Global perspectives on bipolar disorder treatment: in-depth comparative analysis of international guidelines for medication selection.

BACKGROUND: Bipolar disorder, a chronic mental health condition characterised by fluctuations in mood, energy and functionality, affects millions of individuals worldwide. Its management requires a comprehensive approach, and, as such, treatment guidelines have a pivotal role in guiding clinicians to alleviate symptoms, prevent relapse and enhance overall patient well-being. However, the treatment landscape is far from homogenous, with significant variations existing across different countries. AIMS: This study aimed to explore and compare treatment guidelines for bipolar disorder in various regions, shedding light on the factors that influence therapeutic approaches and thus offering insights that could contribute to the ongoing refinement of evidence-based practices in management. METHOD: The study explores various international treatment guidelines for bipolar disorder that have been updated after 2014. Guidelines from the UK, Canada, Australia/New Zealand, South Korea and the International College of Neuropsychopharmacology are scrutinised to identify factors contributing to the observed differences among them. RESULTS: The variations in recommended drugs across guidelines arise from the approaches employed in guideline development - whether relying on expert consensus or meta-analysis results. Timing disparities in conducting these analyses and the selection of studies also exert influence. Moreover, differences in metabolic enzymes among diverse races and the health policies implemented by individual nations play a significant part in shaping these differences. CONCLUSION: The primary hindrance to consistent treatment conclusions lies in the scarcity of high-quality research results, leading to variations in guidelines. Enhancing evidence-based recommendations necessitates the undertaking of large-scale studies dedicated to assessing treatments for bipolar disorder.

The effects of dietary self-monitoring intervention on anthropometric and metabolic changes via a mobile application or paper-based diary: a randomized trial.

BACKGROUND/OBJECTIVES: Weight loss via a mobile application (App) or a paper-based diary (Paper) may confer favorable metabolic and anthropometric changes. SUBJECTS/METHODS: A randomized parallel trial was conducted among 57 adults whose body mass indices (BMIs) were 25 kg/m2 or greater. Participants randomly assigned to either the App group (n = 30) or the Paper group (n = 27) were advised to record their foods and supplements through App or Paper during the 12-week intervention period. Relative changes of anthropometries and biomarker levels were compared between the 2 intervention groups. Untargeted metabolic profiling was identified to discriminate metabolic profiles. RESULTS: Out of the 57 participants, 54 participants completed the trial. Changes in body weight and BMI were not significantly different between the 2 groups (P = 0.11). However, body fat and low-density lipoprotein (LDL)-cholesterol levels increased in the App group but decreased in the Paper group, and the difference was statistically significant (P = 0.03 for body fat and 0.02 for LDL-cholesterol). In the metabolomics analysis, decreases in methylglyoxal and (S)-malate in pyruvate metabolism and phosphatidylcholine (lecithin) in linoleic acid metabolism from pre- to post-intervention were observed in the Paper group. CONCLUSIONS: In the 12-week randomized parallel trial of weight loss through a App or a Paper, we found no significant difference in change in BMI or weight between the App and Paper groups, but improvement in body fatness and LDL-cholesterol levels only in the Paper group under the circumstances with minimal contact by dietitians or health care providers. Trial Registration: Clinical Research Information Service Identifier: KCT0004226.

Identification of Novel Biomarkers for Early Diagnosis of Atherosclerosis Using High-Resolution Metabolomics.

Atherosclerosis (AS) is a metabolic disorder and the pre-stage of several cardiovascular diseases, including myocardial infarction, stroke, and angina pectoris. Early detection of AS can provide the opportunity for effective management and better clinical results, along with the prevention of further progression of the disease. In the current study, an untargeted and targeted metabolomic approach was used to identify possible metabolic signatures that have altered levels in AS patients. A total of 200 serum samples from individuals with AS and normal were analyzed via liquid chromatography-high-resolution mass spectrometry. Univariate and multivariate analysis approaches were used to identify differential metabolites. A group of metabolites associated with bile acids, amino acids, steroid hormones, and purine metabolism were identified that are capable of distinguishing AS-risk sera from normal. Further, the targeted metabolomics approach confirmed that six metabolites, namely taurocholic acid, cholic acid, cortisol, hypoxanthine, trimethylamine N-oxide (TMAO), and isoleucine, were found to be significantly upregulated, while the concentrations of glycoursodeoxycholic acid, glycocholic acid, testosterone, leucine, methionine, phenylalanine, tyrosine, and valine were found to be significantly downregulated in the AS-risk sera. The receiver operating characteristic curves of three metabolites, including cortisol, hypoxanthine, and isoleucine, showed high sensitivity and specificity. Taken together, these findings suggest cortisol, hypoxanthine, and isoleucine as novel biomarkers for the early and non-invasive detection of AS. Thus, this study provides new insights for further investigations into the prevention and management of AS.

Microbiota dysbiosis associated with type 2 diabetes-like effects caused by chronic exposure to a mixture of chlorinated persistent organic pollutants in zebrafish.

Mixtures of chlorinated persistent organic pollutants (C-POPs-Mix) are chemically related risk factors for type 2 diabetes mellitus (T2DM); however, the effects of chronic exposure to C-POPs-Mix on microbial dysbiosis remain poorly understood. Herein, male and female zebrafish were exposed to C-POPs-Mix at a 1:1 ratio of five organochlorine pesticides and Aroclor 1254 at concentrations of 0.02, 0.1, and 0.5 µg/L for 12 weeks. We measured T2DM indicators in blood and profiled microbial abundance and richness in the gut as well as transcriptomic and metabolomic alterations in the liver. Exposure to C-POPs-Mix significantly increased blood glucose levels while decreasing the abundance and alpha diversity of microbial communities only in females at concentrations of 0.02 and 0.1 µg/L. The majorly identified microbial contributors to microbial dysbiosis were Bosea minatitlanensis, Rhizobium tibeticum, Bifidobacterium catenulatum, Bifidobacterium adolescentis, and Collinsella aerofaciens. PICRUSt results suggested that altered pathways were associated with glucose and lipid production and inflammation, which are linked to changes in the transcriptome and metabolome of the zebrafish liver. Metagenomics outcomes revealed close relationships between intestinal and liver disruptions to T2DM-related molecular pathways. Thus, microbial dysbiosis in T2DM-triggered zebrafish occurred as a result of chronic exposure to C-POPs-Mix, indicating strong host-microbiome interactions.

Advanced assessment through intact glycopeptide analysis of Infliximab's biologics and biosimilar.

Characterization of therapeutic monoclonal antibodies (mAbs) represents a major challenge for analytical sciences due to their heterogeneity associated with post-translational modifications (PTMs). The protein glycosylation requires comprehensive identification, which could influence on the mAbs' structure and their function. Here, we demonstrated high-resolution tandem mass spectrometry with an ultra-high-performance liquid chromatography for characterization and comparison between biologics and biosimilar of infliximab at an advanced level. Comparing the N- and O-glycopeptides profiles, a total of 49 and 54 glycopeptides was identified for each product of the biologics and biosimilar, respectively. We also discovered one novel N-glycosylation site at the light chain from both biopharmaceuticals and one novel O-glycopeptide at the heavy chain from only biosimilar. Site-specific glycopeptide analysis process will be a robust and useful technique for evaluating therapeutic mAbs and complex glycoprotein products.

Transcriptome-metabolome-wide association study (TMWAS) in rats revealed a potential carcinogenic effect of DEHP in thyroid associated with eicosanoids.

The incidence of thyroid cancer (TC) has increased considerably in the last few decades. Environmental factors, including plasticizers, are recognized as potential risks leading to thyroid cancer in humans. In this study, we used a transcriptome-metabolome-wide association study to find the unidentified carcinogenic mechanism of di-2-ethylhexyl phthalate (DEHP) in thyroid and biomarkers for non-invasive diagnosis. Rats were treated with different doses of DEHP (0, 0.3, 3, 30, 150 mg DEHP/kg bw/day) for 13 weeks. Then, the thyroids were processed for Ki67 staining and RNA-seq. Also, 17-h urine samples were collected for high-resolution metabolomics analysis. After a high dose of DEHP exposure, the terminal body weights and the thyroid and parathyroid glands weights were not altered. However, the liver weights and numbers of Ki67-positive cells were increased. Further, multivariate statistical analysis revealed that metabolic shifts were considerably altered above 30 mg DEHP/kg bw/day. In RNA-seq analysis, some cancer-related genes were altered, including 18 upregulated and 9 downregulated transcripts. These cancer transcripts and whole metabolome data were integrated to uncover thyroid cancer-related metabolic pathways, which revealed that cancer-related transcripts had a network structure linked to eicosanoids such as leukotriene D4 and prostaglandin. In brief, our study demonstrated that DEHP can induce thyroid hyperplasia through the eicosanoid-associated pathway, providing further insight into the mechanism of DEHP-associated thyroid cancer.

Comparison of protein characterization using In solution and S-Trap digestion methods for proteomics.

Protein extraction and digestion are important analytical steps in the study of proteomics. The use of sodium dodecyl sulfate (SDS) buffer makes it possible to effectively analyze various proteins. Its use was evaluated using the S-Trap digestion method and compared to the traditional In solution digestion method. Differences in protein composition were examined for each protein preparation method. S-Trap digestion followed by SDS buffer extraction clearly increased the number of identified proteins, including more mitochondrial and membrane-related proteins. The S-Trap digestion method with 5% SDS buffer was applied to the pellet remaining from the removal of RIPA buffer-soluble proteins, which identified more extracellular space proteins than the conventional S-Trap digestion method. S-Trap digestion of the pellet was particularly advantageous for identifying proteins located inside multilayer membranes.

Nonmonotonic response of type 2 diabetes by low concentration organochlorine pesticide mixture: Findings from multi-omics in zebrafish.

Exposure to a single organochlorine pesticide (OCP) at high concentration and over a short period of exposure constrain our understanding of the contribution of chemical exposure to type 2 diabetes (T2D). A total of 450 male and female zebrafish was exposed to mixtures of five OCPs at 0, 0.05, 0.25, 2.5, and 25 µg/L for 12 weeks. T2D-related hematological parameters (i.e., glucose, insulin, free fatty acid, and triglycerides) and mitochondrial complex I to IV activities were assessed. Metabolomics, proteomics, and transcriptomics were analyzed in female livers, and their data-driven integration was performed. High fasting glucose and low insulin levels were observed only at 0.05 µg/L of the OCP mixture in females, indicating a nonlinear and sexually dependent response. We found that exposure to the OCP mixture inhibited the activities of mitochondrial complexes, especially III and IV. Combining individual and integrated omics analysis, T2D-linked metabolic pathways that regulate mitochondrial function, insulin signaling, and energy homeostasis were altered by the OCP mixture, which explains the observed phenotypic hematological effects. We demonstrated the cause-and-effect relationship between exposures to OCP mixture and T2D using zebrafish model. This study gives an insight into mechanistic research of metabolic diseases caused by chemical exposure using zebrafish.

An in vitro study on the differentiated metabolic mechanism of chloroquine-resistant Plasmodium falciparum using high-resolution metabolomics.

Chloroquine (CQ) is an important drug used therapeutically for treatment of malaria. However, due to limited number of studies on metabolic targets of chloroquine (CQ), it is difficult to attribute mechanisms underlying resistance associated with usage of this drug. The present study aimed to investigate the metabolic signatures of CQ-resistant Plasmodium falciparum (PfDd2) compared to CQ-sensitive Plasmodium falciparum (Pf3D7). Both Pf3D7 and PfDd2 were treated with CQ at 200 nM for 48 hr; thereafter, the harvested red blood cells (RBCs) and media were subjected to microscopy and high-resolution metabolomics (HRM). Glutathione, γ-L-glutamyl-L-cysteine, spermidine, inosine monophosphate, alanine, and fructose-1,6-bisphosphate were markedly altered in PfDd2 of RBC. In the media, cysteine, cysteic acid, spermidine, phenylacetaldehyde, and phenylacetic acid were significantly altered in PfDd2. These differential metabolic signatures related signaling pathways of PfDd2, such as oxidative stress pathway and glycolysis may provide evidence for understanding the resistance mechanism and pathogenesis of the CQ-resistant parasite.

The Efficacy of Pilates on Urinary Incontinence in Korean Women: A Metabolomics Approach.

Pilates has been known as exercise intervention that improves the function of pelvic floor muscle (PFM) associated with impacting urinary incontinence (UI). This study investigated the effect of Pilates on UI in Korean women by determining the change in functional movement of PFM (FMP) and metabolic profiles. UI group with Pilates (UIP, n = 13) participated in 8-weeks Oov Pilates program, and 8 subjects were assigned to Control and UI group with no Pilates (UINP), respectively. Before and after 8 weeks, plasma samples were collected from all participants, and ultrasonography was used to measure the functional change of PFM for calculating FMP ratio. Plasma samples were analyzed by mass spectrometry to identify the change of metabolic features. After 8-weeks intervention, FMP ratio was remarkably decreased in UIP (48.1% ↓, p < 0.001), but not in Control and UINP (p > 0.05). In metabolic features, L-Glutamine (m/z: 147.07 [M + H]+), L-Cystathionine (m/z: 240.09 [M + NH4]+), L-Arginine (m/z: 197.1 [M + Na]+), and L-1-Pyrroline-3-hydroxy-5-carboxylate (m/z: 147.07 [M + NH4]+) were significantly elevated solely in UIP (p < 0.001). Our study elucidated that Pilates can ameliorate the FMP and enhance the specific metabolic characteristics, which was potentially associated with invigorated PFM contractility to effectively control the bladder base and continence.

Treadmill Exercise Improves Motor Function and Short-term Memory by Enhancing Synaptic Plasticity and Neurogenesis in Photothrombotic Stroke Mice.

PURPOSE: Thrombotic stroke is a type of ischemic stroke characterized by motor dysfunction and memory impairments. In the present study, the effect of treadmill exercise on motor function and short-term memory was evaluated in relation with synaptic plasticity in the mice with photothrombotic stroke. METHODS: Photothrombotic stroke was induced by cortical photothrombotic vascular occlusion. The mice in the treadmill exercise groups performed running on a motorized treadmill for 28 days. Motor function was determined using rota-rod test and foot fault test. Step-through avoidance task was conducted to evaluate short-term memory. Immunohistochemistry for 5-bromo-2'-deoxyuridine and doublecortin was conducted to detect new cell generation. Postsynaptic density protein 95, synaptophysin, brain-derived neurotrophic factor (BDNF), and tyrosine kinase B receptor (TrkB) were determined using western blot. The number of dendritic spines was determined using Golgi stain. RESULTS: Treadmill exercise improved motor function and short-term memory in mice with the photothrombotic stroke. The infarct size was reduced and the number of dendritic spines and expression of postsynaptic density protein 95 and synaptophysin in the peri-infarct cortex and hippocampus were increased by treadmill exercise in photothrombotic stroke mice. Treadmill exercise enhanced neurogenesis through increasing the expression of the hippocampal BDNF and TrkB in photothrombotic stroke mice. CONCLUSION: Treadmill exercise improved motor function and short-term memory through increasing synaptic plasticity and neurogenesis in photothrombotic stroke mice. Treadmill exercise can be used as an effective treatment strategy to improve brain function related to stroke.

Global metabolomics analysis of serum from humans at risk of thrombotic stroke.

We aimed to determine the serum concentrations of altered compounds to understand the changes in metabolism and pathophysiology that occur prior to thrombotic stroke. In this prospective cohort study, high-resolution metabolomics (HRM) was employed to analyze serum samples obtained from patients at risk of stroke (n = 99) and non-risk controls (n = 301). Partial least-squares discriminant analysis (PLS-DA), along with univariate analysis using a false discovery rate (FDR) of q = 0.05 were employed to identify the discriminant metabolic profiles and to determine significantly different metabolites between healthy control and stroke risk groups. PLS-DA satisfactorily separated the stroke risk sera from control sera. Additionally, these discriminant metabolic profiles were not related to hypertension, smoking, diabetes mellitus, or insulin sensitivity. A group of 35 metabolites, most of them amino acids, that were capable of discriminating stroke risk sera from controls were identified using untargeted metabolomics. Further, the targeted metabolomics approach confirmed that the quantified concentrations of l-tryptophan, 3-methoxytyramine, methionine, homocysteinesulfinic acid, cysteine, isoleucine, carnitine, arginine, linoleic acid, and sphingosine were specifically elevated in the sera of patients who were later diagnosed with stroke. Our untargeted and targeted metabolomics approaches support investigating these compounds as novel biomarkers for early and non-invasive detection of thrombotic stroke.

High-resolution metabolomics study revealing l-homocysteine sulfinic acid, cysteic acid, and carnitine as novel biomarkers for high acute myocardial infarction risk.

BACKGROUND: Identifying changes in serum metabolites before the occurrence of acute myocardial infarction (AMI) is an important approach for finding novel biomarkers of AMI. METHODS: In this prospective cohort study, serum samples obtained from patients at risk of AMI (n = 112) and non-risk controls (n = 89) were tested using high-resolution metabolomics (HRM). Partial least-squares discriminant analysis (PLS-DA), along with univariate analysis using a false discovery rate (FDR) of q = 0.05 were performed to discriminate metabolic profiles and to determine significantly different metabolites between healthy control and AMI risk groups. RESULTS: PLS-DA significantly separated the AMI risk sera from control sera. The metabolites associated with amino acid biosynthesis, 2-oxocarboxylic acid, tryptophan, and amino sugar and nucleotide sugar metabolism pathways were mainly elevated in patients at risk of AMI. Further validation and quantification by MS/MS showed that tryptophan, carnitine, L-homocysteine sulfinic acid (L-HCSA), and cysteic acid (CA) were upregulated, while L-cysteine and L-cysteine sulfinic acid (L-CSA) were downregulated, specifically among AMI risk sera. Additionally, these discriminant metabolic profiles were not related to hypertension, smoking or alcoholism. CONCLUSION: In conclusion, detecting upregulated L-HCSA and CA along with carnitine among patients at risk for AMI could serve as promising non-invasive biomarkers for early AMI detection.

Discovery of metabolic alterations in the serum of patients infected with Plasmodium spp. by high-resolution metabolomics.

INTRODUCTION: Despite the advances in diagnosis and treatment, malaria has still not been eradicated. Metabolic interactions between the host and Plasmodium may present novel targets for malaria control, but such interactions are yet to be deciphered. An exploration of metabolic interactions between humans and two Plasmodium species by high-resolution metabolomics may provide fundamental insights that can aid the development of a new strategy for the control of malaria. OBJECTIVES: This study aimed at exploring the metabolic changes in the sera of patients infected with Plasmodium falciparum and Plasmodium vivax. METHODS: Uni- and multivariate metabolomic analyses were performed on the sera of four groups of patients, namely normal control (N, n = 100), P. falciparum-infected patients (PF, n = 21), P. vivax-infected patients (PV, n = 74), and non-malarial pyretic patients (Pyr, n = 25). RESULTS: Univariate and multivariate analyses of N, PF, and PV groups showed differential metabolic phenotypes and subsequent comparisons in pairs revealed significant features. Pathway enrichment test with significant features showed the affected pathways, namely glycolysis/gluconeogenesis for PF and retinol metabolism for PV. The metabolites belonging to the affected pathways included significantly low 2,3-diphosphoglycerate and glyceraldehyde-3-phosphate in the sera of PF. The sera of PV had significantly low levels of retinol but high levels of retinoic acid. CONCLUSION: Our study reveals metabolic alterations induced by Plasmodium spp. in human serum and would serve as a milestone in the development of novel anti-malarial strategies.

Effect of developmental exposure to bisphenol A on steroid hormone and vitamin D3 metabolism.

High exposure to bisphenol A (BPA) in children has been associated with the outcomes of several diseases, including those related to developmental problems. To elucidate the mechanism of BPA mediated developmental toxicity, plasma and urine from rats exposed to BPA was analyzed with high resolution metabolomics, beginning from post-natal day 9, for 91 days. Female and male rats were orally administered 5 different BPA doses to elucidate dose- and sex-specific BPA effects. Regarding dose-specific effects, multivariate statistical analysis showed that metabolic shifts were considerably altered between 5, 50 and 250 mg BPA/kg bw/day in treated rats. A nonmonotonicity and monotonicity between BPA dose and metabolic response were major trajectories, showing overall metabolic changes in plasma and urine, respectively. Metabolic perturbation in the steroid hormone biosynthesis pathway was significantly associated with dose- and sex-specific BPA effects. Intermediate metabolites in the rate-limiting step of steroid hormone biosynthesis down-regulated steroid hormones in the 250 mg treatment. Further, our study identified that BPA increased urinary excretion of vitamin D3 and decreased its concentration in blood, suggesting that perturbation of vitamin D3 metabolism may be mechanistically associated with neurodevelopmental disorders caused by BPA. Three metabolites showed a decrease in sex difference with high BPA dose because female rats were more affected than males, which can be related with early puberty onset in female. In brief, the results demonstrated that BPA induces dose- and sex-specific metabolic shifts and that perturbation of metabolism can explain developmental problems.

Metabolite tracking to elucidate the effects of environmental pollutants.

The purpose of this study was to determine whether behavioral tests and metabolic profiling of organisms can be promising alternatives for assessing the health of aquatic systems. Water samples from four potential pollution sources in South Korea were collected for toxicity evaluation. First, conventional acute toxicity test in Daphnia magna and behavioral test in zebrafish was conducted to assess water quality. Second, metabolomic analysis was performed on zebrafish exposed to water samples and on environmental fish collected from the same source. Acute toxicity test in D. magna showed that none of the water samples exerted significant adverse effects. However, activity of zebrafish larvae exposed to samples from the zinc smelter (ZS) and industrial complex (IND) sites decreased compared to those exposed to samples from the reference site (RS). Metabolomic analysis using the Manhattan plot and Partial Least Square (PLS)/Orthogonal PLS Discriminant Analysis (OPLS-DA) showed differences in metabolic profiles between RS and ZS, and between IND and abandoned mine site (M). Interestingly, applying the same metabolomic analysis to environmental fish revealed patterns similar to those for zebrafish, despite the uncontrollable variables involved in environmental sampling. This study shows that metabolomics is a promising tool in assessing the health of aquatic environments.

Incidence and Risk Factors for Venous Thromboembolism After Spine Surgery in Korean Patients.

BACKGROUND: Data regarding the incidence of venous thromboembolism (VTE) after spine surgery are scarce. Identifying ideal candidates for pharmacologic thromboprophylaxis and balancing the risk of thromboembolic complications against the risk of permanent neurologic deficits from a spinal epidural hematoma (SEH) are difficult. Even guidelines cannot suggest the standard of thromboprophylaxis. OBJECTIVES: This study aimed to identify the incidence of and risk factors for VTE after spine surgery in the Korean population. In addition, the rate of pharmacoprophylaxis and the incidence of SEH after spine surgery were analyzed. METHODS: The study cohort was generated by extracting patients with disease codes of spine surgery and VTE from the Health Insurance Review & Assessment Service National Inpatient Sample in 2014. After analyzing the incidence of VTE after spine surgery, a univariate comparison was performed to examine the possible relationship between the incidence of VTE and the independent variable. Variables found to be significant were included in a multivariable analysis model for further analysis. RESULTS: The incidence of VTE was 2.09% among all 21,261 patients who had spine surgery, and prophylaxis was applied to 7.89% of all patients who had spine surgery. Comorbidities and surgery-related risk factors were venous disease, cancer, respiratory disease, prolonged surgery hours, and increased total blood loss. Hospital-related risk factors were the location and hospital size. CONCLUSIONS: On the basis of the incidence of VTE and the risk factors, more active prophylaxis is suggested for patients in the Korean population who undergo spine surgery.

A Systems Vaccinology Approach Reveals the Mechanisms of Immunogenic Responses to Hantavax Vaccination in Humans.

Hantavax is an inactivated vaccine for hemorrhagic fever with renal syndrome (HFRS). The immunogenic responses have not been elucidated yet. Here we conducted a cohort study in which 20 healthy subjects were administered four doses of Hantavax during 13-months period. Pre- and post- vaccinated peripheral blood mononuclear cells (PBMCs) and sera were analysed by transcriptomic and metabolomic profilings, respectively. Based on neutralizing antibody titers, subjects were subsequently classified into three groups; non responders (NRs), low responders (LRs) and high responders (HRs). Post vaccination differentially expressed genes (DEGs) associated with innate immunity and cytokine pathways were highly upregulated. DEG analysis revealed a significant induction of CD69 expression in the HRs. High resolution metabolomics (HRM) analysis showed that correlated to the antibody response, cholesteryl nitrolinoleate, octanoyl-carnitine, tyrosine, ubiquinone-9, and benzoate were significantly elevated in HRs, while chenodeoxycholic acid and methyl palmitate were upregulated in NRs and LRs, compared with HRs. Additionally, gene-metabolite interaction revealed upregulated gene-metabolite couplings in, folate biosynthesis, nicotinate and nicotinamide, arachidonic acid, thiamine and pyrimidine metabolism in a dose dependent manner in HR group. Collectively, our data provide new insight into the underlying mechanisms of the Hantavax-mediated immunogenicity in humans.

A biplot correlation range for group-wise metabolite selection in mass spectrometry.

BACKGROUND: Analytic methods are available to acquire extensive metabolic information in a cost-effective manner for personalized medicine, yet disease risk and diagnosis mostly rely upon individual biomarkers based on statistical principles of false discovery rate and correlation. Due to functional redundancies and multiple layers of regulation in complex biologic systems, individual biomarkers, while useful, are inherently limited in disease characterization. Data reduction and discriminant analysis tools such as principal component analysis (PCA), partial least squares (PLS), or orthogonal PLS (O-PLS) provide approaches to separate the metabolic phenotypes, but do not offer a statistical basis for selection of group-wise metabolites as contributors to metabolic phenotypes. METHODS: We present a dimensionality-reduction based approach termed 'biplot correlation range (BCR)' that uses biplot correlation analysis with direct orthogonal signal correction and PLS to provide the group-wise selection of metabolic markers contributing to metabolic phenotypes. RESULTS: Using a simulated multiple-layer system that often arises in complex biologic systems, we show the feasibility and superiority of the proposed approach in comparison of existing approaches based on false discovery rate and correlation. To demonstrate the proposed method in a real-life dataset, we used LC-MS based metabolomics to determine spectrum of metabolites present in liver mitochondria from wild-type (WT) mice and thioredoxin-2 transgenic (TG) mice. We select discriminatory variables in terms of increased score in the direction of class identity using BCR. The results show that BCR provides means to identify metabolites contributing to class separation in a manner that a statistical method by false discovery rate or statistical total correlation spectroscopy can hardly find in complex data analysis for predictive health and personalized medicine.

Noninvasive Serum Metabolomic Profiling Reveals Elevated Kynurenine Pathway's Metabolites in Humans with Prostate Cancer.

This study aimed to apply high-resolution metabolomics to detect compounds that may contribute significantly to prostate cancer (PCa) development. The test population's sera for evaluating the metabolic differences consisted of healthy control ( n = 96) and PCa ( n = 50) groups. PCa patients were further divided into two groups based on whether their PSA level was >4 ( n = 25) or <4 ( n = 25). Univariate analysis was performed with the false discovery rate (FDR) at q = 0.05 to determine significantly different metabolites. Principal component analysis (PCA) and hierarchical clustering analysis (HCA) clearly distinguished healthy subjects from PCa groups, while no significant difference was observed in PCa patients with PSA level < 4 or > 4. Mummichog, in combination with the KEGG and MetaboAnalyst, showed that tryptophan metabolism along the kynurenine pathway was most significantly enriched, with -log ( p) < 0.05. l-Tryptophan, kynurenine, anthranilate, isophenoxazine, glutaryl-CoA, ( S)-3-hydroxybutanoyl-CoA, acetoacetyl-CoA, and acetyl-CoA were upregulated in correlation with the PSA level of PCa patients; in contrast, indoxyl, indolelactate, and indole-3-ethanol, involved in the alternative pathway, were downregulated in the PCa patients. Validation and quantification of potential metabolites by MS/MS further confirmed the disruption of tryptophan, kynurenine, and anthranilate, suggesting that the metabolites of this pathway are potential biomarkers in patients with PCa.