| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Bölling, T, et al.
(författare)
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Development of Curative Therapies for Ewing Sarcomas by Interdisciplinary Cooperative Groups in Europe.
- 2015
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Ingår i: Klinische Pädiatrie. - : Georg Thieme Verlag KG. - 1439-3824 .- 0300-8630. ; 227:3, s. 108-115
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Forskningsöversikt (refereegranskat)abstract
- Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.
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| 3. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 1113-1120
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Tidskriftsartikel (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 4. |
- Maxwell, Tania L., et al.
(författare)
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Global dataset of soil organic carbon in tidal marshes
- 2023
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Ingår i: Scientific Data. - : Springer Nature. - 2052-4463. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Tidal marshes store large amounts of organic carbon in their soils. Field data quantifying soil organic carbon (SOC) stocks provide an important resource for researchers, natural resource managers, and policy-makers working towards the protection, restoration, and valuation of these ecosystems. We collated a global dataset of tidal marsh soil organic carbon (MarSOC) from 99 studies that includes location, soil depth, site name, dry bulk density, SOC, and/or soil organic matter (SOM). The MarSOC dataset includes 17,454 data points from 2,329 unique locations, and 29 countries. We generated a general transfer function for the conversion of SOM to SOC. Using this data we estimated a median (± median absolute deviation) value of 79.2 ± 38.1 Mg SOC ha−1 in the top 30 cm and 231 ± 134 Mg SOC ha−1 in the top 1 m of tidal marsh soils globally. This data can serve as a basis for future work, and may contribute to incorporation of tidal marsh ecosystems into climate change mitigation and adaptation strategies and policies.
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| 5. |
- Rheinbay, E, et al.
(författare)
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Analyses of non-coding somatic drivers in 2,658 cancer whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 102-
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of drivers of cancer has traditionally focused on protein-coding genes1–4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53, in the 3′ untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.
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| 6. |
- Bansal, Sheel, et al.
(författare)
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Practical Guide to Measuring Wetland Carbon Pools and Fluxes
- 2023
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Ingår i: Wetlands (Wilmington, N.C.). - : SPRINGER. - 0277-5212 .- 1943-6246. ; 43:8
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Forskningsöversikt (refereegranskat)abstract
- Wetlands cover a small portion of the world, but have disproportionate influence on global carbon (C) sequestration, carbon dioxide and methane emissions, and aquatic C fluxes. However, the underlying biogeochemical processes that affect wetland C pools and fluxes are complex and dynamic, making measurements of wetland C challenging. Over decades of research, many observational, experimental, and analytical approaches have been developed to understand and quantify pools and fluxes of wetland C. Sampling approaches range in their representation of wetland C from short to long timeframes and local to landscape spatial scales. This review summarizes common and cutting-edge methodological approaches for quantifying wetland C pools and fluxes. We first define each of the major C pools and fluxes and provide rationale for their importance to wetland C dynamics. For each approach, we clarify what component of wetland C is measured and its spatial and temporal representativeness and constraints. We describe practical considerations for each approach, such as where and when an approach is typically used, who can conduct the measurements (expertise, training requirements), and how approaches are conducted, including considerations on equipment complexity and costs. Finally, we review key covariates and ancillary measurements that enhance the interpretation of findings and facilitate model development. The protocols that we describe to measure soil, water, vegetation, and gases are also relevant for related disciplines such as ecology. Improved quality and consistency of data collection and reporting across studies will help reduce global uncertainties and develop management strategies to use wetlands as nature-based climate solutions.
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| 7. |
- Benedict, Christian, et al.
(författare)
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Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated With Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly
- 2012
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 35:3, s. 488-494
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVEImpaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.RESEARCH DESIGN AND METHODSInsulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume).RESULTSThe HOMA-IR was negatively correlated with verbal fluency performance, brain size (S1), and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses.CONCLUSIONSThese cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies.
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| 8. |
- Brinkley, T. E., et al.
(författare)
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Changes in Adiposity and Cerebrospinal Fluid Biomarkers Following a Modified Mediterranean Ketogenic Diet in Older Adults at Risk for Alzheimer's Disease
- 2022
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ketogenic diets have been used to treat both obesity and neurological disorders, including epilepsy and more recently Alzheimer's disease (AD), likely due to favorable effects on both central and peripheral metabolism. Improvements in body composition have also been reported; however, it is unclear if diet-induced changes in adiposity are related to improvements in AD and related neuropathology. Purpose: We examined the effects of a Modified Mediterranean Ketogenic (MMK) diet vs. an American Heart Association (AHA) diet on body weight, body composition, and body fat distribution and their association with cerebrospinal fluid (CSF) biomarkers in older adults at risk for AD. Methods: Twenty adults (mean age: 64.3 +/- 6.3 years, 35% Black, 75% female) were randomly assigned to a crossover trial starting with either the MMK or AHA diet for 6 weeks, followed by a 6-week washout and then the opposite diet for 6 weeks. At baseline and after each diet adiposity was assessed by dual-energy x-ray absorptiometry and CSF biomarkers were measured. Linear mixed effect models were used to examine the effect of diet on adiposity. Spearman correlations were examined to assess associations between adiposity and CSF biomarkers. Results: At baseline there was a high prevalence of overweight/obesity and central adiposity, and higher visceral fat and lower peripheral fat were associated with an adverse CSF biomarker profile. The MMK and AHA diets led to similar improvements in body composition and body fat distribution. Significant correlations were found between changes in adiposity and changes in CSF biomarkers (r's = 0.63-0.92, p's < 0.05), with notable differences by diet. Decreases in body fat on the MMK diet were related to changes in A beta biomarkers, whereas decreases in body fat on the AHA diet were related to changes in tau biomarkers and cholinesterase activity. Interestingly, increases in CSF A beta on the MMK diet occurred in those with less fat loss. Conclusion: An MMK diet leads to favorable changes in body composition, body fat distribution, and CSF biomarkers. Our data suggest that modest weight loss that maximizes visceral fat loss and preserves peripheral fat, may have the greatest impact on brain health.
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| 9. |
- Chapman, Colin D, et al.
(författare)
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Intranasal Treatment of Central Nervous System Dysfunction in Humans
- 2013
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 30:10, s. 2475-2484
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Forskningsöversikt (refereegranskat)abstract
- One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke.
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| 10. |
- Gaspar, Nathalie, et al.
(författare)
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Ewing Sarcoma: Current Management and Future Approaches Through Collaboration.
- 2015
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 33:27, s. 140-3036
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Forskningsöversikt (refereegranskat)abstract
- Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.
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