H2dl808 is a deletion mutant of adenovirus type 2 lacking most of transcriptional early region E4. In most normal adenovirus host cells this virus displayed a complex mutant phenotype that included a dramatic reduction in the level of cytoplasmic late RNA, a corresponding defect in late protein synthesis, and a 5-to 10-fold defect in viral DNA accumulation. H5dl1004 is a deletion mutant of adenovirus type 5 that also lacks a portion of E4. It exhibited a reduction in levels of cytoplasmic late RNAs that was somewhat less severe than that of H2dl808 and a corresponding late protein synthetic defect but no defect in the production of viral DNA. In addition to the defect in the accumulation of late cytoplasmic mRNAs, HeLa cells infected by either H2dl808 or H5dl1004 showed substantially reduced levels of viral RNAs in their nuclei at late times after infection. Both mature mRNAs and apparent mRNA precursors were affected. The late transcription rates of the deletion mutant viruses were similar to that of wild-type virus. These results suggest that the underaccumulation of RNA in H2d1808-and 115d11004-infected cells is caused by a reduction in the stability of viral RNA in the nucleus, and they implicate E4 products in a novel aspect of the regulation of viral gene expression.
The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation–arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field.
Bovine papiliomavirus type 1 (BPV-1) is the prototype virus for the study of papillomavirus gene regulation. The functions of the BPV-1 E2 proteins in transcriptional regulation have been well characterized. The BPV-1 El protein is required for viral DNA replication and can bind to the origin of replication alone or in a complex with the E2 transactivator protein. In this study, we demonstrated that the BPV-1 El protein is also involved in transcriptional regulation. The El protein significantly repressed E2-transactivated transcription from the major early promoter P89. This activity is consistent with the elevated level of P89 transcription observed in BPV-1 El open reading frame mutants. Transcriptional repression by El correlated with the ability of an El-E2 protein complex to bind the replication origin but was not dependent on viral DNA replication. These studies identify a new mechanism involved in the regulation of papillomavirus transcription which has implications regarding expression of the viral transforming functions.
CRA6509 Background: Post-activation barriers to oncology clinical trial accruals are well documented; however, potential barriers prior to trial opening are not. We investigate one such barrier: trial development time. Methods: National Cancer Institute Cancer Therapy Evaluation Program (NCI-CTEP) sponsored trials for all therapeutic, non-pediatric phase I,I/II, II, and III studies activated in an eight year period (2000–2007) were investigated (n=553). Successful trials were those achieving 100% of minimum accrual goal. Time to open a study was the calendar time from initial CTEP submission to trialactivation. Multivariable logistic regression analysis was used tocalculate unadjusted and adjusted odds ratios, controlling for study phase and size of expected accruals. Results: 40.0 percent (n=221) of CTEP-approved oncology trials failed to achieve minimum accrual goals, with 49.2 percent (n=30) of phase III trials failing to achieve at least 25 percent of accrual goals. A total of 8,723 patients (17.0% of accruals) accrued to those studies that were unable to achieve the projected minimum accrual goal. Trials requiring 9–12 months development were significantly more likely to achieve accrual goals (odds ratio, 1.94; 95% CI, 1.06 to 3.52, P=0.031) than trials requiring the median time (15–18 months); trials that exceeded 27 months of development time were significantly less likely of achieving accrual goals (odds ratio, 0.14; 95% CI, 0.04 to 0.54, P=0.004). Conclusions: A large percentage of oncology clinical trials do not achieve minimum projected accruals. Trial development time appears to be one important predictor of the likelihood of successfully achieving the minimum accrual goals. [Table: see text] No significant financial relationships to disclose.
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