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Träfflista för sökning "WFRF:(Trainer P.) srt2:(2015-2019)"

Sökning: WFRF:(Trainer P.) > (2015-2019)

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1.
  • Figlioli, G, et al. (författare)
  • The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
  • 2019
  • Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
  • 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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  • Valassi, E., et al. (författare)
  • High mortality within 90 days of diagnosis in patients with Cushing's syndrome: results from the ERCUSYN registry
  • 2019
  • Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 181:5, s. 461-472
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Patients with Cushing's syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. Methods: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2-5.5) years. Results: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. Conclusion: Mortality rate was highest in patients with ectopic CS. Infectious diseases the commonest cause of death soon after diagnosis, emphasizing the need for careful vigilance at that time, especially in patients presenting with concomitant diabetes mellitus.
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  • Johannsson, Gudmundur, 1960, et al. (författare)
  • Growth Hormone Research Society perspective on biomarkers of GH action in children and adults
  • 2018
  • Ingår i: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 7:3, s. R126-R134
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Consensus process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.
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  • Navarro‐González, Rafael, et al. (författare)
  • Abiotic Input of Fixed Nitrogen by Bolide Impacts to Gale Crater During the Hesperian : Insights From the Mars Science Laboratory
  • 2019
  • Ingår i: Journal of Geophysical Research - Planets. - : John Wiley & Sons. - 2169-9097 .- 2169-9100. ; 124:1, s. 94-113
  • Tidskriftsartikel (refereegranskat)abstract
    • Molecular hydrogen (H2) from volcanic emissions is suggested to warm the Martian surface when carbon dioxide (CO2) levels dropped from the Noachian (4100 to 3700 Myr) to the Hesperian (3700 to 3000 Myr). Its presence is expected to shift the conversion of molecular nitrogen (N2) into different forms of fixed nitrogen (N). Here we present experimental data and theoretical calculations that investigate the efficiency of nitrogen fixation by bolide impacts in CO2‐N2 atmospheres with or without H2. Surprisingly, nitric oxide (NO) was produced more efficiently in 20% H2 in spite of being a reducing agent and not likely to increase the rate of nitrogen oxidation. Nevertheless, its presence led to a faster cooling of the shock wave raising the freeze‐out temperature of NO resulting in an enhanced yield. We estimate that the nitrogen fixation rate by bolide impacts varied from 7 × 10−4 to 2 × 10−3 g N·Myr−1·cm−2 and could imply fluvial concentration to explain the nitrogen (1.4 ± 0.7 g N·Myr−1·cm−2) detected as nitrite (NO2−) and nitrate (NO3−) by Curiosity at Yellowknife Bay. One possible explanation is that the nitrogen detected in the lacustrine sediments at Gale was deposited entirely on the crater's surface and was subsequently dissolved and transported by superficial and ground waters to the lake during favorable wet climatic conditions. The nitrogen content sharply decreases in younger sediments of the Murray formation suggesting a decline of H2 in the atmosphere and the rise of oxidizing conditions causing a shortage in the supply to putative microbial life.
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7.
  • Webster, Christopher R., et al. (författare)
  • Background levels of methane in Mars' atmosphere show strong seasonal variations
  • 2018
  • Ingår i: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 360:6393, s. 1093-1096
  • Tidskriftsartikel (refereegranskat)abstract
    • Variable levels of methane in the martian atmosphere have eluded explanation partly because the measurements are not repeatable in time or location. We report in situ measurements at Gale crater made over a 5-year period by the Tunable Laser Spectrometer on the Curiosity rover. The background levels of methane have a mean value 0.41 ± 0.16 parts per billion by volume (ppbv) (95% confidence interval) and exhibit a strong, repeatable seasonal variation (0.24 to 0.65 ppbv). This variation is greater than that predicted from either ultraviolet degradation of impact-delivered organics on the surface or from the annual surface pressure cycle. The large seasonal variation in the background and occurrences of higher temporary spikes (~7 ppbv) are consistent with small localized sources of methane released from martian surface or subsurface reservoirs.
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8.
  • Valassi, E., et al. (författare)
  • Worse Health-Related Quality of Life at long-term follow-up in patients with Cushing's disease than patients with cortisol producing adenoma. Data from the ERCUSYN
  • 2018
  • Ingår i: Clinical Endocrinology. - : Wiley. - 0300-0664. ; 88:6, s. 787-798
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectiveHypercortisolism in Cushing's syndrome (CS) is associated with impaired health-related quality of life (HRQoL), which may persist despite remission. We used the data entered into the European Registry on Cushing's syndrome (ERCUSYN) to evaluate if patients with CS of pituitary origin (PIT-CS) have worse HRQoL, both before and after treatment than patients with adrenal causes (ADR-CS). MethodsData from 595 patients (492 women; 83%) who completed the CushingQoL and/or EQ-5D questionnaires at baseline and/or following treatment were analysed. ResultsAt baseline, HRQoL did not differ between PIT-CS (n=293) and ADR-CS (n=120) on both EuroQoL and CushingQoL. Total CushingQoL score in PIT-CS and ADR-CS was 4118 and 44 +/- 20, respectively (P=.7). At long-time follow-up (>1year after treatment) total CushingQoL score was however lower in PIT-CS than ADR-CS (56 +/- 20 vs 62 +/- 23; P=.045). In a regression analysis, after adjustment for baseline age, gender, remission status, duration of active CS, glucocorticoid dependency and follow-up time, no association was observed between aetiology and HRQoL. Remission was associated with better total CushingQoL score (P<.001), and older age at diagnosis with worse total score (P=.01). Depression at diagnosis was associated with worse total CushingQoL score at the last follow-up (P<.001). ConclusionPIT-CS patients had poorer HRQoL than ADR-CS at long-term follow-up, despite similar baseline scoring. After adjusting for remission status, no interaetiology differences in HRQoL scoring were found. Age and presence of depression at diagnosis of CS may be potential predictors of worse HRQoL regardless of CS aetiology.
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9.
  • G. Trainer, Melissa, et al. (författare)
  • Seasonal Variations in Atmospheric Composition as Measured in Gale Crater, Mars
  • 2019
  • Ingår i: Journal of Geophysical Research - Planets. - : John Wiley & Sons. - 2169-9097 .- 2169-9100. ; 124:11, s. 3000-3024
  • Tidskriftsartikel (refereegranskat)abstract
    • The Sample Analysis at Mars (SAM) instrument onboard the Mars Science Laboratory Curiosity rover measures the chemical composition of major atmospheric species (CO2, N2, 40Ar, O2, and CO) through a dedicated atmospheric inlet. We report here measurements of volume mixing ratios in Gale Crater using the SAM quadrupole mass spectrometer, obtained over a period of nearly 5 years (3 Mars years) from landing. The observation period spans the northern summer of MY 31 and solar longitude (LS) of 175° through spring of MY 34, LS = 12°. This work expands upon prior reports of the mixing ratios measured by SAM QMS in the first 105 sols of the mission. The SAM QMS atmospheric measurements were taken periodically, with a cumulative coverage of four or five experiments per season on Mars. Major observations include the seasonal cycle of CO2, N2, and Ar, which lags approximately 20–40° of LS behind the pressure cycle driven by CO2 condensation and sublimation from the winter poles. This seasonal cycle indicates that transport occurs on faster timescales than mixing. The mixing ratio of O2 shows significant seasonal and interannual variability, suggesting an unknown atmospheric or surface process at work. The O2 measurements are compared to several parameters, including dust optical depth and trace CH4 measurements by Curiosity. We derive annual mean volume mixing ratios for the atmosphere in Gale Crater: CO2 = 0.951 (±0.003), N2 = 0.0259 (±0.0006), 40Ar = 0.0194 (±0.0004), O2 = 1.61 (±0.09) x 10‐3, and CO = 5.8 (±0.8) x 10‐4.
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  • Wells, M. L., et al. (författare)
  • Harmful algal blooms and climate change: Learning from the past and present to forecast the future
  • 2015
  • Ingår i: Harmful Algae. - : Elsevier BV. - 1568-9883. ; 49, s. 68-93
  • Tidskriftsartikel (refereegranskat)abstract
    • Climate change pressures will influence marine planktonic systems globally, and it is conceivable that harmful algal blooms may increase in frequency and severity. These pressures will be manifest as alterations in temperature, stratification, light, ocean acidification, precipitation-induced nutrient inputs, and grazing, but absence of fundamental knowledge of the mechanisms driving harmful algal blooms frustrates most hope of forecasting their future prevalence. Summarized here is the consensus of a recent workshop held to address what currently is known and not known about the environmental conditions that favor initiation and maintenance of harmful algal blooms. There is expectation that harmful algal bloom (HAB) geographical domains should expand in some cases, as will seasonal windows of opportunity for harmful algal blooms at higher latitudes. Nonetheless there is only basic information to speculate upon which regions or habitats HAB species may be the most resilient or susceptible. Moreover, current research strategies are not well suited to inform these fundamental linkages. There is a critical absence of tenable hypotheses for how climate pressures mechanistically affect HAB species, and the lack of uniform experimental protocols limits the quantitative cross-investigation comparisons essential to advancement. A HAB "best practices" manual would help foster more uniform research strategies and protocols, and selection of a small target list of model HAB species or isolates for study would greatly promote the accumulation of knowledge. Despite the need to focus on keystone species, more studies need to address strain variability within species, their responses under multifactorial conditions, and the retrospective analyses of long-term plankton and cyst core data; research topics that are departures from the norm. Examples of some fundamental unknowns include how larger and more frequent extreme weather events may break down natural biogeographic barriers, how stratification may enhance or diminish HAB events, how trace nutrients (metals, vitamins) influence cell toxicity, and how grazing pressures may leverage, or mitigate HAB development. There is an absence of high quality time-series data in most regions currently experiencing HAB outbreaks, and little if any data from regions expected to develop HAB events in the future. A subset of observer sites is recommended to help develop stronger linkages among global, national, and regional climate change and HAB observation programs, providing fundamental datasets for investigating global changes in the prevalence of harmful algal blooms. Forecasting changes in HAB patterns over the next few decades will depend critically upon considering harmful algal blooms within the competitive context of plankton communities, and linking these insights to ecosystem, oceanographic and climate models. From a broader perspective, the nexus of HAB science and the social sciences of harmful algal blooms is inadequate and prevents quantitative assessment of impacts of future HAB changes on human well-being. These and other fundamental changes in HAB research will be necessary if HAB science is to obtain compelling evidence that climate change has caused alterations in HAB distributions, prevalence or character, and to develop the theoretical, experimental, and empirical evidence explaining the mechanisms underpinning these ecological shifts. © 2015 Elsevier B.V.
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