Objetivos: O objetivo deste estudo foi o de identificar compostos seletivamente tóxicos ao carcinoma espinocelular de boca in vitro por meio do reposicionamento de fármacos. Material e Métodos: Por meio de um escaneamento baseado na viabilidade celular de 1.280 fármacos, nós selecionamos três princípios ativos (luteolin, metixene hydrochloride e nitazoxanide) letais às células de câncer de boca SCC-25 e pouco tóxicos às células de queratinócitos cutâneos imortalizados HaCaT. Os fármacos candidatos foram investigados quanto à sua dose- e tempo-resposta bem como comparados e combinados à agentes quimioterápicos padrão por meio do ensaio por colorimetria com brometo de tiazolil azul de tetrazolio (MTT). O impacto dos fármacos na motilidade do SCC-25 e do HaCaT foi verificado pelo ensaio de migração celular e seus mecanismos de ação também foram explorados por meio da verificação dos níveis das proteínas fosforiladas pelo western blotting. Todos os experimentos foram realizados em triplicata e, pelo menos, três vezes independentes. O teste t de student foi utilizado para confrontar as variáveis e nível de significância de 5% foi estabelecido para todos os testes. Resultados: O flavonoide natural luteolin exerceu citotoxicidade potente contra as células de câncer de boca in vitro, apresentando baixa toxicidade ao HaCaT e alta eficiência quando comparado a quimioterápicos como a cisplatina e o AG1478. Do ponto de vista molecular, a luteolin ativou a via de sinalização do dano do DNA e, combinada com um inibidor do Chk, apresentou efeitos potencializados. Além disso, nós demonstramos que a nitazoxanide e o metixene hydrochloride são capazes de destruir células SCC-25 porém não as HaCaT de maneira proporcional à dose e ao tempo de tratamento. As combinações entre os três fármacos hit e com a cisplatina ou o AG1478 potencializaram seus efeitos contra as células malignas. Conclusões: O presente estudo traz a luteolin, o metixene hydrochloride e a nitazoxanide como fortes candidatos a agentes terapêuticos contra o câncer de boca uma vez que estes compostos apresentam maior eficácia contra células de câncer de boca e menor toxicidade contra células não tumorais in vitro do que agentes quimioterápicos convencionais. / Objectives: Here we aimed at identifying and reposition approved drugs that could be selectively toxic towards oral squamous cell carcinoma cells. Materials and Methods: Through a cell-based drug screening of 1,280 chemical molecules, we selected 3 compounds (luteolin, metixene hydrochloride, and nitazoxanide) lethal to oral cancer SCC-25 cells, while sparing immortalized keratinocyte HaCaT cells. The drugs were then further challenged for their time- and dose-responses, as well as their comparison and combination to standard chemotherapeutic agents by colorimetric assay 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan, Thiazolyl blue formazan (MTT). The impact on SCC-25 and HaCaT motility as well as the mode of action of the drugs was then further explored by scratching assay and western blotting, respectively. All the experiments were performed in triplicated and, at least, three independent times. Students t test was performed to verify the differences among the variables and the level of significance was set at 5%. Results: The natural flavonoid luteolin was a potent cytotoxic agent against oral cancer cells in vitro, presenting low toxicity against HaCaT cells and high efficiency as compared to standard-of-care, such as cisplatin and AG1478. From a molecular standpoint, luteolin coopted the DNA-damage pathway and could be efficiently combined with Chk pharmacological inhibitor. Moreover, we demonstrated that nitazoxanide and metixene hydrochloride kill the SCC-25 but not the HaCaT cells in a dose- and time-dependent. The combinations among the three drugs hit and with cisplatin and AG1478 improved their effect against the malignant cells. Conclusions: Luteolin, metixene hydrochloride, and nitazoxanide emerge as strong cytotoxic and/or adjuvant therapy in oral cancer, as these compounds present higher efficiency and lower toxicity against oral cancer cells in vitro than conventional chemotherapeutic agents.

by Mei Choi Tang. / Thesis submitted in 1997. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references. / Abstract also in Chinese. / Chapter Chapter 1. --- Introduction --- p.1-22 / Chapter Chapter 2. --- PAE studies for antimicrobial combinations using the Fractional Maximal Effect method (FME method) --- p.23-64 / Chapter Chapter 3. --- Effect of sequential antibiotic administration on the postantibiotic effect exhibited by an antimicrobial combination: A case for the combination of rifampin and tobramycin against E.coli ATCC 25922 --- p.65-84 / Chapter Chapter 4. --- Effect of antimicrobial resistance to the components of an antimicrobial combination: A pilot study with piperacillin and gentamicin against Ps. aeruginosa --- p.85-100 / Chapter Chapter 5. --- Conclusions --- p.101-106 / Appendix I --- p.107-113 / Appendix II --- p.114-116 / Appendix III --- p.117-120 / Appendix IV --- p.121-138 / Appendix V --- p.139-153

Neste trabalho uma nova estratégia de combinação de filtros adaptativos é apresentada e estudada. Inspirada por esquemas incrementais e filtragem adaptativa cooperativa, a combinação convexa usual de filtros em paralelo e independentes é reestruturada como uma configuração série-cooperativa, sem aumento da complexidade computacional. Dois novos algoritmos são projetados utilizando Recursive Least-Squares (RLS) e Least-Mean-Squares (LMS) como subfiltros que compõem a combinação. Para avaliar a performance da estrutura incremental, uma análise de média quadrática é realizada. Esta é feita assumindo que os combinadores têm valores fixos, de forma a permitir o estudo da universalidade da estrutura desacoplada da dinâmica do supervisor. As simulações realizadas mostram uma boa concordância com o modelo teórico obtido. / In this work a new strategy for combination of adaptive filters is introduced and studied. Inspired by incremental schemes and cooperative adaptive filtering, the standard convex combination of parallel-independent filters is rearranged into a series-cooperative configuration, while preserving computational complexity. Two new algorithms are derived employing Recursive Least-Squares (RLS) and Least-Mean-Squares (LMS) algorithms as the component filters. In order to assess the performance of the incremental structure, tracking and steady-state mean-square analysis is derived. The analysis is carried out assuming the combiners are fixed, so that the universality of the new structure may be studied decoupled from the supervisor\'s dynamics. The resulting analytical model shows good agreement with simulation results.

Neste trabalho uma nova estratégia de combinação de filtros adaptativos é apresentada e estudada. Inspirada por esquemas incrementais e filtragem adaptativa cooperativa, a combinação convexa usual de filtros em paralelo e independentes é reestruturada como uma configuração série-cooperativa, sem aumento da complexidade computacional. Dois novos algoritmos são projetados utilizando Recursive Least-Squares (RLS) e Least-Mean-Squares (LMS) como subfiltros que compõem a combinação. Para avaliar a performance da estrutura incremental, uma análise de média quadrática é realizada. Esta é feita assumindo que os combinadores têm valores fixos, de forma a permitir o estudo da universalidade da estrutura desacoplada da dinâmica do supervisor. As simulações realizadas mostram uma boa concordância com o modelo teórico obtido. / In this work a new strategy for combination of adaptive filters is introduced and studied. Inspired by incremental schemes and cooperative adaptive filtering, the standard convex combination of parallel-independent filters is rearranged into a series-cooperative configuration, while preserving computational complexity. Two new algorithms are derived employing Recursive Least-Squares (RLS) and Least-Mean-Squares (LMS) algorithms as the component filters. In order to assess the performance of the incremental structure, tracking and steady-state mean-square analysis is derived. The analysis is carried out assuming the combiners are fixed, so that the universality of the new structure may be studied decoupled from the supervisor\'s dynamics. The resulting analytical model shows good agreement with simulation results.

Objetivos: O objetivo deste estudo foi o de identificar compostos seletivamente tóxicos ao carcinoma espinocelular de boca in vitro por meio do reposicionamento de fármacos. Material e Métodos: Por meio de um escaneamento baseado na viabilidade celular de 1.280 fármacos, nós selecionamos três princípios ativos (luteolin, metixene hydrochloride e nitazoxanide) letais às células de câncer de boca SCC-25 e pouco tóxicos às células de queratinócitos cutâneos imortalizados HaCaT. Os fármacos candidatos foram investigados quanto à sua dose- e tempo-resposta bem como comparados e combinados à agentes quimioterápicos padrão por meio do ensaio por colorimetria com brometo de tiazolil azul de tetrazolio (MTT). O impacto dos fármacos na motilidade do SCC-25 e do HaCaT foi verificado pelo ensaio de migração celular e seus mecanismos de ação também foram explorados por meio da verificação dos níveis das proteínas fosforiladas pelo western blotting. Todos os experimentos foram realizados em triplicata e, pelo menos, três vezes independentes. O teste t de student foi utilizado para confrontar as variáveis e nível de significância de 5% foi estabelecido para todos os testes. Resultados: O flavonoide natural luteolin exerceu citotoxicidade potente contra as células de câncer de boca in vitro, apresentando baixa toxicidade ao HaCaT e alta eficiência quando comparado a quimioterápicos como a cisplatina e o AG1478. Do ponto de vista molecular, a luteolin ativou a via de sinalização do dano do DNA e, combinada com um inibidor do Chk, apresentou efeitos potencializados. Além disso, nós demonstramos que a nitazoxanide e o metixene hydrochloride são capazes de destruir células SCC-25 porém não as HaCaT de maneira proporcional à dose e ao tempo de tratamento. As combinações entre os três fármacos hit e com a cisplatina ou o AG1478 potencializaram seus efeitos contra as células malignas. Conclusões: O presente estudo traz a luteolin, o metixene hydrochloride e a nitazoxanide como fortes candidatos a agentes terapêuticos contra o câncer de boca uma vez que estes compostos apresentam maior eficácia contra células de câncer de boca e menor toxicidade contra células não tumorais in vitro do que agentes quimioterápicos convencionais. / Objectives: Here we aimed at identifying and reposition approved drugs that could be selectively toxic towards oral squamous cell carcinoma cells. Materials and Methods: Through a cell-based drug screening of 1,280 chemical molecules, we selected 3 compounds (luteolin, metixene hydrochloride, and nitazoxanide) lethal to oral cancer SCC-25 cells, while sparing immortalized keratinocyte HaCaT cells. The drugs were then further challenged for their time- and dose-responses, as well as their comparison and combination to standard chemotherapeutic agents by colorimetric assay 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan, Thiazolyl blue formazan (MTT). The impact on SCC-25 and HaCaT motility as well as the mode of action of the drugs was then further explored by scratching assay and western blotting, respectively. All the experiments were performed in triplicated and, at least, three independent times. Students t test was performed to verify the differences among the variables and the level of significance was set at 5%. Results: The natural flavonoid luteolin was a potent cytotoxic agent against oral cancer cells in vitro, presenting low toxicity against HaCaT cells and high efficiency as compared to standard-of-care, such as cisplatin and AG1478. From a molecular standpoint, luteolin coopted the DNA-damage pathway and could be efficiently combined with Chk pharmacological inhibitor. Moreover, we demonstrated that nitazoxanide and metixene hydrochloride kill the SCC-25 but not the HaCaT cells in a dose- and time-dependent. The combinations among the three drugs hit and with cisplatin and AG1478 improved their effect against the malignant cells. Conclusions: Luteolin, metixene hydrochloride, and nitazoxanide emerge as strong cytotoxic and/or adjuvant therapy in oral cancer, as these compounds present higher efficiency and lower toxicity against oral cancer cells in vitro than conventional chemotherapeutic agents.

Hypertoni är en riskfaktor för allvarliga kardiovaskulära sjukdomar. Olika läkemedelsklasser används vid behandling av hypertoni. Dessa inkluderar angiotensin omvandlade enzymhämmare, angiotensin II-receptorblockerare, kalciumkanalblockerare och tiaziddiuretika. Även om nuvarande läkemedelsterapier kan vara effektiva, är det få som kan uppnå målblodtryck. De flesta patienter med hypertoni kräver minst två antihypertensiva läkemedel för att uppnå sitt målblodtryck. Detta ledde till komplicerade behandlingsmetoder som i sin tur har blivit en stor bidragande faktor till dålig patientföljsamhet. Även om ett stort antal läkemedel finns tillgängliga för behandling, är kontrollen av blodtryck dålig på grund av patienternas dåliga följsamhet till medicinering som vanligtvis är en kombination av flera substanser. Följsamheten minskar med antalet tabletter som en patient behöver ta vilket leder till en komplicerad behandlingsstrategi.  Syftet med detta examensarbete var att undersöka blodtryckssänkande effekt med en enkel tablettform Single-Pill Combination (SPC) som innehåller en kombination av flera antihypertensiva läkemedelsklasser och att undersöka patienternas följsamhet till (SPC) behandling.  Metod det här arbetet är en litteraturstudie utförd i PubMed. Olika sökord användes” single-pill combination in hypertension”, “Fixed dose combination in hypertension “, “Adherence to single-pill combination in hypertension”. Sökningen filtrerades till “Randomized controlled trial”. Nya studier valdes ut som undersökte effekten av SPC och följsamhet till behandling. Resultat Studier 1,2,3 och 4 som undersökte effekten gav positiva resultat som gynnade SPC framför standardmonoterapi och placebo. SPC kunde minska blodtrycket statiskt signifikant i alla studierna. I studie 1 blev den genomsnittliga skillnaden i SBT mellan grupperna (–6,9) mm Hg med (p-värde <0,001). I studie 2 blev skillnaden i genomsnittlig 24-timmars SBT mellan SPC- och placeboperioder (–18,7) mm Hg med p-värde <0,0001. I studie 3 blev SBT-förändringar på klinik -16,5 ± (15,5) mm Hg (p <0,001) med amlodipin/valsartan FDC och -6,9 ± (11,4) mm Hg (p = 0,012) med valsartan monoterapi medan motsvarande förändringar i DBP i Office var -9,8 ± (7,7) mm Hg (p <0,001) respektive -2,5 ± (6,6) mm Hg (p = 0,095). Resultat av studie 4 visade att andelen deltagare som uppnådde målblodtryck efter 6 månader (SBT <140, DBT <90 mm Hg) blev 69% i SPC gruppen och 55,3% i monoterapi gruppen. I studie 5 kunde ingen signifikant skillnad i följsamheten observeras mellan SPC gruppen och FEC gruppen. Följsamhetsgraden var 98% i båda grupperna. Studie 6 rapporterade signifikant resultat där PDT blev 95,1 % i SPC gruppen och 92,1% i kontrollgruppen p-värde <0,05.  Slutsats Alla resultat i studierna 1,2,3 och 4 gynnade signifikant SPC när det gäller effekten. Studie 6 visade att patienternas följsamhet till behandling var bättre i SPC gruppen än kontrollgrupp. Studie 5 kunde inte ge signifikanta resultat avseende följsamheten till SPC jämfört med FEC. Fler RCT studier behövs för att undersöka om SPC kan leda till bättre följsamhet hos hypertonipatienter / Background Hypertension is a risk factor for serious cardiovascular diseases. Different drug classes are used in the treatment of hypertension. These include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and thiazide diuretics. Although current drug therapies can be effective, few are able to achieve target blood pressure therefore it has become well-known that most hypertensive patients require at least two antihypertensive drugs to reach their target blood pressure. This led to complicated treatment methods, which in turn has become a significant contributing factor to poor patient compliance. When two or more drug classes are combined, this contributes to improved efficacy, as different mechanisms of action work together to block different pathways to high blood pressure. This leads to lower doses of the individual components being used, which results in a reduced likelihood of side effects. Although a large number of drugs are available for treatment, there is still poor control of blood pressure due to patients' poor adherence to medication, which is usually a combination of several substances. Adherence decreases with the number of tablets a patient needs to take, leading to a complicated treatment strategy. Lower levels of adherence are associated with poorer blood pressure control. Aim The aim of the work is to investigate the blood pressure-lowering effect with a simple tablet form "Single-Pill Combination" (SPC) that contains a combination of several antihypertensive drug classes and to investigate the patients' adherence to this form of treatment (SPC). Method This work is a literature study carried out in Pubmed. Different search terms were used: "single-pill combination for the treatment of hypertension", "Fixed dose combination in hypertension", and "Adherence to single-pill combination for hypertension". The search was filtered to "Randomized controlled trial". New studies were selected that investigated the effect of single-pill combination and blood pressure control and adherence to treatment. Results Studies 1, 2, 3, and 4 investigating the efficacy produced positive results favoring SPC over standard monotherapy and placebo. SPC was able to reduce blood pressure statically significantly in all studies. In Study 1, the primary outcome variable was the mean difference in SBT between groups (–6.9) mm Hg with (p-value <0.001). In Study 2, the difference in mean 24-hour SBT between SPC and placebo periods was (–18.7) mm Hg with a p-value <0.0001. Whereas in Study 3, in-clinic SBT changes were -16.5 ± (15.5) mm Hg (p < 0.001) with amlodipine/valsartan FDC and -6.9 ± (11.4) mm Hg (p = 0.012) with valsartan monotherapy while the corresponding changes in DBP in Office were -9.8 ± (7.7) mm Hg (p <0.001) and -2.5 ± (6.6) mm Hg (p = 0.095), respectively. The results of study 4 were that the percentage of participants who achieved target blood pressure after 6 months (SBT <140, DBT <90 mm Hg) was 69% in the SPC group and 55.3% in the monotherapy group. In study 5, no significant difference in compliance could be observed between the SPC group and the FEC group. The compliance rate was 98% in both groups. While study 6 reported significant results where PDT was 95.1% in the SPC group and 92.1% in the control group p-value <0.05. Conclusion All results in studies 1,2,3and 4 significantly favored SPC in terms of efficacy. Study 6 showed that patients’ adherence to treatment was better in the SPC group than in the control group. While study 5 which was the first RCT study in this area could not provide positive and significant results regarding the adherence to SPC compared to FEC. More RCT studies are needed to investigate whether SPC can lead to better adherence in hypertensive patients.

Malaria accounts for 198 million cases worldwide; with a high mortality rate. 584000 deaths were reported in 2013. Malaria is a re-emerging disease globally due to drug resistance, parasite recrudescence and non-availability of a vaccine. Chloroquine, quinine and antifolates served as frontline antimalarial drugs for decades. Development of resistance to chloroquine and antifolates, and the decreased efficacy of mefloquine, and even quinine, in malaria-endemic regions, has led to artemisinin derivatives evolving as frontline drugs. Artemisinin is a potent antimalarial compound and clears around 104 parasites per cycle. Despite being a potent antimalarial, artemisinin derivatives suffer from poor pharmacokinetic properties and short half lives. This has led to the development of artemisinin-based combination therapies (ACTs) using a partner drug with a longer half-life. However, resistance to ACTs has been reported in the last few years, perhaps due to lack of adherence to prescribed regimens or suboptimal treatment and the use of counterfeit drugs. Therefore there is an urgent need to develop an alternative ACT which overcomes these limitations. This thesis entitled “Adjunct therapy with curcumin for the treatment of malaria: studies in a murine model” describes the antimalarial activity of curcumin and artemisinin and the adjunct role of curcumin in the prevention of parasite recrudescence and cerebral malaria. The thesis is divided into three chapters: The first chapter entitled “Introduction: Malaria and anti-malarial drugs” consists of a brief introduction of malaria, the parasite life cycle and currently known antimalarial drugs. During the course of infection, the Plasmodium undergoes sporogony in the mosquito, and merogony and schizogony in the human host. All these life cycle stages are briefly described with depictions. A major part of this chapter is dedicated to describe antimalarial compounds under the following headings 1. Quinoline derivatives 2. 4-aminoquinolines 3. Antifolates 4. Artemisinin derivatives 5. Antibiotics and 6. Curcumin. The second chapter is aimed at examining the ability of curcumin-arteether (a synthetic derivative of artemisinin) combination therapy in preventing parasite recrudescence in a murine model through immunomodulation employing various immunological, molecular biological, and biochemical techniques. The use of suboptimal doses of antimalarial drugs leads to recrudescence or relapse of malaria (reappearance of the parasite in blood after antimalarial regimen). In the present study we have addressed this issue by the use of curcumin as an adjunct molecule with α,β arteether (a synthetic derivative of artemisinin). We have studied recrudescence in a Swiss mice model. A suboptimal dose was standardized by the use of different doses of α,β arteether (AE) ranging from 250µg to 1500 µg. We found 750 µg to be a suboptimal dose and studied the adjunct nature of curcumin when animals were treated with AE suboptimal dose or AE+curcumin (AC) combination treatment and monitored the survival of animals. Our results clearly demonstrate that ~95% of animals treated with the suboptimal AE dose died of recrudescent malaria but there was almost 100% survival of AC-treated animals; these animals were under observation for at least 3 months. We have studied the effect of curcumin in a recrudescence model at the molecular level. Curcumin by itself has antimalarial activity, but only in combination with α,β arteether prevented recrudescence. Our results indicate that curcumin has immunomodulatory activity. Serum cytokine analysis and spleen mRNA analysis for proinflammatory and anti-inflammatory mediators indicate that AC treatment effectively reduced both mRNA and serum cytokine levels of IFNγ, TNFα, IL-12 and effectively increased both mRNA and serum levels IL-10 and antibodies of the IgG subclass. Using TLR2 and IL-10 knockout animals, we have conclusively demonstrated that TLR2 is involved in the production of IL-10, and IL-10 is required for the AC-mediated protection of animals during the recrudescence period. We conclude that curcumin is able to prevent parasite recrudescence essentially by switching the Th1 response to a Th2 response. The third chapter deals with the study the effect of areether-curcumin (AC) combination therapy in the prevention of Experimental Cerebral Malaria. Although malaria mortality rates have decreased by an impressive 47% between 2000 and 2013, it is still a major affliction of mankind (WHO 2014). Plasmodium falciparum infection causes human cerebral malaria (HCM). The mortality rate in HCM is unacceptably high (15–20%), despite the availability of artemisinin-based therapy. HCM is characterized by a rapid progression from headache, general malaise, and prostration to hemiparesis, ataxia, unrousable coma, and death. Paediatric HCM deaths are mostly due to respiratory arrest. Alternatively, death may be due to parasite-mediated injury to a sensitive location; a small lesion due to parasite in brain stem can cause sudden respiratory arrest. In HCM, cytoadherence of pRBCs in brain microvasculature has been implicated as a major contributing factor for CM pathology. The failure of a large number of adjunct therapies in HCM demands the development of new intervention strategies. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. In this study, we have demonstrated the efficacy of curcumin and PLGA nanocurcumin in the treatment of Experimental Cerebral Malaria (ECM), using the Plasmodium berghei ANKA-infected mouse model (C57BL/6). Curcumin/PLGA nanocurcumin alone can prevent the onset of ECM. We have shown that curcumin/PLGA nanocurcumin can prevent CD8+ T cell, CXCR3+ CD8 T cell and parasite-infected RBC (pRBC) sequestration in the brain. These are also the essential parameters underlying HCM. We have also demonstrated that curcumin effectively inhibits T cell proliferation in spleen. We have explained the anti-inflammatory effects of curcumin by showing the inhibition of NF-B in both brain and spleen, which is a plausible explanation. But, curcumin/PLGA nanocurcumin treated animals died later due to build up of parasitemia in blood and subsequent anemia. Moreover, a combination therapy with arteether and curcumin given even after the onset of neurological symptoms can completely cure and protect the animals against mortality. We have tested AC-combination after the onset of symptoms to mimic patient conditions in HCM, since the murine regimens reported were not successful in the treatment of HCM. Our results clearly demonstrate that AC treatment even after the onset of symptoms ensures 100% survival. Since the bioavailability of curcumin is reported to be poor, we have also tested the efficacy of PLGA nanocurcumin and find that it is superior to native curcumin in terms of therapeutic effects. It is concluded that curcumin would be an ideal adjunct drug to be used with the artemisinin derivatives to treat malaria, including cerebral malaria.

La fusion d'informations issues de plusieurs sources cherche à améliorer la prise de décision. Pour réaliser cette fusion, la théorie des fonctions de croyance utilise des règles de combinaison faisant bien souvent l'hypothèse de l'indépendance des sources. Cette forte hypothèse n'est, cependant, ni formalisée ni vérifiée. Elle est supposée pour justifier le choix du type de règles à utiliser sans avoir, pour autant, un moyen de la vérifier. Nous proposons dans ce rapport de thèse un apprentissage de l'indépendance cognitive de sources d'information. Nous détaillons également une approche d'apprentissage de la dépendance positive et négative des sources. Les degrés d'indépendance, de dépendance positive et négative des sources ont principalement trois utilités. Premièrement, ces degrés serviront à choisir le type de règles de combinaison à utiliser lors de la combinaison. Deuxièmement, ces degrés exprimés par une fonction de masse sont intégrés par une approche d'affaiblissement avant de réaliser la combinaison d'information. Une troisième utilisation de cette mesure d'indépendance consiste à l'intégrer dans une nouvelle règle de combinaison. La règle que nous proposons est une moyenne pondérée avec ce degré d'indépendance. / The theory of belief functions manages uncertainty and proposes a set of combination rules to aggregate beliefs of several sources. Some combination rules mix evidential information where sources are independent; other rules are suited to combine evidential information held by dependent sources. Information on sources ' independence is required to justify the choice of the adequate type of combination rules. In this thesis, we suggest a method to quantify sources' degrees of independence that may guide the choice of the appropriate type of combination rules. In fact, we propose a statistical approach to learn sources' degrees of independence from all provided evidential information. There are three main uses of estimating sources' degrees of independence: First, we use sources' degree of independence to guide the choice of combination rules to use when aggregating beliefs of several sources. Second, we propose to integrate sources' degrees of independence into sources' beliefs leading to an operator similar to the discounting. Finally, we define a new combination rule weighted with sources' degree of independence.

Despite recent advances, prognosis in metastatic prostate cancer remains poor. As with other cancers, tumor heterogeneity is an increasingly evident contributor in prostate tumorigenesis and developed resistance. Using in vitro and in vivo model systems, we examined novel diagnostic and therapeutic strategies in prostate cancer. In these studies, combination treatment with amuvatinib, a receptor tyrosine kinase inhibitor, and erlotinib, an epidermal growth factor inhibitor, was assessed for its ability to differentially modulate growth signaling in pathway diverse LNCaP (PTEN⁻) and DU-145 (PTEN⁺) human prostate cancer cell and mouse xenograft models. Our results suggest both individual mechanistic signaling activities, as well as benefits of the combination therapy though modulations of MAPK (pERK) and 4EBP1/cyclin D1 in growth signaling divergent PTEN+ and PTEN- prostate cancer cells. Additionally, despite the importance preanalytical tissue preservation on downstream diagnostic assays, exact protocols are not well defined and highly variable clinically and, as such, critical diagnostic information is lost. We show that a novel 2+2 fixation method induces target- and cell-specific alterations in immunostain intensity and efficacy. Importantly, cyclin D1 is increasingly utilized for as a clinical prognostic/diagnostic marker and demonstrated improved immunohistochemical staining efficacy with 2+2 fixation compared with treatment-matched xenograft protein alterations as assessed by western analysis. Finally, pentoxifylline (PTX) is a clinically utilized and well tolerated PDE inhibitor that has shown promise as a radio-/chemo-sensitization and anti-cancer agent against a variety of cancers. In these studies, we demonstrate that PTX induces cell and tumor growth inhibition in LNCaP prostate cancer cells. Mechanistically, PTX induces transient cellular signaling modulations of both the AMPK metabolic and AKT/mTOR growth pathways, while inducing autophagy. Also, PTX sensitizes LNCaP prostate cancer to cytotoxicity induced by first line chemotherapy docetaxel, inducing significant cellular apoptosis and reducing effective docetaxel concentrations by >10 fold for equivalent toxicity in viability assays. These findings nominate PTX as an adjunct therapy for the treatment of prostate cancer. In summary, these studies characterize the targeted signaling modulation by combination erlotinib and amuvatinib therapy, as well as pentoxifylline, for their use as therapies for prostate cancer. A novel fixation protocol was also assessed for improved diagnostic tissue preservation of critical signaling proteins. Further understanding in these areas will aid and expand the development of effective diagnostics, as well as emphasize the benefits of these and similar therapeutics for the treatment of prostate cancer.

ITC/USA 2011 Conference Proceedings / The Forty-Seventh Annual International Telemetering Conference and Technical Exhibition / October 24-27, 2011 / Bally's Las Vegas, Las Vegas, Nevada / Compass-I system is China has built satellite navigation system. It's a kind of regional position system according to the double-star position principle. Commonly, Compass-I system need adopt active position, in the paper several passive position methods are put forward. A combination navigation mode based on GLONASS and Compass-I passive navigation is proposed in this paper. The differences of coordinates and time systems between those two navigation systems are analyzed. User position is calculated by least squares method. Combination Navigation Algorithm can improve visible satellite constellation structure and positioning precision so as to ensure the reliability and continuity of positioning result.