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  • 1
    Publication Date: 2018-01-04
    Description: To identify gene expression biomarkers and pathways targeted by sulindac and erlotinib given in a chemoprevention trial with a significant decrease in duodenal polyp burden at 6 months ( P 〈 0.001) in familial adenomatous polyposis (FAP) patients, we biopsied normal and polyp duodenal tissues from patients on drug versus placebo and analyzed the RNA expression. RNA sequencing was performed on biopsies from the duodenum of FAP patients obtained at baseline and 6-month endpoint endoscopy. Ten FAP patients on placebo and 10 on sulindac and erlotinib were selected for analysis. Purity of biopsied polyp tissue was calculated from RNA expression data. RNAs differentially expressed between endpoint polyp and paired baseline normal were determined for each group and mapped to biological pathways. Key genes in candidate pathways were further validated by quantitative RT-PCR. RNA expression analyses of endpoint polyp compared with paired baseline normal for patients on placebo and drug show that pathways activated in polyp growth and proliferation are blocked by this drug combination. Directly comparing polyp gene expression between patients on drug and placebo also identified innate immune response genes (IL12 and IFN) preferentially expressed in patients on drug. Gene expression analyses from tissue obtained at endpoint of the trial demonstrated inhibition of the cancer pathways COX2/PGE2, EGFR, and WNT. These findings provide molecular evidence that the drug combination of sulindac and erlotinib reached the intended tissue and was on target for the predicted pathways. Furthermore, activation of innate immune pathways from patients on drug may have contributed to polyp regression. Cancer Prev Res; 11(1); 4–15. ©2017 AACR . See related editorial by Shureiqi, p. 1
    Print ISSN: 1940-6207
    Electronic ISSN: 1940-6215
    Topics: Medicine
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  • 2
    Abstract: OBJECTIVE: To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke. DESIGN: Multicentre case-cohort study. SETTING: A study of cardiovascular disease (CVD) determinants within the European Prospective Investigation into Cancer and nutrition cohort (EPIC-CVD) from eight European countries. PARTICIPANTS: 32 549 participants without baseline CVD, comprised of incident CVD cases and a subcohort for comparison. MAIN OUTCOME MEASURES: Non-fatal and fatal CHD and stroke (including ischaemic and haemorrhagic stroke). RESULTS: There were 9307 non-fatal CHD events, 1699 fatal CHD, 5855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0-14.9 g/day, 15.0-29.9 g/day, and 30.0-59.9 g/day of total alcohol intake, respectively, compared with 0.1-4.9 g/day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events. CONCLUSIONS: Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes. This highlights the opposing associations of alcohol intake with different CVD types and strengthens the evidence for policies to reduce alcohol consumption.
    Type of Publication: Journal article published
    PubMed ID: 29844013
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  • 3
    Keywords: COMBINATION ; MODEL ; MODELS ; FOLLOW-UP ; INFORMATION ; DISEASE ; DISEASES ; RISK ; HEART ; TIME ; MARKER ; ASSOCIATION ; ASSAY ; DESIGN ; PLASMA ; NUMBER ; AGE ; meta-analysis ; smoking ; DATABASE ; C-REACTIVE PROTEIN ; MYOCARDIAL-INFARCTION ; HEART-DISEASE ; vascular disease ; REGRESSION ; ASSOCIATIONS ; ISCHEMIC-STROKE ; CORONARY-HEART-DISEASE ; METAANALYSIS ; LEVEL ; methods ; EXTENT ; ARTERY-DISEASE ; MIDDLE-AGED MEN ; ACTIVATING-FACTOR-ACETYLHYDROLASE ; ATHEROSCLEROSIS RISK ; lipoprotein-associated phospholipase A(2) ; LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE-A2 ; REPEAT
    Abstract: Background A large number of observational epidemiological studies have reported generally positive associations' between circulating mass and activity levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA(2) markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. Objectives By combination of data from individual participants from all relevant observational studies in a systematic,meta-analysis, with correction for regression dilution (using available data on serial measurements of Lp-PLA(2)), the Lp-PLA(2) Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA(2) with coronary heart disease (and, where data are sufficient with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA(2) and cardiovascular outcomes. Methods A central database is being established containing data on circulating Lp-PLA(2) values, sex and other potential confounding factors, age at baseline Lp-PLA(2) Measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA(2) will yield information on a total of about 15 000 cardiovascular disease endpoints
    Type of Publication: Journal article published
    PubMed ID: 17301621
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  • 4
    Keywords: MEASUREMENT ERROR ; RELATIVE RISK ; CORONARY-HEART-DISEASE ; REGRESSION DILUTION ; RANDOM-EFFECTS METAANALYSIS ; FLOATING ABSOLUTE RISK ; USUAL BLOOD-PRESSURE ; PATIENT DATA ; PLASMA-FIBRINOGEN ; META-REGRESSION
    Abstract: BACKGROUND: Meta-analysis of individual participant time-to-event data from multiple prospective epidemiological studies enables detailed investigation of exposure-risk relationships, but involves a number of analytical challenges. METHODS: This article describes statistical approaches adopted in the Emerging Risk Factors Collaboration, in which primary data from more than 1 million participants in more than 100 prospective studies have been collated to enable detailed analyses of various risk markers in relation to incident cardiovascular disease outcomes. RESULTS: Analyses have been principally based on Cox proportional hazards regression models stratified by sex, undertaken in each study separately. Estimates of exposure-risk relationships, initially unadjusted and then adjusted for several confounders, have been combined over studies using meta-analysis. Methods for assessing the shape of exposure-risk associations and the proportional hazards assumption have been developed. Estimates of interactions have also been combined using meta-analysis, keeping separate within- and between-study information. Regression dilution bias caused by measurement error and within-person variation in exposures and confounders has been addressed through the analysis of repeat measurements to estimate corrected regression coefficients. These methods are exemplified by analysis of plasma fibrinogen and risk of coronary heart disease, and Stata code is made available. CONCLUSION: Increasing numbers of meta-analyses of individual participant data from observational data are being conducted to enhance the statistical power and detail of epidemiological studies. The statistical methods developed here can be used to address the needs of such analyses.
    Type of Publication: Journal article published
    PubMed ID: 20439481
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  • 5
    ISSN: 0277-5387
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0309-1651
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-072X
    Keywords: Sulfolobus ; Chemolithotrophy ; Autotrophy ; Tetrathionate oxidation ; Glucose oxidation ; CO2-fixation enzymes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Autotrophic growth yields of four strains of Sulfolobus using tetrathionate as sole energy substrate fell in the range 6.2–7.8 g dry weight (mol tetrathionate oxidized)-1. Autotrophic organisms lacked ribulose 1,5-bis-phosphate carboxylase, but contained pyruvate and phosphoenolpyruvate carboxylases. S. brierleyi and strains B6-2 and LM exhibited mixotrophic growth, with tetrathionate oxidation, CO2-fixation and organic substrate assimilation occurring concurrently, using media containing glucose or acetate. Yeast extract or succinate supported heterotrophic growth and showed strain-dependent repression of one or both of tetrathionate oxidation and CO2-fixation resulting in biphasic growth. All four carbon atoms of succinate were assimilated to cell-carbon during growth. Acetate was the major source of cell-carbon during mixotrophic growth. These observations are not inconsistent with the possibility of a reductive carboxylic acid cycle in these organisms. Radiorespirometric analysis of glucose oxidation indicated CO2 release to occur by means of an Entner-Doudoroff pathway (followed by pyruvate decarboxylation) and oxidative pentose phosphate pathway reactions. There was little evidence from the glucose radiorespirometry of the large-scale use of an oxidative tricarboxylic acid cycle for terminal oxidation of acetate derived from pyruvate. These results demonstrate the considerable metabolic versatility of Sulfolobus strains and show that there is significant variation among them.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-072X
    Keywords: Key words Methylobacterium thiocyanatum ; Thiocyanate metabolism ; Cyanase ; 16S rRNA sequence ; SDS-PAGE ; Pink-pigmented facultative methylotroph
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The isolation and properties of a novel species of pink-pigmented methylotroph, Methylobacterium thiocyanatum, are described. This organism satisfied all the morphological, biochemical, and growth-substrate criteria to be placed in the genus Methylobacterium. Sequencing of the gene encoding its 16S rRNA confirmed its position in this genus, with its closest phylogenetic relatives being M. rhodesianum, M. zatmanii and M. extorquens, from which it differed in its ability to grow on several diagnostic substrates. Methanol-grown organisms contained high activities of hydroxypyruvate reductase [3 μmol NADH oxidized min–1 (mg crude extract protein)–1], showing that the serine pathway was used for methylotrophic growth. M. thiocyanatum was able to use thiocyanate or cyanate as the sole source of nitrogen for growth, and thiocyanate as the sole source of sulfur in the absence of other sulfur compounds. It tolerated high concentrations (at least 50 mM) of thiocyanate or cyanate when these were supplied as nitrogen sources. Growing cultures degraded thiocyanate to produce thiosulfate as a major sulfur end product, apparently with the intermediate formation of volatile sulfur compounds (probably hydrogen sulfide and carbonyl sulfide). Enzymatic hydrolysis of thiocyanate by cell-free extracts was not demonstrated. Cyanate was metabolized by means of a cyanase enzyme that was expressed at approximately sevenfold greater activity during growth on thiocyanate [V max 634 ± 24 nmol NH3 formed min–1 (mg protein)–1] than on cyanate [89 ± 9 nmol NH3 min–1 (mg protein)–1]. Kinetic study of the cyanase in cell-free extracts showed the enzyme (1) to exhibit high affinity for cyanate (K m 0.07 mM), (2) to require bicarbonate for activity, (3) to be subject to substrate inhibition by cyanate and competitive inhibition by thiocyanate (K i 0.65 mM), (4) to be unaffected by 1 mM ammonium chloride, (5) to be strongly inhibited by selenocyanate, and (6) to be slightly inhibited by 5 mM thiosulfate, but unaffected by 0.25 mM sulfide or 1 mM thiosulfate. Polypeptides that might be a cyanase subunit (mol.wt. 17.9 kDa), a cyanate (and/or thiocyanate) permease (mol.wt. 25.1 and 27.2 kDa), and a putative thiocyanate hydrolase (mol.wt. 39.3 kDa) were identified by SDS-PAGE. Correlation of the growth rate of cultures with thiocyanate concentration (both stimulatory and inhibitory) and the kinetics of cyanase activity might indicate that growth on thiocyanate involved the intermediate formation of cyanate, hence requiring cyanase activity. The very high activity of cyanase observed during growth on thiocyanate could be in compensation for the inhibitory effect of thiocyanate on cyanase. Alternatively, thiocyanate may be a nonsubstrate inducer of cyanase, while thiocyanate degradation itself proceeds by a carbonyl sulfide pathway not involving cyanate. A formal description of the new species (DSM 11490) is given.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-8798
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Four lamb rotaviruses were characterised serologically by reactions with monoclonal antibodies and genomically by hybridisation assays and sequencing. Each was found to be distinct. Three viruses belonged to the bovine genogroup and were of subgroup I. These viruses possessed serotypes G3, G6, and G10. Their corresponding P types were P1, P11, and P14 respectively. The only previous isolation of a rotavirus with VP4 of type P14 was also from lambs. The fourth isolate was G9P8, which is the first record of a G9 rotavirus from a species other than man.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-8798
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary DIG-labelled ssRNA probes were prepared from variable regions of VP4 and VP7 cognate genes, and used in hybridization assays for P and G genotyping of group A cell culture-adapted equine rotaviruses and fecal samples collected from foals with and without diarrhea. The probes confirmed known P and G serotypes of sixteen cell culture-adapted strains. From one-hundred and twenty-one rotavirus-positive samples, 83 reacted when tested for their P and G genotype specific probes. From these, 71 were found to contain G3 P12 genotypes, and 11 G14 P12 genotypes. No sample reacted with H1 or L338 P and G genotype probes. This suggests that the equine rotavirus population is conservative, containing predominantly one P genotype and two G genotypes. One isolate (26/94) whose dsRNA was visualized in an agarose gel did not react with any of the equine probes, and was found to belong to G8 and P1 genotypes. This is the fourth example of a single unique equine isolate (after H1, L338, and R-22). The remaining thirty-eight untypable field isolates had no detectable dsRNA after storage for 1 to 3 years.
    Type of Medium: Electronic Resource
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