1,720,975 research outputs found
INTEGRATED ROLE OF MITOCHONDRIA IN MULTIPLE MYELOMA
No full textMultiple myeloma (MM), the second most common haematological malignancy, is a still incurable cancer characterized by the proliferation of monoclonal plasma cells (PC) at multiple foci in the bone marrow and by end-stage organ diseases. Identification of new vulnerabilities in myeloma cells is needed to offer additional options for therapeutic interventions.
Mitochondria in cancer cells are attracting special attention, not only for their fundamental energy-producing function, but also for their roles in redox balance, apoptosis, anabolic and catabolic metabolism. Very little is currently known on mitochondrial function in MM cells, but recent reports of abundant mitochondria and sizeable mitophagy predict relevant cell-intrinsic roles. Interestingly, constitutive mild mitochondrial stresses revealed the ability to increase cellular fitness and resistance to subsequent perturbations. This process, known as mitohormesis, proved able to extend healthspan and lifespan in different organisms, including mammals, and we hypothesised it could play beneficial roles for cancer pathobiology. Furthermore, MM is known to develop and progress by establishing vicious interactions within the bone marrow multicellular milieu, including expanded myeloid derived suppressor cells (MDSC). Whether mitochondria in MM cells are involved in these interactions is undetermined.
Building on this rationale, in my PhD project I set out to investigate the existence of constitutive mitochondrial stress in malignant PCs and its cell-intrinsic significance and to explore the involvement of mitochondria in MM cell adaptation to environmental stress. In particular, we tested if arginine deprivation due to MDSC expansion could induce beneficial adaptive changes in MM cells, including mitochondrial metabolic rewiring, heightening fitness and stress resistance.
The results generated provide original evidence of distinctive basal activation of the mitochondrial unfolded protein response, a mitochondrial-to-nuclear transcriptional program activated by several forms of mitochondrial stress, in patient-derived MM cells as well as in human myeloma cell lines, where it sustains cell growth. Moreover, I identified a direct protective role of partial arginine starvation from stress-induced cell death in MM cells and challenged its pathophysiological relevance in vitro and in vivo.
Overall, my work unveils new targetable addictions and paves the way for their mechanistic dissection and further evaluation as novel therapeutic options.Il mieloma multiplo (MM), la seconda neoplasia ematologica maligna più frequente, è un cancro ancora incurabile caratterizzato dalla proliferazione di plasmacellule monoclonali in molteplici foci nel midollo osseo e da malattie d'organo allo stadio terminale. L’identificazione di nuove vulnerabilità nelle cellule di mieloma è necessaria per offrire ulteriori opzioni di trattamento terapeutico.
I mitocondri delle cellule tumorali stanno attirando particolare attenzione, non solo per la loro fondamentale funzione di produzione di energia, ma anche per il loro ruolo nel mantenimento dell’equilibrio di ossido-riduzione, nell’apoptosi, nel metabolismo anabolico e catabolico. Attualmente si sa molto poco sulle funzioni dei mitocondri nelle cellule di mieloma, ma lavori recenti che identificano in queste cellule abbondanti mitocondri e un loro considerevole riciclo tramite mitofagia suggeriscono un ruolo importante per questi organelli.
È stato dimostrato che lievi stress mitocondriali costitutivi hanno la capacità di aumentare la “fitness” cellulare e la resistenza alle successive perturbazioni. Questo processo, noto come mitoormesi, è in grado di estendere la salute e la durata della vita in diversi organismi, compresi i mammiferi. Abbiamo perciò ipotizzato che la mitoormesi possa svolgere un ruolo benefico per la pato-biologia del tumore. Inoltre, essendo noto che il mieloma si sviluppa e progredisce stabilendo interazioni nel contesto dell'ambiente multicellulare del midollo osseo, che comprende le cellule soppressorie di derivazione mieloide (MDSC), ci siamo chiesti se i mitocondri nelle cellule di mieloma risultino coinvolti in queste interazioni.
Basandomi su questi presupposti, nel mio progetto di dottorato ho cercato l'esistenza di uno stress mitocondriale costitutivo nelle plasma cellule maligne e verificato il suo ruolo cellulare intrinseco, inoltre ho esplorato la possibilità che i mitocondri svolgano una funzione nell'adattamento delle cellule di mieloma allo stress ambientale. In particolare, ho verificato se la deprivazione di arginina, come conseguenza dell’espansione delle MDSC nel midollo osseo, potesse indurre cambiamenti adattativi benefici nelle cellule di mieloma, inclusi la modifica del metabolismo mitocondriale, l’aumento della “fitness” e della resistenza allo stress.
I risultati generati hanno fornito prove di un’attivazione basale della UPR mitocondriale, un programma trascrizionale attivato da diverse forme di stress mitocondriale, nelle cellule primarie di mieloma derivate dai pazienti e nelle linee cellulari di mieloma umano, dove sostiene la crescita cellulare. Inoltre, ho identificato un ruolo protettivo diretto della deprivazione parziale di arginina dalla morte cellulare indotta da stress nelle cellule di mieloma e ho verificato la sua rilevanza fisiopatologica sia in vitro che in vivo.
Nel complesso, il mio lavoro ha identificato nuove dipendenze nelle cellule di mieloma e aperto la strada allo studio del loro meccanismo e all’ulteriore valutazione come nuove opzioni terapeutiche
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
No full text“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
No full textWe 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
No full textWe 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
A novel proteomic signature of osteoclast differentiation unveils the deubiquitinase UCHL1 as a necessary osteoclastogenic driver
No full textBone destruction, a major source of morbidity, is mediated by heightened differentiation and activity of osteoclasts (OC), highly specialized multinucleated myeloid cells endowed with unique bone-resorptive capacity. The molecular mechanisms regulating OC differentiation in the bone marrow are still partly elusive. Here, we aimed to identify new regulatory circuits and actionable targets by comprehensive proteomic characterization of OCgenesis from mouse bone marrow monocytes, adopting two parallel unbiased comparative proteomic approaches. This work disclosed an unanticipated protein signature of OCgenesis, with most gene products currently unannotated in bone-related functions, revealing broad structural and functional cellular reorganization and divergence from macrophagic immune activity. Moreover, we identified the deubiquitinase UCHL1 as the most upregulated cytosolic protein in differentiating OCs. Functional studies proved it essential, as UCHL1 genetic and pharmacologic inhibition potently suppressed OCgenesis. Furthermore, proteomics and mechanistic dissection showed that UCHL1 supports OC differentiation by restricting the anti-OCgenic activity of NRF2, the transcriptional activator of the canonical antioxidant response, through redox-independent stabilization of the NRF2 inhibitor, KEAP1. Besides offering a valuable experimental framework to dissect OC differentiation, our study discloses the essential role of UCHL1, exerted through KEAP1-dependent containment of NRF2 anti-OCgenic activity, yielding a novel potential actionable pathway against bone loss
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
Search and multi-frequency follow-up studies of radio transients: novel approaches and large campaigns
No full textOne of the most fascinating phenomena in modern radio astronomy is related to the Fast Radio Bursts (FRBs). FRBs are Jy-intense, ms-duration radio transients of extra-galactic origin, whose nature is not assessed yet. To date, FRBs have been observed only in the radio band. Despite their origin has not been disambiguated yet, observational facts point towards highly magnetised neutron stars, such as magnetars, as the putative sources behind at least some of them. In particular, on April 2020 the Galactic magnetar SGR J1935+2154 emitted a radio flash closely resembling the ones produced by the FRBs, with simultaneous detections in the X-rays. This result remarkably strengthened the FRB/magnetar link and strongly motivates panchromatic campaigns towards FRB sources in order to find, as in the case of SGR J1935+2154, their high-energy and also, possibly, optical/infrared counterparts. On one side, a multi-wavelength (MWL) detection of a FRB would lead to the confirmation of the aforementioned FRB/magnetar connection and/or to the evidence that other classes of astrophysical objects/events could be also responsible for a fraction of these radio transients. On the other hand, the observation of a MWL burst (outside the radio band) might discriminate between various proposed emission models, some of which predict MWL emission(s) simultaneous with the radio, while others prescribe that the MWL emission should occur well before or after the radio burst. However, any panchromatic detection of a FRB will mainly rely on the detection of a burst in radio. In order to detect as many radio bursts as possible, dedicated instruments and tailored search algorithms are a fundamental asset. MWL observations of FRBs are indeed the main driver of this PhD Thesis. On the other hand, MWL campaigns strongly depend on the capability to detect bursts in the radio band, which can happen with the deployment of proper instruments and with the use of dedicated search algorithms. In view of that, the PhD work presented in this Thesis, revolves around the following three main themes: (i) the analysis and possible improvement of the FRB detection algorithms; (ii) the development of radio facilities tailored for the FRB observations, and lastly (iii) a series of large MWL campaigns targeted to some of the FRB sources
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