Cellular factor YY1 downregulates the human papillomavirus 16 E6/E7 promoter, P97, in vivo and in vitro from a negative element overlapping the transcription-initiation site.

Cellular factors that bind to cis sequences in the human papillomavirus 16 (HPV-16) upstream regulatory region (URR) positively and negatively regulate the viral E6 and E7 oncogene promoter, P97. DNase I footprinting has revealed the binding of cellular proteins to two previously undetected cis elements overlapping and 3' of the transcription-initiation site of the P97 promoter. Mutations within homologous motifs found in both of these cis elements abolished their negative function in vivo and the binding of the same cellular complex in vitro. This factor was identified as YY1 by complex mobility and binding specificity in comparison with vaccinia virus-expressed, purified recombinant YY1 protein and by antigenic reactivity with YY1 antisera. Cis mutations in the 'initiator' YY1 site activated the P97 promoter in vivo and in vitro. P97 was also activated threefold in vitro by depletion of endogenous YY1 with wild-type, but not mutant, YY1 oligonucleotides from the IgH kappa E3' enhancer. Furthermore, increasing concentrations of exogenous, purified recombinant YY1 repressed wild-type P97 transcript levels by up to threefold, but did not influence the P97 promoter mutated in the 'initiator' YY1 site. Thus, the promoter-proximal YY1 site was not necessary for correct transcription initiation at the P97 promoter, but was found to be required for downregulation of P97 transcription in vivo and in vitro. In contrast to other viral and cellular promoters, where YY1 is thought to function as a positive transcription-'initiator' factor, HPV-16 P97 transcription is downregulated by YY1 from a critical motif overlapping the transcription start site.

The continuing problem of missed test results in an integrated health system with an advanced electronic medical record.

BACKGROUND: Missed results can cause needless treatment delays. However, there is little data about the magnitude of this problem and the systems that clinics use to manage test results. METHODS: Surveys about potential problems related to test results management were developed and administered to clinical staff in a regional Veterans Administration (VA) health care network. The provider survey, conducted four times between May 2005 and October 2006, sampling VA staff physicians, physician assistants, nurse practitioners, and internal medicine trainees, asked questions about the frequency of missed results and diagnosis or treatment delays seen in the antecedent two weeks in their clinics, or if a trainee, the antecedent month. RESULTS: Clinical staff survey response rate was 39% (143 of 370), with 40% using standard operating procedures to manage test results. Forty-four percent routinely reported all results to patients. The provider survey response rate was 50% (441 of 884) overall, with responses often (37% overall; range 29% to 46%) indicating they had seen patients with diagnosis or treatment delays attributed to a missed result; 15% reported two or more such encounters. DISCUSSION: Even in an integrated health system with an advanced electronic medical record, missed test results and associated diagnosis or treatment delays are common. Additional study and measures of missed results and associated treatment delays are needed.