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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; tumor ; KINASE ; TYROSINE KINASE ; ALGORITHM ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; DIFFERENTIATION ; MECHANISM ; mechanisms ; MOLECULE ; LYMPHOMA ; REED-STERNBERG CELLS ; gene expression ; DESIGN ; PLASMA ; NUMBER ; B-CELLS ; RECEPTORS ; gene expression profiling ; GAINS ; chemokine ; JAK2 ; REL ; B-CELL LYMPHOMA ; FEATURES ; immunoglobulin ; secretion ; CELL LYMPHOMA ; PROFILES ; LYMPHOMAS ; EXPRESSION PROFILES ; HIGH EXPRESSION ; classical Hodgkin lymphoma ; GERMINAL-CENTER ; 9P ; mediastinal grey zone lymphoma ; primary mediastinal B cell lymphoma ; TARC
    Abstract: There are several indications that classical Hodgkin lymphoma (cHL) and at least a proportion of cases of Primary Mediastinal B cell Lymphoma (PMBL) are derived from B cells at similar stages of differentiation and share common pathogenic mechanisms. The first indication was the existence of mediastinal grey zone lymphomas as identified in the 4th International Symposium on HL, with clinical, histological and immunohistochemical features intermediate between cHL and PMBL. Second, both tumor types resemble a cell that is developmentally situated in-between the germinal center reaction and a plasma cell. Third, cHL and PMBL were found to have similar gene expression profiles, including the lack of immunoglobulin expression and low levels of B cell receptor signalling molecules, and the secretion of molecules like the chemokine TARC and the prominent expression of IL-13 receptors. Fourth, both entities were found to have common genomic aberrancies, notably in 2p15 and 9p24, the sites of the REL oncogene and the tyrosine kinase gene JAK2, respectively. Further comparison of both lymphoma types may provide further insight in the pathogenic mechanisms and allow the design of diagnostic algorithms to sort out the small number of so-called mediastinal grey zone lymphomas, that appear to be intermediate between PMBL and cHL
    Type of Publication: Journal article published
    PubMed ID: 16007868
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  • 2
    Keywords: CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; Germany ; human ; GENE ; HYBRIDIZATION ; TISSUE ; LINES ; PATIENT ; MARKER ; TISSUES ; ANTIGEN ; SKIN ; T cells ; T-CELLS ; CELL-LINES ; DOWN-REGULATION ; SIGNAL ; IN-SITU ; DESIGN ; MUTATION ; CELL-LINE ; LINE ; ABERRATIONS ; HETEROZYGOSITY ; MELANOMA ; REGION ; MUTATIONS ; MONOCLONAL-ANTIBODIES ; MHC CLASS-I ; PHENOTYPE ; IMMUNE ESCAPE ; TUMOR ESCAPE ; in situ hybridization ; MALIGNANT-CELLS ; RE ; LEVEL ; EVENTS ; LOSSES ; CD8(+) T cell ; B2M GENE ; MEDIATED LYSIS ; PROCESSING MACHINERY
    Abstract: Purpose: Total loss of surface presentation of human leukocyte antigen (HLA) class I molecules, protecting tumor cells from the recognition by cytotoxic host CD8(+) T cells, is known to be caused by mutations in the beta 2-microglobulin (beta 2m) gene. We asked whether abnormalities of chromosome 15, harboring the beta 2m gene on 15q21, in addition to beta 2m gene mutations, are causative for the HILA class I-negative phenotype of melanoma cells. Experimental Design: To answer this, we established primary cell lines from the beta 2m-negative metastatic melanoma tissues of four different patients and analyzed them for beta 2m gene mutations and chromosome 15 aberrations, the latter by loss of heterozygosity analysis, fluorescence in situ hybridization (FISH), and multicolor FISH. Results: Mutations at the beta 2m gene level were detected in all cell lines. The loss of heterozygosity analysis of microsatellite markers located on chromosome 15 in three of the four cell lines pointed to an extensive loss of chromosome 15 material. Subsequent molecular cytogenetic analysis revealed the coexistence of apparently normal and rearranged versions of chromosome 15 in three cell lines whereas the fourth cell line solely showed rearranged versions. Two of the four cell lines exhibited a special type of intrachromosomal rearrangement characterized by FISH signals specific for the subtelomeric region of 15q at both ends of the chromosome and one centromeric signal in between. Conclusions: Our data indicate that the complete loss of HLA class I expression in melanoma cells is due to the coincidence of the following mutational events: (a) chromosome 15 instability associated with an extensive loss of genetic material and (b) beta 2m gene mutations
    Type of Publication: Journal article published
    PubMed ID: 16740750
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  • 3
    ISSN: 1569-8041
    Keywords: AIDS ; bcl-6 ; genetic lesion ; lymphoma ; oncogene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Non-Hodgkin's lymphoma (NHL) represents a major complicationof AIDS. Systemic AIDS-related NHLs (AIDS-NHLs) derive from B cells and areclassified into four distinct groups, including small noncleaved-celllymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), anaplastic large-celllymphoma (ALCL), and body-cavity-based lymphoma (BCBL). The molecularpathogenesis of AIDS-NHL is characterized by the association of specificgenetic lesions with distinct AIDS-NHL categories. Genetic lesions ofAIDS-NHL involve proto-oncogenes (c-myc, Ras), tumor suppressor loci (p53,6q), and viral infection (Epstein–Barr virus, human herpesvirus type8). Design: The aim of this work was to define the involvement of the bcl-6gene in AIDS-related lymphomagenesis by investigating the distribution ofbcl-6 structural alterations throughout the pathologic spectrum of AIDS-NHL.Both gross rearrangements and mutations in the 5′ noncoding regions ofthe gene were investigated. Results: Gross rearrangements of bcl-6 are confined to a fraction ofAIDS-DLCL cases among AIDS-NHLs. Conversely, mutations of the 5′noncoding regions of bcl-6 are detected in a large proportion ofAIDS-SNCCLs, AIDS-DLCLs and AIDS-ALCLs independent of the concomitantpresence of bcl-6 rearrangements. Conclusions: Mutations of the 5′ noncoding regions of bcl-6 represent the most frequent genetic lesion presently detectable amongsystemic AIDS-NHLs. The frequency of these mutations and their location in theproximity of bcl-6 regulatory regions suggest that they may play a rolein AIDS-related lymphomagenesis.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1569-8041
    Keywords: eosinophils ; Hodgkin's disease ; Reed–;Sternberg cells ; TNF-like ligands
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Even though the presence of a prominent tissue eosinophiliarepresents a common histopathologic feature of Hodgkin's disease (HD),eosinophils have been mainly regarded as ‘innocent’ bystanders recruited andactivated during the cellular reaction typical of HD. To evaluate theputative role of eosinophils or eosinophil-derived cytokines on tumor-cellregulation in HD, we have analyzed these cells for the functional expressionof surface ligands (L) of the tumor necrosis factor (TNF) superfamily, whosespecific receptors are known to transduce proliferation signals at thesurface of Hodgkin (H) and Reed–;Sternberg (RS) cells. Materials and methods: Eosinophils from peripheral blood of healthydonors and patients with HD, primary hypereosinophilic syndrome (HES), orsecondary hypereosinophilia (HE), were purified by density gradientcentrifugation and immunomagnetic depletion of residual granulocytes. Results: By immunostaining and mRNA analysis, we were able to show thateosinophils from normal donors and patients with HD, HES, and HE express anumber of receptors and ligands of the TNF superfamily, including CD40,CD40L, CD30L, CD95/Fas, CD95/FasL and 4-1BB. In addition, we provideevidence that cytokines regulating eosinophil proliferation and activation,i.e., interleukin (IL)-5, IL-3, and granulocyte-macrophagecolony-stimulating factor, are able to enhance the cellular density ofseveral TNF superfamily ligands and/or receptors at the surface of culturedeosinophils. Finally, we have shown that native CD40L and CD30L at thesurface of purified eosinophils are functionally active and able totransduce proliferative signals on CD40+ and CD30+ target cells, includingcultured H-RS cells. Conclusions: Our data suggest that eosinophils may act as importantelements in the pathology of HD by providing cellular ligands forTNF-superfamily receptors (CD40, CD30, CD95/Fas) able to transduceproliferation and antiapoptotic signals at the surface of H-RS cells. Thepresence on eosinophils of receptors for TNF ligands expressed by activatedT cells (i.e., OX40L, FasL, CD40L, 4-1BBL), also suggest that eosinophils maycontribute to the deregulated network of interactive signals between H-RScells, T cells, and other surrounding reactive cells.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1569-8041
    Keywords: eosinophils ; Hodgkin's disease ; Reed–;Sternberg cells ; TNF-like ligands
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Even though the presence of a prominent tissue eosinophilia represents a common histopathologic feature of Hodgkin's disease (HD), eosinophils have been mainly regarded as ‘innocent’ bystanders recruited and activated during the cellular reaction typical of HD. To evaluate the putative role of eosinophils or eosinophil-derived cytokines on tumor-cell regulation in HD, we have analyzed these cells for the functional expression of surface ligands (L) of the tumor necrosis factor (TNF) superfamily, whose specific receptors are known to transduce proliferation signals at the surface of Hodgkin (H) and Reed–;Sternberg (RS) cells. Materials and methods: Eosinophils from peripheral blood of healthy donors and patients with HD, primary hypereosinophilic syndrome (HES), or secondary hypereosinophilia (HE), were purified by density gradient centrifugation and immuno magnetic depletion of residual granulocytes. Results: By immunostaining and mRNA analysis, we were able to show that eosinophils from normal donors and patients with HD, HES, and HE express a number of receptors and ligands of the TNF superfamily, including CD40,CD40L, CD30L, CD95/Fas, CD95/FasL and 4-1BB. In addition, we provide evidence that cytokines regulating eosinophil proliferation and activation, i.e., interleukin (IL)-5, IL-3, and granulocyte-macrophagecolony-stimulating factor, are able to enhance the cellular density of several TNF superfamily ligands and/or receptors at the surface of culture deosinophils. Finally, we have shown that native CD40L and CD30L at the surface of purified eosinophils are functionally active and able to transduce proliferative signals on CD40+ and CD30+ target cells, including cultured H-RS cells. Conclusions: Our data suggest that eosinophils may act as important elements in the pathology of HD by providing cellular ligands for TNF-superfamily receptors (CD40, CD30, CD95/Fas) able to transducer proliferation and antiapoptotic signals at the surface of H-RS cells. The presence on eosinophils of receptors for TNF ligands expressed by activated T cells (i.e., OX40L, FasL, CD40L, 4-1BBL), also suggest that eosinophils may contribute to the deregulated network of interactive signals between H-RS cells, T cells, and other surrounding reactive cells.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1569-8041
    Keywords: AIDS ; bcl-6 ; genetic lesion ; lymphoma ; oncogene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Non-Hodgkin's lymphoma (NHL) represents a major complication of AIDS. Systemic AIDS-related NHLs (AIDS-NHLs) derive from B cells and are classified into four distinct groups, including small noncleaved-cell lymphoma (SNCCL), diffuse large-cell lymphoma (DLCL), anaplastic large-cell lymphoma (ALCL), and body-cavity-based lymphoma (BCBL). The molecular pathogenesis of AIDS-NHL is characterized by the association of specific genetic lesions with distinct AIDS-NHL categories. Genetic lesions of AIDS-NHL involve proto-oncogenes (c-myc, Ras), tumor suppressor loci (p53,6q), and viral infection (Epstein–Barr virus, human herpesvirus type8). Design: The aim of this work was to define the involvement of the bcl-6gene in AIDS-related lymphomagenesis by investigating the distribution ofbcl-6 structural alterations throughout the pathologic spectrum of AIDS-NHL. Both gross rearrangements and mutations in the 5′ non coding regions of the gene were investigated. Results: Gross rearrangements of bcl-6 are confined to a fraction of AIDS-DLCL cases among AIDS-NHLs. Conversely, mutations of the 5′noncoding regions of bcl-6 are detected in a large proportion of AIDS-SNCCLs, AIDS-DLCLs and AIDS-ALCLs independent of the concomitant presence of bcl-6 rearrangements. Conclusions: Mutations of the 5′ noncoding regions of bcl-6 represent the most frequent genetic lesion presently detectable among systemic AIDS-NHLs. The frequency of these mutations and their location in the proximity of bcl-6 regulatory regions suggest that they may play a rolein AIDS-related lymphomagenesis.
    Type of Medium: Electronic Resource
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  • 7
    Publication Date: 2018-02-10
    Description: This study aimed to identify circulating miRNAs as novel non-invasive biomarkers for prognosis and vandetanib response in advanced medullary thyroid cancer (MTC) patients. We prospectively recruited two independent cohorts of locally advanced/metastatic MTC patients including a subgroup of vandetanib-treated subjects: a discovery cohort ( n = 20), including matched plasma/tissue samples ( n = 17/20), and a validation cohort, yielding only plasma samples ( n = 17). Plasma samples from healthy subjects ( n = 36) and MTC patients in remission ( n = 9) were used as controls. MTC ( n = 17 from 8 patients included in discovery cohort) and non-neoplastic thyroid specimens ( n = 3) were assessed by microarray profiling to identify candidate circulating miRNAs. qRT-PCR and in situ hybridization were carried out to validate the expression and localization of a selected miRNA within tissues, and qRT-PCR was also performed to measure miRNA levels in plasma samples. By microarray analysis, we identified 51 miRNAs differentially expressed in MTC. The most overexpressed miR, miR-375, was highly expressed by C cells compared to other thyroid cells, and more expressed in MTC than in reactive C-cell hyperplasia. MTC patients had significantly higher miR-375 plasma levels than healthy controls ( P 〈 0.0001) and subjects in remission ( P = 0.0004) as demonstrated by qRT-PCR analysis. miR-375 plasma levels were not predictive of vandetanib response, but, notably, high levels were associated with significantly reduced overall survival (HR 10.61, P 〈 0.0001) and were a strong prognostic factor of poor prognosis (HR 6.24, P = 0.00025) in MTC patients. Overall, our results unveil plasma miR-375 as a promising prognostic marker for advanced MTC patients, to be validated in larger cohorts.
    Print ISSN: 1351-0088
    Electronic ISSN: 1479-6821
    Topics: Medicine
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  • 8
    Publication Date: 2018-03-06
    Description: Purpose: Refining the selection of HER2-positive metastatic gastric cancer patient candidates for trastuzumab is a challenge of precision oncology. Preclinical studies have suggested several genomic mechanisms of primary resistance, leading to activation of tyrosine kinase receptors other than HER2 or downstream signaling pathways. Experimental Design: We carried out this multicenter, prospective, case-control study to demonstrate the negative predictive impact of a panel of candidate genomic alterations (AMNESIA panel), including EGFR/MET/KRAS/PI3K/PTEN mutations and EGFR/MET/KRAS amplifications. Hypothesizing a prevalence of candidate alterations of 30% and 0% in resistant and sensitive HER2-positive patients, respectively, 20 patients per group were needed. Results: AMNESIA panel alterations were significantly more frequent in resistant (11 of 20, 55%) as compared with sensitive (0% of 17) patients ( P 〈 0.001), and in HER2 IHC 2 + (7 of 13, 53.8%) than 3 + (4 of 24, 16.7%) tumors ( P = 0.028). Patients with tumors bearing no candidate alterations had a significantly longer median progression-free [5.2 vs. 2.6 months; HR, 0.34; 95% confidence interval (CI), 0.07–0.48; P = 0.001] and overall survival (16.1 vs. 7.6 months; HR, 0.38; 95% CI, 0.09–0.75; P = 0.015). The predictive accuracy of the AMNESIA panel and HER2 IHC was 76% and 65%, respectively. The predictive accuracy of the combined evaluation of the AMNESIA panel and HER2 IHC was 84%. Conclusions: Our panel of candidate genomic alterations may be clinically useful to predict primary resistance to trastuzumab in patients with HER2-positive metastatic gastric cancer and should be further validated with the aim of molecularly stratifying HER2-addicted cancers for the development of novel treatment strategies. Clin Cancer Res; 24(5); 1082–9. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 9
    Publication Date: 2018-07-06
    Description: Epstein-Barr virus (EBV)–related and EBV-unrelated classical Hodgkin lymphomas (cHLs) are morphologically and phenotypically indistinguishable. However, the tumor microenvironment of EBV-related cHLs contains higher numbers of macrophages and higher expression levels of PD-L1 than that of EBV-unrelated cHLs. Moreover, viral oncoprotein LMP1 may sustain an immunosuppressive microenvironment by inducing/enhancing production of immunosuppressive cytokines and the expression of PD-1. The presence of enhanced immunosuppressive features in EBV-related cHL should make EBV-related cHL patients more susceptible to checkpoint blockade.
    Keywords: Immunobiology and Immunotherapy, Lymphoid Neoplasia, Blood Spotlight, Clinical Trials and Observations
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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