Summary of Study ST001423

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR000730. The data can be accessed directly via it's Project DOI: 10.21228/M89X1C This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST001423
Study TitleAspirin Metabolomics in Colorectal Cancer Chemoprevention - blood (part-III)
Study SummarySubstantial evidence supports the effectiveness of aspirin for cancer chemoprevention in addition to its well established role in cardiovascular protection. In recent meta-analyses of randomized controlled trials in human, daily aspirin use reduced incidence, metastasis and mortality from several common types of cancer, especially colorectal cancer. The mechanism(s) by which aspirin exerts an anticancer benefit is uncertain; numerous effects have been described involving both cyclooxygenase-dependent and -independent pathways. The goal of this research is to elucidate the key metabolic changes that are responsible for the anticancer effects of aspirin in humans using untargeted metabolomics analysis. Metabolomics, or global metabolite profiling, is an emerging discipline that has the potential to transform the study of pharmaceutical agents. Our innovative approach will use high-resolution mass spectroscopy to detect thousands of metabolites in blood plasma that were collected from participants in the Aspirin/Folate Polyp Prevention Study, a randomized, double-blind, placebo-controlled trial of aspirin for the prevention of colorectal adenomas. Participants in the trial were assigned with equal probability to three aspirin treatment arms (placebo, 81mg, or 325mg daily). Over the three-year period, 81mg/day of aspirin reduced the risk of adenomas, whereas the 325 mg/day dose had less effect. The aims of the current proposal are to identify metabolomic signatures, including specific metabolites and metabolic pathways, that are associated with aspirin treatment in blood after three years of randomized aspirin treatment; and then to assess the associations of these metabolic signatures with adenoma risk and whether they mediate the reductions in risk due to 81 mg/day aspirin treatment. We will prioritize metabolites for study by evaluating metabolite levels in patients from the placebo and treatment arms while controlling the false discovery rate, use correlation analysis to enhance identification of relevant metabolic modules associated with these prioritized metabolites, and apply pathway mapping with post-hoc application of ion dissociation spectroscopy to representative metabolites to confirm pathway identification. Because aspirin is a multifunctional drug that is thought to modify numerous pathways with potential roles in carcinogenesis, a global discovery-based metabolomics approach is the best way to identify its key activities. The public health significance of this work is substantial because understanding the mechanism of aspirin's anticancer effects is key to optimizing its use and to the development of novel drugs targeting the metabolic pathways identified.
Institute
Emory University
DepartmentSchool of Medicine
LaboratoryClincal Biomarkers Laboratory
Last NameUppal
First NameKaran
Address615 Michael St, Suite 225
Emailkuppal2@emory.edu
Phone(404) 727 5027
Submit Date2019-11-07
Total Subjects446
Study CommentsAspirin Metabolomics Priority 2
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2020-07-20
Release Version1
Karan Uppal Karan Uppal
https://dx.doi.org/10.21228/M89X1C
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:


Project:

Project ID:PR000730
Project DOI:doi: 10.21228/M89X1C
Project Title:Aspirin Metabolomics in Colorectal Cancer Chemoprevention (part 1 - Colon)
Project Type:NIH/NCI R01CA188038
Project Summary:Substantial evidence supports the effectiveness of aspirin for cancer chemoprevention in addition to its well established role in cardiovascular protection. In recent meta-analyses of randomized controlled trials in humans, daily aspirin use reduced incidence, metastasis and mortality from several common types of cancer, especially colorectal cancer. The mechanism(s) by which aspirin exerts an anticancer benefit is uncertain; numerous effects have been described involving both cyclooxygenase-dependent and -independent pathways. The goal of this research is to elucidate the key metabolic changes that are responsible for the anticancer effects of aspirin in humans using untargeted metabolomics analysis. Metabolomics, or global metabolite profiling, is an emerging discipline that has the potential to transform the study of pharmaceutical agents. Our innovative approach will use high-resolution mass spectroscopy to detect thousands of metabolites in blood plasma and normal colon mucosa biopsies that were collected from participants in the Aspirin/Folate Polyp Prevention Study, a randomized, double-blind, placebo-controlled trial of aspirin and/or folic acid supplementation for the prevention of colorectal adenomas. Participants in the trial were assigned with equal probability to three aspirin treatment arms (placebo, 81 mg, or 325 mg daily). Over the three-year treatment period, 81 mg/day of aspirin reduced the risk of adenomas, whereas the 325 mg/day dose had less effect. The aims of the current proposal are to identify metabolomic signatures, including specific metabolites and metabolic pathways, that are associated with aspirin treatment in blood and normal colon mucosal tissue of participants after three years of randomized aspirin treatment; and then to assess the associations of these metabolic signatures with adenoma risk and whether they mediate the reductions in risk due to 81 mg/day aspirin treatment. We will prioritize metabolites for study by evaluating metabolite levels in patients from the placebo and treatment arms while controlling the false discovery rate, use correlation analysis to enhance identification of relevant metabolic modules associated with these prioritized metabolites, and apply pathway mapping with post-hoc application of ion dissociation spectroscopy to representative metabolites to confirm pathway identification. Because aspirin is a multifunctional drug that is thought to modify numerous pathways with potential roles in carcinogenesis, a global discovery-based metabolomics approach is the best way to identify its key activities. The public health significance of this work is substantial because understanding the mechanism of aspirin’s anticancer effects is key to optimizing its use and to the development of novel drugs targeting the metabolic pathways identified.
Institute:Emory University
Department:School of Medicine
Laboratory:Clinical Biomarkers Laboratory
Last Name:Uppal
First Name:Karan
Address:615 Michael Street, Atlanta, GA, 30322, USA
Email:kuppal2@emory.edu
Phone:(404) 727 5027
Funding Source:NIH/NCI R01CA188038
Project Comments:Requested embargo date: 8/1/2019
Contributors:Dartmouth: Elizabeth Barry Leila Mott John Baron Christopher Amos Michael Passarelli Emory: Dean Jones Veronika Fedirko Karan Uppal Shuzhao Li Douglas Walker Yutong Jin Chunyu Ma

Subject:

Subject ID:SU001497
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Age Or Age Range:29-82
Gender:Male and female

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Sex Treatment
SA119238400106839_1F 325mg
SA11923940006183_1F 325mg
SA11924040001563_1F 325mg
SA119241400106840_1F 325mg
SA11924240000678_1F 325mg
SA11924340005384_1F 325mg
SA11924440000679_1F 325mg
SA119245400106489_1F 325mg
SA119246400105909_1F 325mg
SA11924740006620_1F 325mg
SA11924840006598_1F 325mg
SA11924940007108_1F 325mg
SA11925040005829_1F 325mg
SA11925140005843_1F 325mg
SA11925240000757_1F 325mg
SA11925340015382_1F 325mg
SA11925440005670_1F 325mg
SA119255400106404_1F 325mg
SA11925640003327_1F 325mg
SA11925740000451_1F 325mg
SA11925840001317_1F 325mg
SA11925940002097_1F 325mg
SA11926040006745_1F 325mg
SA11926140002605_1F 325mg
SA11926240015408_1F 325mg
SA11926340002208_1F 325mg
SA11926440003744_1F 325mg
SA11926540000548_1F 325mg
SA11926640005824_1F 325mg
SA119267400106545_1F 325mg
SA11926840000549_1F 325mg
SA11926940015590_1F 325mg
SA11927040005735_1F 325mg
SA11927140003788_1F 325mg
SA11927240003519_1F 325mg
SA11927340005368_1F 325mg
SA11927440001038_1F 325mg
SA11927540015520_1F 325mg
SA11927640006953_1F 325mg
SA119277400105794_1F 325mg
SA119278400105795_1F 325mg
SA11927940000207_1F 325mg
SA11928040000208_1F 325mg
SA11928140006699_1F 325mg
SA11928240021544_1F 325mg
SA11928340022736_1F 325mg
SA11928440001342_1F 81mg
SA11928540002312_1F 81mg
SA11928640002174_1F 81mg
SA11928740006512_1F 81mg
SA119288400106676_1F 81mg
SA11928940005905_1F 81mg
SA11929040001423_1F 81mg
SA119291400106609_1F 81mg
SA11929240006377_1F 81mg
SA11929340005406_1F 81mg
SA11929440000837_1F 81mg
SA11929540002499_1F 81mg
SA11929640000265_1F 81mg
SA11929740005944_1F 81mg
SA11929840006562_1F 81mg
SA11929940006335_1F 81mg
SA11930040002098_1F 81mg
SA11930140000862_1F 81mg
SA11930240005493_1F 81mg
SA11930340022480_1F 81mg
SA11930440005537_1F 81mg
SA11930540003330_1F 81mg
SA11930640001792_1F 81mg
SA11930740003356_1F 81mg
SA11930840006974_1F 81mg
SA11930940005633_1F 81mg
SA11931040002197_1F 81mg
SA11931140006320_1F 81mg
SA11931240000718_1F 81mg
SA11931340002314_1F 81mg
SA119314400106736_1F 81mg
SA11931540005739_1F 81mg
SA11931640005521_1F 81mg
SA11931740005754_1F 81mg
SA11931840001351_1F 81mg
SA11931940001345_1F 81mg
SA11932040006035_1F 81mg
SA11932140001489_1F 81mg
SA11932240000606_1F 81mg
SA11932340002539_1F 81mg
SA11932440000447_1F 81mg
SA119325400106480_1F 81mg
SA11932640000448_1F 81mg
SA11932740001426_1F 81mg
SA11932840000721_1F 81mg
SA11932940022886_1F 81mg
SA11933040000872_1F 81mg
SA11933140003495_1F 81mg
SA11933240003440_1F 81mg
SA11933340015435_1F 81mg
SA11933440001756_1F 81mg
SA119335400105980_1F 81mg
SA11933640005557_1F 81mg
SA11933740003365_1F 81mg
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Collection:

Collection ID:CO001492
Collection Summary:Blood plasma samples were collected from non-fasting participants in the Aspirin/Folate Polyp Prevention Study at enrollment (baseline) and after three years of study treatment. Blood samples were collected in tubes containing EDTA and after centrifugation aliquots of plasma were transferred to 1.8ml freezer tubes and stored frozen at -20C or lower. The samples were shipped on dry ice from the clinical centers to the Dartmouth biorepository storage facility (for storage at -70C) and subsequently to the metabolomics analysis lab at Emory University.
Sample Type:Blood (plasma)
Storage Conditions:Described in summary

Treatment:

Treatment ID:TR001512
Treatment Summary:Samples were received frozen in aliquouts of <250uL. Prior to analysis, samples were thawed and prepared for HRM analysis using the standard protocols described in the Sample Preparation section.

Sample Preparation:

Sampleprep ID:SP001505
Sampleprep Summary:Samples were prepared for metabolomics analysis using established methods(Johnson et al. (2010). Analyst; Go et al. (2015). Tox Sci). Prior to analysis, plasma aliquots were removed from storage at -80 degrees C and thawed on ice. Each cryotube was then vortexed briefly to ensure homogeneity, and 50 microliters was transferred to a clean microfuge tube. Immediately after, the plasma was treated with 100 microliters of ice-cold LC-MS grade acetonitrile (Sigma Aldrich) containing 2.5 microliters of internal standard solution with eight stable isotopic chemicals selected to cover a range of chemical properties. Following addition of acetonitrile, urine was equilibrated for 30 min on ice, upon which precipitated proteins were removed by centrifuge (14,000rpm at 4 degrees C for 10 min). The resulting supernatant (100 microliters) was removed, added to a low volume autosampler vial and maintained at 4 degrees C until analysis (<22 h).
Sampleprep Protocol ID:HRM_SP_082016_01
Sampleprep Protocol Filename:EmoryUniversity_HRM_SP_082016_01.pdf
Sampleprep Protocol Comments:Date effective: 30 July 2016
Processing Storage Conditions:On ice
Extraction Method:2:1 acetonitrile: sample followed by vortexing and centrifugation
Extract Storage:4℃

Combined analysis:

Analysis ID AN002380 AN002381
Analysis type MS MS
Chromatography type HILIC Reversed phase
Chromatography system Dionex UltiMate 3000 Dionex UltiMate 3000
Column Thermo Fisher Accucore HILIC with guard cartridge(50x2.1mm 2.6u) Thermo Fisher Accucore HILIC with guard cartridge(50x2.1mm 2.6u)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive HF hybrid Orbitrap Thermo Q Exactive HF hybrid Orbitrap
Ion Mode POSITIVE POSITIVE
Units peak area peak area

Chromatography:

Chromatography ID:CH001747
Chromatography Summary:The HILIC column is operated parallel to reverse phase column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6-port switching valves. During operation of HILIC separation method, the MS is operated in positive ion mode and 10 microliters of sample is injected onto the HILIC column while the reverse phase column is flushing with wash solution. Flow rate is maintained at 0.35 mL/min until 2 min, increased to 0.4 mL/min at 6 min and held for 4 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 2% formic acid (v/v) in LC-MS grade water. Initial mobile phase conditions are 25% A, 70% B, 5% C hold for 2 min, with linear gradient to 75% A, 20% B, 5% C at 6 min, hold for 4 min, resulting in a total analytical run time of 10 min. During the flushing phase (reverse phase analytical separation), the HILIC column is equilibrated with a wash solution of 25% A, 70% B, 5% C.
Methods ID:2% formic acid in LC-MS grade water
Methods Filename:20160120_posHILIC120kres10min_ESI_c18poswash_acrore.meth
Chromatography Comments:Triplicate injections for each chromatography mode
Instrument Name:Dionex UltiMate 3000
Column Name:Thermo Fisher Accucore HILIC with guard cartridge(50x2.1mm 2.6u)
Column Temperature:60C
Sample Injection:10 uL
Solvent A:LC-MS grade water
Solvent B:LC-MS grade acetonitrile
Analytical Time:10 min
Sample Loop Size:15 uL
Sample Syringe Size:100 uL
Chromatography Type:HILIC
  
Chromatography ID:CH001748
Chromatography Summary:The C18 column is operated parallel to the HILIC column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6- port switching valves. During operation of the C18 method, the MS is operated in negative ion mode and 10 uL of sample is injected onto the C18 column while the HILIC column is flushing with wash solution. Flow rate is maintained at 0.35 mL/min until 2 min, increased to 0.4 mL/min at 6 min and held for 4 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 2% formic acid (v/v) in LC-MS grade water. Initial mobile phase conditions are 80% A, 15% B, 5% C hold for 0.5 min, with linear gradient to 0% A, 95% B, 5% C at 2 min, hold for 4 min, resulting in a total analytical run time of 10 min. During the flushing phase (HILIC analytical separation), the C18 column is equilibrated with a wash solution of 0% A, 95% B, 5% C until 7.5 min, followed by an equilibration solution of 80% A, 15% B, 5% C for 2.5 min.
Methods Filename:20160120_posC18120kres10mim_ESI_hilicposwash_acore.meth
Instrument Name:Dionex UltiMate 3000
Column Name:Thermo Fisher Accucore HILIC with guard cartridge(50x2.1mm 2.6u)
Column Temperature:60C
Flow Rate:0.35 mL/min for 2 min; linear increase to 0.4 mL/min at 6 min held for 4 min
Sample Injection:10 uL
Solvent A:LC-MS grade water
Solvent B:LC-MS grade acetonitrile
Analytical Time:10 min
Sample Loop Size:15 uL
Sample Syringe Size:100 uL
Chromatography Type:Reversed phase

MS:

MS ID:MS002222
Analysis ID:AN002380
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:None
Ion Mode:POSITIVE
Capillary Temperature:250C
Collision Gas:N2
Dry Gas Flow:45
Dry Gas Temp:150C
Mass Accuracy:< 3ppm
Spray Voltage:3500
Activation Parameter:5.00E+05
Activation Time:118ms
Interface Voltage:S-Lens RF level= 55
Analysis Protocol File:EmoryUniversity_HRM_QEHF-MS_092017_10min_v2
  
MS ID:MS002223
Analysis ID:AN002381
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:None
Ion Mode:POSITIVE
Capillary Temperature:250C
Collision Gas:N2
Dry Gas Flow:45
Dry Gas Temp:150C
Mass Accuracy:< 3ppm
Spray Voltage:-4000
Activation Parameter:5.00E+05
Activation Time:118ms
Interface Voltage:S-Lens RF level= 55
Analysis Protocol File:EmoryUniversity_HRM_QEHF-MS_092017_10min_v2
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