| 1. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 2. |
- Gaulton, Kyle J, et al.
(författare)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Tidskriftsartikel (refereegranskat)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 3. |
- Wuttke, Matthias, et al.
(författare)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 4. |
- Birney, Ewan, et al.
(författare)
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Prepublication data sharing
- 2009
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 461:7261, s. 168-170
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Tidskriftsartikel (refereegranskat)abstract
- Rapid release of prepublication data has served the field of genomics well. Attendees at a workshop in Toronto recommend extending the practice to other biological data sets.
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| 5. |
- Teumer, A, et al.
(författare)
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Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4130-
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Tidskriftsartikel (refereegranskat)abstract
- Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria.
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| 6. |
- Dahlerup, Jens Frederik, et al.
(författare)
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High-dose fast infusion of parenteral iron isomaltoside is efficacious in inflammatory bowel disease patients with iron-deficiency anaemia without profound changes in phosphate or fibroblast growth factor 23
- 2016
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 51:11, s. 1332-1338
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Iron isomaltoside (Monofer®) is a high-dose intravenous iron preparation with good tolerability and efficacy in inflammatory bowel disease (IBD) patients with iron deficiency anaemia (IDA). This trial evaluates the safety and efficacy, including effect on intact fibroblast growth factor 23 (iFGF23) of a high single dose and cumulative doses of iron isomaltoside in IBD patients with IDA. Materials and methods: The trial was a prospective, open-label, multi-centre trial conducted in IBD patients with IDA. Based upon haemoglobin (Hb) levels at baseline and weight, the patients received 1500, 2000, 2500 or 3000 mg of iron isomaltoside infused in single doses up to 2000 mg. The outcome measurements included adverse drug reactions (ADRs) and changes in haematology and biochemistry parameters. Results: Twenty-one IBD patients with IDA were enrolled, receiving 1500 (seven patients), 2000 (eight patients), 2500 mg (four patients) or 3000 (two patients) mg of iron. No serious ADRs were observed. Four patients experienced nine mild to moderate ADRs (hypersensitivity, pyrexia, vomiting, constipation, abdominal pain, dyspepsia (two events) and eye allergy (two events)). In total, 15 (75%) patients had an increase in Hb of ≥2.0 g/dL during the trial, with normalisation of ferritin. No changes in iFGF23 or clinically significant hypophosphataemia were found. Conclusion: Rapid infusions of high-dose iron isomaltoside, administered as single doses up to 2000 mg and cumulative doses up to 3000 mg, were without safety concerns and were efficacious in increasing Hb levels in IBD patients. Iron isomaltoside did not induce profound phosphate wasting via increased iFGF23 levels.
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| 7. |
- Birgegård, Gunnar, et al.
(författare)
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A Randomized Noninferiority Trial of Intravenous Iron Isomaltoside versus Oral Iron Sulfate in Patients with Nonmyeloid Malignancies and Anemia Receiving Chemotherapy : The PROFOUND Trial
- 2016
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Ingår i: Pharmacotherapy. - : Wiley. - 0277-0008 .- 1875-9114. ; 36:4, s. 402-414
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Tidskriftsartikel (refereegranskat)abstract
- Study ObjectiveA safe alternative to erythropoiesis-stimulating agents to treat anemia is warranted in patients with cancer and anemia; thus the objective of this trial was to compare the efficacy and safety of intravenous (IV) iron isomaltoside with oral iron in patients with cancer and anemia by testing the noninferiority of IV versus oral iron. DesignPhase III, prospective, open-label, comparative, randomized, noninferiority, multicenter trial. SettingForty-seven hospitals or private cancer clinics in Asia, the United States, and Europe. PatientsA total of 350 patients with cancer and anemia. InterventionPatients were randomized in a 2:1 ratio to either intravenous iron isomaltoside or oral iron sulfate. Patients in the iron isomaltoside group were then randomized into an infusion subgroup (single intravenous infusions of a maximum dose of 1000 mg over 15 min) or a bolus injection subgroup (bolus injections of 500 mg over 2 min). Measurements and Main ResultsThe primary efficacy outcome was change in hemoglobin concentration from baseline to week 4. Changes in other relevant hematology variables, effect on quality of life, and safety outcomes were also assessed. The primary efficacy outcome was tested for noninferiority, whereas the remaining outcomes were tested for superiority. Iron isomaltoside was noninferior to oral iron in change in hemoglobin concentration from baseline to week 4 (difference estimate 0.016, 95% confidence interval -0.26 to 0.29, p<0.001). A faster onset of the hemoglobin response was observed with infusion of iron isomaltoside (superiority test: p=0.03 at week 1), and a sustained effect on hemoglobin level was shown in both the iron isomaltoside and oral iron treatment groups until week 24. A significant mean decrease in fatigue score was observed from baseline to week 12 in the iron isomaltoside group (p<0.001) but not in the oral iron group (p=0.057). A higher proportion of patients treated with oral iron experienced adverse drug reactions (18.8% vs 6.6%, p<0.001) and discontinued the trial due to intolerance (8.0% vs 0.9%, p=0.001). Transient hypophosphatemia (phosphate level less than 2 mg/dl) was reported at similar low frequencies among the groups: 7.1% in the iron isomaltoside infusion subgroup versus 8.5% in the iron isomaltoside bolus injection subgroup versus 5.4% in the oral iron group. ConclusionThis trial demonstrated comparable sustained increases in hemoglobin concentration over time with both iron isomaltoside and oral iron. Iron isomaltoside was better tolerated than oral iron, and fatigue was significantly decreased with iron isomaltoside. Low rates of clinically insignificant hypophosphatemia were reported in patients receiving both treatments.
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| 8. |
- Dahlin, Lars, et al.
(författare)
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Sequelae following sural nerve biopsy in type 1 diabetic subjects.
- 2008
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 118, s. 193-197
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Tidskriftsartikel (refereegranskat)abstract
- Objectives - To detect post-operative sequelae of sural nerve biopsy. Materials and methods-- A questionnaire mailed to type 1 diabetic patients (n = 24; male/female 23/1; reply n = 23) 2 years after biopsy. Results - Type 1 diabetic patients (age 56 [11]; median [interquartile range]) had a long duration of diabetes (DM; 20 [19] years) and all had neuropathy. Three out of 24 patients developed infection (two superficial and one deep) and one had a post-operative bleeding. Less frequent pain among the patients were reported from one centre. About one-third or more of the patients still complained of pain, mostly mild, in the biopsy area and paraesthesia in the foot 2 years after surgery. More than two-thirds of the patients were reluctant for further biopsy; a crucial information in drug trial planning. Conclusions - Sequelae of a sural nerve biopsy occur in type 1 DM. The risk for wound infections should be considered.
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| 9. |
- Holmes, Natalie P., et al.
(författare)
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Unravelling donor–acceptor film morphologyformation for environmentally-friendly OPV inkformulations
- 2019
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Ingår i: Green Chemistry. - : Royal Society of Chemistry. - 1463-9262 .- 1463-9270. ; 21:18, s. 5090-5103
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Tidskriftsartikel (refereegranskat)abstract
- The challenge of coating organic photovoltaics (OPV) from green solvents is to achieve the requirednanostructured interpenetrating network of donor and acceptor domains based on a rational choice ofsolvent approach as opposed to the usual trial-and-error methods. We demonstrate here that we canachieve a bicontinuous interpenetrating network with nanoscale phase separation for the chosen donor–acceptor material system poly[2,3-bis-(3-octyloxyphenyl)quinoxaline-5,8-diyl-alt-thiophene-2,5-diyl]:phenyl-C61 butyric acid methyl ester (TQ1:PC61BM) when processing from green solvent ink formulations.This structure is achieved by first calculating the Hansen solubility parameters (HSP) of the donor andacceptor materials, followed by careful choice of solvents with selective relative solubilities for the twomaterials based on the desired order of precipitation necessary for forming a nanostructured interdigitatednetwork morphology. We found that the relative distances in Hansen space (Ra) between TQ1 andthe primary solvent, on the one hand, and PC61BM and the primary solvent, on the other hand, could becorrelated to the donor–acceptor morphology for the formulations based on the solvents d-limonene,anisole, and 2-methyl anisole, as well as the halogenated reference solvent o-dichlorobenzene. Thisnanostructured blend film morphology was characterised with scanning transmission X-ray microscopy(STXM) and transmission electron microscopy (TEM), and the film surface composition was analysed bynear edge X-ray absorption fine structure (NEXAFS) spectroscopy. Hansen solubility theory, based onsolution thermodynamics, has been used and we propose an HSP-based method that is a general platformfor the rational design of ink formulations for solution-based organic electronics, in particular facilitatingthe green solvent transition of organic photovoltaics. Our results show that the bulk heterojunctionmorphology for a donor–acceptor system processed from customised solvent mixtures can be predictedby the HSP-based method with good reliability.
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| 10. |
- Jackson, Victoria E, et al.
(författare)
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Meta-analysis of exome array data identifies six novel genetic loci for lung function.
- 2018
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Ingår i: Wellcome open research. - : F1000 Research Ltd. - 2398-502X. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.
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| 11. |
- Johnsen, Nina Fans, et al.
(författare)
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Physical activity and risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 125:4, s. 902-908
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Tidskriftsartikel (refereegranskat)abstract
- The evidence concerning the possible association between physical activity and the risk of prostate cancer is inconsistent and additional data are needed. We examined the association between risk of prostate cancer and physical activity at work and in leisure time in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In our study, including 127,923 men aged 20-97 years from 8 European countries, 2,458 cases of prostate cancer were identified during 8.5 years of followup. Using the Cox proportional hazards model, we investigated the associations between prostate cancer incidence rate and occupational activity and leisure time activity in terms of participation in sports, cycling, walking and gardening; a metabolic equivalent (MET) score based on weekly time spent on the 4 activities; and a physical activity index. MET hours per week of leisure time activity, higher score in the physical activity index, participation in any of the 4 leisure time activities, and the number of leisure time activities in which the participants were active were not associated with prostate cancer incidence. However, higher level of occupational physical activity was associated with lower risk of advanced stage prostate cancer (p(trend) = 0.024). In conclusion, our data support the hypothesis of an inverse association between advanced prostate cancer risk and occupational physical activity, but we found no support for an association between prostate cancer risk and leisure time physical activity. (C) 2009 UICC
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| 12. |
- Leloudas, Giorgos, et al.
(författare)
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An asymmetric electron-scattering photosphere around optical tidal disruption events
- 2022
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Ingår i: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 6:10, s. 1193-1202
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Tidskriftsartikel (refereegranskat)abstract
- A star crossing the tidal radius of a supermassive black hole will be spectacularly ripped apart with an accompanying burst of radiation. A few tens of such tidal disruption events have now been identified in optical wavelengths, but the exact origin of the strong optical emission remains inconclusive. Here we report polarimetric observations of three tidal disruption events. The continuum polarization appears independent of wavelength, while emission lines are partially depolarized. These signatures are consistent with photons being scattered and polarized in an envelope of free electrons. An almost axisymmetric photosphere viewed from different angles is in broad agreement with the data, but there is also evidence for deviations from axial symmetry before the peak of the flare and significant time evolution at early times, compatible with the rapid formation of an accretion disk. By combining a super-Eddington accretion model with a radiative transfer code, we simulate the polarization degree as a function of disk mass and viewing angle and we show that the predicted levels are compatible with the observations for extended reprocessing envelopes of similar to 1,000 gravitational radii. Spectropolarimetry therefore constitutes a new observational test for tidal disruption event models, and opens an important new line of exploration in the study of tidal disruption events.
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| 13. |
- Thomsen, P, et al.
(författare)
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Joint fluid leukocyte activation by preformed immune complexes
- 1986
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Ingår i: Inflammation. - 0360-3997. ; 10:3, s. 243-256
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Tidskriftsartikel (refereegranskat)abstract
- Acute synovitis was induced in rabbit knee joints by intraarticular injection of preformed bovine serum albumin (BSA) -anti BSA immune complexes (ICs). Polymorphonuclear granulocytes (PMNGs) which had migrated into joints injected with ICs were degranulated and contained ICs as revealed by electron microscopy and were activated as revealed by the measurement of chemiluminescence (CL). In contrast, leukocytes from control joints injected with BSA and normal rabbit serum as well as glycogen-elicited peritoneal leukocytes did not display any morphological changes and did not show CL. Compared to cells from other sources, leukocytes from IC joints showed a decreased CL response when stimulated in vitro with ICs but not with opsonized zymosan, suggesting a stimulus-specific modification of the PMNG responsiveness. Inhibition experiments showed that oxygen radicals and formation of arachidonate metabolites, mainly of the lipoxygenase pathway, were involved in the CL response of the IC-stimulated joint fluid PMNGs. Our observations on morphology, activity, and responsiveness of emigrated cells from the various sources suggest, together with previous observations, that the reaction of leukocytes in IC-induced synovitis consists of an initial migration phase not related to an increased CL and a subsequent activation phase characterized by degranulation, phagocytosis of ICs and increased CL.
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| 14. |
- Thomsen, Peter, 1953, et al.
(författare)
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Structure of the interface between rabbit cortical bone and implants of gold, zirconium and titanium.
- 1997
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Ingår i: Journal of materials science. Materials in medicine. - 0957-4530. ; 8:11, s. 653-65
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Tidskriftsartikel (refereegranskat)abstract
- The role of surface properties (chemical and structural) for the interaction between biomaterials and tissue is not yet understood. In the present study, implants made of titanium, zirconium (transition metals with surface oxides) and gold (metallic surface) were inserted into the rabbit tibia. Light microscopic (LM) morphometry showed that after 1 and 6 mo the gold implants had less amount of bone within the threads and a lower degree of bone-implant contact than the titanium and zirconium implants, which did not differ from each other. These quantitative differences were supported by LM and ultrastructural observations of the interface. The ultrastructural observations in addition demonstrated that the layer of non-collagenous amorphous material located between the implant and the calcified bone was appreciably thicker around zirconium than around titanium implants. The factors potentially responsible for the observed morphological differences in the bone around the different material surfaces are discussed.
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| 15. |
- Wikström, Björn, et al.
(författare)
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Iron isomaltoside 1000 : a new intravenous iron for treating iron deficiency in chronic kidney disease
- 2011
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Ingår i: JN. Journal of Nephrology (Milano. 1992). - 1121-8428 .- 1724-6059. ; 24:5, s. 589-596
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with chronic kidney disease (CKD) often suffer from iron deficiency anemia necessitating treatment with intravenous iron. This study was designed to assess the safety of iron isomaltoside 1000 (Monofer) in CKD patients. The secondary objective was to assess its effect on iron deficiency anemia. Methods: This open-label, noncomparative, multi-center trial assigned 182 patients with CKD (n=161 in dialysis and n=21 in predialysis) to iron isomaltoside 1000 either as 4 intravenous bolus injections of 100-200 mg iron per dose or as a fast high-dose infusion at baseline. Patients were generally undergoing erythropoiesis-stimulating agent (ESA) treatment (82%), and the dosage was to be kept constant during the trial. They were either switched from an existing parenteral maintenance therapy (n=144) or were not currently being treated with parenteral iron (n=38). Frequency of adverse events (AEs) and changes in markers of iron deficiency anemia were measured during 8 weeks from baseline. Results: Nineteen treatment-related AEs occurred in 13 patients (7.1%) and after 584 treatments (3.3%). No anaphylactic or delayed allergic reactions were observed. There were no clinically significant changes in routine clinical laboratory tests or vital signs. Hemoglobin increased from 99.2 g/L (SD=9.0) at baseline to 111.2 g/L (SD=14.7) at week 8 in patients not currently treated with parenteral iron (p<0.001) and increased slightly or stabilized in patients in maintenance therapy. S-Ferritin, s-iron and transferrin saturation increased significantly at all visits. Conclusions: Iron isomaltoside 1000 was clinically well tolerated, safe and effective. This new intravenous iron may offer a further valuable choice in treating the anemia of CKD.
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| 16. |
- Zoller, Heinz, et al.
(författare)
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Hypophosphataemia following ferric derisomaltose and ferric carboxymaltose in patients with iron deficiency anaemia due to inflammatory bowel disease (PHOSPHARE-IBD) : A randomised clinical trial
- 2023
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 72:4, s. 644-653
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Intravenous iron - a common treatment for anaemia and iron deficiency due to inflammatory bowel disease (IBD) - can cause hypophosphataemia. This trial compared the incidence of hypophosphataemia after treatment with ferric carboxymaltose (FCM) or ferric derisomaltose (FDI). Design: This randomised, double-blind, clinical trial was conducted at 20 outpatient hospital clinics in Europe (Austria, Denmark, Germany, Sweden, UK). Adults with IBD and iron deficiency anaemia (IDA) were randomised 1:1 to receive FCM or FDI at baseline and at Day 35 using identical haemoglobin- and weight-based dosing regimens. The primary outcome was the incidence of hypophosphataemia (serum phosphate <2.0 mg/dL) at any time from baseline to Day 35 in the safety analysis set (all patients who received ≥1 dose of study drug). Markers of mineral and bone homeostasis, and patient-reported fatigue scores, were measured. Results: A total of 156 patients were screened; 97 (49 FDI, 48 FCM) were included and treated. Incident hypophosphataemia occurred in 8.3% (4/48) FDI-treated patients and in 51.0% (25/49) FCM-treated patients (adjusted risk difference: -42.8% (95% CI -57.1% to -24.6%) p<0.0001). Both iron formulations corrected IDA. Patient-reported fatigue scores improved in both groups, but more slowly and to a lesser extent with FCM than FDI; slower improvement in fatigue was associated with greater decrease in phosphate concentration. Conclusion: Despite comparably effective treatment of IDA, FCM caused a significantly higher rate of hypophosphataemia than FDI. Further studies are needed to address the longer-term clinical consequences of hypophosphataemia and to investigate mechanisms underpinning the differential effects of FCM and FDI on patient-reported fatigue.
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