Professor Shirley Price

The role of apoptosis in acetaminophen (AAP)-induced hepatic injury was investigated. Six hours after AAP administration to BALB/c mice, a significant loss of hepatic mitochondrial cytochrome c was observed that was similar in extent to the loss observed after in vivo activation of CD95 by antibody treatment. AAP-induced loss of mitochondrial cytochrome c coincided with the appearance in the cytosol of a fragment corresponding to truncated Bid (tBid). At the same time, tBid became detectable in the mitochondrial fraction, and concomitantly, Bax was found translocated to mitochondria. However, AAP failed to activate the execution caspases 3 and 7 as evidenced by a lack of procaspase processing and the absence of an increase in caspase-3-like activity. In contrast, the administration of the pan-inhibitor of caspases, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (but not its analogue benzyloxycarbonyl-Phe-Ala-fluoromethylketone) prevented the development of liver injury by AAP and the appearance of apoptotic parenchymal cells. This correlated with the inhibition of the processing of Bid to tBid. The caspase inhibitor failed to prevent both the redistribution of Bax to the mitochondria and the loss of cytochrome c. In conclusion, apoptosis is an important causal event in the initiation of the hepatic injury inflicted by AAP. However, as suggested by the lack of activation of the main execution caspases, apoptosis is not properly executed and degenerates into necrosis.

Allograft and xenograft transplantation into a mouse host is frequently utilized to study cancer biology, tumor behavior, and response to treatment. Preclinical studies employing these models often focus solely upon the intra-tumoral effects of a given treatment, without consideration of systemic toxicity or tumor-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy. Here it is demonstrated that the implantation and growth of a range of human- and mouse-derived cell lines leads to structural vascular and, potentially, functional changes within peripheral endocrine tissues, a process that could conceivably ameliorate the severity of anti-angiogenic-induced fenestrated vessel attenuation. Observations suggest a multifactorial process, which may involve host- and tumor-derived cytokines/growth factors, and the liberation of myeloid-derived suppressor cells. Further investigation revealed a structurally comparable response to the administration of exogenous estrogen. These findings, in addition to providing insight into the development of clinical anti-angiogenic "adaptation," may be of significance within the "cancer-cachexia" and cancer-related anemia syndromes in man.

Toxicologic evaluation of new drug candidates routinely utilizes healthy animals. In oncology, there remains a limited understanding of the effects of novel test candidates in a diseased host. For vascular modulating agents (VMAs), an increased understanding of preclinical tumour–host interaction, and its potential to exacerbate or alleviate ‘off‐target’ effects of anti‐angiogenic administration, could aid in the prediction of adverse clinical outcomes in a defined cancer patient. We have previously reported that the implantation and growth of a range of human‐ and mouse‐derived tumours leads to structural vascular and, potentially, functional signalling changes within host mouse endocrine tissues, indicating possible roles for tumour‐ and host‐derived cytokines/growth factors and the liberation of myeloid‐derived suppressor cells in this phenomenon. Here, we further demonstrate that the growth of the Calu‐6 xenograft is associated with a resistance to VMA‐induced mouse peripheral endocrine vascular rarefaction (toxicity), with potential functional impact, notably with respect to mixed tyrosine kinase inhibition. The pathogenesis of these findings indicates a potential role for both tumour‐ and host‐derived basic fibroblast growth factor (bFGF), with associated upregulation in the intra‐tumoural autotaxin‐lysophosphatic acid signalling axis. The growth of the Calu‐6 xenograft is associated with a resistance to vascular modulating agent‐induced mouse peripheral endocrine vascular rarefaction (toxicity), with potential functional impact, notably with respect to mixed tyrosine kinase inhibition. The pathogenesis of these findings indicates a potential role for basic fibroblast growth factor, with associated upregulation in the autotaxin‐lysophosphatic acid signalling axis.

After spending a year working on the development of a new online Master's programme in higher education, members of the development team were interviewed to reveal their thoughts about the nature of the programme. The dialogue of each interview was summarised as a concept map. Analysis of the resulting maps included a modified Bernsteinian analysis of the focus of the concepts included in terms of their semantic gravity (i.e. closeness to context) and the degree of resonance with the underpinning regulative discourse of the programme. Data highlight a number of potential issues for programme delivery that centre around the use of appropriate language to manage student expectations in relation to the process of learning and the emotional responses this can stimulate, as well as the tensions that can be foregrounded between the demands of teaching and research within a university environment.

•The current testing strategy can be improved by utilising alternative methods.•A better understanding of adverse developmental outcome pathways is required.•Alternative methods should be qualified with harmonised regulatory guidance.•Multidisciplinary cross-sector interactions and data sharing are required.•A ‘Safe Harbour’ approach should be identified to promote data sharing. The framework for developmental toxicity testing has remained largely unchanged for over 50 years and although it remains invaluable in assessing potential risks in pregnancy, knowledge gaps exist, and some outcomes do not necessarily correlate with clinical experience. Advances in omics, in silico approaches and alternative assays are providing opportunities to enhance our understanding of embryo-fetal development and the prediction of potential risks associated with the use of medicines in pregnancy. A workshop organised by the Medicines and Healthcare products Regulatory Agency (MHRA), “Predicting the Safety of Medicines in Pregnancy – a New Era?”, was attended by delegates representing regulatory authorities, academia, industry, patients, funding bodies and software developers to consider how to improve the quality of and access to nonclinical developmental toxicity data and how to use this data to better predict the safety of medicines in human pregnancy. The workshop delegates concluded that based on comparative data to date alternative methodologies are currently no more predictive than conventional methods and not qualified for use in regulatory submissions. To advance the development and qualification of alternative methodologies, there is a requirement for better coordinated multidisciplinary cross-sector interactions coupled with data sharing. Furthermore, a better understanding of human developmental biology and the incorporation of this knowledge into the development of alternative methodologies is essential to enhance the prediction of adverse outcomes for human development. The output of the workshop was a series of recommendations aimed at supporting multidisciplinary efforts to develop and validate these alternative methodologies.