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Ye Lin,1,* Guanqun Huang,2,* Haosheng Jin,1,* Zhixiang Jian1 1Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, People’s Republic of China; 2Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510700, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhixiang JianDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, 106 Zhongshan Er Road, Guangzhou 510080, People’s Republic of ChinaEmail jzx_118@163.comBackground: Circular RNA (circRNA) plays a critical role in tumorigenesis and tumor progression. Many studies indicate that circRNA Gprc5a is significantly upregulated and functions as an oncogene in a variety of cancers. However, the molecular mechanism of circGprc5a in liver cancer remains unclear.Methods: qRT-PCR was used to measure the expression levels of circGprc5a, miR-1283, YAP1 and TEAD1 mRNA in hepatocellular carcinoma (HCC) tissues or cells. YAP1 and TEAD1 protein levels were detected by Western blot. CCK-8 assay, cell colony formation, BrdU incorporation and Annexin V-FITC/PI assays were performed to analyze the effects of circGprc5a and miR-1283 on cell proliferation and apoptosis. The relationship between circGprc5a, miR-1283, YAP1 and TEAD1 was analyzed using bioinformatic analysis and luciferase. The tumor changes in mice were detected by in vivo experiments.Results: CircGprc5a was highly expressed in liver cancer, and closely related poor survival of patients with liver cancer. Knockout of circGprc5a inhibited proliferation of HCC and induced apoptosis. CircGprc5a activated the YAP1/TEAD1 signaling pathway by acting as a sponge for miR-1283. Furthermore, overexpression of miR-1283 abolished the promotion of circGprc5a on HCC cells. Therefore, miR-1283 expression correlated negatively with circGprc5a expression yet positively with the expression of YAP1/TEAD1 in liver cancer.Conclusion: CircGprc5a promoted the development of HCC by inhibiting the expression of miR-1283 and activating the YAP1/TEAD1 signaling pathway.Keywords: circGprc5a, miR-1283, YAP1/TEAD1, HCC, proliferation

The improvement of Gate induced drain leakage (GIDL) is studied in 2T SONOS (silicon-oxide-nitride-oxide-silicon) nonvolatile memory. High GIDL current from the select gate (SG) introduce inhibit disturb to the neighbor SONOS gate. It is found that these leakage bits impact the overall yield and reliability. In this paper, the variation trend of GIDL leakage with LDD dopant dose, energy and tilt is investigated in detail Results show that GIDL leakage is effectively decreased through increasing tilt and energy or decreasing the dose amount of select gate LDD IMP step. In addition, GIDL leakage also decreased by changing SG LDD dopant step from post poly re-oxidation to post spacer1 etch which increased the space of SG gate to drain. The proposed condition improves GIDL current by one order of magnitude; yield and Vt window are also greatly increased.

Guanqun Huang,1,* Hui Jiang,2,* Ye Lin,3 Yanpeng Wu,1 Weilong Cai,1 Boyun Shi,2 Yuanwei Luo,1 Zhixiang Jian,3 Xinke Zhou2 1Department of General Surgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People’s Republic of China; 2Department of Abdominal Oncology, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510700, People’s Republic of China; 3Department of General Surgery, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, People’s Republic of China *These authors contributed equally to this work Background: Elevated plasma fibrinogen levels have been associated with tumor progression in several malignancies. Our study aims to characterize the clinical significance of elevated plasma fibrinogen levels in patients with hepatocellular carcinoma (HCC). Materials and methods: Relevant published articles were systematically searched in electronic databases including PubMed, Embase, and Web of Science. The pooled differences in plasma fibrinogen levels among HCC, cirrhotic, and control groups were expressed as weighted mean differences (WMDs) and their corresponding 95% CIs. The associations between elevated fibrinogen and overall survival (OS) and disease-free survival (DFS)/recurrence-free survival (RFS) were expressed as HRs and their 95% CIs, whereas the associations between elevated fibrinogen and various types of clinical characteristic of patients with HCC were expressed as ORs and their corresponding 95% CIs. Results: Results showed that the plasma fibrinogen levels in patients with HCC were not significantly different than that in healthy controls (WMD = 0.50, 95% CI = [–0.82, 1.82], P=0.457) or patients with cirrhosis (WMD = −0.62, 95% CI = [–1.56, 0.33], P = 0.200). However, our results showed that compared to those with normal levels, patients with HCC and elevated plasma fibrinogen levels showed poorer OS (HR = 2.08, 95% CI = [1.67, 2.59], P < 0.0001) and DFS/RFS (HR = 1.90, 95% CI = [1.52, 2.37], P < 0.0001). Results of trial sequential analysis of the OS indicated that currently available studies were sufficient to validate the negative prognostic value of elevated plasma fibrinogen in patients with HCC. Clinicopathological analyses showed that high plasma fibrinogen levels were associated with tumor progression as indicated by advanced tumor stage, larger tumor size, increased tumor number, and the presence of vascular invasion. Conclusion: Elevated plasma fibrinogen levels are associated with poor prognosis and advanced tumor progression. Plasma fibrinogen may serve as a negative prognostic biomarker in patients with HCC. Keywords: hepatocellular carcinoma, fibrinogen, prognosis, tumor progression, meta-analysis

Background Liver tumor initiating cells (TICs) have self-renewal and differentiate capacities, and largely contribute to tumor initiation, metastasis and drug resistance. MAPK signaling is a critical pathway in many biological processes, while its role in liver TICs hasn’t been explored. Methods Online-available dataset was used for unbiased screening. Liver TICs were examined CD133 FACS or oncosphere formation. TIC self-renewal was detected by oncosphere formation and tumor initiation assay. LncRNA function was detected by loss of function or gain of function assays. The molecular mechanism of lncRNA was explored by RNA pulldown, RNA immunoprecipitation, ChIP, western blot and double FISH. Results Here, we examined the expression profiles of MAPK components (MAPKs, MAP2Ks, MAP3Ks, MAP4Ks), and found MAPK6 is most highly expressed in liver cancer samples. Moreover, a divergent lncRNA (long noncoding RNA) of MAPK6, termed lncMAPK6 here, is also overexpressed along with liver tumorigenesis. LncMAPK6 promotes liver tumor propagation and TIC self-renewal through MAPK6. LncMAPK6 interacts with and recruits RNA polymerase II to MAPK6 promoter, and finally activates the transcription of MAPK6. Through MAPK6 transcriptional regulation, lncMAPK6 drives MARK signaling activation. LncMAPK6-MAPK6 pathway can be used for liver TIC targeting. Altogether, lncMAPK6 promotes MARK signaling and the self-renewal of liver TICs through MAPK6 expression. Conclusion MAPK6 was the most highly expressed MAPK component in liver cancer and liver TICs and lncMAPK6 participated in the transcriptional regulation of MAPK6in cis. This work revealed the importance role of MAPK signaling in liver TIC self-renewal and added a new layer for liver TIC and MAPK6 expression regulation.