PubMed · 9710699
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J Nottingham. 1998. Cervical screening standards.. https://doi.org/10.1046/j.1365-2303.1998.00002.x
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MYC amplification contributes to poor survival and outcome in pancreatic ductal adenocarcinoma (PDAC). Here we show that in PDAC cell lines with amplified MYC, MondoA is required for viability, facilitating proliferation while suppressing apoptosis in vitro and in vivo. Transcriptional and genomic profiling demonstrates that loss of MondoA leads to altered expression of direct MondoA targets as well as MYC target genes and is accompanied by shifts in genomic occupancy of MYC, MNT, and the MondoA paralog ChREBP. This altered genomic binding by MYC network members is associated with transcriptional perturbation of multiple metabolic and stress pathways, as well as global changes in N6-methyladenosine modification (m6A) of mRNA. MondoA inhibition disrupts coordination between MYC network members and the Integrated Stress Response (ISR), resulting in decreased translation of ATF4 mRNA, discordant gene regulation of shared targets of MYC and ATF4 and, ultimately, apoptosis. Re-establishing ATF4 protein expression rescues the diminished viability due to loss of MondoA expression or activity, providing direct evidence of a link between deregulated MYC and the transcriptional machinery of the ISR. Lastly, we find that small-molecule inhibition of MondoA is lethal in a subset of PDAC cell lines, including patient-derived organoids, suggesting that the ability to target MYC via chemical inhibition of MondoA transcriptional activity may have broad efficacy.
In 1853, the British physiologist Thomas Henry Huxley roundly criticized German cell theory. Historians have had difficulty explaining how such a 'progressive' biologist could have rejected cellular autonomy and the central role of the nucleus in cell life. The key to Huxley's thinking is provided by understanding his 'epigenetic' philosophy of biology.
Follow-up of Papanicolaou (Pap) tests diagnosed as atypical squamous cells of undetermined significance (ASCUS) or atypical glandular cells of undetermined significance (AGUS) by a cytotechnologist and downgraded to benign by a pathologist has not been measured. Squamous intraepithelial lesion (SIL) follow-up rates were obtained for Pap tests diagnosed as ASCUS (288) or AGUS (94) and downgraded to benign and for Pap tests diagnosed as repair (231). Statistically significant associations were seen between 7 cytotechnologists and between 7 pathologists and ASCUS, AGUS, downgraded ASCUS, and downgraded AGUS rates. The percentage of downgraded ASCUS cases compared with all ASCUS cases per pathologist ranged from 4.8% to 43.7%. Statistically significant associations between pathologists and SIL follow-up rates for downgraded ASCUS diagnoses were seen. The SIL follow-up rate for repair (7.9%) was similar to that for a downgraded ASCUS (11.0%) or AGUS (7.3%). The parameters of downgraded ASCU and AGUS Pap test interpretations are good quality indicators of individual performance and overall laboratory quality.