| 51. |
- Woll, Petter S, et al.
(författare)
-
Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.
- 2014
-
Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 25:6, s. 794-808
-
Tidskriftsartikel (refereegranskat)abstract
- Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
|
|
| 52. |
- Asai, Masato, et al.
(författare)
-
Loss of Function of the Melanocortin 2 Receptor Accessory Protein 2 Is Associated with Mammalian Obesity
- 2013
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 341:6143, s. 275-278
-
Tidskriftsartikel (refereegranskat)abstract
- Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.
|
|
| 53. |
- Byass, Peter, et al.
(författare)
-
An integrated approach to processing WHO-2016 verbal autopsy data: the InterVA-5 model
- 2019
-
Ingår i: BMC Med. - : Springer Science and Business Media LLC. - 1741-7015. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Verbal autopsy is an increasingly important methodology for assigning causes to otherwise uncertified deaths, which amount to around 50% of global mortality and cause much uncertainty for health planning. The World Health Organization sets international standards for the structure of verbal autopsy interviews and for cause categories that can reasonably be derived from verbal autopsy data. In addition, computer models are needed to efficiently process large quantities of verbal autopsy interviews to assign causes of death in a standardised manner. Here, we present the InterVA-5 model, developed to align with the WHO-2016 verbal autopsy standard. This is a harmonising model that can process input data from WHO-2016, as well as earlier WHO-2012 and Tariff-2 formats, to generate standardised cause-specific mortality profiles for diverse contexts. The software development involved building on the earlier InterVA-4 model, and the expanded knowledge base required for InterVA-5 was informed by analyses from a training dataset drawn from the Population Health Metrics Research Collaboration verbal autopsy reference dataset, as well as expert input. Results: The new model was evaluated against a test dataset of 6130 cases from the Population Health Metrics Research Collaboration and 4009 cases from the Afghanistan National Mortality Survey dataset. Both of these sources contained around three quarters of the input items from the WHO-2016, WHO-2012 and Tariff-2 formats. Cause-specific mortality fractions across all applicable WHO cause categories were compared between causes assigned in participating tertiary hospitals and InterVA-5 in the test dataset, with concordance correlation coefficients of 0.92 for children and 0.86 for adults. The InterVA-5 model's capacity to handle different input formats was evaluated in the Afghanistan dataset, with concordance correlation coefficients of 0.97 and 0.96 between the WHO-2016 and the WHO-2012 format for children and adults respectively, and 0.92 and 0.87 between the WHO-2016 and the Tariff-2 format respectively. Conclusions: Despite the inherent difficulties of determining "truth" in assigning cause of death, these findings suggest that the InterVA-5 model performs well and succeeds in harmonising across a range of input formats. As more primary data collected under WHO-2016 become available, it is likely that InterVA-5 will undergo minor re-versioning in the light of practical experience. The model is an important resource for measuring and evaluating cause-specific mortality globally.
|
|
| 54. |
- Christofer Juhlin, C., et al.
(författare)
-
Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene
- 2015
-
Ingår i: Genes, Chromosomes and Cancer. - : Wiley: 12 months. - 1045-2257 .- 1098-2264. ; 54:9, s. 542-554
-
Tidskriftsartikel (refereegranskat)abstract
- As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.
|
|
| 55. |
- Cooper, Declan L.M., et al.
(författare)
-
Consistent patterns of common species across tropical tree communities
- 2024
-
Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 625:7996, s. 728-734
-
Tidskriftsartikel (refereegranskat)abstract
- Trees structure the Earth’s most biodiverse ecosystem, tropical forests. The vast number of tree species presents a formidable challenge to understanding these forests, including their response to environmental change, as very little is known about most tropical tree species. A focus on the common species may circumvent this challenge. Here we investigate abundance patterns of common tree species using inventory data on 1,003,805 trees with trunk diameters of at least 10 cm across 1,568 locations 1–6 in closed-canopy, structurally intact old-growth tropical forests in Africa, Amazonia and Southeast Asia. We estimate that 2.2%, 2.2% and 2.3% of species comprise 50% of the tropical trees in these regions, respectively. Extrapolating across all closed-canopy tropical forests, we estimate that just 1,053 species comprise half of Earth’s 800 billion tropical trees with trunk diameters of at least 10 cm. Despite differing biogeographic, climatic and anthropogenic histories 7, we find notably consistent patterns of common species and species abundance distributions across the continents. This suggests that fundamental mechanisms of tree community assembly may apply to all tropical forests. Resampling analyses show that the most common species are likely to belong to a manageable list of known species, enabling targeted efforts to understand their ecology. Although they do not detract from the importance of rare species, our results open new opportunities to understand the world’s most diverse forests, including modelling their response to environmental change, by focusing on the common species that constitute the majority of their trees.
|
|
| 56. |
- Cuzzone, Joshua K., et al.
(författare)
-
Final deglaciation of the Scandinavian Ice Sheet and implications for the Holocene global sea-level budget
- 2016
-
Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 0012-821X .- 1385-013X. ; 448, s. 34-41
-
Tidskriftsartikel (refereegranskat)abstract
- The last deglaciation of the Scandinavian Ice Sheet (SIS) from similar to 21,000 to 13,000 yr ago is well constrained by several hundred Be-10 and C-14 ages. The subsequent retreat history, however, is established primarily from minimum-limiting C-14 ages and incomplete Baltic-Sea varve records, leaving a substantial fraction of final SIS retreat history poorly constrained. Here we develop a high-resolution chronology for the final deglaciation of the SIS based on 79 Be-10 cosmogenic exposure dates sampled along three transects spanning southern to northern Sweden and Finland. Combining this new chronology with existing Be-10 ages on deglaciation since the Last Glacial Maximum shows that rates of SIS margin retreat were strongly influenced by deglacial millennial-scale climate variability and its effect on surface mass balance, with regional modulation of retreat associated with dynamical controls. Ice-volume estimates constrained by our new chronology suggest that the SIS contributed 8 m sea-level equivalent to global sea-level rise between similar to 14.5 ka and 10 ka. Final deglaciation was largely complete by similar to 10.5 ka, with highest rates of sea-level rise occurring during the Bolling-Allerod, a 50% decrease during the Younger Dryas, and a rapid increase during the early Holocene. Combining our SIS volume estimates with estimated contributions from other remaining Northern Hemisphere ice sheets suggests that the Antarctic Ice Sheet (AIS) contributed 14.4 +/- 5.9 m to global sea-level rise since 13 ka. This new constraint supports those studies that indicate that an ice volume of 15 m or more of equivalent sea-level rise was lost from the AIS during the last deglaciation.
|
|
| 57. |
- Kun-Rodrigues, Celia, et al.
(författare)
-
A comprehensive screening of copy number variability in dementia with Lewy bodies.
- 2019
-
Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 75
-
Tidskriftsartikel (refereegranskat)abstract
- The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.
|
|
| 58. |
- Kun-Rodrigues, Celia, et al.
(författare)
-
Analysis of C9orf72 repeat expansions in a large international cohort of dementia with Lewy bodies
- 2017
-
Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 49
-
Tidskriftsartikel (refereegranskat)abstract
- . C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of . C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of . C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that . C9orf72 repeat expansions are not causally associated with DLB.
|
|
| 59. |
- Lund, Lars, et al.
(författare)
-
Use of venous-thrombotic-embolic prophylaxis in patients undergoing surgery for renal tumors : a questionnaire survey in the Nordic countries (The NORENCA-2 study)
- 2018
-
Ingår i: Research and Reports in Urology. - : DOVE Medical Press Ltd.. - 2253-2447. ; 10, s. 181-187
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: To examine the variation in venous thromboembolism prophylactic treatment (VTEP) among renal cancer patients undergoing surgery.Materials and methods: An Internet-based questionnaire on renal tumor management before and after surgery was mailed to all Nordic departments of urology. The questions focused on the use of VTEP and were subdivided into different surgical modalities.Results: Questionnaires were mailed to 91 institutions (response rate 53%). None of the centers used VTEP before surgery, unless the patient had a vena caval tumor thrombus. Overall, the VTEP utilized during hospitalization for patients undergoing renal surgery included early mobilization (45%), compression stockings (52%) and low-molecular-weight heparin (89%). In patients undergoing open radical Nx, 80% of institutions used VTEP during their hospitalization (23% compression stockings and 94% low-molecular-weight heparin). After leaving the hospital, the proportion and type of VTEP received varied considerably across institutions. The most common interval, used in 60% of the institutions, was for a period of 4 weeks. The restriction to the Nordic countries was a limitation and, therefore, may not reflect the practice patterns elsewhere. It is a survey study and, therefore, cannot measure the behaviors of those institutions that did not participate.Conclusion: We found variation in the type and duration of VTEP use for each type of local intervention for renal cancer. These widely disparate variations in care strongly argue for the establishment of national and international guidelines regarding VTEP in renal surgery.
|
|
| 60. |
- Mascher, Martin, et al.
(författare)
-
A chromosome conformation capture ordered sequence of the barley genome
- 2017
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 544:7651, s. 427-433
-
Tidskriftsartikel (refereegranskat)abstract
- Cereal grasses of the Triticeae tribe have been the major food source in temperate regions since the dawn of agriculture. Their large genomes are characterized by a high content of repetitive elements and large pericentromeric regions that are virtually devoid of meiotic recombination. Here we present a high-quality reference genome assembly for barley (Hordeum vulgare L.). We use chromosome conformation capture mapping to derive the linear order of sequences across the pericentromeric space and to investigate the spatial organization of chromatin in the nucleus at megabase resolution. The composition of genes and repetitive elements differs between distal and proximal regions. Gene family analyses reveal lineage-specific duplications of genes involved in the transport of nutrients to developing seeds and the mobilization of carbohydrates in grains. We demonstrate the importance of the barley reference sequence for breeding by inspecting the genomic partitioning of sequence variation in modern elite germplasm, highlighting regions vulnerable to genetic erosion.
|
|
