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Objectives: Coronary artery disease (CAD) severity is associated with patient prognosis. However, few efficient scoring systems have been developed to screen severe CAD in patients with stable angina and suspected CAD before coronary angiography. Here, we present a novel scoring system for CAD severity before elective coronary angiography. Methods: Five hundred fifty-one patients with stable angina who were admitted for coronary angiography were enrolled in this study. Patients were divided into training (n = 347) and validation (n = 204) cohorts. Severe CAD was defined as having a Gensini score of 20 or more. All patients underwent echocardiography (ECG) to detect ejection fraction and aortic valve calcification (AVC). Multivariable analysis was applied to determine independent risk factors and develop the scoring system. Results: In the training cohort, age, male sex, AVC, abnormal ECG, diabetes, hyperlipidemia, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were identified as independent factors for severe CAD by multivariable analysis, and the Severe Prediction Scoring (SPS) system was developed. C-indices of receiver operating characteristic (ROC) curves for severe CAD were 0.744 and 0.710 in the training and validation groups, respectively. The SPS system also performed well during calibration, as demonstrated by Hosmer-Lemeshow analysis in the validation group. Compared with the Diamond-Forrester score, the SPS system performed better for severe CAD prediction before elective coronary angiography. Conclusions: Severe CAD prediction was achieved by analyzing age, sex, AVC, ECG, diabetes status, and lipid levels. Angina patients who achieve high scores using this predicting system should undergo early coronary angiography. [ABSTRACT FROM AUTHOR]

The contribution of diabetes to breast cancer remains uncertain among Chinese females, which may result from different genetic factors. We evaluated the associations of diabetes, combined with the polymorphisms in the genes of fat mass and obesity-associated gene (FTO), interleukin 6 (IL-6), and heat shock protein 60 (HSPD1), with breast cancer risk and survival in a Chinese Han population. The information on the history of diabetes was collected from 1551 incident breast cancer cases and 1605 age-frequency matched controls in Guangzhou, China. In total, 1168 cases were followed up. Diabetes was associated with both an increased risk of breast cancer [OR (95%CI): 1.67 (1.11, 2.52)] and a poor overall survival and progression free survival for breast cancer patients [HRs (95%CIs): 2.66 (1.10, 6.44) and 2.46 (1.29, 4.70), respectively]. IL-6 rs1800796 and HSPD1 rs2605039 had interactions with diabetes on breast cancer risk. Among women with CC genotype of IL-6 rs1800796 or GG genotype of HSPD1 rs2605039, diabetic individuals had a remarkably increased risk of breast cancer compared to non-diabetic women with ORs and 95%CIs of 2.53 (1.45, 4.41) and 6.40 (2.29, 17.87), respectively. GT/TT genotypes of HSPD1 rs2605039 was also associated with a better progression free survival for breast cancer patients [HR (95%CI): 0.70 (0.49, 0.99)]. Our results suggest that the contribution of diabetes to breast cancer risk might be modified by IL-6 rs1800796 and HSPD1 rs2605039. Diabetes and HSPD1 rs2605039 might also influence breast cancer prognosis. [ABSTRACT FROM AUTHOR]

Background: The metastatic rate and risk factors of splenic hilar (No.10) lymph nodes (LNs) in gastric adenocarcinoma were still variable and uncertain, and the prognostic significance of No.10 LNs was also controversial. The aim of this retrospective study was to analyze the metastatic rate, risk factors and prognostic significance of No.10 LNs in gastric adenocarcinoma. Methods: From August 2007 to December 2011, 205 patients who were diagnosed with primary gastric adenocarcinoma and underwent total or proximal gastrectomy plus No.10 LNs dissection in West China Hospital were enrolled. Clinicopathological features and survival outcomes were retrospectively analyzed. Results: Mean numbers of harvested LNs and metastatic LNs were 34.8±12.6 (15–73) and 8.7±10.8 (0–67), respectively. The proportion of cases with positive No.10 LNs was 8.8% (18/205). In all 204 dissected No.10 LNs, 47 LNs (23.0%) were metastatic. In 52.2% (107/205) patients, the dissected splenic hilar tissues were histologically determined as only fat tissues but without LNs structure. Histological evidence of LNs structure was found in 98 (47.8%) patients with 18.4% (18/98) metastatic No.10 LNs. In multivariate logistic regression analysis, metastasis of No.10 LNs was significantly correlated with No.4sa LNs (p = 0.010) and pN stage (p = 0.012). Regarding survival analysis, 199 (97.1%) patients were followed up (0.6–74.8 months). In all patients with R0 resection, metastatic No.10 LNs caused significantly worse prognosis both in Kaplan-Meier (p = 0.006) and Cox regression analysis (p = 0.031). Conclusions: Although the metastatic rate of No.10 LNs was 8.8%, dissection of No.10 LNs might be meaningful due to the poor prognosis of positive cases. And attentions should be also paid to its correlated factors including pN stage and No.4sa LNs. [ABSTRACT FROM AUTHOR]

Monocarboxylate transporter 4 (MCT4) is a cell membrane transporter of lactate. Recent studies have shown that MCT4 is over-expressed in various cancers; however, its role in cancer maintenance and aggressiveness has not been fully demonstrated. This study investigated the role of MCT4 in oral squamous cell carcinoma (OSCC), and found that it is highly expressed in OSCC patients by using immunohistochemistry. Moreover, this over-expression of MCT4 was closely associated with tumor size, TNM classification, lymphatic metastasis, distant metastasis and tumor recurrence, and also poor prognosis. To further study mechanisms of MCT4 in vitro, we used small-interfering RNA to silence its expression in OSCC cell lines. The results showed that knock-down of MCT4 decreased cell proliferation, migration, and invasion. The inhibition of proliferation was associated with down-regulation of p-AKT and p-ERK1/2, while decreased cell migration and invasion may be caused by down-regulation of integrin β4-SRC-FAK and MEK-ERK signaling. Together, these findings provide new insight into the critical role of MCT4 in cell proliferation and metastasis in OSCC. [ABSTRACT FROM AUTHOR]

Steroid receptor coactivator 1 (Src-1) and Twist1 are aberrantly upregulated in a variety of tumors and play an important role in tumor progression. However, the exact role of Src-1 and Twist1 in nasopharyngeal carcinoma (NPC) is uncertain. In this study, we investigated the possible prognostic value and biological effect of Src-1 and Twist1 in NPC. Src-1 and Twist1 expression was detected in a cohort of NPC patients (n = 134) by qRT-PCR. Kaplan-Meier survival analysis was used comparing overall survival (OS) and progression-free survival (PFS). Multivariate analysis was performed using the Cox proportional hazard regression model. Biologic effect of Src-1 and Twist1 in NPC cell lines was evaluated by western blot, colony formation assay, soft agar assay, scratch wound healing assay, transwell invasion assay and tumor xenografts growth. We have found that Src-1 and Twist1 were aberrantly upregulated in human NPC tissues, and associated with advanced tumor stage, distant metastasis and unfavorable prognosis. Knockdown of Src-1 or Twist1 in human NPC cell line CNE-1 suppressed colony formation, anchorage-independent growth, cell migration, invasion and tumor xenografts growth, while enforced expression of Src-1 or Twist1 in human NPC cell line HNE-2 promotes anchorage-independent growth, cell migration and invasion. In addition, Src-1 and Twist1 could suppress E-cadherin expression and increase Vimentin expression, thus suggested that Src-1 and Twist1 enhanced the malignant behaviors of NPC cells via inducing epithelial-mesenchymal transition (EMT). Our data indicated that Src-1 and Twist1 could be possible prognostic biomarkers and potential therapy targets for patients with NPC. [ABSTRACT FROM AUTHOR]

FAM64A, a marker of cell proliferation, has been investigated as a potential biomarker in several cancers. In the present study, we examined the value of FAM64A expression in the diagnosis and prognosis of pancreatic cancer through bioinformatics analysis of data obtained from The Cancer Genome Atlas (TCGA) database. The diagnostic value of FAM64A expression in pancreatic cancer tissue was deteremined through receiver operating characteristic (ROC) curve analysis, and based on the obtained cut-off value, patients were divided into two groups (high FAM64A expression and low FAM64A expression). Chi-square and Fisher exact tests were applied to identify associations between FAM64A expression and clinical features. Moreover, the effect of FAM64A expression in the survival of pancreatic cancer patients was observed by Kaplan-Meier and Cox analyses. Gene set enrichment analysis (GSEA) was performed using the TCGA dataset. Our results showed that high FAM64A expression in pancreatic cancer was associated with survival status, overall survival (OS), and recurrence. The area under the ROC curve was 0.736, which indicated modest diagnostic value. Patients with higher FAM64A expression had significantly shorter OS and recurrence-free survival (RFS) times. Multivariate survival analysis demonstrated that high FAM64A expression was an independent risk factor for OS and RFS. GSEA identified mitotic spindles, myc targets, MTORC1 signaling, G2M checkpoint, E2F targets, DNA repair, glycolysis and unfolded protein response as differentially enriched with the high FAM64A expression phenotype. In conclusion, high FAM64A mRNA expression is an independent risk factor for poor prognosis in pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Numerous studies have shown Kinesin family member 20A (KIF20A) may play a critical role in the development and progression of cancer. However, the clinical value of KIF20A in nasopharyngeal carcinoma (NPC) is unknown. Here, we investigated the expression pattern of KIF20A in NPC and its correlation with clinicopathological features of patients. Methods: Real-time PCR and Western blotting were used to quantify KIF20A expression in NPC cell lines and clinical specimens compared with normal controls. KIF20A protein expression was also examined in archived paraffin embedded tumor samples from 105 patients with pathologically confirmed NPC by immunohistochemistry (IHC). Statistical analyses were applied to assess the associations between KIF20A expression and the clinicopathological features and survival outcomes. Effects on migration and invasion were assessed by wound healing and transwell invasion assays after KIF20A silencing. Results: KIF20A was significantly overexpressed at both the mRNA and protein levels in NPC cell lines and human tumor tissues. 45/105 (42.9%) of NPC specimens expressed high levels of KIF20A among the KIF20A detectable cases. Statistical analysis revealed that high KIF20A expression was significantly associated with gender (P = 0.046), clinical stage (P<0.001), T category (P = 0.022), N category (P<0.001), distant metastasis (P = 0.001) and vital status (P = 0.001). Moreover, Higher KIF20A expression patients had shorter overall survival (OS) and progression-free survival (PFS) (P = 0.001 and P = 0.001; log-rank test). In multivariate analysis, KIF20A was an independent prognostic factor for OS and PFS in the entire cohort (P = 0.033, P = 0.008). Knock down of KIF20A expression significantly suppressed NPC cell’s migration and invasion. Conclusions: KIF20A is overexpressed and may serve as an independent prognostic biomarker in NPC. Targeting KIF20A reduces migration and invasion of NPC cells. [ABSTRACT FROM AUTHOR]

Background: Diabetes has been identified as an adverse prognostic variable which associated with an increased mortality in various cancers, including colorectal, lung, and breast cancers. However, previous studies provided inconsistent results on the association between diabetes and nasopharyngeal carcinoma (NPC). The main aim of this study was to investigate the associations between diabetes mellitus and the survival of NPC patients. Methods: This study was designed as a 1:2 matched case–control study. Cases were patients who met the criteria for the diagnosis of type 2 diabetic mellitus (DM) below. Controls, matched 1:2, were patients who were normoglycemic (NDM). The survival rates were assessed by Kaplan–Meier analysis, and the survival curves were compared using a log-rank test. Multivariate analysis was conducted using the Cox proportional hazard regression model. Results: Both locoregional relapse-free survival (LRRFS) and disease-free survival (DFS) in the NDM group were higher than that in the DM group (p = 0.001 and p = 0.033). Additionally, subset analyses revealed that the differences in OS, LRRFS, and DFS were all significant between the two groups in the N0-N1 subset (p = 0.007, p =.000 and p = 0.002). The LRRFS was higher in the NDM group in the III-IV, T3-T4 and N0-N1 subsets (p = 0.004, p = 0.002 and p =.000). In T3-T4 subset, the NDM group experienced higher DFS than the DM group (p = 0.039). In multivariate analysis, T stage and N stage were found to be independent predictors for OS, DMFS and DFS; chemotherapy was a significant prognostic factor for DMFS and DFS, age for OS, and diabetes for LRRFS and DFS. Conclusions: Type 2 diabetic mellitus is associated with poorer prognosis among patients with NPC. [ABSTRACT FROM AUTHOR]

Single nucleotide polymorphisms of XPA gene have been studied in several cancers such as rs10817938, rs2808668. However, the role of XPA polymorphisms in patients with oral squamous cell carcinoma (OSCC) remains unclear. Thus, we analyzed the association of XPA polymorphisms with OSCC risk, clinicopathological characteristics and prognosis in the present study. TaqMan genotyping was used to evaluate the frequency of rs10817938, rs2808668 polymorphisms in OSCC patients. The prognostic significance of these polymorphisms was evaluated using Kaplan-Meier curves, Log-Rank analyses, and the Cox proportional hazard model. Luciferase reporter assay, RT-PCR and western blot were used to determine whether rs10817938 could influence transcription activity and XPA expression. The results showed that individuals carrying TC and CC genotypes had significantly greater risk of developing OSCC (OR = 1.42, 95% CI 1.04–1.93; OR = 2.75, 95% CI 1.32–5.71, respectively) when compared with wild-type TT genotype at rs10817938. OSCC patients with C allele at rs10817938 were more susceptible to lymph metastases, poor pathological differentiation and late TNM stage (OR = 1.67, 95% CI 1.17–2.37; OR = 1.64, 95% CI 1.18–2.28; OR = 1.54, 95% CI 1.11–2.14; respectively). A significant gene-environment interaction between smoking and CC genotype at rs10817938 was observed (COR = 3.60, 95% CI 1.20–10.9) and data also showed that OSCC patients with CC genotype and C allele had worse survival (p<0.001 for both). The T to C substitution at rs10817938 significantly decreased transcription activity of XPA gene, XPA mRNA and protein were also decreased in individuals with C allele at rs10817938. In addition, no significant association of rs2808668 polymorphism with OSCC risk, prognosis could be observed. In conclusion, the present study showed that XPA rs10817938 polymorphism is a functional SNP in vitro and in vivo and a biomarker for poor prognosis in OSCC patients. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 gene mutations are found in most World Health Organization grade II and III gliomas and secondary glioblastomas. Isocitrate dehydrogenase 1 mutations are known to have prognostic value in high-grade gliomas. However, their prognostic significance in low-grade gliomas remains controversial. We determined the predictive and prognostic value of isocitrate dehydrogenase 1 status in low-grade gliomas. The association of isocitrate dehydrogenase 1 status with clinicopathological and genetic factors was also evaluated. Clinical information and genetic data including isocitrate dehydrogenase 1 mutation, O 6-methylguanine DNA methyltransferase promoter methylation, 1p/19q chromosome loss, and TP53 mutation of 417 low-grade gliomas were collected from the Chinese Glioma Genome Atlas database. Kaplan–Meier and Cox proportional hazards regression analyses were performed to evaluate the prognostic effect of clinical characteristics and molecular biomarkers. Isocitrate dehydrogenase 1 mutation was identified as an independent prognostic factor for overall, but not progression-free, survival. Notably, isocitrate dehydrogenase 1 mutation was found to be a significant prognostic factor in patients with oligodendrogliomas, but not in patients with astrocytomas. Furthermore, O 6-methylguanine DNA methyltransferase promoter methylation (p = 0.017) and TP53 mutation (p < 0.001), but not 1p/19q loss (p = 0.834), occurred at a higher frequency in isocitrate dehydrogenase 1-mutated tumors than in isocitrate dehydrogenase 1 wild-type tumors. Younger patient age (p = 0.041) and frontal lobe location (p = 0.010) were significantly correlated with isocitrate dehydrogenase 1 mutation. Chemotherapy did not provide a survival benefit in patients with isocitrate dehydrogenase 1-mutated tumors. Isocitrate dehydrogenase 1 mutation was an independent prognostic factor in low-grade gliomas, whereas it showed no predictive value for chemotherapy response. Isocitrate dehydrogenase 1 mutation was highly associated with O 6-methylguanine DNA methyltransferase promoter methylation and TP53 mutation. [ABSTRACT FROM AUTHOR]

The tissue inhibitors of metalloproteinases (TIMPs) are proteins that specifically inhibit the proteolytic activity of the matrix metalloproteinases (MMPs). TIMP-3, the only member of the TIMPs that can tightly bind to the extracellular matrix, has been identified as a unique tumor suppressor that demonstrates the ability to inhibit tumor angiogenesis, invasion, and metastasis. This study aimed to detect the expression of TIMP-3 in hepatocellular carcinoma (HCC) and investigate the association between TIMP-3 expression and its clinicopathological significance in HCC patients. In the current study, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting of HCC cell lines and one-step quantitative reverse transcription PCR (qPCR) and immunohistochemistry (IHC) analyses in HCC tissues were performed, to characterize the TIMP-3 expression. Kaplan-Meier survival and Cox regression analyses were utilized to evaluate the prognosis of 101 HCC patients. The results showed that the expression of TIMP-3 in HCC was significantly decreased relative to that of non-cancerous cells and tissues. Furthermore, the TIMP-3 expression was statistically associated with malignant behaviors of HCC, including portal vein invasion (p = 0.036) and lymph node metastasis (p = 0.030). Cox regression analysis revealed that TIMP-3 expression was an independent prognostic factor for disease-free survival (p = 0.039) and overall survival (p = 0.049). These data indicate that TIMP-3 expression is a valuable prognostic biomarker for HCC and that TIMP-3 expression suggests a favorable prognosis for HCC patients. [ABSTRACT FROM AUTHOR]

Aims: Multiple studies have investigated the prognostic role of red blood cell distribution width (RDW) for patients with heart failure (HF), but the results have been inconsistent. The aim of the present study was to estimate the impact of RDW on the prognosis of HF by performing a systematic review and meta-analysis. Methods and Results: The Embase, PubMed, and Web of Science databases were searched up to November 16, 2013 to identify eligible cohort studies. The quality of each study was assessed using the Newcastle-Ottawa Scale (NOS). The association between RDW, either on admission or at discharge, and HF outcomes (all-cause mortality [ACM], heart transplantation, cardiovascular mortality, and rehospitalization, etc.) were reviewed. The overall hazard ratio (HR) for the effect of RDW on ACM was pooled using a random-effects model, and the publication bias was evaluated using funnel plots and Eggers' tests. Seventeen studies, with a total of 18288 HF patients, were included for systematic review. All eligible studies indicated that RDW on admission and RDW at discharge, as well as its change during treatment, were of prognostic significance for HF patients. The HR for the effect of a 1% increase in baseline RDW on ACM was 1.10 (95% confidence interval: 1.07–1.13), based on pooling of nine studies that provided related data. However, publication bias was observed among these studies. Conclusions: HF patients with higher RDW may have poorer prognosis than those with lower RDW. Further studies are needed to explore the potential mechanisms underlying this association. [ABSTRACT FROM AUTHOR]

The prognosis of glioma patients is usually poor, especially in patients with glioblastoma (World Health Organization (WHO) grade IV). The regulatory functions of microRNA (miRNA) on genes have important implications in glioma cell survival. However, there are not many studies that have investigated glioma survival by integrating miRNAs and genes while also considering pathway structure. In this study, we performed sample-matched miRNA and mRNA expression profilings to systematically analyze glioma patient survival. During this analytical process, we developed pathway-based random walk to identify a glioma core miRNA-gene module, simultaneously considering pathway structure information and multi-level involvement of miRNAs and genes. The core miRNA-gene module we identified was comprised of four apparent sub-modules; all four sub-modules displayed a significant correlation with patient survival in the testing set (P-values≤0.001). Notably, one sub-module that consisted of 6 miRNAs and 26 genes also correlated with survival time in the high-grade subgroup (WHO grade III and IV), P-value = 0.0062. Furthermore, the 26-gene expression signature from this sub-module had robust predictive power in four independent, publicly available glioma datasets. Our findings suggested that the expression signatures, which were identified by integration of miRNA and gene level, were closely associated with overall survival among the glioma patients with various grades. [ABSTRACT FROM AUTHOR]

Background: Mechanism of radioresistance in rectal carcinoma remains largely unknown. We aimed to evaluate the predictive role of ATP-binding cassette subfamily C member 4 (ABCC4) in locally advanced rectal carcinoma and explore possible molecular mechanisms by which ABCC4 confers the resistance to neoadjuvant radiotherapy. Methods: The expression of ABCC4 and P53 mutant in biopsy tissue specimens from 121 locally advanced rectal carcinoma patients was examined using immunohistochemistry. The factors contributing to 3-year overall survival and disease-free survival were evaluated using the Kaplan-Meier method and Cox proportional hazard model. Lentivirus-mediated small hairpin RNA was applied to inhibit ABCC4 expression in colorectal carcinoma cell line RKO, and investigate the radiosensitivity in xenograft model. Intracellular cyclic adenosine monophosphate concentration and cell cycle distribution following irradiation were detected. Results: High expression of ABCC4 and p53 mutant in pretreated tumors, poor pathological response, and high final tumor staging were significant factors independently predicted an unfavorable prognosis of locally advanced rectal carcinoma patients after neoadjuvant radiotherapy. Down-regulation of ABCC4 expression significantly enhanced irradiation-induced suppression of tumor growth in xenograft model. Furthermore, down-regulation of ABCC4 expression enhanced intracellular cyclic adenosine monophosphate production and noticeable deficiency of G1-S phase checkpoint in cell cycle following irradiation. Conclusions: Our study suggests that ABCC4 serves as a novel predictive biomarker that is responsible for the radioresistance and predicts a poor prognosis for locally advanced rectal carcinoma after neoadjuvant radiotherapy. [ABSTRACT FROM AUTHOR]