Novel inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) and steroid sulfatase (STS) with unique dual mode of action : potential drugs for the treatment of non-small cell lung cancer (NSCLC) and endometriosis

Estrogens, in particular estradiol‎ (E2)‎ play an important role in estrogen-dependent diseases (EDDs), such as non-small-cell lung cancer ‎‎(NSCLC) and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) is frequently expressed in NSCLC tissues, leading to cancer development and progression. Thus, the first objective of this study (chapter 3.1) is the development of a novel series of highly potent non-steroidal, selective ‎‎17β-HSD1 inhibitors in order to enhance the treatment of NSCLC. ‎ This section of the study showed that 17β-HSD1 is a promising therapeutic target for NSCLC, providing new avenues for the treatment of this lethal cancer. Steroid sulfatase (STS) and 17β-HSD1 are promising targets for the treatment of endometriosis because they ‎limit estrogen formation mainly in the target cells, leading to fewer ‎side effects. ‎Thus, the second part of the study ‎(chapter 3.2) ‎aims at developing dual inhibitors of STS and 17β-HSD1, which provide a novel treatment option. The synthesized sulfamates should be drugs for inhibition of STS, and prodrugs for 17β-HSD1 inhibition. The most active compounds of this part showed nanomolar IC50 values for STS in cellular assays ‎and their corresponding phenols displayed potent 17β-HSD1 inhibition in cell-free and cellular ‎assays as well as high selectivity over 17β-HSD2. These findings suggest that the “drug-prodrug concept” ‎has been applied successfully ‎(chapter 3.2).Estrogene, insbesondere Estradiol (E2), spielen eine zentrale Rolle bei Estrogen-abhängigen Erkrankungen (estrogen-dependent diseases, EDD) wie nicht-kleinzellige Bronchialkarzinome (non-small-cell lung cancer, NSCLC) und Endometriose. 17β-Hydroxysteroid Dehydrogenase Typ 1 (17β-HSD1) ist in NSCLC-Gewebe häufig überexprimiert und trägt zu Tumorentstehung und -wachstum bei. Das erste Ziel dieser Arbeit war daher die Entwicklung von neuartigen und hochpotenten, nicht-steroidalen 17β-HSD1 Inhibitoren als potenzielle NSCLC-Therapeutika (Kapitel 3.1). Die Daten zeigen, dass 17β-HSD1 ein vielversprechendes Target darstellt, das neue Möglichkeiten in der NSCLC-Therapie eröffnen kann. Steroid Sulfatase (STS) und 17β-HSD1 sind vielversprechende Wirkstofftargets zur Behandlung der Endometriose, da sie die E2-Produktion lokal im erkrankten Gewebe reduzieren, was im Vergleich zu systemischen Therapien zu weniger Nebenwirkungen führen sollte. Gegenstand des zweiten Teils der Arbeit (Kapitel 3.2) war die Entwicklung von dualen Inhibitoren von STS und 17β-HSD1. Die so synthetisierten Sulfamate sollten Drugs für die Hemmung von STS und gleichzeitig Prodrugs für die Hemmung von 17β-HSD1 darstellen. Die aktivsten Verbindungen dieses Teils zeigten nanomolare IC50-Werte für STS in zellulären Assays und ihre entsprechenden Phenole zeigten eine starke 17β-HSD1-Hemmung in zellfreien und zellulären Assays sowie eine hohe Selektivität gegenüber 17β-HSD2. Die Daten belegen, dass das verfolgte “Drug-Prodrug-Konzept” der dualen Hemmstoffwirkung erfolgreich umgesetzt wurde (Kapitel 3.2)

Deployment of Indoor LTE Small-Cells in TV White Spaces

In this thesis, we present a systematic computer-based approach to solve the problem of optimum transmitter placement for indoor LTE coverage systems operating in the TVWS. This approach is supported with rigorous simulations that reflect very promising results.This work focuses on the deployment of indoor LTE small cells acting as secondary transmitters in TVWS. Proposed methods make use of measurements stored in a Radio Environment Map (REM) that characterizes the DVB-T reception inside the building under consideration. Under this framework, this work analyses two different approaches for the deployment of small cells. First approach is based on maximizing total secondary transmit power inside the building, while the second approach is based on maximizing the percentage of positions having a Signal to Interference and Noise Ratio (SINR) above a desired threshold. Approaches are validated by means of rigorous simulations supported by real measurements of DVB-T signal reception. Results include optimum secondary transmitter placement, and transmit power values for providing indoor LTE coverage considering operating in a channel adjacent to the one used by DVB-T. These results are compared against exhaustive enumeration techniques and proven to provide very accurate results. Results reveal that when considering system capacity or network throughput, the second approach is more efficient and provides better results than the first approach. To the author's best knowledge, this model is the only model that provides an actual deployment strategy of indoor LTE secondary transmitters while considering interference constraints from adjacent channel DVB-T transmission. While our approaches are only tested in the considered building, the methods used are generic and can be applied in the same manner within any indoor environment provided that the REM for that environment is established

Deciphering the Immune Evolution Landscape of Multiple Myeloma Long-Term Survivors Using Single Cell Genomics

Multiple myeloma (MM) is a malignant bone marrow (BM) disease characterized by somatic hypermutation and DNA damage in plasma cells; leading to the overproduction of dysfunctional malignant myeloma cells. Accumulation of myeloma cells has direct and indirect effects on the BM and other organs. Despite the development of new therapeutic options; MM remains incurable and only a small fraction of patients experiences long-term survival (LTS). The past has shown that ultimately all patients still relapse; leading to the hypothesis that a state of active immune-surveillance is required to control the residual disease. To understand the long-term survival phenomenon and its link to the immune-phenotypes in MM disease; we collected paired bone marrow samples from 24 patients who survived for about 7 to 17 years after Autologous Stem Cell Transplant (ASCT), with a high plasma cell infiltration in the BM (median 49.5%) at diagnosis time. Response assessment according to the International Myeloma Working Group (IMWG) revealed that 15 patients were in complete remission (CR), whereas 9 patients were in non-complete remission (non-CR) that had tumor cells which remained stable over recent years. We performed single-cell RNA-seq sequencing on more than 290,000 bone marrow cells from 11 patients before treatment (BT) and in LTS, as well as three healthy controls using 10x Genomics technology. I developed a computational approach using the state-of-the-art single cell methods, statistical inference and machine learning models to decipher the bone marrow immune cell types and states across all clinical groups. I performed in-depth analyses of the bone marrow immune microenvironment across all captured cell types, and provided the global landscape of cellular states across all clinical groups. In this work, I defined new cellular states, marker genes, and gene signatures associated with the patients’ clinical and survival states. Additionally, I defined a new myeloid population termed Myeloma-associated Neutrophils (MAN) cells and a T cell exhaustion population termed Aberrant Memory Cytotoxic (AMC) CD8+ T cells in newly diagnosed Multiple Myeloma patients. Moreover, I propose new therapeutic targets CXCR3 and NR4A2 in AMC CD8+ T cells, which could be further investigated to reverse the T cell exhaustion state in newly diagnosed MM patients. Furthermore, I defined new prognostic markers in the CD8+ T cell compartment which could be predictive for the global disease state. Finally, I propose that MM long-term survivors go through a complex and evolving immune landscape and acquire cellular states in a stepwise manner. Furthermore, I propose the Continuum Immune Landscape (CIL) Model which explains the immune landscape of MM patients before and after long-term survival. Additionally, I introduced the Disease-State Trajectories (DST) hypothesis regarding the disease-associated dysregulated cellular states in MM context, which could be generalized into other tumor entities and diseases

A Riccati-Bernoulli Sub-ODE Method for the Resonant Nonlinear Schrödinger Equation with Both Spatio-Temporal Dispersions and Inter-Modal

This work uses the Riccati-Bernoulli sub-ODE method in constructing various new optical soliton solutionsto the resonant nonlinear Schrodinger equation with both Spatio-temporal dispersion and inter-modal dispersion. Actually, the proposed method is effective tool to solve many other nonlinear partial differential equations in mathematical physics. Moreover this method can give a new infinite sequence of solutions. These solutions are expressed by hyperbolic functions, trigonometric functions and rational functions. Finally, with the aid of Matlab release 15, some graphical simulations were designed to see the behavior of these solutions

Gendering migratory social spaces in Upper Egypt

Male out migration especially to Gulf countries is a well-established phenomenon in Upper Egypt. It is considered the easy way out of poverty and unemployment. Moreover, remittances represent the only monetary source for most migratory families. This thesis explores the impact of male out migration on their community of origin with a special focus on its impact on women. Fieldwork has been conducted in the village of Hekma, Qena, Upper Egypt where everything is influenced by the absence of men. A gendered approach is utilized to understand the everyday life of this community. This thesis consists of three main parts. The first part investigates how the social space is influenced by the absence of men. The second part explores remittances as a process and its role in the economic life with special attention to the role of women in this process. In addition, it discusses women’s empowerment from the understanding of Hekma women. The third part investigates the impact of remittances on consumption at the household level, as well as the difference between remittance receiving and non-receiving households. This thesis contributes to the gender and migration discourse as it offers a new understanding of social space, remittances and consumption in an Upper Egyptian context

Targeting occupant feedback using digital twins: Adaptive spatial-temporal thermal preference sampling to optimize personal comfort models

Collecting intensive longitudinal thermal preference data from building occupants is emerging as an innovative means of characterizing the performance of buildings and the people who use them. These techniques have occupants giving subjective feedback using smartphones or smartwatches frequently over the course of days or weeks. The intention is that the data will be collected with high spatial and temporal diversity to best characterize a building and the occupant's preferences. But in reality, leaving the occupant to respond in an ad-hoc or fixed interval way creates unneeded survey fatigue and redundant data. This paper outlines a scenario-based (virtual experiment) method for optimizing data sampling using a smartwatch to achieve comparable accuracy in a personal thermal preference model with fewer data. This method uses BIM-extracted spatial data and Graph Neural Network-based (GNN) modeling to find regions of similar comfort preference to identify the best scenarios for triggering the occupant to give feedback. This method is compared to two baseline scenarios that use conventional zoning and a generic 4x4 square meter grid method from two field-based data sets. The results show that the proposed Build2Vec method has an 18-23\% higher overall sampling quality than the spaces-based and square-grid-based sampling methods. The Build2Vec method also performs similar to the baselines when removing redundant occupant feedback points but with better scalability potential

Traveling solitary wave solutions for the symmetric regularized long-wave equation

In this paper, we employ the extended tanh function method to nd the exact traveling wave solutions involving parameters of the symmetric regularized long- wave equation. When these parameters are taken to be special values, the solitary wave solutions are derived from the exact traveling wave solutions. These studies reveal that the symmetric regularized long-wave equation has a rich varietyof solutions

Traveling wave solutions for the Couple Boiti-Leon-Pempinelli System by using extended Jacobian elliptic function expansion method

In this work, an extended Jacobian elliptic function expansion method is pro-posed for constructing the exact solutions of nonlinear evolution equations. The validity and reliability of the method are tested by its applications to the Couple Boiti-Leon-Pempinelli System which plays an important role in mathematical physics