Trends in vehicle kilometres of travel in world cities, 1960-1990: underlying drivers and policy responses

Increases in private motorised urban vehicle kilometres of travel are shown to arise from population growth, urban sprawl, increased car ownership and decreases in vehicle occupancy. In particular, the worldwide increase in urban mobility since 1960 has been the direct result of increased affluence and the consequent greater accessibility of private motor vehicles, as well as population growth. Urban sprawl has significantly less influence, although it has been significant in USA, Canadian and Australian cities. Despite this, a number of cities have shown that clear policy initiatives can contain the growth of urban private motorised mobility

Controlled coupling of an ultrapotent auristatin warhead to cetuximab yields a next-generation antibody-drug conjugate for EGFR-targeted therapy of KRAS mutant pancreatic cancer

Background: Antibody-drug conjugate (ADC) construction poses numerous challenges that limit clinical progress. In particular, common bioconjugation methods afford minimal control over the site of drug coupling to antibodies. Here, such difficulties are overcome through re-bridging of the inter-chain disulfides of cetuximab (CTX) with auristatin-bearing pyridazinediones, to yield a highly refined anti-epidermal growth factor receptor (EGFR) ADC. / Methods: In vitro and in vivo assessment of ADC activity was performed in KRAS mutant pancreatic cancer (PaCa) models with known resistance to CTX therapy. Computational modelling was employed for quantitative prediction of tumour response to various ADC dosing regimens. / Results: Site-selective coupling of an auristatin to CTX yielded an ADC with an average drug:antibody ratio (DAR) of 3.9, which elicited concentration- and EGFR-dependent cytotoxicity at sub-nanomolar potency in vitro. In human xenografts, the ADC inhibited tumour growth and prolonged survival, with no overt signs of toxicity. Key insights into factors governing ADC efficacy were obtained through a robust mathematical framework, including target-mediated dispositional effects relating to antigen density on tumour cells. / Conclusions: Together, our findings offer renewed hope for CTX in PaCa therapy, demonstrating that it may be reformatted as a next-generation ADC and combined with a predictive modelling tool to guide successful translation