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Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis.
Salem JE, Allenbach Y, Vozy A, Brechot N, Johnson DB, Moslehi JJ, Kerneis M
(2019) N Engl J Med 380: 2377-2379
MeSH Terms: Abatacept, Aged, Antineoplastic Agents, Immunological, Female, Humans, Immunosuppressive Agents, Lung Neoplasms, Myocarditis, Myositis, Nivolumab, Programmed Cell Death 1 Receptor
Added November 12, 2019
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1 Members
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MeSH Terms
Kidney-specific transposon-mediated gene transfer in vivo.
Woodard LE, Cheng J, Welch RC, Williams FM, Luo W, Gewin LS, Wilson MH
(2017) Sci Rep 7: 44904
MeSH Terms: Acute Kidney Injury, Animals, DNA Transposable Elements, Erythropoietin, Gene Expression, Gene Expression Regulation, Gene Transfer Techniques, Genes, Reporter, Genetic Vectors, Hydrodynamics, Immunosuppressive Agents, Kidney, Male, Mice, Organ Specificity, Promoter Regions, Genetic, Transfection
Show Abstract · Added September 11, 2017
Methods enabling kidney-specific gene transfer in adult mice are needed to develop new therapies for kidney disease. We attempted kidney-specific gene transfer following hydrodynamic tail vein injection using the kidney-specific podocin and gamma-glutamyl transferase promoters, but found expression primarily in the liver. In order to achieve kidney-specific transgene expression, we tested direct hydrodynamic injection of a DNA solution into the renal pelvis and found that luciferase expression was strong in the kidney and absent from extra-renal tissues. We observed heterogeneous, low-level transfection of the collecting duct, proximal tubule, distal tubule, interstitial cells, and rarely glomerular cells following injection. To assess renal injury, we performed the renal pelvis injections on uninephrectomised mice and found that their blood urea nitrogen was elevated at two days post-transfer but resolved within two weeks. Although luciferase expression quickly decreased following renal pelvis injection, the use of the piggyBac transposon system improved long-term expression. Immunosuppression with cyclophosphamide stabilised luciferase expression, suggesting immune clearance of the transfected cells occurs in immunocompetent animals. Injection of a transposon expressing erythropoietin raised the haematocrit, indicating that the developed injection technique can elicit a biologic effect in vivo. Hydrodynamic renal pelvis injection enables transposon mediated-kidney specific gene transfer in adult mice.
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17 MeSH Terms
New onset diabetes mellitus after heart transplantation in children is a common but potentially modifiable burden.
Moore DJ
(2016) Pediatr Transplant 20: 886-887
MeSH Terms: Child, Diabetes Mellitus, Heart Transplantation, Humans, Immunosuppressive Agents, Kidney Transplantation, Risk Factors
Added October 12, 2016
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7 MeSH Terms
Chronic NF-κB activation links COPD and lung cancer through generation of an immunosuppressive microenvironment in the lungs.
Zaynagetdinov R, Sherrill TP, Gleaves LA, Hunt P, Han W, McLoed AG, Saxon JA, Tanjore H, Gulleman PM, Young LR, Blackwell TS
(2016) Oncotarget 7: 5470-82
MeSH Terms: Animals, Blotting, Western, CD8-Positive T-Lymphocytes, Cells, Cultured, Epithelium, Female, Flow Cytometry, Humans, I-kappa B Kinase, Immunosuppressive Agents, Inflammation, Interleukin-10, Lung, Lung Neoplasms, Macrophages, Alveolar, Male, Mice, Mice, Transgenic, NF-kappa B, Pulmonary Disease, Chronic Obstructive, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, T-Lymphocytes, Regulatory, Transforming Growth Factor beta
Show Abstract · Added February 22, 2016
Nuclear Factor (NF)-κB is positioned to provide the interface between COPD and carcinogenesis through regulation of chronic inflammation in the lungs. Using a tetracycline-inducible transgenic mouse model that conditionally expresses activated IκB kinase β (IKKβ) in airway epithelium (IKTA), we found that sustained NF-κB signaling results in chronic inflammation and emphysema by 4 months. By 11 months of transgene activation, IKTA mice develop lung adenomas. Investigation of lung inflammation in IKTA mice revealed a substantial increase in M2-polarized macrophages and CD4+/CD25+/FoxP3+ regulatory T lymphocytes (Tregs). Depletion of alveolar macrophages in IKTA mice reduced Tregs, increased lung CD8+ lymphocytes, and reduced tumor numbers following treatment with the carcinogen urethane. Alveolar macrophages from IKTA mice supported increased generation of inducible Foxp3+ Tregs ex vivo through expression of TGFβ and IL-10. Targeting of TGFβ and IL-10 reduced the ability of alveolar macrophages from IKTA mice to induce Foxp3 expression on T cells. These studies indicate that sustained activation of NF-κB pathway links COPD and lung cancer through generation and maintenance of a pro-tumorigenic inflammatory environment consisting of alternatively activated macrophages and regulatory T cells.
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26 MeSH Terms
Opioid Analgesics and the Risk of Serious Infections Among Patients With Rheumatoid Arthritis: A Self-Controlled Case Series Study.
Wiese AD, Griffin MR, Stein CM, Mitchel EF, Grijalva CG
(2016) Arthritis Rheumatol 68: 323-31
MeSH Terms: Adult, Age Factors, Analgesics, Opioid, Antirheumatic Agents, Arthritis, Rheumatoid, Codeine, Cohort Studies, Delayed-Action Preparations, Dextropropoxyphene, Hospitalization, Humans, Hydrocodone, Immunosuppressive Agents, Incidence, Infection, Medicaid, Middle Aged, Morphine, Oxycodone, Retrospective Studies, Risk Factors, Tennessee, United States
Show Abstract · Added July 27, 2018
OBJECTIVE - Animal studies and in vitro human studies suggest that certain opioid analgesics impair crucial immune functions. This study was undertaken to determine whether opioid use is associated with increased risk of serious infection in patients with rheumatoid arthritis (RA).
METHODS - We conducted a self-controlled case series analysis on a retrospective cohort of 13,796 patients with RA enrolled in Tennessee Medicaid in 1995-2009. Within-person comparisons of the risk of hospitalization for serious infection during periods of opioid use versus non-use were performed using conditional Poisson regression. Fixed confounders were accounted for by design; time-varying confounders included age and use of disease-modifying antirheumatic drugs, glucocorticoids, and proton-pump inhibitors. In additional analyses, risks associated with new opioid use, use of opioids known to have immunosuppressive properties, use of long-acting opioids, and different opioid dosages were assessed. Sensitivity analyses were performed to account for potential protopathic bias and confounding by indication.
RESULTS - Among 1,790 patients with RA who had at least 1 hospitalization for serious infection, the adjusted incidence rate of serious infection was higher during periods of current opioid use compared to non-use, with an incidence rate ratio (IRR) of 1.39 (95% confidence interval [95% CI] 1.19-1.62). The incidence rate was also higher during periods of long-acting opioid use, immunosuppressive opioid use, and new opioid use compared to non-use (IRR 2.01 [95% CI 1.52-2.66], IRR 1.72 [95% CI 1.33-2.23], and IRR 2.38 [95% CI 1.65-3.42], respectively). Results of sensitivity analyses were consistent with the main findings.
CONCLUSION - In within-person comparisons of patients with RA, opioid use was associated with an increased risk of hospitalization for serious infection.
© 2016, American College of Rheumatology.
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Assessment of arterial stiffness using pulse wave velocity in tacrolimus users the first year post kidney transplantation: a prospective cohort study.
Birdwell KA, Jaffe G, Bian A, Wu P, Ikizler TA
(2015) BMC Nephrol 16: 93
MeSH Terms: Adult, Age Factors, Aorta, Diabetes Mellitus, Female, Humans, Immunosuppressive Agents, Kidney Transplantation, Longitudinal Studies, Male, Middle Aged, Prospective Studies, Pulse Wave Analysis, Tacrolimus, Vascular Stiffness
Show Abstract · Added August 5, 2015
BACKGROUND - The leading cause of death in end stage renal disease is cardiovascular disease (CVD). Kidney transplantation is associated with improved survival over dialysis. We hypothesized that arterial stiffness, a marker of CVD, would improve in patients post kidney transplant, potentially explaining one mechanism of survival benefit from transplant.
METHODS - After obtaining Institutional Review Board approval and informed consent, we performed a longitudinal prospective cohort study of 66 newly transplanted adult kidney transplant recipients, using aortic pulse wave velocity (PWV) to assess arterial stiffness over a 12 month period. All patients were assessed within one month of transplant (baseline) and 12 months post transplant. The primary outcome was change in PWV score at 12 months which we assessed using Wilcoxon Signed Rank test. Secondary analyses included correlation of predictors with PWV score at both time points.
RESULTS - The median age of the cohort was 49.7 years at transplant, with 27 % Black and 27 % female. At baseline, 43 % had tobacco use, 30 % had a history of CVD, and 42 % had diabetes. Median baseline calcium was 9.1 mg/dL and median phosphorus was 5.1 mg/dL. Median PWV score was 9.25 and 8.97 m/s at baseline versus month 12, respectively, showing no significant change (median change of -0.07, p = 0.7). In multivariable regression, subjects with increased age at transplant (p = 0.008), diabetes (p = 0.002), and a higher baseline PWV score (p < 0.001) were at increased risk of having a high PWV score 12 months post transplant.
CONCLUSION - Aortic arterial stiffness does not progress in the first year post kidney transplant. Increasing age, diabetes, and higher baseline PWV score identify patients at risk for increased arterial stiffness. Further research that assesses patients for greater than one year and includes a control dialysis group would be helpful in further understanding the change in arterial stiffness post transplantation.
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15 MeSH Terms
Phosphatidylinositol 3-kinase signaling determines kidney size.
Chen JK, Nagai K, Chen J, Plieth D, Hino M, Xu J, Sha F, Ikizler TA, Quarles CC, Threadgill DW, Neilson EG, Harris RC
(2015) J Clin Invest 125: 2429-44
MeSH Terms: Animals, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Immunosuppressive Agents, Kidney, Kidney Diseases, Mechanistic Target of Rapamycin Complex 2, Mice, Mice, Inbred DBA, Mice, Knockout, Multiprotein Complexes, Organ Size, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Ribosomal Protein S6 Kinases, 90-kDa, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases
Show Abstract · Added August 5, 2015
Kidney size adaptively increases as mammals grow and in response to the loss of 1 kidney. It is not clear how kidneys size themselves or if the processes that adapt kidney mass to lean body mass also mediate renal hypertrophy following unilateral nephrectomy (UNX). Here, we demonstrated that mice harboring a proximal tubule-specific deletion of Pten (Pten(ptKO)) have greatly enlarged kidneys as the result of persistent activation of the class I PI3K/mTORC2/AKT pathway and an increase of the antiproliferative signals p21(Cip1/WAF) and p27(Kip1). Administration of rapamycin to Pten(ptKO) mice diminished hypertrophy. Proximal tubule-specific deletion of Egfr in Pten(ptKO) mice also attenuated class I PI3K/mTORC2/AKT signaling and reduced the size of enlarged kidneys. In Pten(ptKO) mice, UNX further increased mTORC1 activation and hypertrophy in the remaining kidney; however, mTORC2-dependent AKT phosphorylation did not increase further in the remaining kidney of Pten(ptKO) mice, nor was it induced in the remaining kidney of WT mice. After UNX, renal blood flow and amino acid delivery to the remaining kidney rose abruptly, followed by increased amino acid content and activation of a class III PI3K/mTORC1/S6K1 pathway. Thus, our findings demonstrate context-dependent roles for EGFR-modulated class I PI3K/mTORC2/AKT signaling in the normal adaptation of kidney size and PTEN-independent, nutrient-dependent class III PI3K/mTORC1/S6K1 signaling in the compensatory enlargement of the remaining kidney following UNX.
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19 MeSH Terms
An unusual cause of respiratory failure in a 25-year-old heart and lung transplant recipient.
Narotzky S, Kennedy CC, Maldonado F
(2015) Chest 147: e185-e188
MeSH Terms: Adult, Female, Heart-Lung Transplantation, Humans, Immunosuppressive Agents, Postoperative Complications, Pulmonary Alveolar Proteinosis, Respiratory Insufficiency, Sirolimus
Show Abstract · Added July 28, 2015
A 25-year-old woman, a never smoker with a history of heart-lung transplantation for World Health Organization group 1 pulmonary arterial hypertension performed 20 months prior to presentation, was evaluated for shortness of breath. Following transplantation, she was initiated on standard therapy of prednisone, tacrolimus, and azathioprine, along with routine antimicrobial prophylaxis. Her posttransplant course was complicated by persistent acute cellular rejection, as determined from a transbronchial biopsy specimen, without evidence of rejection in an endomyocardial biopsy specimen. The immunosuppressive medications were supplemented with pulse-dosed steroids, and the patient was transitioned from azathioprine to mycophenolate mofetil. Sirolimus was added 9 months prior to presentation. Three months prior to presentation, she was admitted for increasing oxygen requirements, shortness of breath, and bilateral infiltrates on the CT scans of the chest.
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9 MeSH Terms
Automatic identification of methotrexate-induced liver toxicity in patients with rheumatoid arthritis from the electronic medical record.
Lin C, Karlson EW, Dligach D, Ramirez MP, Miller TA, Mo H, Braggs NS, Cagan A, Gainer V, Denny JC, Savova GK
(2015) J Am Med Inform Assoc 22: e151-61
MeSH Terms: Algorithms, Arthritis, Rheumatoid, Chemical and Drug Induced Liver Injury, Electronic Health Records, Humans, Immunosuppressive Agents, Liver, Methotrexate
Show Abstract · Added March 14, 2018
OBJECTIVES - To improve the accuracy of mining structured and unstructured components of the electronic medical record (EMR) by adding temporal features to automatically identify patients with rheumatoid arthritis (RA) with methotrexate-induced liver transaminase abnormalities.
MATERIALS AND METHODS - Codified information and a string-matching algorithm were applied to a RA cohort of 5903 patients from Partners HealthCare to select 1130 patients with potential liver toxicity. Supervised machine learning was applied as our key method. For features, Apache clinical Text Analysis and Knowledge Extraction System (cTAKES) was used to extract standard vocabulary from relevant sections of the unstructured clinical narrative. Temporal features were further extracted to assess the temporal relevance of event mentions with regard to the date of transaminase abnormality. All features were encapsulated in a 3-month-long episode for classification. Results were summarized at patient level in a training set (N=480 patients) and evaluated against a test set (N=120 patients).
RESULTS - The system achieved positive predictive value (PPV) 0.756, sensitivity 0.919, F1 score 0.829 on the test set, which was significantly better than the best baseline system (PPV 0.590, sensitivity 0.703, F1 score 0.642). Our innovations, which included framing the phenotype problem as an episode-level classification task, and adding temporal information, all proved highly effective.
CONCLUSIONS - Automated methotrexate-induced liver toxicity phenotype discovery for patients with RA based on structured and unstructured information in the EMR shows accurate results. Our work demonstrates that adding temporal features significantly improved classification results.
© The Author 2014. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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8 MeSH Terms
Development of anti-factor XIII antibodies in a patient with hereditary factor XIII deficiency receiving therapy for chronic hepatitis C.
Sosa R, Gailani D, Neff AT
(2014) Haemophilia 20: e429-32
MeSH Terms: Adult, Antibodies, Antiviral Agents, Blood Coagulation Factor Inhibitors, Factor XIII, Factor XIII Deficiency, Female, Hepatitis C, Chronic, Humans, Immunosuppressive Agents, Treatment Outcome
Added January 20, 2015
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11 MeSH Terms