ABSTRACT
Macrophages mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia. Thus, it's necessary to exploit macrophages based therapeutic targets for ischemic disease. Here, we found mRNA level of SR-A1 was elevated in patients with critical limb ischemia by analysis of gene expression omnibus (GEO) database. Then we investigated the role and the underlined mechanisms of macrophage SR-A1 in a mouse HLI model. Compared with the SR-A1 fl/fl mice, the Lyz Cre/+/SR-A1 flox/flox (SR-A1 ΔMΦ) mice showed significantly lower laser doppler blood flow in the ischemic limb at day 7 after HLI. Consistently, histological analysis exhibited that ischemic limb of SR-A1 ΔMΦ mice displayed more sever and sustained necrotic morphology, inflammation and fibrosis, decreased vessel density and regeneration rate, compared with which of control SR-A1 fl/fl mice. Furthermore, restoration of wild-type myeloid cells to SR-A1 knock-out mice effectively relieved the doppler perfusion in the ischemic limb and restrained skeletal muscle damage 7 days post HLI. In line with in vivo findings, when co-cultivating macrophages with the mouse myoblast line C2C12, SR-A1 -/- bone marrow macrophage significantly inhibited myoblast differentiation in vitro. Mechanically, SR-A1 enhanced skeletal muscle regeneration response to HLI by inhibiting the oncostatin M (OSM) production via suppressed NF-κB signaling activation. These results indicates that SR-A1 is a promising candidate molecule to improve tissue repair and regeneration in peripheral ischemic arterial disease.
ABSTRACT
Balancing is a fundamental task in the motion control of bipedal robots. Compared to two-foot balancing, one-foot balancing introduces new challenges, such as a smaller supporting polygon and control difficulty coming from the kinematic coupling between the center of mass (CoM) and the swinging leg. Although nonlinear model predictive control (NMPC) may solve this problem, it is not feasible to implement it on the actual robot because of its large amount of calculation. This paper proposes the three-particle model predictive control (TP-MPC) approach. It combines with the hierarchical whole-body control (WBC) to solve the one-leg balancing problem in real time. The bipedal robot's torso and two legs are modeled as three separate particles without inertia. The TP-MPC generates feasible swing leg trajectories, followed by the WBC to adjust the robot's center of mass. Since the three-particle model is linear, the TP-MPC requires less computational cost, which implies real-time execution on an actual robot. The proposed method is verified in simulation. Simulation results show that our method can resist much larger external disturbance than the WBC-only control scheme.
ABSTRACT
This study evaluated the efficacy of neoadjuvant immunochemotherapy (Io+Chemo) versus chemotherapy alone (Chemo) in resectable non-small cell lung cancer (NSCLC) in a real-world setting. The association of tumor immune microenvironment (TIME) with pathologic response to different neoadjuvant therapies was also explored.Stage I-III NSCLC patients who received Io+Chemo or Chemo alone followed by surgery were included in the study. Tumor tissues collected during surgery were subjected to TIME evaluation using multiplex immunohistochemistry to measure immune cell subsets, including T cells, B cells, NK cells, and macrophages. Fifty-five patients were included, including 24 treated with neoadjuvant Io+Chemo and 31 with Chemo alone. Io+Chemo induced significantly higher major pathologic response (MPR) (75.0% vs. 38.7%, P = 0.0133) and numerically better pathologic complete response (pCR) (33.3% vs. 12.9%, P = 0.1013) than Chemo. Compared with tumors with Chemo, tumors with Io+Chemo demonstrated a significantly higher ratio of M1 macrophage density in the tumor to that in the stroma (P = 0.0446), more abundant CD8+ cells in the stroma (P = 0.0335), and fewer PD-L1+CD68+ cells in both tumor and stroma. pCR/MPR patients displayed significantly higher density of CD3+, CD3+CD4+, CD20+, CD56 bright cell subsets and more tertiary lymphoid structures and significantly lower density of PD-L1+CD68+ and CD3+CD4+Foxp3+cells in the tumor or stroma. This study favored neoadjuvant Io+Chemo over Chemo and revealed the TIME features underlying the outperformance of Io+Chemo over Chemo.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Neoadjuvant Therapy , B7-H1 Antigen , Tumor Microenvironment , Forkhead Transcription FactorsABSTRACT
This study focused on the epigenetic alterations of DNA methylation and miRNAs for lung adenocarcinoma (LUAD) diagnosis and treatment using bioinformatics analyses. DNA methylation data and mRNA and miRNA expression microarray data were obtained from The Cancer Genome Atlas (TCGA) database. The differentially methylated genes (DMGs), differentially expressed genes (DEGs), and differentially expressed miRNAs were analyzed by using the limma package. The DAVID database performed GO and KEGG pathway enrichment analyses. Using STRING and Cytoscape, we constructed the protein-protein interaction (PPI) network and achieved visualization. The online analysis tool CMap was used to identify potential small-molecule drugs for LUAD. In LUAD, 607 high miRNA-targeting downregulated genes and 925 low miRNA-targeting upregulated genes, as well as 284 hypermethylated low-expression genes and 315 hypomethylated high-expression genes, were obtained. They were mainly enriched in terms of pathways in cancer, neuroactive ligand-receptor interaction, cAMP signaling pathway, and cytosolic DNA-sensing pathway. In addition, 40 upregulated and 84 downregulated genes were regulated by both aberrant alternations of DNA methylation and miRNAs. Five small-molecule drugs were identified as a potential treatment for LUAD, and five hub genes (SLC2A1, PAX6, LEP, KLF4, and FGF10) were found in PPI, and two of them (SLC2A1 and KLF4) may be related to the prognosis of LUAD. In summary, our study identified a series of differentially expressed genes associated with epigenetic alterations of DNA methylation and miRNA in LUAD. Five small-molecule drugs and five hub genes may be promising drugs and targets for LUAD treatment.
