| 1681. |
- Zhao, J. H., et al.
(author)
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Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
- 2023
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In: Nature Immunology. - : Springer Nature. - 1529-2908 .- 1529-2916. ; 24:9, s. 1540-1551
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Journal article (peer-reviewed)abstract
- Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-alpha in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization. Here the authors identify genetic effectors of the level of inflammation-related plasma proteins and use Mendelian randomization to identify proteins that contribute to immune-mediated disease risk.
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| 1682. |
- Zhao, Xiaoyu, et al.
(author)
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Identification of genetically predicted DNA methylation markers associated with non–small cell lung cancer risk among 34,964 cases and 448,579 controls
- 2024
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In: Cancer. - : John Wiley & Sons. - 0008-543X .- 1097-0142. ; 130:6, s. 913-926
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Journal article (peer-reviewed)abstract
- Background: Although the associations between genetic variations and lung cancer risk have been explored, the epigenetic consequences of DNA methylation in lung cancer development are largely unknown. Here, the genetically predicted DNA methylation markers associated with non–small cell lung cancer (NSCLC) risk by a two-stage case-control design were investigated.Methods: The genetic prediction models for methylation levels based on genetic and methylation data of 1595 subjects from the Framingham Heart Study were established. The prediction models were applied to a fixed-effect meta-analysis of screening data sets with 27,120 NSCLC cases and 27,355 controls to identify the methylation markers, which were then replicated in independent data sets with 7844 lung cancer cases and 421,224 controls. Also performed was a multi-omics functional annotation for the identified CpGs by integrating genomics, epigenomics, and transcriptomics and investigation of the potential regulation pathways.Results: Of the 29,894 CpG sites passing the quality control, 39 CpGs associated with NSCLC risk (Bonferroni-corrected p ≤ 1.67 × 10−6) were originally identified. Of these, 16 CpGs remained significant in the validation stage (Bonferroni-corrected p ≤ 1.28 × 10−3), including four novel CpGs. Multi-omics functional annotation showed nine of 16 CpGs were potentially functional biomarkers for NSCLC risk. Thirty-five genes within a 1-Mb window of 12 CpGs that might be involved in regulatory pathways of NSCLC risk were identified.Conclusions: Sixteen promising DNA methylation markers associated with NSCLC were identified. Changes of the methylation level at these CpGs might influence the development of NSCLC by regulating the expression of genes nearby.Plain Language Summary: The epigenetic consequences of DNA methylation in lung cancer development are still largely unknown. This study used summary data of large-scale genome-wide association studies to investigate the associations between genetically predicted levels of methylation biomarkers and non–small cell lung cancer risk at the first time. This study looked at how well larotrectinib worked in adult patients with sarcomas caused by TRK fusion proteins. These findings will provide a unique insight into the epigenetic susceptibility mechanisms of lung cancer.
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| 1683. |
- Zhu, Ying, et al.
(author)
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Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer : A Mendelian Randomization Analysis
- 2019
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In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:5, s. 935-942
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Journal article (peer-reviewed)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.
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| 1684. |
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| 1685. |
- Zuo, H., et al.
(author)
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Vitamin B6 catabolism and lung cancer risk : Results from the Lung Cancer Cohort Consortium (LC3)
- 2019
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 30:3, s. 478-485
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Journal article (peer-reviewed)abstract
- Background Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. Materials and methods For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. Results PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). Conclusion Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.
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| 1686. |
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| 1687. |
- Ångström, Jonas, et al.
(author)
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Hydrogenation-Induced Structure and Property Changes in the Rare-Earth Metal Gallide NdGa : Evolution of a [GaH](2-) Polyanion Containing Peierls-like Ga-H Chains
- 2016
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In: Inorganic Chemistry. - : American Chemical Society (ACS). - 0020-1669 .- 1520-510X. ; 55:1, s. 345-352
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Journal article (peer-reviewed)abstract
- The hydride NdGaH1+x (x approximate to 0.66) and its deuterized analogue were obtained by sintering the Zintl phase NdGa with the CrB structure in a hydrogen atmosphere at pressures of 10-20 bar and temperatures near 300 degrees C. The system NdGa/NdGaH1+x exhibits reversible H storage capability. H uptake and release were investigated by kinetic absorption measurements and thermal desorption mass spectroscopy, which showed a maximum H concentration corresponding to "NdGaH2" (0.93 wt % H) and a two-step desorption process, respectively. The crystal structure of NdGaH1+x was characterized by neutron diffraction (P2(1)/m, a = 4.1103(7), b = 4.1662(7), c = 6.464(1) angstrom, beta = 108.61(1)degrees Z = 2). H incorporates in NdGa by occupying two distinct positions, H1 and H2. HI is coordinated in a tetrahedral fashion by Nd atoms. The H2 position displays flexible occupancy, and H2 atoms attain a trigonal bipyramidal coordination by centering a triangle of Nd atoms and bridging two Ga atoms. The phase stability and electronic structure of NdGaH1+x, were analyzed by first-principles DFT calculations. NdGaH1H2 (NdGaH2) may be expressed as Nd3+(H1(-)[GaH2](2-). The two-dimensional polyanion [GaH](2-) features linear -H-Ga-H-Ga- chains with alternating short (1.8 A) and long (2.4 angstrom) Ga-H distances, which resembles a Peierls distortion. H2 deficiency (x < 1) results in the fragmentation of chains. For x = 0.66 arrangements with five-atom moieties, Ga-H-Ga-H-Ga are energetically most favorable. From magnetic measurements, the Curie-Weiss constant and effective magnetic moment of NdGaH1.66 were obtained. The former indicates antiferromagnetic interactions, and the latter attains a value of similar to 3.6 mu(B), which is typical for compounds containing Nd3 ions.
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| 1688. |
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| 1689. |
- Årzén, Karl-Erik, et al.
(author)
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Conclusions from the European Roadmap on Control of Computing Systems
- 2006
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Conference paper (peer-reviewed)abstract
- The use of control-based methods for resource management in real-time computing and communication systems has gained a substantial interest recently. Applications areas include performance control of web-servers, dynamic resource management in embedded systems, traffic control in communication networks, transaction management in database servers, error control in software systems, and autonomic computing. Within the European EU/IST FP6 Network of Exellence ARTIST2 on Embedded System Design a roadmap on Control of Real-Time Computing Systems has recently been completed. The focus of the roadmap is how flexibility, adaptivity, performance and robustness can be achieved in a real-time computing or communication system through the use of control theory. The item that is controlled is in most cases the allocation of computing and communication resources, e.g., the distribution or scheduling of CPU time among different competing tasks, jobs, requests, or transactions, or the communication resources in a network. Due to this, control of computing systems also goes under the name of feedback scheduling. The roadmap is divided into six research areas: control of server systems, control of CPU resources, control of communication networks, error control of software systems, feedback scheduling of control systems, and control middleware. For each area an overview is given and challenges for future research are stated. The aim of this position paper is to summarize the conclusions concerning these research challenges. In this paper, we will only cover the first four of the areas above. A preliminary version of the roadmap can be found on http://www.control.lth.se/user/karlerik/roadmap1.pdf
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| 1690. |
- Årzén, Karl-Erik, et al.
(author)
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Conclusions of the ARTIST2 Roadmap on Control of Computing Systems
- 2006
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In: ACM SIGBED Review. - 1551-3688. ; 3:3
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Journal article (peer-reviewed)abstract
- he use of control-based methods for resource manage- ment in real-time computing and communication systems has gained a substantial interest recently. Applications ar- eas include performance control of web-servers, dynamic resource management in embedded systems, traffic con- trol in communication networks, transaction management in database servers, error control in software systems, and au- tonomic computing. Within the European EU/IST FP6 Net- work of Exellence ARTIST2 on Embedded System Design a roadmap on Control of Real-Time Computing Systems has recently been completed. The focus of the roadmap is how flexibility, adaptivity, performance and robustness can be achieved in a real-time computing or communication system through the use of control theory. The item that is controlled is in most cases the allocation of computing and communication resources, e.g., the distribution or schedul- ing of CPU time among different competing tasks, jobs, re- quests, or transactions, or the communication resources in a network. Due to this, control of computing systems also goes under the name of feedback scheduling. The roadmap is divided into six research areas: con- trol of server systems, control of CPU resources, control of communication networks, error control of software systems, feedback scheduling of control systems, and control mid- dleware. For each area an overview is given and challenges for future research are stated. The aim of this position paper is to summarize the conclusions concerning these research challenges.
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