Objective To analyze the relationship between cardiac autonomic neuropathy (CAN) and bone mineral density (BMD) reduction and fracture risk in patients with type 2 diabetes mellitus (T2DM). Methods A total of 396 patients with T2DM admitted to Nanchong Mental Health Center of Sichuan Province were selected, and all of them underwent detection of BMD of hip, lumbar vertebra and femoral neck. Fracture risk was evaluated using the probability of major osteoporotic fracture (PMOF) and ten-year probability of hip fracture (PHF). According to the degree of fracture risk, the patients were divided into low-risk group and high-risk group. Clinical data and CAN condition of the two groups were compared. Factors influencing fracture risk in patients with T2DM were analyzed. According to CAN condition, the patients were divided into early group, diagnosed group, and severe group. The correlation between CAN score and BMD was analyzed. Results The proportion of CAN in the high-risk group was significantly higher than that in the low-risk group (P<0.05). The BMD of hip, lumbar vertebra and femoral neck was significantly lower than that in the low-risk group (P<0.05). Logistic regression analysis showed that BMD of hip (OR=0.143, 95%CI: 0.102-0.201), BMD of lumbar vertebra (OR=0.047, 95%CI: 0.022-0.100), BMD of femoral neck (OR=0.208, 95%CI: 0.168-0.257), and CAN (OR=39.409, 95%CI: 14.704-105.623) were risk factors for fracture (P<0.05). The BMD of hip, BMD of lumbar vertebra and BMD of femoral neck in the severe group, the diagnosed group, and the early group increased in order (P<0.05). CAN score was negatively correlated with the BMD of hip, BMD of lumbar vertebra and BMD of femoral neck in patients with T2DM (P<0.05). Conclusion The condition of CAN in patients with T2DM is closely related to BMD reduction, and CAN is a risk factor for fracture.

As a novel and promising antitumor target, AXL plays an important role in tumor growth, metastasis, immunosuppression and drug resistance of various malignancies, which has attracted extensive research interest in recent years. In this study, by employing the structure-based drug design and bioisosterism strategies, we designed and synthesized in total 54 novel AXL inhibitors featuring a fused-pyrazolone carboxamide scaffold, of which up to 20 compounds exhibited excellent AXL kinase and BaF3/TEL-AXL cell viability inhibitions. Notably, compound 59 showed a desirable AXL kinase inhibitory activity (IC₅₀: 3.5 nmol/L) as well as good kinase selectivity, and it effectively blocked the cellular AXL signaling. In turn, compound 59 could potently inhibit BaF3/TEL-AXL cell viability (IC₅₀: 1.5 nmol/L) and significantly suppress GAS6/AXL-mediated cancer cell invasion, migration and wound healing at the nanomolar level. More importantly, compound 59 oral administration showed good pharmacokinetic profile and in vivo antitumor efficiency, in which we observed significant AXL phosphorylation suppression, and its antitumor efficacy at 20 mg/kg (qd) was comparable to that of BGB324 at 50 mg/kg (bid), the most advanced AXL inhibitor. Taken together, this work provided a valuable lead compound as a potential AXL inhibitor for the further antitumor drug development.