Urothelial carcinoembryonic antigen 1 score for early detection of prostate cancer and risk prediction.

UCA1 score appears useful in detecting nonhigh-risk (including very low-, low-, or intermediate-risk) prostate cancer. Combination of the PSA level and the UCA1 score may significantly reduce the burden of prostate biopsy.

The rs2839698 Single Nucleotide Polymorphism of lncRNA H19 is Associated with Post-Operative Prognosis in T3 Gastric Adenocarcinoma.

BACKGROUND: It has been widely demonstrated that long non-coding RNA H19 (lncRNA H19) plays an important role in the progression of various human cancers. However, the associations of common genetic variations with recurrence and survival in gastric adenocarcinoma in this lncRNA remain largely unknown. METHODS: The rs2839698 single nucleotide polymorphism (SNP) of H19 was genotyped in tissue samples from 441 patients with T3 gastric adenocarcinoma who had surgical operations between 2004 to 2009, and the relationships between the different genotypes and recurrence and survival after surgery alone (n = 156) or surgery plus chemotherapy (n = 285) were assessed using 3 different statistical-methods. RESULTS: Based on the final day of investigation (November 2014), the GA genotype was significantly associated with recurrence and survival in patients treated with surgery alone, but not in patients treated with surgery plus chemotherapy. In patients treated with surgery alone, individuals with the GA genotype had significantly lower risks of recurrence and death [adjusted hazard ratio (HR) 0.57, 95% CI 0.37 - 0.88; adjusted HR: 0.58, 95% CI 0.38 - 0.88] than the GG genotype (p = 0.010 and p = 0.010), respectively. More importantly, patients treated with surgery alone who carried the GA genotype achieved significantly longer median disease-free survival time and overall survival than carriers of the GG genotype (45 vs. 26 months, p = 0.010; 44 vs. 23 months, p = 0.013). CONCLUSIONS: The rs2839698 SNP of H19 may have potential as a novel prognostic factor for survival in T3 gastric adenocarcinoma after surgery alone; these finding have special relevance to patients who are not suitable for postoperative chemotherapy.

Polymorphisms in matrix metalloproteinases 2, 3, and 8 increase recurrence and mortality risk by regulating enzyme activity in gastric adenocarcinoma.

The association of polymorphisms in matrix metalloproteinases (MMPs) with clinical outcomes of gastric adenocarcinoma has not been examined. Ten polymorphisms in MMP1, 2, 3, 7, 8, 9, 12, and 13 were genotyped and investigated, and patients were followed for an average of 58 months. The activities of MMP2, 3, and 8 were measured. Recurrence risk increased in patients with the MMP2 rs2285053 CC genotype (hazard ratio [HR], 1.85), MMP3 rs679620 AA genotype (HR, 2.15), and MMP8 rs1940475 TT genotype (HR, 2.22) on recurrence free survival (RFS). Co-presence of the unfavorable MMP2 rs2285053 CC and MMP8 rs1940475 TT genotypes resulted in an additional increased risk of recurrence (RFS: HR, 4.42; 95% confidence interval [CI], 2.15-9.09; p<0.0001) and risk of death (overall survival ( OS) : HR, 6.59; 95% CI, 3.15-13.19; p<0.0001). Theoretical survival tree analysis revealed that recurrence-free survival significantly varied from 15.5 to 87 months among patients with different polymorphisms in MMP2, 3, and 8. The enzymatic activities of MMP2 and MMP3 increased (MMP2 rs2285053 CC: 888.60 vs. CT: 392.00, p <0.0001; MMP3 rs679620 AA: 131.10 vs. GG: 107.74, p=0.015), whereas those of MMP8 decreased (MMP8 rs1940475 TT: 133.78 vs. CC: 147.54, p=0.011) in gastric cancer tissues. These results suggest that polymorphisms in MMP2, 3, and 8 may increase cancer recurrence and patient death by increasing or decreasing enzyme activity in patients with gastric adenocarcinoma.

Circular RNAs expression profiles in human gastric cancer.

Circular RNAs (circRNAs) are implicated in a variety of cancers. However, the roles of circRNAs in gastric cancer (GC) remain largely unknown. In the current study, circRNAs expression profiles were screened in GC, using 5 pairs of GC and matched non-GC tissues with circRNA chip. Preliminary results were verified with quantitative PCR (qRT-PCR). Briefly, total of 713 circRNAs were differentially expressed in GC tissues vs. non-GC tissues (fold change ≥ 2.0, p < 0.05): 191 were upregulated, whereas 522 were downregulated in GC tissues. qRT-PCR analysis of randomly selected 7 circRNAs from the 713 circRNAs in 50 paired of GC vs. non-GC control tissues confirmed the microarray data. Gene ontology (GO) and KEGG pathway analyses showed that many circRNAs are implicated in carcinogenesis. Among differentially expressed circRNAs, hsa_circ_0076304, hsa_circ_0035431, and hsa_circ_0076305 had the highest magnitude of change. These results provided a preliminary landscape of circRNAs expression profile in GC.

High expression of EGFR predicts poor survival in patients with resected T3 stage gastric adenocarcinoma and promotes cancer cell survival.

Epidermal growth factor receptor (EGFR) is an essential regulator and biomarker of several types of cancer. However, the association between its expression and prognosis in patients with resected T3 stage gastric adenocarcinoma (RT3-GA) remains to be determined. In total, 683 patients with resectable T3-GA who underwent surgery were retrospectively included in the present study, and their immunohistochemical data for EGFR expression were collected. The associations between the patients' clinicopathologic characteristics and EGFR immunohistochemistry data were analyzed by multiple statistical methods. Annexin V apoptosis and MTT cell viability assays were performed to explore the effect of EGFR on AGS gastric adenocarcinoma cell survival. EGFR expression levels were categorized into two groups: low (406 cases) and high (277 cases). High EGFR was demonstrated to be significantly associated with distant metastasis (P=0.043) and severely decreased median overall survival time (MOST) and recurrence-free survival time (MRFST). MOST and MRFST in the low EGFR group were 39 and 37 months, respectively; whereas in the high EGFR group these values were only 18 and 13 months (P=3.10×10-9 and P=6.74×10-8, respectively). Multivariate analysis confirmed that high EGFR expression levels were associated with poor survival, which was associated with significantly increased recurrence risk and ~2-fold elevation in mortality risk [hazard ratio (HR), 1.73; 95% confidence interval (CI), 1.43-2.10; P=2.37×10-8 and HR, 1.80; 95% CI, 1.50-2.17; P=3.80×10-10]. Inhibiting EGFR with AG1478 suppressed its effect on promoting AGS cell survival. These results suggest that high EGFR expression indicates poor survival in patients with RT3-GA, which may be correlated with EGFR promoting GA cell survival.

Expression and prognostic significance of cyclin-dependent kinase inhibitor 1A in patients with resected gastric adenocarcinoma.

Cyclin-dependent kinase inhibitor 1A (CDKN1A) is an important cell cycleregulator, and has been identified to exhibit aberrant expression in various types of cancer tissues. However, the association between CDKN1A expression level and prognosis in patients with resected gastric adenocarcinoma (RGA) requires additional elucidation. In the present study, the CDKN1A expression profile in RGA tissues obtained from 217 patients were analyzed using immunohistochemistry. Its prognostic significance was evaluated by using the χ2 test, Kaplan-Meier curves and the log-rank test, and a multivariate Cox model analysis, during a median follow-up time of 51 months. The results demonstrated that CDKN1A expression was significantly correlated with lymph node metastasis (LNM; P=0.001), recurrence (P<0.001) and overall survival (OS; P<0.001). In addition, the recurrence-free survival (RFS) and OS times were significantly shorter in patients with low CDKN1A expression compared with those with high CDKN1A expression (RFS, 20 months vs. 69 months, P<0.001; and OS, 32 months vs. 70 months, P<0.001, respectively). Multivariate analysis additionally confirmed that low CDKN1A expression was significantly correlated with an increased risk of LNM (P=0.001), recurrence (P<0.001) and mortality (P<0.001). Therefore, these data suggest that low expression of CDKN1A has independent prognostic significance indicative of tumor progression and poor survival in patients with RGA. Evaluation of CDKN1A expression may assist in determining prognosis in patients with RGA.

The Value of Preoperative Neutrophil to Lymphocyte Ratio in Indicating Lymph Node Metastasis in Patients with Resectable T2 Stage Gastric Adenocarcinoma.

BACKGROUND: Lymph node metastasis (LNM) is closely associated with poor prognosis in patients with resectable T2 stage gastric adenocarcinoma (RT2-GA). Preoperative blood neutrophil to lymphocyte ratio (NLR) has been identified to be a very valuable predictor for prognosis in patients with diverse cancers. The aim of this investigation was to assess the relationship between NLR and LNM in RT2-GA. METHODS: This retrospective study reviewed 230 patients who underwent surgery for removal of primary T2-GA from August 2002 to December 2013 in a single hospital. Preoperative routine blood test data were collected and the relationship between NLR and LNM in RT2-GA was evaluated by X2 test and multivariate logistic regression analysis. RESULTS: The median value of NLR was 2.18 among 230 patients. Based on the median NLR value, the patients were categorized into two groups: low NLR group (NLR ≤ 2.18) and high NLR group (NLR > 2.18). χ2 test results exhibited that the preoperative NLR was significantly associated with the numbers of metastatic lymph nodes (≤ 6 and > 6) (p = 0.003) and status of lymph node involvement (N0, N1, and N2 stage) (p = 0.032). Multivariate analyses further confirmed that NLR > 2.18 was significantly associated with increased risk of appearing more numbers of metastatic lymph node or higher N stage which exhibited a 4.15- or 7.09-fold elevated risk compared to that of NLR ≤ 2.18. CONCLUSIONS: The preoperative NLR is closely associated with LNM in patients with RT2-GA, which may be used as a predictor indicating more serious LNM in this type of cancer.

SNP rs1059234 in CDKN1A Gene Correlates with Prognosis in Resected Gastric Adenocarcinoma.

BACKGROUND: Cyclin-dependent kinase inhibitor 1A (CDKN1A) and Cyclin D1 (CCND1) play essential roles in the regulation of cell cycle progression and are closely associated with human cancer. CDKN1A and CCND1 single nucleotide polymorphisms (SNPs) have been demonstrated to influence the prognosis in humans with different cancers. However, their roles in the prognosis of patients with resected gastric adenocarcinoma (RGA) remain to be determined. METHODS: Genotypes of CDKN1A rs1059234 and CCND1 rs603965 SNPs were performed in 235 tissue samples from RGA. The association of the genotypes of these two SNPs with the prognosis in the patients with RGA was analyzed by X2 test, multivariate Cox regression analyses, and Kaplan Meier curves. RESULTS: During the 50 months of median follow-up time, the overall recurrence and survival rate in the whole group was 57.4% and 46.8%, respectively. Whereas, recurrence and survival rate in patients with CC genotype of rs1059234 located in 3'UTR of CDKN1A were 78.0% and 27.1% (p = 0.004; p = 0.006). Multivariate analyses further confirmed that the CC genotype was significantly related with both increased recurrence and death risk (HR 3.33, 95% CI 1.95-5.70; p = 1.07 x 10⁻5, and HR 3.45, 95% CI 1.95-6.10; p = 2.03 x 10⁻5). No significant difference among CCND1 rs603965 SNP with the prognosis was determined. CONCLUSIONS: rs1059234 of CDKN1A is closely associated with the prognosis in patients with RGA.

Elevated Preoperative Platelet to Lymphocyte Ratio Indicates Poor Survival in Patients with Resected High-grade Serous Ovarian Carcinoma.

BACKGROUND: Platelet to lymphocyte ratio (PLR) is widely used as an inflammation-related cancer biomarker. However, since its prognostic importance in resected high-grade serous ovarian carcinoma (HGSC) is still unknown, we investigated the association between PLR and the prognosis in resected HGSC in this study. METHODS: Details of 103 patients with HGSC who underwent ovarian resection were collected in this retrospective study. Preoperative PLR was calculated based on platelet and lymphocyte count values. A χ2 test was used to analyze the relationship between PLR and clinical variables, a Kaplan-Meier curve and log rank analysis was used to evaluate overall survival, and multivariable analysis was used to analyze the prognostic factors. RESULTS: The preoperative PLR median value (188.8) was used to divide patients into two groups: the high PLR group (PLR > 188.8) and low PLR group (PLR ≤ 188.8). A high PLR was significantly associated with a higher death rate (81.6% vs. 59.3%, p = 0.013) and a shorter median overall survival time (37 months vs. 58 months, p = 0.035) during follow-up (median length = 43 months). Multivariable data further demonstrated that a high PLR was related to a two-fold increase in risk of death (hazard ratio [HR]: 2.19, 95% confidence interval (CI): 1.30 - 3.68, p = 0.003). In addition, the risk of a CA125 of > 640.0 U/mL was significantly greater in the high PLR group (odds ratio [OR]: 2.72, 95% CI: 1.18 - 6.27, p = 0.019). Multivariable analysis suggests that PLR was an independent prognostic factor for resected HGSC. CONCLUSIONS: PLR has potential as a prognostic biomarker for predicting the survival of patients with resected HGSC.

Single Nucleotide Polymorphism of the Enhancer of Zeste Homolog 2 Gene rs2072408 is Associated with Lymph Node Metastasis and Depth of Primary Tumor Invasion in Gastric Cancer.

BACKGROUND: The single nucleotide polymorphism (SNP) rs2072408 is located in an intron of the enhancer of zeste homolog 2 (EZH2) gene. Its role in gastric cancer (GC) has not been determined. METHODS: In the present study, the genotype of (EZH2) rs2072408 and the relationship of genotype with lymph node metastasis (LNM) and the invasive depth of gastric wall (T stage) was determined in 330 patients with GC, and the association between the genotype and recurrence and survival was determined in 253 patients with GC. RESULTS: The TT genotype was identified to be significantly associated with LNM [P = 0.013; odds ratio (OR), 6.49 (95% confidence interval (CI), 1.47 - 28.59)] and T stage [T1 + T2 vs. T3 + T4, p = 0.017, OR, 3.02 (95% CI, 1.22 - 7.44)]. The overall rates of LNM and T3 + T4 stage in the present study were 70.6% and 60.6%, respectively, the rates increased 23.8% and 20.0% in patients with the TT genotype. CONCLUSIONS: These results suggest that the TT genotype of EZH2 (rs2072408) was associated with LNM and the depth of gastric wall invasion in patients with GC.

Expression and clinical significance of long non-coding RNA HNF1A-AS1 in human gastric cancer.

BACKGROUND: Increasing evidence has demonstrated that long non-coding RNAs (lncRNAs) play essential roles in the occurrence and development of human cancers, including gastric cancer (GC). However, the functional and clinical significance of lncRNAs are still poorly understood. METHODS: In this study, the expression of LncRNA HNF1A antisense RNA 1 (HNF1A-AS1) was first examined by lncRNAs microarray analysis in 6 GC tissues, and was then further verified by real-time quantitative reverse transcription PCR (qRT-PCR) both in 3 GC cell lines and 161 cases of GC tissues. We also evaluated the association between HNF1A-AS1 expression and clinicopathological features of patients with GC. RESULTS: LncRNAs microarray analysis results exhibited that HNF1A-AS1 was downregulated in GCs tissues (mean fold change 2.06, p < 0.05), which was further confirmed by qRT-PCR. The results from qRT-PCR showed that the expression of HNF1A-AS1 was not only downregulated in three GC cell lines (AGS, BGC-823, and MKN-45) relative to that in a normal gastric mucosal epithelial cell line (GES-1), but also decreased in GC tissues relative to that in paired adjacent non-neoplastic tissues (low expression, 94 of 161; low expression rate, 58.38%). Furthermore, low HNF1A-AS1 expression was associated with tumor size/diameter (p = 0.005, multivariate analysis), levels of serum carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9), and RRM1 expression in tissue samples (p = 0.028, p = 0.009, and p = 0.006, respectively). CONCLUSIONS: Taken together, our data indicate that lncRNA HNF1A-AS1 may be a regulator of GC, and thus, it may have potential as a novel biomarker and treatment target for this type of cancer.

BAX and CDKN1A polymorphisms correlated with clinical outcomes of gastric cancer patients treated with postoperative chemotherapy.

This study aims to examine the correlation between two single nucleotide polymorphisms (SNPs) of apoptosis-related genes and clinical outcomes in gastric cancer. A total of 221 patients with stage T2 and T3 gastric cancer treated with postoperative chemotherapy between 2003 and 2008 were retrospectively collected in this study to explore the association of rs4645878 located in BAX gene and rs1801270 located in CDKN1A gene with survival, recurrence, and toxicity to chemotherapy. Additionally, immunohistochemistry was used to detect the BAX expression in gastric cancer tissues. Patients carrying at least one variant genotype in BAX SNP (rs4645878) showed a significantly increased recurrence risk [hazard ratio (HR) 2.63; 95 % confidence internal (95 % CI) 1.71-4.03] and poor survival (HR 2.89; 95 % CI 1.88-4.44). Moreover, the recurrence and survival rate in patients with GA genotype was 72.7 and 24.7 %, respectively, compared with total recurrence rate of 54.8 %, P = 0.006, and compared with total survival rate of 46.6 %, P = 0.001. In addition, the GA genotype was related to lower BAX expression in gastric cancer tissues. The CDKN1A (rs1801270) mutant genotype was associated with a significantly decreased risk of hematologic toxicity [odds ratio (OR) 0.28; 95 % CI 0.12-0.63]. SNPs located in BAX and CDKN1A genes are closely associated with clinical outcomes in patients with gastric cancer.

A GG allele of 3'-side AKT1 SNP is associated with decreased AKT1 activation and better prognosis of gastric cancer.

PURPOSE: v-akt Murine thymoma viral oncogene homolog (AKT) pathway is critically involved in cancer cell growth, invasion, and survival. We examined the correlation between the genetic variations in molecules of AKT pathway and clinical outcomes of gastric cancer. PATIENTS AND METHODS: Six single nucleotide polymorphisms (SNPs) located in the four core genes of AKT pathway, namely the PIK3CA, PTEN, AKT1, and mTOR, were determined in 221 patients with stage T2 and T3 gastric cancer. Additionally, the activation of AKT1 in gastric cancer tissues was examined by immunostaining. The correlation between SNPs, AKT activation, and the progress of gastric cancer was analyzed after an average of 51-month follow-up. RESULTS: The overall recurrence and survival rate in this study group were 54.8 and 46.6 %, respectively. The recurrence rate was reduced 30.4 %, and the survival rate was increased 33.7 % in patients with GG allele of a 3'-side AKT1 SNP (rs2498804). Significantly, GG allele was associated with lower AKT1 activation in gastric cancer tissues. On the contrary, CC allele of PTEN (rs701848) was associated with the increased risk of recurrence (hazard ratio [HR] 2.06, 95 % CI 1.19-3.58) and patient death (HR 2.01, 95 % CI 1.15-3.53). CONCLUSIONS: The genetic variants in the PI3K/PTEN/AKT especially the GG allele in 3' side of AKT1 are closely related to clinical outcomes of gastric cancer.

IL-1ß-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1/c-fos, MMP2 and MMP9.

BACKGROUND: Interleukin-1ß (IL-1ß) has been implicated in the progression of gastric adenocarcinoma (GA); however, the molecular mechanisms of action of IL-1ß in GA are poorly characterized. P38 and JNK are the major MAPK family members that regulate IL-1ß signaling pathways. Here, we investigated the role of both p38 and JNK in IL-1ß-induced GA cell migration, invasion and metastatic potential. METHODS: The effects of IL-1ß-induced p38 and JNK activation in GA cells were determined using in vitro Transwell migration and invasion assays of MKN-45 and AGS cells, or an in vivo metastasis assay in nude mice. The IL-1ß-induced p38 signaling pathway was further characterized in GA cells. Activation of the IL-1ß/p38 signaling pathway was also assessed in human primary GA tissues by immunohistochemistry. RESULTS: IL-1ß-induced activation of p38 increased GA cell migration and invasion in vitro and promoted the metastatic potential of GA cells in vivo; these effects were attenuated by p38 siRNA or the p38 inhibitor SB202190. MMP2 or MMP9 siRNAs and the MMP2/9 inhibitor BiPS also inhibited IL-1ß-induced GA cell migration and invasion in vitro. IL-1ß-induced p38 activation significantly increased MMP2 and MMP9 mRNA and protein expression and activity. Luciferase reporter assays demonstrated that the activator protein-1 (AP-1) and the AP-1 binding sites of the MMP9 promoter (-670/MMP9) were activated by IL-1ß-induced p38 activation. Phospho-p38 was significantly upregulated in human GA tissues (compared to matched non-neoplastic tissues), and significantly associated with lymph node metastasis, and invasion beyond the serosa. Expression of phospho-p38 significantly correlated with IL-1ß, MMP2, MMP9, and c-fos expression in both human GA tissues and GA cell metastases in the lungs of nude mice. IL-1ß was also capable of activating JNK in GA cells, but activation of JNK was not associated with GA cell migration and invasion. Therefore, IL-1ß-induced the migration and invasion in GA cells were regulated by p38, but not by JNK. CONCLUSIONS: IL-1ß-induced p38 activation and the IL-1ß/p38/AP-1(c-fos)/MMP2 & MMP9 pathway play an important role in metastasis in GA; this pathway may provide a novel therapeutic target for GA.

Deterministic global optimization of molecular structures using interval analysis.

The search for the global minimum of a molecular potential energy surface is a challenging problem. The molecular structure corresponding to the global minimum is of particular importance because it usually dictates both the physical and chemical properties of the molecule. The existence of an extremely large number of local minima, the number of which may increase exponentially with the size of the molecule, makes this global minimization problem extremely difficult. A new strategy is described here for solving such global minimization problems deterministically. The methodology is based on interval analysis, and provides a mathematical and computational guarantee that the molecular structure with the global minimum potential energy will be found. The technique is demonstrated using two sets of example problems. The first set involves a relatively simple potential model, and problems with up to 40 atoms. The second set involves a more realistic potential energy function, representative of those in current use, and problems with up to 11 atoms.