1,720,983 research outputs found
Targeting the PI3K/Akt/mTOR signaling pathway as a new therapeutic strategy for personalized treatments in acute lymphoblastic leukemia
No full textAcute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the uncontrolled proliferation of lymphoblasts that accumulate in the blood, bone marrow and other organs. It represents 20% of adult acute leukemia and is the most common leukemia in children.
The signal transduction pathway mediated by phosphatidylinositol 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) plays a key role in the regulation of important events for cells such as proliferation, differentiation and apoptosis, but also for the development of cancer and resistance to chemotherapy. In fact, the genes involved in the PI3K/Akt/mTOR pathway are often mutated and the activation signal mediated by these proteins is frequently altered in many cancer types, including ALL.
Therefore, the components of this pathway are potential new targets for the development of innovative targeted therapies which use molecules that inhibit the key components of those signal transduction pathways with high specificity, and which have a central role in the oncogenesis process.
The aim of this study is to evaluate the effects of small-molecule inhibitors (SMIs) on the PI3K/Akt/mTOR pathway using a panel of human leukemic cell lines and primary patient samples.
Drugs directed against the Akt and mTOR proteins were used, administered either alone or in combination, to assess their synergistic effects on cells. In particular, MK-2206, GSK690693 and Perifosine are specific inhibitors of Akt, while RAD001 and CCI-779 are directed against mTORC1 and Torin-2 is directed against mTORC1/2.
MK-2206, RAD001 and Torin-2 showed a specific cytotoxicity, inducing apoptosis and also caused cell cycle arrest in G0/G1 phase and autophagy both in cell lines and patient samples. They also down-regulated Akt and mTOR, as well as their downstream substrates.
Moreover, potential synergies between drugs that hit at different levels of the PI3K/Akt/mTOR signal transduction pathway have been studied: a dual action on two targets, has been analyzed, using either MK-2206 or GSK690693 and RAD001 or CCI-779, that showed a synergistic effect, not observable with Torin-2. Also the efficacy of a triple hit on the same target, i.e. Akt, has been analyzed using MK-2206, GSK690693 and Perifosine: the three drugs displayed a synergistic effect that allowed to minimize drug concentrations.
These results emphasize the increasing interest in studying pharmacological and personalized strategies for the development of new potential therapeutic protocols for cancer patients’ treatment, in order to overcome resistances and to improve clinical outcome
Hydrogen peroxide toxicity on auditory cells: An in vitro study
No full textIn recent decades, interest has increased in the role of reactive oxygen species (ROS) in health and disease. The ROS are key causative factors in several hearing loss pathologies including ototoxicity, noise trauma, cochlear ageing and ischemic injury. In order to investigate ROS effects on inner ear cells and counteract them, we developed an in vitro model of oxidative stress by exposing the inner ear cell line OC-k3 to hydrogen peroxide (H2O2) at concentrations able to affect in vivo cellular components but allowing cell survival. The treatment with high concentrations (20 and 30 mu M) resulted in reduction of cell viability, activation of apoptosis/necrosis and alteration of morphology, cell cycle progression and antioxidant defences. The ROS effects in inner ear cells are difficult to assess in vivo. Organocultures may provide preservation of tissue architecture but involve ethical issues and can be used only for a limited time. An in vitro model that could be commercially available and easy to handle is necessary to investigate inner ear oxidative stress and the ways to counteract it. The OC-k3 line is a suitable in vitro model to study ROS effects on inner ear cells because the observed cell alterations and damages were similar to those reported in studies investigating ROS effects of ototoxic drugs, noise trauma and cochlear ageing
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
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
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