1,720,962 research outputs found
DISSECTING THE ROLE OF CLPP IN MULTIPLE MYELOMA
No full textDespite the efficacy of targeted treatments, multiple myeloma (MM) is still incurable, urging to identify novel vulnerabilities to design more effective therapies. Mitochondria are emerging therapeutic targets in oncology for their crucial role not only as cellular powerhouses, but also in signalling, redox homeostasis, initiation of apoptosis, production of metabolites, and supply of biosynthetic precursors.
Owing to intensive immunoglobulin production, myeloma cells are heavily reliant on protein homeostasis and experience significant exposure to mitochondrial stressors. We hypothesized that myeloma cells depend on the prototypical mitochondrial stress-adaptive pathway, the mitochondrial unfolded protein response (UPRmt), for their fitness and survival. We tested its activation status and its manipulation as a possible tool against myeloma. We found that while a clear upregulation of the UPRmt signature is evident in MM, its regulation is independent of the master transcription factor ATF5, so far believed to mediate the mammalian UPRmt.
One of the key players of the UPRmt and gatekeeper of mitochondrial homeostasis is ClpP, a resident mitochondrial protease suggested to maintain oxidative phosphorylation efficiency. Prompted by its distinctive expression in malignant plasma cells, we investigated the role of ClpP in multiple myeloma cells and tested it as a possible anti-myeloma target. We found that ClpP downregulation leads to disappearance of MM cells from culture due to apoptosis or cell cycle arrest. Surprisingly, toxicity extends to glycolytic cell lines and we demonstrated that ClpP knockdown has no effects on mitochondrial oxygen consumption by MM cells, thus unveiling an energy-independent vulnerability. By combining RNA-seq, proteomics, and metabolomics we identified unprecedented and unexpected cellular features regulated by ClpP, including protein translation both in the cytosol and in mitochondria, impairment of fatty acid metabolism with accumulation of acyl-carnitines and long chain unsaturated fatty acids, deregulation of the polyamine pathway with depletion of spermine, spermidine and putrescine. Intriguingly, we also detected a strong impact on interferon-regulated pathways, hinting at mitochondria and ClpP as possible tools to manipulate MM immunogenicity.
Our data suggest that ClpP is vital to MM cells due to a novel non-bioenergetic function, and pave the way for its further evaluation as a therapeutic target.Despite the efficacy of targeted treatments, multiple myeloma (MM) is still incurable, urging to identify novel vulnerabilities to design more effective therapies. Mitochondria are emerging therapeutic targets in oncology for their crucial role not only as cellular powerhouses, but also in signalling, redox homeostasis, initiation of apoptosis, production of metabolites, and supply of biosynthetic precursors.
Owing to intensive immunoglobulin production, myeloma cells are heavily reliant on protein homeostasis and experience significant exposure to mitochondrial stressors. We hypothesized that myeloma cells depend on the prototypical mitochondrial stress-adaptive pathway, the mitochondrial unfolded protein response (UPRmt), for their fitness and survival. We tested its activation status and its manipulation as a possible tool against myeloma. We found that while a clear upregulation of the UPRmt signature is evident in MM, its regulation is independent of the master transcription factor ATF5, so far believed to mediate the mammalian UPRmt.
One of the key players of the UPRmt and gatekeeper of mitochondrial homeostasis is ClpP, a resident mitochondrial protease suggested to maintain oxidative phosphorylation efficiency. Prompted by its distinctive expression in malignant plasma cells, we investigated the role of ClpP in multiple myeloma cells and tested it as a possible anti-myeloma target. We found that ClpP downregulation leads to disappearance of MM cells from culture due to apoptosis or cell cycle arrest. Surprisingly, toxicity extends to glycolytic cell lines and we demonstrated that ClpP knockdown has no effects on mitochondrial oxygen consumption by MM cells, thus unveiling an energy-independent vulnerability. By combining RNA-seq, proteomics, and metabolomics we identified unprecedented and unexpected cellular features regulated by ClpP, including protein translation both in the cytosol and in mitochondria, impairment of fatty acid metabolism with accumulation of acyl-carnitines and long chain unsaturated fatty acids, deregulation of the polyamine pathway with depletion of spermine, spermidine and putrescine. Intriguingly, we also detected a strong impact on interferon-regulated pathways, hinting at mitochondria and ClpP as possible tools to manipulate MM immunogenicity.
Our data suggest that ClpP is vital to MM cells due to a novel non-bioenergetic function, and pave the way for its further evaluation as a therapeutic target
The Immunity‐malignancy equilibrium in multiple myeloma: lessons from oncogenic events in plasma cells
No full textMultiple myeloma (MM) is a malignancy of plasma cells (PC) that grow within the bone marrow and maintain massive immunoglobulin (Ig) production. Disease evolution is driven by genetic lesions, whose effects on cell biology and fitness underlie addictions and vulnerabilities of myeloma cells. Several genes mutated in myeloma are strictly involved in dictating PC identity and antibody factory function. Here, we evaluate the impact of mutations in IRF4, PRDM1, and XBP1, essential transcription factors driving the B to PC differentiation, on MM cell biology and homeostasis. These factors are highly specialized, with limited overlap in their downstream transcriptional programs. Indeed, IRF4 sustains metabolism, survival, and proliferation, while PRDM1 and XBP1 are mainly responsible for endoplasmic reticulum expansion and sustained Ig secretion. Interestingly, IRF4 undergoes activating mutations and translocations, while PRDM1 and XBP1 are hit by loss-of-function events, raising the hypothesis that containment of the secretory program, but not its complete extinction, may be beneficial to malignant PCs. Finally, recent studies unveiled that also the PRDM1 target, FAM46C/TENT5C, an onco-suppressor uniquely and frequently mutated or deleted in myeloma, is directly and potently involved in orchestrating ER homeostasis and secretory activity. Inactivating mutations found in this gene and its interactors strengthen the notion that reduced secretory capacity confers advantage to myeloma cells. We believe that dissection of the evolutionary pressure on genes driving PC-specific functions in myeloma will disclose the cellular strategies by which myeloma cells maintain an equilibrium between antibody production and survival, thus unveiling novel therapeutic targets
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
Monoclonal Antibodies in Smoldering Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance: Current Status and Future Directions
Full text linkMonoclonal antibodies (MoAbs) targeting several cellular receptors have significantly improved the prognosis of multiple myeloma (MM). Their high effectiveness and safety raise the question of whether earlier therapeutic intervention in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) influences the natural course of the disease. MM is preceded by clinically recognized conditions such as MGUS and SMM. Numerous studies are investigating the disease biology and immune profile of SMM and MGUS to unravel the intricate relationship between immunosurveillance and disease progression. The standard approach to MGUS and SMM remains close observation. Early studies indicate benefits in terms of progression or even survival for promptly treating high-risk SMM patients. Ongoing debates are focused on which patients with SMM and MGUS to treat, as well as on determining the optimal therapeutic approach. The first approach aims to cure by attempting to eliminate the pathological clone, while the second approach is preventive, aiming to manage disease progression to active MM and restore the immune system. In this review, we focus on the available and emerging data on early treatment, particularly with MoAbs alone or in combination with other therapies, in SMM and MGUS patients
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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