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Sökning: WFRF:(Zwaan C. M.)

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  • Munn-Chernoff, M. A., et al. (författare)
  • Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
  • 2021
  • Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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  • Bryois, J., et al. (författare)
  • Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
  • 2020
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
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  • Watson, H. J., et al. (författare)
  • Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
  • 2019
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness(1), affecting 0.9-4% of women and 0.3% of men(2-4), with twin-based heritability estimates of 50-60%(5). Mortality rates are higher than those in other psychiatric disorders(6), and outcomes are unacceptably poor(7). Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI)(8,9) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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  • Fomalont, E. B., et al. (författare)
  • THE 2014 ALMA LONG BASELINE CAMPAIGN: AN OVERVIEW
  • 2015
  • Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 808:1
  • Tidskriftsartikel (refereegranskat)abstract
    • A major goal of the Atacama Large Millimeter/submillimeter Array (ALMA) is to make accurate images with resolutions of tens of milliarcseconds, which at submillimeter (submm) wavelengths requires baselines up to similar to 15 km. To develop and test this capability, a Long Baseline Campaign (LBC) was carried out from 2014 September to late November, culminating in end-to-end observations, calibrations, and imaging of selected Science Verification (SV) targets. This paper presents an overview of the campaign and its main results, including an investigation of the short-term coherence properties and systematic phase errors over the long baselines at the ALMA site, a summary of the SV targets and observations, and recommendations for science observing strategies at long baselines. Deep ALMA images of the quasar 3C 138 at 97 and 241 GHz are also compared to VLA 43 GHz results, demonstrating an agreement at a level of a few percent. As a result of the extensive program of LBC testing, the highly successful SV imaging at long baselines achieved angular resolutions as fine as 19 mas at similar to 350 GHz. Observing with ALMA on baselines of up to 15 km is now possible, and opens up new parameter space for submm astronomy.
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  • In ’t Veld, Sjors G.J.G., et al. (författare)
  • Detection and localization of early- and late-stage cancers using platelet RNA
  • 2022
  • Ingår i: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 40:9, s. 999-1009.e6
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.
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  • Azevedo, Flavio, et al. (författare)
  • Social and moral psychology of COVID-19 across 69 countries
  • 2023
  • Ingår i: Scientific Data. - : NATURE PORTFOLIO. - 2052-4463. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The COVID-19 pandemic has affected all domains of human life, including the economic and social fabric of societies. One of the central strategies for managing public health throughout the pandemic has been through persuasive messaging and collective behaviour change. To help scholars better understand the social and moral psychology behind public health behaviour, we present a dataset comprising of 51,404 individuals from 69 countries. This dataset was collected for the International Collaboration on Social & Moral Psychology of COVID-19 project (ICSMP COVID-19). This social science survey invited participants around the world to complete a series of moral and psychological measures and public health attitudes about COVID-19 during an early phase of the COVID-19 pandemic (between April and June 2020). The survey included seven broad categories of questions: COVID-19 beliefs and compliance behaviours; identity and social attitudes; ideology; health and well-being; moral beliefs and motivation; personality traits; and demographic variables. We report both raw and cleaned data, along with all survey materials, data visualisations, and psychometric evaluations of key variables.
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  • Van Bavel, Jay J., et al. (författare)
  • National identity predicts public health support during a global pandemic
  • 2022
  • Ingår i: Nature Communications. - : Nature Portfolio. - 2041-1723. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic. Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.
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  • Noort, S., et al. (författare)
  • Analysis of rare driving events in pediatric acute myeloid leukemia
  • 2023
  • Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 108:1, s. 48-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Elucidating genetic aberrations in pediatric acute myeloid leukemia (AML) provides insight in biology and may impact on risk-group stratification and clinical outcome. This study aimed to detect such aberrations in a selected series of samples without known (cyto)genetic aberration using molecular profiling. A cohort of 161 patients was selected from various study groups: DCOG, BFM, SJCRH, NOPHO and AEIOP. Samples were analyzed using RNA sequencing (n=152), whole exome (n=135) and/or whole genome sequencing (n=100). In 70 of 156 patients (45%), of whom RNA sequencing or whole genome sequencing was available, rearrangements were detected, 22 of which were novel; five involving ERG rearrangements and four NPM1 rearrangements. ERG rearrangements showed self-renewal capacity in vitro, and a distinct gene expression pattern. Gene set enrichment analysis of this cluster showed upregulation of gene sets derived from Ewing sarcoma, which was confirmed comparing gene expression profiles of AML and Ewing sarcoma. Furthermore, NPM1-rearranged cases showed cytoplasmic NPM1 localization and revealed HOXA/B gene overexpression, as described for NPM1 mutated cases. Single-gene mutations as identified in adult AML were rare. Patients had a median of 24 coding mutations (range, 7-159). Novel recurrent mutations were detected in UBTF (n=10), a regulator of RNA transcription. In 75% of patients an aberration with a prognostic impact could be detected. Therefore, we suggest these techniques need to become standard of care in diagnostics.
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  • Watson, Hunna J., et al. (författare)
  • Common Genetic Variation and Age of Onset of Anorexia Nervosa
  • 2022
  • Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
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  • Risgaard-Petersen, N., et al. (författare)
  • Evidence for complete denitrification in a benthic foraminifer
  • 2006
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 443:7107, s. 93-96
  • Tidskriftsartikel (refereegranskat)abstract
    • Benthic foraminifera are unicellular eukaryotes found abundantly in many types of marine sediments. Many species survive and possibly reproduce in anoxic habitats(1), but sustainable anaerobic metabolism has not been previously described. Here we demonstrate that the foraminifer Globobulimina pseudospinescens accumulates intracellular nitrate stores and that these can be respired to dinitrogen gas. The amounts of nitrate detected are estimated to be sufficient to support respiration for over a month. In a Swedish fjord sediment where G. pseudospinescens is the dominant foraminifer, the intracellular nitrate pool in this species accounted for 20% of the large, cell-bound, nitrate pool present in an oxygen-free zone. Similarly high nitrate concentrations were also detected in foraminifera Nonionella cf. stella and a Stainforthia species, the two dominant benthic taxa occurring within the oxygen minimum zone of the continental shelf off Chile. Given the high abundance of foraminifera in anoxic marine environments(1-3), these new findings suggest that foraminifera may play an important role in global nitrogen cycling and indicate that our understanding of the complexity of the marine nitrogen cycle is far from complete.
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  • Muller, Sebastien, 1976, et al. (författare)
  • An ALMA Early Science survey of molecular absorption lines toward PKS 1830-211 Analysis of the absorption profiles
  • 2014
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 566
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the first results of an ALMA spectral survey of strong absorption lines for common interstellar species in the z = 0.89 molecular absorber toward the lensed blazar PKS 1830-211. The dataset brings essential information on the structure and composition of the absorbing gas in the foreground galaxy. In particular, we find absorption over large velocity intervals (greater than or similar to 100 km s(-1)) toward both lensed images of the blazar. This suggests either that the galaxy inclination is intermediate and that we sample velocity gradients or streaming motions in the disk plane, that the molecular gas has a large vertical distribution or extraplanar components, or that the absorber is not a simple spiral galaxy but might be a merger system. The number of detected species is now reaching a total of 42 different species plus 14 different rare isotopologues toward the SW image, and 14 species toward the NE line-of-sight. The abundances of CH, H2O, HCO+, HCN, and NH3 relative to H-2 are found to be comparable to those in the Galactic diffuse medium. Of all the lines detected so far toward PKS 1830-211, the ground-state line of ortho-water has the deepest absorption. We argue that ground-state lines of water have the best potential for detecting diffuse molecular gas in absorption at high redshift.
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  • Theilgaard-Moench, Kim, et al. (författare)
  • Gene expression profiling in MDS and AML: potential and future avenues.
  • 2011
  • Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 25:6, s. 909-920
  • Tidskriftsartikel (refereegranskat)abstract
    • Today, the classification systems for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) already incorporate cytogenetic and molecular genetic aberrations in an attempt to better reflect disease biology. However, in many MDS/AML patients no genetic aberrations have been identified yet, and even within some cytogenetically well-defined subclasses there is considerable clinical heterogeneity. Recent advances in genomics technologies such as gene expression profiling (GEP) provide powerful tools to further characterize myeloid malignancies at the molecular level, with the goal to refine the MDS/AML classification system, incorporating as yet unknown molecular genetic and epigenetic pathomechanisms, which are likely reflected by aberrant gene expression patterns. In this study, we provide a comprehensive review on how GEP has contributed to a refined molecular taxonomy of MDS and AML with regard to diagnosis, prediction of clinical outcome, discovery of novel subclasses and identification of novel therapeutic targets and novel drugs. As many challenges remain ahead, we discuss the pitfalls of this technology and its potential including future integrative studies with other genomics technologies, which will continue to improve our understanding of malignant transformation in myeloid malignancies and thereby contribute to individualized risk-adapted treatment strategies for MDS and AML patients.Leukemia advance online publication, 29 March 2011; doi:10.1038/leu.2011.48.
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  • Marti-Vidal, Ivan, 1980, et al. (författare)
  • Probing the jet base of the blazar PKS 1830-211 from the chromatic variability of its lensed images. Serendipitous ALMA observations of a strong gamma-ray flare
  • 2013
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 558, s. 123-
  • Tidskriftsartikel (refereegranskat)abstract
    • The launching mechanism of the jets of active galactic nuclei is poorly constrained observationally, owing to the large distances to these objects and the very small scales (sub-parsec) involved. To better constrain theoretical models, it is especially important to get information from the region close to the physical base of the jet, where the plasma acceleration takes place. In this paper, we report multi-epoch and multifrequency continuum observations of the z = 2.5 blazar PKS 1830−211 with ALMA, serendipitously coincident with a strong γ-ray flare reported by Fermi-LAT. The blazar is lensed by a foreground z = 0.89 galaxy, with two bright images of the compact core separated by 1′′. Our ALMA observations individually resolve these two images (although not any of their substructures), and we study the change in their relative flux ratio with time (four epochs spread over nearly three times the time delay between the two lensed images) and frequency (between 350 and 1050 GHz, rest frame of the blazar), during the γ-ray flare. In particular, we detect a remarkable frequency-dependent behavior of the flux ratio, which implies the presence of a chromatic structure in the blazar (i.e., a core-shift effect). We rule out the possibility of micro- and milli-lensing effects and propose instead a simple model of plasmon ejection in the blazar’s jet to explain the time and frequency variability of the flux ratio. We suggest that PKS 1830−211 is likely to be one of the best sources to probe the activity at the base of a blazar’s jet at submillimeter wavelengths, thanks to the peculiar geometry of the system. The implications of the core shift in absorption studies of the foreground z = 0.89 galaxy (e.g., constraints on the cosmological variations of fundamental constants) are discussed.
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  • Muller, Sebastien, 1976, et al. (författare)
  • Detection of CH+, SH+, and their C-13- and S-34-isotopologues toward PKS 1830-211
  • 2017
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 606
  • Tidskriftsartikel (refereegranskat)abstract
    • The z = 0.89 molecular absorber toward PKS 1830-211 provides us with the opportunity to probe the chemical and physical properties of the interstellar medium in the disk of a galaxy at a look-back time of half the present age of the Universe. Recent ALMA observations of hydrides have unveiled the multi-phase composition of this source's interstellar medium along two absorbing sightlines. Here, we report ALMA observations of CH+ and SH+, and of their C-13- and S-34-isotopologues, as potential tracers of energetic processes in the interstellar medium. CH+ and (CH+)-C-13 are detected toward both images of PKS 1830-211, CH+ showing the deepest and broadest absorption among all species observed so far. The [CH+]/[(CH+)-C-13] abundance ratio is similar to 100 in the south-west line of sight. This value is larger than any previous [(CX)-C-12]/[(CX)-C-13] ratios determined from other species toward this source and suggests either that the latter might be affected by fractionation or that CH+ might be tracing a different gas component. Toward the north-east image, we find an even larger value of [CH+]/[(CH+)-C-13], 146 +/- 43, although with a large uncertainty. This sightline intercepts the absorber at a larger galactocentric radius than the southwestern one, where material might be less processed in stellar nucleosynthesis. In contrast to CH+ and its C-13 isotopologue, SH+ and (SH+)-S-34 are only detected on the south-west sightline. These are the first detections of extragalactic SH+ and interstellar (SH+)-S-34. The spectroscopic parameters of SH+ are reevaluated and improved rest frequencies of (SH+)-S-34 are obtained. The [CH+]/[SH+] column density ratios show a large difference between the two lines of sight: similar to 25 and > 600 toward the SW and NE image, respectively. We are not able to shed light on the formation process of CH+ and SH+ with these data, but the differences between the two sightlines toward PKS 1830-211 suggest that their absorptions arise from gas with a molecular fraction of greater than or similar to 10%, with SH+ tracing significantly higher molecular fractions than CH+.
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32.
  • Muller, Sebastien, 1976, et al. (författare)
  • Detection of chloronium and measurement of the Cl-35/Cl-37 isotopic ratio at z=0.89 toward PKS 1830-211
  • 2014
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 566
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the first extragalactic detection of chloronium (H2Cl+) in the z = 0.89 absorber in front of the lensed blazar PKS 1830-211. The ion is detected through its 1(11)-0(00) line along two independent lines of sight toward the North-East and South-West images of the blazar. The relative abundance of H2Cl+ is significantly higher (by a factor similar to 7) in the NE line of sight, which has a lower H-2/H fraction, indicating that H2Cl+ preferably traces the diffuse gas component. From the ratio of the (H2Cl+)-Cl-35 and (H2Cl+)-Cl-37 absorptions toward the SW image, we measure a Cl-35/Cl-37 isotopic ratio of 3.1(-0.2)(+0.3) at z = 0.89, similar to that observed in the Galaxy and the solar system.
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33.
  • Muller, Sebastien, 1976, et al. (författare)
  • OH+ and H2O+ absorption toward PKS 1830-211
  • 2016
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 595, s. A128(1-10)
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the detection of OH+ and H2O+ in the z = 0.89 absorber toward the lensed quasar PKS 1830-211. The abundance ratio of OH+ and H2O+ is used to quantify the molecular hydrogen fraction (fH2) and the cosmic-ray ionization rate of atomic hydrogen (ζH) along two lines of sight, located at 2 kpc and 4 kpc to either side of the absorber's center. The molecular fraction decreases outward, from 0.04 to 0.02, comparable to values measured in the Milky Way at similar galactocentric radii. For ζH , we find values of 2 × 10-14 s-1 and 3 × 10-15 s-1, respectively, which are slightly higher than in the Milky Way at comparable galactocentric radii, possibly due to a higher average star formation activity in the z = 0.89 absorber. The ALMA observations of OH+, H2O+, and other hydrides toward PKS 1830-211reveal the multi-phase composition of the absorbing gas. Taking the column density ratios along the southwest and northeast lines of sight as a proxy of molecular fraction, we classify the species ArH+, OH+, H2Cl+, H2O+, CH, and HF as tracing gases increasingly more molecular. Incidentally, our data allow us to improve the accuracy of H2O+ rest frequencies and thus refine the spectroscopic parameters.
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34.
  • Pearson, A. D. J., et al. (författare)
  • Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration
  • 2020
  • Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 136, s. 116-129
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes. (C) 2020 Elsevier Ltd. All rights reserved.
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35.
  • Weng, S., et al. (författare)
  • MUSE-ALMA Haloes – VIII. Statistical study of circumgalactic medium gas
  • 2023
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 519:1, s. 931-947
  • Tidskriftsartikel (refereegranskat)abstract
    • The distribution of gas and metals in the circumgalactic medium (CGM) plays a critical role in how galaxies evolve. The MUSE-ALMA Haloes survey combines MUSE, ALMA, and HST observations to constrain the properties of the multiphase gas in the CGM and the galaxies associated with the gas probed in absorption. In this paper, we analyse the properties of galaxies associated with 32 strong HI Ly-α absorbers at redshift 0.2 ≲ z ≲ 1.4. We detect 79 galaxies within ±500 kms−1 of the absorbers in our 19 MUSE fields. These associated galaxies are found at physical distances from 5.7 kpc and reach star formation rates as low as 0.1 M⊙ yr−1. The significant number of associated galaxies allows us to map their physical distribution on the Δv and b plane. Building on previous studies, we examine the physical and nebular properties of these associated galaxies and find the following: (i) 27/32 absorbers have galaxy counterparts and more than 50 per cent of the absorbers have two or more associated galaxies, (ii) the HIHI column density of absorbers is anticorrelated with the impact parameter (scaled by virial radius) of the nearest galaxy as expected from simulations, (iii) the metallicity of associated galaxies is typically larger than the absorber metallicity, which decreases at larger impact parameters. It becomes clear that while strong HIHI absorbers are typically associated with more than a single galaxy, we can use them to statistically map the gas and metal distribution in the CGM.
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36.
  • Janssen, Julie M, et al. (författare)
  • A Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic Model of Bortezomib in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.
  • 2020
  • Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 59:2, s. 207-216
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: The pharmacokinetics (PK) of the 20S proteasome inhibitor bortezomib are characterized by a large volume of distribution and a rapid decline in plasma concentrations within the first hour after administration. An increase in exposure was observed in the second week of treatment, which has previously been explained by extensive binding of bortezomib to proteasome in erythrocytes and peripheral tissues. We characterized the nonlinear population PK and pharmacodynamics (PD) of bortezomib in children with acute lymphoblastic leukemia.METHODS: Overall, 323 samples from 28 patients were available from a pediatric clinical study investigating bortezomib at an intravenous dose of 1.3 mg/m2 twice weekly (Dutch Trial Registry number 1881/ITCC021). A semi-physiological PK model for bortezomib was first developed; the PK were linked to the decrease in 20S proteasome activity in the final PK/PD model.RESULTS: The plasma PK data were adequately described using a two-compartment model with linear elimination. Increased concentrations were observed in week 2 compared with week 1, which was described using a Langmuir binding model. The decrease in 20S proteasome activity was best described by a direct effect model with a sigmoidal maximal inhibitory effect, representing the relationship between plasma concentrations and effect. The maximal inhibitory effect was 0.696 pmol AMC/s/mg protein (95% confidence interval 0.664-0.728) after administration.CONCLUSION: The semi-physiological model adequately described the nonlinear PK and PD of bortezomib in plasma. This model can be used to further optimize dosing of bortezomib.
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37.
  • Janssen, Julie M, et al. (författare)
  • Pharmacokinetic Targets for Therapeutic Drug Monitoring of Small Molecule Kinase Inhibitors in Pediatric Oncology.
  • 2020
  • Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 108:3, s. 494-505
  • Tidskriftsartikel (refereegranskat)abstract
    • In recent years new targeted small molecule kinase inhibitors have become available for pediatric patients with cancer. Relationships between drug exposure and treatment response have been established for several of these drugs in adults. Following these exposure-response relationships, pharmacokinetic (PK) target minimum plasma rug concentration at the end of a dosing interval (Cmin ) values to guide therapeutic drug monitoring (TDM) in adults have been proposed. Despite the fact that variability in PK may be even larger in pediatric patients, TDM is only sparsely applied in pediatric oncology. Based on knowledge of the PK, mechanism of action, molecular driver, and pathophysiology of the disease, we bridge available data on the exposure-efficacy relationship from adults to children and propose target Cmin values to guide TDM for the pediatric population. Dose adjustments in individual pediatric patients can be based on these targets. Nevertheless, further research should be performed to validate these targets.
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38.
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39.
  • Péroux, C., et al. (författare)
  • MUSE-ALMA haloes VII : survey science goals & design, data processing and final catalogues
  • 2022
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 516:4, s. 5618-5636
  • Tidskriftsartikel (refereegranskat)abstract
    • The gas cycling in the circumgalactic regions of galaxies is known to be multi-phase. The MUSE–ALMA Haloes survey gathers a large multi-wavelength observational sample of absorption and emission data with the goal to significantly advance our understanding of the physical properties of such CGM gas. A key component of the MUSE–ALMA Haloes survey is the multi-facility observational campaign conducted with VLT/MUSE, ALMA, and HST. MUSE–ALMA Haloes targets comprise 19 VLT/MUSE IFS quasar fields, including 32 zabs <0.85 strong absorbers with measured N(H I) ≥1018 cm−2 from UV-spectroscopy. We additionally use a new complementary HST medium program to characterize the stellar content of the galaxies through a 40-orbit three-band UVIS and IR WFC3 imaging. Beyond the absorber-selected targets, we detect 3658 sources all fields combined, including 703 objects with spectroscopic redshifts. This galaxy-selected sample constitutes the main focus of the current paper. We have secured millimeter ALMA observations of some of the fields to probe the molecular gas properties of these objects. Here, we present the overall survey science goals, target selection, observational strategy, data processing and source identification of the full sample. Furthermore, we provide catalogues of magnitude measurements for all objects detected in VLT/MUSE, ALMA, and HST broad-band images and associated spectroscopic redshifts derived from VLT/MUSE observations. Together, this data set provides robust characterization of the neutral atomic gas, molecular gas and stars in the same objects resulting in the baryon census of condensed matter in complex galaxy structures.
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40.
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41.
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42.
  • Balgobind, Brian V, et al. (författare)
  • Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia : results of an international retrospective study.
  • 2009
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 114:12, s. 2489-2496
  • Tidskriftsartikel (refereegranskat)abstract
    • Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.
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43.
  • Blink, Marjolein, et al. (författare)
  • Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome : a retrospective, international study
  • 2014
  • Ingår i: Haematologica. - : Ferrata Storti Foundation. - 0390-6078 .- 1592-8721. ; 99:2, s. 299-307
  • Tidskriftsartikel (refereegranskat)abstract
    • Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (± 2%), with the overall survival rate being 79% (± 2%), the cumulative incidence of relapse 12% (± 2%), and the cumulative incidence of toxic death 7% (± 1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%± 4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (± 2%) (P=0.004). Multivariate analyses revealed that white blood cell count ≥ 20 × 10(9)/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols.
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44.
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45.
  • Buitenkamp, Trudy D., et al. (författare)
  • Acute lymphoblastic leukemia in children with Down syndrome : a retrospective analysis from the Ponte di Legno study group
  • 2014
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 123:1, s. 70-77
  • Tidskriftsartikel (refereegranskat)abstract
    • Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Munster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% +/- 2% vs 15% +/- 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% +/- 1% vs 2.0% +/- < 1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% +/- 2% vs 81% +/- 2%, P < .0001) and overall survival (74% +/- 2% vs 89% +/- 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 x 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.
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46.
  • Coenen, Eva A, et al. (författare)
  • Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients : results of an international study
  • 2011
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 117:26, s. 7102-7111
  • Tidskriftsartikel (refereegranskat)abstract
    • We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.
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47.
  • Hasle, Henrik, et al. (författare)
  • Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype
  • 2022
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 139:21, s. 3159-3165
  • Tidskriftsartikel (refereegranskat)abstract
    • Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.
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48.
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49.
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50.
  • Klitsch, Anne, et al. (författare)
  • Almacal – VI. Molecular gas mass density across cosmic time via a blind search for intervening molecular absorbers
  • 2019
  • Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 490:1, s. 1220-1230
  • Tidskriftsartikel (refereegranskat)abstract
    • We are just starting to understand the physical processes driving the dramatic change in cosmic star formation rate between z ∼ 2 and the present day. A quantity directly linked to star formation is the molecular gas density, which should be measured through independent methods to explore variations due to cosmic variance and systematic uncertainties. We use intervening CO absorption lines in the spectra of mm-bright background sources to provide a census of the molecular gas mass density of the Universe. The data used in this work are taken from ALMACAL, a wide and deep survey utilizing the ALMA calibrator archive. While we report multiple Galactic absorption lines and one intrinsic absorber, no extragalactic intervening molecular absorbers are detected. However, due to the large redshift path surveyed (z = 182), we provide constraints on the molecular column density distribution function beyond z ∼ 0. In addition, we probe column densities of N(H2) > 1016 atoms cm−2, 5 orders of magnitude lower than in previous studies. We use the cosmological hydrodynamical simulation IllustrisTNG to show that our upper limits of ρ(H2) 108.3 M Mpc−3 at 0 < z ≤ 1.7 already provide new constraints on current theoretical predictions of the cold molecular phase of the gas. These results are in agreement with recent CO emission-line surveys and are complementary to those studies. The combined constraints indicate that the present decrease of the cosmic star formation rate history is consistent with an increasing depletion of molecular gas in galaxies compared to z ∼ 2.
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