Structures of signaling complexes of lipid receptors S1PR1 and S1PR5 reveal mechanisms of activation and drug recognition.

Sphingosine-1-phosphate (S1P) is an important bioactive lipid molecule in cell membrane metabolism and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, physiological homeostasis, and pathogenic processes in various organs. S1PRs are lipid-sensing receptors and are therapeutic targets for drug development, including potential treatment of COVID-19. Herein, we present five cryo-electron microscopy structures of S1PRs bound to diverse drug agonists and the heterotrimeric Gi protein. Our structural and functional assays demonstrate the different binding modes of chemically distinct agonists of S1PRs, reveal the mechanical switch that activates these receptors, and provide a framework for understanding ligand selectivity and G protein coupling.

Computed tomographic-guided iodine-125 interstitial implants for malignant thoracic tumors.

PURPOSE: To evaluate the feasibility and efficacy of percutaneous interstitial brachytherapy using iodine-125 ((125)I) radioactive seeds under computed tomographic (CT) guidance for malignant thoracic tumors. MATERIALS AND METHODS: Forty-one patients (34 males, 7 females; 18-90 years; mean, 63.7 years) with 77 lesions (3 in the mediastinum, 7 in the chest wall, 67 in the lung) underwent percutaneous interstitial implantation of (125)I radioactive seeds under CT guidance. A treatment planning system (TPS) was employed to calculate the number and distribution of seeds preoperatively. An 18-G needle was inserted into the lesions under CT guidance and send the seeds according to TPS. Two patients with mediastinal lesions undergoing seed implantation received an artificial pneumothorax. One patient with lung carcinoma adjacent to the anterior mediastinum underwent seed implantation through the sternum. Follow-up CT was done every 2 months postoperatively. RESULTS: The procedure was successful in all patients. No major procedure-associated death occurred. The mean duration of follow-up was 19.4 ± 1.3 months (3-49 months). A complete response (CR) was seen in 49 lesions (63.6%), partial response (PR) in 9 lesions (11.7%), stable disease (SD) in 12 lesions (12.8%), and progressive disease (PD) in 7 lesions (7.4%). The overall response rate (CR+PR) was 75.3%; the local control rate (CR+PR+SD) was 90.9%. The 1-, 2- and 3-year progression-free rates for local tumors were 91%, 88% and 88%, respectively. The 1-, 2- and 3-year survival rates were 87%, 74% and 68%, respectively. CONCLUSION: Implantation of CT-guided (125)I seeds is feasible and effective for patients with malignant thoracic tumors.