No description available.

The high-mobility group A protein 2 (HMGA2) is a non-histone chromatin factor highly expressed in fetal tissue and malignant tumors but rarely detected within normal adult tissues. The clinical implications and biological functions of HMGA2 in endometrial carcinoma are largely unknown. Here we report that HMGA2 expression was barely detected in benign endometrium samples (2 of 28 samples). However, HMGA2 expression increased significantly from precancerous lesion endometrial glandular dysplasia (7 of 17, 41.2%), to serous endometrial intraepithelial carcinoma (5 of 8, 62.5%) and to full blown endometrial serous carcinoma (39 of 59, 66.1%). Functional characterization of HMGA2 revealed that the gene has both tumor growth promotion and metastasis. In addition, HMGA2 induced epithelial-mesenchymal transition (EMT) through modulation vimentin and β-catenin. Furthermore, HMGA2 overexpression started from endometrial serous precancers, non-invasive cancers, as well as in full blown carcinomas in a p53 knockout mouse model we recently established in our laboratory. Our findings suggest that HMGA2 may serve as a useful diagnostic marker in the assessment of endometrial serous cancer and its precursor lesions.

The problem with which this investigation is concerned is that of determining the nature of events leading to the change. of normal cells into malignant cells. The design of the study is multi-phasic: (A) to establish the presence or absence of an oncogenic virion, (B) to demonstrate by use of the electron microscopy any ultracellular alteration in malignant or transformed tissues, (C) to investigate the nature of the transforming agent in the murine lymphosarcoma, and (D) to employ various methods to demonstrate cellular transformations in vivo and in vitro. It is concluded that the transforming and tumorinducing agent in this' investigation was not a virion, but an infectious ribonucleic acid genome or a segment of a viral genome which had become integrated into the genome of the mouse cells. The vision has lost its ability to form a protein coat; therefore it is not demonstrable as a virion. But the ribonucleic acid is able to infect other cells and transform them from normal to neoplastic tissues.

Cancer is a complex, multi-scale disease marked by unchecked cellular growth and proliferation. As a tumor grows, it is known to lose its capacity to maintain a compact structure. This stage of development, known as invasion, is marked by the disaggregation and dispersion of peripheral cells, and the formation of finger-like margins. This thesis provides an overview of three multi-scale models of tumor growth and invasion. The hybrid discrete-continuum (HDC) model couples a cellular automaton approach, which is used to direct the behavior and interactions of individual cells, with a system of reaction-diffusion-chemotaxis equations that describe the micro-environment. The evolutionary hybrid cellular automaton (EHCA) model maintains the core of the HDC approach, but employs an artificial response network to describe cellular dynamics. In contrast to these two, the immersed boundary (IBCell) model describes cells as fully deformable, viscoelastic entities that interact with each other using membrane bound receptors. As part of this thesis, the HDC model has been modified to examine the role of the ECM as a barrier to cellular expansion. The results of these simulations will be presented and discussed in the context of tumor progression.

In recent decade, lung cancers had the highest incidence and mortality rate among all cancers in Taiwan. Among lung cancers, adenocarcinoma was the most frequent type. The chemotherapy was still the main choice in treating lung cancer by the mechanism of destroying DNA, but the response rate kept low. The function of DNA repair makes cancer cells resistant to chemotherapy. Therefore, this study focused on the effect of cancer cell growth by silencing Mre11. The first part of this study was to make a tissue microarray consisting of adenocarcinoma from 57 patients. Immunohistochemistry staining for Mre11 was done. The correlation of Mre11 expression and clinical variables with survival was analyzed. The second part was tried to knockdown Mre11 in A549 cell by shRNA. Another A549 cell line containing empty vector was selected as control group. These cell lines were then ready for XTT method, soft agar colony formation assay, flow cytometry and nude mice assay. In the clinical data, the absence of lymph node and distant site metastasis were good prognosis factor for longer survival. Although the high expression on Mre11 had longer survival, this variable was not a true independent factor. On XTT method and soft agar colony formation assay, the A549 cells with Mre11 knockdown had a slower proliferation and fewer colony numbers, respectively. The cell cycle demonstrated an elevated G0/G1 and S phase and depressed G2/M phase in A549 cells with Mre11 knockdown. The tumor arising from A549 cells with Mre11 knockdown in the nude mice also had a smaller size. Based on the above study, inhibition of Mre11 may result in a reduction of tumor growth and provide another choice to treat lung cancer.

Cancer is a complex, multi-scale disease marked by unchecked cellular growth and proliferation. As a tumor grows, it is known to lose its capacity to maintain a compact structure. This stage of development, known as invasion, is marked by the disaggregation and dispersion of peripheral cells, and the formation of finger-like margins. This thesis provides an overview of three multi-scale models of tumor growth and invasion. The hybrid discrete-continuum (HDC) model couples a cellular automaton approach, which is used to direct the behavior and interactions of individual cells, with a system of reaction-diffusion-chemotaxis equations that describe the micro-environment. The evolutionary hybrid cellular automaton (EHCA) model maintains the core of the HDC approach, but employs an artificial response network to describe cellular dynamics. In contrast to these two, the immersed boundary (IBCell) model describes cells as fully deformable, viscoelastic entities that interact with each other using membrane bound receptors. As part of this thesis, the HDC model has been modified to examine the role of the ECM as a barrier to cellular expansion. The results of these simulations will be presented and discussed in the context of tumor progression.

No description available.

<p>Shb is a ubiquitously expressed adaptor protein with the ability to bind several tyrosine kinase receptors and intracellular signaling proteins. Previous studies have implied a wide spectrum of Shb-mediated cellular responses, which motivated me to further investigate the role of Shb in differentiation and angiogenesis. Embryonic stem (ES) cells differentiate into endoderm and mesoderm from a bipotent mesendodermal cell population. Interregulatory signals between these germlayers are required for further specification. ES cells overexpressing Shb with an inactive SH2 domain (R522K-Shb) altered the expression of endodermal genes as a consequence of upregulated FGF expression. This response was enhanced by addition of activin A, suggesting a synergistic mechanism operative between FGF and activin A signaling in endoderm specification. To investigate a role for Shb in mesodermal specification, Shb knockout ES cells were established. These cells showed a reduced ability to form blood vessels after VEGF stimulation and delayed downregulation of genes associated with mesendoderm, indicating a reduced capacity for these cells to enter later stages.</p><p>To assess a role for Shb in tumor cell apoptosis, Shb expression was silenced in angiosarcoma endothelial cells. FAK-phosphorylation was reduced in Shb knockdown cells and this made them more susceptible to apoptotic stimuli both in vitro and in vivo.</p><p>Shb knockout microvasculature in mouse kidney, liver, and heart showed irregular endothelial linings with cytoplasmic projections toward the lumen, a feature that was also related to increased vascular permeability. VEGF treatment failed to stimulate vascular permeability in Shb knockout mice.</p><p>In order to elucidate whether these features relate to reduced angiogenesis, tumor growth was examined. Tumors grown in knockout mice showed reduced growth capacity and lower vessel density. In conclusion, Shb is a multifunctional adaptor protein that may be involved in several cellular responses both during embryonic development and adult life. </p>

O crescimento de tumores vem chamando a atenção de físicos e matemáticos há mais de sessenta anos. Entretanto, a conversa com biólogos e a interação teoria-experimento têm aparecido apenas recentemente. Equações fenomenológicas e simulações computacionais continuam sendo uma ferramenta comum entre todos os modelos que conhecemos. Assim, nesse trabalho nós estudamos o problema do crescimento de tumores monocamada através das abordagens experimental, teórica e computacional, fortalecendo assim a interação teoria-experimento. Cultivamos células das linhagens HeLa (carcinoma cervical humano), HCT-15 (adenocarcinoma coloretal humano), NIH-HN-13 (carcinoma de células escamosas humanas) e U-251 (glioblastoma neuronal humano), obtendo a dimensão fractal e o comportamento do raio médio com o número de células, além de analisarmos os dados da literatura para a linhagem HT-29 (adenocarcinoma coloretal humano). A seguir nós modelamos a taxa de crescimento do raio médio através de uma curva sigmoidal. A solução analítica dessa equação nos permitiu ajustar bem os dados obtidos experimentalmente, e os parâmetros obtidos serviram para a simulação Monte Carlo dinâmico. Para essa, transformamos a taxa de crescimento do raio em taxa de crescimento do número de células, cujos resultados novamente concordaram muito bem com os dados experimentais. A dimensão fractal dos agregados esteve entre 1; 12 df 1; 21, e concordou com os dados da literatura. Novos resultados foram produzidos: i) O raio médio como uma função do número de células nos permitiu um ajuste do tipo Rc(t) = a[Nc(t) ? N~0]1=2 + R~0, mais geral que a comumente aceita relação Rc(t) = cNc(t)1=2; e ii) os tempos de espera no procedimento MCD se distribuem log-normalmente (ou Gaussianamente em alguns casos), diferentemente da distribuição Poissoniana frequêntemente assumida. A distribuição log-normal nos permitiu também conjecturar que um parâmetro , da relação ht(nT)i / n? T , possa caracterizar o crescimento monocamada de tumores devido à sua estreita abrangência 0; 69 0; 81. Nossos resultados nos permitiram concluir que diferentes condições de cultivo podem gerar diferentes respostas dos parâmetros, além disso, dois fenômenos podem caracterizar esse crescimento no âmbito mesoscópico: A competição por espaços livres e a cooperação entre as células. / Tumor growth has been calling attention of physicists and mathematicians for more than sixty years. However, cross-talking with biologists and the interplay between theory and experiment have emerged just recently. Phenomenological equations and computational simulations are still the common toolbox among all the models we know. Thus, in this work, we have studied the problem of monolayer tumor growth through the experimental, theoretical and computational approaches, enhancing the interaction between theory and experiment. We cultivate HeLa (human cervical carcinoma), HCT-15 (human colorectal adenocarcinoma), NIH-HN-13 (human squamous cell carcinoma) and U-251 (human neuronal glioblastoma) cells, calculating the fractal dimension and the behavior of the mean radius with cell number, and analyzing the literature data from HT-29 (human colorectal adenocarcinoma) lineage. Then we modeled the growth rate of mean radius through a sigmoidal curve. The analytical solution of this equation allowed us to fit well the experimental data and the obtained parameters were used into dynamical Monte Carlo simulation. To do this, we transform the radius growth rate in number of cells growth rate, which again agreed with the experimental data. The fractal dimensions of the aggregates ranged from 1; 12 df 1; 21, and agree with the literature. New findings were produced: i) the mean radius as a function of the number of cells enabled us to adjust the function Rc(t) = a[Nc(t) ? N~0]1=2 + R~0, differently from widely accepted relation Rc(t) = cNc(t)1=2; and ii) the waiting times in the MCD procedure are log-normally distributed (sometimes Gaussian), unlike the Poisson distribution often used. The lognormal distribution also allowed us to conjecture that a parameter , from the power law relation ht(nT)i / n? T , might caracterize the tumor monolayer growth due to its narrow range 0; 69 0; 81. Our findings led us to conclude that different culture conditions may produce different parameter responses, furthermore, two phenomenona can describe the growth in mesoscopic level: the competition for free space and the cooperation between cells.

Made available in DSpace on 2017-07-21T19:25:46Z (GMT). No. of bitstreams: 1 Regiane Siqueira.pdf: 5314044 bytes, checksum: c87c036209bfc1afaae749bad20579fb (MD5) Previous issue date: 2015-04-16 / This study proposes to analyze mathematical models that describe the dynamics of populations, namely, sets of organisms that may or may not belong to the same species but have similar behavior as relates to their dynamics. It is specially treated with models of cell populations that consider the delay time, which are described by dierential equations with delay. The analysis is realized in two mathematical with models, the rst describes the interaction of tumor cells with the immune system. It is considered that the immune system is constituted by resting cells and hunting cells, as well as, the resting cells become cells hunting but the conversion is not straightforward, requiring shaping by delayed dierential equations. The second describes a model for treatment of cancer by chemotherapy where there is metastasis of a primary to a secondary focus by tumor cells. We observe the interactions between normal and tumor cells as being competitive for the available resources, and it is thought the chemotherapy agent as a predator in normal and cancer cells. Metastasis can occur with a delay time, which leads to delayed dierential equations. Next study is a model for treating of brain tumor by chemotherapy. We propose a system of coupled dierential equations that model brain tumour with treatment by chemotherapy, which considers interactions among the glial cells, the glioma, the neurons, and the chemotherapeutic agents. We study the conditions for the glioma growth to be eliminated, and identify values of the parameters for which the inhibition of the glioma growth is obtained with a minimal loss of healthy cells. / Neste trabalho, propoe-se analisar modelos matematicos que descrevem a dinâmica de populações, ou seja, conjuntos de organismos que podem ou n~ao pertencer a mesma espécie, porem possuem comportamento semelhante no que refere-se a sua dinâmica. São tratados de forma especial os modelos de populações de celulas onde considera-se o tempo de retardo, isto e, aqueles descritos por equações diferenciais com atraso. Primeiramente e realizada a análise em dois modelos matemáticos, o primeiro descreve a interação das células tumorais com o sistema imunologico. Considera-se que o sistema imunologico e constituído por células de repouso e células de caça, sendo que as de repouso se convertem em celulas de caça, mas a conversão não e imediata, havendo necessidade de modelar por equações diferencias com atraso. O segundo descreve um modelo para tratamento do câncer por quimioterapia, onde ha metástase de um foco primário para um foco secundário pelas células tumorais. Observa-se as interações entre as células normais e tumorais como sendo competitivas para os recursos disponiveis, e e pensado no agente de quimioterapia como um predador em ambas as celulas, normais e cancer genas. A metastase pode ocorrer com um tempo de retardo, o que da origem a equações diferencias com atraso. Em seguida e descrito um modelo para o tratamento de um tumor cerebral por quimioterapia. E proposto um sistema de equações diferenciais ordinarias para modelar o tumor no cerebro em tratamento por quimioterapia, que considera as interações entre as celulas da glia, o glioma, os neurônios e os agentes quimioterapicos. Analisa-se as condições para o crescimento do glioma a ser eliminado, e identica-se os valores de parâmetros para os quais a inibição do crescimento do glioma e obtida com um mínimo de perda de células saudáveis.