PubMed

A MALDI-MS-based quantitative analytical method for endogenous estrone in human breast cancer cells. Sci Rep. 2016;6:24489 Authors: Kim KJ, Kim HJ, Park HG, Hwang CH, Sung C, Jang KS, Park SH, Kim BG, Lee YK, Yang YH, Jeong JH, Kim YG Abstract The level of endogenous estrone, one of the three major naturally occurring estrogens, has a significant correlation with the incidence of post-menopausal breast cancer. However, it is challenging to quantitatively monitor it owing to its low abundance. Here, we develop a robust and highly sensitive mass-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based quantitative platform to identify the absolute quantities of endogenous estrones in a variety of clinical specimens. The one-step modification of endogenous estrone provided good linearity (R(2) > 0.99) and significantly increased the sensitivity of the platform (limit of quantitation: 11 fmol). In addition, we could identify the absolute amount of endogenous estrones in cells of the breast cancer cell line MCF-7 (34 fmol/10(6) cells) by using a deuterated estrone as an internal standard. Finally, by applying the MALDI-MS-based quantitative method to endogenous estrones, we successfully monitored changes in the metabolic expression level of estrones (17.7 fmol/10(6) letrozole-treated cells) in MCF-7 cells resulting from treatment with an aromatase inhibitor. Taken together, these results suggest that this MALDI-MS-based quantitative approach may be a general method for the targeted metabolomics of ketone-containing metabolites, which can reflect clinical conditions and pathogenic mechanisms. PMID: 27091422 [PubMed - in process]

Metabotypes with properly functioning mitochondria and anti-inflammation predict extended productive life span in dairy cows. Sci Rep. 2016;6:24642 Authors: Huber K, Dänicke S, Rehage J, Sauerwein H, Otto W, Rolle-Kampczyk U, von Bergen M Abstract The failure to adapt metabolism to the homeorhetic demands of lactation is considered as a main factor in reducing the productive life span of dairy cows. The so far defined markers of production performance and metabolic health in dairy cows do not predict the length of productive life span satisfyingly. This study aimed to identify novel pathways and biomarkers related to productive life in dairy cows by means of (targeted) metabolomics. In a longitudinal study from 42 days before up to 100 days after parturition, we identified metabolites such as long-chain acylcarnitines and biogenic amines associated with extended productive life spans. These metabolites are mainly secreted by the liver and depend on the functionality of hepatic mitochondria. The concentrations of biogenic amines and some acylcarnitines differed already before the onset of lactation thus indicating their predictive potential for continuation or early ending of productive life. PMID: 27089826 [PubMed - in process]

Related Articles Spatial distribution of metabolites in the human lens. Exp Eye Res. 2016 Feb;143:68-74 Authors: Tamara SO, Yanshole LV, Yanshole VV, Fursova AZh, Stepakov DA, Novoselov VP, Tsentalovich YP Abstract Spatial distribution of 34 metabolites along the optical and equatorial axes of the human lens has been determined. For the majority of metabolites, the homogeneous distribution has been observed. That suggests that the rate of the metabolite transformation in the lens is low due to the general metabolic passivity of the lens fiber cells. However, the redox processes are active in the lens; as a result, some metabolites, including antioxidants, demonstrate the "nucleus-depleted" type of distribution, whereas secondary UV filters show the "nucleus-enriched" type. The metabolite concentrations at the lens poles and equator are similar for all metabolites under study. The concentric pattern of the "nucleus-depleted" and "nucleus-enriched" distributions testifies that the metabolite distribution inside the lens is mostly governed by a passive diffusion, relatively free along the fiber cells and retarded in the radial direction across the cells. No significant difference in the metabolite distribution between the normal and cataractous human lenses was found. PMID: 26500196 [PubMed - indexed for MEDLINE]

Related Articles RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-κB pathway. Nat Commun. 2015;6:7367 Authors: Murakawa Y, Hinz M, Mothes J, Schuetz A, Uhl M, Wyler E, Yasuda T, Mastrobuoni G, Friedel CC, Dölken L, Kempa S, Schmidt-Supprian M, Blüthgen N, Backofen R, Heinemann U, Wolf J, Scheidereit C, Landthaler M Abstract The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNFα mRNA decay via a 3'UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ∼ 3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-κB pathway regulators such as IκBα and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3'UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with IκB kinase and NF-κB activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-κB pathway. PMID: 26170170 [PubMed - indexed for MEDLINE]

Related Articles The pervasiveness and plasticity of circadian oscillations: the coupled circadian-oscillators framework. Bioinformatics. 2015 Oct 1;31(19):3181-8 Authors: Patel VR, Ceglia N, Zeller M, Eckel-Mahan K, Sassone-Corsi P, Baldi P Abstract MOTIVATION: Circadian oscillations have been observed in animals, plants, fungi and cyanobacteria and play a fundamental role in coordinating the homeostasis and behavior of biological systems. Genetically encoded molecular clocks found in nearly every cell, based on negative transcription/translation feedback loops and involving only a dozen genes, play a central role in maintaining these oscillations. However, high-throughput gene expression experiments reveal that in a typical tissue, a much larger fraction ([Formula: see text]) of all transcripts oscillate with the day-night cycle and the oscillating species vary with tissue type suggesting that perhaps a much larger fraction of all transcripts, and perhaps also other molecular species, may bear the potential for circadian oscillations. RESULTS: To better quantify the pervasiveness and plasticity of circadian oscillations, we conduct the first large-scale analysis aggregating the results of 18 circadian transcriptomic studies and 10 circadian metabolomic studies conducted in mice using different tissues and under different conditions. We find that over half of protein coding genes in the cell can produce transcripts that are circadian in at least one set of conditions and similarly for measured metabolites. Genetic or environmental perturbations can disrupt existing oscillations by changing their amplitudes and phases, suppressing them or giving rise to novel circadian oscillations. The oscillating species and their oscillations provide a characteristic signature of the physiological state of the corresponding cell/tissue. Molecular networks comprise many oscillator loops that have been sculpted by evolution over two trillion day-night cycles to have intrinsic circadian frequency. These oscillating loops are coupled by shared nodes in a large network of coupled circadian oscillators where the clock genes form a major hub. Cells can program and re-program their circadian repertoire through epigenetic and other mechanisms. AVAILABILITY AND IMPLEMENTATION: High-resolution and tissue/condition specific circadian data and networks available at http://circadiomics.igb.uci.edu. CONTACT: pfbaldi@ics.uci.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID: 26049162 [PubMed - indexed for MEDLINE]

Related Articles Recent advances in omic technologies for meat quality management. Meat Sci. 2015 Nov;109:18-26 Authors: Picard B, Lebret B, Cassar-Malek I, Liaubet L, Berri C, Le Bihan-Duval E, Hocquette JF, Renand G Abstract The knowledge of the molecular organization of living organisms evolved considerably during the last years. The methodologies associated also progressed with the development of the high-throughput sequencing (SNP array, RNAseq, etc.) and of genomic tools allowing the simultaneous analysis of hundreds or thousands of genes, proteins or metabolites. In farm animals, some proteins, mRNAs or metabolites whose abundance has been associated with meat quality traits have been detected in pig, cattle, chicken. They constitute biomarkers for the assessment and prediction of qualities of interest in each species, with potential biomarkers across species. The ongoing development of rapid methods will allow their use for decision-making and management tools in slaughterhouses, to better allocate carcasses or cuts to the appropriate markets. Besides, their application on living animals will help to improve genetic selection and to adapt a breeding system to fulfill expected quality level. The ultimate goal is to propose effective molecular tools for the management of product quality in meat production chains. PMID: 26002117 [PubMed - indexed for MEDLINE]

Related Articles Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment. Oncotarget. 2015 May 30;6(15):13416-33 Authors: Schumann T, Adhikary T, Wortmann A, Finkernagel F, Lieber S, Schnitzer E, Legrand N, Schober Y, Nockher WA, Toth PM, Diederich WE, Nist A, Stiewe T, Wagner U, Reinartz S, Müller-Brüsselbach S, Müller R Abstract The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma. PMID: 25968567 [PubMed - indexed for MEDLINE]

Related Articles Metabolism and disposition of a potent and selective JNK inhibitor [14C]tanzisertib following oral administration to rats, dogs and humans. Xenobiotica. 2015 May;45(5):428-41 Authors: Atsriku C, Hoffmann M, Ye Y, Kumar G, Surapaneni S Abstract 1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [(14)C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL). 2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (Tmax: 1-2 h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas <34% was observed in rats. Variable amounts of unchanged tanzisertib (1.5-32% of dose) was recovered in urine/feces across all species, the highest in human feces. 3. Metabolic profiling revealed that tanzisertib was primarily metabolized via oxidation and conjugation pathways, but extensively metabolized in rats relative to dogs/humans. CC-418424 (S-cis isomer of tanzisertib) was the major plasma metabolite in rats (38.4-46.4% of plasma radioactivity), while the predominant plasma metabolite in humans and dogs was M18 (tanzisertib-/CC-418424 glucuronide), representing 7.7 and 3.2% of plasma radioactivity, respectively. Prevalent biliary metabolite in rats and dogs, M18 represented 16.8 and 17.1% of dose, respectively. 4. In vitro studies using liver subcellular fractions and expressed enzymes characterized involvement of novel human aldo-keto reductases for oxido-reduction and UDP-glucuronosyltransferases for conjugation pathways. PMID: 25482583 [PubMed - indexed for MEDLINE]

Related Articles An in vitro approach to investigate ocular metabolism of a topical, selective β1-adrenergic blocking agent, betaxolol. Xenobiotica. 2015 May;45(5):396-405 Authors: Bushee JL, Dunne CE, Argikar UA Abstract 1. Topical glaucoma treatments have often been limited by poor absorption and bioavailability. Betaxolol, a selective β1-blocker, has been well studied for its pharmacokinetics and disposition. Limited ocular, betaxolol metabolism data is available despite a growing number of novel ocular treatments. 2. In vitro ocular fractions indicated the formation of an active metabolite, across rat, rabbit and human, which was only observed historically in the liver. 3. Ocular metabolic profiles of preclinical toxicology species, rat and rabbit, were not predictive of human in vitro ocular data. M1 was specific to human and only captured by the liver data. 4. Liver S9 over predicted the extent of ocular metabolism compared to ocular fractions. Rabbit liver S9 fractions demonstrated extensive glucuronidation and higher parent turn-over in 1 h as compared to other matrices. 5. This research assesses in vitro species and organ differences across preclinical species and human. The complex data set highlights the need for an in vitro ocular system to explore poorly documented ocular metabolism. PMID: 25475994 [PubMed - indexed for MEDLINE]

Metabolomics by (1)H-HRMAS-NMR of Tomato Plants Treated with two Secondary Metabolites Isolated from Trichoderma. J Agric Food Chem. 2016 Apr 18; Authors: Mazzei P, Vinale F, Woo SL, Pascale A, Lorito M, Piccolo A Abstract Trichoderma fungi release 6-pentyl-2H-pyran-2-one, 1, and, harzianic acid, 2, secondary metabolites to improve plant growth and health protection. We isolated 1 and 2 from Trichoderma strains, whose different concentrations were used to treat seeds of Solanum lycopersicum. The metabolic profile in the resulting 15 d old tomato leaves was studied by high-resolution magic-angle-spinning (HRMAS) NMR spectroscopy directly on the whole samples without any preliminary extraction. PCA of HRMAS-NMR showed significantly enhanced acetylcholine and GABA content accompanied by variable amount of amino-acids in samples treated with both Trichoderma secondary metabolites. Seed germination rates, seedling fresh weight and the metabolome of tomato leaves were also dependent on doses of 1 and 2 treatments. HRMAS-NMR spectroscopy was proved to represent a rapid and reliable technique for evaluating specific changes in the metabolome of plant leaves and calibrating the best concentration of bioactive compounds required to stimulate plant growth. PMID: 27088924 [PubMed - as supplied by publisher]

A guide to the identification of metabolites in NMR-based metabonomics/metabolomics experiments. Comput Struct Biotechnol J. 2016;14:135-53 Authors: Dona AC, Kyriakides M, Scott F, Shephard EA, Varshavi D, Veselkov K, Everett JR Abstract Metabonomics/metabolomics is an important science for the understanding of biological systems and the prediction of their behaviour, through the profiling of metabolites. Two technologies are routinely used in order to analyse metabolite profiles in biological fluids: nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS), the latter typically with hyphenation to a chromatography system such as liquid chromatography (LC), in a configuration known as LC-MS. With both NMR and MS-based detection technologies, the identification of the metabolites in the biological sample remains a significant obstacle and bottleneck. This article provides guidance on methods for metabolite identification in biological fluids using NMR spectroscopy, and is illustrated with examples from recent studies on mice. PMID: 27087910 [PubMed]

The individual human metabolic phenotype analyzed by (1)H-NMR of saliva samples. J Proteome Res. 2016 Apr 18; Authors: Wallner-Liebmann S, Tenori L, Mazzoleni A, Dieber-Rotheneder M, Konrad M, Hofmann P, Luchinat C, Turano P, Zatloukal K Abstract Saliva is an important physiological fluid, which contains a complex mixture of analytes that may produce a character-is-tic individual signature. In recent years, it has been demonstrated that urine possesses a clear signature of the indi-vidual metabolic phenotype. Here, NMR based metabolomics was employed to analyze saliva from 23 healthy volun-teers. About six saliva samples were collected daily from each individual, for 10 consecutive days: 7 days in a real life situ-ation (days 1-7, Phase I) and 3 days (days 8-10, Phase II) under a standardized diet plus a physical exercise program at day 10. The result is the first demonstration of the existence of an individual metabolic phenotype in saliva. A systematic comparative analysis with urine samples from the same collection scheme demonstrates that the individual phenotype in saliva is slightly weaker than in urine, but less influenced by diet. PMID: 27087681 [PubMed - as supplied by publisher]

Halogenated hydrocarbon solvent-related cholangiocarcinoma risk: biliary excretion of glutathione conjugates of 1,2-dichloropropane evidenced by untargeted metabolomics analysis. Sci Rep. 2016;6:24586 Authors: Toyoda Y, Takada T, Suzuki H Abstract Recently, the International Agency for Research on Cancer issued a warning about the carcinogenicity of 1,2-dichloropropane (1,2-DCP) to humans based on an epidemiological study suggesting a relationship between the incidence of cholangiocarcinoma and occupational exposure to halogenated hydrocarbon solvent comprised mostly of 1,2-DCP. Although this dihaloalkane has been used in various industrial fields, there has been no biological evidence explaining the cholangiocarcinoma latency, as well as little understanding of general cholangiocarcinoma risk. In the present study, we explored the biliary excretion of 1,2-DCP metabolites by an untargeted metabolomics approach and the related molecular mechanism with in vitro and in vivo experiments. We hypothesized that the biliary excretion of carcinogens derived from 1,2-DCP contribute to the increased cholangiocarcinoma risk. We found that 1,2-DCP was conjugated with glutathione in the liver, and that the glutathione-conjugated forms of 1,2-DCP, including a potential carcinogen that contains a chloride atom, were excreted into bile by the bile canalicular membrane transporter, ABCC2. These results may reflect a risk in the backfiring of biliary excretion as a connatural detoxification systems for xenobiotics. Our findings would contribute to uncover the latent mechanism by which the chronic exposure to 1,2-DCP increases cholangiocarcinoma risk and future understanding of cholangiocarcinoma biology. PMID: 27087417 [PubMed - in process]

Objective Definition of Monofloral and Polyfloral Honeys Based on NMR Metabolomic Profiling. J Agric Food Chem. 2016 Apr 17; Authors: Schievano E, Finotello C, Uddin J, Mammi S, Piana L Abstract This paper describes a remarkably precise, simple and objective definition of monofloral and polyfloral honey based on NMR metabolomics. The spectra of organic extracts of 983 samples of 16 botanical origins were used to derive one-vs-all OPLS-DA classification models. The predictive components of the statistical models reveal not only the principal but also the secondary floral origins present in a sample of honey, a novel feature with respect to the methods present in the literature that are able to confirm the authenticity of monofloral honeys but not to characterize a mixture of honey types. This result descends from the peculiar features of the chloroform spectra that show diagnostic resonances for almost each botanical origin, making these NMR spectra suitable fingerprints. The reliability of the method was tested with additional 120 samples and the class assignments were compared with those obtained by traditional analysis. The two approaches are in excellent agreement in identifying the floral species present in honeys and in the botanical classification. Therefore, the NMR method may prove to be a valid solution to the huge limitations of the traditional classification that is very demanding and complex. PMID: 27086991 [PubMed - as supplied by publisher]

Recurrent Clostridium difficile infection associates with distinct bile acid and microbiome profiles. Aliment Pharmacol Ther. 2016 Apr 18; Authors: Allegretti JR, Kearney S, Li N, Bogart E, Bullock K, Gerber GK, Bry L, Clish CB, Alm E, Korzenik JR Abstract BACKGROUND: The healthy microbiome protects against the development of Clostridium difficile infection (CDI), which typically develops following antibiotics. The microbiome metabolises primary to secondary bile acids, a process if disrupted by antibiotics, may be critical for the initiation of CDI. AIM: To assess the levels of primary and secondary bile acids associated with CDI and associated microbial changes. METHODS: Stool and serum were collected from patients with (i) first CDI (fCDI), (ii) recurrent CDI (rCDI) and (iii) healthy controls. 16S rRNA sequencing and bile salt metabolomics were performed. Random forest regression models were constructed to predict disease status. PICRUSt analyses were used to test for associations between predicted bacterial bile salt hydrolase (BSH) gene abundances and bile acid levels. RESULTS: Sixty patients (20 fCDI, 19 rCDI and 21 controls) were enrolled. Secondary bile acids in stool were significantly elevated in controls compared to rCDI and fCDI (P < 0.0001 and P = 0.0007 respectively). Primary bile acids in stool were significantly elevated in rCDI compared to controls (P < 0.0001) and in rCDI compared to fCDI (P = 0.02). Using random forest regression, we distinguished rCDI and fCDI patients 84.2% of the time using bile acid ratios. Stool deoxycholate to glycoursodeoxycholate ratio was the single best predictor. PICRUSt analyses found significant differences in predicted abundances of bacterial BSH genes in stool samples across the groups. CONCLUSION: Primary and secondary bile acid composition in stool was different in those with rCDI, fCDI and controls. The ratio of stool deoxycholate to glycoursodeoxycholate was the single best predictor of disease state and may be a potential biomarker for recurrence. PMID: 27086647 [PubMed - as supplied by publisher]

Related Articles Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion. Cancer Cell. 2015 Dec 14;28(6):773-84 Authors: Tateishi K, Wakimoto H, Iafrate AJ, Tanaka S, Loebel F, Lelic N, Wiederschain D, Bedel O, Deng G, Zhang B, He T, Shi X, Gerszten RE, Zhang Y, Yeh JR, Curry WT, Zhao D, Sundaram S, Nigim F, Koerner MV, Ho Q, Fisher DE, Roider EM, Kemeny LV, Samuels Y, Flaherty KT, Batchelor TT, Chi AS, Cahill DP Abstract Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers. PMID: 26678339 [PubMed - indexed for MEDLINE]

Related Articles Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015 Dec 14;28(6):690-714 Authors: Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G Abstract The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy. PMID: 26678337 [PubMed - indexed for MEDLINE]

Related Articles Development of metabolic and inflammatory mediator biomarker phenotyping for early diagnosis and triage of pediatric sepsis. Crit Care. 2015;19:320 Authors: Mickiewicz B, Thompson GC, Blackwood J, Jenne CN, Winston BW, Vogel HJ, Joffe AR, Alberta Sepsis Network Abstract INTRODUCTION: The first steps in goal-directed therapy for sepsis are early diagnosis followed by appropriate triage. These steps are usually left to the physician's judgment, as there is no accepted biomarker available. We aimed to determine biomarker phenotypes that differentiate children with sepsis who require intensive care from those who do not. METHODS: We conducted a prospective, observational nested cohort study at two pediatric intensive care units (PICUs) and one pediatric emergency department (ED). Children ages 2-17 years presenting to the PICU or ED with sepsis or presenting for procedural sedation to the ED were enrolled. We used the judgment of regional pediatric ED and PICU attending physicians as the standard to determine triage location (PICU or ED). We performed metabolic and inflammatory protein mediator profiling with serum and plasma samples, respectively, collected upon presentation, followed by multivariate statistical analysis. RESULTS: Ninety-four PICU sepsis, 81 ED sepsis, and 63 ED control patients were included. Metabolomic profiling revealed clear separation of groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.89, area under the receiver operating characteristic curve (AUROC) of 0.96 (standard deviation [SD] 0.01), and predictive ability (Q(2)) of 0.60. Protein mediator profiling also showed clear separation of the groups, differentiating PICU sepsis from ED sepsis with accuracy of 0.78 and AUROC of 0.88 (SD 0.03). Combining metabolomic and protein mediator profiling improved the model (Q(2) =0.62), differentiating PICU sepsis from ED sepsis with accuracy of 0.87 and AUROC of 0.95 (SD 0.01). Separation of PICU sepsis or ED sepsis from ED controls was even more accurate. Prespecified age subgroups (2-5 years old and 6-17 years old) improved model accuracy minimally. Seventeen metabolites or protein mediators accounted for separation of PICU sepsis and ED sepsis with 95% confidence. CONCLUSIONS: In children ages 2-17 years, combining metabolomic and inflammatory protein mediator profiling early after presentation may differentiate children with sepsis requiring care in a PICU from children with or without sepsis safely cared for outside a PICU. This may aid in making triage decisions, particularly in an ED without pediatric expertise. This finding requires validation in an independent cohort. PMID: 26349677 [PubMed - indexed for MEDLINE]

Related Articles Lipid and Metabolic Changes in Rheumatoid Arthritis. Curr Rheumatol Rep. 2015 Sep;17(9):57 Authors: McGrath CM, Young SP Abstract While the most obvious manifestations of rheumatoid arthritis (RA) involve inflammation and damage in the synovial joints, the systemic effects of the condition are widespread and life-threatening. Of particular interest is the 'lipid paradox' of RA, where patients with a numerically equivocal starting lipid profile have a significantly raised risk of cardiovascular (CV) events and response to therapy results in a 'normalization' of lipid levels and reduction in events. Changes in lipids can be seen before overt disease manifestations which suggest that they are closely linked to the more widespread inflammation-driven metabolic changes associated with tumour necrosis factor (TNF). Cachexia involves a shift in body mass from muscle to fat, which may or may not directly increase the cardiovascular risk. However, since TNF inhibition is associated with reduction in cardiovascular events, it does suggest that these widespread metabolic changes involving lipids are of importance. Analysis of single lipids or metabolites have been used to identify some of the key changes, but more recently, metabolomic and lipidomic approaches have been applied to identify a broad spectrum of small molecule changes and identify potentially altered metabolic pathways. Further work is needed to understand fully the metabolic changes in lipid profiles and identify novel ways of targeting desired profile changes, but work so far does suggest that a better understanding may allow management of patients to downregulate the systemic effects of their disease that puts them at risk of cardiovascular complications. PMID: 26210510 [PubMed - indexed for MEDLINE]

Related Articles Macroscopic optical physiological parameters correlate with microscopic proliferation and vessel area breast cancer signatures. Breast Cancer Res. 2015;17:72 Authors: Chung SH, Feldman MD, Martinez D, Kim H, Putt ME, Busch DR, Tchou J, Czerniecki BJ, Schnall MD, Rosen MA, DeMichele A, Yodh AG, Choe R Abstract INTRODUCTION: Non-invasive diffuse optical tomography (DOT) and diffuse correlation spectroscopy (DCS) can detect and characterize breast cancer and predict tumor responses to neoadjuvant chemotherapy, even in patients with radiographically dense breasts. However, the relationship between measured optical parameters and pathological biomarker information needs to be further studied to connect information from optics to traditional clinical cancer biology. Thus we investigate how optically measured physiological parameters in malignant tumors such as oxy-, deoxy-hemoglobin concentration, tissue blood oxygenation, and metabolic rate of oxygen correlate with microscopic histopathological biomarkers from the same malignant tumors, e.g., Ki67 proliferation markers, CD34 stained vasculature markers and nuclear morphology. METHODS: In this pilot study, we investigate correlations of macroscopic physiological parameters of malignant tumors measured by diffuse optical technologies with microscopic histopathological biomarkers of the same tumors, i.e., the Ki67 proliferation marker, the CD34 stained vascular properties marker, and nuclear morphology. RESULTS: The tumor-to-normal relative ratio of Ki67-positive nuclei is positively correlated with DOT-measured relative tissue blood oxygen saturation (R = 0.89, p-value: 0.001), and lower tumor-to-normal deoxy-hemoglobin concentration is associated with higher expression level of Ki67 nuclei (p-value: 0.01). In a subset of the Ki67-negative group (defined by the 15 % threshold), an inverse correlation between Ki67 expression level and mammary metabolic rate of oxygen was observed (R = -0.95, p-value: 0.014). Further, CD34 stained mean-vessel-area in tumor is positively correlated with tumor-to-normal total-hemoglobin and oxy-hemoglobin concentration. Finally, we find that cell nuclei tend to have more elongated shapes in less oxygenated DOT-measured environments. CONCLUSIONS: Collectively, the pilot data are consistent with the notion that increased blood is supplied to breast cancers, and it also suggests that less conversion of oxy- to deoxy-hemoglobin occurs in more proliferative cancers. Overall, the observations corroborate expectations that macroscopic measurements of breast cancer physiology using DOT and DCS can reveal microscopic pathological properties of breast cancer and hold potential to complement pathological biomarker information. PMID: 26013572 [PubMed - indexed for MEDLINE]