Evaluating the role of RAD52 and its interactors as novel potential molecular targets for hepatocellular carcinoma.

BACKGROUND: Radiation sensitive 52 (RAD52) is an important protein that mediates DNA repair in tumors. However, little is known about the impact of RAD52 on hepatocellular carcinoma (HCC). We investigated the expression of RAD52 and its values in HCC. Some proteins that might be coordinated with RAD52 in HCC were also analyzed. METHODS: Global RAD52 mRNA levels in HCC were assessed using The Cancer Genome Atlas (TCGA) database. RAD52 expression was analyzed in 70 HCC tissues and adjacent tissues by quantitative real-time PCR (qRT-PCR), Western blotting and immunohistochemistry. The effect of over-expressed RAD52 in Huh7 HCC cells was investigated. The String database was then used to perform enrichment and functional analysis of RAD52 and its interactome. Cytoscape software was used to create a protein-protein interaction network. Molecular interaction studies with RAD52 and its interactome were performed using the molecular docking tools in Hex8.0.0. Finally, these DNA repair proteins, which interact with RAD52, were also analyzed using the TCGA dataset and were detected by qRT-PCR. Based on the TCGA database, algorithms combining ROC between RAD52 and RAD52 interactors were used to diagnose HCC by binary logistic regression. RESULTS: In TCGA, upregulated RAD52 related to gender was obtained in HCC. The area under the receiver operating characteristic curve (AUC) of RAD52 was 0.704. The results of overall survival (OS) and recurrence-free survival (RFS) indicated no difference in the prognosis between patients with high and low RAD52 gene expression. We validated that RAD52 expression was increased at the mRNA and protein levels in Chinese HCC tissues compared with adjacent tissues. Higher RAD52 was associated with older age, without correlation with other clinicopathological factors. In vitro, over-expressed RAD52 significantly promoted the proliferation and migration of Huh7 cells. Furthermore, RAD52 interactors (radiation sensitive 51, RAD51; X-ray repair cross complementing 6, XRCC6; Cofilin, CFL1) were also increased in HCC and participated in some biological processes with RAD52. Protein structure analysis showed that RAD52-RAD51 had the firmest binding structure with the lowest E-total energy (- 1120.5 kcal/mol) among the RAD52-RAD51, RAD52-CFL1, and RAD52-XRCC6 complexes. An algorithm combining ROC between RAD52 and its interactome indicated a greater specificity and sensitivity for HCC screening. CONCLUSIONS: Overall, our study suggested that RAD52 plays a vital role in HCC pathogenesis and serves as a potential molecular target for HCC diagnosis and treatment. This study's findings regarding the multigene prediction and diagnosis of HCC are valuable.

The HLA-DRB1 allele polymorphisms and nasopharyngeal carcinoma.

Human leukocyte antigen (HLA)-DRB1 has been reported to influence individual's susceptibility to nasopharyngeal carcinoma (NPC) by many studies in recent years; however, these studies provided controversial results. The meta-analysis was thus conducted here to estimate the relationship between HLA-DRB1 polymorphisms and NPC. After an extensive review of journals from various databases (PubMed, the Web of Science, Embase, China National Knowledge Internet (CNKI), and Wanfang Database), 8 out of 69 case-control studies, including 778 cases and 1148 controls, were extracted. The results showed that 4 of 13 polymorphisms allele are statistically significantly associated with NPC, among them, HLA-DRB1*3, HLA-DRB1*9, and HLA-DRB1*10 may increase the risk of NPC while HLA-DRB1*01 has the opposite effect. The pooled odds ratio and 95 % confidence interval (CI) were 1.702 [95 % CI (1.047, 2.765)], 1.363 [95 % CI (1.029, 1.806)], 1.989 [95 % CI (1.042, 3.799)], and 0.461 [95 % CI (0.315, 0.676)], respectively. In a further ethnicity-based subgroup analysis, HLA-DRB1*08, HLA-DRB1*11, and HLA-DRB1*16 were found to be linked with NPC in Asian, Tunisian, and Caucasian, respectively. In Asian, HLA-DRB1*03, 08, and 10 may elevate the risk whereas HLA-DRB1*09 could lower it. In Tunisian, HLA-DRB1*01 and 11 are the protective factors while HLA-DRB1*03 is the only risk factor. In Caucasian, HLA-DRB1*01 and 03 increase the risk and HLA-DRB1*16 lowers it. The most frequent statistically associated gene is found to be HLA-DRB1*03 which has protective influence on Asian and Tunisian. In conclusion, HLA-DRB1*01, DRB1*03, DRB1*09, and DRB1*10 are related with NPC susceptibility, and the association of HLA-DRB1*08, DRB1*11, and DRB1*16 with NPC risk are significantly different in different ethnicities.

Impact of CAG repeat length in the androgen receptor gene on male infertility - a meta-analysis.

CAG repeats are polymorphic nucleotide repeats present in the androgen receptor gene. Many studies have estimated the association between CAG repeat length and male infertility, but the conclusions are controversial. Previous meta-analyses have come to different conclusions; however, new studies have been published. An updated meta-analysis was conducted. PubMed, CBM, CNKI and Web of Science databases were systematically searched for studies published from 1 January 2000 to 1 October 2015. Case-control studies on the association between CAG repeat length and male infertility using appropriate methodology were included. Forty studies were selected, including 3858 cases and 3161 controls. Results showed statistically significantly longer CAG repeat length among cases compared with controls (SMD = 0.14; 95% CI, 0.02-0.26). Shorter repeat length was associated with a lower risk of male infertility compared with a longer repeat length in the overall analysis (OR = 0.79, 95% CI: 0.66-0.95). Moreover, CAG repeat length was associated with male infertility in Caucasian populations, but not Asian or Egyptian populations. Subgroup analysis revealed no significant difference in German populations, but CAG repeat length was associated with male infertility in China and the USA. There were no significant differences between cases and controls in azoospermia and severe oligozoospermia.

Schweinfurthin induces ICD without ER stress and caspase activation.

Our previous study showed that one of the schweinfurthin compounds, 5'-methoxyschweinfurthin G (MeSG), not only enhances the anti-tumor effect of anti-PD1 antibody in the B16F10 murine melanoma model, but also provokes durable, protective anti-tumor immunity. Here we further investigated the mechanisms by which MeSG treatment induces immunogenic cell death (ICD). MeSG induced significant cell surface calreticulin (CRT) exposure in a time and concentration dependent manner as well as increased phagocytosis of tumor cells by dendritic cells in vitro. Interestingly, this CRT exposure differs from the canonical pathway in several aspects. MeSG does not cause ER stress and does not require PERK to induce CRT exposure. Caspase inhibitors partially rescue cells from MeSG-induced apoptosis, but fail to reduce CRT exposure. MeSG does not cause ERp57 exposure and the absence of ERp57 expression does not reduce CRT exposure. Finally, an intact ER to Golgi transport system is required for this phenomenon. These results lend support to the development of the schweinfurthin family as drugs to enhance clinical response to immunotherapy and highlight the need for additional research on the mechanisms of ICD induction.

Cause Analysis of the Large-Scale LPG Explosion Accident Based on Key Investigation Technology: A Case Study.

Blending dimethyl ether (DME) into liquefied petroleum gas (LPG) has become a common phenomenon. On December 3, 2019, an LPG/DME explosion occurred in Beijing, resulting in 4 deaths and 10 injuries. To deeply investigate the cause and explosion process of the explosion accident, the accident investigation method combining on-site inspection, material evidence analysis, experimental verification, and logical reasoning was used. In addition, the location of the ignition point, the explosive substances, the cause of the gas leakage, the process and the distribution characteristics of the gas leakage, and the ignition process were successively reasoned and analyzed in detail. The results show that the LPG/DME-blended gas can effectively corrode silicone flange gaskets, forming laminar fractures and radial cracks on the gasket. As a result, the tensile strength of the gasket decreased. Under the action of the gas pressure inside the pipeline, the gasket was torn and a leakage hole was formed. The leaked combustible gas formed at least 305 m3 of the explosive gas mixture inside and outside the refrigerated storage. The investigation and research results have important scientific guiding significance for revealing the cause and preventing similar accidents.

IVS8-5T Allele of CFTR is the Risk Factor in Chronic Pancreatitis, Especially in Idiopathic Chronic Pancreatitis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator IVS8-5T gene variation appears to be associated with a higher risk of chronic pancreatitis (CP); however, there is inconsistency between previous reported studies. Here, we performed a meta-analysis to investigate this relationship. MATERIALS AND METHODS: PubMed and WANFANG databases were searched for the case-control studies that contained Patients with CP with IVS8-5T variation. Odd ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the relevance of IVS8-5T gene variation and CP. RESULTS: Analysis showed that the frequency of the 5T allele was significantly higher in CP subjects than that in control subjects (OR = 1.43, 95% CI: 1.13-1.81, I2 = 1.2%). Based on the subgroup analysis stratified by etiology, the 5T allele was associated with a higher risk of idiopathic chronic pancreatitis (ICP) (OR = 1.80, 95% CI: 1.18-2.76, I2 = 0.0%) and not alcoholic CP (OR = 2.14, 95% CI: 0.98-4.66, I2 = 0.0%). Further study indicated that the 5T allele was related to higher ICP prevalence in the European population (OR = 1.79, 95% CI: 1.06-3.03, I2 = 0.0%). In contrast, there was no significant difference between ICP subjects and healthy controls within the Asian population (OR = 1.84, 95% CI: 0.91-3.72, I2 = 38.0%). CONCLUSIONS: Cystic fibrosis transmembrane conductance regulator IVS8-5T is a risk factor in patients with CP. IVS8-5T variation may play a significant role in the occurrence of ICP, especially in the European population.

Association Between the Asp312Asn, Lys751Gln, and Arg156Arg Polymorphisms in XPD and the Risk of Prostate Cancer.

Prostate cancer is the most common solid cancer and genetic factors play important roles in its pathogenesis. XPD is one of the 8 core genes involved in the nucleotide excision repair pathway. The relationship between Asp312Asn, Lys751Gln, and Arg156Arg polymorphisms in XPD and prostate cancer risk is a controversial topic. Therefore, we conducted a meta-analysis to explore the relationship between these 3 polymorphisms and the risk of developing prostate cancer. We searched the electronic literature in PubMed and Google Scholar for all relevant studies (last updated January 1, 2017). The pooled odds ratios and 95% confidence intervals for the associations between the Asp312Asn, Lys751Gln, or Arg156Arg polymorphisms in XPD and prostate cancer risk were calculated. To evaluate the effects of specific study characteristics on the association of these 3 polymorphisms and prostate cancer risk, we performed subgroup analysis if 2 or more studies were available. After an extensive literature review, 7 publications regarding Asp312Asn genotype distribution with 8 case-controls, 9 publications regarding Lys751Gln genotype distribution with 10 case-controls, and 3 publications regarding Arg156Arg genotype distribution with 4 case-controls were selected. The results showed that Asp312Asn (odds ratio = 1.34, 95% confidence interval: 0.96-1.87, P = .000), Lys751Gln (odds ratio = 0.98, 95% confidence interval: 0.89-1.08, P = .986), and Arg156Arg (odds ratio = 1.05, 95% confidence interval: 0.91-1.22, P = .57) polymorphisms do not increase the risk of prostate cancer in the dominant model. Further, in the subgroup analysis by ethnicity, no relationships were observed between Lys751Gln and Arg156Arg polymorphisms and prostate cancer risk. However, stratified analysis by ethnicity revealed that Asp312Asn affects African (odds ratio = 1.57, 95% confidence interval: 1.06-2.33, P = .382) and Asian populations (odds ratio = 2.09, 95% confidence interval: 1.39-3.14, P = .396) in homozygote comparison. In conclusion, this meta-analysis suggests that there is no general association between the Asp312Asn, Lys751Gln, and Arg156Arg polymorphisms in XPD and prostate cancer susceptibility.

Shorter GGN Repeats in Androgen Receptor Gene Would Not Increase the Risk of Prostate Cancer.

The association between the polymorphic GGN repeat in androgen receptor gene and prostate cancer susceptibility has been studied extensively. But the results of these polymorphisms with prostate cancer risk remain inconclusive. Previous meta-analysis showed short GGN repeats (≤16 repeats) had high risks for prostate cancer compared with longer GGN repeats (>16 repeats). Many studies have been published since the release of the previous meta-analysis. Here, we conducted an updated meta-analysis to demonstrate whether short repeats have higher risks for prostate cancer compared to long repeats. Five databases (PubMed, EMBASE, Cochrane Library, The China National Knowledge Infrastructure, and Web of Science) were last searched until January 1, 2016. Random- or fixed-effects model was performed based on the heterogeneity among studies. The potential publication bias was assessed via Begg funnel plot and Egger regression test. Twelve out of 157 studies were extracted. The result indicated that there was no significant difference between short repeat group and long repeat group in the overall analysis ( I2 = 80.6%, P = .000, odds ratio = 1.31, 95% confidence interval: 0.93-1.83). There was no association between the length of GGN repeats and the occurrence of prostate cancer in both Caucasian and African American ( I2 = 6.7%, P = .359, odds ratio = 1.11, 95% confidence interval: 0.94-1.32; and I2 = 74.1%, P = .050, odds ratio = 0.963, 95% confidence interval: 0.36-2.58). Our result demonstrated that a shorter GGN repeat polymorphism cannot increase the risk of prostate cancer compared to the longer GGN repeats. That's different with previous meta-analysis.

Methylation of S100A8 is a promising diagnosis and prognostic marker in hepatocellular carcinoma.

The abnormality of DNA methylation is one of the major epigenetic alterations in the human hepatocellular carcinoma (HCC). We have assessed the global genomic DNA methylation profiles in human HCC patients by using the Infinium Human Methylation27 BeadChip. A CpG loci of S100A8 was found to be significantly hypomethylated in HCC.Pooled meta-analysis of five validation public datasets demonstrated its methylation level was significantly lower for HCC compared to paired adjacent normal tissues. Quantitative pyrosequencing analysis also showed that the S100A8 methylation level was decreased in cancer tissues (31.90%±13.31%) than that in the paired adjacent normal tissues (65.33%±3.64%, p<0.01). The area under the ROC curve (AUC) value was 0.950 (p<0.01). Kaplan-Meier survival curves revealed that hypomethylation of S100A8 was associated with shortened overall survival (OS) and progression-free survival (PFS) (log rank p<0.05). Multivariate Cox proportional hazards model also indicated significantly shorter OS (HR, 1.709; 95 % CI, 1.127-2.591) and PFS (HR, 1.767; 95 % CI, 1.168-2.974) were observed in the low-methylation-level group compared to the high-methylation-level group. Furthermore, S100A8 overexpression in Huh7 and MHCC-97H hepatoma cell lines led to increased cell proliferation, migration, invasion, and tumor growth. These findings suggested S100A8 methylation to be served as potential diagnosis and prognosis marker for HCC. S100A8 also may play as a tumor promoter in HCC.