The development of non-genotoxic therapies that activate wild-type p53 in tumors is of great interest since the discovery of p53 as a tumor suppressor. Here we report the identification of over 100 small-molecules activating p53 in cells. We elucidate the mechanism of action of a chiral tetrahydroindazole (HZ00), and through target deconvolution, we deduce that its active enantiomer (R)-HZ00, inhibits dihydroorotate dehydrogenase (DHODH). The chiral specificity of HZ05, a more potent analog, is revealed by the crystal structure of the (R)-HZ05/DHODH complex. Twelve other DHODH inhibitor chemotypes are detailed among the p53 activators, which identifies DHODH as a frequent target for structurally diverse compounds. We observe that HZ compounds accumulate cancer cells in S-phase, increase p53 synthesis, and synergize with an inhibitor of p53 degradation to reduce tumor growth in vivo. We, therefore, propose a strategy to promote cancer cell killing by p53 instead of its reversible cell cycle arresting effect.

Background The declaration of COVID-19 a pandemic by the World Health Organization on 11 March 2020 marked the beginning of a global health crisis of an unprecedented nature and scale. The approach taken by countries across the world varied widely, however, the delivery of frontline healthcare was consistently recognised as being central to the pandemic response. This study aimed to identify and explore the issues currently facing pharmacy teams across Commonwealth countries during the COVID-19 pandemic. The study also evaluates pharmacy professionals’ understanding of key knowledge areas from the COVID-19 webinar hosted by the Commonwealth Pharmacists’ Association (CPA). Method A quantitative survey-based approach was adopted, using a 32-item questionnaire developed from the literature on pharmacy and pandemic response. The survey was hosted on Survey Monkey and pilot tested. The final survey was disseminated by CPA member organisations. A 6-item online questionnaire was sent via email to all attendees of CPA's COVID-19 webinar. Descriptive statistics on frequency distributions and percentages were used to analyse the responses. Data were analysed using Microsoft® Excel (2010). Results There were 545 responses from pharmacy professionals across 31/54 Commonwealth countries in Africa, Asia, the Americas, Europe and the Pacific. Majority of the respondents reported being at least somewhat worried (90%) and more than 65% were very worried or extremely about the impact of COVID-19 on them personally and professionally. Nearly two-thirds of respondents stated finding it somewhat difficult or very difficult to work effectively during the pandemic. Challenges mostly faced by pharmacy professionals working remotely included; general anxiety about the impact of COVID-19 on their lives (12%), and difficulties in communicating with their co-workers (12%). Most pharmacy professionals had not previously been actively involved in a global health emergency (82%) nor obtained training on global/public health emergency preparedness (62%). Between 45 and 97% of the COVID-19 webinar attendees provided the correct answers to post-webinar questions, suggesting some improvement in knowledge. Conclusion Our study confirms pharmacy professionals’ concerns about practice during a pandemic and provides preliminary data on the challenges and learning needs of the profession. The CPA has since acted on these findings, providing ongoing opportunities to develop and refine resources for the profession as the pandemic evolves. Pharmacy professionals have also demonstrated improved knowledge on the management of COVID-19 and resources available for professionals.

Smartphone apps have proven to be an effective and acceptable resource for accessing information on antimicrobial prescribing. The purpose of the study is to highlight the development and implementation of a smartphone/mobile app (app) for antimicrobial prescribing guidelines (the Commonwealth Partnerships for Antimicrobial Stewardship—CwPAMS App) in Ghana, Tanzania, Uganda and Zambia and to evaluate patients’ and healthcare providers’ perspectives on the use of the App in one of the participating institutions. Two structured cross-sectional questionnaires containing Likert scale, multiple-choice, and open-ended questions were issued to patients and healthcare workers six months after the introduction of the app at one of the hospital sites. Metrics of the use of the app for a one-year period were also obtained. Download and use of the app peaked between September and November 2019 with pharmacists accounting for the profession that the most frequently accessed the app. More than half of the responding patients had a positive attitude to the use of the app by health professionals. Results also revealed that more than 80% of health care workers who had used the CwPAMS App were comfortable using a smartphone/mobile device on a ward round, considered the app very useful, and found it to improve their awareness of antimicrobial stewardship, including documentation of the indication and duration for antimicrobials on the drug chart. It also encouraged pharmacists and nurses to challenge inappropriate antimicrobial prescribing. Overall, our findings suggest that its use as a guide to antimicrobial prescribing sparked positive responses from patients and health professionals. Further studies will be useful in identifying the long-term consequences of the use of the CwPAMS App and scope to implement in other settings, in order to guide future innovations and wider use.

The world currently faces unprecedented health challenges as COVID-19 poses a huge threat to health systems, economies and societies as we know it. The events of the current COVID-19 pandemic have further emphasised existing issues within our health systems. There is no better time than now to come together in global solidarity to tackle these evolving threats of COVID-19 pandemic. The Commonwealth is an ideally placed network to tackle these global health challenges, with its wide-reaching networks of governmental, non-governmental and civil society organisations across all continents. Although the biennial Commonwealth Heads of Government Meeting (CHOGM) originally scheduled to take place in Kigali in Rwanda 22-27 June 2020 has been postponed in view of COVID-19, Commonwealth country discussions are continuing, centred on the CHOGM key theme of 'Delivering a Common Future: Connecting, Innovating, Transforming', and five subthemes of Information and Communications Technology (ICT) and Innovation; Trade; Environment; Governance and the Rule of Law; and Youth. The planned CHOGM and Commonwealth itself provides all members a timely platform to consider innovative ways to connect, innovate and transform healthcare to meet the needs of their populations. This commentary considers these five CHOGM subthemes and how member nations can be supported to achieve universal health coverage through optimising medicines use and outcomes, in the midst of a global pandemic in line with the global health agenda.

SummaryCell cycle events are driven by Cyclin dependent kinases (CDKs) and by their counter-acting phosphatases. Activation of the Cdk1:Cyclin B complex during mitotic entry is controlled by the Wee1/Myt1 inhibitory kinases and by Cdc25 activatory phosphatase, which are themselves regulated by Cdk1:Cyclin B within two positive circuits. Impairing these two feedbacks with chemical inhibitors induces a transient entry into M phase referred to as mitotic collapse. The pathology of mitotic collapse reveals that the positive circuits play a significant role in maintaining the M phase state. To better understand the function of these feedback loops during G2/M transition, we propose a simple model for mitotic entry in mammalian cells including spatial control over Greatwall kinase phosphorylation. After parameter calibration, the model is able to recapture the complex and non-intuitive molecular dynamics reported by Potapova et al. (Potapova et al., 2011). Moreover, it predicts the temporal patterns of other mitotic regulators which have not yet been experimentally tested and suggests a general design principle of cell cycle control: latching switches buffer the cellular stresses which accompany cell cycle processes to ensure that the transitions are smooth and robust.