31 research outputs found

    Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke

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    Background Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes. Objectives This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH). Methods In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker. Results Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. Conclusions Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non–lipid-related metabolites associated with all 3 diseases.published versionpeerReviewe

    Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer

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    Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication

    The rapid photochemical reduction of U(VI) at high uranium concentrations relevant to spent nuclear fuel recycle processes

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    An Advanced PUREX process for the recycling of spent nuclear fuel is currently under active development in the UK. Its key aims are to avoid pure separated plutonium at all stages of the process to enhance the level of proliferation resistance, and to achieve a single cycle flowsheet that has a smaller plant footprint with consequent decreases in the capital cost and secondary wastes generated. Addressing these aims, a significant feature of the process is the co-treatment of U and Pu and thus the in situ co-conversion of mixed actinide metal nitrate solutions into oxide powders, suitable for the fabrication of new mixed metal oxide (MOx) fuel. The baseline industrial process for plutonium recovery is by oxalate precipitation; however, in order to quantitatively recover both U and Pu the uranium must be in the U(IV) oxidation state due to the high solubility of U(VI) oxalate. The first stage of this co-conversion, the development of which is reported on here, is the rapid, clean photochemical co-reduction of a mixed U(VI)/Pu(IV) nitrate stream to U(IV)/Pu(III). Here we describe a study of the reduction of U(VI) in preparation for mixed U(VI)/Pu(IV) reduction trials. Exploiting the photochemistry of U, we demonstrate the convenient and efficient photo-excitation and chemical reduction of U(VI) upon exposure to 407 nm wavelength light in the presence of alcohol-based reductants. Using a purpose built laboratory-scale photochemical reactor, U(VI) solutions of up to process-relevant concentrations of 630 mmol/dm3 (150 g/l) U have been successfully converted to a U(IV) product, achieving a conversion efficiency of ∼98% within 1.5–15 min when using propan-2-ol as a sacrificial reductant. Modelling of the dependence of the rate of U(IV) generation on initial U(VI) concentration reveals the importance of light penetration depth and effective solution mixing in determining the efficiency of the photochemical process at high U-loadings. It also reveals that the photoreduction of U(VI) to U(IV) occurs by two sequential 1-electron reductions: (i) the photochemically driven reduction of UO22+ to UO2+ by propan-2-ol, which itself is oxidised to form an α-hydroxyalkyl radical, immediately followed by (ii) a second chemical reduction of UO22+ to UO2+ and/or UO2+ to U4+ by the so-formed radical. With the addition of a nitrous acid scavenger to prevent re-oxidation of the photochemically generated U(IV), a stable product is maintained indefinitely, and the solution is suitable for subsequent oxalate co-precipitation as part of a MOx fuel fabrication process

    Response to comment on “Evaluating the cardiovascular safety of sclerostin inhibition using evidence from meta-analysis of clinical trials and human genetics”

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    Triangulation of evidence from clinical trials and human genetics suggests a potential excess risk of cardiovascular disease events arising from therapeutic inhibition of sclerostin

    Genome-wide Studies of Verbal Declarative Memory in Nondemented Older People: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium

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    BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 � 10) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 � 10) and replication cohorts (p = 5.65 � 10). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 � 10, and rs6813517 [SPOCK3], p = 2.58 � 10) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ∼40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways

    Lipids, lipoproteins, and metabolites and risk of myocardial infarction and stroke

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    Abstract Background: Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes. Objectives: This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH). Methods: In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker. Results: Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. Conclusions: Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non–lipid-related metabolites associated with all 3 diseases

    Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium

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    Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.; We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p &lt; 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.; rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.; This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways

    Lipids, Lipoproteins, and Metabolites and Risk of Myocardial Infarction and Stroke

    Get PDF
    AbstractBackground Blood lipids are established risk factors for myocardial infarction (MI), but uncertainty persists about the relevance of lipids, lipoprotein particles, and circulating metabolites for MI and stroke subtypes. Objectives This study sought to investigate the associations of plasma metabolic markers with risks of incident MI, ischemic stroke (IS), and intracerebral hemorrhage (ICH). Methods In a nested case-control study (912 MI, 1,146 IS, and 1,138 ICH cases, and 1,466 common control subjects) 30 to 79 years of age in China Kadoorie Biobank, nuclear magnetic resonance spectroscopy measured 225 metabolic markers in baseline plasma samples. Logistic regression was used to estimate adjusted odds ratios (ORs) for a 1-SD higher metabolic marker. Results Very low-, intermediate-, and low-density lipoprotein particles were positively associated with MI and IS. High-density lipoprotein (HDL) particles were inversely associated with MI apart from small HDL. In contrast, no lipoprotein particles were associated with ICH. Cholesterol in large HDL was inversely associated with MI and IS (OR: 0.79 and 0.88, respectively), whereas cholesterol in small HDL was not (OR: 0.99 and 1.06, respectively). Triglycerides within all lipoproteins, including most HDL particles, were positively associated with MI, with a similar pattern for IS. Glycoprotein acetyls, ketone bodies, glucose, and docosahexaenoic acid were associated with all 3 diseases. The 225 metabolic markers showed concordant associations between MI and IS, but not with ICH. Conclusions Lipoproteins and lipids showed similar associations with MI and IS, but not with ICH. Within HDL particles, cholesterol concentrations were inversely associated, whereas triglyceride concentrations were positively associated with MI. Glycoprotein acetyls and several non–lipid-related metabolites associated with all 3 diseases
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