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Consent, ethics and genetic biobanks: the case of the Athlome project.

Fri, 11/17/2017 - 13:29

Consent, ethics and genetic biobanks: the case of the Athlome project.

BMC Genomics. 2017 Nov 14;18(Suppl 8):830

Authors: Thompson R, McNamee MJ

Abstract
This article provides a critical overview of the ethics and governance of genetic biobank research, using the Athlome Consortium as a large scale instance of collaborative sports genetic biobanking. We present a traditional model of written informed consent for the acquisition, storage, sharing and analysis of genetic data and articulate the challenges to it from new research practices such as genetic biobanking. We then articulate six possible alternative consent models: verbal consent, blanket consent, broad consent, meta consent, dynamic consent and waived consent. We argue that these models or conceptions of consent must be articulated in the context of the complexities of international legislation and non legislative national and international biobank governance frameworks and policies, those which govern research in the field of sports genetics. We discuss the tensions between individual rights and public benefits of genomic research as a critical ethical issue, particularly where benefits are less obvious, as in sports genomics. The inherent complexities of international regulation and biobanking governance are challenging in a relatively young field. We argue that there is much nuanced ethical work still to be done with regard to governance of sports genetic biobanking and the issues contained therein.

PMID: 29143655 [PubMed - in process]

Cardiovascular Disease Biomarkers and suPAR in Predicting Decline in Renal Function: A Prospective Cohort Study.

Fri, 11/17/2017 - 13:29

Cardiovascular Disease Biomarkers and suPAR in Predicting Decline in Renal Function: A Prospective Cohort Study.

Kidney Int Rep. 2017 May;2(3):425-432

Authors: Hayek SS, Ko YA, Awad M, Ahmed H, Gray B, Hosny KM, Aida H, Tracy MJ, Wei C, Sever S, Reiser J, Quyyumi AA

Abstract
Introduction: Soluble urokinase-type plasminogen activator receptor (suPAR) strongly predicts outcomes and incident chronic kidney disease (CKD) in patients with cardiovascular disease (CVD). Whether the association between suPAR and CKD is a reflection of its overall association with chronic inflammation and poor CVD outcomes is unclear. We examined whether CVD biomarkers, including high-sensitivity C-reactive protein (hs-CRP), fibrin-degradation products (FDPs), heat-shock protein 70 (HSP-70), and high-sensitivity troponin I (hs-TnI) were associated with a decline in kidney function in the Emory Cardiovascular Biobank cohort, in which suPAR levels were shown to be predictive of both incident CKD and CVD outcomes.
Methods: We measured suPAR, hs-CRP, HSP-70, FDP, and hs-TnI plasma levels in 3282 adults (mean age 63 years, 64% male, 75% estimated glomerular filtration rate [eGFR] >60 ml/min per 1.73 m(2)). Glomerular filtration rate was estimated using Chronic Kidney Disease-Epidemiology Collaboration (eGFR) at enrollment (n = 3282) and follow-up (n = 2672; median 3.5 years). Urine protein by dipstick at baseline was available for 1335 subjects.
Results: There was a weak correlation among biomarkers (r range: 0.17-0.28). hs-CRP, FDPs, hs-TnI, and suPAR were independently associated with baseline eGFR and proteinuria. The median yearly decline in eGFR was -0.6 ml/min per 1.73 m(2). hs-CRP (β: -0.04; P = 0.46), FDPs (β: -0.13; P = 0.08), HSP-70 (β: 0.05; P = 0.84), or hs-TnI (β: -0.01; P = 0.76) were associated with eGFR decline. suPAR remained predictive of eGFR decline even after adjusting for all biomarkers.
Discussion: hs-CRP, FDP, HSP-70, and hs-TnI were not associated with eGFR decline. The specific association of suPAR with eGFR decline supported its involvement in pathways specific to the pathogenesis of kidney disease.

PMID: 29142970 [PubMed]

Social relations and healthcare utilisation among middle-aged and older people: study protocol for an implementation and register-based study in Denmark.

Fri, 11/17/2017 - 13:29

Social relations and healthcare utilisation among middle-aged and older people: study protocol for an implementation and register-based study in Denmark.

BMC Health Serv Res. 2017 Nov 15;17(1):728

Authors: Mikkelsen ASB, Lund R, Kristiansen M

Abstract
BACKGROUND: While previous research establishes an association between social relations, health and use of healthcare services among older people, how to implement this knowledge in real-life settings has received much less attention. This study will explore the relationship between social relations, health and use of healthcare services in a Danish mid-life population sample. In addition, the study will explore individual and contextual factors affecting the implementation of a group-based life story intervention aimed at establishing and strengthening social relations among older people at nursing homes in Denmark.
METHODS/DESIGN: A combined quantitative register-based approach and a qualitative implementation approach will be applied in this study. First, we will quantitatively analyse the relationship between social relations, health status and use of healthcare services among middle-aged people in Denmark by linking survey data on social relations, loneliness, self-perceived health and disease status from the Copenhagen Aging and Midlife Biobank (CAMB) (n = 7191) with national registries through the Public Health Database on use of healthcare services and demographic and socioeconomic factors. Second, we will qualitatively analyse individual and contextual factors affecting the implementation process of the group-based life story intervention based on semi-structured interviews (n = 16), observations and field notes with and among intervention stakeholders, i.e., participants and group leaders facilitating the intervention.
DISCUSSION: The results of this study are expected to improve knowledge about mechanisms through which social relations are associated with health status and use of healthcare services and to inform the implementation of future interventions targeting social relations among older people at nursing homes.
TRIAL REGISTRATION: The study has been registered and approved by the Danish Data Protection Agency. Seperate approvals have been attained for the qualitative data (Approval No. SUND-2016-08), and for the quantitative data in the CAMB database which has also received approval from the local ethical committee (approval No.H-A-2008-126 and No. 2013-41-1814, respectively).

PMID: 29141610 [PubMed - in process]

[Gender differences in stressful life events and depression in Chinese adults aged 30-79 years].

Fri, 11/17/2017 - 13:29
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[Gender differences in stressful life events and depression in Chinese adults aged 30-79 years].

Zhonghua Liu Xing Bing Xue Za Zhi. 2017 Nov 10;38(11):1449-1453

Authors: Wu M, Li JC, Yu CQ, Chen YP, Lyu J, Guo Y, Bian Z, Tan YL, Pei P, Chen JS, Chen ZM, Li LM, China Kadoorie Biobank (CKB) Collaborative Group

Abstract
Objective: To investigate gender specific differences in the association between stressful life events (SLEs) and depression in Chinese adults aged 30-79 years. Methods: In the baseline survey during 2004-2008, the China Kadoorie Biobank (CKB) recruited 512 891 men and women aged 30-79 years from 10 areas of China. Detailed information on SLEs, including demographic and socio-economic status, smoking, alcohol drinking and history of chronic disease, as well as depression symptoms and major depressive episodes (MDEs) in preceding 12 months, was collected by using standardized questionnaire. Multinomial logistic regression model was employed to estimate the relative risk ratio (RRR) and 95%CI of SLEs (3 categories, 10 items) on depression and the dose-response relationship between the number of SLEs experienced and depression. The interactions between gender and SLEs on depression were examined with likelihood ratio test. Results: Among the 512 891 participants, 35 085 (6.8%) reported family-related events, 5 972 (1.2%) reported finance-related events, and 4 453 (0.9%) reported other stressful life events. Females had a higher occurrence of family-related events, while males had a higher occurrence of finance-related and other events (all P-value <0.001). After adjusted for potential confounders, SLEs were significantly associated with MDEs (RRR=11.99, 95%CI: 10.49-13.71 for males; RRR=14.15, 95%CI: 12.97-15.43 for females), and with depressive symptoms (RRR=7.43, 95%CI: 6.94-7.95 for males; RRR=8.30, 95%CI: 7.91-8.72 for females). And the associations were stronger in females than in males (P for interaction=0.049). In the three categories of SLEs, family-related events showed stronger association in female (P for interaction <0.001), while no gender specific differences were observed for the other two categories (all P-value>0.05). Furthermore, the effect of the number of SLEs experienced increased in a dose-response manner on depressive symptoms and MDEs for both genders, but no gender specific differences were found. Conclusions: The gender modifies the association between stressful life events and depression in Chinese adults, and women experienced family-related events have a greater risk of depression. The more the stressful events experienced, the more likely to have depression.

PMID: 29141327 [PubMed - in process]

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.

Thu, 11/16/2017 - 15:07

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.

JAMA Cardiol. 2017 Nov 15;:

Authors: Millwood IY, Bennett DA, Holmes MV, Boxall R, Guo Y, Bian Z, Yang L, Sansome S, Chen Y, Du H, Yu C, Hacker A, Reilly DF, Tan Y, Hill MR, Chen J, Peto R, Shen H, Collins R, Clarke R, Li L, Walters RG, Chen Z, China Kadoorie Biobank Collaborative Group

Abstract
Importance: Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD).
Objective: To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes.
Design, Setting, and Participants: This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries.
Exposures: Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels.
Main Outcomes and Measures: Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases.
Results: Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003).
Conclusions and Relevance: CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

PMID: 29141072 [PubMed - as supplied by publisher]

Addressing the Perfect Storm: Biomarkers in Obesity and Pathophysiology of Cardiometabolic Risk.

Thu, 11/16/2017 - 15:07
Related Articles

Addressing the Perfect Storm: Biomarkers in Obesity and Pathophysiology of Cardiometabolic Risk.

Clin Chem. 2017 Nov 14;:

Authors: Aleksandrova K, Mozaffarian D, Pischon T

Abstract
BACKGROUND: The worldwide rise of obesity has provoked intensified research to better understand its pathophysiology as a means for disease prevention. Several biomarkers that may reflect various pathophysiological pathways that link obesity and cardiometabolic diseases have been identified over the past decades.
CONTENT: We summarize research evidence regarding the role of established and novel obesity-related biomarkers, focusing on recent epidemiological evidence for detrimental associations with cardiometabolic diseases including obesity-related cancer. The reviewed biomarkers include biomarkers of glucose-insulin homeostasis (insulin, insulin growth factors, and C-peptide), adipose tissue biomarkers (adiponectin, omentin, apelin, leptin, resistin, and fatty-acid-binding protein-4), inflammatory biomarkers (C-reactive protein, interleukin 6, tumor necrosis factor α), and omics-based biomarkers (metabolites and microRNAs).
SUMMARY: Although the evidence for many classical obesity biomarkers, including adiponectin and C-reactive protein (CRP), in disease etiology has been initially promising, the evidence for a causal role in humans remains limited. Further, there has been little demonstrated ability to improve disease prediction beyond classical risk factors. In the era of "precision medicine", there is an increasing interest in novel biomarkers, and the extended list of potentially promising biomarkers, such as adipokines, cytokines, metabolites, and microRNAs, implicated in obesity may bring new promise for improved, personalized prevention. To further evaluate the role of obesity-related biomarkers as etiological and early-disease-prediction targets, well-designed studies are needed to evaluate temporal associations, replicate findings, and test clinical utility of novel biomarkers. In particular, studies to determine the therapeutic implications of novel biomarkers beyond established metabolic risk factors are highly warranted.

PMID: 29138271 [PubMed - as supplied by publisher]

Immediate Label-Free Ex Vivo Evaluation of Human Brain Tumor Biopsies With Confocal Reflectance Microscopy.

Wed, 11/15/2017 - 13:29

Immediate Label-Free Ex Vivo Evaluation of Human Brain Tumor Biopsies With Confocal Reflectance Microscopy.

J Neuropathol Exp Neurol. 2017 Dec 01;76(12):1008-1022

Authors: Eschbacher JM, Georges JF, Belykh E, Yazdanabadi MI, Martirosyan NL, Szeto E, Seiler CY, Mooney MA, Daniels JK, Goehring KY, Van Keuren-Jensen KR, Preul MC, Coons SW, Mehta S, Nakaji P

Abstract
Confocal microscopy utilizing fluorescent dyes is widely gaining use in the clinical setting as a diagnostic tool. Reflectance confocal microscopy is a method of visualizing tissue specimens without fluorescent dyes while relying on the natural refractile properties of cellular and subcellular structures. We prospectively evaluated 76 CNS lesions with confocal reflectance microscopy (CRM) to determine cellularity, architecture, and morphological characteristics. A neuropathologist found that all cases showed similar histopathological features when compared to matched hematoxylin and eosin-stained sections. RNA isolated from 7 tissues following CRM imaging retained high RNA integrity, suggesting that CRM does not alter tissue properties for molecular studies. A neuropathologist and surgical pathologist masked to the imaging results independently evaluated a subset of CRM images. In these evaluations, 100% of images reviewed by the neuropathologist and 95.7% of images reviewed by the surgical pathologist were correctly diagnosed as lesional or nonlesional. Furthermore, 97.9% and 91.5% of cases were correctly diagnosed as tumor or not tumor by the neuropathologist and surgical pathologist, respectively, while 95.8% and 85.1% were identified with the correct diagnosis. Our data indicate that CRM is a useful tool for rapidly screening patient biopsies for diagnostic adequacy, molecular studies, and biobanking.

PMID: 29136454 [PubMed - in process]

Age at natural menopause and risk of diabetes in adult women: findings from the China Kadoorie Biobank study in Zhejiang area.

Wed, 11/15/2017 - 13:29

Age at natural menopause and risk of diabetes in adult women: findings from the China Kadoorie Biobank study in Zhejiang area.

J Diabetes Investig. 2017 Nov 14;:

Authors: Wang M, Hu RY, Wang H, Gong WW, Wang CM, Xie KX, Chen ZM, Guo Y, Yu M, Li LM

Abstract
AIMS: There has been considerable professional debate on the association between age at menopause and diabetes risk, while the findings are controversial. This study explored the association between late menopause and the prevalence of diabetes in the Chinese population.
MATERIAL AND METHODS: The data were part of the baseline survey of China Kadoorie Biobank from Zhejiang Province. A total of 17,076 postmenopausal women were included in the present study. Logistic regression models were used to calculate the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs).
RESULTS: Of the participating women, 1,288 (7.54%) had type 2 diabetes. In comparison with those with menopause at 46-52 years, women with menopause at a later age (≥ 53 years) were 1.21 (95% CI: 1.03-1.43) times more likely to have diabetes.
CONCLUSIONS: Our findings suggested that later age at menopause was associated with an increased prevalence of diabetes. This article is protected by copyright. All rights reserved.

PMID: 29136356 [PubMed - as supplied by publisher]

Evaluation of Two Matrices for Long-Term, Ambient Storage of Bacterial DNA.

Tue, 11/14/2017 - 12:53

Evaluation of Two Matrices for Long-Term, Ambient Storage of Bacterial DNA.

Biopreserv Biobank. 2017 Nov 13;:

Authors: Miernyk KM, DeByle CK, Rudolph KM

Abstract
BACKGROUND: Culture-independent molecular analyses allow researchers to identify diverse microorganisms. This approach requires microbiological DNA repositories. The standard for DNA storage is liquid nitrogen or ultralow freezers. These use large amounts of space, are costly to operate, and could fail. Room temperature DNA storage is a viable alternative. In this study, we investigated storage of bacterial DNA using two ambient storage matrices, Biomatrica DNAstable(®) Plus and GenTegra(®) DNA.
METHODS: We created crude and clean DNA extracts from five Streptococcus pneumoniae isolates. Extracts were stored at -30°C (our usual DNA storage temperature), 25°C (within the range of temperatures recommended for the products), and 50°C (to simulate longer storage time). Samples were stored at -30°C with no product and dried at 25°C and 50°C with no product, in Biomatrica DNAstable Plus or GenTegra DNA. We analyzed the samples after 0, 1, 2, 4, 8, 16, 32, and 64 weeks using the Nanodrop 1000 to determine the amount of DNA in each aliquot and by real-time PCR for the S. pneumoniae genes lytA and psaA. Using a 50°C storage temperature, we simulated 362 weeks of 25°C storage.
RESULTS: The average amount of DNA in aliquots stored with a stabilizing matrix was 103%-116% of the original amount added to the tubes. This is similar to samples stored at -30°C (average 102%-121%). With one exception, samples stored with a stabilizing matrix had no change in lytA or psaA cycle threshold (Ct) value over time (Ct range ≤2.9), similar to samples stored at -30°C (Ct range ≤3.0). Samples stored at 25°C with no stabilizing matrix had Ct ranges of 2.2-5.1.
CONCLUSION: DNAstable Plus and GenTegra DNA can protect dried bacterial DNA samples stored at room temperature with similar effectiveness as at -30°C. It is not effective to store bacterial DNA at room temperature without a stabilizing matrix.

PMID: 29130748 [PubMed - as supplied by publisher]

Influence of Storage and Inter- and Intra-Assay Variability on the Measurement of Inflammatory Biomarkers in Population-Based Biobanking.

Tue, 11/14/2017 - 12:53

Influence of Storage and Inter- and Intra-Assay Variability on the Measurement of Inflammatory Biomarkers in Population-Based Biobanking.

Biopreserv Biobank. 2017 Nov 13;:

Authors: van Waateringe RP, Muller Kobold AC, van Vliet-Ostaptchouk JV, van der Klauw MM, Koerts J, Anton G, Peters A, Trischler G, Kvaløy K, Naess M, Videm V, Hveem K, Waldenberger M, Koenig W, Wolffenbuttel BHR

Abstract
BACKGROUND: In the present study, we examined the effect of sample storage on the reproducibility of several inflammatory biomarkers, including high-sensitivity C-reactive protein (hsCRP), high-sensitivity interleukin-6 (hsIL6), and high-sensitivity tumor necrosis factor alpha (hsTNFα). In addition, we assessed inter- and intra-assay variability between collaborating biobanks.
METHODS: In total, 240 fasting plasma samples were obtained from the LifeLines biobank. Samples had been stored for less than 2 or more than 4 years at -80°C. Measurements were performed at three different laboratories. hsCRP was measured by immunonephelometry and ELISA, hsIL6, and hsTNFα samples were measured with ELISAs from two different manufacturers. For confirmation, similar analyses were performed on samples obtained from a subpopulation of 80 obese individuals. Passing-Bablok regression analysis and Bland-Altman plots were used to compare the results.
RESULTS: We observed good stability of samples stored at -80°C. hsCRP measured on the day of blood draw was similar to levels measured after more than 4 years of storage. There were small interlaboratory differences with the R&D ELISAs for hsIL6 and hsTNFα. We found a linear correlation between the Bender Medsystems ELISA and the R&D ELISA for hsIL6, with significantly higher levels measured with the R&D ELISA. Over 90% of hsTNFα samples measured with the IBL ELISA were below the detection limit of 0.13 ng/L, rendering this assay unsuitable for large-scale analysis. Similar results were found in the confirmation study.
CONCLUSION: In summary, plasma hsCRP showed good stability in samples stored for either less than 2 years or more than 4 years at -80°C. Both the R&D and Bender Medsystems for hsIL6 measurement yielded similar results. The IBL hsTNFα assay is not suited for use in biobanking samples. Assays for the measurement of inflammatory biomarker assays should be rigorously tested before large sample sets are measured.

PMID: 29130747 [PubMed - as supplied by publisher]

Ethylene Glycol and Dimethyl Sulfoxide Combination Reduces Cryoinjuries and Apoptotic Gene Expression in Vitrified Laying Hen Ovary.

Tue, 11/14/2017 - 12:53

Ethylene Glycol and Dimethyl Sulfoxide Combination Reduces Cryoinjuries and Apoptotic Gene Expression in Vitrified Laying Hen Ovary.

Biopreserv Biobank. 2017 Nov 13;:

Authors: Nateghi R, Alizadeh A, Jafari Ahangari Y, Fathi R, Akhlaghi A

Abstract
Successful cryopreservation of avian gonads is important not only for avian breeding but is also crucial for preservation of species, especially of endangered birds. The aim of this study was to evaluate the effect of vitrification by several cryoprotectants on the ovarian tissues of laying hens. Ovarian tissues were randomly divided into six groups: control (nonvitrified: C), dehydrated using ethylene glycol (EG), dehydrated with propylene glycol (PROH), dehydrated using dimethyl sulfoxide (DMSO), and two combined groups, EG+DMSO and EG+PROH. The composition of vitrification solutions was as follows: EG group: V1 = 7.5% EG and V2 = 15% EG +0.5 M sucrose, DMSO group: V1 = 7.5% DMSO and V2 = 15% DMSO +0.5 M sucrose, PROH group: V1 = 7.5% PROH and V2 = 15% PROH +0.5 M sucrose, EG+DMSO group: V1 = 7.5% EG +7.5% DMSO and V2 = 15% EG +15% DMSO +0.5 M sucrose and EG+PROH group: V1 = 7.5% EG +7.5% PROH and V2 = 15% EG +15% PROH +0.5 M sucrose. Ovarian tissues of each group were dehydrated for 10 minutes with V1 solution and 2 minutes with V2. Among the vitrified groups, intact primordial and primary follicles showed significant increase in EG+DMSO, but follicular attrition had the highest rate in the PROH group (p < 0.05). Immunohistochemical analysis showed that the percentage of active caspase 3-positive cells was lower (p < 0.05) when using EG+DMSO versus PROH. Further gene expression of caspase 3, 8, and 9 was highest in the PROH group (p < 0.05). Vitrification of ovaries of laying hens using EG+DMSO can afford effective protection of primordial and primary follicles during preservation and may therefore be successfully used for storing avian gonadal tissues.

PMID: 29130738 [PubMed - as supplied by publisher]

The ISBER Strategic Plan: Growing Stronger Through International Cooperation.

Tue, 11/14/2017 - 12:53

The ISBER Strategic Plan: Growing Stronger Through International Cooperation.

Biopreserv Biobank. 2017 Nov 13;:

Authors: Kozlakidis Z

PMID: 29130736 [PubMed - as supplied by publisher]

Differentiation of human olfactory bulb-derived neural stem cells toward oligodendrocyte.

Tue, 11/14/2017 - 12:53
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Differentiation of human olfactory bulb-derived neural stem cells toward oligodendrocyte.

J Cell Physiol. 2018 Feb;233(2):1321-1329

Authors: Marei HE, Shouman Z, Althani A, Afifi N, A AE, Lashen S, Hasan A, Caceci T, Rizzi R, Cenciarelli C, Casalbore P

Abstract
In the central nervous system (CNS), oligodendrocytes are the glial element in charge of myelin formation. Obtaining an overall presence of oligodendrocyte precursor cells/oligodendrocytes (OPCs/OLs) in culture from different sources of NSCs is an important research area, because OPCs/OLs may provide a promising therapeutic strategy for diseases affecting myelination of axons. The present study was designed to differentiate human olfactory bulb NSCs (OBNSCs) into OPCs/OLs and using expression profiling (RT-qPCR) gene, immunocytochemistry, and specific protein expression to highlight molecular mechanism(s) underlying differentiation of human OBNSCs into OPCs/OLs. The differentiation of OBNSCs was characterized by a simultaneous appearance of neurons and glial cells. The differentiation medium, containing cAMP, PDGFA, T3, and all-trans-retinoic acid (ATRA), promotes OBNSCs to generate mostly oligodendrocytes (OLs) displaying morphological changes, and appearance of long cytoplasmic processes. OBNSCs showed, after 5 days in OLs differentiation medium, a considerable decrease in the number of nestin positive cells, which was associated with a concomitant increase of NG2 immunoreactive cells and few O4(+)-OPCs. In addition, a significant up regulation in gene and protein expression profile of stage specific cell markers for OPCs/OLs (CNPase, Galc, NG2, MOG, OLIG1, OLIG2, MBP), neurons, and astrocytes (MAP2, β-TubulinIII, GFAP) and concomitant decrease of OBNSCs pluripotency markers (Oct4, Sox2, Nestin), was demonstrated following induction of OBNSCs differentiation. Taken together, the present study demonstrate the marked ability of a cocktail of factors containing PDGFA, T3, cAMP, and ATRA, to induce OBNSCs differentiation into OPCs/OLs and shed light on the key genes and pathological pathways involved in this process.

PMID: 28500734 [PubMed - indexed for MEDLINE]

Environmental Enteric Dysfunction Is Associated With Poor Linear Growth and Can Be Identified by Host Fecal mRNAs.

Tue, 11/14/2017 - 12:53
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Environmental Enteric Dysfunction Is Associated With Poor Linear Growth and Can Be Identified by Host Fecal mRNAs.

J Pediatr Gastroenterol Nutr. 2016 Nov;63(5):453-459

Authors: Ordiz MI, Shaikh N, Trehan I, Maleta K, Stauber J, Shulman R, Devaraj S, Tarr PI, Manary MJ

Abstract
OBJECTIVE: Environmental enteric dysfunction (EED) can be assessed by the lactulose:mannitol (L:M) test. Our objective was to determine if selected host fecal transcripts were correlated with EED, and whether transcripts and clinical characteristics could be used to predict EED in rural African children.
METHODS: Demographic and sanitation characteristics, along with L:M testing and host fecal transcript analyses from 798 asymptomatic Malawian children aged 12 to 61 months were compared with linear growth over the subsequent 3 months. Fecal host mRNA analysis included quantification of expression of 18 transcripts associated with L:M. Permeability was categorized as normal (L:M ≤ 0.15), moderate (0.15<L:M<0.45) and severe (L:M ≥ 0.45), and random forest predictive models were created.
RESULTS: L:M was inversely correlated with linear growth over the subsequent 3 months (r = -0.32, P < 0.001) and severe EED was associated with stunting (P < 0.0001). Age younger than 24 months, weight-for-height z score <0, domesticated animals in the child's sleep environment, lack of a pit latrine combined with a potentially contaminated water source, and a recent history of diarrhea were associated with severe EED. A random forest model using CD53, HLA-DRA, MUC12, and TNF was 84% sensitive for severe EED and 83% sensitive for no EED.
CONCLUSIONS: Selected host fecal transcripts can be used in a random forest model as a noninvasive biomarker for categories of EED in rural African children.

PMID: 27347722 [PubMed - indexed for MEDLINE]

Thyroid Hormone, Cancer, and Apoptosis.

Tue, 11/14/2017 - 12:53
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Thyroid Hormone, Cancer, and Apoptosis.

Compr Physiol. 2016 Jun 13;6(3):1221-37

Authors: Lin HY, Chin YT, Yang YC, Lai HY, Wang-Peng J, Liu LF, Tang HY, Davis PJ

Abstract
Thyroid hormones play important roles in regulating normal metabolism, development, and growth. They also stimulate cancer cell proliferation. Their metabolic and developmental effects and growth effects in normal tissues are mediated primarily by nuclear hormone receptors. A cell surface receptor for the hormone on integrin [alpha]vβ3 is the initiation site for effects on tumor cells. Clinical hypothyroidism may retard cancer growth, and hyperthyroidism was recently linked to the prevalence of certain cancers. Local levels of thyroid hormones are controlled through activation and deactivation of iodothyronine deiodinases in different organs. The relative activities of different deiodinases that exist in tissues or organs also affect the progression and development of specific types of cancers. In this review, the effects of thyroid hormone on signaling pathways in breast, brain, liver, thyroid, and colon cancers are discussed. The importance of nuclear thyroid hormone receptor isoforms and of the hormone receptor on the extracellular domain of integrin [alpha]vβ3 as potential cancer risk factors and therapeutic targets are addressed. We analyze the intracellular signaling pathways activated by thyroid hormones in cancer progression in hyperthyroidism or at physiological concentrations in the euthyroid state. Determining how to utilize the deaminated thyroid hormone analog (tetrac), and its nanoparticulate derivative to reduce risks of cancer progression, enhance therapeutic outcomes, and prevent cancer recurrence is also deliberated. © 2016 American Physiological Society. Compr Physiol 6:1221-1237, 2016.

PMID: 27347891 [PubMed - indexed for MEDLINE]

Platinum, palladium, rhodium, molybdenum and strontium in blood of urban women in nine countries.

Sun, 11/12/2017 - 13:23

Platinum, palladium, rhodium, molybdenum and strontium in blood of urban women in nine countries.

Int J Hyg Environ Health. 2017 Nov 02;:

Authors: Rentschler G, Rodushkin I, Cerna M, Chen C, Harari F, Harari R, Horvat M, Hruba F, Kasparova L, Koppova K, Krskova A, Krsnik M, Laamech J, Li YF, Löfmark L, Lundh T, Lundström NG, Lyoussi B, Mazej D, Osredkar J, Pawlas K, Pawlas N, Prokopowicz A, Skerfving S, Snoj Tratnik J, Spevackova V, Spiric Z, Sundkvist A, Strömberg U, Vadla D, Wranova K, Zizi S, Bergdahl IA

Abstract
BACKGROUND: There is little reliable information on human exposure to the metals platinum (Pt), palladium (Pd) and rhodium (Rh), despite their use in enormous quantities in catalytic converters for automobile exhaust systems.
OBJECTIVES: To evaluate blood concentrations of Pt (B-Pt), Pd (B-Pd) and Rh (B-Rh) in women from six European and three non-European countries, and to identify potentially influential factors. In addition, molybdenum (Mo) and strontium (Sr) were analysed.
METHODS: Blood from 248 women aged 47-61 was analysed by high resolution inductively coupled plasma mass spectrometry under strict quality control.
RESULTS: The medians were: B-Pt 0.8 (range <0.6-5.2), B-Pd <5 (<5-9.3), B-Rh <0.4 (<0.4-3.6)ng/L and B-Mo 2.0 (0.2-16) and B-Sr 16.6 (3.5-49) μg/L. Two women with highly elevated B-Pt (242 and 60ng/L), previously cancer treated with cis-platinum, were not included in the data analysis. All elements varied geographically (2-3 times) (B-Pd P=0.05; all other elements P<0.001); variations within each area were generally 5-10 times. Traffic was not associated with increased concentrations.
CONCLUSIONS: General population blood concentrations of Pt, Pd and Rh are within or below the single digit ng/L range, much lower than in most previous reports. This is probably due to improved analytical performance, allowing for more reliable information at ultra-trace levels. In general, Mo and Sr agreed with previously reported concentrations. All elements showed geographical and inter-individual variations, but no convincing relationships with self-reported traffic intensity were found. Pt from the antineoplastic drug cis-platinum is retained in the body for years.

PMID: 29126886 [PubMed - as supplied by publisher]

Liquid Biopsy and Therapeutic Targets: Present and Future Issues in Thoracic Oncology.

Sat, 11/11/2017 - 15:02

Liquid Biopsy and Therapeutic Targets: Present and Future Issues in Thoracic Oncology.

Cancers (Basel). 2017 Nov 10;9(11):

Authors: Hofman P

Abstract
The practice of liquid biopsy (LB) has revolutionized the care of patients with metastatic lung cancer. Many oncologists now use this approach in daily practice, applying precise procedures for the detection of activating or resistance mutations in EGFR. These tests are performed with plasma DNA and have been approved as companion diagnostic test for patients treated with tyrosine kinase inhibitors. ALK is another important target in lung cancer since it leads to treatment of patients who are positive for a rearrangement in ALK identified with tumor tissue. By analogy with EGFR, LB for detection of genomic alterations in ALK (rearrangements or mutations) has been rapidly adopted in the clinic. However, this promising approach has some limitations and has not yet been disseminated as much as the blood test targeting EGFR. In addition to these two therapeutic targets LB can be used for evaluation of the genomic status of other genes of interest of patients with lung cancer (ROS1, RET, NTRK MET, BRAF, HER2, etc.). LB can be performed to evaluate a specific target or for a more or less complex panel of genes. Considering the number of potential targets for clinical trials, techniques of next-generation sequencing of circulating DNA are on the rise. This review will provide an update on the contribution of LB to care of patients with metastatic lung cancer, including the present limits of this approach, and will consider certain perspectives.

PMID: 29125548 [PubMed]

Complete Annotated Genome Sequences of Four Klebsiella pneumoniae Phages Isolated from Sewage in Poland.

Sat, 11/11/2017 - 15:02

Complete Annotated Genome Sequences of Four Klebsiella pneumoniae Phages Isolated from Sewage in Poland.

Genome Announc. 2017 Nov 09;5(45):

Authors: Labudda Ł, Strapagiel D, Karczewska-Golec J, Golec P

Abstract
Four lytic phages, vB_KpnP_BIS33, vB_KpnP_IL33, and vB_KpnP_PRA33 of the Podoviridae family and vB_KpnM_BIS47 of the Myoviridae family, which act against animal-pathogenic Klebsiella pneumoniae strains, were isolated from sewage plants in Poland. They possess double-stranded DNA genomes of 41,697 bp, 41,335 bp, 40,605 bp, and 147,443 bp, respectively.

PMID: 29122855 [PubMed]

CNS penetration of ART in HIV-infected children.

Sat, 11/11/2017 - 12:00

CNS penetration of ART in HIV-infected children.

J Antimicrob Chemother. 2017 Nov 08;:

Authors: Van den Hof M, Blokhuis C, Cohen S, Scherpbier HJ, Wit FWNM, Pistorius MCM, Kootstra NA, Teunissen CE, Mathot RAA, Pajkrt D

Abstract
Background: Paediatric data on CNS penetration of antiretroviral drugs are scarce.
Objectives: To evaluate CNS penetration of antiretroviral drugs in HIV-infected children and explore associations with neurocognitive function.
Patients and methods: Antiretroviral drug levels were measured in paired CSF and blood samples of clinically stable HIV-infected children between 8 and 18 years old on long-term combined ART. Plasma drug concentrations were corrected for protein binding. We evaluated CNS penetration using CSF/plasma ratios and compared CSF concentrations with the IC50 as a surrogate marker for effectiveness. Blood-brain barrier permeability was assessed for possible confounding. Associations with neurocognitive function were explored using linear regression analysis.
Results: Median CSF/plasma ratios (IQR) were: lopinavir 0.059 (0.024-0.157, n = 7), efavirenz 0.681 (0.555-0.819, n = 12), tenofovir 0.021 (0.020-0.024, n = 4), lamivudine 0.464 (0.331-0.607, n = 17), emtricitabine 0.365 (0.343-0.435, n = 3), nevirapine 1.203 (n = 1), zidovudine 0.718 (0.711-1.227, n = 5) and abacavir 1.344 (0.670-2.450, n = 10). CSF concentrations were below the IC50 for tenofovir (100%), emtricitabine (100%), abacavir (50%) and zidovudine (17%). Lamivudine, lopinavir, efavirenz and nevirapine concentrations were all above the IC50. All participants were virologically suppressed in blood and CSF. CSF drug concentrations were not associated with blood-brain barrier permeability or neurocognitive function.
Conclusions: We showed adequate CSF concentrations of lamivudine, lopinavir, efavirenz and nevirapine, and potential suboptimal CSF concentrations of tenofovir, abacavir and emtricitabine in long-term treated HIV-infected children. None the less, the use of combined antiretroviral drugs led to adequate viral suppression.

PMID: 29126299 [PubMed - as supplied by publisher]

Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

Sat, 11/11/2017 - 12:00

Nuclear IGF-1R predicts chemotherapy and targeted therapy resistance in metastatic colorectal cancer.

Br J Cancer. 2017 Nov 09;:

Authors: Codony-Servat J, Cuatrecasas M, Asensio E, Montironi C, Martínez-Cardús A, Marín-Aguilera M, Horndler C, Martínez-Balibrea E, Rubini M, Jares P, Reig O, Victoria I, Gaba L, Martín-Richard M, Alonso V, Escudero P, Fernández-Martos C, Feliu J, Méndez JC, Méndez M, Gallego J, Salud A, Rojo F, Castells A, Prat A, Rosell R, García-Albéniz X, Camps J, Maurel J

Abstract
BACKGROUND: Although chemotherapy is the cornerstone treatment for patients with metastatic colorectal cancer (mCRC), acquired chemoresistance is common and constitutes the main reason for treatment failure. Monoclonal antibodies against insulin-like growth factor-1 receptor (IGF-1R) have been tested in pre-treated mCRC patients, but results have been largely deceiving.
METHODS: We analysed time to progression, overall survival, and the mutational status of RAS, BRAF and nuclear p-IGF-1R expression by immunohistochemistry, in 470 metastatic CRC patients. The effect of IGF-1R activation and distribution was also assessed using cellular models of CRC and RNAi for functional validation.
RESULTS: Nuclear IGF-1R increased in metastatic tumours compared to paired untreated primary tumours, and significantly correlated with poor overall survival in mCRC patients. In vitro, chemo-resistant cell lines presented significantly higher levels of IGF-1R expression within the nuclear compartment, and PIAS3, a protein implicated also in the sumoylation process of intranuclear proteins, contributed to IGF-1R nuclear sequestration, highlighting the essential role of PIAS3 in this process. Intriguingly, we observed that ganitumab, an IGF-1R blocking-antibody used in several clinical trials, and dasatinib, an SRC inhibitor, increased the nuclear localisation of IGF-1R.
CONCLUSIONS: Our study demonstrates that IGF-1R nuclear location might lead to chemotherapy and targeted agent resistance.British Journal of Cancer advance online publication: 9 November 2017; doi:10.1038/bjc.2017.279 www.bjcancer.com.

PMID: 29123263 [PubMed - as supplied by publisher]