Potentially functional genetic variants in interferon regulatory factor family genes are associated with colorectal cancer survival.

Interferon regulatory factor (IRF) family genes play a critical role in colorectal cancer (CRC) development and impact patient survival. This study evaluated the influence of functional single nucleotide polymorphisms (SNPs) in IRF genes on CRC survival, including functional predictions and experimental validations. Multivariate Cox regression analysis identified three linked SNPs as significant survival predictors, with the rs141112353 T/T genotype in the 3'UTR region of IRF6 significantly associated with decreased survival (HR = 1.60, P = 6E-04). Expression quantitative trait loci (eQTL) analysis indicated that the rs141112353 TA > T alteration reduced IRF6 expression. Dual luciferase assays showed lower activity for the T allele in the presence of hsa-miR-548ap-3p. Data from The Cancer Genome Atlas (TCGA) and other databases confirmed lower IRF6 levels in CRC tissues, correlating with worse survival and inversely with M2 macrophage infiltration. In vitro, IRF6 overexpression inhibited CRC cell proliferation and M2 macrophage polarization by downregulating MIF expression. These findings suggest that the IRF6 rs141112353 TA > T variant significantly affects CRC survival, potentially by enhancing miR-548-ap-3p binding affinity.

An overview on the current status and future prospects in Aspergillus cellulase production.

Cellulase is a new research point besides glucoamylase, amylase, and protease in the enzyme industry. Cellulase can decompose lignocellulosic biomass into small-molecule sugars, which facilitates microbial utilization; thus, it has a vast market potential in the field of feed, food, energy, and chemistry. The Aspergillus was the first strain used in cellulase preparation because of its safety and non-toxicity, strong growth ability, and high enzyme yield. This review provides the latest research and advances on preparing cellulase from Aspergillus. The metabolic mechanisms of cellulase secretion by Aspergillus, the selection of fermentation substrates, the comparison of the fermentation modes, and the effect of fermentation conditions have been discussed in this review. Also, the subsequent separation and purification techniques of Aspergillus cellulase, including salting out, organic solvent precipitation, ultrafiltration, and chromatography, have been declared. Further, bottlenecks in Aspergillus cellulase preparation and corresponding feasible approaches, such as genetic engineering, mixed culture, and cellulase immobilization, have also been proposed in this review. This paper provides theoretical support for the efficient production and application of Aspergillus cellulase.

Complement system-related genes in stomach adenocarcinoma: Prognostic signature, immune landscape, and drug resistance.

Stomach adenocarcinoma (STAD) is one of the most common malignant tumors of the digestive tract, and its survival predictors are critical for precision medicine but have not been fully investigated. The complement system is a complex multistep cascade at the interface of innate and adaptive immunity, which augments the function of antibodies and phagocytes. This study aimed to construct and validate a CSRG signature based on TCGA (The Cancer Genome Atlas) STAD dataset and revalidated it in an external GEO (Gene Expression Omnibus) STAD cohort. Subsequently, we assessed the association of risk levels with the stromal and immune cell infiltration level in STAD using the ESTIMATE, single-sample Gene Set Enrichment Analysis (ssGSEA), and Microenvironment Cell Populations-counter (MCP-counter) algorithm. It was found that the CSRG signature, based on three genes (SERPINE1, PROC, and CFHR3), was significantly and independently associated with the OS in TCGA STAD patients (p < 0.001). Subsequently, we found that the high-risk STAD harbors more immune cell infiltration than the low-risk group, and the ESTIMATE results indicated that there exists a more stromal component in the tumor microenvironment of the high-risk groups. Compared to the low-risk group, the high-risk STAD patients had higher expressions of marker genes for immune checkpoint inhibitors (ICIs) and showed higher sensitivity to the chemotherapy agents (rapamycin, nilotinib, 5-fluorouracil, axitinib, DMOG, and JNK inhibitor VIII). The prognostic value of the CSRGs was further validated by nomogram plots, which revealed that it was superior to tumor TNM and pathologic stage. Finally, the three expression levels were evaluated in GES-1, HGC27, and AGS cells by qRT-PCR.

Non-point source pollution loads estimation in Three Gorges Reservoir Area based on improved observation experiment and export coefficient model.

The non-point source (NPS) pollution has become an important limitation to the sustainable development of the Three Gorges Reservoir Area (TGRA) water resources. NPS load estimation research has theoretical and realistic significance for water environment security and water pollution control. Therefore, the TGRA was chosen to be the study area, and the export coefficients of different land-use type were calculated through literature consultation method combined with improved observation experiment. The load of total nitrogen (TN) and total phosphorus (TP) of NPS from different pollution sources including farmland, decentralized livestock and poultry breeding and domestic pollution sources were estimated. The results are shown as follows: the order of TN load of different sources in the TGRA from high to low was land use, livestock and poultry breeding, rural life; the TN from land use was 372% higher than that of rural; the order of TP load of different sources in the TGRA from high to low was livestock and poultry breeding, rural life, land use; the TP from livestock and poultry breeding was 114.5% higher than that of land use. Therefore, control of livestock and poultry sewage discharges was the key practice to limit the TP loss, while the optimization of agricultural management was the key practice to control the loss of TN.

A Four-Gene-Based Prognostic Model Predicts Overall Survival in Patients With Cutaneous Melanoma.

BACKGROUND: Cutaneous melanoma (CM) is one of the most aggressive cancers with highly metastatic ability. To make things worse, there are limited effective therapies to treat advanced CM. Our study aimed to investigate new biomarkers for CM prognosis and establish a novel risk score system in CM. METHODS: Gene expression data of CM from Gene Expression Omnibus (GEO) datasets were downloaded and analyzed to identify differentially expressed genes (DEGs). The overlapped DEGs were then verified for prognosis analysis by univariate and multivariate COX regression in The Cancer Genome Atlas (TCGA) datasets. Based on the gene signature of multiple survival associated DEGs, a risk score model was established, and its prognostic and predictive role was estimated through Kaplan-Meier (K-M) analysis and log-rank test. Furthermore, the correlations between prognosis related genes expression and immune infiltrates were analyzed via Tumor Immune Estimation Resource (TIMER) site. RESULTS: A total of 103 DEGs were obtained based on GEO cohorts, and four genes were verified in TCGA datasets. Subsequently, four genes (ADAMDEC1, GNLY, HSPA13, and TRIM29) model was developed by univariate and multivariate Cox regression analyses. The K-M plots showed that the high-risk group was associated with shortened survival than that in the low-risk group (P < 0.0001). Multivariate analysis suggested that the model was an independent prognostic factor (high-risk vs. low-risk, HR= 2.06, P < 0.001). Meanwhile, the high-risk group was prone to have larger breslow depth (P< 0.001) and ulceration (P< 0.001). CONCLUSIONS: The four-gene risk score model functions well in predicting the prognosis and treatment response in CM and will be useful for guiding therapeutic strategies for CM patients. Additional clinical trials are needed to verify our findings.

Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer.

Notch signaling pathway plays crucial roles in progression of colorectal cancer (CRC), likely affecting overall survival (OS). In a two-stage survival analysis of 1116 CRC patients in East China, we found that one locus at MINAR1 out of 133 genes in the Notch signaling pathway was significantly associated with OS (P < 1 × 10-6 , false discovery rate < 0.01). This locus containing seven single-nucleotide polymorphisms (SNPs) in high linkage disequilibrium (R2 = 1) is located on chromosome 15, of which the MINAR1 rs72430409 G allele was associated with a greater death risk (HR = 1.98, 95% CI = 1.55-2.54, P = 6.8 × 10-8 ). Further analysis of ChIP-sequencing data from the encyclopedia of DNA Elements showed that rs72430409 and rs72630408 were potential cis-regulatory elements for the MINAR1 promoter. Additional expression quantitative trait loci analysis revealed that rs72430409 G>A and rs72630408 A>G were correlated with increased MINAR1 expression levels in both blood cells and colon tissues. Dual luciferase assays revealed that the rs72430409 A allele increased MINAR1 promoter activity. The Cancer Genome Atlas data showed that expression levels of MINAR1 in CRC samples were significantly higher than that in normal colorectal tissue and that high expression of MINAR1 was associated with a shortened OS, likely via activating the epithelial mesenchymal transition (EMT) pathway as shown in the gene-set enrichment analysis. In vitro, RNAi-mediated silencing of MINAR1 led to decreased migration and proliferation in CRC cancer cells, and MINAR1 silencing could downregulate the expression of key effector genes in EMT and glycolysis. Larger cohort studies and further experiments are needed to validate our findings.

Functional genetic variants of CTNNBIP1 predict platinum treatment response of Chinese epithelial ovarian cancer patients.

Chemotherapy resistance remains a blockade for successful treatment and longer overall survival of patients with epithelial ovarian cancer (EOC). CTNNBIP1 is an inhibitor of ß-catenin that is a chemotherapeutic target for EOC treatment. In the present study, we investigated associations between single nucleotide polymorphisms (SNPs) of CTNNBIP1 and platinum treatment response of Han Chinese EOC patients and subsequently performed functional prediction and validation of the resultant SNPs. We found that CTNNBIP1 rs935072 AT/TT variant genotypes were associated with platinum treatment response in the multivariate logistic regression analysis of EOC patients. Specifically, the CTNNBIP1 rs935072 AT/TT genotypes were associated with a decreased risk of developing chemoresistance ([adjusted odds ratio (OR)] = 0.89, 95% confidence interval (CI) = 0.82-0.97 and P=0.010), compared with the AA genotype. Further experiments showed that the underlying mechanism for the CTNNBIP1 rs935072 A>T change in chemotherapy treatment response resulted from a lower binding affinity of miR-27a-3p, thereby leading to up-regulation of the CTNNBIP1 expression. We further found that overexpression of CTNNBIP1 sensitized ovarian cancer cells to platinum treatment. Thus, the present study provides evidence that functional variants of CTNNBIP1 may regulate the expression of CTNNBIP1, a possible mechanism affecting platinum treatment response of EOC patients.

Functional genetic variants of RUVBL1 predict overall survival of Chinese patients with epithelial ovarian cancer.

To date, the 5-year overall survival of epithelial ovarian cancer (EOC) remains poor. Because studies suggest that RUVBL1 may be a chemotherapeutic target for the treatment of cancer, in this study, therefore, we investigated the role of potentially functional single nucleotide polymorphisms (SNPs) of RUVBL1 in the survival of Chinese patients with EOC, and we subsequently performed functional prediction and validation of the identified significant SNPs. We found that RUVBL1 rs1057156 A>G and RUVBL1 rs149652370 A>G were associated with survival of EOC patients in the multivariate Cox proportional hazards regression analysis. Specifically, the RUVBL1 rs149652370 AG genotype was associated with a shorter progression-free survival ([adjusted hazards ratio (HR)] = 3.32, 95% confidence interval (CI) = 1.76-6.25 and P = 2.01E-04), compared with the AA genotype. The RUVBL1 rs1057156 AG (only nine had GG) genotype was also associated with a poor overall survival (adjusted HR = 1.73, 95% CI = 1.19-2.52, P = 0.004), compared with the AA genotype. Further experiments showed that the RUVBL1 rs1057156 A>G change lowered its binding affinity to microRNA-4294 and led to upregulation of the RUVBL1 expression. We further found that overexpression of RUVBL1 promoted cell proliferation and metastatic potential. Overall, RUVBL1 enhanced EOC cell proliferation, invasion and migration presumably by stimulating the process of glycolysis. Thus, this study provides evidence that functional variants of RUVBL1 may regulate its gene expression, a possible mechanism affecting survival of EOC patients and that RUVBL1 may be a potential chemotherapeutic target for the treatment of EOC patients.

Prognostic Significance of Lymph Node Ratio in Ovarian Cancer.

Lymphadenectomy is critical in the clinical prognosis of ovarian cancer patients. Therefore, we assessed whether lymph node ratio (LNR) has predictive value on overall survival (OS) of patients with serous epithelial ovarian cancer (SEOC). A total of 7,815 eligible SEOC patients were identified from the Surveillance, Epidemiology, and End Results (SEER) database, who underwent surgical resection between 1973 and 2013. We used the time-dependent receiver operating characteristic (ROC) curve and the area under curve to determine the optimal cut-off value of LNR. The predictive role of LNR was analyzed by Cox proportional hazards regression model. The effects of LNR and positive lymph nodes (PLN) on OS were evaluated by comparing the time-dependent ROC curves. The time-dependent ROC curves showed that the optimal LNR cut-off value was 42.0% for nodal-positive SEOC. As shown in Kaplan-Meier survival curves, survival was significantly poorer for all patients with LNR≥42.0% (log-rank test: P<0.0001), regardless of the stage. In the multivariate Cox analysis, LNR≥42.0% remained a significant and independent predictor of mortality risk for all patients [hazards ratio: 1.526, 95% confidence interval: 1.415-1.647; P<0.0001], compared with those LNR<42.0%. These results suggest that LNR, rather than the number of PLN or stage, could be regarded as a promising predictor of mortality risk, particularly in stage-III SEOC patients.

How to evaluate the adequacy of staging for nodal-negative epithelial ovarian cancer? Use of nodal staging score.

OBJECTIVE: No guideline has been provided to assess the minimal number of lymph nodes (LNs) that should be dissected for accurate staging in patients with epithelial ovarian cancer (EOC). The aim of the study was to develop a nodal staging score (NSS) as an index to assess whether a pathologic (p)N0 EOC patient is indeed free of a nodal disease. METHODS: A total of 16,361 EOC patients staged I-III between 2004 and 2013 were identified from the Surveillance, Epidemiology and End Result database. With a ß-binomial model, NSS was calculated to assess the probability of true-negative findings of LN status. RESULTS: With an increased number of LNs examined, the probability of missing a nodal disease decreased and varied among different pT stages. Given 1 LN examined, an NSS of 93.76% calculated could ensure a high adequacy of nodal-negative classification for pT1N0 EOC patients. For pT2N0 patients, 5 LNs examined could guarantee an NSS of 90% for adequate staging. Likewise, 11 and 29 LNs examined in pT3N0 patients could maintain NSS at the level of 80% and 90%, respectively. Our study suggested the optimal number of LNs that could be examined and stratified by the pT stages for EOC patients based on this statistical model derived from large pathologic data of clinical surgery patients. CONCLUSION: NSS, as an auxiliary tool, not only could assist the International Federation of Gynecology and Obstetrics staging more precisely, but also would provide a statistical basis for postoperative evaluation for further clinical decision-making.