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Publication Record


Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity.
Koyner JL, Davison DL, Brasha-Mitchell E, Chalikonda DM, Arthur JM, Shaw AD, Tumlin JA, Trevino SA, Bennett MR, Kimmel PL, Seneff MG, Chawla LS
(2015) J Am Soc Nephrol 26: 2023-31
MeSH Terms: Acute Kidney Injury, Acute-Phase Proteins, Aged, Albuminuria, Biomarkers, Creatinine, Disease Progression, Diuretics, Female, Furosemide, Hepatitis A Virus Cellular Receptor 1, Humans, Insulin-Like Growth Factor Binding Proteins, Interleukin-18, Lipocalin-2, Lipocalins, Male, Membrane Glycoproteins, Middle Aged, Proto-Oncogene Proteins, Receptors, Virus, Severity of Illness Index, Sodium, Tissue Inhibitor of Metalloproteinase-2, Uromodulin
Show Abstract · Added October 20, 2015
Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.
Copyright © 2015 by the American Society of Nephrology.
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25 MeSH Terms
Tissue Inhibitor Metalloproteinase-2 (TIMP-2)⋅IGF-Binding Protein-7 (IGFBP7) Levels Are Associated with Adverse Long-Term Outcomes in Patients with AKI.
Koyner JL, Shaw AD, Chawla LS, Hoste EA, Bihorac A, Kashani K, Haase M, Shi J, Kellum JA, Sapphire Investigators
(2015) J Am Soc Nephrol 26: 1747-54
MeSH Terms: Acute Kidney Injury, Adult, Biomarkers, Cohort Studies, Female, Follow-Up Studies, Humans, Insulin-Like Growth Factor Binding Proteins, Kaplan-Meier Estimate, Kidney Function Tests, Male, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Renal Dialysis, Risk Assessment, Sensitivity and Specificity, Severity of Illness Index, Survival Analysis, Time Factors, Tissue Inhibitor of Metalloproteinase-2, Treatment Outcome
Show Abstract · Added October 20, 2015
Tissue inhibitor metalloproteinase-2 (TIMP-2) and IGF-binding protein-7 (IGFBP7) have been validated for risk stratification in AKI. However, the association of urinary TIMP-2 and IGFBP7 with long-term outcomes is unknown. We evaluated the 9-month incidence of a composite end point of all-cause mortality or the need for RRT in a secondary analysis of a prospective observational international study of critically ill adults. Two predefined [TIMP-2]⋅[IGFBP7] cutoffs (0.3 for high sensitivity and 2.0 for high specificity) for the development of AKI were evaluated. Cox proportional hazards models were used to determine risk for the composite end point. Baseline [TIMP-2]⋅[IGFBP7] values were available for 692 subjects, of whom 382 (55.2%) subjects developed stage 1 AKI (defined by Kidney Disease Improving Global Outcomes guidelines) within 72 hours of enrollment and 217 (31.4%) subjects met the composite end point. Univariate analysis showed that [TIMP-2]⋅[IGFBP7]>2.0 was associated with increased risk of the composite end point (hazard ratio [HR], 2.11; 95% confidence interval [95% CI], 1.37 to 3.23; P<0.001). In a multivariate analysis adjusted for the clinical model, [TIMP-2]⋅[IGFBP7] levels>0.3 were associated with death or RRT only in subjects who developed AKI (compared with levels≤0.3: HR, 1.44; 95% CI, 1.00 to 2.06 for levels>0.3 to ≤2.0; P=0.05 and HR, 2.16; 95% CI, 1.32 to 3.53 for levels>2.0; P=0.002). In conclusion, [TIMP-2]⋅[IGFBP7] measured early in the setting of critical illness may identify patients with AKI at increased risk for mortality or receipt of RRT over the next 9 months.
Copyright © 2015 by the American Society of Nephrology.
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24 MeSH Terms
Value of circulating insulin-like growth factor-associated proteins for the detection of stage I non-small cell lung cancer.
Kubasiak JC, Seder CW, Pithadia R, Basu S, Fhied C, Phillips WW, Daly S, Shersher DD, Yoder MA, Chmielewski G, Edell ES, Maldonado F, Liptay MJ, Borgia JA
(2015) J Thorac Cardiovasc Surg 149: 727-34.e1-3; discussion 734
MeSH Terms: Adult, Aged, Aged, 80 and over, Algorithms, Area Under Curve, Biomarkers, Tumor, Carcinoma, Non-Small-Cell Lung, Cytokines, Female, Humans, Illinois, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Lung Neoplasms, Male, Middle Aged, Minnesota, Multivariate Analysis, Neoplasm Staging, Predictive Value of Tests, ROC Curve, Reproducibility of Results, Retrospective Studies, Tomography, X-Ray Computed, Young Adult
Show Abstract · Added July 28, 2015
OBJECTIVE - Circulating biomarkers related to insulin-like growth factor (IGF) signaling are associated with disease progression in multiple carcinomas, but their potential diagnostic value for lung cancer screening has been inadequately examined. We evaluated 9 circulating IGF-related factors for their ability to assign clinical significance to indeterminate pulmonary nodules identified via computed tomography-based radiologic studies.
METHODS - Patients (n = 224 stage I non-small cell lung cancer; n = 123 benign) were enrolled by Rush University and the Mayo Clinic and had pretreatment serum evaluated for levels of IGF-1, IGF-2, and insulin-like growth factor binding proteins (IGFBPs) 1-7. The Mann-Whitney rank-sum test and receiver-operator characteristics curves were used to assess differences in biomarker concentrations relevant to malignant versus benign pathology. These targets were used to help refine our companion blood test for assigning clinical significance to computed tomography-detected solitary nodules (discovery cohort, n = 94) and were validated against an independent cohort from the Mayo Clinic (n = 81).
RESULTS - Patients with benign pulmonary nodules were found to have serum concentrations of IGFBP-3, IGFBP-5, IGF-1, and IGF-2 that were higher (P = .001, P < .001, P = .002, and P = .011, respectively) than those with non-small cell lung cancer, with distinct associations with histologic subtypes observed. Refinement of our multianalyte classification algorithm using IGF-related factors provided a new panel consisting of interleukin-6, interleukin-1 receptor antagonist, interleukin-10, stromal cell-derived factor-1(α + β), IGFBP-4, IGFBP-5, and IGF-2 with improved assay performance-achieving a (validated) negative predictive value of 100%.
CONCLUSIONS - Our findings suggest a divergent role for IGF signaling in the biology of benign and malignant pulmonary nodules. Upon further validation, these observations may help identify cases of false positives resulting from computed tomography-based screening studies.
Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.
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26 MeSH Terms
Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers.
Hoste EA, McCullough PA, Kashani K, Chawla LS, Joannidis M, Shaw AD, Feldkamp T, Uettwiller-Geiger DL, McCarthy P, Shi J, Walker MG, Kellum JA, Sapphire Investigators
(2014) Nephrol Dial Transplant 29: 2054-61
MeSH Terms: Acute Kidney Injury, Aged, Biomarkers, Cell Cycle Checkpoints, Female, Follow-Up Studies, Humans, Insulin-Like Growth Factor Binding Proteins, Male, Middle Aged, Predictive Value of Tests, ROC Curve, Tissue Inhibitor of Metalloproteinase-2
Show Abstract · Added October 20, 2015
BACKGROUND - Acute kidney injury (AKI) remains a deadly condition. Tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein (IGFBP)7 are two recently discovered urinary biomarkers for AKI. We now report on the development, and diagnostic accuracy of two clinical cutoffs for a test using these markers.
METHODS - We derived cutoffs based on sensitivity and specificity for prediction of Kidney Disease: Improving Global Outcomes Stages 2-3 AKI within 12 h using data from a previously published multicenter cohort (Sapphire). Next, we verified these cutoffs in a new study (Opal) enrolling 154 critically ill adults from six sites in the USA.
RESULTS - One hundred subjects (14%) in Sapphire and 27 (18%) in Opal met the primary end point. The results of the Opal study replicated those of Sapphire. Relative risk (95% CI) in both studies for subjects testing at ≤0.3 versus >0.3-2 were 4.7 (1.5-16) and 4.4 (2.5-8.7), or 12 (4.2-40) and 18 (10-37) for ≤0.3 versus >2. For the 0.3 cutoff, sensitivity was 89% in both studies, and specificity 50 and 53%. For 2.0, sensitivity was 42 and 44%, and specificity 95 and 90%.
CONCLUSIONS - Urinary [TIMP-2]•[IGFBP7] values of 0.3 or greater identify patients at high risk and those >2 at highest risk for AKI and provide new information to support clinical decision-making.
CLINICAL TRIALS REGISTRATION - Clintrials.gov # NCT01209169 (Sapphire) and NCT01846884 (Opal).
© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA.
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13 MeSH Terms
Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication.
Bihorac A, Chawla LS, Shaw AD, Al-Khafaji A, Davison DL, Demuth GE, Fitzgerald R, Gong MN, Graham DD, Gunnerson K, Heung M, Jortani S, Kleerup E, Koyner JL, Krell K, Letourneau J, Lissauer M, Miner J, Nguyen HB, Ortega LM, Self WH, Sellman R, Shi J, Straseski J, Szalados JE, Wilber ST, Walker MG, Wilson J, Wunderink R, Zimmerman J, Kellum JA
(2014) Am J Respir Crit Care Med 189: 932-9
MeSH Terms: Acute Kidney Injury, Aged, Aged, 80 and over, Biomarkers, Cell Death, Cohort Studies, Critical Illness, Female, Humans, Insulin-Like Growth Factor Binding Proteins, Male, Middle Aged, Predictive Value of Tests, Prospective Studies, Protease Inhibitors, Sensitivity and Specificity, Severity of Illness Index, Time Factors, Tissue Inhibitor of Metalloproteinase-2, United States
Show Abstract · Added October 20, 2015
RATIONALE - We recently reported two novel biomarkers for acute kidney injury (AKI), tissue inhibitor of metalloproteinases (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both related to G1 cell cycle arrest.
OBJECTIVES - We now validate a clinical test for urinary [TIMP-2]·[IGFBP7] at a high-sensitivity cutoff greater than 0.3 for AKI risk stratification in a diverse population of critically ill patients.
METHODS - We conducted a prospective multicenter study of 420 critically ill patients. The primary analysis was the ability of urinary [TIMP-2]·[IGFBP7] to predict moderate to severe AKI within 12 hours. AKI was adjudicated by a committee of three independent expert nephrologists who were masked to the results of the test.
MEASUREMENTS AND MAIN RESULTS - Urinary TIMP-2 and IGFBP7 were measured using a clinical immunoassay platform. The primary endpoint was reached in 17% of patients. For a single urinary [TIMP-2]·[IGFBP7] test, sensitivity at the prespecified high-sensitivity cutoff of 0.3 (ng/ml)(2)/1,000 was 92% (95% confidence interval [CI], 85-98%) with a negative likelihood ratio of 0.18 (95% CI, 0.06-0.33). Critically ill patients with urinary [TIMP-2]·[IGFBP7] greater than 0.3 had seven times the risk for AKI (95% CI, 4-22) compared with critically ill patients with a test result below 0.3. In a multivariate model including clinical information, urinary [TIMP-2]·[IGFBP7] remained statistically significant and a strong predictor of AKI (area under the curve, 0.70, 95% CI, 0.63-0.76 for clinical variables alone, vs. area under the curve, 0.86, 95% CI, 0.80-0.90 for clinical variables plus [TIMP-2]·[IGFBP7]).
CONCLUSIONS - Urinary [TIMP-2]·[IGFBP7] greater than 0.3 (ng/ml)(2)/1,000 identifies patients at risk for imminent AKI. Clinical trial registered with www.clinicaltrials.gov (NCT 01573962).
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20 MeSH Terms
Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.
Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, Bihorac A, Birkhahn R, Cely CM, Chawla LS, Davison DL, Feldkamp T, Forni LG, Gong MN, Gunnerson KJ, Haase M, Hackett J, Honore PM, Hoste EA, Joannes-Boyau O, Joannidis M, Kim P, Koyner JL, Laskowitz DT, Lissauer ME, Marx G, McCullough PA, Mullaney S, Ostermann M, Rimmelé T, Shapiro NI, Shaw AD, Shi J, Sprague AM, Vincent JL, Vinsonneau C, Wagner L, Walker MG, Wilkerson RG, Zacharowski K, Kellum JA
(2013) Crit Care 17: R25
MeSH Terms: Acute Kidney Injury, Aged, Biomarkers, Cell Cycle Checkpoints, Cohort Studies, Female, Humans, Insulin-Like Growth Factor Binding Proteins, Male, Middle Aged, Tissue Inhibitor of Metalloproteinase-2
Show Abstract · Added October 20, 2015
INTRODUCTION - Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.
METHODS - We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.
RESULTS - Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.
CONCLUSIONS - Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.
TRIAL REGISTRATION - ClinicalTrials.gov number NCT01209169.
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11 MeSH Terms
Maternal and cord blood hormone levels in the United States and China and the intrauterine origin of breast cancer.
Lagiou P, Samoli E, Okulicz W, Xu B, Lagiou A, Lipworth L, Georgila C, Vatten L, Adami HO, Trichopoulos D, Hsieh CC
(2011) Ann Oncol 22: 1102-8
MeSH Terms: Adiponectin, Adult, Breast Neoplasms, China, Female, Fetal Blood, Gonadal Steroid Hormones, Hormones, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Pregnancy, Prolactin, Sex Hormone-Binding Globulin, Statistics, Nonparametric, United States, Young Adult
Show Abstract · Added March 1, 2014
BACKGROUND - Breast cancer is less common in China than in the United States and perinatal characteristics predict breast cancer risk in the offspring. We determined levels of pregnancy hormones in Boston and Shanghai to identify those possibly involved in the intrauterine origin of breast cancer.
PARTICIPANTS AND METHODS - We compared maternal and cord blood levels of estradiol, estriol, testosterone, progesterone, prolactin, insulin-like growth factors (IGF) 1 and 2, insulin-like growth factor-binding protein 3, adiponectin and sex hormone-binding globulin (SHBG) in 241 Caucasian and 295 Chinese women.
RESULTS - In both centers, hormone levels at the 16th were predictive of those at the 27th gestational week, but there was little correlation between maternal and cord blood levels. In cord blood, we found significantly (P < 0.01) higher levels of estradiol (44.2%), testosterone (54.5%), IGF-2 (22.7%) and strikingly SHBG (104.6%) in Shanghai women, whereas the opposite was true for IGF-1 (-36.8%).
CONCLUSIONS - Taking into account the current understanding of the plausible biological role of the examined endocrine factors, those likely to be involved in the intrauterine origin of breast cancer are SHBG and IGF-2, with higher cord blood levels among Chinese, and IGF-1, with higher cord blood levels among Caucasian women.
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18 MeSH Terms
Circulating insulin-like growth factor-1 and its binding protein-3: metabolic and genetic correlates in the community.
Lam CS, Chen MH, Lacey SM, Yang Q, Sullivan LM, Xanthakis V, Safa R, Smith HM, Peng X, Sawyer DB, Vasan RS
(2010) Arterioscler Thromb Vasc Biol 30: 1479-84
MeSH Terms: Adult, Biomarkers, Cardiovascular Diseases, Cross-Sectional Studies, Female, Genetic Testing, Genome-Wide Association Study, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Linear Models, Male, Middle Aged, Pedigree, Quantitative Trait, Heritable, Risk Assessment, Risk Factors, United States
Show Abstract · Added May 21, 2014
OBJECTIVE - The metabolic and genetic correlates of circulating insulin-like growth factor-1 (IGF-1) and its main circulating carrier, IGF-1-binding-protein-3 (IGFBP-3), are unclear.
METHODS AND RESULTS - We measured serum IGF-1 and IGFBP-3 concentrations in a sample of the Framingham Heart Study (N=3977, aged 40+/-9 years, 46% male) and evaluated their relations to cardiovascular risk factors using multivariable regression. Serum IGF-1 was inversely correlated with age, body mass index, total cholesterol, the presence of diabetes, alcohol consumption, and glomerular filtration rate (all P<0.01), whereas the ratio of IGF-1:IGFBP-3 was lower in women and inversely related to age, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, and alcohol consumption (all P<0.0001). Circulating IGF-1 correlated negatively with insulin resistance (homeostatic model assessment) (r=-0.1; P<0.0001) and was lower in participants with more components of the metabolic syndrome (Adult Treatment Panel III criteria) (P<0.0001). Additive genetic factors (heritability) accounted for 43% and 39% of the variation of IGF-1 and IGFBP-3, respectively (both P<10(-27)).
CONCLUSIONS - Our cross-sectional observations in a large community-based sample link lower circulating IGF-1 to greater metabolic risk burden and underscore substantial genetic influences on IGF-1 concentrations. Prospective studies are warranted to elucidate whether lower IGF-1 concentrations predict greater metabolic risk longitudinally.
1 Communities
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19 MeSH Terms
Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis.
Lee JJ, Natsuizaka M, Ohashi S, Wong GS, Takaoka M, Michaylira CZ, Budo D, Tobias JW, Kanai M, Shirakawa Y, Naomoto Y, Klein-Szanto AJ, Haase VH, Nakagawa H
(2010) Carcinogenesis 31: 427-34
MeSH Terms: Carcinoma, Squamous Cell, Cell Hypoxia, Cell Line, Cobalt, Cyclooxygenase 2, Dinoprostone, Enzyme Activation, Epithelial Cells, Esophageal Neoplasms, Gene Expression Profiling, Humans, Hydroxyprostaglandin Dehydrogenases, Hypoxia-Inducible Factor 1, alpha Subunit, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Interleukin-1beta, Intramolecular Oxidoreductases, Neoplasm Proteins, Oxygen, Prostaglandin-E Synthases, RNA Interference, RNA, Messenger, RNA, Neoplasm, RNA, Small Interfering, Recombinant Fusion Proteins, Tumor Cells, Cultured
Show Abstract · Added August 19, 2013
Hypoxia-inducible factors (HIFs), in particular HIF-1alpha, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1alpha target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1alpha by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1alpha. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E(2) (PGE(2)) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE(2) production in a HIF-1alpha-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1alpha and IGFBP3. Activation of the COX-2-PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1beta and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1alpha target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin.
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26 MeSH Terms
Racial differences in the association between body mass index and serum IGF1, IGF2, and IGFBP3.
Fowke JH, Matthews CE, Yu H, Cai Q, Cohen S, Buchowski MS, Zheng W, Blot WJ
(2010) Endocr Relat Cancer 17: 51-60
MeSH Terms: Adult, African Americans, Age of Onset, Aged, Body Mass Index, Breast Neoplasms, Cross-Sectional Studies, European Continental Ancestry Group, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Insulin-Like Growth Factor II, Middle Aged, Postmenopause, Premenopause, Prospective Studies, Southeastern United States, Young Adult
Show Abstract · Added December 10, 2013
African-American (AA) race/ethnicity, lower body mass index (BMI), and higher IGF1 levels are associated with premenopausal breast cancer risk. This cross-sectional analysis investigated whether BMI or BMI at age 21 years contributes to racial differences in IGF1, IGF2, IGF-binding protein 3 (IGFBP3), or free IGF1. Participants included 816 white and 821 AA women between ages 40 and 79 years across a wide BMI range (18.5-40 kg/m(2)). Compared with white women, AA women had higher mean IGF1 (146.3 vs 134.4 ng/ml) and free IGF1 (0.145 vs 0.127) levels, and lower IGF2 (1633.0 vs 1769.3 ng/ml) and IGFBP3 (3663.3 vs 3842.5 ng/ml) levels (all P<0.01; adjusted for age, height, BMI, BMI at age 21 years, and menopausal status). Regardless of race, IGF1 and free IGF1 levels rose sharply as BMI increased to 22-24 kg/m(2), and then declined thereafter, while IGF2 and IGFBP3 levels tended to rise with BMI. In contrast, BMI at age 21 years was inversely associated with all IGF levels, but only among white women (P-interaction=0.01). With the decline in IGF1 with BMI at age 21 years among whites, racial differences in IGF1 significantly increased among women who were obese in early adulthood. In summary, BMI was associated with IGF1 levels regardless of race/ethnicity, while obesity during childhood or young adulthood may have a greater impact on IGF1 levels among white women. The effects of obesity throughout life on the IGF axis and racial differences in breast cancer risk require study.
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22 MeSH Terms