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Search Results: 1 - 10 of 461929 matches for " Bjarni A Agnarsson "
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Evidence against PALB2 involvement in Icelandic breast cancer susceptibility
Haukur Gunnarsson, Adalgeir Arason, Elizabeth M Gillanders, Bjarni A Agnarsson, Gudrun Johannesdottir, Oskar Johannsson, Rosa B Barkardottir
Journal of Negative Results in BioMedicine , 2008, DOI: 10.1186/1477-5751-7-5
Abstract: Breast cancer is among the most frequent human cancers and the most common carcinoma in women in the Western world, where one out of every ten women is affected. A dominant pattern of inheritance is evident in approximately 5–10% of all breast cancers. To date, two main breast cancer susceptibility genes have been identified; BRCA1 and BRCA2 accounting for nearly half of high-incidence breast cancer families and an increased relative risk of breast cancer by 10- to 20- fold [1,2]. Other known breast cancer susceptibility genes such as CHEK2 and ATM have a more moderate penetrance with an increased lifetime risk of about 2- to 3- fold [2].The PALB2 gene is a BRCA2 binding factor that ensures BRCA2 function as a tumor suppressor and has been shown to cause Fanconi anemia subtype FA-N when biallelic germ-line mutations occur in the gene [3-5]. Recent studies have reported several mutations in PALB2 to be associated with an increased risk of breast cancer [6-9]. One is the founder mutation 1592delT which has been found to be present at a significantly elevated frequency in breast cancer families in Finland, resulting in a 4-fold increased risk to mutation carriers [6]. Although predisposing PALB2 mutations generally appear to cause moderate risk of breast cancer [8], mutations have also been found in strong hereditary breast cancer families [7,9] and might thus be worthwhile searching for by linkage analysis in e.g. geographically confined populations.Only two BRCA1 and BRCA2 mutations have been found in the Icelandic population, BRCA2 999del5 and BRCA1 G5193A, both being founder mutations explaining a large proportion of familial breast cancer in Iceland [10]. The BRCA2 999del5 mutation is much more frequent, accounting for around 40% of the hereditary cases and found in about 8% of unselected breast cancer cases and 0,4% of population based control [11]. A BRCA2 999del5 mutation is also the most frequently occurring BRCA1/2 mutation in Finland [12], and haplotype anal
Endothelial Induced EMT in Breast Epithelial Cells with Stem Cell Properties
Valgardur Sigurdsson, Bylgja Hilmarsdottir, Hekla Sigmundsdottir, Agla J. R. Fridriksdottir, Markus Ringnér, Rene Villadsen, Ake Borg, Bjarni A. Agnarsson, Ole William Petersen, Magnus K. Magnusson, Thorarinn Gudjonsson
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023833
Abstract: Epithelial to mesenchymal transition (EMT) is a critical event in cancer progression and is closely linked to the breast epithelial cancer stem cell phenotype. Given the close interaction between the vascular endothelium and cancer cells, especially at the invasive front, we asked whether endothelial cells might play a role in EMT. Using a 3D culture model we demonstrate that endothelial cells are potent inducers of EMT in D492 an immortalized breast epithelial cell line with stem cell properties. Endothelial induced mesenchymal-like cells (D492M) derived from D492, show reduced expression of keratins, a switch from E-Cadherin (E-Cad) to N-Cadherin (N-Cad) and enhanced migration. Acquisition of cancer stem cell associated characteristics like increased CD44high/CD24low ratio, resistance to apoptosis and anchorage independent growth was also seen in D492M cells. Endothelial induced EMT in D492 was partially blocked by inhibition of HGF signaling. Basal-like breast cancer, a vascular rich cancer with stem cell properties and adverse prognosis has been linked with EMT. We immunostained several basal-like breast cancer samples for endothelial and EMT markers. Cancer cells close to the vascular rich areas show no or decreased expression of E-Cad and increased N-Cad expression suggesting EMT. Collectively, we have shown in a 3D culture model that endothelial cells are potent inducers of EMT in breast epithelial cells with stem cell properties. Furthermore, we demonstrate that basal-like breast cancer contains cells with an EMT phenotype, most prominently close to vascular rich areas of these tumors. We conclude that endothelial cells are potent inducers of EMT and may play a role in progression of basal-like breast cancer.
High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer
Johan Staaf, G?ran J?nsson, Markus Ringnér, Johan Vallon-Christersson, Dorthe Grabau, Adalgeir Arason, Haukur Gunnarsson, Bjarni A Agnarsson, Per-Olof Malmstr?m, Oskar Johannsson, Niklas Loman, Rosa B Barkardottir, ?ke Borg
Breast Cancer Research , 2010, DOI: 10.1186/bcr2568
Abstract: Genome-wide DNA copy number profiling, using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH), and global gene expression profiling were performed on 200 and 87 HER2+ tumors, respectively. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number alterations (CNAs) in HER2+ tumors, which were related to a set of 554 non-HER2 amplified (HER2-) breast tumors. High-resolution oligonucleotide aCGH was used to delineate the 17q12-q21 region in high detail.The HER2-amplicon was narrowed to an 85.92 kbp region including the TCAP, PNMT, PERLD1, HER2, C17orf37 and GRB7 genes, and higher HER2 copy numbers indicated worse prognosis. In 31% of HER2+ tumors the amplicon extended to TOP2A, defining a subgroup of HER2+ breast cancer associated with estrogen receptor-positive status and with a trend of better survival than HER2+ breast cancers with deleted (18%) or neutral TOP2A (51%). HER2+ tumors were clearly distinguished from HER2- tumors by the presence of recurrent high-level amplifications and firestorm patterns on chromosome 17q. While there was no significant difference between HER2+ and HER2- tumors regarding the incidence of other recurrent high-level amplifications, differences in the co-amplification pattern were observed, as shown by the almost mutually exclusive occurrence of 8p12, 11q13 and 20q13 amplification in HER2+ tumors. GISTIC analysis identified 117 significant CNAs across all autosomes. Supervised analyses revealed: (1) significant CNAs separating HER2+ tumors stratified by clinical variables, and (2) CNAs separating HER2+ from HER2- tumors.We have performed a comprehensive survey of CNAs in HER2+ breast tumors, pinpointing significant genomic alterations including both known and potentially novel therapeutic targets. Our analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer.Gene a
Genome-wide search for breast cancer linkage in large Icelandic non-BRCA1/2 families
Adalgeir Arason, Haukur Gunnarsson, Gudrun Johannesdottir, Kristjan Jonasson, P?r-Ola Bendahl, Elizabeth M Gillanders, Bjarni A Agnarsson, G?ran J?nsson, Katri Pylk?s, Aki Mustonen, Tuomas Heikkinen, Kristiina Aittom?ki, Carl Blomqvist, Beatrice Melin, Oskar TH Johannsson, P?l M?ller, Robert Winqvist, Heli Nevanlinna, ?ke Borg, Rosa B Barkardottir
Breast Cancer Research , 2010, DOI: 10.1186/bcr2608
Abstract: GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene.The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer.Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.Increased susceptibility to breast cancer (BC) has been shown to be caused by germline segregation of three different classes of alleles: 1) high-penetrance genes with rare risk variants, 2) moderate-penetrance genes, also with rare variants and 3) low-penetrance alleles of common frequency [1]. Hereditary BC, defined by a significant familial aggregation of BC and explaining approximately 5 to 10% of cases diagnosed with BC, is as yet seen to arise from the first allele class whenever the causative gene is known. Genetic counselling c
Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics
G?ran J?nsson, Johan Staaf, Johan Vallon-Christersson, Markus Ringnér, Karolina Holm, Cecilia Hegardt, Haukur Gunnarsson, Rainer Fagerholm, Carina Strand, Bjarni A Agnarsson, Outi Kilpivaara, Lena Luts, P?ivi Heikkil?, Kristiina Aittom?ki, Carl Blomqvist, Niklas Loman, Per Malmstr?m, H?kan Olsson, Oskar Th Johannsson, Adalgeir Arason, Heli Nevanlinna, Rosa B Barkardottir, ?ke Borg
Breast Cancer Research , 2010, DOI: 10.1186/bcr2596
Abstract: We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer.We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis.Global DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may pro
Bioprospecting Finds the Toughest Biological Material: Extraordinary Silk from a Giant Riverine Orb Spider
Ingi Agnarsson,Matja? Kuntner,Todd A. Blackledge
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0011234
Abstract: Combining high strength and elasticity, spider silks are exceptionally tough, i.e., able to absorb massive kinetic energy before breaking. Spider silk is therefore a model polymer for development of high performance biomimetic fibers. There are over 41.000 described species of spiders, most spinning multiple types of silk. Thus we have available some 200.000+ unique silks that may cover an amazing breadth of material properties. To date, however, silks from only a few tens of species have been characterized, most chosen haphazardly as model organisms (Nephila) or simply from researchers' backyards. Are we limited to ‘blindly fishing’ in efforts to discover extraordinary silks? Or, could scientists use ecology to predict which species are likely to spin silks exhibiting exceptional performance properties?
How Did the Spider Cross the River? Behavioral Adaptations for River-Bridging Webs in Caerostris darwini (Araneae: Araneidae)
Matja? Gregori?, Ingi Agnarsson, Todd A. Blackledge, Matja? Kuntner
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026847
Abstract: Background Interspecific coevolution is well described, but we know significantly less about how multiple traits coevolve within a species, particularly between behavioral traits and biomechanical properties of animals' “extended phenotypes”. In orb weaving spiders, coevolution of spider behavior with ecological and physical traits of their webs is expected. Darwin's bark spider (Caerostris darwini) bridges large water bodies, building the largest known orb webs utilizing the toughest known silk. Here, we examine C. darwini web building behaviors to establish how bridge lines are formed over water. We also test the prediction that this spider's unique web ecology and architecture coevolved with new web building behaviors. Methodology We observed C. darwini in its natural habitat and filmed web building. We observed 90 web building events,?and compared web building behaviors to other species of orb web spiders. Conclusions Caerostris darwini uses a unique set of behaviors, some unknown in other spiders, to construct its enormous webs. First, the spiders release unusually large amounts of bridging silk into the air, which is then carried downwind, across the water body, establishing bridge lines. Second, the spiders perform almost no web site exploration. Third, they construct the orb capture area below the initial bridge line. In contrast to all known orb-weavers, the web hub is therefore not part of the initial bridge line but is instead built de novo. Fourth, the orb contains two types of radial threads, with those in the upper half of the web doubled. These unique behaviors result in a giant, yet rather simplified web. Our results continue to build evidence for the coevolution of behavioral (web building), ecological (web microhabitat) and biomaterial (silk biomechanics) traits that combined allow C. darwini to occupy a unique niche among spiders.
On multipartite posets
Geir Agnarsson
Mathematics , 2007,
Abstract: A poset $\mathbf{P} = (X,\preceq)$ is {\em $m$-partite} if $X$ has a partition $X = X_1 \cup ... \cup X_m$ such that (1) each $X_i$ forms an antichain in $\mathbf{P}$, and (2) $x\prec y$ implies $x\in X_i$ and $y\in X_j$ where $i
The flag polynomial of the Minkowski sum of simplices
Geir Agnarsson
Mathematics , 2010,
Abstract: For a polytope we define the {\em flag polynomial}, a polynomial in commuting variables related to the well-known flag vector and describe how to express the the flag polynomial of the Minkowski sum of $k$ standard simplices in a direct and canonical way in terms of the {\em $k$-th master polytope} $P(k)$ where $k\in\nats$. The flag polynomial facilitates many direct computations. To demonstrate this we provide two examples; we first derive a formula for the $f$-polynomial and the maximum number of $d$-dimensional faces of the Minkowski sum of two simplices. We then compute the maximum discrepancy between the number of $(0,d)$-chains of faces of a Minkowski sum of two simplices and the number of such chains of faces of a simple polytope of the same dimension and on the same number of vertices.
On the number of hypercubic bipartitions of an integer
Geir Agnarsson
Mathematics , 2011,
Abstract: We revisit a well-known divide-and-conquer maximin recurrence $f(n) = \max(\min(n_1,n_2) + f(n_1) + f(n_2))$ where the maximum is taken over all proper bipartitions $n = n_1+n_2$, and we present a new characterization of the pairs $(n_1,n_2)$ summing to $n$ that yield the maximum $f(n) = \min(n_1,n_2) + f(n_1) + f(n_2)$. This new characterization allows us, for a given $n\in\nats$, to determine the number $h(n)$ of these bipartitions that yield the said maximum $f(n)$. We present recursive formulae for $h(n)$, a generating function $h(x)$, and an explicit formula for $h(n)$ in terms of a special representation of $n$.
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