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A case report of clonal EBV-like memory CD4 T cell activation in fatal checkpoint inhibitor-induced encephalitis.
Johnson DB, McDonnell WJ, Gonzalez-Ericsson PI, Al-Rohil RN, Mobley BC, Salem JE, Wang DY, Sanchez V, Wang Y, Chastain CA, Barker K, Liang Y, Warren S, Beechem JM, Menzies AM, Tio M, Long GV, Cohen JV, Guidon AC, O'Hare M, Chandra S, Chowdhary A, Lebrun-Vignes B, Goldinger SM, Rushing EJ, Buchbinder EI, Mallal SA, Shi C, Xu Y, Moslehi JJ, Sanders ME, Sosman JA, Balko JM
(2019) Nat Med 25: 1243-1250
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, CD4-Positive T-Lymphocytes, Encephalitis, Female, Herpesvirus 4, Human, Humans, Immunologic Memory, Lymphocyte Activation, Male, Middle Aged, Programmed Cell Death 1 Receptor, Young Adult
Show Abstract · Added November 12, 2019
Checkpoint inhibitors produce durable responses in numerous metastatic cancers, but immune-related adverse events (irAEs) complicate and limit their benefit. IrAEs can affect organ systems idiosyncratically; presentations range from mild and self-limited to fulminant and fatal. The molecular mechanisms underlying irAEs are poorly understood. Here, we report a fatal case of encephalitis arising during anti-programmed cell death receptor 1 therapy in a patient with metastatic melanoma. Histologic analyses revealed robust T cell infiltration and prominent programmed death ligand 1 expression. We identified 209 reported cases in global pharmacovigilance databases (across multiple cancer types) of encephalitis associated with checkpoint inhibitor regimens, with a 19% fatality rate. We performed further analyses from the index case and two additional cases to shed light on this recurrent and fulminant irAE. Spatial and multi-omic analyses pinpointed activated memory CD4 T cells as highly enriched in the inflamed, affected region. We identified a highly oligoclonal T cell receptor repertoire, which we localized to activated memory cytotoxic (CD45ROGZMBKi67) CD4 cells. We also identified Epstein-Barr virus-specific T cell receptors and EBV lymphocytes in the affected region, which we speculate contributed to neural inflammation in the index case. Collectively, the three cases studied here identify CD4 and CD8 T cells as culprits of checkpoint inhibitor-associated immune encephalitis.
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MeSH Terms
Transposon-modified antigen-specific T lymphocytes for sustained therapeutic protein delivery in vivo.
O'Neil RT, Saha S, Veach RA, Welch RC, Woodard LE, Rooney CM, Wilson MH
(2018) Nat Commun 9: 1325
MeSH Terms: Adoptive Transfer, Animals, Cell Engineering, Cell- and Tissue-Based Therapy, DNA Transposable Elements, Erythropoietin, Gene Expression, Genetic Vectors, Hematopoiesis, Herpesvirus 4, Human, Humans, Mice, Ovalbumin, Receptors, Antigen, T-Cell, T-Lymphocytes, Transgenes, Vaccination
Show Abstract · Added September 24, 2018
A cell therapy platform permitting long-term delivery of peptide hormones in vivo would be a significant advance for patients with hormonal deficiencies. Here we report the utility of antigen-specific T lymphocytes as a regulatable peptide delivery platform for in vivo therapy. piggyBac transposon modification of murine cells with luciferase allows us to visualize T cells after adoptive transfer. Vaccination stimulates long-term T-cell engraftment, persistence, and transgene expression enabling detection of modified cells up to 300 days after adoptive transfer. We demonstrate adoptive transfer of antigen-specific T cells expressing erythropoietin (EPO) elevating the hematocrit in mice for more than 20 weeks. We extend our observations to human T cells demonstrating inducible EPO production from Epstein-Barr virus (EBV) antigen-specific T lymphocytes. Our results reveal antigen-specific T lymphocytes to be an effective delivery platform for therapeutic molecules such as EPO in vivo, with important implications for other diseases that require peptide therapy.
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17 MeSH Terms
Beyond Epstein-Barr virus: genetic predisposition of natural killer T-cell lymphoma.
Reddy NM, Sethi TK
(2016) Lancet Oncol 17: 1176-7
MeSH Terms: Genetic Predisposition to Disease, Herpesvirus 4, Human, Humans, Killer Cells, Natural, Lymphoma, Natural Killer T-Cells
Added August 3, 2016
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6 MeSH Terms
Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns.
Treece AL, Duncan DL, Tang W, Elmore S, Morgan DR, Dominguez RL, Speck O, Meyers MO, Gulley ML
(2016) Lab Invest 96: 661-71
MeSH Terms: Adenocarcinoma, Aged, Aged, 80 and over, Case-Control Studies, Epstein-Barr Virus Infections, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Herpesvirus 4, Human, Humans, Male, MicroRNAs, Middle Aged, Pilot Projects, RNA, Neoplasm, RNA, Viral, Stomach Neoplasms
Show Abstract · Added May 18, 2016
MicroRNA expression in formalin-fixed paraffin-embedded tissue (FFPE) or plasma may add value for cancer management. The GastroGenus miR Panel was developed to measure 55 cancer-specific human microRNAs, Epstein-Barr virus (EBV)-encoded microRNAs, and controls. This Q-rtPCR panel was applied to 100 FFPEs enriched for adenocarcinoma or adjacent non-malignant mucosa, and to plasma of 31 patients. In FFPE, microRNAs upregulated in malignant versus adjacent benign gastric mucosa were hsa-miR-21, -155, -196a, -196b, -185, and -let-7i. Hsa-miR-18a, 34a, 187, -200a, -423-3p, -484, and -744 were downregulated. Plasma of cancer versus non-cancer controls had upregulated hsa-miR-23a, -103, and -221 and downregulated hsa-miR-378, -346, -486-5p, -200b, -196a, -141, and -484. EBV-infected versus uninfected cancers expressed multiple EBV-encoded microRNAs, and concomitant dysregulation of four human microRNAs suggests that viral infection may alter cellular biochemical pathways. Human microRNAs were dysregulated between malignant and benign gastric mucosa and between plasma of cancer patients and non-cancer controls. Strong association of EBV microRNA expression with known EBV status underscores the ability of microRNA technology to reflect disease biology. Expression of viral microRNAs in concert with unique human microRNAs provides novel insights into viral oncogenesis and reinforces the potential for microRNA profiles to aid in classifying gastric cancer subtypes. Pilot studies of plasma suggest the potential for a noninvasive addition to cancer diagnostics.
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17 MeSH Terms
Anti-Helicobacter pylori Antibody Profiles in Epstein-Barr virus (EBV)-Positive and EBV-Negative Gastric Cancer.
Camargo MC, Kim KM, Matsuo K, Torres J, Liao LM, Morgan DR, Michel A, Waterboer T, Zabaleta J, Dominguez RL, Yatabe Y, Kim S, Rocha-Guevara ER, Lissowska J, Pawlita M, Rabkin CS
(2016) Helicobacter 21: 153-7
MeSH Terms: Aged, Antibodies, Bacterial, Female, Helicobacter Infections, Helicobacter pylori, Herpesvirus 4, Human, Humans, Male, Middle Aged, Stomach Neoplasms, United States
Show Abstract · Added May 18, 2016
BACKGROUND - Helicobacter pylori is the primary cause of gastric cancer, but about 9% of cases harbor Epstein-Barr virus (EBV) in the tumor cells. There is limited evidence on the possible interaction or antagonism between these infectious agents in gastric carcinogenesis.
METHODS - We compared H. pylori serologic profiles of EBV-positive (n = 58) and EBV-negative (n = 111) noncardia gastric cancer patients from the United States National Cancer Institute's International EBV-Gastric Cancer Consortium. EBV positivity of tumors was assessed by in situ hybridization. Serum levels of 15 antibodies to immunogenic proteins of H. pylori (Cad, CagA, Cagδ, CagM, Catalase, GroEL, HcpC, HP0231, HP0305, HpaA, HyuA, NapA, Omp, UreA, VacA) were assessed using bead-based multiplex serology. Logistic regression models were used to adjust odds ratios (OR) for country, age, sex, and year of diagnosis.
RESULTS - Seropositivity to individual proteins ranged up to 90% overall. Antibodies to Catalase were borderline associated with tumor EBV positivity (adjusted OR = 3.15, p = .0024, Bonferroni corrected p = .036). Distributions of other antibodies did not vary by tumor EBV status.
CONCLUSION - Similarity of host-response indicates the essential etiological role of H. pylori in EBV-positive gastric cancer.
© 2015 John Wiley & Sons Ltd.
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Three Molecular Subtypes of Gastric Adenocarcinoma Have Distinct Histochemical Features Reflecting Epstein-Barr Virus Infection Status and Neuroendocrine Differentiation.
Speck O, Tang W, Morgan DR, Kuan PF, Meyers MO, Dominguez RL, Martinez E, Gulley ML
(2015) Appl Immunohistochem Mol Morphol 23: 633-45
MeSH Terms: Adenocarcinoma, Carcinoma, Neuroendocrine, Cell Differentiation, Chromogranin A, Epithelial Cells, Epstein-Barr Virus Infections, Gastric Mucosa, Gastrins, Gene Expression, Genetic Heterogeneity, Herpesvirus 4, Human, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Lectins, C-Type, Pancreatitis-Associated Proteins, Prognosis, Stomach, Stomach Neoplasms
Show Abstract · Added May 18, 2016
Current histopathologic classification schemes for gastric adenocarcinoma have limited clinical utility and are difficult to apply due to tumor heterogeneity. Elucidation of molecular subtypes of gastric cancer may contribute to our understanding of gastric cancer biology and to the development of new molecular markers that may lead to improved diagnosis, therapy, or prognosis. We previously demonstrated that Epstein-Barr virus (EBV)-infected gastric cancers have a distinct human gene expression profile compared with uninfected cancers. We now examine the histopathologic features characterizing infected (n=14) and uninfected (n=89) cancers; the latter of which are now further divided into 2 major molecular subtypes based on expression patterns of 93 RNAs. One uninfected gastric cancer subtype was distinguished by upregulation of 3 genes with neuroendocrine (NE) function (CHGA, GAST, and REG4 encoding chromogranin, gastrin, and the secreted peptide REG4 involved in epithelial cell regeneration), implicating hormonal factors in the pathogenesis of a major class of gastric adenocarcinomas. Evidence of NE differentiation (molecular, immunohistochemical, or morphologic) was mutually exclusive of EBV infection. EBV-infected tumors tended to have solid-type morphology with lymphoid stroma. This study reveals novel molecular subtypes of gastric cancer and their associated morphologies that demonstrate divergent NE features.
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Comprehensive molecular characterization of gastric adenocarcinoma.
Cancer Genome Atlas Research Network
(2014) Nature 513: 202-9
MeSH Terms: Adenocarcinoma, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Herpesvirus 4, Human, Humans, Male, Mutation, Proteome, Stomach Neoplasms
Show Abstract · Added August 8, 2016
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein-Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
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10 MeSH Terms
Case-case comparison of smoking and alcohol risk associations with Epstein-Barr virus-positive gastric cancer.
Camargo MC, Koriyama C, Matsuo K, Kim WH, Herrera-Goepfert R, Liao LM, Eurgast-EPIC Group, Yu J, Carrasquilla G, Sung JJ, Alvarado-Cabrero I, Lissowska J, Meneses-Gonzalez F, Yatabe Y, Ding T, Hu N, Taylor PR, Morgan DR, Gulley ML, Torres J, Akiba S, Rabkin CS
(2014) Int J Cancer 134: 948-53
MeSH Terms: Adenocarcinoma, Adult, Aged, Aged, 80 and over, Alcohol Drinking, Case-Control Studies, Epstein-Barr Virus Infections, Female, Follow-Up Studies, Herpesvirus 4, Human, Humans, Male, Middle Aged, Neoplasm Staging, Odds Ratio, Prognosis, Risk Factors, Smoking, Stomach Neoplasms
Show Abstract · Added May 18, 2016
Helicobacter pylori is the primary cause of gastric cancer. However, monoclonal Epstein-Barr virus (EBV) nucleic acid is also present in up to 10% of these tumors worldwide. EBV prevalence is increased with male sex, nonantral localization and surgically disrupted anatomy. To further examine associations between EBV and gastric cancer, we organized an international consortium of 11 studies with tumor EBV status assessed by in situ hybridization. We pooled individual-level data on 2,648 gastric cancer patients, including 184 (7%) with EBV-positive cancers; all studies had information on cigarette use (64% smokers) and nine had data on alcohol (57% drinkers). We compared patients with EBV-positive and EBV-negative tumors to evaluate smoking and alcohol interactions with EBV status. To account for within-population clustering, multilevel logistic regression models were used to estimate interaction odds ratios (OR) adjusted for distributions of sex (72% male), age (mean 59 years), tumor histology (56% Lauren intestinal-type), anatomic subsite (61% noncardia) and year of diagnosis (1983-2012). In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 [95% confidence interval (CI) 1.6-3.2]. The OR was attenuated to 1.5 (95% CI 1.01-2.3) by adjustment for the possible confounders. There was no significant interaction of EBV status with alcohol drinking (crude OR 1.4; adjusted OR 1.0). Our data indicate the smoking association with gastric cancer is stronger for EBV-positive than EBV-negative tumors. Conversely, the null association with alcohol does not vary by EBV status. Distinct epidemiologic characteristics of EBV-positive cancer further implicate the virus as a cofactor in gastric carcinogenesis.
© 2013 UICC.
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19 MeSH Terms
Human monoclonal antibodies derived from memory B cells following live attenuated dengue virus vaccination or natural infection exhibit similar characteristics.
Smith SA, de Alwis R, Kose N, Durbin AP, Whitehead SS, de Silva AM, Crowe JE
(2013) J Infect Dis 207: 1898-908
MeSH Terms: Antibodies, Monoclonal, Antibodies, Neutralizing, Antibodies, Viral, Antibody-Dependent Enhancement, Antigens, Viral, B-Lymphocytes, California, Cell Line, Cross Reactions, Dengue, Dengue Vaccines, Dengue Virus, Herpesvirus 4, Human, Humans, Hybridomas, Neutralization Tests, North Carolina, Recombinant Proteins, Vaccination, Vaccines, Attenuated
Show Abstract · Added March 7, 2014
The immunopathogenesis of severe dengue is poorly understood, but there is concern that induction of cross-reactive nonneutralizing antibodies by infection or vaccination may increase the likelihood of severe disease during a subsequent infection. We generated a total of 63 new human monoclonal antibodies to compare the B-cell response of subjects who received the National Institutes of Health live attenuated dengue vaccine rDEN1Δ30 to that of subjects following symptomatic primary infection with DENV1. Both infection and vaccination induced serum neutralizing antibodies and DENV1-reactive peripheral blood B cells, but the magnitude of induction was lower in vaccinated individuals. Serotype cross-reactive weakly neutralizing antibodies dominated the response in both vaccinated and naturally infected subjects. Antigen specificities were very similar, with a slightly greater percentage of antibodies targeting E protein domain I/II than domain III. These data shed light on the similarity of human B-cell response to live attenuated DENV vaccine or natural infection.
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20 MeSH Terms
Oral cavity tumors in younger patients show a poor prognosis and do not contain viral RNA.
Brägelmann J, Dagogo-Jack I, El Dinali M, Stricker T, Brown CD, Zuo Z, Khattri A, Keck M, McNerney ME, Longnecker R, Bieging K, Kocherginsky M, Alexander K, Salgia R, Lingen MW, Vokes EE, White KP, Cohen EE, Seiwert TY
(2013) Oral Oncol 49: 525-33
MeSH Terms: Adult, Algorithms, Female, Herpesvirus 4, Human, Humans, Male, Mouth Neoplasms, Papillomaviridae, Prognosis, RNA, Viral, Survival Analysis
Show Abstract · Added March 28, 2014
BACKGROUND - Oral cavity and in particular oral tongue cancers occur with a rising incidence in younger patients often lacking the typical risk factors of tobacco use, alcohol use, and human papilloma virus (HPV) infection. Their prognosis when treated with chemoradiation has not been well studied and responsible risk factors remain elusive. A viral etiology (other than HPV) has been hypothesized.
METHODS - First we analyzed outcomes from 748 head and neck cancer patients with locoregionally advanced stage tumors treated with curative-intent chemoradiation by anatomic site. Second, we analyzed seven oral tongue (OT) tumors from young, non-smokers/non-drinkers for the presence of viral mRNA using short-read massively-parallel sequencing (RNA-Seq) in combination with a newly-developed digital subtraction method followed by viral screening and discovery algorithms. For positive controls we used an HPV16-positive HNC cell line, a cervical cancer, and an EBV-LMP2A transgene lymphoma.
RESULTS - Younger patients with oral cavity tumors had worse outcomes compared to non-oral cavity patients. Surprisingly none of the seven oral tongue cancers showed significant presence of viral transcripts. In positive controls the expected viral material was identified.
CONCLUSION - Oral cavity tumors in younger patients have a poor prognosis and do not appear to be caused by a transcriptionally active oncovirus.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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11 MeSH Terms