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BACKGROUND: High glycemic index (GI) diets have been linked to elevated risk of cardiometabolic diseases. One possible underlying mechanism comes from high GI diet's potential to promote lipid peroxidation. OBJECTIVES: We aim to evaluate whether and to what extent dietary carbohydrate quality and quantity are associated with systemic levels of lipid peroxidation in females. METHODS: In this cross-sectional analysis of 2163 middle-aged women, a subset of the Shanghai Women's Health Study, we measured lipid peroxidation biomarkers F(2)-isoprostanes (F(2)-IsoPs) and its metabolite, 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (F(2)-IsoP-M), in urine. The quality of carbohydrate was defined by dietary GI, assessed using a validated FFQ via in-person interviews. A multivariable linear regression model with restricted cubic spline functions was used to evaluate the association of measured biomarkers with carbohydrate intake and dietary GI. RESULTS: After adjustment for potential confounding factors such as cigarette smoking, BMI, and comorbidities, among others, we found that F(2)-IsoP-M concentrations were positively associated with both carbohydrate intake and dietary GI. Carbohydrate intake and dietary GI were weakly correlated (r = 0.12). When further mutually adjusted for the 2 factors, the positive association with F(2)-IsoP-M remained statistically significant for GI (P = 0.004) but not for carbohydrate intake (P = 0.50). Compared with those in the 10th percentile of dietary GI, fold increases (95% CI) in F(2)-IsoP-M concentrations for those in the 30th, 50th, 70th, and 90th percentiles were 1.03 (1.00, 1.07), 1.06 (1.01, 1.10), 1.09 (1.03, 1.14), and 1.13 (1.05, 1.21), respectively. Moreover, there appeared a threshold regarding the association between dietary GI and F(2)-IsoP-M concentrations, with the dose-effect slope of GI being 2.3 times greater when GI was ≥75 relative to GI

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Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)–derived prostaglandin E2 (PGE2) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE2 biosynthesis. We show that low-dose aspirin inhibits systemic PGE2 biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE2 biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE2 production by the platelet–tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE2 biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855–65. ©2016 AACR.

Obesity affects over 40% of the adult population and is a major risk factor for morbidity and mortality due to cardiovascular disease. Black women have one of the highest prevalence of obesity in the United States and approximately 80% are overweight or obese with increased insulin resistance, hypertension, and cardiovascular events. We previously found that isolevuglandins formed in the F2-isoprostane pathway of free radical–mediated lipid peroxidation contributes to IL-6 production in dendritic cells leading to inflammation and hypertension. Thus, we hypothesized that F2-isoprostanes contribute to increased inflammation and IL-6 production among obese Black women. We recruited 88 Black women of age 42.0±9.8 years, weight 102±16 kg, body mass index (BMI) 37.68±5.08, systolic blood pressure 124±14 mmHg, diastolic blood pressure 76.2±9.9 mmHg, and insulin 15.0±8.7 uU/ml. We measured plasma F2-isoprostane levels using gas chromatography/negative ion chemical ionization mass spectrometry (GC/NICI-MS) at the Eicosanoid Core at Vanderbilt University Medical Center. We also measured plasma cytokines including TNF-α 68±174, IL-1β 135±372, IL-6 1615±2769, IL-8 3536±1901, and IL-10 324±633 pg/mL. Using Pearson’s correlation analysis, we found that increased BMI correlated with increased plasma F2-isoprostane levels (Fig. 1A, R=0.23, p=0.037). Interestingly among all the inflammatory cytokines, elevated IL-6 correlated with increased F2-isoprostanes (Fig. 1B, R= 0.44, p=.0025). These results suggest that F2-isoprostanes may contribute to the obesity-induced cardiovascular risk in Black women by increasing production of inflammatory cytokine IL-6.

OBJECTIVE: We aim to investigate whether and how lipid peroxidation markers are associated with height and obesity measures. METHODS: In two independent samples of women (Study-1, n=1005; Study-2, n=1158), systemic levels of lipid peroxidation were assessed by urinary markers F(2)-isoprostanes (F(2)-IsoPs) and its major metabolite (F(2)-IsoP-M), with GC/NICI MS assays. Anthropometric parameters were directly measured and were genetically estimated, used in the primary analysis and in a Mendelian randomization analysis in relation to lipid peroxidation, respectively, with general linear models. RESULTS: After adjusted for potential confounders, we found that measured adult height was inversely associated with levels of F(2)-IsoPs (β=−0.89, P

This prospective observational study evaluated preoperative predictors of complex regional pain syndrome (CRPS) outcomes in the 6 months following total knee arthroplasty (TKA). Participants were n = 110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and pro-inflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6-week and 6-month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a "warm CRPS" phenotype. Six-week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (P'slt; .05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (P'slt; .05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (P'slt; .01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (P'slt; .05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk. PERSPECTIVE: This article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.

Total knee arthroplasty (TKA) is effective for pain reduction in most patients, but 15% or more report unsatisfactory long-term pain outcomes. We tested whether oxidative stress (OS) related to extended tourniquet application during TKA and subsequent ischemic reperfusion (IR) contributed to adverse post-TKA pain outcomes. Blood samples were obtained in 91 patients with osteoarthritis (63% female) undergoing TKA before tourniquet placement (T1), 45 minutes after tourniquet inflation (T2), and 15 minutes after tourniquet removal (T3). Plasma levels of F 2 -isoprostanes and isofurans, the most specific measures of in vivo OS, were quantified. Pain intensity and function were assessed at baseline and again at 6 weeks and 6 months after TKA. Results indicated that higher Combined OS (F 2 -isoprostanes + isofurans/2) at T1 baseline and larger increases in Combined OS from T1 to T2 were associated with higher baseline-corrected past 24-hour worst and average pain intensity (numeric rating scale) and higher past week McGill Pain Questionnaire-2 total scores at 6-month follow-up ( P 's0.05). Increases in Combined OS from T1 to T3, which should most directly capture OS and IR injury related to tourniquet use, were not associated with short-term or long-term post-TKA pain outcomes. Longer ischemia duration was unexpectedly associated with lower baseline-corrected pain intensity at 6-month follow-up. Combined OS was not linked to functional outcomes at either follow-up. Elevated perioperative OS seems to exert small but significant adverse effects on long-term post-TKA pain outcomes, although this OS seems unrelated to IR injury associated with extended tourniquet use.

F2-Isoprostanes (F2-IsoPs) and Isofurans (IsoF), specific markers of lipid peroxidation in vivo, have been reported to be elevated and have prognostic implications following subarachnoid hemorrhage (SAH). Platelet activation and vasoconstriction are attributed to these compounds. Elevated IsoF to F2-IsoPs ratios have been proposed as in vivo biomarkers of mitochondrial dysfunction. In this pilot study, we examined their performance as specific biomarkers for delayed cerebral ischemia (DCI) development following SAH.Eighteen patients with SAH and six controls with normal neuroimaging and cerebrospinal fluid (CSF) analysis results underwent CSF sampling and abstraction of clinical, demographic, and laboratory data. Samples (two) of CSF were collected on day 1 and once on days 5-8 post bleed. F2-IsoP and IsoF assays were performed by gas chromatography/mass spectroscopy methods. Levels are expressed in median (interquartile range) for nonnormally distributed data. Repeated sample measurements were compared using the Wilcoxon signed-rank test, whereas the Mann-Whitney U-test was used for other nonnormally distributed data.Mean age was 61 ± 15.7 (SAH cases) versus 48 ± 10 (controls) years, and 80% of patients with SAH were women. Median Hunt and Hess score was 3 (2-4), and modified Fisher scale was 3 (3-4). Thirty nine percent of patients developed DCI. F2-IsoP were significantly higher in SAH cases than in controls [47.5 (30.2-53.5) vs. 26.0 (21.2-34.5) pg/mL]. No significant differences were observed in patients with or without DCI [41 (33.5-52) vs. 44 (28.5-55.5) pg/mL]. IsoF were elevated in the second CSF sample in nine patients but were undetectable in the remainder cases and all controls. Patients who developed DCI had significantly higher IsoF than those who did not [57 (34-72) vs. 0 (0-34) pg/mL]. Patients who met criteria for DCI had a significantly higher IsoF to F2IsoPs ratio on the late CSF sample [1.03 (1-1.38) vs. 0 (0-0.52)].Preliminary findings from this study suggest that IsoF may represent a specific biomarker predicting DCI following SAH. Future studies to further explore the value of IsoF as biomarkers of secondary brain injury following SAH seem warranted.

C-reactive protein (CRP) is a pro-inflammatory protein with potential as a biomarker in predicting colon cancer risk. However, little is known regarding its association with risk of colorectal adenomas, particularly by subtypes. We conducted a colonoscopy-based matched case-control study to assess whether elevated plasma CRP levels may be associated with colorectal adenoma risk and further whether this association may be modified by urinary prostaglandin E2 metabolite (PGE-M), a biomarker of systemic prostaglandin E2 production. Included in the study were 226 cases with a single small tubular adenoma, 198 cases with multiple small tubular adenomas, 283 cases with at least one advanced adenoma, and 395 polyp-free controls. No apparent association between CRP level and risk of single small tubular adenomas was found (ptrend = 0.59). A dose-response relationship with CRP level was observed for risk of either multiple small tubular adenomas (OR = 2.01, 95%CI = 1.10-3.68 for the highest versus lowest tertile comparison; ptrend = 0.03) or advanced adenomas (OR = 1.81, 95%CI = 1.10-2.96 for the highest versus lowest tertile comparison; ptrend = 0.02). In a joint analysis of CRP level and PGE-M, risk of multiple or advanced adenoma was greatest among those with highest levels of both CRP and PGE-M in comparison to those with low CRP and low PGE-M (OR = 3.72, 95%CI = 1.49-9.72). Our results suggest that elevated CRP, particularly in the context of concurrent elevated PGE-M, may be a biomarker of multiple or advanced adenoma risk in a screening age population. © 2015 Wiley Periodicals, Inc.

Patients with Barrett's Esophagus (BE) have an increased risk of developing esophageal adenocarcinoma. Preclinical models of BE and esophageal cancer have demonstrated the antitumor activity of the green-tea derived Polyphenon E (Poly E) and identified potential biomarkers for following its activity in clinical specimens. We conducted a multicenter trial of Poly E in patients with BE with or without low-grade dysplasia. Subjects were randomized to a 6-month, twice daily (BID) treatment of either placebo or Poly E (200 mg, 400 mg, 600 mg dose cohorts). Endoscopic evaluation, including multiple biopsies, was performed at baseline and after treatment. The primary objective of this study was to demonstrate safety (i.e., determine the maximum tolerated dose (MTD). Secondary objectives investigated accumulation of Poly E catechin constituents (e.g., EGCG) in esophageal tissue and biologic effects of Poly E in clinical specimens, including high throughput effects on mucosal protein expression using functional proteomics. Of the 44 randomized subjects, 11 received placebo, and 33 received Poly E (200 mg (6), 400 mg (7), 600 mg (20)). No dose-limiting toxicities were encountered, and the MTD was 600 mg BID. The most common treatment-related adverse events (AEs) reported in Poly E-treated subjects were grade 1-2 nausea (12%), grade 1 burping (6%), and grade 1 elevated serum LDH (6%). No treatment-related AEs were reported in placebo-treated subjects, aside from grade 1 laboratory abnormalities. Pill counts and daily patient diaries were not consistently collected, and compliance was difficult to determine for the majority of subjects. However, based on an intention-to-treat analysis there was a dose-exposure relationship (p=0.01, Spearman correlation test) between the dose of Poly E and EGCG levels in esophageal mucosa – mean changes (pmol/g) with treatment were 1.68 (placebo; n=9), 6.06 (200 mg; n=5), 31.66 (400 mg; n=6), and 30.86 (600 mg, n=10). There was a possible relationship between the dose of Poly E and urine PGEM concentration – mean urine PGEM concentrations (ng/mg creatinine) with treatment were 4.86 (placebo; n=9), 6.78 (200 mg; n=3), 9.02 (400 mg; n=5), and 7.89 (600 mg; n=11); however, this was not statistically significant. Treatment with Poly E or placebo did not reduce the length of Barrett's epithelium and did not lead to any statistically significant changes in mucosal protein expression. However, Poly E treatment may have affected the expression of stearoyl-CoA desaturase (SD1), PI3Kinase-alpha, and acetyl Coenzyme A Carboxylase (ACC); p-values ≥ 0.05, although false discovery rates were 0.93. In conclusion, Poly E was well-tolerated in all dose cohorts, with only grade 1 AEs seen more commonly in Poly E-treated subjects. There were no apparent significant effects of treatment on either tissue histology or mucosal biomarker expression. However, treatment with Poly E (400 mg and 600 mg) but not Poly E (200 mg) or placebo resulted in clinically relevant and detectable EGCG accumulation in the target organ, esophageal mucosa. Clinical development of this compound may include a phase 2 trial of Poly E administered at the 600 mg BID dose for a longer duration. Supported by NCI, DCP Contract N01-CN-035159 to the UT MD Anderson Early Phase Chemoprevention Consortium Citation Format: Andrew K. Joe, Felice Schnoll-Sussman, Robert S. Bresalier, Julian A. Abrams, Hanina H. Hibshoosh, Kenneth Cheung, Richard A. Friedman, Chung S. Yang, Ginger Milne, Diane D. Liu, Kazeem Abdul, Michelle Bigg, Jessica Foreman, Shing Lee, Tao Su, Aqeel Ahmed, Alfred I. Neugut, Esther Akpa, Scott Lippman, Marjorie Perloff, Powel H. Brown, Charles J. Lightdale. Phase Ib randomized, double-blinded, placebo-controlled, dose escalation study of Polyphenon E in patients with Barrett's esophagus. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C48.

Context Postoperative atrial fibrillation or flutter (AF) is one of the most common complications of cardiac surgery and significantly increases morbidity and health care utilization. A few small trials have evaluated whether long-chain n-3-polyunsaturated fatty acids (PUFAs) reduce postoperative AF, with mixed results. Objective To determine whether perioperative n-3-PUFA supplementation reduces postoperative AF. Design, Setting, and Patients The Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) double-blind, placebo-controlled, randomized clinical trial. A total of 1516 patients scheduled for cardiac surgery in 28 centers in the United States, Italy, and Argentina were enrolled between August 2010 and June 2012. Inclusion criteria were broad; the main exclusions were regular use of fish oil or absence of sinus rhythm at enrollment. Intervention Patients were randomized to receive fish oil (1-g capsules containing ≥840 mg n-3-PUFAs as ethyl esters) or placebo, with preoperative loading of 10 g over 3 to 5 days (or 8 g over 2 days) followed postoperatively by 2 g/d until hospital discharge or postoperative day 10, whichever came first. Main Outcome Measure Occurrence of postoperative AF lasting longer than 30 seconds. Secondary end points were postoperative AF lasting longer than 1 hour, resulting in symptoms, or treated with cardioversion; postoperative AF excluding atrial flutter; time to first postoperative AF; number of AF episodes per patient; hospital utilization; and major adverse cardiovascular events, 30-day mortality, bleeding, and other adverse events. Results At enrollment, mean age was 64 (SD, 13) years; 72.2% of patients were men, and 51.8% had planned valvular surgery. The primary end point occurred in 233 (30.7%) patients assigned to placebo and 227 (30.0%) assigned to n-3-PUFAs (odds ratio, 0.96 [95% CI, 0.77-1.20]; P = .74). None of the secondary end points were significantly different between the placebo and fish oil groups, including postoperative AF that was sustained, symptomatic, or treated (231 [30.5%] vs 224 [29.6%], P = .70) or number of postoperative AF episodes per patient (1 episode: 156 [20.6%] vs 157 [20.7%]; 2 episodes: 59 [7.8%] vs 49 [6.5%]; ≥3 episodes: 18 [2.4%] vs 21 [2.8%]) (P = .73). Supplementation with n-3-PUFAs was generally well tolerated, with no evidence for increased risk of bleeding or serious adverse events. Conclusion In this large multinational trial among patients undergoing cardiac surgery, perioperative supplementation with n-3-PUFAs, compared with placebo, did not reduce the risk of postoperative AF. Trial Registration clinicaltrials.gov Identifier: NCT00970489