<p>The Ras family of proteins, composed of H, N, and KRas, function as small GTPases that act as "molecular switches" relaying signals from the cell membrane to the rest of the cell in a highly regulated manner. However, Ras signaling is aberrantly activated in a majority of human cancers either through an activating mutation or by activation or overexpression of upstream or downstream elements in the Ras pathway, endowing cells with many tumorigenic phenotypes. Ras is known to promote tumorigenesis through activation of cell intrinsic signaling including the Raf, PI3K, and RalGEF pathways. In regards to the latter, RalGEFs activate two other small GTPases, RalA and RalB. The role of these two proteins in Ras-mediated cancer was poorly understood. I thus assessed the requirement of RalA and RalB in tumor metastasis discovering that both proteins promote this critical step in cancer.</p><p>Ras does not, however, function solely by intrinsic cell signaling. Indeed, it was recently shown that oncogenic Ras signaling induces secretion of cytokines, a category of small molecules involved in cell to cell communication and inflammatory response. Moreover, the release of these cytokines was shown to promote tumorigenesis in an extrinsic fashion by increasing tumor vasculature, or angiogenesis. I noted that one of these cytokines hCXCL-8 (IL-8) belonged to the ELR+ CXC family of cytokines, suggesting that the entire family of ELR+ CXC cytokines may promote Ras driven tumorigenesis. Indeed, I found that expression of oncogenic Ras led to secretion of all ELR+ CXC chemokines in oncogenic Ras driven tumor cell lines, a mouse tumor, a human tumor, and were sometimes elevated in the serum of pancreatic cancer patients, the cancer most associated with oncogenic Ras mutations. Moreover, knockdown of one of these chemokines, hCXCL-1, in pancreatic cancer cells or genetic ablation of the receptor for these cytokines in mice, reduced Ras driven tumorigenesis. Taken together, these results suggest that oncogenic Ras also promotes tumorigenesis through a cell extrinsic pathway by secretion of ELR+ CXC chemokines.</p> / Dissertation

Future manufacturing will be characterized by the complementarity between humans and automation (human-robot collaboration). This requires new methods and tools for the design and operation of optimized manufacturing workplaces in terms of ergonomics, safety, efficiency, complexity management and work satisfaction. There have been some efforts in the recent years to propose a tool for determining optimal human-automation levels for load balancing. Although the topic is quite new, it shares some similarities with some of the existing research in the area of robotic assembly line balancing. Therefore, it is crucial to review the existing literature and find the most similar models and methods to facilitate the development of new optimization models and algorithms. One of the two contributions that this thesis gives to the research world in the RALBP context is a literature review that involves high quality articles from 1993 to beginning 2018. This literature review includes visual and comprehensive tables—and a label system— where previous research patterns and trends are highlighted. Visualization of data and results obtained by assembly line optimization tools is a very important topic that has rarely been studied. Data visualization would provide a: 1. better comprehension of patterns, trends and qualitative data 2. more constructive information absorption 3. better visualization of relationships and patterns between operations, and 4. better contribution to data manipulation and interaction. The second contribution to research found in this thesis is the use of a human modelling (DHM) tool (called IPS), which is proposed as an assessment to the ergonomic risk that a robotic assembly line may involve. This kind of studies are necessary in order to reduce one of the most frequent reasons of work absence in our today society i.e. musculoskeletal disorders (MSDs). MSDs are often the result of poor work environments and they lead to reduced productivity and quality losses at companies. In view of the above, IPS was used in order to resolve the load handling problem between human and robot, depending on their skills and availability, while fulfilling essential ISO standards i.e. 15066 and 10218:1 and :2. The literature review made it possible to select highly useful documents in developing assumptions for the experiment and contributed to consider real features detected in the industry. Results show that even though IPS is not capable of calculating an entire robotic assembly with human-robot collaboration, it is able to simulate a workstation constituted of one robot and one human. Finite and assembly motions for both human and robot are expected to be implemented in future versions of the software. Finally, the main advantages of using DHM tools in assessing ergonomic risks in RALB can be extracted from the results of this thesis. This advantages include 1. ergonomic evaluation for assembly motions 2. ergonomic evaluation for a full working day (available in future version) and 3. essential ISO standard testing (available in future version).