RESUMEN
AIM: The aim of this study was to investigate whether the consecutive administration of recombinant thrombomodulin (r-TM) for 4 days improves maternal and fetal conditions and physiological outcomes in an N'-nitro-L-arginine-methyl ester hydrochloride-induced and low-dose endotoxin-induced pre-eclampsia (PE). METHODS: r-TM or saline was administrated i.v. to normal pregnant and experimental PE rats for 4 days. The maternal condition, vascular endothelial growth factor receptor-1 (VEGFR-1), fetal conditions, uteroplacental blood flow (UPBF), and oxygenation in the placenta and fetal brain was evaluated on gestational day 21. RESULTS: Significant increases in the mean arterial blood pressure, VEGFR-1 values and fetal death rate were observed in PE rats compared with control rats, while maternal and fetal bodyweight and fetal brain weight were substantially lower. Hypoperfusion and hypo-oxygenation in both the placenta and fetal brain tissues occurred in PE rats. Although r-TM failed to improve hypertension and affect the differences in maternal bodyweight between the groups, r-TM significantly improved hypoperfusion and fetal and maternal conditions, including VEGFR-1 values (6.5 ± 4.0 vs 2.2 ± 2.7 ng/mL, PE vs PE with r-TM, respectively; P < 0.05). Although not significant, a decrease in the fetal death rate was observed in PE rats administrated r-TM (36.1 ± 17.6% vs 25.0 ± 23.8%, P = 0.077). CONCLUSION: The severe reductions in the UPBF and the placental oxygenation imply that regional hypoperfusion occurs in association with systemic mean arterial pressure. r-TM may be a candidate medical treatment for PE complications.
Asunto(s)
Feto/efectos de los fármacos , Preeclampsia/tratamiento farmacológico , Trombomodulina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Femenino , Placenta/irrigación sanguínea , Preeclampsia/fisiopatología , Embarazo , Ratas , Ratas Wistar , Proteínas Recombinantes/uso terapéutico , Flujo Sanguíneo Regional/efectos de los fármacos , Útero/irrigación sanguíneaRESUMEN
BACKGROUND: Gene amplifications are implicated in cancer development and progression. In this study we investigated the clinicopathologic characteristics associated with EGFR or TTF-1 amplification in lung adenocarcinomas and its prognostic significance. METHODS: We analyzed 118 cases of surgically resected primary lung adenocarcinomas. Amplification of the EGFR or TTF-1 gene was evaluated by fluorescence in situ hybridization and correlated with patients' clinicopathologic features, including disease-free survival (DFS) and overall survival (OS), in all patients and a subset that were TTF-1 positive or had EGFR mutation. Progression-free survival (PFS) also was analyzed among patients with EGFR mutation who had recurred cancer that was treated with EGFR tyrosine kinase inhibitors. RESULTS: EGFR or TTF-1 gene amplification was an independent poor prognostic factor for DFS in all patients (p=0.001), in patients with TTF-1 positivity (p=0.010), and in patients with EGFR mutation (p<0.001) and for OS in patients with TTF-1 positivity (p=0.021) and patients with EGFR mutation (p<0.001). Patients with TTF-1 amplification had a shorter PFS following EGFR TKI treatment (p=0.040). CONCLUSIONS: EGFR or TTF-1 gene amplification was a predictive factor for poor prognosis in terms of DFS and OS, especially in patients with TTF-1 positivity or EGFR mutation. Our results also suggested that TTF-1 amplification might be a predictive marker of poor response to EGFR-TKI therapy in patients with recurrent tumor after surgical resection.