The association between aging and cancer is complex. Recent studies have developed measures of biological aging based on DNA methylation and called them “age acceleration.” We aimed to assess the ...associations of age acceleration with risk of and survival from seven common cancers. Seven case–control studies of DNA methylation and colorectal, gastric, kidney, lung, prostate and urothelial cancer and B‐cell lymphoma nested in the Melbourne Collaborative Cohort Study were conducted. Cancer cases, vital status and cause of death were ascertained through linkage with cancer and death registries. Conditional logistic regression and Cox models were used to estimate odds ratios (OR) and hazard ratios (HR) and 95% confidence intervals (CI) for associations of five age acceleration measures derived from the Human Methylation 450 K Beadchip assay with cancer risk (N = 3,216 cases) and survival (N = 1,726 deaths), respectively. Epigenetic aging was associated with increased cancer risk, ranging from 4% to 9% per five‐year age acceleration for the 5 measures considered. Heterogeneity by study was observed, with stronger associations for risk of kidney cancer and B‐cell lymphoma. An associated increased risk of death following cancer diagnosis ranged from 2% to 6% per five‐year age acceleration, with no evidence of heterogeneity by cancer site. Cancer risk and mortality were increased by 15–30% for the fourth versus first quartile of age acceleration. DNA methylation‐based measures of biological aging are associated with increased cancer risk and shorter cancer survival, independently of major health risk factors.
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Aging is associated with profound changes in DNA methylation levels. These can be used to build accurate age predictors (“epigenetic clocks”) that deviate from chronological age by only a few years, a phenomenon named “age acceleration”. In this study of seven types of cancer, the authors found that age acceleration was associated with both increased cancer risk and decreased cancer survival, independently of major health risk factors. These results support the usefulness of methylation markers of biological aging as a tool to predict health outcomes and may provide valuable insight into the relationship between aging and cancer.
The efficacy of empirical non-carbapenem antibiotics for extended-spectrum beta-lactamase-producing Enterobacteriaceae bacteremia (ESBL-B) is still inconclusive. We conducted a multicenter ...retrospective cohort study to evaluate the efficacy of empirical non-carbapenem antibiotics for treating ESBL-B. Electronic medical records of individuals who were diagnosed with ESBL-B were reviewed between January 2010 and December 2014 at four university hospitals in Korea. Patients were classified into non-carbapenem and carbapenem groups according to the empirical antibiotic regimen. Patients treated with appropriate empirical antibiotics and who subsequently received carbapenems as definitive therapy were included in the analysis. The inverse probability of treatment weights, a statistical method that adjusts baseline statistics by giving weights based on propensity score, was used. During the study period, 232 adequately treated patients with ESBL-B were included in the analysis: 49 patients in the non-carbapenem group and 183 in the carbapenem group. The baseline characteristics and severity of infection were similar after propensity score weighting. The 30-day mortality rates for the two groups were not statistically significantly different (non-carbapenems 6.3% and carbapenems 11.4%;
P
= 0.42). In a multivariate analysis, empirical treatment with non-carbapenem antibiotics was not associated with 30-day all-cause mortality (HR 1.02, 95% CI 0.99–1.06,
P
= 0.14). In a subgroup analysis, empirical treatment with piperacillin-tazobactam was also not associated with 30-day all-cause mortality (HR 1.21, 95% CI 0.37–4.00,
P
= 0.75). Appropriate non-carbapenems were not inferior to carbapenems as initial empirical therapy for ESBL-B.
Proteins often exist and function as part of higher-order complexes or networks. A challenge is to identify the universe of proximal and interacting partners for a given protein. We describe how the ...high-activity promiscuous biotin ligase called TurboID is fused to the actin-binding peptide LifeAct to label by biotinylation proteins that bind, or are in close proximity, to actin. The rapid enzyme kinetics of TurboID allows the profiles of actin-binding proteins to be compared under different conditions, such as acute disruption of filamentous actin structures with cytochalasin D.
The design of tunnels and groundwater collection and filtration systems requires evaluation of water pressure on the structures and/or leakage into the structures. However, a great deal of ...uncertainty remains concerning the control of pore-water pressure and inflow rate in underwater tunnels, because there are various factors that influence the hydraulic interaction between the structure and the groundwater. In this paper, the relationship between pore-water pressure (p) and inflow rate (Q) is investigated using a theoretical method for laminar and turbulent flow. The p-Q relationship is validated by performing simple experimental studies.
Although much is known about how individual cytoskeletal systems contribute to physiological processes such as cell migration and branching morphogenesis, little is known about how these different ...systems actively coordinate their functions after polymerization. Here we show that both fibroblasts and developing glands reciprocally coordinate levels of cellular contractility and microtubule acetylation. We find that this balance is achieved by interaction of the myosin phosphatase target subunit of myosin phosphatase with either myosin light chain or HDAC6, a microtubule deacetylase. This balance of contractility and microtubule acetylation controls progression of adhesion maturation by regulating surface density of α5β1 integrin and fibronectin. Thus, we propose that a homeostatic balance between contractility and microtubule acetylation is mediated by myosin phosphatase via controlled activation and deactivation of myosin II and HDAC6. This regulates the surface density of α5β1 integrin to modulate fibronectin matrix assembly and governs rates of cell migration and branching morphogenesis.
Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic ...variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.
Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast ...cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.
Methylation marks of exposure to health risk factors may be useful markers of cancer risk as they might better capture current and past exposures than questionnaires, and reflect different individual ...responses to exposure. We used data from seven case-control studies nested within the Melbourne Collaborative Cohort Study of blood DNA methylation and risk of colorectal, gastric, kidney, lung, prostate and urothelial cancer, and B-cell lymphoma (N cases = 3123). Methylation scores (MS) for smoking, body mass index (BMI), and alcohol consumption were calculated based on published data as weighted averages of methylation values. Rate ratios (RR) and 95% confidence intervals for association with cancer risk were estimated using conditional logistic regression and expressed per SD increase of the MS, with and without adjustment for health-related confounders. The contribution of MS to discriminate cases from controls was evaluated using the area under the curve (AUC). After confounder adjustment, we observed: large associations (RR = 1.5-1.7) with lung cancer risk for smoking MS; moderate associations (RR = 1.2-1.3) with urothelial cancer risk for smoking MS and with mature B-cell neoplasm risk for BMI and alcohol MS; moderate to small associations (RR = 1.1-1.2) for BMI and alcohol MS with several cancer types and cancer overall. Generally small AUC increases were observed after inclusion of several MS in the same model (colorectal, gastric, kidney, urothelial cancers: +3%; lung cancer: +7%; B-cell neoplasms: +8%). Methylation scores for smoking, BMI and alcohol consumption show independent associations with cancer risk, and may provide some improvements in risk prediction.
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