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Supplementary Methods provide experimental details on bioinformatics analysis, standard assays using commercial reagents and kits; Supplementary Figures S1-8 describe additional data to support the function of MNX1-AS1, which promotes the tumorigenesis in both CRC cells and tissues; Supplementary tables S1-6 show clinical information of sequenced patients, detailed screening candidates for validation, regression analysis together with mass spectrometry data used in this study.

Long noncoding RNAs (lncRNA) are involved in tumorigenesis and drug resistance. However, the roles and underlying mechanisms of lncRNAs in colorectal cancer are still unknown. In this work, through transcriptomic profiling analysis of 21 paired tumor and normal samples, we identified a novel colorectal cancer–related lncRNA, MNX1-AS1. MNX1-AS1 expression was significantly upregulated in colorectal cancer and associated with poor prognosis. In vitro and in vivo gain- and loss-of-function experiments showed that MNX1-AS1 promotes the proliferation of colorectal cancer cells. MNX1-AS1 bound to and activated Y-box-binding protein 1 (YB1), a multifunctional RNA/DNA-binding protein, and prevented its ubiquitination and degradation. A marked overlap between genes that are differentially expressed in MNX1-AS1 knockdown cells and transcriptional targets of YB1 was observed. YB1 knockdown mimicked the loss of viability phenotype observed upon depletion of MNX1-AS1. In addition, MYC bound the promoter of the MNX1-AS1 locus and activated its transcription. In vivo experiments showed that ASO inhibited MNX1-AS1, which suppressed the proliferation of colorectal cancer cells in both cell-based and patient-derived xenograft models. Collectively, these findings suggest that the MYC–MNX1-AS1–YB1 axis might serve as a potential biomarker and therapeutic target in colorectal cancer.Significance:This study highlights the discovery of a novel colorectal cancer biomarker and therapeutic target, MNX1-AS1, a long noncoding RNA that drives proliferation via a MYC/MNX1-AS1/YB1 signaling pathway.

In this paper, innovative test methods including aerodynamic acceleration, PIV measurement, separate statistics of incidence and rebound information were used to systematically investigate the rebound characteristics of flaky oxide particles and angular quartz sand impacting stainless steel at high temperature. Through the statistical analysis of a large number of experimental results and the measurement of the microscopic erosion morphology of the target surface, combined with the numerical simulation of the gas-solid two-phase flow of the test section, the intrinsic relationship between the rebound behavior of the particles and their erosion behavior was systematically explored for the first time. Meanwhile, the effects of the incident parameters, particle size and accelerated airflow on the rebound characteristics of the particles were revealed. The results have important guiding significance for further understanding the physical properties of particle-wall interaction and predicting the particle erosion characteristics and erosion distribution of industrial equipment components.

We extend the contents of the standard model (SM) by introducing TeV-scale scalar leptoquarks to generate neutrino masses and explain some current observed deviations from the SM predictions, including the anomalous magnetic moments of charged leptons (electron and muon) and $B$-physics anomalies ($R_{K^{(*)}}$ and $R_{D^{(*)}}$). The model consists of $\text{SU}(2)_L$ singlet leptoquark $S_1\sim (\bar{3}, 1, 1/3)$, doublet leptoquark $\tilde{R}_2\sim (3, 2, 1/6)$ and triplet leptoquark $S_3\sim (\bar{3}, 3, 1/3)$. We combine the constraints arising from the low-energy lepton flavor violation, meson decay and mixing observables. We perform a detailed phenomenological analysis and identify the minimized texture of leptoquark Yukawa matrices to accommodate a unified explanation of the anomalies and neutrino oscillation data., Comment: 30 pages, 5 figures, matches published version

T cell acute lymphoblastic leukemia (T-ALL) is invasive and heterogeneous, and existing therapies are sometimes unsuccessful. Chimeric antigen receptor (CAR) T cell therapy is a breakthrough tumor treatment method, particularly for B cell acute lymphoblastic leukemia. We found that CD147 was highly expressed in tumor T cells of T-ALL patients and T cell lymphoma. Therefore, CD147-CAR T cells that contain a humanized single-chain variable fragment targeting human CD147 and a second-generation CAR frame were constructed for treating T-ALL. CD147-CAR T cells were able to maintain a healthy proliferation rate, preserving a subset of CD62L+/CCR7+ memory T cells. CD147-CAR T cells showed a potent anti-tumor activity against human T-ALL cell line and T-ALL blasts, releasing high level of cytokines in the process. However, CD147-CAR T cells exhibited potential safety toward human normal cells and CD147-deficent cells. NOD/ShiLtJGpt-Prkdc

We perform a detailed study of scalar dark matter with triplet Higgs extensions of the Standard Model in order to explain the cosmic ray electron and positron excesses reported by AMS-02 and DAMPE. A detailed analysis of AMS-02 positron excess reveals that for different orderings (normal, inverted and quasi-degenerate) of neutrino mass, the hybrid triplet Higgs portal framework is more favored with respect to the single triplet Higgs portal for TeV scale dark matter. We also show that the resonant peak and continuous excess in DAMPE cosmic ray data can be well explained with the hybrid triplet Higgs portal dark matter when a dark matter sub-halo nearby is taken into account., 21 pages, 5 figures, to be published in Chinese Physics C

Non-small cell lung cancer (NSCLC) is a fatal disease, and its metastatic process is poorly understood. Although aberrant methylation is involved in tumor progression, the mechanisms underlying dynamic DNA methylation remain to be elucidated. It is significant to study the molecular mechanism of NSCLC metastasis and identify new biomarkers for NSCLC early diagnosis. Here, we performed MeDIP-seq and hMeDIP-seq analyses to detect the genes regulated by dynamic DNA methylation. Comparison of the 5mC and 5hmC sites revealed that the CD147 gene underwent active demethylation in NSCLC tissues compared with normal tissues, and this demethylation upregulated CD147 expression. Significantly high levels of CD147 expression and low levels of promoter methylation were observed in NSCLC tissues. Then, we identified the CD147 promoter as a target of KLF6, MeCP2, and DNMT3A. Treatment of cells with TGF-β triggered active demethylation involving loss of KLF6/MeCP2/DNMT3A and recruitment of Sp1, Tet1, TDG, and SMAD2/3 transcription complexes. A dCas9-SunTag-DNMAT3A-sgCD147-targeted methylation system was constructed to reverse CD147 expression. The targeted methylation system downregulated CD147 expression and inhibited NSCLC proliferation and metastasis in vitro and in vivo. Accordingly, we used cfDNA to detect the levels of CD147 methylation in NSCLC tissues and found that the CD147 methylation levels exhibited an inverse relationship with tumor size, lymphatic metastasis, and TNM stage. In conclusion, this study clarified the mechanism of active demethylation of CD147 and suggested that the targeted methylation of CD147 could inhibit NSCLC invasion and metastasis, providing a highly promising therapeutic target for NSCLC.

The γ-secretase complex is a presenilin-dependent aspartyl protease involved in the intramembranous cleavage of various type I transmembrane proteins. As a type I transmembrane protein, CD147 is highly expressed in hepatoma cells and promotes cell proliferation, migration, and invasion. However, the direct underlying mechanism of how CD147 promotes cancer cell proliferation is unknown. Here, we demonstrated that CD147 undergoes an intramembranous cleavage by the γ-secretase at lysine 231 to release its intracellular domains (ICDs). The nuclear translocation of the CD147ICD regulated Notch1 expression by directly binding to the NOTCH1 promoter and promoted the activation of the Notch signaling pathway. Simultaneously, overexpression of CD147ICD promoted cancer cell proliferation via Notch1 signaling. In 102 cases of human hepatocellular carcinoma (HCC) tissues, patients with a high positive rate of nuclear CD147ICD expression had a significantly poor overall survival compared with patients with a low positive rate of nuclear CD147ICD expression. We confirmed that nuclear CD147ICD predicted a poor prognosis in human HCC. The combined therapy of the γ-secretase complex inhibitor and CD147-directed antibody showed better efficacy than monotherapy in orthotopic transplantation HCC mouse models. In conclusion, CD147 is cleaved by the γ-secretase and releases CD147ICD to the cell nucleus, promoting Notch1 expression via direct binding to the NOTCH1 promoter. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

4054 Background: Circulating tumor DNA (ctDNA) is a promising biomarker for detecting molecular residual disease (MRD) and relapse after definitive treatment in multiple solid cancers. However, the significance of ctDNA is rarely clarified in locoregional gastric cancer (GC). Here, we conducted a prospective and observational study to evaluate the utility of ctDNA in predicting the recurrence risk of GC. Methods: From October 2016 to June 2019, 100 patients with stage II/III resectable GC were recruited in this study (NCT02887612). Primary tumors and plasma samples were collected perioperatively and after adjuvant chemotherapy (ACT). Somatic variants were captured via a targeted sequencing panel of 425 cancer-related genes. The plasma of patients was defined as ctDNA positive only if one or more variants detected in the plasma presented in at least 2% of the primary tumors. All the patients received curative-intent standard-of-care therapy. Results: Preoperative ctDNA was detectable in 38 (38.0%) patients but showed limited value for predicting recurrence. After surgery (median days, 4), the plasma of 25 (25.0%) patients were still ctDNA positive and they had higher recurrence risk than the non-positive patients (hazard ratio [HR], 2.74 (95% CI: 1.37–5.48); P = 0.003). Forty-one patients had evaluable plasma after ACT and 10 (24.4%) of them who were ctDNA positive had remarkably higher recurrence and death risk compared with ctDNA-negative patients (recurrence-free survival [RFS] HR = 14.99 (95% CI: 3.08–72.96); P < 0.001; overall survival HR, 11.88 (95% CI: 2.38–59.24); P < 0.001). In particular, post-ACT ctDNA achieved better predictive performance (sensitivity, 77.8%; specificity, 90.6%) than both postoperative ctDNA and post-treatment tumor biomarkers (i.e., CEA, CA199, and CA72-4). In all multivariate analyses, ctDNA positivity was an independent factor of RFS. Patients with ERBB4 mutation in their primary tumors had poorer RFS compared to those were ERBB4 wildtype (HR = 3.46 (95% CI: 1.32–9.03); P = 0.007). A comprehensive model incorporating ctDNA status for recurrence risk prediction showed a higher concordance index (0.78; 95%CI, 0.71–0.84) than the model without ctDNA status (0.71; 95%CI, 0.64–0.79; P = 0.009). Conclusions: Postoperative and post-ACT ctDNA was associated with MRD and high risk of relapse in patients with stage II/III GC and can be utilized to guide GC management in post-surgical settings.

CD147, encoded by BSG, is a highly glycosylated transmembrane protein that belongs to the immunological superfamily and expressed on the surface of many types of cancer cells. While CD147 is best known as a potent inducer of extracellular matrix metalloproteinases, it can also function as a key mediator of inflammatory and immune responses. To systematically elucidate the function of CD147 in cancer cells, we performed an analysis of genome-wide profiling across the Cancer Cell Line Encyclopedia (CCLE). We showed that CD147 mRNA expression was much higher than that of most other genes in cancer cell lines. CD147 varied widely across these cell lines, with the highest levels in the ovary (COLO704) and stomach (SNU668), intermediate levels in the lung (RERFLCKJ, NCIH596 and NCIH1651) and lowest levels in hematopoietic and lymphoid tissue (UT7, HEL9217, HEL and MHHCALL3) and the kidney (A704 and SLR20). Genome-wide analyses showed that CD147 expression was significantly negatively correlated with immune-related genes. Our findings implicated CD147 as a novel regulator of immune-related genes and suggest its important role as a master regulator of immune-related responses in cancer cell lines. We also found a high correlation between the expression of CD147 and FOXC1, and proved that CD147 was a direct transcriptional target of FOXC1. Our findings demonstrate that FOXC1 is a novel regulator of CD147 and confirms its role as a master regulator of the immune response.

In this study, the high temperature erosion mechanisms and damage characteristics of a boronized coating have been systematically studied by employing an improved high-temperature accelerated erosion test bench and impact contact theory analyses. Within the scope of the experimental parameters, the erosion rate of the boronized coating under the same erosion conditions was observed to be only one half to one-twelfth of the erosion rate of the substrate. Furthermore, the boronized coating was noted to be less sensitive to the speed of the erosion particles than the plastic substrate, thus, indicating superior and more stable erosion resistance than the base material. The boronized coating exhibited typical brittle fracture characteristics under impact by the high-speed particles. When the particle impact normal stress exceeded the critical stress for crack propagation owing to the coating defects, the surface and subsurface layers of the coating initially formed horizontal and vertical micro-cracks, followed by their gradual expansion and intersection. After destabilization, the brittle coating material was peeled layer-by-layer from the surface of the test piece. At the same incident speed, as the particle size was increased from 65 &mu, m to 226 &mu, m and 336 &mu, m, the size (width) of the erosion cracks on the coating surface increased from 1 &mu, m to 30 &mu, m and 100 &mu, m respectively. Correspondingly, the erosion damage thickness of the coating was enhanced from 15 &mu, m to 50 &mu, m. In the case of the quartz sand particle size exceeding 300 &mu, m, the dual-phase boronized coating did not provide effective protection to the substrate. Furthermore, based on the elastoplastic fracture theory, a prediction model for the erosion weight loss of the boronized coatings within the effective thickness range has been proposed in this study.

As a member of the Rab GTPase family, Rab11a plays an important role in vesicle transport and tumor progression. However, it is not clear whether it can also be used as an oncoprotein in hepatocellular carcinoma (HCC). In this study, database and immunohistochemical analyses showed that Rab11a was highly expressed in HCC tissues, and associated with poor clinical prognosis. Rab11a overexpression promoted the proliferation, migration, invasion, and anti-apoptosis of human HCC cell lines, MHCC-97H and HCC-LM3, whereas the downregulation of Rab11a inhibited these biological tumor activities. Nude mice xenograft demonstrated that Rab11a had a positive effect on the growth of hepatocellular carcinoma cells in vivo. Further studies found that the PI3K/AKT pathway and matrix metalloproteinase 2 (MMP2) upregulation can be activated by over-expression of Rab11a. However, MMP2 upregulation induced by Rab11a can be inhibited by the PI3K/AKT pathway inhibitor, LY294002. Altogether, our study established for the first time that Rab11a can play a pro-cancer role in HCC, as a novel oncoprotein, by activating the PI3K/AKT pathway to regulate MMP2 expression.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma. Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research.

The cold stamping forming processes of the car transverse reinforcing beam were designed and analyzed using the CAD/CAE technology and related software. The numerical model of the car transverse reinforcing beam was established by the UG software, and then the model was imported into the DYNAFORM software to perform the finite element simulation. The obtained forming limit diagram and the thickness distribution diagram were adopted to analyze the feasibility of the forming process. The influences of different forming schemes and parameters (including blank-holder force, lubrication condition, drawing speed, etc) on the forming effect were investigated. In consequence, the reasonable process design and optimum parameters were acquired, which could reduce the tendencies of wrinkling, cracking and thickness reduction. And the optimum process parameters were obtained by orthogonal experiment to ensure the forming quality of the product.

In order to more effectively remove noise in partial discharge signals, it is proposed a new threshold selection method in this paper. This method firstly takes the signals before the partial discharge starting to happen as only contain noise signal, and then applies a wavelet transform to the only contain noise signal. Secondly record every detail part and the maximum value of wavelet coefficients of last layer approximation part, and take this value as its layer threshold. And then applies a wavelet transform to the partial discharge signals which contains noises. Next is to process wavelet coefficient of each layer using the selected threshold. Finally, the already handled wavelet coefficients is used to reconstruction the signals. The whole process of threshold choosing is automatic without human intervention. Simulation experiment show that compared with the traditional threshold selection method, this method can be better to remove the noise of the partial discharge signals, and it has a strong practical value.

The BP neural network is a classifier commonly used in partial discharge type recognition, but the traditional BP algorithm with defects cannot satisfy the actual need. So the optimization algorithm of BP network was studied intensively. DPSO algorithm was used for optimizing the network, and DPSO-BP algorithm is applied to analyze typical defects of GIS, which can be identified by the types of partial discharge. Compared with traditional BP algorithm, DPSO-BP algorithm occupied obvious advantage in recognition effect. It has improved the learning speed of the algorithm, effectively avoid network training going into local minimum point, and maintain the generalization ability and fault tolerance of BP neural network at the same time.

During circuit breaker risk condition assessment, the most important thing is to calculate the circuit breaker health index (HI). Aiming at the collected data for risk assessment is incomplete or it is not useful for the assessment, this paper analyzed the principle from of the health index calculation process, finding the various characteristics, which has an effect on the health, further more calculated the contribution to the health index, streamlining the data list for assessment. It has an important guiding significance for the future data collection.

Rapid advancements in next generation sequencing (NGS) technologies, coupled with the dramatic decrease in cost, have made NGS one of the leading approaches applied in cancer research. In addition, it is increasingly used in clinical practice for cancer diagnosis and treatment. Somatic (cancer‑only) single nucleotide variants and small insertions and deletions (indels) are the simplest classes of mutation, however, their identification in whole exome sequencing data is complicated by germline polymorphisms, tumor heterogeneity and errors in sequencing and analysis. An increasing number of software and methodological guidelines are being published for the analysis of sequencing data. Usually, the algorithms of MuTect, VarScan and Genome Analysis Toolkit are applied to identify the variants. However, one of these algorithms alone results in incomplete genomic information. To address this issue, the present study developed a systematic pipeline for analyzing the whole exome sequencing data of hepatocellular carcinoma (HCC) using a combination of the three algorithms, named the three‑caller pipeline. Application of the three‑caller pipeline to the whole exome data of HCC, improved the detection of true positive mutations and a total of 75 tumor‑specific somatic variants were identified. Functional enrichment analysis revealed the mutations in the genes encoding cell adhesion and regulation of Ras GTPase activity. This pipeline provides an effective approach to identify variants from NGS data for subsequent functional analyses.

This study reviews the current status of the understanding and development of laser shock peening(LSP) on various metals. The influence of processing parameters on residual stresses, microstructure and properties are discussed. Special emphasis is placed on analyzing their underlying interrelationship between the LSP induced modifications. Finally, recommendations for further study are listed. Results indicate that the combination of uniquely flexible process and excellent performance makes the laser shock peening an attractive candidate for surface optimization applications.

The carcinogenesis of hepatocellular carcinoma (HCC) is a complex process, starting from a chronically altered hepatic microenvironment due to liver cirrhosis and ultimately progressing to HCC. However, the sequential molecular alterations driving the malignant transformation in liver cirrhosis are not clearly defined.In this study, we obtained gene expression profiles of HCC, including 268 tumor tissues, 243 adjacent tumor tissues, and 40 cirrhotic tissues (GSE25097) from Gene Expression Omnibus (GEO), to comprehensively define changes in the transcriptome of HCC during the sequential evolution of liver cirrhosis into HCC.We showed that changes in the molecular profiles of cirrhotic and adjacent tumor samples were small and quite uniform, whereas there was a striking increase in the heterogeneity of tumors in HCC tissues at the mRNA level. A massive deregulation of key oncogenic molecules and pathways was observed from cirrhosis to HCC tumors. In addition, we focused on FOXO1 and DCN, 2 critical tumor suppressor genes that play an important role in liver cirrhosis and HCC development. FOXO1 and DCN expression levels were significantly reduced in tumor tissues compared with adjacent tumor tissues in HCC. Kaplan-Meier analysis revealed that FOXO1 and DCN expression was positively correlated with overall survival, defining FOXO1 and DCN as adverse prognostic biomarkers for HCC.This system-level research provided new insights into the molecular mechanisms of HCC carcinogenesis. FOXO1 and DCN may be applied as potential targets for HCC treatment in the future.

Using the weight-average molecular weight 50 000 polylactic acid (PLA) as a carrier, and a certain proportion of erythromycin (EM) and prednisone acetate (PNA) to mixed prepare the compound erythromycin sustained release preparation (sustained-release tablets). Using ultraviolet spectrophotometry and high performance liquid chromatography (HPLC) to detect separately the release amount of EM and PNA in vitro medium. The sustained-release tablets release for about 21 days, the average content of EM is 99.7 mg/table, RSD = 0.82%; and the average content of PNA is 10.03 mg/table, RSD = 0.93%. Within 21 days, the cumulative releases of EM and PNA are 86.1% and 78.3%, respectively. The drug release is steady and slow after 5 days, the burst release phenomenon in early stage is more significant. The results showed that the sustained-release tablet preparation method is feasible, the release performance is good and the clinical efficacy is significant.