Made available in DSpace on 2014-06-12T23:13:24Z (GMT). No. of bitstreams: 2 arquivo2646_1.pdf: 4881014 bytes, checksum: c2c2e45d96e51c21b4c76b3c12792f5d (MD5) license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) Previous issue date: 2009 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Radiomodificadores são substâncias que podem se comportar como radioprotetores ou radiosensibilizadores. E ainda podem alterar o metabolismo e captação dos radiofármacos na biodistribuição, o que pode resultar em erros no diagnóstico em medicina nuclear. Muitos produtos naturais podem se comportar como radiomodificadores, e a Punica granatum L. (Romã) apresenta diversas características, como a capacidade antioxidativa, que a indica como um provável radiomodificador. Dessa forma, o presente trabalho teve o objetivo de avaliar a capacidade que a polpa da Romã possui em alterar a captação do tecnécio-99m (99mTc) na biodistribuição, e comparar se essa captação modifica frente a animais sadios e com Sarcoma 180, bem como em relação a forma que é administrada. Associado a estes aspectos, avaliar a capacidade antitumoral, antinflamatória e radioprotetora. Em todo os experimentos foram empregados camundongos machos Swiss. Os animais sadios, receberam a implantação do Sarcoma 180 na região subaxilar direita. A biodistribuição foi realizada 24 horas após o tratamento com a Punica granatum L., e os animais foram eutanasiados rapidamente após 30 minutos da administração do 99mTc. Os órgãos foram retirados para pesagem e contagem da radiação em contador gama. A atividade antitumoral foi analisada baseada no indice de inibição tumoral (TWI). A avaliação antinflamatória foi realizada empregando o modelo da carragenina para provocar a ação inflamatória. E para avaliação do aspecto radioprotetor foi utilizada a dosagem da glutationa reduzida (GSH) após irradiação com cobalto-60 (60Co). Os resultados obtidos destacam-se pela possibilidade de demonstrar a ação da polpa de uma fruta tão exótica e de grande emprego pela população nordestina, resaltando que sua atividade pode ser modificada dependentemente da presença do câncer, e da sua forma de administração. Na biodistribuição foi demonstrado que a polpa da romã, nos animais que não tinham tumor, reduziu a captação do 99mTc apenas no intestino grosso e estomago, enquanto aumentou a captação na tireóide. Em animais com sarcoma 180, que foram tratados após a implantação do tumor ocorreu redução significativa da captação na grande maioria dos órgãos. Mas, nos animais que foram tratados antes e após a implantação do Sarcoma 180, ocorreu aumento da captação no pulmão, coração, pâncreas, estômago, tireóide e tumor. Estes resultados demonstram a capacidade que a polpa da romã possui em alterar a biodistribuição nos tecidos. A polpa da romã também apresentou atividade antitumoral, antinflamatória e provável ação radioprotetora decorrente da elevação dos níveis de GSH nos animais irradiados

Abstract Laminins are basement membrane glycoproteins consisting of three polypeptide chains α, β and γ. Until now 12 members of the protein family have been characterized and all isoforms have an αβγ chain composition, but they assemble in varying combinations of chain variants. The functional properties of laminins include cell adhesion, proliferation, differentiation, growth and migration. Laminin-5 has a chain composition of α3β3γ2 with the distribution mainly restricted to epithelial basement membranes, where its biological functions involve anchorage and locomotion of cells. The importance of this protein for the attachment of basal keratinocytes is clearly demonstrated by the fact that all genes encoding its chains have been shown to be mutated in the severe skin blistering disease Epidermolysis bullosa junctionalis. The present study focused on investigations of the role of the laminin-5 isoform and particularly its γ2 chain in cell adhesion and migration. The role of the short arm of the laminin γ2 chain in the process of epithelial cell attachment is to serve as a kind of a bridging molecule to the extracellular environment, because it does not have any cell binding activity by itself. It was also shown that the newly synthesized γ2 chain participates in the complex process of cell migration, probably as one of the first attachment components for moving cells. Thus, as a migration and differentiation-associated molecule, laminin-5 was considered a potential marker for detection of malignant processes where cell movement plays a role. Subsequently it was shown that the γ2 chain is expressed not only in a restricted manner in human epithelial tissues, but also in a number of human epithelium-derived cancers. In some carcinomas, expression of the γ2 chain appeared to be a characteristic of cancer cells with invasive properties. Examination of over 50 dysplasias and cervical tumors revealed that γ2 chain antibodies were able to distinguish between lesions with or without invasive capacity. This is the first systematic study of epithelial cancers where γ2 chain antibodies have been shown to be a useful marker in the histopathological diagnostics. In addition, this study showed in a mouse tumor model that the γ2 chain of laminin-5 has a potential for being of use for in vivo tumor imaging.

Tumor biopsies may help to reliably distinguish hepatocellular carcinoma (HCC) from other tumors, mostly cholangiocarcinoma as well as to identify the patient populations who most benefit from target-driven HCC treatments, in order to improve the success rate of experimental therapies. Clarifying tumor biology may also lead to identify biomarkers with prognostic role and/or enabling to predict response or resistance to therapies. Recently, clinical trials have more efficiently included biomarker endpoints and increasingly collected tumor tissue from enrolled patients. Due to their frail status and sometimes fast-progressing disease, the performance status of patients with HCC progressing on first-line therapy can deteriorate quickly, preventing their enrollment in clinical trials. However, the challenge of identifying the proper patient at the proper time can be overcome by periodic inter-department meetings involving the key specialists taking care of HCC patients, and solid networks between research centers and referring institutions. An early planned biopsy would also facilitate timely inclusion of patients in biology-driven clinical trials. Ultimately, institution of multidisciplinary teams can optimize treatment choice, biopsy timing, and quick enrollment of patients in clinical trials, before their performance status deteriorates.

Abstract In malignancies many alterations involving matrix macromolecule synthesis, secretion and assembly into basement membranes (BMs) as well as their degradation are present. The most important groups associated with matrix turnover are matrix metalloproteinases (MMPs) and their inhibitors (TIMPs). In this study altogether 285 tissue samples were investigated comprising various malignant epithelial tumors and normal tissue structures, in which the distribution of different laminin chains was studied immunohistochemically. Laminin α5, β1 and γ1 were detected almost in all the BMs studied including normal tissues and malignancies, whereas α1 chain of laminin was present only in certain BMs. Laminin γ2 chain was solely expressed by epithelial BMs and was present in intracellular space especially in individual carcinoma cells infiltrating in the tumor stroma and in tumor cells in close contact with BM zone. Generally epithelial tumors contained quite well-formed BMs around their tumor clusters, except for infiltrative breast carcinoma and diffuse type gastric carcinoma. In situ hybridization revealed that only epithelial cells contained mRNAs for laminin α1 and γ2 chains, whereas laminin β1 chain and α1(IV) collagen were synthesized mainly by stromal cells. mRNA for MMP-2 was produced mainly by stromal cells in hepatocellular carcinoma of liver (HCC) and pancreatic adenocarcinoma, whereas MMP-9 and MT1-MMP were equally synthesized by carcinoma cells and cells of tumor stroma. However, in HCCs of grade III carcinoma cells predominated in their MT1-MMP expression. All three MMPs were immunolocalized to malignant epithelial cells and showed variably stromal cell positivity. Statistically mRNA synthesis for MT1-MMP was significantly associated with the shortened survival of patients with HCC (P ≤ 0.01). TIMP-1-3 mRNA, and especially TIMP-3, expressions in normal endometrium were significantly increased in endometrial stromal cells towards the secretory phase. In various endometrial hyperplasias TIMPs and MT1-MMP expressions were quite comparable to those seen in proliferating endometrium. In endometrial adenocarcinomas their expressions were significantly increased and the most intensified mRNA expressions were seen in grade III adenocarcinomas. Especially TIMP-3 and MT1-MMP mRNAs were synthesized by carcinoma cells. The results indicate that epithelial malignancies are capable of active synthesis and assembly of BM macromolecules. Simultaneous matrix synthesis and degradation seen in malignancies suggest that the mechanisms involved in matrix turnover are not lost during malignant transformation. mRNA synthesis for MMPs and TIMPs is generally increased in epithelial malignancies. The results therefore strongly support the concept that MMPs have an active role in carcinoma cell invasion.

The principal purpose of this work was to determine the effect of immunized guinea pig serum upon the survival time of tumor infected mice, and to make a correlation between this effect and the complement titer.

Primitive neuroectodermal tumor (PNET) is part of the Ewing sarcoma family of tumors. The present case reports a primitive neuroectodermal tumor (PNET) of rare location in the bladder in a newborn. It was evaluated with prenatal ultrasound and postnatal tomography that revealed a mass in the posterior wall of the bladder. The patient underwent partial cystectomy with subsequent analysis of the surgical piece removed, the histopathological study indicated a tumor of mesenchymal origin, and immunohistochemical staining confirmed the diagnosis of PNET of the bladder. Satisfactory result and short-term follow-up. / Revisión por pares

Making up just over 3% of all new cancer cases in the United States, pancreatic cancer is not inherently a common malignant disease. Yet, it continuously is shown to be one of the most lethal and common causes of cancer death. Early detection is critical among all cancer types. However, oncologists and researchers have struggled to find effective strategies or tests to detect cancer of the pancreas early on in development. Thus, the cancer is often found late stage and requires significant chemotherapy intervention. These multi-drug treatment cocktails have shown benefit, but only in added months and not years to a patient’s life. Significant adverse effects often limit the full effective doses of treatment. In order to limit these adverse effects, as well as increase the effectiveness of treatment, we have designed, optimized, and tested unique drug carriers known as polymersomes. Using characteristics of the localized environment surrounding pancreatic tumors and the cells found therein, we created targeted therapies that are responsive and relatively selective toward cancerous cells. Herein, are found two distinct polymersomes. The first, is a low oxygen reactive drug carrier with an additional small peptide molecule that is able to penetrate dense tumor tissue and has shown decreased tumor growth of as much as 260% as compared to control samples in an animal model of pancreatic cancer. The chemical make-up of this polymersome allows for extended circulation time and a high accumulation at the tumor site. A second design, uses an intracellular enzyme to destabilize the polymersomes’ structure, which in turn, releases a selected chemotherapy drug near its intended site of action. This strategy, has shown a 10 fold increase in potency of the chemotherapy drug, as compared to when the drug is given alone and showed decreased toxicity to non-cancerous cells. It is certain that thoughtful drug delivery strategies and not just drug molecule design will be instrumental in the paradigm shift of pancreatic cancer from likely death to survival. / NIH grant 1 R01GM 114080; Grand Challenge Initiative; Office of the Dean, College of Health Professions

Orientador: Andrigo Barboza de Nardi / Resumo: Este estudo teve como objetivo analisar os casos de mastocitomas em 192 cães atendidos no Hospital Veterinário Governador Laudo Natel da Faculdade de Ciências Agrárias e Veterinárias (FCAV)-UNESP-Câmpus Jaboticabal, no período de 2005 a 2015, além de analisar a ocorrência dessa neoplasia em relação à raça, idade e sexo; determinar quais as regiões corpóreas foram mais acometidas e as características neoplásicas observadas; avaliar quais são os métodos de diagnóstico mais utilizados no setor; estabelecer os principais graus histológicos diagnosticados, os tratamentos preconizados, avaliar a taxa de recidiva e metástase. Foram avaliados 192 pacientes e foi observado que setenta e seis animais apresentavam múltiplos nódulos (39,6%), e os nódulos acima de três centímetros perfaziam 39,1% das amostras (n=75). Sessenta e um casos de lesões metastáticas em linfonodos regionais – N1 (31,8%) foram encontrados e 71,9% dos nódulos identificados tiveram crescimento rápido, sendo 16,7% (n= 32) localizados em membro pélvico. Foi observada associação estatística entre a presença de nódulos solitários/múltiplos e o grau histológico segundo Kiupel et al. (2011) (p=0,004). Em relação à classificação de Patnaik et al. (1984), as variáveis raça e sexo diferem proporcionalmente entre os grupos histológicos (p=0,008 e 0,040 respectivamente), a presença de linfonodo comprometido por metástase e velocidade de crescimento rápido também tiveram associação com o grau histológico (p=0,002 e 0,001). Além... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

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Non-invasive measurement of pH provides multiple potential benefits in oncology such as better identifying the type of drug that can be more effective in chemotherapy, potentially identifying tumors that are more likely to metastasize and also better assessing the treatment effects. Chemical Exchange Saturation Transfer (CEST) Magnetic Resonance Imaging (MRI) is a versatile non-invasive technique for molecular imaging. AcidoCEST MRI techniques have been developed over the recent years to perform tumor pH measurements by utilizing a contrast agent for which chemical exchange saturation transfer effects depend on the pH of the microenvironment. Quantitative description of CEST MRI signals are generally done via modeling Bloch-McConnell equations by incorporating pH as a parameter or by fitting Lorentzian line shapes to observed z-spectra and then computing a log ratio of the CEST effects from multiple labile protons of the same molecule (ratiometric method). Modeling using Bloch-McConnell equations is complicated and requires careful inclusion of many scan parameters to infer pH. The ratiometric method requires contrast agents that have multiple labile protons, thus making it unsuitable to use for molecules with a single labile proton. Furthermore, depending on the pH, sometimes it might not be possible to numerically compute the ratio due to the inability of detecting signal peaks for certain labile protons. Our aim here is to develop a machine learning based method that learns the CEST signal patterns from observed z-spectra on temperature and concentration-controlled contrast agent phantoms independent of the type of the contrast agent. Our results indicate that the machine learning method provides more general and accurate prediction of pH in comparison to the ratiometric method based on the phantom CEST dataset. Our method is more general in the sense that it does not require explicit modeling of signal peaks that are dependent on the type of contrast agent. We also describe a state of the art variational autoencoder based algorithm extending our machine learning method to measure tumor pH in vivo using AcidoCEST MRI on mouse tumor models.