1,720,973 research outputs found
Inhibition of the PI3K/Akt/mTOR signaling pathway as a therapeutic target for Acute Lymphoblastic Leukemia
No full textAcute Lymphoblastic Leukemia (ALL) is a malignant disorder characterized by the abnormal clonal proliferation of B-cell progenitors (B-ALL) or immature stage thymocytes (T-ALL).
Constitutive activation of the PI3K/Akt/mTOR network is a common feature of B- and T-ALL, influencing cell growth and survival. The PI3K/Akt/mTOR inhibitors are currently being developed for clinical use either as single agents or in combination with conventional chemotherapy for T-ALL patient treatment.
In this study it has been investigated the effects of a panel of PI3K/Akt/mTOR inhibitors on healthy human CD4+ T-cells when compared with T-ALL cell lines. Then, it has been verified whether a multi-inhibition treatment against Akt protein could enhance the efficacy of individual drug administration and overcome drug resistance as well as to obtain a decrease in single drug concentration, by testing the effects of combined treatments with three Akt inhibitors with different mode of action, GSK690693, MK-2206 and Perifosine on T-ALL cell lines. Combined administration of the drugs displayed a significant synergistic cytotoxic effect and affected PI3K/Akt/mTOR pathway at much lower concentration than single drug use. Highest synergistic effect for full inhibition of Akt was also related to the timing of every drug administration. The results obtained suggested that targeting Akt as a key protein of PI3K/Akt/mTOR pathway with multiple drugs might represent a new and promising pharmacological strategy for treatment of T-ALL patients.
It has also been investigated the role of microRNAs (miRNAs), a class of small noncoding RNAs, which play a role in various biological processes, including proliferation, apoptosis and tumorigenesis. The dysregulation of miRNAs is implicated in invasion in several human cancer types and leukemia is not an exception. By using in vitro models, it has been done an analysis of the effect of PI3K signaling inhibitors on expression of miRNA level involved in ALL disease and PI3K activation. The results obtained have shown that these drugs could modulate miRNA expression. Therefore, the regulation of miRNA expression profiling in ALL by using PI3K signaling inhibitors could be used as a new therapeutic approach in the near future.
In addition, it has been analyzed the efficacy of PI3K signaling pathway inhibitors in B- and T-ALL cell lines harboring the Abl1 tyrosine kinase gene fusion that lead to an aberrant cell proliferation.
It has been studied the effects of anti Bcr-Abl1 drugs such as Imatinib, Nilotinib and GZD824 associated with PI3K signaling inhibitors.
Drugs against PI3K/Akt/mTOR cascade administered in combination with Imatinib, Nilotinib and GZD824 decreased cell viability, induced apoptosis and autophagy in a marked synergistic manner.
These findings suggested that selected PI3K/Akt/mTOR inhibitors used in combination with anti Bcr-Abl1 drugs may be an attractive novel therapeutic intervention in Ph+ B- and T-ALL.La Leucemia Linfoblastica Acuta (LLA) è un tumore maligno ematologico caratterizzato da una proliferazione clonale incontrollata di progenitori della linea cellulare di tipo B (LLA-B) o timociti allo stadio immaturo (LLA-T).
L’attivazione della via di trasduzione del segnale di PI3K/Akt/mTOR è una caratteristica comune della LLA-B e T ed influisce sulla crescita e sopravvivenza cellulare.
Gli inibitori della via di PI3K/Akt/mTOR sono attualmente in fase di studio per uso clinico, sia come singoli agenti che in combinazione con la convenzionale chemioterapia utilizzata nel trattamento dei pazienti affetti da LLA-T.
In questo studio sono stati analizzati gli effetti di un pannello di inibitori della via di PI3K/Akt/mTOR su linfociti T-CD4+ di individui sani e confrontati con linee cellulari tumorali umane di LLA-T.
Successivamente è stato verificato se il trattamento di inibizione multipla della proteina Akt potesse aumentare l’efficacia dei farmaci somministrati singolarmente e superare la resistenza al farmaco ottenendo la riduzione della concentrazione del singolo agente. Pertanto, sono stati studiati e testati gli effetti di tre inibitori su linee cellulari umane di LLA-T diretti contro Akt ma con differenti modi di azione: GSK690693, MK-2206 e Perifosina.
Questa combinata somministrazione di farmaci ha mostrato un significativo effetto sinergico ed ha influito sulla via di PI3K/Akt/mTOR ad una concentrazione molto più bassa rispetto a quella del singolo farmaco. Il più elevato effetto sinergico per una totale inibizione di Akt è stato associato alla tempistica adottata per ciascuna somministrazione. I risultati ottenuti hanno suggerito che, mirare Akt come bersaglio chiave nella via del segnale di PI3K/Akt/mTOR con la somministrazione multipla di farmaci, potrebbe rappresentare una nuova e promettente strategia per il trattamento dei pazienti affetti da LLA-T.
E’ stato inoltre studiata l’azione dei microRNA (miRNA), una classe di piccoli RNA non codificanti che giocano un ruolo in vari processi biologici, quali la proliferazione, la morte cellulare e la genesi del cancro. La regolazione incontrollata dei miRNA è implicata nell’invasione di diversi tumori umani e la leucemia non è esclusa. Usando modelli in vitro è stata eseguita un’analisi degli effetti degli inibitori della via del segnale di PI3K sui livelli di espressione dei miRNA coinvolti nella LLA e nell’attivazione di PI3K. I risultati emersi hanno mostrato che questi farmaci potrebbero modulare l’espressione dei miRNA, pertanto, la regolazione dei loro profili di espressione nella LLA, utilizzando gli inibitori diretti contro la via di PI3K, potrebbe costituire un nuovo terapeutico approccio per il prossimo futuro.
Infine, è stata valutata l’efficacia degli inibitori della via del segnale di PI3K nelle linee cellulari di LLA-B e T caratterizzate dalla proteina di fusione Abl1 che causa una proliferazione cellulare incontrollata. Sono stati studiati gli effetti di farmaci contro il gene Bcr-Abl1 come Imatinib, Nilotinib e GZD824 utilizzati in combinazione con i farmaci diretti contro la via di PI3K.
La combinazione di questi farmaci ha mostrato una ridotta vitalità cellulare, innescando il processo di morte e autofagia cellulare in maniera sinergica. Questi dati hanno suggerito che la selezione di inibitori diretti contro la via di PI3K/Akt/mTOR somministrati in combinazione con farmaci contro il gene di fusione Bcr-Abl1, potrebbe rappresentare un allettante nuovo intervento terapeutico da prendere in considerazione nel trattamento della LLA-B e T portatrice del cromosoma Philadelphia (Ph+)
Physical training interventions for children and teenagers affected by acute lymphoblastic leukemia and related treatment impairments
No full text
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
- …
