[ES] El cáncer es la segunda causa de muerte en el mundo y se caracteriza principalmente por la proliferación descontrolada de las células que forman el tumor. Aunque el desarrollo de un tumor es posible debido a ciertos procesos comunes desencadenados por la desregulación del equilibrio existente entre los componentes moleculares de una célula y sus elementos de control, existe una gran heterogeneidad en los mecanismos a través de los cuales ocurre dicha desregulación. Gracias al desarrollo de nuevas tecnologías de secuenciación ha sido posible observar como esta heterogeneidad no solo se observa entre los distintos tipos de tumores sino entre las propias células de un mismo tumor. La caracterización de la heterogeneidad tumoral ha tenido un gran impacto en la comprensión de la enfermedad y el desarrollo de nuevas terapias dirigidas. Por este motivo, con el fin de mejorar la caracterización de alteraciones en los distintos mecanismos regulatorios, en esta tesis se han desarrollado dos metodologías con gran potencial para su aplicación en la medicina personalizada y que permiten estudiar la heterogeneidad inter e intratumoral de los estados de activación de elementos reguladores. En primer lugar, se desarrolló una metodología que permite determinar en una muestra el estado de activación de los factores de transcripción (FTs) a partir de la expresión de los genes a los que regula. Se aplicó la metodología para realizar un análisis sistemático de varios cánceres (conocido como estudios pan-cáncer) en el que se caracterizó por primera vez el escenario regulatorio de 52 FTs en 11 tipos de cáncer distintos. Además, al poder obtener valores de activación individuales para cada muestra, fue posible observar correlaciones entre la activación de algunos FTs con la supervivencia, sugiriendo así su uso como marcadores pronósticos. En segundo lugar, se desarrolló otra metodología en la que se emplea un modelo mecanístico para determinar el estado de activación de alrededor de 1000 circuitos de señalización a partir de datos de experimentos transcriptómicos de células únicas (scRNAseq). El uso de este modelo mecanístico en datos de scRNAseq de 4 pacientes de glioblastoma, además de mostrar la heterogeneidad intratumoral presente en las muestras, ha permitido realizar intervenciones in silico para simular el efecto de distintas drogas sobre las células. De esta manera, ha sido posible describir posibles mecanismos mediante los cuales un grupo de células pueden evitar el efecto de una terapia dirigida. Las metodologías desarrolladas en esta tesis, así como los resultados obtenidos tras su aplicación supone una valiosa fuente de información para el desarrollo de marcadores de diagnóstico, pronóstico y respuesta que ayuden a entender mejor los distintos niveles de heterogeneidad presentes en cáncer, y así, poder aumentar la eficacia de las terapias dirigidas. / [CA] El càncer és la segona causa de mort al món i es caracteritza principalment per la proliferació descontrolada de les cèl·lules que formen el tumor. Encara que el desenvolupament d'un tumor és possible a causa de certs processos comuns desencadenats per la desregulació de l'equilibri existent entre els components moleculars d'una cèl·lula i els seus elements de control, hi ha una gran heterogeneïtat en els mecanismes a través dels quals s'aconseguix aquesta desregulació. Gràcies a el desenvolupament de noves tecnologies de seqüenciació ha sigut possible observar com aquesta heterogeneïtat no només s'observa entre els diferents tipus de tumors sinó entre les pròpies cèl·lules d'un mateix tumor. La caracterització de l'heterogeneïtat tumoral ha tingut un gran impacte en la comprensió de la malaltia i el desenvolupament de noves teràpies dirigides. Per aquest motiu, per tal de millorar la caracterització d'alteracions en els diferents mecanismes reguladors, en aquesta tesi s'han desenvolupat dues metodologies amb gran potencial per a la seua aplicació en la medicina personalitzada i que permeten estudiar l'heterogeneïtat inter i intratumoral dels estats de activació d'elements reguladors. En primer lloc es va desenvolupar una metodologia que permet determinar en una mostra l'estat d'activació dels factors de transcripció (FTs) a partir de l'expressió dels gens als que regula. Es va aplicar la metodologia per a realitzar una anàlisi de pan-cancer en el qual es va caracteritzar per primera vegada l'escenari regulatori de 52 FTs a 11 tipus de càncer diferents. A més, al poder obtenir valors d'activació individuals per a cada mostra, va ser possible observar correlacions entre l'activació d'alguns FTs amb la supervivència, suggerint així el seu ús com a marcadors pronòstics. En segon lloc, es va desenvolupar una altra metodologia en la qual s'empra un model mecanístic per determinar l'estat d'activació d'al voltant de 1000 circuits de senyalització a partir d'experiments transcriptòmics de cèl·lules úniques (scRNAseq). L'ús d'aquest model mecanístic en dades de scRNAseq de 4 pacients de glioblastoma, a més de mostrar l'heterogeneïtat intratumoral present en les mostres, ha permès realitzar intervencions in silico per simular l'efecte de diferents drogues sobre les cèl·lules. D'aquesta manera, ha estat possible descriure possibles mecanismes mitjançant els quals un grup de cèl·lules poden evitar l'efecte d'una teràpia dirigida. Les metodologies desenvolupades en aquesta tesi, així com els resultats obtinguts després de la seva aplicació suposa una valuosa font d'informació per al desenvolupament de marcadors de diagnòstic, pronòstic i resposta que ajudin a entendre millor els diferents nivells d'heterogeneïtat presents en càncer, i així, poder augmentar l'eficàcia de les teràpies dirigides. / [EN] Cancer is the second leading cause of death in the world and is characterized mainly by the uncontrolled proliferation of the cells that make up the tumor. Although the development of a tumor is possible due to certain common processes triggered by the dysregulation of the existing balance between the molecular components of a cell and its control elements, there is great heterogeneity in the mechanisms through which this dysregulation is achieved. Thanks to the development of new sequencing technologies, it has been possible to observe how this heterogeneity is not only observed between the different types of tumors but also between the cells of the same tumor. The characterization of tumor heterogeneity has had a great impact on the understanding of the disease and the development of new targeted therapies. For this reason, in order to improve the characterization of alterations in the different regulatory mechanisms, in this thesis two methodologies have been developed that allow studying the inter- and intratumoral heterogeneity of the activation states of regulatory elements and with great potential for their application in personalized medicine. In the first place, a methodology that allows determining in a sample the activation state of the transcription factors (FTs) from the expression of the genes that it regulates was developed. The methodology was applied to perform a pan-cancer analysis in which the regulatory scenario of 52 FTs was characterized for the first time in 11 different types of cancer. Furthermore, by being able to obtain individual activation values for each sample, it was possible to observe correlations between the activation of some FTs with survival, thus suggesting their use as prognostic markers. Second, another methodology was developed using a mechanistic model to determine the activation state of around 1000 signaling circuits in single cell transcriptomic experiments (scRNAseq). The use of this mechanistic model in scRNAseq data from 4 glioblastoma patients, in addition to showing the intratumoral heterogeneity present in the samples, has allowed in silico interventions to simulate the effect of different drugs on cells. In this way, it has been possible to describe possible mechanisms by which a group of cells can avoid the effect of a targeted therapy. The methodologies developed in this thesis, as well as the results obtained after its application, is a valuable source of information for the development of diagnostic, prognostic and response markers that help to better understand the different levels of heterogeneity present in cancer, and thus, be able increase the effectiveness of targeted therapies. / Marín Falco, M. (2021). Estudio de la heterogeneidad regulatoria en cáncer y sus implicaciones en la medicina personalizada [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/165413 / TESIS

El presente proyecto consiste en realizar ciertas investigaciones con la finalidad de analizar y brindar soluciones hacia un problema, la cual es la falta de accesibilidad y tiempo de las personas para realizar la impresión de sus fotografías. Hoy en día, se ha perdido la costumbre de tener un álbum de manera física con recuerdos especiales, ya que las personas prefieren subir sus fotografías a las redes sociales. Sin embargo, en las investigaciones y entrevistas realizadas se encuentra que la mayoría de personas no adquieren un álbum, porque no existen muchos lugares donde se imprima fotos a un precio razonable. Por ello, nuestro equipo de trabajo de la Universidad Peruana de Ciencias Aplicadas ha determinado que, si hay intención de las personas a adquirir un álbum, pero que sea accesible y original para el cliente, según sus gustos y preferencias, por lo que, para satisfacer a nuestro público objetivo se realizará álbumes personalizados con precios desde los S/50 soles hasta S/80 soles dependiendo de la cantidad de fotos que deseen, el consumidor elegirá la temática para su álbum, las fotografías serán editadas por nosotros y en diferentes tamaños, contaremos con una aplicación móvil donde se contará con una base de datos del usuario, para así escoger y editar las fotos de sus mejores recuerdos, al finalizar el álbum será enviado hasta su hogar. Con este fin, se ha llevado a cabo una serie de investigaciones y experimentos, con la cual se respalda nuestra propuesta con el planteamiento del problema, soluciones y una proyección rentable del negocio. / The present project consists of carrying out certain investigations in order to analyze and provide solutions to a problem, which is the lack of accessibility and time for people to print their photographs. Today, the habit of physically having an album with special memories has been lost, since people prefer to upload their photos to social networks. However, research and interviews found that most people do not buy an album, because there are not many places where photos are printed at a reasonable price. For this reason, our team at the Peruvian University of Applied Sciences has determined that, if there is the intention of people to purchase an album, but that it is accessible and original for the client, according to their tastes and preferences, so, for To satisfy our target audience, personalized albums will be made with prices from S / 50 soles to S / 80 soles depending on the number of photos they want, the consumer will choose the theme for their album, the photographs will be edited by us and in different sizes , we will have a mobile application where there will be a user database, in order to choose and edit the photos of your best memories, at the end of the album it will be sent to your home. To this end, a series of investigations and experiments has been carried out, with which our proposal is supported with the problem statement, solutions and a profitable projection of the business. / Trabajo de investigación

The growing technology has changed the form of advertising and user behavior. Recent years, the amount of personalized advertising is on a steady rise. Personalized advertising is based on a method called retargeting to tailor the advertisements to individual consumers by inferring their interests and preferences.However, there are still many deficiencies in personalized advertising that reduce the user experience. Understanding the attitudes of users and companies to personalized advertising can help improve these deficiencies. Hence, the purpose of this study is to compare different opinions regarding personalized advertising from Chinese consumers and companies towards Taobao respectively.This investigation uses a case study method to study the purpose. Taobao is an e-commerce platform with a high frequency of personalized advertising and has a great impact on China. Therefore, Taobao has been chosen as our case. First the background of personalized advertising is introduced, and then personalized advertising in Taobao is described. The different opinions of both consumers and companies are studied. In general, consumers have a positive attitude towards personalized advertising. However, there is a need for improvement in terms of privacy, trust and effectiveness. For companies, the effect of personalized advertising is satisfying, but the price makes is difficult for them to afford it.

Indiana University-Purdue University Indianapolis (IUPUI) / The marker strategy design (MSGD) has been proposed to assess and validate predictive markers for targeted therapies and immunotherapies. Under this design, patients are randomized into two strategies: the marker-based strategy, which treats patients based on their marker status, and the non-marker-based strategy, which randomizes patients into treatments independent of their marker status in the same way as in a standard randomized clinical trial. The strategy effect is then tested by comparing the response rate between the two strategies and this strategy effect is commonly used to evaluate the predictive capability of the markers. We show that this commonly used between-strategy test is flawed, which may cause investigators to miss the opportunity to discover important predictive markers or falsely claim an irrelevant marker as predictive. Then we propose new procedures to improve the power of the MSGD to detect the predictive marker effect. One is based on a binary response endpoint; the second is based on survival endpoints. We conduct simulation studies to compare the performance of the MSGD with the widely used marker stratified design (MSFD). Numerical studies show that the MSGD and MSFD has comparable performance. Hence, contrary to popular belief that the MSGD is an inferior design compared with the MSFD, we conclude that using the MSGD with the proposed tests is an efficient and ethical way to find predictive markers for targeted therapies.

<div>The advent of Patient-Centric therapy demands technologies capable of producing multiple versions of a given product, each tailored for specific segments of the population/individual, but in a time- and cost-effective manner. Prevailing manufacturing methods for oral dosage forms do not easily lend themselves for the transition to the Patient-Centric area. The purpose of this research was to develop a formulation/manufacturing platform technology meeting the flexibility requirements for Patient-Centric formulation and product development for oral dosage forms. The approach is based on the molecular designing and manufacturing of the dosage form. The dosage form consists of a 3D assembly of prefabricated functional modules, each with a specific pharmaceutical performance function. </div><div>The characterization of individual modules showed that solvent casting produced API-loaded HPMC films with homogeneous content distribution. The release profile of 3D assemblies was significantly influenced by the physicochemical properties of single modules. API-loading, thickness, and diameter had a significant effect on the release kinetics. In contrast, the hydrophobicity of the casting substrate did not affect the release kinetics. The initial geometry of the final 3D assembly given by the number of modules and their diameter was proved to have a significant impact on the release kinetics as well. </div><div>The 3D assemblies were used to produce dosage forms with customizable release profiles. Two API-loaded thin HPMC-based films with fast (FRA) and slow (SRB) release rates were produced by the solvent casting method. Accurate dose control (API loading) was accomplished by varying the number of individual modules in the 3D assemblies, whereas control of release kinetics was achieved by combining different ratios FRA and SRB film modules in the assembled dosage form. </div><div>The modular design was also tested for its ability to generate a dosage form of a weak-base API. This part was accomplished using a module containing citric acid (CA) interspaced between weak-base loaded FRA modules. Characterization of the 3D assemblies that were devoid of CA modules showed that the API release rate from modular assemblies containing weekly basic API exhibited strong pH-dependence. The 3D assemblies featuring CA modules in their design exhibited nearly pH-independent release kinetics. </div><div>Electrospinning was used as an enabling technology to produce HPMC-based fibrous films. HPMC films were able to encapsulate a wide variety of APIs with different aqueous solubility. All fibers produced were in the range of a few hundred nanometers to a few microns. X-ray diffraction and differential scanning calorimetry exhibited the amorphous or crystalline state of the API dispersed. Disintegration and release tests showed the fast dissolution of the fibrous system. </div><div><br></div>

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Many airborne diseases such as Coronavirus variants are spread from person to person by indoor air movement. This is of particular concern in healthcare environments such as hospitals. There is a significant body of research that suggests that indoor ventilation strategies such as personalized ventilation systems my help reduce the spread of these viruses. While there are studies related to the efficacy of air movement from personalized ventilation, there are very few studies that explore how best to integrate these systems into the design process for hospital patient rooms. This study focuses on how to integrate personalized ventilation (PV) and displacement ventilation (DPV) systems into patient room design. The aims of this study are to first, develop a procedure using the Choosing By Advantages approach to make design decisions related to the implementation for personalized ventilation and displacement ventilation in private and semi-private patient rooms to prevent cross-infection. Secondly, using this approach, design solutions are proposed for patient room layouts with PV and DPV in different locations. The study proposes the best locations and components of the PV and DPV ventilation air supply and exhaust. Further practical models/simulation rooms are required to test the impact of PV systems on patients' and nurses' daily activities. / Master of Science / Many airborne diseases such as Coronavirus variants are spread from person to person by indoor air movement. This is of particular concern in healthcare environments such as hospitals. New personalized ventilation systems place ventilation air directly at the patient bed and consequently can reduce the spread of these viruses by effectively managing in-room air movement. This study explores how best to make design decisions for the implementation of personalized ventilation systems into hospital patient rooms. Applying this decision-making approach, design solutions are proposed that integrate personalized ventilation with commonly used displacement ventilation in patient rooms.