Life-long exposure to estrogen is an established risk factor for breast cancer development. The underlying mechanism has been suggested to be the binding of estrogen-to-estrogen receptors in mammary tissue, which in turn promotes the proliferation and differentiation of breast tissue. Polymorphisms and haplotypes in estrogen receptor alpha (ESR1) have been reportedly associated with breast cancer risk; however, the results are not fully consistent. In this study, we investigated breast cancer risk associated with genotypes and haplotypes resulting from four ESR1 single nucleotide polymorphisms (SNPs), rs746432, rs2234693, rs9340799, and rs1801132. Genotyping has been performed on 393 breast cancer cases and 790 randomly selected controls in 1,183 Caucasian women over age 65 from the Study of Osteoporotic Fractures (SOF). We observed an allelic protective effect for SNP rs9340799 with an estimated odds ratio (OR) of 0.82 (95% CI = 0.68-1.00; P = 0.04) after adjustment for age, BMI and hip BMD. A protective effect of this SNP has been reported before in several different studies. We did not replicate the previously reported C-C-A-G haplotype association to breast cancer-the C-C-A-G haplotype from these SNPs was rare in this study (estimated frequency below 0.001% in cases and controls). No other statistically significant associations were observed between ESR1 haplotypes from the same four SNPs and the risk of breast cancer in older Caucasian women.

AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K-mutant (n = 153) and AKT1-wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to defi ne outcomes in a rare genomically defi ned cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17Kmutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.

Objective To evaluate the extent of variability in functional responses among participants in the LIFE study, and to identify the relative contributions of intervention adherence, physical activity, and demographic and health characteristics to this variability. Design Secondary analysis of the Lifestyle Interventions and Independence for Elders (LIFE) study. Setting Multicenter U.S. institutions participating in the LIFE study. Participants A volunteer sample of 1635 sedentary men and women aged 70 to 89 years who were able to walk 400 m, but had physical limitations, defined as a score on the Short Physical Performance Battery (SPPB) of ≤9. Interventions Moderate-intensity physical activity (PA, n=818) consisting of aerobic, resistance and flexibility exercises performed both center-based (twice/wk) and in or around the home environment (3-4 times/wk) or health education (HE, n=817) consisting of weekly to monthly workshops covering relevant health information. Main Outcome Measures Physical function: gait speed over 400-m and lower extremity function (SPPB) assessed at baseline, six, twelve, and 24 months. Results Greater baseline physical function (gait speed and SPPB score) was inversely associated with Δ gait speed (regression coefficient β=−0.185, p<0.001) and ΔSPPB score (β=−0.365, p<0.001), while greater number of steps per day measured by accelerometry was positively associated with Δ gait speed (β=0.035, p<0.001) and Δ SPPB score (β=0.525, p<0.001). Other baseline factors associated with positive Δ gait speed and/or SPPB score include younger age (p<0.001), lower body mass index (p<0.001), and higher self-reported physical activity (p=0.002). Conclusions Several demographic and physical activity-related factors were associated with the extent of Δ functional outcomes among participants in the LIFE study. These factors should be considered when designing interventions for improving physical function among older adults with limited mobility.

Both Icon and control surfaces exhibit stain penetration by different beverages (iced tea, grape juice, and coffee). However, resin-infiltrated enamel surfaces allow significantly less depth of stain penetration compared to untreated surfaces. The iced tea group presents greatest depth of stain penetration, followed by grape juice, methylene blue, and coffee.

Poxviridae is a diverse family of large dsDNA viruses (130 to 300 kb) which replicate exclusively in the cytoplasm of infected cells and exhibit a varied host range (1). Some members are specific to a single host, such as variola virus, the causative agent of smallpox, while others, such as vaccinia virus, display a broad host range. Poxviruses encode a number of immunomodulatory proteins, e.g., host range proteins (2). Orthopoxviruses encode a number of host range genes, such as SPI-1, K1L, C7L, p28/N1R, B5R, K3L, and E3L, the alteration or deletion of which restricts the virus replication in specific cell lines (3). These host range genes display varied restrictions and biological functions. For example, SPI-1 is required for vaccinia virus replication in PK15 and A549 cells and in mice (4, 5). K1L, an ankyrin repeat-containing protein which inhibits IkB-␣ degradation and interferon (IFN)-stimulated effectors, is required for replication in RK13 cells (6). A double deletion of C7L and K1L leads to restriction of the virus replication in PK1, RK13, and multiple human cell lines, while C7L deletion alone suppresses apoptosis and limits replication in hamster Dede cells (7). P28/N1R, an E3-RING finger ubiquitin ligase involved in protein degradation and apoptosis suppression, is required for replication in mouse macrophage (8, 9), while B5R, a membrane glycoprotein, activates Src, allowing growth in VERO, CEF, PK15, and quail (QT-6) cells (10).The most studied vaccinia host range gene is E3L. E3 protein is expressed early in the virus replication cycle and is known to suppress multiple innate immune pathways (3,11,12). E3 protein possesses biochemical capacities to bind Z-form DNA via the Z-DNA binding domain (ZBD) toward the N terminus and to bind to dsRNA through the C-terminal dsRNA binding domain (DRBD) (13,14). Since the best characterized biological functions of vaccinia virus E3 protein, such as host range function and inhibition of innate immune responses (e.g., cytokine expression, apoptosis and interferon-induced antiviral activity), all are mediated primarily via the DRBD region of E3 protein (15-17), generally it has been believed that E3 protein functions through seques-