Development and Characterization of Single-Molecule Switching Nanoscopy Approaches for Deeper and Faster Imaging

Novel single-molecule switching super-resolution microscopy overcomes the diffraction limit of far-field fluorescence microscopy by precisely localizing individual fluorescent molecules from thousands of images of stochastic, sparse blinking-molecule distributions. However, this technique has so far mostly been limited to thin, fixed samples: usually, fluorescent molecules are activated throughout the whole depths of the sample and not just in the 1 - 2 μm thick optical section where they can be localized. In thick samples, this incurs excessive background and unwanted bleaching of probe molecules out of focus. Using two-photon absorption allows to limit activation of photo-activatable fluorescent proteins to the optical section where they can be localized. However, no spectroscopic information about the two-photon activation of the most commonly used molecules has been available so far. Live-cell imaging is additionally hampered by the typically used EM-CCD cameras which can only record up to 60 full frames/second. Novel sCMOS cameras feature much higher readout speeds and have the potential for fast live-cell imaging, but artifact-free performance at high speed has not been demonstrated yet. In this thesis, I have realized a new super-resolution microscope capable of two-photon activation of photo-activatable probes. I have characterized PAmCherry1, PA-GFP and PAmKate, three of the most popular photo-activatable fluorescent proteins, spectroscopically for two-photon activation. My results suggest a modified model of photo-activation of PAmCherry1. Super-resolution images of ring canals in thick Drosophila egg chambers have been recorded in three dimensions using this new microscope. Furthermore, I present the first artifact-free super-resolution microscopy using a sCMOS camera. Microtubules could be imaged at 32 nm spatial resolution in only 33 ms

Effect of exercise on peritoneal microenvironment and progression of ovarian cancer

Ovarian cancer is one of the deadliest gynecological malignancies and lacks treatments that do not significantly impact patient health-related quality of life. Exercise has been associated with reduced cancer risk and improved clinical outcomes; however the underlying molecular mechanisms are unknown. In this study, we utilized a treadmill-running exercise model to investigate the effects of exercise on high-grade serous ovarian carcinoma (HGSOC) progression and chemotherapy outcomes. We found that treadmill-running suppressed peritoneal colonization of tumors in a syngeneic mouse ovarian cancer model. Acute exercise stimulated the production of CCL2 and IL-15 in the peritoneal microenvironment while downregulating CCL22, VEGF, and CCL12. Using a co-culture model, we demonstrated the role of CCL2 in mediating the activity of peritoneal cells to inhibit cancer cell viability. We showed that the activation of M1 macrophages may contribute to the exercise-induced changes in the peritoneal microenvironment. We identified that chronic exercise modulates gene expression of intraperitoneal fat tissues related to lipid formation, thermogenesis, browning, and inflammation, which can contribute to inhibiting the colonization of metastatic ovarian cancer. Treadmill running also lowered blood urea nitrogen levels and reduced incidence of neutropenia and thrombocytopenia during chemotherapy in a mouse model, suggesting the potential beneficial effects of exercise in improving chemotherapy outcomes. Our data provided new insights into the acute and chronic effects of physical activity on ovarian cancer at the molecular and in vivo levels

Presence of Concomitant Systemic Cancer is Not Associated with Worse Functional Long-Term Outcome in Patients with Intracerebral Hemorrhage

Background: Data on clinical characteristics and outcome of patients with intracerebral hemorrhage (ICH) and concomitant systemic cancer disease are very limited. Methods: Nine hundred and seventy three consecutive primary ICH patients were analyzed using our prospective institutional registry over a period of 9 years (2006-2014). We compared clinical and radiological parameters as well as outcome - scored using the modified Rankin Scale (mRS) and analyzed in a dichotomized fashion as favorable outcome (mRS = 0-3) and unfavorable outcome (mRS = 4-6) - of ICH patients with and without cancer. Relevant imbalances in baseline clinical and radiological characteristics were adjusted using propensity score (PS) matching. Results: Prevalence of systemic cancer among patients with ICH was 8.5% (83/973). ICH patients with cancer were older (77 [70-82] vs. 72 [63-80] years; p = 0.002), had more often prior renal dysfunction (19/83 [22.9%] vs.107/890 [12.0%]; p = 0.005), and smaller hemorrhage volumes (10.1 [4.8-24.3] vs. 15.3 [5.4-42.9] mL; p = 0.017). After PS-matching there were no significant differences neither in mortality nor in functional outcome both at 3 months (mortality: 33/81 [40.7%] vs. 55/158 [34.8%]; p = 0.368; mRS = 0-3: 28/81 [34.6%] vs. 52/158 [32.9%]; p = 0.797) and 12 months (mortality: 39/78 [50.0%] vs. 70/150 [46.7%]; p = 0.633; mRS = 0-3: 25/78 [32.1%] vs. 53/150 [35.3%]; p = 0.620) among patients with and without concomitant systemic cancer. ICH volume tended to be highest in patients with hematooncologic malignancy and smallest in urothelial cancer. Conclusions: Patients with ICH and concomitant systemic cancer on average are older; however, they show smaller ICH volumes compared to patients without cancer. Yet, mortality and functional outcome is not different in ICH patients with and without cancer. Thus, the clinical history or the de novo diagnosis of concomitant malignancies in ICH patients should not lead to unjustified treatment restrictions

Content choice in media markets

Die Dissertation "Content Choice in Media Markets" ist eine kumulative Arbeit, welche sich in vier Abhandlungen mit der Frage beschäftigt, wie im Wettbewerb miteinander stehende, gewinnmaximierende Medienunternehmen ihre Programminhalte wählen. Der erste Teil der Arbeit ist ein Literaturüberblick, welcher die bisherige Forschung im Bereich der Programmwahl zusammenfasst und klassifiziert. Die restlichen in der Arbeit enthaltenen Abhandlungen stellen industrieökonomische Modelle dar, welche für verschiedene Modellrahmen die endogene Programmwahl von Medienanbietern betrachten. Diese Modellrahmen modellieren die Inhaltswahl bei zweidimensionalen Programminhalten, mit unterstellter Existenz von Premium-Programmen und unter Berücksichtigung der Netzwerkeffekte, die einen zweiseitigen Markt gerade ausmachen. Allen Modellen ist gemein, dass sie auf dem Grundmodell des Einheitsintervalls von Hotelling (1929) aufbauen und Werbung als für den Zuschauern nutzenmindernd ansehen

Classification and development of new component tests for aircraft cabin interior

Honeycomb sandwich structures are widely used for cabin interior components in passenger aircrafts. The load introduction into the sandwich structure proves to be particularly critical. However, the verification takes place based on non-standardized tests abstracted from the application so that influences caused by boundary conditions and multiple load introduction points cannot be investigated. Moreover, these tests also do not allow comparisons of different designs. The variety of different test setups on component level has made the comparability of published results more difficult. This paper summarizes the state of the art of existing component tests. Based on that and using the example of an aircraft cabin partition, the existing test setups are checked for their suitability to cover all given load cases. New test setups with extended boundary conditions and several load introduction points are developed. For one test setup, test results are shown and compared to a conventional component test.Bundesministerium für Wirtschaft und Klimaschutz (BMWK

The influence of the manufacturing process and test boundary conditions on the buckling load of thin-walled cylindrical CFRP shells

Thin-walled cylindrical CFRP shells tend to buckle under compressive loads. The experimental buckling load is significantly lower than the theoretical one. The reason for this are various kinds of imperfections which are partially caused by the manufacturing process and the test conditions. A major challenge in the design of these shells is the lack of experimental data. Additionally, the quality of test results is rarely critically reviewed in the validation of design approaches. In this paper, the influence of two different manufacturing processes on the geometric imperfections and the influence of three different test rigs on the buckling load are investigated in an experimental campaign with 12 cylindrical CFRP shells. Furthermore, the influence of varying the test rig boundary conditions is analysed

Trastuzumab deruxtecan in recurrent uterine serous carcinoma resistant to trastuzmab based-chemotherapy

Background: Treatment of uterine serous carcinoma (USC) is challenging; effective treatment options for metastatic and recurrent disease are needed. Case: A 68-year-old woman with recurrent, metastatic, USC overexpressing HER2/neu experienced durable response to the antibody drug conjugate (ADC) trastuzumab-deruxtecan (T-DXd), after failing multiple standard and experimental treatments targeting HER2/neu. She experienced a significant reduction in disease burden, disappearance of metastatic back bone pain as well as normalization of CA-125 quickly after starting treatment. Her disease continued to show response to treatment over 5 months and 7 cycles of T-DXd therapy. She did not experience any dose-limiting side effects and tolerated treatment with 5.4 mg/kg T-DXd without issue. Conclusion: T-DXd may present a new treatment option for chemotherapy-resistant uterine serous carcinoma

Pembrolizumab and lenvatinib in recurrent ovarian clear cell carcinoma resistant to chemotherapy

Background: Treatment of ovarian clear cell carcinoma (CCC) poses many challenges. Effective treatment options for recurrent and metastatic disease remain limited. Case: A 70-year-old woman with recurrent metastatic ovarian CCC experienced durable response to the combination of pembrolizumab, a PD-1 targeting monoclonal antibody and lenvatinib, an oral multikinase inhibitor, after failing standard and experimental treatments. She experienced a 40.1% reduction of target lesions over 26 weeks of therapy. CA-125 trends confirmed serial CT scan findings of shrinking disease burden. She experienced overall mild side effects from the drug combination, and lenvatinib dosage was decreased from 20 to 10 mg/day over her 10 cycles. Conclusion: The combination of pembrolizumab and lenvatinib may represent a new treatment option for chemotherapy-resistant ovarian CCC