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- Campbell, PJ, et al.
(author)
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Pan-cancer analysis of whole genomes
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Journal article (peer-reviewed)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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- Kanai, M, et al.
(author)
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- 2023
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swepub:Mat__t
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- Hsieh, HC, et al.
(author)
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Can a Bayesian belief network for survival prediction in patients with extremity metastases (PATHFx) be externally validated in an Asian cohort of 356 surgically treated patients?
- 2022
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In: Acta orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 93, s. 721-731
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Journal article (peer-reviewed)abstract
- Background and purpose: Predicted survival may influence the treatment decision for patients with skeletal extremity metastasis, and PATHFx was designed to predict the likelihood of a patient dying in the next 24 months. However, the performance of prediction models could have ethnogeographical variations. We asked if PATHFx generalized well to our Taiwanese cohort consisting of 356 surgically treated patients with extremity metastasis.Patients and methods: We included 356 patients who underwent surgery for skeletal extremity metastasis in a tertiary center in Taiwan between 2014 and 2019 to validate PATHFx’s survival predictions at 6 different time points. Model performance was assessed by concordance index (c-index), calibration analysis, decision curve analysis (DCA), Brier score, and model consistency (MC).Results: The c-indexes for the 1-, 3-, 6-, 12-, 18-, and 24-month survival estimations were 0.71, 0.66, 0.65, 0.69, 0.68, and 0.67, respectively. The calibration analysis demonstrated positive calibration intercepts for survival predictions at all 6 timepoints, indicating PATHFx tended to underestimate the actual survival. The Brier scores for the 6 models were all less than their respective null model’s. DCA demonstrated that only the 6-, 12-, 18-, and 24-month predictions appeared useful for clinical decision-making across a wide range of threshold probabilities. The MC was < 0.9 when the 6- and 12-month models were compared with the 12-month and 18-month models, respectively.Interpretation: In this Asian cohort, PATHFx’s performance was not as encouraging as those of prior validation studies. Clinicians should be cognizant of the potential decline in validity of any tools designed using data outside their particular patient population. Developers of survival prediction tools such as PATHFx might refine their algorithms using data from diverse, contemporary patients that is more reflective of the world’s population.
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| 24. |
- Huynh-Le, MP, et al.
(author)
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Polygenic hazard score is associated with prostate cancer in multi-ethnic populations
- 2021
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 1236-
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Journal article (peer-reviewed)abstract
- Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10−180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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- Kinyoki, DK, et al.
(author)
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Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017
- 2020
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In: Nature medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 26:5, s. 750-759
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Journal article (peer-reviewed)abstract
- A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic.
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- Menden, MP, et al.
(author)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Journal article (peer-reviewed)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 43. |
- Rvachev, MM, et al.
(author)
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Quasielastic He-3(e,e(')p)H-2 reaction at Q(2)=1.5 GeV2 for recoil momenta up to 1 GeV/c
- 2005
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In: Physical Review Letters. - 1079-7114. ; 94:19
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Journal article (peer-reviewed)abstract
- We have studied the quasielastic He-3(e,e(')p)H-2 reaction in perpendicular coplanar kinematics, with the energy and the momentum transferred by the electron fixed at 840 MeV and 1502 MeV/c, respectively. The He-3(e,e(')p)H-2 cross section was measured for missing momenta up to 1000 MeV/c, while the A(TL) asymmetry was extracted for missing momenta up to 660 MeV/c. For missing momenta up to 150 MeV/c, the cross section is described by variational calculations using modern He-3 wave functions. For missing momenta from 150 to 750 MeV/c, strong final-state interaction effects are observed. Near 1000 MeV/c, the experimental cross section is more than an order of magnitude larger than predicted by available theories. The A(TL) asymmetry displays characteristic features of broken factorization with a structure that is similar to that generated by available models.
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| 45. |
- Schael, S, et al.
(author)
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Precision electroweak measurements on the Z resonance
- 2006
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In: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 427:5-6, s. 257-454
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Research review (peer-reviewed)abstract
- We report on the final electroweak measurements performed with data taken at the Z resonance by the experiments operating at the electron-positron colliders SLC and LEP. The data consist of 17 million Z decays accumulated by the ALEPH, DELPHI, L3 and OPAL experiments at LEP, and 600 thousand Z decays by the SLID experiment using a polarised beam at SLC. The measurements include cross-sections, forward-backward asymmetries and polarised asymmetries. The mass and width of the Z boson, m(Z) and Gamma(Z), and its couplings to fermions, for example the p parameter and the effective electroweak mixing angle for leptons, are precisely measured: m(Z) = 91.1875 +/- 0.0021 GeV, Gamma(Z) = 2.4952 +/- 0.0023 GeV, rho(l) = 1.0050 +/- 0.0010, sin(2)theta(eff)(lept) = 0.23153 +/- 0.00016. The number of light neutrino species is determined to be 2.9840 +/- 0.0082, in agreement with the three observed generations of fundamental fermions. The results are compared to the predictions of the Standard Model (SM). At the Z-pole, electroweak radiative corrections beyond the running of the QED and QCD coupling constants are observed with a significance of five standard deviations, and in agreement with the Standard Model. Of the many Z-pole measurements, the forward-backward asymmetry in b-quark production shows the largest difference with respect to its SM expectation, at the level of 2.8 standard deviations. Through radiative corrections evaluated in the framework of the Standard Model, the Z-pole data are also used to predict the mass of the top quark, m(t) = 173(+10)(+13) GeV, and the mass of the W boson, m(W) = 80.363 +/- 0.032 GeV. These indirect constraints are compared to the direct measurements, providing a stringent test of the SM. Using in addition the direct measurements of m(t) and m(W), the mass of the as yet unobserved SM Higgs boson is predicted with a relative uncertainty of about 50% and found to be less than 285 GeV at 95% confidence level. (c) 2006 Elsevier B.V. All rights reserved.
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| 46. |
- Sun, ND, et al.
(author)
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Modified VEGF-A mRNA induces sustained multifaceted microvascular response and accelerates diabetic wound healing
- 2018
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1, s. 17509-
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Journal article (peer-reviewed)abstract
- Capable of mediating efficient transfection and protein production without eliciting innate immune responses, chemically modified mRNA holds great potential to produce paracrine factors at a physiologically beneficial level, in a spatiotemporally controlled manner, and with low toxicity. Although highly promising in cardiovascular medicine and wound healing, effects of this emerging therapeutic on the microvasculature and its bioactivity in disease settings remain poorly understood. Here, we longitudinally and comprehensively characterize microvascular responses to AZD8601, a modified mRNA encoding vascular endothelial growth factor A (VEGF-A), in vivo. Using multi-parametric photoacoustic microscopy, we show that intradermal injection of AZD8601 formulated in a biocompatible vehicle results in pronounced, sustained and dose-dependent vasodilation, blood flow upregulation, and neovessel formation, in striking contrast to those induced by recombinant human VEGF-A protein, a non-translatable variant of AZD8601, and citrate/saline vehicle. Moreover, we evaluate the bioactivity of AZD8601 in a mouse model of diabetic wound healing in vivo. Using a boron nanoparticle-based tissue oxygen sensor, we show that sequential dosing of AZD8601 improves vascularization and tissue oxygenation of the wound bed, leading to accelerated re-epithelialization during the early phase of diabetic wound healing.
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| 49. |
- Wang, HD, et al.
(author)
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Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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In: Lancet (London, England). - : Elsevier. - 1474-547X .- 0140-6736. ; 388:10053, s. 1725-1774
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Journal article (peer-reviewed)
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