Navegando por Palavras-chave "heterogeneity"
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- ItemSomente MetadadadosAvaliação da heterogeneidade das mutações do gene braf (7q34) no melanoma acral lentiginoso(Universidade Federal de São Paulo (UNIFESP), 2014-10-09) Fernandes, Mariana [UNIFESP]; Landman, Gilles Landman [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Cutaneous melanomas are malignant neoplasms arising from the uncontrolled proliferation of melanocytes skin. Acral lentiginous melanomas occur in non-exposed to solar radiation areas, such as palms, soles and subungual regions, is more common in Asian and African-descent population, accounting for 2-3% of all melanoma cases. Evaluation of signaling pathways in melanoma progression of this subtype contribute to prognostic and establish therapeutic targets. The MAP kinase pathway is responsible for cell growth, differentiation and cell proliferation. Mutations induce constitutive activation of this pathway. Most BRAF mutations (50 to 70%) appear in exons 11 and 15, being V600E by far the most frequent. This mutation activates ERK. Mutations in this gene promote tumorigenesis, angiogenesis and melanoma progression. Objective: To evaluate the mutation heterogeneity of gene BRAF belonging to the MAP kinase pathway in different areas of primary cutaneous acral lentiginous. Patients and Methods: Samples were selected from patients diagnosed as acral lentiginous between 1996 and 2010 in the Department of Pathology, Escola Paulista de Medicina - UNIFESP, a total of 26 cases. Mutations of the BRAF were analized by Sanger sequencing. Results: In acral lentiginous melanomas the mean age of patients was 62.3 years and most African descent (34.6%), the tumors had a mean of 7.2 mm Breslow thickness and 3 mitoses/mm and ulceration in 65.4%. BRAF mutations were identified in 76,9% of the samples had all these were heterogeneous. 59.4% of these mutations have been previously described and 53.1% had functional change in the protein The presence of the mutation and heterogeneity BRAF were correlated with the Breslow thickness less (p = 0.017) and presence of peritumoral inflammatory infiltrate (p = 0.038). Conclusions: Mutations in the BRAF gene were present in acral lentiginous melanomas and in most cases there intratumoral heterogeneity.
- ItemSomente MetadadadosAvaliação da heterogeneidade intratumoral e intermetástases do éxon 15 do gene braf (7q34) em amostras de melanoma metastático(Universidade Federal de São Paulo (UNIFESP), 2015-06-05) Guimaraes, Daiane Pereira [UNIFESP]; Landman, Gilles Landman [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Introduction: Approximately a half of cutaneous melanoma has a BRAF V600E mutation and benefits from treatment with BRAF and MEK inhibitors, showing rapid tumor regression. However, most of these patients had progression of disease within 6 to 12 months after initiation of treatment. The intratumoral heterogeneity has been demonstrated and may contribute to the failure to treatment and drug resistance and may have important consequences to personalized cancer therapy Objective: To study the heterogeneity of mutations in genes belonging to the MAPK pathway in metastatic melanoma, in different areas of the same tumor and among tumors of the same patient. Methods: Analysis of mutations in exon 15 of BRAF, by Sanger sequencing, in metastatic melanoma paraffin samples stored in the Department of Pathology, from 1996 to 2012. Results: 86 samples of metastatic melanoma were analyzed from 54 patients. 17 (31.5%) patients had at least one mutation in exon 15 and ten patients (18.5%) had V600E mutation. 22.2% (12) of the cases, at least one sample presented intratumoral heterogeneity related to the expression of exon 15. When just codon V600 was observed, 7 (13%) patients had at least one sample with intratumoral heterogeneity related to V600E mutation. Twelve (22.2%) patients had at least two samples of metastasis and among them, nine (75%) was exon 15 mutaded and all of them presented both intratumoral and intermetastatic heterogeneity. Conclusion: Intratumoral and intermetastatic heterogeneity of the expression of exon 15 of BRAF was observed in metastatic melanoma samples.
- ItemSomente MetadadadosCritical interpretation of Cochran's Q test depends on power and prior assumptions about heterogeneity(Wiley-Blackwell, 2010-04-01) Pereira, Tiago V. [UNIFESP]; Patsopoulos, Nikolaos A.; Salanti, Georgia; Ioannidis, John P. A.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Univ Ioannina; Harvard Univ; Fdn Res & Technol Hellas; Tufts Univ; Stanford UnivWe describe how an appropriate interpretation of the Q-test depends on its power to detect a given typical amount of between-study variance (tau(2)) as well as prior beliefs on heterogeneity. We illustrate these concepts in an evaluation of 1011 meta-analyses of clinical trials with >= 4 studies and binary outcomes. These concepts can be seen as an application of the Bayes theorem. Across the 1011 meta-analyses, power to detect typical heterogeneity was low in most situations. Thus, usually a non-significant Q test did not change perceptibly prior convictions on heterogeneity. Conversely, significant results for the Q test typically augmented considerably the probability of heterogeneity. the posterior probability of heterogeneity depends on what tau(2) we want to detect. With the same approach, one may also estimate the posterior probability for the presence of heterogeneity that is large enough to annul statistically significant summary effects; that is half the average within-study variance of the combined studies; and that is able to change the summary effect estimate of the meta-analysis by 20%. the discussed analyses are exploratory, and may depend heavily on prior assumptions when power for the Q-test is low. Statistical heterogeneity in meta-analyses should be cautiously interpreted considering the power to detect a specific tau(2) and prior assumptions about the presence of heterogeneity. Copyright (C) 2010 John Wiley & Sons, Ltd.
- ItemSomente MetadadadosDivergence of HIV-1 quasispecies in an epidemiologic cluster(Rapid Science Publishers, 1997-03-15) Diaz, Ricardo Sobhie [UNIFESP]; Zhang, L. Q.; Busch, Michael P. [UNIFESP]; Mosley, J. W.; Mayer, A.; IRWIN MEM BLOOD CTR; Universidade Federal de São Paulo (UNIFESP); AARON DIAMOND AIDS RES CTR; UNIV CALIF SAN FRANCISCO; UNIV SO CALIFBackground: During treatment with blood components prepared from an HIV-infected donation, two recipients became infected in 1985. One recipient infected her sexual partner.Objective: To evaluate the evolution of the originally-shared HIV-1 quasispecies in different human hosts over lime, sequence data were obtained from serum from the actual donation sample of blood, and from plasma samples collected from the four members of the epidemiologic cluster over a period extending from 1986 to 1993.Methods: the V3 hypervariable region of env and the gag p17 gene were analysed. CD4 and CD8 counts, as well as HIV RNA burden data, were collected.Results: One patient died from AIDS during the study. This patient showed a greater degree of diversity in the V3 region, with a higher positive charge over time, than the other individuals. Phylogenetic analysis revealed that the V3 sequences from each of the four individuals occupied separate branches of a phylogenetic reconstruction (tree). Two distinct subgroups evolved in the donor, one with GPGR and the other with GSGR/GSGK at the tip of the V3 loop. This latter group was not detected in the other individuals. the sequences in the sexual partner were no more related to those in the infecting transfusion recipient than to sequences from the other members of the cluster, consistent with sexual transmission having occurred at a time shortly after the recipient was infected.Conclusion: the shared HIV-1 quasispecies in this epidemiologic cluster diverged in an individual-specific manner.
- ItemAcesso aberto (Open Access)Insights into the posttranslational structural heterogeneity of thyroglobulin and its role in the development, diagnosis, and management of benign and malignant thyroid diseases(Sbem-Soc Brasil Endocrinologia & Metabologia, 2016) Xavier, Ana Carolina W. [UNIFESP]; Maciel, Rui M. B. [UNIFESP]; Vieira, Jose Gilberto H. [UNIFESP]; Dias-da-Silva, Magnus R. [UNIFESP]; Martins, Joao R. M. [UNIFESP]Thyroglobulin (Tg) is the major glycoprotein produced by the thyroid gland, where it serves as a template for thyroid hormone synthesis and as an intraglandular store of iodine. Measurement of Tg levels in serum is of great practical importance in the follow-up of differentiated thyroid carcinoma (DTC), a setting in which elevated levels after total thyroidectomy are indicative of residual or recurrent disease. The most recent methods for serum Tg measurement are monoclonal antibody-based and are highly sensitive. However, major challenges remain regarding the interpretation of the results obtained with these immunometric methods, particularly in patients with endogenous antithyroglobulin antibodies or in the presence of heterophile antibodies, which may produce falsely low or high Tg values, respectively. The increased prevalence of antithyroglobulin antibodies in patients with DTC, as compared with the general population, raises the very pertinent possibility that tumor Tg may be more immunogenic. This inference makes sense, as the tumor microenvironment (tumor cells plus normal host cells) is characterized by several changes that could induce posttranslational modification of many proteins, including Tg. Attempts to understand the structure of Tg have been made for several decades, but findings have generally been incomplete due to technical hindrances to analysis of such a large protein (660 kDa). This review article will explore the complex structure of Tg and the potential role of its marked heterogeneity in our understanding of normal thyroid biology and neoplastic processes.
- ItemSomente MetadadadosInvestigação da expressão dos marcadores de células tronco em linhagem celular de melanoma murino e sua reprogramação em células pluripotentes induzidas(Universidade Federal de São Paulo (UNIFESP), 2015-02-26) Camara, Diana Aparecida Dias [UNIFESP]; Kerkis, Irina Kerkis [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)Malignant melanoma is a heterogeneous tumor that originates from melanocytes that have suffered genetic and epigenetic mutations. Some studies have shown reversal of the phenotype of human metastatic melanoma cells at the embryonic microenvironment via a cellular reprogramming. The use of reprogramming is a good starting point, which can significantly contribute to the understanding of the main molecular mechanism related to the pathogenesis of this aggressive tumor and develop new biological strategies based on anticancer therapies. Objective: The objectives of this paper were to study the expression of stem cell markers in a murine melanoma cell line and establish a model for studying the possible cellular mechanisms of loss of malignancy through reprogramming of tumor cells in ?normal? IPS. Materials and Methods: Seven clones were isolated using the limiting dilution assay from the cell line B16F10. These clones were characterized by flow cytometry with surface markers (CD271, CD146 and CD44, CD24) by qPCR for pluripotency markers. Cell cycle analysis was performed and some proteins were analyzed by Western blot, such as cyclin D and cyclin DNMT1. Each clone was tested for the UFC, sphere formation and tumorigenic ability in vivo. The individual sensitivity of each clone and the parent strain in the presence of antitumor drugs was evaluated in vitro. One clone was chosen and transfection was performed using circular plasmid DNA containing -2 Sox genes, Oct4, Nanog, Lin28 and GFP. Results: the clones showed different patterns of cell proliferation, expression of surface markers, tumorigenicity, metastatic capacity and drug resistance. This heterogeneous and divergent character between clones occurred spontaneously under the same culture conditions showing tumor plasticity. Clone 7, which was used for the reprogramming assays, obtained high efficiency in transfection when compared to the fibroblasts used for control, however reprogramming showed low efficiency as evidenced by the appearance of a small number of colonies morphologically similar to melanospheres. Conclusions: We conclude that heterogeneity is an intrinsic characteristic of melanomas that contributes to the wide phenotypic diversity found in these tumors. An interesting way to modulate this phenomenon is the reprogramming of these tumor cells and the verification of what it entails in terms of expression of tumor markers and also of CTT.
- ItemSomente MetadadadosRetinal pigment epithelial cells are heterogeneous in their expression of MHC-II after stimulation with interferon-gamma(Academic Press Ltd, 1999-04-01) Casella, AMB; Taba, K. E.; Kimura, H.; Spee, C.; Cardillo, J. A.; Ryan, S. J.; Hinton, D. R.; Univ So Calif; Universidade Estadual de Londrina (UEL); Universidade Federal de São Paulo (UNIFESP)The pattern of interferon-gamma-induced major histocompatibility complex Class II antigen expression was evaluated on the retinal pigment epithelium. Experiments were performed in vitro using explant cultures of aged and fetal human eyes and in vivo in albino rabbits. the human explants were stimulated with 50 U ml(-1) interferon-gamma for 3 days prior to immunostaining for Class II. the rabbit eyes were subretinally injected in vivo with 50 mu l of interferon-gamma (500 U ml(-1)) and analyzed immunohistochemically 3 days later. A heterogeneous pattern of Class LI expression was present in the interferon-gamma-stimulated retinal pigment epithelial cells, in both the in vivo and the in vitro experiments. in aged human eyes the percent of Class-II positive cells was higher in the periphery than in the posterior pole (macular region) after interferon-gamma stimulation (P < 0.01). No such difference was found in the fetal eyes. These data demonstrate that retinal pigment epithelial cells are heterogeneous in their response to interferon-gamma. the results are supportive of previous studies demonstrating the structural and proliferative heterogeneity of the retinal pigment epithelium. Together, these studies provide support for the possibility of functional retinal pigment epithelial heterogeneity. (C) 1999 Academic Press.