ABSTRACT
TGF-ß contributes to drug resistance and the invasiveness of tumor cells and weakens the anti-tumor immune responses. The present study aimed at examining the efficacy of the combination of SB431542, as a specific inhibitor of TGF-ßR, and doxorubicin in controlling the melanoma tumor in mice. The impact of the combination of the doxorubicin and SB431542 on the cell growth, apoptosis, migration, and invasiveness of B16-F10 cells was examined. Besides, the B16-F10 tumor was induced in C57BL/6 mice, and the effects of the mentioned treatment on the tumor volume, survival, and the exhaustion state of T cells were evaluated. Although the combination of doxorubicin and SB431542 did not exhibit synergism in the inhibition of cell growth and apoptosis induction, it efficiently prohibited the migration and the epithelial to mesenchymal transition of B16-F10 cells, and the combination of doxorubicin and SB431542 caused an increase in mRNA levels of E-cadherin and, on the other hand, led to a decline in the expression of Vimentin. Tumor volume and the survival of tumor-bearing mice were efficiently controlled by the combination therapy. This treatment also eventuated in a decrease in the percentage of PD-L1+, TCD4+, and TCD8+ cells as indicators of exhausted T cells within the spleens of tumor-bearing mice. Blockade of TGF-ßR also propelled the RAW 264.7 cells towards an anti-tumor M1 macrophage phenotype. The inhibition of TGF-ßR demonstrated a potential to increase the efficacy of doxorubicin chemotherapy by the means of affecting cellular motility and restoring the anti-tumor immune responses.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Melanoma, Experimental/drug therapy , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Benzamides/administration & dosage , Cadherins/genetics , Cell Movement/drug effects , Dioxoles/administration & dosage , Doxorubicin/administration & dosage , Epithelial-Mesenchymal Transition/drug effects , Female , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Neoplasm Invasiveness/prevention & control , RAW 264.7 Cells , Vimentin/geneticsABSTRACT
Introduction: Cardioembolic events are accompanied by left atrial appendage (LAA) in patients suffering from atrial fibrillation (AF); therefore, the LAA closure is implemented as a preventive strategy. The detection of LAA morphologies and function is a paramount step before establishing the LAA closure. Herein, we sought to determine the morphologic features of the LAA in an Iranian population using echocardiographic evaluation. Methods: Seventy-two near-normal heart patients were investigated by conducting a cross-sectional study. All patients were examined using the 2-dimensional and 3-dimensional transesophageal echocardiography (2D- and 3D-TEE) method. The anatomical features and functions of LAA were examined. All images were stored and analyzed offline. Results: The patients' mean age was 39 ± 15.5 year and 33 (45.8%) were female. The most frequent shape of LAA was wind sock . More LAA lobes was observed in patients with AF compared to those with NSR. In comparison with AF group, the NSR had higher LAA flow velocity (P < 0.01). The paroxysmal AF had greater LAA flow velocity and LAA ejection fraction in comparison with the chronic AF (39 ± 19 vs. 75 ± 22, P < 0.01; and 49±4 vs. 72±14, P < 0.003; respectively). The paroxysmal AF had smaller systolic LAA orifice area in comparison with the chronic AF (P < 0.02). Conclusion: The morphologic features of LAA in Iranian population were within the range of other studies and LAA length and orifice diameters in 2D- and 3D-TEE were consistent. In addition, AF influenced the morphologies and functions of LAA compared to sinus rhythm.