RESUMO
The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.
Assuntos
Suscetibilidade a Doenças , Variação Genética , Imunidade/genética , Leucemia Mieloide Aguda/etiologia , Adulto , Idoso , Alelos , Biomarcadores Tumorais , Suscetibilidade a Doenças/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Imunomodulação/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Esteroides/metabolismoAssuntos
Proteínas de Ligação a DNA/genética , Cariótipo , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Medula Óssea/patologia , Análise Mutacional de DNA , Humanos , Contagem de Leucócitos , Masculino , Transtornos Mieloproliferativos/tratamento farmacológico , UltrassonografiaRESUMO
Recent studies suggest that immune-modulating single-nucleotide polymorphisms (SNPs) influence the risk of developing cancer-related infections. Here, we evaluated whether 36 SNPs within 14 immune-related genes are associated with the risk of invasive aspergillosis (IA) and whether genotyping of these variants might improve disease risk prediction. We conducted a case-control association study of 781 immunocompromised patients, 149 of whom were diagnosed with IA. Association analysis showed that the IL4Rrs2107356 and IL8rs2227307 SNPs (using dbSNP numbering) were associated with an increased risk of IA (IL4Rrs2107356 odds ratio [OR], 1.92; 95% confidence interval [CI], 1.20 to 3.09; IL8rs2227307 OR, 1.73; 95% CI, 1.06 to 2.81), whereas the IL12Brs3212227 and IFNγrs2069705 variants were significantly associated with a decreased risk of developing the infection (IL12Brs3212227 OR, 0.60; 95% CI, 0.38 to 0.96; IFNγrs2069705 OR, 0.63; 95% CI, 0.41 to 0.97). An allogeneic hematopoietic stem cell transplantation (allo-HSCT)-stratified analysis revealed that the effect observed for the IL4Rrs2107356 and IFNγrs2069705 SNPs was stronger in allo-HSCT (IL4Rrs2107356 OR, 5.63; 95% CI, 1.20 to 3.09; IFNγrs2069705 OR, 0.24; 95% CI, 0.10 to 0.59) than in non-HSCT patients, suggesting that the presence of these SNPs renders patients more vulnerable to infection, especially under severe and prolonged immunosuppressive conditions. Importantly, in vitro studies revealed that carriers of the IFNγrs2069705C allele showed a significantly increased macrophage-mediated neutralization of fungal conidia (P = 0.0003) and, under stimulation conditions, produced higher levels of gamma interferon (IFNγ) mRNA (P = 0.049) and IFNγ and tumor necrosis factor alpha (TNF-α) cytokines (P value for 96 h of treatment with lipopolysaccharide [PLPS-96 h], 0.057; P value for 96 h of treatment with phytohemagglutinin [PPHA-96 h], 0.036; PLPS+PHA-96 h = 0.030; PPHA-72 h = 0.045; PLPS+PHA-72 h = 0.018; PLPS-96 h = 0.058; PLPS+PHA-96 h = 0.0058). Finally, we also observed that the addition of SNPs significantly associated with IA to a model including clinical variables led to a substantial improvement in the discriminatory ability to predict disease (area under the concentration-time curve [AUC] of 0.659 versus AUC of 0.564; P-2 log likehood ratio test = 5.2 · 10(-4) and P50.000 permutation test = 9.34 · 10(-5)). These findings suggest that the IFNγrs2069705 SNP influences the risk of IA and that predictive models built with IFNγ, IL8, IL12p70, and VEGFA variants can used to predict disease risk and to implement risk-adapted prophylaxis or diagnostic strategies.
Assuntos
Aspergilose/genética , Aspergilose/imunologia , Predisposição Genética para Doença , Interferon gama/genética , Subunidade p40 da Interleucina-12/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Interleucina-8/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Hospedeiro Imunocomprometido/genética , Interferon gama/imunologia , Subunidade p40 da Interleucina-12/imunologia , Subunidade alfa de Receptor de Interleucina-4/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-IdadeRESUMO
Similarly to Epstein-Barr virus (EBV), the human herpesvirus-8 (HHV-8) is a γ-herpesvirus, recently recognized to be associated with the occurrence of rare B cell lymphomas and atypical lymphoproliferations, especially in the human immunodeficiency virus (HIV) infected subjects. Moreover, the human herpesvirus-6 (HHV-6), a ß-herpesvirus, has been shown to be implicated in some non-malignant lymph node proliferations, such as the Rosai Dorfman disease, and in a proportion of Hodgkin's lymphoma cases. HHV-6 has a wide cellular tropism and it might play a role in the pathogenesis of a wide variety of human diseases, but given its ubiquity, disease associations are difficult to prove and its role in hematological malignancies is still controversial. The involvement of another ß-herpesvirus, the human cytomegalovirus (HCMV), has not yet been proven in human cancer, even though recent findings have suggested its potential role in the development of CD4(+) large granular lymphocyte (LGL) lymphocytosis. Here, we review the current knowledge on the pathogenetic role of HHV-8 and human ß-herpesviruses in human lymphoproliferative disorders.
RESUMO
Creatine monohydrate (Cr), the most diffuse supplement in the sports industry, is receiving greater attention because of its beneficial effects in a wide number of human degenerative diseases and conditions. These effects can be barely explained on the basis of the sole ergogenic role of the Cr/CrP system. Indeed, a wide number of research articles indicate that Cr is capable of exerting multiple, non-energy related, effects on diverse and relevant cellular targets. Among these effects, the antioxidant activity of Cr emerges as an additional mechanism which is likely to play a supportive role in the Cr-cytoprotection paradigm.
Assuntos
Antioxidantes , Creatina , Animais , Antioxidantes/administração & dosagem , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Creatina/administração & dosagem , Creatina/metabolismo , Creatina/farmacologia , Suplementos Nutricionais , Humanos , Espécies Reativas de Oxigênio/metabolismoRESUMO
The unique phenomenon of human herpesvirus-6 (HHV-6) chromosomal integration (CIHHV-6) may account for clinical drawbacks in transplant setting, being misinterpreted as active infection and leading to unnecessary and potentially harmful treatments. We have investigated the prevalence of CIHHV-6 in 205 consecutive solid organ (SO) and allogeneic stem cell transplant (alloSCT) Italian patients. Fifty-two (38.5%) of 135 solid organ transplant (SOT) and 16 (22.8%) of 70 alloSCT patients resulted positive for plasma HHV-6 DNA by real-time polymerase chain reaction. Seven SOT and three alloSCT patients presented HHV-6-related diseases, requiring antivirals. Two further patients (0.9%) were identified, presenting high HHV-6 loads. The quantification of HHV-6 on hair follicles disclosed the integrated state, allowing the discontinuation of antivirals. Before starting specific treatments, CIHHV-6 should be excluded in transplant patients with HHV-6 viremia by the comparison of HHV-6 loads on different fluids and tissues. Pretransplantation screening of donors and recipients may further prevent the misdiagnosis of CIHHV-6.
Assuntos
Herpesvirus Humano 6/genética , Herpesvirus Humano 6/patogenicidade , Transplante de Células-Tronco , Transplantes , Integração Viral/genética , Adulto , Estudos de Coortes , DNA Viral/sangue , DNA Viral/genética , Herpesvirus Humano 6/isolamento & purificação , Herpesvirus Humano 6/fisiologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Infecções por Roseolovirus/diagnóstico , Infecções por Roseolovirus/etiologia , Infecções por Roseolovirus/virologia , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo , Transplantes/efeitos adversos , Viremia/diagnóstico , Viremia/etiologia , Viremia/virologiaAssuntos
Apendicite/etiologia , Neoplasias Hematológicas/complicações , Neutropenia/etiologia , Doença Aguda , Idoso , Apendicite/cirurgia , Feminino , Neoplasias Hematológicas/terapia , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapiaRESUMO
Potentially fatal lung toxicity occurs in 12-20% of leukemic patients treated with cytarabine especially at intermediate to high doses, usually presenting as noncardiogenic pulmonary edema (NCPE). Anecdotally the association between cytarabine and the onset of bronchiolitis obliterans organizing pneumonia (BOOP) has been reported. We describe here three cases of patients affected by acute myeloid leukemia (AML) treated with chemotherapeutic regimens including high dose cytarabine, who developed early onset of fever, mild dyspnea, moderate hypoxemia on arterial blood gas analysis and lung infiltrates documented by high-resolution computerized tomography (HRCT), with a more indolent behaviour and a benign clinical outcome, compared with similar cases previously reported in the literature. Our cases widen the spectrum of clinical features of cytarabine-related toxicity in leukemic patients.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Citarabina/efeitos adversos , Leucemia Mieloide/tratamento farmacológico , Pneumopatias/induzido quimicamente , Doença Aguda , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Gasometria , Transplante de Medula Óssea , Citarabina/uso terapêutico , Dispneia , Feminino , Febre , Humanos , Hipóxia , Leucemia Mieloide/diagnóstico , Pneumopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Hemophagocytic syndrome (HS) may occur as a consequence of herpes viral infections. Human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus has so far been recognized as a trigger of HS only in immunosuppressed subjects or in patients with Kaposi sarcoma and/or HHV-8-related lymphoproliferative diseases. We report two Italian human immunodeficiency virus (HIV)-negative elderly men who developed an HS with a rapidly fatal course, following treatment with corticosteroids for autoimmune hemolytic anemia. An overwhelming active infection with HHV-8 was unequivocally documented by molecular and immunohistochemical methods, in the absence of HHV-8-related tumors. The occurrence of HHV-8-associated HS, although rare, may be considered, even out of the HIV or the transplantation settings, at least in areas endemic for HHV-8 infection.
Assuntos
Anemia Hemolítica Autoimune/complicações , Infecções por Herpesviridae/diagnóstico , Herpesvirus Humano 8/isolamento & purificação , Linfo-Histiocitose Hemofagocítica/virologia , Corticosteroides/uso terapêutico , Idoso , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/tratamento farmacológico , Evolução Fatal , Feminino , Infecções por Herpesviridae/complicações , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/cirurgia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeAssuntos
Aspergilose/diagnóstico , Leucemia Mieloide/complicações , Pneumopatias Fúngicas/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Células Th1/imunologia , Células Th2/imunologia , Doença Aguda , Adulto , Antifúngicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/etiologia , Aspergilose/imunologia , Aspergilose/patologia , Aspergilose/cirurgia , Terapia Combinada , Ensaio de Imunoadsorção Enzimática , Evolução Fatal , Feminino , Humanos , Hospedeiro Imunocomprometido , Interferon gama/metabolismo , Interleucina-10/metabolismo , Leucemia Mieloide/tratamento farmacológico , Pneumopatias Fúngicas/etiologia , Pneumopatias Fúngicas/imunologia , Pneumopatias Fúngicas/patologia , Linfoma de Células B/complicações , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/complicações , Pneumonectomia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Púrpura Trombocitopênica Trombótica/complicações , Especificidade do Receptor de Antígeno de Linfócitos T , Células Th1/metabolismo , Células Th2/metabolismo , Cirurgia Torácica VídeoassistidaAssuntos
Leucemia de Células Pilosas/complicações , Leucemia de Células Pilosas/diagnóstico , Linfócitos T/imunologia , Tuberculose/complicações , Tuberculose/diagnóstico , Idoso , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Contagem de Células , Feminino , Humanos , Leucemia de Células Pilosas/microbiologia , Técnicas de Diagnóstico Molecular , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/isolamento & purificação , Sensibilidade e Especificidade , Teste Tuberculínico , Tuberculose/sangueAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Herpes Simples/induzido quimicamente , Leucemia de Células B/tratamento farmacológico , Pneumonia Viral/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Aciclovir/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , Daunorrubicina/administração & dosagem , Feminino , Herpes Simples/complicações , Humanos , Pessoa de Meia-Idade , Pneumonia Viral/etiologia , Prednisona/administração & dosagem , Simplexvirus/patogenicidade , Vincristina/administração & dosagemAssuntos
Antineoplásicos/administração & dosagem , Citosina/análogos & derivados , Citosina/administração & dosagem , Herpesvirus Humano 8/efeitos dos fármacos , Linfoma de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Organofosfonatos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cidofovir , Citosina/uso terapêutico , Humanos , Injeções Intralesionais , Linfoma de Células B/virologia , Linfoma não Hodgkin/virologia , Masculino , Organofosfonatos/uso terapêutico , Indução de Remissão , Fatores de TempoAssuntos
Antivirais/uso terapêutico , Hepacivirus/patogenicidade , Hepatite C/tratamento farmacológico , Linfoma de Células B/virologia , Quimioterapia Combinada , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C/complicações , Hepatite C/virologia , Humanos , Interferon-alfa/uso terapêutico , Linfoma de Células B/complicações , Linfoma de Células B/tratamento farmacológico , Ribavirina/uso terapêutico , Resultado do TratamentoRESUMO
Mitochondrial binary division is a complex process occurring in multiple steps, mediated by several proteins. In Saccharomyces cerevisiae, a mitochondrial membrane protein, Fis1p, is required for the proper assembly of the mitochondrial division apparatus. In this study, we report the cloning, characterisation and phylogenetic analysis of Tbfis1, a gene from the ectomycorrhizal ascomycetous truffle Tuber borchii, encoding for an orthologue of S. cerevisiae Fis1p. The Tbfis1 coding region consists of a 468-nucleotide open reading frame interrupted by four introns, which encodes for a polypeptide of 155 amino acids, having a predicted transmembrane domain structure typical of the Fis1p Family. Southern blot analysis revealed that Tbfis1 is a single-copy gene in the T. borchii genome. Tbfis1 is highly expressed during the first stages of T. borchii fruit body ripening, while its expression decreases during T. borchii mycelium ageing. Also, Virtual Northern blot analysis revealed Tbfis1 expression in the symbiotic phase of the fungus life cycle. Phylogenetic analysis allowed the identification of Tbfis1 orthologues in filamentous fungi, yeasts, plants, worms, flies and mammals, indicating that the function of the protein coded by this gene has been conserved during evolution.