RESUMO
BACKGROUND: In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed. RESULTS: Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035). CONCLUSION: Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients.
Assuntos
Antígenos de Neoplasias/biossíntese , Biomarcadores Tumorais/biossíntese , Anidrase Carbônica IX/biossíntese , Neoplasias Bucais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Fator A de Crescimento do Endotélio Vascular/biossíntese , Idoso , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Anidrase Carbônica IX/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Análise Multivariada , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
AIMS: Fructose administration induces hepatic oxidative stress, insulin resistance, inflammatory and metabolic changes. We tested their potential pathogenic relationship and whether these alterations can be prevented by R/S-α-lipoic acid. MAIN METHODS: Wistar rats received during 21days a commercial diet or the same diet supplemented with 10% fructose in drinking water without/with R/S-α-lipoic acid injection. After this period, we measured a) serum glucose, triglyceride, insulin, homeostasis model assessment-insulin resistance (HOMA-IR), insulin glucose ratio (IGR) and Matsuda indexes and b) liver oxidative stress, inflammatory markers and insulin signaling pathway components. KEY FINDINGS: Fructose fed rats had hyperinsulinemia, hypertriglyceridemia, higher HOMA-IR, IGR and lower Matsuda indices compared to control animals, together with increased oxidative stress markers, TNFα, IL1ß and PAI-1 gene expression, and TNFα and COX-2 protein content. Whereas insulin receptor level was higher in fructose fed rats, their tyrosine-residue phosphorylation was lower. IRS1/IRS2 protein levels and IRS1 tyrosine-phosphorylation rate were lower in fructose fed rats. All changes were prevented by R/S-α-lipoic acid co-administration. SIGNIFICANCE: Fructose-induced hepatic oxidative stress, insulin resistance and inflammation form a triad that constitutes a vicious pathogenic circle. This circle can be effectively disrupted by R/S-α-lipoic acid co-administration, thus suggesting mutual positive interaction among the triad components.
Assuntos
Frutose/efeitos adversos , Inflamação/dietoterapia , Resistência à Insulina , Fígado/efeitos dos fármacos , Fígado/patologia , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Ácido Tióctico/uso terapêutico , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Glicemia/metabolismo , Ciclo-Oxigenase 2/biossíntese , Suplementos Nutricionais , Expressão Gênica/efeitos dos fármacos , Inflamação/sangue , Inflamação/induzido quimicamente , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina/genética , Interleucina-1beta/biossíntese , Fígado/metabolismo , Masculino , Fosforilação/efeitos dos fármacos , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Ratos , Ratos Wistar , Receptor de Insulina/biossíntese , Triglicerídeos/sangue , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as hormone refractory. In recent years, the concept of hormone refractoriness has been challenged and replaced by castration resistance, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.
Assuntos
Animais , Ratos , Angiotensina II/fisiologia , Fibronectinas/biossíntese , Células Mesangiais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Poli(ADP-Ribose) Polimerases/fisiologia , Células Cultivadas , Fibronectinas/genética , Regulação Enzimológica da Expressão Gênica , Mesângio Glomerular/citologia , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Células Mesangiais/enzimologia , Células Mesangiais/patologia , Inibidor 1 de Ativador de Plasminogênio/genética , Poli(ADP-Ribose) Polimerases/biossíntese , Poli(ADP-Ribose) Polimerases/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologiaRESUMO
We examine whether feeding pregnant and lactating rats hydrogenated fats rich in trans fatty acids modifies the plasma lipid profiles and the expression of adipokines involved with insulin resistance and cardiovascular disease in their 90-day-old offspring. Pregnant and lactating Wistar rats were fed with either a control diet (C group) or one enriched with hydrogenated vegetable fat (T group). Upon weaning, the male pups were sorted into four groups: CC, mothers were receiving C and pups were kept on C; CT, mothers were receiving C and pups were fed with T; TT, mothers were receiving T and pups were kept on T; TC, mothers were receiving T and pups were fed with C. Pups' food intake and body weight were quantified weekly and the pups were killed at day 90 of life by decapitation. Blood and carcass as well as retroperitoneal, epididymal, and subcutaneous white adipose tissues were collected. Food intake and body weight were lower in TC and TT, and metabolic efficiency was reduced in TT. Offspring of TT and TC rats had increased white adipose tissue PAI-1 gene expression. Insulin receptor was higher in TT than other groups. Ingestion of hydrogenated vegetable fat by the mother during gestation and lactation could promote deleterious consequences, even after the withdrawal of the causal factor.