Purpose-Tumor hypoxia fuels an aggressive tumor phenotype and confers resistance to anticancer treatments. We conducted a clinical trial to determine whether the antimalarial drug atovaquone, a known mitochondrial inhibitor, reduces hypoxia in non-small cell lung cancer (NSCLC).Patients and methods-Patients with NSCLC scheduled for surgery were recruited sequentially into two cohorts: Cohort 1 received oral atovaquone at the standard clinical dose 750 mg twice-daily, whilst Cohort 2 did not. Primary imaging endpoint was change in tumor hypoxic volume (HV) measured by hypoxia PET-CT. Inter-cohort comparison of hypoxia gene expression signatures using RNA sequencing from resected tumors was performed.Results-Thirty patients were evaluable for hypoxia PET-CT analysis, 15 per cohort. Median treatment duration was 12 days. Eleven (73.3%) atovaquone-treated patients had meaningful HV reduction with median change −28.0% [95% confidence interval (CI), −58.2 to −4.4]. In contrast, median change in untreated patients was +15.5% (95% CI, −6.5 to 35.5). Linear regression estimated the expected mean HV was 55% (95% CI, 24% to 74%) lower in Cohort 1 compared to Cohort 2 (p=0.004), adjusting for cohort, tumor volume and baseline HV. A key pharmacodynamic endpoint was reduction in hypoxia regulated genes, which were significantly downregulated in atovaquone-treated tumors. Data from multiple additional measures of tumor hypoxia and perfusion are presented. No atovaquone-related adverse events were reported.Conclusions-This is the first clinical evidence that targeting tumor mitochondrial metabolism can reduce hypoxia and produce relevant anti-tumor effects at the mRNA level. Repurposing atovaquone for this purpose may improve treatment outcomes for NSCLC.

This ex-vivo study investigated the effect that repeated bracket displacement has on sliding friction and the magnitude of bracket displacement, and hence tooth movement, required to release bracket/archwire binding. The design consisted of an ex-vivo laboratory study. A jig was designed that allowed repeated displacement of a bracket to occur, while the resistance to sliding (friction) was measured using an Instron universal testing machine. One type of stainless steel bracket was used in conjunction with four archwire types (0.016-inch stainless steel, 0.019 x 0.025-inch stainless steel, 0.021 x 0.025-inch stainless steel, 0.019 x 0.025-inch beta-titanium) and four magnitudes of displacement. Repeated bracket displacement has a significant effect on the sliding resistance at the bracket/archwire interface (P < 0.001). The reduction in sliding resistance noted with displacement depended on the archwire. Over the range of displacements tested, there was an 85 and 80 per cent reduction associated with 0.021 x 0.025-inch and 0.019 x 0.025-inch stainless steel, respectively. For 0.019 x 0.025-inch beta-titanium and 0.016-inch stainless steel, these reductions were 27 and 19 per cent, respectively. The importance of true friction, given the likelihood of bracket and/or archwire displacements in vivo, may be lessened.

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