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ABSTRACT: The control of tumor growth by the host's immunosurveillance is centered on the activation of interferon (IFN) pathways. In particular, direct study of tumors by various groups has uncovered an IFN-γ-related signature whose presence is consistently associated with better prognosis, predisposition to respond to immunotherapy, and, in its extreme manifestation, the acute phases of tumor rejection. Together, and related to the IFN-γ-associated signature, a cluster of genes are coordinately expressed that we refer to as the immunologic constant of rejection (ICR). Activation of ICR components is observed in all forms of immune-mediated, tissue-specific destruction, including autoimmunity, allograft rejection, graft-versus-host disease, and killing of affected cells during the acute phases of infection that leads to clearance of pathogens. Thus, tumor rejection is a facet of a general and conserved mechanism that favors (tumor rejection, clearance of pathogen) or encumbers (graft rejection, autoimmunity) the organism. Here, we summarize progress in the understanding of its genesis, outline the difficulties, and propose a strategy for understanding the causes of tumor rejection.
Annals of the New York Academy of Sciences 05/2013; 1284(1):75-9. · 3.15 Impact Factor
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ABSTRACT: Hepatocellular carcinomas (HCCs) are a heterogeneous group of tumors that differ in risk factors and genetic alterations. In Italy, particularly Southern Italy, chronic hepatitis C virus (HCV) infection represents the main cause of HCC. Using high-density oligoarrays, we identified consistent differences in gene-expression between HCC and normal liver tissue. Expression patterns in HCC were also readily distinguishable from those associated with liver metastases. To characterize molecular events relevant to hepatocarcinogenesis and identify biomarkers for early HCC detection, gene expression profiling of 71 liver biopsies from HCV-related primary HCC and corresponding HCV-positive non-HCC hepatic tissue, as well as gastrointestinal liver metastases paired with the apparently normal peri-tumoral liver tissue, were compared to 6 liver biopsies from healthy individuals. Characteristic gene signatures were identified when normal tissue was compared with HCV-related primary HCC, corresponding HCV-positive non-HCC as well as gastrointestinal liver metastases. Pathway analysis classified the cellular and biological functions of the genes differentially expressed as related to regulation of gene expression and post-translational modification in HCV-related primary HCC; cellular Growth and Proliferation, and Cell-To-Cell Signaling and Interaction in HCV-related non HCC samples; Cellular Growth and Proliferation and Cell Cycle in metastasis. Also characteristic gene signatures were identified of HCV-HCC progression for early HCC diagnosis. CONCLUSIONS: A diagnostic molecular signature complementing conventional pathologic assessment was identified.
PLoS ONE 01/2013; 8(2):e56153. · 4.09 Impact Factor
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Luciano Castiello,
Marianna Sabatino,
Yingdong Zhao,
Barbara Tumaini,
Jiaqiang Ren,
Jin Ping, Ena Wang,
Lauren V Wood,
Francesco M Marincola,
Raj K Puri,
David F Stroncek
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ABSTRACT: Cell-based immunotherapies are among the most promising approaches for developing effective and targeted immune response. However, their clinical usefulness and the evaluation of their efficacy rely heavily on complex quality control assessment. Therefore, rapid systematic methods are urgently needed for the in-depth characterization of relevant factors affecting newly developed cell product consistency and the identification of reliable markers for quality control. Using dendritic cells (DCs) as a model, we present a strategy to comprehensively characterize manufactured cellular products in order to define factors affecting their variability, quality and function. After generating clinical grade human monocyte-derived mature DCs (mDCs), we tested by gene expression profiling the degrees of product consistency related to the manufacturing process and variability due to intra- and interdonor factors, and how each factor affects single gene variation. Then, by calculating for each gene an index of variation we selected candidate markers for identity testing, and defined a set of genes that may be useful comparability and potency markers. Subsequently, we confirmed the observed gene index of variation in a larger clinical data set. In conclusion, using high-throughput technology we developed a method for the characterization of cellular therapies and the discovery of novel candidate quality assurance markers.Molecular Therapy (2012); doi:10.1038/mt.2012.89.
Molecular Therapy 11/2012; · 6.87 Impact Factor
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Jennifer Reinboth,
Maria L Ascierto,
Nanhai G Chen,
Qian Zhang,
Yong A Yu,
Richard J Aguilar,
Rafael Carretero,
Andrea Worschech,
Yingdong Zhao, Ena Wang,
Francesco M Marincola,
Aladar A Szalay
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ABSTRACT: Abstract Vaccinia virus (VACV) has emerged as an attractive tool in oncolytic virotherapy. VACV replication efficiency plays a crucial role in the therapeutic outcome. However, little is known about the influence of host factors on viral replication efficiency and permissiveness of a host cell line to infection and oncolysis. In this study, replication of the attenuated VACV GLV-1h68 strain and three wild-type VACV isolates was determined in two autologous human melanoma cell lines (888-MEL and 1936-MEL). Host gene expression and viral gene expression in infected cells were evaluated via respective expression array platforms. Microarray analyses followed by sequential statistical approaches characterized human genes that change specifically due to virus infection. Viral gene transcription correlated with viral replication in a time-dependent manner. A set of human genes revealed strong correlations with the respective viral gene expression. Finally we identified a set of human genes with possible predictive value for viral replication in an independent dataset. The results demonstrate a probable correlation between viral replication, early gene expression, and the respective host response, and thus a possible involvement of human host factors in viral early replication. The characterization of human target genes that influence viral replication could help answer the question of host cell permissiveness to oncolytic virotherapy and provide important information for the development of novel recombinant vaccinia viruses with improved features to enhance replication rate and hence trigger therapeutic outcome.
Human gene therapy methods. 11/2012;
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Francesco M Marincola,
Luca Gattinoni,
David A Price,
Mario Roederer,
Daniel C Douek,
Jorge R Almeida,
Máire F Quigley,
Nicholas P Restifo,
Chrystal M Paulos, Ena Wang,
Zoltan Pos,
Carl H June,
Yun Ji,
Carmine Carpenito,
Enrico Lugli,
Zhiya Yu,
Emma Gostick
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Jennifer Reinboth,
Maria Libera Ascierto,
Nanhai G Chen,
Qian Zhang,
Yong A Yu,
Richard J Aguilar,
Rafael Carretero,
Andrea Worschech,
Yingdong Zhao, Ena Wang,
Francesco M Marincola,
Aladar A Szalay
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ABSTRACT: Vaccinia virus (VACV) has emerged as an attractive tool in oncolytic virotherapy. VACV replication efficiency plays a crucial role in the therapeutic outcome. However, little is known about the influence of host factors on viral replication efficiency and permissiveness of a host cell line to infection and oncolysis. In this study, replication of the attenuated VACV GLV-1h68 strain and 3 wild type VACV isolates was determined in two autologous human melanoma cell lines (888-MEL and 1936-MEL). Host gene expression and viral gene expression in infected cells were evaluated via respective expression array platforms. Microarray analyses followed by sequential statistical approaches characterized human genes which change specifically due to virus infection. Viral gene transcription correlated with viral replication in a time-dependent manner. A set of human genes revealed strong correlations with the respective viral gene expression. Finally we identified a set of human genes with possible predictive value for viral replication in an independent dataset. The results demonstrate a probable correlation between viral replication, early gene expression and the respective host response and thus a possible involvement of human host factors in viral early replication. The characterization of human target genes that influence viral replication could help answering the question of host cell permissiveness to oncolytic virotherapy and provide important information for the development of novel recombinant vaccinia viruses with improved features to enhance replication rate and hence trigger therapeutic outcome.
Human gene therapy methods. 10/2012;
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ABSTRACT: BACKGROUND: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined. METHODS: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR-based analyses, we compared the expression of miRs (n=198) between lung cancer cases consuming high-versus-low quercetin-rich food intake using multivariate ANOVA tests. In family-miR-based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miRs families. We accounted for multiple testing using 10,000 global permutations (significance at p-value(global) <0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers). RESULTS: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (p-value(FCS)<0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (p-values(FCS)<0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest-and-lowest quercetin-rich food consumers (23 expected by chance; p-value(global) = 0.047). CONCLUSIONS: We observed differential expression of key biologically functional miRNAs between high-versus-low consumers of quercetin-rich foods in adenocarcinoma cases. Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis.
Cancer Epidemiology Biomarkers & Prevention 10/2012; · 4.12 Impact Factor
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Jérôme Galon,
Pagès Franck,
Francesco M Marincola,
Helen K Angell,
Magdalena Thurin,
Alessandro Lugli,
Inti Zlobec,
Anne Berger,
Carlo Bifulco,
Gerardo Botti, [......],
Richard Palmqvist,
Iris D Nagtegaal,
Yili Wang,
Corrado D'Arrigo,
Scott Kopetz,
Frank A Sinicrope,
Giorgio Trinchieri,
Thomas F Gajewski,
Paolo A Ascierto,
Bernard A Fox
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ABSTRACT: Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).
Journal of Translational Medicine 10/2012; 10(1):205. · 3.41 Impact Factor
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Francesco M Marincola,
Luca Gattinoni,
David A Price,
Mario Roederer,
Daniel C Douek,
Jorge R Almeida,
Máire F Quigley,
Nicholas P Restifo,
Chrystal M Paulos, Ena Wang,
Zoltan Pos,
Carl H June,
Yun Ji,
Carmine Carpenito,
Enrico Lugli,
Zhiya Yu,
Emma Gostick
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Lorenzo Uccellini,
Valeria De Giorgi,
Yingdong Zhao,
Barbara Tumaini,
Narnygerel Erdenebileg,
Mark E Dudley,
Sara Tomei,
Davide Bedognetti,
Maria Libera Ascierto,
Qiutzhen Liu,
Richard Simon,
Leah Kottyan,
Kenneth M Kaufman,
John B Harley, Ena Wang,
Steve A Rosenberg,
Franscesco M Marincola
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ABSTRACT: BACKGROUND: Interferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs). METHODS: 140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array. RESULTS: Lack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma. CONCLUSIONS: This study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness.
Journal of Translational Medicine 08/2012; 10(1):170. · 3.41 Impact Factor
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ABSTRACT: A cancer immune signature implicating good prognosis and responsiveness to immunotherapy was described that is observed also in other aspects of immune-mediated, tissue-specific destruction (TSD). Its determinism remains, however, elusive. Based on limited but unique clinical observations, we propose a multifactorial genetic model of human cancer immune responsiveness.
Oncoimmunology. 07/2012; 1(4):520-525.
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ABSTRACT: Single-cell network profiling (SCNP) is a multi-parametric flow cytometry-based approach that simultaneously measures basal and modulated intracellular signaling activity in multiple cell subpopulations. Previously, SCNP analysis of a broad panel of immune signaling pathways in cell subsets within PBMCs from 60 healthy donors identified a race-associated difference in B cell anti-IgD-induced PI3K pathway activity.
The present study extended this analysis to a broader range of signaling pathway components downstream of the B cell receptor (BCR) in European Americans and African Americans using a subset of donors from the previously analyzed cohort of 60 healthy donors. Seven BCR signaling nodes (a node is defined as a paired modulator and intracellular readout) were measured at multiple time points by SCNP in PBMCs from 10 healthy donors [5 African Americans (36-51 yrs), 5 European Americans (36-56 yrs), all males].
Analysis of BCR signaling activity in European American and African American PBMC samples revealed that, compared to the European American donors, B cells from African Americans had lower anti-IgD induced phosphorylation of multiple BCR pathway components, including the membrane proximal proteins Syk and SFK as well as proteins in the PI3K pathway (S6 and Akt), the MAPK pathways (Erk and p38), and the NF-κB pathway (NF-κB). In addition to differences in the magnitude of anti-IgD-induced pathway activation, racial differences in BCR signaling kinetic profiles were observed. Further, the frequency of IgD+ B cells differed by race and strongly correlated with BCR pathway activation. Thus, the race-related difference in BCR pathway activation appears to be attributable at least in part to a race-associated difference in IgD+ B cell frequencies.
SCNP analysis enabled the identification of statistically significant race-associated differences in BCR pathway activation within PBMC samples from healthy donors. Understanding race-associated contrasts in immune cell signaling responses may be one critical component for elucidation of differences in immune-mediated disease prevalence and treatment responses.
Journal of Translational Medicine 06/2012; 10:113. · 3.41 Impact Factor
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Sara Tomei,
Sharon Adams,
Lorenzo Uccellini,
Davide Bedognetti,
Valeria De Giorgi,
Narnygerel Erdenebileg,
Maria Libera Ascierto,
Jennifer Reinboth,
Qiuzhen Liu,
Generoso Bevilacqua, Ena Wang,
Chiara Mazzanti,
Francesco M Marincola
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ABSTRACT: HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case-control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690.
Medical Oncology 05/2012; · 2.14 Impact Factor
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ABSTRACT: Immune-mediated rejection of human cancer is a relatively rare but well-documented phenomenon. Its rate of occurrence progressively increases from the occasional observation of spontaneous regressions to the high rate of complete remissions observed in response to effective treatments. For two decades, our group has focused its interest in understanding this phenomenon by studying humans following an inductive approach. Sticking to a sequential logic, we dissected the phenomenon by studying to the best of our capability both peripheral and tumor samples and reached the conclusion that immune-mediated cancer rejection is a facet of autoimmunity where the target tissue is the cancer itself. As we are currently defining the strategy to effectively identify the mechanisms leading in individual patients to rejection of their own tumors, we considered useful to summarize the thought process that guided us to our own interpretation of the mechanisms of immune responsiveness.
Cancer Immunology and Immunotherapy 05/2012; 61(6):761-70. · 3.70 Impact Factor
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Paolo A Ascierto,
Antonio M Grimaldi,
Brendan Curti,
Mark B Faries,
Soldano Ferrone,
Keith Flaherty,
Bernard A Fox,
Thomas F Gajewski,
Jeffrey E Gershenwald,
Helen Gogas, [......],
Michele Maio,
Richard Marais,
Giuseppe Palmieri,
Donald L Morton,
Antoni Ribas,
David F Stroncek,
Rodney Stewart, Ena Wang,
Nicola Mozzillo,
Franco M Marincola
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ABSTRACT: After more than 30 years, landmark progress has been made in the treatment of cancer, and melanoma in particular, with the success of new molecules such as ipilimumab, vemurafenib and active specific immunization.After the first congress in December 2010, the second edition of "Melanoma Research: a bridge from Naples to the World" meeting, organized by Paolo A. Ascierto (INT, Naples, Italy), Francesco M. Marincola (NIH, Bethesda, USA), and Nicola Mozzillo (INT, Naples, Italy) took place in Naples, on 5-6 December 2011. We have identified four new topics of discussion: Innovative Approaches in Prevention, Diagnosis and Surgical Treatment, New Pathways and Targets in Melanoma: An Update about Immunotherapy, and Combination Strategies. This international congress gathered more than 30 international faculty members and was focused on recent advances in melanoma molecular biology, immunology and therapy, and created an interactive atmosphere which stimulated discussion of new approaches and strategies in the field of melanoma.
Journal of Translational Medicine 05/2012; 10:83. · 3.41 Impact Factor
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Tara L Spivey,
Valeria De Giorgi,
Yingdong Zhao,
Davide Bedognetti,
Zoltan Pos,
Qiuzhen Liu,
Sara Tomei,
Maria Libera Ascierto,
Lorenzo Uccellini,
Jennifer Reinboth,
Lotfi Chouchane,
David F Stroncek, Ena Wang,
Francesco M Marincola
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ABSTRACT: The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number.
Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis.
This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.
BMC Genomics 04/2012; 13:156. · 4.07 Impact Factor
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Diane M Longo,
Brent Louie,
Santosh Putta,
Erik Evensen,
Jason Ptacek,
James Cordeiro, Ena Wang,
Zoltan Pos,
Rachael E Hawtin,
Francesco M Marincola,
Alessandra Cesano
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ABSTRACT: A greater understanding of the function of the human immune system at the single-cell level in healthy individuals is critical for discerning aberrant cellular behavior that occurs in settings such as autoimmunity, immunosenescence, and cancer. To achieve this goal, a systems-level approach capable of capturing the response of the interdependent immune cell types to external stimuli is required. In this study, an extensive characterization of signaling responses in multiple immune cell subpopulations within PBMCs from a cohort of 60 healthy donors was performed using single-cell network profiling (SCNP). SCNP is a multiparametric flow cytometry-based approach that enables the simultaneous measurement of basal and evoked signaling in multiple cell subsets within heterogeneous populations. In addition to establishing the interindividual degree of variation within a broad panel of immune signaling responses, the possible association of any observed variation with demographic variables including age and race was investigated. Using half of the donors as a training set, multiple age- and race-associated variations in signaling responses in discrete cell subsets were identified, and several were subsequently confirmed in the remaining samples (test set). Such associations may provide insight into age-related immune alterations associated with high infection rates and diminished protection following vaccination and into the basis for ethnic differences in autoimmune disease incidence and treatment response. SCNP allowed for the generation of a functional map of healthy immune cell signaling responses that can provide clinically relevant information regarding both the mechanisms underlying immune pathological conditions and the selection and effect of therapeutics.
The Journal of Immunology 02/2012; 188(4):1717-25. · 5.79 Impact Factor
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Lorenzo Uccellini,
Fan-Chen Tseng,
Alessandro Monaco,
Fatma M Shebl,
Ruth Pfeiffer,
Myhanh Dotrang,
Dianna Buckett,
Michael P Busch, Ena Wang,
Brian R Edlin,
Francesco M Marincola,
Thomas R O'Brien
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ABSTRACT: In patients with chronic hepatitis C, the hepatitis C virus (HCV) RNA level is an important predictor of treatment response. To explore the relationship of HCV RNA with viral and demographic factors, as well as IL28B genotype, we examined viral levels in an ethnically diverse group of injection drug users (IDUs). Between 1998 and 2000, the Urban Health Study (UHS) recruited IDUs from street settings in San Francisco Bay area neighborhoods. Participants who were positive by HCV enzyme immunoassay were tested for HCV viremia by a branched-chain DNA assay. HCV genotype was determined by sequencing the HCV nonstructural 5B protein region. For a subset of participants, IL28B rs12979860 genotype was determined by Taqman. Among 1,701 participants with HCV viremia, median age was 46 years and median duration of injection drug use was 26 years; 56.0% were African American and 34.0% were of European ancestry (non-Hispanic). Human immunodeficiency virus type 1 (HIV-1) prevalence was 13.9%. The overall median HCV RNA level was 6.45 log(10) copies/mL. In unadjusted analyses, higher levels were found with older age, male gender, African-American ancestry, hepatitis B virus infection, HIV-1 infection, and IL28B rs12979860-CC genotype; compared to participants infected with HCV genotype 1, HCV RNA was lower in participants with genotypes 3 or 4. In an adjusted analysis, age, gender, racial ancestry, HIV-1 infection, HCV genotype, and IL28B rs12979860 genotype were all independently associated with HCV RNA. CONCLUSION: The level of HCV viremia is influenced by a large number of demographic, viral, and human genetic factors.
Hepatology 02/2012; 56(1):86-94. · 11.66 Impact Factor
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ABSTRACT: IFNa was the first cytokine to demonstrate anti-tumor activity in advanced melanoma. Despite the ability of high-dose IFNa reducing relapse and mortality by up to 33%, large majority of patients experience side effects and toxicity which outweigh the benefits. The current study attempts to identify genetic markers likely to be associated with benefit from IFN-a2b treatment and predictive for survival.
We tested the association of variants in FOXP3 microsatellites, CTLA4 SNPs and HLA genotype in 284 melanoma patients and their association with prognosis and survival of melanoma patients who received IFNa adjuvant therapy.
Univariate survival analysis suggested that patients bearing either the DRB1*15 or HLA-Cw7 allele suffered worse OS while patients bearing either HLA-Cw6 or HLA-B44 enjoyed better OS. DRB1*15 positive patients suffered also worse RFS and conversely HLA-Cw6 positive patients had better RFS. Multivariate analysis revealed that a five-marker genotyping signature was prognostic of OS independent of disease stage. In the multivariate Cox regression model, HLA-B38 (p = 0.021), HLA-C15 (p = 0.025), HLA-C3 (p = 0.014), DRB1*15 (p = 0.005) and CT60*G/G (0.081) were significantly associated with OS with risk ratio of 0.097 (95% CI, 0.013-0.709), 0.387 (95% CI, 0.169-0.889), 0.449 (95% CI, 0.237-0.851), 1.948 (95% CI, 1.221-3.109) and 1.484 (95% IC, 0.953-2.312) respectively.
These results suggest that gene polymorphisms relevant to a biological occurrence are more likely to be informative when studied in concert to address potential redundant or conflicting functions that may limit each gene individual contribution. The five markers identified here exemplify this concept though prospective validation in independent cohorts is needed.
PLoS ONE 01/2012; 7(7):e40805. · 4.09 Impact Factor
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Annacarmen Petrizzo,
Maria Lina Tornesello,
Maria Napolitano,
Giovanna D'Alessio,
Angelo Salomone Megna,
Riccardo Dolcetti,
Valli De Re, Ena Wang,
Franco M Marincola,
Franco M Buonaguro,
Luigi Buonaguro
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ABSTRACT: Hepatitis C virus (HCV) has been identified as one of the major risk factors for type II mixed cryoglobulinemia (MC), during the clinical evolution of chronic hepatitis, which may lead to development of B cell non-Hodgkin's lymphoma (NHL). We have previously shown that the candidate idiotype vaccine, based on the IGKV3-20 light chain protein, is able to induce activation and maturation of circulating antigen presenting cells (APCs) in both HCV-positive and HCV-negative healthy control subjects, with production of Th2-type cytokines. Here, the effect of the recombinant IGKV3-20 protein on human peripheral blood mononuclear cells (PBMCs) from HCV-positive subjects, with known blood levels of cryoglobulins, is shown via gene expression profiling analysis combined to multiparameter flow cytometry and multiplex analyses of cytokines.
PLoS ONE 01/2012; 7(9):e44870. · 4.09 Impact Factor
