In this paper, a material structural model is constructed based on a cubic lattice, and applied with a fixed load and an impact load.To provide the basis for parameter selection in modelling, the error and efficiency of structural calculation are analyzed by changing the two parameters in the peridynamics (PD) computation model: near-field region radius δ and m value.During modelling, when δ is given a fixed value, the calculation accuracy will increase with the m value, but the calculation efficiency will change in the opposite trend, thus affecting the path and direction of crack propagation; when m is given a fixed value, the number of point units in the near-field region and the calculation accuracy will not change with δ, but will still affect the path and direction of crack propagation.
Abstract Disclosure: L.T. Brea: None. H. Shi: None. V. Keo: None. W. Xie: None. X. Lu: None. G. Gritsina: None. X. Wang: None. S.H. Park: None. J. Zhao: None. J. Yu: None. Background: Castration resistant prostate cancer (CRPC) has shown a poor response to immune checkpoint inhibitors due to its immunosuppressive nature. CRPC is infiltrated by tumor-associated macrophages (TAMs) and T regulatory cells (Tregs), which induce an immunosuppressive tumor immune microenvironment (TIME) and promote tumor progression. A deeper understanding of tumor intrinsic mechanisms shaping the TIME in prostate cancer (PCa) is needed to harness immunotherapies for PCa patients. Previous studies have found that epithelial transcription factor FOXA1 is downregulated in CRPC. In accordance, we have reported that FOXA1 loss induces tumor cell invasion and macrophage recruitment in vitro through HIF1A-CCL2 signaling. However, the extent to which FOXA1 loss regulates the TIME in PCa remains unclear, largely due to the lack of immune-proficient mouse models for the study of FOXA1 function in the context of PCa. Methods: To examine how FOXA1 loss regulates the PCa TIME, we generated a novel genetically engineered mouse model (GEMM) with prostate-specific deletion of Pten and Foxa1 (PbCre4:Ptenf/fFoxa1f/f) to compare with the established Pten-null PCa mouse model (PbCre4:Ptenf/f). We performed immunohistochemistry analyses on the GEMM prostate tumor tissues to characterize histopathology changes and assess tumor immune infiltration. We also performed spatial transcriptomics and scRNA-seq analyses of the GEMMs to comprehensively evaluate the effect of Foxa1 loss on downstream pathways and the surrounding TIME. Finally, we performed bioinformatics analysis of PCa patient datasets to validate the clinical relevance. Results: We found PbCre4:Ptenf/fFoxa1f/f mouse prostate tumors exhibited a more aggressive histopathologic tumor phenotype compared to age-matched PbCre4:Ptenf/f. Notably, immunohistochemistry staining and spatial transcriptomic analysis of the GEMMs revealed striking remodeling of the TIME upon Foxa1 loss, with marked increases in tumor infiltration by Tregs and TAMs. Moreover, CIBERSORTx analysis of patient datasets revealed FOXA1 expression negatively correlates with Treg and M2-macrophage infiltration. We also found pro-tumorigenic inflammatory cytokine signaling genes, linked to the recruitment of immunosuppressive cells, were upregulated in PbCre4:Ptenf/fFoxa1f/f prostate tumors. Furthermore, we confirmed inflammatory pathways were upregulated among FOXA1-low patient samples. Additional studies are ongoing to further elucidate the mechanisms by which FOXA1 regulates inflammatory cytokine signaling and the TIME in PCa.Conclusion: This study presents a novel GEMM for the study of FOXA1 function in an immunocompetent setting. Our data supports FOXA1 as a critical tumor intrinsic regulator of the TIME. This will have important implications on the design of immunotherapeutic approaches for late-stage PCa often with FOXA1 loss. Presentation: Thursday, June 15, 2023
The metastasis-associated phosphatase of regenerating liver-3 (PRL-3) plays multiple roles in progression of various human cancers; however, significance of its role during development has not been addressed. Here we cloned and characterized the expression pattern of zebrafish prl-3 transcript and showed that it is ubiquitiously expressed in the first 24 h of development with both maternal and zygotic expressions. The transcripts become progressively restricted to the notochord, vessels and the intestine by 96 h post-fertilization. Notably, overexpression of zebrafish Prl-3 (zPrl-3) and human PRL-3 induces notochord malformation in zebrafish. This phenotype resembles chordoma and is confirmed by associated misexpression of notochord-specific markers. Clinical significance of the PRL-3 in chordoma is strongly suggested by detection of PRL-3 antigen in clinical chordoma specimens. Collectively, our results uncovered that aberrant overexpression of PRL-3 could initiate chordoma in early development and suggest the use of PRL-3 could be used as a predictor and a therapeutic target for chordoma.
Poly C Binding Protein 1 (PCBP1) is an RNA-binding protein that binds and regulates translational activity of subsets of cellular mRNAs. Depletion of PCBP1 is implicated in various carcinomas, but the underlying mechanism in tumorigenesis remains elusive.We performed a transcriptome-wide screen to identify novel bounding mRNA of PCBP1. The bind regions between PCBP1 with target mRNA were investigated by using point mutation and luciferase assay. Cell proliferation, cell cycle, tumorigenesis and cell apoptosis were also evaluated in ovary and colon cancer cell lines. The mechanism that PCBP1 affects p27 was analyzed by mRNA stability and ribosome profiling assays. We analyzed PCBP1 and p27 expression in ovary, colon and renal tumor samples and adjacent non-tumor tissues using RT-PCR, Western Blotting and immunohistochemistry. The prognostic significance of PCBP1 and p27 also analyzed using online databases.We identified cell cycle inhibitor p27Kip1 (p27) as a novel PCBP1-bound transcript. We then demonstrated that binding of PCBP1 to p27 3'UTR via its KH1 domain mainly stabilizes p27 mRNA, while enhances its translation to fuel p27 expression, prior to p27 protein degradation. The upregulated p27 consequently inhibits cell proliferation, cell cycle progression and tumorigenesis, whereas promotes cell apoptosis under paclitaxel treatment. Conversely, knockdown of PCBP1 in turn compromises p27 mRNA stability, leading to lower p27 level and tumorigenesis in vivo. Moreover, forced depletion of p27 counteracts the tumor suppressive ability of PCBP1 in the same PCBP1 over-expressing cells. Physiologically, we showed that decreases of both p27 mRNA and its protein expressions are well correlated to PCBP1 depletion in ovary, colon and renal tumor samples, independent of the p27 ubiquitin ligase Skp2 level. Correlation of PCBP1 with p27 is also found in the tamoxifen, doxorubincin and lapatinib resistant breast cancer cells of GEO database.Our results thereby indicate that loss of PCBP1 expression firstly attenuates p27 expression at post-transcriptional level, and subsequently promotes carcinogenesis. PCBP1 could be used as a diagnostic marker to cancer patients.
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