39 research outputs found

    MAGE expression in head and neck squamous cell carcinoma primary tumors, lymph node metastases and respective recurrences-implications for immunotherapy

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    Melanoma associated antigens (MAGE) are potential targets for immunotherapy and have been associated with poor overall survival (OS) in head and neck squamous cell carcinoma (HNSCC). However, little is known about MAGE in lymph node metastases (LNM) and recurrent disease (RD) of HNSCC. To assess whether MAGE expression increases with metastasis or recurrence, a tissue microarray (TMA) of 552 primary tumors (PT), 219 LNM and 75 RD was evaluated by immunohistochemistry for MAGE antigens using three monoclonal antibodies to multiple MAGE family members. Mean expression intensity (MEI) was obtained from triplicates of each tumor specimen. The median MEI compared between PT, LNM and RD was significantly higher in LNM and RD. In paired samples, MEI was comparable in PT to respective LNM, but significantly different from RD. Up to 25% of patients were negative for pan-MAGE or MAGE-A3/A4 in PT, but positive in RD. The prognostic impact of MAGE expression was validated in the TMA cohort and also in TCGA data (mRNA). OS was significantly lower for patients expressing pan-MAGE or MAGE-A3/A4 in both independent cohorts. MAGE expression was confirmed as a prognostic marker in HNSCC and may be important for immunotherapeutic strategies as a shared antigen

    Plasmids and Rickettsial Evolution: Insight from Rickettsia felis

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    BACKGROUND: The genome sequence of Rickettsia felis revealed a number of rickettsial genetic anomalies that likely contribute not only to a large genome size relative to other rickettsiae, but also to phenotypic oddities that have confounded the categorization of R. felis as either typhus group (TG) or spotted fever group (SFG) rickettsiae. Most intriguing was the first report from rickettsiae of a conjugative plasmid (pRF) that contains 68 putative open reading frames, several of which are predicted to encode proteins with high similarity to conjugative machinery in other plasmid-containing bacteria. METHODOLOGY/PRINCIPAL FINDINGS: Using phylogeny estimation, we determined the mode of inheritance of pRF genes relative to conserved rickettsial chromosomal genes. Phylogenies of chromosomal genes were in agreement with other published rickettsial trees. However, phylogenies including pRF genes yielded different topologies and suggest a close relationship between pRF and ancestral group (AG) rickettsiae, including the recently completed genome of R. bellii str. RML369-C. This relatedness is further supported by the distribution of pRF genes across other rickettsiae, as 10 pRF genes (or inactive derivatives) also occur in AG (but not SFG) rickettsiae, with five of these genes characteristic of typical plasmids. Detailed characterization of pRF genes resulted in two novel findings: the identification of oriV and replication termination regions, and the likelihood that a second proposed plasmid, pRFδ, is an artifact of the original genome assembly. CONCLUSION/SIGNIFICANCE: Altogether, we propose a new rickettsial classification scheme with the addition of a fourth lineage, transitional group (TRG) rickettsiae, that is unique from TG and SFG rickettsiae and harbors genes from possible exchanges with AG rickettsiae via conjugation. We offer insight into the evolution of a plastic plasmid system in rickettsiae, including the role plasmids may have played in the acquirement of virulence traits in pathogenic strains, and the likely origin of plasmids within the rickettsial tree

    Emergence and Spread of the SARS-CoV-2 Omicron Variant in Alberta Communities Revealed by Wastewater Monitoring

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    Wastewater monitoring of SARS-CoV-2 allows for early detection and monitoring of COVID-19 burden in communities and can track specific variants of concern. Targeted assays enabled relative proportions of SARS-CoV-2 Omicron and Delta variants to be determined across 30 municipalities covering >75% of the province of Alberta (pop. 4.5M) in Canada, from November 2021 to January 2022. Larger cities like Calgary and Edmonton exhibited a more rapid emergence of Omicron relative to smaller and more remote municipalities. Notable exceptions were Banff, a small international resort town, and Fort McMurray, a more remote northern city with a large fly-in worker population. The integrated wastewater signal revealed that the Omicron variant represented close to 100% of SARS-CoV-2 burden prior to the observed increase in newly diagnosed clinical cases throughout Alberta, which peaked two weeks later. These findings demonstrate that wastewater monitoring offers early and reliable population-level results for establishing the extent and spread of emerging pathogens including SARS-CoV-2 variants.Alberta Healt

    Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

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    Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

    Enlivened Worship with the Divine: Evaluation and Innovative Application of the Liturgical Arts for Worship Renewal

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    Liturgical arts are meaningful resources and vessels for reclaiming and renewing the storytelling abilities of dynamic worship. This thesis explores a strategic evaluation of liturgical arts through the foundational and relational subjects of theology, ritual studies, and liturgical theology. Through the Holy Spirit, liturgical arts have formative powers that lead congregations into a deeper meeting with God—sending them forth as renewed signposts of Christ’s transcendence. They provide the space where pain and brokenness meet hope and grace for the renewal of the world. This thesis examines those powers in combination with a foundational and contextual evaluation to restore and apply innovative liturgical art that allows for the possibility of a vibrant and active dialogue between worshipers and the Triune God. A series of liturgies are included as examples highlighting these powers. Through a continuous process of evaluation and innovative application of the liturgical arts, a worshiping community has a foundational strategy to actively maintain, reimagine, and renew an ever-evolving, enlivened worship experience that intersects with the Divine
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