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Sequence analyses of the molecular drivers TERT/DLST in cancer and tissue-wide transcript analysis of adhesion GPCRs
No full textBig data and the revolution in sequencing technologies have transformed the way biomedical research is conducted. To unravel the underlying biological mechanisms of tumor development, treatment efficiency and to find new treatments for diseases such as cancer, it is necessary to use bioinformatic tools addressing the challenges posed by big data. This dissertation demonstrated how vast amounts of publicly available high-throughput sequencing data can be used to address open questions that relate to data-driven research. These include how genetic information can be used to assess therapeutic efficacy and drug repurposing, and how the analysis of tissue-specific transcriptional patterns can improve our understanding of the transcriptional repertoire of human genes.
First study: This study investigates the prognostic and predictive value of TERT promoter mutations (TERTpm) and TERT expression in melanoma patients, particularly those undergoing immune checkpoint inhibition (ICI) therapy (anti-CTLA4 and anti-PD1/L1). Leveraging data from highly annotated melanoma cohorts, the study aims to evaluate how TERTpm and TERT expression influence tumor survival and immune response. Additionally, it seeks to address gaps in understanding the non-canonical roles of TERT in malignant melanoma by analyzing clinicopathological and demographic factors, as well as co-regulated gene expression, to provide deeper insights into its broader biological impact.
Main findings first study:
As comprehensive multivariate survival analyses were not available, the prognostic value of TERTpm and expression was tested in several melanoma ICI and non-ICI cohorts, including important clinical variables such as tumor mutational burden (TMB). However, the prognostic value for melanoma was not supported, as neither TERTpm nor TERT expression were associated with longer survival. As the proposed predictive value of TERTpm for anti-CTLA4 therapy was not statistically supported, we emphasize the inclusion of discussed biomarkers such as TMB in multivariate survival analysis.
Incorporating immune signatures, TERT expression as a potential proxy for immune response was assessed. Although TERT expression was associated with elevated CD4+ T cells, its association with exhaustion markers suggests a dysfunctional T-cell response in TERT-high tumors. Defining phenotypic exhaustion in the CD4+ T-cells could be crucial to understanding missing immune responses in TERT-high tumors.
TERT expression was increased in metastases arising from thinner primaries compared to metastases arising from thicker primaries. This raises the question of whether upregulation of TERT expression promotes early efficient metastasis, a function that may exist in addition to canonical telomerase activity. This was further supported by the enrichment of genes with upregulated TERT expression that are involved in extracellular matrix remodeling and thus would promote invasion of primary melanoma cells.
Extending the non-canonical functions of TERT expression, its co-expression with DNA repair-genes, even across tumor types, hints toward a function of TERT in establishing genomic stability under stress in line with many previous studies. This could be useful in the context of chemotherapy and radiotherapy resistance of melanoma and also in other cancers such as glioblastoma, where in addition to TERTpm, TERT expression could also be measured to test for sensitivity to DNA damaging agents. This highlights the relevance of assessing TERT expression, besides the promoter mutation status.
In summary, this study highlights the importance of across-cohort replication to re-evaluate potential biomarkers. While the extent of which TERT promoter mutations govern survival under anti-CTLA4 therapy was inconclusive, this study emphasizes the importance of a comprehensive multivariate analysis that accounts for confounding factors to identify robust biomarkers. Moreover, this data-driven analysis highlights the non-canonical functions of TERT expression, which are currently of great interest as it appears to contribute to early metastasis and the establishment of genomic stability. As our analysis revealed a potentially dysfunctional immune response in patients with high levels of TERT, it would be highly interesting to see whether the combination of currently tested TERT-based vaccines and immune checkpoint inhibition could achieve better results than ICI alone.
Second study: This study aimed to identify potential drug candidates for tumors with DLST overexpression, which is linked to poor outcomes in triple-negative breast cancer and neuroblastoma and associated with the oxidative phosphorylation (OXPHOS) pathway. By integrating drug sensitivity data from over 250 drugs (GDSC project) and genomic data from over 800 cell lines (CCLE database), the research tested whether DLST amplification or elevated DLST mRNA levels make tumors more or less sensitive to OXPHOS inhibitors or other approved drugs, providing a foundation for targeted therapeutic strategies.
Main results second study:
Vulnerabilities of DLST-high tumors were identified for seven different drugs. Those drug candidates proposed could be subject to further rigorous tests using knock-out and knock-in experiments of cell lines, xenografts in animal models to evaluate their therapeutic potential for DLST-high tumors.
DLST-activated cell lines were more sensitive to the BCL-2 inhibitor (obatoclax mesylate), a drug which has previously been shown to reduce OXPHOS in human leukemia stem cells. This was consistent with the hypothesis that some tumor cells may activate OXPHOS via DLST upregulation to ensure increased energy production.
Several protein kinase inhibitors were identified, which hints toward a link between DLST and the extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK/MAPK) signaling pathways. This was further supported by increased DLST expression in cell lines with driver mutations in KRAS and therefore serves as a starting point for understanding the role of ERK/MAPK inhibitors in DLST-activated cancer.
I showed that using genomic information in conjunction with drug sensitivity data can provide drug candidates for drug repurposing. In a wider scope, these analyses could be transferred to analyses of other genes in association with drugs and hence, this study could serve as a prime example of how to approach questions of drug resistance in the presence of genetic changes.
Third study: a browser-based application was developed to investigate tissue-specific transcript variability using deep-sequenced data from 927 human samples across 48 tissues. As the full picture of the human transcriptome is still incomplete, new non-canonical transcript variants and tissue-specificity may help to explain cellular mechanisms and may change the interpretation of disease-relevant mutations. We applied the webtool to the class of adhesion G protein-coupled receptors (aGPCRs), a class of receptors with a complex exon-intron structure.
Main results third study:
A vast transcript variety was identified by using deliberately relaxed parameters, with an average of 24 different transcript variants per all 33 aGPCR genes, where several of the priorly expressed variants had not yet been annotated. Therefore, future experimental planning should consider that the annotated aGPCR transcript variants may not be the dominant transcript variants.
Adhesion GPCR transcript variants showed variable transcription starts and their complex exon-intron structures encoded for a flexible protein domain architecture of the N and C termini and the seven-helix transmembrane domain (7TMD). Of particular interest, we found that ADGRG7 has a transcript variant with an extra helix in the transmembrane domain. This was further supported by functional experiments using immunofluorescence studies and indirect cellular enzyme-linked immunosorbent assays, making it the first aGPCR with an eight-helix TMD.
Tissue-specific expression patterns of transcript variants were observed, which may explain the phenotypic variation between tissues. This could also affect the assessment of disease-causing mutations as shown in the case of ADGRC1/CELSR1 where some transcript variants might not be affected by a specific mutation. Therefore querying other sets of genes in the application, where disease-causing mutations are described, may explain tissue-specific phenotypes.
The development of the user-friendly browser-based application Splice-O-Mat, has demonstrated the feasibility of the analysis of tissue-specific transcriptomes. All accumulated data are presented in a browser-based application at: https://tools.hornlab.org/Splice-O-Mat/. Hence, this application serves as a starting point for in-depth analysis of genes, their splicing patterns and (alternative) promoter usage across human tissues.
This dissertation highlights the importance of sequence analysis and bioinformatics in addressing clinically relevant questions in cancer, such as therapy efficacy and drug resistance. By leveraging publicly available data and large-scale analyses, it reduces biases from small datasets and uncovers key mechanistic insights. The development of a browser-based tool for tissue-specific splicing further advances understanding of protein diversity and genomic changes, emphasizing the critical role of big data in medical research.:Chapter I - Introduction 1
Big data in biomedicine 1
Challenges and potentials in data-driven biomedical research 4
Data-driven aspects of basic and translational cancer research 6
Clinical relevance of RNA and transcriptomics 8
Chapter II - Objectives 11
Chapter III - Publications 14
Publication 1: TERT expression is associated with metastasis from thin primaries, exhausted CD4+ T cells in melanoma and with DNA repair across cancer entities 14
Publication 2: Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels 33
Publication 3: The repertoire and structure of adhesion GPCR transcript variants assembled from publicly available deep-sequenced human samples 42
Chapter IV - Summary 69
References 75
Supplementary Material 82
Supplementary material for “TERT expression is associated with metastasis from thin primaries, exhausted CD4+ T cells in melanoma and with DNA repair across cancer entities” 82
Supplementary material for “Candidate drugs associated with sensitivity of cancer cell lines with DLST amplification or high mRNA levels” 96
Supplementary material for “The repertoire and structure of adhesion GPCR transcript variants assembled from publicly available deep-sequenced human samples” 98
Spezifizierung des wissenschaftlichen Beitrags 108
Erklärung über die eigenständige Abfassung der Arbeit 111
Curriculum vitae 112
Publikationen und Präsentationen 114
Artikel 114
Präsentationen 115
Poster 115
Danksagungen 11
Essays on success factors in imperfect markets for corporate control
No full textMarkets for corporate control can foster innovation and growth due to the reallocation of resources and are thus vital for the efficiency of global economies. But, to efficiently reallocate resources, markets for corporate control have to be efficient themselves. The aim of this dissertation is to shed light on both, inefficiencies such as persistent principle-agent conflicts and the effect of the regulatory environment on corporate transactions in Germany.
The first section serves as an introduction to reflect on research regarding corporate transactions, the principle- agent theory and market regulations as well as to summarize the three research papers and their current publication status. The first paper focusses on the effect of personal preferences of target CEOs on corporate transactions and is presented in the second section. Based on these insights, the second paper is dedicated to Fairness Opinions and their effect on corporate transactions and is presented in the third section. To further analyze the regulatory environment, the third paper focusses on legal thresholds that bidders have to surpass to gain full control over targets in the German market for corporate control and is presented in the fourth section
First Report on Ovine Paratuberculosis in the Sudan: Diagnosis Using Different Techniques
No full textParatuberculosis (PTB) has been reported in the Sudan in cattle and goats for more than
50 years but has never been reported in sheep. However, suspicion of the disease in a breeding
flock of sheep in Khartoum North locality was made due to a history of unknown cause of loss of
weight. Blood and faecal samples were collected from all animals (N = 59): harvested sera were
tested for anti-Mycobacterium avium subsp. paratuberculosis (MAP) antibodies by Enzyme Linked
Immunosorbent Assay (ELISA); faeces were screened for acid-fast bacilli by Ziehl–Neelsen staining,
tested for MAP DNA by recombinase polymerase amplification (RPA) and some faecal samples were
cultured for MAP isolation. Typical MAP acid-fast bacilli were seen in 10.2% (6/59) of the faecal
smears, 37.5% of the tested faecal samples (12/32) were positive for MAP DNA and only 3 (5.1%)
animals were seropositive for MAP. MAP positive cultures were obtained from 2 out the 6 samples
showing typical MAP acid-fast bacilli; the isolates were confirmed by real-time PCR and sequencing.
As sheep are animals of utmost economic importance as the main export animals for the country,
this first report of ovine PTB warrants special considerations and more investigations for planning
control programmes of the disease
Franz Metz, Musikstadt Begapolis. Armin Rippka und die Musik der Banater Stadt Großbetscherek, München: Edition Musik Südost, 2023. XVI, 148 S., Abb.
No full textJulian Kujumdzhiev, Архивът на Димитър Ненов в Дрезден (Das Archiv von Dimitar Nenov in Dresden), Sofia: NMA „Prof. Pancho Vladigerov“, 2023 (Abstract)
No full textWASSERSTOFFTECHNOLOGIEN. EFFIZIENT PRODUZIERT: CHEMNITZER BRENNSTOFFZELLENKONFERENZ 2024
No full textZwei Tage, 63 internationale Fachvorträge und 270 Teilnehmende aus Wissenschaft und Industrie: Die dritte FC3 Fuel Cell Conference Chemnitz zeigt eindrucksvoll, wie vielfältig und aktuell relevant die Forschung im Bereich der Wasserstofftechnologien ist. Als Schlüsseltechnologie für das Energiesystem der Zukunft ist Wasserstoff Treiber einer emissionsarmen Mobilität und das Fundament für eine nachhaltige
Energieversorgung und industrielle Transformation. Der globale Wettbewerb um die Führungsrolle bei Wasserstofftechnologien ist bereits in vollem Gange und zeigt, wie dringend Innovationen in den Technologien zur Produktion, Speicherung und Nutzung benötigt werden.
Bevor diese Technologien jedoch breit verfügbar sind, stehen intensive Forschung, gezielte Entwicklung und die Industrialisierung im Fokus – Herausforderungen, denen wir uns in Chemnitz, Deutschlandund ganz Europa stellen. Die diesjährige Konferenz bringt erneut führende Köpfe aus Wissenschaft und Industrie
zusammen, um sich über aktuelle Trends und innovative Projekte auszutauschen. In diesem Konferenzband präsentieren wir Ihnen die neuesten Entwicklungen in den Bereichen PEM-Brennstoffzellen und Komponenten, Simulation, Produktion, Anwendung, Analyse- und Messmethoden sowie Elektrolyseure.
Der Wasserstoffcluster HZwo und das Fraunhofer-Institut für Werkzeugmaschinen und Umformtechnik IWU freuen sich, Ihnen einen kompakten Überblick über die Fachvorträge und Veröffentlichungen zu bieten. Wir danken allen Mitwirkenden, Vortragenden und Partnern für ihr Engagement und freuen uns auf ein
Wiedersehen hier in Chemnitz im Jahr 2026!Two days, 63 international specialist presentations and 270 participants from science and industry: the third FC3 Fuel Cell Conference Chemnitz impressively demonstrated the diversity and current relevance of research in the field of hydrogen technologies. As a key technology for the energy system of the future, hydrogen is
not only seen as a driver of low-emission mobility, but also as the foundation for a sustainable energy supply and industrial transformation. The global competition for leadership in hydrogen technologies is already in full swing and shows how urgently innovations in hydrogen production, storage and utilisation are needed.
However, before these technologies are widely available, intensive research, targeted development and industrialisation are the focus - challenges that we are facing in Chemnitz, Saxony and throughout Europe. This year‘s conference once again brought together leading minds from science and industry to discuss
current trends and innovative projects. In this conference volume, we present the latest developments in the fields of PEM fuel cells and components, simulation, production, application, analysis and measurement methods as well as electrolysers.
The HZwo e.V. and the Fraunhofer Institute for Machine Tools and Forming Technology IWU are pleased to offer you a compact overview of the technical presentations and publications. We would like to thank all contributors, speakers and partners for their commitment and look forward to seeing you again here in
Chemnitz in 2026
Optoelectronic performance of indium tin oxide thin flms structured by sub‑picosecond direct laser interference patterning
No full textA route to increase the efciency of thin flm solar cells is improving the lighttrapping capacity by texturing the top Transparent Conductive Oxide (TCO) so that the sunlight reaching the solar absorber scatters into multiple directions. In this study, Indium Tin Oxide (ITO) thin flms are treated by infrared subpicosecond Direct Laser Interference Patterning (DLIP) to modify the surface topography. Surface analysis by scanning electron microscopy and confocal microscopy reveals the presence of periodic microchannels with a spatial period of 5 µm and an average height between 15 and 450 nm decorated with LaserInduced Periodic Surface Structures (LIPSS) in the direction parallel to the microchannels. A relative increase in the average total and difuse optical transmittances up to 10.7% and 1900%, respectively, was obtained in the 400–1000 nm spectral range as an outcome of the interaction of white light with the generated micro and nanostructures. The estimation of Haacke’s fgure of merit suggests that the surface modifcation of ITO with fuence levels near the ablation threshold might enhance the performance of solar cells that employ ITO as a front electrode