NSAIDs Modulate Clonal Evolution in Barrett's Esophagus

Cancer is considered an outcome of decades-long clonal evolution fueled by acquisition of somatic genomic abnormalities (SGAs). Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce cancer risk, including risk of progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA). However, the cancer chemopreventive mechanisms of NSAIDs are not fully understood. We hypothesized that NSAIDs modulate clonal evolution by reducing SGA acquisition rate. We evaluated thirteen individuals with BE. Eleven had not used NSAIDs for 6.2±3.5 (mean±standard deviation) years and then began using NSAIDs for 5.6±2.7 years, whereas two had used NSAIDs for 3.3±1.4 years and then discontinued use for 7.9±0.7 years. 161 BE biopsies, collected at 5–8 time points over 6.4–19 years, were analyzed using 1Million-SNP arrays to detect SGAs. Even in the earliest biopsies there were many SGAs (284±246 in 10/13 and 1442±560 in 3/13 individuals) and in most individuals the number of SGAs changed little over time, with both increases and decreases in SGAs detected. The estimated SGA rate was 7.8 per genome per year (95% support interval [SI], 7.1–8.6) off-NSAIDs and 0.6 (95% SI 0.3–1.5) on-NSAIDs. Twelve individuals did not progress to EA. In ten we detected 279±86 SGAs affecting 53±30 Mb of the genome per biopsy per time point and in two we detected 1,463±375 SGAs affecting 180±100 Mb. In one individual who progressed to EA we detected a clone having 2,291±78 SGAs affecting 588±18 Mb of the genome at three time points in the last three of 11.4 years of follow-up. NSAIDs were associated with reduced rate of acquisition of SGAs in eleven of thirteen individuals. Barrett's cells maintained relative equilibrium level of SGAs over time with occasional punctuations by expansion of clones having massive amount of SGAs

The presence of African American race predicts improvement in coronary endothelial function after supplementary L-arginine

AbstractObjectivesThe purpose of our study was to determine if the presence of African American ethnicity modulates improvement in coronary vascular endothelial function after supplementary L-arginine.BackgroundEndothelial dysfunction is an early stage in the development of coronary atherosclerosis and has been implicated in the pathogenesis of hypertension and cardiomyopathy. Amelioration of endothelial dysfunction has been demonstrated in patients with established coronary atherosclerosis or with risk factors in response to infusion of L-arginine, the precursor of nitric oxide. Racial and gender patterns in L-arginine responsiveness have not, heretofore, been studied.MethodsInvasive testing of coronary artery and microvascular reactivity in response to graded intracoronary infusions of acetylcholine (ACh) ± L-arginine was carried out in 33 matched pairs of African American and white subjects with no angiographic coronary artery disease. Pairs were matched for age, gender, indexed left ventricular mass, body mass index and low-density lipoprotein cholesterol.ResultsIn addition to the matching parameters, there were no significant differences in peak coronary blood flow (CBF) response to intracoronary adenosine or in the peak CBF response to ACh before L-arginine infusion. However, absolute percentile improvement in CBF response to ACh infusion after L-arginine, as compared with before, was significantly greater among African Americans as a group (45 ± 10% vs. 4 ± 6%, p = 0.0016) and after partitioning by gender. The mechanism of this increase was mediated through further reduction in coronary microvascular resistance. L-arginine infusion also resulted in greater epicardial dilator response after ACh among African Americans.ConclusionsWe conclude that intracoronary infusion of L-arginine provides significantly greater augmentation of endothelium-dependent vascular relaxation in those of African American ethnicity when compared with matched white subjects drawn from a cohort electively referred for coronary angiography. Our findings suggest that there are target populations in which supplementary L-arginine may be of therapeutic benefit in the amelioration of microvascular endothelial dysfunction. In view of the excess prevalence of cardiomyopathy among African Americans, pharmacologic correction of microcirculatory endothelial dysfunction in this group is an important area of further investigation and may ultimately prove to be clinically indicated

Correction to: NSAID use and somatic exomic mutations in Barrett’s esophagus

It was highlighted that in the original article [1] the Availability of data and materials section was incorrect

NSAID use and somatic exomic mutations in Barrett’s esophagus

Abstract Background Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett’s esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE. Methods Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs. Results NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users. Conclusions These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs

Clonal evolution in individuals b and j.

<p>(Panel A) Solid lines connect the mean amount of SGA detected across biopsies at each time point; dots correspond to individual biopsies. In individual b (black line), we observed evolutionary stasis with mean SGA remaining at 119±79 Mb over more than a decade of follow-up. In individual j (red line), a massive burst of SGA was detected in year 8.5; three years later individual j progressed to esophageal adenocarcinoma. Individual b started NSAIDs after year 5, while individual j started NSAIDs only after year 10. (Panels B and C) Circos plots showing genome-wide views of SGA over time. Each ring, labeled with a biopsy number, represents whole-genome SGA data from a different biopsy, with earlier samples toward the center. Thin black line rings separate endoscopies (time points), white background shows time periods off-NSAIDs and gray background shows time periods on-NSAIDs. Within the rings, black segments designate homozygous deletion, red single copy loss, orange copy-neutral LOH, and green copy gain. (Panel B) Circos plot of individual b. Note the appearance of “new” whole chromosome LOH at chromosome 6 and 11 in biopsy 5, taken during the off-NSAIDs period, and the detection of a minimally mutated clone in biopsies 9 and 7, taken during the on-NSAIDs period. (Panel C) Circos plot of individual j. A massive burst of SGAs was detected first in biopsy 8, in year 8.5, before the individual began regular NSAID use. Biopsy 2 (second inner ring), taken at the baseline endoscopy 8.5 years prior to the burst, shared a subset of the SGAs seen in the massively altered clone (chromosomes 10, 12, 17 and 18), and thus is likely an early example of its lineage. (Panels D and G) Consensus phylogenetic trees estimated by BEAST reveal long-term co-existence of clones. Branch lengths are scaled according to time, the tips of the phylogeny are biopsies aligned on the x-axis according to their sampling time, and all internal nodes are estimated coalescence times assuming a logistic population growth. Dashed gray line represents the start of NSAID use. (Panels E, F, H, I) Maximum parsimony trees estimated by PAUP reveal the ancestral relationships among biopsies based on shared SGA characters. Differences between the topology of the trees estimated by PAUP and BEAST are typically due to poorly supported short branches and do not affect the analyses of SGA acquisition rates. Branch lengths are scaled according to estimated number of SGAs (Panels E, H) or the amount of genome affected by SGA (Panels F, I). Note that these trees appear very different from those estimated by BEAST as the BEAST branch lengths are scaled by inferred time depth, and the rate of SGA accumulation appears highly variable with time.</p

SGA remains approximately constant over time in most individuals.

<p>Black lines indicate 10 individuals with apparent evolutionary stasis and red lines indicate 3 individuals with apparent increase in SGA over time. (Panel A) Mean number of SGA lesions. Solid lines connect the means at each time point for all individuals (a–m), where the symbols a–m are plotted at the end of the lines. (Panel B) Mean amount of genome affected by SGA.</p

Study design and biopsy sampling.

<p>Throughout this figure, white indicates time off NSAIDs and gray indicates time on NSAIDs. (Panel A) Thirteen individuals with BE, showing times of endoscopies as black x's, and indicating time on and off NSAIDs. (Panel B) The temporal and spatial location of all biopsies in the study. Red lines show the extent of Barrett's segment from the gastroesophageal junction (GEJ) to the squamocolumnar junction (SCJ). The Y-axis is measured in cm from the GEJ. The X-axis is scaled in years of follow-up, with the total amount of follow-up for each individual indicated below the data for that individual. Small black circles indicate the locations of the biopsies that were assayed in this study.</p