Publications by authors named "Darryl C Zeldin"

315 Publications

Natural Products in the Prevention of Metabolic Diseases: Lessons Learned from the 20th KAST Frontier Scientists Workshop.

Nutrients 2021 May 31;13(6). Epub 2021 May 31.

College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.

The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases.
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http://dx.doi.org/10.3390/nu13061881DOI Listing
May 2021

Albuminuria as a Predictor of Mortality from Chronic Lower Respiratory Disease and from Influenza and Pneumonia.

Ann Am Thorac Soc 2021 May 12. Epub 2021 May 12.

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, United States;

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http://dx.doi.org/10.1513/AnnalsATS.202009-1226RLDOI Listing
May 2021

Soluble Epoxide Hydrolase in Aged Female Mice and Human Explanted Hearts Following Ischemic Injury.

Int J Mol Sci 2021 Feb 8;22(4). Epub 2021 Feb 8.

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB T6G 2H7, Canada.

Myocardial infarction (MI) accounts for a significant proportion of death and morbidity in aged individuals. The risk for MI in females increases as they enter the peri-menopausal period, generally occurring in middle-age. Cytochrome (CYP) 450 metabolizes N-3 and N-6 polyunsaturated fatty acids (PUFA) into numerous lipid mediators, oxylipids, which are further metabolised by soluble epoxide hydrolase (sEH), reducing their activity. The objective of this study was to characterize oxylipid metabolism in the left ventricle (LV) following ischemic injury in females. Human LV specimens were procured from female patients with ischemic cardiomyopathy (ICM) or non-failing controls (NFC). Female C57BL6 (WT) and sEH null mice averaging 13-16 months old underwent permanent occlusion of the left anterior descending coronary artery (LAD) to induce myocardial infarction. WT (wild type) mice received vehicle or sEH inhibitor, trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (AUCB), in their drinking water ad libitum for 28 days. Cardiac function was assessed using echocardiography and electrocardiogram. Protein expression was determined using immunoblotting, mitochondrial activity by spectrophotometry, and cardiac fibre respiration was measured using a Clark-type electrode. A full metabolite profile was determined by LC-MS/MS. sEH was significantly elevated in ischemic LV specimens from patients, associated with fundamental changes in oxylipid metabolite formation and significant decreases in mitochondrial enzymatic function. In mice, pre-treatment with AUCB or genetic deletion of sEH significantly improved survival, preserved cardiac function, and maintained mitochondrial quality following MI in female mice. These data indicate that sEH may be a relevant pharmacologic target for women with MI. Although future studies are needed to determine the mechanisms, in this pilot study we suggest targeting sEH may be an effective strategy for reducing ischemic injury and mortality in middle-aged females.
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http://dx.doi.org/10.3390/ijms22041691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915306PMC
February 2021

Furin cleavage of the SARS-CoV-2 spike is modulated by O-glycosylation.

bioRxiv 2021 Feb 5. Epub 2021 Feb 5.

The SARS-CoV-2 coronavirus responsible for the global pandemic contains a unique furin cleavage site in the spike protein (S) that increases viral infectivity and syncytia formation. Here, we show that O-glycosylation near the furin cleavage site is mediated by specific members of the GALNT enzyme family and is dependent on the novel proline at position 681 (P681). We further demonstrate that O-glycosylation of S decreases furin cleavage. Finally, we show that GALNT family members capable of glycosylating S are expressed in human respiratory cells that are targets for SARS-CoV-2 infection. Our results suggest that O-glycosylation may influence viral infectivity/tropism by modulating furin cleavage of S and provide mechanistic insight into the potential role of P681 mutations in the recently identified, highly transmissible B.1.1.7 variant.
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http://dx.doi.org/10.1101/2021.02.05.429982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872346PMC
February 2021

POLM 2020 special issue preface.

Prostaglandins Other Lipid Mediat 2021 Apr 9;153:106526. Epub 2021 Jan 9.

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, United States.

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http://dx.doi.org/10.1016/j.prostaglandins.2021.106526DOI Listing
April 2021

Soluble epoxide hydrolase deficiency attenuates lipotoxic cardiomyopathy via upregulation of AMPK-mTORC mediated autophagy.

J Mol Cell Cardiol 2021 05 27;154:80-91. Epub 2020 Dec 27.

Guangdong Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Cardiology, RNA Biomedical Institute, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yanjiang Road, Guangzhou 510120, China; Department of Cardiology, The Eighth Affiliated Hospital of Sun Yat-sen University, 3025 Shennan Middle Road, Shen Zhen 518033, China. Electronic address:

Obesity-driven cardiac lipid accumulation can progress to lipotoxic cardiomyopathy. Soluble epoxide hydrolase (sEH) is the major enzyme that metabolizes epoxyeicosatrienoic acids (EETs), which have biological activity of regulating lipid metabolism. The current study explores the unknown role of sEH deficiency in lipotoxic cardiomyopathy and its underlying mechanism. Wild-type and Ephx2 knock out (sEH KO) C57BL/6 J mice were fed with high-fat diet (HFD) for 24 weeks to induce lipotoxic cardiomyopathy animal models. Palmitic acid (PA) was utilized to induce lipotoxicity to cardiomyocytes for in vitro study. We found sEH KO, independent of plasma lipid and blood pressures, significantly attenuated HFD-induced myocardial lipid accumulation and cardiac dysfunction in vivo. HFD-induced lipotoxic cardiomyopathy and dysfunction of adenosine 5'-monophosphate-activated protein kinase-mammalian target of rapamycin complex (AMPK-mTORC) signaling mediated lipid autophagy in heart were restored by sEH KO. In primary neonatal mouse cardiomyocytes, both sEH KO and sEH substrate EETs plus sEH inhibitor AUDA treatments attenuated PA-induced lipid accumulation. These effects were blocked by inhibition of AMPK or autophagy. The outcomes were supported by the results that sEH KO and EETs plus AUDA rescued HFD- and PA-induced impairment of autophagy upstream signaling of AMPK-mTORC, respectively. These findings revealed that sEH deficiency played an important role in attenuating myocardial lipid accumulation and provided new insights into treating lipotoxic cardiomyopathy. Regulation of autophagy via AMPK-mTORC signaling pathway is one of the underlying mechanisms.
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http://dx.doi.org/10.1016/j.yjmcc.2020.12.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068623PMC
May 2021

Epoxide hydrolase 3 (Ephx3) gene disruption reduces ceramide linoleate epoxide hydrolysis and impairs skin barrier function.

J Biol Chem 2020 Dec 17. Epub 2020 Dec 17.

Department of Pharmacology, Vanderbilt University, United States.

The mammalian epoxide hydrolase EPHX3 is known from in vitro experiments to efficiently hydrolyze the linoleate epoxides 9,10-epoxyoctadecamonoenoic acid (EpOME) and epoxyalcohol 9,10-trans-epoxy-11-13-hydroxy-octadecenoate to corresponding diols and triols, respectively. Herein we examined the physiological relevance of EPHX3 to hydrolysis of both substrates in vivo.  Ephx3 mice show no deficiency in EpOME-derived plasma diols, discounting a role for EPHX3 in their formation, whereas epoxyalcohol-derived triols esterified in acylceramides of the epidermal 12-lipoxygenase pathway are reduced. Although the Ephx3 pups appear normal, measurements of trans-epidermal water loss detected a modest and statistically significant increase compared to the wild-type or heterozygote mice, reflecting a skin barrier impairment that was not evident in the knockouts of mouse microsomal epoxide hydrolase (EPHX1/mEH) or soluble epoxide hydrolase (EPHX2/sEH). This barrier phenotype in the Ephx3 pups was associated with a significant decrease in the covalently bound ceramides in the epidermis (40% reduction, p<0.05), indicating a corresponding structural impairment in the integrity of the water barrier. Quantitative LC-MS analysis of the esterified linoleate-derived triols in the murine epidermis revealed a marked and isomer-specific reduction (~85%) in the Ephx3 epidermis of the major trihydroxy isomer 9,10,13-trihydroxy-11-octadecenoate. We conclude EPHX3 (and not EPHX1 or EPHX2) catalyzes hydrolysis of the 12-LOX/eLOX3-derived epoxyalcohol esterified in acylceramide, and may function to control flux through the alternative and crucial route of metabolism via the dehydrogenation pathway of SDR9C7. Importantly, our findings also identify a functional role for EPHX3 in transformation of a naturally esterified epoxide substrate, pointing to its potential contribution in other tissues.
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http://dx.doi.org/10.1074/jbc.RA120.016570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948417PMC
December 2020

Lrp1 Regulation of Pulmonary Function. Follow-Up of Human GWAS in Mice.

Am J Respir Cell Mol Biol 2021 03;64(3):368-378

Immunity, Inflammation, and Disease Laboratory.

Human genome-wide association studies (GWASs) have identified more than 270 loci associated with pulmonary function; however, follow-up studies to determine causal genes at these loci are few. SNPs in low-density lipoprotein receptor-related protein 1 (LRP1) are associated with human pulmonary function in GWASs. Using murine models, we investigated the effect of genetic disruption of the gene in smooth muscle cells on pulmonary function in naive animals and after exposure to bacterial LPS or house dust mite extract. Disruption of in smooth muscle cells leads to an increase in tissue resistance, elastance, and tissue elastance at baseline. Furthermore, disruption of in smooth muscle increases airway responsiveness as measured by increased total lung resistance and airway resistance after methacholine. Immune cell counts in BAL fluid were increased in animals with disruption. The difference in airway responsiveness by genotype observed in naive animals was not observed after LPS or house dust mite extract exposure. To further explore the mechanisms contributing to changes in pulmonary function, we identified several ligands dysregulated with disruption in smooth muscle cells. These data suggest that dysregulation of LRP1 in smooth muscle cells affects baseline pulmonary function and airway responsiveness and helps establish as the causal gene at this GWAS locus.
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http://dx.doi.org/10.1165/rcmb.2019-0444OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909338PMC
March 2021

Soluble Epoxide Hydrolase Inhibition by -TUCB Promotes Brown Adipogenesis and Reduces Serum Triglycerides in Diet-Induced Obesity.

Int J Mol Sci 2020 Sep 24;21(19). Epub 2020 Sep 24.

Department of Nutrition, University of Tennessee, Knoxville, TN 37996, USA.

Brown adipose tissue (BAT) is an important target for obesity treatment and prevention. Soluble epoxide hydrolase (sEH) converts bioactive epoxy fatty acids (EpFAs) into less active diols. sEH inhibitors (sEHI) are beneficial in many chronic diseases by stabilizing EpFAs. However, roles of sEH and sEHI in brown adipogenesis and BAT activity in treating diet-induced obesity (DIO) have not been reported. sEH expression was studied in in vitro models of brown adipogenesis and the fat tissues of DIO mice. The effects of the sEHI, -4-{4-[3-(4-trifluoromethoxy-phenyl)-ureido]-cyclohexyloxy-benzoic acid (-TUCB), were studied in vitro and in the obese mice via mini osmotic pump delivery. sEH expression was increased in brown adipogenesis and the BAT of the DIO mice. -TUCB promoted brown adipogenesis in vitro. Although -TCUB did not change body weight, fat pad weight, or glucose and insulin tolerance in the obese mice, it decreased serum triglycerides and increased protein expression of genes important for lipid metabolism in the BAT. Our results suggest that sEH may play a critical role in brown adipogenesis, and sEHI may be beneficial in improving BAT protein expression involved in lipid metabolism. Further studies using the sEHI combined with EpFA generating diets for obesity treatment and prevention are warranted.
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http://dx.doi.org/10.3390/ijms21197039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582898PMC
September 2020

Good or bad: Application of RAAS inhibitors in COVID-19 patients with cardiovascular comorbidities.

Pharmacol Ther 2020 11 9;215:107628. Epub 2020 Jul 9.

Division of Cardiology, Department of Internal Medicine and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic is caused by a newly emerged coronavirus (CoV) called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2). COVID-19 patients with cardiovascular disease (CVD) comorbidities have significantly increased morbidity and mortality. The use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor type 1 blockers (ARBs) improve CVD outcomes; however, there is concern that they may worsen the prognosis of CVD patients that become infected with SARS-CoV-2 because the virus uses the ACE2 receptor to bind to and subsequently infect host cells. Thus, some health care providers and media sources have questioned the continued use of ACE inhibitors and ARBs. In this brief review, we discuss the effect of ACE inhibitor-induced bradykinin on the cardiovascular system, on the renin-angiotensin-aldosterone system (RAAS) regulation in COVID-19 patients, and analyze recent clinical studies regarding patients treated with RAAS inhibitors. We propose that the application of RAAS inhibitors for COVID-19 patients with CVDs may be beneficial rather than harmful.
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http://dx.doi.org/10.1016/j.pharmthera.2020.107628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346797PMC
November 2020

Role of linoleic acid-derived oxylipins in cancer.

Cancer Metastasis Rev 2020 09;39(3):581-582

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Building 101, Room A214, Research Triangle Park, Durham, NC, 27709, USA.

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http://dx.doi.org/10.1007/s10555-020-09904-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487010PMC
September 2020

Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.

FASEB J 2020 08 27;34(8):10027-10040. Epub 2020 Jun 27.

Centre for Immunobiology, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A , a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA , prostaglandin (PG) F , 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA and PGE . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI and PGD at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.
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http://dx.doi.org/10.1096/fj.202000312RDOI Listing
August 2020

Phl p 4: An early indicator of grass pollen allergy?

J Allergy Clin Immunol 2020 06;145(6):1556-1557

National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.011DOI Listing
June 2020

Higher Epoxyeicosatrienoic Acids in Cardiomyocytes-Specific CYP2J2 Transgenic Mice Are Associated with Improved Myocardial Remodeling.

Biomedicines 2020 May 30;8(6). Epub 2020 May 30.

Department of Medicinal Chemistry, University of Washington, Box 357610, Seattle, WA 98195, USA.

Elevated epoxyeicosatrienoic acids (EETs) are known to be cardioprotective during ischemia-reperfusion injury in cardiomyocyte-specific overexpressing cytochrome P450 2J2 (CYP2J2) transgenic (Tr) mice. Using the same Tr mice, we measured changes in cardiac and erythrocyte membranes EETs following myocardial infarction (MI) to determine if they can serve as reporters for cardiac events. Cardiac function was also assessed in Tr vs. wild-type (WT) mice in correlation with EET changes two weeks following MI. Tr mice (N = 25, 16 female, nine male) had significantly higher cardiac and EETs compared to their WT counterparts (N=25, 18 female, seven male). Total cardiac EETs in Tr mice were positively correlated with total EETs in erythrocyte membrane, but there was no correlation with EETs or in WT mice. Following MI, and EETs were elevated in the erythrocyte membrane and cardiac tissue in Tr mice, accounting for the improved cardiac outcomes observed. Tr mice showed significantly better myocardial remodeling following MI, evidenced by higher % fractional shortening, smaller infarct size, lower reactive oxygen species (ROS) formation, reduced fibrosis and apoptosis, and lower pulmonary edema. A positive correlation between total cardiac EETs and total erythrocyte membrane EETs in a Tr mouse model suggests that erythrocyte EETs may be used as predictive markers for cardiac events. All EET regioisomers displayed similar trends following acute MI; however, the magnitude of change for each regioisomer was markedly different, warranting measurement of each individually.
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http://dx.doi.org/10.3390/biomedicines8060144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344501PMC
May 2020

Vascular Lipidomic Profiling of Potential Endogenous Fatty Acid PPAR Ligands Reveals the Coronary Artery as Major Producer of CYP450-Derived Epoxy Fatty Acids.

Cells 2020 04 29;9(5). Epub 2020 Apr 29.

North Cornwall Research Institute, Bude, Cornwall EX23 9EE, UK.

A number of oxylipins have been described as endogenous PPAR ligands. The very short biological half-lives of oxylipins suggest roles as autocrine or paracrine signaling molecules. While coronary arterial atherosclerosis is the root of myocardial infarction, aortic atherosclerotic plaque formation is a common readout of in vivo atherosclerosis studies in mice. Improved understanding of the compartmentalized sources of oxylipin PPAR ligands will increase our knowledge of the roles of PPAR signaling in diverse vascular tissues. Here, we performed a targeted lipidomic analysis of ex vivo-generated oxylipins from porcine aorta, coronary artery, pulmonary artery and perivascular adipose. Cyclooxygenase (COX)-derived prostanoids were the most abundant detectable oxylipin from all tissues. By contrast, the coronary artery produced significantly higher levels of oxylipins from CYP450 pathways than other tissues. The TLR4 ligand LPS induced prostanoid formation in all vascular tissue tested. The 11-HETE, 15-HETE, and 9-HODE were also induced by LPS from the aorta and pulmonary artery but not coronary artery. Epoxy fatty acid (EpFA) formation was largely unaffected by LPS. The pig CYP2J homologue CYP2J34 was expressed in porcine vascular tissue and primary coronary artery smooth muscle cells (pCASMCs) in culture. Treatment of pCASMCs with LPS induced a robust profile of pro-inflammatory target genes: and . The soluble epoxide hydrolase inhibitor TPPU, which prevents the breakdown of endogenous CYP-derived EpFAs, significantly suppressed LPS-induced inflammatory target genes. In conclusion, PPAR-activating oxylipins are produced and regulated in a vascular site-specific manner. The CYP450 pathway is highly active in the coronary artery and capable of providing anti-inflammatory oxylipins that prevent processes of inflammatory vascular disease progression.
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http://dx.doi.org/10.3390/cells9051096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290345PMC
April 2020

Use of National Asthma Guidelines by Allergists and Pulmonologists: A National Survey.

J Allergy Clin Immunol Pract 2020 10 25;8(9):3011-3020.e2. Epub 2020 Apr 25.

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.

Background: Little is known about specialist-specific variations in guideline agreement and adoption.

Objective: To assess similarities and differences between allergists and pulmonologists in adherence to cornerstone components of the National Asthma Education and Prevention Program's Third Expert Panel Report.

Methods: Self-reported guideline agreement, self-efficacy, and adherence were assessed in allergists (n = 134) and pulmonologists (n = 99) in the 2012 National Asthma Survey of Physicians. Multivariate models were used to assess if physician and practice characteristics explained bivariate associations between specialty and "almost always" adhering to recommendations (ie, ≥75% of the time).

Results: Allergists and pulmonologists reported high guideline self-efficacy and moderate guideline agreement. Both groups "almost always" assessed asthma control (66.2%, standard error [SE] 4.3), assessed school/work asthma triggers (71.3%, SE, 3.9), and endorsed inhaled corticosteroids use (95.5%, SE 2.0). Repeated assessment of the inhaler technique, use of asthma action/treatment plans, and spirometry were lower (39.7%, SE 4.0; 30.6%, SE 3.6; 44.7%, SE 4.1, respectively). Compared with pulmonologists, more allergists almost always performed spirometry (56.6% vs 38.6%, P = .06), asked about nighttime awakening (91.9% vs 76.5%, P = .03) and emergency department visits (92.2% vs 76.5%, P = .03), assessed home triggers (70.5% vs 52.6%, P = .06), and performed allergy testing (61.8% vs 21.3%, P < .001). In multivariate analyses, practice-specific characteristics explained differences except for allergy testing.

Conclusions: Overall, allergists and pulmonologists adhere to the asthma guidelines with notable exceptions, including asthma action plan use and inhaler technique assessment. Recommendations with low implementation offer opportunities for further exploration and could serve as targets for increasing guideline uptake.
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http://dx.doi.org/10.1016/j.jaip.2020.04.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554121PMC
October 2020

Identification of a homozygous recessive variant in resulting in a congenital aspirin-like defect in platelet function.

Haematologica 2021 05 1;106(5):1423-1432. Epub 2021 May 1.

Queen Mary University of London.

We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in PTGS1 (the gene encoding cyclo-oxygenase 1, COX-1, the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COX-derived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 (TXA2) formation by platelets, urinary TXA2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.
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http://dx.doi.org/10.3324/haematol.2019.235895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094108PMC
May 2021

Increasing Prevalence of Antinuclear Antibodies in the United States.

Arthritis Rheumatol 2020 06 30;72(6):1026-1035. Epub 2020 Apr 30.

National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina.

Objective: Growing evidence suggests increasing frequencies of autoimmunity and certain autoimmune diseases, but findings are limited by the lack of systematic data and evolving approaches and definitions. This study was undertaken to investigate whether the prevalence of antinuclear antibodies (ANA), the most common biomarker of autoimmunity, changed over a recent 25-year span in the US.

Methods: Serum ANA were measured by standard indirect immunofluorescence assays on HEp-2 cells in 14,211 participants age ≥12 years from the National Health and Nutrition Examination Survey, with approximately one-third from each of 3 time periods: 1988-1991, 1999-2004, and 2011-2012. We used logistic regression adjusted for sex, age, race/ethnicity, and survey design variables to estimate changes in ANA prevalence across the time periods.

Results: The prevalence of ANA was 11.0% (95% confidence interval [95% CI] 9.7-12.6%) in 1988-1991, 11.5% (95% CI 10.3-12.8%) in 1999-2004, and 15.9% (95% CI 14.3-17.6%) in 2011-2012 (P for trend < 0.0001), which corresponds to ~22 million, ~27 million, and ~41 million affected individuals, respectively. Among adolescents age 12-19 years, ANA prevalence increased substantially, with odds ratios (ORs) of 2.02 (95% CI 1.16-3.53) and 2.88 (95% CI 1.64-5.04) in the second and third time periods relative to the first (P for trend < 0.0001). ANA prevalence increased in both sexes (especially in men), older adults (age ≥50 years), and non-Hispanic whites. These increases in ANA prevalence were not explained by concurrent trends in weight (obesity/overweight), smoking exposure, or alcohol consumption.

Conclusion: The prevalence of ANA in the US has increased considerably in recent years. Additional studies to determine factors underlying these increases in ANA prevalence could elucidate causes of autoimmunity and enable the development of preventative measures.
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http://dx.doi.org/10.1002/art.41214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255943PMC
June 2020

Endotoxin clustering with allergens in house dust and asthma outcomes in a U.S. national study.

Environ Health 2020 03 16;19(1):35. Epub 2020 Mar 16.

Department of Occupational and Environmental Health, University of Iowa, Iowa City, Iowa, USA.

Background: Endotoxin is ubiquitous in the environment, but its clustering with indoor allergens is not well characterized. This study examined the clustering patterns of endotoxin with allergens in house dust and their association with asthma outcomes.

Methods: We analyzed data from 6963 participants of the 2005-2006 National Health and Nutrition Examination Survey. House dust sampled from bedroom floor and bedding was evaluated for endotoxin and allergens from fungi, cockroach, dog, cat, mites, and rodents. Two-step cluster analysis and logistic regressions were performed to identify the clustering patterns and their associations with current asthma and wheeze in the past 12 months, adjusting for covariates.

Results: Of the homes, 17.8% had low endotoxin and allergen levels in house dust (Cluster 1). High endotoxin level clustered with Alternaria and pet allergens in the homes of participants with a high socioeconomic status who own pets (Cluster 2) (48.9%). High endotoxin clustered with Aspergillus, dust mites, cockroach, and rodent allergens in the homes of participants with low socioeconomic status (Cluster 3) (33.3%). Compared to Cluster 1, Cluster 2 was associated with higher asthma prevalence (OR 1.42, 95% CI: 1.06-1.91) and wheeze (OR 1.32, 95% CI: 1.07-1.63). Cluster 3 was positively associated with wheeze only in participants sensitized to inhalant allergens (OR 1.42, 95% CI: 1.06-1.91) or exposed to tobacco smoke (OR 1.72, 95% CI: 1.15-2.60).

Conclusions: The clustering of endotoxin with allergens in dust from homes with pets or of people with low socioeconomic status is associated with asthma and wheeze.
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http://dx.doi.org/10.1186/s12940-020-00585-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077112PMC
March 2020

-Gene Deletion Affects on Acetylcholine and Adenosine-Induced Relaxation in Mice: Role of Angiotensin-II and CYP-Epoxygenase Inhibitor.

Front Pharmacol 2020 5;11:27. Epub 2020 Feb 5.

Pharmaceutical Sciences, School of Pharmacy, Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV, United States.

Previously, we showed vascular endothelial overexpression of human-CYP2J2 enhances coronary reactive hyperemia in Tie2-CYP2J2 Tr mice, and eNOS mice had overexpression of CYP2J-epoxygenase with adenosine A receptor-induced enhance relaxation, but we did not see the response in CYP2J-epoxygenase knockout mice. Therefore, we hypothesized that -gene deletion affects acetylcholine- and 5'-N-ethylcarboxamidoadenosine (NECA) (adenosine)-induced relaxation and their response is partially inhibited by angiotensin-II (Ang-II) in mice. Acetylcholine (Ach)-induced response was tested with -(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH, CYP-epoxygenase inhibitor; 10M) and Ang-II (10M). In mice, ACh-induced relaxation was different from C57Bl/6 mice, at 10 M (76.1 ± 3.3 58.3 ± 5.2, < 0.05). However, ACh-induced relaxation was not blocked by MS-PPOH in : 58.5 ± 5.0%, > 0.05, but blocked in C57Bl/6: 52.3 ± 7.5%, < 0.05, and Ang-II reduces ACh-induced relaxation in both and C57Bl/6 mice (38.8 ± 3.9% and 45.9 ± 7.8, 0.05). In addition, NECA-induced response was tested with Ang-II. In mice, NECA-induced response was not different from C57Bl/6 mice at 10M (23.1 ± 2.1 21.1 ± 3.8, > 0.05). However, NECA-induced response was reduced by Ang-II in both and C57Bl/6 mice (-10.8 ± 2.3% and 3.2 ± 2.7, 0.05). Data suggest that ACh-induced relaxation in mice depends on nitric oxide (NO) but not CYP-epoxygenases, and the NECA-induced different response in male female mice when Ang-II treated.
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http://dx.doi.org/10.3389/fphar.2020.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014568PMC
February 2020

Validation of Questionnaire-based Case Definitions for Chronic Obstructive Pulmonary Disease.

Epidemiology 2020 05;31(3):459-466

Division of Intramural Research, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC.

Background: Various questionnaire-based definitions of chronic obstructive pulmonary disease (COPD) have been applied using the US representative National Health and Nutrition Examination Survey (NHANES), but few have been validated against objective lung function data. We validated two prior definitions that incorporated self-reported physician diagnosis, respiratory symptoms, and/or smoking. We also validated a new definition that we developed empirically using gradient boosting, an ensemble machine learning method.

Methods: Data came from 7,996 individuals 40-79 years who participated in NHANES 2007-2012 and underwent spirometry. We considered participants "true" COPD cases if their ratio of postbronchodilator forced expiratory volume in 1 second to forced vital capacity was below 0.7 or the lower limit of normal. We stratified all analyses by smoking history. We developed a gradient boosting model for smokers only; predictors assessed (25 total) included sociodemographics, inhalant exposures, clinical variables, and respiratory symptoms.

Results: The spirometry-based COPD prevalence was 26% for smokers and 8% for never smokers. Among smokers, using questionnaire-based definitions resulted in a COPD prevalence ranging from 11% to 16%, sensitivity ranging from 18% to 35%, and specificity ranging from 88% to 92%. The new definition classified participants based on age, bronchodilator use, body mass index (BMI), smoking pack-years, and occupational organic dust exposure, and resulted in the highest sensitivity (35%) and specificity (92%) among smokers. Among never smokers, the COPD prevalence ranged from 4% to 5%, and we attained good specificity (96%) at the expense of sensitivity (9-10%).

Conclusion: Our results can be used to parametrize misclassification assumptions for quantitative bias analysis when pulmonary function data are unavailable.
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http://dx.doi.org/10.1097/EDE.0000000000001176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138734PMC
May 2020

Association of urinary levels of bisphenols F and S used as bisphenol A substitutes with asthma and hay fever outcomes.

Environ Res 2020 04 22;183:108944. Epub 2019 Nov 22.

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. Electronic address:

Background: Bisphenols F (BPF) and S (BPS) are bisphenol A (BPA) analogs used as substitutes in consumer products. Despite previous reports of BPA's association with asthma, no studies have examined its structural analogs in relation to asthma and allergy outcomes.

Objective: To examine the association of urinary BPF, BPS, and BPA with asthma and hay fever in a US representative sample.

Methods: We analyzed data from 3,538 participants aged 12 years or older in the 2013-2016 National Health and Nutrition Examination Survey (NHANES). Children aged 6-11 years (N = 738), who did not have all covariate data available, were analyzed separately. Covariate-adjusted logistic regression was used to assess the association of the exposures with the outcomes.

Results: BPF, BPS, and BPA were detected in 57.1%, 88.4%, and 94.8% of the urine samples, respectively. Urinary BPF detection was positively associated with current asthma (odds ratio [OR]: 1.54, 95% confidence interval [CI]: 1.16-2.04) and hay fever (OR: 1.66, 95% CI: 1.12-2.46). Urinary BPS was associated with increased odds of current asthma in men (OR: 1.64, 95% CI: 1.13-2.40) and urinary BPA was associated with increased odds of asthma without hay fever in children aged 6-11 years (OR: 2.65, 95% CI: 1.05-6.68).

Conclusion: Our nationally-representative findings document that BPF and BPS exposure is common in the US and that exposure to these BPA analogs is associated with asthma and/or hay fever. Our results suggest that BPF and BPS may not be safe alternatives to BPA; however, prospective studies should be conducted to confirm these results.
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http://dx.doi.org/10.1016/j.envres.2019.108944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167336PMC
April 2020

Ephx2-gene deletion affects acetylcholine-induced relaxation in angiotensin-II infused mice: role of nitric oxide and CYP-epoxygenases.

Mol Cell Biochem 2020 Feb 4;465(1-2):37-51. Epub 2019 Dec 4.

Pharmaceutical Sciences, School of Pharmacy, West Virginia University, Morgantown, WV, USA.

Previously, we showed that adenosine A receptor induces relaxation independent of NO in soluble epoxide hydrolase-null mice (Nayeem et al. in Am J Physiol Regul Integr Comp Physiol 304:R23-R32, 2013). Currently, we hypothesize that Ephx2-gene deletion affects acetylcholine (Ach)-induced relaxation which is independent of AAR but dependent on NO and CYP-epoxygenases. Ephx2 aortas showed a lack of sEH (97.1%, P < 0.05) but an increase in microsomal epoxide hydrolase (mEH, 37%, P < 0.05) proteins compared to C57Bl/6 mice, and no change in CYP2C29 and CYP2J protein (P > 0.05). Ach-induced response was tested with nitro-L-arginine methyl ester (L-NAME) NO-inhibitor; 10 M), N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) (CYP-epoxygenase inhibitor; 10 M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10 M), SCH-58261 (AAR-antagonist; 10 M), and angiotensin-II (Ang-II, 10 M). In Ephx2 mice, Ach-induced relaxation was not different from C57Bl/6 mice except at 10 M (92.75 ± 2.41 vs. 76.12 ± 3.34, P < 0.05). However, Ach-induced relaxation was inhibited with L-NAME (Ephx2: 23.74 ± 3.76% and C57Bl/6: 11.61 ± 2.82%), MS-PPOH (Ephx2: 48.16 ± 6.53% and C57Bl/6: 52.27 ± 7.47%), and 14,15-EEZE (Ephx2: 44.29 ± 8.33% and C57Bl/6: 39.27 ± 7.47%) vs. non-treated (P < 0.05). But, it did not block with SCH-58261 (Ephx2: 68.75 ± 11.41% and C57Bl/6: 66.26 ± 9.43%, P > 0.05) vs. non-treated (P > 0.05). Interestingly, Ang-II attenuates less relaxation in Ehx2 vs. C57Bl/6 mice (58.80 ± 7.81% vs. 45.92 ± 7.76, P < 0.05). Our data suggest that Ach-induced relaxation in Ephx2 mice depends on NO and CYP-epoxygenases but not on A AR, and Ephx2-gene deletion attenuates less Ach-induced relaxation in Ang-II-infused mice.
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http://dx.doi.org/10.1007/s11010-019-03665-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957727PMC
February 2020

Transethnic associations among immune-mediated diseases and single-nucleotide polymorphisms of the aryl hydrocarbon response gene ARNT and the PTPN22 immune regulatory gene.

J Autoimmun 2020 02 21;107:102363. Epub 2019 Nov 21.

Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, USA; Research Triangle Park, NC, USA; Bethesda, MD, USA. Electronic address:

Background: Because immune responses are sensitive to environmental changes that drive selection of genetic variants, we hypothesized that polymorphisms of some xenobiotic response and immune response genes may be associated with specific types of immune-mediated diseases (IMD), while others may be associated with IMD as a larger category regardless of specific phenotype or ethnicity.

Objective: To examine transethnic gene-IMD associations for single nucleotide polymorphism (SNP) frequencies of prototypic xenobiotic response genes-aryl hydrocarbon receptor (AHR), AHR nuclear translocator (ARNT), AHR repressor (AHRR) - and a prototypic immune response gene, protein tyrosine phosphatase, non-receptor type 22 (PTPN22), in subjects from the Environmental Polymorphisms Registry (EPR).

Methods: Subjects (n = 3731) were genotyped for 14 SNPs associated with functional variants of the AHR, ARNT, AHRR, and PTPN22 genes, and their frequencies were compared among African Americans (n = 1562), Caucasians (n = 1838), and Hispanics (n = 331) with previously reported data. Of those genotyped, 2015 EPR subjects completed a Health and Exposure survey. SNPs were assessed via PLINK for associations with IMD, which included those with autoimmune diseases, allergic disorders, asthma, or idiopathic pulmonary fibrosis. Transethnic meta-analyses were performed using METAL and MANTRA approaches.

Results: ARNT SNP rs11204735 was significantly associated with autoimmune disease by transethnic meta-analyses using METAL (odds ratio, OR [95% confidence interval] = 1.29 [1.08-1.55]) and MANTRA (ORs ranged from 1.29 to 1.30), whereas ARNT SNP rs1889740 showed a significant association with autoimmune disease by METAL (OR = 1.25 [1.06-1.47]). For Caucasian females, PTPN22 SNP rs2476601 was significantly associated with autoimmune disease by allelic association tests (OR = 1.99, [1.30-3.04]). In Caucasians and Caucasian males, PTPN22 SNP rs3811021 was significantly associated with IMD (OR = 1.39 [1.12-1.72] and 1.50 [1.12-2.02], respectively) and allergic disease (OR = 1.39 [1.12-1.71], and 1.62 [1.19-2.20], respectively). In the transethnic meta-analysis, PTPN22 SNP rs3811021 was significantly implicated in IMD by METAL (OR = 1.31 [1.10-1.56]), and both METAL and MANTRA suggested that rs3811021 was associated with IMD and allergic disease in males across all three ethnic groups (IMD METAL OR = 1.50 [1.15-1.95]; IMD MANTRA ORs ranged from 1.47 to 1.50; allergic disease METAL OR = 1.58 [1.20-2.08]; allergic disease MANTRA ORs ranged from 1.55 to 1.59).

Conclusions: Some xenobiotic and immune response gene polymorphisms were shown here, for the first time, to have associations across a broad spectrum of IMD and ethnicities. Our findings also suggest a role for ARNT in the development of autoimmune diseases, implicating environmental factors metabolized by this pathway in pathogenesis. Further studies are needed to confirm these data, assess the implications of these findings, define gene-environment interactions, and explore the mechanisms leading to these increasingly prevalent disorders.
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http://dx.doi.org/10.1016/j.jaut.2019.102363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237321PMC
February 2020

Expression of / subfamily members and oxylipin levels during LPS-induced inflammation and resolution in mice.

FASEB J 2019 12 5;33(12):14784-14797. Epub 2019 Nov 5.

Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA.

Inflammatory stimuli, such as bacterial LPS, alter the expression of many cytochromes P450. CYP2C and CYP2J subfamily members actively metabolize fatty acids to bioactive eicosanoids, which exhibit potent anti-inflammatory effects. Herein, we examined mRNA levels of the 15 mouse and 7 mouse isoforms in liver, kidney, duodenum, and brain over a 96-h time course of LPS-induced inflammation and resolution. Plasma and liver eicosanoid levels were also measured by liquid chromatography with tandem mass spectrometry. Expression changes in and isoforms were both isoform and tissue specific. Total liver and mRNA content was reduced by 80% 24 h after LPS but recovered to baseline levels by 96 h. Total and mRNA in kidney (-19%) and duodenum (-64%) were reduced 24 h after LPS but recovered above baseline by 72 h. Total and mRNA content in brain was elevated at all time points after LPS dosing. Plasma eicosanoids transiently increased 3-6 h after administration of LPS. In liver, esterified oxylipin levels decreased during acute inflammation and before recovering. The biphasic suppression and recovery of mouse and isoforms and associated changes in eicosanoid levels during LPS-induced inflammation and resolution may have important physiologic consequences.-Graves, J. P., Bradbury, J. A., Gruzdev, A., Li, H., Duval, C., Lih, F. B., Edin, M. L., Zeldin, D. C. Expression of / subfamily members and oxylipin levels during LPS-induced inflammation and resolution in mice.
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http://dx.doi.org/10.1096/fj.201901872RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894073PMC
December 2019

Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.

Cardiovasc Res 2020 10;116(12):1972-1980

National Heart & Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.

Aims: Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA.

Methods And Results: Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors.

Conclusion: These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA.
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http://dx.doi.org/10.1093/cvr/cvz290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519887PMC
October 2020

The Distinguished Legacy of Linda S. Birnbaum, an Environmental Health Champion.

Environ Health Perspect 2019 10 22;127(10):101001. Epub 2019 Oct 22.

Division of Intramural Research, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, USA.

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http://dx.doi.org/10.1289/EHP6332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910772PMC
October 2019

Introduction.

Adv Exp Med Biol 2019 ;1161:1-2

Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.

In addition to this introduction, this book contains 18 outstanding chapters based on comprehensive and detailed reviews of timely topics presented at the 15th International Conference on Bioactive Lipids in Cancer, Inflammation and Related Diseases held in Puerto Vallarta, Mexico on October 22-25, 2017.
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http://dx.doi.org/10.1007/978-3-030-21735-8_1DOI Listing
October 2019

Author Correction: Epoxyeicosatrienoic acids enhance embryonic haematopoiesis and adult marrow engraftment.

Nature 2019 Sep;573(7772):E1

Stem Cell Program and Division of Haematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA, 02115, USA.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41586-019-1489-4DOI Listing
September 2019