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Roles of Necroptosis, Apoptosis, and Inflammation in Colorectal Carcinogenesis: A Longitudinal Human Study

Su, Timothy; Zhu, Xiangzhu; Li, Yong; Yu, Chang; Deng, Xinqing; Shubin, Eugene; Hou, Lifang; Zhao, Jing; Fan, Lei; Zhang, Heping; Murff, Harvey J; Ness, Reid M; Shrubsole, Martha J; Dai, Qi
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.
PMCID:11790375
PMID: 39637028
ISSN: 1940-6215
CID: 5783462

Association of Male Sex With Worse Right Ventricular Function and Survival in Pulmonary Hypertension in the Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics Cohort

Shelburne, Nicholas J; Nian, Hui; Beck, Gerald J; Casanova, Nancy G; Desai, Ankit A; DuBrock, Hilary M; Erzurum, Serpil; Frantz, Robert P; Hassoun, Paul M; Hill, Nicholas S; Horn, Evelyn M; Jacob, Miriam S; Jellis, Christine L; Joseloff, Elizabeth; Kwon, Deborah H; Brett Larive, A; Leopold, Jane A; Park, Margaret M; Rischard, Franz P; Rosenzweig, Erika B; Vanderpool, Rebecca R; Yu, Chang; Hemnes, Anna R; ,
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.
PMCID:11548889
PMID: 39524046
ISSN: 2949-7892
CID: 5752512

Association between COVID-19 convalescent plasma antibody levels and COVID-19 outcomes stratified by clinical status at presentation

Park, Hyung; Yu, Chang; Pirofski, Liise-Anne; Yoon, Hyunah; Wu, Danni; Li, Yi; Tarpey, Thaddeus; Petkova, Eva; Antman, Elliott M; Troxel, Andrea B; ,
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.
PMCID:11201301
PMID: 38926676
ISSN: 1471-2334
CID: 5682172

Weight Loss-Independent Effect of Liraglutide on Insulin Sensitivity in Individuals With Obesity and Prediabetes

Mashayekhi, Mona; Nian, Hui; Mayfield, Dustin; Devin, Jessica K; Gamboa, Jorge L; Yu, Chang; Silver, Heidi J; Niswender, Kevin; Luther, James M; Brown, Nancy J
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.
PMID: 37874653
ISSN: 1939-327x
CID: 5612992

Associations between traditional Chinese medicine body constitution and obesity risk among US adults

Zhu, Xiangzhu; Yin, Xiaolin; Deng, Xinqing; Shubin, Yevheniy Eugene; Murff, Harvey J; Ness, Reid M; Yu, Chang; Shrubsole, Martha J; Dai, Qi
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.
PMCID:11142465
PMID: 38827360
ISSN: 2616-2806
CID: 5664862

Comparative effects of weight loss and incretin-based therapies on vascular endothelial function, fibrinolysis and inflammation in individuals with obesity and prediabetes: A randomized controlled trial

Mashayekhi, Mona; Beckman, Joshua A; Nian, Hui; Garner, Erica M; Mayfield, Dustin; Devin, Jessica K; Koethe, John R; Brown, Jonathan D; Cahill, Katherine N; Yu, Chang; Silver, Heidi; Niswender, Kevin; Luther, James M; Brown, Nancy J
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.
PMID: 36306151
ISSN: 1463-1326
CID: 5359672

Electronic cigarette use during pregnancy and the risk of adverse birth outcomes: A cross-sectional surveillance study of the US Pregnancy Risk Assessment Monitoring System (PRAMS) population

Ammar, Lin; Tindle, Hilary A; Miller, Angela M; Adgent, Margaret A; Nian, Hui; Ryckman, Kelli K; Mogos, Mulubrhan; Piano, Mariann R; Xie, Ethan; Snyder, Brittney M; Ramesh, Abhismitha; Yu, Chang; Hartert, Tina V; Wu, Pingsheng
BACKGROUND:Research on health effects and potential harms of electronic cigarette (EC) use during pregnancy is limited. We sought to determine the risks of pregnancy EC use on pregnancy-related adverse birth outcomes and assess whether quitting ECs reduces the risks. METHODS:Women with singleton live births who participated in the US Pregnancy Risk Assessment Monitoring System (PRAMS) survey study 2016-2020 were classified into four mutually exclusive groups, by their use of ECs and combustible cigarettes (CCs) during pregnancy: non-use, EC only use, CC only use, and dual use. We determined the risk of preterm birth, low birth weight, and small-for-gestational-age (SGA) by comparing cigarette users to non-users with a modified Poisson regression model adjusting for covariates. In a subset of women who all used ECs prior to pregnancy, we determined whether quitting EC use reduces the risk of preterm birth, low birth weight, and SGA by comparing to those who continued its use. All analyses were weighted to account for the PRAMS survey design and non-response rate. RESULTS:Of the 190,707 women (weighted N = 10,202,413) included, 92.1% reported cigarette non-use, 0.5% EC only use, 6.7% CC only use, and 0.7% dual use during pregnancy. Compared with non-use, EC only use was associated with a significantly increased risk of preterm birth (adjusted risk ratio [aRR]: 1.29, 95% confidence interval [CI]: 1.00, 1.65) and low birth weight (aRR: 1.38, 95%CI: 1.09, 1.75), but not SGA (aRR: 1.04, 95%CI: 0.76, 1.44). Among 7,877 (weighted N = 422,533) women EC users, quitting use was associated with a significantly reduced risk of low birth weight (aRR: 0.76, 95%CI: 0.62, 0.94) and SGA (aRR: 0.77, 95%CI: 0.62, 0.94) compared to those who continued to use ECs during pregnancy. CONCLUSIONS:Pregnancy EC use, by itself or dual use with CC, is associated with preterm birth and low birth weight. Quitting use reduces that risk. ECs should not be considered as a safe alternative nor a viable gestational smoking cessation strategy.
PMCID:10597477
PMID: 37874824
ISSN: 1932-6203
CID: 5614302

Regression methods for the appearances of extremes in climate data

Yu, Chang; Blaha, Ondrej; Kane, Michael; Wei, Wei; Esserman, Denise; Zelterman, Daniel
For any given city, on any calendar day, there will be record high and low temperatures. Which record occurred earlier? If there is a trend towards warming then, intuitively, there should be a preponderance of record highs occurring more recently than the record lows for each of the 365 calendar days. We are interested in modeling the joint distribution of appearances of the extremes but not these values themselves. We develop a bivariate discrete distribution modeling the joint indices of maximum and minimum in a sequence of independent random variables sampled from different distributions. We assume these distributions share a proportional hazard rate and develop regression methods for these paired values. This approach has reasonable power to detect a small mean change over a decade. Using readily available public data, we examine the daily calendar extreme values of five US cities for the decade 2011"“2020. We develop linear regression models for these data, describe models to account for calendar-date dependence, and use diagnostic measures to detect remarkable observations.
SCOPUS:85137993390
ISSN: 1180-4009
CID: 5330802

Factors influencing intent to receive COVID-19 vaccination among Black and White adults in the southeastern United States, October - December 2020

Cunningham-Erves, Jennifer; Mayer, Carol S; Han, Xijing; Fike, Landon; Yu, Chang; Tousey, Phyllis M; Schlundt, David G; Gupta, Deepak K; Mumma, Michael T; Walkley, David; Steinwandel, Mark D; Edwards, Kathryn M; Lipworth, Loren; Sanderson, Maureen; Shu, Xiao-Ou; Shrubsole, Martha J
Vaccination intent is foundational for effective COVID-19 vaccine campaigns. To understand factors and attitudes influencing COVID-19 vaccination intent in Black and White adults in the US south, we conducted a mixed-methods cross-sectional survey of 4512 adults enrolled in the Southern Community Cohort Study (SCCS), an ongoing study of racial and economic health disparities. Vaccination intent was measured as "If a vaccine to prevent COVID-19 became available to you, how likely are you to choose to get the COVID-19 vaccination?" with options of "very unlikely," "somewhat unlikely," "neither unlikely nor likely," "somewhat likely," and "very likely." Reasons for intent, socio-demographic factors, preventive behaviors, and other factors were collected. 46% of participants had uncertain or low intent. Lower intent was associated with female gender, younger age, Black race, more spiritual/religious, lower perceived COVID-19 susceptibility, living in a greater deprivation area, lower reading ability, and lack of confidence in childhood vaccine safety or COVID-19 vaccine effectiveness or safety (p < .05 for all). Most factors were present in all racial/gender groups. Contextual influences, vaccine/vaccination specific issues, and personal/group influences were identified as reasons for low intent. Reasons for higher intent included preventing serious illness, life returning to normal, and recommendation of trusted messengers. Hesitancy was complex, suggesting tailored interventions may be required to address low intent.
PMID: 34847822
ISSN: 2164-554x
CID: 5162862

Impact of renin-angiotensin-aldosterone system inhibition on morbidity and mortality during long-term continuous-flow left ventricular assist device support: An IMACS report

Brinkley, D Marshall; Wang, Li; Yu, Chang; Grandin, E Wilson; Kiernan, Michael S
BACKGROUND:Inhibition of the renin angiotensin aldosterone system (RAAS) improves survival and reduces adverse cardiac events in heart failure with reduced ejection fraction, but the benefit is not well-defined following left ventricular assist device (LVAD). METHODS:We analyzed the ISHLT IMACS registry for adults with a primary, continuous-flow LVAD from January 2013 to September 2017 who were alive at postoperative month 3 without a major adverse event, and categorized patients according to treatment an angiotensin converting enzyme inhibitor (ACEI/ARB) or mineralocorticoid receptor antagonist (MRA). Propensity score matching was performed separately for ACEI/ARB vs none (n = 4,118 each) and MRA vs none (n = 3,892 each). RESULTS:Of 11,494 patients included, 50% were treated with ACEI/ARB and 38% with MRA. Kaplan-Meier survival was significantly better for patients receiving ACEI/ARB (p < 0.001) but not MRA (p = 0.31). In Cox proportional hazards analyses adjusted for known predictors of mortality following LVAD, ACEI/ARB use (hazard ratio 0.81 [95% confidence interval 0.71-0.93], p < 0.0001) but not MRA use (hazard ratio 1.03 [95% confidence interval 0.88-1.21], p = 0.69) was independently associated with lower mortality. Among patients treated with an ACEI/ARB, there was a significantly lower unadjusted risk of cardiovascular death (p < 0.001), risk of gastrointestinal bleeding (p = 0.01), and creatinine level (p < 0.001). MRA therapy was associated with lower risk of gastrointestinal bleeding (p = 0.01) but higher risk of hemolysis (p < 0.01). Potential limitations include residual confounding and therapy crossover. CONCLUSION:These findings suggest a benefit for ACEI/ARB therapy in patients with heart failure after LVAD implantation.
PMCID:8627474
PMID: 34663529
ISSN: 1557-3117
CID: 5162882