PubMed

Nat Commun. 2023 Aug 22;14(1):5112. doi: 10.1038/s41467-023-40715-x.ABSTRACTThe molecular heterogeneity and distinct features of HER2-low breast cancers, particularly in the Chinese population, are not well understood, limiting its precise management in the era of antibody‒drug conjugates. To address this issue, we established a cohort of 434 Chinese patients with HER2-low breast cancer (433 female and one male) and integrated genomic, transcriptomic, proteomic, and metabolomic profiling data. In this cohort, HER2-low tumors are more distinguished from HER2-0 tumors in the hormone receptor-negative subgroup. Within HER2-low tumors, significant interpatient heterogeneity also exists in the hormone receptor-negative subgroup: basal-like tumors resemble HER2-0 disease, and non-basal-like HER2-low tumors mimic HER2-positive disease. These non-basal-like HER2-low tumors are enriched in the HER2-enriched subtype and the luminal androgen receptor subtype and feature PIK3CA mutation, FGFR4/PTK6/ERBB4 overexpression and lipid metabolism activation. Among hormone receptor-positive tumors, HER2-low tumors show less loss/deletion in 17q peaks than HER2-0 tumors. In this work, we reveal the heterogeneity of HER2-low breast cancers and emphasize the need for more precise stratification regarding hormone receptor status and molecular subtype.PMID:37607916 | DOI:10.1038/s41467-023-40715-x

Funct Plant Biol. 2023 Aug 23. doi: 10.1071/FP23033. Online ahead of print.ABSTRACTThe flower buds of Lonicera japonica are widely used for its high medicinal value. It is reported that the accumulation of phenylpropanoids in the buds of L. japonica is affected by the stage at which it is harvested. However, the changes of active components and the underlying mechanisms in flower buds at different harvesting stages have not been reported. Integrative analyses of transcriptomics and metabolomics was used to explore the underlying mechanism of harvesting stages (green bud, GB; and white bud, WB) on the phenylpropanoids metabolites accumulation in L. japonica. The result showed that 3735 differentially expressed genes were identified, and the genes related to glycolysis/gluconeogenesis and phenylalanine biosynthesis pathway were significantly upregulated in GB stage. A total of 510 differential metabolites were identified in GB stage. Among them, 14 phenylpropanoids were changed during the GB and WB, seven of which increased in GB, including caffeic acid, sauchinone, coniferin, secoisolariciresinol diglucoside, scopolin, methyl cinnamate, chlorogenic acid, 7-hydroxycoumarin, while others such as sibiricose A6, coumarin, eleutheroside E decreased. Further correlation analysis showed that the unigenes for CSE, CAD, bg1, ADH, ALDH, DLAT and ENO significantly correlated with the 10 phenylpropanoid. The above results would provide basic data for the selection of harvesting stages in the production of L. japonica.PMID:37607828 | DOI:10.1071/FP23033

Small. 2023 Aug 22:e2303498. doi: 10.1002/smll.202303498. Online ahead of print.ABSTRACTAchieving rapid and effective hemostasis remains a multidisciplinary challenge. Here, distinctive functional carbon dots derived from carbonized Platycladus orientalis (CPO-CDs) are developed using one-step hydrothermal method. The negatively charged surface of CPO-CDs retains partial functional groups from CPO precursor, exhibiting excellent water solubility and high biocompatibility. Both rat liver injury model and tail amputation model have confirmed the rapid and effective hemostatic performance of CPO-CDs on exogenous hemorrhage. Further, on endogenous blood-heat hemorrhage syndrome rat model, CPO-CDs could inhibit hemorrhage and alleviate inflammation response. Interestingly, the excellent hemostasis performance of CPO-CDs is ascribed to activate exogenous coagulation pathway and common coagulation pathway. More importantly, metabolomics of rat plasma suggests that the hemostasis effect of CPO-CDs is closely related to platelet functions. Therefore, the designed in vitro experiments are performed and it is discovered that CPO-CDs significantly promote platelets adhesion, activation, and aggregation. Further, the underlying mechanism investigation suggests that Src/Syk signal pathway plays a key role in platelets activation triggered by CPO-CDs. Overall, CPO-CDs with rapid and excellent hemostatic performance are discovered for the first time, which could be an excellent candidate for the treatment of hemorrhagic diseases.PMID:37607318 | DOI:10.1002/smll.202303498

Proc Natl Acad Sci U S A. 2023 Aug 29;120(35):e2308500120. doi: 10.1073/pnas.2308500120. Epub 2023 Aug 22.ABSTRACTWhen insect herbivores attack plants, elicitors from oral secretions and regurgitants (OS) enter wounds during feeding, eliciting defense responses. These generally require plant jasmonate (JA) signaling, specifically, a jasmonoyl-L-isoleucine (JA-Ile) burst, for their activation and are well studied in the native tobacco Nicotiana attenuata. We used intraspecific diversity captured in a 26-parent MAGIC population planted in nature and an updated genome assembly to impute natural variation in the OS-elicited JA-Ile burst linked to a mutation in the JA-Ile biosynthetic gene NaJAR4. Experiments revealed that NaJAR4 variants were associated with higher fitness in the absence of herbivores but compromised foliar defenses, with two NaJAR homologues (4 and 6) complementing each other spatially and temporally. From decade-long seed collections of natural populations, we uncovered enzymatically inactive variants occurring at variable frequencies, consistent with a balancing selection regime maintaining variants. Integrative analyses of OS-induced transcriptomes and metabolomes of natural accessions revealed that NaJAR4 is embedded in a nonlinear complex gene coexpression network orchestrating responses to OS, which we tested by silencing four hub genes in two connected coexpressed networks and examining their OS-elicited metabolic responses. Lines silenced in two hub genes (NaGLR and NaFB67) co-occurring in the NaJAR4/6 module showed responses proportional to JA-Ile accumulations; two from an adjacent module (NaERF and NaFB61) had constitutively expressed defenses with high resistance. We infer that mutations with large fitness consequences can persist in natural populations due to compensatory responses from gene networks, which allow for diversification in conserved signaling pathways and are generally consistent with predictions of an omnigene model.PMID:37607232 | DOI:10.1073/pnas.2308500120

Angew Chem Int Ed Engl. 2023 Aug 21:e202307165. doi: 10.1002/anie.202307165. Online ahead of print.ABSTRACTDiatoms are abundant unicellular microalgae, responsible for ~ 20% of global photosynthetic CO2 fixation. Nevertheless, we know little about fundamental aspects of their biology, such as their sexual reproduction. Pheromone-mediated chemical communication is crucial for successful mating. An attraction pheromone was identified in the diatom Seminavis robusta, but metabolites priming cells for sex and synchronizing search and mating behavior remained elusive. These sex-inducing pheromones (SIP) induce cell cycle arrest and trigger the production of the attraction pheromone. Here we describe the challenging structure elucidation of an S. robusta SIP. Guided by metabolomics, a candidate metabolite was identified and elucidated by labeling experiments, NMR, ESI MSn analyses, and chemical transformations. Essential was the use of negative ion mode MS to decipher the unprecedented hydroxyproline and β-sulfated aspartate-containing cyclic heptapeptide that acts in femtomolar concentrations.PMID:37607131 | DOI:10.1002/anie.202307165

Microbiol Spectr. 2023 Aug 21:e0117523. doi: 10.1128/spectrum.01175-23. Online ahead of print.ABSTRACTPeople with cystic fibrosis (pwCF) experience a range of persistent gastrointestinal symptoms throughout life. There is evidence indicating interaction between the microbiota and gut pathophysiology in CF. However, there is a paucity of knowledge on the potential effects of CF transmembrane conductance regulator (CFTR) modulator therapies on the gut microbiome. In a pilot study, we investigated the impact of Tezacaftor/Ivacaftor dual combination CFTR modulator therapy on the gut microbiota and metabolomic functioning in pwCF. Fecal samples from 12 pwCF taken at baseline and following placebo or Tezacaftor/Ivacaftor administration were subjected to microbiota sequencing and to targeted metabolomics to assess the short-chain fatty acid (SCFA) composition. Ten healthy matched controls were included as a comparison. Inflammatory calprotectin levels and patient symptoms were also investigated. No significant differences were observed in overall gut microbiota characteristics between any of the study stages, extended also across intestinal inflammation, gut symptoms, and SCFA-targeted metabolomics. However, microbiota and SCFA metabolomic compositions, in pwCF, were significantly different from controls in all study treatment stages. CFTR modulator therapy with Tezacaftor/Ivacaftor had negligible effects on both the gut microbiota and SCFA composition across the course of the study and did not alter toward compositions observed in healthy controls. Future longitudinal CFTR modulator studies will investigate more effective CFTR modulators and should use prolonged sampling periods, to determine whether longer-term changes occur in the CF gut microbiome. IMPORTANCE People with cystic fibrosis (pwCF) experience persistent gastrointestinal (GI) symptoms throughout life. The research question "how can we relieve gastrointestinal symptoms, such as stomach pain, bloating, and nausea?" remains a top priority for clinical research in CF. While CF transmembrane conductance regulator (CFTR) modulator therapies are understood to correct underlying issues of CF disease and increasing the numbers of pwCF are now receiving some form of CFTR modulator treatment. It is not known how these therapies affect the gut microbiome or GI system. In this pilot study, we investigated, for the first time, effects of the dual combination CFTR modulator medicine, Tezacaftor/Ivacaftor. We found it had negligible effects on patient GI symptoms, intestinal inflammation, or gut microbiome composition and functioning. Our findings are important as they fill important knowledge gaps on the relative effectiveness of these widely used treatments. We are now investigating triple combination CFTR modulators with prolonged sampling periods.PMID:37607068 | DOI:10.1128/spectrum.01175-23

JAMA Netw Open. 2023 Aug 1;6(8):e2330255. doi: 10.1001/jamanetworkopen.2023.30255.ABSTRACTIMPORTANCE: Maternal suboptimal nutrition and high stress levels are associated with adverse fetal and childhood neurodevelopment.OBJECTIVE: To test the hypothesis that structured interventions based on a Mediterranean diet or mindfulness-based stress reduction (MBSR) during pregnancy improve child neurodevelopment at age 2 years.DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified analysis of the parallel-group Improving Mothers for a Better Prenatal Care Trial Barcelona (IMPACT BCN) randomized clinical trial, which was conducted at a university hospital in Barcelona, Spain, from February 2017 to March 2020. A total of 1221 singleton pregnancies (19 to 23 weeks' gestation) with high risk of delivering newborns who were small for gestational age were randomly allocated into 3 groups: a Mediterranean diet intervention, an MBSR program, or usual care. A postnatal evaluation with the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III), was performed. Data were analyzed from July to November 2022.INTERVENTIONS: Participants in the Mediterranean diet group received monthly individual and group educational sessions and free provision of extra virgin olive oil and walnuts. Those in the stress reduction group underwent an 8-week MBSR program adapted for pregnancy. Individuals in the usual care group received pregnancy care per institutional protocols.MAIN OUTCOMES AND MEASURES: Neurodevelopment in children was assessed by Bayley-III at 24 months of corrected postnatal age.RESULTS: A total of 626 children (293 [46.8%] female and 333 [53.2%] male) participated at a mean (SD) age of 24.8 (2.9) months. No differences were observed in the baseline characteristics between intervention groups. Compared with children from the usual care group, children in the Mediterranean diet group had higher scores in the cognitive domain (β, 5.02; 95% CI, 1.52-8.53; P = .005) and social-emotional domain (β, 5.15; 95% CI, 1.18-9.12; P = .01), whereas children from the stress reduction group had higher scores in the social-emotional domain (β, 4.75; 95% CI, 0.54-8.85; P = .02).CONCLUSIONS AND RELEVANCE: In this prespecified analysis of a randomized clinical trial, maternal structured lifestyle interventions during pregnancy based on a Mediterranean diet or MBSR significantly improved child neurodevelopmental outcomes at age 2 years.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03166332.PMID:37606923 | DOI:10.1001/jamanetworkopen.2023.30255

Food Funct. 2023 Aug 22. doi: 10.1039/d3fo01782f. Online ahead of print.ABSTRACTHigh-fat diet (HFD) induced obesity and its associated conditions, such as hepatic steatosis and steatohepatitis, are major health concerns worldwide. Previous studies have reported the excellent efficiency of Fuzhuan brick tea (FBT) in attenuating HFD-induced obesity and metabolic disorders. In this study, we investigated the effects of FBT on hepatic steatosis and simple steatohepatitis in HFD-induced obese mice, as well as the metabolic function of the gut microbiome using metagenomics and metabolomics. The results showed that FBT ameliorated dyslipidemia, hepatic steatosis and steatohepatitis in HFD-induced obese mice by normalizing the gut microbiota structure and tryptophan metabolism. FBT increased the cecal abundance of aryl hydrocarbon receptor (AhR)-ligand producing bacteria such as Lactobacillus_reuteri and Lactobacillus_johnsonii, at the expense of AhR-ligand consuming bacteria, such as Faecalibaculum_rodentium and Escherichia_coli, and elevated the cecal contents of AhR-ligands such as IAA, IPA, and KYNA. Furthermore, FBT regulated the expressions of AhR and its targeted lipometabolic genes such as Pemt, Fasn, and SREBP-1c, as well as other inflammatory genes including TNF-α, IL-6, and IL-1β in the liver of mice. Overall, these findings highlight the beneficial effects of FBT on obesity-related hepatic steatosis and steatohepatitis via microbiota-derived AhR signaling.PMID:37606634 | DOI:10.1039/d3fo01782f

Clin Chem Lab Med. 2023 Aug 23. doi: 10.1515/cclm-2023-0468. Online ahead of print.ABSTRACTOBJECTIVES: Accumulating evidence argues for a more widespread use of therapeutic drug monitoring (TDM) to support individualized medicine, especially for therapies where toxicity and efficacy are critical issues, such as in oncology. However, development of TDM assays struggles to keep pace with the rapid introduction of new drugs. Therefore, novel approaches for faster assay development are needed that also allow effortless inclusion of newly approved drugs as well as customization to smaller subsets if scientific or clinical situations require.METHODS: We applied and evaluated two machine-learning approaches i.e., a regression-based approach and an artificial neural network (ANN) to retention time (RT) prediction for efficient development of a liquid chromatography mass spectrometry (LC-MS) method quantifying 73 oral antitumor drugs (OADs) and five active metabolites. Individual steps included training, evaluation, comparison, and application of the superior approach to RT prediction, followed by stipulation of the optimal gradient.RESULTS: Both approaches showed excellent results for RT prediction (mean difference ± standard deviation: 2.08 % ± 9.44 % ANN; 1.78 % ± 1.93 % regression-based approach). Using the regression-based approach, the optimum gradient (4.91 % MeOH/min) was predicted with a total run time of 17.92 min. The associated method was fully validated following FDA and EMA guidelines. Exemplary modification and application of the regression-based approach to a subset of 14 uro-oncological agents resulted in a considerably shortened run time of 9.29 min.CONCLUSIONS: Using a regression-based approach, a multi drug LC-MS assay for RT prediction was efficiently developed, which can be easily expanded to newly approved OADs and customized to smaller subsets if required.PMID:37606251 | DOI:10.1515/cclm-2023-0468

J Proteome Res. 2023 Aug 22. doi: 10.1021/acs.jproteome.3c00224. Online ahead of print.ABSTRACTSickle cell disease and β-thalassemia represent hemoglobinopathies arising from dysfunctional or underproduced β-globin chains, respectively. In both diseases, red blood cell injury and anemia are the impetus for end organ injury. Because persistent erythrophagocytosis is a hallmark of these genetic maladies, it is critical to understand how macrophage phenotype polarizations in tissue compartments can inform on disease progression. Murine models of sickle cell disease and β-thalassemia allow for a basic understanding of the mechanisms and provide for translation to human disease. A multi-omics approach to understanding the macrophage metabolism and protein changes in two murine models of β-globinopathy was performed on peripheral blood mononuclear cells as well as spleen and liver macrophages isolated from Berkley sickle cell disease (Berk-ss) and heterozygous B1/B2 globin gene deletion (Hbbth3/+) mice. The results from these experiments revealed that the metabolome and proteome of macrophages are polarized to a distinct phenotype in Berk-ss and Hbbth3/+ compared with each other and their common-background mice (C57BL6/J). Further, spleen and liver macrophages revealed distinct disease-specific phenotypes, suggesting that macrophages become differentially polarized and reprogrammed within tissue compartments. We conclude that tissue recruitment, polarization, and metabolic and proteomic reprogramming of macrophages in Berk-ss and Hbbth3/+ mice may be relevant to disease progression in other tissue.PMID:37606205 | DOI:10.1021/acs.jproteome.3c00224

JCI Insight. 2023 Aug 22;8(16):e167007. doi: 10.1172/jci.insight.167007.ABSTRACTSpatially resolved metabolomics enables the investigation of tumoral metabolites in situ. Inter- and intratumor heterogeneity are key factors associated with patient outcomes. Adrenocortical carcinoma (ACC) is an exceedingly rare tumor associated with poor survival. Its clinical prognosis is highly variable, but the contributions of tumor metabolic heterogeneity have not been investigated thus far to our knowledge. An in-depth understanding of tumor heterogeneity requires molecular feature-based identification of tumor subpopulations associated with tumor aggressiveness. Here, using spatial metabolomics by high-mass resolution MALDI Fourier transform ion cyclotron resonance mass spectrometry imaging, we assessed metabolic heterogeneity by de novo discovery of metabolic subpopulations and Simpson's diversity index. After identification of tumor subpopulations in 72 patients with ACC, we additionally performed a comparison with 25 tissue sections of normal adrenal cortex to identify their common and unique metabolic subpopulations. We observed variability of ACC tumor heterogeneity and correlation of high metabolic heterogeneity with worse clinical outcome. Moreover, we identified tumor subpopulations that served as independent prognostic factors and, furthermore, discovered 4 associated anticancer drug action pathways. Our research may facilitate comprehensive understanding of the biological implications of tumor subpopulations in ACC and showed that metabolic heterogeneity might impact chemotherapy.PMID:37606037 | DOI:10.1172/jci.insight.167007

Anal Methods. 2023 Aug 22. doi: 10.1039/d3ay01046e. Online ahead of print.ABSTRACTMatrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) of metabolites can reveal how metabolism is altered throughout heterogeneous tissues. Here negative ion mode MALDI-MSI has been coupled with laser post-ionisation (MALDI-2) and applied to the MSI of low molecular weight (LMW) metabolites (<m/z 600) to investigate the benefits MALDI-2 offers for spatial metabolomics in terms of metabolite coverage and sensitivity. When applied to mouse kidney tissue MALDI-2 provided almost double the number of on-tissue specific mass features compared to conventional MALDI. MALDI-2 also resulted in not only the increased detection sensitivity for multiple metabolite species but also permitted the imaging of LMW metabolites (e.g. uridine) that were not detected using conventional MALDI-MSI. When compared against ∼140 publically available kidney datasets submitted through the METASPACE analysis platform using the same N-(1-naphthyl) ethylenediamine dihydrochloride (NEDC) matrix, MALDI-2 provided 34 unique metabolite m/z features that were not consistently annotated previously. To further evaluate the usefulness of this MALDI-2 approach to metabolite imaging, MALDI-2 was applied to the imaging of mouse liver tissue containing a metastasised breast cancer at a pixel size of 20 μm. Using a co-localisation analysis, MALDI-2 detected six tumour-specific metabolites that were not detected using conventional MALDI, as well as providing an up to 20-fold increase in signal intensities for many others (e.g., glutamate). This work provides one of the first reports of MALDI-2 applied to metabolite imaging and demonstrates the dramatic improvements in sensitivity and metabolite coverage it provides.PMID:37605803 | DOI:10.1039/d3ay01046e

Tob Induc Dis. 2023 Aug 21;21:106. doi: 10.18332/tid/168568. eCollection 2023.ABSTRACTINTRODUCTION: Alterations in DNA methylation profiles have been associated with cancer, and can be influenced by environmental factors such as smoking. A small but growing literature indicates there are reproducible and robust differences in methylation levels among smokers, never smokers, and ex-smokers. Here, we compared differences in salivary DNA methylation levels among current and ex-smokers (at least 2 years abstinent).METHODS: Smokers (n=26) and ex-smokers (n=30) provided detailed smoking histories, completed the Paced Auditory Serial Addition Test (PASAT), and submitted a saliva sample. Whole-genome DNA methylation from saliva was performed, and ANCOVA models and a receiver operating characteristic (ROC) curve were used for the differences between groups and the performance of significant CpG sites.RESULTS: After controlling for race, age, and gender, smokers had significantly lower methylation levels than ex-smokers in two CpG sites: cg05575921 (AHRR) and cg21566642 (ALPPL2). Based on the ROC analyses, both CpGs had strong classification potentials (cg05575921 AUC=0.97 and cg21566642 AUC=0.93) in differentiating smoking status. Across all subjects, the percent methylation of cg05575921 (AHRR) and cg21566642 (ALPPL2) positively correlated with the length of the last quit attempt (r=0.65 and 0.64, respectively, p<0.001) and PASAT accuracy (r=0.29 and 0.30, respectively, p<0.05).CONCLUSIONS: In spite of the small sample size and preliminary research, our results replicate previously reported differences in AHRR hypomethylation among smokers. Furthermore, we show that the duration of smoking abstinence is associated with a recovery of methylation in ex-smokers, which may be linked to a reduced risk of smoking-associated diseases. The association with cognitive performance suggests that the hypomethylation of AHRR in saliva may reflect systemic exposure to cigarette-related toxicants that negatively affect cognitive performance, and should be validated in larger studies.PMID:37605769 | PMC:PMC10405227 | DOI:10.18332/tid/168568

Biomed Chromatogr. 2023 Aug 22:e5719. doi: 10.1002/bmc.5719. Online ahead of print.ABSTRACTLarge intestine dampness-heat syndrome (LIDHS) is a common syndrome type in animal diarrheal diseases. Yujin powder (YJP) is one of the classic prescriptions for treating damp-heat diarrhea. The aim of this study was to investigate the regulatory effects of YJP on gut microbiota and serum metabolism in LIDHS rats using 16S rRNA sequencing and nontargeted metabolomics. The LIDHS rat model was induced through a high-sugar and high-fat diet, exposure to a high-temperature and high-humidity environment, and infection with Escherichia coli. The results demonstrated that the administration of YJP resulted in a decrease in the abundance of Desulfovibrio, Parabacteroides, Bacteroides, Allobaculum, Escherichia, Butyricimonas, Parasutterella, and Blautia and an increase in Ruminococcus, Akkermansia, Roseburia, and Lachnoclostridium. A total of 25 potential biomarkers were identified in three groups of rats. These metabolites were primarily involved in glycerophospholipid metabolism, taurine and hypotaurine metabolism, glycerol ester metabolism, arachidonic acid metabolism, primary bile acid synthesis, and tryptophan metabolism. Our study demonstrated that YJP has the potential to alleviate LIDHS by modulating gut microbial and serum metabolic homeostasis. These results establish a foundation and offer valuable guidance for the utilization of YJP in the treatment of LIDHS.PMID:37605605 | DOI:10.1002/bmc.5719

Cancer Med. 2023 Aug 21. doi: 10.1002/cam4.6446. Online ahead of print.ABSTRACTBACKGROUND: Anti-folate drug pemetrexed is a vital chemotherapy medication for non-small cell lung cancer (NSCLC). Its response varies widely and often develops resistance to the treatment. Therefore, it is urgent to identify biomarkers and establish models for drug efficacy evaluation and prediction for rational drug use.METHODS: A total of 360 subjects were screened and 323 subjects were recruited. Using metabolomics in combination with machine learning methods, we are trying to select potential biomarkers to diagnose NSCLC and evaluate the efficacy of pemetrexed in treating NSCLC. Furtherly, we measured the concentration of eight metabolites in the tryptophan metabolism pathway in the validation set containing 201 subjects using a targeted metabolomics method with UPLC-MS/MS.RESULTS: In the discovery set containing 122 subjects, the metabolic profile of healthy controls (H), newly diagnosed NSCLC patients (ND), patients who responded well to pemetrexed treatment (S) and pemetrexed-resistant patients (R) differed significantly on the PLS-DA scores plot. Pathway analysis showed that glycine, serine and threonine metabolism occurred in every two group comparisons. TCA cycle, pyruvate metabolism and glycerolipid metabolism are the most significantly changed pathways between ND and H group, pyruvate metabolism was the most altered pathway between S and ND group, and tryptophan metabolism was the most changed pathway between S and R group. We found Random forest method had the maximum area under the curve (AUC) and can be easily interpreted. The AUC is 0.981 for diagnosing patients with NSCLC and 0.954 for evaluating pemetrexed efficiency.CONCLUSION: We compared eight mathematical models to evaluate pemetrexed efficiency for treating NSCLC. The Random forest model established with metabolic markers tryptophan, kynurenine and xanthurenic acidcan accurately diagnose NSCLC and evaluate the response of pemetrexed.PMID:37605514 | DOI:10.1002/cam4.6446

Anal Chem. 2023 Aug 21. doi: 10.1021/acs.analchem.3c02073. Online ahead of print.ABSTRACTResistance to clinical therapies remains a major barrier in cancer management. There is a critical need for rapid and highly sensitive diagnostic tools that enable early prediction of treatment response to allow accurate clinical decisions. Here, Raman spectroscopy was employed to monitor changes in key metabolites as early predictors of response in KRAS-mutant colorectal cancer (CRC) cells, HCT116, treated with chemotherapies. We show at the single cell level that HCT116 is resistant to cetuximab (CTX), the first-line treatment in CRC, but this resistance can be overcome with pre-sensitization of cells with oxaliplatin (OX). In combination treatment of CTX + OX, sequential delivery of OX followed by CTX rather than simultaneous administration of drugs was observed to be critical for effective therapy. Our results demonstrated that metabolic changes are well aligned to cellular mechanical changes where Young's modulus decreased after effective treatment, indicating that both changes in mechanical properties and metabolism in cells are likely responsible for cancer proliferation. Raman findings were verified with mass spectrometry (MS) metabolomics, and both platforms showed changes in lipids, nucleic acids, and amino acids as predictors of resistance/response. Finally, key metabolic pathways enriched were identified when cells are resistant to CTX but downregulated with effective treatment. This study highlights that drug-induced metabolic changes both at the single cell level (Raman) and ensemble level (MS) have the potential to identify mechanisms of response to clinical cancer therapies.PMID:37605298 | DOI:10.1021/acs.analchem.3c02073

Nat Metab. 2023 Aug 21. doi: 10.1038/s42255-023-00855-2. Online ahead of print.ABSTRACTT cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.PMID:37605057 | DOI:10.1038/s42255-023-00855-2

Nat Commun. 2023 Aug 21;14(1):5062. doi: 10.1038/s41467-023-40569-3.ABSTRACTWe evaluate the shared genetic regulation of mRNA molecules, proteins and metabolites derived from whole blood from 3029 human donors. We find abundant allelic heterogeneity, where multiple variants regulate a particular molecular phenotype, and pleiotropy, where a single variant associates with multiple molecular phenotypes over multiple genomic regions. The highest proportion of share genetic regulation is detected between gene expression and proteins (66.6%), with a further median shared genetic associations across 49 different tissues of 78.3% and 62.4% between plasma proteins and gene expression. We represent the genetic and molecular associations in networks including 2828 known GWAS variants, showing that GWAS variants are more often connected to gene expression in trans than other molecular phenotypes in the network. Our work provides a roadmap to understanding molecular networks and deriving the underlying mechanism of action of GWAS variants using different molecular phenotypes in an accessible tissue.PMID:37604891 | DOI:10.1038/s41467-023-40569-3

Sci Rep. 2023 Aug 21;13(1):13564. doi: 10.1038/s41598-023-40560-4.ABSTRACTOxidative stress (OS), which impacts lipid metabolic reprogramming, can affect the biological activities of cancer cells. How oxidative stress and phospholipid metabolism (OSPM) influence the prognosis of pancreatic cancer (PC) needs to be elucidated. The metabolic data of 35 pancreatic tumor samples, 34 para-carcinoma samples, and 31 normal pancreatic tissues were obtained from the previously published literature. Pan-cancer samples were obtained from The Cancer Genome Atlas (TCGA). And the Gene Expression Omnibus (GEO), International Cancer Genome Consortium (ICGC), ArrayExpress, and the Genotype-Tissue Expression (GTEx) databases were searched for more PC and normal pancreatic samples. The metabolites in PC were compared with normal and para-carcinoma tissues. The characteristics of the key OSPM genes were summarized in pan-cancer. The random survival forest analysis and multivariate Cox regression analysis were utilized to construct an OSPM-related signature. Based on this signature, PC samples were divided into high- and low-risk subgroups. The dysregulations of the tumor immune microenvironment were further investigated. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was conducted to investigate the expression of genes in the signature in PC and normal tissues. The protein levels of these genes were further demonstrated. In PC, metabolomic studies revealed the alteration of PM, while transcriptomic studies showed different expressions of OSPM-related genes. Then 930 PC samples were divided into three subtypes with different prognoses, and an OSPM-related signature including eight OSPM-related genes (i.e., SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, ECT2, SLC22A3, and FGD6) was developed. High- and low-risk subgroups divided by the signature showed different prognoses, expression levels of immune checkpoint genes, immune cell infiltration, and tumor microenvironment. The risk score was negatively correlated with the proportion of TIL, pDC, Mast cell, and T cell co-stimulation. The expression levels of genes in the signature were verified in PC and normal samples. The protein levels of SLC2A1, MMP14, TOP2A, MBOAT2, ANLN, and SLC22A3 showed up-regulation in PC samples compared with normal tissues. After integrating metabolomics and transcriptomics data, the alterations in OSPM in PC were investigated, and an OSPM-related signature was developed, which was helpful for the prognostic assessment and individualized treatment for PC.PMID:37604837 | DOI:10.1038/s41598-023-40560-4

Anal Chim Acta. 2023 Oct 9;1277:341655. doi: 10.1016/j.aca.2023.341655. Epub 2023 Jul 26.ABSTRACTAlthough various metabolomic methods have been reported in recent years, simultaneous detection of hydrophilic and hydrophobic metabolites in a single analysis remains a technical challenge. In this study, based on the combination of hydrophilic interaction liquid chromatography (HILIC) and reversed phase liquid chromatography (RPLC), an online two-dimensional liquid chromatography/triple quadrupole mass spectrometry method (2D-LC/TQMS) was developed for the simultaneous analysis of hydrophilic and hydrophobic metabolites of various biological samples. The method can measure 417 biologically important metabolites (e.g., amino acids and peptides, pyrimidines, purines, monosaccharides, fatty acids and conjugates, organic dicarboxylic acids, and others) with logP values ranging from -10.3 to 21.9. The metabolites are involved in a variety of metabolic pathways (e.g., purine metabolism, pyrimidine metabolism, tyrosine metabolism, galactose metabolism, gluconeogenesis, and TCA cycle). The developed method has good intra- and inter-day reproducibility (RSD of retention time <2%, RSD of peak area <30%), good linearity (R2 > 0.9) and wide linear range (from 0.0025 μg/mL to 5 μg/mL). The applicability of the method was tested using different biological samples (i.e., plasma, serum, urine, fecal, seminal plasma and liver) and it was found that 208 (out of 417) identical metabolites were detected in all biological samples. Furthermore, the metabolomic method was applied to a case/control study of urinary of bladder cancer. Thirty differential metabolites were identified that were involved in carbohydrate and amino acid metabolism.PMID:37604610 | DOI:10.1016/j.aca.2023.341655