| 11. |
- Gaudet, Mia M., et al.
(författare)
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Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer
- 2010
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (, 40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (lambda) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values, 10 25 and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p = 3: 8 x 10(-5)) and for rs311499 was 0.72 (95% CI 0.61-0.85, p = 6: 6 x 10(-5)). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p = 1: 2 x 10(-8)). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
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| 12. |
- Hastie, Roxanne, et al.
(författare)
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Associations Between Soluble fms-Like Tyrosine Kinase-1 and Placental Growth Factor and Disease Severity Among Women With Preterm Eclampsia and Preeclampsia
- 2022
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Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 11:16
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe angiogenic factors soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF) are postulated to be pathogenic disease drivers of preeclampsia. If true, then circulating levels should become more deranged with increasing disease severity.Methods and ResultsWe investigated the association between circulating sFlt‐1 and PlGF levels and severe adverse maternal outcomes among 348 women with preeclampsia. Compared with 125 women with preeclampsia without severe features, 25 women with preeclampsia and any of hemolysis, elevated liver enzymes, low platelet count syndrome, disseminated intravascular coagulation, or severe renal involvement had sFlt‐1 levels that were 2.63‐fold higher (95% CI, 1.81–3.82), sFlt‐1/PlGF levels that were 10.07‐fold higher (95% CI, 5.36–18.91) and PlGF levels that were 74% lower (adjusted fold change, 0.26 [95% CI, 0.18–0.39]). Compared with 125 women with preeclampsia without severe features, 37 with eclampsia had sFlt‐1 levels that were 2‐fold higher (2.02 [95% CI, 1.32–3.09]), sFlt‐1/PIGF levels that were 4.71‐fold higher (95% CI, 2.30–9.66) and PIGF levels that were 63% lower (0.43‐fold change [95% CI, 0.27–0.68]). Compared with those without severe features, preeclampsia with severe hypertension (n=146) was also associated with altered angiogenic levels (sFlt‐1, 1.71‐fold change [95% CI, 1.39–2.11]; sFlt/PlGF, 2.91 [95% CI, 2.04–4.15]; PlGF, 0.59 [95%CI 0.47–0.74]). We also found that sFlt‐1 and PlGF levels were altered by the number of maternal complications experienced.ConclusionsFurther angiogenic imbalance among women with preeclampsia is likely a pathogenic disease driver responsible for the life‐threatening maternal complications.
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| 13. |
- Hastie, Roxanne, et al.
(författare)
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Predictive Value of the Signs and Symptoms Preceding Eclampsia : A Systematic Review
- 2019
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Ingår i: Obstetrics and Gynecology. - 0029-7844 .- 1873-233X. ; 134:4, s. 677-684
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVE: To estimate the predictive value of signs and symptoms that occur before onset of eclampsia among pregnant women.DATA SOURCES: Electronic databases, including MEDLINE, EMBASE, Cochrane, and ClinicalTrials.gov were searched from inception to 2018. Search terms included eclampsia, predict, likelihood ratio, predictive value, and risk.METHODS OF STUDY SELECTION: Abstracts and later full texts were selected for review if a diagnosis of eclampsia was made, a comparator arm included (women without a diagnosis of eclampsia), and predictors of imminent eclampsia reported. Of 2,791 retrieved records, 11 were selected. Significant heterogeneity existed between studies, with differing designs, settings, participants, and signs or symptoms. In total, 28 signs or symptoms were reported, with visual disturbances and epigastric pain most common (six studies), followed by headache (five studies), and any edema (four studies).TABULATION, INTEGRATION, AND RESULTS: Data on study characteristics and predictive value of signs or symptoms were extracted, and, where appropriate, bivariate mixed-effect meta-analysis was applied to raw data. None of the pooled estimates were able to accurately predict eclampsia nor rule out eclampsia in their absence, with moderate specificity (83-94%) and poor sensitivity (29-56%).CONCLUSION: There is a dearth of high-quality studies investigating the predictive value of imminent signs and symptoms of eclampsia. Owing to the small number of studies, heterogeneity, and inconsistent reporting, it is difficult to provide accurate estimates of the predictive value of prodromal symptoms of eclampsia. Of the most commonly reported symptoms-visual disturbances, epigastric pain, and headache-none were able to accurately predict, nor rule out, imminent eclampsia.
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| 14. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 15. |
- McArthur, Jason D, et al.
(författare)
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Allelic variants of streptokinase from Streptococcus pyogenes display functional differences in plasminogen activation.
- 2008
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Ingår i: The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 22:9, s. 3146-3153
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Tidskriftsartikel (refereegranskat)abstract
- A common mammalian defense mechanism employed to prevent systemic dissemination of invasive bacteria involves occlusion of local microvasculature and encapsulation of bacteria within fibrin networks. Acquisition of plasmin activity at the bacterial cell surface circumvents this defense mechanism, allowing invasive disease initiation. To facilitate this process, S. pyogenes secretes streptokinase, a plasminogen-activating protein. Streptokinase polymorphism exhibited by S. pyogenes isolates is well characterized. However, the functional differences displayed by these variants and the biological significance of this variation has not been elucidated. Phylogenetic analysis of ska sequences from 28 S. pyogenes isolates revealed 2 main sequence clusters (clusters 1 and 2). All strains secreted streptokinase, as determined by Western blotting, and were capable of acquiring cell surface plasmin activity after incubation in human plasma. Whereas culture supernatants from strains containing cluster 1 ska alleles also displayed soluble plasminogen activation activity, supernatants from strains containing cluster 2 ska alleles did not. Furthermore, plasminogen activation activity in culture supernatants from strains containing cluster 2 ska alleles could only be detected when plasminogen was prebound with fibrinogen. This study indicates that variant streptokinase proteins secreted by S. pyogenes isolates display differing plasminogen activation characteristics and may therefore play distinct roles in disease pathogenesis.-McArthur, J. D., McKay, F. C., Ramachandran, V., Shyam, P., Cork, A. J., Sanderson-Smith, M. L., Cole, J. N., Ringdahl, U., Sjöbring, U., Ranson, M., Walker, M. J. Allelic variants of streptokinase from Streptococcus pyogenes display functional differences in plasminogen activation.
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| 16. |
- Miller, Fiona, et al.
(författare)
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Resilience and vulnerability : complementary or conflicting concepts?
- 2010
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Ingår i: Ecology and Society. - 1708-3087. ; 15:3, s. 11-
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Tidskriftsartikel (refereegranskat)abstract
- Resilience and vulnerability represent two related yet different approaches to understanding the response of systems and actors to change; to shocks and surprises, as well as slow creeping changes. Their respective origins in ecological and social theory largely explain the continuing differences in approach to social-ecological dimensions of change. However, there are many areas of strong convergence. This paper explores the emerging linkages and complementarities between the concepts of resilience and vulnerability to identify areas of synergy. We do this with regard to theory, methodology, and application. The paper seeks to go beyond just recognizing the complementarities between the two approaches to demonstrate how researchers are actively engaging with each field to coproduce new knowledge, and to suggest promising areas of complementarity that are likely to further research and action in the field.
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| 17. |
- Mitchell, Jonathan S., et al.
(författare)
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Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
- 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
- Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P = 1.31 x 10(-8)), 6q21 (rs9372120, P = 9.09 x 10(-15)), 7q36.1 (rs7781265, P = 9.71 x 10(-9)), 8q24.21 (rs1948915, P = 4.20 x 10(-11)), 9p21.3 (rs2811710, P = 1.72 x 10(-13)), 10p12.1 (rs2790457, P = 1.77 x 10(-8)), 16q23.1 (rs7193541, P = 5.00 x 10(-12)) and 20q13.13 (rs6066835, P = 1.36 x 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
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| 18. |
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| 19. |
- Walker, Logan C, et al.
(författare)
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Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
- 2010
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Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X .- 1465-5411. ; 12:6
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Tidskriftsartikel (refereegranskat)abstract
- Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies.
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| 20. |
- Weinhold, Niels, et al.
(författare)
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The CCND1 c.870G > A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:5, s. 522-525
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Tidskriftsartikel (refereegranskat)abstract
- A number of specific chromosomal abnormalities define the subgroups of multiple myeloma. In a meta-analysis of two genome-wide association studies of multiple myeloma including a total of 1,661 affected individuals, we investigated risk for developing a specific tumor karyotype. The t(11;14)(q13;q32) translocation in which CCND1 is placed under the control of the immunoglobulin heavy chain enhancer was strongly associated with the CCND1 c.870G>A polymorphism (P = 7.96 x 10(-11)). These results provide a model in which a constitutive genetic factor is associated with risk of a specific chromosomal translocation.
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