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High Resolution Melting (HRM) for High-Throughput Genotyping-Limitations and Caveats in Practical Case Studies.

Sat, 11/04/2017 - 13:35
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High Resolution Melting (HRM) for High-Throughput Genotyping-Limitations and Caveats in Practical Case Studies.

Int J Mol Sci. 2017 Nov 03;18(11):

Authors: Słomka M, Sobalska-Kwapis M, Wachulec M, Bartosz G, Strapagiel D

Abstract
High resolution melting (HRM) is a convenient method for gene scanning as well as genotyping of individual and multiple single nucleotide polymorphisms (SNPs). This rapid, simple, closed-tube, homogenous, and cost-efficient approach has the capacity for high specificity and sensitivity, while allowing easy transition to high-throughput scale. In this paper, we provide examples from our laboratory practice of some problematic issues which can affect the performance and data analysis of HRM results, especially with regard to reference curve-based targeted genotyping. We present those examples in order of the typical experimental workflow, and discuss the crucial significance of the respective experimental errors and limitations for the quality and analysis of results. The experimental details which have a decisive impact on correct execution of a HRM genotyping experiment include type and quality of DNA source material, reproducibility of isolation method and template DNA preparation, primer and amplicon design, automation-derived preparation and pipetting inconsistencies, as well as physical limitations in melting curve distinction for alternative variants and careful selection of samples for validation by sequencing. We provide a case-by-case analysis and discussion of actual problems we encountered and solutions that should be taken into account by researchers newly attempting HRM genotyping, especially in a high-throughput setup.

PMID: 29099791 [PubMed - in process]

Neurocognitive Graphs of First-Episode Schizophrenia and Major Depression Based on Cognitive Features.

Sat, 11/04/2017 - 13:35
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Neurocognitive Graphs of First-Episode Schizophrenia and Major Depression Based on Cognitive Features.

Neurosci Bull. 2017 Nov 02;:

Authors: Liang S, Vega R, Kong X, Deng W, Wang Q, Ma X, Li M, Hu X, Greenshaw AJ, Greiner R, Li T

Abstract
Neurocognitive deficits are frequently observed in patients with schizophrenia and major depressive disorder (MDD). The relations between cognitive features may be represented by neurocognitive graphs based on cognitive features, modeled as Gaussian Markov random fields. However, it is unclear whether it is possible to differentiate between phenotypic patterns associated with the differential diagnosis of schizophrenia and depression using this neurocognitive graph approach. In this study, we enrolled 215 first-episode patients with schizophrenia (FES), 125 with MDD, and 237 demographically-matched healthy controls (HCs). The cognitive performance of all participants was evaluated using a battery of neurocognitive tests. The graphical LASSO model was trained with a one-vs-one scenario to learn the conditional independent structure of neurocognitive features of each group. Participants in the holdout dataset were classified into different groups with the highest likelihood. A partial correlation matrix was transformed from the graphical model to further explore the neurocognitive graph for each group. The classification approach identified the diagnostic class for individuals with an average accuracy of 73.41% for FES vs HC, 67.07% for MDD vs HC, and 59.48% for FES vs MDD. Both of the neurocognitive graphs for FES and MDD had more connections and higher node centrality than those for HC. The neurocognitive graph for FES was less sparse and had more connections than that for MDD. Thus, neurocognitive graphs based on cognitive features are promising for describing endophenotypes that may discriminate schizophrenia from depression.

PMID: 29098645 [PubMed - as supplied by publisher]

Fetal sex influences maternal fasting plasma glucose levels and basal β-cell function in pregnant women with normal glucose tolerance.

Sat, 11/04/2017 - 13:35
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Fetal sex influences maternal fasting plasma glucose levels and basal β-cell function in pregnant women with normal glucose tolerance.

Acta Diabetol. 2017 Nov 02;:

Authors: Geng X, Geng L, Zhang Y, Lu H, Shen Y, Chen R, Fang P, Tao M, Wang C, Jia W

Abstract
AIMS: Fetal sex has recently emerged as a new factor that is related to maternal glucose homeostasis during pregnancy. The present study aimed to investigate the effect of fetal sex on maternal glucose metabolism in women with normal glucose tolerance (NGT) during pregnancy in the Chinese population.
METHODS: A total of 877 pregnant women with NGT were recruited at 24-28 weeks of gestation and underwent a 75-g oral glucose tolerance test (OGTT). Pregnant women were divided into two groups according to fetal sex. Physical examinations and laboratory tests were performed. Pancreatic β-cell function and insulin sensitivity were evaluated using OGTT-derived indices.
RESULTS: Compared with women bearing female fetuses, women who delivered male fetuses had higher fasting plasma glucose (FPG) concentrations [4.5 (4.2-4.8) vs. 4.4 (4.2-4.7) mmol/L, P < 0.05], but lower HOMA-β [161.9 (118.2-238.8) vs. 181.0 (131.7-260.9), P < 0.05] and Stumvoll first phase of insulin secretion [1230.2 (1077.9-1433.7) vs. 1290.9 (1134.0-1493.2), P < 0.05]. Multiple linear regression analysis indicated that the sex of the fetus was independently associated with maternal FPG and HOMA-β. Further binary logistic regression analyses revealed that the presence of a male fetus was significantly associated with elevated FPG [odds ratio (OR) 1.50; 95% confidence interval (CI) 1.12-2.00; P = 0.006] and lower HOMA-β (OR 0.70; 95% CI 0.52-0.94; P = 0.018) even after adjustment for potential confounders.
CONCLUSIONS: This study provided evidence that maternal glucose metabolism could be affected by fetal sex even in NGT pregnant women. Our results suggest that the presence of male fetuses was independently associated with maternal elevated FPG and lower basal β-cell function.

PMID: 29098391 [PubMed - as supplied by publisher]

MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies.

Sat, 11/04/2017 - 13:35
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MDS1 and EVI1 complex locus (MECOM): a novel candidate gene for hereditary hematological malignancies.

Haematologica. 2017 Nov 02;:

Authors: Ripperger T, Hofmann W, Koch JC, Shirneshan K, Haase D, Wulf G, Issing PR, Karnebogen M, Schmidt G, Auber B, Schlegelberger B, Illig T, Zirn B, Steinemann D

PMID: 29097497 [PubMed - as supplied by publisher]

Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer.

Sat, 11/04/2017 - 13:35
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Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer.

Cancer Discov. 2016 Jul;6(7):754-69

Authors: Kitai H, Ebi H, Tomida S, Floros KV, Kotani H, Adachi Y, Oizumi S, Nishimura M, Faber AC, Yano S

Abstract
UNLABELLED: KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.
SIGNIFICANCE: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non-small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754-69. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.

PMID: 27154822 [PubMed - indexed for MEDLINE]

Meta-analysis of safety and efficacy for direct oral anticoagulation treatment of non-valvular atrial fibrillation in relation to renal function.

Fri, 11/03/2017 - 12:19

Meta-analysis of safety and efficacy for direct oral anticoagulation treatment of non-valvular atrial fibrillation in relation to renal function.

Thromb Res. 2017 Oct 26;160:41-50

Authors: Zou R, Tao J, Shi W, Yang M, Li H, Lin X, Yang S, Hua P

Abstract
INTRODUCTION: We performed a meta-analysis of the safety and efficacy of anticoagulation treatment for atrial fibrillation (AF) in relation to renal function. We also examined the change in estimated glomerular filtration rate (eGFR) from baseline and compared the outcomes for patients with stable and worsening renal function.
MATERIALS AND METHODS: We selected studies that used randomized controlled trials in which outcomes for direct oral anticoagulants (DOACs) (dabigatran, rivaroxaban, apixaban, or edoxaban) were compared with those for warfarin in AF patients with normal, mild or moderate renal function, except the severe one (creatinine clearance<30).
RESULTS: We assessed five clinical trials, involving 72,608 patients. Pooled analysis indicated that the risk of stroke was lower for DOACs than for warfarin among patients with mild renal impairment (Risk ratio, 0.79; 95% confidence interval, 0.68-0.91) and moderate renal impairment (0.80, 0.69-0.92). No major differences were found in patients with normal renal function. Additionally, DOACs were associated with fewer major bleeds among patients with normal (0.77, 0.70-0.84), mild (0.86, 0.77-0.95), and moderate renal impairment (0.73, 0.65-0.82). Among those treated with DOACs, a lower dosage was associated with lower risk of major bleeding (0.75, 0.68-0.83) and higher risk of stroke or systemic embolism (1.28, 1.12-1.47). Further, DOACs tended to be associated with a lower estimated glomerular filtration rate (eGFR) than warfarin even after 30months. Finally, we found significant differences in the risk of stroke (2.09, 1.64-2.68) and major bleeding (2.01, 1.66-2.42) between patients with stable and worsening renal function.
CONCLUSIONS: DOACs have a greater clinical benefit than warfarin with respect to renal function. They are associated with a comparatively lower risk of stroke and major bleeding, as well lower eGFR. This suggests these agents are a better choice in patients with renal disease.

PMID: 29096154 [PubMed - as supplied by publisher]

High prevalence of carriers of variant c.1528G>C of HADHA gene causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the population of adult Kashubians from North Poland.

Fri, 11/03/2017 - 12:19

High prevalence of carriers of variant c.1528G>C of HADHA gene causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the population of adult Kashubians from North Poland.

PLoS One. 2017;12(11):e0187365

Authors: Nedoszytko B, Siemińska A, Strapagiel D, Dąbrowski S, Słomka M, Sobalska-Kwapis M, Marciniak B, Wierzba J, Skokowski J, Fijałkowski M, Nowicki R, Kalinowski L

Abstract
BACKGROUND/OBJECTIVES: The mitochondrial β-oxidation of fatty acids is a complex catabolic pathway. One of the enzymes of this pathway is the heterooctameric mitochondrial trifunctional protein (MTP), composed of four α- and β-subunits. Mutations in MTP genes (HADHA and HADHB), both located on chromosome 2p23, cause MTP deficiency, a rare autosomal recessive metabolic disorder characterized by decreased activity of MTP. The most common MTP mutation is long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency caused by the c.1528G>C (rs137852769, p.Glu510Gln) substitution in exon 15 of the HADHA gene.
SUBJECTS/METHODS: We analyzed the frequency of genetic variants in the HADHA gene in the adults of Kashubian origin from North Poland and compared this data in other Polish provinces.
RESULTS: We found a significantly higher frequency of HDHA c.1528G>C (rs137852769, p.Glu510Gln) carriers among Kashubians (1/57) compared to subjects from other regions of Poland (1/187). We found higher frequency of c.652G>C (rs71441018, pVal218Leu) polymorphism in the HADHA gene within population of Silesia, southern Poland (1/107) compared to other regions.
CONCLUSION: Our study indicate described high frequency of c.1528G>C variant of HADHA gene in Kashubian population, suggesting the founder effect. For the first time we have found high frequency of rs71441018 in the South Poland Silesian population.

PMID: 29095929 [PubMed - in process]

Freeze-dried plasma proteins are stable at room temperature for at least 1 year.

Fri, 11/03/2017 - 12:19

Freeze-dried plasma proteins are stable at room temperature for at least 1 year.

Clin Proteomics. 2017;14:35

Authors: Dufresne J, Hoang T, Ajambo J, Florentinus-Mefailoski A, Bowden P, Marshall J

Abstract
Thirty human EDTA plasma samples from male and female subjects ranging in age from 24 to 74 years were collected on ice, processed ice cold and stored frozen at -80 °C, in liquid nitrogen (LN2), or freeze dried and stored at room temperature in a desiccator (FDRT) or freeze dried and stored at -20 °C for 1 year (FD-20). In a separate experiment, EDTA plasma samples were collected onto ice, processed ice cold and maintained on ice ± protease inhibitors versus incubated at room temperature for up to 96 h. Random and independent sampling by liquid chromatography and tandem mass spectrometry (LC-ESI-MS/MS), as correlated by the MASCOT, OMSSA, X!TANDEM and SEQUEST algorithms, showed that tryptic peptides from complement component 4B (C4B) were rapidly released in plasma at room temperature. Random sampling by LC-ESI-MS/MS showed that peptides from C4B were undetectable on ice, but peptides were cleaved from the mature C4B protein including NGFKSHALQLNNR within as little as 1 h at room temperature. The frequency and intensity of precursors within ± 3 m/z of the C4B peptide NGFKSHALQLNNR was confirmed by automated targeted analysis where the precursors from MS/MS spectra that correlated to the target sequence were analyzed in SQL/R. The C4B preproprotein was processed at the N terminus to release the mature chain that was cleaved on the carboxyl side of the isoprene C2 domain within a polar C terminal sequence of the mature C4B protein, to reveal the thioester reaction site, consistent with LC-ESI-MS/MS and Western blot. Random sampling showed that proteolytic peptides from complement component C4B were rarely observed with long term storage at - 80 °C in a freezer or in liquid nitrogen (LN2), freeze drying with storage at - 20 °C (FD-20 °C) or freeze drying and storage at room temperature (FDRT). Plasma samples maintained at room temperature (RT) showed at least 10-fold to 100-fold greater frequency of peptide correlation to C4B and measured peptide intensity compared to samples on ice for up to 72 h or stored at - 80 °C, LN2, FDRT or FD-20 °C for up to a year.

PMID: 29093647 [PubMed]

Sleep During Menopausal Transition: A 6-Year Follow-Up.

Fri, 11/03/2017 - 12:19
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Sleep During Menopausal Transition: A 6-Year Follow-Up.

Sleep. 2017 Jul 01;40(7):

Authors: Lampio L, Polo-Kantola P, Himanen SL, Kurki S, Huupponen E, Engblom J, Heinonen OJ, Polo O, Saaresranta T

Abstract
Study Objectives: Menopausal transition is associated with increased dissatisfaction with sleep, but the effects on sleep architecture are conflicting. This prospective 6-year follow-up study was designed to evaluate the changes in sleep stages and sleep continuity that occur in women during menopausal transition.
Methods: Sixty women (mean age 46.0 years, SD 0.9) participated. All women were premenopausal at baseline, and at the 6-year follow-up, women were in different stages of menopausal transition. Polysomnography was used to study sleep architecture at baseline and follow-up. The effects of aging and menopause (assessed as change in serum follicle-stimulating hormone [S-FSH]) on sleep architecture were evaluated using linear regression models.
Results: After controlling for body mass index, vasomotor, and depressive symptoms, aging of 6 years resulted in shorter total sleep time (B -37.4, 95% confidence interval [CI] -71.5 to (-3.3)), lower sleep efficiency (B -6.5, 95%CI -12.7 to (-0.2)), as well as in increased transitions from slow-wave sleep (SWS) to wakefulness (B 1.0, 95%CI 0.1 to 1.9), wake after sleep onset (B 37.7, 95%CI 12.5 to 63.0), awakenings per hour (B 1.8, 95%CI 0.8 to 2.8), and arousal index (B 2.3, 95%CI 0.1 to 4.4). Higher S-FSH concentration in menopausal transition was associated with increased SWS (B 0.09, 95%CI 0.01 to 0.16) after controlling for confounding factors.
Conclusions: A significant deterioration in sleep continuity occurs when women age from 46 to 52 years, but change from premenopausal to menopausal state restores some SWS.

PMID: 28525646 [PubMed - indexed for MEDLINE]

MicroRNA-130a-3p suppresses cell migration and invasion by inhibition of TBL1XR1-mediated EMT in human gastric carcinoma.

Thu, 11/02/2017 - 14:01

MicroRNA-130a-3p suppresses cell migration and invasion by inhibition of TBL1XR1-mediated EMT in human gastric carcinoma.

Mol Carcinog. 2017 Nov 01;:

Authors: Wang S, Han H, Hu Y, Yang W, Lv Y, Wang L, Zhang L, Ji J

Abstract
MiR-130a-3p was found to play tumor suppressor role in most human cancers, except for gastric cancer. However, in this study, we demonstrated that miR-130a-3p was significantly down-regulated in gastric carcinoma (GC) tissues compared with adjacent non-neoplastic tissues, and decreased miR-130a-3p expression was associated with shorter overall survival (OS) and was an independent prognostic factor for OS in GC patients. Over-expression of miR-130a-3p remarkably inhibited not only GC cell migration, invasion, and epithelial-mesenchymal transition (EMT) in vitro, but also tumorigenesis and lung metastasis in the chick embryo chorioallantoic membrane (CAM) assay in vivo. Conversely, inhibition of miR-130a-3p resulted in opposite phenotype changes in GC cells. Furthermore, TBL1XR1 was identified as a direct target of miR-130a-3p, and reintroduction of TBL1XR1 into miR-130a-3p-transfected MGC-803 cells reversed the inhibitory effects of miR-130a-3p on GC cell migration, invasion and EMT. Taken together, our data suggested that miR-130a-3p suppressed aggressive phenotype of GC cells partially by direct targeting and decreasing TBL1XR1 and subsequent EMT process. This article is protected by copyright. All rights reserved.

PMID: 29091326 [PubMed - as supplied by publisher]

Carbosilane dendrons with fatty acids at the core as a new potential microbicide against HSV-2/HIV-1 co-infection.

Thu, 11/02/2017 - 14:01
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Carbosilane dendrons with fatty acids at the core as a new potential microbicide against HSV-2/HIV-1 co-infection.

Nanoscale. 2017 Nov 01;:

Authors: Guerrero-Beltrán C, Ceña-Diez R, Sepúlveda-Crespo D, De la Mata J, Gómez R, Leal M, Muñoz-Fernández MA, Jiménez JL

Abstract
Herpes simplex virus type 2 (HSV-2) and human immunodeficiency virus type 1 (HIV-1) represent the two most frequent sexually transmitted infections (STI) worldwide. Epidemiological studies suggest that HSV-2 increases the risk of HIV-1 acquisition approximately 3-fold mainly due to the clinical and immunological manifestations. In the absence of vaccines against both STI, the development of new preventive strategies has become essential for further studies. We performed the screening of six novel polyanionic carbosilane dendrons to elucidate their potential activity against HSV-2/HIV-1 co-infection and their mechanism of action. These new nanoparticles are carbosilane branched dendrons from first to third generation, with palmitic or hexanoic fatty acids as the core and capped with sulfonate groups, named G1d-STE2Hx, G2d-STE4Hx, G3d-STE8Hx, G1d-STE2Pm, G2d-STE4Pm and G3d-STE8Pm. G3d-STE8Hx and G3d-STE8Pm carbosilane branched dendrons showed high viability. These dendrons also showed a great broad-spectrum antiviral activity, as well as a suitable efficacy against HIV-1 even if the mucosal disruption occurs as a consequence of HSV-2 infection. Our results exert high inhibition against HSV-2 and HIV-1 by blocking the entry of both viruses with the median effective concentration EC50 values in the nanomolar range. Additionally, G3d-STE8Hx and G3d-STE8Pm retained their anti-HSV-2/HIV-1 activity at different pH values. G3d-STE8Hx and G3d-STE8Pm dendrons may be potential candidates as dual-acting microbicides against HSV-2/HIV-1 co-infection.

PMID: 29090302 [PubMed - as supplied by publisher]

Genetic Variation at the ADAMTS7 Locus is Associated With Reduced Severity of Coronary Artery Disease.

Thu, 11/02/2017 - 14:01
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Genetic Variation at the ADAMTS7 Locus is Associated With Reduced Severity of Coronary Artery Disease.

J Am Heart Assoc. 2017 Oct 31;6(11):

Authors: Chan K, Pu X, Sandesara P, Poston RN, Simpson IA, Quyyumi AA, Ye S, Patel RS

Abstract
BACKGROUND: Genome-wide association studies identified ADAMTS7 as a risk locus for coronary artery disease (CAD). Functional studies suggest that ADAMTS7 may promote cellular processes in atherosclerosis. We sought to examine the association between genetic variation at ADAMTS7 and measures of atherosclerosis using histological, angiographic, and clinical outcomes data.
METHODS AND RESULTS: The lead CAD-associated single-nucleotide polymorphism rs3825807 at the ADAMTS7 locus was genotyped. The G allele (reduced ADAMTS7 function) was associated with a smaller fibrous cap (P=0.017) and a smaller percentage area of α-actin (smooth muscle cell marker) in the intima (P=0.017), but was not associated with calcification or plaque thickness, following ex vivo immunohistochemistry analysis of human coronary plaques (n=50; mean age 72.2±11.3). In two independent cohorts (Southampton Atherosclerosis Study [n=1359; mean age 62.5±10.3; 70.1% men] and the Emory Cardiovascular Biobank [EmCAB; n=2684; mean age 63.8±11.3; 68.7% men]), the G allele was associated with 16% to 19% lower odds of obstructive CAD (Southampton Atherosclerosis Study: odds ratio, 0.81; 95% confidence interval, 0.67-0.98; EmCAB: odds ratio, 0.84; 95% confidence interval, 0.75-0.95) with similar effects for multivessel, left anterior descending, and proximal CAD. Furthermore, each copy of the G allele was associated with lower angiographic severity Gensini score (Southampton Atherosclerosis Study, P=0.026; EmCAB, P<0.001), lower Sullivan Extent score (Southampton Atherosclerosis Study, P=0.029; EmCAB, P<0.001), and a 23% lower risk of incident revascularization procedures (EmCAB: hazard ratio, 0.76; 95% confidence interval, 0.59-0.98). There were no associations with all-cause mortality or incident myocardial infarction.
CONCLUSIONS: Genetic variation at the ADAMTS7 locus is associated with several complementary CAD phenotypes, supporting the emerging role of ADAMTS7 in atherosclerosis and may represent a potential drug target.

PMID: 29089340 [PubMed - in process]

Molecular profiling identifies prognostic markers of stage IA lung adenocarcinoma.

Thu, 11/02/2017 - 14:01
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Molecular profiling identifies prognostic markers of stage IA lung adenocarcinoma.

Oncotarget. 2017 Sep 26;8(43):74846-74855

Authors: Zhang J, Shao J, Zhu L, Zhao R, Xing J, Wang J, Guo X, Tu S, Han B, Yu K

Abstract
We previously showed that different pathologic subtypes were associated with different prognostic values in patients with stage IA lung adenocarcinoma (AC). We hypothesize that differential gene expression profiles of different subtypes may be valuable factors for prognosis in stage IA lung adenocarcinoma. We performed microarray gene expression profiling on tumor tissues micro-dissected from patients with acinar and solid predominant subtypes of stage IA lung adenocarcinoma. These patients had undergone a lobectomy and mediastinal lymph node dissection at the Shanghai Chest Hospital, Shanghai, China in 2012. No patient had preoperative treatment. We performed the Gene Set Enrichment Analysis (GSEA) analysis to look for gene expression signatures associated with tumor subtypes. The histologic subtypes of all patients were classified according to the 2015 WHO lung Adenocarcinoma classification. We found that patients with the solid predominant subtype are enriched for genes involved in RNA polymerase activity as well as inactivation of the p53 pathway. Further, we identified a list of genes that may serve as prognostic markers for stage IA lung adenocarcinoma. Validation in the TCGA database shows that these genes are correlated with survival, suggesting that they are novel prognostic factors for stage IA lung adenocarcinoma. In conclusion, we have uncovered novel prognostic factors for stage IA lung adenocarcinoma using gene expression profiling in combination with histopathology subtyping.

PMID: 29088828 [PubMed]

ERG overexpression plus SLC45A3 (prostein) and PTEN expression loss: Strong association of the triple hit phenotype with an aggressive pathway of prostate cancer progression.

Thu, 11/02/2017 - 14:01
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ERG overexpression plus SLC45A3 (prostein) and PTEN expression loss: Strong association of the triple hit phenotype with an aggressive pathway of prostate cancer progression.

Oncotarget. 2017 Sep 26;8(43):74106-74118

Authors: Hernández-Llodrà S, Juanpere N, de Muga S, Lorenzo M, Gil J, Font-Tello A, Agell L, Albero-González R, Segalés L, Merino J, Serrano L, Fumadó L, Cecchini L, Trull JL

Abstract
TMPRSS2 and SLC45A3 rearrangements may coexist in the same tumor. ERG rearrangements and PTEN loss are concomitant events in prostate cancer (PrCa), and can cooperate in progression. We have reported that mRNA expression of TMPRSS2-ERG and SLC45A3-ERG rearrangements plus PTEN loss define an aggressive tumor subset. The aim of this study has been to validate these results by immunohistochemistry in a large cohort of tumors. ERG, SLC45A3 and PTEN immunostaining and their association with pathological features and PSA progression-free survival were analyzed in 220 PrCa (PSMAR-Biobank, Barcelona, Spain). ERG protein expression was found in 46.8% and SLC45A3 and PTEN loss in 30% and 34% tumors, respectively. Single ERG positive immunostaining was associated with GS = 6 tumors (p = 0.016), double ERG+/PTEN loss with GS = 7 (p = 0.008) and Grade Group 2 (GG) or GG3 cases (p = 0.042), ERG+/SLC45A3 loss/PTEN loss ("triple hit") with GS ≥ 8 (p < 0.0001) and GG4 or GG5 tumors (p = 0.0003). None of GS = 6 nor = GG1 cases showed this combination. In the GS ≥ 8 group, ERG+ (p = 0.002), PTEN loss (p = 0.009) and "triple hit" (p = 0.003) were associated with Gleason pattern 3 component, and single SLC45A3 loss (p = 0.036) with GS ≥ 8 without pattern 3. The number of aberrant events and the triple hit were strongly associated with shorter PSA progression-free survival. In GS = 6 PrCa, single ERG+ was also associated with progression. ERG+ identifies a distinct pathway of PrCa. Additional assessment of PTEN and SLC45A3 adds relevant prognostic information. The triple hit phenotype (ERG+/SLC45A3 loss/PTEN loss) is associated with progression and could be used for patient stratification, treatment and follow-up.

PMID: 29088771 [PubMed]

Implementation of an in-house quantitative real-time polymerase chain reaction method for Hepatitis B virus quantification in West African countries.

Thu, 11/02/2017 - 14:01
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Implementation of an in-house quantitative real-time polymerase chain reaction method for Hepatitis B virus quantification in West African countries.

J Viral Hepat. 2016 Nov;23(11):897-904

Authors: Ghosh S, Sow A, Guillot C, Jeng A, Ndow G, Njie R, Toure S, Diop M, Mboup S, Kane CT, Lemoine M, Thursz M, Zoulim F, Mendy M, Chemin I

Abstract
Hepatitis B virus (HBV) is a major cause of chronic liver disease worldwide. HBV infection is diagnosed by serological tests, while real-time polymerase chain reaction (qRT-PCR) assays are used to quantify viral load, which is a crucial parameter to determine viral replication and to monitor antiviral treatments. However, measuring viral load in resource-limited countries remains nonsystematic, due to the high cost of commercial kits. Here, we describe the development, validation and implementation of a low-cost, in-house qRT-PCR assay to monitor HBV viral load in chronic carriers enrolled in the PROLIFICA programme in the Gambia and Senegal. Over 1500 HBsAg-positive patients, including 210 chronically infected HBV patients, who were given antiviral treatment (tenofovir), were monitored by qRT-PCR using the SYBR Green- and HBV-specific primers. Twenty-four tenofovir-treated patients were followed up and their viral load was tested every 3 months over the 12-month experimental time course. Compared to commercial assays, our in-house assay was shown to be (i) highly reliable, with good intra- and interassay reproducibility over a wide range (45-4.5 × 10(8) copies mL(-1) ), (ii) very similar in the viral loads detected (R(2 ) = .90), (iii) highly sensitive, as it detected loads as low as 30 copies mL(-1) (~5 IU mL(-1) ), (iv) cheaper (2- to 3-fold), (v) easier to implement and (vi) more rapid. Based on our experience, we recommend this assay as a reliable alternative to commercial assays, for monitoring HBV viraemia in resource-limited, highly endemic countries to reduce the cost and technical obstacles associated with commercial kits.

PMID: 27353593 [PubMed - indexed for MEDLINE]

Malignant Mesothelioma Effusions Are Infiltrated by CD3(+) T Cells Highly Expressing PD-L1 and the PD-L1(+) Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab.

Thu, 11/02/2017 - 14:01
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Malignant Mesothelioma Effusions Are Infiltrated by CD3(+) T Cells Highly Expressing PD-L1 and the PD-L1(+) Tumor Cells within These Effusions Are Susceptible to ADCC by the Anti-PD-L1 Antibody Avelumab.

J Thorac Oncol. 2016 Nov;11(11):1993-2005

Authors: Khanna S, Thomas A, Abate-Daga D, Zhang J, Morrow B, Steinberg SM, Orlandi A, Ferroni P, Schlom J, Guadagni F, Hassan R

Abstract
INTRODUCTION: The functional aspects of programmed death 1 (PD-1) and PD ligand 1 (PD-L1) immune checkpoints in malignant mesothelioma have not been studied.
METHODS: Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry, and its prognostic significance was examined. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1-positive and PD-L1-positive infiltrating lymphocytes and their role in inducing PD-L1 expression in tumor cells. Antibody-dependent cellular cytotoxicity (ADCC) of avelumab, a fully humanized immunoglobulin G1 anti PD-L1 antibody against primary mesothelioma cell lines, was evaluated in presence of autologous and allogeneic natural killer cells.
RESULTS: Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63%) were PD-L1-positive, which was associated with slightly inferior overall survival compared to patients with PD-L1-negative tumors (median 23.0 versus 33.3 months, p = 0.35). The frequency of PD-L1 expression was similar in patients with pleural and peritoneal mesothelioma, with 62% and 64% of samples testing positive, respectively. In nine mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12% to 83%. In seven patients with paired malignant effusion and peripheral blood mononuclear cell (PBMC) samples, PD-L1 expression was significantly higher on CD3-positive T cells present in malignant effusions as compared with PBMCs (p = 0.016). In addition, the numbers of CD14-positive PD-1-positive cells were increased in malignant effusions compared with PBMCs (p = 0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced interferon-γ-mediated PD-L1 expression on the tumor cell surface. Of the three primary mesothelioma cell lines tested, two were susceptible to avelumab-mediated ADCC in the presence of autologous natural killer cells.
CONCLUSIONS: Most pleural as well as peritoneal mesotheliomas express PD-L1. Malignant effusions in this disease are characterized by the presence of tumor cells and CD3-positive T cells that highly express PD-L1. In addition, mesothelioma tumor cells are susceptible to ADCC by the anti-PD-L1 antibody avelumab.

PMID: 27544053 [PubMed - indexed for MEDLINE]

Ginkgetin induces cell death in breast cancer cells via downregulation of the estrogen receptor.

Wed, 11/01/2017 - 12:32

Ginkgetin induces cell death in breast cancer cells via downregulation of the estrogen receptor.

Oncol Lett. 2017 Oct;14(4):5027-5033

Authors: Park Y, Woo SH, Seo SK, Kim H, Noh WC, Lee JK, Kwon BM, Min KN, Choe TB, Park IC

Abstract
Ginkgetin is a natural biflavonoid isolated from the leaves of Ginkgo biloba, and is characterized by its anti-inflammatory and anti-viral activities. Although numerous studies state that it has also antitumor activity, the anti-proliferative effect of ginkgetin and the underlying mechanism in breast cancer cells have not yet been investigated. In the present study, ginkgetin inhibited the cell viability of MCF-7 and T-47D cells dose-dependently, and suppressed the expression of the estrogen receptor (ER) at the mRNA and protein levels. Among the targets of the ER, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), cyclin D1 and survivin were also downregulated by ginkgetin treatment. The anti-proliferative effects of ginkgetin were sufficient to suppress the growth by estradiol stimulation. However, ginkgetin did not significantly affect the viability of MDA-MB-231 cells, which are ER-negative cells. Furthermore, the knockdown of the ER and an inhibitor of PFKFB3 significantly sensitized MCF-7 and T-47D cells to ginkgetin. These findings suggest that ginkgetin induces cell death in ER-positive breast cancer cells via the inhibition of ER expression and that it is a promising agent for breast cancer treatment.

PMID: 29085516 [PubMed]

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

Wed, 11/01/2017 - 12:32
Related Articles

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

Hum Mol Genet. 2017 Jul 01;26(13):2577-2588

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 G, 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

Abstract
Periodontitis is one of the most common inflammatory diseases, with a prevalence of 11% worldwide for the severe forms and an estimated heritability of 50%. The disease is characterized by destruction of the alveolar bone due to an aberrant host inflammatory response to a dysbiotic oral microbiome. Previous genome-wide association studies (GWAS) have reported several suggestive susceptibility loci. Here, we conducted a GWAS using a German and Dutch case-control sample of aggressive periodontitis (AgP, 896 cases, 7,104 controls), a rare but highly severe and early-onset form of periodontitis, validated the associations in a German sample of severe forms of the more moderate phenotype chronic periodontitis (CP) (993 cases, 1,419 controls). Positive findings were replicated in a Turkish sample of AgP (223 cases, 564 controls). A locus at SIGLEC5 (sialic acid binding Ig-like lectin 5) and a chromosomal region downstream of the DEFA1A3 locus (defensin alpha 1-3) showed association with both disease phenotypes and were associated with periodontitis at a genome-wide significance level in the pooled samples, with P = 1.09E-08 (rs4284742,-G; OR = 1.34, 95% CI = 1.21-1.48) and P = 5.48E-10 (rs2738058,-T; OR = 1.28, 95% CI = 1.18-1.38), respectively. SIGLEC5 is expressed in various myeloid immune cells and classified as an inhibitory receptor with the potential to mediate tyrosine phosphatases SHP-1/-2 dependent signaling. Alpha defensins are antimicrobial peptides with expression in neutrophils and mucosal surfaces and a role in phagocyte-mediated host defense. This study identifies the first shared genetic risk loci of AgP and CP with genome-wide significance and highlights the role of innate and adaptive immunity in the etiology of periodontitis.

PMID: 28449029 [PubMed - indexed for MEDLINE]

Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination.

Wed, 11/01/2017 - 12:32
Related Articles

Motivations for (non)participation in population-based health studies among the elderly - comparison of participants and nonparticipants of a prospective study on influenza vaccination.

BMC Med Res Methodol. 2017 Feb 02;17(1):18

Authors: Akmatov MK, Jentsch L, Riese P, May M, Ahmed MW, Werner D, Rösel A, Prokein J, Bernemann I, Klopp N, Prochnow B, Illig T, Schindler C, Guzman CA, Pessler F

Abstract
BACKGROUND: Participation in epidemiological studies has strongly declined in recent years. We examined the reasons for (non)participation in population-based health studies among participants and nonparticipants of a prospective study on influenza vaccination among the elderly.
METHODS: Males and females between 65 and 80 years of age (N = 5582) were randomly selected from the residents' registration office in Hannover, Germany, and were invited to participate in a study featuring vaccination with a seasonal adjuvanted influenza vaccine (Fluad™, Novartis) including five follow-up visits (day 0, 1/3, 7, 21, 70 with respect to vaccination). A 24-item nonresponder questionnaire, including 10 items on reasons for participating in a hypothetical health study, was mailed to 1500 randomly selected nonparticipants. The same 10 items were included in the end-of-study questionnaire administered to the participants in the vaccination study (n = 200). Logistic regression analysis with backward elimination was used to identify the reasons most strongly associated with nonparticipation.
RESULTS: Five hundred thirty-one (35%) nonparticipants and 200 participants (100%) returned the respective questionnaires. Nonparticipation was associated with a lower interest in obtaining personal health information (OR = 3.32) and a preference for less invasive (OR = 3.01) and less time-demanding (OR = 2.19) studies. Responses to other items, e.g. regarding altruistic motives, monetary compensation, general interest of the study, or study approval through ethics committee and data security authority, did not differ between participants and nonparticipants.
CONCLUSIONS: Participation rates in health studies among elderly individuals could potentially be improved by reducing interventions and time demand, for instance by implementing methods of self-sampling and remote data collection.
TRIAL REGISTRATION: No. 1100359 (ClinicalTrials.gov, date of registration: 09.02.2015).

PMID: 28148221 [PubMed - indexed for MEDLINE]

Dietary Magnesium May Be Protective for Aging of Bone and Skeletal Muscle in Middle and Younger Older Age Men and Women: Cross-Sectional Findings from the UK Biobank Cohort.

Tue, 10/31/2017 - 11:11

Dietary Magnesium May Be Protective for Aging of Bone and Skeletal Muscle in Middle and Younger Older Age Men and Women: Cross-Sectional Findings from the UK Biobank Cohort.

Nutrients. 2017 Oct 30;9(11):

Authors: Welch AA, Skinner J, Hickson M

Abstract
Although fragility fractures, osteoporosis, sarcopenia, and frailty are becoming more prevalent in our aging society the treatment options are limited and preventative strategies are needed. Despite magnesium being integral to bone and muscle physiology, the relationship between dietary magnesium and skeletal muscle and bone health has not been investigated concurrently to date. We analysed cross-sectional associations between dietary magnesium and skeletal muscle mass (as fat free mass-FFM), grip strength, and bone density (BMD) in 156,575 men and women aged 39-72 years from the UK Biobank cohort. FFM was measured with bioelectrical impedance and was expressed as the percentage of body weight (FFM%) or as divided by body mass index (FFMBMI). Adjusted mean grip strength, FFM%, FFMBMI, and BMD were calculated according to quintiles of dietary magnesium, while correcting for covariates. Significant inter-quintile differences across intakes of magnesium existed in men and women, respectively, of 1.1% and 2.4% for grip strength, 3.0% and 3.6% for FFM%, 5.1% and 5.5% for FFMBMI, and 2.9% and 0.9% for BMD. These associations are as great or greater than annual measured losses of these musculoskeletal outcomes, indicating potential clinical significance. Our study suggests that dietary magnesium may play a role in musculoskeletal health and has relevance for population prevention strategies for sarcopenia, osteoporosis, and fractures.

PMID: 29084183 [PubMed - in process]