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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. |
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| 6. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 9. |
- Dobbins, Sara E., et al.
(författare)
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Common variation at 10p12.31 near MLLT10 influences meningioma risk
- 2011
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Ingår i: Nature Genetics. - London : Nature America, Inc.. - 1061-4036 .- 1546-1718. ; 43:9, s. 825-827
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Tidskriftsartikel (refereegranskat)abstract
- To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 x 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.
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| 11. |
- Rajaraman, Preetha, et al.
(författare)
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Genome-wide association study of glioma and meta-analysis
- 2012
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Ingår i: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 131:12, s. 1877-1888
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.
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| 14. |
- Andersson, Ulrika, et al.
(författare)
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A comprehensive study of the association between the EGFR and ERBB2 genes and glioma risk
- 2010
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Ingår i: Acta Oncologica. - : Informa Healthcare. - 0284-186X .- 1651-226X. ; 12, s. 17-17
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Tidskriftsartikel (refereegranskat)abstract
- Glioma is the most common type of adult brain tumor and glioblastoma, its most aggressive form, has a dismal prognosis. Receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR, ERBB2, ERBB3, ERBB4) family, and the vascular endothelial growth factor receptor (VEGFR), play a central role in tumor progression. We investigated the genetic variants of EGFR, ERBB2, VEGFR and their ligands, EGF and VEGF on glioma and glioblastoma risk. In addition, we evaluated the association of genetic variants of a newly discovered family of genes known to interact with EGFR: LRIG2 and LRIG3 with glioma and glioblastoma risk. Methods. We analyzed 191 tag single nucleotide polymorphisms (SNPs) capturing all common genetic variation of EGF, EGFR, ERBB2, LRIG2, LRIG3, VEGF and VEGFR2 genes. Material from four case-control studies with 725 glioma patients (329 of who were glioblastoma patients) and their 1 610 controls was used. Haplotype analyses were conducted using SAS/Genetics software. Results. Fourteen of the SNPs were significantly associated with glioma risk at p< 0.05, and 17 of the SNPs were significantly associated with glioblastoma risk at p< 0.05. In addition, we found that one EGFR haplotype was related to increased glioblastoma risk at p=0.009, Odds Ratio [OR] = 1.67 (95% confidence interval (CI): 1.14, 2.45). The Bonferroni correction made all p-values non-significant. One SNP, rs4947986 next to the intron/exon boundary of exon 7 in EGFR, was validated in an independent data set of 713 glioblastoma and 2 236 controls, [OR] = 1.42 (95% CI: 1.06,1.91). Discussion. Previous studies show that regulation of the EGFR pathway plays a role in glioma progression but the present study is the first to find that certain genotypes of the EGFR gene may be related to glioblastoma risk. Further studies are required to reinvestigate these findings and evaluate the functional significance.
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| 15. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 16. |
- Hamrin, Kerstin, et al.
(författare)
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Prolonged Exercise-Induced Stimulation of Skeletal Muscle Glucose Uptake Is due to Sustained Increases in Tissue Perfusion and Fractional Glucose Extraction
- 2011
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 96:4, s. 1085-1092
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Tidskriftsartikel (refereegranskat)abstract
- Context: The mechanisms behind the positive effects of physical activity on glucose metabolism in skeletal muscle and the time course of the effects need to be more elucidated. Objective: The aim was to examine the prolonged effects of an acute bout of one-legged exercise on local skeletal muscle glucose utilization and tissue perfusion. Design and Setting: Interstitial glucose concentration, local tissue perfusion, glucose uptake, and effects of insulin infusion were studied 12 h after an acute bout of exercise and without prior exercise. Participants: Ten healthy subjects, five women and five men, participated in the study. Intervention: Microdialysis measurements, (133)Xe clearance, and a 2-h hyperinsulinemic euglycemic clamp were performed on two occasions. Main Outcome Measures: We measured interstitial glucose concentration and tissue perfusion in the quadriceps femoris muscle of both legs. Results: Tissue perfusion (3.3 +/- 0.6 ml x 100 g(-1) x min(-1) vs. 1.4 +/- 0.2 ml x 100 g(-1) x min(-1); P = 0.007) and basal glucose uptake (2.3 +/- 0.5 mu mol x 100 g(-1) x min(-1) vs. 0.9 +/- 0.2 mu mol x 100 g(-1) x min(-1); P = 0.006) were increased in the leg that had exercised compared to the resting leg; the findings in the resting leg were comparable to those in the control experiment without prior exercise. The relative effect of insulin on fractional skeletal muscle glucose uptake was the same in all experimental settings, and insulin did not affect tissue perfusion. Conclusions: The prolonged stimulatory effect of physical exercise on skeletal muscle glucose uptake was mediated via vascular effects combined with an increase in basal glucose transport independent of enhancement of insulin responses.
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| 17. |
- Hemingway, H, et al.
(författare)
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The effectiveness and cost-effectiveness of biomarkers for the prioritisation of patients awaiting coronary revascularisation: a systematic review and decision model.
- 2010
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Ingår i: Health Technology Assessment. - : National Coordinating Centre for Health Technology Assessment. - 1366-5278 .- 2046-4924. ; 14:9, s. 1-178
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine the effectiveness and cost-effectiveness of a range of strategies based on conventional clinical information and novel circulating biomarkers for prioritising patients with stable angina awaiting coronary artery bypass grafting (CABG).DATA SOURCES: MEDLINE and EMBASE were searched from 1966 until 30 November 2008.REVIEW METHODS: We carried out systematic reviews and meta-analyses of literature-based estimates of the prognostic effects of circulating biomarkers in stable coronary disease. We assessed five routinely measured biomarkers and the eight emerging (i.e. not currently routinely measured) biomarkers recommended by the European Society of Cardiology Angina guidelines. The cost-effectiveness of prioritising patients on the waiting list for CABG using circulating biomarkers was compared against a range of alternative formal approaches to prioritisation as well as no formal prioritisation. A decision-analytic model was developed to synthesise data on a range of effectiveness, resource use and value parameters necessary to determine cost-effectiveness. A total of seven strategies was evaluated in the final model.RESULTS: We included 390 reports of biomarker effects in our review. The quality of individual study reports was variable, with evidence of small study (publication) bias and incomplete adjustment for simple clinical information such as age, sex, smoking, diabetes and obesity. The risk of cardiovascular events while on the waiting list for CABG was 3 per 10,000 patients per day within the first 90 days (184 events in 9935 patients with a mean of 59 days at risk). Risk factors associated with an increased risk, and included in the basic risk equation, were age, diabetes, heart failure, previous myocardial infarction and involvement of the left main coronary artery or three-vessel disease. The optimal strategy in terms of cost-effectiveness considerations was a prioritisation strategy employing biomarker information. Evaluating shorter maximum waiting times did not alter the conclusion that a prioritisation strategy with a risk score using estimated glomerular filtration rate (eGFR) was cost-effective. These results were robust to most alternative scenarios investigating other sources of uncertainty. However, the cost-effectiveness of the strategy using a risk score with both eGFR and C-reactive protein (CRP) was potentially sensitive to the cost of the CRP test itself (assumed to be 6 pounds in the base-case scenario).CONCLUSIONS: Formally employing more information in the prioritisation of patients awaiting CABG appears to be a cost-effective approach and may result in improved health outcomes. The most robust results relate to a strategy employing a risk score using conventional clinical information together with a single biomarker (eGFR). The additional prognostic information conferred by collecting the more costly novel circulating biomarker CRP, singly or in combination with other biomarkers, in terms of waiting list prioritisation is unlikely to be cost-effective.
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| 18. |
- Kitahara, Cari M., et al.
(författare)
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Association between adult height, genetic susceptibility and risk of glioma
- 2012
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 41:4, s. 1075-1085
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Tidskriftsartikel (refereegranskat)abstract
- Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub- types, and investigated effect modification by genetic susceptibility to the disease. Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case-control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants. Results Among men, we found a positive association between height and glioma risk (epsilon 190 vs 170-174 cm, pooled OR = 1.70, 95% CI: 1.11-2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17-3.38; P-trend = 0.02). Among women, these associations were less clear (epsilon 175 vs 160-164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70-1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77-2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk. Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.
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| 20. |
- Moussas, X., et al.
(författare)
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The gears of the Antikythera Mechanism : an educational pathfinder to the solar system
- 2011
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Ingår i: IAU Symposium.
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Konferensbidrag (refereegranskat)abstract
- The Antikythera Mechanism is the most sophisticated extant ancient astronomical instrument and analogue computer known and was assembled sometime between 150 and 100 BCE, almost a century after the death of Archimedes. The mechanism has a great educational potential as it appeals to inquiring minds as an astonishing artefact of science and technology. The latest research findings reveal significant cultural and social functions in its operations. This astonishing astronomical instrument has a clear interdisciplinary valueand it has that it may be used as an educational medium, to engage the general public, and especially to attract students both to/from exact sciences and to/from the humanities. The astronomical and technical knowledge embedded in the mechanism can also be used to introduce some aspects of modern science through the unknown technological achievements of Hellenic antiquity.
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| 21. |
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| 22. |
- Shete, Sanjay, et al.
(författare)
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Genome-wide high-density SNP linkage search for glioma susceptibility loci : results from the gliogene consortium
- 2011
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 71:24, s. 7568-7575
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Tidskriftsartikel (refereegranskat)abstract
- Gliomas, which generally have a poor prognosis, are the most common primary malignant brain tumors in adults. Recent genome-wide association studies have shown that inherited susceptibility plays a role in the development of glioma. Although first-degree relatives of patients exhibit a two-fold increased risk of glioma, the search for susceptibility loci in familial forms of the disease has been challenging because the disease is relatively rare, fatal, and heterogeneous, making it difficult to collect sufficient biosamples from families for statistical power. To address this challenge, the Genetic Epidemiology of Glioma International Consortium (Gliogene) was formed to collect DNA samples from families with two or more cases of histologically confirmed glioma. In this study, we present results obtained from 46 U.S. families in which multipoint linkage analyses were undertaken using nonparametric (model-free) methods. After removal of high linkage disequilibrium single-nucleotide polymorphism, we obtained a maximum nonparametric linkage score (NPL) of 3.39 (P = 0.0005) at 17q12-21.32 and the Z-score of 4.20 (P = 0.000007). To replicate our findings, we genotyped 29 independent U.S. families and obtained a maximum NPL score of 1.26 (P = 0.008) and the Z-score of 1.47 (P = 0.035). Accounting for the genetic heterogeneity using the ordered subset analysis approach, the combined analyses of 75 families resulted in a maximum NPL score of 3.81 (P = 0.00001). The genomic regions we have implicated in this study may offer novel insights into glioma susceptibility, focusing future work to identify genes that cause familial glioma. Cancer Res; 71(24); 7568-75. (C) 2011 AACR.
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| 23. |
- Sonkoly, E, et al.
(författare)
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MicroRNA-203 functions as a tumor suppressor in basal cell carcinoma.
- 2012
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Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 1
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Tidskriftsartikel (refereegranskat)abstract
- Basal cell carcinoma (BCC) of the skin represents the most common malignancy in humans. MicroRNAs (miRNAs), small regulatory RNAs with pleiotropic function, are commonly misregulated in cancer. Here we identify miR-203, a miRNA abundantly and preferentially expressed in skin, to be downregulated in BCCs. We show that activation of the Hedgehog (HH) pathway, critically involved in the pathogenesis of BCCs, as well as the EGFR/MEK/ERK/c-JUN signaling pathway suppresses miR-203. We identify c-JUN, a key effector of the HH pathway, as a novel direct target for miR-203 in vivo. Further supporting the role of miR-203 as a tumor suppressor, in vivo delivery of miR-203 mimics in a BCC mouse model results in the reduction of tumor growth. Our results identify a regulatory circuit involving miR-203 and c-JUN, which provides functional control over basal cell proliferation and differentiation. We propose that miR-203 functions as a 'bona fide' tumor suppressor in BCC, whose suppressed expression contributes to oncogenic transformation via derepression of multiple stemness- and proliferation-related genes, and its overexpression could be of therapeutic value.
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| 26. |
- Antinyan, Vard, 1984, et al.
(författare)
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Identifying risky areas of software code in Agile/Lean software development: An industrial experience report
- 2014
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Ingår i: 2014 Software Evolution Week - IEEE Conference on Software Maintenance, Reengineering, and Reverse Engineering, CSMR-WCRE 2014 - Proceedings. - : IEEE. - 9781479941742
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Konferensbidrag (refereegranskat)abstract
- Modern software development relies on incremental delivery to facilitate quick response to customers' requests. In this dynamic environment the continuous modifications of software code can cause risks for software developers; when developing a new feature increment, the added or modified code may contain fault-prone or difficult-to-maintain elements. The outcome of these risks can be defective software or decreased development velocity. This study presents a method to identify the risky areas and assess the risk when developing software code in Lean/Agile environment. We have conducted an action research project in two large companies, Ericsson AB and Volvo Group Truck Technology. During the study we have measured a set of code properties and investigated their influence on risk. The results show that the superposition of two metrics, complexity and revisions of a source code file, can effectively enable identification and assessment of the risk. We also illustrate how this kind of assessment can be successfully used by software developers to manage risks on a weekly basis as well as release-wise. A measurement system for systematic risk assessment has been introduced to two companies. © 2014 IEEE.
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| 29. |
- Areskogh, Dimitri, 1982-
(författare)
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Structural Modifications of Lignosulphonates
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Lignosulphonates are by‐products from the sulphite pulping process for the manufacture ofspecialty dissolving pulps and paper. During the liberation of the cellulose, the lignin isfractionated and solubilised through covalent addition of sulphonic acid groups at variouspositions in the structure. The formed sulphonated lignin, lignosulphonate is then furtherisolated and refined. The amphiphilic nature of lignosulphonates has enabled them to be used as additives to varioussuspensions to improve their dispersion and stability. The by far largest utilisation oflignosulphonates is as dispersants in concrete. Here, lignosulphonates act by dispersing cementparticles to prevent flocculation, un‐even particle distribution and reduced strengthdevelopment. The dispersion is achieved through steric and electrostatic repulsion of the cementparticles by the lignosulphonate polymer. This behaviour is intimately linked with the overallsize and amount of charged groups in the dispersing polymer. Traditional modifications oflignosulphonates have been limited to removal of sugars, filtration and fractionation. Thesemodifications are not sufficient for utilisation of lignosulphonates in high‐strength concrete. Heresynthetic dispersants and superplasticisers are used which are considerably more efficient evenat low dosages. To compete with these, additional modifications of lignosulphonates are likely tobe necessary. The molecular weight and functional group composition have been identified anddescribed as the most interesting parameters that can be modified. Currently, no suitable method exists to increase the molecular weight of lignosulphonates.Oxidation by the natural radical initiating enzyme laccase is an interesting tool to achieve suchmodifications. In this thesis several aspects of the mechanism through which this enzyme reactswith lignin and lignosulphonate structures have been elucidated through model compoundstudies. Further studies showed that laccase alone was a highly efficient tool for increasing themolecular weight of commercial lignosulphonates at low dosages and in short incubation times.Immobilisation of the laccase to a solid support to enable re‐utilisation was also investigated. Modification of functional group composition of lignosulphonates was achieved throughozonolysis and the Fenton’s reagent, a mixture of hydrogen peroxide and iron(II)acetate.Introduction of charged carboxylic groups was achieved through opening of the benzyl rings oflignosulphonates. It was found that a two‐stage process consisting of laccase oxidation followedby ozonolysis was an efficient technique to create a polymer enriched with carboxylic acidgroups with a sufficient molecular size. Oxidation by the Fenton’s reagent was shown to yield similar modifications as the combinedlaccase/ozonolysis treatment albeit with less pronounced results but with a large level of controlthrough variation of a number of reaction parameters. The Fenton’s reagent can therefore be aninteresting alternative to the aforementioned two‐stage treatment. These modifications are interesting for large‐scale applications not only because of theirsimplicity in terms of reaction parameters but also because of the ubiquity of the used enzymeand the chemicals in the pulp and paper industry.
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| 30. |
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| 31. |
- Benziane, B, et al.
(författare)
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Effect of exercise and training on phospholemman phosphorylation in human skeletal muscle
- 2011
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 301:3, s. E456-E466
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Tidskriftsartikel (refereegranskat)abstract
- Phospholemman (PLM, FXYD1) is a partner protein and regulator of the Na+-K+-ATPase (Na+-K+pump). We explored the impact of acute and short-term training exercise on PLM physiology in human skeletal muscle. A group of moderately trained males ( n = 8) performed a 1-h acute bout of exercise by utilizing a one-legged cycling protocol. Muscle biopsies were taken from vastus lateralis at 0 and 63 min (non-exercised leg) and 30 and 60 min (exercised leg). In a group of sedentary males ( n = 9), we determined the effect of a 10-day intense aerobic cycle training on Na+-K+-ATPase subunit expression, PLM phosphorylation, and total PLM expression as well as PLM phosphorylation in response to acute exercise (1 h at ∼72% V̇o2peak). Biopsies were taken at rest, immediately following, and 3 h after an acute exercise bout before and at the conclusion of the 10-day training study. PLM phosphorylation was increased both at Ser63and Ser68immediately after acute exercise (75%, P < 0.05, and 30%, P < 0.05, respectively). Short-term training had no adaptive effect on PLM phosphorylation at Ser63and Ser68, nor was the total amount of PLM altered posttraining. The protein expressions of α1-, α2-,and β1-subunits of Na+-K+-ATPase were increased after training (113%, P < 0.05, 49%, P < 0.05, and 27%, P < 0.05, respectively). Whereas an acute bout of exercise increased the phosphorylation of PKCα/βII on Thr638/641pre- and posttraining, phosphorylation of PKCζ/λ on Thr403/410was increased in response to acute exercise only after the 10-day training. In conclusion, we show that only acute exercise, and not short-term training, increases phosphorylation of PLM on Ser63and Ser68, and data from one-legged cycling indicate that this effect of exercise on PLM phosphorylation is not due to systemic factors. Our results provide evidence that phosphorylation of PLM may play a role in the acute regulation of the Na+-K+-ATPase response to exercise.
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| 34. |
- Berntsson, Shala Ghaderi, et al.
(författare)
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Analysis of DNA repair gene polymorphisms and survival in low-grade and anaplastic gliomas
- 2011
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Ingår i: Journal of Neuro-Oncology. - : Springer Science and Business Media LLC. - 0167-594X .- 1573-7373. ; 105:3, s. 531-538
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to explore the variation in DNA repair genes in adults with WHO grade II and III gliomas and their relationship to patient survival. We analysed a total of 1,458 tagging single-nucleotide polymorphisms (SNPs) that were selected to cover DNA repair genes, in 81 grade II and grade III gliomas samples, collected in Sweden and Denmark. The statistically significant genetic variants from the first dataset (P < 0.05) were taken forward for confirmation in a second dataset of 72 grade II and III gliomas from northern UK. In this dataset, eight gene variants mapping to five different DNA repair genes (ATM, NEIL1, NEIL2, ERCC6 and RPA4) which were associated with survival. Finally, these eight genetic variants were adjusted for treatment, malignancy grade, patient age and gender, leaving one variant, rs4253079, mapped to ERCC6, with a significant association to survival (OR 0.184, 95% CI 0.054-0.63, P = 0.007). We suggest a possible novel association between rs4253079 and survival in this group of patients with low-grade and anaplastic gliomas that needs confirmation in larger datasets.
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| 39. |
- Farnebo, Simon, et al.
(författare)
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Urea clearance: a new method to register local changes in blood flow in rat skeletal muscle based on microdialysis
- 2010
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Ingår i: Clinical Physiology and Functional Imaging. - 1475-0961 .- 1475-097X. ; 30:1, s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- Pgreater thanIncreasing evidence suggests that local blood flow should be monitored during microdialysis (MD) as the recovery of analytes is affected by local blood flow. At present ethanol clearance is the standard technique for this purpose, but it is not functional at very low perfusion velocities. Here, we introduce a technique for MD whereby local tissue blood flow is recorded by the use of urea clearance (changes inflow/outflow concentration), in conjunction with measurements of tissue metabolism (glucose, lactate and puruvate). MD probes were inserted into the gracilis muscle of 15 rats and perfused with a medium containing urea (20 mmol l-1). Changes in muscle blood flow were made by addition of noradrenaline (5 mu g ml-1) to the perfusion medium at two perfusion velocities (0 center dot 6 and 0 center dot 4 mu l min-1). The clearance of urea from the perfusion medium was then calculated and examined in relation to the dose of noradrenaline and to the coexisting changes in extracellular metabolites. The results showed reproducible and dose-dependent changes in blood flow that were induced by noradrenaline. These were characterized by dose-dependent changes in the urea clearance as well as blood-flow-specific changes in the MD metabolic markers (reduction in glucose and increase in lactate). The sensitivity for blood flow changes as assessed by urea clearance (MD) was increased at 0 center dot 4 compared with the 0 center dot 6 mu l min-1 perfusion speed. The results indicate that inclusion of urea to the perfusion medium may be used to monitor changes in skeletal muscle blood flow at low perfusion velocities and in parallel assess metabolic variables with a high recovery (greater than 90%).
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| 40. |
- Fei, Y Y, et al.
(författare)
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Use of real-time, label-free analysis in revealing low-affinity binding to blood group antigens by Helicobacter pylori
- 2011
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 83:16, s. 6336-6341
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Tidskriftsartikel (refereegranskat)abstract
- Infectious diseases are often initiated by microbial adherence that is mediated by the binding of attachment molecules, termed adhesins, to cell surface receptors on host cells. We present an experimental system, oblique-incidence reflectivity difference (OI-RD) microscopy, which allows the detection of novel, low-affinity microbial attachment mechanisms that may be essential for infectious processes. OI-RD microscopy was used to analyze direct binding of the oncopathogen, Helicobacter pylori ( H. pylori ) to immobilized glycoconjugates in real time with no need for labeling tags. The results suggest the presence of additional Lewis b blood group antigen (Le(b)) binding adhesins that have not been detected previously. OI-RD microscopy also confirmed the high-affinity binding of H. pylori outer-membrane protein BabA to Le(b). The OI-RD microscopy method is broadly applicable to real-time characterization of intact microbial binding to host receptors and offers new strategies to elucidate the molecular interactions of infectious agents with human host cells.
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| 41. |
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| 42. |
- Gustafsson, Sofia B, et al.
(författare)
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High tumour cannabinoid CB(1) receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer
- 2011
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Ingår i: PLOS ONE. - San Francisco, CA : Public Library of Science. - 1932-6203. ; 6:8, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome. Methodology/Principal Findings: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and >= 2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB1IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 8565 and 66+/-8%; tumour interior, 86+/-4% and 63+/-8% for the CB(1)IR<2 and CB(1)IR >= 2 groups, respectively. Conclusions/Significance: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.
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| 43. |
- Henriksson, Catrin, et al.
(författare)
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Influence of health related quality of life on time from symptom onset to hospital arrival and the risk of readmission in patients with myocardial infarction
- 2014
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Ingår i: Open heart. - : BMJ. - 2053-3624. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Despite increased awareness of the importance of early treatment in acute myocardial infarction (AMI), the delay from symptom onset to hospital arrival is still too long and rehospitalisations are frequent. Little is known about how health-related quality of life (HRQL) affects delay time and the frequency of readmissions. METHOD: We used quality registers to investigate whether patients' HRQL has any impact on delay time with a new AMI, and on the rate of readmissions during the first year. Patients with AMI <75 years, with HRQL assessed with EQ-5D at 1-year follow-up, and who thereafter had a new AMI registered, were evaluated for the correlation between HRQL and delay time (n=454). The association between HRQL and readmissions was evaluated among those who had an additional AMI and a new 1-year follow-up registration (n=216). RESULTS: Patients who reported poor total health status (EQ-VAS ≤50), compared to those who reported EQ-VAS 81-100, had tripled risk to delay ≥2 h from symptom onset to hospital arrival (adjusted OR 3.01, 95% CI 1.43 to 6.34). Patients scoring EQ-VAS ≤50 had also a higher risk of readmissions in the univariate analysis (OR 3.08, 95% CI 1.71 to 5.53). However, the correlation did not remain significant after adjustment (OR 1.99, 95% CI 0.90 to 4.38). EQ-index was not independently associated with delay time or readmissions. CONCLUSIONS: Aspects of total health status post-AMI were independently associated with delay time to hospital arrival in case of a new AMI. However, the influence of total health status on the risk of readmissions was less clear.
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| 44. |
- Henriksson, J., et al.
(författare)
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A Model of Sympatric Speciation Through Reinforcement
- 2010
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Ingår i: Kinetic and Related Models. - : American Institute of Mathematical Sciences (AIMS). - 1937-5093 .- 1937-5077. ; 3:1, s. 143-163
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Tidskriftsartikel (refereegranskat)abstract
- Sympatric speciation, i.e. the evolutionary split of one species into two in the same environment, has been a highly troublesome concept. It has been a questioned if it is actually possible. Even though there have been a number of reported results both in the wild and from controlled experiments in laboratories, those findings are both hard to get and hard to analyze, or even repeat. In the current study we propose a mathematical model which addresses the question of sympatric speciation and the evolution of reinforcement. Our aim has been to capture some of the essential features such as: phenotype, resources, competition, heritage, mutation, and reinforcement, in as simple a way as possible. Still, the resulting model is not too easy to grasp with purely analytical tools, so we have also complemented those studies with stochastic simulations. We present a few results that both illustrates the usefulness of such a model, but also rises new biological questions about sympatric speciation and reinforcement in particular.
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| 45. |
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| 46. |
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| 47. |
- Henriksson, J
(författare)
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Human movement science
- 2012
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Ingår i: Acta physiologica (Oxford, England). - : Wiley. - 1748-1716 .- 1748-1708. ; 205:3, s. 321-323
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 48. |
- Henriksson, Martin, et al.
(författare)
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Assessing the cost effectiveness of using prognostic biomarkers with decision models: case study in prioritising patients waiting for coronary artery surgery
- 2010
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Ingår i: BRITISH MEDICAL JOURNAL. - : BMJ. - 0959-535X. ; 340
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Tidskriftsartikel (refereegranskat)abstract
- Objective To determine the effectiveness and cost effectiveness of using information from circulating biomarkers to inform the prioritisation process of patients with stable angina awaiting coronary artery bypass graft surgery. Design Decision analytical model comparing four prioritisation strategies without biomarkers (no formal prioritisation, two urgency scores, and a risk score) and three strategies based on a risk score using biomarkers: a routinely assessed biomarker (estimated glomerular filtration rate), a novel biomarker (C reactive protein), or both. The order in which to perform coronary artery bypass grafting in a cohort of patients was determined by each prioritisation strategy, and mean lifetime costs and quality adjusted life years (QALYs) were compared. Data sources Swedish Coronary Angiography and Angioplasty Registry (9935 patients with stable angina awaiting coronary artery bypass grafting and then followed up for cardiovascular events after the procedure for 3.8 years), and meta-analyses of prognostic effects (relative risks) of biomarkers. Results The observed risk of cardiovascular events while on the waiting list for coronary artery bypass grafting was 3 per 10 000 patients per day within the first 90 days (184 events in 9935 patients). Using a cost effectiveness threshold of 20 pound 000-30 pound 000 ((sic)22 000-(sic)33 000; $32 000-$48 000) per additional QALY, a prioritisation strategy using a risk score with estimated glomerular filtration rate was the most cost effective strategy (cost per additional QALY was andlt;410 pound compared with the Ontario urgency score). The impact on population health of implementing this strategy was 800 QALYs per 100 000 patients at an additional cost of 245 pound 000 to the National Health Service. The prioritisation strategy using a risk score with C reactive protein was associated with lower QALYs and higher costs compared with a risk score using estimated glomerular filtration rate. Conclusion Evaluating the cost effectiveness of prognostic biomarkers is important even when effects at an individual level are small. Formal prioritisation of patients awaiting coronary artery bypass grafting using a routinely assessed biomarker (estimated glomerular filtration rate) along with simple, routinely collected clinical information was cost effective. Prioritisation strategies based on the prognostic information conferred by C reactive protein, which is not currently measured in this context, or a combination of C reactive protein and estimated glomerular filtration rate, is unlikely to be cost effective. The widespread practice of using only implicit or informal means of clinically ordering the waiting list may be harmful and should be replaced with formal prioritisation approaches.
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| 49. |
- Henriksson, M., et al.
(författare)
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Health-care costs of losartan and candesartan in the primary treatment of hypertension
- 2011
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Ingår i: Journal of Human Hypertension. - : Springer Science and Business Media LLC. - 0950-9240 .- 1476-5527. ; 25:2, s. 130-136
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Tidskriftsartikel (refereegranskat)abstract
- A recent study of two widely used angiotensin receptor blockers reported a reduced risk of cardiovascular events (-14.4%) when using candesartan compared with losartan in the primary treatment of hypertension. In addition to clinical benefits, costs associated with treatment strategies must be considered when allocating scarce health-care resources. The aim of this study was to assess resource use and costs of losartan and candesartan in hypertensive patients. Resource use (drugs, outpatient contacts, hospitalizations and laboratory tests) associated with losartan and candesartan treatment was estimated in 14 100 patients in a real-life clinical setting. We electronically extracted patient data from primary care records and mandatory Swedish national registers for death and hospitalization. Patients treated with losartan had more outpatient contacts (+15.6%), laboratory tests (+13.8%) and hospitalizations (+13.8%) compared with the candesartan group. During a maximum observation time of 9 years, the mean total costs per patient were 10 369 Swedish kronor (95% confidence interval: 3109-17 629) higher in the losartan group. In conclusion, prescribing candesartan for the primary treatment of hypertension results in lower long-term health-care costs compared with losartan.
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| 50. |
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