1,083 research outputs found
Decoding the B cell receptor in endemic Burkitt Lymphoma: Insights into pathogenesis and implications for disease detection
No full textThesis (Ph.D.)--University of Washington, 2017-09The African endemic form of Burkitt Lymphoma (BL) is one of the most common pediatric malignancies in sub-Saharan Africa. BL is particularly prevalent in certain geographic regions, likely due to both environmental and genetic influences. BL is a malignancy of antigen-experienced, germinal center centroblasts. Normal B cells express a functional B cell receptor on their surface that is generated from ordered chromosomal rearrangements at the immunoglobulin (Ig) loci. We performed high-throughput sequencing on genomic DNA extracted from primary BL tumors. The sequencing was focused on the Ig loci from three independent BL patient cohorts to assess the complete repertoire of Ig rearrangements contained in BL tumors. This analysis demonstrated that 55 of 69 tumors harbored a clonal Ig heavy chain (IGH) repertoire. Amongst clonal tumors, a second rearranged IGH allele was only detected in 11 cases, suggesting widespread monoallelic IGH rearrangements in BL tumors. Most tumors were characterized by extensive Ig sequence variation; hundreds of related, but unique, nucleotide sequences were detected in most tumors. These sequence families were associated with both complete VDJ rearrangements and incomplete DJ rearrangements, demonstrating the activity of active mutational processes at the Ig loci in BL tumors. IGH sequences are highly specific and can serve as a molecular barcode for each B cell. Assessment of matched patient blood samples demonstrated that tumor-associated IGH sequences were regularly detected in circulation at diagnosis. Positive detection of circulating tumor DNA at diagnosis was associated with inferior patient survival than when tumor DNA was not detected, suggesting that tumor-specific IGH sequences may have prognostic value for BL patients. The data presented in this dissertation suggest an alternative model of BL pathogenesis and assess the utility of IGH sequences as a biomarker for BL detection. The goal of this work is to expand the BL research repertoire to provide insights that will contribute to disease prevention efforts and ultimately improve the outcome for BL patients
Cellular and Molecular Dissection of the CD8+ T-Cell Response to Kaposi Sarcoma: Implications for Immunotherapeutic Strategies
No full textThesis (Ph.D.)--University of Washington, 2025Kaposi sarcoma-associated herpesvirus (KSHV) is one of two known tumorigenic human herpesviruses and the etiologic agent of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD), malignancies that predominantly arise in the context of T-cell deficiency or dysfunction. There are no approved vaccines, antiviral drugs, or immunotherapies that can prevent or eliminate KSHV infection. The impact of this therapeutic gap is most pronounced in sub-Saharan Africa (SSA), where the burden of KS morbidity and mortality is highest, KSHV is endemic, and HIV-1, the greatest risk factor for KS, is highly prevalent. All other human herpesviruses elicit potent and durable antiviral T-cell responses to control infection. However, studies of circulating T-cell responses to KSHV in the blood suggest that this response is heterogeneous, infrequent, and low-intensity, with the identity of their peptide-MHC targets poorly defined. Given the consistent expression of KSHV in KS tumors, we hypothesized that KSHV-specific T cells would be frequently recruited to KS tumors. We therefore analyzed the TCR repertoire of tumor biopsies from 144 Ugandan adults with KS, 106 of whom were people living with HIV (PLWH). Clusters of T cells with predicted shared specificity for uncharacterized antigens comprised approximately 25% of the T-cell repertoire in the KS tumor microenvironment, representing 4,283 unique αβ TCRs potentially recognizing KSHV- or HIV-encoded peptide antigens. From 25 reconstructed TCRs, we identified two ORF6-specific, HLA-B*45:01-restricted TCRs, one HLA-B*57:03-restricted TCR with specificity for ORF59, and one HLA-A*66:01-restricted TCR recognizing ORF57. The ORF6- and ORF59-specific TCRs were detected in 27-29 and 30 tumors from 14 HLA-B*45:01+ and 10 HLA-B*57:03+ individuals, respectively. Therefore, these TCRs provide the first evidence of a shared, i.e., “public,” T-cell response to KSHV. Primary CD8+ T cells engineered with KSHV-specific TCRs from KS tumor-infiltrating lymphocytes displayed high-avidity, MHC-restricted recognition of two distinct cell types infected with KSHV, B cells (PEL) and endothelial cells (iTIME.219). In parallel, we characterized three novel HIV-specific TCRs within KS tumors from PLWH, two targeting Nef71-79 and one recognizing Vpr34-42, and confirmed the presence of a previously described public HIV-specific TCR recognizing Pol982-990. HIV-specific T cells remained detectable in KS tumors from individuals who had been on antiretroviral therapy for up to five months. Together, these findings demonstrate that KS tumors recruit polyclonal, high-avidity CD8+ T cells recognizing multiple lytic KSHV and in PLWH, HIV antigens. The identification of CD8+ T cells capable of killing diverse KSHV-infected cell types will provide the foundation for rational vaccine design and TCR-based immunotherapeutic strategies to prevent or treat KS
Letter to Will H. Hays, August 14, 1920
No full textDated August 14, 1920, this letter is from an unidentified sender to Will H. Hays, Chairman of the Republican National Committee, regarding a bust sculpture of Senator Warren G. Harding on exhibition in Marion, Ohio. The author, possibly Harding's personal secretary George B. Christian, suggests that the Committee might want to use the bust to promote Harding during the final stage of his presidential campaign, as he has spent most of his campaign in Marion and many Americans have never seen him.
This letter is part of the Warren G. Harding Papers (MSS 345). This collection includes correspondence, business records, and other materials documenting Harding’s business career as owner and editor-in-chief of The Daily Marion Star, as well as the various stages of his political career. A significant portion of the collection, and what’s available on Ohio Memory, highlights his 1920 presidential campaign, spanning just before publicly announcing his candidacy to handily defeating Ohio Governor James M. Cox in the election. Correspondents include both Ohio and national businessmen, political figures, and ordinary citizens writing with questions, support, congratulatory notes, and campaign advice. Some of the most interesting insights into the tumultuous political climate in the U.S., the extreme factionalism within the Republican Party in Ohio, and Harding’s campaign strategies are described in letters between Harding and his campaign manager, Harry M. Daugherty. Some of the topics addressed include women’s suffrage, Prohibition, the League of Nations, African American representation and issues, and lingering peace negotiations following World War I
Will H. Hays letter, August 16, 1920
No full textIn this letter dated August 16, 1920, an unidentified author writes to Will H. Hays, Chairman of the Republican National Committee, about the Committee's Publicity Department's efforts to create campaign press targeted to women voters. Gus Karger, a Washington correspondent for the Cincinnati-Times Star suggests that women's votes will be influenced by what a candidate has done for home life, women and children, and suggests the Committee focus on any child labor reform work.
This letter is part of the Warren G. Harding Papers (MSS 345). This collection includes correspondence, business records, and other materials documenting Harding’s business career as owner and editor-in-chief of The Daily Marion Star, as well as the various stages of his political career. A significant portion of the collection, and what’s available on Ohio Memory, highlights his 1920 presidential campaign, spanning just before publicly announcing his candidacy to handily defeating Ohio Governor James M. Cox in the election. Correspondents include both Ohio and national businessmen, political figures, and ordinary citizens writing with questions, support, congratulatory notes, and campaign advice. Some of the most interesting insights into the tumultuous political climate in the U.S., the extreme factionalism within the Republican Party in Ohio, and Harding’s campaign strategies are described in letters between Harding and his campaign manager, Harry M. Daugherty. Some of the topics addressed include women’s suffrage, Prohibition, the League of Nations, African American representation and issues, and lingering peace negotiations following World War I
Chronicles of Oklahoma
No full textArticle describes the 1893 opening of the Cherokee Strip as experienced by the author and her family. Clara Williamson Warren Bullard describes her family's settlement of their claim, water scarcity, growth of communities, and the cultivation of land
Robins letter to Will H. Hays, August 11, 1920
No full textIn this letter dated August 11, 1920, an author by the name of Robins writes to Will H. Hays, Chairman of the Republican National Committee, regarding Senator Harding's position on the League of Nations. The body of the letter contains large block quotes from California Senator Hiram Johnson, who suggests that Harding clearly state he opposes President Wilson's League of Nations, and that he "'will first declare peace and then leisurely and reflectively take up with the nations of the earth plans for disarmament and the prevention of war.'" Johnson warns against presenting his own version of the League of Nations, but suggests to instead refuse to go into further detail than making peace and discuss another world covenant later.
This letter is part of the Warren G. Harding Papers (MSS 345). This collection includes correspondence, business records, and other materials documenting Harding’s business career as owner and editor-in-chief of The Daily Marion Star, as well as the various stages of his political career. A significant portion of the collection, and what’s available on Ohio Memory, highlights his 1920 presidential campaign, spanning just before publicly announcing his candidacy to handily defeating Ohio Governor James M. Cox in the election. Correspondents include both Ohio and national businessmen, political figures, and ordinary citizens writing with questions, support, congratulatory notes, and campaign advice. Some of the most interesting insights into the tumultuous political climate in the U.S., the extreme factionalism within the Republican Party in Ohio, and Harding’s campaign strategies are described in letters between Harding and his campaign manager, Harry M. Daugherty. Some of the topics addressed include women’s suffrage, Prohibition, the League of Nations, African American representation and issues, and lingering peace negotiations following World War I
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