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Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort.

Sat, 01/20/2018 - 14:59

Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort.

Diabetologia. 2018 Jan 18;:

Authors: Shi L, Brunius C, Lehtonen M, Auriola S, Bergdahl IA, Rolandsson O, Hanhineva K, Landberg R

Abstract
AIMS/HYPOTHESIS: The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction.
METHODS: We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case-control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case-control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index.
RESULTS: We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors.
CONCLUSIONS/INTERPRETATION: Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.

PMID: 29349498 [PubMed - as supplied by publisher]

Effect of deliberation on the public's attitudes toward consent policies for biobank research.

Sat, 01/20/2018 - 14:59

Effect of deliberation on the public's attitudes toward consent policies for biobank research.

Eur J Hum Genet. 2018 Jan 18;:

Authors: Tomlinson T, De Vries RG, Kim HM, Gordon L, Ryan KA, Krenz CD, Jewell S, Kim SYH

Abstract
In this study, we evaluate the effect of education and deliberation on the willingness of members of the public to donate tissue to biobank research and on their attitudes regarding various biobank consent policies. Participants were randomly assigned to a democratic deliberation (DD) group, an education group that received only written materials, and a control group. Participants completed a survey before the deliberation and two surveys post-deliberation: one on (or just after) the deliberation day, and one 4 weeks later. Subjects were asked to rate 5 biobank consent policies as acceptable (or not) and to identify the best and worst policies. Analyses compared acceptability of different policy options and changes in attitudes across the three groups. After deliberation, subjects in the DD group were less likely to find broad consent (defined here as consent for the use of donations in an unspecified range of future research studies, subject to content and process restrictions) and study-by-study consent acceptable. The DD group was also significantly less likely to endorse broad consent as the best policy (OR = 0.34), and more likely to prefer alternative consent options. These results raise ethical challenges to the current widespread reliance on broad consent in biobank research, but do not support study-by-study consent.

PMID: 29348694 [PubMed - as supplied by publisher]

Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers.

Sat, 01/20/2018 - 14:59

Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers.

Oncogene. 2018 Jan 19;:

Authors: Kotani H, Adachi Y, Kitai H, Tomida S, Bando H, Faber AC, Yoshino T, Voon DC, Yano S, Ebi H

Abstract
BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.

PMID: 29348459 [PubMed - as supplied by publisher]

Quantitative analysis of ChIP-seq data uncovers dynamic and sustained H3K4me3 and H3K27me3 modulation in cancer cells under hypoxia.

Sat, 01/20/2018 - 14:59
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Quantitative analysis of ChIP-seq data uncovers dynamic and sustained H3K4me3 and H3K27me3 modulation in cancer cells under hypoxia.

Epigenetics Chromatin. 2016;9:48

Authors: Adriaens ME, Prickaerts P, Chan-Seng-Yue M, van den Beucken T, Dahlmans VEH, Eijssen LM, Beck T, Wouters BG, Voncken JW, Evelo CTA

Abstract
BACKGROUND: A comprehensive assessment of the epigenetic dynamics in cancer cells is the key to understanding the molecular mechanisms underlying cancer and to improving cancer diagnostics, prognostics and treatment. By combining genome-wide ChIP-seq epigenomics and microarray transcriptomics, we studied the effects of oxygen deprivation and subsequent reoxygenation on histone 3 trimethylation of lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in a breast cancer cell line, serving as a model for abnormal oxygenation in solid tumors. A priori, epigenetic markings and gene expression levels not only are expected to vary greatly between hypoxic and normoxic conditions, but also display a large degree of heterogeneity across the cell population. Where traditionally ChIP-seq data are often treated as dichotomous data, the model and experiment here necessitate a quantitative, data-driven analysis of both datasets.
RESULTS: We first identified genomic regions with sustained epigenetic markings, which provided a sample-specific reference enabling quantitative ChIP-seq data analysis. Sustained H3K27me3 marking was located around centromeres and intergenic regions, while sustained H3K4me3 marking is associated with genes involved in RNA binding, translation and protein transport and localization. Dynamic marking with both H3K4me3 and H3K27me3 (hypoxia-induced bivalency) was found in CpG-rich regions at loci encoding factors that control developmental processes, congruent with observations in embryonic stem cells.
CONCLUSIONS: In silico-identified epigenetically sustained and dynamic genomic regions were confirmed through ChIP-PCR in vitro, and obtained results are corroborated by published data and current insights regarding epigenetic regulation.

PMID: 27822313 [PubMed - indexed for MEDLINE]

A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis.

Fri, 01/19/2018 - 12:47

A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis.

Hum Mol Genet. 2018 Jan 16;:

Authors: Munz M, Willenborg C, Richter GM, Jockel-Schneider Y, Graetz C, Staufenbiel I, Wellmann J, Berger K, Krone B, Hoffmann P, van der Velde N, Uitterlinden AG, de Groot LCPGM, Sawalha AH, Direskeneli H, Saruhan-Direskeneli G, Guzeldemir-Akcakanat E, Keceli HG, Laudes M, Noack B, Teumer A, Holtfreter B, Kocher T, Eickholz P, Meyle J, Doerfer C, Bruckmann C, Lieb W, Franke A, Schreiber S, Nohutcu RM, Erdmann J, Loos BG, Jepsen S, Dommisch H, Schaefer AS

PMID: 29346566 [PubMed - as supplied by publisher]

Involvement of breast cancer stem cells in tumor angiogenesis.

Fri, 01/19/2018 - 12:47
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Involvement of breast cancer stem cells in tumor angiogenesis.

Oncol Lett. 2017 Dec;14(6):8150-8155

Authors: Wang Y, Li C, Li Y, Zhu Z

Abstract
The aim of the present study was to investigate the role of breast cancer stem cells (BCSCs) in the angiogenesis of breast cancer tumors. The expression levels of mutant p53, cluster of differentiation (CD)31, vascular endothelial factor (VEGF), in addition to human epidermal growth factor (HER)2, were detected in the blood vessels of human breast cancer (BC) tissue samples. CD44+/CD24-/low cells were selected from single-cell suspensions of BC tissues to assess the expression of CD31 and CD105, in addition to the ability of these cells to metabolize acetylated low-density lipoprotein (Ac-LDL). Furthermore, vascular-like structures were observed histologically. Mutant p53, CD31 and VEGF were all expressed in these tissues. CD44+ cells comprised 7.5±2.6 and 94.3±4.7% of the cell population prior to and following sorting, respectively. CD24+ cells comprised 48.2±9.4 and 4.3±4% of the cell population prior to and following sorting, respectively. A low proportion of CD24+ cells corresponded to a high proportion of CD24-/low cells. The percentages of CD105+ and CD31+ glomus cells in the mammary gland were 4.5±0.9 and 6.2±1.3%, respectively, and following passaging for three generations, these increased to 79.6±9.3 and 84.1±10.7%, respectively (P<0.05). Cells were cultured using an endothelial cell culture system, and they internalized DiL-Ac-LDL. Here, vascular endothelial cells formed vascular-like structures, whereas the control group demonstrated no such structures. Overall, the results suggest that BCSCs-derived endothelial cells may contribute to tumor angiogenesis.

PMID: 29344258 [PubMed]

An oncogenic function of retinoic acid receptor-α in the development of laryngeal squamous cell carcinoma.

Fri, 01/19/2018 - 12:47
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An oncogenic function of retinoic acid receptor-α in the development of laryngeal squamous cell carcinoma.

Oncol Lett. 2017 Dec;14(6):7896-7902

Authors: Cai CF, Liu CS, Shang-Guan HJ, Yang CH, Luo XY, Shen DY, Yang SY

Abstract
The aberrant expression of retinoic acid receptor-α (RARα) has been reported in various types of cancer. However, its association with the prognosis and development of laryngeal squamous cell carcinoma (LSCC) has not yet been determined. Therefore, the present study aimed to examine the expression and function of RARα in patients with LSCC. The expression of RARα in LSCC tissues was investigated using immunostaining. An MTT assay and flow cytometry analysis were also performed to investigate the function of RARα in the proliferation and cell cycle of LSCC cells. The expression of RARα was significantly elevated in LSCC tissues compared with adjacent noncancerous tissues (78.1 vs. 6.3%, P<0.05). The overexpression of RARα was associated with poorly differentiated features of LSCC (P<0.05). Furthermore, the downregulation of RARα inhibited the proliferation of LSCC cells, and arrested the cell cycle at the G1 phase via upregulation of cyclin dependent kinase inhibitor 1A, which may be associated with inhibition of the protein kinase B signaling pathway. Therefore, the overexpression of RARα may contribute to the development of LSCC through the regulation of the cell cycle. The results of the present study provide evidence that RARα serves an important function in LSCC development and may be a potential therapeutic target or prognostic predictor for LSCC.

PMID: 29344234 [PubMed]

Smoking affects the interferon beta treatment response in multiple sclerosis.

Fri, 01/19/2018 - 12:47
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Smoking affects the interferon beta treatment response in multiple sclerosis.

Neurology. 2018 Jan 17;:

Authors: Petersen ER, Oturai AB, Koch-Henriksen N, Magyari M, Sørensen PS, Sellebjerg F, Søndergaard HB

Abstract
OBJECTIVE: To investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)-DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 (NAT1) variant rs7388368A.
METHODS: DNA from 834 IFN-β-treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.
RESULTS: We found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021-1.416, p = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056-1.537, p = 0.012). We found no association or interaction with HLA and the NAT1 variant.
CONCLUSION: In this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.

PMID: 29343473 [PubMed - as supplied by publisher]

Retrospectively assessed psychosocial working conditions as predictors of prospectively assessed sickness absence and disability pension among older workers.

Fri, 01/19/2018 - 12:47
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Retrospectively assessed psychosocial working conditions as predictors of prospectively assessed sickness absence and disability pension among older workers.

BMC Public Health. 2018 Jan 17;18(1):149

Authors: Sundstrup E, Hansen ÅM, Mortensen EL, Poulsen OM, Clausen T, Rugulies R, Møller A, Andersen LL

Abstract
BACKGROUND: The aim was to explore the association between retrospectively assessed psychosocial working conditions during working life and prospectively assessed risk of sickness absence and disability pension among older workers.
METHODS: The prospective risk of register-based long-term sickness absence (LTSA) and disability pension was estimated from exposure to 12 different psychosocial work characteristics during working life among 5076 older workers from the CAMB cohort (Copenhagen Aging and Midlife Biobank). Analyses were censored for competing events and adjusted for age, gender, physical work environment, lifestyle, education, and prior LTSA.
RESULTS: LTSA was predicted by high levels of cognitive demands (HR 1.31 (95% CI 1.10-1.56)), high levels of emotional demands (HR 1.26 (95% CI 1.07-1.48)), low levels of influence at work (HR 1.30 (95% CI 1.03-1.64)), and high levels of role conflicts (HR 1.34 (95% CI 1.09-1.65)). Disability pension was predicted by low levels of influence at work (HR 2.73 (95% CI 1.49-5.00)) and low levels of recognition from management (HR 2.04 (95% CI 1.14-3.67)).
CONCLUSIONS: This exploratory study found that retrospectively assessed high cognitive demands, high and medium emotional demands, low influence at work, low recognition from management, medium role clarity, and high role conflicts predicted LTSA and/or disability pension.

PMID: 29343243 [PubMed - in process]

Overexpression of regulator of G protein signaling 11 promotes cell migration and associates with advanced stages and aggressiveness of lung adenocarcinoma.

Fri, 01/19/2018 - 12:47
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Overexpression of regulator of G protein signaling 11 promotes cell migration and associates with advanced stages and aggressiveness of lung adenocarcinoma.

Oncotarget. 2016 May 24;7(21):31122-36

Authors: Yang SH, Li CF, Chu PY, Ko HH, Chen LT, Chen WW, Han CH, Lung JH, Shih NY

Abstract
Regulator of G protein signaling 11 (RGS11), a member of the R7 subfamily of RGS proteins, is a well-characterized GTPase-accelerating protein that is involved in the heterotrimeric G protein regulation of the amplitude and kinetics of receptor-promoted signaling in retinal bipolar and nerve cells. However, the role of RGS11 in cancer is completely unclear. Using subtractive hybridization analysis, we found that RGS11 was highly expressed in the lymph-node metastatic tissues and bone-metastatic tumors obtained from patients with lung adenocarcinoma. Characterization of the clinicopathological features of 91 patients showed that around 57.1% of the tumor samples displayed RGS11 overexpression that was associated with primary tumor status, nodal metastasis and increased disease stages. Its high expression was an independent predictive factor for poor prognosis of these patients. Cotransfection of guanine nucleotide-binding protein beta-5 (GNB5) markedly increased RGS11 expression. Enhancement or attenuation of RGS11 expression pinpointed its specific role in cell migration, but not in cell invasion and proliferation. Signaling events initiated by the RGS11-GNB5 coexpression activated the c-Raf/ERK/FAK-mediated pathway through upregulation of the Rac1 activity. Consistently, increasing the cell invasiveness of the transfectants by additional cotransfection of the exogenous urokinase-plasminogen activator gene caused a significant promotion in cell invasion in vitro and in vivo, confirming that RGS11 functions in cell migration, but requires additional proteolytic activity for cell and tissue invasion. Collectively, overexpression of RGS11 promotes cell migration, participates in tumor metastasis, and correlates the clinicopathological conditions of patients with lung adenocarcinoma.

PMID: 27105500 [PubMed - indexed for MEDLINE]

Human teeth biobank: Microbiological analysis of the teeth storage solution.

Thu, 01/18/2018 - 13:33

Human teeth biobank: Microbiological analysis of the teeth storage solution.

Microsc Res Tech. 2018 Jan 17;:

Authors: Curylofo-Zotti FA, Lorencetti-Silva F, de Almeida Coelho J, Monteiro RM, Watanabe E, Corona SAM

Abstract
The cross-infections may occur during handling of dental elements, affecting the health of dental practitioners and researchers. This study aimed to analyze the influence of the storage medium temperature on the bacterial contingent of the human teeth used for research purposes. Thirty human teeth were donated to the Human Teeth Biobank immediately after extraction. The teeth were cleaned with tap water and neutral soap. The teeth were randomly distributed according to the temperature of the storage solution (deionized water): at 4 °C (refrigerator) or at -10 °C (freezer) and were stored individually in sterile vials during 60 days. After this period, a microbiological analysis (CFU/mL) of the storage solutions was performed and teeth were submitted to SEM analysis. Data were analyzed by Kruskal-Wallis test followed by Dunn's post-test (p ≤ .05). Total aerobic bacteria ranged from 5.8 to 8.4 log10 CFU/mL for refrigerated solution and from 1.9 to 8.5 log10 CFU/mL for frozen solution. No statistical differences were found between the storage solutions (p > .05). The counts of Streptococcus spp., Lactobacillus spp., and Staphylococcus spp. were similar for both storage solutions (p > .05). SEM analysis showed spiral- and rod-shaped bacteria attached on teeth stored under 4 °C, which may suggest the presence of Treponema spp. and Lactobacillus spp. Similar morphological forms were found on teeth stored under -10 °C. A biofilm organized in honeycomb-like form was found in the frozen teeth. Cocci were eventually found in all the samples. It was concluded that bacterial growth and survival were not influenced by the temperature of the teeth storage solution.

PMID: 29341338 [PubMed - as supplied by publisher]

Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study.

Thu, 01/18/2018 - 13:33
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Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density: Mendelian Randomization Study.

J Bone Miner Res. 2018 Jan 16;:

Authors: Larsson SC, Melhus H, Michaëlsson K

Abstract
There is considerable discussion of the importance for increased serum 25-hydroxyvitamin D (S-25OHD) concentration associated with adequacy for bone health. Accordingly, whether long-term high S-25OHD concentration in general positively affects bone mineral density (BMD) is uncertain. We used a Mendelian randomization design to determine the association between genetically increased S-25OHD concentrations and BMD. Five single-nucleotide polymorphisms (SNPs) in or near genes encoding enzymes and carrier proteins involved in vitamin D synthesis or metabolism were used as instrumental variables to genetically predict one standard deviation increase in S-25OHD concentration. Summary statistics data for the associations of the S-25OHD-associated SNPs with DXA-derived femoral neck and lumbar spine BMD were obtained from the GEnetic Factors for OSteoporosis Consortium (32,965 individuals) and ultrasound-derived heel estimated BMD from the UK Biobank (142,487 individuals). None of the SNPs was associated with BMD at Bonferroni-corrected significance level but there was a suggestive association between rs6013897 near CYP24A1 and femoral neck BMD (p = 0.01). In Mendelian randomization analysis, genetically predicted one standard deviation increment of S-25OHD was not associated with higher femoral neck BMD (standard deviation change in BMD 0.02; 95% CI, -0.03 to 0.07; p = 0.37), lumbar spine BMD (standard deviation change in BMD 0.02; 95% CI, -0.04 to 0.08; p = 0.49), or estimated BMD (g/cm2 change in BMD -0.03; 95% CI, -0.05 to -0.01; p = 0.02). This study does not support a causal association between long-term elevated S-25OHD concentrations and higher BMD in in generally healthy populations. These results suggest that more emphasis should be placed on the development of evidence-based cutoff points for vitamin D inadequacy rather than a general recommendation to increase S-25OHD. This article is protected by copyright. All rights reserved.

PMID: 29338102 [PubMed - as supplied by publisher]

Women's reproductive factors and incident cardiovascular disease in the UK Biobank.

Thu, 01/18/2018 - 13:33
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Women's reproductive factors and incident cardiovascular disease in the UK Biobank.

Heart. 2018 Jan 15;:

Authors: Peters SA, Woodward M

Abstract
BACKGROUND: Studies have suggested that women's reproductive factors are associated with the risk of cardiovascular disease (CVD); however, findings are mixed. We assessed the relationship between reproductive factors and incident CVD in the UK Biobank.
METHODS: Between 2006 and 2010, the UK Biobank recruited over 500 000 participants aged 40-69 years across the UK. During 7 years of follow-up, 9054 incident cases of CVD (34% women), 5782 cases of coronary heart disease (CHD) (28% women), and 3489 cases of stroke (43% women) were recorded among 267 440 women and 215 088 men without a history of CVD at baseline. Cox regression models yielded adjusted hazard ratios (HRs) for CVD, CHD and stroke associated with reproductive factors.
RESULTS: Adjusted HRs (95% CI) for CVD were 1.10 (1.01 to 1.30) for early menarche (<12 years), 0.97 (0.96 to 0.98) for each year increase in age at first birth, 1.04 (1.00 to 1.09) for each miscarriage, 1.14 (1.02 to 1.28) for each stillbirth, and 1.33 (1.19 to 1.49) for early menopause (<47 years). Hysterectomy without oophorectomy or with previous oophorectomy had adjusted HRs of 1.16 (1.06 to 1.28) and 2.30 (1.20 to 4.43) for CVD. Each additional child was associated with a HR for CVD of 1.03 (1.00 to 1.06) in women and 1.03 (1.02 to 1.05) in men.
CONCLUSIONS: Early menarche, early menopause, earlier age at first birth, and a history of miscarriage, stillbirth or hysterectomy were each independently associated with a higher risk of CVD in later life. The relationship between the number of children and incident CVD was similar for men and women.

PMID: 29335253 [PubMed - as supplied by publisher]

Tea and coffee consumption in relation to DNA methylation in four European cohorts.

Thu, 01/18/2018 - 13:33
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Tea and coffee consumption in relation to DNA methylation in four European cohorts.

Hum Mol Genet. 2017 Aug 15;26(16):3221-3231

Authors: Ek WE, Tobi EW, Ahsan M, Lampa E, Ponzi E, Kyrtopoulos SA, Georgiadis P, Lumey LH, Heijmans BT, Botsivali M, Bergdahl IA, Karlsson T, Rask-Andersen M, Palli D, Ingelsson E, Hedman ÅK, Nilsson LM, Vineis P, Lind L, Flanagan JM, Johansson Å, Epigenome-Wide Association Study Consortium

Abstract
Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea have been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation. To investigate if DNA methylation in blood is associated with coffee and tea consumption, we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed. After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated with men or with the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption.

PMID: 28535255 [PubMed - indexed for MEDLINE]

Cortisol, Chromogranin A, and Pupillary Responses Evoked by Speech Recognition Tasks in Normally Hearing and Hard-of-Hearing Listeners: A Pilot Study.

Thu, 01/18/2018 - 13:33
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Cortisol, Chromogranin A, and Pupillary Responses Evoked by Speech Recognition Tasks in Normally Hearing and Hard-of-Hearing Listeners: A Pilot Study.

Ear Hear. 2016 Jul-Aug;37 Suppl 1:126S-35S

Authors: Kramer SE, Teunissen CE, Zekveld AA

Abstract
Pupillometry is one method that has been used to measure processing load expended during speech understanding. Notably, speech perception (in noise) tasks can evoke a pupil response. It is not known if there is concurrent activation of the sympathetic nervous system as indexed by salivary cortisol and chromogranin A (CgA) and whether such activation differs between normally hearing (NH) and hard-of-hearing (HH) adults. Ten NH and 10 adults with mild-to-moderate hearing loss (mean age 52 years) participated. Two speech perception tests were administered in random order: one in quiet targeting 100% correct performance and one in noise targeting 50% correct performance. Pupil responses and salivary samples for cortisol and CgA analyses were collected four times: before testing, after the two speech perception tests, and at the end of the session. Participants rated their perceived accuracy, effort, and motivation. Effects were examined using repeated-measures analyses of variance. Correlations between outcomes were calculated. HH listeners had smaller peak pupil dilations (PPDs) than NH listeners in the speech in noise condition only. No group or condition effects were observed for the cortisol data, but HH listeners tended to have higher cortisol levels across conditions. CgA levels were larger at the pretesting time than at the three other test times. Hearing impairment did not affect CgA. Self-rated motivation correlated most often with cortisol or PPD values. The three physiological indicators of cognitive load and stress (PPD, cortisol, and CgA) are not equally affected by speech testing or hearing impairment. Each of them seem to capture a different dimension of sympathetic nervous system activity.

PMID: 27355762 [PubMed - indexed for MEDLINE]

Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques.

Thu, 01/18/2018 - 00:46
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Synergistic Expression of Histone Deacetylase 9 and Matrix Metalloproteinase 12 in M4 Macrophages in Advanced Carotid Plaques.

Eur J Vasc Endovasc Surg. 2017 May;53(5):632-640

Authors: Oksala NKJ, Seppälä I, Rahikainen R, Mäkelä KM, Raitoharju E, Illig T, Klopp N, Kholova I, Laaksonen R, Karhunen PJ, Hytönen VP, Lehtimäki T

Abstract
OBJECTIVE/BACKGROUND: Expression patterns and association with cell specific gene expression signatures of the epigenetic regulator histone deacetylase 9 (HDAC9) and matrix metalloproteinase 12 (MMP12) in human plaque are not known.
METHODS: This was a prospective cohort study. Genome wide expression analysis was performed in carotid, femoral, aortic plaques (n = 68) and left internal thoracic (LITA) controls (n = 28) and plaque histological severity assessed. Correlation and hierarchical cluster analysis was utilised.
RESULTS: HDAC9 was associated with MMP12 expression in carotid plaques (r = .46, p = .012) and controls (r = -.44, p = .034). HDAC9 and MMP12 clustered with inflammatory macrophage markers but not with smooth muscle cell (SMC) rich markers. In plaques from all arterial sites, MMP12 but not HDAC9 showed positive correlation (p < .05) with M2 and M4 polarized macrophage markers, and negative correlation with SMC rich signatures. In the carotid plaques, all M4 macrophage markers associated with MMP12 and HDAC9. The negative association of MMP12 with SMC rich signatures was pronounced in the carotid plaques. Neither HDAC9 nor MMP12 associated consistently with plaque stabilisation or thrombosis related genes. Immunohistochemistry further supported the association between HDAC9 and MMP12 in atherosclerotic plaques.
CONCLUSION: M4 macrophages are a possible source for HDAC9 and MMP12 expression in advanced human plaques.

PMID: 28343758 [PubMed - in process]

Isolation of Hepatocytes and Stellate Cells from a Single Piece of Human Liver.

Thu, 01/18/2018 - 00:46
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Isolation of Hepatocytes and Stellate Cells from a Single Piece of Human Liver.

Methods Mol Biol. 2017;1506:247-258

Authors: Lee SM, Schiergens TS, Demmel M, Thasler RM, Thasler WE

Abstract
Co-transplantation of hepatocytes and hepatic stellate cells has been shown to increase the engraftment of transplanted hepatocytes in the liver. Here, we describe a method for the simultaneous isolation of human primary hepatocytes and hepatic stellate cells from the same donor for co-transplantation or for use in in vitro cell culture models.

PMID: 27830558 [PubMed - in process]

Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure.

Thu, 01/18/2018 - 00:46
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Excess sphingomyelin disturbs ATG9A trafficking and autophagosome closure.

Autophagy. 2016 May 03;12(5):833-49

Authors: Corcelle-Termeau E, Vindeløv SD, Hämälistö S, Mograbi B, Keldsbo A, Bräsen JH, Favaro E, Adam D, Szyniarowski P, Hofman P, Krautwald S, Farkas T, Petersen NH, Rohde M, Linkermann A, Jäättelä M

Abstract
Sphingomyelin is an essential cellular lipid that traffics between plasma membrane and intracellular organelles until directed to lysosomes for SMPD1 (sphingomyelin phosphodiesterase 1)-mediated degradation. Inactivating mutations in the SMPD1 gene result in Niemann-Pick diseases type A and B characterized by sphingomyelin accumulation and severely disturbed tissue homeostasis. Here, we report that sphingomyelin overload disturbs the maturation and closure of autophagic membranes. Niemann-Pick type A patient fibroblasts and SMPD1-depleted cancer cells accumulate elongated and unclosed autophagic membranes as well as abnormally swollen autophagosomes in the absence of normal autophagosomes and autolysosomes. The immature autophagic membranes are rich in WIPI2, ATG16L1 and MAP1LC3B but display reduced association with ATG9A. Contrary to its normal trafficking between plasma membrane, intracellular organelles and autophagic membranes, ATG9A concentrates in transferrin receptor-positive juxtanuclear recycling endosomes in SMPD1-deficient cells. Supporting a causative role for ATG9A mistrafficking in the autophagy defect observed in SMPD1-deficient cells, ectopic ATG9A effectively reverts this phenotype. Exogenous C12-sphingomyelin induces a similar juxtanuclear accumulation of ATG9A and subsequent defect in the maturation of autophagic membranes in healthy cells while the main sphingomyelin metabolite, ceramide, fails to revert the autophagy defective phenotype in SMPD1-deficient cells. Juxtanuclear accumulation of ATG9A and defective autophagy are also evident in tissues of smpd1-deficient mice with a subsequent inability to cope with kidney ischemia-reperfusion stress. These data reveal sphingomyelin as an important regulator of ATG9A trafficking and maturation of early autophagic membranes.

PMID: 27070082 [PubMed - in process]

Lessons from ten years of genome-wide association studies of asthma.

Tue, 01/16/2018 - 12:41

Lessons from ten years of genome-wide association studies of asthma.

Clin Transl Immunology. 2017 Dec;6(12):e165

Authors: Vicente CT, Revez JA, Ferreira MAR

Abstract
Twenty-five genome-wide association studies (GWAS) of asthma were published between 2007 and 2016, the largest with a sample size of 157242 individuals. Across these studies, 39 genetic variants in low linkage disequilibrium (LD) with each other were reported to associate with disease risk at a significance threshold of P<5 × 10-8, including 31 in populations of European ancestry. Results from analyses of the UK Biobank data (n=380 503) indicate that at least 28 of the 31 associations reported in Europeans represent true-positive findings, collectively explaining 2.5% of the variation in disease liability (median of 0.06% per variant). We identified 49 transcripts as likely target genes of the published asthma risk variants, mostly based on LD with expression quantitative trait loci (eQTL). Of these genes, 16 were previously implicated in disease pathophysiology by functional studies, including TSLP, TNFSF4, ADORA1, CHIT1 and USF1. In contrast, at present, there is limited or no functional evidence directly implicating the remaining 33 likely target genes in asthma pathophysiology. Some of these genes have a known function that is relevant to allergic disease, including F11R, CD247, PGAP3, AAGAB, CAMK4 and PEX14, and so could be prioritized for functional follow-up. We conclude by highlighting three areas of research that are essential to help translate GWAS findings into clinical research or practice, namely validation of target gene predictions, understanding target gene function and their role in disease pathophysiology and genomics-guided prioritization of targets for drug development.

PMID: 29333270 [PubMed]

Examining patterns of multimorbidity, polypharmacy and risk of adverse drug reactions in chronic obstructive pulmonary disease: a cross-sectional UK Biobank study.

Tue, 01/16/2018 - 12:41

Examining patterns of multimorbidity, polypharmacy and risk of adverse drug reactions in chronic obstructive pulmonary disease: a cross-sectional UK Biobank study.

BMJ Open. 2018 Jan 14;8(1):e018404

Authors: Hanlon P, Nicholl BI, Jani BD, McQueenie R, Lee D, Gallacher KI, Mair FS

Abstract
OBJECTIVE: This study aims: (1) to describe the pattern and extent of multimorbidity and polypharmacy in UK Biobank participants with chronic obstructive pulmonary disease (COPD) and (2) to identify which comorbidities are associated with increased risk of adverse drug reactions (ADRs) resulting from polypharmacy.
DESIGN: Cross-sectional.
SETTING: Community cohort.
PARTICIPANTS: UK Biobank participants comparing self-reported COPD (n=8317) with no COPD (n=494 323).
OUTCOMES: Multimorbidity (≥4 conditions) and polypharmacy (≥5 medications) in participants with COPD versus those without. Risk of ADRs (taking ≥3 medications associated with falls, constipation, urinary retention, central nervous system (CNS) depression, bleeding or renal injury) in relation to the presence of COPD and individual comorbidities.
RESULTS: Multimorbidity was more common in participants with COPD than those without (17% vs 4%). Polypharmacy was highly prevalent (52% with COPD taking ≥5 medications vs 18% in those without COPD). Adjusting for age, sex and socioeconomic status, those with COPD were significantly more likely than those without to be prescribed ≥3 medications contributing to falls (OR 2.27, 95% CI 2.13 to 2.42), constipation (OR 3.42, 95% CI 3.10 to 3.77), urinary retention (OR 3.38, 95% CI 2.94 to 3.87), CNS depression (OR 3.75, 95% CI 3.31 to 4.25), bleeding (OR 4.61, 95% CI 3.35 to 6.19) and renal injury (OR 2.22, 95% CI 1.86 to 2.62). Concomitant cardiovascular disease was associated with the greatest risk of taking ≥3 medications associated with falls/renal injury. Concomitant mental health conditions were most strongly associated with medications linked with CNS depression/urinary retention/bleeding.
CONCLUSIONS: Multimorbidity is common in COPD and associated with high levels of polypharmacy. Co-prescription of drugs with various ADRs is common. Future research should examine the effects on healthcare outcomes of co-prescribing multiple drugs with similar potential ADRs. Clinical guidelines should emphasise assessment of multimorbidity and ADR risk.

PMID: 29332840 [PubMed - in process]