Abstract
Background
In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the ...development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.
Methods
We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.
Results
All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 × 10–4, 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 × 10–4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 × 10–19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 × 10–6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor ER-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.
Conclusions
We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
Telomeres are functionally distinct from ends generated by chromosome breakage, in that telomeres, unlike double-strand breaks, are insulated from recombination with other chromosomal termini 1. We ...report that the Ku heterodimer and the Rad50/Mre11/Xrs2 complex, both of which are required for repair of double-strand breaks 2–5, have separate roles in normal telomere maintenance in yeast. Using epistasis analysis, we show that the Ku end-binding complex defined a third telomere-associated activity, required in parallel with telomerase 6 and Cdc13, a protein binding the single-strand portion of telomere DNA 7,8. Furthermore, loss of Ku function altered the expression of telomere-located genes, indicative of a disruption of telomeric chromatin. These data suggest that the Ku complex and the Cdc13 protein function as terminus-binding factors, contributing distinct roles in chromosome end protection. In contrast, MRE11 and RAD50 were required for the telomerase-mediated pathway, rather than for telomeric end protection; we propose that this complex functions to prepare DNA ends for telomerase to replicate. These results suggest that as a part of normal telomere maintenance, telomeres are identified as double-strand breaks, with additional mechanisms required to prevent telomere recombination. Ku, Cdc13 and telomerase define three epistasis groups required in parallel for telomere maintenance.
Data are limited with regard to the relations of low-grade albuminuria (below the microalbuminuria threshold) and incidence of cardiovascular disease (CVD) events in nondiabetic, nonhypertensive ...individuals.
We examined the association of urinary albumin excretion (spot urine albumin indexed to creatinine UACR) and the incidence of CVD events and all-cause mortality in 1568 nonhypertensive, nondiabetic Framingham Offspring Study participants (mean age, 55 years; 58% women) free of CVD. On follow-up (median, 6 years), 54 participants (20 women) developed a first CVD event, and 49 (19 women) died. After adjustment for established risk factors, increasing UACR was associated with greater risk of CVD (hazards ratio HR per SD increment in log UACR, 1.36; 95% CI, 1.00 to 1.87) and death (HR per SD increment in log UACR, 1.55; 95% CI, 1.10 to 2.20). Participants with UACR greater than or equal to the sex-specific median (> or =3.9 microg/mg for men, > or =7.5 microg/mg for women) experienced a nearly 3-fold risk of CVD (adjusted HR, 2.92; 95% CI, 1.57 to 5.44; P<0.001) and a borderline significantly increased risk of death (adjusted HR, 1.75; 95% CI, 0.95 to 3.22; P=0.08) compared with those with UACR below the median. The increased CVD risk associated with UACR at or above the median remained robust in analyses restricted to individuals without microalbuminuria (n=1470) and in subgroups with intermediate (n=1469) and low (n=1186) pretest probabilities of CVD.
In our community-based sample of middle-aged nonhypertensive, nondiabetic individuals, low levels of urinary albumin excretion well below the current microalbuminuria threshold predicted the development of CVD. Our observations add to the growing body of evidence that challenges the notion that UACR <30 microg/mg indicates "normal" albumin excretion.
The Society of Radiologists in Ultrasound convened a panel of specialists from a variety of medical disciplines to come to a consensus on the management of thyroid nodules identified with thyroid ...ultrasonography (US), with particular focus on which nodules should be subjected to US-guided fine needle aspiration and which thyroid nodules need not be subjected to fine-needle aspiration. The panel met in Washington, DC, October 26-27, 2004, and created this consensus statement. The recommendations in this consensus statement, which are based on analysis of the current literature and common practice strategies, are thought to represent a reasonable approach to thyroid nodular disease.
•We analyze a model of amoeboidal cell motion.•A centroid model is introduced and analyzed using Markov chain theory.•Numerical results are given which support the analysis.•The centroid model is ...heuristically linked to the full cell motion model.•Cell speed is determined by binding dynamics of the cell and not cell force.
In this paper the motion of a single cell is modeled as a nucleus and multiple integrin based adhesion sites. Numerical simulations and analysis of the model indicate that when the stochastic nature of the adhesion sites is a memoryless and force independent random process, the cell speed is independent of the force these adhesion sites exert on the cell. Furthermore, understanding the dynamics of the attachment and detachment of the adhesion sites is key to predicting cell speed. We introduce a differential equation describing the cell motion and then introduce a conjecture about the expected drift of the cell, the expected average velocity relation conjecture. Using Markov chain theory, we analyze our conjecture in the context of a related (but simpler) model of cell motion, and then numerically compare the results for the simpler model and the full differential equation model. We also heuristically describe the relationship between the simplified and full models as well as provide a discussion of the biological significance of these results.
Far-UV images of Jupiter from the Hubble Space Telescope Wide Field Planetary Camera 2 reveal polar auroral emissions at 300 kilometer resolution and three times higher sensitivity than previously ...achieved.
Cellulose-derived pyrolysis products and selected primary products, 5-hydroxymethyl furfural (5-HMF), levoglucosan and hydroxyacetaldehyde (HAA) were used as starting materials for kinetic studies of ...gas-phase pyrolysis by using flow tube reactors and product detection with molecular beam mass spectrometry (MBMS). Multivariate data analysis was used to identify major product classes for lumped product kinetic analysis. The methodology employed in this work was verified using ethyl allyl ether (EAE) pyrolysis. Two-step sequential models based on lumped primary, secondary and tertiary products were developed for levoglucosan, 5-HMF and cellulose derived pyrolysis products. A one-step model was developed for HAA. Reaction rates and Arrhenius parameters are presented based on these empirical models.
The vast majority of epithelial ovarian cancer arises from tissues that are embryologically derived from the Müllerian Duct. Here, we demonstrate that a DNA methylation signature in easy-to-access ...Müllerian Duct-derived cervical cells from women with and without ovarian cancer (i.e. referred to as the Women's risk IDentification for Ovarian Cancer index or WID-OC-index) is capable of identifying women with an ovarian cancer in the absence of tumour DNA with an AUC of 0.76 and women with an endometrial cancer with an AUC of 0.81. This and the observation that the cervical cell WID-OC-index mimics the epigenetic program of those cells at risk of becoming cancerous in BRCA1/2 germline mutation carriers (i.e. mammary epithelium, fallopian tube fimbriae, prostate) further suggest that the epigenetic misprogramming of cervical cells is an indicator for cancer predisposition. This concept has the potential to advance the field of risk-stratified cancer screening and prevention.
Sarcopenia, the age-associated loss of skeletal muscle mass and function, has considerable societal consequences for the development of frailty, disability, and health care planning. A group of ...geriatricians and scientists from academia and industry met in Rome, Italy, on November 18, 2009, to arrive at a consensus definition of sarcopenia. The current consensus definition was approved unanimously by the meeting participants and is as follows: Sarcopenia is defined as the age-associated loss of skeletal muscle mass and function. The causes of sarcopenia are multifactorial and can include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia may be a component of sarcopenia, the 2 conditions are not the same. The diagnosis of sarcopenia should be considered in all older patients who present with observed declines in physical function, strength, or overall health. Sarcopenia should specifically be considered in patients who are bedridden, cannot independently rise from a chair, or who have a measured gait speed less that 1 m/s(-1). Patients who meet these criteria should further undergo body composition assessment using dual energy x-ray absorptiometry with sarcopenia being defined using currently validated definitions. A diagnosis of sarcopenia is consistent with a gait speed of less than 1 m·s(-1) and an objectively measured low muscle mass (eg, appendicular mass relative to ht(2) that is ≤ 7.23 kg/m(2) in men and ≤ 5.67 kg/m(2) in women). Sarcopenia is a highly prevalent condition in older persons that leads to disability, hospitalization, and death.
Abstract
Background
Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we ...used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk.
Methods
Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression were used to test the robustness of the results.
Results
The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10−43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size odds ratio (ORIVW): 2.06 (1.80–2.35), P = 1.38x10−26 and lower overall breast cancer risk ORIVW: 0.81 (0.74–0.89), P = 9.44x10−6. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050).
Conclusion
Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.
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