1,721,098 research outputs found
Biological rationale for targeting MEK/ERK pathways in anti-cancer therapy and to potentiate tumour responses to radiation
Full text linkERK1 and ERK2 (ERKs), two extracellular regulated kinases (ERK1/2), are evolutionary-conserved and ubiquitous serine-threonine kinases involved in regulating cell signalling in normal and pathological tissues. The expression levels of these kinases are almost always different, with ERK2 being the more prominent. ERK1/2 activation is fundamental for the development and progression of cancer. Since their discovery, much research has been dedicated to their role in mitogen-activated protein kinases (MAPK) pathway signalling and in their activation by mitogens and mutated RAF or RAS in cancer cells. In order to gain a better understanding of the role of ERK1/2 in MAPK pathway signalling, many studies have been aimed at characterizing ERK1/2 splicing isoforms, mutants, substrates and partners. In this review, we highlight the differences between ERK1 and ERK2 without completely discarding the hypothesis that ERK1 and ERK2 exhibit functional redundancy. The main goal of this review is to shed light on the role of ERK1/2 in targeted therapy and radiotherapy and highlight the importance of identifying ERK inhibitors that may overcome acquired resistance. This is a highly relevant therapeutic issue that needs to be addressed to combat tumours that rely on constitutively active RAF and RAS mutants and the MAPK pathway
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
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
Integration and spatial organization of signaling by g protein-coupled receptor homo-and heterodimers
No full textInformation flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hor-mones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be per-ceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo-and hetero-oligomerization in cell biology
Current status and perspectives of interventional clinical trials for brain metastases: analysis of ClinicalTrials.gov
Full text linkBackground: The management of brain metastases (BM), the major cause of cancer morbidity and mortality, is becoming an emerging area of interest. Surgery, whole brain radiation therapy (WBRT), or stereotactic radiosurgery (SRS), have historically been the main focal treatments for BM. However, the introduction of innovative targeted- and immune-based therapies is progressively changing the paradigm of BM treatment, resulting in an increase in clinical trials investigating new therapeutic strategies. Methods: Using ClinicalTrials.gov, the largest clinical trial registry with over 400,000 registered trials, we performed an analysis of phase II and phase III ongoing trials evaluating different systemic therapies, radiotherapy (RT), and surgery given alone or in combination in patients with BM. Results: One hundred sixty-eight trials, 133 phase II and 35 phase III; the largest part having primarily the curative treatment of patients with BM from lung cancer, breast cancer and melanoma, were selected. One hundred sixty-three trials used systemic therapies. One hundred thirteen used tyrosine kinase inhibitors, more frequently Osimertinib, Icotinib and Pyrotinib, 50 used monoclonal antibodies, more frequently Trastuzumab, Pembrolizumab, Nivolumab, 20 used conventional chemotherapies whilst no oncological active drugs were used in 6 trials. Ninety-six trials include RT; 54 as exclusive treatment and 42 in combination with systemic therapies. Conclusion: Systemic targeted- and/or immune-based therapies, combined or not with RT, are increasingly used in the routine of BM treatment. SRS is progressively replacing WBRT. All these trials intend to address multiple questions on the management of patients with BMs, including the recommended upfront treatment for different cancer histologies and the optimal timing between systemic therapies and radiation regarding brain control and neurocognitive outcome and quality of life
MEK/ERK inhibitor U0126 affects in vitro and in vivo growth of embryonal rhabdomyosarcoma.
No full textWe reported previously that the disruption of c-Myc
through mitogen-activated protein kinase kinase (MEK)/
extracellular signal-regulated kinase (ERK) inhibition blocks
the expression of the transformed phenotype in the
embryonal rhabdomyosarcoma (ERMS) cell line (RD),
thereby inducing myogenic differentiation in vitro. In this
article, we investigate whether MEK/ERK inhibition, by the
MEK/ERK inhibitor U0126, affects c-Myc protein level and
growth of RMS tumor in an in vivo xenograft model.
U0126 significantly reduced RMS tumor growth in RD
cell line-xenotransplanted mice. Immunobiochemical and
immunohistochemical analysis showed (a) phospho-active
ERK levels were reduced by U0126 therapy and unaltered
in normal tissues, (b) phospho-Myc and c-Myc was reduced
commensurate with phospho-ERK inhibition, and (c)
reduction in Ki-67 and endothelial (CD31) marker expression.
These results indicate that MEK/ERK inhibition
affects growth and angiogenic signals in tumor. The RDM1
cultured xenograft tumor-derived cell line and the
ERMS cell line TE671 responded to U0126 by arresting
growth, down-regulating c-Myc, and initiating myogenesis.
All these results suggest a tight correlation of MEK/
ERK inhibition with c-Myc down-regulation and arrest of
tumor growth. Thus, MEK inhibitors may be investigated
for a signal transduction-based targeting of the c-Myc as a
therapeutic strategy in ERMS. [Mol Cancer Ther 2009;
8(3):543–51
p21WAF1 expression induced by MEK/ERK pathway activation or inhibition correlates with growth arrest, myogenic differentiation and onco-phenotype reversal in rhabdomyosarcoma cells
No full textBackground: p21WAF1, implicated in the cell cycle control of both normal and malignant cells, can be induced by p53-dependent
and independent mechanisms. In some cells, MEKs/ERKs regulate p21WAF1 transcriptionally, while in others they also affect the
post-transcriptional processes. In myogenic differentiation, p21WAF1 expression is also controlled by the myogenic transcription
factor MyoD. We have previously demonstrated that the embryonal rhabdomyosarcoma cell line undergoes growth arrest and
myogenic differentiation following treatments with TPA and the MEK inhibitor U0126, which respectively activate and inhibit
the ERK pathway.
In this paper we attempt to clarify the mechanism of ERK-mediated and ERK-independent growth arrest and myogenic
differentiation of embryonal and alveolar rhabdomyosarcoma cell lines, particularly as regards the expression of the cell cycle
inhibitor p21WAF1.
Results: p21WAF1 expression and growth arrest are induced in both embryonal (RD) and alveolar (RH30) rhabdomyosarcoma
cell lines following TPA or MEK/ERK inhibitor (U0126) treatments, whereas myogenic differentiation is induced in RD cells
alone. Furthermore, the TPA-mediated post-transcriptional mechanism of p21WAF1-enhanced expression in RD cells is due to
activation of the MEK/ERK pathway, as shown by transfections with constitutively active MEK1 or MEK2, which induces p21WAF1
expression, and with ERK1 and ERK2 siRNA, which prevents p21WAF1 expression. By contrast, U0126-mediated p21WAF1
expression is controlled transcriptionally by the p38 pathway. Similarly, myogenin and MyoD expression is induced both by
U0126 and TPA and is prevented by p38 inhibition. Although MyoD and myogenin depletion by siRNA prevents U0126-mediated
p21WAF1 expression, the over-expression of these two transcription factors is insufficient to induce p21WAF1. These data suggest
that the transcriptional mechanism of p21WAF1 expression in RD cells is rescued when MEK/ERK inhibition relieves the functions
of myogenic transcription factors. Notably, the forced expression of p21WAF1 in RD cells causes growth arrest and the reversion
of anchorage-independent growth.
Conclusion: Our data provide evidence of the key role played by the MEK/ERK pathway in the growth arrest of
Rhabdomyosarcoma cells. The results of this study suggest that the targeting of MEK/ERKs to rescue p21WAF1 expression and
myogenic transcription factor functions leads to the reversal of the Rhabdomyosarcoma phenotype
Dichlorodiphenyltrichloroethane, an old pesticide with a new mechanism of toxicity
No full textDichlorodiphenyltrichloroethane (DDT) is an organochlorine derivative known for its detrimental effect on human health. It was abundantly used as a pesticide and finally banned in many countries for its toxicity. Because of its extremely long half-life (up to 10 years), DDT is still blamed to cause health problems, due to the accumulation in the environment. We have previously shown that in vitro exposure to DDT causes severe membrane shedding with the release of vesicular organelles such as exosomes and/or ectosomes. A large body of evidence has shown that these vesicles, other than being directly involved in physiological exchanges of cellular materials, are implicated in the pathogenesis of several diseases such as viral and neurodegenerative diseases as well as tumorigenesis. In this short review, we discuss how the increased release of extracellular vesicles could explain the enhanced risk of diseases in patients exposed to organochlorine derivatives such as DDT
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