Summary of study ST001422

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 IDST001422
Study TitleAspirin Metabolomics in Colorectal Cancer Chemoprevention - blood (part-II)
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 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
DepartmentSchool of Medicine
LaboratoryClincal Biomarkers Laboratory
Last NameUppal
First NameKaran
Address615 Michael St, Suite 225
Emailkuppal2@emory.edu
Phone(404) 727 5027
Submit Date2019-10-31
Total Subjects600
Study CommentsAspirin Metabolomics Priority 1
Raw Data AvailableYes
Raw Data File Type(s).raw
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:SU001496
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
SA11854640002307_1F 325mg
SA11854740003627_1F 325mg
SA118548400106135_1F 325mg
SA11854940003566_1F 325mg
SA118550400106172_1F 325mg
SA118551400106587_1F 325mg
SA118552400106762_1F 325mg
SA11855340005601_1F 325mg
SA11855440001335_1F 325mg
SA11855540005940_1F 325mg
SA11855640005639_1F 325mg
SA118557400106173_1F 325mg
SA11855840006268_1F 325mg
SA11855940006802_1F 325mg
SA11856040003761_1F 325mg
SA11856140006950_1F 325mg
SA11856240005399_1F 325mg
SA11856340005504_1F 325mg
SA11856440000801_1F 325mg
SA118565400105963_1F 325mg
SA11856640003806_1F 325mg
SA11856740001011_1F 325mg
SA11856840001944_1F 325mg
SA11856940005762_1F 325mg
SA118570400105906_1F 325mg
SA11857140003700_1F 325mg
SA118572400106136_1F 325mg
SA11857340003635_1F 325mg
SA118574400106435_1F 325mg
SA118575400106434_1F 325mg
SA11857640006814_1F 325mg
SA11857740002253_1F 325mg
SA11857840000285_1F 325mg
SA118579400106156_1F 325mg
SA11858040002305_1F 325mg
SA11858140002465_1F 325mg
SA11858240015321_1F 325mg
SA11858340000005_1F 325mg
SA11858440001180_1F 325mg
SA11858540001816_1F 325mg
SA11858640003374_1F 325mg
SA11858740003336_1F 325mg
SA11858840001338_1F 325mg
SA11858940015178_1F 325mg
SA118590400106181_1F 325mg
SA11859140002047_1F 325mg
SA118592400106182_1F 325mg
SA11859340005486_1F 325mg
SA118594400106350_1F 325mg
SA11859540006697_1F 325mg
SA118596400106617_1F 325mg
SA11859740003483_1F 325mg
SA11859840003452_1F 325mg
SA11859940000431_1F 325mg
SA11860040001996_1F 325mg
SA11860140001410_1F 325mg
SA11860240005761_1F 325mg
SA11860340002184_1F 325mg
SA11860440006523_1F 325mg
SA11860540006375_1F 325mg
SA118606400105626_1F 325mg
SA118607400106472_1F 325mg
SA11860840005617_1F 325mg
SA11860940006540_1F 325mg
SA11861040005902_1F 325mg
SA11861140005779_1F 325mg
SA118612400106611_1F 325mg
SA11861340005878_1F 325mg
SA11861440001464_1F 325mg
SA11861540000347_1F 325mg
SA11861640006211_1F 325mg
SA11861740015354_1F 325mg
SA11861840000439_1F 81mg
SA11861940002591_1F 81mg
SA11862040001152_1F 81mg
SA11862140001975_1F 81mg
SA11862240000381_1F 81mg
SA118623400106178_1F 81mg
SA11862440006968_1F 81mg
SA11862540005529_1F 81mg
SA11862640007018_1F 81mg
SA11862740006272_1F 81mg
SA11862840001964_1F 81mg
SA11862940003359_1F 81mg
SA11863040006286_1F 81mg
SA11863140001659_1F 81mg
SA11863240000490_1F 81mg
SA11863340006820_1F 81mg
SA11863440006432_1F 81mg
SA11863540001366_1F 81mg
SA118636400106248_1F 81mg
SA11863740003350_1F 81mg
SA11863840000554_1F 81mg
SA11863940015952_1F 81mg
SA11864040002751_1F 81mg
SA11864140006979_1F 81mg
SA11864240001398_1F 81mg
SA11864340001937_1F 81mg
SA11864440000604_1F 81mg
SA11864540000603_1F 81mg
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Collection:

Collection ID:CO001491
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 metabolimics analysis lab at Emory University.
Sample Type:Blood (plasma)
Storage Conditions:Described in summary

Treatment:

Treatment ID:TR001511
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:SP001504
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 30min 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
Extraction Method:2:1 acetonitrile: sample followed by vortexing and centrifugation

Combined analysis:

Analysis ID AN002378 AN002379
Analysis type MS MS
Chromatography type HILIC Reversed phase
Chromatography system Dionex UltiMate 3000 Dionex UltiMate 3000
Column Thermo Fisher Accucore HILIC 50x2.1mm 2.6u with Thermo accucore HILIC guard cartridge Thermo Fisher Accucore C18 50x2.1mm 2.6u with Thermo accucore
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:CH001745
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 50x2.1mm 2.6u with Thermo accucore HILIC guard cartridge
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:CH001746
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 4min, 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 C18 50x2.1mm 2.6u with Thermo accucore
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:MS002220
Analysis ID:AN002378
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
  
MS ID:MS002221
Analysis ID:AN002379
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
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