LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis.

Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1α at lysine (K) 391, which protects HIF1α against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1α hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1α methylation. Moreover, the HIF1α acetylation that occurs in a HIF1α methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1α stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)-induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1α/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1α protein degradation.

Conservative management of bilateral femoral neck fractures in a child with autosomal dominant osteopetrosis.

Management of minimally displaced femoral neck fractures in paediatric patients with autosomal dominant osteopetrosis (ADO) remains unclear as only small numbers have been reported. There are no detailed reports on successful conservative treatment. Common causes of failure in this particular area include non-union and development of coxa vara. Although there are no quantitative studies, case reports have influenced most authors to recommend operative treatment. It is well recognised that operative treatment of osteopetrotic bone is challenging. Problems arise intraoperatively due to the bone hardness, and postoperatively due to altered biomechanics and defective remodelling. This case of a child with ADO who suffered two asynchronous compression-side stress fractures in the femoral neck demonstrates that non-operative management can be satisfactory. After 8 weeks with partial weight-bearing the fractures were stable. At the latest follow-up 2.5 and 4 years after the fractures the patient presented with an excellent clinical and radiological outcome. There was no development of coxa vara.

Hybrid external fixation in complex tibial plateau and plafond fractures: an Australian audit of outcomes.

Hybrid external fixators are useful for the management of complex tibial plateau and plafond fractures, as they provide rigid fixation with relatively minimal soft tissue disruption. We reviewed the outcomes of patients with proximal (plateau) and distal (plafond) tibial fractures who were treated with hybrid frames at the Royal North Shore Hospital from 1998 to 2001. Twenty-four patients were identified from the hospital operating records and chart, X-ray and clinical reviews were performed. Follow-up periods averaged 13 months. Fractures were classified using the Ruedi classification for ankle fractures, and the Schatzker classification for the knee fractures. Clinical outcome was assessed using the Iowa knee score and the AOFAS ankle score. As one of the first Australian audits our outcomes were consistent with international standards.