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2021 ◽  
Vol 21 (1) ◽  
Tian Xia ◽  
Lian Meng ◽  
Zhijuan Zhao ◽  
Yujun Li ◽  
Hao Wen ◽  

Abstract Background Rhabdomyosarcoma (RMS) is a malignant soft-tissue tumour. In recent years, the tumour microenvironment (TME) has been reported to be associated with the development of tumours. However, the relationship between the occurrence and development of RMS and TME is unclear. The purpose of this study is to identify potential tumor microenvironment-related biomarkers in rhabdomyosarcoma and analyze their molecular mechanisms, diagnostic and prognostic significance. Methods We first applied bioinformatics method to analyse the tumour samples of 125 patients with rhabdomyosarcoma (RMS) from the Gene Expression Omnibus database (GEO). Differential genes (DEGs) that significantly correlate with TME and the clinical staging of tumors were extracted. Immunohistochemistry (IHC) was applied to validate the expression of mitotic arrest deficient 2 like 1 (MAD2L1) and cyclin B2 (CCNB2) in RMS tissue. Then, we used cell function and molecular biology techniques to study the influence of MAD2L1 and CCNB2 expression levels on the progression of RMS. Results Bioinformatics results show that the RMS TME key genes were screened, and a TME-related tumour clinical staging model was constructed. The top 10 hub genes were screened through the establishment of a protein–protein interaction (PPI) network, and then Gene Expression Profiling Interactive Analysis (GEPIA) was conducted to measure the overall survival (OS) of the 10 hub genes in the sarcoma cases in The Cancer Genome Atlas (TCGA). Six DEGs of statistical significance were acquired. The relationship between these six differential genes and the clinical stage of RMS was analysed. Further analysis revealed that the OS of RMS patients with high expression of MAD2L1 and CCNB2 was worse and the expression of MAD2L1 and CCNB2 was related to the clinical stage of RMS patients. Gene set enrichment analysis (GSEA) revealed that the genes in MAD2L1 and CCNB2 groups with high expression were mainly related to the mechanism of tumour metastasis and recurrence. In the low-expression MAD2L1 and CCNB2 groups, the genes were enriched in the metabolic and immune pathways. Immunohistochemical results also confirmed that the expression levels of MAD2L1 (30/33, 87.5%) and CCNB2 (33/33, 100%) were remarkably higher in RMS group than in normal control group (0/11, 0%). Moreover, the expression of CCNB2 was related to tumour size. Downregulation of MAD2L1 and CCNB2 suppressed the growth, invasion, migration, and cell cycling of RMS cells and promoted their apoptosis. The CIBERSORT immune cell fraction analysis indicated that the expression levels of MAD2L1 and CCNB2 affected the immune status in the TME. Conclusions The expression levels of MAD2L1 and CCNB2 are potential indicators of TME status changes in RMS, which may help guide the prognosis of patients with RMS and the clinical staging of tumours.

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Qianhong Yang ◽  
Xiaolu Bai ◽  
Xiang Li ◽  
Wei Hu

Purpose. Heart failure (HF) is a clinical syndrome caused by ventricular insufficiency. In order to further explore the biomarkers related to HF, we apply the high-throughput database. Materials and Methods. The GSE21610 was applied for the differentially expressed gene (DEG) analysis. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was performed to assess Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The Gene Set Enrichment Analysis (GSEA) was used for gene expression profile GSE21610. The Protein-Protein Interaction (PPI) network and modules were also constructed for research. These hub gene function pathways were estimated in HF progression. Result. We have identified 434 DEGs in total, including 304 downregulated DEGs and 130 upregulated DEGs. GO and KEGG illustrated that DEGs in HF were significantly enriched in G protein-coupled receptor binding, peroxisome, and cAMP signaling pathway. GSEA results showed gene set GSE21610 was gathered in lipid digestion, defense response to fungus, and intestinal lipid absorption. Finally, through analyzing the PPI network, we screened hub genes CDH1, TFRC, CCL2, BUB1B, and CD19 by the Cytoscape software. Conclusion. This study uses a series of bioinformatics technologies to obtain hug genes and key pathways related to HF. These analysis results provide us with new ideas for finding biomarkers and treatment methods for HF.

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12536
Tao Yan ◽  
Kai Wang ◽  
Qidi Zhao ◽  
Junjie Zhuang ◽  
Hongchang Shen ◽  

As an innate feature of human beings, gender differences have an influence on various biological phenotypes, yet it does not attract enough attention in genomics studies. The prognosis of multiple carcinomas usually exhibits a favorable ending for female patients, but the neglect of gender differences can cause serious bias in survival analysis. Enhancer RNAs (eRNAs) are mostly downstream of androgens or estrogen. The present study was aimed to screen eRNAs in patients with non-small-cell lung cancer. The findings revealed that eRNA TBX5-AS1 was expressed differently between female and male patients. Meanwhile, its prognostic significance appeared only in male patients with squamous cell carcinoma (SCC) type. The Gene Set Enrichment Analysis proved that the expression level of TBX5-AS1 increased following the activation of the androgen signaling pathway. In pan-cancer analysis, the prognostic prediction based on gender grouping obtained more meaningful results, and the synergy between TBX5-AS1 and its homologous target was more consistent. Furthermore, immunity variations between sexes prompted us to explore the role that TBX5-AS1 played in tumor microenvironment and immunotherapy. The robust evidence proved that male patients with high expression of TBX5-AS1 possessed a malignant immune microenvironment and urgently needed immune checkpoint inhibitor treatment. In conclusion, TBX5-AS1 may be one of the strongest candidates to predict prognosis for male patients with SCC and provide a reference for immunotherapy.

2021 ◽  
Tanner Koomar ◽  
Lucas Casten ◽  
Taylor R Thomas ◽  
Jin-Young Koh ◽  
Dabney Hofamann ◽  

Language is the foundation of human social interaction, education, commerce, and mental health. The heritability underlying language is well-established, but our understanding of its genetic basis - and how it compares to that of more general cognitive functioning - remains unclear. To illuminate the language-specific contributions of rare and common variation, we performed whole genome sequencing in N=350 individuals, who were characterized with seven latent language phenotypes. We conducted region, gene, and gene set-based analyses to identify patterns of genetic burden that disproportionately explained these language factors compared to nonverbal IQ. These analyses identified language-specific associations with NDST4 and GRIN2A, with common variant replication of NDST4 in an independent sample. Rare variant burden analyses revealed three distinct functional profiles of genes that make contributions to language: a prenatally-expressed profile with enrichment for chromatin modifiers and broad neuropsychiatric risk, a postnatal cortex-expressed profile with enrichment for ion channels and cognitive/neuropsychiatric associations, and a postnatal, subcortically-expressed profile with enrichment of cilium-related proteins. Compared to a profile strongly associated with nonverbal IQ, these language-related profiles showed less intolerance to damaging variation, suggesting that the selection patterns acting on language differ from patterns linked to intellectual disability. Furthermore, we found evidence that rare potential reversions to an ancestral state are associated with poorer overall specific language ability. The breadth of these variant, gene, and profile associations suggest that while human-specific selection patterns do contribute to language, these are distributed broadly across numerous key mechanisms and developmental periods, and not in one or a few "language genes".

2021 ◽  
Min-Rui Ding ◽  
Yan-Jie Qu ◽  
Xiao Peng ◽  
Jin-Fang Chen ◽  
Meng-Xue Zhang ◽  

Abstract Background: Glioblastoma (GBM) has a high incidence rate, invasive growth, and easy recurrence, and the current therapeutic effect is less than satisfying. Pyroptosis plays an important role in morbidity and progress of GBM. Meanwhile, the tumor microenvironment (TME) is involved in the progress and treatment tolerance of GBM. In the present study, we analyzed prognosis model, immunocyte infiltration characterization, and competing endogenous RNA (ceRNA) network of GBM on the basis of pyroptosis-related genes (PRGs).Methods: The transcriptome and clinical data of 155 patients with GBM and 120 normal subjects were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). Lasso (Least absolute shrinkage and selection operator) Cox expression analysis was used in predicting prognostic markers, and its predictive ability was tested using a nomogram. A prognostic risk score formula was constructed, and CIBERSORT, ssGSEA algorithm, Tumor IMmune Estimation Resource (TIMER), and TISIDB database were used in evaluating the immunocyte infiltration characterization and tumor immune response of differential risk samples. A ceRNA network was constructed with Starbase, mirtarbase, and lncbase, and the mechanism of this regulatory axis was explored using Gene Set Enrichment Analysis (GSEA). Results: Five PRGs (CASP3, NLRP2, TP63, GZMB, and CASP9) were identified as the independent prognostic biomarkers of GBM. Prognostic risk score formula analysis showed that the low-risk group had obvious survival advantage compared with the high-risk group, and significant differences in immunocyte infiltration and immune related function score were found. In addition, a ceRNA network of messenger RNA (CASP3, TP63)–microRNA (hsa-miR-519c-5p)–long noncoding RNA (GABPB1-AS1) was established. GSEA analysis showed that the regulatory axis played a considerable role in the extracellular matrix (ECM) and immune inflammatory response.Conclusions: Pyroptosis and TME-related independent prognostic markers were screened in this study, and a prognosis risk score formula was established for the first time according to the prognosis PRGs. TME immunocyte infiltration characterization and immune response were assessed using ssGSEA, CIBERSORT algorithm, TIMER, and TISIDB database. Besides a ceRNA network was built up. This study not only laid foundations for further exploring pyroptosis and TME in improving prognosis of GBM, but also provided a new idea for more effective guidance on clinical immunotherapy to patients and developing new immunotherapeutic drugs.

2021 ◽  
Yiming Li ◽  
Cong Xu ◽  
Bo Sun ◽  
Fangjing Zhong ◽  
Momo Cao ◽  

Abstract Background Piezo1 plays critical roles in vascular development during early embryogenesis. However, the function of Piezo1 in hepatocellular carcinoma (HCC) remain elusive. This study aimed to explore the function and mechanisms of Piezo1 in HCC. Methods qRT-PCR, western blot and immunohistochemistry analyses were used to determine Piezo1 expression in HCC samples and cell lines. The clinical significance of Piezo1 was assessed in two independent study cohorts containing 280 patients with HCC. Gene set enrichment analysis (GSEA) was performed to explore the signaling pathway of Piezo1. A series of in vitro and in vivo experiments were used to determine the role and molecular mechanism of Piezo1 in HCC progression. Results Piezo1 expression was significantly upregulated in HCC tissues and cell lines. High Piezo1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes of HCC patients. Moreover, knockdown of Piezo1 in HCCLM3 and Hep3B cells significantly inhibited proliferation, migration, invasion and epithelial–mesenchymal transition (EMT) of HCC cells in vitro, and tumor growth, EMT and metastasis in vivo. Further mechanism study indicated that these phenotypic and function changes were mediated by TGF-β signaling pathway. Finally, we proved that Piezo1 exerted its tumor promotion effect by recruiting Rab5c to activating TGF-β signaling pathway. Conclusions We proved Piezo1 promotes progression of hepatocellular carcinoma via TGF-β signaling, which may serve as a novel prognostic predictor and the potential therapeutic target for HCC patients.

2021 ◽  
George C Murray ◽  
Jason Bubier ◽  
Oraya J Zinder ◽  
Belinda Harris ◽  
James Clark ◽  

Rorb encodes the Retinoic Acid Receptor-related orphan receptor beta. Mutations in either of the two transcripts of Rorb cause defects in multiple systems, including abnormal photoreceptor abundance and morphology in the retina and a characteristic high-stepper or duck-like gait arising from dysfunction of interneurons in the spinal cord. Rorb is also important for cortical development and cell fate specification in mice. Rorb variants segregate with epilepsy and comorbidities such as intellectual disability in numerous clinical cases. Here we describe five mouse strains with spontaneous mutations in Rorb identified by their gait phenotype. These mutations affect different domains and isoforms of Rorb, which correspond to the spectrum of anatomical and physiological phenotypes exhibited by these mice. Gene set analysis in Rorb mutants implicates pathways associated with development and nervous system function, and differential gene expression analysis indicates changes in numerous genes related to epilepsy, bipolar disorder, and autism spectrum disorder (ASD). Many of these genes and their protein products are known to interact during synapse formation and neuronal activity. These findings further illuminate the role of Rorb in nervous system development, provide further evidence for an association between Rorb and several neurological conditions, and describe an allelic series of Rorb mutant mice that will be useful for dissecting thalamocortical afferent(TCA) development, neural cell fate determination, and as animal models exhibiting transcriptomic shifts in neurological conditions such as epilepsy, bipolar disorder, and ASD.

2021 ◽  
Ya Yang ◽  
Xintan Zhang ◽  
Tingxuan Li ◽  
Yue Zhang ◽  
Xiaoxiao Zuo

Abstract Background: Immune infiltrated genes (IIGs) have been identified to associated with the prognosis of various cancers, but their expression and prognostic significance remain largely unclear in stomach adenocarcinoma (STAD).Methods: Gene expression profiles and clinical data of STAD patients were downloaded from The Cancer Genome Atlas (TCGA) as a training dataset (n = 375) and Gene Expression Omnibus (GEO) databases as a validation dataset (n = 300). Construction of high and low immune cell infiltration groups was performed by single sample gene set enrichment analysis (ssGSEA) and evaluated by ESTIMATE algorithm-derived immune scores. The overlapping differentially expressed genes (DEGs) in tumor vs. normal and Immunity-H vs. Immunity-L were selected as differentially expressed immune infiltrated genes (DEIIGs), which were used to construct DEIIG prognostic signature and its performance was validated using validation dataset. Moreover, the association between clinical data and immune features were explored. Furthermore, ADH4 and ANGPT2 were selected for analyzing their expression and prognostic values in STAD patients.Results: A total of 191 overlapping DEGs, including 6 lnRNAs and 185 mRNA were identified. Consecutively, 9 DEIIG prognostic signature (LINC00843, ADH4, ANGPT2, APOA1, ASLC2, GFRA1, KIAA1549L, MTTP and PROC) were identified as risk signature and Kaplan-Meier curve and ROC curve verified its performance in TCGA and GEO datasets. Total five clinical outcomes (age, pathologic T, radiotherapy, tumor recurrence and prognostic score model status) were identified to be associated with the survival prognosis of STAD patients. The TIMER algorithm revealed that B cell, T cell CD4+, neutrophil, macrophage and myeloid dendritic cell were positively correlated with STAD prognosis, while CD8+ was negatively correlated with STAD prognosis. Additionally, we validated that higher ADH4 and lower ANGPT2 predicted better survival prognosis in STAD patients.Conclusion: We constructed and verified a robust signature of nine DEIIG prognostic signature for the prediction of STAD patient survival.

2021 ◽  
Vol 11 ◽  
Yanyan He ◽  
Lin Duan ◽  
Haigang Wu ◽  
Song Chen ◽  
Taoyuan Lu ◽  

Blood vessels in the brain tissue form a compact vessel structure and play an essential role in maintaining the homeostasis of the neurovascular system. The low dosage of photodynamic intervention (PDT) significantly affects the expression of cellular biomarkers. To understand the impact of photodynamic interventions on cerebrovascular endothelial cells, we evaluated the dosage-dependent impact of porfimer sodium-mediated PDT on B.END3 cells using flow cytometer, comet assay, RNA sequencing, and bioinformatics analysis. To examine whether PDT can induce disorder of intracellular organelles, we did not observe any significance damage of DNA and cellular skeleton. Moreover, expression levels of cellular transporters-related genes were significantly altered, implying the drawbacks of PDT on cerebrovascular functions. To address the potential molecular mechanisms of these phenotypes, RNA sequencing and bioinformatics analysis were employed to identify critical genes and pathways among these processes. The gene ontology (GO) analysis and protein-protein interaction (PPI) identified 15 hub genes, highly associated with cellular mitosis process (CDK1, CDC20, MCM5, MCM7, MCM4, CCNA2, AURKB, KIF2C, ESPL1, BUB1B) and DNA replication (POLE2, PLOE, CDC45, CDC6). Gene set enrichment analysis (GSEA) reveals that TNF-α/NF-κB and KRAS pathways may play a critical role in regulating expression levels of transporter-related genes. To further perform qRT-PCR assays, we find that TNF-α/NF-κB and KRAS pathways were substantially up-regulated, consistent with GSEA analysis. The current findings suggested that a low dosage of PDT intervention may be detrimental to the homeostasis of blood-brain barrier (BBB) by inducing the inflammatory response and affecting the expression of surface biomarkers.

Brooke Sadler ◽  
Charles Minard ◽  
Gabe Haller ◽  
Christina A Gurnett ◽  
Sarah H. O'Brien ◽  

Adolescents with low von Willebrand factor (VWF) levels and heavy menstrual bleeding (HMB) experience significant morbidity. There is a need to better genetically characterize these patients and improve our understanding of the pathophysiology of bleeding. We performed whole-exome sequencing on 86 post-menarchal patients diagnosed with low-VWF levels (30-50 IU/dL) and HMB and compared them to 660 in-house controls. We compared the number of rare stop-gain/stop-loss and rare ClinVar pathogenic variants between cases and controls, as well as performed gene-burden and gene-set burden analyses. We found an enrichment in cases of rare stop-gain/stop-loss variants in genes involved in bleeding disorders, and an enrichment of rare ClinVar pathogenic variants in genes involved in anemias. The two most significant genes in the gene-burden analysis, CFB and DNASE2, are associated with atypical hemolytic uremia (aHUS) and severe anemia, respectively. VWF also surpassed exome-wide significance in the gene-burden analysis (p=7.31x10-6). Gene-set burden analysis revealed an enrichment of rare nonsynonymous variants in cases in several hematologically relevant pathways. Further, common variants in FERMT2, a gene involved in regulation of hemostasis and angiogenesis surpassed genome-wide significance. We demonstrate that adolescents with HMB and low-VWF have an excess of rare nonsynonymous and pathogenic variants in genes involved in disorders of bleeding and anemia. Variants of variable penetrance in these genes may contribute to the spectrum of phenotypes observed in HMB patients, and could partially explain the bleeding phenotype. By identifying the HMB patients who possess these variants, we may be able to improve risk stratification and patient outcomes.

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