5,668 research outputs found
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
A Floating Question Mark: An Interview with Sara Hawys Roberts, Author of Withdrawn Traces: Searching For The Truth About Richey Manic
No full textAn interview with Sara Hawys Roberts, co-author of 'Withdrawn Traces: Searching For The Truth About Richey Manic' about the researching and writing of this much-anticipated book about the missing Manic Street Preacher.</p
A Floating Question Mark: An Interview with Sara Hawys Roberts, Author of Withdrawn Traces: Searching For The Truth About Richey Manic
No full textAn interview with Sara Hawys Roberts, co-author of 'Withdrawn Traces: Searching For The Truth About Richey Manic' about the researching and writing of this much-anticipated book about the missing Manic Street Preacher.</p
Sara Gossett Crigler Collection - Accession 614
Get PDFThe Sara Gossett Crigler Collection consists of a microfiche copy of her book titled, Education For Girls And Women In Upper South Carolina Prior to 1890 with Related Miscellaneous Articles: A Compilation by Mrs. Henry Towles Crigler (Sara Gossett Crigler), self-published in Greenville, SC on April 15, 1956. This book also includes many anecdotes and reminiscences of Sara’ family including a section devoted to the slaves owned and later freed after the Civil War by her family. The book is dedicated by the author, Sara Gossett Crigler (1886-1966), to her mother Sallie Brown Gossett (1859-1942) and her aunt Mary Brown Mahon (1861-1948) who were both graduates of Williamston Female College in 1877 and 1879 respectively. The 170 page volume would be useful to anyone doing research on the education of women in South Carolina during the 19th century. The original copy is housed at the South Carolina Historical Society as SCHS 509 and was dedicated and signed by the author, “For the Charleston Library Society” on July 10, 1964.
*Please see attached Table of Contentshttps://digitalcommons.winthrop.edu/manuscriptcollection_findingaids/1527/thumbnail.jp
Materia-autore = Author-Matter
Get PDFThe etymology of the word author refers to an act of creation, an act of augmentation, from the Latin verb augere. Author instantiates creation, the expansion of the pre-existing. In 1967 Roland Barthes declared the death of the author in his famous essay to state once more that the crisis is that of the author as a single subjectivity and as a term that condenses prestige, undermined by the de-subjectivation strategies of automatism, fortuity and fragmentation of the historical avant-gardes, as well as by the machinic act and by the reproducibility of the second avant-gardes.
Fifty years after Barthes’ paradigmatic formula, this lack of authorship appears to be a successful brand. The ten- sions between the anomie of matter, the law that establishes authorship and the economy that makes the work pos- sible, invoke discordant perspectives. Artists make the self-destruction of their work the real work, and appeal is made for the demolition of architectures, whether by a recognised author or not, in order to re-design, or better still, re-claim the territory. Artificial intelligence consolidates its logics and its design by progressively shedding human ingenuity. The space of criticism becomes, finally, increasingly ephemeral. However, there is an acceptation of criti- cism that is, rather than an individual ‘signature’, an exploration and explanation of how design makes theory.
The binomial author-matter seeks to mark these tensions and contradictions: the featured term author is main- tained to underline the persistence of that prestigious subjectivity, at the very moment when the rhetoric of “mat- ter as an author” promises other forms of authorship
Sara Winthrop Smith letter to Frances Casement, August 14, 1887
No full textLetter written to Frances Casement from Sara Winthrop Smith of Cincinnati, Ohio, August 14, 1887. Winthrop expresses the challenges of generating support for the suffrage movement among the conservative residents of her city, and encourages the creation of clear materials that make the argument for women's suffrage to be more widely distributed.
This item comes from the Frances Jennings Casement Papers, a manuscript collection comprised of letters and association records related to the founding and leadership of the Ohio Woman Suffrage Association. Casement (1840-1928) was born in Painesville, Ohio, and graduated from Painesville Academy and Willoughby Female Seminary. Her father, Charles Casement, supported abolition and women's suffrage and encouraged Frances to be active in social causes. Frances Casement established the Painesville Equal Rights Association in 1883, and shortly after became involved in the Ohio Woman Suffrage Association, serving as its president from 1885 to 1888
Sara Brown
No full textSara E. Brown is the Executive Director of Chhange, the Center for Holocaust, Human Rights & Genocide Education. Brown holds the first Ph.D. in comparative genocide studies from Clark University\u27s Strassler Center for Holocaust and Genocide Studies. She has presented at an array of professional conferences around the world, published pieces in academic journals, news outlets, and edited volumes, and currently serves on the Advisory Board for the International Association of Genocide Scholars.
Brown has worked and conducted research in Rwanda since 2004, served as a project coordinator in refugee camps in Tanzania, worked in refugee resettlement in Texas, and researched conflict globalization and conflict in Israel. Prior to coming to Chhange, she developed and managed post-secondary education programming for USC Shoah Foundation. She has designed and taught courses on human rights, mass violence, and history at San Diego State University, Mt San Jacinto Community College, and Worcester State University. Brown served as an academic consultant for Aegis Trust in Rwanda and as the scholarly advisor on the Genocide against the Tutsi in Rwanda for Chhange\u27s museum-quality exhibit, Journeys Beyond Genocide: The Human Experience.
She is the author of Gender and the Genocide in Rwanda: Women as Perpetrators and Rescuers and the co-editor of the forthcoming Routledge Handbook on Religion and Genocide.https://commons.erau.edu/genocide-bios/1059/thumbnail.jp
- …
