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Enhancing Reuse of Data and Biological Material in Medical Research: From FAIR to FAIR-Health.

Wed, 01/24/2018 - 12:21

Enhancing Reuse of Data and Biological Material in Medical Research: From FAIR to FAIR-Health.

Biopreserv Biobank. 2018 Jan 23;:

Authors: Holub P, Kohlmayer F, Prasser F, Mayrhofer MT, Schlünder I, Martin GM, Casati S, Koumakis L, Wutte A, Kozera Ł, Strapagiel D, Anton G, Zanetti G, Sezerman OU, Mendy M, Valík D, Lavitrano M, Dagher G, Zatloukal K, van Ommen GB, Litton JE

Abstract
The known challenge of underutilization of data and biological material from biorepositories as potential resources for medical research has been the focus of discussion for over a decade. Recently developed guidelines for improved data availability and reusability-entitled FAIR Principles (Findability, Accessibility, Interoperability, and Reusability)-are likely to address only parts of the problem. In this article, we argue that biological material and data should be viewed as a unified resource. This approach would facilitate access to complete provenance information, which is a prerequisite for reproducibility and meaningful integration of the data. A unified view also allows for optimization of long-term storage strategies, as demonstrated in the case of biobanks. We propose an extension of the FAIR Principles to include the following additional components: (1) quality aspects related to research reproducibility and meaningful reuse of the data, (2) incentives to stimulate effective enrichment of data sets and biological material collections and its reuse on all levels, and (3) privacy-respecting approaches for working with the human material and data. These FAIR-Health principles should then be applied to both the biological material and data. We also propose the development of common guidelines for cloud architectures, due to the unprecedented growth of volume and breadth of medical data generation, as well as the associated need to process the data efficiently.

PMID: 29359962 [PubMed - as supplied by publisher]

The ISBER Self-Assessment Tool Indicates Main Pathways for Improvement in Biobanks and Supports International Standardization.

Wed, 01/24/2018 - 12:21

The ISBER Self-Assessment Tool Indicates Main Pathways for Improvement in Biobanks and Supports International Standardization.

Biopreserv Biobank. 2018 Jan 23;:

Authors: Betsou F

PMID: 29359960 [PubMed - as supplied by publisher]

Neural correlates of lower limbs proprioception: An fMRI study of foot position matching.

Wed, 01/24/2018 - 12:21

Neural correlates of lower limbs proprioception: An fMRI study of foot position matching.

Hum Brain Mapp. 2018 Jan 22;:

Authors: Iandolo R, Bellini A, Saiote C, Marre I, Bommarito G, Oesingmann N, Fleysher L, Mancardi GL, Casadio M, Inglese M

Abstract
Little is known about the neural correlates of lower limbs position sense, despite the impact that proprioceptive deficits have on everyday life activities, such as posture and gait control. We used fMRI to investigate in 30 healthy right-handed and right-footed subjects the regional distribution of brain activity during position matching tasks performed with the right dominant and the left nondominant foot. Along with the brain activation, we assessed the performance during both ipsilateral and contralateral matching tasks. Subjects had lower errors when matching was performed by the left nondominant foot. The fMRI analysis suggested that the significant regions responsible for position sense are in the right parietal and frontal cortex, providing a first characterization of the neural correlates of foot position matching.

PMID: 29359521 [PubMed - as supplied by publisher]

Relationship of Arterial Stiffness Index and Pulse Pressure With Cardiovascular Disease and Mortality.

Wed, 01/24/2018 - 12:21

Relationship of Arterial Stiffness Index and Pulse Pressure With Cardiovascular Disease and Mortality.

J Am Heart Assoc. 2018 Jan 22;7(2):

Authors: Said MA, Eppinga RN, Lipsic E, Verweij N, van der Harst P

Abstract
BACKGROUND: Vascular aging results in stiffer arteries and may have a role in the development of cardiovascular disease (CVD). Arterial stiffness index (ASI), measured by finger photoplethysmography, and pulse pressure (PP) are 2 independent vascular aging indices. We investigated whether ASI or PP predict new-onset CVD and mortality in a large community-based population.
METHODS AND RESULTS: We studied 169 613 UK Biobank participants (mean age 56.8 years; 45.8% males) who underwent ASI measurement and blood pressure measurement for PP calculation. Mean±SD ASI was 9.30±3.1 m/s and mean±SD PP was 50.98±13.2 mm Hg. During a median disease follow-up of 2.8 years (interquartile range 1.4-4.0), 18 190 participants developed CVD, of which 1587 myocardial infarction (MI), 4326 coronary heart disease, 1192 heart failure, and 1319 stroke. During a median mortality follow-up of 6.1 years (interquartile range 5.8-6.3), 3678 participants died, of which 1180 of CVD. Higher ASI was associated with increased risk of overall CVD (unadjusted hazard ratio 1.27; 95% confidence interval [CI], 1.25-1.28), myocardial infarction (1.38; 95% CI, 1.32-1.44), coronary heart disease (1.31; 95% CI, 1.27-1.34), and heart failure (1.31; 95% CI 1.24-1.37). ASI also predicted mortality (all-cause, CVD, other). Higher PP was associated with overall CVD (1.57; 95% CI, 1.55-1.59), myocardial infarction (1.48; 95% CI, 1.42-1.54), coronary heart disease (1.47; 95% CI, 1.43-1.50), heart failure (1.47; 95% CI, 1.40-1.55), and CVD mortality (1.47; 95% CI, 1.40-1.55). PP improved risk reclassification of CVD in a non-laboratory-based Framingham Risk Score by 5.4%, ASI by 2.3%.
CONCLUSIONS: ASI and PP are independent predictors of CVD and mortality outcomes. Although both improved risk prediction for new-onset disease, PP appears to have a larger clinical value than ASI.

PMID: 29358193 [PubMed - in process]

AZGP1 inhibits soft tissue sarcoma cells invasion and migration.

Wed, 01/24/2018 - 12:21

AZGP1 inhibits soft tissue sarcoma cells invasion and migration.

BMC Cancer. 2018 Jan 22;18(1):89

Authors: Liu J, Han H, Fan Z, El Beaino M, Fang Z, Li S, Ji J

Abstract
BACKGROUND: One of the major challenges in soft tissue sarcomas is to identify factors that predict metastasis. AZGP1 is a potential biomarker of cancer progression, but its value in soft tissue sarcomas remains unknown. The aim of this study is to determine the expression level of AZGP1 in soft tissue sarcomas, and to analyze its influence on tumor progression.
METHODS: AZGP1 immunohistochemistry (IHC) and RT-PCR were performed in 86 patients with soft tissue sarcomas. The relationships between AZGP1 levels and clinicopathologic features were analyzed. In vitro experiments were performed using fibrosarcoma (HT1080), rhabdomyosarcoma (RD) and synovial sarcoma (SW982) cell lines to corroborate our findings. We used lentiviral over-expression and knockdown assays to examine how changes of AZGP1 expressions might affect cellular migration and invasion.
RESULTS: The quantitative RT-PCR results showed that AZGP1 expression was negatively correlated with metastasis and overall survival in soft tissue sarcomas (p < 0.05). Immunohistochemical staining showed lower expression of AZGP1 in patients with metastasis than in those without. Kaplan-Meier survival analysis showed that patients with low expression of AZGP1 had shorter overall (p = 0.056) and metastasis-free survivals (p = 0.038). These findings were corroborated by our in vitro experiments. Over-expression of AZGP1 significantly decreased RD cellular migration and invasion by 64% and 78%, respectively. HT1080 cells migration was inhibited by 2-fold, whereas their invasion was repressed by 7-fold after AZGP1 knockdown.
CONCLUSIONS: Our study reveals that reduced AZGP1 expression correlates with in vitro cellular migration and invasion. In vivo, it is associated with higher metastatic risk and shorter survival in patients with soft tissue sarcomas.

PMID: 29357838 [PubMed - in process]

A Biomimetic Emu Oil-Blended Electrospun Nanofibrous Mat for Maintaining Stemness of Adipose Tissue-Derived Stem Cells.

Tue, 01/23/2018 - 12:59

A Biomimetic Emu Oil-Blended Electrospun Nanofibrous Mat for Maintaining Stemness of Adipose Tissue-Derived Stem Cells.

Biopreserv Biobank. 2018 Jan 22;:

Authors: Jalilzadeh-Tabrizi S, Pilehvar-Soltanahmadi Y, Alizadeh E, Alipour S, Dadashpour M, Nejati-Koshki K, Zarghami N

Abstract
BACKGROUND: Emu oil (EO) with anti-inflammatory, antioxidative, and wound healing properties can be blended for preparing bioactive nanofibrous scaffold. Adipose tissue-derived stem cells (ADSCs) are promising candidates for tissue engineering, and preserving their stemness potential is vital for further therapeutic applications.
AIM: The aim of this study was to fabricate EO-blended nanofiber and investigate its effect on proliferation, survival, and stemness preservation of ADSCs.
MATERIALS AND METHODS: Pure EO composition was characterized using a gas chromatograph mass spectrometer. EO-PCL-polyethylene glycol (PEG) nanofibers were successfully fabricated using an electrospinning technique and characterized by field emission scanning electron microscopy (FE-SEM) and fourier-transform infrared spectroscopy (FTIR). Cell viability and adhesion were measured using the MTT assay and FE-SEM. Finally, quantitative PCR (qPCR) was used to quantify the expression level of cell cycle regulated genes and pluripotency-associated transcription factors.
RESULTS: Findings showed that 20% (w/w) of EO is the optimum oil content in the electrospun solution to achieve good morphology and ultrafine fibers. The relatively high optical densities and FE-SEM images indicated that EO highly supported cell adhesion and proliferation on the matrices. In addition, EO-PCL-PEG electrospun nanofibrous mats significantly upregulated the expression levels of cell cycle regulated genes (Cyclin D1, pRb, and P53) and stemness markers (Nanog, OCT-4, Rex-1, and Sox-2) than PCL-PEG nanofiber and tissue culture polystyrene in 7 and 14 days of cell culture.
CONCLUSION: These results demonstrate that the EO-blended nanofibrous mat can be used as a bioactive scaffold to support cell adhesion and proliferation while simultaneously maintaining the stemness of ADSCs.

PMID: 29356571 [PubMed - as supplied by publisher]

Increased risk of psoriasis following scabies infection: A nationwide population-based matched-cohort study.

Tue, 01/23/2018 - 12:59

Increased risk of psoriasis following scabies infection: A nationwide population-based matched-cohort study.

J Dermatol. 2018 Jan 21;:

Authors: Liu JM, Lin CY, Chang FW, Liu YP, Liang CP, Hsu RJ

Abstract
Both scabies and psoriasis are pruritic inflammatory skin diseases. The clinical manifestations are similar and provocation of psoriasis by mite bite was reported. The association between scabies and psoriasis was not investigated before. We conducted this nationwide population-based matched-cohort study to describe if patients with a diagnosis of scabies have a different risk of developing new psoriasis. From the National Health Insurance Research Database of Taiwan, patients with scabies (n = 5137) were identified and matched for age and sex with non-scabies controls (n = 19 142). We tracked them for a 7-year period to identify the incidence of psoriasis. One hundred and ninety (0.8%) patients with newly diagnosed psoriasis were identified; 91 (1.8%) from the scabies group and 99 (0.5%) from the control group. Patients with scabies had a higher risk of subsequent psoriasis, with a crude hazard ratio of 3.45 and an adjusted hazard ratio (aHR) of 3.03 (95% confidence interval, 2.24-4.11). An increased risk for psoriasis among patients with scabies was observed (aHR, 3.03). Immunopathology involving the T-helper 17 cell-mediated inflammatory pathway may contribute to this association. Physicians may consider implementing assessments of psoriatic symptoms in patients with scabies.

PMID: 29356052 [PubMed - as supplied by publisher]

Vitreoretinal interface abnormalities in middle-aged adults with visual impairment in the UK Biobank study: prevalence, impact on visual acuity and associations.

Tue, 01/23/2018 - 12:59

Vitreoretinal interface abnormalities in middle-aged adults with visual impairment in the UK Biobank study: prevalence, impact on visual acuity and associations.

BMJ Open Ophthalmol. 2017;1(1):e000057

Authors: McKibbin M, Farragher T, Shickle D

Abstract
Objective: The aim of this study was to determine the prevalence of vitreoretinal interface abnormalities (VRIA), the degree of visual impairment and associations with VRIA among adults, aged 40-69 years, in the UK Biobank study.
Methods and analysis: Colour fundus photographs and spectral domain optical coherence tomography images were graded for 25% of the 8359 UK Biobank participants with mild visual impairment or worse (LogMAR >0.3 or Snellen <6/12) in at least one eye. The prevalence and contribution of VRIA to visual impairment was determined and multinomial logistic regression models were used to investigate association with known risk factors and other predetermined socioeconomic, biometric, lifestyle and medical variables for cases and matched controls.
Results: The minimum prevalence of any VRIA was 17.6% and 8.1% in the eyes with and without visual impairment, respectively. VRIA were identified as the primary cause of visual impairment in 3.6% of eyes. Although epiretinal membrane and vitreomacular traction were the most common VRIA, the degree of visual impairment was typically milder with these than with other VRIA. Visual impairment with a VRIA was positively associated with increasing age (relative risk ratio (RRR) 1.22 (95% CI 1.07 to 1.40)), female gender (RRR 1.28; 1.08 to 1.52) and Asian or Asian British ethnicity (RRR 1.60; 1.10 to 2.32).
Conclusions: VRIA are common in middle-aged adults in the UK Biobank study, especially in eyes with visual impairment. VRIA were considered to be the primary cause of visual impairment in 3.6% of all eyes with visual impairment, although there was variation in the degree of visual impairment for each type of VRIA.

PMID: 29354705 [PubMed]

MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma.

Tue, 01/23/2018 - 12:59
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MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma.

Oncotarget. 2016 Jul 05;7(27):42461-42473

Authors: Han SY, Han HB, Tian XY, Sun H, Xue D, Zhao C, Jiang ST, He XR, Zheng WX, Wang J, Pang LN, Li XH, Li PP

Abstract
MicroRNAs (miRNAs) have been shown to function as either oncogenes or tumor suppressors by negatively regulating target genes involved in tumor initiation and progression. In this study, we demonstrated that down-regulation of miR-33a-3p in human primary hepatocellular cancer (HCC) specimens was significantly associated with metastases and poor survival. Over-expression of miR-33a-3p in HepG2 cells remarkably suppressed not only cell growth, migration and invasion, but also tumor growth and metastases in the chick embryo chorioallantoic membrane (CAM) assay, and down-regulated Pre-B-Cell Leukemia Homeobox 3 (PBX3) expression. Conversely, inhibition of miR-33a-3p in Bel-7402 cells resulted in increased of cell growth, spreading and invasion. Furthermore, rescue experiments by over-expression PBX3 completely eliminated the inhibitory effects of miR-33a-3p on tumor growth and metastasis, both in vitro and in vivo. The luciferase assay showed that 3'-untranslated regions (3'-UTRs) of PBX3 were inhibited significantly by miR-33a-3p, while mutations in the miR-33a-3p pairing residues rescued the luciferase expression. Taken together, our findings suggest that miR-33a-3p suppressed the malignant phenotype while also inhibiting PBX3 expression in hepatocellular cancer, implying that miR-33a-3p may be a promising biomarkers and therapy target for HCC intervention.

PMID: 27285759 [PubMed - indexed for MEDLINE]

Pyrosequencing analysis of methylation levels of clock genes in leukocytes from Parkinson's disease patients.

Mon, 01/22/2018 - 12:48

Pyrosequencing analysis of methylation levels of clock genes in leukocytes from Parkinson's disease patients.

Neurosci Lett. 2018 Jan 17;668:115-119

Authors: Mao W, Zhao C, Ding H, Liang K, Xue J, Chan P, Cai Y

Abstract
DNA methylation of neuronal PAS domain protein 2 (NPAS2) and cryptochrome circadian clock 1 (CRY1) promoters may be associated with Parkinson's disease (PD). However, there is no simple and cost-effective method to quantify DNA methylation in these regions. Additionally, it is not clear whether DNA methylation of NPAS2 and CRY1 promoters is altered in peripheral blood of PD patients, especially newly diagnosed drug-naïve PD patients, and thus can be used as a PD biomarker. In the present study, we utilized bisulfite pyrosequencing assays to examine DNA methylation levels of six CpG sites in the NPAS2 promoter and five CpG sites in the CRY1 promoter. We compared DNA methylation levels at these sites in leukocytes from 80 medicated PD patients, 30 drug-naïve PD patients, and 80 healthy controls. Our results indicate that NPAS2 hypomethylation occurs at the early stage of PD and is a moderate biomarker for distinguishing PD patients from healthy subjects.

PMID: 29353016 [PubMed - as supplied by publisher]

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]