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- Ederle, Joerg, et al.
(författare)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 4. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 5. |
- Cederwall, Bo, et al.
(författare)
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Evidence for a spin-aligned neutron-proton paired phase from the level structure of 92Pd
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 469:7328, s. 68-71
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Tidskriftsartikel (refereegranskat)abstract
- Shell structure and magic numbers in atomic nuclei were generally explained by pioneering work(1) that introduced a strong spin-orbit interaction to the nuclear shell model potential. However, knowledge of nuclear forces and the mechanisms governing the structure of nuclei, in particular far from stability, is still incomplete. In nuclei with equal neutron and proton numbers (N = Z), enhanced correlations arise between neutrons and protons (two distinct types of fermions) that occupy orbitals with the same quantum numbers. Such correlations have been predicted to favour an unusual type of nuclear superfluidity, termed isoscalar neutron-proton pairing(2-6), in addition to normal isovector pairing. Despite many experimental efforts, these predictions have not been confirmed. Here we report the experimental observation of excited states in the N = Z = 46 nucleus Pd-92. Gamma rays emitted following the Ni-58(Ar-36,2n)Pd-92 fusion-evaporation reaction were identified using a combination of state-of-the-art high-resolution c-ray, charged-particle and neutron detector systems. Our results reveal evidence for a spin-aligned, isoscalar neutron-proton coupling scheme, different from the previous prediction(2-6). We suggest that this coupling scheme replaces normal superfluidity (characterized by seniority coupling(7,8)) in the ground and low-lying excited states of the heaviest N = Z nuclei. Such strong, isoscalar neutron-proton correlations would have a considerable impact on the nuclear level structure and possibly influence the dynamics of rapid proton capture in stellar nucleosynthesis.
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| 6. |
- Godoy, Patricio, et al.
(författare)
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
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Forskningsöversikt (refereegranskat)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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| 7. |
- Ghazi Moradi, Farnaz, et al.
(författare)
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High-spin study of 162Ta
- 2011
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 84:6, s. 064312-
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Tidskriftsartikel (refereegranskat)abstract
- Excited states in the odd-odd neutron deficient nucleus (162)Ta (Z = 73, N = 89) have been studied for the first time. The gamma spectroscopy analysis using gamma - gamma - gamma coincidences revealed a strongly coupled rotational structure that was established up to large angular momentum states. The rotational band was assigned to the configuration pi h(11/2)[514]9/2 circle times nu i(13/2)[660]1/2 based on its rotational and electromagnetic properties. The data are interpreted within the framework of total Routhian surface calculations, which suggests an axially symmetric shape with a gamma-softminimum at beta(2) approximate to 0.16 and gamma approximate to 6 degrees. The crossing of the signature partners observed in heavier (N >= 91) odd-odd nuclides in this mass region is found to be absent at N = 89. This might be correlated with a change in S-band structure above the paired band crossing at these neutron numbers.
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| 8. |
- Ghazi Moradi, Farnaz, et al.
(författare)
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Spectroscopy of the neutron-deficient N=50 nucleus Rh-95
- 2014
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 89:4, s. 044310-
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Tidskriftsartikel (refereegranskat)abstract
- The neutron-deficient semimagic (neutron number N = 50) Rh-95 nucleus has been produced at high spins using the projectile-target system Ca-40 + Ni-58 at 125 MeV beam energy. The gamma-decays of levels populated by the 3p fusion evaporation reaction channel were studied using gamma-gamma coincidences, and 20 new gamma-ray transitions involving 15 new positive-and negative-parity states were observed. Spin and parity for many of the excited states were firmly deduced for the first time using the combined directional angular correlation and direction-polarization techniques. The observed structures are discussed within the framework of large-scale shell model calculations. E1 transition strengths were deduced and used together with the results of the shell model calculations to study the contribution of different particle-hole configurations, in particular for analyzing contributions from core-excited configurations.
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| 9. |
- Anderson, Beverley H., et al.
(författare)
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Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 338-342
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Tidskriftsartikel (refereegranskat)abstract
- Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous gamma H2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the alpha-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-alpha primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity.
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| 10. |
- Bäck, Torbjörn, et al.
(författare)
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Lifetime measurement of the first excited 2(+) state in (108)Te
- 2011
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Ingår i: Physical Review C. Nuclear Physics. - 0556-2813 .- 1089-490X. ; 84:4, s. 041306-
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Tidskriftsartikel (refereegranskat)abstract
- The lifetime of the first excited 2(+) state in the neutron deficient nuclide (108)Te has been measured for the first time, using a combined recoil decay tagging and recoil distance Doppler shift technique. The deduced reduced transition probability is B(E2;0(g.s.)(+) -> 2(+)) = 0.39(-0.04)(+0.05)e(2)b(2). Compared to previous experimental data on neutron deficient tellurium isotopes, the new data point constitutes a large step (six neutrons) toward the N = 50 shell closure. In contrast to what has earlier been reported for the light tin isotopes, our result for tellurium does not show any enhanced transition probability with respect to the theoretical predictions and the tellurium systematics including the new data is successfully reproduced by state-of-the-art shell model calculations.
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