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- Meeths, M, et al.
(författare)
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Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D
- 2011
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Ingår i: Blood. - Washington : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:22, s. 5783-5793
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Tidskriftsartikel (refereegranskat)abstract
- Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive, often-fatal hyperinflammatory disorder. Mutations in PRF1, UNC13D, STX11, and STXBP2 are causative of FHL2, 3, 4, and 5, respectively. In a majority of suspected FHL patients from Northern Europe, sequencing of exons and splice sites of such genes required for lymphocyte cytotoxicity revealed no or only monoallelic UNC13D mutations. Here, in 21 patients, we describe 2 pathogenic, noncoding aberrations of UNC13D. The first is a point mutation localized in an evolutionarily conserved region of intron 1. This mutation selectively impairs UNC13D transcription in lymphocytes, abolishing Munc13-4 expression. The second is a 253-kb inversion straddling UNC13D, affecting the 3'-end of the transcript and likewise abolishing Munc13-4 expression. Carriership of the intron 1 mutation was found in patients across Europe, whereas carriership of the inversion was limited to Northern Europe. Notably, the latter aberration represents the first description of an autosomal recessive human disease caused by an inversion. These findings implicate an intronic sequence in cell-type specific expression of Munc13-4 and signify variations outside exons and splice sites as a common cause of FHL3. Based on these data, we propose a strategy for targeted sequencing of evolutionary conserved noncoding regions for the diagnosis of primary immunodeficiencies.
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| 2. |
- Schleiermacher, G., et al.
(författare)
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Emergence of New ALK Mutations at Relapse of Neuroblastoma
- 2014
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 32:25, s. 2727-2734
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Tidskriftsartikel (refereegranskat)abstract
- Purpose In neuroblastoma, the ALK receptor tyrosine kinase is activated by point mutations. We investigated the potential role of ALK mutations in neuroblastoma clonal evolution. We analyzed ALK mutations in 54 paired diagnosis-relapse neuroblastoma samples using Sanger sequencing. When an ALK mutation was observed in one paired sample, a minor mutated component in the other sample was searched for by more than 100,000 x deep sequencing of the relevant hotspot, with a sensitivity of 0.17%. All nine ALK-mutated cases at diagnosis demonstrated the same mutation at relapse, in one case in only one of several relapse nodules. In five additional cases, the mutation seemed to be relapse specific, four of which were investigated by deep sequencing. In two cases, no mutation evidence was observed at diagnosis. In one case, the mutation was present at a subclonal level (0.798%) at diagnosis, whereas in another case, two different mutations resulting in identical amino acid changes were detected, one only at diagnosis and the other only at relapse. Further evidence of clonal evolution of ALK-mutated cells was provided by establishment of a fully ALK-mutated cell line from a primary sample with an ALK-mutated cell population at subclonal level (6.6%). In neuroblastoma, subclonal ALK mutations can be present at diagnosis with subsequent clonal expansion at relapse. Given the potential of ALK-targeted therapy, the significant spatiotemporal variation of ALK mutations is of utmost importance, highlighting the potential of deep sequencing for detection of subclonal mutations with a sensitivity 100-fold that of Sanger sequencing and the importance of serial samplings for therapeutic decisions.
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| 3. |
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| 4. |
- Choudhary, Mariam B, et al.
(författare)
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Low atrial fibrillatory rate is associated with spontaneous conversion of recent-onset atrial fibrillation.
- 2013
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Ingår i: Europace. - : Oxford University Press (OUP). - 1532-2092. ; 15:10, s. 1445-1452
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Atrial fibrillatory rate (AFR) is considered a non-invasive index of atrial remodelling. Low AFR has been associated with favourable outcome of interventions in patients with persistent atrial fibrillation (AF). However, AFR has never been studied in unselected patients with short duration of AF, prone to regain sinus rhythm (SR) spontaneously. The aim of the study was to assess if AFR can predict spontaneous conversion in patients with recent-onset AF.METHODS AND RESULTS: Files of consecutive patients with AF < 48 h seeking emergency room care during a 12-month period were screened (n = 225). Patients with thyroid illness, acute ischaemic heart disease (IHD) or acute congestive heart failure, significant valvular heart disease, congenital heart disease, history of cardiac surgery or catheter ablation, or on class I/III antiarrhythmics were excluded. Atrial fibrillatory rate was obtained by QRST cancellation and time frequency analysis of electrocardiogram at admission. The study population comprised 148 patients (age 64 ± 13 years, 52 men), of whom 48 converted to SR within 18 h. Those converting spontaneously comprised more women, had a higher prevalence of first-ever AF episode, IHD, and a lower AFR. The multivariate analysis revealed: AFR < 350 fibrillations per minute [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-10.5, P = 0.016], IHD (OR 5.7, 95% CI 1.5-22.4, P = 0.012) and first-ever AF episode (OR 4.1, 95% CI 1.3-13.0, P = 0.015) as independent predictors of spontaneous conversion.CONCLUSION: A low AFR was predictive of spontaneous conversion in patients with recent-onset AF. Along with first-ever AF episode and IHD, AFR can be used in assessing likelihood of spontaneous conversion, if proven in prospective studies.
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| 7. |
- Issa, Shams A. M., et al.
(författare)
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Proton-induced production of residual radionuclides in Re-nat up to 2590 MeV
- 2013
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Ingår i: Nuclear Instruments and Methods in Physics Research Section B. - : Elsevier BV. - 0168-583X .- 1872-9584. ; 298, s. 19-32
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Tidskriftsartikel (refereegranskat)abstract
- The excitation functions for residual nuclide production by proton reactions on rhenium was investigated using activated targets from irradiation experiments at the cyclotron of the Svedberg Laboratory at Uppsala up to 180 MeV and the higher energies were used at the Laboratoire Saturne at Saclay. The measured experimental results were compared with previous published and theoretical models calculations by the codes TALYS, INCL4 + ABLA and Bertini/Dresner. A total of 5252 cross-section was determined covering 54 residual nuclides in the energy range from 78.2 to 2590 MeV.
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