La extensión linfática es el factor pronóstico más importante en el momento del diagnóstico del cáncer de mama. La Biopsia Selectiva del Ganglio Centinela (BSGC) es el procedimiento actualmente indicado para la estadificación regional de las pacientes con cáncer de mama precoz. La BSGC permite una estadificación más exacta que la linfadenectomía axilar tradicional (LDNA), gracias a la identificación de drenajes extra-axilares y de micrometástasis en el GC, de modo que el manejo terapeútico posterior de las pacientes ha de ser más acertado y la evolución clínica mejor. El objetivo de este trabajo es evaluar la eficiencia y seguridad de la aplicación clínica de la BSGC en las pacientes con cáncer de mama, perfilando la metodología óptima en cuanto al radiotrazador y la vía de administración, y analizando la indicación en situaciones clínicas especiales: carcinoma in situ, múltiple, o cirugía mamaria previa. Se estudian los primeros 600 procedimientos de BSGC realizados en fase clínica, a 591 pacientes con cáncer de mama estadio I y II. La eficiencia de detección gammagráfica e intraoperatoria del GC fue 94,5% y 90,5% respectivamente. El procedimiento de BSGC evita una LDNA innecesaria en el 68,9% de los pacientes, que presentan GC benigno. Después de un seguimiento medio de 47,4 meses, ha aparecido una única recaída axilar en las pacientes con GC benigno (tasa 0,24%). Este aspecto probablemente se relaciona con la exéresis sistemática de otros ganglios “sospechosos”. El 8,3 % de los pacientes incluidos han sido re-estadificados por la identificación de micrometástasis en el GC, hallando otros ganglios positivos en la LDNA en el 12,1%. La tasa de enfermedad es 8,1% en estas pacientes. La eficiencia de detección del GC no ha diferido significativamente al comparar radiotrazadores de distinto tamaño (coloide de estaño vs sulfuro de renio) y diferentes vías de administración (profunda, periareolar, combinada), aunque se debe considerar la fuerte dependencia entre ambos aspectos técnicos. Los drenajes extra-axilares son más frecuentes cuando se emplea un radiocoloide de menor tamaño. El análisis histopatológico final revela invasión en el 45,6% de los pacientes incluidos con el diagnóstico inicial de carcinoma in situ. El porcentaje de afectación del GC en estos pacientes es 6,9%. La tasa de identificación del GC en el carcinoma múltiple de mama es 95,5% en la gammagrafía y 92,1% en la detección intraoperatoria; 93,7% y 87,5% respectivamente en los tumores multicéntricos, en los que se observa además mayor número de GC por paciente y de GC extra-axilares. La eficiencia de detección gammagráfica y quirúrgica del GC en las pacientes con cirugía mamaria previa (inyección superficial) es 92,3% y 82% respectivamente. El número de GC por paciente y el porcentaje de drenajes extra-axilares son significativamente elevados, sobre todo cuando existe algún antecedente quirúrgico extenso antiguo (cirugía conservadora) y/o localizado en el CSE. En conclusión, la BSGC es una técnica eficaz, segura y fiable que permite una estadificación exacta de los pacientes y contribuye al control locorregional de la enfermedad. La inyección periareolar se confirma como método seguro y altamente eficaz, aún cuando se emplean radiocoloides de tamaño grande. El procedimiento de BSGC está indicado en cáncer in situ de alto riesgo o con indicación de mastectomía, y puede realizarse con seguridad en tumores múltiples, incluso multicéntricos, y en pacientes con antecedentes quirúrgicos, aunque sean relativamente extensos o afecten al CSE. En todas estas circunstancias es apropiada también la administración periareolar del radiocoloide. / Lymphatic status is the most important prognostic factor in breast cancer. Sentinel lymph node biopsy (SLNB) is the current elective procedure for regional staging in patients with early breast cancer. SLNB allows more exact staging than traditional axillary lymphadenectomy (ALDN), on the basis of the identification of extra-axillary drainages and sentinel node (SN) micrometastasis, what results in more appropriate adjuvant theraphy and better outcome of the patients. The aim of this study was to establish the efficiency and safety of SLNB in its clinical application to breast cancer patients, as well as the optimal methodology (particle size of the colloid, site of injection) and controversial indications (intraductal carcinoma, multifocal/multicentric breast cancer, patients with previous breast surgery). This study included the first 600 SLNB procedures, performed in 591 patients with breast cancer, I and II stage. The scintigraphic and intraoperative detection rate of SN were respectively 94.5% and 90.5%.The procedure avoided unnecesary ALDN in 68.9% of the patients, those without SN involvement. After a median follow-up of 47.4 months, the incidence of axillary recurrence after tumor negative SN is low (0.24%), probably related to the systematic removal of “suspicious” nodes during the surgical act. The identification of micrometastasis in SN implied the upstaging of 8.3% of patients included. The subsequent ALDN performed showed non-sentinel node metastasis in 12.1%. Disease rate in these patients is 8.1%. The efficiency of SN detection did not varied significantly when comparing radiotracers of different size (stannous fluorid vs rhenium sulphide colloid), or different sites of injection (deep, areolar or combined). However, the strong correlation between these two technical aspects must be taken into account. Extra-axillary drainages are more frequent when a smaller radiotracer is used. Final pathologic diagnosis revealed invasion in 45.6% of patients included with the initial diagnosis of ductal carcinoma in situ. The percentage of positive SN was 6.9% in these patients. The identification rate of SN in patients with multiple breast cancer was 93.7% in lymphoscintigraphy and 92.1% in surgical detection. These percentages were respectively 93.7% and 87.5% in multicentric cases, in that higher number of SN per patient and extra-axillary nodes were found. Scintigraphic and surgical detection rate in patients with previous breast surgery was 92.3% and 82%. The number of SN per patient and the percentage of extra-axillary drainages were higher, especially after wide ancient surgery (conservative) in outer-upper quadrant. In conclusion, SLNB is an efficient, safe and accurate procedure. It achieves an exact staging of the patients, and contributes to local control of the disease. Periareolar injection is a reliable method, even though large colloids are used. SLNB is indicated in high risk ductal carcinoma in situ or programmed to mastectomy, multiple breast cancer, multicentric included, and breast cancer in patients with prior breast surgery, even though wide or external. In these clinical circumstances, the periareolar injection is also appropiate.

No description available.

<p>Mast cells, best known for their pathologic role in allergy, have recently been shown to have key roles in the initiation of adaptive immune responses. These cells are located throughout the body just beneath barriers separating host from environment, possess multiple pathogen recognition systems, and store large quantities of fully active inflammatory mediators. These key features make them uniquely situated to act as sentinels of immunity, releasing the very earliest alarm signals when a pathogen is present. As a testament to the importance of these cells, mast cell-deficient mice have suboptimal immune responses, and mast cell activators can act as potent adjuvants for experimental immunizations. Specifically, mast cells have been shown to enhance the number of naive lymphocytes in infection site-draining lymph nodes, and to encourage the migration of dendritic cells to responding lymph nodes.</p><p>Although infections usually occur at peripheral sites, adaptive immune responses are initiated in distant lymph nodes. Despite the distance, signals from the site of infection result in dramatic, rapid reorganization of the node, including massive recruitment of naive lymphocytes from the circulation and extensive vascular restructuring to accommodate the increase in size. How such signals reach the lymph node is not well understood.</p><p>When mast cells degranulate, in addition to releasing soluble mediators such as histamine, they expel large, stable, insoluble particles composed primarily of heparin and cationic proteins. The work presented herein demonstrates that these particles act as extracellular chaperones for inflammatory mediators, protecting them from dilution into the interstitial space, degradation, and interaction with non-target host cells and molecules. The data show clearly that mast cells release such particles, that they are highly stable, that they contain tumor necrosis factor (a critically important immunomodulator), and that they can traffic from peripheral sites to draining lymph nodes via lymphatic vessels. Furthermore, extensive biochemical characterization of purified mast cell-derived particles was performed. Finally, evidence is presented that such particles can elicit lymph node enlargement, an infection-associated phenomenon that favors the development of adaptive immunity, by delivering peripheral TNF to draining lymph nodes. </p><p>This signaling concept, that particles may chaperone signals between distant sites, also has important implications for adjuvant design. The evidence presented here shows that encapsulation of TNF into synthetic particles similar to mast cell-derived particles greatly enhances its potency for eliciting lymph node enlargement, an indication that adaptive immunity may be improved. This delivery system should ensure that more adjuvant arrives in the draining lymph node intact, where it would lead to changes favorable to the development of the immune response. Such a system would also facilitate the delivery of multi-component adjuvants that would act synergistically at the level of the lymph node when gradually released from microparticle carriers. An additional advantage of microparticle encapsulation is that vaccine formulations of this type may require much lower doses of expensive antigen and adjuvants.</p><p>The delivery of inflammatory mediators to lymph nodes during immune responses may be an important general feature of host defense. Although the action of mediators of peripheral origin on draining lymph nodes has been described before, this is the first demonstration of a specific adaptation to deliver such mediators. Not only is the characterization of mast cell-derived particles important to basic immunology, but mimicking this adaptation may also lead to improved therapeutics.</p> / Dissertation

<p>Lymph nodes are organs of efficiency. Once activated, they essentially function to optimize and accelerate the production of the adaptive immune response, which has the potential to determine survival of the host during an initial infection and protect against repeated infections, should specific and appropriate immunological memory be sufficiently induced. We now have an understanding of the fundamental structure of lymph nodes and many of the interactions that occur within them throughout this process. Yet, lymph nodes are dynamic and malleable organs and much remains to be investigated with regards to their responses to various types of challenges. In this work, we examined multiple inflammatory scenarios and sought to understand the complex ways that lymph nodes can be externally targeted to impact immunity. First, we outline a novel mechanism of cellular communication, where cytokine messages from the periphery are delivered to draining lymph nodes during inflammation. These signals are sent as particles, released by mast cells, and demonstrate the ability of the infected tissue to communicate to lymph nodes and shape their responses. Based on these interactions, we also explored the ability to therapeutically or prophylactically modulate lymph node function, using bioengineered particles based on mast cell granules, containing encapsulated cytokines. When we used these particles as a vaccine adjuvant, we were able to polarize adaptive immune responses, such as to promote a Th1 phenotype, or enhance a specific attribute of the immune response, such as the production of high avidity antibodies. We then explore three examples of lymph node-targeting pathogens: Salmonella typhimurium, Yersinia pestis and Dengue virus. Each of these pathogens has a well-characterized lifecycle including colonization of draining lymph node tissue. In the case of S. typhimurim, we report that the virulence this pathogen depends on a specific shut down of the chemotactic signals in the lymph node that are required to maintain appropriate cellular localization within it. Our results demonstrate that these architecture changes allow S. typhimurim to target the adaptive immune process in lymph nodes and contribute to its spread in vivo and lethality to the host. With Y. pestis, similar targeting of cellular trafficking pathways occurs through the modulation of chemokine expression. Y. pestis appears to use the host's cellular trafficking pathways to spread to lymph nodes in two distinct waves, first exploiting dendritic cell movement to lymph nodes and then enhancing monocyte chemoattractants to replicate within monocytes in draining lymph nodes. These processes also promote bacterial spread in vivo and we further demonstrate that blocking monocyte chemotaxis can prolong the host's survival. In the third example of pathogen challenge, we report for the first time that mast cells can contribute functionally to immunosurveillance for viral pathogen, here, promoting cellular trafficking of innate immune cells, including NK cells, and limiting the spread of virus to draining lymph nodes. For each of these three examples of lymph node targeting by microbial pathogens, we provide data that modulation of cellular trafficking to and within lymph nodes can drastically influence the nature of the adaptive immune response and, therefore, the appropriateness of that response for meeting a unique infectious challenge. Cumulatively this work highlights that a balance exists between host and pathogen-driven modulation of lymph nodes, a key aspect of which is movement of cells within and into this organ. Cytokine and chemokine pathways are an area of vulnerability for the host when faced with host-adapted pathogens, yet the lymph node's underlying plasticity and the observation that slight modulations can be beneficial or detrimental to immunity also suggests the targeting of these pathways with therapeutic intentions and during vaccine design.</p> / Dissertation

In wireless positioning system, in addition to channel error, the geometric re- lationship between sensor nodes and the target may also affect the positioning accuracy. The effect is called geometric dilution of precision (GDOP). GDOP is determined as ratio factor between location error and measurement error. A higher GDOP value indicates a larger location error in location estimation. Accordingly, the location performance will be poor. The GDOP can therefore be used as an in- dex of the positioning performance. In this thesis, approaches of tracking a moving target with extended Kalman filter (EKF) in a time-difference-of-arrival (TDOA) wireless positioning system are discussed. While the target changes its position with time, the geometric layout between sensor nodes and the target will become differ- ent. To maintain the good layout, the positioning system with mobile sensor nodes is considered. Therefore, the geometric layout can be possibly improved and GDOP effect can be reduced by the mobility of mobile sensor nodes. In order to find the positions that mobile sensor nodes should move to, a time-varying function based on the GDOP distribution is defined for finding the best solutions. Since the simu- lated annealing is capable of escaping local minima and finding the global minimum in an objective function, the simulated annealing algorithm is used in finding the best solutions in the defined function. Thus the best solutions can be determined as the destinations of mobile sensor nodes. When relocating mobile sensor nodes from their current positions to the destinations, they may pass through or stay in high GDOP regions before arriving at the destinations. To avoid the problem, we establish an objective function for path planning of mobile sensor nodes in order to minimize the overall positioning accuracy. Simulation results show that the mobile sensor nodes will accordingly change their positions while the target is moving. All the sensor nodes will maintain a surrounding region to localize the target and the GDOP effect can be effectively reduced.

Wireless sensor networks (WSNs) have been widely used in many areas, such as early earthquake monitoring, building structure monitoring, and military surveillance. In this thesis, we focus on the wireless sensor network deployed in the battlefield, using random key predistribution scheme. Firstly we presented an analysis of the security impacts by node capture attack. Also, based on the node cloning attack, we proposed a new attack scheme, called compromised key redistribution attack, and discussed related attack scenarios. Besides, we have found out and conjectured that, when the overlapping factor of compromised key set is larger than 0.05, it is very possible (almost 90%) that the number of distinct compromised keys is 10.5% of the original key pool. This conjecture helps the adversary estimate the approximated size of original key pool by calculating the overlapping factor, thus calculate the probability that malicious nodes successfully establish connections with legitimate nodes.

Broadcasting is a communication model for a node to emit the packets via wireless channels to its neighbor nodes. In mobile ad hoc networks (MANETs), it is commonly implemented through flooding to find routes, send alarm signals and page a particular host. Conventionally, ad hoc routing protocols, such as AODV, use blind flooding extensively for on-demand route discovery, which could result in a high number of redundant retransmissions, leading to serious contention and collisions referred to as the broadcast storm problem. A gossip-based approach, in which each node forwards a message with some probability, has been proposed in past years to alleviate this problem. The approach combines gossiping with AODV (denoted as AODV+G) and exhibits a significant performance improvement in simulations. In this paper, we make a mathematical inference from observing the behavior of the gossip-based approach, and improve the gossip-based approach by employing the remaining energy of nodes in the gossip mechanism (denoted as AODV+GE) to extend the lifetime of the entire network and improve the packet delivery ratio. Through mathematical inference and simulations we show that AODV+GE outperforms AODV+G in terms of the lifetime of the whole network, average node energy consumption, and packet delivery ratio.

This dissertation presents a novel modeling framework for understanding the dynamics of peer-to-peer (P2P) networks under churn (i.e., random user arrival/departure) and designing systems more resilient against node failure. The proposed models are applicable to general distributed systems under a variety of conditions on graph construction and user lifetimes. The foundation of this work is a new churn model that describes user arrival and departure as a superposition of many periodic (renewal) processes. It not only allows general (non-exponential) user lifetime distributions, but also captures heterogeneous behavior of peers. We utilize this model to analyze link dynamics and the ability of the system to stay connected under churn. Our results offers exact computation of user-isolation and graph-partitioning probabilities for any monotone lifetime distribution, including heavy-tailed cases found in real systems. We also propose an age-proportional random-walk algorithm for creating links in unstructured P2P networks that achieves zero isolation probability as system size becomes infinite. We additionally obtain many insightful results on the transient distribution of in-degree, edge arrival process, system size, and lifetimes of live users as simple functions of the aggregate lifetime distribution. The second half of this work studies churn in structured P2P networks that are usually built upon distributed hash tables (DHTs). Users in DHTs maintain two types of neighbor sets: routing tables and successor/leaf sets. The former tables determine link lifetimes and routing performance of the system, while the latter are built for ensuring DHT consistency and connectivity. Our first result in this area proves that robustness of DHTs is mainly determined by zone size of selected neighbors, which leads us to propose a min-zone algorithm that significantly reduces link churn in DHTs. Our second result uses the Chen-Stein method to understand concurrent failures among strongly dependent successor sets of many DHTs and finds an optimal stabilization strategy for keeping Chord connected under churn.

Wireless sensor networks (WSNs) have emerged in strategic applications such as target detection, localization, and tracking in battlefields, where the large-scale na- ture renders centralized control prohibitive. In addition, the finite batteries in sensor nodes demand energy-aware network control. In this thesis, we propose an energy- efficient topology management model inspired by biological inter-cellular signaling schemes. The model allows sensor nodes to cluster around imminent targets in a purely distributed and autonomous fashion. In particular, nodes in the target vicinity collaborate to form clusters based on their relative observation quality values. Sub- sequently, the clustered sensor nodes compete based on their energy levels until some of them gain active status while the rest remain idle, again according to a distributed algorithm based on biological processes. A final phase of the model has the active cluster members compete until one of them becomes the clusterhead. We examine the behavior of such a model in both finite-size and infinite-size networks. Specifically, we show that the proposed model is inherently stable and achieves superior energy efficiency against reference protocols for networks of finite size. Furthermore, we dis- cuss the behavior of the model in the asymptotic case when the number of nodes goes to infinity. In this setting, we study the average number of cluster members.

This thesis reports the development and analysis of high performance CMOS readout electronics for increasing the performance of MEMS gyroscopes developed at Middle East Technical University (METU). These readout electronics are based on unity gain buffers implemented with source followers. High impedance node biasing problem present in capacitive interfaces is solved with the implementation of a transistor operating in the subthreshold region. A generalized fully differential gyroscope model with force feedback electrodes has been developed in order to simulate the capacitive interfaces with the model of the gyroscope. This model is simplified for the single ended gyroscopes fabricated at METU, and simulations of resonance characteristics are done. Three gyroscope interfaces are designed by considering the problems faced in previous interface architectures. The first design is implemented using a single ended source follower biased with a subthreshold transistor. From the simulations, it is observed that biasing impedances up to several gigaohms can be achieved. The second design is the fully differential version of the first design with the addition of a self biasing scheme. In another interface, the second design is modified with an instrumentation amplifier which is used for fully differential to single ended conversion. All of these interfaces are fabricated in a standard 0.6 &micro / m CMOS process. Fabricated interfaces are characterized by measuring their ac responses, noise response and transient characteristics for a sinusoidal input. It is observed that, biasing impedances up to 60 gigaohms can be obtained with subthreshold transistors. Self biasing architecture eliminates the need for biasing the source of the subthreshold transistor to set the output dc point to 0 V. Single ended SOG gyroscopes are characterized with the single ended capacitive interfaces, and a 45 dB gain improvement is observed with the addition of capacitive interface to the drive mode. Minimum resolvable capacitance change and displacement that can be measured are found to be 58.31 zF and 38.87 Fermi, respectively. The scale factor of the gyroscope is found to be 1.97 mV/(&deg / /sec) with a nonlinearity of only 0.001% in &plusmn / 100 &deg / /sec measurement range. The bias instability and angle random walk of the gyroscope are determined using Allan variance method as 2.158 &deg / /&amp / #8730 / hr and 124.7 &deg / /hr, respectively.