1) Neuroprotection in Adults
The candidate detailed the signaling pathways that xenon perturbs to produce a pro-survival phenotype; this series of studies formed the basis for a successful Phase 2 randomized clinical trial (NCT 00879892). On the basis of the candidate’s preclinical data and the results of the Phase 2 RCT, the regulatory agencies in the US and Europe granted a New Drug Application for an International multi-centre Phase 3 clinical trial (NCT 03176186) to study the safety and efficacy of xenon to mitigate the ischaemic-reperfusion injury to the brain and heart in post-cardiac arrest patients (this industry-led study was halted during the pandemic).
2) Perinatal Asphyxia
The candidate identified the neuroprotective efficacy of the noble gas xenon in the setting of hypothermia in a series of in vitro and in vivo models of neuronal injury in neonates. These studies led to a Phase 2 randomized clinical trial of the combination of xenon and hypothermia for perinatal asphyxia (NCT00934700).
3) Cognitive Dysfunction and Alzheimer’s Disease
The candidate was the first to demonstrate that peripheral surgery produces neuro-inflammation, synaptic dysfunction and post-operative cognitive decline in rodents; the neuro-inflammatory basis for Postoperative Neurocognitive Disorders is now widely accepted and formed the basis for two RCTs to investigate the safety and efficacy of xenon anaesthesia for hip fracture surgery (NCT01199276) and for the use of dexmedetomidine (ChiCTR-TRC-10000802) to prevent postoperative delirium. The candidate’s initial findings in this form of cognitive decline may extend to Alzheimers Disease as he has now shown older mice that undergo surgery develop the pathological hallmarks of beta-amyloid accumulation, [tau] protein hyperphosphorylation and astrogliosis/microgliosis.
4) Anaesthetics and Cancer
The candidate discovered the prominent effect of anaesthetics on hypoxic-inducible factor (HIF-1a) that prompted exploration of anaesthetic effects on cancer. Volatile anaesthetics increased the malignant potential of ovarian, prostate and renal cancer cells in vitro, a finding that has been reproduced in vivo. Furthermore, a restrospective analysis of surgical cancer database from the Royal Marsden and Taiwan confirmed the preclinical findings. These preclinical studies has resulted in an ongoing RCT to investigate the safety and efficacy of intravenous vs inhalational anaesthesia for cancer patients (NCT02662257).
5) Renoprotection – Ischaemia-Reperfusion Injury & Kidney Transplantation
The candidate employed intra-strain (isograft) or inter-strain (allograft) kidney transplantation models to test the renoprotective efficacy of xenon. In in vivo studies, xenon was administered to the donor before graft retrieval (pre-conditioning), or to the recipient immediately after engraftment (post-conditioning). In an additional ex vivo model, the kidney graft was stored in xenon-saturated cold preservative solution for extended period to mimic hypothermic-ischaemia. In all treatment paradigms, xenon conferred potent renoprotection as evidenced by attenuated inflammation in transplanted kidney graft, upregulated expression of pro-survival proteins, reduced graft tubular cell death, as well as reduced acute and chronic graft rejection rates (allograft model), improved graft morphology & function and prolonged survival. The candidate has shown that the onset of injury to the lung following kidney transplantation may be due to pathophysiologic mechanisms that include necroptosis and sterile inflammation (non-pathogen driven engagement of the innate immune system) and can be prevented by xenon-induced upregulation of pro-survival proteins. Clinical trials using xenon to improve kidney graft quality before engraftment are ongoing.
Impact of Research Findings
Three Phase 2 RCTs and two Phase 3 RCTs have evolved directly from the candidate’s studies (see above). The World Anti-Doping Agency (WADA) banned the use of xenon and argon by competitive athletes based upon the candidate’s reports on the effect of these noble gases on HIF-1a and the downstream effector, erythropoeitin. Based upon the candidate’s work on the effects of anaesthetics on cancer, a restrospective analysis of surgical cancer database from the Royal Marsden and Taiwan confirmed the preclinical findings. Given that various anaesthetic regimens/techniques are available clinically and the choice of use is mainly by each anaesthetist’s preference, changing practice based on the candidate’s findings would result in no further significant cost to health services and will likely improve post-operative cancer outcomes worldwide.
“Dexmedetomidine in preventing postoperative delirium” (clinical trial; published in Lancet 2016) now became a clinical standard intervention to prevent and/or treat postoperative delirium worldwide.
Research Student Supervision
Jaffer,T, The Effects of Anaesthetics on Ovarian Cancer Malignancy