| 11. |
- Nymo, St., et al.
(författare)
-
Serum neutrophil gelatinase-associated lipocalin (NGAL) concentration is independently associated with mortality in patients with acute coronary syndrome.
- 2018
-
Ingår i: International journal of cardiology. - : Elsevier BV. - 1874-1754 .- 0167-5273. ; 262, s. 79-84
-
Tidskriftsartikel (refereegranskat)abstract
- Circulating neutrophil gelatinase-associated lipocalin (NGAL) concentration increases in cardiovascular disease, but the long-term prognostic value of NGAL concentration has not been evaluated in acute coronary syndrome (ACS). We examined the association between NGAL concentration and prognosis in patients with ACS after non-ST-elevation myocardial infarction (NSTEMI) or STEMI.NGAL concentration was measured in blood from 1121 consecutive ACS patients (30% women, mean age 65years) on the first morning after admission. After adjustment for 14 variables, NGAL concentration predicted long-term (median 167months) mortality (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.10-1.61, P=0.003) for quartile (q) 4 of NGAL concentration. NGAL concentrations also predicted long-term mortality (HR=1.63, 95% CI 1.31-2.03, P<0.001, N=741) when adjusting for Global Registry of Acute Coronary Events (GRACE) score, left ventricular ejection fraction (LVEF), and pro-B-type natriuretic peptide (proBNP) and C-reactive protein (CRP) concentrations. With these adjustments, NGAL concentration predicted long-term mortality in NSTEMI patients (HR=2.02, 95% CI 1.50-2.72, P<0.001) but not in STEMI patients (HR=1.32, 95% CI 0.95-1.83, P=0.100). In all patients, the combination of NGAL concentration and GRACE score yielded an HR of 5.56 (95% CI 4.37-7.06, P<0.001) for q4/q4 for both variables.NGAL concentration in ACS is associated with long-term prognosis after adjustment for clinical confounders. Measuring circulating NGAL concentration may help to identify patients-particularly those with NSTEMI-needing closer follow-up after ACS.
|
|
| 12. |
- Olsson, Mia, et al.
(författare)
-
A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs
- 2011
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3, s. e1001332-
-
Tidskriftsartikel (refereegranskat)abstract
- Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (p(raw) = 2.3 x 10(-6), p(genome) = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p, < 0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.
|
|
| 13. |
- Parris, Toshima Z, 1978, et al.
(författare)
-
Genome-wide multi-omics profiling of the 8p11-p12 amplicon in breast carcinoma.
- 2018
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 9:35, s. 24140-24154
-
Tidskriftsartikel (refereegranskat)abstract
- Genomic instability contributes to the neoplastic phenotype by deregulating key cancer-related genes, which in turn can have a detrimental effect on patient outcome. DNA amplification of the 8p11-p12 genomic region has clinical and biological implications in multiple malignancies, including breast carcinoma where the amplicon has been associated with tumor progression and poor prognosis. However, oncogenes driving increased cancer-related death and recurrent genetic features associated with the 8p11-p12 amplicon remain to be identified. In this study, DNA copy number and transcriptome profiling data for 229 primary invasive breast carcinomas (corresponding to 185 patients) were evaluated in conjunction with clinicopathological features to identify putative oncogenes in 8p11-p12 amplified samples. Illumina paired-end whole transcriptome sequencing and whole-genome SNP genotyping were subsequently performed on 23 samples showing high-level regional 8p11-p12 amplification to characterize recurrent genetic variants (SNPs and indels), expressed gene fusions, gene expression profiles and allelic imbalances. We now show previously undescribed chromothripsis-like patterns spanning the 8p11-p12 genomic region and allele-specific DNA amplification events. In addition, recurrent amplification-specific genetic features were identified, including genetic variants in the HIST1H1E and UQCRHL genes and fusion transcripts containing MALAT1 non-coding RNA, which is known to be a prognostic indicator for breast cancer and stimulated by estrogen. In summary, these findings highlight novel candidate targets for improved treatment of 8p11-p12 amplified breast carcinomas.
|
|
| 14. |
|
|
| 15. |
- Purhonen, J., et al.
(författare)
-
A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- We previously observed an unexpected fivefold (35 vs. 200 days) difference in the survival of respiratory chain complex III (CIII) deficient Bcs1/(p.S78G) mice between two congenic backgrounds. Here, we identify a spontaneous homoplasmic mtDNA variant (m.G14904A, mt-Cyb(p.D254N)), affecting the CIII subunit cytochrome b (MT-CYB), in the background with short survival. We utilize maternal inheritance of mtDNA to confirm this as the causative variant and show that it further decreases the low CIII activity in Bcs1/(p.S78G) tissues to below survival threshold by 35 days of age. Molecular dynamics simulations predict D254N to restrict the flexibility of MT-CYB ef loop, potentially affecting RISP dynamics. In Rhodobacter cytochrome bc(1) complex the equivalent substitution causes a kinetics defect with longer occupancy of RISP head domain towards the quinol oxidation site. These findings represent a unique case of spontaneous mitonuclear epistasis and highlight the role of mtDNA variation as modifier of mitochondrial disease phenotypes.
|
|
| 16. |
- Sun, Ying, et al.
(författare)
-
Glomerular Transcriptome Changes Associated with Lipopolysaccharide-Induced Proteinuria
- 2009
-
Ingår i: American Journal of Nephrology. - : S. Karger AG. - 0250-8095 .- 1421-9670. ; 29:6, s. 558-570
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Global gene expression patterns have recently been characterized in normal glomeruli, but gene expression changes that accompany glomerular disease remain poorly characterized. Method: Here, we mapped global glomerular gene expression profile changes occurring in conjunction with lipopolysaccharide (LPS)-induced proteinuria in mice. Results: We observed dramatic transcriptional reprogramming in glomeruli in response to LPS, representing some 20% of all genes and about 45% of the genes that are normally highly expressed in glomeruli. Bioinformatic analysis revealed significant changes in transcripts encoding proteins involved in the regulation of adherence junctions, actin cytoskeleton and survival in podocytes. In the LPS-treated mice, we observed dysregulation of genes expressed in glomerular endothelial and mesangial cells and in podocytes, there was also a significant decrease in podocyte number. Moreover, collagen alpha 1, alpha 2 (IV) and laminin 10 (laminin alpha 5 beta 1 gamma 1), which are expressed in immature glomeruli, were upregulated in the glomeruli of LPS-treated mice, suggesting remodeling of the glomerular basement membrane and activation of mesangial cells. By superimposing the LPS-induced changes onto GlomNet, a protein-protein interaction network was predicted for podocyte proteins affected by LPS. Conclusions: The detected changes in glomerular gene expression and their involvement in protein interaction networks provide putative markers for early and transient glomerular injury and proteinuria. Copyright (c) 2009 S. Karger AG, Basel
|
|
| 17. |
- Tesan, Tajana, 1977, et al.
(författare)
-
A new GTF2I-BRAF fusion mediating MAPK pathway activation in pilocytic astrocytoma
- 2017
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
-
Tidskriftsartikel (refereegranskat)abstract
- Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. A recurrent feature of PA is deregulation of the mitogen activated protein kinase (MAPK) pathway most often through KIAA1549-BRAF fusion, but also by other BRAF- or RAF1-gene fusions and point mutations (e.g. BRAFV600E). These features may serve as diagnostic and prognostic markers, and also facilitate development of targeted therapy. The aims of this study were to characterize the genetic alterations underlying the development of PA in six tumor cases, and evaluate methods for fusion oncogene detection. Using a combined analysis of RNA sequencing and copy number variation data we identified a new BRAF fusion involving the 5' gene fusion partner GTF2I (7q11.23), not previously described in PA. The new GTF2I-BRAF 19-10 fusion was found in one case, while the other five cases harbored the frequent KIAA1549-BRAF 16-9 fusion gene. Similar to other BRAF fusions, the GTF2I-BRAF fusion retains an intact BRAF kinase domain while the inhibitory N-terminal domain is lost. Functional studies on GTF2I-BRAF showed elevated MAPK pathway activation compared to BRAF WT. Comparing fusion detection methods, we found Fluorescence in situ hybridization with BRAF break apart probe as the most sensitive method for detection of different BRAF rearrangements (GTF2I-BRAF and KIAA1549-BRAF). Our finding of a new BRAF fusion in PA further emphasis the important role of B-Raf in tumorigenesis of these tumor types. Moreover, the consistency and growing list of BRAF/RAF gene fusions suggests these rearrangements to be informative tumor markers in molecular diagnostics, which could guide future treatment strategies.
|
|
| 18. |
- Truvé, Katarina
(författare)
-
Bioinformatics mining for disease causing mutations : using the dog genome as a model for human disease
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Humans and dogs share many common diseases, and it has been shown that the identification of mutations that cause disease in dogs can help unravel the genetic basis for a similar disease in humans. Mapping of traits and disease in dogs is not a new idea, but the sequencing of the whole dog genome, the creation of a dense SNP maps followed by the development of SNP arrays for high throughput genotyping has led to new facilitated mapping procedures. Each dog breed can be seen as a genetic isolate and certain breeds are often predisposed to specific diseases. Because of the genomic structure of the dog genome and the availability of new resources for disease mapping, the dog has been proposed to be especially advantageous for the mapping of complex disease that is difficult to map in human outbred populations. In this thesis, the aim has been to identify disease-causing mutations for three complex diseases in dogs with the presence of similar conditions in humans. Emphasis has been on bioinformatics analyses of genome-wide SNP and large re-sequencing data. In the dog breed Nova Scotia duck tolling retriever it is common with an immune-mediated disease complex that resembles human systemic lupus erythematosus (SLE). In paper I we used a two-stage genome-wide association mapping method and successfully located several susceptibility loci in dogs for this disease complex. In paper II we identified a mutation that had been under selection in the Shar-Pei breed, causing both a breed-defining wrinkled skin phenotype and an autoinflammatory fever disease. Because the locus had been under selection we used an alternative mapping approach, called homozygosity mapping to identify the locus, followed by re-sequencing using next generation sequencing technologies. In paper III we report the development of a web-based tool that facilitates analyses and extraction of essential information from the large amount of data produced by next generation sequencing projects. In paper IV we used across-breed genome-wide association mapping to identify risk factors for glioma, a type of malignant brain tumor fatal to both human and dogs. For the three diseases excellent candidate genes have been identified, and continued research might has the potential to lead to better treatment options and thus benefit both dogs and humans.
|
|
| 19. |
|
|
| 20. |
|
|
