This editorial aims to refine the severe polytrauma management principles. While keeping ABCDE priorities, the termination of futile resuscitation and the early use of tourniquet to stop exsanguinating limb bleeding are crucial. Difficult-airway-management (DAM) is by a structured 5-level approach. The computerised tomography (CT) scanner is the tunnel to death for hemodynamically unstable patients. Focused Abdominal Sonography for Trauma–Ultrasonography (FAST USG) has replaced diagnostic peritoneal lavage (DPL) and is expanding to USG life support. Direct whole-body multidetector-row computed tomography (MDCT) expedites diagnosis & treatment. Non-operative management is a viable option in rapid responders in shock. Damage control resuscitation comprising of permissive hypotension, hemostatic resuscitation & damage control surgery (DCS) help prevent the lethal triad of trauma. Massive transfusion protocol reduces mortality and decreases the blood requirement. DCS attains rapid correction of the deranged physiology. Mortality reduction in major pelvic disruption requires a multi-disciplinary protocol, the novel pre-peritoneal pelvic packing and the angio-embolization. When operation is the definitive treatment for injury, prevention is best therapy.

Temozolomide(TMZ)is an anticancer agent used to treat glioblastoma,typically following radiation therapy and/or surgical resection.However,despite its effectiveness,at least 50％of patients do not respond to TMZ,which is associated with repair and/or tolerance of TMZ-induced DNA lesions.Studies have demonstrated that alkyladenine DNA glycosylase(AAG),an enzyme that triggers the base excision repair(BER)pathway by excising TMZ-induced N3-methyladenine(3meA)and N7-methylguanine le-sions,is overexpressed in glioblastoma tissues compared to normal tissues.Therefore,it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glio-blastomas.Herein,we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods.As a proof-of-concept,this assay was used to screen 1440 food and drug administration-approved drugs against AAG,resulting in the repurposing of sunitinib as a potential AAG inhibitor.Sunitinib restored glioblastoma(GBM)cancer cell sensitivity to TMZ,inhibited GBM cell proliferation and stem cell char-acteristics,and induced GBM cell cycle arrest.Overall,this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.

We report in this study the identification of a natural product-like antagonist () of Vps34 as a potent autophagy modulator structure-based virtual screening. Aurone derivative strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. modeling and kinetic data revealed that could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy and without inducing heart or liver damage in mice. could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.

In an effort to understand the molecular events contributing to the cytotoxicity activity of resveratrol (RSV), we investigated its effects on human lung adenocarcinoma epithelial cell line A549 at different concentrations. Cellular nucleoside metabolic profiling was determined by an established liquid chromatography-mass spectrometry method in A549 cells. RSV resulted in significant decreases and imbalances of deoxyribonucleoside triphosphates (dNTPs) pools suppressing subsequent DNA synthesis. Meanwhile, RSV at high concentration caused significant cell cycle arrest at S phase, in which cells required the highest dNTPs supply than other phases for DNA replication. The inhibition of DNA synthesis thus blocked subsequent progression through S phase in A549 cells, which may partly contribute to the cytotoxicity effect of RSV. However, hydroxyurea (HU), an inhibitor of RNR activity, caused similar dNTPs perturbation but no S phase arrest, finally no cytotoxicity effect. Therefore, we believed that the dual effect of high concentration RSV, including S phase arrest and DNA synthesis inhibition, was required for its cytotoxicity effect on A549 cells. In summary, our results provided important clues to the molecular basis for the anticancer effect of RSV on epithelial cells.

Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9-cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.