Faculty Bibliography

INTRODUCTION/BACKGROUND:Esophageal adenocarcinoma (EAC) develops through histopathological stages, including Barrett's esophagus (BE). We analyzed the associations between plasma levels of one-carbon metabolism factors and risks of long-segment BE or EAC. METHODS:Plasma levels were measured from an Irish population-based case-control study [Factors INfluencing the Barrett's Adenocarcinoma Relationship (FINBAR) study; 204 long-segment BE cases, 211 EAC cases, and 251 controls]. A "methyl replete score" was derived by assigning a score of 0 (< median) or 1 (> median) to the levels of three dietary methyl donors (methionine, choline, and betaine) and summing across the metabolites. Multinomial logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between EAC or BE and sex-specific quartiles or score using the lowest level as the reference category and adjusted for potential confounders. RESULTS:Highest methionine, betaine, vitamin B6 (PLP), and choline levels were all associated with 62-82% reduced risks of EAC (ptrends <0.001). Conversely, S-adenosylmethionine (SAM), the SAM/S-adenosylhomocysteine (SAH) ratio, total homocysteine (tHcy), and cystathionine were associated with a greater than two-fold increased EAC risk. A higher methyl replete score was associated with reduced EAC risk (OR 0·33; 95%CI: 0·16-0·66). The highest versus lowest plasma methionine levels were borderline statistically significantly associated long-segment BE (OR 0·55; 95%CI: 0·28-1·07), but all other associations were null. CONCLUSIONS:Several biomarkers of one-carbon metabolism are associated with EAC risk, particularly markers of dietary methyl group donors. Future studies to replicate and prospectively evaluate these markers are warranted.

The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.

BACKGROUND:Carnobacterium maltaromaticum and Faecalibacterium prausnitzii induce de novo gut synthesis of vitamin D to inhibit colorectal carcinogenesis in mice. Magnesium (Mg) treatment increases circulating vitamin D and Mg homeostasis is dependent on TRPM7 genotype. OBJECTIVE:We hypothesize that Mg treatment increases gut C. maltaromaticum and F. prausnitzii and the effect differs by TRPM7 polymorphism. METHODS:The Personalized Prevention of Colorectal Cancer Trial is a double-blind, precision-based randomized controlled trial with 240 participants randomized by both treatment and TRPM7 genotype. Stool, rectal swabs, and rectal mucosa were collected. RESULTS:Of 239 participants that completed the trial, 226 with valid microbiome data were analyzed (treatment n=112, placebo n=114). The interaction between treatment and TRPM7 genotype was only significant for C. maltaromaticum (p=0.001) and F. prausnitzii (p=0.02) in rectal swabs. In a stratified analysis by TRPM7 genotype without the missense variant, Mg treatment compared to placebo significantly increased abundance of C. maltaromaticum (0.217±0.615 (23.01%) compared to -0.065±0.588 (-6.30%); P=0.006) and F. prausnitzii (0.105±0.817 (2.13%) compared to -0.095±0.856 (-1.92%); P =0.04) in rectal swabs. The effect on C. maltaromaticum remained after multiple comparisons (Q=0.05 for C. maltaromaticum across all sample types and genotypes). In those with the TRPM7 missense variant, Mg decreased C. maltaromaticum, but not F. prausnitzii, compared to placebo in rectal swabs (-0.065±0.511 (-6.54%) compared to 0.133±0.503 (13.30%); adjusted P=0.04). The effect did not remain after FDR correction. Mg treatment's effect on C. maltaromaticum in rectal swabs primarily appeared in females, and the treatment-genotype interaction remained significant. CONCLUSION/CONCLUSIONS:In individuals with adequate TRPM7 function, Mg supplementation increases abundance of C. maltaromaticum and F. prausnitzii. CLINICAL TRIAL REGISTRY/BACKGROUND:This trial was registered on ClinicalTrials.gov as NCT04229992 (https://clinicaltrials.gov/study/NCT04229992?term=NCT04229992&rank=1). The parent study is registered as NCT03265483, and another relevant study is registered as NCT01105169.

BACKGROUND:We previously reported that individuals with the Transient receptor potential melastatin 7 (TRPM7) GA/AA genotype and consumed diets high in Ca:Mg ratio had an increased risk of colorectal polyps. OBJECTIVE:The aim was to identify if the gut microbiota plays a role in the association of TRPM7 genotype, Ca:Mg intake ratio and risk of colorectal polyps. METHODS:We analyzed the gut microbiota of 240 participants in a double-blind 2x2 factorial (TRPM7 genotype and Ca:Mg intake ratios) randomized trial by sequencing the stool, rectal swab, and rectal mucosa tissue samples of each participant. RESULTS:The gut microbiota of participants with the GA genotype significantly differed from those with the GG genotype in all three sample types, with an altered abundance of Prevotella and Bacteroides in swab samples. Prevotella in rectal mucosa and Bacteroides in swab were associated with an increased risk of metachronous colorectal polyps. Optimizing high diet Ca:Mg ratios to 2.3 through Mg supplementation resulted in a reduced abundance of Prevotella in rectal swabs and Bacteroides in stool samples. We identified multiple microbes in all three sample types linked to the risk of metachronous colorectal polyps. CONCLUSIONS:Our findings indicate that the gut microbiota in stool, rectal swab and mucosa are associated with the risk of metachronous colorectal polyps, and diet changes could modify the abundance of TRPM7-related microbes. CLINICAL TRIAL REGISTRATION/BACKGROUND:The study was registered as NCT01105169 at ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT01105169.

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer development. We conducted quantitative analysis of biomarkers for necroptosis [transient receptor potential cation channel subfamily M member 7 (TRPM7) and phosphorylated mixed lineage kinase domain-like protein], inflammation [cyclooxygenase-2 (COX-2)], apoptosis [BCL2-associated X (BAX) and terminal deoxynucleotidyl transferase dUTP nick end labeling], and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early colorectal cancer stages (Ptrend = 0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend = 0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio = 3.04; 95% confidence interval, 1.07-8.61; Ptrend = 0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps, whereas combined scores of phosphorylated mixed lineage kinase domain-like protein or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis. Prevention Relevance: Our findings suggest that COX-2 expression and combined scores of COX-2, TRPM7, and BAX hold promise for predicting the risk of metachronous polyps and could potentially serve as a tool for assessing the effectiveness of chemopreventive agents in preventing colorectal cancer during intervention trials.

BACKGROUND:Sex-based differences are important in the development and progression of pulmonary arterial hypertension. However, it is not established whether these differences are generalizable to all forms of pulmonary hypertension (PH). RESEARCH QUESTION/OBJECTIVE:What are the sex-based differences in right ventricle (RV) function and transplant-free survival in patients with PH from the Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort? STUDY DESIGN AND METHODS/METHODS:Patients with PH enrolled in the PVDOMICS cohort study underwent right heart catheterization, cardiac MRI, and echocardiography. A multivariable linear regression model was used to investigate the interactive effect between sex and pulmonary vascular resistance (PVR) on RV ejection fraction (RVEF). Effects of sex, RVEF, and PVR on transplant-free survival were assessed using a Cox proportional hazards model. RESULTS:= .003). INTERPRETATION/CONCLUSIONS:In patients with PH in the PVDOMICS study, female sex was more common, whereas male sex was associated with worse RV function and decreased transplant-free survival, most notably at mild to moderate elevation of PVR.

BACKGROUND:There is a need to understand the relationship between COVID-19 Convalescent Plasma (CCP) anti-SARS-CoV-2 IgG levels and clinical outcomes to optimize CCP use. This study aims to evaluate the relationship between recipient baseline clinical status, clinical outcomes, and CCP antibody levels. METHODS:The study analyzed data from the COMPILE study, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) assessing the efficacy of CCP vs. control, in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. SARS-CoV-2 IgG levels, referred to as 'dose' of CCP treatment, were retrospectively measured in donor sera or the administered CCP, semi-quantitatively using the VITROS Anti-SARS-CoV-2 IgG chemiluminescent immunoassay (Ortho-Clinical Diagnostics) with a signal-to-cutoff ratio (S/Co). The association between CCP dose and outcomes was investigated, treating dose as either continuous or categorized (higher vs. lower vs. control), stratified by recipient oxygen supplementation status at presentation. RESULTS:A total of 1714 participants were included in the study, 1138 control- and 576 CCP-treated patients for whom donor CCP anti-SARS-CoV2 antibody levels were available from the COMPILE study. For participants not receiving oxygen supplementation at baseline, higher-dose CCP (/control) was associated with a reduced risk of ventilation or death at day 14 (OR = 0.19, 95% CrI: [0.02, 1.70], posterior probability Pr(OR < 1) = 0.93) and day 28 mortality (OR = 0.27 [0.02, 2.53], Pr(OR < 1) = 0.87), compared to lower-dose CCP (/control) (ventilation or death at day 14 OR = 0.79 [0.07, 6.87], Pr(OR < 1) = 0.58; and day 28 mortality OR = 1.11 [0.10, 10.49], Pr(OR < 1) = 0.46), exhibiting a consistently positive CCP dose effect on clinical outcomes. For participants receiving oxygen at baseline, the dose-outcome relationship was less clear, although a potential benefit for day 28 mortality was observed with higher-dose CCP (/control) (OR = 0.66 [0.36, 1.13], Pr(OR < 1) = 0.93) compared to lower-dose CCP (/control) (OR = 1.14 [0.73, 1.78], Pr(OR < 1) = 0.28). CONCLUSION/CONCLUSIONS:Higher-dose CCP is associated with its effectiveness in patients not initially receiving oxygen supplementation, however, further research is needed to understand the interplay between CCP anti-SARS-CoV-2 IgG levels and clinical outcome in COVID-19 patients initially receiving oxygen supplementation.

UNLABELLED:Metabolic effects of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and not fully recapitulated by increasing endogenous GLP-1. We tested the hypothesis that GLP-1 receptor (GLP-1R) agonists exert weight loss-independent, GLP-1R-dependent effects that differ from effects of increasing endogenous GLP-1. Individuals with obesity and prediabetes were randomized to receive for 14 weeks the GLP-1R agonist liraglutide, a hypocaloric diet, or the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin. The GLP-1R antagonist exendin(9-39) and placebo were administered in a two-by-two crossover study during mixed-meal tests. Liraglutide and diet, but not sitagliptin, caused weight loss. Liraglutide improved insulin sensitivity measured by HOMA for insulin resistance (HOMA-IR), the updated HOMA model (HOMA2), and the Matsuda index after 2 weeks, prior to weight loss. Liraglutide decreased fasting and postprandial glucose levels, and decreased insulin, C-peptide, and fasting glucagon levels. In contrast, diet-induced weight loss improved insulin sensitivity by HOMA-IR and HOMA2, but not the Matsuda index, and did not decrease glucose levels. Sitagliptin increased endogenous GLP-1 and GIP values without altering insulin sensitivity or fasting glucose levels, but decreased postprandial glucose and glucagon levels. Notably, sitagliptin increased GIP without altering weight. Acute GLP-1R antagonism increased glucose levels in all groups, increased the Matsuda index and fasting glucagon level during liraglutide treatment, and increased endogenous GLP-1 values during liraglutide and sitagliptin treatments. Thus, liraglutide exerts rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity that are not achieved by increasing endogenous GLP-1. ARTICLE HIGHLIGHTS/UNASSIGNED:Metabolic benefits of glucagon-like peptide 1 (GLP-1) receptor agonists are confounded by weight loss and are not fully achieved by increasing endogenous GLP-1 through dipeptidyl peptidase 4 (DPP-4) inhibition. We investigated weight loss-independent, GLP-1 receptor (GLP-1R)-dependent metabolic effects of liraglutide versus a hypocaloric diet or the DPP-4 inhibitor sitagliptin. GLP-1R antagonism with exendin(9-39) was used to assess GLP-1R-dependent effects during mixed meals. Liraglutide improved insulin sensitivity and decreased fasting and postprandial glucose prior to weight loss, and these benefits were reversed by exendin(9-39). GLP-1R agonists exert rapid, weight loss-independent, GLP-1R-dependent effects on insulin sensitivity not achieved by increasing endogenous GLP-1.

BACKGROUND/UNASSIGNED:Traditional Chinese medicine (TCM) body constitution (BC), primarily determined by physiological and clinical characteristics, is an important process for clinical diagnosis and treatment and play a critical role in precision medicine in TCM. The purpose of the study was to explore whether the distributions of BC types differed by obesity status. METHODS/UNASSIGNED:We conducted a study to evaluate BC type in US population during 2012-2016. A total of 191 White participants from Personalized Prevention of Colorectal Cancer Trial (PPCCT) completed a self-administered Traditional Chinese Medicine Questionnaire (TCMQ, English version). In this study, we further compared the distribution of major types of TCM BC in the PPCCT to those Chinese populations stratified by obesity status. RESULTS/UNASSIGNED:We found the Blood-stasis frequency was higher in US White adults, 22.6% for individuals with BMI <30 and 11.2% for obese individuals, compared to 1.4% and 1.8%, respectively, in Chinese populations. We also found the percentages Inherited-special and Qi-stagnation were higher in US White adults than those in Chinese populations regardless of obesity status. However, the proportions of Yang-deficiency were higher in Chinese populations than those in our study conducted in US White adults regardless of obesity status. CONCLUSIONS/UNASSIGNED:These new findings indicate the difference in distribution of BC types we observed between US and Chinese populations cannot be explained by the differences in prevalence of obesity. Further studies are needed to confirm our findings and understand the potential mechanism including genetic background and/or environmental factors.

AIM/OBJECTIVE:To test the hypothesis that glucagon-like peptide-1 receptor (GLP-1R) agonists have beneficial effects on vascular endothelial function, fibrinolysis and inflammation through weight loss-independent mechanisms. MATERIALS AND METHODS/METHODS:Individuals with obesity and prediabetes were randomized to 14 weeks of the GLP-1R agonist liraglutide, hypocaloric diet or the dipeptidyl peptidase-4 inhibitor sitagliptin in a 2:1:1 ratio. Treatment with drug was double blind and placebo-controlled. Measurements were made at baseline, after 2 weeks prior to significant weight loss and after 14 weeks. The primary outcomes were measures of endothelial function: flow-mediated vasodilation (FMD), plasminogen activator inhibitor-1 (PAI-1) and urine albumin-to-creatinine ratio (UACR). RESULTS:Eighty-eight individuals were studied (liraglutide N = 44, diet N = 22, sitagliptin N = 22). Liraglutide and diet reduced weight, insulin resistance and PAI-1, while sitagliptin did not. There was no significant effect of any treatment on endothelial vasodilator function measured by FMD. Post hoc subgroup analyses in individuals with baseline FMD below the median, indicative of greater endothelial dysfunction, showed an improvement in FMD by all three treatments. GLP-1R antagonism with exendin (9-39) increased fasting blood glucose but did not change FMD or PAI-1. There was no effect of treatment on UACR. Finally, liraglutide, but not sitagliptin or diet, reduced the chemokine monocyte chemoattractant protein-1 (MCP-1). CONCLUSION/CONCLUSIONS:Liraglutide and diet reduce weight, insulin resistance and PAI-1. Liraglutide, sitagliptin and diet do not change FMD in obese individuals with prediabetes with normal endothelial function. Liraglutide alone lowers the pro-inflammatory and pro-atherosclerotic chemokine MCP-1, indicating that this beneficial effect is independent of weight loss.