| 1. |
- Block, Keith I., et al.
(författare)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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| 2. |
- Shrine, N, et al.
(författare)
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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
- 2023
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 55:3, s. 410-
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Tidskriftsartikel (refereegranskat)abstract
- Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
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| 3. |
- Eggink, E, et al.
(författare)
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Prevention of dementia using mobile phone applications (PRODEMOS): protocol for an international randomised controlled trial
- 2021
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 11:6, s. e049762-
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Tidskriftsartikel (refereegranskat)abstract
- Profiles of high risk for future dementia are well understood and are likely to concern mostly those in low-income and middle-income countries and people at greater disadvantage in high-income countries. Approximately 30%–40% of dementia cases have been estimated to be attributed to modifiable risk factors, including hypertension, smoking and sedentary lifestyle. Tailored interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile health (mHealth) improves accessibility of such prevention strategies in hard-to-reach populations while at the same time tailoring such approaches. In the current study, we will investigate the effectiveness and implementation of a coach-supported mHealth intervention, targeting dementia risk factors, to reduce dementia risk.Methods and analysisThe prevention of dementia using mobile phone applications (PRODEMOS) randomised controlled trial will follow an effectiveness–implementation hybrid design, taking place in the UK and China. People are eligible if they are 55–75 years old, of low socioeconomic status (UK) or from the general population (China); have ≥2 dementia risk factors; and own a smartphone. 2400 participants will be randomised to either a coach-supported, interactive mHealth platform, facilitating self-management of dementia risk factors, or a static control platform. The intervention and follow-up period will be 18 months. The primary effectiveness outcome is change in the previously validated Cardiovascular Risk Factors, Ageing and Incidence of Dementia dementia risk score. The main secondary outcomes include improvement of individual risk factors and cost-effectiveness. Implementation outcomes include acceptability, adoption, feasibility and sustainability of the intervention.Ethics and disseminationThe PRODEMOS trial is sponsored in the UK by the University of Cambridge and is granted ethical approval by the London—Brighton and Sussex Research Ethics Committee (reference: 20/LO/01440). In China, the trial is approved by the medical ethics committees of Capital Medical University, Beijing Tiantan Hospital, Beijing Geriatric Hospital, Chinese People’s Liberation Army General Hospital, Taishan Medical University and Xuanwu Hospital. Results will be published in a peer-reviewed journal.Trial registration numberISRCTN15986016.
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| 4. |
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| 5. |
- Vermunt, L., et al.
(författare)
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Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:7, s. 888-898
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration. Methods: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration. Results: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE epsilon 4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage. Discussion: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 6. |
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| 7. |
- Buchert, T., et al.
(författare)
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Is there proof that backreaction of inhomogeneities is irrelevant in cosmology?
- 2015
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Ingår i: Classical and quantum gravity. - : IOP PUBLISHING LTD. - 0264-9381 .- 1361-6382. ; 32:21
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Tidskriftsartikel (refereegranskat)abstract
- No. In a number of papers, Green and Wald argue that the standard FLRW model approximates our Universe extremely well on all scales, except close to strong-field astrophysical objects. In particular, they argue that the effect of inhomogeneities on average properties of the Universe (backreaction) is irrelevant. We show that this latter claim is not valid. Specifically, we demonstrate, referring to their recent review paper, that (i) their two-dimensional example used to illustrate the fitting problem differs from the actual problem in important respects, and it assumes what is to be proven; (ii) the proof of the trace-free property of backreaction is unphysical and the theorem about it fails to be a mathematically general statement; (iii) the scheme that underlies the trace-free theorem does not involve averaging and therefore does not capture crucial non-local effects; (iv) their arguments are to a large extent coordinate-dependent, and (v) many of their criticisms of backreaction frameworks do not apply to the published definitions of these frameworks. It is therefore incorrect to infer that Green and Wald have proven a general result that addresses the essential physical questions of backreaction in cosmology.
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| 8. |
- Cumnock, J. A., et al.
(författare)
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Interplanetary magnetic field control of theta aurora development
- 2002
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Ingår i: Journal of Geophysical Research. - : American Geophysical Union (AGU). - 0148-0227 .- 2156-2202. ; 107:A7
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Tidskriftsartikel (refereegranskat)abstract
- [1] We ascertain the influence of the B-y component of the interplanetary magnetic field (IMF) on theta aurora evolution. During most cases where a transpolar arc is observed to move across the polar region, and form a theta aurora, there are brief (minutes) southward excursions of IMF B-z, however northward IMF is required prior to theta aurora formation. Observations show that theta aurora can form during strictly northward IMF with its motion consistent with a change in sign of IMF B-y. It is important to note that since transpolar arcs can persist for 20-30 min after the IMF turns southward, errors will occur in assigning instantaneous IMF conditions to snapshots'' of particular auroral patterns. We consider the entire evolution of the theta aurora and the changing IMF conditions. The influence of IMF B-y is best illustrated by examples which occur during steady northward IMF as compared to times when the IMF is northward on average. We show examples, provided by the Polar UV imager, when the IMF is steady northward. For one case, DMSP F13 and F14 provide in situ measurements of precipitating particles, ionospheric plasma flows and ion density. This unique data set enables us to analyze in detail the evolution of a theta aurora, in one case crossing the entire polar region. No sign change in B-z is needed for theta aurora formation.
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| 9. |
- Cumnock, Judy, et al.
(författare)
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POLAR UVI Observations of Auroral Oval Intensifications During a Transpolar Arc Event on December 7, 1996
- 2000
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The evolution of the northern hemisphere aurora is examined during a time when the IMF makes three brief southward excursions after a change in the sign of By during an extended period of northward IMF. POLAR UVI provides images of the aurora while DMSP F13 and F14 provide in situ measurements of precipitating particles, ionospheric plasma flows and ion density. Three different intensifications located in the nightside auroral oval occur during northward turnings of the IMF after brief periods of southward IMF. Spatial expansion, intensity of emissions and their duration are related to the length of time the IMF is southward prior to the northward turning. Thus the longer the period of enhanced magnetospheric convection the more intense the ionospheric response. Observations of a transpolar arc indicate that when the transpolar arc reaches highest latitudes it is located on a spatially narrow region of closed field lines, which extends along the noon-midnight meridian. UV observations indicate a connection between the transpolar arc and the nightside auroral enhancements. Precipitating particles associated with both features are attributed to a plasma sheet boundary layer source in the magnetotail implying a magnetospheric connection between the transpolar arc and the nightside auroral oval intensification.
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| 10. |
- Hafdi, M, et al.
(författare)
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Design and Development of a Mobile Health (mHealth) Platform for Dementia Prevention in the Prevention of Dementia by Mobile Phone Applications (PRODEMOS) Project
- 2021
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 12, s. 733878-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mobile health (mHealth) has the potential to bring preventive healthcare within reach of populations with limited access to preventive services, by delivering personalized support at low cost. Although numerous mHealth interventions are available, very few have been developed following an evidence-based rationale or have been tested for efficacy. This article describes the systematic development of a coach-supported mHealth application to improve healthy lifestyles for the prevention of dementia and cardiovascular disease in the United Kingdom (UK) and China.Methods: Development of the Prevention of Dementia by Mobile Phone applications (PRODEMOS) platform built upon the experiences with the Healthy Aging Through Internet Counseling in the Elderly (HATICE) eHealth platform. In the conceptualization phase, experiences from the HATICE trial and needs and wishes of the PRODEMOS target population were assessed through semi-structured interviews and focus group sessions. Initial technical development of the platform was based on these findings and took place in consecutive sprint sessions. Finally, during the evaluation and adaptation phase, functionality and usability of the platform were evaluated during pilot studies in UK and China.Results: The PRODEMOS mHealth platform facilitates self-management of a healthy lifestyle by goal setting, progress monitoring, and educational materials on healthy lifestyles. Participants receive remote coaching through a chat functionality. Based on lessons learned from the HATICE study and end-users, we made the intervention easy-to-use and included features to personalize the intervention. Following the pilot studies, in which in total 77 people used the mobile application for 6 weeks, the application was made more intuitive, and we improved its functionalities.Conclusion: Early involvement of end-users in the development process and during evaluation phases improved acceptability of the mHealth intervention. The actual use and usability of the PRODEMOS intervention will be assessed during the ongoing PRODEMOS randomized controlled trial, taking a dual focus on effectiveness and implementation outcomes.
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