An engineered ultrahigh affinity bi-paratopic uPAR targeting agent confers enhanced tumor targeting.

Urokinase-type plasminogen activator receptor (uPAR) is overexpressed on tumor cells in multiple types of cancer and contributes to disease progression and metastasis. In this work, we engineered a novel bi-paratopic uPAR targeting agent by fusing the binding domains of two native uPAR ligands: uPA and vitronectin, with a flexible peptide linker. The linker length was optimized to facilitate simultaneous engagement of both domains to their adjacent epitopes on uPAR, resulting in a high affinity and avid binding interaction. Furthermore, the individual domains were affinity-matured using yeast surface display and directed evolution, resulting in a bi-paratopic protein with affinity in the picomolar to femtomolar range. This engineered uPAR targeting agent demonstrated significantly enhanced tumor localization in mouse tumor models compared to the native uPAR ligand and warrants further investigation as a diagnostic and therapeutic agent for cancer.

Effect of the COVID-19 pandemic on the mental health of carers of people with intellectual disabilities.

INTRODUCTION: The measures implemented to manage the COVID-19 pandemic have been shown to impair mental health. This problem is likely to be exacerbated for carers. METHOD: Informal carers (mainly parents) of children and adults with intellectual disabilities, and a comparison group of parents of children without disabilities, completed an online questionnaire. Almost all the data were collected while strict lockdown conditions were in place. RESULTS: Relative to carers of children without intellectual disability, carers of both children and adults with intellectual disability had significantly greater levels of a wish fulfilment coping style, defeat/entrapment, anxiety, and depression. Differences were 2-3 times greater than reported in earlier pre-pandemic studies. Positive correlations were found between objective stress scores and all mental health outcomes. Despite their greater mental health needs, carers of those with intellectual disability received less social support from a variety of sources. CONCLUSIONS: The greater mental health needs of carers in the context of lesser social support raises serious concerns. We consider the policy implications of these findings.