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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]

Novel leptin OB3 peptide-induced signaling and progression in thyroid cancers: Comparison with leptin.

Tue, 01/16/2018 - 12:41
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Novel leptin OB3 peptide-induced signaling and progression in thyroid cancers: Comparison with leptin.

Oncotarget. 2016 May 10;7(19):27641-54

Authors: Yang YC, Chin YT, Hsieh MT, Lai HY, Ke CC, Crawford DR, Lee OK, Fu E, Mousa SA, Grasso P, Liu LF, Chang HY, Tang HY, Lin HY, Davis PJ

Abstract
Obesity results in increased secretion of cytokines from adipose tissue and is a risk factor for various cancers. Leptin is largely produced by adipose tissue and cancer cells. It induces cell proliferation and may serve to induce various cancers. OB3-leptin peptide (OB3) is a new class of functional leptin peptide. However, its mitogenic effect has not been determined. In the present study, because of a close link between leptin and the hypothalamic-pituitary-thyroid axis, OB3 was compared with leptin in different thyroid cancer cells for gene expression, proliferation and invasion. Neither agent stimulated cell proliferation. Leptin stimulated cell invasion, but reduced adhesion in anaplastic thyroid cancer cells. Activated ERK1/2 and STAT3 contributed to leptin-induced invasion. In contrast, OB3 did not affect expression of genes involved in proliferation and invasion. In vivo studies in the mouse showed that leptin, but not OB3, significantly increased circulating levels of thyrotropin (TSH), a growth factor for thyroid cancer. In summary, OB3 is a derivative of leptin that importantly lacks the mitogenic effects of leptin on thyroid cancer cells.

PMID: 27050378 [PubMed - indexed for MEDLINE]

Sucrase-isomaltase 15Phe IBS risk variant in relation to dietary carbohydrates and faecal microbiota composition.

Mon, 01/15/2018 - 14:53

Sucrase-isomaltase 15Phe IBS risk variant in relation to dietary carbohydrates and faecal microbiota composition.

Gut. 2018 Jan 13;:

Authors: Thingholm L, Rühlemann M, Wang J, Hübenthal M, Lieb W, Laudes M, Franke A, D'Amato M

PMID: 29331942 [PubMed - as supplied by publisher]

Perceptions of legislation relating to the sharing of genomic biobank results with donors-a survey of BBMRI-ERIC biobanks.

Sun, 01/14/2018 - 14:10
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Perceptions of legislation relating to the sharing of genomic biobank results with donors-a survey of BBMRI-ERIC biobanks.

Eur J Hum Genet. 2018 Jan 12;:

Authors: Brunfeldt M, Teare H, Soini S, Kääriäinen H

Abstract
Biobanks accumulate huge amounts of research findings, including participants' genomic data. Increasingly this leads to biobanks receiving research results that could be of clinical significance to biobank participants. The EU Horizon 2020 Project 'Genetics Clinic of the Future' surveyed European biobanks' perceptions of the legal and regulatory requirements for communicating individual research results to donors. The goal was to gain background knowledge for possible future guidelines, especially relating to the consent process. The Survey was implemented using a web-based Webropol tool. The questionnaire was sent at the end of 2015 to 351 European biobanks in 13 countries that are members of BBMRI-ERIC (Biobanking and Biomolecular Resources Research Infrastructure-European Research Infrastructure Consortium). Seventy-two biobanks responded to the survey, representing each of the 13 BBMRI Member States. Respondents were mainly individuals responsible for the governance of biobanks. The replies indicate that the majority of the respondents thought that their national legislation allowed them to contact participants to communicate results, and that research participants had the right to request their results. However, respondents' understanding of their national legislation varied even within member states. Our results indicate that legislation applied to biobanks in many countries may be scattered and difficult to interpret. In BBMRI-ERIC, there is an ongoing discussion about the need for European recommendations on sharing genomic biobank results with donors, which may pave the way for more coherent global guidelines. Our results form a basis for this work.

PMID: 29330544 [PubMed - as supplied by publisher]

Seasonality of depressive symptoms in women but not in men: A cross-sectional study in the UK Biobank cohort.

Sat, 01/13/2018 - 12:41

Seasonality of depressive symptoms in women but not in men: A cross-sectional study in the UK Biobank cohort.

J Affect Disord. 2018 Jan 04;229:296-305

Authors: Lyall LM, Wyse CA, Celis-Morales CA, Lyall DM, Cullen B, Mackay D, Ward J, Graham N, Strawbridge RJ, Gill JMR, Ferguson A, Bailey MES, Pell JP, Curtis AM, Smith DJ

Abstract
BACKGROUND: We examined whether seasonal variations in depressive symptoms occurred independently of demographic and lifestyle factors, and were related to change in day length and/or outdoor temperature.
METHODS: In a cross-sectional analysis of >150,000 participants of the UK Biobank cohort, we used the cosinor method to assess evidence of seasonality of a total depressive symptoms score and of low mood, anhedonia, tenseness and tiredness scores in women and men. Associations of depressive symptoms with day length and mean outdoor temperature were then examined.
RESULTS: Seasonality of total depressive symptom scores, anhedonia and tiredness scores was observed in women but not men, with peaks in winter. In women, increased day length was associated with reduced reporting of low mood and anhedonia, but with increased reporting of tiredness, independent of demographic and lifestyle factors. Associations with day length were not independent of the average outdoor temperature preceding assessment.
LIMITATIONS: This was a cross-sectional investigation - longitudinal studies of within-subject seasonal variation in mood are necessary. Outcome measures relied on self-report and measured only a subset of depressive symptoms.
CONCLUSION: This large, population-based study provides evidence of seasonal variation in depressive symptoms in women. Shorter days were associated with increased feelings of low mood and anhedonia in women. Clinicians should be aware of these population-level sex differences in seasonal mood variations in order to aid recognition and treatment of depression and subclinical depressive symptoms.

PMID: 29329063 [PubMed - as supplied by publisher]

Human cytomegalovirus UL141 protein interacts with CELF5 and affects viral DNA replication.

Sat, 01/13/2018 - 12:41

Human cytomegalovirus UL141 protein interacts with CELF5 and affects viral DNA replication.

Mol Med Rep. 2018 Jan 10;:

Authors: Zou F, Lu ZT, Wang S, Wu S, Wu YY, Sun ZR

Abstract
Human cytomegalovirus (HCMV) infection is the primary viral cause of congenital abnormalities and mental retardation in newborns. The HCMV UL141‑encoded glycoprotein has been previously revealed to inhibit the cell‑surface expression of cluster of differentiation (CD)155, CD122, tumor necrosis factor‑related apoptosis‑inducing ligand death (TRAIL)‑receptor 1 (R1) and TRAIL‑receptor 2 (R2), thus protecting virally‑infected cells by allowing them to escape natural killer cell‑mediated cytotoxicity. The present study investigated the interaction between HCMV UL141 and human fetal brain cDNA to elucidate the possible effects of UL141 on the nervous system. The findings of the current study demonstrate that the HCMV UL141 protein directly interacts with the human protein CUGBP Elav‑like family member 5 (CELF5) via yeast two‑hybrid screening, this interaction was confirmed by glutathione S‑transferase pull‑down and co‑immunoprecipitation assays. Additionally, the present study demonstrated that the UL141 protein co‑localizes with CELF5 in the cytoplasm of 293 cells using fluorescence confocal microscopy. CELF5 overexpression in a stably‑expressing cell line significantly increased viral DNA copy number and titer in HCMV‑infected U373MG cells. However, reducing CELF5 expression via specific small interfering RNAs did not affect viral DNA copy number or titer in HCMV‑infected cells. The current findings suggest that the interaction between UL141 and CELF5 may be involved in modulating viral DNA synthesis and progeny production. Therefore, CELF5 may represent a possible mechanism for regulation of HCMV genomic DNA synthesis, which is a key step during HCMV infection leading to neurological disease.

PMID: 29328469 [PubMed - as supplied by publisher]

MicroRNA expression in SMARCB1/INI1-deficient sinonasal carcinoma: a clinicopathological and molecular genetic study.

Sat, 01/13/2018 - 12:41

MicroRNA expression in SMARCB1/INI1-deficient sinonasal carcinoma: a clinicopathological and molecular genetic study.

Virchows Arch. 2018 Jan 11;:

Authors: Laco J, Kovaříková H, Chmelařová M, Vošmiková H, Sieglová K, Baranová I, Dundr P, Němejcová K, Michálek J, Šatanková J, Vošmik M, Ryška A

PMID: 29327137 [PubMed - as supplied by publisher]

The relationship between alcohol use and long-term cognitive decline in middle and late life: a longitudinal analysis using UK Biobank.

Sat, 01/13/2018 - 12:41
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The relationship between alcohol use and long-term cognitive decline in middle and late life: a longitudinal analysis using UK Biobank.

J Public Health (Oxf). 2018 Jan 09;:

Authors: Piumatti G, Moore SC, Berridge DM, Sarkar C, Gallacher J

Abstract
Background: Using UK Biobank data, this study sought to explain the causal relationship between alcohol intake and cognitive decline in middle and older aged populations.
Methods: Data from 13 342 men and women, aged between 40 and 73 years were used in regression analysis that tested the functional relationship and impact of alcohol on cognitive performance. Performance was measured using mean reaction time (RT) and intra-individual variation (IIV) in RT, collected in response to a perceptual matching task. Covariates included body mass index, physical activity, tobacco use, socioeconomic status, education and baseline cognitive function.
Results: A restricted cubic spline regression with three knots showed how the linear (β1 = -0.048, 95% CI: -0.105 to -0.030) and non-linear effects (β2 = 0.035, 95% CI: 0.007-0.059) of alcohol use on mean RT and IIV in RT (β1 = -0.055, 95% CI: -0.125 to -0.034; β2 = 0.034, 95% CI: 0.002-0.064) were significant adjusting for covariates. Cognitive function declined as alcohol use increased beyond 10 g/day. Decline was more apparent as age increased.
Conclusions: The relationship between alcohol use and cognitive function is non-linear. Consuming more than one UK standard unit of alcohol per day is detrimental to cognitive performance and is more pronounced in older populations.

PMID: 29325150 [PubMed - as supplied by publisher]

Sample handling of gastric tissue and O-glycan alterations in paired gastric cancer and non-tumorigenic tissues.

Sat, 01/13/2018 - 12:41
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Sample handling of gastric tissue and O-glycan alterations in paired gastric cancer and non-tumorigenic tissues.

Sci Rep. 2018 Jan 10;8(1):242

Authors: Adamczyk B, Jin C, Polom K, Muñoz P, Rojas-Macias MA, Zeeberg D, Borén M, Roviello F, Karlsson NG

Abstract
Sample collection, handling and storage are the most critical steps for ensuring the highest preservation of specimens. Pre-analytical variability can influence the results as protein signatures alter rapidly after tissue excision or during long-term storage. Hence, we evaluated current state-of-the-art biobank preservation methods from a glycomics perspective and analyzed O-glycan alterations occurring in the gastric cancer tissues. Paired tumor and adjacent normal tissue samples were obtained from six patients undergoing gastric cancer surgery. Collected samples (n = 24) were either snap-frozen or heat stabilized and then homogenized. Glycans were released from extracted glycoproteins and analyzed by LC-MS/MS. In total, the relative abundance of 83 O-glycans and 17 derived structural features were used for comparison. There was no statistically significant difference found in variables between snap frozen and heat-stabilized samples, which indicated the two preservation methods were comparable. The data also showed significant changes between normal and cancerous tissue. In addition to a shift from high sialylation in the cancer area towards blood group ABO in the normal area, we also detected that the LacdiNAc epitope (N,N'-diacetyllactosamine) was significantly decreased in cancer samples. The O-glycan alterations that are presented here may provide predictive power for the detection and prognosis of gastric cancer.

PMID: 29321476 [PubMed - in process]

Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

Sat, 01/13/2018 - 12:41
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Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

Hum Mutat. 2017 Jan;38(1):78-85

Authors: Radian S, Diekmann Y, Gabrovska P, Holland B, Bradley L, Wallace H, Stals K, Bussell AM, McGurren K, Cuesta M, Ryan AW, Herincs M, Hernández-Ramírez LC, Holland A, Samuels J, Aflorei ED, Barry S, Dénes J, Pernicova I, Stiles CE, Trivellin G, McCloskey R, Ajzensztejn M, Abid N, Akker SA, Mercado M, Cohen M, Thakker RV, Baldeweg S, Barkan A, Musat M, Levy M, Orme SM, Unterländer M, Burger J, Kumar AV, Ellard S, McPartlin J, McManus R, Linden GJ, Atkinson B, Balding DJ, Agha A, Thompson CJ, Hunter SJ, Thomas MG, Morrison PJ, Korbonits M

Abstract
The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

PMID: 27650164 [PubMed - indexed for MEDLINE]

Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers.

Sat, 01/13/2018 - 12:41
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Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers.

Clin Cancer Res. 2016 Dec 15;22(24):5983-5991

Authors: Facchinetti F, Loriot Y, Kuo MS, Mahjoubi L, Lacroix L, Planchard D, Besse B, Farace F, Auger N, Remon J, Scoazec JY, André F, Soria JC, Friboulet L

Abstract
BACKGROUND: The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.
METHODS: A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.
RESULTS: Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.
CONCLUSIONS: Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983-91. ©2016 AACR.

PMID: 27401242 [PubMed - indexed for MEDLINE]