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Sökning: WFRF:(Hallberg Jenny)

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1.
  • 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. ; 7:11375, s. 1-13
  • Tidskriftsartikel (refereegranskat)abstract
    • Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 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 similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
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2.
  • 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. - : Springer Science and Business Media LLC. - 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.
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3.
  • 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.
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4.
  • 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/konstnärligt)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.
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5.
  • 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 BV. - 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 methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed K-i values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 mu M and 0.33 mu M 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 M461, V82F, and 184V 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 21 enabling facile modifications of the overall properties in this inhibitor class.
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6.
  • 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 BV. - 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-I IC50 value of 140 nM. The synthesis of these BACE-I inhibitors utilizes readily available starting materials, furnishing the target compounds in good overall yields.
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7.
  • 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 BV. - 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.
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8.
  • 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.
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9.
  • 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.
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10.
  • 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. ; 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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11.
  • Brolin, Erika, et al. (författare)
  • The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration
  • 2017
  • Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 646, s. 15-20
  • Tidskriftsartikel (refereegranskat)abstract
    • In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.
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12.
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13.
  • Ekegren, Jenny, 1976- (författare)
  • Design and Synthesis of Novel HIV-1 Protease Inhibitors Comprising a Tertiary Alcohol in the Transition-State Mimic
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'.Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.
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14.
  • Ekegren, Jenny K, et al. (författare)
  • A new class of HIV-1 protease inhibitors containing a tertiary alcohol in the transition-state mimicking scaffold
  • 2005
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:25, s. 8098-8102
  • Tidskriftsartikel (refereegranskat)abstract
    • Novel HIV-1 protease inhibitors encompassing a tertiary alcohol as part of the transition-state mimicking unit have been synthesized. Variation of the P1‘−P3‘ residues and alteration of the tertiary alcohol absolute stereochemistry afforded 10 inhibitors. High potencies for the compounds with (S)-configuration at the carbon carrying the tertiary hydroxyl group were achieved with Ki values down to 2.4 nM. X-ray crystallographic data for a representative compound in complex with HIV-1 protease are presented.
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15.
  • Ekegren, Jenny K, et al. (författare)
  • Microwave-accelerated synthesis of P1'-extended HIV-1 protease inhibitors encompassing a tertiary alcohol in the transition-state mimicking scaffold
  • 2006
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 49:5, s. 1828-1832
  • Tidskriftsartikel (refereegranskat)abstract
    • Two series of P1'-extended HIV-1 protease inhibitors comprising a tertiary alcohol in the transition-state mimic exhibiting Ki values ranging from 2.1 to 93 nM have been synthesized. Microwave-accelerated palladium-catalyzed cross-couplings were utilized to rapidly optimize the P1' side chain. High cellular antiviral potencies were encountered when the P1' benzyl group was elongated with a 3- or 4-pyridyl substituent (EC50 = 0.18-0.22 microM). X-ray crystallographic data were obtained for three inhibitors cocrystallized with the enzyme.
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16.
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17.
  • Ekegren, Jenny, et al. (författare)
  • Variations of the P2 Group in HIV-1 Protease Inhibitors Containing a Tertiary Alcohol in the Transition-State Mimicking Scaffold
  • 2006
  • Ingår i: Organic and biomolecular chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 4:16, s. 3040-3043
  • Tidskriftsartikel (refereegranskat)abstract
    • The development of synthetic protocol leading to HIV-1 protease inhibitors with a tertiary alcohol based transition-state mimicking unit and different P2 side chains was investigated. (2S)-2-benztloxirane-2-carboxylic acid ((S)-5) was used as a key intermediate in the synthesis of the new HIV-1 protease inhibitors. (S)-5 was coupled with different amines using EDC, NMM, and HOBT, resulting in the corresponding amides at low to moderate yields. The observation supports the hypothesis that intramolecular hydrogen bonding to the tertiary alcohol in the transition-state mimic is present in these molecules. Purification by reverse-phase LC-MS resulted in moderate to good yields of most target compounds. The HIV-1 protease inhibition data suggest that the size and polarity of the P2 substituent are crucial to allow proper accommodation in the S2 sub-site.
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18.
  • Ekström, Sandra, et al. (författare)
  • Dietary intake and plasma concentrations of PUFAs in childhood and adolescence in relation to asthma and lung function up to adulthood
  • 2022
  • Ingår i: American Journal of Clinical Nutrition. - : Oxford University Press (OUP). - 0002-9165 .- 1938-3207. ; 115:3, s. 886-896
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: PUFAs may influence the risk of asthma; however, long-term prospective studies including objective biomarkers of PUFA intake are lacking.Objectives The objective was to investigate the role of dietary intake and plasma concentrations of n–3 and n–6 (ω-3 and ω-6) PUFAs in childhood and adolescence for the development of asthma and lung function up to young adulthood.Methods: The study included participants from the Swedish prospective birth cohort BAMSE. Dietary intake of PUFAs was calculated from FFQs (n = 1992) and plasma proportions of PUFAs were measured in phospholipids (n = 831). We analyzed the n–3 PUFA α-linolenic acid (ALA; 18:3n–3); the sum of very-long-chain (VLC) n–3 PUFAs: EPA (20:5n–3), DHA (22:6n–3), and docosapentaenoic acid (22:5n–3); and the n–6 PUFAs linoleic acid (LA; 18:2n–6) and arachidonic acid (AA; 20:4n–6). Asthma was assessed by questionnaires at 8, 16, and 24 y and lung function was measured by spirometry at 24 y.Results: A high (≥median) self-reported dietary intake of LA at 8 y and AA at 16 y was associated with increased risk of prevalent asthma at 24 y (OR: 1.41; 95% CI: 1.10, 1.82 and OR: 1.32; 95% CI: 1.02, 1.70, respectively). In contrast, plasma proportions of ALA, ∑VLC n–3 PUFAs, and AA at 8 y, as well as LA at 16 y, were inversely associated with prevalent asthma at 24 y (e.g., OR: 0.55; 95% CI: 0.38, 0.81 for ∑VLC n–3 PUFAs). No consistent associations were observed with lung function.Conclusions: High dietary intake of certain n–6 PUFAs in childhood or adolescence may be associated with increased risk of asthma up to young adulthood, whereas dietary biomarkers of certain n–3 and n–6 PUFAs in plasma may be associated with decreased risk. Thus, the role of diet compared with altered metabolism of PUFAs needs further investigation to improve dietary preventive strategies for asthma.
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19.
  • Grönbladh, Alfhild, et al. (författare)
  • Administration of growth hormone and nandrolone decanoate alters mRNA expression of the GABAB receptor subunits as well as GH receptor, IGF-1, and IGF-2 in rat brain
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The illicit use of anabolic androgenic steroids (AAS), especially among young adults, is of major concern. Among AAS users it is common to combine the AAS nandrolone decanoate (ND), with intake of growth hormone (GH) and a connection between gonadal steroids and the GH system has been suggested. Both AAS and GH affect functions in the brain, for example those associated with the hypothalamus and pituitary, and several GH actions are mediated by growth factors such as insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The GABAergic system is implicated in actions induced by AAS and previous studies have provided evidence for a link between GH and GABAB receptors in the brain. Our aim was to examine the impact of a combined administration of AAS and GH on expression of GABAB receptors and important GH mediators in rat brainDesign: In the present study, male rats were administered a high dose of ND every third day during three weeks, and subsequently the rats were given recombinant human GH (rhGH) during ten days. Quantitative PCR (qPCR) was used to analyze gene expression in hypothalamus, anterior pituitary, caudate putamen, nucleus accumbens, and amygdala.Results: In the pituitary gland, the expression of GABAB receptor subunits was affected differently by the steroid treatment; the GABAB1 mRNA expression was decreased whereas a distinct elevation of the GABAB2 expression was found. Administration of ND also caused a decrease of GHR, IGF-1, and IGF-2 mRNA expression in the pituitary while the corresponding expression in the hypothalamus, caudate putamen, nucleus accumbens, and amygdala was unaffected. The rhGH administration did not alter the GABAB2 expression but increased the GABAB1 gene expression in the hypothalamus as compared the AAS treated group.Conclusions: These results provide new insights on the impact of ND and GH on the brain and highlight the interaction of these hormones with systems influencing GABAB receptor expression. The physiological significance of the observed effects of these hormones is discussed.
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20.
  • Grönbladh, Alfhild, et al. (författare)
  • Administration of growth hormone and nandrolone decanoate alters mRNA expression of the GABAB receptor subunits as well as of the GH receptor, IGF-1, and IGF-2 in rat brain.
  • 2014
  • Ingår i: Growth Hormone & IGF Research. - : Elsevier BV. - 1096-6374 .- 1532-2238. ; 24:2-3, s. 60-66
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: The illicit use of anabolic androgenic steroids (AAS), especially among young adults, is of major concern. Among AAS users it is common to combine the AAS nandrolone decanoate (ND), with intake of growth hormone (GH) and a connection between gonadal steroids and the GH system has been suggested. Both AAS and GH affect functions in the brain, for example those associated with the hypothalamus and pituitary, and several GH actions are mediated by growth factors such as insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The GABAergic system is implicated in actions induced by AAS and previous studies have provided evidence for a link between GH and GABAB receptors in the brain. Our aim was to examine the impact of AAS administration and a subsequent administration of GH, on the expression of GABAB receptors and important GH mediators in rat brain.DESIGN: The aim was to investigate the CNS effects of a high-dose ND, and to study if a low, but physiological relevant, dose of GH could reverse the ND-induced effects. In the present study, male rats were administered a high dose of ND every third day during three weeks, and subsequently the rats were given recombinant human GH (rhGH) during ten days. Quantitative PCR (qPCR) was used to analyze gene expression in hypothalamus, anterior pituitary, caudate putamen, nucleus accumbens, and amygdala.RESULTS: In the pituitary gland, the expression of GABAB receptor subunits was affected differently by the steroid treatment; the GABAB1 mRNA expression was decreased whereas a distinct elevation of the GABAB2 expression was found. Administration of ND also caused a decrease of GHR, IGF-1, and IGF-2 mRNA expression in the pituitary while the corresponding expression in the hypothalamus, caudate putamen, nucleus accumbens, and amygdala was unaffected. The rhGH administration did not alter the GABAB2 expression but increased the GABAB1 gene expression in the hypothalamus as compared to the AAS treated group.CONCLUSIONS: These results provide new insights on the impact of ND and GH on the brain and highlight the interaction of these hormones with systems influencing GABAB receptor expression. The physiological significance of the observed effects of these hormones is discussed.
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21.
  • Grönbladh, Alfhild, et al. (författare)
  • GH (Growth hormone) improves spatial memory and reverses certain anabolic androgenic steroid-induced effects in intact rats
  • 2013
  • Ingår i: Journal of Endocrinology. - 0022-0795 .- 1479-6805. ; 216:1, s. 31-41
  • Tidskriftsartikel (refereegranskat)abstract
    • Growth hormone (GH) has previously been shown to promote cognitive functions in GH deficient rodents. In this study we report effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone. Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for three weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) or saline for ten consecutive days. During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM). Also, plasma levels of insulin-like growth factor 1 (IGF1) were assessed and the gene expression of the GH receptor, Igf1, and Igf2 in hippocampus and frontal cortex was analyzed. The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH. In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone treated animals. In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared to controls in the MWM, and in many cases GH did not induce any alteration. Regarding target zone crossings, considered to be associated to spatial memory, the difference between GH and steroid treated animals was significant and administration of GH improved this parameter in the latter group. In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by AAS (anabolic androgenic steroid).
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22.
  • Grönbladh, Alfhild, et al. (författare)
  • Recombinant Human Growth Hormone Affects the Density and Functionality of GABAB receptors in the Male Rat Brain
  • 2013
  • Ingår i: Neuroendocrinology. - : S. Karger AG. - 0028-3835 .- 1423-0194. ; 97:3, s. 203-211
  • Tidskriftsartikel (refereegranskat)abstract
    • The beneficial effects of growth hormone (GH) on memory and learning have previously been confirmed in both humans and in animal models. An important role of GABA(B) receptors for multiple forms of learning and memory has also been reported. In this study, we examined the effect of GH on the density and functionality of the metabotropic GABA(B) receptors in the rat brain. Male Sprague-Dawley rats (n = 24) divided into 3 groups were injected twice daily with recombinant human GH (0.07 or 0.7 IU/kg) for 7 days. The effects of the hormone were determined by quantitative autoradiography and by GABA(B) stimulated [(35)S]-GTPγS binding using the selective GABA(B) receptor agonist baclofen. The results demonstrate moderate but significant alterations in both receptor density and functionality in a number of brain regions. For example, a dose-dependent upregulation of GABA(B) receptors was found in the cingulate cortex, primary motor cortex and caudate putamen, whereas attenuation in the receptor density was encountered in, for example, the medial geniculate nucleus. Although the GH-induced effects on the GABA(B) receptor in brain areas associated with cognition were fairly pronounced, they were significant and we propose that the physiological responses observed after GH administration at least partly can be mediated through a mechanism involving GABA(B) receptors.
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23.
  • Grönbladh, Alfhild, et al. (författare)
  • The impact of nandrolone decanoate and growth hormone on biosynthesis of steroids in rats
  • 2013
  • Ingår i: Steroids. - : Elsevier. - 0039-128X .- 1878-5867. ; 78:12-13, s. 1192-1199
  • Tidskriftsartikel (refereegranskat)abstract
    • Growth hormone (GH) and anabolic androgenic steroids (AAS) are commonly used in sports communities. Several studies have suggested an association between GH and AAS. We have investigated the impact of GH in rats treated with nandrolone decanoate (ND). Male Wistar rats received ND (15 mg/kg) every third day during three weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) for ten consecutive days. Plasma samples were collected and peripheral organs (i.e. heart, liver, testis and thymus) were dissected and weighed. Concentration of thirteen endogenous steroids was measured in the rat plasma samples using high specificity LC-MS/MS methods. Seven steroids were detected and quantified, and concentrations of estrone, testosterone, and androstenedione were significantly different among the groups, while concentrations of pregnenolone, DHEA, 17- hydroxyprogesterone and corticosterone were not altered. Administration of rhGH alone altered the plasma steroid distribution, and the results demonstrated significantly increased concentrations of plasma estrone as well as decreased concentrations of testosterone and androstenedione in the ND-treated rats. Administration of rhGH to ND-pretreated rats did not reverse the alteration of the steroid distribution induced by ND. Administration of ND decreased the weight of the thymus, and addition of rhGH did not reverse this reduction. However, rhGH administration induced an enlargement of thymus. Taken together, the plasma steroid profile differed in the four groups, i.e. controls, AAS, rhGH and the combination of AAS and rhGH treatment.
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24.
  • Hallberg, Jenny (författare)
  • Factors associated with lung function impairment in children and adults with obstructive lung disease
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Obstructive lung diseases are a group of diseases in which there is a limitation in the flow of air into or out of the lungs. Two common such diseases are asthma, which is found in both children and adults, and chronic obstructive pulmonary disease (COPD), mainly found in the population over 50 years of age. Both asthma and COPD seem to have with several different subgroups, or phenotypes, which may be associated with different long term consequences in regard to morbidity and in some cases also mortality. To be able to prevent and treat these diseases in the best possible way, we need to learn more about the different phenotypes and the mechanisms behind them. The aim of this thesis was to study factors that are associated with lung function impairment in children and adults with obstructive lung diseases. The factors that are in focus are age of onset, duration of symptoms, sex, allergy, smoking and the contribution of genes and environment. We have, in the two first papers, measured lung function at age 4 and 8 years in a birth cohort of 4,000 children and found that asthma symptom onset in the first 4 years of life was, on a group level, associated with impaired exhaled flows. This was found irrespective of the persistence of symptoms between the age of 4 and 8. We could also show tracking of impaired flows between the age of 4 and 8. Sensitization to airway allergens was associated with lung function impairment only in children with symptom onset after the age of 4. While male sex was a risk factor for asthma symptoms, girls with asthma symptoms showed a larger negative effect on exhaled flows, at least in the four first years. In paper 3 and 4, we studied symptom data from 45,000 twins from the Swedish Twin Registry to quantify heritability for chronic bronchitis and emphysema, two of the main components seen in COPD. As smoking behaviour has genetic influences, it was necessary to study how heritability for disease was associated with heritability for smoking. The results showed that ~40% of the individuals liability to developing chronic bronchitis/emphysema can be attributed to genetic factors, and that only a small part of these factors were found to be in common with those influencing smoking habits. Women more often reported chronic bronchitis/emphysema, compared to men, and this could not be explained by different smoking habits or different genes. Two hundred of the twins took part in a clinical testing of different lung function measures. The results from this study showed that all lung function measures that were studied had a heritable component, and that it was larger for women than for men. In conclusion, we have studied how several different factors are associated with lung function impairment in children and adults with obstructive lung disease. In summary, the first years of life are of importance for future lung function. Children that outgrow their asthma seem, on a group level, to loose their symptoms rather their lung function impairment, which might be present through life. We have furthermore shown that genes are important for the individuals liability to disease in adult life. Sex differences exist both in children and adult disease, and there are indications of a less favourable outcome for girls/women. More work is now needed to find the individuals that belong to these susceptible groups, and to develop and apply methods to prevent and treat impaired lung function and disease.
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25.
  • Hallberg, Jenny, et al. (författare)
  • Genetic and environmental influence on lung function impairment in Swedish twins
  • 2010
  • Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 11
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The understanding of the influence of smoking and sex on lung function and symptoms is important for understanding diseases such as COPD. The influence of both genes and environment on lung function, smoking behaviour and the presence of respiratory symptoms has previously been demonstrated for each of these separately. Hence, smoking can influence lung function by co-varying not only as an environmental factor, but also by shared genetic pathways. Therefore, the objective was to evaluate heritability for different aspects of lung function, and to investigate how the estimates are affected by adjustments for smoking and respiratory symptoms. Methods: The current study is based on a selected sample of adult twins from the Swedish Twin Registry. Pairs were selected based on background data on smoking and respiratory symptoms collected by telephone interview. Lung function was measured as FEV1, VC and DLco. Pack years were quantified, and quantitative genetic analysis was performed on lung function data adjusting stepwise for sex, pack years and respiratory symptoms. Results: Fully adjusted heritability for VC was 59% and did not differ by sex, with smoking and symptoms explaining only a small part of the total variance. Heritabilities for FEV1 and DLco were sex specific. Fully adjusted estimates were 10 and 15% in men and 46% and 39% in women, respectively. Adjustment for smoking and respiratory symptoms altered the estimates differently in men and women. For FEV1 and DLco, the variance explained by smoking and symptoms was larger in men. Further, smoking and symptoms explained genetic variance in women, but was primarily associated with shared environmental effects in men. Conclusion: Differences between men and women were found in how smoking and symptoms influence the variation in lung function. Pulmonary gas transfer variation related to the menstrual cycle has been shown before, and the findings regarding DLco in the present study indicates gender specific environmental susceptibility not shown before. As a consequence the results suggest that patients with lung diseases such as COPD could benefit from interventions that are sex specific.
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26.
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27.
  • Heiman, Jenny, 1980, et al. (författare)
  • Breast-conserving surgery using an inframammary fold incision technique for breast cancer.
  • 2017
  • Ingår i: Journal of plastic surgery and hand surgery. - 2000-6764. ; 51:2, s. 105-111
  • Tidskriftsartikel (refereegranskat)abstract
    • Breast-conserving surgery is an established alternative for the majority of women with early stage breast cancer. Consensus on negative margins (no ink on tumour) for invasive cancer makes mutilating extensive lumpectomies unnecessary. Several breast-conserving surgical methods are described in the literature. The aim of this study was to describe and evaluate a technique using the inframammary fold incision.Twenty-seven patients with suspected breast cancer (stage I-II) underwent breast-conserving surgery using the inframammary fold incision. Data regarding tumour characteristics, margin status, complications, oncologic and aesthetic outcome was analysed retrospectively.After a median follow-up of 35 months, 23 of the 24 patients with breast cancer (95.8%) had no evidence of disease. Post-operative complications (as defined by infection requiring antibiotic treatment and/or seroma requiring drainage) were seen in three of the 27 patients (11.1%). The final pathological examination revealed a positive excision margin in four patients (16.7%). Post-operative evaluation with the BREAST-Q™ BCT module showed a mean RASCH score of 72.5 regarding 'Satisfaction with breast'. The aesthetic result with a hidden scar is exemplified.Breast-conserving surgery using the inframammary fold incision seems to be a safe method with better cosmesis; however, further research is needed.
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28.
  • Jiao, Xiang, et al. (författare)
  • PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
  • 2017
  • Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
  • Tidskriftsartikel (refereegranskat)abstract
    • Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
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29.
  • Johansson, Jenny, 1980-, et al. (författare)
  • Application of in vitro [(35)S]GTPγ-S autoradiography in studies of growth hormone effects on opioid receptors in the male rat brain
  • 2013
  • Ingår i: Brain Research Bulletin. - : Elsevier BV. - 0361-9230 .- 1873-2747. ; 90, s. 100-106
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic treatment with opiates may inhibit cell growth and trigger apoptosis. On the contrary, growth hormone (GH) has been demonstrated to stimulate neurogenesis and counteract apoptosis. We recently demonstrated that recombinant human GH (rhGH) may reverse opiate-induced apoptosis in cells derived from prenatal mouse hippocampus. Thus, GH might be able to prevent the impaired cognitive capabilities that may occur in both humans and other mammals in connection to chronic opiate treatment. In order to explore the mechanism by which GH exerts its beneficial effects we here examined the impact of GH treatment on the levels of delta and mu opioid peptide (DOP and MOP, respectively) receptors in the male rat brain. The rats were treated with rhGH (Genotropin(®)) at two different doses (0.07 and 0.7IU/kg), twice daily, during 7 days. Following decapitation, the levels of DOP and MOP receptor functionality were determined using [(35)S]GTPγS autoradiography. The results demonstrate that rhGH affects the levels of the MOP receptor functionality in certain areas of the brain. These alterations were seen in e.g. amygdala and thalamus, i.e. regions that recently have been implicated in learning and memory. The activity level of DOP receptors was not affected. Thus, the data support that the beneficial effect of GH on counteracting apoptosis might involve a direct or indirect effect on the MOP but not the DOP receptor.
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30.
  • Johansson, Jenny, et al. (författare)
  • Gamma-Hydroxybutyrate (GHB) elevates Met-enkephalin-Arg6Phe7 (MEAP) levels in the frontal cortex of the male rat brain
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Gamma-hydroxybutyrate (GHB) has increased in popularity among adolescents during recent years. Predominantly it is used as a recreational drug, but frequently also as an anabolic agent due to its ability of releasing growth hormone. The fact that GHB has been reported to be highly addictive and can cause cognitive deficiencies has become a major concern. In this study, we investigated the impact of GHB treatment in rats on the levels of the endogenous opioid peptides Met-enkephalin-Arg6Phe7 (MEAP) and Dynorphin B (DYNB) in various regions of the brain and on the levels of insulin-like growth factor 1 (IGF-1) in plasma. Furthermore, spontaneous explorative behavior and locomotor activity after GHB administration was analyzed in an Open field (OF). The results demonstrated that treatment with GHB did not affect the parameters that were assessed in the OF, nor did it affect the plasma levels of IGF-1. Regarding the opioid peptide levels, the GHB treated rats demonstrated increased immunoreactive (ir) MEAP but not DYNB levels in the frontal cortex, while no significant alterations were observed in caudate putamen, hypothalamus, nucleus accumbens, amygdala, hippocampus and periaqueductal grey. Moreover, in control rats the levels of ir MEAP and ir DYNB seemed well-balanced in many regions and the peptide levels correlated in amygdala, hippocampus and hypothalamus. However, in the GHB-treated animals no such correlation was observed. In conclusion, GHB treatment created an imbalance regarding the opioids MEAP/DYNB and increased the levels of MEAP significantly in regions of the brain that are of importance for the development of drug dependence.
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31.
  • Johansson, Jenny, et al. (författare)
  • Gamma-Hydroxybutyrate (GHB) induces cognitive deficits and affects GABAB receptors and IGF-1 receptors in male rats
  • 2014
  • Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328 .- 1872-7549. ; 269, s. 164-174
  • Tidskriftsartikel (refereegranskat)abstract
    • In recent years, the abuse of the club drug Gamma-hydroxy butyric acid (GHB) has become increasingly frequent among adolescents. The drug induces euphoria but can also result in sedation, anaesthesia as well as short-term amnesia. In addition, the abuse of GHB is reported to cause cognitive impairments. The mechanism by which GHB induces impairment in learning and memory has not been fully clarified. The present study investigates the impact on spatial learning and memory using a water maze test in rats treated with GHB. The behavioural data is combined with an autoradiographic analysis of the GABAB and the IGF-1 receptor systems. The results demonstrate that the GHB treated animals display an impaired performance in the water maze test as compared to controls. In addition, significant alterations in GABAB and IGF-1 receptor density as well as GABAB receptor functionality, were observed in several brain regions associated with cognitive functions e.g. hippocampus. To conclude, our findings suggest that GHB treatment can affect spatial learning and memory, and that this outcome at least to some extent is likely to involve both GABAB and IGF-1 receptors.
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32.
  • Johansson, Jenny, 1980- (författare)
  • The Impact of Growth Hormone and Gamma-Hydroxybutyrate (GHB) on Systems Related to Cognition
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Drug dependence is a serious and increasing problem in our society, especially among adolescents. The use of the large variety of substances available can result in a range of physiological and psychological adverse effects on individuals and negative consequences on the society overall. Several different types of drugs induce neurotoxicological damages, which in turn can generate impairment in for example the reward system and affect cognitive parameters. The drug gamma-hydroxybutyrate (GHB) is usually considered a harmless compound among abusers, but has now shown to be highly addictive. Furthermore, GHB can cause memory impairments in both humans and animals. On the contrary, growth hormone (GH) and its main mediator insulin-like growth factor 1 (IGF-1) have recently been suggested to improve memory and learning in several studies. The hormones exhibit certain neuroprotective capabilities and have also previously been demonstrated to reverse opioid induced apoptosis in hippocampal cells. These effects and the fact that GHB is shown to increase GH secretion, which attracted considerable attention among body builders, led us to initiate studies on GHB and its impact on relevant systems in the central nervous system (CNS). Thus, the main purpose of the present investigation was to elucidate some of the underlying mechanisms that could account for the effects exerted by GH and GHB in the CNS.We found that a) GH affects the density and functionality of GABAB-receptors and opioid receptors in the male rat brain, b) GHB induces cognitive deficits and down-regulates GABAB-receptors, c) GHB treatment creates an imbalance between the endogenous opioids Met-enkaphalin-Arg6Phe7 (MEAP) and dynorphin B and increases the levels of MEAP in regions of the brain that are associated with drug dependence, and d) GHB affects the expression of IGF-1 receptors but not the plasma levels of IGF-1. In conclusion, the present work demonstrates that GH interacts with both opioid and GABAB-receptors in the male rat CNS and that GHB has an impact on brain regions associated with cognition and the development of dependence. These observations may be of relevance in many aspects related to addiction and might be translated into humans.
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33.
  • Mahalingam, A. Kannan, et al. (författare)
  • HIV-1 Protease Inhibitors with a Transition-State Mimic Comprising a Tertiary Alcohol : Improved Antiviral Activity in Cells
  • 2010
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 53:2, s. 607-615
  • Tidskriftsartikel (refereegranskat)abstract
    • By a small modification in the core structure of the previously reported series of HIV-1 protease inhibitors that encompasses a tertiary alcohol as part of the transition-state mimicking scaffold, up to 56 times more potent compounds were obtained exhibiting EC50 values down to 3 nM. Three of the inhibitors also displayed excellent activity against selected resistant isolates of HIV-1. The synthesis of 25 new and optically pure HIV-1 protease inhibitors is reported, along with methods for elongation of the inhibitor Pl' side chain using microwave-accelerated, palladium-catalyzed cross-coupling reactions, the biological evaluation, and X-ray data obtained from one of the most potent analogues cocrystallized with both the wild type and the L63P, V82T, 184 V mutant of the HIV-1 protease.
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34.
  • Malinovschi, Andrei, 1978-, et al. (författare)
  • Reliability of external impulse oscillometry reference values for assessing respiratory health in Swedish adults.
  • 2022
  • Ingår i: Clinical and Experimental Allergy. - : John Wiley & Sons. - 0954-7894 .- 1365-2222. ; 52:2, s. 355-358
  • Tidskriftsartikel (refereegranskat)abstract
    • Impulse oscillometry (IOS) can be used to assess the mechanical properties of the respiratory airways. The method is easy to perform as it requires only tidal breathing and may provide complimentary information beyond that from dynamic spirometry. For the method to be clinically useful, reference values appropriate with regard to methodology and population are needed. The IOS equipment producer recommended reference values are derived from a German population[1], while method specific reference values for healthy non-smoking adult Caucasian are available from smaller datasets from Europe[2] and Australia[3].
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35.
  • Melen, Erik, et al. (författare)
  • Spirometric phenotypes from early childhood to young adulthood - A CADSET (Chronic Airway Disease Early Stratification) study
  • 2020
  • Ingår i: European Respiratory Journal. - : ERS Publications. - 0903-1936 .- 1399-3003. ; 56:Suppl 64
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Results from longitudinal cohort studies show that the lower the lung function in childhood and adulthood, the higher the risk of later chronic airway disease such as COPD. Yet, reliable data is sparse on the prevalence of different types of lung function impairments in the general population of children and young adults, as well as their major determinants.Aim: To report age- and sex-specific prevalences and characteristics of spirometric phenotypes from childhood up to young adulthood.Methods: Lung function data from independent European population-based cohorts involved in the CADSET collaboration were analysed. Pre-bronchodilator FEV1 and FVC data from each cohort were converted into z-scores according to the Global Lung Initiative (GLI) reference system. Overall fit with the GLI spirometry equations was assessed. Airway limitation was defined as a FEV1/FVC z-score < -1.65.Results: Five cohorts provided spirometry data from 10,842 observations in subjects aged 7 to 25 years. Airway limitation was found in around 6-10% across all ages in the cohorts. No evidence of differences between males and females in different age groups were observed. In unadjusted analyses of all cohorts, we found maternal smoking during pregnancy to be associated with airway limitation (p<0.05).Conclusion: Analyses of spirometry data from population-based cohorts in Europe show that the prevalence of airflow limitation according to GLI is substantial (6-10%) and quite similar across cohorts and age groups. These results suggest that airflow limitation can develop early in life and that there are rather small changes in prevalence during childhood.
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36.
  • Mitselou, Niki, 1982-, et al. (författare)
  • Adverse pregnancy outcomes and risk of later allergic rhinitis-Nationwide Swedish cohort study
  • 2020
  • Ingår i: Pediatric Allergy and Immunology. - : John Wiley & Sons. - 0905-6157 .- 1399-3038. ; 31:5, s. 471-479
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Perinatal conditions may be associated with future allergic disease; however, data are conflicting and incomplete for childhood allergic rhinitis (AR). The aim of this study was to examine pregnancy outcome (cesarean delivery, preterm birth, low birthweight) and offspring AR as defined by national registers.Methods: Nationwide longitudinal cohort study using prospectively recorded register data from 1 059 600 singleton livebirths born in Sweden in 2001-2012. Cox regression adjusted for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index, and asthma/pulmonary disease) estimated hazard ratios (HRs) for AR during childhood.Results: During the study period 2001-2013, 22 386 (2.11%) children were diagnosed with AR. AR was more common in infants born through cesarean delivery (2.34%) than in those born vaginally (2.10%) (HR = 1.12; 95% confidence interval [95% CI] = 1.08-1.16). This was equivalent to one extra case of AR in 383 children followed up in our study. AR was also associated with moderately preterm birth (>= 32-36 weeks of gestation: HR = 1.12, 95% CI = 1.04-1.20), large for gestational age (HR = 1.05, 95% CI = 1.01-1.10), and low (<7) 5-minute Apgar score (HR = 1.15, 95% CI = 1.02-1.30). Similar risk estimates were obtained when we restricted the outcome to >= 2 hospital-based records of AR. No association was observed between very preterm birth, post-term birth, low birthweight, or small for gestational age and AR. Conclusion Our study indicates an association between pregnancy outcomes and childhood AR, although observed effect sizes were generally modest.
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37.
  • Mitselou, Niki, 1982-, et al. (författare)
  • Cesarean delivery, preterm birth, and risk of food allergy : Nationwide Swedish cohort study of more than 1 million children
  • 2018
  • Ingår i: Journal of Allergy and Clinical Immunology. - Stockholm : Elsevier. - 0091-6749 .- 1097-6825. ; 142:5, s. 1510-1514e.2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Little is known about early-life risk factors for food allergy in children.Objectives: We examined the association between perinatal characteristics and future risk of food allergy in offspring.Methods: This nationwide Swedish cohort study of 1,086,378 children born in Sweden in 2001-2012 used prospectively recorded data from health care registers. Using Cox regression, we estimated hazard ratios (HRs) with 95% CIs for the association between perinatal characteristics (eg, cesarean delivery and preterm birth) and food allergy as defined by diagnoses in the National Patient Register, adjusting for infant sex and maternal factors (age at delivery, country of birth, parity, smoking, body mass index, and asthma/pulmonary disease).Results: During the 13-year follow-up, 26,732 (2.5%) children were given a diagnosis of food allergy. Food allergy was positively associated with cesarean delivery (HR, 1.21; 95% CI, 1.18-1.25), large for gestational age (HR, 1.15; 95% CI, 1.10-1.19), and low 5-minute Apgar score (HR, 1.22; 95% CI, 1.10-1.36) but negatively associated with very preterm birth (<32 weeks of gestation: HR, 0.74; 95% CI, 0.56-0.98). No association was found between food allergy and moderately preterm birth, low birth weight, or small for gestational age. Risk estimates were similar when the outcome was restricted to 2 records of diagnosed food allergy. In 1,000 children undergoing cesarean delivery, an extra 5 developed food allergy compared with the reference group, suggesting that 17% of food allergy in children born by means of cesarean delivery can be explained by this exposure (attributable fraction).Conclusions: Cesarean delivery was associated with increased risk of food allergy, whereas very preterm birth decreased risk.
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38.
  • Mogensen, Ida, et al. (författare)
  • Lung function before and after COVID-19 in young adults : A population-based study.
  • 2022
  • Ingår i: The journal of allergy and clinical immunology. Global. - : University of Wisconsin Press. - 2772-8293. ; 1:2, s. 37-42
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: There is limited evidence on the long-term impact of mild-to-moderate coronavirus disease 2019 (COVID-19) on lung function among young adults.OBJECTIVES: We aimed to assess whether COVID-19 has a negative impact on lung function in young adults and whether asthma, allergic sensitization, or use of inhaled corticosteroids (ICSs) modifies a potential association.METHODS: Participants from the population-based BAMSE (Barn, Allergi, Miljö, Stockholm, Epidemiologi) cohort with spirometry assessed before (2016-2019) and after onset of the COVID-19 pandemic (2020-2021) were included. Serum levels of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain-specific IgG, IgM, and/or IgA (determined with ELISA) defined seropositivity. Mean change in lung function (ie, change in FEV1, forced vital capacity [FVC], and FEV1/FVC ratio expressed as percent of predicted [pp]) from before to after onset of the pandemic were compared between the seronegative and seropositive participants. In seropositive participants, change in lung function was assessed in relation to allergic sensitization and self-reported ICS use.RESULTS: Of the 853 included participants, 29% (n = 243) were seropositive. There were no differences in change in lung function between the seronegative and seropositive participants (for mean change in FEV1 pp [SD], seropositivity = 0.87% [4.79%] and seronegativity = 1.03% (4.76%) [P = .66] for difference using a t test; FVC pp (SD), seropositivity = 1.34% (4.44%) and seronegativity = 1.29% (4.27%) [P = .87]; and for FEV1/FVC pp (SD), seropositivity = -0.25% (3.13%) and seronegativity = -0.13% (3.15%) [P = .61]). Similar results were observed among participants with asthma (n = 147 [17%]). Among seropositive participants, allergic sensitization or ICS use did not influence lung function.CONCLUSION: We found no evidence of mild-to-moderate COVID-19 affecting lung function long term in a population-based cohort of young adults. Moreover, neither asthma nor allergic sensitization nor ICS use affected the results.
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39.
  • Mohlkert, Lilly-Ann, et al. (författare)
  • Lung function and pulmonary vascular resistance are not associated in 6-year-old children born extremely preterm
  • 2020
  • Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 109:4, s. 746-753
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Children born preterm are at increased risk of reduced lung function. The aim was to test whether lung function was associated with pulmonary vascular resistance.Methods: Participants were recruited from a population-based cohort born in 2004-2007. Lung function was assessed with spirometry after administration of a beta2-agonist. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were determined. Estimations of pulmonary vascular resistance, arterial dimensions, right ventricular wall thickness, sphericity, and systolic (TAPSE) and diastolic functions were performed with echocardiography. Adjusted regression analyses were used to study associations.Results: Sixty-six children (33 boys) born at 22-26 weeks of gestational age (birthweights 460-1134 g) were assessed at a mean age of 6.7 years. Despite large variations in lung function with FVCz-scores ranging from -4.6 to +2.8, there were no associations between lung function and pulmonary arterial pressure, right ventricular structure or function. Children with higher FVCz-scores (r = .52, beta = .55 mm,P = .015) and higher FEV(1)z-scores (r = .58, beta = .73 mm,P = .001) exhibited larger pulmonary arteries.Conclusion: In children born extremely preterm, lung function was not associated with pulmonary vascular resistance. Routine echocardiographic evaluation of extremely preterm children may not be indicated at age 6.5 years.
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40.
  • Mohlkert, Lilly -Ann, et al. (författare)
  • Preterm arteries in childhood : dimensions, intima-media thickness, and elasticity of the aorta, coronaries, and carotids in 6-y-old children born extremely preterm
  • 2017
  • Ingår i: Pediatric Research. - : NATURE PUBLISHING GROUP. - 0031-3998 .- 1530-0447. ; 81:2, s. 299-306
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Preterm birth increases risk for adult cardiovascular disease. We hypothesized that arteries in 6-y-old children born preterm are narrower, with thicker intima-media and stiffer than in peers born at term. METHODS: Children born extremely preterm (EXP, n = 176, birthweights: 348-1,161 g) and at term (CTRL, n = 174, birth weights: 2,430-4,315 g) were included. Using ultrasonography, we determined diameters of the coronaries (CA), common carotid arteries (CCA) and aorta, the carotid intima media thickness (CIMT), and the stiffness index of the CCA and aorta. RESULTS: Arteries were 5-10% narrower in EXP than in CTRL (P < 0.005) but after adjustment for body surface area, diameter differences diminished or disappeared. EXP-children born small for gestational age exhibited similar arterial dimensions as those born appropriate for date. The cIMT was 0.38 (SD = 0.04) mm and did not differ between groups. Carotid but not aortic stiffness was lower in EXP than in CTRL. CONCLUSION: In 6-y-old children born extremely preterm, conduit arteries are of similar or smaller size than in controls born at term, and they have no signs of accelerated intima media thickening or arterial stiffening. While these findings are reassuring for these children and their families, the causal pathways from preterm birth to adult cardiovascular disease remain unknown.
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41.
  • Mohlkert, Lilly-Ann, et al. (författare)
  • Right Heart Structure, Geometry and Function Assessed by Echocardiography in 6-Year-Old Children Born Extremely Preterm-A Population-Based Cohort Study
  • 2021
  • Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Preterm birth has been associated with altered cardiac phenotype in adults. Our aim was to test the hypothesis that children surviving extremely preterm birth have important structural or functional changes of the right heart or pulmonary circulation. We also examined relations between birth size, gestational age, neonatal diagnoses of bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA) with cardiac outcomes. We assessed a population-based cohort of children born in Sweden before 27 weeks of gestation with echocardiography at 6.5 years of age (n = 176). Each preterm child was matched to a healthy control child born at term. Children born preterm had significantly smaller right atria, right ventricles with smaller widths, higher relative wall thickness and higher estimated pulmonary vascular resistance (PVR) than controls. In preterm children, PVR and right ventricular myocardial performance index (RVmpi') were significantly higher in those with a PDA as neonates than in those without PDA, but no such associations were found with BPD. In conclusion, children born extremely preterm exhibit higher estimated PVR, altered right heart structure and function compared with children born at term.
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42.
  • Mohlkert, Lilly-Ann, et al. (författare)
  • The Preterm Heart in Childhood : Left Ventricular Structure, Geometry, and Function Assessed by Echocardiography in 6-Year-Old Survivors of Periviable Births
  • 2018
  • Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 7:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Preterm birth has been associated with increased risk of cardiovascular morbidity in adult life. We evaluated whether preterm birth is associated with deviating cardiac structure and function before school start. Methods and Results: In total, 176 children aged 6 years and born extremely preterm (EXPT; gestational age of 22-26weeks) and 134 children born at term (control [CTRL]) were studied. We used echocardiography to assess left heart dimensions, geometry, and functions. Recording and off-line analyses of echocardiographic images were performed by operators blinded to group belonging. Body size, blood pressure, and heart rate were also measured. Rates of family history of cardiovascular disease and sex distribution were similar in the EXPT and CTRL groups. Heart rate and systolic blood pressure did not differ, whereas diastolic blood pressure was slightly higher in EXPT than CTRL participants. After adjusting for body surface area, left ventricular length, width, and aortic valve annulus diameter were 3% to 5% smaller in EXPT than CTRL participants. Left ventricular longitudinal shortening and systolic tissue velocity were 7% to 11% lower, and transversal shortening fraction was 6% higher in EXPT than CTRL participants. The EXPT group also exhibited lower atrial emptying velocities than the CTRL group. Sex, fetal growth restriction, or a patent ductus arteriosus in the neonatal period did not contribute to cardiac dimensions or performance. Conclusions: Six-year-old children born extremely preterm exhibit a unique cardiac phenotype characterized by smaller left ventricles with altered systolic and diastolic functions than same-aged children born at term.
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43.
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44.
  • Norman, Elisabeth, et al. (författare)
  • Individual variations in fentanyl pharmacokinetics and pharmacodynamics in preterm infants
  • 2019
  • Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 108:8, s. 1441-1446
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim Fentanyl pharmacokinetics and pharmacodynamics are lacking in preterm infants. Our aim was to study these and their relation with a new formulation of fentanyl 5 mu g/mL for procedural pain. Methods Preterm infants were given 0.5 (n = 20, median gestational age 26.5; range 23.3-34.1 weeks) and 2 mu g/kg (n = 8, 27.4; 25.3-30.7 weeks) fentanyl, respectively, before skin-breaking procedures or tracheal intubation. Blood samples were collected after ten minutes, two, four, eight and 24 hours. Physiologic parameters were monitored and pain scores assessed. Results The median fentanyl concentrations were 0.18, 0.15, 0.15 and 0.57, 0.37, 0.35 ng/mL at 15-31 minutes, two and four hours and the half-lives were 1.6 to 20.5 or 4.1 to 32.6 hours for the low- and high-dose groups, respectively. A significant correlation was seen between weight at study inclusion and half-life (Spearman ' s r = -0.9, p < 0.001), volume of distribution (r = -0.8, p < 0.01) and clearance (r = -0.9, p < 0.01) in the low-dose group (n = 9). Pain assessment results were not correlated to pharmacokinetic variables. Fentanyl was well tolerated. Conclusion The inter-individual variation of fentanyl pharmacokinetics is large in preterm infants, and the dose of 0.5 mu g/kg seems not effective for skin-breaking procedures.
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45.
  • Panasevich, Sviatlana, et al. (författare)
  • Investigation of novel genes for lung function in children and their interaction with tobacco smoke exposure : a preliminary report.
  • 2013
  • Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 102:5, s. 498-503
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: To replicate newly reported single nucleotide polymorphism (SNP) associations with adult lung function in a cohort of children and to investigate interactions with tobacco smoke exposure on lung function.METHODS: Of 37 reported SNPs in adults, 21 were available in our genome-wide association study data set, either directly genotyped or as proxy SNPs. We tested for association with lung function (FEV1 , FVC, FEV1 /FVC%) in 8-year-old children and analysed interaction with tobacco smoke exposure both prenatally and/or during infancy, as well as at the age of 8 years.RESULTS: SNPs in TNS1, ADAM19, THSD4 and ADCY2 showed significant association with lung function in children, although ADCY2 variants not in the expected direction. For example, variant allele A in THSD4 rs12899618 was associated with 50.2 mL higher FEV1 (p = 0.007) and variant allele C in ADAM19 rs2277027 with 1% unit lower FEV1 /FVC% (p = 0.03) per allele. DAAM2 rs2395730 showed interaction with current tobacco smoke exposure, with variant C allele associated with 1.3% unit decrease in FEV1 /FVC% in exposed children, but not in unexposed (p for interaction 0.04).CONCLUSION: Our data replicate in children an association for TNS1, ADAM19, THSD4 and ADCY2 gene variants with lung function and suggest that interaction with tobacco smoke exposure may be of importance.
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46.
  • Rebbeck, Timothy R., et al. (författare)
  • Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women
  • 2016
  • Ingår i: Breast Cancer Research. - : Springer Science and Business Media LLC. - 1465-5411 .- 1465-542X. ; 18:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood. Methods: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2. Results: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC. Conclusions: Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
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47.
  • Rydberg, Tomas, 1962, et al. (författare)
  • Emissions of additives from plastics in the societal material stock – a case study for Sweden
  • 2012
  • Ingår i: Handbook of Environmental Chemistry. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 1867-979X. ; 18, s. 253-264, s. 253-264
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
    • Estimating the size of the problems related to release, fate, exposure and effects from the human use of chemical substances in materials and consumer products is daunting. More than 100,000 chemical substances are in commercial use and a reasonable description of their existence in, and release from, plastic polymers, glues, paints, fibres, lubricants etc. comprise a big challenge. Here we report the initial results from a generic emission model that has been developed and applied to estimate emissions of a set of organic chemicals from products. The scope of the study was to estimate emissions from products containing plastic materials during their average lifetime within the geographical boundaries of Sweden. The results show that approximately 2% of the plastic additives are emitted annually. Plasticisers, flame retardants, organic pigments and stabilizers are the use categories of additives that are emitted in the largest quantities. Until now, the method has only been used to estimate emissions of additives from plastic materials, but it is believed to also be applicable to other materials.
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48.
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49.
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50.
  • Sdona, Emmanouela, et al. (författare)
  • Dietary antioxidant intake in school age and lung function development up to adolescence
  • 2020
  • Ingår i: European Respiratory Journal. - : EUROPEAN RESPIRATORY SOC JOURNALS LTD. - 0903-1936 .- 1399-3003. ; 55:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Dietary antioxidant intake has been hypothesised to influence lung function. The association between total antioxidant capacity (TAC) of the diet at age 8 years and lung function development up to 16 years in 2307 participants from the Swedish population-based birth cohort BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiology) was investigated. Information on TAC was obtained from a food frequency questionnaire at 8 years. Lung function was measured by spirometry at 8 and 16 years, impulse oscillometry (IOS) and exhaled nitric oxide fraction (F-eNO) at 16 years. Low lung function was defined as forced expiratory volume in 1 s (FEV1) z-score below the 25th percentile. Longitudinal associations between TAC and lung function were analysed by mixed effect models adjusted for potential confounders. Stratification by asthma at 8 years was performed to examine effect modification. The median TAC intake was 10 067 mu mol Trolox equivalents (TE).g(-1), with males having a lower mean compared to females (9963 versus 10819 mu mol TE.g(-1)). In analyses of lung function change between 8 and 16 years, there were no statistically significant associations between TAC in tertiles and spirometry results for the total study population. Among children with asthma at 8 years (prevalence 7%), higher TAC was associated with higher mean FEV1 (0.46 SD, 95% CI 0.11-0.80) and decreased odds of low lung function at 16 years (OR 0.28, 95% CI 0.12-0.65). There were no associations between TAC and forced vital capacity or IOS/F-eNO results. High dietary antioxidant intake in school age may be associated with improved lung function development from school age to adolescence among children with asthma.
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