It has been reported that tumor-associated macrophages (TAMs) play a complicated role in cancer occurrence and development, immune escape, and immune checkpoint blockade (ICB) resistance. However, the role of granulin precursor (GRN) highly expressed macrophages (hereafter refer to GRN + macrophages) in hepatocellular carcinoma (HCC) remains poorly understood. Herein, we systematically integrated multiomics analysis of human tumor tissues to illustrate the functional role of GRN + macrophages in HCC. GRN is selectively expressed by TAMs in different type of cancers including HCC, and was significantly associated with poor prognosis in several type of cancer. GRN was closely correlated with infiltration levels of most immune cells, especially the M2 macrophage cells in various cancers. In particular, both mRNA and protein expression level of GRN was significantly upregulated in HCC. Compared with tumor tissue, GRN was more significantly expressed in the stroma area between HCC tissues and adjacent non-tumor tissues. High expression of GRN was significantly correlated with M2-polarization of macrophages and T-cell exhaustion in HCC. GRN + macrophages communicated with intratumoral immune cells, especially CD8 + T cells. Functionally, GRN + macrophages contacted with CD8 + T cells, which inducing T-cell exhaustion. Our study offers a comprehensive understanding of the clinical relevance and immunological role of GRN + macrophages in HCC, indicating its potential role as a promising target for immunotherapeutic strategies.
Given that the proteasome is essential for multiple cellular processes by degrading diverse regulatory proteins, inhibition of the proteasome has emerged as an attractive target for anti-cancer therapy.YSY01A is a novel small molecule compound targeting the proteasome.The compound was found to suppress viability of MCF-7 cells and cause limited cell membrane damage as determined by sulforhodamine B assay (SRB) and CytoTox 96 ® non-radioactive cytotoxicity assay.High-content screening (HCS) further shows that YSY01A treatment induces cell cycle arrest on G2 phase within 24 hrs.Label-free quantitative proteomics (LFQP), which allows extensive comparison of cellular responses following YSY01A treatment, suggests that various regulatory proteins including cell cycle associated proteins and PI3K/Akt pathway may be affected.Furthermore, YSY01A increases p-CDC-2, p-FOXO3a, p53, p21 Cip1 and p27 Kip1 but decreases p-Akt, p-ERα as confirmed by Western blotting.Therefore, YSY01A represents a potential therapeutic for breast cancer MCF-7 by inducing G2 phase arrest via ERα and PI3K/Akt pathways.
Rationale: The adverse health effects of nano-particulate pollutants have attracted much attention in recent years. Carbon nanomaterials are recognized as risk factors for prolonged inflammatory responses and diffuse alveolar injury. Previous research indicated a central role of alveolar macrophages in the pathogenesis of particle-related lung disease, but the underlying mechanism remains largely unknown. Methods: C57BL/6 mice were intratracheally instilled with carbon black nanoparticles (CBNPs). Cell necrosis and the infiltrated neutrophils in the lungs were detected by flow cytometry. Release of mitochondria was observed with Mito Tracker and mitochondrial DNA (mtDNA) was quantified by qPCR via Taqman probes. TLR9-p38 MAPK signaling pathway was detected by Western blotting. The production of lipid chemoattractant leukotriene B4 (LTB4) in the supernatant and bronchoalveolar lavage fluid (BALF) was quantitated using an enzyme immunoassay (EIA). Results: In the present study, we found that a single instillation of CBNPs induced neutrophil influx in C57BL/6 mice as early as 4 h post-exposure following the rapid appearance of cell damage indicators in BALF at 30 min. Macrophages exposed to CBNPs showed necrotic features and were characterized by lysosome rupture, cathepsin B release, reactive oxygen species generation, and reduced intracellular ATP level. Necrosis was partly inhibited by a specific lysosomal cathepsin B inhibitor CA074 Me. Further analyses suggested that the resulting leakage of mtDNA from the necrotic cells activated neutrophils and triggered severe inflammation in vivo. Pulmonary neutrophilic inflammation induced by mtDNA was reduced in TLR9-/- mice. Additionally, mtDNA induced LTB4 production from macrophages, which may contribute to neutrophil recruitment. Conclusion: We demonstrated here that CBNPs induce acute cell necrosis through lysosomal rupture and that mtDNA released from necrotic cells functions as a key event mediating pulmonary neutrophilic inflammation. This study described a novel aspect of the pathogenesis of particle-induced inflammatory response and provided a possible therapeutic target for the regulation of inflammation.
Encapsulated by cytidinyl lipid, G-quadruplex based aptamer AS1411 etc. entered nucleus and targeted to KRAS promoter/hnRNP A1 complex, showed higher activity against drug-resistant lung cancer.
Evidence shows that tropomodulin 1 (TMOD1) is a powerful diagnostic marker in the progression of several cancer types. However, the regulatory mechanism of TMOD1 in tumor progression is still unclear. Here, we showed that TMOD1 was highly expressed in acute myeloid leukemia (AML) specimens, and TMOD1-silencing inhibited cell proliferation by inducing autophagy in AML THP-1 and MOLM-13 cells. Mechanistically, the C-terminal region of TMOD1 directly bound to KPNA2, and TMOD1-overexpression promoted KPNA2 ubiquitylation and reduced KPNA2 levels. In contrast, TMOD1-silencing increased KPNA2 levels and facilitated the nuclear transfer of KPNA2, then subsequently induced autophagy and inhibited cell proliferation by increasing the nucleocytoplasmic transport of p53 and AMPK activation. KPNA2/p53 inhibitors attenuated autophagy induced by silencing TMOD1 in AML cells. Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.
Background: Diffusion weighted imaging (DWI) is recently developed for identifying different malignant tumors. In this article the diagnostic accuracy of DWI for ovarian cancer was evaluated by synthesis of published data. Methods: A comprehensive literature search was conducted in PubMed/MEDLINE and Embase databases on the diagnostic performance of DWI for ovarian cancer published in English. Methodological quality was evaluated following Quality Assessment for Studies of Diagnostic Accuracy 2 (QUADAS 2) tool. We adopted the summary receiver operating characteristic (SROC) curve to assess the DWI accuracy. Results: Twelve studies including 1142 lesions were analyzed in this meta-analysis to estimate the pooled Sen (sensitivity), Spe (specificity), PLR (positive likelihood ratio), NLR (negative likelihood ratio), and construct SROC (summary receiver operating characteristics) curve. The pooled Sen and Spe were 0.86 (95% confidence interval [CI], 0.83–0.89) and 0.81 (95%CI, 0.77–0.84), respectively. The pooled PLR and pooled NLR were 5.07 (95%CI, 3.15–8.16) and 0.17 (95%CI, 0.10–0.30), respectively. The pooled diagnostic odds ratio (DOR) was 35.23 (95%CI, 17.21–72.14). The area under the curve (AUC) was 0.9160. Conclusion: DWI had moderately excellent diagnostic ability for ovarian cancer and promised to be a helpful diagnostic tool for patients of ovarian cancer.
BACKGROUND This study evaluated how the expression of miR-31 can be used to detect gastric cancer (GC) to help illuminate the role of miR-31 and RhoA in GC cells. MATERIAL AND METHODS We carried out our experiments using tissue specimens from 70 GC patients. The relative expression of miR-31 and RhoA mRNA in tissues and cells was detected by RT-PCR. The expression level of RhoA protein was detected by immunohistochemistry. GC cell line BGC-823 was transfected with six groups of vectors: blank group, NC (negative control) group, miR-31 mimics group, miR-31 mimics + RhoA group, miR-31 mimics + ROCK group, and miR-31 mimics + MLCK agonist group. AGS cells were also transfected with six groups of vectors: blank group, NC group, miR-31 inhibitor group, miR-31 inhibitor + RhoA siRNA group, miR-31 inhibitor + ROCK siRNA group, and miR-31 inhibitor + MLCK inhibitor group. Transwell assay was performed to detect the invasion and migration of cells. The protein expression in different transfected groups was detected using Western blotting. RESULTS GC tissues exhibited significantly lower levels of miR-31 expression compared to pericarcinous tissues (p<0.01). Moreover, a significantly higher expression of RhoA in GC tissues was observed (p<0.05). MiR-31 inhibited RhoA expression by binding to 3'UTR of mRNA, whereas miR-31 mimics significantly decreased the number of invaded and migrated cells (p<0.05). The activation of RhoA, ROCK, and phosphorylation of MLC remarkably exacerbate the invasion and migration ability of GC cells (p<0.05). CONCLUSIONS We found miR-31 could downregulate the ROCK/MLC pathway by inhibiting the expression of RhoA in order to suppress the invasion and migration of GC cells.
Targeting immune cells or factors are effective for patients with solid tumors. Myeloid-derived suppressor cells (MDSCs) are known to have immunosuppressive functions, and the levels of MDSCs in patients with solid tumor are assumed to have prognostic values. This meta-analysis aimed at evaluating the relationship between MDSCs and the prognosis of patients with solid tumors. We searched articles in PUBMED and EMBASE comprehensively, updated to March 2016. Eight studies with 442 patients were included in the meta-analysis. We analyzed pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). The results showed that MDSCs were associated with poor OS (HR, 1.94; 95% confidence interval [CI], 1.42–2.66; P < 0.0001) in patients with solid tumors. PFS/RFS (HR, 1.85; 95% CI, 1.16–2.97; P = 0.01) also indicated the association between MDSCs and prognosis. The HRs and 95% CIs for OS in Asian and non-Asian patients were 2.53 (95% CI 1.61–3.42, p < 0.00001) and 1.67 (95% CI 1.14–2.46, p < 0.0001), respectively. We further analyzed the data according to tumor types. The combined HRs and 95% CIs for OS were 1.26 (95% CI 1.10–1.44, p = 0.0003) for gastrointestinal (GI) cancer, 2.59 (95% CI 1.69–3.98, p < 0.0001) for hepatocellular carcinoma (HCC) and 1.86 (95% CI 1.26–2.75, p = 0.002) for other tumor types. In conclusion, MDSCs had a fine prognostic value for OS and PFS/RFS in patients with solid tumors. MDSCs could be used as biomarkers to evaluate prognosis in clinical practice.
We present a new approach for the accurate reconstruction of three-dimensional skeletal positions using roentgen single-plane photogrammetric analysis (RSPA). This technique uses a minimum of three markers embedded in each segment which allow continuous, real-time, internal skeletal movement to be measured from single-plane images, provided that the precise distance between the markers is known. A simulation study indicated that the error propagation in this approach is influenced by focus position, object position, the number of control points, the accuracy of the previous measurement of the distance between markers and the accuracy of image measurement. For reconstruction of normal movement of the knee with an input measurement error of sd = 0.02 mm, the rotational and translational differences between reconstructed and original movement were less than 0.27° and 0.9 mm, respectively. Our results showed that the accuracy of RSPA is sufficient for the analysis of most movement of joints. This approach can be applied in combination with force measurements for dynamic studies of the musculoskeletal system.
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