Kinetic modelling of in vitro data of PI3K, mTOR1, PTEN enzymes and on-target inhibitors Rapamycin, BEZ235, and LY294002

The phosphatidylinositide 3-kinases (PI3K) and mammalian target of rapamycin-1 (mTOR1) are two key targets for anti-cancer therapy. Predicting the response of the PI3K/AKT/mTOR1 signalling pathway to targeted therapy is made difficult because of network complexities. Systems biology models can help explore those complexities but the value of such models is dependent on accurate parameterisation. Motivated by a need to increase accuracy in kinetic parameter estimation, and therefore the predictive power of the model, we present a framework to integrate kinetic data from enzyme assays into a unified enzyme kinetic model. We present exemplar kinetic models of PI3K and mTOR1, calibrated on in vitro enzyme data and founded on Michaelis-Menten (MM) approximation. We describe the effects of an allosteric mTOR1 inhibitor (Rapamycin) and ATP-competitive inhibitors (BEZ2235 and LY294002) that show dual inhibition of mTOR1 and PI3K. We also model the kinetics of phosphatase and tensin homolog (PTEN), which modulates sensitivity of the PI3K/AKT/mTOR1 pathway to these drugs. Model validation with independent data sets allows investigation of enzyme function and drug dose dependencies in a wide range of experimental conditions. Modelling of the mTOR1 kinetics showed that Rapamycin has an IC50 independent of ATP concentration and that it is a selective inhibitor of mTOR1 substrates S6K1 and 4EBP1: it retains 40% of mTOR1 activity relative to 4EBP1 phosphorylation and inhibits completely S6K1 activity. For the dual ATP-competitive inhibitors of mTOR1 and PI3K, LY294002 and BEZ235, we derived the dependence of the IC50 on ATP concentration that allows prediction of the IC50 at different ATP concentrations in enzyme and cellular assays. Comparison of the drug effectiveness in enzyme and cellular assays showed that some features of these drugs arise from signalling modulation beyond the on-target action and MM approximation and require a systems-level consideration of the whole PI3K/PTEN/AKT/mTOR1 network in order to understand mechanisms of drug sensitivity and resistance in different cancer cell lines. We suggest that using these models in systems biology investigation of the PI3K/AKT/mTOR1 signalling in cancer cells can bridge the gap between direct drug target action and the therapeutic response to these drugs and their combinations

The Saudi Critical Care Society practice guidelines on the management of COVID-19 in the ICU: Therapy section

BACKGROUND: The rapid increase in coronavirus disease 2019 (COVID-19) cases during the subsequent waves in Saudi Arabia and other countries prompted the Saudi Critical Care Society (SCCS) to put together a panel of experts to issue evidence-based recommendations for the management of COVID-19 in the intensive care unit (ICU). METHODS: The SCCS COVID-19 panel included 51 experts with expertise in critical care, respirology, infectious disease, epidemiology, emergency medicine, clinical pharmacy, nursing, respiratory therapy, methodology, and health policy. All members completed an electronic conflict of interest disclosure form. The panel addressed 9 questions that are related to the therapy of COVID-19 in the ICU. We identified relevant systematic reviews and clinical trials, then used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach as well as the evidence-to-decision framework (EtD) to assess the quality of evidence and generate recommendations. RESULTS: The SCCS COVID-19 panel issued 12 recommendations on pharmacotherapeutic interventions (immunomodulators, antiviral agents, and anticoagulants) for severe and critical COVID-19, of which 3 were strong recommendations and 9 were weak recommendations. CONCLUSION: The SCCS COVID-19 panel used the GRADE approach to formulate recommendations on therapy for COVID-19 in the ICU. The EtD framework allows adaptation of these recommendations in different contexts. The SCCS guideline committee will update recommendations as new evidence becomes available

Changes in the prevalence of influenza-like illness and influenza vaccine uptake among Hajj pilgrims: A 10-year retrospective analysis of data

Background: Influenza is an important health hazard among Hajj pilgrims. For the last ten years, pilgrims are being recommended to take influenza vaccine before attending Hajj. Vaccination coverage has increased in recent years, but whether there has been any change in the prevalence of influenza-like illness (ILI) is not known. In this analysis, we examined the changes in the rate of ILI against seasonal influenza vaccine uptake among Hajj pilgrims over the last decade. Method: Data for this analysis is a synthesis of raw and published data from eleven Hajj seasons between 2005 and 214. For seven Hajj seasons the data were obtained from studies involving pilgrims of UK, Saudi Arabia and Australia; and for the remaining four Hajj seasons data were abstracted from published studies involving pilgrims from multiple countries. The data from both sources were synthesised to estimate the relative risk (RR) of acquisition of ILI in vaccinated versus unvaccinated pilgrims. Results: The pooled sample size of the included studies was 33,213 with most pilgrims being in the age band of 40-60 years (range: 0.5 to 95 years) and a male to female ratio of 1.6. The pilgrims originated, in order of frequency, from Iran, Australia, France, UK, Saudi Arabia, Indonesia, India, Algeria, Ivory Coast, Nigeria, Somalia, Turkey, Syria, Sierra Leone and USA. Except for one year (2008), data from individual years did not demonstrate a noticeable change in the rate of ILI against influenza vaccine coverage, however the combined data from all studies suggest that the prevalence of ILI decreased among Hajj pilgrims as the vaccine coverage increased over the last decade (RR 0.2,