Regulation of Ligand and Shear Stress-induced Insulin-like Growth Factor 1 (IGF1) Signaling by the Integrin Pathway.

Mechanical loading of the skeleton, as achieved during daily movement and exercise, preserves bone mass and stimulates bone formation, whereas skeletal unloading from prolonged immobilization leads to bone loss. A functional interplay between the insulin-like growth factor 1 receptor (IGF1R), a major player in skeletal development, and integrins, mechanosensors, is thought to regulate the anabolic response of osteogenic cells to mechanical load. The mechanistic basis for this cross-talk is unclear. Here we report that integrin signaling regulates activation of IGF1R and downstream targets in response to both IGF1 and a mechanical stimulus. In addition, integrins potentiate responsiveness of IGF1R to IGF1 and mechanical forces. We demonstrate that integrin-associated kinases, Rous sarcoma oncogene (SRC) and focal adhesion kinase (FAK), display distinct actions on IGF1 signaling; FAK regulates IGF1R activation and its downstream effectors, AKT and ERK, whereas SRC controls signaling downstream of IGF1R. These findings linked to our observation that IGF1 assembles the formation of a heterocomplex between IGF1R and integrin ß3 subunit indicate that the regulation of IGF1 signaling by integrins proceeds by direct receptor-receptor interaction as a possible means to translate biomechanical forces into osteoanabolic signals.

Screening History in 313 Cases of Invasive Cancer: A Retrospective Review of Cervical Cancer Screening in Alberta, Canada.

OBJECTIVE: To examine the screening history of invasive cervical cancer (ICC) cases in Alberta, Canada to identify areas for improvement of the population-based cervical cancer screening program. METHODS: Retrospective review of ICC cases diagnosed in 2 cities in Alberta between 2007 and 2012. Cancer morphology and staging were elicited from the Alberta Cancer Registry; cancer screening history and Pap test results were extracted from the Provincial Cervical Cancer Screening database. Women were classified as adequately screened, underscreened, and unscreened depending on time from last screening Pap test to diagnosis. RESULTS: Of the 280 cases that occurred in women eligible for screening, 125 (44.6%) were adequately screened, 18 (6.4%) were underscreened, and 137 (49%) were unscreened. Among the adequately screened, 71 (56.8%) had normal Pap test results, but 48 (38%) had less than 3 previous Pap tests (p = .003). Cancer stages I to II were diagnosed in 48.8% and 44.1% of adequately screened and unscreened women and cancer stages III to IV in 30.6% and 66.1% in each group, respectively (p = .0058). Squamous cell carcinoma (SCC) was diagnosed in 189 women (67.5%). The proportion of SCCs was similar in adequately screened and unscreened women. CONCLUSIONS: The proportion of SCCs and advanced stages of ICC seems to be decreased. The results of quality improvement initiatives such as enhanced surveillance of high-grade Pap test results and histology-cytology correlation will be monitored and are expected to result in better outcomes for adequately screened women.

Effect of human papillomavirus vaccination on cervical cancer screening in Alberta.

BACKGROUND: A school-based program with quadrivalent human papillomavirus (HPV) vaccination was implemented in Alberta in 2008. We assessed the impact of this program on Pap test cytology results using databases of province-wide vaccination and cervical cancer screening. METHODS: We conducted a nested case-control study involving a cohort of women in Alberta born between 1994 and 1997 who had at least 1 Pap test between 2012 and 2015. Women with negative cytology results were controls. Women with low-grade (atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion) and high-grade (atypical squamous cells, cannot rule out a high-grade lesion; or high-grade squamous intraepithelial lesion) cervical abnormalities were cases. Exposure status was assigned according to records of HPV vaccination. Odds ratios (ORs) for abnormal cytology results by vaccination status were adjusted for neighbourhood income, laboratory service, rural versus urban residency, and age. RESULTS: The total study population was 10 204. Adjusting for age, vaccinated women had a higher screening rate than unvaccinated women (13.0% v. 11.4%, p < 0.001). Among women who received full vaccination (≥ 3 doses), the adjusted OR for cervical abnormalities was 0.72 (95% confidence interval [CI] 0.63-0.82). For high-grade lesions, the adjusted OR was 0.50 (95% CI 0.30-0.85). With 2-dose HPV vaccination, the adjusted OR for cervical abnormalities was 1.08 (95% CI 0.84-1.38). INTERPRETATION: Quadrivalent HPV vaccination significantly reduced high-grade cervical abnormalities but required 3 doses. Vaccination against HPV was associated with screening uptake. Population-based vaccination and screening programs should work together to optimize cervical cancer prevention.

Impact of switching from digital mammography to tomosynthesis plus digital mammography on breast cancer screening in Alberta, Canada.

OBJECTIVES: To compare abnormal call rates (ACR), cancer detection rates (CDR), positive predictive values (PPVs), and annual return to screen recommendations after switching from digital mammography (DM) to digital breast tomosynthesis plus DM (DBT + DM) for breast cancer screening. SETTING: The Alberta Breast Cancer Screening Program collects screening data from clinics throughout the province of Alberta, Canada. METHODS: This study retrospectively collected data, between 2015 and 2018, on women aged 40+ who underwent breast cancer screening at two large volume multisite radiology groups to compare metrics one year prior and one year after DBT + DM implementation. Comparisons between modalities were carried out within age groups, within breast density categories, and for initial vs. subsequent screens. RESULTS: A total of 125,432 DM and 128,912 DBT + DM screening exams were performed. For women aged 50-74, the DBT + DM group had a higher ACR (p < 0.01) but lower annual return to screens (p < 0.01). CDR was higher post-DBT + DM implementation for women with scattered (6.0 per 1000 vs. 4.4 per 1000; p = 0.001) or heterogeneously dense breasts (6.5 per 1000 vs. 4.2 per 1000; p < 0.001). PPV was higher with DBT + DM for all age groups, with women 50-74 having a PPV of 8.3% using DBT + DM vs. 7.1% with DM (p = 0.009). CONCLUSION: All metrics improved or stayed the same after switching to DBT + DM except for ACR. However, the increase in ACR could be attributed to a trend already occurring prior to the switch. Longer term monitoring is needed to confirm these findings.