Genome-wide association analysis identifies three new breast cancer susceptibility loci

Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ～8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ～70,000 cases and ～68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.     

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.     

Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with complex etiology but strong clustering in families (lambda(S) = approximately 30). We performed a genome-wide association scan using 317,501 SNPs in 720 women of European ancestry with SLE and in 2,337 controls, and we genotyped consistently associated SNPs in two additional independent sample sets totaling 1,846 affected women and 1,825 controls. Aside from the expected strong association between SLE and the HLA region on chromosome 6p21 and the previously confirmed non-HLA locus IRF5 on chromosome 7q32, we found evidence of association with replication (1.1 x 10(-7) < P(overall) < 1.6 x 10(-23); odds ratio = 0.82-1.62) in four regions: 16p11.2 (ITGAM), 11p15.5 (KIAA1542), 3p14.3 (PXK) and 1q25.1 (rs10798269). We also found evidence for association (P < 1 x 10(-5)) at FCGR2A, PTPN22 and STAT4, regions previously associated with SLE and other autoimmune diseases, as well as at > or =9 other loci (P < 2 x 10(-7)). Our results show that numerous genes, some with known immune-related functions, predispose to SLE.     

NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer

NQO1 guards against oxidative stress and carcinogenesis and stabilizes p53. We find that a homozygous common missense variant (NQO1(*)2, rs1800566(T), NM_000903.2:c.558C>T) that disables NQO1 strongly predicts poor survival among two independent series of women with breast cancer (P = 0.002, N = 1,005; P = 0.005, N = 1,162), an effect particularly evident after anthracycline-based adjuvant chemotherapy with epirubicin (P = 7.52 x 10(-6)) and in p53-aberrant tumors (P = 6.15 x 10(-5)). Survival after metastasis was reduced among NQO1(*)2 homozygotes, further implicating NQO1 deficiency in cancer progression and treatment resistance. Consistently, response to epirubicin was impaired in NQO1(*)2-homozygous breast carcinoma cells in vitro, reflecting both p53-linked and p53-independent roles of NQO1. We propose a model of defective anthracycline response in NQO1-deficient breast tumors, along with increased genomic instability promoted by elevated reactive oxygen species (ROS), and suggest that the NQO1 genotype is a prognostic and predictive marker for breast cancer.     

机器人辅助柔性针穿刺路径的悬臂梁预测模型

路径操控技术是机器人辅助柔性针穿刺的重要技术之一。软组织变形、多层软组织相对滑移和针挠曲是引起靶点位置移动,降低穿刺精度的3个主要原因。该文在研究针受力的基础上,利用柔性针挠曲规律提出了一种预测穿刺路径的悬臂梁模型,通过准静态过程将柔性针分为有限段并将每段都视为一个悬臂梁,从而建立起三维空间中针体路径预测算法。仿真实验表明,该模型能够实现柔性针路径预测功能,为机器人辅助柔性针穿刺路径规划和避障运动提供了理论基础。     

Science and the romantic movement

Several authors have used the expression ‘formal asymmetry’ to characterize Einstein's method of introducing conceptual innovations. Prior to his use of formal asymmetries, however, Einstein relied upon analogy to introduce his major concepts, but without satisfactory results. He gradually refined another technique, reflection upon empirical problems, into the method of formal asymmetries, with impressive results. This historical study, based upon a textual analysis of Einstein's publications, raises a series of questions regarding the place of formal asymmetries in his work.     

Large mixed-species dispersal flights for predatory and scavenging aquatic Heteroptera and Coleoptera, northern Arizona, USA

We report 4 incidents of large (hundreds to hundreds of thousands of individuals) mixed-species flights of predatory and scavenging aquatic Heteroptera and Coleoptera. The events occurred on normal (mostly clear, calm) autumn 2005 and spring 2006 late afternoons near Flagstaff, Arizona. Flight days were either near the full moon or in advanced waning lunar periods. At least 18 species were involved in the flights, with as many as 16 species (7 species of Heteroptera in 3 families, 9 species of Coleoptera in 2 families) in a single flight. Heteroptera (especially from the family Corixidae) were 2–4 orders of magnitude more numerous than Coleoptera. The diasporas plummeted, with much direct mortality, onto green metal roofs, and the largest event lasted more than 2 hours. Even after 2 days, uninjured individuals failed to resume their flights. The literature suggests that such flights occur for autumn movement to winter habitats or for location of springtime habitats for reproduction. The relative proportions of species in flocks were similar neither to the relative proportions in the region nor to those in nearby livestock watering tanks, indicating that the flights consisted of nonrandom assemblages of species. These events are rare or unique observations of coordinated movement of mixed predatory and scavenging invertebrate species.     

The directionality of distinctively mathematical explanations

In “What Makes a Scientific Explanation Distinctively Mathematical?” (2013b), Lange uses several compelling examples to argue that certain explanations for natural phenomena appeal primarily to mathematical, rather than natural, facts. In such explanations, the core explanatory facts are modally stronger than facts about causation, regularity, and other natural relations. We show that Lange's account of distinctively mathematical explanation is flawed in that it fails to account for the implicit directionality in each of his examples. This inadequacy is remediable in each case by appeal to ontic facts that account for why the explanation is acceptable in one direction and unacceptable in the other direction. The mathematics involved in these examples cannot play this crucial normative role. While Lange's examples fail to demonstrate the existence of distinctively mathematical explanations, they help to emphasize that many superficially natural scientific explanations rely for their explanatory force on relations of stronger-than-natural necessity. These are not opposing kinds of scientific explanations; they are different aspects of scientific explanation.