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1.
Molecules ; 28(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36677874

RESUMO

Distant metastasis remains the primary cause of treatment failure and suggests a poor prognosis in nasopharyngeal carcinoma (NPC). Epithelial-mesenchymal transition (EMT) is a critical cellular process for initiating a tumor invasion and remote metastasis. Our previous study showed that the blockage of the stromal interaction molecule 1 (STIM1)-mediated Ca2+ signaling blunts the Epstein-Barr virus (EBV)-promoted cell migration and inhibits the dissemination and lymphatic metastasis of NPC cells. However, the upstream signaling pathway that regulates the STIM1 expression remains unknown. In this follow-up study, we demonstrated that the miRNA-185-5p/STIM1 axis is implicated in the regulation of the metastatic potential of 5-8F cells, a highly invasive NPC cell line. We demonstrate that the knockdown of STIM1 attenuates the migration ability of 5-8F cells by inhibiting the epidermal growth factor receptor (EGFR) phosphorylation-induced switch from E- to N-cadherin in vitro. In addition, the STIM1 knockdown inhibited the locoregional lymphatic invasion of the 5-8F cells in mice. Furthermore, we identified miRNA-185-5p as an upstream regulator that negatively regulates the expression of STIM1. Our findings suggest that the miRNA-185-5p/STIM1 axis regulates the invasiveness of NPC cell lines by affecting the EGFR activation-modulated cell adhesiveness. The miRNA-185-5p/STIM1 axis may serve as a potentially effective therapeutic target for the treatment of NPC.


Assuntos
Infecções por Vírus Epstein-Barr , MicroRNAs , Neoplasias Nasofaríngeas , Animais , Camundongos , Carcinoma Nasofaríngeo/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo , Caderinas/genética , Caderinas/metabolismo , Seguimentos , Linhagem Celular Tumoral , Herpesvirus Humano 4 , Receptores ErbB/genética , Receptores ErbB/metabolismo , Movimento Celular/genética , Transição Epitelial-Mesenquimal/genética , Invasividade Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Proliferação de Células
2.
Rev Esp Patol ; 56(1): 45-57, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36599600

RESUMO

The treatment of head and neck and salivary gland tumours is complicated and is constantly evolving. Prognostic and predictive indicators of response to treatment are enormously valuable for designing individualized therapies, which justifies their research and validation. Some biomarkers, such as p16, Epstein-Barr virus, PD-L1, androgen receptors and HER-2, are already used routinely in clinical practice. These biomarkers, along with other markers that are currently under development, and the massively parallel sequencing of genes, ensure future advances in the treatment of these neoplasms. In this consensus, a group of experts in the diagnosis and treatment of tumours of the head and neck and salivary glands were selected by the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica - SEAP) and the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica - SEOM) to evaluate the currently available information and propose a series of recommendations to optimize the determination and daily clinical use of biomarkers.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias de Cabeça e Pescoço , Neoplasias das Glândulas Salivares , Humanos , Consenso , Herpesvirus Humano 4 , Oncologia , Biomarcadores Tumorais , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética
3.
PLoS One ; 18(1): e0280443, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36652488

RESUMO

INTRODUCTION: Herpesviruses are recognized as major causes of human diseases. Following initial infection, Herpesviruses can undergo cycles of reactivation controlled largely by the immune system. Cigarette smoking is an important modulator of the immune system particularly in individuals with serious mental illness where smoking is associated with increased rates of cardiopulmonary diseases and mortality. However, the effect of smoking on Herpesviruses has not been extensively studied. METHODS: In this nested cohort study, cigarette smoking was assessed in 1323 persons with serious mental illness or without a psychiatric disorder ascertained in a psychiatric health care system and the adjacent community. Participants provided a blood sample from which were measured IgG class antibodies to five human Herpesviruses: Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus-Type 1 (HSV-1); Varicella Zoster Virus (VZV); and Human Herpes Virus-Type 6 (HHV-6). The associations between smoking variables and antibody levels to the Herpesviruses were analyzed among diagnostic groups in multiple regression models adjusted for age, sex, and race. RESULTS: Current smoking was significantly associated with higher levels of antibodies to CMV (coefficient .183, 95% CI .049, .317, p<.001, q<.007) and the three EBV proteins (EBV NA -(coefficient .088, 95% CI .032, .143, p = .002, q<.014; EBV Virion - coefficient .100, 95% CI .037, .163, p = .002, q<.014; and EBV VCA - coefficient .119, 95% CI .061, .177, p = .00004, q<.0016). The amount of cigarettes smoked was also correlated with higher levels of antibodies to the three EBV proteins. Interaction analyses indicated that the association between cigarette smoking and levels of antibodies to CMV and EBV was independent of diagnostic group. Cigarette smoking was not significantly associated with the level of antibodies to HSV-1, VZV, or HHV-6. CONCLUSIONS: Individuals who smoke cigarettes have increased levels of IgG antibodies to CMV and EBV. Cigarette smoking may be a contributory factor in the relationship between CMV, EBV and chronic somatic disorders associated with these viruses.


Assuntos
Fumar Cigarros , Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Herpesvirus Humano 1 , Herpesvirus Humano 6 , Produtos do Tabaco , Vírus , Humanos , Herpesvirus Humano 4 , Estudos de Coortes , Fumar/efeitos adversos , Herpesvirus Humano 3 , Citomegalovirus , Imunoglobulina G , Anticorpos Antivirais
4.
Clin Cancer Res ; 29(2): 324-330, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36628536

RESUMO

PURPOSE: Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus. PATIENTS AND METHODS: We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either unresponsive to or patients were unable to tolerate standard antiviral therapies. Fifty-eight adult and pediatric patients were enrolled and treated. RESULTS: Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion. CONCLUSIONS: In this open-label trial, treatment of refractory viral infections/disease in allo-HCT recipients with posoleucel was feasible, safe, and effective.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Transplante de Células-Tronco Hematopoéticas , Viroses , Adulto , Criança , Humanos , Antivirais/efeitos adversos , Terapia Baseada em Transplante de Células e Tecidos/efeitos adversos , Infecções por Vírus Epstein-Barr/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4 , Viroses/epidemiologia , Viroses/prevenção & controle
5.
Zhonghua Bing Li Xue Za Zhi ; 52(1): 37-42, 2023 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-36617904

RESUMO

Objective: To study the clinicopathological characteristics, and further understand primary central nervous system T-cell lymphoma (PCNSTCL) in children and adolescents. Methods: Five cases of PCNSTCL in children and adolescents were collected from December 2016 to December 2021 at the First Affiliated Hospital of Zhengzhou University. The clinicopathological characteristics, immunophenotypic, and molecular pathologic features were analyzed, and relevant literatures reviewed. Results: There were two male and three female patients with a median age of 14 years (range 11 to 18 years). There were two peripheral T-cell lymphomas, not otherwise specified, two anaplastic large cell lymphoma, ALK-positive and one NK/T cell lymphoma. Pathologically, the tumor cells showed a variable histomorphologic spectrum, including small, medium and large cells with diffuse growth pattern and perivascular accentuation. Immunohistochemistry and in situ hybridization showed CD3 expression in four cases, and CD3 was lost in one case. CD5 expression was lost in four cases and retained in one case. ALK and CD30 were expressed in two cases. One tumor expressed CD56 and Epstein-Barr virus-encoded RNA. All cases showed a cytotoxic phenotype with expression of TIA1 and granzyme B. Three cases had a high Ki-67 index (>50%). T-cell receptor (TCR) gene rearrangement was clonal in two cases. Conclusions: PCNSTCL is rare, especially in children and adolescents. The morphology of PCNSTCL is diverse. Immunohistochemistry and TCR gene rearrangement play important roles in the diagnosis.


Assuntos
Neoplasias do Sistema Nervoso Central , Infecções por Vírus Epstein-Barr , Linfoma de Células T Periférico , Linfoma de Células T , Feminino , Humanos , Masculino , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Herpesvirus Humano 4 , Linfoma de Células T/genética , Linfoma de Células T/patologia , Linfoma de Células T Periférico/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Antígenos de Linfócitos T , Criança , Adolescente
6.
BMC Cancer ; 23(1): 47, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639629

RESUMO

BACKGROUND: New concepts for a more effective anti-cancer therapy are urgently needed. Experimental flaws represent a major counter player of this development and lead to inaccurate and unreproducible data as well as unsuccessful translation of research approaches into clinics. In a previous study we have created epithelial cell cultures from head and neck squamous cell carcinoma (HNSCC) tissue. METHODS: We characterize primary cell populations isolated from human papillomavirus positive HNSCC tissue for their marker expression by RT-qPCR, flow cytometry, and immunofluorescence staining. Their sensitivity to MDM2-inhibition was measured using cell viability assays. RESULTS: Primary HNSCC cell cultures showed the delayed formation of spheroids at higher passages. These spheroids mimicked the morphology and growth characteristics of other established HNSCC spheroid models. However, expression of epithelial and mesenchymal markers could not be detected in these cells despite the presence of the HNSCC stem cell marker aldehyde dehydrogenase 1 family member A1. Instead, strong expression of B- and T-lymphocytes markers was observed. Flow cytometry analysis revealed a heterogeneous mixture of CD3 + /CD25 + T-lymphocytes and CD19 + B-lymphocytes at a ratio of 4:1 at passage 5 and transformed lymphocytes at late passages (≥ passage 12) with CD45 + CD19 + CD20 + , of which around 10 to 20% were CD3 + CD25 + CD56 + . Interestingly, the whole population was FOXP3-positive indicative of regulatory B-cells (Bregs). Expression of transcripts specific for the Epstein-Barr-virus (EBV) was detected to increase in these spheroid cells along late passages, and this population was vulnerable to MDM2 inhibition. HPV + HNSCC cells but not EBV + lymphocytes were detected to engraft into immunodeficient mice. CONCLUSIONS: In this study we present a primary cell culture of EBV-infected tumor-infiltrating B-lymphocytes, which could be used to study the role of these cells in tumor biology in future research projects. Moreover, by describing the detailed characteristics of these cells, we aim to caution other researchers in the HNSCC field to test for EBV-infected lymphocyte contaminations in primary cell cultures ahead of further experiments. Especially researchers who are interested in TIL-based adopted immunotherapy should exclude these cells in their primary tumor models, e.g. by MDM2-inhibitor treatment. BI-12-derived xenograft tumors represent a suitable model for in vivo targeting studies.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias de Cabeça e Pescoço , Humanos , Camundongos , Animais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Herpesvirus Humano 4 , Linfócitos , Proliferação de Células , Técnicas de Cultura de Células
7.
Int J Mol Sci ; 24(2)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675014

RESUMO

(1) Multiple sclerosis (MS) is a chronic inflammatory disease of autoimmune origin. The Epstein-Barr virus (EBV) is associated with the onset of MS, as almost all patients have high levels of EBV-specific antibodies as a result of a previous infection. We evaluated longitudinally the effects of dimethyl fumarate (DMF), a first-line treatment of MS, on the quantity and quality of EBV-specific IgG in MS patients. (2) Serum samples from 17 MS patients receiving DMF were taken before therapy (T0) and after 1 week (T1) and 1 (T2), 3 (T3) and 6 (T4) months of treatment. Anti-EBV nuclear antigen (EBNA)-1 and capsid antigen (CA) IgG levels and anti-CA IgG avidity were measured in all samples. (3) Serum levels of anti-CA IgG were lower at T1 (p = 0.0341), T2 (p = 0.0034), T3 (p < 0.0001) and T4 (p = 0.0023) than T0. These differences were partially confirmed also in anti-EBNA-1 IgG levels (T3 vs. T0, p = 0.0034). All patients had high-avidity anti-CA IgG at T0, and no changes were observed during therapy. (4): DMF can reduce the amount but not the avidity of the anti-EBV humoral immune response in MS patients from the very early stages of treatment.


Assuntos
Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Humanos , Herpesvirus Humano 4 , Antígenos Virais , Projetos Piloto , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Capsídeo , Formação de Anticorpos , Imunoglobulina G , Anticorpos Antivirais , Proteínas do Capsídeo
8.
Am Fam Physician ; 107(1): 71-78, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36689975

RESUMO

Infectious mononucleosis is a viral syndrome characterized by fever, pharyngitis, and posterior cervical lymphadenopathy. It is usually caused by Epstein-Barr virus and most often affects adolescents and young adults 15 to 24 years of age. Primary transmission is through close personal contact with a person who is infected, particularly their saliva. Cost-effective, efficient initial laboratory testing for acute infectious mononucleosis includes complete blood count with differential (to assess for greater than 40% lymphocytes and greater than 10% atypical lymphocytes) and a rapid heterophile antibody test. The heterophile antibody test has a sensitivity of 87% and specificity of 91% but can have a false-negative result in children younger than five years and in adults during the first week of illness. The presence of elevated liver enzymes increases clinical suspicion for infectious mononucleosis in the setting of a negative heterophile antibody test result. Epstein-Barr viral capsid antigen-antibody testing is more sensitive and specific but more expensive and takes longer to process than the rapid heterophile antibody test. Treatment of infectious mononucleosis is supportive; routine use of antivirals and corticosteroids is not recommended. Current guidelines recommend that patients with infectious mononucleosis not participate in athletic activity for three weeks from onset of symptoms. Shared decision-making should be used to determine the timing of return to activity. Immunosuppressed populations are at higher risk of severe disease and significant morbidity. Epstein-Barr virus infection has been linked to nine types of cancer, including Hodgkin lymphoma, non-Hodgkin lymphoma, and nasopharyngeal carcinoma, and some autoimmune diseases.


Assuntos
Doenças Autoimunes , Infecções por Vírus Epstein-Barr , Mononucleose Infecciosa , Criança , Adolescente , Humanos , Mononucleose Infecciosa/diagnóstico , Mononucleose Infecciosa/terapia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4 , Anticorpos Heterófilos , Anticorpos Antivirais
9.
RMD Open ; 9(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36690384

RESUMO

Macrophage activation syndrome (MAS) is a subtype of haemophagocytic lymphohistiocytosis (HLH), and a well-described complication of systemic juvenile idiopathic arthritis (SJIA), triggered by disease onset or flare, infection, or some medications. Here, we report a 20-year-old man with previously well-controlled SJIA, who developed first time MAS after acute Epstein-Barr virus (EBV) infection, with MAS recurrence due to a drug reaction, '3-week sulfasalazine syndrome', secondary to prophylactic trimethoprim/sulfamethoxazole. Both episodes of MAS were minimally responsive to pulse corticosteroids. Initial EBV-driven MAS was treated with multiple doses of emapalumab prior to resolution, while MAS secondary to sulfasalazine-induced 3-week syndrome required the initiation of ruxolitinib. This case exhibits two rare but life-threatening causes of MAS/secondary HLH in a single patient and the difficulties in their diagnosis and management.


Assuntos
Artrite Juvenil , Infecções por Vírus Epstein-Barr , Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Masculino , Humanos , Adulto Jovem , Adulto , Síndrome de Ativação Macrofágica/complicações , Infecções por Vírus Epstein-Barr/complicações , Artrite Juvenil/complicações , Sulfassalazina , Herpesvirus Humano 4 , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico
10.
J Pediatr Hematol Oncol ; 45(1): e145-e149, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36598967

RESUMO

Rituximab (RTX) is widely employed to treat Epstein-Barr virus reactivation in children undergoing Hematopoietic Cell Transplantation (HCT). The resulting loss of B cells may cause persistent hypogammaglobulinemia. This retrospective cross-sectional study aims to identify flow cytometry biomarkers associated with persistent hypogammaglobulinemia in patients receiving RTX after HCT. We analyzed 5 patients (cases group) requiring immunoglobulin substitution due to low level of IgG (IgG <5 g/L) detected after RTX treatment and 5 patients (controls group) not requiring long-term immunoglobulin (Ig) substitution. We investigated the B cell reconstitution, and in patients group we observed a significantly lower count in B total, IgD+CD27+ marginal B cells and IgD-CD27+ switched-memory B cells, after a median of 5 years from HCT, compared with the control group. Despite the importance limits of our study and the heterogeneity of our data (age of included patients, time of evaluation, interval between RTX dose and assessment) we conclude that RTX given early after HCT might cause a deranged B cell maturation, contributing to the delation in B cell recovery following HCT, and switched memory and marginal zone B cell counts could be a promising biomarker to identify patients requiring long-term Ig substitution.


Assuntos
Agamaglobulinemia , Subpopulações de Linfócitos B , Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Rituximab/uso terapêutico , Agamaglobulinemia/terapia , Agamaglobulinemia/induzido quimicamente , Estudos Retrospectivos , Estudos Transversais , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/etiologia , Anticorpos Monoclonais Murinos/uso terapêutico , Herpesvirus Humano 4 , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Biomarcadores , Imunoglobulina G
11.
Diagn Pathol ; 18(1): 2, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627681

RESUMO

BACKGROUND: Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT), is a rare, aggressive subtype of non-Hodgkin lymphoma, and it usually presents as a destructive sinus mass that may attend epistaxis. However, ENKTCL-NT with the manifestation of peripheral neuropathy is pretty unusual. CASE PRESENTATION: A 17-year-old Chinese patient presented with peripheral neuropathy and positive auto-antibodies. However, she failed methylprednisolone pulse therapy and developed hemophagocytic syndrome. The diagnosis of CD30-positive primary cutaneous ENKTCL-NT was confirmed by pathological biopsy. Her disease was brought under control after five cycles of chemotherapy. CONCLUSIONS: The report findings are helpful in the differential diagnosis of peripheral neuropathy and autoimmune disease. We should be alert for the development of ENKTCL-NT when the rash and peripheral neuropathy are the first symptoms and are accompanied by Epstein-Barr virus (EBV) infection.


Assuntos
Infecções por Vírus Epstein-Barr , Exantema , Linfoma Extranodal de Células T-NK , Linfoma de Células T Periférico , Doenças do Sistema Nervoso Periférico , Feminino , Humanos , Adolescente , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Exantema/etiologia , Exantema/complicações , Linfoma Extranodal de Células T-NK/complicações , Linfoma Extranodal de Células T-NK/diagnóstico , Linfoma Extranodal de Células T-NK/patologia , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/complicações
12.
Theranostics ; 13(2): 458-471, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36632221

RESUMO

Nasopharyngeal carcinoma (NPC) is a diverse cancer with no well-defined tumor antigen, associated with oncogenic Epstein-Barr Virus (EBV), and with usually late-stage diagnosis and survival <40%. Current radiotherapy and chemotherapy have low effectiveness and cause adverse effects, which calls for the need of new therapy. In this regard, adoptive immunotherapy using γδ T cells has potential, but needs to be coupled with butyrophilin 2A1 and 3A1 protein expression to achieve tumoricidal effect. Methods: Human γδ T cells were expanded (with Zol or PTA) and used for cytotoxicity assay against NPC cells, which were treated with the EBV EBNA1-targeting peptide (L2)P4. Effect of (L2)P4 on BTN2A1/BTN3A1 expression in NPC cells was examined by flow cytometry and Western blot. An NPC-bearing NSG mice model was established to test the effectiveness of P4 and adoptive γδ T cells. Immunofluorescence was performed on NPC tissue sections to examine the presence of γδ T cells and expression of BTN2A1 and BTN3A1. EBV gene expression post-(L2)P4 treatment was assessed by qRT-PCR, and the relationship of LMP1, NLRC5 and BTN2A1/BTN3A1 was examined by transfection, reporter assay, Western blot, and inhibition experiments. Results: Zol- or PTA-expanded the Vδ2 subset of γδ T cells that exerted killing against certain NPC cells. (L2)P4 reactivates latent EBV, which increased BTN2A1 and BTN3A1 expression and conferred higher susceptibility towards Vδ2 T cells cytotoxicity in vitro, as well as enhanced tumor regression in vivo by adoptive transfer of Vδ2 T cells. Mechanistically, (L2)P4 induced EBV LMP1, leading to IFN-γ/p-JNK and NLRC5 activation, and subsequently stimulated the expression of BTN2A1 and BTN3A1. Conclusions: This study demonstrated the effectiveness of using the EBV-targeting probe (L2)P4 and adoptive γδ T cells as a promising combinatorial immunotherapy against NPC. The identification of the LMP1-IFN-γ/p-JNK-NLRC5-BTN2A1/BTN3A1 axis may lead to new insight and therapeutic targets against NPC and other EBV+ tumors.


Assuntos
Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Camundongos , Animais , Humanos , Carcinoma Nasofaríngeo/terapia , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Carcinoma/terapia , Carcinoma/patologia , Neoplasias Nasofaríngeas/metabolismo , Butirofilinas , Peptídeos e Proteínas de Sinalização Intracelular , Antígenos CD
13.
Ann Med ; 55(1): 388-400, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36629738

RESUMO

BACKGROUND: Venetoclax monotherapy is an effective option for patients with acute myeloid leukemia (AML). Venetoclax has also been used in non-myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk AML with a tolerable toxicity profile. However, the efficacy and safety of a venetoclax-containing myeloablative conditioning (MAC) allo-HSCT regimen for high-risk AML have not been evaluated. OBJECTIVE: To evaluate the safety and efficacy of a MAC regimen containing venetoclax for high-risk AML. STUDY DESIGN: From 25 February 2021 to 4 September 2022, a total of 31 patients with high-risk AML who underwent allo-HSCT and a MAC regimen with venetoclax were analyzed. RESULTS: At the time of transplantation, 21 patients were in first complete remission (CR1), 4 were in a second complete remission (CR2), and 6 in non-remission (NR). Twenty-four patients (77.4%) were minimal residual disease (MRD)-positive before transplant. The FLT3-ITD gene mutation was present in 51.6% of patients. NUP98 rearrangement, MLL rearrangement or MLL-PTD and DEK::CAN fusion genes were found in 5 (16.1%), 7(22.6%) and 2 (6.5%) patients, respectively. Twenty-nine (93.6%) patients underwent haploidentical allo-HSCT. The median follow-up time was 278 days (range: 52-632 days). The 100-day cumulative incidence of grade 3 to 4 acute graft-versus-host disease (aGVHD) was 16.1% (95%CI, 7.2-36.0%). The 180-day cumulative incidence of moderate to severe chronic graft-versus-host disease (cGVHD) was 7.1% (95%CI, 1.9-26.9%). Cumulative incidence of 100-day cytomegalovirus (CMV) viraemia and 100-day Epstein-Barr virus (EBV) viraemia was 61.6% (95%CI, 46.5-81.4%) and 3.2% (95%CI, 0.4-22.2%), respectively. The 600-day overall survival (OS) and leukemia-free survival (LFS) were 80.9% (95%CI, 63.5-93.6%) and 81.3% (95%CI, 64.2-93.7%), respectively. The 600-day relapse incidence (RI) and non-relapse mortality (NRM) was 6.9% (95%CI, 1.8-26.3%) and 11.7% (95%CI, 3.9-35.0%). CONCLUSION: Our study shows that the addition of venetoclax to a MAC allo-HSCT was feasible, safe and effective for high-risk AML patients.


Assuntos
Infecções por Citomegalovirus , Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Infecções por Vírus Epstein-Barr/complicações , Viremia/complicações , Estudos Retrospectivos , Transplante Homólogo/efeitos adversos , Herpesvirus Humano 4 , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Condicionamento Pré-Transplante/efeitos adversos , Proteínas de Ligação a Poli-ADP-Ribose , Proteínas Cromossômicas não Histona , Proteínas Oncogênicas
14.
Viruses ; 15(1)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36680216

RESUMO

Epstein-Barr virus (EBV) is a gamma-herpesvirus associated with 10% of all gastric cancers (GCs) and 1.5% of all human cancers. EBV-associated GCs (EBVaGCs) are pathologically and clinically distinct entities from EBV-negative GCs (EBVnGCs), with EBVaGCs exhibiting differential molecular pathology, treatment response, and patient prognosis. However, the tumor immune landscape of EBVaGC has not been well explored. In this study, a systemic and comprehensive analysis of gene expression and immune landscape features was performed for both EBVaGC and EBVnGC. EBVaGCs exhibited many aspects of a T cell-inflamed phenotype, with greater T and NK cell infiltration, increased expression of immune checkpoint markers (BTLA, CD96, CTLA4, LAG3, PD1, TIGIT, and TIM3), and multiple T cell effector molecules in comparison with EBVnGCs. EBVaGCs also displayed a higher expression of anti-tumor immunity factors (PDL1, CD155, CEACAM1, galectin-9, and IDO1). Six EBV-encoded miRNAs (miR-BARTs 8-3p, 9-5p, 10-3p, 22, 5-5p, and 14-3p) were strongly negatively correlated with the expression of immune checkpoint receptors and multiple markers of anti-tumor immunity. These profound differences in the tumor immune landscape between EBVaGCs and EBVnGCs may help explain some of the observed differences in pathological and clinical outcomes, with an EBV-positive status possibly being a potential biomarker for the application of immunotherapy in GC.


Assuntos
Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Herpesvirus Humano 4/genética , Neoplasias Gástricas/genética , Linfócitos T/metabolismo , Biomarcadores , Expressão Gênica
15.
Radiat Oncol ; 18(1): 15, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36681832

RESUMO

BACKGROUND: The high heterogeneity of de novo metastatic nasopharyngeal carcinoma (dmNPC) makes its prognosis and treatment challenging. We aimed to accurately stage dmNPC and assess the patterns of treatment strategies for different risk groups. METHODS: The study enrolled a total of 562 patients, 264 from 2007 to 2013 in the training cohort and 298 from 2014 to 2017 in the validation cohort. Univariate and multivariate Cox regression analyses were conducted to determine the independent variables for overall survival (OS). Recursive partitioning analysis (RPA) was applied to establish a novel risk-stratifying model based on these variables. RESULTS: After pairwise comparisons of OS, three risk groups were generated: low-risk (involved lesions ≤ 4 without liver involvement), intermediate-risk (involved lesions ≤ 4 with liver involvement or involved lesions > 4 with Epstein-Barr virus (EBV)-DNA < 62,000 copies/ml), and high-risk (involved lesions > 4 with EBV-DNA > 62,000 copies/ml). The 3-year OS rate differed significantly between groups (80.4%, 42.0%, and 20.4%, respectively, all P < 0.05). Adding locoregional intensity-modulated radiotherapy (LRRT) followed by palliative chemotherapy (PCT) resulted in a significant OS benefit over PCT alone for the low- and intermediate-risk groups (P = 0.0032 and P = 0.0014, respectively). However, it provided no survival benefits for the high-risk group (P = 0.6). Patients did not benefit from concurrent chemotherapy during LRRT among the three subgroups (P = 0.12, P = 0.13, and P = 0.3, respectively). These results were confirmed with the validation cohort. CONCLUSIONS: The novel RPA model revealed superior survival performance in subgroup stratification and could facilitate more effective treatment strategies for dmNPC.


Assuntos
Infecções por Vírus Epstein-Barr , Neoplasias Nasofaríngeas , Radioterapia de Intensidade Modulada , Humanos , Carcinoma Nasofaríngeo/patologia , Prognóstico , Estudos Retrospectivos , Neoplasias Nasofaríngeas/patologia , Herpesvirus Humano 4/genética , DNA Viral , Tomada de Decisão Clínica
16.
J Exp Med ; 220(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36652203

RESUMO

20 yr ago, a tribute appeared in this journal on the 70th anniversary of an animal model of disseminated encephalomyelitis, abbreviated EAE for experimental autoimmune encephalomyelitis. "Observations on Attempts to Produce Disseminated Encephalomyelitis in Monkeys" appeared in the Journal of Experimental Medicine on February 21, 1933. Rivers and colleagues were trying to understand what caused neurological reactions to viral infections like smallpox, vaccinia, and measles, and what triggered rare instances of encephalomyelitis to smallpox vaccines. The animal model known as EAE continues to display its remarkable utility. Recent research, since the 70th-anniversary tribute, helps explain how Epstein-Barr virus triggers multiple sclerosis via molecular mimicry to a protein known as GlialCAM. Proteins with multiple domains similar to GlialCAM, tenascin, neuregulin, contactin, and protease kinase C inhibitors are present in the poxvirus family. These observations take us a full circle back to Rivers' first paper on EAE, 90 yr ago.


Assuntos
Encefalomielite Autoimune Experimental , Encefalomielite , Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Varíola , Vírus , Animais , Herpesvirus Humano 4 , Modelos Animais de Doenças
17.
Int J Mol Sci ; 24(2)2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36675141

RESUMO

EBV and Helicobacter pylori (H. pylori) cause highly prevalent persistent infections as early as in childhood. Both pathogens are associated with gastric carcinogenesis. H. pylori interferes with iron metabolism, enhancing the synthesis of acute-phase proteins hepcidin, C-reactive protein (CRP), and α-1 glycoprotein (AGP), but we do not know whether EBV does the same. In this study, we correlated the EBV antibody levels and the serum levels of hepcidin, CRP, and AGP in 145 children from boarding schools in Mexico City. We found that children IgG positive to EBV antigens (VCA, EBNA1, and EA) presented hepcidin, AGP, and CRP levels higher than uninfected children. Hepcidin and AGP remained high in children solely infected with EBV, while CRP was only significantly high in coinfected children. We observed positive correlations between hepcidin and EBV IgG antibodies (p < 0.5). Using the TCGA gastric cancer database, we also observed an association between EBV and hepcidin upregulation. The TCGA database also allowed us to analyze the two important pathways controlling hepcidin expression, BMP-SMAD and IL-1ß/IL-6. We observed only the IL-1ß/IL-6-dependent inflammatory pathway being significantly associated with EBV infection. We showed here for the first time an association between EBV and enhanced levels of hepcidin. Further studies should consider EBV when evaluating iron metabolism and anemia, and whether in the long run this is an important mechanism of undernourishment and EBV gastric carcinogenesis.


Assuntos
Infecções por Vírus Epstein-Barr , Helicobacter pylori , Neoplasias Gástricas , Criança , Humanos , Herpesvirus Humano 4 , Interleucina-6/metabolismo , Hepcidinas/metabolismo , Proteína C-Reativa/metabolismo , Ferro/metabolismo , Imunoglobulina G/metabolismo , Helicobacter pylori/metabolismo
18.
Int J Mol Sci ; 24(2)2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36675232

RESUMO

Despite recent advances in oncology, cancer has remained an enormous global health burden, accounting for about 10 million deaths in 2020. A third of the cancer cases in developing counties are caused by microbial infections such as human papillomavirus (HPV), Epstein-Barr Virus (EBV), and hepatitis B and C viruses. EBV, a member of the human gamma herpesvirus family, is a double-stranded DNA virus and the primary cause of infectious mononucleosis. Most EBV infections cause no long-term complications. However, it was reported that EBV infection is responsible for around 200,000 malignancies worldwide every year. Currently, there are no vaccines or antiviral drugs for the prophylaxis or treatment of EBV infection. Recently, the gut microbiota has been investigated for its pivotal roles in pathogen protection and regulating metabolic, endocrine, and immune functions. Several studies have investigated the efficacy of antiviral agents, gut microbial metabolites, and natural products against EBV infection. In this review, we aim to summarise and analyse the reported molecular mechanistic and clinical studies on the activities of gut microbial metabolites and natural medicines against carcinogenic viruses, with a particular emphasis on EBV. Gut microbial metabolites such as short-chain fatty acids were reported to activate the EBV lytic cycle, while bacteriocins, produced by Enterococcus durans strains, have shown antiviral properties. Furthermore, several natural products and dietary bioactive compounds, such as curcumin, epigallocatechin gallate, resveratrol, moronic acid, and andrographolide, have shown antiviral activity against EBV. In this review, we proposed several exciting future directions for research on carcinogenic viruses.


Assuntos
Infecções por Vírus Epstein-Barr , Microbioma Gastrointestinal , Neoplasias , Humanos , Herpesvirus Humano 4/fisiologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Carcinógenos/metabolismo , Neoplasias/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêutico , Antivirais/metabolismo , Carcinogênese
19.
Am J Dermatopathol ; 45(2): 73-80, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36669068

RESUMO

ABSTRACT: Primary cutaneous T-cell lymphoma is distinct from nodal T-cell lymphoma clinically and pathologically. Recently, primary cutaneous follicular helper T-cell lymphoma (PC-TFHL) has been described as a peripheral T-cell lymphoma with T-follicular helper (TFH) cell phenotype. PC-TFHL usually presents as multiple plaques and nodules of skin with an indolent clinical course, but without association with Epstein-Barr virus. In this article, we report 2 rare cases of PC-TFHL which are Epstein-Barr virus-positive and with an aggressive clinical course. We discuss the challenges in the differential diagnoses, particularly with primary cutaneous extranodal NK/T-cell lymphoma, and nodal T-cell lymphoma of TFH origin with secondary cutaneous involvement.


Assuntos
Infecções por Vírus Epstein-Barr , Linfoma Extranodal de Células T-NK , Linfoma Cutâneo de Células T , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/patologia , Herpesvirus Humano 4/genética , Infecções por Vírus Epstein-Barr/diagnóstico , Linfócitos T Auxiliares-Indutores/patologia , Linfoma Extranodal de Células T-NK/patologia , Fenótipo , Progressão da Doença , Linfoma Cutâneo de Células T/patologia
20.
Sci Adv ; 9(1): eabq6978, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36598996

RESUMO

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Although various viruses have been proposed to contribute to MS pathology, the etiology of MS remains unknown. Since intrathecal antibody synthesis is well documented in chronic viral infection and neuroinflammatory diseases, we hypothesized whether the patterns of antigen-specific antibody responses associated with various viral exposures may define patients with CNS chronic immune dysregulation. The pan-viral antibody profiling in cerebrospinal fluid (CSF) and serum of patients with MS showed significant differences from those in healthy volunteers and a pattern of antibody responses against multiple viruses, including the previously identified Epstein-Barr virus. These findings demonstrate that virus-specific antibody signatures might be able to reflect disease-associated inflammatory milieu in CSF of subjects with neuroinflammatory diseases.


Assuntos
Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Humanos , Herpesvirus Humano 4 , Doenças Neuroinflamatórias , Antivirais
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