Transcription factor E2F3 activates CDC25B to regulate DNA damage and promote mitoxantrone resistance in stomach adenocarcinoma.

BACKGROUND: CDC25B, as a member of the cell cycle regulating protein family, is located in the cytoplasm and is involved in the transition of the cell cycle and mitosis. CDC25B is highly expressed in various tumors and is a newly discovered oncogene. This study aimed to investigate the impact of CDC25B on mitoxantrone resistance in stomach adenocarcinoma (STAD) and its possible mechanisms. METHODS: This study analyzed the expression of CDC25B and its potential transcription factor E2F3 in STAD, as well as the IC50 values of tumor tissues by bioinformatics analysis. Expression levels of CDC25B and E2F3 in STAD cells were measured by qRT-PCR. MTT was utilized to evaluate cell viability and IC50 values of STAD cells, and comet assay was utilized to analyze the level of DNA damage in STAD cells. Western blot was used to analyze the expression of DNA damage-related proteins. The targeting relationship between E2F3 and CDC25B was validated by dual-luciferase and ChIP assays. RESULTS: Bioinformatics analysis and molecular experiments showed that CDC25B and E2F3 were highly expressed in STAD, and CDC25B was enriched in the mismatch repair and nucleotide excision repair pathways. The IC50 values of tumor tissues with high expression of CDC25B were relatively high. Dual-luciferase and ChIP assays confirmed that CDC25B could be transcriptionally activated by E2F3. Cell experiments revealed that CDC25B promoted mitoxantrone resistance in STAD cells by regulating DNA damage. Further research found that low expression of E2F3 inhibited mitoxantrone resistance in STAD cells by DNA damage, but overexpression of CDC25B reversed the impact of E2F3 knockdown on mitoxantrone resistance in STAD cells. CONCLUSION: This study confirmed a novel mechanism by which E2F3/CDC25B mediated DNA damage to promote mitoxantrone resistance in STAD cells, providing a new therapeutic target for STAD treatment.

E2F1 Facilitates the Proliferation and Stemness of Gastric Cancer Cells by Activating CDC25B Transcription and Modulating the MAPK Pathway.

Gastric cancer (GC) is a health problem that concerns people around the world. CDC25B is an essential cell cycle regulatory factor that is overexpressed in a variety of tumor cells. CDC25B plays a vital part in the progression and proliferation of malignant tumors. However, it is not yet clear that how CDC25B affects the stemness of GC cells. The study used bioinformatics to detect the expression of E2F1 and CDC25B in GC tissues and their correlation, as well as pathways enriched by CDC25B. We detected the expression of E2F1 and CDC25B in GC cell lines using quantitative reverse transcription polymerase chain reaction and tested the combination relationship between E2F1 and CDC25B using chromatin immunoprecipitation (ChIP) and dual-luciferase assays. We measured cell viability using CCK-8 assay, evaluated sphere-forming efficiency using sphere formation assay, and determined cell proliferation ability using colony formation assay. We also analyzed the expression of stemness markers and MAPK pathway-related proteins using western blot. In GC tissues and cells, CDC25B was upregulated. Silencing CDC25B could affect the MAPK pathway, thereby repressing the proliferation and stemness of GC cells. As predicted by bioinformatics, CDC25B had an upstream transcription factor, E2F1, which also had a high expression level in GC. Dual-luciferase and ChIP assays confirmed the combination relationship between the two. Rescue experiments uncovered that overexpression of CDC25B could reverse the impact induced by E2F1 knockdown on proliferation and stemness of cells. In conclusion, E2F1 could activate CDC25B transcription to regulate the MAPK pathway and enhance the proliferation and stemness of GC cells. We revealed a potential regulatory pathway of stemness of GC cells that was mediated by CDC25B, providing new ideas for improving and innovating GC treatment.

Deep brain stimulation of the thalamic ventral intermediate nucleus for Benedikt's syndrome mainly present as tremor: a long-term case observation.

Benedikt's syndrome (BS) is caused by the lesion in the midbrain and specifically manifests a series of symptoms, including ipsilateral third nerve palsy, contralateral tremor, hemiataxia, and hyperactive tendon reflexes. Deep brain stimulation (DBS) for BS emerges as a new approach and achieves successfully results. We report a successful case report of thalamic ventral intermediate (VIM) nucleus DBS for a patient with BS. During follow-up of 3 years, DBS successfully control the tremor and greatly improve his living and working quality. We consider that VIM DBS may have sustained benefit for refractory BS that mainly presents as tremor.

Fatty Acid Metabolism Signature Contributes to the Molecular Diagnosis of a Malignant Gastric Cancer Subtype with Poor Prognosis and Lower Mutation Burden.

BACKGROUND: Gastric cancer (GC) is a common gastrointestinal tumor with high morbidity and mortality. Fatty acid metabolism (FAM) contributes to GC development. Patents have been issued for the use of compositions comprising fatty acid analogues for the treatment of many clinical conditions. However, its clinical significance and its relationship with tumor-related mutations have not been thoroughly discovered. This study was conducted to analyze and explore FAM-related genes' molecular characteristics, prognostic significance, and association with tumor-related mutations. METHODS: The gastric adenocarcinoma's transcriptome, clinical data, and tumor mutation load (TMB) data were downloaded from TCGA and GEO databases. The differentially expressed FAM genes (FAM DEGs) between cancer and control samples were screened, and their correlation with TMB and survival was analyzed. A PPI network of FAM DEGs was constructed, and a downscaling clustering analysis was performed based on the expression of the FAM DEGs. Further immuno-infiltration and GO/KEGG enrichment analyses of the identified FAM clusters were performed to explore their heterogeneity in biological functions. The effects of FAM score and gastric cancer (STAD) on TMB, MSI, survival prognosis, and drug sensitivity were jointly analyzed, and finally, a single-gene analysis of the obtained core targets was performed. RESULTS: Through differential analysis, 68 FAM DEGs were obtained, and they were highly associated with STAD tumor mutation load. In addition, a high FAM DEGs CNV rate was observed. The PPI network showed a complex mutual correlation between the FAM DEGs. Consensus clustering classified the patients into three clusters based on the FAM DEGs, and the clusters presented different survival rates. The GSVA and immune infiltration analysis revealed that metabolism, apoptosis, and immune infiltration-related pathways were variated. In addition, FAM genes, STAD prognostic risk genes, and PCA scores were closely associated with the survival status of STAD patients. FAM score was closely correlated with STAD TMB, MSI, and immunotherapy, and the TMB values in the low FAM score group were significantly higher than those in the high FAM score group. Finally, combining the above results, it was found that the core gene PTGS1 performed best in predicting STAD survival prognosis and TMB/MSI/immunotherapy. CONCLUSION: Fatty acid metabolism genes affect the development of gastric adenocarcinoma and can predict the survival prognosis, tumor mutational load characteristics, and drug therapy sensitivity of STAD patients, which can help explore more effective immunotherapy targets for GC.

Construction of a Prognostic Evaluation Model for Stomach Adenocarcinoma on the Basis of Immune-Related lncRNAs.

Progression, prognosis, and therapeutic strategy of stomach adenocarcinoma (STAD) have a close connection with tumor microenvironment (TME). Thus, it is pivotal to delve into the TME and immune-related genes, which may bring possibilities for improving patient's prognosis. TCGA-STAD dataset was analyzed to acquire differentially expressed lncRNAs in tumor samples, which were overlapped with the immune-related lncRNA datasets in the ImmLnc database. Twenty-six lncRNAs related to STAD immunity and patient's prognosis were acquired by univariate Cox analysis. Following lncRNA expression patterns, STAD samples could be classified into two clusters with completely different immune patterns. We performed multivariate Cox regression analysis on lncRNAs to identify 7-feature lncRNAs and constructed a corresponding prognostic model. The model validity was verified by survival analysis and ROC curve in validation and training sets. To explore connection between model and TME and tumor drug resistance, this study analyzed differences in immune cell infiltration between samples from high- and low-risk groups and then revealed immune cells follicular helper with significant differences in tumor tissue infiltration. Analysis of resistance to chemotherapeutic drugs revealed that samples in the high-risk group had resistance to cisplatin, doxorubicin, bleomycin, and gemcitabine. Through univariate and multivariate Cox analyses, we manifested that risk score could be an independent prognostic factor. Combining risk score and clinical factors, a nomogram was constructed to accurately predict patient's prognosis. This model can effectively predict prognosis, TME, and drug resistance of STAD patients, which may provide a reference for tumor development evaluation and precise treatment for clinical STAD.

lncRNA DSCR8 mediates miR-137/Cdc42 to regulate gastric cancer cell proliferation, invasion, and cell cycle as a competitive endogenous RNA.

lncRNA DSCR8 (Down syndrome critical region 8) is involved in progression of many cancers, but its specific role in gastric cancer (GC) is still unclear. Here, qRT-PCR detected upregulated expression of DSCR8 and Cdc42 and downregulated expression of miR-137 in GC. The protein expression level of Cdc42 in GC was upregulated as tested by western blot. Statistical analysis showed that DSCR8 was closely associated with some malignant clinicopathological features (such as tumor size, metastasis, and stage) in GC patients. Fluorescence in situ hybridization showed that DSCR8 was localized in the nucleus and cytoplasm. Dual-luciferase reporter gene, RNA immunoprecipitation, and biotin pull-down assays showed that DSCR8 could bind to miR-137 could bind to Cdc42. In vitro and in vivo assays showed that DSCR8 could promote proliferation, invasion, and the cycle of GC cells and inhibit cell apoptosis. In addition, a rescue experiment showed that DSCR8 regulated progression of GC cells via miR-137. Furthermore, DSCR8 regulated Cdc42 in GC cells by inhibiting miR-137. Taken together, these data indicated that DSCR8 could adsorb miR-137 to reduce its inhibitory effect on Cdc42 expression, thereby promoting the progression of GC cells and regulating the cell cycle. These results provide a novel direction for DSCR8 as a target of GC.

Effects of bilateral subthalamic nucleus deep brain stimulation on motor symptoms in Parkinson's disease: a retrospective cohort study.

Deep brain stimulation of the bilateral subthalamic nucleus (STN) is a therapeutic option for patients with Parkinson's disease (PD) in whom medical therapies have been ineffective. This retrospective cohort study analyzed the motor function of 27 patients with advanced PD, from the First Affiliated Hospital of Guangzhou Medical University, China, who received deep brain stimulation of the bilateral subthalamic nucleus and evaluated its therapeutic effects. The 10-year follow-up data of patients was analyzed in Qingyuan People's Hospital, Sixth Affiliated Hospital of Guangzhou Medical University, China. The follow-up data were divided into two categories based on patients during levodopa treatment (on-medication) and without levodopa treatment (off-medication). Compared with baseline, the motor function of on-medication PD patients improved after deep brain stimulation of the bilateral subthalamic nucleus. Even 2 years later, the motor function of off-medication PD patients had improved. On-medication PD patients exhibited better therapeutic effects over the 5 years than off-medication PD patients. On-medication patients' akinesia, speech, postural stability, gait, and cognitive function worsened only after 5 years. These results suggest that the motor function of patients with advanced PD benefitted from treatment with deep brain stimulation of the bilateral subthalamic nucleus over a period up to 5 years. The overall therapeutic effects were more pronounced when levodopa treatment was combined with deep brain stimulation of the bilateral subthalamic nucleus. This study was approved by Institutional Review Board of Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, China (approval No. QPH-IRB-A0140) on January 11, 2018.

Expression of HER2/c-erbB-2, EGFR Protein in Gastric Carcinoma and its Clinical Significance.

OBJECTIVE: To investigate the HER2/c-erbB-2, epidermal growth factor receptor (EGFR) protein expression in gastric cancer and association with patients' clinical pathology characteristics and prognosis. METHODS: HER2/c-erbB-2 and EGFR protein expression was examined by immunohistochemical assay in gastric cancer tissue and corresponding paired normal gastric tissue of 67 patients of gastric carcinoma. The HER2/c-erbB-2, EGFR protein positive expression rate in cancer tissue and normal gastric tissue were compared. The correlation between HER2/c-erbB-2, EGFR protein positive expression and patients' clinical pathology characteristics and survival was evaluated. RESULTS: The positive expression rate of HER2/c-erbB-2 in the cancer and paired normal gastric tissues were 32.8% (22/67) and 4.5% (3/67), respectively with statistical difference (p<0.05). And the positive expression rate of EGFR in cancer and paired normal gastric tissues were 41.8% (28/67) and 5.9 (4/67), respectively, with statistical difference (p<0.05). HER2/c-erbB-2 positive expression in cancer tissue was significant correlated with the pathology grading (p<0.05), tumor invasion depth (p<0.05) and local regional lymph node metastasis (p<0.05); EGFR positive expression in cancer tissue was significant correlated with the tumor invasion depth (p<0.05) and local regional lymph node metastasis (p<0.05). The median survival time was 13.14 and 23.6 months respectively for HER2/c-erbB-2 positive and negative expression groups respectively with statistical difference ( HR=2.26, 9%CI:1.06-4.80, p<0.05). However, the median survival time was 15.47 and 22.87 months for EGFR positive and negative expression groups respectively, without statistical difference (HR=1.78, 9%CI:0.96-3.29, p>0.05). CONCLUSION: Positive expression of HER2/c-erbB-2 and EGFR proteins in cancer tissue was significant higher than normal gastric tissue and have significant correlation with prognosis.