RESUMEN
BACKGROUND: Activation of the PI3K/mTOR and Hedgehog (Hh) signalling pathways occurs frequently in biliary tract cancer (BTC). Crosstalk between these pathways occurs in other gastrointestinal cancers. The respective signalling inhibitors rapamycin and vismodegib may inhibit BTC synergistically and suppress cancer stem cells (CSCs). METHODS: Gene expression profiling for p70S6k and Gli1 was performed with BTC cell lines. Tumour and pathway inhibitory effects of rapamycin and vismodegib were investigated in BTC preclinical models and CSCs. RESULTS: Rapamycin and vismodegib synergistically reduced BTC cell viability and proliferation. This drug combination arrested BTC Mz-ChA-1 cells in the G1 phase but had no significant effect on the cell cycle of BTC Sk-ChA-1 cells. Combined treatment inhibited the proliferation of CSCs and ALDH-positive cells. Nanog and Oct-4 expression in CSCs was decreased by the combination treatment. Western blotting results showed the p-p70S6K, p-Gli1, p-mTOR, and p-AKT protein expression were inhibited by the combination treatment in BTC cells. In an Mz-ChA-1 xenograft model, combination treatment resulted in 80% inhibition of tumour growth and prolonged tumour doubling time. In 4 of 10 human BTC specimens, tumour p-p70S6K and Gli1 protein expression levels were decreased with the combination treatment. CONCLUSIONS: Targeted inhibition of the PI3K/mTOR and Hhpathways indicates a new avenue for BTC treatment with combination therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Proteínas Hedgehog/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Anilidas/administración & dosificación , Animales , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/metabolismo , Neoplasias del Sistema Biliar/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fase G1/efectos de los fármacos , Fase G1/genética , Perfilación de la Expresión Génica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Ratones , Ratones Desnudos , Proteína Homeótica Nanog , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Piridinas/administración & dosificación , Proteínas Quinasas S6 Ribosómicas 70-kDa/genética , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Sirolimus/administración & dosificación , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína con Dedos de Zinc GLI1Asunto(s)
Glucemia/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Deficiencia de Glucosafosfato Deshidrogenasa/sangre , Deficiencia de Glucosafosfato Deshidrogenasa/complicaciones , Hemólisis , Adulto , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/terapia , Dieta para Diabéticos , Glucosafosfato Deshidrogenasa/sangre , Deficiencia de Glucosafosfato Deshidrogenasa/terapia , Humanos , Insulina/uso terapéutico , Masculino , Oxidación-ReducciónAsunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Insulina/biosíntesis , Saccharomyces cerevisiae/genética , Adulto , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 1/sangre , Femenino , Estudios de Seguimiento , Ingeniería Genética , Humanos , Insulina/genética , Insulina/uso terapéutico , MasculinoRESUMEN
To delineate the spectrum of childhood bacteremia in a tertiary medical center in Israel and to define the historical, clinical and environmental variables that affect it, 339 bacteremic episodes were studied. Ten of the episodes (3%) were polymicrobial and 148 (44%) were hospital acquired. Staphylococcus epidermidis (17%), Staph. aureus (10%), gram-negative bacilli and Haemophilus influenzae (7%) were the most frequent etiologic pathogens. Some organisms (e.g., H. influenzae, Streptococcus pneumoniae) caused mainly community-acquired bacteremia, while Klebsiella sp., Enterococcus faecalis, and Acinetobacter sp. caused mainly nosocomial bacteremia. Underlying conditions were noted in 72% of the bacteremic children. A source of the bacteremia was identified in 60% of the episodes; the most common was i.v.-line infection. Age, underlying condition, source and location in the hospital markedly affected the profile of microorganisms causing childhood bacteremia. Each of these variables defined 3-5 organisms that were most prominent. In each episode of suspected bacteremia, these variables should be considered, thus defining the most likely causative pathogen(s), which should be covered by appropriate empiric antimicrobial treatment.