Introduction: Epithelial-mesenchymal transition (EMT) is a process of epithelial transformation into mesenchymal cells. It is also a process that contributes to the progression of fibrosis and cancer metastasis. Transforming growth factor-beta (TGF-β), as a potent inducer of EMT, has therefore became a potential therapeutic target. However, clinical developments of TGF-β inhibitors have been un-successful due to safety risks. Hence, drug repurposing of existing safe-to-use drugs could over-come this issue. Methods: In this study, the TGF-β receptor type 1 (ALK5) was selected as the target protein. Molecular docking was performed using known ALK5 inhibitors as positive controls. Clinical drugs with similar binding affinity and amino acid interaction were selected for in vitro experimental validation. Results: ALK5 inhibitor demonstrated binding affinities ranging from -11.2 to -9.5 kcal/mol. Analysis of amino acid interaction revealed that Val219, Ala230, Lys232, and Leu340 amino acid residues are crucial for binding. Subsequent screening of clinically approved drugs against ALK5 showed top five potential drugs (ergotamine, telmisartan, saquinavir, indinavir, and nelfinavir). The selected drugs were tested in TGF-β1-induced normal human bronchial epithelial cell line, BEAS-2B. Western blot analysis showed that the drugs did not exhibit inhibitory effects on the downregulation of epithelial proteins (E-cadherin) and upregulation of mesenchymal proteins (vimentin and α-smooth muscle actin). Conclusion: Based on these experimental outcome, it is postulated that the results from molecular docking were false positives. The tested drugs in this study could serve as negative controls in future screening against ALK5 protein.

INTRODUCTIONEarly use of mechanical cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest (OHCA) may improve survival outcomes. Current evidence for such devices uses outcomes from an intention-to-treat (ITT) perspective. We aimed to determine whether early use of mechanical CPR using a LUCAS 2 device results in better outcomes.

METHODSA prospective, randomised, multicentre study was conducted over one year with LUCAS 2 devices in 14 ambulances and manual CPR in 32 ambulances to manage OHCA. The primary outcome was return of spontaneous circulation (ROSC). Secondary outcomes were survival at 24 hours, discharge from hospital and 30 days.

RESULTSOf the 1,274 patients recruited, 1,191 were eligible for analysis. 889 had manual CPR and 302 had LUCAS CPR. From an ITT perspective, outcomes for manual and LUCAS CPR were: ROSC 29.2% and 31.1% (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.82-1.45; p = 0.537); 24-hour survival 11.2% and 13.2% (OR 1.20, 95% CI 0.81-1.78; p = 0.352); survival to discharge 3.6% and 4.3% (OR 1.20, 95% CI 0.62-2.33; p = 0.579); and 30-day survival 3.0% and 4.0% (OR 1.32, 95% CI 0.66-2.64; p = 0.430), respectively. By as-treated analysis, outcomes for manual, early LUCAS and late LUCAS CPR were: ROSC 28.0%, 36.9% and 24.5%; 24-hour survival 10.6%, 15.5% and 8.2%; survival to discharge 2.9%, 5.8% and 2.0%; and 30-day survival 2.4%, 5.8% and 0.0%, respectively. Adjusted OR for survival with early LUCAS vs. manual CPR was 1.47 after adjustment for other variables (p = 0.026).

CONCLUSIONThis study showed a survival benefit with LUCAS CPR as compared to manual CPR only, when the device was applied early on-site.