Background In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov ( NCT04381936 ). Findings Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding UK Research and Innovation (Medical Research Council) and National Institute of Health Research.

Backward inhibition (BI) refers to a reaction time cost incurred when returning to a recently abandoned task compared to returning to a task not recently performed. The effect has been proposed to reflect an inhibitory mechanism that aids transition from one task to another. The question arises as to precisely what aspects of a task may be inhibited and when the process takes place. Recent work has suggested a crucial role for response-related components of the task, which occur late in the typical trial structure (cue-target-response). In contrast to this suggestion, the authors present evidence that the way in which the task is cued can also modulate BI. Specifically, they find that the less transparent the cue-target relationship, the greater the level of BI. This also demonstrates that BI can be triggered at early stages of the trial structure, specifically during task preparation and prior to response processes. The authors conclude that BI is not tied to any particular component of the task structure but arises from whatever component generates the greatest intertrial conflict.

These novel findings for direct effects of celecoxib on mitochondria to induce metastatic cancer cell death via a ROS-dependent pro-oxidative mechanism provide supportive evidence for its combinatorial use as a chemosensitizing agent complementing chemotherapies to improve response rates in patients with advanced metastatic cancers.

Tumor metastases that impede the function of vital organs are a major cause of cancer related mortality. Mitochondrial oxidative stress induced by hypoxia, low nutrient levels, or other stresses, such as genotoxic events, act as key drivers of the malignant changes in primary tumors to enhance their progression to metastasis. Emerging evidence now indicates that mitochondrial modifications and mutations resulting from oxidative stress, and leading to OxPhos stimulation and/or enhanced reactive oxygen species (ROS) production, are essential for promoting and sustaining the highly metastatic phenotype. Moreover, the modified mitochondria in emerging or existing metastatic cancer cells, by their irreversible differences, provide opportunities for selectively targeting their mitochondrial functions with a one-two punch. The first blow would block their anti-oxidative defense, followed by the knockout blow—promoting production of excess ROS, capitulating the terminal stage—activation of the mitochondrial permeability transition pore (mPTP), specifically killing metastatic cancer cells or their precursors. This review links a wide area of research relevant to cellular mechanisms that affect mitochondria activity as a major source of ROS production driving the pro-oxidative state in metastatic cancer cells. Each of the important aspects affecting mitochondrial function are discussed including: hypoxia, HIFs and PGC1 induced metabolic changes, increased ROS production to induce a more pro-oxidative state with reduced antioxidant defenses. It then focuses on how the mitochondria, as a major source of ROS in metastatic cancer cells driving the pro-oxidative state of malignancy enables targeting drugs affecting many of these altered processes and why the NSAIDs are an excellent example of mitochondria-targeted agents that provide a one-two knockout activating the mPTP and their efficacy as selective anticancer metastasis drugs.

Intermittent hypoxia within tumor microenvironments causes pro-oxidative stress impairing oxidative phosphorylation (OxPhos) and increases mitochondrial production of reactive oxygen species (ROS). In primary tumors this provokes metabolic reprogramming of both tumor cells and cancer stem cells and emergence of highly metastatic cancer cells. Tumor reprogramming is initiated by activating nuclear respiratory factors and hypoxiainducible factors in response to changes in oxygen and ROS levels. Hence, hypoxia-induced pro-oxidative stress drives invasion and metastasis. However, it is also the Achilles' heel of metastatic cancer cells because pro-oxidative agents further overload the mitochondria and intracellular milieu with excessive ROS to trigger apoptosis, whereas antioxidant agents promote their survival and tumor progression. Herein lies the metastatic tumor cell sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) and we and others have shown that the NSAID celecoxib exerts powerful pro-oxidative anticancer effects by directly targeting mitochondria to increase ROS production and trigger cancer cell death, including metastatic cancer cells and cancer stem cells. This review highlights the considerable benefits from appropriate NSAID use in humans against post-diagnosis metastatic tumors and the need to further develop their use as adjuvant therapy for advanced stage metastatic disease where they are already showing significantly improved clinical outcomes.