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Suppression of PTPN3 increased the cell colony numbers. Representative micrographs and quantification of crystal violet stained cells from 3 independent experiments. Columns, average of three independent experiments; bars, SD. *P < 0.05, **P < 0.01, Student t test.

Supplementary Table S1. Clinical characteristics of 534 NPC patients. Supplementary Table S2. Sequences used for shRNA construction and siRNAs. Supplementary Table S3. Primers used for real-time PCR. Supplementary Table S4. Association of SPINK6 expression with clinicopathological characteristics of NPC patients.

Supplementary Materials and Methods

Supplementary Fig. S1. Expression of SPINK6 in condition medium of NPC cells. Supplementary Fig. S2. Cellular growth of NPC cells. Supplementary Fig. S3. Wound-healing ability of NPC cells upon SPINK6 knockdown. Supplementary Fig. S4. Migration and invasion of NPC cells upon silencing of KLKs. Supplementary Fig. S5. Promoted motility of NPC cells by recombinant SPINK6. Supplementary Fig. S6. Interaction between SPINK6 and EGFR. Supplementary Fig. S7. Phosphorylation of EGFR and downstream signaling molecules in NPC cells. Supplementary Fig. S8. Wound-healing ability of NPC cells. Supplementary Fig. S9. The expression of E-cadherin and vimentin in NPC cells. Supplementary Fig. S10. The expression of EGF, EGFR and KLKs in NPC and NP tissues.

Nasopharyngeal carcinoma has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of nasopharyngeal carcinoma metastasis are not fully understood. Here, we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of nasopharyngeal carcinoma metastasis via EGFR signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic nasopharyngeal carcinoma cells. Immunohistochemical staining of 534 nasopharyngeal carcinomas revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis–free survival. Ectopic SPINK6 expression promoted in vitro migration and invasion as well as in vivo lymph node metastasis and liver metastasis of nasopharyngeal carcinoma cells, whereas silencing SPINK6 exhibited opposing effects. SPINK6 enhanced epithelial–mesenchymal transition by activating EGFR and the downstream AKT pathway. Inhibition of EGFR with a neutralizing antibody or erlotinib reversed SPINK6-induced nasopharyngeal carcinoma cell migration and invasion. Erlotinib also inhibited SPINK6-induced metastasis in vivo. Notably, SPINK6 bound to the EGFR extracellular domain independent of serine protease–inhibitory activity. Overall, our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis, with possible implications as a prognostic indicator in nasopharyngeal carcinoma patients. Cancer Res; 77(2); 579–89. ©2016 AACR.

Nasopharyngeal carcinoma (NPC) originates in the nasopharyngeal epithelium and has the highest metastatic rate among head and neck cancers. Distant metastasis is the main reason for treatment failure with the underlying mechanisms remaining unclear. By comparing the expression profiling of NPCs versus non-cancerous nasopharyngeal tissues, we found LACTB was highly expressed in the tumor tissues. We found that elevated expression of the LACTB protein in primary NPCs correlated with poorer patient survival. LACTB is known to be a serine protease and a ubiquitous mitochondrial protein localized in the intermembrane space. Its role in tumor biology remains controversial. We found that the different methylation pattern of LACTB promoter led to its differential expression in NPC cells. Overexpressing LACTB in NPC cells promoted their motility in vitro and metastasis in vivo. While knocking down LACTB reduced the metastasis capability of NPC cells. However, LACTB did not influence cellular proliferation. We further found the role of LACTB in promoting NPC metastasis depended on the activation of ERBB3/EGFR-ERK signaling, which in turn, affected the stability and the following acetylation of histone H3. These findings may shed light on unveiling the mechanisms of NPC metastasis.

It is believed that the alteration of tissue microenvironment would affect cancer initiation and progression. However, little is known in terms of the underlying molecular mechanisms that would affect the initiation and progression of breast cancer. In the present study, we use two murine mammary tumor models with different speeds of tumor initiation and progression for whole genome expression profiling to reveal the involved genes and signaling pathways. The pathways regulating PI3K-Akt signaling and Ras signaling were activated in Fvb mice and promoted tumor progression. Contrastingly, the pathways regulating apoptosis and cellular senescence were activated in Fvb.B6 mice and suppressed tumor progression. We identified distinct patterns of oncogenic pathways activation at different stages of breast cancer, and uncovered five oncogenic pathways that were activated in both human and mouse breast cancers. The genes and pathways discovered in our study would be useful information for other researchers and drug development.

The underlying molecular mechanism driving clear cell renal cell carcinoma (ccRCC) progression is still to be explored. The significant downregulation of protein tyrosine phosphatase nonreceptor type 3 (PTPN3) expression in the tumor tissues suggested its protective role in ccRCC progression. IHC analysis of PTPN3 protein in 172 ccRCC tissue revealed that PTPN3 was an independently favorable prognostic factor for progression-free survival (P = 0.0166) and overall survival (P = 0.0343) of patients. The ccRCC cell lines SN12C, 1932, ACHN, and Caki-1 were used to evaluate, both in vitro and in vivo, the biological roles of PTPN3. We observed that overexpression of PTPN3 significantly inhibited the proliferation, migration, and invasion of ccRCC cells. In contrast, the knocking down of PTPN3 elicited opposite effects. Overexpressing PTPN3 inhibited xenograft tumor growth and lung metastasis displayed by the in vivo mice models. PTPN3 inhibited tumor cell motility by suppressing the phosphorylation of AKT, and subsequently inactivating the PI3K/AKT signaling pathway of renal cell carcinoma cells. Furthermore, the inhibition of phospho-AKTThr308 and phospho-AKTSer473 reversed PTPN3-induced silencing in tumor cell migration. Our work revealed that the overexpression of PTPN3 could suppress kidney cancer progression by negatively regulating the AKT signaling pathway, and served as a favorable prognostic factor in patients with ccRCC. Our findings provided insight that PTPN3 could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC. Implications: PTPN3 is an independent favorable prognostic factor for patients with ccRCC and could be a potential target for therapy aiming to inhibit the malignant behaviors of ccRCC.

Clear cell renal cell carcinoma (ccRCC) is a common pathological subtype of renal cancer. Although the recent application of molecular-targeted agents has modestly improved the prognosis of ccRCC patients, their outcome is still poor. It is therefore important to characterize the molecular and biological mechanisms responsible for the development of ccRCC. Approximately 25% ccRCC patients involves the loss of RNA-binding protein QKI at 6q26, but the role of QKI in ccRCC is unknown. Here, we found that QKI-5 was frequently downregulated in ccRCC patients and its down-regulation was significantly associated with clinical features including T status, M status, and differentiation grade, and poorer patient prognosis. Moreover, QKI-5 inhibited the proliferation of kidney cancer cells both in vitro and in vivo. The subsequent functional studies showed that QKI-5 stabilized RASA1 mRNA via directly binding to the QKI response element region of RASA1, which in turn prevented the activation of the Ras-MAPK signaling pathway, suppressed cellular proliferation and induced cell cycle arrest. Overall, our data demonstrate a suppressive role of QKI in ccRCC tumourigenesis that involves the QKI-mediated post-transcriptional regulation of the Ras-MAPK signaling pathway.

Background: No study has integrated multiple levels of biological datasets to predict outcome in lung cancer patients. We aimed to develop and validate a prognostic model integrating copy number variation (CNV), DNA methylation, mRNA, and miRNA expression data to predict recurrence in patients with stage I-IIIA non-small cell lung cancer (NSCLC) after surgery. Methods: 509 NSCLC patients with the clinical and four types omics data collected from The Cancer Genome Atlas database were assigned into the discovery (n=237) and validation (n=272) cohorts according to resource of cases. We adopted principal component analysis to reduce the dimension of multi-omics data, and built a multi-omics signature for resected NSCLC using the LASSO Cox regression model. We assessed the predictive ability of the signature with the Harrell's concordance index (C-index). Findings: We built a multi-omics signature (MOSLC) based on 5 CNVs, 14 DNA methylations, 2 miRNAs, and 27 miRNAs. Using this signature, patients were classified into high- or low-risk groups with significant differences in recurrence-free survival in the discovery (hazard ratio [HR] 5.81, 95%CI 3.74-9.03; P

Nasopharyngeal carcinoma (NPC) is well known as one of the most common malignancies in southern China and Southeast Asia. However, the mechanisms underlying NPC progression remain poorly understood. Herein, through overlapping the differentially expressed genes from 3 microarray data sets with the human kinome, we identified PBK, a serine-threonine kinase, is highly upregulated and has not been intensively investigated in NPC. PBK was required for malignant phenotypes of NPC, as PBK depletion by RNAi and inhibition by specific inhibitor HI-TOPK-032 obviously reduced cell proliferation and xenograft tumor growth in mice. Moreover, we determined that targeting PBK could accelerate apoptosis by inducing ROS that activates JNK/p38 signaling pathway. In NPC patients, elevated PBK expression in primary tumor positively correlated to clinical severity such as advanced T stage, high death risk and disease progression, and it could serve as an unfavorable independent indicator of overall survival and disease-free survival. Altogether, our results indicate that PBK is a novel significant regulator of NPC progression and a potential therapeutic target for NPC patients.

PURPOSE To investigate the influence of exogenous p53 upregulated modulator of apoptosis (PUMA) expression on cell proliferation and apoptosis in human non-small cell lung cancer A549 cells and transplanted tumor cell growth in nude mice. MATERIALS AND METHODS A549 cells were divided into the following groups: control, non- carrier (NC), PUMA (transfected with pCEP4- (HA) 2-PUMA plasmid), DDP (10 μg/mL cisplatin treatment) and PUMA+DDP (transfected with pCEP4-(HA)2-PUMA plasmid and 10 μg/mL cisplatin treatment). The MTT method was used to detect the cell survival rate. Cell apoptosis rates were measured by flow cytometry, and PUMA, Bax and Bcl-2 protein expression levels were measured by Western blotting. RESULTS Compared to the control group, the PUMA, DDP and PUMA+DDP groups all had significantly decreased A549 cell proliferation (p

Purpose: To compare the long-term survival outcomes and acute toxicity between locoregionally advanced nasopharyngeal carcinoma (NPC) patients who received either weekly or 3-weekly cisplatin during concurrent chemoradiotherapy (CCRT). Methods: Between November 2008 and August 2011, 241 biopsy-proved NPC patients receiving concurrent cisplatin with intensity modulated radiotherapy (IMRT) were included. 90 patients treated with 4-7 weeks of 30-40 mg/m2 cisplatin weekly were matched with 90 patients who received two or three cycles of 80 mg/m2 cisplatin three-weekly by sex, age, T stage, N stage, Karnosky performance score (KPS). IMRT was presented to the nasopharyngeal gross target volume at 66-72 Gy/30-32 fractions and those involved neck area at 60-66 Gy/30-32 fractions. Results: The median follow-up time was 69 months (range, 2-91 months), and the 5-year overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) rates were 85.6% vs. 90.0% (P = 0.207), 85.6% vs. 92.6% (P = 0.152), 94.4% vs. 96.7% (P = 0.411), and 88.9% vs. 95.6% (P = 0.107) for the group treated weekly and 3-weekly cisplatin, respectively. No statistically significant survival differences were found between the two treatment groups in both univariate and multivariate analyses. The similar incidence of acute toxicities was observed between two groups. Conclusions: Concurrent cisplatin-based chemotherapy administered weekly or three-weekly in combination with IMRT leads to similar acute toxicities and long-term survival outcomes in locoregionally advanced NPC patients.

The goal of the present contribution is to propose a new control strategy of drive train for the improvement of efficiency of regenerative braking system. In this new control strategy, the backward numerical solution is utilized to realize the cooperative operation of the electric machine and CVT. The analysis for the proposed control strategy is fulfilled based on the vehicle model. The results show that, compared to the existing one without considering the affect of CVT’s efficiency, the proposed control strategy could make more kinetic energies in the vehicle be recaptured.

Although anti-angiogenic drugs were used as first-line treatment in metastatic clear cell renal cell cancer (ccRCC), some patients with metastatic ccRCC still had limited survival benefit from anti-angiogenic therapy. The main reason was resistance to anti-angiogenesis treatment. Tumor blood vessel could be divided into endothelial cell-derived or tumor cell-derived vessels. Tumor cell-derived vascular channel was called as tumor vascular mimicry (VM). PAS-CD34 staining in ccRCC tissues revealed that the expression status of VM was different in ccRCC patients. And the progression-free survival and overall survival were significantly shorter in ccRCC patients with high VM expression level. To explore the effect of VM on the resistance to anti-angiogenesis treatment and the molecular mechanism of VM, we successfully established a three-dimensional culture model for the formation of tumor cell-derived vessel-like structures. We found the formation of blood vessel-like structures in kidney cancer cells was not affected by the anti-angiogenic drug, such as Sunitinib, suggesting that VM was closely associated with resistance to anti-angiogenic therapy. Moreover, we had discovered the “molecular signature of vascular mimicry in renal cancer”. Using this signature, 531 ccRCC patients in TCGA could be divided into two groups with different prognosis. More importantly, we found that HGF/c-MET signaling pathway regulated the expression of Serpinb2 through the downstream AKT pathway, and thus affected the formation of vascular mimicry in SN12C, 786-O cells. In addition, we also had found that HGF could promote the formation of blood vessel-like structure in lung and bladder cancer cells, and the " molecular signature of vascular mimicry in renal cancer " also could differentiate patients with renal papillary carcinoma, bladder cancer, endometrial cancer, lung adenocarcinoma cancer, and pancreatic cancer. These finding suggested that the molecular mechanism of vascular mimicry in renal cancer was universal, to some extent. This project partially elucidated the molecular mechanism of vascular mimicry in renal cancer and its clinical significance, laying a theoretical foundation for the development of more effective anti-angiogenic drugs. Citation Format: Jun-Ping Yang, Xing-Si Peng, Chao-Nan Qian. The mechanism of vascular mimicry in clear cell renal cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 201.

Nasopharyngeal carcinoma has the highest rate of metastasis among head and neck cancers, and distant metastasis is the major reason for treatment failure. The underlying molecular mechanisms of nasopharyngeal carcinoma metastasis are not fully understood. Here, we report the identification of serine protease inhibitor Kazal-type 6 (SPINK6) as a functional regulator of nasopharyngeal carcinoma metastasis via EGFR signaling. SPINK6 mRNA was upregulated in tumor and highly metastatic nasopharyngeal carcinoma cells. Immunohistochemical staining of 534 nasopharyngeal carcinomas revealed elevated SPINK6 expression as an independent unfavorable prognostic factor for overall, disease-free, and distant metastasis–free survival. Ectopic SPINK6 expression promoted in vitro migration and invasion as well as in vivo lymph node metastasis and liver metastasis of nasopharyngeal carcinoma cells, whereas silencing SPINK6 exhibited opposing effects. SPINK6 enhanced epithelial–mesenchymal transition by activating EGFR and the downstream AKT pathway. Inhibition of EGFR with a neutralizing antibody or erlotinib reversed SPINK6-induced nasopharyngeal carcinoma cell migration and invasion. Erlotinib also inhibited SPINK6-induced metastasis in vivo. Notably, SPINK6 bound to the EGFR extracellular domain independent of serine protease–inhibitory activity. Overall, our results identified a novel EGFR-activating mechanism in which SPINK6 has a critical role in promoting nasopharyngeal carcinoma metastasis, with possible implications as a prognostic indicator in nasopharyngeal carcinoma patients. Cancer Res; 77(2); 579–89. ©2016 AACR.

Seismic analysis and design based on collapse probability under intense earthquakes is the main trend in the field of earthquake engineering. Accurate evaluation of collapse resistance capacity is necessary to achieve this target. Due to the accumulated deformation during seismic excitations, structural components would have different stiffness and strength deterioration characteristics. For evaluating the collapse capacity of the structure, it is important to take into account the deterioration characteristics in the analytical model. In this paper, the constitutive models for concrete and reinforcing steel, especially those adopted in OpenSees analytical software, are reviewed first. Then, a reinforced concrete single-storey planar frame structure with one bay is taken as case study and the effect of post-capping strength deterioration of reinforcing steel on evaluation results of global collapse resistance capacity is mainly investigated by incremental dynamic analysis (IDA) via OpenSees software. Analytical results show that global collapse resistance capacity will be significantly overestimated without considering the effect of post-capping strength deterioration of reinforcing steel.

In order to analyze the influence on the motion state of on-off pressure mechanism with flexible link of offset press, pneumatic on-off pressure was as the research object, the three-dimensional model of on-off pressure mechanism was established by using ADAMS, the kinematics simulations of the on-off pressure process was carried out, the curve of the angular velocity, angle acceleration and displacement between rollers of eccentric bushing in both rigid and the rigid-flexible coupled system was got, the significant basis of optimal design for on-off pressure mechanism was provided.

In order to analyze the influence on the printing graphics from the deformation of the printing cylinders and blankets, in this paper, offset printing unit was as the research object, the three-dimensional assembly model of printing cylinders was established by using SolidWorks , the model was imported into finite element software ANSYS, by using ANSYS nonlinear contact calculated functionality, the face-to-face contact of impression surface between plate cylinder and blanket cylinder, blanket cylinder and impression cylinder were established, the stress and strain distribution of blanket were obtained, and the elongation value of circumferential and radial direction of blanket were got, the dot enlargement value was received by simulation analysis.

The impression on-off mechanism is an important part of the offset press, the design and manufacture have relationship with the performance of the printing presses and the quality of the printed products. Pneumatic impression on-off mechanism has the advantages of high position accuracy, reliable and highly automation. This article takes pneumatic impression on-off mechanism as the object of study, the three-dimensional digital model of the impression on-off mechanism is established and the process of on-off pressure is analyzed by using ADAMS software, the piston minimum velocity when the cylinders rotates in different angular velocity is obtained, through simulation, the relation between the motion of impression on-off mechanism and cylinder angular displacement is analyzed. Finally, an important basis to adjust the piston velocity under different speed of cylinders rotation will be provided.

Plate cylinder is the core component of the offset printing unit to complete the image transfer. The plate cylinder’s deformation will occur under pressure, resulting in the image’s deformation on the plate and the low printing quality. In this article, the three-dimensional digital model of plate, packing and cylinder are established by using solidworks software, they are assembled as a whole, the whole is imported into ANSYS finite element analysis software. The shaft of both sides of the cylinder are fixed, and the contact relations between plate, packing and cylinder body are defined, the pressure are load on the area with 5mm width on the surface of the plate cylinder. After solving, the flexural deformation of plate, packing and cylinder are obtained, through analyzing the axial and radial deformation of the plate, the graphic’s elongation which transferred from plate to blanket are received, consequently, an important basis of researching the image expansion will be provided.

The effects of seven key technological properties(ink viscosity, anilox screen, type of doctor blade, plate shore hardness, plate relief depth, type of mounting tape and printing speed) in flexographic printing on printing quality properties(printing density, print contrast and run lengths) were investigated. And the best interactions were analyzed by orthogonal design of seven factors and two levels experiments. Predictive models were built by linear multiple regression analysis(MRA) and BP(Back Propagation) neural network respectively. A comparison of accuracy for models were discussed by a brief statistical analysis of their predictive errors. Results indicated that the most important factor influencing print density, print contrast and run length was type of doctor blade, plate relief depth and print speed respectively. The model of BP neural network provided higher prediction than that use of linear MRA. However, the linear MRA model was convenient to be used in production.

The on-off pressure mechanism has an important function to the printing press, the quality of which concerns the working performance of the printing machine and the quality of printed products directly. In this paper, the pneumatic on-off pressure mechanism is discussed; the work demand of order on-off pressure is analyzed. In addition, the three-dimensional digital model and the kinematic analysis process can be achieved on the basis of ADAMS software. What’s more, the on pressure value in the process of on pressure is derived from the kinematic analysis. Lastly, the relation between the motion of on-off pressure mechanism and cylinder’s angular displacement is analyzed, an important basis to the on-off pressure mechanism’s optimal design will be provided.

Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen, nutrients, and other essential factors. The well-known vascular endothelial growth factor (VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature, which has become therapeutic targets in clinical practice. However, the survival benefits gained from targeting VEGF signaling have been very limited, with the inevitable development of treatment resistance. In this article, we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy, with a special focus on vessel co-option, vessel remodeling, and tumor cell-derived vasculature establishment. Vessel co-option may occur in tumors independently of sprouting angiogenesis, and sprouting angiogenesis is not always required for tumor growth. The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced. The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.

Vasculogenic mimicry (VM) is the formation of vascular channels by tumor cells or tumor cell-derived, trans-differentiated cells in highly aggressive, solid tumors. However, the disease features and prognostic value of VM for overall survival of cancer patients remain controversial. To systematically investigate the roles of VM in cancer progression and its prognostic values, we performed a meta-analysis based on 36 studies (33 eligible articles) including 3609 patients. The pooled hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) were used to assess the relationship between VM and overall survival in cancer patients. Vasculogenic mimicry was significantly associated with cancer differentiation, lymph node metastasis, distant metastasis, and TNM stage. The prognostic value of VM was significant in overall survival (HR 2.16; 95 % CI 1.98–2.38; P

Nasopharyngeal carcinoma (NPC) has the highest metastasis potential among head and neck cancers. Distant metastasis is the major cause of treatment failure. Recent studies from our laboratory have revealed that IL-8 promotes NPC metastasis via activation of AKT signaling and induction of epithelial-mesenchymal transition (EMT) in the cells. In the present study, we found that IL-8 treatment for NPC cells resulted in an accumulation of DNMT1 protein through activating AKT1 pathway and consequent DNMT1 protein stabilization. Then DNMT1 suppressed E-cadherin expression by increasing the methylation of its promoter region. LY-294002 blocked IL-8-induced p-AKT1 activation resulting in reduction of DNMT1 and increase of E-cadherin expression, whereas forced demethylation using 5-aza-2'-deoxycytidine restored E-cadherin expression. In conclusion, our study, for the first time, shows that the IL-8/AKT1 signaling pathway stabilizes DNMT1 protein, consequently enhancing hypermethylation of E-cadherin promoter regions and downregulating E-cadherin protein level in NPC cells. Upon blockage of the IL-8/AKT pathway and inhibition of DNMT1, E-cadherin expression can be reversed. These data suggest that targeting the IL-8/AKT1 signaling pathway and DNMT1 may provide a potential therapeutic approach for blocking NPC metastasis.

Background:Numerous studies have focused on the association of methionine synthase (MS) A2756G polymorphism and acute hematological cancer risk. However, the results remain inconsistent. Therefore, a meta-analysis was performed to derive a more precise estimate of the association between the

Nasopharyngeal carcinoma (NPC), is one of the most common human malignancies in south China, it has the highest recurrence rate and treatment resistance. The underlying molecular mechanisms of NPC relapse and treatment tolerance are not fully understood. In this study, the effects of NEDD8 and NEDD8-activating enzyme inhibitor (MLN4924) on NPC were studied both in vitro and in vivo. Immunohistochemical staining of 197 NPC tissues revealed an elevated NEDD8 expression as an unfavorable independent factor in overall survival and disease-free survival rates. NEDD8 expression was positively correlated with a high risk of death and positivity of lymph node metastasis. Depleted NEDD8 expression by shRNA and inhibited by specific inhibitor MLN4924 dramatically suppressed cell proliferation, cell apoptosis, cell cycle arrest, while ectopic NEDD8 exhibited opposing effects. NEDD8 affected cancer stem cell phenotypes of NPC as assessed in vitro using the cell number of side population (SP) by flow cytometry analysis, colony formation assay, sphere formation assay, and tumor initiation ability in vivo. Downregulation of NEDD8 enhanced the susceptibility of NPC cells to cisplatin and radiation. Moreover, we found that MLN4924 suppressed c-Jun degradation in human NPC cells. Taken together, this report revealed that NEDD8 may act as a novel prognostic marker and MLN4924 may serve as a promising therapeutic target for patients with NPC.

Forty-five C57BL/6 mice were randomly divided into five groups (A-E). Group B and D served as the control group of A and C. Each mouse of group A was intraperitoneally injected with 0.1 ml whole worm extract of Ascaris lumbricoides every other day, and 10 days later injected with 0.1 ml Lewis lung carcinoma (LLC) cells at right axillary subcutaneously region. Mice of group B were injected with normal saline and then developed tumor model. Each mouse of group C was injected with 0.1 ml LLC cells, and two days later, injected with 0.1 ml whole worm extract of A. lumbricoides every other day for 5 times. After the tumor model developed, mice in group D were injected with normal saline. Group E was the negative control group. Time intervals between implantation and active growth and tumor weight were recorded. Tumor inhibition rate was calculated. The average time interval between tumor implantation and measurable tumor growth for groups A, B, C and D was (7.0 +/-1.1), (6.0 +/- 0.7), (9.0 +/- 1.2) and (7.0 +/- 0.9) days. Tumor weight of [(338.9 +/- 282.2) mg] (P0.05). The tumor inhibition rate group A [(722.2 +/- 413.5) mg] was heavier than that of group B was the highest in group C (33.3%). Tumor weight of group C [(237.8 +/- 101.8) mg] was lighter than that of group D [(356.7 +/- 176.9) mg] (P0.05). The results indicated that the tumor formation is affected by the whole worm extract of A. lumbricoides which may have an inhibitory effect on tumour growth.

BACKGROUND: Myeloperoxidase (MPO) is an endogenous oxidant enzyme that produces reactive oxygen species (ROS) and may be involved in lung carcinogenesis. The MPO-463G>A polymorphism influences MPO transcription and has been associated with lung cancer susceptibility. However, the association between the MPO-463G>A polymorphism and lung cancer risk remains controversial. METHOD: To investigate the effect of this polymorphism on lung cancer susceptibility, we performed a meta-analysis based on 22 published case-control studies including 7,520 patients with lung cancer and 8,600 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. RESULTS: Overall, there was no evidence for significant association between MPO-463G>A polymorphism and lung cancer susceptibility (for AA versus GG: OR = 0.91, 95%CI = 0.67-1.24; for GA versus GG: OR = 0.87, 95% CI = 0.78-0.98; for AA/GA versus GG: OR = 0.90, 95% CI = 0.80-1.01; for AA versus GA/GG: OR = 0.96, 95% CI = 0.72-1.28). In the stratified analyses by ethnicity, source of controls and smoking status, we also did not find any significant association between them. CONCLUSIONS: In summary, this meta-analysis suggests MPO-463G>A polymorphism may not be a risk factor for developing lung cancer. However, further prospective well-designed population-based studies with larger sample size are expected to validate the results.

Although entrepreneurial learning is an important mean to transform and utilize the tacit knowledge contained in entrepreneurial network, little research has focused on how different entrepreneurial learning (explorative learning and exploitative learning) would impact the relationship between the two typical entrepreneurial networks (formal network and informal network) effects on the growth performance of new ventures, which resulted that it’s unable to guide entrepreneurship practice well. This paper analyzes formal and informal entrepreneurial network’s impact on new venture growth performance along with explorative and exploitative entrepreneurial learning’s influence on that process. Empirical tests found that both different types of entrepreneurial network and entrepreneurial learning have a positive impact on the growth performance of new ventures, and explorative learning help to the positive impact of formal entrepreneurial network effectively on growth performance of new ventures.

Entrepreneurial network possesses a significant influence on new venture performance, but there are little articles studied it on the basis of entrepreneurs’ characteristics in a certain region. Based on social network theory, entrepreneurial theories, and previous researches, this paper analyzed the characteristics of Zhejiang entrepreneurs and their social networks in detail, discussed the impact that social networks exerted on new venture performance. With the data of 130 valid samples in Zhejiang, through an empirical analysis, we found that highly educated Zhejiang entrepreneur groups showed a rising trend, entrepreneurial network was equally important for different entrepreneurs and new start-ups, and that entrepreneurs’ social network size and network strength can indeed promote the development of enterprises and the economic efficiency.

Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia. In this study, we investigated the functional and molecular mechanisms by which CDC42-interacting protein 4 (CIP4) influences NPC. The expression levels of CIP4 were examined by Western blot, qRT-PCR or IHC. MTT assay was used to detect the proliferative rate of NPC cells. The invasive abilities were examined by matrigel and transwell assay. The metastatic abilities of NPC cells were revealed in BALB/c nude mice. We report that CIP4 is required for NPC cell motility and invasion. CIP4 promotes the activation of N-WASP that controls invadopodia formation and activates EGFR signaling, which induces downstream MMP2 (matrix metalloproteinase 2) upregulation. In addition, CIP4 could promote NPC metastasis by activating the EGFR pathway. In nude mouse models, distant metastasis was significantly inhibited in CIP4-silenced groups. High CIP4 expression is an independent adverse prognostic factor of overall survival (OS) and distant metastasis-free survival (DMFS). We identify the critical role of CIP4 in metastasis of NPC which suggest that CIP4 may be a potential therapeutic target of NPC patients.