ORCID Profile
0000-0003-1625-9853
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.CRITREVONC.2011.12.004
Abstract: Substantial progress has been made in the management of breast cancer by targeting HER2 and VEGF pathways. Although the efficacy and safety of target therapy in breast cancer have been established, no specific phase III trial has addressed these issues in the elderly population and the only data available derive from subanalyses or retrospective series. The aim of this review is to summarize the available evidence in this special population and to encourage further well designed studies in elderly breast cancer patients.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2012
DOI: 10.1038/BJC.2012.2
Publisher: Oxford University Press (OUP)
Date: 05-03-2007
DOI: 10.1111/J.1365-2249.2007.03348.X
Abstract: An aberrant T cell population is the basis for diagnosis of refractory coeliac disease and determines the risk of enteropathy-associated T cell lymphoma. This disease is serious with a poor survival. Pathogenetic mechanisms sustaining aberrant T cell proliferation remain unknown. Recently, alemtuzumab has been proposed as a promising new approach to treat these patients. Only few single cases have been tested at present nevertheless, in all the cases a clinical improvement was observed. However, whether intraepithelial lymphocytes have been targeted effectively by alemtuzumab is still debated. This study reports, using two-dimensional difference gel electrophoresis (2D DIGE), hyperexpressed proteins associated specifically with aberrant T cells found in a patient with coeliac disease by comparison of the protein expression of this s le with that of patients with coeliac disease and polyclonal T cells or with control subjects. The data demonstrated a significantly higher expression of IgM, apolipoprotein C-III and Charcot–Leyden crystal proteins in a duodenal biopsy specimen of the patient with clonal T cells compared with that of other patients. These preliminary results allow hypothesizing different clinical effects of alemtuzumab in patients with coeliac disease and aberrant T cell proliferation, because as well as the probable effect on T cells, alemtuzumab could exert its effect by acting on inflammatory associated CD52+ IgM+ B cells and eosinophil cells, known to produce IgM and Charcot–Leyden crystal proteins, that we demonstrated to be altered in this patient. The results also emphasize the possible association of apolipoprotein with aberrant T cell proliferation.
Publisher: Elsevier BV
Date: 07-2016
DOI: 10.1016/J.IMLET.2016.04.015
Abstract: Immune selective pressure occurring during cancer immunoediting shapes tumor features revealed at clinical presentation. However, in the "Escape" phase, the tumor itself has the chance to influence the immunological response. Therefore, the capacity of the immune response to sculpt the tumor characteristics is only one side of the coin and even the opposite is likely true, i.e. that an antigen can shape the immune response in a sort of "reverse immunoediting". This reciprocal modeling probably occurs continuously, whenever the immune system encounters a tumor/foreign antigen, and can be operative in the pathogen/immune system interplay, thus possibly permeating the protective immunity as a whole. In line with this view, the characterization of a T cell response as well as the design of both active and passive immunotherapy strategies should also take into account all Ag features (type, load and presentation). Overall, we suggest that the "reverse immunoediting" hypothesis could help to dissect the complex interplay between antigens and the immune repertoire, and to improve the outcome of immunotherapeutic approaches, where T cell responses are manipulated and reprogrammed.
Publisher: Informa UK Limited
Date: 12-2001
Publisher: Elsevier BV
Date: 09-1999
Publisher: Wiley
Date: 10-06-2008
DOI: 10.1002/IJC.23621
Abstract: Immunotherapy approaches targeting Epstein-Barr virus (EBV)-encoded antigens induce objective clinical responses only in a fraction of patients with undifferentiated nasopharyngeal carcinoma (UNPC). In the present study, we have characterized the immunogenicity of the EBV-encoded BARF1 oncogene with the aim to assess whether this protein could constitute a new target antigen for immunotherapy in this setting. Spontaneous CD4+ and CD8+ T cell responses specific for the recombinant p29 BARF1 protein were detected by IFNgamma-ELISPOT in both EBV-seropositive donors and UNPC patients, but not in EBV-seronegative in iduals. Using immunoinformatic prediction tools, we have selected 5 different candidate BARF1 T cell epitopes presented by HLA-A*0201. Although only one of these peptides was able to bind HLA-A2 with low affinity in the T2 stabilization assay, all 5 BARF1 nonamers readily elicited specific CD8+ T cell responses in EBV-seropositive HLA-A*0201+ donors and UNPC patients. Notably, the magnitude of CD8+ T cell responses to the whole BARF1 protein and derived A*0201 peptides was significantly higher in UNPC patients than in healthy donors. Moreover, cytotoxic T lymphocytes specific for the p2-10, p23-31, or p49-57 BARF1 peptides were easily obtained from HLA-A*0201+ donors. These cultures were not only able to lyse autologous targets loaded with the antigenic peptide, but also recognized tumor cells endogenously expressing BARF1 in an antigen-specific and HLA-A2-restricted manner. These findings, indicate that BARF1 is a particularly attractive antigen with immunogenic properties in most UNPC patients and provide valuable information to develop new strategies to improve the efficacy of EBV-targeting immunotherapy of UNPC patients.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6549799
Abstract: Abstract Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8 sup + /sup T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8 sup + /sup dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α sup + /sup DCs to drive efficient cross-priming of antigen-specific CD8 sup + /sup T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α sup + /sup DCs, and polyfunctional CD8 sup + /sup T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8 sup + /sup T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8 sup + /sup T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8 sup + /sup T-cell responses for control of solid tumors. /
Publisher: Wiley
Date: 18-06-2020
DOI: 10.1111/BCP.14338
Publisher: Springer Science and Business Media LLC
Date: 07-1991
DOI: 10.1007/BF00176755
Publisher: The American Association of Immunologists
Date: 03-2000
DOI: 10.4049/JIMMUNOL.164.5.2815
Abstract: Anti-latent membrane protein-1 (LMP-1) is an EBV-encoded type III integral membrane protein with oncogenic potential that is expressed most consistently in various EBV-associated malignancies. Unlike many other EBV proteins, LMP-1 Abs have rarely been demonstrated in EBV-associated disease conditions. We established a high level LMP-1-expressing cell clone and used it for the detection, quantitation, and characterization of these Abs in various human sera in immunoblots and ELISA. Our results demonstrate that, in contrast to the commonly held notion, LMP-1 induces significant humoral immune responses in EBV-associated malignant conditions especially in nasopharyngeal carcinoma (NPC) patients in whom & % sera are positive for these Abs, and their titers correlate with the clinical condition of the tumors. Interestingly, anti-LMP-1 Abs of IgA isotype were found only in NPC patients. These Abs were absent from the sera of infectious mononucleosis and chronic EBV infection patients, whereas a small fraction (∼5%) of the healthy, EBV-seropositive in iduals were positive for them however, their OD values were much lower than those of NPC patients. These studies demonstrate, for the first time, the potential significance of LMP-1-specific Abs for the diagnosis and prognosis of EBV-associated malignancies, especially of NPC.
Publisher: Oxford University Press (OUP)
Date: 1988
Abstract: DPOAE (2f(1)-f(2)) phase was measured across a 3-octave frequency range from two groups of newborns using ER10B+ and ER10C probe microphones. A marked phase shift was noted in the mid-to-high frequency range for newborn data recorded with the ER10C only. In contrast, the ER10B+ produced phase that was approximately invariant as a function of frequency for most of the range. Probe-related phase shifts can be effectively eliminated by correcting for variations in the phases of the primary tones. Results highlight the importance of detecting and correcting for system-related phase shifts so they are not misinterpreted as cochlear in origin.
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.BBCAN.2022.188784
Abstract: Head and neck squamous cell carcinomas (HNSCCs) are aggressive and clinically challenging tumours that require a multidisciplinary management approach. Despite significant therapy improvements, HNSCC patients have a poor prognosis with a 5-year survival rate of about 65%. As recently recognised key players in cancer, exosomes are extracellular vesicles (EVs) with a diameter of nearly 50-120 nm which transport information from one cell to another. Exosomes are actively involved in various aspects of tumour initiation, development, metastasis, immune regulation, therapy resistance, and therapeutic applications. However, current knowledge of the role of exosomes in the pathophysiological processes of HNSCC is still in its infancy, and additional studies are needed. In this review, we summarise and discuss the relevance of exosomes in mediating local immunosuppression and therapy resistance of HNSCC. We also review the most recent studies that have explored the therapeutic potential of exosomes as cancer vaccines, drug carriers or tools to reverse the drug resistance of HNSCC.
Publisher: American Society for Clinical Investigation
Date: 09-04-2018
DOI: 10.1172/JCI96791
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22542109
Abstract: Supplementary Figures 1-3
Publisher: Elsevier BV
Date: 07-2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2008
Publisher: Wiley
Date: 09-12-1998
DOI: 10.1002/(SICI)1097-0215(19981209)78:6<669::AID-IJC1>3.0.CO;2-B
Abstract: SV40 sequences were investigated by PCR DNA lification followed by filter hybridization in a series of human lymphoproliferative disorders obtained from human-immunodeficiency-virus (HIV)-seronegative and HIV-infected patients. Our PCR and filter-hybridization conditions enabled us to detect SV40 sequences in the range of 10(-4) to 10(-2) genome equivalents per cell. In non-Hodgkin's lymphomas (NHL) from HIV- patients, SV40 footprints were found in 11 out of 79 (13.9%) s les, while in NHL from HIV+ patients SV40 DNA sequences were detected in 2/16 (12.5%). In Hodgkin's disease (HD), SV40 sequences were found in 7/43 (16.3%) and 1/12 (8.3%) in HIV- and HIV+ patients respectively. A slightly higher prevalence of SV40 footprints was observed in reactive lympho-adenopathies both in HIV- (3/9, 33.3%) and in HIV+ (6/17, 35.3%) patients. Sequence analysis of 2 NHL and 2 HD DNA s les established that the lified PCR products belong to the SV40 sequences. SV40 prevalence and load were similar in s les from HIV-seronegative and HIV-infected in iduals, suggesting that SV40 probably does not undergo strong reactivation phenomena in the context of HIV-related immunosuppression. Moreover, the large T-antigen(Tag) expression was detected by immunohistochemistry in 5/18 SV40-DNA-positive s les analyzed however, few tumor cells (<1%) in 3/5 s les displayed positivity for SV40 Tag, while this viral oncoprotein was revealed in several reactive histiocytes present in all 5 SV40-positive tissues. These results suggest that the lymphoid tissue could represent a reservoir for SV40 and may constitute the first step in understanding whether this DNA tumor polyomavirus has a role in the pathogenesis of human lymphoproliferative disorders.
Publisher: Wiley
Date: 14-06-2010
DOI: 10.1002/MED.20211
Abstract: Telomerase is a ribonucleoprotein complex critically involved in extending and maintaining telomeres. Unlike the majority of somatic cells, in which hTERT and telomerase activity are generally silent, normal lymphocytes show transient physiological hTERT expression and telomerase activity according to their differentiation/activation status. During lymphomagenesis, induction of persistent telomerase expression and activity may occur before or after telomere shortening, as a consequence of the different mechanisms through which transforming factors/agents may activate telomerase. Available data indicate that the timing of telomerase activation may allow the distinction of two different lymphomagenetic models: (i) an early activation of telomerase via exogenous regulators of hTERT, along with an increased lymphocyte growth and a subsequent selection of cells with increased transforming potential may characterize several virus-related lymphoid malignancies (ii) a progressive shortening of telomeres, leading to genetic instability which favors a subsequent activation of telomerase via endogenous regulators may occur in most virus-unrelated lymphoid tumors. These models may have clinically relevant implications, particularly for the tailoring of therapeutic strategies targeting telomerase.
Publisher: Springer Science and Business Media LLC
Date: 19-02-2011
DOI: 10.1007/S12185-011-0782-2
Abstract: Since 1995 to date, more than 250 patients with EBV-related diseases received virus-specific CTL. Cell therapy proved to be safe and effective, and achieved some complete remissions also in patients who failed all previous standard treatments. The first clinical results with EBV-specific CTL were obtained for both prophylaxis and treatment of post-transplant lymphoproliferative disease arising in stem cell transplant or solid organ transplant recipients. Based on such encouraging results, the same approach was then extended to other EBV-related diseases, namely Hodgkin's lymphoma, nasopharyngeal carcinoma, and chronic active infection. Nowadays, the modification of the CTL generation protocols and the introduction of new specificities into EBV-specific CTL lines by chimeric antigen receptor transfer allow targeting other viral infections and also non-EBV related malignancies. Aim of this review is to summarize clinical results obtained thus far in adoptive cell therapy approaches with EBV-specific CTL. Moreover, by analyzing ongoing clinical trials, we also provide some insights on the potential future of a successful and paradigmatic history.
Publisher: MDPI AG
Date: 14-03-2019
DOI: 10.3390/IJMS20061280
Abstract: Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For ex le, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery.
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Oxford University Press (OUP)
Date: 23-04-2012
Publisher: Frontiers Media SA
Date: 23-08-2022
Abstract: Metastatic breast cancer (mBC) is a heterogeneous disease with varying responses to treatments and clinical outcomes, still requiring the identification of reliable predictive biomarkers. In this context, liquid biopsy has emerged as a powerful tool to assess in real-time the evolving landscape of cancer, which is both orchestrated by the metastatic process and immune-surveillance mechanisms. Thus, we investigated circulating tumor cells (CTCs) coupled with peripheral T-cell immunity to uncover their potential clinical relevance in mBC. A cohort of 20 mBC patients was evaluated, before and one month after starting therapy, through the following liquid biopsy approaches: CTCs enumerated by a metabolism-based assay, T-cell responses against tumor-associated antigens (TAA) characterized by interferon-γ enzyme-linked immunosorbent spot (ELISpot), and the T-cell receptor (TCR) repertoire investigated by a targeted next-generation sequencing technique. TCR repertoire features were characterized by the Morisita’s overlap and the Productive Simpson Clonality indexes, and the TCR richness. Differences between groups were calculated by Fisher’s, Mann-Whitney or Kruskal-Wallis test, as appropriate. Prognostic data analysis was estimated by Kaplan-Meier method. Stratifying patients for their prognostic level of 6 CTCs before therapy, TAA specific T-cell responses were detected only in patients with a low CTC level. By analyzing the TCR repertoire, the highest TCR clonality was observed in the case of CTCs under the cut-off and a positive ELISpot response (p=0.03). Whereas, at follow-up, patients showing a good clinical response coupled with a low number of CTCs were characterized by the most elevated TCR clonality (p& .05). The detection of CTCs≥6 in at least one time-point was associated with a lower TCR clonality (p=0.02). Intriguingly, by combining overall survival analysis with TCR repertoire, we highlighted a potential prognostic role of the TCR clonality measured at follow-up (p=0.03). These data, whether validated in a larger cohort of patients, suggest that the combined analysis of CTCs and circulating anti-tumor T-cell immunity could represent a valuable immune-oncological biomarker for the liquid biopsy field. The clinical application of this promising tool could improve the management of mBC patients, especially in the setting of immunotherapy, a rising approach for BC treatment requiring reliable predictive biomarkers.
Publisher: Proceedings of the National Academy of Sciences
Date: 02-11-2015
Abstract: Non-Hodgkin lymphomas (NHLs) are associated with HIV-1 infection, but the HIV1 genome is not detectable in malignant B cells. Here we show that variants of the HIV-1 matrix protein p17 (vp17s) are detected in the NHL specimens of HIV+ patients. These vp17s are more frequently detected in HIV+ patients with NHL than in patients without NHL. These vp17s display a potent B-cell growth-promoting activity, which is exerted by activating the Akt signaling pathway. Results obtained by CD spectroscopy and thermal denaturation suggest that mutation-induced protein destabilization may lead to a conformational change potentially responsible for the viral protein to promote B-cell growth. Our results suggest that vp17s may have a role in sustaining lymphomagenesis, thus offering new opportunities to prevent and/or treat HIV-associated NHLs.
Publisher: Informa UK Limited
Date: 31-07-2017
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/931952
Abstract: The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this strategy of intervention. In particular, clinical trials using adoptive T-cell therapies disclosed encouraging results, particularly in the context of Epstein-Barr-virus- (EBV-) related tumors. Nevertheless, the rate of complete clinical responses is still limited, thus stimulating the development of more effective therapeutic protocols. Considering the relevance of innate immunity in controlling both infections and cancers, innovative immunotherapeutic approaches should take into account also this compartment to improve clinical efficacy. Evidence accumulated so far indicates that innate immunity effectors, particularly NK cells, can be exploited with therapeutic purposes and new targets have been recently identified. We herein review the complex interactions between EBV and innate immunity and summarize the therapeutic strategies involving both adaptive and innate immune system, in the light of a fruitful integration between these immunotherapeutic modalities for a better control of EBV-driven tumors.
Publisher: Elsevier BV
Date: 03-1995
DOI: 10.1016/0046-8177(95)90070-5
Abstract: In the present study the clinical and pathological evolution of a reactive-like B-cell lymphoproliferative disorder with an unusually high content of T cells is described. Immunogenotypic analysis showed that the same phenotypically atypical B-cell clone, characterized by the unusual presence of an immunoglobulin (Ig)K gene rearrangement, with the heavy chain (IgH) gene in germline configuration, was invariantly present in all phases of the disease. The disorder showed an indolent course for a long period of time during which the clonal B-cell population coexisted with an abundant, reactive T-cell component in different locations of the disease. These findings, together with the observation of spontaneous progression and regression phases of the disorder and its responsiveness to corticosteroids, suggest that functional interactions between the B-cell clone and the polyclonal infiltrating T cells probably were involved in the pathogenesis of the disease. After the administration of the antiblastic treatment, a progressive reduction of the reactive T-cell component was observed with the concomitant evolution to a diffuse large cell (immunoblastic) B-cell lymphoma and the appearance of an IgH gene rearrangement. The biological characteristics and the clinical evolution of the case described here are similar to those reported for the so-called "T-cell-rich B-cell lymphomas" (TCRBCLs). These findings suggest that the T-cell-rich pattern may identify a group of B-cell lymphoproliferations with common pathogenetic mechanisms and clinical behavior.
Publisher: Wiley
Date: 06-11-2018
DOI: 10.1002/HON.2562
Abstract: Despite antiretroviral therapy, HIV+ in iduals still have increased risk to develop lymphomas, including marginal zone lymphomas, suggesting that factors other than HIV-related immunosuppression are probably acting as lymphomagenic factors in the HIV setting. The possible pathogenic involvement of HIV p17 protein variants was investigated in a particularly informative case of HIV-related splenic marginal zone lymphoma, which was negative for oncogenic virus infections, thus allowing us to assess the possible direct contribution of these HIV-encoded proteins to lymphomagenesis. The presence of p17 protein was analyzed by immunohistochemistry in lymphoma tissue. Recombinant p17 protein derived from the dominant sequence detected in plasma and lymphoma biopsy was characterized for B-cell proliferation, clonogenicity in soft agar, in vitro tube formation and wound healing. Intracellular signaling was investigated by immunoblotting. HIV p17 protein was detected in reactive lymphoid follicles but not within lymphoma cells. An identical dominant variant p17 sequence, p17-Lyrm, carrying a 117 to 118 Ala-Ala insertion was detected in both plasma and lymphoma tissue. Recombinant p17-Lyrm enhanced B-cell proliferation and clonogenicity promoted the formation of capillary-like structures and enhanced endothelial cell migration. Unlike reference p17, the p17-Lyrm variant enhanced the activation of Akt and ERK, critical kinases in lymphomagenesis. p17-Lyrm clonogenic activity was dependent on the activation of Akt but not of ERK1/2. These results indicated that HIV p17 variants with distinct molecular signatures and functional properties may accumulate in lymphoid tissues of HIV-infected in iduals where they may act as a local stimulus promoting the development of lymphomas.
Publisher: Wiley
Date: 24-09-1999
DOI: 10.1002/(SICI)1097-0215(19990924)83:1<5::AID-IJC2>3.0.CO;2-U
Abstract: The heritable defects of BRCA1 and BRCA2 genes have been shown to predispose to breast and ovarian cancers. In a previous report, we analyzed 46 Italian families with breast and/or ovarian cancer for BRCA1 mutations. In the present study, those families and 11 others were screened for BRCA2 mutations the newly enrolled families were also analyzed for the BRCA1 gene. The coding region and splice boundaries of BRCA2 and BRCA1 genes were assessed by the protein-truncation test and single-strand conformational polymorphism. A total of 20 different mutations were found in 21 families (37%). A total of 9 families (16%) showed mutations in the BRCA1 gene, including the one new mutation identified in this study (5382insC), and 12 families (21%) presented mutations in the BRCA2 gene. BRCA2-mutated families presented breast and ovarian cancers or breast cancers only, whereas most BRCA1-mutated families presented ovarian cancer alone or in association with breast cancer. All the BRCA2 mutations led to a truncated protein: 6 were frameshift mutations, 4 were non-sense mutations and 2 involved the intronic invariant region leading to splice variants. Therefore, in the Italian population, the cumulative proportion of BRCA1 and BRCA2 mutations was within the range observed in other studies (37%), with higher involvement of BRCA2 than of BRCA1. Many families in which no mutations were found presented a very high incidence of breast and/or ovarian cancer. Among the 36 BRCA1 and BRCA2 wild-type families, 24 presented at least 4 cancer cases, indicating the existence of other important predisposing genes.
Publisher: American Association for Cancer Research (AACR)
Date: 15-04-2013
DOI: 10.1158/1078-0432.CCR-12-2537
Abstract: Purpose: Induction of viral lytic cycle, which induces death of host cells, may constitute a useful adjunct to current therapeutic regimens for Epstein–Barr virus (EBV)-driven malignancies. Human telomerase reverse transcriptase (hTERT), essential for the oncogenic process, may modulate the switch from latent to lytic infection. The possible therapeutic role of hTERT inhibition combined with antiviral drugs was investigated. Experimental Design: EBV-negative BL41 and convertant EBV-positive BL41/B95.8 Burkitt's lymphoma cell lines and lymphoblastoid cell lines (LCL) were infected with retroviral vector encoding short hairpin RNA (shRNA) anti-hTERT and cultured with or without the prodrug ganciclovir. The effects on EBV lytic replication, cell proliferation, and apoptosis were characterized. Results: hTERT silencing by shRNA induced the expression of BZLF1, EA-D, and gp350 EBV lytic proteins and triggered a complete lytic cycle. This effect was associated with downregulation of BATF, a negative regulator of BZLF1 transcription. hTERT silencing also resulted in antiproliferative and proapoptotic effects. In particular, hTERT inhibition induced an accumulation of cells in the S-phase, an effect likely due to the dephosphorylation of 4E-BP1, an AKT1-dependent substrate, which results in a decreased availability of proteins needed for cell-cycle progression. Besides inducing cell death through activation of complete EBV lytic replication, hTERT inhibition triggered AKT1/FOXO3/NOXA–dependent apoptosis in EBV-positive and -negative Burkitt's lymphoma cells. Finally, ganciclovir enhanced the apoptotic effect induced by hTERT inhibition in EBV-positive Burkitt's lymphomas and LCLs. Conclusions: These results suggest that combination of antiviral drugs with strategies able to inhibit hTERT expression may result in therapeutically relevant effects in patients with EBV-related malignancies. Clin Cancer Res 19(8) 2036–47. ©2013 AACR.
Publisher: Elsevier BV
Date: 2006
Publisher: American Association for Cancer Research (AACR)
Date: 06-2019
DOI: 10.1158/2326-6066.CIR-18-0650
Abstract: Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8+ T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8+ dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α+ DCs to drive efficient cross-priming of antigen-specific CD8+ T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α+ DCs, and polyfunctional CD8+ T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8+ T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8+ T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8+ T-cell responses for control of solid tumors.
Publisher: American Society of Hematology
Date: 15-10-2009
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.JID.2018.06.190
Abstract: EGFR overexpression is associated with squamous cell carcinoma development. Altered endocytosis and polarization of receptor tyrosine kinases, including EGFR, affect migration and invasion in three-dimensional culture. These studies have been completed via genetic sequencing, cell line, or three-dimensional in vitro and in vivo murine models. Here, we describe an imaging method that allows ex vivo examination of ligand-induced endocytosis of EGFR in non-dissociated human tumors. We analyzed sets of tumor s les from advanced cutaneous squamous cell carcinoma and head and neck squamous cell carcinoma, actinic keratosis, intraepidermal carcinoma, and cutaneous squamous cell carcinoma. We show that EGFR endocytosis is dysregulated in advanced SCC and correlates with anti-EGFR monoclonal antibody therapy outcomes. In actinic keratosis, intraepidermal carcinoma, and well-differentiated cutaneous squamous cell carcinoma, different patterns of epidermal growth factor ligand uptake and binding were observed at the leading edge of different dysplastic lesions, suggesting that these differences in EGFR endocytosis might influence the metastatic potential of dysplastic squamous epithelium. These studies in live ex vivo human tumors confirm that endocytosis dysregulation is a physiological event in human tumors and has therapeutic implications.
Publisher: Springer Science and Business Media LLC
Date: 02-2012
DOI: 10.1186/BCR3121
Publisher: MDPI AG
Date: 25-07-2021
Abstract: Drugs selectively targeting replication stress have demonstrated significant preclinical activity, but this has not yet translated into an effective clinical treatment. Here we report that targeting increased replication stress with a combination of Checkpoint kinase 1 inhibitor (CHK1i) with a subclinical dose of hydroxyurea targets also promotes pro-inflammatory cytokine/chemokine expression that is independent of cGAS-STING pathway activation and immunogenic cell death in human and murine melanoma cells. In vivo, this drug combination induces tumour regression which is dependent on an adaptive immune response. It increases cytotoxic CD8+ T cell activity, but the major adaptive immune response is a pronounced NKT cell tumour infiltration. Treatment also promotes an immunosuppressive tumour microenvironment through CD4+ Treg and FoxP3+ NKT cells. The number of these accumulated during treatment, the increase in FoxP3+ NKT cells numbers correlates with the decrease in activated NKT cells, suggesting they are a consequence of the conversion of effector to suppressive NKT cells. Whereas tumour infiltrating CD8+ T cell PD-1 and tumour PD-L1 expression was increased with treatment, peripheral CD4+ and CD8+ T cells retained strong anti-tumour activity. Despite increased CD8+ T cell PD-1, combination with anti-PD-1 did not improve response, indicating that immunosuppression from Tregs and FoxP3+ NKT cells are major contributors to the immunosuppressive tumour microenvironment. This demonstrates that therapies targeting replication stress can be well tolerated, not adversely affect immune responses, and trigger an effective anti-tumour immune response.
Publisher: Wiley
Date: 15-05-1990
Abstract: Understanding of the leukemic evolution of human non-Hodgkin's lymphomas is hindered by the lack of appropriate animal models. For this purpose, a highly leukemic cell line NQ22, derived from a MCF 247 murine leukemia virus (MuLV)-induced murine T-cell lymphoma, was established, and its preliminary characterization is described. The NQ22 cell line is easily transplantable subcutaneously (s.c.) into syngeneic AKR mice exhibiting early peripheral blood invasion and widespread dissemination with a leukemic pattern of infiltration. Such peculiar in vivo behavior is a stable phenotypic feature, probably determined genetically. Biological and differentiation characteristics of the NQ22 cell line were analyzed and compared to those of other non-leukemic T-lymphoma lines. In addition, no evidence of possible involvement of plasminogen activator (PA) enzymes and of their inhibitors (PAI) in the spreading ability of NQ22 cells was observed.
Publisher: Oxford University Press (OUP)
Date: 11-09-2007
DOI: 10.1093/JNCI/DJM118
Publisher: Wiley
Date: 08-1993
Publisher: Oxford University Press (OUP)
Date: 20-04-2004
DOI: 10.1093/JNCI/DJH102
Abstract: Ocular adnexal lymphomas may be antigen-driven disorders however, the source of the putative antigen or antigens is still unknown. Hence, we assessed whether Chlamydiae infection is associated with the development of ocular adnexal lymphomas. The presence of Chlamydia psittaci, trachomatis, and pneumoniae DNA was investigated by polymerase chain reaction in 40 ocular adnexal lymphoma s les, 20 nonneoplastic orbital biopsies, 26 reactive lymphadenopathy s les, and peripheral blood mononuclear cells (PBMCs) from 21 lymphoma patients and 38 healthy in iduals. Seven patients with chlamydia-positive PBMCs were treated with the antibiotic doxycycline, and objective response was assessed in four patients with measurable lymphoma lesions. Differences in Chlamydiae DNA detection between the case patients and the control subjects were analyzed using the Fisher exact test. All statistical tests were two-sided. Thirty-two of the 40 (80%) ocular adnexal lymphoma s les carried C. psittaci DNA, whereas all lymphoma s les were negative for C. trachomatis and C. pneumoniae. In contrast, none of the 20 nonneoplastic orbital biopsies (0% versus 80% P<.001) and only three of 26 (12%) reactive lymphadenopathy s les (12% versus 80% P<.001) carried the C. psittaci DNA. Nine of 21 (43%) patients with chlamydia-positive lymphomas carried C. psittaci DNA in their PBMCs, whereas none (0%) of the healthy PBMC donors carried C. psittaci DNA in their PBMCs (43% versus 0% P<.001). One month after doxycycline treatment, chlamydial DNA was no longer detectable in the PBMCs of all seven treated patients, and objective response was observed in two of the four evaluable patients. Patients with ocular adnexal lymphoma had a high prevalence of C. psittaci infection in both tumor tissue and PBMCs. Persistent C. psittaci infection may contribute to the development of these lymphomas, as was also supported by the clinical responses observed in this study with C. psittaci-eradicating antibiotic therapy.
Publisher: Wiley
Date: 11-06-2003
DOI: 10.1002/JCP.10263
Abstract: Epstein-Barr virus (EBV), a ubiquitous human herpes virus, is associated with an increasing number of lymphoid and epithelial malignancies. The ability of the virus to establish life-long persistent infections and induce growth transformation is related to the function of a set of viral proteins that are variously expressed in both normal and malignant cells. Recent evidence indicates that these viral proteins are able to usurp cellular pathways that promote the cell growth and survival, while impairing anti-viral immune responses. Elucidation of the mechanisms by which EBV induces cell transformation and escapes host immune control provides the rational background for the design of new strategies of intervention for EBV-related malignancies.
Publisher: Springer Science and Business Media LLC
Date: 04-1993
DOI: 10.1038/BJC.1993.125
Abstract: The effects of dexamethasone, a synthetic glucocorticoid, and of N,N-dimethylformamide on in vitro growth and differentiation and on proto-oncogene expression of human rhabdomyosarcoma cells were studied. RD/18 clone cells (derived from the embryonal rhabdomyosarcoma cell line RD) treated with 100 nM dexamethasone showed an almost complete block of differentiation: about 5% myosin-positive cells were observed after 2 weeks of culture in dexamethasone-supplemented differentiation medium, compared to 20% of untreated cultures. Dexamethasone also induced a 20-30% growth inhibition and a more flattened morphology. The treatment with N,N-dimethylformamide induced a significantly increased proportion of myosin-positive cells (reaching about 30%) and a 40% growth inhibition. Induction of differentiation inversely correlated with the levels of c-myc proto-oncogene expression: after a 2 week culture dexamethasone-treated cells showed the highest c-myc expression and N,N-dimethylformamide-treated cells the lowest. Culture conditions per se down-modulated c-erbB1 and up-regulated c-jun expression, with no relationship to the differentiation pattern. Other proto-oncogenes were not expressed (c-sis, N-myc, c-mos, c-myb) or were not modulated (c-fos, c-raf). Therefore dexamethasone and N,N-dimethylformamide, both causing a decreased growth rate, showed opposing actions on myogenic differentiation and on c-myc proto-oncogene expression of human rhabdomyosarcoma cells.
Publisher: Wiley
Date: 05-2000
DOI: 10.1002/(SICI)1097-0215(20000501)86:3<375::AID-IJC12>3.0.CO;2-Z
Abstract: We have previously demonstrated that 13-cis-retinoic acid (RA), 9-cis-RA and all-trans-RA (ATRA) powerfully inhibit the proliferation of Epstein-Barr virus-immortalized B-lymphoblastoid cell lines (LCLs). The aim of the present study was to assess whether these compounds are effective at inhibiting the growth of B cells at more advanced stages of lymphomagenesis, including fully transformed B lymphocytes. To this end, c-myc-transfected LCLs (myc-LCLs) and Burkitt's lymphoma (BL) cell lines were used. We report that 13-cis-RA, 9-cis-RA and ATRA also markedly inhibit the proliferation of myc-LCLs by inducing G(0)/G(1) growth arrest as well as enhancing rates of apoptosis. Conversely, all but 1 (DG75) of the 8 BL cell lines investigated were poorly RA-responsive. Moreover, unlike LCLs and myc-LCLs, RA-treated DG75 cells rapidly resumed proliferation upon drug removal. Analysis of cell cycle-regulatory proteins showed that, as in LCLs, strong up-regulation of p27(Kip-1) and increased levels of under-phosphorylated pRb and p130 were detected in RA-treated DG75 cells. While the catalytic activity of all 3 G(1)-associated CDKs (CDK2, CDK4 and CDK6) was strongly inhibited in RA-treated LCLs, only CDK2-associated kinase activity was reduced in DG75 cells arrested in G(0)/G(1) by RA. Moreover, RA-treated DG75 cells failed to show the down-regulation of cyclin D3 observed in LCLs. Use of receptor-selective agonists and antagonists showed that in LCLs and RA-responsive BL cells, RA-induced growth arrest is mainly mediated by RARalpha. The RARalpha-selective agonist Ro 40-6055 was also effective at very low concentrations (10(-10) M). Nevertheless, comparable levels of RARalpha mRNA were found in RA-responsive and -resistant BL cell lines, indicating that mechanisms different from transcriptional deregulation of RARalpha probably underlie the differential responsiveness of BL cells.
Publisher: Elsevier BV
Date: 02-2022
DOI: 10.1016/J.TRECAN.2022.10.009
Abstract: Enhancing natural killer (NK) cell-based innate immunity has become a promising strategy for immunotherapy against hard-to-cure solid cancers. Monoclonal antibody (mAb) therapy has been used to activate NK-cell-mediated antibody-dependent cellular cytotoxicity (ADCC) towards solid cancers. Cancer cells, however, can subvert immunosurveillance using multiple immunosuppressive mechanisms, which may h er NK cell ADCC. Mechanisms to safely enhance ADCC by NK cells, such as utilizing temporary inhibition of receptor endocytosis to increase antibody presentation from target to effector cells can now be used to enhance NK-cell-mediated ADCC against solid tumors. This review summarizes and discusses the recent advances in the field and highlights current and potential future use of immunotherapies to maximize the therapeutic efficacy of innate anticancer immunity.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.CANLET.2015.08.007
Abstract: Post-transplant lymphoproliferative disorders (PTLDs) represent the most severe complication of both solid organ and hematopoietic stem cell transplantation. The Epstein-Barr Virus (EBV) is the main driver of PTLD, particularly those occurring early after transplantation. EBV-driven malignancies are associated with selective expression of latent viral proteins, but uncontrolled lytic replication may favor early phases of cell transformation. Besides immunodepression, persistent immune activation and chronic inflammation play an important role in both virus reactivation and expansion of EBV-infected B cells. EBV-induced immortalization requires the expression of telomerase. TERT, the rate-limiting component of the telomerase complex, is central in the switch from the lytic to the latent viral program, and TERT inhibition induces the EBV lytic cycle and cell death. Immunotherapy and combination of EBV lytic cycle inducers with antiviral drugs are promising strategies to improve the treatment of PTLD patients. This review is aimed at providing an update on the intriguing association between EBV and PTLD, mainly focusing on cases arising after kidney and liver transplantation, which account for the vast majority of transplants.
Publisher: Frontiers Media SA
Date: 12-01-2022
DOI: 10.3389/FIMMU.2021.791958
Abstract: Trastuzumab induced a high rate of pathological Complete Response (pCR) in patients affected by locally advanced HER2-positive Breast Cancer (HER2-BC), by exploiting immune-mediated mechanisms as Antibody-Dependent Cell Cytotoxicity (ADCC) involving Natural Killer (NK) cells. Host’s immune genetics could influence the response to therapy, through the expression of variants that characterize NK receptors involved in ADCC effectiveness. Killer cell immunoglobin-like receptors (KIRs) modulate NK cell activity through their binding to class-I Human Leukocyte Antigens (HLA). The impact of the KIR/HLA repertoire in HER2-BC is under study. We characterized KIR genotypes of 36 patients with locally advanced HER2-BC treated with neoadjuvant chemotherapy including trastuzumab. We monitored pCR achievement before surgery and Disease-Free Survival (DFS) and Overall Survival (OS) after adjuvant therapy. HLA, and Fc gamma receptor IIIa (FcγR3A) and IIa (FcγR2A) were genotyped through targeted PCR and Sanger sequencing in 35/36 patients. The KIR-HLA combinations were then described as functional haplotypes and ided in two main categories as inhibitory tel A and stimulatory tel B. Trastuzumab-dependent ADCC activity was monitored with an in vitro assay using a HER2-BC model and patients’ NK cells.We observed a higher frequency of KIR activators in patients who achieved a pCR compared to partial responders. During the study of functional haplotypes, in iduals carrying a tel B haplotype showed greater ADCC efficiency than tel A cases. In subjects with the tel A haplotype the presence of the favorite V allele in FcγR3A receptor improved their low ADCC levels. Regardless of the haplotypes detected, the presence of KIR3DL2/HLA-A03 or A11 was always associated with the FcγR3A V allele, and therefore correlated with greater ADCC efficiency. However, this particular KIR receptor appeared to harm DFS and OS. Indeed, patients with tel B haplotype without KIR3DL2/HLA-A03 or A11 showed a better outcome. Our data, although preliminary, suggested a potential predictive role for KIR haplotype tel B, in identifying patients who achieve a pCR after neoadjuvant treatment with trastuzumab, and supported a negative prognostic impact of KIR3DL2/HLA-A03 or A11 in the adjuvant setting.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2002
Publisher: Springer Science and Business Media LLC
Date: 28-05-2015
Abstract: Epstein–Barr virus (EBV)-associated malignancies, as well as lymphoblastoid cell lines (LCLs), obtained in vitro by EBV infection of B cells, express latent viral proteins and maintain their ability to grow indefinitely through inappropriate activation of telomere-specific reverse transcriptase (TERT), the catalytic component of telomerase. Our previous studies demonstrated that high levels of TERT expression in LCLs prevent the activation of EBV lytic cycle, which is instead triggered by TERT silencing. As lytic infection promotes the death of EBV-positive tumor cells, understanding the mechanism(s) by which TERT affects the latent/lytic status of EBV may be important for setting new therapeutic strategies. BATF, a transcription factor activated by NOTCH2, the major NOTCH family member in B cells, negatively affects the expression of BZLF1 , the master regulator of viral lytic cycle. We therefore analyzed the interplay between TERT, NOTCH and BATF in LCLs and found that high levels of endogenous TERT are associated with high NOTCH2 and BATF expression levels. In addition, ectopic expression of TERT in LCLs with low levels of endogenous telomerase was associated with upregulation of NOTCH2 and BATF at both mRNA and protein levels. By contrast, infection of LCLs with retroviral vectors expressing functional NOTCH2 did not alter TERT transcript levels. Luciferase reporter assays, demonstrated that TERT significantly activated NOTCH2 promoter in a dose-dependent manner. We also found that NF- κ B pathway is involved in TERT-induced NOTCH2 activation. Lastly, pharmacologic inhibition of NOTCH signaling triggers the EBV lytic cycle, leading to the death of EBV-infected cells. Overall, these results indicate that TERT contributes to preserve EBV latency in B cells mainly through the NOTCH2/BAFT pathway, and suggest that NOTCH2 inhibition may represent an appealing therapeutic strategy against EBV-associated malignancies.
Publisher: Elsevier BV
Date: 06-1999
Publisher: American Society for Microbiology
Date: 15-02-2005
DOI: 10.1128/JVI.79.4.2643-2649.2005
Abstract: The origin and biological significance of deletions at the 3′ end of the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) gene are still controversial. We herein demonstrate that LMP-1 deletion mutants are highly associated with human immunodeficiency virus-related Hodgkin's lymphoma (HIV-HL) of Italian patients (29 of 31 cases 93.5%), a phenomenon that is not due to a peculiar distribution of EBV strains in this area. In fact, although HIV-HL patients are infected by multiple EBV variants, we demonstrate that LMP-1 deletion mutants preferentially accumulate within neoplastic tissues. Subcloning and sequencing of the 3′ LMP-1 ends of two HIV-HL genes in which both variants were present showed the presence of molecular signatures suggestive of a likely derivation of the LMP-1 deletion mutant from a nondeletion ancestor. This phenomenon likely occurs within tumor cells in vivo, as shown by the detection of both LMP-1 variants in single microdissected Reed-Sternberg cells, and may at least in part explain the high prevalence of LMP-1 deletions associated with HIV-HL.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.22542109.V1
Abstract: Supplementary Figures 1-3
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-08-2012
Abstract: The pathogenic association between Chlamydophila psittaci (Cp) and ocular adnexal marginal zone lymphoma (OAMZL) and the efficacy of doxycycline monotherapy have been investigated in retrospective series with variations in stage, management, and follow-up duration. To our knowledge, this is the first international phase II trial aimed at clarifying Cp prevalence and activity of first-line doxycycline in a homogeneous series of consecutive patients with newly diagnosed stage I OAMZL. Forty-seven patients were registered. Tumor tissue, conjunctival swabs, and peripheral blood from 44 patients were assessed for seven Chlamydiaceae infections by three polymerase chain reaction protocols. Thirty-four patients with measurable or parametrable disease were treated with doxycycline and assessed for chlamydial eradication and lymphoma response (primary end point). Cp DNA was detected in biopsies of 39 patients (89%) no other Chlamydiaceae were detected. Twenty-nine patients had Cp DNA in baseline swabs and/or blood s les and were evaluable for chlamydial eradication, which was achieved in 14 patients (48%). Lymphoma regression was complete in six patients and partial in 16 (overall response rate, 65% 95% CI, 49% to 81%) 11 had stable disease, and one had progressive disease. At a median follow-up of 37 months (range, 15 to 62 months), 20 patients remained relapse free (5-year progression-free survival [PFS] ± standard deviation, 55% ± 9%). Cp eradication was associated with improved response rate (86% v 47% P = .02) and 5-year PFS (68% v 47% P = .11). Upfront doxycycline is a rational and active treatment for patients with stage I Cp-positive OAMZL. Lymphoma regression is consequent to Cp eradication, which can easily be monitored on conjunctival and blood s les. Prospective trials aimed at identifying more effective administration schedules for doxycycline are warranted.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2000
Abstract: Primary effusion lymphoma (PEL) selectively involves the serous body cavities, occurs predominantly in immunodeficient patients and is infected consistently by human herpesvirus type-8. PEL is also frequently infected by Epstein-Barr virus (EBV). The precise pathogenetic role of EBV coinfection in PEL is not fully understood. The lymphoma fails to express the EBV transforming proteins EBNA-2 and LMP-1, whereas it expresses EBNA-1 (latency I phenotype). Some studies have hypothesized that other EBV-positive lymphomas expressing the latency I phenotype may associate with specific molecular variants of EBNA-1, although this issue has not been addressed in PEL. On this basis, this study is aimed at a detailed molecular characterization of EBV in PEL. Fifteen EBV positive PEL (12 AIDS-related, one post-transplant, two arising in immunocompetent hosts) were subjected to molecular characterization of the viral genes EBNA-1 and LMP-1, as well as definition of EBV type-1/type-2. The EBNA-1 gene displayed a high degree of heterogeneity in different cases of PEL, with seven distinct recognizable variants and subvariants. A wild-type LMP-1 gene was detected in 10/15 cases, whereas in 5/15 cases the LMP-1 gene harbored a deletion spanning codons 346-355. EBV type-1 occurred in 11/15 PEL whereas EBV type-2 occurred in 4/15 cases. Despite a high degree of genetic variability of the virus in different PEL cases, each single PEL harbored only one EBV variant, consistent with monoclonality of infection and suggesting that infection preceded clonal expansion. Overall, our results indicate that: (1) in idual PEL cases consistently harbor a single EBV strain (2) EBNA-1 displays a high degree of heterogeneity in different PEL cases (3) no specific EBV genotype preferentially associates with PEL.
Publisher: American Society for Microbiology
Date: 15-05-2014
DOI: 10.1128/JVI.03142-13
Abstract: Exogenous HIV-1 matrix protein p17 (p17) deregulates the function of different cells after its N-terminal loop (AT20) binding to the chemokine receptors CXCR1 and CXCR2. One site within AT20 has been recently found to be the major determinant of viral fitness following transmission of simian immunodeficiency virus (SIV) to the human host. Therefore, we sought to determine whether SIV matrix protein (MA) was already capable of interacting with CXCR1 and CXCR2 and mimic p17 biological activities rather than this being a newly acquired function during host adaptation. We show here that SIV MA binds with the same affinity of p17 to CXCR1 and CXCR2 and displays both p17 proangiogenic on human primary endothelial cells and chemotactic activity on human primary monocytes and B cells. However, SIV MA exhibited a higher degree of plasticity than p17 in the C terminus, a region known to play a role in modulating B cell growth. Indeed, in contrast to p17, SIV MA was found to activate the phosphatidylinositol 3-kinase/Akt signaling pathway and strongly promote B cell proliferation and clonogenic activity. Interestingly, we have recently highlighted the existence of a Ugandan HIV-1 strain-derived p17 variant (S75X) with the same B cell growth-promoting activity of SIV MA. Computational modeling allowed us to hypothesize an altered C terminus/core region interaction behind SIV MA and S75X activity. Our findings suggest the appearance of a structural constraint in the p17 C terminus that controls B cell growth, which may help to elucidate the evolutionary trajectory of HIV-1. IMPORTANCE The HIV-1 matrix protein p17 (p17) deregulates the biological activities of different cells after binding to the chemokine receptors CXCR1 and CXCR2. The p17 functional domain responsible for receptors interaction includes an amino acid which is considered the major determinant of SIV replication in humans. Therefore, we sought to determine whether SIV matrix protein (SIV MA) already had the ability to bind to both chemokine receptors rather than being a function newly acquired during host adaptation. We show here that SIV MA binds to CXCR1 and CXCR2 and fully mimics the p17 proangiogenic and chemokine activity. However, it differs from p17 in its ability to signal into B cells and promote B cell growth and clonogenicity. Computational analysis suggests that the accumulation of mutations in the C-terminal region may have led to a further SIV MA adaptation to the human host. This finding in turn sheds light on the evolutionary trajectory of HIV-1.
Publisher: MDPI AG
Date: 11-05-2021
Abstract: The heterogeneity of tumor infiltrating lymphocytes (TILs) is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune-cell subsets in brain metastasis tissues to test immunosuppressive routes involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune-cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and IBA-1, and analyzed an average of 15,000 cells per s le. Classifying tumors as either high ( %) or low ( %) TILs, we found that increased TILs density correlated with survival. Phenotyping these TILs we found tumors with low TILs had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p 0.01) as well as in their microenvironment (p 0.001). Contrastingly, the tumors with high TILs displayed higher levels of microglia, as measured by IBA-1 expression. Low TILs-tumors displayed CD8+ T-cells that co-express VISTA (p 0.01) significantly more compared to high TILs group, where CD8+cells significantly co-express IBA-11 (p 0.05). These results were supported by RNA analysis of a publicly available, independent cohort. Our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1157
Publisher: Bentham Science Publishers Ltd.
Date: 06-2009
DOI: 10.2174/187153009788452435
Abstract: Retinoids are vitamin A derivatives that critically regulate several physiological and pathological processes, including immune functions and cancer development. These biological response modifiers exert their pleiotropic effects through the interaction with nuclear receptors, defined as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These ligand-activated nuclear receptors induce the transcription of target genes by binding to responsive elements in the promoter regions. RARs and RXRs are also capable to interact with other nuclear receptors, thus expanding their spectrum of action on gene expression. Evidence has been accumulated indicating that retinoids may exert beneficial effects in both immune-mediated disorders and tumors. With regard to cancer, retinoids directly target neoplastic cells by inducing differentiation, inhibiting cell growth or promoting survival. However, the efficacy of these compounds in cancer treatment probably resides in their ability to modulate also the function of immune effectors. Vitamin A derivatives are currently used in the therapy of acute promyelocytic leukemia and of cutaneous T cell lymphomas, but they could be effective also on B-cell malignancies. Clinical trials are ongoing to test their efficacy in solid tumors. In this review, we give a broad depiction of how retinoids influence the function of immune effectors and affect growth and survival of hematological malignancies. This with the aim to better understand the clinical effects of retinoid-based therapies and provide the rationale to combine retinoids with other active compounds in new synergistic treatment strategies.
Publisher: Wiley
Date: 02-2010
DOI: 10.1111/J.1399-0039.2009.01414.X
Abstract: This investigation was focused on the contribution of in idual human leukocyte antigen (HLA)-DR and -DQ alleles to the human hepatitis C virus (HCV)(+) non-Hodgkin's lymphoma (NHL), with and without mixed cryoglobulinemia (MC), to study whether in idual HLA class II alleles are expressed preferentially or equally in human HCV-specific NHL. For this purpose, peripheral blood mononuclear cells were obtained from two groups of patients with HCV(+) NHL and with or without MC (70 and 71 cases, respectively), and from 4575 blood donors. Eighty-three subjects with HCV infection only, and 118 patients with MC, only without lymphoma, were added as additional control groups. In idual HLA-DR and -DQ alleles were determined using high-resolution sequence-based typing and then data were collected by considering the HLA-DRB1 and DQB1 supertypes on the basis of common structural and functional features, proposed by in silico Bioinformatic studies. From the data, it is evidenced that the DR5-DQ3 HLA combination was strongly associated with the HCV (+) MC (+) NHL group of patients compared with bone marrow donor population (P<or= 0.001, RR = 2.498), while the contribution of DR1-DQ1 was higher in HCV (+) NHL without MC (P<or= 0.001, RR = 2.519). Thus, cryoglobulinemia clinical manifestation was found to be correlated with the preferential use of HLA DR-DQ combination in HCV-associated NHL. These data provide new insight into HCV-associated lymphoproliferative pathogenesis.
Publisher: Wiley
Date: 23-10-1998
DOI: 10.1002/(SICI)1097-0215(19981023)79:5<481::AID-IJC6>3.0.CO;2-X
Abstract: gp350 of Epstein-Barr virus (EBV) induces a strong immune response in EBV-infected in iduals, but relatively little is known about the clinical relevance of this response in patients with different EBV-associated malignancies and other diseases. Using our gp350-expressing cell clones, we studied gp350-specific humoral immune responses in the sera of in iduals with nasopharyngeal carcinoma (NPC), chronic symptomatic EBV infection (CEI), Hodgkin's disease (HD), acute infectious mononucleosis (IM) and healthy EBV-seropositive in iduals (HI). The titres of antibody-dependent cellular cytotoxicity (ADCC) antibodies were highest in HI followed by CEI, HD and NPC. EBV-neutralizing (NA) and gp350-specific IgG antibody profiles in these conditions were: CEI > HI > NPC > HD, whereas IgA titres were the highest in NPC sera followed by CEI and HD. The sera from IM patients were found to be negative for gp350-specific ADCC and IgA activities. Sera from HI were also negative for gp350-specific IgA. A significant positive correlation was found between serum gp350 IgA and viral capsid antigen IgA and a significant negative one between IgM and ADCC titres. High IgA titres were also found in CEI and EBV-genome positive HD in addition to NPC. Importantly, gp350-specific IgA titres were of prognostic value in NPC patients. Our data provide new insights about the clinical relevance of gp350-specific immune responses in these diseases.
Publisher: Wiley
Date: 29-12-2020
DOI: 10.1111/LIV.14667
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2014
Publisher: Wiley
Date: 15-05-1990
Abstract: Six AIDS-related NHLs from direct blood-stream HIV-infected patients were characterized for clonality, maturation cell characteristics, activation of c-myc proto-oncogene and presence of HIV and EBV genomes. Four out of the 6 AIDS-related NHLs were of immature B-cell origin, contrasting with the lower frequency (2 out of 31) of immature B-cell NHLs occurring in HIV-negative patients. Moreover, 3 out of the 4 AIDS-related pre-B-NHLs were extranodal lymphomas. C-myc translocations or rearrangements were not found in Italian AIDS-related NHLs, unlike c-myc activation which had a high prevalence in the American series of AIDS-related NHLs. HIV and EBV are not, or only occasionally, directly involved in AIDS-related NHL pathogenesis since HIV genome has never been found in the neoplastic clones and EBV genome was detected in only 1 out of the 6 lymphomas analyzed.
Publisher: MDPI AG
Date: 21-03-2022
Abstract: Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease. To target nPKC-θ, we designed a novel PKC-θ peptide inhibitor (nPKC-θi2) that selectively inhibits nPKC-θ nuclear translocation but not PKC-θ signaling in healthy T cells. Targeting nPKC-θ reduced mesenchymal cancer stem cell signatures in immunotherapy-resistant CTCs and TNBC xenografts. PKC-θ was also enriched in the nuclei of CD8+ T cells isolated from stage IV immunotherapy-resistant metastatic cancer patients. We show for the first time that nPKC-θ complexes with ZEB1, a key repressive transcription factor in epithelial-to-mesenchymal transition (EMT), in immunotherapy-resistant dysfunctional PD1+/CD8+ T cells. nPKC-θi2 inhibited the ZEB1/PKC-θ repressive complex to induce cytokine production in CD8+ T cells isolated from patients with immunotherapy-resistant disease. These data establish for the first time that nPKC-θ mediates immunotherapy resistance via its activity in CTCs and dysfunctional CD8+ T cells. Disrupting nPKC-θ but retaining its cytoplasmic function may offer a means to target metastases in combination with chemotherapy or immunotherapy.
Publisher: Springer Science and Business Media LLC
Date: 22-11-2010
Abstract: Recent preclinical adoptive immunotherapy studies in murine models prompt to employ "proper" rather than "as many as possible" antigen-specific T cells to gain better therapeutic results. Ideally, "proper" T cells are poorly differentiated in vitro , but retain the capacity to fully differentiate into effector cells in vivo , where they can undergo long-term survival and strong proliferation. Such requirements can be achieved by modifying culture conditions, namely using less "differentiating" cytokines than IL-2. To evaluate this issue in human T cell cultures, we exploited a well characterized and clinical-grade protocol finalized at generating EBV-specific CTL for adoptive immunotherapy. In particular, we studied the impact of IL-7, IL-15 and IL-21 compared to IL-2 on different aspects of T cell functionality, namely growth kinetics, differentiation/activation marker expression, cytokine production, and short-term and long-term cytotoxicity. Results disclosed that the culture modifications we introduced in the standard protocol did not improve activity nor induce substantial changes in differentiation marker expression of EBV-specific CTL. Our data indicated that the addition of γ-chain cytokines other than IL-2 for the generation of EBV-specific T cell cultures did not produce the improvements expected on the basis of recent published literature. This fact was likely due to the intrinsic differences between murine and human models and highlights the need to design ad hoc protocols rather than simply modify the cytokines added in culture.
Publisher: Springer Science and Business Media LLC
Date: 14-02-2005
Abstract: Retinoic acid (RA) arrests the growth of EBV-immortalized lymphoblastoid B cell lines (LCLs) by upregulating the cyclin-dependent kinase inhibitor p27Kip1. Here, we show that in LCLs, RA inhibits ubiquitination and proteasome-dependent degradation of p27Kip1, a phenomenon that is associated with downregulation of Thr187 phosphorylation of the protein, whereas the phosphorylation on Ser10 is unaffected. Furthermore, we demonstrate that RA downregulates the expression of the p45Skp2 and Cks1 proteins, two essential components of the SCF(Skp2) ubiquitin ligase complex that target p27Kip1 for degradation. Downregulation of p45Skp2)and Cks1 occurs before the onset of growth arrest and is due to enhanced proteasome-mediated proteolysis of these proteins. Moreover, overexpression of p45Skp2 in DG75 cells prevents p27Kip1 protein accumulation and promotes resistance to the antiproliferative effects of RA. Treatment with Leptomycin B (LMB) blocked the translocation of p27Kip1 to the cytoplasm and prevented its degradation, indicating that CRM1-dependent nuclear export is required for p27Kip1 degradation. The shuttle protein p38Jab1, however, does not accumulate in the nucleus upon LMB treatment, nor does it interact with p27Kip1. Conversely, p45Skp2 is associated with p27Kip1 both in the nucleus and in the cytoplasm, accumulating within the nuclei after exposure to LMB and co-localizing with the exportin CRM1, suggesting a possible involvement of p45Skp2 in CRM1-dependent nuclear export of p27Kip1. These results indicate that downregulation of p45Skp2 is a key element underlying RA-induced p27Kip1 stabilization in B cells, resulting in an impaired targeting of the protein to the ubiquitin-proteasome pathway and probably contributing to the nuclear accumulation of p27Kip1.
Publisher: Springer Science and Business Media LLC
Date: 25-10-2011
DOI: 10.1038/LEU.2011.276
Abstract: Evidence from certain geographical areas links lymphomas of the ocular adnexa marginal zone B-cell lymphomas (OAMZL) with Chlamydophila psittaci (Cp) infection, suggesting that lymphoma development is dependent upon chronic stimulation by persistent infections. Notwithstanding that, the actual immunopathogenetical mechanisms have not yet been elucidated. As in other B-cell lymphomas, insight into this issue, especially with regard to potential selecting ligands, could be provided by analysis of the immunoglobulin (IG) receptors of the malignant clones. To this end, we studied the molecular features of IGs in 44 patients with OAMZL (40% Cp-positive), identifying features suggestive of a pathogenic mechanism of autoreactivity. Herein, we show that lymphoma cells express a distinctive IG repertoire, with electropositive antigen (Ag)-binding sites, reminiscent of autoantibodies (auto-Abs) recognizing DNA. Additionally, five (11%) cases of OAMZL expressed IGs homologous with autoreactive Abs or IGs of patients with chronic lymphocytic leukemia, a disease known for the expression of autoreactive IGs by neoplastic cells. In contrast, no similarity with known anti-Chlamydophila Abs was found. Taken together, these results strongly indicate that OAMZL may originate from B cells selected for their capability to bind Ags and, in particular, auto-Ags. In OAMZL associated with Cp infection, the pathogen likely acts indirectly on the malignant B cells, promoting the development of an inflammatory milieu, where auto-Ags could be exposed and presented, driving proliferation and expansion of self-reactive B cells.
Publisher: Oxford University Press (OUP)
Date: 04-10-2006
DOI: 10.1093/JNCI/DJJ373
Abstract: An association between ocular adnexal MALT lymphoma (OAL) and Chlamydia psittaci (Cp) infection has been proposed, and recent reports suggest that doxycycline treatment causes tumor regression in patients with Cp-related OAL. The effectiveness of doxycycline treatment in Cp-negative OAL has not been tested. In a prospective trial, 27 OAL patients (15 newly diagnosed and 12 having experienced relapse) were given a 3-week course of doxycycline therapy. Objective lymphoma response was assessed by computerized tomography scans or magnetic resonance imaging at 1, 3, and 6 months after the conclusion of therapy and every 6 months during follow-up. Cp infection in patients was determined by touchdown enzyme time-release polymerase chain reaction (TETR-PCR). Statistical tests were two-sided. Eleven patients were Cp DNA-positive and 16 were Cp DNA negative. Doxycycline was well tolerated. At a median follow-up of 14 months, lymphoma regression was complete in six patients, and a partial response (> or = 50% reduction of all measurable lesions) was observed in seven patients (overall response rate [complete and partial responses] = 48%). Lymphoma regression was observed in both Cp DNA-positive patients (seven of 11 experienced regression) and Cp DNA-negative patients (six of 16 experienced regression) (64% versus 38% P = .25, Fisher's exact test). The three patients with regional lymphadenopathies and three of the five patients with bilateral disease achieved objective response. In relapsed patients, response was observed both in previously irradiated and nonirradiated patients. The 2-year failure-free survival rate among the doxycycline-treated patients was 66% (95% confidence interval = 54 to 78), and 20 of the 27 patients were progression free. Doxycycline is a fast, safe, and active therapy for Cp DNA-positive OAL that was effective even in patients with multiple failures involving previously irradiated areas or regional lymphadenopathies. The responses observed in PCR-negative OAL may suggest a need for development of more sensitive methods for Cp detection and investigation of the potential role of other doxycycline-sensitive bacteria.
Publisher: Elsevier BV
Date: 07-2001
DOI: 10.1016/S0959-8049(01)00105-8
Abstract: Compared with the cases in the general population, Hodgkin's disease (HD) arising in the HIV setting shows distinctive features in terms of epidemiology, aetiopathogenesis, histopathology and clinical behaviour. Although HD does not represent an AIDS-defining condition, recent evidence consistently indicates that HIV-infected in iduals have a significantly increased risk of developing HD. HIV-related HD is characterised by the preponderance of aggressive histological subtypes, advanced stage at presentation, and highly malignant clinical course. Moreover, unlike HD in the general population, the large majority of HIV-related HD cases are pathogenetically linked to Epstein-Barr virus (EBV), with rates of EBV positivity ranging from 80 to 100%. Hodgkin and Reed-Sternberg cells of these cases invariably show a strong expression of the EBV-encoded latent membrane protein-1 (LMP-1), which functions as a constitutively activated tumour necrosis factor (TNF) receptor-like molecule. Usurpation of physiologically relevant pathways by LMP-1 may lead to the simultaneous or sequential activation of signalling pathways involved in the promotion of cell activation, growth, and survival, contributing thus to most of the features of HIV-related HD.
Publisher: Elsevier BV
Date: 07-2021
Publisher: Bentham Science Publishers Ltd.
Date: 31-10-2013
DOI: 10.2174/18715206113136660348
Abstract: Aging is a complex phenomenon involving multiple physiological functions. Among these, very important are the modifications induced in the immune system these modifications may be related to cancer development, a disease of older people. We herein describe the age-dependent alterations observed in the various arms of the immune system. Both innate and adaptive immunity are compromised during aging, a condition where an inflammatory status contributes to promote immune suppression and tumour growth. Collectively, aging of the immune system may produce detrimental consequences on the response against tumours in old patients. In fact, preclinical studies and clinical observations in humans have demonstrated age-associated alterations in antitumor immunity. Immunological recovery of old patients after conventional chemotherapy (CT) has not been fully investigated, while several studies conducted in patients undergoing blood stem cell transplantation have demonstrated that a delayed immune reconstitution associated with older age results in increased susceptibility to opportunistic infections and risk of tumour relapse. Cellular immunotherapy and vaccination are becoming viable options for improving survival and quality of life of cancer patients targeting both the host defences and the tumour. The clinical experience in elderly patients is still in its infancy, but available data indicate that these approaches are feasible and promising. A key problem in the studies on aging, immunity and cancer is that it is difficult to distinguish changes related to age from those related to cancer-dependent immunosuppression, but independent from the age of the subject. Longitudinal studies on aged healthy and cancer persons and the use of new immunological techniques may be required to clarify these issues.
Publisher: Elsevier BV
Date: 05-2006
Abstract: A pathogenic link between hepatitis C virus (HCV) and MALT-type lymphomas has been suggested. However, studies assessing the role of HCV infection separately in different forms of MALT lymphomas are not available. The prevalence and clinical implications of HCV seropositivity were analyzed in 55 patients with ocular adnexa lymphoma (OAL) of MALT-type. HCV seropositivity was detected in seven (13%) patients. At presentation, HCV infection was significantly associated with concomitant extra-orbital disease, lymph node dissemination and involvement of additional extranodal organs. HCV seropositivity was associated also with a higher relapse rate and worse progression-free survival. In fact, 16 patients experienced relapse after first-line treatment: five (71%) were HCV-seropositive and 11 (23%) were HCV-seronegative, with a median TTP of 31 and 50+ months (P = 0.01), and a 5-year progression-free survival of 43 +/- 18% and 77 +/- 7% (P = 0.005), respectively. HCV-seropositive patients experienced frequent relapses despite further lines of therapy relapses were systemic in all cases but one multiple subcutaneous nodules were common at relapse. HCV seropositivity is present in 13% of OAL of MALT-type. Concomitant HCV infection is associated with more disseminated disease and aggressive behavior in OAL, with a consequent potential negative impact in patients managed with radiotherapy alone.
Publisher: Informa UK Limited
Date: 15-09-2008
DOI: 10.4161/CC.7.18.6733
Abstract: Strategies able to downregulate the aberrant expression of cyclin D1 may prove of therapeutic relevance in cancer patients. This is particularly true for mantle cell lymphoma (MCL) in which cyclin D1 is overexpressed as a consequence of the t(11 )(q13 q32) translocation. We have recently demonstrated that an increased cyclin D1 stability also contributes to the high levels of this protein observed in MCL cells. This effect is mediated by a constitutive activation of PI3-K/Akt, which keeps GSK-3beta inhibited. Here we show that inhibition of PI3-K/Akt induces a 40% decrease of cyclin D1 half-life as a result of accumulation of the dephosphorylated/active form of GSK-3beta within the nucleus, where this kinase can phosphorylate cyclin D1 on Thr286 thereby promoting its nuclear export. Translocation of cyclin D1 into the cytoplasm is mediated by the nuclear exportin CRM1, whose association with cyclin D1 increases following PI3-K/Akt inhibition. Notably, rapamycin downregulated GSK-3beta Ser9 phosphorylation with concurrent nuclear export of cyclin D1 only in MCL cells in which GSK-3beta is under the control of mTOR. These findings suggest that the ability to downregulate cyclin D1 through GSK-3beta may identify subsets of MCL patients who may benefit from the treatment with mTOR inhibitors and stimulate further studies to assess whether the inability to affect GSK-3beta activity may constitute a clinically relevant resistance factor to mTOR inhibitors.
Publisher: Elsevier BV
Date: 05-2008
Abstract: Non-Hodgkin's lymphomas constitute one half of malignancies arising in the orbit and the ocular adnexae. Mucosa-associated lymphoid tissue (MALT)-type lymphoma is the most common histological category in this anatomic region. The incidence of ocular adnexal lymphoma of mucosa-associated lymphoid tissue-type (OAML) is increasing and recent studies offered new relevant insights in molecular, pathogenetic and therapeutic issues on these neoplasms. A pathogenetic model of antigen-driven lymphoproliferation similar to that reported for Helicobacter pylori-related gastric MALT lymphomas has been hypothesized for OAML. This notion is supported by the association between OAML and Chlamydophila psittaci infection, an association that is of likely pathogenetic relevance and may influence both the biological behavior and the therapeutic management of these neoplasms. However, this association displays evident geographical variability indicating that other etiopathogenic agents could be involved. These recent acquisitions coupled with the occurrence of chromosomal translocations and other genetic alterations, as well as additional risk factors like autoimmune disorders have contributed to render OAML an exciting challenge for a broad group of physicians and scientists. OAML is an indolent and rarely lethal malignancy that, in selected patients, can be managed with observation alone. Lymphomatous lesions are frequently responsible for symptoms affecting patient's quality of life, requiring, therefore, immediate treatment. Several therapeutic strategies are available, often associated with relevant side-effects. However, the therapeutic choice in OAML is not supported by consolidated evidence due to the lack of prospective trials. In this review, we analyze the most relevant biological, molecular, pathological and clinical features of OAML and propose some therapeutic guidelines for patients affected by this malignancy.
Publisher: Informa UK Limited
Date: 11-08-2008
DOI: 10.1517/14712598.8.9.1265
Abstract: Epstein-Barr Virus (EBV) infection is associated with a heterogeneous group of tumors, including lymphoproliferative disorders, Hodgkin's disease, nasopharyngeal carcinoma and Burkitt's lymphoma. As such neoplastic disorders express viral antigens, they can be treated by adoptive immunotherapy strategies relying mostly on in vitro generation and expansion of virus-specific cytotoxic T lymphocytes (CTL), which can be administered to patients for both prophylaxis and treatment. We reviewed results obtained in all clinical trials reported thus far employing anti-EBV adoptive immunotherapy for different virus-related malignancies. 'PTLD after HSCT', 'PTLD after SOT', 'NPC', 'HD', 'SCAEBV' and 'extranodal NK/T cell lymphoma', in combination with 'Adoptive immunotherapy' and 'Adoptive transfer', were used as search keys for papers in PubMed. Although the heterogeneity of different studies precludes their collection for a meta-analysis, it can be inferred that adoptive therapy with EBV-specific CTL is safe, well tolerated and particularly effective in the case of most immunogenic tumors, like post-transplant lymphoproliferative disease.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.SEMCANCER.2013.08.004
Abstract: Lymphomas that develop in HIV positive patients are predominantly aggressive B-cell malignancies. The most common HIV-associated lymphomas are Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL). Lymphomas that occur specifically in HIV positive patients include primary effusion lymphoma (PEL) and its solid variants, plasmablastic lymphoma of the oral cavity type and lymphoma associated with Kaposi sarcoma herpesvirus (KSHV)-related multicentric Castleman disease. These lymphomas, together with BL and immunoblastic lymphoma subtypes with plasmacytoid differentiation, carry Epstein-Barr virus (EBV) infection and display a phenotype related to plasma cells. Globally, EBV is identified in the neoplastic cells of approximately 40% of HIV-associated lymphomas, but the detection of EBV varies considerably with the site of presentation and the histological subtype. EBV infection occurs in 80-100% of primary central nervous system lymphomas and PELs, 80% of DLBCLs with immunoblastic-plasmacytoid features, and 30-50% of BL-plasmacytoid. KSHV is specifically associated with PEL, which usually occurs in a setting of profound immunosuppression. Current knowledge about HIV-associated lymphomas can be summarized as follows: (1) lymphomas specifically occurring in patients with HIV infection are closely linked to other viral diseases (2) most of these lymphomas exhibit plasmablastic differentiation.
Publisher: American Society of Hematology
Date: 15-05-2008
DOI: 10.1182/BLOOD-2007-07-103481
Abstract: Functional characterization of signaling pathways that critically control mantle cell lymphoma (MCL) cell growth and survival is relevant to designing new therapies for this lymphoma. We herein demonstrate that the constitutive activation of Akt correlates with the expression of the phosphorylated, inactive form of PTEN. Phosphatidyl-inositol-3 kinase (PI3-K)/Akt or mammalian target of rapamycin (mTOR) inhibition decreased the growth of both primary MCL cultures and established cell lines and antagonizes the growth-promoting activity of CD40 triggering and IL-4. These effects are mediated by nuclear accumulation of the p27Kip1 inhibitor induced by down-regulation of the p45Skp2 and Cks1 proteins, which target p27Kip1 for degradation. Moreover, Akt inhibition down-regulated cyclin D1 by promoting its proteasome-dependent degradation driven by GSK-3. Intriguingly, mTOR inhibition affected cyclin D1 proteolysis only in MCL cells in which GSK-3 is under the direct control of mTOR, suggesting that different MCL subsets could be differently responsive to mTOR inhibition. Finally, PI3-K/Akt inhibitors, but not rapamycin, induced variable levels of caspase-dependent apoptosis and reduced telomerase activity. These results indicate that Akt and mTOR activation have distinct functional relevance in MCL and suggest that targeting Akt may result in more effective therapeutic effects compared with mTOR inhibition.
Publisher: Informa UK Limited
Date: 11-08-2008
DOI: 10.1517/14712598.8.9.1265
Abstract: Epstein-Barr Virus (EBV) infection is associated with a heterogeneous group of tumors, including lymphoproliferative disorders, Hodgkin's disease, nasopharyngeal carcinoma and Burkitt's lymphoma. As such neoplastic disorders express viral antigens, they can be treated by adoptive immunotherapy strategies relying mostly on in vitro generation and expansion of virus-specific cytotoxic T lymphocytes (CTL), which can be administered to patients for both prophylaxis and treatment. We reviewed results obtained in all clinical trials reported thus far employing anti-EBV adoptive immunotherapy for different virus-related malignancies. 'PTLD after HSCT', 'PTLD after SOT', 'NPC', 'HD', 'SCAEBV' and 'extranodal NK/T cell lymphoma', in combination with 'Adoptive immunotherapy' and 'Adoptive transfer', were used as search keys for papers in PubMed. Although the heterogeneity of different studies precludes their collection for a meta-analysis, it can be inferred that adoptive therapy with EBV-specific CTL is safe, well tolerated and particularly effective in the case of most immunogenic tumors, like post-transplant lymphoproliferative disease.
Publisher: Informa UK Limited
Date: 09-2010
DOI: 10.1586/ERA.10.125
Publisher: Springer Science and Business Media LLC
Date: 19-02-2010
Publisher: Wiley
Date: 09-03-2015
DOI: 10.1002/IJC.29494
Abstract: Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein-Barr virus (EBV)-infected primary and fully transformed B-lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative B-cells up-regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV-infected primary B-cells more efficiently bind and internalize p17 proteins as compared with activated B-lymphocytes. The S75X variant bound more efficiently to EBV-infected primary and fully transformed B-lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up-regulation and increased interleukin-6 production. Notably, the S75X variant markedly up-regulated latent membrane protein-1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV(+) B-cell growth promotion. These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting.
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0753-3322(97)86237-3
Abstract: Epidemiologic and clinico-pathologic features of Hodgkin's disease suggest that an infectious agent may be involved in the pathogenesis of this puzzling disorder. Recently accumulated data provide direct evidence supporting a causal role of Epstein-Barr virus in a significant proportion of cases. In addition to allowing a better understanding of the complex pathogenesis of Hodgkin's disease, these virological advances, briefly reviewed herein, also constitute an important basis for the development of new therapeutic strategies.
Publisher: Springer Science and Business Media LLC
Date: 08-10-1998
Abstract: EBV-immortalized lymphoblastoid B cell lines (LCLs) are a suitable in vitro model for the study of EBV-related lymphoproliferative disorders of immunosuppressed patients. We have previously shown that 9-cis-, 13-cis- and all-trans-retinoic acid (RA) powerfully inhibit LCL proliferation at concentrations corresponding to therapeutically achievable plasma levels (10(-6) M). Herein we show that RA-induced LCL accumulation in the G0/G1 phases correlated with the loss of the catalytic activity of all three G1-associated CDKs (CDK2, CDK4 and CDK6) and with increased levels of underphosphorylated pRb and, in some LCLs, p130. LCLs arrested in G0/G1 by RA also showed a significant decrease in the protein levels of cyclins D2, D3 and A, together with a reduction in the amount of cyclin D associated with CDK4 and CDK6, probably accounting for the inhibition of the relative kinase activity. In addition, RA-treated LCLs showed a marked up-regulation of the CDK inhibitor (CKI) p27Kip-1 at the protein but not mRNA level, which correlated with a progressive increase of p27Kip-1 in CDK2 complexes (more than 2.5-fold) and with a reduction in the active phosphorylated form of CDK2. p27Kip-1 may also contribute to the inhibition of CDK4 kinase activity, as the amount of CDK4-associated p27Kip-1 was increased by 50% after RA exposure. p27Kip-1 up-regulation stably persisted for more than one week after RA withdrawal concomitantly with the maintenance of the proliferative block. Moreover, neutralization of TGFbeta did not affect the growth inhibitory activity of RA, suggesting that LCL growth arrest induced by these retinoids is probably not mediated by a pathway directly involving TGFbeta. Overall, these results demonstrate that RA treatment of EBV-immortalized B lymphocytes is associated with multiple effects on G1 regulatory proteins, including p27Kip1 up-regulation, decreased levels of cyclins D2, D3 and A, and inhibition of CDK2, CDK4 and CDK6 activity, which ultimately result in reduced pRb phosphorylation and G0/G1 growth arrest.
Publisher: Informa UK Limited
Date: 07-2010
DOI: 10.3109/08830185.2010.489658
Abstract: Our knowledge on the physiological role of CD4(+) T lymphocytes has improved in the last decade: available data convincingly demonstrate that, besides the 'helper' activity, CD4(+) T cells may be also endowed with lytic properties. The cytotoxic function of these effector cells has a relevant role in the control of pathogenic infections and in mediating antitumor immune responses. On these bases, several immunotherapeutic approaches exploiting the cytotoxic properties of CD4(+) T cells are under investigation. This review summarizes available data supporting the functional and therapeutic relevance of cytotoxic CD4(+) T cells, with a particular focus on Epstein-Barr virus (EBV)-related disorders.
Publisher: Wiley
Date: 06-1995
Publisher: American Society of Hematology
Date: 17-03-2016
DOI: 10.1182/BLOOD-2015-11-681411
Abstract: Despite the immune reconstitution promoted by combined antiretroviral therapy (cART), lymphomas still represent the most common type of cancer in HIV-infected in iduals. Cofactors related to immunodeficiency such as oncogenic viruses, chronic antigenic stimulation, and cytokine overproduction are thought to be the main drivers of HIV lymphomagenesis, although the current scenario does not convincingly explain the still-high incidence of lymphomas and the occurrence of peculiar lymphoma histotypes in HIV-infected patients under cART. Recent findings are challenging the current view of a mainly indirect role of HIV in lymphoma development and support the possibility that HIV may directly contribute to lymphomagenesis. In fact, mechanisms other than immune suppression involve biologic effects mediated by HIV products that are secreted and accumulate in lymphoid tissues, mainly within lymph node germinal centers. Notably, HIV-infected patients with lymphomas, but not those not affected by these tumors, were recently shown to carry HIV p17 protein variants with enhanced B-cell clonogenic activity. HIV p17 protein variants were characterized by the presence of distinct insertions at the C-terminal region of the protein responsible for a structural destabilization and the acquisition of novel biologic properties. These data are changing the current paradigm assuming that HIV is only indirectly related to lymphomagenesis. Furthermore, these recent findings are consistent with a role of HIV as a critical microenvironmental factor promoting lymphoma development and pave the way for further studies that may lead to the design of more effective strategies for an early identification and improved control of lymphomas in the HIV setting.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2020
DOI: 10.1038/S41417-020-00246-9
Abstract: Combined antiretroviral therapy (cART) for HIV-1 dramatically slows disease progression among HIV + in iduals. Currently, lymphoma represents the main cause of death among HIV-1-infected patients. Detection of p17 variants (vp17s) endowed with B-cell clonogenic activity in HIV-1-seropositive patients with lymphoma suggests their possible role in lymphomagenesis. Here, we demonstrate that the clonogenic activity of vp17s is mediated by their binding to PAR1 and to PAR1-mediated EGFR transactivation through Gq protein. The entire vp17s-triggered clonogenic process is MMPs dependent. Moreover, phosphoproteomic and bioinformatic analysis highlighted the crucial role of EGFR/PI3K/Akt pathway in modulating several molecules promoting cancer progression, including RAC1, ABL1, p53, CDK1, NPM, Rb, PTP-1B, and STAT1. Finally, we show that a peptide (F1) corresponding to the vp17s functional epitope is sufficient to trigger the PAR1/EGFR/PI3K/Akt pathway and bind PAR1. Our findings suggest novel potential therapeutic targets to counteract vp17-driven lymphomagenesis in HIV + patients.
Publisher: Wiley
Date: 02-11-2022
DOI: 10.1111/CODI.16369
Abstract: Patients diagnosed with a malignant polyp generally have favourable overall survival (OS) and cancer-specific survival (CSS). However, it is unclear how choice in management for malignant polyps may affect survival. Data from the Queensland Oncology Repository was analysed to derive a population wide assessment of the impact of management strategy on OS and CSS for patients diagnosed with malignant polyps. Log-rank testing, Kaplan-Meier and Cox-regression models were performed. Patients were matched using propensity score and Mahalanobis distance matching. A total of 1,646 patients were included with 240 deaths and 52 colorectal cancer related deaths until censor date. Following propensity score and Mahalanobis distance matching of patients undergoing polypectomy alone versus colorectal resection, there was no significant difference in the age groups (<60 years of age or ≥60 years of age), American Society of Anesthesiology score, comorbidity count or Association of ColoProctology of Great Britain and Ireland risk category. However, of note Log-rank testing demonstrated a significant difference in OS (p < 0.001) and CSS (p = 0.0061) between management strategies. Multivariable Cox-regression models in matched and un-matched patient cohorts demonstrated significantly lower hazards of death for OS with resection (p < 0.001). However, CSS was no longer significantly different between management groups in multivariable Cox-regression analysis (p = 0.073). Patients who underwent colorectal resection had significantly improved OS and CSS compared with polypectomy alone. Improved OS was furthermore seen on multivariable analysis, and in matched cohorts. Future research should investigate why this unexpected finding may be the case and whether updates to guidelines should be considered.
Publisher: The American Association of Immunologists
Date: 11-2014
Abstract: Immunodominance is a complex phenomenon that relies on a mere numerical concept, while being potentially influenced at every step of the immune response. We investigated the mechanisms leading to the establishment of CTL immunodominance in a retroviral model and found that the previously defined subdominant Env-specific CD8+ T cells are endowed with an unexpectedly higher functional avidity than is the immunodominant Gag-recognizing counterpart. This high avidity, along with the Env Ag overload, results in a supraoptimal TCR engagement. The overstimulation makes Env-specific T lymphocytes more susceptible to apoptosis, thus h ering their expansion and leading to an unintentional “immune kamikazing.” Therefore, Ag-dependent, hyperactivation-induced cell death can be regarded as a novel mechanism in the establishment of the immunodominance that restrains and opposes the expansion of high-avidity T cells in favor of lower-affinity populations.
Publisher: Informa Healthcare
Date: 06-2007
DOI: 10.1517/14656566.8.8.1073
Abstract: Non-Hodgkin lymphomas constitute 50% of all orbital malignancies. Mucosa-associated lymphoid tissue (MALT)-type lymphoma is the most common histology category in this anatomic region. Ocular adnexal lymphoma of MALT-type is an indolent and rarely lethal malignancy that can often be managed with observation alone. Occasionally, lymphomatous lesions determine the symptoms that condition a patient's quality of life, and so require an immediate antineoplastic treatment. Several strategies are available, but reliable indications supported by prospective trials do not exist. Some therapeutic strategies are associated with substantial side effects and require a well-balanced therapeutic decision, which should take into account several variables related to the patient, the lymphoma, and the treatment itself. In this review, the authors analyze related literature and propose therapeutic guidelines for the management of ocular adnexal lymphoma of MALT-type.
Publisher: Wiley
Date: 14-07-2009
DOI: 10.1002/IJC.24515
Abstract: The role of genetic factors involved in the development of undifferentiated nasopharyngeal carcinoma (UNPC) in nonendemic areas has been poorly investigated. High-resolution human leukocyte antigen (HLA) class I genotyping carried out in 82 Italian UNPC patients and 286 bone marrow donors born in the same province showed that A*0201, B*1801, and B*3501, known to efficiently present Epstein-Barr virus (EBV)-derived epitopes, were significantly under-represented in UNPC patients. Moreover, the A*0201/B*1801 haplotype was significantly less frequent in UNPC cases, with a 90% reduced risk (odds ratio [OR] 0.1, 95% confidence interval [CI] = 0.0-0.5) to develop UNPC, suggesting an additive effect. Notably, all 5 BARF1 epitopes and 7 of the 8 LMP-2 epitopes known to bind A*0201 showed a fully conserved sequence in all the 31 Italian EBV isolates investigated. The 4 amino acid changes affecting the 436-447 LMP-2 epitope do not reduce, but rather increase in two cases, the predicted ability of "variant" epitopes to bind the HLA-A*0201 allele, as shown by immunoinformatic analysis. Moreover, a significantly increased risk for UNPC was associated with A*2601 (OR 2.4, 95% CI = 1.1-4.9) and B*4101 (OR 9.2, 95% CI = 2.5-34.3). These findings indicate that Italian UNPC patients have a distinct HLA-A and -B genotypic profile and suggest that the decreased risk for UNPC conferred by definite HLA class I molecules is probably related to their ability to efficiently present LMP-2 and BARF1 epitopes that are highly conserved in EBV isolates from this geographic region. These results have practical implications for the immunotherapy of UNPC.
Publisher: Wiley
Date: 22-04-1993
Abstract: A series of selected lymphoid malignancies (LMs) occurring in Italian HIV-1-infected (HIV+) patients, principally intravenous drug users, was investigated. In addition to small non-cleaved-cell (SNCC) and large-cell immunoblastic (LCI) non-Hodgkin's lymphomas (NHLs), a relatively high occurrence of anaplastic large-cell Ki-I-positive (ALC Ki-I+) lymphomas and Hodgkin's disease (HD) was observed, at variance with other reported series of HIV+ patients. Combined results of in situ hybridization and Southern-blot analyses, in conjunction with immunohistochemical detection of Epstein-Barr virus (EBV)-encoded latent membrane protein-I (LMP-I), showed an almost complete association of ALC Ki-I+ lymphomas and HD cases with EBV. The neoplastic cells of both these LMs also showed common immunophenotypic features such as frequent absence of B- and T-cell differentiation markers and expression of the Ki-I activation marker, while SNCC and LCI lymphomas were mainly of mature B-cell origin and Ki-I-. The concomitant high incidence of ALC Ki-I+ lymphomas and HD in a specific group of HIV+ patients, their almost complete association with EBV in clonal and episomal form and the great similarity in differentiation, activation and virological markers which they display suggest that these LMs are pathological variants of a continuous spectrum of HIV-I-associated disorders etiopathologically linked to EBV.
Publisher: Elsevier BV
Date: 11-2004
DOI: 10.1016/J.HUMIMM.2004.08.183
Abstract: Comparison of human leukocyte antigen (HLA) frequencies in patients with hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) and in patients with HCV-associated non-Hodgkin's lymphoma (NHL) has not been addressed previously. To this aim, we investigated the distribution of HLA class II alleles in two selected groups of HCV-infected patients. Group 1 included 50 patients with HCV-associated NHL group 2 included 29 patients with HCV-associated HCC. A control group included 144 hospitalized patients without NHL or HCC and who were negative for HCV, hepatitis B virus, and human immunodeficiency virus antibodies. Polymerase chain reaction sequence DRB1 and DQB1 specific-primer methods were used. DRB1*1101/DQB1*0301 haplotype, which mainly favors the spontaneous clearance of HCV infection, was lower in HCC subjects than in controls, whereas HLA-DRB1*1104/DQB1*0301, was higher in NHL patients. These findings suggest different pathogenic pathways in HCC and in NHL development. In patients with HCV-associated HCC, a major protective role of DQB1*0301 allele, rather than DRB1*11, was found, probably because of a better HLA class II-associated virus clearance. By contrast, the same allele as HLA-DRB1*04 showed an increase in HCV-associated NHL. These data suggest that NHL and HCC development may be associated to a different response with respect to chronic HLA class II-restricted antigen presentation (perhaps a switch toward CD4+Th2 response in NHL?) or, alternatively, that these alleles could be in linkage disequilibrium to unrelated gene(s), or are in synergy with other immunomodulatory genes that may confer increased risk for NHL.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2011
Publisher: Mary Ann Liebert Inc
Date: 2002
DOI: 10.1089/088922202753394682
Abstract: In the present study sequence variations at the C terminus of the Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA-1), EBV-encoded latent membrane protein 1 (LMP-1), and EBNA-2 and EBNA-3C genes were investigated in 64 cases of EBV-positive AIDS-related diffuse large cell lymphoma (AIDS-DLCL), both systemic (12) and localized primarily to the central nervous system (52), and in 12 cases of EBV-positive AIDS-related Burkitt's lymphoma (AIDS-BL). Sequence analysis of the EBNA-1 C-terminal region led to the distinction of two major unrelated EBV strains, termed strain P (prototype) and strain V (variant), and their related subtypes, namely P-ala, P-thr, V-leu, V-val, and V-pro. Analysis of the LMP-1 gene was performed to assess the frequency of the C-terminus deletion variant, whereas analysis of EBNA-2 and EBNA-3C genes led to the identification of the distribution of the EBV type 1 and type 2 strains. The frequency of EBNA-1 subtypes was assessed in 49 cases of AIDS-NHL, including 37 cases of AIDS-DLCL and 12 cases of AIDS-BL. The P strain was detected in 45 of 49 cases (91.8%) whereas the V strain was found in 4 of 49 s les (8.1%). A significant difference in the distribution of the P and V strains was found between AIDS-DLCL and AIDS-BL (p < 0.01), because of the exclusive infection by the P strain of the AIDS-DLCL s les analyzed. The frequency of LMP-1 deletion variants and of EBV type 1 and type 2 strains in AIDS-DLCL overlapped with that of the general population, and no correlation was found with the evaluated clinicoepidemiological data of patients, that is, disease site, tumor histology, CD4(+) cell counts, and HIV transmission route. In conclusion, we found that the distribution of the EBV genotype in all of the AIDS-NHL s les analyzed is similar to the viral representation found in control in iduals of both immunocompetent and immunocompromised populations.
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.SEMCANCER.2015.06.002
Abstract: Patients with HIV infection are at increased risk of developing non-Hodgkin lymphoma and Hodgkin lymphoma. While the pathogenesis of these lymphomas is incompletely understood, evidence indicates that immune deregulation, genetic alterations and cytokine production play an important role in HIV lymphomagenesis. The lymphoma microenvironment in this heterogeneous group of lymphomas plays an equally critical role in their development, growth and progression. Important components of the microenvironment in HIV-related lymphomas include EBV and/or HHV-8 coinfection, reactive inflammatory cells, tumor microvasculature, and soluble factors. This paper provides a brief overview of HIV-related lymphomas and focuses on their lymphomagenesis and microenvironment.
Publisher: MDPI AG
Date: 07-2020
Abstract: Recent Advancements in Hematology: Knowledge, Methods and Dissemination is a series of editorials which is published on a biannual basis by the editorial board of the journal Bloods [...]
Publisher: MDPI AG
Date: 20-03-2020
Abstract: Communication in the field of biomedical research today involves professionals of numerous backgrounds, including researchers, doctors, public administrators, politicians, and health journalists [...]
Publisher: Springer Science and Business Media LLC
Date: 04-07-2005
Abstract: The clinical and pathological characteristics and the clinical course of patients with breast cancer and BRCA 1–2 mutation are poorly known. From 1997, patients with breast cancer and a family history of breast or ovarian cancer were offered BRCA testing. The clinical and pathological features of patients with known BRCA status were retrospectively assessed and comparisons were made between cancers arising in BRCA positive and BRCA wild type (WT) patients respectively. Type of treatment, pattern of relapse, event (local relapse, contralateral breast cancer, metastases) free and overall survival were also compared in the two groups. Out of the 210 patients tested, 125 had been treated and followed-up at our Institution and were evaluated in this study. BRCA positive patients tended to be more often premenopausal (79% vs 65%) and to have positive lymphnodes (63% vs 49%), poorly differentiated tumours (76% vs 40% – p = 0.002 at univariate analysis, not significant at multivariate analysis) and negative estrogen receptors (43% vs 29%). Treatment was not different in the two groups. In the 86 BRCA-WT patients, the first event was a local relapse in 3 (3%), metachronous contralateral breast cancer in 7 (8%) and distant metastases in 16 (19%). In the 39 BRCA positive patients, the corresponding figures were 3 (8%), 8 (21%) and 3 (8%). There was no difference in event free survival, with a median of 180 months in both groups of patients. At 20 years, projected survival was 85% for BRCA positive patients and 55% for BRCA-WT, but this difference was not statistically significant. Although BRCA positive patients have more frequently negative prognostic factors, their prognosis appears to be equal to or better than in patients with BRCA-WT.
Publisher: Springer Science and Business Media LLC
Date: 12-2022
DOI: 10.1186/S13148-022-01386-5
Abstract: Currently, human papillomavirus (HPV) positivity represents a strong prognostic factor for both reduced risk of relapse and improved survival in patients with oropharyngeal squamous cell carcinoma (OPSCC). However, a subset of HPV-positive OPSCC patients still experience poor outcomes. Furthermore, HPV-negative OPSCC patients, who have an even higher risk of relapse, are still lacking suitable prognostic biomarkers for clinical outcome. Here, we evaluated the prognostic value of LINE-1 methylation level in OPSCC patients and further addressed the relationship between LINE-1 methylation status and p53 protein expression as well as genome-wide/gene-specific DNA methylation. In this study, DNA was extracted from 163 formalin-fixed paraffin-embedded tissue s les retrospectively collected from stage III-IVB OPSCC patients managed with curative intent with up-front treatment. Quantitative methylation-specific PCR revealed that LINE-1 hypomethylation was directly associated with poor prognosis (5-year overall survival—OS: 28.1% for LINE-1 methylation 35% vs. 69.1% for ≥ 55% p 0.0001). When LINE-1 methylation was dichotomized as 55% versus ≥ 55%, interaction with HPV16 emerged: compared with hypermethylated HPV16-positive patients, subjects with hypomethylated HPV16-negative OPSCC reported an adjusted higher risk of death (HR 4.83, 95% CI 2.24–10.38) and progression (HR 4.54, 95% CI 2.18–9.48). Tumor protein p53 ( TP53 ) gene is often mutated and overexpressed in HPV-negative OPSCC. Since p53 has been reported to repress LINE-1 promoter, we then analyzed the association between p53 protein expression and LINE-1 methylation levels. Following p53 immunohistochemistry, results indicated that among HPV16-negative patients with p53 ≥ 50%, LINE-1 methylation levels declined and remained stable at approximately 43% any HPV16-positive patient reported p53 ≥ 50%. Finally, DNA methylation analysis demonstrated that genome-wide average methylation level at cytosine–phosphate–guanine sites was significantly lower in HPV16-negative OPSCC patients who relapsed within two years. The subsequent integrative analysis of gene expression and DNA methylation identified 20 up-regulated/hypomethylated genes in relapsed patients, and most of them contained LINE-1 elements in their promoter sequences. Evaluation of the methylation level of LINE-1 may help in identifying the subset of OPSCC patients with bad prognosis regardless of their HPV status. Aberrant LINE-1 hypomethylation might occur along with TP53 mutations and lead to altered gene expression in OPSCC.
Publisher: Springer Science and Business Media LLC
Date: 26-02-2014
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 26-04-2010
Publisher: Oxford University Press (OUP)
Date: 03-2006
DOI: 10.1093/JNCI/DJJ079
Publisher: Elsevier BV
Date: 06-2021
Publisher: American Society for Microbiology
Date: 03-2000
DOI: 10.1128/JVI.74.5.2443-2446.2000
Abstract: Transforming growth factor β (TGF-β) is an immunosuppressive cytokine which can induce immunoglobulin A (IgA) switch and Epstein-Barr virus (EBV) replication in latently infected cells. Here we report elevated serum levels of TGF-β in various EBV-associated diseases correlating positively with EBV-specific IgA titers and negatively with IgM titers, suggesting a role for this cytokine in the pathogenesis of these diseases.
Publisher: Wiley
Date: 02-1997
Abstract: To determine whether the prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome (SS) may be better characterized by the integration of clinical, pathologic, and molecular data, the latter focusing on the expansion, persistence, and dissemination of clonal B cells in the course of the disease. Multiple tissue lesions (synchronous from different tissues and metachronous from the same tissue) were evaluated in biopsy specimens obtained from 6 consecutive patients with SS who had an associated lymphoproliferative disorder. Fully benign gastric lesions were evaluated in tissue from an additional 11 patients with SS who had no associated lymphoproliferative disorder. Multiple and complementary molecular analyses of B cell clonality were used: Southern blot, polymerase chain reaction, single-strand conformation polymorphism, DNA sequencing, and hybridization with clonospecific oligoprobes. All the patients were then strictly followed up for the appearance of lymphoma. Different scenarios of SS-associated B cell lymphoproliferation were identified: 1) the ongoing expansion of the same dominant clone, localized or disseminated, in tissue from 2 patients, 1 of whom later developed an overt B cell lymphoma 2) different dominant clones in different synchronous or metachronous tissues from the remaining 4 patients with an associated lymphoproliferative disorder and 3) small oligoclonal expansions in 7 of the 11 benign gastric lymphoid infiltrates. Prelymphomatous B cell lymphoproliferation in SS was better characterized following integration of the findings. The different types of B cell clonal expansion (oligoclonal or monoclonal, smaller or larger in size, fluctuating or established, localized or disseminated) may imply a different risk of lymphoma progression. An accurate clinical, histopathologic, and molecular characterization may therefore be crucial in future studies aimed at clarifying the pathobiology of SS-associated lymphoproliferation.
Publisher: Springer Science and Business Media LLC
Date: 27-01-2011
Publisher: Springer Science and Business Media LLC
Date: 27-10-2022
DOI: 10.1007/S00216-022-04376-X
Abstract: Glycosylation is the most common post-translational modification of proteins, and glycosylation changes at cell surfaces are frequently associated with malignant epithelia including head and neck squamous cell carcinoma (HNSCC). In HNSCC, 5-year survival remains poor, averaging around 50% globally: this is partly related to late diagnosis. Specific protein glycosylation signatures on malignant keratinocytes have promise as diagnostic and prognostic biomarkers and as therapeutic targets. Nevertheless, HNSCC-specific glycome is to date largely unknown. Herein, we tested six established HNSCC cell lines to capture the qualitative and semi-quantitative N-glycome using porous graphitized carbon liquid chromatography coupled to electrospray ionisation tandem mass spectrometry. Oligomannose-type N-glycans were the predominant features in all HNSCC cell lines analysed (57.5–70%). The levels of sialylated N-glycans showed considerable cell line-dependent differences ranging from 24 to 35%. Importantly, α2-6 linked sialylated N-glycans were dominant across most HNSCC cell lines except in SCC-9 cells where similar levels of α2-6 and α2-3 sialylated N-glycans were observed. Furthermore, we found that HPV-positive cell lines contained higher levels of phosphorylated oligomannose N-glycans, which hint towards an upregulation of lysosomal pathways. Almost all fucose-type N-glycans carried core-fucose residues with just minor levels ( 4%) of Lewis-type fucosylation identified. We also observed paucimannose-type N-glycans (2–5.5%), though in low levels. Finally, we identified oligomannose N-glycans carrying core-fucose residues and confirmed their structure by tandem mass spectrometry. This first systematic mapping of the N-glycome revealed erse and specific glycosylation features in HNSCC, paving the way for further studies aimed at assessing their possible diagnostic relevance.
Publisher: American Society for Microbiology
Date: 15-01-2003
DOI: 10.1128/JVI.77.2.1595-1597.2003
Abstract: Human Epstein-Barr virus-immortalized lymphoblastoid B-cell lines tested positive by PCR for simian virus 40 (SV40) DNA (22 of 42 cell lines, 52.3%). B lymphocytes or tissues from which B-cell lines derived were also SV40 positive. In situ hybridization showed that SV40 DNA was present in the nucleus of a small fraction (1/250) of cells. SV40 T-antigen mRNA was detected by reverse transcription-PCR. Lymphoblastoid B-cell lines ( n = 4) infected with SV40 remained SV40 positive for 4 to 6 months. SV40-positive B-cell lines were more tumorigenic in SCID mice than were SV40-negative cell lines (4 of 5 [80%] SV40-positive cell lines versus 2 of 4 [50%] SV40-negative cell lines). These results suggest that SV40 may play a role in the early phases of human lymphomagenesis.
Publisher: Wiley
Date: 15-04-1994
Abstract: Human interleukin-10 (h-IL-10) is a pleiotropic cytokine with stimulatory activity on B-lymphocytes. Recent evidence indicates that infection with Epstein-Barr virus (EBV) induces h-IL-10 production in B-cells and that this cytokine may contribute to EBV-induced B-cell transformation. It is not known whether h-IL-10 induction by EBV correlates with distinct phenotypic features of the infected cells or with the expression of particular viral genes. We have approached these questions by investigating the expression of h-IL-10 mRNA in a panel of B-cell lines including: in vitro EBV-transformed lymphoblastoid cell lines (LCLs), EBV-carrying Burkitt lymphoma (BL) lines, EBV-negative BL lines and their sublines infected with different EBV strains, or transfected with the transformation-associated viral gene. h-IL-10 mRNA was detected by reverse-transcriptase-assisted (RT)-PCR in a subset of EBV-negative BLs and in all EBV-positive BL lines and LCLs investigated except Daudi. This cell line carries an EBV nuclear antigen (EBNA)-2 gene-defective virus strain. h-IL-10 mRNA was induced by conversion of 3 EBV-negative and h-IL-10-negative BL lines (BL41, BL47 and BL49) with the transforming, B95.8-derived EBV strain. P3HR-I virus convertants that do not express the viral EBNA-2 and the EBV latent membrane protein (LMP)-1, and fail to progress towards a LCL-like cell phenotype, showed no evidence of h-IL-10 up-regulation. Expression of LMP1 was sufficient to induce h-IL-10 mRNA in transfected sublines of the EBV-negative DG75 and BL41 cell lines, whereas expression of EBNA1, 2, 5, or 6 had no effect. h-IL-10 was detected in the culture supernatants of the LMP1 transfectants by specific ELISA assays. The present findings confirm the role of LMP1 in the transactivation of a wide variety of cellular genes which may be involved in EBV-induced B-cell transformation.
Publisher: American Society of Hematology
Date: 10-09-2009
Publisher: American Association for Cancer Research (AACR)
Date: 04-2012
DOI: 10.1158/0008-5472.CAN-11-2505
Abstract: Mantle cell lymphoma (MCL) is characterized by a profound deregulation of the mechanisms controlling cell-cycle progression and survival. We herein show that the combination of 9-cis-retinoic acid (RA) and IFN-α induces marked antiproliferative and proapoptotic effects in MCL cells through the modulation of critical targets. Particularly, IFN-α enhances RA-mediated G0–G1 cell accumulation by downregulating cyclin D1 and increasing p27Kip1 and p21WAF1/Cip1 protein levels. Furthermore, RA/IFN-α combination also induces apoptosis by triggering both caspases-8 and -9 resulting in Bax and Bak activation. In particular, RA/IFN-α treatment downregulates the antiapoptotic Bcl-xL and Bfl-1 proteins and upregulates the proapoptotic BH3-only Noxa protein. Sequestration of Mcl-1 and Bfl-1 by upregulated Noxa results in the activation of Bid, and the consequent induction of apoptosis is inhibited by Noxa silencing. Noxa upregulation is associated with nuclear translocation of the FOXO3a transcription factor as consequence of RA/IFN-α–induced Akt inhibition. Pharmacologic suppression of Akt, but not of TORC1, increases Noxa protein levels and downregulates Bfl-1 protein supporting the conclusion that the inhibition of the Akt pathway, the resulting FOXO3a activation and Noxa upregulation are critical molecular mechanisms underlying RA/IFN-α—dependent MCL cell apoptosis. These results support the potential therapeutic value of RA/IFN-α combination in MCL management. Cancer Res 72(7) 1825–35. ©2012 AACR.
Publisher: Wiley
Date: 2010
DOI: 10.1002/HON.934
Publisher: Elsevier BV
Date: 10-2015
DOI: 10.1016/J.SEMCANCER.2015.04.006
Abstract: Epstein-Bar virus (EBV) is known to directly drive the neoplastic transformation of lymphoid cells resulting in the development of a variety of lymphoproliferative disorders. Emerging evidence however indicates that this final outcome is also related to the ability of EBV to shape microenvironment making it more conducive to cell transformation. Indeed, EBV up-regulates the production of several soluble factors promoting the growth and/or the survival of lymphoid cells and orchestrates a variety of complex mechanisms favoring their escape from anti-tumor immune responses. Furthermore, EBV-infected B lymphocytes actively secrete exosomes and recent investigation is now shedding light on the content and functional impact that these bioactive vesicles may have in bystander recipient cells. The complex interplay existing between EBV-carrying lymphoid cells and tumor microenvironment is now offering attractive targets of therapy that can be exploited to improve current therapeutic strategies for EBV-driven lymphoid malignancies.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.HUMPATH.2010.08.014
Abstract: Extranodal marginal zone B-cell lymphomas are linked to bacterial infections that vary according to the anatomical site. The occurrence of these lymphomas in the central nervous system is a very rare event, and the identification of specific bacteria in this setting has not been previously addressed. Herein, we report for the first time a case of primary central nervous system marginal zone B-cell lymphoma involving the choroid plexus associated with Chlamydophila psittaci infection. No concomitant ocular involvement was detected. C psittaci was identified with 3 independent methods, and through immunohistochemistry, it was visualized in the cytoplasm of monocytes/macrophages present within lymphomatous tissues. This observation points toward the opportunity to investigate the prevalence of C psittaci infection in central nervous system lymphomas, particularly in those with low-grade histologic features.
Publisher: Wiley
Date: 15-02-1994
Abstract: The present study was undertaken in order to determine whether the expression of specific surface molecules which mediate immune recognition as well as cell-cell and cell-matrix interactions is associated with the leukemic evolution of T-cell lymphomas. To this end, we have investigated the in vivo phenotypic characteristics and the in vitro natural-killer(NK)-cell susceptibility of a group of MCF-247-induced AKR/J T-cell lymphomas with different leukemic potential. We found that in the AKR/J model, the biological aggressiveness of leukemic cells is not dependent upon an escape from host immune surveillance as a consequence of an in vivo down-regulation of H2-Kk determinants or a resistance to NK lysis. Moreover, NK susceptibility of AKR/J lymphomas does not seem to correlate with the level of H2-antigen expression. No obvious correlation was found between the leukemic phenotype and the amount of MEL-14, LFA-1, ICAM-1, Pgp-1/CD44 and THAM/CD26 antigen expression. An in vivo coordinated up-regulation of alpha 4 and beta 7 integrin chains, with the highest levels of expression detected in secondary sites of leukemic infiltration, was observed in the highly leukemic lymphoma NQ22 and, albeit to a lesser extent, in lymphomas with moderate leukemic potential. Conversely, non-leukemic lymphomas were repeatedly alpha 4- and beta 7-negative. These findings suggest that in the AKR/J system the expression of alpha 4 beta 7 integrin may contribute to leukemic spreading of T-cell lymphomas.
Publisher: The American Association of Immunologists
Date: 15-05-2010
Abstract: Although adoptive immunotherapy with CD8+ CTL is providing clinically relevant results against EBV-driven malignancies, the effector role of CD4+ T cells has been poorly investigated. We addressed this issue in a lymphoblastoid cell line-induced mouse model of posttransplant lymphoproliferative disease (PTLD) by comparing the therapeutic efficacy of EBV-specific CD4+ and CD8+ T cell lines upon adoptive transfer. CD4+ T cells disclosed a long-lasting and stronger proliferative potential than CD8+ T cells, had a similar activation and differentiation marker profile, efficiently killed their targets in a MHC class II-restricted manner, and displayed a lytic machinery comparable to that of cognate CD8+ T cells. A detailed analysis of Ag specificity revealed that CD4+ T cells potentially target EBV early lytic cycle proteins. Nonetheless, when assessed for the relative therapeutic impact after in vivo transfer, CD4+ T cells showed a reduced activity compared with the CD8+ CTL counterpart. This feature was apparently due to a strong and selective downmodulation of MHC class II expression on the tumor cells surface, a phenomenon that could be reverted by the demethylating agent 5-aza-2′-deoxycytidine, thus leading to restoration of lymphoblastoid cell line recognition and killing by CD4+ T cells, as well as to a more pronounced therapeutic activity. Conversely, immunohistochemical analysis disclosed that HLA-II expression is fully retained in human PTLD s les. Our data indicate that EBV-specific cytotoxic CD4+ T cells are therapeutic in mice bearing PTLD-like tumors, even in the absence of CD8+ T cells. These findings pave the way to use cultures of pure CD4+ T cells in immunotherapeutic approaches for EBV-related malignancies.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 08-2005
Abstract: Some infectious agents contributing to lymphomagenesis have been considered targets for new therapeutic strategies. Chlamydia psittaci DNA has been detected in 80% of ocular adnexal lymphomas. The present pilot study was carried out to assess whether C psittaci–eradicating antibiotic therapy is associated with tumor regression in ocular adnexal lymphomas. Nine patients with C psittaci–positive marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in seven patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up. All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all four positive patients. Objective response was complete in two patients, partial response ( 50%) was observed in two patients, and minimal response ( 50%) was observed in three patients. Duration of response in the seven responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively. C psittaci–eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2003
Publisher: Springer Science and Business Media LLC
Date: 25-04-2015
Publisher: Elsevier BV
Date: 11-2006
Publisher: Wiley
Date: 04-1993
DOI: 10.1111/J.1432-1033.1993.TB17825.X
Abstract: Exhaustive extraction of mouse tissues with perchloric acid has been used together with reverse-phase HPLC and electrophoresis to quantify the amounts of chromosomal proteins HMG17, HMG14 and HMGI, relative to histone H1. Normal lung and thymus contain approximately 3% HMG17/HMG14 but only approximately 2% HMGI. In tumor tissues (Lewis lung carcinoma and lymphoma NQ35), the amount of HMG17/HMG14 is not greatly altered but HMGI levels rise considerably, reaching 10% in Lewis lung carcinoma. HMGI synthesis does not replace HMG17/HMG14 proteins, suggesting that HMGI proteins contribute to the structure of chromatin regions in a manner distinct from those of HMG17/HMG14. Ion-spray mass spectrometry has been used to determine the molecular masses of H1 subtypes from the same four mouse tissues. In addition to the six known species H1 zero, H1a, H1b, H1c, H1d and H1e, a newly defined subtype of mass 21,756 Da from Lewis lung carcinoma, named H1L was identified. Several phosphorylated H1 subtypes have also been defined by mass spectrometry. The combined use of reverse-phase HPLC and electrophoresis permitted quantification of these seven histone H1 subtypes in the four mouse tissues. Increased phosphorylation of H1 subtypes in tumors parallels the phosphorylation of HMGI proteins which are present in great amounts, showing that both are involved as post-translational-modified forms in the structure of the chromatin of neoplastic systems.
Publisher: Elsevier BV
Date: 2003
DOI: 10.1016/S0065-230X(03)87191-9
Abstract: Undifferentiated nasopharyngeal carcinoma (UCNT) is characterized by its unique epidemiologic, immunobiologic, virologic, and clinicopathologic features. Aside from environmental risk factors and possible genetic susceptibility, infection by the Epstein-Barr virus (EBV) constitutes a well-documented link for the development of UCNT. However, despite the fact that UCNT is the human tumor associated most consistently with EBV, the role played by this virus in the pathogenesis of UCNT is still largely speculative and is a matter of ongoing debate. The purpose of this article is to review recent advances, particularly at the immunovirological and molecular levels, linking EBV infection to UCNT, and to discuss those aspects that may be of relevance for a better diagnosis and/or prognosis of this tumor, as well as for development of novel therapeutic strategies.
Publisher: Wiley
Date: 16-06-2015
DOI: 10.1002/HED.23879
Abstract: The association between undifferentiated nasopharyngeal carcinoma (NPC) and Epstein-Barr virus (EBV) is well established. Nevertheless, available evidence suggests that other cofactors are required for the development of undifferentiated NPC. Several investigations reported simian virus 40 (SV40) footprints in human tumors of different histotypes. Serum s les from patients with undifferentiated NPC (n = 64) and healthy subjects (n = 130) were analyzed by an indirect enzyme-linked immunosorbent assay (ELISA) with SV40 synthetic peptides to detect antibodies against viral peptide (VP) capsid proteins VP1, 2, and 3. Immunologic data indicate that in sera from patients with undifferentiated NPC, the prevalence of SV40 antibodies was 25%, whereas in controls it was 16%. This difference is not statistically significant (p > .05). A similar prevalence of SV40 antibodies was detected in undifferentiated NPC and healthy subjects. Our serologic data suggest no association between undifferentiated NPC and SV40 infection. This investigation may stimulate further studies aimed at determining the possible contribution of other risk factors in the pathogenesis of undifferentiated NPC.
Publisher: Springer Science and Business Media LLC
Date: 06-02-2016
Publisher: Wiley
Date: 17-02-2022
DOI: 10.1002/CNCR.34148
Abstract: Although the majority of human papillomavirus (HPV) infections are cleared by the immune system, a small percentage of them progress to develop HPV-driven cancers. Cervical cancer studies highlight that HPV persistence and cancer risk are associated with genetic factors, especially at the human leukocyte antigen (HLA) genes. This study was conducted to investigate such associations in head and neck cancer (HNC). In all, 192 patients with HNC and 384 controls were genotyped with the Infinium Global Screening Array (Illumina, Inc). HLA variants were imputed with SNP2HLA, and an association analysis was performed by logistic regression. HPV-positive HNCs were significantly associated with single-nucleotide polymorphisms (SNPs) at DRB1_32660090 (P = 1.728 × 10 HPV-positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV-positive HNC. Human papillomavirus (HPV)-positive head and neck cancer (HNC) risk is associated with distinct human leukocyte antigen variants, and some of them are shared by both cervical cancer and HPV-positive HNC. Cervical cancer studies highlight that human papillomavirus (HPV)-driven cancer risk is linked with human leukocyte antigen (HLA) polymorphism. Hence, the current study was designed to investigate the HLA associations in HPV-positive and HPV-negative head and neck cancer (HNC) and compare these associations with cervical cancer. Several lead signals reported by previous HNC and cervical genome-wide association studies were replicated in the current study. However, these associations were limited to the HPV-positive HNC group, and this suggests that HPV-positive HNC risk is associated with distinct HLA variants, and some of them are shared by both cervical cancer and HPV-positive HNC.
Publisher: Elsevier BV
Date: 11-2012
DOI: 10.1038/JID.2012.179
Abstract: The identification of intracellular signaling pathways that promote cell proliferation and resistance to cell death may lead to the development of improved treatment for advanced melanoma. Here we show that the calcineurin/nuclear factor of activated T cells c2 (NFATc2) pathway has an antiapoptotic role in melanoma cells. Expression of NFATc2 was constitutive in vitro and in vivo in human melanoma, and cyclosporin A (CsA) treatment of melanoma cells led to downmodulation of NFATc2. Inhibition of the calcineurin/NFAT pathway by CsA, or by NFATc2 silencing, led to modulation of cell cycle inhibitors and apoptosis-related proteins such as Apollon, and promoted caspase-dependent apoptosis of neoplastic cells. Calcineurin/NFATc2 targeting significantly enhanced melanoma cell death induced by antitumor agents, such as MEK- or BRAF(V600E)-specific inhibitors, and tumor necrosis factor-related apoptosis-inducing ligand, which trigger the intrinsic or extrinsic pathway of apoptosis, respectively. These findings identify NFATc2 as a potential therapeutic target in melanoma.
Publisher: Frontiers Media SA
Date: 21-10-2021
Abstract: De novo tumors are a major cause of morbidity and mortality after long-term solid organ transplantation. Chronic immunosuppression strongly affects solid organ transplanted (SOT) patients’ immune system by promoting immune evasion strategies and reactivations of viruses with oncogenic potential, ultimately leading to cancer onset. In this scenario, an oncological Surveillance Protocol integrated with biobanking of peripheral blood s les and evaluation of immunovirological and molecular parameters was activated for SOT patients at CRO-IRCCS Aviano, with the aim of identifying suitable biomarkers of cancer development. An exploratory longitudinal study was designed based on two serial peripheral blood s les collected at least three months apart. Forty nine SOT patients were selected and stratified by tumor onset during follow-up. Spontaneous T-cell responses to EBV, CMV and tumor associated antigens, EBV-DNA and CMV-DNA loads, and circulating TERT mRNA levels were investigated. Significantly higher levels of circulating TERT mRNA were observed 3.5-23.5 months before and close to the diagnosis of cancer as compared to tumor-free patients. Plasmatic TERT mRNA levels & .73 copies/mL at baseline were significantly associated with the risk of developing de novo tumors (HR=4.0, 95%C.I. = 1.4-11.5, p=0.01). In particular, the risk significantly increased by 4% with every ten-unit increment in TERT mRNA (HR=1.04, 95%C.I. = 1.01-1.07, p=0.01). Although obtained in an exploratory study, our data support the importance of identifying early biomarkers of tumor onset in SOT patients useful to modulate the pace of surveillance visits.
Publisher: MDPI AG
Date: 29-05-2018
DOI: 10.3390/IJMS19061602
Publisher: Informa UK Limited
Date: 14-05-2013
DOI: 10.4161/HV.23970
Publisher: Springer Science and Business Media LLC
Date: 27-04-2016
DOI: 10.1038/NCOMMS11375
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations ( P × 10 −8 ) with oestrogen receptor (ER)-negative breast cancer and BRCA1 -associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5 , a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations ( P .05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1016/J.HUMIMM.2012.02.009
Abstract: Simian virus 40 (SV40), a small DNA tumor virus, was inadvertently administered to human populations with the use of contaminated vaccines. SV40 sequences have mainly been detected in healthy in iduals and cancer patients using polymerase chain reaction techniques. However, some studies have failed to reveal the presence of SV40 in human specimens. These conflicting results indicate the need for new research to verify whether SV40 is circulating in humans. Mimotopes from SV40 structural peptides were tested to investigate for specific reactions to human sera antibodies. An indirect enzyme-linked immunosorbent assay with synthetic peptides from SV40 viral capsid proteins 1-2-3 (VPs 1-2-3) was set up and employed to test 855 serum s les from healthy blood donors. Data from immunologic assays indicate that serum antibodies against SV40 VP mimotopes are detectable, although with a low titer, in blood donors 18 to 65 years old. The overall prevalence of serum s les that reacted with the 2 SV40 VP peptides was 18%. The strong points for this novel method include the simplicity of its approach and the potential to discriminate between SV40-specific antibody responses and to draw correlations between responses to the 2 independent SV40 peptides. These data suggest that SV40, or a yet undetected closely related polyomavirus, is circulating in human populations, but with lower prevalence than that of the ubiquitous BK and JC human polyomaviruses.
Publisher: Springer Science and Business Media LLC
Date: 09-06-2006
Abstract: Breast cancer in men is an infrequent occurrence, accounting for ~1% of all breast tumors with an incidence of about 1:100,000. The relative rarity of male breast cancer (MBC) limits our understanding of the epidemiologic, genetic and clinical features of this tumor. From 1997 to 2003, 10 MBC patients were referred to our Institute for genetic counselling and BRCA1/2 testing. Here we report on the genetic and phenotypic characterization of 10 families with MBC from the North East of Italy. In particular, we wished to assess the occurrence of specific cancer types in relatives of MBC probands in families with and without BRCA2 predisposing mutations. Moreover, families with recurrent BRCA2 mutations were also characterized by haplotype analysis using 5 BRCA2-linked dinucleotide repeat markers and 8 intragenic BRCA2 polymorphisms. Two pathogenic mutations in the BRCA2 gene were observed: the 9106C T (Q2960X) and the IVS16-2A G (splicing) mutations, each in 2 cases. A BRCA1 mutation of uncertain significance 4590C G (P1491A) was also observed. In families with BRCA2 mutations, female breast cancer was more frequent in the first and second-degree relatives compared to the families with wild type BRCA1/2 (31.9% vs . 8.0% p = 0.001). Reconstruction of the chromosome phasing in three families and the analysis of three isolated cases with the IVS16-2A G BRCA2 mutation identified the same haplotype associated with MBC, supporting the possibility that this founder mutation previously detected in Slovenian families is also present in the North East of our Country. Moreover, analysis of one family with the 9106C T BRCA2 mutation allowed the identification of common haplotypes for both microsatellite and intragenic polymorphisms segregating with the mutation. Three isolated cases with the same mutation shared the same intragenic polymorphisms and three 5' microsatellite markers, but showed a different haplotype for 3' markers, which were common to all three cases. The 9106C T and the IVS16-2A G mutations constitute recurrent BRCA2 mutations in MBC cases from the North-East of Italy and may be associated with a founder effect. Knowledge of these two recurrent BRCA2 mutations predisposing to MBC may facilitate the analyses aimed at the identification of mutation carriers in our geographic area.
Publisher: Elsevier BV
Date: 10-2012
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0145-2126(90)90007-V
Abstract: Proto-oncogene transcriptional activation was analyzed in a group of MCF 247 MuLv-induced T-cell lymphomas to identify transformation-specific gene activations and determine whether the proviral insertion near a myc gene could promote a peculiar mechanism of transformation through a differential proto-oncogene expression pattern. Of the six lymphomas analyzed, three showed the MCF 247 provirus integrated within the N-myc locus, one carried the provirus integrated near c-myc, whereas for the remaining two, no evidence of proviral integrations in any of the known myc loci was obtained. Independently of the integrative events, the pattern of proto-oncogene expression was almost identical in all six lymphomas. These findings seem to rule out the existence of a peculiar pathway of transformation associated with the proviral insertion near a myc locus. Moreover, the transcription pattern observed was qualitatively identical to that displayed by normal thymocytes only quantitative differences in c- or N-myc, c-myb and Ha-ras were observed. These results suggest that the T-cell proto-oncogene activation program is not qualitatively affected by the transforming event(s).
Publisher: Springer Science and Business Media LLC
Date: 22-08-2015
Publisher: Springer Science and Business Media LLC
Date: 22-11-2010
Publisher: Wiley
Date: 23-11-1998
DOI: 10.1002/(SICI)1097-0215(19981123)78:5<581::AID-IJC9>3.0.CO;2-G
Abstract: Most familial breast or ovarian cancers are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. The cloning of these genes has opened a new era for the genetic counseling of women with a family history of breast or ovarian cancer. To estimate the incidence of detectable BRCA1 mutations and to define the eligibility criteria for genetic testing in the Italian population, a total of 53 patients belonging to 46 families clustering multiple cases of breast and/or ovarian cancer were investigated. Seven families presented with ovarian cancer only, 16 had both ovarian and breast cancers, and 23 were characterized by breast cancer only. Using a combination of protein truncation test (PTT) and single strand conformational polymorphism (SSCP) analysis followed, when necessary, by direct sequencing, we found 8 distinct mutations, 2 of these not reported before. Five frameshift and 2 nonsense mutations led to a truncated protein. One mutation was a missense substitution involving a cysteine in the zinc finger domain. One variant creating an ETS binding site in intron I was found but its role was not defined. The percentage of families carrying mutations was 17%. Among the families characterized by ovarian cancer only and by breast and ovarian cancer, the percentage of BRCA1 mutations was 57% and 12.5%, respectively. In contrast, the percentage of altered BRCA1 in families with only breast cancers was 9%. In the 46 Italian families studied, BRCA1 mutations were detected in fewer kindreds than those previously hypothesized based on linkage analysis, especially when these were characterized by breast cancers only. Our results indicate that families with a low number of cancer patients should be referred for BRCA1 genetic testing mainly when ovarian cancer is present.
Publisher: Oxford University Press (OUP)
Date: 11-2011
DOI: 10.1634/THEONCOLOGIST.2011-0108
Abstract: Borrelia burgdorferi has been variably associated with different forms of primary cutaneous lymphoma. Differences in prevalence rates among reported studies could be a result of geographic variability or heterogeneity in the molecular approaches that have been employed. In the present study, we investigated the prevalence of Borrelia burgdorferi sensu lato DNA in diagnostic tissue s les from fresh cutaneous biopsies of 98 primary cutaneous lymphomas and 19 normal skin controls. Three different polymerase chain reaction (PCR) protocols targeting the hbb, flagellin, and Osp-A genes were used. Direct sequencing of both sense and antisense strands of purified PCR products confirmed the specificity of the lified fragments. Sequence specificity was assessed using the Basic Local Alignment Search Tool, and MultAlin software was used to investigate the heterogeneity of target gene sequences across the different s les. Borrelia DNA was not detected in 19 controls, 23 cases of follicular lymphoma, 31 cases of extranodal marginal zone lymphoma, or 30 cases of mycosis fungoides. A single case of 14 diffuse large B-cell lymphoma cases was positive for B. burgdorferi. This study does not support a pathogenic role of B. burgdorferi in primary cutaneous B- and T-cell lymphomas from areas nonendemic for this microorganism and the consequent rationale for the adoption of antibiotic therapy in these patients.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 23-10-2014
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2326-6066.C.6549799.V1
Abstract: Abstract Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8 sup + /sup T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8 sup + /sup dendritic cells (DC). We demonstrate that, even in the absence of exogenous glycolipid, iNKT cells supported the maturation of CD8α sup + /sup DCs to drive efficient cross-priming of antigen-specific CD8 sup + /sup T cells upon delivery of Clec9a/OVA-TNE. The addition of αGC to the TNE (Clec9a/OVA/αGC) further enhanced activation of iNKT cells, NK cells, CD8α sup + /sup DCs, and polyfunctional CD8 sup + /sup T cells. When tested therapeutically against HPVE7-expressing TC-1 tumors, long-term tumor suppression was achieved with a single administration of Clec9a/E7 peptide/αGC TNE. Antitumor activity was correlated with the recruitment of mature DCs, NK cells, and tumor-specific effector CD8 sup + /sup T cells to the tumor-draining lymph node and tumor tissue. Thus, Clec9a-TNE codelivery of CD8 sup + /sup T-cell epitopes with αGC induces alternative helper signals from activated iNKT cells, elicits innate (iNKT, NK) immunity, and enhances antitumor CD8 sup + /sup T-cell responses for control of solid tumors. /
Publisher: American Medical Association (AMA)
Date: 07-04-2015
Publisher: Wiley
Date: 2006
DOI: 10.1002/HON.768
Abstract: The prevalence and the clinical impact of gastric Helicobacter pylori (Hp) infection, as well as its possible correlation with Chlamydia psittaci (Cps) infection and the lymphoma regression rate produced by Hp eradicating antibiotic therapy were investigated in patients with MALT-type lymphoma of the ocular adnexa (OAL). During staging, the presence of gastric Hp infection was assessed by gastroscopy and multiple biopsies in 31 OAL patients. Immediately after, Hp-positive patients were treated with eradicating antibiotic therapy, alone or associated with other therapies. Gastric Hp infection was detected in 10 (32%) patients this feature did not correlate with patients' characteristics and disease. Four Hp-positive patients were treated with Hp-eradicating antibiotics therapy as exclusive strategy (assessable for response), none of them showed lymphoma regression. Conversely, 6 Hp-positive patients were treated with antibiotic therapy concurrently with other therapies, achieving lymphoma regression in all cases. Three Hp-positive patients with Cps-positive lymphoma were treated with doxycycline at relapse, resulting in two CR and one PR, which lasted 24+, 20+, and 18+ months, respectively. One of these patients achieved a CR after doxycycline despite the chronic persistence of Hp infection, whereas Cps-eradication was confirmed in the analysis of PBMC s les. Gastric Hp infection, even if common among OAL patients, does not influence clinical presentation. Hp-eradicating antibiotic therapy is not active against OAL. Cps-eradicating antibiotic therapy with doxycycline induces lymphoma remission irrespectively of the persistence of Hp infection.
Publisher: Informa UK Limited
Date: 16-05-2017
DOI: 10.1080/17474086.2017.1326815
Abstract: Primary effusion lymphoma (PEL) is a rare B-cell lymphoid neoplasm mainly associated with HIV infection, presenting as pleural, peritoneal, and pericardial effusions. A defining property of PEL is its consistent association with Kaposi sarcoma associated herpesvirus (KSHV) infection, and, in most cases, Epstein Barr virus (EBV) co-infection. On these grounds, a review of the literature related to viral cooperation and lymphomagenesis can help to understand the complex interplay between KSHV and EBV in PEL pathogenesis. Areas covered: In this review, the authors highlight clinical, pathologic, genetic and proteomic features of PEL, in the context of viral cooperation in PEL lymphomagenesis. Expert commentary: Tumour cells are characterized by the overexpression of genes that are involved in inflammation and invasion. Coherently, PEL secretomes are enriched in proteins probably responsible for the particular tropism (cell adhesion and migration) of PEL cells. The development of PEL in HIV+ patients is multifactorial and involves a complex interplay among co-infection with oncogenic viruses (EBV and KSHV), inflammatory factors, and environmental conditions.
Publisher: Elsevier BV
Date: 2008
Publisher: American Society for Microbiology
Date: 15-10-2008
DOI: 10.1128/JVI.00321-08
Abstract: Transformation of primary B lymphocytes by Epstein-Barr virus requires the establishment of a strictly latent infection, the expression of several latent viral proteins, and sustained telomerase activity. Our previous findings indicated that induction of hTERT, the rate-limiting catalytic unit of the telomerase complex, was associated with the expression of the viral latent membrane protein 1 (LMP1). In the present study, we demonstrate that ectopic expression of LMP1 in BJAB and Ramos B cells resulted in an increase of hTERT transcripts, thus suggesting that LMP1 acts at the transcriptional level. This was confirmed by transient expression of a luciferase reporter plasmid containing the hTERT promoter cotransfected with an LMP1-expressing vector or transfected into B cells in which LMP1 expression was inducible. Consistently, silencing of LMP1 by small interfering RNA resulted in a reduction of hTERT transcripts. We also provide evidence indicating that LMP1-induced hTERT activation is independently mediated by NF-κB and by mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways, whereas CD40, Akt, and mTOR signaling has no involvement. Moreover, our results do not support a role for c-Myc in mediating these effects on hTERT , since ectopic expression of LMP1 did not upregulate c-Myc and silencing of this oncogene or E box mutagenesis failed to inhibit LMP1-induced hTERT activation. These findings indicate that LMP1 simultaneously modulates multiple signal transduction pathways in B cells to transactivate the hTERT promoter and enhance telomerase activity, thus confirming the pleiotropic nature of this viral oncoprotein.
Publisher: Bentham Science Publishers Ltd.
Date: 2011
DOI: 10.2174/156800911793743664
Abstract: The topic of this review covers a very important branch of cancer research, cancer vaccination. The growing knowledge in tumor immunology has evolved rapidly, starting from nonspecific generic stimulation of the immune system to more specific approaches based on the availability of tumor antigens. The review covers molecular and cell biology, and pharmaceutical technology of cancer vaccines. Particularly, it is aimed at highlighting the results of cancer vaccines from phase II and III clinical trials, an issue that is of relevance to better understand how cancer vaccines can successfully complement antitumor therapy, including conventional chemotherapy and the recently developed target-based drugs.
Publisher: Elsevier BV
Date: 08-1988
DOI: 10.1016/0277-5379(88)90223-4
Abstract: We have examined 44 cases of human colonic and rectal carcinomas for structural rearrangement and lification of c-myc, N-myc, L-myc, c-myb and p53 oncogenes. DNA hybridization showed evidence of c-myc lification in only one of the s les tested. In addition, the same tumour also showed a rearrangement immediately 3' to the c-myc locus. No rearrangement could be found at the c-myc locus in the other 43 cases. Moreover, our molecular analysis of N-myc, L-myc, c-myb and p53 genes indicated no relevant alteration of the copy number and/or genomic structure of these nuclear oncogenes. Thus, at least in human colorectal malignancies, it is unlikely that nuclear oncogene structural alterations and/or lification plays a major role in tumour induction or progression.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2011
DOI: 10.1007/S00262-011-1157-5
Abstract: The generation of efficacious vaccines against self-antigens expressed in tumor cells requires breakage of tolerance, and the refocusing of immune responses toward epitopes for which tolerance may not be established. While the presentation of tumor antigens by mature dendritic cells (mDC) may surpass tolerance, broadening of the antigenic repertoire remains an issue. We report that fusion of the candidate idiotype vaccine IGKV3-20 to the Gly-Ala repeat (GAr) of the Epstein-Barr virus nuclear antigen (EBNA)-1 inhibits degradation by the proteasome and redirects processing to the lysosome. mDCs transduced with a recombinant lentivirus encoding the chimeric idiotype efficiently primed CD4+ and CD8+ cytotoxic T-cell (CTL) responses that lysed autologous blasts expressing IGKV3-20 or pulsed with IGKV3-20 synthetic peptides, and HLA-matched IGKV3-20-positive tumor cell lines. Comparison of the cytotoxic response of CD4+ and CD8+ T lymphocytes activated by mDCs expressing the wild-type or chimeric IGKV3-20 reveled largely non-overlapping epitope repertoires in both CD4+ and CD8+ effectors. Thus, fusion to the GAr may provide an effective means to broaden the immune response to an endogenous protein by promoting the presentation of antigenic epitopes that require a lysosome-dependent processing step.
Publisher: Wiley
Date: 2006
DOI: 10.1002/GCC.20342
Abstract: The presence of genomic rearrangements of the BRCA1 gene in breast and/or ovarian cancer families has been intensively investigated in patients from various countries over the last years. A number of different rearrangements have been reported by several studies that clearly document the involvement of this mutation type in genetic predisposition to breast and ovarian cancer. Population-specific studies are now needed to evaluate the prevalence of genomic rearrangements before deciding whether to include ad hoc screening procedures into standard diagnostic mutation detection approaches. Indeed, the vast majority of the studies have been performed on small, highly selected, s le sets because of the limitations imposed by the laborious technical approaches. Moreover, prevalence figures are likely to differ across different countries according to the ethnic origin of each specific population. Here we analyze a large cohort of 653 Italian probands, negative for BRCA1 and BRCA2 point mutations, gathered from four National Institutions. We report the identification of BRCA1 genomic rearrangements in 12 independent families. Noteworthy, half of the probands carry mutations that recur in more than one Italian family. Considering the whole spectrum of Italian BRCA1 gene rearrangements identified thus far in consecutive patients, we estimate that alterations of this type account for 19% (95% CI: 0.11 < 0.19 < 0.28) of the BRCA1 mutation positive families. We conclude that the search for major genomic rearrangements is essential for an accurate and comprehensive BRCA1 mutation detection strategy in Italy.
Publisher: Wiley
Date: 18-01-1999
DOI: 10.1002/(SICI)1097-0215(19990118)80:2<240::AID-IJC13>3.0.CO;2-J
Abstract: Epstein-Barr virus (EBV) isolates show a wide genomic heterogeneity, and a key issue is whether distinct strain variations may contribute to the development and/or malignancy of EBV-related disorders. Herein, we report on the virologic and biologic characterization of an EBV strain derived from a cyto-histologically aggressive EBV-related Hodgkin's disease (HD) (case HD-3) showing a high number of "anaplastic" Reed-Sternberg cells expressing markedly high levels of CD30, CD40 and LMP-1. The HD-3-derived EBV showed strong in vitro immortalizing properties, as suggested by the unusually high number of spontaneous lymphoblastoid cell lines (LCLs) obtained from the patient. Immunofluorescence and immuno-cytochemical analyses showed that HD-3 LCLs expressed significantly higher levels of CD23, CD30, CD38, CD39, CD40 and CD71 antigens and CD54 and CD58 adhesion molecules than B95.8 LCLs. In contrast, the expression of CD11a, CD24, CD95, bcl-2, LMP-1 and EBNA-2 was similar in both groups of LCLs. These phenotypic changes are consistent with the induction of a pronounced activation status and are not dependent on the cellular background, having been closely reproduced by the same virus in LCLs from an unrelated donor (DEN-HD-3 LCLs). HD-3 LCLs were able to grow in vitro at low serum concentrations (up to 0.1%) and were significantly more clonogenic in soft agarose than B95.8 LCLs. Moreover, although no evidence of tumor formation was observed in nude mice injected with B95.8 LCLs, all 5 spontaneous LCLs of patient HD-3 and the 2 DEN-HD-3 LCLs grew in transplanted animals as lymphoproliferations composed of EBER+, LMP-1+ cells. Our findings indicate that the biologic properties of the HD-3 EBV strain are significantly different from those of the B95.8 virus and may have contributed to the cytologic and histo-pathologic malignancy of this HD case. Moreover, molecular characterization of the HD-3 EBV genome identified a 63-bp deletion within the 3' end of the LMP-1 gene as a likely significant change that may be responsible, at least in part, for the biologically relevant phenotypic modifications and enhanced in vitro and in vivo growth potential induced in B lymphocytes by this virus strain.
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1016/J.AUTREV.2007.02.012
Abstract: Epstein-Barr virus (EBV) is a ubiquitous human gamma-herpes virus that establishes a life-long asymptomatic infection in immunocompetent hosts by colonizing memory B lymphocytes and hijacking cellular signaling pathways that regulate antigen-dependent B-cell activation and differentiation. In patients with solid organ or hematopoietic stem cell transplantation, the defect in EBV-specific immune responses may allow the outgrowth of EBV-carrying B lymphocytes that may give rise to a spectrum of different clinico-pathologic entities encompassed by the term post-transplantation lymphoproliferative disorders (PTLD). EBV-driven immortalization of B-cells is mediated by the cooperative activity of viral proteins that derange critical cellular pathways controlling growth and/or survival of B lymphocytes. Full transformation of infected B-cells is achieved by the contribution of poorly defined additional co-factors, including microenvironmental stimuli, genetic and epigenetic alterations. The quantification of circulating EBV DNA and EBV-specific T cells are valuable tools in the clinical monitoring of EBV-associated PTLD. The recent advances in elucidation of the mechanisms underlying EBV-induced growth transformation will be instrumental in guiding the design of novel approaches for the treatment of these often life-threatening lymphoproliferative disorders.
Publisher: American Association for Cancer Research (AACR)
Date: 14-09-2008
DOI: 10.1158/1078-0432.CCR-08-0676
Abstract: Purpose: Chlamydia psittaci (Cp) has been associated to ocular adnexal lymphomas (OAL) with variable geographic distribution. Herein, we used multiple Chlamydia detection tools to identify Cp elementary bodies–containing cell and to assess Cp prevalence in both nodal and extranodal lymphomas. Experimental Design: TETR-PCR, immunohistochemistry, immunofluorescence, electron microscopy, and laser-capture microdissection were done in 35 OALs to define their effect in Chlamydia detection and, moreover, to identify the Cp cellular carrier. Cp prevalence was screened by TETR-PCR in 205 extraorbital lymphomas and 135 nonneoplastic controls. Results: Twenty-six (74%) OALs were associated with Cp infection: immunohistochemistry, immunofluorescence, and laser-capture microdissection-assisted PCR showed that monocytes/macrophages were the Cp carriers electron microscopy showed the presence of intact Cp elementary bodies into these cells. Immunohistochemistry and TETR-PCR showed a 70% concordance rate (P = 0.001). Cp DNA was equally prevalent in non-OAL, nodal, and extranodal lymphomas: among the latter, it was more common in diffuse large B-cell lymphomas of the skin (P = 0.03) and Waldeyer's ring. Conclusions: This multiparametric approach shows, for the first time, that monocytes/macrophages are the carriers of Cp, Cp seems preferentially associated with lymphomas arising in organs primarily exposed to antigens. The clinical implications of these findings deserve to be prospectively investigated.
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.SEMCANCER.2013.07.005
Abstract: Epstein-Barr virus (EBV) is a ubiquitous human γ-herpes virus that has established an elegant strategy to persist as a life-long asymptomatic infection in memory B lymphocytes. EBV has potent transforming properties for B lymphocytes and it is pathogenically associated with a variety of lymphomas of B or NK/T cell origin. The viral latency programs expressed can hijack or deregulate cellular pathways critical for cell proliferation and survival, while impairing anti-viral immune responses. Similar effects may also be induced by EBV-encoded micro-RNAs, which may have a pathogenic role particularly in lymphomas showing a restricted expression of viral proteins. Of note, recent data have challenged the view that only the EBV latency is relevant for lymphomagenesis, suggesting that lytic EBV replication may also contribute to the development of EBV-associated lymphoproliferations. The recent advances in the elucidation of the mechanisms underlying EBV-induced cell transformation and immune evasion are providing the rationale for innovative and tailored treatment approaches for EBV-driven lymphomas.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2009
DOI: 10.1038/NRCLINONC.2009.147
Abstract: Chlamydiae are obligate intracellular bacteria that grow in eukaryotic cells and cause a wide spectrum of diseases. They can establish persistent infections, are mitogenic in vitro, promote polyclonal cell proliferation in vivo and induce resistance to apoptosis in infected cells-properties that might contribute to tumorigenesis. In fact, Chlamydophila psittaci (Cp) has been linked to the development and maintenance of ocular adnexal marginal zone B-cell lymphoma (OAMZL). In this indolent malignancy, Cp is transported by monocytes and macrophages and causes both local and systemic infection. Cp elementary bodies are viable and infectious in the conjunctiva and peripheral blood of patients with OAMZL. Bacterial eradication with antibiotic therapy is often followed by lymphoma regression. Despite recent advances in the understanding of this bacterium-lymphoma association, several questions remain unanswered. For instance, prevalence variations among different geographical areas and related diagnostic and therapeutic implications remain a major investigational issue. We will focus on clinical and therapeutic implications of chlamydial infections in patients with lymphomas and summarize the current knowledge on the association between Cp infection and OAMZL. Available data on the epidemiology, biology and pathogenesis of this association are analyzed and new investigative and clinical approaches are discussed.
Publisher: MDPI AG
Date: 18-08-2023
Abstract: Vaccines have been hailed as one of the most remarkable medical advancements in human history, and their potential for treating cancer by generating or expanding anti-tumor T cells has garnered significant interest in recent years. However, the limited efficacy of therapeutic cancer vaccines in clinical trials can be partially attributed to the inadequacy of current preclinical mouse models in recapitulating the complexities of the human immune system. In this study, we developed two innovative humanized mouse models to assess the immunogenicity and therapeutic effectiveness of vaccines targeting human papillomavirus (HPV16) antigens and delivering tumor antigens to human CD141+ dendritic cells (DCs). Both models were based on the transference of human peripheral blood mononuclear cells (PBMCs) into immunocompromised HLA-A*02-NSG mice (NSG-A2), where the use of fresh PBMCs boosted the engraftment of human cells up to 80%. The dynamics of immune cells in the PBMC-hu-NSG-A2 mice demonstrated that T cells constituted the vast majority of engrafted cells, which progressively expanded over time and retained their responsiveness to ex vivo stimulation. Using the PBMC-hu-NSG-A2 system, we generated a hyperplastic skin graft model expressing the HPV16-E7 oncogene. Remarkably, human cells populated the skin grafts, and upon vaccination with a DNA vaccine encoding an HPV16-E6/E7 protein, rapid rejection targeted to the E7-expressing skin was detected, underscoring the capacity of the model to mount a vaccine-specific response. To overcome the decline in DC numbers observed over time in PBMC-hu-NSG-A2 animals, we augmented the abundance of CD141+ DCs, the specific targets of our tailored nanoemulsions (TNEs), by transferring additional autologous PBMCs pre-treated in vitro with the growth factor Flt3-L. The Flt3-L treatment bolstered CD141+ DC numbers, leading to potent antigen-specific CD4+ and CD8+ T cell responses in vivo, which caused the regression of pre-established triple-negative breast cancer and melanoma tumors following CD141+ DC-targeting TNE vaccination. Notably, using HLA-A*02-matching PBMCs for humanizing NSG-A2 mice resulted in a delayed onset of graft-versus-host disease and enhanced the efficacy of the TNE vaccination compared with the parental NSG strain. In conclusion, we successfully established two humanized mouse models that exhibited strong antigen-specific responses and demonstrated tumor regression following vaccination. These models serve as valuable platforms for assessing the efficacy of therapeutic cancer vaccines targeting HPV16-dysplastic skin and erse tumor antigens specifically delivered to CD141+ DCs.
Publisher: MDPI AG
Date: 16-11-2020
Abstract: Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable therapies for the treatment of sarcomas. In recent years immunotherapies have revolutionised the treatment of a variety of cancers by restoring patient anti-tumour immune responses or through the adoptive infusion of immune effectors able to kill and eliminate malignant cells. The clinicopathologic and genetic heterogeneity of sarcomas, together with the generally low burden of somatic mutations potentially generating neoantigens, are currently limited to broad application of immunotherapy for patients with sarcomas. Nevertheless, a better understanding of the microenvironmental factors h ering the efficacy of immunotherapy and the identification of new and suitable therapeutic targets may help to overcome current limitations. Moreover, the recent advances in the development of immunotherapies based on the direct exploitation or targeting of T cells and/or NK cells may offer new opportunities to improve the treatment of sarcomas, particularly those showing recurrence or resistance to standard of care treatments.
Publisher: Wiley
Date: 25-05-2007
DOI: 10.1002/IJC.22661
Abstract: Transformation of primary B lymphocytes by Epstein-Barr Virus (EBV) requires the establishment of a latent infection, the expression of several latent viral proteins and a sustained telomerase activity. We investigated the interplay between the activation of human telomerase reverse transcriptase (hTERT), the catalytic rate-limiting component of the telomerase complex, and the expression of latent/lytic EBV genes during the establishment of a stably latent EBV infection of normal B lymphocytes. Cell cultures at early passages after EBV infection greatly differed in their timing of hTERT expression and telomerase activation. Induction of hTERT was dependent on the balance between latent and lytic EBV gene expression, being positively associated with a high ratio of latent/lytic isoforms of latent membrane protein 1, and negatively associated with the expression of BZLF1 gene, the main activator of the viral lytic cycle. In turn, hTERT expression was followed by a decrease in EBV lytic gene expression and virus production. Ectopic expression of hTERT in BZLF1-positive B cell cultures resulted in BZLF1 down-regulation, increased resistance to lytic cycle induction, and enhanced in vitro growth properties, whereas hTERT inhibition by siRNA triggered the activation of the EBV lytic cycle. These findings indicate that hTERT contributes by multiple mechanisms to the EBV-driven transformation of B lymphocytes and suggest that hTERT may constitute a therapeutic target for EBV-associated B cell lymphomas.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2015
DOI: 10.1038/NG.3185
Publisher: MDPI AG
Date: 06-06-2018
DOI: 10.3390/IJMS19061683
Publisher: Frontiers Media SA
Date: 06-04-2023
DOI: 10.3389/FIMMU.2023.1127896
Abstract: Suitable methods to assess in vivo immunogenicity and therapeutic efficacy of cancer vaccines in preclinical cancer models are critical to overcome current limitations of cancer vaccines and enhance the clinical applicability of this promising immunotherapeutic strategy. In particular, availability of methods allowing the characterization of T cell responses to endogenous tumor antigens is required to assess vaccine potency and improve the antigen formulation. Moreover, multiparametric assays to deeply characterize tumor-induced and therapy-induced immune modulation are relevant to design mechanism-based combination immunotherapies. Here we describe a versatile multiparametric flow cytometry method to assess the polyfunctionality of tumor antigen-specific CD4 + and CD8 + T cell responses based on their production of multiple cytokines after short-term ex vivo restimulation with relevant tumor epitopes of the most common mouse strains. We also report the development and application of two 21-color flow cytometry panels allowing a comprehensive characterization of T cell and natural killer cell exhaustion and memory phenotypes in mice with a particular focus on preclinical cancer models.
Publisher: Wiley
Date: 27-11-1995
Abstract: The present study was performed with the aim of better defining the possible role of Epstein-Barr-virus (EBV)-infected cells in the pathogenesis of HIV-related lymphadenopathy syndrome (LAS). In addition, since LAS has been considered as a pre-lymphomatous lesion, we also wished to elucidate the possible contribution of EBV-carrying cells present in LAS tissues to the development of HIV-associated malignant lymphomas. To this end, we have characterized EBV-infected cells in LAS lymph nodes in terms of EBV DNA prevalence, tissue distribution in relation to HIV-carrying cells, virus sub-type, expression of latent and replicative antigens, and presence of clonal EBV episomes. When compared with HIV-unrelated lymphadenopathies (4/10, 40%), LAS showed a higher prevalence of EBV DNA (14/20, 70%). Comparable values of EBV prevalence were detected in LAS with follicular hyperplasia (12/16, 75%) and with follicular involution (4/4, 100%). All EBV+ non-neoplastic lymph nodes from HIV-seronegative patients carried type-I EBV, whereas LAS specimens showed almost equivalent distribution of the 2 EBV sub-types. Of the 14 EBV-carrying LAS, 4 (29%) were positive by Southern-blot analysis for the BamHI-W region of the virus genome but negative for the presence of monoclonal EBV episomes. In situ hybridization revealed a remarkably higher load of EBV-infected cells in LAS than in HIV-unrelated lymphadenopathies. In LAS lymph nodes, EBV-carrying cells were identified as isolated, cytologically normal elements, sometimes with immunoblastic morphology, usually scattered throughout the interfollicular areas. By contrast, the expression of HIV p24 was restricted to germinal center cells. All the EBV+ LAS s les were negative for the expression of EBV-encoded latent (LMP-1 and EBNA-2) and replicative proteins (BZLF-1, BHLF-1, EA-D, EA-R and VCA). In addition, lification of the immunoglobulin heavy-chain genes using 2 different polymerase-chain-reaction protocols showed evidence of B-cell clonal expansion in 2/20 (10%) LAS, one EBV- case, and one s le with low numbers of EBV-infected cells. These results suggest that (i) EBV-carrying cells are probably not involved in the development of LAS, either directly or indirectly (ii) type-2-EBV-infected cells are present in LAS lymph nodes from the early phases of HIV infection (iii) EBV-carrying LAS per se probably does not constitute a lesion at high risk for subsequent development of EBV+ lymphomas (iv) it is unlikely that a high viral load or strong EBV-mediated antigenic stimulation plays a contributory role in the development of EBV-unrelated lymphomas of HIV-seropositive in iduals.
Publisher: Public Library of Science (PLoS)
Date: 18-09-2012
Publisher: MDPI AG
Date: 05-08-2022
DOI: 10.3390/BIOMEDICINES10081896
Abstract: Immunogenic cell death (ICD) in cancer represents a functionally unique therapeutic response that can induce tumor-targeting immune responses. ICD is characterized by the exposure and release of numerous damage-associated molecular patterns (DAMPs), which confer adjuvanticity to dying cancer cells. The spatiotemporally defined emission of DAMPs during ICD has been well described, whereas the epigenetic mechanisms that regulate ICD hallmarks have not yet been deeply elucidated. Here, we aimed to examine the involvement of miRNAs and their putative targets using well-established in vitro models of ICD. To this end, B cell lymphoma (Mino) and breast cancer (MDA-MB-231) cell lines were exposed to two different ICD inducers, the combination of retinoic acid (RA) and interferon-alpha (IFN-α) and doxorubicin, and to non ICD inducers such as gamma irradiation. Then, miRNA and mRNA profiles were studied by next generation sequencing. Co-expression analysis identified 16 miRNAs differentially modulated in cells undergoing ICD. Integrated miRNA-mRNA functional analysis revealed candidate miRNAs, mRNAs, and modulated pathways associated with Immune System Process (GO Term). Specifically, ICD induced a distinctive transcriptional signature hallmarked by regulation of antigen presentation, a crucial step for proper activation of immune system antitumor response. Interestingly, the major histocompatibility complex class I (MHC-I) pathway was upregulated whereas class II (MHC-II) was downregulated. Analysis of MHC-II associated transcripts and HLA-DR surface expression confirmed inhibition of this pathway by ICD on lymphoma cells. miR-4284 and miR-212-3p were the strongest miRNAs upregulated by ICD associated with this event and miR-212-3p overexpression was able to downregulate surface expression of HLA-DR. It is well known that MHC-II expression on tumor cells facilitates the recruitment of CD4+ T cells. However, the interaction between tumor MHC-II and inhibitory coreceptors on tumor-associated lymphocytes could provide an immunosuppressive signal that directly represses effector cytotoxic activity. In this context, MHC-II downregulation by ICD could enhance antitumor immunity. Overall, we found that the miRNA profile was significantly altered during ICD. Several miRNAs are predicted to be involved in the regulation of MHC-I and II pathways, whose implication in ICD is demonstrated herein for the first time, which could eventually modulate tumor recognition and attack by the immune system.
Publisher: Wiley
Date: 30-07-1993
Abstract: Epstein-Barr virus (EBV) type 2 is considered to be a much less potent transformer of lymphocytes than type 1. However, type-2 EBV may be involved in the pathogenesis of non-Hodgkin's lymphomas (NHLs) arising in immunocompromised patients, i.e., subjects with malaria or HIV-1 infection. To determine whether type-2 EBV may also play a role in Hodgkin's disease (HD) developing in immunocompromised patients, we characterized EBV subtypes in EBV-positive HD s les from 10 HIV-1-positive patients as well as from a control population of 24 HIV-1-negative patients. Type-2 EBV was detected in 5/10 HD s les from the HIV-1-positive group (1 case showed concomitant type-1 EBV positivity), but only in 1/20 HD s les from the HIV-1-negative group, indicating that, during HIV-1-induced immunodepression, type-2 EBV may be pathogenetically involved also in HD, as previously reported for HIV-associated NHLs.
Publisher: MDPI AG
Date: 09-02-2021
Abstract: Recent Advancements in Hematology: Knowledge, Methods and Dissemination is a series of commentary article which is published on a biannual basis by the editorial board of the journal Hemato [...]
Publisher: Wiley
Date: 04-06-2008
DOI: 10.1002/IJC.23596
Abstract: Ocular adnexal MALT lymphoma (OAML) is linked to Chlamydophila psittaci (Cp) infection. Viability and infectivity of Cp, demonstrated by growth in culture, has not been yet investigated in these patients. We conducted a single-center prospective case-control study to assess the prevalence, viability and infectivity of Cp in 20 OAML patients and 42 blood donors registered in a 6-month period. The presence of Cp in conjunctival swabs and peripheral blood mononuclear cells (PBMC) of patients and donors was assessed by TETR-PCR and in vitro cultures. From an epidemiological point of view, OAML patients often resided in rural areas, and reported a history of chronic conjunctivitis and prolonged contact with household animals (85% vs. 38% of donors p = 0.00001). Cp was detected in lymphoma tissue in 15 (75%) patients. Cp DNA was detected in conjunctival swabs and/or PBMC from 10 (50%) patients and in PBMC from 1 (2%) donor (p = 0.01). Viability and infectivity of Cp, demonstrated by growth in culture, were confirmed in conjunctival swabs and/or PBMC from 5 (25%) patients, but not in donors (p = 0.002). This prospective study demonstrates, for the first time, that Cp present in the conjunctiva and PBMC of OAML patients is capable to grow and be isolated in cell cultures. Cp infection is common in OAML patients and exceptional in blood donors. Epidemiological data of OAML patients (prolonged contact with household animals and chronic conjunctivitis) are consistent with Cp exposure risk.
Publisher: MDPI AG
Date: 11-06-2023
Abstract: Cellular plasticity in cancer enables adaptation to selective pressures and stress imposed by the tumor microenvironment. This plasticity facilitates the remodeling of cancer cell phenotype and function (such as tumor stemness, metastasis, chemo/radio resistance), and the reprogramming of the surrounding tumor microenvironment to enable immune evasion. Epithelial plasticity is one form of cellular plasticity, which is intrinsically linked with epithelial–mesenchymal transition (EMT). Traditionally, EMT has been regarded as a binary state. Yet, increasing evidence suggests that EMT involves a spectrum of quasi-epithelial and quasi-mesenchymal phenotypes governed by complex interactions between cellular metabolism, transcriptome regulation, and epigenetic mechanisms. Herein, we review the complex cross-talk between the different layers of epithelial plasticity in cancer, encompassing the core layer of transcription factors, their interacting epigenetic modifiers and non-coding RNAs, and the manipulation of cancer immunogenicity in transitioning between epithelial and mesenchymal states. In examining these factors, we provide insights into promising therapeutic avenues and potential anti-cancer targets.
Publisher: Wiley
Date: 08-2007
Abstract: One complication of celiac disease (CD) is refractory CD. These patients frequently show aberrant intraepithelial T cell clones and an increasing risk of evolution into enteropathy-associated T cell lymphoma (EATL). There is debate in the literature whether these cases are actually a smoldering lymphoma from the outset. The mechanism inducing T cell proliferation and prognosis remains unknown. Recently, alemtuzumab has been proposed as a promising new approach to treat these patients. Only few single cases have been tested presently, nevertheless, in all of them a clinical improvement has been observed, while intraepithelial lymphocytes (IELs) effectively targeted by alemtuzumab are still a debated issue. Using 2D-DIGE, we found hyperexpressed proteins specifically associated with aberrant T cell in a patient with CD by comparing the protein expression with that of patients with CD and polyclonal T cell or with that of control subjects (patients with polyclonal T cell and no CD). Proteins with a higher expression in duodenal biopsy of the patient with aberrant T cell were identified as IgM, apolipoprotein C-III, and Charcot-Leyden crystal proteins. These preliminary data allow hypothesizing different clinical effects of alemtuzumab in patients with CD, since besides the probable effect of alemtuzumab on T cell, it could effect inflammatory-associated CD52(+) IgM(+)B cell and eosinophils cells, known to produce IgM and Charcot-Leyden crystal proteins, which we demonstrated to be altered in this patient. Results also emphasize the possible association of apolipoprotein with aberrant T cell proliferation.
No related grants have been discovered for Riccardo Dolcetti.