Prognostic factors of patients with small cell lung cancer after surgical treatment.

BACKGROUND: The current National Comprehensive Cancer Network guidelines recommend surgical treatment for patients with stages I-IIA small cell lung cancer (SCLC), but it still cannot deny the effect of surgical treatment on other limited-stage SCLC. Although more advanced diagnostic methods are now used for the diagnosis and classification of SCLC, the selection of surgical candidates is still arbitrary. METHODS: Data were collected from patients with SCLC who underwent surgery at the First Affiliated Hospital of Zhengzhou University from January 2011 to January 2021. Kaplan-Meier method was used to calculate cumulative survival curves, and log-rank test was used to evaluate differences among different subgroups. The Cox proportional hazard regression model was used to assess the predictive power of the variables for prognosis and survival. RESULTS: Smoking index, surgical resection method, TNM stage of postoperative pathology, and postoperative chemotherapy were significantly correlated with postoperative survival (P<0.05), which were independent predictors for postoperative survival. Patients with a smoking index >800 had a higher risk of death after surgery [hazard ratio (HR): 7.050, 95% confidence interval (CI): 3.079-16.143, P<0.001]. Compared with patients who underwent pulmonary lobectomy, those who underwent other pneumoresections (e.g., wedge resection, segmental resection, sleeve resection) had an increased risk of death (HR: 2.822, 95% CI: 1.030-7.734, P=0.044). Compared with stage I patients, stage II and stage III patients had an increased risk of death, with HRs of 6.039 and 3.145, respectively. Compared with those who received ≤4 courses of postoperative chemotherapy, those who received >4 courses of postoperative chemotherapy had reduced postoperative mortality risk (HR: 0.211, 95% CI: 0.097-0.459, P<0.001). CONCLUSIONS: A high smoking index suggests worse prognosis; therefore, patients who smoke should be advised to quit smoking. Compared with stage II and stage III patients, surgical treatment is recommended for stage I SCLC patients. TNM staging, especially N staging, should be evaluated prior to surgery. Pulmonary lobectomy with mediastinal lymph node dissection should be the preferred surgical treatment for patients with SCLC. Patients should receive at least 5 courses of adjuvant chemotherapy after surgery.

Structure-Based Design and Preclinical Characterization of Selective and Orally Bioavailable Factor XIa Inhibitors: Demonstrating the Power of an Integrated S1 Protease Family Approach.

The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1ß, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

Inhibition of autophagy by 3-MA potentiates cisplatin-induced apoptosis in esophageal squamous cell carcinoma cells.

Cisplatin (DDP)-based adjuvant chemotherapy is widely used for the treatment of esophageal cancer. However, DDP resistance has become more common and thus new approaches are required to be explored. Cisplatin was used to induce autophagy in the human esophageal cancer cell line, EC9706 cells, and the effect of autophagy on the survival of EC9706 cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by CCK8 assay. Apoptosis and cell cycle were detected by flow cytometry. Monodansylcadaverine (MDC) was used to detect autophagy. Western blotting assay was used to investigate the molecular changes that occurred in the course of treatment. DDP inhibited cell proliferation, induced cell death and cell cycle arrest at S phage. Moreover, autophagy was activated through class III PI3K pathway. The expression of autophagy-related Beclin1 and LC3-I was up-regulated and part of LC3-I was converted into LC3-II. However, after the combination treatment of 3-MA and DDP, the cell inhibitory rate increased; the apoptosis rate and the numbers of cells in S phase also increased. Furthermore, the accumulation of autophagic vacuoles was decreased; the expression of Beclin1 and LC3 was significantly down-regulated and the release of cytochrome c was decreased. DDP-induced apoptosis in EC9706 cells can be enhanced by the inhibitor of autophagy, 3-MA. Autophagy might play a role as a self-protective mechanism in DDP-treated esophageal cancer cells, and its inhibition could be a novel strategy for the adjuvant chemotherapy of esophageal cancer.