The upregulation and transcriptional regulatory mechanisms of Extra spindle pole bodies like 1 in bladder cancer: An immunohistochemistry and high-throughput screening Evaluation.

Background: This study aimed to explore the expression level and transcriptional regulation mechanism of Extra Spindle Pole Bodies Like 1 (ESPL1) in bladder cancer (BC). Methods: A multicentre database of samples (n = 1391) was assayed for ESPL1 mRNA expression in BC and validated at the protein level by immunohistochemical (IHC) staining of in-house samples (n = 202). Single-cell sequencing (scRNA-seq) analysis and enrichment analysis explored ESPL1 distribution and their accompanying molecular mechanisms. ATAC-seq, ChIP-seq and Hi-C data from multiple platforms were used to investigate ESPL1 upstream transcription factors (TFs) and potential epigenetic regulatory mechanisms. Immune-related analysis, drug sensitivity and molecular docking of ESPL1 were also calculated. Furthermore, upstream microRNAs and the binding sites of ESPL1 were predicted. The expression level and early screening efficacy of miR-299-5p in blood (n = 6625) and tissues (n = 537) were examined. Results: ESPL1 was significantly overexpressed at the mRNA level (p < 0.05, SMD = 0.75; 95 % CI = 0.09, 1.40), and IHC staining of in-house samples verified this finding (p < 0.0001). ESPL1 was predominantly distributed in BC epithelial cells. Coexpressed genes of ESPL1 were enriched in cell cycle-related signalling pathways, and ESPL1 might be involved in the communication between epithelial and residual cells in the Hippo, ErbB, PI3K-Akt and Ras signalling pathways. Three TFs (H2AZ, IRF5 and HIF1A) were detected upstream of ESPL1 and presence of promoter-super enhancer and promoter-typical enhancer loops. ESPL1 expression was correlated with various immune cell infiltration levels. ESPL1 expression might promote BC growth and affect the sensitivity and therapeutic efficacy of paclitaxel and gemcitabine in BC patients. As an upstream regulator of ESPL1, miR-299-5p expression was downregulated in both the blood and tissues, possessing great potential for early screening. Conclusions: ESPL1 expression was upregulated in BC and was mainly distributed in epithelial cells. Elevated ESPL1 expression was associated with TFs at the upstream transcription start site (TSS) and distant chromatin loops of regulatory elements. ESPL1 might be an immune-related predictive and diagnostic marker for BC, and the overexpression of ESPL1 played a cancer-promoting role and affected BC patients' sensitivity to drug therapy. miR-299-5p was downregulated in BC blood and tissues and was also expected to be a novel marker for early screening.

Impact of catheter-tissue contact force on lesion size during right ventricular outflow tract ablation in a swine model.

BACKGROUND: The catheter-tissue contact force (CF) is one of the significant determinants of lesion size and thus has a considerable impact on the effectiveness of ablation procedures. This study aimed to evaluate the impact of CF on the lesion size during right ventricular outflow tract (RVOT) ablation in a swine model. METHODS: Twelve Guangxi Bama miniature male pigs weighing 40 to 50 kg were studied. After general anesthesia, a ThermoCool SmartTouch contact-sensing ablation catheter was introduced to the RVOT via the femoral vein under the guidance of the CARTO 3 system. The local ventricular voltage amplitude and impedance were measured using different CF levels. We randomly divided the animals into the following four groups according to the different CF levels: group A (3-9 g); group B (10-19 g); group C (20-29 g); and group D (30-39 g). Radiofrequency ablations were performed at three points in the free wall and septum of the RVOT in power control mode at 30 W for 30 s while maintaining the saline irrigation rate at 17 mL/min. At the end of the procedures, the maximum depth, surface diameter, and lesion volume were measured and recorded. A linear regression analysis was performed to determine the relationship between continuous variables. RESULTS: A total of 72 ablation lesions were created in the RVOT of the 12 Bama pigs. The maximum depth, surface diameter, and volume of the lesions measured were well correlated with the CF (free wall: ß = 0.105, ß = 0.162, ß = 3.355, respectively, P < 0.001; septum: ß = 0.093, ß = 0.150, ß = 3.712, respectively, P < 0.001). The regional ventricular bipolar voltage amplitude, unipolar voltage amplitude, and impedance were weakly positively associated with the CF (ß = 0.065, ß = 0.125, and ß = 1.054, respectively, P < 0.001). There was a significant difference in the incidence of steam pops among groups A, B, C, and D (free wall: F = 7.3, P = 0.032; septum: F = 10.5, P = 0.009); and steam pops occurred only when the CF exceeded 20 g. Trans-mural lesions were observed when the CF exceeded 10 g in the free wall, while the lesions in the septum were non-trans-mural even though the CF reached 30 g. CONCLUSIONS: CF seems to be a leading predictive factor for the size of formed lesions in RVOT ablation. Maintaining the CF value between 3 and 10 g may be reasonable and effective for creating the necessary lesion size and reducing the risk of complications, such as steam pops and perforations.

The clinical efficacy and safety of paclitaxel combined with avastin for NSCLC patients diagnosed with malignant pleural effusion.

OBJECTIVE: The current study aimed to investigate the clinical efficacy of paclitaxel combined with avastin for non-small cell lung cancer (NSCLC) patients diagnosed with malignant pleural effusion (MPE). METHOD: Total of 33 patients diagnosed with NSCLC as well as malignant pleural effusion were included. All of them received paclitaxel (175 mg/m2) and avastin (5 mg/kg). Clinical efficacy was evaluated using the total response rate, overall survival, progression-free survival and changes in MPE volume. Adverse events and rates of toxicities were examined as well. RESULTS: The total response rate reached 77% while the overall survival and the median progression-free survival were respectively 22.2 months and 8.4 months. Toxicities of grade 3-4 consisted of neutropenia in 57% of patients, anemia in 17% of them, febrile neutropenia in 11%, as well as anorexia in 7%. No treatment-correlated deaths were found. CONCLUSION: Paclitaxel combined with avastin decreased MPE volume and increased survival rate of NSCLC patients via inhibiting vascular endothelial growth factor expression.

The clinical efficacy and safety of paclitaxel combined with avastin for NSCLC patients diagnosed with malignant pleural effusion

Summary Objective: The current study aimed to investigate the clinical efficacy of paclitaxel combined with avastin for non-small cell lung cancer (NSCLC) patients diagnosed with malignant pleural effusion (MPE). Method: Total of 33 patients diagnosed with NSCLC as well as malignant pleural effusion were included. All of them received paclitaxel (175 mg/m2) and avastin (5 mg/kg). Clinical efficacy was evaluated using the total response rate, overall survival, progression-free survival and changes in MPE volume. Adverse events and rates of toxicities were examined as well. Results: The total response rate reached 77% while the overall survival and the median progression-free survival were respectively 22.2 months and 8.4 months. Toxicities of grade 3-4 consisted of neutropenia in 57% of patients, anemia in 17% of them, febrile neutropenia in 11%, as well as anorexia in 7%. No treatment-correlated deaths were found. Conclusion: Paclitaxel combined with avastin decreased MPE volume and increased survival rate of NSCLC patients via inhibiting vascular endothelial growth factor expression.

Thymosin α1 promotes the activation of myeloid-derived suppressor cells in a Lewis lung cancer model by upregulating Arginase 1.

Thymosin α1 (Tα1) has been tested for cancer therapy for several years, in most cases, the anti-tumor effect of Tα1 was limited, especially when Tα1 was used as a single agent. The role of Tα1 in cancer treatment and the regulatory mechanisms by which Ta1 takes effects are not yet completely understood. Using a Lewis lung caner model, here we report that Tα1 used alone elevated CD8(+) T cells, but failed to inhibit tumor growth. Furthermore, immunosuppressive myeloid-derived suppressor cells (MDSCs) showed heightened Arginase 1 production in response to Tα1 treatment, which led to stronger suppression of anti-tumor immunity. In addition, the upregulation of ARG1 was dependent on TLRs/MyD88 signaling, blocking MyD88 signaling abrogated the enhanced ARG1 expression and restored the anti-tumor efficacy of Tα1. This study provides the first demonstration that Tα1 treatment activates but not expands MDSCs via MyD88 signaling, which indicates better immunotherapeutic strategy of Tα1 against cancer.

Analysis of microRNA expression profile identifies novel biomarkers for non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer mortality. MicroRNAs (miRNAs), small noncoding RNAs, regulate the expression of genes that play roles in human cancer via posttranscriptional inhibition. METHODS: To identify the potential miRNA biomarkers in NSCLC, we downloaded the miRNA expression profile (ID: GSE29248) of NSCLC from the Gene Expression Omnibus (GEO) database and analyzed the differentially expressed miRNAs in NSCLC tissue compared with normal control tissue. Then the targets of these differentially expressed miRNAs were screened and used in network construction and functional enrichment analysis. RESULTS: We identified a total of 17 miRNAs that showed a significantly differential expression in NSCLC tissue. We found that miR-34b and miR-520h might play important roles in the regulation of NSCLC, miR-22 might be a novel biomarker as an oncogene, and miR-448 might promote, while miR-654-3p prevents, NSCLC progression. CONCLUSIONS: Our study may provide the groundwork for further clinical molecular target therapy experiments in NSCLC.BAC

Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells.

Cimetidine, a histamine type-2 receptor antagonist, is known to inhibit the growth of several tumors in human and animals, however the mechanism of action underlying this effect remains largely unknown. Here, in the mice model of 3LL lung tumor, cimetidine showed significant inhibition of tumor growth. However, an in vitro study demonstrated that cimetidine showed no effect on proliferation, survival, migration and invasion of 3LL cells. We found that cimetidine reduced CD11b(+)Gr-1(+) myeloid derived-suppressive cell (MDSC) accumulation in spleen, blood and tumor tissue of tumor-bearing mice. In vitro coculture assay showed that cimetidine reversed MDSC-mediated T-cell suppression, and improved IFN-γ production. Further investigation demonstrated that the NO production and arginase I expression of MDSCs were reduced, and MDSCs prone to apoptosis by cimetidine treatment. However, MDSC differentiation was not affect by cimetidine. Importantly, although histamine H2 receptor was expressed in MDSC surface, histamine could not reverse the proapoptosis of cimetidine. Moreover, famotidine also did not have this capacity. We found that cimetidine could induce Fas and FasL expression in MDSC surface, and sequentially regulate caspase-dependent apoptosis pathway. Thus, these findings revealed a novel mechanism for cimetidine to inhibit tumor via modulation of MDSC apoptosis.