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Experimentelle und klinische Untersuchungen zur Entwicklung digitaler Prozesse in der Zahnmedizin und Kieferorthopädie
Full text linkEngineered mesenchymal stem cells as therapeutic vehicles for tumor therapy
Full text linkNew approaches are slowly improving the outcomes of cancer patients. The use of engineered versions of mesenchymal stem cells (MSCs) is currently under investigation as a platform to deliver therapeutic genes to solid tumors.
This approach makes use of the robust tumor tropism of adoptively applied mesenchymal stem cells to deliver a therapeutic gene such as a suicide gene or cytokine deep into the tumor environment.
This thesis focused on the effect of thyroid hormones in the context of mesenchymal stem cell biology, and specifically, on the influence of thyroid hormones on tumor angiogenesis.
To this end, an in vitro angiogenesis assay was established. (See results 4.1.) In parallel, a novel cloning platform was applied for the expression of novel reporter transgenes linked to tumor hypoxia and angiogenesis biology. (See results 4.2.)
Stable transgenes were introduced into primary human mesenchymal stem cells making use of gene promoters activated in the context of the tumor stroma and tumor angiogenesis. These included a synthetic Hif-1α - driven promoter that is responsive to hypoxia, a human VEGF promoter thought to be activated in early angiogenesis, and the Tie2 promoter, the promoter driving expression of the TEK receptor tyrosine kinase receptor that binds angiopoietin and plays an important role in late angiogenesis. The gene promoters were engineered to drive expression of a secreted version of the Gaussia luciferase as a reporter gene.
While the synthetic Hif-1α - responsive promoter did show induction following treatment of MSCs with CoCl2, an agent that can mimic a hypoxic milieu, in a significant dosis-dependant way, similar stimulation of MSCs containing the VEGF promoter reporter constructs did show a significant activation, but not in a dosis-depandant way. Stimulation of MSCs, transfected with the Tie2 promoter, with CoCl2 not induce promoter activity.
The study then focused on the influence of thyroid hormones on tumor angiogenesis in context of MSC biology. MSCs containing one of the three reporter constructs Hif-1α, Tie2 and VEGF were then stimulated with thyroid hormones with and without CoCl2. For all constructs a slight enhancement in Gaussia light reaction was seen for T3, especially in combination with CoCl2. (See results 4.3.)
When applying the in vitro angiogenesis assay, human endothelial cells (HUVECS) and mesenchymal stem cells (MSCs) were both shown to generate solid tube formation in vitro while the hepatocellular carcinoma cell line (HUH7) used in this study did not.
Thyroid hormones have been previously shown to influence aspects of MSC biology and angiogenesis. A dose-dependent activation could be seen for T3 and T4 stimulation of endothelial cells in the context of the angiogenesis assay. Stimulation of HUVECs with MSC conditioned media plus T3 or T4 lead to an increase in experimental angiogenesis. (See results 4.4.)
The last series of experiments combined the angiogenesis assay and the genetically modified transgene MSCs. MSCs containing Hif-1α, Tie2 and VEGF reporter plasmids were tested in the angiogenesis assay with and without thyroid hormones. While most of the results were not significant, a significant result was seen for MSCs containing Hif-1α in the angiogenesis after stimulation with T3. (See results 4.5.)
The results suggest that thyroid hormones T3 and T4 influence tumor angiogenesis and partly through activation of MSCs. Next to the goals stated above, the aim was to lay the foundation of future individualized tumor-target therapy to enhance the outcome of cancer patients
Untersuchung zum Vorkommen von Encephalitozoon spp. bei Europäischen Wildkaninchen (Oryctolagus cuniculus) in Süddeutschland (Bayern)
Full text linkRegional-scale forward modeling and inversion of 3D wave propagation and dynamic rupture processes with nonlinear mechanical models of rocks and soils
Full text linkEarthquakes are catastrophic geohazards with severe impacts on life and property. Emerging evidence suggests that linear mechanical models are inadequate for fully explaining the origins and consequences of devastating earthquakes. There is a critical need for adequate physics-based rock models and efficient numerical algorithms to explore how nonlinearities affect our understanding of earthquake mechanisms, in-situ rock conditions along seismic paths, and the resulting ground motions. In this dissertation, I focus on enhancing the representation and simulation of nonlinear rock behaviors under dynamic loading across multiple scales, i.e., from laboratory rock samples to regional-scale earthquakes. The advancement incorporates physics-based nonlinear rock models derived from laboratory experiments, scalable software for physics-based earthquakes simulation from source to site on supercomputers, and innovative inversion algorithms aimed at accurately determining nonlinear parameters of both laboratory and in-situ rocks.
The first part of the dissertation introduces two continuum damage models that aligns with observations of nonlinear behaviors in rock samples from two commonly utilized laboratory experiment setups. In the second part, I propose an algorithm based on the discontinuous Galerkin method to model wave propagation through nonlinear rock rheologies in 3D. This algorithm is designed for regional-scale simulations that involve complex geometries. I verify the algorithm against three sets of analytical solutions and confirm that the algorithm scales effectively on supercomputers. I demonstrate the applicability of the framework to simulating co-seismic wave speed changes and ground motions during the 2015 Mw 7.8 Ghorka earthquake in Kathmandu valley. In the third part, the numerical solver is extended to incorporate 3D dynamic rupture modeling. This extension allows us to illustrate the off-fault co-seismic damage patterns and the high-frequency seismic radiation. In addition, I demonstrate that in the tensile step-over configuration, localized damage zones extending from one fault can induce heterogeneous stress perturbations on a neighboring fault, thereby triggering nucleation. This capability enables detailed simulations of dynamic rupture processes, including off-fault co-seismic moduli reduction at regional scales.
Based on the earthquake simulation software developed in this dissertation, I propose two Markov chain Monte Carlo (MCMC) sampling methods to perform Bayesian inversion of nonlinear material parameters. At the laboratory scale, the forward simulations are computationally inexpensive. I demonstrate, in the first part of the dissertation, that the Adaptive Metropolis MCMC algorithm can be utilized to illustrate the precision with which material parameters can be constrained from the existing experiment setups. At the regional scale, each forward simulation takes thousands of core hours on modern compute clusters. To accelerate the inversion, I propose, in the fourth part of this work, a more effective sampling algorithm, i.e., the Multi-level Delayed Acceptance (MLDA) MCMC algorithm. In the fifth part of this work, I then show how the MLDA algorithm can be optimized for nonlinear inversion of parameters in dynamic rupture models, specifically for the 2019 Mw
7.1 Ridgecrest earthquake, leveraging geological, seismic, and geodetic observations
Digital transformation of dentistry through novel numerical and manufacturing approaches
Full text linkStoffwechselbeeinflussung vom Bacille Calmette-Guérin (BCG) Modellorganismus durch antimykobakterielle Substanzen in der massenspektrometrischen Analyse von Proteinextrakten nach stabiler Isotopenmarkierung
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Etablierung einer multizentrischen Datenbank – Epidemiologie und klinisches Outcome von Tibiakopffrakturen
Full text linkThe primary objective of the first study was to provide updated epidemiological data on tibial plateau fractures (TPF) in Germany. For this purpose, all TPF treated at the LMU Clinic over the past ten years (from January 2011 to Decem- ber 2020) were retrospectively analyzed regarding various epidemiological data. This analysis resulted in a database comprising 607 cases of TPF, which served as the foundation for numerous studies. This established database now provides the basis for prospective data collection on TPF across multiple regional trauma centers. The focus of the first study was twofold: first, to describe and analyze changes in fracture incidence in Germany for the first time, and second, to examine trends regarding fracture morphology, patients age, injury mechanism, and imaging modalities used for diagnosis.
The main finding of the study is a significant increase in the incidence of TPF by 68% over the last decade. By the end of the study period, the incidence of TPF in Germany was reported as 23,4 per 100,000 peoples per year in 2020. Notably, the incidence in females (12,1/100,000) was significantly higher than in males (8,5/100,000) over the decade. Furthermore, there was a notably higher fracture incidence among elderly females (76-85 years), which was discussed in the con- text of osteoporosis. Regarding imaging techniques, it was demonstrated that computed tomography (CT) has become the standard modality for fracture diagnosis, with 91% of patients receiving CT imaging. In contrast, only 22% of patients underwent magnetic resonance imaging (MRI), which is discussed in more detail in the second study. Analysis of injury mechanisms revealed the following: the primary cause of injury across the patient cohort was falls, accounting for 32,9%. A closer look at young patients, those younger than the average cohort age (52,9 years), showed that most were male, and that the trauma mechanism was classified as “high-energy” (e.g., traffic accidents). In contrast, the older patient cohort was predominantly female, with “low-energy” trauma (e.g., falls) being the primary cause. Comparative analysis over the decade indicated that high-energy trauma mechanisms decreased overall, while low-energy mechanisms became more preva- lent. The second study aimed to analyze risk factors of the development of post-traumatic osteoarthritis (PTOA). This objective arose from the findings of the first study, which identified a significant increase in fracture incidence and noted that MRI is not a standard diagnostic tool for TPF. Additionally, other studies have shown high rates of PTOA following TPF. This led to a focus on a key risk factor for PTOA: post-traumatic knee instability. To investigate this, the database created in the first study was searched based on specific inclusion criteria to clinically assess knee instability in 54 patients. The main result of the study was a significant difference in anterior-posterior tibial translation as well as in tibial translation during internal rotation in the fractured knee compared to the healthy knee. Additionally, the injured knee showed signif- icant restrictions in range of motion. In conclusion, the study indicates that surgically treated TPF exhibit significant knee instability. Since knee instability is a known risk factor for PTOA, these findings explain the high rates of PTOA observed following tibial plateau fractures