O transtorno de humor associado ao transtorno de estresse pós-traumático (TEPT) tem, em geral, desfechos clínicos mais graves. Embora essa associação esteja consolidada no transtorno depressivo, esse não é o caso no transtorno bipolar (TB). Os poucos estudos realizados acerca dessa comorbidade demonstraram piora na qualidade de vida e aumento no número de tentativas de suicídio associado aos pacientes com TEPT e TB. Nenhum estudo, entretanto, avaliou o impacto do TEPT em características centrais do TB, como o número de episódios de humor ou funcionamento psicossocial. Por outro lado, estudos pré-clínicos sugerem que existe um fenômeno de sensibilização cruzada entre o TB e o TEPT. Foi proposto que a redução do brain-derived neurotrophic fator (BDNF) e alterações de marcadores inflamatórios poderiam ser mecanismos associados a esta sensibilização. Com relação a última hipótese, as alterações em marcadores inflamatórios estão bem consolidadas no TB, porém esse não é o caso no TEPT. Com a finalidade de aprofundar o estudo dessas questões, os dois primeiros estudos que compõem essa tese abordaram aspectos clínicos e biológicos relacionados a esses transtornos. O primeiro é uma metanálise e metaregressão que demonstrou que o TEPT está associado a níveis aumentados de IL-6, IL-1β, TNF-α e interferon-γ na circulação periférica. Além disso, o tempo de doença foi positivamente associado aos níveis de IL-1β, enquanto a gravidade dos sintomas foi positivamente associada aos níveis de IL-6. Esses achados podem não só apresentar um novo mecanismo biológico para explicar o fenômeno de sensibilização cruzada entre TEPT e TB, mas também abre novos horizontes na busca de novas estratégias terapêuticas e diagnósticas para o TEPT. O segundo foi um estudo caso-controle que avaliou características clínicas centrais do TB e demonstrou pela primeira vez que indivíduos com TB e comorbidade com TEPT apresentam mais episódios maníacos e pior funcionamento psicossocial. Ademais, o início dos episódios maníacos e o uso de substâncias de abuso surgiram de maneira mais precoce nesses indivíduos. Além desses dois estudos, optamos por abordar a influência da comorbidade com os transtornos ansiosos (como o TEPT) em um desfecho clínico trágico em pacientes com transtorno de humor: o suicídio. Esse estudo foi realizado em uma população diferente da do estudo clínico anterior, incluindo pacientes com depressão maior ou com TB, e foi focado em apenas um desfecho. Nosso objetivo era criar uma ferramenta que pudesse gerar um escore de probabilidade para cada paciente com transtorno de humor que refletisse o risco de tentar suicídio. Utilizando técnicas de machine learning, demonstramos que o risco de suicídio em indivíduos com transtorno de humor pode ser estimado objetivamente a partir de variáveis clínicas facilmente obtidas e variáveis demográficas. Embora tenhamos encontrado uma boa acurácia (72%) e área (area under the curve) (77%), futuros estudos podem integrar dados de variáveis de marcadores biológicos (genética, neuroimagem, neurocognição, etc.), usando também técnicas de machine learning, para atingir uma acurácia ainda maior. O uso de um instrumento objetivo é o primeiro passo na busca de um tratamento mais personalizado para aqueles pacientes com alto risco de se suicidar. / The comorbidity between mood disorders and posttraumatic stress disorder (PTSD) is associated with poorer clinical outcomes. Although this association is well established in major depressive disorder, fewer studies included patients with bipolar disorder (BD). These studies report that patients with BD and PTSD show increased number of suicide attempts and worse quality of life. However, no clinical studies so far have reported the impact of comorbid PTSD on core features of BD, such as number of mood episodes and functional impairment. On the other hand, preclinical studies showed that there is a cross-sensitization between BD and PTSD. Accordingly, it was proposed that the brain-derived neurotrophic factor (BDNF) and changes of inflammatory markers might be the biological underpinnings of this cross-sensitization. Although the changes in inflammatory markers are well established in BD, this is not the case for PTSD. In view of the above, the first two studies of this thesis addressed clinical and biological issues related to BD and PTSD. The first is a meta-analysis and metaregression study that showed increased levels of IL-6, IL-1β, TNF-α and interferon-γ in peripheral circulation among patients with PTSD. Furthermore, illness duration was positively associated with IL-1β levels, while the severity of the symptoms was positively associated with IL-6 levels. These findings may not only provide a new biological mechanism to explain the cross-sensitization between PTSD and BD, but also opens a new avenue in the search for new therapeutic targets and diagnostic strategies for PTSD. The second was a case-control study that assessed core clinical features of BD showed increased manic episodes and functional impairment among patients with BD and comorbid PTSD. In addition, those patients were younger when they started the manic episodes and substance use. Moreover, we chose to address the influence of comorbid anxiety disorders (such as PTSD) in suicide in patients with mood disorders. This study was conducted in a different population, including patients with major depressive disorder or BD, and it was focused on only one outcome. Suicide is a tragic clinical outcome, but highly preventable. Our aim was to develop a clinical tool using machine learning techniques to estimate a probability score at individual level to stratify the risk of a patient with a mood disorder attempts suicide. Therefore, our study showed that the risk of suicide in individuals with a mood disorder can be objectively estimated from easily assessed clinical and demographic variables. Although we have found a good accuracy (72%) and area under the curve (77%), future studies may integrate data from biological markers (genetic, neuroimaging, neurocognition, etc.) also using machine learning techniques to achieve a higher accuracy. This objective instrument is the first step towards a more personalized treatment for those patients at high risk of suicide.

Estudos no campo de conforto personalizado demonstram a necessidade de se desenvolver um sistema de distribuição de ar que permita ao usuário controlar, individualmente, as condições térmicas no seu posto de trabalho. Neste contexto, um equipamento dessa natureza foi idealizado pela orientadora deste trabalho e nesse processo foi identificada a necessidade de se elaborar um método de desenvolvimento de produto com características acadêmicas para ser usado na concepção e construção do dispositivo em questão. Para atender a essa necessidade, um método de projeto foi proposto neste trabalho para ser aplicado na área de desenvolvimento tecnológico de produto e/ou novos produtos, tendo como estudo de caso o dispositivo de conforto personalizado que foi desenvolvido paralelamente por um escritório de design. O método proposto se baseou em outros métodos de projeto já consagrados e foi adequado para o que se propõe considerando seus aspectos positivos. O método proposto neste trabalho é aberto e adota três processos criativos, baseado em pesquisas nas áreas de estética, materiais, ergonomia e comportamento humano e na pesquisa científica. O método permite a inter-relação de design, tecnologia de material e engenharia para satisfazer aos pré-requisitos técnicos quanto à funcionalidade, forma, estética e custo. O método é um modelo totalmente desenvolvido no âmbito acadêmico e foi validado pelo estudo de caso, quando se procedeu à comparação do método proposto com o utilizado pelo escritório de design que desenvolveu o dispositivo propriamente dito. Pela análise comparativa dos dois métodos foi possível concluir que o método proposto é adequado para se desenvolver um produto tanto no meio acadêmico quanto na indústria. Além disso, ele apresenta um diferencial com relação aos métodos considerados: sua estrutura aberta circular e radial estimula as interferências no decorrer do projeto, fazendo com que etapas sejam acrescentadas, retiradas e/ou desdobradas de acordo com os objetivos específicos do produto em questão. / Studies in the field of personalized thermal comfort demonstrate the necessity of developing an air distribution system that allows the user to control individually the thermal conditions in their work station. In this context, such an equipment is designed for guiding this study and this process has identified the need of devising a method of product development with academic characteristics to be used in the design and construction of the device in question. To attend this need, a design method was proposed in this work to be applied in the area of technological development of products and / or new products, taking as a case study of the personal comfort device which was developed in parallel by a design office. The proposed method was based on other design methods already established and was adequate to what is proposed considering its positive aspects. The method proposed in this work is open and takes three creative processes, based on research in the areas of aesthetics, materials, ergonomics and human behavior and in scientific research. The method allows the interrelation of design, material technology and engineering to meet the technical prerequisites for functionality, shape, aesthetics, and cost. The method is a model totally developed in the academic area and was validated by case study, when compared to the proposed method used by the office design that developed the device itself. After comparative analysis of both methods it was possible to conclude that the proposed method is suitable to develop a product both in the university, and in the industry. Furthermore, it has a differential with regard to the methods considered: open structure - circular and radial that stimulates interference during the project, making steps are added, removed and / or deployed according to the specific goals of the product in question.

A disseminação de agentes infecciosos em ambientes interiores é um assunto de interesse da sociedade em geral e uma questão de saúde pública, tendo em vista os surtos recentes do vírus SARS, gripe suína, gripe aviária, etc. Em particular, o sistema com suprimento de ar individualizado têm se mostrado eficaz, atuando como barreira contra contaminação cruzada entre ocupantes. Diversas metodologias têm sido aplicadas nesses estudos, tal como gás traçador, geradores de partículas e simulação CFD, muitas vezes sem muito critério, ou com equipamentos e simulações excessivamente complexas. Neste contexto, o objetivo do presente trabalho é desenvolver um processo robusto e com menor complexidade do que os utilizados atualmente para avaliar a dispersão de contaminantes aéreos em ambientes interiores. O processo desenvolvido é aplicado em um estudo de caso onde a influência de um sistema de ventilação personalizado de cabine de aeronave é avaliado sobre a ótica da infecção cruzada. O trabalho contempla a realização de atividades de simulação computacional (CFD) e medições experimentais no ambiente interno de uma cabine de avião (mock-up), onde os campos de velocidade do ar são medidos com Velocimetria por Imagem de Partículas (PIV), partículas entre 2 e 10m são geradas com um gerador de aerossol e contadas com contadores ópticos portáteis. Obteve-se boa correlação entre os resultados numéricos e experimentais para o campo de velocidades e boa concordância qualitativa entre as contagens de partículas no experimento e nas simulações CFD Lagrangeanas. Observou-se, dentre outros aspectos, que a válvula gasper, tal como ensaiada no presente trabalho, contribui para a qualidade do ar na zona de respiração dos ocupantes sentados, promovendo um aumento nas taxas de deposição de partículas nas superfícies internas do mock-up. / The indoor dispersion of infections agents still concern the society, and has become a matter of public health, taken into account the outbreak of SARS in 2003, and the recent cases of influenza strains (H1N1, avian flu, SARS, etc). The use of personalized ventilation has improved the occupants\' air quality on recent evaluations, working as a contaminant spread barrier. Different kinds of methodologies are usually applied for those studies, such as tracer gas, particle generators and CFD simulations, sometimes without adequate criteria, or applying quite complex equipment and simulation methodologies such as transient analysis. Therefore, the main objective of the present work is to develop a robust method, and if possible less complicated than the current ones, to evaluate the dispersion of indoor airborne contaminants. Moreover, one\'s intend to apply the proposed method in a case study to evaluate the influence of a personalized ventilation system to the spread of indoor air contaminants. The study is composed by CFD simulations and experimental measurements inside an aircraft cabin mock-up, where the velocity and temperature field, as well as particle concentration are measured. Particle Image Velocimetry technique is used to analyse air flow velocities. Particles from 2 to 10µm are produced with aerosol generator and injected into the cabine. Finally, particle distributions are measured with hand held optical counters to evaluate air quality at the breathing zone. Good correlation between numerical and experimental results was obtained for velocity field, and adequate qualitative agreement was obtained for concentration field. One\'s conclude the investigated personalized ventilation system has improved the air quality around occupants breathing zone, mainly by increasing the deposition rates at the internal cabin surfaces.

O transtorno de humor associado ao transtorno de estresse pós-traumático (TEPT) tem, em geral, desfechos clínicos mais graves. Embora essa associação esteja consolidada no transtorno depressivo, esse não é o caso no transtorno bipolar (TB). Os poucos estudos realizados acerca dessa comorbidade demonstraram piora na qualidade de vida e aumento no número de tentativas de suicídio associado aos pacientes com TEPT e TB. Nenhum estudo, entretanto, avaliou o impacto do TEPT em características centrais do TB, como o número de episódios de humor ou funcionamento psicossocial. Por outro lado, estudos pré-clínicos sugerem que existe um fenômeno de sensibilização cruzada entre o TB e o TEPT. Foi proposto que a redução do brain-derived neurotrophic fator (BDNF) e alterações de marcadores inflamatórios poderiam ser mecanismos associados a esta sensibilização. Com relação a última hipótese, as alterações em marcadores inflamatórios estão bem consolidadas no TB, porém esse não é o caso no TEPT. Com a finalidade de aprofundar o estudo dessas questões, os dois primeiros estudos que compõem essa tese abordaram aspectos clínicos e biológicos relacionados a esses transtornos. O primeiro é uma metanálise e metaregressão que demonstrou que o TEPT está associado a níveis aumentados de IL-6, IL-1β, TNF-α e interferon-γ na circulação periférica. Além disso, o tempo de doença foi positivamente associado aos níveis de IL-1β, enquanto a gravidade dos sintomas foi positivamente associada aos níveis de IL-6. Esses achados podem não só apresentar um novo mecanismo biológico para explicar o fenômeno de sensibilização cruzada entre TEPT e TB, mas também abre novos horizontes na busca de novas estratégias terapêuticas e diagnósticas para o TEPT. O segundo foi um estudo caso-controle que avaliou características clínicas centrais do TB e demonstrou pela primeira vez que indivíduos com TB e comorbidade com TEPT apresentam mais episódios maníacos e pior funcionamento psicossocial. Ademais, o início dos episódios maníacos e o uso de substâncias de abuso surgiram de maneira mais precoce nesses indivíduos. Além desses dois estudos, optamos por abordar a influência da comorbidade com os transtornos ansiosos (como o TEPT) em um desfecho clínico trágico em pacientes com transtorno de humor: o suicídio. Esse estudo foi realizado em uma população diferente da do estudo clínico anterior, incluindo pacientes com depressão maior ou com TB, e foi focado em apenas um desfecho. Nosso objetivo era criar uma ferramenta que pudesse gerar um escore de probabilidade para cada paciente com transtorno de humor que refletisse o risco de tentar suicídio. Utilizando técnicas de machine learning, demonstramos que o risco de suicídio em indivíduos com transtorno de humor pode ser estimado objetivamente a partir de variáveis clínicas facilmente obtidas e variáveis demográficas. Embora tenhamos encontrado uma boa acurácia (72%) e área (area under the curve) (77%), futuros estudos podem integrar dados de variáveis de marcadores biológicos (genética, neuroimagem, neurocognição, etc.), usando também técnicas de machine learning, para atingir uma acurácia ainda maior. O uso de um instrumento objetivo é o primeiro passo na busca de um tratamento mais personalizado para aqueles pacientes com alto risco de se suicidar. / The comorbidity between mood disorders and posttraumatic stress disorder (PTSD) is associated with poorer clinical outcomes. Although this association is well established in major depressive disorder, fewer studies included patients with bipolar disorder (BD). These studies report that patients with BD and PTSD show increased number of suicide attempts and worse quality of life. However, no clinical studies so far have reported the impact of comorbid PTSD on core features of BD, such as number of mood episodes and functional impairment. On the other hand, preclinical studies showed that there is a cross-sensitization between BD and PTSD. Accordingly, it was proposed that the brain-derived neurotrophic factor (BDNF) and changes of inflammatory markers might be the biological underpinnings of this cross-sensitization. Although the changes in inflammatory markers are well established in BD, this is not the case for PTSD. In view of the above, the first two studies of this thesis addressed clinical and biological issues related to BD and PTSD. The first is a meta-analysis and metaregression study that showed increased levels of IL-6, IL-1β, TNF-α and interferon-γ in peripheral circulation among patients with PTSD. Furthermore, illness duration was positively associated with IL-1β levels, while the severity of the symptoms was positively associated with IL-6 levels. These findings may not only provide a new biological mechanism to explain the cross-sensitization between PTSD and BD, but also opens a new avenue in the search for new therapeutic targets and diagnostic strategies for PTSD. The second was a case-control study that assessed core clinical features of BD showed increased manic episodes and functional impairment among patients with BD and comorbid PTSD. In addition, those patients were younger when they started the manic episodes and substance use. Moreover, we chose to address the influence of comorbid anxiety disorders (such as PTSD) in suicide in patients with mood disorders. This study was conducted in a different population, including patients with major depressive disorder or BD, and it was focused on only one outcome. Suicide is a tragic clinical outcome, but highly preventable. Our aim was to develop a clinical tool using machine learning techniques to estimate a probability score at individual level to stratify the risk of a patient with a mood disorder attempts suicide. Therefore, our study showed that the risk of suicide in individuals with a mood disorder can be objectively estimated from easily assessed clinical and demographic variables. Although we have found a good accuracy (72%) and area under the curve (77%), future studies may integrate data from biological markers (genetic, neuroimaging, neurocognition, etc.) also using machine learning techniques to achieve a higher accuracy. This objective instrument is the first step towards a more personalized treatment for those patients at high risk of suicide.

Privacidade é um termo de grande amplitude. Uma característica comum às definições é a ênfase dada ao direito individual de revelar-se seletivamente ao mundo. Originalmente, a utilização do termo privacidade relacionava-se a direitos como o corporal e o direito territorial. Com a revolução da informática e, posteriormente, com o surgimento da Internet e o fácil acesso a dados pessoais por parte das empresas e governos, uma nova questão surge: a discussão sobre o direito à privacidade informacional. Por sua vez, as empresas do século XXI e a nova comunicação de Marketing passam por grandes transformações associadas ao desenvolvimento de bancos de dados de consumidores e de novas mídias. O e-mail e as redes sociais tornaram-se formas novas de se comunicar com o consumidor, individualmente. Associadas à informação sobre cada uma das pessoas, essas ferramentas permitem que a comunicação seja mais assertiva e, potencialmente, mais relevante para o consumidor. Isso porque uma de suas características fundamentais é a menor dispersão da mensagem, quando comparadas com mídias como a televisão. Entretanto, quanto mais a comunicação de Marketing procura o alvo, mais tênue fica a linha que separa a relevância da sensação de invasão de privacidade. O presente trabalho buscou compreender como o consumidor, alvo da comunicação, entende o processo de decisão entre defesa da sua privacidade e acesso a serviços personalizados, ou seja, como se dá esse trade off . Há carência de trabalhos nessa área, e a contribuição das pesquisas de Allan Westin (2003), realizadas na área do Direito Público, serviu como arcabouço teórico para o desenvolvimento de um questionário estruturado e para os tipos de análises que foram realizadas. Foram coletados dados de 1.791 internautas, que responderam ao questionário. Esses dados foram analisados com o auxílio de técnicas estatísticas univariadas e multivariadas, como análise de regressão e análise de cluster. O resultado da pesquisa engloba a análise dos dados primários e a revisão da literatura. Uma das conclusões é que o comportamento dos consumidores não é uniforme em relação ao tema. Confirmando as descobertas de Westin, foram identificados grupos de consumidores que valorizam mais a privacidade, e outros que valorizam mais os benefícios da personalização. Outra descoberta sugere que essa escolha não é um processo completamente consciente, e ele se dá, algumas vezes, de forma involuntária e até contraditória. Ao focar os benefícios, o consumidor parece esquecer a privacidade. Ao focar a privacidade, ele parece querer colocar limites à personalização. / Privacy is a broad-spectrum word. A common feature among the different definitions of the term is the emphasis placed on the right of the individual to reveal his or her self to the world in a selective way. Originally, the use of the word privacy was related to rights such as bodily rights and territorial rights. With the computer revolution and, later, the advent of the Internet and easy access to personal data by companies and government agencies, a new issue arose: the debate about the right to informational privacy. On the other hand, the companies of the 21th century and the new marketing communication have undergone great changes connected to the development of consumer databases and new medias. E-mail and the social networks have become new ways to establish communication with the consumer on an individual basis. Associated to information about each individual, such tools can make communication more assertive and, potentially, more relevant for the consumer. The reason is that one of its fundamental traits is the small degree of message dispersion, in comparison with medias such as television. However, the more Marketing communication seeks its target, the thinner is the line that separates relevance from the feeling of privacy invasion. The purpose of the present study is to verify how the consumer, the target of communication, understands the decision-making process involving the protection of his/her privacy versus the access to customized services, in other words, how such trade-off takes place. There are insufficient studies in this area; the research conducted by Allan Westin (2003) in the field of Public Law was the theoretical framework for the preparation of a structured survey and for the type of analysis carried out in this project. Data from 1,791 Internet-users was collected based on their answers to the survey. Such data was analyzed using uni- and multi-varied statistical techniques, such as regression analysis and cluster analysis. The result of the said survey comprises the analysis of primary data and a review of the corresponding literature. One of the conclusions is that the consumers behavior is not uniform in relation to this topic. In confirmation of Westin´s findings, there are groups of consumers who value their privacy more and others who prefer the benefits of customization. Another finding suggests that such choice is not completely conscious, and sometimes happens in an involuntary and even contradictory form. When the focus is on benefits, the consumer seems to forget his/her privacy. When the focus is on privacy, the consumer apparently wants to set some limits to customization.

Due to a rapid increase in aging population, demand for personalized health care increases proportionally. Personalized patient data can be a helpful way of catering the needs and requirements of elderly people staying at home. Indirectly, it can be a manner of providing better eHealth services according to their needs. Another interesting aspect of providing better personalized eHealth services is to make patient information systems interoperable. Interoperability of eHealth systems is an issue of great concern to current research and development but in this study, we focus on patient information systems. Like in some other European countries, introduction of open source platform to achieve interoperability and personalization of patient information system could save money for health care organizations and make the procedure easier in Sweden also. The purpose of this study is to identify what standards are available for interoperability and what are the benefits and challenges of introducing open source systems for achieving personalized interoperable patient information systems (PIPIS). In light of this investigation, author has identified the benefits and challenges of introducing OSS for achieving PIPIS. Author has also made several recommendations regarding the challenges identified. / In the name of ALLAH, the most gracious and merciful. I extend my gratitude to the beautiful creator of this beautiful universe that He made for us to conquer. Without the love of my parents this thesis report could never be possible for me to write. All my love and care is for them which no one else can share. I thank Mr. Hans Kyhlbäck whose supervision is a source of inspiration for doing this study. He is definitely the best supervisor to work with. In the end, I would like to thank my friends and colleagues whose help just kept me going despite of many hurdles that I faced.

The utilization of mathematical tools within biology and medicine has traditionally been less widespread compared to other hard sciences, such as physics and chemistry. However, an increased need for tools such as data processing, bioinformatics, statistics, and mathematical modeling, have emerged due to advancements during the last decades. These advancements are partly due to the development of high-throughput experimental procedures and techniques, which produce ever increasing amounts of data. For all aspects of biology and medicine, these data reveal a high level of inter-connectivity between components, which operate on many levels of control, and with multiple feedbacks both between and within each level of control. However, the availability of these large-scale data is not synonymous to a detailed mechanistic understanding of the underlying system. Rather, a mechanistic understanding is gained first when we construct a hypothesis, and test its predictions experimentally. Identifying interesting predictions that are quantitative in nature, generally requires mathematical modeling. This, in turn, requires that the studied system can be formulated into a mathematical model, such as a series of ordinary differential equations, where different hypotheses can be expressed as precise mathematical expressions that influence the output of the model. Within specific sub-domains of biology, the utilization of mathematical models have had a long tradition, such as the modeling done on electrophysiology by Hodgkin and Huxley in the 1950s. However, it is only in recent years, with the arrival of the field known as systems biology that mathematical modeling has become more commonplace. The somewhat slow adaptation of mathematical modeling in biology is partly due to historical differences in training and terminology, as well as in a lack of awareness of showcases illustrating how modeling can make a difference, or even be required, for a correct analysis of the experimental data. In this work, I provide such showcases by demonstrating the universality and applicability of mathematical modeling and hypothesis testing in three disparate biological systems. In Paper II, we demonstrate how mathematical modeling is necessary for the correct interpretation and analysis of dominant negative inhibition data in insulin signaling in primary human adipocytes. In Paper III, we use modeling to determine transport rates across the nuclear membrane in yeast cells, and we show how this technique is superior to traditional curve-fitting methods. We also demonstrate the issue of population heterogeneity and the need to account for individual differences between cells and the population at large. In Paper IV, we use mathematical modeling to reject three hypotheses concerning the phenomenon of facilitation in pyramidal nerve cells in rats and mice. We also show how one surviving hypothesis can explain all data and adequately describe independent validation data. Finally, in Paper I, we develop a method for model selection and discrimination using parametric bootstrapping and the combination of several different empirical distributions of traditional statistical tests. We show how the empirical log-likelihood ratio test is the best combination of two tests and how this can be used, not only for model selection, but also for model discrimination. In conclusion, mathematical modeling is a valuable tool for analyzing data and testing biological hypotheses, regardless of the underlying biological system. Further development of modeling methods and applications are therefore important since these will in all likelihood play a crucial role in all future aspects of biology and medicine, especially in dealing with the burden of increasing amounts of data that is made available with new experimental techniques. / Användandet av matematiska verktyg har inom biologi och medicin traditionellt sett varit mindre utbredd jämfört med andra ämnen inom naturvetenskapen, såsom fysik och kemi. Ett ökat behov av verktyg som databehandling, bioinformatik, statistik och matematisk modellering har trätt fram tack vare framsteg under de senaste decennierna. Dessa framsteg är delvis ett resultat av utvecklingen av storskaliga datainsamlingstekniker. Inom alla områden av biologi och medicin så har dessa data avslöjat en hög nivå av interkonnektivitet mellan komponenter, verksamma på många kontrollnivåer och med flera återkopplingar både mellan och inom varje nivå av kontroll. Tillgång till storskaliga data är emellertid inte synonymt med en detaljerad mekanistisk förståelse för det underliggande systemet. Snarare uppnås en mekanisk förståelse först när vi bygger en hypotes vars prediktioner vi kan testa experimentellt. Att identifiera intressanta prediktioner som är av kvantitativ natur, kräver generellt sett matematisk modellering. Detta kräver i sin tur att det studerade systemet kan formuleras till en matematisk modell, såsom en serie ordinära differentialekvationer, där olika hypoteser kan uttryckas som precisa matematiska uttryck som påverkar modellens output. Inom vissa delområden av biologin har utnyttjandet av matematiska modeller haft en lång tradition, såsom den modellering gjord inom elektrofysiologi av Hodgkin och Huxley på 1950‑talet. Det är emellertid just på senare år, med ankomsten av fältet systembiologi, som matematisk modellering har blivit ett vanligt inslag. Den något långsamma adapteringen av matematisk modellering inom biologi är bl.a. grundad i historiska skillnader i träning och terminologi, samt brist på medvetenhet om exempel som illustrerar hur modellering kan göra skillnad och faktiskt ofta är ett krav för en korrekt analys av experimentella data. I detta arbete tillhandahåller jag sådana exempel och demonstrerar den matematiska modelleringens och hypotestestningens allmängiltighet och tillämpbarhet i tre olika biologiska system. I Arbete II visar vi hur matematisk modellering är nödvändig för en korrekt tolkning och analys av dominant-negativ-inhiberingsdata vid insulinsignalering i primära humana adipocyter. I Arbete III använder vi modellering för att bestämma transporthastigheter över cellkärnmembranet i jästceller, och vi visar hur denna teknik är överlägsen traditionella kurvpassningsmetoder. Vi demonstrerar också frågan om populationsheterogenitet och behovet av att ta hänsyn till individuella skillnader mellan celler och befolkningen som helhet. I Arbete IV använder vi matematisk modellering för att förkasta tre hypoteser om hur fenomenet facilitering uppstår i pyramidala nervceller hos råttor och möss. Vi visar också hur en överlevande hypotes kan beskriva all data, inklusive oberoende valideringsdata. Slutligen utvecklar vi i Arbete I en metod för modellselektion och modelldiskriminering med hjälp av parametrisk ”bootstrapping” samt kombinationen av olika empiriska fördelningar av traditionella statistiska tester. Vi visar hur det empiriska ”log-likelihood-ratio-testet” är den bästa kombinationen av två tester och hur testet är applicerbart, inte bara för modellselektion, utan också för modelldiskriminering. Sammanfattningsvis är matematisk modellering ett värdefullt verktyg för att analysera data och testa biologiska hypoteser, oavsett underliggande biologiskt system. Vidare utveckling av modelleringsmetoder och tillämpningar är därför viktigt eftersom dessa sannolikt kommer att spela en avgörande roll i framtiden för biologi och medicin, särskilt när det gäller att hantera belastningen från ökande datamängder som blir tillgänglig med nya experimentella tekniker.

La radiothérapie est souvent utilisée pour contrôler la progression d'un cancer. Cependant, la mauvaise spécificité de ciblage de la plupart des techniques de radiothérapie peut entraîner une réponse clinique ambiguë. Une stratégie alternative - et complémentaire - est d'utiliser des matériaux possédant un numéro atomique élevé et qui peuvent ainsi agir en synergie avec les rayonnements ionisants pour améliorer le ratio thérapeutique de la radiothérapie. Dans ce contexte, une nanoparticule (NP) théranostique à base de gadolinium (Gd) est particulièrement adaptée pour fournir simultanément une plus grande précision en Imagerie par Résonance Magnétique (IRM) et une meilleure efficacité en radiothérapie clinique. Au cours de cette thèse, nous avons étudié d'un point de vue préclinique la pharmacocinétique et le métabolisme de ces NP chez des rongeurs et des primates non humains afin d'élucider leurs voies d'élimination et de calculer la dose sans effet nocif observé (NOAEL). De plus, nous avons démontré la capacité d'imagerie et de thérapie de ces particules sur un modèle de souris porteuses de mélanome cérébral, ceci afin d'appuyer le potentiel des NP pour la radiothérapie guidée par IRM en clinique. Ces travaux de thèse - ainsi que des résultats précédents - ont contribué au début d'un essai clinique actuellement en cours / Combinations of chemotherapy and radiotherapy are often used to control cancer progression. However, the poor targeting specificity of most chemotherapies and radiotherapies can cause toxicity and ambiguous clinical response. In particular, dose escalation in radiotherapy inevitably increases radiation exposure for some surroundings normal tissues and organs, putting them at risk for debilitating damage. An alternative – and complementary – strategy is the use of materials with high atomic numbers (Z) that strongly interact with low energy photons to produce photoelectrons and Auger electrons In this context, a new efficient type of gadolinium (Gd)-based theranostic agent (AGuIX®) has recently been developed by the team of Prof. Tillement for MRI-guided radiotherapy. AGuIX® is a 3-nm size nanoparticles of 9 kDa, consist of a polysiloxane network surrounded by Gd chelates. In this thesis, we investigated the elimination kinetics of AGuIX nanoparticle’s (NPs) from sub-cellular to whole organ scale using original and complementary techniques. This combination of techniques allows the exact mechanism of AGuIX NPs elimination to be elucidated. We reported the preclinical pharmacokinetics and toxicology studies of intravenous AGuIX NPs administration in healthy and atherosclerosis non-human primates (NHP), the goal of which is to demonstrate the safety of AGuIX NPs, in particular, for pre-clinical evaluation. Subsequently, we performed experimental and theoretical studies to investigate the radiosensitization of AGuIX NPs, in particular with B16F10 mouse melanoma as a model for brain metastases. After, we implemented experimental and theoretical studies to precisely understand the mechanism of this radiosensitization, we suggest additional mechanism, potentially caused by chemical and biological effects induced by the combination of Gd and radiation (i.e. high yield of radicals formation and combination, and bystander effect)

A major challenge of cancer treatment is successful discrimination of cancer cells from healthy cells. Nanotechnology offers multiple venues for efficient cancer targeting. Magnetoelectric nanoparticles (MENs) are a novel, multifaceted, physics-based cancer treatment platform that enables high specificity cancer targeting and externally controlled loaded drug release. The unique magnetoelectric coupling of MENs allows them to convert externally applied magnetic fields into intrinsic electric signals, which allows MENs to both be drawn magnetically towards the cancer site and to electrically interface with cancer cells. Once internalized, the MEN payload release can be externally triggered with a magnetic field. MENs uniquely allow for discrete manipulation of the drug delivery and drug release mechanisms to allow an unprecedented level of control in cancer targeting. In this study, we demonstrate the physics behind the MEN drug delivery platform, test the MEN drug delivery platform for the first time in a humanized mouse model of cancer, and characterize the biodistribution and clearance of MENs. We found that MENs were able to fully cure the model cancer, which in this case was human ovarian carcinoma treated with paclitaxel. When compared to conventional magnetic nanoparticles and FDA approved organic PLGA nanoparticles, MENs are the highest performing treatment, even in the absence of peripheral active targeting molecules. We also mapped the movement through peripheral organs and established clearance trends of the MENs. The MENs cancer treatment platform has immense potential for future medicine, as it is generalizable, personalizable, and readily traceable in the context of treating essentially any type of cancer.

In my dissertation, I try to clarify the personalization of content based on the input data. Thesis deals with relatively new area of direct marketing in personalised documents delivered to end-beneficiaries through various channels, which features a classic print and e-mail. It also highlighted the importance of evaluating and analyzing the data recipient and based on feedback to modify future communications. The aim is to describe the development of application software for managing customer communication and demonstrate its effect.