Correlation between UGT1A1 gene polymorphism and irinotecan chemotherapy in metastatic colorectal cancer: a study from Guangxi Zhuang.

BACKGROUND: There are obviously ethnic differences between the UGT1A1 gene polymorphisms. Due to the difference of genetic background and environment, the treatment with colorectal cancer patients of Guangxi Zhuang should not completely follow the Euramerican or Chinese han patients. The study aimed to explore the correlation of UGT1A1 gene polymorphism of Guangxi Zhuang metastatic colorectal cancer (mCRC) with irinotecan -based chemotherapy, in order to develop an individualized irinotecan regimen for mCRC patients of Guangxi Zhuang. METHODS: From June 2013 and June 2015, a total of 406 patients of Guangxi who were histologically diagnosed as metastatic colorectal cancer with 102 patients of this cohort with three generations of Zhuang, and 86 patients that conformed to inclusion and exclusion criteria were competitively enrolled. The distribution of UGT1A1 gene polymorphism was analyzed-retrospectively in all patients. Pyrosequencing method was used to detect the UGT1A1*28 and*6 gene polymorphism in the 86 Guangxi Zhuang mCRC patients. After first-line chemotherapy with FOLFIRI regimen, the relationship between gene polymorphism of UGT1A1 and adverse reactions, and efficacy of Irinotecan were analyzed with χ2 test and Kaplan-Meier method. RESULTS: UGT1A1*28 wild-type (TA6/6), heterozygous mutant (TA6/7) and homozygous mutant (TA7/7) accounted for 69.8, 30.2 and 0%, respectively. UGT1A1*6 wild type (G/G), heterozygous mutation type (G/A) and homozygous mutant (A/A) accounted for 76.7%, 20.9 and 2.3%, respectively. UGT1A1*28 TA6/7 type could increase the risk of grade 3~4 diarrhea (p = 0.027), which did not increase the risk of grade 3~4 neutropenia (p = 0.092). UGT1A1*6G/A and A/A type could increase the risk of grade 3~4 diarrhea and neutropenia (p = 0.001; p = 0.017). After chemotherapy with FOLFIRI, there was no significant difference in response rate (RR) (p = 0.729; p = 0.745) or in median progression-free survival (mPFS) between the wild-type, mutant treatment of UGT1A1*28 and UGT1A1*6 (7.0 m vs 7.4 m, p = 0.427; 6.9 m vs 7.0 m p = 0.408). CONCLUSIONS: The distribution of UGT1A1*28 and UGT1A1*6 gene polymorphism in Guangxi Zhuang patients were differed from the existing reported of European people and Chinese Han population. The UGT1A1 gene polymorphism with irinotecan chemotherapy-associated diarrhea and neutropenia were closely related. There was no significant association between UGT1A1 gene polymorphism and therapeutic efficacy of irinotecan.

PGM5 is a promising biomarker and may predict the prognosis of colorectal cancer patients.

BACKGROUND: Phosphoglucomutase (PGM), a key enzyme in the metabolism of glucose-1-phosphate and glucose-6-phosphate, has been found to be associated with proliferation, invasion, and metastasis of cancer. However, the expression and function of PGM5 in colorectal cancer (CRC) remains unknown. METHODS: We tested PGM5 mRNA and protein expression levels in 79 CRC tissue and their matched adjacent tissue samples by qRT-PCR and immunohistochemistry, respectively. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the log-rank test. We performed multivariable Cox regression analyses to identify factors associated with CRC risk. The cell proliferation, migration and invasion abilities of CRC cells were detected by using CCK-8, Transwell migration and invasion assays, respectively. RESULTS: The PGM5 protein levels expression in CRC tissues were significantly lower than those in the adjacent tissues (t = 5.035, P < 0.001), and Kaplan-Meier analysis indicated that low PGM5 expression were significantly associated with poor overall survival (P = 0.0069). Univariate and multivariate analyses demonstrated that PGM5 was an independent risk factor for overall survival (hazard ratio = 0.3951, P = 0.014). PGM5 overexpression significantly inhibited the proliferation, invasion and migration abilities of CRC cells. On the contrary, knockdown of PGM5 promotes the invasion and migration of CRC cells. CONCLUSIONS: PMG5 regulates proliferation, invasion, and migration in the CRC and decreased PGM5 is associated with poor prognosis. Therefore, PGM5 is a promising biomarker in CRC and decreased PGM5 may predict poor overall survival in patients with CRC.

Validation of CDC45 as a novel biomarker for diagnosis and prognosis of gastric cancer.

Background: Cell division cycle protein 45 (CDC45) has been demonstrated to play vital roles in the progression of various malignancies. However, the clinical significance of CDC45 in gastric cancer (GC) remains unreported. Method: In this study, we employed the TCGA database and the TCGA & GTEx dataset to compare the mRNA expression levels of CDC45 between gastric cancer tissues and adjacent or normal tissues (p < 0.05 was considered statistically significant), which was further validated in multiple datasets including GSE13911, GSE29272, GSE118916, GSE66229, as well as RT-qPCR. Furthermore, we harnessed the Human Protein Atlas (HPA) to evaluate the protein expression of CDC45, which was subsequently verified through immunohistochemistry (IHC). To ascertain the diagnostic utility of CDC45, receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were calculated in TCGA database, and further validated it in TCGA & GTEx and GSE66229 datasets. The Kaplan-Meier method was used to reveal the prognostic importance of CDC45 in The Cancer Genome Atlas (TCGA) database and authenticated through the GSE66229, GSE84433, and GSE84437 datasets. Through cBioPortal, we identified co-expressed genes of CDC45, and pursued enrichment analysis. Additionally, we availed gene set enrichment analysis (GSEA) to annotate the biological functions of CDC45. Results: Differential expression analysis revealed that CDC45 was significantly upregulated at both the mRNA and protein levels in GC (all p < 0.05). Remarkably, CDC45 emerged as a promising prognostic indicator and a novel diagnostic biomarker for GC. In a comprehensive the drug susceptibility analysis, we found that patients with high expression of CDC45 had high sensitivity to various chemotherapeutic agents, among which 5-fluorouracil, docetaxel, cisplatin, and elesclomol were most evident. Furthermore, our findings suggested a plausible association between CDC45 and immune cell infiltration. Enrichment analysis revealed that CDC45 and its associated genes may play crucial roles in muscle biofunction, whereas GSEA demonstrated significant enrichment of gene sets pertaining to G protein-coupled receptor ligand binding and G alpha (i) signaling events. Conclusion: Our study elucidates that upregulation of CDC45 is intricately associated with immune cell infiltration and holds promising potential as a favorable prognostic marker and a novel diagnostic biomarker for GC.

Prognostic and Diagnostic Values of Semaphorin 5B and Its Correlation With Tumor-Infiltrating Immune Cells in Kidney Renal Clear-Cell Carcinoma.

Background: Semaphorin 5B (SEMA5B) has been described to be involved in the development and progression of cancer. However, the potential diagnostic and prognosis roles and its correlation with tumor-infiltrating immune cells in KIRC have not been clearly reported yet. Methods: The mRNA level of SEMA5B was analyzed via the TCGA and GTEx database as well as the CCLE dataset and verified by GSE53757 and GSE40435 datasets. Meanwhile, the protein level of SEMA5B was analyzed by CPTAC and validated by HPA. The diagnostic value of SEMA5B was analyzed according to the TCGA database and validated by GSE53757, GSE46699, and GSE11024 + GSE46699 datasets. Then, the survival analysis was conducted using GEPIA2. R software (v3.6.3) was applied to investigate the relevance between SEMA5B and immune checkpoints and m6A RNA methylation regulator expression. The correlation between SEMA5B and MMRs and DNMT expression and tumor-infiltrating immune cells was explored via TIMER2. Co-expressed genes of SEMA5B were assessed by cBioPortal, and enrichment analysis was conducted by Metascape. The methylation analysis was conducted with MEXPRESS and MethSurv online tools. Gene set enrichment analysis (GSEA) was applied to annotate the biological function of SEMA5B. Results: SEMA5B was significantly upregulated at both the mRNA and protein levels in KIRC. Further analysis demonstrated that the mRNA expression of SEMA5B was significantly correlated with gender, age, T stage, pathologic stage, and histologic grade. High levels of SEMA5B were found to be a favorable prognostic factor and novel diagnostic biomarker for KIRC. SEMA5B expression was shown to be significantly associated with the abundance of immune cells in KIRC. Also, SEMA5B expression was significantly correlated with the abundance of MMR genes, DNMTs, and m6A regulators in KIRC. Enrichment analysis indicated that the co-expressed genes may involve in crosslinking in the extracellular matrix (ECM). GSEA disclosed that SYSTEMIC_LUPUS_ERYTHEMATOSUS and NABA_ECM_REGULATORS were prominently enriched in the SEMA5B low-expression phenotype. Finally, the methylation analysis demonstrated a correlation between hypermethylation of the SEMA5B gene and a poor prognosis in KIRC. Conclusion: Increased SEMA5B expression correlated with immune cell infiltration, which can be served as a favorable prognostic factor and a novel diagnostic biomarker for KIRC.

Predictive Value of ERCC1 mRNA Level from Receiver-Operator Characteristic and Pretreatment EBV-DNA Virus Load in Stage II Nasopharyngeal Carcinoma Patients Receiving Intensity-Modulated Radiotherapy with Concurrent Cisplatin.

Background: The molecular mechanisms underlying chemoresistance are still poorly understood in nasopharyngeal cancer. The protein expression of ERCC1 in DNA repair genes has been reported related to resistance platinum and predicting treatment outcomes in various malignant carcinomas, but the benefit for predicting outcomes with optimal cutoff value of ERCC1mRNA is controversial. The level of plasma Epstein-Barr virus (EBV) DNA is positively correlated with clinical stages of nasopharyngeal carcinoma (NPC). The predictive value of ERCC1mRNA from receiver-operator characteristic (ROC) and EBV-DNA level for stratified treatment with stage II NPC is exactly unclear. This study aims to assess the predictive value of combined EBV-DNA and ERCC1 in stage II nasopharyngeal cancer (NPC) patients treated with intensity-modulated radiotherapy (IMRT) with concurrent cisplatin, and provide guidance for future stratified treatment. Methods: A total of 86 stage II NPC patients who received IMRT and concurrent cisplatin-based chemotherapy with or without cisplatin-based adjuvant chemotherapy had measurements of ERCC1 mRNA, and pretreatment EBV-DNA levels were analyzed by real-time PCR (RT-PCR). Associations of ERCC1 mRNA and pretreatment EBV-DNA levels with clinical characteristics and survivals were evaluated. Results: Cutoff value of ERCC1 mRNA obtained from ROC curve was used, and there were significant differences in progression-free survival (PFS) and overall survival (OS) and overall response rate (ORR) between high expression group and low expression group (p = 0.021 and 0.030 and 0.000, respectively). Patients with pretreatment EBV-DNA <2000 copies/mL had significantly better PFS and ORR (p = 0.024 and 0.043, respectively) and a marginally significant impact on OS (p = 0.062) than those with pretreatment EBV-DNA ≥2000 copies/mL. Patients were divided into three groups by combination of ERCC1 mRNA and EBV-DNA level: ERCC1 mRNA low expression/pre-EBV-DNA <2000 copies/mL, ERCC1 mRNA low expression/pre-EBV-DNA ≥2000 copies/mL, and ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL. There were significant differences in ORR among the three groups (p = 0.005). The median follow-up was 62 months (range 22-84) with a follow-up rate of 90.70%. In these groups by combination of ERCC1 mRNA and EBV-DNA level, 1, 3, 5-year OS were 100%, 100%, 100%; 100%, 94.1%, 90.9%; and 100%, 85%, 72.9%, respectively (p = 0.038); 1, 3, 5-year PFS were 100%, 100%, 100%; 97.1%, 91.2%, 84.8%; and 95%, 85%, 71.4%, respectively (p = 0.028). Multivariate analysis showed that combination of ERCC1 mRNA and EBV-DNA levels remained independent prognostic factor but not ERCC1 mRNA and EBV-DNA alone. Conclusions: Combined ERCC1 mRNA and pre-EBV-DNA is a better prognostic biomarker in stage II NPC patients treated with concurrent chemoradiation. Patients with ERCC1 mRNA high expression/pre-EBV-DNA ≥2000 copies/mL may benefit from more aggressive treatment.

Pan-Cancer Study of SHC-Adaptor Protein 1 (SHC1) as a Diagnostic, Prognostic and Immunological Biomarker in Human Cancer.

Background: Recent studies highlight the carcinogenesis role of SHC-adaptor protein 1 (SHC1) in cancer initiation, development, and progression. However, its aberrant expression, diagnostic and prognostic value remain unknown in a variety of tumors. Methods: The SHC1 expression profiles were analyzed using GTEx database, TCGA database, Oncomine and CPTAC database. The survival analysis was conducted using GEPIA2, Kaplan-Meier Plotter, UALCAN, and PrognoScan. The diagnostic values of SHC1 were calculated with the "pROC" package in R software. The genetic alteration of SHC1 and mutations were analyzed using cBioPortal. TIMER2 was employed to estimate the correlations between SHC1 expression and tumor-infiltrating immune cells in the TCGA cohort. Enrichment analysis of SHC1 was conducted using the R package "clusterProfiler." Results: SHC1 was ubiquitously highly expressed and closely associated with worse prognosis of multiple major cancer types (all p < 0.05). Further, SHC1 gene mutations were strongly linked to poor OS and DFS in SKCM (all p < 0.05). An enhanced phosphorylation level of SHC1 at the S139 site was observed in clear cell RCC. Additionally, the results revealed SHC1 expression was strongly linked to TMB, MMRs, MSI, TAMs, DNA methylation, m6A RNA methylation, tumor-associated immune infiltration, and immune checkpoints in multiple cancers (all p < 0.05). In addition, the results of the ROC analysis indicated the SHC1 exhibited strong diagnostic capability for KICH (AUC = 0.92), LIHC (AUC = 0.95), and PAAD (AUC = 0.95). Finally, enrichment analysis indicated that SHC1 may potentially involve in the regulation of numerous signaling pathways in cancer metabolism and protein phosphorylation-related functions. Conclusions: These findings highlight that SHC1 plays an important role in the tumor immune microenvironment, and SHC1 has been identified to have prognostic and diagnostic value in multiple cancers. Thus, SHC1 is a potential target for cancer immunotherapy and effective prognostic and diagnostic biomarker.

Genome-scale CRISPR-Cas9 knockout screening in hepatocellular carcinoma with lenvatinib resistance.

Lenvatinib is the first target drug approved for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance is common, and the mechanisms of lenvatinib resistance and resistant targets in HCC are poorly understood. By using CRISPR/Cas9 library screening, we screened out two key resistance genes, neurofibromin 1(NF1), and dual specificity phosphatase 9 (DUSP9), as critical drivers for lenvatinib resistance in HCC. With RNAi knockdown and CRISPR/Cas9 knockout models, we further clarified the mechanisms by which NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways, while DUSP9 loss activates the MAPK/ERK signaling pathways, thereby inactivating FOXO3, followed by degradation of FOXO3, finally induced lenvatinib resistance. We also screened out trametinib, a small molecule pathway inhibitor for MEK, that can be used to reverse resistance induced by NF1 and DUSP9 loss in HCC cells. Trametinib was still able to halt HCC growth even when NF1 was knocked out in mice. Collectively, the findings indicate that NF1 and DUSP9 takes critical role in lenvatinib resistance and may be novel specific targets and predictive markers for lenvatinib resistance in HCC.

Diagnostic value and clinical significance of circulating miR-650 and CA211 in detecting of gastric carcinoma.

The present study determined the levels of plasma biomarkers in patients with gastric carcinoma (GC) and investigated their clinical significance and diagnostic value. Between April 2014 and December 2018, 90 patients with GC, 90 patients with precancerous lesions (Pre) and 45 healthy controls (NC) were recruited from the Affiliated Liutie Central Hospital of Guangxi Medical University. Five markers were measured: microRNA-650 (miRNA-650; using reverse transcription-quantitative polymerase chain reaction), and carcinoembryonic antigen (CEA), carbohydrate antigen (CA)125, CA211 and CA50 using electrochemiluminescence. Circulating markers were all upregulated in patients with GC (P<0.05), and CA211 and CA50 were significantly increased in patients with Pre. The miRNA-650 and CA211 had an area under the curve (AUC) of 0.700 (moderate) and 0.866 (high), respectively, in the diagnosis of GC. Differentiation of GC from Pre yielded an AUC of 0.665 (low) and 0.708 (moderate), respectively. The combination model of miRNA-650 and CA211 showed an appropriate value of AUC (0.887) to discriminate the GC patients from the healthy subjects with a sensitivity and specificity of 82.5 and 97.7%. Additionally, differentiating GC from Pre yielded an AUC of 0.767 with a sensitivity of 57.1% and a specificity of 95%, respectively. In terms of clinicopathological features, the expression of miRNA-650 and CA211 in plasma was not associated with the patients' age, sex, Tumor-Node-Metastasis stage, or histological type. In conclusion, plasma miRNA-650 and CA211 is a promising and powerful non-invasive marker for the detection of GC.

WO3­x@Au@MnO2 core­shell nanowires on carbon fabric for high-performance flexible supercapacitors.

WO3­x@Au@MnO2 core­shell nanowires (NWs) are synthesized on a flexible carbon fabric and show outstanding electrochemical performance in supercapacitors such as high specific capacitance, good cyclic stability, high energy density, and high power density. These results suggest that the WO3­x@Au@MnO2 NWs have promising potential for use in high-performance flexible supercapacitors.

Three-dimensional WO3 nanostructures on carbon paper: photoelectrochemical property and visible light driven photocatalysis.

Three-dimensional (3D) WO(3) nanostructures were grown on carbon paper by a catalyst-free high temperature reactive vapor deposition process, which exhibit a good photoelectrochemical property and visible light driven photocatalytic performance.