PubMed

Related Articles Serum metabolomics uncovering specific metabolite signatures of intra- and extrahepatic cholangiocarcinoma. Mol Biosyst. 2015 Dec 8; Authors: Liang Q, Liu H, Zhang T, Jiang Y, Xing H, Zhang H Abstract Cholangiocarcinoma (CC) accounts for approximately 25% of all hepatobiliary malignancies, including intra- and extrahepatic cholangiocarcinoma (ICC and ECC) and has a high mortality rate. The clinical manifestations of and liver function tests for the ICC and ECC diseases are too similar to distinguish between them. Diagnosis of ICC and ECC remains difficult because of the lack of sensitive diagnostic tests, although MRI and CT with endoscopic ultrasound provide useful diagnostic information in certain patients, but are invasive, time-consuming or expensive. Early detection is the most effective way to improve the clinical outcome of CC. Serum metabolomics provides a powerful platform for discovering novel biomarkers to improve early diagnosis. This study was performed using a metabolomics method which was used to select serum metabolites to be used for the early diagnosis of CC and to distinguish ICC from ECC. We comprehensively analyzed the serum metabolites in a total of 261 blood samples from CC patients and normal individuals. We found that 75 metabolites were filtered and identified from the serum metabolome, and the levels of 21-deoxycortisol and bilirubin significantly increased while the levels of lysoPC(14:0) and lysoPC(15:0) were significantly reduced in the CC group compared with the control groups. We measured the 4 metabolites of interest in an independent sample comprising 225 cases and 101 controls. Noticeably, external validation of the serum specimens further showed that the biomarker combination could differentiate ECC and ICC patients with high accuracy. This provides a new foundation for serum metabolomics to provide potential biomarkers for the early detection of CC. PMID: 26646623 [PubMed - as supplied by publisher]

Related Articles A global perspective on assisted reproductive technology fertility treatment: an 8-country fertility specialist survey. Reprod Biol Endocrinol. 2015;13(1):133 Authors: Audibert C, Glass D Abstract BACKGROUND: Procedures that may optimize success in achieving live births from assisted reproductive technology (ART) continue to be examined. Not yet considered are the perspectives of fertility specialists regarding important developments in the fertility treatment field, current unmet needs, and anticipated future advances. In the current study, an 8-country survey of fertility specialists was conducted to provide a comprehensive, global depiction of fertility treatments across different regions. METHODS: Fertility specialists from France, Germany, Italy, Spain, the United Kingdom (UK), the United States (US), China, and Japan were invited to participate in an online survey. Participants were eligible if they personally managed ≥25 patients/month who were experiencing difficulty conceiving, and if they had performed ART fertility treatment with ≥1 patient in the previous month. Quantitative questions addressed the number of patients seen, main infertility causes, number of cycles performed, ART procedure type, and ART outcomes. Qualitative questions covered diagnostic trends, unmet needs, important advances, and expected future developments. RESULTS: The number of fertility specialists who completed the survey included 29 in France, 33 in Germany, 23 in Italy, 38 in Spain, 34 in the UK, 91 in the US, 50 in China, and 65 in Japan. Patient volume increased over the prior 2 years according to 67 % (242/363) of the fertility specialists. As expected, ART outcomes all declined with age in all countries. ART outcomes varied by country, with the highest implantation, pregnancy, and live birth rates reported by fertility specialists in the US and China and the lowest rates reported in France and Italy. The most frequently reported unmet needs in fertility treatment were financial coverage, improved implantation rate, and egg donation. Most frequently named future advancements expected to change the fertility treatment field included improved embryo selection through imaging and/or metabolomics, improved embryo implantation rate, and use of preimplantation genetic diagnosis. CONCLUSIONS: This study, which follows a rigorous survey methodology, elucidates the current state of fertility specialists' practices and perspectives on the global fertility treatment field, which highlights differences and similarities among countries. This research may inform further studies and procedural developments that might better improve and standardize ART. PMID: 26645803 [PubMed - in process]

Related Articles (1)H-NMR urinary metabolomic profiling for diagnosis of gastric cancer. Br J Cancer. 2015 Dec 8; Authors: Chan AW, Mercier P, Schiller D, Bailey R, Robbins S, Eurich DT, Sawyer MB, Broadhurst D Abstract BACKGROUND: Metabolomics has shown promise in gastric cancer (GC) detection. This research sought to identify whether GC has a unique urinary metabolomic profile compared with benign gastric disease (BN) and healthy (HE) patients. METHODS: Urine from 43 GC, 40 BN, and 40 matched HE patients was analysed using (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopy, generating 77 reproducible metabolites (QC-RSD <25%). Univariate and multivariate (MVA) statistics were employed. A parsimonious biomarker profile of GC vs HE was investigated using LASSO regularised logistic regression (LASSO-LR). Model performance was assessed using Receiver Operating Characteristic (ROC) curves. RESULTS: GC displayed a clear discriminatory biomarker profile; the BN profile overlapped with GC and HE. LASSO-LR identified three discriminatory metabolites: 2-hydroxyisobutyrate, 3-indoxylsulfate, and alanine, which produced a discriminatory model with an area under the ROC of 0.95. CONCLUSIONS: GC patients have a distinct urinary metabolite profile. This study shows clinical potential for metabolic profiling for early GC diagnosis.British Journal of Cancer advance online publication 8 December 2015. doi:10.1038/bjc.2015.414 www.bjcancer.com. PMID: 26645240 [PubMed - as supplied by publisher]

Comparative Circadian Metabolomics reveal Differential Effects of Nutritional Challenge in the Serum and Liver. J Biol Chem. 2015 Dec 7; Authors: Abbondante S, Eckel-Mahan KL, Ceglia NJ, Baldi P, Sassone-Corsi P Abstract Diagnosis and therapeutic interventions in pathological conditions rely upon clinical monitoring of key metabolites in the serum. Recent studies show that a wide range of metabolic pathways is controlled by circadian rhythms whose oscillation is affected by nutritional challenges, underscoring the importance to assess a temporal window for clinical testing and thereby questioning the accuracy of the reading of critical pathological markers in circulation. We have been interested in studying the communication between peripheral tissues under metabolic homeostasis perturbation. Here we present a comparative circadian metabolomic analysis on serum and liver in mice under high fat diet. Our data reveal that the nutritional challenge induces a loss of serum metabolites rhythmicity compared to liver, indicating a circadian misalignment between the tissues analyzed. Importantly, our results show that the levels of serum metabolites do not reflect the circadian liver metabolic signature, nor the effect of nutritional challenge. This notion reveals the possibility that misleading reads of metabolites in circulation may result in misdiagnosis and improper treatments. Our findings also demonstrate a tissue-specific and time-dependent disruption of metabolic homeostasis in response to altered nutrition. PMID: 26644470 [PubMed - as supplied by publisher]

Integrative Proteomics and Metabolomics Analysis of Insect Larva Brain: Novel Insights into the Molecular Mechanism of Insect Wandering Behavior. J Proteome Res. 2015 Dec 8; Authors: Li Y, Wang X, Hou Y, Zhou X, Chen Q, Guo C, Xia Q, Zhang Y, Zhao P Abstract Before metamorphosis, most holometabolous insects, such as the silkworm studied here, undergo a special phase called the wandering stage. Insects in this stage often display enhanced locomotor activity (ELA). The ELA is vital because it ensures that the insect finds a safe and suitable place to live through the pupal stage. The physiological mechanisms of wandering behavior are still unclear. Here, we integrated proteomics and metabolomics approaches to analyze the brain of the lepidopteran insect, silkworm, at feeding and wandering stages. Using LC-MS/MS and GC-MS, in all we identified 3004 proteins and 37 metabolites at these two stages. Among them, 465 proteins and 22 metabolites were changed. Neural signal transduction proteins and metabolites, such as neurofilament, dopaminergic synapse related proteins, and glutamic acid, were significantly altered, which suggested that active neural conduction occurred in the brain at wandering stage. We also found decreased dopamine degradation at wandering stage. The proposed changes in active neural conduction and increased dopamine concentration might induce the ELA. In addition, proteins involved in the ubiquitin proteasome system and lysosome pathway were up-regulated, revealing that the brain experiences morphological remodeling during metamorphosis. These findings yielded novel insights into the molecular mechanism underlying insect wandering behavior. PMID: 26644297 [PubMed - as supplied by publisher]

Similar local but different systemic metabolomic responses of closely related pine subspecies to folivory by caterpillars of the processionary moth. Plant Biol (Stuttg). 2015 Dec 8; Authors: Rivas-Ubach A, Sardans J, Hódar JA, Garcia-Porta J, Guenther A, Oravec M, Urban O, Peñuelas J Abstract Plants respond locally and systemically to herbivore attack. Most of the research conducted on plant-herbivore relationships at elemental and molecular levels have focused on the elemental composition or/and certain molecular compounds or specific families of defensive metabolites showing that herbivores tend to select plant individuals or species with higher nutrient concentrations and to avoid those with higher levels of defensive compounds. We performed stoichiometric and metabolomics, local and systemic, analyses in two subspecies of Pinus sylvestris under the attack by the caterpillars of the pine processionary moth, an important pest in the Mediterranean Basin. Both pine subspecies responded locally to folivory mainly by increasing the relative concentrations of terpenes and some phenolics. Systemic responses differed between subspecies and most of the metabolites presented intermediate concentrations between those of the affected parts and unattacked trees. Our results support the hypothesis that foliar nutrient concentrations are not a key factor of an alleged plant selection by adult female processionary moths for oviposition since folivory was not associated with any of the elements analyzed. Phenolic compounds did not generally increase in the attacked trees questioning thus their commonly proposed induction by folivory attack and their anti-feeding properties. Herbivory attack produced a general systemic shift in pines, including both primary and secondary metabolisms, that was less intense and chemically different from the local responses. Local pine responses were similar between subspecies while systemic responses were more distant between them. This article is protected by copyright. All rights reserved. PMID: 26642818 [PubMed - as supplied by publisher]

Physio-Biochemical Composition and Untargeted Metabolomics of Cumin (Cuminum cyminum L.) Make It Promising Functional Food and Help in Mitigating Salinity Stress. PLoS One. 2015;10(12):e0144469 Authors: Pandey S, Patel MK, Mishra A, Jha B Abstract Cumin is an annual, aromatic, herbaceous, medicinal, spice plant, most widely used as a food additive and flavoring agent in different cuisines. The study is intended to comprehensively analyse physiological parameters, biochemical composition and metabolites under salinity stress. Seed germination index, rate of seed emergence, rate of seed germination, mean germination time, plant biomass, total chlorophyll and carotenoid contents decreased concomitantly with salinity. In contrast, total antioxidant activity, H2O2, proline and MDA contents increased concurrently with stress treatments. Total phenolic and flavonoid contents were decreased initially about 1.4-fold at 50 mM, and thereafter increased about 1.2-fold at 100 mM NaCl stress. Relative water content remained unchanged up to 50 mM NaCl stress, and thereafter decreased significantly. About 2.8-fold electrolyte leakage was found in 50 mM, which increases further 4-fold at 100 mM NaCl stress. Saturated fatty acids (FAs) increased gradually with salinity, whereas unsaturation index and degree of unsaturation change arbitrarily along with the percent quantity of unsaturated FAs. Total lipid and fatty acid composition were significantly influenced by salinity stress. A total of 45 differentially expressed metabolites were identified, including luteolin, salvianolic acid, kaempferol and quercetin, which are phenolic, flavonoid or alkaloids in nature and contain antioxidant activities. Additionally, metabolites with bioactivity such as anticancerous (docetaxel) and antimicrobial (megalomicin) properties were also identified. The study evidenced that plant shoots are a rich source of metabolites, essential amino acids, phenolic compounds and fatty acids, which unveil the medicinal potential of this plant, and also provide useful insight about metabolic responses under salinity stress. PMID: 26641494 [PubMed - as supplied by publisher]

Metabolomic Responses of Guard Cells and Mesophyll Cells to Bicarbonate. PLoS One. 2015;10(12):e0144206 Authors: Misra BB, de Armas E, Tong Z, Chen S Abstract Anthropogenic CO2 presently at 400 ppm is expected to reach 550 ppm in 2050, an increment expected to affect plant growth and productivity. Paired stomatal guard cells (GCs) are the gate-way for water, CO2, and pathogen, while mesophyll cells (MCs) represent the bulk cell-type of green leaves mainly for photosynthesis. We used the two different cell types, i.e., GCs and MCs from canola (Brassica napus) to profile metabolomic changes upon increased CO2 through supplementation with bicarbonate (HCO3-). Two metabolomics platforms enabled quantification of 268 metabolites in a time-course study to reveal short-term responses. The HCO3- responsive metabolomes of the cell types differed in their responsiveness. The MCs demonstrated increased amino acids, phenylpropanoids, redox metabolites, auxins and cytokinins, all of which were decreased in GCs in response to HCO3-. In addition, the GCs showed differential increases of primary C-metabolites, N-metabolites (e.g., purines and amino acids), and defense-responsive pathways (e.g., alkaloids, phenolics, and flavonoids) as compared to the MCs, indicating differential C/N homeostasis in the cell-types. The metabolomics results provide insights into plant responses and crop productivity under future climatic changes where elevated CO2 conditions are to take center-stage. PMID: 26641455 [PubMed - as supplied by publisher]

Plasma metabolomics indicates metabolic perturbations in low birth weight piglets supplemented with arginine. J Anim Sci. 2015 Dec;93(12):5754-5763 Authors: Getty CM, Almeida FN, Baratta AA, Dilger RN Abstract Large profit losses in the swine industry can be attributed to morbidity and mortality of piglets before weaning, especially in the low birth weight (LBW) piglet. Recent evidence suggests sow's milk contains insufficient concentrations of Arg to support optimal growth and health of piglets. Therefore, our objective was to assess global metabolomic profiles and the potential for Arg supplementation to promote growth of LBW (≤0.9 kg BW) and average birth weight (ABW; 1.3 to 1.5 kg BW) piglets. Piglets were selected in littermate pairs at processing to receive either Arg or an isonitrogenous control (Ala) and weighed daily to assess growth rate, and blood was collected at approximately 16 d of age for metabolomics analysis. In terms of growth, LBW and ABW piglets supplemented with Arg weighed 22.3 and 12.7% less, respectively, at d 16 compared with Ala-supplemented piglets of the same birth weight group. Overall, differences ( < 0.05) were observed among treatments for metabolic pathways involving energy (i.e., tricarboxylic acid cycle intermediates), AA, nucleotides, and fatty acids. Increased nucleotide turnover, indicative of an increase in DNA damage and cell death, was particularly noted in the LBW piglet. However, Arg supplementation reduced these effects to levels comparable to those observed in ABW piglets. Moreover, changes in glucose metabolism suggested a compromised ability to extract energy from dietary sources may have occurred in the LBW piglet, but these effects were partially recovered by Arg supplementation. We conclude that a reduction in the growth potential of LBW piglets may be associated with alterations in multiple metabolic pathways, and further reduction due to Arg supplementation may have resulted from perturbations in multiple metabolic pathways. PMID: 26641185 [PubMed - as supplied by publisher]

Deconstructing the pig sex metabolome: Targeted metabolomics in heavy pigs revealed sexual dimorphisms in plasma biomarkers and metabolic pathways. J Anim Sci. 2015 Dec;93(12):5681-5693 Authors: Bovo S, Mazzoni G, Calò DG, Galimberti G, Fanelli F, Mezzullo M, Schiavo G, Scotti E, Manisi A, Samoré AB, Bertolini F, Trevisi P, Bosi P, Dall'Olio S, Pagotto U, Fontanesi L Abstract Metabolomics has opened new possibilities to investigate metabolic differences among animals. In this study, we applied a targeted metabolomic approach to deconstruct the pig sex metabolome as defined by castrated males and entire gilts. Plasma from 545 performance-tested Italian Large White pigs (172 castrated males and 373 females) sampled at about 160 kg live weight were analyzed for 186 metabolites using the Biocrates AbsoluteIDQ p180 Kit. After filtering, 132 metabolites (20 AA, 11 biogenic amines, 1 hexose, 13 acylcarnitines, 11 sphingomyelins, 67 phosphatidylcholines, and 9 lysophosphatidylcholines) were retained for further analyses. The multivariate approach of the sparse partial least squares discriminant analysis was applied, together with a specifically designed statistical pipeline, that included a permutation test and a 10 cross-fold validation procedure that produced stability and effect size statistics for each metabolite. Using this approach, we identified 85 biomarkers (with metabolites from all analyzed chemical families) that contributed to the differences between the 2 groups of pigs ( < 0.05 at the stability statistic test). All acylcarnitines and almost all biogenic amines were higher in castrated males than in gilts. Metabolites involved in tryptophan catabolism had the largest differences (i.e., delta = 20% for serotonin) between castrated males (higher) and gilts (lower). The level of several AA (Ala, Arg, Gly, His, Lys, Ser, Thr, and Trp) was higher in gilts (delta was from approximately 1.0 to approximately 4.8%) whereas products of AA catabolism (taurine, 2-aminoadipic acid, and methionine sulfoxide) were higher in castrated males (delta was approximately 5.0-6.0%), suggesting a metabolic shift in castrated males toward energy storage and lipid production. Similar general patterns were observed for most sphingomyelins, phosphatidylcholines, and lysophosphatidylcholines. Metabolomic pathway analysis and pathway enrichment identified several differences between the 2 sexes. This metabolomic overview opened new clues on the biochemical mechanisms underlying sexual dimorphism that, on one hand, might explain differences in terms of economic traits between castrated male pigs and entire gilts and, on the other hand, could strengthen the pig as a model to define metabolic mechanisms related to fat deposition. PMID: 26641177 [PubMed - as supplied by publisher]

A Decade of Molecular Understanding of Withanolide Biosynthesis and In vitro Studies in Withania somnifera (L.) Dunal: Prospects and Perspectives for Pathway Engineering. Front Plant Sci. 2015;6:1031 Authors: Dhar N, Razdan S, Rana S, Bhat WW, Vishwakarma R, Lattoo SK Abstract Withania somnifera, a multipurpose medicinal plant is a rich reservoir of pharmaceutically active triterpenoids that are steroidal lactones known as withanolides. Though the plant has been well-characterized in terms of phytochemical profiles as well as pharmaceutical activities, limited attempts have been made to decipher the biosynthetic route and identification of key regulatory genes involved in withanolide biosynthesis. This scenario limits biotechnological interventions for enhanced production of bioactive compounds. Nevertheless, recent emergent trends vis-à-vis, the exploration of genomic, transcriptomic, proteomic, metabolomics, and in vitro studies have opened new vistas regarding pathway engineering of withanolide production. During recent years, various strategic pathway genes have been characterized with significant amount of regulatory studies which allude toward development of molecular circuitries for production of key intermediates or end products in heterologous hosts. Another pivotal aspect covering redirection of metabolic flux for channelizing the precursor pool toward enhanced withanolide production has also been attained by deciphering decisive branch point(s) as robust targets for pathway modulation. With these perspectives, the current review provides a detailed overview of various studies undertaken by the authors and collated literature related to molecular and in vitro approaches employed in W. somnifera for understanding various molecular network interactions in entirety. PMID: 26640469 [PubMed - as supplied by publisher]

Nanotechnology-based inhalation treatments for lung cancer: state of the art. Nanotechnol Sci Appl. 2015;8:55-66 Authors: Ahmad J, Akhter S, Rizwanullah M, Amin S, Rahman M, Ahmad MZ, Rizvi MA, Kamal MA, Ahmad FJ Abstract Considering the challenges associated with conventional chemotherapy, targeted and local delivery of chemotherapeutics via nanoparticle (NP) carriers to the lungs is an emerging area of interest. Recent studies and growing clinical application in cancer nanotechnology showed the huge potential of NPs as drug carriers in cancer therapy, including in lung carcinoma for diagnosis, imaging, and theranostics. Researchers have confirmed that nanotechnology-based inhalation chemotherapy is viable and more effective than conventional chemotherapy, with lesser side effects. Recently, many nanocarriers have been investigated, including liposomes, polymeric micelles, polymeric NPs, solid lipid NPs, and inorganic NPs for inhalation treatments of lung cancer. Yet, the toxicity of such nanomaterials to the lungs tissues and further distribution to other organs due to systemic absorption on inhalation delivery is a debatable concern. Here, prospect of NPs-based local lung cancer targeting through inhalation route as well as its associated challenges are discussed. PMID: 26640374 [PubMed - as supplied by publisher]

Urinary Metabolites from Mango (Mangifera indica L. cv. Keitt) Galloyl Derivatives and In Vitro Hydrolysis of Gallotannins in Physiological Conditions. Mol Nutr Food Res. 2015 Dec 7; Authors: Barnes RC, Krenek KA, Meibohm B, Mertens-Talcott1 SU, Talcott ST Abstract SCOPE: The absorption, metabolism, and excretion of mango galloyl derivatives (GD) has not yet been investigated in humans, and studies investigating repeated dosages of polyphenols are limited. METHODS AND RESULTS: In this human pilot trial, healthy volunteers (age= 21-38y, n=11) consumed 400g/day of mango-pulp (cv. Keitt) for 10 days, and seven metabolites of gallic acid (GA) were characterized and quantified in urine excreted over a 12 h period. Pyrogallol-O-sulfate and deoxypyrogallol-O-sulfate were found to be significantly more excreted between days 1 and 10 (p < 0.05) from 28.5 mg to 55.4 mg and 23.6 mg to 47.7 mg respectively. Additionally, the in vitro hydrolysis of gallotannins (GTs) was monitored at physiological pH and temperature conditions, and after 4 h a significant (p< 0.05) shift in composition from relativity high to low molecular weight GTs was observed. CONCLUSION: Seven metabolites of GA were identified in the urine of healthy volunteers, and two microbial metabolites were found to be significantly more excreted following 10 days of mango consumption. Mango GTs were also found to release free GA in conditions similar to the intestines. GTs may serve as a pool of pro-GA compounds that can be absorbed or undergo microbial metabolism. This article is protected by copyright. All rights reserved. PMID: 26640139 [PubMed - as supplied by publisher]

Evidence-based pharmacogenetics: Is it possible? Int J Risk Saf Med. 2015 Nov 27;27 Suppl 1:S97-8 Authors: Sychev DA, Malova EU Abstract BACKGROUND: For improving quality, safety and efficiency of care, health systems perform a paradigm change towards personalized medicine, also referred to as genomic medicine. It uses combined knowledge (genomics, transcriptomics, proteomics, metabolomics) about a person to predict disease susceptibility, disease prognosis or treatment response and thereby to improve the person's health. The last decade has witnessed a steady embrace of personalized medicine by senior government officials, industry leadership and health care providers [1]. On the 12th December of 2013 Russian President Vladimir Putin in his annual address to the Federal Assembly said: "The Ministry of Health and the Russian Academy of Sciences must give priority to fundamental and applied research in medicine, including genomic studies" [2]. A year earlier, in 2012 the Ministry of Health of the Russian Federation, headed by Veronika Skvortsova established the strategy of personalized medicine development in Russia [3]. But still a lot of work is focused on using clinical research findings to aid the delivery of optimum clinical care to patients. Pharmacogenetic testing (using genetic information to guide drug therapy) is an actively developing field of personalized medicine and its current state indicates that it can be usefully introduced into clinical practice in the nearest future. In Russia pharmacogenetic testing is already used for personalizing prescription of certain drugs [4]. OBJECTIVE: To assess the extent of genetic testing use for improving use of medicines. METHODS: PubMed and E-Library searches for the period of 2004-2015. RESULTS: The number of publications retrieved in PubMed search for the term "pharmacogenetics" for 2004 year was 538 and was more than 15500 publications for 2015. 800 Russian-language publications in total were retrieved using a domestic scientific database E-Library search for the term "pharmacogenetics" for 2015 year. The sharp rise in the number of publications (including Russia) reflects growing interest not only among scientists, but also among practitioners. However evidence that is actually available on some key topics may not be of sufficiently high quality to support confident conclusions. As a rule, retrospective cohort studies, also known as historical cohort studies, are carried out. The number of randomized, prospective studies is not large, though in recent years, there has been an increase in their number. However, surrogate outcomes are commonly used in the mentioned studies as trial end points. The main reason for this is the lack of sponsorship. Quite often studies are not interesting for pharmaceutical companies and are carried out within the confines of the small grants. Nevertheless, systematic reviews and meta-analyses of some pharmacogenetic tests provide the high level of evidence (pharmacogenetic testing for clopidogrel, abacavir and antineoplastic drugs) so they appear even in clinical guidelines with the evidence level IIb. It is important to mention that for certain drugs FDA has already approved pharmacogenetic testing [5]. CONCLUSIONS: Evidence is often inconsistent. This leads to the fact that clinical use of pharmacogenetic testing seems to be most appropriate for the management of patients with high risk of adverse drug reactions. PMID: 26639733 [PubMed - in process]

geoRge: a computational tool to detect the presence of stable isotope labeling in LC/MS-based untargeted metabolomics. Anal Chem. 2015 Dec 6; Authors: Capellades J, Navarro M, Samino S, Garcia-Ramirez M, Hernandez C, Simo R, Vinaixa M, Yanes O Abstract Studying the flow of chemical moieties through the complex set of metabolic reactions that happen in the cell is essential to understanding the alterations in homeostasis that occur in disease. Recently, LC/MS-based untargeted metabolomics and isotopically labeled metabolites have been used to facilitate the unbiased mapping of labeled moieties through metabolic pathways. However, due to the complexity of the resulting experimental datasets few computational tools are available for data analysis. Here we introduce geoRge, a novel computational approach capable of analyzing untargeted LC/MS data from stable isotope-labeling experiments. geoRge is written in the open language R and runs on the output structure of the widespreadly-used XCMS package. Unlike other existing tools, geoRge benefits from the fact that mass spectral peaks originated from labeled metabolites show higher intensity and may even appear anew in the mass spectra. We demonstrate that a statistical comparison between unlabeled and labeled samples that identifies significant up-regulated features in the labeled samples is more robust method for tracking stable isotopes than iterating over all MS signal data using the theoretical mass difference between the light and heavy stable isotopes. The automated untargeted isotope annotation and relative quantification capabilities of geoRge are demonstrated by the analysis of LC/MS data from a human retinal pigment epithelium cell line (ARPE-19) grown on normal and high glucose concentrations mimicking diabetic retinopathy conditions in vitro. To ensure data traceability and reproducibility, and enabling for comparison with other existing and future approaches, raw LC/MS files have been deposited in MetaboLights (MTBLS213) and geoRge is available as an R script at https://github.com/jcapelladesto/geoRge. PMID: 26639619 [PubMed - as supplied by publisher]

Related Articles Multiple Hepatic Regulatory Variants at the GALNT2 GWAS Locus Associated with High-Density Lipoprotein Cholesterol. Am J Hum Genet. 2015 Dec 3;97(6):801-15 Authors: Roman TS, Marvelle AF, Fogarty MP, Vadlamudi S, Gonzalez AJ, Buchkovich ML, Huyghe JR, Fuchsberger C, Jackson AU, Wu Y, Civelek M, Lusis AJ, Gaulton KJ, Sethupathy P, Kangas AJ, Soininen P, Ala-Korpela M, Kuusisto J, Collins FS, Laakso M, Boehnke M, Mohlke KL Abstract Genome-wide association studies (GWASs) have identified more than 150 loci associated with blood lipid and cholesterol levels; however, the functional and molecular mechanisms for many associations are unknown. We examined the functional regulatory effects of candidate variants at the GALNT2 locus associated with high-density lipoprotein cholesterol (HDL-C). Fine-mapping and conditional analyses in the METSIM study identified a single locus harboring 25 noncoding variants (r(2) > 0.7 with the lead GWAS variants) strongly associated with total cholesterol in medium-sized HDL (e.g., rs17315646, p = 3.5 × 10(-12)). We used luciferase reporter assays in HepG2 cells to test all 25 variants for allelic differences in regulatory enhancer activity. rs2281721 showed allelic differences in transcriptional activity (75-fold [T] versus 27-fold [C] more than the empty-vector control), as did a separate 780-bp segment containing rs4846913, rs2144300, and rs6143660 (49-fold [AT(-) haplotype] versus 16-fold [CC(+) haplotype] more). Using electrophoretic mobility shift assays, we observed differential CEBPB binding to rs4846913, and we confirmed this binding in a native chromatin context by performing chromatin-immunoprecipitation (ChIP) assays in HepG2 and Huh-7 cell lines of differing genotypes. Additionally, sequence reads in HepG2 DNase-I-hypersensitivity and CEBPB ChIP-seq signals spanning rs4846913 showed significant allelic imbalance. Allelic-expression-imbalance assays performed with RNA from primary human hepatocyte samples and expression-quantitative-trait-locus (eQTL) data in human subcutaneous adipose tissue samples confirmed that alleles associated with increased HDL-C are associated with a modest increase in GALNT2 expression. Together, these data suggest that at least rs4846913 and rs2281721 play key roles in influencing GALNT2 expression at this HDL-C locus. PMID: 26637976 [PubMed - in process]

Related Articles Whole-genome duplication increases tumor cell sensitivity to MPS1 inhibition. Oncotarget. 2015 Nov 30; Authors: Jemaà M, Manic G, Lledo G, Lissa D, Reynes C, Morin N, Chibon F, Sistigu A, Castedo M, Vitale I, Kroemer G, Abrieu A Abstract Several lines of evidence indicate that whole-genome duplication resulting in tetraploidy facilitates carcinogenesis by providing an intermediate and metastable state more prone to generate oncogenic aneuploidy. Here, we report a novel strategy to preferentially kill tetraploid cells based on the abrogation of the spindle assembly checkpoint (SAC) via the targeting of TTK protein kinase (better known as monopolar spindle 1, MPS1). The pharmacological inhibition as well as the knockdown of MPS1 kills more efficiently tetraploid cells than their diploid counterparts. By using time-lapse videomicroscopy, we show that tetraploid cells do not survive the aborted mitosis due to SAC abrogation upon MPS1 depletion. On the contrary diploid cells are able to survive up to at least two more cell cycles upon the same treatment. This effect might reflect the enhanced difficulty of cells with whole-genome doubling to tolerate a further increase in ploidy and/or an elevated level of chromosome instability in the absence of SAC functions. We further show that MPS1-inhibited tetraploid cells promote mitotic catastrophe executed by the intrinsic pathway of apoptosis, as indicated by the loss of mitochondrial potential, the release of the pro-apoptotic cytochrome c from mitochondria, and the activation of caspases. Altogether, our results suggest that MPS1 inhibition could be used as a therapeutic strategy for targeting tetraploid cancer cells. PMID: 26637805 [PubMed - as supplied by publisher]

Towards merging untargeted and targeted methods in mass spectrometry-based metabolomics and lipidomics. Anal Chem. 2015 Dec 4; Authors: Cajka T, Fiehn O Abstract Advances in mass spectrometry (MS) and data processing have led to discoveries in regulation of cellular metabolism by using metabolomics and lipidomics approaches. Mass spectrometry is by far the dominating analytical platform in metabolomics and lipidomics, surpassing the use of nuclear magnetic resonance (NMR) at a 5:2 ratio according to our citation analysis. PMID: 26637011 [PubMed - as supplied by publisher]

Diagnosis and treatment of small intestinal bacterial overgrowth. Expert Rev Gastroenterol Hepatol. 2015 Dec 4;:1-13 Authors: Ponziani FR, Gerardi V, Gasbarrini A Abstract A huge number of bacteria are hosted in the gastrointestinal tract, following a gradient increasing towards the colon. Gastric acid secretion and intestinal clearance provide the qualitative and quantitative partitioning of intestinal bacteria; small intestinal bacteria overgrowth (SIBO) occurs when these barrier mechanisms fail. Diagnosis of SIBO is challenging due to the low specificity of symptoms, the frequent association with other diseases of the gastrointestinal tract and the absence of optimal objective diagnostic tests. The therapeutic approach to SIBO is oriented towards resolving predisposing conditions, and is supported by antibiotic treatment to restore the normal small intestinal microflora and by modifications of dietary habits for symptomatic relief. In the near future, metagenomics and metabolomics will help to overcome the uncertainties of SIBO diagnosis and the pitfalls of therapeutic management, allowing the design of a personalized strategy based on the direct insight into the small intestinal microbial community. PMID: 26636484 [PubMed - as supplied by publisher]

Metabolomics and Type 2 Diabetes: Translating Basic Research into Clinical Application. J Diabetes Res. 2016;2016:3898502 Authors: Klein MS, Shearer J Abstract Type 2 diabetes (T2D) and its comorbidities have reached epidemic proportions, with more than half a billion cases expected by 2030. Metabolomics is a fairly new approach for studying metabolic changes connected to disease development and progression and for finding predictive biomarkers to enable early interventions, which are most effective against T2D and its comorbidities. In metabolomics, the abundance of a comprehensive set of small biomolecules (metabolites) is measured, thus giving insight into disease-related metabolic alterations. This review shall give an overview of basic metabolomics methods and will highlight current metabolomics research successes in the prediction and diagnosis of T2D. We summarized key metabolites changing in response to T2D. Despite large variations in predictive biomarkers, many studies have replicated elevated plasma levels of branched-chain amino acids and their derivatives, aromatic amino acids and α-hydroxybutyrate ahead of T2D manifestation. In contrast, glycine levels and lysophosphatidylcholine C18:2 are depressed in both predictive studies and with overt disease. The use of metabolomics for predicting T2D comorbidities is gaining momentum, as are our approaches for translating basic metabolomics research into clinical applications. As a result, metabolomics has the potential to enable informed decision-making in the realm of personalized medicine. PMID: 26636104 [PubMed - in process]