Tracheal stenosis: Preventable morbidity on the increase in our intensive care units

Following a marked increase in patients with tracheal stenosis at Groote Schuur Hospital, we re-examined this problem to identify new trends. Practitioners should be aware of this problem and that tracheal stenosis is an avoidable complication of endotracheal (ET) intubation. It is invariably difficult to treat, a heavy treatment burden and has an associated significant morbidity and reduction in quality of life. A 10-year retrospective review of patients that presented with or were referred to our service with tracheal stenosis showed no new patterns to be responsible for the increase incidence of stenosis. Therefore we conducted a survey of endotracheal tube (ETT) cuff pressures and cuff monitoring practises in local intensive care units (ICUs). This revealed that cuff pressures were dangerously elevated in 30% of all intubated patients surveyed in the ICUs. We are concerned that poor cuff pressure monitoring practises may be responsible for the increase in tracheal stenosis

Molecular basis of USP7 inhibition by selective small-molecule inhibitors

Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice