ABSTRACT
Abstract Objective Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes. Method Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting. Results The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels. Conclusions Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.
ABSTRACT
Objective @#To analyze the effect of different cavosurface angles on the stress distribution of ClassⅠ cavity composite resin filling of molars through the three-dimensional finite element method and to provide references for the preparation of ClassⅠ cavities.@*Methods@#Three-dimensional finite element models of ClassⅠ composite resin filling of mandibular first molars with three different cavosurface angles (group A: 90°, group B: 120°, group C: 135°) were established. Polymerization shrinkage of composites was simulated with a thermal expansion approach. The mechanical behavior of the restored models in terms of stress and displacement distributions under the combined effects of polymerization shrinkage and occlusal load (600 N) was analyzed.@*Results@# For ClassⅠ cavities with the same cavity size, the total stress of the restoration model and the maximum stress of the enamel in group A were less than those in groups B and C after cavity composite resin restoration with three cavity cavosurface angles (in which the width of the enamel bevel was 1 mm in groups B and C). The maximum stress of the dentin and adhesive was similar in the three groups, the maximum stress of the composite in group C was the largest, and the maximum stress of the composite in group B was the smallest. In terms of stress distribution, the maximum stress in each restoration model was mainly concentrated in the enamel at the cavosurface, near the enamel-dentin interface and at the edge of the restoration material.@*Conclusion@#From the point of reducing the stress of residual tooth tissue, the preparation of 90° angle without enamel bevel is an ideal method for cavity preparation when composite resin is used to fill ClassⅠ cavities of molars.