1,720,968 research outputs found
Protein kinase CK2 in diffuse large b-cell lymphoma: defining its role to shape new therapies
Get PDFCK2 is a highly conserved Ser/Thr protein kinase, consisting of two catalytic (a) and two regulatory (b) subunits assembled to form a tetramer. It is involved in a broad variety of cellular processes, among which survival, proliferation, differentiation, DNA damage and other stress responses, leading to the activation of context-specific transcription factors such as c-Myc and NF-kB. This kinase has been found overexpressed in several solid tumors and hematologic malignancies, and its overexpression seems to be an unfavorable prognostic marker. It has been fully demonstrated that CK2 acts as a potent antiapoptotic factor that promotes a “non-oncogene addiction” phenotype in cancer cells. In other words, high CK2 levels and activity contribute to create a cellular environment favorable to the establishment and maintenance of a neoplastic phenotype. In particular, it was recently shown that many B-cell derived tumors, like multiple myeloma, mantle cell lymphoma and chronic lymphocytic leukemia, rely on high CK2 activity and that its downmodulation induces malignant cell death without significantly affecting normal B lymphocytes.
Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive B-cell derived neoplasia that originates from follicles and is the most common type of non-Hodgkin lymphoma, accounting for about 40% of all cases. It is divided into two subtypes: Germinal Center B-cell like (GCB) and Activated B-Cell like (ABC) DLBCL, characterized by different genetic lesions and, therefore, variable response to therapy. Up to one-third of patients does not achieve cure with initial therapy and has refractory disease or relapse. The standard salvage treatment for these patients is autologous stem cell transplantation, but success rates are poor and most of them succumb to the disease. These facts clearly demonstrate the need for new rational combination therapeutics.
It is well known that the B-Cell Receptor (BCR) signalling strongly influences B-cell development and is fundamental for peripheral B-cell survival. After BCR ligation by the antigen, the signal is transduced across the plasma membrane and propagated inside the cell through a group of intracellular proteins, which interact to form a complex, called signalosome. Among these proteins there are the tyrosine kinases SYK and BTK, the phospholipase PLCg2 and the adaptor BLNK. Once activated by SYK, BTK phosphorylates PLCg2, which in turn generates IP3 thus causing Ca++ release from the endoplasmic reticulum stores. Ca++ acts in the cytoplasm as a second messenger that binds several Ca++-dependent proteins that are then able to activate transcription factors, like NFAT and NF-kB, modifying gene expression. The result of this process consists in activation, expansion, antigen presentation and B-cell differentiation. For these reasons, it comes as no surprise that inhibitors targeting the BCR signalling have shown promising therapeutic outcomes for patients with B-cell lymphomas.
Here we show that a and b subunits of protein kinase CK2 are overexpressed in ABC- and GCB-DLBCL primary patient samples and immortalized cell lines when compared with normal counterparts. Moreover, we demonstrate that CK2 inhibition with CX-4945, an ATP-competitive CK2 inhibitor currently under clinical trials, causes apoptosis of DLBCL cell lines in a dose and time dependent fashion, and that malignant cell death is significative even at low drug doses not toxic to normal counterparts. We also reveal that the downmodulation of CK2 catalytic activity leads to a reduction in Ca++ release from the endoplasmic reticulum stores, and impairs AKT and NF-kB RELA phosphorylation after BCR stimulation. These findings propose a role for CK2 downstream of the BCR engagement, in controlling survival pathways crucial for B-cell endurance. Furthermore, we found out that CX-4945 synergises with inhibitors of kinases, like SYK and BTK, essential in spreading the BCR signal, thus proving that this drug combination enhances DLBCL cell death and could be considered an effective therapeutic strategy
Editorial: Immune system interactions in hematological tumor microenvironments: pathways to innovative treatments
Get PDFTargeting CK2-driven non-oncogene addiction in B-cell tumors
No full textGenetic mutations of oncogenes often underlie deranged cell growth and altered differentiation pathways leading to malignant transformation of B-lymphocytes. However, addiction to oncogenes is not the only drive to lymphoid tumor pathogenesis. Dependence on non-oncogenes, which act by propelling basic mechanisms of cell proliferation and survival, has also been recognized in the pathobiology of lymphoid leukemias, lymphomas and multiple myeloma. Among the growing number of molecules that may uphold non-oncogene addiction, a key place is increasingly being recognized to the serine-threonine kinase CK2. This enzyme is overexpressed and overactive in B-acute lymphoblastic leukemia, multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphomas, such as mantle cell, follicular, Burkitt's and diffuse large B-cell lymphomas. In these tumors, CK2 may serve the activity of oncogenes, similar to BCR-ABL and c-MYC, control the activation of critical signaling cascades, such as NF-κB (nuclear factor-κB), STAT3 (signal transducer and activator of transcription 3) and PTEN/PI3K/AKT (phosphatase and tensin homolog protein/phosphoinositide 3-kinase/AKR thymoma), and sustain multiple cellular stress-elicited pathways, such as the proteotoxic stress, unfolded protein and DNA-damage responses. CK2 has also been shown to have an essential role in tuning signals derived from the stromal tumor microenvironment. Not surprisingly, targeting CK2 in lymphoid tumor cell lines or mouse xenograft models can boost the cytotoxic effects of both conventional chemotherapeutics and novel agents, similar to heat-shock protein 90, proteasome and tyrosine kinases inhibitors. In this review, we summarize the evidence indicating how CK2 embodies most of the features of a cancer growth-promoting non-oncogene, focusing on lymphoid tumors. We further discuss the preclinical data of the use of small ATP-competitive CK2 inhibitors, which hold the promise to be additional options in novel drug combinations for the therapy of lymphoid and plasmacellular malignancies
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
Variations 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
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe 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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