| 1. |
- Ruilope, LM, et al.
(author)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 2. |
- Dork, T, et al.
(author)
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Two truncating variants in FANCC and breast cancer risk
- 2019
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1, s. 12524-
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Journal article (peer-reviewed)abstract
- Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
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| 3. |
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| 4. |
- Schmit, Stephanie L, et al.
(author)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Journal article (peer-reviewed)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 5. |
- Yang, Yaohua, et al.
(author)
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Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk
- 2019
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In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:3, s. 505-517
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Journal article (peer-reviewed)abstract
- DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 x 10(-7). Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
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| 6. |
- Hashimoto, Takuya, et al.
(author)
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Big Three Dragons: A z=7.15 Lyman-break galaxy detected in [Oiii] 88 mu m, [Cii] 158 mu m, and dust continuum with ALMA
- 2019
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In: Publication of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 2053-051X .- 0004-6264. ; 71:4
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Journal article (peer-reviewed)abstract
- We present new ALMA observations and physical properties of a Lyman break galaxy at z = 7.15. Our target, B14-65666, has a bright ultra-violet (UV) absolute magnitude, M-UV approximate to -22.4, and has been spectroscopically identified in Ly alpha with a small rest-frame equivalent width of approximate to 4 angstrom. A previous Hubble Space TElescope (HST) image has shown that the target is composed of two spatially separated clumps in the rest-frame UV. With ALMA, we have newly detected spatially resolved [Oiii] 88 mu m, [Cii] 158 mu m, and their underlying dust continuum emission. In the whole system of B14-65666, the [Oiii] and [Cii] lines have consistent redshifts of 7.1520 +/- 0.0003, and the [Oiii] luminosity, (34.4 +/- 4.1)x 10(8)L(circle dot), is about three times higher than the [Cii] luminosity, (11.0 +/- 1.4) x 10(8)L(circle dot). With our two continuum flux densities, the dust temperature is constrained to be T-d approximate to 50-60K under the assumption of a dust emissivity index of beta(d) = 2.0-1.5, leading to a large total infrared luminosity of L-TIR approximate to 1 x 10(12)L(circle dot). Owing to our high spatial resolution data, we show that the [Oiii] and [Cii] emission can be spatially decomposed into two clumps associated with the two rest-frame UV clumps whose spectra are kinematically separated by approximate to 200kms(-1). We also find these two clumps have comparable UV, infrared, [Oiii], and [Cii] luminosities. Based on these results, we argue that B14-65666 is a starburst galaxy induced by a major merger. The merger interpretation is also supported by the large specific star formation rate (defined as the star formation rate per unit stellar mass), sSFR Gyr(-1), inferred from our SED fitting. Probably, a strong UV radiation field caused by intense star formation contributes to its high dust temperature and the [Oiii]-to-[Cii] luminosity ratio.
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| 7. |
- Tamura, Yoichi, et al.
(author)
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Detection of the Far-infrared [O III] and Dust Emission in a Galaxy at Redshift 8.312 : Early Metal Enrichment in the Heart of the Reionization Era
- 2019
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In: Astrophysical Journal. - : IOP PUBLISHING LTD. - 0004-637X .- 1538-4357. ; 874:1
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Journal article (peer-reviewed)abstract
- We present the Atacama Large Millimeter/submillimeter Array detection of the [O III] 88 mu m line and rest-frame 90 mu m dust continuum emission in a Y-dropout Lyman break galaxy (LBG), MACS0416_Y1 lying behind the Frontier Field cluster MACS J0416.1-2403. This [O III] detection confirms the LBG with a spectroscopic redshift of z = 8.3118 +/- 0.0003, making this object one of the farthest galaxies ever identified spectroscopically. The observed 850 mu m flux density of 137 +/- 26 mu Jy corresponds to a de-lensed total infrared (IR) luminosity of L-IR = (1.7 +/- 0.3) x 10(11) L-circle dot if assuming a dust temperature of T-dust = 50 K and an emissivity index of beta = 1.5, yielding a large dust mass of 4 x 10(6) M-circle dot. The ultraviolet-to-far-IR spectral energy distribution modeling where the [O III] emissivity model is incorporated suggests the presence of a young (tau(age) approximate to 4 Myr), star-forming (SFR approximate to 60 M-circle dot yr(-1)), moderately metal-polluted (Z approximate to 0.2 Z(circle dot)) stellar component with a mass of M-star = 3 x 10(8) M-circle dot. An analytic dust mass evolution model with a single episode of star formation does not reproduce the metallicity and dust mass in tau(age) approximate to 4 Myr, suggesting a pre-existing evolved stellar component with M-star similar to 3 x 10(9) M-circle dot and tau(age) similar to 0.3 Gyr as the origin of the dust mass.
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