| 1. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 2. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 3. |
- Gombert, Michael, et al.
(författare)
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CCL1-CCR8 interactions : an axis mediating the recruitment of T cells and Langerhans-type dendritic cells to sites of atopic skin inflammation.
- 2005
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 174:8, s. 5082-91
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Tidskriftsartikel (refereegranskat)abstract
- Atopic dermatitis represents a chronically relapsing skin disease with a steadily increasing prevalence of 10-20% in children. Skin-infiltrating T cells, dendritic cells (DC), and mast cells are thought to play a crucial role in its pathogenesis. We report that the expression of the CC chemokine CCL1 (I-309) is significantly and selectively up-regulated in atopic dermatitis in comparison to psoriasis, cutaneous lupus erythematosus, or normal skin. CCL1 serum levels of atopic dermatitis patients are significantly higher than levels in healthy individuals. DC, mast cells, and dermal endothelial cells are abundant sources of CCL1 during atopic skin inflammation and allergen challenge, and Staphylococcus aureus-derived products induce its production. In vitro, binding and cross-linking of IgE on mast cells resulted in a significant up-regulation of this inflammatory chemokine. Its specific receptor, CCR8, is expressed on a small subset of circulating T cells and is abundantly expressed on interstitial DC, Langerhans cells generated in vitro, and their monocytic precursors. Although DC maintain their CCR8+ status during maturation, brief activation of circulating T cells recruits CCR8 from intracytoplamic stores to the cell surface. Moreover, the inflammatory and atopy-associated chemokine CCL1 synergizes with the homeostatic chemokine CXCL12 (SDF-1alpha) resulting in the recruitment of T cell and Langerhans cell-like DC. Taken together, these findings suggest that the axis CCL1-CCR8 links adaptive and innate immune functions that play a role in the initiation and amplification of atopic skin inflammation.
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| 4. |
- Göpfert, Caroline, et al.
(författare)
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Biomechanical characteristics and speed adaptation during kick double poling on roller skis in elite cross-country skiers
- 2013
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Ingår i: Sports Biomechanics. - : Informa UK Limited. - 1476-3141 .- 1752-6116. ; 12:2, s. 154-174
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Tidskriftsartikel (refereegranskat)abstract
- Recent developments in cross-country ski racing should promote the use of kick double poling. This technique, however, has not been the focus in athletes' training and has barely been investigated. The aims of the present study were to develop a function-based phase definition and to analyse speed adaptation mechanisms for kick double poling in elite cross-country skiers. Joint kinematics and pole/plantar forces were recorded in 10 athletes while performing kick double poling at three submaximal roller skiing speeds. A speed increase was associated with increases in cycle length and rate, while absolute poling and leg push-off durations shortened. Despite maintained impulses of force, the peak and average pole/leg forces increased. During double poling and leg push-off, ranges of motion of elbow flexion and extension increased (p < 0.05) and were maintained for hip/knee flexion and extension. Cycle length increase was correlated to increases in average poling force (r = 0.71) and arm swing time (r = 0.88; both p < 0.05). The main speed adaptation was achieved by changes in double poling technique; however, leg push-off showed high variability among elite skiers, thus illustrating important aspects for technique training.
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| 5. |
- Hippe, Andreas, et al.
(författare)
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EGFR/Ras-induced CCL20 production modulates the tumour microenvironment.
- 2020
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 123:6, s. 942-954
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The activation of the EGFR/Ras-signalling pathway in tumour cells induces a distinct chemokine repertoire, which in turn modulates the tumour microenvironment.METHODS: The effects of EGFR/Ras on the expression and translation of CCL20 were analysed in a large set of epithelial cancer cell lines and tumour tissues by RT-qPCR and ELISA in vitro. CCL20 production was verified by immunohistochemistry in different tumour tissues and correlated with clinical data. The effects of CCL20 on endothelial cell migration and tumour-associated vascularisation were comprehensively analysed with chemotaxis assays in vitro and in CCR6-deficient mice in vivo.RESULTS: Tumours facilitate progression by the EGFR/Ras-induced production of CCL20. Expression of the chemokine CCL20 in tumours correlates with advanced tumour stage, increased lymph node metastasis and decreased survival in patients. Microvascular endothelial cells abundantly express the specific CCL20 receptor CCR6. CCR6 signalling in endothelial cells induces angiogenesis. CCR6-deficient mice show significantly decreased tumour growth and tumour-associated vascularisation. The observed phenotype is dependent on CCR6 deficiency in stromal cells but not within the immune system.CONCLUSION: We propose that the chemokine axis CCL20-CCR6 represents a novel and promising target to interfere with the tumour microenvironment, and opens an innovative multimodal strategy for cancer therapy.
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| 6. |
- Holmberg, Hans-Christer, 1958-, et al.
(författare)
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Biomechanical analyses and predictors of diagonal stride performance in elite cross-country skiers
- 2008
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Ingår i: Proceedings of the 13th Annual Congress of the European College of Sports Science. - Cologne : Sportools. - 9789727351565 ; , s. 568-
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Konferensbidrag (refereegranskat)abstract
- Introduction: In cross-country (XC) skiing classical style was the only racing style until the mid 1980s and the main focus of early biomechanical studies was on the diagonal technique (DIAG). With the introduction of the new free style, research became more oriented toward this although both styles have gone through substantial development during the last decade (Smith, 2002). Recently, modern double poling technique has been thoroughly analyzed as regards its biomechanical characteristics and factors related to performance (Holmberg et al., 2005; 2006). However, there is still a lack of biomechanical data describing modern DIAG. Therefore, the aims of the present study were 1) to perform a basic biomechanical description of modern DIAG, and 2) to detect decisive factors related to DIAG performance. Methods: Twelve Swedish elite XC skiers (VO2max-DIAG: 72.3 ± 3.8 ml kg-1 min-1) performed DIAG roller skiing at a treadmill inclination of 9° at 11 km h-1 for biomechanical analyses. DIAG performance was defined by time to exhaustion (TTEDIAG) during a DIAG incremental pre-test (4°-11° [1°/min]; with a constant velocity of 11 km/h). Leg and arm joint angles (goniometers), pole forces (strain gauge transducers; 2000 Hz) and plantar forces (Pedar Mobile; 100 Hz) were recorded continuously. Correlations between DIAG performance (TTEDIAG) and biomechanical variables was examined using Pearson product-moment correlation coefficient tests (P<0.05). Results: Correlations were found for cycle time and cycle length (r=0.688; P<0.01), cycle rate (r=-0.731; P<0.01), relative foot ground contact time (r=-0.658; P<0.05), absolute and relative leg swing time (r=0.756, P<0.01; r=0.658; P<0.05), amplitude and angular velocity of hip angle during leg swing (r=0.634; r=0.652; P<0.05), hip angle at ski plant (r=-0.616; P<0.05), absolute and relative hip extension time (gliding phase) (r=0.689, P<0.01; r=0.592, P<0.05), absolute peak foot force (r=0.606, P<0.05), duration and amplitude of the knee angle extension from ski in, e.g. when the skis came in contact with the ground, to the knee angle maximum (r=0.743; r=0.710, P<0.01), rear foot force at minimal hip angle before push-off (r=-0.634; P<0.05), relative (%BW) peak pole force (r=-0.706; P<0.01), pole force at start of forward swing of the opposite leg (r=-0.681; P<0.01), amplitude of elbow extension during poling (r=0.741; P<0.01) and duration of elbow extension after pole out (r=-0.615; P<0.01). Discussion: It can be concluded that better DIAG skiers have 1) a longer and more distinct forward swing in their legs, 2) shorter ground contact, characterised by a lower body position when the skis come into contact with the ground, 3) a more distinct hip and knee angle extension (preparation) just before push-off, 4) a higher absolute production of leg force during push-off and 5) arm work characterised by lower and later peak pole forces (late accentuation).
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| 7. |
- Holmberg, Hans-Christer, et al.
(författare)
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Biomechanical analysis of double poling in elite cross-country skiers
- 2005
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Ingår i: Medicine & Science in Sports & Exercise. - 0195-9131 .- 1530-0315. ; 37:5, s. 807-818
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To further the understanding of double poling (DP) through biomechanical analysis of upper and lower body movements during DP in cross-country (XC) skiing at racing speed. METHODS: Eleven elite XC skiers performed DP at 85% of their maximal DP velocity (V85%) during roller skiing at 1 degrees inclination on a treadmill. Pole and plantar ground reaction forces, joint angles (elbow, hip, knee, and ankle), cycle characteristics, and electromyography (EMG) of upper and lower body muscles were analyzed. RESULTS: 1) Pole force pattern with initial impact force peak and the following active force peak (PPF) correlated to V85%, (r = 0.66, P < 0.05); 2) active flexion-extension pattern in elbow, hip, knee, and ankle joints with angle minima occurring around PPF, correlated to hip angle at pole plant (r = -0.89, P < 0.01), minimum elbow angle (r = -0.71), and relative poling time (r = -0.72, P < 0.05); 3) two different DP strategies (A and B), where strategy A (best skiers) was characterized by higher angular elbow- and hip-flexion velocities, smaller minimum elbow (P < 0.01) and hip angles (P < 0.05), and higher PPF (P < 0.05); 4) EMG activity in trunk and hip flexors, shoulder, and elbow extensors, and several lower body muscles followed a specific sequential pattern with changing activation levels; and 5) EMG activity in lower body muscles showed DP requires more than upper body work. CONCLUSIONS: DP was found to be a complex movement involving both the upper and lower body showing different strategies concerning several biomechanical aspects. Future research should further investigate the relationship between biomechanical and physiological variables and elaborate training models to improve DP performance.
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| 8. |
- Holmberg, Hans-Christer, et al.
(författare)
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Contribution of the legs to double-poling performance in elite cross-country skiers.
- 2006
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Ingår i: Medicine and science in sports and exercise. - : Ovid Technologies (Wolters Kluwer Health). - 0195-9131 .- 1530-0315. ; 38:10, s. 1853-60
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Tidskriftsartikel (refereegranskat)abstract
- In the classical style of cross-country skiing, the double-poling (DP) technique, which is regarded as an upper-body exercise, is used on the flatter parts of a course. Limited biomechanical and physiological data are available about DP compared with other cross-country skiing techniques. The purpose of the present study was to evaluate the possible role of the lower body during DP.Eleven elite cross-country skiers performed two incremental tests using DP roller skiing at 1 degree inclination on a treadmill with or without locking the knee and ankle joints (DPLOCKED and DPFREE). Maximal and peak oxygen uptake (VO2max and VO2peak) during classic diagonal skiing and DP, respectively, were measured. In addition, heart rate, blood lactate concentration, and maximal DP velocity (Vmax) were determined. Pole-ground reaction forces and joint angles (elbow, hip, knee, and ankle) were analyzed.The skiers obtained 7.7% higher VO2peak, 9.4% higher Vmax, and 11.7% longer time to exhaustion during DPFREE compared with DPLOCKED (all P < 0.05). There was a higher heart rate and blood lactate concentration in DPLOCKED at submaximal stages (all P < 0.05), with no difference in oxygen consumption. At 85% Vmax, corresponding to approximately 81% VO2peak FREE, the differences in physiological variables were accompanied by a 13.6% higher poling frequency, a 4.9% shorter poling phase, 13.3% shorter recovery phase, and 10.9% lower relative pole force in DPLOCKED (all P < 0.05).Movements of the knee and ankle joints are an integrative part in the skillful use of the DP technique, and restriction of the motion in these joints markedly affects both biomechanical and physiological variables, impairing DP performance.
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| 9. |
- Ji, Xuemei, et al.
(författare)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 10. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 11. |
- Li, Yafang, et al.
(författare)
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Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development
- 2019
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 10:19, s. 1760-1774
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Tidskriftsartikel (refereegranskat)abstract
- The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
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| 12. |
- Li, Yafang, et al.
(författare)
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Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population
- 2018
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 39:3, s. 336-346
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Tidskriftsartikel (refereegranskat)abstract
- Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13 336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13 970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.
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| 13. |
- Lindinger, Stefan, et al.
(författare)
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Control of speed during the double poling technique performed by elite cross-country skiers
- 2009
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Ingår i: Medicine & Science in Sports & Exercise. - 0195-9131 .- 1530-0315. ; 41:1, s. 210-220
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Double poling (DP) as a main technique in cross-country skiing has developed substantially over the last 15 yr. The purpose of the present study was to analyze the question, "How do modern elite skiers control DP speed?" METHODS: Twelve male elite cross-country skiers roller skied using DP at 9, 15, 21, and 27 km.h(-1) and maximum velocity (V(max)). Cycle characteristics, pole and plantar forces, and elbow, hip, and knee joint angles were analyzed. RESULT: Both poling frequency and cycle length increased up to 27 km.h (-1)(P < 0.05), with a further increase in poling frequency at V(max) (P < 0.05). Peak pole force, rate of force development, and rearfoot plantar force increased with submaximal velocities (V(sm)), whereas poling time and time-to-peak pole force gradually shortened (P < 0.05). Changes in elbow joint kinematics during the poling phase were characterized by a decreased angle minimum and an increased flexion and extension ranges of motion as well as angular velocities across V(sm) (P < 0.05), with no further changes at V(max). Hip and knee joint kinematics adapted across V(sm) by 1) decreasing angles at pole plant and angle minima during the poling phase, 2) increasing the ranges of motion and angular velocities during the flexion phases occurring around pole plant, and 3) increasing extension ranges of motion and angular velocities during the recovery phase (all P values <0.05), with no further changes at V(max). CONCLUSIONS: Elite skiers control DP speed by increasing both poling frequency and cycle length; the latter is achieved by increased pole force despite reduced poling time. Adaptation to higher speeds was assisted by an increased range of motion, smaller angle minima, and higher angular velocities in the elbow, the hip, and the knee joints.
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| 14. |
- Mauritsen, Thorsten, et al.
(författare)
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Developments in the MPI-M Earth System Model version 1.2 (MPI-ESM1.2) and Its Response to Increasing CO2
- 2019
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Ingår i: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 11:4, s. 998-1038
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Tidskriftsartikel (refereegranskat)abstract
- A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI-ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low-level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two-layer model.
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| 15. |
- McKay, James D., et al.
(författare)
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
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Tidskriftsartikel (refereegranskat)abstract
- Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
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| 16. |
- Pattaro, Cristian, et al.
(författare)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 17. |
- Pivarcsi, Andor, et al.
(författare)
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Tumor immune escape by the loss of homeostatic chemokine expression.
- 2007
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:48, s. 19055-60
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Tidskriftsartikel (refereegranskat)abstract
- The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.
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| 18. |
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| 19. |
- Werren, John H, et al.
(författare)
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Functional and evolutionary insights from the genomes of three parasitoid Nasonia species.
- 2010
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 327:5963, s. 343-8
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Tidskriftsartikel (refereegranskat)abstract
- We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis, N. giraulti, and N. longicornis. Parasitoids are important regulators of arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model, particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specific genes including diverse venoms; lateral gene transfers among Pox viruses, Wolbachia, and Nasonia; and the rapid evolution of genes involved in nuclear-mitochondrial interactions that are implicated in speciation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents.
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| 20. |
- Yamazaki, Junya, et al.
(författare)
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Analysis of a Severe Head Injury in World Cup Alpine Skiing : A Case Report.
- 2015
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Ingår i: Medicine & Science in Sports & Exercise. - 0195-9131 .- 1530-0315. ; 47:6, s. 1113-1118
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Tidskriftsartikel (refereegranskat)abstract
- Traumatic brain injury (TBI) is the leading cause of death in alpine skiing. It has been found that helmet use can reduce the incidence of head injuries between 15% and 60%. However, knowledge on optimal helmet performance criteria in World Cup alpine skiing is currently limited owing to the lack of biomechanical data from real crash situations. Purpose: This study aimed to estimate impact velocities in a severe TBI case in World Cup alpine skiing. Methods: Video sequences from a TBI case in World Cup alpine skiing were analyzed using a model-based image matching technique. Video sequences from four camera views were obtained in full high-definition (1080p) format. A three-dimensional model of the course was built based on accurate measurements of piste landmarks and matched to the background video footage using the animation software Poser 4. A trunk-neck-head model was used for tracking the skier's trajectory. Results: Immediately before head impact, the downward velocity component was estimated to be 8 m.s(-1). After impact, the upward velocity was 3 m.s(-1), whereas the velocity parallel to the slope surface was reduced from 33 m.s(-1) to 22 m.s(-1). The frontal plane angular velocity of the head changed from 80 radIsj1 left tilt immediately before impact to 20 rad.s(-1) right tilt immediately after impact. Conclusions: A unique combination of high-definition video footage and accurate measurements of landmarks in the slope made possible a high-quality analysis of head impact velocity in a severe TBI case. The estimates can provide crucial information on how to prevent TBI through helmet performance criteria and design.
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