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Self-Rated Health Status and Risk of Ischemic Heart Disease in the China Kadoorie Biobank Study: A Population-Based Cohort Study.

Sun, 09/24/2017 - 13:15

Self-Rated Health Status and Risk of Ischemic Heart Disease in the China Kadoorie Biobank Study: A Population-Based Cohort Study.

J Am Heart Assoc. 2017 Sep 22;6(9):

Authors: Dong W, Pan XF, Yu C, Lv J, Guo Y, Bian Z, Yang L, Chen Y, Wu T, Chen Z, Pan A, Li L, China Kadoorie Biobank Collaborative Group

Abstract
BACKGROUND: Self-rated health (SRH) is a strong predictor of mortality in different populations. However, the associations between SRH measures and risk of ischemic heart disease (IHD) have not been extensively explored, especially in a Chinese population.
METHODS AND RESULTS: More than 500 000 adults from 10 cities in China were followed from baseline (2004-2008) through December 31, 2013. Global and age-comparative SRH were reported from baseline questionnaires. Incident IHD cases were identified through links to well-established disease registry systems and the national health insurance system. During 3 423 542 person-years of follow-up, we identified 24 705 incident cases of IHD. In multivariable-adjusted models, both global and age-comparative SRH was significantly associated with incident IHD. Compared with excellent SRH, the hazard ratios for good, fair, and poor SRH were 1.02 (95% confidence interval [CI], 0.98-1.07), 1.32 (95% CI, 1.27-1.37), and 1.76 (95% CI, 1.68-1.85), respectively. Compared with better age-comparative SRH, the hazard ratios for same and worse age-comparative SRH were 1.23 (95% CI, 1.19-1.27) and 1.78 (95% CI, 1.70-1.86), respectively. The associations persisted in all subgroup analyses, although they were slightly modified by study location, education, and income levels.
CONCLUSIONS: A simple questionnaire for self-assessment of health status was significantly associated with incident IHD in Chinese adults. Individuals and healthcare providers can use SRH measures as a convenient tool for assessing future IHD risk.

PMID: 28939702 [PubMed - in process]

Where Are They Now? ISBER Travel Award Winners 2014-2017.

Sat, 09/23/2017 - 15:13

Where Are They Now? ISBER Travel Award Winners 2014-2017.

Biopreserv Biobank. 2017 Sep 22;:

Authors: Seiler CY

PMID: 28937806 [PubMed - as supplied by publisher]

Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117).

Sat, 09/23/2017 - 15:13

Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in UK Biobank (N=112 117).

Mol Psychiatry. 2017 Oct;22(10):1376-1384

Authors: Clarke TK, Adams MJ, Davies G, Howard DM, Hall LS, Padmanabhan S, Murray AD, Smith BH, Campbell A, Hayward C, Porteous DJ, Deary IJ, McIntosh AM

Abstract
Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10(-23)). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.

PMID: 28937693 [PubMed - in process]

Differentially expressed genes and canonical pathways in the ascending thoracic aortic aneurysm - The Tampere Vascular Study.

Sat, 09/23/2017 - 15:13
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Differentially expressed genes and canonical pathways in the ascending thoracic aortic aneurysm - The Tampere Vascular Study.

Sci Rep. 2017 Sep 21;7(1):12127

Authors: Sulkava M, Raitoharju E, Mennander A, Levula M, Seppälä I, Lyytikäinen LP, Järvinen O, Illig T, Klopp N, Mononen N, Laaksonen R, Kähönen M, Oksala N, Lehtimäki T

Abstract
Ascending thoracic aortic aneurysm (ATAA) is a multifactorial disease with a strong inflammatory component. Surgery is often required to prevent aortic rupture and dissection. We performed gene expression analysis (Illumina HumanHT-12 version 3 Expression BeadChip) for 32 samples from ATAA (26 without/6 with dissection), and 28 left internal thoracic arteries (controls) collected in Tampere Vascular study. We compared expression profiles and conducted pathway analysis using Ingenuity Pathway Analysis (IPA) to reveal differences between ATAA and a healthy artery wall. Almost 5000 genes were differentially expressed in ATAA samples compared to controls. The most downregulated gene was homeobox (HOX) A5 (fold change, FC = -25.3) and upregulated cadherin-2 (FC = 12.6). Several other HOX genes were also found downregulated (FCs between -25.3 and -1.5, FDR < 0.05). 43, mostly inflammatory, canonical pathways in ATAA were found to be significantly (p < 0.05, FDR < 0.05) differentially expressed. The results remained essentially the same when the 6 dissected ATAA samples were excluded from the analysis. We show for the first time on genome level that ATAA is an inflammatory process, revealing a more detailed molecular pathway level pathogenesis. We propose HOX genes as potentially important players in maintaining aortic integrity, altered expression of which might be important in the pathobiology of ATAA.

PMID: 28935963 [PubMed - in process]

Gprc5a-knockout mouse lung epithelial cells predicts ceruloplasmin, lipocalin 2 and periostin as potential biomarkers at early stages of lung tumorigenesis.

Sat, 09/23/2017 - 15:13
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Gprc5a-knockout mouse lung epithelial cells predicts ceruloplasmin, lipocalin 2 and periostin as potential biomarkers at early stages of lung tumorigenesis.

Oncotarget. 2017 Feb 21;8(8):13532-13544

Authors: Sun B, Guo W, Hu S, Yao F, Yu K, Xing J, Wang R, Song H, Liao Y, Wang T, Jiang P, Han B, Deng J

Abstract
Lung cancer is the leading cause of cancer death. As most of lung cancer patients were diagnosed with the advanced stage, early detection is considered as the most effective strategy to reduce high mortality. Thus, it is desirable to identify specific biomarkers at early stages of lung tumorigenesis. GPRC5A is a lung tumor suppressor gene. GPRC5A deficiency is linked to lung cancer development. We hyposthesized that, dysregulated gene expression that results from Gprc5a deficiency may provide potential biomarkers at early stages of lung tumorigenesis. By analysis of top 20 upregulated genes in mouse tracheal epithelial cells (MTEC) of Gprc5a knockout (KO) vs wild-type (WT), we found that ceruloplasmin, lipocalin-2, and periostin are not only upregulated in lung epithelial cells of Gprc5a-ko mice, but also expressed at high levels in lung tumor tissues of Gprc5a-ko mice. This suggests that increased expression of these genes is associated with lung tumorigenesis. Importantly, expression of ceruloplasmin, lipocalin-2, and periostin has also been found to be significantly increased, both at mRNA and protein levels, in the lung tissues from NSCLC patients, which is correlated with repressed GPRC5A. Thus, dysregulated ceruloplasmin, lipocalin-2, and periostin may be used as potential biomarkers at early stages of lung tumorigenesis.

PMID: 28088789 [PubMed - indexed for MEDLINE]

A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.

Sat, 09/23/2017 - 15:13
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A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.

Oncotarget. 2017 Feb 28;8(9):15924-15933

Authors: Levy A, Bardet E, Lacas B, Pignon JP, Adam J, Lacroix L, Artignan X, Verrelle P, Le Péchoux C

Abstract
BACKGROUND: Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer.
PATIENTS AND METHODS: This phase II study evaluated the efficacy of gefitinib 250 mg once daily in combination with thoracic radiotherapy (66 Gy in 6.5 weeks, 2 Gy/day, 5 fractions/week) followed by consolidation chemotherapy (IV cisplatin and vinorelbine) as first line treatment in a population of unselected stage IIIB NSCLC patients according to EGFR mutation status.
RESULTS: Due to a low accrual rate in this study, the sample size (n = 50) was not reached. Sixteen patients were included in four centers, 50% had adenocarcinoma and 75% were male. Genomic alterations (7 patients studied) retrieved TP53 mutation in 2 patients and no EGFR mutation. Four weeks after radiotherapy, 3 patients (19%) had a partial response, 6 (38%) had a stable disease, and 7 had a progression (44%). Median overall survival was 11 months and median progression-free survival was 5 months. At the time of the last contact, 5 patients (31%) were still alive. Main toxicities were gastrointestinal (81%), cutaneous (81%), general (56%), and respiratory (50%). There were 12>G3 adverse events in 7 (47%) patients, and there was one toxic-death during the concomitant period due to an interstitial pneumonitis. There were two possible adverse events-related deaths during the chemotherapy period (pulmonary embolism (n = 1) and sudden death after the administration of the 3rd course of chemotherapy (n = 1)).
CONCLUSION: The benefit of Gefitinib-RT could not be confirmed due to premature trial discontinuation. Further evaluation is required, especially in patients with EGFR mutated NSCLC.

PMID: 27764781 [PubMed - indexed for MEDLINE]

Response to first line chemotherapy regimen is associated with efficacy of nivolumab in non-small-cell lung cancer.

Fri, 09/22/2017 - 13:41
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Response to first line chemotherapy regimen is associated with efficacy of nivolumab in non-small-cell lung cancer.

Oncoimmunology. 2017;6(9):e1339856

Authors: Kaderbhai CG, Richard C, Fumet JD, Aarnink A, Ortiz-Cuaran S, Pérol M, Foucher P, Coudert B, Favier L, Lagrange A, Limagne E, Boidot R, Ladoire S, Poudenx M, Ilie M, Hofman P, Saintigny P, Ghiringhelli F

Abstract
Nivolumab, an anti PD-1 checkpoint inhibitor has demonstrated efficacy in metastatic non-small-cell lung cancer (NSCLC) patients after failure to standard chemotherapy. Standard chemotherapy agents could promote antitumor immune response. We thus examined whether the response to first line chemotherapy could impact on nivolumab benefit. One hundred and 15 patients with NSCLC were included in this retrospective study from 4 different French centers. Forty-three squamous cell carcinomas (SCC), and 72 non-SCC received nivolumab between 2015 and 2016 (3 mg/kg IV Q2W). Response to first-line chemotherapy and to nivolumab was retrospectively assessed on CT-scan by central review. The association between RECIST response to first-line chemotherapy and nivolumab efficacy were determined using Fisher's exact test and Cox proportional hazard model. Respectively 46 (40%), 44 (38%) and 25 (22%) patients experienced partial response (PR), stable disease (SD), or progressive disease (PD) in response to first-line platinum- based chemotherapy. Twenty 5 (21%), 34 (30%), 56 (49%) respectively experienced PR, SD and PD in response to nivolumab. 60% (54/90) of patients who experienced clinical benefit (PR + SD) after first-line chemotherapy also had clinical benefit after nivolumab, while only 20% (5/25) of patients with initial PD subsequently experienced clinical benefit with nivolumab (Fisher's exact test, P = 0.001). The type of first-line doublet chemotherapy did not influence the response rate to nivolumab. Univariate and multivariate analyses showed that patients with clinical benefit from first-line chemotherapy had higher second-line PFS (P = 0.003) (median PFS on nivolumab of 5, 3.3 and 1.9 months for patients with PR, SD and PD in response to first-line therapy, respectively). Similar results were obtained for OS. Thus this study suggests that the efficacy of first-line chemotherapy may be a valuable surrogate marker of the benefit of nivolumab in terms of PFS and OS.

PMID: 28932641 [PubMed]

Cohort Profile Update: The Amirkola Health and Ageing Project (AHAP).

Fri, 09/22/2017 - 13:41
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Cohort Profile Update: The Amirkola Health and Ageing Project (AHAP).

Caspian J Intern Med. 2017;8(3):205-212

Authors: Bijani A, Ghadimi R, Mikaniki E, Kheirkhah F, Mozaffarpur SA, Motallebnejad M, Esmaili H, Majidi F, Cumming RG, Hosseini SR

Abstract
The original cohort study of AHAP started in 2011 on 1616 elderly residents of Amirkola, northern part of Iran near the Caspian Sea. The main goal of this study was to comprehensively evaluate the health of the elderly in the region with the emphasis on chronic diseases such as osteoporosis. The first cohort profile was published in the International Journal of Epidemiology in 2014. The phase 1 AHAP showed the elevated level of some diseases and conditions including osteoporosis, metabolic syndrome, obesity, vision problems and relatively low levels of oral health. Therefore, the second phase of this cohort started with more complete population coverage in 2016, not only to collect and record the information based on previous protocol, but also consider new areas such as nutritional status, complete eye and dental examinations and health assessment on the basis of Iranian Traditional Medicine. The new aspect of this project is to conduct clinical and laboratory examinations at the health center to extend more facilities to the elderly. In addition to serum and DNA, samples of saliva, hair and nails are collected and kept under standard conditions in the biobank of this cohort. Researchers can apply for access to data or suggest a collaborative study by submitting the proposal to AHAP committee.

PMID: 28932373 [PubMed]

Delivery of a chemotherapeutic drug using novel hollow carbon spheres for esophageal cancer treatment.

Fri, 09/22/2017 - 13:41
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Delivery of a chemotherapeutic drug using novel hollow carbon spheres for esophageal cancer treatment.

Int J Nanomedicine. 2017;12:6759-6769

Authors: Zhang L, Yao M, Yan W, Liu X, Jiang B, Qian Z, Gao Y, Lu XJ, Chen X, Wang QL

Abstract
Low toxicity and high efficacy are the key factors influencing the real-world clinical applications of nanomaterial-assisted drug delivery. In this study, novel hollow carbon spheres (HCSs) with narrow size distribution were developed. In addition to demonstrating their ease of synthesis for large-scale production, we also demonstrated in vitro that the HCSs possessed high drug-loading capacity, lower cell toxicity, and optimal drug release profile at low pH, similar to the pH in the tumor microenvironment. The HCSs also displayed excellent immunocompatibility and could rapidly distribute themselves in the cytoplasm to escape lysosomal clearance. More importantly, the HCSs could efficiently deliver doxorubicin (a representative chemotherapeutic drug) to tumor sites, which resulted in significant inhibition of tumor growth in an esophageal xenograft cancer model. This also prolonged the circulation time and altered the biodistribution of the drug. In conclusion, this study revealed a novel drug delivery system for targeted tumor therapy.

PMID: 28932119 [PubMed - in process]

Whole-exome sequencing implicates DGKH as a risk gene for panic disorder in the Faroese population.

Fri, 09/22/2017 - 13:41
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Whole-exome sequencing implicates DGKH as a risk gene for panic disorder in the Faroese population.

Am J Med Genet B Neuropsychiatr Genet. 2016 Dec;171(8):1013-1022

Authors: Gregersen NO, Lescai F, Liang J, Li Q, Als T, Buttenschøn HN, Hedemand A, Biskopstø M, Wang J, Wang AG, Børglum AD, Mors O, Demontis D

Abstract
The demographic history of the isolated population of the Faroe Islands may have induced enrichment of variants rarely seen in outbred European populations, including enrichment of risk variants for panic disorder (PD). PD is a common mental disorder, characterized by recurring and unprovoked panic attacks, and genetic factors have been estimated to explain around 40% of the risk. In this study the potential enrichment of PD risk variants was explored based on whole-exome sequencing of 54 patients with PD and 211 control individuals from the Faroese population. No genome-wide significant associations were found, however several single variants and genes showed strong association with PD, where DGKH was found to be the strongest PD associated gene. Interestingly DGKH has previously demonstrated genome-wide significant association with bipolar disorder as well as evidence of association to other mental disorders. Additionally, we found an enrichment of PD risk variants in the Faroese population; variants with otherwise low frequency in more outbreed European populations. © 2016 Wiley Periodicals, Inc.

PMID: 27255576 [PubMed - indexed for MEDLINE]

Genome-wide association study of serum coenzyme Q10 levels identifies susceptibility loci linked to neuronal diseases.

Fri, 09/22/2017 - 13:41
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Genome-wide association study of serum coenzyme Q10 levels identifies susceptibility loci linked to neuronal diseases.

Hum Mol Genet. 2016 Jul 01;25(13):2881-2891

Authors: Degenhardt F, Niklowitz P, Szymczak S, Jacobs G, Lieb W, Menke T, Laudes M, Esko T, Weidinger S, Franke A, Döring F, Onur S

Abstract
Coenzyme Q10 (CoQ10) is a lipophilic redox molecule that is present in membranes of almost all cells in human tissues. CoQ10 is, amongst other functions, essential for the respiratory transport chain and is a modulator of inflammatory processes and gene expression. Rare monogenetic CoQ10 deficiencies show noticeable symptoms in tissues (e.g. kidney) and cell types (e.g. neurons) with a high energy demand. To identify common genetic variants influencing serum CoQ10 levels, we performed a fixed effects meta-analysis in two independent cross-sectional Northern German cohorts comprising 1300 individuals in total. We identified two genome-wide significant susceptibility loci. The best associated single nucleotide polymorphism (SNP) was rs9952641 (P value = 1.31 × 10 (-)(8), β = 0.063, CI0.95 [0.041, 0.085]) within the COLEC12 gene on chromosome 18. The SNP rs933585 within the NRXN-1 gene on chromosome 2 also showed genome wide significance (P value = 3.64 × 10 (-)(8), β = -0.034, CI0.95 [-0.046, -0.022]). Both genes have been previously linked to neuronal diseases like Alzheimer's disease, autism and schizophrenia. Among our 'top-10' associated variants, four additional loci with known neuronal connections showed suggestive associations with CoQ10 levels. In summary, this study demonstrates that serum CoQ10 levels are associated with common genetic loci that are linked to neuronal diseases.

PMID: 27149984 [PubMed - indexed for MEDLINE]

The Impact of Repeated Freeze-Thaw Cycles on the Quality of Biomolecules in Four Different Tissues.

Thu, 09/21/2017 - 14:55
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The Impact of Repeated Freeze-Thaw Cycles on the Quality of Biomolecules in Four Different Tissues.

Biopreserv Biobank. 2017 Sep 20;

Authors: Ji X, Wang M, Li L, Chen F, Zhang Y, Li Q, Zhou J

Abstract
High-quality biosamples are valuable resources for biomedical research. However, some tissues are stored without being sectioned into small aliquots and have to undergo repeated freeze-thaw cycles throughout prolonged experimentation. Little is known regarding the effects of repeated freeze-thaw cycles on the quality of biomolecules in tissues. The aim of this study was to evaluate the impact of repeated freeze-thaw (at room temperature or on ice) cycles on biomolecules and gene expression in four different types of tissues. Each fresh tissue was sectioned into seven aliquots and snap-frozen before undergoing repeated freeze-thaw cycles at room temperature or on ice. Biomolecules were extracted and analyzed. Both relative and absolute quantification were used to detect the changes in gene expression. The results indicated that the impact of repeated freeze-thaw cycles on RNA integrity varied by tissue type. Gene expression, including the housekeeping gene, was affected in RNA-degraded samples according to absolute quantification rather than relative quantification. Furthermore, our results suggest that thawing on ice could protect RNA integrity compared with thawing at room temperature. No obvious degradation of protein or DNA was observed with repeated freeze-thaw cycles either at room temperature or on ice. This research provides ample evidence for the necessity of sectioning fresh tissues into small aliquots before snap-freezing, thus avoiding degradation of RNA and alteration of gene expression resulting from repeated freeze-thaw cycles. For frozen tissue samples that were already in storage and had to be used repeatedly during their lifecycle, thawing on ice or sectioned at ultralow temperature is recommended.

PMID: 28930488 [PubMed - as supplied by publisher]

Genetics of Tinnitus: Time to Biobank Phantom Sounds.

Thu, 09/21/2017 - 14:55
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Genetics of Tinnitus: Time to Biobank Phantom Sounds.

Front Genet. 2017;8:110

Authors: Cederroth CR, Kähler AK, Sullivan PF, Lopez-Escamez JA

Abstract
Tinnitus is a common phantom sensation resulting most often from sensory deprivation, and for which little knowledge on the molecular mechanisms exists. While the existing evidence for a genetic influence on the condition has been until now sparse and underpowered, recent data suggest that specific forms of tinnitus have a strong genetic component revealing that not all tinnitus percepts are alike, at least in how they are genetically driven. These new findings pave the way for a better understanding on how phantom sensations are molecularly driven and call for international biobanking efforts.

PMID: 28928766 [PubMed]

Sex-Genetic Interaction in the Risk for Cerebrovascular Disease.

Thu, 09/21/2017 - 14:55
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Sex-Genetic Interaction in the Risk for Cerebrovascular Disease.

Curr Med Chem. 2017;24(24):2687-2699

Authors: Pastore D, Pacifici F, Capuani B, Palmirotta R, Dong C, Coppola A, Abete P, Roselli M, Sbraccia P, Guadagni F, Lauro D, Rundek T, Della-Morte D

Abstract
Cerebrovascular disease (CeVD) is one of the major causes of death and a leading cause of disability worldwide. CeVD is a complex and multifactorial disease caused by the interaction of environment and genetic factors. Women have lower CeVD incidence than men until an advanced age, when the incidence of CeVD rises dramatically in women. Therefore, sex has been validated as an important risk factor in the etiology of CeVD, especially ischemic stroke. Although the importance of sex steroids have been heavily studied in the mechanism of neuronal injury, the experimental and clinical data suggest that hormones do not fully account for male versus female CeVD patterns. Sex-specific genetic processes have been implicated in the different rate of risk for atherosclerosis and CeVD. In this review, we discuss sex-specific CeVD processes, describe the hormonal impact on the risk for CeVD, the results from studies in transgenic animals, and from human genetic studies. Moreover, heritability of ischemic stroke in women and men as well as identification of possible sex-specific biomarkers for CeVD are discussed. Understanding the complex interactions between hormonal and genetic mechanisms in the CeVD risk will allow for new sex-specific approaches in disease treatment and prevention in clinical practice.

PMID: 28413964 [PubMed - indexed for MEDLINE]

Gender Differences in Cancer-associated Venous Thromboembolism.

Thu, 09/21/2017 - 14:55
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Gender Differences in Cancer-associated Venous Thromboembolism.

Curr Med Chem. 2017;24(24):2589-2601

Authors: Riondino S, Guadagni F, Formica V, Ferroni P, Roselli M

Abstract
Venous thromboembolism (VTE) is a commonly diagnosed multifactorial condition with significant morbidity and mortality, occurring in up to 20% of cancer patients. Indeed, patients with cancer are in a higher pro-thrombotic state due to alterations in their haemostatic- coagulative system, stasis and blood flow slowdown, endothelial dysfunction, vascular inflammation and platelet activation. Moreover, several cancer-dependent factors can sum up to trigger a first episode of VTE or to cause its recurrence in the course of anticoagulant treatment. Such a pro-thrombotic condition is further worsened by additional favoring risks such as immobilization, infection, surgery, or insertion of a central venous catheter, and anti-cancer therapy. Furthermore, in the secondary prevention setting, the anticoagulant therapy is accompanied by a high incidence of bleeding complications. Given the above, understanding and identifying the factors associated with the incidence and clinical outcome of VTE in cancer patients might be of great value in the prevention and management of VTEattributable complications, including death. Differences associated to gender on cancerrelated VTEs are not yet fully defined; many of the studies that addressed the question have been biased by erroneous/non homogeneous inclusion criteria. In the present review, we analyzed the potential differences in VTEs occurrence in cancer patients, by reporting the most significant findings in the recent literature. The identification of a differential clinical approach according to patient sex, might prompt the design of personalized treatment options tailored and optimized according to algorithms for oncological VTE prevention.

PMID: 27758714 [PubMed - indexed for MEDLINE]

Protocol and quality assurance for carotid imaging in 100,000 participants of UK Biobank: development and assessment.

Wed, 09/20/2017 - 12:36

Protocol and quality assurance for carotid imaging in 100,000 participants of UK Biobank: development and assessment.

Eur J Prev Cardiol. 2017 Jan 01;:2047487317732273

Authors: Coffey S, Lewandowski AJ, Garratt S, Meijer R, Lynum S, Bedi R, Paterson J, Yaqub M, Noble JA, Neubauer S, Petersen SE, Allen N, Sudlow C, Collins R, Matthews PM, Leeson P

Abstract
Background Ultrasound imaging is able to quantify carotid arterial wall structure for the assessment of cerebral and cardiovascular disease risks. We describe a protocol and quality assurance process to enable carotid imaging at large scale that has been developed for the UK Biobank Imaging Enhancement Study of 100,000 individuals. Design An imaging protocol was developed to allow measurement of carotid intima-media thickness from the far wall of both common carotid arteries. Six quality assurance criteria were defined and a web-based interface (Intelligent Ultrasound) was developed to facilitate rapid assessment of images against each criterion. Results and conclusions Excellent inter and intra-observer agreements were obtained for image quality evaluations on a test dataset from 100 individuals. The image quality criteria then were applied in the UK Biobank Imaging Enhancement Study. Data from 2560 participants were evaluated. Feedback of results to the imaging team led to improvement in quality assurance, with quality assurance failures falling from 16.2% in the first two-month period examined to 6.4% in the last. Eighty per cent had all carotid intima-media thickness images graded as of acceptable quality, with at least one image acceptable for 98% of participants. Carotid intima-media thickness measures showed expected associations with increasing age and gender. Carotid imaging can be performed consistently, with semi-automated quality assurance of all scans, in a limited timeframe within a large scale multimodality imaging assessment. Routine feedback of quality control metrics to operators can improve the quality of the data collection.

PMID: 28925747 [PubMed - as supplied by publisher]

The common variants implicated in microstructural abnormality of first episode and drug-naïve patients with schizophrenia.

Wed, 09/20/2017 - 12:36
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The common variants implicated in microstructural abnormality of first episode and drug-naïve patients with schizophrenia.

Sci Rep. 2017 Sep 18;7(1):11750

Authors: Ren HY, Wang Q, Lei W, Zhang CC, Li YF, Li XJ, Li ML, Deng W, Huang CH, Du F, Zhao LS, Wang YC, Ma XH, Hu X, Li T

Abstract
Both post-mortem and neuroimaging studies have identified abnormal white matter (WM) microstructure in patients with schizophrenia. However, its genetic underpinnings and relevant biological pathways remain unclear. In order to unravel the genes and the pathways associated with abnormal WM microstructure in schizophrenia, we recruited 100 first-episode, drug-naïve patients with schizophrenia and 140 matched healthy controls to conduct genome-wide association analysis of fractional anisotropy (FA) value measured using diffusing tensor imaging (DTI), followed by multivariate association study and pathway enrichment analysis. The results showed that one intergenic SNP (rs11901793), which is 20 kb upstream of CXCR7 gene on chromosome 2, was associated with the total mean FA values with genome-wide significance (p = 4.37 × 10(-8)), and multivariate association analysis identified a strong association between one region-specific SNP (rs10509852), 400 kb upstream of SORCS1 gene on chromosome 10, and the global trait of abnormal WM microstructure (p = 1.89 × 10(-7)). Furthermore, one pathway that is involved in cell cycle regulation, REACTOME_CHROMOSOME _MAINTENANCE, was significantly enriched by the genes that were identified in our study (p = 1.54 × 10(-17)). In summary, our study provides suggestive evidence that abnormal WM microstructure in schizophrenia is associated with genes that are likely involved in diverse biological signals and cell-cycle regulation although further replication in a larger independent sample is needed.

PMID: 28924203 [PubMed - in process]

The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders.

Wed, 09/20/2017 - 12:36
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The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders.

Mol Psychiatry. 2017 Sep 19;:

Authors: Pedersen CB, Bybjerg-Grauholm J, Pedersen MG, Grove J, Agerbo E, Bækvad-Hansen M, Poulsen JB, Hansen CS, McGrath JJ, Als TD, Goldstein JI, Neale BM, Daly MJ, Hougaard DM, Mors O, Nordentoft M, Børglum AD, Werge T, Mortensen PB

Abstract
The Integrative Psychiatric Research (iPSYCH) consortium has established a large Danish population-based Case-Cohort sample (iPSYCH2012) aimed at unravelling the genetic and environmental architecture of severe mental disorders. The iPSYCH2012 sample is nested within the entire Danish population born between 1981 and 2005, including 1 472 762 persons. This paper introduces the iPSYCH2012 sample and outlines key future research directions. Cases were identified as persons with schizophrenia (N=3540), autism (N=16 146), attention-deficit/hyperactivity disorder (N=18 726) and affective disorder (N=26 380), of which 1928 had bipolar affective disorder. Controls were randomly sampled individuals (N=30 000). Within the sample of 86 189 individuals, a total of 57 377 individuals had at least one major mental disorder. DNA was extracted from the neonatal dried blood spot samples obtained from the Danish Neonatal Screening Biobank and genotyped using the Illumina PsychChip. Genotyping was successful for 90% of the sample. The assessments of exome sequencing, methylation profiling, metabolome profiling, vitamin-D, inflammatory and neurotrophic factors are in progress. For each individual, the iPSYCH2012 sample also includes longitudinal information on health, prescribed medicine, social and socioeconomic information, and analogous information among relatives. To the best of our knowledge, the iPSYCH2012 sample is the largest and most comprehensive data source for the combined study of genetic and environmental aetiologies of severe mental disorders.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.196.

PMID: 28924187 [PubMed - as supplied by publisher]

Genetic contributions to Trail Making Test performance in UK Biobank.

Wed, 09/20/2017 - 12:36
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Genetic contributions to Trail Making Test performance in UK Biobank.

Mol Psychiatry. 2017 Sep 19;:

Authors: Hagenaars SP, Cox SR, Hill WD, Davies G, Liewald DCM, CHARGE consortium Cognitive Working Group, Harris SE, McIntosh AM, Gale CR, Deary IJ

Abstract
The Trail Making Test (TMT) is a widely used test of executive function and has been thought to be strongly associated with general cognitive function. We examined the genetic architecture of the TMT and its shared genetic aetiology with other tests of cognitive function in 23 821 participants from UK Biobank. The single-nucleotide polymorphism-based heritability estimates for trail-making measures were 7.9% (part A), 22.4% (part B) and 17.6% (part B-part A). Significant genetic correlations were identified between trail-making measures and verbal-numerical reasoning (rg>0.6), general cognitive function (rg>0.6), processing speed (rg>0.7) and memory (rg>0.3). Polygenic profile analysis indicated considerable shared genetic aetiology between trail making, general cognitive function, processing speed and memory (standardized β between 0.03 and 0.08). These results suggest that trail making is both phenotypically and genetically strongly associated with general cognitive function and processing speed.Molecular Psychiatry advance online publication, 19 September 2017; doi:10.1038/mp.2017.189.

PMID: 28924184 [PubMed - as supplied by publisher]

ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility.

Wed, 09/20/2017 - 12:36
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ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility.

Oncol Res. 2017 Sep 18;:

Authors: Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Satoh H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

Abstract
We previously identified novel S100A8/A9 receptors, Extracellular Matrix Metalloproteinase Inducer (EMMPRIN), MelanomaCell Adhesion Molecule (MCAM), Activated Leukocyte Cell Adhesion Molecule (ALCAM) and Neuroplastin (NPTN) ß, that are critically involved in S100A8/A9-mediated cancer metastasis and inflammation when expressed at high levels. However, little is known about the presence of any cancerspecific mechanism(s) that modifies these receptors, further inducing upregulation at protein levels without any transcriptional regulation. Expression levels of glycosyltransferase-encoding genes were examined by a PCR-based profiling array followed by confirmation with quantitative real time PCR. Cell migration and invasion were assessed by a using Boyden chamber. Western blotting was used to examine the protein level, and the RNA level was examined by Northern blotting. Immunohistochemistry was used to examine the expression pattern of GCNT3 and MCAM in melanoma tissue. We found that ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 (GCNT3) is overexpressed in highly metastatic melanomas. Silencing and functional inhibition of GCNT3 greatly suppressed migration and invasion of melanoma cells, resulting in the loss of S100A8/A9 responsiveness. Among the novel S100A8/A9 receptors, GCNT3 favorably glycosylates the MCAM receptor, extending its half-life and leading to further elevation of S100A8/A9-mediated cellular motility in melanoma cells. GCNT3 expression is positively correlated to MCAM expression in patients with high-grade melanomas. Collectively, our results showed that GCNT3 is an upstream regulator of MCAM protein and indicate the possibility of a potential molecular target in melanoma therapeutics through abrogation of the S100A8/A9-MCAM axis.

PMID: 28923134 [PubMed - as supplied by publisher]