Large granular lymphocyte (LGL) leukemia comprises a group of rare lymphoproliferative disorders whose molecular landscape is incompletely defined. We leveraged paired whole exome and transcriptome sequencing in the largest LGL leukemia cohort to date, which included 105 patients (93 TCRab T-LGL and 12 TCRγδ T-LGL). 76 mutations were observed in three or more patients in the cohort, and out of those, STAT3, KMT2D, PIK3R1, TTN, EYS, and SULF1 mutations were shared between both subtypes. We identified ARHGAP25, ABCC9, PCDHA11, SULF1, SLC6A15, DDX59, DNMT3A, FAS, KDM6A, KMT2D, PIK3R1, STAT3, STAT5B, TET2, and TNFAIP3 as recurrently mutated putative drivers using an unbiased driver analysis approach leveraging our whole exome cohort. Hotspot mutations in STAT3, PIK3R1, and FAS were detected, whereas truncating mutations in epigenetic modifying enzymes such as KMT2D and TET2 were observed. Moreover, STAT3 mutations co-occurred with mutations in chromatin and epigenetic modifying genes, especially KMT2D and SETD1B (p < 0.01, p < 0.05 respectively). STAT3 was mutated in 50.5% of the patients. Most common Y640F STAT3 mutation was associated with lower ANC values, and N647I mutation was associated with lower hemoglobin values. Somatic activating mutations (Q160P, D170Y, L287F) in the STAT3 coiled-coil domain were characterized. STAT3 mutant patients exhibited increased mutational burden and enrichment of a mutational signature associated with increased spontaneous deamination of 5-methylcytosine. Finally, gene expression analysis revealed enrichment of interferon gamma signaling and decreased PI3K-Akt signaling for STAT3 mutant patients. These findings highlight the clinical and molecular heterogeneity of this rare disorder.
Genetic studies in fruit flies have implicated the chromatin remodeling complex NURF in immunity, but it has yet to be studied in mammals. Here we show that its targeting in mice enhances antitumor immunity in two syngeneic models of cancer. NURF was disabled by silencing of BPTF, the largest and essential subunit of NURF. We found that both CD8+ and CD4+ T cells were necessary for enhanced antitumor activity, with elevated numbers of activated CD8+ T cells observed in BPTF-deficient tumors. Enhanced cytolytic activity was observed for CD8+ T cells cocultured with BPTF silenced cells. Similar effects were not produced with TCR transgenic CD8+ T cells, implicating the involvement of novel antigens. Accordingly, enhanced activity was observed for individual CD8+ T cell clones from mice bearing BPTF silenced tumors. Mechanistic investigations revealed that NURF directly regulated the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2. The PSMB8 inhibitor ONX-0914 reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor antigenicity and its depletion improves antigen processing, CD8 T cell cytotoxicity and antitumor immunity, identifying NURF as a candidate therapeutic target to enhance antitumor immunity.
Medical education is constantly evolving, especially as students were forced to study from home during the coronavirus disease 2019 (COVID-19) pandemic, and new technologies have driven the rapid development of supplemental online educational resources. In this study, we examine if 360° videos can promote increased engagement over standard two-dimensional (2D) videos among medical students learning anatomy. We enrolled 39 fourth-year medical students to watch two four-minute videos of anatomy lab exercises in a 360° three-dimensional format using an immersive headset or in a 2D format on a laptop computer. Every two minutes, students were asked to rate their engagement from 0-100. Following the videos, they reported their degree of agreement with 14 statements related to engagement, practicality, and interest in the technology. While watching the videos, the average engagement reported by the 360° video group was higher at each time point than the engagement reported by the two-dimensional group. Further, the engagement remained high in the 360° group through the six- and eight-minute timepoints. In the post-video survey, the 360° group reported a statistically significantly higher average engagement in seven of eight measures on the assessment. A 360° video was rated as more practical and interesting than a two-dimensional video. No significant difference existed in the perceived ease of learning. Overall, the use of 360° video may improve engagement for short videos used in medical education. However, developing a better understanding of its impact on learning outcomes will be critical for determining the overall value and effectiveness of this tool.
This study investigated contributions to the peer-reviewed library and information science (LIS) journal literature by U.S. academic librarian (USAL) authors over a ten-year period (2003–2012). The results were compared to those of two previous five-year studies that covered the time periods of 1993–1997 and 1998–2002 to examine longitudinal trends. For USAL authors as a group, publication productivity, the proportion of peer-reviewed articles contributed to the LIS literature, and sole-authorship declined. Among USALs who did publish, productivity patterns remained similar over twenty years, with a slight increase in the percentage of USAL authors who published three or more articles in five years. The top twenty high-publication libraries from 2003 to 2012 were from public research universities, unlike two earlier studies that found private university libraries among the top twenty.
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