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Search Results: 1 - 10 of 167683 matches for " Jorunn E Eyfjord "
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The Icelandic founder mutation BRCA2 999del5: analysis of expression
Evgenia K Mikaelsdottir, Sigridur Valgeirsdottir, Jorunn E Eyfjord, Thorunn Rafnar
Breast Cancer Research , 2004, DOI: 10.1186/bcr785
Abstract: The presence of BRCA2 999del5 transcripts in fibroblasts from heterozygous individuals was assayed by cDNA synthesis and sequencing. The potential protein-coding portion of BRCA2 999del5 was cloned into the pIND(SP1)/V5-His vector and expressed in COS7 cells. The presence of the mutant protein in cell lysates from heterozygous fibroblasts and from COS7 cells was tested by a number of methods including immunoprecipitation, affinity purification with nickel-coated agarose beads, Western blotting and ELISA, using antibodies to the N-terminal end of BRCA2, antiserum specific for the 16 nonrelevant amino acids at the carboxyl end and antibodies to fusion partners of recombinant proteins.The frequency of the BRCA2 999del5 transcript in heterozygous fibroblasts was about one-fifth of the wild-type transcript; however, no mutant protein could be detected. Overexpression of BRCA2 999del5 mRNA in COS7 cells failed to produce a mutant protein unless degradation by proteasomes was blocked.Our results show that the protein product of BRCA2 999del5 is extremely unstable. Therefore, an increase in breast cancer risk in BRCA2 999del5 carriers is due to haploinsufficiency at the BRCA2 locus.Mutations in BRCA1 and BRCA2 are associated with a high risk of developing cancer of the breast, of the ovaries and of other organs [1]. A large number of cancer-associated mutations in these genes have been described to date; however, few studies have directly probed the functional consequences of individual mutations [2-5]. One question that has thus rarely been addressed is whether the increased risk of cancer is simply due to the lack of one healthy copy of the gene (haploinsufficiency) or whether the gene produces a protein product that interferes with normal cellular processes.Most nonsense (insertion/deletion) mutants are thought to result in unstable transcripts and in little or no mutant protein production [6]. Exceptions to this rule are found, however, also among the BRCA genes where p
Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer
Valgerdur Birgisdottir, Olafur A Stefansson, Sigridur K Bodvarsdottir, Holmfridur Hilmarsdottir, Jon G Jonasson, Jorunn E Eyfjord
Breast Cancer Research , 2006, DOI: 10.1186/bcr1522
Abstract: Primary sporadic breast tumours were analysed for BRCA1α promoter methylation by methylation specific PCR and for allelic imbalance (AI) at BRCA1 and BRCA2 loci by microsatellite analysis and TP53 (also known as p53) mutations by constant denaturing gel electrophoresis. The BRCA1 methylated tumours were analysed for BRCA1 copy alterations by fluorescence in situ hybridisation and BRCA1 expression by immunostaining.BRCA1 methylation was found in 13/143 (9.1%) sporadic breast tumours. The BRCA1 methylated tumours were significantly associated with estrogen receptor (ER) negativity (P = 0.0475) and displayed a trend for BRCA1 AI (P = 0.0731) as well as young-age at diagnosis (≤ 55; P = 0.0898). BRCA1 methylation was not associated with BRCA2 AI (P = 0.5420), although a significant association was found between BRCA1 AI and BRCA2 AI (P < 0.0001).Absent/markedly reduced BRCA1 expression was observed in 9/13 BRCA1 methylated tumours, most of which had BRCA1 deletion. An elevated TP53 mutation frequency was found among BRCA1 methylated tumours (38.5%) compared with non-methylated tumours (17.2%). The BRCA1 methylated tumours were mainly of tumour grade 3 (7/13) and infiltrating ductal type (12/13). Only one methylated tumour was of grade 1.BRCA1 methylation is frequent in primary sporadic breast tumours. We found an indication for BRCA1 methylation to be associated with AI at the BRCA1 locus. Almost all BRCA1 methylated tumours with absent/markedly reduced BRCA1 expression (8/9) displayed BRCA1 deletion. Thus, epigenetic silencing and deletion of the BRCA1 gene might serve as Knudson's two 'hits' in sporadic breast tumorigenesis. We observed phenotypic similarities between BRCA1 methylated and familial BRCA1 tumours, based on BRCA1 deletion, TP53 mutations, ER status, young age at diagnosis and tumour grade.Germline mutations in one allele of the BRCA1 or BRCA2 genes significantly increase the risk of developing early-onset breast cancer [1]. Tumour cells from predisposed
BRCA2 mutation carriers, reproductive factors and breast cancer risk
Laufey Tryggvadottir, Elinborg J Olafsdottir, Sigfridur Gudlaugsdottir, Steinunn Thorlacius, Jon G Jonasson, Hrafn Tulinius, Jorunn E Eyfjord
Breast Cancer Research , 2003, DOI: 10.1186/bcr619
Abstract: In a case–control study, nested in a population-based cohort of the Icelandic Cancer Detection Clinic, two groups of cases were defined, matched on year of birth, on age at diagnosis and on age when giving information on reproductive factors: 100 carriers of the Icelandic founder BRCA2 mutation 999del5, and 361 BRCA2-negative cases. The mean age at diagnosis was 48 years. There were 1000 women in a matched group of unaffected controls. Conditional logistic regression was used for the analysis.An increased number of births was associated with a decreased risk of breast cancer in BRCA2-negative cases but not in BRCA2-positive cases. A negative association between risk and duration of breast feeding was observed only in the mutation carriers. These associations were not statistically significant, but the effects of the two variables differed significantly according to mutation status (P = 0.007 and P = 0.045 for interaction with number of births and with duration of breast feeding, respectively). This was maintained when limiting the analysis to women diagnosed older than the age of 40 years.The association between breast cancer and the number of pregnancies and between breast cancer and the duration of breast feeding was not the same for carriers and noncarriers of a detrimental BRCA2 mutation. In the context of other epidemiological and laboratory studies, this may indicate that the product of the BRCA2 gene has a function relating to the differentiation of epithelial tissue in the breast.Mutations in the BRCA1 and BRCA2 genes dramatically increase the risk of breast cancer. Numerous mutations in each gene have been found in most populations studied, but only one mutation in each gene has been identified to date in the Icelandic population of 285,000; a rare mutation in the BRCA1 gene, and a much more frequent mutation in the BRCA2 gene. The BRCA2 mutation (999del5) is present in 7–8% of unselected breast cancer patients in Iceland [1-3], and it has a much higher pre
Genomic and phenotypic analysis of BRCA2 mutated breast cancers reveals co-occurring changes linked to progression
Olafur A Stefansson, Jon G Jonasson, Kristrun Olafsdottir, Hordur Bjarnason, Oskar Th Johannsson, Sigridur K Bodvarsdottir, Sigridur Valgeirsdottir, Jorunn E Eyfjord
Breast Cancer Research , 2011, DOI: 10.1186/bcr3020
Abstract: Breast tumors (n = 33) derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH (array comparative genomic hybridization) containing 385 thousand probes (about one for each 7 kbp) and expression of phenotypic markers on TMAs (tissue microarrays). The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy.Tumors from BRCA2 carriers of luminal and basal/triple-negative phenotypes (TNPs) differ with respect to patterns of DNA copy-number changes. The basal/TNP subtype was characterized by lack of pRb (RB1) coupled with high/intense expression of p16 (CDKN2A) gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type (wt) BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal/TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis.The results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.Germline mutations in one allele of the BRCA2 tumor-suppressor gene confer greatly increased risk of developing breast cancer [1]. The BRCA2 gene is known to be involved in error-free DNA repair of double-strand breaks (DSBs) through homologous recombination (HR) [2]. Defects in this mechanism lead to repair of DSBs by error-prone nonhomologous end joining (NH
Correction: Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes
Olafur Stefansson, Jon Jonasson, Oskar Johannsson, Kristrun Olafsdottir, Margret Steinarsdottir, Sigridur Valgeirsdottir, Jorunn Eyfjord
Breast Cancer Research , 2009, DOI: 10.1186/bcr2355
Abstract: Due to a production error, the final two sentences of the legend to figure 2a are incomplete. These two sentences should appear as follows:The characters represent cluster memberships of each tumour with BRCA1 and BRCA2 abnormalities indicated, see bottom of the figure. It can be hypothesised here that component three reflects differences between BRCA1- and BRCA2-related tumours whereas component two reflects their similarities, see further in Additional data file 3.
Genomic profiling of breast tumours in relation to BRCA abnormalities and phenotypes
Olafur Stefansson, Jon Jonasson, Oskar Johannsson, Kristrun Olafsdottir, Margret Steinarsdottir, Sigridur Valgeirsdottir, Jorunn Eyfjord
Breast Cancer Research , 2009, DOI: 10.1186/bcr2334
Abstract: The study group consisted of 67 primary breast tumours with and without BRCA1 or BRCA2 abnormalities. Genomic alterations were profiled by high-resolution (~7 kbp) comparative genome hybridisation (CGH) microarrays. Tumour phenotypes were analysed by immunohistochemistry on tissue microarrays using selected biomarkers (ER, PR, HER-2, EGFR, CK5/6, CK8, CK18).Classification of genomic profiles through cluster analysis revealed four subgroups, three of which displayed high genomic instability indices (GII). Two of these GII-high subgroups were enriched with either BRCA1- or BRCA2-related tumours whereas the third was not BRCA-related. The BRCA1-related subgroup mostly displayed non-luminal phenotypes, of which basal-like were most prominent, whereas the other two genomic instability subgroups BRCA2- and GII-high-III (non-BRCA), were almost entirely of luminal phenotype. Analysis of genome architecture patterns revealed similarities between the BRCA1- and BRCA2 subgroups, with long deletions being prominent. This contrasts with the third instability subgroup, not BRCA-related, where small gains were more prominent.The results suggest that BRCA1- and BRCA2-related tumours develop largely through distinct genetic pathways in terms of the regions altered while also displaying distinct phenotypes. Importantly, we show that the development of a subset of sporadic tumours is similar to that of either familial BRCA1- or BRCA2 tumours. Despite their differences, we observed clear similarities between the BRCA1- and BRCA2-related subgroups reflected in the type of genomic alterations acquired with deletions of long DNA segments being prominent. This suggests similarities in the mechanisms promoting genomic instability for BRCA1- and BRCA2-associated tumours, possibly relating to deficiency in DNA repair through homologous recombination. Indeed, this feature characterized both familial and sporadic tumours displaying BRCA1- or BRCA2-like spectrums of genomic alterations. The impo
Preconceptions and expectations of older adults about getting hearing aids
Jorunn Solheim
Journal of Multidisciplinary Healthcare , 2011, DOI: http://dx.doi.org/10.2147/JMDH.S14949
Abstract: econceptions and expectations of older adults about getting hearing aids Original Research (3800) Total Article Views Authors: Jorunn Solheim Published Date January 2011 Volume 2011:4 Pages 1 - 8 DOI: http://dx.doi.org/10.2147/JMDH.S14949 Jorunn Solheim ENT Department, Lovisenberg Diakonale Hospital, Oslo, Norway Aim: The objectives of this study were to describe preconceptions and expectations of older adults about getting hearing aids and to explore the influence of hearing loss (HL), hearing aid experience, gender, age, and marital status on these preconceptions and expectations. Methods: A total of 174 participants aged above 65 years were randomly selected from a waiting list for hearing aid fitting. Hearing threshold was tested using pure tone audiometry. A self-report questionnaire with a specific focus on preconceptions and expectations about getting hearing aids, external influences, and the psychosocial problems associated with HL and the use of a hearing aid was administered. Results: A factor analysis revealed three factors: positive expectations, barriers, and social pressure. Cronbach's a was 0.847 for positive expectations and 0.591 for barriers. Cronbach's a was not statistically applicable to the social pressure factor, as it consisted of only one item. Adjusted linear regression analysis revealed that participants with moderate to severe HL and hearing aid experience had a significant increase in positive expectations. Male gender was associated with fewer barriers to hearing aids. Age and marital status had no influence on the three factors. Conclusion: Less positive expectations and more problem-oriented preconceptions among subjects with mild HL may explain why hearing aids are scarcely used. Additionally, lower estimated need and modest plans for regular use among this group could mean hearing aids are not used. Rehabilitation should focus on investment of time, continuity of use, realistic expectations, and follow-up support.
Preconceptions and expectations of older adults about getting hearing aids
Jorunn Solheim
Journal of Multidisciplinary Healthcare , 2011,
Abstract: Jorunn SolheimENT Department, Lovisenberg Diakonale Hospital, Oslo, NorwayAim: The objectives of this study were to describe preconceptions and expectations of older adults about getting hearing aids and to explore the influence of hearing loss (HL), hearing aid experience, gender, age, and marital status on these preconceptions and expectations.Methods: A total of 174 participants aged above 65 years were randomly selected from a waiting list for hearing aid fitting. Hearing threshold was tested using pure tone audiometry. A self-report questionnaire with a specific focus on preconceptions and expectations about getting hearing aids, external influences, and the psychosocial problems associated with HL and the use of a hearing aid was administered.Results: A factor analysis revealed three factors: positive expectations, barriers, and social pressure. Cronbach's a was 0.847 for positive expectations and 0.591 for barriers. Cronbach's a was not statistically applicable to the social pressure factor, as it consisted of only one item. Adjusted linear regression analysis revealed that participants with moderate to severe HL and hearing aid experience had a significant increase in positive expectations. Male gender was associated with fewer barriers to hearing aids. Age and marital status had no influence on the three factors.Conclusion: Less positive expectations and more problem-oriented preconceptions among subjects with mild HL may explain why hearing aids are scarcely used. Additionally, lower estimated need and modest plans for regular use among this group could mean hearing aids are not used. Rehabilitation should focus on investment of time, continuity of use, realistic expectations, and follow-up support.Keywords: hearing aid, older adults, preconceptions, expectations, barriers
A Functional Genomics Approach Identifies Candidate Effectors from the Aphid Species Myzus persicae (Green Peach Aphid)
Jorunn I. B. Bos,David Prince,Marco Pitino,Massimo E. Maffei,Joe Win,Saskia A. Hogenhout
PLOS Genetics , 2010, DOI: 10.1371/journal.pgen.1001216
Abstract: Aphids are amongst the most devastating sap-feeding insects of plants. Like most plant parasites, aphids require intimate associations with their host plants to gain access to nutrients. Aphid feeding induces responses such as clogging of phloem sieve elements and callose formation, which are suppressed by unknown molecules, probably proteins, in aphid saliva. Therefore, it is likely that aphids, like plant pathogens, deliver proteins (effectors) inside their hosts to modulate host cell processes, suppress plant defenses, and promote infestation. We exploited publicly available aphid salivary gland expressed sequence tags (ESTs) to apply a functional genomics approach for identification of candidate effectors from Myzus persicae (green peach aphid), based on common features of plant pathogen effectors. A total of 48 effector candidates were identified, cloned, and subjected to transient overexpression in Nicotiana benthamiana to assay for elicitation of a phenotype, suppression of the Pathogen-Associated Molecular Pattern (PAMP)–mediated oxidative burst, and effects on aphid reproductive performance. We identified one candidate effector, Mp10, which specifically induced chlorosis and local cell death in N. benthamiana and conferred avirulence to recombinant Potato virus X (PVX) expressing Mp10, PVX-Mp10, in N. tabacum, indicating that this protein may trigger plant defenses. The ubiquitin-ligase associated protein SGT1 was required for the Mp10-mediated chlorosis response in N. benthamiana. Mp10 also suppressed the oxidative burst induced by flg22, but not by chitin. Aphid fecundity assays revealed that in planta overexpression of Mp10 and Mp42 reduced aphid fecundity, whereas another effector candidate, MpC002, enhanced aphid fecundity. Thus, these results suggest that, although Mp10 suppresses flg22-triggered immunity, it triggers a defense response, resulting in an overall decrease in aphid performance in the fecundity assays. Overall, we identified aphid salivary proteins that share features with plant pathogen effectors and therefore may function as aphid effectors by perturbing host cellular processes.
Characterization of Arabidopsis Transcriptional Responses to Different Aphid Species Reveals Genes that Contribute to Host Susceptibility and Non-host Resistance
Ma?lle Jaouannet?,Jenny A. Morris?,Peter E. Hedley?,Jorunn I. B. Bos
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1004918
Abstract: Aphids are economically important pests that display exceptional variation in host range. The determinants of diverse aphid host ranges are not well understood, but it is likely that molecular interactions are involved. With significant progress being made towards understanding host responses upon aphid attack, the mechanisms underlying non-host resistance remain to be elucidated. Here, we investigated and compared Arabidopsis thaliana host and non-host responses to aphids at the transcriptional level using three different aphid species, Myzus persicae, Myzus cerasi and Rhopalosiphum pisum. Gene expression analyses revealed a high level of overlap in the overall gene expression changes during the host and non-host interactions with regards to the sets of genes differentially expressed and the direction of expression changes. Despite this overlap in transcriptional responses across interactions, there was a stronger repression of genes involved in metabolism and oxidative responses specifically during the host interaction with M. persicae. In addition, we identified a set of genes with opposite gene expression patterns during the host versus non-host interactions. Aphid performance assays on Arabidopsis mutants that were selected based on our transcriptome analyses identified novel genes contributing to host susceptibility, host defences during interactions with M. persicae as well to non-host resistance against R. padi. Understanding how plants respond to aphid species that differ in their ability to infest plant species, and identifying the genes and signaling pathways involved, is essential for the development of novel and durable aphid control in crop plants.
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