RESUMO
RAC1 activity is critical for intestinal homeostasis, and is required for hyperproliferation driven by loss of the tumour suppressor gene Apc in the murine intestine. To avoid the impact of direct targeting upon homeostasis, we reasoned that indirect targeting of RAC1 via RAC-GEFs might be effective. Transcriptional profiling of Apc deficient intestinal tissue identified Vav3 and Tiam1 as key targets. Deletion of these indicated that while TIAM1 deficiency could suppress Apc-driven hyperproliferation, it had no impact upon tumourigenesis, while VAV3 deficiency had no effect. Intriguingly, deletion of either gene resulted in upregulation of Vav2, with subsequent targeting of all three (Vav2-/- Vav3-/- Tiam1-/-), profoundly suppressing hyperproliferation, tumourigenesis and RAC1 activity, without impacting normal homeostasis. Critically, the observed RAC-GEF dependency was negated by oncogenic KRAS mutation. Together, these data demonstrate that while targeting RAC-GEF molecules may have therapeutic impact at early stages, this benefit may be lost in late stage disease.
Assuntos
Carcinogênese/metabolismo , Carcinogênese/patologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Intestinos/patologia , Transdução de Sinais , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína da Polipose Adenomatosa do Colo/metabolismo , Animais , Carcinogênese/genética , Homeostase , Intestinos/ultraestrutura , Camundongos Knockout , Mutação/genética , Especificidade de Órgãos , Fenótipo , Proteínas Proto-Oncogênicas c-vav/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína 1 Indutora de Invasão e Metástase de Linfoma de Células T/metabolismo , Regulação para Cima , Via de Sinalização WntRESUMO
Three patients with recurrent affective disorders experienced polydipsia and the syndrome of inappropriate secretion of antidiuretic hormone in association with acute exacerbations of their affective disorders. These disturbances of water homeostasis responded to treatment of the affective disorders.
Assuntos
Transtorno Bipolar/complicações , Comportamento de Ingestão de Líquido , Síndrome de Secreção Inadequada de HAD/complicações , Sede , Doença Aguda , Adulto , Idoso , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Feminino , Haloperidol/uso terapêutico , Humanos , Hiponatremia/complicações , Masculino , Pessoa de Meia-Idade , Perfenazina/uso terapêutico , Tioridazina/uso terapêutico , Sede/efeitos dos fármacos , Equilíbrio HidroeletrolíticoRESUMO
All children seen by a pediatrician in a suburban practice during an 18-month interval were examined carefully for the presence of an abnormal uvula. Isolated bifid uvula, without overt cleft palate, was detected among 44 children who had been followed in the practice during the first three years of life. A chart review was performed to determine the frequency of acute otitis media (AOM) and of insertion of tympanostomy tubes among these study patients and among age-matched controls with normal uvulas. Compared to control children, a slightly higher proportion of children with bifid uvulas had experienced more than one episode of AOM (64% vs. 49%) and more than three episodes of AOM (16% vs. 8%) during the first year of life, but these differences were not statistically significant. By age 3 years, the incidences of AOM in the compared groups were more nearly equal. Insertion of tympanostomy tubes during the first three years of life for persistent middle ear effusion was slightly more common among the bifid uvula group than among the controls (14% vs. 10%), but this difference again was not statistically significant. Children with bifid uvula may be at slightly increased risk of middle ear problems during the first years of life, but the magnitude of this increase, if any, appears small.