Breast cancer chemotherapeutic options: a general overview on the preclinical validation of a multi-target ruthenium(III) complex lodged in nucleolipid nanosystems

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium‐based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple‐negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced nextgeneration metallotherapeutics, with NAMI‐A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well‐known NAMI‐A complex, information on non‐nanostructured Ru‐based anticancer agents have been included in a precise manner

Clayful Phenomenology and material engagement: explorations in contemporary cognitive archaeology

The thesis explores the phenomenology of creative cognition from the viewpoint of a contemporary ceramic workshop. Over five chapters, six clay sculptural projects track the development of a method I call ‘clayful phenomenology’. Informed by Material Engagement Theory (MET), the method takes sculptural development (normally understood to be the realization of an artist’s vision) and reformulates it so that a body of clay becomes a transient, diffuse, knowledge-producing assembly. The reformulation replaces subjective experience with a systemic, phenomenological proposal for extended sentience. Clayful Phenomenology turns material culture from an object of study into a method for investigating its own creative becoming. Videos, photos and written notes record the materialization and evolution of ideation as it is enacted in the gestural relationship between clay and hand, what Malafouris calls “creative thinging”. This account of sculpting by sculpting gives unique access to the three principles of MET and focuses on how: 1. thoughts, feelings and sensations establish themselves through gestural activity in the workshop rather than neural activity in the brain, thus extending the mind; 2. intention develops through the making and breaking of habitual practices imbuing material with agency; 3. signification, enacted and ideated through material change, enables each project to learn itself into existence. Clayful phenomenology gives reason to question the meaning of ‘cognitive’ in ‘cognitive archaeology’ by suggesting the discipline might move away from retrofitting cognitive science models to past human thinking and towards using the archaeological study of material culture to challenge neuro-centric conceptions of the mind. The first three chapters develop the method by elaborating five contemporary examples of creative thinging. The final two chapters introduce a form of experimental cognitive archaeology during which clayful phenomenology explores the enactive signification of a prehistoric artefact: a Jōmon flame pot. This diffractive analogical approach does not attempt to uncover past meanings but to make sense of the archaeological record by creating new experiences of its traces in the present. The thesis concludes with a review of extended sentience in relation to the ownership of feelings and letting go of affective intentions

Procesos creativos en entornos musicales inmersivos: un estudio de caso a través del análisis de metaversos. La Avatar Orchestra Metaverse en Second Life

La virtualidad se presenta como un espacio de creación y expansión de la realidad física. La percepción y la relación de los procesos creativos que giran en torno a lo virtual en lo referente a la música, la performance y la experimentación rigen e interaccionan nuestras realidades físicas, aún estando offline. Dichos procesos creativos son estudiados en la Orquesta virtual Avatar Orchestra Metaverse. Hemos navegado a través de la realidad creada por la Orquesta en el ciberespacio, bajo una metodología de estudio de caso -al que hemos llamado cybercase-, asistiendo y participando durante un tiempo en sus ensayos, junto a una posterior actuación. A través de un enfoque interdisciplinar basado en un proceso de análisis de material audiovisual y textual mediado por la presencia, entendida desde lo físico y lo virtual, exponemos los procesos creativos encontrados que subyacen bajo los miembros de la Orquesta, de modo descriptivo, y mediante el empleo de la teoría fundamentada. Como marco teórico mostramos los conceptos de música, espacio, tiempo y los procesos de comunicación gestados por la máquina y la virtualidad, todo ello mediado desde la percepción del ambiente y el interaccionismo simbólico. Presentamos dentro de este marco una revisión teórica del concepto de la creatividad enfocado desde la mecánica cuántica..

Embodiment in Evolution and Culture

From its beginnings, the theory of evolution has unsettled fundamental anthropological assumptions about the place of human beings in nature. The integration of human origins into natural history by Darwinism was countered by the philosophical anthropologies of the 20th century. Their attempts were to hold on even more resolutely to the special status of humans as beings 'open towards the world'. Today, evolutionary and philosophical anthropology have moved closer together via the paradigm of embodiment. Building on embodied cognitive science, this volume aims to establish how far the human mind and human cultural cognition can be attributed to the structures of human existence, structures which have emerged in the course of evolution and have in turn been affected by culture. The traditional dualism of nature and culture is transformed into an explanation of an evolutionary process in which body and mind are understood to be intertwined and mutually constitutive

Screening and Surveillance of the Gastrointestinal Tract

This thesis aims to optimise prevention programmes for gastric- and colorectal cancer. The first part consists of studies on surveillance of premalignant gastric lesions. Prospectively, we evaluated current guidelines on the proper identification of patients with premalignant gastric lesions that deserve further follow up. After one extra gastro endoscopy – were guidelines would advise to stop further surveillance - it appeared that a considerable part would have an indication for further surveillance after all. We investigated several possibilities for the improvement of surveillance programmes. To name; the use of a new endoscopy technique, evaluating risk factors within patients (such as smoking and a family history of gastric cancer), and the new possibility of detecting the most important risk factor for the occurrence of gastric cancer – Helicobacter Pylori bacterium – in the fecal test used in colorectal cancer screening. The second part of this thesis consist of studies on colorectal cancer screening. First, the video capsule was used to determine prevalence rates of several abnormalities (benign or malignant) in a general population. Further, a comprehensive retrospective study in 20 European countries was performed on the incidence of colorectal cancer over time within different age groups. This showed that the incidence is increasing mostly at younger ages. Lastly, literature studies were performed in order to further improve and innovate the current colorectal cancer screening programme. We showed that the use of anticoagulants do not affect the fecal blood test used in screening. Also, the video capsule appeared to be a good alternative beside colonoscopy.<br/

Validation of biomarkers and digital image analysis in breast pathology

For women worldwide, the risk of developing breast cancer is second only to that of nonmelanoma skin cancer. Significant improvements have been made in survival over the past decades and today about 80 % of the patients survive 10 years or more after their breast cancer diagnosis. Still, far from all patients enjoy the relatively good survival indicated by statistics on breast cancer patients as one homogenous group. Improving prognostication of aggressive vs. less aggressive disease, and to separate tumors based on genetic differences for optimal treatment strategies, is therefore the focus of intensive research, including this thesis. In paper I, we compared if tumor characteristics differ depending on what method of sampling the tumor that have been used for analysis. We compared routine immunohistochemistry on surgically resected breast specimens, including stains of the Estrogen receptor alpha (ER), the Progesterone receptor (PR), Human Epidermal growth factor receptor 2 (HER2) and the proliferation-associated protein Ki67, with analysis of the same stains done on material obtained from fine needle aspiration (immunocytochemistry). We found that there were substantial differences in the expression of these biomarkers between the two methods. Thus, the same rules for interpretation of biomarkers cannot be used for immunohistochemistry and immunocytochemistry, and consequently, validation of each method should be performed individually. In paper II, we explored the scope of digital image analysis in biomarker evaluations. We scored ER, PR, HER2 and Ki67 status in several different regions of breast tumors by both manual methods and digital image analysis. The outcomes of the scoring of these biomarkers were then combined into IHC surrogate subtypes and compared to PAM50 gene expression-based subtypes as well as patient survival. All tested methods of automated digital image analysis of Ki67 outperformed manual scores in terms of sensitivity and specificity for the Luminal B subtype. Comparing digital versus manual testing concordance to all breast cancer subtypes as determined by PAM50 assays, the digital approach was superior to the manual method. The manual and digital image analysis methods matched each other in hazard ratio for all-cause mortality of patients with tumors with a “high” vs “low” Ki67 index. Manual assessments of the biomarkers ER, PR, HER2 and Ki67 were in most aspects less precise than digital image analysis. In paper III, we evolved the concept of paper I with an evaluation of the concordance of consecutive Ki67 assessments performed on fine needle aspiration cytology versus resected tumor specimens. We investigated how a status of Ki67 “low” and “high” as determined by immunohistochemistry and immunocytochemistry corresponded to overall survival, respectively. Again, Ki67-index varied when the two methods were used on the same tumors, and was prone to switch the classification between low and high proliferation. ER evaluations were discordant in 5.3 % of the tumors, which in the clinical setting would mean that 1 in 20 patients would risk being left out of beneficial endocrine treatment or being given it without benefit. Ki67 “high”, as determined by immunohistochemistry, defined as a proportion of Ki67-positive cells above the 67th percentile of the material, was significantly associated with poor overall survival and a significantly higher probability of axillary lymph node metastasis. This could not be reproduced for immunocytochemistry. In summary, this study adds to the results of paper I, in which we showed discordance between the methods. By including survival data, we now conclude that not merely are the methods discordant, but immunocytochemistry fails to provide prognostic information. Consequently, immunohistochemistry should be regarded as the superior method. In paper IV, we focused on proliferation comparing the results in the tumors’ hot spot, in the tumor periphery, and as the average proportion of Ki67-positive cells across the whole tumor section. Both manual and digital scores of Ki67 and the recently described marker for mitotic activity, PHH3, were evaluated along with mitotic counts. Their sensitivity and specificity for the gene expression based Luminal B versus A breast cancer subtypes, for the high versus low transcriptomic grade, for axillary lymph node status as well as for their prognostic value for breast cancer specific and overall survival were analyzed. Digital image analysis of Ki67 in hot spots outperformed the other markers in sensitivity and specificity both for gene expression subtypes and transcriptomic grade. In contrast to mitotic counts, tumors with high expression of Ki67, as defined by digital image analysis and high numbers of PHH3-positive cells, had significantly increased HR for all-cause mortality at 10 years from diagnosis. When we replaced the manual mitotic counts with digital image analysis of Ki67 in hot spots as the marker for proliferation when determining histological grade, the differences in estimated mean overall survival between the highest and lowest grades increased. It also added significantly more prognostic information to the classic Nottingham combined histological grade. We conclude that digital image analysis of Ki67 in hot spots might be suggested as the marker of choice for proliferative activity in breast cancer

Using serious games for improving medical education: an application to cytopathology

El objetivo principal del proyecto es desarrollar una plataforma compuesta por aplicaciones educativas gamificadas para el entrenamiento de personal médico en países de recursos limitados en citopatología mediante dispositivos Android de bajo presupuesto. Antes de desplegar la plataforma en países con recursos limitados, va a ser probada en un curso de Introducción a Citopatología de la Escuela Médica de Harvard. El proyecto final debe funcionar tanto en PCs como en dispositivos Android de bajo coste (p.e. 50 dólares americanos, Amazon Kindle Fire 7 pulgadas) y no puede depender de una conexión a internet continua. Se han analizado algunas aplicaciones con propósito de juego y simulaciones gamificadas para tener una base de conocimiento común entre expertos médicos y desarrolladores. También se han estudiado juegos y aplicaciones cuyo objetivo es hacer uso de imágenes médicas para entrenamiento de personal médico o están enfocadas al diagnóstico mediante colaboración por parte de personal no-médico. Esto nos ha permitido identificar las mejores mecánicas de juego para nuestro caso de uso. A continuación, se han comparado diferentes herramientas de edición y motores de juegos desde el punto de vista del rendimiento ofrecido, las plataformas soportadas, su documentación y licencia. Todo ello nos ha permitido elegir la tecnología de desarrollo (libGDX). Finalmente, diseñamos e implementamos un sistema integrado de aplicaciones (editor de contenido y generador de juegos). El sistema está enfocado a reducir la dependencia entre el personal experto y los desarrolladores para crear y mantener contenido educativo. Se trata de una arquitectura formada por un servicio RESTful, y un editor asociado, orientado a la gestión de contenido educativo orientado para citopatología y dos clientes para diferentes plataformas (PC y Android) que consumen dicho servicio. Finalmente, se presentan las conclusiones y el trabajo futuro del proyecto

Faculty Publications and Creative Works 2003

Faculty Publications & Creative Works is an annual compendium of scholarly and creative activities of University of New Mexico faculty during the noted calendar year. It serves to illustrate the robust and active intellectual pursuits conducted by the faculty in support of teaching and research at UNM