In vivo and in vitro models for the therapeutic targeting of Wnt signaling using a Tet-OΔN89ß-catenin system.

Although significant progress has been made in understanding the importance of Wnt signaling in the initiation of colorectal cancer, less is known about responses that accompany the reversal of oncogenic Wnt signaling. The aim of this study was to analyze in vivo and in vitro responses to an 'ideal' Wnt pathway inhibitor as a model for the therapeutic targeting of the pathway. A tetracycline-inducible transgenic mouse model expressing truncated ß-catenin (ΔN89ß-catenin) that exhibited a strong intestinal hyperplasia was analyzed during the removal of oncogenic ß-catenin expression both in 3D 'crypt culture' and in vivo. Oncogenic Wnt signaling was rapidly and completely reversed. The strongest inhibition of Wnt target gene expression occurred within 24 h of doxycycline removal at which time the target genes Ascl2, Axin2 and C-myc were downregulated to levels below that in the control intestine. In vitro, the small molecule Wnt inhibitor CCT036477 induced a response within 4 h of treatment. By 7 days following doxycycline withdrawal, gene expression, cell proliferation and tissue morphology were undistinguishable from control animals.In conclusion, these results demonstrate that the reversal of Wnt signaling by inhibitors should ideally be studied within hours of treatment. The reversible system described, involving medium throughput in vitro approaches and rapid in vivo responses, should allow the rapid advance of early stage compounds into efficacy models that are more usually considered later in the drug discovery pipeline.

Routine daily chest radiographs in ventilated, very low birth weight infants.

The aim of this study was to assess the frequency of new abnormalities on routine chest radiographs of ventilated, very low birth weight (VLBW) infants during the acute stage of their illness. Infants were identified who had had at least three daily routine chest radiographs. The appearance of their subsequent radiographs was compared to that obtained on the 1st day of ventilatory support and the timing of new abnormalities (malposition of the endotracheal or nasogastric tube, pulmonary interstitial emphysema, pleural effusion, pulmonary oedema, lobar collapse or consolidation) noted. A total of 100 radiographs were examined from 30 VLBW infants, median gestational age 27 weeks (range 23-32 weeks). New abnormalities were present on the radiographs of 24 infants and on 50% of the radiographs examined. The commonest abnormalities noted were pulmonary interstitial emphysema, collapse and consolidation. Conclusion. Routine daily chest radiographs in mechanically ventilated, very low birth weight infants during the acute stage of their respiratory illness can yield new information important in patient care, new abnormalities being demonstrated in 50% of radiographs examined.

Presença de linhas de Park na extremidade proximal dos úmeros em telerradiografias de crianças eutróficas e desnutridas na faixa etária de 0 a 5 / The presence of transverse lines of Park in the proximal en for humeri in teleradiographies of eutrophic and undernourished children aged 0-5 years

O presente trabalho analisou a presença de linhas densas de Park na extremidade proximal dos úmeros em telerradiografias de 126 crianças eutróficas e desnutridas na faixa etária de 0 a 5 anos. Foi demonstrada a relaçäo existente entre o agravamento do estado nutricional e a presença de linhas transversais de Park, as quais foram mais frequentes nos desnutridos de terceiro grau e nas crianças situadas na faixa etária de 0 a 12 meses

Avaliaçäo radiológica dos tecidos moles da parede torácica em crianças eutróficas e desnutridas, na faixa etária de 0 a 2 anos / Radiologic evaluation of soft tissues of the thoracic wall in eutrophic and undernourished children aged 0-2

Analisaram-se os tecidos moles da parede torácia em telerradiografias de 101 ciranças eutróficas e desnutridas na faixa etária de 0 a 2 anos. Foi demonstrada a relaçäo existente entre o agravamento do estado nutricional e a reduçäo na espessura desses tecidos, a qual foi mais severa em faixa etária de 0 a 12 meses e nas crianças desnutridas de terceiro grau