Objective To investigate the expressions of spleen tyrosine kinase (Syk), c-Jun amino terminal kinase (JNK) and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the heart tissue in SD rat model of diabetic cardiomyopathy, and to explore the relationship between Syk, JNK and NLRP3. Methods Clean male SD rats were randomly divided into the control (Ctrl) group and diabetic cardiomyopathy model (DCM) group. Rats of DCM group were treated with a single intraperitoneal injection of streptozotocin (STZ), while rats of Ctrl group were injected with the same dose of citrate buffer. The random blood glucose level and body weight were monitored every week until 20 weeks after STZ or citrate buffer injection, then all the rats were killed and their hearts were obtained. Rat H 9c2 cardiomyocytes were randomly divided into normal glucose treatment (NG) group, high glucose treatment (HG) group, Syk inhibitor control (BAY) group and Syk inhibitor high glucose (HG+BAY) group. The Syk and JNK phosphorylations and NLRP3 protein expression were detected by Western blot assay in the heart tissue of SD rats and H9c2 cardiomyocytes. The NLRP3, cysteine-containing aspartate specific protease 1(caspase-1) and interleukin (IL)-1β expressions at mRNA level were detected by reverse transcription-polymerase chain reaction (RT-PCR). Results The random blood glucose level was significantly increased (P<0.05) and the body weight was significantly decreased (P<0.05) in DCM group compared with those of Ctrl group. The expressions of cardiac p-Syk, p-JNK and NLRP3 at protein level were significantly increased in DCM group compared with those of Ctrl group (P<0.05). Furthermore, the mRNA levels of NLRP3, caspase-1 and IL-1β were significantly up-regulated (P < 0.05). BAY treatment significantly inhibited the high glucose-induced NLRP3, caspase-1 and IL-1β mRNA expressions and p-JNK, NLRP3 protein expressions in H9c2 cardiomyocytes (P < 0.05). Conclusion JNK phosphorylation and NLRP3 inflammasome activation induced by Syk play an important role in the pathogenesis of diabetic cardiomyopathy.

Purpose: This study aims to evaluate the efficacy and safety of a new combination treatment of vinorelbine and pyrotinib in human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) and provide higher level evidence for clinical practice. Materials and Methods: This was a prospective, single-arm, phase 2 trial conducted at three institutions in China. Patients with HER2-positive MBC, who had previously been treated with trastuzumab plus a taxane or trastuzumab plus pertuzumab combined with a chemotherapeutic agent, were enrolled between March 2020 and December 2021. All patients received pyrotinib 400 mg orally once daily plus vinorelbine 25 mg/m2 intravenously or 60-80 mg/m2 orally on day 1 and day 8 of 21-day cycle. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included the objective response rate (ORR), disease control rate (DCR), overall survival, and safety. Results: A total of 39 patients were enrolled. All patients had been pretreated with trastuzumab and 23.1% (n=9) of them had accepted trastuzumab plus pertuzumab. The median follow-up time was 16.3 months (95% confidence interval [CI], 5.3 to 27.2), and the median PFS was 6.4 months (95% CI, 4.0 to 8.8). The ORR was 43.6% (95% CI, 27.8% to 60.4%) and the DCR was 84.6% (95% CI, 69.5% to 94.1%). The median PFS of patients with versus without prior pertuzumab treatment was 4.6 and 8.3 months (p=0.017). The most common grade 3/4 adverse events were diarrhea (28.2%), neutrophil count decreased (15.4%), white blood cell count decreased (7.7%), vomiting (5.1%), and anemia (2.6%). Conclusion Pyrotinib plus vinorelbine showed promising efficacy and tolerable toxicity as second-line treatment in patients with HER2-positive MBC.