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Sökning: WFRF:(Hallberg Jenny)

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  • Couch, Fergus J, et al. (författare)
  • Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
  • 2016
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10-8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
  • 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. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
  • Zeng, Chenjie, et al. (författare)
  • Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus
  • 2016
  • Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk. Method: We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation. Results: Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06-1.12; P = 3 x 10(-9)), rs805510 (OR = 1.08, 95 % CI = 1.04-1.12, P = 2 x 10(-5)), and rs1871152 (OR = 1.04, 95 % CI = 1.02-1.06; P = 2 x 10(-4)) identified in the general populations, and rs113824616 (P = 7 x 10(-5)) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05. Conclusion: This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
  • Adrian Meredith, Jenny, 1971-, et al. (författare)
  • Design and Synthesis of BACE-1 Inhibitors Containing a New Hydroxyethylene (HE) Scaffold: Potent activities in a cellular assay
  • Annan publikation (övrigt vetenskapligt)abstract
    • In a preceding report from our group we disclosed the development of a novel HE transition state isostere with a difluorophenoxymethyl side chain in the P1 position and a methoxy group in the P1’ position furnishing highly potent inhibitors of BACE-1 (i.e. lead compound 1), which moreover exhibit very promising selectivity over cathepsin D. In a continuation of this work with the aim at improving on the cell-based activity and pharmacokinetic properties, we have further developed the SAR for the P1 side chain of inhibitor 1 whereby the P1 side chain oxygen has been substituted for an amine, a carbon or a bond. The chemistry developed for the previous HE inhibitor structure 1 has now been extended to readily accommodate the introduction of new P1 side chains into this new HE scaffold. These modifications have given rise to several highly potent inhibitors where the most potent displayed a BACE-1 Ki value of 0.2 nM and a cell-based Aβ40 IC50 value of 9 nM. Thus, regarding the enzyme inhibition in the cell assay a more than 600-fold improvement compared to compound 1 was achieved via minor structural alterations.
  • Adrian Meredith, Jenny, 1971-, et al. (författare)
  • Design and Synthesis of Novel P2 Substituents in Diol-based HIV Protease Inhibitors
  • 2010
  • Ingår i: European Journal of Medicinal Chemistry. - : Elsevier Masson SAS. - 0223-5234 .- 1768-3254. ; 45:1, s. 160-170
  • Tidskriftsartikel (refereegranskat)abstract
    • The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an L-Val-methylamide P2 motif by appending hydrogen bonding moieties from either the isopropyl side chain or from the methylamide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 µM and 0.33 µM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone x enabling facile modifications of the overall properties in this inhibitor class.
  • Adrian Meredith, Jenny, 1971-, et al. (författare)
  • P2’-truncated BACE-1 inhibitors with a novel hydroxethylene-like core
  • 2010
  • Ingår i: European Journal of Medicinal Chemistry. - : Elsevier Masson SAS. - 0223-5234 .- 1768-3254. ; 45:2, s. 542-554
  • Tidskriftsartikel (refereegranskat)abstract
    • Highly potent BACE-1 protease inhibitors derived from a novel hydroxyethylene-like core structure were recently developed by our group using X-ray crystal structure data and molecular modelling. In a continuation of this work guided by molecular modelling we have explored a truncated core motif where the P2’ amide group is replaced by an ether linkage resulting in a set of alkoxy, aryloxy and alkylaryl groups, with the overall aim to reduce molecular weight and the number of amide bonds to increase permeability and bestow the inhibitors with drug-like features. The most potent of these inhibitors displayed a BACE-1 IC50 value of 140 nM. The synthesis of these BACE-1 inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.
  • Alhamdow, Ayman, et al. (författare)
  • Low-level exposure to polycyclic aromatic hydrocarbons is associated with reduced lung function among Swedish young adults
  • 2021
  • Ingår i: Environmental Research. - : Elsevier. - 0013-9351 .- 1096-0953. ; 197
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) has been linked to adverse pulmonary effects. However, the impact of low-level environmental PAH exposure on lung function in early adulthood remains uncertain. Objectives: To evaluate the associations between urinary PAH metabolites and lung function parameters in young adults. Methods: Urinary metabolites of pyrene, phenanthrene, and fluorene were analysed in 1000 young adults from Sweden (age 22–25 years) using LC-MS/MS. Lung function and eosinophilic airway inflammation were measured by spirometry and exhaled nitric oxide fraction (FeNO), respectively. Linear regression analysis was used to evaluate associations between PAH metabolites and the outcomes. Results: Median urinary concentrations of 1-OH-pyrene, ∑OH-phenanthrene, and ∑OH-fluorene were 0.066, 0.36, 0.22 μg/L, respectively. We found inverse associations of ∑OH-phenanthrene and ∑OH-fluorene with FEV1 and FVC, as well as between 1-OH-pyrene and FEV1/FVC ratio (adjusted P < 0.05; all participants). An increase of 1% in ∑OH-fluorene was associated with a decrease of 73 mL in FEV1 and 59 mL in FVC. In addition, ∑OH-phenanthrene concentrations were, in a dose-response manner, inversely associated with FEV1 (B from −109 to −48 compared with the lowest quartile of ∑OH-phenanthrene; p trend 0.004) and FVC (B from −159 to −102 compared with lowest quartile; p-trend <0.001). Similar dose-response associations were also observed between ∑OH-fluorene and FEV1 and FVC, as well as between 1-OH-pyrene and FEV1/FVC (p-trend <0.05). There was no association between PAH exposure and FeNO, nor was there an interaction with smoking, sex, or asthma. Conclusion: Low-level PAH exposure was, in a dose-response manner, associated with reduced lung function in young adults. Our findings have public health implications due to i) the widespread occurrence of PAHs in the environment and ii) the clinical relevance of lung function in predicting all-cause and cardiovascular disease mortality.
  • Bernson, Jenny M, et al. (författare)
  • 'Making dental care possible - a mutual affair'. A grounded theory relating to adult patients with dental fear and regular dental treatment
  • 2011
  • Ingår i: European Journal of Oral Sciences. - Copenhagen : Munksgaard Forlag. - 0909-8836 .- 1600-0722. ; 119:5, s. 373-380
  • Tidskriftsartikel (refereegranskat)abstract
    • Dental fear is a common and widespread problem, which can cause severe stress. Even so, most patients with dental fear undergo regular dental treatment in spite of their fear and many enjoy good oral health. The aim of this study was to obtain a deeper understanding of how patients with dental fear manage to undergo dental treatment. Fourteen patients with dental fear, who undergo regular dental care, were interviewed. Qualitative analysis of the transcribed interviews was performed according to the principles of grounded theory. A conceptual framework was generated, and the main concern was identified as 'making dental care possible - a mutual affair'. Four additional categories explained how patients handled their dental fear and how dental care became possible. The strategies were labelled 'taking part in a mental wrestling match', 'trust-filled interaction with dental staff', 'striving for control' and 'seeking and/or receiving social support'. The results showed that making dental care possible for patients with dental fear is a mutual challenge that requires interplay between dental staff and patients, involving verbal and non-verbal communication reflecting respect, attention, and empathy. Moreover, a balance between nearness and distance and between professional and personal treatment is required.
  • Björkander, Sophia, et al. (författare)
  • The allergic phenotype during the first 10 years of life in a prospective cohort
  • 2019
  • Ingår i: Immunity, Inflammation and Disease. - : Wiley. - 2050-4527. ; 7:3, s. 170-182
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundHeredity and environmental parameters jointly affect allergy development. Here, we used a Swedish prospective cohort to study the influence of heredity and factors usually associated with allergic disease and the development of allergic manifestations in combination with immunoglobulin E (IgE) sensitization at four different time points until 10 years of age.MethodsParents‐to‐be were characterized concerning allergy and their children (n = 281) were divided based on allergic heredity and followed from birth and clinically examined for IgE‐associated allergic symptoms until 10 years of age. The relation between allergy and early‐life parameters was analyzed by logistic regression. Group‐wise comparisons were made by nonparametrical tests.ResultsEarly life eczema and/or asthma in combination with IgE sensitization, was a strong indicator of allergy at a later time point. Further, the early occurrence of multiple allergic symptoms among IgE‐sensitized children predisposed for a more complex allergic phenotype at later ages, independently of allergic heredity. At 10 years of age, allergic children had higher fractional exhaled nitrogen oxide (FeNO) levels, regardless of asthma, and FeNO levels were also influenced by heredity. Birth season was strongly associated with allergy development, but only in children with two allergic parents.ConclusionAllergic eczema/asthma in early life, being born during the autumn/winter, having multiple allergic symptoms and two allergic parents were all strong predictors for having allergic diseases at 5 and 10 years of age. However, the allergic march seems to be independent of heredity, as IgE‐mediated allergies follow the same trajectories in children with and without allergic heredity.
  • Bonamy, Anna-Karin Edstedt, et al. (författare)
  • Blood Pressure in 6-Year-Old Children Born Extremely Preterm
  • 2017
  • Ingår i: Journal of the American Heart Association. - : WILEY. - 2047-9980 .- 2047-9980. ; 6:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Background-Advances in perinatal medicine have increased infant survival after very preterm birth. Although this progress is welcome, there is increasing concern that preterm birth is an emerging risk factor for hypertension at young age, with implications for the lifetime risk of cardiovascular disease. Methods and Results-We measured casual blood pressures (BPs) in a population-based cohort of 6-year-old survivors of extremely preterm birth (< 27 gestational weeks; n=171) and in age-and sex-matched controls born at term (n=172). Measured BP did not differ, but sex, age-, and height-adjusted median z scores were 0.14 SD higher (P=0.02) for systolic BP and 0.10 SD higher (P=0.01) for diastolic BP in children born extremely preterm than in controls. Among children born extremely preterm, shorter gestation, higher body mass index, and higher heart rate at follow-up were all independently associated with higher BP at 6 years of age, whereas preeclampsia, smoking in pregnancy, neonatal morbidity, and perinatal corticosteroid therapy were not. In multivariate regression analyses, systolic BP decreased by 0.10 SD (P=0.08) and diastolic BP by 0.09 SD (P=0.02) for each week-longer gestation. Conclusions-Six-year-old children born extremely preterm have normal but slightly higher BP than their peers born at term. Although this finding is reassuring for children born preterm and their families, follow-up at older age is warranted.
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