Cancer is one of the major causes of death in the western world. Resistance to anti-cancer drugs and diagnostic difficulties are major obstacles to successful treatment. This thesis describes studies based on microarray expression analysis and high-throughput compound screening for identification of resistance mechanisms, drug targets and diagnostic markers. In paper I-IV, we applied global expression analysis and measurements of drug response in a human tumor cell line panel to identify drug targets and resistance mechanisms. In paper I, we identified gene transcript levels that correlate with drug resistance and sensitivity. Both well known and new potential markers and mechanisms were identified. In paper II, we showed that STAT1 activity is associated with cross-resistance to both doxorubicin and radiation in vitro and that fludarabine can counteract STAT1 activity and reduce resistance. In Paper III-IV, cell lines were exposed to a compound library consisting of more than thousand different substances in a high-throughput screening effort. These studies revealed that cell line models of squamous cell carcinoma (Paper III) and drug resistant myeloma (Paper IV) are sensitive to phosphodiesterase inhibitors and glucocorticoids respectively. The target molecules for these drugs were over-expressed at the mRNA level and constitute likely explanations for the observed drug potency. In paper V, we identified mRNA markers for the distinction between two types of thyroid tumors, thyroid follicular adenomas and thyroid follicular carcinomas, by means of microarray expression analysis. Our results indicated that distinction between the two tumor types is possible with a small number of markers.

Until recently, multiple SPME fibres could not be automatically evaluated in a single sequence without manual intervention. This drawback had been a critical issue until recently, particularly during the analysis of numerous on-site samples. Recently, GERSTEL® has developed and commercialized a Multi-Fibre Exchanger (MFX) system designed to overcome this drawback. In this research, a critical evaluation of the MFX performance in terms of storage stability and long term operation is presented. It was established in the course of our research that the MFX can operate continuously and precisely for over 200 extraction/injection cycles. However, when the effect of residence time of commercial fibres on the MFX tray was evaluated, the results have shown that amongst the evaluated fibre coatings, carboxen/polydimethylsiloxane (CAR/PDMS) was the only coating capable of efficient storage on the MFX tray for up to 24 hours after field sampling without suffering significant loss of analytes. Additionally, the MFX system capability for high-throughput analysis was demonstrated by the unattended desorption of multiple fibres after on-site sampling of two different systems, indoor air and biogenic emissions. Subsequently, a protocol based on a new, fast, reproducible, reusable and completely automated method that enables quick assessment of SPME coatings was developed. The protocol consists of an innovative in-vial standard generator containing vacuum pump oil doped with McReynolds probes and subsequently mixed with a polystyrene-divinylbenzene resin. According to our results, the protocol has proven to be a useful tool for the quick assessment of inter-fibre reproducibility prior to their application in on-site analysis. The implications of such protocols include, but are not limited to: time-saving, assurance of reliable and reproducible data, and a dependable guide for novice users of the technique. Finally, an innovative, reusable and readily deployable pen-like diffusive sampler for needle traps (PDS-NT) is proposed. Results have shown that the new PDS-NT is effective for air analysis of benzene, toluene, and o-xylene (BTX). In addition, no statistically significant effects of pen geometry on the uptake of analytes were found.

Highway lane closures cause reductions in the traffic throughput which lead to premature queuing. To minimize user delays, contractors are required to keep highway lanes open during the peak traffic hours and work at nights. However, these limitations can reduce the quality of the work and extend project duration. Finding a right balance between the times that the lanes can be closed and the times they should be kept open can increase the efficiency of the contractors’ work. Over 100 hours of throughput data were collected in two phases from 2007 to 2010 from Southern Ontario highways. Using regression analysis, a generic and a highway specific model were developed predicting the mean throughput in approximately 50% of cases within one hundred vehicles per hour per lane of the actual mean. Also the Simplified Work Zone User Delay Analysis model, developed in Phase 1, was refined to investigate the resulting queues.

Highway lane closures cause reductions in the traffic throughput which lead to premature queuing. To minimize user delays, contractors are required to keep highway lanes open during the peak traffic hours and work at nights. However, these limitations can reduce the quality of the work and extend project duration. Finding a right balance between the times that the lanes can be closed and the times they should be kept open can increase the efficiency of the contractors’ work. Over 100 hours of throughput data were collected in two phases from 2007 to 2010 from Southern Ontario highways. Using regression analysis, a generic and a highway specific model were developed predicting the mean throughput in approximately 50% of cases within one hundred vehicles per hour per lane of the actual mean. Also the Simplified Work Zone User Delay Analysis model, developed in Phase 1, was refined to investigate the resulting queues.

Today’s wireless users expect great things from tomorrow’s wireless networks. These expectations have been fueled by hype about what the next generations of wireless networks will offer. The rapid increase of wireless subscribers increases the quality of services anytime, anywhere, and by any-media becoming indispensable. Integration of various networks such as CDMA2000 and wireless LAN into IP-based networks is required in these kinds of services, which further requires a seamless vertical handoff to 4th generation wireless networks. The proposed handoff algorithm between WLAN and CDMA2000 cellular network is implemented. The results of the simulation shows the behavior of the handoff and the time spent in WLAN or CDMA. The number of weak signal beacons determines whether a handoff is required or not. In this algorithm, traffic is classified into real-time and non real-time services.

Fatty acid profiling provides information on dietary intakes and an understanding of lipid metabolism. High throughput techniques such as fingertip prick (FTP) sampling has gained popularity in recent years as a simplified method for basic research, and could be further used to assess disease risk in the population, and other similar high-throughput techniques have the potential to assist in the monitoring and labeling of fatty acids in the food supply. With the advancement of high-throughput sample analysis techniques, a more complete understanding of storage stability is required as a larger volume of samples are produced with equal amounts of time to analyze them. Energy-assisted analysis techniques have the potential to help ameliorate some of these issues. Presently, FTP blood, whole blood and salmon storage stability is assessed under various storage conditions, and both microwave-assisted direct transesterification and indirect ultrasound-assisted extraction techniques are assessed. It is determined that storage of FTP blood and whole blood samples at -20°C results in significant and nearly complete highly unsaturated fatty acid (HUFA) degradation compared to all other temperatures examined. This degradation is determined to be the result of hemolysis and subsequent iron release from erythrocytes initiating fatty acid peroxidation reactions. Direct transesterification of FTP blood is reduced from as long as three hours to one minute with microwave-assisted energy and fatty acid extraction from ground flaxseed is reduced to 40 minutes from as long as 24 hours without compromising fatty acid profiles. Results of the current study provides insight into the storage stability of food sample and blood samples collected via high-throughput techniques, and provides support for the utilization of further high-throughput energy-assisted analytical methods that can help to minimize the potentially detrimental effects that long-term storage can have on fatty acid profiles.

Consider a cognitive overlaid network (CON) that has two tiers with different priorities: a primary tier vs. a secondary tier, which is an emerging network scenario with the advancement of cognitive radio (CR) technologies. The primary tier consists of randomly distributed primary radios (PRs) of density n, which have an absolute priority to access the spectrum. The secondary tier consists of randomly distributed CRs of density m = n^y with y greater than or equal to 1, which can only access the spectrum opportunistically to limit the interference to PRs. In this dissertation, the fundamental limits of such a network are investigated in terms of the asymptotic throughput and packet delay performance when m and n approaches infinity. The following two types of CONs are considered: 1) selfish CONs, in which neither the primary tier nor the secondary tier is willing to route the packets for the other, and 2) supportive CONs, in which the secondary tier is willing to route the packets for the primary tier while the primary tier does not. It is shown that in selfish CONs, both tiers can achieve the same throughput and delay scaling laws as a stand-alone network. In supportive CONs, the throughput and delay scaling laws of the primary tier could be significantly improved with the aid of the secondary tier, while the secondary tier can still achieve the same throughput and delay scaling laws as a stand-alone network. Finally, the throughput and packet delay of a CON with a small number of nodes are investigated. Specifically, we investigate the power and rate control schemes for multiple CR links in the same neighborhood, which operate over multiple channels (frequency bands) in the presence of PRs with a delay constraint imposed on data transmission. By further considering practical limitations in spectrum sensing, an efficient algorithm is proposed to maximize the average sum-rate of the CR links over a finite time horizon under the constraints on the CR-to-PR interference and the average transmit power for each CR link. In the proposed algorithm, the PR occupancy of each channel is modeled as a discrete-time Markov chain (DTMC). Based on such a model, a novel power and rate control strategy based on dynamic programming (DP) is derived, which is a function of the spectrum sensing output, the instantaneous channel gains for the CR links, and the remaining power budget for the CR transmitter. Simulation results show that the proposed algorithm leads to a significant performance improvement over heuristic algorithms.

In this thesis, we propose a dynamic traffic adjustment scheme for end-to-end proportional differentiated services (EEPDS) on MPLS networks. When the Egress LSR (Label Switch Router) first observes that the proportional ratio of multiple flows could not be maintained, it will locate the performance bottlenecks by sending control messages to all the traversed LSR. In the proposed scheme, the identified bottleneck routers may have to drop the packets of traffic flows that do not require any QoS assurance (for example, the best-effort flows). Moreover, if dropping packets of the best-effort flows could not meet the goals of maintaining proportional ratios, the Ingress LSR would have to shape the traffic rates of sending flows proportionally based on the throughput values observed by the Egress LSR. Once a bottleneck router regains its sufficient bandwidth released by other traffic flows, it will send out control packets to notify the Ingress LSR to recover the original sending rates. Eventually, the proposed EEPDS mechanism can meet the goals of maintaining the proportional ratios by dynamically tuning the traffic flows. For the purpose of demonstration, we implement the EEPDS scheme by using MNS simulator. According to the experimental results, the EEPDS scheme has shown that it can meet the proportional ratios of multiple traffic flows even under severe network congestions, where multiple performance bottlenecks may occur. Finally, we observe that the processing overhead of the proposed EEPDS scheme is very small, since it is triggered only when the Egress LSR detects the situation of unsatisfied proportional ratios.

No description available.

No description available.