Combining [(11)C]-AnxA5 PET imaging with serum biomarkers for improved detection in live mice of modest cell death in human solid tumor xenografts

BACKGROUND: In vivo imaging using Annexin A5-based radioligands is a powerful technique for visualizing massive cell death, but has been less successful in monitoring the modest cell death typically seen in solid tumors after chemotherapy. Here we combined dynamic positron emission tomography (PET) imaging using Annexin A5 with a serum-based apoptosis marker, for improved sensitivity and specificity in assessment of chemotherapy-induced cell death in a solid tumor model. METHODOLOGY/PRINCIPAL FINDINGS: Modest cell death was induced by doxorubicin in a mouse xenograft model with human FaDu head and neck cancer cells. PET imaging was based on (11)C-labeled Sel-tagged Annexin A5 ([(11)C]-AnxA5-ST) and a size-matched control. 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]-FDG) was utilized as a tracer of tissue metabolism. Serum biomarkers for cell death were ccK18 and K18 (M30 Apoptosense® and M65). Apoptosis in tissue sections was verified ex vivo for validation. Both PET imaging using [(11)C]-AnxA5-ST and serum ccK18/K18 levels revealed treatment-induced cell death, with ccK18 displaying the highest detection sensitivity. [(18)F]-FDG uptake was not affected by this treatment in this tumor model. [(11)C]-AnxA5-ST gave robust imaging readouts at one hour and its short half-life made it possible to perform paired scans in the same animal in one imaging session. CONCLUSIONS/SIGNIFICANCE: The combined use of dynamic PET with [(11)C]-AnxA5-ST, showing specific increases in tumor binding potential upon therapy, with ccK18/K18 serum measurements, as highly sensitive markers for cell death, enabled effective assessment of modest therapy-induced cell death in this mouse xenograft model of solid human tumors.VetenskapsrådetPublishe

Gene-based meta-analysis of genome-wide association studies implicates new loci involved in obesity

To date, genome-wide association studies (GWASs) have identified >100 loci with single variants associated with body mass index (BMI). This approach may miss loci with high allelic heterogeneity; therefore, the aim of the present study was to use gene-based meta-analysis to identify regions with high allelic heterogeneity to discover additional obesity susceptibility loci. We included GWAS data from 123 865 individuals of European descent from 46 cohorts in Stage 1 and Metabochip data from additional 103 046 individuals from 43 cohorts in Stage 2, all within the Genetic Investigation of ANthropometric Traits (GIANT) consortium. Each cohort was tested for association between ∼2.4 million (Stage 1) or ∼200 000 (Stage 2) imputed or genotyped single variants and BMI, and summary statistics were subsequently meta-analyzed in 17 941 genes. We used the ‘VErsatile Gene-based Association Study’ (VEGAS) approach to assign variants to genes and to calculate gene-based P-values based on simulations. The VEGAS method was applied to each cohort separately before a gene-based meta-analysis was performed. In Stage 1, two known (FTO and TMEM18) and six novel (PEX2, MTFR2, SSFA2, IARS2, CEP295 and TXNDC12) loci were associated with BMI (P < 2.8 × 10−6 for 17 941 gene tests). We confirmed all loci, and six of them were gene-wide significant in Stage 2 alone. We provide biological support for the loci by pathway, expression and methylation analyses. Our results indicate that gene-based meta-analysis of GWAS provides a useful strategy to find loci of interest that were not identified in standard single-marker analyses due to high allelic heterogeneity

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertilit

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause

notes: PMCID: PMC3976329This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10(-9)), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.UK Medical Research CouncilWellcome Trus

DNA methylation signatures of aggression and closely related constructs : A meta-analysis of epigenome-wide studies across the lifespan

DNA methylation profiles of aggressive behavior may capture lifetime cumulative effects of genetic, stochastic, and environmental influences associated with aggression. Here, we report the first large meta-analysis of epigenome-wide association studies (EWAS) of aggressive behavior (N = 15,324 participants). In peripheral blood samples of 14,434 participants from 18 cohorts with mean ages ranging from 7 to 68 years, 13 methylation sites were significantly associated with aggression (alpha = 1.2 x 10(-7); Bonferroni correction). In cord blood samples of 2425 children from five cohorts with aggression assessed at mean ages ranging from 4 to 7 years, 83% of these sites showed the same direction of association with childhood aggression (r = 0.74, p = 0.006) but no epigenome-wide significant sites were found. Top-sites (48 at a false discovery rate of 5% in the peripheral blood meta-analysis or in a combined meta-analysis of peripheral blood and cord blood) have been associated with chemical exposures, smoking, cognition, metabolic traits, and genetic variation (mQTLs). Three genes whose expression levels were associated with top-sites were previously linked to schizophrenia and general risk tolerance. At six CpGs, DNA methylation variation in blood mirrors variation in the brain. On average 44% (range = 3-82%) of the aggression-methylation association was explained by current and former smoking and BMI. These findings point at loci that are sensitive to chemical exposures with potential implications for neuronal functions. We hope these results to be a starting point for studies leading to applications as peripheral biomarkers and to reveal causal relationships with aggression and related traits.Peer reviewe

Vit, vacker, värdefull:en kvalitativ studie av vithetsideal och dess betydelse på Bali, Indonesien.

Using interviews and observations, this qualitative study examines the value of bright and white skin in Bali, Indonesia, and how this correlates to social and economic status. The study uses a postcolonial framework to discuss the topic, but it also shows the need for a more contextual understanding of the phenomenon. Using Bourdieu’s theories of capital, I argue for how white skin in Indonesia can be understood as a form of symbolic capital, an important asset for achieving other forms of social, economic, and cultural capital. The paper starts with an introduction to the history of this value, showing the pre-colonial and traditional idealization in Indonesia, further reinforced and restructured as a result of Dutch and Japanese colonization, as well as an import of Western media. After introducing my theoretical framework, I will present my material, gathered from observations and interviews in both Bali and Sweden. The results show that beauty ideals regarding white skin are still strong and important in Bali, resulting in a discriminatory colorism, affecting people’s employment, self-esteem, and social relations. Furthermore, the study shows that these ideals affect women and men differently and that women are more judged by their skin

On the pathogenesis of glomerular lesions in the alloxan diabetic rat : a light microscopic, immunofluorescent and ultrastructural study, including the effects of insulin treatment and immunosuppression

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Ett produktionssystem under förändring : ergonomisk och teknisk utvärdering

A production system change : ergonomic and technical evaluations An evaluation of the impact of partial automation strategies on productivity and ergonomics at an electronics company was performed. This change included adoption of a serial line flow from a parallel batch flow strategy. The change process, which used both a project head group and a work organisation group, was also studied. The partial automation of assembly operations reduced the total repetitive assembly work at the system level and increased productivity. At the remaining assembly stations however, the repetitive assembly work increased due to the automation of the transportation functions and increased work-pace. The operators found the mental work load was higher in the new system. They also experienced the manual assembly station in the beginning of the line as the worst job in the system . Lack of management continuity at the department was identified as one of the largest process problems. The manager set his view on how the production and work environment goals should be met. Thus the manager set the work organisation without adopting the plan of work rotation that the work organisation group had presented. This contributed to dissatisfaction amongst the operators involved in the development process. Keywords: Automation, change process, ergonomics, manual assembly, mental workload, productivityEn ergonomisk och teknisk utvärdering genomfördes av en förändring av produktionssystemet i ett elektronikföretag som innebar en ökad automatisering. Själva förändringsprocessen utvärderades också. Automatiseringen av den manuella monteringen och transporten minskade exponeringstiden för manuell montering på systemnivå samt ökade produktiviteten. För den kvarstående manuella monteringen ökade dock repetitiviteten och ensidigheten. Montörerna upplevde också att den psykiska arbetsbelastningen var större i det nya systemet jämfört med det gamla. De ansåg också att de manuella monteringsstationerna som helhet var dåliga arbetsuppgifter. I den studerade förändringsprocessen var bristen på kontinuitet i arbetsledning ett av avdelningens huvudproblem. Arbetsledaren fick också sätta sin prägel på hur produktionsmålen skulle uppfyllas och hur arbetsförhållandena skulle utformas. Därigenom blev det arbetsledaren och inte den handlingsplan med arbetsrotation som en arbetsorganisationsgrupp utformade som avgjorde hur arbetsorganisationen utformades

The effects of GH replacement therapy on cardiac morphology and function, exercise capacity and serum lipids in elderly patients with GH deficiency.

objectives To assess effects of GH replacement therapy on cardiac structure and function, exercise capacity as well as serum lipids in elderly patients with GH deficiency (GHD). patients and methods Thirty-one patients (six females, 25 males), aged 60-79 years (mean 68 years) with GHD on stable cortisone and thyroxine substitution were studied. All men with gonadotropin deficiency had testosterone and one woman had oestrogen replacement. They were randomized in a double-blind manner to GH or placebo treatment for 6 months, followed by another 12 months GH (Humatrope, Eli Lilly & Co, Uppsala, Sweden). GH dose was 0·017 mg/kg/week for 1 month and then 0·033 mg/kg/week divided into daily subcutaneous injections at bedtime. Echocardiography, exercise capacity tests and serum lipid measurements were performed at 0, 6, 12 and 18 months. results During the 6-month placebo-controlled period there were no significant changes in the placebo group, but in the GH-treated group there was a significant increase in IGF-I to normal levels for age, with median IGF-I from 6·9 to 18·5 nmol/l, increase in resting heart rate and maximal working capacity. During the open GH study, IGF-I increased from 8·7 to 19·2 nmol/l at 6 months and 18·8 nmol/l at 12 months (P <= 0·001). At 6 months, in the open GH study group, a minor decrease in aortic outflow tract integral (VTI) from 21·8 to 20·7 cm (P = 0·031) and an increase in heart rate at rest from 63 to 67 bpm (P = 0·017), heart rate at maximum exercise from 138 to 144 bpm (P = 0·005) and maximum load at exercise from 142 to 151 Watts (P = 0·014) were seen. These changes were temporary and returned at 12 months with no significant difference from baseline values. Left ventricular dimensions and blood pressure showed no significant changes. At 6 months, in the open GH study group, there was a significant decrease in serum low-density lipoprotein (LDL) cholesterol from 3·7 to 3·4 mmol/l (P = 0·006), a decrease in LDL/HDL ratio from 3·4 to 3·1 (P = 0·036) and a decrease in serum total cholesterol from 5·6 to 5·3 mmol/l (P = 0·036). At 12 months, serum lipids showed same changes with a significant decrease in serum LDL cholesterol (P = 0·0008), in LDL/HDL ratio (P = 0·0005) and in serum total cholesterol (P = 0·049). Serum HDL cholesterol showed no significant change at 6 months, at 12 months a significant increase was seen from 1·2 to 1·4 mmol/l (P = 0·007). There were no significant changes in serum triglycerides. conclusions GH substitution to elderly patients with GHD caused only a transient increase in heart rate. At the end of the 12 months there were no significant changes on cardiac noninvasive structural and functional parameters. Maximal working capacity transiently improved. Thus, the therapy was safe without negative effects on cardiac structural and functional noninvasive parameters. Lipid profiles improved with reduction of serum LDL cholesterol accompanied by significant improvement of LDL/HDL ratio and serum HDL cholesterol after 12 months treatment