In yeast and humans, interaction of a nuclear pore protein with promoters alters chromatin structure and allows RNA polymerase II to bind, poising them for faster reactivation for several generations.

Transcription factors IRF3 and NFκB, are activated by external stimuli, including virus infection, to translocate to the nucleus and bind genomic targets important for immunity and inflammation. To investigate RNA polymerase II (Pol II) recruitment and elongation in the human antiviral gene regulatory network, a comprehensive genome-wide analysis was conducted during the initial phase of virus infection. Results reveal extensive integration of IRF3 and NFκB, with Pol II and associated machinery, and implicate new partners for antiviral transcription. Analysis indicates that both de novo polymerase recruitment and stimulated release of paused polymerase work together to control virus-induced gene activation. In addition to known mRNA-encoding loci, IRF3 and NFκB, stimulate transcription at regions not previously associated with antiviral transcription, including abundant unannotated loci that encode novel virus-inducible RNAs (nviRNAs). These nviRNAs are widely induced by virus infections in diverse cell types and represent a previously overlooked cellular response to virus infection.

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e16226 Background: PDA is an aggressive disease with a dismal prognosis. Advances in next-generation sequencing (NGS) have enabled targeted therapies, revolutionizing treatments of several solid tumors. Their role in the management of PDA is limited, in part due to the paucity in our understanding of targetable genomic events. We sought to evaluate genomic differences between PPDA and MPDA in the tumor and tumor immune microenvironment (TIME). The genomic changes after chemotherapy (CTX) administration were also evaluated. Methods: NGS data derived from tumor samples of 150 unique patients was analyzed. Targeted 648 gene DNA sequencing was performed using the Tempus xT and xO assays. Patients were allocated into 2 cohorts: PPDA (n = 75) and MPDA (n = 75), which were overall similar in terms of their demographics. The frequencies of somatic mutations were compared. The immune infiltrate was imputed from RNAseq. Proportions of immune cells (IC), and the tumor mutational burden (TMB) relative to the proportion of IC in the TIME, were also analyzed. Kaplan Meier Survival estimates for most frequent mutations and TMB were calculated. Results: The most frequently mutated genes amongst the 150 study subjects were: KRAS (92.7%), TP53 (76.7%), CDKN2A (45.3%), SMAD4 (31.3%), ATM (12.7%) and ARID1A (10.7%). Patients in the MPDA cohort had a higher rate of mutation in several genes when compared to PPDA, most notably in TP53 (85.3% vs 68.0%, p = 0.010), ARID1A (16.0 vs 5.3%, p = 0.037) CDKN2A (49.3 vs. 41.3%, p = 0.3) and SMAD4 (33.3 vs. 29.3 p = 0.7). We also evaluated if the genetic changes between PPDA and MPDA are associated with alterations in the TMB and differences in the TIME. A higher TMB was seen amongst patients in the MPDA vs PPDA cohort (2.73 vs 1.73 Mut/Mb, p = 0.008). TMB was also significantly increased after CTX (2.22 vs 1.63 Mut/Mb p = 0.049). TMB ≥ 3 was associated with decreased odds of progression free survival ≥ 12 months (OR 0.26 95% CI 0.078-0.822, p = 0.023). Regarding immune infiltrate, the proportion of CD4 and CD8 T cells were higher in the PPDA cohort. Macrophages and NK cells were more prevalent the MPDA cohort. TMB had a positive correlation with the degree of macrophage infiltration in the TIME (Multivariate estimate: 1.70, p value 0.01). Conclusions: PPDA and MPDA are biologically dissimilar entities with genomic disparity. Associated differences were observed in TMB and TIME. There is a differential increase in the spectrum of mutations in MPDA as compared to PPDA, specifically in p53, ARID1A, CDKN2A and SMAD4. The burden of increased mutations in MPDA is associated with an increase in the TMB and tumor associated macrophages. The role of serial NGS in the management of PDA both in early and late disease should be investigated further to identify evolving genomic changes that correlate with outcome.

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Aldehydes P 0170The Role of Imine-Enamine Tautomerism in Effecting Cross-Aldol Condensations. -The tert-alkyl imine (I) of an enolizable aldehyde is coupled with aldehydes (II) in the presence of CoCl2 on Drierite. Since the imine products (III) are highly unstable, they are directly hydrolyzed after spectroscopic identification to the known aldehydes (IV). -(BABLER*, J. H.; ATWOOD, M. C.; FREANEY, J. E.; VISZLAY, A. R.; Tetrahedron Lett. 48 (2007) 43, 7665-7667; Dep. Chem., Loyola Univ., Chicago, IL 60626, USA; Eng.) -Mais 04-052