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The Influence of Social Interaction and Physical Health on the Association Between Hearing and Depression With Age and Gender.

Sat, 07/29/2017 - 12:52

The Influence of Social Interaction and Physical Health on the Association Between Hearing and Depression With Age and Gender.

Trends Hear. 2017 Jan-Dec;21:2331216517706395

Authors: Keidser G, Seeto M

Abstract
Recent epidemiological data suggest the relation between hearing difficulty and depression is more evident in younger and middle-aged populations than in older adults. There are also suggestions that the relation may be more evident in specific subgroups; that is, other factors may influence a relationship between hearing and depression in different subgroups. Using cross-sectional data from the UK Biobank on 134,357 community-dwelling people and structural equation modelling, this study examined the potential mediating influence of social isolation and unemployment and the confounding influence of physical illness and cardiovascular conditions on the relation between a latent hearing variable and both a latent depressive episodes variable and a latent depressive symptoms variable. The models were stratified by age (40s, 50s, and 60s) and gender and further controlled for physical illness and professional support in associations involving social isolation and unemployment. The latent hearing variable was primarily defined by reported hearing difficulty in noise. For all subgroups, poor hearing was significantly related to both more depressive episodes and more depressive symptoms. In all models, the direct and generally small association exceeded the indirect associations via physical health and social interaction. Significant (depressive episodes) and near significant (depressive symptoms) higher direct associations were estimated for males in their 40s and 50s than for males in their 60s. There was at each age-group no significant difference in estimated associations across gender. Irrespective of the temporal order of variables, findings suggest that audiological services should facilitate psychosocial counselling.

PMID: 28752806 [PubMed - in process]

Occupational Social Class and Personality Traits in Relation to Leisure-Time Physical Activity Level: Cross-Sectional Results From the Copenhagen Aging and Midlife Biobank.

Sat, 07/29/2017 - 12:52

Occupational Social Class and Personality Traits in Relation to Leisure-Time Physical Activity Level: Cross-Sectional Results From the Copenhagen Aging and Midlife Biobank.

J Aging Health. 2017 Jun 01;:898264317714928

Authors: Petersen GL, Mortensen EL, Rod NH, Lange T, Flensborg-Madsen T, Hansen ÅM, Lund R

Abstract
OBJECTIVE: To investigate separate and combined associations of occupational social class and personality traits with late midlife leisure-time physical activity duration and intensity.
METHOD: Cross-sectional data from the Copenhagen Aging and Midlife Biobank ( N = 4,649) were analyzed using linear regression models with leisure-time physical activity (metric equivalence) as outcome.
RESULTS: Low versus high occupational social class was associated with 4% (95% confidence interval [CI] = [3%, 5%]) greater leisure-time physical activity duration, but 2% (CI = [1%, 3%]) lower intensity. Each 10-unit increase in extraversion was associated with 5% (CI = [2%, 8%]) greater duration. Intensity increased by each 10-unit increase in conscientiousness (6%, CI = [4%, 7%]), openness (3%, CI = [1%, 4%]), neuroticism (3%, CI = [1%, 4%]), and extraversion (5%, CI = [4%, 7%]). Conscientiousness was positively associated with duration in low, but not in high, occupational social class (interaction p value = .002).
DISCUSSION: Higher occupational social class was associated with lower leisure-time physical activity duration, but higher intensity. Extraversion was positively associated with duration and intensity. Conscientiousness, openness, and neuroticism were positively associated with intensity. Overall, interactions were not consistent.

PMID: 28752788 [PubMed - as supplied by publisher]

The Munich MIDY Pig Biobank - A unique resource for studying organ crosstalk in diabetes.

Sat, 07/29/2017 - 12:52
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The Munich MIDY Pig Biobank - A unique resource for studying organ crosstalk in diabetes.

Mol Metab. 2017 Aug;6(8):931-940

Authors: Blutke A, Renner S, Flenkenthaler F, Backman M, Haesner S, Kemter E, Ländström E, Braun-Reichhart C, Albl B, Streckel E, Rathkolb B, Prehn C, Palladini A, Grzybek M, Krebs S, Bauersachs S, Bähr A, Brühschwein A, Deeg CA, De Monte E, Dmochewitz M, Eberle C, Emrich D, Fux R, Groth F, Gumbert S, Heitmann A, Hinrichs A, Keßler B, Kurome M, Leipig-Rudolph M, Matiasek K, Öztürk H, Otzdorff C, Reichenbach M, Reichenbach HD, Rieger A, Rieseberg B, Rosati M, Saucedo MN, Schleicher A, Schneider MR, Simmet K, Steinmetz J, Übel N, Zehetmaier P, Jung A, Adamski J, Coskun Ü, Hrabě de Angelis M, Simmet C, Ritzmann M, Meyer-Lindenberg A, Blum H, Arnold GJ, Fröhlich T, Wanke R, Wolf E

Abstract
OBJECTIVE: The prevalence of diabetes mellitus and associated complications is steadily increasing. As a resource for studying systemic consequences of chronic insulin insufficiency and hyperglycemia, we established a comprehensive biobank of long-term diabetic INS(C94Y) transgenic pigs, a model of mutant INS gene-induced diabetes of youth (MIDY), and of wild-type (WT) littermates.
METHODS: Female MIDY pigs (n = 4) were maintained with suboptimal insulin treatment for 2 years, together with female WT littermates (n = 5). Plasma insulin, C-peptide and glucagon levels were regularly determined using specific immunoassays. In addition, clinical chemical, targeted metabolomics, and lipidomics analyses were performed. At age 2 years, all pigs were euthanized, necropsied, and a broad spectrum of tissues was taken by systematic uniform random sampling procedures. Total beta cell volume was determined by stereological methods. A pilot proteome analysis of pancreas, liver, and kidney cortex was performed by label free proteomics.
RESULTS: MIDY pigs had elevated fasting plasma glucose and fructosamine concentrations, C-peptide levels that decreased with age and were undetectable at 2 years, and an 82% reduced total beta cell volume compared to WT. Plasma glucagon and beta hydroxybutyrate levels of MIDY pigs were chronically elevated, reflecting hallmarks of poorly controlled diabetes in humans. In total, ∼1900 samples of different body fluids (blood, serum, plasma, urine, cerebrospinal fluid, and synovial fluid) as well as ∼17,000 samples from ∼50 different tissues and organs were preserved to facilitate a plethora of morphological and molecular analyses. Principal component analyses of plasma targeted metabolomics and lipidomics data and of proteome profiles from pancreas, liver, and kidney cortex clearly separated MIDY and WT samples.
CONCLUSIONS: The broad spectrum of well-defined biosamples in the Munich MIDY Pig Biobank that will be available to the scientific community provides a unique resource for systematic studies of organ crosstalk in diabetes in a multi-organ, multi-omics dimension.

PMID: 28752056 [PubMed - in process]

Leptin OB3 peptide suppresses leptin-induced signaling and progression in ovarian cancer cells.

Sat, 07/29/2017 - 12:52
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Leptin OB3 peptide suppresses leptin-induced signaling and progression in ovarian cancer cells.

J Biomed Sci. 2017 Jul 27;24(1):51

Authors: Chin YT, Wang LM, Hsieh MT, Shih YJ, Nana AW, Changou CA, Yang YSH, Chiu HC, Fu E, Davis PJ, Tang HY, Lin HY

Abstract
BACKGROUND: Obesity and its comorbidities constitute a serious health burden worldwide. Leptin plays an important role in diet control; however, it has a stimulatory potential on cancer cell proliferation. The OB3 peptide, a synthetic peptide, was shown to be more active than leptin in regulating metabolism but with no mitogenic effects in cancer cells.
METHODS: In this study, we investigated the proliferative effects, gene expressions and signaling pathways modulated by leptin and OB3 in human ovarian cancer cells. In addition, an animal study was performed.
RESULTS: Leptin, but not OB3, induced the proliferation of ovarian cancer cells. Interestingly, OB3 blocked the leptin-induced proliferative effect when it was co-applied with leptin. Both leptin and OB3 activated the phosphatidylinositol-3-kinase (PI3K) signal transduction pathway. In addition, leptin stimulated the phosphorylation of signal transducer and activator of transcription-3 (STAT3) Tyr-705 as well as estrogen receptor (ER)α, and the expression of ERα-responsive genes. Interestingly, all leptin-induced signal activation and gene expressions were blocked by the co-incubation with OB3 and the inhibition of extracellular signal-regulated kinase (ERK)1/2. Coincidently, leptin, but not OB3, increased circulating levels of follicle-stimulating hormone (FSH) which is known to play important roles in the initiation and proliferation of ovarian cancer cells.
CONCLUSIONS: In summary, our findings suggest that the OB3 peptide may prevent leptin-induced ovarian cancer initiation and progression by disrupting leptin-induced proliferative signals via STAT3 phosphorylation and ERα activation. Therefore, the OB3 peptide is a potential anticancer agent that might be employed to prevent leptin-induced cancers in obese people.

PMID: 28750624 [PubMed - in process]

Mitochondria-Associated Apoptosis in Human Melanoma Cells Induced by Cardanol Monoene from Cashew Nut Shell Liquid.

Sat, 07/29/2017 - 12:52
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Mitochondria-Associated Apoptosis in Human Melanoma Cells Induced by Cardanol Monoene from Cashew Nut Shell Liquid.

J Agric Food Chem. 2017 Jul 19;65(28):5620-5631

Authors: Su WC, Lin YF, Yu XP, Wang YX, Lin XD, Su QZ, Shen DY, Chen QX

Abstract
Cardanol monoene (CM) is the major phenolic component extracted from cashew nut shell liquid (CNSL), which has been relevant to wide range of biological effects. In this study, we found that CM could inhibit the M14 human melanoma cells proliferation in a dose dependent and time dependent manner, and the IC50 values were determined to be 23.15 ± 2.42 μM and 12.30 ± 1.67 μM after 24 and 48 h treatment, respectively. The flow cytometric analysis demonstrated that CM induced M14 cell cycle arrest at the S phase, along with the collapse of mitochondrial membrane potential (ΔΨm) and the accumulation of reactive oxygen species (ROS) level in cells, but the apoptotic cells reduced when treated with Z-VAD-FMK (pan-caspase inhibitor). Western blotting showed that the expressions of p53, cytosol cytochrome C, cleaved-caspase-3, and cleaved-PARP were up-regulated, and the expression level of Bax/Bcl-2 ratio increased significantly. The 2527 significant differentially expressed genes were obtained by RNA-seq, which were assigned to 270 KEGG pathways. These results indicated that CM induced M14 cells apoptosis via the ROS triggered mitochondrial-associated pathways, which supports the potential application of CM for the therapy of melanoma cancer.

PMID: 28627168 [PubMed - indexed for MEDLINE]

Heteronemin Is a Novel c-Met/STAT3 Inhibitor Against Advanced Prostate Cancer Cells.

Sat, 07/29/2017 - 12:52
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Heteronemin Is a Novel c-Met/STAT3 Inhibitor Against Advanced Prostate Cancer Cells.

Prostate. 2016 Dec;76(16):1469-1483

Authors: Wu JC, Wang CT, Hung HC, Wu WJ, Wu DC, Chang MC, Sung PJ, Chou YW, Wen ZH, Tai MH

Abstract
BACKGROUND: Prostate cancer is one of the most prevalent cancers in men worldwide. Aberrant activation of c-Met/signal transducer and activator of transcription-3 (STAT3) signaling is involved in prostate carcinogenesis, underscoring the demand for developing c-Met/STAT3-targeting drugs. Thus, we first utilized virtual screening strategy to identify STAT3-inhibiting marine compound, heteronemin, and then validated the STAT3-inhibiting function of heteronemin in prostate cancer cells.
METHODS: Human prostate cancer LNCaP, DU145, and PC-3 cell lines were treated with heteronemin for 24 hr, then the cell viability was evaluated by MTT assay. Flow cytometry was performed to analyze the apoptosis in heteronemin-treated cells. Western blot and quantitative real-time PCR were executed to further confirm the c-Met/STAT3 signaling inhibition by heteronemin in DU145 and PC-3 cells.
RESULTS: In this study, we employed the virtual screening strategy to identify heteronemin, a spongean sesterterpene, as a potential STAT3 inhibitor from Taiwan marine drugs library. Application of heteronemin potently suppressed the viability and anchorage-independent growth of human prostate cancer cells. Besides, heteronemin induced apoptosis in prostate cancer cells by activation of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways. By luciferase assay and expression analysis, it was confirmed that heteronemin inhibited the phosphorylation of c-Met/src/STAT3 signaling axis, STAT3-driven luciferase activities and expression of STAT3-regulated genes including Bcl-xL, Bcl-2, and Cyclin D1. Finally, heteronemin effectively antagonized the hepatocyte growth factor (HGF)-stimulated c-Met/STAT3 activation as well as the proliferation and colonies formation in refractory prostate cancer cells.
CONCLUSIONS: These findings suggest that heteronemin may constitute a novel c-Met/STAT3-targeting agent for prostate cancer. Prostate 76:1469-1483, 2016. © 2016 Wiley Periodicals, Inc.

PMID: 27416770 [PubMed - indexed for MEDLINE]

Genomic Justice and Imagined Communities.

Fri, 07/28/2017 - 14:32
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Genomic Justice and Imagined Communities.

Hastings Cent Rep. 2017 Jul;47(4):30-31

Authors: Schwartz-Marin E

Abstract
In this issue of the Hastings Center Report, Maya Sabatello and Paul Appelbaum explore the assumptions about community embedded in the U.S. Precision Medicine Initiative, which aims to recruit donor-partners who reflect the United States' racial and ethnic diversity. As Sabatello and Appelbaum discuss, the initiative is like other national biobanking efforts in bringing to life an imagined genetic community in need of critical attention, and given the public-private forms of partnership at the heart of the PMI, such efforts could become avenues to deepen existing inequalities rather than to alleviate them. The notion of justice has underwritten debates about genomic medicine, informed consent, citizenship, benefit sharing, and profit making since the first national biobanking project emerged at the dawn of the twenty-first century. In a paradigmatic case, the creation, by an Icelandic company, of the deCODE genomic biobank opened up fierce debates about the proper relationship between public good and private gain and became the first global example of the economic and political implications that imagined genetic communities could have in our shared future. In Mexico, in 2001, the Icelandic case fueled a policy agenda to deal with global health justice and the prospects of a future market-based colonialism predicated on the intimate knowledge of DNA.

PMID: 28749051 [PubMed - in process]

Bayesian association scan reveals loci associated with human lifespan and linked biomarkers.

Fri, 07/28/2017 - 14:32
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Bayesian association scan reveals loci associated with human lifespan and linked biomarkers.

Nat Commun. 2017 Jul 27;8:15842

Authors: McDaid AF, Joshi PK, Porcu E, Komljenovic A, Li H, Sorrentino V, Litovchenko M, Bevers RPJ, Rüeger S, Reymond A, Bochud M, Deplancke B, Williams RW, Robinson-Rechavi M, Paccaud F, Rousson V, Auwerx J, Wilson JF, Kutalik Z

Abstract
The enormous variation in human lifespan is in part due to a myriad of sequence variants, only a few of which have been revealed to date. Since many life-shortening events are related to diseases, we developed a Mendelian randomization-based method combining 58 disease-related GWA studies to derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, for parental age of death in the UK Biobank study (n=116,279) revealed 16 independent SNPs with significant Bayes factor at a 5% false discovery rate (FDR). Eleven of them replicate (5% FDR) in five independent longevity studies combined; all but three are depleted of the life-shortening alleles in older Biobank participants. Further analysis revealed that brain expression levels of nearby genes (RBM6, SULT1A1 and CHRNA5) might be causally implicated in longevity. Gene expression and caloric restriction experiments in model organisms confirm the conserved role for RBM6 and SULT1A1 in modulating lifespan.

PMID: 28748955 [PubMed - in process]

Germline variations at JAK2, TERT, HBS1L-MYB and MECOM and the risk of myeloproliferative neoplasms in Taiwanese population.

Fri, 07/28/2017 - 14:32
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Germline variations at JAK2, TERT, HBS1L-MYB and MECOM and the risk of myeloproliferative neoplasms in Taiwanese population.

Oncotarget. 2017 Jul 12;:

Authors: Chiang YH, Chang YC, Lin HC, Huang L, Cheng CC, Wang WT, Cheng HI, Su NW, Chen CG, Lin J, Chang YF, Chang MC, Hsieh RK, Chou WC, Lim KH, Kuo YY

Abstract
Germline variations at JAK2, TERT, HBS1L-MYB and MECOM have been found to associate with myeloproliferative neoplasms (MPNs) in European populations. Whether these germline variations are associated with MPNs in Taiwanese population is obscure. Here we aimed to evaluate the association of five germline variations (JAK2 46/1 haplotype tagged by rs12343867, JAK2 intron 8 rs12339666, TERT rs2736100, HBS1L-MYB rs9376092 and MECOM rs2201862) and the risk of MPNs in Taiwanese population. A total of 178 MPN patients (109 essential thrombocythemia, 54 polycythemia vera and 15 primary myelofibrosis) were enrolled into this study. The information of 17033 control subjects was obtained from Taiwan Biobank database. The JAK2 46/1 haplotype, JAK2 rs12339666 and TERT rs2736100 were significantly associated with Taiwanese MPNs (P = 3.6x10-19, 1.9x10-19 and 3.1x10-6, respectively), and JAK2V617F-positive MPNs (n=121) (P = 5.6x10-21, 4.4x10-21 and 8.6x10-7, respectively). In JAK2V617F-negative cases (n=55), only the JAK2 46/1 haplotype and JAK2 rs12339666 remained statistically significant (P= 0.009 and 0.007, respectively). When stratified by disease subtypes, the JAK2 46/1 haplotype and JAK2 rs12339666 were significantly associated with all three MPN subtypes, but TERT rs2736100 was only associated with essential thrombocythemia and polycythemia vera. We did not find any association of these five SNPs with CALR mutations in our cohort. Furthermore, the risk alleles of MECOM rs2201862 and HBS1L-MYB rs9376092 were demonstrated to be negatively associated with the risk of developing polycythemia vera. In conclusion, germline variations at JAK2 (both the 46/1 haplotype and rs12339666) and TERT rs2736100 were associated with MPNs in Taiwanese population.

PMID: 28747560 [PubMed - as supplied by publisher]

Detection and quantification of inbreeding depression for complex traits from SNP data.

Fri, 07/28/2017 - 14:32
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Detection and quantification of inbreeding depression for complex traits from SNP data.

Proc Natl Acad Sci U S A. 2017 Jul 26;:

Authors: Yengo L, Zhu Z, Wray NR, Weir BS, Yang J, Robinson MR, Visscher PM

Abstract
Quantifying the effects of inbreeding is critical to characterizing the genetic architecture of complex traits. This study highlights through theory and simulations the strengths and shortcomings of three SNP-based inbreeding measures commonly used to estimate inbreeding depression (ID). We demonstrate that heterogeneity in linkage disequilibrium (LD) between causal variants and SNPs biases ID estimates, and we develop an approach to correct this bias using LD and minor allele frequency stratified inference (LDMS). We quantified ID in 25 traits measured in ∼140,000 participants of the UK Biobank, using LDMS, and confirmed previously published ID for 4 traits. We find unique evidence of ID for handgrip strength, waist/hip ratio, and visual and auditory acuity (ID between -2.3 and -5.2 phenotypic SDs for complete inbreeding; [Formula: see text]). Our results illustrate that a careful choice of the measure of inbreeding combined with LDMS stratification improves both detection and quantification of ID using SNP data.

PMID: 28747529 [PubMed - as supplied by publisher]

The biobank for the molecular classification of kidney disease: research translation and precision medicine in nephrology.

Fri, 07/28/2017 - 14:32
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The biobank for the molecular classification of kidney disease: research translation and precision medicine in nephrology.

BMC Nephrol. 2017 Jul 26;18(1):252

Authors: Muruve DA, Mann MC, Chapman K, Wong JF, Ravani P, Page SA, Benediktsson H

Abstract
BACKGROUND: Advances in technology and the ability to interrogate disease pathogenesis using systems biology approaches are exploding. As exemplified by the substantial progress in the personalized diagnosis and treatment of cancer, the application of systems biology to enable precision medicine in other disciplines such as Nephrology is well underway. Infrastructure that permits the integration of clinical data, patient biospecimens and advanced technologies is required for institutions to contribute to, and benefit from research in molecular disease classification and to devise specific and patient-oriented treatments.
METHODS AND RESULTS: We describe the establishment of the Biobank for the Molecular Classification of Kidney Disease (BMCKD) at the University of Calgary, Alberta, Canada. The BMCKD consists of a fully equipped wet laboratory, an information technology infrastructure, and a formal operational, ethical and legal framework for banking human biospecimens and storing clinical data. The BMCKD first consolidated a large retrospective cohort of kidney biopsy specimens to create a population-based renal pathology database and tissue inventory of glomerular and other kidney diseases. The BMCKD will continue to prospectively bank all kidney biopsies performed in Southern Alberta. The BMCKD is equipped to perform molecular, clinical and epidemiologic studies in renal pathology. The BMCKD also developed formal biobanking procedures for human specimens such as blood, urine and nucleic acids collected for basic and clinical research studies or for advanced diagnostic technologies in clinical care. The BMCKD is guided by standard operating procedures, an ethics framework and legal agreements with stakeholders that include researchers, data custodians and patients. The design and structure of the BMCKD permits its inclusion in a wide variety of research and clinical activities.
CONCLUSION: The BMCKD is a core multidisciplinary facility that will bridge basic and clinical research and integrate precision medicine into renal pathology and nephrology.

PMID: 28747168 [PubMed - in process]

Cancer donor preferences for disposition of their biospecimens after biobank closure.

Thu, 07/27/2017 - 13:07

Cancer donor preferences for disposition of their biospecimens after biobank closure.

Cancer. 2017 Jul 26;:

Authors: Allen SC, Dixon MD, Switchenko JM, Pentz RD

Abstract
BACKGROUND: Biobank funding is unstable and biobank administrators are concerned about loss of funding and subsequent biobank closure. Nevertheless, only a minority of biobanks have policies regarding the distribution or destruction of tissue if the biobank were to close. To the authors' knowledge, the current study is the first to report on the preferences of oncology biospecimen donors regarding the handling of their biospecimens in the event of biobank closure.
METHODS: A total of 98 biospecimen donors who were diagnosed with cancer at the Georgia Cancer Center for Excellence at Grady Memorial Hospital or the Winship Cancer Institute were interviewed concerning their preferences for the handling of their biospecimens in the event of biobank closure.
RESULTS: The majority of biospecimen donors who expressed a preference (62 of 83 donors; 75%) wanted their biological materials transferred to another biobank, specifically an academic bank or a national bank. The most unacceptable options for the handling of tissue were transfer to a for-profit/pharmaceutical biobank (39 of 98 donors; 40%) or a biobank based outside of the United States (31 of 98 donors; 32%). Nonwhite participants were more likely to view the transfer of their tissue to a for-profit/pharmaceutical tissue bank, international tissue bank, or a national tissue bank as unacceptable compared with white participants.
CONCLUSIONS: According to these biospecimen donors, the most acceptable options for the handling of biospecimens after biobank closure were transfer to an academic or national bank. The most objectionable options were transfer to a for-profit/pharmaceutical biobank or a biobank based outside of the United States. These findings can be used as the basis for educational interventions directed at the public and can inform the policies of biobanks that serve oncology research. Cancer 2017. © 2017 American Cancer Society.

PMID: 28746751 [PubMed - as supplied by publisher]

Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function.

Thu, 07/27/2017 - 13:07

Identification of Genetic Loci Jointly Influencing Schizophrenia Risk and the Cognitive Traits of Verbal-Numerical Reasoning, Reaction Time, and General Cognitive Function.

JAMA Psychiatry. 2017 Jul 26;:

Authors: Smeland OB, Frei O, Kauppi K, Hill WD, Li W, Wang Y, Krull F, Bettella F, Eriksen JA, Witoelar A, Davies G, Fan CC, Thompson WK, Lam M, Lencz T, Chen CH, Ueland T, Jönsson EG, Djurovic S, Deary IJ, Dale AM, Andreassen OA, NeuroCHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Cognitive Working Group

Abstract
Importance: Schizophrenia is associated with widespread cognitive impairments. Although cognitive deficits are one of the factors most strongly associated with functional outcome in schizophrenia, current treatment strategies largely fail to ameliorate these impairments. To develop more efficient treatment strategies in patients with schizophrenia, a better understanding of the pathogenesis of these cognitive deficits is needed. Accumulating evidence indicates that genetic risk of schizophrenia may contribute to cognitive dysfunction.
Objective: To identify genomic regions jointly influencing schizophrenia and the cognitive domains of reaction time and verbal-numerical reasoning, as well as general cognitive function, a phenotype that captures the shared variation in performance across cognitive domains.
Design, Setting, and Participants: Combining data from genome-wide association studies from multiple phenotypes using conditional false discovery rate analysis provides increased power to discover genetic variants and could elucidate shared molecular genetic mechanisms. Data from the following genome-wide association studies, published from July 24, 2014, to January 17, 2017, were combined: schizophrenia in the Psychiatric Genomics Consortium cohort (n = 79 757 [cases, 34 486; controls, 45 271]); verbal-numerical reasoning (n = 36 035) and reaction time (n = 111 483) in the UK Biobank cohort; and general cognitive function in CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) (n = 53 949) and COGENT (Cognitive Genomics Consortium) (n = 27 888).
Main Outcomes and Measures: Genetic loci identified by conditional false discovery rate analysis. Brain messenger RNA expression and brain expression quantitative trait locus functionality were determined.
Results: Among the participants in the genome-wide association studies, 21 loci jointly influencing schizophrenia and cognitive traits were identified: 2 loci shared between schizophrenia and verbal-numerical reasoning, 6 loci shared between schizophrenia and reaction time, and 14 loci shared between schizophrenia and general cognitive function. One locus was shared between schizophrenia and 2 cognitive traits and represented the strongest shared signal detected (nearest gene TCF20; chromosome 22q13.3), and was shared between schizophrenia (z score, 5.01; P = 5.53 × 10-7), general cognitive function (z score, -4.43; P = 9.42 × 10-6), and verbal-numerical reasoning (z score, -5.43; P = 5.64 × 10-8). For 18 loci, schizophrenia risk alleles were associated with poorer cognitive performance. The implicated genes are expressed in the developmental and adult human brain. Replicable expression quantitative trait locus functionality was identified for 4 loci in the adult human brain.
Conclusions and Relevance: The discovered loci improve the understanding of the common genetic basis underlying schizophrenia and cognitive function, suggesting novel molecular genetic mechanisms.

PMID: 28746715 [PubMed - as supplied by publisher]

A Dry Method for Preserving Tear Protein Samples.

Thu, 07/27/2017 - 13:07

A Dry Method for Preserving Tear Protein Samples.

Biopreserv Biobank. 2017 Jul 26;:

Authors: Qin W, Zhao C, Zhang L, Wang T, Gao Y

Abstract
Tears covering the ocular surface are important biofluids containing thousands of molecules, including proteins, lipids, metabolites, nucleic acids, and electrolytes. Tears are valuable resources for biomarker research of ocular and even systemic diseases. For application in biomarker studies, tear samples should ideally be stored using a simple, lowcost, and efficient method along with the patient's medical records. For this purpose, we developed a novel Schirmer's strip-based dry method that allows for storage of tear samples in vacuum bags at room temperature. Using this method, tear protein patterns can also be preserved. Liquid chromatography-mass spectrometry/mass spectrometry analysis of proteins recovered by the dry method and traditional wet method showed no significant difference. Some tissue/organ-enriched proteins were identified in tear samples, thus tears might be a good window for monitoring changes of these tissues or organs. This dry method facilitates sample transportation and enables the storage of tear samples on a large scale, increasing the availability of samples for studying disease biomarkers in tears.

PMID: 28745913 [PubMed - as supplied by publisher]

Participants' Understanding of Informed Consent for Biobanking: A Systematic Review.

Thu, 07/27/2017 - 13:07

Participants' Understanding of Informed Consent for Biobanking: A Systematic Review.

Clin Nurs Res. 2017 Jul 01;:1054773817722690

Authors: Eisenhauer ER, Tait AR, Rieh SY, Arslanian-Engoren CM

Abstract
Nurses are increasingly asked to obtain consent from participants for biobanking studies. Biobanking has added unique complexities to informed consent. The purpose of this systematic review was to evaluate participants' level of understanding of the information presented during the informed consent process unique to the donation of biological specimens for research. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were utilized to conduct the review. PubMed, EMBASE, CINAHL, PsycINFO, Scopus, Web of Science, and ProQuest bibliographic databases were searched. Results indicated that elements of informed consent unique to biobanking were poorly understood. Most studies had authors or funding associated with a biobank. Only one study disclosed and assessed participants' understanding of moral risks. Increased disclosures, values-clarification, and presenting information via multiple modalities may facilitate understanding. There is a need to improve the quality of informed consent for biobanking studies by utilizing standardized instruments, definitions, and encouraging research about informed choice outside the biobanking industry.

PMID: 28745067 [PubMed - as supplied by publisher]

Polypeptide N-acetylgalactosaminyltransferase-6 expression in gastric cancer.

Thu, 07/27/2017 - 13:07
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Polypeptide N-acetylgalactosaminyltransferase-6 expression in gastric cancer.

Onco Targets Ther. 2017;10:3337-3344

Authors: Guo Y, Shi J, Zhang J, Li H, Liu B, Guo H

Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related deaths, with limited improvement in its clinical outcome worldwide. Aberrant mucin-type O-glycosylation is a critical event widespread in the development of GC. Polypeptide N-acetylgalactosaminyltransferases (GALNTs) regulate the initial step and determine the sites of mucin-type O-glycoprotein bio-synthesis. GALNT6 has considerable potential as a biomarker in various cancers. The roles of GALNT6 in GC were analyzed, and the results showed that GALNT6 expression markedly increased in GC tissues compared with those in adjacent gastric tissues. High intratumoral GALNT6 density was associated with the clinicopathological parameters of TNM stage and distant metastasis. GALNT6 was identified as an independent prognosticator for the poor prognosis of GC patients. Moreover, the high expression level of GALNT6 was significantly associated with the low expression levels of E-cadherin and β-catenin and the high expression levels of MMP9. These findings indicated that GALNT6 could provide new insights into the characterization of GC as well as contribute to the development of an efficient prognostic indicator and novel therapeutic modalities for GC.

PMID: 28744137 [PubMed]

Genetic determination of the vascular reactions in humans in response to the diving reflex.

Thu, 07/27/2017 - 13:07
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Genetic determination of the vascular reactions in humans in response to the diving reflex.

Am J Physiol Heart Circ Physiol. 2017 Mar 01;312(3):H622-H631

Authors: Baranova TI, Berlov DN, Glotov OS, Korf EA, Minigalin AD, Mitrofanova AV, Ahmetov II, Glotov AS

Abstract
The purpose of this study was to investigate the genetic mechanisms of the defense vascular reactions in response to the diving reflex in humans with polymorphisms in the genes ADBR2, ACE, AGTR1, BDKRB2, and REN We hypothesized that protective vascular reactions, in response to the diving reflex, are genetically determined and are distinguished in humans with gene polymorphisms of the renin-angiotensin and kinin-bradykinin system. A total of 80 subjects (19 ± 1.4 yr) participated in the study. The intensity of the vascular response was estimated using photoplethysmogram. The I/D polymorphism (rs4340) of ACE was analyzed by PCR. REN (G/A, rs2368564), AGTR1 (A/C, rs5186), BDKRB2 (T/C, rs1799722), and ADBR2 (A/G, rs1042713) polymorphisms were examined using the two-step multiplex PCR followed by carrying allele hybridization on the biochip. Subjects with the BDKRB2 (C/C), ACE (D/D), and ADBR2 (G/G, G/A) genotypes exhibited the strongest peripheral vasoconstriction in response to diving. In subjects with a combination of the BDKRB2 (C/C) plus ACE (D/D) genotypes, we observed the lowest pulse wave amplitude and pulse transit time values and the highest arterial blood pressure during face immersion compared with the heterozygous individuals, suggesting that these subjects are more susceptible to diving hypoxia. This study observed that humans with gene polymorphisms of the renin-angiotensin and kinin-bradykinin systems demonstrate various expressions of protective vascular reactions in response to the diving reflex. The obtained results might be used in estimation of resistance to hypoxia of any origin in human beings or in a medical practice.NEW & NOTEWORTHY Our study demonstrates that the vascular reactions in response to the diving reflex are genetically determined and depend on gene polymorphisms of the kinin-bradykinin and the renin-angiotensin systems.

PMID: 27923785 [PubMed - indexed for MEDLINE]

Liquid biopsy for early detection of lung cancer.

Thu, 07/27/2017 - 13:07
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Liquid biopsy for early detection of lung cancer.

Curr Opin Oncol. 2017 Jan;29(1):73-78

Authors: Hofman P

Abstract
PURPOSE OF REVIEW: The possibility of complete recovery for a lung cancer patient depends on very early diagnosis, as it allows total surgical resection. Screening for this cancer in a high-risk population can be performed using a radiological approach, but this holds a certain number of limitations. Liquid biopsy could become an alternative and complementary screening approach to chest imaging for early diagnosis of lung cancer.
RECENT FINDINGS: Several circulating biomarkers indicative of lung cancer can be investigated in blood, such as circulating tumor cells, circulating free nucleic acids (RNA and DNA) and proteins. However, none of these biomarkers have yet been adopted in routine clinical practice and studies are ongoing to confirm or not the usefulness and practical interest in routine early diagnosis and screening for lung cancers.
SUMMARY: Several potential circulating biomarkers for the early detection of lung cancer exist. When coupled to thoracic imaging, these biomarkers must give diagnosis of a totally resectable lung cancer and potentially provide new recommendations for surveillance by imagery of high-risk populations without a detectable nodule. Optimization of the specificity and sensitivity of the detection methods as well as standardization of the techniques is essential before considering for daily practice a liquid biopsy as an early diagnostic tool, or possibly as a predictive test, of lung cancer.

PMID: 27906860 [PubMed - indexed for MEDLINE]

Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

Thu, 07/27/2017 - 13:07
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Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

PLoS One. 2016;11(8):e0160316

Authors: Horne HN, Chung CC, Zhang H, Yu K, Prokunina-Olsson L, Michailidou K, Bolla MK, Wang Q, Dennis J, Hopper JL, Southey MC, Schmidt MK, Broeks A, Muir K, Lophatananon A, Fasching PA, Beckmann MW, Fletcher O, Johnson N, Sawyer EJ, Tomlinson I, Burwinkel B, Marme F, Guénel P, Truong T, Bojesen SE, Flyger H, Benitez J, González-Neira A, Anton-Culver H, Neuhausen SL, Brenner H, Arndt V, Meindl A, Schmutzler RK, Brauch H, Hamann U, Nevanlinna H, Khan S, Matsuo K, Iwata H, Dörk T, Bogdanova NV, Lindblom A, Margolin S, Mannermaa A, Kosma VM, Chenevix-Trench G, kConFab/AOCS Investigators, Wu AH, Ven den Berg D, Smeets A, Zhao H, Chang-Claude J, Rudolph A, Radice P, Barile M, Couch FJ, Vachon C, Giles GG, Milne RL, Haiman CA, Marchand LL, Goldberg MS, Teo SH, Taib NA, Kristensen V, Borresen-Dale AL, Zheng W, Shrubsole M, Winqvist R, Jukkola-Vuorinen A, Andrulis IL, Knight JA, Devilee P, Seynaeve C, García-Closas M, Czene K, Darabi H, Hollestelle A, Martens JW, Li J, Lu W, Shu XO, Cox A, Cross SS, Blot W, Cai Q, Shah M, Luccarini C, Baynes C, Harrington P, Kang D, Choi JY, Hartman M, Chia KS, Kabisch M, Torres D, Jakubowska A, Lubinski J, Sangrajrang S, Brennan P, Slager S, Yannoukakos D, Shen CY, Hou MF, Swerdlow A, Orr N, Simard J, Hall P, Pharoah PD, Easton DF, Chanock SJ, Dunning AM, Figueroa JD

Abstract
The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

PMID: 27556229 [PubMed - indexed for MEDLINE]

Activation of the IL-2 Receptor in Podocytes: A Potential Mechanism for Podocyte Injury in Idiopathic Nephrotic Syndrome?

Thu, 07/27/2017 - 13:07
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Activation of the IL-2 Receptor in Podocytes: A Potential Mechanism for Podocyte Injury in Idiopathic Nephrotic Syndrome?

PLoS One. 2016;11(7):e0157907

Authors: Zea AH, Stewart T, Ascani J, Tate DJ, Finkel-Jimenez B, Wilk A, Reiss K, Smoyer WE, Aviles DH

Abstract
The renal podocyte plays an important role in maintaining the structural integrity of the glomerular basement membrane. We have previously reported that patients with idiopathic nephrotic syndrome (INS) have increased IL-2 production. We hypothesized that podocytes express an IL-2 receptor (IL-2R) and signaling through this receptor can result in podocyte injury. To confirm the presence of the IL-2R, we tested a conditionally immortalized murine podocyte cell line by flow cytometry, qPCR, and Western blot. To test for the presence of the IL-2R in vivo, immunohistochemical staining was performed on human renal biopsies in children with FSGS and control. Podocytes were stimulated with IL-2 in vitro, to study signaling events via the JAK/STAT pathway. The results showed that stimulation with IL-2 resulted in increased mRNA and protein expression of STAT 5a, phosphorylated STAT 5, JAK 3, and phosphorylated JAK 3. We then investigated for signs of cellular injury and the data showed that pro-apoptotic markers Bax and cFLIP were significantly increased following IL-2 exposure, whereas LC3 II was decreased. Furthermore, mitochondrial depolarization and apoptosis were both significantly increased following activation of the IL-2R. We used a paracellular permeability assay to monitor the structural integrity of a podocyte monolayer following IL-2 exposure. The results showed that podocytes exposed to IL-2 have increased albumin leakage across the monolayer. We conclude that murine podocytes express the IL-2R, and that activation through the IL-2R results in podocyte injury.

PMID: 27389192 [PubMed - indexed for MEDLINE]