Numerous c-mesenchymal-epithelial transition(c-MET)inhibitors have been reported as potential anticancer agents.However,most fail to enter clinical trials owing to poor efficacy or drug resistance.To date,the scaffold-based chemical space of small-molecule c-MET inhibitors has not been analyzed.In this study,we constructed the largest c-MET dataset,which included 2,278 molecules with different struc-tures,by inhibiting the half maximal inhibitory concentration(IC50)of kinase activity.No significant differences in drug-like properties were observed between active molecules(1,228)and inactive mol-ecules(1,050),including chemical space coverage,physicochemical properties,and absorption,distri-bution,metabolism,excretion,and toxicity(ADMET)profiles.The higher chemical diversity of the active molecules was downscaled using t-distributed stochastic neighbor embedding(t-SNE)high-dimensional data.Further clustering and chemical space networks(CSNs)analyses revealed commonly used scaffolds for c-MET inhibitors,such as M5,M7,and M8.Activity cliffs and structural alerts were used to reveal"dead ends"and"safe bets"for c-MET,as well as dominant structural fragments consisting of pyr-idazinones,triazoles,and pyrazines.Finally,the decision tree model precisely indicated the key structural features required to constitute active c-MET inhibitor molecules,including at least three aromatic het-erocycles,five aromatic nitrogen atoms,and eight nitrogen-oxygen atoms.Overall,our analyses revealed potential structure-activity relationship(SAR)patterns for c-MET inhibitors,which can inform the screening of new compounds and guide future optimization efforts.

Objective:To explore the tracking accuracy of the surface optically guided tracking system (OGTS) in radiotherapy.Methods:Phantom verification and clinical trial verification were adopted. Specialized equipment was employed for the phantom verification. Specifically, the displacement of the optical markers as they moved from a predetermined position to the target position on the reflector ball platform was captured using the OGTS, and then the obtained displacement was compared with the fixed distance within the phantom to calculate the accuracy and repeatability of the OGTS. For the clinical trial verification, 45 patients treated with radiotherapy, which consisted of 15 cases with head, breast, and rectal tumors each, were selected to investigate the tracking accuracy and repeatability of the OGTS. For each patient, the values derived from the image-guided positioning system (IGPS) and the OGTS before and after image-guided setup error correction during three times of fractionated radiotherapy were randomly obtained. The translational errors of each error correction were also recorded. Before radiotherapy, patients′ setup errors were corrected and relevant data were obtained using the IGPS. The correction result of translation errors obtained using the IGPS served as a gold standard to verify the accuracy of the OGTS in monitoring the translational motion of patients. Finally, the comprehensive translational deviation of both method was calculated.Results:The phantom measurements showed that the comprehensive translational deviation for tracking accuracy and tracking repeatability of the OGTS had a maximum deviation and a standard deviation of 0.18 mm and 0.03 mm, respectively. The clinical trial result indicated that the tracking accuracy of IGPS and OGTS exhibited statistically significant differences only for the head in the z direction ( t = 2.21, P < 0.05). Conversely, no statistically significant differences were observed for the head in the remaining directions or for the breast and rectum in the three translational directions ( P > 0.05). The analysis showed that comprehensive translational deviations for the head, breast, and rectum derived from OGTS and IGPS were (0.91±0.62), (1.64±1.30), and (1.52±1.29) mm, respectively, satisfying the requirement that the deviations should be below 2 mm. Conclusions:The OGTS, featuring easy operation and high tracking accuracy, can assist the IGPS in real-time respiratory monitoring during radiotherapy.

Objective:To evaluate the feasibility of a novel liver fiducial marker implantation method for internal fixation and removal of rabbit livers, in order to use in Cyberknife tracking therapy.Methods:Experiments were conducted in vivo and in vitro. In the in vivo experiment, three fiducial markers were implanted percutaneously in each liver of ten rabbits under anesthesia, and the fourth fiducial marker with an external catheter and fixed thin wire was implanted ten days later. After the reference group (the first and the second maker), and the casing group (the first and the fourth marker) were respectively registered and tracked with the Cyberknife, the implantation success rate, registration accuracy, and removal safety of fiducial markers were assessed. The tensile test was performed using liver in vitro by measuring the resistance required to dislodge the spring coil fiducial markers and the fiducial markers without spring coil from liver. Results:The intrahepatic catheter implantation and removal of fiducial marker in rabbit liver had a success rate of 100% and no distant migration. The operation-related and postoperative complications were not occurred. All fiducial markers were successfully traced. Compared to the reference group, the casing group had slightly higher translational errors in supero-inferior and antero-posterior directions ( Z=-11.77, -4.57, P<0.05), and lower translational errors in left-right direction ( Z=-2.52, P<0.05). The dislodgement forces for spring coil fiducial markers was (2.23±0.85) N, significantly different with (0.81±0.13) N for fiducial markers without spring coil ( Z=- 2.31, P < 0.05). Conclusions:The spiral coil structure provides superior fixation in the punctured needle channel, the thin line limits the distant displacement of the fiducial marker outside the liver, and the catheter establishes a channel for the removal. The general operation is simple and easy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) , which suppressed SARS-CoV-2 replication . In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers ( < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.