| 1. |
- Jiang, X., et al.
(författare)
-
Shared heritability and functional enrichment across six solid cancers
- 2019
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
|
|
| 2. |
- Aartsen, M. G., et al.
(författare)
-
The IceCube Neutrino Observatory : instrumentation and online systems
- 2017
-
Ingår i: Journal of Instrumentation. - : IOP PUBLISHING LTD. - 1748-0221. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- The IceCube Neutrino Observatory is a cubic-kilometer-scale high-energy neutrino detector built into the ice at the South Pole. Construction of IceCube, the largest neutrino detector built to date, was completed in 2011 and enabled the discovery of high-energy astrophysical neutrinos. We describe here the design, production, and calibration of the IceCube digital optical module (DOM), the cable systems, computing hardware, and our methodology for drilling and deployment. We also describe the online triggering and data filtering systems that select candidate neutrino and cosmic ray events for analysis. Due to a rigorous pre-deployment protocol, 98.4% of the DOMs in the deep ice are operating and collecting data. IceCube routinely achieves a detector uptime of 99% by emphasizing software stability and monitoring. Detector operations have been stable since construction was completed, and the detector is expected to operate at least until the end of the next decade.
|
|
| 3. |
- Aartsen, M. G., et al.
(författare)
-
PINGU : a vision for neutrino and particle physics at the South Pole
- 2017
-
Ingår i: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 44:5
-
Tidskriftsartikel (refereegranskat)abstract
- The Precision IceCube Next Generation Upgrade (PINGU) is a proposed low-energy in-fill extension to the IceCube Neutrino Observatory. With detection technology modeled closely on the successful IceCube example, PINGU will provide a 6 Mton effective mass for neutrino detection with an energy threshold of a few GeV. With an unprecedented sample of over 60 000 atmospheric neutrinos per year in this energy range, PINGU will make highly competitive measurements of neutrino oscillation parameters in an energy range over an order of magnitude higher than long-baseline neutrino beam experiments. PINGU will measure the mixing parameters theta(23) and Delta m(32)(2), including the octant of theta(23) for a wide range of values, and determine the neutrino mass ordering at 3 sigma median significance within five years of operation. PINGU's high precision measurement of the rate of nu(T) appearance will provide essential tests of the unitarity of the 3 x 3 PMNS neutrino mixing matrix. PINGU will also improve the sensitivity of searches for low mass dark matter in the Sun, use neutrino tomography to directly probe the composition of the Earth's core, and improve IceCube's sensitivity to neutrinos from Galactic supernovae. Reoptimization of the PINGU design has permitted substantial reduction in both cost and logistical requirements while delivering performance nearly identical to configurations previously studied.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Zhu, Ying, et al.
(författare)
-
Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer : A Mendelian Randomization Analysis
- 2019
-
Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:5, s. 935-942
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall nonsmall cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
|
|
| 7. |
- Bannuru, R. R., et al.
(författare)
-
OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis
- 2019
-
Ingår i: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584.
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data. Methods: We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and meta-analyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation. Results: Core Treatments for Knee OA included arthritis education and structured land-based exercise programs with or without dietary weight management. Core Treatments for Hip and Polyarticular OA included arthritis education and structured land-based exercise programs. Topical non-steroidal anti-inflammatory drugs (NSAIDs) were strongly recommended for individuals with Knee OA (Level 1A). For individuals with gastrointestinal comorbidities, COX-2 inhibitors were Level 1B and NSAIDs with proton pump inhibitors Level 2. For individuals with cardiovascular comorbidities or frailty, use of any oral NSAID was not recommended. Intra-articular (IA) corticosteroids, IA hyaluronic acid, and aquatic exercise were Level 1B/Level 2 treatments for Knee OA, dependent upon comorbidity status, but were not recommended for individuals with Hip or Polyarticular OA. The use of Acetaminophen/Paracetamol (APAP) was conditionally not recommended (Level 4A and 4B), and the use of oral and transdermal opioids was strongly not recommended (Level 5). A treatment algorithm was constructed in order to guide clinical decision-making for a variety of patient profiles, using recommended treatments as input for each decision node. Conclusion: These guidelines offer comprehensive and patient-centered treatment profiles for individuals with Knee, Hip, and Polyarticular OA. The treatment algorithm will facilitate individualized treatment decisions regarding the management of OA.
|
|
| 8. |
- McKay, James D., et al.
(författare)
-
Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
- 2017
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
-
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.
|
|
| 9. |
|
|
| 10. |
- Thorgeirsson, T. E., et al.
(författare)
-
A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences
- 2016
-
Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 21:5, s. 594-600
-
Tidskriftsartikel (refereegranskat)abstract
- Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency = 0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P = 1.2 x 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P = 4.0 x 10(-4)), chronic obstructive pulmonary disease (COPD; P = 9.3 x 10(-4)), peripheral artery disease (PAD; P = 0.090) and abdominal aortic aneurysms (AAAs; P = 0.12), and the variant associates strongly with the early-onset forms of LC (OR = 4.49, P = 2.2 x 10(-4)), COPD (OR = 3.22, P = 2.9 x 10(-4)), PAD (OR = 3.47, P = 9.2 x 10(-3)) and AAA (OR = 6.44, P = 6.3 x 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P = 6.8 x 10(-5)), particularly for early-onset cases (P = 2.1 x 10(-7)). Our results are in agreement with functional studies showing that the human alpha 4 beta 2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.
|
|
