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microRNAs (miRNA) are promising predictors in colorectal cancer (CRC). We investigated whether miRNAs could predict adenoma recurrence in patients with advanced colorectal adenoma (ACRA) after polypectomy. miRNA expression profiling was performed by miRNA microarray to identify recurrence-related miRNAs. Candidate miRNAs extracted from formalin-fixed paraffin-embedded blocks of patients with ACRA were measured using real-time PCR. Logistic regression analysis was conducted to investigate whether validated miRNA expression profiles were independent from other known adenoma recurrence risk factors. The prognostic values of six miRNAs and three independent risk factors were assessed by the area under the receiver operating characteristic (ROC) curve analysis. The expressions of six candidate miRNAs were significantly decreased from levels in normal colorectal tissue compared with ARCA with adenoma recurrence (RACRA) in this retrospective cohort. However, only miRNA (miR)-194 emerged as a practical predictor. The sensitivity and specificity of miR-194 as a predictor were 71.0% and 78.0%, respectively, at a cutoff value of 0.1311 in the retrospective cohort. Sensitivity and specificity were 76.1% and 77.2%, respectively, in the prospective cohort using the same cutoff value. Low expression levels of miR-194, adenoma size ≥2 cm, and ≥3 adenomas were independent risk factors for adenoma recurrence. Moreover, low expression of miR-194 was a better predictor of adenoma recurrence than the adenoma size and numbers according to ROC curve analysis. miR-194 may be an independent predictor for adenoma recurrence in patients with ACRA after polypectomy. Cancer Prev Res; 7(6); 607–16. ©2014 AACR.

PDF - 114K, Differential miRs expression levels between NRACRA tissues and RACRA tissues in miR microarray.

PDF - 114K, Differential miRs expression levels between normal colorectal tissues (Normal) and NRACRA tissues in miR microarray.

PDF - 111K, Characteristics of study population and advanced colorectal adenoma.

Hepatocellular carcinoma (HCC), a primary liver tumor, is the third leading cause of cancer-related mortality worldwide. The proteasome system is overactivated in the majority of tumors, including HCC. However, targeting the proteasome system in HCC is not as effective as in other types of cancer. Therefore, a new target of HCC therapy needs to be identified, and the potential mechanism must be studied. Using the The Cancer Gene Genome Atlas and GEO datasets, the present investigation demonstrated for the first time that ADRM1 is overexpressed in HCC, and the high level of its expression predicts poor overall survival in HCC patients. The high expression of ADRM1 in HCC was verified using tumor tissue arrays. By comparing paired tumor and nontumor tissues, it was shown that the majority of HCC patients (76.25%) exhibited higher ADRM1 expression in the tumor than in normal tissues. in vitro experiments demonstrated that targeting ADRM1 with shRNAs significantly suppressed the proliferation of HCC cells. RA190, a specific inhibitor of ADRM1, suppressed cell proliferation and colony formation by HCC cells in a concentration-dependent manner. The study of the mechanism of the effects of RA190 revealed that targeting ADRM1 blocked the G2/M transition in the cell cycle and induced apoptosis of HCC cells. Together, the obtained results indicate that ADRM1 is a promising target for HCC therapy and suggest that ADRM1 inhibitors, such as RA190, have the potential for clinical application in the treatment of HCC.

Background Chemotherapy resistance is the major cause of recurrence in patients with colorectal cancer (CRC). A previous study found that Fusobacterium (F.) nucleatum promoted CRC chemoresistance. Additionally, metformin rescued F. nucleatum-induced tumorigenicity of CRC. Here, we aimed to investigate whether metformin could revert F. nucleatum-induced chemoresistance and explore the mechanism. Methods The role of metformin in F. nucleatum-infected CRC cells was confirmed using cell counting kit 8 assays and CRC xenograft mice. Stemness was identified by tumorsphere formation. Bioinformatic analyses were used to explore the regulatory molecules involved in metformin and F. nucleatum-mediated regulation of the sonic hedgehog pathway. Results We found that metformin abrogated F. nucleatum-promoted CRC resistance to chemotherapy. Furthermore, metformin attenuated F. nucleatum-stimulated stemness by inhibiting sonic hedgehog signaling. Mechanistically, metformin diminished sonic hedgehog signaling proteins by targeting the MYC/miR-361-5p cascade to reverse F. nucleatum-induced stemness, thereby rescuing F. nucleatum-triggered chemoresistance in CRC. Conclusions Metformin acts on F. nucleatum-infected CRC via the MYC/miR-361-5p/sonic hedgehog pathway cascade, subsequently reversing stemness and abolishing F. nucleatum-triggered chemoresistance. Our results identified metformin intervention as a potential clinical treatment for patients with chemoresistant CRC with high amounts of F. nucleatum.

We aimed to develop an HCC classification model based on the integrated gene expression and methylation data of methylation-driven genes. Genome, methylome, transcriptome, proteomics and clinical data of 369 HCC patients from The Cancer Genome Atlas Network were retrieved and analyzed. Consensus clustering of the integrated gene expression and methylation data from methylation-driven genes identified 4 HCC subclasses with significant prognosis difference. HS1 was well differentiated with a favorable prognosis. HS2 had high serum α-fetoprotein level that was correlated with its poor outcome. High percentage of CTNNB1 mutations corresponded with its activation in WNT signaling pathway. HS3 was well differentiated with low serum α-fetoprotein level and enriched in metabolism signatures, but was barely involved in immune signatures. HS3 also had high percentage of CTNNB1 mutations and therefore enriched in WNT activation signature. HS4 was poorly differentiated with the worst prognosis and enriched in immune-related signatures, but was barely involved in metabolism signatures. Subsequently, a prediction model was developed. The prediction model had high sensitivity and specificity in distributing potential HCC samples into groups identical with the training cohort. In conclusion, this work sheds light on HCC patient prognostication and prediction of response to targeted therapy.

Some reservoirs in Jilantai oilfield are loose sand conglomerates with high clay minerals. The cores are seriously argillized and poorly cemented, which are very sensitive to various types of damage, especially water sensitive damage, Which may cause clay minerals to expand and block the flow channel. Traditionally, after the completion of production it requires to lift out the oil string in the well and then put the completion string into the well with killing the well. In the process of operation, the fluid in the wellbore enters the formation and causes damage to the reservoir, resulting in a sharp decline in productivity after operation. In order to realize the high-efficiency construction and production of oil field in the early stage of exploration and development, this paper studies the integrated technology of well testing and completion and the supporting tools, comprehensively applies the perforating and down pumping technology, develops the supporting tools such as hanging packer and anti-pollution valve, which realizes the protection of oil well from reservoir pollution in the process of operation by automatically controlling the opening and closing state of wellbore and reservoir channel through the differential pressure, which also develops a perforation, pump down and reservoir protection integrated completion technology of water sensitive reservoir. The field application shows that the process is easy to operate, with strong adaptability to the field and high success rate, leading to stable production and achieve the purpose of reservoir protection, obvious economic benefits and good prospects for development.

Background The effect of metformin on gut microbiota has been reported, but whether metformin can suppress colorectal cancer (CRC) by affecting gut microbiota composition and rescue F. nucleatum-induced tumourigenicity remains unclear. Methods To identify microbiota associated with both CRC occurrence and metformin treatment, first, we reanalyzed the gut microbiome of our previous data on two human cohorts of normal and CRC individuals. Subsequently, we summarized microbiota altered by metformin from published literatures. Several taxa, including Fusobacterium, were associated with both CRC occurrence and metformin treatment. We investigated the effect of metformin on APCMin/+ mice given with or without F. nucleatum. 16S rRNA gene sequencing was performed. Findings We summarized 131 genera altered by metformin from 18 published literatures. Five genera reported to be changed by metformin, including Bacteroides, Streptococcus, Achromobacter, Alistipes and Fusobacterium, were associated with CRC in both of our human cohorts. Metformin relieved the symptoms caused by F. nucleatum administration in APCMin/+ mice, and showed promise in suppressing intestinal tumour formation and rescuing F. nucleatum-induced tumourigenicity. Administration of F. nucleatum and/or metformin had effect on gut microbiome structure, composition and functions of APCMin/+ mice. Interpretation This study pioneers in predicting critical CRC-associated taxa contributing to the antitumour effect of metformin, and correlating gut microbiome with the antitumour effect of metformin in experimental animals. We presented a basis for future investigations into metformin's potential effect on suppressing F. nucleatum-induced tumor formation in vivo. Funding This work was supported by grants from the National Natural Science Foundation of China (31701250).

Activation of hedgehog (Hh) signaling contributes to the progression of Barrett’s esophagus (BE), which increases the risk of esophageal adenocarcinoma. Recent clinical studies revealed that proton-pump inhibitors (PPIs) but not H2 receptor antagonists (H2RAs) were associated with a decreased risk of esophageal adenocarcinoma. We would like to know whether PPIs interfere with BE progression during BE treatment. Here, we explored the role of omeprazole on Hh signaling and expression of two crucial biomarkers of BE, SOX9 and CDX2. We demonstrated that bile acids elevated expression of Hh pathway target genes, such as GLI1 and PTCH1, and induced SOX9 and CDX2 up-regulation in both CP-A and CP-B cells. Omeprazole, but not famotidine, down-regulated these genes induced by bile acids. In addition, omeprazole-induced down-regulation of SOX9 and CDX2 was mediated by Hh signaling. To explore the mechanisms by which omeprazole inhibits Hh signaling, we performed luciferase assay but did not find any effects of omeprazole on the activity of GLI1 promoter, the critical transcription factor of Hh signaling. Therefore, we used miRNA sequencing and a bioinformatics tool in our study to identify the differently expressed miRNAs in BE organoids treated with or without omeprazole, and we identified miR-2116-3p was involved in omeprazole-mediated inhibition of Hh signaling and subsequent down-regulation of SOX9 and CDX2. Collectively, our data indicate omeprazole inhibits Hh signaling and subsequent SOX9 and CDX2 expression via up-regulating miR-2116-3p. We have demonstrated a novel acid-independent mechanism of omeprazole that might yield valuable insight into clinical management of BE progression, irrespective of acid reflux symptoms.

Objective Fusobacterium nucleatum (F. nucleatum) has been reported to be enriched in patients with inflammatory bowel disease (IBD). This study aimed to explore the role of F. nucleatum in IBD and its pathogenic mechanism. Methods Several bacteria that have been reported to be associated with IBD or colorectal cancer were measured in the fecal samples of 91 patients with IBD and 43 healthy individuals. Mice with dextran sulfate sodium (DSS)-induced colitis and a Caco-2 cell line were used to explore the pathogenicity of F. nucleatum. Barrier damage was evaluated by a transmission electron microscope, the permeability of fluorescein isothiocyanate-dextran, transepithelial electrical resistance and immunofluorescence. Protein levels of the cell-cell junction and activation of the STAT3 signaling pathway were detected by immunohistochemistry and immunoblot. Cytokine secretion and T-cell differentiation were measured by quantitative real-time polymerase chain reaction and flow cytometry. Results F. nucleatum was significantly enriched in the feces of patients with IBD and its abundance correlated with disease activity. Administration of F. nucleatum markedly exacerbated colitis in a DSS mouse model. Mechanistically, F. nucleatum damaged epithelial integrity and increased permeability by regulating the expression and distribution of tight junction proteins zonula occludens-1 and occludin. Moreover, F. nucleatum promoted the secretion of cytokines (tumor necrosis factor-α, interferon-γ, interleukin [IL]-1β, IL-6, and IL-17), activated the STAT3 signaling pathway, and induced CD4+ T cell proliferation and Th1 and Th17 subset differentiations. Conclusion F. nucleatum can damage the intestinal barrier and induce aberrant inflammation, which exacerbates colitis.

Immune checkpoint blockade (ICB) has been proven to be an effective strategy for enhancing the effector activity of anti-tumor T cells, and checkpoint blockers targeting CTLA-4, PD-1, and PD-L1 have displayed strong and durable clinical responses in certain cancer patients. The new hope brought by ICB therapy has led to the boost in therapeutic development of ICBs in recent years. Nonetheless, the therapeutic efficacy of ICBs varies substantially among cancer types and patients, and only a proportion of cancer patients could benefit from ICBs. The emerging targets and molecules for enhancing anticancer immunity may bring additional therapeutic opportunities for cancer patients. The current challenges in the ICB therapy have been discussed, aimed to provide further strategies for maximizing the efficacy of ICB therapy.

BACKGROUND PD-L1 expression on tumor-infiltrating lymphocytes (TILs) has recently been reported as a biomarker for colorectal cancer (CRC). However, the prognostic and clinical significance of PD-L1 on TILs in CRC remains controversial. We performed this meta-analysis to evaluate the association between the PD-L1 expression on TILs and clinicopathological features and prognosis of CRC patients. METHODS A comprehensive literature search for relevant studies published up to Feb 2020 was performed using Medline, Embase, and Web of Science. Odds ratio (OR) with 95% CI was selected to appraise the correlation between PD-L1 expression on TILs with prognostic and clinicopathological characteristics of CRC patients. Begg's and Egger's test were used to assess publication bias. The statistical analysis was conducted using Stata software. RESULTS A total of 19 studies including 5,213 CRC cases were included in this meta-analysis. The pooled results showed that PD-L1 overexpression on TILs was relevant to longer OS (OR = 1.36, 95% CI = 1.19 - 1.55, p < 0.01) and longer DFS/RFS (OR = 1.22, 95% CI = 1.03 - 1.44, p = 0.02). Moreover, CRC patients with high expression of PD-L1 on TILS was associated with lower T stage (OR = 2.30, 95% CI = 1.85 - 2.87, p < 0.01), less lymph node in-vasion (OR = 1.48, 95% CI = 1.03 - 2.13, p = 0.03), less distant metastasis (OR = 2.56, 95% CI = 1.81 - 3.64, p < 0.01), earlier TNM stage (OR = 1.93, 95% CI = 1.34 - 2.66, p < 0.01), later tumor grade (OR = 0.38, 95% CI = 0.23 - 0.62, p < 0.01) and high MSI status (OR = 0.36, 95% CI = 0.25 - 0.52, p < 0.01). But it is not related to tumor size, tumor differentiation, MMR status, BRAF mutant, and KRAS mutant. CONCLUSIONS This meta-analysis revealed that PD-L1 expression on TILs can serve as a significant biomarker for positive prognosis and clinicopathological features of CRC. Our results may provide some useful information when using PD-L1 expression to predict the survival of CRC patients and to select the beneficial CRC patients from PD-1/PD-L1 antibody treatment.

// Ji-Lin Wang 1, * , Wen-Yu Su 1, * , Yan-Wei Lin 2 , Hua Xiong 1 , Ying-Xuan Chen 1 , Jie Xu 1 , Jing-Yuan Fang 1 1 Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200001, China 2 Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China * These authors have contributed equally to this work Correspondence to: Ji-Lin Wang, email: wangjilin811123@163.com Jie Xu, email: xujieletter@163.com Jing-Yuan Fang, email: jingyuanfang@sjtu.edu.cn Keywords: CD44v6, prognosis, colorectal cancer, meta-analysis Received: October 04, 2016 Accepted: November 24, 2016 Published: December 24, 2016 ABSTRACT CD44v6 has recently been reported as a biomarker for colorectal cancer. However, the clinical and prognostic significance of CD44v6 in colorectal cancer remains controversial. Therefore, we performed a meta-analysis to clarify this issue. A comprehensive literature search was performed using Medline, Embase and Web of Science, and the statistical analysis was conducted using Stata software. A total of twenty-one studies including 3918 colorectal cancer cases were included. The pooled analysis showed that CD44v6 overexpression in colorectal cancer was an independent prognostic marker correlating with lower 5-year overall survival rate (OR=0.78, 95%CI =0.67-0.91, p=0.001). CD44v6 overexpression was also associated with more lymph node invasion (OR=1.48, 95%CI= 1.02-2.15, p=0.04), and advanced Dukes stage (OR=2.47, 95%CI= 1.29-4.73, p=0.01). In addition, while excluding Zolbec’s study, CD44v6 overexpression was associated with distance metastasis (OR=1.65, 95%CI =1.13-2.40, p=0.01). Taken together, this meta-analysis suggested that CD44v6 is an efficient prognostic factor in colorectal cancer.

Background Cluster of differentiation 24 (CD24) has recently been reported as a biomarker for colorectal cancer. However, the clinical and prognostic significance of CD24 in colorectal cancer remains controversial. Therefore, we performed a meta-analysis to clarify this issue. Methods A comprehensive literature search was performed using Medline, Embase, Web of Science, and CNKI, and the statistical analysis was conducted using Stata software. Results A total of thirteen studies including 2,180 cases were included in this meta-analysis. The pooled analysis indicated that CD24 expression was associated with lymph node invasion (RR = 0.71 (negative versus positive), 95% CI = 0.52 - 0.96, p = 0.02, Figure 3), differentiation (RR = 0.81 (well versus poor), 95% CI = 0.67 - 0.99, p = 0.04), and T stage (RR = 0.74 (T1 + T2 versus T3 + T4), 95% CI = 0.65 - 0.85, p = 0.00). The prognosis analysis also suggested CD24 overexpression indicating poorer 5-year OS rate (RR = 0.74, 95% CI = 0.58 - 0.93, p = 0.01) However, CD24 was not associated with other clinicopathological features such as tumor size, tumor grade, distant metastasis, TNM stage and Dukes stage. Conclusions Taken together, this meta-analysis suggested that CD24 is an efficient prognostic factor in colorectal cancer.

Background H. pylori infection has been reported as a risk factor for colorectal adenoma (CRA); however, the clinical results were controversial. Therefore, we performed a meta-analysis to evaluate the association of H. pylori infection and CRA risk. Methods A comprehensive literature search for relevant studies published up to November 2017 was performed using Medline and Embase, and the statistical analysis was conducted using Stata software. Results A total of twenty-five studies including 8,675 cases and 15,275 controls were included in the analysis. The pooled analysis showed that H. pylori infection was associated with an increased risk of CRA (OR = 1.86, 95% CI = 1.55 - 2.23). Subgroup analyses according to the ethnicity, study type, and H. pylori detection method were further conducted. The results showed that H. pylori infection was associated with an increased risk of CRA both in Caucasian (OR = 2.23, 95% CI = 1.36 - 3.66) and Asian population (OR = 1.58, 95% CI = 1.36 - 1.82). Both the case-control studies and cross sectional studies suggested the H. pylori infection could promote the risk of CRA (case control: OR was 2.00, 95% CI = 1.22 - 3.28; cross-sectional: OR was 1.68, 95% CI = 1.43 - 1.99). For H. pylori infection detection methods, there is significant association between H. pylori infection and CRA risk using the serum IgG method and RUT, but not with the UBT and IHC method. Conclusions This analysis suggests that H. pylori infection may be a risk factor for CRA.

It is increasingly evident that long noncoding RNAs (lncRNA) have causative roles in carcinogenesis. In this study, we report findings implicating a novel lncRNA in gastric cancer, termed GAPLINC (gastric adenocarcinoma predictive long intergenic noncoding RNA), based on the use of global microarray and in situ hybridization (ISH) analyses to identify aberrantly expressed lncRNA in human gastric cancer specimens. GAPLINC is a 924-bp-long lncRNA that is highly expressed in gastric cancer tissues. GAPLINC suppression and with gene expression profiling in gastric cancer cells revealed alterations in cell migration pathways, with CD44 expression the most highly correlated. Manipulating GAPLINC expression altered CD44 mRNA abundance and the effects of GAPLINC on cell migration and proliferation were neutralized by suppressing CD44 expression. Mechanistic investigations revealed that GAPLINC regulates CD44 as a molecular decoy for miR211-3p, a microRNA that targets both CD44 and GAPLINC. Tissue ISH analysis suggested that GAPLINC overexpression defines a subgroup of patients with gastric cancer with very poor survival. Taken together, our results identify a noncoding regulatory pathway for the CD44 oncogene, shedding new light on the basis for gastric cancer cell invasiveness. Cancer Res; 74(23); 6890–902. ©2014 AACR.

microRNAs (miRNA) are promising predictors in colorectal cancer (CRC). We investigated whether miRNAs could predict adenoma recurrence in patients with advanced colorectal adenoma (ACRA) after polypectomy. miRNA expression profiling was performed by miRNA microarray to identify recurrence-related miRNAs. Candidate miRNAs extracted from formalin-fixed paraffin-embedded blocks of patients with ACRA were measured using real-time PCR. Logistic regression analysis was conducted to investigate whether validated miRNA expression profiles were independent from other known adenoma recurrence risk factors. The prognostic values of six miRNAs and three independent risk factors were assessed by the area under the receiver operating characteristic (ROC) curve analysis. The expressions of six candidate miRNAs were significantly decreased from levels in normal colorectal tissue compared with ARCA with adenoma recurrence (RACRA) in this retrospective cohort. However, only miRNA (miR)-194 emerged as a practical predictor. The sensitivity and specificity of miR-194 as a predictor were 71.0% and 78.0%, respectively, at a cutoff value of 0.1311 in the retrospective cohort. Sensitivity and specificity were 76.1% and 77.2%, respectively, in the prospective cohort using the same cutoff value. Low expression levels of miR-194, adenoma size ≥2 cm, and ≥3 adenomas were independent risk factors for adenoma recurrence. Moreover, low expression of miR-194 was a better predictor of adenoma recurrence than the adenoma size and numbers according to ROC curve analysis. miR-194 may be an independent predictor for adenoma recurrence in patients with ACRA after polypectomy. Cancer Prev Res; 7(6); 607–16. ©2014 AACR.

Objective Octamer transcription factor 1 (OCT1) was found to be expressed in intestinal metaplasia and gastric cancer (GC), but the exact roles of OCT1 in GC remain unclear. The objective of this study was to determine the functional and prognostic implications of OCT1 in GC. Design Expression of OCT1 was examined in paired normal and cancerous gastric tissues and the prognostic significance of OCT1 was analysed by univariate and multivariate survival analyses. The functions of OCT1 on synbindin expression and extracellular signal-regulated kinase (ERK) phosphorylation were studied in vitro and in xenograft mouse models. Results The OCT1 gene is recurrently amplified and upregulated in GC. OCT1 overexpression and amplification are associated with poor survival in patients with GC and the prognostic significance was confirmed by independent patient cohorts. Combining OCT1 overexpression with American Joint Committee on Cancer staging improved the prediction of survival in patients with GC. High expression of OCT1 associates with activation of the ERK mitogen-activated protein kinase signalling pathway in GC tissues. OCT1 functions by transactivating synbindin, which binds to ERK DEF domain and facilitates ERK phosphorylation by MEK. OCT1-synbindin signalling results in the activation of ERK substrates ELK1 and RSK, leading to increased cell proliferation and invasion. Immunofluorescent study of human GC tissue samples revealed strong association between OCT1 protein level and synbindin expression/ERK phosphorylation. Upregulation of OCT1 in mouse xenograft models induced synbindin expression and ERK activation, leading to accelerated tumour growth in vivo. Conclusions OCT1 is a driver of synbindin-mediated ERK signalling and a promising marker for the prognosis and molecular subtyping of GC.

Persistent infection with Helicobacter pylori (H. pylori) contributes to gastric diseases including chronic gastritis and gastric cancer. However, the pathogenesis of this carcinogenic bacterium has not been completely elucidated. Here, we report that H. pylori rapidly triggers STAT3 signaling and induces STAT3-dependent COX-2 expression both in vitro and in vivo. STAT3 upregulates COX-2 by binding to and increasing the activity of COX-2 promoter. COX-2 in turn regulates IL-6/STAT3 signaling under basal conditions and during H. pylori infection. These findings suggest that a positive feedback loop between STAT3 and COX-2 exists in the basal condition and H. pylori infectious condition. Immunohistochemical staining revealed that H. pylori-positive gastritis tissues exhibited markedly higher levels of pSTAT3(Tyr705) than H. pylori-negative ones. High pSTAT3(Tyr705) levels are correlated with intestinal metaplasia and dysplasia, suggesting pSTAT3(Tyr705) may be useful in the early detection of gastric tumorigenesis. Additionally, a strong positive correlation between STAT3/pSTAT3(Tyr705) levels and COX-2 expression was identified in gastritis and gastric cancer tissues. Together, these findings provide new evidence for a positive feedback loop between STAT3 signaling and COX-2 in H. pylori pathogenesis and may lead to new approaches for early detection and effective therapy of gastric cancer

Zinc finger protein X-linked (ZFX) is a zinc finger transcription factor encoded on the X chromosome. Here, we found that ZFX expression was significantly upregulated in gastric cancer (GC) cell lines and tissues. Knockdown of ZFX induced significant apoptosis and cell cycle arrest in SGC7901 and MGC803 cells. Moreover, we demonstrated for the first time that knockdown of ZFX inhibited gastric cancer cell growth in vitro and in vivo via downregulating the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK-MAPK) pathway. Therefore, ZFX play a prominent role in GC tumorigenicity and may have potential applications in the diagnosis or treatment of GC.

Based on SVD decomposition, an digital watermarking algorithm with the method of wavelet transform is proposed. By means of singular value decomposition to realize blind extracting, the watermarking image is embedded into intermediate frequency sub bands of wavelet composition. Finally, applying normalized cross-correlation function (NC) and peak signal to noise ratio (PSNC), it has proved that this algorithm has better invisibility and robustness.

The polycomb group protein enhancer of zeste homologue 2 (EZH2), which has histone methyltransferase (HMT) activity, is overexpressed in malignant tumours. However, the role of EZH2 in colorectal cancer (CRC) invasion is little known. Here we investigated the clinical significance, biological effects, and mechanisms of EZH2 signalling. Knockdown of EZH2 significantly reduced cell invasion and secretion of matrix metalloproteinases 2/9 (MMP2/9) in in vitro studies. Knockdown of EZH2 dramatically increased overall survival and decreased metastasis of lung in in vivo studies. Conversely, overexpression of EZH2 significantly increased lung metastasis and shortened overall survival when compared with control tumours. EZH2-induced CRC cell invasion may depend on down-regulation of vitamin D receptor (VDR), which is considered to be a marker of CRC invasion. EZH2 regulates the histone trimethylation of lysine 27 (H3K27me3) in the VDR promoter. Moreover, we found that STAT3 directly binds to the EZH2 promoter and regulates VDR down-regulation in CRC cells. Significant inverse correlations were observed between the expression of EZH2 and pSTAT3 and that of VDR in CRC tissues compared with normal tissue in patients. We show the role of EZH2 in CRC metastasis and identify VDR as a target gene of EZH2. EZH2 expression may be directly regulated by STAT3, and STAT3 may play an important role in EZH2-mediated VDR down-regulation in CRC. This pathway may provide potential targets in aggressive CRC.

Background: Accumulating evidence indicates that diet is one of the most important environmental factors involved in the progression from advanced colorectal adenoma (A-CRA) to colorectal cancer. Objective: We evaluated the possible effects of dietary fiber on the fecal microbiota of patients with A-CRA. Design: Patients with a diagnosis of A-CRA by pathological examination were enrolled in the A-CRA group. Patients with no obvious abnormalities or histopathological changes were enrolled in the healthy control (HC) group. Dietary fiber intake was assessed in all patients. Short-chain fatty acids (SCFAs) in feces were detected by gas chromatography. The fecal microbiota community was analyzed by 454 pyrosequencing based on 16S ribosomal RNA. Results: Lower dietary fiber patterns and consistently lower SCFA production were observed in the A-CRA group (n = 344). Principal component analysis showed distinct differences in the fecal microbiota communities of the 2 groups. Clostridium, Roseburia ,a nd Eubacterium spp. were significantly more prevalent in the A-CRA group (n = 47) than in the HC group (n = 47), whereas Enterococcus and Streptococcus spp. were more prevalent in the A-CRA group (n = 47) (all P , 0.05). Butyrate and butyrate-producing bacteria were more prevalent in a subgroup of HC subjects with a high fiber intake than in those in both the low-fiber HC subgroup and the high-fiber A-CRA subgroup (all P , 0.05). Conclusion: A high-fiber dietary pattern and subsequent consistent production of SCFAs and healthy gut microbiota are associated with a reduced risk of A-CRA. This trial was registered at www.chictr.org as ChiCTR-TRC-00000123. Am J Clin Nutr doi: 10.3945/ajcn. 112.046607.

SummaryMany Rho GTPase activation proteins (RhoGAPs) are deleted or downregulated in cancers, but the functional consequences are still unclear. Here, we show that the RhoGAP ArhGAP11A induces cell-cycle arrest and apoptosis by binding to the tumor suppressor p53. The RhoGAP domain of ArhGAP11A binds to the tetramerization domain of p53, but not to its family members p63 or p73. The interaction stabilizes the tetrameric conformation of p53 and enhances its DNA-binding activity, thereby inducing cell-cycle arrest and apoptosis. Upon DNA damage stress, ArhGAP11A accumulates in the nucleus and interacts with p53, whereas knockdown of ArhGAP11A partially blocks p53 transcriptional activity. These findings explain why RhoGAPs are frequently deleted in cancers and suggest that the RhoGAP family sits at the crossroads between the cell-migration and proliferation pathways.

Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread, and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative therapeutic approaches. Here we demonstrate a critical role of ASAP3 in regulating the microvilli structure of parietal cells in vivo, and reveal the feasibility of controlling gastric acidity by targeting ASAP3. Conditional knockout of ASAP3 in mice caused elongation and stacking of microvilli in parietal cells, and substantially decreased gastric acid secretion. These were associated with active assembly of F-actin caused by a higher level of GTP-bound Arf6 GTPase. Consistently, a small molecular compound QS11 inhibited ASAP3 function and significantly reduced gastric acidity in vivo. Of note, the expression of ASAP3 was positively correlated with gastric acid secretion in 90 human cases, and high expression of ASAP3 was associated with reflux disease and peptic ulcer. These results reveal for the first time that ASAP3 regulates the microvilli structures in parietal cells. Our data also suggest ASAP3 as a feasible and drugable therapeutic target for gastric acidity-associated diseases. A drug that blocks a protein found in the minute projections of acid-secreting cells of the stomach could help treat ulcers and reflux. A team led by Jing-Yuan Fang and Jie Xu from Shanghai Jiao Tong University, China, investigated the function of a protein called ASAP3 in regulating the tiny protrusions (called microvilli) of parietal cells, which secrete hydrochloric acid and other digestive juices in the stomach. In mice with depleted ASAP3 activity, the microvilli became elongated and produced far less gastric acid. Also, mice injected with a compound that blocks ASAP3 had reduced acid levels. Human patients suffering from reflux disease and peptic ulcer disease exhibited elevated ASAP3 activity, which further suggests that drugs directed at blocking ASAP3 could help people with acid-associated stomach conditions.

Sub-pixel positioning is a key technology in geometry measurement field. Reckoning on the low accuracy of ordinary polynomial interpolation for sub-pixel positioning method because of losing the position of edge points, an improved Sobel edge detection method is first proposed, and then is applied to the thickness measurement system of cable sheath material. The experiment shoes that the edge coordinateonthe detected by our proposed interpolation method is more colse to the real edge than the original method.

To evaluate the relationship between age and clinicopathological characteristics in gastric carcinoma patients, we performed the meta-analysis based on nine retrospective clinical trials. Comparing elderly patients with young patients it showed lower male/female ratio, more diffuse GC, more Borrmann type IV, more poorly differentiated carcinoma, more peritoneal metastasis, less vascular invasion, fewer partial resections, and better 5-year survival rate. These particular age-related characteristics need to be further investigated.

Abnormalities in signal transducer and activator of transcription (STAT) signaling, especially STAT3 and STAT5, are involved in the oncogenesis of several human cancers, including gastric cancer (GC). However, the downstream targets of STAT3 and STAT5 are not fully identified, and the precise roles and the prognostic value of STAT3 and STAT5 in GC have not been fully characterized. In this study, we used ChIP-on-chip to identify STAT3 and STAT5 target genes on a whole genome scale in AGS cells, a human GC cell line. A total of 2,514 and 1,314 genes were identified as STAT3 and STAT5 target genes, which were mainly related to cell growth, metabolism, differentiation, adhesion, immune response, and stress response. Furthermore, we depleted STAT3 and STAT5 with a small interfering RNA, respectively. Our results demonstrate that STAT3, but not STAT5, is involved in GC cell growth and cell cycle progression through regulation of gene expression, such as Bcl-2, p16(ink4a) and p21(waf1/cip1). Moreover, expression of pSTAT3(Tyr705) correlates with TNM stage, differentiation and survival, and is a significant prognostic factor in GC. Therefore, our findings provide novel evidence that STAT3 may be a potential therapeutic target for GC treatment and pSTAT3(Tyr705) expression can predict prognosis in GC.

Randomized controlled trials (RCTs) are considered the gold standard for evaluating the efficacy of clinical interventions and developing evidence-based clinical practice guidelines; however, they can yield biased results when their methodology is less than rigorous, or their published reports fail to report key items. A number of RCTs have been carried out to explore the relationship between Helicobacter pylori eradication and gastric cancer, but their results remain controversial. In this article, we will comprehensively review searched medical electronic databases, and appraise the reporting and methodological quality of these relevant RCTs according to the Consolidated Standards of Reporting Trials 2010 statement and the Cochrane Handbook in order to learn about the internal and external validity of these RCTs.

The temperature characteristics of semiconductor will make the zero point and sensitivity of the piezoresistive pressure sensor drift with the temperature,that is the main factor of the measurement error caused by pressure sensor.For high precision pressure detecting system, temperature drift has become the important obstacles when needing to increase the performance of the system,especially in the domain where the environment temperature changes greatly . Based on comparing the advantages and disadvantages with other methods ,this paper puts forward a kind of temperature compensation method which combines polynomial curve fitting and cubic spline interpolation, it can improve the performance of the system well.

The study area is located in the south of Huanxian county, in Yan'an and Puxian counties and to the north of Xi'an. The Shanxi and lower Shihezi formations are important gas-bearing formations. Given our analysis of the direction of rivers, the contents of stable heavy minerals and of feldspar of palaeo river systems, the study area is divided into six palaeodrainage patterns corresponding to six feldspar regions and six sedimentary facies regions. On this basis, the distribution of sedimentary facies was also analyzed. During the Shanxi stage, a delta front was deposited in the Huanxian region and delta plains and fronts were deposited in the Pingliang, Chunhua-Yaoxian and Hancheng-Chengcheng regions. In the Yan'an-Daning region, only a delta front was developed. The distribution of sedimentary facies in the earlier Shihezi stage originated from the Shanxi stage. A delta front was developed in the Huanxian region while a delta plain and front developed in the Pingliang-Zhenyuan region during the same time. Lakes originated only in the Zhenyuan-Huanxian-Huachi-Zhengning and Daning-Jixian zones. This analytical method shows that different palaeodrainage patterns can be effectively distinguished in order to forecast sedimentary facies.

Aims: To investigate the antitumor effects of probiotics Clostridium butyricum and Bacillus subtilis on colorectal cancer (CRC) progression. Materials & methods: The effects of C. butyricum and B. subtilis on CRC cells were studied. Male C57BL/6 mice with 1,2-dimethylhydrazine dihydrochloride (DMH)-induced CRC were intervened by these two probiotics and the antitumor effects were examined by comparing the tumor incidence and detecting the inflammatory and immune-related markers. Results & conclusions: C. butyricum and B. subtilis inhibited the proliferation of CRC cells, caused cell cycle arrest and promoted apoptosis. In vivo, these two probiotics inhibited the development of DMH-induced CRC. The molecular mechanism involved reduced inflammation and improved immune homeostasis. This work establishes a basis for the protective role of probiotics B. subtilis and C. butyricum in intestinal tumorigenesis.

Calculations of the critical properties of binary mixtures are reported using the Carnahan–Starling–van der Waals (CSvdW) equation of state in conjunction with the one-fluid model and the Lorentz–Berthelot combining rules for unlike interactions. The calculations are used to determine the global phase diagram of binary mixtures. A feature of the calculations is that no adjustable parameters were used in the combining rules. This means that the global phase diagram can be constructed solely in terms of experimentally measurable quantities such as the ratio of the critical temperatures and critical volumes of the component molecules. The global phase diagram accounts for almost all of the known types of fluid phase behaviour, including closed-loop liquid–liquid immiscibility. Comparisons with experimental data indicate that the global phase diagram is a good qualitative predictor of phase behaviour. Therefore, the phase behaviour type of a binary mixture can be confidently predicted solely from the ratios of critical temperatures and volumes of the pure components.

Calculations of the critical properties of anisotropic binary mixtures are reported using the hard convex body-van der Waals equation of state in conjunction with conformal solution theory and the one-fluid model. The calculations are used to determine the global phase diagram for anisotropic binary mixtures of molecules of identical size. In the absence of other influences, mixtures with a moderate degree of anisotropy between the component molecules are only observed to exhibit type I, II or III behaviour. For highly anisotropic mixtures, a new type of behaviour is observed which we describe as ‘reverse type IV’.

The change of electrical performance of SiGc HBT and Si BJT is studied after irradiation with 1.3×1013 and 1.0×1014 reactor fast neutrons cm−2. Ic and β decrease, while Ib increases generally with an increasing neutron irradiation fluence for SiGe HBT. For Si BJT, Ic increases at low Vbe bias, decreases at high Vbe bias; Ib increases; and β decreases much more than a SiGe HBT at the same fluence. It is shown that a SiGe HBT has much better anti-radiation performance than a Si BJT. The mechanism of performance changes induced by irradiation is discussed.

In this study we investigated the biological role and mechanism of miR-198 in colorectal carcinoma (CRC). MiR-198 expression was shown to exhibit a strongly negative correlation with lymph node invasion, distant metastasis and patient survival in examinations of colorectal cancer tissues and paired normal colorectal mucosa tissues. fucosyl transferase 8 (FUT8) was identified as a potential target of miR-198 in bioinformatics analysis and luciferase reporter assays. Overexpression of miR-198 in CRC cell lines decreased FUT8 levels as shown by immunofluorescence analysis, and inhibited cell proliferation, migration, and invasion. These anti-tumor phenotypes were rescued by reconstitution of FUT8 expression. Furthermore, miR-198 was shown to target the 3'UTR of FUT8 directly to downregulate FUT8 expression at both mRNA and protein levels in qRT-PCR and Western blot analyses, respectively. In vivo, restoration of miR-198 significantly inhibited xenograft growth and invasion of CRC tumors in nude mice. Therefore, it could be concluded that miR-198 suppresses the proliferation and invasion of CRC by directly targeting FUT8.

Covalent modification adding acetyl groups to the C terminus of the p53 protein has been suggested to be required for its functional activation as a tumour suppressor. However, it remains largely unknown how p53 acetylation is deregulated in colorectal cancer (CRC), which is the third most commonly diagnosed cancer worldwide. Here we show that ArhGAP30, a Rho GTPase-activating protein, is a pivotal regulator for p53 acetylation and functional activation in CRC. ArhGAP30 binds to p53 C-terminal domain and P300, facilitating P300-mediated acetylation of p53 at lysine 382. ArhGAP30 expression is required for p53 activation upon DNA damage stress, and the level of ArhGAP30 correlates with p53 acetylation and functional activation in CRC tissues. Moreover, low level of ArhGAP30 expression associates with poor survival of CRC patients. In summary, ArhGAP30 is required for p53 acetylation and functional activation in CRC, and the expression of ArhGAP30 is a potential prognostic marker for CRC.

Mutations of p53 cause not only loss of wild-type function but also gain of novel oncogenic functions (GOF). Accumulating evidence suggest that p53 hotspot mutations may confer different types and magnitudes of GOF. Here we add support to the heterogeneity of mutant p53 GOF by showing their unequal association with early tumor onset and spectrum of tumor types. We stratified Li-Fraumeni syndrome (LFS) patients according to carried p53 mutations using data from the updated p53 germline mutation database. When compared to loss-of-function nonsense mutations, the R282 GOF mutation associated with significantly earlier onset, while the G245 mutation displayed later onset. The R175, Y220, R248, R282 and nonsense mutations showed preferential distribution in certain cancer types, which varied in the age of onset. Multivariate COX regression model adjusting for cancer types and patient sex suggested that nonsense and G245 mutations had lower risk than R248 for early onset, suggesting unequal strengths of mutant GOF effects. Our results suggest that Li-Fraumeni syndrome can be subdivided into subtypes linking to unequal GOF effects of p53 mutations. These findings have potential implications in the prevention, early detection and targeted treatment of LFS tumors.

MicroRNAs (miRNAs) participate in diverse biological pathways and may act as oncogenes or tumor suppressors. Single nucleotide polymorphisms (SNPs) in miRNAs (MirSNPs) might promote carcinogenesis by affecting miRNA function and/or maturation; however, the association between MirSNPs reported and cancer risk remain inconsistent. Here, we investigated the association between nine common MirSNPs and cancer risk using data from large scale case-control studies. Eight precursor-miRNA (pre-miRNA) SNPs (rs2043556/miR-605, rs3746444/miR-499a/b, rs4919510/miR-608, rs2910164/miR-146a, rs11614913/miR-196a2, rs895819/miR-27a, rs2292832/miR-149, rs6505162/miR-423) and one primary-miRNA (pri-miRNA) SNP (rs1834306/miR-100) were analyzed in 16399 cases and 21779 controls from seven published studies in eight common cancers. With a novel statistic, Cross phenotype meta-analysis (CPMA) of the association of MirSNPs with multiple phenotypes indicated rs2910164 C (P = 1.11E-03), rs2043556 C (P = 0.0165), rs6505162 C (P = 2.05E-03) and rs895819 (P = 0.0284) were associated with a significant overall risk of cancer. In conclusion, MirSNPs might affect an individual's susceptibility to various types of cancer.

The development of gastric cancer (GC) is a complex multistep process, including numerous genetic and epigenetic changes. CD24 is associated with enhanced invasiveness of GC and a poor prognosis. However, the mechanism by which CD24 induces GC progression remains poorly characterized. Here, we found that the expression of CD24 gradually increased in samples of normal gastric mucosa, non-atrophic chronic gastritis, chronic atrophic gastritis (CAG), CAG with intestinal metaplasia, dysplasia and GC. Moreover, the knockdown of CD24 induced significant levels of apoptosis in GC cells via the mitochondrial apoptotic pathway. CD24 may also promote cellular invasion and regulate the expression of E-cadherin, fibronectin and vitamin D receptor in GC cells. The activation of signal transducer and activator of transcription 3 (STAT3) may mediate CD24-induced GC survival and invasion in vitro. Furthermore, CD24-induced GC progression and STAT3 activation could also be detected in vivo and in clinical GC tissues samples. Taken together, our results indicate that CD24 mediates gastric carcinogenesis and may promote GC progression by suppressing apoptosis and promoting invasion, with the activation of STAT3 playing a critical role.