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1.
Cancer Immunol Immunother ; 71(1): 13-24, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33993319

RESUMO

Around 30-50% of classical Hodgkin lymphoma (cHL) cases in immunocompetent individuals from industrialized countries are associated with the B-lymphotropic Epstein-Barr virus (EBV). Although natural killer (NK) cells exhibit anti-viral and anti-tumoral functions, virtually nothing is known about quantitative and qualitative differences in NK cells in patients with EBV+ cHL vs. EBV- cHL. Here, we prospectively investigated 36 cHL patients without known immune suppression or overt immunodeficiency at diagnosis. All 10 EBV+ cHL patients and 25 out 26 EBV- cHL were seropositive for EBV antibodies, and EBV+ cHL patients presented with higher plasma EBV DNA levels compared to EBV- cHL patients. We show that the CD56dim CD16+ NK cell subset was decreased in frequency in EBV+ cHL patients compared to EBV- cHL patients. This quantitative deficiency translates into an impaired CD56dim NK cell mediated degranulation toward rituximab-coated HLA class 1 negative lymphoblastoid cells in EBV+ compared to EBV- cHL patients. We finally observed a trend to a decrease in the rituximab-associated degranulation and ADCC of in vitro expanded NK cells of EBV+ cHL compared to healthy controls. Our findings may impact on the design of adjunctive treatment targeting antibody-dependent cellular cytotoxicity in EBV+ cHL.


Assuntos
Anticorpos/imunologia , Antígeno CD56/biossíntese , Doença de Hodgkin/metabolismo , Doença de Hodgkin/terapia , Receptores de IgG/biossíntese , Adulto , Idoso , Antineoplásicos/farmacologia , Infecções por Vírus Epstein-Barr/complicações , Feminino , Proteínas Ligadas por GPI/biossíntese , Herpesvirus Humano 4/metabolismo , Doença de Hodgkin/complicações , Humanos , Imunoterapia , Técnicas In Vitro , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/citologia , Linfócitos/metabolismo , Proteína 1 de Membrana Associada ao Lisossomo/biossíntese , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Prospectivos , Rituximab/farmacologia
2.
J Clin Microbiol ; 59(7): e0074821, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-33853838

RESUMO

Factors leading to the wide range of manifestations associated with Mycoplasma pneumoniae infection are unclear. We investigated whether M. pneumoniae genotypes are associated with specific clinical outcomes. We compared M. pneumoniae loads and genotypes of children with mucocutaneous disease to those of children with pneumonia, family members with upper respiratory tract infection (URTI), and carriers from a prospective cohort study (n = 47; 2016 to 2017) and to those of other children with mucocutaneous disease from a case series (n = 7; 2017 to 2020). Genotyping was performed using macrolide resistance determination, P1 subtyping, multilocus variable-number tandem-repeat analysis (MLVA), and multilocus sequence typing (MLST). Comparisons were performed with a pairwise Wilcoxon rank sum test and a Fisher exact test with corrections for multiple testing, as appropriate. M. pneumoniae loads did not statistically differ between patients with mucocutaneous disease and those with pneumonia or carriers. Macrolide resistance was detected in 1 (1.9%) patient with mucocutaneous disease. MLVA types from 2016 to 2017 included 3-5-6-2 (n = 21 [46.7%]), 3-6-6-2 (n = 2 [4.4%]), 4-5-7-2 (n = 14 [31.1%]), and 4-5-7-3 (n = 8 [17.8%]), and they correlated with P1 subtypes and MLST types. MLVA types were not associated with specific outcomes such as mucocutaneous disease, pneumonia, URTI, or carriage. They were almost identical within families but varied over geographic location. MLVA types in patients with mucocutaneous disease differed between 2016 to 2017 (3-5-6-2, n = 5 [62.5%]) and 2017 to 2020 (4-5-7-2, n = 5 [71.4%]) (P = 0.02). Our results suggest that M. pneumoniae genotypes may not determine specific clinical outcomes.


Assuntos
Mycoplasma pneumoniae , Pneumonia por Mycoplasma , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Criança , Farmacorresistência Bacteriana , Genótipo , Humanos , Macrolídeos , Tipagem de Sequências Multilocus , Mycoplasma pneumoniae/genética , Pneumonia por Mycoplasma/tratamento farmacológico , Pneumonia por Mycoplasma/epidemiologia , Estudos Prospectivos
5.
Oncotarget ; 8(44): 77819-77835, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-29100428

RESUMO

Besides hypoxia, other factors and molecules such as lactate, succinate, and reactive oxygen species activate transcription factor hypoxia-inducible factor-1 (HIF-1) even in normoxia. One of the main target gene products of HIF-1 is carbonic anhydrase IX (CA IX). CA IX is overexpressed in many tumors and serves as prognostic factor for hypoxic, aggressive and malignant cancers. CA IX is also induced in normoxia in high cell density. In this study, we observed that lactate induces CA IX expression in normoxic cancer cells in vitro and in vivo. We further evidenced that participation of both HIF-1 and specificity protein 1 (SP1) transcription factors is crucial for lactate-driven normoxic induction of the CA9 gene. By inducing CA IX, lactate can facilitate the maintenance of cancer cell aggressive behavior in normoxia.

6.
Int J Oncol ; 49(4): 1277-88, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27431580

RESUMO

Dexamethasone is a synthetic glucocorticoid frequently used to suppress side-effects of anticancer chemotherapy. In the present study, we showed that dexamethasone treatment leads to concentration-dependent downregulation of cancer-associated marker, carbonic anhydrase IX (CA IX), at the level of promoter activity, mRNA and protein expression in 2D and 3D cancer cell models. The effect of dexamethasone on CA IX expression under hypoxic conditions is predominantly mediated by impaired transcriptional activity and decreased protein level of the main hypoxic transcription factor HIF-1α. In addition, CA9 downregulation can be caused by protein-protein interactions between activated glucocorticoid receptors, major effectors of glucocorticoid action, and transcription factors that trigger CA9 transcription (e.g. AP-1). Moreover, we identified a potential NF-κB binding site in the CA9 promoter and propose the involvement of NF-κB in the dexamethasone-mediated inhibition of CA9 transcription. As high level of CA IX is often linked to aggressive tumor behavior, poor prognosis and chemo- and radiotherapy resistance, uncovering its reduction after dexamethasone treatment and implication of additional regulatory mechanisms can be relevant for the CA IX-related clinical applications.


Assuntos
Antígenos de Neoplasias/metabolismo , Anidrase Carbônica IX/metabolismo , Dexametasona/farmacologia , Regulação para Baixo , Glucocorticoides/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , NF-kappa B/metabolismo , Antígenos de Neoplasias/genética , Sítios de Ligação , Anidrase Carbônica IX/genética , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Células MCF-7 , Regiões Promotoras Genéticas , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia
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