Reduced cervical cancer incidence and mortality in Canada: national data from 1932 to 2006.

BACKGROUND: High levels of participation in cervical screening are reported in Canada from the 1970's as a result of early uptake of the Pap smear and universal Medicare. Despite recommendations to the contrary, the programs have featured early age of initiation of screening and frequent screening intervals. Other countries have achieved successful outcomes without such features. We analyzed national data to better understand mortality and incidence trends, and their relationships to screening. METHODS: The Canadian Cancer Registry, National Cancer Incidence Reporting System, and the Canadian Vital Statistics Database were used to measure mortality and incidence rates. Cases and deaths from invasive cervical cancer were classified by 5 year age groups at diagnosis and death (15 to 19 years through to 80 to 84 years), year of diagnosis (1972 to 2006), and year of death (1932 to 2006). Probabilities of developing and dying from cervical cancer were calculated for age-specific mortality and incidence. The proportion of women reporting a timely Pap test was estimated for 1978 to 2006. RESULTS: Cervical cancer mortality has declined steadily from a peak of 13.5 to 2.2 per 100,000 (83%,) between 1952 and 2006, and 71% between 1972 and 2006. Incidence of invasive cervical cancer has declined by 58% since 1972. These declines have occurred more among older age groups than younger. Invasive cervical cancer incidence and mortality is less in each successive birth cohort of women. Participation rates in screening are high especially in women under age 50. CONCLUSIONS: Despite increasing risk factors for cervical cancer, both incidence and mortality have declined over time, across age groups, and across birth cohorts. Earlier increasing mortality (1932 - 1950) was likely related to improved classification of cancers and the early subsequent reduction (1950 - 1970) to improved treatment. Recent improvements in incidence and mortality are likely due to high rates of screening. For women under age 30 years there are low rates of disease but lesser improvement related to screening.

The transcriptional activity of Pygopus is enhanced by its interaction with cAMP-response-element-binding protein (CREB)-binding protein.

Pygopus is a core component of the beta-catenin/TCF (T-cell factor) transcriptional activation complex required for the expression of canonical Wnt target genes. Recent evidence suggests that Pygopus could interpret histone methylation associated with target genes and it was shown to be required for histone acetylation. The involvement of a specific acetyltransferase, however, was not determined. In this report, we demonstrate that Pygopus can interact with the HAT (histone acetyltransferase) CBP [CREB (cAMP-responsive-element-binding protein)-binding protein]. The interaction is via the NHD (N-terminal homology domain) of Pygopus, which binds to two regions in the vicinity of the HAT domain of CBP. Transfected and endogenous hPygo2 (human Pygopus2) and CBP proteins co-immunoprecipitate in HEK-293 (human embryonic kidney 293) cells and both proteins co-localize in SW480 colorectal cancer cells. The interaction with CBP also enhances both DNA-tethered and TCF/LEF1 (lymphoid enhancing factor 1)-dependent transcriptional activity of Pygopus. Furthermore, immunoprecipitated Pygopus protein complexes displayed CBP-dependent histone acetyltransferase activity. Our data support a model in which the NHD region of Pygopus is required to augment TCF/beta-catenin-mediated transcriptional activation by a mechanism that includes both transcriptional activation and histone acetylation resulting from the recruitment of the CBP histone acetyltransferase.

Oncogenic activation of the human Pygopus2 promoter by E74-like factor-1.

Pygopus is a component of the T-cell factor/beta-catenin transcriptional complex essential for activation of Wnt target genes and is also required for cell regulation in the absence of Wnt signaling. Human Pygopus2 (hPygo2) is overexpressed in a high proportion of breast and epithelial ovarian malignant tumors and is required for the growth of several cell lines derived from these carcinomas. The mechanisms regulating hPygo2 gene activation, however, are unknown. Here, we have determined cis- and trans-interacting factors responsible for hPygo2 expression in cancer. The minimal region required for a maximal 109-fold activation of the hPygo2 promoter in MCF-7 breast cancer cells is 48 bp upstream of the start of transcription. Within 25 bp of the transcriptional start, there are two overlapping tandem Ets transcription factor-binding sites, which are critical for hPygo2 promoter activity. In vitro DNA pull-down assays and proteomic analyses identified the Ets family members Elk-1 and E74-like factor-1 (Elf-1) as potential hPygo2 promoter binding factors, whereas in vivo chromatin immunoprecipitation assays verified that only Elf-1 specifically bound to the hPygo2 promoter in MCF-7 cells. Modulation of elf-1 in MCF-7 cells by silencing via RNA interference or overexpression caused a corresponding decrease or increase, respectively, in hPygo2 promoter activity. Overexpression of Elf-1 in HeLa cells, in which Elf-1 is expressed at a lower level than in MCF-7 cells, caused a 4-fold increase in endogenous hPygo2 mRNA levels. These results provide new evidence that Elf-1 is involved in transcriptional activation of hPygo2. Like hPygo2, previous studies implicated Elf-1 in breast and ovarian cancer and our present findings suggest that the oncogenic requirement of hPygo2 is fulfilled, in part, by Elf-1.

Antisense suppression of pygopus2 results in growth arrest of epithelial ovarian cancer.

PURPOSE: The Pygopus proteins are critical elements of the canonical Wnt/beta-catenin transcriptional complex. In epithelial ovarian cancer, constitutively active Wnt signaling is restricted to one (endometrioid) tumor subtype. The purpose of this study was to determine the level of expression and growth requirements of human Pygopus2 (hPygo2) protein in epithelial ovarian cancer. EXPERIMENTAL DESIGN: Expression and subcellular localization of hPygo2 was determined in epithelial ovarian cancer cell lines and tumors using Northern blot, immunoblot, and immunofluorescence. Immunohistochemistry was done on 125 archived patient epithelial ovarian cancer tumors representing all epithelial ovarian cancer subtypes. T-cell factor-dependent transcription levels were determined in epithelial ovarian cancer cells using TOPflash/FOPflash in vivo assays. Phosphorothioated antisense oligonucleotides were transfected into cell lines and growth assayed by cell counting, anchorage-independent colony formation on soft agar, and xenografting into severe combined immunodeficient mice. RESULTS: All six epithelial ovarian cancer cell lines and 82% of the patient samples overexpressed nuclear hPygo2 compared with control cells and benign disease. Depletion of hPygo2 by antisense oligonucleotides in both Wnt-active (TOV-112D) and Wnt-inactive serous (OVCAR-3, SKOV-3) and clear cell (TOV-21G) carcinoma cell lines halted growth, assessed using tissue culture, anchorage-independent, and xenograft assays. CONCLUSIONS: hPygo2 is unexpectedly widely expressed in, and required in the absence of, Wnt signaling for malignant growth of epithelial ovarian cancer, the deadliest gynecologic malignancy. These findings strongly suggest that inhibition of hPygo2 may be of therapeutic benefit for treating this disease.

Teaching digital rectal examinations to medical students: an evaluation study of teaching methods.

PURPOSE: The digital rectal examination (DRE) is a necessary part of a complete physical examination and evaluation of a patient, yet teaching of this examination to medical students is often inadequate. This study was a comparative evaluation of the effectiveness of the rectal teaching associate (RTA), lecture, role-playing, and simulated models as methods for teaching the DRE procedure to undergraduate medical students at Memorial University of Newfoundland Faculty of Medicine. METHOD: A total of 65 third-year medical students were randomly assigned to either an experimental or control group. Both groups received a lecture and practiced the DRE on a simulated model. The experimental group received further training from an RTA. Students completed a pre- and post-intervention knowledge assessment, an objective structured clinical exam (OSCE) measuring performance of the DRE, and a satisfaction survey. RESULTS: Mean knowledge scores increased significantly for both groups (18.73 to 22.32, p <.0001). The control group scored significantly higher on the post-intervention assessment than did the experimental group (23.11 versus 21.47, p =.025) The experimental group scored higher on the OSCE (27.52 versus 23.80, p =.001) and rated the RTA as a more effective method for learning the DRE. CONCLUSIONS: This first study using RTAs to teach the DRE as a global skill for evaluating the rectum suggests that the RTA method is effective for increasing skills and students' confidence in the procedure.