| 1. |
- Albrecht, Inka, et al.
(författare)
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Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
- 2015
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 125:12, s. 4612-4624
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Tidskriftsartikel (refereegranskat)abstract
- Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
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| 2. |
- Harnek, Jan, et al.
(författare)
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The 2011 outcome from the Swedish Health Care Registry on Heart Disease (SWEDEHEART)
- 2013
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Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 47, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) collects data to support the improvement of care for heart disease. Design. SWEDEHEART collects on-line data from consecutive patients treated at any coronary care unit n = (74), followed for secondary prevention, undergoing any coronary angiography, percutaneous coronary intervention, percutaneous valve or cardiac surgery. The registry is governed by an independent steering committee, the software is developed by Uppsala Clinical Research Center and it is funded by The Swedish national health care provider independent of industry support. Approximately 80,000 patients per year enter the database which consists of more than 3 million patients. Results. Base-line, procedural, complications and discharge data consists of several hundred variables. The data quality is secured by monitoring. Outcomes are validated by linkage to other registries such as the National Cause of Death Register, the National Patient Registry, and the National Registry of Drug prescriptions. Thanks to the unique social security number provided to all citizens follow-up is complete. The 2011 outcomes with special emphasis on patients more than 80 years of age are presented. Conclusion. SWEDEHEART is a unique complete national registry for heart disease.
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| 3. |
- Lazarevic, Vladimir, et al.
(författare)
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Failure matters : unsuccessful cytogenetics and unperformed cytogenetics are associated with a poor prognosis in a population-based series of acute myeloid leukaemia
- 2015
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Ingår i: European Journal of Haematology. - Hoboken, USA : Wiley-Blackwell. - 0902-4441 .- 1600-0609. ; 94:5, s. 419-423
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Tidskriftsartikel (refereegranskat)abstract
- Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis.
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| 4. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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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.
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| 5. |
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| 6. |
- Lazarevic, Vladimir, et al.
(författare)
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Prognostic significance of high hyperdiploid and triploid/tetraploid adult acute myeloid leukemia
- 2015
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Ingår i: American Journal of Hematology. - : WILEY-BLACKWELL. - 0361-8609 .- 1096-8652. ; 90:9, s. 800-805
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Tidskriftsartikel (refereegranskat)abstract
- To ascertain the clinical implications of high hyperdiploid (HH; 49-65 chromosomes) and triploid/tetraploid (TT; greater than65 chromosomes) adult acute myeloid leukemia (AML), all such cases were retrieved from the Swedish AML Registry. Of the 3,654 cytogenetically informative cases diagnosed between January 1997 and May 2014, 68 (1.9%) were HH (n=50)/TT (n=18). Patients with HH/TT were older than those with intermediate risk (IR) AML (median 71 years vs. 67 years; P=0.042) and less often had de novo AML (63% vs. 79%; P=0.004); no such differences were observed between HH/TT and complex karyotype (CK) AML. The overall survival (OS) was similar between patients with HH/TT and CK AML (median 0.9 years vs. 0.6 years; P=0.082), whereas OS was significantly longer (median 1.6 years; P=0.028) for IR AML. The OS was shorter for cases with HH than with TT (median 0.6 years vs. 1.4 years; P=0.032) and for HH/TT AMLs with adverse abnormalities (median 0.8 years vs. 1.1 years; P=0.044). In conclusion, HH/TT AML is associated with a poor outcome, but chromosome numbers greater than65 and absence of adverse aberrations seem to translate into a more favorable prognosis. Thus, HH/TT AMLs are clinically heterogeneous and should not automatically be grouped as high risk.Am. J. Hematol. 90:800-805, 2015. (c) 2015 Wiley Periodicals, Inc.
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| 7. |
- Pelaseyed, Thaher, 1979, et al.
(författare)
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Unfolding dynamics of the mucin SEA domain probed by force spectroscopy suggest that it acts as a cell-protective device.
- 2013
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Ingår i: The FEBS journal. - : Wiley. - 1742-4658 .- 1742-464X. ; 280:6, s. 1491-501
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Tidskriftsartikel (refereegranskat)abstract
- MUC1 and other membrane-associated mucins harbor long, up to 1 μm, extended highly glycosylated mucin domains and sea urchin sperm protein, enterokinase and agrin (SEA) domains situated on their extracellular parts. These mucins line luminal tracts and organs, and are anchored to the apical cell membrane by a transmembrane domain. The SEA domain is highly conserved and undergoes a molecular strain-dependent autocatalytic cleavage during folding in the endoplasmic reticulum, a process required for apical plasma membrane expression. To date, no specific function has been designated for the SEA domain. Here, we constructed a recombinant protein consisting of three SEA domains in tandem and used force spectroscopy to assess the dissociation force required to unfold individual, folded SEA domains. Force-distance curves revealed three peaks, each representing unfolding of a single SEA domain. Fitting the observed unfolding events to a worm-like chain model yielded an average contour length of 32 nm per SEA domain. Analysis of forces applied on the recombinant protein revealed an average unfolding force of 168 pN for each SEA domain at a loading rate of 25 nN·s(-1). Thus, the SEA domain may act as a breaking point that can dissociate before the plasma membrane is breached when mechanical forces are applied to cell surfaces.
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| 8. |
- Bohman, Anton, et al.
(författare)
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Heredity of nasal polyps
- 2015
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Ingår i: Rhinology. - 0300-0729 .- 1996-8604. ; 53:1, s. 25-28
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Tidskriftsartikel (refereegranskat)abstract
- Background: Nasal polyps is a common disease but little is known about its' pathogenesis. Our hypothesis was that there are genetic factors involved in the development of this disease. The aim of this study was to examine close relatives of patients with nasal polyps and comparing them with a general population with regard to prevalence of polyps. Methodology: Patients with nasal polyps who attended the clinic were recruited to the study and were asked whether they had any close adult relatives (siblings, parents or children). We intended to recruit two relatives per patient, one of each gender, for nasal endoscopy. The prevalence of nasal polyps in these relatives was compared with the prevalence of nasal polyps in a general population. Results: During a 4-year period, 368 patients and 410 relatives were recruited to the study. Although we were unable to recruit two close relatives for every patient, we were able to calculate nasal polyp prevalence within families as being 19.2%. Compared with the prevalence of nasal polyps among individuals in a general Swedish population from the same geographical area, the relative risk for polyps among relatives was almost five times higher. Conclusion: This study strongly indicates that heredity is a factor of importance for development of nasal polyps.
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| 9. |
- Hjelmervik, Trond Ove R., et al.
(författare)
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The influence of the NOD Nss1/Idd5 loci on sialadenitis and gene expression in salivary glands of congenic mice
- 2007
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- The nonobese diabetic ( NOD) Nss1 and Idd5 loci have been associated with sialadenitis development in mice. In this study the NOD Nss1 and Idd5 loci were backcrossed onto the healthy control strain B10. Q by using the speed congenic breeding strategy, resulting in three congenic strains: B10. Q. Nss1, B10. Q. Nss1/Idd5 heterozygous and B10. Q. Nss1/Idd5 homozygous. We investigated the effects of the Nss1 and Idd5 loci on sialadenitis and gene expression in NOD congenic mice. One submandibular salivary gland from each mouse was used for histological analysis of sialadenitis, whereas the contralateral salivary gland was used for gene expression profiling with the Applied Biosystems Mouse Genome Survey chip v. 1.0. The results were validated using quantitative reverse transcriptase PCR. The NOD Nss1 and Idd5 loci had clear influence on the onset and progression of sialadenitis in congenic mice. Double congenic mice exhibited the most severe phenotype. We successfully identified several genes that are located in the NOD congenic regions to be differentially expressed between the congenic strains and the control strain. Several of these were found to be co-regulated, such as Stat1, complement component C1q genes and Tlr12. Also, a vast contingency of interferon-regulated genes ( such as Ltb, Irf7 and Irf8) and cytokine and chemokine genes ( such as Ccr7 and Ccl19) were differentially expressed between the congenic strains and the control strain. Over-representation of inflammatory signalling pathways was observed among the differentially expressed genes. We have found that the introgression of the NOD loci Nss1 and Idd5 on a healthy background caused sialadenitis in NOD congenic mouse strains, and we propose that genes within these loci are important factors in the pathogenesis. Furthermore, gene expression profiling has revealed several differentially expressed genes within and outside the NOD loci that are similar to genes found to be differentially expressed in patients with Sjogren's syndrome, and as such are interesting candidates for investigation to enhance our understanding of disease mechanisms and to develop future therapies.
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| 10. |
- Moayyeri, Alireza, et al.
(författare)
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Genetic determinants of heel bone properties : genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:11, s. 3054-3068
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 x 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 x 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 x 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
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