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- Ruilope, LM, et al.
(författare)
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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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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)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. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 8. |
- Masson-Delmotte, V., et al.
(författare)
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Sensitivity of interglacial Greenland temperature and δ 18O : Ice core data, orbital and increased CO 2 climate simulations
- 2011
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Ingår i: Climate of the Past. - : Copernicus GmbH. - 1814-9324 .- 1814-9332. ; 7:3, s. 1041-1059
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Tidskriftsartikel (refereegranskat)abstract
- The sensitivity of interglacial Greenland temperature to orbital and CO 2 forcing is investigated using the NorthGRIP ice core data and coupled ocean-atmosphere IPSL-CM4 model simulations. These simulations were conducted in response to different interglacial orbital configurations, and to increased CO 2 concentrations. These different forcings cause very distinct simulated seasonal and latitudinal temperature and water cycle changes, limiting the analogies between the last interglacial and future climate. However, the IPSL-CM4 model shows similar magnitudes of Arctic summer warming and climate feedbacks in response to 2 × CO 2 and orbital forcing of the last interglacial period (126 000 years ago). The IPSL-CM4 model produces a remarkably linear relationship between TOA incoming summer solar radiation and simulated changes in summer and annual mean central Greenland temperature. This contrasts with the stable isotope record from the Greenland ice cores, showing a multi-millennial lagged response to summer insolation. During the early part of interglacials, the observed lags may be explained by ice sheet-ocean feedbacks linked with changes in ice sheet elevation and the impact of meltwater on ocean circulation, as investigated with sensitivity studies. A quantitative comparison between ice core data and climate simulations requires stability of the stable isotope - temperature relationship to be explored. Atmospheric simulations including water stable isotopes have been conducted with the LMDZiso model under different boundary conditions. This set of simulations allows calculation of a temporal Greenland isotope-temperature slope (0.3-0.4% per °C) during warmer-than-present Arctic climates, in response to increased CO 2, increased ocean temperature and orbital forcing. This temporal slope appears half as large as the modern spatial gradient and is consistent with other ice core estimates. It may, however, be model-dependent, as indicated by preliminary comparison with other models. This suggests that further simulations and detailed inter-model comparisons are also likely to be of benefit. Comparisons with Greenland ice core stable isotope data reveals that IPSL-CM4/LMDZiso simulations strongly underestimate the amplitude of the ice core signal during the last interglacial, which could reach +8-10 °C at fixed-elevation. While the model-data mismatch may result from missing positive feedbacks (e.g. vegetation), it could also be explained by a reduced elevation of the central Greenland ice sheet surface by 300-400 m.
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| 9. |
- Mazzuca, Silvia, et al.
(författare)
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Establishing research strategies, methodologies and technologies to link genomics and proteomics to seagrass productivity, community metabolism, and ecosystem carbon fluxes
- 2013
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Ingår i: Frontiers in Plant Science. - : Frontiers Media SA. - 1664-462X. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- A complete understanding of the mechanistic basis of marine ecosystem functioning is only possible through integrative and interdisciplinary research. This enables the prediction of change and possibly the mitigation of the consequences of anthropogenic impacts. One major aim of the European Cooperation in Science and Technology (COST) Action ES0609 Seagrasses productivity. From genes to ecosystem management, is the calibration and synthesis of various methods and the development of innovative techniques and protocols for studying seagrass ecosystems. During 10 days, 20 researchers representing a range of disciplines (molecular biology, physiology, botany, ecology, oceanography, and underwater acoustics) gathered at The Station de Recherches Sous-marines et Oceanographiques (STARESO, Corsica) to study together the nearby Posidonia oceanica meadow. STARESO is located in an oligotrophic area classified as pristine site where environmental disturbances caused by anthropogenic pressure are exceptionally low. The healthy P. oceanica meadow, which grows in front of the research station, colonizes the sea bottom from the surface to 37 m depth. During the study, genomic and proteomic approaches were integrated with ecophysiological and physical approaches with the aim of understanding changes in seagrass productivity and metabolism at different depths and along daily cycles. In this paper we report details on the approaches utilized and we forecast the potential of the data that will come from this synergistic approach not only for P. oceanica but for seagrasses in general.
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