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1.
Neural Netw ; 135: 1-12, 2021 Mar.
Article in English | MEDLINE | ID: mdl-33310193

ABSTRACT

Knowledge graph reasoning aims to find reasoning paths for relations over incomplete knowledge graphs (KG). Prior works may not take into account that the rewards for each position (vertex in the graph) may be different. We propose the distance-aware reward in the reinforcement learning framework to assign different rewards for different positions. We observe that KG embeddings are learned from independent triples and therefore cannot fully cover the information described in the local neighborhood. To this effect, we integrate a graph self-attention (GSA) mechanism to capture more comprehensive entity information from the neighboring entities and relations. To let the model remember the path, we incorporate the GSA mechanism with GRU to consider the memory of relations in the path. Our approach can train the agent in one-pass, thus eliminating the pre-training or fine-tuning process, which significantly reduces the problem complexity. Experimental results demonstrate the effectiveness of our method. We found that our model can mine more balanced paths for each relation.


Subject(s)
Databases, Factual , Deep Learning , Pattern Recognition, Automated/methods , Reinforcement, Psychology , Algorithms , Databases, Factual/trends , Deep Learning/trends , Humans , Knowledge , Pattern Recognition, Automated/trends
2.
Front Hum Neurosci ; 14: 128, 2020.
Article in English | MEDLINE | ID: mdl-32372933

ABSTRACT

Large-scale neuroscience literature call for effective methods to mine the knowledge from species perspective to link the brain and neuroscience communities, neurorobotics, computing devices, and AI research communities. Structured knowledge can motivate researchers to better understand the functionality and structure of the brain and link the related resources and components. However, the abstracts of massive scientific works do not explicitly mention the species. Therefore, in addition to dictionary-based methods, we need to mine species using cognitive computing models that are more like the human reading process, and these methods can take advantage of the rich information in the literature. We also enable the model to automatically distinguish whether the mentioned species is the main research subject. Distinguishing the two situations can generate value at different levels of knowledge management. We propose SpecExplorer project which is used to explore the knowledge associations of different species for brain and neuroscience. This project frees humans from the tedious task of classifying neuroscience literature by species. Species classification task belongs to the multi-label classification which is more complex than the single-label classification due to the correlation between labels. To resolve this problem, we present the sequence-to-sequence classification framework to adaptively assign multiple species to the literature. To model the structure information of documents, we propose the hierarchical attentive decoding (HAD) to extract span of interest (SOI) for predicting each species. We create three datasets from PubMed and PMC corpora. We present two versions of annotation criteria (mention-based annotation and semantic-based annotation) for species research. Experiments demonstrate that our approach achieves improvements in the final results. Finally, we perform species-based analysis of brain diseases, brain cognitive functions, and proteins related to the hippocampus and provide potential research directions for certain species.

3.
Cancer Invest ; 26(9): 868-77, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18798056

ABSTRACT

The anti-tumor effect of non-steroidal anti-inflammatory drugs (NSAIDs) remains unclear. Here, we found that the susceptibility for NSAIDs-induced apoptosis might correlate with the status of the p53 gene in gastric cancer cells. Apoptosis in gastric cancer cells expressing wild-type p53 is induced through up-regulation of bax and down-regulation of bcl-2 and that regulation of the bax-bcl-2 heterodimer may be a major target of NSAIDs. As to gastric cancer cells expressing mutant-type p53, other key factors may exist in the NSAIDs' growth inhibition action.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis , Drug Resistance, Neoplasm , Stomach Neoplasms/metabolism , Tumor Suppressor Protein p53/metabolism , Apoptosis/genetics , Aspirin/pharmacology , Cell Line, Tumor , Dimerization , Down-Regulation , Humans , Indomethacin/pharmacology , Mutation , Proto-Oncogene Proteins c-bcl-2/metabolism , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Tumor Suppressor Protein p53/genetics , Up-Regulation , bcl-2-Associated X Protein/metabolism
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 24(4): 387-91, 2007 Aug.
Article in Chinese | MEDLINE | ID: mdl-17680526

ABSTRACT

OBJECTIVE: To evaluate the relationship between mammalian target of rapamycin (mTOR) signaling pathway and histone acetylation in cell survival, cell cycle, gene expression and protein level on human gastric cancer cells. METHODS: Human gastric cancer cell lines, MKN45 and SGC7901 were treated with trichostatin A, rapamycin and/or LY294002, a PI3K inhibitor. Cell viability was analyzed by methylthiazolyl tetrazolium. Cell cycle distribution was evaluated by flow cytometry. The transcription level of p21(WAF1) gene was detected by using real-time polymerase chain reaction. Proteins were detected by Western blotting. RESULTS: Cell viability remarkably reduced after treatment by more than two drugs (P< 0.01). Through flow cytometry assessment, MKN45 cells were arrested in G2 phase (P< 0.05), while SGC7901 cells were in G2 or G1 phase (P< 0.05) whether treated with single or more than two drugs. The expression of p21(WAF1) mRNA was remarkably increased in the gastric cancer cells treated with conjoined drugs (P< 0.01). Phosphorylation of Akt, p70S6K and 4E-BP1 was significantly reduced in cells treated with conjoined drugs (P< 0.01). And histone acetylation of H4/H3 was also increased in cells treated with conjoined drugs (P< 0.01). CONCLUSION: mTOR singnaling pathway has an important relationship with histone acetylation in gastric cancer cell lines. There is a co-effect of mTOR inhibitor and histone deacetylase inhibitor on gastric cancer cells.


Subject(s)
Histones/metabolism , Protein Kinases/metabolism , Signal Transduction/physiology , Acetylation/drug effects , Adaptor Proteins, Signal Transducing/metabolism , Blotting, Western , Cell Cycle/drug effects , Cell Cycle Proteins , Cell Line, Tumor , Cell Survival/drug effects , Chromones/pharmacology , Cyclin-Dependent Kinase Inhibitor p21/genetics , Flow Cytometry , Humans , Hydroxamic Acids/pharmacology , Morpholines/pharmacology , Phosphoproteins/metabolism , Phosphorylation/drug effects , Polymerase Chain Reaction , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Signal Transduction/drug effects , Sirolimus/pharmacology , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Stomach Neoplasms/physiopathology , TOR Serine-Threonine Kinases
5.
Zhonghua Zhong Liu Za Zhi ; 29(12): 889-93, 2007 Dec.
Article in Chinese | MEDLINE | ID: mdl-18478925

ABSTRACT

OBJECTIVE: To investigate the synergistic effect of rapamycin (RPM) and PD98059 on human colorectal cancer cells and its potential mechanisms. METHODS: Three human colorectal cancer cell lines SW480, HCT116 and HT29 were treated with RPM 10 nmol/L, PD98059 (10 micromol/L, 20 micromol/L, 40 micromol/L, 50 micromol/L), or RPM plus PD98059, respectively, and the sensitivity was analyzed by MTT assay. The cell cycle progression was evaluated by flow cytometry. Western blotting analysis was performed to examine the total and phosphorylated levels of mammalian target of rapamycin (mTOR) and its downstream translational signaling intermediates, 70 kDa ribosomal protein S6 kinase (p70s6k) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). RESULTS: Both RPM and PD98059 could inhibit viability of the three cell lines. The anti-proliferative effect of PD98059 exhibited a time/dose dependent manner and was strengthen by RPM. All the treatment with RPM, PD98059, and RPM + PD98059 induced arrest of cell cycle, although the arrest was confined at different cell cycle phases. In addition to their effect on proliferation and cell cycle, both inhibitors also reduced phosphorylation levels of mTOR, p70s6k, and 4E-BP1, as well as total 4E-BP1 levels in SW480 and HCT116 cells. That effect was reinforced when cells were treated with RPM plus PD98059 simultaneously, whereas total protein levels of mTOR and p70s6k remained unchanged. CONCLUSION: RPM and PD98059 inhibit proliferation of colorectal cancer cells synergistically, and induce cell cycle arrest. The modulation of mammalian target of rapamycin signaling pathway is involved in its potential mechanisms.


Subject(s)
Cell Cycle/drug effects , Colorectal Neoplasms/pathology , Flavonoids/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Sirolimus/pharmacology , Adaptor Proteins, Signal Transducing/metabolism , Antibiotics, Antineoplastic/pharmacology , Calcium-Calmodulin-Dependent Protein Kinases/antagonists & inhibitors , Cell Cycle Proteins , Cell Proliferation , Colorectal Neoplasms/metabolism , Drug Synergism , HCT116 Cells , HT29 Cells , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoproteins/metabolism , Phosphorylation , Protein Serine-Threonine Kinases/antagonists & inhibitors , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , TOR Serine-Threonine Kinases
6.
World J Gastroenterol ; 12(47): 7591-7, 2006 Dec 21.
Article in English | MEDLINE | ID: mdl-17171786

ABSTRACT

AIM: To evaluate whether folate levels in mucosal tissue and some common methylenetetrahydrofolate reductase (MTHFR) variants are associated with the risk of gastric cancer through DNA methylation. METHODS: Real-time PCR was used to study the expression of tumor related genes in 76 mucosal tissue samples from 38 patients with gastric cancer. Samples from the gastroscopic biopsy tissues of 34 patients with chronic superficial gastritis (CSG) were used as controls. Folate concentrations in these tissues were detected by the FOL ACS:180 automated chemiluminescence system. MTHFR polymorphisms were analyzed by PCR-RFLP, and the promoter methylation of tumor-related genes was determined by methylation-specific PCR (MSP). RESULTS: Folate concentrations were significantly higher in CSG than in cancerous tissues. Decreased expression and methylation of c-myc accompanied higher folate concentrations. Promoter hypermethylation and loss of p16(INK4A) in samples with MTHFR 677CC were more frequent than in samples with the 677TT or 677CT genotype. And the promoter hypermethylation and loss of p21(WAF1) in samples with MTHFR 677CT were more frequent than when 677CC or 677TT was present. The 677CT genotype showed a non-significant higher risk for gastric cancer as compared with the 677CC genotype. CONCLUSION: Lower folate levels in gastric mucosal tissue may confer a higher risk of gastric carcinogenesis through hypomethylation and overexpression of c-myc.


Subject(s)
Folic Acid/metabolism , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Genetic , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Gastric Mucosa/metabolism , Genotype , Humans , Risk Factors , Stomach Neoplasms/epidemiology
7.
World J Gastroenterol ; 10(23): 3394-8, 2004 Dec 01.
Article in English | MEDLINE | ID: mdl-15526354

ABSTRACT

AIM: To explore the effect of DNA methyltransferase, demethylase and methyl-CpG binding protein MeCP2 on the expressions and methylation of hMSH2 and proto-oncogene in human gastric cancer. METHODS: Paired samples of primary gastric cancer and corresponding para-cancerous, non-cancerous gastric mucosae were obtained from surgically resected specimens of 28 patients. Transcription levels of Dnmt1, mbd2, MeCP2, p16(INK4A), hMSH2 and c-myc were detected by using real-time PCR or RT-PCR. Promoter methylation of p16(INK4A), c-myc and hMSH2 genes was assayed by methylation-specific PCR (MSP) and sequencing (mapping). Their relationships were analyzed by Fisher's exact test using the software SPSS. RESULTS: The average mRNA level of Dnmt1 gene from cancerous tissue was higher and that of mbd2 gene from cancerous tissue was lower than that from non-cancerous tissue, respectively. mbd2 was lower in cancerous tissue than in non-cancerous tissue in 14 (50.0%) of patients but higher in 3 cases (10.7%) of non-cancerous gastric tissue (P<0.001). c-myc expression was up-regulated in cancer tissues (P<0.05). The up-regulation of mbd2 was found in all patients with hypomethylated c-myc. The transcriptional levels of p16(INK4A) and MeCP2 genes did not display any difference between gastric cancerous and matched non-cancerous tissues. There were down-regulation and hypermethylation of hMSH2 in cancer tissues, and the hypermethylation of hMSH2 coexisted with down-regulated transcription. However, the transcription level of the above genes was not associated with biological behaviours of gastric cancers. CONCLUSION: The up-regulation of proto-oncogene may be the consequence of epigenetic control of gene expression by demethylase, and mbd2 is involved in the regulation of hMSH2 expression in human gastric cancer.


Subject(s)
Chromosomal Proteins, Non-Histone/genetics , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methylation , DNA-Binding Proteins/genetics , Repressor Proteins/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/physiopathology , Aged , Cyclin-Dependent Kinase Inhibitor p16/genetics , DNA (Cytosine-5-)-Methyltransferase 1 , Female , Gastric Mucosa/physiology , Gene Expression Regulation, Neoplastic , Humans , Male , Methyl-CpG-Binding Protein 2 , Middle Aged , MutS Homolog 2 Protein , Promoter Regions, Genetic/physiology , Proto-Oncogene Mas , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-myc/genetics , RNA, Messenger/analysis , Stomach Neoplasms/pathology , Transcription, Genetic
8.
World J Gastroenterol ; 10(18): 2643-6, 2004 Sep 15.
Article in English | MEDLINE | ID: mdl-15309711

ABSTRACT

AIM: To investigate the effect of histone acetylation on regulation of p21WAF1 gene expression in human colon cancer cell lines. METHODS: Two cell lines, Colo-320 and SW1116 were treated with either trichostatin or sodium butyrate. Expressions of p21WAF1 mRNA and protein were detected by real-time RT-PCR and Western blotting, respectively. Acetylation of two regions of p21WAF1 gene-associated histones and total cellular histones were examined by chromatin immunoprecipitation assay and Western blotting. RESULTS: Trichostatin or sodium butyrate re-activated p21WAF1 transcription resulted in up-regulated p21WAF1 protein level in colon cancer cell lines. Those effects were accompanied by an accumulation of acetylated histones in total cellular chromatin and p21WAF1 gene-associated region of chromatin. CONCLUSION: Histone acetylation regulates p21WAF1 expression in human colon cancer cell lines, Colo-320 and SW1116.


Subject(s)
Cell Cycle Proteins/genetics , Colonic Neoplasms , Gene Expression Regulation, Neoplastic/physiology , Histones/metabolism , Acetylation , Butyrates/pharmacology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p21 , Gene Expression Regulation, Neoplastic/drug effects , Humans , Hydroxamic Acids/pharmacology , Protein Synthesis Inhibitors/pharmacology , RNA, Messenger/analysis
9.
Zhonghua Yi Xue Za Zhi ; 84(12): 1014-7, 2004 Jun 17.
Article in Chinese | MEDLINE | ID: mdl-15312538

ABSTRACT

OBJECTIVE: To analyze the effect of eukaryotic plasmids containing sense or antisense DNA methyltransferase (Dnmt1) genes on the methylation status and transcription level of DNA mismatch repair (MMR) genes and microsatellite instability (MSI) in human colon cancer cell line. METHODS: Human colorectal cells of the SW1116 line were cultured. Recombinant plasmids containing sense Dnmt1 (HMT) or antisense Dnmt1 (THM) gene, pCMV-HMT and pCMV-THM, were constructed. Then pCMV-HMT, pCMV-THM, and pcMV blank plasmid were transfected into SW1116 cells respectively by using lipofectAMINE. The expression of Dnmt1 protein was examined by Western blotting. The transcription levels of hMLH1 and hMSH2 genes were detected by using real-time (RT-PCR). The status of methylation in promoters of hMLH1 and hMSH2 genes were examined with methylation specific PCR (MSP). The MSI of DNA in SW1116 cells was evaluated by silver-stained polyacrylamide gel electrophoresis. RESULTS: Both the expressions of the hMLH1 and hMSH2 gene mRNAs were remarkably decreased in the SW1116-HMT cells in comparison with those in the untransfected cells. The expression of hMSH2 gene mRNA in the SW1116-THM cells was remarkably increased in comparison with that in the untransfected cells. No significant difference in the expressions of the hMLH1 and hMSH2 gene mRNAs was found between the SW1116 cells transfected with blank pCMV and the untransfected SW1116 cells. MSP showed that the methylation level in the regions of hMLH1 and hMSH2 promoters was remarkably increased in the SW1116 cells transfected with sense Dnmtl plasmid. However, in the SW1116 cells the hMSH2 promoter region was changed from partially-methylated into de-methylated, and the hMLH1 promoter region remained non-methylated. MST test showed that extra bands indicating MSI were seen only in the D2S123 groups. CONCLUSION: Dnmt1 regulates the expression and methylation status of MMR genes and affects MSI in human colon cancer cell line SW1116.


Subject(s)
Base Pair Mismatch , Colonic Neoplasms/genetics , DNA Repair , Neoplasm Proteins/genetics , Adaptor Proteins, Signal Transducing , Carrier Proteins , Cell Line, Tumor , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , DNA Methylation , DNA-Binding Proteins/genetics , Eukaryotic Cells/metabolism , Humans , Microsatellite Repeats , MutL Protein Homolog 1 , MutS Homolog 2 Protein , Mutation , Nuclear Proteins , Promoter Regions, Genetic , Protein-Arginine N-Methyltransferases/biosynthesis , Protein-Arginine N-Methyltransferases/genetics , Proto-Oncogene Proteins/genetics
10.
Chin Med J (Engl) ; 117(1): 99-103, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14733783

ABSTRACT

BACKGROUND: To investigate the effects of DNA methylation on the expression of tumor-associated genes and the cell cycle in human gastric cancer cells. METHODS: Two gastric cancer cell lines (MKN-45 and HGC-27) were treated with DNA methyltransferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine (5-aza-dC). The expressions of p16INK4A, p21WAF1, p53, p73, c-Ha-ras and c-myc genes mRNA were detected by using reverse transcription PCR (RT-PCR). DNA methylation status of p16INK4A gene promoter was assayed by bisulfite modification and sequencing. The cell cycle was analyzed by using flow cytometry (FCM). RESULTS: 5-aza-dC induced the demethylation of p16INK4A gene promoter. The expression of p16INK4A mRNA was obviously up-regulated by treatment with 10 micro mol/L (MKN-45 cells) or 5 micro mol/L (HGC-27 cells) of 5-aza-dC for 24 hours. However, 5-aza-dC treatment failed to regulate the expressions of p21WAF1, p53, p73, c-Ha-ras and c-myc genes in MKN-45 and HGC-27 cells. Furthermore, 5-aza-dC induced the cell cycle arrest in G1 phase in HGC-27 cell, but not in MKN-45 cell. CONCLUSIONS: DNA methylation regulates the transcription of p16INK4A but not p21WAF1 and proto-oncogenes in human gastric cancer cell lines MKN-45 and HGC-27.


Subject(s)
Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Enzyme Inhibitors/pharmacology , Genes, p16/physiology , Stomach Neoplasms/genetics , Transcription, Genetic , Cell Line, Tumor , DNA Methylation , Decitabine , Flow Cytometry , Gene Expression , Genes, Tumor Suppressor/physiology , Humans , Reverse Transcriptase Polymerase Chain Reaction , Up-Regulation
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