Publications (18)75.09 Total impact
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Article: HCV RNA levels in a multiethnic cohort of injection drug users: human genetic, viral and demographic associations.
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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 -
Article: A multi-factorial genetic model for prognostic assessment of high risk melanoma patients receiving adjuvant interferon.
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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 -
Article: RH genotyping in a sickle cell disease patient contributing to hematopoietic stem cell transplantation donor selection and management.
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ABSTRACT: African individuals harbor molecular RH variants, which permit alloantibody formation to high-prevalence Rh antigens after transfusions. Genotyping identifies such RH variants, which are often missed by serologic blood group typing. Comprehensive molecular blood group analysis using 3 genotyping platforms, nucleotide sequencing, and serologic evaluation was performed on a 7-year-old African male with sickle cell disease who developed an "e-like" antibody shortly after initiating monthly red blood cell (RBC) transfusions for silent stroke. Genotyping of the RH variant predicted a severe shortage of compatible RBCs for long-term transfusion support, which contributed to the decision for hematopoetic stem cell transplantation. RH genotyping confirmed the RH variant in the human leukocyte antigen-matched sibling donor. The patient's (C)ce(s) type 1 haplotype occurs in up to 11% of African American sickle cell disease patients; however, haplotype-matched RBCs were serologically incompatible. This case documents that blood unit selection should be based on genotype rather than one matching haplotype.Blood 10/2010; 116(15):2836-8. · 9.90 Impact Factor -
Article: Genomic scale analysis of racial impact on response to IFN-alpha.
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ABSTRACT: Limited responsiveness to IFN-alpha in hepatitis C virus (HCV)-infected African-Americans compared to European Americans (AAs vs. EAs) hinders the management of HCV. Here, we studied healthy non-HCV-infected AA and EA subjects to test whether immune cell response to IFN-alpha is determined directly by race. We compared baseline and IFN-alpha-induced signal transducer and activator of transcription (STAT)-1, STAT-2, STAT-3, STAT-4, and STAT-5 protein and phosphorylation levels in purified T cells, global transcription, and a genomewide single-nucleotide polymorphism (SNP) profile of healthy AA and EA blood donors. In contrast to HCV-infected individuals, healthy AAs displayed no evidence of reduced STAT activation or IFN-alpha-stimulated gene expression compared to EAs. Although >200 genes reacted to IFN-alpha treatment, race had no impact on any of them. The only gene differentially expressed by the two races (NUDT3, P < 10(-7)) was not affected by IFN-alpha and bears no known relationship to IFN-alpha signaling or HCV pathogenesis. Genomewide analysis confirmed the self-proclaimed racial attribution of most donors, and numerous race-associated SNPs were identified within loci involved in IFN-alpha signaling, although they clearly did not affect responsiveness in the absence of HCV. We conclude that racial differences observed in HCV-infected patients in the responsiveness to IFN-alpha are unrelated to inherent racial differences in IFN-alpha signaling and more likely due to polymorphisms affecting the hosts' response to HCV, which in turn may lead to a distinct disease pathophysiology responsible for altered IFN signaling and treatment response.Proceedings of the National Academy of Sciences 01/2010; 107(2):803-8. · 9.68 Impact Factor -
Article: Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma.
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ABSTRACT: Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The molecular mechanisms of HCV-induced hepatocarcinogenesis are not yet fully elucidated. Besides indirect effects as tissue inflammation and regeneration, a more direct oncogenic activity of HCV can be postulated leading to an altered expression of cellular genes by early HCV viral proteins. In the present study, a comparison of gene expression patterns has been performed by microarray analysis on liver biopsies from HCV-positive HCC patients and HCV-negative controls. Gene expression profiling of liver tissues has been performed using a high-density microarray containing 36'000 oligos, representing 90% of the human genes. Samples were obtained from 14 patients affected by HCV-related HCC and 7 HCV-negative non-liver-cancer patients, enrolled at INT in Naples. Transcriptional profiles identified in liver biopsies from HCC nodules and paired non-adjacent non-HCC liver tissue of the same HCV-positive patients were compared to those from HCV-negative controls by the Cluster program. The pathway analysis was performed using the BRB-Array- Tools based on the "Ingenuity System Database". Significance threshold of t-test was set at 0.001. Significant differences were found between the expression patterns of several genes falling into different metabolic and inflammation/immunity pathways in HCV-related HCC tissues as well as the non-HCC counterpart compared to normal liver tissues. Only few genes were found differentially expressed between HCV-related HCC tissues and paired non-HCC counterpart. In this study, informative data on the global gene expression pattern of HCV-related HCC and non-HCC counterpart, as well as on their difference with the one observed in normal liver tissues have been obtained. These results may lead to the identification of specific biomarkers relevant to develop tools for detection, diagnosis, and classification of HCV-related HCC.Journal of Translational Medicine 10/2009; 7:85. · 3.41 Impact Factor -
Article: Molecular immune signatures of HIV-1 vaccines in human PBMCs.
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ABSTRACT: The global transcriptional profile of peripheral blood mononuclear cells (PBMCs) stimulated with HIV candidate vaccine (virus-like particles, VLPs) has been evaluated in HIV-infected patients with low/high viral load compared to healthy volunteers. Baseline activation of chemokine production was observed in PBMC from HIV-infected patients and innate immune stimulation with HIV-VLPs was not blunted. The immune profile among HIV-infected patients was found to be qualitatively similar but quantitatively extremely variable. This diversity was independent of viral load and it might be dependent on individual immunogenetic traits or concurrent immunological status. This ex vivo screening strategy represents an efficient tool for guiding modifications/optimizations of vaccination strategies and understanding failures in individuals enrolled in clinical trials.FEBS letters 09/2009; 583(18):3004-8. · 3.54 Impact Factor -
Article: Antitumor vaccines, immunotherapy and the immunological constant of rejection.
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ABSTRACT: Anticancer vaccines have not matched the clinical expectations projected from their ability to induce consistently systemic anticancer T-cell responses. Thus, a dichotomy is observed between the immunological and clinical endpoints of anticancer immunization. Anticancer vaccines have clearly demonstrated that highly specific T-cell responses can be induced that can recognize autologous cancer antigens in patients with cancer. This ability is an outstanding achievement of modern biotechnology, yielding one of the most specific types of potential anticancer reagents. However, systemic, vaccine-induced anticancer responses exemplify a broader immunological paradox: cytotoxic T-cells can coexist within the same organism with their target cells not only in the context of cancer, but also in the context of chronic infections, well-controlled allo-transplant reactions and autoimmunity. According to this view, anticancer immune responses are a facet of a tissue-specific autoimmune phenomenon specific for cancer tissue that may or may not result in the successful immune-destruction of target cells, depending on an assortment of genetic factors related to the background of the host or evolving phenotypes of a heterogeneous cancer environment. This feature article summarizes the current understanding of the mechanisms leading to tumor rejection in humans as well as in experimental models, in the context of the broader immunological phenomenon leading to tissue-specific destruction. Anticancer vaccines that may not induce clinically significant anticancer responses independently could function as a unique tool to enhance the specificity of the response of the host against cancer, provided that strategies are implemented to amplify the immune reaction initiated by vaccine-induced antibodies and/or T-cells.IDrugs: the investigational drugs journal 06/2009; 12(5):297-301. · 2.28 Impact Factor -
Article: Systemic treatment of xenografts with vaccinia virus GLV-1h68 reveals the immunologic facet of oncolytic therapy.
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ABSTRACT: GLV-1h68 is an attenuated recombinant vaccinia virus (VACV) that selectively colonizes established human xenografts inducing their complete regression. Here, we explored xenograft/VACV/host interactions in vivo adopting organism-specific expression arrays and tumor cell/VACV in vitro comparing VACV replication patterns. There were no clear-cut differences in vitro among responding and non-responding tumors, however, tumor rejection was associated in vivo with activation of interferon-stimulated genes (ISGs) and innate immune host's effector functions (IEFs) correlating with VACV colonization of the xenografts. These signatures precisely reproduce those observed in humans during immune-mediated tissue-specific destruction (TSD) that causes tumor or allograft rejection, autoimmunity or clearance of pathogens. We recently defined these common pathways in the "immunologic constant of rejection" hypothesis (ICR). This study provides the first prospective validation of a universal mechanism associated with TSD. Thus, xenograft infection by oncolytic VACV, beyond offering a promising therapy of established cancers, may represent a reliable pre-clinical model to test therapeutic strategies aimed at modulating the central pathways leading to TSD; this information may lead to the identification of principles that could refine the treatment of cancer and chronic infection by immune stimulation or autoimmunity and allograft rejection through immune tolerance.BMC Genomics 02/2009; 10:301. · 4.07 Impact Factor -
Article: Gene profiling, biomarkers and pathways characterizing HCV-related hepatocellular carcinoma
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ABSTRACT: Abstract Background Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The molecular mechanisms of HCV-induced hepatocarcinogenesis are not yet fully elucidated. Besides indirect effects as tissue inflammation and regeneration, a more direct oncogenic activity of HCV can be postulated leading to an altered expression of cellular genes by early HCV viral proteins. In the present study, a comparison of gene expression patterns has been performed by microarray analysis on liver biopsies from HCV-positive HCC patients and HCV-negative controls. Methods Gene expression profiling of liver tissues has been performed using a high-density microarray containing 36'000 oligos, representing 90% of the human genes. Samples were obtained from 14 patients affected by HCV-related HCC and 7 HCV-negative non-liver-cancer patients, enrolled at INT in Naples. Transcriptional profiles identified in liver biopsies from HCC nodules and paired non-adjacent non-HCC liver tissue of the same HCV-positive patients were compared to those from HCV-negative controls by the Cluster program. The pathway analysis was performed using the BRB-Array- Tools based on the "Ingenuity System Database". Significance threshold of t -test was set at 0.001. Results Significant differences were found between the expression patterns of several genes falling into different metabolic and inflammation/immunity pathways in HCV-related HCC tissues as well as the non-HCC counterpart compared to normal liver tissues. Only few genes were found differentially expressed between HCV-related HCC tissues and paired non-HCC counterpart. Conclusion In this study, informative data on the global gene expression pattern of HCV-related HCC and non-HCC counterpart, as well as on their difference with the one observed in normal liver tissues have been obtained. These results may lead to the identification of specific biomarkers relevant to develop tools for detection, diagnosis, and classification of HCV-related HCC.Journal of Translational Medicine. 01/2009; -
Article: Molecular and in silico analysis of BRCA1 and BRCA2 variants.
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ABSTRACT: Germline mutations of high penetrant BRCA1 and BRCA2 genes have been associated to hereditary breast cancer risk, while polymorphic variants of the two genes still have an unknown role in breast pathogenesis. The aim of our study was to characterize BRCA1 and BRCA2 genes polymorphic variants in familial breast cancer. 110 patients affected by familial breast and/or ovarian cancer have been consecutively enrolled according to family history and BRCA mutation risk. All of them have been screened for BRCA1 and BRCA2 pathogenetic mutations, SNPs and intronic variants. In silico analysis have been also performed using different computational methods to individualize genetic variations that can alter the two genes expression and function. BRCA1 resulted mutated in 14% while BRCA2 in 3% of cases, while 80% of patients presented at least one polymorphism. A neural network splicing prediction model individualized one BRCA1 and one BRCA2 intronic variants able to determine alternative splicing. Furthermore, Q356R BRCA1 and N289H BRCA2 appear to show a possible harmful role also due to their location in functional regions of the two genes. However, in silico data are not always consistent with biological evidences. In conclusion, SNPs profile provides a basis for DNA-based cancer risk classification and help to define the gene alterations that could influence biochemistry activity protein or could modify drug sensitivity.Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 10/2008; 644(1-2):64-70. · 2.85 Impact Factor -
Article: Spontaneous and treatment-induced cancer rejection in humans.
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ABSTRACT: Experimental observations suggest that human cancer cells actively interact with normal host cells and this cross-talk results, in most instances, in an increased potential of cancer cells to survive. On the other hand, it is also well documented that on rare occasions tumors can be dramatically destroyed by the host's immune response. In this review, we argue that understanding the mechanisms that bring about the immune response and lead to cancer destruction is of paramount importance for the design of future rational therapies. Here we summarize the present understanding of the phenomenology leading to cancer regression in humans and propose novel strategies for a more efficient study of human cancer under natural conditions and during therapy. The understanding of tumor/host interactions within the tumor microenvironment is a key component of the study of tumor immunology in humans, much can be learned by a dynamic study of such interactions at time points related to the natural history of the disease or its response to therapy. Such understanding will eventually lead to novel and more effective therapies.Expert opinion on biological therapy 04/2008; 8(3):337-49. · 3.22 Impact Factor -
Article: Conservation of genetic alterations in recurrent melanoma supports the melanoma stem cell hypothesis.
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ABSTRACT: It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study, we expanded our previous observations comparing these autologous cell lines of clonal derivation with allogeneic ones and correlated array comparative genomic hybridization (aCGH) with gene expression profiling to determine their relative contribution to the dynamics of disease progression. aCGH and gene expression profiling were performed on autologous cell lines and allogeneic melanoma cell lines originating from other patients. A striking correlation existed between total extent of genetic imbalances, global transcriptional patterns, and cellular phenotypes. They did not follow a strict temporal progression but stemmed independently at various time points from a central core of genetic stability best explained according to the cancer stem cell hypothesis. Although their contribution was intertwined, genomic imbalances detectable by aCGH contributed only 25% of the transcriptional traits determining autologous tumor distinctiveness. Our study provides important insights about the dynamics of cancer progression and supports the development of targeted anticancer therapies aimed against stable genetic factors that are maintained throughout the end stage of disease.Cancer Research 02/2008; 68(1):122-31. · 7.86 Impact Factor -
Article: Gene expression profile of peripheral blood mononuclear cells in response to HIV-VLPs stimulation.
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ABSTRACT: Baculovirus-expressed HIV-1 Pr55gag Virus-Like Particles (HIV-VLPs) induce maturation and activation of monocyte-derived dendritic cells (MDDCs) with a production of Th1- and Th2-specific cytokines. The analysis of genomic transcriptional profile of MDDCs, obtained from normal healthy donors and activated by HIV-VLPs, show the modulation of genes involved in the morphological and functional changes characterizing the MDDCs activation and maturation. Similar data are obtained using peripheral blood mononuclear cells (PBMCs), without further selection, showing the feasibility of a direct and "simplified" experimental procedure. The results here described show that the maturation pattern induced by HIV-VLPs in ex vivo generated MDDCs, can be observed also in CD14-expressing freshly derived PBMCs, with the possible identification of genetic predictors of individual response to immunogens.BMC Bioinformatics 02/2008; 9 Suppl 2:S5. · 2.75 Impact Factor -
Article: "Sequencing-grade" screening for BRCA1 variants by oligo-arrays.
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ABSTRACT: The need for fast, efficient, and less costly means to screen genetic variants associated with disease predisposition led us to develop an oligo-nucleotide array-based process for gene-specific single nucleotide polymorphism (SNP) genotyping. This cost-effective, high-throughput strategy has high sensitivity and the same degree of accuracy as direct sequencing, the current gold standard for genetic screening. We used the BRCA1 breast and ovarian cancer predisposing gene model for the validation of the accuracy and efficiency of our strategy. This process could detect point mutations, insertions or deletions of any length, of known and unknown variants even in heterozygous conditions without affecting sensitivity and specificity. The system could be applied to other disorders and can also be custom-designed to include a number of genes related to specific clinical conditions. This system is particularly useful for the screening of long genomic regions with relatively infrequent but clinically relevant variants, while drastically cutting time and costs in comparison to high-throughput sequencing.Journal of Translational Medicine 02/2008; 6:64. · 3.41 Impact Factor -
Article: Gene expression profile of peripheral blood mononuclear cells in response to HIV-VLPs stimulation
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ABSTRACT: Abstract Background Baculovirus-expressed HIV-1 Pr55gag Virus-Like Particles (HIV-VLPs) induce maturation and activation of monocyte-derived dendritic cells (MDDCs) with a production of Th1- and Th2-specific cytokines. Results The analysis of genomic transcriptional profile of MDDCs, obtained from normal healthy donors and activated by HIV-VLPs, show the modulation of genes involved in the morphological and functional changes characterizing the MDDCs activation and maturation. Similar data are obtained using peripheral blood mononuclear cells (PBMCs), without further selection, showing the feasibility of a direct and “simplified” experimental procedure. Conclusions The results here described show that the maturation pattern induced by HIV-VLPs in ex vivo generated MDDCs, can be observed also in CD14-expressing freshly derived PBMCs, with the possible identification of genetic predictors of individual response to immunogens.BMC Bioinformatics. 01/2008; -
Article: Impact of sample preparation in peptide/protein profiling in human serum by MALDI-TOF mass spectrometry.
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ABSTRACT: The low molecular weight (LMW) serum proteome (<15 kDa) is the most generally informative from a medical point of view. Different sample pre-treatment approaches and devices for serum depletion in high-abundant proteins were tested in order to analyze, by MALDI-TOF-MS (both in "linear" and "reflectron" acquisition mode), the serum low molecular weight proteins/peptides. The best results in terms of detected ions number and abundance were obtained by using ultrafiltration of serum on 30 kDa molecular weight cut off membranes followed by miniaturized reverse-phase solid-phase extraction (mu-SPE) as sample pre-treatment; this procedure yielded also satisfactory within-sample and sample-to-sample repeatability (on both m/z values and peak intensity of the main observable ions). The procedure was finally applied to serum samples of breast cancer patients, and the relevant results compared to "normal" samples seem to be promising for the individuation of different profiles ("linear" and "reflectron" mode) and/or peptides capable of differentiating for malignancies ("reflectron" mode).Journal of Pharmaceutical and Biomedical Analysis 01/2008; 46(1):157-64. · 2.97 Impact Factor -
Article: Gene expression profile of peripheral blood mononuclear cells in response to HIV-VLPs stimulation.
BMC Bioinformatics. 01/2008; 9. -
Article: Associations between HLA class I alleles and the prevalence of nasopharyngeal carcinoma (NPC) among Tunisians.
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ABSTRACT: The high prevalence of nasopharyngeal cancer (NPC) in Southern Asia and Mediterranean Northern Africa suggests genetic predisposition among other factors. While Human Leukocyte Antigen (HLA) haplotypes have been conclusively associated with NPC predisposition in Asians, Northern African Maghrebians have been less intensely studied. However, low resolution serological methods identified weak positive associations with HLA-B5, B13 and B18 and a negative with HLA-B14. Using sequence based typing (SBT), we performed a direct comparison of HLA class I frequencies in a cohort of 136 Tunisian patients with NPC matched for gender, age and geographical residence to 148 normal Tunisians. The bimodal age distribution of NPC in Maghrebians was also taken into account. HLA frequencies in normal Tunisians were also compared with those of Northern Moroccan Berbers (ME) to evaluate whether the Tunisian population in this study could be considered representative of other Maghrebian populations. HLA-B14 and -Cw08 were negatively associated with NPC (odd ratio = 0.09 and 0.18 respectively, Fisher p(2)-value = 0.0001 and = 0.003). Moreover, positive associations were observed for HLA-B-18, -B51 (split of -B5) and -B57 (p(2)-value < 0.025 in all) confirming previous findings in Maghrebs. The HLA-B14/Cw*08 haplotype frequency (HF) was 0.007 in NPC patients compared to 0.057 in both Tunisian (OR = 0.12; p(2)-value = 0.001) and Moroccan controls. This study confirms several previous associations noted by serologic typing between HLA class I alleles and the prevalence of NPC in Maghrebians populations. In addition, we identified a putative haplotype rare in Tunisian patients with NPC that may serve as a genetic marker for further susceptibility studies.Journal of Translational Medicine 02/2007; 5:22. · 3.41 Impact Factor
Top co-authors
Top Journals
Institutions
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2007–2010
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National Institutes of Health
- Center for Clinical Research
Bethesda, MD, USA
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2009
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Naval Medical Center San Diego
San Diego, CA, USA
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2008
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Istituto Nazionale Tumori "Fondazione Pascale"
Marano di Napoli, Campania, Italy
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