| 1. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 2. |
- Holmfeldt, Linda, et al.
(författare)
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The genomic landscape of hypodiploid acute lymphoblastic leukemia
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:3, s. 242-252
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Tidskriftsartikel (refereegranskat)abstract
- The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.
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| 3. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 4. |
- Andersson, Kristin, et al.
(författare)
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Prospective Study of Human Papillomavirus Seropositivity and Risk of Nonmelanoma Skin Cancer
- 2012
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 175:7, s. 685-695
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Tidskriftsartikel (refereegranskat)abstract
- Cutaneous human papillomaviruses (HPVs) have been associated with squamous cell carcinoma (SCC) in case-control studies, but there are limited data from prospective studies assessing whether virus exposure predicts risk of future cancer development. Two major biobanks, the Southern Sweden Microbiology Biobank (1971-2003) and the Janus Biobank (1973-2003) in Norway, containing samples from 850,000 donors, were searched for incident skin cancer for up to 30 years using registry linkages. Altogether, 2,623 donors with samples taken before diagnosis of SCC or basal cell carcinoma (BCC) of the skin were identified. Prediagnostic samples and samples from 2,623 matched controls were tested for antibodies against 33 types of HPV. Baseline seropositivity to HPV types in genus beta species 2 was associated with SCC risk (odds ratio = 1.3, 95% confidence interval: 1.1, 1.7); this was also the case for samples taken more than 18 years before diagnosis (odds ratio = 1.8, 95% confidence interval: 1.1, 2.8). Type-specific persistent seropositivity entailed elevated point estimates for SCC risk for 29 HPV types and decreased point estimates for only 3 types. After multiple hypothesis adjustment, HPV 76 was significantly associated with SCC risk and HPV 9 with BCC risk. In summary, seropositivity for certain HPV types was associated with an increased risk for future development of SCC and BCC.
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| 5. |
- Haggblade, Steven, et al.
(författare)
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Cassava Commercialization in Southeastern Africa
- 2012
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Ingår i: Journal of Agribusiness in Developing and Emerging Economies. - : Emerald. - 2044-0839 .- 2044-0847. ; 2:1, s. 4-40
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Tidskriftsartikel (refereegranskat)abstract
- Purpose – Cassava production surged noticeably in Southeastern Africa beginning in the 1990s. The purpose of this paper is to examine the commercial responses and food security consequences of cassava production growth in the region. Design/methodology/approach – The paper incorporates a mix of quantitative analysis, based primarily on original analysis of national farm household survey data, together with key informant interviews with value chain participants in the three neighboring countries of Malawi, Mozambique and Zambia. Findings – In the cassava production zones, cassava's high productivity translates into per kilogram carbohydrate costs 60 per cent to 70 per cent of the cost of cereals such as maize and wheat, thereby opening up a range of profitable opportunities for commercialization of cassava-based foods, feeds and industrial products. Despite this potential, cassava commercialization in Southeastern Africa remains in its formative stages, with only 10 per cent to 30 per cent of production currently marketed. Unlike West Africa, where cassava commercialization has centered on marketing prepared cassava-based convenience foods, the emerging cassava markets in Southeastern Africa have centered on fresh cassava, low value-added cassava flour, and experiments in industrial processing of cassava-based starches, biofuels and feeds. Strategic investment in a set of key public goods (breeding, training in food sciences and food safety, and research on in-ground cassava storage) can help to shape this transition in ways that benefit both commercial interests and the food security of vulnerable households. Originality/value – The paper compares cassava commercialization across differing agro-climatic zones, policy environments and food staple zones.
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| 6. |
- Nielsen, Niklas, et al.
(författare)
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Target temperature management after out-of-hospital cardiac arrest-a randomized, parallel-group, assessor-blinded clinical trial-rationale and design
- 2012
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Ingår i: American Heart Journal. - : Elsevier. - 0002-8703 .- 1097-6744. ; 163:4, s. 541-548
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Tidskriftsartikel (refereegranskat)abstract
- Background Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32 degrees C to 34 degrees C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known. less thanbrgreater than less thanbrgreater thanMethods The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33 degrees C or 36 degrees C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm. less thanbrgreater than less thanbrgreater thanDiscussion The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.
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| 7. |
- Abdul Kader, Hale, et al.
(författare)
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The determinants of reinsurance in the Swedish property fire insurance market during the interwar years, 1919–39
- 2010
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Ingår i: Business History. - : Taylor & Francis Group. - 0007-6791 .- 1743-7938. ; 52:2, s. 268-284
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Tidskriftsartikel (refereegranskat)abstract
- Drawing a framework from agency theory, we use a panel data design to examine the factors motivating the level of demand for reinsurance in the rapidly developing Swedish property fire insurance market during the interwar period 1919–39. We find that as hypothesised, reinsurance enabled Swedish fire insurers to mitigate underwriting and solvency risks and thus increased their capacity to underwrite new business in uncertain economic times. This in turn helped to increase the supply of indemnity coverage for property (buildings) fire risks in the Swedish insurance market. We also find that as expected, investment earnings are inversely related to reinsurance purchases. However, contrary to what was hypothesised, reinsurance appears to be positively related to liquidity levels, suggesting that over our period of analysis, fire insurers could have been reinsuring to ‘protect’ earnings and accumulated cash reserves therefore enabling investment opportunities to be realised. Analysis of the sub-period 1919–28 further supports this contention, while our results for the economic depression years after 1929 show that reinsurance helped mitigate underwriting and insolvency risks, suggesting that the reinsurance decision of fire insurance companies could be motivated by macroeconomic factors.
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| 8. |
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| 9. |
- Andersson, Bo, et al.
(författare)
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Accentuated Factors of Handheld Computing
- 2013
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Ingår i: Information Systems Development : Reflections, Challenges and New Directions - Reflections, Challenges and New Directions. - New York, NY : Springer New York. - 9781461449508 - 9781461449515 ; , s. 293-304
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Konferensbidrag (refereegranskat)abstract
- The recent years of rapid development of mobile technologies creates opportunities for new user-groups in the mobile workforce to take advantage of in-formation systems (IS). However, to apprehend and harness these opportunities for mobile IS it is crucial to fully understand the user group and the mobile tech-nology. In this paper we deductively, from previous research on aspects on mobili-ty, synthesize a tentative analytical framework capturing factors accentuated in mobile IS design. We evaluate the framework based on criteria of completeness, distinctiveness, and simplicity. Eventually, these two steps develop the framework towards a theoretical contribution as theory for describing handheld computing from a designer’s perspective. Thirteen semi-structured interviews were made and the tentative framework was elaborated and confirmed.
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| 10. |
- Andersson, Daniel, 1979, et al.
(författare)
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Plasticity Response in the Contralesional Hemisphere after Subtle Neurotrauma: Gene Expression Profiling after Partial Deafferentation of the Hippocampus
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7
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Tidskriftsartikel (refereegranskat)abstract
- Neurotrauma or focal brain ischemia are known to trigger molecular and structural responses in the uninjured hemisphere. These responses may have implications for tissue repair processes as well as for the recovery of function. To determine whether the plasticity response in the uninjured hemisphere occurs even after a subtle trauma, we subjected mice to a partial unilateral deafferentation of the hippocampus induced by stereotactically performed entorhinal cortex lesion (ECL). The expression of selected genes was assessed by quantitative real-time PCR in the hippocampal tissue at the injured side and the contralesional side at day 4 and 14 after injury. We observed that expression of genes coding for synaptotagmin 1, ezrin, thrombospondin 4, and C1q proteins, that have all been implicated in the synapse formation, re-arrangement and plasticity, were upregulated both in the injured and the contralesional hippocampus, implying a plasticity response in the uninjured hemisphere. Several of the genes, the expression of which was altered in response to ECL, are known to be expressed in astrocytes. To test whether astrocyte activation plays a role in the observed plasticity response to ECL, we took advantage of mice deficient in two intermediate filament (nanofilament) proteins glial fibrillary acidic protein (GFAP) and vimentin (GFAP(-/-) Vim(-/-)) and exhibiting attenuated astrocyte activation and reactive gliosis. The absence of GFAP and vimentin reduced the ECL-induced upregulation of thrombospondin 4, indicating that this response to ECL depends on astrocyte activation and reactive gliosis. We conclude that even a very limited focal neurotrauma triggers a distinct response at the contralesional side, which at least to some extent depends on astrocyte activation.
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