abstract: Cancer is a major public health challenge and the second leading cause of death in the United States. Large amount of effort has been made to achieve sensitive and specific detection of cancer, and to predict the course of cancer. Glycans are promising avenues toward the diagnosis and prognosis of cancer, because aberrant glycosylation is a prevalent hallmark of diverse types of cancer. A bottom-up “glycan node analysis” approach was employed as a useful tool, which captures most essential glycan features from blood plasma or serum (P/S) specimens and quantifies them as single analytical signals, to a lung cancer set from the Women Epidemiology Lung Cancer (WELCA) study. In addition, developments were performed to simplify a relatively cumbersome step involved in sample preparation of glycan node analysis. Furthermore, as a biomarker discovery research, one crucial concern of the glycan node analysis is to ensure that the specimen integrity has not been compromised for the employed P/S samples. A simple P/S integrity quality assurance assay was applied to the same sample set from WELCA study, which also afford the opportunity to evaluate the effects of different collection sites on sample integrity in a multisite clinical trial. Here, 208 samples from lung cancer patients and 207 age-matched controls enrolled in the WELCA study were analyzed by glycan node analysis. Glycan features, quantified as single analytical signals, including 2-linked mannose, α2‐6 sialylation, β1‐4 branching, β1‐6 branching, 4-linked GlcNAc, and outer-arm fucosylation, exhibited abilities to distinguish lung cancer cases from controls and predict survival in patients. To circumvent the laborious preparation steps for permethylation of glycan node analysis, a spin column-free (SCF) glycan permethylation procedure was developed, applicable to both intact glycan analysis or glycan node analysis, with improved or comparable permethylation efficiency relative to some widely-used spin column-based procedures. Biospecimen integrity of the same set of plasma samples from WELCA study was evaluated by a simple intact protein assay (ΔS-Cysteinylated-Albumin), which quantifies cumulative exposure of P/S to thawed conditions (-30 °C). Notable differences were observed between different groups of samples with various initial handling/storage conditions, as well as among the different collection sites. / Dissertation/Thesis / Doctoral Dissertation Biochemistry 2019

Large-scale wireless sensor networks consist of thousands of tiny and low cost nodes with very limited energy, computing power and communication capabilities. They have a myriad of possible applications. They can be used in hazardous and hostile environments to sense for deadly gases and high temperatures, in personal area networks to monitor vital signs, in military and civilian environments for intrusion detection and tracking, emergency operations, etc. In large scale wireless sensor networks the protocols need to be scalable and energy-efficient. Further, new strategies are needed to address the well-known energy depletion problem that nodes close to the sink node face. In this thesis the Scalable Energy-efficient Location-Aided Routing (SELAR) protocol for wireless sensor networks is proposed to solve the above mentioned problems. In SELAR, nodes use location and energy information of the neighboring nodes to perform the routing function. Further, the sink node is moved during the network operation to increase the network lifetime. By means of simulations, the SELAR protocol is evaluated and compared with two very well-known protocols - LEACH (Low-Energy Adaptive-Clustering Hierarchy) and MTE (Minimum Transmission Energy). The results indicate that in realistic senarios,SELAR delivers up to 12 times more and up to 1.4 times more data packets to the base station than LEACH and MTE respectively. It was also seen from the results that for realistic scenarios, SELAR with moving base station has up to 5 times and up to 27 times more lifetime duration compared to MTE and LEACH respectively.

Real graph datasets are important for many science domains, from understanding epidemics to modeling traffic congestion. To facilitate access to realistic graph datasets, researchers proposed various graph generators typically aimed at representing particular graph properties. While many such graph generators exist, there are few techniques for generating graphs where the nodes have binary attributes. Moreover, generating such graphs in which the distribution of the node attributes preserves real-world characteristics is still an open challenge. This thesis introduces Borromean, a graph generating algorithm that creates synthetic graphs with binary node attributes in which the attributes obey an attribute-specific joint degree distribution. We show experimentally the accuracy of the generated graphs in terms of graph size, distribution of attributes, and distance from the original joint degree distribution. We also designed a parallel version of Borromean in order to generate larger graphs and show its performance. Our experiments show that Borromean can generate graphs of hundreds of thousands of nodes in under 30 minutes, and these graphs preserve the distribution of binary node attributes within 40% on average.

<p>The two purposes of this thesis were to evaluate new diagnostic techniques of lymphnode staging in invasive bladder cancer and to evaluate the results of neoadjuvant chemotherapy in invasive bladder cancer.</p><p>Sentinel node detection was performed in 13 patients in preparation for radical cystectomy. The method showed to be feasible, and the results displayed the occurrence of metastatic nodes outside the traditional area of diagnostic dissection in a majority of patients. Four patients were metastasized, each one with one metastatic node detected with the help of the sentinel node procedure.</p><p>Four randomly selected sentinel nodes from four different unmetastasized patients were compared to the four metastatic sentinel nodes from the first series. After microdissection, p53 genomic structure, immunohistochemical expression and MVD (microvessel density) were assessed in the primary tumors and corresponding sentinel nodes. The results suggested that invasive bladder cancer mainly involved monoclonal proliferation with predominantly homogenous biomarker profile, but there were also signs of clonal evolution.</p><p>The Nordic Cystectomy Trial 2 (NCT2), is a randomized prospective trial investigating the possible benefit of neoadjuvant chemotherapy versus cystectomy only, in 311 eligible patients with urinary bladder cancer T2-T4aNXM0.Evaluation of overall survival did not show any statistically significant benefit in the experimental arm. This probably due to lack of statistical power.</p><p>To increase the statistical power we performed a combined analysis of randomized patients from both the Nordic Cystectomy Trial 1 (NCT1) and NCT2, n = 620. Eligible patients from NCT1 had T1G3, T2-T4a NXM0 urinary bladder cancer. Standard meta-analysis methods were used. The only end-point analysed was overall survival. Neoadjuvant platinum based combination therapy was associated with a 20 % reduction in the relative hazard in probability of death.</p>

<p>The most important prognostic factor in breast cancer is the axillary lymph node status. The sentinel node biopsy (SNB) is reported to stage the axilla with an accuracy > 95 % in early breast cancer. Tumour-related perturbation of T-cell function has been observed in patients with malignancies, including breast cancer. The down-regulation of the important T-cell activation molecules CD3-ζ and CD28 may cause T-cell dysfunction, anergy, tolerance and deletion.</p><p>The expression of CD3-ζ and CD28 was evaluated in 25 sentinel node biopsies. The most pronounced down-regulation was seen in the paracortical area, where the best agreement between both parameters was observed. CD28 expression was significantly more suppressed in CD4+ than in CD8+ T-cells.</p><p>From the Swedish sentinel node database, 109 patients with breast cancer > 3 cm planned for both SNB and a subsequent axillary dissection were identified. The false negative rate (FNR) was 12.5%. Thirteen cases of tumour multifocality were detected on postoperative pathology. The FNR in this subgroup was higher (30.8%) than in patients with unifocal disease (7.8%; P = 0.012).</p><p>From the Swedish SNB multicentre cohort trial, 2246 sentinel node-negative patients who had not undergone further axillary surgery were selected for analysis. After a median follow-up time of 37 months (range 0-75), 13 isolated axillary recurrences (13/2246; 0.6%) were found. In another 14 cases, local or distant failure preceded or coincided with axillary relapse (27/2246; 1.2%). </p><p>In conclusion, the immunological analysis of the sentinel node might provide valuable prognostic information and aid selection of patients for immunotherapy. SNB is encouraged in breast cancer larger than 3 cm, if no multifocal growth pattern is present. The axillary recurrence rate after a negative SNB in Sweden is in accordance with international figures. However, a longer follow-up is mandatory before the true failure rate of the SNB can be determined.</p>

The two purposes of this thesis were to evaluate new diagnostic techniques of lymphnode staging in invasive bladder cancer and to evaluate the results of neoadjuvant chemotherapy in invasive bladder cancer. Sentinel node detection was performed in 13 patients in preparation for radical cystectomy. The method showed to be feasible, and the results displayed the occurrence of metastatic nodes outside the traditional area of diagnostic dissection in a majority of patients. Four patients were metastasized, each one with one metastatic node detected with the help of the sentinel node procedure. Four randomly selected sentinel nodes from four different unmetastasized patients were compared to the four metastatic sentinel nodes from the first series. After microdissection, p53 genomic structure, immunohistochemical expression and MVD (microvessel density) were assessed in the primary tumors and corresponding sentinel nodes. The results suggested that invasive bladder cancer mainly involved monoclonal proliferation with predominantly homogenous biomarker profile, but there were also signs of clonal evolution. The Nordic Cystectomy Trial 2 (NCT2), is a randomized prospective trial investigating the possible benefit of neoadjuvant chemotherapy versus cystectomy only, in 311 eligible patients with urinary bladder cancer T2-T4aNXM0.Evaluation of overall survival did not show any statistically significant benefit in the experimental arm. This probably due to lack of statistical power. To increase the statistical power we performed a combined analysis of randomized patients from both the Nordic Cystectomy Trial 1 (NCT1) and NCT2, n = 620. Eligible patients from NCT1 had T1G3, T2-T4a NXM0 urinary bladder cancer. Standard meta-analysis methods were used. The only end-point analysed was overall survival. Neoadjuvant platinum based combination therapy was associated with a 20 % reduction in the relative hazard in probability of death.

The most important prognostic factor in breast cancer is the axillary lymph node status. The sentinel node biopsy (SNB) is reported to stage the axilla with an accuracy &gt; 95 % in early breast cancer. Tumour-related perturbation of T-cell function has been observed in patients with malignancies, including breast cancer. The down-regulation of the important T-cell activation molecules CD3-ζ and CD28 may cause T-cell dysfunction, anergy, tolerance and deletion. The expression of CD3-ζ and CD28 was evaluated in 25 sentinel node biopsies. The most pronounced down-regulation was seen in the paracortical area, where the best agreement between both parameters was observed. CD28 expression was significantly more suppressed in CD4+ than in CD8+ T-cells. From the Swedish sentinel node database, 109 patients with breast cancer &gt; 3 cm planned for both SNB and a subsequent axillary dissection were identified. The false negative rate (FNR) was 12.5%. Thirteen cases of tumour multifocality were detected on postoperative pathology. The FNR in this subgroup was higher (30.8%) than in patients with unifocal disease (7.8%; P = 0.012). From the Swedish SNB multicentre cohort trial, 2246 sentinel node-negative patients who had not undergone further axillary surgery were selected for analysis. After a median follow-up time of 37 months (range 0-75), 13 isolated axillary recurrences (13/2246; 0.6%) were found. In another 14 cases, local or distant failure preceded or coincided with axillary relapse (27/2246; 1.2%). In conclusion, the immunological analysis of the sentinel node might provide valuable prognostic information and aid selection of patients for immunotherapy. SNB is encouraged in breast cancer larger than 3 cm, if no multifocal growth pattern is present. The axillary recurrence rate after a negative SNB in Sweden is in accordance with international figures. However, a longer follow-up is mandatory before the true failure rate of the SNB can be determined.

The main focus of the work presented in this licentiate thesis concerns antenna design, adaptive antenna control and investigation on how the performance of small wireless nodes can be increased by inclusion of multiple antennas. In order to provide an end-user suitable solution for wireless nodes the devices require both small form factor and good performance in order to be competitive on the marked and thus the main part of this thesis focuses on techniques developed to achieve these goals. Two prototype systems have been developed where one has been used by National Defence Research Agency (FOI) to successfully monitor a test-subject moving in an outdoor terrain. The other prototype system shows the overall performance gain achievable in a wireless sensor node when multiple antennas and antenna beam steering is used. As an example of how to include multiple antennas in a wireless node the concept of using dual conformal patch antennas for wireless nodes is presented. The proposed antenna showed an excess of 10 dB gain when using a single driven antenna element as would be the case in a system utilizing antenna selection combining. When used as a 2-element phased array, up to 19 dB gain was obtained in a multiscattering environment. Using the second order resonance the proposed antenna structure achieves low mutual coupling and a reflection coefficient lower than -15 dB. The presented antenna design shows how a dual antenna wireless node can be designed using discrete phase control with passive matching which provides a good adaptive antenna solution usable for wireless sensor networks. The inclusion of discrete phase sweep diversity in a wireless node has been evaluated and shown to provide a significant diversity gain. The diversity gain of a discrete phase sweep diversity based system was measured in both a reverberation chamber and a real life office environment. The former environment showed between 5.5 to 10.3 dB diversity gain depending on the detector architecture and the latter showed a diversity gain ranging from 1 to 5.4 dB. Also the performance of nodes designed to be placed in a high temperature and multiscattering environment (the fan stage of a jet engine) has been evaluated. The work was carried out in order to verify that a wireless sensor network is able to operate in such a multiscattering environment. It was shown that the wireless nodes are able to operate in an emulated turbine environment based on real-life measured turbine fading data. The tested sensor network was able to transmit 32 byte packages using cyclic redundancy check at 2 Mbps at an engine speed of 13.000 rpm. / WISENET / WISEJET

Enhancing route request broadcasting protocols constitutes a substantial part of research in mobile ad hoc network routing. In the thesis, enhancements of ad hoc routing protocols, energy efficiency metrics and clustered topology generators are discussed. The contributions include the followings. First, a node caching enhancement of Ad-hoc On-demand Distance Vector (AODV) routing protocol is introduced. Extensive simulation studies of the enhanced AODV in NS2 shows up to 9-fold reduction in the routing overhead, up to 20% improvement in the packet delivery ratio and up to 60% reduction in the end-to-end delay. The largest improvement happens to highly stressed situations. Secondly, new metrics for evaluating energy efficiency of routing protocols are suggested. New node cached AODV protocols employing non-adaptive and adaptive load balancing techniques were proposed for extending network lifetime and increasing network throughput. Finally, the impact of node clustered topology on ad hoc network is explored. A novel method for generating clustered layout in NS2 is introduced and experiments indicate performance degradation of AODV protocols for the case of two clusters.

Coverage in a Wireless Sensor Network reflects how well a sensor network monitors an area. Many times it is impossible to provide full coverage. The key challenges are to prolong the lifetime and ensure connectivity to provide a stable network. In this thesis we first define p-percent coverage problem in which we require only p% of the whole area to be monitored. We propose two algorithms, Connected P-Percent Coverage Depth First Search (CpPCA-DFS) and Connected P-Percent Connected Dominating Set (CpPCA-CDS). Through simulations we then compare and analyze them for their efficiency and lifetime. Finally in conclusion we prove that CpPCA-CDS provides 5 to 20 percent better active node ratio at low density. At high node density it achieves better distribution of covered area however the lifetime is only 5 to10 percent shorter then CpPCA-DFS. Overall CpPCA-CDS provides up to 30 percent better distribution of covered area.