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Sökning: WFRF:(Khan Sofia)

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  • Föregående 123[4]5Nästa
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31.
  • Lawrenson, Kate, et al. (författare)
  • Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
  • 2016
  • Ingår i: Nature Communications. - Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 <em>BRCA1</em> mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (<em>P</em>=9.2 × 10<sup>−20</sup>), ER-negative BC (<em>P</em>=1.1 × 10<sup>−13</sup>), <em>BRCA1</em>-associated BC (<em>P</em>=7.7 × 10<sup>−16</sup>) and triple negative BC (<em>P</em>-diff=2 × 10<sup>−5</sup>). Genotype-gene expression associations are identified for candidate target genes <em>ANKLE1</em> (<em>P</em>=2 × 10<sup>−3</sup>) and <em>ABHD8</em> (<em>P</em>&lt;2 × 10<sup>−3</sup>). Chromosome conformation capture identifies interactions between four candidate SNPs and <em>ABHD8</em>, and luciferase assays indicate six risk alleles increased transactivation of the <em>ADHD8</em> promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces <em>ANKLE1</em> downregulation; and mRNA stability assays indicate functional effects for an <em>ANKLE1</em> 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate <em>ABHD8</em> and perhaps <em>ANKLE1</em> expression, and indicate common mechanisms underlying breast and ovarian cancer risk.</p>
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32.
  • Lindahl, Sofia, et al. (författare)
  • An on-line method for pressurized hot water extraction and enzymatic hydrolysis of quercetin glucosides from onions.
  • 2013
  • Ingår i: Analytica Chimica Acta. - Elsevier. - 1873-4324. ; 785, s. 50-59
  • Tidskriftsartikel (refereegranskat)abstract
    • A novel environmentally sound continuous-flow hot water extraction and enzymatic hydrolysis method for determination of quercetin in onion raw materials was successfully constructed using a stepwise optimization approach. In the first step, enzymatic hydrolysis of quercetin-3,4'-diglucoside to quercetin was optimized using a three level central composite design considering temperature (75-95°C), pH (3-6) and volume concentration of ethanol (5-15%). The enzyme used was a thermostable β-glucosidase variant (termed TnBgl1A_N221S/P342L) covalently immobilized on either of two acrylic support-materials (Eupergit(®) C 250L or monolithic cryogel). Optimal reaction conditions were irrespective of support 84°C, 5% ethanol and pH 5.5, and at these conditions, no significant loss of enzyme activity was observed during 72h of use. In a second step, hot water extractions from chopped yellow onions, run at the optimal temperature for hydrolysis, were optimized in a two level design with respect to pH (2.6 and 5.5), ethanol concentration (0 and 5%) and flow rate (1 and 3mLmin(-1)) Obtained results showed that the total quercetin extraction yield was 1.7 times higher using a flow rate of 3mLmin(-1) (extraction time 90min), compared to a flow rate of 1mLmin(-1) (extraction time 240min). Presence of 5% ethanol was favorable for the extraction yield, while a further decrease in pH was not, not even for the extraction step alone. Finally, the complete continuous flow method (84°C, 5% ethanol, pH 5.5, 3mLmin(-1)) was used to extract quercetin from yellow, red and shallot onions and resulted in higher or similar yield (e.g. 8.4±0.7μmolg(-1) fresh weight yellow onion) compared to a conventional batch extraction method using methanol as extraction solvent.
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33.
  • Lindahl, Sofia, et al. (författare)
  • Exploring the possibility of using a thermostable mutant of beta-glucosidase for rapid hydrolysis of quercetin glucosides in hot water
  • 2010
  • Ingår i: Green Chemistry. - Royal Society of Chemistry. - 1463-9270. ; 12:1, s. 159-168
  • Tidskriftsartikel (refereegranskat)abstract
    • The antioxidant quercetin was extracted from yellow onion waste and converted to its aglycone form by a combination of subcritical water extraction and enzymatic hydrolysis. The hydrolytic step was catalysed by a double residue (N221S, P342L) mutant of the thermostable beta-glucosidase (TnBgl1A), isolated from the thermophile Thermotoga neapolitana and cloned and produced in E. coli. The activity of wt TnBgl1A was shown to be dependent on the position of the glucosylation on the quercetin backbone, favouring hydrolysis of quercetin-4'-glucoside over quercetin-3-glucoside. The mutated variant of the enzyme harboured a mutation in the +2 sub-site (N221S) and showed increased catalytic efficiency in quercetin-3-glucoside hydrolysis and also to a certain extent hydrolysis of quercetin-4'-glucoside. The mutated enzyme was used directly in yellow onion extracts, prepared by subcritical water extraction, resulting in complete hydrolysis of the glucosylated flavonoids quercetin-3,4'-diglucoside, quercetin-4'-glucoside, quercetin-3-glucoside, isorhamnetin-4'-glucoside and isorhamnetin-3,4'-diglucoside. To complete hydrolysis within five minutes, 3 mg of TnBgl1A_N221S was used per gramme of onion (dry weight). A life cycle assessment was done to compare the environmental impact of the new method with a conventional solid-liquid extraction-and-hydrolysis method utilising aqueous methanol and hydrochloric acid. Comparison of the methods showed that the new method is preferable regarding primary energy consumption and global warming potential. Another advantage of this method is that handling of toxic chemicals (methanol and HCl) is avoided. This shows that combined subcritical water extraction/enzyme hydrolysis is both a fast and sustainable method to obtain quercetin from onion waste.
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34.
  • Lindahl, Sofia, et al. (författare)
  • Exploring the possibility of using a thermostable mutant of β-glucosidase for rapid hydrolysis of quercetin glucosides in hot water
  • 2010
  • Ingår i: Green Chemistry. - The Royal Society of Chemistry. - 1463-9262 .- 1463-9270. ; 12:1, s. 159-168
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>The antioxidant quercetin was extracted from yellow onion waste and converted to its aglycone form by a combination of subcritical water extraction and enzymatic hydrolysis. The hydrolytic step was catalysed by a double residue (N221S, P342L) mutant of the thermostable beta-glucosidase (TnBgl1A), isolated from the thermophile Thermotoga neapolitana and cloned and produced in E. coli. The activity of wt TnBgl1A was shown to be dependent on the position of the glucosylation on the quercetin backbone, favouring hydrolysis of quercetin-4'-glucoside over quercetin-3-glucoside. The mutated variant of the enzyme harboured a mutation in the +2 sub-site (N221S) and showed increased catalytic efficiency in quercetin-3-glucoside hydrolysis and also to a certain extent hydrolysis of quercetin-4'-glucoside. The mutated enzyme was used directly in yellow onion extracts, prepared by subcritical water extraction, resulting in complete hydrolysis of the glucosylated flavonoids quercetin-3,4'-diglucoside, quercetin-4'-glucoside, quercetin-3-glucoside, isorhamnetin-4'-glucoside and isorhamnetin-3,4'-diglucoside. To complete hydrolysis within five minutes, 3 mg of TnBgl1A_N221S was used per gramme of onion (dry weight). A life cycle assessment was done to compare the environmental impact of the new method with a conventional solid-liquid extraction-and-hydrolysis method utilising aqueous methanol and hydrochloric acid. Comparison of the methods showed that the new method is preferable regarding primary energy consumption and global warming potential. Another advantage of this method is that handling of toxic chemicals (methanol and HCl) is avoided. This shows that combined subcritical water extraction/enzyme hydrolysis is both a fast and sustainable method to obtain quercetin from onion waste.</p>
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35.
  • Liu, Wennuan, et al. (författare)
  • Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer.
  • 2009
  • Ingår i: Nature Medicine. - Nature Publishing Group. - 1546-170X. ; 15:5, s. 559-565
  • Tidskriftsartikel (refereegranskat)abstract
    • Many studies have shown that primary prostate cancers are multifocal and are composed of multiple genetically distinct cancer cell clones. Whether or not multiclonal primary prostate cancers typically give rise to multiclonal or monoclonal prostate cancer metastases is largely unknown, although studies at single chromosomal loci are consistent with the latter case. Here we show through a high-resolution genome-wide single nucleotide polymorphism and copy number survey that most, if not all, metastatic prostate cancers have monoclonal origins and maintain a unique signature copy number pattern of the parent cancer cell while also accumulating a variable number of separate subclonally sustained changes. We find no relationship between anatomic site of metastasis and genomic copy number change pattern. Taken together with past animal and cytogenetic studies of metastasis and recent single-locus genetic data in prostate and other metastatic cancers, these data indicate that despite common genomic heterogeneity in primary cancers, most metastatic cancers arise from a single precursor cancer cell. This study establishes that genomic archeology of multiple anatomically separate metastatic cancers in individuals can be used to define the salient genomic features of a parent cancer clone of proven lethal metastatic phenotype.
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36.
  • Meeks, Huong D., et al. (författare)
  • BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers
  • 2016
  • Ingår i: Journal of the National Cancer Institute. - Oxford University Press. - 0027-8874. ; 108:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The K3326X variant in BRCA2 (BRCA2∗c.9976A>T p.Lys3326∗rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormonerelated cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9×10-6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8×10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor-negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4×10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1×10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations.
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37.
  • Michailidou, Kyriaki, et al. (författare)
  • Association analysis identifies 65 new breast cancer risk loci.
  • 2017
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 551:7678, s. 92-94
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P &lt; 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.</p>
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38.
  • Michailidou, Kyriaki, et al. (författare)
  • Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer
  • 2015
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 47:4, s. 373-U127
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining similar to 14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P &lt; 5 x 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.</p>
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39.
  • Milne, Roger L, et al. (författare)
  • Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.
  • 2017
  • Ingår i: Nature Genetics. - 1061-4036 .- 1546-1718. ; 49:12, s. 1767-1778
  • Tidskriftsartikel (refereegranskat)abstract
    • <p>Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P &lt; 5 × 10-8 with ten variants at nine new loci. At P &lt; 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.</p>
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40.
  • Pärssinen, Jenita, et al. (författare)
  • Identification of differentially expressed genes after PPM1D silencing in breast cancer.
  • 2008
  • Ingår i: Cancer Letters. - Elsevier. - 1872-7980. ; 259:1, s. 61-70
  • Tidskriftsartikel (refereegranskat)abstract
    • Amplification and overexpression of PPM1D (protein phosphatase magnesium-dependent 1 delta) has been observed in various cancer cell lines and primary tumors and has also been associated with cancers of poor prognosis. In addition to the negative feedback regulation of p38-p53 signaling, PPM1D inhibits other tumor suppressor activities and is involved in the control of DNA damage and repair pathways. To elucidate the functional significance of PPM1D in breast cancer, we employed RNA interference to downregulate PPM1D expression in BT-474, MCF7, and ZR-75-1 breast cancer cell lines and then investigated the effects of PPM1D silencing on global gene expression patterns and signaling pathways using oligonucleotide microarrays. We identified 1798 differentially expressed (at least a two-fold change) gene elements with functions related to key cellular processes, such as regulation of cell cycle, assembly of various intracellular structures and components, and regulation of signaling pathways and metabolic cascades. For instance, genes involved in apoptosis (NR4A1, RAB25, PLK1), formation of nucleosome structure (HIST1H2AC, HIST1H2BF, HIST1H2BO, HIST1H1D), and hormone related activities (NR4A1, ESR1, STC1) were among the differentially expressed genes. Overall, our findings suggest that PPM1D contributes to breast cancer associated phenotypic characteristics by directly or indirectly affecting several important cellular signaling pathways.
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