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  • 1
    Keywords: CANCER ; CELLS ; DISTINCT ; CENTRAL-NERVOUS-SYSTEM ; METHYLATION ; ADULT ; BRAIN-TUMORS ; TELOMERASE ACTIVITY ; RISK STRATIFICATION ; SELF-RENEWAL
    Abstract: Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in 〈5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.
    Type of Publication: Journal article published
    PubMed ID: 24174164
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  • 2
    Keywords: POOR-PROGNOSIS ; BRAIN-TUMORS ; CHILDHOOD MEDULLOBLASTOMA ; RISK STRATIFICATION ; outcome prediction ; TP53 MUTATIONS ; PATHWAY ACTIVATION ; MOLECULAR SUBGROUPS ; NEUROTROPHIN RECEPTOR TRKC ; MYCN AMPLIFICATION
    Abstract: Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
    Type of Publication: Journal article published
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  • 3
    Abstract: BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12.5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5.6 years [5th-95th percentile 1.04-13.5]) from 71 011 participants from 37 studies. FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5.4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1.14, 95% CI, 1.10-1.17), coronary disease excluding myocardial infarction (1.06, 1.00-1.11), heart failure (1.09, 1.03-1.15), fatal hypertensive disease (1.24, 1.15-1.33); and fatal aortic aneurysm (1.15, 1.03-1.28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0.94, 0.91-0.97). In comparison to those who reported drinking 〉0-〈/=100 g per week, those who reported drinking 〉100-〈/=200 g per week, 〉200-〈/=350 g per week, or 〉350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.
    Type of Publication: Journal article published
    PubMed ID: 29676281
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  • 4
    ISSN: 0168-9002
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 0271-7123
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0920-9964
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Animal Behaviour 6 (1958), S. 245 
    ISSN: 0003-3472
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  The mouse Bp3 antigen is a variably glycosylated phosphatidylinositol-linked cell surface glycoprotein expressed on early B and T lineage cells, myeloid cells, intestinal epithelial cells, and a discrete population of reticular cells in peripheral lymphoid tissues. The deduced amino acid sequence of Bp3 cDNA shares significant similarity to human and mouse CD38 and molluscan ADP-ribosyl cyclase, enzymes that generate the calcium mobilizing agent cyclic ADP-ribose from NAD. In this study, we cloned and characterized the Bp3 gene. The gene consists of nine exons and spans approximately 27 kilobases. The overall exon organization is very similar to that reported for the ADP-ribosyl cyclase gene in the mollusc Aplysia kurodai. The Bp3 gene is located on mouse chromosome 5 very near the gene for CD38, suggesting that this family arose by gene duplication. The major transcriptional start site of the Bp3 gene in a pro-B cell line (–17 from the ATG start codon) contains a weak initiator sequence. The upstream region lacks a TATA box, but contains consensus recognition sequences for the PU.1, Ikaros/LyF-1, E2A, and TCF-1 transcriptional factors that regulate gene expression in lymphoid and myeloid cells. Consensus motifs for cytokine responsive factors NF-IL6/C-EBP, H-APF-1/APRF, and AP-1 are also present in the flanking region, and interleukin-6 treatment enhances expression of the Bp3 antigen by a myeloblastoid cell line.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-2242
    Keywords: Keywords CIMMYT ; ISWYN ; Mega-environments ; Retrospective analysis ; Pattern analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract  CIMMYT (the International Maize and Wheat Improvement Center) has routinely conducted international wheat yield trials to study the adaptation of spring bread wheat. The first of these, the International Spring Wheat Yield Nursery (ISWYN), was conducted for 31 years from 1964 to 1994 inclusive (30 cycles were conducted as no nursery was distributed in 1993 because of Karnal Bunt). Recently, pattern analysis methods have been developed and a set of computer programs written, which enable retrospective analyses of such historical databases to appraise the relationships among test environments in a way that discriminates among genotypes. Such an analysis was conducted on the 30 years of yield data from ISWYN and the classification derived from these analyses was compared with an agroecological classification of spring wheat test environments derived by CIMMYT. The incidence of foliar diseases (stem rust, leaf rust, yellow rust, Septoria spp. and Fusarium spp.) was important in the distinction between the high-rainfall low-latitude (mega-environment 2) and the high-input-irrigated low-latitude (mega-environment 1) environment types. The accumulation of resistance genes for these diseases has been an objective of the CIMMYT wheat breeding program. It was hypothesized that, as the relevant resistance genes were successfully pyramided into the germplasm, the distinction between these two mega-environment types would disappear. The results of the retrospective analyses support this hypothesis.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-2242
    Keywords: Cluster Analysis ; Genotype x environment interaction ; Heritability ; Repeatability ; Structure-recovery
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary Several subjective choices must be made when classifying genotypes based on data from plant breeding trials. One choice involves the method used to weight the contribution each environment makes to the classification. A second involves the use of either genotype-means for each environment or genotypevalues for each block, i.e., considering each block to be a different environment. Another involves whether environments (or blocks) in which genotypes are nonsignificantly different should be included or excluded from such classifications. An alternative to the use of raw or standardized data, is proposed in which each environment is weighted by a discrimination index (DI) that is based on the concept of repeatability. In this study the effect of three weighting methods (raw, standardized and DI), the choice of using environments or blocks, and the choice of including or excluding environments or blocks in which genotypic effects were not significant, were considered in factorial combination to give 12 options. A data set comprised of five check cultivars each repeated six times in each of three blocks at six environments was used. The effect of these options on the ability of a hierarchical clustering technique to correctly classify the repeats into five groups, each consisting of all the six repeats of a particular check cultivar, was investigated. It was found that the DI weighting method generally led to better recovery of the known structure. Using block data rather than environmental data also improved structure recovery for each of the three weighting methods. The exclusive use of environments in which genotypic effects were significant decreased structure recovery while the contrary generally occurred for blocks. The best structure recovery was obtained from the DI weighting applied to blocks (whether genotypes were significant or not).
    Type of Medium: Electronic Resource
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