The relative signal from the test line versus the control line was found to scale linearly upon dilution (R2 = 0.98), indicating that other pooling regimes are conceivable. A pilot project involving 14 participants and 18 pooled tests in a laboratory course at our university did not give any false positives, and an individual case study confirmed the ability to detect a SARS-CoV-2 infection with five-fold or six-fold pooling, including one swab from a PCR-confirmed COVID patient. These findings suggest that pooling can make frequent testing more affordable for schools, universities, and similar institutions, without decreasing sensitivity to an unacceptable level.