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A Journey through the Multifaceted Landscape of Prostate Cancer: from Bench to Bedside Studies
No full textIntroduzione
Il tumore alla prostata è una delle cause oncologiche più frequenti di decesso nell'uomo nel mondo. La prognosi è tuttavia strettamente collegata dallo stadio di malattia.
L'immunoterapia ha fallito in questo tumore, che è considerato un tumore freddo in quanto caratterizzato da un elevato numero di linfociti T regolatori e cellule mieloidi soppressive che promuovono un ambiente immunosoppressivo. La fase metastatica sensibile a castrazione è caratterizzata da un estremo range di andamenti clinici e una volta in progressione verso la resistenza a castrazione, è caratterizzata da una prognosi infausta.
Scopo del lavoro e Metodi
La presente tesi consta di 3 lavori.
Il primo è uno studio traslazionale incentrato sulla rappresentazione della risposta immunitaria sistemica nel tumore alla prostata in stadio precoce, in pazienti candidati a prostatectomia. L'obiettivo è indagare le popolazioni di cellule immunitarie coinvolte e analizzare se esistono differenze nelle diverse classi di rischio. Pertanto, sono stati raccolti campioni di sangue e di tumore di pazienti sottoposti a chirurgia curativa e analizzati rispettivamente con FACS e in patologia.
La seconda parte è il disegno di uno studio clinico in pazienti con tumore prostatico metastatico ormono-sensibile, che prevede un approccio innovativo caratterizzato dal trattamento con terapia di deprivazione androgenica, darolutamide +/- un agente senolitico (S64315). L’obiettivo è studiare se la riduzione della senescenza, mediante questa strategia, possa ritardare l'insorgenza della fase di resistenza a castrazione e quindi migliorare la prognosi.
Il terzo è un lavoro clinico retrospettivo, monocentrico, volto a studiare l’outcome della presenza di mutazioni dei geni oncosoppressori TP53, PTEN e RB1, identificate mediante sequenziamento (NGS) in pazienti affetti da tumore prostatico avanzato ormono-sensibile.
Risultati
Nei 79 pazienti arruolati nello studio traslazionale. Tra questi abbiamo osservato livelli relativamente elevati di cellule CD11b+CD33+ circolanti e questa tendenza era significativamente più rappresentato nei pazienti con tumore ad alto rischio (p=0,018). Questo potrebbe suggerire come anche in tumori indolenti e in fase precoce, le cellule mieloidi immature siano implicate. Contrariamente, l'analisi dell'infiltrato peri-tumorale nei campioni tumorali non ha mostrato alcuna variazione tra le diverse classi di rischio.
Abbiamo arruolato 158 pazienti nello studio clinico retrospettivo. I pazienti che non presentavano alcuna alterazione dei tre geni soppressori tumorali presentavano una sopravvivenza libera da progressione (HR 0,58, p=0,012) e una sopravvivenza globale (HR 0,48, p=0,025) significativamente più lunghe. Inoltre, integrando lo stato mutazionale dei tre geni target con i noti fattori prognostici clinici (criteri CHAARTED), si è ottenuta una maggiore discriminazione prognostica e predittiva in questo stadio, creando tre classi che presentano una prognosi significativamente differente.
Conclusioni
I risultati evidenziano la complessità di questo tumore, e mostrano la presenza di una risposta immunitaria sistemica già nella malattia localizzata. Abbiamo inoltre rinforzato l'impatto prognostico sfavorevole delle alterazioni a carico geni oncosoppressori nella malattia avanzata ormono-sensibile. Ulteriori studi sono necessari per validare l’impatto di questi risultati.Background
Prostate cancer (PCa) is one of the main causes of death from cancer in men worldwide, however, the prognosis is mainly influenced by the stage. Immunotherapy has failed in PCa, which is considered a cold tumor as it is characterized by a high amount of regulatory T lymphocytes (T-reg) and myeloid-derived suppressor cells (MDSCs) that turn off the anti-tumor immune response and sustain tumor progression. Metastatic hormone-sensitive prostate cancer (mHSPC) presents a wide range of clinical outcomes, and once progressing to the castration-resistant (CR) phase, it is characterized by a poor prognosis.
Aim of the work and methods
This thesis consists of 3 works.
The first is a translational study focused on depicting the systemic immune response in localized PCa, in patients candidates for radical prostatectomy. The aim is to investigate the immune cell populations involved in this stage and analyze whether there are differences among different risk classes of tumors. Therefore, blood and tumor samples from patients undergoing curative surgery were collected and analyzed with flow cytometry assay and in pathology, respectively.
The second part is the design of a clinical trial for mHSPC patients, involving an innovative approach characterized by treatment with a senolytic agent (S64315) in addition to standard of care therapy, to study whether the reduction of tumoral senescent cells can delay the onset of the CR phase and thus improve prognosis.
The third is a retrospective, single-center clinical study investigating the impact of tumor suppressor gene (TSG) alterations, specifically in TP53, PTEN, and RB1, identified through next-generation sequencing (NGS), on progression-free survival (PFS) and overall survival (OS) in patients with mHSPC.
Results
We enrolled 79 patients in the translational study. We observed a relatively high amount of circulating CD11b+CD33+ cells in PCa patients. Furthermore, patients with high-risk diseases exhibited an even greater expansion of CD11b+CD33+ cells and a broader increase in the immature myeloid compartment, suggesting that systemic immunosuppression may escalate in parallel with tumor aggressiveness. Differently, the analysis of the peri-tumoral infiltrate in the tumoral specimens did not show any variation among the different risk classes.
We enrolled 158 patients in the retrospective clinical trial. Patients who did not present any alteration of the three TSG presented a significantly longer PFS (HR 0.58, p=0.012) and OS (HR 0.48, p=0.025). Moreover, integrating the AVPC-TSG status with the known clinical prognostic factors CHAARTED criteria, the results were an enhanced prognostic and predictive discrimination in mHSPC, creating three classes that present significantly different PFS.
Conclusions
The results highlight the complexity of this disease, where the presence of a systemic immune response is revealed since the early stages. The unfavourable prognostic impact of TSG alteration in mHSPC has been clarified. Further analyses are needed to reinforce the impact of these evaluations
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
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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