Modification of mutagen sensitivity by chemopreventive agents {\it in vitro\/}

The clinical application of chemopreventive agents is expected to prevent the appearance of cancer by arresting carcinogenesis or reversing it in the precancerous stages. The hypothesis of the present investigations was that chemopreventive agents (retinoids and antioxidant vitamins) may counteract the clastogenic effects of bleomycin in vitro in both lymphoblastoid cell lines and primary lymphocyte cultures and that a similar phenomenon can be detected in lymphocytes from individuals treated with 13-cis-retinoic acid. The efficacy of 13-cis-retinoic acid, n-(4-hydroxyphenyl)-retinamide, ascorbic acid, n-acetyl-l-cysteine, alpha-tocopherol, and alpha-tocopherol-acid succinate was tested against bleomycin-induced chromosomal breakage.^ The results provided direct evidence of the concentration-related protective effects of these agents against bleomycin-induced clastogenicity in cultures of human lymphoblastoid cell lines in vitro. Similar anticlastogenic protection was demonstrated with 13-cis-retinoic acid, ascorbic acid, n-acetyl-l-cysteine, and alpha-tocopherol-acid succinate in primary lymphocyte cultures in vitro. The in vitro anticlastogenic effect of 13-cis-retinoic acid was also demonstrated in lymphocyte cultures from peripheral blood samples from patients treated with this retinoid.^ An important consideration is that the concentrations used in the present investigations are comparable to those achieved in clinical situations.^ The in vitro anticlastogenic effect of these retinoids and antioxidants may constitute an important element of their chemopreventive properties. The results corroborate the hypothesis that these compounds may be effective in clinical chemoprevention trials. The bleomycin-assay may also be used as a short-term test to evaluate the antimutagenic effects of various agents. ^

Design, Synthesis and Development of Transporter Targeting Agents for Image-guided Therapy and Drug Delivery

The purpose of this study was to design, synthesize and develop novel transporter targeting agents for image-guided therapy and drug delivery. Two novel agents, N4-guanine (N4amG) and glycopeptide (GP) were synthesized for tumor cell proliferation assessment and cancer theranostic platform, respectively. N4amG and GP were synthesized and radiolabeled with 99mTc and 68Ga. The chemical and radiochemical purities as well as radiochemical stabilities of radiolabeled N4amG and GP were tested. In vitro stability assessment showed both 99mTc-N4amG and 99mTc-GP were stable up to 6 hours, whereas 68Ga-GP was stable up to 2 hours. Cell culture studies confirmed radiolabeled N4amG and GP could penetrate the cell membrane through nucleoside transporters and amino acid transporters, respectively. Up to 40% of intracellular 99mTc-N4amG and 99mTc-GP was found within cell nucleus following 2 hours of incubation. Flow cytometry analysis revealed 99mTc-N4amG was a cell cycle S phase-specific agent. There was a significant difference of the uptake of 99mTc-GP between pre- and post- paclitaxel-treated cells, which suggests that 99mTc-GP may be useful in chemotherapy treatment monitoring. Moreover, radiolabeled N4amG and GP were tested in vivo using tumor-bearing animal models. 99mTc-N4amG showed an increase in tumor-to-muscle count density ratios up to 5 at 4 hour imaging. Both 99mTc-labeled agents showed decreased tumor uptake after paclitaxel treatment. Immunohistochemistry analysis demonstrated that the uptake of 99mTc-N4amG was correlated with Ki-67 expression. Both 99mTc-N4amG and 99mTc-GP could differentiate between tumor and inflammation in animal studies. Furthermore, 68Ga-GP was compared to 18F-FDG in rabbit PET imaging studies. 68Ga-GP had lower tumor standardized uptake values (SUV), but similar uptake dynamics, and different biodistribution compared with 18F-FDG. Finally, to demonstrate that GP can be a potential drug carrier for cancer theranostics, several drugs, including doxorubicin, were selected to be conjugated to GP. Imaging studies demonstrated that tumor uptake of GP-drug conjugates was increased as a function of time. GP-doxorubicin (GP-DOX) showed a slow-release pattern in in vitro cytotoxicity assay and exhibited anti-cancer efficacy with reduced toxicity in in vivo tumor growth delay study. In conclusion, both N4amG and GP are transporter-based targeting agents. Radiolabeled N4amG can be used for tumor cell proliferation assessment. GP is a potential agent for image-guided therapy and drug delivery.

Intrinsic oxidative stress in cancer cells: A biochemical basis for therapeutic selectivity using ROS -generating agents

A major goal of chemotherapy is to selectively kill cancer cells while minimizing toxicity to normal cells. Identifying biological differences between cancer and normal cells is essential in designing new strategies to improve therapeutic selectivity. Superoxide dismutases (SOD) are crucial antioxidant enzymes required for the elimination of superoxide (O2·− ), a free radical produced during normal cellular metabolism. Previous studies in our laboratory demonstrated that 2-methoxyestradiol (2-ME), an estradiol derivative, inhibits the function of SOD and selectively kills human leukemia cells without exhibiting significant cytotoxicity in normal lymphocytes. The present work was initiated to examine the biochemical basis for the selective anticancer activity of 2-ME. Investigations using two-parameter flow cytometric analyses and ROS scavengers established that O2·− is a primary and essential mediator of 2-ME-induced apoptosis in cancer cells. In addition, experiments using SOD overexpression vectors and SOD knockout cells found that SOD is a critical target of 2-ME. Importantly, the administration of 2-ME resulted in the selective accumulation of O 2·− and apoptosis in leukemia and ovarian cancer cells. The preferential activity of 2-ME was found to be due to increased intrinsic oxidative stress in these cancer cells versus their normal counterparts. This intrinsic oxidative stress was associated with the upregulation of the antioxidant enzymes SOD and catalase as a mechanism to cope with the increase in ROS. Furthermore, oxygen consumption experiments revealed that normal lymphocytes decrease their respiration rate in response to 2-ME-induced oxidative stress, while human leukemia cells seem to lack this regulatory mechanism. This leads to an uncontrolled production of O2·−, severe accumulation of ROS, and ultimately ROS-mediated apoptosis in leukemia cells treated with 2-ME. The biochemical differences between cancer and normal cells identified here provide a basis for the development of drug combination strategies using 2-ME with other ROS-generating agents to enhance anticancer activity. The effectiveness of such a combination strategy in killing cancer cells was demonstrated by the use of 2-ME with agents/modalities such as ionizing radiation and doxorubicin. Collectively, the data presented here strongly suggests that 2-ME may have important clinical implications for the selective killing of cancer cells. ^

A role for p53 in sensing DNA damage and triggering apoptotic responses to anticancer agents

The p53 tumor suppressor protein plays a major role in cellular responses to anticancer agents that target DNA. DNA damage triggers the accumulation of p53, resulting in the transactivation of genes, which induce cell cycle arrest to allow for repair of the damaged DNA, or signal apoptosis. The exact role that p53 plays in sensing DNA damage and the functional consequences remain to be investigated. The main goal of this project was to determine if p53 is directly involved in sensing DNA damage induced by anticancer agents and in mediating down-stream cellular responses. This was tested in two experimental models of DNA damage: (1) DNA strand termination caused by anticancer nucleoside analogs and (2) oxidative DNA damage induced by reactive oxygen species (ROS). Mobility shift assays demonstrated that p53 and DNA-PK/Ku form a complex that binds DNA containing the anticancer nucleoside analog gemcitabine monophosphate in vitro. Binding of the p53-DNA-PK/Ku complex to the analog-containing DNA inhibited DNA strand elongation. Furthermore, treatment of cells with gemcitabine resulted in the induction of apoptosis, which was associated with the accumulation of p53 protein, its phosphorylation, and nuclear localization, suggesting the activation of p53 to trigger apoptosis following gemcitabine induced DNA strand termination. The role of p53 as a DNA damage sensor was further demonstrated in response to oxidative DNA damage. Protein pull-down assays demonstrated that p53 complexes with OGG1 and APE, and binds DNA containing the oxidized DNA base 8-oxoG. Importantly, p53 enhances the activities of APE and OGG1 in excising the 8-oxoG residue as shown by functional assays in vitro. This correlated with the more rapid removal of 8-oxoG from DNA in intact cells with wild-type p53 exposed to exogenous ROS stress. Interestingly, persistent exposure to ROS resulted in the accelerated onset of apoptosis in cells with wild-type p53 when compared to isogenic cells lacking p53. Apoptosis in p53+/+ cells was associated with accumulation and phosphorylation of p53 and its nuclear localization. Taken together, these results indicate that p53 plays a key role in sensing DNA damage induced by anticancer nucleoside analogs and ROS, and in triggering down-stream apoptotic responses. This study provides new mechanistic insights into the functions of p53 in cellular responses to anticancer agents. ^

Modelización de performance de aprendizaje en sistemas tutores inteligentes (Software Agents)

Fil: Palacios, Analía Mirta. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Cloud Computing Service for Managing Large Medical Image Data-Sets Using Balanced Collaborative Agents

Managing large medical image collections is an increasingly demanding important issue in many hospitals and other medical settings. A huge amount of this information is daily generated, which requires robust and agile systems. In this paper we present a distributed multi-agent system capable of managing very large medical image datasets. In this approach, agents extract low-level information from images and store them in a data structure implemented in a relational database. The data structure can also store semantic information related to images and particular regions. A distinctive aspect of our work is that a single image can be divided so that the resultant sub-images can be stored and managed separately by different agents to improve performance in data accessing and processing. The system also offers the possibility of applying some region-based operations and filters on images, facilitating image classification. These operations can be performed directly on data structures in the database.

User-centric need-driven affect modeling for spoken conversational agents: design and evaluation

It is easy to get frustrated at spoken conversational agents (SCAs), perhaps because they seem to be callous. By and large, the quality of human-computer interaction is affected due to the inability of the SCAs to recognise and adapt to user emotional state. Now with the mass appeal of artificially-mediated communication, there has been an increasing need for SCAs to be socially and emotionally intelligent, that is, to infer and adapt to their human interlocutors’ emotions on the fly, in order to ascertain an affective, empathetic and naturalistic interaction. An enhanced quality of interaction would reduce users’ frustrations and consequently increase their satisfactions. These reasons have motivated the development of SCAs towards including socio-emotional elements, turning them into affective and socially-sensitive interfaces. One barrier to the creation of such interfaces has been the lack of methods for modelling emotions in a task-independent environment. Most emotion models for spoken dialog systems are task-dependent and thus cannot be used “as-is” in different applications. This Thesis focuses on improving this, in which it concerns computational modeling of emotion, personality and their interrelationship for task-independent autonomous SCAs. The generation of emotion is driven by needs, inspired by human’s motivational systems. The work in this Thesis is organised in three stages, each one with its own contribution. The first stage involved defining, integrating and quantifying the psychological-based motivational and emotional models sourced from. Later these were transformed into a computational model by implementing them into software entities. The computational model was then incorporated and put to test with an existing SCA host, a HiFi-control agent. The second stage concerned automatic prediction of affect, which has been the main challenge towards the greater aim of infusing social intelligence into the HiFi agent. In recent years, studies on affect detection from voice have moved on to using realistic, non-acted data, which is subtler. However, it is more challenging to perceive subtler emotions and this is demonstrated in tasks such as labelling and machine prediction. In this stage, we attempted to address part of this challenge by considering the roles of user satisfaction ratings and conversational/dialog features as the respective target and predictors in discriminating contentment and frustration, two types of emotions that are known to be prevalent within spoken human-computer interaction. The final stage concerned the evaluation of the emotional model through the HiFi agent. A series of user studies with 70 subjects were conducted in a real-time environment, each in a different phase and with its own conditions. All the studies involved the comparisons between the baseline non-modified and the modified agent. The findings have gone some way towards enhancing our understanding of the utility of emotion in spoken dialog systems in several ways; first, an SCA should not express its emotions blindly, albeit positive. Rather, it should adapt its emotions to user states. Second, low performance in an SCA may be compensated by the exploitation of emotion. Third, the expression of emotion through the exploitation of prosody could better improve users’ perceptions of an SCA compared to exploiting emotions through just lexical contents. Taken together, these findings not only support the success of the emotional model, but also provide substantial evidences with respect to the benefits of adding emotion in an SCA, especially in mitigating users’ frustrations and ultimately improving their satisfactions. Resumen Es relativamente fácil experimentar cierta frustración al interaccionar con agentes conversacionales (Spoken Conversational Agents, SCA), a menudo porque parecen ser un poco insensibles. En general, la calidad de la interacción persona-agente se ve en cierto modo afectada por la incapacidad de los SCAs para identificar y adaptarse al estado emocional de sus usuarios. Actualmente, y debido al creciente atractivo e interés de dichos agentes, surge la necesidad de hacer de los SCAs unos seres cada vez más sociales y emocionalmente inteligentes, es decir, con capacidad para inferir y adaptarse a las emociones de sus interlocutores humanos sobre la marcha, de modo que la interacción resulte más afectiva, empática y, en definitiva, natural. Una interacción mejorada en este sentido permitiría reducir la posible frustración de los usuarios y, en consecuencia, mejorar el nivel de satisfacción alcanzado por los mismos. Estos argumentos justifican y motivan el desarrollo de nuevos SCAs con capacidades socio-emocionales, dotados de interfaces afectivas y socialmente sensibles. Una de las barreras para la creación de tales interfaces ha sido la falta de métodos de modelado de emociones en entornos independientes de tarea. La mayoría de los modelos emocionales empleados por los sistemas de diálogo hablado actuales son dependientes de tarea y, por tanto, no pueden utilizarse "tal cual" en diferentes dominios o aplicaciones. Esta tesis se centra precisamente en la mejora de este aspecto, la definición de modelos computacionales de las emociones, la personalidad y su interrelación para SCAs autónomos e independientes de tarea. Inspirada en los sistemas motivacionales humanos en el ámbito de la psicología, la tesis propone un modelo de generación/producción de la emoción basado en necesidades. El trabajo realizado en la presente tesis está organizado en tres etapas diferenciadas, cada una con su propia contribución. La primera etapa incluyó la definición, integración y cuantificación de los modelos motivacionales de partida y de los modelos emocionales derivados a partir de éstos. Posteriormente, dichos modelos emocionales fueron plasmados en un modelo computacional mediante su implementación software. Este modelo computacional fue incorporado y probado en un SCA anfitrión ya existente, un agente con capacidad para controlar un equipo HiFi, de alta fidelidad. La segunda etapa se orientó hacia el reconocimiento automático de la emoción, aspecto que ha constituido el principal desafío en relación al objetivo mayor de infundir inteligencia social en el agente HiFi. En los últimos años, los estudios sobre reconocimiento de emociones a partir de la voz han pasado de emplear datos actuados a usar datos reales en los que la presencia u observación de emociones se produce de una manera mucho más sutil. El reconocimiento de emociones bajo estas condiciones resulta mucho más complicado y esta dificultad se pone de manifiesto en tareas tales como el etiquetado y el aprendizaje automático. En esta etapa, se abordó el problema del reconocimiento de las emociones del usuario a partir de características o métricas derivadas del propio diálogo usuario-agente. Gracias a dichas métricas, empleadas como predictores o indicadores del grado o nivel de satisfacción alcanzado por el usuario, fue posible discriminar entre satisfacción y frustración, las dos emociones prevalentes durante la interacción usuario-agente. La etapa final corresponde fundamentalmente a la evaluación del modelo emocional por medio del agente Hifi. Con ese propósito se llevó a cabo una serie de estudios con usuarios reales, 70 sujetos, interaccionando con diferentes versiones del agente Hifi en tiempo real, cada uno en una fase diferente y con sus propias características o capacidades emocionales. En particular, todos los estudios realizados han profundizado en la comparación entre una versión de referencia del agente no dotada de ningún comportamiento o característica emocional, y una versión del agente modificada convenientemente con el modelo emocional propuesto. Los resultados obtenidos nos han permitido comprender y valorar mejor la utilidad de las emociones en los sistemas de diálogo hablado. Dicha utilidad depende de varios aspectos. En primer lugar, un SCA no debe expresar sus emociones a ciegas o arbitrariamente, incluso aunque éstas sean positivas. Más bien, debe adaptar sus emociones a los diferentes estados de los usuarios. En segundo lugar, un funcionamiento relativamente pobre por parte de un SCA podría compensarse, en cierto modo, dotando al SCA de comportamiento y capacidades emocionales. En tercer lugar, aprovechar la prosodia como vehículo para expresar las emociones, de manera complementaria al empleo de mensajes con un contenido emocional específico tanto desde el punto de vista léxico como semántico, ayuda a mejorar la percepción por parte de los usuarios de un SCA. Tomados en conjunto, los resultados alcanzados no sólo confirman el éxito del modelo emocional, sino xv que constituyen además una evidencia decisiva con respecto a los beneficios de incorporar emociones en un SCA, especialmente en cuanto a reducir el nivel de frustración de los usuarios y, en última instancia, mejorar su satisfacción.

Leadership and project management competences in executive women: different styles from the agents' perceptions

The exercise of management and leadership are key aspects to achieve objectives, goals and relationships in the current knowledge society marked by increasingly competitive environments in which cognitive factors, creativity, knowledge and information determine the success of organizations. Both concepts have been historically associated with the male domain because of the underrepresentation of women in managerial positions. However, the increasing participation of women in the workplace has led to the development of an extensive literature on the possible existence of differences between the styles of male and female leadership, although it has not been addressed from the analysis of competences associated with each sex. Through a participatory process the abilities and skills related to women managers are analyzed and the differences in leadership styles. The results indicate that women particularly value the skills associated with human relationships, and that female leadership style tends to be transformational.

Analysis of behavior directed towards changing the innovation agents. Case study of the Canary Islands

In 2005 the Directorate General for Industrial Development and Technological Innovation of the Canary Islands proceeded to carry out a project to measure the behavioral skills of various government agencies and companies in the Canary Islands in order to prepare a White Paper to assess the most effective measures for the stimulation of innovation in this autonomous community and to facilitate the objectives of public subsidies. This paper shows a portion of the work performed comparing the activity oriented towards innovation and the one aimed at sustaining the status quo of the organizations in the sample.

I feel you: Towards affect-sensitive domotic Spoken Conversational Agents

We describe the work on infusion of emotion into limitedtask autonomous spoken conversational agents (SCAs) situated in the domestic environment, using a Need-inspired task-independentEmotion model (NEMO). In order to demonstrate the generation of a?ect through the use of the model, we describe the work of integrating it with a naturallanguage mixed-initiative HiFi-control SCA. NEMO and the host system communicates externally, removing the need for the Dialog Manager to be modi?ed as done in most existing dialog systems, in order to be adaptive. We also summarize the work on automatic a?ect prediction, namely frustration and contentment from dialog features, a non-conventional source, in the attempt of moving towards a more user-centric approach.

Los agentes de la edificación desde el punto de vista de la Gestión Integral de Proyectos: diferencias y semejanzas entre la Legislación Española y los Estándares Internacionales = Expert agents in the Global Development of a building project: differences and similarities between Spanish and International contexts.

Desde los años 60, crece en Europa y Estados Unidos la preocupación y la necesidad de mejorar los procesos de gerencia de los proyectos de construcción al volverse estos más complejos. Esto ha llevado a la continua aparición de nuevos profesionales desde la fecha citada hasta nuestros días. De ahí la complejidad de conocer las cualidades de cada uno de ellos, así como las funciones a realizar o la formación que deben tener para poder desarrollar el puesto de trabajo según el papel que desempeñan para cada actividad. Muchos agentes son los que pueden intervenir en la edificación, muchas son las funciones que llevan a cabo estos agentes, muchas son las habilidades que se necesitan para realizar estas misiones, y una buena gestión de la edificación es la que hay que desarrollar para lograr el gran éxito. El presente trabajo fin de máster, dirigido a arquitectos, arquitectos técnicos, ingenieros, abogados, economistas y todos los profesionales del sector inmobiliario y de la construcción, trata de resolver todas aquellas dudas sobre los diferentes sujetos que estarán presentes desde la definición del proyecto en la fase inicial hasta el final de la obra, pasando por las fases de pre-construcción, construcción y post-construcción. (ENGLISH VERSION) Since the 1960s, most construction projects have become more and more complex, and new concerns and necessities related to the management of a project have been on the rise in Europe and in the United States. Thence, the need for more specialized professionals in the field has become a common fact, as well as the inclusion of new curricular subjects in most building engineering studies. There are different agents that play a relevant role in a building project; some of them are expected to perform a highly specialized set of functions that require specific management skills for the work to be successful. This research work—aimed mainly at engineers, quantity surveyors, lawyers, economists, real estate and construction professionals—shows the major implications of the building construction process including both pre-tender/construction and post-tender/construction stages as far as the main expert agents are involved.

MAIA: an event-based modular architecture for intelligent agents

Online services are no longer isolated. The release of public APIs and technologies such as web hooks are allowing users and developers to access their information easily. Intelligent agents could use this information to provide a better user experience across services, connecting services with smart automatic. behaviours or actions. However, agent platforms are not prepared to easily add external sources such as web services, which hinders the usage of agents in the so-called Evented or Live Web. As a solution, this paper introduces an event-based architecture for agent systems, in accordance with the new tendencies in web programming. In particular, it is focused on personal agents that interact with several web services. With this architecture, called MAIA, connecting to new web services does not involve any modification in the platform.

Toxicity and sublethal effects of six insecticides to last instar larvae and adults of the biocontrol agents Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae) and Adalia bipunctata (L.) (Coleoptera: Coccinellidae)

To further develop Integrated Pest Management (IPM) strategies against crop pests, it is important to evaluate the effects of insecticides on biological control agents. Therefore, we tested the toxicity and sublethal effects (fecundity and fertility) of flonicamid, flubendiamide, metaflumizone, spirotetramat, sulfoxaflor and deltamethrin on the natural enemies Chrysoperla carnea and Adalia bipunctata. The side effects of the active ingredients of the insecticides were evaluated with residual contact tests for the larvae and adults of these predators in the laboratory. Flonicamid, flubendiamide, metaflumizone and spirotetramat were innocuous to last instar larvae and adults of C. carnea and A. bipunctata. Sulfoxaflor was slightly toxic to adults of C. carnea and was highly toxic to the L4 larvae of A. bipunctata. For A. bipunctata, sulfoxaflor and deltamethrin were the most damaging compounds with a cumulative larval mortality of 100%. Deltamethrin was also the most toxic compound to larvae and adults of C. carnea. In accordance with the results obtained, the compounds flonicamid, flubendiamide, metaflumizone and spirotetramat might be incorporated into IPM programs in combination with these natural enemies for the control of particular greenhouse pests. Nevertheless, the use of sulfoxaflor and deltamethrin in IPM strategies should be taken into consideration when releasing either of these biological control agents, due to the toxic behavior observed under laboratory conditions. The need for developing sustainable approaches to combine the use of these insecticides and natural enemies within an IPM framework is discussed.