1,721,078 research outputs found
Differential modulation of P-glycoprotein expression by dexamethasone and 3-methylcholanthrene in rat hepatocyte primary cultures
No full textBAG2, MAD2L1, and MDK are cancer-driver genes and candidate targets for novel therapies in malignant pleural mesothelioma
No full textMalignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and the identification of novel druggable targets is urgently needed. In previous work, we identified 15 deregulated genes highly expressed in MPM tissues and correlated with a poor prognosis. Here, we validated these findings on an independent dataset of 211 MPM patients (EGA, EGAD00001001915) and on a panel of MPM cell lines. Furthermore, we carried out in vitro gene silencing followed by proliferation, cytotoxicity, caspase, and migration assays to define whether these targets could be cancer-driver genes. We ended up with three novel candidates (i.e., BAG2, MAD2L1, and MDK), whose encoded proteins could be exploited as druggable targets. Moreover, of novelty, immunohistochemistry analysis on tissues revealed that the overexpression of BAG2 and MAD2L1 could differentiate MPM from RMP patients. Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies
Epigenetical regulation of microRNA-126 in malignant pleural mesothelioma
No full textMany studies have shown that aberrant expression of microRNAs (miRNAs) is involved in the initiation and progression of cancer, and several miRNAs have shown tumor suppressor or oncogenic functions. Restoring the expression of tumor suppressor genes by epigenetic therapy has great potential in cancer treatment and it has been shown that the expression of some miRNAs in cancer cells can be directly regulated by epigenetic changes in their own promoters. However, the majority of miRNAs are located within intronic regions of transcription units and it remains unclear if intronic miRNAs can also be epigenetically regulated. The miR-126 is located within intron 7 of the proangiogenic Epidermal Growth Factor-like domain 7 (EGFL7) gene that is highly expressed in endothelial cells and vascularized tissues. MiR-126 acts as a tumor suppressor gene in certain types of cancers while other reports have described an oncogenic role. These contradictory findings suggest that miR-126 may have several functions specific to each type of malignancy. Mature miR-126 can be generated from three different transcripts of EGFL7 with each one having its own promoter with CpG island, and different studies have shown expression correlation between the miR-126 and its host gene.
Since the Laboratory of Mol. Pathol. has recently found miR-126 down-regulation in Malignant Pleural Mesothelioma (MPM), an aggressive cancer originating from the mesothelial cells lining the pleura, in my study, we used Real-time quantitative RT-PCR (RT-qPCR) to correlate the expression of miR-126 with one of EGFL7 transcripts in patient-matched preoperative diagnostic pleura biopsies and surgical tissue specimens of MPM as well as corresponding non-neoplastic pleura (NNP). Patients diagnosed with MPM typically have a history of long-term exposure to asbestos and poor prognosis with a median survival of 12 months from the time of diagnosis. Our attention was placed also on studying chromatin structural changes, such as DNA methylation, which are important in epigenetic research and clinical diagnostics because the aberrant methylation has been associated with transcriptional inactivation of defined tumor suppressor genes in human cancers. To adress this issue we have used two different methods: Methylation Sensitive PCR (MSP) and pyrosequencing.
The results of RT-qPCR show that the primary transcript of miR-126 corresponds to an alternative transcript of EGFL7 (S2) with a CpG island promoter and that miR-126 and S2 are concomitantly downregulated in MPM as compared to NNP. Our MSP and pyrosequensing data suggest that this could be due to different regulation by DNA methylation of the CpG island in the S2 promoter in MPM and NNP, as MPM shows a greater level of methylation than NNP.
This work has improved our comprehension of the mechanism by which miR-126 is regulated in MPM. It would be interesting in the future to analyze histone modifications in chromatin structure to confirm the importance of the epigenetic mechanisms regulating miRNA expression in MPM
To progress or not to progress:new insights into the evolution of pleuropulmonary blastomas come from studying lung cysts in adolescents and adults with <i>DICER1</i>-related tumour predisposition
No full textAlmost all cases of pleuropulmonary blastoma (PPB), the most common lung malignancy in childhood, are related to biallelic pathogenic variants in DICER1, a gene encoding an RNase III involved in the biogenesis of micro-RNAs, organogenesis and tumor suppression.1 2 Over 70% of patients with PPB are affected by the pleiotropic DICER1-related tumour susceptibility syndrome caused by heterozygous germline DICER1 loss-of-function variants. After a second somatic DICER1 missense mutation has occurred, these individuals may develop PPB, other tumours and non-neoplastic conditions in the thyroid gland, genitourinary system, and several other extrapulmonary sites
[Lack of uniformity in the treatment of thymomas].
No full textThymomas are the most frequently occurring tumours of the anterior mediastinum. However, they only constitue less than 1% of the total number of malignant diseases. The incidence in the USA is 0.15 per 100.000 persons per year, and the disease is most frequent in persons between 40 and 60 years of age. Because of the rarity of thymomas, lack of uniformity in treatment has been a major problem over the years. Therefore, international collaborations have been established, and national oncological centralisation of management has been arranged in order to improve the treatment and prognosis
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
C4.4A som biomarkør for solid tumorvækst og dårlig prognose i patienter med lungeadenokarcinom
No full textVariations on the Author
Get PDF“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
Get PDFWe 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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