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Grant Details

Grant Number: 3R01CA044684-18S1 Interpret this number
Primary Investigator: Sandler, Robert
Organization: Univ Of North Carolina Chapel Hill
Project Title: Inflammation, Obesity and Risk of Colorectal Adenomas
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is common in the United States and other Western countries. Compelling evidence indicates that environmental factors increase the risk of CRC. It is generally accepted that colorectal adenomas are precursors to CRC. Defining environmental and lifestyle factors that favor adenoma formation is integral to improved surveillance and prevention. Our group found that lower levels of apoptosis in normal appearing rectal mucosa and increased BMI were strong predictors of adenoma risk. This competing renewal will test the central hypothesis that systemic cytokines and adipokines or local biomarkers of inflammation predict risk for colorectal adenomas and low apoptosis within the normal colonic epithelium. The specific aims are: (1) To measure circulating biomarkers of inflammation, C- reactive protein, interleukin-6 (IL-6), and TNFa, and test for associations with adenomas and apoptosis. (2) To measure circulating adipokines leptin and adiponectin and test for associations with adenomas and apoptosis. (3) To assay local activation or expression of TNFa and IL6 to test the hypothesis that high levels these local biomarkers of inflammation correlate with increased adenoma risk or low apoptosis. (4) To assess activation of NFkB and STATS, anti-apoptotic transcription factors in colonic epithelial cells; these factors are activated by multiple cytokines, adipokines and insulin, and are linked to colorectal neoplasia. Study subjects will be 600 consenting male and female patients who meet eligibility criteria. Blood samples will be collected immediately before routine colonoscopy and pinch biopsies of normal rectal mucosa will be collected during colonoscopy. Apoptosis will be measured in biopsies using morphological light microscopy-based assays and caspase-3 immunohistochemistry. Plasma levels of cytokines and adipokines will be measured by ELISA. Local expression of TNFa and IL6 will be measured by real time PCR. Tissue levels of activated NFkB and STATS will be measured by electromobility shift assay. This study is a logical extension of previous research. The proposal has the potential to improve our understanding of the role of obesity and inflammation in the development of colorectal neoplasia and to predict mechanistic links between inflammation and adenoma risk. Ultimately the results may inform surveillance and prevention strategies.

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Publications

Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans.
Authors: Sanapareddy N, Legge RM, Jovov B, McCoy A, Burcal L, Araujo-Perez F, Randall TA, Galanko J, Benson A, Sandler RS, Rawls JF, Abdo Z, Fodor AA, Keku TO
Source: ISME J, 2012 Oct;6(10), p. 1858-68.
EPub date: 2012 May 24.
PMID: 22622349
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A high-fiber diet does not protect against asymptomatic diverticulosis.
Authors: Peery AF, Barrett PR, Park D, Rogers AJ, Galanko JA, Martin CF, Sandler RS
Source: Gastroenterology, 2012 Feb;142(2), p. 266-72.e1.
EPub date: 2011 Nov 4.
PMID: 22062360
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Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer.
Authors: Tippin BL, Levine AJ, Materi AM, Song WL, Keku TO, Goodman JE, Sansbury LB, Das S, Dai A, Kwong AM, Lin AM, Lin JM, Park JM, Patterson RE, Chlebowski RT, Garavito RM, Inoue T, Cho W, Lawson JA, Kapoor S, Kolonel LN, Le Marchand L, Haile RW, Sandler RS, Lin HJ
Source: Prostaglandins Other Lipid Mediat, 2012 Jan;97(1-2), p. 22-8.
EPub date: 2011 Jul 28.
PMID: 21821144
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Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas.
Authors: Shen XJ, Rawls JF, Randall T, Burcal L, Mpande CN, Jenkins N, Jovov B, Abdo Z, Sandler RS, Keku TO
Source: Gut Microbes, 2010 May-Jun;1(3), p. 138-47.
EPub date: 2010 May 13.
PMID: 20740058
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Apoptosis in normal rectal mucosa, baseline adenoma characteristics, and risk of future adenomas.
Authors: Keku TO, Amin A, Galanko J, Martin C, Schliebe B, Sandler RS
Source: Cancer Epidemiol Biomarkers Prev, 2008 Feb;17(2), p. 306-10.
PMID: 18268113
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Cell-specific effects of insulin receptor substrate-1 deficiency on normal and IGF-I-mediated colon growth.
Authors: Simmons JG, Ling Y, Wilkins H, Fuller CR, D'Ercole AJ, Fagin J, Lund PK
Source: Am J Physiol Gastrointest Liver Physiol, 2007 Nov;293(5), p. G995-1003.
EPub date: 2007 Sep 6.
PMID: 17823215
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Moderate alcohol consumption protects against colorectal adenomas in smokers.
Authors: Austin GL, Galanko JA, Martin CF, Sandler RS
Source: Dig Dis Sci, 2008 Jan;53(1), p. 116-22.
EPub date: 2007 May 18.
PMID: 17510802
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A diet high in fruits and low in meats reduces the risk of colorectal adenomas.
Authors: Austin GL, Adair LS, Galanko JA, Martin CF, Satia JA, Sandler RS
Source: J Nutr, 2007 Apr;137(4), p. 999-1004.
PMID: 17374667
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Suppressor of cytokine signaling-2 limits intestinal growth and enterotrophic actions of IGF-I in vivo.
Authors: Michaylira CZ, Simmons JG, Ramocki NM, Scull BP, McNaughton KK, Fuller CR, Lund PK
Source: Am J Physiol Gastrointest Liver Physiol, 2006 Sep;291(3), p. G472-81.
EPub date: 2006 Mar 30.
PMID: 16574995
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Selenium, apoptosis, and colorectal adenomas.
Authors: Connelly-Frost A, Poole C, Satia JA, Kupper LL, Millikan RC, Sandler RS
Source: Cancer Epidemiol Biomarkers Prev, 2006 Mar;15(3), p. 486-93.
PMID: 16537706
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Haplotype insufficiency for suppressor of cytokine signaling-2 enhances intestinal growth and promotes polyp formation in growth hormone-transgenic mice.
Authors: Michaylira CZ, Ramocki NM, Simmons JG, Tanner CK, McNaughton KK, Woosley JT, Greenhalgh CJ, Lund PK
Source: Endocrinology, 2006 Apr;147(4), p. 1632-41.
EPub date: 2006 Jan 12.
PMID: 16410303
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Does physical activity modify the association between body mass index and colorectal adenomas?
Authors: Guilera M, Connelly-Frost A, Keku TO, Martin CF, Galanko J, Sandler RS
Source: Nutr Cancer, 2005;51(2), p. 140-5.
PMID: 15860435
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Calcium, vitamin D, and apoptosis in the rectal epithelium.
Authors: Miller EA, Keku TO, Satia JA, Martin CF, Galanko JA, Sandler RS
Source: Cancer Epidemiol Biomarkers Prev, 2005 Feb;14(2), p. 525-8.
PMID: 15734982
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Vitamin C intake and apoptosis in normal rectal epithelium.
Authors: Connelly AE, Satia-Abouta J, Martin CF, Keku TO, Woosley JT, Lund PK, Sandler RS
Source: Cancer Epidemiol Biomarkers Prev, 2003 Jun;12(6), p. 559-65.
PMID: 12815003
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Outcomes of colorectal cancer in the United States: no change in survival (1986-1997).
Authors: Rabeneck L, El-Serag HB, Davila JA, Sandler RS
Source: Am J Gastroenterol, 2003 Feb;98(2), p. 471-7.
PMID: 12591071
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Suppressors of cytokine signaling: Relevance to gastrointestinal function and disease.
Authors: Greenhalgh CJ, Miller ME, Hilton DJ, Lund PK
Source: Gastroenterology, 2002 Dec;123(6), p. 2064-81.
PMID: 12454862
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Prostaglandin H synthase 2 variant (Val511Ala) in African Americans may reduce the risk for colorectal neoplasia.
Authors: Lin HJ, Lakkides KM, Keku TO, Reddy ST, Louie AD, Kau IH, Zhou H, Gim JS, Ma HL, Matthies CF, Dai A, Huang HF, Materi AM, Lin JH, Frankl HD, Lee ER, Hardy SI, Herschman HR, Henderson BE, Kolonel LN, Le Marchand L, Garavito RM, Sandler RS, Haile RW, Smith WL
Source: Cancer Epidemiol Biomarkers Prev, 2002 Nov;11(11), p. 1305-15.
PMID: 12433707
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Disposable versus reusable biopsy forceps for colorectal epithelial cell proliferation in humans.
Authors: Sandler RS, Cummings MS, Keku TO, Terse A, Mehta N
Source: Cancer Epidemiol Biomarkers Prev, 2000 Oct;9(10), p. 1123-5.
PMID: 11045798
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Rectal mucosal proliferation and risk of colorectal adenomas: results from a randomized controlled trial.
Authors: Sandler RS, Baron JA, Tosteson TD, Mandel JS, Haile RW
Source: Cancer Epidemiol Biomarkers Prev, 2000 Jul;9(7), p. 653-6.
PMID: 10919733
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A second look at the relation between colorectal adenomas and consumption of foods containing partially hydrogenated oils.
Authors: McKelvey W, Greenland S, Sandler RS
Source: Epidemiology, 2000 Jul;11(4), p. 469-73.
PMID: 10874557
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Colorectal cancer screening.
Authors: Helm JF, Sandler RS
Source: Med Clin North Am, 1999 Nov;83(6), p. 1403-22, vi.
PMID: 10584600
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Aspirin and nonsteroidal anti-inflammatory agents and risk for colorectal adenomas.
Authors: Sandler RS, Galanko JC, Murray SC, Helm JF, Woosley JT
Source: Gastroenterology, 1998 Mar;114(3), p. 441-7.
PMID: 9496933
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Phenolphthalein-containing laxative use in relation to adenomatous colorectal polyps in three studies.
Authors: Longnecker MP, Sandler DP, Haile RW, Sandler RS
Source: Environ Health Perspect, 1997 Nov;105(11), p. 1210-2.
PMID: 9370521
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Reproductive history, use of exogenous hormones, and risk of colorectal adenomas.
Authors: Peipins LA, Newman B, Sandler RS
Source: Cancer Epidemiol Biomarkers Prev, 1997 Sep;6(9), p. 671-5.
PMID: 9298573
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Epidemiology and risk factors for colorectal cancer.
Authors: Sandler RS
Source: Gastroenterol Clin North Am, 1996 Dec;25(4), p. 717-35.
PMID: 8960889
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Micronutrients and the risk of colorectal adenomas.
Authors: Tseng M, Murray SC, Kupper LL, Sandler RS
Source: Am J Epidemiol, 1996 Dec 1;144(11), p. 1005-14.
PMID: 8942430
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Physical activity and the risk of colorectal adenomas.
Authors: Sandler RS, Pritchard ML, Bangdiwala SI
Source: Epidemiology, 1995 Nov;6(6), p. 602-6.
PMID: 8589091
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Comparison of rectal mucosal proliferation measured by proliferating cell nuclear antigen (PCNA) immunohistochemistry and whole crypt dissection.
Authors: Murray SC, Sandler RS, Keku TO, Lyles CM, Millikan RC, Bangdiwala SI, Kupper LL, Jiang W, Ulshen MH
Source: Cancer Epidemiol Biomarkers Prev, 1995 Oct-Nov;4(7), p. 715-20.
PMID: 8672987
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Rational approach to small polyps found on sigmoidoscopy.
Authors: Sandler RS, Eisen GM, Talal A, Wurzelmann JI
Source: J Clin Gastroenterol, 1995 Jun;20(4), p. 317-20.
PMID: 7665822
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Reproducibility and variability of the rectal mucosal proliferation index using proliferating cell nuclear antigen immunohistochemistry.
Authors: Lyles CM, Sandler RS, Keku TO, Kupper LL, Millikan RC, Murray SC, Bangdiwala SI, Ulshen MH
Source: Cancer Epidemiol Biomarkers Prev, 1994 Oct-Nov;3(7), p. 597-605.
PMID: 7827591
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Are women with breast cancer more likely to develop colorectal cancer? Critical review and meta-analysis.
Authors: Eisen GM, Sandler RS
Source: J Clin Gastroenterol, 1994 Jul;19(1), p. 57-63.
PMID: 7930436
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Epidemiology of colorectal adenomas.
Authors: Peipins LA, Sandler RS
Source: Epidemiol Rev, 1994;16(2), p. 273-97.
PMID: 7713180
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