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Despite overall improvements in breast cancer management, breast cancer continues to be a major health challenge worldwide, with high mortality rates. Following initially successful therapies, some cells are able to evade the treatment and remain in the body at undetectable levels (known as minimal residual disease) and could eventually lead to a lethal tumor recurrence. Understanding the nature of this elusive cell population is of a great importance in tumor eradication and relapse prevention. Nevertheless, the intricate mechanistic details about these processes and the nature of these cells remain poorly understood, mainly due to difficulties in obtaining patient material of MRD and being able to study them over the course of treatment. To characterize MRD in breast cancer, we employed an inducible TetO-MYC/TetO-Neu/MMTV-rtTA mouse model and primary 3D cultures of mammary organoids that yield a correlate of MRD upon oncogene silencing. A combination of immunofluorescence, RNA sequencing, lipidomics and metabolomics revealed the unique nature of the residual cells. Despite the phenotypic similarity to the normal population, the residual cells exhibited a distinct transcriptional profile. This profile was also different when compared to the tumor, highlighting the unique properties of the residual cell population. In addition, lipid profiles of the residual cells were also distinguished from both normal and tumor populations. Surprisingly, despite the inactivated oncogenes and seemingly normal phenotype of the residual structures, the residual cells bore a metabolic resemblance to tumor cells. They retained some tumor metabolic hallmarks, which persevered long after the oncogenes were silenced and tumors had regressed. This was demonstrated in our 3D cultures and verified in vivo on histological sections and fresh samples of the mammary glands following tumor regression. Enhanced glycolysis, the urea cycle and NOS2 activity were the most prominent features preserved in the residual cells. As shown in correlation with publicly available microarray datasets of patient samples following neoadjuvant treatment, these traits could be particularly important in MRD of the basal-like HER2 positive and HER2 negative breast cancer subtypes. In conclusion, our findings suggest vast and profound effects of the changes happening over the course of tumor progression, which result in an altered metabolic network even in the absence of oncogene signaling, implying the existence of a “metabolic memory” probably imprinted through the changes in the epigenetic landscape. This phenomenon, particularly its potential driver(s), remains to be investigated. Furthermore, enhanced glycolysis, urea cycle and NOS2 activity in the residual cells compared to the normal, could provide an opportunity to interfere with MRD, offering the potential of preventing tumor recurrences.
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In Correlative Light and Electron Microscopy (CLEM), two imaging modalities are combined to take advantage of the localization capabilities of light microscopy (LM) to guide the capture of high-resolution details in the electron microscope (EM). However, traditional approaches have proven to be very laborious, thus yielding a too low throughput for quantitative or exploratory studies of populations. Recently, in the electron microscopy field, FIB-SEM (Focused Ion Beam -Scanning Electron Microscope) tomography has emerged as a flexible method that enables semi-automated 3D volume acquisitions. During my thesis, I developed CLEMSite, a tool that takes advantage of the semi-automation and scanning capabilities of the FIB-SEM to automatically acquire volumes of adherent cultured cells. CLEMSite is a combination of computer vision and machine learning applications with a library for controlling the microscope ( product from a collaboration with Carl Zeiss GmbH and Fibics Inc.). Thanks to this, the microscope was able to automatically track, find and acquire cell regions previously identified in the light microscope. More specifically, two main modules were implemented. First, a correlation module was designed to detect and record reference points from a grid pattern present on the culture substrate in both modalities (LM and EM). Second, I designed a module that retrieves the regions of interest in the FIB-SEM and that drives the acquisition of image stacks between different targets in an unattended fashion. The automated CLEM approach is demonstrated on a project where 3D EM volumes are examined upon multiple siRNA treatments for knocking down genes involved in the morphogenesis of the Golgi apparatus. Additionally, the power of CLEM approaches using FIB-SEM is demonstrated with the detailed structural analysis of two events: the breakage of the nuclear envelope within constricted cells and an intriguing catastrophic DNA Damage Response in binucleated cells. Our results demonstrate that executing high throughput volume acquisition in electron microscopy is possible and that EM can provide incredible insights to guide new biological discoveries.
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Rezension zu: Michel Feugère, Les fibules en Gaule méridionale de la conquête à la fin du Ve siècle après J.-C. Revue Archéologique de Narbonnaise, Supplement 12, Paris 1985. 503 Seiten mit 72 Abbildungen, 174 Tafeln,Bonner Jahrbücher, Bd. 188.1988: Bonner Jahrbücher,
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outlines
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Deutscher Volksbote
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Rezension zu: Margarethe Weidemann, Kulturgeschichte der Merowingerzeit nach den Werken Gregors von Tours. Römisch-Germanisches Zentralmuseum, Forschungsinstitut für Vor- und Frühgeschichte, Monographien III 1 und III 2. Verlag des Römisch-Germanischen Zentralmuseums, Bonn 1982. XIV und 375 Seiten; XII und 400 Seiten,Bonner Jahrbücher, Bd. 188.1988: Bonner Jahrbücher,
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Lucid dreamers were considered as a whole population in most of the studies. Accordingly, this study purpose was to divide them into two groups of spontaneous and self-trained lucid dreamers and also to investigate lucid dreaming frequency, and its association with big five personality traits and dream recall frequency in both spontaneous vs. self-trained lucid dreamers. A total of 324 individuals participated in an online survey and filled out NEO Five-Factor Inventory, and some other questions along with that about lucid dream different aspects and dream recall frequency. The results indicated that there were certain differences established in both spontaneous and self-trained lucid dreamers. In addition, agreeableness and openness to experience were negatively associated with lucid dreaming frequency amongst self-trained lucid dreamers, while the relationship was positive for extraversion. The only factor that could affect lucid dreaming frequency in both spontaneous and self-trained lucid dreamers groups was dream recall frequency with a significant and positive association. As it was observed, there are some personality traits that make self-trained lucid dreamers interested in lucid dreaming, and also lead them to deliberately experience this phenomenon.,International Journal of Dream Research, Vol 12, No 2 (October 2019),
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Rezension zu: Hans-Joachim Schalles, Untersuchungen zur Kulturpolitik der pergamenischen Herrscher im 3 . Jahrhundert vor Christus. Istanbuler Forschungen 36. Verlag Ernst Wasmuth, Tübingen 1985. XIII, 174 Seiten mit 14 Abbildungen und 3 Karten, 7 Tafeln mit 12 Abbildungen.,Bonner Jahrbücher, Bd. 189.1989: Bonner Jahrbücher,
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