1,720,995 research outputs found
Metabolic starvation triggered by l-asparaginase sensitizes multiple myeloma cells to proteasome inhibitors by inducing DNA damage accumulation
No full textMultiple Myeloma (MM) is a malignant proliferation of clonal bone marrow (BM)
plasma cells (PCs) in association with monoclonal protein. Despite the dramatic
improvements in MM treatment achieved in the last decade, it is still an incurable
disease. A better knowledge of the biological mechanisms involved in disease
occurrence and progression has led to the development of several new, innovative,
drugs that significantly improved patients outcome and renewed the therapeutic
approach to the disease in the last years. However, resistance develops with a 40%
survival at five-years. Moreover, despite the improvement of patient riskstratification
systems at diagnosis, treatment outcome is often unpredictable due to the high degree of genomic heterogeneity and genomic instability which characterize the disease. In this view, novel therapeutic strategies capable to overcome disease heterogeneity and improve patient outcome are strongly needed.
A fundamental feature of all cancers is the metabolic reprogramming to promote
growth, survival, proliferation, and long-term maintenance. The common feature of
this altered metabolism is increased glucose uptake and fermentation of glucose to
lactate, the so called “Warburg Effect”. Moreover, the non essential amino acid
Glutamine complements glucose to meet cancer cells metabolic demands. In
particular, some human tumors exhibit a high requirement for Gln for anabolic and
metabolic processes, a condition that has been defined “Gln-addiction” leading to the
investigation of such Gln-dependence as therapeutic target in human cancers. Beside its role of carbon and nitrogen source for macromolecules synthesis, the
metabolism of this non-essential amino acid support tumor growth by inducing
essential amino acids uptake and activation of mTORC1 signaling pathways, which acts
as regulator for protein translation and autophagy. Moreover, Gln maintains
mitochondrial membrane potential and prevents oxidative damage driving Glutathione
(GSH) and NADPH synthesis.
In the recent years the importance of Gln metabolism as therapeutic target began to
be explored and emerging data suggest that inhibition of glutamine metabolism with
small molecules results in an energetic crisis leading to cellular death. Emerging
data suggest efficacy of Gln-deprivation also in MM cells which are unable to
synthesize adequate amounts of Gln and, therefore, result highly sensitive to Glntransporters blockade or glutaminase inhibition.
Several approaches are reported to achieve Glu-depletion including: uptake inhibition
(Gln-transporters inhibitors), metabolism targeting (Glutaminase inhibitors) or serum
depletion exploiting the glutaminase-activity of L-asparaginase drug (L-ASP). L-ASP is a
bacterial-derived enzyme that induces serum aminoacidic deprivation by catalyzing the
hydrolysis of asparagine in aspartic acid and ammonium and glutamine in glutamic acid
and ammonium. Among the above mentioned strategies to obtain Gln-deprivation,
L-ASP is already available in clinic as it represents a cornerstone for acute
lymphoblastic leukemia (ALL) and some aggressive lymphomas treatment.
Based on these observations, we aim to explore the therapeutic relevance of
Asparaginase-induced Gln depletion alone and in combination with currently usedanti-MM drugs. Moreover we will analyze biological mechanisms supporting the
effectiveness of the identified therapeutic strategies
Chronic graft versus host disease as a weapon for treating chronic myelomonocytic leukemia
No full textIntesive fludarabine-high dose cytarabine-idarubicin combination as induction therapy with risk-adapted consolidation may improve treatment efficacy in younger Acute Myeloid Leukemia (AML) patients: Rationales, evidences and future perspectives
No full textAcute Myeloid Leukemia (AML) is the commonest form of leukemia in the adults, with an incidence of 3-4 cases per 100,000 people/year. After the first description of the effective cytarabine + antracycline (3+7) induction regimen, in the last 3 decades, no effective targeted drug has been included in the standard treatment of AML. Many efforts of modifying 3+7 adding a third drug or increasing the dose of anthracycline, cytarabine or both did not lead to substantial improvements, mainly due to increased toxicity. Many in vitro and in vivo evidences suggested that fludarabine may increase efficacy of cytarabine through a synergistic effect. Considering the continuous improvements in supportive care and management of infectious complications the feasibility of more intensive induction strategies have increased and a renewed interest in fludarabine-containing induction strategies arose. The recent MRC AML 15 trial has shown that a fludarabine-containing induction, FLAG-Ida, resulted superior to conventional 3+7 in terms of complete remission rates, relapse incidence and survival, although only a minority of patients could complete the whole planned consolidation program due to an excessive hematological toxicity. Our group recently published a 10-year experience with a fludarabine-containing induction that slightly differed from the MRC one and resulted in good efficacy and higher feasibility. In this commentary we review the major evidences supporting the employ of a fludarabine-containing induction in AML, and discuss the future perspectives
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
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