Lipid metabolism-associated genes serve as potential predictive biomarkers in neoadjuvant chemoradiotherapy combined with immunotherapy in rectal cancer.

BACKGROUND: The aim of this study was to investigate the potential role of lipid metabolism-associated genes (LMAGs) in neoadjuvant chemoradiotherapy (nCRT) and immunotherapy for rectal cancer. METHODS: Differential LMAGs were characterized and functional enrichment analysis was performed. Multiple machine learning algorithms were combined to explore candidate LMAGs. ROC analysis was performed to evaluate the predicting accuracy of candidate LMAGs. The expression patterns, prognostic value, genetic alterations, and immune cell infiltration of the top-ranked LMAGs were investigated. RESULTS: We identified 45 LMAGs that were differentially expressed in tumor samples of nCRT responders and non-responders. These LMAGs were closely associated with lipid metabolism-related biological processes and pathways. ROC analysis revealed that the SREBF2 gene, an important transcription factor in regulating lipid metabolism, was the highest predictor of nCRT in rectal cancer. SREBF2 was highly expressed in rectal cancer tissues and high expression of SREBF2 was associated with favorable prognosis. Multivariate analysis showed that SREBF2 was an independent prognostic factor, and we integrated it with other clinical factors to establish an effective prognostic nomogram. SREBF2 also played a synergistic role with its co-expressed genes in the prognostic process of rectal cancer. Furthermore, SREBF2 was demonstrated to be closely associated with multiple immune infiltrating cells, and immunotherapy-related genes and may be used to predict the response to immunotherapy. CONCLUSION: Our study suggests that LMAGs may serve as promising biomarkers in nCRT combined with immunotherapy for rectal cancer. However, large-scale clinical trials and biological experiments are necessary to demonstrate the efficacy and underlying mechanisms.

CYFIP2 serves as a prognostic biomarker and correlates with tumor immune microenvironment in human cancers.

BACKGROUND: The mechanisms whereby CYFIP2 acts in tumor development and drives immune infiltration have been poorly explored. Thus, this study aimed to identifying the role of CYFIP2 in tumors and immune response. METHODS: In this study, we first explored expression patterns, diagnostic role and prognostic value of CYFIP2 in cancers, particularly in lung adenocarcinoma (LUAD). Then, we performed functional enrichment, genetic alterations, DNA methylation analysis, and immune cell infiltration analysis of CYFIP2 to uncover its potential mechanisms involved in immune microenvironment. RESULTS: We found that CYFIP2 significantly differentially expressed in different tumors including LUAD compared with normal tissues. Furthermore, CYFIP2 was found to be significantly correlated with clinical parameters in LUAD. According to the diagnostic and survival analysis, CYFIP2 may be employed as a potential diagnostic and prognostic biomarker. Moreover, genetic alterations revealed that mutation of CYFIP2 was the main types of alterations in different cancers. DNA methylation analysis indicated that CYFIP2 mRNA expression correlated with hypomethylation. Afterwards, functional enrichment analysis uncovered that CYFIP2 was involved in tumor-associated and immune-related pathways. Immune infiltration analysis indicated that CYFIP2 was significantly correlated with immune cells infiltration. In particular, CYFIP2 was strongly linked with immune microenvironment scores. Additionally, CYFIP2 exhibited a significant relationship with immune regulators and immune-related genes including chemokines, chemokines receptors, and MHC genes. CONCLUSION: Our results suggested that CYFIP2 may serve as a prognostic cancer biomarker for determining prognosis and might be a promising therapeutic strategy for tumor immunotherapy.

The clinical implications of circulating microRNAs as potential biomarkers in screening oral squamous cell carcinoma.

Background: Recent studies have highlighted the biomarker role of circulating miRNAs in oral squamous cell carcinoma (OSCC), indicating their potential application as early diagnostic markers for OSCC. However, the diagnostic results have proven inconclusive. This study was conducted to evaluate the diagnostic value of circulating miRNAs for OSCC diagnosis. Methods: Eligible published studies were identified by a literature search carried out in several databases by using combinations of keywords associated with OSCC, circulating miRNAs, and diagnosis. The bivariate meta-analysis model was adopted to summarize the pooled parameters. Afterwards, we thoroughly explored the sources of heterogeneity after evaluating the risk of bias. Results: A total of 60 studies focusing on 41 circulating miRNAs were included. The pooled sensitivity, specificity, and AUC were 0.75 (95%CI: 0.69-0.80), 0.76 (0.70-0.81), 0.82 (0.79-0.85), respectively. Subgroup analyses showed that miRNA combinations were more accurate than single miRNAs. Additionally, plasma may be a better matrix for miRNAs assays in OSCC diagnosis as the plasma-based miRNA assay had a higher level of diagnostic accuracy than serum-based miRNA assay. Subgroup analyses also suggested that using circulating miRNAs for OSCC diagnosis is more effective in Caucasians than in Asian ethnic groups. Finally, circulating miRNA assays based on large sample sizes have superior diagnostic accuracy than small sample sizes. Conclusion: Circulating miRNAs might be applied as effective surrogate biomarkers for early diagnosis of OSCC. Nevertheless, future larger-scale prospective studies should be performed to enhance the diagnostic efficiency and investigate the miRNA combinations with more pronounced accuracy.

Comprehensive evaluation of microRNA-10b in digestive system cancers reveals prognostic implication and signaling pathways associated with tumor progression.

Background: Digestive system cancers (DSCs) have been recognized to be linked with high morbidity and mortality. Recent studies have reported that microRNA-10b (miR-10b) is abnormally expressed in DSCs and associated with prognosis. However, the inconclusive results and unknown underlying mechanisms promoted us to perform this study. Methods: We systematic searched several databases for eligible studies and conducted quantitative analysis for evidence regarding the associations between miR-10b and survival outcome of DSCs. We also performed a series of bioinformatics analyses to uncover the potential mechanisms. Results: A total of 32 eligible studies with 3392 patients were included. Increased miR-10b expression was linked with unfavorable overall survival (OS) in DSCs (HR=1.72; 95% CI: 1.30-2.27; P <0.001). When stratified by tumor type, the impact of miR-10b overexpression on poor prognosis was observed in colorectal cancer, gastric cancer, hepatocellular carcinoma, and esophageal carcinoma, but not in pancreatic cancer. Subsequently, we predicted the targets of miR-10b and conducted functional enrichment analyses. The results disclosed that miR-10b targets were predominantly enriched in some vital biological terms and pivotal signaling pathways associated with tumor progression including cell cycle, FoxO, proteoglycans, central carbon metabolism, p53, Notch, HIF-1, focal adhesion, AMPK, and pancreatic cancer. Moreover, a protein-protein interaction (PPI) network was also constructed to identify the top ten hub genes and significant modules and demonstrated the underlying interactions among them. Conclusion: Our results indicated that miR-10b could act as a significant biomarker in the prognosis DSCs. However, more research should be performed to test these findings.

Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer.

PURPOSE: Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS: We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively (P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION: Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.

Biomarker exploration of microRNA-203 as a promising substrate for predicting poor survival outcome in colorectal cancer.

BACKGROUND: Increasing studies indicated that microRNA-203 (miR-203) may play an important part in the prognosis of CRC. Nevertheless, the prognostic and influential mechanism of miR-203 expression in CRC remains to be inconclusive. Accordingly, we conducted the current study to investigate the biomarker performance of miR-203 in CRC. METHODS: In the present study, we conducted an evidence synthesis of the published literatures to identify the prognostic roles of miR-203 in patients with CRC. Moreover, several bioinformatics methods were applied for exploring the biomarker roles of miR-203. RESULTS: It was demonstrated that elevated miR-203 expression was clearly related to worse overall survival (HR: 1.55, 95% CI: 1.07-2.24, P = 0.021) for CRC. The gene Ontology (GO) analysis indicated that miR-203 targets were primarily involved in a series of GO items closely associated with the molecular pathogenesis of CRC. The pathway analysis exhibited the potential signal pathways of miR-203 involved in CRC including pathways in cancer, wnt pathway, prolactin signaling pathway, proteoglycans in cancer, FoxO pathway, focal adhesion and Ras pathway. By constructing a protein-protein interaction (PPI) network of the targets of miR-203, ten crucial proteins and a significant network module were retrieved and found to serve important roles in the molecular pathogenesis of CRC. CONCLUSIONS: Our results indicated that miR-203 may function as a promising biomarker to monitor CRC survival outcomes and progression. Notably, large-scale prospective cohort studies and biological experiments are required to confirm our conclusions.

Biomarker implication of kallikrein-related peptidases as prognostic tissue substrates of poor survival in colorectal cancer.

BACKGROUND: Recent studies have demonstrated that the kallikrein and kallikrein-related peptidases (KLKs) exhibit aberrant expression in patients with colorectal cancer (CRC) and might be considered as potential prognostic biomarkers of CRC. However, inconsistent findings have been reported, which promote us to summarize the global prognostic roles of KLKs for survival in CRC patients. METHODS: Eligible published studies were identified by searching electronic databases with several search strategies. The patients' baseline characteristics and survival results were extracted from enrolled studies and pooled as combined hazard ratio (HR) with 95% confidence interval (95% CI) to estimate the effect size. RESULTS: A total of 25 and 22 eligible studies were included in the meta-analysis to evaluate the prognostic roles of KLKs on overall survival (OS) and disease-free survival (DFS), respectively. KLKs overexpression was significantly associated with worse OS (pooled HR = 1.43, 95% CI 1.27-1.60, P < 0.001) and short DFS (pooled HR = 1.35, 95% CI 1.21-1.51, P < 0.001). Importantly, subgroup and meta-regression analyses revealed the survival differences among different races and detection methods of KLKs. Furthermore, several specific members of KLKs were identified to be more significantly related to worse OS and DFS compared with other members. CONCLUSION: The present study demonstrated that KLKs may have the potential to serve as promising biomarkers to monitor CRC prognosis and progression. The promising results concerning the utility of KLKs in clinical practice encourage the further investigation of their clinical utility applicability as tumor markers of CRC.

Biomarker roles identification of miR-106 family for predicting the risk and poor survival of colorectal cancer.

BACKGROUND: Recent studies have extensively investigated the roles of miR-106 in colorectal cancer (CRC). However, the associations and molecular mechanism underlying the roles of miR-106 in CRC remain unclear. We aimed to thoroughly investigate the biomarker roles of miR-106 for predicting the risk and survival outcome in CRC. METHODS: We first conducted a comprehensive meta-analysis to quantitatively evaluate the roles of miR-106 in the diagnosis and prognosis of CRC. Then, we qualitatively explored the biomarker roles of miR-106 in CRC through an integrative bioinformatics analysis. RESULTS: The results indicated that miR-106 yielded a combined AUC of 0.79 (95% CI: 0.76-0.83), with a pooled sensitivity of 0.50 (95% CI: 0.32-0.68) and a pooled specificity of 0.93 (95% CI: 0.79-0.98) for discriminating CRC cases from normal controls. Moreover, patients with higher expression of miR-106 were significantly associated with shorter disease-free survival (HR: 1.73; 95%CI: 1.23-2.44) and overall survival (HR: 1.39; 95%CI: 1.09-1.77). Finally, gene ontology and pathway analysis demonstrated that miR-106 family was highly involved in the initiation and progression of CRC and indicated the potential molecular mechanism for miR-106 in CRC. CONCLUSIONS: Our results indicated that miR-106 showed promising potential as diagnostic and prognostic biomarker for CRC. Nevertheless, the underlying molecular mechanism of miR-106 family involved in CRC requires further investigation.

Prognostic implication and functional exploration for microRNA-20a as a molecular biomarker of gastrointestinal cancer.

BACKGROUND: It is generally accepted that microRNA-20a (miR-20a) is aberrantly expressed in gastrointestinal cancer (GIC), and may be associated with the prognosis of GIC patients. Nevertheless, the clinical prognostic value of miR-20a expression in GIC remains controversial. METHODS: We first conducted a comprehensive literature search of the clinical data and pooled them for evidence in assessing prognostic significance of miR-20a expression in GIC. Afterwards, we applied some bioinformatic analysis methods to explore the biological function of miR-20a and explain why miR-20a could act as an effective biomarker. RESULTS: The pooled results showed that enhanced miR-20a expression was significantly associated with poor survival in GIC patients (HR: 1.36; 95%CI: 1.21-1.52; P < 0.001). According to the subgroup analysis, the ethnicity, cancer type, sample source, and sample size may have an impact on the predictive roles for miR-20a. The gene ontologies enriched by the predicted miR-20a targets were highly associated with some important biological processes, cell components and molecular functions. Moreover, a series of prominent pathways linked with GIC carcinogenesis were identified. Ultimately, the crucial targets and modules were identified by constructing the protein-protein interaction network of miR-20a targets, which were highly associated with the initiation and progression of GIC according to previous molecular biology experiments. CONCLUSIONS: Our results indicated that high expression of miR-20a may be a credible indicator of worse prognosis in GIC. Further studies involving biological experiments and larger sample sizes should be performed to validate these findings.

The role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 in esophageal squamous cell carcinoma.

6-phosphofructo-kinase-2/fructose diphosphatase-2 isoenzyme 3 (PFKFB3) is closely related to the growth of many types of cancer cells. Glycolysis not only provides Adenosine triphosphate for the growth of tumor cells, but also protects them from acid products, which is beneficial to the invasion and metastasis of tumors. However, PFKFB3 expression in esophageal squamous cell carcinoma (ESCC) has been scarcely reported. In this study, the role of PFKFB3 was studied in 120 ESCC samples using immunohistochemistry technique (IHC), western blotting, and reverse transcriptase-polymerase chain reaction (RT-PCR). Both PFKFB3 protein and gene expression in ESCC tissues were significantly higher than in adjacent non-tumor tissues (P < .05). Single factor analysis showed that both PFKFB3 protein and gene expression are related to infiltration depth, stage, tumor metastasis, and the degree of tumor differentiation in ESCC. Multifactor Cox survival analysis revealed that PFKFB3 protein expression, tumor location, tumor metastasis, tumor differentiation degree, and tumor stage were independent factors affecting the overall survival of postoperative patients. Multivariate Cox survival analysis showed that PFKFB3 mRNA has a good performance for predicting 3-year survival of patients with ESCC 0.89 (0.79-0.99), with a sensitivity of 0.85 and specificity of 0.77. Encouragingly, the sensitivity and specificity of PFKFB3 in the diagnosis of early ESCC (stage I and stage II) can reach 87.8% and 91.5%. In conclusion, high PFKFB3 protein and gene expression may be associated with the occurrence, development, and prognosis of ESCC. PFKFB3 could be used to help develop new therapeutic and diagnostic strategies for ESCC patients.

Integrated characterization and validation of the prognostic significance of microRNA-200s in colorectal cancer.

BACKGROUND: Accumulating evidence has demonstrated that microRNA-200s (miR-200a, miR-200b and miR-200c) could serve as promising molecular biomarkers for cancer prognosis. Nevertheless, the associations between miR-200s expression and colorectal cancer (CRC) prognosis remain controversial. METHODS: We applied two mainstream approaches combining meta-analysis and bioinformatics analysis to answer whether miR-200s were associated with the prognosis of CRC patients and why miR-200s could be used as prognostic biomarkers for CRC. RESULTS: Consequently, low expression of miR-200s was associated with unfavorable overall survival (OS) in CRC patients (HR: 1.09; 95% CI 1.01-1.17; P = 0.025). According to the subgroup analysis, the prognostic role of miR-200s was more significant for tissue samples, large samples, American patients and miR-200a subgroups. Then the target genes of miR-200s were predicted and applied for functional enrichment analyses. The results showed that the target genes of miR-200s were mainly enriched into some vital ontology subjects such as regulation ability, key cell structures and binding function. Moreover, a series of important signaling pathways were identified, which were significantly linked with the initiation and progression of CRC. Additionally, a protein­protein interaction (PPI) network of miR-200s targets was constructed to screen hub genes and modules. The identified hub genes and modules were validated to be highly involved in the occurrence and development of CRC. CONCLUSIONS: Current evidences revealed that miR-200s could be promising biomarkers for CRC prognosis. However, the findings still need to be validated with more larger-scale prospective studies and biological experiments before miR-200s could be applied into clinical application.

Appropriate reduction of the fragmentation level of subfield sequences to improve the accuracy of field delivery in IMRT for nasopharyngeal carcinoma.

OBJECTIVE: Due to the influence of gravity, inertia and friction, there will be deviation between the position of multileaf collimator (MLC) in the delivered field and the initial intensity modulated radiotherapy (IMRT) plan. This study explores the effects of the fragmentation level of subfield sequences on this deviation and seeks ways to improve the accuracy of field delivery in IMRT for nasopharyngeal carcinoma (NPC). METHODS: 30 patients with NPC were selected, and two groups (groups A and B) of IMRT plans were made in Pinnacle planning system. Different planning parameters were used for optimization so that the subfield sequence fragmentation level of Group B was significantly lower than that of Group A. With the MapCheck2, verification plan was implemented in two ways: 0o gantry angle and the actual treatment angle, then the differences between the two verification results of each group plan were analyzed. RESULTS: The γ-passing rate verified at the actual treatment angle was lower than that of 0o gantry angle for each group plan, whereas the Group B plan shows small reduction. Mean change value (Δ) was decreased from 1.01% (Group A) to 0.40% (Group B) with 3%/3 mm criteria and 2.88% (Group A) to 1.52% (Group B) with 2%/2 mm criteria, respectively. The smaller the difference (Δ), the actual output dose of the field is more consistent with the original plan. There was no significant correlation between this change and the angle of the field. CONCLUSION: Appropriately reducing the fragmentation level of subfield sequence can reduce the effect of field angle on MLC position and improve the delivery accuracy of IMRT plan. ADVANCES IN KNOWLEDGE: The fragmentation level of the subfield sequence may have an impact on the accuracy of the delivery of the plan. This study demonstrates this assumption by comparing the differences between 0° and actual angle verification. Mean change value (Δ) was decreased from Group A to Group B. The smaller the difference (Δ), the actual output dose of the field is more consistent with the original plan. The result of this study may help us to understand that appropriately increasing the subfield area and reducing the fragmentation level of the subfield sequence can reduce the difference between the two verification results, which can further improve the accuracy of the plan delivery in IMRT and tumor treatment.

Comparing hypofractionated to conventional fractionated radiotherapy in postmastectomy breast cancer: a meta-analysis and systematic review.

PURPOSE: To compare the efficacy and toxicity of hypofractionated radiotherapy versus conventional fractionated radiotherapy in postmastectomy breast cancer using meta-analysis. METHODS: The PubMed, EMbase, Cochrane Library, Google Scholar, Wan Fang and CNKI databases were searched to identify controlled clinical trials comparing hypofractionated radiotherapy versus conventional fractionated radiotherapy in postmastectomy breast cancer. Overall survival (OS) was the primary endpoint, and disease-free survival (DFS), locoregional recurrence (LRR), distant metastasis (DM), acute skin toxicity, acute lung toxicity, late skin toxicity, lymphedema,, shoulder restriction, and late cardiac related toxicity were the secondary endpoints. RESULTS: Twenty-five controlled clinical trials involving 3871 postmastectomy breast cancer patients were included in this meta-analysis according to the selection criteria. The meta-analysis revealed that there were no significant differences in OS (OR = 1.08, 95% CI = 0.87~1.33, P = 0.49), DFS (OR = 1.13, 95% CI = 0.91~1.40, P = 0.28), LRR (OR = 1.01, 95% CI = 0.76~1.33, P = 0.96), DM (OR = 1.16, 95% CI = 0.85~1.58, P = 0.34), acute skin toxicity (OR = 0.94, 95% CI = 0.67~1.32, P = 0.72), acute lung toxicity (OR = 0.94, 95% CI = 0.74~1.20, P = 0.62), late skin toxicity (OR = 0.98, 95% CI = 0.75~1.27, P = 0.88), lymphedema (OR = 0.99, 95% CI = 0.77~1.28, P = 0.94), shoulder restriction (OR = 0.75, 95% CI = 0.43~1.31, P = 0.31), or late cardiac related toxicity (OR = 1.17, 95% CI = 0.82~1.65, P = 0.39) between the two groups. CONCLUSIONS: The results of this study show that compared to conventional fractionated radiotherapy, hypofractionated radiotherapy is not significantly different with respect to efficacy or toxicity in postmastectomy breast cancer. Additional large randomized clinical trials are needed to further confirm this conclusion.

Identification of miR-210 and combination biomarkers as useful agents in early screening non-small cell lung cancer.

BACKGROUND: Recently, extensive researches have explored the potential biomarker roles of microRNA-210 (miR-210) in non-small cell lung cancer (NSCLC). Inconsistent results, however, have prevented its widespread use in diagnosis. In the present study, we aimed to clarify the biomarker roles of miR-210 in NSCLC through a comprehensive meta-analysis and an integrative bioinformatics analysis. METHODS: Relevant studies were searched from several literature databases and included for qualitative synthesis based on the bivariate random-effects meta-analysis model. At the same time, we combined several bioinformatics analysis methods for exploring the potential mechanism of miR-210 involved in NSCLC. RESULTS: Overall, miR-210 yieled the area under curve (AUC) of 0.80 (95%CI: 0.76-0.83) with sensitivity of 0.66 (0.59-0.73) and specificity of 0.79 (0.74-0.84) for being applied to discriminate NSCLC cases from normal individuals. Besides, the combination biomarkers based on miR-210 had a higher diagnostic value accuracy than individual miR-210, with the sensitivity of 0.76 (0.72-0.79), specificity of 0.88 (0.86-0.90) and AUC of 0.91 (0.88-0.93). Through bioinformatics analysis including gene ontology, pathway enrichment, protein-protein interaction networks construction and analysis, crucial genes, pathways, modules and functional terms were identified, which were proved highly involved in the initiation and development of NSCLC. CONCLUSIONS: In summary, the current study suggests that miR-210 may function as a potential biomarker in NSCLC detection. Particularly, combination biomarkers may be more comprehensive indicators than single miR-210. However, the clinical diagnostic utilization and additional exploration still remain to be further tested and verified through more future studies.

Development and validation of nomogram combining serum biomarker for predicting survival in patients with resected rectal cancer.

PURPOSE: Nomogram is a widely used tool that precisely predicts individualized cancer prognoses. We aimed to develop and validate a reliable nomogram including serum tumor biomarkers to predict individual overall survival (OS) for patients with resected rectal cancer (RC) and compare the predictive value with the American Joint Committee on Cancer (AJCC) stages. PATIENTS AND METHODS: We analyzed 520 patients who were diagnosed with non-metastatic rectal cancer as training cohort. External validation was performed in a cohort of 11851 patients from the Surveillance, Epidemiology, and End Results (SEER) database. Independent prognostic factors were identified and integrated to build a nomogram using the Cox proportional hazard regression model. The nomogram was evaluated by Harrell's concordance index (C-index) and calibration plots in both training and validation cohort. RESULTS: The calibration curves for probability of 1-, 3-, and 5-year OS in both cohorts showed favorable accordance between the nomogram prediction and the actual observation. The C-indices of the nomograms to predict OS were 0.71 in training cohort and 0.69 in the SEER cohort, which were higher than that of the seventh edition American Joint Committee on Cancer TNM staging system for predicting OS (training cohort, 0.71 vs. 0.58, respectively; P-value < 0.001; validation cohort, 0.69 vs. 0.57, respectively; P-value < 0.001). CONCLUSION: We developed and validated a novel nomogram based on CEA and other factors for predicting OS in patients with resected RC, which could assist clinical decision making and improvement of prognosis prediction for individual RC patients after surgery.

mRNA and lncRNA Expression Profiling of Radiation-Induced Gastric Injury Reveals Potential Radiation-Responsive Transcription Factors.

Radiation-induced gastric injury is a serious concern that may limit the duration and the delivered dose of radiation. However, the genome-wide molecular changes in stomach upon ionizing radiation have not been reported. In this study, mouse stomach was irradiated with 6 or 12 Gy X-ray irradiation and we found that radiation resulted in the atrophy of gastric mucosa and abnormal morphology of chief and parietal cells. Radiation-induced gastric injury was accompanied by an increase in the serum levels of pepsinogen A and pepsinogen C but not gastrin-17. The expression profiles of messenger RNA (mRNA) and long noncoding RNA (lncRNA) in normal and irradiated gastric tissues were measured by microarray analysis. Results revealed 17 upregulated and 10 downregulated mRNAs were consistent in 6 and 12 Gy irradiated gastric tissues, including D site-binding protein (Dbp) and fibrinogen-like protein 1 (Fgl1). Thirteen upregulated and 96 downregulated lncRNAs were commonly changed in 6 and 12 Gy irradiated gastric tissues. The dysregulated mRNAs were implicated in multiple pathways and showed coexpression with lncRNAs. To identify motifs for transcription factors and coactivators in the proximal promoter regions of the dysregulated RNAs, the bioinformatic tool Biopython was used. A variety of common motifs that are associated with transcription factors were identified, including ZNF263, LMX1B, and Dlx1. Our findings illustrate the molecular changes during radiation-induced gastric injury and the potential transcription factors driving this alteration.

Identification of biomarker microRNA-mRNA regulatory pairs for predicting the docetaxel resistance in prostate cancer.

Background: Docetaxel resistance is a cursing problem with adverse effects on the therapeutic efficacy of prostate cancer (PCa), involving interactions among multiple molecular components. Single or limited molecules are not strong enough as prediction biomarkers of drug resistance. Network biomarkers are considered to outperform individual markers in disease characterization. Methods: In this study, key microRNAs (miRNAs) as biomarkers were identified from the PubMed citations and miRNA expression profiles. Targets of miRNAs were predicted and enriched by biological function analysis. Key target mRNAs of the biomarker miRNAs were screened from protein-protein interaction network and gene expression profiles, respectively. The results were validated by the assessment of their predictive power and system biological analysis. Results: With this approach, we identified 13 miRNAs and 31 target mRNAs with 66 interactions in the constructed network. Integrative functional enrichment analysis and literature exploration further confirmed that the network biomarkers were highly associated with the development of docetaxel resistance. Conclusions: The findings from our results demonstrated that the identified network biomarkers provide a useful tool for predicting the docetaxel resistance and may be helpful for serving as prediction biomarkers and therapeutic targets. However, it is necessary to conduct biological experiments for further investigating their roles in the development of docetaxel resistance.

Identification of microRNA-181 as a promising biomarker for predicting the poor survival in colorectal cancer.

BACKGROUND: A series of studies have investigated the vital role of microRNA-181 (miR-181) in the initiation and development of colorectal cancer (CRC), and demonstrated that it might be associated with the prognosis of CRC. However, inconsistent findings have hindered its clinical application. METHODS: A comprehensive meta-analysis and an integrative bioinformatics analysis were carried out for concluding current available evidence, clarifying the preliminary prognostic value and unfolding the underlying biological function of miR-181 in CRC patients. RESULTS: The findings revealed that elevated expression levels of miR-181 were associated with significantly poorer overall survival rates (HR = 1.75, 95% CI: 1.26-2.43, P < .05). Meanwhile, the target genes of miR-181 were identified and enriched into several important gene ontology (GO) categories and signaling pathways including miRNAs in cancer, pathways in cancer, proteoglycans in cancer, colorectal cancer, FoxO signaling pathway, PI3K-Akt signaling pathway, VEGF signaling pathway, HIF-1 signaling pathway, mTOR signaling pathway, and cAMP signaling pathway, which were confirmed highly involved in the initiation and progression of CRC. In addition, the protein-protein interaction (PPI) networks were set up by miR-181 targets to screen hub nodes and significant modules, which were also considerably associated with the molecular pathogenesis of CRC. CONCLUSIONS: The present study demonstrated that miR-181 could be a promising biomarker with predictive value for prognosis for CRC patients. However, future studies comprising large cohorts from multicenter are warranted to further investigate the biomarker value of miR-181.

Integrated analyses of microRNA-29 family and the related combination biomarkers demonstrate their widespread influence on risk, recurrence, metastasis and survival outcome in colorectal cancer.

BACKGROUND: Emerging evidence has revealed miR-29 family as promising biomarkers for colorectal cancer (CRC), but their biomarker potential and molecular mechanisms remain poorly understood. METHODS: We performed a comprehensive meta-analysis to evaluate the biomarker performance of individual miR-29 and the related miRNA combination biomarkers. Meanwhile, we conducted an integrative bioinformatics analysis to unfold the underlying biological function of miR-29 and their relationship with CRC. RESULTS: Using miR-29 expression to diagnose CRC produced 0.82 area under the curve, 70% sensitivity and 81% specificity while the combination biomarkers based on miR-29 enhanced the diagnostic power with an AUC of 0.86, a sensitivity of 78% and a specificity of 91%. For the prognosis evaluation, patients with higher expression of miR-29 had better survival outcome (pooled HR 0.78; 95% CI 0.56-1.07). In addition, miR-29 has also been identified as potential biomarker for predicting recurrence and metastasis in CRC. Then the genes regulated by the miR-29 family were retrieved and found closely associated with the molecular pathogenesis of CRC according to the gene ontology and pathway analysis. Furthermore, hub nodes and significant modules were identified from the protein-protein interaction network constructed with miR-29 family targets, which were also confirmed highly involved in the establishment and development of CRC. CONCLUSIONS: Current evidences suggest miR-29 family may become promising biomarkers for risk, recurrence, metastasis and survival outcome of CRC. Meanwhile our data highlight the potential clinical use of miRNA combination biomarkers. Nevertheless, further prospective studies are warranted before the application of the useful biomarkers in the clinical.

Identification of microRNA-92a and the related combination biomarkers as promising substrates in predicting risk, recurrence and poor survival of colorectal cancer.

Background: Previous studies demonstrated that microRNA-92a (miR-92a) may serve as a novel promising biomarker in colorectal cancer (CRC) patients. However, a comprehensive analysis of the contribution of miR-92a in CRC is lacking. We aimed to systematically summarize the diagnostic and prognostic values of miR-92a in CRC. Methods: The diagnostic and prognostic roles of individual miR-92a and the combination biomarkers based on miR-92a were evaluated through comprehensive meta-analyses. Meanwhile, the function and potential mechanisms of miR-92a were assessed by an integrative bioinformatics analysis. Results: According to the results, we found that miR-92a yielded a pooled area under ROC curve (AUC) of 0.82 (sensitivity: 76%, specificity: 75%) in discriminating CRC from controls. Notably, the combination biomarkers based on miR-92a increased the diagnostic performance, yielding an AUC of 0.91, with a sensitivity of 83% and a specificity of 87%. For the prognostic meta-analysis, patients with higher expression of miR-92a had significant shorter overall survival (pooled HR: 2.30; 95% CI: 1.03-5.12). In addition, the regulated genes of miR-92a were retrieved and enriched through gene ontology and pathway analysis, indicating their correlations with the initiation and progression of CRC. Furthermore, protein-protein interaction network was set up with miR-92a targets and screened for hub nodes and significant modules, which were confirmed strongly involved in the occurrence and development of CRC again. Conclusions: Current evidences suggest miR-92a is a promising biomarker for early detection and prognosis of CRC while miRNA combination biomarkers may be considered as the right way for clinical practice. However, more prospective studies are required to highlight the theoretical strengths.