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| 11. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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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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- Fomalont, E. B., et al.
(författare)
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THE 2014 ALMA LONG BASELINE CAMPAIGN: AN OVERVIEW
- 2015
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 808:1
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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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| 13. |
- Bryois, J., et al.
(författare)
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Genetic identification of cell types underlying brain complex traits yields insights into the etiology of Parkinson’s disease
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 52:5, s. 482-493
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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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| 14. |
- Watson, H. J., et al.
(författare)
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Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa
- 2019
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:8
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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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- Andreani, P., et al.
(författare)
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The European ALMA Regional Centre: a model of user support
- 2014
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Ingår i: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 0277-786X .- 1996-756X. - 9780819496171 ; 9149, s. Art. no. 91490Y-
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Konferensbidrag (refereegranskat)abstract
- The ALMA Regional Centres (ARCs) form the interface between the ALMA observatory and the user community from the proposal preparation stage to the delivery of data and their subsequent analysis. The ARCs provide critical services to both the ALMA operations in Chile and to the user community. These services were split by the ALMA project into core and additional services. The core services are financed by the ALMA operations budget and are critical to the successful operation of ALMA. They are contractual obligations and must be delivered to the ALMA project. The additional services are not funded by the ALMA project and are not contractual obligations, but are critical to achieve ALMA full scientific potential. A distributed network of ARC nodes (with ESO being the central ARC) has been set up throughout Europe at the following seven locations: Bologna, Bonn-Cologne, Grenoble, Leiden, Manchester, Ondrejov, Onsala. These ARC nodes are working together with the central node at ESO and provide both core and additional services to the ALMA user community. This paper presents the European ARC, and how it operates in Europe to support the ALMA community. This model, although complex in nature, is turning into a very successful one, providing a service to the scientific community that has been so far highly appreciated. The ARC could become a reference support model in an age where very large collaborations are required to build large facilities, and support is needed for geographically and culturally diverse communities.
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| 20. |
- Azevedo, Flavio, et al.
(författare)
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Social and moral psychology of COVID-19 across 69 countries
- 2023
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Ingår i: Scientific Data. - : NATURE PORTFOLIO. - 2052-4463. ; 10:1
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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)
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National identity predicts public health support during a global pandemic
- 2022
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Ingår i: Nature Communications. - : Nature Portfolio. - 2041-1723. ; 13:1
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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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| 23. |
- Arabsalmani, M., et al.
(författare)
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A Superluminous Supernova in High Surface Density Molecular Gas within the Bar of a Metal-rich Galaxy
- 2019
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 882:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the Atacama Large Millimeter/submillimeter Array observations of the metal-rich host galaxy of superluminous supernova (SLSN) PTF10tpz, a barred spiral galaxy at z = 0.03994. We find the CO(1-0) emission to be confined within the bar of the galaxy. The distribution and kinematics of molecular gas in the host galaxy resemble gas flows along two lanes running from the tips of the bar toward the galaxy center. These gas lanes end in a gaseous structure in the inner region of the galaxy, likely associated with an inner Lindblad resonance. The interaction between the large-scale gas flows in the bar and the gas in the inner region plausibly leads to the formation of massive molecular clouds and consequently massive clusters. This in turn can result in formation of massive stars, and thus the likely progenitor of the SLSN in a young, massive cluster. This picture is consistent with SLSN PTF10tpz being located near the intersection regions of the gas lanes and the inner structure. It is also supported by the high molecular gas surface densities that we find in the vicinity of the SLSN, surface densities that are comparable with those in interacting galaxies or starburst regions in nearby galaxies. Our findings therefore suggest in situ formation of massive stars due to the internal dynamics of the host galaxy and also lend support to high densities being favorable conditions for formation of SLSN progenitors.
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| 24. |
- Arabsalmani, M., et al.
(författare)
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Local Starburst Conditions and Formation of GRB 980425/SN 1998bw within a Collisional Ring
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 899:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the first spatially resolved study of molecular gas in the vicinity of a gamma-ray burst (GRB), using CO(2-1) emission-line observations with the Atacama Large Millimetre Array at ∼50 pc scales. The host galaxy of GRB 980425 contains a ring of high column density H i gas, which is likely to have formed due to a collision between the GRB host and its companion galaxy, within which the GRB is located. We detect 11 molecular gas clumps in the galaxy, 7 of which are within the gas ring. The clump closest to the GRB position is at a projected separation of ∼280 pc. Although it is plausible that the GRB progenitor was ejected from clusters formed in this clump, we argue that the in situ formation of the GRB progenitor is the most likely scenario. We measure the molecular gas masses of the clumps and find them to be sufficient for forming massive star clusters. The molecular gas depletion times of the clumps show a variation of ∼2 dex, comparable with the large variation in depletion times found in starburst galaxies in the nearby universe. This demonstrates the presence of starburst modes of star formation on local scales in the galaxy, even while the galaxy as a whole cannot be categorized as a starburst based on its global properties. Our findings suggest that the progenitor of GRB 9802425 was originated in a young massive star cluster formed in the starburst mode of star formation.
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- Pearson, A. D. J., et al.
(författare)
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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
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049. ; 136, s. 116-129
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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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| 30. |
- Porkka, Kimmo, et al.
(författare)
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Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 112:4, s. 1005-12
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Tidskriftsartikel (refereegranskat)abstract
- Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph(+)) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasa-tinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a preclinical mouse model of intracranial Ph(+) leukemia. Clinical dasatinib treatment in patients with CNS Ph(+) leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasa-tinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph(+) leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials.gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097).
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| 31. |
- Watson, Hunna J., et al.
(författare)
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Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
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Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
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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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| 36. |
- Hasle, Henrik, et al.
(författare)
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Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype
- 2022
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 139:21, s. 3159-3165
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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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| 37. |
- In ’t Veld, Sjors G.J.G., et al.
(författare)
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Detection and localization of early- and late-stage cancers using platelet RNA
- 2022
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Ingår i: Cancer Cell. - : Elsevier. - 1535-6108 .- 1878-3686. ; 40:9, s. 999-1009.e6
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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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| 38. |
- Janssen, Julie M, et al.
(författare)
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A Semi-Mechanistic Population Pharmacokinetic/Pharmacodynamic Model of Bortezomib in Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.
- 2020
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Ingår i: Clinical Pharmacokinetics. - : Springer Science and Business Media LLC. - 0312-5963 .- 1179-1926. ; 59:2, s. 207-216
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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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| 39. |
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| 40. |
- Marti-Vidal, Ivan, 1980, et al.
(författare)
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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
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 558, s. 123-
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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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| 41. |
- Muller, Sebastien, 1976, et al.
(författare)
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An ALMA Early Science survey of molecular absorption lines toward PKS 1830-211 Analysis of the absorption profiles
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 566
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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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| 42. |
- Muller, Sebastien, 1976, et al.
(författare)
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Detection of CH+, SH+, and their C-13- and S-34-isotopologues toward PKS 1830-211
- 2017
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 606
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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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| 43. |
- Muller, Sebastien, 1976, et al.
(författare)
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Detection of chloronium and measurement of the Cl-35/Cl-37 isotopic ratio at z=0.89 toward PKS 1830-211
- 2014
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 566
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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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| 44. |
- Muller, Sebastien, 1976, et al.
(författare)
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OH+ and H2O+ absorption toward PKS 1830-211
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 595, s. A128(1-10)
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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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| 45. |
- Noort, S., et al.
(författare)
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Analysis of rare driving events in pediatric acute myeloid leukemia
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 108:1, s. 48-60
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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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| 46. |
- van Weelderen, Romy E., et al.
(författare)
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Measurable residual disease and fusion partner independently predict survival and relapse risk in childhood KMT2A-rearranged acute myeloid leukemia : a study by the international Berlin-Frankfurt-Münster study group
- 2023
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 41:16, s. 2963-2974
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease.Methods: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS).Results: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS.Conclusion: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.
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| 47. |
- van Weelderen, Romy E., et al.
(författare)
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Optimized cytogenetic risk-group stratification of KMT2A-rearranged pediatric acute myeloid leukemia
- 2024
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 8:12, s. 3200-3213
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Tidskriftsartikel (refereegranskat)abstract
- A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying biological pathogenesis of KMT2A fusions and ACAs.
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| 48. |
- White, T., et al.
(författare)
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Clinical outcomes of second relapsed and refractory first relapsed paediatric AML: A retrospective study within the NOPHO-DB SHIP consortium
- 2022
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 197:6, s. 755-765
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Tidskriftsartikel (refereegranskat)abstract
- As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third-line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO-DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5-year pOS were 22±3% and 14±3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third-line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third-line therapy can be cured. © 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
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