A deep learning algorithm with good prediction efficacy for cancer-specific survival in osteosarcoma: A retrospective study.

OBJECTIVE: Successful prognosis is crucial for the management and treatment of osteosarcoma (OSC). This study aimed to predict the cancer-specific survival rate in patients with OSC using deep learning algorithms and classical Cox proportional hazard models to provide data to support individualized treatment of patients with OSC. METHODS: Data on patients diagnosed with OSC from 2004 to 2017 were obtained from the Surveillance, Epidemiology, and End Results database. The study sample was then divided randomly into a training cohort and a validation cohort in the proportion of 7:3. The DeepSurv algorithm and the Cox proportional hazard model were chosen to construct prognostic models for patients with OSC. The prediction efficacy of the model was estimated using the concordance index (C-index), the integrated Brier score (IBS), the root mean square error (RMSE), and the mean absolute error (SME). RESULTS: A total of 3218 patients were randomized into training and validation groups (n = 2252 and 966, respectively). Both DeepSurv and Cox models had better efficacy in predicting cancer-specific survival (CSS) in OSC patients (C-index >0.74). In the validation of other metrics, DeepSurv did not have superiority over the Cox model in predicting survival in OSC patients. CONCLUSIONS: After validation, our CSS prediction model for patients with OSC based on the DeepSurv algorithm demonstrated satisfactory prediction efficacy and provided a convenient webpage calculator.

Copper deprivation enhances the chemosensitivity of pancreatic cancer to rapamycin by mTORC1/2 inhibition.

Cuproplasia, or copper-dependent cell proliferation, has been observed in varieties of solid tumors along with aberrant copper homeostasis. Several studies reported good response of patients to copper chelator assisted neoadjuvant chemotherapy, however, the internal target molecules are still undetermined. Unravel copper-associated tumor signaling would be valuable to forge new links to translate biology of copper into clinical cancer therapies. We evaluated the significance of high-affinity copper transporter-1 (CTR1) by bioinformatic analysis, and in 19 pairs of clinical specimens. Then, with the help of gene interference and chelating agent, enriched signaling pathways were identified by KEGG analysis and immunoblotting. Accompanying biological capability of pancreatic carcinoma-associated proliferation, cell cycle, apoptosis, and angiogenesis were investigated. Furthermore, a combination of mTOR inhibitor and CTR1 suppressor has been assessed in xenografted tumor mouse models. Hyperactive CTR1 was investigated in pancreatic cancer tissues and proven to as the key point of cancer copper homeostasis. Intracellular copper deprivation induced by CTR1 gene knock-down or systematic copper chelation by tetrathiomolybdate suppressed proliferation and angiogenesis of pancreatic cancer cell. PI3K/AKT/mTOR signaling pathway was suppressed by inhibiting the activation of p70(S6)K and p-AKT, and finally inhibited mTORC1 and mTORC2 after copper deprivation. Additionally, CTR1 gene silencing successfully improved the anti-cancer effect of mTOR inhibitor rapamycin. Our study reveals that CTR1 contributes to pancreatic tumorigenesis and progression, by up-regulating the phosphorylation of AKT/mTOR signaling molecules. Recovering copper balance by copper deprivation addresses as promising strategy for improved cancer chemotherapy.

GARS is implicated in poor survival and immune infiltration of hepatocellular carcinoma.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a malignant cancer with poor survival rates. Glycyl-tRNA synthetase (GARS) is a tRNA-charging enzyme that can serve as a biomarker for multiple tumors. Nevertheless, the role of GARS in HCC remains unclear. METHODS: The expression, clinical significance, prognostic value, genetic alterations, immune infiltration and histone modification of GARS in HCC were assessed using multiple databases. The role of GARS in HCC cells was also verified by CCK-8, cell cycle analysis and apoptosis assays in vitro and by a xenograft model in vivo. RESULTS: GARS levels were upregulated in HCC tissues and cells. GARS was confirmed to be a prognostic factor in HCC patients and was significantly correlated with immune infiltration. Enhanced GARS expression in HCC was induced by histone modification of the GARS promotor. Functional network analysis showed that GARS and its coexpressed genes regulate the cell cycle, lysosome and spliceosome. Furthermore, we found that GARS depletion inhibited HCC cell proliferation and cell cycle progression and promoted apoptosis in vitro. GARS overexpression promoted growth, reduced xenograft apoptosis and enhanced CD206+ tumor-associated macrophage infiltration in vivo. CONCLUSION: Our study indicates that GARS is a promising prognostic and therapeutic marker in HCC and might provide new directions and strategies for HCC treatment.

Abnormal Activations of Super-Enhancers Enhance the Carcinogenicity in Lung Adenocarcinoma.

BACKGROUND: Lung tumors and normal lung tissues show large differences in epigenetic modification which can affect the chromosome structure and expression of genes. However, the epigenetic reprogramming in lung adenocarcinoma remains unclear. METHODS AND RESULTS: With the bioinformatics analysis, we found that some activated super-enhancers (SEs) only appear in lung adenocarcinoma cells, and 781 abnormal activated super-enhancers (AASEs) were found. Not only are the traditional oncogenes found to be activated by AASEs, such as MET and SLC2A1, but also some new genes were activated by AASEs, which probably contributes to the carcinogenic process in lung cancer. The enrichment analysis of the genes activated by AASEs shows that the glycolysis process and cell proliferation were enhanced and the apoptotic process was negatively regulated. Two AASEs were separately knockout by CRISPR/Cas9 in A549, PC-9, and H1299 cell lines and the expression of target genes decreased. The motif of CTCF, SMARCA1, SOX4, FOXM1, IRF3, IRF7, and STAT2 was enriched in AASEs, supporting that the chromosome structure changed and these transcription factors would be the master regulators on the formation of AASEs. CONCLUSION: This study provided comprehensive insight into the mechanisms of SEs, as well as a potential therapeutic target for lung cancer.

LncRNA SNHG9 is Downregulated in Non-Small Cell Lung Cancer and Suppressed miR-21 Through Methylation to Promote Cell Proliferation.

BACKGROUND: LncRNA SNHG9 has been shown to be an oncogenic lncRNA in glioblastoma, while its role in other cancers is unknown. The aim of this study was to investigate the role of SNHG9 in non-small cell lung cancer (NSCLC). METHODS: The differential expression of SNHG9 in NSCLC was first explored by analyzing the TCGA dataset, followed by measuring the expression levels of SNHG9 in paired NSCLC and non-tumor tissues by RT-qPCR. Expression of miR-21 was also determined by RT-qPCR. Correlations were analyzed by linear regression. The interaction between miR-21 and SNHG9 was detected using RNA pull-down. The expression relationship between SNHG9 and miR-21 was analyzed by SNHG9 or miR-21 overexpression experiments. The effects of overexpression of SNHG9 on the methylation of miR-21 were analyzed by methylation-specific PCR (MSP). Cell proliferation was evaluated by CCK-8 assay. RESULTS: By analyzing the TCGA dataset, we observed downregulation of SNHG9 in NSCLC, which was confirmed by measuring the expression levels of SNHG9 in paired NSCLC tumor tissues and non-tumor tissues from NSCLC patients involved in this study. MiR-21 was upregulated in NSCLC tumor tissues and inversely correlated with SNHG9 in cancer tissues but not in non-tumor tissues. The interaction between SNHG9 and miR-21 was predicted by bioinformatic analyses, which was further verified by RNA pull-down. In NSCLC cells, overexpression of SNHG9 led to downregulated miR-21 and increased methylation of miR-21 gene. In contrast, miR-21 did not affect the expression of SNHG9. In addition, overexpression of SNHG9 attenuated the enhancing effects of miR-21 on NSCLC proliferation. CONCLUSION: SNHG9 might downregulate miR-21 through methylation to suppress cancer cell proliferation.

Expression and clinical significance of CD74 and MMP-9 in colon adenocarcinomas.

PURPOSE: To detect the expressions of CD74 and matrix metalloproteinase-9 (MMP-9) in colon adenocarcinomas, and to explore the relationship between the expressions and clinicopathological characteristics and prognosis. METHODS: 98 cases of colon adenocarcinoma tissues from patients who underwent colon cancer resection in the Sixth Affiliated Hospital, Sun Yat-sen University from January 2013 to March 2015 comprised the experimental group, while 71 cases of colon mucosa tissues from patients who underwent colon polypectomy during the same period comprised the control group. qRT-PCR was used to detect the expressions of CD44 and MMP-9 mRNAs in the two groups, in order to analyze their correlation in colon adenocarcinomas, and to also analyze their relationship with clinicopathological characteristics and prognosis. RESULTS: The expressions of CD74 and MMP-9 mRNAs in colon adenocarcinoma tissues were significantly higher than those in normal colon mucosa tissues (p<0.05). The expressions of CD74 and MMP-9 mRNAs had no significant relationship with the patient's gender, age, differentiation grade and tumor type in colon adenocarcinoma tissues (p>0.05), but had significant correlation with lymph node metastasis and pathological stage (p<0.05). According to the average expressions of CD74 and MMP-9 mRNAs, the patients were divided into low and high expression groups. The 3-year survival rate of patients in the low expression group was significantly higher than that in the high expression group (p<0.05). Moreover, the expressions of CD74 and MMP-9 were positively correlated (r = 0.853, p<0.001). CONCLUSION: CD74 and MMP-9 are highly expressed in colon adenocarcinomas, and their expressions are closely related to the pathological stage, lymph node metastasis and prognosis of colon adenocarcinoma patients. Therefore, they can be used as important biological markers for diagnosis and prognosis prediction of colon adenocarcinoma.

Effective Chemotherapy of Lung Cancer Using Bovine Serum Albumin-Coated Hydroxyapatite Nanoparticles.

BACKGROUND Successful chemotherapy of lung cancer relies largely on the use of a good drug delivery system (DDS). We successfully constructed a hybrid DDS comprised of hydroxyapatite (HAP) nanoparticles and bovine serum albumin (BSA). MATERIAL AND METHODS The HAP nanoparticles were selected as the core to encapsulate the anticancer drug doxorubicin (DOX), followed by surface modification of BSA as a stabilizer and shielding corona to finally prepare the hybrid DDS (BSA/HAP/DOX). RESULTS The following characterizations revealed that BSA/HAP nanoparticles have high stability, high biocompatibility, and good DOX-loading capability to meet in vivo applications. Moreover, BSA/HAP/DOX can enhance the cellular uptake of drug in A549 cells (lung cancer cells). Most importantly, BSA/HAP had better in vivo tumor targetability than bare HAP nanoparticles, which resulted in stronger anticancer efficacy both in vitro and in vivo than free DOX or HAP/DOX, and greatly decreased the adverse effects of free DOX. CONCLUSIONS Our hybrid DDS shows potential to be applied in more advanced application of cancer therapy.

LncRNA LUADT1 sponges miR-15a-3p to upregulate Twist1 in small cell lung cancer.

Lung adenocarcinoma associated transcript 1 (LUADT1) has been reported as an oncogenic long non-coding RNA (lncRNA) in lung adenocarcinoma, while its roles in small cell lung cancer (SCLC) are unknown. Our RNA interaction bioinformatics prediction showed that LUADT1 could form strong base pairing with miR-15a-3p, which is a tumor-suppressive miRNA that can target Twist1. We found that LUADT1 and Twist1 were upregulated in SCLC, while miR-15a-3p was downregulated in SCLC. However, LUADT1 was posively correlated with Twist1 but was not significnatly correlated with miR-15a-3p. Overexpression experiments showed that and LUADT1 and miR-15a-3p did not significantly affect the expression of each other. Moreover, LUADT1 overexpression mediated the upregualtion of Twist1, and miR-15a-3p overexpression played an oppsoite role. Transwell assays showed that LUADT1 and Twist1 overexpression mediated the increased rate of cell invasion and migration, while miR-15a-3p overexpression mediated the decreased rate of cell invasion and migration. In addition, miR-15a-3p overexpression played an oppsoite role and attenuated the effects of LUADT1 overexpression. Therefore, LUADT1 may sponge miR-15a-3p to upregulate Twist1 in SCLC, thereby promoting cancer cell invasion and migration. TRIAL REGISTRATION: 2017GZH-1-201,746,382, registered at Jan 02,2017.

Study on the Mechanism of Cell Cycle Checkpoint Kinase 2 (CHEK2) Gene Dysfunction in Chemotherapeutic Drug Resistance of Triple Negative Breast Cancer Cells.

BACKGROUND This study aimed to investigate the mechanism of CHEK2 gene dysfunction in drug resistance of triple negative breast cancer (TNBC) cells. MATERIAL AND METHODS To perform our study, a stable CHEK2 wild type (CHEK2 WT) or CHEK2 Y390C mutation (CHEK2 Y390C) expressed MDA-MB-231 cell line was established. MTT assay, cell apoptosis assay and cell cycle assay were carried out to analyze the cell viability, apoptosis, and cell cycle respectively. Western blotting and qRT-PCR were applied for related protein and gene expression detection. RESULTS We found that the IC50 value of DDP (Cisplatin) to CHEK2 Y390C expressed MDA-MB-231 cells was significantly higher than that of the CHEK2 WT expressed cells and the control cells. After treatment with DDP for 48 h, cells expressing CHEK2 WT showed lower cell viability than that of the CHEK2 Y390C expressed cells and the control cells; compared with the CHEK2 Y390C expressed cells and the control cells, cells expressing CHEK2 WT showed significant G1/S arrest. Meanwhile, we found that compared with the CHEK2 Y390C expressed cells and the control cells, cell apoptosis was significantly increased in CHEK2 WT expressed cells. Moreover, our results suggested that cells expressing CHEK2 WT showed higher level of p-CDC25A, p-p53, p21, Bax, PUMA, and Noxa than that of the CHEK2 Y390C expressed cells and the control cells. CONCLUSIONS Our findings indicated that CHEK2 Y390C mutation induced the drug resistance of TNBC cells to chemotherapeutic drugs through administrating cell apoptosis and cell cycle arrest via regulating p53 activation and CHEK2-p53 apoptosis pathway.

Combination adjuvant chemotherapy with targeted drugs for treatment of colorectal cancer: A network meta-analysis.

Colorectal cancer (CRC) is one of the most fatal diseases in the world. The efficacy of present chemotherapy treatments are limited and the addition of targeted drugs have been put into practice. However, the preferred treatments among adjuvant chemotherapies still remain controversial and uncertain. To evaluate the efficacy of different adjuvant chemotherapies combined with or without targeted drugs to determine the optimal treatment for patients with CRC in clinical practice. PubMed and Embase were searched for eligible articles and only randomized controlled trials (RCTs) were included. R (Version 3.2.5) software was utilized to conduct the Bayesian network meta-analysis (NMA). Outcomes including overall survival (OS) and progression-free survival (PFS) were displayed using hazard ratios. And the rank probabilities of each treatment were evaluated using the surface under cumulative ranking curve. A total of 75 RCTs published after 1997 were included in the data analysis. Overall, FOLFIRI+ cetuximab was found to be the most effective treatment in terms of long-term survival and FOLFOX was the most effective pure chemotherapy treatment. The addition of targeted drugs will greatly improve the efficacy of chemotherapy. Targeted drug cetuximab combined with the chemotherapy regiment FOLFIRI is the preferable treatment for patients with CRC in clinical practice.