Publications by authors named "Dean E Brenner"

99 Publications

Changes in Serum, Red Blood Cell, and Colonic Fatty Acids in a Personalized Omega-3 Fatty Acid Supplementation Trial.

Nutr Cancer 2021 Mar 24:1-14. Epub 2021 Mar 24.

Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.

This study evaluated changes in fatty acids from sera, red blood cells, and colonic biopsies from a phase Ib clinical trial of personalized ω-3 fatty acid dosing in 47 healthy volunteers. The trial aimed to reduce colonic prostaglandin E (PGE), a pro-inflammatory product of arachidonic acid (AA) oxidation. The personalized doses ranged 2-10 grams/day (54% eicosapentaenoic acid, EPA, 24% other ω-3 fatty acids). In colon, increases in ω-3 highly unsaturated fatty acids (HUFA) and EPA:AA ratios each were correlated with decreases in PGE. Changes in either colonic EPA:AA ratios or ω-3 HUFA were significantly correlated with changes in the same fatty acid measures in red blood cells or serum. The only blood-based measure significantly correlated with changes in colonic PGE was change in red blood cell ω-3 HUFA (ρ = -0.39), and the increase in red blood cell ω-3 HUFA was significantly greater in participants who had at least a median reduction in colonic PGE vs. those who did not. In summary, fatty acid changes in blood did reflect fatty acid changes in the colon, but additional factors will be needed for optimizing dosing models that seek to predict the anti-inflammatory effects of ω-3 fatty acids on the colon.
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http://dx.doi.org/10.1080/01635581.2021.1903950DOI Listing
March 2021

An Adaptive Bayesian Design for Personalized Dosing in a Cancer Prevention Trial.

Am J Prev Med 2020 10;59(4):e167-e173

Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.

Introduction: In biomarker-driven clinical trials, translational strategies typically involve moving findings from animal experiments to human trials. Typically, the translation is static, using a fixed model derived from animal experiments for the duration of the trial. Bayesian designs, capable of incorporating information external to the experiment, provide a dynamic translational strategy. This article demonstrates an example of such a dynamic Bayesian strategy in a clinical trial.

Methods: This study explored the effect of a personalized dose of fish oil for reducing prostaglandin E, an inflammatory marker linked to colorectal cancer. A Bayesian design was implemented for the dose-finding algorithm that adaptively updated a dose-response model derived from a previously completed animal study during the clinical trial. In the initial stages of the trial, the dose-response model parameters were estimated from the rodent data. The model was updated following a Bayesian algorithm after data on every 10‒15 subjects were obtained until the model stabilized. Subjects were enrolled in the study between 2013 and 2015, and the data analysis was carried out in 2016.

Results: The 3 dosing models were used for groups of 16, 15, and 15 subjects. The mean target dose significantly decreased from 6.63 g/day (Model 1) to 4.06 g/day (Model 3) (p=0.001). Compared with the static strategy of dosing with a single model, the dynamic modeling reduced the dose significantly by about 1.38 g/day on average.

Conclusions: A Bayesian design was effective in adaptively revising the dosing algorithm, resulting in a lower pill burden.

Trial Registration: This study is registered at www.clinicaltrials.gov NCT01860352.
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http://dx.doi.org/10.1016/j.amepre.2020.04.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531353PMC
October 2020

How Does Obesity Drive Human Carcinogenesis? Challenges in Dissecting the Mechanisms of Adipose-Epithelial Signaling.

Cancer Prev Res (Phila) 2020 10 24;13(10):803-806. Epub 2020 Aug 24.

Division of Hematology-Oncology, Department of Internal Medicine and Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan.

Obesity is the second leading environmental association with cancer risk; yet, the mechanisms by which obesity drives carcinogenesis are poorly understood. The paper published in this issue of Cancer Prevention Research by Holowatyj and colleagues explores the mechanisms of human visceral adipose-epithelial signaling using samples collected at surgery in patients with invasive colorectal cancer. They identify pathway intermediates potentially involved in the regulation of fibrosis, inflammation, glycosis, and epithelial-mesenchymal transition in neoplastic tissue. 'Omics-based profiling of perioperative human biosamples has potential for inherent biases (preoperative and intraoperative drug therapies, hydration, dynamics, inflammatory response to surgical intervention) and appropriate control samples are difficult to identify and collect. Solutions to this dilemma may include strategies to identify patients undergoing similar surgical procedures but who are without neoplasms, for example, patients with gynecologic problems, abdominal exploration for suspected appendicitis, symptoms or resection of gall stone disease or undergoing bariatric surgery. As the field continues to grow, studies incorporating robust statistical analyses, validation of findings in diverse cohorts, and public data sharing will be essential to identify biological pathways linking obesity and carcinogenesis to be further interrogated using focused, hypothesis-driven approaches..
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0367DOI Listing
October 2020

Dietary polyunsaturated fatty acids modulate adipose secretome and is associated with changes in mammary epithelial stem cell self-renewal.

J Nutr Biochem 2019 09 24;71:45-53. Epub 2019 May 24.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

Chronic low-grade adipose inflammation, characterized by aberrant adipokine production and pro-inflammatory macrophage activation/polarization is associated with increased risk of breast cancer. Adipocyte fatty acid composition is influenced by dietary availability and may regulate adipokine secretion and adipose inflammation. After feeding F344 rats for 20 weeks with a Western diet or a fish oil-supplemented diet, we cultured primary rat adipose tissue in a three-dimensional explant culture and collected the conditioned medium. The rat adipose tissue secretome was assayed using the Proteome Profiler Cytokine XL Array, and adipose tissue macrophage polarization (M1/M2 ratio) was assessed using the iNOS/ARG1 ratio. We then assessed the adipokine's effects upon stem cell self-renewal using primary human mammospheres from normal breast mammoplasty tissue. Adipose from rats fed the fish oil diet had an ω-3:ω-6 fatty acid ratio of 0.28 compared to 0.04 in Western diet rats. The adipokine profile from the fish oil-fed rats was shifted toward adipokines associated with reduced inflammation compared to the rats fed the Western diet. The M1/M2 macrophage ratio decreased by 50% in adipose of fish oil-fed rats compared to that from rats fed the Western diet. Conditioned media from rats fed the high ω-6 Western diet increased stem cell self-renewal by 62%±9% (X¯%±SD) above baseline compared to only an 11%±11% increase with the fish oil rat adipose. Modulating the adipokine secretome with dietary interventions therefore may alter stromal-epithelial signaling that plays a role in controlling mammary stem cell self-renewal.
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http://dx.doi.org/10.1016/j.jnutbio.2019.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917480PMC
September 2019

Increases in Colonic Bacterial Diversity after ω-3 Fatty Acid Supplementation Predict Decreased Colonic Prostaglandin E2 Concentrations in Healthy Adults.

J Nutr 2019 07;149(7):1170-1179

Family and Community Medicine, Penn State Health, Milton S Hershey Medical Center, Hershey, PA.

Background: The intestinal microbiome is an important determinant of inflammatory balance in the colon that may affect response to dietary agents.

Objective: This is a secondary analysis of a clinical trial, the Fish Oil Study, to determine whether interindividual differences in colonic bacteria are associated with variability in the reduction of colonic prostaglandin E2 (PGE2) concentrations after personalized supplementation with ω-3 (n-3) fatty acids.

Methods: Forty-seven healthy adults (17 men, 30 women, ages 26-75 y) provided biopsy samples of colonic mucosa and luminal stool brushings before and after personalized ω-3 fatty acid supplementation that was based on blood fatty acid responses. Samples were analyzed using 16S ribosomal RNA sequencing. The data analyses focused on changes in bacterial community diversity. Linear regression was used to evaluate factors that predict a reduction in colonic PGE2.

Results: At baseline, increased bacterial diversity, as measured by the Shannon and Inverse Simpson indexes in both biopsy and luminal brushing samples, was positively correlated with dietary fiber intakes and negatively correlated with fat intakes. Dietary supplementation with ω-3 fatty acids increased the Yue and Clayton community dis-similarity index between the microbiome in luminal brushings and colon biopsy samples post-supplementation (P = 0.015). In addition, there was a small group of individuals with relatively high Prevotella abundance who were resistant to the anti-inflammatory effects of ω-3 fatty acid supplementation. In linear regression analyses, increases in diversity of the bacteria in the luminal brushing samples, but not in the biopsy samples, were significant predictors of lower colonic PGE2 concentrations post-supplementation in models that included baseline PGE2, baseline body mass index, and changes in colonic eicosapentaenoic acid-to-arachidonic acid ratios. The changes in bacterial diversity contributed to 6-8% of the interindividual variance in change in colonic PGE2 (P = 0.001).

Conclusions: Dietary supplementation with ω-3 fatty acids had little effect on intestinal bacteria in healthy humans; however, an increase in diversity in the luminal brushings significantly predicted reductions in colonic PGE2. This trial was registered at www.clinicaltrials.gov as NCT01860352.
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http://dx.doi.org/10.1093/jn/nxy255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602899PMC
July 2019

Higher baseline expression of the PTGS2 gene and greater decreases in total colonic fatty acid content predict greater decreases in colonic prostaglandin-E concentrations after dietary supplementation with ω-3 fatty acids.

Prostaglandins Leukot Essent Fatty Acids 2018 12 2;139:14-19. Epub 2018 Nov 2.

Department of Nutritional Sciences, University of Michigan, Ann Arbor, MI; Department of Family Medicine, University of Michigan, Ann Arbor, MI. Electronic address:

This study evaluated whether mRNA expression of major genes regulating formation of prostaglandin (PG)E in the colon and colonic fatty acid concentrations are associated with the reduction in colonic mucosal PGE after dietary supplementation with omega-3 (ω-3) fatty acids. Supplementation with ω-3 fatty acids was done for 12 weeks using personalized dosing that was expected to reduce colonic PGE by 50%. In stepwise linear regression models, the ω-3 fatty acid dose and baseline BMI explained 16.1% of the inter-individual variability in the fold change of colonic PGE post-supplementation. Increases in mRNA gene expression after supplementation were, however, modest and were not associated with changes in PGE. When baseline expression of PTGS1, PTGS2 and HPGD genes was included in the linear regression model containing dose and BMI, only PTGS2, the gene coding for the inducible form cyclooxygenase, was a significant predictor. Higher relative expression of PTGS2 predicted greater decreases in colonic PGE, accounting for an additional 13.6% of the inter-individual variance. In the final step of the regression model, greater decreases in total colonic fatty acid concentrations predicted greater decreases in colonic PGE, contributing to an additional 18.7% of the variance. Overall, baseline BMI, baseline expression of PTGS2 and changes in colonic total fatty acids together accounted for 48% of the inter-individual variability in the change in colonic PGE. This is consistent with biochemical data showing that fatty acids which are not substrates for cyclooxygenases can activate cyclooxygenase-2 allosterically. Further clinical trials are needed to elucidate the factors that regulate the fatty acid milieu of the human colon and how this interacts with key lipid metabolizing enzymes. Given the central role of PGE in colon carcinogenesis, these pathways may also impact on colon cancer prevention by other dietary and pharmacological approaches.
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http://dx.doi.org/10.1016/j.plefa.2018.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343141PMC
December 2018

Performance of multitarget stool DNA testing in African American patients.

Cancer 2018 10 7;124(19):3876-3880. Epub 2018 Sep 7.

Case Comprehensive Cancer Center, Cleveland, Ohio.

Background: Multitarget stool DNA (mt-sDNA) is an approved method for colon cancer screening that is especially relevant for patients who cannot undergo colonoscopy. Although the test performance has been evaluated in a large clinical trial, it was limited to a predominantly white population. Given differences in the epidemiology and biology of colon cancer in African American individuals, the authors sought to compare the performance of mt-sDNA between racial groups.

Methods: The authors prospectively identified patients aged ≥40 years who were referred for colonoscopy at an academic medical center and 2 satellite facilities. Prior to the colonoscopy, the authors collected stool for mt-sDNA and fecal immunochemical testing (FIT). They compared the sensitivity, specificity, and receiver operating characteristic curve between African American and white patients for the detection of advanced lesions or any adenoma.

Results: A total of 760 patients were included, 34.9% of whom were African American. The prevalence of any adenoma (38.9% for African American patients and 33.9% for white patients) and that for advanced lesions (6.8% and 6.7%, respectively) were similar between groups. The overall sensitivities of mt-sDNA for the detection of advanced lesions and any adenoma were 43% and 19%, respectively, and the specificities were 91% and 93%, respectively. In general, mt-sDNA was more sensitive and less specific than FIT. When stratified by race, the sensitivity, specificity, and receiver operating characteristic curve area were similar between African American and white patients for both mt-sDNA and FIT.

Conclusions: Test performance characteristics of mt-sDNA were comparable in African American and white patients. Given the lower uptake of colonoscopy in African American individuals, mt-sDNA may offer a promising screening alternative in this patient population.
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http://dx.doi.org/10.1002/cncr.31660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226346PMC
October 2018

Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing.

Dig Dis Sci 2018 06 7;63(6):1449-1453. Epub 2018 Mar 7.

Department of Family Medicine and Community Health, Case Comprehensive Cancer Center, University Hospitals Cleveland Medical Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44016, USA.

Background: There is uncertainty as to the appropriate follow-up of patients who test positive on multimarker stool DNA (sDNA) testing and have a colonoscopy without neoplasia.

Aims: To determine the prevalence of missed colonic or occult upper gastrointestinal neoplasia in patients with an apparent false positive sDNA.

Methods: We prospectively identified 30 patients who tested positive with a commercially available sDNA followed by colonoscopy without neoplastic lesions. Patients were invited to undergo repeat sDNA at 11-29 months after the initial test followed by repeat colonoscopy and upper endoscopy. We determined the presence of neoplastic lesions on repeat evaluation stratified by results of repeat sDNA.

Results: Twelve patients were restudied. Seven patients had a negative second sDNA test and a normal second colonoscopy and upper endoscopy. In contrast, 5 of 12 subjects had a persistently positive second sDNA test, and 3 had positive findings, including a 3-cm sessile transverse colon adenoma with high-grade dysplasia, a 2-cm right colon sessile serrated adenoma with dysplasia, and a nonadvanced colon adenoma (p = 0.045). These corresponded to a positive predictive value of 0.60 (95% CI 0.17-1.00) and a negative predictive value of 1.00 (95% CI 1.00-1.00) for the second sDNA test. In addition, the medical records of all 30 subjects with apparent false positive testing were reviewed and no documented cases of malignant tumors were recorded.

Conclusions: Repeat positive sDNA testing may identify a subset of patients with missed or occult colorectal neoplasia after negative colonoscopy for an initially positive sDNA. High-quality colonoscopy with careful attention to the right colon in patients with positive sDNA is critically important and may avoid false negative colonoscopy.
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http://dx.doi.org/10.1007/s10620-018-5001-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5960589PMC
June 2018

Identification, isolation and characterization of human LGR5-positive colon adenoma cells.

Development 2018 03 14;145(6). Epub 2018 Mar 14.

Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA

The intestine is maintained by stem cells located at the base of crypts and distinguished by the expression of LGR5. Genetically engineered mouse models have provided a wealth of information about intestinal stem cells, whereas less is known about human intestinal stem cells owing to difficulty detecting and isolating these cells. We established an organoid repository from patient-derived adenomas, adenocarcinomas and normal colon, which we analyzed for variants in 71 colorectal cancer (CRC)-associated genes. Normal and neoplastic colon tissue organoids were analyzed by immunohistochemistry and fluorescent-activated cell sorting for LGR5. LGR5-positive cells were isolated from four adenoma organoid lines and were subjected to RNA sequencing. We found that LGR5 expression in the epithelium and stroma was associated with tumor stage, and by integrating functional experiments with LGR5-sorted cell RNA sequencing data from adenoma and normal organoids, we found correlations between LGR5 and CRC-specific genes, including dickkopf WNT signaling pathway inhibitor 4 () and SPARC-related modular calcium binding 2 (). Collectively, this work provides resources, methods and new markers to isolate and study stem cells in human tissue homeostasis and carcinogenesis.
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http://dx.doi.org/10.1242/dev.153049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897593PMC
March 2018

The Anti-inflammatory Effect of Personalized Omega-3 Fatty Acid Dosing for Reducing Prostaglandin E in the Colonic Mucosa Is Attenuated in Obesity.

Cancer Prev Res (Phila) 2017 Dec 13;10(12):729-737. Epub 2017 Nov 13.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

This clinical trial developed a personalized dosing model for reducing prostaglandin E (PGE) in colonic mucosa using ω-3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, ω-3):arachidonic acid (AA, ω-6) ratios as biomarkers of colonic mucosal PGE concentration. Normal human volunteers were given low and high ω-3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE Mean colonic mucosal PGE concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-17-0091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767924PMC
December 2017

Fatty acid and lipidomic data in normal and tumor colon tissues of rats fed diets with and without fish oil.

Data Brief 2017 Aug 23;13:661-666. Epub 2017 Jun 23.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, United States.

Data is provided to show the detailed fatty acid and lipidomic composition of normal and tumor rat colon tissues. Rats were fed either a Western fat diet or a fish oil diet, and half the rats from each diet group were treated with chemical carcinogens that induce colon cancer (azoxymethane and dextran sodium sulfate). The data show total fatty acid profiles of sera and of all the colon tissues, namely normal tissue from control rats and both normal and tumor tissues from carcinogen-treated rats, as obtained by gas chromatography with mass spectral detection. Data from lipidomic analyses of a representative subset of the colon tissue samples is also shown in heat maps generated from hierarchical cluster analysis. These data display the utility lipidomic analyses to enhance the interpretation of dietary feeding studies aimed at cancer prevention and support the findings published in the companion paper (Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors, Djuric et al., 2017 [1]).
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http://dx.doi.org/10.1016/j.dib.2017.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503825PMC
August 2017

Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors.

J Nutr Biochem 2017 08 25;46:90-99. Epub 2017 Apr 25.

Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.

Dietary fish oils have potential for prevention of colon cancer, and yet the mechanisms of action in normal and tumor colon tissues are not well defined. Here we evaluated the impact of the colonic fatty acid milieu on the formation of prostaglandins and other eicosanoids. Distal tumors in rats were chemically induced to model inflammatory colonic carcinogenesis. After 21 weeks of feeding with either a fish oil diet containing an eicosapentaenoic acid/ω-6 fatty acid ratio of 0.4 or a Western fat diet, the relationships between colon fatty acids and prostaglandin E (PGE) concentrations were evaluated. PGE is a key proinflammatory mediator in the colon tightly linked with the initiation and progression of colon cancer. The fish oil vs. the Western fat diet resulted in reduced total fatty acid concentrations in serum but not in colon. In the colon, the effects of the fish oil on fatty acids differed in normal and tumor tissue. There were distinct lipodomic patterns consistent with a lipogenic phenotype in tumors. In tumor tissue, the eicosapentaenoic acid/arachidonic acid ratio, cyclooxygenase-2 expression and the mole percent of saturated fatty acids were significant predictors of inter-animal variability in colon PGE after accounting for diet. In normal tissues from either control rats or carcinogen-treated rats, only diet was a significant predictor of colon PGE. These results show that the fatty acid milieu can modulate the efficacy of dietary fish oils for colon cancer prevention, and this could extend to other preventive agents that function by reducing inflammatory stress.
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http://dx.doi.org/10.1016/j.jnutbio.2017.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503762PMC
August 2017

A Multicenter Study of a Fluorescence In Situ Hybridization Probe Set for Diagnosing High-Grade Dysplasia and Adenocarcinoma in Barrett's Esophagus.

Dig Dis Sci 2017 May 6;62(5):1216-1222. Epub 2017 Mar 6.

Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First SW, Rochester, MN, 55905, USA.

Background And Aims: Preliminary single-institution data suggest that fluorescence in situ hybridization (FISH) may be useful for detecting high-grade dysplasia (HGD) and esophageal adenocarcinoma (EA) in patients with Barrett's esophagus (BE). This multicenter study aims to validate the measurement of polysomy (gain of at least two loci) by FISH as a way to discriminate degrees of dysplasia in BE specimens.

Methods: Tissue specimens were collected from four different hospitals and read by both the local pathology department ("Site diagnosis") and a single central pathologist ("Review diagnosis") at a separate institution. The specimens then underwent FISH analysis using probes 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217) for comparison. A total of 46 non-BE, 42 non-dysplastic specialized intestinal metaplasia (SIM), 23 indefinite-grade dysplasia (IGD), 10 low-grade dysplasia (LGD), 29 HGD, and 42 EA specimens were analyzed.

Results: We found that polysomy, as detected by FISH, was the predominant chromosomal abnormality present as dysplasia increased. Polysomy was also the best predictor for the presence of dysplasia or EA when comparing its area under the curve to that of other FISH abnormalities. We observed that if at least 10% of cells had polysomy within a specimen, the FISH probe was able to differentiate between EA/HGD and the remaining pathologies with a sensitivity of 80% and a specificity of 88%.

Conclusions: This study demonstrates that using FISH to determine the percentage of cells with polysomy can accurately and objectively aid in the diagnosis of HGD/EA in BE specimens.
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http://dx.doi.org/10.1007/s10620-017-4517-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052443PMC
May 2017

Protein and glycomic plasma markers for early detection of adenoma and colon cancer.

Gut 2018 03 7;67(3):473-484. Epub 2016 Nov 7.

Translational Research Program, Public Health Sciences Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Objective: To discover and confirm blood-based colon cancer early-detection markers.

Design: We created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.

Results: In the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.

Conclusions: A panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.
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http://dx.doi.org/10.1136/gutjnl-2016-312794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420499PMC
March 2018

Bringing Curcumin to the Clinic in Cancer Prevention: a Review of Strategies to Enhance Bioavailability and Efficacy.

AAPS J 2017 01 25;19(1):54-81. Epub 2016 Oct 25.

Division of Hematology-Oncology, Department of Internal Medicine, Medical School, University of Michigan, 2150 Cancer Center, University of Michigan Medical Center, Ann Arbor, 48109-5930, Michigan, USA.

Curcumin is widely available, inexpensive spice that has been used in ancient folk medicine for millennia, especially in India. Curcumin has the pharmacological properties that slow or reverse cellular proliferation and enhance apoptosis and differentiation associated with a diverse array of molecular effects. Despite its effective anticarcinogenesis properties, curcumin's poor solubility, instability, and extensive metabolism result in poor oral bioavailability. Strategies to enhance curcumin delivery include encapsulating or incorporating curcumin in a nanoparticle or microparticle drug delivery system, synthesizing more stable curcumin analogs that resist metabolism while retaining curcumin's pharmacological properties, and adding another natural product that has bioenhancing properties to curcumin or combination of two of these strategies. This review comprehensively explores curcumin's chemistry and pharmacology followed by comparing and contrasting a vast number of strategies designed to enhance curcumin's bioavailability and its therapeutic effects. The review provides insights into which curcumin formulation strategies have the greatest promise to reach clinical application.
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http://dx.doi.org/10.1208/s12248-016-0003-2DOI Listing
January 2017

Colonic Saturated Fatty Acid Concentrations and Expression of COX-1, but not Diet, Predict Prostaglandin E2 in Normal Human Colon Tissue.

Nutr Cancer 2016 10 22;68(7):1192-201. Epub 2016 Aug 22.

a Department of Family Medicine , University of Michigan , Ann Arbor , MI , USA.

Prostaglandin E2 (PGE2) in the colon is a pro-inflammatory mediator that is associated with increased risk of colon cancer. In this study, expression of genes in the PGE2 pathway were quantified in colon biopsies from a trial of a Mediterranean versus a Healthy Eating diet in 113 individuals at high risk for colon cancer. Colon biopsies were obtained before and after 6 months of intervention. Quantitative, real-time PCR was used to measure mRNA expression of prostaglandin H synthases (PTGS1 and 2), prostaglandin E synthases (PTGES1 and 3), prostaglandin dehydrogenase (HPGD), and PGE2 receptors (PTGER2, PTGER4). The most highly expressed genes were HPGD and PTGS1. In multivariate linear regression models of baseline data, both colon saturated fatty acid concentrations and PTGS1 expression were significant, positive predictors of colon PGE2 concentrations after controlling for nonsteroidal anti-inflammatory drug use, gender, age, and smoking status. The effects of dietary intervention on gene expression were minimal with small increases in expression noted for PTGES3 in both arms and in PTGER4 in the Mediterranean arm. These results indicate that short-term dietary change had little effect on enzymes in the prostaglandin pathway in the colon and other factors, such as differences in fatty acid metabolism, might be more influential.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5061293PMC
http://dx.doi.org/10.1080/01635581.2016.1213866DOI Listing
October 2016

Methylated B3GAT2 and ZNF793 Are Potential Detection Biomarkers for Barrett's Esophagus.

Cancer Epidemiol Biomarkers Prev 2015 Dec 6;24(12):1890-7. Epub 2015 Nov 6.

Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington School of Medicine, Seattle, Washington.

Background: Barrett's esophagus (BE) is a preneoplastic condition in which normal esophageal squamous epithelium (SQ) is replaced by specialized intestinal metaplasia. It is the presumed precursor for esophageal adenocarcinoma (EAC) as well as the strongest risk factor for this cancer. Unfortunately, many patients with BE go undiagnosed under the current BE screening guidelines. The development of noninvasive and accurate BE detection assays could potentially identify many of these undiagnosed BE patients.

Methods: DNA methylation is a common epigenetic alteration in BE. Therefore, we conducted a genome-wide methylation screen to identify potential BE biomarkers. Samples from SQ (N = 12), stomach (N = 28), and BE (N = 29) were analyzed and methylation levels at over 485,000 CpG sites were compared. Pyrosequencing assays were used to validate the results and MethyLight assays were developed to detect the methylated alleles in endoscopic brushings.

Results: We discovered two genes, B3GAT2 and ZNF793, that are aberrantly methylated in BE. Clinical validation studies confirmed B3GAT2 and ZNF793 methylation levels were significantly higher in BE samples (median = 32.5% and 33.1%, respectively) than in control tissues (median = 2.29% and 2.52%, respectively; P < 0.0001 for both genes). Furthermore, gene-specific MethyLight assays could accurately detect BE (P < 0.0001 for both) in endoscopic brushing samples.

Conclusion: B3GAT2 and ZNF793 are hypermethylated in BE, and the methylation status of these genes can be used to detect BE in tissue samples.

Impact: These findings support the development of methylated B3GAT2 and ZNF793 as biomarkers for noninvasive assays for the detection of BE.
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http://dx.doi.org/10.1158/1055-9965.EPI-15-0370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670566PMC
December 2015

Leptin and Adiponectin Modulate the Self-renewal of Normal Human Breast Epithelial Stem Cells.

Cancer Prev Res (Phila) 2015 Dec 20;8(12):1174-83. Epub 2015 Oct 20.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. Department of Internal Medicine Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan. VA Medical Center, Ann Arbor, Michigan.

Multiple mechanisms are likely to account for the link between obesity and increased risk of postmenopausal breast cancer. Two adipokines, leptin and adiponectin, are of particular interest due to their opposing biologic functions and associations with breast cancer risk. In the current study, we investigated the effects of leptin and adiponectin on normal breast epithelial stem cells. Levels of leptin in human adipose explant-derived conditioned media positively correlated with the size of the normal breast stem cell pool. In contrast, an inverse relationship was found for adiponectin. Moreover, a strong linear relationship was observed between the leptin/adiponectin ratio in adipose conditioned media and breast stem cell self-renewal. Consistent with these findings, exogenous leptin stimulated whereas adiponectin suppressed breast stem cell self-renewal. In addition to local in-breast effects, circulating factors, including leptin and adiponectin, may contribute to the link between obesity and breast cancer. Increased levels of leptin and reduced amounts of adiponectin were found in serum from obese compared with age-matched lean postmenopausal women. Interestingly, serum from obese women increased stem cell self-renewal by 30% compared with only 7% for lean control serum. Taken together, these data suggest a plausible explanation for the obesity-driven increase in postmenopausal breast cancer risk. Leptin and adiponectin may function as both endocrine and paracrine/juxtacrine factors to modulate the size of the normal stem cell pool. Interventions that disrupt this axis and thereby normalize breast stem cell self-renewal could reduce the risk of breast cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-14-0334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670788PMC
December 2015

Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1.

Sci Signal 2015 Oct 6;8(397):ra98. Epub 2015 Oct 6.

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.

Yes-associated protein 1 (YAP1) is a transcriptional coactivator in the Hippo signaling pathway. Increased YAP1 activity promotes the growth of tumors, including that of colorectal cancer (CRC). Verteporfin, a drug that enhances phototherapy to treat neovascular macular degeneration, is an inhibitor of YAP1. We found that verteporfin inhibited tumor growth independently of its effects on YAP1 or the related protein TAZ in genetically or chemically induced mouse models of CRC, in patient-derived xenografts, and in enteroid models of CRC. Instead, verteporfin exhibited in vivo selectivity for killing tumor cells in part by impairing the global clearance of high-molecular weight oligomerized proteins, particularly p62 (a sequestrome involved in autophagy) and STAT3 (signal transducer and activator of transcription 3; a transcription factor). Verteporfin inhibited cytokine-induced STAT3 activity and cell proliferation and reduced the viability of cultured CRC cells. Although verteporfin accumulated to a greater extent in normal cells than in tumor cells in vivo, experiments with cultured cells indicated that the normal cells efficiently cleared verteporfin-induced protein oligomers through autophagic and proteasomal pathways. Culturing CRC cells under hypoxic or nutrient-deprived conditions (modeling a typical CRC microenvironment) impaired the clearance of protein oligomers and resulted in cell death, whereas culturing cells under normoxic or glucose-replete conditions protected cell viability and proliferation in the presence of verteporfin. Furthermore, verteporfin suppressed the proliferation of other cancer cell lines even in the absence of YAP1, suggesting that verteporfin may be effective against multiple types of solid cancers.
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http://dx.doi.org/10.1126/scisignal.aac5418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818013PMC
October 2015

MAPRE1 as a plasma biomarker for early-stage colorectal cancer and adenomas.

Cancer Prev Res (Phila) 2015 Nov 4;8(11):1112-9. Epub 2015 Sep 4.

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Blood-based biomarkers for early detection of colorectal cancer could complement current approaches to colorectal cancer screening. We previously identified the APC-binding protein MAPRE1 as a potential colorectal cancer biomarker. Here, we undertook a case-control validation study to determine the performance of MAPRE1 in detecting early colorectal cancer and colon adenoma and to assess the potential relevance of additional biomarker candidates. We analyzed plasma samples from 60 patients with adenomas, 30 with early colorectal cancer, 30 with advanced colorectal cancer, and 60 healthy controls. MAPRE1 and a set of 21 proteins with potential biomarker utility were assayed using high-density antibody arrays, and carcinoembryonic antigen (CEA) was assayed using ELISA. The biologic significance of the candidate biomarkers was also assessed in colorectal cancer mouse models. Plasma MAPRE1 levels were significantly elevated in both patients with adenomas and patients with colorectal cancer compared with controls (P < 0.0001). MAPRE1 and CEA together yielded an area under the curve of 0.793 and a sensitivity of 0.400 at 95% specificity for differentiating early colorectal cancer from controls. Three other biomarkers (AK1, CLIC1, and SOD1) were significantly increased in both adenoma and early colorectal cancer patient plasma samples and in plasma from colorectal cancer mouse models at preclinical stages compared with controls. The combination of MAPRE1, CEA, and AK1 yielded sensitivities of 0.483 and 0.533 at 90% specificity and sensitivities of 0.350 and 0.467 at 95% specificity for differentiating adenoma and early colorectal cancer, respectively, from healthy controls. These findings suggest that MAPRE1 can contribute to the detection of early-stage colorectal cancer and adenomas together with other biomarkers.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4633385PMC
November 2015

Markers of systemic exposures to products of intestinal bacteria in a dietary intervention study.

Eur J Nutr 2016 Mar 24;55(2):793-798. Epub 2015 Apr 24.

Department of Family Medicine, University of Michigan, 1500 E. Medical Center Drive, Room 2150 Cancer Center, Ann Arbor, MI, 48109-5930, USA.

Purpose: Systemic exposures to intestinal bacteria may play a role in the etiology of the chronic, low-grade inflammation that is associated with western diets. Production of lipopolysaccharide-binding protein (LBP) is one biomarker of increased exposures to intestinal bacteria. This study evaluated whether changes in diet quality could affect serum LBP.

Methods: This was a randomized, controlled trial of Mediterranean and Healthy Eating diets over 6 months in 120 healthy subjects at increased risk of colon cancer. Blood samples obtained before and after intervention were analyzed for LBP, branched-chain fatty acids characteristic of intestinal bacteria, micronutrients and cytokines. Data were analyzed for changes in LBP over time and for predictors of LBP.

Results: Serum concentrations of branched-chain bacterial fatty acids declined significantly in both diet groups. However, there was no significant change in mean serum LBP concentrations with either diet intervention. In serum, LBP was positively associated with CRP and negatively associated with carotenoids both before and after intervention. After intervention, LBP was predicted positively by both CRP and bacterial fatty acid concentrations in serum, and negatively by serum carotenoids and the ω3/ω6 fatty acid ratio. This model accounted for 30 % of the inter-individual variation in serum LBP after intervention.

Conclusions: These results indicate that dietary intervention over 6 months was insufficient to alter serum LBP. The relationships with inflammation-related markers, however, indicate that anti-inflammatory strategies other than changes in diet quality, such as weight loss or improved fitness, may have more potential for reducing systemic markers of LPS exposures in well-nourished populations.
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http://dx.doi.org/10.1007/s00394-015-0900-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619169PMC
March 2016

Effects of a Mediterranean Diet Intervention on Anti- and Pro-Inflammatory Eicosanoids, Epithelial Proliferation, and Nuclear Morphology in Biopsies of Normal Colon Tissue.

Nutr Cancer 2015 14;67(5):721-9. Epub 2015 Apr 14.

a Department of Family Medicine and Department of Environmental Health Sciences , University of Michigan , Ann Arbor , Michigan , USA.

This randomized trial evaluated the effects of intervention with either a Healthy Eating or a Mediterranean diet on colon biomarkers in 120 healthy individuals at increased colon cancer risk. The hypothesis was that eicosanoids and markers of proliferation would be favorably affected by the Mediterranean diet. Colon epithelial biopsy tissues and blood samples were obtained at baseline and after 6 mo of intervention. Colonic eicosanoid concentrations were evaluated by HPLC-MS-MS, and measures of epithelial proliferation and nuclear morphology were evaluated by image analysis of biopsy sections. There was little change in proinflammatory eicosanoids and in plasma cytokine concentrations with either dietary intervention. There was, however, a 50% increase in colonic prostaglandin E3 (PGE3), which is formed from eicosapentanoic acid, in the Mediterranean arm. Unlike PGE2, PGE3, was not significantly affected by regular use of non-steroidal anti-inflammatory drugs at baseline, and normal weight subjects had significantly higher colon PGE3 than overweight or obese subjects. Increased proliferation in the colon at baseline, by Ki67 labeling, was associated with morphological features that defined smaller nuclei in the epithelial cells, lower colon leukotriene concentrations and higher plasma cytokine concentrations. Dietary intervention had little effect on measures of epithelial proliferation or of nuclear morphology. The increase in PGE3 with a Mediterranean diet indicates that in normal colon, diet might affect protective pathways to a greater extent than proinflammatory and proliferative pathways. Hence, biomarkers from cancer models might not be relevant in a true prevention setting.
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http://dx.doi.org/10.1080/01635581.2015.1029637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486634PMC
May 2016

Blood-based tests for colorectal cancer screening: do they threaten the survival of the FIT test?

Dig Dis Sci 2015 Mar 14;60(3):664-71. Epub 2015 Feb 14.

Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1466, Houston, TX, 77030, USA,

Colorectal cancer is the second leading cause of cancer death in industrialized nations, accounting for 10% of the total cancer burden with an individual lifetime risk of ~6% in the USA (Siegel et al. in CA Cancer J Clin 62:9-29, 2014, American Cancer Society in Colorectal cancer facts and figures 2011-2013. American Cancer Society, Atlanta, 2011, Siegel et al. in CA Cancer J Clin 61:212-236, 2011). Although numerous screening methods have been incorporated into guidelines for colorectal cancer screening, no guideline includes a noninvasive blood-based test as a recommended option.
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http://dx.doi.org/10.1007/s10620-015-3575-2DOI Listing
March 2015

Effects of vitamin E from supplements and diet on colonic α- and γ-tocopherol concentrations in persons at increased colon cancer risk.

Nutr Cancer 2015 5;67(1):73-81. Epub 2014 Nov 5.

a Department of Family Medicine , University of Michigan , Ann Arbor , Michigan , USA.

The available evidence indicates that γ-tocopherol has more potential for colon cancer prevention than α-tocopherol, but little is known about the effects of foods and supplements on tocopherol levels in human colon. This study randomized 120 subjects at increased colon cancer risk to either a Mediterranean or a Healthy Eating diet for 6 mo. Supplement use was reported by 39% of the subjects, and vitamin E intake from supplements was twofold higher than that from foods. Serum α-tocopherol at baseline was positively predicted by dietary intakes of synthetic vitamin E in foods and supplements but not by natural α-tocopherol from foods. For serum γ-tocopherol, dietary γ-tocopherol was not a predictor, but dietary α-tocopherol was a negative predictor. Unlike with serum, the data supported a role for metabolic factors, and not a direct effect of diet, in governing concentrations of both α- and γ-tocopherol in colon. The Mediterranean intervention increased intakes of natural α-tocopherol, which is high in nuts, and decreased intakes of γ-tocopherol, which is low in olive oil. These dietary changes had no significant effects on colon tocopherols. The impact of diet on colon tocopherols therefore appears to be limited.
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http://dx.doi.org/10.1080/01635581.2015.965333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281489PMC
September 2015

Biomarkers for personalizing omega-3 fatty acid dosing.

Cancer Prev Res (Phila) 2014 Oct 19;7(10):1011-22. Epub 2014 Aug 19.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan. VA Medical Center, Ann Arbor, Michigan.

Prostaglandin E2 (PGE2) has been linked to a higher risk of colorectal cancer. PGE2 in colon tissue can be reduced by increasing dietary eicosapentaenoic acid (EPA). The dose-dependent relationships between dietary EPA, serum EPA:arachidonate (AA) ratio, urinary PGE2 metabolites, and colonic eicosanoids were evaluated to develop biomarkers for prediction of colonic PGE2. Male rats were fed diets containing EPA:ω6 fatty acid ratios of 0, 0.1, 0.2, 0.4, or 0.6 for 5 weeks. Increasing the dietary EPA:ω6 fatty acid ratio increased EPA:AA ratios in serum and in the proximal, transverse, and distal colon (P < 0.001). The urinary PGE2 metabolite was reduced (P = 0.006). EPA-rich diets reduced colonic tissue PGE2 concentrations by 58% to 66% and increased PGE3 by 19- to 28-fold. Other AA-derived eicosanoids were reduced by 35% to 83%. The changes were not linear, with the largest changes in eicosanoids observed with the lower doses. A mathematical model predicts colonic tissue eicosanoids from the EPA:AA ratio in serum and the EPA dose. Every 10% increase in serum EPA:AA was associated with a 2% decrease in the (geometric) mean of PGE2 in the distal colon. These mathematical relationships can now be applied to individualized EPA dosing in clinical trials.
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http://dx.doi.org/10.1158/1940-6207.CAPR-14-0134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185239PMC
October 2014

Pilot clinical study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased risk for colorectal cancer.

Mol Carcinog 2015 Sep 24;54(9):908-15. Epub 2014 Apr 24.

Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan.

Colorectal cancer (CRC) remains a significant cause of mortality. Inhibitors of cyclooxygenase (COX) and thus prostaglandin E2, are promising CRC preventives, but have significant toxicities. Ginger has been shown to inhibit COX, to decrease the incidence and multiplicity of adenomas, and decrease PGE2 concentrations in subjects at normal risk for CRC. This study was conducted to determine the effects of 2.0 g/d of ginger given orally on the levels of PGE2, leukotriene B4 (LTB4), 13-hydroxy-octadecadienoic acids, and 5-, 12-, & 15-hydroxyeicosatetraenoic acid, in the colonic mucosa of subjects at increased risk for CRC. We randomized 20 subjects to 2.0 g/d ginger or placebo for 28 d. At baseline and Day 28, a flexible sigmoidoscopy was used to obtain colon biopsies. A liquid chromatography mass spectrometry method was used to determine eicosanoid levels in the biopsies, and levels were expressed per amount of protein or free arachidonic acid (AA). There was a significant decrease in AA between baseline and Day 28 (P = 0.05) and significant increase in LTB4 (P = 0.04) when normalized to protein, in subjects treated with ginger versus placebo. No other changes in eicosanoids were observed. There was no difference between the groups in total adverse events (AE; P = 0.06). Ginger lacks the ability to decrease eicosanoid levels in people at increased risk for CRC. Ginger did appear to be both tolerable and safe; and could have chemopreventive effects through other mechanisms. Further investigation should focus on other markers of CRC risk in those at increased CRC risk.
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http://dx.doi.org/10.1002/mc.22163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208969PMC
September 2015

Human colonic crypts in culture: segregation of immunochemical markers in normal versus adenoma-derived.

Lab Invest 2014 Feb 23;94(2):222-34. Epub 2013 Dec 23.

Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

In order to advance a culture model of human colonic neoplasia, we developed methods for the isolation and in vitro maintenance of intact colonic crypts from normal human colon tissue and adenomas. Crypts were maintained in three-dimensional Matrigel culture with a simple, serum-free, low Ca(2+) (0.15 mM) medium. Intact colonic crypts from normal human mucosa were viably maintained for 3-5 days with preservation of the in situ crypt-like architecture, presenting a distinct base and apex. Abnormal structures from adenoma tissue could be maintained through multiple passages (up to months), with expanding buds/tubules. Immunohistochemical markers for intestinal stem cells (Lgr5), growth (Ki67), differentiation (E-cadherin, cytokeratin 20 (CK20) and mucin 2 (MUC2)) and epithelial turnover (Bax, cleaved Caspase-3), paralleled the changes in function. The epithelial cells in normal crypts followed the physiological sequence of progression from proliferation to differentiation to dissolution in a spatially and temporally appropriate manner. Lgr5 expression was seen in a few basal cells of freshly isolated crypts, but was not detected after 1-3 days in culture. After 24 h in culture, crypts from normal colonic tissue continued to show strong Ki67 and MUC2 expression at the crypt base, with a gradual decrease over time such that by days 3-4 Ki67 was not expressed. The differentiation marker CK20 increased over the same period, eventually becoming intense throughout the whole crypt. In adenoma-derived structures, expression of markers for all stages of progression persisted for the entire time in culture. Lgr5 showed expression in a few select cells after months in culture. Ki67 and MUC2 were largely associated with the proliferative budding regions while CK20 was localized to the parent structure. This ex vivo culture model of normal and adenomatous crypts provides a readily accessible tool to help understand the growth and differentiation process in human colonic epithelium.
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http://dx.doi.org/10.1038/labinvest.2013.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108175PMC
February 2014

Discovery of sialyl Lewis A and Lewis X modified protein cancer biomarkers using high density antibody arrays.

J Proteomics 2014 Jan 1;96:291-9. Epub 2013 Nov 1.

Translational Research Program, Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA. Electronic address:

Unlabelled: We report on a high-dimensional method to globally profile glycoproteins that are modified with sialyl Lewis A or Lewis X glycans. Specifically, glycoproteins in serum or plasma are fractionated on a high-density antibody microarray (i.e., each are localized to their specific antibody spot) and are specifically detected via fluorescently labeled anti-sialyl Lewis A or anti-Lewis X antibodies with quantification in a microarray scanner. Non-glycosylated proteins or glycoproteins with other glycan motifs do not interfere with this assay. The whole process is very rapid and applicable for high-throughput screening without the need for purification of glycoproteins from the samples. Using these methods, sialyl Lewis A or Lewis X moieties were found to be expressed on many previously unreported secreted or membrane associated proteins. Furthermore, the combination of sialyl Lewis A or Lewis X content with protein level increased the ability of certain glycoproteins to distinguish 30 patients with stage III and IV colon cancer from 60 control samples. Thus, this highly sensitive method is capable of discovering novel specific glycan modifications on proteins, many of which will likely be useful for disease detection and monitoring.

Biological Significance: In this paper, we show that we can detect cancer-specific glycan modifications on thousands of proteins using a high-density antibody array paired with a glycan specific antibody to probe the bound glycoproteins. To our knowledge, our array is by far the largest and densest that has ever been used for global profiling of specific glycan modification on proteins. Analysis of colon cancer patient plasma for sialyl Lewis A and Lewis X modifications revealed previously unknown protein carriers of these modifications and significant increases in these specific glycans on some proteins in people with cancer versus healthy controls, suggesting this method could be used to discover novel biomarkers.
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http://dx.doi.org/10.1016/j.jprot.2013.10.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946870PMC
January 2014

Sulfate metabolites provide an intracellular pool for resveratrol generation and induce autophagy with senescence.

Sci Transl Med 2013 Oct;5(205):205ra133

Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester LE2 7LX, UK.

The phytochemical resveratrol has been shown to exert numerous health benefits in preclinical studies, but its rapid metabolism and resulting poor bioavailability may limit translation of these effects to humans. Resveratrol metabolites might contribute to in vivo activity through regeneration of the parent compound. We present quantitation of sulfate and glucuronide conjugates of resveratrol in human plasma and tissue after repeated ingestion of resveratrol by volunteers and cancer patients, respectively. Subsequent pharmacokinetic characterization of a mixture of resveratrol-3-O-sulfate and resveratrol-4'-O-sulfate in mice showed that these metabolites are absorbed orally but have low bioavailabilities of ~14 and 3%, respectively. Sulfate hydrolysis in vivo liberated free resveratrol, which accounted for ~2% of the total resveratrol species present in mouse plasma. Monosulfate metabolites were also converted to the parent in human colorectal cells. The extent of cellular uptake was dependent on specific membrane transporters and dictated antiproliferative activity. Sulfate metabolites induced autophagy and senescence in human cancer cells; these effects were abrogated by inclusion of a sulfatase inhibitor, which reduced intracellular resveratrol. Together, our findings suggest that resveratrol is delivered to target tissues in a stable sulfate-conjugated form and that the parent compound is gradually regenerated in selected cells and may give rise to the beneficial effects in vivo. At doses considered to be safe in humans, resveratrol generated via this route may be of greater importance than the unmetabolized form.
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http://dx.doi.org/10.1126/scitranslmed.3005870DOI Listing
October 2013

Relationships between serum and colon concentrations of carotenoids and fatty acids in randomized dietary intervention trial.

Cancer Prev Res (Phila) 2013 Jun 16;6(6):558-65. Epub 2013 Apr 16.

Department of Family Medicine, University of Michigan Medical Center, 1018 Fuller St., Ann Arbor, MI 48104, USA.

Little is known about the effect of preventive diets on colonic nutrient concentrations. This study randomized 120 persons at increased risk of colon cancer to a Mediterranean versus a Healthy Eating diet for six months. The former targeted increases in whole grains, fruits, vegetables, monounsaturated, and n3 fats. The Healthy Eating diet was based on Healthy People 2010 recommendations. At baseline, dietary fat and carotenoid intakes were poorly associated (Spearman ρ < 0.4) with serum and colon concentrations. Strong associations were observed between serum and colon measurements of β-cryptoxanthin (ρ = 0.58; P < 0.001), α-carotene (ρ = 0.48; P < 0.001), and β-carotene (ρ = 0.45; P < 0.001). After six months, the Healthy Eating intervention increased serum lutein, β-, and α-carotene significantly (P < 0.05). In the Mediterranean arm, the significant increases were in serum lutein, β-cryptoxanthin, β-carotene, monounsaturated, and n3 fats. A significant group-by-time interaction (P = 0.03) was obtained for monounsaturated fats. Colonic increases in carotenoids and n3 fats were significant only in Healthy Eating arm, whereas the group-by-time interaction was significant for β-carotene (P = 0.02) and α-carotene (P = 0.03). Changes in colon concentrations were not significantly associated with reported dietary changes. Changes in colon and serum concentrations were strongly associated for β-cryptoxanthin (ρ = 0.56; P < 0.001) and α-carotene (ρ = 0.40; P < 0.001). The associations between colonic and serum concentrations suggest the potential use of using serum concentration as a target in dietary interventions aimed at reducing colon cancer risk.
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http://dx.doi.org/10.1158/1940-6207.CAPR-13-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021591PMC
June 2013