Extending OWns to include protection functionality

The objective of this dissertation is to enhance the functionality of an existing simulation package that is used to simulate fiber optic networks. These enhancements include the capability to simulate protection mechanisms following link failure, which is a necessity in real-world optical networks to ensure the continued flow of information following a failure in a part of the network. The capability for network traffic to choose from additional paths is also an addition to the software. The enhanced, as well as the original simulation software, are open source: this allows anyone to freely modify and improve the source code to suit his or her requirements. This dissertation will focus on mesh-based optical network topologies, which are commonly found in regional optical backbone networks, but which are also increasingly found in metropolitan areas. The regional networks all make use of wavelength division multiplexing (WDM), which consists of putting multiple different wavelengths of light on the same physical fiber. A single fiber breakage will therefore disrupt multiple fiber-optic connections. A fiber-optic network designer has to satisfy various conflicting requirements when designing a network: it must satisfy current and predicted future traffic requirements, it must be immune to equipment failure, but it must also be as inexpensive as possible. The network designer therefore has to evaluate different topologies and scenarios, and a good network simulator will provide invaluable assistance in finding an optimal solution. Protection and restoration need to be looked at in conjunction with routing and wavelength assignment (RWA), to ensure that resources in a network are used at maximum efficiency. Connection restoration time will also be looked at: this should be minimised to ensure minimal network downtime and ensuing loss of revenue. The chosen alternate connection path should also be as short as possible to minimise use of resources and maximise the carrying capacity of the network. Blocking probability (the inability to establish a connection due to a congested network) is a crucial factor and is also investigated. The topologies investigated in this dissertation consist of various mesh based real-world regional WDM fiber-optic networks. The impact of various link failures, the addition of additional alternate paths, as well as the effect of a protection mechanism on these topologies are also investigated. The proposed goals were all successfully achieved. The capability of simulating single as well as multiple link failures was introduced to the simulation package. The blocking probability of various network topologies was compared to each other in the presence of link failures. Success was also achieved in the introduction of a third alternate path to the simulation package.Dissertation (MEng(Electronic))--University of Pretoria, 2005.Electrical, Electronic and Computer Engineeringunrestricte

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival