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Met protein and hepatocyte grwth factor (HGF) in papillary carcinoma of the thyroid: evidence for a pathogenetic role in tumorigenesis.
No full textIn the last 10 years, evidence has accumulated that overexpression of Met protein is a distinguishing feature of almost every case of well-differentiated papillary carcinoma. Increased expression of the protein is probably due to enhanced transcription of the MET gene and/or to post-transcriptional mechanisms. So far, alterations of the MET gene have not been recognized, but evidence has been provided that activated RAS and RET can cause accumulation of MET RNA. Thus, the possibility exists that dysregulation of MET is the final result of different molecular pathways capable of inducing thyroid cell transformation; RET rearrangements might account for some of the cases, but the demonstration that the majority of papillary carcinomas do not have recognized alterations of the RET gene strongly suggests that MET gene dysregulation can also be achieved through other molecular pathways. Dysregulation of MET causes marked accumulation of Met protein in tumour cells that is promptly detected by immunohistochemistry. Thus, overexpression of Met protein might represent an immunohistochemical marker of papillary carcinoma, potentially helpful in problematic cases, but caution is required; moderate expression of Met protein is observed in non-neoplastic thyroid diseases, such as Graves' and Hashimoto's thyroiditis, and reagents active on paraffin sections may have a low affinity and/or low specificity for Met protein, leading to artifactual staining. Met protein-positive papillary carcinoma cells may produce hepatocyte growth factor (HGF) and may activate HGF through the urokinase-type plasminogen activator (uPA) bound to urokinase-type plasminogen activator receptor (uPA-R). Thus, papillary carcinoma cells possess the molecular machinery necessary for a productive HGF/Met interaction. In vitro studies have demonstrated that HGF enhances the motility and invasiveness of tumour cells and induces the synthesis and release of chemokines active in the recruitment of dendritic cells. These observations provide a rational basis for the understanding of two distinguishing features of papillary carcinoma. First, the tumour is often characterized by early metastatic spread to regional lymph nodes and by multifocal involvement of the gland, which suggests highly invasive behaviour. Second, a prominent peritumoural inflammatory reaction is often observed, which suggests cross-talk between tumour cells and the immune system
COX-2 is induced by HGF stimulation in Met-positive thyroid papillary carcinoma cells and is involved in tumour invasiveness
No full textThyroid papillary carcinoma (TPC) cells express high levels of cytoplasmic cyclo-oxygenase 2 protein. Analysis of microdissected samples of the tumour and of the paired normal thyroid tissue confirmed that mRNA transcripts for cyclo-oxygenase 2 (COX-2) were significantly more numerous in the tumour (7.6 +/- 13-fold; p = 0.01). High levels of COX-2 mRNA were not associated with age, sex, tumour size or lymph node metastasis. COX-2 was not homogeneously expressed throughout the tumour, but was significantly higher at the tumour invasion front. Hepatocyte growth factor (HGF) can up-regulate (he expression of COX-2 mRNA. A marked increase in COX-2 mRNA levels was observed in 8/8 primary TPC cultures after HGF stimulation (6.3 +/- 6-fold) and in two papillary carcinoma cell lines (TPC-1 and NPA). Specific involvement of the high-affinity HGF receptor (Met protein) was suggested by the observation that PHA-665752, an inhibitor of the catalytic activity of c-Met kinase, caused a 54% reduction of the hepatocyte growth factor-induced COX-2 up-regulation. The possibility that HGF-Met interactions also had a causative role in the up-regulation of COX-2 in vivo was investigated in 30 tumour samples, where it was found that there was a statistically significant correlation (p = 0.001, r = 0.85) in the levels of expression of MET and COX-2 RNAs. The biological role of COX-2 in TPC cells was investigated by treating the TPC cell lines with the specific COX-2 inhibitor NS-398. It was found that NS-398 treatment significantly reduced the migration (50-75%) and invasiveness (47-92%) of tumour cells, but did not alter cell proliferation. Our data suggest that the increased expression of Met protein in TPC cells has a role in up-regulating the expression of COX-2, which in turn contributes to the invasive capacity of TPC cells. Copyright (C) 2009 Pathological Society of Great Britain and Ireland. Published by, John Wiley & Sons, Ltd
EGFR mutation testing in pulmonary adenocarcinoma. Evaluation of tumor cell number and tumor percent in paraffin sections of 120 small biopsies
No full textOBJECTIVES: Successful evaluation of EGFR mutational status in small biopsies may be hampered by the number of tumor cells present in the tissue section. The aim of the present study was to determine the minimal number of tumor cells necessary for a reliable EGFR mutation testing in lung adenocarcinoma.
MATERIALS AND METHODS: The minimal number of tumor cells was determined experimentally in surgical specimens of 12 EGFR-mutated cases. DNA was extracted from progressively smaller tumor areas obtained with laser capture microdissection and was tested using a real-time PCR technique. The results were then validated in tissue sections of 120 small biopsies, where total number of tumor cells and percent tumor cells were determined in H&E digitalized slides.
RESULTS: The laser capture microdissection study revealed that a tumor area of 0.12 mm(2), containing 140 ± 34 tumor cells, was large enough to allow detection of EGFR mutations in 11 of 12 cases. Moreover, it was also demonstrated that EGFR gene amplification and/or chromosomal polysomy could cause a 2-4-fold increase in the sensitivity of the assay. The reliability of these findings was tested in 120 small biopsies containing 26 EGFR-mutated cases. It was found that only a single case had <200 tumor cells, that the EGFR-mutated case with the lowest tumor content had 364 tumor cells occupying a tumor area of 0.12 mm(2), and that 11 of the 26 EGFR-mutated cases (42%) had <20% tumor cells. Finally, the incidence of EGFR-mutated cases in 145 small biopsies (21.4%) was similar to that detected in 132 surgical specimens (20.5%).
CONCLUSIONS: Our findings suggest that when a small biopsy contains enough tumor cells to allow a histological diagnosis of adenocarcinoma it probably contains also an adequate number of tumor cells for a successful EGFR mutation testing if a real-time PCR technique is used
Papillary carcinoma of the thyroid: evidence for a role of hepatocyte growth factor (HGF) in promoting tumour angiogenesis
No full textIncreased expression of Met protein is associated with up-regulation of hypoxia inducible factor-I (HIF-I) in tumour cells in papillary carcinoma of the thyroid
No full textMet protein, the high affinity receptor for hepatocyte growth factor (HGF), was highly expressed by the tumour cells of 64 well-differentiated papillary carcinomas of the thyroid. The p145 mature form and the p170 precursor form of the protein were both isolated from the tumours. Enhanced expression of Met protein was associated with a 9.5 ± 5-fold increase in MET RNA transcript levels, suggesting increased transcription of the gene. In the same tumours, the levels of RNA transcripts for hypoxia inducible factor-1 (HIF-1), a potent stimulator of met gene transcription, were 4.5 ± 3-fold higher than those present in the surrounding normal thyroid tissues. HIF-1 is generally induced by hypoxia. Histological features suggestive of a hypoxia were observed in 37 of 50 tumours and included coagulative necrosis, psammoma bodies, cystic changes, intratumoural haemorrhage, and hyalinization of the fibrous stroma. Immunostaining for Met protein was particularly intense in some cells located at the tumour periphery which were characterized by an invasive phenotype. Microdissection of tumour cell nests from the invading front revealed that the levels of RNA transcripts for MET/HIF were higher than in the centre of the tumour in four of nine cases. Taken together, the findings of this study suggest that HIF-1, perhaps driven by hypoxia, may be one of the factors leading to the increased transcription of met gene in papillary carcinoma and that this event is often more pronounced at the tumour periphery
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
High prevalence of ALK+/ROS1+ cases in pulmonary adenocarcinoma of adoloscents and young adults
No full textOBJECTIVES: To investigate prevalence and age-distribution of ALK- or ROS1-translocated adenocarcinomas in patients ≤50 years of age.
MATERIALS AND METHODS: Paraffin sections of pulmonary adenocarcinoma were analyzed for ALK (637 cases) and ROS1 (376 cases) translocations using FISH, and for EGFR mutations (789 cases) using mutant-specific Real-Time PCR.
RESULTS: ALK or ROS1 fusions were detected in 55 of 637 cases (8.6%). When patients were stratified for age, it was found that six of six cases (100%) of lung adenocarcinoma diagnosed in patients <30 years of age were translocated for ALK (4 cases) or ROS1 (2 cases). With the increase of age, there was a gradual decrease in the percentage of positive cases. In fact, ALK-translocated or ROS1-translocated cases were 5 of 17 cases (29%) in the 31-40 years age-group, 6 of 46 cases (13%) in the 41-50 years age-group, and 38 of 568 cases (7.0%) in patients older than 50 years. The six patients <30 years of age (5F/1M), including two pediatric patients (≤18 years old), presented with stage IV disease, were never or light smoker, and had no family history of pulmonary tumours. Four of the six patients, were treated with crizotinib and had an objective response.
CONCLUSIONS: Our findings provide evidence that ALK or ROS1 translocations are crucial events in tumourigenesis of pulmonary adenocarcinoma of very young patients, including pediatric patients
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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