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Caratterizzazione clinica e molecolare del Linfoma Diffuso a Grandi cellule B: studio del trascrittoma e del microambiente tumorale per l’identificazione di nuovi sottotipi molecolari
No full textIntroduzione
Il Linfoma diffuso a grandi cellule B (DLBCL) è il tipo di linfoma maggiormente diagnosticato. Sono noti due sottogruppi della Cell of Origin: germinal center-like (GCB) e activated-like (ABC).
Il tasso di risposta alla terapia con R-CHOP è circa 60%. Attualmente, la stratificazione del rischio include l'International Prognostic Score, PET-CT, la classificazione COO e l'espressione/traslocazione di BCL2/BCL6/MYC. Nessun marcatore molecolare è stato correlato al rischio di fallimento del trattamento.
Obiettivi
Lo studio si propone di fornire un’analisi completa dei classici fattori prognostici e di valutare nuovi potenziali protagonisti della fitta complessità molecolare e instabilità genomica.
Metodi
Il progetto comprende una coorte di DLBCL ben caratterizzata a livello clinico di 204 pazienti trattati uniformemente con R-CHOP. La COO è stata valutata attraverso immunoistochimica (IHC - algoritmo di Hans) e il pannello Lymph2Cx (Nanostring). L'espressione di BCL2/MYC è stata valutata tramite IHC. RNAseq è stato eseguito utilizzando un approccio total-RNA e sequenziato su piattaforma NovaSeq 6000 (ILLUMINA). L'analisi dell'espressione è stata condotta utilizzando algoritmi Ecotyper pubblicati di recente. La Progression Free Survival (PFS) è stata stimata con il metodo Kaplan-Meier.
Risultati
Algoritmo di Hans: 41% dei casi come GCB e 59% come ABC. Lymph2Cx: 47% come GCB, 35% come ABC, 18% come Unclassified (concordanza=0,719). I casi GCB mostravano PFS significativamente più lunga rispetto al sottogruppo ABC sia utilizzando IHC (p=0,011) che Lymph2cx (p=0,027). I casi BCL2+ erano 67%, mentre quelli c-MYC+ 15%. I casi Double Expressor erano 12%. L'analisi di regressione Cox ha mostrato PFS a 5 anni dell'87% per BCL2-/c-MYC-, del 60% per BCL2+/c-MYC+ e del 45% per BCL2+/c-MYC-. 186 campioni sono stati amplificati e sequenziati con successo. RNASeq è stato in grado di ricapitolare correttamente il profilo di espressione genica totale mostrando risultati sovrapponibili con Lymph2cx.
L'analisi attraverso Ecotyper ha consentito una deconvoluzione di 13 tipi cellulari (cellule B + 12 cellule TME) indicando diversi programmi trascrizionali, noti come cell states, per ciascun tipo di cellula. I linfociti B mostravano 5 stati cellulari (S1-S5), dove S1 rappresenta una firma del centro germinale e S5 una firma correlata alle plasmacellule. La PFS era significativamente differente tra gli stati delle cellule B (p=0,0059), con prognosi peggiore per i casi S5. I cell states di diversi tipi cellulari sembrano coesistere, pertanto, attraverso l'analisi di clustering è stato possibile notare come più cell states siano assemblati in comunità che massimizzano i modelli di co-associazione, formando 9 diversi ecotipi (LE). I casi ABC sono più frequentemente associati a LE1 e 2 dove l'infiltrazione dei linfociti B è più evidente, mentre i GCB sono correlati agli ecotipi con attività del microambiente più forte. La PFS è risultata significativamente differente tra i vari LE (p=0,028) con distanza massima tra LE1 e LE9, quest'ultimo avente esito migliore.
Conclusioni
Lo studio mostra quindi il significato prognostico della COO e dell'espressione BCL2 nel contesto real-life. La over espressione di BCL2, rispetto a c-MYC, può essere responsabile della prognosi infausta dei casi di Double Expressor. Inoltre, i dati di RNA-seq hanno dimostrato di essere estremamente informativi per l'esito dei pazienti con DLBCL. Queste osservazioni portano alla possibilità di migliorare la stratificazione del rischio dei pazienti con DLBCL sfruttando nuovi strumenti bioinformatici in grado di osservare nuovi pattern molecolari all'interno dei sottogruppi COO, indicando casi che potrebbero essere potenzialmente eleggibili per diversi approcci terapeutici.Background
Diffuse Large B-cell Lymphoma (DLBCL) is the most common hematologic malignancy, originating either from the germinal-center (GCB) or post-germinal cells (ABC). Despite a ~60% response rate to first-line therapy, DLBCL remains incurable for ~40% of patients. Currently, risk stratification includes the International Prognostic Index, PET-CT scans, Cell-Of-Origin (COO), and expression/translocation of BCL2/BCL6/c-MYC. Nevertheless, no molecular marker has been widely correlated with the risk of treatment failure.
Objectives
We aim to provide a study of the existing prognostic tools for DLBCL and to evaluate potentially key players of the genomic instability and molecular complexity related to prognosis.
Methods
The project comprises a well characterized DLBCL cohort (204 patients), uniformly treated and with clinical data. COO classification has been analyzed through immunohistochemistry (IHC - Hans’ algorithm) and Lymph2Cx assay (Nanostring). BCL2/MYC expression has been evaluated through IHC. RNAseq has been performed using a total RNA approach and sequenced on a NovaSeq 6000 (ILLUMINA). Expression analysis was based on “Ecotyper algorithms”. Progression free survival (PFS) has been estimated by the Kaplan–Meier method.
Results
Hans’ algorithm on 84 patients identified 41% GCB, and 59% ABC cases. Among 191 patients, Lymph2Cx discovered 47% GCB, 35% ABC, and 18% unclassified cases (concordance between methods=0.719 k-statistic). In keeping with literature data, GCB patients showed significantly longer PFS compared to ABC subset both using Hans’ algorithm (p=0.011) and Lymph2cx (p=0.027). Unclassified patients showed an intermediate PFS between GCB and ABC. Analysis of BCL2 and MYC expression in 201 cases showed 57% of BCL2+/c-MYC-, 2.6% BCL2-/c-MYC+, and 12% BCL2+/c-MYC+ cases. Cox regression analysis showed a 5-year PFS of 92% for BCL2-/c-MYC-, 62% for BCL2+/c-MYC+ and 64% for BCL2+/c-MYC-. These data support the idea that BCL2 overexpression could be responsible for poor prognosis of DLBCL patients. RNASeq on 186 cases correctly recapitulated the total gene expression profile showing superimposable results with Lymph2cx classification. We then applied EcoTyper, a machine-learning tool able to derive 44 cell states related to malignant B cells and other cell types in the DLBCL tumor microenvironment (TME). Among the most important cell states for DLBCL, B cells showed 5 cell states (S1-S5). In our cohort, S1 showed a significantly longer PFS respect to the other cell states, with S5 cell state displaying the worse prognosis. The difference in term of survival outcome appeared even more evident when B cell states were stratified for the COO, showing how S1 and S5 tend to be mutually exclusive with the S1 cell state displaying a GCB-like signature and S5 cell state an ABC-like signature. Ecotyper assembled the cell states into communities generating 9 different Lymphoma Ecotypes (LEs) subgroups. Again, PFS analysis showed significant differences between LEs (p=0.028) with the maximum distance between LE1 and LE9, the latter showing a better outcome. In keeping, ABC cases are more frequently associated with LE1 and LE2 due to the high B cell infiltration, whereas GCB cases are more related to Ecotypes with stronger TME activity.
Conclusions
Here we confirm in a real-life cohort of DLBCL patients the prognostic significance of COO classification and BCL2 expression. In addition, RNASeq data demonstrated to be independently informative for DLBCL patient’s outcome. These observation lead to the possibility to improve the risk stratification of DLBCL patients taking advantage of new bioinformatic tools selecting cases that might be potentially eligible for different therapy approaches
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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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