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Associa??o entre polimorfismos funcionais nos genes da MMP-7 e MMP-9 e o perfil clinicopatol?gico do carcinoma epiderm?ide de l?nguaNascimento, George Jo?o Ferreira do 18 February 2010 (has links)
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Previous issue date: 2010-02-18 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Matrix metalloproteinase-7 (MMP-7) and -9 (MMP-9) modulate important functions strictly related to the development, invasion and metastasis of several human cancers among them the squamous cell carcinoma of the tongue (SCCT). However, individual genetic factors such as the functional single nucleotide polymorphisms (SNPs) influence the pattern of protein expression of these MMPs and thus may be related to the variability observed in the clinical behavior of patients with SCCT. In this context, the present cross-sectional study aimed to evaluate the association between the frequency of the functional SNPs MMP-7 -181 A/G and MMP-9 -1562 C/T and the clinical (age, gender and metastasis) and pathological (malignancy histological grading and immunohistochemistry expression) features of SCCT cases. Genotyping of these SNPs were performed by PCR-RFLP on DNA samples from 71 cases of SCCT and 60 individuals without cancer who constitute the control group. Among the results of this research, it was observed that the frequency of the polymorphic alleles MMP-7 -181 G and MMP-9 -1562 T in SCCT patients was 28% and 12%, respectively, and the frequency of the heterozygotes A/G (PR = 2.00; p < 0.001) and C/T (PR = 1.54; p = 0.014) were significantly higher in the patient group than in the controls. The prevalence of patients carrying the combination of SNPs studied was significantly associated with SCCT cases (PR = 2.00; p = 0.011) and metastasis (PR = 2.00; p < 0.001). Furthermore, with the frequency of SNPs analyzed, the age, gender, histological grading and immunoreactivity of MMP-7 and MMP-9 formed clinical and pathological parameters relevant to the identification of population subgroups more related to the development of SCCT and metastasis. Based on these results, it is suggested that the protein expression levels of MMP-7 and -9 substantially influence the balance between their pro- and anticancer biological functions and hence the clinicopathological profile of the squamous cell carcinoma of the tongue / As metaloproteinases da matriz extracelular-7 (MMP-7) e -9 (MMP-9) modulam importantes fun??es relacionadas ao desenvolvimento, invas?o e met?stase de diversos c?nceres humanos, dentre os quais o carcinoma epiderm?ide de l?ngua (CEL). Entretanto, fatores gen?ticos individuais, tais como polimorfismos de nucleot?deo ?nico (SNPs) funcionais, influenciam no padr?o de express?o proteica dessas MMPs, podendo estar relacionados ? variabilidade no comportamento cl?nico tumoral observado em pacientes com CEL. Neste contexto, o presente trabalho objetivou, atrav?s de an?lise em sec??o transversal, estudar a associa??o entre a frequ?ncia dos SNPs funcionais MMP-7 -181 A/G e MMP-9 -1562 C/T e as caracter?sticas cl?nicas (idade, sexo e met?stase) e patol?gicas (grada??o histol?gica e express?o imuno-histoqu?mica) em uma s?rie de casos de CEL. A genotipagem dos referidos SNPs foi executada por PCR-RFLP em amostras de DNA de 71 casos de CEL e de 60 indiv?duos sem c?ncer, que constitu?ram o grupo controle. Dentre os resultados da presente pesquisa, evidenciou-se que a frequ?ncia dos alelos polim?rficos MMP-7 -181 G e MMP-9 -1562 T nos pacientes com CEL foi de 28% e 12%, respectivamente, sendo as frequ?ncias dos heterozigotos A/G (RP = 2.00; p < 0.001) e C/T (RP = 1.54; p = 0.014) significativamente maiores neste grupo de pacientes que no grupo controle. A preval?ncia dos pacientes portadores da combina??o dos SNPs estudados associou-se significativamente aos casos de CEL (RP = 2.00; p = 0.011) e ? met?stase (RP = 2.00; p < 0.001). Ademais, junto ? frequ?ncia dos SNPs analisados, a idade, sexo, grada??o histol?gica e imunoexpress?o da MMP-7 e -9 constitu?ram par?metros clinicopatol?gicos relevantes para a identifica??o de subgrupos populacionais mais predispostos ao desenvolvimento do CEL e met?stase. Frente a estes resultados, sugere-se que os n?veis de express?o da MMP-7 e -9 influenciam consideravelmente no balan?o entre suas fun??es pr? e antineopl?sicas e, consequentemente, no perfil clinicopatol?gico do carcinoma epiderm?ide de l?ngua.
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Imunoexpress?o de VEGF-C, VEGFR-3 e HIF-1? e mensura??o da densidade linf?tica em carcinomas epiderm?ides de l?bio inferior metast?ticos e n?o-metast?ticos: uma rela??o com par?metros clinicopatol?gicos e progn?sticosMartins, Ana Rafaela Luz de Aquino 19 July 2012 (has links)
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Previous issue date: 2012-07-19 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Squamous cell carcinoma of the lower lip is among the most common malignant tumors of the
oral and maxillofacial region, with good prognosis in more than 90% of patients with 5-year
survival. In these carcinomas, the development of lymph node metastasis decreases the
prognosis and it has been associated with the formation of new lymphatic vessels. It has been
suggested the important role of vascular endothelial growth factor-C (VEGF-C), the receptor
type 3 VEGF (VEGFR-3) and hypoxia-induced factor 1 (HIF-1) in this process. The aim of
this study was to evaluate the immunoexpression of VEGF-C, VEGFR-3 and HIF-1? and
correlate with intra and peritumoral lymphatic density in squamous cell carcinomas of the
lower lip metastatic and non-metastatic. The sample consisted of 50 cases of squamous cell
carcinoma of lower lip, of which 25 had regional lymph node metastasis and 25, absence of
metastasis. The percentages of cells immunostained for VEGF-C, VEGFR-3 and HIF-1? in
front of tumor invasion and in the center of tumor were evaluated. Microvessel density
lymphatic (MDL) was determined by the counting of lymph microvessels immunostained by
the anti-D2-40 in five fields (200?), in an area of evaluation with 0.7386 mm2. The invasion
of the lymph vessels by malignant cells was also evaluated. Immunostaining was correlated
with the presence and absence of metastasis, TNM clinical stage, local recurrence, disease
outcome (remission of injury or patient death) and histological grading. The analysis of intra
and peritumoral lymphatic density showed no significant association with clinicopathological
parameters and immunoexpressions of VEGF-C, VEGFR-3 and HIF-1? (p > 0,05). There was
a weak positive correlation, significant, between intra and peritumoral lymphatic density (r =
0,405; p = 0,004). VEGF-C showed no significant association with clinicopathological and
prognosis parameters (p > 0,05). For VEGFR-3, there was scarce membrane staining and
intense and homogenous cytoplasmic staining in neoplastic cells. Percentage of positive
cytoplasmic VEGFR-3 in center of tumor, exhibited a statistically significant association with
metastasis (p = 0,009), patient death (p = 0,008) and histological grades of malignancy
proposed by Bryne et al. (1992) (p = 0,002) and World Health Organization (p = 0,003). A
low positive correlation was statistically significant between the immunoreactivity of VEGFC
and VEGFR-3 cytoplasmic (r = 0,358; p = 0,011) and between the percentage of positive
cytoplasmic VEGFR-3 in front of tumor invasion and in the center of the tumor (r = 0,387; p
= 0,005) was also demonstrated. There was no association between HIF-1?,
clinicopathological and prognosis parameters, and VEGF-C and VEGFR-3. The percentage of
nuclear positivity for HIF-1? was significantly higher in cases without invasion of peritumoral
lymphatic (p = 0,040). Based on the results we can conclude that most cytoplasmic expression
of VEGFR-3 in center of tumor in metastatic cases, high degree of malignancy and poorly
differentiated, contributes to poor outcome of squamous cell carcinoma of the lower lip,
including patient death. Intra and peritumoral lymphatic density seems to be not associated
with lymph node metastasis in these carcinomas / O carcinoma epiderm?ide de l?bio inferior est? entre as les?es malignas mais comuns da
regi?o oral e maxilofacial, com progn?stico bom, em mais de 90% dos pacientes com
sobrevida de 5 anos. Nestas les?es, o desenvolvimento de met?stase linfonodal diminui
sobremaneira o progn?stico e tem sido associado ? forma??o de novos vasos linf?ticos. Tem
sido sugerido o importante papel do fator de crescimento endotelial vascular-C (VEGF-C), do
receptor tipo 3 do VEGF (VEGFR-3) e do fator 1 induzido por hip?xia (HIF-1) neste
processo. O objetivo desta pesquisa foi avaliar as imunoexpress?es de VEGF-C, VEGFR-3,
HIF-1? e a densidade linf?tica intra e peritumoral em carcinomas epiderm?ides de l?bio
inferior metast?ticos e n?o-metast?ticos, correlacionando-as com par?metros
clinicopatol?gicos e progn?sticos. A amostra foi constitu?da por 50 casos de carcinoma
epiderm?ide de l?bio inferior, 25 com met?stase linfonodal regional e 25 sem met?stase.
Foram avaliados os percentuais de c?lulas imunomarcadas para os anticorpos anti-VEGF-C,
anti-VEGFR-3 e anti-HIF-1?, no front de invas?o e no centro tumoral. A densidade
microvascular linf?tica (LMVD) foi estabelecida por meio da soma da contagem de
microvasos linf?ticos imunomarcados pelo anticorpo anti-D2-40, em cinco campos (200?),
em uma ?rea de avalia??o com 0,7386 mm2. A invas?o dos vasos linf?ticos por c?lulas
neopl?sicas tamb?m foi avaliada. A imunomarca??o foi relacionada com a presen?a e
aus?ncia de met?stase, estadiamento cl?nico TNM, recidiva local, desfecho da doen?a
(remiss?o da les?o ou ?bito dos pacientes) e grada??o histol?gica. A an?lise das densidades
linf?ticas intra e peritumorais n?o demonstrou associa??o significativa com os par?metros
clinicopatol?gicos, progn?sticos e imunoexpress?es de VEGF-C, VEGFR-3 e HIF-1? (p >
0,05). Houve fraca correla??o positiva, significativa, entre as densidades linf?ticas intra e
peritumorais (r = 0,405; p = 0,004). O VEGF-C n?o exibiu associa??o significativa entre os
par?metros clinicopatol?gicos e progn?sticos avaliados (p > 0,05). Para o VEGFR-3, houve
escassa marca??o membranar e intensa e homog?nea marca??o citoplasm?tica nas c?lulas
neopl?sicas. O percentual de positividade citoplasm?tica do VEGFR-3, no centro tumoral,
exibiu associa??o estatisticamente significativa com a presen?a de met?stase (p = 0,009),
?bito dos pacientes (p = 0,008) e grada??es histol?gicas de malignidade proposta por Bryne et
al. (1992) (p = 0,002) e pela Organiza??o Mundial de Sa?de (p = 0,003). Uma fraca
correla??o, estatisticamente significativa, entre a imunoexpress?o de VEGF-C e VEGFR-3
citoplasm?tica (r = 0,358; p = 0,011) e entre os percentuais de positividade citoplasm?tica de
VEGFR-3 no front de invas?o e no centro tumoral (r = 0,387; p = 0,005) tamb?m foi
demonstrada. N?o foi observada associa??o entre o HIF-1? os par?metros clinicopatol?gicos,
progn?sticos e o VEGF-C e VEGFR-3. O percentual de positividade nuclear para HIF-1? foi
significativamente maior nos casos sem invas?o dos linf?ticos peritumorais (p = 0,040). Com
base nos resultados pode-se concluir que a maior express?o citoplasm?tica de VEGFR-3, no
centro tumoral, nos casos metast?ticos, de alto grau de malignidade e pobremente
diferenciados, contribui para pior evolu??o dos carcinomas epiderm?ides de l?bio inferior,
incluindo o ?bito dos pacientes. As densidades linf?ticas intra e peritumorais parecem n?o
estar associadas ao densenvolvimento de met?stase linfonodal nestes carcinomas
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Estudo in vitro dos efeitos da BMP-2 e do seu antagonista Noggin sobre a prolifera??o e migra??o celulares em carcinoma epiderm?ide de l?nguaCarvalho, Cyntia Helena Pereira de 27 February 2014 (has links)
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Previous issue date: 2014-02-27 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Oral squamous cell carcinoma (OSCC) is the most prevalent malignancy in the oral cavity and
reach a large number of individuals, has become an important public health problem. Studies
have demonstrated changes in pathway components BMP in various types of cancers as
prostate, colon, breast, gastric and OSCCs. Is the current knowledge that these proteins may
exert pro-tumor effect in more advanced stages of neoplastic development coming to favor
progression and invasion tumor. The inhibition of the signaling pathway BMP-2 through its
antagonists, have shown positive results of antitumor activity and use of Noggin may be a novel
therapeutic target for cancer. Given this evidence and the few studies with BMP-2, Noggin and
OSCC, the objective of this research was to evaluate the effect of BMP-2 and its antagonist
Noggin on proliferation and migration cell in line of cell cultures of human tongue squamous
cell carcinoma (SCC25). The study was divided in three groups, a control group, where SCC25
cells suffered no treatment, a BMP-2 group, in which cells were treated with 100ng/ml of BMP-2 and a group of cells that were treated with 100ng/ml of Noggin. For the proliferation assay
and cell cycle were established three time intervals (24, 48 and 72 hours). Proliferative activity
was investigated by trypan blue and cell cycle analysis by staining with propidium iodide flow
cytometry. The potential for migration / invasion of SCC25 cells was performing by a cell
invasion assay using Matrigel in a 48-hour interval. The proliferation curve showed a higher
proliferation in cells treated with BMP-2 in 72 hours (p < 0.05), and lower overgrowth and cell
viability in Noggin group. Recombinant proteins favored a greater percentage of cells in cell
cycle phase Go/G1 with a statistically significant difference in the interval of 24 hours (p <
0.05). BMP- 2 produced a greater invasion of cells studied as well as its antagonist Noggin
inhibits invasion of cells (p < 0.05). Thus, these results indicate that BMP-2 promotes malignant
phenotype, dues stimulates proliferation and invasion of SCC25 cells and, its antagonist Noggin
may be an alternative treatment, due to inhibit the tumor progression / O carcinoma epiderm?ide oral (CEO) representa a neoplasia maligna mais prevalente na
cavidade oral e por atingir um grande n?mero de indiv?duos, acaba se tornado um relevante
problema de sa?de p?blica. Muitos estudos demonstram altera??es nos componentes da via
BMP em v?rios tipos de tumores, como os de pr?stata, c?lon, mama, g?stricos e CEOs. ? do
conhecimento atual que essas prote?nas podem exercer efeito pr?-tumoral em est?gios mais
avan?ados do desenvolvimento neopl?sico vindo a favorecer a progress?o e invas?o tumoral.
A inibi??o da via de sinaliza??o da BMP-2, atrav?s dos seus antagonistas, tem mostrado
resultados positivos de a??o antitumoral e que assim, o uso do Noggin pode ser um novo alvo
terap?utico contra o c?ncer. Diante destas evid?ncias e dos escassos trabalhos com BMP-2,
Noggin e CEO, o objetivo desta pesquisa foi avaliar o efeito da BMP-2 e seu antagonista
Noggin sobre a prolifera??o e migra??o celulares em culturas de c?lulas de carcinoma
epiderm?ide de l?ngua humana (SCC25). Foi feita a divis?o em tr?s grupos de estudo, um grupo
controle, onde as c?lulas SCC25 n?o sofriam tratamento com subst?ncia alguma, um grupo
BMP-2, no qual as c?lulas eram tratadas com 100ng/ml de BMP-2 e um grupo de c?lulas que
eram tratadas com 100ng/ml de Noggin. Para o ensaio de prolifera??o e ciclo celular foram
estabelecidos tr?s intervalos de tempo (24, 48 e 72 horas). A atividade proliferativa foi
investigada por azul de tripan e a an?lise do ciclo celular atrav?s da marca??o por iodeto de
prop?dio em Citometria de fluxo. O potencial de migra??o/invas?o das c?lulas SCC25 foi
avaliado atrav?s da realiza??o de um ensaio de invas?o celular utilizando o matrigel em um
intervalo de 48 horas. A curva de prolifera??o revelou maior crescimento celular nas c?lulas
tratadas com BMP-2 no intervalo de 72 horas (p<0.05) e menor crecimento e viabilidade celular
no grupo Noggin. As prote?nas recombinantes favoreceram a maior porcentagem das c?lulas na
fase do ciclo celular Go/G1 com diferen?a estatisticamente significativa no intervalo de 24
horas (p<0,05). A BMP-2 promoveu uma maior invas?o das c?lulas estudadas, assim como o
seu antagonista Noggin inibiu a invas?o das c?lulas estudadas (p<0,05). Dessa forma, os
resultados indicam que a BMP-2 favorece o fen?tipo maligno, pois estimula a prolifera??o e
invas?o das c?lulas SCC25 e seu antagonista Noggin pode ser uma alternativa terap?utica pois
inibiu essas caracter?sticas pr?-tumorais
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Estudo comparativo da express?o imuno-histoqu?mica do Ki-67 em carcinoma epiderm?ide de l?ngua em pacientes jovens e idososBenevenuto, Tha?s Gomes 26 February 2010 (has links)
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Previous issue date: 2010-02-26 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / The squamous cell carcinoma (SCC) is the most common malignant neoplasm of epithelial origin in oral cavity and present high capacity to invade adjacent structures. Traditionally, SCC has a predominance of 50 years male patients with long-time use of tobacco and alcohol, and the tongue is the most affected anatomic site. At present, there is an increasing incidence of SCC in patients below 40 years of age, who has been exposed or not to risk factors, mainly for tongue lesions. This study aims to analyze cell proliferation index using Ki-67 antigen in SCC of the tongue for two groups of different age range: until 40 years and older than 50 years. The first group was composed by 16 patients and the second one was
composed by 20 patients. Clinicopathological features of the cases were also assessed. There was a male predominance in both groups. Tobacco and alcohol habits were common for
patients until 40 years (72,2%), as well as for patients older than 50 years (52,9%). The first group had statistical association with the presence of regional metastases (p = 0,036) and with the most advanced stages of the disease (p = 0,012). Considering the histological malignancy grading, there was higher incidence (56,2%) of high malignancy grade tumors in the group of patients until 40 years old, but no statistical difference has found between groups and histologic malignancy grading. Regarding the immunohistochemical expression of Ki-67,
there was no statistically significant difference between the antibody expression of the groups, as well as between other clinical and histopathological parameters. This study identified no
significant difference regarding cell proliferation between the analyzed groups / O Carcinoma Epiderm?ide (CE) ? a neoplasia maligna de origem epitelial que
mais ocorre na cavidade oral, com alta capacidade de invadir estruturas adjacentes. Classicamente, o CEO ocorre mais em homens com idade acima de 50 anos, que fazem uso de tabaco e ?lcool por longos per?odos de tempo, sendo a l?ngua, o s?tio anat?mico mais frequentemente acometido. Atualmente, vem se percebendo um aumento na incid?ncia dessa les?o em pacientes com idade abaixo dos 40 anos expostos ou n?o a fatores de risco, principalmente as les?es de l?ngua. O objetivo desta pesquisa foi analisar o ?ndice de prolifera??o celular, utilizando o anticorpo Ki-67em CEs de l?ngua em dois grupos de faixas
et?rias distintas. Tamb?m, avaliaram-se as caracter?sticas cl?nico-patol?gicas dos casos constantes do estudo. A amostra se constituiu de 16 casos de pacientes com idade at? 40 anos e 20 casos de pacientes com idade acima de 50 anos. Em rela??o ?s caracter?sticas cl?nicopatol?gicas das les?es, o sexo masculino foi o mais acometido para os dois grupos, sendo evidenciado que o h?bito de beber e fumar foi frequente tanto para os pacientes com idade at?
40 anos (72,7%) como para os pacientes com idade acima dos 50 anos (52,9%). Foi poss?vel observar que houve uma associa??o estatisticamente significativa entre o grupo de pacientes com idade at? 40 anos e a presen?a de met?stase regional (p = 0,036), bem como entre o mesmo grupo e os est?gios mais avan?ados da doen?a (p = 0,012). Em rela??o ? grada??o histol?gica de malignidade, houve uma maior frequ?ncia de tumores classificados em alto
grau de malignidade no grupo de pacientes com at? 40 anos (56,2%), mas n?o foi evidenciada diferen?a estat?stica entre os grupos e a grada??o histol?gica de malignidade. Quanto ? an?lise da express?o imuno-histoqu?mica pelo Ki-67, n?o houve diferen?a estatisticamente significativa entre a express?o do anticorpo para os grupos et?rios estudados nesta pesquisa, assim como n?o houve associa??o do ?ndice de positividade para o Ki-67 com os par?metros
cl?nicos e histomorfol?gicos. Pode-se concluir que a prolifera??o celular n?o foi
significativamente diferente entre os grupos que constitu?ram o presente estudo
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