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Background: Intervertebral disk degeneration (IDD) is a degenerative disease characterized by cytoplasm loss and extracellular matrix degradation. Numerous evidence reported that miRNAs participated in IDD development. Nevertheless, the function of miR-142-3p in IDD development remains unknown. This study mainly explored the potential role and function of miR-142-3p in IDD development., Methods: One percent fetal bovine serum was used to induce the degeneration of ATDC5 cells, and miR-142-3p level was examined by qRT-PCR. Then, miR-142-3p mimic/inhibitor and its corresponding negative control were transfected into ATDC5 normal and degenerative cells. Viability, migration, invasion, apoptosis, cycle, Bax, Bcl-2, P62, and Beclin1 expression levels were assessed using CCK8, wound healing assay, annexin V-FITC/PI staining, western blot, and qRT-PCR, respectively., Results: The results revealed that the expression levels of MMP13, ADAMTS5, MMP3, and Col-X were increased as well as the expression levels of SOX-9 and Col-II were reduced in ATDC5 degenerative cells, indicating the degeneration model was constructed. We observed that miR-142-3p was decreased in ATDC5 degenerative cells and its suppression could promote ATDC5 cell degeneration. However, miR-142-3p overexpression could reverse the cell viability inhibition, as well as apoptosis and autophagy enhancement in ATDC5 degenerative cells., Conclusions: Our results proved that miR-142-3p may play an important role in disk degeneration. Further animal study is needed to illustrate the role of the miR-142-3p in IDD development.

Background: Endometriosis is a benign gynecological disease with obviously feature of estrogen-dependence and inflammatory response. The applications of primary endometriotic stromal cells in research of endometriosis are restricted for short life span, dedifferentiation of hormone and cytokine responsiveness. The objective of this study was to establish and characterize immortalized human endometriotic stromal cells (ihESCs)., Methods: The endometriotic samples were from a patient with ovarian endometriosis and the primary endometriotic stromal cells were isolated from the endometriotic tissues. The primary cells were infected by lentivirus to establish telomerase reverse transcriptase (hTERT)-induced immortalized cells. Quantification of mRNA and proteins was examined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western Blot. CCK-8 assay and EdU labeling assay were assigned to assess the growth of ihESCs. Karyotype assay was performed to detect the chromosomes of ihESCs. Colony formation assay and nude mouse tumorigenicity assay were used to evaluate colony-formation and tumorigenesis abilities., Results: ihESCs continuously overexpressed hTERT via infection of lentivirus and significant extended the life span reaching 31 passages. The morphology, proliferation and karyotype of ihESCs remained unchanged. The expression of epithelial-mesenchymal transition (EMT) markers, estrogen-metabolizing proteins and estrogen/progesterone receptors (ERs and PRs) were unaltered. Furthermore, the treatment of estrogen increased the proliferation and EMT of ihESCs. Lipopolysaccharides (LPS) and IL-1β remarkably induced inflammatory response. The clonogenesis ability of ihESCs was consistent with primary cells, which were much lower than Ishikawa cells. In addition, nude mouse tumorigenicity assay demonstrated that ihESCs were unable to trigger tumor formation., Conclusion: This study established and characterized an immortalized endometriotic stromal cell line that exhibited longer life span and kept the cellular morphology and physiological function as the primary cells. The immortalized cells remained normal feedback to estrogen and inflammatory response. Moreover, the immortalized cells were not available with tumorigenic ability. Therefore, ihESCs would be serviceable as in vitro cell tool to investigate the pathogenesis of endometriosis.

Background: Lipid droplet (LD)-laden microglia is a key pathological hallmark of multiple sclerosis. The recent discovery of this novel microglial subtype, lipid-droplet-accumulating microglia (LDAM), is notable for increased inflammatory factor secretion and diminished phagocytic capability. Lipophagy, the autophagy-mediated selective degradation of LDs, plays a critical role in this context. This study investigated the involvement of microRNAs (miRNAs) in lipophagy during demyelinating diseases, assessed their capacity to modulate LDAM subtypes, and elucidated the potential underlying mechanisms involved. Methods: C57BL/6 mice were used for in vivo experiments. Two weeks post demyelination induction at cervical level 4 (C4), histological assessments and confocal imaging were performed to examine LD accumulation in microglia within the lesion site. Autophagic changes were observed using transmission electron microscopy. miRNA and mRNA multi-omics analyses identified differentially expressed miRNAs and mRNAs under demyelinating conditions and the related autophagy target genes. The role of miR-223 in lipophagy under these conditions was specifically explored. In vitro studies, including miR-223 upregulation in BV2 cells via lentiviral infection, validated the bioinformatics findings. Immunofluorescence staining was used to measure LD accumulation, autophagy levels, target gene expression, and inflammatory mediator levels to elucidate the mechanisms of action of miR-223 in LDAM. Results: Oil Red O staining and confocal imaging revealed substantial LD accumulation in the demyelinated spinal cord. Transmission electron microscopy revealed increased numbers of autophagic vacuoles at the injury site. Multi-omics analysis revealed miR-223 as a crucial regulatory gene in lipophagy during demyelination. It was identified that cathepsin B (CTSB) targets miR-223 in autophagy to integrate miRNA, mRNA, and autophagy gene databases. In vitro, miR-223 upregulation suppressed CTSB expression in BV2 cells, augmented autophagy, alleviated LD accumulation, and decreased the expression of the inflammatory mediator IL-1β. Conclusion: These findings indicate that miR-223 plays a pivotal role in lipophagy under demyelinating conditions. By inhibiting CTSB, miR-223 promotes selective LD degradation, thereby reducing the lipid burden and inflammatory phenotype in LDAM. This study broadens the understanding of the molecular mechanisms of lipophagy and proposes lipophagy induction as a potential therapeutic approach to mitigate inflammatory responses in demyelinating diseases. [ABSTRACT FROM AUTHOR]

Background: This study aimed to explore the expression, molecular mechanism and its biological function of potassium two pore domain channel subfamily K member 1 (KCNK1) in bladder cancer (BC). Methods: We integrated large numbers of external samples (n = 1486) to assess KCNK1 mRNA expression levels and collected in-house samples (n = 245) for immunohistochemistry (IHC) experiments to validate at the KCNK1 protein level. Single-cell RNA sequencing (scRNA-seq) analysis was performed to further assess KCNK1 expression and cellular communication. The transcriptional regulatory mechanisms of KCNK1 expression were explored by ChIP-seq, ATAC-seq and ChIA-PET data. Highly expressed co-expressed genes (HECEGs) of KCNK1 were used to explore potential signalling pathways. Furthermore, the immunoassay, clinical significance and molecular docking of KCNK1 were calculated. Results: KCNK1 mRNA was significantly overexpressed in BC (SMD = 0.58, 95% CI [0.05; 1.11]), validated at the protein level (p < 0.0001). Upregulated KCNK1 mRNA exhibited highly distinguishing ability between BC and control samples (AUC = 0.82 [0.78–0.85]). Further, scRNA-seq analysis revealed that KCNK1 expression was predominantly clustered in BC epithelial cells and tended to increase with cellular differentiation. BC epithelial cells were involved in cellular communication mainly through the MK signalling pathway. Secondly, the KCNK1 transcription start site (TSS) showed promoter-enhancer interactions in three-dimensional space, while being transcriptionally regulated by GRHL2 and FOXA1. Most of the KCNK1 HECEGs were enriched in cell cycle–related signalling pathways. KCNK1 was mainly involved in cellular metabolism–related pathways and regulated cell membrane potassium channel activity. KCNK1 expression was associated with the level of infiltration of various immune cells. Immunotherapy and chemotherapy (docetaxel, paclitaxel and vinblastine) were more effective in BC patients in the high KCNK1 expression group. KCNK1 expression correlated with age, pathology grade and pathologic_M in BC patients. Conclusions: KCNK1 was significantly overexpressed in BC. A complex and sophisticated three-dimensional spatial transcriptional regulatory network existed in the KCNK1 TSS and promoted the upregulated of KCNK1 expression. The high expression of KCNK1 might be involved in the cell cycle, cellular metabolism, and tumour microenvironment through the regulation of potassium channels, and ultimately contributed to the deterioration of BC. [ABSTRACT FROM AUTHOR]

Background: The pathogenesis of adult non-cystic fibrosis (CF) bronchiectasis is complex, and the relevant molecular mechanism remains ambiguous. Versican (VCAN) is a key factor in inflammation through interactions with adhesion molecules. This study constructs a stable panoramic map of mRNA, reveals the possible pathogenesis of bronchiectasis, and provides new ideas and methods for bronchiectasis. Methods: Peripheral blood and tissue gene expression data from patients with bronchiectasis and normal control were selected by bioinformatics analysis. The expression of VCAN in peripheral blood and bronchial tissues of bronchiectasis were obtained by transcriptome sequencing. The protein expression levels of VCAN in serums were verified by the enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of VCAN in co-culture of Pseudomonas aeruginosa and bronchial epithelial cells were verified by real-time quantitative polymerase chain reaction (RT-qPCR). In addition, the biological function of VCAN was detected by the transwell assay. Results: The expression of VCAN was upregulated in the bronchiectasis group by sequencing analysis (P < 0.001). The expression of VCAN in the bronchial epithelial cell line BEAS-2B was increased in P. aeruginosa (P.a), which was co-cultured with BEAS-2B cells (P < 0.05). The concentration of VCAN protein in the serum of patients with bronchiectasis was higher than that in the normal control group (P < 0.05). Transwell experiments showed that exogenous VCAN protein induced the migration of neutrophils (P < 0.0001). Conclusions: Our findings indicate that VCAN may be involved in the development of bronchiectasis by increasing the migration of neutrophils and play an important role in bronchial pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Although great progress has been made in anti-cancer therapy, the prognosis of laryngeal squamous cell carcinoma (LSCC) patients remains unsatisfied. Quantities of studies demonstrate that glycolytic reprograming is essential for the progression of cancers, where triosephosphate isomerase 1 (TPI1) serves as a catalytic enzyme. However, the clinicopathological significance and potential biological functions of TPI1 underlying LSCC remains obscure. Methods: We collected in-house 82 LSCC tissue specimens and 56 non-tumor tissue specimens. Tissue microarrays (TMA) and immunohistochemical (IHC) experiments were performed. External LSCC microarrays and bulk RNA sequencing data were integrated to evaluate the expression of TPI1. We used a log-rank test and the CIBERSORT algorithm to assess the prognostic value of TPI1 and its association with the LSCC microenvironment. Malignant laryngeal epithelial cells and immune-stromal cells were identified using inferCNV and CellTypist. We conducted a comprehensive analysis to elucidate the molecular functions of TPI1 in LSCC tissue and single cells using Pearson correlation analysis, high dimensional weighted gene co-expression analysis, gene set enrichment analysis, and clustered regularly interspaced short palindromic repeats (CRISPR) screen. We explored intercellular communication patterns between LSCC single cells and immune-stromal cells and predicted several therapeutic agents targeting TPI1. Results: Based on the in-house TMA and IHC analysis, TPI1 protein was found to have a strong positive expression in the nucleus of LSCC cells but only weakly positive activity in the cytoplasm of normal laryngeal cells (p < 0.0001). Further confirmation of elevated TPI1 mRNA expression was obtained from external datasets, comparing 251 LSCC tissue samples to 136 non-LSCC tissue samples (standardized mean difference = 1.06). The upregulated TPI1 mRNA demonstrated a high discriminative ability between LSCC and non-LSCC tissue (area under the curve = 0.91; sensitivity = 0.87; specificity = 0.79), suggesting its potential as a predictive marker for poor prognosis (p = 0.037). Lower infiltration abundance was found for plasma cells, naïve B cells, monocytes, and neutrophils in TPI-high expression LSCC tissue. Glycolysis and cell cycle were significantly enriched pathways for both LSCC tissue and single cells, where heat shock protein family B member 1, TPI1, and enolase 1 occupied a central position. Four outgoing communication patterns and two incoming communication patterns were identified from the intercellular communication networks. TPI1 was predicted as an oncogene in LSCC, with CRISPR scores less than -1 across 71.43% of the LSCC cell lines. TPI1 was positively correlated with the half maximal inhibitory concentration of gemcitabine and cladribine. Conclusions: TPI1 is dramatically overexpressed in LSCC than in normal tissue, and the high expression of TPI1 may promote LSCC deterioration through its metabolic and non-metabolic functions. This study contributes to advancing our knowledge of LSCC pathogenesis and may have implications for the development of targeted therapies in the future. [ABSTRACT FROM AUTHOR]

The progression of prostate cancer (PCa) leads to poor prognosis. However, the molecular mechanism of PCa is still not completely clear. This study aimed to elucidate the important role of centromere protein A (CENPA) in PCa. Large numbers of bulk RNA sequencing (RNA‐seq) data and in‐house immunohistochemistry data were used in analysing the expression level of CENPA in PCa and metastatic PCa (MPCa). Single‐cell RNA‐seq data was used to explore the expression status of CENPA in different prostate subpopulations. Enrichment analysis was employed to detect the function of CENPA in PCa. Clinicopathological parameters analysis was utilised in analysing the clinical value of CENPA. The results showed that CENPA was upregulated in PCa (standardised mean difference [SMD] = 0.83, p = 0.001) and MPCa (SMD = 0.61, p = 0.029). CENPA was overexpressed in prostate cancer stem cells (CSCs) with androgen receptor (AR) negative compared to epithelial cells with AR positive. CENPA may influence the development of PCa through affecting cell cycle. Patients with nodal metastasis had higher expression level of CENPA. And patients with high CENPA expression had poor disease‐free survival. Taken together, Overexpression of CENPA may influence the development of PCa by regulating cell cycle and promoting metastasis. [ABSTRACT FROM AUTHOR]

Background and Aim: The biological functions and clinical implications of lysophosphatidylcholine acyltransferase 1 (LPCAT1) remain unclarified in gastric cancer (GC). The aim of the current study was to explore the possible clinicopathological significance of LPCAT1 and its perspective mechanism in GC tissues. Materials and Methods: The protein expression and mRNA levels of LPCAT1 were detected from in‐house immunohistochemistry and public high‐throughput RNA arrays and RNA sequencing. To have a comprehensive understanding of the clinical value of LPCAT1 in GC, all enrolled data were integrated to calculate the expression difference and standard mean difference (SMD). The biological mechanism of LPCAT1 in GC was confirmed by computational biology and in vitro experiments. Migration and invasion assays were also conducted to confirm the effect of LPCAT1 in GC. Results: Both protein and mRNA expression levels of LPCAT1 in GC were remarkably higher than those in noncancerous controls. Comprehensively, the SMD of LPCAT1 mRNA was 1.11 (95% CI = 0.86–1.36) in GC, and the summarized AUC was 0.85 based on 15 datasets containing 1727 cases of GC and 940 cases of non‐GC controls. Moreover, LPCAT1 could accelerate the invasion and migration of GC by boosting the neutrophil degranulation pathway and disturbing the immune microenvironment. Conclusion: An increased level of LPCAT1 may promote the progression of GC. [ABSTRACT FROM AUTHOR]

Background: Centrosomal protein 55 (CEP55) plays a significant role in specific cancers. However, comprehensive research on CEP55 is lacking in pan-cancer. Methods: In-house and multi-center samples (n = 15,823) were used to analyze CEP55 in 33 cancers. The variance of CEP55 expression levels among tumor and control groups was evaluated by the Wilcoxon rank-sum test and standardized mean difference (SMD). The clinical value of CEP55 in cancers was assessed using receiver operating characteristic (ROC) curves, Cox regression analysis, and Kaplan-Meier curves. The correlations between CEP55 expression and the immune microenvironment were explored using Spearman's correlation coefficient. Results: The data of clustered regularly interspaced short palindromic repeats confirmed that CEP55 was essential for the survival of cancer cells in multiple cancer types. Elevated CEP55 mRNA expression was observed in 20 cancers, including glioblastoma multiforme (p < 0.05). CEP55 mRNA expression made it feasible to distinguish 21 cancer types between cancer specimens and their control samples (AUC = 0.97), indicating the potential of CEP55 for predicting cancer status. Overexpression of CEP55 was correlated with the prognosis of cancer individuals for 18 cancer types, exhibiting its prognostic value. CEP55 expression was relevant to tumor mutation burden, microsatellite instability, neoantigen counts, and the immune microenvironment in various cancers (p < 0.05). The expression level and clinical relevance of CEP55 in cancers were verified in lung squamous cell carcinoma using in-house and multi-center samples (SMD = 4.07; AUC > 0.95; p < 0.05). Conclusion: CEP55 may be an immune-related predictive and prognostic marker for multiple cancers, including lung squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is a common cancer worldwide with a high prevalence. This study was conducted to elucidate the expression and clinical significance of Sorbin and SH3 domain‐containing protein 1 (SORBS1) in BC as well as to explore its molecular mechanism in BC tumourigenesis. RNA‐sequencing data, microarray, and Immunohistochemistry (IHC) were applied to elucidated the SORBS1 expression at multiple levels. After that, the relationship between tumour‐immune infiltration and SORBS1 was also explored. Finally, SORBS1‐related genes in BC were identified to perform functional enrichment analyses. The expression integration revealed that the comprehensive expression of SORBS1 at the mRNA level was −1.02 and that at the protein level was −3.73, based on 12 platforms, including 1221 BC and 187 non‐BC samples. SORBS1 was negatively correlated with tumour purity (correlation = −0.342, p < 0.001) and positively correlated with macrophage (correlation = 0.358, p < 0.001). The results of enrichment analyses revealed that the most significant biological pathways of SORBS1‐related genes were epithelial‐mesenchymal transition. SORBS1 was significantly down‐regulated in BC and may play a role as tumour suppressor. This study provides new directions and biomarkers for future BC diagnosis. [ABSTRACT FROM AUTHOR]

Spermidine synthase (SPDS) is a key enzyme in the polyamine anabolic pathway. SPDS genes help regulate plant response to environmental stresses, but their roles in pepper remain unclear. In this study, we identified and cloned a SPDS gene from pepper (Capsicum annuum L.), named CaSPDS (LOC107847831). Bioinformatics analysis indicated that CaSPDS contains two highly conserved domains: an SPDS tetramerisation domain and a spermine/SPDS domain. Quantitative reverse-transcription polymerase chain reaction results showed that CaSPDS was highly expressed in the stems, flowers, and mature fruits of pepper and was rapidly induced by cold stress. The function of CaSPDS in cold stress response was studied by silencing and overexpressing it in pepper and Arabidopsis, respectively. Cold injury was more serious and reactive oxygen species levels were greater in the CaSPDS-silenced seedlings than in the wild-type (WT) seedlings after cold treatment. Compared with the WT plants, the CaSPDS-overexpression Arabidopsis plants were more tolerant to cold stress and showed higher antioxidant enzyme activities, spermidine content, and cold-responsive gene (AtCOR15A, AtRD29A, AtCOR47, and AtKIN1) expression. These results indicate that CaSPDS plays important roles in cold stress response and is valuable in molecular breeding to enhance the cold tolerance of pepper. [ABSTRACT FROM AUTHOR]

In recent times, the excessive accumulation of nitrate has been one of the main reasons for the secondary salinization of greenhouse soils. Light plays a key role in a plant's growth, development, and response to stress. A low-red to far-red (R:FR) light ratio could enhance plant salinity tolerance, but the mechanism at a molecular level is unclear. Thus, we analyzed the transcriptome responses of tomato seedlings to calcium nitrate stress under either a low R:FR ratio (0.7) or normal light conditions. Under calcium nitrate stress, a low R:FR ratio enhanced both the antioxidant defense system and the rapid physiological accumulation of proline in tomato leaves, which promoted plant adaptability. Using weighted gene co-expression network analysis (WGCNA), three modules including 368 differentially expressed genes (DEGs) were determined to be significantly associated with these plant traits. Functional annotations showed that the responses of these DEGs to a low R:FR ratio under excessive nitrate stress were enriched in the areas of hormone signal transduction, amino acid biosynthesis, sulfide metabolism, and oxidoreductase activity. Furthermore, we identified important novel hub genes encoding certain proteins, including FBNs, SULTRs, and GATA-like transcription factor, which may play a vital role in low R:FR light-induced salt responses. These findings offer a new perspective on the mechanisms and environmental implications behind low R:FR ratio light-modulated tomato saline tolerance. [ABSTRACT FROM AUTHOR]

Nasopharyngeal carcinoma (NPC) has insidious onset, late clinical diagnosis and high recurrence rate, which leads to poor quality of patient life. Therefore, it is necessary to further explore the pathogenesis and therapy targets of NPC. BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) was found to be up-regulated in a variety of cancers, but only two previous study showed that BUB1B was overexpressed in NPC and the sample size was small. The clinical role of BUB1B expression and its underlying mechanism in NPC require more in-depth research. Immunohistochemical samples and public RNA-seq data indicated that BUB1B protein and mRNA expression levels were up-regulated in NPC, and summary receiver operating characteristic curve indicated that BUB1B expression level had a strong ability to distinguish NPC tissues from non-NPC tissues. Gene ontology and Kyoto Encyclopedia of genes and genomes were performed and revealed that BUB1B and its related genes were mainly involved in cell cycle and DNA replication. Protein- Protein Interaction were built to interpret the BUB1B molecular mechanism. Histone deacetylase 2 (HDAC2) could be the upstream regulation factor of BUB1B, which was verified by Chromatin Immunoprecipitation Sequencing samples. In summary, BUB1B was highly expressed in NPC, and HDAC2 may affect cell cycle by regulating BUB1B to promote cancer progression. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive impairment and abnormal mental behaviour. There is currently no effective cure. The development of early diagnostic markers and the mining of potential therapeutic targets are one of the important strategies. This study aimed to explore potential biomarkers or therapeutic targets related to AD in the hippocampus and prefrontal cortex, two brain regions highly related to AD. Differentially expressed genes and miRNAs between AD patients and healthy controls were obtained from the Gene Expression Omnibus database. The mRNA‐miRNA network was constructed and key genes involved in AD were screened out by protein–protein interaction analysis, and were subsequently verified by independent datasets and qPCR in an AD mouse model. Our findings showed that six hub genes including CALN1, TRPM7, ATR, SOCS3, MOB3A and OGDH were believed to be involved in the pathogenesis of AD. Western blot analysis further determined that CALN1, ATR and OGDH were the possible biomarkers and therapeutic targets for AD. In addition, 6 possible miRNAs biomarkers have also been verified by qPCR on AD animal models. Our findings may benefit clinical diagnosis and early prevention of AD. [ABSTRACT FROM AUTHOR]

Background: The molecular mechanism of laryngeal squamous cell carcinoma (LSCC) is not completely clear, which leads to poor prognosis and treatment difficulties for LSCC patients. To date, no study has reported the exact expression level of zinc finger protein 71 (ZNF71) and its molecular mechanism in LSCC. Methods: In-house immunohistochemistry (IHC) staining (33 LSCC samples and 29 non-LSCC samples) was utilized in analyzing the protein expression level of ZNF71 in LSCC. Gene chips and high-throughput sequencing data collected from multiple public resources (313 LSCC samples and 192 non-LSCC samples) were utilized in analyzing the exact mRNA expression level of ZNF71 in LSCC. Single-cell RNA sequencing (scRNA-seq) data was used to explore the expression status of ZNF71 in different LSCC subpopulations. Enrichment analysis of ZNF71, its positively and differentially co-expressed genes (PDCEGs), and its downstream target genes was employed to detect the potential molecular mechanism of ZNF71 in LSCC. Moreover, we conducted correlation analysis between ZNF71 expression and immune infiltration. Results: ZNF71 was downregulated at the protein level (area under the curve [AUC] = 0.93, p < 0.0001) and the mRNA level (AUC = 0.71, p = 0.023) in LSCC tissues. Patients with nodal metastasis had lower protein expression level of ZNF71 than patients without nodal metastasis (p < 0.05), and male LSCC patients had lower mRNA expression level of ZNF71 than female LSCC patients (p < 0.01). ZNF71 was absent in different LSCC subpopulations, including cancer cells, plasma cells, and tumor-infiltrated immune cells, based on scRNA-seq analysis. Enrichment analysis showed that ZNF71 and its PDCEGs may influence the progression of LSCC by regulating downstream target genes of ZNF71. These downstream target genes of ZNF71 were mainly enriched in tight junctions. Moreover, downregulation of ZNF71 may influence the development and even therapy of LSCC by reducing immune infiltration. Conclusion: Downregulation of ZNF71 may promote the progression of LSCC by reducing tight junctions and immune infiltration; this requires further study. [ABSTRACT FROM AUTHOR]

Early diagnosis of psoriatic arthritis (PSA) is important for successful therapeutic intervention but currently remains challenging due, in part, to the scarcity of non-invasive biomarkers. In this study, we performed single cell profiling of transcriptome and cell surface protein expression to compare the peripheral blood immunocyte populations of individuals with PSA, individuals with cutaneous psoriasis (PSO) alone, and healthy individuals. We identified genes and proteins differentially expressed between PSA, PSO, and healthy subjects across 30 immune cell types and observed that some cell types, as well as specific phenotypic subsets of cells, differed in abundance between these cohorts. Cell type-specific gene and protein expression differences between PSA, PSO, and healthy groups, along with 200 previously published genetic risk factors for PSA, were further used to perform machine learning classification, with the best models achieving AUROC ≥ 0.87 when either classifying subjects among the three groups or specifically distinguishing PSA from PSO. Our findings thus expand the repertoire of gene, protein, and cellular biomarkers relevant to PSA and demonstrate the utility of machine learning-based diagnostics for this disease. [ABSTRACT FROM AUTHOR]

Hydrophilic polyethylene glycol monomethyl ether (mPEG) was grafted onto Icariin (ICA) by succinic anhydride to form a polyethylene glycol-Icariin (mPEG-ICA) polymer. The structure of the polymer was characterized by Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR). mPEG-ICA nanoparticles loaded with ICA were prepared by physical embedding of ICA by dialysis. The particle size was determined to be (220 ± 13.7) nm, and the ζ potential was (2.30 ± 1.33) mV by dynamic light scattering (DLS). Under a transmission electron microscope (TEM), the nanoparticles were spherical, and the morphology was regular. In the medium with pH 7.4, the drug release rate of mPEG-ICA nanoparticles reached (52.80 ± 1.70)% within 72 h. At pH 6.8, the cumulative drug release of nanoparticles reached (75.66 ± 0.17)% within 48 h. Treatment of the nanoparticles with LPS-treated H9c2 cells maintained cell viability, reduced LDH release and exerted antiapoptotic effects. Moreover, ICA-loaded mPEG-ICA nanoparticles significantly decreased the mRNA expression of the myocardial inflammatory cytokines TNF-α, IL-1β and IL-6M. In conclusion, ICA-loaded mPEG-ICA nanoparticles protected against LPS-induced H9c2 cell injury. [ABSTRACT FROM AUTHOR]

Esophageal squamous cell carcinoma (ESCC) is the major histological type of esophageal cancers worldwide. Transcription factor PTTG1 was seen highly expressed in a variety of tumors and was related to the degree of tumor differentiation, invasion, and metastasis. However, the clinical significance of PTTG1 had yet to be verified, and the mechanism of abnormal PTTG1 expression in ESCC was not clear. In this study, the comprehensive analysis and evaluation of PTTG1 expression in ESCC were completed by synthesizing in-house immunohistochemistry (IHC), clinical sample tissue RNA-seq (in-house RNA-seq), public high-throughput data, and literature data. We also explored the possible signaling pathways and target genes of PTTG1 in ESCC by combining the target genes of PTTG1 (displayed by ChIP-seq), differentially expressed genes (DEGs) of ESCC, and PTTG1 -related genes, revealing the potential molecular mechanism of PTTG1 in ESCC. In the present study, PTTG1 protein and mRNA expression levels in ESCC tissues were all significantly higher than in non-cancerous tissues. The pool standard mean difference (SMD) of the overall PTTG1 expression was 1.17 (95% CI: 0.72–1.62, P < 0.01), and the area under curve (AUC) of the summary receiver operating characteristic (SROC) was 0.86 (95% CI: 0.83–0.89). By combining the target genes displayed by ChIP-seq of PTTG1 , DEGs of ESCC, and PTTG1 -related genes, it was observed that PTTG1 may interact with these genes through chemokines and cytokine signaling pathways. By constructing a protein–protein interaction (PPI) network and combining ChIP-seq data, we obtained four PTTG1 potential target genes, SPTAN1 , SLC25A17 , IKBKB , and ERH. The gene expression of PTTG1 had a strong positive correlation with SLC25A17 and ERH , which suggested that PTTG1 might positively regulate the expression of these two genes. In summary, the high expression of PTTG1 may play an important role in the formation of ESCC. These roles may be completed by PTTG1 regulating the downstream target genes SLC25A17 and ERH. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) brains are characterized by progressive neuron loss and gliosis. Previous studies of gene expression using bulk tissue samples often fail to consider changes in cell-type composition when comparing AD versus control, which can lead to differences in expression levels that are not due to transcriptional regulation. We mined five large transcriptomic AD datasets for conserved gene co-expression module, then analyzed differential expression and differential co-expression within the modules between AD samples and controls. We performed cell-type deconvolution analysis to determine whether the observed differential expression was due to changes in cell-type proportions in the samples or to transcriptional regulation. Our findings were validated using four additional datasets. We discovered that the increased expression of microglia modules in the AD samples can be explained by increased microglia proportions in the AD samples. In contrast, decreased expression and perturbed co-expression within neuron modules in the AD samples was likely due in part to altered regulation of neuronal pathways. Several transcription factors that are differentially expressed in AD might account for such altered gene regulation. Similarly, changes in gene expression and co-expression within astrocyte modules could be attributed to combined effects of astrogliosis and astrocyte gene activation. Gene expression in the astrocyte modules was also strongly correlated with clinicopathological biomarkers. Through this work, we demonstrated that combinatorial analysis can delineate the origins of transcriptomic changes in bulk tissue data and shed light on key genes and pathways involved in AD. [ABSTRACT FROM AUTHOR]

Background. The expression and mechanism of microRNA-205 (miRNA-205) in prostate cancer (PCa) and its bone metastasis remain controversial. Materials and Methods. The expression and discriminating capability of miRNA-205 were assessed by drawing a forest plot and a summarized receiver operating characteristic (SROC) curve, using data available from 27 miRNA-array and miRNA-sequencing datasets. The miRNA-205 target genes were acquired from online prediction tools, differentially upregulated genes in PCa, and differentially expressed genes (DEGs) after miRNA-205 transfection into PCa cell lines. Functional enrichment analysis was conducted to explore the biological mechanism of miRNA-205 targets. Immunohistochemistry (IHC) was applied to verify the protein level of the hub gene. Results. The expression of miRNA-205 in the PCa group (1,461 samples) was significantly lower than that in the noncancer group (510 samples), and the downregulation of miRNA-205 showed excellent sensitivity and specificity in differentiating between the two groups. In bone metastatic PCa, the miRNA-205 level was further reduced than in nonbone metastatic PCa, and it showed a good capability in distinguishing between the two groups. In total, 153 miRNA-205 targets were screened through the three aforementioned methods. Based on the results of functional enrichment analysis, the targets of miRNA-205 were mainly enriched during chromosome segregation and phospholipid-translocating ATPase activity and in the spindle microtubule and the p53 signaling pathway. CDK1 had the highest connectivity in the PPI network analysis and was screened as one of the hub genes. A statistically significant negative correlation between miRNA-205 and CDK1 was observed. The expression of CDK1 in PCa samples was pronouncedly upregulated in terms of both the mRNA level and the protein level when compared with noncancer samples. Conclusion. miRNA-205 may play a vital role in PCa tumorigenesis and bone metastasis by targeting CDK1. [ABSTRACT FROM AUTHOR]

IL24 mRNA is known to have an apoptotic effect on cancer cells but not on noncancer cells. However, the expression level of the IL24 mRNA in head and neck squamous cell carcinoma (HNSCC) and its subgroups is rarely studied. In this study, the clinical implication of IL24 mRNA was evaluated in the common subgroups of HNSCC, including oral squamous cell carcinoma (OSCC), nasopharyngeal carcinoma (NPC), and laryngeal squamous cell carcinoma (LSCC) for analysis. Substantial IL24 mRNA expression data were calculated from several databases, such as the Gene Expression Omnibus (GEO), ArrayExpress, Sequence Read Archive (SRA), ONCOMINE, and The Cancer Genome Atlas (TCGA) databases. We ultimately collected a total of 41 microarrays and RNA-seq including 1,564 HNSCC and 603 noncancer tissue samples. IL24 mRNA was highly expressed in OSCC, LSCC, and NPC as shown by the separated standard mean difference (SMD), as well as HNSCC as a whole part (SMD = 1.47, 95% confdence interval (CI) = 1.24−1.70, P < 0.0001). In all subgroups, the IL24 mRNA upregulation had the ability to distinguish cancer from noncancer tissue with area under the curves (AUCs) of the summary receiver operating characteristic (sROC) higher than 0.85. In conclusion, IL24 mRNA may be used as a potential marker for cancer screening, and its clinical diagnostic value needs to be further studied. It also provides a new idea for the treatment of the IL24 gene in HNSCC and its subgroups in the future. [ABSTRACT FROM AUTHOR]

We explored the difference in expression of tubulin alpha 1b (TUBA1B) between Wilms' tumor (WT) and normal tissues (NT) from in-house patients and databases, to determine TUBA1B expression in WT and the predictive pathways of coexpressed genes. In-house RNA-sequencing data were performed with WT and NT from three patients from our institute. Other four RNA-sequencing and microarray data were also downloaded from multiple public databases. The TUBA1B expression between WT and NT was analyzed by Student's t -test and meta-analysis. The correlation between the expression of TUBA1B and other genes in each study was analyzed. Genes with p < 0.05 and r > 0. 5 were considered as the coexpressing genes of TUBA1B. Overlapping the coexpressed genes of the five studies, including three in-house patients (3 WT vs. 3 NT), GTEx-TARGET (126 WT vs. 51 NT), GSE2172 (18 WT vs. 3 NT), GSE11024 (27 WT vs. 12 NT), and GSE73209 (32 WT vs. 6 NT), were performed with limma and VennDiagram packages in R software. The website of WEB-based GEne SeT AnaLysis toolkit were used to analyze the gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations for the overlapped genes. The results showed that the relative expression of TUBA1B in WT tissues from in-house three patients was 280.0086, 141.7589, and 303.8292 and that in NT was 16.5836, 104.8141, and 12.79 (3 WT vs. 3 NT, p = 0.0285 , ROC = 100 % , SMD = 2.74). Student's t -test and meta-analysis in all studies revealed that the expression of TUBA1B was upregulated in WT tissues compared to that in NT (p < 0.05 , SMD = 2.89 , sROC = 0.98). Finally, the research identified the expression of TUBA1B in WT tissues was significantly upregulated than that in NT. The coexpressed genes of TUBA1B were enriched in the pathway of DNA replication, mismatch repair, cell cycle, pathogenic Escherichia coli infection, and spliceosome. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) is the main pathological type of pulmonary malignant tumors; at present, less than 10% of patients with advanced metastatic LUSC live for more than 5 years. We previously reported that low expression of miRNA‐126‐3p is associated with the occurrence and progression of lung adenocarcinoma (LUAD). Here, we examined expression of miRNA‐126‐3p in 23 samples from patients with LUSCs and 23 normal control specimens by quantitative real‐time PCR (RT‐qPCR). Associations between miRNA‐126‐3p expression and clinical features were studied from materials derived from Gene Expression Omnibus (GEO) chips and The Cancer Genome Atlas (TCGA) database. Twelve online platforms were used to identify candidate target genes of miRNA‐126‐3p. Further analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and protein–protein interaction (PPI) network were performed on the target genes. GEO microarray analysis, TCGA data mining, RT‐qPCR, and integration analysis consistently reported low expression of miRNA‐126‐3p in LUSC. A total of 42 genes were identified as potential target genes of miRNA‐126‐3p from online platforms, GEO microarrays, and the TCGA database. GO and KEGG analyses demonstrated that the target genes are involved in several biological processes that promote the progression of LUSC. SOX2, E2F2, and E2F3 were selected as hub genes from the PPI network for further analysis. In summary, our results suggest that the low expression of miRNA‐126‐3p may play a role in promoting the development of LUSC and miRNA‐126‐3p may be a biomarker for LUSC early diagnosis and prognosis. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are known to be important in a variety of cancer types. The specific expression and roles of miR-520f-3p in the context of gastric cancer (GC), however, remains unknown. Herein we determined miR-520f-3p expression to be significantly reduced in human GC cells compared to cells of the gastric epithelium, with comparable down-regulation also being evident in gastric cancer tissue samples and the low expression of this miRNA was positively correlated with features of more aggressive large tumor size (p = 0.019), depth of invasion (p = 0.008), and distant metastasis (p = 0.037). We further found that lower levels of miR-520f-3p corresponded with poorer GC patient overall (p = 0.003) and disease-free (p = 0.036) survival. When over-expressed in GC cells, miR-520f-3p was able to impair their growth, proliferation, and survival, instead leading to the induction of apoptosis. We further found that miR-520f-3p was able to bind the SOX9 3′-UTR, thereby negatively regulating its expression in GC cells. Consistent with this model, SOX9 and miR-520f-3p expression were negatively correlated with one another in GC tissues. When SOX9 was upregulated, this was also able to abrogate miR-520f-3p-mediated inactivation of Wnt/β-catenin signaling. Together our findings thus suggest that miR-520f-3p can act to suppress GC progression, at least in part via suppressing SOX9 expression and thus disrupting Wnt/β-catenin signaling. Our results thus highlight potential novel therapeutic targets in GC worthy of future investigation. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) has two clinical precursor stages of disease: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). However, the mechanism of progression is not well understood. Because gene co-expression network analysis is a well-known method for discovering new gene functions and regulatory relationships, we utilized this framework to conduct differential co-expression analysis to identify interesting transcription factors (TFs) in two publicly available datasets. We then used copy number variation (CNV) data from a third public dataset to validate these TFs. First, we identified co-expressed gene modules in two publicly available datasets each containing three conditions: normal, MGUS, and SMM. These modules were assessed for condition-specific gene expression, and then enrichment analysis was conducted on condition-specific modules to identify their biological function and upstream TFs. TFs were assessed for differential gene expression between normal and MM precursors, then validated with CNV analysis to identify candidate genes. Functional enrichment analysis reaffirmed known functional categories in MM pathology, the main one relating to immune function. Enrichment analysis revealed a handful of differentially expressed TFs between normal and either MGUS or SMM in gene expression and/or CNV. Overall, we identified four genes of interest (MAX , TCF4 , ZNF148 , and ZNF281) that aid in our understanding of MM initiation and progression. [ABSTRACT FROM AUTHOR]

From transcriptional noise to dark matter of biology, the rapidly changing view of long non-coding RNA (lncRNA) leads to deep understanding of human complex diseases induced by abnormal expression of lncRNAs. There is urgent need to discern potential functional roles of lncRNAs for further study of pathology, diagnosis, therapy, prognosis, prevention of human complex disease and disease biomarker detection at lncRNA level. Computational models are anticipated to be an effective way to combine current related databases for predicting most potential lncRNA functions and calculating lncRNA functional similarity on the large scale. In this review, we firstly illustrated the biological function of lncRNAs from five biological processes and briefly depicted the relationship between mutations or dysfunctions of lncRNAs and human complex diseases involving cancers, nervous system disorders and others. Then, 17 publicly available lncRNA function–related databases containing four types of functional information content were introduced. Based on these databases, dozens of developed computational models are emerging to help characterize the functional roles of lncRNAs. We therefore systematically described and classified both 16 lncRNA function prediction models and 9 lncRNA functional similarity calculation models into 8 types for highlighting their core algorithm and process. Finally, we concluded with discussions about the advantages and limitations of these computational models and future directions of lncRNA function prediction and functional similarity calculation. We believe that constructing systematic functional annotation systems is essential to strengthen the prediction accuracy of computational models, which will accelerate the identification process of novel lncRNA functions in the future. [ABSTRACT FROM AUTHOR]

Background/Aims: Current practical advances in high-throughput data technologies including RNA-sequencing have led to the identification of long non-coding RNAs (lncRNAs) for potential clinical application against bladder urothelial cancer (BLCA). However, most previous studies focused on the clinical value of individual lncRNAs, which has limited the potential for future clinical application. Methods: In this study, RNA-sequencing data of lncRNAs was downloaded from The Cancer Genome Atlas database. Risk score was constructed based on survival-associated lncRNAs identified using differential expression analysis as well as univariate and multivariate Cox proportional hazards regression analysis. Receiver operating characteristic and Kaplan-Meier curve analyses were employed to evaluate the clinical and prognostic value of risk scores. Bioinformatics analyses were used to investigate the potential mechanisms of newly identified lncRNAs. Results: Among 2,127 differentially expressed lncRNAs (DELs), four new lncRNAs (AC145124.1, AC010168.2, MIR200CHG, and AC098613.1) showed valuable prognostic effects in BLCA patients. More importantly, the four-DEL-based risk score had the potential to become an independent marker for the survival status prediction of BLCA patients. Distinct co-expressed genes and signaling pathways were identified when BLCA was categorized into low- and high-risk groups. Furthermore, a protein-coding gene, HIST4H4 was found only 68 bp from the AC010168.2 DEL. HIST4H4 expression level was evidently up-regulated and positively correlated with AC010168.2 in BLCA patients. Conclusion: This in silico investigation pioneers the future investigation of the utility of prognostic lncRNAs for BLCA. [ABSTRACT FROM AUTHOR]

Introduction: Dynamin 3 (DNM3) is a large GTPase that possesses mechanochemical properties and has been shown to be involved in malignancies. However, most studies about DNM3 are observational, and knowledge of the precise molecular mechanism of DNM3 remains limited. Materials and methods: We constructed a PCDH-CMV-MCS-EF1a-GFP-Puro-DNM3 recombinant eukaryotic expression vector, which was then transfected into SW620 and LoVo cells. One cell line was divided into three groups. DNM3 mRNA and protein expression was analyzed by quantitative real-time PCR and Western blot assay. To investigate DNM3 biological activity in colon cancer SW620 and LoVo cell line, we performed cell proliferation, transwell migration, and invasion assay. Matrix metalloproteinase (MMP)-2 and MMP-9 protein expressions were detected by Western blot. Result: We successfully constructed a PCDH-CMV-MCS-EF1a-GFP-Puro-DNM3 recombinant eukaryotic expression vector, and stable DNM3 expression was observed in SW620 and LoVo cell lines. The vector overexpressing DNM3 inhibited the proliferation, weak invasion, and migration ability of colon cancer SW620 and LoVo cells relative to those in the control group (all P,0.001). DNM3 downregulated the protein expression of MMP-2 and MMP-9. Conclusion: DNM3 may weaken the malignant behavior of colon cancer and may have promoted the invasion and migration of colon cancer by regulating the expression of MMP-2 and MMP-9. [ABSTRACT FROM AUTHOR]

This study aimed to identify the potential key genes associated with severe pneumonia using mRNA-seq. Nine peripheral blood samples from patients with severe pneumonia alone (SP group, n=3) and severe pneumonia accompanied with chronic obstructive pulmonary disease (COPD; CSP group, n=3), as well as volunteers without pneumonia (control group, n=3) underwent mRNA-seq. Based on the sequencing data, differentially expressed genes (DEGs) were identified by Limma package. Following the pathway enrichment analysis of DEGs, the genes that were differentially expressed in the SP and CSP groups were selected for pathway enrichment analysis and coexpression analysis. In addition, potential genes related to pneumonia were identified based on the information in the Comparative Toxicogenomics Database. In total, 645 and 528 DEGs were identified in the SP and CSP groups, respectively, compared with the normal controls. Among these DEGs, 88 upregulated genes and 80 downregulated genes were common between the two groups. The functions of the common DEGs were similar to those of the DEGs in the SP group. In the coexpression network, the commonly downregulated genes (including ND1, ND3, ND4L, and ND6) and the commonly upregulated genes (including TSPY6P and CDY10P) exhibited a higher degree. In addition, 131 DEGs (including ND1, ND3, ND6, MIR449A and TAS2R43) were predicted to be potential pneumonia-related genes. In conclusion, the present study demonstrated that the common DEGs may be associated with the progression of severe pneumonia. [ABSTRACT FROM AUTHOR]

The clinicopathological value and exploration of the potential molecular mechanism of microRNA-183-5p (miR-183-5p) have been investigated in various cancers; however, to the best of the author's knowledge, no similar research has been reported for bladder cancer. In the present study, it was revealed that the expression level of miR-183-5p was notably increased in bladder cancer tissues compared with adjacent non-cancerous tissues (P=0.001) and was markedly increased in the tissue samples of papillary, pathological T stage (T0-T2) and pathological stage (I-II) compared with tissue samples of their counterparts (P=0.05), according to data from The Cancer Genome Atlas. Receiver operating characteristic analysis revealed the robust diagnostic value of miR-183-5p for distinguishing bladder cancer from non-cancerous bladder tissues (area under curve=0.948; 95% confidence interval: 0.919-0.977). Amplification and deep deletion of miR-183-5p were indicated by cBioPortal, accounting for 1% (4/412) of bladder cancer cases. Data from YM500v3 demonstrated that compared with other cancers, bladder cancer exhibited high expression levels of miR-183-5p, and miR-183-5p expression in primary solid tumors was much higher compared with solid normal tissues. A meta-analysis indicated that miR-183-5p was more highly expressed in bladder cancer samples compared with normal counterparts. A total of 88 potential target genes of miR-183-5p were identified, 13 of which were discerned as hub genes by protein-protein interaction. The epithelial-to-mesenchymal transition pathway was the most significantly enriched pathway by FunRich (P=0.0001). In summary, miR-183-5p may participate in the tumorigenesis and development of bladder cancer via certain signaling pathways, particularly the epithelial-to-mesenchymal transition pathway. However, the exact molecular mechanism of miR-183-5p in bladder cancer must be validated by in vitro and in vivo experiments. [ABSTRACT FROM AUTHOR]

In the recent few years, an increasing number of studies have shown that microRNAs (miRNAs) play critical roles in many fundamental and important biological processes. As one of pathogenetic factors, the molecular mechanisms underlying human complex diseases still have not been completely understood from the perspective of miRNA. Predicting potential miRNA-disease associations makes important contributions to understanding the pathogenesis of diseases, developing new drugs, and formulating individualized diagnosis and treatment for diverse human complex diseases. Instead of only depending on expensive and time-consuming biological experiments, computational prediction models are effective by predicting potential miRNA-disease associations, prioritizing candidate miRNAs for the investigated diseases, and selecting those miRNAs with higher association probabilities for further experimental validation. In this study, ath-ased iRNA-isease ssociation (PBMDA) prediction model was proposed by integrating known human miRNA-disease associations, miRNA functional similarity, disease semantic similarity, and Gaussian interaction profile kernel similarity for miRNAs and diseases. This model constructed a heterogeneous graph consisting of three interlinked sub-graphs and further adopted depth-first search algorithm to infer potential miRNA-disease associations. As a result, PBMDA achieved reliable performance in the frameworks of both local and global LOOCV (AUCs of 0.8341 and 0.9169, respectively) and 5-fold cross validation (average AUC of 0.9172). In the cases studies of three important human diseases, 88% (Esophageal Neoplasms), 88% (Kidney Neoplasms) and 90% (Colon Neoplasms) of top-50 predicted miRNAs have been manually confirmed by previous experimental reports from literatures. Through the comparison performance between PBMDA and other previous models in case studies, the reliable performance also demonstrates that PBMDA could serve as a powerful computational tool to accelerate the identification of disease-miRNA associations. [ABSTRACT FROM AUTHOR]

Background: Lumbar disc herniation (LDH) is a common musculoskeletal disorder affliction and associated with several genes polymorphism. Storkhead box 1 (STOX1) gene is a transcriptional factor related with several signaling pathways including inflammatory pathway. However, little is known about single‐nucleotide polymorphisms (SNPs) of STOX1 associated with LDH risk. Methods: We conducted a case–control study among 508 LDH cases and well‐matched 508 controls, and six candidate SNPs in STOX1 were genotyped by Agena MassARRAY. Chi‐squared test, genetic model, and haploview analysis were used to evaluate associations. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. Results: In the allelic model analysis, we found the minor allele "T" of rs7903209 and "A" of rs4472827 were associated with an increased risk of LDH (p =.029, p =.016). Furthermore, in the genotype model analysis, rs7903209 polymorphism was associated with the increased susceptibility of LDH based on dominant (p =.033) and additive model (p =.024); and rs4472827 variant was found to play a harmful role in the LDH risk based on genotype (p =.014), dominant (p =.012), and additive model (p =.015). In the haplotype analysis, the haplotype "GT" in block (rs10998461 and rs10998468) decreased LDH risk (OR = 0.7, 95% CI = 0.52–0.93, p =.016). Functional assessment indicated that rs7903209 and rs4472827 polymorphisms may influence the expression of STOX1. Conclusion: Our results provide evidence for polymorphisms of rs7903209 and rs4472827 in STOX1 associated with LDH risk in Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Plenty of evidence has suggested that autophagy plays a crucial role in the biological processes of cancers. This study aimed to screen autophagy-related genes (ARGs) and establish a novel a scoring system for colorectal cancer (CRC). Methods: Autophagy-related genes sequencing data and the corresponding clinical data of CRC in The Cancer Genome Atlas were used as training data set. The GSE39582 data set from the Gene Expression Omnibus was used as validation set. An autophagy-related signature was developed in training set using univariate Cox analysis followed by stepwise multivariate Cox analysis and assessed in the validation set. Then we analyzed the function and pathways of ARGs using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Finally, a prognostic nomogram combining the autophagy-related risk score and clinicopathological characteristics was developed according to multivariate Cox analysis. Results: After univariate and multivariate analysis, 3 ARGs were used to construct autophagy-related signature. The KEGG pathway analyses showed several significantly enriched oncological signatures, such as p53 signaling pathway, apoptosis, human cytomegalovirus infection, platinum drug resistance, necroptosis, and ErbB signaling pathway. Patients were divided into high- and low-risk groups, and patients with high risk had significantly shorter overall survival (OS) than low-risk patients in both training set and validation set. Furthermore, the nomogram for predicting 3- and 5-year OS was established based on autophagy-based risk score and clinicopathologic factors. The area under the curve and calibration curves indicated that the nomogram showed well accuracy of prediction. Conclusions: Our proposed autophagy-based signature has important prognostic value and may provide a promising tool for the development of personalized therapy. [ABSTRACT FROM AUTHOR]

Background Long thought "relics" of evolution, not until recently have pseudogenes been of medical interest regarding regulation in cancer. Often, these regulatory roles are a direct by-product of their close sequence homology to protein-coding genes. Novel pseudogene-gene (PGG) functional associations can be identified through the integration of biomedical data, such as sequence homology, functional pathways, gene expression, pseudogene expression, and microRNA expression. However, not all of the information has been integrated, and almost all previous pseudogene studies relied on 1:1 pseudogene–parent gene relationships without leveraging other homologous genes/pseudogenes. Results We produce PGG families that expand beyond the current 1:1 paradigm. First, we construct expansive PGG databases by (i) CUDAlign graphics processing unit (GPU) accelerated local alignment of all pseudogenes to gene families (totaling 1.6 billion individual local alignments and >40,000 GPU hours) and (ii) BLAST-based assignment of pseudogenes to gene families. Second, we create an open-source web application (PseudoFuN [Pseudogene Functional Networks]) to search for integrative functional relationships of sequence homology, microRNA expression, gene expression, pseudogene expression, and gene ontology. We produce four "flavors" of CUDAlign-based databases (>462,000,000 PGG pairwise alignments and 133,770 PGG families) that can be queried and downloaded using PseudoFuN. These databases are consistent with previous 1:1 PGG annotation and also are much more powerful including millions of de novo PGG associations. For example, we find multiple known (e.g. miR-20a - PTEN - PTENP1) and novel (e.g. miR-375 - SOX15 - PPP4R1L) microRNA-gene-pseudogene associations in prostate cancer. PseudoFuN provides a "one stop shop" for identifying and visualizing thousands of potential regulatory relationships related to pseudogenes in The Cancer Genome Atlas cancers. Conclusions Thousands of new PGG associations can be explored in the context of microRNA-gene-pseudogene co-expression and differential expression with a simple-to-use online tool by bioinformaticians and oncologists alike. [ABSTRACT FROM AUTHOR]

Background: Gene co-expression network (GCN) mining is a systematic approach to efficiently identify novel disease pathways, predict novel gene functions and search for potential disease biomarkers. However, few studies have systematically identified GCNs in multiple brain transcriptomic data of Alzheimer's disease (AD) patients and looked for their specific functions. Methods: In this study, we first mined GCN modules from AD and normal brain samples in multiple datasets respectively; then identified gene modules that are specific to AD or normal samples; lastly, condition-specific modules with similar functional enrichments were merged and enriched differentially expressed upstream transcription factors were further examined for the AD/normal-specific modules. Results: We obtained 30 AD-specific modules which showed gain of correlation in AD samples and 31 normal-specific modules with loss of correlation in AD samples compared to normal ones, using the network mining tool lmQCM. Functional and pathway enrichment analysis not only confirmed known gene functional categories related to AD, but also identified novel regulatory factors and pathways. Remarkably, pathway analysis suggested that a variety of viral, bacteria, and parasitic infection pathways are activated in AD samples. Furthermore, upstream transcription factor analysis identified differentially expressed upstream regulators such as ZFHX3 for several modules, which can be potential driver genes for AD etiology and pathology. Conclusions: Through our state-of-the-art network-based approach, AD/normal-specific GCN modules were identified using multiple transcriptomic datasets from multiple regions of the brain. Bacterial and viral infectious disease related pathways are the most frequently enriched in modules across datasets. Transcription factor ZFHX3 was identified as a potential driver regulator targeting the infectious diseases pathways in AD-specific modules. Our results provided new direction to the mechanism of AD as well as new candidates for drug targets. [ABSTRACT FROM AUTHOR]

Background: Current knowledge and data on miRNA-lncRNA interactions is still limited and little effort has been made to predict target lncRNAs of miRNAs. Accumulating evidences suggest that the interaction patterns between lncRNAs and miRNAs are closely related to relative expression level, forming a titration mechanism. It could provide an effective approach for characteristic feature extraction. In addition, using the coding non-coding co-expression network and sequence data could also help to measure the similarities among miRNAs and lncRNAs. By mathematically analyzing these types of similarities, we come up with two findings that (i) lncRNAs/miRNAs tend to collaboratively interact with miRNAs/lncRNAs of similar expression profiles, and vice versa, and (ii) those miRNAs interacting with a cluster of common target genes tend to jointly target at the common lncRNAs. Methods: In this work, we developed a novel group preference Bayesian collaborative filtering model called GBCF for picking up a top-k probability ranking list for an individual miRNA or lncRNA based on the known miRNA-lncRNA interaction network. Results: To evaluate the effectiveness of GBCF, leave-one-out and k-fold cross validations as well as a series of comparison experiments were carried out. GBCF achieved the values of area under ROC curve of 0.9193, 0.8354+/− 0.0079, 0.8615+/− 0.0078, and 0.8928+/− 0.0082 based on leave-one-out, 2-fold, 5-fold, and 10-fold cross validations respectively, demonstrating its reliability and robustness. Conclusions: GBCF could be used to select potential lncRNA targets of specific miRNAs and offer great insights for further researches on ceRNA regulation network. [ABSTRACT FROM AUTHOR]

Background: MicroRNA (miRNA) plays a key role in regulation mechanism of human biological processes, including the development of disease and disorder. It is necessary to identify potential miRNA biomarkers for various human diseases. Computational prediction model is expected to accelerate the process of identification. Results: Considering the limitations of previously proposed models, we present a novel computational model called FMSM. It infers latent miRNA biomarkers involved in the mechanism of various diseases based on the known miRNA-disease association network, miRNA expression similarity, disease semantic similarity and Gaussian interaction profile kernel similarity. FMSM achieves reliable prediction performance in 5-fold and leave-one-out cross validations with area under ROC curve (AUC) values of 0.9629+/− 0.0127 and 0.9433, respectively, which outperforms the state-of-the-art competitors and classical algorithms. In addition, 19 of top 25 predicted miRNAs have been validated to have associations with Colonic Neoplasms in case study. Conclusions: A factored miRNA similarity based model and miRNA expression similarity substantially contribute to the well-performing prediction. The list of the predicted most latent miRNA biomarkers of various human diseases is publicized. It is anticipated that FMSM could serve as a useful tool guiding the future experimental validation for those promising miRNA biomarker candidates. [ABSTRACT FROM AUTHOR]

Background. Currently, the benefits of nasopharyngeal carcinoma (NPC) therapy are limited, and it is necessary to further explore possible therapeutic targets. Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) has been extensively studied in other cancer species, but little has been explored in NPC. The aim of this study was to verify the expression level of ARNT2 and its underlying mechanism in NPC. Methods. Datasets containing ARNT2 mRNA expression levels were retrieved and collected from various databases to explore the expression status of ARNT2 in NPC. ARNT2-related coexpressed genes, differential expressed genes, and target genes were obtained for functional enrichment analysis. The potential target gene of ARNT2 and their regulatory relationship were studied through ChIP-seq data. CIBERSORTx was used to assess the immune infiltration of NPC, and the association with ARNT2 expression was calculated through correlation analysis. Results. ARNT2 was upregulated and possessed an excellent discriminatory capability in NPC samples. ARNT2 positively correlated target genes were clustered in pathways in cancer, while negatively correlated target genes were enriched in immune-related pathway. The ChIP-seq information of ARNT2 and histone showed that prostaglandin-endoperoxide synthase 2 (PTGS2) was a potential target gene of ARNT2. CIBERSORTx revealed the immunity status in NPC, and ARNT2 expression was correlated with infiltration of five immune cells. Conclusions. ARNT2 is overexpressed in NPC and may regulate PTGS2 to participate in the cancer process. ARNT2 serves as a key oncogenic target in NPC patients. [ABSTRACT FROM AUTHOR]

Male juvenile zebra finches learn to sing by imitating songs of adult males early in life. The development of the song control circuit and song learning and maturation are highly intertwined processes, involving gene expression, neurogenesis, circuit formation, synaptic modification, and sensory‐motor learning. To better understand the genetic and genomic mechanisms underlying these events, we used RNA‐Seq to examine genome‐wide transcriptomes in the song control nucleus HVC of male juvenile (45 d) and adult (100 d) zebra finches. We report that gene groups related to axon guidance, RNA processing, lipid metabolism, and mitochondrial functions show enriched expression in juvenile HVC compared to the rest of the brain. As juveniles mature into adulthood, massive gene expression changes occur. Expression of genes related to amino acid metabolism, cell cycle, and mitochondrial function is reduced, accompanied by increased and enriched expression of genes with synaptic functions, including genes related to G‐protein signaling, neurotransmitter receptors, transport of small molecules, and potassium channels. Unexpectedly, a group of genes with immune system functions is also developmentally regulated, suggesting potential roles in the development and functions of HVC. These data will serve as a rich resource for investigations into the development and function of a neural circuit that controls vocal behavior. [ABSTRACT FROM AUTHOR]

[Display omitted] • Various acridone derivatives were synthesized and evaluated for anticancer activity. • C4 exhibited potent activity against Hep-G2 cells with IC 50 value of 6.29 ± 0.93 μM. • C4 could specifically bind to and destabilize Kras gene promoter i-motif structure. • C4 down-regulated Kras gene expression possibly through its promoter i-motif. • C4 induced cell apoptosis possibly related to its effect on mitochondrial dysfunction. Two series of novel acridone derivatives were designed and synthesized, with their anticancer activity evaluated. Most of these compounds showed potent antiproliferative activity against cancer cell lines. Among them, compound C4 with dual 1,2,3-triazol moieties exhibited the most potent activity against Hep-G2 cells with IC 50 value determined to be 6.29 ± 0.93 μM. Subsequent experiments showed that C4 could bind to and destabilize Kras gene promoter i-motif structure without significant interaction with its corresponding G-quadruplex. C4 could down-regulate Kras expression in Hep-G2 cells, possibly due to its interaction with the Kras i-motif. Further cellular studies indicated that C4 could induce apoptosis of Hep-G2 cells, possibly related to its effect on mitochondrial dysfunction. These results indicated that C4 could be further developed as a promising anticancer agent. [ABSTRACT FROM AUTHOR]