Identification of functional genes regulating gastric cancer progression using integrated bioinformatics analysis.

BACKGROUND: Gastric cancer (GC) is one of the most common cancers and has a poor prognosis. Treatment of GC has remained unchanged over the past few years. AIM: To investigate the potential therapeutic targets and related regulatory biomarkers of GC. METHODS: We obtained the public GC transcriptome sequencing dataset from the Gene Expression Omnibus database. The datasets contained 348 GC tissues and 141 healthy tissues. In total, 251 differentially expressed genes (DEGs) were identified, including 187 down-regulated genes and 64 up-regulated genes. The DEGs' enriched functions and pathways include Progesterone-mediated oocyte maturation, cell cycle, and oocyte meiosis, Hepatitis B, and the Hippo signaling pathway. Survival analysis showed that BUB1, MAD2L1, CCNA2, CCNB1, and BIRC5 may be associated with regulation of the cell cycle phase mitotic spindle checkpoint pathway. We selected 26 regulated genes with the aid of the protein-protein interaction network analyzed by Molecular Complex Detection. RESULTS: We focused on three critical genes, which were highly expressed in GC, but negatively related to patient survival. Furthermore, we found that knockdown of BIRC5, TRIP13 or UBE2C significantly inhibited cell proliferation and induced cell apoptosis. In addition, knockdown of BIRC5, TRIP13 or UBE2C increased cellular sensitivity to cisplatin. CONCLUSION: Our study identified significantly upregulated genes in GC with a poor prognosis using integrated bioinformatics methods.

Atranorin driven by nano materials SPION lead to ferroptosis of gastric cancer stem cells by weakening the mRNA 5-hydroxymethylcytidine modification of the Xc-/GPX4 axis and its expression.

Gastric cancer is a highly malignant tumor. Gastric cancer stem cells (GCSCs) are the main causes of drug resistance, metastasis, recurrence, and poor prognosis. As a secondary metabolite of lichen, Atranorin has a variety of biological effects, such as antibacterial, anti-inflammatory, analgesic, and wound healing; however, its killing effect on GCSCs has not been reported. In this study, we constructed Atranorin complexes comprising superparamagnetic iron oxide nanoparticles (SPION) (Atranorin@SPION). In vitro and in vivo experiments confirmed that Atranorin@SPION could significantly inhibit the proliferation, invasion, angiogenesis, and tumorigenicity of CD44+/ CD24+ GCSCs, and induce oxidative stress injury, Fe2+ accumulation, and ferroptosis. Quantitative real-time reverse transcription PCR and western blotting results showed that Atranorin@SPION not only reduced the expression levels of GCSC stem cell markers and cell proliferation and division markers, but also significantly inhibited the expression levels of key molecules in the cystine/glutamate transporter (Xc-)/glutathione peroxidase 4 (GPX4) and Tet methylcytosine dioxygenase (TET) family proteins. The results of high performance liquid chromatography-mass spectrometry and Dot blotting showed that Atranorin@SPION significantly inhibited the mRNA 5­hydroxymethylcytidine modification of GCSCs. Meanwhile, the results of RNA immunoprecipitation-PCR also indicated that Atranorin@SPIONs significantly reduced the 5-hydroxymethylcytidine modification level of GPX4 and SLC7A11 mRNA 3' untranslated region in GCSCs, resulting in a decrease in their stability, shortening their half-lives and reducing translation activity. Therefore, this study revealed that Atranorin@SPIONs induced ferroptosis of GCSCs by weakening the expression of the Xc-/GPX4 axis and the 5-hydroxymethylcytidine modification of mRNAs in the pathway, thereby achieving their therapeutic effect on gastric cancer.

Evaluating drivers and flow patterns of inter-provincial grain virtual water trade in China.

China's food security is facing serious threats because the virtual water triggered by grain trade flows from the water-scarce north region to the water-rich south region in recent years. Thus, quantitatively evaluating grain virtual water flow is increasingly important. We established a multi-objective linear optimization model based on analyzing drivers of grain trade by the entropy method, and the two drivers of transport cost and grain consumption structure between provinces were analyzed. The results show that the virtual water flow of inter-provincial grain trade of China was 98.38 Gm3 in 2015, accounting for 15% of the total water consumption of grain production. The impact weights of grain transportation cost and difference of grain consumption structure between provinces on virtual water flow were 0.665 and 0.335, respectively. Although the production and consumption of grain in northern region were almost the same, the virtual water imbedded in grain trade still flowed from the north to the south under the influence of grain imports from abroad and grain consumption structure. Compared to previous methods, the model added the principle of the entropy method into linear programming analysis. This innovative model not only quantitatively evaluated the driving forces of grain trade through the weight coefficient, but also established a universal model of quantifying grain virtual water flow. Moreover, we reduced data assumptions, such as not considering actual grain imports and transport modes of grain, which improves the credibility of quantitative results. The model quantified virtual water from the perspective of driving impacts and precluded the limitations of trade data. The model can be used in other countries and regions, where trade data is difficult to obtain, to calculate trade patterns. The results are useful for decision makers to implement virtual water strategies, mitigate national water scarcity, and facilitate sustainable development of grain production.

Superparamagnetic iron oxide nanoparticles drive miR-485-5p inhibition in glioma stem cells by silencing Tie1 expression.

Gliomas are highly malignant nervous system tumours. Studies shown that cancer stem cells are one of the main reasons underlying recurrence, metastasis, and poor prognosis in glioma cases. Our previous studies have found that superparamagnetic iron oxide nanoparticles (SPIONs) can act as nucleic acid carriers to drive intracellular overexpression of these nucleic acids. In this study, CD44+/CD133+ glioma stem cells (HuGSCs) were first isolated from surgically resected tissues from patients. qPCR and western blot results showed that Tie1 expression in HuGSCs was significantly higher thanexpression in CD44-/CD133- glioma cells. Bioinformatic analysis and luciferase reporter assays showed that miR-485-5p binds to specific loci on the 3'-UTR of Tie1 mRNA to inhibit Tie1 expression. Subsequently, miR-485-5p/miR-mut and SPION complexes were transfected into HuGSCs. Transmission electron microscopy showed that a highly dense metallic electron cloud is present in HuGSCs. At the same time, in vivo and in vitro studies showed that miR-485-5p@SPIONs can significantly inhibit HuGSC proliferation, invasion, tumourigenicity, and angiogenesis. In-depth analysis showed that Tie1 interacts with neuronal growth factors such as FGF2, BDNF, GDNF, and GFAP. qPCR and western blot results showed that in miR-485-5p@SPIONs-HuGSCs, the expression levels of Tie1 and stem cell markers (Oct4, Sox2, Nanog, CD44, and CD133), and even FGF2, BDNF, GDNF, and GFAP were significantly lower than thelevels in the control group (miR-mut@SPIONs-HuGSCs). Therefore, this study showedthat Tie1 is an important factor that maintains glioma stem cell activity. SPIONs drive miR-485-5p overexpression in cells and inhibit endogenous Tie1 expression to downregulate the protein expression levels of Fgf2/GDNF/GFAP/BDNF and significantly weaken the in vivo and in vitro viability of gliomas.

Celiac disease diagnosis from videocapsule endoscopy images with residual learning and deep feature extraction.

BACKGROUND AND OBJECTIVE: Videocapsule endoscopy (VCE) is a relatively new technique for evaluating the presence of villous atrophy in celiac disease patients. The diagnostic analysis of video frames is currently time-consuming and tedious. Recently, computer-aided diagnosis (CAD) systems have become an attractive research area for diagnosing celiac disease. However, the images captured from VCE are susceptible to alterations in light illumination, rotation direction, and intestinal secretions. Moreover, textural features of the mucosal villi obtained by VCE are difficult to characterize and extract. This work aims to find a novel deep learning feature learning module to assist in the diagnosis of celiac disease. METHODS: In this manuscript, we propose a novel deep learning recalibration module which shows significant gain in diagnosing celiac disease. In this recalibration module, the block-wise recalibration component is newly employed to capture the most salient feature in the local channel feature map. This learning module was embedded into ResNet50, Inception-v3 to diagnose celiac disease using a 10-time 10-fold cross-validation based upon analysis of VCE images. In addition, we employed model weights to extract feature points from training and test samples before the last fully connected layer, and then input to a support vector machine (SVM), k-nearest neighbor (KNN), and linear discriminant analysis (LDA) for differentiating celiac disease images from heathy controls. RESULTS: Overall, the accuracy, sensitivity and specificity of the 10-time 10-fold cross-validation were 95.94%, 97.20% and 95.63%, respectively. CONCLUSIONS: A novel deep learning recalibration module, with global response and local salient factors is proposed, and it has a high potential for utilizing deep learning networks to diagnose celiac disease using VCE images.

Superparamagnetic iron oxide nanoparticle-mediated expression of miR-326 inhibits human endometrial carcinoma stem cell growth.

Background: Previously, our group confirmed the presence of a subset of cancer stem cells in the tissues of endometrial carcinoma (ie, human endometrial carcinoma stem cells [HuECSCs]). However, the mechanisms by which microRNAs regulate the growth of HuECSCs remain elusive. Methods: We loaded miR-326 onto superparamagnetic iron oxide nanoparticles (miR-326@SPION) and transfected them into HuECSCs. Results: In the present study, we found that the expression levels of members of the G-protein coupled receptor 91 (GPR91)/signal transducer and activator of transcription 3 (STAT3)/vascular endothelial growth factor (VEGF) pathway were significantly elevated in CD44+/CD133+ HuECSCs. Luciferase reporter assays indicated that the succinate receptor 1 (SUCNR1) gene, also known as the G-protein coupled receptor 91 (GPR91) gene, was one of the potential targets of miR-326. Transmission electron microscopy revealed that the SPIONs could cross the cell membrane and accumulate in the cytoplasm. The overexpression of miR-326 significantly inhibited the proliferation and cell cycle progression of HuECSCs in vitro. MiR-326 overexpression also effectively inhibited the invasion and angiogenic capacities of HuECSCs in the extracellular matrix. Meanwhile, miR-326 overexpression significantly inhibited the tumorigenicity and tumour neovascularization capacity of HuECSCs in nude mice. Both quantitative real-time PCR and Western blotting confirmed that overexpression of miR-326 significantly reduced the expression of members of the GPR91/STAT3/VEGF pathway in HuECSCs, and the activity (level of phosphorylation) of key molecules in this pathway was also reduced. Conclusion: Collectively, we confirmed that SPIONs are highly efficient nanocarriers for nucleic acids, on which the loading of miR-326 inhibited the activation of the GPR91/STAT3/VEGF signaling pathway and significantly attenuated the activity of stem cells in endometrial carcinoma, both in vitro and in vivo.

[Analysis on the incidence of coal workers' pneumoconiosis from 2003 to 2008 in a coal mining group].

OBJECTIVE: Analyzed associations among the incidence of coal workers' pneumoconiosis from 2003 to 2008, jobs, exposure years and cumulative total dust exposure levels (CTE) and found the current characteristics of the mine incidence of pneumoconiosis disease. METHODS: collected the health care information of the new diagnosed pneumoconiosis of underground mine workers from 2003 to 2008 and the dust monitoring data of underground mine from 1949 and estimated the personnel cumulative total dust exposure levels (CTE); analyzed the incidence features of the new diagnosed pneumoconiosis. RESULTS: The rates of health surveillance of workers were gradually improved from 2003 to 2008 and 296 new coal workers pneumoconiosis were diagnosed. The total incidence was 0.57%, and the average annual rate was 0.32%. Among the new diagnosed cases, phase I accounted for 90.5% and the 87.2% from coal mine drillers. The shortest exposure period was 3 years and the longest was 38 years, and the cumulative total dose of dust was varied between 86.1 and 4926 mg/m(3) per year. The total dust accumulated limited dose was calculated by the percentile method to prevent 99% of miners from pneumoconiosis, which was 120.6 mg/m(3) per year, so we suggested that the exposure years should be shorter than 13 years under the current working conditions. CONCLUSIONS: Preventive coal workers' pneumoconiosis should be focused on mine drillers and their limited exposure years should be within 13 years.

[Polymorphisms in Fas pathway genes and risk of coal worker pneumoconiosis].

OBJECTIVE: To explore the possible association between six single nucleotide polymorphisms (SNPs) of Fas pathway genes and the risks of coal worker pneumoconiosis (GWP). METHODS: This case-control study consisted of 511 male patients with CWP and 530 male controls from the same coal mines. Five SNPs of Fas pathway genes were detected by restriction fragment length polymorphisms (PCR-RFLP) and CASP3 (rs6948) was genotyped by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: There were no differences of genotype frequencies of 6 SNPs between cases with CWP and controls. A significant increased risk of CWP was found in subjects with CASP8-652DD genotype as compared to subjects with CASP8-652II genotype (P < 0.05), and the further stratification analysis showed that smoking cases with CWP stage I, long exposure time and CASP8-652DD genotype had high risk of CWP (P < 0.05). The analysis of gene-gene interactions indicated that the carriers with FAS-1377GG/CASP8-652DD, FAS-670AG/CASP8-652DD and FASL-844CT/CASP8-652DD had the increased risk of CWP, and the carriers with FAS-1377GA/CASP8-652ID had the reduced risk of CWP. There were no significant differences of exposure times among the cases with CWP stage I and 3 genotypes of CASP8-652. CONCLUSION: CASP8-652 6N DD genotype may play a role in CWP development and interact with SNPs of FAS-1377, FAS-670 and FASL-844.

Common genetic variants in pre-microRNAs are associated with risk of coal workers' pneumoconiosis.

microRNAs (miRNAs) are an abundant class of small noncoding RNA molecules thought to be involved in biological functions, including embryonic development, chromosome architecture, cell proliferation and apoptosis. We hypothesized that common variants in the miRNAs are associated with risk of coal workers' pneumoconiosis (CWP). In a case-control study of 496 CWP patients and 513 control subjects frequency matched by exposure years and work types, we genotyped four single-nucleotide polymorphisms (SNPs) (rs2910164, rs2292832, rs11614913 and rs3746444) in pre-miRNAs (miR-146a, miR-149, miR-196a2 and miR-499) and assessed the associations with risk of CWP. A significantly increased risk of CWP was found for the miR-149 rs2292832 TT genotype (odds ratio (OR), 1.31; 95% confidence interval (CI), 1.01-1.69), compared with the CT/CC genotypes, and this increased risk was evident among subgroups of those aged > or =68 years (OR=1.52, 95% CI=1.03-2.25), dust exposure > or =26 years (OR=1.42, 95% CI=1.04-1.93) and ever smokers (OR=1.48, 95% CI=1.00-2.20). Furthermore, a significant association was observed between the genotypes and patients with stages II and III (OR=1.50, 95% CI=1.05-2.14 for stage II, and OR=3.33, 95% CI=1.67-6.65 for stage III). These results suggest that miR-149 rs2292832 polymorphism is involved in susceptibility to developing CWP.

Association of transforming growth factor-ß1 gene variants with risk of coal workers' pneumoconiosis.

OBJECTIVE: The aim of this case-control study was to explore whether five tagging single nucleotide polymorphisms (tSNPs) within the transforming growth factor-ß1 (TGF-ß1) gene were involved in manifestation of inflammatory and fibrotic processes associated with coal workers' pneumoconiosis (CWP). METHODS: The study included 508 CWP patients and 526 controls who were underground coal miners from Xuzhou Mining Business Group. Five tSNPs were selected from the HapMap and detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: The single SNP analysis showed that the genotype frequencies of SNP2 (rs1800470, +869T/C, extron 1) and SNP5 (rs11466345, intron 5) in CWP cases were significantly different from those in controls. Multivariate logistic regression analysis revealed that SNP2 (rs1800470) CC genotype was associated with decreased risk of CWP (OR = 0.50, 95% CI = 0.32-0.78), which was evident among subgroups of those never smoke (OR = 0.40, 95%CI = 0.24-0.66), cases with stage II (OR = 0.41, 95%CI = 0.22-0.76) and exposure period (< 28 y: OR = 0.54, 95%CI = 0.31-0.95; ≥28 y: OR = 0.52, 95%CI = 0.32-0.96). However, the SNP5 (rs11466345) GG genotype was associated with an increased risk of CWP (OR = 2.5, 95%CI = 1.36-4.57), and further stratification analysis showed that the risk of CWP was increased in both smoking and nonsmoking groups, shorter and longer exposure groups, while the risk of CWP was only increased in patients with stage I and II. CONCLUSION: This study suggests that TGF-ß1 polymorphisms may contribute to susceptibility of CWP.

A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with risk of coal workers' pneumoconiosis.

Coal workers' pneumoconiosis (CWP) is a chronic interstitial lung disease with a complex etiology that can occur after cumulative dust exposure. A case-control study was conducted to test the hypothesis that single-nucleotide polymorphisms (SNP) within CASPASE-8 (CASP8) promoter involved in resolution of inflammatory processes modulate the risk of CWP development. The study population consisted of 619 underground coal miners in the 5 coal mines of Xuzhou Mining Business Group Co. Ltd., China, of whom 315 were diagnosed with CWP. The association study between CASP8 -652 6N ins/del polymorphism with CWP by multiple logistic regression analysis showed a significant association of the genotype del/del with CWP compared with to ins/ins genotypes, and showed that the risk was significantly higher for stage I CWP. Further analysis showed that in subjects with the del/del genotype there was significantly increased risk for CWP occurrence among younger individuals (<66 yr) or those with longer duration dust exposure (>or=26 yr). These findings suggested that CASP8-652 6N ins/del polymorphism may contribute to the genetic susceptibility for CWP development.