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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
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
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
A longitudinal study of physical activity and menstrual cycle characteristics in healthy Norwegian women – The Nord-Tr ndelag Health Study
Sigridur Lara Gudmundsdottir,William Dana Flanders,Liv Berit Augestad
Norsk Epidemiologi , 2011,
Abstract: Background: Long menstrual cycles have been associated with anovulation, infertility and spontaneous abortion. Elite athletes have been found at risk of menstrual dysfunction. We evaluated the longitudinal association between leisure time physical activity (LTPA) and menstrual function in healthy non-athletic women. Methods: A population-based health survey (HUNT 1) was conducted during 1984-1986 in Nord-Tr ndelag county, Norway, with follow-up in 1995-1997 (HUNT 2). The current study included 3,097 women, <45 years old in HUNT 2. LTPA was assessed by questionnaire in HUNT 1, and menstrual function by questionnaire in HUNT 2. Data focused on overall occurrence of menstrual disorders in the population. Results were adjusted for age, education, psychological health, smoking and alcohol intake. Additional analyses included BMI as a potential confounder. Results: The median cycle length was 30 days and median number of days bleeding was 5. In women with normal cycle length, mean (SD) cycle length and duration of bleeding was 29.3 (2.8) and 5.6 (1.7) respectively. Cycle length increased with higher frequency of LTPA for women >25 years old. Women, 20-25 years old at baseline who were active most days had increased odds of short cycles, more bleeding days and increased odds of having irregular cycles, OR=4.7; 95% CI = 1.2-18.0). Number of bleeding days decreased with longer duration (p<0.05) and higher intensity (p=0.065) in young women. Adjustment for BMI did not affect the results. Conclusion: Leisure time physical activity may affect menstrual function, although in our study, the results were modified by age
Prepregnancy Physical Activity in relation to Offspring Birth Weight: A Prospective Population-Based Study in Norway—The HUNT Study
Silje Krogsgaard,Sigridur L. Gudmundsdottir,Tom I. L. Nilsen
Journal of Pregnancy , 2013, DOI: 10.1155/2013/780180
Prepregnancy Physical Activity in relation to Offspring Birth Weight: A Prospective Population-Based Study in Norway—The HUNT Study
Silje Krogsgaard,Sigridur L. Gudmundsdottir,Tom I. L. Nilsen
Journal of Pregnancy , 2013, DOI: 10.1155/2013/780180
Abstract: Background. The objective was to examine the association between prepregnancy physical exercise and offspring birth weight and to assess the combined association of pre-pregnancy body mass index (BMI) and physical exercise on birth weight. Methods. The study included 2,026 women aged 20–39 years participating in the Norwegian HUNT study and linked with the Medical Birth Registry. We calculated mean differences in birth weight and odds ratios (ORs) for a macrosomic infant (i.e., birth weight ?g) using linear and logistic regression analysis. Results. There was no clear association between leisure time physical exercise and mean birth weight. Women who reported no exercise had reduced risk of a macrosomic infant (OR, 0.6; 95% confidence interval (CI), 0.4–0.9) compared to women with a high exercise level. Overweight ( ?kg/m2) was associated with an OR of 1.9 (95% CI, 1.2–2.9) for a macrosomic infant among women who reported low exercise levels, whereas the OR was 1.2 (95% CI, 0.8–1.8) among women with higher exercise levels. Conclusion. There was some evidence that women who reported no exercise before pregnancy had lower risk for a macrosomic infant than women who exercised. Pre-pregnancy BMI was positively associated with birth weight and risk of macrosomia but only among the least active women. 1. Introduction The proportion of women giving birth to large infants has increased around the world [1, 2], most likely because of the rising rates of maternal overweight and obesity [3–7]. Whereas consequences of low birth weight may include infant mortality and morbidity [8], high birth weight has been related to increased risk for caesarean section, chorioamnionitis, fourth degree perinatal lacerations, postpartum haemorrhage, shoulder dystocia [9–11], and low Apgar score [12]. Additionally, high birth weight has been positively associated with obesity [13] and type 2 diabetes [14] in adulthood. Previous studies have reported that physical activity in pregnancy is related to foetal growth rate and birth weight [15, 16], and that physically active women have a reduced risk of delivering a large infant [17, 18], possibly by increased insulin sensitivity [6]. However, not all studies have reported consistent inverse associations between physical activity in pregnancy and birth weight [19–22]. Although women who exercise regularly before pregnancy are more likely to continue to exercise during pregnancy [23–25], few studies have examined the associations between prepregnancy physical activity and birthweight, and the results have been inconsistent [18, 20, 26,
Net current generation in a 1D quantum ring at zero magnetic field
Sigridur Sif Gylfadottir,Marian Nita,Vidar Gudmundsson,Andrei Manolescu
Physics , 2004, DOI: 10.1016/j.physe.2004.12.002
Abstract: We study a non-adiabatic excitation of an electron system in a 1D quantum ring radiated by a short THz pulse. The response of two models, a continuous and discrete, is explored. By introducing a spatial asymmetry in the external perturbation a net current can be generated in the ring at a zero magnetic field. Effect of impurities and ratchets are investigated in combination with symmetric and asymmetric external excitation.
Radiographic closure time of appendicular growth plates in the Icelandic horse
Eric Strand, Linn Braathen, Mia C Hellsten, Lisel Huse-Olsen, Sigridur Bjornsdottir
Acta Veterinaria Scandinavica , 2007, DOI: 10.1186/1751-0147-49-19
Abstract: The radiographic closure time of the appendicular growth plates was studied in 64 young Icelandic horses. The results were compared with previously published closure times reported for other, larger horse breeds. The radiographs were also examined for any signs of developmental orthopaedic diseases. In order to describe further the growth pattern of the Icelandic horse, the total serum alkaline phosphatase (ALP) activity was determined and the height at the withers was measured.Most of the examined growth plates were fully closed at the age of approximately three years. The horses reached adult height at this age; however ALP activity was still mildly increased over baseline values. The growth plates in the digits were the first to close at 8.1 to 8.5 months of age, and those in the regions of the distal radius (27.4 to 32.0 months), tuber olecrani (31.5 to 32.2 months), and the stifle (27.0 to 40.1 months) were the last to close. No horse was found to have osteochondrosis type lesions in the neighbouring joints of the evaluated growth plates.The Icelandic horse appears to have similar radiographic closure times for most of the growth plates of its limbs as reported for large new breeds of horses developed during the past few centuries. It thus appears that different breeding goals and the intensity of breeding have not altered the length of the growth period in horses. Instead, it can be assumed that the pristine and relatively small Icelandic horse has a slower rate of growth. The appendicular skeleton of Icelandic horses has completed its bone growth in length at approximately 3 years of age, and therefore may be able to enter training at this time.The growth plates at the distal radius and the tuber calcaneus have been used as indicators of skeletal maturity in Thoroughbred and Standardbred racing horses [1-3]. These breeds typically enter light training at 1.5 years of age, and formal race training at 2 years of age. It is widely thought among horsemen and vete
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
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