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- Jaiswal, Siddhartha, et al.
(författare)
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Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes.
- 2014
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 371:26, s. 2488-2498
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Tidskriftsartikel (refereegranskat)abstract
- Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).
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| 2. |
- Lis, D. C., et al.
(författare)
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Widespread Rotationally Hot Hydronium Ion in the Galactic Interstellar Medium
- 2014
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 785:2, s. A135, pp. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- We present new Herschel observations of the (6,6) and (9,9) inversion transitions of the hydronium ion toward Sagittarius B2(N) and W31C. Sensitive observations toward Sagittarius B2(N) show that the high, ~500 K, rotational temperatures characterizing the population of the highly excited metastable H3O+ rotational levels are present over a wide range of velocities corresponding to the Sagittarius B2 envelope, as well as the foreground gas clouds between the Sun and the source. Observations of the same lines toward W31C, a line of sight that does not intersect the Central Molecular Zone but instead traces quiescent gas in the Galactic disk, also imply a high rotational temperature of ~380 K, well in excess of the kinetic temperature of the diffuse Galactic interstellar medium. While it is plausible that some fraction of the molecular gas may be heated to such high temperatures in the active environment of the Galactic center, characterized by high X-ray and cosmic-ray fluxes, shocks, and high degree of turbulence, this is unlikely in the largely quiescent environment of the Galactic disk clouds. We suggest instead that the highly excited states of the hydronium ion are populated mainly by exoergic chemical formation processes and the temperature describing the rotational level population does not represent the physical temperature of the medium. The same arguments may be applicable to other symmetric top rotors, such as ammonia. This offers a simple explanation of the long-standing puzzle of the presence of a pervasive, hot molecular gas component in the central region of the Milky Way. Moreover, our observations suggest that this is a universal process not limited to the active environments associated with galactic nuclei.
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| 3. |
- Mulrane, Laoighse, et al.
(författare)
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miR-187 Is an Independent Prognostic Factor in Breast Cancer and Confers Increased Invasive Potential In Vitro
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 18:24, s. 6702-6713
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Here, we describe an integrated bioinformatics, functional analysis, and translational pathology approach to identify novel miRNAs involved in breast cancer progression. Experimental Design: Coinertia analysis (CIA) was used to combine a database of predicted miRNA target sites and gene expression data. Using two independent breast cancer cohorts, CIA was combined with correspondence analysis and between group analysis to produce a ranked list of miRNAs associated with disease progression. Ectopic expression studies were carried out in MCF7 cells and miRNA expression evaluated in two additional cohorts of patients with breast cancer by in situ hybridization on tissue microarrays. Results: CIA identified miR-187 as a key miRNA associated with poor outcome in breast cancer. Ectopic expression of miR-187 in breast cancer cells resulted in a more aggressive phenotype. In a test cohort (n = 117), high expression of miR-187 was associated with a trend toward reduced breast cancer-specific survival (BCSS; P = 0.058), and a significant association with reduced BCSS in lymph node-positive patients (P = 0.036). In a validation cohort (n = 470), high miR-187 was significantly associated with reduced BCSS in the entire cohort (P = 0.021) and in lymph node-positive patients (P = 0.012). Multivariate Cox regression analysis revealed that miR-187 is an independent prognostic factor in both cohorts [cohort 1: HR, 7.37; 95% confidence interval (CI), 2.05-26.51; P = 0.002; cohort 2: HR, 2.80; 95% CI, 1.52-5.16; P = 0.001] and in lymph node-positive patients in both cohorts (cohort 1: HR, 13.74; 95% CI, 2.62-72.03; P = 0.002; cohort 2: HR, 2.77; 95% CI, 1.32-5.81; P = 0.007). Conclusions: miR-187 expression in breast cancer leads to a more aggressive, invasive phenotype and acts as an independent predictor of outcome. Clin Cancer Res; 18(24); 6702-13. (C) 2012 AACR.
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