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Objective: To evaluate the clinical correlation of epithelial-mesenchymal transition (EMT) with PRL-3 and MMP9 expression in the circulating tumor cells (CTCs) of patients with colorectal cancer (CRC). Materials and Methods: Between January 2016 and December 2018, the EMT phenotype-based subsets of CTCs and the expression levels of PRL-3 and MMP9 in CTCs were identified, and their clinical values in 172 patients were evaluated. The CTCs were isolated, classified, and counted using the CanPatrol™ CTC filtration system. The CTC subsets (epithelial cells, mesenchymal cells and biphenotypic cells), as well as PRL-3 and MMP9 expression, were detected by RNA in situ hybridization. Results: CTCs were detected in 93.0% (160/172) of the included patients with CRC. Positive PRL-3 and MMP9 expression in CTC and M-CTC was found in 75.0% (102/136) and 80.8% (97/120) of the patients, respectively. The proportion of patients with positive PRL-3 and MMP9 expression in M-CTC was significantly associated with distant metastasis (p<0.05). The patients with ≥6 CTCs tended to show poorer progression-free survival (PFS) and overall survival (OS) rates (p=0.016, 0.02, respectively), and the patients with ≥3 M-CTC also showed poor PFS (p=0.0013). Additionally, the patients with positive PRL-3 and MMP9 expression in CTCs had significantly poorer PFS (p=0.0024) and OS (p=0.095) than the patients with negative PRL-3 and MMP9 expression. Multivariate Cox analysis uncovered that positive PRL-3 and MMP9 expression in CTCs may be an independent prognostic factor for worse PFS. Conclusion: EMT phenotypes and CTC numbers can be used as prognostic indicators for metastasis and survival in patients with CRC, and the combination of PRL-3 and MMP9 expression in CTCs is a promising clinical marker for patients with CRC. [ABSTRACT FROM AUTHOR]

Background: Vestibular schwannoma (VS) is the most common benign tumor of the posterior fossa. The recurrence of VS has always received widespread attention. This study aimed to develop a nomogram to predict Recurrence-free survival (RFS) following resection of VS. Methods: A total of 425 patients with VS who underwent resection at the Department of Neurosurgery in Chinese PLA General Hospital between January 2014 and December 2020 were enrolled in this retrospective study. The medical records and follow-up data were collected. Cox regression analysis was used to screen prognostic factors and construct the nomogram. The predictive accuracy and clinical benefits of the nomogram were validated using the area under the curve (AUC), calibration curves, and decision curve analysis (DCA). Results: The Cox regression analysis revealed that age (HR = 0.96; 95% CI 0.94 - 0.99; p < 0.01), EOR (HR = 4.65; 95% CI 2.22 - 9.74; p < 0.001), and Ki-67 (HR = 1.16; 95% CI 1.09 - 1.23; p < 0.001) were all significantly correlated with recurrence, and they were finally included in the nomogram model. The concordance index of the nomogram was 0.86. The areas under the curve (AUCs) of the nomogram model of 3-, 4- and 5-year were 0.912, 0.865, and 0.809, respectively. A well-fitted calibration curve was also generated for the nomogram model. The DCA curves also indicated that the nomogram model had satisfactory clinical utility compared to the single indicators. Conclusions: We developed a nomogram that has high accuracy in predicting RFS in patients after resection of VS. All of the included prognostic factors are easy to obtain. The nomogram can improve the postoperative management of patients and assist clinicians in individualized clinical treatment. Furthermore, we generated a web-based calculator to facilitate clinical application: https://abc123-123.shinyapps.io/VS-RFS/. [ABSTRACT FROM AUTHOR]

Abnormal DNA methylation contributes to breast cancer (BC). Immune-related genes play crucial roles in BC development and progression. This study aims to investigate the effect of methylation of immune-related genes in peripheral blood leukocytes (PBLs) on BC risk. GSE51032 and GSE104942 datasets were used to identify significantly differentially methylated CpG sites (DMCs) of immune-related genes. A case-control study was conducted using MethylTarget sequencing to validate the relationship between the methylation levels of the screened genes and BC risk. We also evaluated the association between methylation haplotypes of screened genes and BC risk. Moreover, we sorted the blood leukocytes into T cells, B cells, and monocytes to detect the difference of DNA methylation in different cell subtypes. A total of five DMCs were screened from GEO datasets, including cg01760846 (PSMC1), cg07141527 (SPPL3), cg15658543 (CARD11), cg21568368 (PSMB8), and cg24045276 (NCF2). In the case-control study, there were significant associations between methylation of the CpG sites in the five genes and BC risk. Methylation haplotype burdens of PSMC1 , CARD11 , and PSMB8 were associated with reduced BC risk. Moreover, there were heterogeneities in the methylation levels of the genes in different cell subtypes. In conclusion, methylation of PSMC1 , SPPL3 , CARD11 , PSMB8 , and NCF2 in PBLs were associated with BC risk. The five-gene methylation could be the potential biomarkers for predicting BC risk. [ABSTRACT FROM AUTHOR]

Tumor mutation burden (TMB) is associated with immune infiltration, while its underlying mechanism in hepatocellular carcinoma (HCC) remains unclear. A long noncoding RNA (lncRNA)-related competitive endogenous RNA (ceRNA) network can regulate various tumor behaviors, and research about its correlation with TMB and immune infiltration is warranted. Data were downloaded from TCGA and ArrayExpress databases. Cox analysis and machine learning algorithms were employed to establish a lncRNA-based prognostic model for HCC. We then developed a nomogram model to predict overall survival and odds of death for HCC patients. The association of this prognostic model with TMB and immune infiltration was also analyzed. In addition, a ceRNA network was constructed by using DIANA-LncBasev2 and the starBase database and verified by luciferase reporter and colocalization analysis. Multiplex immunofluorescence was applied to determine the correlation between ULBP1 and PD-L1. An eight-lncRNA (SLC25A30-AS1, HPN-AS1, LINC00607, USP2-AS1, HCG20, LINC00638, MKLN1-AS and LINC00652) prognostic score model was constructed for HCC, which was highly associated with TMB and immune infiltration. Next, we constructed a ceRNA network, LINC00638/miR-4732-3p/ULBP1, that may be responsible for NK cell infiltration in HCC with high TMB. However, patients with high ULBP1 possessed a poorer prognosis. Using multiplex immunofluorescence, we found a significant correlation between ULBP1 and PD-L1 in HCC, and patients with high ULBP1 and PD-L1 had the worst prognosis. In brief, the eight-lncRNA model is a reliable tool to predict the prognosis of HCC patients. The LINC00638/miR-4732-3p/ULBP1 axis may regulate immune escape via PD-L1 in HCC with high TMB. [ABSTRACT FROM AUTHOR]

Background: Aberrant DNA methylation is a critical regulator of gene expression and plays a crucial role in the occurrence, progression, and prognosis of colorectal cancer (CRC). We aimed to identify methylation-driven genes by integrative epigenetic and transcriptomic analysis to predict the prognosis of CRC patients. Methods: Methylation-driven genes were selected for CRC using a MethylMix algorithm and LASSO regression screening strategy, and were further used to construct a prognostic risk-assessment model. The Cancer Genome Atlas (TCGA) database was obtained as the training set for both the screening of methylation-driven genes and the effect of genes signature on CRC prognosis. Then, the prognostic genes signature was validated in three independent expression arrays of CRC data from Gene Expression Omnibus (GEO). Results: We identified 143 methylation-driven genes, of which the combination of BATF , PHYHIPL , RBP1 , and PNPLA4 expression levels was screened as a better prognostic model with the best area under the curve (AUC) (AUC = 0.876). Compared with patients in the low-risk group, CRC patients in the high-risk group had significantly poorer overall survival in the training set (HR = 2.184, 95% CI: 1.404–3.396, P < 0.001). Similar results were observed in the validation set. Moreover, VanderWeele's mediation analysis indicated that the effect of methylation on prognosis was mediated by the levels of their expression (HRindirect = 1.473, P = 0.001, Proportion mediated, 69.10%). Conclusions: We identified a four-gene prognostic signature by integrative analysis and developed a risk-assessment model that is significantly associated with patients' survival. Methylation-driven genes might be a potential prognostic signature for CRC patients. [ABSTRACT FROM AUTHOR]

Background: Systemic inflammation is associated with the prognosis of colorectal cancer (CRC). The current study aimed to construct a comprehensively inflammatory prognostic scoring system named risk score (RS) based on eosinophil- and basophil-related markers and assess its prognostic value in patients with stage II and stage III CRC., Patients and Methods: A total of 3,986 patients were enrolled from January 2007 to December 2013. The last follow-up time was January 2019. They were randomly assigned to the training set and testing set in a 3:2 split ratio. Least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was performed to select the optimal prognostic factors in the construction of RS. The Kaplan-Meier curve, time-dependent receiver operating characteristic (ROC), and Cox analysis were used to evaluate the association between RS and overall survival (OS)., Results: In the training set, all inflammatory markers showed certain prognostic values. Based on LASSO-Cox analysis, nine markers were integrated to construct RS. The Kaplan-Meier curve showed that a higher RS (RS > 0) had a significantly worse prognosis (log-rank p < 0.0001). RS (>0) remained an independent prognostic factor for OS (hazard ratio (HR): 1.70, 95% confidence interval (CI), 1.43-2.03, p < 0.001). The prognostic value of RS was validated in the entire cohort. Time-dependent ROC analysis showed that RS had a stable prognostic effect throughout the follow-up times and could enhance the prognostic ability of the stage by combination. Nomogram was established based on RS and clinicopathological factors for predicting OS in the training set and validated in the testing set. The area under the curve (AUC) values of the 3-year OS in the training and testing sets were 0.748 and 0.720, respectively. The nomogram had a satisfactory predictive accuracy and had better clinical application value than the tumor stage alone., Conclusions: RS might be an independent prognostic factor for OS in patients with stage II and III CRC, which is helpful for risk stratification of patients. Additionally, the nomogram might be used for personalized prediction and might contribute to formulating a better clinical treatment plan., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gao, Yuan, Fu, Tian, Huang, Zhang, Li, Liu, Meng, Liu, Zhang, Xu, Jia, Zhang, Zheng, Fu, Tan, Lan, Yang, Zhao and Liu.)

Background and Aims: Intestinal flora is closely associated with the occurrence and development of hepatocellular carcinoma (HCC). However, gut microbial changes and biological mechanisms in HCC after transarterial chemoembolization (TACE) treatment are rarely reported., Methods: We evaluated changes in intestinal flora after TACE in rabbit HCC models and assessed the impact of these changes on the disease. Twenty-four rabbit VX2 HCC models were established and intestinal flora structures, intestinal barrier function, changes in blood lipopolysaccharide (LPS) levels, Toll-like receptor 4 (TLR4), Cyclooxygenase-2 (COX-2), and p-signal transducer and activator of transcription 3(p-STAT3) protein expression levels were studied after TACE treatment., Results: Compared with healthy rabbits, the intestinal flora in HCC models exhibited structural changes; intestinal barrier function was decreased, and increased LPS levels entered the circulation. A short-term follow-up after TACE showed the procedure partially reversed the intestinal microflora disorder caused by the tumor: intestinal barrier and liver functions were improved, intestinal LPS levels in the blood were reduced, and liver metabolism toward LPS was enhanced. Correlation analyses of the first 75 significantly changed bacteria with clinical factors showed that harmful bacteria had decreased and beneficial bacteria increased. Blood LPS levels and downstream signaling molecule TLR4, COX-2, and p-STAT3 protein expression levels were reduced, which correlated with tumor drug resistance and invasion capabilities., Conclusions: We first characterized gut microbiota changes and biological mechanisms in HCC after TACE treatment. Our data provide a theoretical research basis for TACE combined with an intestinal flora intervention and systemic chemotherapy., Competing Interests: DZ was employed by the company 3D Medicines Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bian, Wang, Yu, Fu, Zhang, Zhu and Lv.)

Colorectal cancer (CRC) remains one of the most common malignancies worldwide and its mechanism is unclear. Polymeric immunoglobulin receptor (PIGR) which plays an important role in mucosal immunity is widely expressed in the mucosal epithelium and is dysregulated in different tumors. However, the role and underlying mechanisms of PIGR in CRC remain unclear. Here, we demonstrated that PIGR was hypermethylated and downregulated in our cohort (N = 272), and these features were associated with reduced overall survival in patients (HR methylation 1.61, 95% CI [1.11-2.33]). These findings were validated by external TCGA and GEO data. Moreover, PIGR overexpression inhibits CRC cell malignant phenotypes in vitro and impedes CRC cells growth in male BALB/c nude mice. Mechanistically, PIGR physically associates with RE1 silencing transcription factor (REST) and blocks the transcription of laminin subunit beta 3 (LAMB3). Subsequently, the AKT-FOXO3/4 axis was suppressed by downregulated LAMB3. In the drug sensitive assay, PIGR-overexpressing cells were more sensitive to cisplatin and gemcitabine. Together, PIGR may serve as a powerful prognostic biomarker and putative tumor suppressor by suppressing the AKT-FOXO3/4 axis by downregulating LAMB3 in CRC. Our study may offer a novel therapeutic strategy for treating CRC patients who highly express PIGR with cisplatin and gemcitabine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Huang, Zheng, Zhang, Cui, Liu, Tan, Zhao, Tian, Gao, Fu, Cheng and Zhao.)

Glioblastoma multiforme (GBM) is the most common, malignant, and deadly primary brain tumor in adults. Brain-expressed X-link (BEX) protein family is involved in tumorigenesis. Here, we have explored the biological function and the prognostic value of the BEX family in GBM. Differentially expressed BEX genes between GBM and normal tissue were screened by using The Cancer Genome Atlas (TCGA) database. Univariate and multivariate Cox regression analyses identified the prognosis-related genes BEX1, BEX2, and BEX4, which were involved in the regulation of immune response. The results of correlation analysis and protein-protein interaction network (PPI network) showed that there was a significant correlation between the BEX family and TCEAL family in GBM. Furthermore, the expression of transcription elongation factor A (SII)-like (TCEAL) family is generally decreased in GBM and related to poor prognosis. With the use of the least absolute shrinkage and selection operator (LASSO) Cox regression, a prognostic model including the BEX family and TCEAL family was built to accurately predict the likelihood of overall survival (OS) in GBM patients. Therefore, we demonstrated that the BEX family and TCEAL family possessed great potential as therapeutic targets and prognostic biomarkers in GBM. Further investigations in large-scale, multicenter, and prospective clinical cohorts are needed to confirm the prognostic model developed in our study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aisa, Tan, Li, Zhang, Shi and Yuan.)

Objective: The imaging features of peritoneal carcinomatosis (PC) with different locations and pathological types of colorectal cancer (CRC) on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) were analyzed and discussed., Methods: The PET/CT data of 132 patients with colorectal peritoneal carcinomatosis (CRPC) who met the inclusion and exclusion criteria between May 30, 2016, and December 31, 2019, were collected and analyzed. Observations included the location and pathological type of CRC, the peritoneal cancer index (PCI), standardized uptake maximum value (SUV max ), and retention index (RI) of the CRPC. Statistical analysis was performed using SPSS 20.0 software, and P < 0.05 was considered statistically significant., Results: (1) The range of the PCI in the 132 patients studied was 2-30, with a mean value of 7.40 ± 8.14. The maximum long diameter of the CRPC lesions ranged from 0.6 to 12.1 cm, with an average of 3.23 ± 1.94 cm. The SUV max ranged from 1.2 to 31.0, with a mean value of 9.65 ± 6.01. The SUV max and size correlation coefficient for maximal CRPC lesions was r = 0.47 ( P < 0.001). The RI range of the 72 patients who underwent time-lapse scanning was -10.0-112.2%, with RI quartiles of 13.5-48.9%; RI was ≥5% in 65 cases and <5% in seven cases. (2) The patients were grouped by the location of their CRC: the right-sided colon cancer (RCC, n = 37), left-sided colon cancer (LCC, n = 44), and rectal cancer groups (RC, n = 51). There were significant differences in the CRC pathological types ( P = 0.009) and PCI scores ( P = 0.02) between the RCC and RC groups and the RI between the RCC group and the other two groups ( P < 0.001). (3) There were 88 patients organized into three groups by the pathology of their CRC: the moderately well-differentiated adenocarcinoma (group A, n = 57), poorly differentiated adenocarcinoma (group B, n = 16), and mucinous adenocarcinoma groups (group C, n = 15 cases, including one case of signet-ring cell carcinoma). There were significant differences in the CRC position ( P = 0.003) and SUV max ( P = 0.03) between groups A and C., Conclusion: The PCI, SUV max , and RI of peritoneal metastatic carcinoma caused by CRC in different locations and pathological types vary. Mucinous adenocarcinoma and poorly differentiated adenocarcinoma are relatively common in the right colon, and the PCI of peritoneal metastatic carcinoma is fairly high, but the SUV max and RI are somewhat low., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Zhang, Gao, Mao, Tan, Bao and Shen.)