A Amiotrofia Espinhal Progressiva (AEP) é uma doença autossômica recessiva que afeta os motoneurônios do corno anterior da medula espinhal, acarretando hipotonia e fraqueza muscular. A partir do conhecimento do mecanismo molecular da AEP, abriu-se um campo para testes clínicos com agentes farmacológicos que possam aumentar o nível da proteína SMN2. Diversas drogas com esta ação estão sendo testadas na tentativa de encontrar um possível tratamento para esta trágica doença. O ácido valpróico (AV), droga muito utilizada para o tratamento da epilepsia mostrou ter a propriedade de ativar o promotor do gene da proteína SMN2, aumentando a sua produção. Tendo em vista que não há uniformização do sistema de avaliação clínica dos resultados do tratamento em diferentes países, foi elaborado um protocolo selecionando métodos de avaliação fáceis, rápidos e já validados a fim de verificar se o AV é eficaz para manter ou melhorar a força muscular dos pacientes com AEP. Os métodos selecionados foram: escala Medical Research Council (MRC) para força muscular; Hammersmith motor ability score para habilidade motora; goniometria das principais articulações; cronometragem de tempo despendido para deambular, quando possível; índice de Barthel para atividades da vida diária e, por fim, um questionário para verificar as modalidades de fisioterapia e hidroterapia em uso. Vinte e dois pacientes com AEP tipo II e III, com idades variando de 2 a 18 anos, medicados com AV, foram avaliados a cada três meses durante um ano, totalizando cinco visitas, das quais a primeira ocorreu nos dias anteriores ao início do tratamento. Os resultados dos testes demonstraram que, durante o seguimento de um ano, os pacientes obtiveram melhora na habilidade motora, porém não na força muscular, o que é um resultado extremamente positivo. Crianças com idade menor ou igual a 6 anos mostraram melhores ganhos quanto à habilidade motora. / Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder that affects the spinal motoneurons, resulting in hypotonia and muscle weakness. The knowledge of the molecular mechanism of SMA has originated new researches including clinical trials with pharmacological agents that increase SMN2 protein level. Many drugs with this action are being tested with the aim of finding a possible treatment for this severe disease. The valproic acid (VA), a well-known drug used to treat epilepsy has the property of activating the SMN2 gene promoter and then to increase SMN2 protein level. Since there isnt an uniform system for the clinical evaluation of the treatment results, we selected a set of easy, fast and already validated methods to evaluate if the VA is effective to stabilize or improve the motor function in patients with SMA. The selected methods were: Medical Research Council scale (MRC) to muscular strength; Hammersmith motor ability score to motor ability; goniometry of the main joints; time to walk when possible; Barthel índex for daily activities, and a questionnaire to verify the types of physiotherapy and hydrotherapy in use. Twenty two patients with SMA II and III, aged between 2 and 19 years, and treated with VA were evaluated every three months during the period of one year; the first evaluation occurred immediately before the onset of the treatment. The results of the tests demonstrated that along the period of 12 months the patients didnt gain muscle strength but improved their motor ability, that can be considered a positive result. Children aged six years or younger had a higher gain in motor ability along the period of the study.

Bakgrund Kroniskt obstruktiv lungsjukdom (KOL) är en av de sjukdomar som orsakar flest dödsfall världen över. Personer med KOL når sällan upp till rekommenderade aktivitetsnivåer, kan erhålla ett långsammare sjukdomsförlopp, en bättre bättre livskvalitet (QoL), samt bättre hälso relaterad livskvalitet (HRQoL) om de upprätthåller rekomenderade fysiska aktivitetsnivåer.  Syfte Syftet med denna studie är att undersöka sambandet mellan objektivt mätt intensitet vid fysisk aktivitet och QoL samt HRQoL hos personer med KOL, samt skillnader mellan män och kvinnor. Vidare undersöka sambandet mellan objektivt mätt fysisk aktivitet mätt i antal steg och QoL samt HRQoL. Metod  Antal steg  i vardagen samt durationen i moderat till hög intensitet (MVPA) mättes objektivt med en accelerometer (DynaPort, McRoberts BV, The Netherlands). QoL mättes med en visuell ordinalskala i EuroQol-5D (EQ-5D) och HRQoL skattades med formulären COPD Assessment Test (CAT), Modified Medical Research Council Questionnaire (mMRC). Spearman´s rangkorrelationskoefficiet (rho) användes för att undersöka korrelationen i statistikprogramvaran Jamovi.  Resultat Sambandet mellan MVPA och QoL (EQ-5D) HRQoL (CAT, mMRC) samt HRQoL (CAT, mMRC)  för hela gruppen visade liten eller ingen korrelation förutom för mMRC som visade en låg korrelation, (rho= -.327, p= <0.001). Sambandet mellan MVPA och QoL (EQ-5D)  samt  HRQoL (CAT, mMRC) för gruppen kvinnor visade alla på en liten eller ingen korrelation. Sambandet mellan MVPA och QoL (EQ-5D) samt HRQoL (CAT, mMRC) för gruppen män visade alla på en låg korrelation. Sambandet mellan antal steg och QoL (EQ-5D) samt HRQoL (CAT, mMRC) samt för hela gruppen visade på en låg korrelation förutom för CAT som visade en liten eller ingen korrelation. Slutsats  Resultatet i denna studie visade tecken på att personer med KOL som spenderar mer tid i MVPA skattar något bättre HRQoL utifrån lägre skattad dyspné jämfört de forskningspersoner som spenderar mindre tid på samma intensitet. Resultatet visade även att duration i MVPA och antal steg per dag är två variabler som kan ha minst lika stor betydelse bland personer med KOL, då de ska skatta QoL och HRQoL. Dataanalysen i denna studie visade även på att det fanns ett starkare samband för män vad gäller totalt tid spenderad i MVPA och QoL samt HRQoL än vad det gör för kvinnor.

Objectives: Adherence to psychotropic medication is poor among individuals with bipolar disorder (BD). To understand treatment experiences and associated adherence among these individuals, we developed a novel construct of Clinical Net Benefit (CNB) using psychiatric symptoms, adverse effects and overall functioning assessments. We tested whether adherence differed across classes of CNB, whether individuals transitioned between classes over time, and whether these transitions were differentially associated with adherence. Methods: Data come from individuals aged 18+ during five years of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Latent class analysis identified groups of CNB. Latent transition analysis determined probabilities of transitioning between classes over time. Adherence was defined as taking 75%+ of medications as prescribed. Associations between CNB and adherence were tested using multiple logistic regression adjusting for sociodemographic characteristics. Results: Five classes of CNB were identified during the first two years (high, moderately high, moderate, moderately low, low), and four classes (removing moderately high) during the last three years. Adherence did not differ across classes or time points. Medication regimens differed by class; those with higher CNB taking fewer medications had lower odds of adherence while those with lower CNB taking more medications had higher odds of adherence compared with monotherapy. Probability of transitioning from higher to lower CNB, and lower to higher CNB was greatest over time. Conclusions: CNB is heterogeneous in individuals treated for BD, and movement between classes is not uncommon. Understanding why individuals adhere despite suboptimal CNB may provide novel insights into aspects influencing adherence.

Immunotherapy of cancer has been shown to be promising in prolonging patient survival. However, complete elimination of cancer and life-long relapse-free survival remain to be major challenge for anti-cancer therapeutics. We have previously reported that ex vivo reprogramming of tumor-sensitized immune cells by bryostatin 1/ionomycin (B/I) and the gamma-chain (γ-c) cytokines IL-2, IL-7, and IL-15 resulted in the generation of memory T cells as well as CD25+ NKT cells and CD25+ NK cells. Adoptive cellular therapy (ACT) utilizing these reprogrammed immune cells protected FVBN202 mice from tumor challenge, and overcame the suppressive functions of myeloid-derived suppressor cells (MDSCs). We then demonstrated that the presence of CD25+ NKT cells was required for anti-tumor efficacy of T cells as well as their resistance to MDSCs. Similar results were obtained by reprogramming of peripheral blood mononuclear cells (PBMC) from patients with early stage breast cancer, demonstrating that an increased frequency of CD25+ NKT cells in reprogrammed immune cells was associated with modulation of MDSCs to CD11b-HLA-DR+ immune stimulatory cells. Here, we tested the efficacy of immunotherapy in a therapeutic setting against established primary breast cancer (Chapter One), experimental metastatic breast cancer (Chapter Three) as well as against minimal residual disease (MRD) in patients with multiple myeloma (Chapter Two). We evaluated the ability of reprogrammed immune cells, including CD25+ NKT cells, to convert MDSCs to myeloid immune stimulatory cells, in vivo; this resulted in the identification and characterization of a novel antigen presenting cell (APC). These novel immune stimulatory cells differed from conventional APCs, including dendritic cells (DCs) and macrophages. We have also demonstrated that enhancing immunogenicity of mammary tumors by treatment with Decitabine (Dec) along with overcoming MDSCs by utilizing reprogrammed T cells and NKT cells in ACT prolongs survival of animals, but fails to eliminate the tumor. However, targeting cancer during a setting of MDR, when tumor cells are dormant, results in objective responses as evidenced in our multiple myeloma studies. This suggests that targeting breast cancer with immunotherapy following conventional therapies, in a setting of residual disease when tumor cells are dormant, may be effective in eliminating such residual cells or maintaining dormancy and extending time-to-relapse for breast cancer patients.

Cancer involves the dysregulated proliferation and growth of cells throughout the body. C-terminal binding proteins (CtBP) 1 and 2 are transcriptional co-regulators upregulated in several cancers, including breast, colorectal, and ovarian tumors. CtBPs drive oncogenic properties, including migration, invasion, proliferation, and survival, in part through repression of tumor suppressor genes. CtBPs encode an intrinsic dehydrogenase activity, utilizing intracellular NADH concentrations and the substrate 4-methylthio-2-oxobutyric acid (MTOB), to regulate the recruitment of transcriptional regulatory complexes. High levels of MTOB inhibit CtBP dehydrogenase function and induce cytotoxicity among cancer cells in a CtBP-dependent manner. While encouraging, a good therapeutic would utilize >100-fold lower concentrations. Therefore, we endeavored to design better CtBP-specific therapeutics. The best of these drugs, 3-Cl and 4-Cl HIPP, exhibit nanomolar enzymatic inhibition and micromolar cytotoxicity and showed that CtBP enzymatic function is subject to allosteric interactions. Additionally, the function of the substrate-binding domain has yet to be examined in context of CtBP’s oncogenic activity. To this end, we created several point mutations in the CtBP substrate-binding pocket and determined key residues for CtBP’s enzymatic activity. We found that a conserved tryptophan in the catalytic domain is imperative for function and unique to CtBPs among dehydrogenases. Knowledge of this and other residues allows the directed synthesis of drugs with increased potency and higher CtBP specificity. Early work interrogated the importance of these residues in cell migration. Taken together, this work addresses the utility of the CtBP substrate-binding domain as a target for cancer therapeutics.

In order to reduce the time associated with and the costs of drug discovery, machine learning is being used to automate much of the work in this process. However the size and complex nature of molecular data makes the application of machine learning especially challenging. Much work must go into the process of engineering features that are then used to train machine learning models, costing considerable amounts of time and requiring the knowledge of domain experts to be most effective. The purpose of this work is to demonstrate data driven approaches to perform the feature selection and extraction steps in order to decrease the amount of expert knowledge required to model interactions between proteins and drug molecules.

Psychiatric genetics is a basic science field that has potential for practical application and effective translation. To date, translational frameworks utilized by this field have been linear (e.g., sequential) in nature, focusing on molecular genetic information. It is proposed that non-linear (e.g., socio-ecological) frameworks are a better way to immediately translate non-molecular genetic information. This dissertation explored the translation of psychiatric genetic information in two ways. First, a survey was sent to academic stakeholders to assess the state of the science regarding the translation of genetic information to the clinical care of mental health disorders. Findings from this indicate a translation-genetic competence gap whereby genetic knowledge reinforces linear frameworks and genetic competence is needed to achieve effective translation in this content area. Second, a new risk factor model for social anxiety was created that incorporated genetic, environmental, and neurophysiological risk factors (behavioral inhibition, parental bonding, emotion reactivity). Findings indicate that genetic etiology is more informative knowledge that can influence risk factor models and possibly prevention and intervention efforts for social anxiety. Overall this dissertation paves the way for examining the translational capacity of psychiatric genetics in a clinical setting. It constitutes the first examination of barriers to and a potential solution for the most effective translation of psychiatric genetic information.

Plus souvent étudiée dans le cadre états-unien, la philanthropie fait l’objet d’un nombre accru de travaux en France aussi. Il s’agit ici d’examiner les organismes à but non-lucratif se consacrant aux sciences de la santé, à la jonction d’une histoire de la recherche médicale et d’une histoire des fondations. Le premier objectif est de recenser et de décrire ces organisations : actions, fonctionnements, modèles économiques. Le deuxième d’interpréter leur essor depuis la fin du XXe siècle – le nombre de fondations françaises tous domaines confondus a doublé en quinze ans, comme leurs dépenses et leurs actifs. De nouveaux statuts ont été créés, en particulier celui du fonds de dotation en 2008, la législation dans ce domaine, de manière générale, s’étoffant significativement au cours de cette décennie. En encourageant ainsi les instruments visant à lever de l’argent privé, la puissance publique initie-t-elle une forme de désengagement, ou du moins un redéploiement de ses missions ? Si la réponse ne peut être que nuancée, il est notable que l’étude des fonds et fondations nous place au cœur d’une histoire des transformations récentes de l’État, sur laquelle elle ambitionne d’apporter un éclairage spécifique, en faisant voir notamment ses implications pour les médecins chercheurs, confrontés à une complexité croissante des modes de financement. / Usually considered in the american context, philanthropy is the subject of a growing number of studies in France also. We here examine non-profits that are dedicated to health sciences, at the juncture of two distinct fields: history of medical research and history of charitable foundations. Our first objective is to list and describe these organizations: their actions, functioning and economic models. The second one is to interpret their expansion since the end of the 20th century – the number of French foundations all types combined doubled in 15 years, as did their assets and expenditures. New legal forms were created, most notably the endowment fund («fonds de dotation») in 2008, as legislation in this field developed. By encouraging tools whose purpose is to collect private money, are public authorities initiating a form of disengagement, or at least a restructuring of their missions? The answer must remain nuanced, but it is notable that studying charitable funds and foundations places us at the heart of another field: history of State transformation, which we hope to shed some light on, by showing its implications for researchers, who are facing a growing complexity in science funding.

Pour progresser sans cesse, guérir ou accroitre les connaissances, le prélèvement d’origine humaine devient le support de la recherche. Celui-ci réunit alors une diversité de réalités médicales et juridiques.De plus, l’évolution historique et médicale a transcendé la matérialité du corps pour devenir immatérialité de l’être. Le polymorphisme de l’objet le rend complexe et connexe à d’autres disciplines pour en déterminer ses fins. D’un tableau du prélèvement, il faut alors en dessiner les contours, les cadres pour en préciser les usages : sans structure pas d’ossature. Son intérêt dans la recherche comme sa nature rendent essentiel l’encadrement de son utilisation. De cette ambivalence de l’outil scientifique s’associe celle de l’outil juridique qui fonde l’équilibre dans son usage. Celui-ci doit s’accommoder. D’une part des nouvelles résonances juridiques du corps, marquées de la distanciation qui s’opère en fait en en droit entre le prélevé et le prélèvement. D’autre part des progrès de la science, dont les connaissances dépassent notre essence risquant de faire perdre alors à la société tout son sens / To increase permanently the knowledge of the Science, the human sample becomes the basis of the Research. Indeed, it symbolizes the scales of the diversity embodied by the medicine and the law. Moreover, the evolution of the medical history allows the body through its materiality to become an immateriality with this spirit and the numeric. The object, which is the body, is complex and attached to lots of different fields that determine its aims. The painting of the human sample is drawn. To go further this thesis will try to lay the foundations of the rules of the human sample. This Research will try to fix the structure of the sample to find the rules and the procedure of the human sample thanks to the law. Without skeleton, no human sample. This is merely bare bone. The interest of the human sample as its nature itself is essential to characterize its interest and the process of its utility. Thanks to this dual image ¬ legal and medical ¬ of the human sample we can find a balance for its using. On one hand to be well-balance the human sample must adapt itself to the new laws taking into account the difference between the status of the human and the status of the human sample. On the other hand, the human sample is just a small thing compared with the financial or scientist stakes due to the globalization. What is the real place of the human sample then ?

This thesis is made up of two parts. Part A - describes the construction of a scintillation counter and its operation, as an instrument for use in medical research. Part B - is a study of the stopping of mesons in various absorbers as a preliminary to the investigation of the meson decay process. / Thesis / Master of Science (MS)