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  • 1
    Abstract: Objective: The association between consumption of fruit and vegetables and risk of ovarian cancer is still unclear from a prospective point of view. Methods: Female participants (n = 325,640) of the European Prospective Investigation into Cancer and Nutrition study, free of any cancer at baseline, were followed on average for 6.3 years to develop ovarian cancer. During 2,049,346 person-years, 581 verified cases of primary, invasive epithelial ovarian cancer were accrued. Consumption of fruits and vegetables as well as subgroups of vegetables, estimated from validated dietary questionnaires and calibrated thereafter, was related to ovarian cancer incidence in multivariable hazard regression models. Histologic subtype specific analyses were done. Results: Total intake of fruit and vegetables, separately or combined, as well as subgroups of vegetables (fruiting, root, leafy vegetables, cabbages) was unrelated to risk of ovarian cancer. A high intake of garlic/onion vegetables was associated with a borderline significant reduced risk of this cancer. The examination by histologic subtype indicated some differential effects of fruit and vegetable intake on ovarian cancer risk. Conclusion: Overall, a high intake of fruits and vegetables did not seem to protect from ovarian cancer. Garlic/onion vegetables may exert a beneficial effect. The study of the histologic subtype of the tumor warrants further investigation
    Type of Publication: Journal article published
    PubMed ID: 16284374
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  • 2
    Abstract: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 x 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
    Type of Publication: Journal article published
    PubMed ID: 23544012
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  • 3
    Abstract: SCOPE: We reevaluated previously reported associations between variants in pathways of one-carbon (1-C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake. METHODS AND RESULTS: Odds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 x 10(-5) ) and rs828054 (OR = 1.06; p = 1 x 10(-4) ). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 x 10(-6) ) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1-C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03-0.006). CONCLUSION: Variation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP-by-folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.
    Type of Publication: Journal article published
    PubMed ID: 25066213
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  • 4
    Abstract: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, Cl)] for the minor allele of 1.05(1.03-1.07), P = 1 x 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 x 10(-6)), yielding a combined OR (95% Cl) of 1.06(1.04-1.08), P = 1 x 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
    Type of Publication: Journal article published
    PubMed ID: 25168388
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  • 5
    Publication Date: 2015-08-08
    Description: The specifics of how galaxies form from, and are fuelled by, gas from the intergalactic medium remain uncertain. Hydrodynamic simulations suggest that 'cold accretion flows'--relatively cool (temperatures of the order of 10(4) kelvin), unshocked gas streaming along filaments of the cosmic web into dark-matter halos--are important. These flows are thought to deposit gas and angular momentum into the circumgalactic medium, creating disk- or ring-like structures that eventually coalesce into galaxies that form at filamentary intersections. Recently, a large and luminous filament, consistent with such a cold accretion flow, was discovered near the quasi-stellar object QSO UM287 at redshift 2.279 using narrow-band imaging. Unfortunately, imaging is not sufficient to constrain the physical characteristics of the filament, to determine its kinematics, to explain how it is linked to nearby sources, or to account for its unusual brightness, more than a factor of ten above what is expected for a filament. Here we report a two-dimensional spectroscopic investigation of the emitting structure. We find that the brightest emission region is an extended rotating hydrogen disk with a velocity profile that is characteristic of gas in a dark-matter halo with a mass of 10(13) solar masses. This giant protogalactic disk appears to be connected to a quiescent filament that may extend beyond the virial radius of the halo. The geometry is strongly suggestive of a cold accretion flow.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martin, D Christopher -- Matuszewski, Mateusz -- Morrissey, Patrick -- Neill, James D -- Moore, Anna -- Cantalupo, Sebastiano -- Prochaska, J Xavier -- Chang, Daphne -- England -- Nature. 2015 Aug 13;524(7564):192-5. doi: 10.1038/nature14616. Epub 2015 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cahill Center for Astrophysics, California Institute of Technology, 1216 East California Boulevard, Mail code 278-17, Pasadena, California 91125, USA. ; Caltech Optical Observatories, Cahill Center for Astrophysics, California Institute of Technology, 1216 East California Boulevard, Mail code 11-17, Pasadena, California 91125, USA. ; ETH Zurich, Institute for Astronomy, Wolfgang-Pauli-Strasse 27 8093, Zurich, Switzerland. ; 1] Department of Astronomy and Astrophysics, University of California, 1156 High Street, Santa Cruz, California 95064, USA [2] University of California Observatories, Lick Observatory, 1156 High Street, Santa Cruz, California 95064, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    American Association for the Advancement of Science (AAAS)
    In: Science
    Publication Date: 2018-08-31
    Description: Three-dimensional genome structures play a key role in gene regulation and cell functions. Characterization of genome structures necessitates single-cell measurements. This has been achieved for haploid cells but has remained a challenge for diploid cells. We developed a single-cell chromatin conformation capture method, termed Dip-C, that combines a transposon-based whole-genome amplification method to detect many chromatin contacts, called META (multiplex end-tagging amplification), and an algorithm to impute the two chromosome haplotypes linked by each contact. We reconstructed the genome structures of single diploid human cells from a lymphoblastoid cell line and from primary blood cells with high spatial resolution, locating specific single-nucleotide and copy number variations in the nucleus. The two alleles of imprinted loci and the two X chromosomes were structurally different. Cells of different types displayed statistically distinct genome structures. Such structural cell typing is crucial for understanding cell functions.
    Keywords: Molecular Biology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2018-09-06
    Description: The Triassic represented an important period that witnessed the diversification of marine and terrestrial ecosystems. The radiations of terrestrial plants and vertebrates during this period have been widely investigated; however, the Triassic history of insects, the most diverse group of organisms on Earth, remains enigmatic because of the rarity of Early-Middle Triassic fossils. We report new insect fossils from a Ladinian deposit (Tongchuan entomofauna) dated to approximately 238 to 237 million years ago and a Carnian deposit (Karamay entomofauna) in northwestern China, including the earliest definite caddisfly cases (Trichoptera), water boatmen (Hemiptera), diverse polyphagan beetles (Coleoptera), and scorpionflies (Mecoptera). The Tongchuan entomofauna is near the Ladinian-Carnian boundary in age, providing a calibration date for correlation to contemporaneous biotas. Our findings confirm that the clade Holometabola, comprising most of the modern-day insect species, experienced extraordinary diversification in the Middle-Late Triassic. Moreover, our results suggest that the diversification of aquatic insects (a key event of the "Mesozoic Lacustrine Revolution") had already begun by the Middle Triassic, providing new insights into the early evolution of freshwater ecosystems.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 8
    Publication Date: 2018-11-21
    Description: Genetically encoded inhibitors for voltage-dependent Ca2+ (CaV) channels (GECCIs) are useful research tools and potential therapeutics. Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like G proteins that potently inhibit high voltage-activated (HVA) Ca2+ (CaV1/CaV2 family) channels, but their nonselectivity limits their potential applications. We hypothesized that nonselectivity of RGK inhibition derives from their...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 9
    Publication Date: 2018-03-29
    Description: Splicing of pre-mRNA involves two consecutive trans -esterification steps that take place in the spliceosome, a large dynamic ribonucleoprotein complex situated in the nucleus. In addition to core spliceosomal proteins, each catalytic step requires step-specific factors. Although the Arabidopsis thaliana genome encodes around 430 predicted splicing factors, functional information about these proteins is limited. In a forward genetic screen based on an alternatively-spliced GFP reporter gene in Arabidopsis thaliana , we identified a mutant impaired in putative step II factor PRP18a, which has not yet been investigated for its role in pre-mRNA splicing in plants. Step II entails cleavage at the 3' splice site accompanied by ligation of the 5' and 3' exons and intron removal. In the prp18 mutant, splicing of a U2-type intron with non-canonical AT-AC splice sites in GFP pre-mRNA is reduced while splicing of a canonical GT-AG intron is enhanced, resulting in decreased levels of translatable GFP mRNA and GFP protein. These findings suggest that wild-type PRP18a may in some cases promote splicing at weak, non-canonical splice sites. Analysis of genome-wide changes in alternative splicing in the prp18a mutant identified numerous cases of intron retention and a preponderance of altered 3' splice sites, suggesting an influence of PRP18a on 3' splice site selection. The prp18a mutant featured short roots on synthetic medium and small siliques, illustrating that wild-type PRP18a function is needed for a normal phenotype. Our study expands knowledge of plant splicing factors and provides foundational information and resources for further functional studies of PRP18 proteins in plants.
    Electronic ISSN: 2160-1836
    Topics: Biology
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  • 10
    Publication Date: 2018-02-03
    Description: Biochemistry DOI: 10.1021/acs.biochem.7b01207
    Print ISSN: 0006-2960
    Electronic ISSN: 1520-4995
    Topics: Biology , Chemistry and Pharmacology
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