An endogenous inhibitor of angiogenesis downregulated by hypoxia in human aortic valve stenosis promotes disease pathogenesis

Acknowledgements The authors would like to acknowledge the NHS Grampian Biorepository for their support and assistance with all immunohistochemistry. Sources of funding This work was generously funded by the British Heart Foundation, UK (FS/17/28/32807) and Grampian NHS Endowments.Peer reviewedPublisher PD

Not for glory: a century of service by medical women to the Australian army and its allies

Susan J. Neuhaus and Sharon Mascall-Dar

A woman at war: the life and times of Dr Phoebe Chapple MM (1879-1967), an Australian doctor on the Western Front

Susan J Neuhaus, Sharon Mascall-Dar

Quality assurance aspects of the environmental code NECTAR

SIGLEAvailable from British Library Document Supply Centre- DSC:1769.7F(TPRD/B--0754/R86)(fiche) / BLDSC - British Library Document Supply CentreGBUnited Kingdo

A synthetic anti-Frizzled antibody engineered for broadened specificity exhibits enhanced anti-tumor properties

Secreted Wnt ligands play a major role in the development and progression of many cancers by modulating signaling through cell-surface Frizzled receptors (FZDs). In order to achieve maximal effect on Wnt signaling by targeting the cell surface, we developed a synthetic antibody targeting six of the 10 human FZDs. We first identified an anti-FZD antagonist antibody (F2) with a specificity profile matching that of OMP-18R5, a monoclonal antibody that inhibits growth of many cancers by targeting FZD7, FZD1, FZD2, FZD5 and FZD8. We then used combinatorial antibody engineering by phage display to develop a variant antibody F2.A with specificity broadened to include FZD4. We confirmed that F2.A blocked binding of Wnt ligands, but not binding of Norrin, a ligand that also activates FZD4. Importantly, F2.A proved to be much more efficacious than either OMP-18R5 or F2 in inhibiting the growth of multiple RNF43-mutant pancreatic ductal adenocarcinoma cell lines, including patient-derived cells