Development and application of DNA techniques for validating and improving pinniped diet estimates

Polymerase chain reaction techniques were developed and applied to identify DNA from .40 species of prey contained in fecal (scat) soft-part matrix collected at terrestrial sites used by Steller sea lions (Eumetopias jubatus) in British Columbia and the eastern Aleutian Islands, Alaska. Sixty percent more fish and cephalopod prey were identified by morphological analyses of hard parts compared with DNA analysis of soft parts (hard parts identified higher relative proportions of Ammodytes sp., Cottidae, and certain Gadidae). DNA identified 213 prey occurrences, of which 75 (35%) were undetected by hard parts (mainly Salmonidae, Pleuronectidae, Elasmobranchii, and Cephalopoda), and thereby increased species occurrences by 22% overall and species richness in 44% of cases (when comparing 110 scats that amplified prey DNA). Prey composition was identical within only 20% of scats. Overall, diet composition derived from both identification techniques combined did not differ significantly from hard-part identification alone, suggesting that past scat-based diet studies have not missed major dietary components. However, significant differences in relative diet contributions across scats (as identified using the two techniques separately) reflect passage rate differences between hard and soft digesta material and highlight certain hypothesized limitations in conventional morphological-based methods (e.g., differences in resistance to digestion, hard part regurgitation, partial and secondary prey consumption), as well as potential technical issues (e.g., resolution of primer efficiency and sensitivity and scat subsampling protocols). DNA analysis of salmon occurrence (from scat soft-part matrix and 238 archived salmon hard parts) provided species-level taxonomic resolution that could not be obtained by morphological identification and showed that Steller sea lions were primarily consuming pink (Oncorhynchus gorbuscha) and chum (Oncorhynchus keta) salmon. Notably, DNA from Atlantic salmon (Salmo salar) that likely originated from a distant fish farm was also detected in two scats from one site in the eastern Aleutian Islands. Overall, molecular techniques are valuable for identifying prey in the fecal remains of marine predators. Combining DNA and hard-part identification will effectively alleviate certain predicted biases and will ultimately enhance measures of diet richness, fisheries interactions (especially salmon-related ones), and the ecological role of pinnipeds and other marine predators, to the benefit of marine wildlife conservationists and fisheries managers.

Description of a new species of Calliostoma (Gastropoda, Calliostomatidae) from Southeastern Brazil

Calliostoma tupinamba is a new species from Southeastern Brazil, ranging from southern Rio de Janeiro to northern Sao Paulo, and found only on coastal islands, on rocks and sessile invertebrates at 3 to 5 meters of depth. Shell and soft part morphology is described here in detail. Calliostoma tupinamba is mainly characterized by a depressed trochoid shell; eight slightly convex whorls; a sharply suprasutural carina starting on the third whorl and forming a peripheral rounded keel; and a whitish, funnel-shaped and deep umbilicus, measuring about 5%-10% of maximum shell width. Calliostoma tupinamba resembles C. bullisi Clench & Turner, 1960 in shape, but differs from it in being taller and wider, having a smaller umbilicus and lacking a strong and large innermost spiral cord at its base. Finally, an identification key of Brazilian Calliostoma species is presented.

New molecular approaches to control rhabdomyosarcoma onset and metastasis in preclinical systems

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. The aim of this study was to identify molecular events involved in rhabdomyosarcoma onset for the development of new therapeutic approaches against specific molecular targets. BALB-p53neu mice develop pelvic rhabdomyosarcoma and combines the activation of HER-2/neu oncogene with the inactivation of an allele of p53 oncosuppressor gene. Gene expression profiling led to the identification of genes potentially involved in rhabdomyosarcoma genesis and therefore of candidate targets. The pattern of expression of p53, HER-2/neu, CDKN2A/p19ARF and IGF-2 suggested that these alterations might be involved in gender-, site- and strain-specific development of rhabdomyosarcoma. Other genes such as CDKN1A/p21 might be involved. The role of IGF-2, CDKN2A/p19ARF and CDKN1A/p21 in tumor growth was investigated with siRNA in murine rhabdomyosarcoma cells. Silencing of p19ARF and p21 induced inhibition of growth and of migration ability, indicating a possible pro-tumor and pro-metastatic role in rhabdomyosarcoma in absence of p53. In addition the autocrine IGF-2/IGF-1R loop found in early phases of cancer progression strengthens its key role in sustaining rhabdomyosarcoma growth. As rhabdomyosarcoma displays defective myogenic differentiation, a therapeutic approach aimed at enhancing myogenic differentiation of rhabdomyosarcoma cells. Forced expression of myogenin was able to restore myogenic differentiation, significantly reduced cell motility and impaired tumor growth and metastatic spread. IL-4 treatment increased rhabdomyosarcoma cell growth, decreased myogenin expression and promoted migration of cells lacking myogenin. Another approach was based on small kinase inhibitors. Agents specifically targeting members of the HER family (Lapatinib), of the IGF system (NVP-AEW541) or downstream signal transducers (NVP-BEZ235) were investigated in vitro in human rhabdomyosarcoma cell lines as therapeutic anti-tumor and anti-metastatic tools. The major effects were obtained with NVP-BEZ235 treatment that was able to strongly inhibit cell growth in vitro and showed anti-metastatic effects in vivo.

Synovial sarcomas usually metastasize after >5 years: a multicenter retrospective analysis with minimum follow-up of 10 years for survivors

Synovial sarcoma (SS) is a malignant soft tissue sarcoma with a poor prognosis because of late local recurrence and distant metastases. To our knowledge, no studies have minimum follow-up of 10 years that evaluate long-term outcomes for survivors.

Projector-based augmented reality for intuitive intraoperative guidance in image-guided 3D interstitial brachytherapy

PURPOSE: The aim of this study is to implement augmented reality in real-time image-guided interstitial brachytherapy to allow an intuitive real-time intraoperative orientation. METHODS AND MATERIALS: The developed system consists of a common video projector, two high-resolution charge coupled device cameras, and an off-the-shelf notebook. The projector was used as a scanning device by projecting coded-light patterns to register the patient and superimpose the operating field with planning data and additional information in arbitrary colors. Subsequent movements of the nonfixed patient were detected by means of stereoscopically tracking passive markers attached to the patient. RESULTS: In a first clinical study, we evaluated the whole process chain from image acquisition to data projection and determined overall accuracy with 10 patients undergoing implantation. The described method enabled the surgeon to visualize planning data on top of any preoperatively segmented and triangulated surface (skin) with direct line of sight during the operation. Furthermore, the tracking system allowed dynamic adjustment of the data to the patient's current position and therefore eliminated the need for rigid fixation. Because of soft-part displacement, we obtained an average deviation of 1.1 mm by moving the patient, whereas changing the projector's position resulted in an average deviation of 0.9 mm. Mean deviation of all needles of an implant was 1.4 mm (range, 0.3-2.7 mm). CONCLUSIONS: The developed low-cost augmented-reality system proved to be accurate and feasible in interstitial brachytherapy. The system meets clinical demands and enables intuitive real-time intraoperative orientation and monitoring of needle implantation.

TEMOZOLOMIDE AND BEVACIZUMAB THERAPY IN ADVANCED HEMANGIOPERICYTOMA/ SOLITARY FIBROUS TUMOR

Tumors comprising the spectrum of hemangiopericytoma/ malignant solitary fibrous tumor (HPC/SFT) are thought to arise from fibroblasts and represent a small subset of soft tissue sarcomas. Surgery is typically the treatment of choice for localized disease, with reported 10-year overall survival rates of 54-89% after complete surgical resection. However, for the approximately 20% of HPC/SFT patients who eventually develop local recurrences and/or distant metastases, options for effective treatment are limited and are poorly defined. Alternative therapeutic options are therefore needed for improved palliation and disease control. We hypothesize that HPC/SFT are a spectrum of soft tissue tumors with unique clinical, pathological, and molecular makeup and clinical behavior. HPC/SFT respond to unique therapeutic agents that specifically target aberrations specific to these tumors. We retrospectively reviewed the characteristics and the clinical outcomes for all HPC/SFT patients whose tumor specimens have been reviewed at the MD Anderson Cancer Center from January 1993 to June 2007 by a MD Anderson pathologist and were treated at the institution with available electronic medical records. We identified 128 patients, 79 with primary localized disease and 49 with recurrent and/or metastatic disease. For the 23 patients with advanced HPC/SFT who received adriamycin-based, gemcitabine based, or paclitaxel chemotherapy as first- or second-line therapy, the overall RECIST response rate was 0%. Most patients achieved a brief duration of disease stabilization on chemotherapy, with median progression-free survival (PFS) period of 4.6 months. For the 14 patients with advanced HPC/SFT who received temozolomide and bevacizumab systemic therapy, the overall RECIST response rate was 14%, with the overall Choi response rate of 79%. The median PFS for the cohort was 9.7 months with a median 6-month progression free rate of 78.6%. The most frequently observed toxic effect of temzolomide-bevacizumab therapy was myelosuppression. We have designed a phase II study to evaluate the safety and efficacy of temozolomide-bevaciumab in locally advanced, recurrent, and metastatic HPC/SFT in a prospective manner. Combination therapy with temozolomide and bevacizumab may be a potentially clinically beneficial regimen for advanced HPC/SFT patients.

Role of germ line p53 mutations in aneuploidy and immortalization of dermal fibroblasts from Li-Fraumeni cancer patients

Pedigree analysis of certain families with a high incidence of tumors suggests a genetic predisposition to cancer. Li and Fraumeni described a familial cancer syndrome that is characterized by multiple primary tumors, early age of onset, and marked variation in tumor type. Williams and Strong (1) demonstrated that at least 7% of childhood soft tissue sarcoma patients had family histories that is readily explained by a highly penetrant autosomal dominant gene. To characterize the mechanism for genetic predisposition to many tumor types in these families, we have studied genetic alterations in fibroblasts, a target tissue from patients with the Li-Fraumeni Syndrome (LFS).^ We have observed spontaneous changes in initially normal dermal fibroblasts from LFS patients as they are cultured in vitro. The cells acquire an altered morphology, chromosomal anomalies, and anchorage-independent growth. This aberrant behavior of fibroblasts from LFS patients had never been observed in fibroblasts from normal donors. In addition to these phenotypic alterations, patient fibroblasts spontaneously immortalize by 50 population doublings (pd) in culture; unlike controls that remain normal and senesce by 30-35 (2). At 50 pd, immortal fibroblasts from two patients were found to be susceptible to tumorigenic transformation by an activated T24 H-ras oncogene (3). Approximately 80% of the oncogene expressing transfectants were capable of forming tumors in nude mice within 2-3 weeks. p53 has been previously associated with immortalization of cells in culture and cooperation with ras in transfection assays. Therefore, patients' fibroblast and lymphocyte derived DNA was tested for point mutations in p53. It was shown that LFS patients inherited certain point mutations in one of the two p53 alleles (4). Further studies on the above LFS immortal fibroblasts have demonstrated loss of the remaining p53 allele concomitant with escape from senescence. While the loss of the second allele correlates with immortalization it is not sufficient to transformation by an activated H-ras or N-ras oncogene. These immortal fibroblasts are resistant to tumorigenic transformation by v-abl, v-src, c-neu or v-mos oncogene; implying that additional steps are required in the tumorigenic progression of LFS patients' fibroblasts.^ References. (1) Williams et al., J. Natl. Cancer Inst. 79:1213, 1987. (2) Bischoff et al., Cancer Res. 50:7979, 1990. (3) Bischoff et al., Oncogene 6:183, 1991. (4) Malkin et al., Science 250:1233, 1990. ^

A relation between screening masses and real-time rates

Thermal screening masses related to the conserved vector current are determined for the case that the current carries a non-zero Matsubara frequency, both in a weak-coupling approach and through lattice QCD. We point out that such screening masses are sensitive to the same infrared physics as light-cone real-time rates. In particular, on the perturbative side, the inhomogeneous Schrödinger equation determining screening correlators is shown to have the same general form as the equation implementing LPM resummation for the soft-dilepton and photon production rates from a hot QCD plasma. The static potential appearing in the equation is identical to that whose soft part has been determined up to NLO and on the lattice in the context of jet quenching. Numerical results based on this potential suggest that screening masses overshoot the free results (multiples of 2πT) more strongly than at zero Matsubara frequency. Four-dimensional lattice simulations in two-flavour QCD at temperatures of 250 and 340 MeV confirm the non-static screening masses at the 10% level. Overall our results lend support to studies of jet quenching based on the same potential at T ≳ 250 MeV.

A multivariate frailty model for disease recurrences and survival

A multivariate frailty hazard model is developed for joint-modeling of three correlated time-to-event outcomes: (1) local recurrence, (2) distant recurrence, and (3) overall survival. The term frailty is introduced to model population heterogeneity. The dependence is modeled by conditioning on a shared frailty that is included in the three hazard functions. Independent variables can be included in the model as covariates. The Markov chain Monte Carlo methods are used to estimate the posterior distributions of model parameters. The algorithm used in present application is the hybrid Metropolis-Hastings algorithm, which simultaneously updates all parameters with evaluations of gradient of log posterior density. The performance of this approach is examined based on simulation studies using Exponential and Weibull distributions. We apply the proposed methods to a study of patients with soft tissue sarcoma, which motivated this research. Our results indicate that patients with chemotherapy had better overall survival with hazard ratio of 0.242 (95% CI: 0.094 - 0.564) and lower risk of distant recurrence with hazard ratio of 0.636 (95% CI: 0.487 - 0.860), but not significantly better in local recurrence with hazard ratio of 0.799 (95% CI: 0.575 - 1.054). The advantages and limitations of the proposed models, and future research directions are discussed. ^

Parametric and structural self-adaptation of embedded systems using evolvable hardware

Los sistemas empotrados han sido concebidos tradicionalmente como sistemas de procesamiento específicos que realizan una tarea fija durante toda su vida útil. Para cumplir con requisitos estrictos de coste, tamaño y peso, el equipo de diseño debe optimizar su funcionamiento para condiciones muy específicas. Sin embargo, la demanda de mayor versatilidad, un funcionamiento más inteligente y, en definitiva, una mayor capacidad de procesamiento comenzaron a chocar con estas limitaciones, agravado por la incertidumbre asociada a entornos de operación cada vez más dinámicos donde comenzaban a ser desplegados progresivamente. Esto trajo como resultado una necesidad creciente de que los sistemas pudieran responder por si solos a eventos inesperados en tiempo diseño tales como: cambios en las características de los datos de entrada y el entorno del sistema en general; cambios en la propia plataforma de cómputo, por ejemplo debido a fallos o defectos de fabricación; y cambios en las propias especificaciones funcionales causados por unos objetivos del sistema dinámicos y cambiantes. Como consecuencia, la complejidad del sistema aumenta, pero a cambio se habilita progresivamente una capacidad de adaptación autónoma sin intervención humana a lo largo de la vida útil, permitiendo que tomen sus propias decisiones en tiempo de ejecución. Éstos sistemas se conocen, en general, como sistemas auto-adaptativos y tienen, entre otras características, las de auto-configuración, auto-optimización y auto-reparación. Típicamente, la parte soft de un sistema es mayoritariamente la única utilizada para proporcionar algunas capacidades de adaptación a un sistema. Sin embargo, la proporción rendimiento/potencia en dispositivos software como microprocesadores en muchas ocasiones no es adecuada para sistemas empotrados. En este escenario, el aumento resultante en la complejidad de las aplicaciones está siendo abordado parcialmente mediante un aumento en la complejidad de los dispositivos en forma de multi/many-cores; pero desafortunadamente, esto hace que el consumo de potencia también aumente. Además, la mejora en metodologías de diseño no ha sido acorde como para poder utilizar toda la capacidad de cómputo disponible proporcionada por los núcleos. Por todo ello, no se están satisfaciendo adecuadamente las demandas de cómputo que imponen las nuevas aplicaciones. La solución tradicional para mejorar la proporción rendimiento/potencia ha sido el cambio a unas especificaciones hardware, principalmente usando ASICs. Sin embargo, los costes de un ASIC son altamente prohibitivos excepto en algunos casos de producción en masa y además la naturaleza estática de su estructura complica la solución a las necesidades de adaptación. Los avances en tecnologías de fabricación han hecho que la FPGA, una vez lenta y pequeña, usada como glue logic en sistemas mayores, haya crecido hasta convertirse en un dispositivo de cómputo reconfigurable de gran potencia, con una cantidad enorme de recursos lógicos computacionales y cores hardware empotrados de procesamiento de señal y de propósito general. Sus capacidades de reconfiguración han permitido combinar la flexibilidad propia del software con el rendimiento del procesamiento en hardware, lo que tiene la potencialidad de provocar un cambio de paradigma en arquitectura de computadores, pues el hardware no puede ya ser considerado más como estático. El motivo es que como en el caso de las FPGAs basadas en tecnología SRAM, la reconfiguración parcial dinámica (DPR, Dynamic Partial Reconfiguration) es posible. Esto significa que se puede modificar (reconfigurar) un subconjunto de los recursos computacionales en tiempo de ejecución mientras el resto permanecen activos. Además, este proceso de reconfiguración puede ser ejecutado internamente por el propio dispositivo. El avance tecnológico en dispositivos hardware reconfigurables se encuentra recogido bajo el campo conocido como Computación Reconfigurable (RC, Reconfigurable Computing). Uno de los campos de aplicación más exóticos y menos convencionales que ha posibilitado la computación reconfigurable es el conocido como Hardware Evolutivo (EHW, Evolvable Hardware), en el cual se encuentra enmarcada esta tesis. La idea principal del concepto consiste en convertir hardware que es adaptable a través de reconfiguración en una entidad evolutiva sujeta a las fuerzas de un proceso evolutivo inspirado en el de las especies biológicas naturales, que guía la dirección del cambio. Es una aplicación más del campo de la Computación Evolutiva (EC, Evolutionary Computation), que comprende una serie de algoritmos de optimización global conocidos como Algoritmos Evolutivos (EA, Evolutionary Algorithms), y que son considerados como algoritmos universales de resolución de problemas. En analogía al proceso biológico de la evolución, en el hardware evolutivo el sujeto de la evolución es una población de circuitos que intenta adaptarse a su entorno mediante una adecuación progresiva generación tras generación. Los individuos pasan a ser configuraciones de circuitos en forma de bitstreams caracterizados por descripciones de circuitos reconfigurables. Seleccionando aquellos que se comportan mejor, es decir, que tienen una mejor adecuación (o fitness) después de ser evaluados, y usándolos como padres de la siguiente generación, el algoritmo evolutivo crea una nueva población hija usando operadores genéticos como la mutación y la recombinación. Según se van sucediendo generaciones, se espera que la población en conjunto se aproxime a la solución óptima al problema de encontrar una configuración del circuito adecuada que satisfaga las especificaciones. El estado de la tecnología de reconfiguración después de que la familia de FPGAs XC6200 de Xilinx fuera retirada y reemplazada por las familias Virtex a finales de los 90, supuso un gran obstáculo para el avance en hardware evolutivo; formatos de bitstream cerrados (no conocidos públicamente); dependencia de herramientas del fabricante con soporte limitado de DPR; una velocidad de reconfiguración lenta; y el hecho de que modificaciones aleatorias del bitstream pudieran resultar peligrosas para la integridad del dispositivo, son algunas de estas razones. Sin embargo, una propuesta a principios de los años 2000 permitió mantener la investigación en el campo mientras la tecnología de DPR continuaba madurando, el Circuito Virtual Reconfigurable (VRC, Virtual Reconfigurable Circuit). En esencia, un VRC en una FPGA es una capa virtual que actúa como un circuito reconfigurable de aplicación específica sobre la estructura nativa de la FPGA que reduce la complejidad del proceso reconfiguración y aumenta su velocidad (comparada con la reconfiguración nativa). Es un array de nodos computacionales especificados usando descripciones HDL estándar que define recursos reconfigurables ad-hoc: multiplexores de rutado y un conjunto de elementos de procesamiento configurables, cada uno de los cuales tiene implementadas todas las funciones requeridas, que pueden seleccionarse a través de multiplexores tal y como ocurre en una ALU de un microprocesador. Un registro grande actúa como memoria de configuración, por lo que la reconfiguración del VRC es muy rápida ya que tan sólo implica la escritura de este registro, el cual controla las señales de selección del conjunto de multiplexores. Sin embargo, esta capa virtual provoca: un incremento de área debido a la implementación simultánea de cada función en cada nodo del array más los multiplexores y un aumento del retardo debido a los multiplexores, reduciendo la frecuencia de funcionamiento máxima. La naturaleza del hardware evolutivo, capaz de optimizar su propio comportamiento computacional, le convierten en un buen candidato para avanzar en la investigación sobre sistemas auto-adaptativos. Combinar un sustrato de cómputo auto-reconfigurable capaz de ser modificado dinámicamente en tiempo de ejecución con un algoritmo empotrado que proporcione una dirección de cambio, puede ayudar a satisfacer los requisitos de adaptación autónoma de sistemas empotrados basados en FPGA. La propuesta principal de esta tesis está por tanto dirigida a contribuir a la auto-adaptación del hardware de procesamiento de sistemas empotrados basados en FPGA mediante hardware evolutivo. Esto se ha abordado considerando que el comportamiento computacional de un sistema puede ser modificado cambiando cualquiera de sus dos partes constitutivas: una estructura hard subyacente y un conjunto de parámetros soft. De esta distinción, se derivan dos lineas de trabajo. Por un lado, auto-adaptación paramétrica, y por otro auto-adaptación estructural. El objetivo perseguido en el caso de la auto-adaptación paramétrica es la implementación de técnicas de optimización evolutiva complejas en sistemas empotrados con recursos limitados para la adaptación paramétrica online de circuitos de procesamiento de señal. La aplicación seleccionada como prueba de concepto es la optimización para tipos muy específicos de imágenes de los coeficientes de los filtros de transformadas wavelet discretas (DWT, DiscreteWavelet Transform), orientada a la compresión de imágenes. Por tanto, el objetivo requerido de la evolución es una compresión adaptativa y más eficiente comparada con los procedimientos estándar. El principal reto radica en reducir la necesidad de recursos de supercomputación para el proceso de optimización propuesto en trabajos previos, de modo que se adecúe para la ejecución en sistemas empotrados. En cuanto a la auto-adaptación estructural, el objetivo de la tesis es la implementación de circuitos auto-adaptativos en sistemas evolutivos basados en FPGA mediante un uso eficiente de sus capacidades de reconfiguración nativas. En este caso, la prueba de concepto es la evolución de tareas de procesamiento de imagen tales como el filtrado de tipos desconocidos y cambiantes de ruido y la detección de bordes en la imagen. En general, el objetivo es la evolución en tiempo de ejecución de tareas de procesamiento de imagen desconocidas en tiempo de diseño (dentro de un cierto grado de complejidad). En este caso, el objetivo de la propuesta es la incorporación de DPR en EHW para evolucionar la arquitectura de un array sistólico adaptable mediante reconfiguración cuya capacidad de evolución no había sido estudiada previamente. Para conseguir los dos objetivos mencionados, esta tesis propone originalmente una plataforma evolutiva que integra un motor de adaptación (AE, Adaptation Engine), un motor de reconfiguración (RE, Reconfiguration Engine) y un motor computacional (CE, Computing Engine) adaptable. El el caso de adaptación paramétrica, la plataforma propuesta está caracterizada por: • un CE caracterizado por un núcleo de procesamiento hardware de DWT adaptable mediante registros reconfigurables que contienen los coeficientes de los filtros wavelet • un algoritmo evolutivo como AE que busca filtros wavelet candidatos a través de un proceso de optimización paramétrica desarrollado específicamente para sistemas caracterizados por recursos de procesamiento limitados • un nuevo operador de mutación simplificado para el algoritmo evolutivo utilizado, que junto con un mecanismo de evaluación rápida de filtros wavelet candidatos derivado de la literatura actual, asegura la viabilidad de la búsqueda evolutiva asociada a la adaptación de wavelets. En el caso de adaptación estructural, la plataforma propuesta toma la forma de: • un CE basado en una plantilla de array sistólico reconfigurable de 2 dimensiones compuesto de nodos de procesamiento reconfigurables • un algoritmo evolutivo como AE que busca configuraciones candidatas del array usando un conjunto de funcionalidades de procesamiento para los nodos disponible en una biblioteca accesible en tiempo de ejecución • un RE hardware que explota la capacidad de reconfiguración nativa de las FPGAs haciendo un uso eficiente de los recursos reconfigurables del dispositivo para cambiar el comportamiento del CE en tiempo de ejecución • una biblioteca de elementos de procesamiento reconfigurables caracterizada por bitstreams parciales independientes de la posición, usados como el conjunto de configuraciones disponibles para los nodos de procesamiento del array Las contribuciones principales de esta tesis se pueden resumir en la siguiente lista: • Una plataforma evolutiva basada en FPGA para la auto-adaptación paramétrica y estructural de sistemas empotrados compuesta por un motor computacional (CE), un motor de adaptación (AE) evolutivo y un motor de reconfiguración (RE). Esta plataforma se ha desarrollado y particularizado para los casos de auto-adaptación paramétrica y estructural. • En cuanto a la auto-adaptación paramétrica, las contribuciones principales son: – Un motor computacional adaptable mediante registros que permite la adaptación paramétrica de los coeficientes de una implementación hardware adaptativa de un núcleo de DWT. – Un motor de adaptación basado en un algoritmo evolutivo desarrollado específicamente para optimización numérica, aplicada a los coeficientes de filtros wavelet en sistemas empotrados con recursos limitados. – Un núcleo IP de DWT auto-adaptativo en tiempo de ejecución para sistemas empotrados que permite la optimización online del rendimiento de la transformada para compresión de imágenes en entornos específicos de despliegue, caracterizados por tipos diferentes de señal de entrada. – Un modelo software y una implementación hardware de una herramienta para la construcción evolutiva automática de transformadas wavelet específicas. • Por último, en cuanto a la auto-adaptación estructural, las contribuciones principales son: – Un motor computacional adaptable mediante reconfiguración nativa de FPGAs caracterizado por una plantilla de array sistólico en dos dimensiones de nodos de procesamiento reconfigurables. Es posible mapear diferentes tareas de cómputo en el array usando una biblioteca de elementos sencillos de procesamiento reconfigurables. – Definición de una biblioteca de elementos de procesamiento apropiada para la síntesis autónoma en tiempo de ejecución de diferentes tareas de procesamiento de imagen. – Incorporación eficiente de la reconfiguración parcial dinámica (DPR) en sistemas de hardware evolutivo, superando los principales inconvenientes de propuestas previas como los circuitos reconfigurables virtuales (VRCs). En este trabajo también se comparan originalmente los detalles de implementación de ambas propuestas. – Una plataforma tolerante a fallos, auto-curativa, que permite la recuperación funcional online en entornos peligrosos. La plataforma ha sido caracterizada desde una perspectiva de tolerancia a fallos: se proponen modelos de fallo a nivel de CLB y de elemento de procesamiento, y usando el motor de reconfiguración, se hace un análisis sistemático de fallos para un fallo en cada elemento de procesamiento y para dos fallos acumulados. – Una plataforma con calidad de filtrado dinámica que permite la adaptación online a tipos de ruido diferentes y diferentes comportamientos computacionales teniendo en cuenta los recursos de procesamiento disponibles. Por un lado, se evolucionan filtros con comportamientos no destructivos, que permiten esquemas de filtrado en cascada escalables; y por otro, también se evolucionan filtros escalables teniendo en cuenta requisitos computacionales de filtrado cambiantes dinámicamente. Este documento está organizado en cuatro partes y nueve capítulos. La primera parte contiene el capítulo 1, una introducción y motivación sobre este trabajo de tesis. A continuación, el marco de referencia en el que se enmarca esta tesis se analiza en la segunda parte: el capítulo 2 contiene una introducción a los conceptos de auto-adaptación y computación autonómica (autonomic computing) como un campo de investigación más general que el muy específico de este trabajo; el capítulo 3 introduce la computación evolutiva como la técnica para dirigir la adaptación; el capítulo 4 analiza las plataformas de computación reconfigurables como la tecnología para albergar hardware auto-adaptativo; y finalmente, el capítulo 5 define, clasifica y hace un sondeo del campo del hardware evolutivo. Seguidamente, la tercera parte de este trabajo contiene la propuesta, desarrollo y resultados obtenidos: mientras que el capítulo 6 contiene una declaración de los objetivos de la tesis y la descripción de la propuesta en su conjunto, los capítulos 7 y 8 abordan la auto-adaptación paramétrica y estructural, respectivamente. Finalmente, el capítulo 9 de la parte 4 concluye el trabajo y describe caminos de investigación futuros. ABSTRACT Embedded systems have traditionally been conceived to be specific-purpose computers with one, fixed computational task for their whole lifetime. Stringent requirements in terms of cost, size and weight forced designers to highly optimise their operation for very specific conditions. However, demands for versatility, more intelligent behaviour and, in summary, an increased computing capability began to clash with these limitations, intensified by the uncertainty associated to the more dynamic operating environments where they were progressively being deployed. This brought as a result an increasing need for systems to respond by themselves to unexpected events at design time, such as: changes in input data characteristics and system environment in general; changes in the computing platform itself, e.g., due to faults and fabrication defects; and changes in functional specifications caused by dynamically changing system objectives. As a consequence, systems complexity is increasing, but in turn, autonomous lifetime adaptation without human intervention is being progressively enabled, allowing them to take their own decisions at run-time. This type of systems is known, in general, as selfadaptive, and are able, among others, of self-configuration, self-optimisation and self-repair. Traditionally, the soft part of a system has mostly been so far the only place to provide systems with some degree of adaptation capabilities. However, the performance to power ratios of software driven devices like microprocessors are not adequate for embedded systems in many situations. In this scenario, the resulting rise in applications complexity is being partly addressed by rising devices complexity in the form of multi and many core devices; but sadly, this keeps on increasing power consumption. Besides, design methodologies have not been improved accordingly to completely leverage the available computational power from all these cores. Altogether, these factors make that the computing demands new applications pose are not being wholly satisfied. The traditional solution to improve performance to power ratios has been the switch to hardware driven specifications, mainly using ASICs. However, their costs are highly prohibitive except for some mass production cases and besidesthe static nature of its structure complicates the solution to the adaptation needs. The advancements in fabrication technologies have made that the once slow, small FPGA used as glue logic in bigger systems, had grown to be a very powerful, reconfigurable computing device with a vast amount of computational logic resources and embedded, hardened signal and general purpose processing cores. Its reconfiguration capabilities have enabled software-like flexibility to be combined with hardware-like computing performance, which has the potential to cause a paradigm shift in computer architecture since hardware cannot be considered as static anymore. This is so, since, as is the case with SRAMbased FPGAs, Dynamic Partial Reconfiguration (DPR) is possible. This means that subsets of the FPGA computational resources can now be changed (reconfigured) at run-time while the rest remains active. Besides, this reconfiguration process can be triggered internally by the device itself. This technological boost in reconfigurable hardware devices is actually covered under the field known as Reconfigurable Computing. One of the most exotic fields of application that Reconfigurable Computing has enabled is the known as Evolvable Hardware (EHW), in which this dissertation is framed. The main idea behind the concept is turning hardware that is adaptable through reconfiguration into an evolvable entity subject to the forces of an evolutionary process, inspired by that of natural, biological species, that guides the direction of change. It is yet another application of the field of Evolutionary Computation (EC), which comprises a set of global optimisation algorithms known as Evolutionary Algorithms (EAs), considered as universal problem solvers. In analogy to the biological process of evolution, in EHW the subject of evolution is a population of circuits that tries to get adapted to its surrounding environment by progressively getting better fitted to it generation after generation. Individuals become circuit configurations representing bitstreams that feature reconfigurable circuit descriptions. By selecting those that behave better, i.e., with a higher fitness value after being evaluated, and using them as parents of the following generation, the EA creates a new offspring population by using so called genetic operators like mutation and recombination. As generations succeed one another, the whole population is expected to approach to the optimum solution to the problem of finding an adequate circuit configuration that fulfils system objectives. The state of reconfiguration technology after Xilinx XC6200 FPGA family was discontinued and replaced by Virtex families in the late 90s, was a major obstacle for advancements in EHW; closed (non publicly known) bitstream formats; dependence on manufacturer tools with highly limiting support of DPR; slow speed of reconfiguration; and random bitstream modifications being potentially hazardous for device integrity, are some of these reasons. However, a proposal in the first 2000s allowed to keep investigating in this field while DPR technology kept maturing, the Virtual Reconfigurable Circuit (VRC). In essence, a VRC in an FPGA is a virtual layer acting as an application specific reconfigurable circuit on top of an FPGA fabric that reduces the complexity of the reconfiguration process and increases its speed (compared to native reconfiguration). It is an array of computational nodes specified using standard HDL descriptions that define ad-hoc reconfigurable resources; routing multiplexers and a set of configurable processing elements, each one containing all the required functions, which are selectable through functionality multiplexers as in microprocessor ALUs. A large register acts as configuration memory, so VRC reconfiguration is very fast given it only involves writing this register, which drives the selection signals of the set of multiplexers. However, large overheads are introduced by this virtual layer; an area overhead due to the simultaneous implementation of every function in every node of the array plus the multiplexers, and a delay overhead due to the multiplexers, which also reduces maximum frequency of operation. The very nature of Evolvable Hardware, able to optimise its own computational behaviour, makes it a good candidate to advance research in self-adaptive systems. Combining a selfreconfigurable computing substrate able to be dynamically changed at run-time with an embedded algorithm that provides a direction for change, can help fulfilling requirements for autonomous lifetime adaptation of FPGA-based embedded systems. The main proposal of this thesis is hence directed to contribute to autonomous self-adaptation of the underlying computational hardware of FPGA-based embedded systems by means of Evolvable Hardware. This is tackled by considering that the computational behaviour of a system can be modified by changing any of its two constituent parts: an underlying hard structure and a set of soft parameters. Two main lines of work derive from this distinction. On one side, parametric self-adaptation and, on the other side, structural self-adaptation. The goal pursued in the case of parametric self-adaptation is the implementation of complex evolutionary optimisation techniques in resource constrained embedded systems for online parameter adaptation of signal processing circuits. The application selected as proof of concept is the optimisation of Discrete Wavelet Transforms (DWT) filters coefficients for very specific types of images, oriented to image compression. Hence, adaptive and improved compression efficiency, as compared to standard techniques, is the required goal of evolution. The main quest lies in reducing the supercomputing resources reported in previous works for the optimisation process in order to make it suitable for embedded systems. Regarding structural self-adaptation, the thesis goal is the implementation of self-adaptive circuits in FPGA-based evolvable systems through an efficient use of native reconfiguration capabilities. In this case, evolution of image processing tasks such as filtering of unknown and changing types of noise and edge detection are the selected proofs of concept. In general, evolving unknown image processing behaviours (within a certain complexity range) at design time is the required goal. In this case, the mission of the proposal is the incorporation of DPR in EHW to evolve a systolic array architecture adaptable through reconfiguration whose evolvability had not been previously checked. In order to achieve the two stated goals, this thesis originally proposes an evolvable platform that integrates an Adaptation Engine (AE), a Reconfiguration Engine (RE) and an adaptable Computing Engine (CE). In the case of parametric adaptation, the proposed platform is characterised by: • a CE featuring a DWT hardware processing core adaptable through reconfigurable registers that holds wavelet filters coefficients • an evolutionary algorithm as AE that searches for candidate wavelet filters through a parametric optimisation process specifically developed for systems featured by scarce computing resources • a new, simplified mutation operator for the selected EA, that together with a fast evaluation mechanism of candidate wavelet filters derived from existing literature, assures the feasibility of the evolutionary search involved in wavelets adaptation In the case of structural adaptation, the platform proposal takes the form of: • a CE based on a reconfigurable 2D systolic array template composed of reconfigurable processing nodes • an evolutionary algorithm as AE that searches for candidate configurations of the array using a set of computational functionalities for the nodes available in a run time accessible library • a hardware RE that exploits native DPR capabilities of FPGAs and makes an efficient use of the available reconfigurable resources of the device to change the behaviour of the CE at run time • a library of reconfigurable processing elements featured by position-independent partial bitstreams used as the set of available configurations for the processing nodes of the array Main contributions of this thesis can be summarised in the following list. • An FPGA-based evolvable platform for parametric and structural self-adaptation of embedded systems composed of a Computing Engine, an evolutionary Adaptation Engine and a Reconfiguration Engine. This platform is further developed and tailored for both parametric and structural self-adaptation. • Regarding parametric self-adaptation, main contributions are: – A CE adaptable through reconfigurable registers that enables parametric adaptation of the coefficients of an adaptive hardware implementation of a DWT core. – An AE based on an Evolutionary Algorithm specifically developed for numerical optimisation applied to wavelet filter coefficients in resource constrained embedded systems. – A run-time self-adaptive DWT IP core for embedded systems that allows for online optimisation of transform performance for image compression for specific deployment environments characterised by different types of input signals. – A software model and hardware implementation of a tool for the automatic, evolutionary construction of custom wavelet transforms. • Lastly, regarding structural self-adaptation, main contributions are: – A CE adaptable through native FPGA fabric reconfiguration featured by a two dimensional systolic array template of reconfigurable processing nodes. Different processing behaviours can be automatically mapped in the array by using a library of simple reconfigurable processing elements. – Definition of a library of such processing elements suited for autonomous runtime synthesis of different image processing tasks. – Efficient incorporation of DPR in EHW systems, overcoming main drawbacks from the previous approach of virtual reconfigurable circuits. Implementation details for both approaches are also originally compared in this work. – A fault tolerant, self-healing platform that enables online functional recovery in hazardous environments. The platform has been characterised from a fault tolerance perspective: fault models at FPGA CLB level and processing elements level are proposed, and using the RE, a systematic fault analysis for one fault in every processing element and for two accumulated faults is done. – A dynamic filtering quality platform that permits on-line adaptation to different types of noise and different computing behaviours considering the available computing resources. On one side, non-destructive filters are evolved, enabling scalable cascaded filtering schemes; and on the other, size-scalable filters are also evolved considering dynamically changing computational filtering requirements. This dissertation is organized in four parts and nine chapters. First part contains chapter 1, the introduction to and motivation of this PhD work. Following, the reference framework in which this dissertation is framed is analysed in the second part: chapter 2 features an introduction to the notions of self-adaptation and autonomic computing as a more general research field to the very specific one of this work; chapter 3 introduces evolutionary computation as the technique to drive adaptation; chapter 4 analyses platforms for reconfigurable computing as the technology to hold self-adaptive hardware; and finally chapter 5 defines, classifies and surveys the field of Evolvable Hardware. Third part of the work follows, which contains the proposal, development and results obtained: while chapter 6 contains an statement of the thesis goals and the description of the proposal as a whole, chapters 7 and 8 address parametric and structural self-adaptation, respectively. Finally, chapter 9 in part 4 concludes the work and describes future research paths.

Evaluation of the antioxidant activity and antitumor activity of marine invertebrates extracts

Dissertação de Mestrado, Biologia Marinha, Faculdade de Ciências e Tecnologias, Universidade do Algarve, 2014

Loss of pulp sensitivity and pain as the first symptoms of a Ewing's sarcoma in the right maxillary sinus and alveolar process: report of a case

This case report describes the diagnosis and treatment of a Ewing's sarcoma in the right maxillary sinus and alveolar bone of a 19-year-old female patient. The first clinical symptoms were a loss of sensitivity of the premolars and first molar in the right maxilla and acute pain located in the area of these teeth. Initially, the referring dentist had treated these findings as an acute apical periodontitis with root canal medication. Because swellings on the palatal and buccal aspects of the teeth occurred and could not be treated with incision and drainage, the dentist referred the patient. Cone-beam computed tomography revealed a proliferation of soft tissue in the right maxillary sinus, with a radiopaque material at the tip of the mesiobuccal root of the first molar and resorptive signs of the mesiobuccal and distobuccal roots of the first molar. The palatal cortical bone of the right alveolar process seemed to be intact. After explorative surgery with biopsies from the buccal, palatal, and sinus proliferation areas, the pathologist diagnosed the lesion as a Ewing's sarcoma. Treatment of the patient consisted of initial chemotherapy, hemimaxillectomy, and postsurgical chemoradiotherapy.

Utility of sarcoma-specific fusion gene analysis in paraffin-embedded material for routine diagnosis at a specialist centre.

AIMS: Diagnosis of soft tissue sarcomas can be difficult. It can be aided by detection of specific genetic aberrations in many cases. This study assessed the utility of a molecular genetics/cytogenetics service as part of the routine diagnostic service at the Royal Marsden Hospital. METHODS: A retrospective audit was performed over a 15-month period to evaluate the diagnostic usefulness for soft tissue sarcomas with translocations of fluorescence in situ hybridisation (FISH) and reverse-transcriptase PCR (RT-PCR) in paraffin-embedded (PE) material. Results were compared with histology, and evaluated. RESULTS: Molecular investigations were performed on PE material in 158 samples (total 194 RT-PCR and 174 FISH tests), of which 85 were referral cases. Synovial sarcoma, Ewing sarcoma and low-grade fibromyxoid sarcoma were the most commonly tested tumours. Myxoid liposarcoma showed the best histological and molecular concordance, and alveolar rhabdomyosarcoma showed the best agreement between methods. FISH had a higher sensitivity for detecting tumours (73%, compared with 59% for RT-PCR) with a better success rate than RT-PCR, although the latter was specific in identifying the partner gene for each fusion. In particular, referral blocks in which methods of tissue fixation and processing were not certain resulted in higher RT-PCR failure rates. CONCLUSIONS: FISH and RT-PCR on PE tissue are practical and effective ancillary tools in the diagnosis of soft tissue sarcomas. They are useful in confirming doubtful histological diagnoses and excluding malignant diagnoses. PCR is less sensitive than FISH, and the use of both techniques is optimal for maximising the detection rate of translocation-positive sarcomas.

Maxillo-mandibular counter-clockwise rotation and mandibular advancement with TMJ Concepts (R) total joint prostheses Part IV - Soft tissue response

The purpose of this Study was to evaluate Soft tissue response to rnaxillo-mandibular counter-clockwise rotation, with TMJ reconstruction and mandibular advancement using TMJ Concepts (R) total joint prostheses, and maxillary osteotomies in 44 females. All patients were operated at Baylor University Medical Center, Dallas TX, USA, by one Surgeon (Wolford). Eighteen patients had genioplasties with either porous block hydroxyapatite or hard tissue replacement implants (Group 2) 26 had no genioplasty (Group 1). Surgically, the maxilla moved forward and upward by counter-clockwise maxillo-mandibular rotation with greater horizontal movement in Group 2. Vertically, both groups showed diversity of maxillo-mandibular mean movement. Group I showed a consistent 1:0.97 ratio of hard to soft tissue advancement at pogonion; Group 2 results were less consistent, with ratios between 1:0.84 and 1:1.02. Horizontal changes in upper lip morphology after maxillary advancement/impaction, VY closure, and alar base cinch sutures showed greater movement in both groups, than observed in hard tissue. Counter-clockwise rotation of the maxillo-mandibular complex using TMJ Concepts total joint prostheses resulted in similar soft tissue response as previously reported for traditional maxillo-mandibular advancement without counter-clockwise rotation of the occlusal plane. The association of chin implants, in the present sample, showed higher variability of soft tissue response.