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Background Pancreatic cancer is one of the most common malignant tumors of the digestive tract, and it has a poor prognosis. Traditional methods are not effective to accurately assess the prognosis of patients with pancreatic cancer. Immunotherapy is a new promising approach for the treatment of pancreatic cancer; however, some patients do not respond well to immunotherapy, which may be related to tumor microenvironment regulation. In this study, we use gene expression database to mine important immune genes and establish a prognostic prediction model for pancreatic cancer patients. We hope to provide a feasible method to evaluate the prognosis of pancreatic cancer and provide valuable targets for pancreatic cancer immunotherapy. Results We used univariate COX proportional hazard regression analysis, the least absolute shrinkage and selection operator, and multivariate COX regression analysis to screen 8 genes related to prognosis from the 314 immune-related genes, and used them to construct a new clinical prediction model in the TCGA pancreatic cancer cohort. Subsequently, we evaluated the prognostic value of the model. The Kaplan–Meier cumulative curve showed that patients with low risk scores survived significantly longer than patients with high risk scores. The area under the ROC curve (AUC value) of the risk score was 0.755. The univariate COX analysis showed that the risk score was significantly related to overall survival (HR 1.406, 95% CI 1.237–1.598, P Conclusions Based on the TCGA-PAAD cohort, we identified immune-related markers with independent prognostic significance, validated, and analyzed their biological functions, to provide a feasible method for the prognosis of pancreatic cancer and provide potentially valuable targets for pancreatic cancer immunotherapy.

Background Among manufactured or engineered nanoparticles, carbon black (CB) has largest production worldwide and is also an occupational respiratory hazard commonly seen in rubber industry. Few studies have assessed the risk for cardiovascular disease in carbon black exposed populations. An endothelial biosensor assay was used to quantify the capacity of sera from 82 carbon black packers (CBP) and 106 non-CBPs to induce endothelial cell activation ex vivo. The mediation effect of circulatory proinflammatory factors on the association between carbon black exposure and endothelial cell activation was assessed and further validated using in vitro intervention experiments. Results The average elemental carbon level inside carbon black bagging facilities was 657.0 μg/m3, which was 164-fold higher than that seen in reference areas (4.0 μg/m3). A global index was extracted from mRNA expression of seven candidate biosensor genes using principal component analysis and used to quantify the magnitude of endothelial cell activation. This global index was found to be significantly altered in CBPs compared to non-CBPs (P P = 0.74). Individual gene analyses identified that de novo expression of key adhesion molecules (e.g., ICAM and VCAM) and chemotactic factors (e.g., CCL2, CCL5, and CXCL8) responsible for the recruitment of leukocytes was dramatically induced in CBPs with CXCL8 showing the highest fold of induction (relative quantification = 9.1, P Conclusions Inflammatory mediators in sera from CBPs may bridge carbon black exposure and endothelial cell activation response assessed ex vivo. CBPs may have elevated risk for cardiovascular diseases when comorbidity exists. Our study may serve as a benchmark for understanding health effects of engineered carbon based nanoparticles with environmental and occupational health relevance.

// Dongfang Tang 1 , Lu Yue 2 , Ruyong Yao 3 , Lin Zhou 4 , Yuqin Yang 4 , Liming Lu 4 and Wen Gao 1 1 Department of Thoracic Surgery, Huadong Hospital Affiliated to FuDan University, Huadong, China 2 Department of Oncology of the Qingdao Municipal Hospital, Qingdao, China 3 Central Laboratory of the Affiliated Hospital of Medical College Qingdao University, Qingdao, China 4 Central Laboratory of Shanghai Chest Hospital Affiliated to Shanghai Jiaotong University, China Correspondence to: Wen Gao, email: gaowenchest@163.com Keywords: lung cancer, IDO signaling, p53, metastasis Received: February 10, 2017 Accepted: March 29, 2017 Published: April 25, 2017 ABSTRACT In present study, we are to clear demonstrate the genetic evidence of IDO signaling’s impact on invasion and metastasis in lung cancer. Here we examined IDO1 expression levels in non-small cell lung cancer (NSCLC) patients (64) tumor/normal pairs underwent RT-PCR and comprehensive histological, immunohistochemica and clinical analysis. The NSCLC cells stably expressing IDO1 was analyzed for migration and invasion assays and the regulatory mechanism in vitro and metastasis assays in vivo . As results, we reported that IDO1 expression increased by more than 3.2-fold in lung cancer compared with their corresponding non-tumor tissues, and the up-regulation of IDO1 is significantly correlated to TNM stage and lymph node-metastasis. The over-expression of IDO1 significantly encouraged the metastasis and invasion of lung cancer cells, and IDO1 could promote metastasis formation in vivo . Furthermore, we further found that p53 could attenuate IDO signaling in lung cancer cell migration partly. In conclusion, these results demonstrate that the IDO signaling’s impact on invasion and metastasis and the suppressive effect of p53 on IDO1 in lung cancer, present one novel therapeutic strategy for early metastatic lung cancer in clinical.

Oxaliplatin (L-OHP) is a platinum compound that is widely used to treat certain solid tumors, including gastric tumors. L-OHP is an effective anti-cancer treatment; however, its usage increases the probability of patients developing hepatic injury with inflammation, referred to as chemotherapy-associated steatohepatitis. The present study aimed to evaluate the outcome of L-OHP treatment combined with polyenephosphatidylcholine (PPC), a major component of essential phospholipids used to treat steatohepatitis, on SGC-7901 gastric cancer cell proliferation. This would help to determine whether combination therapy with L-OHP and PPC is clinically beneficial for patients with gastric cancer. The viability of SGC-7901 cells was verified by an MTT assay; flow cytometry was used to analyze the cell cycle and rates of cell apoptosis; oxidation-related indicators were measured by spectrophotometry, and the expression of cell cycle- and apoptosis-related proteins was determined by western blotting. The results demonstrated that L-OHP significantly inhibited SGC-7901 cell growth in a dose- and time-dependent manner (F=194.193, P

Insulin-like growth factor (IGF) signaling plays an important role in tumorigenesis and metastasis. Here, we analyzed insulin-like growth factor (IGF) binding protein-2 (IGFBP2) expression in 81 lung cancer patients and 36 controls consisting of healthy and benign pulmonary lesion participants for comparison, then validated the IGFBP2 expression in additional 84 lung cancer patients, and evaluated the prognostic and chemoresistant significance of IGFBP2 in two cohorts respectively. Next we detected the reversal effect of trichostatin A (TSA) on chemoresistance in cell lines with high IGFBP2 expression. As a result, the mean expression of IGFBP2 in lung cancer patients was significantly higher than that in controls and increased with lung cancer progressed to advanced stage. In addition, high IGFBP2 expression was independently predictive for chemoresistance; over-expressed IGFBP2 enhances cell activity and TSA can reverse the chemoresistance induced by high IGFBP2 expression through enhancing autophagy. Furthermore, multivariate analysis showed that lung cancer patients whose blood IGFBP2 was higher had a poor survival outcome, with a hazard ratio of 8.22 (95%CI 1.78–37.92, P = 0.007) after adjustment for stage, histopathology, EGFR mutation, age, smoking and surgery.

Background The brain is a frequent site of metastases from non-small cell lung cancer (NSCLC). The purpose of this study was to detect the expression of CUG-binding protein 1 (CUGBP1) messenger ribonucleic acid (mRNA) and Ki-67 in metastasized brain tissue from NSCLC and determine the relationship between CUGBP1 and brain metastases. Methods The expression of CUGBP1 mRNA and Ki-67 in metastasized brain tissue from NSCLC was investigated by semiquantitative polymerase chain reaction and immunohistochemistry, respectively. The expression of CUGBP1 and Ki-67 in metastasized brain tissue from NSCLC was related to clinical characteristics, as assessed using the chi-square test. The prognostic significance was assessed by univariate and multivariate analyses using the Cox hazard model. Results The expression of CUGBP1 mRNA and Ki-67 was overexpressed in metastasized brain tissue from NSCLC and was correlated with differentiation. In addition, by both univariate and multivariate survival analyses, CUGBP1 expression, Ki-67 expression, and age were noted to be independent indicators of a shorter postsurgical survival. Conclusion The expression of CUGBP1 is an important factor in the development of brain metastases from NSCLC.

Resistance to docetaxel, a chemotherapy drug for breast cancer (BC) treatment, occurs in ~50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through miR-141 has been proven to play an important role in cancer drug resistance. The present study investigated the role of miR-141 expression in BC cells of acquired docetaxel resistance. Inhibition of miR-141 enhanced the response to docetaxel in docetaxel-resistant cells (MCF-7/DTX and MDA-MB-231/DTX, respectively), whereas overexpression of miR-141 confered resistance in docetaxel-sensitive cells (MCF-7 and MDA-MB-231, respectively). By directly targeting the eukaryotic translation initiation factor 4E (EIF4E) mRNA, miR-141 acts on genes that are necessary for drug induced apoptosis rendering the cells drug resistant. Modulation of miR-141 expression was correlated with EIF4E expression changes and a direct interaction of miR-141 with EIF4E was shown by a luciferase assay. Thus, the present study is the first to show an increased expression of miR-141 in an acquired model of docetaxel resistance in BC. This serves as a mechanism of acquired docetaxel resistance in BC cells, possibly through direct interactions with EIF4E, therefore presenting a potential therapeutic target for the treatment of docetaxel resistant BC.

MicroRNAs (miRNAs) have been identified as important post-transcriptional regulators involved in various biological and pathological processes of cells. In the present study, we investigated the roles and mechanisms of miR-200b in human breast cancer (BC). MiR-200b expression was carried out by qRT-PCR in human BC cell lines and clinical samples and the prognostic potential of miR-200b expression was further evaluated. In vitro, effects of miR-200b on BC cell proliferation, apoptosis and cell cycle distribution were tested by CCK-8 kit, flow cytometric analysis respectively. Luciferase assay and Western blot analysis were performed to validate the potential targets of miR-200b after the preliminary screening by employing open access software. We found that miR-200b was significantly down-regulated in both BC tissues and cell lines. The low expression of miR-200b was correlated with late TNM stage, negative oestrogen receptor and positive HER-2 status. Multivariate analysis showed that miR-200b expression was an independent prognostic predictor for BC patients. Integrated analysis identified Sp1 as a direct and functional target of miR-200b. Knockdown of Sp1 inhibited cell proliferation, induce apoptosis and act on cell cycle resembling that of miR-200b high expression. Our data demonstrates that miR-200b has potential to serve as prognostic biomarker and tumour suppressor for BC patients. As a direct and functional target of miR-200b, Sp1 and miR-200b both could be an exciting target for BC treatment strategy.

Background At present, the expression of MOR1 and its function in gastric cancer remains unclear with evidence suggesting that it is to be involved in tumor progression and metastasis. The study was to assess the clinicopathologic relevance and prognostic value of MOR1 expression in gastric cancer. Methods Real-time quantitative RT-PCR and immunohistochemical staining were used to detect MOR1 expression in primary gastric cancerous surgical specimens and adjacent nontumorous tissues. Results High MOR1 expression was detected in cancerous tumor compared with their adjacent nontumorous tissues. In addition, the chi-square test revealed that high MOR1 expression was significantly correlated with depth of invasion (p = 0.006), lymph node metastasis (p = 0.001), distant metastasis (p = 0.017), and TNM staging (p = 0.027). Moreover, Kaplan–Meier analysis revealed a significant association between MOR1 expression and overall survival. High expression of MOR1 was identified as an independent and significant predictor gene of reduced postoperative survival. Conclusion We conclude that MOR1 expression may be a useful biomarker for better prediction of the clinical outcome and management of gastric cancer patients.

The aim of the present study was to investigate the role of miR-124 in lung cancer and identify the potential predictive value of miR-124 in postoperative non-small cell lung cancer (NSCLC) patients. We detected miR-124 expression in A549, NCL-H460 and normal lung epithelial BEAS-2E cells and showed a significantly lower expression level of miR-124 in NSCLC cells than in BEAS-2E cells. Upregulation of miR-124 expression levels in both A549 and NCL-H460 cells by transfection with miR-124 mimics suppressed cell proliferation and induced apoptosis. Further investigation revealed that miR-124 bound directly to the 3' UTR region of STAT3, thereby inhibiting STAT3 expression. In addition, miR-124 levels detected in NSCLC tissues were lower than those in adjacent normal lung tissues, while the opposite was observed for STAT3. In NSCLC, the expression levels of miR-124 and STAT3 correlated significantly with the tumor node metastases (TNM) stage, differentiation grade and lymph node metastasis, while the levels of these molecules did not differ significantly by gender, age, location, smoking index, pleural invasion or pathological type. The expression level of miR-124 was significantly associated with disease-free survival (DFS) in both positive and negative lymph node groups. Furthermore, patients with low miR-124 or high STAT3 expression generally received a worse prognosis in terms of both overall survival (OS) and DFS. In conclusion, our findings suggest that miR-124 functions as a tumor suppressor by targeting STAT3, and that miR-124 may potentially serve as a useful biomarker for the prognosis of NSCLC patients.

It is less known about miRNA3127‐5p induced up‐regulation of PD‐L1, immune escape and drug resistance caused by increased PD‐L1 in lung cancer. In this study, lentivirus was transduced into lung cancer cells, and quantitative PCR and Western blot were used to detect the expression of PD‐L1. Then immunofluorescence assay was applied to detect autophagy, finally we explored the relationship between PD‐L1 expressions and chemoresistance in patients. As a result, we found that microRNA‐3127‐5p promotes pSTAT3 to induce the expression of PD‐L1; microRNA‐3127‐5p promotes STAT3 phosphorylation through suppressing autophagy, and autophagy could retaine pSTAT3 into the nucleus in miRNA‐3127‐5p knocked cells, and immune escape induced by elevated level of PD‐L1 results in chemoresistance of lung cancer. In conclusion, microRNA‐3127‐5p induces PD‐L1 elevation through regulating pSTAT3 expression. We also demonstrate that immune escape induced by PD‐L1 can be dismissed by corresponding monoclonal antibody.

Rnf2 is a fundamental component of the polycomb repressive complex 1and acts as the really interesting new gene finger E3 ligase, which is responsible for histone 2A modification. Previous studies have shown that the ring finger protein 2 (Rnf2) is overexpressed in various types of tumor and has a close association with tumor development. However, few studies have been carried out into the expression and biological function of Rnf2 in gastric cancer cells. The present study measured the expression of Rnf2 in gastric cancer cells and normal epithelial gastric cells. The results demonstrate that Rnf2 is upregulated in gastric cancer cells. In addition, the knockdown of Rnf2 inhibited the cell viability and induced increased G1 phase followed by a substantial reduction of the G2/M phase. The expression levels of p21 and p27 were also significantly elevated by the knockdown of Rnf2. These results provide evidence of the oncogenic function of Rnf2 in gastric cancer, possibly through an inhibition of cellular proliferation and a delay of the G2/M phase. Therefore, Rnf2 may be a novel target for the prognosis and therapy of gastric cancer.

Docetaxel is commonly used as an effective chemotherapeutic drug for gastric cancer patients recently. With the increasing emergence of docetaxel resistance nowadays, identification of suitable biomarkers for predicting chemosensitivity to docetaxel may be a key role for improving therapeutic effects for gastric cancer patients. In this study, we investigated the correlation between the expression of transcription factor forkhead box protein M1 (FOXM1) and chemotherapy response to docetaxel in gastric cancer, the possible mechanism for which was further explored. As a result, FOXM1 overexpression was shown to mediate resistance to docetaxel in gastric cancers. It altered microtubule dynamics to protect tumour cells from docetaxel-induced apoptosis. Mechanistic investigations revealed that tubulin-destabilizing protein Stathmin, which mediated docetaxel resistance in FOXM1-silenced gastric cancer cells, is a direct down-stream target of FOXM1, whereas another microtubule dynamics protein mitotic centromere–associated kinesin (MCAK), shown to be related to docetaxel resistance in gastric cancer cells, is not associated with FOXM1 expression significantly. These results were further provided by immunohistochemical analysis, indicating that FOXM1 and Stathmin expression levels were correlated in 103 post-operational gastric cancer specimens. Moreover, when we attenuated FOXM1 expression with FOXM1 inhibitor thiostrepton, docetaxel resistance in gastric cancers was found to be reversed, simultaneously with the down-regulation of FOXM1 and Stathmin. Therefore, FOXM1 can be a useful marker for predicting and monitoring docetaxel response. Through the inhibition of FOXM1, docetaxel resistance can be reversed, and thus FOXM1 could be a new therapeutic target in docetaxel-resistant gastric cancer.

Since anoctamin 1 ANO1 (TMEM16A) was found to be a molecular component of Ca(2+) -activated Cl(-) channels, its role in tumorigenesis has gained attention at a fast pace. ANO1 overexpression frequently occurs in the cancer tissues along with 11q13 chromosome amplification. Poor prognosis of many types of cancers has been closely correlated with ANO1 gene amplification and protein overexpression. ANO1 is now considered an excellent biomarker for certain cancers. Recent research suggests that it is the channel function of ANO1 that is involved in the tumorigenesis. However, how the overexpression of the functional ANO1 causes malignant transformation of tissues via signaling pathways, for example, MAPK remains to be investigated. Clarification of the reasons in future will avail to make ANO1 as a target for cancer treatment.

It is known that mitochondrial ATP-sensitive potassium channels (mitoKATP) play a significant role in protecting cerebral function from ischemia-reperfusion injury, which is related with a decrease in the mitochondrial matrix calcium. However, the effect of mitochondrial calcium uniporter (MCU) on diazoxide-induced cerebral protection is still indistinct. The purpose of the present paper is to further observe the relationship between mitoKATP and MCU, and to probe the mechanism. Adult male Wistar rats were randomly divided into five groups: the Sham group, the I-R group, the Dzx+I-R group, the Dzx+Sper+I-R group, and the Sper+I-R group. Rats not in the Sham group were exposed to 2-hour ischemia followed by 24-hour reperfusion. Diazoxide and spermine were administrated 30 minutes before ischemia or 10 minutes before reperfusion, respectively. After 24-hour reperfusion, animals were given neurological performance tests, overdosed with general anesthesia, and then their brains were excised for infarct volume, pathological changes, and apoptosis analysis. The beneficial effects of diazoxide (improved neurological deficits, decreased infarct volume, and apoptosis, evidenced by the decreased expression of cytochrome c and Bax) were significantly neutralized by spermine. The results of the present work suggest that diazoxide-induced cerebral protection against ischemia-reperfusion injury is mediated by spermine through apoptotic pathway.

The ability of differentiated thyroid cancer and adjacent thyroid cells to concentrate iodine is dependent on their expression of a functional NA(+)/I(-) symporter (NIS). Thyroid cancer is insensitive to (131)I treatment if the thyroid cells lack the ability to concentrate iodide. Thus, in this study, we aimed to determine whether the NIS protein was differentially expressed in thyroid cancer and various surrounding tissues. We recruited 114 cases of papillary thyroid carcinoma (PTC) and divided them into two groups: 60 patients of 9 males and 51 females with a mean age of 49.55 years who had PTC with surrounding nodular goiter tissue (simplified as G(NG)), and 54 patients of 8 males and 46 females with a mean age of 45.78 years who had PTC with surrounding normal tissue (G(normal)) after total or near total thyroidectomy. Formalin-fixed and paraffin-embedded tissue sections were prepared for immunohistochemical staining of the NIS protein and semi-quantitative analysis. The NIS protein was expressed in the basolateral membrane of the normal epithelium, while PTC and nodular goiter cells expressed NIS in the cytoplasm and basolateral membrane. The expression levels of the NIS protein were higher in the adjacent normal tissues compared with those of the surrounding nodular goiter tissues (P=0.002) and expression levels of the NIS protein were higher in PTC tissues compared with the surrounding nodular goiter tissues (P=0.008). The data from this study indicate that cancer-surrounding tissues may play a significant role in mediating the sensitivity of PTC patients to radioactive iodine treatment.

Objective The aim of this study was to investigate the molecular mechanism of anti-apoptotic action of survivin to the hepatoma-cellular carcinoma cell line HepG2.

To evaluate the effect of excision repair cross-complementing group 1 (ERCC1) and X-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcome in patients receiving oxaliplatin-based regimens for metastatic colorectal cancer.Hundred and thirteen patients with a diagnosis of metastatic colorectal cancer were treated with oxaliplatin-based chemotherapy. ERCC1 codon 118C/T and XRCC1 codon 399A/G polymorphisms were tested by real-time polymerase chain reaction (RT-PCR) method in peripheral blood lymphocytes of these patients. Disease control rates and survivals were compared by types of genotypes.Analyses of the patterns of the polymorphism located at ERCC1 codon 118 showed that 55 (48.67%) patients were homozygous for C/C genotype, 15 (13.27%) were homozygous for the T/T genotype, and 43 (38.06%) were heterozygous for C/T genotype. Analyses of the polymorphism located at XRCC1 codon 399 showed that 61 (53.98%) patients were homozygous for A/A genotype, 13 (11.50%) were homozygous for the G/G genotype, and 39 (34.52%) were heterozygous for A/G genotype. After two cycles of chemotherapy, there was complete response (CR) in 1 patient, partial response (PR) in 24 patients, and stable disease (SD) in 56 patients. Altogether in 81 (71.68%) patients the disease was controlled after chemotherapy. Thirty-two (28.32%) patients showed disease progression. After adjusting for some clinical factors, both the ERCC1 polymorphism and the XRCC1 polymorphism lost their roles in predicting DCR (P = 0.662, P = 0.631) and MST (P = 0.692, P = 0.572). But the combination of ERCC1 and XRCC1 polymorphisms was significantly associated with DCR (P = 0.01) and MST (P = 0.000) independently.This is the first study which showed that polymorphisms of ERCC1 and XRCC1, in combination not individually, were independent predictors for DCR and OS. This may contribute to the selection of patients who would benefit from oxaliplatin-based chemotherapy for metastatic colorectal cancer.

Nucleophosmin (NPM) and human epidermal growth factor receptor-2 (Her-2) are abnormally expressed in various types of human malignant tumors, including gastric cancer, and have been closely associated with cancer chemoresistance. However, their interaction and roles in oxaliplatin resistance are not fully understood. Therefore, the present study aimed to elucidate the relationship between NPM and Her-2 in gastric cancer cell lines and clinical samples, and further investigated their role in the resistance of gastric cancer to oxaliplatin. Western blotting and reverse transcription-quantitative polymerase chain reaction confirmed that NPM and Her-2 expression were significantly upregulated in gastric cancer cells and clinical samples, and that their expression levels were strongly correlated. However, Her-2 expression was not affected by upregulation or downregulation of NPM expression in gastric cancer cells. Cell counting kit-8 assays demonstrated that the cell sensitivity to oxaliplatin decreased simultaneously with an increase in NPM expression. Furthermore, inhibition of Her-2 expression using trastuzumab significantly increased the sensitivity of the cells to oxaliplatin, which occurred simultaneously with the downregulation of NPM. These results indicated that inhibition of NPM, as a Her-2 downstream signal, may be a novel strategy to overcome oxaliplatin-resistant gastric cancer, and that trastuzumab and oxaliplatin may exhibit a synergistic antitumor effect in Her-2-positive gastric cancer cells.

The mechanism of action of oncogenic or tumor suppressor microRNAs is not well understood. We examined the microRNA expression profile in completely resected lung adenocarcinoma and examined the associated response to erlotinib. The lung adenocarcinoma tissue and adjacent normal lung parenchyma of 226 stage IIB and IIIA patients who underwent complete resection were obtained for two separate retrospective cohorts. In cohort 1 (119 patients; 80 with epidermal growth factor receptor (EGFR) mutations and 39 without), miRNA microarrays were used to identify EGFR-related miRNAs and their association with survival. In cohort 2 (107 patients with EGFR mutations), the miRNAs and their association with survival and response to erlotinib were analyzed by qRT-PCR. Cox proportional hazards regression was used to evaluate the effect of treatment on survival. As a result, erlotinib is associated with a significant improvement in overall survival (P = 0.0075, cohort 1; P = 0.0372, cohort 2) and disease progression (P = 0.6929, cohort 1; P = 0.3347, cohort 2) in patients with reduced miRNA-21 expression. Additionally, miRNA-145 is strongly associated with overall survival (P = 0.0008, cohort 1; P = 0.0131, cohort 2) and progression-free survival (P = 0.0198, cohort 1; P = 0.0269, cohort 2). Understanding the response rate to erlotinib relative to miRNA-21 (77.3 vs. 41.7 %, P

Although a number of studies have indicated that the positive expression of nucleophosmin (NPM) and trefoil factor 3 (TFF3) is associated with oncogenesis and poor prognosis in several tumor types, the prognostic value of the co-expression of NPM and TFF3 in gastric cancer (GC) has not been fully elucidated. Therefore, in this study, we aimed to investigate the role of NPM and TFF3 in GC and determine their prognostic value. We retrospectively reviewed 108 patients who had undergone radical gastric tumor resection. The expression of NPM and TFF3 was detected by immunohistochemistry and the association of NPM and TFF3 with clinicopathological characteristics was investigated using the Chi-square test. Furthermore, univariate and multivariate analyses were conducted to determine the prognostic value of these markers. Of the 108 samples, NPM was positive in 57 (53%) and TFF3 was positive in 54 samples (50%). The positive expression of NPM was correlated with advanced tumor stage and recurrence (P=0.0333 and P

The transcription factor, forkhead box protein M1 (FoxM1), and the tyrosine kinase receptor, human epidermal growth factor receptor-2 (Her-2), are aberrantly expressed in a number of human malignancies, and are closely associated with the development of cancer. However, their regulatory mechanisms and their involvement in tumor development have not been extensively investigated, particularly in gastric cancer. In the present study, we examined the expression levels of FoxM1 and Her-2 in samples from patients with gastric cancer, as well as gastric cancer cell lines. Their regulatory mechanisms and the connection between them were also explored. We found that FoxM1 and Her-2 expression was markedly higher in the gastric cancer samples, while a strong association was found between them at the mRNA and protein level. When we regulated the levels of Her-2 in the gastric cancer cell lines, the expression of FoxM1 changed accordingly. Following the transfection of Her-2 expression vectors into the gastric cell lines, the luciferase activity of the FoxM1 promoter positively increased along with the concentration of pcDNA3.1-Her-2. However, Her-2-siRNA inverted this variation, which was further confirmed by treatment with the Her-2 inhibitor, trastuzumab, revealing that Her-2 regulates FoxM1 expression at the promoter level in gastric cancer cells. Our results suggest that FoxM1 and Her-2 are important diagnostic markers for gastric cancer. FoxM1 may be a potential cellular target for therapeutic intervention, particularly in gastric cancers resistant to Her-2-targeted therapy.

microRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumor suppressors, the role of microRNAs in mediating cancer progression remains unexplored. And whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in radically resected non-small-cell lung carcinoma (NSCLC) patients still needs to be further validated. Our analyses involved two separated, retrospective cohorts. Firstly, microRNA expression profile was performed in a cohort consisted of 128 radically resected NSCLC patients [60 were positive to epidermal growth factor receptor (EGFR) mutation and 68 were negative] and 32 healthy providers to identify EGFR mutation-related microRNAs and to determine their association with survival. In addition, to validate our findings, we used quantitative reverse transcriptase polymerase chain reaction assays to measure microRNAs and assess their association with disease progression, survival, and response to gefitinib in an independent cohort of 201 patients with EGRF mutation. In radically resected NSCLC patients, the expression levels of miR-21, 10b in patients with EGFR mutation were much higher than those without mutation. We used Cox proportional-hazards regression to evaluate the effect of treatment on survival. In both univariate and multivariate analyses, gefitinib was associated with a significant improvement in overall survival in patients with reduced miR-21 expression. Thus, miR-21 expression emerged as an independent predictor of the response to gefitinib. Additionally, miR-10b is highly expressed in progressive disease compared with complete remission or stable disease (P < 0.001). However, miR-21 expression has no significant prognosis for disease progression (P = 0.720). Meanwhile, when overall survival was considered as the end point, miR-10b did not have a significant difference between different subgroups (P = 0.634). The expression patterns of microRNAs differ significantly between patients with positive and negative EGFR mutation. And the expression status of miR-21 and 10b in such patients is associated with disease progression, survival, and response to adjuvant therapy with gefitinib.

Gastric cancer (GC) is a highly aggressive malignant tumor. Its high mortality rate prompts the urgent need for novel therapeutic agents. The aim of this study is to detect the expression of CRM1 in GC, which has not been reported to date. The expression of CRM1 in GC and adjacent noncancerous tissues (ANCT) of gastrectomy specimens from 120 GC patients was measured by immunohistochemistry. In addition, correlations between the CRM1 staining and the clinicopathologic features as well as survival were analyzed. Positive expression rates of CRM1 in GC and ANCT were 57.8 and 6.7 %, respectively. High expression of CRM1 was significantly associated with increased serum level of carcinoma embryonic antigen (CEA, P = 0.02) but not associated with that of carbohydrate antigen 19–9 (P = 0.38). CRM1 levels were correlated with more advanced tumor stages (P = 0.01), positive Her2 status (P = 0.01), and distant metastasis (P = 0.02). Univariate analysis showed that CEA (P = 0.0076), TNM stage (P = 0.0001), metastasis (P = 0.027), and CRM1 expression (P = 0.0019) were significant risk factors affecting overall survival of GC patients. The multivariate analysis indicated that the CRM1 was an independent indicator for GC survival (P = 0.0048). The current results indicated that CRM1 expressed in a subpopulation of GC with aggressive behavior and could serve as a prognosis marker for poor outcome.

BackgroundForkhead box transcription factor 1 (FOXM1) has been reported to overexpress and correlate with pathogenesis in a variety of human malignancies. However, little research has been done to investigate its clinical significance in gastric cancer.MethodsWe examined the expression of FOXM1 in 103 postoperational gastric cancer tissues and 5 gastric cell lines by immunohistochemistry and western blot analysis respectively. Data on clinic-pathological features and relevant prognostic factors in these patients were then analyzed. Moreover, the association of FOXM1 expression and chemosensitivity to docetaxel in gastric cancer cells was further explored.ResultsOur study demonstrated that the level of FOXM1 expression was significantly higher in gastric cancer than in para-cancer tissues (P 0.1). FOXM1 amplification was identified as an independent prognostic factor in gastric cancer (P = 0.001), and its affection is more significant in patients with tumor size larger than 5 cm (P = 0.004), pT3-4 (P = 0.003) or pIII-IV (P = 0.001). Additionally, shown to mediate docetaxel resistance in gastric cancers by our research, FOXM1 was revealed to alter microtubule dynamics in response to the treatment of docetaxel, and the drug resistance could be reversed with FOXM1 inhibitor thiostrepton treatment.ConclusionsFOXM1 can be a useful marker for predicting patients’ prognosis and monitoring docetaxel response, and might be a new therapeutic target in docetaxel resistant gastric cancer.

The mitochondrial calcium uniporter (MCU) maintains intracellular Ca2+ homeostasis by transporting Ca2+ from the cell cytosol into the mitochondrial matrix and is important for shaping Ca2+ signals and the activation of programmed cell death. Inhibition of MCU by ruthenium red (RR) or Ru360 has previously been reported to protect against neuronal death. The aim of the present study was to analyze the mechanisms underlying the effects of MCU activity in a rat model of cerebral ischemia/reperfusion (I/R) injury. Adult male Wistar rats were divided into 4 groups; sham, I/R, I/R + RR and I/R + spermine (Sper) and were subjected to reversible middle cerebral artery occlusion for 2 h followed by 24 h of reperfusion. A bolus injection of RR administered 30 min prior to ischemia was found to significantly decrease the total infarct volume and reduce neuronal damage and cell apoptosis compared with ischemia/reperfusion values. However, treatment with Sper, an activator of the MCU, increased the injury induced by I/R. Analysis of energy metabolism revealed that I/R induced progressive inhibition of complexes I‑IV of the electron transport chain, decreased ATP production, dissipated the mitochondrial membrane potential and increased the generation of reactive oxygen species. Treatment with RR ameliorated the condition, while spermine had the opposite effect. In conclusion, blocking MCU was demonstrated to exert protective effects against I/R injury and this process may be mediated by the prevention of energy failure.

Cytokeratin 19 (CK-19) is a prognostic indicator of recurrence and metastasis of hepatocellular carcinoma (HCC) following radical resection. To investigate the role of CK-19 in assessment of early recurrence and prognosis in patients with hepatitis B virus (HBV)-related HCC following radical resection. In total, 235 patients with HBV-related HCC (age, 15–82 years; mean age, 54 ± 10 years) undergoing radical resection were screened for inclusion from January 2005 to December 2010. Malignant tissues and adjacent non-malignant tissues were sampled during surgery, and CK-19 and Ki-67 expression was determined by tissue microarray and immunohistochemistry. CK-19 mRNA levels in 30 randomly selected frozen HCC specimens were examined by reverse transcription polymerase chain reaction from January 2011 to June 2011. Correlations of CK-19 and Ki-67 expression with tumor recurrence, metastasis, disease-free survival (DFS), and overall survival (OS) were analyzed. Elevated CK-19 expression was correlated with early recurrence (P = 0.001), shorter DFS (P = 0.001), and reduced OS (P = 0.010). CK-19 expression was correlated with the Ki-67 index (P = 0.037), histological differentiation (P = 0.016), focal number (P = 0.044), and blood vessel tumor embolism (P = 0.002). Patients with metastasis within 1 year exhibited stronger CK-19 expression than did patients without metastasis (P < 0.05). Furthermore, early recurrence was associated with elevated CK-19 mRNA levels (χ2 = 5.761, P = 0.016).When confirmed by a low alpha-fetoprotein concentration (

Summary PRINCIPLES: Platinum agents cause DNA cross-linking and oxidative damage. Genetic polymorphisms of GSTP1 and XRCC1 involved in glutathione metabolic and DNA repair pathways may explain inter individual differences in chemosensitivity and clinical outcome in NSCLC patients treated with platinum-based regimens. METHODS: We used DNA sequencing methods to evaluate genetic polymorphisms of the GSTP1A313G and XRCC1G28152A in 111 patients with stage IV NSCLC treated with platinum-based chemotherapy. Clinical response was evaluated according to RECIST criteria after 2–3 cycles of chemotherapy and time to progression (TTP) was calculated from the time of initial treatment to disease progression. RESULTS: GSTP1A313G and XRCC1G28152A polymorphisms, both alone and in combination, were significantly associated with response to treatment and clinical outcome (p

e12007 Background: Resistance to docetaxel, a chemotherapy drug for breast cancer treatment, occurs in about 50% of patients, and the underlying molecular mechanisms of drug resistance are not fully understood. Gene regulation through miR-141 has been shown to play an important role in cancer drug resistance. This study investigated the role of miR-141 expression in breast cancer cells of acquired docetaxel resistance. Methods: We detected miR-141 expression in docetaxel-resistant (MCF-7/DTX, MDA-MB-231/DTX) and docetaxel-sensitive (MCF-7, MDA-MB-231) breast cancer cells and then focused on its roles in regulation of docetaxel chemoresistance. We also identified EIF4E as a novel target of miR-141 by luciferase assay. Results: Inhibition of miR-141 enhanced response to docetaxel in MCF-7/DTX and MDA-MB-231/DTX cells, respectively; whereas overexpression of miR-141 confered the resistance in MCF-7, MDA-MB-231 cells, respectively. By directly targeting EIF4E mRNA, miR-141 acts on genes that are necessary for...

Background NPM, TFF3 and TACC1 are molecular markers that play important roles in cell differentiation. Herein, we investigated their prognostic impact in patients with primary gastric cancer (GC) and determined whether they could be used as markers of more aggressive gastric carcinomas by detecting the extent of expression in human gastric carcinoma samples. Methodology/Principal Findings Tumor tissue specimens from 142 GC patients were retrospectively retrieved and immunohistochemically evaluated. Correlations between NPM, TFF3 and TACC1 over-expression and clincopathologic parameters, and their prognostic values were investigated with χ2, Kaplan-Meier method, and Cox uni- and multivariate survival models. NPM, TFF3 and TACC1 expression was significantly higher in GC patients with poorly differentiated histologic type than that in patients with well differentiated histologic type. NPM expression was significantly higher in patients with hepatic metastasis or recurrence than that in patients without metastasis. TFF3 expression was significantly higher in patients with positive lymph node metastasis than that in patients with negative lymph node metastasis. Age, lymph node metastasis, and TFF3 and TACC1 over-expression were significantly correlated with low survival (P