| 1. |
- de las Fuentes, Lisa, et al.
(författare)
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Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci
- 2021
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Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578. ; 26:6, s. 2111-2125
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Tidskriftsartikel (refereegranskat)abstract
- Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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| 2. |
- Pennells, Lisa, et al.
(författare)
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Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
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Tidskriftsartikel (refereegranskat)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
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| 3. |
- Bernal, Ximena E., et al.
(författare)
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Empowering Latina scientists
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 363:6429, s. 825-826
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 4. |
- Michaut, Magali, et al.
(författare)
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Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.
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| 5. |
- Walsh, Louise, et al.
(författare)
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BET Inhibition as a Rational Therapeutic Strategy for Invasive Lobular Breast Cancer
- 2019
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 25:23, s. 7139-7150
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Invasive lobular carcinoma (ILC) is a subtype of breast cancer accounting for 10% of breast tumors. The majority of patients are treated with endocrine therapy; however, endocrine resistance is common in estrogen receptor-positive breast cancer and new therapeutic strategies are needed. Bromodomain and extraterminal inhibitors (BETi) are effective in diverse types of breast cancer but they have not yet been assessed in ILC.EXPERIMENTAL DESIGN: We assessed whether targeting the BET proteins with JQ1 could serve as an effective therapeutic strategy in ILC in both 2D and 3D models. We used dynamic BH3 profiling and RNA-sequencing (RNA-seq) to identify transcriptional reprograming enabling resistance to JQ1-induced apoptosis. As part of the RATHER study, we obtained copy-number alterations and RNA-seq on 61 ILC patient samples.RESULTS: Certain ILC cell lines were sensitive to JQ1, while others were intrinsically resistant to JQ1-induced apoptosis. JQ1 treatment led to an enhanced dependence on antiapoptotic proteins and a transcriptional rewiring inducing fibroblast growth factor receptor 1 (FGFR1). This increase in FGFR1 was also evident in invasive ductal carcinoma (IDC) cell lines. The combination of JQ1 and FGFR1 inhibitors was highly effective at inhibiting growth in both 2D and 3D models of ILC and IDC. Interestingly, we found in the RATHER cohort of 61 ILC patients that 20% had FGFR1 amplification and we showed that high BRD3 mRNA expression was associated with poor survival specifically in ILC.CONCLUSIONS: We provide evidence that BETi either alone or in combination with FGFR1 inhibitors or BH3 mimetics may be a useful therapeutic strategy for recurrent ILC patients.
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| 6. |
- S., Acharya, et al.
(författare)
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Centrality and transverse momentum dependence of inclusive J/ψ production at midrapidity in Pb–Pb collisions at sNN=5.02 TeV
- 2020
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Ingår i: Physics Letters, Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 805
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Tidskriftsartikel (refereegranskat)abstract
- The inclusive J/ψ meson production in Pb–Pb collisions at a center-of-mass energy per nucleon–nucleon collision of sNN=5.02 TeV at midrapidity (|y|<0.9) is reported by the ALICE Collaboration. The measurements are performed in the dielectron decay channel, as a function of event centrality and J/ψ transverse momentum pT, down to pT=0. The J/ψ mean transverse momentum 〈pT〉 and rAA ratio, defined as 〈pT2〉PbPb/〈pT2〉pp, are evaluated. Both observables show a centrality dependence decreasing towards central (head-on) collisions. The J/ψ nuclear modification factor RAA exhibits a strong pT dependence with a large suppression at high pT and an increase to unity for decreasing pT. When integrating over the measured momentum range pT<10 GeV/c, the J/ψ RAA shows a weak centrality dependence. Each measurement is compared with results at lower center-of-mass energies and with ALICE measurements at forward rapidity, as well as to theory calculations. All reported features of the J/ψ production at low pT are consistent with a dominant contribution to the J/ψ yield originating from charm quark (re)combination. © 2020 European Organization for Nuclear Research
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| 7. |
- S., Acharya, et al.
(författare)
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Investigations of Anisotropic Flow Using Multiparticle Azimuthal Correlations in pp, p-Pb, Xe-Xe, and Pb-Pb Collisions at the LHC
- 2019
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Ingår i: Physical Review Letters. - 0031-9007. ; 123:14
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Tidskriftsartikel (refereegranskat)abstract
- Measurements of anisotropic flow coefficients (vn) and their cross-correlations using two- and multiparticle cumulant methods are reported in collisions of pp at s=13 TeV, p-Pb at a center-of-mass energy per nucleon pair sNN=5.02 TeV, Xe-Xe at sNN=5.44 TeV, and Pb-Pb at sNN=5.02 TeV recorded with the ALICE detector. The multiplicity dependence of vn is studied in a very wide range from 20 to 3000 particles produced in the midrapidity region |η|v3>v4 is found in pp and p-Pb collisions, similar to that seen in large collision systems, while a weak v2 multiplicity dependence is observed relative to nucleus-nucleus collisions in the same multiplicity range. Using a novel subevent method, v2 measured with four-particle cumulants is found to be compatible with that from six-particle cumulants in pp and p-Pb collisions. The magnitude of the correlation between vn2 and vm2, evaluated with the symmetric cumulants SC(m,n) is observed to be positive at all multiplicities for v2 and v4, while for v2 and v3 it is negative and changes sign for multiplicities below 100, which may indicate a different vn fluctuation pattern in this multiplicity range. The observed long-range multiparticle azimuthal correlations in high multiplicity pp and p-Pb collisions can neither be described by pythia 8 nor by impact-parameter-Glasma, music, and ultrarelativistic quantum molecular dynamics model calculations, and hence, provide new insights into the understanding of collective effects in small collision systems. © 2019 CERN, for the ALICE Collaboration.
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| 8. |
- S., Acharya, et al.
(författare)
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Multiplicity dependence of (multi-)strange hadron production in proton-proton collisions at √s = 13 TeV
- 2020
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Ingår i: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 80:2
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Tidskriftsartikel (refereegranskat)abstract
- The production rates and the transverse momentum distribution of strange hadrons at mid-rapidity (| y| < 0.5) are measured in proton-proton collisions at s = 13 TeV as a function of the charged particle multiplicity, using the ALICE detector at the LHC. The production rates of KS0, Λ , Ξ , and Ω increase with the multiplicity faster than what is reported for inclusive charged particles. The increase is found to be more pronounced for hadrons with a larger strangeness content. Possible auto-correlations between the charged particles and the strange hadrons are evaluated by measuring the event-activity with charged particle multiplicity estimators covering different pseudorapidity regions. When comparing to lower energy results, the yields of strange hadrons are found to depend only on the mid-rapidity charged particle multiplicity. Several features of the data are reproduced qualitatively by general purpose QCD Monte Carlo models that take into account the effect of densely-packed QCD strings in high multiplicity collisions. However, none of the tested models reproduce the data quantitatively. This work corroborates and extends the ALICE findings on strangeness production in proton-proton collisions at 7 TeV. © 2020, CERN for the benefit of the ALICE collaboration.
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| 9. |
- S., Acharya, et al.
(författare)
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Production of (anti-) He 3 and (anti-) H 3 in p-Pb collisions at sNN =5.02 TeV
- 2020
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Ingår i: Physical Review C. - 2469-9985. ; 101:4
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Tidskriftsartikel (refereegranskat)abstract
- The transverse momentum (pT) differential yields of (anti-)He3 and (anti-)H3 measured in p-Pb collisions at sNN = 5.02 TeV with ALICE at the Large Hadron Collider (LHC) are presented. The ratios of the pT-integrated yields of (anti-)He3 and (anti-)H3 to the proton yields are reported, as well as the pT dependence of the coalescence parameters B3 for (anti-)He3 and (anti-)H3. For (anti-)He3, the results obtained in four classes of the mean charged-particle multiplicity density are also discussed. These results are compared to predictions from a canonical statistical hadronization model and coalescence approaches. An upper limit on the total yield of 4Hē is determined. © 2020 CERN.
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| 10. |
- S., Acharya, et al.
(författare)
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Production of charged pions, kaons, and (anti-)protons in Pb-Pb and inelastic pp collisions at sNN =5.02 TeV
- 2020
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Ingår i: Physical Review C. - 2469-9985. ; 101:4
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Tidskriftsartikel (refereegranskat)abstract
- Midrapidity production of π±, K±, and (p¯)p measured by the ALICE experiment at the CERN Large Hadron Collider, in Pb-Pb and inelastic pp collisions at sNN=5.02 TeV, is presented. The invariant yields are measured over a wide transverse momentum (pT) range from hundreds of MeV/c up to 20 GeV/c. The results in Pb-Pb collisions are presented as a function of the collision centrality, in the range 0-90%. The comparison of the pT-integrated particle ratios, i.e., proton-to-pion (p/π) and kaon-to-pion (K/π) ratios, with similar measurements in Pb-Pb collisions at sNN=2.76 TeV show no significant energy dependence. Blast-wave fits of the pT spectra indicate that in the most central collisions radial flow is slightly larger at 5.02 TeV with respect to 2.76 TeV. Particle ratios (p/π, K/π) as a function of pT show pronounced maxima at pT≈3GeV/c in central Pb-Pb collisions. At high pT, particle ratios at 5.02 TeV are similar to those measured in pp collisions at the same energy and in Pb-Pb collisions at sNN=2.76 TeV. Using the pp reference spectra measured at the same collision energy of 5.02 TeV, the nuclear modification factors for the different particle species are derived. Within uncertainties, the nuclear modification factor is particle species independent for high pT and compatible with measurements at sNN=2.76 TeV. The results are compared to state-of-the-art model calculations, which are found to describe the observed trends satisfactorily. © 2020 American Physical Society. All rights reserved.
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