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Sökning: WFRF:(Keun Hector)

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  • Antti, Henrik, et al. (författare)
  • Statistical experimental design and partial least squares regression analysis of biofluid metabonomic NMR and clinical chemistry data for screening of adverse drug effects
  • 2004
  • Ingår i: Chemometrics and Intelligent Laboratory Systems. ; 73:1, s. 139-49
  • Tidskriftsartikel (refereegranskat)abstract
    • Metabonomic analysis is increasingly recognised as a powerful approach for delineating the integrated metabolic changes in biofluids and tissues due to toxicity, disease processes or genetic modification in whole animal systems. When dealing with complex biological data sets, as generated within metabonomics, as well as related fields such as genomics and proteomics, reliability and significance of identified biomarkers associated with specific states related to toxicity or disease are crucial in order to gain detailed and relevant interpretations of the metabolic fluxes in the studied systems. Since various physiological factors, such as diet, state of health, age, diurnal cycles, stress, genetic drift, and strain differences, affect the metabolic composition of biological matrices, it is of great importance to create statistically reliable decision tools for distinguishing between physiological and pathological responses in animal models. In the screening for new biomarkers or patterns of pathological dysfunction, methods providing statistically valid measures of effect-related changes will become increasingly important as the data within areas such as genomics, proteomics and metabonomics continues to grow in size and complexity. 1H NMR spectroscopy and mass spectrometry are the principal analytical platforms used to derive the data and, because extensively large data sets are required, as much consideration has to be given to optimum design of experiments (DoE) as for subsequent data analysis. Thus, statistical experimental design combined with partial least squares (PLS) regression is proposed as an efficient approach for undertaking metabonomic studies and for analysis of the results. The method was applied to data from a liver toxicology study in the rat using hydrazine as a model toxin. 1D projections of 2D J-resolved (J-RES) 1H NMR spectra and the corresponding clinical chemistry parameters of blood serum samples from control and dosed rats (30 and 90 mg/kg) collected at 48 and 168 h post dose were analysed. Confidence intervals for the PLS regression coefficients were used to create a statistical means for screening of biomarkers in the two combined data blocks (NMR and clinical chemistry data). PLS analysis was also used to reveal the correlation pattern between the two blocks of data as well as the within the two blocks according to dose, time and the interaction dose×time.
  • Berger, Eloise, et al. (författare)
  • Association between low-grade inflammation and Breast cancer and B-cell Myeloma and Non-Hodgkin Lymphoma : Findings from two prospective cohorts
  • 2018
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and Β-cell Non-Hodgkin Lymphoma (B-cell NHL, including 68 multiple myeloma cases) onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases (β = -1.28, p = 0.012), and, to lesser, extent with BC (β = -0.96, p = 0.33) compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers.
  • Bollard, Mary E, et al. (författare)
  • Comparative metabonomics of differential hydrazine toxicity in the rat and mouse
  • 2005
  • Ingår i: Toxicology and Applied Pharmacology. ; 204:2, s. 135-51
  • Tidskriftsartikel (refereegranskat)abstract
    • Interspecies variation between rats and mice has been studied for hydrazine toxicity using a novel metabonomics approach. Hydrazine hydrochloride was administered to male Sprague–Dawley rats (30 mg/kg, n = 10 and 90 mg/kg, n = 10) and male B6C3F mice (100 mg/kg, n = 8 and 250 mg/kg, n = 8) by oral gavage. In each species, the high dose was selected to produce the major histopathologic effect, hepatocellular lipid accumulation. Urine samples were collected at sequential time points up to 168 h post dose and analyzed by 1H NMR spectroscopy. The metabolites of hydrazine, namely diacetyl hydrazine and 1,4,5,6-tetrahydro-6-oxo-3-pyridazine carboxylic acid (THOPC), were detected in both the rat and mouse urine samples. Monoacetyl hydrazine was detected only in urine samples from the rat and its absence in the urine of the mouse was attributed to a higher activity of N-acetyl transferases in the mouse compared with the rat. Differential metabolic effects observed between the two species included elevated urinary β-alanine, 3-d-hydroxybutyrate, citrulline, N-acetylcitrulline, and reduced trimethylamine-N-oxide excretion unique to the rat. Metabolic principal component (PC) trajectories highlighted the greater degree of toxic response in the rat. A data scaling method, scaled to maximum aligned and reduced trajectories (SMART) analysis, was used to remove the differences between the metabolic starting positions of the rat and mouse and varying magnitudes of effect, to facilitate comparison of the response geometries between the rat and mouse. Mice followed “biphasic” open PC trajectories, with incomplete recovery 7 days after dosing, whereas rats followed closed “hairpin” time profiles, indicating functional reversibility. The greater magnitude of metabolic effects observed in the rat was supported by the more pronounced effect on liver pathology in the rat when compared with the mouse.
  • Chatziioannou, Aristotelis, et al. (författare)
  • Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases
  • 2017
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment.
  • Hebels, Dennie G. A. J., et al. (författare)
  • Performance in omics analyses of blood samples in long-term storage : opportunities for the exploitation of existing biobanks in environmental health research
  • 2013
  • Ingår i: Journal of Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 121:4, s. 480-487
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The suitability for omic analysis of biosamples collected in previous decades and currently stored in biobanks is unknown.Objectives: We evaluated the influence of handling and storage conditions of blood-derived biosamples on transcriptomic, epigenomic (CpG methylation), plasma metabolomic [UPLC-ToFMS (ultra performance liquid chromatography-time-of-flight mass spectrometry)], and wide-target proteomic profiles.Methods: We collected fresh blood samples without RNA preservative in heparin, EDTA, or citrate and held them at room temperature for ≤ 24 hr before fractionating them into buffy coat, erythrocytes, and plasma and freezing the fractions at -80oC or in liquid nitrogen. We developed methodology for isolating RNA from the buffy coats and conducted omic analyses. Finally, we analyzed analogous samples from the EPIC-Italy and Northern Sweden Health and Disease Study biobanks.Results: Microarray-quality RNA could be isolated from buffy coats (including most biobank samples) that had been frozen within 8 hr of blood collection by thawing the samples in RNA preservative. Different anticoagulants influenced the metabolomic, proteomic, and to a lesser extent transcriptomic profiles. Transcriptomic profiles were most affected by the delay (as little as 2 hr) before blood fractionation, whereas storage temperature had minimal impact. Effects on metabolomic and proteomic profiles were noted in samples processed ≥ 8 hr after collection, but no effects were due to storage temperature. None of the variables examined significantly influenced the epigenomic profiles. No systematic influence of time-in-storage was observed in samples stored over a period of 13-17 years.Conclusions: Most samples currently stored in biobanks are amenable to meaningful omics analysis, provided that they satisfy collection and storage criteria defined in this study.
  • Vermeulen, Roel, et al. (författare)
  • Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma : univariate and functionally informed multivariate analyses
  • 2018
  • Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 143:6, s. 1335-1347
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent prospective studies have shown that dysregulation of the immune system may precede the development of B‐cell lymphomas (BCL) in immunocompetent individuals. However, to date, the studies were restricted to a few immune markers, which were considered separately. Using a nested case–control study within two European prospective cohorts, we measured plasma levels of 28 immune markers in samples collected a median of 6 years before diagnosis (range 2.01–15.97) in 268 incident cases of BCL (including multiple myeloma [MM]) and matched controls. Linear mixed models and partial least square analyses were used to analyze the association between levels of immune marker and the incidence of BCL and its main histological subtypes and to investigate potential biomarkers predictive of the time to diagnosis. Linear mixed model analyses identified associations linking lower levels of fibroblast growth factor‐2 (FGF‐2 p = 7.2 × 10−4) and transforming growth factor alpha (TGF‐α, p = 6.5 × 10−5) and BCL incidence. Analyses stratified by histological subtypes identified inverse associations for MM subtype including FGF‐2 (p = 7.8 × 10−7), TGF‐α (p = 4.08 × 10−5), fractalkine (p = 1.12 × 10−3), monocyte chemotactic protein‐3 (p = 1.36 × 10−4), macrophage inflammatory protein 1‐alpha (p = 4.6 × 10−4) and vascular endothelial growth factor (p = 4.23 × 10−5). Our results also provided marginal support for already reported associations between chemokines and diffuse large BCL (DLBCL) and cytokines and chronic lymphocytic leukemia (CLL). Case‐only analyses showed that Granulocyte‐macrophage colony stimulating factor levels were consistently higher closer to diagnosis, which provides further evidence of its role in tumor progression. In conclusion, our study suggests a role of growth‐factors in the incidence of MM and of chemokine and cytokine regulation in DLBCL and CLL.
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