Citations

Abstract Purpose: The purpose of this study was to describe breast cancer risk factors and screening patterns in a sample of American Indian and Alaska Native (AI/AN) women from four tribes within the Bemidji Area of the Indian Health Service (Northern Plains region), and to ascertain the association between risk factors and adherence to mammographic screening guidelines. The IHS has noted that economic factors make increases in screening participation difficult. In this light, understanding the relationship between risk factors and screening adherence is an important first step in developing interventions to improve screening participation, especially for women at higher risk of breast cancer. Lending importance to the role of screening in reducing breast cancer deaths in Northern Plains AI/AN women are rates of later stage (regional or distant disease) diagnoses that are equal to the Non-Hispanic White (NHW) population (95.8 and 95.4/100,000 respectively). Later stage at diagnosis is associated with worse survival profiles. Procedures/Methods: Criteria for inclusion in this study were: ≥ 40 years of age, at least one mammogram on file, and no history of breast cancer. We reviewed the charts of 20% of eligible women in four tribes (1190 records). The study collected Gail Model risk factor data and also assigned BIRADS scores to at least one mammogram for each woman. For each Gail Model risk factor (age, age at menarche, age at first live birth, number of first degree relatives with a breast cancer history, breast biopsy, number of biopsies, history or atypical hyperplasia), women were assigned to higher or lower risk categories by comparison with calculated scores for women of the same age. Overall five-year and lifetime Gail Model risk scores also were calculated for each woman and compared with predicted risk for women of equivalent ages. For breast density, women were determined to be at lower risk if their BIRADS score was 1 or 2, and at higher risk if they were scored 3 or 4. To ascertain levels of screening adherence, we followed American Cancer Society (ACS) guidelines which recommend an annual mammogram beginning at age 40. We used this standard because it is the recommendation given to women in the clinics where the study was conducted. All women who received screening exams within 1.2 years (14.4 months) were considered adherent. Summary of Findings: There was no significant difference between overall Gail Model 5-year risk scores of Bemidji Area AI/AN women and the predicted scores. Bemidji Area women have a significantly lower lifetime risk than what is predicted. For individual risk factors, high screening adherence was significantly associated only with chronological age (p = 0.04) and history of biopsy (p =0.02). There was no significant association between screening adherence and BIRADS density scores. Conclusions: Absence of a relationship between risk and adherence, which is low generally, suggests that women are not using their individual risk factors or their overall risk to guide their screening decisions. This suggests that personal and clinic-centered mediators should be identified to guide future interventions to increase the proportion of women who adhere to screening guidelines, especially women who are at greater risk. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B106.

Rationale Carotid endarterectomy (CEA) and medical therapy were shown superior to medical therapy alone for symptomatic (ge;50%) and asymptomatic (≥60%) stenosis. Carotid angioplasty stenting (CAS) offers a less invasive alternative. Establishing safety, efficacy, and durability of CAS requires rigorous comparison with CEA in symptomatic and asymptomatic patients. Aims The objective is to compare the efficacy of CAS versus CEA in patients with symptomatic (≥50%) or asymptomatic (≥60%) extracranial carotid stenosis. Design The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) is a prospective, randomized, parallel, two-arm, multi-center trial with blinded endpoint adjudication. Primary endpoints are analyzed using standard time-to-event statistical modeling with adjustment for major baseline covariates. Primary analysis is on an intent-to-treat basis. Study Outcomes The primary outcome is the occurrence of any stroke, myocardial infarction, or death during a 30-day peri-procedural period, and ipsilateral stroke during follow-up of up to four years. Secondary outcomes include restenosis and health-related quality of life.

Abstract IGF-I and their binding proteins are important in bone health. Examination of BMD, osteoblast proliferation, and markers of bone resorption in transgenic mice that constitutively overexpress IGFBP-3 indicates that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation. Introduction: Low serum insulin-like growth factor I (IGF-I) levels correlate with an increased risk of osteoporotic fractures. Serum IGF-I is largely bound to IGF-binding protein-3 (IGFBP-3), which can inhibit IGF-I action and enhance delivery of IGF-I to tissues. Its role in bone biology is unclear. Methods: Bone mineral density (BMD), osteoblast proliferation, and markers of bone resorption were examined in transgenic (Tg) mice that constitutively overexpressed human IGFBP-3 cDNA driven by either the cytomegalovirus (CMV) or phosphoglycerate kinase (PGK) promoter. Results: Cultured calvarial osteoblasts from Tg mice expressed the transgene and grew more slowly than cells from wild-type (Wt) mice, and the mitogenic response to IGF-I was attenuated in osteoblasts from Tg mice. Total volumetric BMD and cortical BMD, measured in the femur using peripheral quantitative computed tomography (pQCT) were significantly reduced in both Tg mouse strains compared with Wt mice. PGKBP-3 Tg mice showed the most marked reduction in bone density. Osteocalcin levels were similar in Wt and CMVBP-3 Tg mice but were significantly reduced in PGKBP-3 Tg mice. Urinary deoxypyridinoline and osteoclast perimeter, markers of bone resorption, were significantly increased in both Tg mouse strains compared with Wt mice. Using double labeling with tetracycline, we demonstrated that pericortical and endocortical mineral apposition rate was significantly reduced in PGKBP-3 Tg mice compared with Wt mice. Conclusions: These data show that overexpression of IGFBP-3 increases osteoclast number and bone resorption, impairs osteoblast proliferation, and has a significant negative effect on bone formation.

Two substrates of insulin-degrading enzyme (IDE), amyloid β-protein (Aβ) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Aβ levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Aβ and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE −/−). IDE deficiency resulted in a >50% decrease in Aβ degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE −/− mice showed increased cerebral accumulation of endogenous Aβ, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the β-amyloid precursor protein, which was recently found to be degraded by IDE in vitro . Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.