scholarly journals Downregulated miR-383-5p contributes to the proliferation and migration of gastric cancer cells and is associated with poor prognosis

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7882 ◽  
Author(s):  
Chao Wei ◽  
Jian-Jun Gao
Keyword(s):  
Gastric Cancer ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Qrt Pcr ◽  
And Migration ◽  
Proliferation And Migration

Aim The study aims to identify differentially expressed microRNAs (DEMs) in gastric cancer (GC) and explore the expression, prognosis and downstream regulation role of miR-383-5p in GC. Methods The GC miRNA-Seq and clinical information were downloaded from Firebrowse which stores integrated data sourced from The Cancer Genome Atlas database. The DEMs were identified with limma package in R software at the cut-off criteria of P < 0.05 and |log2 fold change| > 1.0 (|log2FC| > 1.0). The expression of miR-383-5p in GC cell lines and 54 paired GC tissues was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The overall survival curve of miR-383-5p and the association between its expression and clinicopathological features were explored. Wound healing and cell counting kit-8 assays were performed to investigate the capacity of miR-383-5p in cell proliferation and migration. The downstream target genes were predicted by bioinformatics tools (miRDB, TargetScan and starBase). The consensus target genes were selected for gene functional enrichment analysis by FunRich v3.0 software. The luciferase reporter assay was performed to verify the potential targeting sites of miR-383-5p on lactate dehydrogenase A (LDHA). Results A total of 21 down-regulated miRNAs (including miR-383-5p) and 202 up-regulated miRNAs were identified by analyzing GC miRNA-Seq data. Survival analysis found that patients with low miR-383-5p expression had a shorter survival time (median survival time 21.1 months) than those with high expression (46.9 months). The results of qRT-PCR indicated that miR-383-5p was downregulated in GC cell lines and tissues, which was consistent with miRNA-Seq data. The expression of miR-383-5p was significantly associated with tumor size and differentiation grade. Besides, overexpression of miR-383-5p suppressed GC cells proliferation and migration. A total of 49 common target genes of miR-383-5p were obtained by bioinformatics tools and gene functional enrichment analysis showed that these predicted genes participated in PI3K, mTOR, c-MYC, TGF-beta receptor, VEGF/VEGFR and E-cadherin signaling pathways. The data showed that expression of miR-383-5p was negatively correlated with target LDHA (r = −0.203). Luciferase reporter assay suggested that LDHA was a target of miR-383-5p. Conclusion The present study concluded that miR-383-5p was downregulated and may act as a tumor suppressor in GC. Furthermore, its target genes were involved in important signaling pathways. It could be a prognostic biomarker and play a vital role in exploring the molecular mechanism of GC.

scholarly journals Lactate induces aberration in the miR-30a–DBF4 axis to promote the development of gastric cancer and weakens the sensitivity to 5-Fu

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Tengkai Wang ◽  
Rui Ji ◽  
Guanqun Liu ◽  
Beilei Ma ◽  
Zehua Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Molecular Mechanism ◽  
Gastric Cancer Cell Line ◽  
Luciferase Reporter ◽  
Aberrant Expression ◽  
Qrt Pcr ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Proliferation And Migration

Abstract Background Gastric cancer (GC) is one of the most common malignancies, molecular mechanism of which is still not clear. Aberrant expression of tumor-associated genes is the major cause of tumorigenesis. DBF4 is an important factor in cancers, although there is yet no report on its function and molecular mechanism in GC. Methods The expression of DBF4 in tumor tissues or cells of GC was detected by qRT-PCR and western blotting. Gastric cancer cell line MGC-803 and AGS were transfected with DBF4 siRNA or overexpression vector to detect the function of DBF4 in proliferation, migration and the sensitivity to 5-Fu with CCK-8 assay, colony formation assay, transwell assay, and wound healing assay. miR-30a was found to be the regulator of DBF4 by online bioinformatics software and confirmed with qRT-PCR, western blot and dual-luciferase reporter assays. Results In our study, increased expression of DBF4 in GC tissues was first identified through The Cancer Genome Atlas (TCGA) and later confirmed using specimens from GC patients. Furthermore, functional experiments were applied to demonstrate that DBF4 promotes cell proliferation and migration in GC cell lines, moreover weakens the sensitivity of MGC803 and AGS cells to 5-Fu. We further demonstrated that miR-30a showed significantly lower expression in GC cells and inhibited the expression of DBF4 through 3ʹ-UTR suppression. Furthermore, rescue experiments revealed that the miR-30a-DBF4 axis regulated the GC cell proliferation, migration and the sensitivity to 5-Fu. The important composition in tumor microenvironment, lactate, may be the primary factor that suppressed miR-30a to strengthen the expression of DBF4. Conclusions Taken together, our study was the first to identify DBF4 as a regulator of cell proliferation and migration in GC. Furthermore, our study identified the lactate-miR-30a-DBF4 axis as a crucial regulator of tumor progression and the tumor sensitivity to 5-Fu, which maybe serve useful for the development of novel therapeutic targets.

scholarly journals LncRNA AC007255.1, an immune-related prognostic enhancer RNA in esophageal cancer

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11698
Author(s):  
Qingqing Wang ◽  
Xiaoyan Yu ◽  
Ningning Yang ◽  
Lu Xu ◽  
Yunfeng Zhou
Keyword(s):  
Esophageal Cancer ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Rna Seq ◽  
Normal Tissues ◽  
Qrt Pcr ◽  
Enhancer Rna ◽  
Active Enhancer

Background Growing evidence has suggested that enhancer RNAs (eRNAs), a set of long non-coding RNAs (lncRNAs) that were derived from active enhancer regions, play critical roles in regulating gene expression in human cancers. Nevertheless potential functions of eRNAs in esophageal cancer ESCA have not yet been expounded. Here, this study aimed to explore key prognostic eRNAs in ESCA. Methods LncRNAs that were transcribed from active enhancer regions were analyzed utilizing the PreSTIGE algorithm, followed by prediction of their target genes. Based on the ESCA RNA-seq data from the TANRIC database, overall survival (OS)-related eRNAs were determined. The correlation between AC007255.1 expression and various clinical traits of ESCA was calculated. Functional enrichment analysis was presented based on its co-expressed genes. Based on the TIMER database, we analyzed correlations between AC007255.1 expression and immune infiltration levels. qRT-PCR was utilized to validate the expression of AC007255.1 and PRR15 in ESCA and normal tissues. Results Totally, 2,695 lncRNAs were transcribed from active enhancer regions. Among them, 33 were significantly related to OS. AC007255.1 was a key eRNA. PRR15 was a target gene of AC007255.1 (correlation coefficient r = 0.936). Patients with high AC007255.1 expression indicated poor OS time. There were significant correlations between AC007255.1 expression and clinical characteristics like pathological TNM, grade and stage. AC007255.1 was closely related to tight junction and neutrophil activation involved in immune response. Moreover, AC007255.1 expression was related to the infiltration levels of B cell, dendritic cell and neutrophil. qRT-PCR results confirmed that AC007255.1 and PRR15 were both up-regulated in ESCA tissues, and there was a positive correlation between the two. Conclusion Our findings identified a novel immune-related eRNA AC007255.1 in ESCA, which could be a promising prognostic factor for ESCA.

scholarly journals Downregulation of microRNA-376a in Gastric Cancer and Association with Poor Prognosis

2018 ◽  
Vol 51 (5) ◽  
pp. 2010-2018 ◽  
Author(s):  
Cheng Zhang ◽  
Yu Liang ◽  
Ming-Hui Ma ◽  
Kun-Zhe Wu ◽  
Chun-Dong Zhang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Control Group ◽  
Mesenchymal Transition ◽  
Tumorigenesis And Progression ◽  
The Common

Background/Aims: MicroRNAs have a significant role in the tumorigenesis and progression of cancers, including gastric cancer (GC). Our study aimed to identify a novel biomarker to predict the prognosis of patients with GC. Methods: The GC microarray dataset, GSE28700, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed miRNAs (DEMs). The downregulation of miR-376a expression was verified in GC cell lines and 82 paired GC tissues by performing RT-qPCR and the correlation between its expression and clinicopathological characteristics was also explored. The target genes of miR-376a were predicted using TargetScan7.1, miRDB, and DIANA website tools. A functional enrichment analysis was performed to explore the biological role of the common target genes. Results: Bioinformatics analysis found that miR-376a was downregulated in GC tissues. Compared with the control group, RT-qPCR results showed that the expression of miR-376a in GC cell lines and tissues were also significantly decreased. The expression of miR-376a was statistically associated with T and N stage. Survival analysis with Kaplan–Meier showed that GC patients in the low expression group had a poorer prognosis than those in the high expression group (median survival of 26.4 and 46.9 months, respectively). Univariate and multivariate analysis demonstrated that low miR-376a expression was an independent prognostic marker for poor survival. Functional enrichment analysis indicated that the common targets genes were involved in cell–cell communication, VEGF and mTOR1-mediated signaling, and epithelial-to-mesenchymal transition (EMT). Conclusion: The results suggest that miR-376a could play an important role in the tumorigenesis and progression of GC and act as a novel therapeutic target and prognostic indicator in patients with GC.

scholarly journals Exosomal circRNA in Digestive System Tumors: The Main Player or Coadjuvants?

2021 ◽  
Vol 11 ◽  
Author(s):  
Haoying Wang ◽  
Xi Zeng ◽  
Ya Zheng ◽  
Yuping Wang ◽  
Yongning Zhou
Keyword(s):  
Colorectal Cancer ◽  
Gastric Cancer ◽  
Hepatocellular Carcinoma ◽  
Digestive System ◽  
Target Genes ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Circular Rna ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment

Exosomes are a type of extracellular microvesicles with a diameter of 40–160 nm. Circular RNA (circRNA) is a type of closed circular RNA molecule that is highly conserved in evolution. Exosomal circRNA plays a vital role in the proliferation, invasion, migration, and drug resistance of digestive system tumors. In this study, we used The Cancer Genome Atlas (TCGA) database, UALCAN, Python crawler, miRTargetLink Human, Database for Annotation, Visualization, and Integrated Discovery (DAVID), micBioinformatic online tool, and Cytoscape software (3.7.1). The results showed that circ-RanGAP1 in gastric cancer, circUHRF1 in hepatocellular carcinoma, and circFMN2 in colorectal cancer regulate the malignant behavior of tumors and affect the expression of their host gene through sponging miR-877-3p, miR-449c-5p, and miR-1182, respectively. Twenty exosomal circRNAs regulate 6,570 target genes through sponging 23 miRNAs. Firstly, 270 of those target genes are regulated by two or more miRNAs, which are highly correlated with 83 tumor-related pathways and six Kyoto Encyclopedia of Genes and Genomes pathways. Secondly, 1,146 target genes were significantly differentially expressed in corresponding digestive system tumors, and functional enrichment analysis revealed that 78 of those were involved in 20 cancer-related pathways. In short, the bioinformatics analysis showed that these exosomal circRNAs are stably expressed in body fluids, and regulate the occurrence and development of gastric cancer, hepatocellular carcinoma, colorectal cancer, and other digestive system tumors through sponging miRNAs. Exosomal circRNAs may be used as biomarkers for the diagnosis of disease and identification of effective therapeutic targets in the future, as well as improve the prognosis of patients with digestive system tumors.

Circ_002059 suppresses cell proliferation and migration of gastric cancer via miR-182/MTSS1 axis

2021 ◽  
Vol 53 (4) ◽  
pp. 454-462
Author(s):  
Ting Li ◽  
Xiaomin Zuo ◽  
Xiangling Meng
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Tumor Growth ◽  
Luciferase Reporter ◽  
Metastasis Suppressor ◽  
Xenograft Tumor ◽  
Cell Proliferation And Migration ◽  
And Migration ◽  
Xenograft Tumor Growth ◽  
Proliferation And Migration

Abstract Circular RNAs (circRNAs) play either oncogenic or tumor suppressive roles in gastric cancer (GC). A previous study demonstrated that circ_002059, a typical circRNA, was downregulated in GC tissues. However, the role and mechanism of circ_002059 in GC development are still unknown. In this study, the levels of circ_002059, miR-182, and metastasis suppressor-1 (MTSS1) were examined by real-time quantitative polymerase chain reaction and western blot analysis. Cell proliferation and migration were evaluated by MTT assay and Transwell migration assay, respectively. The interactions between miR-182 and circ_002059 or MTSS1 were analyzed by dual-luciferase reporter assay. A GC xenograft model was established to validate the role of circ_002059 in GC progression in vivo. Overexpression of circ_002059 significantly inhibited, whereas knockdown of circ_002059 notably facilitated, cell proliferation and migration in GC cells. MTSS1 was found to be a direct target of miR-182 and circ_002059 upregulated MTSS1 expression by competitively sponging miR-182. Transfection with miR-182 mimic and MTSS1 silencing abated the inhibitory effect of circ_002059 on GC progression. Circ_002059 inhibited GC cell xenograft tumor growth by regulating miR-182 and MTSS1 expression. Collectively, Circ_002059 inhibited GC cell proliferation and migration in vitro and xenograft tumor growth in mice, by regulating the miR-182/MTSS1 axis.

scholarly journals Identification of Tumorigenic and Prognostic Biomarkers in Colorectal Cancer Based on microRNA Expression Profiles

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yuntao Shi ◽  
Yingying Zhuang ◽  
Jialing Zhang ◽  
Mengxue Chen ◽  
Shangnong Wu
Keyword(s):  
Target Genes ◽  
Cox Regression ◽  
Expression Profiles ◽  
Survival Rates ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Risk Groups ◽  
Normal Mucosa ◽  
Microrna Expression ◽  
Functional Enrichment

Objective. Although noncoding RNAs, especially the microRNAs, have been found to play key roles in CRC development in intestinal tissue, the specific mechanism of these microRNAs has not been fully understood. Methods. GEO and TCGA database were used to explore the microRNA expression profiles of normal mucosa, adenoma, and carcinoma. And the differential expression genes were selected. Computationally, we built the SVM model and multivariable Cox regression model to evaluate the performance of tumorigenic microRNAs in discriminating the adenomas from normal tissues and risk prediction. Results. In this study, we identified 20 miRNA biomarkers dysregulated in the colon adenomas. The functional enrichment analysis showed that MAPK activity and MAPK cascade were highly enriched by these tumorigenic microRNAs. We also investigated the target genes of the tumorigenic microRNAs. Eleven genes, including PIGF, TPI1, KLF4, RARS, PCBP2, EIF5A, HK2, RAVER2, HMGN1, MAPK6, and NDUFA2, were identified to be frequently targeted by the tumorigenic microRNAs. The high AUC value and distinct overall survival rates between the two risk groups suggested that these tumorigenic microRNAs had the potential of diagnostic and prognostic value in CRC. Conclusions. The present study revealed possible mechanisms and pathways that may contribute to tumorigenesis of CRC, which could not only be used as CRC early detection biomarkers, but also be useful for tumorigenesis mechanism studies.

scholarly journals miRNA Mediated Noise Making of 3′UTR Mutations in Cancer

Genes ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 545 ◽  
Author(s):  
Wei Wu ◽  
Lingxiang Wu ◽  
Mengyan Zhu ◽  
Ziyu Wang ◽  
Min Wu ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Target Genes ◽  
Expression Profiles ◽  
Tumor Development ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Messenger Rnas ◽  
Cellular Functions ◽  
Mrna Binding

Somatic mutations in 3′-untranslated regions (3′UTR) do not alter amino acids and are considered to be silent in cancers. We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA–mRNA interactions. We identified 67,159 somatic mutations located in the 3′UTRs of messenger RNAs (mRNAs) which can alter miRNA–mRNA interactions (functional somatic mutations, funcMutations), and 69.3% of these funcMutations (the degree of energy change > 12 kcal/mol) were identified to significantly promote loss of miRNA-mRNA binding. By integrating mRNA expression profiles of 21 cancer types, we found that the expression of target genes was positively correlated with the loss of absolute affinity level and negatively correlated with the gain of absolute affinity level. Functional enrichment analysis revealed that genes carrying funcMutations were significantly enriched in the MAPK and WNT signaling pathways, and analysis of regulatory modules identified eighteen miRNA modules involved with similar cellular functions. Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3′UTR mutations may play an important role in tumor development.

scholarly journals 3131 ONCOSTREAMS: NOVEL DYNAMICS PATHOLOGICAL MULTICELLULAR STRUCTURES INVOLVED IN GLIOBLATOMA GROWTH AND INVASION

2019 ◽  
Vol 3 (s1) ◽  
pp. 111-111 ◽  
Author(s):  
Andrea Comba ◽  
Patrick Dunn ◽  
Anna E Argento ◽  
Padma Kadiyala ◽  
Sebastien Motsch ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Target Genes ◽  
Collective Motion ◽  
Malignant Tumors ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Genetically Engineered ◽  
Functional Enrichment ◽  
Low Grade ◽  
Normal Brain

OBJECTIVES/SPECIFIC AIMS: Oncostreams represent a novel growth pattern of GBM. In this study we uncovered the cellular and molecular mechanism that regulates the oncostreams function in GBM growth and invasion. METHODS/STUDY POPULATION: We studied oncostreams organization and function using genetically engineered mouse gliomas models (GEMM), mouse primary patient derived GBM model and human glioma biopsies. We evaluated the molecular landscape of oncostreams by laser capture microdissection (LCM) followed by RNA-Sequencing and bioinformatics analysis. RESULTS/ANTICIPATED RESULTS: Oncostreams are multicellular structures of 10-20 cells wide and 2-400 μm long. They are distributed throughout the tumors in mouse and human GBM. Oncostreams are heterogeneous structures positive for GFAP, Nestin, Olig2 and Iba1 cells and negative for Neurofilament. Using GEMM we found a negative correlation between oncostream density and animal survival. Moreover, examination of patient’s glioma biopsies evidenced that oncostreams are present in high grade but no in low grade gliomas. This suggests that oncostreams may play a role in tumor malignancy. Our data also indicated that oncostreams aid local invasion of normal brain. Transcriptome analysis of oncostreams revealed 43 differentially expressed (DE) genes. Functional enrichment analysis of DE genes showed that “collagen catabolic processes”, “positive regulation of cell migration”, and “extracellular matrix organization” were the most over-represented GO biological process. Network analysis indicated that Col1a1, ACTA2, MMP9 and MMP10 are primary target genes. These genes were also overexpressed in more malignant tumors (WT-IDH) compared to the less malignant (IDH1- R132H) tumors. Confocal time lapse imagining of 3D tumor slices demonstrated that oncostreams display a collective motion pattern within gliomas that has not been seen before. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, oncostreams are anatomically and molecularly distinctive, regulate glioma growth and invasion, display collective motion and are regulated by the extracellular matrix. We propose oncostreams as novel pathological markers valuable for diagnosis, prognosis and designing therapeutics for GBM patients.

scholarly journals Immunological pathways of macrophage response to Brucella ovis infection

2020 ◽  
Vol 26 (7) ◽  
pp. 635-648
Author(s):  
Zhixiong Zhou ◽  
Guojing Gu ◽  
Yichen Luo ◽  
Wenjie Li ◽  
Bowen Li ◽  
...  
Keyword(s):  
Immune Response ◽  
Molecular Mechanisms ◽  
Group Versus ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Sequencing Data ◽  
Brucella Ovis ◽  
Qrt Pcr ◽  
Raw264.7 Macrophage

As the molecular mechanisms of Brucella ovis pathogenicity are not completely clear, we have applied a transcriptome approach to identify the differentially expressed genes (DEGs) in RAW264.7 macrophage infected with B. ovis. The DEGs related to immune pathway were identified by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) functional enrichment analysis. Quantitative real-time PCR (qRT-PCR) was performed to validate the transcriptome sequencing data. In total, we identified 337 up-regulated and 264 down-regulated DEGs in B. ovis-infected group versus mock group. Top 20 pathways were enriched by KEGG analysis and 20 GO by functional enrichment analysis in DEGs involved in the molecular function, cellular component, and biological process and so on, which revealed multiple immunological pathways in RAW264.7 macrophage cells in response to B. ovis infection, including inflammatory response, immune system process, immune response, cytokine activity, chemotaxis, chemokine-mediated signaling pathway, chemokine activity, and CCR chemokine receptor binding. qRT-PCR results showed Ccl2 (ENSMUST00000000193), Ccl2 (ENSMUST00000124479), Ccl3 (ENSMUST00000001008), Hmox1 (ENSMUST00000005548), Hmox1 (ENSMUST00000159631), Cxcl2 (ENSMUST00000075433), Cxcl2 (ENSMUST00000200681), Cxcl2 (ENSMUST00000200919), and Cxcl2 (ENSMUST00000202317). Our findings firstly elucidate the pathways involved in B. ovis-induced host immune response, which may lay the foundation for revealing the bacteria–host interaction and demonstrating the pathogenic mechanism of B. ovis.

scholarly journals Circular RNA CircITGA7 Promotes Tumorigenesis of Osteosarcoma via miR-370/PIM1 Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Chuanwu Fang ◽  
Xiaohong Wang ◽  
Dongliang Guo ◽  
Run Fang ◽  
Ting Zhu
Keyword(s):  
Circular Rna ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Functional Assay ◽  
Transwell Assay ◽  
Qrt Pcr ◽  
Proliferation And Metastasis ◽  
And Migration ◽  
Dual Luciferase Reporter Assay ◽  
Proliferation And Migration

Many studies have shown that there are many circular RNA (circRNA) expression abnormalities in osteosarcoma (OS), and this abnormality is related to the development of osteosarcoma. But at present, it is unclear as to what circITGA7 has in the OS and what it does. In this study, qRT-PCR was used to detect the expression of circITGA7, miR-370, and PIM1 mRNA in OS tissues and cells. The CCK-8 assay was used to detect the effect of circITGA7 on cell proliferation. Later, the transwell assay was used to detect cell migration and invasion. The dual-luciferase reporter assay confirmed the existence of the targeting relationship between circITGA7 and miR-370, and miR-370 and PIM1. We found that circITGA7 was upregulated in OS tissues and cell lines. Knockdown of circITGA7 weakened the cell’s ability to proliferate and metastasize. Furthermore, we observed that miR-370 was negatively regulated by circITGA7, while PIM1 was positively regulated by it. A functional assay validated that circITGA7 promoted OS progression via suppressing miR-370 and miR-370 affected OS proliferation and migration via PIM6 in OS. In summary, this study shows that circITGA7 promotes OS proliferation and metastasis via miR-370/PIM1.

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