Publications by authors named "Caroline H Johnson"

66 Publications

ENT2 facilitates brain endothelial cell penetration and blood-brain barrier transport by a tumor-targeting anti-DNA autoantibody.

JCI Insight 2021 Jun 15. Epub 2021 Jun 15.

Department of Therapeutic Radiology, Yale School of Medicine, New Haven, United States of America.

The blood-brain barrier (BBB) prevents antibodies from penetrating the CNS and limits conventional antibody-based approaches to brain tumors. We now show that ENT2, a transporter that regulates nucleoside flux at the BBB, may offer an unexpected path to circumventing this barrier to allow targeting of brain tumors with an anti-DNA autoantibody. Deoxymab-1 (DX1) is a DNA-damaging autoantibody that localizes to tumors and is synthetically lethal to cancer cells with defects in the DNA damage response. We find DX1 penetrates brain endothelial cells and crosses the BBB, and mechanistic studies identify ENT2 as the key transporter. In efficacy studies DX1 crosses the BBB to suppress orthotopic glioblastoma and breast cancer brain metastases. ENT2-linked transport of autoantibodies across the BBB has potential to be exploited in brain tumor immunotherapy, and its discovery raises new hypotheses on actionable mechanisms of CNS penetration by neurotoxic autoantibodies in CNS lupus.
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http://dx.doi.org/10.1172/jci.insight.145875DOI Listing
June 2021

Intratumour microbiome associated with the infiltration of cytotoxic CD8+ T cells and patient survival in cutaneous melanoma.

Eur J Cancer 2021 Jul 4;151:25-34. Epub 2021 May 4.

Department of Chronic Disease Epidemiology, Yale School of Public Health, School of Medicine, Yale Cancer Center, Yale University, New Haven, CT, USA. Electronic address:

Objective: The gut microbiome plays an important role in systemic inflammation and immune response. Microbes can translocate and reside in tumour niches. However, it is unclear how the intratumour microbiome affects immunity in human cancer. The purpose of this study was to investigate the association between intratumour bacteria, infiltrating CD8+ T cells and patient survival in cutaneous melanoma.

Methods: Using The Cancer Genome Altas's cutaneous melanoma RNA sequencing data, levels of intratumour bacteria and infiltrating CD8+ T cells were determined. Correlation between intratumour bacteria and infiltrating CD8+ T cells or chemokine gene expression and survival analysis of infiltrating CD8+ T cells and Lachnoclostridium in cutaneous melanoma were performed.

Results: Patients with low levels of CD8+ T cells have significantly shorter survival than those with high levels. The adjusted hazard ratio was 1.57 (low vs high) (95% confidence interval: 1.17-2.10, p = 0.002). Intratumour bacteria of the Lachnoclostridium genus ranked top in a positive association with infiltrating CD8+ T cells (correlation coefficient = 0.38, p = 9.4 × 10), followed by Gelidibacter (0.31, p = 1.13 × 10), Flammeovirga (0.29, p = 1.96 × 10) and Acinetobacter (0.28, p = 8.94 × 10). These intratumour genera positively correlated with chemokine CXCL9, CXCL10 and CCL5 expression. The high Lachnoclostridium load significantly reduced the mortality risk (p = 0.0003). However, no statistically significant correlation was observed between intratumour Lachnoclostridium abundance and the levels of either NK, B or CD4+ T cells.

Conclusion: Intratumour-residing gut microbiota could modulate chemokine levels and affect CD8+ T-cell infiltration, consequently influencing patient survival in cutaneous melanoma. Manipulating the intratumour gut microbiome may benefit patient outcomes for those undergoing immunotherapy.
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http://dx.doi.org/10.1016/j.ejca.2021.03.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184628PMC
July 2021

Identification of dose-dependent DNA damage and repair responses from subchronic exposure to 1,4-dioxane in mice using a systems analysis approach.

Toxicol Sci 2021 Mar 10. Epub 2021 Mar 10.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, 06250, USA.

1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, female BDF-1 mice were exposed to 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks, to explore the toxic effects. Histopathological studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Immunohistochemical analysis of the liver revealed increased H2AXγ-positive hepatocytes (a marker of DNA double strand breaks), and an expansion of precholangiocytes (reflecting both DNA damage and repair mechanisms) after exposure. Liver transcriptomics revealed 1,4-DX-induced perturbations in signaling pathways predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, feces and urine metabolomic profiling revealed no effect of 1,4-DX exposure, and bile acid quantification in liver and feces similarly showed no effect of exposure. We speculate that the results may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death but have activated the repair systems in response to 1,4-DX exposure.
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http://dx.doi.org/10.1093/toxsci/kfab030DOI Listing
March 2021

Use of Untargeted Metabolomics to Explore the Air Pollution-Related Disease Continuum.

Curr Environ Health Rep 2021 03 9;8(1):7-22. Epub 2021 Jan 9.

Department of Surgery, School of Medicine, Yale University, New Haven, USA.

Purpose Of Review: The purpose of this review is to summarize the application of untargeted metabolomics to identify the perturbation of metabolites or metabolic pathways associated with air pollutant exposures.

Recent Findings: Twenty-three studies were included in this review, in adults, children, or pregnant women. The most commonly measured air pollutant is particulate matter smaller than 2.5 μm. Size-fractioned particles, particle chemical species, gas pollutants, or organic compounds were also investigated. The reviewed studies used a wide range of air pollution measurement techniques and metabolomics analyses. Identified metabolites were primarily related to oxidative stress and inflammatory responses, and a few were related to the alterations of steroid metabolic pathways. The observed metabolic perturbations can differ by disease status, sex, and age. Air pollution-related metabolic changes were also associated with health outcomes in some studies. Our review shows that air pollutant exposures are associated with metabolic pathways primarily related to oxidative stress, inflammation, as assessed through untargeted metabolomics in 23 studies. More metabolomic studies with larger sample sizes are needed to identify air pollution components most responsible for adverse health effects, elaborate on mechanisms for subpopulation susceptibility, and link air pollution exposure to specific adverse health effects.
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http://dx.doi.org/10.1007/s40572-020-00298-xDOI Listing
March 2021

Gene Alterations of N6-Methyladenosine (mA) Regulators in Colorectal Cancer: A TCGA Database Study.

Biomed Res Int 2020 19;2020:8826456. Epub 2020 Dec 19.

Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT 06520-8034, USA.

N6-methyladenosine (mA) plays an important role in many cancers. However, few studies have examined the role of m6A in colorectal CRC. To examine the effect of m6A on CRC, we studied the genome of 591 CRC cases from The Cancer Genome Atlas (TCGA). The relationship between the messenger RNA (mRNA) expression, copy number variation (CNVs), and mutations of m6A "Writers," "Readers," and "Erasers," prognosis, immune cell infiltration, and genetic mutations in CRC cases were analyzed. CNVs and mutations were found in thirteen m6A regulators. As expected, gain and amplification of m6A regulators increased the mRNA expression of these regulators, while deletion led to reduction in the mRNA expression. Moreover, CNVs and mutation of these regulators were significantly associated with APC, TP53, and microsatellite instability (MSI) status ( < 0.001, < 0.001, and = 0.029, respectively). CNVs of m6A regulators also correlated with inferred immune cell infiltration in CRC tissues, especially in colon tissues. Additionally, alterations of RBM15, YTHDF2, YTHDC1, YTHDC2, and METTL14 genes were related to the worse overall survival and disease-free survival (DFS) of CRC patients. Specifically, the deletion status of "Writers" was also correlated to the DFS of CRC patients ( = 0.02). Gene set enrichment analysis found that FTO was involved in mRNA 3' end processing, polyubiquitin binding, and RNA polymerase promoter elongation, while YTHDC1 was related to interferon-alpha and gamma response. In conclusion, a novel relationship was identified between CNVs and mutations of m6A regulators with prognosis and inferred immune function of CRC. These findings will improve the understanding of the relationship of m6A in CRC.
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http://dx.doi.org/10.1155/2020/8826456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769650PMC
December 2020

Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients.

J Transl Med 2021 01 7;19(1):27. Epub 2021 Jan 7.

Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.

Background: KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated.

Methods: 535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated.

Results: NF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes.

Conclusions: KRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.
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http://dx.doi.org/10.1186/s12967-020-02638-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789428PMC
January 2021

Kynurenic acid underlies sex-specific immune responses to COVID-19.

medRxiv 2020 Sep 8. Epub 2020 Sep 8.

Coronavirus disease-2019 (COVID-19) has poorer clinical outcomes in males compared to females, and immune responses underlie these sex-related differences in disease trajectory. As immune responses are in part regulated by metabolites, we examined whether the serum metabolome has sex-specificity for immune responses in COVID-19. In males with COVID- 19, kynurenic acid (KA) and a high KA to kynurenine (K) ratio was positively correlated with age, inflammatory cytokines, and chemokines and was negatively correlated with T cell responses, revealing that KA production is linked to immune responses in males. Males that clinically deteriorated had a higher KA:K ratio than those that stabilized. In females with COVID-19, this ratio positively correlated with T cell responses and did not correlate with age or clinical severity. KA is known to inhibit glutamate release, and we observed that serum glutamate is lower in patients that deteriorate from COVID-19 compared to those that stabilize, and correlates with immune responses. Analysis of Genotype-Tissue Expression (GTEx) data revealed that expression of kynurenine aminotransferase, which regulates KA production, correlates most strongly with cytokine levels and aryl hydrocarbon receptor activation in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes, in COVID-19 infection.
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http://dx.doi.org/10.1101/2020.09.06.20189159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491534PMC
September 2020

Tumor Tissue-Specific Biomarkers of Colorectal Cancer by Anatomic Location and Stage.

Metabolites 2020 Jun 19;10(6). Epub 2020 Jun 19.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT 06520, USA.

The progress in the discovery and validation of metabolite biomarkers for the detection of colorectal cancer (CRC) has been hampered by the lack of reproducibility between study cohorts. The majority of discovery-phase biomarker studies have used patient blood samples to identify disease-related metabolites, but this pre-validation phase is confounded by non-specific disease influences on the metabolome. We therefore propose that metabolite biomarker discovery would have greater success and higher reproducibility for CRC if the discovery phase was conducted in tumor tissues, to find metabolites that have higher specificity to the metabolic consequences of the disease, that are then validated in blood samples. This would thereby eliminate any non-tumor and/or body response effects to the disease. In this study, we performed comprehensive untargeted metabolomics analyses on normal (adjacent) colon and tumor tissues from CRC patients, revealing tumor tissue-specific biomarkers ( = 39/group). We identified 28 highly discriminatory tumor tissue metabolite biomarkers of CRC by orthogonal partial least-squares discriminant analysis (OPLS-DA) and univariate analyses (VIP > 1.5, < 0.05). A stepwise selection procedure was used to identify nine metabolites that were the most predictive of CRC with areas under the curve (AUCs) of >0.96, using various models. We further identified five biomarkers that were specific to the anatomic location of tumors in the colon ( = 236). The combination of these five metabolites (S-adenosyl-L-homocysteine, formylmethionine, fucose 1-phosphate, lactate, and phenylalanine) demonstrated high differentiative capability for left- and right-sided colon cancers at stage I by internal cross-validation (AUC = 0.804, 95% confidence interval, CI 0.670-0.940). This study thus revealed nine discriminatory biomarkers of CRC that are now poised for external validation in a future independent cohort of samples. We also discovered a discrete metabolic signature to determine the anatomic location of the tumor at the earliest stage, thus potentially providing clinicians a means to identify individuals that could be triaged for additional screening regimens.
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http://dx.doi.org/10.3390/metabo10060257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345993PMC
June 2020

Accounting for urinary dilution in peri-implantation samples: implications for creatinine adjustment and specimen pooling.

J Expo Sci Environ Epidemiol 2021 03 18;31(2):356-365. Epub 2020 May 18.

Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, NC, USA.

This study examines critical issues in accounting for urinary dilution in peri-implantation samples used to assess environmental exposures. Early pregnancy could impact creatinine excretion, which could bias biomarker measurement and interpretation when creatinine adjustment is used. We compared creatinine levels pre-implantation with levels soon after implantation at 3-6 weeks gestation. Using data and urine specimens from 145 women who conceived, we used linear mixed models to estimate the effect of pregnancy on creatinine concentrations. We also studied whether creatinine adjustment is biased when using pooled, within-person samples rather than averaging individually-adjusted results. For this, we grouped 2655 daily urinary estrogen metabolite and associated creatinine measures into 762 mathematically-constructed sample pools, and compared averaged individual measures with pooled measures using weighted kappa coefficients and t-tests. Urinary creatinine concentration declined an average of 14% (95% CI: -19, -11%) from pre- to post-implantation. While there was strong correlation between results based on the two creatinine adjustment methods, adjustment based on pooled specimens introduced a small 3% (95% CI: 2, 4%) underestimation of the analyte compared with averaging individually-adjusted samples. Postimplantation creatinine declines could introduce errors in biomonitoring results when comparing exposure measures from pre- and post-implantation. Though pooled creatinine adjustment underestimated adjusted analyte concentrations, the bias was small and agreement excellent between pooled and averaged individually-adjusted assessments.
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http://dx.doi.org/10.1038/s41370-020-0227-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671945PMC
March 2021

Joint effect of pre-operative anemia and perioperative blood transfusion on outcomes of colon-cancer patients undergoing colectomy.

Gastroenterol Rep (Oxf) 2020 Apr 9;8(2):151-157. Epub 2019 Aug 9.

Department of Surgery, Yale School of Medicine, New Haven, CT, USA.

Background: Both pre-operative anemia and perioperative (intra- and/or post-operative) blood transfusion have been reported to increase post-operative complications in patients with colon cancer undergoing colectomy. However, their joint effect has not been investigated. The purpose of this study was to evaluate the joint effect of pre-operative anemia and perioperative blood transfusion on the post-operative outcome of colon-cancer patients after colectomy.

Methods: We identified patients from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database 2006-2016 who underwent colectomy for colon cancer. Multivariate logistic regression analysis was employed to assess the independent and joint effects of anemia and blood transfusion on patient outcomes.

Results: A total of 35,863 patients-18,936 (52.8%) with left-side colon cancer (LCC) and 16,927 (47.2%) with right-side colon cancer (RCC)-were identified. RCC patients were more likely to have mild anemia (62.7%) and severe anemia (2.9%) than LCC patients (40.2% mild anemia and 1.4% severe anemia). A total of 2,661 (7.4%) of all patients (1,079 [5.7%] with LCC and 1,582 [9.3%] with RCC) received a perioperative blood transfusion. Overall, the occurrence rates of complications were comparable between LCC and RCC patients (odds ratio [OR]=1.01; 95% confidence interval [CI]=0.95-1.07; =0.750). There were significant joint effects of anemia and transfusion on complications and the 30-day death rate ( for interaction: 0.010). Patients without anemia who received a transfusion had a higher risk of any complications (LCC, OR=3.51; 95% CI=2.55-4.85; <0.001; RCC, OR=3.74; 95% CI=2.50-5.59; <0.001), minor complications (LCC, OR=2.54; 95% CI=1.63-3.97; <0.001; RCC, OR=2.27; 95% CI=1.24-4.15; =0.008), and major complications (LCC, OR=5.31; 95% CI=3.68-7.64; <0.001; RCC, OR=5.64; 95% CI=3.61-8.79; <0.001), and had an increased 30-day death rate (LCC, OR=6.97; 95% CI=3.07-15.80; <0.001; RCC, OR=4.91; 95% CI=1.88-12.85; =0.001) than patients without anemia who did not receive a transfusion.

Conclusions: Pre-operative anemia and perioperative transfusion are associated with an increased risk of post-operative complications and increased death rate in colon-cancer patients undergoing colectomy.
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http://dx.doi.org/10.1093/gastro/goz033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136710PMC
April 2020

Sex Differences in Colon Cancer Metabolism Reveal A Novel Subphenotype.

Sci Rep 2020 03 17;10(1):4905. Epub 2020 Mar 17.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.

Women have a lower incidence of colorectal cancer (CRC) than men, however, they have a higher incidence of right-sided colon cancer (RCC). This is of concern as patients with RCC have the poorest clinical outcomes among all CRC patients. Aberrant metabolism is a known hallmark and therapeutic target for cancer. We propose that metabolic subphenotypes exist between CRCs due to intertumoral molecular and genomic variation, and differences in environmental milieu of the colon which vary between the sexes. Metabolomics analysis of patient colon tumors (n = 197) and normal tissues (n = 39) revealed sex-specific metabolic subphenotypes dependent on anatomic location. Tumors from women with RCC were nutrient-deplete, showing enhanced energy production to fuel asparagine synthesis and amino acid uptake. The clinical importance of our findings were further investigated in an independent data set from The Cancer Genomic Atlas, and demonstrated that high asparagine synthetase (ASNS) expression correlated with poorer survival for women. This is the first study to show a unique, nutrient-deplete metabolic subphenotype in women with RCC, with implications for tumor progression and outcomes in CRC patients.
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http://dx.doi.org/10.1038/s41598-020-61851-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078199PMC
March 2020

Molecular Pathway Analysis Indicates a Distinct Metabolic Phenotype in Women With Right-Sided Colon Cancer.

Transl Oncol 2020 Jan 21;13(1):42-56. Epub 2019 Nov 21.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT USA. Electronic address:

Colon cancer is the third most commonly diagnosed cancer in the United States. Recent reports have shown that the location of the primary tumor is of clinical importance. Patients with right-sided colon cancers (RCCs) (tumors arising between the cecum and proximal transverse colon) have poorer clinical outcomes than those with left-sided colon cancers (LCCs) (tumors arising between the distal transverse colon and sigmoid colon, excluding the rectum). Interestingly, women have a lower incidence of colon cancer than men, but have a higher propensity for RCC. The reason for this difference is not known; however, identification of sex-specific differences in gene expression by tumor anatomical location in the colon could provide further insight. Moreover, it could reveal important predictive markers for response to various treatments. This study provides a comprehensive bioinformatic analysis of various genes and molecular pathways that correlated with sex and anatomical location of colon cancers using four publicly available annotated data sets housed in the National Center for Biotechnology Information's Gene Expression Omnibus. We identified differentially expressed genes in tumor tissues from women with RCC, which showed attenuated energy and nutrient metabolism when compared with women with LCC. Specifically, we showed the downregulation of 5' AMP-activated protein kinase alpha subunit (AMPKα) and anti-tumor immune responses in women with RCC. This difference was not seen when comparing tumor tissues from men with RCC to men with LCC. Therefore, women with RCC may have a specific metabolic and immune phenotype which accounts for differences in prognosis and treatment response.
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http://dx.doi.org/10.1016/j.tranon.2019.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883319PMC
January 2020

Metabolic dysregulation in vitamin E and carnitine shuttle energy mechanisms associate with human frailty.

Nat Commun 2019 11 5;10(1):5027. Epub 2019 Nov 5.

School of Chemistry, Manchester Institute for Biotechnology, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.

Global ageing poses a substantial economic burden on health and social care costs. Enabling a greater proportion of older people to stay healthy for longer is key to the future sustainability of health, social and economic policy. Frailty and associated decrease in resilience plays a central role in poor health in later life. In this study, we present a population level assessment of the metabolic phenotype associated with frailty. Analysis of serum from 1191 older individuals (aged between 56 and 84 years old) and subsequent longitudinal validation (on 786 subjects) was carried out using liquid and gas chromatography-mass spectrometry metabolomics and stratified across a frailty index designed to quantitatively summarize vulnerability. Through multivariate regression and network modelling and mROC modeling we identified 12 significant metabolites (including three tocotrienols and six carnitines) that differentiate frail and non-frail phenotypes. Our study provides evidence that the dysregulation of carnitine shuttle and vitamin E pathways play a role in the risk of frailty.
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http://dx.doi.org/10.1038/s41467-019-12716-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831565PMC
November 2019

Normalizing Untargeted Periconceptional Urinary Metabolomics Data: A Comparison of Approaches.

Metabolites 2019 Sep 21;9(10). Epub 2019 Sep 21.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.

Metabolomics studies of the early-life exposome often use maternal urine specimens to investigate critical developmental windows, including the periconceptional period and early pregnancy. During these windows changes in kidney function can impact urine concentration. This makes accounting for differential urinary dilution across samples challenging. Because there is no consensus on the ideal normalization approach for urinary metabolomics data, this study's objective was to determine the optimal post-analytical normalization approach for untargeted metabolomics analysis from a periconceptional cohort of 45 women. Urine samples consisted of 90 paired pre- and post-implantation samples. After untargeted mass spectrometry-based metabolomics analysis, we systematically compared the performance of three common approaches to adjust for urinary dilution-creatinine adjustment, specific gravity adjustment, and probabilistic quotient normalization (PQN)-using unsupervised principal components analysis, relative standard deviation (RSD) of pooled quality control samples, and orthogonal partial least-squares discriminant analysis (OPLS-DA). Results showed that creatinine adjustment is not a reliable approach to normalize urinary periconceptional metabolomics data. Either specific gravity or PQN are more reliable methods to adjust for urinary concentration, with tighter quality control sample clustering, lower RSD, and better OPLS-DA performance compared to creatinine adjustment. These findings have implications for metabolomics analyses on urine samples taken around the time of conception and in contexts where kidney function may be altered.
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http://dx.doi.org/10.3390/metabo9100198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835889PMC
September 2019

1,4-Dioxane as an emerging water contaminant: State of the science and evaluation of research needs.

Sci Total Environ 2019 Nov 28;690:853-866. Epub 2019 Jun 28.

Department of Environmental Health Sciences, School of Public Health, Yale University, New Haven, CT 06510, United States. Electronic address:

1,4-Dioxane has historically been used to stabilize chlorinated solvents and more recently has been found as a contaminant of numerous consumer and food products. Once discharged into the environment, its physical and chemical characteristics facilitate migration in groundwater, resulting in widespread contamination of drinking water supplies. Over one-fifth of U.S. public drinking water supplies contain detectable levels of 1,4-dioxane. Remediation efforts using common adsorption and membrane filtration techniques have been ineffective, highlighting the need for alternative removal approaches. While the data evaluating human exposure and health effects are limited, animal studies have shown chronic exposure to cause carcinogenic responses in the liver across multiple species and routes of exposure. Based on this experimental evidence, the U.S. Environmental Protection Agency has listed 1,4-dioxane as a high priority chemical and classified it as a probable human carcinogen. Despite these health concerns, there are no federal or state maximum contaminant levels for 1,4-dioxane. Effective public health policy for this emerging contaminant requires additional information about human health effects, chemical interactions, environmental fate, analytical detection, and treatment technologies. This review highlights the current state of knowledge, key uncertainties, and data needs for future research on 1,4-dioxane.
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http://dx.doi.org/10.1016/j.scitotenv.2019.06.443DOI Listing
November 2019

Palbociclib and Fulvestrant Act in Synergy to Modulate Central Carbon Metabolism in Breast Cancer Cells.

Metabolites 2019 Jan 2;9(1). Epub 2019 Jan 2.

The Scripps Research Institute, Scripps Center for Metabolomics and Mass Spectrometry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

The aims of this study were to determine whether combination chemotherapeutics exhibit a synergistic effect on breast cancer cell metabolism. Palbociclib, is a selective inhibitor of cyclin-dependent kinases 4 and 6, and when patients are treated in combination with fulvestrant, an estrogen receptor antagonist, they have improved progression-free survival. The mechanisms for this survival advantage are not known. Therefore, we analyzed metabolic and transcriptomic changes in MCF-7 cells following single and combination chemotherapy to determine whether selective metabolic pathways are targeted during these different modes of treatment. Individually, the drugs caused metabolic disruption to the same metabolic pathways, however fulvestrant additionally attenuated the pentose phosphate pathway and the production of important coenzymes. A comprehensive effect was observed when the drugs were applied together, confirming the combinatory therapy's synergism in the cell model. This study also highlights the power of merging high-dimensional datasets to unravel mechanisms involved in cancer metabolism and therapy.
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http://dx.doi.org/10.3390/metabo9010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359333PMC
January 2019

Defining Early-Onset Colon and Rectal Cancers.

Front Oncol 2018 6;8:504. Epub 2018 Nov 6.

Section of Surgical Oncology, Department of Surgery, Yale University School of Medicine, New Haven, CT, United States.

Colorectal cancer (CRC) incidence is rising in the young, yet the age of those affected is not clearly defined. In this study, we identify such cohorts and define clinicopathological features of early-onset colon and rectal cancers. The Surveillance, Epidemiology and End Results Program (SEER) database was queried to compare clinicopathological characteristics of colon and rectal cancers diagnosed during 1973-1995 with those diagnosed during 1995-2014. We identified 430,886 patients with colon and rectal cancers. From 1973-1995 to 1995-2014, colon cancer incidence increased in patients aged 20-44 years, while rectal cancer incidence increased in patients aged ≤54 years. The percent change of cancer incidence was greatest for rectal cancer with a 41.5% (95% confidence interval (CI): 37.4-45.8%) increase compared to a 9.8% (CI: 6.2-13.6%) increase in colon cancer. Colon cancer has increased in tumors located in ascending, sigmoid, and rectosigmoid locations. Adenocarcinoma histology has increased in both colon and rectal cancers ( < 0.01), but mucinous and signet ring cell subtypes have not increased ( = 0.13 and 0.08, respectively). Incidence increases were race-specific, with rectal cancer seeing similar rises in white (38.4%, CI: 33.8-43.1%) and black populations (38.0%, CI: 26.2-51.2%), while colon cancer as a whole saw a rise in white (11.5%, CI: 7.2-15.9%) but not black populations (-6.8%, CI: -14.6-1.9%). Our study underscores the existence of key differences between early-onset colon (20-44 years) and rectal cancers (≤54 years) and provides evidence-based inclusion criteria for future investigations. We recommend that future research of CRC in the young should avoid investigating these cases as a single entity.
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http://dx.doi.org/10.3389/fonc.2018.00504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232522PMC
November 2018

Evaluation of potential carcinogenicity of organic chemicals in synthetic turf crumb rubber.

Environ Res 2019 02 24;169:163-172. Epub 2018 Oct 24.

Department of Environmental Health Sciences, Yale School of Public Health, 60 College St, New Haven, CT 06250, USA. Electronic address:

Currently, there are >11,000 synthetic turf athletic fields in the United States and >13,000 in Europe. Concerns have been raised about exposure to carcinogenic chemicals resulting from contact with synthetic turf fields, particularly the infill material ("crumb rubber"), which is commonly fabricated from recycled tires. However, exposure data are scant, and the limited existing exposure studies have focused on a small subset of crumb rubber components. Our objective was to evaluate the carcinogenic potential of a broad range of chemical components of crumb rubber infill using computational toxicology and regulatory agency classifications from the United States Environmental Protection Agency (US EPA) and European Chemicals Agency (ECHA) to inform future exposure studies and risk analyses. Through a literature review, we identified 306 chemical constituents of crumb rubber infill from 20 publications. Utilizing ADMET Predictor™, a computational program to predict carcinogenicity and genotoxicity, 197 of the identified 306 chemicals met our a priori carcinogenicity criteria. Of these, 52 chemicals were also classified as known, presumed or suspected carcinogens by the US EPA and ECHA. Of the remaining 109 chemicals which were not predicted to be carcinogenic by our computational toxicology analysis, only 6 chemicals were classified as presumed or suspected human carcinogens by US EPA or ECHA. Importantly, the majority of crumb rubber constituents were not listed in the US EPA (n = 207) and ECHA (n = 262) databases, likely due to an absence of evaluation or insufficient information for a reliable carcinogenicity classification. By employing a cancer hazard scoring system to the chemicals which were predicted and classified by the computational analysis and government databases, several high priority carcinogens were identified, including benzene, benzidine, benzo(a)pyrene, trichloroethylene and vinyl chloride. Our findings demonstrate that computational toxicology assessment in conjunction with government classifications can be used to prioritize hazardous chemicals for future exposure monitoring studies for users of synthetic turf fields. This approach could be extended to other compounds or toxicity endpoints.
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http://dx.doi.org/10.1016/j.envres.2018.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396308PMC
February 2019

Distinctive features of gastrointestinal stromal tumors arising from the colon and rectum.

J Gastrointest Oncol 2018 Apr;9(2):231-240

Department of Surgery, Section of Surgical Oncology, Yale University School of Medicine, New Haven, CT, USA.

Background: Colon and rectal gastrointestinal stromal tumors (GISTs) are rare and poorly characterized. Because the majority of treatment guidelines for GISTs are extrapolated from tumors of gastric and small bowel origin, our aim was to better characterize the unique clinicopathologic features and prognostic factors of colon and rectal GISTs to guide clinical care.

Methods: The National Cancer Data Base (NCDB) was queried from 2006 to 2013 for cases of GISTs in the stomach, colon, and rectum. Patient demographics, clinical characteristics, and survival were compared.

Results: A total of 11,302 gastric GISTs were compared to 398 colon and 393 rectal GISTs. After propensity matching, compared to gastric GISTs, rectal GISTs had improved overall survival (HR =0.695, P=0.0264), while colon GISTs had worse overall survival (HR =1.6, P=0.0005). Surgical treatment for rectal GISTs was more likely to be local excision compared to colonic GISTs (51.1% 8.4%, P<0.0001). Colon and gastric GISTs were less likely to receive systemic therapy compared to rectal GISTs (34.2% 34.0% 55.2%, P<0.0001). Adjuvant systemic therapy conveyed a survival advantage to rectal GISTs (HR =0.47, P=0.042) but not colon GISTs. There was a negative impact of adjuvant therapy on survival for colon GISTs <5 cm (HR =3.41, P=0.032).

Conclusions: Patients with rectal GISTs live longer than those with colon and gastric GISTs, and adjuvant therapy prolongs their survival. Many patients with colon GISTs are treated with adjuvant therapy despite a detrimental effect on survival. Tumor biology of colon and rectal GISTs needs to be better studied to tailor treatment.
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http://dx.doi.org/10.21037/jgo.2017.11.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934147PMC
April 2018

Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging.

Redox Biol 2018 07 13;17:259-273. Epub 2018 Apr 13.

University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA.

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1 mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1 mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1 mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1 mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1 mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1 and aged WT mice. Chronic treatment of Ercc1 mice with the mitochondrial-targeted radical scavenger XJB-5-131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline.
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http://dx.doi.org/10.1016/j.redox.2018.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006678PMC
July 2018

Re-engineering and evaluation of anti-DNA autoantibody 3E10 for therapeutic applications.

Biochem Biophys Res Commun 2018 02 31;496(3):858-864. Epub 2018 Jan 31.

Department of Therapeutic Radiology, Yale School of Medicine, Yale University, New Haven, CT, USA; Yale Cancer Center, New Haven, CT, USA. Electronic address:

A key challenge in the development of novel chemotherapeutics is the design of molecules capable of selective toxicity to cancer cells. Antibodies have greater target specificity compared to small molecule drugs, but most are unable to penetrate cells, and predominantly target extracellular antigens. A nuclear-penetrating anti-DNA autoantibody isolated from the MRL/lpr lupus mouse model, 3E10, preferentially localizes to tumors, inhibits DNA repair, and selectively kills cancer cells with defects in DNA repair. A murine divalent single chain variable fragment of 3E10 with mutations for improved DNA binding affinity, 3E10 (D31N) di-scFv, has previously been produced in P. pastoris and yielded promising pre-clinical findings, but is unsuitable for clinical testing. The present study reports the design, expression and testing of a panel of humanized 3E10 (D31N) di-scFvs, some of which contain CDR substitution. These variants were expressed in a modified CHO system and evaluated for their physicochemical attributes and ability to penetrate nuclei to selectively cause DNA damage accumulation in and kill cancer cells with DNA repair defects. Secondary structure was conserved and most variants retained the key characteristics of the murine 3E10 (D31N) di-scFv produced in P. pastoris. Moreover, several variants with CDR substitutions outperformed the murine prototype. In conclusion, we have designed several humanized variants of 3E10 (D31N) di-scFv that have potential for application as monotherapy or conjugates for targeted nuclear drug delivery.
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http://dx.doi.org/10.1016/j.bbrc.2018.01.139DOI Listing
February 2018

Beyond genomics: understanding exposotypes through metabolomics.

Hum Genomics 2018 01 26;12(1). Epub 2018 Jan 26.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA.

Background: Over the past 20 years, advances in genomic technology have enabled unparalleled access to the information contained within the human genome. However, the multiple genetic variants associated with various diseases typically account for only a small fraction of the disease risk. This may be due to the multifactorial nature of disease mechanisms, the strong impact of the environment, and the complexity of gene-environment interactions. Metabolomics is the quantification of small molecules produced by metabolic processes within a biological sample. Metabolomics datasets contain a wealth of information that reflect the disease state and are consequent to both genetic variation and environment. Thus, metabolomics is being widely adopted for epidemiologic research to identify disease risk traits. In this review, we discuss the evolution and challenges of metabolomics in epidemiologic research, particularly for assessing environmental exposures and providing insights into gene-environment interactions, and mechanism of biological impact.

Main Text: Metabolomics can be used to measure the complex global modulating effect that an exposure event has on an individual phenotype. Combining information derived from all levels of protein synthesis and subsequent enzymatic action on metabolite production can reveal the individual exposotype. We discuss some of the methodological and statistical challenges in dealing with this type of high-dimensional data, such as the impact of study design, analytical biases, and biological variance. We show examples of disease risk inference from metabolic traits using metabolome-wide association studies. We also evaluate how these studies may drive precision medicine approaches, and pharmacogenomics, which have up to now been inefficient. Finally, we discuss how to promote transparency and open science to improve reproducibility and credibility in metabolomics.

Conclusions: Comparison of exposotypes at the human population level may help understanding how environmental exposures affect biology at the systems level to determine cause, effect, and susceptibilities. Juxtaposition and integration of genomics and metabolomics information may offer additional insights. Clinical utility of this information for single individuals and populations has yet to be routinely demonstrated, but hopefully, recent advances to improve the robustness of large-scale metabolomics will facilitate clinical translation.
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http://dx.doi.org/10.1186/s40246-018-0134-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787293PMC
January 2018

Metabolomics Reveals that Dietary Xenoestrogens Alter Cellular Metabolism Induced by Palbociclib/Letrozole Combination Cancer Therapy.

Cell Chem Biol 2018 03 11;25(3):291-300.e3. Epub 2018 Jan 11.

The Scripps Research Institute, Scripps Center for Metabolomics and Mass Spectrometry, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; The Scripps Research Institute, Department of Integrative and Computational Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

Recently, the palbociclib/letrozole combination therapy was granted accelerated US FDA approval for the treatment of estrogen receptor (ER)-positive breast cancer. Since the underlying metabolic effects of these drugs are yet unknown, we investigated their synergism at the metabolome level in MCF-7 cells. As xenoestrogens interact with the ER, we additionally aimed at deciphering the impact of the phytoestrogen genistein and the estrogenic mycotoxin zearalenone. A global metabolomics approach was applied to unravel metabolite and pathway modifications. The results clearly showed that the combined effects of palbociclib and letrozole on cellular metabolism were far more pronounced than that of each agent alone and potently influenced by xenoestrogens. This behavior was confirmed in proliferation experiments and functional assays. Specifically, amino acids and central carbon metabolites were attenuated, while higher abundances were observed for fatty acids and most nucleic acid-related metabolites. Interestingly, exposure to model xenoestrogens appeared to counteract these effects.
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http://dx.doi.org/10.1016/j.chembiol.2017.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856613PMC
March 2018

Carnitine palmitoyltransferase 1C regulates cancer cell senescence through mitochondria-associated metabolic reprograming.

Cell Death Differ 2018 03 9;25(4):735-748. Epub 2018 Jan 9.

School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.

Cellular senescence is a fundamental biological process that has profound implications in cancer development and therapeutics, but the underlying mechanisms remain elusive. Here we show that carnitine palmitoyltransferase 1C (CPT1C), an enzyme that catalyzes carnitinylation of fatty acids for transport into mitochondria for β-oxidation, plays a major role in the regulation of cancer cell senescence through mitochondria-associated metabolic reprograming. Metabolomics analysis suggested alterations in mitochondria activity, as revealed by the marked decrease in acylcarnitines in senescent human pancreatic carcinoma PANC-1 cells, indicating low CPT1C activity. Direct analyses of mRNA and protein show that CPT1C is significantly reduced in senescent cells. Furthermore, abnormal mitochondrial function was observed in senescent PANC-1 cells, leading to lower cell survival under metabolic stress and suppressed tumorigenesis in a mouse xenograft model. Knock-down of CPT1C in PANC-1 cells induced mitochondrial dysfunction, caused senescence-like growth suppression and cellular senescence, suppressed cell survival under metabolic stress, and inhibited tumorigenesis in vivo. Further, CPT1C knock-down suppressed xenograft tumor growth in situ. Silencing of CPT1C in five other tumor cell lines also caused cellular senescence. On the contrary, gain-of-function of CPT1C reversed PANC-1 cell senescence and enhanced mitochondrial function. This study identifies CPT1C as a novel biomarker and key regulator of cancer cell senescence through mitochondria-associated metabolic reprograming, and suggests that inhibition of CPT1C may represent a new therapeutic strategy for cancer treatment through induction of tumor senescence.
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http://dx.doi.org/10.1038/s41418-017-0013-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864250PMC
March 2018

Yale school of public health symposium on lifetime exposures and human health: the exposome; summary and future reflections.

Hum Genomics 2017 Dec 8;11(1):32. Epub 2017 Dec 8.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT, USA.

The exposome is defined as "the totality of environmental exposures encountered from birth to death" and was developed to address the need for comprehensive environmental exposure assessment to better understand disease etiology. Due to the complexity of the exposome, significant efforts have been made to develop technologies for longitudinal, internal and external exposure monitoring, and bioinformatics to integrate and analyze datasets generated. Our objectives were to bring together leaders in the field of exposomics, at a recent Symposium on "Lifetime Exposures and Human Health: The Exposome," held at Yale School of Public Health. Our aim was to highlight the most recent technological advancements for measurement of the exposome, bioinformatics development, current limitations, and future needs in environmental health. In the discussions, an emphasis was placed on moving away from a one-chemical one-health outcome model toward a new paradigm of monitoring the totality of exposures that individuals may experience over their lifetime. This is critical to better understand the underlying biological impact on human health, particularly during windows of susceptibility. Recent advancements in metabolomics and bioinformatics are driving the field forward in biomonitoring and understanding the biological impact, and the technological and logistical challenges involved in the analyses were highlighted. In conclusion, further developments and support are needed for large-scale biomonitoring and management of big data, standardization for exposure and data analyses, bioinformatics tools for co-exposure or mixture analyses, and methods for data sharing.
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http://dx.doi.org/10.1186/s40246-017-0128-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723043PMC
December 2017

Metabolomics guided pathway analysis reveals link between cancer metastasis, cholesterol sulfate, and phospholipids.

Cancer Metab 2017 31;5. Epub 2017 Oct 31.

Scripps Center for Metabolomics, The Scripps Research Institute, La Jolla, CA USA.

Background: Cancer cells that enter the metastatic cascade require traits that allow them to survive within the circulation and colonize distant organ sites. As disseminating cancer cells adapt to their changing microenvironments, they also modify their metabolism and metabolite production.

Methods: A mouse xenograft model of spontaneous tumor metastasis was used to determine the metabolic rewiring that occurs between primary cancers and their metastases. An "autonomous" mass spectrometry-based untargeted metabolomic workflow with integrative metabolic pathway analysis revealed a number of differentially regulated metabolites in primary mammary fat pad (MFP) tumors compared to microdissected paired lung metastases. The study was further extended to analyze metabolites in paired normal tissues which determined the potential influence of metabolites from the microenvironment.

Results: Metabolomic analysis revealed that multiple metabolites were increased in metastases, including cholesterol sulfate and phospholipids (phosphatidylglycerols and phosphatidylethanolamine). Metabolite analysis of normal lung tissue in the mouse model also revealed increased levels of these metabolites compared to tissues from normal MFP and primary MFP tumors, indicating potential extracellular uptake by cancer cells in lung metastases. These results indicate a potential functional importance of cholesterol sulfate and phospholipids in propagating metastasis. In addition, metabolites involved in DNA/RNA synthesis and the TCA cycle were decreased in lung metastases compared to primary MFP tumors.

Conclusions: Using an integrated metabolomic workflow, this study identified a link between cholesterol sulfate and phospholipids, metabolic characteristics of the metastatic niche, and the capacity of tumor cells to colonize distant sites.
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http://dx.doi.org/10.1186/s40170-017-0171-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663111PMC
October 2017

Exposome-Scale Investigations Guided by Global Metabolomics, Pathway Analysis, and Cognitive Computing.

Anal Chem 2017 11 9;89(21):11505-11513. Epub 2017 Oct 9.

National Center for Computational Toxicology, U.S. Environmental Protection Agency , 109 T.W. Alexander Drive, Research Triangle Park, North Carolina 27711, United States.

Concurrent exposure to a wide variety of xenobiotics and their combined toxic effects can play a pivotal role in health and disease, yet are largely unexplored. Investigating the totality of these exposures, i.e., the "exposome", and their specific biological effects constitutes a new paradigm for environmental health but still lacks high-throughput, user-friendly technology. We demonstrate the utility of mass spectrometry-based global exposure metabolomics combined with tailored database queries and cognitive computing for comprehensive exposure assessment and the straightforward elucidation of biological effects. The METLIN Exposome database has been redesigned to help identify environmental toxicants, food contaminants and supplements, drugs, and antibiotics as well as their biotransformation products, through its expansion with over 700 000 chemical structures to now include more than 950 000 unique small molecules. More importantly, we demonstrate how the XCMS/METLIN platform now allows for the readout of the biological effect of a toxicant through metabolomic-derived pathway analysis, and further, artificial intelligence provides a means of assessing the role of a potential toxicant. The presented workflow addresses many of the methodological challenges current exposomics research is facing and will serve to gain a deeper understanding of the impact of environmental exposures and combinatory toxic effects on human health.
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http://dx.doi.org/10.1021/acs.analchem.7b02759DOI Listing
November 2017

Environmental influences in the etiology of colorectal cancer: the premise of metabolomics.

Curr Pharmacol Rep 2017 Jun 7;3(3):114-125. Epub 2017 Apr 7.

Department of Environmental Health Sciences, Yale School of Public Health, Yale University, New Haven, CT, USA, 06520.

Purpose Of Review: In this review we discuss how environmental exposures predominate the etiology of colorectal cancer (CRC). With CRC being a personalized disease influenced by genes and environment, our goal was to explore the role metabolomics can play in identifying exposures, assessing the interplay between co-exposures, and the development of personalized therapeutic interventions.

Recent Findings: Approximately 10 % of CRC cases can be explained by germ-line mutations, whereas the prevailing majority are caused by an initiating exposure event occurring decades prior to diagnosis. Recent research has shown that dietary metabolites are linked to a procarcinogenic or protective environment in the colon which is modulated by the microbiome. In addition, excessive alcohol has been shown to increase the risk of CRC and is dependent on diet (folate), the response of microbiome, and genetic polymorphisms within the folate and alcohol metabolic pathways. Metabolomics can not only be used to identify this modulation of host metabolism, which could affect the progression of the tumors but also response to targeted therapeutics.

Summary: This review highlights the current understanding of the multifaceted etiology and mechanisms of CRC development but also highlights where the field of metabolomics can contribute to a greater understanding of environmental exposure in CRC.
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http://dx.doi.org/10.1007/s40495-017-0088-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5475285PMC
June 2017