Prognostic effect of DNA methylation of BTG2 gene in Chinese hepatocellular carcinoma.

Background: This study aims to develop a prognostic model for overall survival based on potential methylation sites within B-cell translocation gene 2 (BTG2) in Chinese patients with hepatocellular carcinoma (HCC). Methods: This is a retrospective study. The beta values of nine CpG sites and RSEM normalized count values of BTG2 gene were extracted from the Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) (TCGA-LIHC) dataset, with the beta value representing the methylation level by indicating the ratio of the intensity of the methylated bead type to the combined locus intensity. Pyrosequencing was performed to determine the range of methylation values surrounding cg01798157 site in BTG2 gene. A weighted linear model was developed to predict the overall survival (OS). Results: The beta value of cg01798157 was significantly negatively associated with the mRNA expression of BTG2 in the TCGA-LIHC dataset (Spearman's rho = -0.5306, P = 2.27 × 10-27). The methylation level of cg01798157 was significantly associated with OS in the cohort of 51 Chinese HCC patients (Hazard ratio = 0.597, 95% CI: 0.434-0.820, P = 0.001). Multivariate Cox regression analysis identified methylation level of cg01798157, cirrhosis, and microvascular invasion as independent prognostic factors. The prognostic efficiency of death risk score was superior to that of cirrhosis or microvascular invasion alone. Conclusions: The methylation level of cg01798157 in BTG2 may be an epigenetic biomarker in Chinese patients with resectable HCC.

E3 ubiquitin ligase TRIM21 targets TIF1γ to regulate ß-catenin signaling in glioblastoma.

Background: Elucidation of the mechanism of ubiquitation has led to novel ways to treat glioblastoma (GBM). A tripartite motif (TRIM) protein mediates a reversible, stringent ubiquitation which is closely related to glioma malignancy. This study intends to screen the most vital and abnormal regulating component of the tripartite motif protein and to explore its underlying mechanisms. Methods: TRIM21 is identified as an important oncogene that accelerates the progression of glioma cell through database in a multidimensional way and this is confirmed in human samples and cells. Tandem Mass Tags (TMT) and MS analysis are performed to discover the substrates of TRIM21.The underlying mechanisms are further investigated by CO-IP, luciferase reporter assays and gain and loss of function assays. In vivo treatment with siRNA is applied to evaluate the therapeutic significance of TRIM21. Result: We screened a panel of TRIM proteins and identified TRIM21, a E3 ubiquitin-protein ligase and autoantigen, as well as a prognostic biomarker for GBM. Functionally, high expression of wild-type TRIM21 accelerates tumor progression in vitro and in vivo, whereas TRIM21 mutants, including one with a critical RING-finger deletion, do not. Mechanistically, TRIM21 stimulates K63-linked ubiquitination and subcellular translocation of active ß-catenin from the cytoplasm to the nucleus. Moreover, TRIM21 forms a complex with the ß-catenin upstream regulator, TIF1γ, in the nucleus and accelerated its degradation by inducing K48-linked ubiquitination at K5 site, consequently increasing further nuclear ß-catenin presence. Endogenous TRIM21 levels are found to be inversely correlated with TIF1γ but positively correlated with ß-catenin in glioma tissue microarray experiments. Furthermore, direct injection of TRIM21 small interfering RNA (siRNA) into U87 cell-derived tumors (in vivo treatment with siRNA) is proved to inhibit tumor growth in nude mice. Conclusion: This work suggests that TRIM21/TIF1γ/ß-catenin axis is involved in the progression of human GBM. TRIM21 is a promising therapeutic and prognostic biomarker for glioma with hyperactive ß-catenin.

Rapid Progress in Intelligent Radiotherapy and Future Implementation.

Radiotherapy is one of the major approaches to cancer treatment. Artificial intelligence in radiotherapy (shortly, Intelligent radiotherapy) mainly involves big data, deep learning, extended reality, digital twin, radiomics, Internet plus and Internet of Things (IoT), which establish an automatic and intelligent network platform consisting of radiotherapy preparation, target volume delineation, treatment planning, radiation delivery, quality assurance (QA) and quality control (QC), prognosis judgment and post-treatment follow-up. Intelligent radiotherapy is an interdisciplinary frontier discipline in infancy. The review aims to summary the important implements of intelligent radiotherapy in various areas and put forward the future of unmanned radiotherapy center.

Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC.

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.

Clinical significance of interleukin-10 concentration in the cerebrospinal fluid of patients with primary central nervous system lymphoma.

The diagnostic and prognostic evaluation of primary central nervous system lymphoma (PCNSL) is challenging due to the lack of sensitive biomarkers. The present study aimed to evaluate the value of interleukin (IL)-10 in this context. Between October 2016 and December 2018, 91 patients with suspected intracranial neoplasms were recruited, and the concentrations of IL-10 or IL-6 in both the cerebrospinal fluid (CSF) and blood were measured and analyzed by the Kruskal-Wallis test. The correlation between CSF IL-6 or IL-10 levels and tumor size was determined by Spearman's coefficient analysis. The receiver operating characteristic curve was used to evaluate the diagnostic value of CSF IL-6 and IL-10 levels. Median progression-free survival (PFS) and overall survival time were calculated using Kaplan-Meier survival analysis. Among the 91 patients, 3 were diagnosed with PCNSL on the basis of neuroimaging data and CSF IL-10 levels. A total of 35 cases were verified to show diffuse large B-cell lymphoma on histological assessment, 17 of which were diagnosed as PCNSL by MRI. The median PFS and OS were 8.00 months [95% confidence interval (CI), 3.94-12.06) and 17.5 months (95% CI, 11.55-23.45) respectively in the 12 PNCSL cases with regular follow up. The diagnostic efficiency of serum IL-6 levels was lower than that of serum IL-10 levels (P=0.030), which, in turn, was lower than that of CSF IL-10 levels (P<0.001). The decline and increase in CSF IL-10 levels was concurrent with improvement and deterioration in manifestation, respectively, which predated the MRI variation. High CSF IL-10 levels indicated low Karnofsky performance scale scores and shortened PFS times. CSF IL-10 levels higher than 1,000 pg/ml signified disease progression. CSF IL-10 levels could be a sensitive biomarker guiding the differential diagnosis, early recurrence detection, prognostic evaluation and therapeutic strategy establishment in cases of PCNSL.

The diagnostic role and dynamic changes in cerebrospinal fluid neopterin during treatment of patients with primary central nervous system lymphoma.

This study aimed at evaluating the diagnostic and prognostic role of neopterin (Npt) concentration in the cerebrospinal fluid (CSF) of patients with primary central nervous system lymphoma (PCNSL). Ninety-nine patients were enrolled in this retrospective study; these included patients with PCNSL (n = 21), other brain tumors (n = 44), and inflammatory diseases (n = 34). CSF Npt concentration was measured using ELISA. Receiver operating characteristic (ROC) curve analysis was performed to assess the discriminative ability of CSF Npt concentration for the diagnosis of PCNSL. CSF Npt concentration in patients with PCNSL was significantly higher than that in patients with other brain tumors and inflammatory diseases (P < .001). On ROC curve analysis, the optimal cutoff CSF Npt level of 10.77 ng/mL for the diagnosis of PCNSL and the diagnostic yield of MRI were increased when used in conjunction with CSF Npt concentration. The CSF Npt concentrations in PCNSL patients with multiple lesions were significantly higher than those in patients with a single lesion. Changes in CSF Npt concentration were consistent with post-treatment changes in tumor sizes. The CSF Npt concentration may be a good biomarker for the diagnosis, for monitoring of disease course, and for prognostic evaluation of patients with PCNSL.

The predictive value of pre- and post-induction chemotherapy plasma EBV DNA level and tumor volume for the radiosensitivity of locally advanced nasopharyngeal carcinoma.

This study was dedicated to investigate the predictive value of pre- and post-induction chemotherapy plasma EBV (Epstein-Barr Virus) DNA level and tumor volume for the radiosensitivity of locally advanced NPC. 129 previously untreated locally advanced NPC patients were enrolled. Plasma EBV-DNA copy number and tumor volume was detected before and after induction chemotherapy. The tumor volume was also measured after radiotherapy. Among 129 patients, 98 were positive for EBV DNA. The residual gross target volume of the primary tumor (GTVnx) and GTVnd after radiotherapy was positively correlated with post-induction chemotherapy EBV copy number (rho=0.357, P<0.001; rho=0.356, P<0.001, respectively). Univariate logistic regression analyses showed that the AUC of ROC curves of post-induction chemotherapy tumor volume, tumor regression rate before and after induction chemotherapy, post-induction EBV copy number, EBV decrease rate for predicting no residual nasopharyngeal tumor were 0.859, 0.782, 0.678 and 0.657, respectively. Multivariate logistic analyses showed that T stage, post-induction chemotherapy EBV copy number and tumor volume were independent predictors for no residual nasopharyngeal tumor after radiotherapy. The changes in plasma EBV DNA and tumor volume during treatment could be used to predict the sensitivity of locally advanced NPC patients in response to intensity-modulated radiation therapy (IMRT).