PROBLEMA: ¿Cuál será la frecuencia de cáncer de próstata (CPI), de muestras aparentes de Hiperplasia Prostática Benigna (HPB) obtenidas por adenomectomías prostáticas (APRP)? OBJETIVOS: Determinar el estadio mediante la escala de Gleason del cáncer de próstata. Correlacionar el cáncer incidental con el PSA, la densidad de PSA, PSA libre y la velocidad del PSA. Correlacionar el CPl con la edad y el antecedente familiar de cáncer de próstata (CaP). MATERIAL Y MÉTODOS: Estudio descriptivo retrospectivo. Muestra: 1587 pacientes sometidos a APRP con diagnóstico de HPB previo a la cirugía. Criterios de Inclusión: Pacientes del Hospital Hipólito Unanue –Lima-Perú-– servicio de Urología, periodo Enero 2000 - Diciembre 2005, con diagnóstico previo a la cirugía de HPB, sin diagnóstico de cáncer de próstata (CaP) (PSA<4ng/ml y tacto rectal- fibroelastica, no nódulos). RESULTADOS: Datos de Enero del 2000 - Diciembre del 2005. Se operaron 1159 pacientes (73%) por APRP, y 428 pac. (27%) por Resección Transuretral Prostática (RTU). Hallándose 64 (4%) pac. con CPI con PSA en 8 pacientes (12.5 %) en PSA 0-2 ng/ml y 35 pac. (54.7 %) en 2.1-4 ng/ml. La velocidad de PSA, en el grupo con CPI: 44 (68.7%) pac. Que estuvieron en rango normal y 6 (9.4%) en el rango de 0.76-0.85 ng/ml. Sus edades estuvieron en el rango de edad entre 71 – 80 años a más con 50 pac. (78.1%). Además 11 pac. (17.2%) sin familiares con CaP y 49 pac. (76.6 %) con por lo menos un familiar con CaP y aún mas se encontró 4 pac. (6.25%) que tuvieron 2 o más familiares con el antecedente de CaP. Se halló un Volumen prostático en 20 pac. (31.3 %) entre 31-60 gr. y luego en 26 pac. (40.6 %) en el grupo de 61-80 gr. Presenta en el grupo de 81-100 gr. con 18 pac. (28.1%). y luego disminuye marcadamente en el grupo de 101 a más hasta 0 pacientes. Se halló 62 pacientes (96.7%) con adenocarcinoma de próstata y 2 pac. (3.3%) con cáncer de tipo transicional. 23 pacientes (37%) presentan un valor de Gleason bajo, 20 pacientes (31%) con Gleason entre 3-4; si observamos en general menos de Gleason 7 son 53 pacientes (82.8%). Con estadío T1a en 44 pac. (68.8 %), mientras que T1b eran solo 20 pac. (31.2%). CONCLUSIONES: De 1587 pac. operados, 1159 pac. (73%) se operaron por APRP y 428 pac. (27%) por RTU. Hallándose 64 (4%) pac. con CPI frecuentemente del tipo adenocarcinoma de próstata, con Escala de Gleason de bajo grado, (menos de 7). Siendo del tipo T1a la más común. El PSA está en el límite superior de su rango normal en los pacientes con CPI. No hay asociación entre el CPI Y la velocidad de PSA, índice del PSA, edad, tacto rectal, volumen prostático. Hay correlación entre el antecedente familiar y el CPI.

Les mécanismes cellulaires activés par la mélatonine pour synchroniser l’alternance entre la saison dereproduction et l’anoestrus sont encore mal compris. Les niveaux et l’importance fonctionnelle de la plasticitéinduite par une transition photopériodique ont été étudiés dans des régions du cerveau impliquées dans lasynchronisation saisonnière de la reproduction chez les ovins. Nos résultats suggèrent qu’un changement dephotopériode seule serait capable d’induire, dans plusieurs régions hypothalamiques, des variations d’unmarqueur de la plasticité, la PSA-NCAM, qui participeraient à la régulation de la reproduction saisonnée enparticulier dans l’aire préoptique. Des populations neuronales affectées par des réarrangementsmorphologiques ont également été identifiées. La PSA-NCAM est plus présente au contact des neurones àGnRH et à β-endorphine au moment le plus opportun pour l’activité du neurone suggérant que la plasticitéaffectant ces deux populations cellulaires serait essentielle au déroulement de la reproduction saisonnée. Lesneurones à kisspeptine sont également plus nombreux chez des animaux ayant un axe gonadotrope actifsuggérant que cette population serait un des derniers éléments activés par l’augmentation de la durée desécrétion de la mélatonine.Nos travaux montrent qu’un changement de photopériode est suffisant pour induire des remaniementsmorphologiques dans des régions hypothalamiques nécessaires à la synchronisation saisonnière de lareproduction chez les ovins. Ces remaniements affectent des populations neuronales spécifiques. / Cellular mechanisms induced by melatonin to synchronize seasonal reproduction are still unclear. Thescale and functional significance of neuronal plasticity induced by a photoperiodic transition have been studiedin brain regions involved in the seasonal synchronization of sheep reproduction. Our results suggested that achange of photoperiod alone seems able to induce variations of PSA-NCAM, a plasticity marker, in severalhypothalamic areas that may participate to the regulation of seasonal reproduction particularly in the preopticarea. Neuronal populations affected by morphological rearrangements have been identified. PSA-NCAM waspresent in contact with GnRH and β-endorphin neurons when the neuropeptide secreted by that population isrequired for the timing of seasonal breeding activity. Kisspeptin neurons were more numerous in ewes havingan active gonadotrope axis suggesting that kisspeptine is one of the last element activated by the increase of theduration of melatonin secretion.All together, our results suggest that a change of photoperiod alone is essential to induce morphologicalreorganizations in hypothalamic regions necessary for the seasonal synchronization of sheep reproduction.Plasticity affects specific neuronal populations.

This study is centered around the spatial distribution and age structure of PSA in a section of floodplain in the upper reaches of Clear Creek Watershed in east central Iowa. The study area topography, climate, soil, and pre-settlement tallgrass prairie landcover are representative of the headwaters of many Midwest watersheds, making the findings applicable in other parts of the region. Through this investigation, I aim to further understand the volume and age structure of PSA sediments deposited on the floodplain after Euroamerican settlement. This will be done through multiple methods: the collection and measurement of PSA in soil cores, visual and spatial analysis of land use and stream channel morphology, PSA volume calculations, and isotope geochemistry. Using 210Lead (Pb) and 137Cesium (Cs) isotope geochemistry to calculate age structures of the PSA will provide a more detailed, temporal resolution of physical data than erosion and deposition model predictions can generate. A detailed land use history will further facilitate the understanding of depositional processes that have occurred in the study area and region. By understanding the age structure of the sediment on the floodplain, as well as sediment volumes that are stored in floodplain headwaters, tangible connections can be made between agricultural land use and floodplain sedimentation rates and the impact (if any) assessed of potential conservation practices. This research is supported by the Intensively Managed Landscape Critical Zone Observatory (IML-CZO) of the National Science Foundation’s CZO network, which aims to understand how land use changes affect the long-term resilience of the critical zone, where water, atmosphere, ecosystems, soil, and bedrock interact.

Actualmente, el antígeno prostático específico (PSA) se considera el marcador más sensible para la detección de cáncer de próstata. Hasta la fecha anticuerpos monoclonales y policlonales se han utilizado para detectar el PSA debido a su alta especificidad y sensibilidad. Sin embargo, la producción de anticuerpos es lenta y cara. En el otro lado, los aptámeros con especificidad y afinidad iguales a los de los anticuerpos podría ser una forma alternativa para la detección de PSA. El objetivo de este trabajo es la selección de aptámeros contra el PSA. Aspectos fundamentales como la caracterización de la PSA, la evaluación de las estrategias de inmovilización, la preparación de la biblioteca de oligonucleótidos y de la cadena simple de ADN (ssDNA) han sido evaluados con el fin de alcanzar el objetivo principal de esta tesis. Finalmente, la selección de aptámeros contra el PSA y su uso potencial en aplicaciones de diagnóstica y terapéutica han sido descritos. / Currently, PSA is considered the most sensitive marker available for prostate cancer detection and for monitoring its progression. To date monoclonal/polyclonal antibodies have been used to detect PSA due to their high specificity and sensitivity. However, the production of antibodies is time-consuming and expensive. On the other hand aptamers with specificity and affinity equal to those of antibodies could be an alternative way for the detection of PSA. This work overviews the selection of aptamers against prostate specific antigen (PSA). Fundamental aspects such as the characterization of PSA, evaluation of immobilization strategies, the preparation of oligonucleotide library and single stranded DNA (ssDNA) have been evaluated in order to reach the main objective of this thesis. Finally, selection of DNA and RNA based aptamers against PSA and their potential use in diagnostic and therapeutic applications have been described

This thesis outlines a methodology for formatting and applying stress models, collecting visco-elastic material properties, and presenting the material data for use in adhesive joint designs. There are a number of models/theories that can be applied to the design of Pressure Sensitive Adhesive (PSA) joints. Unfortunately, few design engineers are familiar with these models and the models are not formatted in a manner that can easily be applied to joint designs. By developing a format that is based on the existing knowledge of the designer and presenting them in a familiar manner the theories/models can easily be used in joint designs. This technique was demonstrated with Beam-on-Elastic Foundation, Shear Lag, and Shape Factors. Design examples successfully demonstrated the application of all of these models in the analysis and design of simple adhesive joints. The material properties of PSAs are a function of loading/displacement rate, temperature, relative humidity, and stress state. The Arcan_m fixture was used to test VHB&trade; 4950 over a range loading and stress states including fixed load and displacement rates. Several bond widths were tested to determine the extent of the shape factor effect. A second fixture was used to determine the impact of gradient-tensile stresses on the failure strength. All of the collected data was used to generate design plots. The strength data was presented as allowable strength envelopes with respect to rate. The moduli were calculated from the load-displacement data and plotted with respect to the displacement rate. The failure strength from the fixed load and displacement data were used to transform from one loading case to the other and a plot was generated. These three plots were used in the design and analysis of several adhesive joints. The methods demonstrated in this thesis show a great deal of promises as a design tool, but there is still a large amount of work to be done. The design space for this material is much larger than what was covered by this work. Additional strength testing needs to be conducted to fully characterize the material for all key applications. The principle of time-temperature superposition, beam-on-elastic foundation, shear lag, and shape factors all need to be validated for this material. / Master of Science

O interesse em utilizar terras raras para investigar propriedades e funções de sistemas bioquímicos tanto quanto de determinar substâncias biológicas tem crescido em diferentes áreas, incluindo biomarcadores em imunologia (fluoroimunoensaios). Atualmente, o uso de terras raras no diagnóstico de diversas doenças tem se tornado muito importante com o desenvolvimento de kits de diagnóstico. Como característica principal, as terras raras podem apresentar longo tempo de vida, fotoestabilidade e bandas de emissão finas e bem definidas na região do visível, demonstrando vantagens únicas quando comparadas a outras espécies luminescentes. O presente trabalho teve como objetivo sintetizar molibdatos de terras raras pelo método de coprecipitação, assim como caracterizá-los através de técnicas como: difração de raios X, espectroscopia do infravermelho, análise termogravimétrica, microscopia eletrônica de varredura, microscopia eletrônica de transmissão e estudos de luminescência. Nesse trabalho foram desenvolvidos três diferentes estudos de síntese: a influência da variação da velocidade do dispersor no momento da precipitação; a influência do tratamento térmico na estrutura, morfologia e propriedades luminescentes; e a influência da concentração do íon dopante nas propriedades estruturais e espectroscópicas. Outro passo importante desse trabalho foi o de aminofuncionalizar as nanopartículas utilizando um organosilano (APTES) para recobrir e estabelecer pontos para que essas partículas pudessem se ligar a espécies biológicas. Foi comprovado pelos resultados das caracterizações que esse processo foi eficiente e a incorporação da sílica foi bem sucedida. O Antígeno Específico da Próstata (PSA) foi então ligado às nanopartículas funcionalizadas para possibilitar o diagnóstico de câncer de próstata através de fluoroimunoensaios e dessa forma, níveis de detecção foram estabelecidos. / The interest in using rare earths to investigate the properties and functions of biochemical systems as well as to determinate biological substances has increased in several fields, including biomarkers in immunology (fluoroimmunoassays). Nowadays the use of lanthanides in the diagnosis of various diseases have become more important through the development of commercial diagnostic kits. As main feature, these rare earths can show a long lifetime, photostability and emission bands of atomic like behavior and well defined, in the visible region, demonstrating unique advantages when compared to other luminescent species. The present work had as its goal to synthesize rare earth molybdates by the co-precipitation method as well as to characterize these materials by X-ray diffraction, near infrared spectroscopy, thermogravimetric analysis, scanning electronic microscopy, transmission electronic microscopy and luminescent studies. In this work, three different studied were developed: the influence of the vortex speed variation during co-precipitation in the structure of the final product, morphology and luminescence properties; the influence of the annealing temperature also in the structure, morphology and luminescence properties; and the influence of concentration of the doping in the luminescence properties. Another important step of this work was the functionalization of nanoparticles using an organosilane (APTES) to coat and establish points for binding the particles to biological species. It was proved that this process was very efficient by the characterization results and the silica incorporation was well succeeded. Specific prostatic cancer (PSA) was then linked to the functionalized nanoparticles to diagnostic prostatic cancer by fluoroimmunoassay and levels for detection were established.

O interesse em utilizar terras raras para investigar propriedades e funções de sistemas bioquímicos tanto quanto de determinar substâncias biológicas tem crescido em diferentes áreas, incluindo biomarcadores em imunologia (fluoroimunoensaios). Atualmente, o uso de terras raras no diagnóstico de diversas doenças tem se tornado muito importante com o desenvolvimento de kits de diagnóstico. Como característica principal, as terras raras podem apresentar longo tempo de vida, fotoestabilidade e bandas de emissão finas e bem definidas na região do visível, demonstrando vantagens únicas quando comparadas a outras espécies luminescentes. O presente trabalho teve como objetivo sintetizar molibdatos de terras raras pelo método de coprecipitação, assim como caracterizá-los através de técnicas como: difração de raios X, espectroscopia do infravermelho, análise termogravimétrica, microscopia eletrônica de varredura, microscopia eletrônica de transmissão e estudos de luminescência. Nesse trabalho foram desenvolvidos três diferentes estudos de síntese: a influência da variação da velocidade do dispersor no momento da precipitação; a influência do tratamento térmico na estrutura, morfologia e propriedades luminescentes; e a influência da concentração do íon dopante nas propriedades estruturais e espectroscópicas. Outro passo importante desse trabalho foi o de aminofuncionalizar as nanopartículas utilizando um organosilano (APTES) para recobrir e estabelecer pontos para que essas partículas pudessem se ligar a espécies biológicas. Foi comprovado pelos resultados das caracterizações que esse processo foi eficiente e a incorporação da sílica foi bem sucedida. O Antígeno Específico da Próstata (PSA) foi então ligado às nanopartículas funcionalizadas para possibilitar o diagnóstico de câncer de próstata através de fluoroimunoensaios e dessa forma, níveis de detecção foram estabelecidos. / The interest in using rare earths to investigate the properties and functions of biochemical systems as well as to determinate biological substances has increased in several fields, including biomarkers in immunology (fluoroimmunoassays). Nowadays the use of lanthanides in the diagnosis of various diseases have become more important through the development of commercial diagnostic kits. As main feature, these rare earths can show a long lifetime, photostability and emission bands of atomic like behavior and well defined, in the visible region, demonstrating unique advantages when compared to other luminescent species. The present work had as its goal to synthesize rare earth molybdates by the co-precipitation method as well as to characterize these materials by X-ray diffraction, near infrared spectroscopy, thermogravimetric analysis, scanning electronic microscopy, transmission electronic microscopy and luminescent studies. In this work, three different studied were developed: the influence of the vortex speed variation during co-precipitation in the structure of the final product, morphology and luminescence properties; the influence of the annealing temperature also in the structure, morphology and luminescence properties; and the influence of concentration of the doping in the luminescence properties. Another important step of this work was the functionalization of nanoparticles using an organosilane (APTES) to coat and establish points for binding the particles to biological species. It was proved that this process was very efficient by the characterization results and the silica incorporation was well succeeded. Specific prostatic cancer (PSA) was then linked to the functionalized nanoparticles to diagnostic prostatic cancer by fluoroimmunoassay and levels for detection were established.

Src signaling plays an important role in prostate cancer (PrCa) progression. It has previously been shown that Src interacts with androgen receptor (AR) and enhances AR transactivation. Although it has been shown that Src promotes AR activity, the underlying pathway has not been defined. To help characterize the Src-AR pathway, the cellular localizations of Src, p-Src, AR, pAR, and Prostate Specific Antigen (PSA, an AR target gene) were analyzed in androgen-dependent (AD) LNCaP cells and in androgen-independent (AI) castration-resistant C4-2B cells. Using sub-cellular fractionation, the data showed that treatment of AD cells with synthetic androgen R1881 increased p-Src, AR, pAR, and PSA in the nucleus, while the levels of c-Src remained unchanged. Treatment of AI cells with R1881 increased pSrc and AR in the nucleus, while the levels of c-Src and PSA remained unchanged. When using immunofluorescence microscopy, R1881 did not appear to increase the nuclear levels of p-Src or c-Src, so perhaps this technique is not as sensitive or quantitative as subcellular fractionation immunoblots. The presence of PSA in the nucleus was unexpected given its well proven role as a secreted protein. Nuclear PSA was observed upon androgen stimulation in AD and AI cells, and in the nucleus of AI cells upon androgen deprivation. Given PSA's ability to induce cell division and decrease apoptosis when transfected into cells, its presence in the nucleus may imply that PSA acts there to help induce tumorigenesis. The effect of Src on AR activity was further studied by transfection of a dominant negative src (SrcK298M) in AD and AI cells. Transfection with SrcK298M did not affect PSA expression in LNCaP cells, but strongly inhibited PSA levels in AI cells. Integrin signaling through Src was investigated in PrCa by ligand binding assay in AD and AI cells. The data showed that alpha v beta 3 integrin (but not alpha v beta 6) upon attachment to fibronectin or TGF-beta-latency associated peptide (TGF- beta-LAP) increases p-Src levels in AD and AI cells, while the levels of c-Src, PSA, and AKT remain unchanged. Thus, alpha v beta 3 integrin facilitates Src signaling, but the activation does not appear to affect AR transactivation. In conclusion, these data show that Src is required for AR activity and, consequently, PSA expression in AI prostate cancer cells, but not in AD cells. These data also suggest that the nuclear co-localization of p-Src, AR and PSA might allow macromolecular interactions, which can further enhance AR transactivation and promote disease progression. With respect to the switch in tumor progression from an AD to AI state, the data indicate that the integrin-Src pathway does not include AKT or PSA (and not AR by deduction), so perhaps other non-AR pathways help facilitate tumor growth at the AI state.

Background: The prostate specific antigen (PSA) test has been available for physicians and free of charge to residents in Saskatchewan since 1990. The PSA test witnessed great growth in use indicative of screening but it was unknown who was being tested, how often, which physicians were ordering PSA tests, or what the variation in utilization was in the population. Whether widespread use of the PSA test resulted in a stage shift among newly diagnosed prostate cancers or changed the clinical management of the disease was also unknown. The purpose of this research was to describe in detail how the PSA test is being used in the Saskatchewan population and investigate the impact of testing on the diagnosis and clinical management of prostate cancer during the PSA era.<p> Methods: Individual records were retrieved from the two labs in Saskatchewan capable of analyzing PSA serum samples. The PSA data represented almost all PSA tests in the population for the five-year period 1997-2001. The PSA data included date of the PSA test, a unique identifier of the men tested, test results including total PSA and the free-PSA amount (for November 1999 to December 2001), and an ID of the physician who ordered the test. This data was linked to the population-based Saskatchewan Cancer Registry to determine who had a previous or subsequent prostate cancer diagnosis and to secure tumour characteristics and clinical management data. This combined data was then linked to Saskatchewan Health data files to obtain information about biopsy procedures and to determine the geographic residence of men at the time of their PSA tests. De-identified data was returned for descriptive analysis.<p> Results: Over 60% of men aged 50 and over had at least one PSA test during 1997 to 2001. Even among men 40-49, 27% had at least one PSA test and there were over 5,300 tests done in men under 40 years of age. Sixteen percent of men 40-49 who had PSA tests had more than one and this percentage increased with age to 59.4% for men in their 70s. Over 80% of all PSA tests were ordered by general practitioners and there were significant geographic variations in testing patterns. Knowledge of the free-PSA-ratio, which began in 1999, reduced biopsy rates 4.7% and increased cancer detection 8.7% for men with total PSA test results in the 4.0-10.0ng/ml range, however these rates were also very age specific. The age-adjusted incidence rate of organ confined disease increased from 38.5 per 100,000 to 108.8 per 100,000 from 1985 to 2001. Almost 80% of prostate cancers were detected by needle biopsy in 2001 compared to only 34% in 1985, while 20% of cases in 2001 were treated with radical surgery compared to only 2% for 1985. Mortality rates have remained stable up to 2001.<p> Conclusion: PSA testing is very common in Saskatchewan consistent with extensive screening activity. Conflicting guidelines and the universal availability of the test has resulted in significant inappropriate testing and considerable variation of use. Most prostate cancers are now found by needle biopsy and are organ confined at the time of diagnosis. No benefit in prostate cancer mortality has yet been realized in Saskatchewan from extensive PSA testing.

Background: The prostate specific antigen (PSA) test has been available for physicians and free of charge to residents in Saskatchewan since 1990. The PSA test witnessed great growth in use indicative of screening but it was unknown who was being tested, how often, which physicians were ordering PSA tests, or what the variation in utilization was in the population. Whether widespread use of the PSA test resulted in a stage shift among newly diagnosed prostate cancers or changed the clinical management of the disease was also unknown. The purpose of this research was to describe in detail how the PSA test is being used in the Saskatchewan population and investigate the impact of testing on the diagnosis and clinical management of prostate cancer during the PSA era.<p> Methods: Individual records were retrieved from the two labs in Saskatchewan capable of analyzing PSA serum samples. The PSA data represented almost all PSA tests in the population for the five-year period 1997-2001. The PSA data included date of the PSA test, a unique identifier of the men tested, test results including total PSA and the free-PSA amount (for November 1999 to December 2001), and an ID of the physician who ordered the test. This data was linked to the population-based Saskatchewan Cancer Registry to determine who had a previous or subsequent prostate cancer diagnosis and to secure tumour characteristics and clinical management data. This combined data was then linked to Saskatchewan Health data files to obtain information about biopsy procedures and to determine the geographic residence of men at the time of their PSA tests. De-identified data was returned for descriptive analysis.<p> Results: Over 60% of men aged 50 and over had at least one PSA test during 1997 to 2001. Even among men 40-49, 27% had at least one PSA test and there were over 5,300 tests done in men under 40 years of age. Sixteen percent of men 40-49 who had PSA tests had more than one and this percentage increased with age to 59.4% for men in their 70s. Over 80% of all PSA tests were ordered by general practitioners and there were significant geographic variations in testing patterns. Knowledge of the free-PSA-ratio, which began in 1999, reduced biopsy rates 4.7% and increased cancer detection 8.7% for men with total PSA test results in the 4.0-10.0ng/ml range, however these rates were also very age specific. The age-adjusted incidence rate of organ confined disease increased from 38.5 per 100,000 to 108.8 per 100,000 from 1985 to 2001. Almost 80% of prostate cancers were detected by needle biopsy in 2001 compared to only 34% in 1985, while 20% of cases in 2001 were treated with radical surgery compared to only 2% for 1985. Mortality rates have remained stable up to 2001.<p> Conclusion: PSA testing is very common in Saskatchewan consistent with extensive screening activity. Conflicting guidelines and the universal availability of the test has resulted in significant inappropriate testing and considerable variation of use. Most prostate cancers are now found by needle biopsy and are organ confined at the time of diagnosis. No benefit in prostate cancer mortality has yet been realized in Saskatchewan from extensive PSA testing.