Preclinical evaluation of nanoparticle enhanced breast cancer diagnosis and radiation therapy

Triple negative breast cancer (TNBC) is an aggressive type of cancer which makes up 15-20% of all newly diagnosed cases, lacking the main target molecules for tumor specific treatment. Surgery or systemic therapy by chemotherapy are frequently used in the clinic and combined with radiation therapy to improve locoregional control in breast cancer patients after surgery. With a poor prognosis, there is a clear need to explore new treatment options for TNBC. The aim of the here presented PhD project was to evaluate the feasibility to enhance the biological effect of radiation therapy and increase tumor contrast for diagnosis by applying an in vivo microCT imaging system in combination with barium nanoparticles (BaNPs) in a pH8N8 WAP-T-NP8 mouse model for TNBC. Characterization of the BaNPs revealed strong x-ray attenuation and no toxic effects in different cancer and normal cell lines. Furthermore, irradiation of cancer cells using low energy x-rays in the keV range by a microCT resulted in a significant reduction on colony formation capability. In vitro, this low energy irradiation effect on clonogenic tumor cell survival was enhanced in the presence of BaNPs. Next, a subcutaneous lung cancer mouse model in immunodeficient mice and an orthotopic syngeneic mouse model for breast cancer was applied for further in vivo evaluation. Once the treatment plan was optimized regarding the applied x-ray doses and the frequency of irradiation, low energy radiation therapy within a classical in vivo microCT significantly reduced tumor growth or even resulted in shrinkage of the tumors without visible side effects and weight loss in comparison to untreated controls. However, the intratumoral application of BaNPs was not able to increase the irradiation effect on tumor growth kinetics. This might be in part due to inhomogeneous distribution of BaNPs within the tumor observed by microCT imaging. K-edge subtraction imaging as well as x-ray fluorescence of explanted tumor samples confirmed these findings. To localize the BaNPs in 3D to specific sites within the tumor environment and to detect morphological alterations within the tumor due to irradiation in proximity to BaNPs an ex-vivo imaging based analytic platform was established, utilizing co-registration of microCT and histology data. This imaging approach co-localized BaNPs with CD68 positive phagocytic cells and revealed a non-uniform distribution of the BaNPs within the tumor, however with no signs of locally enhanced radiation effects. Furthermore, antibody functionalized BaNPs were generated for systemic application. Analysis of biodistribution revealed that EpCAM labeled BaNPs did not reach the tumor after intra-venous administration, but accumulated in liver and spleen, demonstrated by a strong CT contrast within these organs. In summary, I showed that low energy radiation therapy by applying an in vivo microCT significantly reduced tumor volumes in comparison to untreated tumors in a syngeneic breast cancer tumor mouse model resembling TNBC. However, BaNPs while enhancing the effectiveness of irradiation on tumor cells in vitro, did not improve the irradiation effect on tumor growth in vivo.2021-07-1

Dealing with development risk and complexity in planning situations within product engineering processes

Every product development process is unique and individual. Nevertheless, patterns of recurring and similar elements exist in different processes which experience specific characteristics depending on the type of project. In addition to the different objectives that form the basis of a product development process, projects differ primarily in their share of new development and their degree of complexity. In order to deal appropriately with the resulting uncertainty, implementing agile approaches in processes of mechatronic system development is becoming more popular with the aim of making the development project more flexible. However, it must be borne in mind that not every development process requires an agile approach. Although plan-driven approaches have a poor ability to react to changes, they provide clear structure that leads to a common understanding of the process and a clear definition of objectives. Since a development project does not only contain problems that are well-suited for an agile or a sequential approach it is important to adapt the process to the underlying situation and requirements. In sufficiently plannable situations a purely agile approach would entail the loss of structure. On the other hand, a purely sequential approach for highly uncertain problems means that the process has to be adapted frequently in order to react appropriately to changes and newly acquired knowledge. The approach of ASD – Agile Systems design helps developers to implement suitable development procedures at different process levels depending on the degree of planning stability. In this context, this contribution presents a methodology that examines the influence of new development and complexity on different elements and supports developers in process planning by combining flexible and structuring elements to avoid multiple replanning

A guideline for modelling relations of embodiment and function in agile development

Abstract In current product development, the increased usage of agile approaches from software development is observable. With these approaches, improved responsiveness of developer teams to the dynamics of today's markets is desired. However, the gain of technical knowledge in these approaches has so far received little support, leading to difficulties in implementation in engineering design projects that deal with physical product aspects. This contribution aims to provide a guideline to gain technical knowledge about physical products in agile processes through the usage of qualitative modelling of embodiment function relations. This guideline is developed by integrating and adapting the Contact and Channel approach into the agile approach Agile Systems Design. It aims at aiding the evolutionary and iterative development in rapid cycles through fractal modelling of qualitative technical knowledge. The guideline is applied in two development projects. It shows potential to support developer teams by providing different aspects of the Contact and Channel approach in different phases of agile projects, depending on the tackled task

Quantum Test of the Universality of Free Fall

We simultaneously measure the gravitationally-induced phase shift in two Raman-type matter-wave interferometers operated with laser-cooled ensembles of $^{87}$Rb and $^{39}$K atoms. Our measurement yields an E\"otv\"os ratio of $\eta_{\text{Rb,K}}=(0.3\pm 5.4)\times 10^{-7}$. We briefly estimate possible bias effects and present strategies for future improvements