The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing ...guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This study aimed to establish the frequency of PVs and remaining risks of breast cancer for each gene in women over age 65 years.
A total of 26,707 women over age 65 years from population-based studies (51.5% with breast cancer and 48.5% unaffected) were tested for PVs in germline predisposition gene. Frequencies of PVs and associations between PVs in each gene and breast cancer were assessed, and remaining lifetime breast cancer risks were estimated for non-Hispanic White women with PVs.
The frequency of PVs in predisposition genes was 3.18% for women with breast cancer and 1.48% for unaffected women over age 65 years. PVs in
,
, and
were found in 3.42% of women diagnosed with estrogen receptor (ER)-negative, 1.0% with ER-positive, and 3.01% with triple-negative breast cancer. Frequencies of PVs were lower among women with no first-degree relatives with breast cancer. PVs in
,
,
, and
were associated with increased risks (odds ratio = 2.9-4.0) of breast cancer. Remaining lifetime risks of breast cancer were ≥ 15% for those with PVs in
,
, and
.
This study suggests that all women diagnosed with triple-negative breast cancer or ER-negative breast cancer should receive genetic testing and that women over age 65 years with
and
PVs and perhaps with
and
PVs should be considered for magnetic resonance imaging screening.
Abstract only Background: Being physically active has been associated with lower risks of cardiometabolic diseases. However, the biological mechanisms underlying these associations remain unclear, ...and can be investigated using a metabolomics approach. Objective: To identify plasma metabolites associated with habitual physical activity in a U.S. population. Methods: Our study population included 4119 participants in the Nurses’ Health Study (NHS), NHS II, and Health Professionals Follow-up Study (HPFS). Physical activity was assessed periodically by self-reported questionnaire starting from 1984 in NHS, 1989 in NHSII, and 1986 in HPFS. We used physical activity measured closest before blood collection as exposure. Metabolic profiling was conducted by liquid chromatography-mass spectrometry (LC-MS). Our study included 287 known metabolites, with 64% of them classified as lipids (58 triglycerides TAGs, 13 diglycerides DAGs, 13 cholesteryl esters CEs, 6 lysophosphatidylethanolamines LPEs, 37 phosphocholines PCs, 10 lysophosphatidylcholines LPCs, 24 phosphatidylethanolamines PEs, and 25 carnitines). We examined associations of physical activity with plasma metabolites using linear regression, and corrected for multiple testing using tail probability of the proportion of false positives (TPPFP) and accounting for correlated tests using bootstrapping. Results: Using linear model adjusting for age, case-control status, labcode, smoking status, fasting status, alcohol intake, and diet quality, physical activity was significantly associated with 27 metabolites after correcting for multiple testing (TPPFP <0.05). Among the 27 identified metabolites, four CEs, eight PCs, and three LPCs were positively associated with physical activity, and five TAGs and four DAGs were inversely associated. After additionally adjusting for body mass index (BMI), the associations of physical activity with the majority of identified metabolites were attenuated; physical activity remained positively associated with three CEs (C18:2, C16:0, and C18:1), three PCs (C36:4 PC-A, C36:0 PC, C34:3 PC plasmalogen), and one LPC (C18:2). Enrichment analysis showed that physical activity was significantly positively associated with the CE category (P value for enrichment=0.048). Conclusions: We identified seven metabolites that were significantly associated with physical activity after adjusting for BMI, which may help identify biomarkers of physical activity and provide insight into biological mechanisms underlying the beneficial effect of being physically active on cardiometabolic health.
In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European ...descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10−8) and rs11057830 on 12q24.31 (P= 2.0 × 10−8) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10−10). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10−12 (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10−10 (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10−9 (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), no SNPs were significantly associated with gamma-tocopherol concentrations after including data from the replication sample for 71 independent SNPs with P< 1 × 10−4 identified.
The earliest ostracods from the Bohemian Massif (Central European Variscides) have been recorded from the Middle Ordovician of the Prague Basin (Barrandian area), in the upper Klabava Formation, and ...became an abundant component of fossil assemblages in the overlying Šarka Formation. Both early ostracod associations consist of eight species in total, representing mainly eridostracans, palaeocopids, and binodicopids. The revision, description, or redescription of all species and their distribution in the basin is provided. Their diversification patterns and palaeogeographical relationships to ostracod assemblages from other regions are discussed.
Admixture mapping has led to the discovery of many genes associated with differential disease risk by ancestry, highlighting the importance of ancestry-based approaches to association studies. ...However, the potential of admixture mapping in deciphering the interplay between genes and environment exposures has been seldom explored. Here we performed a genome-wide screening of local ancestry-smoking interactions for five spirometric lung function phenotypes in 3300 African Americans from the COPDGene study. To account for population structure and outcome heterogeneity across exposure groups, we developed a multi-component linear mixed model for mapping gene-environment interactions and empirically showed its robustness and increased power. When applied to the COPDGene study, our approach identified two 11p15.2-3 and 2q37 loci, exhibiting local ancestry-smoking interactions at genome-wide significant level, which would have been missed by standard single-nucleotide polymorphism analyses. These two loci harbor the PARVA and RAB17 genes previously recognized to be involved in smoking behavior. Overall, our study provides the first evidence for potential synergistic effects between African ancestry and smoking on pulmonary function, and underlines the importance of ethnic diversity in genetic studies.
Key Takeaways
At ACE19, AWWA's Asset Management Subcommittee led a session on operational asset management titled the “Gamification of Asset Management.”
Participants discussed the different stages ...of maturity utilities face in developing their programs and how using sports terminology can help utilities form a better game plan and team‐centered approach.
A challenging aspect of asset management is ensuring there is on‐the‐ground acceptance, interdepartmental coordination, and good data that can measure results.
Luminescent cadmium phthalate coordination polymers with 4-pyridylnicotinamide (4-pna) or 3-pyridylisonicotinamide (3-pina) show very similar tetramer-based Cd4(phthalate)4(H2O)2n ribbon motifs but ...different dimensionality and topology. {Cd2(phth)2(4-pna)(H2O)·0.25H2O}n shows 4-connected 2-D (4,4) layers while Cd2(phth)2(3-pina)(H2O)n (2) has a 6-connected 3-D 41263pcu network. Display omitted
•Cadmium phthalate coordination polymers with isomeric dipyridylamide coligands.•Cd4(phthalate)4(H2O)2 ribbons based on tetranuclear clusters in both cases.•With 4-pyridylnicotinamide ligands, 2D grid topology observed.•With 3-pyridylisonicotinamide ligands, 3D primitive cubic topology observed.•Luminescent and thermal properties reported.
Hydrothermal reaction of cadmium nitrate, potassium hydrogen phthalate (KHphth), and either 4-pyridylnicotinamide (4-pna) or 3-pyridylisonicotinamide (3-pina) afforded two new luminescent coordination polymers with similar structural components but different dimensionality. {Cd2(phth)2(4-pna)(H2O)·0.25H2O}n (1, phth=phthalate) manifests Cd4(phth)4(H2O)2 ribbons based on tetranuclear clusters, connected to two others by pairs of tethering 4-pna ligands to afford 4-connected 2D (4,4) layers. Cd2(phth)2(3-pina)(H2O)n (2) has similar tetranuclear clusters and Cd4(phth)4(H2O)2 ribbons, which are linked to four others by 3-pina tethers to construct a 6-connected 3D 41263pcu network. Subtle differences in phth binding and bridging mode, along with changes in coordination environment, serve to influence the dimensionality of the resulting coordination polymer. Thermal decomposition behavior is also discussed.
Circulating adiponectin and leptin have been associated with risk of pancreatic cancer. However, the relationship between long-term exposure to these adipokines in the prediagnostic period with ...patient survival has not been investigated.
Adipokine levels were measured in prospectively collected samples from 472 patients with pancreatic cancer. Because of sex-specific differences in adipokine levels, associations were evaluated separately for men and women. In a subset of 415 patients, we genotyped 23 SNPs in adiponectin receptor genes (ADIPOR1 and ADIPOR2) and 30 SNPs in the leptin receptor gene (LEPR).
Adiponectin levels were inversely associated with survival in women HR, 1.71; 95% confidence interval (CI), 1.15-2.54; comparing top with bottom quartile but not in men (HR, 0.89; 95% CI, 0.46-1.70). The SNPs rs10753929 and rs1418445 in ADIPOR1 were associated with survival in the combined population (per minor allele HR, 0.66; 95% CI, 0.51-0.84, and HR, 1.33; 95% CI, 1.12-1.58, respectively). Among SNPs in LEPR, rs12025906, rs3790431, and rs17127601 were associated with survival in the combined population HRs, 1.54 (95% CI, 1.25-1.90), 0.72 (95% CI, 0.59-0.88), and 0.70 (95% CI, 0.56-0.89), respectively, whereas rs11585329 was associated with survival in men only (HR, 0.39; 95% CI, 0.23-0.66; Pinteraction = 0.0002).
High levels of adiponectin in the prediagnostic period were associated with shorter survival among women, but not among men with pancreatic cancer. Several polymorphisms in ADIPOR1 and LEPR are associated with patient survival.
Our findings reveal the association between adipokine signaling and pancreatic cancer survival and demonstrate the importance of examining obesity-associated pathways in relation to pancreatic cancer in a sex-specific manner.
Endogenous hormones are risk factors for postmenopausal breast cancer, and their measurement may improve our ability to identify high-risk women. Therefore, we evaluated whether inclusion of plasma ...estradiol, estrone, estrone sulfate, testosterone, dehydroepiandrosterone sulfate, prolactin, and sex hormone-binding globulin (SHBG) improved risk prediction for postmenopausal invasive breast cancer (n = 437 patient cases and n = 775 controls not using postmenopausal hormones) in the Nurses' Health Study.
We evaluated improvement in the area under the curve (AUC) for 5-year risk of invasive breast cancer by adding each hormone to the Gail and Rosner-Colditz risk scores. We used stepwise regression to identify the subset of hormones most associated with risk and assessed AUC improvement; we used 10-fold cross validation to assess model overfitting.
Each hormone was associated with breast cancer risk (odds ratio doubling, 0.82 SHBG to 1.37 estrone sulfate). Individual hormones improved the AUC by 1.3 to 5.2 units relative to the Gail score and 0.3 to 2.9 for the Rosner-Colditz score. Estrone sulfate, testosterone, and prolactin were selected by stepwise regression and increased the AUC by 5.9 units (P = .003) for the Gail score and 3.4 (P = .04) for the Rosner-Colditz score. In cross validation, the average AUC change across the validation data sets was 6.0 (P = .002) and 3.0 units (P = .03), respectively. Similar results were observed for estrogen receptor-positive disease (selected hormones: estrone sulfate, testosterone, prolactin, and SHBG; change in AUC, 8.8 P < .001 for Gail score and 5.8 P = .004 for Rosner-Colditz score).
Our results support that endogenous hormones improve risk prediction for invasive breast cancer and could help identify women who may benefit from chemoprevention or more screening.
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