Histone methyltransferase SETD1A interacts with notch and promotes notch transactivation to augment ovarian cancer development.

BACKGROUND: High expression of SETD1A, a histone methyltransferase that specifically methylates H3K4, acted as a key oncogene in several human cancers. However, the function and underlying molecular mechanism of SETD1A in ovarian cancer (OV) remain markedly unknown. METHODS: The expression of SETD1A in OV were detected by Western blot and analyzed online, and the prognosis of STED1A in OV were analyzed online. The protein and mRNA levels were determined by Western blot and RT-qPCR. The cell proliferatin, migration and invasion were measured by CCK-8 and transwell assays. The protein interaction was detected by co-IP assay. The interaction between protein and DNA was performed by ChIP assay. The tumor growth in vivo was performed by xenograft tumor model. RESULTS: SETD1A was overexpressed in OV and a predictor of poor prognosis. Overexpression of SETD1A augmented the abilities of cell proliferation, migration, and invasion in MRG1 and OVCAR5 cells. In comparison, SETD1A knockdown suppressed cell growth, migration, and invasion in SKOV3 and Caov3 cells. Specifically, SETD1A enhanced Notch signaling by promoting the expression of Notch target genes, such as Hes1, Hey1, Hey2, and Heyl. Mechanistically, SETD1A interacted with Notch1 and methylated H3K4me3 at Notch1 targets to enhance Notch signaling. In addition, restoration of Notch1 in SETD1A-knockdown OV cells recovered cell proliferation, migration and invasion, which was inhibited by SETD1A knockdown. Furthermore, reduction of SETD1A suppressed tumorigenesis in vivo. CONCLUSION: In conclusion, our results highlighted the key role of SETD1A in OV development and proved that SETD1A promotes OV development by enhancing Notch1 signaling, indicating that SETD1A may be a novel target for OV treatment.

Effect of complete reduction of hernia sac and transection of hernia sac during laparoscopic indirect inguinal hernia repair on seroma.

INTRODUCTION: This study investigated the effect of complete reduction and transection of the hernia sac during laparoscopic indirect inguinal hernia repair on seroma. METHODS: Retrospective analysis was performed on 1763 cases undergoing laparoscopic indirect inguinal hernia repair in three centers from January 2017 to September 2019, among them, 311 patients with transection of hernia sac and 1452 patients with reduction of hernia sac, the data of the two groups were tested by t-test. Logistic univariate analysis was performed on 233 cases of postoperative seroma, and variables p < 0.05 in univariate analysis were included for multivariate analysis. Then, the transection group and the reduction group were matched with 1:1 propensity score matching, and the caliper value was set at 0.05. Finally, 274 patients matched in each group were analyzed by univariate analysis again to evaluate whether the transection of hernia sac had an impact on postoperative seroma. RESULTS: The results of univariate analysis of 233 patients with postoperative seroma showed that: ASA-3 p = 0.031, classification-L3 p < 0.001, surgery-TEP p < 0.001, transect group p = 0.005. The results of multivariate analysis show that: ASA-3 p < 0.001, classification-L3 p < 0.001, surgery-TEP p < 0.001, transect group p = 0.020. The results of univariate analysis after propensity score matching showed that transection of the hernia sac is significant for postoperative seroma (p < 0.001). CONCLUSION: Transection of the hernia sac during laparoscopic indirect inguinal hernia repair can significantly lead to postoperative seroma.

Hsa_circ_0008434 regulates USP9X expression by sponging miR-6838-5p to promote gastric cancer growth, migration and invasion.

BACKGROUND: The role of circular RNAs (circRNAs) in the occurrence and development of gastric cancer (GC) has recently attracted increasing interest. The following study investigates the role of a newly discovered hsa_circ_0008434, which has been confirmed to be highly expressed in GC tissues, in regulating GC biological behaviour. METHODS: High-throughput RNA sequencing was used to identify differentially expressed genes between normal gastric tissues and GC tissues; actinomycin D and RNase R assays were used to determine the stability and loop structure of hsa_circ_0008434; and the miRanda database was used to predict the target genes of hsa_circ_0008434. The role of hsa_circ_0008434 in cell proliferation, migration, and invasion was examined using CCK-8, wound healing, Transwell and colony formation assays. The regulatory relationships among hsa_circ_0008434, microRNA-6838 (miR-6838), and ubiquitin-specific peptidase 9X (USP9X) were determined by dual-luciferase activity assays. The expression of hsa_circ_0008434 and miR-6838 was measured by qPCR; the expression of USP9X was detected by immunohistochemistry and Western blotting. The effects of hsa_circ_0008434 on in vivo tumour growth were assessed in xenograft models. RESULTS: We found that hsa_circ_0008434 was one of the most upregulated circRNAs in GC tissue versus normal tissue. Further in vitro testing indicated that by acting as a miRNA sponge for miR-6838-5p, hsa_circ_0008434 promotes the expression of USP9X and further increases the proliferation, migration, and invasion of GC cells. In addition, animal studies indicated that hsa_circ_0008434 could promote tumour growth in vivo. CONCLUSIONS: Hsa_circ_0008434 may promote GC proliferation, invasion and migration by regulating the expression of miR-6838 and USP9X.

Histone Methyltransferase SETD1A Induces Epithelial-Mesenchymal Transition to Promote Invasion and Metastasis Through Epigenetic Reprogramming of Snail in Gastric Cancer.

Aberrant epigenetic modification induces oncogene expression and promotes cancer development. The histone lysine methyltransferase SETD1A, which specifically methylates histone 3 lysine 4 (H3K4), is involved in tumor growth and metastasis, and its ectopic expression has been detected in aggressive malignancies. Our previous study reported that SETD1A promotes gastric cancer (GC) proliferation and tumorigenesis. However, the function and molecular mechanisms of SETD1A in GC metastasis remain to be elucidated. In this study, we found that overexpression of SETD1A promoted GC migration and invasion, whereas knockdown of SETD1A suppressed GC migration and invasion in vitro. Moreover, knockdown of SETD1A suppressed GC epithelial-mesenchymal transition (EMT) by increasing the expression of epithelial marker E-cadherin and decreasing the expression of mesenchymal markers, including N-cadherin, Fibronectin, Vimentin, and α-smooth muscle actin (α-SMA). Mechanistically, knockdown of SETD1A reduced the EMT key transcriptional factor snail expression. SETD1A was recruited to the promoter of snail, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on the snail promoter. Furthermore, SETD1A could be a coactivator of snail to induce EMT gene expression. Rescue of snail restored SETD1A knockdown-induced GC migration and invasion inhibition. In addition, knockdown of SETD1A suppressed GC metastasis in vivo. In summary, our data revealed that SETD1A mediated the EMT process and induced metastasis through epigenetic reprogramming of snail.

Central pattern generator-based coupling control method for synchronously controlling the two-degrees-of-freedom robot.

Synchronous control is a fundamental and significant problem for controlling a multi-joint robot. In this article, by applying two coupled Rayleigh oscillators as the referred central pattern generator models for the two joints of a two-degrees-of-freedom robot, the central pattern generator-based coupling control method is proposed for controlling the two-degrees-of-freedom robot's joints. On these bases, the co-simulation model of the two-degrees-of-freedom robot with the proposed central pattern generator-based coupling control method is established via ADAMS and MATLAB/Simulink, and the performance of the central pattern generator-based coupling control method on synchronizing two motions of two-degrees-of-freedom robot's joints is numerically simulated. Furthermore, the experimental setup of a two-degrees-of-freedom robot is established based on the real-time simulations system via the proposed central pattern generator-based coupling control method. And experiments are carried out on the established setup. Simulations and experimental results show that the phase of the controlled two-degrees-of-freedom robot's joints is mutual locked to other, and their motion pattern can be adjusted through the coupling parameter in the central pattern generator-based coupling control method. In conclusion, the proposed central pattern generator-based coupling control method can control the two-degrees-of-freedom robot's joints to produce the coordinated motions and adjust the rhythmic pattern of the two-degrees-of-freedom robot.

Population-based analysis on predictors for lymph node metastasis in T1 colon cancer.

BACKGROUND: In this study, we aimed to identify independent predictive factors for lymph node metastasis (LNM) in T1 colon cancer. METHODS: Data of 8056 eligible patients were retrospectively collected from the Surveillance, Epidemiology, and End Results (SEER) database during 2004-2012. We performed logistic regression analysis to identify predictive factors for LNM. Both unadjusted and adjusted Cox regression analyses were used to determine the association between LNM and patient survival. Finally, we used competing risks analysis and the cumulative incidence function (CIF) to further confirm the prognostic role of LNM in cancer-specific survival (CSS). RESULTS: The overall risk of LNM in patients with T1 colon cancer was 12.0% (N = 967). Adjusted logistic regression models revealed that mucinous carcinoma [odds ratio (OR) = 2.26, P < 0.001], moderately differentiated (OR 1.74, P < 0.001), poorly differentiated (OR 5.16, P < 0.001), and undifferentiated carcinoma (OR 3.01, P = 0.003); older age (OR 0.66, P < 0.001 for age 65-79 years, OR 0.44, P < 0.001 for age over 80 years); and carcinoma located in the ascending colon (OR 0.77, P = 0.018) and sigmoid colon (OR 1.24, P = 0.014) were independent predictive factors for LNM. Adjusted Cox regression analysis showed that positive lymph node involvement was significantly associated with CSS [hazard ratio (HR) = 3.02, P < 0.001], which was further robustly confirmed using a competing risks model and the CIF. CONCLUSIONS: This population-based study showed that mucinous carcinoma, tumor grade, age, and primary tumor location were independent predictive factors for LNM in T1 colon cancer. The risk of LNM should be carefully evaluated in patients with T1 colon cancer, before clinical management.

A 5 g Inertial Micro-Switch with Enhanced Threshold Accuracy Using Squeeze-Film Damping.

Our previous report based on a 10 g (gravity) silicon-based inertial micro-switch showed that the contact effect between the two electrodes can be improved by squeeze-film damping. As an extended study toward its potential applications, the switch with a large proof mass suspended by four flexible serpentine springs was redesigned to achieve 5 g threshold value and enhanced threshold accuracy. The impact of the squeeze-film damping on the threshold value was theoretically studied. The theoretical results show that the threshold variation from the designed value due to fabrication errors can be reduced by optimizing the device thickness (the thickness of the proof mass and springs) and then establishing a tradeoff between the damping and elastic forces, thus improving the threshold accuracy. The design strategy was verified by FEM (finite-element-method) simulation and an experimental test. The simulation results show that the maximum threshold deviation was only 0.15 g, when the device thickness variation range was 16⁻24 µm, which is an adequately wide latitude for the current bulk silicon micromachining technology. The measured threshold values were 4.9⁻5.8 g and the device thicknesses were 18.2⁻22.5 µm, agreeing well with the simulation results. The measured contact time was 50 µs which is also in good agreement with our previous work.

Andrographolide causes apoptosis via inactivation of STAT3 and Akt and potentiates antitumor activity of gemcitabine in pancreatic cancer.

Gemcitabine is a first-line drug utilised in the chemotherapy of pancreatic cancer; however, this drug induces chemo-resistance and toxicity to normal tissue during treatment. Here, we firstly report that andrographolide (ANDRO) alone not only has anti-pancreatic cancer activity, but it also potentiates the anti-tumour activity of gemcitabine. Treatment with ANDRO alone inhibits proliferation of the pancreatic cancer cell lines in a dose- and time-dependent manner in vitro. Interestingly, ANDRO induces cell cycle arrest and apoptosis of pancreatic cancer cells by inhibiting STAT3 and Akt activation, upregulating the expression of p21(WAF1) and Bax, and downregulating the expression of cyclinD1, cyclinE, survivin, X-IAP and Bcl-2. Additionally, ANDRO combined with gemcitabine significantly induce stronger cell cycle arrest and more obvious apoptosis than each single treatment. The mechanistic study demonstrates that this synergistic effect is also dependent on the inhibition of STAT3 and Akt activations which subsequently regulates the pathways involved in the apoptosis and cell cycle arrest. Furthermore, both ANDRO alone and the combination treatments exhibit efficacious anti-tumour activity in vivo. Overall, our results provide solid evidence supporting that ANDRO alone or its combination with gemcitabine is a potential chemotherapeutic approach for treating human pancreatic cancer in clinical practice.