PubMed

OpenMS: a flexible open-source software platform for mass spectrometry data analysis. Nat Methods. 2016 Aug 30;13(9):741-748 Authors: Röst HL, Sachsenberg T, Aiche S, Bielow C, Weisser H, Aicheler F, Andreotti S, Ehrlich HC, Gutenbrunner P, Kenar E, Liang X, Nahnsen S, Nilse L, Pfeuffer J, Rosenberger G, Rurik M, Schmitt U, Veit J, Walzer M, Wojnar D, Wolski WE, Schilling O, Choudhary JS, Malmström L, Aebersold R, Reinert K, Kohlbacher O Abstract High-resolution mass spectrometry (MS) has become an important tool in the life sciences, contributing to the diagnosis and understanding of human diseases, elucidating biomolecular structural information and characterizing cellular signaling networks. However, the rapid growth in the volume and complexity of MS data makes transparent, accurate and reproducible analysis difficult. We present OpenMS 2.0 (http://www.openms.de), a robust, open-source, cross-platform software specifically designed for the flexible and reproducible analysis of high-throughput MS data. The extensible OpenMS software implements common mass spectrometric data processing tasks through a well-defined application programming interface in C++ and Python and through standardized open data formats. OpenMS additionally provides a set of 185 tools and ready-made workflows for common mass spectrometric data processing tasks, which enable users to perform complex quantitative mass spectrometric analyses with ease. PMID: 27575624 [PubMed - as supplied by publisher]

Metabolic responses to metal pollution in shrimp Crangon affinis from the sites along the Laizhou Bay in the Bohai Sea. Mar Pollut Bull. 2016 Aug 26; Authors: Xu L, Ji C, Zhao J, Wu H Abstract Marine environment in the Laizhou Bay is potentially contaminated by metals from industrial discharges. In this study, metal concentrations in shrimps Crangon affinis indicated that two typical sites (S6283 and S5283) close to Longkou and Zhaoyuan cities along the Laizhou Bay have been contaminated by metals, including Cd, As, Cu, Ni, Co, and Mn. In particular, Cd and As were the main metal contaminants in S6283. In S5283, however, Cu was the most important metal contaminant. The metabolic responses in the shrimps indicated that the metal pollution in S6283 and S5283 induced disturbances in osmotic regulation and energy metabolism and reduced anaerobiosis, lipid metabolism, and muscle movement. However, alteration in the levels of dimethylglycine, dimethylamine, arginine, betaine, and glutamine indicated that the metal pollution in S5283 induced osmotic stress through different pathways compared to that in S6283. In addition, dimethylamine might be the biomarker of Cu in shrimp C. affinis. PMID: 27575396 [PubMed - as supplied by publisher]

Allergen-Induced IL-6 Regulates IL-9/IL-17A Balance in CD4+ T Cells in Allergic Airway Inflammation. J Immunol. 2016 Aug 29; Authors: Schütze N, Trojandt S, Kuhn S, Tomm JM, von Bergen M, Simon JC, Polte T Abstract IL-9-secreting Th9 cells have been considered to play a pivotal role in the pathogenesis of atopic diseases. To what extent IL-9-producing cells are induced or regulated by sensitization with naturally occurring allergens is not yet clear. Naturally occurring allergens are capable of inducing IL-6 production in dendritic cells (DCs). Whether allergen-induced IL-6 supports a Th9 subtype by increasing IL-9 production, as observed in in vitro studies, or rather favors Th17 differentiation is not finally resolved. Therefore, in the present study we have investigated the impact of IL-6 on the Th9/Th17 balance depending on the predominant cytokine milieu and, additionally, in vivo using a DC-driven murine asthma model. In vitro, IL-6 increases Th9 cells under strong IL-4 and TGF-β activation, whereas under moderate IL-4 and TGF-β activation the presence of IL-6 shifts naive CD4(+) cells to Th17 cells. To induce allergic airway inflammation, OVA-pulsed DCs from IL-6-deficient or wild-type donors were adoptively transferred into BALB/c mice. Recipients receiving IL-6-producing wild-type DCs showed a significant decrease of Th9- and IL-4-producing Th2 cells but an increase of Th17 cells in lung tissue in comparison with recipients sensitized with IL-6-deficient DCs. Our data suggest that the IL-6-mediated reduction of Th2-related IL-4 leads to a decline of the Th9 immune response and allows Th17 differentiation. PMID: 27574298 [PubMed - as supplied by publisher]

Metabolic features of chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2016 Aug 29; Authors: Naviaux RK, Naviaux JC, Li K, Bright AT, Alaynick WA, Wang L, Baxter A, Nathan N, Anderson W, Gordon E Abstract More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS. We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were 53 (±2.8) y old (mean ± SEM; range, 21-67 y). Females were 52 (±2.5) y old (range, 20-67 y). The Karnofsky performance scores were 62 (±3.2) for males and 54 (±3.3) for females. We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism. Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84-100%] in males using eight metabolites and 96% (95% CI, 86-100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer. PMID: 27573827 [PubMed - as supplied by publisher]

Assessment of dietary exposure and effect in humans: The role of NMR. Prog Nucl Magn Reson Spectrosc. 2016 Aug;96:58-72 Authors: van Duynhoven JP, Jacobs DM Abstract In human nutritional science progress has always depended strongly on analytical measurements for establishing relationships between diet and health. This field has undergone significant changes as a result of the development of NMR and mass spectrometry methods for large scale detection, identification and quantification of metabolites in body fluids. This has allowed systematic studies of the metabolic fingerprints that biological processes leave behind, and has become the research field of metabolomics. As a metabolic profiling technique, NMR is at its best when its unbiased nature, linearity and reproducibility are exploited in well-controlled nutritional intervention and cross-sectional population screening studies. Although its sensitivity is less good than that of mass spectrometry, NMR has maintained a strong position in metabolomics through implementation of standardisation protocols, hyphenation with mass spectrometry and chromatographic techniques, accurate quantification and spectral deconvolution approaches, and high-throughput automation. Thus, NMR-based metabolomics has contributed uniquely to new insights into dietary exposure, in particular by unravelling the metabolic fates of phytochemicals and the discovery of dietary intake markers. NMR profiling has also contributed to the understanding of the subtle effects of diet on central metabolism and lipoprotein metabolism. In order to hold its ground in nutritional metabolomics, NMR will need to step up its performance in sensitivity and resolution; the most promising routes forward are the analytical use of dynamic nuclear polarisation and developments in microcoil construction and automated fractionation. PMID: 27573181 [PubMed - in process]

Metabolomics-based screening of the Malaria Box reveals both novel and established mechanisms of action. Antimicrob Agents Chemother. 2016 Aug 29; Authors: Creek DJ, Chua HH, Cobbold SA, Nijagal B, Macrae JI, Dickerman BK, Gilson PR, Ralph SA, McConville MJ Abstract High-throughput phenotypic screening of chemical libraries has resulted in the identification of thousands of compounds with potent antimalarial activity, although in most cases, the mechanism(s) of action of these compounds remain unknown. Here we have investigated the mode of action of 90 antimalarial compounds derived from the Malaria Box collection using high-coverage, untargeted metabolomics analysis. Approximately half of the tested compounds induced significant metabolic perturbations in in vitro cultures of P. falciparum In most cases, the metabolic profiles were highly correlated with known antimalarials, in particular artemisinin, the 4-aminoquinolines, or atovaquone. Select Malaria Box compounds also induced changes in intermediates in essential metabolic pathways such as isoprenoid biosynthesis (i.e. 2-C-methyl-D-erythritol 2,4-cyclodiphosphate), and linolenic acid metabolism (i.e. traumatic acid). This study provides a comprehensive database of the metabolic perturbations induced by chemically diverse inhibitors and highlights the utility of metabolomics for triaging new lead compounds and defining specific modes of action, which will assist with the development and optimization of new antimalarial drugs. PMID: 27572396 [PubMed - as supplied by publisher]

Metabolomic responses to sub-lethal contaminant exposure in neonate and adult Daphnia magna. Environ Toxicol Chem. 2016 Aug 30; Authors: Wagner ND, Simpson AJ, Simpson MJ Abstract The use of consumer products and pharmaceuticals that act as contaminants entering waterways through runoff and wastewater effluents alter aquatic ecosystem health. Traditional toxicological end points may underestimate the toxicity of contaminants as lethal concentrations are often orders of magnitude higher than that found within freshwater ecosystems. While newer techniques examine the metabolic responses of sub-lethal contaminant exposure, there has been no direct comparison with ontogeny in Daphnia. We hypothesize that Daphnia magna will have distinct metabolic changes to 3 different sub-lethal contaminant exposures caused by differences in the toxic mode of action and ontogeny. To test this hypothesis, we measured the proton nuclear magnetic resonance metabolomic profiles in D. magna aged day 0 and 18 after exposure to 28% of the lethal concentration of 50% of organisms tested (LC50) of atrazine, propranolol and perfluorooctanesulfonic acid (PFOS) for 48 hours. Principal component analysis revealed significant separation of contaminants from the control daphnids in both neonates and adults exposed to propranolol and PFOS. In contrast, atrazine exposure caused separation from the controls in only the adult D. magna. Propranolol exposure displayed minimal ontogenetic changes in the targeted metabolites. For both atrazine and PFOS exposures ontogeny exhibited unique changes in the targeted metabolites. These results indicate that depending on the contaminant studied, neonates and adults respond uniquely to sub-lethal contaminant exposure. This article is protected by copyright. All rights reserved. PMID: 27571995 [PubMed - as supplied by publisher]

Urinary biomarker and treatment mechanism of Rhizoma Alismatis on hyperlipidemia. Biomed Chromatogr. 2016 Aug 29; Authors: Miao H, Zhang L, Chen DQ, Chen H, Zhao YY, Ma SC Abstract Rhizoma Alismatis (RA), a diuretic in Asia and Europe, was found to possess anti-hyperlipidemic activity. Since the biomarkers and mechanisms of RA in the treatment of hyperlipidemia is inadequate, ultra performance liquid chromatography coupled with quadrupole time-of-flight synapt high-definition mass spectrometry and multivariate data analysis were employed to investigate the urinary metabolomics of RA on hyperlipidemic rats induced by high fat diet. The metabolic profile of RA-treated hyperlipidemic group located between control and diet-induced hyperlipidemic groups. Nineteen metabolites with significant fluctuations were identified as potential biomarkers related to the hyperlipidemia and anti-hyperlipidemia of RA using partial least-squares-discriminate analysis, heatmap analysis and correlation coefficient analysis. The fluctuations of these biomarkers represented the disturbances in amino acid metabolism, purine metabolism, pyrimidine metabolism and energy metabolism. After RA treatment, these perturbed metabolites were restored to normal or nearly normal levels. RA can alleviate high fat diet-induced dysfunctions in these metabolic pathways. This article is protected by copyright. All rights reserved. PMID: 27571931 [PubMed - as supplied by publisher]

The WEIZMASS spectral library for high-confidence metabolite identification. Nat Commun. 2016;7:12423 Authors: Shahaf N, Rogachev I, Heinig U, Meir S, Malitsky S, Battat M, Wyner H, Zheng S, Wehrens R, Aharoni A Abstract Annotation of metabolites is an essential, yet problematic, aspect of mass spectrometry (MS)-based metabolomics assays. The current repertoire of definitive annotations of metabolite spectra in public MS databases is limited and suffers from lack of chemical and taxonomic diversity. Furthermore, the heterogeneity of the data prevents the development of universally applicable metabolite annotation tools. Here we present a combined experimental and computational platform to advance this key issue in metabolomics. WEIZMASS is a unique reference metabolite spectral library developed from high-resolution MS data acquired from a structurally diverse set of 3,540 plant metabolites. We also present MatchWeiz, a multi-module strategy using a probabilistic approach to match library and experimental data. This strategy allows efficient and high-confidence identification of dozens of metabolites in model and exotic plants, including metabolites not previously reported in plants or found in few plant species to date. PMID: 27571918 [PubMed - in process]

Related Articles Circulating mitochondrial biomarkers for drug-induced liver injury. Biomark Med. 2015;9(11):1215-23 Authors: Shi Q, Yang X, Mattes WB, Mendrick DL, Harrill AH, Beger RD Abstract Liver mitochondria affected by drugs can be released into circulation and serve as biomarkers for drug-induced liver injury (DILI). The tissue specificity of ALT was improved by differentiating cytosolic ALT1 and mitochondrial ALT2 isoforms released in circulation. Prior to ALT elevation, mitochondrial cytochrome c, OCT, GLDH, CPS1 and DNA were increased in circulation following DILI. The baseline expression of mt-Nd6 was predictive of individual DILI susceptibility in animals. As mitochondrial DILI biomarkers appeared to be drug or species dependent, they might have value in clinical scenarios when culprit drugs are established, but may not be ideal tools to assess DILI potentials of new drugs. PMID: 26507261 [PubMed - indexed for MEDLINE]

Plasma Biomarkers for Monitoring Brain Pathophysiology in FMR1 Premutation Carriers. Front Mol Neurosci. 2016;9:71 Authors: Giulivi C, Napoli E, Tassone F, Halmai J, Hagerman R Abstract Premutation carriers have a 55-200 CGG expansion in the fragile X mental retardation 1 (FMR1) gene. Currently, 1.5 million individuals are affected in the United States, and carriers are at risk of developing the late-onset neurodegenerative disorder Fragile X-associated tremor ataxia syndrome (FXTAS). Limited efforts have been made to develop new methods for improved early patient monitoring, treatment response, and disease progression. To this end, plasma metabolomic phenotyping was obtained for 23 premutation carriers and 16 age- and sex-matched controls. Three biomarkers, phenylethylamine normalized by either aconitate or isocitrate and oleamide normalized by isocitrate, exhibited excellent model performance. The lower phenylethylamine and oleamide plasma levels in carriers may indicate, respectively, incipient nigrostriatal degeneration and higher incidence of substance abuse, anxiety and sleep disturbances. Higher levels of citrate, isocitrate, aconitate, and lactate may reflect deficits in both bioenergetics and neurotransmitter metabolism (Glu, GABA). This study lays important groundwork by defining the potential utility of plasma metabolic profiling to monitor brain pathophysiology in carriers before and during the progression of FXTAS, treatment efficacy and evaluation of side effects. PMID: 27570505 [PubMed]

Quantitative Metabolomic Profiling of Plasma, Urine and Liver Extracts by 1H NMR Spectroscopy Characterizes Different Stages of Atherosclerosis in Hamsters. J Proteome Res. 2016 Aug 29; Authors: Guo W, Jiang C, Yang L, Li T, Liu X, Jin M, Qu K, Chen H, Jin X, Liu H, Zhu H, Wang Y Abstract Atherosclerosis (AS) is a progressive disease that contributes to cardiovascular disease and shows a complex etiology, including genetic and environmental factors. To understand systemic metabolic changes and to identify potential biomarkers correlated with the occurrence and perpetuation of diet-induced AS, we applied 1H NMR-based metabolomics to detect the time-related metabolic profiles of plasma, urine and liver extracts from male hamsters fed a high fat/high cholesterol (HFHC) diet. Conventional biochemical assays and histopathological examinations as well as protein expression analyses were performed to provide complementary information. We found that diet treatment caused obvious aortic lesions, lipid accumulation and inflammatory infiltration in hamsters. Down-regulation of proteins related to cholesterol metabolism, including hepatic SREBP2, LDL-R, CYP7A1, SR-BI, HMGCR, LCAT and SOAT1 was detected, which elucidated the perturbation of cholesterol homeostasis during the HFHC diet challenge. Using "targeted analysis", we quantified 40 plasma, 80 urine and 60 liver hydrophilic extract metabolites. Multivariate analyses of the identified metabolites elucidated sophisticated metabolic disturbances in multiple matrices, including energy homeostasis, inflammation, oxidative stress and intestinal microbiota functions coupled with the metabolism of saccharides, fatty acids, choline, amino acids and nucleotides. For the first time, our results demonstrate a time-dependent metabolic progression of multiple biological matrices in hamsters from physiological status to early AS and further to late-stage AS, demonstrating that 1H NMR-based metabolomics is a reliable tool for early diagnosis and monitoring of the progression of AS. PMID: 27570155 [PubMed - as supplied by publisher]

Metabolomic determination of pathogenesis of late-onset preeclampsia. J Matern Fetal Neonatal Med. 2016 Aug 28;:1-7 Authors: Bahado-Singh RO, Syngelaki A, Mandal R, Graham SF, Akolekar R, Han B, Bjondahl TC, Dong E, Bauer S, Alpay-Savasan Z, Turkoglu O, Ogunyemi D, Poon LC, Wishart DS, Nicolaides KH Abstract OBJECTIVE: Our primary objective was to apply metabolomic pathway analysis of first trimester maternal serum to provide an insight into the pathogenesis of late-onset preeclampsia (late-PE) and thereby identify plausible therapeutic targets for PE. METHODS: NMR-based metabolomics analysis was performed on 29 cases of late-PE and 55 unaffected controls. In order to achieve sufficient statistical power to perform the pathway analysis, these cases were combined with a group of previously analyzed specimens, 30 late-PE cases and 60 unaffected controls. Specimens from both groups of cases and controls were collected in the same clinical centers during the same time period. In addition, NMR analyses were performed in the same lab and using the same techniques. RESULTS: We identified abnormalities in branch chain amino acids (valine, leucine and isoleucine) and propanoate, glycolysis, gluconeogenesis and ketone body metabolic pathways. The results suggest insulin resistance and metabolic syndrome, mitochondrial dysfunction and disturbance of energy metabolism, oxidative stress and lipid dysfunction in the pathogenesis of late PE and suggest a potential role for agents that reduce insulin resistance in PE. CONCLUSIONS: Branched chain amino acids are known markers of insulin resistance and strongly predict future diabetes development. The analysis provides independent evidence linking insulin resistance and late-PE and suggests a potentially important therapeutic role for pharmacologic agents that reduce insulin resistance for late-PE. PMID: 27569705 [PubMed - as supplied by publisher]

Association of maternal pre-pregnancy BMI with metabolomic profile across gestation. Int J Obes (Lond). 2016 Aug 29; Authors: Hellmuth C, Lindsay KL, Uhl O, Buss C, Wadhwa PD, Koletzko B, Entringer S Abstract BACKGROUND/OBJECTIVES: Elevated pre-pregnancy BMI (pBMI) and excess gestational weight gain (GWG) constitute important prenatal exposures which may program adiposity and disease risk in offspring. The objective of this study is to investigate the influence of pBMI and GWG on the maternal metabolomic profile across pregnancy, and to identify associations with birthweight. SUBJECTS/METHODS: This is a longitudinal prospective study of 167 non-diabetic women carrying a singleton pregnancy. Women were recruited between March 2011-December 2013 from antenatal clinics affiliated to the University of California, Irvine, Medical Center. Seven women were excluded from analyses due to a diagnosis of diabetes during pregnancy. A total of 254 plasma metabolites known to be related to obesity in non-pregnant populations were analyzed in each trimester using targeted metabolomics. The effects of pBMI and GWG on metabolites were tested through linear regression and principle component analysis, adjusting for maternal sociodemographic factors, diet, and insulin resistance. A Bonferroni correction was applied for multiple comparison testing. RESULTS: pBMI was significantly associated with 40 metabolites. Non-esterified fatty acids (NEFA) showed a strong positive association with pBMI, with specificity for mono-unsaturated and omega-6 NEFA. Among phospholipids, sphingomyelins with two double bonds and phosphatidylcholines containing 20:3 fatty acid chain, indicative of omega-6 NEFA, were positively associated with pBMI. Few associations between GWG, quality and quantity of the diet, insulin resistance and the maternal metabolome throughout gestation were detected. NEFA levels in the first and, to a lesser degree, in the second trimester were positively associated with birthweight percentiles. CONCLUSION: Pre-conception obesity appears to have a stronger influence on the maternal metabolic milieu than gestational factors such as weight gain, dietary intake and insulin resistance, highlighting the critical importance of pre-conception health. NEFA in general, as well as particular mono-unsaturated and omega-6 fatty acid species, represent key metabolites for a potential mechanism of intergenerational transfer of obesity risk.International Journal of Obesity accepted article preview online, 29 August 2016. doi:10.1038/ijo.2016.153. PMID: 27569686 [PubMed - as supplied by publisher]

The antiandrogen flutamide is a novel aryl hydrocarbon receptor ligand that disrupts bile acid homeostasis in mice through induction of Abcc4. Biochem Pharmacol. 2016 Aug 25; Authors: Gao X, Xie C, Wang Y, Luo Y, Yagai T, Sun D, Qin X, Krausz KW, Gonzalez FJ Abstract Flutamide (FLU), an oral, nonsteroidal antiandrogen drug used in the treatment of prostate cancer, is associated with idiosyncratic hepatotoxicity that sometimes causes severe liver damage, including cholestasis, jaundice, and liver necrosis. To understand the mechanism of toxicity, a combination of aryl hydrocarbon receptor (Ahr)-deficient (Ahr(-/-)) mice, primary hepatocytes, luciferase reporter gene assays, in silico ligand docking and ultra-performance chromatography-quadrupole time-of-flight mass spectrometry-based metabolomics were used. A significant increase of liver weights, and liver and serum bile acid levels was observed after FLU treatment, indicating hepatomegaly and disrupted bile acid homeostasis. Expression of the AhR gene battery was markedly increased in livers of wild-type mice Ahr(+/+) treated with FLU, while no change was noted in Ahr(-/-) mice. Messenger RNAs encoded by AhR target genes were induced in primary mouse hepatocytes cultured with FLU, which confirmed the in vivo results. Ligand-docking analysis further predicted that FLU is an AhR agonist ligand which was confirmed by luciferase reporter gene assays. Multivariate data analysis showed that bile acids were responsible for the separation of vehicle- and FLU-treated Ahr(+/+) mice, while there was no separation in Ahr(-/-) mice. Expression of mRNA encoding the bile acid transporter ABCC4 was increased and farnesoid X receptor signaling was inhibited in the livers of Ahr(+/+) mice, but not in Ahr(-/-) mice treated with FLU, in agreement with the observed downstream metabolic alterations. These findings provide new insights into the mechanism of liver injury caused by FLU treatment involving activation of AhR and the alterations of bile acid homeostasis, which could guide clinical application. PMID: 27569425 [PubMed - as supplied by publisher]

Tumor eradication by cisplatin is sustained by CD80/86-mediated costimulation of CD8+ T cells. Cancer Res. 2016 Aug 28; Authors: Beyranvand Nejad E, van der Sluis TC, van Duikeren S, Yagita H, Janssen GM, van Veelen PA, Melief CJ, van der Burg SH, Arens R Abstract Certain cytotoxic chemotherapeutic drugs are immunogenic, stimulating tumor immunity through mechanisms that are not completely understood. Here we show how the DNA damaging drug cisplatin modulates tumor immunity. At the maximum tolerated dose (MTD), cisplatin cured 50% of mice with established murine TC-1 or C3 tumors, which are preclinical models of human papilloma virus (HPV)-associated cancer. Notably, the curative benefit of cisplatin relied entirely upon induction of tumor-specific CD8+ T cells. Mechanistic investigations showed that cisplatin stimulated tumor infiltration of inflammatory antigen-presenting cells (APCs) expressing relatively higher levels of the T-cell costimulatory ligands CD70, CD80 and CD86. Cell death triggered by cisplatin was associated with the release of at least 19 proteins in the tumor environment that could act as damage-related molecular patterns (DAMPs) and upregulate costimulatory molecules, either alone or in concert, but the responsible proteins remain unknown. Essentially, the curative effect of cisplatin was abrogated in mice lacking expression of CD80 and CD86 on APCs. Further, cisplatin treatment was improved by CTLA-4 blockade, which increases the availability of CD80/86 to bind to CD28. In contrast, there was no effect of CD27 stimulation, which replaces CD70 interaction. At the cisplatin MTD, cure rates could also be increased by vaccination with synthetic long peptides, whereas cures could also be achieved at similar rates at 80% of the MTD with reduced side effects. Our findings reveal an essential basis for the immunogenic properties of cisplatin, which are mediated by induction of costimulatory signals for CD8+ T cell-dependent tumor destruction. PMID: 27569212 [PubMed - as supplied by publisher]

Related Articles Five omic technologies are concordant in differentiating the biochemical characteristics of the berries of five grapevine (Vitis vinifera L.) cultivars. BMC Genomics. 2015;16:946 Authors: Ghan R, Van Sluyter SC, Hochberg U, Degu A, Hopper DW, Tillet RL, Schlauch KA, Haynes PA, Fait A, Cramer GR Abstract BACKGROUND: Grape cultivars and wines are distinguishable by their color, flavor and aroma profiles. Omic analyses (transcripts, proteins and metabolites) are powerful tools for assessing biochemical differences in biological systems. RESULTS: Berry skins of red- (Cabernet Sauvignon, Merlot, Pinot Noir) and white-skinned (Chardonnay, Semillon) wine grapes were harvested near optimum maturity (°Brix-to-titratable acidity ratio) from the same experimental vineyard. The cultivars were exposed to a mild, seasonal water-deficit treatment from fruit set until harvest in 2011. Identical sample aliquots were analyzed for transcripts by grapevine whole-genome oligonucleotide microarray and RNAseq technologies, proteins by nano-liquid chromatography-mass spectroscopy, and metabolites by gas chromatography-mass spectroscopy and liquid chromatography-mass spectroscopy. Principal components analysis of each of five Omic technologies showed similar results across cultivars in all Omic datasets. Comparison of the processed data of genes mapped in RNAseq and microarray data revealed a strong Pearson's correlation (0.80). The exclusion of probesets associated with genes with potential for cross-hybridization on the microarray improved the correlation to 0.93. The overall concordance of protein with transcript data was low with a Pearson's correlation of 0.27 and 0.24 for the RNAseq and microarray data, respectively. Integration of metabolite with protein and transcript data produced an expected model of phenylpropanoid biosynthesis, which distinguished red from white grapes, yet provided detail of individual cultivar differences. The mild water deficit treatment did not significantly alter the abundance of proteins or metabolites measured in the five cultivars, but did have a small effect on gene expression. CONCLUSIONS: The five Omic technologies were consistent in distinguishing cultivar variation. There was high concordance between transcriptomic technologies, but generally protein abundance did not correlate well with transcript abundance. The integration of multiple high-throughput Omic datasets revealed complex biochemical variation amongst five cultivars of an ancient and economically important crop species. PMID: 26573226 [PubMed - indexed for MEDLINE]

Related Articles Editorial: Would You Like A Hypothesis With Those Data? Omics and the Age of Discovery Science. Mol Endocrinol. 2015 Nov;29(11):1531-4 Authors: Kraus WL PMID: 26524008 [PubMed - indexed for MEDLINE]

Quality evaluation of green tea leaf cultured under artificial light condition using gas chromatography/mass spectrometry. J Biosci Bioeng. 2016 Aug 24; Authors: Miyauchi S, Yonetani T, Yuki T, Tomio A, Bamba T, Fukusaki E Abstract For an experimental model to elucidate the relationship between light quality during plant culture conditions and plant quality of crops or vegetables, we cultured tea plants (Camellia sinensis) and analyzed their leaves as tea material. First, metabolic profiling of teas from a tea contest in Japan was performed with gas chromatography/mass spectrometry (GC/MS), and then a ranking predictive model was made which predicted tea rankings from their metabolite profile. Additionally, the importance of some compounds (glutamine, glutamic acid, oxalic acid, epigallocatechin, phosphoric acid, and inositol) was elucidated for measurement of the quality of tea leaf. Subsequently, tea plants were cultured in artificial conditions to control these compounds. From the result of prediction by the ranking predictive model, the tea sample supplemented with ultraviolet-A (315-399 nm) showed the highest ranking. The improvement in quality was thought to come from the high amino-acid and decreased epigallocatechin content in tea leaves. The current study shows the use and value of metabolic profiling in the field of high-quality crops and vegetables production that has been conventionally evaluated by human sensory analysis. Metabolic profiling enables us to form hypothesis to understand and develop high quality plant cultured under artificial condition. PMID: 27568369 [PubMed - as supplied by publisher]

Metabolic adaptations to HFHS overfeeding: how whole body and tissues postprandial metabolic flexibility adapt in Yucatan mini-pigs. Eur J Nutr. 2016 Aug 27; Authors: Polakof S, Rémond D, Bernalier-Donadille A, Rambeau M, Pujos-Guillot E, Comte B, Dardevet D, Savary-Auzeloux I Abstract PURPOSE: In the present study, we aimed to metabolically characterize the postprandial adaptations of the major tissues involved in energy, lipids and amino acids metabolisms in mini-pigs. METHOD: Mini-pigs were fed on high-fat-high-sucrose (HFHS) diet for 2 months and several tissues explored for metabolic analyses. Further, the urine metabolome was followed over the time to picture the metabolic adaptations occurring at the whole body level following overfeeding. RESULTS: After 2 months of HFHS consumption, mini-pigs displayed an obese phenotype characterized by high circulating insulin, triglycerides and cholesterol levels. At the tissue level, a general (muscle, adipose tissue, intestine) reduction in the capacity to phosphorylate glucose was observed. This was also supported by the enhanced hepatic gluconeogenesis potential, despite the concomitant normoglycaemia, suggesting that the high circulating insulin levels would be enough to maintain glucose homoeostasis. The HFHS feeding also resulted in a reduced capacity of two other pathways: the de novo lipogenesis, and the branched-chain amino acids transamination. Finally, the follow-up of the urine metabolome over the time allowed determining breaking points in the metabolic trajectory of the animals. CONCLUSIONS: Several features confirmed the pertinence of the animal model, including increased body weight, adiposity and porcine obesity index. At the metabolic level, we observed a perturbed glucose and amino acid metabolism, known to be related to the onset of the obesity. The urine metabolome analyses revealed several metabolic pathways potentially involved in the obesity onset, including TCA (citrate, pantothenic acid), amino acids catabolism (cysteine, threonine, leucine). PMID: 27568059 [PubMed - as supplied by publisher]