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1.
J Immunother Cancer ; 7(1): 140, 2019 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-31138333

RESUMEN

BACKGROUND: Tumor-associated macrophages (TAM) are expanded and exhibit tumor-promoting properties within the tumor microenvironment. Current methods to study TAM have not been replicated across cancer types and often do not include exogenous growth factors from the tumor, a key factor in TAM differentiation in vivo. METHODS: In this study, an in vitro method to generate monocyte- derived TAM using tumor- conditioned media (TCM) and a cytokine cocktail containing IL-4, IL-10, and M-CSF was utilized to study the phenotype, morphology, and function of TAM across multiple cancer types. TCM was generated from two breast cancer cell lines and an Epstein-Barr virus-positive lymphoma cell line. The properties of in vitro generated TAM were compared to in vitro generated M1 and M2- like macrophages and TAM isolated from patients with cancer. RESULTS: TAM generated in this fashion displayed an increase in CD163/CD206 co-expression compared to M2- like macrophages (87 and 36%, respectively). TAM generated in vitro exhibited increased transcript levels of the functional markers IL-6, IL-10, CCL2, c-Myc, iNOS, and arginase compared to in vitro generated M2-like macrophages. Functionally, in vitro generated TAM inhibited the proliferation of T cells (47% decrease from M1-like macrophages) and the production of IFN-γ by natural killer cells was inhibited (44%) when co-cultured with TAM. Furthermore, in vitro generated TAM secreted soluble factors that promote the growth and survival of tumor cells. CONCLUSIONS: Limited access to patient TAM highlights the need for methods to generate TAM in vitro. Our data confirm that monocyte-derived TAM can be generated reliably using TCM plus the cytokine cocktail of IL-4, IL-10, and M-CSF. Given the ability of TAM to inhibit immune cell function, continued study of methods to deplete or deactivate TAM in the setting of cancer are warranted.

2.
World Neurosurg ; 2019 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-31128312

RESUMEN

BACKGROUND: Myelopathy of the dorsal columns is a rare complication of intrathecal chemotherapy, most frequently with intrathecal methotrexate and cytarabine. Currently, this diagnosis is made with a combination of magnetic resonance imaging (MRI), somatosensory-evoked potentials, and elevated cerebrospinal fluid (CSF) protein levels, particularly myelin basic protein. CASE DESCRIPTION: A 73-year-old male with blastic plasmacytoid dendritic cell neoplasm (BPDCN) and known central nervous system involvement underwent standard treatment, including five doses of intrathecal cytosine arabinoside. Following this, he had documented CSF clearance of his disease. One year later, he developed progressive lower extremity weakness, numbness and bowel/bladder dysfunction. MRI and repeat CSF analysis demonstrated recurrence, and he underwent further intrathecal administration of methotrexate and cytarabine. CSF clearance of malignant cells was again established, but the weakness progressed to quadriplegia, loss of bowel/bladder control and severe sensory loss, particularly vibration and proprioception. Repeat MRI demonstrated high signal intensity in bilateral posterior columns. Ultimately, a lower thoracic spine dorsal column biopsy revealed cord destruction and diffuse macrophage infiltration with profound destruction of the neuropil. CONCLUSIONS: While dorsal column myelopathy has previously been described in association with intrathecal chemotherapy, this has solely been diagnosed on the basis of clinical examination, electrodiagnostic criteria, radiographic findings, and CSF analysis. This case provides a pathologic evaluation of an ante-mortem obtaimed specimen revealing a diffuse macrophage infiltration and profound destruction of the neuropil. While the mechanism underlying spinal cord toxicity following intrathecal chemotherapy remains largely unknown, this demonstrates a potentially macrophage-mediated process.

3.
Leuk Lymphoma ; : 1-10, 2019 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-30821551

RESUMEN

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy for which novel therapeutics with improved efficacy are greatly needed. To provide support for clinical immune checkpoint blockade, we comprehensively evaluated the expression of therapeutically targetable immune checkpoint molecules on primary MCL cells. MCL cells showed constitutive expression of Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1), variable CD200, absent PD-L2, Lymphocyte Activation Gene 3 (LAG-3), and Cytotoxic T-cell Associated Protein 4 (CTLA-4). Effector cells from MCL patients expressed PD-1. Co-culture of MCL cells with T-cells induced PD-L1 surface expression, a phenomenon regulated by IFNγ and CD40:CD40L interaction. Induction of PD-L1 was attenuated by concurrent treatment with ibrutinib or duvelisib, suggesting BTK and PI3K are important mediators of PD-L1 expression. Overall, our data provide further insight into the expression of checkpoint molecules in MCL and support the use of PD-L1 blocking antibodies in MCL patients.

4.
J Biol Chem ; 294(19): 7692-7710, 2019 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-30885941

RESUMEN

Epigenetic regulation by the type II protein arginine methyltransferase, PRMT5, plays an essential role in the control of cancer cell proliferation and tumorigenesis. In this report, we investigate the relationship between PRMT5 and WNT/ß-CATENIN as well as AKT/GSK3ß proliferative signaling in three different types of non-Hodgkin's lymphoma cell lines, clinical samples, and mouse primary lymphoma cells. We show that PRMT5 stimulates WNT/ß-CATENIN signaling through direct epigenetic silencing of pathway antagonists, AXIN2 and WIF1, and indirect activation of AKT/GSK3ß signaling. PRMT5 inhibition with either shRNA-mediated knockdown or a specific small molecule PRMT5 inhibitor, CMP-5, not only leads to derepression of WNT antagonists and decreased levels of active phospho-AKT (Thr-450 and Ser-473) and inactive phospho-GSK3ß (Ser-9) but also results in decreased transcription of WNT/ß-CATENIN target genes, CYCLIN D1, c-MYC, and SURVIVIN, and enhanced lymphoma cell death. Furthermore, PRMT5 inhibition leads to reduced recruitment of co-activators CBP, p300, and MLL1, as well as enhanced recruitment of co-repressors HDAC2 and LSD1 to the WNT/ß-CATENIN target gene promoters. These results indicate that PRMT5 governs expression of prosurvival genes by promoting WNT/ß-CATENIN and AKT/GSK3ß proliferative signaling and that its inhibition induces lymphoma cell death, which warrants further clinical evaluation.

6.
J Cell Physiol ; 2018 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-30387140

RESUMEN

LL-37, the only known human cathelicidin which is encoded by the human antimicrobial peptide (CAMP) gene, plays a critical role in protection against bacterial infection. We previously demonstrated that cathelicidin is induced by 1,25-dihydroxyvitamin D3 (1,25(OH) 2 D 3 ) in human airway epithelial cells with a resultant increase in bactericidal activity. In this study we identify key factors that co-operate with 1,25(OH) 2 D 3 in the regulation of CAMP. Our results show for the first time that PU.1, the myeloid transcription factor (which has also been identified in lung epithelial cells), co-operates with the vitamin D receptor and CCAAT/enhancer binding protein α (CEBPα) to enhance the induction of CAMP in lung epithelial cells. Our findings also indicate that enhancement of 1,25(OH) 2 D 3 regulation of CAMP by histone deacetylase inhibitors involves co-operation between acetylation and chromatin remodeling through Brahma-related gene 1 (BRG1; a component of the SWItch/sucrose nonfermentable [SWI/SNF] complex). BRG1 can be an activator or repressor depending on BRG1-associated factors. Protein arginine methyltransferase 5 (PRMT5), a methlytransferase which interacts with BRG1, represses 1,25(OH) 2 D 3 induced CAMP in part through dimethylation of H4R3. Our findings identify key mediators involved in the regulation of the CAMP gene in lung epithelial cells and suggest new approaches for therapeutic manipulation of gene expression to increase the antibacterial capability of the airway.

7.
Expert Opin Ther Targets ; 22(6): 527-545, 2018 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-29781349

RESUMEN

INTRODUCTION: Exploration in the field of epigenetics has revealed the diverse roles of the protein arginine methyltransferase (PRMT) family of proteins in multiple disease states. These findings have led to the development of specific inhibitors and discovery of several new classes of drugs with potential to treat both benign and malignant conditions. Areas covered: We provide an overview on the role of PRMT enzymes in healthy and malignant cells, highlighting the role of arginine methylation in specific pathways relevant to cancer pathogenesis. Additionally, we describe structure and catalytic activity of PRMT and discuss the mechanisms of action of novel small molecule inhibitors of specific members of the arginine methyltransferase family. Expert opinion: As the field of PRMT biology advances, it's becoming clear that this class of enzymes is highly relevant to maintaining normal physiologic processes as well and disease pathogenesis. We discuss the potential impact of PRMT inhibitors as a broad class of drugs, including the pleiotropic effects, off target effects the need for more detailed PRMT-centric interactomes, and finally, the potential for targeting this class of enzymes in clinical development of experimental therapeutics for cancer.

8.
Head Neck Pathol ; 2018 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-29700722

RESUMEN

Mycosis fungoides (MF) and Sézary syndrome are clonal T-cell proliferations that exhibit skin homing and represent the majority of cutaneous T-cell lymphomas. Early MF is a diagnostic challenge as both the clinical and microscopic features often mimic benign inflammatory conditions. Oral MF is very rare and has been associated in the past with advanced disease and a poor prognosis. Skin lesions are present for an average of > 6 years before oral involvement occurs. The clinical appearance is highly variable with tongue, palate and gingiva most often affected. We report 3 additional cases of oral MF, including one in which oral lesions are the initial disease presentation. Survival in patients presenting with oral MF is improving and can be attributed to advances in therapy.

9.
Clin Cancer Res ; 24(14): 3273-3281, 2018 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-29632007

RESUMEN

Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273-81. ©2018 AACR.

10.
Cancer Discov ; 8(4): 458-477, 2018 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29386193

RESUMEN

Bromodomain and extra-terminal (BET) family proteins are key regulators of gene expression in cancer. Herein, we utilize BRD4 profiling to identify critical pathways involved in pathogenesis of chronic lymphocytic leukemia (CLL). BRD4 is overexpressed in CLL and is enriched proximal to genes upregulated or de novo expressed in CLL with known functions in disease pathogenesis and progression. These genes, including key members of the B-cell receptor (BCR) signaling pathway, provide a rationale for this therapeutic approach to identify new targets in alternative types of cancer. Additionally, we describe PLX51107, a structurally distinct BET inhibitor with novel in vitro and in vivo pharmacologic properties that emulates or exceeds the efficacy of BCR signaling agents in preclinical models of CLL. Herein, the discovery of the involvement of BRD4 in the core CLL transcriptional program provides a compelling rationale for clinical investigation of PLX51107 as epigenetic therapy in CLL and application of BRD4 profiling in other cancers.Significance: To date, functional studies of BRD4 in CLL are lacking. Through integrated genomic, functional, and pharmacologic analyses, we uncover the existence of BRD4-regulated core CLL transcriptional programs and present preclinical proof-of-concept studies validating BET inhibition as an epigenetic approach to target BCR signaling in CLL. Cancer Discov; 8(4); 458-77. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.

12.
Discov Med ; 23(126): 189-199, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28472613

RESUMEN

Extranodal NK/T-cell lymphoma (ENKTL) is a rare aggressive extranodal non-Hodgkin lymphoma (NHL) universally associated with Epstein-Barr virus (EBV). ENKTL most commonly occurs in non-elderly immune competent males in Asia and South America. A number of antecedent lymphoproliferative disorders (LPDs) have been described in Asian and South American patients, but the majority of Caucasian ENKTL patients have no known preceding LPD or underlying immunodeficiency. Other than EBV, no environmental or extrinsic factor has been implicated in oncogenesis. The precise mechanisms by which EBV infects NK or T cells and the virus' role in the pathogenesis of ENKTL have not been fully deciphered. However, a number of recent discoveries including disturbances in cell signaling and mutations in tumor suppressor genes have been identified, which are providing insights into the pathogenesis of ENKTL. In this review, we highlight the molecular, viral, and genetic underpinnings of ENKTL and discuss potential therapeutic implications.


Asunto(s)
Linfoma Extranodal de Células NK-T/etiología , Linfoma Extranodal de Células NK-T/terapia , Infecciones por Virus de Epstein-Barr/complicaciones , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genómica , Herpesvirus Humano 4/fisiología , Humanos , Linfoma Extranodal de Células NK-T/genética , Linfoma Extranodal de Células NK-T/virología
13.
Leuk Lymphoma ; 58(10): 2310-2318, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28270022

RESUMEN

Histone deacetylase inhibitors (HDACi) have proven activity in hematologic malignancies, and their FDA approval in multiple myeloma (MM) and T-cell lymphoma highlights the need for further development of this drug class. We investigated AR-42, an oral pan-HDACi, in a first-in-man phase 1 dose escalation clinical trial. Overall, treatment was well tolerated, no DLTs were evident, and the MTD was defined as 40 mg dosed three times weekly for three weeks of a 28-day cycle. One patient each with MM and mantle cell lymphoma demonstrated disease control for 19 and 27 months (ongoing), respectively. Treatment was associated with reduction of serum CD44, a transmembrane glycoprotein associated with steroid and immunomodulatory drug resistance in MM. Our findings indicate that AR-42 is safe and that further investigation of AR-42 in combination regimens for the treatment of patients with lymphoma and MM is warranted. TRIAL REGISTRATION: http://clinicaltrials.gov/ct2/show/NCT01129193.

14.
J Immunol ; 198(4): 1439-1451, 2017 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-28087667

RESUMEN

In the autoimmune disease multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), expansion of pathogenic, myelin-specific Th1 cell populations drives active disease; selectively targeting this process may be the basis for a new therapeutic approach. Previous studies have hinted at a role for protein arginine methylation in immune responses, including T cell-mediated autoimmunity and EAE. However, a conclusive role for the protein arginine methyltransferase (PRMT) enzymes that catalyze these reactions has been lacking. PRMT5 is the main PRMT responsible for symmetric dimethylation of arginine residues of histones and other proteins. PRMT5 drives embryonic development and cancer, but its role in T cells, if any, has not been investigated. In this article, we show that PRMT5 is an important modulator of CD4+ T cell expansion. PRMT5 was transiently upregulated during maximal proliferation of mouse and human memory Th cells. PRMT5 expression was regulated upstream by the NF-κB pathway, and it promoted IL-2 production and proliferation. Blocking PRMT5 with novel, highly selective small molecule PRMT5 inhibitors severely blunted memory Th expansion, with preferential suppression of Th1 cells over Th2 cells. In vivo, PRMT5 blockade efficiently suppressed recall T cell responses and reduced inflammation in delayed-type hypersensitivity and clinical disease in EAE mouse models. These data implicate PRMT5 in the regulation of adaptive memory Th cell responses and suggest that PRMT5 inhibitors may be a novel therapeutic approach for T cell-mediated inflammatory disease.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Memoria Inmunológica , Proteína-Arginina N-Metiltransferasas/antagonistas & inhibidores , Proteína-Arginina N-Metiltransferasas/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Citocinas/inmunología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Regulación de la Expresión Génica , Humanos , Inflamación , Interleucina-2/biosíntesis , Interleucina-2/inmunología , Activación de Linfocitos , Metilación , Ratones , FN-kappa B/inmunología , Proteína-Arginina N-Metiltransferasas/genética , Células TH1/inmunología , Células Th2/inmunología , Regulación hacia Arriba
15.
Oncotarget ; 8(9): 14847-14859, 2017 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-28107179

RESUMEN

Protein arginine methyltransferase-5 (PRMT5) plays an important role in cancer progression by repressing the expression of key tumor suppressor genes via the methylation of transcriptional factors and chromatin-associated proteins. However, very little is known about the expression and biological role of PRMT5 in head and neck cancer. In this study, we examined expression profile of PRMT5 at subcellular levels in oropharyngeal squamous cell carcinoma (OPSCC) and assessed its correlation with disease progression and patient outcome. Our results show that nuclear PRMT5 was associated with poor overall survival (p < 0.012) and these patients had 1.732 times higher hazard of death (95% CI: 1.127-2.661) as compared to patients in whom PRMT5 was not present in the nucleus of the tumors. Nuclear PRMT5 expression was inversely correlated with p16-status (p < 0.001) and was significantly higher in tumor samples from patients who smoked > 10 pack-years (p = 0.013). In addition, nuclear PRMT5 was directly correlated with cyclin D1 (p = 0.0101) and IL-6 expression (p < 0.001). In a subgroup survival analysis, nuclear PRMT5-positive/IL-6-positive group had worst survival, whereas nuclear PRMT5-negative/IL-6-negative group had the best survival. Similarly, patients with p16-negative/nuclear PRMT5-positive tumors had worse survival compared to patients with p16-positive/nuclear PRMT5-negative tumors. Our mechanistic results suggest that IL-6 promotes nuclear translocation of PRMT5. Taken together, our results demonstrate for the first time that nuclear PRMT5 expression is associated with poor clinical outcome in OPSCC patients and IL-6 plays a role in the nuclear translocation of PRMT5.


Asunto(s)
Carcinoma de Células Escamosas/mortalidad , Núcleo Celular/metabolismo , Ciclina D1/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Interleucina-6/metabolismo , Neoplasias Orofaríngeas/mortalidad , Proteína-Arginina N-Metiltransferasas/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Citoplasma/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/patología , Pronóstico , Tasa de Supervivencia
16.
Int J Cancer ; 140(8): 1899-1906, 2017 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-27943278

RESUMEN

Epstein-Barr virus (EBV)-encoded RNAs (EBER) in tumor tissue and cell-free plasma EBV-DNA (pEBVd) are detected in EBV-associated lymphomas. Studies have suggested that EBER+ peripheral T-cell lymphomas (PTCL) have worse prognosis but the role of EBV in these neoplasms remains unclear. pEBVd is quantitative and more easily amenable to standardization than EBER, but frequency of pEBVd detection, clinical impact and agreement with EBER status in PTCL are unknown. We retrospectively assessed frequency of detectable pre-treatment pEBVd, presence of EBER in tumor tissue, and outcomes in 61 of 135 EBV-assessable PTCL patients. Fifteen of 61 patients (24.5%, 95% CI: 14-37%) were pre-treatment pEBVd+, with no significant differences in baseline characteristics or treatment between pEBVd+ and pEBVd- patients. EBER-ISH was performed on 10 pEBVd+ and 35 pEBVd- tumors. All 10 pEBVd+ patients were EBER+, but 9 pEBVd- patients were also EBER+. With median follow up of 24 months (range 1-96), overall survival (OS) was shorter in pEBVd+ compared to pEBVd- patients (13 vs. 72 months; p = 0.04). In our retrospective study, pre-treatment pEBVd was elevated in 25% of PTCL patients, was highly specific for EBER+ tumors, and was associated with shorter survival. pEBVd should be further explored as a prognostic variable and tumor biomarker in PTCL.


Asunto(s)
ADN Viral/sangre , Herpesvirus Humano 4/aislamiento & purificación , Linfoma de Células T Periférico/sangre , Pronóstico , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Supervivencia sin Enfermedad , Femenino , Herpesvirus Humano 4/patogenicidad , Humanos , Hibridación in Situ , Linfoma de Células T Periférico/patología , Linfoma de Células T Periférico/virología , Masculino , Persona de Mediana Edad
17.
Curr Hematol Malig Rep ; 11(6): 514-527, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27778143

RESUMEN

PURPOSE OF REVIEW: Extranodal NK/T cell lymphoma, nasal type (ENKTL-NT) is an aggressive extranodal non-Hodgkin lymphoma most commonly occurring in East Asia and Latin America but with increasing incidence in the United States. Data on epidemiology, disease presentation, and outcome for European and North American ("Western") cases are very limited. We review published landmark clinical studies on ENKTL-NT in the West and report in detail recent data, including our institutional experience. RECENT FINDINGS: We highlight key observations in its epidemiology, natural history, and trends in clinical management. In the USA, ENKTL-NT is more common among Asian Pacific Islanders (API) and Hispanics compared to non-Hispanic whites. Published studies indicate less heterogeneity in clinical presentation in Western ENKTL-NT compared to Asian patients. While there is variation in age at diagnosis, presence of antecedent lymphoproliferative disorders, and outcomes among racial/ethnic groups, the universal association of ENKTL-NT with EBV and the poor response of this neoplasm to anthracycline-based therapy is consistent across all geographic areas. Data on epidemiology, disease presentation, and clinical outcomes in mature T cell and NK cell (T/NK cell) neoplasms, including ENKTL-NT, in Europe and North America are very limited. As the classification and diagnostic characterization of the currently recognized T/NK cell lymphoma disease entities continue to evolve, gaps and inconsistencies in data reporting across different studies are being recognized. Despite these limitations, several studies from the USA suggest that the incidence of ENKTL-NT is higher in Asian Pacific Islanders (API) and non-white Hispanics and that outcomes may be worse in non-whites. However, the universal association of ENKTL-NT with Epstein-Barr virus (EBV) across all ethnic groups suggests a common pathogenesis. Given the overlap between the entities included in the category of T/NK cell neoplasms, there is a need to further define biological and clinical differences that may affect diagnosis, treatment, and outcome.


Asunto(s)
Linfoma Extranodal de Células NK-T/patología , Antineoplásicos/uso terapéutico , Asparaginasa/uso terapéutico , Biomarcadores/sangre , ADN Viral/análisis , Europa (Continente)/epidemiología , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/aislamiento & purificación , Herpesvirus Humano 4/fisiología , Humanos , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/epidemiología , Linfoma Extranodal de Células NK-T/virología , América del Norte/epidemiología
18.
Clin Lymphoma Myeloma Leuk ; 16 Suppl: S181-S190.e4, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27521316

RESUMEN

INTRODUCTION: Outcomes in advanced stage (AS) cutaneous T-cell lymphomas (CTCL) are poor but with great variability. Epstein-Barr virus (EBV) is associated with a subset of non-Hodgkin lymphomas. Frequency of plasma EBV-DNA (pEBVd) detection, concordance with EBV RNA (EBER) in tumor tissue, codetection of plasma cytomegalovirus DNA (pCMVd), and prognostic effect in AS CTCL are unknown. PATIENTS AND METHODS: Patients (n = 46; 2006-2013) with AS CTCL (≥IIB) were retrospectively studied. pEBVd and pCMVd were longitudinally measured using quantitative real-time polymerase chain reaction. EBER in situ hybridization (ISH) was performed on tumor samples. Survival from time of diagnosis (ToD) and time of progression to AS was assessed. RESULTS: Plasma EBV-DNA and pCMVd were detected in 37% (17 of 46) and 17% (8 of 46) of AS CTCL patients, respectively. pCMVd detection was significantly more frequent in pEBVd-positive (pEBVd(+)) than pEBVd(-) patients (35% vs. 7%; P = .038). Tumor tissue for EBER-ISH was available in 14 of 17 pEBVd(+) and 22 of 29 pEBVd(-) patients; 12 of 14 (85.7%) pEBVd(+) patients were EBER(+) versus 0 of 22 pEBVd(-) patients. Frequency of large cell transformation (LCT) tended to be greater in pEBVd(+) patients, but was not significant (10 of 14 pEBVd(+) vs. 10 of 23 pEBVd(-); P = .17). No notable differences in rates of increased levels of serum lactate dehydrogenase (LDH) were observed (17 of 17 pEBVd(+) vs. 27 of 29 pEBVd(-)). pEBVd detection was associated with significantly worse survival from ToD (P = .021) and time of progression to AS (P = .0098). CONCLUSION: Detection of cell-free plasma EBV-DNA was highly concordant with the presence of EBERs in tumor tissue, predicted survival independent of LDH and LCT, and should be further studied as a biomarker in AS CTCL.


Asunto(s)
Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/genética , Linfoma Cutáneo de Células T/diagnóstico , Linfoma Cutáneo de Células T/mortalidad , Carga Viral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Biopsia , ADN Viral , Infecciones por Virus de Epstein-Barr/complicaciones , Femenino , Estudios de Seguimiento , Humanos , Linfoma Cutáneo de Células T/etiología , Linfoma Cutáneo de Células T/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Piel/patología , Análisis de Supervivencia , Resultado del Tratamiento
19.
Cell Rep ; 16(2): 379-391, 2016 07 12.
Artículo en Inglés | MEDLINE | ID: mdl-27373165

RESUMEN

Human natural killer (NK) cells develop in secondary lymphoid tissues (SLTs) through distinct stages. We identified two SLT lineage (Lin)(-)CD34(-)CD117(+/-)CD94(+)CD16(-) "stage 4" subsets according to expression of the C-type lectin-like surface-activating receptor, NKp80: NKp80(-) (stage "4a") and NKp80(+) (stage "4b"). Whereas stage 4b cells expressed more of the transcription factors T-BET and EOMES, produced interferon-gamma, and were cytotoxic, stage 4a cells expressed more of the transcription factors RORγt and AHR and produced interleukin-22, similar to SLT Lin(-)CD34(-)CD117(+)CD94(-)CD16(-) "stage 3" cells, whose phenotype overlaps with that of group 3 innate lymphoid cells (ILC3s). Co-culture with dendritic cells or transplantation into immunodeficient mice produced mature NK cells from stage 3 and stage 4a populations. These data identify NKp80 as a marker of NK cell maturity in SLTs and support a model of human NK cell development through a stage 4a intermediate with ILC3-associated features.


Asunto(s)
Células Asesinas Naturales/fisiología , Lectinas Tipo C/metabolismo , Receptores de Células Asesinas Naturales/metabolismo , Animales , Células Cultivadas , Células Dendríticas/fisiología , Femenino , Humanos , Células Asesinas Naturales/trasplante , Tejido Linfoide/citología , Ratones Endogámicos NOD , Ratones SCID
20.
ILAR J ; 57(1): 55-62, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27034395

RESUMEN

The Epstein-Barr virus (EBV) is a B-lymphotropic gamma herpes virus associated with a number of malignancies. Most EBV-related cancers present complex medical management challenges; thus it has been essential to develop preclinical in vivo models allowing for the study of pathogenesis, prevention, and treatment of these diseases. Early in vivo models used nonhuman primates; however, such models were limited by the inability of EBV to achieve viral latency, availability, and cost. Immunodeficient mouse strains emerged as efficient models that allow for engraftment of human mononuclear cells and controlled evaluation of EBV-driven lymphoproliferative disease (EBV-LPD). By using highly immunodeficient strains of mice such as severe combined immune deficiency (SCID) and NOD/LtSz-scid ILrg(-/-)(NOG) mice, investigators have developed efficient platforms for evaluating pathogenesis of benign (HLH) and malignant (EBV-LPD) diseases associated with EBV. Humanized murine chimeric models have been essential tools for evaluating preventive strategies with vaccine and adoptive cellular approaches, as well as development of experimental therapeutic strategies. Manipulation of the human immune cells before engraftment or mutation of viral lytic and latent genes has enhanced our understanding of the oncogenic nature of EBV and the complexity of human immune responses to EBV. In this review, we discuss how the EBV murine models have evolved to become essential tools for studying the virology of EBV as it relates to human EBV-LPD pathogenesis, the immunobiology of innate and adaptive responses, and limitations of these models.


Asunto(s)
Herpesvirus Humano 4/fisiología , Linfoma/virología , Animales , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos NOD , Ratones SCID
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