Characterizing and forecasting neoantigens-resulting from MUC mutations in COAD.

BACKGROUND: The treatment for colon adenocarcinoma (COAD) faces challenges in terms of immunotherapy effectiveness due to multiple factors. Because of the high tumor specificity and immunogenicity, neoantigen has been considered a pivotal target for cancer immunotherapy. Therefore, this study aims to identify and predict the potential tumor antigens of MUC somatic mutations (MUCmut) in COAD. METHODS: Three databases of TCGA, TIMER2.0, and cBioPortal were used for a detailed evaluation of the association between MUCmut and multi-factors like tumor mutation burden (TMB), microsatellite instability (MSI), prognosis, and the tumor microenvironment within the context of total 2242 COAD patients. Next, TSNAdb and the differential agretopicity index (DAI) were utilized to predict high-confidence neopeptides for MUCmut based on 531 COAD patients' genomic information. DAI was calculated by subtraction of its predicted HLA binding affinity of the MUCmut peptide from the corresponding wild-type peptide. RESULTS: The top six mutation frequencies (14 to 2.9%) were from MUC16, MUC17, MUC5B, MUC2, MUC4 and MUC6. COAD patients with MUC16 and MUC4 mutations had longer DFS and PFS. However, patients with MUC13 and MUC20 mutations had shorter OS. Patients with the mutation of MUC16, MUC5B, MUC2, MUC4, and MUC6 exhibited higher TMB and MSI. Moreover, these mutations from the MUC family were associated with the infiltration of diverse lymphocyte cells and the expression of immune checkpoint genes. Through TSNAdb 1.0/NetMHCpan v2.8, 452 single nucleotide variants (SNVs) of MUCmut peptides were identified. Moreover, through TSNAdb2.0/NetMHCpan v4.0, 57 SNVs, 1 Q-frame shift (TS), and 157 short insertions/deletions (INDELs) of MUCmut were identified. Finally, 10 high-confidence neopeptides of MUCmut were predicted by DAI. CONCLUSIONS: Together, our findings establish the immunogenicity and therapeutic potential of mutant MUC family-derived neoantigens. Through combining the tools of TSNAdb and DAI, a group of novel MUCmut neoantigens were identified as potential targets for immunotherapy.

Comprehensive Profiling of Amine-Containing Metabolite Isomers with Chiral Phosphorus Reagents.

Metabolite isomers play diverse and crucial roles in various metabolic processes. However, in untargeted metabolomics analysis, it remains a great challenge to distinguish between the constitutional isomers and enantiomers of amine-containing metabolites due to their similar chemical structures and physicochemical properties. In this work, the triplex stable isotope N-phosphoryl amino acids labeling (SIPAL) is developed to identify and relatively quantify the amine-containing metabolites and their isomers by using chiral phosphorus reagents coupled with high-resolution tandem mass spectroscopy. The constitutional isomers could be effectively distinguished with stereo isomers by using the diagnosis ions in MS/MS spectra. The in-house software MS-Isomerism has been parallelly developed for high-throughput screening and quantification. The proposed strategy enables the unbiased detection and relative quantification of isomers of amine-containing metabolites. Based on the characteristic triplet peaks with SIPAL tags, a total of 854 feature peaks with 154 isomer groups are successfully recognized as amine-containing metabolites in liver cells, in which 37 amine-containing metabolites, including amino acids, polyamines, and small peptides, are found to be significantly different between liver cancer cells and normal cells. Notably, it is the first time to identify S-acetyl-glutathione as an endogenous metabolite in liver cells. The SIPAL strategy could provide spectacular insight into the chemical structures and biological functions of the fascinating amine-containing metabolite isomers. The feasibility of SIPAL in isomeric metabolomics analysis may reach a deeper understanding of the mirror-chemistry in life and further advance the discovery of novel biomarkers for disease diagnosis.

Identification and validation of ubiquitin-proteasome system related genes as a prognostic signature for papillary renal cell carcinoma.

Dysregulation of the ubiquitin-proteasome system (UPS) pathway greatly affects uncontrolled proliferation, genomic instability, and carcinogenesis, particularly in those with renal papillary cell carcinoma (PRCC). However, there is little information at the molecular level about the full link between changes in the genes involved in ubiquitin-mediated proteolysis and PRCC. METHODS: The Cancer Genome Atlas (TCGA) and GeneCards databases were utilized to find the clinical data and gene expression patterns of patients with PRCC. Univariate Cox regression analysis and absolute shrinkage and selection operator (LASSO) analyses identified a risk signature formed by ten optimal UPS genes. The predictive value of the risk signature in TCGA-PRCC cohorts was evaluated using Kaplan-Meier analysis and receiver operating characteristic (ROC) curves. By utilizing GO enrichment and the KEGG pathway, the interactions of differentially expressed genes connected to ubiquitin-mediated proteolysis were functionally examined. The protein expression of the hub genes was affirmed using the Human Protein Atlas (HPA) database. The effectiveness of particular CDC20 and UBE2C in vitro was confirmed by experimental research. RESULTS: Ten of the best ubiquitin-mediated proteolysis genes (UBE2C, DDB2, CBLC, BIRC3, PRKN, UBE2O, SIAH1, SKP2, UBC, and CDC20) were detected to create a risk signature. The high-risk score group stratified was associated with advanced tumor status and poor survival of PRCC patients. 10 genes were also found to be associated with the cell cycle pathway and ubiquitin-mediated proteolysis to GO and KEGG analysis. Of these 10 genes, CDC20 and UBE2C are highly expressed in tumor tissue and correlated with cancer immunity founded on the analyses of the expression of human protein atlas and TISIDB. The downregulation of UBE2C facilitated tumor inhibition and the anti-immune effect was confirmed by in vitro experiments. CONCLUSION: Our results indicate that the risk model created from the ubiquitin-mediated proteolysis genes can be reliably and accurately predict the prognosis of PRCC patients, highlighting its targeted value for PRCC treatment. Particularly, the expression of UBE2C may be crucial for the prognosis and immunological treatment of renal cancer.

An integrative pan-cancer analysis revealing the difference in small ring finger family of SCF E3 ubiquitin ligases.

Background: The SCF (Skp1-cullin-F-box proteins) complex is the largest family of E3 ubiquitin ligases that mediate multiple specific substrate proteins degradation. Two ring-finger family members RBX1/ROC1 and RBX2/RNF7/SAG are small molecular proteins necessary for ubiquitin ligation activity of the multimeric SCF complex. Accumulating evidence indicated the involvement of RBX proteins in the pathogenesis and development of cancers, but no research using pan-cancer analysis for evaluating their difference has been directed previously. Methods: We investigated RBX1/2 expression patterns and the association with clinicopathological features, and survivals of cancer patients obtained from the TCGA pan-cancer data. The binding energies of RBX1/2-CUL1 complexes were preliminarily calculated by using molecular dynamics simulations. Meanwhile, we assessed their immune infiltration level across numerous databases, including TISIDB and Timer database. Results: High expression levels of RBX1/2 were observed in most cancer types and correlated with poor prognosis of patients analyzed. Nonetheless, exceptions were observed: RBX2 expression in KICH was higher than normal renal tissues and played a detrimental role in KICH. The expression of RBX1 was not associated with the prognostic risk of KICH. Moreover, the combination of RBX1 and CUL1 expression is more stable than that of RBX2 and CUL1. RBX1/2 expression showed their own specific characteristics in tumor pathological stages and grades, copy number variation and immune components. Conclusions: These findings not only indicated that the difference of RBX1/2 might result in varying degrees of tumor progression, but also suggested that they might serve as biomarkers for immune infiltration in cancers, shedding new light on therapeutics of cancers.

The function and pathogenic mechanism of filamin A.

Filamin A(FLNa) is an actin-binding protein, which participates in the formation of the cytoskeleton, anchors a variety of proteins in the cytoskeleton and regulates cell adhesion and migration. It is involved in signal transduction, cell proliferation and differentiation, pseudopodia formation, vesicle transport, tumor resistance and genetic diseases by binding with interacting proteins. In order to fully elucidate the structure, function and pathogenesis of FLNa, we summarized all substances which directly or indirectly act on FLNa so far, upstream and downstream targets which having effect on it, signaling pathways and their functions. It also recorded the expression and effect of FLNa in different diseases, including hereditary disease and tumors.

Current management of chemotherapy-induced neutropenia in adults: key points and new challenges: Committee of Neoplastic Supportive-Care (CONS), China Anti-Cancer Association Committee of Clinical Chemotherapy, China Anti-Cancer Association.

Chemotherapy-induced neutropenia (CIN) is a potentially fatal and common complication in myelosuppressive chemotherapy. The timing and grade of CIN may play prognostic and predictive roles in cancer therapy. CIN is associated with older age, poor functional and nutritional status, the presence of significant comorbidities, the type of cancer, previous chemotherapy cycles, the stage of the disease, specific chemotherapy regimens, and combined therapies. There are many key points and new challenges in the management of CIN in adults including: (1) Genetic risk factors to evaluate the patient's risk for CIN remain unclear. However, these risk factors urgently need to be identified. (2) Febrile neutropenia (FN) remains one of the most common reasons for oncological emergency. No consensus nomogram for FN risk assessment has been established. (3) Different assessment tools [e.g., Multinational Association for Supportive Care in Cancer (MASCC), the Clinical Index of Stable Febrile Neutropenia (CISNE) score model, and other tools] have been suggested to help stratify the risk of complications in patients with FN. However, current tools have limitations. The CISNE score model is useful to support decision-making, especially for patients with stable FN. (4) There are still some challenges, including the benefits of granulocyte colony stimulating factor treatment and the optimal antibiotic regimen in emergency management of FN. In view of the current reports, our group discusses the key points, new challenges, and management of CIN.

Acetylation and Deacetylation of DNA Repair Proteins in Cancers.

Hundreds of DNA repair proteins coordinate together to remove the diverse damages for ensuring the genomic integrity and stability. The repair system is an extensive network mainly encompassing cell cycle arrest, chromatin remodeling, various repair pathways, and new DNA fragment synthesis. Acetylation on DNA repair proteins is a dynamic epigenetic modification orchestrated by lysine acetyltransferases (HATs) and lysine deacetylases (HDACs), which dramatically affects the protein functions through multiple mechanisms, such as regulation of DNA binding ability, protein activity, post-translational modification (PTM) crosstalk, and protein-protein interaction. Accumulating evidence has indicated that the aberrant acetylation of DNA repair proteins contributes to the dysfunction of DNA repair ability, the pathogenesis and progress of cancer, as well as the chemosensitivity of cancer cells. In the present scenario, targeting epigenetic therapy is being considered as a promising method at par with the conventional cancer therapeutic strategies. This present article provides an overview of the recent progress in the functions and mechanisms of acetylation on DNA repair proteins involved in five major repair pathways, which warrants the possibility of regulating acetylation on repair proteins as a therapeutic target in cancers.

Discovery of plasma messenger RNA as novel biomarker for gastric cancer identified through bioinformatics analysis and clinical validation.

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, partially due to the lack of effective screening strategies. Thus, there is a stringent need for non-invasive biomarkers to improve patient diagnostic efficiency in GC. METHODS: This study initially filtered messenger RNAs (mRNAs) as prospective biomarkers through bioinformatics analysis. Clinical validation was conducted using circulating mRNA in plasma from patients with GC. Relationships between expression levels of target genes and clinicopathological characteristics were calculated. Then, associations of these selected biomarkers with overall survival (OS) were analyzed using the Kaplan-Meier plotter online tool. RESULTS: Based on a comprehensive analysis of transcriptional expression profiles across 5 microarrays, top 3 over- and underexpressed mRNAs in GC were generated. Compared with normal controls, expression levels of collagen type VI alpha 3 chain (COL6A3), serpin family H member 1 (SERPINH1) and pleckstrin homology and RhoGEF domain containing G1 (PLEKHG1) were significantly upregulated in GC plasmas. Receiver-operating characteristic (ROC) curves on the diagnostic efficacy of plasma COL6A3, SERPINH1 and PLEKHG1 mRNAs in GC showed that the area under the ROC (AUC) was 0.720, 0.698 and 0.833, respectively. Combined, these three biomarkers showed an elevated AUC of 0.907. Interestingly, the higher COL6A3 level was significantly correlated with lymph node metastasis and poor prognosis in GC patients. High level of SERPINH1 mRNA expression was correlated with advanced age, poor differentiation, lower OS, and PLEKHG1 was also associated with poor OS in GC patients. CONCLUSION: Our results suggested that circulating COL6A3, SERPINH1 and PLEKHG1 mRNAs could be putative noninvasive biomarkers for GC diagnosis and prognosis.

JAM3 functions as a novel tumor suppressor and is inactivated by DNA methylation in colorectal cancer.

PURPOSE: JAM3, an adhesion and transmigration regulatory element, is abundantly expressed in intestinal epithelial cells. However, its expression and function in colorectal cancer (CRC) remain unknown. In this study, we explored its epigenetic mechanism and biological role in CRC. PATIENTS AND METHODS: Bioinformatics analysis was used to analyze the expression and methylation level of JAM3 in CRC. Methylation and expression status of JAM3 were then validated by quantitative methylation-specific PCR (qMSP) and quantitative PCR in tissues, plasma samples, and cell lines. Flow cytometry, Western blot, transwell, siRNA, colony formation, and transfection were used to evaluate the biological function of JAM3. RESULTS: We initially found that JAM3 was frequently methylated and downregulated in CRC based on bioinformatics tools. qMSP validation showed that the methylation levels of JAM3 were increased in 75% (18/24) of CRC tissues, 61% (11/18) plasma samples, and all four CRC cell lines and were significantly associated with tumor stage in CRC tissues. Moreover, JAM3 was downregulated in primary CRC tissues, plasma samples, and CRC cell lines as compared with that in nonmalignant controls, although its expression could be recovered after demethylation treatment. Restoration of JAM3 repressed CRC cell viability, colony formation, and migration. In addition, siRNA-mediated depletion of JAM3 in NCM460 cells improved the clonogenicity and migration capability, whereas it suppressed cell apoptosis and cell-cycle arrest. These functional effects were accompanied with alterations of several epithelial cell markers, including E-cadherin, vimentin, phosphor-ß-catenin (ser552), and TJP1, which were responsible for epithelial-mesenchymal transition. CONCLUSION: The findings indicated that JAM3 may be a novel tumor suppressor gene with epigenetic reduction in CRC and can be used as a potential noninvasive biomarker for CRC diagnosis.

Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have obtained excellent therapeutic effects against non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. However, some patients have exhibited primary resistance which becomes a major obstacle in effective treatment of NSCLC. The mechanisms of EGFR-TKIs resistance involved are still poorly understood. Many studies suggest that miRNAs play an important role in regulating drug sensitivity of EGFR-TKIs. The aim of the present study was to examine differentially expressed miRNAs in plasma between EGFR-TKIs sensitive and EGFR-TKIs primary resistance patients. MiRNA microarray of plasma from patients' blood identified 16 differentially expressed miRNAs of which 15 (hsv2-miR-H19, hsa-miR-744-5p, hsa-miR-3196, hsa-miR-3153, hsa-miR-4791, hsa-miR-4803, hsa-miR-4796-3p, hsa-miR-372-5p, hsa-miR-138-2-3p, hsa-miR-16-1-3p, hsa-miR-1469, hsa-miR-585-3p, ebv-miR-BART14-5p, hsa-miR-769-3p, hsa-miR-548aq-5p) were down regulated while only hsa-miR-503-3p was up regulated in primary resistant patients' plasma. Volcano plot and hierarchical clustering were performed to examine the accuracy of the miRNAs. Then validation with quantitative real-time PCR was performed and the result was in accordance with the array data. Functional analysis of these differentially expressed miRNAs with Ingenuity Pathway Analysis (IPA) revealed a common signaling network including MYC, CCND1, IGF1 and RELA. In conclusion, our finding may play important role in understanding the mechanisms underlying the problem and should be further evaluated as potential biomarkers in primary resistance of NSCLC.

Clinicopathological and prognostic significance of cyclin D1 amplification in patients with breast cancer: a meta-analysis.

PURPOSE: Cyclin D1 plays a critical role in tumorigenesis and the regulation of the G1/S transition in the cell cycle. The relationship between cyclin D1 amplification and clinicopathological parameters in patients with breast cancer remains controversial and its impact on survival outcome is not completely clear. We conducted a meta-analysis to investigate the associations between cyclin D1 gene amplification and certain clinicopathological characteristics and the prognosis in breast cancer. METHODS: Literature search of PubMed (up to August 3, 2016) was performed. We used Stata 12.0 (Stata Corporation, Texas, US) to analyze the correlations between cyclin D1 amplification and clinicopathological features and the prognostic indicator relapse free survival (RFS) and overall survival (OS) in patients with breast cancer. Publication bias analysis and sensitivity analysis were performed. RESULTS: A total of 9,238 breast cancer patients from 21 studies were included. The pooled odds ratios (ORs) indicated that cyclin D1 amplification was significantly associated with estrogen receptor (ER), progesterone receptor (PR), histological grade and lymph node status, but not associated with human epidermal growth factor receptor-2 (HER2) and tumor size. The combined hazard ratios (HRs) for RFS and OS showed that patients with cyclin D1 amplification displayed a 1.31-fold higher risk of recurrence (HR =1.31, 95% confidence interval (95% CI):1.02-1.60, p<0.01), and a risk of mortality 1.22-fold higher times greater than those without cyclin D1 amplification (HR=1.22, 95% CI:0.99- 1.44, p<0.01), respectively. CONCLUSION: Our meta-analysis indicated that cyclin D1 amplification is significantly associated with established clinicopathological variables and can be used as a poor prognostic indicator for patients with breast cancer.

PCDH18 is frequently inactivated by promoter methylation in colorectal cancer.

Protocadherin18 (PCDH18) was found to be preferentially methylated and inactivated in colorectal cancer (CRC) using bioinformatics tools. However, its biologic role in tumorgenesis remains unclear. Herein, we aimed to elucidate its epigenetic regulation and biological functions in CRC. The methylation status of PCDH18 was significant higher in CRC tissues than in adjacent non-tumor tissues (median, 15.17% vs. median, 0.4438%). Expression level of PCDH18 was significantly lower in primary CRCs than in nonmalignant tissues. Importantly, methylation status of PCDH18 in cell-free DNA of CRC patients was also significantly higher than in healthy subjects. PCDH18 was readily expressed in NCM460 cells, but downregulated in 100% (4/4) of CRC cell lines by promoter methylation, despite its expression could be restored through demethylation treatment. Overexpression of PCDH18 suppressed CRC cell viability, colony formation and migration. Meanwhile, the depletion of PCDH18 by siRNA in NCM460 cells enhanced the colonogenicity and migration ability and promoted ß-catenin nuclear accumulation, whereas it inhibited cell cycle arrest. These effects were associated with upregulation of phospho-GSK-3ß and cyclin D1, and downregulation of caspase3 and p21. Our results suggested that PCDH18 was a putative tumor suppressor with epigenetic silencing in CRC and a potential biomarker for CRC diagnosis.

Clinical verification of plasma messenger RNA as novel noninvasive biomarker identified through bioinformatics analysis for lung cancer.

Lung cancer (LC) remains associated with significant mortality worldwide. The lack of reliable noninvasive biomarkers and targeted therapies contributes to poor survival rate. Herein, we initially took advantage of the public microarray data from Oncomine database to filter messenger RNAs (mRNAs) as potential biomarkers. Subsequently, clinical validation was applied to identify candidate noninvasive biomarkers in plasma from patients with LC. Through comprehensive analysis of transcriptional expression profiles across 12 studies, top 6 over- and underexpressed mRNAs were generated. Then, a pair of matched plasma samples from LC patient and normal control was detected by RT-PCR, and three genes with positive bands were selected for further validation. Finally, qPCR was conducted to further assess values of the three identified genes. We displayed with high confidence that two cell-free mRNAs (HJURP and ADAMTS8) were expressed at significantly levels compared to normal controls. Receiver-operating characteristic (ROC) curves on the diagnostic efficacy of plasma HJURP and ADAMTS8 mRNAs in LC diagnosis showed that the area under the ROC (AUC) was 0.6960 and 0.6877; sensitivity was 66.0% and 83.7%; specificity was 78.6% and 71.4%, respectively. Combined ROC analyses using these two biomarkers revealed an elevated AUC of 0.75. Furthermore, the higher HJURP level could be associated with early-stage LC while lower ADAMTS8 level could be correlated with non-small cell lung cancer. Collectively, circulating HJURP and ADAMTS8 mRNAs are promising noninvasive biomarkers for LC diagnosis. Our integrative strategy provides new insights into novel noninvasive biomarker identification for other types of cancer.

The relative change in regulatory T cells / T helper lymphocytes ratio as parameter for prediction of therapy efficacy in metastatic colorectal cancer patients.

PURPOSE: The evaluation of regulatory T (Treg) (CD4+CD25high CD127neg) lymphocyte count with respect to the T helper (TH) (CD4) number has been shown to represent the main immune parameters capable of signifying the functional status of the anticancer immunity in cancer patients. This study is aimed to explore a correlation between therapy efficacy and changes in Treg/TH ratio and other biochemical and haematological parameters in patients with metastatic colorectal cancer (mCRC). EXPERIMENTAL DESIGN: Measurements of regulatory T cells were performed by flow cytometric analysis pre- and post-therapies in a prospective study. RESULTS: We investigated levels of Treg/TH ratio in the peripheral blood of 25 mCRC patients pre- and post-chemotherapy ± targeted therapy. There were significant differences in levels of Treg/TH ratio pre- and post-treatments among patients on study, patients with partial response (PR), stable disease (SD) and progressive disease (PD) (P= 0.012, P= 0.011, and P= 0.043, respectively). Moreover, the relative change in Treg/TH ratio showed statistically significant difference among patients with PD as compared to those with PR and SD. Our findings demonstrated a statistically significant strong correlation between the relative change in Treg/TH ratio and therapeutic response. (Spearman's rho= 0.788/p<0.001). CONCLUSIONS: The monitoring of the relative change in Treg/TH ratio could constitute a promising clinical index for response prediction and a timely change in regimen. Further prospective evaluations of these parameters investigated, particularly their association with overall survival, are warranted.

Repurposing the anti-malarial drug dihydroartemisinin suppresses metastasis of non-small-cell lung cancer via inhibiting NF-κB/GLUT1 axis.

Non-small-cell lung cancer (NSCLC) is an aggressive malignancy and long-term survival remains unsatisfactory for patients with metastatic and recurrent disease. Repurposing the anti-malarial drug dihydroartemisinin (DHA) has been proved to possess potent antitumor effect on various cancers. However, the effects of DHA in preventing the invasion of NSCLC cells have not been studied. In the present study, we determined the inhibitory effects of DHA on invasion and migration and the possible mechanisms involved using A549 and H1975 cells. DHA inhibited in vitro migration and invasion of NSCLC cells even in low concentration with little cytotoxicity. Additionally, low concentration DHA also inhibited Warburg effect in NSCLC cells. Mechanically, DHA negatively regulates NF-κB signaling to inhibit the GLUT1 translocation. Blocking the NF-κB signaling largely abolishes the inhibitory effects of DHA on the translocation of GLUT1 to the plasma membrane and the Warburg effect. Furthermore, GLUT1 knockdown significantly decreased the inhibition of invasion, and migration by DHA. Our results suggested that DHA can inhibit metastasis of NSCLC by targeting glucose metabolism via inhibiting NF-κB signaling pathway and DHA may deserve further investigation in NSCLC treatment.

Association between aberrant APC promoter methylation and breast cancer pathogenesis: a meta-analysis of 35 observational studies.

Background. Adenomatous polyposis coli (APC) is widely known as an antagonist of the Wnt signaling pathway via the inactivation of ß-catenin. An increasing number of studies have reported that APC methylation contributes to the predisposition to breast cancer (BC). However, recent studies have yielded conflicting results. Methods. Herein, we systematically carried out a meta-analysis to assess the correlation between APC methylation and BC risk. Based on searches of the Cochrane Library, PubMed, Web of Science and Embase databases, the odds ratio (OR) with 95% confidence interval (CI) values were pooled and summarized. Results. A total of 31 articles involving 35 observational studies with 2,483 cases and 1,218 controls met the inclusion criteria. The results demonstrated that the frequency of APC methylation was significantly higher in BC cases than controls under a random effect model (OR = 8.92, 95% CI [5.12-15.52]). Subgroup analysis further confirmed the reliable results, regardless of the sample types detected, methylation detection methods applied and different regions included. Interestingly, our results also showed that the frequency of APC methylation was significantly lower in early-stage BC patients than late-stage ones (OR = 0.62, 95% CI [0.42-0.93]). Conclusion. APC methylation might play an indispensable role in the pathogenesis of BC and could be regarded as a potential biomarker for the diagnosis of BC.

Plasma MiRNA alterations between NSCLC patients harboring Del19 and L858R EGFR mutations.

Based on recognition of driver mutations, treatment paradigm for non-small-cell lung cancer (NSCLC) patients has been shifted. However, recently exon 19 deletion mutation (del19) of epidermal growth factor receptor (EGFR) clearly shows better clinical benefit over single-point substitution mutation L858R in exon 21 (L858R). The aim of this study was to investigate the difference by analyzing the expression of plasma microRNAs (miRNAs) of NSCLC patients with EGFR mutation del19 or L858R. MiRNA microarray of plasma from patients' blood identified 79 mapped, network-eligible miRNAs (fold > 5), of which 76 were up regulated and 3 were down regulated. Genetic network was performed with Ingenuity Pathway Analysis (IPA). Among analysis, MYC, Argonaute2 (AGO2), Y-box binding protein 1 (YBX1), cyclin E1 (CCNE1) were involved in organismal abnormalities and cancer. Our findings provide information on the epigenetic signature of the two major sensitive mutations among NSCLC and add to the understanding of mechanisms underlying the different outcomes.

Clinicopathological and prognostic significance of programmed cell death ligand1 (PD-L1) expression in patients with non-small cell lung cancer: a meta-analysis.

OBJECTIVE: Programmed cell death 1 (PD-1) and one of its ligands, PD-L1, are key immune checkpoint proteins. Evidences showed PD-L1 is an emerging biomarker for immunotherapy by anti-PD-1 and anti-PD-L1 antibody in non-small cell lung cancer (NSCLC). To investigate the association of PD-L1 protein expression with clinicopathological features and its impact on survival outcome, we conducted a meta-analysis. METHODS: A comprehensive literature search of electronic databases (up to July 10, 2014) was performed. Correlation between PD-L1 expression and clinicopathological features and overall survival (OS) was analyzed by synthesizing the qualified data. Publication biases were examined. RESULTS: A total of 1,550 NSCLC patients from 9 studies were included. The pooled odds ratios (ORs) indicated high PD-L1 expression was associated with poor tumor differentiation [OR =0.53, 95% confidence interval (CI): 0.39-0.72, P<0.0001]. Whereas, none of other clinicopathological characteristics [gender, smoking status, histological type, invasive depth of tumor, status of lymph node metastasis and tumor node metastasis (TNM) stage] were correlated with PD-L1 expression in current analysis. The combined hazard ratio (HR) for OS showed high expression of PD-L1 impaired the OS in NSCLC (HRpositive/negative =1.47, 95% CI: 1.19-1.83, P=0.0004). CONCLUSIONS: Our meta-analysis indicated PD-L1 protein expression in NSCLC was not associated with common clinicopathological characteristics, except tumor differentiation. It was a poor prognostic biomarker for NSCLC. Further research should be performed to investigate the precise clinicopathological and prognostic significance of PD-L1 in NSCLC under uniform testing standard.

3'-deoxy-3'-[¹8F]-fluorothymidine PET/CT in early determination of prognosis in patients with esophageal squamous cell cancer: comparison with [¹8F]-FDG PET/CT.

PURPOSE: The purpose of this work was to investigate the prognostic value of response analysis using early 3'-deoxy-3'-[(18)F]-fluorothymidine ((18)F-FLT) PET/CT in esophageal squamous cancer patients and make a comparison with [(18)F]-fluorodeoxyglucose ((18)F-FDG) PET/CT. PATIENTS AND MATERIALS: For 34 patients with esophageal squamous cell cancer, both (18)F-FLT PET/CT and (18)F-FDG PET/CT scans were performed at baseline (pre), 4 weeks after the start of radiotherapy or chemoradiotherapy (interim), and 2 weeks after therapy completion (final). SUVmax1, SUVmax2, and SUVmax3 represent SUVmax (SUV: standard uptake values) measured on the pre, interim, and final scans, respectively. GTVFLT-PET and GTVFDG-PET (GTV: gross tumor volume) were measured on the pre and interim scans. ΔSUV/ΔGTV represents the fractional changes of SUVmax/GTV between two different time points. PET parameters were evaluated for correlations with outcome. RESULTS: Regarding (18)F-FLT PET/CT, according to receiver operating characteristic (ROC) curve analysis, parameters for predicting 2-year progression-free survival (PFS) and locoregional control (LRC) showed the highest area under curve (AUC) on interim (18)F-FLT PET/CT scans (ΔSUV12, AUC of 0.812 for PFS, 0.775 for LRC, with a cutoff of 60 %; P = 0.008), compared with the parameters on pre and final scans. Patients with a ΔSUV12 greater than 60 %, who were defined as interim PET-negative group, were associated with better 2-year PFS and LRC than the interim PET-positive group (PFS: 70.6 % vs. 35.2 %, P = 0.025; LRC: 84.2 % vs 52.9, P = 0.046). In terms of (18)F-FDG PET/CT, ΔSUV13 on the final 18F-FDG PET/CT scan demonstrated better prediction (AUC of 0.812 for PFS, 0.807 for LRC, with a cutoff of 75 %; P = 0.016) than the parameters on pre and interim scans. An SUVmax decrease ≥ 75 % on the final (18)F-FDG PET/CT scan was associated with better clinical outcome (PFS: 73.3 % vs. 36.8 %, P = 0.022; LRC: 86.7 % vs 52.6, P = 0.029). These correlations were most prominent in the subgroup of patients treated with chemoradiotherapy. CONCLUSION: Early interim (18)F-FLT PET/CT is a significant predictor of 2-year PFS and LRC, which is correlated better with early responses and late outcomes than interim (18)F-FDG PET/CT in esophageal squamous cancer patients.