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PEDF, a pleiotropic WTC-LI biomarker: Machine learning biomarker identification and validation

Crowley, George; Kim, James; Kwon, Sophia; Lam, Rachel; Prezant, David J; Liu, Mengling; Nolan, Anna
Biomarkers predict World Trade Center-Lung Injury (WTC-LI); however, there remains unaddressed multicollinearity in our serum cytokines, chemokines, and high-throughput platform datasets used to phenotype WTC-disease. To address this concern, we used automated, machine-learning, high-dimensional data pruning, and validated identified biomarkers. The parent cohort consisted of male, never-smoking firefighters with WTC-LI (FEV1, %Pred< lower limit of normal (LLN); n = 100) and controls (n = 127) and had their biomarkers assessed. Cases and controls (n = 15/group) underwent untargeted metabolomics, then feature selection performed on metabolites, cytokines, chemokines, and clinical data. Cytokines, chemokines, and clinical biomarkers were validated in the non-overlapping parent-cohort via binary logistic regression with 5-fold cross validation. Random forests of metabolites (n = 580), clinical biomarkers (n = 5), and previously assayed cytokines, chemokines (n = 106) identified that the top 5% of biomarkers important to class separation included pigment epithelium-derived factor (PEDF), macrophage derived chemokine (MDC), systolic blood pressure, macrophage inflammatory protein-4 (MIP-4), growth-regulated oncogene protein (GRO), monocyte chemoattractant protein-1 (MCP-1), apolipoprotein-AII (Apo-AII), cell membrane metabolites (sphingolipids, phospholipids), and branched-chain amino acids. Validated models via confounder-adjusted (age on 9/11, BMI, exposure, and pre-9/11 FEV1, %Pred) binary logistic regression had AUCROC [0.90(0.84-0.96)]. Decreased PEDF and MIP-4, and increased Apo-AII were associated with increased odds of WTC-LI. Increased GRO, MCP-1, and simultaneously decreased MDC were associated with decreased odds of WTC-LI. In conclusion, automated data pruning identified novel WTC-LI biomarkers; performance was validated in an independent cohort. One biomarker-PEDF, an antiangiogenic agent-is a novel, predictive biomarker of particulate-matter-related lung disease. Other biomarkers-GRO, MCP-1, MDC, MIP-4-reveal immune cell involvement in WTC-LI pathogenesis. Findings of our automated biomarker identification warrant further investigation into these potential pharmacotherapy targets.
PMID: 34288906
ISSN: 1553-7358
CID: 4979682


Mirabal, Susan C.; Theprungsirikul, Poy; Zullow, Samantha; Sterling, Stephanie; Kim, James
ISSN: 0884-8734
CID: 4851722


Kim, James; Schattner, Mark A.; Ludwig, Emmy; Mendelsohn, Robin; Markowitz, Arnold J.; Flynn, Jessica; Riedel, Elyn; Gerdes, Hans; Shah, Pari
ISSN: 0016-5107
CID: 3236692

In-Hospital Cardiovascular Complications After Pancreas Transplantation in the United States from 2003 to 2012

Kim, Jim; Schulman-Marcus, Joshua; Watkins, Anthony C; Feldman, Dmitriy N; Swaminathan, Rajesh; Lee, Jun B; Muthukumar, Thangamani; Serur, David; Kim, Luke; Hartono, Choli
Large database studies detailing the risk of perioperative cardiovascular complications after pancreas transplant has been limited, perhaps because these outcomes are not captured by transplant registries. Greater data on the incidence and risks of such outcomes could provide additional insight for referring physicians and inform potential recipients of their risk. We performed a serial, cross-sectional analysis of the National Inpatient Sample, the largest publicly available inpatient database in the United States, to assess for the risk of cardiovascular complications after pancreas transplants in the United States from 2003 to 2012 (n = 13,399). Using multivariable logistic regression models, the risk of cardiovascular outcomes after simultaneous pancreas-kidney transplants (SPK) was compared with solitary pancreas transplants (pancreas after kidney and pancreas transplant alone [PAK + PTA]). The unadjusted prevalence of in-hospital cardiovascular complications was higher in SPK than PAK + PTA (5.5% vs 3.7%, p <0.001). After multivariable adjustment, SPK remained associated with significantly higher odds of any cardiovascular complication (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.21 to 1.80, p = 0.01), and particularly stroke (OR 13.41, 95% CI 4.78 to 37.63, p <0.001), compared with PAK + PTA. However, there was no difference in perioperative mortality (OR 0.78, 95% CI 0.54 to 1.12, p = 0.18). In conclusion, these findings highlight the association between uremia and stroke in pancreas transplant patients, as well as the need for improved preoperative cardiac risk assessment and perioperative management, especially in those who underwent SPK.
PMID: 28683901
ISSN: 1879-1913
CID: 4428762


Kim, James; Shia, Jinru; Schattner, Mark A.; Gerdes, Hans; Markowitz, Arnold J.; Kurtz, Robert C.; Ludwig, Emmy; Shah, Pari; Gambarin-Gelwan, Maya; Sinha, Smrita; Mendelsohn, Robin
ISSN: 0016-5085
CID: 3236702

Renal allograft outcomes following early corticosteroid withdrawal in Hispanic transplant recipients

Afaneh, Cheguevara; Cheng, Elaine; Aull, Meredith J; Watkins, Anthony C; Kim, Jim; Leeser, David B; Kapur, Sandip
BACKGROUND:Renal transplant outcomes in Hispanics have been conflicting regarding acute rejection (AR) and allograft survival. Additionally, the feasibility of early corticosteroid withdrawal (ECW) regimens among Hispanics has not been adequately addressed. The purpose of this study is to report outcomes following ECW among Hispanic renal transplant recipients. METHODS:We retrospectively reviewed 498 consecutive renal transplants performed at our institution between July 2005 and October 2007, including 73 Hispanic and 146 white recipients who had ECW (median follow-up 49 months). Demographics, transplant data, and outcomes of Hispanic and white recipients (WR) were analyzed. RESULTS:Hispanics had a higher incidence of diabetes mellitus and hypertension (p = 0.007), a higher proportion of blood type O (p = 0.006), and a higher serum panel reactive antibody at the time of transplantation (p = 0.02) compared with WR. Additionally, Hispanics were on dialysis longer than WR prior to transplantation (p = 0.03). Nevertheless, the incidence of AR, patient, and graft survival rates was similar (p > 0.05) between Hispanics and WR. Ethnicity was not an independent predictor of inferior patient and graft outcomes in multivariate analyses. CONCLUSION/CONCLUSIONS:Our single-center experience indicates that ECW can be performed in Hispanic renal transplant recipients, with patient and allograft outcomes comparable with those observed in WR.
PMID: 24033380
ISSN: 1399-0012
CID: 4428722

Na-glucose and Na-neutral amino acid cotransport are uniquely regulated by constitutive nitric oxide in rabbit small intestinal villus cells

Coon, Steven; Kim, James; Shao, Guohong; Sundaram, Uma
Na-nutrient cotransport processes are not only important for the assimilation of essential nutrients but also for the absorption of Na in the mammalian small intestine. The effect of constitutive nitric oxide (cNO) on Na-glucose (SGLT-1) and Na-amino acid cotransport (NAcT) in the mammalian small intestine is unknown. Inhibition of cNO synthase with N(G)-nitro-l-arginine methyl ester (L-NAME) resulted in the inhibition of Na-stimulated (3)H-O-methyl-D-glucose uptake in villus cells. However, Na-stimulated alanine uptake was not affected in these cells. The L-NAME-induced reduction in SGLT-1 in villus cells was not secondary to an alteration in basolateral membrane Na-K-ATPase activity, which provides the favorable Na gradient for this cotransport process. In fact, SGLT-1 was inhibited in villus cell brush-border membrane (BBM) vesicles prepared from animals treated with L-NAME. Kinetic studies demonstrated that the mechanism of inhibition of SGLT-1 was secondary to a decrease in the affinity for glucose without a change in the maximal rate of uptake of glucose. Northern blot studies demonstrated no change in the mRNA levels of SGLT-1. Western blot studies demonstrated no significant change in the immunoreactive protein levels of SGLT-1 in ileal villus cell BBM from L-NAME-treated rabbits. These studies indicate that inhibition of cNO production inhibits SGLT-1 but not NAcT in the rabbit small intestine. Therefore, whereas cNO promotes Na-glucose cotransport, it does not affect NAcT in the mammalian small intestine.
PMID: 16099871
ISSN: 0193-1857
CID: 3236722