1. |
- Campbell, PJ, et al.
(författare)
-
Pan-cancer analysis of whole genomes
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
|
|
2. |
- Bar, N., et al.
(författare)
-
A reference map of potential determinants for the human serum metabolome
- 2020
-
Ingår i: Nature. - : Nature Research. - 0028-0836 .- 1476-4687. ; 588:7836, s. 135-140
-
Tidskriftsartikel (refereegranskat)abstract
- The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites.
|
|
3. |
- Gilbert, M. R., et al.
(författare)
-
Perspectives on multiscale modelling and experiments to accelerate materials development for fusion
- 2021
-
Ingår i: Journal of Nuclear Materials. - : Elsevier BV. - 0022-3115 .- 1873-4820. ; 554
-
Forskningsöversikt (refereegranskat)abstract
- Prediction of material performance in fusion reactor environments relies on computational modelling, and will continue to do so until the first generation of fusion power plants come on line and allow long-term behaviour to be observed. In the meantime, the modelling is supported by experiments that attempt to replicate some aspects of the eventual operational conditions. In 2019, a group of leading experts met under the umbrella of the IEA to discuss the current position and ongoing challenges in modelling of fusion materials and how advanced experimental characterisation is aiding model improvement. This review draws from the discussions held during that workshop. Topics covering modelling of irradiation-induced defect production and fundamental properties, gas behaviour, clustering and segregation, defect evolution and interactions are discussed, as well as new and novel multiscale simulation approaches, and the latest effort s to link modelling to experiments through advanced observation and characterisation techniques.
|
|
4. |
- Heggebo, L. C., et al.
(författare)
-
Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden
- 2023
-
Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 13:3
-
Tidskriftsartikel (refereegranskat)abstract
- IntroductionThe use of proton therapy increases globally despite a lack of randomised controlled trials demonstrating its efficacy and safety. Proton therapy enables sparing of non-neoplastic tissue from radiation. This is principally beneficial and holds promise of reduced long-term side effects. However, the sparing of seemingly non-cancerous tissue is not necessarily positive for isocitrate dehydrogenase (IDH)-mutated diffuse gliomas grade 2-3, which have a diffuse growth pattern. With their relatively good prognosis, yet incurable nature, therapy needs to be delicately balanced to achieve a maximal survival benefit combined with an optimised quality of life.Methods and analysisPRO-GLIO (PROton versus photon therapy in IDH-mutated diffuse grade 2 and 3 GLIOmas) is an open-label, multicentre, randomised phase III non-inferiority study. 224 patients aged 18-65 years with IDH-mutated diffuse gliomas grade 2-3 from Norway and Sweden will be randomised 1:1 to radiotherapy delivered with protons (experimental arm) or photons (standard arm). First intervention-free survival at 2 years is the primary endpoint. Key secondary endpoints are fatigue and cognitive impairment, both at 2 years. Additional secondary outcomes include several survival measures, health-related quality of life parameters and health economy endpoints.Ethics and disseminationTo implement proton therapy as part of standard of care for patients with IDH-mutated diffuse gliomas grade 2-3, it should be deemed safe. With its randomised controlled design testing proton versus photon therapy, PRO-GLIO will provide important information for this patient population concerning safety, cognition, fatigue and other quality of life parameters. As proton therapy is considerably more costly than its photon counterpart, cost-effectiveness will also be evaluated. PRO-GLIO is approved by ethical committees in Norway (Regional Committee for Medical & Health Research Ethics) and Sweden (The Swedish Ethical Review Authority) and patient inclusion has commenced. Trial results will be published in international peer-reviewed journals, relevant conferences, national and international meetings and expert forums.Trial registration numberClinicalTrials.gov Registry (NCT05190172).
|
|
5. |
|
|
6. |
- Nordenskjöld, Anna, 1977-, et al.
(författare)
-
Randomized evaluation of beta blocker and ACE-inhibitor/angiotensin receptor blocker treatment in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA-BAT): Rationale and design
- 2021
-
Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 231, s. 96-104
-
Tidskriftsartikel (refereegranskat)abstract
- Background Myocardial infarction with non-obstructive coronary arteries (MINOCA) is common and occurs in 6-8% of all patients fulfilling the diagnostic criteria for acute myocardial infarction (AMI). This paper describes the rationale behind the trial 'Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment (ACEI/ARB) of MINOCA patients' (MINOCA-BAT) and the need to improve the secondary preventive treatment of MINOCA patients. Methods MINOCA-BAT is a registry-based, randomized, parallel, open-label, multicenter trial with 2:2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce the composite endpoint of death of any cause, readmission because of AMI, ischemic stroke or heart failure in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction >= 40%. A total of 3500 patients will be randomized into four groups; e.g. ACEI/ARB and beta blocker, beta blocker only, ACEI/ARB only and neither ACEI/ARB nor beta blocker, and followed for a mean of 4 years. Summary While patients with MINOCA have an increased risk of serious cardiovascular events and death, whether conventional secondary preventive therapies are beneficial has not been assessed in randomized trials. There is a limited basis for guideline recommendations in MINOCA. Furthermore, studies of routine clinical practice suggest that use of secondary prevention therapies in MINOCA varies considerably. Thus results from this trial may influence future treatment strategies and guidelines specific to MINOCA patients.
|
|
7. |
|
|
8. |
|
|
9. |
|
|
10. |
- Alexandrov, Ludmil B, et al.
(författare)
-
The repertoire of mutational signatures in human cancer
- 2020
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 578:7793, s. 94-101
-
Tidskriftsartikel (refereegranskat)abstract
- Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3-15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
|
|
11. |
- Bak-Coleman, Joseph B., et al.
(författare)
-
Stewardship of global collective behavior
- 2021
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 118:27
-
Tidskriftsartikel (refereegranskat)abstract
- Collective behavior provides a framework for understanding how the actions and properties of groups emerge from the way individuals generate and share information. In humans, information flows were initially shaped by natural selection yet are increasingly structured by emerging communication technologies. Our larger, more complex social networks now transfer high-fidelity information over vast distances at low cost. The digital age and the rise of social media have accelerated changes to our social systems, with poorly understood functional consequences. This gap in our knowledge represents a principal challenge to scientific progress, democracy, and actions to address global crises. We argue that the study of collective behavior must rise to a crisis discipline just as medicine, conservation, and climate science have, with a focus on providing actionable insight to policymakers and regulators for the stewardship of social systems.
|
|
12. |
|
|
13. |
|
|
14. |
|
|
15. |
|
|
16. |
- Lonnblom, E, et al.
(författare)
-
AUTOANTIBODIES TO JOINT PROTEINS AS NOVEL BIOMARKERS FOR THE DIAGNOSIS OF UNTREATED EARLY RHEUMATOID ARTHRITIS
- 2022
-
Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 546-546
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Autoantibodies to citrullinated protein (ACPA; measured as anti-CCP; aCCP) and rheumatoid factor (RF) appear years before clinical onset of RA and are essential tools in today’s classification criteria for RA. In animal models, antibodies to joint specific proteins (JP) can induce arthritis, and they are also present at onset of RA [1]. As there is a need for increased precision for early diagnosis of RA as well as identification of different subtypes of the disease, we aim to assess whether autoantibodies to native or modified JP can be used for early and precise diagnosis of RA.ObjectivesTo study whether antibodies to JP, alone or in combination with ACPA/RF, could increase the diagnostic sensitivity and specificity in untreated early (ue)RA patients.MethodsAntibodies to JP were analysed in serum from patients in three independent ueRA cohorts as well as from population controls without rheumatic diseases (WINGA, Gothenburg and MFM-ÅUS, Malmö n=1062). ERAp (n=66), the smallest and most recent cohort was chosen for screening, and BARFOT and TIRA-2 (n=1939) for validation. We have developed a bead-based multianalyte flow immunoassay [2] and screened approx. 350 peptides derived from JPs of interest. We included monoclonal antibodies as assay calibrators and determined limit of detection (LoD). To assess positivity for autoantibodies to JP of interest above LoD, we used 5MAD (median absolute deviation) of the control populations as the cut-off.ResultsIn the ERAp cohort, 5 autoantibodies discriminated RA patients from controls with 81% sensitivity and 100% specificity (Table 1). The same autoantibodies had 68% sensitivity and 98% specificity in the combined BARFOT and TIRA-2 cohorts. Together with RF and aCCP, only 2 of the 5 autoantibodies added statistically significant diagnostic value, increasing the sensitivity from 48% to 61% with 99% specificity. In aCCP- and RF-negative ueRA patients (n=536), the novel biomarkers identified 22.5% of the patients with 99% specificity compared to controls.Table 1.Diagnostic capacity of the joint-specific antibodiesTest panelPerformanceGroup of patientsaCCP+RF+JP+SensitivitySpecificityAUC(ROC)ERApAll patients (n=66)--X81%100%89%RF and aCCP-neg patients (n=7)1------BARFOT and TIRA-2, combined dataAll patients (N=1939)--X68%98%86%All patients (N=1939)X--58%99%78%All patients (N=1939)2XX-48%100%84%All patients (N=1939)2, 3XXX61%99%86%RF and/or aCCP-pos patients (N=1403)--X84%99%93%RF and aCCP-neg patients (N=536)--X22%99%67%RA, literature valuesAnti-CCP testXN/AN/A53–71%95–96%N/A1Not analysed due to lack of power2This patient population is both aCCP+ and RF+3Only 2 of the 5 autoantibodies added statistically significant to the diagnostic valueAUC, Area under the curve; ROC, receiver operating characteristic curve; N/A, not applicable. Controls without rheumatic diseases: N=935 for BARFOT / TIRA-2 and N=27 for ERAp.ConclusionAutoantibodies to JP discriminate ueRA patients better then aCCP and RF alone and add an increased diagnostic value in particular for seronegative patients.References[1]Holmdahl, R., V. Malmstrom, and H. Burkhardt, Autoimmune priming, tissue attack and chronic inflammation - the three stages of rheumatoid arthritis. Eur J Immunol, 2014. 44(6): p. 1593-9.[2]Viljanen, J., et al., Synthesis of an Array of Triple-Helical Peptides from Type II Collagen for Multiplex Analysis of Autoantibodies in Rheumatoid Arthritis. ACS Chem Biol, 2020. 15(9): p. 2605-2615. Correction: ACS Chem Biol, 2020. 15(11): p. 3072AcknowledgementsBARFOT study group.Disclosure of InterestsErik Lönnblom: None declared, Monica Leu Agelii: None declared, Outi Sareila Employee of: Part time employee in Vacara AB, Ingiäld Hafström: None declared, Maria Andersson: None declared, Lei Cheng: None declared, Göran Bergström: None declared, Anna-Karin H Ekwall: None declared, Anna Rudin: None declared, Alf Kastbom: None declared, Christopher Sjowall: None declared, Bingze Xu: None declared, Lennart T.H. Jacobsson: None declared, Johan Viljanen: None declared, Jan Kihlberg: None declared, Inger Gjertsson: None declared, Rikard Holmdahl Shareholder of: Rikard Holmdahl the founder of Vacara AB.
|
|
17. |
|
|
18. |
|
|
19. |
|
|
20. |
|
|
21. |
- Vertzoni, M., et al.
(författare)
-
UNGAP best practice for improving solubility data quality of orally administered drugs
- 2022
-
Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier. - 0928-0987 .- 1879-0720. ; 168
-
Tidskriftsartikel (refereegranskat)abstract
- An important goal of the European Cooperation in Science and Technology (COST) Action UNGAP (UNder-standing Gastrointestinal Absorption-related Processes, www.ungap.eu) is to improve standardization of methods relating to the study of oral drug absorption. Solubility is a general term that refers to the maximum achievable concentration of a compound dissolved in a liquid medium. For orally administered drugs, relevant information on drug properties is crucial during drug (product) development and at the regulatory level. Collection of reliable and reproducible solubility data requires careful application and understanding of the limitations of the selected experimental method. In addition, the purity of a compound and its solid state form, as well as experimental parameters such as temperature of experimentation, media related factors, and sample handling procedures can affect data quality. In this paper, an international consensus developed by the COST UNGAP network on recommendations for collecting high quality solubility data for the development of orally administered drugs is proposed.
|
|
22. |
|
|
23. |
|
|
24. |
|
|
25. |
|
|
26. |
|
|
27. |
|
|
28. |
|
|
29. |
|
|
30. |
|
|
31. |
- Bräutigam, Matilda, 1975, et al.
(författare)
-
Linguistic and content validity of the Swedish version of the PedsQL (TM) gastrointestinal symptoms scales and symptoms module for paediatric patients
- 2021
-
Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 110:11, s. 3124-3130
-
Tidskriftsartikel (refereegranskat)abstract
- Aim To describe the process of linguistic and content validity of the Swedish version of the PedsQL (TM) Gastrointestinal Symptoms Scales and Symptoms Module, measuring health-related quality of life (HRQOL) in children with gastrointestinal (GI) disorders. Methods The establishment of linguistic and content validity was carried out in compliance with international standards on patient-reported outcome measurements. The process included forward translation, expert review and reconciliation, backward translation, backward translation review and interviews with 15 children aged 5-18 years with GI tract symptoms and 20 parents of children with GI tract symptoms aged 2-18 years. Results The Swedish version of the PedsQL (TM) Gastrointestinal Symptoms Scales and Symptoms Module (child report 5-18 years, parent report for children 2-18 years) was achieved without major difficulties. Eight issues needed discussion after forward translation, and there was one change after backward translation and three revisions following patient and parent testing. Conclusion A conceptually equivalent Swedish language version of PedsQL (TM) Gastrointestinal Symptoms Scale and Symptoms Module for children aged 2-18 years old was developed. This enables improved HRQOL evaluations in children with GI disorders in Sweden. Future research using a larger sample is recommended to evaluate validity and reliability of the Swedish language version of the module.
|
|
32. |
|
|
33. |
|
|
34. |
|
|
35. |
|
|
36. |
|
|
37. |
|
|
38. |
|
|
39. |
|
|
40. |
|
|
41. |
- Kivisto, JE, et al.
(författare)
-
Paediatric asthma hospitalisations continue to decrease in Finland and Sweden between 2015 and 2020
- 2023
-
Ingår i: Thorax. - : BMJ. - 1468-3296 .- 0040-6376. ; 78:3, s. 313-315
-
Tidskriftsartikel (refereegranskat)abstract
- We previously reported a decreasing incidence of paediatric asthma hospitalisations in Finland, but a rather stable trend in Sweden, between 2005 and 2014. We now aimed to investigate the incidence of paediatric asthma hospitalisations in these countries between 2015 and 2020, using Finland’s National Hospital Discharge Register and Sweden’s National Patient Register, which cover all hospitalisations in the respective countries. From 2015 to 2019, the incidence of paediatric asthma hospitalisations decreased by 36.7% in Finland and by 39.9% in Sweden and are increasingly approaching parity. In 2020, despite differences in COVID-19-related restrictions, asthma hospitalisations decreased by over 40%, thus warranting future research on the subject.
|
|
42. |
|
|
43. |
|
|
44. |
|
|
45. |
|
|
46. |
|
|
47. |
- Mogensen, I, et al.
(författare)
-
Lung function in young adulthood: differences between males and females with asthma
- 2022
-
Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 8:2
-
Tidskriftsartikel (refereegranskat)abstract
- There are phenotypic differences in asthma in males and females. Differences in lung function between the sexes at the peak lung function level in young adulthood are so far not directly addressed. The aim of the present study was to assess lung function in early adulthood in males and females depending on asthma onset and remission.MethodsParticipants were included from the population-based birth cohort BAMSE and classified as having: never asthma, childhood asthma in remission, adolescent onset asthma or persistent asthma. Pre- and post-bronchodilator lung function (in Z-score) and lung clearance index (LCI) were measured at age 24 years. Lung function was compared stratified for sex between the never asthma and asthma groups univariately and in multiple linear regression analyses adjusted for maternal and paternal asthma, maternal smoking during pregnancy, secondary smoking, daily smoking, early respiratory syncytial virus infection, traffic pollution, childhood allergic sensitisation, and body mass index at age 24 years.ResultsAll asthma phenotypes were associated with a lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) post-bronchodilation at 24 years. This was most pronounced in males with persistent asthma compared to males with never asthma (regression coefficient: −0.503; 95% CI: −0.708– −0.298). Childhood asthma (in remission or persistent) was associated with a lower FEV1. After adjustment, the associations remained significant for males. For females, the significant associations with lower FEV1 and FEV1/FVC remained only for subjects with asthma in remission. Persistent asthma was associated with higher LCI in females.ConclusionsIn females, in contrast to males, the association between asthma and lower lung function was attenuated after adjustment for known risk factors.
|
|
48. |
|
|
49. |
- Mogensen, I, et al.
(författare)
-
Uncontrolled asthma from childhood to young adulthood associates with airflow obstruction
- 2021
-
Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 7:4
-
Tidskriftsartikel (refereegranskat)abstract
- Lung function development from childhood to young adulthood is important for lung health later in life. We investigated the association between asthma control and lung function from 8 to 24 years of age.MethodsA total of 668 participants from the population-based BAMSE cohort study, with persistent or incidental asthma and between 8 and 24 years of age, were included. Asthma was defined as controlled or uncontrolled at each examination based on the Global Initiative for Asthma (GINA) criteria. Dynamic spirometry was performed at 8, 16 and 24 years of age. Associations between uncontrolled asthma and pre-bronchodilation forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were evaluated with a generalised estimating equation model, as overall associations and at each examination. Unadjusted and adjusted (for sex, current asthma, allergic sensitisation, body mass index, smoking, smoke exposure, inhaled corticosteroid use) analyses were done; and were thereafter stratified by sex, elevated blood eosinophils (≥0.3×109 cells·µL−1), elevated FENO (≥25 ppb), allergic sensitisation and ever/never smoking.ResultsUncontrolled asthma was associated with a lower overall FEV1/FVC z-score from 8 to 24 years of age (adjusted regression coefficient −0.11; 95% CI (−0.20 to −0.02; p=0.016). After stratification, this association was primarily seen among females (adjusted regression coefficient −0.170; 95% CI (−0.298 to −0.044; p=0.009) and participants with elevated FENO (regression coefficient −0.207; 95% CI −0.342 to −0.073; p=0.002), in contrast to males and participants with normal FENO.ConclusionUncontrolled asthma is associated with airflow obstruction from childhood to young adulthood. This highlights the importance of active management of asthma during growth.
|
|
50. |
|
|