Background: Lung cancer was the fifth leading cause of mortality globally in 2010, and the leading cause of cancer mortality in Canada, representing 26% of all cancer deaths for both men and women in 2017. Radon is a very modifiable environmental exposure that is the second most important cause of lung cancer. Objectives: The objectives of this thesis are to quantify the lung cancer burden associated with residential radon and to identify the most cost effective mitigation options to reduce residential radon in Canada. Methods: The global burden of lung cancer mortality attributable to radon in 2012 was estimated from the 66 countries for which a representative national radon survey was available, using several different models for excess relative risk (ERR) of lung cancer from radon studies. Cost-utility analyses are conducted for 20 practical radon interventions scenarios to reduce residential radon exposures in new and existing housing in Canada, each province/territory and 17 census metropolitan areas. A societal perspective and a lifetime horizon are adopted. A Markov cohort model and a discrete event simulation are used to model residents by household, based on a period-life table analysis, at a discount rate of 1.5%. Results: The estimates of the global median PAR were consistent, ranging from 16.5% to 13.6% for the three ERR models based on miners, and the mean estimates of PAR for Canada ranged from 16.3% to 14.6%. It is very cost effective to install radon preventive measures in new construction compared to no radon control in all regions across Canada. At a radon mitigation threshold of 100 Bq/m3, the sequential analysis recommends the combination of the activation of preventive measures in new housing with the mitigation of existing housing at current testing and mitigation rates for cost effectiveness thresholds between 51,889 and 92,072 $/QALY for Canada, between 27,558 and 85,965 $/QALY for Manitoba, and between 15,801 and 36,547 $/QALY for the Yukon. The discounted ICER for screening and mitigation of existing housing at current rates relative to no radon control measures is 62,451 (66,421) $/QALY using a Markov cohort model (discrete event simulation model) for mitigation of housing above a threshold of 200 Bq/m3, and is 58,866 (59,556) $/QALY using a Markov cohort model (discrete event simulation model) for mitigation of housing above a threshold of 100 Bq/m3. Conclusions: Cost effective residential radon interventions should be implemented across Canada to reduce exposures to this very modifiable cause of lung cancer and to help reduce the increasing lung cancer burden in an ageing Canadian population.

Objetivos: Desenvolver e caracterizar nanocápsulas poliméricas contendo erlotinib, bem como avaliar sua atividade antitumoral in vitro em células de adenocarcinoma de pulmão humano. Metodologia: As nanocápsulas contendo erlotinib (0,5 mg.mL-1) foram obtidas pelo método de nanoprecipitação utilizando poli(ε-caprolactona) e óleo de copaíba como parede polimérica e núcleo oleoso, respectivamente. Os parâmetros físico-químicos avaliados foram: diâmetro médio e distribuição de tamanho, índice de polidispersão, potencial zeta, concentração de partículas e pH. Para determinação do teor e eficiência de encapsulação do erlotinib, utilizou-se metodologia validada por CLAE-UV. O estudo de liberação in vitro, utilizando sacos de diálise, foi realizado para obter o perfil de liberação do fármaco a partir das nanocápsulas. As nanocápsulas contendo erlotinib foram avaliadas quanto ao seu potencial de inibir o crescimento, induzir a apoptose, interferir com o ciclo celular e sobrevivência clonogênica de células de adenocarcinoma de pulmão, linhagem A549. Resultados: As nanocápsulas apresentaram diâmetro médio de 171 ± 2 (PDI < 0, 10), potencial zeta de −8,17 ± 2.26 mV, número de partículas por mL de 6,97 ± 0,22 × 1013 e pH de 6,24 ± 0,02. O teor e a eficiência de encapsulação foram próximos de 100%. Com exceção do pH, todos parâmetros mantiveram-se iguais após 30 dias de armazenamento em temperatura ambiente. Observou-se uma liberação controlada do fármaco devido à nanoencapsulação. Os ensaios de citotoxicidade demonstraram que as nanocápsulas contendo erlotinib apresentaram maior atividade antitumoral quando comparado com o fármaco livre. Também foi demonstrado indução de apoptose, pela análise de ciclo celular e marcação por Anexina-V conjugada ao 7-AAD. No ensaio clonogênico, as nanocápsulas contendo erlotinib reduziram 100% o número de colônias formadas. Conclusões: Foram obtidas nanocápsulas com propriedades nanotécnologicas adequadas e capazes de controlar a liberação do erlotinib. Os estudos in vitro na linhagem celular A549 demonstraram aumento no efeito antitumoral e foi demonstrado que o encapsulamento do fármaco é imprescindível para essa melhor atividade. / Purpose: To develop and characterise erlotinib-loaded polymeric nanocapsules and to evaluate its in vitro antitumor activity in human lung adenocarcinoma cells. Methodology: The erlotinib-loaded nanocapsules (0.5 mg.mL-1) were obtained by nanoprecipitation method using poly (ε-caprolactone) and copaiba oil as the polymeric wall and oily core, respectively. The physicochemical parameters evaluated were: mean diameter and size distribution, polydispersity index, zeta potential, particle concentration and pH. An HPLC-UV validated method was used to determine the drug content and encapsulation efficiency. The in vitro release study using dialysis bags was performed to obtain the drug release profile from nanocapsules. The erlotinib-loaded nanocapsules were evaluated regarding their potential to inhibit the growth, induce apoptosis, interfere with the cell cycle and clonogenic survival of lung adenocarcinoma cell (A549). Results: The nanocapsule formulation presented z-average diameter of 171 ± 2 (PDI <0.10), zeta potential value of -8.17 ± 2.26 mV, number of particles per mL of 6.97 ± 0.22 × 1013, and pH value of 6.24 ± 0.02. The drug content and the encapsulation efficiency were nearly 100%. Except for the pH value, all these parameters remained the same after 30 days of storage. A controlled release of the drug was observed due to nanoencapsulation. The cytotoxicity assays demonstrated that the erlotinib-loaded nanocapsules showed higher antitumor activity compared to free drug. Induction of apoptosis was demonstrated by cell cycle analysis and Annexin-V/7AAD staining. In the clonogenic assay, erlotinib-loaded nanocapsules reduced 100% the number of colonies formed. Conclusions: Nanocapsules with appropriate nanotechnological properties and capable of controlling the erlotinib release were obtained. The in vitro studies in the A549 cell line showed an increase in antitumor effect and was demonstrated that the drug encapsulation is essential for this better activity.

With ever increasing advancements in imaging, there is an increasing abundance of images being acquired in the clinical environment. However, this increase in information can be a burden as well as a blessing as it may require significant amounts of time to interpret the information contained in these images. Computer assisted evaluation is one way in which better use could be made of these images. This thesis presents the combination of texture analysis of images acquired during the treatment of cancer with machine learning in order to improve radiotherapy. The first application is to the prediction of radiation induced pneumonitis. In 13- 37% of cases, lung cancer patients treated with radiotherapy develop radiation induced lung disease, such as radiation induced pneumonitis. Three dimensional texture analysis, combined with patient-specific clinical parameters, were used to compute unique features. On radiotherapy planning CT data of 57 patients, (14 symptomatic, 43 asymptomatic), a Support Vector Machine (SVM) obtained an area under the receiver operator curve (AUROC) of 0.873 with sensitivity, specificity and accuracy of 92%, 72% and 87% respectively. Furthermore, it was demonstrated that a Decision Tree classifier was capable of a similar level of performance using sub-regions of the lung volume. The second application is related to prostate cancer identification. T2 MRI scans are used in the diagnosis of prostate cancer and in the identification of the primary cancer within the prostate gland. The manual identification of the cancer relies on the assessment of multiple scans and the integration of clinical information by a clinician. This requires considerable experience and time. As MRI becomes more integrated within the radiotherapy work flow and as adaptive radiotherapy (where the treatment plan is modified based on multi-modality image information acquired during or between RT fractions) develops it is timely to develop automatic segmentation techniques for reliably identifying cancerous regions. In this work a number of texture features were coupled with a supervised learning model for the automatic segmentation of the main cancerous focus in the prostate - the focal lesion. A mean AUROC of 0.713 was demonstrated with 10-fold stratified cross validation strategy on an aggregate data set. On a leave one case out basis a mean AUROC of 0.60 was achieved which resulted in a mean DICE coefficient of 0.710. These results showed that is was possible to delineate the focal lesion in the majority (11) of the 14 cases used in the study.

Au cours de cette thèse, nous nous sommes intéressés à l’implication de la kallicréine-12 (KLK12), une protéase à sérine, dans la cancérogenèse pulmonaire. La KLK12 est connue comme étant surexprimée dans les tumeurs pulmonaires non à petites cellules mais son rôle dans la cancérogenèse n’est pas clairement établi. Nos travaux ont permis de lui attribuer un effet proangiogénique vis-à-vis des cellules endothéliales pulmonaires. En effet, la KLK12 peut stimuler la migration des cellules endothéliales pulmonaires en modifiant l’architecture de la matrice extracellulaire. D’autre part, elle est impliquée dans la régulation de la biodisponibilité de facteurs de croissance associés à l’angiogenèse tels que le Platelet-derived growth factor-B. De plus, nos travaux ont permis d’identifier une possible régulation de l’expression de la KLK12 par l’hypoxie, ce qui expliquerait sa surexpression dans les tumeurs pulmonaires et conforterait son implication dans l’angiogenèse. La confirmation in vivo des mécanismes d’action de la KLK12 pourrait permettre d’envisager son utilisation comme cible thérapeutique afin de réguler la néoangiogenèse tumorale. / In this thesis, we studied the involvement of the serine protease kallikrein-12 (KLK12), in lung carcinogenesis. The KLK12 is known to be overexpressed in non-small cell lung cancer but its role in carcinogenesis is not clearly established. Our work shows that it possesses a proangiogenic effect on pulmonary endothelial cells. Indeed, KLK12 stimulates lung endothelial cells migration notably by modulating the extracellular matrix architecture. On the other hand, KLK12 regulates the bioavailability of growth factors associated with angiogenesis such as plateletderived growth factor-B. In addition, our work has identified a possible regulation of the expression of KLK12 by hypoxia, which would explain its overexpression in lung tumors and would reinforce its involvement in angiogenesis. The confirmation in vivo of these mechanisms could help consider KLK12 as a therapeutic target for regulating tumor angiogenesis.

Galectin-3 is a β-galactoside binding lectin expressed in tumour cells and macrophages and has been associated with increased malignancy in a variety of cancers. Previous work has shown that galectin-3 is an important regulator of macrophage function, promoting an alternative (M2) phenotype which potentiates chronic inflammation and fibrosis. Tumour associated macrophages (TAMs) adopt an M2 phenotype and are thought to promote tumour growth by down regulating T cell effector function and promoting angiogenesis. This project examines the hypothesis that host galectin-3 promotes lung cancer growth and spread. In order to test this hypothesis, Lewis Lung Carcinoma tumour growth and metastasis was investigated in strain matched mice either expressing or deficient in galectin-3. The Lewis Lung Carcinoma cell line (LLC1) is a spontaneous lung carcinoma line, derived from C57BL/6 mice, which readily forms tumours when transplanted. Furthermore, LLC1 cells were stably transfected with a Luciferase expressing vector in order to assist detection of tumour growth and metastasis in vivo. An orthotopic model of LLC1 growth suggested that galectin-3-/- animals do not support lung carcinoma growth and spread. This finding was confirmed by a subcutaneous model of cancer growth, where it was found that wild type animals display a higher proportion of macrophages expressing a prototypic M2 marker around tumour sites compared to galectin-3-/- animals. M2-promoting cytokine transcripts were also reduced in galectin-3-/- mice. Additionally, tumours of wild type mice were more invasive and presented more mature blood vessels compared to galectin-3-/- mice. To specifically address the role of recruited cells on tumour growth, metastasis and the inflammation profile around tumour sites, in relation to galectin-3 expression, bone marrow cells (BMCs) were transplanted from wild type to galectin-3-/- mice and vice versa. It was shown that galectin-3 positive BMCs restore the wild type phenotype of tumour growth in galectin-3-/- mice, while galectin-3 deficient BMCs impair tumour growth in wild type animals. Furthermore, macrophage ablation experiments demonstrated incapacity for tumour establishment in the absence of macrophages. A series of experiments investigating reported inhibition of galectin-3 by modified citrus pectin (MCP) via competitive inhibition did not provide conclusive results. MCP had no effect in vivo, but was able to inhibit LLC1 cell growth in vitro. Most importantly though, results were inconclusive as to whether galectin-3 binds MCP. Some ligand displacement was seen, but direct binding of the molecules could not be shown. In general, the results obtained demonstrate a strong pro-tumoural effect of galectin-3 on growth, tissue invasion and metastasis of LLC1 tumours via an increased proportion of Ym1-expressing macrophages around tumour sites. It was shown that macrophages are key cells for tumour initiation and that BMC phenotype in relation to galectin-3 expression determines the phenotype of tumour development in subcutaneous and orthotopic LLC1 models. Therefore, galectin-3 has a strong regulatory effect on tumour phenotype and could present a key target in the management of lung carcinomas.

Objetivo: O câncer de pulmão é a primeira causa de morte relacionada ao câncer quando considerados ambos os sexos. Os grandes esforços para a redução do tabagismo e para a introdução do filtro de cigarro mudaram a epidemiologia do câncer de pulmão. Em países desenvolvidos, a ascensão do adenocarcinoma e o declínio do epidermoide são de notório conhecimento. Outra característica é o aumento da incidência da doença entre mulheres. Um entendimento melhor da atual epidemiologia do câncer de pulmão é necessário para o desenvolvimento de estratégias de saúde pública de prevenção, diagnóstico e tratamento. Métodos: Análise retrospectiva de todos os pacientes com CPNPC tratados com ressecção pulmonar entre 1986 e 2010 em um hospital universitário do Sul do Brasil. As análises foram divididas em três períodos: 1986-1990, 1991-2000 e 2001-2010. O mesmo grupo de patologistas realizou o diagnóstico, e os estágios foram atualizados para a nova classificação da IASLC, 7ª edição. Todas as análises foram realizadas utilizando o programa SAS, versão 13. Resultados: Foram estudados 817 pacientes submetidos à ressecção pulmonar por CPNPC entre 1986 e 2010. Setenta por cento eram homens, média de idade de 61,4 anos, 44,2% carcinoma epidermoide e 40% adenocarcinoma, 26,7% estágio IIIA. A proporção de mulheres apresentou um aumento de 22% no primeiro período para 36% na última década. A idade média no momento da cirurgia era de 52,7 anos para mulheres e 57,3 para homens no primeiro período, e 60,1 para mulheres e 63,9 para homens no último período (p<0.001). A proporção de carcinoma epidermoide modificou de 49,1% inicialmente para 38,7% no último período (p=0.017). Em comparação, a prevalência do adenocarcinoma cresceu de 35,4% para 39,6% e, mais recentemente, para 41,2%. Em relação ao número total de pessoas acometidas pela doença, mulheres com adenocarcinoma representavam 9,4% no primeiro período, 12,5% no segundo e 16,8% no último período. Pacientes com estágio IIIA representavam 27,9% na última década. O tipo de cirurgia predominante foi a lobectomia. A pneumonectomia foi o procedimento cirúrgico em 21,9%, 18,8% e 16,8% dos casos em cada período, em ordem crescente, respectivamente (p<0.03). Conclusão: Neste estudo de pacientes no Sul do Brasil, a análise de gênero demonstrou que a taxa de câncer de pulmão entre as mulheres está aumentando nas últimas três décadas, mas ainda não chegou a ultrapassar a taxa masculina. A proporção de adenocarcinoma em mulheres aumentou. O significativo declínio da quantidade proporcional de pneumonectomia provavelmente reflete a mudança da indicação e técnica cirúrgica. A idade média de pacientes submetidos a tratamento cirúrgico aumentou tanto para homens quanto para mulheres, mas não alcançou a média de países desenvolvidos de 71 anos. A mudança da proporção do tipo histológico e de mulheres está de acordo com os dados de países desenvolvidos. / Objective: Lung cancer is the leading cause of cancer-related death worldwide when considering both genders. The great effort to reduce smoking and to introduce the usage of cigarette filter has changed lung cancer epidemiology. In developed countries, the increasing incidence of adenocarcinoma and the decrease of squamous cell carcinoma are well known. Other characteristic reported is the rising number of women with the disease. Better understanding of current lung cancer epidemiology is necessary for the appropriate design of public health strategies for prevention, diagnosis and treatment. Methods: Retrospective analysis of all patients with non-small cell lung cancer (NSCLC) treated with lung resection between 1986 and 2010 in a university hospital of Southern Brazil. Analysis was divided in three periods: 1986-1990, 1991-2000 and 2001-2010. The same pathology group performed histological diagnosis and all staging was updated according to the new IASLC, 7th edition. All analyses were performed using the SAS program, version 13. Results: We studied 817 patients who underwent lung resection for NSCLC from 1986 to 2010. Seventy percent were males, average age 61.4 years old, 44.2% squamous cell carcinoma and 40% adenocarcinoma, 26.7% stage IIIA. The female proportion increased from 22% in the first period to 36% in the last decade. Mean age at surgery treatment was 52.7 years old for women and 57.3 years old for men in the first period, and 60.1 for women and 63.9 for men in the last period (p<0.001). The proportion of squamous cell changed from 49.1% initially to 38.7% in the last period (p=0.017). In comparison, the adenocarcinoma prevalence increased from 35.4% to 39.6% and, most recently, to 41.21%. Of the total NSCLC patients, females with adenocarcinoma represented 9.4% in the first period, 12.5% in the second and 16.8% in last period. Patients with stage IIIA represented 27.9% in the last decade. Lobectomy was the predominant type of surgery. Pneumonectomy was the surgical procedure in 21.9%, 18.8% and 16.8% of the cases in each period, respectively (p<0.03). Conclusions: In this cohort of patients in Southern Brazil, gender analysis shows that rates of lung cancer in females are rising over the last three decades, but have not surpassed men rates. The proportion of adenocarcinoma in females has increased. The significant decrease of pneumonectomy rates probably reflects changes on surgical management techniques and indication. The mean age of patients undergoing surgical treatment has increased for both men and women, but has not reached the average age reported in developed countries, 71 years old. The histological and gender findings for lung cancer are in accordance with the data of developed countries.

Lung cancer is the leading cause of death from cancer in the world. First, we hypothesized that microRNA expression is altered in the bronchial epithelium of patients with lung cancer and that incorporating microRNA expression into an existing mRNA biomarker may improve its performance. Using bronchial brushings collected from current and former smokers, we profiled microRNA expression via small RNA sequencing for 347 patients with available mRNA data. We found that four microRNAs were under-expressed in cancer patients compared to controls (p<0.002, FDR<0.2). We explored the role of these microRNAs and their gene targets in cancer. In addition, we found that adding a microRNA feature to an existing 23-gene biomarker significantly improves its performance (AUC) in a test set (p<0.05). Next, we generalized the biomarker discovery process, and developed a visualization tool for biomarker selection. We built upon an existing biomarker discovery pipeline and created a web-based interface to visualize the performance of multiple predictors. The “visualization” component is the key to sorting through a thousand potential biomarkers, and developing clinically useful molecular predictors. Finally, we explored the molecular events leading to the development of COPD and ILD, two heterogeneous diseases with high mortality. We hypothesized that integrative genetic and expression networks can help identify drivers and elucidate mechanisms of genetic susceptibility. We utilized 262 lung tissue specimens profiled with microRNA sequencing, microarray gene expression and SNP chip genotyping. Next, we built condition specific integrative networks using a causality inference test for predicting SNP-microRNA-mRNA associations, where the microRNA is a predicted mediator of the SNP’s effect on gene expression. We identified the microRNAs predicted to affect the most genes within each network. Members of miR-34/449 family, known to promote airway differentiation by repressing the Notch pathway, were among the top ranked microRNAs in COPD and ILD networks, but not in the non-disease network. In addition, the miR-34/449 gene module was enriched among genes that increase in expression over time when airway basal cells are differentiated at an air-liquid interface and among genes that increase in expression with the airway wall thickening in patients with emphysema. / 2019-07-31T00:00:00Z

Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-&#945; tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 &#177; 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (&#177; 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados. / Nanocrystals are drug particles with an average size in the sub-micron range, generally between 200 and 500 nm, stabilized by steric or electrostatic agents adsorbed on the surface of the drug particles. The reduced size provides special properties such as mucosal adhesiveness, increase in surface area and saturation solubility, which significantly improves the bioavailability of poorly water-soluble drugs. Another emerging application of nanocrystals is in the enhancement of drug delivery and retention in tumor tissues. Studies have shown that flubendazole is a drug capable of inducing cell death in malignant tumors and decelerating their growth, by altering the structure of the microtubules and inhibiting the tubulin polymerization. Antiproliferative activity has been demonstrated in leukemia, myeloma, intestinal cancer, breast cancer and neuroblastoma lines. In addition, flubendazole is also an effective drug against helminths, demonstrating superior activity in eliminating adult worms when compared to diethylcarbamazine. Although flubendazole appears to be a promising molecule, it is an insoluble drug in water (0.005 mg / mL). To achieve the desired therapeutic effect, it is necessary the development of a formulation with better solubility and bioavailability. In this context, the present research reports the physico-chemical preparation and characterization of flubendazole nanocrystals through microfluidization. Exploratory experiments were carried out to evaluate the performance of different stabilizing agents in formulations: polysorbate 80, polaxamer 188 and D-&#945; tocopherol polyethylene glycol 1000 succinate (TPGS). The determination of the particle size distribution determination was performed by laser light scattering (LLS), dynamic light scattering (DLS), nanoparticle scanning (NTA) and scanning electron microscopy (SEM). The use of TPGS favored the preparation of a nanosuspension with the lowest mean hydrodynamic size of the particles, of 253.9 &#177; 3 nm. In the exploratory studies, the optimum grinding parameters were also determined: 35,000 psi of microfluidizer pressure, product temperature of 30 ° C (&#177; 5 ° C) and recirculation time of 2 hours for each 100 grams of suspension. In order to reach the lowest average hydrodynamic diameter, a statistical design was applied in which the influence of flubendazole concentration (% w / w) and TPGS (% w / w) on the formulation was evaluated. The analysis revealed a significant influence of TPGS concentration on the particle size reduction and on the physicochemical stability of the nanosuspension. Complementary solubility tests showed that the nanocrystal provided an increase in solubility of 2.3, 3.2 and 5.2-fold in 0.1 N HCl, phosphate buffer pH 6.8 and phosphate buffer saline pH 7.4, respectively. In the dissolution test performed in 0.1 N HCl with 0.1% TPGS, a 41% increase of the drug dissolved after 60 minutes was achieved, when compared to micronized flubendazole. The solid-state characteristics of the nanocrystal were accessed through thermal analysis (differential scanning calorimetry and thermogravimetry) and X-ray diffraction and the results indicated that the crystal structure was not significantly altered. This research also evaluated the action of flubendazole nanocrystals in lung tumors, demonstrating expressive ability to retard growth and decrease the size of these tumors in xenotransplanted mice.

No description available.

Lung cancer is the leading cause of cancer-related death for both men and women in the United States, despite being the second-most frequent cancer diagnosis for both sexes. This high mortality rate is due to the majority of cases being diagnosed after the primary lung cancer has metastasized. In an effort to reduce mortality associated with lung cancer by diagnosing lung cancer at an earlier stage, screening of high-risk populations has been employed. One screening tool, computed tomography (CT), has been shown to reduce mortality by 20%, compared to screening for lung cancer by chest x-ray. This was achieved by earlier stage diagnosis of lung cancer in participants screened with CT. The use of chest CT in lung cancer screening has also led to increased numbers of false-positives - benign lung nodules that are marked as suspicious for lung cancer. These false-positives result in unnecessary invasive follow-up procedures and costs while incurring additional emotional stress on the patient. In an effort to reduce the number of false-positives, a computer-aided diagnostic (CAD) tool can be designed to determine the probability of malignancy of a lung nodule based on objective measurements. While current CAD models characterize the pulmonary nodule's shape, density, and border, analyzing the parenchyma surrounding the nodule is an area that has been minimally explored. By quantifying characteristics, or features, of the surrounding tissue, this project explores the hypothesis that textural differences in both the nodule and surrounding parenchyma exist between malignant and benign cases. By incorporating these features, performance in the measures of sensitivity, specificity and accuracy can be improved over CAD tools that rely on nodule characteristics alone. A CAD program was developed for the computation of features from a pulmonary nodule. A region of interest containing a nodule and surrounding parenchyma was extracted from a CT scan. Several novel feature extraction techniques were developed, including a three-dimensional application of Laws' Texture Energy Measures to quantify the textures of the parenchyma surrounding the nodule and the nodule itself. In addition, the densities of the nodule and surrounding parenchyma were summarized through metrics such as mean, variance, and entropy of the intensities within each region. Finally, the margins of the nodule were characterized by analyzing mean and variance of border irregularity. A total of 299 features were extracted. To illustrate proof of concept, the CAD program was applied to 27 regions of interest - 10 benign and 17 malignant. Through feature selection, 36 significant features were recognized (p-values < 0.05), including many textural and parenchymal features. These features were further reduced by forward feature selection to two features that summarized the dataset. A neural network was used to classify the cases in a leave-one-out method. Preliminary results yielded 92.6% accuracy in classification of test cases, with two benign nodules incorrectly classified as malignant. The significance of texture and parenchymal features supports the hypothesis that features extracted from the parenchyma have the potential to improve classification of nodules, aiding in the reduction of false-positives identified through CT screening. As more cases are incorporated into the database, these textural features will play a larger role.