In this thesis, the theory of poroelasticity, namely the Mixture Theory version -- a homogenized, macroscopic scale approach used to describe fluid flow through a porous medium -- is employed in three separate cases pertaining to a biological phenomenon. The first investigation explores the behavior of interstitial fluid pressure (IFP) in solid tumors. Thus, in Chapter 2, a Mixture Theory based approach is developed to describe the evolution of the IFP from that in a healthy interstitium to the elevated levels in cancerous tumors. Attention is focused on angiogenesis, a tightly regulated process in healthy tissue that provides all necessary nutrients through the creation of new blood vessels. Once this process becomes unruly within a tumor, angiogenesis gives rise to an abnormal vasculature by forming convoluted and leaky blood vessels. Thus, the primary focus of the model is on the capillary filtration coefficient and vascular density as they increase in time, which in turn elevates the tumor IFP. Later, the Mixture Theory model is extended to simulate the effects of vascular normalization, where the cancer therapy not only prunes blood vessels, but reverts the chaotic vasculature to a somewhat normal state, thereby temporarily lowering the tumor IFP. In Chapter 3, the validity of an assumption that was made in order to facilitate the mathematical calculations is investigated. In addition to all of the Mixture Theory assumptions, it is assumed that the pore pressure p is proportional to the tissue dilatation e. This assumption is examined to determine how appropriate and accurate it is, by using a heat type equation without the presence of sources and sinks under the assumption of a spherical geometry. The results obtained under the proportionality of p and e, are compared with the results obtained without this assumption. A substantial difference is found, which suggests that great care must be exercised in assuming the proportionality of p and e. The last application is reported in Chapter 4 and it investigates the pathogenesis of normal pressure hydrocephalus. In a normal brain, cerebrospinal fluid (CSF) is created by the choroid plexus, circulates around the brain and the spinal cord without any impediment, and then is absorbed at various sites. However, normal pressure hydrocephalus occurs when there is an imbalance between the production and absorption of CSF in the brain that causes the impaired clearance of CSF and the enlargement of ventricles; however, the ventricular pressure in this case is frequently measured to be normal. Thus, a mathematical model using Mixture Theory is formulated to analyze a possible explanation of this brain condition. Levine (1999) proposed the hypothesis that CSF seeps from the ventricular space into the brain parenchyma and is efficiently absorbed in the bloodstream. To test this hypothesis, Levine used the consolidation theory version of poroelasticity theory, with the addition of Starling's law to account for the absorption of CSF in the brain parenchyma at steady state. However, the Mixture Theory model does not agree with the results obtained by Levine (1999) which leads one to conclude that the pathogenesis of normal pressure hydrocephalus remains unknown. To conclude the thesis, all three applications of Mixture Theory are discussed and the importance and contribution of this work is highlighted. In addition, possible future directions are indicated based on the findings of this thesis.

Yes / Currently, out of the 82 US FDA-approved targeted therapies for adult cancer treatments, only three are approved for use in children irrespective of their genomic status. Apart from leukemia, only a handful of genomic-based trials involving children with solid tumors are ongoing. Emerging genomic data for pediatric solid tumors may facilitate the development of precision medicine in pediatric patients. Here, we provide an up-to-date review of all reported genomic aberrations in the eight most common pediatric solid tumors with whole-exome sequencing or whole-genome sequencing data (from cBioPortal database, Pediatric Cancer Genome Project, Therapeutically Applicable Research to Generate Effective Treatments) and additional non-whole-exome sequencing studies. Potential druggable events are highlighted and discussed so as to facilitate preclinical and clinical research in this area. / Seed Grant of Strategic Research Theme for Cancer, The University of Hong Kong of AKSC. VWY Lui is funded by the Research Grant Council, Hong Kong (#17114814, #17121616, General Research Fund; T12–401/13-R, Theme-based Research Scheme), and the Start-up Fund, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong. W Piao is funded by the Faculty Postdoctoral Fellowship Scheme, Faculty of Medicine, the Chinese University of Hong Kong.

abstract: The rate of progress in improving survival of patients with solid tumors is slow due to late stage diagnosis and poor tumor characterization processes that fail to effectively reflect the nature of tumor before treatment or the subsequent change in its dynamics because of treatment. Further advancement of targeted therapies relies on advancements in biomarker research. In the context of solid tumors, bio-specimen samples such as biopsies serve as the main source of biomarkers used in the treatment and monitoring of cancer, even though biopsy samples are susceptible to sampling error and more importantly, are local and offer a narrow temporal scope. Because of its established role in cancer care and its non-invasive nature imaging offers the potential to complement the findings of cancer biology. Over the past decade, a compelling body of literature has emerged suggesting a more pivotal role for imaging in the diagnosis, prognosis, and monitoring of diseases. These advances have facilitated the rise of an emerging practice known as Radiomics: the extraction and analysis of large numbers of quantitative features from medical images to improve disease characterization and prediction of outcome. It has been suggested that radiomics can contribute to biomarker discovery by detecting imaging traits that are complementary or interchangeable with other markers. This thesis seeks further advancement of imaging biomarker discovery. This research unfolds over two aims: I) developing a comprehensive methodological pipeline for converting diagnostic imaging data into mineable sources of information, and II) investigating the utility of imaging data in clinical diagnostic applications. Four validation studies were conducted using the radiomics pipeline developed in aim I. These studies had the following goals: (1 distinguishing between benign and malignant head and neck lesions (2) differentiating benign and malignant breast cancers, (3) predicting the status of Human Papillomavirus in head and neck cancers, and (4) predicting neuropsychological performances as they relate to Alzheimer’s disease progression. The long-term objective of this thesis is to improve patient outcome and survival by facilitating incorporation of routine care imaging data into decision making processes. / Dissertation/Thesis / Doctoral Dissertation Biomedical Informatics 2017

Made available in DSpace on 2014-06-11T19:23:07Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-04-01Bitstream added on 2014-06-13T20:29:57Z : No. of bitstreams: 1 oliveira_ct_me_botfm.pdf: 2586546 bytes, checksum: 0fa98dd82d7160414a5cffb84658a089 (MD5) / Fundação Amaral Carvalho / A infiltração de MO por tumores não-hematológicos tem sido descrita desde 1935 e, mais recentemente, desperta interesse da comunidade científica, pois inúmeros trabalhos têm relacionado a presença de células tumorais na MO com o processo de carcinogênese e a progressão tumoral. O presente estudo teve por objetivo o levantamento dos casos com diagnóstico de mielopatia infiltrativa por tumores nãohematológicos, provenientes da Faculdade de Medicina de Botucatu – UNESP e do Hospital Amaral Carvalho – Jaú, avaliados, retrospectivamente, no período de 1998 a 2008 (num universo de 15.191 coletas de MO). Incluímos 193 pacientes, dos quais 171 eram adultos e 22 crianças (idade ≤ 21 anos), com paridade entre os sexos (1:1) e mediana de idade de 55 anos. Foram analisados dados clínicos, diagnóstico e estadiamento do tumor primário, sítios de metástases, características laboratoriais (hemograma e marcadores tumorais séricos), características da MO, tratamento e a relação desses fatores com a sobrevida dos pacientes, através do programa de estatística SPSS®. Os resultados encontrados apontam que os tumores que mais frequentemente infiltraram a MO nos adultos foram: tumores de mama, próstata e sítio primário indeterminado, e neuroblastoma nas crianças. A análise da MO revelou positividade de 80% para mielograma e BMO, e presença de fibrose em 32% dos pacientes (40%, quando associados a áreas de necrose no mesmo material). Na avaliação hematológica observamos: anemia, alteração de leucócitos e plaquetopenia. Houve diferença, estatisticamente significante, com maior mediana de sobrevida global (p= 0,000) para pacientes do sexo feminino, portadores de adenocarcinoma de mama, em estádios iniciais e que receberam algum tipo de tratamento (quimio, radio e/ou hormonioterapia). Na análise de sobrevida, a partir do diagnóstico de mielopatia infiltrativa, houve... / Bone marrow (BM) infiltration by nonhematopoietic tumors has been described since 1935, and a increased number of papers about this topic have been published. Some of the studies have related the relationship between the presence of peripheral circulating tumors cells, bone marrow infiltration, carcinogenesis and tumor progression. This study has, as essential objective, the evaluation of infiltrative mielopathy by nonhematopoietic tumors from Faculdade de Medicina de Botucatu - UNESP and Hospital Amaral Carvalho – Jaú. Data were analised retrospectively from 1998 January to 2008 August (15.191 bone marrow samples). We have included 193 patients. One hundred seventy one were adults and 22 were children (considered age ≤ 21 years), with similar number of patients by gender, and median age 55 years. Medical records from the selected patients were analised, with focus on clinical aspects, primary site of tumor, initial stage, metastatic sites, hematologic and bone marrow features, treatment and the relationship between this data and survival. Results have demonstrated that most frequent solid tumors in adults were breast cancer, prostate cancer and undetermined primary site, and neuroblastoma among children. Bone marrow revealed infiltration in 80% of samples by myelogram and BM biopsy, and fibrosis in 32% (40% when associated with necrosis area). We observed anaemia, leukocyte alterations and thrombocytopenia as hematologic features. There were significant differences in global survival, wich was better among female patients, diagnosis of breast cancer, initial clinical stages and who has received any type of treatment (chemotherapy, radiotherapy and/or hormoniotherapy). When we analised survival since diagnosis of infiltrative mielopathy, adult patients with leucoeritroblastic reaction and trombocytopenia, and undetermined primary site tumors, melanoma or gastrointestinal tumors had... (Complete abstract click electronic access below)

Intravenously delivered cancer drugs face transport limitations at the tumor site and cannot reach all parts of tumors at therapeutically effective concentrations. Transport limitations also prevent oxygen from distributing evenly in tumors resulting in hypoxia, which plays a critical role in cancer progression. In this dissertation, I present the development of micro-devices that mimic transport limitations of drugs and nutrients on three dimensional tumor tissues, enable visualization and quantification of the ensuing gradients, and enable simple analysis and mathematical modeling of obtained data. To measure the independent effects of oxygen gradients on tumor tissues, an oxygen delivery device that used microelectrodes to generate oxygen directly underneath three-dimensional tumor cylindroids was developed. Supplying oxygen for 60 hours eliminated the necrotic region typically found in the center of cylindroids. Dead cells were observed moving away from the location of oxygen delivery. These measurements show that oxygen gradients are an important determinant of cell viability and rearrangement. Another micro-device was developed to mimic the delivery and systemic clearance of therapeutic agents. This microfluidic device consisted of cuboidal tumor tissue subjected to continuous medium perfusion along one face. The device was used to measure the spatiotemporal dynamics of the accumulation of therapeutic bacteria in tumors. Suspensions of Salmonella typhimurium and Escherichia coli strains were delivered to tumor tissues for 1 hour. Bacterial motility strongly correlated (R2 = 99.3%) with the extent of tissue accumulation. Based on spatio-temporal profiles and a mathematical model of motility and growth, bacterial dispersion was found to be necessary for deep penetration into tissue. These results show that motility is critical for effective distribution of bacteria in tumors. The microfluidic device was further used to mimic the delivery and clearance of equal concentrations of doxorubicin and liposome-encapsulated doxorubicin (Doxil). A pharmacokinetic/pharmacodynamic model incorporating mechanisms of tissue-level diffusion and binding was developed and experimental data was fit to this model. Doxorubicin was found to have the optimal diffusivity and binding for maximizing therapeutic effect. Doxil was severely limited by low intratumor drug release. These results show that in-vitro models mimicking tissue-level transport limitations more accurately predict the therapeutic response of drugs.

No description available.

Orientador: Lígia Niero-Melo / Banca: Lucilene Silva Ruiz e Rezende / Banca: Eduardo Moreira de Queiroga / Resumo: A infiltração de MO por tumores não-hematológicos tem sido descrita desde 1935 e, mais recentemente, desperta interesse da comunidade científica, pois inúmeros trabalhos têm relacionado a presença de células tumorais na MO com o processo de carcinogênese e a progressão tumoral. O presente estudo teve por objetivo o levantamento dos casos com diagnóstico de mielopatia infiltrativa por tumores nãohematológicos, provenientes da Faculdade de Medicina de Botucatu - UNESP e do Hospital Amaral Carvalho - Jaú, avaliados, retrospectivamente, no período de 1998 a 2008 (num universo de 15.191 coletas de MO). Incluímos 193 pacientes, dos quais 171 eram adultos e 22 crianças (idade ≤ 21 anos), com paridade entre os sexos (1:1) e mediana de idade de 55 anos. Foram analisados dados clínicos, diagnóstico e estadiamento do tumor primário, sítios de metástases, características laboratoriais (hemograma e marcadores tumorais séricos), características da MO, tratamento e a relação desses fatores com a sobrevida dos pacientes, através do programa de estatística SPSS®. Os resultados encontrados apontam que os tumores que mais frequentemente infiltraram a MO nos adultos foram: tumores de mama, próstata e sítio primário indeterminado, e neuroblastoma nas crianças. A análise da MO revelou positividade de 80% para mielograma e BMO, e presença de fibrose em 32% dos pacientes (40%, quando associados a áreas de necrose no mesmo material). Na avaliação hematológica observamos: anemia, alteração de leucócitos e plaquetopenia. Houve diferença, estatisticamente significante, com maior mediana de sobrevida global (p= 0,000) para pacientes do sexo feminino, portadores de adenocarcinoma de mama, em estádios iniciais e que receberam algum tipo de tratamento (quimio, radio e/ou hormonioterapia). Na análise de sobrevida, a partir do diagnóstico de mielopatia infiltrativa, houve... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Bone marrow (BM) infiltration by nonhematopoietic tumors has been described since 1935, and a increased number of papers about this topic have been published. Some of the studies have related the relationship between the presence of peripheral circulating tumors cells, bone marrow infiltration, carcinogenesis and tumor progression. This study has, as essential objective, the evaluation of infiltrative mielopathy by nonhematopoietic tumors from Faculdade de Medicina de Botucatu - UNESP and Hospital Amaral Carvalho - Jaú. Data were analised retrospectively from 1998 January to 2008 August (15.191 bone marrow samples). We have included 193 patients. One hundred seventy one were adults and 22 were children (considered age ≤ 21 years), with similar number of patients by gender, and median age 55 years. Medical records from the selected patients were analised, with focus on clinical aspects, primary site of tumor, initial stage, metastatic sites, hematologic and bone marrow features, treatment and the relationship between this data and survival. Results have demonstrated that most frequent solid tumors in adults were breast cancer, prostate cancer and undetermined primary site, and neuroblastoma among children. Bone marrow revealed infiltration in 80% of samples by myelogram and BM biopsy, and fibrosis in 32% (40% when associated with necrosis area). We observed anaemia, leukocyte alterations and thrombocytopenia as hematologic features. There were significant differences in global survival, wich was better among female patients, diagnosis of breast cancer, initial clinical stages and who has received any type of treatment (chemotherapy, radiotherapy and/or hormoniotherapy). When we analised survival since diagnosis of infiltrative mielopathy, adult patients with leucoeritroblastic reaction and trombocytopenia, and undetermined primary site tumors, melanoma or gastrointestinal tumors had... (Complete abstract click electronic access below) / Mestre

The majority of human cancers arise due to cells inabitily to maintain genomic stability. Cytogenetic changes (especially chromosomal aberrations) in peripheral blood lymphocytes which reflect not only the individual exposure to genotoxic factors, but also individual sensitivity to genotoxic effect and the tumor is late consequence to genotoxic effect. Summary epidemiological prospective studies over the last ten years have shown that increased level of chromosomal aberrations in peripheral blood lymphocytes is predictive of cancer risk. This thesis is focused on the detection of particular types of chromosomal damage in patients with choosed types of newly diagnosed cancers compared to healthy control persons. We cytogenetically analyzed 100 patients with colorectal cancer and 298 controls and 123 patients with breast cancer and 123 controls - healthy women. We compared the percentage of aberrant cells, the percentage of total aberrations, the percentages of chromatid and chromosome aberrations found in patients with both types of tumors and in controls and we verified the predictive value of chromosomal aberrations as a biomarker of cancer risk. In patients with colorectal cancer was statistically significantly increased only the level of chromatid aberrations (CHTA) (1,45±1,28) compared to...

Ce projet vise à développer et à analyser de nouveaux nanovecteurs pour des applications biomédicales. Nous travaillons en étroite collaboration avec des chimistes pour mettre au point des nanoparticules hautement efficaces (principalement des nanoparticules de silicium poreux - pSiNPs). Mon travail consiste à évaluer la toxicité des nano-objets développés et à établir leur potentiel en terme de thérapie photodynamique et d'imagerie. Les nanovecteurs sont recouverts de sucres reconnus par les lectines surexprimées par les cellules cancéreuses. Cette interaction permet le ciblage spécifique des cellules cancéreuses par les nanovecteurs. Lors des études in vitro, nous sélectionnerons les nano-objets les plus prometteurs pour réaliser des études préliminaires in vivo. / The focus of this project concerns the development and the analysis of new nanocarriers for biomedical applications. We work in collaboration with chemists to design efficient nanoparticles (mainly porous silicon nanoparticles - pSiNPs). Then, I evaluate their cytotoxic activity and their photodynamic therapeutic effect as well as their imaging potential. Nanovectors are coated with sugar recognized by lectins overexpressed on the surface of cancer cells. This interaction permits the specific targeting of cancer cells by nanovectors synthesized. During the study in vitro, we will select the most promising nanotools for preliminary studies in vivo.

Orientador: Luiz Carlos Zeferino / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T23:00:31Z (GMT). No. of bitstreams: 1 Silva_LeonardoRobertoda_M.pdf: 1256988 bytes, checksum: f80a4677bb94a6755e6004d6c8021f20 (MD5) Previous issue date: 2015 / Resumo: Introdução: Os carcinomas luminais de mama apresentam resposta variável à quimioterapia neoadjuvante. A identificação precoce das pacientes que se beneficiarão desse tratamento é importante para se evitar tratamento desnecessário e suas decorrentes toxicidades. O objetivo desse estudo é identificar preditores de resposta à quimioterapia neoadjuvante no carcinoma luminal de mama. Metodologia: Nós incluímos pacientes com carcinoma luminal de mama tratadas com quimioterapia pré-operatória em nosso serviço, no anos de 2013 e 2014. Dados demográficos, clínicos e patológicos foram coletados. Análises de imunoistoquímica para receptores de estrogênio e progesterona, HER2 e Ki67 foram realizadas em amostras obtidas antes do tratamento. A quimioterapia foi composta por esquema baseado em antraciclinas e taxanos. Resposta patológica completa (RPC) foi definida como ausência de doença invasora nas peças cirúrgicas da mama e da axila. Resultados: Foram incluídas cento e vinte pacientes, totalizando 131 tumores. As taxas de RPC foram de 6,11% na amostra geral, 5,26% para tumores luminais B-like (HER2-negativos) e 12,9% para luminais B-like (HER2-positivos). Nenhum preditor independente de RPC foi identificado. Cinquenta e dois tumores (39,7%) apresentaram resposta clínica completa, e grau histológico III (OR=9,05; IC95% 1,07-7,98; p=0,04), status pré-menopausal (OR=9,05; IC95% 2,01-40,87; p=0,004), e índice de Ki67 ? 20% (OR=2,71; IC95% 1,04-6,99; p=0,04) foram preditores independentes desse desfecho. A análise da curva ROC mostrou que o índice de Ki67 pré-tratamento tem baixo desempenho na identificação de pacientes que apresentarão resposta clínica completa (área sob a curva=0,660; IC95% 0,563-0,758). Pacientes com resposta clínica completa apresentaram maior chance de serem submetidas a cirurgia conservadora. Conclusões: A taxa de RPC é baixa entre os carcinomas luminais de mama submetidos a quimioterapia neoadjuvante. No entanto, parâmetros clinico-patológicos podem ajudar a identificar pacientes que apresentarão resposta clínica completa / Abstract: Purpose: Luminal breast cancers show a variable response to neoadjuvant chemotherapy. The early determination of those patients who will benefit from this treatment is important to avoid overtreatment and the resulting toxicity. The purpose of this study is to identify predictors of response to neoadjuvant chemotherapy in luminal breast cancer. Methods: We included patients with luminal breast cancer treated with neoadjuvant chemotherapy at the institution in 2013 and 2014. Demographic, clinical, and pathological data were collected. Immunohistochemistry analyses of estrogen and progesteron receptors, HER2 and Ki67 were conducted in samples obtained before treatment. Chemotherapy consisted in anthracycline/taxane-based scheme. Pathologic complete response was defined as the absence of invasive disease in the breast and axilla surgical specimens. Results: One hundred and twenty patients, totaling 131 tumors were included. Pathologic complete response rates were 6.11% in the overall sample, 5.26% for luminal B-like (HER2-negative) tumors and 12.9% for luminal B-like (HER2-positive) tumors. None independent predictor of pathologic complete response was identified. Fifty-two tumors (39,7%) showed complete clinical response, and histologic grade III (OR=2.92; 95% CI 1.07-7.98; p = 0.04), premenopausal status (OR=9.05, 95% CI 2.01-40.87; p = 0.004), Ki67 index ? 20% (OR=2.71, 95% CI 1.04 to 6,99; p = 0.04) were independent predictors for this outcome. ROC curve analysis showed that Ki67 index has a poor performance in identifying patients who will present complete clinical response (area under the curve=0.660, 95% CI 0.563-0.758). Patients with complete clinical response were more likely to be submitted to conservative surgery. Conclusions: Pathologic complete response rate is low among luminal tumors undergoing neoadjuvant chemotherapy. However, clinicopathological parameters can help identify patients who will present complete clinical response / Mestrado / Oncologia Ginecológica e Mamária / Mestre em Ciências da Saúde