PubMed

Related Articles CD38-Mediated Immunosuppression as a Mechanism of Tumor Cell Escape from PD-1/PD-L1 Blockade. Cancer Discov. 2018 09;8(9):1156-1175 Authors: Chen L, Diao L, Yang Y, Yi X, Rodriguez BL, Li Y, Villalobos PA, Cascone T, Liu X, Tan L, Lorenzi PL, Huang A, Zhao Q, Peng D, Fradette JJ, Peng DH, Ungewiss C, Roybal J, Tong P, Oba J, Skoulidis F, Peng W, Carter BW, Gay CM, Fan Y, Class CA, Zhu J, Rodriguez-Canales J, Kawakami M, Byers LA, Woodman SE, Papadimitrakopoulou VA, Dmitrovsky E, Wang J, Ullrich SE, Wistuba II, Heymach JV, Qin FX, Gibbons DL Abstract Although treatment with immune checkpoint inhibitors provides promising benefit for patients with cancer, optimal use is encumbered by high resistance rates and requires a thorough understanding of resistance mechanisms. We observed that tumors treated with PD-1/PD-L1 blocking antibodies develop resistance through the upregulation of CD38, which is induced by all-trans retinoic acid and IFNβ in the tumor microenvironment. In vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T-cell function via adenosine receptor signaling and that CD38 or adenosine receptor blockade are effective strategies to overcome the resistance. Large data sets of human tumors reveal expression of CD38 in a subset of tumors with high levels of basal or treatment-induced T-cell infiltration, where immune checkpoint therapies are thought to be most effective. These findings provide a novel mechanism of acquired resistance to immune checkpoint therapy and an opportunity to expand their efficacy in cancer treatment.Significance: CD38 is a major mechanism of acquired resistance to PD-1/PD-L1 blockade, causing CD8+ T-cell suppression. Coinhibition of CD38 and PD-L1 improves antitumor immune response. Biomarker assessment in patient cohorts suggests that a combination strategy is applicable to a large percentage of patients in whom PD-1/PD-L1 blockade is currently indicated. Cancer Discov; 8(9); 1156-75. ©2018 AACR.See related commentary by Mittal et al., p. 1066This article is highlighted in the In This Issue feature, p. 1047. PMID: 30012853 [PubMed - indexed for MEDLINE]

Related Articles Identification of Novel Pathways of Osimertinib Disposition and Potential Implications for the Outcome of Lung Cancer Therapy. Clin Cancer Res. 2018 05 01;24(9):2138-2147 Authors: MacLeod AK, Lin, Huang JT, McLaughlin LA, Henderson CJ, Wolf CR Abstract Purpose: Osimertinib is a third-generation inhibitor of the epidermal growth factor receptor used in treatment of non-small cell lung cancer. A full understanding of its disposition and capacity for interaction with other medications will facilitate its effective use as a single agent and in combination therapy.Experimental Design: Recombinant cytochrome P450s and liver microsomal preparations were used to identify novel pathways of osimertinib metabolism in vitro A panel of knockout and mouse lines humanized for pathways of drug metabolism were used to establish the relevance of these pathways in vivoResults: Although some osimertinib metabolites were similar in mouse and human liver samples there were several significant differences, in particular a marked species difference in the P450s involved. The murine Cyp2d gene cluster played a predominant role in mouse, whereas CYP3A4 was the major human enzyme responsible for osimertinib metabolism. Induction of this enzyme in CYP3A4 humanized mice substantially decreased circulating osimertinib exposure. Importantly, we discovered a further novel pathway of osimertinib disposition involving CPY1A1. Modulation of CYP1A1/CYP1A2 levels markedly reduced parent drug concentrations, significantly altering metabolite pharmacokinetics (PK) in humanized mice in vivoConclusions: We demonstrate that a P450 enzyme expressed in smokers' lungs and lung tumors has the capacity to metabolise osimertinib. This could be a significant factor in defining the outcome of osimertinib treatment. This work also illustrates how P450-humanized mice can be used to identify and mitigate species differences in drug metabolism and thereby model the in vivo effect of critical metabolic pathways on anti-tumor response. Clin Cancer Res; 24(9); 2138-47. ©2018 AACR. PMID: 29437786 [PubMed - indexed for MEDLINE]

29 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/14PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/13PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/12PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

18 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/12PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

19 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/11PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/09PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles Effects of Selective Exclusion of Patients on Preterm Birth Test Performance. Obstet Gynecol. 2019 Nov 04;: Authors: Boniface JJ, Burchard J, Saade GR Abstract The need to reduce the rate of preterm delivery and the recent emergence of technologies that measure hundreds of biological analytes (eg, genomics, transcriptomics, metabolomics, proteomics; collectively referred to as "omics approaches") have led to proliferation of potential diagnostic biomarkers. On review of the literature, a concern must be raised regarding experimental design and data analysis reporting. Specifically, inaccurate performance has often been reported after selective exclusion of patients around the definition boundary of preterm birth. For example, authors may report the performance of a preterm delivery predictor by using patients who delivered early preterm compared with deliveries at 37 weeks of gestation or greater. A key principle that must be maintained during the development of any predictive test is to communicate performance for all patients for whom the test will be applicable clinically (ie, the intended-use population), which for prediction of preterm birth includes patients delivering throughout the spectrum of gestational ages, as this is what is to be predicted, and not known at the time of testing. Using biomarker data collected from the U.S.-based Proteomic Assessment of Preterm Risk clinical trial, we provide examples where the area under the receiver operating characteristic curve for the same test artifactually improves from 0.68 (for preterm delivery at less than 37 weeks of gestation) or 0.76 (for preterm delivery at less than 32 weeks of gestation) to 0.91 when patients who deliver late preterm are excluded. We review this phenomenon in this commentary and offer recommendations for clinicians and investigators going forward. FUNDING SOURCE:: Sera Prognostics. PMID: 31698391 [PubMed - as supplied by publisher]

Related Articles Coupling metabolomics analysis and DOE optimization strategy towards enhanced IBDV production by chicken embryo fibroblast DF-1 cells. J Biotechnol. 2019 Nov 04;: Authors: Lin J, Yi X, Zhuang Y Abstract Infectious bursal disease (IBD) caused by IBD virus (IBDV) is highly contagious viral and vaccination in chicken embryo has been an effective mean to prevent acute infection. However, the current production of IBDV vaccine faces serious batch instability and external contamination. The chicken embryonic fibroblast cell line DF-1 is widely used for the proliferation of avian viruses and vaccine production. Thus, optimizing the production of IBDV by DF-1 cells has an important application value. Combining metabolomics analysis and a Design of Experiments (DOE) statistical strategy, this study successfully optimized the process of IBDV production by DF-1 cells. Differential analysis and time series analysis of metabolite data in both IBDV-infected and uninfected DF-1 cells were performed by multivariate statistical analysis. The results showed that the intracellular metabolite intensities of glycolysis, the pentose phosphate pathway, the nucleoside synthesis pathway, lipid metabolism, and glutathione metabolism were upregulated, and the TCA cycle underwent a slight downregulation after IBDV infection of DF-1 cells. Based on the metabolome results and DOE statistical optimization method, the additive components suitable for IBDV proliferation were determined. The IBDV titer increased by 20.7 times upon exogenous addition of cysteine, methionine, lysine and nucleosides in the control medium, which is consistent with the predicted result (20.0 times) by a multivariate quadratic equation. This study provides a strategy for the efficient production of IBDV vaccines and could potentially be utilized to improve the production of other viral vaccines and biologics. PMID: 31697974 [PubMed - as supplied by publisher]

Related Articles High-Resolution Ion Mobility Spectrometry-Mass Spectrometry of Isomeric/Isobaric Ribonucleotide Variants. J Mass Spectrom. 2019 Nov 07;: Authors: Kenderdine T, Nemati R, Baker A, Palmer M, Ujma J, Fitzgibbon M, Deng L, Royzen M, Langridge J, Fabris D Abstract In this report, we explored the benefits of cyclic ion mobility (cIM) mass spectrometry in the analysis of isomeric post-transcriptional modifications of RNA. Standard methyl-cytidine samples were initially utilized to test the ability to correctly distinguish different structures sharing the same elemental composition, and thus molecular mass. Analyzed individually, the analytes displayed characteristic arrival times (tD ) determined by the different positions of the modifying methyl groups onto the common cytidine scaffold. Analyzed in mixture, the widths of the respective signals resulted in significant overlap that initially prevented their resolution on the tD scale. The separation of the four isomers was achieved by increasing the number of passes through the cIM device, which enabled to fully differentiate the characteristic ion mobility behaviors associated with very subtle structural variations. The placement of the cIM device between the mass-selective quadrupole and the time-of-flight analyzer allowed us to perform gas-phase activation of each of these ion populations, which had been first isolated according to a common mass-to-charge ratio, and then separated on the basis of different ion mobility behaviors. The observed fragmentation patterns confirmed the structures of the various isomers, thus substantiating the benefits of complementing unique tD information with specific fragmentation data to reach more stringent analyte identification. These capabilities were further tested by analyzing natural mono-nucleotide mixtures obtained by exonuclease digestion of total RNA extracts. In particular, the combination of cIM separation and post-mobility dissociation allowed us to establish the composition of methyl-cytidine and methyl-adenine components present in the entire transcriptome of HeLa cells. For this reason, we expect that this technique will benefit not only epitranscriptomics studies requiring the determination of identity and expression levels of RNA modifications, but also metabolomics investigations involving the analysis of natural extracts that may possibly contain subsets of isomeric/isobaric species. PMID: 31697854 [PubMed - as supplied by publisher]

Related Articles Metabolomics profiles associated with HbA1c levels in patients with type 2 diabetes. PLoS One. 2019;14(11):e0224274 Authors: Yun JH, Lee HS, Yu HY, Kim YJ, Jeon HJ, Oh T, Kim BJ, Choi HJ, Kim JM Abstract Glycated hemoglobin (HbA1c) is an indicator of the average blood glucose concentration. Failing to control HbA1c levels can accelerate the development of complications in patients with diabetes. Although metabolite profiles associated with HbA1c level in diabetes patients have been characterized using different platforms, more studies using high-throughput technology will be helpful to identify additional metabolites related to diabetes. Type 2 diabetes (T2D) patients were divided into two groups based on the HbA1c level: normal (HbA1c ≤6%) and high (HbA1c ≥9%) in both discovery and replication sets. A targeted metabolomics approach was used to quantify serum metabolites and multivariate logistic regression was used to identify significant differences between groups. The concentrations of 22 metabolites differed significantly between the two groups in the discovery set. In the replication set, the levels of 21 metabolites, including 16 metabolites identified in the discovery set, differed between groups. Among these, concentrations of eleven amino acids and one phosphatidylcholine (PC), lysoPC a C16:1, were higher and four metabolites, including three PCs (PC ae C36:1, PC aa C26:0, PC aa C34:2) and hexose, were lower in the group with normal HbA1c group than in the group with high HbA1c. Metabolites with high concentrations in the normal HbA1c group, such as glycine, valine, and PCs, may contribute to reducing HbA1c levels in patients with T2D. The metabolite signatures identified in this study provide insight into the mechanisms underlying changes in HbA1c levels in T2D. PMID: 31697702 [PubMed - in process]

Related Articles The MRL/MpJ mouse strain is not protected from muscle atrophy and weakness after rotator cuff tear. J Orthop Res. 2019 Nov 07;: Authors: Talarek JR, Piacentini AN, Konja AC, Wada S, Swanson JB, Nussenzweig SC, Dines JS, Rodeo SA, Mendias CL Abstract Chronic rotator cuff tears are a common source of shoulder pain and disability. Patients with rotator cuff tears often have substantial weakness, fibrosis, and fat accumulation which limit successful surgical repair and postoperative rehabilitation. The Murphy Roths Large (MRL) strain of mice have demonstrated superior healing and protection against pathological changes in several disease and injury conditions. We tested the hypothesis that, compared to the commonly used C57Bl/6 (B6) strain, MRL mice would have less muscle fiber atrophy and fat accumulation, and be protected against the loss in force production that occurs after cuff tear. Adult male B6 and MRL mice were subjected to a rotator cuff tear, and changes in muscle fiber contractility and histology were measured. RNA sequencing, and shotgun metabolomics and lipidomics were also performed. Muscles were harvested one month after tear. B6 and MRL mice had a 40% reduction in relative muscle force production after rotator cuff tear. RNA sequencing identified an increase in fibrosis-associated genes and a reduction in mitochondrial metabolism genes. Markers of glycolytic metabolism increased in B6 mice, while MRL mice appeared to increase amino acid metabolism after tear. There was an accumulation of lipid after injury, although there was a divergent response between B6 and MRL mice in the types of lipid species that accrued. There were strain-specific differences between the transcriptome, metabolome, and lipidome of B6 and MRL mice, but these differences did not protect MRL mice from weakness and pathological changes after rotator cuff tear. This article is protected by copyright. All rights reserved. PMID: 31696955 [PubMed - as supplied by publisher]

Related Articles Metabolic framework for the improvement of autism spectrum disorders by a modified ketogenic diet: a pilot study. J Proteome Res. 2019 Nov 07;: Authors: Mu C, Corley MJ, Lee RWY, Wong M, Pang A, Arakaki G, Miyamoto R, Rho JM, Mickiewicz B, Dowlatabadi R, Vogel HJ, Korchemagin Y, Shearer J Abstract The ketogenic diet (KD) can improve the core features of autism spectrum disorders (ASD) in some children, but the effects on overall metabolism remain unclear. This pilot study investigated behavioural parameters in relation to blood metabolites and trace elements in a cohort of 10 typically developed controls (TC) and 17 children with ASD at baseline and following a 3-month treatment with a modified KD regimen. A non-targeted, multiplatform metabolomics approach was employed, including Gas Chromatography-Mass Spectrometry, 1H Nuclear Magnetic Resonance Spectroscopy, and Inductively Coupled Plasma-Mass Spectrometry. Associations between plasma metabolites, trace elements, and behavior scores were investigated. Employing a combination of metabolomics platforms, 118 named metabolites and 73 trace elements were assessed. Relative to TC, a combination of glutamate, galactonate, and glycerol discriminated ASD with 88% accuracy. ASD had higher concentrations of galactose intermediates, gut microbe-derived trimethylamine N-oxide and N-acetylserotonin, and lower concentrations of 3-hydroxybutyrate and selenium at baseline. Following 3mo KD intervention, levels of circulating ketones and acetylcarnitine were increased. KD restored lower selenium levels in ASD to that of controls and correlation analysis identified a novel negative correlation between changes in selenium and behaviour scores. Based on the different behavior responses to the KD, we found that high responders had greater concentrations of 3-hydroxybutyrate and ornithine, with lower galactose. These findings enhance our current understanding of metabolic derangements present in ASD and may be of utility in predicting favorable responses to KD intervention. PMID: 31696714 [PubMed - as supplied by publisher]

Related Articles Ammonium accumulation and chemokine decrease in culture media of Gcdh-/- 3D reaggregated brain cell cultures. Mol Genet Metab. 2019 04;126(4):416-428 Authors: Cudré-Cung HP, Remacle N, do Vale-Pereira S, Gonzalez M, Henry H, Ivanisevic J, Schmiesing J, Mühlhausen C, Braissant O, Ballhausen D Abstract Glutaric Aciduria type I (GA-I) is caused by mutations in the GCDH gene. Its deficiency results in accumulation of the key metabolites glutaric acid (GA) and 3-hydroxyglutaric acid (3-OHGA) in body tissues and fluids. Present knowledge on the neuropathogenesis of GA-I suggests that GA and 3-OHGA have toxic properties on the developing brain. We analyzed morphological and biochemical features of 3D brain cell aggregates issued from Gcdh-/- mice at two different developmental stages, day-in-vitro (DIV) 8 and 14, corresponding to the neonatal period and early childhood. We also induced a metabolic stress by exposing the aggregates to 10 mM l-lysine (Lys). Significant amounts of GA and 3-OHGA were detected in Gcdh-/- aggregates and their culture media. Ammonium was significantly increased in culture media of Gcdh-/- aggregates at the early developmental stage. Concentrations of GA, 3-OHGA and ammonium increased significantly after exposure to Lys. Gcdh-/- aggregates manifested morphological alterations of all brain cell types at DIV 8 while at DIV 14 they were only visible after exposure to Lys. Several chemokine levels were significantly decreased in culture media of Gcdh-/- aggregates at DIV 14 and after exposure to Lys at DIV 8. This new in vitro model for brain damage in GA-I mimics well in vivo conditions. As seen previously in WT aggregates exposed to 3-OHGA, we confirmed a significant ammonium production by immature Gcdh-/- brain cells. We described for the first time a decrease of chemokines in Gcdh-/- culture media which might contribute to brain cell injury in GA-I. PMID: 30686684 [PubMed - indexed for MEDLINE]

Related Articles Metabolic Response of the Immature Right Ventricle to Acute Pressure Overloading. J Am Heart Assoc. 2018 05 30;7(11): Authors: Kajimoto M, Nuri M, Isern NG, Robillard-Frayne I, Des Rosiers C, Portman MA Abstract BACKGROUND: Surgical palliation or repair of complex congenital heart disease in early infancy can produce right ventricular (RV) pressure overload, often leading to acute hemodynamic decompensation. The mechanisms causing this acute RV dysfunction remain unclear. We tested the hypothesis that the immature right ventricle lacks the ability to modify substrate metabolism in order to meet increased energy demands induced by acute pressure overloading. METHODS AND RESULTS: Twenty-two infant male mixed breed Yorkshire piglets were randomized to a sham operation (Control) or pulmonary artery banding yielding >2-fold elevation over baseline RV systolic pressure. We used carbon 13 (13C)-labeled substrates and proton nuclear magnetic resonance to assess RV energy metabolism. [Phosphocreatine]/[ATP] was significantly lower after pulmonary artery banding. [Phosphocreatine]/[ATP] inversely correlated with energy demand indexed by maximal sustained RV systolic pressure/left ventricular systolic pressure. Fractional contributions of fatty acids to citric acid cycle were significantly lower in the pulmonary artery banding group than in the Control group (medium-chain fatty acids; 14.5±1.6 versus 8.2±1.0%, long-chain fatty acids; 9.3±1.5 versus 5.1±1.1%). 13C-flux analysis showed that flux via pyruvate decarboxylation did not increase during RV pressure overloading. CONCLUSIONS: Acute RV pressure overload yielded a decrease in [phosphocreatine]/[ATP] ratio, implying that ATP production did not balance the increasing ATP requirement. Relative fatty acids oxidation decreased without a reciprocal increase in pyruvate decarboxylation. The data imply that RV inability to adjust substrate oxidation contributes to energy imbalance, and potentially to contractile failure. The data suggest that interventions directed at increasing RV pyruvate decarboxylation flux could ameliorate contractile dysfunction associated with acute pressure overloading. PMID: 29848498 [PubMed - indexed for MEDLINE]

56 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/07PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

41 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/05PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

69 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/04PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

52 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/11/02PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.