35 resultados para CANCRO CUTÂNEO


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Recentemente foi desenvolvido um dosímetro baseado em fibras cintilantes (BCF-12 da companhia Saint Gobain Crystals com 1 e 0,5 mm de diâmetro e 5 mm de comprimento) para braquiterapia de baixa taxa de dose, em particular a braquiterapia direcionada para o tratamento do cancro da próstata. Este utiliza um novo fotomultiplicador de estado sólido dado pelo nome de MPPC - MultiPixel Photon Counter da companhia Hamamatsu Photonics (Japão). Nesta dissertação é estudado o mesmo dosímetro para a modalidade de braquiterapia de elevada taxa de dose (HDR). A informação sobre a dose neste tipo de dosímetros é obtida a partir de sinais óticos (em vez de sinais elétricos), que são imunes a interferências elétricas e eletromagnéticas. Adicionalmente as pequenas dimensões das fibras oferecem uma excelente resolução espacial e uma invasão mínima para uso em dosimetria in vivo, permitindo medir a dose diretamente ou próximo ao tumor e em tempo real. A sua utilização em braquiterapia para o cancro da próstata constitui-se assim como uma vantagem, uma vez que as fibras podem ser inseridas diretamente nos aplicadores utilizados neste tipo de tratamentos. Apesar de tudo, este tipo de dosímetros possui algumas desvantagens, como por exemplo a luz de Cherenkov e a fluorescência (forma de ruído dada pelo nome de stem effect) que, e a contrário da luz produzida pela fibra cintilante, não são diretamente proporcionais à energia depositada. Contudo, e para energias praticadas em braquiterapia de HDR, nesta dissertação, mostrou-se que este problema é pouco significativo dado que a percentagem de contribuição destes efeitos para o sinal medido é menor que 1% (ou 5% para distâncias menores que 25 mm). Ao longo desta dissertação é feita a caraterização do dosímetro (em modo corrente e impulso) e das suas várias partes em ambiente de laboratório e clínico. Nestes estudos o dosímetro, além de exibir uma boa reprodutibilidade (variação máxima de 3% entre medidas), mostrou uma alta linearidade para uma ampla gama de doses, assim como uma sensibilidade (µGy) semelhante à de uma câmara de ionização, tornando-o adequado para braquiterapia de HDR (tratamento que envolve altos gradientes de dose). Complementarmente, a sua grande versatilidade e simples utilização possibilita a sua aplicação prática em outras modalidades radioterapêuticas.

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Mesenchymal stem cells (MSCs) are non-hematopoietic multipotent stem cells capable to self-renew and differentiate along different cell lineages. MSCs can be found in adult tissues and extra embryonic tissues like the umbilical cord matrix/Wharton’s Jelly (WJ). The latter constitute a good source of MSCs, being more naïve and having a higher proliferative potential than MSCs from adult tissues like the bone marrow, turning them more appealing for clinical use. It is clear that MSCs modulate both innate and adaptive immune responses and its immunodulatory effects are wide, extending to T cells and dendritic cells, being therapeutically useful for treatment of immune system disorders. Mechanotransduction is by definition the mechanism by which cells transform mechanical signals translating that information into biochemical and morphological changes. Here, we hypothesize that by culturing WJ-MSCs on distinct substrates with different stiffness and biochemical composition, may influence the immunomodulatory capacity of the cells. Here, we showed that WJ-MSCs cultured on distinct PDMS substrates presented different secretory profiles from cells cultured on regular tissue culture polystyrene plates (TCP), showing higher secretion of several cytokines analysed. Moreover, it was also shown that WJ-MSCs cultured on PDMS substrates seems to possess higher immunomodulatory capabilities and to differentially regulate the functional compartments of T cells when compared to MSCs maintained on TCP. Taken together, our results suggest that elements of mechanotransduction seem to be influencing the immunomodulatory ability of MSCs, as well as their secretory profile. Thus, future strategies will be further explored to better understand these observation and to envisage new in vitro culture conditions for MSCs aiming at distinct therapeutic approaches, namely for immune-mediated disorders.

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Head and Neck Cancers (HNC) are a group of tumours located in the upper aero-digestive tract. Head and Neck Squamous Cell Carcinoma (HNSCC) represent about 90% of all HNC cases. It has been considered the sixth most malignant tumour worldwide and, despite clinical and technological advances, the five-year survival rate has not improved much in the last years. Nowadays, HNSCC is well established as a heterogeneous disease and that its development is due to accumulation of genetic events. Apart from the majority of the patients being diagnosed in an advanced stage, HNSCC is also a disease with poor therapeutic outcome. One of the therapeutic approaches is radiotherapy. However, this approach has different drawbacks like the radioresistance acquired by some tumour cells, leading to a worse prognosis. A major knowledge in radiation biology is imperative to improve this type of treatment and avoid late toxicities, maintaining patient quality of life in the subsequent years after treatment. Then, identification of genetic markers associated to radiotherapy response in patients and possible alterations in cells after radiotherapy are essential steps towards an improved diagnosis, higher survival rate and a better life quality. Not much is known about the radiation effects on cells, so, the principal aim of this study was to contribute to a more extensive knowledge about radiation treatment in HNSCC. For this, two commercial cell lines, HSC-3 and BICR-10, were used and characterized resorting to karyotyping, aCGH and MS-MLPA. These cell lines were submitted to different doses of irradiation and the resulting genetic and methylation alterations were evaluated. Our results showed a great difference in radiation response between the two cell lines, allowing the conclusion that HSC-3 was much more radiosensitive than BICR-10. Bearing this in mind, analysis of cell death, cell cycle and DNA damages was performed to try to elucidate the motifs behind this difference. The characterization of both cell lines allowed the confirmation that HSC-3 was derived from a metastatic tumour and the hypothesis that BICR-10 was derived from a dysplasia. Furthermore, this pilot study enabled the suggestion of some genetic and epigenetic alterations that cells suffer after radiation treatment. Additionally, it also allowed the association of some genetic characteristics that could be related to the differences in radiation response observable in this two cell lines. Taken together all of our results contribute to a better understanding of radiation effects on HNSCC allowing one further step towards the prediction of patients’ outcome, better choice of treatment approaches and ultimately a better quality of life.

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Lipids can modulate the risk of developing sporadic colorectal adenocarcinoma (SCA), since alterations into lipid metabolism and transport pathways influence directly cholesterol and lipids absorption by colonic cells and indirectly reactive oxygen species (ROS) synthesis in rectum cells due to lipid accumulation. Lipid metabolism is regulated by several proteins APOA1, APOB, APOC3, APOE, CETP, NPY, PON1 and PPARG that could influence both metabolism and transport processes. Is been reported that several common single-nucleotide polymorphisms (SNPs) in these genes could influence their function and/or expression, changing lipid metabolism balance. Thus, genetic changes in those genes can influence SCA development, once the majority of them were never studied in this disease. Furthermore, there are contradictory results between some studied polymorphisms and SCA risk. Thus, the aim of this study was to explore and describe lipid metabolism-associated genes common polymorphisms (APOA1 -75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) status among SCA, and their relationship with SCA risk. Genotyping of common lipid metabolism genes polymorphisms (APOA1 75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) were done by PCR-SSP techniques, from formalin-fixed and paraffin-embedded biopsies of 100 healthy individuals and 68 SCA subjects. Mutant genotypes of APOA1 -75AA (32% vs 12%; p=0.001; OR=3.51; 95% CI 1.59-7.72); APOB 3500AA (7% vs 0%; p=0.01); APOC3 3175GG (19% vs 2%; p=0.0002; OR=11.58; 95% CI 2.52-53.22), APOC3 3206GG (19% vs 0%; p<0.0001); CETP 279AA (12% vs 1%; p=0.003; OR=13.20; 95% CI 1.61-108.17), CETP 451AA (16% vs 0%; p<0.0001); NPY 7CC (15% vs 0%; p<0.0001); PPARG 12GG (10% vs 0%; p=0.001); and heterozygote genotype PON1 192AG (56% vs 22%; p<0.0001; OR=4.49; 95% CI 2.298.80) were found associated with SCA prevalence. While, APOE E4/E4 (0% vs 8%; p=0.02) mutant haplotype seemed to have a protective effect on SCA. Moreover, it also been founded differences between APOB 3500GA, APOC3 3206TG, CETP 279AA genotypes and PPARG 12Ala allele prevalence and tissue localization (colon vs rectum). These findings suggest a positive association between most of common lipid metabolism genes polymorphisms studied and SCA prevalence. Dysregulation of APOA1, APOB, APOC3, CETP, NPY, PON1 and PPARG genes could be associated with lower cholesterol plasma levels and increase ROS among colon and rectum mucosa. Furthermore, these results also support the hypothesis that CRC is related with intestinal lipid absorption decrease and secondary bile acids production increase. Moreover, the polymorphisms studied may play an important role as biomarkers to SCA susceptibility.

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Lipids can modulate the risk of developing sporadic colorectal adenocarcinoma (SCA), since alterations into lipid metabolism and transport pathways influence directly cholesterol and lipids absorption by colonic cells and indirectly reactive oxygen species (ROS) synthesis in rectum cells due to lipid accumulation. Lipid metabolism is regulated by several proteins APOA1, APOB, APOC3, APOE, CETP, NPY, PON1 and PPARG that could influence both metabolism and transport processes. Is been reported that several common single-nucleotide polymorphisms (SNPs) in these genes could influence their function and/or expression, changing lipid metabolism balance. Thus, genetic changes in those genes can influence SCA development, once the majority of them were never studied in this disease. Furthermore, there are contradictory results between some studied polymorphisms and SCA risk. Thus, the aim of this study was to explore and describe lipid metabolism-associated genes common polymorphisms (APOA1 -75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) status among SCA, and their relationship with SCA risk. Genotyping of common lipid metabolism genes polymorphisms (APOA1 75 G>A; APOB R3500Q; APOC3 C3175G, APOC3 T3206G; APOE Cys112/158Arg; CETP G279A, CETP R451Q; NPY Leu7Pro; PON1 Q192R; PPARG Pro12Ala) were done by PCR-SSP techniques, from formalin-fixed and paraffin-embedded biopsies of 100 healthy individuals and 68 SCA subjects. Mutant genotypes of APOA1 -75AA (32% vs 12%; p=0.001; OR=3.51; 95% CI 1.59-7.72); APOB 3500AA (7% vs 0%; p=0.01); APOC3 3175GG (19% vs 2%; p=0.0002; OR=11.58; 95% CI 2.52-53.22), APOC3 3206GG (19% vs 0%; p<0.0001); CETP 279AA (12% vs 1%; p=0.003; OR=13.20; 95% CI 1.61-108.17), CETP 451AA (16% vs 0%; p<0.0001); NPY 7CC (15% vs 0%; p<0.0001); PPARG 12GG (10% vs 0%; p=0.001); and heterozygote genotype PON1 192AG (56% vs 22%; p<0.0001; OR=4.49; 95% CI 2.298.80) were found associated with SCA prevalence. While, APOE E4/E4 (0% vs 8%; p=0.02) mutant haplotype seemed to have a protective effect on SCA. Moreover, it also been founded differences between APOB 3500GA, APOC3 3206TG, CETP 279AA genotypes and PPARG 12Ala allele prevalence and tissue localization (colon vs rectum). These findings suggest a positive association between most of common lipid metabolism genes polymorphisms studied and SCA prevalence. Dysregulation of APOA1, APOB, APOC3, CETP, NPY, PON1 and PPARG genes could be associated with lower cholesterol plasma levels and increase ROS among colon and rectum mucosa. Furthermore, these results also support the hypothesis that CRC is related with intestinal lipid absorption decrease and secondary bile acids production increase. Moreover, the polymorphisms studied may play an important role as biomarkers to SCA susceptibility.