A Novel lncRNA lncRNA-4045 Promotes the Progression of Hepatocellular Carcinoma by Affecting the Expression of AKR1B10.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been shown to be related to the occurrence and development of a variety of cancers including hepatocellular carcinoma (HCC). However, a large number of potential HCC-related lncRNAs remain undiscovered and are yet to be fully understood. METHODS: Differentially expressed lncRNAs were first obtained from the tumor tissues and adjacent normal tissues of five HCC patients using high-throughput microarray chips. Then the expression levels of 10 differentially expressed lncRNAs were verified in 50 pairs of tissue samples from patients with HCC by quantitative real-time PCR (qRT-PCR). The oncogenic effects of lncRNA-4045 (ENST00000524045.6) in HCC cell lines were verified through a series of in vitro experiments including CCK-8 assay, plate clone formation assay, transwell assay, scratch assay, and flow cytometry. Subsequently, the potential target genes of lncRNA-4045 were predicted by bioinformatics analysis, fluorescence in situ hybridization assay, and RNA sequencing. The mechanism of lncRNA-4045 in HCC was explored by WB assay as well as rescue and enhancement experiments. RESULTS: The results from microarray chips showed 1,708 lncRNAs to have been significantly upregulated and 2725 lncRNAs to have been significantly downregulated in HCC tissues. Via validation in 50 HCC patients, a novel lncRNA lncRNA-4045 was found significantly upregulated in HCC tissues. Additionally, a series of in vitro experiments showed that lncRNA-4045 promoted the proliferation, invasion, and migration of HCC cell lines, and inhibited the apoptosis of HCC cell lines. The results of qRT-PCR in HCC tissues showed that the expression levels of AKR1B10 were significantly positively correlated with lncRNA-4045. LncRNA-4045 knockdown significantly down-regulated AKR1B10 protein expression, and overexpression of lncRNA-4045 led to significant up-regulation of AKR1B10 protein in HCC cell lines. Lastly, down-regulation of AKR1B10 could partially eliminate the enhancement of cell proliferation induced by lncRNA-4045 overexpression, while up-regulation of AKR1B10 was shown to enhance those effects. CONCLUSION: LncRNA-4045 may promote HCC via enhancement of the expression of AKR1B10 protein.

Low expression of GOT2 promotes tumor progress and predicts poor prognosis in hepatocellular carcinoma.

Background: To explore the biological function and the underlying mechanisms of GOT2 in hepatocellular carcinoma (HCC). Materials & methods: The expression level and prognostic value of GOT2 were examined using International Cancer Genome Consortium and International Cancer Proteogenome Consortium databases. The cell counting kit-8 method, clone formation, Transwell® assays and western blotting were used to evaluate the effects of GOT2 on the biological function and autophagy of HCC cells. Results: The expression of GOT2 was downregulated in HCC tissues and correlated with poor prognosis of HCC patients. Knockdown of GOT2 promoted proliferation, migration and invasion of HCC cells and promoted cells' proliferation by inducing autophagy. Conclusion: GOT2 plays a tumor-inhibitory role in HCC and may be a potential therapeutic target for HCC.

Identification and verification of novel ferroptosis biomarkers predicts the prognosis of hepatocellular carcinoma.

BACKGROUND: Big data mining and experiments are widely used to mine new prognostic markers. METHODS: Candidate genes were identified from CROEMINE and FerrDb. Kaplan-Meier survival and Cox regression analysis were applied to assess the association of genes with Overall survival time (OS) and Disease-free survival time (DFS) in two HCC cohorts. Real-time quantitative polymerase chain reaction (RT-qPCR) and Immunohistochemistry were performed in HCC samples. RESULTS: 21 and 15 genes that can predict OS and DFS, which had not been reported before, were identified from 719 genes, respectively. Survival analysis showed elevated mRNA expression of GLMP, SLC38A6, and WDR76 were associated with poor prognosis, and three genes combination signature was an independent prognostic factor in HCC. RT-qPCR and Immunohistochemistry confirmed the results. CONCLUSIONS: We established a novel computational process, which identified the expression levels of GLMP, SLC38A6, and WDR76 as potential ferroptosis-related biomarkers indicating the prognosis of HCC.

circELMOD3 increases and stabilizes TRIM13 by sponging miR-6864-5p and direct binding to inhibit HCC progression.

Many circular RNAs (circRNAs) have been identified to be associated with hepatocellular carcinoma (HCC) progression. We aim to explore the diagnostic potential, functions, and mechanism of circELMOD3 in HCC. Differentially expressed circRNAs in HCC and its paired adjacent tissues were identified by RNA sequencing. circELMOD3 was downregulated in HCC tissues and was related to clinicopathological characteristics of HCC patients. Additionally, plasma circELMOD3 was shown to be a highly sensitive and non-invasive biomarker to distinguish HCC from healthy controls. Functional assays showed that circELMOD3 inhibited proliferation and induced apoptosis of HCC cells both in vitro and in vivo. Mechanistically, RNA antisense purification (RAP) and luciferase reporter assays verified that circELMOD3 functioned as a sponge for miR-6864-5p leading to increased expression of its target gene TRIM13. Interestingly, RNA stability test demonstrated that circELMOD3 overexpression led to enhanced stability of its directly bound TRIM13 mRNA, which in turn co-activated the p53 signaling pathway.

Nucleus-localized circSLC39A5 suppresses hepatocellular carcinoma development by binding to STAT1 to regulate TDG transcription.

Accumulating evidence indicates that circular RNAs (circRNAs) are inextricably linked to cancer development. However, the function and mechanism of nucleus-localized circRNAs in hepatocellular carcinoma (HCC) still require investigation. Here, qRT-PCR and receiver-operating characteristic curve were used to detect the expression and diagnostic potential of circSLC39A5 for HCC. The biological function of circSLC39A5 in HCC was investigated in vitro and in vivo. Nucleoplasmic separation assay, fluorescence in situ hybridization, RNA pulldown, RNA immunoprecipitation, the HDOCK Server, the NucleicNet Webserver, crosslinking-immunoprecipitation, MG132 treatment, and chromatin immunoprecipitation were utilized to explore the potential molecular mechanism of circSLC39A5 in HCC. The results showed that circSLC39A5 was downregulated in both HCC tissues and plasma and was associated with satellite nodules and lymph node metastasis/vascular invasion. CircSLC39A5 was stably expressed in plasma samples under different storage conditions, showing good diagnostic potential for HCC (AUC = 0.915). CircSLC39A5 inhibited proliferation, migration, and invasion, facilitated the apoptosis of HCC cells, and was associated with low expression of Ki67 and CD34. Remarkably, circSLC39A5 is mainly localized in the nucleus and binds to the transcription factor signal transducer and activator of transcription 1 (STAT1), affecting its stabilization and expression. STAT1 binds to the promoter of thymine DNA glycosylase (TDG). Overexpression of circSLC39A5 elevates TDG expression and reverses the increase of proliferating cell nuclear antigen (PCNA) expression and the overactive cell proliferation caused by TDG silencing. Our findings uncovered a novel plasma circRNA, circSLC39A5, which may be a potential circulating diagnostic marker for HCC, and the mechanism by which nucleus-localized circSLC39A5 exerts a transcriptional regulatory role in HCC by affecting STAT1/TDG/PCNA provides new insights into the mechanism of circRNAs.

Artificial Intelligence and Machine (Deep) Learning in Otorhinolaryngology: A Bibliometric Analysis Based on VOSviewer and CiteSpace.

BACKGROUND: Otorhinolaryngology diseases are well suited for artificial intelligence (AI)-based interpretation. The use of AI, particularly AI based on deep learning (DL), in the treatment of human diseases is becoming more and more popular. However, there are few bibliometric analyses that have systematically studied this field. OBJECTIVE: The objective of this study was to visualize the research hot spots and trends of AI and DL in ENT diseases through bibliometric analysis to help researchers understand the future development of basic and clinical research. METHODS: In all, 232 articles and reviews were retrieved from The Web of Science Core Collection. Using CiteSpace and VOSviewer software, countries, institutions, authors, references, and keywords in the field were visualized and examined. RESULTS: The majority of these papers came from 44 nations and 498 institutions, with China and the United States leading the way. Common diseases used by AI in ENT include otosclerosis, otitis media, nasal polyps, sinusitis, and so on. In the early years, research focused on the analysis of hearing and articulation disorders, and in recent years mainly on the diagnosis, localization, and grading of diseases. CONCLUSIONS: The analysis shows the periodical hot spots and development direction of AI and DL application in ENT diseases from the time dimension. The diagnosis and prognosis of otolaryngology diseases and the analysis of otolaryngology endoscopic images have been the focus of current research and the development trend of future.

CircFAM114A2 inhibits the progression of hepatocellular carcinoma via miR-630/HHIP axis.

BACKGROUND: Many studies have shown that circular RNAs (circRNAs) are abnormally expressed in various tumor tissues and served as a key regulator in the occurrence and development of cancer. However, in hepatocellular carcinoma (HCC), the molecular mechanism of circRNAs in body fluids remains to be further explored. METHODS: The expression levels of genes and proteins were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU), wound healing assay, Transwell assays, flow cytometry, and tumor formation models in nude mice were conducted to investigate the effects of circFAM114A2 on HCC cells both in vitro and in vivo. RNA antisense purification (RAP), dual luciferase reporter assays and rescue assays were carried out to verify the interaction between circFAM114A2, miR-630 and HHIP. RESULTS: CircFAM114A2 was significantly downregulated in HCC tissues and was associated with microvascular invasion and lymph node metastasis of HCC patients. We also observed that circFAM114A2 was lowly expressed in HCC plasma, which may serve as an effective biomarker to screen HCC patients from healthy controls (area under curve (AUC)=0.922). In vitro, circFAM114A2 overexpression significantly blunted HCC cell proliferation, migration, invasion, and promoted apoptosis, whereas circFAM114A2 silencing posed opposite effects. In vivo, circFAM114A2 overexpression inhibited the growth of HCC cells. Mechanistically, circFAM114A2 could increase the expression of the tumor suppressor HHIP via acting as a sponge for miR-630. CONCLUSIONS: CircFAM114A2 exerts a tumor suppressor role in HCC through miR-630/HHIP axis, and may be served as a potential diagnostic and therapeutic biomarker for HCC patients.

High Prevalence of Hyperuricemia and Associated Factors among Zhuang Adults: A Cross-Sectional Study Based on the Ethnic Minority Population Cohort in the Southwestern China.

The highest prevalence of hyperuricemia was found in Zhuang minority adults in two national surveys in China, with only 1% Zhuang study subjects. However, the prevalence of hyperuricemia and the associated factors in Zhuang adults have not been well-addressed. A cross-sectional study was conducted to explore the prevalence of hyperuricemia and the common comorbidities, and the associated factors in Zhuang adults based on the Guangxi Ethnic Minority Population Cohort. Among 11,175 Zhuang adults aged 35-74 years, the age- and sex-standardized prevalence rate was 18.1% for hyperuricemia and 1.1% for gout. The standardized prevalence rate and awareness rate were 31.6% and 32.3%, respectively, for hypertension, and were 5.1% and 48.2%, respectively, for diabetes. High education level, history of coronary heart disease (CHD), hypertension, being a current drinker, high body mass index (BMI), central obesity, hyper-triglyceride (hyper-TG), hyper-total cholesterol (hyper-TC), hypo-high density lipoprotein cholesterol (hypo-HDL-C), and abnormal aspartate aminotransferase (AST) were risk factors, while smoking and diabetes were protective factors of hyperuricemia in males. Older age, being single/divorced, having a high education level, hypertension, drinking tea, high BMI, central obesity, hyper-TG, hyper-TC, hypo-HDL-C, and abnormal alanine aminotransferase (ALT) were risk factors in females. The high prevalence of hyperuricemia but low prevalence of gout and common comorbidities in Zhuang adults may be due to a lag effect of lifestyle changes. Health education and health management should be strengthened to prevent the progression of comorbidities, considering the lag effect and low awareness rate.

Liver-specific lncRNA FAM99A may be a tumor suppressor and promising prognostic biomarker in hepatocellular carcinoma.

BACKGROUND: Increasing evidence shows that liver-specific long non-coding RNAs (lncRNAs) play important roles in the development of hepatocellular carcinoma (HCC). We identified a novel liver-specific lncRNA, FAM99A, and examined its clinical significance and biological functions in HCC. METHODS: The expression level and clinical value of FAM99A in HCC were examined using The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases, and were further verified using quantitative real-time polymerase chain reaction (qRT-PCR) in our HCC cohort. Univariate and multivariate Cox proportional hazards regression models were also applied to identify independent prognostic indicators for HCC patients. Cell counting kit-8, colony formation, and Transwell assays were performed to evaluate the effects of FAM99A on the proliferation, migration, and invasion abilities of HCC cells in vitro. A subcutaneous xenograft tumor model was implemented to determine the effect of FAM99A on the tumor growth of HCC cells in vivo. RNA pull-down and mass spectrometry assays were performed to reveal the potential molecular mechanisms of FAM99A in HCC. RESULTS: The three public online databases and qRT-PCR data showed that FAM99A was frequently downregulated in HCC tissues and inversely correlated with microvascular invasion and advanced histological grade of HCC patients. Kaplan-Meier survival analysis indicated that decreased FAM99A was significantly associated with poor overall survival of HCC patients based on TCGA database (P = 0.040), ICGC data portal (P < 0.001), and our HCC cohort (P = 0.010). A multivariate Cox proportional hazards regression model based on our HCC cohort suggested that FAM99A was an independent prognostic factor of overall survival for HCC patients (hazard ratio: 0.425, P = 0.039). Upregulation of FAM99A suppressed the proliferation, colony formation, migration, and invasion capacities of HCC cells in vitro, and knockdown of FAM99A had the opposite effects. A subcutaneous xenograft tumor model demonstrated that overexpression of FAM99A significantly inhibited the tumor growth of HCC cells in vivo. Seven tumor-related proteins (PCBP1, SRSF5, SRSF6, YBX1, IGF2BP2, HNRNPK, and HNRNPL) were recognized as possible FAM99A-binding proteins by the RNA pull-down and mass spectrometry assays. CONCLUSION: Our results suggest that FAM99A exerts cancer-inhibiting effects on HCC progression, and it may be a promising prognostic indicator for HCC patients.

The association between iron status and thyroid hormone levels during pregnancy.

BACKGROUND: Iron deficiency may be a risk factor for thyroid disorder; however, the relationship between iron deficiency and thyroid disorder as well as mechanism involved remain unclear. METHODS: A hospital-based cross-sectional study was conducted to analyze the correlation between iron status and thyroid hormone levels in pregnant women. A total of 2218 pregnant women were recruited, and iron status and thyroid hormones were measured. Canonical correlation, Lasso regression, and Receiver operator characteristic (ROC) curve analysis were used to determine the association and related factors. RESULTS: There were 219 cases with iron deficiency anemia (IDA), 168 cases with iron deficiency (ID), and 1831 subjects with normal iron status. Compared with normal group, free triiodothyronine (FT3) and free thyroxine (FT4) in ID group and IDA group had a significant decreasing trend (P < 0.05), with the lowest levels in IDA group. Thyroid stimulating hormone (TSH) was significantly increased in ID group and IDA group (P < 0.05). Moreover, the proportion of hypothyroidism in both ID group and IDA group was higher than the normal group, meanwhile the proportion of hyperthyroidism was lower in both groups (P < 0.05). Serum ferritin (SF) and hemoglobin (Hb) were positively correlated with FT3 and FT4 but negatively correlated with TSH. Correlation analysis indicated that iron status was associated with thyroid hormone levels (P < 0.05). Lasso regression analysis showed that SF, Hb and other variables could be included in the prediction model of FT4. The variables selected by Lasso model were used for ROC curve analysis, and the prediction accuracy was acceptable (AUC=0.778, P < 0.05). CONCLUSION: Our study indicated that there is an association between iron status and thyroid hormone levels in pregnant women, and the level of FT4 may change with iron status. Our findings provide new ideas for regulating the thyroid hormone levels to prevent thyroid dysfunction during pregnancy.

4-hydroxybenzophenone exposure inhibits mouse hippocampal neural stem cell proliferation in vitro by upregulating Cxcl1.

Benzophenones are widely used in industry and commonly added in many personal care products. However, the neurotoxicity, in particular neurodevelopmental toxicity, of benzophenone family chemicals and metabolites has not been fully elucidated. Our recent mechanistic study in mice showed that early life exposure to a major benzophenone metabolite, 4-hydroxybenzophenone (4HBP), disrupted endoplasmic reticulum (ER) proteostasis and evoked inflammatory response in hippocampal neural stem cells (NSCs), leading to cognitive dysfunction. Despite so, detailed inflammatory cytokine(s) that possibly mediate this toxicity remains to be defined and validated. In this study, we confirmed that 4HBP treatment inhibited the viability and sphere growth of mouse NSCs in vitro. Importantly, re-interrogation of the transcriptomic data of NSCs treated with 4HBP identified the top upregulated genes, wherein the chemokine Cxcl1 ranked first. Immunofluorescent staining and qRT-PCR validated the robust induction of Cxcl1 on the protein and mRNA levels upon 4HBP treatment. Furthermore, siRNA-mediated knockdown of Cxcl1 transiently blocked its expression and led to enhanced NSCs viability in the presence of 4HBP. Together, these in vitro results indicated that the adverse effect of benzophenones on NSCs is mediated, at least in part, by induction of the chemokine Cxcl1.

Construction and Comprehensive Analysis of a circRNA-miRNA-mRNA Regulatory Network to Reveal the Pathogenesis of Hepatocellular Carcinoma.

Background: Circular RNAs (circRNAs) have been demonstrated to be closely related to the carcinogenesis of human cancer in recent years. However, the molecular mechanism of circRNAs in the pathogenesis of hepatocellular carcinoma (HCC) has not been fully elucidated. We aimed to identify critical circRNAs and explore their potential regulatory network in HCC. Methods: The robust rank aggregation (RRA) algorithm and weighted gene co-expression network analysis (WGCNA) were conducted to unearth the differentially expressed circRNAs (DEcircRNAs) in HCC. The expression levels of DEcircRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). A circRNA-miRNA-mRNA regulatory network was constructed by computational biology, and protein-protein interaction (PPI) network, functional enrichment analysis, survival analysis, and infiltrating immune cells analysis were performed to uncover the potential regulatory mechanisms of the network. Results: A total of 22 DEcircRNAs were screened out from four microarray datasets (GSE94508, GSE97332, GSE155949, and GSE164803) utilizing the RRA algorithm. Meanwhile, an HCC-related module containing 404 circRNAs was identified by WGCNA analysis. After intersection, only four circRNAs were recognized in both algorithms. Following qRT-PCR validation, three circRNAs (hsa_circRNA_091581, hsa_circRNA_066568, and hsa_circRNA_105031) were chosen for further analysis. As a result, a circRNA-miRNA-mRNA network containing three circRNAs, 17 miRNAs, and 222 mRNAs was established. Seven core genes (ESR1, BUB1, PRC1, LOX, CCT5, YWHAZ, and DDX39B) were determined from the PPI network of 222 mRNAs, and a circRNA-miRNA-hubgene network was also constructed. Functional enrichment analysis suggested that these seven hub genes were closely correlated with several cancer related pathways. Survival analysis revealed that the expression levels of the seven core genes were significantly associated with the prognosis of HCC patients. In addition, we also found that these seven hub genes were remarkably related to the infiltrating levels of immune cells. Conclusion: Our research identified three pivotal HCC-related circRNAs and provided novel insights into the underlying mechanisms of the circRNA-miRNA-mRNA regulatory network in HCC.

Liver-specific LINC01146, a promising prognostic indicator, inhibits the malignant phenotype of hepatocellular carcinoma cells both in vitro and in vivo.

BACKGROUND: Long non-coding RNAs (lncRNAs) are involved in the development of hepatocellular carcinoma (HCC). We aimed to investigate the function of LINC01146 in HCC. METHODS: The expression of LINC01146 in HCC tissues was explored via The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and was verified using quantitative real-time polymerase chain reaction (qRT-PCR) in our HCC cohort. Kaplan-Meier analysis was used to assess the relationship between LINC01146 and the prognosis of HCC patients. Cell Counting Kit 8, colony formation assays, Transwell assays, flow cytometric assays, and tumour formation models in nude mice were conducted to reveal the effects of LINC01146 on HCC cells both in vitro and in vivo. Bioinformatic methods were used to explore the possible potential pathways of LINC01146 in HCC. RESULTS: LINC01146 was significantly decreased in HCC tissues compared with adjacent normal tissues and was found to be related to the clinical presentations of malignancy and the poor prognosis of HCC patients. Overexpression of LINC01146 inhibited the proliferation, migration, and invasion of HCC cells in vitro, while promoting their apoptosis. In contrast, downregulation of LINC01146 exerted the opposite effects on HCC cells in vitro. In addition, overexpression of LINC01146 significantly inhibited tumour growth, while downregulation of LINC01146 promoted tumour growth in vivo. Furthermore, the coexpressed genes of LINC01146 were mainly involved in the "metabolic pathway" and "complement and coagulation cascade pathway". CONCLUSION: LINC01146 expression was found to be decreased in HCC tissues and associated with the prognosis of HCC patients. It may serve as a cancer suppressor and prognostic biomarker in HCC.

A cohort study of dysmenorrhea and risk of low birth weight.

OBJECTIVE: Little is known about the association between maternal history of dysmenorrhea and perinatal outcomes. The aim of this study was to investigate the association between maternal history of dysmenorrhea and low birth weight (LBW). METHODS: A total of 6754 pregnant women were recruited from the ongoing prospective cohort study in Guangxi, China, in 2015-2018. Information on the maternal history of dysmenorrhea was obtained by questionnaires including visual analog scale (VAS) questions during the first antenatal care visit. The association of maternal history of dysmenorrhea and LBW was evaluated using logistic regression analyses adjusted for confounding factors (infant sex, maternal age, parity, pre-pregnancy body mass index (BMI) (kg/m2), gestational age, alcohol use during pregnancy, passive smoking, and occupational status). RESULTS: Mothers with a history of dysmenorrhea were more likely to give birth to LBW infants (adjusted odds ratio (OR)=1.44; 95% confidence interval (CI): 1.12, 1.83). Among women with a history of dysmenorrhea, women ≥29 years old (adjusted OR 1.46; 95% CI 1.02, 2.10), multiparous (adjusted OR 1.59, 95% CI 1.12, 2.25), and women gave birth to female infant (adjusted OR = 1.53, 95% CI = 1.11, 2.11) had a higher risk of LBW. CONCLUSIONS: As the first cohort study to investigate the association between maternal history of dysmenorrhea and LBW, our study shows that dysmenorrhea may increase the risk of LBW.

Predicting cancer-specific mortality in patients with parotid gland carcinoma by competing risk nomogram.

BACKGROUND: The aim of the present study was to establish a competing risk nomogram to predict parotid gland cancer-specific mortality (PGC-SM). METHODS: Seven thousand nine hundred and sixty-two patients extracted from SEER database were randomly categorized into training and validation sets. The competing risk model was used to identify factors associated with PGC-SM. The nomogram was evaluated via concordance indexes (C-indexes), calibration plots, and decision curve analysis (DCA). RESULTS: Male, elderly, white, widowed, larger tumor, no surgery, advanced tumor grade, lymph node (LN) metastasis, adenocarcinoma (ADC), and higher TNM stage were associated with higher incidence of PGC-SM. Calibration plots showed that the nomogram was well calibrated. C-indexes for nomogram were 0.84 (95% CI: 0.81-0.86) and 0.84 (95% CI: 0.82-0.86) in training and validation sets, respectively. DCA demonstrated the clinical usefulness of nomogram. CONCLUSIONS: The competing risk nomogram shows high performance in predicting PGC-SM, which might enable clinicians formulate suitable treatment protocols for patients with parotid gland carcinoma (PGC).

Integrated profiling identifies ITGB3BP as prognostic biomarker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a highly malignant tumor. In this study, we sought to identify a novel biomarker for HCC by analyzing transcriptome and clinical data. The R software was used to analyze the differentially expressed genes (DEGs) in the datasets GSE74656 and GSE84598 downloaded from the Gene Expression Omnibus database, followed by a functional annotation. A total of 138 shared DEGs were screened from two datasets. They were mainly enriched in the "Metabolic pathways" pathway (Padj = 8.21E-08) and involved in the carboxylic acid metabolic process (Padj = 0.0004). The top 10 hub genes were found by protein-protein interaction analysis and were upregulated in HCC tissues compared to normal tissues in The Cancer Genome Atlas database. Survival analysis distinguished 8 hub genes CENPE, SPDL1, Hyaluronan-mediated motility receptor, Rac GTPase activating protein 1, Thyroid hormone receptor interactor 13, cytoskeleton-associated protein (CKAP) 2, CKAP5, and Integrin subunit beta 3 binding protein (ITGB3BP) were considered as prognostic hub genes. Multivariate cox regression analysis indicated that all the prognostic hub genes were independent prognostic factors for HCC. Furthermore, the receiver operating characteristic curve revealed that the 8-hub genes model had better prediction performance for overall survival compared to the T stage (p = 0.008) and significantly improved the prediction value of the T stage (p = 0.002). The Human Protein Atlas showed that the protein expression of ITGB3BP was upregulated in HCC, so the expression of ITGB3BP was further verified in our cohort. The results showed that ITGB3BP was upregulated in HCC tissues and was significantly associated with lymph node metastasis.

Identification of a tumor microenvironment-related gene signature to improve the prediction of cervical cancer prognosis.

BACKGROUND: Previous studies have found that the microenvironment of cervical cancer (CESC) affects the progression and treatment of this disease. Thus, we constructed a multigene model to assess the survival of patients with cervical cancer. METHODS: We scored 307 CESC samples from The Cancer Genome Atlas (TCGA) and divided them into high and low matrix and immune scores using the ESTIMATE algorithm for differential gene analysis. Cervical cancer patients were randomly divided into a training group, testing group and combined group. The multigene signature prognostic model was constructed by Cox analyses. Multivariate Cox analysis was applied to evaluate the significance of the multigene signature for cervical cancer prognosis. Prognosis was assessed by Kaplan-Meier curves comparing the different groups, and the accuracy of the prognostic model was analyzed by receiver operating characteristic-area under the curve (ROC-AUC) analysis and calibration curve. The Tumor Immune Estimation Resource (TIMER) database was used to analyze the relationship between the multigene signature and immune cell infiltration. RESULTS: We obtained 420 differentially expressed genes in the tumor microenvironment from 307 patients with cervical cancer. A three-gene signature (SLAMF1, CD27, SELL) model related to the tumor microenvironment was constructed to assess patient survival. Kaplan-Meier analysis showed that patients with high risk scores had a poor prognosis. The ROC-AUC value indicated that the model was an accurate predictor of cervical cancer prognosis. Multivariate cox analysis showed the three-gene signature to be an independent risk factor for the prognosis of cervical cancer. A nomogram combining the three-gene signature and clinical features was constructed, and calibration plots showed that the nomogram resulted in an accurate prognosis for patients. The three-gene signature was associated with T stage, M stage and degree of immune infiltration in patients with cervical cancer. CONCLUSIONS: This research suggests that the developed three-gene signature may be applied as a biomarker to predict the prognosis of and personalized therapy for CESC.

Big Data-Based Identification of Multi-Gene Prognostic Signatures in Liver Cancer.

Simultaneous identification of multiple single genes and multi-gene prognostic signatures with higher efficacy in liver cancer has rarely been reported. Here, 1,173 genes potentially related to the liver cancer prognosis were mined with Coremine, and the gene expression and survival data in 370 samples for overall survival (OS) and 319 samples for disease-free survival (DFS) were retrieved from The Cancer Genome Atlas. Numerous survival analyses results revealed that 39 genes and 28 genes significantly associated with DFS and OS in liver cancer, including 18 and 12 novel genes that have not been systematically reported in relation to the liver cancer prognosis, respectively. Next, totally 9,139 three-gene combinations (including 816 constructed by 18 novel genes) for predicting DFS and 3,276 three-gene combinations (including 220 constructed by 12 novel genes) for predicting OS were constructed based on the above genes, and the top 15 of these four parts three-gene combinations were selected and shown. Moreover, a huge difference between high and low expression group of these three-gene combination was detected, with median survival difference of DFS up to 65.01 months, and of OS up to 83.57 months. The high or low expression group of these three-gene combinations can predict the longest prognosis of DFS and OS is 71.91 months and 102.66 months, and the shortest is 6.24 months and 13.96 months. Quantitative real-time polymerase chain reaction and immunohistochemistry reconfirmed that three genes F2, GOT2, and TRPV1 contained in one of the above combinations, are significantly dysregulated in liver cancer tissues, low expression of F2, GOT2, and TRPV1 is associated with poor prognosis in liver cancer. Overall, we discovered a few novel single genes and multi-gene combinations biomarkers that are closely related to the long-term prognosis of liver cancer, and they can be potential therapeutic targets for liver cancer.

Clinical significance and biological mechanisms of glutathione S-transferase mu gene family in colon adenocarcinoma.

BACKGROUND: Colon adenocarcinoma (COAD) is the most common form of colon cancer. The glutathione S-transferase Mu (GSTM) gene belongs to the GST gene family, which functions in cell metabolism and detoxification. The relationship between GSTM and COAD and the underlying mechanism remain unknown. METHODS: Data extracted from The Cancer Genome Atlas included mRNA expression and clinical information such as gender, age, and tumor stage. Prognostic values of GSTM genes were identified by survival analysis. Function and mechanism of prognostic GSTM genes were identified by gene set enrichment analysis. A nomogram was used to predict the contribution of risk factors to the outcome of COAD patients. RESULTS: Low expression of GSTM1 and GSTM2 was related to favorable OS (adjusted P = 0.006, adjusted HR = 0.559, 95% CI = 0.367-0.849 and adjusted P = 0.002, adjusted HR = 0.519, 95% CI = 0.342-0.790, respectively) after adjusting for tumor stage. Enrichment analysis also showed that genes involved were related to cell cycle, metabolism, and detoxification processes, as well as the Wnt signaling and NF-κB pathways. CONCLUSIONS: In conclusion, low expression of GSTM1 and GSTM2 were significantly associated with favorable prognosis in COAD. These two genes may serve as potential biomarkers of COAD prognosis.

Cerebral Ischemia-Reperfusion Injury: Lysophosphatidic Acid Mediates Inflammation by Decreasing the Expression of Liver X Receptor.

Lysophosphatidic acid (LPA), a ubiquitous phospholipid, plays a crucial role in the pathogenesis and pathophysiological process of neurological diseases, which constitute the pathological course after cerebral ischemia. Nevertheless, the molecular mechanisms associated with the pathogenic roles of LPA remain elusive. In this study, we evaluated the expression of the liver X receptor (LXR) and nuclear factor kappa B (NFκB) by Western blotting, quantified the levels of IL-1ß, IL-6, TNF-α, and LPA by ELISA, and evaluated apoptosis and infarct by TUNEL (terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling) and TTC (triphenyltetrazolium chloride) staining respectively in Sprague-Dawley (SD) rats after middle cerebral artery occlusion (MCAO). The levels of LPA, an extracellular signaling molecule, increased after ischemia and caused neurological injury effect, decreased the expression level of LXR, and increased the expression level of inflammatory factors (IL-1ß, IL-6, and TNF-α) via the NFκB signaling pathway. This elevated LPA-induced pathological process is one of the pathological reactions associated with ischemic brain injury. We present a direct or indirect connection between LPA and LXR in the pathophysiological process. In conclusion, we speculate that the inhibition of LPA generation and administration of LXR agonist may be explored as potential cerebral infarction treatment strategies.