| 1. |
- Thomas, HS, et al.
(författare)
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- 2019
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swepub:Mat__t
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| 2. |
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| 3. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 4. |
- Dangardt, Frida, 1977, et al.
(författare)
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Association between fat mass through adolescence and arterial stiffness: a population-based study from The Avon Longitudinal Study of Parents and Children
- 2019
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Ingår i: Lancet Child & Adolescent Health. - : Elsevier BV. - 2352-4642. ; 3:7, s. 474-481
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Tidskriftsartikel (refereegranskat)abstract
- Background The link between adiposity, metabolic abnormalities, and arterial disease progression in children and adolescents remains poorly defined. We aimed to assess whether persistent high adiposity levels are associated with increased arterial stiffness in adolescence and any mediation effects by common metabolic risk factors. Methods We included participants from the Avon Longitudinal Study of Parents and Children (ALSPAC) who had detailed adiposity measurements between the ages 9-17 years and arterial stiffness (carotid to femoral pulse wave velocity [PWV]) measured at age 17 years. Body-mass index (BMI) and waist-to-height ratio were calculated from weight, height, and waist circumference measurements whereas fat mass was assessed using repeated dual-energy x-ray absorptiometry (DEXA) scans. We used total and trunk fat mass indices (FMIs) to classify participants as normal (< 75th percentile) or high (> 75th percentile) FMI. We classified participants as being metabolically unhealthy if they had three or more of the following risk factors: high levels of systolic blood pressure, triglycerides, or glucose (all > 75th percentile) or low levels of high-density lipoprotein (< 25th percentile). We used multivariable linear regression analysis to assess the relationship between PWV and exposure to adiposity, and tested for linear trend of PVW levels across ordinal groups. We used latent class growth mixture modelling analysis to assess the effect of longitudinal changes in adiposity indices through adolescence on arterial stiffness. Findings We studied 3423 participants (1866 [54.5%] female and 1557 [45.5%] male). Total fat mass was positively associated with PWV at age 17 years (0.004 m/s per kg, 95% CI 0.001-0.006; p= 0.0081). Persistently high total FMI and trunk FMI between ages 9 and 17 years were related to greater PWV (0.15 m/s per kg/m(2), 0.05-0.24; p= 0.0044 and 0.15 m/s per kg/m(2), 0.06-0.25; p= 0.0021) compared with lower FMI. Metabolic abnormalities amplified the adverse effect of high total FMI on arterial stiffness (PWV 6.0 m/s [95% CI 5.9-6.0] for metabolically healthy participants and 6.2 m/s [5.9-6.4] for metabolically unhealthy participants). Participants who restored normal total FMI in adolescence (PWV 5.8 m/s [5.7-5.9] for metabolically healthy and 5.9 m/s [5.6-6.1] for metabolically unhealthy) had comparable PWV to those who had normal FMI throughout (5.7 m/s [5.7-5.8] for metabolically healthy and 5.9 m/s [5.8-5.9] for metabolically unhealthy). Interpretation Persistently high fat mass during adolescence was associated with greater arterial stiffness and was further aggravated by an unfavourable metabolic profile. Reverting to normal FMI in adolescence was associated with normal PWV, suggesting adolescence as an important period for interventions to tackle obesity in the young to maximise long-term vascular health. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.
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| 5. |
- Dangardt, Frida, 1977, et al.
(författare)
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Intimal and medial arterial changes defined by ultra-high-frequency ultrasound: Response to changing risk factors in children with chronic kidney disease
- 2018
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:6
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Tidskriftsartikel (refereegranskat)abstract
- Background Patients with chronic kidney disease (CKD) are exposed to both traditional 'Framingham' and uremia related cardiovascular risk factors that drive atherosclerotic and arteriosclerotic disease, but these cannot be differentiated using conventional ultrasound. We used ultrahigh-frequency ultrasound (UHFUS) to differentiate medial thickness (MT) from intimal thickness (IT) in CKD patients, identify their determinants and monitor their progression. Fifty-four children and adolescents with CKD and 12 healthy controls underwent UHFUS measurements using 55-70MHz transducers in common carotid and dorsal pedal arteries. Annual follow-up imaging was performed in 31 patients. CKD patients had higher carotid MT and dorsal pedal IT and MT compared to controls. The carotid MT in CKD correlated with serum phosphate (p<0.001, r = 0.42), PTH (p = 0.03, r = 0.36) and mean arterial pressure (p = 0.03, r = 0.34). Following multivariable analysis, being on dialysis, serum phosphate levels and mean arterial pressure remained the only independent predictors of carotid MT (R-2 64%). Transplanted children had lower carotid and dorsal pedal MT compared to CKD and dialysis patients (p = 0.02 and p = 0.01 respectively). At 1-year follow-up, transplanted children had a decrease in carotid MT (p = 0.01), but an increase in dorsal pedal IT (p = 0.04) that independently correlated with annualized change in BMI. Using UHFUS, we have shown that CKD is associated with exclusively medial arterial changes that attenuate when the uremic milieu is ameliorated after transplantation. In contrast, after transplantation intimal disease develops as hypertension and obesity become prevalent, representing rapid vascular remodeling in response to a changing cardiovascular risk factor profile.
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| 6. |
- Vergallo, A., et al.
(författare)
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Plasma amyloid beta 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:6, s. 764-775
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Blood-based biomarkers of pathophysiological brain amyloid beta (A beta) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the A beta(1-40)/A beta(1-42) ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain A beta positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-apriori hypothesis study using machine learning. Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma A beta(1-40)/A beta(1-42) ratio. The accuracy is not affected by the apolipoprotein E (APOE) epsilon 4 allele, sex, or age. Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma A beta(1-40)/A beta(1-42) ratio, assessed via Simoa, may improve future standard of care and clinical trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 8. |
- Chiesa, Marco, 1987-, et al.
(författare)
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Inter-domain networking innovation on steroids : Empowering IXPs with SDN capabilities
- 2016
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Ingår i: IEEE Communications Magazine. - : Institute of Electrical and Electronics Engineers (IEEE). - 0163-6804 .- 1558-1896. ; 54:10, s. 102-108
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Tidskriftsartikel (refereegranskat)abstract
- While innovation in inter-domain routing has remained stagnant for over a decade, Internet exchange points (IXPs) are consolidating their role as economically advantageous interconnection points for reducing path latencies and exchanging ever increasing amounts of traffic. As such, IXPs appear as a natural place to foster network innovation and assess the benefits of SDN, a recent technological trend that has already boosted innovation within data center networks. In this article, we give a comprehensive overview of use cases for SDN at IXPs, which leverage the superior vantage point of an IXP to introduce advanced features like load balancing and DDoS mitigation. We discuss the benefits of SDN solutions by analyzing real-world data from one of the largest IXPs. We also leverage insights into IXP operations to shape benefits not only for members but also for operators.
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| 9. |
- Chiesa, Marco, 1987-, et al.
(författare)
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SIXPACK : Securing internet eXchange points against curious onlookers
- 2017
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Ingår i: CoNEXT 2017 - Proceedings of the 2017 13th International Conference on emerging Networking EXperiments and Technologies. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450354226 ; , s. 120-133
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Konferensbidrag (refereegranskat)abstract
- Internet eXchange Points (IXPs) play an ever-growing role in Internet inter-connection. To facilitate the exchange of routes amongst their members, IXPs provide Route Server (RS) services to dispatch the routes according to each member's peering policies. Nowadays, to make use of RSes, these policies must be disclosed to the IXP. This poses fundamental questions regarding the privacy guarantees of route-computation on confidential business information. Indeed, as evidenced by interaction with IXP administrators and a survey of network operators, this state of affairs raises privacy concerns among network administrators and even deters some networks from subscribing to RS services. We design sixpack1, an RS service that leverages Secure Multi-Party Computation (SMPC) to keep peering policies confidential, while extending, the functionalities of today's RSes. As SMPC is notoriously heavy in terms of communication and computation, our design and implementation of sixpack aims at moving computation outside of the SMPC without compromising the privacy guarantees. We assess the effectiveness and scalability of our system by evaluating a prototype implementation using traces of data from one of the largest IXPs in the world. Our evaluation results indicate that sixpack can scale to support privacy-preserving route-computation, even at IXPs with many hundreds of member networks.
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| 10. |
- Chiesa, Marco, 1987-, et al.
(författare)
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Towards securing internet eXchange points against curious onlooKers
- 2016
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Ingår i: ANRW 2016 - Proceedings of the ACM, IRTF and ISOC Applied Networking Research Workshop. - New York, NY, USA : Association for Computing Machinery (ACM). - 9781450344432 ; , s. 32-34
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Konferensbidrag (refereegranskat)abstract
- The growing relevance of Internet eXchange Points (IXPs), where an increasing number of networks exchange routing information, poses fundamental questions regarding the privacy guarantees of confidential business information. To facilitate the exchange of routes among their members, IXPs provide Route Server (RS) services to dispatch the routes according to each member's export policies. Nowadays, to make use of RSes, these policies must be disclosed to the IXP. This state of affairs raises privacy concerns among network administrators and even deters some networks from subscribing to RS services. We design SIXPACK (which stands for "Securing Internet eXchange Points Against Curious onlooKers"), a RS service that leverages Secure Multi-Party Computation (SMPC) techniques to keep export policies confidential, while maintaining the same functionalities as today's RSes. We assess the effectiveness and scalability of our system by evaluating our prototype implementation and using traces of data from one of the largest IXPs in the world.
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