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Development and validation of a plasma biomarker panel for discerning clinical significance of indeterminate pulmonary nodules.
Daly S, Rinewalt D, Fhied C, Basu S, Mahon B, Liptay MJ, Hong E, Chmielewski G, Yoder MA, Shah PN, Edell ES, Maldonado F, Bungum AO, Borgia JA
(2013) J Thorac Oncol 8: 31-6
MeSH Terms: Adult, Aged, Aged, 80 and over, Area Under Curve, Biomarkers, Tumor, Chemokine CCL3, Chemokine CXCL12, Cytokines, Female, Granuloma, Humans, Interleukin 1 Receptor Antagonist Protein, Interleukin-10, Interleukin-2 Receptor alpha Subunit, Interleukin-6, Lung Neoplasms, Male, Middle Aged, Multiple Pulmonary Nodules, Pneumonia, Predictive Value of Tests, ROC Curve, Radiography, Respiratory Tract Infections, Solitary Pulmonary Nodule, Tumor Necrosis Factor-alpha, Young Adult
Show Abstract · Added February 1, 2016
INTRODUCTION - The recent findings of the National Lung Screening Trial showed 24.2% of individuals at high risk for lung cancer having one or more indeterminate nodules detected by low-dose computed tomography-based screening, 96.4% of which were eventually confirmed as false positives. These positive scans necessitate additional diagnostic procedures to establish a definitive diagnosis that adds cost and risk to the paradigm. A plasma test able to assign benign versus malignant pathology in high-risk patients would be an invaluable tool to complement low-dose computed tomography-based screening and promote its rapid implementation.
METHODS - We evaluated 17 biomarkers, previously shown to have value in detecting lung cancer, against a discovery cohort, comprising benign (n = 67) cases and lung cancer (n = 69) cases. A Random Forest method based analysis was used to identify the optimal biomarker panel for assigning disease status, which was then validated against a cohort from the Mayo Clinic, comprising patients with benign (n = 61) or malignant (n = 20) indeterminate lung nodules.
RESULTS - Our discovery efforts produced a seven-analyte plasma biomarker panel consisting of interleukin 6 (IL-6), IL-10, IL-1ra, sIL-2Rα, stromal cell-derived factor-1α+β, tumor necrosis factor α, and macrophage inflammatory protein 1 α. The sensitivity and specificity of our panel in our validation cohort is 95.0% and 23.3%, respectively. The validated negative predictive value of our panel was 93.8%.
CONCLUSION - We developed a seven-analyte plasma biomarker panel able to identify benign nodules, otherwise deemed indeterminate, with a high degree of accuracy. This panel may have clinical utility in risk-stratifying screen-detected lung nodules, decrease unnecessary follow-up imaging or invasive procedures, and potentially avoid unnecessary morbidity, mortality, and health care costs.
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27 MeSH Terms
An important role of prostanoid receptor EP2 in host resistance to Mycobacterium tuberculosis infection in mice.
Kaul V, Bhattacharya D, Singh Y, Van Kaer L, Peters-Golden M, Bishai WR, Das G
(2012) J Infect Dis 206: 1816-25
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, Disease Models, Animal, Forkhead Transcription Factors, Gene Expression, Gene Expression Profiling, Immunophenotyping, Interleukin-2 Receptor alpha Subunit, Mice, Mice, Inbred C57BL, Mycobacterium tuberculosis, Receptors, Prostaglandin E, EP2 Subtype, T-Lymphocytes, Regulatory, Tuberculosis
Show Abstract · Added March 20, 2014
Mycobacterium tuberculosis, the causative agent of tuberculosis, resides and replicates within susceptible hosts by inhibiting host antimicrobial mechanisms. Prostaglandin E(2) (PGE(2)), produced by M. tuberculosis-infected macrophages, exerts a variety of immunomodulatory functions via 4 receptors (EP1-EP4), each mediating distinct PGE(2) functions. Here, we show that M. tuberculosis infection selectively upregulates EP2 messenger RNA expression in CD4(+) T cells. We found that EP2 deficiency in mice increases susceptibility to M. tuberculosis infection, which correlated with reduced antigen-specific T-cell responses and increased levels of CD4(+)CD25(+)Foxp3(+) T-regulatory cells. These findings have revealed an important role for EP2 in host immune defense against tuberculosis. As a G protein-coupled receptor, EP2 could serve as a target for immunotherapy of tuberculosis.
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14 MeSH Terms
A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network.
Aslibekyan S, Kabagambe EK, Irvin MR, Straka RJ, Borecki IB, Tiwari HK, Tsai MY, Hopkins PN, Shen J, Lai CQ, Ordovas JM, Arnett DK
(2012) Pharmacogenet Genomics 22: 191-7
MeSH Terms: Adult, C-Reactive Protein, Chemokine CCL2, Female, Fenofibrate, Gene Frequency, Genome-Wide Association Study, Genotyping Techniques, Humans, Hypolipidemic Agents, Inflammation, Interleukin-2 Receptor alpha Subunit, Interleukin-6, Male, Middle Aged, Polymorphism, Single Nucleotide, Tumor Necrosis Factor-alpha
Show Abstract · Added March 7, 2014
OBJECTIVE - Despite the evidence in support of the anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation.
METHODS - Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns [high-sensitivity C-reactive protein-interleukin-6 and monocyte chemoattractant protein-1-tumor necrosis factor (MCP1-TNF-α)] were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect.
RESULTS - Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the high-sensitivity C-reactive protein-interleukin-6 (IL6) pattern (rs7911500, P=5×10 and rs12722605, P=5×10). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes [CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)] approached genome-wide significance (P=3×10, 5×10, 6×10, and 7×10, respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10).
CONCLUSION - We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.
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17 MeSH Terms
Increased frequency of regulatory T cells and T lymphocyte activation in persons with previously treated extrapulmonary tuberculosis.
de Almeida AS, Fiske CT, Sterling TR, Kalams SA
(2012) Clin Vaccine Immunol 19: 45-52
MeSH Terms: Adult, Aged, Antitubercular Agents, CD4 Antigens, Case-Control Studies, Forkhead Transcription Factors, Humans, Interleukin-2 Receptor alpha Subunit, Interleukin-7 Receptor alpha Subunit, Lymphocyte Activation, Male, Middle Aged, Mycobacterium tuberculosis, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory, Tuberculosis
Show Abstract · Added May 29, 2014
Extrapulmonary tuberculosis may be due to underlying immune compromise. Immunosuppressive regulatory T cells (Treg cells), and CD4(+) T lymphocytes in general, are important in the host immune response to Mycobacterium tuberculosis. We evaluated T lymphocytes from patients after recovery from extrapulmonary tuberculosis, which may reflect conditions before M. tuberculosis infection. A case-control study was conducted among HIV-uninfected adults with previously treated extrapulmonary tuberculosis and 3 sets of controls: (i) subjects with previously treated pulmonary tuberculosis, (ii) close tuberculosis contacts with M. tuberculosis infection, and (iii) close tuberculosis contacts with no infection. Monocyte-depleted peripheral blood mononuclear cells (PBMC-M) were stained for CD4(+) CD25(hi) CD127(low) FoxP3(+) cell (Treg cell) and T lymphocyte activation. Both characteristics were compared as continuous variables between groups with the Kruskal-Wallis test. There were 7 extrapulmonary tuberculosis cases, 18 pulmonary tuberculosis controls, 17 controls with M. tuberculosis infection, and 18 controls without M. tuberculosis infection. The median Treg cell proportion was highest among persons with previous extrapulmonary tuberculosis (1.23%) compared to subjects with pulmonary tuberculosis (0.56%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.20%) (P = 0.001). The median proportion of CD4(+) T lymphocytes that expressed the activation markers HLA-DR and CD38 was highest for CD4(+) T lymphocytes from persons with previous extrapulmonary tuberculosis (0.79%) compared to subjects with pulmonary tuberculosis (0.44%), latent M. tuberculosis infection (0.14%), or no M. tuberculosis infection (0.32%) (P = 0.005). Compared with controls, persons with previously treated extrapulmonary tuberculosis had the highest Treg cell frequency, but also the highest levels of CD4(+) T lymphocyte activation. Immune dysregulation may be a feature of individuals at risk for extrapulmonary tuberculosis.
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16 MeSH Terms
Podocyte injury damages other podocytes.
Matsusaka T, Sandgren E, Shintani A, Kon V, Pastan I, Fogo AB, Ichikawa I
(2011) J Am Soc Nephrol 22: 1275-85
MeSH Terms: Animals, Chimerism, Female, Interleukin-2 Receptor alpha Subunit, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nephrosclerosis, Podocytes, Transgenes
Show Abstract · Added January 25, 2012
Loss of podocytes promotes glomerulosclerosis, but whether this results from a continued primary insult or a secondary mechanism triggered by the initial loss of podocytes is unknown. We generated chimeric mice in which only a subpopulation of podocytes expressed hCD25, which is the receptor for the immunotoxin LMB2. In addition, genetic labeling of hCD25-negative cells with human placental alkaline phosphatase allowed the study of these two distinct podocyte populations. Administration of LMB2 did not cause podocyte injury in hCD25-negative control mice. In contrast, LMB2 severely damaged or sloughed off the subpopulation of hCD25-positive podocytes within the chimeric glomeruli. Moreover, hCD25-negative podocytes, which were immune to the initial toxin injury, developed injury as early as 4 d after LMB2 injection, evidenced by foot process effacement, upregulation of desmin, and downregulation of nephrin, podocin, and podocalyxin. Furthermore, the magnitude of secondary injury correlated with the magnitude of primary injury, supporting the concept of an amplified cascade of podocyte injury. In conclusion, podocyte damage can propagate injury by triggering secondary damage of "remnant" intact podocytes, even when the primary insult is short-lived. This transmission of podocyte injury may form a vicious cycle leading to accelerated podocyte deterioration and glomerulosclerosis.
Copyright © 2011 by the American Society of Nephrology
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11 MeSH Terms
Impaired T-cell receptor activation in IL-1 receptor-associated kinase-4-deficient patients.
McDonald DR, Goldman F, Gomez-Duarte OD, Issekutz AC, Kumararatne DS, Doffinger R, Geha RS
(2010) J Allergy Clin Immunol 126: 332-7, 337.e1-2
MeSH Terms: Adaptive Immunity, Antigens, CD, Antigens, Differentiation, T-Lymphocyte, Case-Control Studies, Cytokines, Female, Genetic Diseases, Inborn, Humans, Immunologic Deficiency Syndromes, Interleukin-1 Receptor-Associated Kinases, Interleukin-2 Receptor alpha Subunit, Lectins, C-Type, Lymphocyte Activation, Male, Receptors, Antigen, T-Cell, T-Lymphocytes, Up-Regulation
Show Abstract · Added May 27, 2014
BACKGROUND - IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood.
OBJECTIVE - We sought to evaluate T-cell function in IRAK-4 deficient patients.
METHODS - We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-gamma after stimulation of PBMCs from 4 IRAK-4-deficient patients and healthy control subjects with anti-CD3 and anti-CD28.
RESULTS - Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-gamma, but not IL-2, was significantly reduced in IRAK-4-deficient patients.
CONCLUSIONS - IRAK-4-deficient patients have defects in T-cell activation.
Copyright 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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17 MeSH Terms
The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR.
Liu G, Burns S, Huang G, Boyd K, Proia RL, Flavell RA, Chi H
(2009) Nat Immunol 10: 769-77
MeSH Terms: Adoptive Transfer, Animals, Animals, Newborn, CD4-Positive T-Lymphocytes, Carrier Proteins, Cell Differentiation, Colon, Female, Flow Cytometry, Forkhead Transcription Factors, Homeostasis, Immune Tolerance, Interleukin-2 Receptor alpha Subunit, Leukocyte Common Antigens, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Phosphotransferases (Alcohol Group Acceptor), Proto-Oncogene Proteins c-akt, Receptors, Lysosphingolipid, Signal Transduction, T-Lymphocytes, Regulatory, TOR Serine-Threonine Kinases, Thymus Gland
Show Abstract · Added March 5, 2014
Regulatory T cells (T(reg) cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of T(reg) cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T(reg) precursors and function of mature T(reg) cells and affected T(reg) cell-mediated immune tolerance. S1P1 induced selective activation of the Akt-mTOR kinase pathway to impede the development and function of T(reg) cells. Dynamic regulation of S1P1 contributed to lymphocyte priming and immune homeostasis. Thus, by antagonizing T(reg) cell-mediated immune suppression, the lipid-activated S1P1-Akt-mTOR pathway orchestrates adaptive immune responses.
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26 MeSH Terms
Megalin contributes to the early injury of proximal tubule cells during nonselective proteinuria.
Motoyoshi Y, Matsusaka T, Saito A, Pastan I, Willnow TE, Mizutani S, Ichikawa I
(2008) Kidney Int 74: 1262-9
MeSH Terms: Absorption, Albumins, Animals, Female, Humans, Immunoglobulin A, Immunoglobulin G, Interleukin-2 Receptor alpha Subunit, Kidney Tubules, Proximal, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Knockout, Mice, Transgenic, Proteins, Proteinuria
Show Abstract · Added January 25, 2012
Megalin, a member of the LDL receptor family, is expressed on the apical membrane of proximal tubules and serves as an endocytic scavenger of filtered proteins and hence might contribute to the tubule injury as a consequence of glomerular disease. To study its role, we crossed megalin knockout mosaic mice (lacking megalin expression in 60% of proximal tubule cells) with NEP25 mice (a transgenic line expressing human CD25 in the podocyte). Treatment of this transgenic mouse with the immunotoxin causes nephrotic syndrome, focal segmental glomerulosclerosis and tubule-interstitial injury. Following this treatment, the double transgenic mice had massive non-selective proteinuria and mild glomerular and tubular injury. Comparison of megalin-containing to megalin-deficient proximal tubule cells within each kidney showed that albumin, immunoglobulin light chain, IgA and IgG were preferentially accumulated in proximal tubule cells expressing megalin. Tubule injury markers such as heme-oxygenase-1, monocyte chemoattractant protein-1 and cellular apoptosis were also preferentially found in these megalin-expressing cells. These results show that megalin plays a pivotal role in the reabsorption of small to large molecular size proteins and provides direct in vivo evidence that reabsorption of filtered proteins triggers events leading to tubule injury.
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16 MeSH Terms