| 1. |
- Fryknäs, Mårten, et al.
(författare)
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Iron chelators target both proliferating and quiescent cancer cells
- 2016
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.
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| 2. |
- Kaufmann, Tobias, et al.
(författare)
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Common brain disorders are associated with heritable patterns of apparent aging of the brain
- 2019
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Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 22:10, s. 1617-
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Tidskriftsartikel (refereegranskat)abstract
- Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.
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| 3. |
- Mullins, Niamh, et al.
(författare)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 4. |
- Arthur Hvidtfeldt, Ulla, et al.
(författare)
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Long-term exposure to fine particle elemental components and lung cancer incidence in the ELAPSE pooled cohort
- 2021
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Ingår i: Environmental Research. - : Elsevier BV. - 0013-9351 .- 1096-0953. ; 193
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Tidskriftsartikel (refereegranskat)abstract
- Background: An association between long-term exposure to fine particulate matter (PM2.5) and lung cancer has been established in previous studies. PM2.5 is a complex mixture of chemical components from various sources and little is known about whether certain components contribute specifically to the associated lung cancer risk. The present study builds on recent findings from the Effects of Low-level Air Pollution: A Study in Europe (ELAPSE) collaboration and addresses the potential association between specific elemental components of PM2.5 and lung cancer incidence.Methods: We pooled seven cohorts from across Europe and assigned exposure estimates for eight components of PM2.5 representing non-tail pipe emissions (copper (Cu), iron (Fe), and zinc (Zn)), long-range transport (sulfur (S)), oil burning/industry emissions (nickel (Ni), vanadium (V)), crustal material (silicon (Si)), and biomass burning (potassium (K)) to cohort participants' baseline residential address based on 100 m by 100 m grids from newly developed hybrid models combining air pollution monitoring, land use data, satellite observations, and dispersion model estimates. We applied stratified Cox proportional hazards models, adjusting for potential confounders (age, sex, calendar year, marital status, smoking, body mass index, employment status, and neighborhood-level socio-economic status).Results: The pooled study population comprised 306,550 individuals with 3916 incident lung cancer events during 5,541,672 person-years of follow-up. We observed a positive association between exposure to all eight components and lung cancer incidence, with adjusted HRs of 1.10 (95% CI 1.05, 1.16) per 50 ng/m(3) PM2.5 K, 1.09 (95% CI 1.02, 1.15) per 1 ng/m3 PM2.5 Ni, 1.22 (95% CI 1.11, 1.35) per 200 ng/m(3) PM2.5 S, and 1.07 (95% CI 1.02, 1.12) per 200 ng/m(3) PM2.5 V. Effect estimates were largely unaffected by adjustment for nitrogen dioxide (NO2). After adjustment for PM2.5 mass, effect estimates of K, Ni, S, and V were slightly attenuated, whereas effect estimates of Cu, Si, Fe, and Zn became null or negative.Conclusions: Our results point towards an increased risk of lung cancer in connection with sources of combustion particles from oil and biomass burning and secondary inorganic aerosols rather than non-exhaust traffic emissions. Specific limit values or guidelines targeting these specific PM2.5 components may prove helpful in future lung cancer prevention strategies.
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| 5. |
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| 6. |
- Bergman, Åke, et al.
(författare)
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Manufacturing doubt about endocrine disrupter science : A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"
- 2015
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Ingår i: Regulatory toxicology and pharmacology. - : Academic Press. - 0273-2300 .- 1096-0295. ; 73:3, s. 1007-1017
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Tidskriftsartikel (refereegranskat)abstract
- We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford-Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.
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| 7. |
- Bergman, Åke, et al.
(författare)
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Science and policy on endocrine disrupters must not be mixed : a reply to a "common sense" intervention by toxicology journal editors
- 2013
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Ingår i: Environmental Health. - : BioMed Central (BMC). - 1476-069X. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.
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| 8. |
- Ekelund, A, et al.
(författare)
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Additional colloids have only a minor haemodilutive effect after surgery for aneurysmal subarachnoid haemorrhage
- 1999
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Ingår i: British Journal of Neurosurgery. - : Informa UK Limited. - 0268-8697 .- 1360-046X. ; 13:4, s. 399-404
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Tidskriftsartikel (refereegranskat)abstract
- Haemodilution is commonly used as prophylaxis, as well as treatment for cerebral ischaemia after aneurysmal subarachnoid haemorrhage (SAH). Thirty-six patients operated for aneurysmal SAH were evaluated retrospectively; 24 received haemodilutive therapy and 12 patients, as a control group, received no additional therapy. There was a 'spontaneous' drop in haematocrit by 22% in both groups, and a corresponding drop in haemoglobin by 23% in the treatment group and 19% in the non-haemodiluted group, during the first 4 days after the SAH. After the initial decrease the haematocrit remained stable between 0.28 and 0.33 until day 14 in both groups. The haemodilutive group had only a minor lower haematocrit level during days 8-12 as the additional fluid resulted in increased renal excretion. This minor difference was, however, significant (p < 0.02).
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| 9. |
- Ekelund, A, et al.
(författare)
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Transcranial cerebral oximetry related to transcranial Doppler after aneurysmal subarachnoid haemorrhage
- 1998
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Ingår i: Acta Neurochirurgica. - : Springer Science and Business Media LLC. - 0001-6268 .- 0942-0940. ; 140:10, s. 1029-1036
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Tidskriftsartikel (refereegranskat)abstract
- Noninvasive methods for detecting cerebral artery vasospasm, still a serious complication following aneurysmal subarachnoid haemorrhage, are of vital interest. Up-to-date transcranial Doppler ultrasound (TCD) has proved to be sensitive in detecting vasospasm in the middle cerebral artery, but has less accuracy for other cerebral arteries. Transcranial cerebral oximetry (TCCO) is a new non-invasive technique which may increase the reliability for detecting cerebral ischaemia. The purpose of the present study was to evaluate a putative correlation between TCCO and TCD. We examined the two hemispheres in 14 patients with the aim of evaluating a proposed correlation between TCD and TCCO. Analysis of all absolute values (maximum TCD mFV and minimum TCCO saturation, respectively) in all series indicate a correlation between TCCO and TCD, p < 0.01, r = -0.62. All patients with TCD mean flow velocity > 120 cm/s also presented TCCO saturation < 60%. Conversely, all patients with normal TCCO saturation (> or = 63%) presented normal or moderately increased TCD velocities. In clinical neurosurgical practice it is of great interest if a true correlation between TCD and TCCO exists. The present results support the assumption that TCCO may enhance the reliability for detecting cerebral ischaemia after aneurysmal subarachnoid haemorrhage.
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| 10. |
- Fernström, Maria, 1960-, et al.
(författare)
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Improved Muscle Mitochondrial Capacity Following Gastric Bypass Surgery in Obese Subjects
- 2016
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Ingår i: Obesity Surgery. - New York, USA : Springer. - 0960-8923 .- 1708-0428. ; 26:7, s. 1391-1397
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Tidskriftsartikel (refereegranskat)abstract
- Background: Weight loss resulting from low-calorie diets is often less than expected. We hypothesized that energy restriction would influence proton leakage and improve mitochondrial efficiency, leading to reduced energy expenditure, partly explaining the difficulties in weight loss maintenance.Methods: Eleven women with a median BMI of 38.5 kg/m(2) (q-range 37-40), and referred to gastric bypass surgery participated. Before surgery, and at 6 months of follow-up, muscle biopsies were collected from the vastus lateralis muscle. Mitochondria were isolated and analyzed for coupled (state 3) and uncoupled (state 4) respiration and mitochondrial capacity (P/O ratio).Results: At follow-up, the participants had a median BMI of 29.6 kg/m(2) (28.3-32.0). State 3 increased from 20.6 (17.9-28.9) to 34.9 nmol O2/min/U citrate synthase (CS) (27.0-49.0), p = 0.01, while state 4 increased from 2.8 (1.8-4.2) to 4.2 nmol O2/min/U CS (3.1-6.1), although not statistically significant. The P/O ratio increased from 2.7 (2.5-2.8) to 3.2 (3.0-3.4), p = 0.02, indicating improved mitochondrial efficiency.Conclusions: Six months after gastric bypass surgery, the mitochondrial capacity for coupled, i.e., ATP-generating, respiration increased, and the P/O ratio improved. Uncoupled respiration was not enhanced to the same extent. This could partly explain the decreased basal metabolism and the reduced inclination for weight loss during energy restriction.
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