AJTR Copyright © 2020.Oncogenic KRAS mutations are frequently found in non-small cell lung carcinoma (NSCLC) and cause constitutive activation of the MEK-ERK pathway. Many cancer types have been shown to overexpress PD-L1 to escape immune surveillance. FRA1 is a MEK/ERK-dependent oncogenic transcription factor and a member of the AP-1 transcriptional factor superfamily. This study assesses the hypothesis that KRAS mutation directly regulates PD-L1 expression through the MEK-ERK pathway mediated by FRA1. Premalignant human bronchial epithelial cell (HBEC) lines harboring the KRAS mutationV12, EGFR mutation, p53 knock-down, or both KRAS mutation and p53 knock-down were tested for levels of PD-L1, FRA1, and ERK activation (pERK). Our results showed that KRAS mutation alone, but not other genetic alterations, induced significantly higher expression of PD-L1 compared to its vector counterparts. The increased PD-L1 expression in the KRAS mutated cells was dramatically reduced by inhibition of ERK activation. Furthermore, the MEK-ERK pathway-dependent PD-L1 expression was markedly reduced by FRA1 silencing. Interestingly, FRA1 silencing led to inhibition of ERK activation, indicating that FRA1 plays a role in PD-L1 regulation via positive feedback of ERK activation. Correlation of PD-L1 and FRA1 mRNA expression was validated using human lung cancer specimens from The Cancer Genome Atlas (TCGA) and established NSCLC cell lines from Cancer Cell Line Encyclopedia (CCLE). FRA1 expression was significantly associated with PD-L1 expression, and high FRA1 expression was correlated with poor overall survival. Our findings suggest that oncogenic KRAS-driven PD-L1 expression is dependent on MEK-ERK and FRA1 in high risk, premalignant HBEC. AJTR Copyright © 2020.This study elaborated on the function of Low-density lipoprotein receptor-related protein 6 (LRP6), a critical component of Wnt signaling, in liver fibrosis. This study enrolled sixty-eight patients with liver fibrosis, with ten healthy liver tissue samples, served as the controls.  https://www.selleckchem.com/products/LBH-589.html  A lentiviral vector expressing LRP6-CRISPR was constructed. Immortalized HSC-T6 cells were transfected with LRP6-CRISPR. A rat model of CCl4-induced liver fibrosis was established, and rats were injected with lentiviral vectors expressing LRP6-CRISPR. LRP6 expression and fibrosis biomarkers were examined by PCR, Western blot, and immunofluorescence assay, respectively. HSC growth and its ability of migration and invasion were evaluated by MTT and Transwell assay, separately. Wnt signaling activity was examined by Luciferase reporter assay. LRP6 was overexpressed in human fibrotic-liver tissues, and the expression of LRP6 was correlated with liver fibrosis stages. LRP6 knockout with CRISPR suppressed the Wnt signaling activities and consequently repressed HSC activation and relived liver injury in fibrotic-liver model rats. Our data revealed that the knockout of LRP6 weakens the binding of Wnt ligand with its cell surface receptors, the first step of Wnt transduction cascade, and consequently repressed HSC activation. AJTR Copyright © 2020.This finite element (FE) study of lumbar biomechanics aims to predict how the parameters like range of motion (ROM), intervertebral disc pressure (IDP), cage stress and screw stress are affected by different direction-changeable cage positions. Firstly, the three-dimensional FE model of L3-L5 segment was developed, and the model was adjusted to adapt different direction-changeable cage positions at the L4-L5 level though transforaminal lumbar interbody fusion (TLIF) with pedicle screws. The effects of Type A (the lateral region), Type B (the lateralcentral region) and Type C (the anteriocentral region) on ROM, IDP, cage stress and screw stress were examined. The results showed that after implantation of interbody cages at different positions, the ROM at surgical level L4-L5 decreased substantially in all motion modes. The maximal stress in cage decreased with Type A, B and C in all motion modes except flexion and extension. The maximal cage stress was observed in Type A with 720.5 MPa in left rotation, in Type B with 707 MPa in flexion, in Type C with 397.3 MPa in left rotation, respectively. The maximal IDP was similar in three types, with 1.6 MPa in left lateral bending in Type A, 1.5 MPa in flexion in Type B, and 1.4 MPa in flexion in Type C. The range of screw peak stress was 16.4 to 61.1 MPa in Type A, 15.9 to 50.9 MPa in Type B, and 14.6 to 46.1 MPa Type C. In conclusion, comparing the cages with different positions, anteriocentral position cage has more advantages like lower cage stress, ODL and screw stress. AJTR Copyright © 2020.Immunotherapy using antibodies blocking the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has achieved great success in preclinical models and the clinical treatment of esophageal squamous cell carcinoma (ESCC). The c-Myc proto-oncogene helps prevent immune cells from attacking tumor cells by inducing PD-L1 expression. However, the underlying mechanisms of c-Myc and PD-L1 in ESCC remain unclear, and a thorough understanding of this regulation would allow the development of new approaches to enhance antitumor immunity. In the present study, the positive relationship between c-Myc and PD-L1 was explored in the Cancer Genome Atlas dataset using the bioinformatics tool GEPIA, and was confirmed in 105 ESCC tissues by immunostaining (r=0.516, P less then 0.001). The patients positive for both proteins had a poorer overall survival (P=0.032). Furthermore, in ESCC cell lines, c-Myc overexpression, depletion, and inhibition was able to regulate the expression of PD-L1. Also, the ChIP assays showed that the increase in PD-L1 expression was likely due to the binding of c-Myc to the PD-L1 promoter. Taken together, c-Myc and PD-L1 levels were significantly correlated, and c-Myc expression regulated the expression of PD-L1 in ESCC cells. In addition, a small molecule inhibitor of c-Myc effectively regulated PD-L1 expression. This indicates that synergistic therapy combining a c-Myc inhibitor with PD-L1 immunotherapy might be a promising new treatment strategy for ESCC. AJTR Copyright © 2020.