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- Nath, Bejugam Nagender, et al.
(författare)
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Record of carbonate preservation and the Mid-Brunhes climatic shift from a seamount top with low sedimentation rates in the Central Indian Basin
- 2013
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Ingår i: Boreas. - : Wiley. - 0300-9483 .- 1502-3885. ; 42:3, s. 762-778
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Tidskriftsartikel (refereegranskat)abstract
- In the present investigation, an age model of carbonate-rich cores from a seamount top in the Central Indian Basin (CIB) was constructed using both isotopic (230Thexcess, AMS 14C, oxygen isotopes) and biostratigraphic methods. The chronologies using the two methods are in good agreement, yielding a record of the late Middle Pleistocene to the Pleistocene-Holocene transition (550 to 11.5ka). The first appearance datum (FAD) of the radiolarian Buccinosphaera invaginata (180ka) and coccolith Emiliania huxleyi (268ka) and the last appearance datum (LAD) of the radiolarian Stylatractus universus (425ka) were used. A monsoon-induced productivity increase was inferred from carbonate, organic carbon and 13C records in response to the Mid-Brunhes Climatic Shift (MBCS), consistent with an increased global productivity. While the coccolith diversity increased, a decrease in coccolith productivity was found during the MBCS. At nearly the same time period, earlier records from the equatorial Indian Ocean, western Indian Ocean and eastern Africa have shown an increased productivity in response to the influence of westerlies and increased monsoon. The influence of easterlies from Australia and the intensification of aridity are evidenced by increased kaolinite content and clay-sized sediments in response to the MBCS. An increased abundance of Globorotalia menardii and other resistant species beginning from marine isotope stage (MIS) 11 and the proliferation of coccolith Gephyrocapsa spp. indicate increased dissolution, which is consistent with the widespread global carbonate dissolution during this period. The relatively high carbonate dissolution during the transition period of MIS 3/2 and glacial to interglacial periods (MIS 6, 7 and 8) may be due to the enhanced flow of corrosive Antarctic Bottom Water (AABW) into the CIB.
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- Waszak, S. M., et al.
(författare)
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Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
- 2018
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Ingår i: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 19:6, s. 785-798
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Tidskriftsartikel (refereegranskat)abstract
- Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 4069) and 5-year overall survival was 65% (95% CI 5281); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.
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- Nath, B. N., et al.
(författare)
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Pb-210, Th-230, and Be-10 in Central Indian Basin seamount sediments : Signatures of degassing and hydrothermal alteration of recent origin
- 2008
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 35:9, s. L09603-
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Tidskriftsartikel (refereegranskat)abstract
- Isotopic (Pb-210, U-238-Th-230, Be-10), major and trace elements, and micromorphological and microchemical data, were used to identify recent (similar to 100 yrs) hydrothermal alteration of a >200 kyr sedimentary record from the flank of a seamount in the Central Indian Basin located at the edge of the 75 degrees 30'E fracture zone. Alteration effects are also reflected in 1) the depleted sedimentary organic carbon, 2) dissolution features of radiolarian skeletons, 3) the presence of altered minerals such as smectite and zeolites, and 4) distinctly different magnetic properties in the altered sediments. We interpret a predominant influence of neutral chloride type hydrothermal fluids. This is the first report of recently occurring sediment alteration by shallow circulating sub-surface fluids along the Indian Ocean intra-plate seamount environment.
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- Campbell, Brittany B., et al.
(författare)
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Comprehensive Analysis of Hypermutation in Human Cancer
- 2017
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 171:5
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 Elsevier Inc. We present an extensive assessment of mutation burden through sequencing analysis of > 81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design. A large-scale analysis of hypermutation in human cancers provides insights into tumor evolution dynamics and identifies clinically actionable mutation signatures.
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- Foox, Jonathan, et al.
(författare)
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The SEQC2 epigenomics quality control (EpiQC) study
- 2021
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Ingår i: Genome Biology. - : BioMed Central (BMC). - 1465-6906 .- 1474-760X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCytosine modifications in DNA such as 5-methylcytosine (5mC) underlie a broad range of developmental processes, maintain cellular lineage specification, and can define or stratify types of cancer and other diseases. However, the wide variety of approaches available to interrogate these modifications has created a need for harmonized materials, methods, and rigorous benchmarking to improve genome-wide methylome sequencing applications in clinical and basic research. Here, we present a multi-platform assessment and cross-validated resource for epigenetics research from the FDA’s Epigenomics Quality Control Group.ResultsEach sample is processed in multiple replicates by three whole-genome bisulfite sequencing (WGBS) protocols (TruSeq DNA methylation, Accel-NGS MethylSeq, and SPLAT), oxidative bisulfite sequencing (TrueMethyl), enzymatic deamination method (EMSeq), targeted methylation sequencing (Illumina Methyl Capture EPIC), single-molecule long-read nanopore sequencing from Oxford Nanopore Technologies, and 850k Illumina methylation arrays. After rigorous quality assessment and comparison to Illumina EPIC methylation microarrays and testing on a range of algorithms (Bismark, BitmapperBS, bwa-meth, and BitMapperBS), we find overall high concordance between assays, but also differences in efficiency of read mapping, CpG capture, coverage, and platform performance, and variable performance across 26 microarray normalization algorithms.ConclusionsThe data provided herein can guide the use of these DNA reference materials in epigenomics research, as well as provide best practices for experimental design in future studies. By leveraging seven human cell lines that are designated as publicly available reference materials, these data can be used as a baseline to advance epigenomics research.
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