| 11. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 12. |
- Nimmo, K., et al.
(författare)
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Burst timescales and luminosities as links between young pulsars and fast radio bursts
- 2022
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Ingår i: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 6:3, s. 393-401
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Tidskriftsartikel (refereegranskat)abstract
- Fast radio bursts (FRBs) are extragalactic radio flashes of unknown physical origin. Their high luminosities and short durations require extreme energy densities, such as those found in the vicinity of neutron stars and black holes. Studying the burst intensities and polarimetric properties on a wide range of timescales, from milliseconds down to nanoseconds, is key to understanding the emission mechanism. However, high-time-resolution studies of FRBs are limited by their unpredictable activity levels, available instrumentation and temporal broadening in the intervening ionized medium. Here we show that the repeating FRB 20200120E can produce isolated shots of emission as short as about 60 nanoseconds in duration, with brightness temperatures as high as 3 × 1041 K (excluding relativistic effects), comparable with ‘nano-shots’ from the Crab pulsar. Comparing both the range of timescales and luminosities, we find that FRB 20200120E observationally bridges the gap between known Galactic young pulsars and magnetars and the much more distant extragalactic FRBs. This suggests a common magnetically powered emission mechanism spanning many orders of magnitude in timescale and luminosity. In this Article, we probe a relatively unexplored region of the short-duration transient phase space; we highlight that there probably exists a population of ultrafast radio transients at nanosecond to microsecond timescales, which current FRB searches are insensitive to.
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| 13. |
- Thomas, Minta, et al.
(författare)
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Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values < 0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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| 14. |
- Thomas, M, et al.
(författare)
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Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity
- 2023
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Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.
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| 15. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 16. |
- ten Broeke, SW, et al.
(författare)
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Cancer Risks for PMS2-Associated Lynch Syndrome
- 2018
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Ingår i: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. - 1527-7755. ; 36:29, s. 2961-
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Tidskriftsartikel (refereegranskat)
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| 17. |
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| 18. |
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| 19. |
- Ahsant, Mehran, et al.
(författare)
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Streamlining Grid Operations : Definition and Deployment of a Portal-based User Registration Service
- 2006
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Ingår i: Journal of Grid Computing. - : Springer Science and Business Media LLC. - 1572-9184 .- 1570-7873. ; 4:2, s. 135-144
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Tidskriftsartikel (refereegranskat)abstract
- Manual management of public key credentials can be a significant and often off-putting obstacle to Grid use, particularly for casual users. We describe the Portal-based User Registration Service (PURSE), a set of tools for automating user registration, credential creation, and credential management tasks. PURSE provides the system developer with a set of customizable components, suitable for integration with portals, that can be used to address the full lifecycle of Grid credential management. We describe the PURSE design and its use in portals for two systems, the Earth System Grid data access system and the Swegrid computational Grid. In both cases, the user is entirely freed from the need to create or manage public key credentials, thus simplifying the Grid experience and reducing opportunities for error. We argue that this capturing of common use cases in a reusable ‘solution’ can be a model for how Grid ease-of-use can be addressed in other domains as well.
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| 20. |
- Burdge, Kevin B., et al.
(författare)
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A 62-minute orbital period black widow binary in a wide hierarchical triple
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 605:7908, s. 41-45
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Tidskriftsartikel (refereegranskat)abstract
- Over a dozen millisecond pulsars are ablating low-mass companions in close binary systems. In the original 'black widow', the eight-hour orbital period eclipsing pulsar PSR J1959+2048 (PSR B1957+20)(1), high-energy emission originating from the pulsar2 is irradiating and may eventually destroy(3) a low-mass companion. These systems are not only physical laboratories that reveal the interesting results of exposing a close companion star to the relativistic energy output of a pulsar, but are also believed to harbour some of the most massive neutron stars(4), allowing for robust tests of the neutron star equation of state. Here we report observations of ZTF J1406+1222, a wide hierarchical triple hosting a 62-minute orbital period black widow candidate, the optical flux of which varies by a factor of more than ten. ZTF J1406+1222 pushes the boundaries of evolutionary models(5), falling below the 80-minute minimum orbital period of hydrogen-rich systems. The wide tertiary companion is a rare low-metallicity cool subdwarf star, and the system has a Galactic halo orbit consistent with passing near the Galactic Centre, making it a probe of formation channels, neutron star kick physics(6) and binary evolution.
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