RESUMO
BACKGROUND: HeberFERON is a co-formulation of α2b and γ interferons, based on their synergism, which has shown its clinical superiority over individual interferons in basal cell carcinomas. In glioblastoma (GBM), HeberFERON has displayed promising preclinical and clinical results. This led us to design a microarray experiment aimed at identifying the molecular mechanisms involved in the distinctive effect of HeberFERON compared to the individual interferons in U-87MG model. METHODS: Transcriptional expression profiling including a control (untreated) and three groups receiving α2b-interferon, γ-interferon and HeberFERON was performed using an Illumina HT-12 microarray platform. Unsupervised methods for gene and sample grouping, identification of differentially expressed genes, functional enrichment and network analysis computational biology methods were applied to identify distinctive transcription patterns of HeberFERON. Validation of most representative genes was performed by qPCR. For the cell cycle analysis of cells treated with HeberFERON for 24 h, 48 and 72 h we used flow cytometry. RESULTS: The three treatments show different behavior based on the gene expression profiles. The enrichment analysis identified several mitotic cell cycle related events, in particular from prometaphase to anaphase, which are exclusively targeted by HeberFERON. The FOXM1 transcription factor network that is involved in several cell cycle phases and is highly expressed in GBMs, is significantly down regulated. Flow cytometry experiments corroborated the action of HeberFERON on the cell cycle in a dose and time dependent manner with a clear cellular arrest as of 24 h post-treatment. Despite the fact that p53 was not down-regulated, several genes involved in its regulatory activity were functionally enriched. Network analysis also revealed a strong relationship of p53 with genes targeted by HeberFERON. We propose a mechanistic model to explain this distinctive action, based on the simultaneous activation of PKR and ATF3, p53 phosphorylation changes, as well as its reduced MDM2 mediated ubiquitination and export from the nucleus to the cytoplasm. PLK1, AURKB, BIRC5 and CCNB1 genes, all regulated by FOXM1, also play central roles in this model. These and other interactions could explain a G2/M arrest and the effect of HeberFERON on the proliferation of U-87MG. CONCLUSIONS: We proposed molecular mechanisms underlying the distinctive behavior of HeberFERON compared to the treatments with the individual interferons in U-87MG model, where cell cycle related events were highly relevant.
Assuntos
Glioblastoma , Neoplasias Cutâneas , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Interferon-alfa/farmacologia , Anáfase , Interferon gama/farmacologiaRESUMO
Human interferon alpha (hIFN-α) administration constitutes the current FDA approved therapy for chronic Hepatitis B and C virus infections. Additionally, hIFN-α treatment efficacy was recently demonstrated in patients with COVID-19. Thus, hIFN-α constitutes a therapeutic alternative for those countries where vaccination is inaccessible and for people who did not respond effectively to vaccination. However, hIFN-α2b exhibits a short plasma half-life resulting in the occurrence of severe side effects. To optimize the cytokine's pharmacokinetic profile, we developed a hyperglycosylated IFN, referred to as GMOP-IFN. Given the significant number of reports showing neutralizing antibodies (NAb) formation after hIFN-α administration, here we applied the DeFT (De-immunization of Functional Therapeutics) approach to develop functional, de-immunized versions of GMOP-IFN. Two GMOP-IFN variants exhibited significantly reduced ex vivo immunogenicity and null antiproliferative activity, while preserving antiviral function. The results obtained in this work indicate that the new de-immunized GMOP-IFN variants constitute promising candidates for antiviral therapy.
Assuntos
Hepatite B Crônica/imunologia , Hepatite C Crônica/imunologia , Interferon-alfa/imunologia , Proteínas Recombinantes/imunologia , Adulto , Sequência de Aminoácidos , Animais , Anticorpos Neutralizantes/imunologia , Antivirais/imunologia , Antivirais/farmacologia , Células CHO , COVID-19/imunologia , COVID-19/virologia , Bovinos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Cricetinae , Cricetulus , Estabilidade de Medicamentos , Células HEK293 , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Interferon-alfa/genética , Interferon-alfa/farmacologia , Proteínas Recombinantes/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Tratamento Farmacológico da COVID-19RESUMO
Brazil is one of the 22 countries that concentrates 80% of global tuberculosis cases concomitantly to a large number of hepatitis C carriers and some epidemiological risk scenarios are coincident for both diseases. We analyzed tuberculosis cases that occurred during α-interferon-based therapy for hepatitis C in reference centers in Brazil between 2001 and 2012 and reviewed their medical records. Eighteen tuberculosis cases were observed in patients submitted to hepatitis C α-interferon-based therapy. All patients were human immunodeficiency virus-negative. Nine patients (50%) had extra-pulmonary tuberculosis; 15 (83%) showed significant liver fibrosis. Hepatitis C treatment was discontinued in 12 patients (67%) due to tuberculosis reactivation and six (33%) had sustained virological response. The majority of patients had a favorable outcome but one died. Considering the evidences of α-IFN interference over the containment of Mycobacterium tuberculosis, the immune impairment of cirrhotic patients, the increase of tuberculosis case reports during hepatitis C treatment with atypical and severe presentations and the negative impact on sustained virological response, we think these are strong arguments for latent tuberculosis infection screening before starting α-interferon-based therapy for any indication and even to consider IFN-free regimens against hepatitis C when a patient tests positive for latent tuberculosis infection.
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Antivirais/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/efeitos adversos , Tuberculose/epidemiologia , Adulto , Antivirais/uso terapêutico , Brasil/epidemiologia , Coinfecção/epidemiologia , Feminino , Hepatite C Crônica/epidemiologia , Humanos , Incidência , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tuberculose/imunologiaRESUMO
Los tumores benignos del esófago son raros, constituyendo solo el 0,5 al 0,8 por ciento de todos los tumores esofágicos. Aproximadamente el 60 por ciento de los tumores benignos del esófago son leiomiomas, el 20 por ciento son quistes y el 5 por ciento son pólipos. El resto de las lesiones ocurren con una frecuencia menor del 2 por ciento y constituyen curiosidades y dentro de ellas tenemos al papiloma. Los papilomas son tumores benignos fibrosos y sésiles cubiertos por epitelio escamoso producidos por el papilomavirus humano (VPH), que tienen la capacidad de producir lesiones proliferativas en piel y/o mucosas. En el tubo digestivo se localizan más frecuentes hacia los extremos proximales (boca) y dístales (recto). El caso que se presentó se trata de una localización esofágica distal en un paciente de 49 años de edad, masculino, con sintomatología sugestiva de una enfermedad por reflujo gastroesofágico y/o un trastorno de la motilidad esofágica, diagnosticándosele -por endoscopia y biopsia- lesiones elevadas esofágicas y la presencia de coilocitos. Se le indicó tratamiento con interferón alfa 2 recombinante, quedando pendiente de evolución endoscópica e histológica post-tratamiento.
The benign tumors of the esophagus are rare, being only the 0,5-0,8 percent of all the esophageal tumors. Around the 60 percent of the benign esophageal tumors are leiomyomas, 20 percent are cists and 5 percent are polyps. The rest of the lesions occur with a frequency less than 2 percent being curiosities, and among them there is the papilloma. The papilloma are benign, fibrous and sessile tumors covered by a squamous epithelium produced by the human papilloma virus (HPV), having the capacity of producing proliferative lesions in the skin and/or mucosa. In the digestive tract they are more frequently located to the proximal (mouth) and distal (rectum) endings. In the case we present, it is a distal esophageal location in a male patient aged 49, with symptoms suggesting a disease by gastro-esophageal reflux and/or disturbances of the esophageal motility, arriving to the diagnosis by endoscopy and biopsy: elevated esophageal lesions and the presence of koilocytes. We indicated a treatment with Recombinant Alpha 2 Interferon, being pending the post-treatment endoscopic and histological evolution.
RESUMO
INTRODUÇÃO: Manifestações auto-imunes são frequentes na infecção pelo vírus da hepatite C (VHC). Apesar da associação com doenças auto-imunes de tireóide (DAIT) ser controversa, sabe-se que distúrbios tireoidianos podem surgir ou piorar com tratamento com IFN e ribavirina. Os objetivos deste estudo foram avaliar a função tireoidiana em pacientes infectados pelo VHC, caracterizar distúrbios tireoidianos antes, durante e após tratamento com IFN e estudar as frequências dos genótipos dos polimorfismos do gene CTLA4, correlacionando-os com características clínicas e laboratoriais, presença de disfunção tireoidiana e evolução durante tratamento com IFN. MÉTODOS: Avaliação prospectiva de 112 indivíduos com infecção crônica pelo VHC, 30 tratados com IFN, e 183 controles. Realizaram-se avaliações clínica, hormonal e de auto-imunidade tireoidiana e ultra-sonografia de tireóide no início e durante tratamento. Avaliações de globulina transportadora de hormônios tireoidianos (TBG), de CXCL10 e de biópsia hepática foram feitas pré-tratamento. Análises dos polimorfismos do gene CTLA4 -318C>T, A49G e CT60 foram realizadas por PCR-RFLP e de AT(n) por análise de fragmento através de eletroforese capilar. RESULTADOS: A frequência de DAIT entre infectados por VHC não diferiu dos controles (10,7 vs 13,5%, p=0,585). Os limites de distribuição dos níveis de T3 (T3T) e T4 (T4T) totais foram superiores aos de referência (T3T 112-246 ng/dL; T4T 7,8-15,2 g/dL), assim como de TBG (17-47 mg/L). TBG correlacionou-se com T3T (r=0,654, p<0,001) e T4T (r=0,741, p<0,001). Heterogeneidade (p=0,027) e hipoecogenicidade de parênquima (p=0,002) foram mais frequentes nos pacientes com DAIT. Aumento de vascularização esteve presente em 49,2% dos infectados sem distúrbio tireoidiano. CXCL10 esteve aumentada nos infectados (p=0,006), mas não se relacionou com disfunção tireoidiana. Sua elevação correspondeu ao grau de atividade necro-inflamatória na biópsia hepática...
INTRODUCTION: Autoimmune disorders are frequent in patients infected by the hepatitis C virus (HCV). Although the association with autoimmune thyroid diseases (AITD) is controversial, thyroid disturbance could occur or worsen with IFN and ribavirin treatment. The aims of the study were evaluate thyroid function in HCV-infected patients, characterize thyroid disturbance prior and after IFN treatment and analyze the frequency of the genotypes of the polymorphisms of CTLA4 gene, and their relation to clinical and laboratorial features, presence of thyroid dysfunction and disturbance along IFN treatment. METHODS: Prospective evaluation of 112 chronically HCV-infected subjects, 30 treated with IFN, and 183 controls. Clinical, hormonal, thyroid autoimmunity and ultrasound exams were performed before and during treatment. Thyroxine-binding globulin (TBG), CXCL10 and hepatic biopsies were also evaluated before treatment. Analysis of polymorphisms of CTLA4 gene -318C>T, A49G and CT60 were made by PCR-RFLP and AT(n) polymorphism analysis by capillary electrophoresis in automatic sequencer. RESULTS: The frequency of AITD among HCV-infected subjects was similar to the rate among controls (10.7 vs 13.5%, p=0.585). Total T3 (T3T) and T4 (T4T) distributions were right shifted (T3T 112-246 ng/dL; T4T 7.8-15.2 g/dL), as was TBG (17-47 mg/L). TBG correlated to both T3T (r=0.654, p<0.001) and T4T (r=0.741, p<0.001). Thyroid heterogeneity (p=0.027) and hipoechogenicity (p=0.002) were associated with AITD and, most notably, increased vascularization was present in 49.2% of HCV-infected patients without thyroid disturbance. CXCL10 was higher in HCV-infected group (p=0.006) but was not related to thyroid dysfunction. Increase in CXCL10 levels were consistent with hepatic necroinflammatory activity (p=0.006) and correlated to T3T (r=0.388, p=0.003), T4T (r=0.444, p=0.001) and TBG (r=0.551, p<0.001). Nineteen percent of subjects treated with IFN presented autoimmune thyroiditis and...
Assuntos
Doenças Autoimunes , Hepatite C , Interferon-alfa , Glândula Tireoide , Proteínas de Ligação a TiroxinaRESUMO
O objetivo do trabalho é descrever o uso de interferon alfa no tratamento de pacientes com hemangioma gigante. Os autores relatam e analisam dois casos de hemangioma gigante em tratamento com interferon alfa. IBS, 3 anos, em acompanhamento no Ambulatório de Hematologia desde um ano de idade com quadro de lesão angiomatosa em praticamente toda hemiface direita, acompanhada de sangramentos gengivais importantes. Após a realização de exames complementares (Angiorressonância magnética) e feito o diagnóstico de hemangioma gigante em face, foi iniciado tratamento com prednisona e, posteriormente, associação com interferon alfa e observada importante melhora do quadro, resultando na diminuição dos episódios de sangramento e no tamanho do tumor. C.N.P., 12 anos, apresentando nódulo em região lateral de joelho esquerdo há 2 anos, com aumento progressivo do tamanho e dor local. Fez uso de prednisona e, sem melhora do quadro, introduzido interferon alfa com regressão importante do tamanho do tumor. O tratamento com interferon alfa deve ser considerado no tratamento de hemangiomas, pois apresenta bons resultados em relação à diminuição do tamanho do tumor e, conseqüentemente, reduz as intercorrências clínicas associadas à sua presença, principalmente os sangramentos.
The aim of this study is to describe the treatment using interferon-alpha of giant hemangiomas in children. The authors report two cases of children presenting with giant hemangiomas treated using interferon-alpha and analyze the results. IBS, 3 years-old, has been followed up in Famema Hemathology Service since she was 1 year-old with a tumor on the face and persistent bleeding. After clinical and radiologic evaluations and suggested the diagnosis of giant hemangioma, she started treatment with interferon-alpha. A great clinical improvement was observed a reducing of the number of episodes of bleedings and a decrease in of the tumor size. CNP, 12 years-old, came to this service in the last year presenting with a small painful tumor on the left knee. She had already tried a treatment with Prednisone with no improvement. Treatment with interferon-alpha was initiated with a significant decrease in its size. The use of interferon-alpha should be considered in the treatment of giant hemangioma due to its favorable results related to a reduction in the tumor size and the episodes of bleeding.