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Personalized Therapy Against Preeclampsia by Replenishing Placental Protein 13 (PP13) Targeted to Patients With Impaired PP13 Molecule or Function.

Tue, 10/17/2017 - 14:39
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Personalized Therapy Against Preeclampsia by Replenishing Placental Protein 13 (PP13) Targeted to Patients With Impaired PP13 Molecule or Function.

Comput Struct Biotechnol J. 2017;15:433-446

Authors: Meiri H, Osol G, Cetin I, Gizurarson S, Huppertz B

Abstract
Hypertensive disorders affect about one third of all people aged 20 and above, and are treated with anti-hypertensive drugs. Preeclampsia (PE) is one form of such disorders that only develops during pregnancy. It affects ten million pregnant women globally and additionally causes fetal loss and major newborn disabilities. The syndrome's origin is multifactorial, and anti-hypertensive drugs are ineffective in treating it. Biomarkers are helpful for predict its development. Generic drugs, such as low dose aspirin, were proven effective in preventing preterm PE. However, it does not cure the majority of cases and many studies are underway for fighting PE with extended use of additional generic drugs, or through new drug development programs. This review focuses on placental protein 13 (PP13). This protein is only expressed in the placenta. Impaired PP13 DNA structure and/or its reduced mRNA expression leads to lower blood PP13 level that predict a higher risk of developing PE. Two polymorphic PP13 variants have been identified: (1) The promoter PP13 variant with an "A/A" genotype in the -98 position (versus "A/C" or "C/C"). Having the "A/A" genotype is coupled to lower PP13 expression, mainly during placental syncytiotrophoblast differentiation and, if associated with obesity and history of previous preeclampsia, it accurately predicts higher risk for developing the disorder. (2) A thymidine deletion at position 221 causes a frame shift in the open reading frame, and the formation of an early stop codon resulting in the formation of DelT221, a truncated variant of PP13. In pregnant rodents, both short- and long- term replenishment of PP13 causes reversible hypotension and vasodilation of uterine vessels. Long-term exposure is also accompanied by the development of larger placentas and newborns. Also, only w/t PP13 is capable of inducing leukocyte apoptosis, providing maternal immune tolerance to pregnancy. Based on published data, we propose a targeted PP13 therapy to fight PE, and consider the design and conduct of animal studies to explore this hypothesis. Accordingly, a new targeted therapy can be implemented in humans combining prediction and prevention.

PMID: 29034064 [PubMed]

Genetic association analysis of vitamin D receptor gene polymorphisms and obesity-related phenotypes.

Tue, 10/17/2017 - 14:39
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Genetic association analysis of vitamin D receptor gene polymorphisms and obesity-related phenotypes.

Gene. 2017 Oct 12;:

Authors: María CR, Antonio CJ, Jacqueline SR, Emilio GJ, Sofia V, Javier M, Blanca RM

Abstract
Vitamin D has been established as a key factor in the development of obesity through the vitamin D receptor (VDR). The aim of this study was to investigate the contribution of the VDR gene to obesity-related phenotypes in a population of Caucasian young adults. The study population consisted of 701 healthy Spanish young adults (mean age 20.41±2.48). Three single-nucleotide polymorphisms (SNPs) of VDR (TaqI, BsmI and FokI) were selected as genetic markers. Body composition measurements including weight, body mass index (BMI), fat mass (FM), percentage of fat mass (PFM), fat-free mass (FFM) and visceral fat level (VFL) were analysed. Differences in obesity traits across the genotypes were determined using analysis of covariance (ANCOVA). The FokI polymorphism showed a significant association with PFM across the whole population after adjusting for age and sex (p=0.022). Age-adjusted analysis revealed an association between body weight and the TaqI and BsmI SNPs in males (p=0.033 and p=0.028, respectively). However, these positive findings did not remain significant after applying the Bonferroni correction for multiple testing. Our findings suggest that VDR genetic variants are unlikely to play a major role in obesity-related phenotypes in a population of Caucasian young adults.

PMID: 29032145 [PubMed - as supplied by publisher]

Sleep and cognitive performance: cross-sectional associations in the UK Biobank.

Tue, 10/17/2017 - 14:39
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Sleep and cognitive performance: cross-sectional associations in the UK Biobank.

Sleep Med. 2017 Oct;38:85-91

Authors: Kyle SD, Sexton CE, Feige B, Luik AI, Lane J, Saxena R, Anderson SG, Bechtold DA, Dixon W, Little MA, Ray D, Riemann D, Espie CA, Rutter MK, Spiegelhalder K

Abstract
OBJECTIVE: The relationship between insomnia symptoms and cognitive performance is unclear, particularly at the population level. We conducted the largest examination of this association to date through analysis of the UK Biobank, a large population-based sample of adults aged 40-69 years. We also sought to determine associations between cognitive performance and self-reported chronotype, sleep medication use and sleep duration.
METHODS: This cross-sectional, population-based study involved 477,529 participants, comprising 133,314 patients with frequent insomnia symptoms (age: 57.4 ± 7.7 years; 62.1% female) and 344,215 controls without insomnia symptoms (age: 56.1 ± 8.2 years; 52.0% female). Cognitive performance was assessed by a touchscreen test battery probing reasoning, basic reaction time, numeric memory, visual memory, and prospective memory. Adjusted models included relevant demographic, clinical, and sleep variables.
RESULTS: Frequent insomnia symptoms were associated with cognitive impairment in unadjusted models; however, these effects were reversed after full adjustment, leaving those with frequent insomnia symptoms showing statistically better cognitive performance over those without. Relative to intermediate chronotype, evening chronotype was associated with superior task performance, while morning chronotype was associated with the poorest performance. Sleep medication use and both long (>9 h) and short (<7 h) sleep durations were associated with impaired performance.
CONCLUSIONS: Our results suggest that after adjustment for potential confounding variables, frequent insomnia symptoms may be associated with a small statistical advantage, which is unlikely to be clinically meaningful, on simple neurocognitive tasks. Further work is required to examine the mechanistic underpinnings of an apparent evening chronotype advantage in cognitive performance and the impairment associated with morning chronotype, sleep medication use, and sleep duration extremes.

PMID: 29031762 [PubMed - in process]

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.

Tue, 10/17/2017 - 14:39
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New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.

Circ Cardiovasc Genet. 2017 Oct;10(5):

Authors: Kraja AT, Cook JP, Warren HR, Surendran P, Liu C, Evangelou E, Manning AK, Grarup N, Drenos F, Sim X, Smith AV, Amin N, Blakemore AIF, Bork-Jensen J, Brandslund I, Farmaki AE, Fava C, Ferreira T, Herzig KH, Giri A, Giulianini F, Grove ML, Guo X, Harris SE, Have CT, Havulinna AS, Zhang H, Jørgensen ME, Käräjämäki A, Kooperberg C, Linneberg A, Little L, Liu Y, Bonnycastle LL, Lu Y, Mägi R, Mahajan A, Malerba G, Marioni RE, Mei H, Menni C, Morrison AC, Padmanabhan S, Palmas W, Poveda A, Rauramaa R, Rayner NW, Riaz M, Rice K, Richard MA, Smith JA, Southam L, Stančáková A, Stirrups KE, Tragante V, Tuomi T, Tzoulaki I, Varga TV, Weiss S, Yiorkas AM, Young R, Zhang W, Barnes MR, Cabrera CP, Gao H, Boehnke M, Boerwinkle E, Chambers JC, Connell JM, Christensen CK, de Boer RA, Deary IJ, Dedoussis G, Deloukas P, Dominiczak AF, Dörr M, Joehanes R, Edwards TL, Esko T, Fornage M, Franceschini N, Franks PW, Gambaro G, Groop L, Hallmans G, Hansen T, Hayward C, Heikki O, Ingelsson E, Tuomilehto J, Jarvelin MR, Kardia SLR, Karpe F, Kooner JS, Lakka TA, Langenberg C, Lind L, Loos RJF, Laakso M, McCarthy MI, Melander O, Mohlke KL, Morris AP, Palmer CNA, Pedersen O, Polasek O, Poulter NR, Province MA, Psaty BM, Ridker PM, Rotter JI, Rudan I, Salomaa V, Samani NJ, Sever PJ, Skaaby T, Stafford JM, Starr JM, van der Harst P, van der Meer P, Understanding Society Scientific Group, van Duijn CM, Vergnaud AC, Gudnason V, Wareham NJ, Wilson JG, Willer CJ, Witte DR, Zeggini E, Saleheen D, Butterworth AS, Danesh J, Asselbergs FW, Wain LV, Ehret GB, Chasman DI, Caulfield MJ, Elliott P, Lindgren CM, Levy D, Newton-Cheh C, Munroe PB, Howson JMM, CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group†

Abstract
BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association.
METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10(-)(8)) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant.
CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

PMID: 29030403 [PubMed - in process]

Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

Tue, 10/17/2017 - 14:39
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Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.

Lancet Neurol. 2017 Nov;16(11):898-907

Authors: Schormair B, Zhao C, Bell S, Tilch E, Salminen AV, Pütz B, Dauvilliers Y, Stefani A, Högl B, Poewe W, Kemlink D, Sonka K, Bachmann CG, Paulus W, Trenkwalder C, Oertel WH, Hornyak M, Teder-Laving M, Metspalu A, Hadjigeorgiou GM, Polo O, Fietze I, Ross OA, Wszolek Z, Butterworth AS, Soranzo N, Ouwehand WH, Roberts DJ, Danesh J, Allen RP, Earley CJ, Ondo WG, Xiong L, Montplaisir J, Gan-Or Z, Perola M, Vodicka P, Dina C, Franke A, Tittmann L, Stewart AFR, Shah SH, Gieger C, Peters A, Rouleau GA, Berger K, Oexle K, Di Angelantonio E, Hinds DA, Müller-Myhsok B, Winkelmann J, 23andMe Research Team, DESIR study group

Abstract
BACKGROUND: Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets.
METHODS: In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10(-8)) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest.
FINDINGS: We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85-1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1).
INTERPRETATION: Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations.
FUNDING: Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München-Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.

PMID: 29029846 [PubMed - in process]

An increased concentration of receptor activator of nuclear factor kappa-B ligand pre-dates the onset of rheumatoid arthritis.

Sun, 10/15/2017 - 21:43

An increased concentration of receptor activator of nuclear factor kappa-B ligand pre-dates the onset of rheumatoid arthritis.

Rheumatology (Oxford). 2017 Sep 25;:

Authors: Johansson L, Ärlestig L, Kokkonen H, Brink M, Rantapää-Dahlqvist S

Abstract
Objectives: RANK ligand (RANKL) is involved in destruction and osteoporosis in RA. In this study, the relationships between RANKL and ACPA, anti-carbamylated protein antibodies (anti-CarP), cytokines and chemokines were analysed in individuals before the onset of RA symptoms, and their associations with radiological findings at disease onset were assessed.
Methods: This was a case-control study performed within the Medical Biobank of Northern Sweden that included 470 pre-symptomatic individuals [334 women and 136 men; mean (s.d.) age 52.3 (9.4) years] using blood samples donated before symptom onset (pre-dating time; 5.0 years) and 96 controls (60 women and 36 men). Plasma was analysed for RANKL (BioVendor, Karasek, Brno, Czech Republic), anti-CCP2 antibodies (Eurodiagnostics, Malmö, Sweden), anti-CarP antibodies (in-house ELISA), ACPA specificities (ISAC-platform, Phadia AB, Uppsala, Sweden) and cytokines/chemokines (Meso Scale Discovery methods, Rockville, MD, USA). Radiographs of hands and feet were graded using the Larsen score.
Results: The concentration of RANKL was higher in the pre-symptomatic individuals compared with controls; mean (s.e.m.): 0.50 (0.03) vs 0.22 (0.02) nmol/l (P < 0.001). The concentration increased gradually over time until symptom onset but appeared later than ACPA/RF/anti-CarP antibodies. Positivity for these antibodies yielded higher levels of RANKL compared with seronegativity (P < 0.001). RANKL concentrations were significantly associated with IL-6 and IL-10 concentrations. The combination of positivity for RANKL and anti-CarP antibodies resulted in a higher Larsen score at diagnosis β = 6.18 (95% CI: 0.93, 11.43; P = 0.022).
Conclusion: RANKL concentrations were increased several years before symptom onset for RA, particularly in ACPA/RF/anti-CarP-positive individuals, all detectable earlier than RANKL. Positivity for RANKL and anti-CarP antibodies yielded the highest Larsen score at disease onset.

PMID: 29029341 [PubMed - as supplied by publisher]

Age at menarche and depressive symptoms in older Southern Chinese women: A Mendelian randomization study in the Guangzhou Biobank Cohort Study.

Sun, 10/15/2017 - 21:43

Age at menarche and depressive symptoms in older Southern Chinese women: A Mendelian randomization study in the Guangzhou Biobank Cohort Study.

Psychiatry Res. 2017 Sep 19;259:32-35

Authors: Au Yeung SL, Jiang C, Cheng KK, Xu L, Zhang W, Lam TH, Leung GM, Schooling CM

Abstract
To clarify the causal role of age at menarche in depressive symptoms we conducted a Mendelian randomization study using a large Southern Chinese cohort (n = 12,233). A genetic allele score was derived using stepwise regression with cross validation. Older age at menarche was not associated with geriatric depression scale score. Our findings suggest that higher rates of depression in women are likely attributable to other factors which require investigation.

PMID: 29028521 [PubMed - as supplied by publisher]

Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates.

Fri, 10/13/2017 - 13:37

Alcohol consumption in 0.5 million people from 10 diverse regions of China: prevalence, patterns and socio-demographic and health-related correlates.

Int J Epidemiol. 2017 Sep 14;:

Authors: Millwood IY, Li L, Smith M, Guo Y, Yang L, Bian Z, Lewington S, Whitlock G, Sherliker P, Collins R, Chen J, Peto R, Wang H, Xu J, He J, Yu M, Liu H, China Kadoorie Biobank collaborative group

PMID: 29025163 [PubMed - as supplied by publisher]

Heavier smoking increases coffee consumption: findings from a Mendelian randomization analysis.

Fri, 10/13/2017 - 13:37

Heavier smoking increases coffee consumption: findings from a Mendelian randomization analysis.

Int J Epidemiol. 2017 Aug 14;:

Authors: Bjørngaard JH, Nordestgaard AT, Taylor AE, Treur JL, Gabrielsen ME, Munafò MR, Nordestgaard BG, Åsvold BO, Romundstad P, Davey Smith G

Abstract
Background: There is evidence for a positive relationship between cigarette and coffee consumption in smokers. Cigarette smoke increases metabolism of caffeine, so this may represent a causal effect of smoking on caffeine intake.
Methods: We performed Mendelian randomization analyses in the UK Biobank ( N  = 114 029), the Norwegian HUNT study ( N  = 56 664) and the Copenhagen General Population Study (CGPS) ( N  = 78 650). We used the rs16969968 genetic variant as a proxy for smoking heaviness in all studies and rs4410790 and rs2472297 as proxies for coffee consumption in UK Biobank and CGPS. Analyses were conducted using linear regression and meta-analysed across studies.
Results: Each additional cigarette per day consumed by current smokers was associated with higher coffee consumption (0.10 cups per day, 95% CI: 0.03, 0.17). There was weak evidence for an increase in tea consumption per additional cigarette smoked per day (0.04 cups per day, 95% CI: -0.002, 0.07). There was strong evidence that each additional copy of the minor allele of rs16969968 (which increases daily cigarette consumption) in current smokers was associated with higher coffee consumption (0.16 cups per day, 95% CI: 0.11, 0.20), but only weak evidence for an association with tea consumption (0.04 cups per day, 95% CI: -0.01, 0.09). There was no clear evidence that rs16969968 was associated with coffee or tea consumption in never or former smokers or that the coffee-related variants were associated with cigarette consumption.
Conclusions: Higher cigarette consumption causally increases coffee intake. This is consistent with faster metabolism of caffeine by smokers, but could also reflect a behavioural effect of smoking on coffee drinking.

PMID: 29025033 [PubMed - as supplied by publisher]

A computable pathology report for precision medicine: extending an observables ontology unifying SNOMED CT and LOINC.

Fri, 10/13/2017 - 13:37

A computable pathology report for precision medicine: extending an observables ontology unifying SNOMED CT and LOINC.

J Am Med Inform Assoc. 2017 Sep 13;:

Authors: Campbell WS, Karlsson D, Vreeman DJ, Lazenby AJ, Talmon GA, Campbell JR

Abstract
Background: The College of American Pathologists (CAP) introduced the first cancer synoptic reporting protocols in 1998. However, the objective of a fully computable and machine-readable cancer synoptic report remains elusive due to insufficient definitional content in Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT) and Logical Observation Identifiers Names and Codes (LOINC). To address this terminology gap, investigators at the University of Nebraska Medical Center (UNMC) are developing, authoring, and testing a SNOMED CT observable ontology to represent the data elements identified by the synoptic worksheets of CAP.
Methods: Investigators along with collaborators from the US National Library of Medicine, CAP, the International Health Terminology Standards Development Organization, and the UK Health and Social Care Information Centre analyzed and assessed required data elements for colorectal cancer and invasive breast cancer synoptic reporting. SNOMED CT concept expressions were developed at UNMC in the Nebraska Lexicon© SNOMED CT namespace. LOINC codes for each SNOMED CT expression were issued by the Regenstrief Institute. SNOMED CT concepts represented observation answer value sets.
Results: UNMC investigators created a total of 194 SNOMED CT observable entity concept definitions to represent required data elements for CAP colorectal and breast cancer synoptic worksheets, including biomarkers. Concepts were bound to colorectal and invasive breast cancer reports in the UNMC pathology system and successfully used to populate a UNMC biobank.
Discussion: The absence of a robust observables ontology represents a barrier to data capture and reuse in clinical areas founded upon observational information. Terminology developed in this project establishes the model to characterize pathology data for information exchange, public health, and research analytics.

PMID: 29024958 [PubMed - as supplied by publisher]

Loss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence.

Fri, 10/13/2017 - 13:37

Loss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence.

Br J Cancer. 2017 Oct 12;:

Authors: Letellier E, Schmitz M, Ginolhac A, Rodriguez F, Ullmann P, Qureshi-Baig K, Frasquilho S, Antunes L, Haan S

Abstract
BACKGROUND: Selecting the most beneficial treatment regimens for colorectal cancer (CRC) patients remains challenging due to a lack of prognostic markers. Members of the Myosin family, proteins recognised to have a major role in trafficking and polarisation of cells, have recently been reported to be closely associated with several types of cancer and might thus serve as potential prognostic markers in the context of CRC.
METHODS: We used a previously established meta-analysis of publicly available gene expression data to analyse the expression of different members of the Myosin V family, namely MYO5A, 5B, and 5C, in CRC. Using laser-microdissected material as well as tissue microarrays from paired human CRC samples, we validated both RNA and protein expression of Myosin Vb (MYO5B) and its known adapter proteins (RAB8A and RAB25) in an independent patient cohort. Finally, we assessed the prognostic value of both MYO5B and its adapter-coupled combinatorial gene expression signatures.
RESULTS: The meta-analysis as well as an independent patient cohort study revealed a methylation-independent loss of MYO5B expression in CRC that matched disease progression. Although MYO5B mutations were identified in a small number of patients, these cannot be solely responsible for the common downregulation observed in CRC patients. Significantly, CRC patients with low MYO5B expression displayed shorter overall, disease-, and metastasis-free survival, a trend that was further reinforced when RAB8A expression was also taken into account.
CONCLUSIONS: Our data identify MYO5B as a powerful prognostic biomarker in CRC, especially in early stages (stages I and II), which might help stratifying patients with stage II for adjuvant chemotherapy.British Journal of Cancer advance online publication 12 October 2017; doi:10.1038/bjc.2017.352 www.bjcancer.com.

PMID: 29024942 [PubMed - as supplied by publisher]

Long-Term Room Temperature Storage of Dry Ribonucleic Acid for Use in RNA-seq Analysis.

Fri, 10/13/2017 - 13:37

Long-Term Room Temperature Storage of Dry Ribonucleic Acid for Use in RNA-seq Analysis.

Biopreserv Biobank. 2017 Oct 12;:

Authors: Li Q, Wang X, Liu X, Liao Q, Sun J, He X, Yang T, Yin J, Jia J, Li X, Colotte M, Bonnet J

Abstract
RNA is an essential biological material for research in genomics and translational medicine. As such, its storage for biobanking is an important field of study. Traditionally, long-term storage in the cold (generally freezers or liquid nitrogen) is used to maintain high-quality (in terms of quantity and integrity) RNA. Room temperature (RT) preservation provides an alternative to the cold, which is plagued by serious problems (mainly cost and safety), for RNA long-term storage. In this study, we evaluated the performance of several RT storage procedures, including the RNAshell(®) from Imagene, where the RNA is dried and kept protected from the atmosphere, and the vacuum drying of RNA with additives such as the Imagene stabilization solution and a home-made trehalose solution. This evaluation was performed through accelerated (equivalent to 10 years for RNAshell) aging and real-time studies (4 years). To check RNA quality and integrity, we used RNA integrity number values and RNA-seq. Our study shows that isolation from atmosphere offers a superior protective effect for RNA storage compared with vacuum drying alone, and demonstrates that RNAshell permits satisfactory RNA quality for long-term RT storage. Thus, the RNA quality could meet the demand of downstream applications such as RNA-seq.

PMID: 29022740 [PubMed - as supplied by publisher]

Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD.

Fri, 10/13/2017 - 13:37
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Impaired β-Oxidation and Altered Complex Lipid Fatty Acid Partitioning with Advancing CKD.

J Am Soc Nephrol. 2017 Oct 11;:

Authors: Afshinnia F, Rajendiran TM, Soni T, Byun J, Wernisch S, Sas KM, Hawkins J, Bellovich K, Gipson D, Michailidis G, Pennathur S

Abstract
Studies of lipids in CKD, including ESRD, have been limited to measures of conventional lipid profiles. We aimed to systematically identify 17 different lipid classes and associate the abundance thereof with alterations in acylcarnitines, a metric of β-oxidation, across stages of CKD. From the Clinical Phenotyping Resource and Biobank Core (CPROBE) cohort of 1235 adults, we selected a panel of 214 participants: 36 with stage 1 or 2 CKD, 99 with stage 3 CKD, 61 with stage 4 CKD, and 18 with stage 5 CKD. Among participants, 110 were men (51.4%), 64 were black (29.9%), and 150 were white (70.1%), and the mean (SD) age was 60 (16) years old. We measured plasma lipids and acylcarnitines using liquid chromatography-mass spectrometry. Overall, we identified 330 different lipids across 17 different classes. Compared with earlier stages, stage 5 CKD associated with a higher abundance of saturated C16-C20 free fatty acids (FFAs) and long polyunsaturated complex lipids. Long-chain-to-intermediate-chain acylcarnitine ratio, a marker of efficiency of β-oxidation, exhibited a graded decrease from stage 2 to 5 CKD (P<0.001). Additionally, multiple linear regression revealed that the long-chain-to-intermediate-chain acylcarnitine ratio inversely associated with polyunsaturated long complex lipid subclasses and the C16-C20 FFAs but directly associated with short complex lipids with fewer double bonds. We conclude that increased abundance of saturated C16-C20 FFAs coupled with impaired β-oxidation of FFAs and inverse partitioning into complex lipids may be mechanisms underpinning lipid metabolism changes that typify advancing CKD.

PMID: 29021384 [PubMed - as supplied by publisher]

Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative.

Fri, 10/13/2017 - 13:37
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Recommendations for collaborative paediatric research including biobanking in Europe: a Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative.

Ann Rheum Dis. 2017 Oct 11;:

Authors: Kuemmerle-Deschner JB, Hansmann S, Wulffraat NM, Vastert SJ, Hens K, Anton J, Avcin T, Martini A, Koné-Paut I, Uziel Y, Ravelli A, Wouters C, Shaw D, Özen S, Eikelberg A, Prakken BJ, Ruperto N, Horneff G, Constantin T, Beresford MW, Sikken M, Foster HE, Haug I, Schuller S, Jägle C, Benseler SM

Abstract
Innovative research in childhood rheumatic diseases mandates international collaborations. However, researchers struggle with significant regulatory heterogeneity; an enabling European Union (EU)-wide framework is missing. The aims of the study were to systematically review the evidence for best practice and to establish recommendations for collaborative research. The Paediatric Rheumatology European Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) project enabled a scoping review and expert discussion, which then informed the systematic literature review. Published evidence was synthesised; recommendations were drafted. An iterative review process and consultations with Ethics Committees and European experts for ethical and legal aspects of paediatric research refined the recommendations. SHARE experts and patient representatives vetted the proposed recommendations at a consensus meeting using Nominal Group Technique. Agreement of 80% was mandatory for inclusion. The systematic literature review returned 1319 records. A total of 223 full-text publications plus 22 international normative documents were reviewed; 85 publications and 16 normative documents were included. A total of 21 recommendations were established including general principles (1-3), ethics (4-7), paediatric principles (8 and 9), consent to paediatric research (10-14), paediatric databank and biobank (15 and 16), sharing of data and samples (17-19), and commercialisation and third parties (20 and 21). The refined recommendations resulted in an agreement of >80% for all recommendations. The SHARE initiative established the first recommendations for Paediatric Rheumatology collaborative research across borders in Europe. These provide strong support for an urgently needed European framework and evidence-based guidance for its implementation. Such changes will promote research in children with rheumatic diseases.

PMID: 29021237 [PubMed - as supplied by publisher]

Association of walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality: a UK Biobank observational study.

Thu, 10/12/2017 - 15:03

Association of walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality: a UK Biobank observational study.

Eur Heart J. 2017 Aug 21;:

Authors: Yates T, Zaccardi F, Dhalwani NN, Davies MJ, Bakrania K, Celis-Morales CA, Gill JMR, Franks PW, Khunti K

Abstract
Aims: To quantify the association of self-reported walking pace and handgrip strength with all-cause, cardiovascular, and cancer mortality.
Methods and results: A total of 230 670 women and 190 057 men free from prevalent cancer and cardiovascular disease were included from UK Biobank. Usual walking pace was self-defined as slow, steady/average or brisk. Handgrip strength was assessed by dynamometer. Cox-proportional hazard models were adjusted for social deprivation, ethnicity, employment, medications, alcohol use, diet, physical activity, and television viewing time. Interaction terms investigated whether age, body mass index (BMI), and smoking status modified associations. Over 6.3 years, there were 8598 deaths, 1654 from cardiovascular disease and 4850 from cancer. Associations of walking pace with mortality were modified by BMI. In women, the hazard ratio (HR) for all-cause mortality in slow compared with fast walkers were 2.16 [95% confidence interval (CI): 1.68-2.77] and 1.31 (1.08-1.60) in the bottom and top BMI tertiles, respectively; corresponding HRs for men were 2.01 (1.68-2.41) and 1.41 (1.20-1.66). Hazard ratios for cardiovascular mortality remained above 1.7 across all categories of BMI in men and women, with modest heterogeneity in men. Handgrip strength was associated with cardiovascular mortality in men only (HR tertile 1 vs. tertile 3 = 1.38; 1.18-1.62), without differences across BMI categories, while associations with all-cause mortality were only seen in men with low BMI. Associations for walking pace and handgrip strength with cancer mortality were less consistent.
Conclusion: A simple self-reported measure of slow walking pace could aid risk stratification for all-cause and cardiovascular mortality within the general population.

PMID: 29020281 [PubMed - as supplied by publisher]

Atherosclerotic plaque characteristics are not associated with future cardiovascular events in patients undergoing iliofemoral endarterectomy.

Thu, 10/12/2017 - 15:03

Atherosclerotic plaque characteristics are not associated with future cardiovascular events in patients undergoing iliofemoral endarterectomy.

J Vasc Surg. 2017 Oct 07;:

Authors: van Haelst STW, Haitjema S, Derksen W, van Koeverden I, de Vries JPM, Moll FL, den Ruijter HM, Pasterkamp G, de Borst GJ

Abstract
BACKGROUND: Plaque characteristics such as intraplaque hemorrhage (IPH) have been associated with secondary cardiovascular events (CVE) in patients undergoing carotid endarterectomy. In addition, carotid plaques containing macrophage infiltration or a large lipid core size were associated with less restenosis. It is currently unknown whether iliofemoral plaque histopathologic characteristics are predictive for secondary CVE in patients with peripheral arterial disease undergoing iliofemoral endarterectomy. The aim of this study was to examine the association between iliofemoral atherosclerotic plaque characteristics and secondary CVE in patients undergoing iliofemoral endarterectomy.
METHODS: There were 497 patients with iliofemoral atherosclerotic disease who underwent primary endarterectomy of the iliac or femoral artery from 2002 to 2013 included. All specimen were uptaken in the Athero Express biobank and 7 histologic plaque characteristics were analyzed: calcification, collagen, fat content, IPH, macrophages, smooth muscle cells, and vessel density. The composite CVE consisted of myocardial infarction, cerebrovascular accident, peripheral (re-)interventions, and cardiovascular death. Multivariate Cox regression models were used to examine the association between plaque and the composite end point during a follow-up period of 3 years.
RESULTS: Of the 497 patients, 225 (46.4%) experienced a composite CVE within 3 years after the initial surgery. Calcified plaques were univariably associated with composite CVE (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.00-1.73; P = .049). After correction for confounders, multivariable analyses showed no association between calcified plaques and composite CVE (HR, 1.13; 95% CI, 0.85-1.50; P = .413). IPH was not predictive of secondary CVE (HR, 1.02; 95% CI, 0.79-1.33; P = .867).
CONCLUSIONS: In this cohort of patients with peripheral arterial disease undergoing iliofemoral endarterectomy, investigated atherosclerotic plaque characteristics were not independently associated with secondary CVE during follow-up.

PMID: 29017805 [PubMed - as supplied by publisher]

Patterns and correlates of active commuting in adults with type 2 diabetes: cross-sectional evidence from UK Biobank.

Wed, 10/11/2017 - 14:11

Patterns and correlates of active commuting in adults with type 2 diabetes: cross-sectional evidence from UK Biobank.

BMJ Open. 2017 Oct 08;7(10):e017132

Authors: Falconer CL, Cooper AR, Flint E

Abstract
OBJECTIVES: To describe the active commuting (AC) patterns of adults with type 2 diabetes and how these relate to physical activity and sedentary behaviour in UK Biobank. Social and environmental correlates of AC will also be explored.
DESIGN: Cross-sectional analysis of a cohort study.
SETTINGS: This is a population cohort of over 500 000 people recruited from 22 centres across the UK. Participants aged between 37 and 73 years were recruited between 2006 and 2010.
PARTICIPANTS: 6896 participants with a self-reported type 2 diabetes diagnosis who reported commuting to work and had complete covariate data were included in the analysis.
EXPOSURE MEASURES: Exposure measures were AC to work, measured as usual mode of transport.
OUTCOME MEASURES: Outcome measures were weekly minutes of moderate to vigorous physical activity (MVPA), hours/day of sedentary time and participation in active travel.
RESULTS: AC (reporting walking or cycling to work only) was reported by 5.5% of participants, with the great majority using the car to commute (80%). AC was associated with an additional 73 (95% CI 10.8 to 134.9) and 105 (95% CI 41.7 to 167.2) weekly minutes of MVPA for men and women, respectively. AC was associated with reduced sedentary time (β -1.1, 95% CI -1.6 to -0.7 hours/day for men; and β -0.8, 95% CI -1.2 to -0.3 hours/day for women). Deprivation and distance from home to work were identified as correlates of AC behaviour.
CONCLUSIONS: Rates of AC are very low in adults with type 2 diabetes. However, AC offers a potentially sustainable solution to increasing physical activity and reducing sedentary behaviour. Therefore, strategies to improve the environment and encourage AC may help to increase population levels of physical activity and reduce the disease burden associated with type 2 diabetes.

PMID: 28993386 [PubMed - in process]

α-lipoic acid inhibits human lung cancer cell proliferation through Grb2-mediated EGFR downregulation.

Wed, 10/11/2017 - 14:11

α-lipoic acid inhibits human lung cancer cell proliferation through Grb2-mediated EGFR downregulation.

Biochem Biophys Res Commun. 2017 Oct 06;:

Authors: Yang L, Wen Y, Lv G, Lin Y, Tang J, Lu J, Zhang M, Liu W, Sun X

Abstract
BACKGROUND: Alpha lipoic acid (α -LA) is a naturally occurring antioxidant and metabolic enzyme co-factor. Recently, α -LA has been reported to inhibit the growth of various cancer cells, but the precise signaling pathways that mediate the effects of α -LA on non-small cell lung cancer (NSCLC) development remain unclear.
METHODS: The CCK-8 assay was used to assess cell proliferation in NSCLC cell lines after α -LA treatment. The expression of growth factor receptor-bound protein 2 (Grb2), cyclin-dependent kinase (CDK)-2, CDK4, CDK6, Cyclin D3, Cyclin E1, Ras, c-Raf, epidermal growth factor receptor (EGFR), ERK1/2 and activated EGFR and ERK1/2 was evaluated by western blotting. Grb2 levels were restored in α-LA-treated cells by transfection of a plasmid carrying Grb2 and were reduced in NSCLC cells via specific siRNA-mediated knockdown.
RESULTS: α -LA dramatically decreased NSCLC cell proliferation by downregulating Grb2; in contrast, Grb2 overexpression significantly prevented α-LA-induced decrease in cell growth in vitro. Western blot analysis indicated that α-LA decreased the levels of phospho-EGFR, CDK2/4/6, Cyclins D3 and E1, which are associated with the inhibition of G1/S-phase transition. Additional experiments indicated that Grb2 inhibition partially abolished EGF-induced phospho-EGFR and phospho-ERK1/2 activity. In addition, α-LA exerted greater inhibitory effects than gefitinib on NSCLC cells by preventing EGF-induced EGFR activation.
CONCLUSION: For the first time, these findings provide the first evidence that α-LA inhibits cell proliferation through Grb2 by suppressing EGFR phosphorylation and that MAPK/ERK is involved in this pathway.

PMID: 28993193 [PubMed - as supplied by publisher]

Associations between sedentary behaviours and cognitive function: cross-sectional and prospective findings from the UK Biobank.

Wed, 10/11/2017 - 14:11

Associations between sedentary behaviours and cognitive function: cross-sectional and prospective findings from the UK Biobank.

Am J Epidemiol. 2017 Jul 13;:

Authors: Bakrania K, Edwardson CL, Khunti K, Bandelow S, Davies MJ, Yates T

Abstract
We investigate the cross-sectional and prospective associations between different sedentary behaviours and cognitive function in a large sample of UK Biobank adults. Baseline data were available on 502,643 participants (years 2006-2010). Cognitive tests included prospective memory [n = 171,585 (baseline only)], visual-spatial memory [round 1 (n = 483,832); round 2 (n = 482,762)], fluid intelligence [n = 165,492], and short-term numeric memory [n = 50,370]. After a mean period of 5.3-years, between 12,091 and 114,373 participants also provided follow-up cognitive data. Sedentary behaviours [Television (TV) viewing, driving, and non-occupational computer use time] were measured at baseline. At baseline, both TV viewing and driving time were inversely associated with cognitive function across all outcomes [e.g. for each additional hour spent watching TV, the total number of correct answers in the fluid intelligence test was 0.15 (99% confidence interval: 0.14, 0.16) lower]. Computer use time was positively associated with cognitive function across all outcomes. Both TV viewing and driving time at baseline were positively associated with the odds of having cognitive decline at follow-up across most outcomes. Conversely, computer use time at baseline was inversely associated with the odds of having cognitive decline at follow-up across most outcomes. This study supports health policies designed to reduce TV viewing and driving in adults.

PMID: 28992036 [PubMed - as supplied by publisher]

Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study.

Wed, 10/11/2017 - 14:11

Bone mineral density and risk of type 2 diabetes and coronary heart disease: A Mendelian randomization study.

Wellcome Open Res. 2017;2:68

Authors: Gan W, Clarke RJ, Mahajan A, Kulohoma B, Kitajima H, Robertson NR, Rayner NW, Walters RG, Holmes MV, Chen Z, McCarthy MI

Abstract
Background: Observational studies have demonstrated that increased bone mineral density is associated with a higher risk of type 2 diabetes (T2D), but the relationship with risk of coronary heart disease (CHD) is less clear. Moreover, substantial uncertainty remains about the causal relevance of increased bone mineral density for T2D and CHD, which can be assessed by Mendelian randomisation studies.  Methods: We identified 235 independent single nucleotide polymorphisms (SNPs) associated at p<5×10 (-8) with estimated heel bone mineral density (eBMD) in 116,501 individuals from the UK Biobank study, accounting for 13.9% of eBMD variance. For each eBMD-associated SNP, we extracted effect estimates from the largest available GWAS studies for T2D (DIAGRAM: n=26,676 T2D cases and 132,532 controls) and CHD (CARDIoGRAMplusC4D: n=60,801 CHD cases and 123,504 controls). A two-sample design using several Mendelian randomization approaches was used to investigate the causal relevance of eBMD for risk of T2D and CHD. In addition, we explored the relationship of eBMD, instrumented by the 235 SNPs, on 12 cardiovascular and metabolic risk factors. Finally, we conducted Mendelian randomization analysis in the reverse direction to investigate reverse causality. Results: Each one standard deviation increase in genetically instrumented eBMD (equivalent to 0.14 g/cm (2)) was associated with an 8% higher risk of T2D (odds ratio [OR] 1.08; 95% confidence interval [CI]: 1.02 to 1.14; p=0.012) and 5% higher risk of CHD (OR 1.05; 95%CI: 1.00 to 1.10; p=0.034). Consistent results were obtained in sensitivity analyses using several different Mendelian randomization approaches. Equivalent increases in eBMD were also associated with lower plasma levels of HDL-cholesterol and increased insulin resistance. Mendelian randomization in the reverse direction using 94 T2D SNPs or 52 CHD SNPs showed no evidence of reverse causality with eBMD. Conclusions: These findings suggest a causal relationship between elevated bone mineral density with risks of both T2D and CHD.

PMID: 28989980 [PubMed]