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Exome-wide association study of plasma lipids in >300,000 individuals.

Tue, 10/31/2017 - 11:11

Exome-wide association study of plasma lipids in >300,000 individuals.

Nat Genet. 2017 Oct 30;:

Authors: Liu DJ, Peloso GM, Yu H, Butterworth AS, Wang X, Mahajan A, Saleheen D, Emdin C, Alam D, Alves AC, Amouyel P, Di Angelantonio E, Arveiler D, Assimes TL, Auer PL, Baber U, Ballantyne CM, Bang LE, Benn M, Bis JC, Boehnke M, Boerwinkle E, Bork-Jensen J, Bottinger EP, Brandslund I, Brown M, Busonero F, Caulfield MJ, Chambers JC, Chasman DI, Chen YE, Chen YI, Chowdhury R, Christensen C, Chu AY, Connell JM, Cucca F, Cupples LA, Damrauer SM, Davies G, Deary IJ, Dedoussis G, Denny JC, Dominiczak A, Dubé MP, Ebeling T, Eiriksdottir G, Esko T, Farmaki AE, Feitosa MF, Ferrario M, Ferrieres J, Ford I, Fornage M, Franks PW, Frayling TM, Frikke-Schmidt R, Fritsche LG, Frossard P, Fuster V, Ganesh SK, Gao W, Garcia ME, Gieger C, Giulianini F, Goodarzi MO, Grallert H, Grarup N, Groop L, Grove ML, Gudnason V, Hansen T, Harris TB, Hayward C, Hirschhorn JN, Holmen OL, Huffman J, Huo Y, Hveem K, Jabeen S, Jackson AU, Jakobsdottir J, Jarvelin MR, Jensen GB, Jørgensen ME, Jukema JW, Justesen JM, Kamstrup PR, Kanoni S, Karpe F, Kee F, Khera AV, Klarin D, Koistinen HA, Kooner JS, Kooperberg C, Kuulasmaa K, Kuusisto J, Laakso M, Lakka T, Langenberg C, Langsted A, Launer LJ, Lauritzen T, Liewald DCM, Lin LA, Linneberg A, Loos RJF, Lu Y, Lu X, Mägi R, Malarstig A, Manichaikul A, Manning AK, Mäntyselkä P, Marouli E, Masca NGD, Maschio A, Meigs JB, Melander O, Metspalu A, Morris AP, Morrison AC, Mulas A, Müller-Nurasyid M, Munroe PB, Neville MJ, Nielsen JB, Nielsen SF, Nordestgaard BG, Ordovas JM, Mehran R, O'Donnell CJ, Orho-Melander M, Molony CM, Muntendam P, Padmanabhan S, Palmer CNA, Pasko D, Patel AP, Pedersen O, Perola M, Peters A, Pisinger C, Pistis G, Polasek O, Poulter N, Psaty BM, Rader DJ, Rasheed A, Rauramaa R, Reilly DF, Reiner AP, Renström F, Rich SS, Ridker PM, Rioux JD, Robertson NR, Roden DM, Rotter JI, Rudan I, Salomaa V, Samani NJ, Sanna S, Sattar N, Schmidt EM, Scott RA, Sever P, Sevilla RS, Shaffer CM, Sim X, Sivapalaratnam S, Small KS, Smith AV, Smith BH, Somayajula S, Southam L, Spector TD, Speliotes EK, Starr JM, Stirrups KE, Stitziel N, Strauch K, Stringham HM, Surendran P, Tada H, Tall AR, Tang H, Tardif JC, Taylor KD, Trompet S, Tsao PS, Tuomilehto J, Tybjaerg-Hansen A, van Zuydam NR, Varbo A, Varga TV, Virtamo J, Waldenberger M, Wang N, Wareham NJ, Warren HR, Weeke PE, Weinstock J, Wessel J, Wilson JG, Wilson PWF, Xu M, Yaghootkar H, Young R, Zeggini E, Zhang H, Zheng NS, Zhang W, Zhang Y, Zhou W, Zhou Y, Zoledziewska M, Charge Diabetes Working Group, EPIC-InterAct Consortium, EPIC-CVD Consortium, GOLD Consortium, VA Million Veteran Program, Howson JMM, Danesh J, McCarthy MI, Cowan CA, Abecasis G, Deloukas P, Musunuru K, Willer CJ, Kathiresan S

Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

PMID: 29083408 [PubMed - as supplied by publisher]

Germline mutations in BRCA1 and BRCA2 incidentally revealed in a biobank research study: experiences from re-contacting mutation carriers and relatives.

Tue, 10/31/2017 - 11:11

Germline mutations in BRCA1 and BRCA2 incidentally revealed in a biobank research study: experiences from re-contacting mutation carriers and relatives.

J Community Genet. 2017 Oct 30;:

Authors: Nilsson MP, Emmertz M, Kristoffersson U, Borg Å, Larsson C, Rehn M, Winter C, Saal LH, Brandberg Y, Loman N

Abstract
Once an incidental finding (IF) is discovered in the course of genomic research, the researchers are faced with the question of whether or not that finding should be reported back to the study participant. A large number of hypothetical studies and policy documents on this issue have been published, but there are very few empirical studies to inform the bioethics debate. Within a biobank research study of somatic mutations in breast carcinomas, ten germline BRCA1/2 mutations were incidentally detected. After thorough discussions within a group of experts, the mutation carriers (n = 7) or relatives of deceased carriers (n = 3) were re-contacted and informed about the findings. Eight out of ten accepted to receive the information and underwent confirmatory testing. One year later, semi-structured interviews were undertaken with three of the study participants. All of them felt that BRCA mutations discovered in the course of research should be reported back to the individual study participants. In this paper, we report our step-by-step experiences of the re-contacting process. We hope that our detailed reporting will be helpful for other researchers and clinicians that are faced with similar situations. The results of our study lend empirical support to opinion that IFs that meet the three baseline criteria of analytic validity, clinical significance, and actionability should be reported back to the individual study participants.

PMID: 29082482 [PubMed - as supplied by publisher]

[A cryobank as an attribute of omics technologies].

Tue, 10/31/2017 - 11:11
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[A cryobank as an attribute of omics technologies].

Biomed Khim. 2017 Oct;63(5):428-431

Authors: Sazanov AA, Erganokov KK, Pfeifer E

Abstract
Biobanks are systematic and annotated collections of biological samples based on the system of standard operating procedures (SOP) and corresponding to the recommendations of the International Society for Biological and Environmental Repositories (ISBER). Standardization of conditions of obtaining, processing, storage of samples and providing to an end user are crucial in the activities of the biobank. The attributes of biobanks include common principles of labeling and annotation of biological samples using specialized software, an automated monitoring system of storage conditions, and registration of biosamples. Cryobanks are the biobanks maintained at the storage conditions from -196°C to -150°C that provide better cell viability and the highest preservation of biological molecules. Cryobanking is the most essential part of the infrastructure of population and personalized medicine, pharmaceuticals and biopharmacology, conservation of rare and endangered species, as well as biotechnology in general. Next Generation Biobanking, a concept especially designed for omics technologies, involves annotating biological samples on many biomarkers based on Next Generation Sequencing techniques, as well as collecting biological material from the same patient at different time points (for example, at different stages of the disease, before and after the operation, at different periods of therapy) with a detailed annotation of physiological, biochemical and clinical data. Epigenetic studies (DNA methylation, microRNA, etc.), as well as bioinformatic data analysis are of great importance in the activity of Next Generation Biobanking. Such biobanks should function based on the new ethical principles of the post-genomic era.

PMID: 29080876 [PubMed - in process]

Selective impairment of hippocampus and posterior hub areas in Alzheimer's disease: an MEG-based multiplex network study.

Tue, 10/31/2017 - 11:11
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Selective impairment of hippocampus and posterior hub areas in Alzheimer's disease: an MEG-based multiplex network study.

Brain. 2017 May 01;140(5):1466-1485

Authors: Yu M, Engels MMA, Hillebrand A, van Straaten ECW, Gouw AA, Teunissen C, van der Flier WM, Scheltens P, Stam CJ

Abstract
Although frequency-specific network analyses have shown that functional brain networks are altered in patients with Alzheimer's disease, the relationships between these frequency-specific network alterations remain largely unknown. Multiplex network analysis is a novel network approach to study complex systems consisting of subsystems with different types of connectivity patterns. In this study, we used magnetoencephalography to integrate five frequency-band specific brain networks in a multiplex framework. Previous structural and functional brain network studies have consistently shown that hub brain areas are selectively disrupted in Alzheimer's disease. Accordingly, we hypothesized that hub regions in the multiplex brain networks are selectively targeted in patients with Alzheimer's disease in comparison to healthy control subjects. Eyes-closed resting-state magnetoencephalography recordings from 27 patients with Alzheimer's disease (60.6 ± 5.4 years, 12 females) and 26 controls (61.8 ± 5.5 years, 14 females) were projected onto atlas-based regions of interest using beamforming. Subsequently, source-space time series for both 78 cortical and 12 subcortical regions were reconstructed in five frequency bands (delta, theta, alpha 1, alpha 2 and beta band). Multiplex brain networks were constructed by integrating frequency-specific magnetoencephalography networks. Functional connections between all pairs of regions of interests were quantified using a phase-based coupling metric, the phase lag index. Several multiplex hub and heterogeneity metrics were computed to capture both overall importance of each brain area and heterogeneity of the connectivity patterns across frequency-specific layers. Different nodal centrality metrics showed consistently that several hub regions, particularly left hippocampus, posterior parts of the default mode network and occipital regions, were vulnerable in patients with Alzheimer's disease compared to control subjects. Of note, these detected vulnerable hubs in Alzheimer's disease were absent in each individual frequency-specific network, thus showing the value of integrating the networks. The connectivity patterns of these vulnerable hub regions in the patients were heterogeneously distributed across layers. Perturbed cognitive function and abnormal cerebrospinal fluid amyloid-β42 levels correlated positively with the vulnerability of the hub regions in patients with Alzheimer's disease. Our analysis therefore demonstrates that the magnetoencephalography-based multiplex brain networks contain important information that cannot be revealed by frequency-specific brain networks. Furthermore, this indicates that functional networks obtained in different frequency bands do not act as independent entities. Overall, our multiplex network study provides an effective framework to integrate the frequency-specific networks with different frequency patterns and reveal neuropathological mechanism of hub disruption in Alzheimer's disease.

PMID: 28334883 [PubMed - indexed for MEDLINE]

Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology.

Tue, 10/31/2017 - 11:11
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Childhood cancer predisposition syndromes-A concise review and recommendations by the Cancer Predisposition Working Group of the Society for Pediatric Oncology and Hematology.

Am J Med Genet A. 2017 Apr;173(4):1017-1037

Authors: Ripperger T, Bielack SS, Borkhardt A, Brecht IB, Burkhardt B, Calaminus G, Debatin KM, Deubzer H, Dirksen U, Eckert C, Eggert A, Erlacher M, Fleischhack G, Frühwald MC, Gnekow A, Goehring G, Graf N, Hanenberg H, Hauer J, Hero B, Hettmer S, von Hoff K, Horstmann M, Hoyer J, Illig T, Kaatsch P, Kappler R, Kerl K, Klingebiel T, Kontny U, Kordes U, Körholz D, Koscielniak E, Kramm CM, Kuhlen M, Kulozik AE, Lamottke B, Leuschner I, Lohmann DR, Meinhardt A, Metzler M, Meyer LH, Moser O, Nathrath M, Niemeyer CM, Nustede R, Pajtler KW, Paret C, Rasche M, Reinhardt D, Rieß O, Russo A, Rutkowski S, Schlegelberger B, Schneider D, Schneppenheim R, Schrappe M, Schroeder C, von Schweinitz D, Simon T, Sparber-Sauer M, Spix C, Stanulla M, Steinemann D, Strahm B, Temming P, Thomay K, von Bueren AO, Vorwerk P, Witt O, Wlodarski M, Wössmann W, Zenker M, Zimmermann S, Pfister SM, Kratz CP

Abstract
Heritable predisposition is an important cause of cancer in children and adolescents. Although a large number of cancer predisposition genes and their associated syndromes and malignancies have already been described, it appears likely that there are more pediatric cancer patients in whom heritable cancer predisposition syndromes have yet to be recognized. In a consensus meeting in the beginning of 2016, we convened experts in Human Genetics and Pediatric Hematology/Oncology to review the available data, to categorize the large amount of information, and to develop recommendations regarding when a cancer predisposition syndrome should be suspected in a young oncology patient. This review summarizes the current knowledge of cancer predisposition syndromes in pediatric oncology and provides essential information on clinical situations in which a childhood cancer predisposition syndrome should be suspected.

PMID: 28168833 [PubMed - indexed for MEDLINE]

Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program.

Tue, 10/31/2017 - 11:11
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Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program.

Circ Cardiovasc Genet. 2016 Dec;9(6):495-503

Authors: Varga TV, Winters AH, Jablonski KA, Horton ES, Khare-Ranade P, Knowler WC, Marcovina SM, Renström F, Watson KE, Goldberg R, Florez JC, Pollin TI, Franks PW

Abstract
BACKGROUND: We assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial.
METHODS AND RESULTS: We tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre-diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated at P<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10(-4)>P>1.1×10(-16)) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (β=-0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, -0.188 to -0.033; P=5×10(-3); Pinteraction=1×10(-3) for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits.
CONCLUSIONS: Improvements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.

PMID: 27784733 [PubMed - indexed for MEDLINE]

Transplantation of RADA16-BDNF peptide scaffold with human umbilical cord mesenchymal stem cells forced with CXCR4 and activated astrocytes for repair of traumatic brain injury.

Tue, 10/31/2017 - 11:11
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Transplantation of RADA16-BDNF peptide scaffold with human umbilical cord mesenchymal stem cells forced with CXCR4 and activated astrocytes for repair of traumatic brain injury.

Acta Biomater. 2016 Nov;45:247-261

Authors: Shi W, Huang CJ, Xu XD, Jin GH, Huang RQ, Huang JF, Chen YN, Ju SQ, Wang Y, Shi YW, Qin JB, Zhang YQ, Liu QQ, Wang XB, Zhang XH, Chen J

Abstract
Due to the poor self-regeneration of brain tissue, stem cell transplantation therapy is purported to enable the replacement of lost neurons after traumatic brain injury (TBI). The main challenge of brain regeneration is whether the transplanted cells can survive and carry out neuronal functions in the lesion area. The brain is a complex neuronal network consisting of various types of cells that significantly influence on each other, and the survival of the implanted stem cells in brain is critically influenced by the surrounding cells. Although stem cell-based therapy is developing rapidly, most previous studies just focus on apply single type of stem cells as cell source. Here, we found that co-culturing human umbilical cord mesenchymal stem cells (hUC-MSCs) directly with the activated astrocytes benefited to the proliferation and neuron differentiation of hUC-MSCs in vitro. In this study, hUC-MSCs and the activated astrocytes were seeded in RADA16-BDNF peptide scaffold (R-B-SPH scaffold), a specifical self-assembling peptide hydrogel, in which the environment promoted the differentiation of typical neuron-like cells with neurites extending in three-dimensional directions. Moreover, the results showed co-culture of hUC-MSCs and activated astrocytes promoted more BDNF secretion which may benefit to both neural differentiation of ectogenic hUC-MSCs and endogenic neurogenesis. In order to promote migration of the transplanted hUC-MSCs to the host brain, the hUC-MSCs were forced with CXC chemokine receptor 4 (CXCR4). We found that the moderate-sized lesion cavity, but not the large cavity caused by TBI was repaired via the transplantation of hUC-MSCs(CXCR4) and activated astrocytes embedded in R-B-SPH scaffolds. The functional neural repair for TBI demonstrated in this study is mainly due to the transplantation system of double cells, hUC-MSCs and activated astrocytes. We believe that this novel cell transplantation system offers a promising treatment option for cell replacement therapy for TBI.
STATEMENT OF SIGNIFICANCE: In this reach, we specifically linked RGIDKRHWNSQ, a functional peptide derived from BDNF, to the C-terminal of RADARADARADARADA (RADA16) to structure a functional self-assembling peptide hydrogel scaffold, RADA16-BDNF (R-B-SPH scaffold) for the better transplantation of the double cell unit. Also, the novel scaffold was used as cell-carrier for transplantation double cell unit (hUC-MSCs/astrocyte) for treating traumatic brain injury. The results of this study showing that R-B-SPH scaffold was pliancy and flexibility to fit the brain lesion cavity and promotes the outgrowth of axons and dendrites of the neurons derived from hUC-MSCs in vitro and in vivo, indicating the 3D R-B-SPH scaffold provided a suitable microenvironment for hUC-MSC survival, proliferation and differentiation. Also, our results showing the double-cells transplantation system (hUC-MSCs/astrocyte) may be a novel cell-based therapeutic strategy for neuroregeneration after TBI with potential value for clinical application.

PMID: 27592818 [PubMed - indexed for MEDLINE]

Côte d'Ivoire Dual Burden of Disease (CoDuBu): Study Protocol to Investigate the Co-occurrence of Chronic Infections and Noncommunicable Diseases in Rural Settings of Epidemiological Transition.

Sun, 10/29/2017 - 11:39
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Côte d'Ivoire Dual Burden of Disease (CoDuBu): Study Protocol to Investigate the Co-occurrence of Chronic Infections and Noncommunicable Diseases in Rural Settings of Epidemiological Transition.

JMIR Res Protoc. 2017 Oct 27;6(10):e210

Authors: Eze IC, Esse C, Bassa FK, Koné S, Acka F, Yao L, Imboden M, Jaeger FN, Schindler C, Dosso M, Laubhouet-Koffi V, Kouassi D, N'Goran EK, Utzinger J, Bonfoh B, Probst-Hensch N

Abstract
BACKGROUND: Individual-level concomitance of infectious diseases and noncommunicable diseases (NCDs) is poorly studied, despite the reality of this dual disease burden for many low- and middle-income countries (LMICs).
OBJECTIVE: This study protocol describes the implementation of a cohort and biobank aiming for a better understanding of interrelation of helminth and Plasmodium infections with NCD phenotypes like metabolic syndrome, hypertension, and diabetes.
METHODS: A baseline cross-sectional population-based survey was conducted over one year, in the Taabo health and demographic surveillance system (HDSS) in south-central Côte d'Ivoire. We randomly identified 1020 consenting participants aged ≥18 years in three communities (Taabo-Cité, Amani-Ménou, and Tokohiri) reflecting varying stages of epidemiological transition. Participants underwent health examinations consisting of NCD phenotyping (anthropometry, blood pressure, renal function, glycemia, and lipids) and infectious disease testing (infections with soil-transmitted helminths, schistosomes, and Plasmodium). Individuals identified to have elevated blood pressure, glucose, lipids, or with infections were referred to the central/national health center for diagnostic confirmation and treatment. Aliquots of urine, stool, and venous blood were stored in a biobank for future exposome/phenome research. In-person interviews on sociodemographic attributes, risk factors for infectious diseases and NCDs, medication, vaccinations, and health care were also conducted. Appropriate statistical techniques will be applied in exploring the concomitance of infectious diseases and NCDs and their determinants. Participants' consent for follow-up contact was obtained.
RESULTS: Key results from this baseline study, which will be published in peer-reviewed literature, will provide information on the prevalence and co-occurrence of infectious diseases, NCDs, and their risk factors. The Taabo HDSS consists of rural and somewhat more urbanized areas, allowing for comparative studies at different levels of epidemiological transition. An HDSS setting is ideal as a basis for longitudinal studies since their sustainable field work teams hold close contact with the local population.
CONCLUSIONS: The collaboration between research institutions, public health organizations, health care providers, and staff from the Taabo HDSS in this study assures that the synthesized evidence will feed into health policy towards integrated infectious disease-NCD management. The preparation of health systems for the dual burden of disease is pressing in low- and middle-income countries. The established biobank will strengthen the local research capacity and offer opportunities for biomarker studies to deepen the understanding of the cross-talk between infectious diseases and NCDs.
TRIAL REGISTRATION: International Standard Randomized Controlled Trials Number (ISRCTN): 87099939; http://www.isrctn.com/ISRCTN87099939 (Archived by WebCite at http://www.webcitation.org/6uLEs1EsX).

PMID: 29079553 [PubMed]

Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.

Sun, 10/29/2017 - 11:39
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Image processing and Quality Control for the first 10,000 brain imaging datasets from UK Biobank.

Neuroimage. 2017 Oct 24;:

Authors: Alfaro-Almagro F, Jenkinson M, Bangerter NK, Andersson JLR, Griffanti L, Douaud G, Sotiropoulos SN, Jbabdi S, Hernandez-Fernandez M, Vallee E, Vidaurre D, Webster M, McCarthy P, Rorden C, Daducci A, Alexander DC, Zhang H, Dragonu I, Matthews PM, Miller KL, Smith SM

Abstract
UK Biobank is a large-scale prospective epidemiological study with all data accessible to researchers worldwide. It is currently in the process of bringing back 100,000 of the original participants for brain, heart and body MRI, carotid ultrasound and low-dose bone/fat x-ray. The brain imaging component covers 6 modalities (T1, T2 FLAIR, susceptibility weighted MRI, Resting fMRI, Task fMRI and Diffusion MRI). Raw and processed data from the first 10,000 imaged subjects has recently been released for general research access. To help convert this data into useful summary information we have developed an automated processing and QC (Quality Control) pipeline that is available for use by other researchers. In this paper we describe the pipeline in detail, following a brief overview of UK Biobank brain imaging and the acquisition protocol. We also describe several quantitative investigations carried out as part of the development of both the imaging protocol and the processing pipeline.

PMID: 29079522 [PubMed - as supplied by publisher]

PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival.

Sun, 10/29/2017 - 11:39
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PTTG1-interacting protein (PTTG1IP/PBF) predicts breast cancer survival.

BMC Cancer. 2017 Oct 27;17(1):705

Authors: Repo H, Gurvits N, Löyttyniemi E, Nykänen M, Lintunen M, Karra H, Kurki S, Kuopio T, Talvinen K, Söderström M, Kronqvist P

Abstract
BACKGROUND: PTTG1-interacting protein (PTTG1IP) is an oncogenic protein, which participates in metaphase-anaphase transition of the cell cycle through activation of securin (PTTG1). PTTG1IP promotes the shift of securin from the cell cytoplasm to the nucleus, allowing the interaction between separase and securin. PTTG1IP overexpression has been previously observed in malignant disease, e.g. in breast carcinoma. However, the prognostic value of PTTG1IP in breast carcinoma patients has not previously been revealed.
METHODS: A total of 497 breast carcinoma patients with up to 22-year follow-up were analysed for PTTG1IP and securin immunoexpression. The results were evaluated for correlations with the clinical prognosticators and patient survival.
RESULTS: In our material, negative PTTG1IP immunoexpression predicted a 1.5-fold risk of breast cancer death (p = 0.02). However, adding securin immunoexpression to the analysis indicated an even stronger and independent prognostic power in the patient material (HR = 2.5, p < 0.0001). The subcellular location of securin was found with potential prognostic value also among the triple-negative breast carcinomas (n = 96, p = 0.052).
CONCLUSIONS: PTTG1IP-negativity alone and in combination with high securin immunoexpression indicates a high risk of breast cancer death, resulting in up to 14-year survival difference in our material.

PMID: 29078751 [PubMed - in process]

A gene signature to predict high tumour-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple negative breast cancer.

Sat, 10/28/2017 - 14:33
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A gene signature to predict high tumour-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple negative breast cancer.

Ann Oncol. 2017 Oct 25;:

Authors: Criscitiello C, Bayar MA, Curigliano G, Symmans FW, Desmedt C, Bonnefoi H, Sinn B, Pruneri G, Vicier C, Pierga JY, Denkert C, Loibl S, Sotiriou C, Michiels S, André F

Abstract
INTRODUCTION: In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease (RD) after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pre-treatment samples to predict the extent of TILs after NACT, and then to test its prognostic value on survival.
PATIENTS AND METHODS: Using 99 pre-treatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n = 99) and then on an independent validation set (n = 115).
RESULTS: A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS (HR: 0.28 for a one-unit increase in the value of the four-gene signature, 95%CI: 0.13-0.63). In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95%CI: 0.06-0.43). The four-gene signature added significant prognostic information when compared to the clinicopathologic pre-treatment model (likelihood ratio test in the training set p = 0.004 and in the validation set p = 0.002).
CONCLUSION: A four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.

PMID: 29077781 [PubMed - as supplied by publisher]

Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.

Sat, 10/28/2017 - 14:33
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Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.

World J Biol Psychiatry. 2017 Oct 27;:1-85

Authors: Lewczuk P, Riederer P, O'Bryant SE, Verbeek MM, Dubois B, Visser PJ, Jellinger KA, Engelborghs S, Ramirez A, Parnetti L, Jack CR, Teunissen CE, Hampel H, Lleó A, Jessen F, Glodzik L, de Leon MJ, Fagan AM, Molinuevo JL, Jansen WJ, Winblad B, Shaw LM, Andreasson U, Otto M, Mollenhauer B, Wiltfang J, Turner MR, Zerr I, Handels R, Thompson AG, Johansson G, Ermann N, Trojanowski JQ, Karaca I, Wagner H, Oeckl P, van Waalwijk van Doorn L, Bjerke M, Kapogiannis D, Kuiperij HB, Farotti L, Li Y, Gordon BA, Epelbaum S, Vos SJB, Klijn CJM, Van Nostrand WE, Minguillon C, Schmitz M, Gallo C, Lopez Mato A, Thibaut F, Lista S, Alcolea D, Zetterberg H, Blennow K, Kornhuber J, Members of the WFSBP Task Force Working on this Topic: Peter Riederer, Carla Gallo, Dimitrios Kapogiannis, Andrea Lopez Mato, Florence Thibaut

Abstract
In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-β positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.

PMID: 29076399 [PubMed - as supplied by publisher]

iASPP facilitates tumor growth by promoting mTOR-dependent autophagy in human non-small-cell lung cancer.

Fri, 10/27/2017 - 22:48
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iASPP facilitates tumor growth by promoting mTOR-dependent autophagy in human non-small-cell lung cancer.

Cell Death Dis. 2017 Oct 26;8(10):e3150

Authors: Xue Y, Han H, Wu L, Pan B, Dong B, Yin CC, Tian Z, Liu X, Yang Y, Zhang H, Chen Y, Chen J

Abstract
Autophagy serves a critical function in the pathogenesis, response to therapy and clinical outcome in cancers. Although a recent report showed a role of iASPP in suppressing autophagy, its potential activity as a regulator of autophagy has not been investigated in lung cancer. Here we investigated the potential function and molecular mechanism of iASPP in mediating autophagy in human non-small-cell lung cancer. Our data suggested that forced expression of iASPP triggered autophagic flux, while inhibition of iASPP suppressed autophagy at the autophagsome formation stage in vitro. Furthermore, in vivo overexpression of iASPP in SCID/NOD mice promoted tumorigenesis and autophagy, with an increase in the conversion from LC3-I to LC3-II. The effects of iASPP were mediated through activation of mTOR pathway. Finally, cytoplasmic iASPP expression was upregulated in lung cancer patients, and was identified as an independent poor prognostic factor for lung cancer-specific death in patient samples. Taken together, our data showed that iASPP could promote tumor growth by increasing autophagic flux, and iASPP could serve as a poor prognostic factor and a potential therapeutic target in lung cancer.

PMID: 29072696 [PubMed - in process]

Cancer Registry follow-up for 17 million person-years of a nationwide maternity cohort.

Fri, 10/27/2017 - 22:48
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Cancer Registry follow-up for 17 million person-years of a nationwide maternity cohort.

Cancer Med. 2017 Oct 25;:

Authors: Lehtinen M, Surcel HM, Natunen K, Pukkala E, Dillner J

Abstract
Population-based Finnish Maternity Cohort (FMC) comprises 2M first trimester sera collected from 1M women during 33 years. Informed consent is by the opt-out principle, and linkages with cancer and population registries provide a base for over time and over generation studies. Follow-up for 17M person-years by the end of 2014 can identify 39,700 cases of invasive cancer and 18,900 cases of premalignant breast and cervix lesions, and basal cell carcinoma diagnosed after serum sampling. For women with multiple pregnancies, serial samples taken before cancer diagnosis are available. Offspring of the women have developed more than 4000 cancers. For 100,000 individuals, samples taken during the pregnancies of both their mothers and grandmothers enable familial cancer studies. FMC continues to collect samples, and surveillance of exposures or interventions like vaccination programs is feasible. In summary, the FMC is a unique, accessible biobank for epidemiological, biomarker, and surveillance studies on cancer.

PMID: 29071810 [PubMed - as supplied by publisher]

The liquid biopsy: a tool for a combined diagnostic and theranostic approach for care of a patient with late-stage lung carcinoma presenting with bilateral ocular metastases.

Fri, 10/27/2017 - 22:48
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The liquid biopsy: a tool for a combined diagnostic and theranostic approach for care of a patient with late-stage lung carcinoma presenting with bilateral ocular metastases.

Expert Rev Anticancer Ther. 2017 Oct 26;:

Authors: Bouhlel L, Hofman V, Maschi C, Ilié M, Allégra M, Marquette CH, Audigier-Valette C, Thariat J, Hofman P

Abstract
INTRODUCTION: The adoption of liquid biopsies (LB) has modified the care of patients with late stage non-small-cell lung cancer (NSCLC). LB are used routinely in clinical practice in two situations for these patients, i) at the initial diagnosis when looking for activating mutations in EGFR in the absence of analyzable or available tissue DNA and, ii) during tumor progression on a tyrosine kinase inhibitor (TKI) treatment to look for the resistance mutation T790M in EGFR. Treatment with TKI may be adapted after detection of mutations using circulating cell-free DNA in plasma. However, despite promising research, LB are not presently recommended in daily practice for the diagnosis of NSCLC. Areas covered: This article reports the diagnosis of a NSCLC in a non-smoker patient with bilateral ocular metastases after detection of a deletion in exon 19 of EGFR when using plasma DNA. Detection of this mutation thereby resulted in treatment with TKI. Without histological analysis, the origin of the primary ocular metastasis was uncertain. In this context, a LB showing an activating mutation in EGFR and circulating tumor cells positive for TTF1 led to the diagnosis of NSCLC and targeted therapy. Expert commentary: When no tumor tissue sample is available a LB can be used to diagnose for metastatic NSCLC, when a mutation in EGFR is identified, and with subsequent delivery of targeted treatment for this mutation. While a tissue biopsy is still the gold standard approach for the diagnosis of a NSCLC and for identification of activating mutations that can be treated with targeted therapy, this case report shows that LB can exceptionally provide both a diagnosis of the primitive tumor and indicate appropriate therapies based on a molecular analysis.

PMID: 29069959 [PubMed - as supplied by publisher]

Inhibition of extracellular matrix mediated TGF-β signalling suppresses endometrial cancer metastasis.

Fri, 10/27/2017 - 22:48
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Inhibition of extracellular matrix mediated TGF-β signalling suppresses endometrial cancer metastasis.

Oncotarget. 2017 Sep 22;8(42):71400-71417

Authors: Sahoo SS, Quah MY, Nielsen S, Atkins J, Au GG, Cairns MJ, Nahar P, Lombard JM, Tanwar PS

Abstract
Although aggressive invasion and distant metastases are an important cause of morbidity and mortality in patients with endometrial cancer (EC), the requisite events determining this propensity are currently unknown. Using organotypic three-dimensional culture of endometrial cancer cell lines, we demonstrated anti-correlated TGF-β signalling gene expression patterns that arise among extracellular matrix (ECM)-attached cells. TGF-β pathway seemed to be active in EC cells forming non-glandular colonies in 3D-matrix but weaker in glandular colonies. Functionally we found that out of several ECM proteins, fibronectin relatively promotes Smad phosphorylation suggesting a potential role in regulating TGF-β signalling in non-glandular colonies. Importantly, alteration of TGF-β pathway induced EMT and MET in both type of colonies through slug protein. The results exemplify a crucial role of TGF-β pathway during EC metastasis in human patients and inhibition of the pathway in a murine model impaired tumour cell invasion and metastasis depicting an attractive target for therapeutic intervention of malignant tumour progression. These findings provide key insights into the role of ECM-derived TGF-β signalling to promote endometrial cancer metastasis and offer an avenue for therapeutic targeting of microenvironment derived signals along with tumour cells.

PMID: 29069715 [PubMed]

The Validity and Value of Self-reported Physical Activity and Accelerometry in People With Schizophrenia: A Population-Scale Study of the UK Biobank.

Fri, 10/27/2017 - 22:48
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The Validity and Value of Self-reported Physical Activity and Accelerometry in People With Schizophrenia: A Population-Scale Study of the UK Biobank.

Schizophr Bull. 2017 Oct 24;:

Authors: Firth J, Stubbs B, Vancampfort D, Schuch FB, Rosenbaum S, Ward PB, Firth JA, Sarris J, Yung AR

Abstract
Background: Previous physical activity (PA) research in schizophrenia has relied largely upon self-report measures. However, the accuracy of this method is questionable. Obtaining accurate measurements, and determining what may influence PA levels in schizophrenia, is essential to understand physical inactivity in this population. This study examined differences in self-reported and objectively measured PA in people with schizophrenia and the general population using a large, population-based dataset from the UK Biobank.
Methods: Baseline data from the UK Biobank (2007-2010) were analyzed; including 1078 people with schizophrenia (54.19 ± 8.39 years; 55% male) and 450549 without (56.44 ± 8.11; 46% male). We compared self-reported PA with objectively measured accelerometry data in schizophrenia and comparison samples. We also examined correlations between self-report and objective measures.
Results: People with schizophrenia reported the same PA levels as those without, with no differences in low, moderate, or vigorous intensity activity. However, accelerometry data showed a large and statistically significant reduction of PA in schizophrenia; as people with schizophrenia, on average, engaged in less PA than 80% of the general population. Nonetheless, within the schizophrenia sample, total self-reported PA still held significant correlations with objective measures.
Conclusions: People with schizophrenia are significantly less active than the general population. However, self-report measures in epidemiological studies fail to capture the reduced activity levels in schizophrenia. This also has implications for self-report measures of other lifestyle factors which may contribute toward the poor health outcomes observed in schizophrenia. Nonetheless, self-report measures may still be useful for identifying how active individuals with schizophrenia relative to other patients.

PMID: 29069474 [PubMed - as supplied by publisher]

Sex-specific associations of different anthropometric indices with acute and chronic insomnia.

Fri, 10/27/2017 - 22:48
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Sex-specific associations of different anthropometric indices with acute and chronic insomnia.

Eur J Public Health. 2017 Oct 23;:

Authors: Andreeva VA, Torres MJ, Druesne-Pecollo N, Léger D, Gonzalez P, Bayon V, Hercberg S, Galan P

Abstract
Background: Sleep disorders, including insomnia, are risk factors for weight gain. However, few epidemiological studies have investigated the association of anthropometric markers with insomnia as an outcome.
Methods: In this observational, cross-sectional study, we assessed the association of 3 different anthropometric indices with acute and chronic insomnia. We used data from 13 389 French adults (mean age= 51.9 ± 13.1 years; 70.3% women) enrolled in the NutriNet-Santé-Biobank cohort. Body weight, height, waist and hip circumference were measured once during a clinic visit (2011-14). Body mass index (BMI), waist circumference (WC) and waist-to-hip ratio (WHR) were the main predictors. Acute (past 8 days) and chronic (≥3 months) insomnia were assessed in 2014 via a self-report questionnaire. We fit multivariable logistic regression models providing odds ratios (OR) and 95% confidence intervals (CI).
Results: Overweight (25.0 ≤ BMI < 30.0 kg/m2) and general obesity (BMI ≥ 30.0 kg/m2) appeared to have an inverse association with acute insomnia only among men (overweight: OR= 0.80, 95% CI: 0.70, 0.92; obesity: OR= 0.78, 95% CI: 0.63, 0.98). Obesity assessed by BMI and WHR appeared to be positively associated with chronic insomnia only among women (BMI: OR= 1.23, 95% CI: 1.04, 1.45; WHR: OR= 2.24, 95% CI: 1.07, 4.72). WC did not display any significant associations in either sex.
Conclusions: These cross-sectional results revealed sex-specific associations of overweight/obesity with different types of insomnia, and merit confirmation longitudinally with objectively assessed sleep parameters. Nonetheless, the findings reinforce the critical importance of joint health behaviour promotion.

PMID: 29069319 [PubMed - as supplied by publisher]

Serum suppression of tumorigenicity 2 level is an independent predictor of all-cause mortality in HIV-infected patients.

Fri, 10/27/2017 - 22:48
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Serum suppression of tumorigenicity 2 level is an independent predictor of all-cause mortality in HIV-infected patients.

AIDS. 2017 Nov 13;31(17):2355-2365

Authors: Thiébaut R, Hue S, Le Marec F, Lelièvre JD, Dupon M, Foucat E, Lazaro E, Dabis F, Duffau P, Wittkop L, Surenaud M, Pellegrin I, Lacabaratz C, Bonnet F, Lévy Y, ANRS CO3 Aquitaine Cohort

Abstract
OBJECTIVE: To evaluate the predictive value of soluble suppression of tumorigenicity 2 (sST2), a decoy receptor of IL-33 involved in several inflammatory and immune diseases, for death in HIV infection.
DESIGN: Patients enrolled in the ANRS CO3 Aquitaine Cohort, a prospective hospital-based cohort of HIV-1-infected patients, who had a plasma sample available in the biobank were systematically eligible.
METHODS: sST2, soluble CD14 (sCD14) and IL-6 were measured using Luminex multiplex bead-based technology (R&D Systems) and a Bio-Plex 200 instrument (BioRad). Predictive capacities of sST2, sCD14, IL-6 and of the Veterans Aging Cohort Study clinical score at baseline on overall mortality were compared using multivariable Cox proportional hazards models.
RESULTS: During a median follow-up of 7.2 years [interquartile range (IQR): 6.0; 7.9], 93 deaths from all causes (incidence rate 9.9 per 1000 patient-years; 95% confidence interval 7.9-11.9) were reported in 1414 patients. The median sST2 baseline concentration was 22.9 ng/ml (IQR: 17.7; 30.3) and was higher (30.8 ng/ml, IQR: 21.5; 42.1) in patients who died as compared with those who stayed alive (22.6 ng/ml; IQR: 17.5; 29.6) (P < 10). An increased risk of death of 21% for a concentration 10.0 ng/ml higher of sST2 remained after adjustment for sCD14, IL-6 and Veterans Aging Cohort Study score (adjusted hazard ratio: 1.21; P < 10). The predictive capacity of sST2 was confirmed in a validation cohort (n = 386, 31 deaths) with an improved area c-index from 0.804 without sST2 to 0.811 with sST2.
CONCLUSION: sST2 is a new valuable biomarker to evaluate the risk of all-cause mortality in HIV disease.

PMID: 29068834 [PubMed - in process]

Design of the ExCersion-VCI study: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment.

Fri, 10/27/2017 - 22:48
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Design of the ExCersion-VCI study: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment.

Alzheimers Dement (N Y). 2017 Jun;3(2):157-165

Authors: Leeuwis AE, Hooghiemstra AM, Amier R, Ferro DA, Franken L, Nijveldt R, Kuijer JPA, Bronzwaer AGT, van Lieshout JJ, Rietberg MB, Veerbeek JM, Huijsmans RJ, Backx FJG, Teunissen CE, Bron EE, Barkhof F, Prins ND, Shahzad R, Niessen WJ, de Roos A, van Osch MJP, van Rossum AC, Biessels GJ, van der Flier WM, Heart Brain Connection study group

Abstract
There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status.

PMID: 29067325 [PubMed]