| 1. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 2. |
- Engert, Andreas, et al.
(författare)
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The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
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Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
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Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
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| 3. |
- Tazelaar, Gijs H. P., et al.
(författare)
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Association of NIPA1 repeat expansions with amyotrophic lateral sclerosis in a large international cohort
- 2019
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Ingår i: Neurobiology of Aging. - : Elsevier. - 0197-4580 .- 1558-1497. ; 74, s. 234.e9-234.e15
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Tidskriftsartikel (refereegranskat)abstract
- NIPA1 (nonimprinted in Prader-Willi/Angelman syndrome 1) mutations are known to cause hereditary spastic paraplegia type 6, a neurodegenerative disease that phenotypically overlaps to some extent with amyotrophic lateral sclerosis (ALS). Previously, a genomewide screen for copy number variants found an association with rare deletions in NIPA1 and ALS, and subsequent genetic analyses revealed that long (or expanded) polyalanine repeats in NIPA1 convey increased ALS susceptibility. We set out to perform a large-scale replication study to further investigate the role of NIPA1 polyalanine expansions with ALS, in which we characterized NIPA1 repeat size in an independent international cohort of 3955 patients with ALS and 2276 unaffected controls and combined our results with previous reports. Meta-analysis on a total of 6245 patients with ALS and 5051 controls showed an overall increased risk of ALS in those with expanded (>8) GCG repeat length (odds ratio = 1.50, p = 3.8×10−5). Together with previous reports, these findings provide evidence for an association of an expanded polyalanine repeat in NIPA1 and ALS.
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| 4. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 5. |
- Van der Poel, Henk G., et al.
(författare)
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Sentinel node biopsy for prostate cancer : Report from a consensus panel meeting
- 2017
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Ingår i: BJU International. - : Wiley. - 1464-4096. ; 120:2, s. 204-211
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To explore the evidence and knowledge gaps in sentinel node biopsy (SNB) in prostate cancer through a consensus panel of experts. Methods: A two-round Delphi survey among experts was followed by a consensus panel meeting of 16 experts in February 2016. Agreement voting was performed using the research and development project/University of California, Los Angeles Appropriateness Methodology on 150 statements in nine domains. The disagreement index based on the interpercentile range, adjusted for symmetry score, was used to assess consensus and non-consensus among panel members. Results: Consensus was obtained on 91 of 150 statements (61%). The main outcomes were: (1) the results from an extended lymph node dissection (eLND) are still considered the 'gold standard', and sentinel node (SN) detection should be combined with eLND, at least in patients with intermediate- and high-risk prostate cancer; (2) the role of SN detection in low-risk prostate cancer is unclear; and (3) future studies should contain oncological endpoints as number of positive nodes outside the eLND template, false-negative and false-positive SN procedures, and recurrence-free survival. A high rate of consensus was obtained regarding outcome measures of future clinical trials on SNB (89%). Consensus on tracer technology was only obtained in 47% of statements, reflecting a need for further research and standardization in this area. The low-level evidence in the available literature and the composition of mainly SNB users in the panel constitute the major limitations of the study. Conclusions: Consensus on a majority of elementary statements on SN detection in prostate cancer was obtained.; therefore, the results from this consensus report will provide a basis for the design of further studies in the field. A group of experts identified evidence and knowledge gaps on SN detection in prostate cancer and its application in daily practice. Information from the consensus statements can be used to direct further studies.
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| 6. |
- Wit, Esther M K, et al.
(författare)
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Sentinel Node Procedure in Prostate Cancer : A Systematic Review to Assess Diagnostic Accuracy
- 2017
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Ingår i: European Urology. - : Elsevier BV. - 0302-2838. ; 71:4, s. 596-605
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Forskningsöversikt (refereegranskat)abstract
- Context: Extended pelvic lymph node dissection (ePLND) is the gold standard for detecting lymph node (LN) metastases in prostate cancer (PCa). The benefit of sentinel node biopsy (SNB), which is the first draining LN as assessed by imaging of locally injected tracers, remains controversial. Objective: To assess the diagnostic accuracy of SNB in PCa. Evidence acquisition: A systematic literature search of Medline, Embase, and the Cochrane Library (1999-2016) was undertaken using PRISMA guidelines. All studies of SNB in men with PCa using PLND as reference standard were included. The primary outcomes were the nondiagnostic rate (NDR), sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and false positive (FP) and false negative (FN) rates. Relevant sensitivity analyses based on SN definitions, ePLND as reference standard, and disease risk were undertaken, including a risk of bias (RoB) assessment. Evidence synthesis: Of 373 articles identified, 21 studies recruiting a total of 2509 patients were eligible for inclusion. Median cumulative percentage (interquartile range) results were 4.1% (1.5-10.7%) for NDR, 95.2% (81.8-100%) for sensitivity, 100% (95.0-100%) for specificity, 100% (87.0-100%) for PPV, 98.0% (94.3-100%) for NPV, 0% (0-5.0%) for the FP rate, and 4.8% (0-18.2%) for the FN rate. The findings did not change significantly on sensitivity analyses. Most studies (17/22) had low RoB for index test and reference standard domains. Conclusions: SNB appears to have diagnostic accuracy comparable to ePLND, with high sensitivity, specificity, PPV and NPV, and a low FN rate. With a low FP rate (rate of detecting positive nodes outside the ePLND template), SNB may not have any additional diagnostic value over and above ePLND, although SNB appears to increase nodal yield by increasing the number of affected nodes when combined with ePLND. Thus, in high-risk disease it may be prudent to combine ePLND with SNB. Patient summary: This literature review showed a high diagnostic accuracy for sentinel node biopsy in detecting positive lymph nodes in prostate cancer, but further studies are needed to explore the effect of sentinel node biopsy on complications and oncologic outcome. The accuracy of sentinel node biopsy (SNB) in detecting positive lymph nodes in prostate cancer appears to have diagnostic accuracy comparable to that of extended pelvic lymph node dissection (ePLND). However, SNB may not have any additional diagnostic value over and above ePLND.
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| 7. |
- Bouwman, Henk, et al.
(författare)
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DDT : Fifty years since silent spring
- 2013
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Ingår i: Late lessons from early warnings. - Copenhagen : European Environment Agency. - 9789292133498 ; , s. 272-291
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- 'There was a strange stillness. The birds for example — where had they gone? Many people spoke about them, puzzled and disturbed. The feeding stations in the backyards were deserted. The few birds seen anywhere were moribund: they trembled violently and could not fly. It was a spring without voices ... only silence lay over the fields and woods and marsh.'The book Silent Spring by Rachel Carson is mainly about the impacts of chemicals (in particular in particular dichlorodiphenyltrichlorethane also known as DDT) on the environment and human health. Indeed, the close association between humans and birds remains very apt. Representing the only two warm-blooded groups of life on Earth, mammals and birds share the same environments and threats.Carson's claim that she lived in 'an era dominated by industry, in which the right to make a dollar at whatever cost is seldom challenged' still resonates strongly with the problems that societies face all over the world. One chapter heading, 'The obligation to endure', derived from the French biologist and philosopher Jean Rostand's famous observation that, 'the obligation to endure gives us the right to know'. United States President John F. Kennedy responded to the challenge posed by Carson by investigating DDT, leading to its complete ban in the US. The ban was followed by a range of institutions and regulations concerned with environmental issues in the US and elsewhere, driven by public demand for knowledge and protection.DDT was the primary tool used in the first global malaria eradication programme during the 1950s and 1960s. The insecticide is sprayed on the inner walls and ceilings of houses. Malaria has been successfully eliminated from many regions but remains endemic in large parts of the world. DDT remains one of the 12 insecticides — and the only organochlorine compound — currently recommended by the World Health Organization (WHO), and under the Stockholm Convention on Persistent Organic Pollutants, countries may continue to use DDT. Global annual use of DDT for disease vector control is estimated at more than 5 000 tonnes.It is clear that the social conscience awakened by Rachel Carson 50 years ago gave momentum to a groundswell of actions and interventions that are slowly but steadily making inroads at myriad levels. Chapter 17 of her book, 'The other road' reminds the reader of the opportunities that should have been seized much earlier. With more than 10 % of bird species worldwide now threatened in one way or another, it is clear that we missed early warnings or failed to act on them. Will we continue to miss signposts to 'other roads'? Are our obligations to endure met by our rights to know? As Carson said 50 years ago: 'The choice, after all, is ours to make.'
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| 8. |
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| 9. |
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| 10. |
- Bouwman, Henk, et al.
(författare)
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Letter: DDT Paradox: Bouwman et al. Respond
- 2011
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Ingår i: Journal of Environmental Health Perspectives. - : National Institute of Environmental Health Sciences (NIEHS), USA. - 0091-6765 .- 1552-9924. ; 119:10, s. A424-A425
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
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