Nomograms for prognostic risk assessment in glioblastoma multiforme: Applications and limitations.

Glioblastoma multiforme (GBM) is the most common and aggressive form of brain cancer. Prognosis evaluation is of great significance in guiding individualized treatment and monitoring of GBM. By integrating different prognostic variables, nomograms simplify the statistical risk prediction model into numerical estimates for death or recurrence, and are hence widely applied in prognosis prediction. In the past two decades, the application of high-throughput profiling technology and the establishment of TCGA database and other public data deposits have provided opportunities to identify cancer-related molecules and prognostic biomarkers. As a result, both molecular features and clinical characteristics of cancer have been reported to be the key factors in nomogram model construction. This article comprehensively reviewed 35 studies of GBM nomograms, analyzed the present situation of GBM nomograms, and discussed the role and significance of nomograms in personalized risk assessment and clinical treatment decision-making. To facilitate the application of nomograms in the prognostic prediction of GBM patients, a website has been established for the online access of nomograms based on the studies of this review, which is called Consensus Nomogram Spectrum for Glioblastoma (CNSgbm) and is accessible through https://bioinfo.henu.edu.cn/nom/NomList.jsp.

A Comprehensive Prognostic Analysis of Tumor-Related Blood Group Antigens in Pan-Cancers Suggests That SEMA7A as a Novel Biomarker in Kidney Renal Clear Cell Carcinoma.

Blood group antigen is a class of heritable antigenic substances present on the erythrocyte membrane. However, the role of blood group antigens in cancer prognosis is still largely unclear. In this study, we investigated the expression of 33 blood group antigen genes and their association with the prognosis of 30 types of cancers in 31,870 tumor tissue samples. Our results revealed that blood group antigens are abnormally expressed in a variety of cancers. The high expression of these antigen genes was mainly related to the activation of the epithelial-mesenchymal transition (EMT) pathway. High expression of seven antigen genes, i.e., FUT7, AQP1, P1, C4A, AQP3, KEL and DARC, were significantly associated with good OS (Overall Survival) in six types of cancers, while ten genes, i.e., AQP1, P1, C4A, AQP3, BSG, CD44, CD151, LU, FUT2, and SEMA7A, were associated with poor OS in three types of cancers. Kidney renal clear cell carcinoma (KIRC) is associated with the largest number (14 genes) of prognostic antigen genes, i.e., CD44, CD151, SEMA7A, FUT7, CR1, AQP1, GYPA, FUT3, FUT6, FUT1, SLC14A1, ERMAP, C4A, and B3GALT3. High expression of SEMA7A gene was significantly correlated with a poor prognosis of KIRC in this analysis but has not been reported previously. SEMA7A might be a putative biomarker for poor prognosis in KIRC. In conclusion, our analysis indicates that blood group antigens may play functional important roles in tumorigenesis, progression, and especially prognosis. These results provide data to support prognostic marker development and future clinical management.

Systemic analysis of the expression and prognostic significance of PAKs in breast cancer.

PAKs (p21-activated kinases) are reported to play crucial roles in a variety of cellular processes and participate in the progression of human cancers. However, the expression and prognostic values of PAKs remain poorly explored in breast cancers. In our study, we examined the mRNA and protein expression levels of PAKs and the prognostic value. We also analyzed the interaction network, genetic alteration, and functional enrichment of PAKs. The results showed that the mRNA levels of PAK1, PAK2, PAK4 and PAK6 were significantly up-regulated in breast cancer compared with normal tissues, while the reverse trend for PAK3 and PAK5 was found, furthermore, the proteins expression of PAK1, PAK2 and PAK4 in breast cancer tissues were higher than that in normal breast tissues. Survival analysis revealed breast cancer patients with low mRNA expression of PAK3 and PAK5 showed worse RFS, conversely, elevated PAK4 levels predicted worse RFS. In addition, the breast cancer patients with PAKs genetic alterations correlated with worse OS. These results indicated that PAKs might be promising potential biomarkers for breast cancer.

Identification of hub genes and pathways in adrenocortical carcinoma by integrated bioinformatic analysis.

Adrenocortical carcinoma (ACC), a rare malignant neoplasm originating from adrenal cortical cells, has high malignancy and few treatments. Therefore, it is necessary to explore the molecular mechanism of tumorigenesis, screen and verify potential biomarkers, which will provide new clues for the treatment and diagnosis of ACC. In this paper, three gene expression profiles (GSE10927, GSE12368 and GSE90713) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained using the Limma package. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched by DAVID. Protein-protein interaction (PPI) network was evaluated by STRING database, and PPI network was constructed by Cytoscape. Finally, GEPIA was used to validate hub genes' expression. Compared with normal adrenal tissues, 74 up-regulated DEGs and 126 down-regulated DEGs were found in ACC samples; GO analysis showed that up-regulated DEGs were enriched in organelle fission, nuclear division, spindle, et al, while down-regulated DEGs were enriched in angiogenesis, proteinaceous extracellular matrix and growth factor activity; KEGG pathway analysis showed that up-regulated DEGs were significantly enriched in cell cycle, cellular senescence and progesterone-mediated oocyte maturation; Nine hub genes (CCNB1, CDK1, TOP2A, CCNA2, CDKN3, MAD2L1, RACGAP1, BUB1 and CCNB2) were identified by PPI network; ACC patients with high expression of 9 hub genes were all associated with worse overall survival (OS). These hub genes and pathways might be involved in the tumorigenesis, which will offer the opportunities to develop the new therapeutic targets of ACC.

OSskcm: an online survival analysis webserver for skin cutaneous melanoma based on 1085 transcriptomic profiles.

BACKGROUND: Cutaneous melanoma is one of the most aggressive and lethal skin cancers. It is greatly important to identify prognostic biomarkers to guide the clinical management. However, it is technically challenging for untrained researchers to process high dimensional profiling data and identify potential prognostic genes in profiling datasets. METHODS: In this study, we developed a webserver to analyze the prognostic values of genes in cutaneous melanoma using data from TCGA and GEO databases. The webserver is named Online consensus Survival webserver for Skin Cutaneous Melanoma (OSskcm) which includes 1085 clinical melanoma samples. The OSskcm is hosted in a windows tomcat server. Server-side scripts were developed in Java script. The database system is managed by a SQL Server, which integrates gene expression data and clinical data. The Kaplan-Meier (KM) survival curves, Hazard ratio (HR) and 95% confidence interval (95%CI) were calculated in a univariate Cox regression analysis. RESULTS: In OSskcm, by inputting official gene symbol and selecting proper options, users could obtain KM survival plot with log-rank P value and HR on the output web page. In addition, clinical characters including race, stage, gender, age and type of therapy could also be included in the prognosis analysis as confounding factors to constrain the analysis in a subgroup of melanoma patients. CONCLUSION: The OSskcm is highly valuable for biologists and clinicians to perform the assessment and validation of new or interested prognostic biomarkers for melanoma. OSskcm can be accessed online at: http://bioinfo.henu.edu.cn/Melanoma/MelanomaList.jsp.

Characterization and genome analysis of novel Klebsiella phage Henu1 with lytic activity against clinical strains of Klebsiella pneumoniae.

Klebsiella pneumoniae is an important human pathogen that is associated with a wide range of diseases, including pneumonia and septicemia. Because of the threat of drug-resistant K. pneumoniae to humans, especially carbapenem-resistant K. pneumoniae, which is becoming a growing threat to hospitalized patients, the potential use of phage therapy has generated considerable interest. Henu1, isolated from a sewage sample, was identified as a linear double-stranded DNA phage of 40,352 bp with 53.14% G + C content and 143-bp terminal repeats. The Henu1 genome contains 45 open reading frames, and no tRNA genes were found. K. pneumoniae clinical strains with the capsular types K-1, K-2, and K-57 could be infected by Henu1. No human-virulence-related genes or lysogen-formation gene clusters were detected in this phage genome, suggesting that Henu1 is a virulent phage in its bacterial host and is safe for humans.

OScc: an online survival analysis web server to evaluate the prognostic value of biomarkers in cervical cancer.

Aim: To establish a web server that can mutually validate prognostic biomarkers of cervical cancer. Methods: Four datasets including expression profiling and relative clinical follow-up data were collected from Gene Expression Omnibus and The Cancer Genome Atlas. The web server was developed by R software. Results: The web server was named OScc including 690 patients and can be accessed at http://bioinfo.henu.edu.cn/CESC/CESCList.jsp. The Kaplan-Meier survival curves with log-rank p-value and hazard ratio will be generated of interested gene in OScc. Compared with previous predictive tools, OScc had the advantages of registration-free, larger sample size and subgroup analysis. Conclusion: The OScc is highly valuable to perform the preliminary assessment and validation of new or interested prognostic biomarkers for cervical cancer.

OSkirc: a web tool for identifying prognostic biomarkers in kidney renal clear cell carcinoma.

Aim: To develop a free and quick analysis online tool that allows users to easily investigate the prognostic potencies of interesting genes in kidney renal clear cell carcinoma (KIRC). Patients & methods: A total of 629 KIRC cases with gene expression profiling data and clinical follow-up information are collected from public Gene Expression Omnibus and The Cancer Genome Atlas databases. Results: One web application called Online consensus Survival analysis for KIRC (OSkirc) that can be used for exploring the prognostic implications of interesting genes in KIRC was constructed. By OSkirc, users could simply input the gene symbol to receive the Kaplan-Meier survival plot with hazard ratio and log-rank p-value. Conclusion: OSkirc is extremely valuable for basic and translational researchers to screen and validate the prognostic potencies of genes for KIRC, publicly accessible at http://bioinfo.henu.edu.cn/KIRC/KIRCList.jsp.

Roles of Multifunctional COP9 Signalosome Complex in Cell Fate and Implications for Drug Discovery.

The eight subunits containing COP9 signalosome (CSN) complex, is highly conserved among eukaryotes. CSN, identified as a negative regulator of photomorphogenesis, has also been demonstrated to be important in proteolysis, cellular signal transduction and cell cycle regulation in various eukaryotic organisms. This review mainly summarizes the roles of CSN in cell cycle regulation, signal transduction and apoptosis, and its potential as diagnostic biomarkers, drug targets for cancer and infectious diseases. J. Cell. Physiol. 232: 1246-1253, 2017. © 2016 Wiley Periodicals, Inc.

Molecular Mechanisms Underlying the Function Diversity of ArsR Family Metalloregulator.

The ArsR family of transcriptional regulators are widespread among microorganisms and are involved in various important cellular events, such as metal ion homeostasis, biofilm formation, primary and secondary metabolism, symbiosis, response to adverse condition, and virulence. Its N-terminus contains a winged helix-turn-helix DNA-binding domain that can repress or activate transcription by binding to downstream target promoters. With the increasing number of members in this family identified over the past few decades, the ArsR family members have been intensively explored. In this review, we summarize the function of ArsR family of transcriptional regulators and the mechanisms of metal-regulated gene expression.

Mycobacterium tuberculosis Major Facilitator Superfamily Transporters.

The cell membrane or biofilm serve as permeable barrier for xenobiotics to maintain the homeostasis of cells or bacterial community. Transport systems are essential for the uptake of nutrients and substances necessary for biofilm formation, efflux of deleterious compounds, as well as communication between cells and environment. Major facilitator superfamily (MFS) represents the largest secondary transporter family and is responsible for the transport of a broad spectrum of substrates with diverse physiochemical properties by utilizing the energy stored in electrochemical gradient across the membrane. Importantly, multidrug efflux pumps belonging to the major facilitator superfamily are important contributing factors to drug resistance and biofilm formation in many clinical strains like Mycobacterium tuberculosis. This review summarized the structural properties and functions of M. tuberculosis MFS transporters, molecular mechanisms of substrates transfer, and efflux pump inhibitors for better control of biofilm-associated infections.

Mycobacterium tuberculosis rv1400c encodes functional lipase/esterase.

Lipases catalyze the hydrolysis of triglycerides (TAG). Open reading frames (ORF) predicted to encode enzymes involved in fatty acids breakdown are abundant in Mycobacterium tuberculosis genome. To define the function of M. tuberculosis rv1400c (LipI), a putative Hormone Sensitive Lipase (HSL) subfamily ORF, the rv1400c was cloned, expressed and purified in Escherichia coli as fusion protein. The purified LipI preferred short carbon chain substrates with an optimal activity at 37 °C/pH 8.0 and stable between pH 6.0 to 9.0. Its specific activity was calculated to 35.71 U/mg with pNP-butyrate as a preferred substrate. SDS, CTAB and Zn2+ can inhibit this enzyme. The conserved residues Ser165 and His291 were shown to be important for the catalysis activity of Rv1400c by site-directed mutagenesis. The biochemical and genetical data showed M. tuberculosis LipI might be a good candidate catalyst for polyunsaturated fatty acids.

Band structure analysis of phononic crystals based on the Chebyshev interval method.

Due to environmental changes and manufacturing errors, uncertainties inherently exist in phononic crystals, especially in the material properties and geometric parameters. To handle the uncertainties with limited information, two different methods are proposed for band structure analysis of phononic crystals with uncertainties. One is the Monte Carlo method (MCM). The main shortcoming of it is the high computational cost. The other is the simplex Chebyshev polynomial expansion (SPCE) method. In addition, the computational efficiency of the SPCE method is much higher. In the SPCE method, the simplex Chebyshev is employed to estimate the band structures of phononic crystals. Meanwhile, the simplified incremental sampling strategy is introduced for the simplex Chebyshev to retain calculation accuracy and improve computational efficiency simultaneously. In the Chebyshev surrogate model, the samples yielded with the MCM are used to calculate the interval ranges of the band structures in phononic crystals. Three numerical examples, including a two-dimensional (2D) Helmholtz resonator phononic crystal, a 2D solid-solid phononic crystal, and a three-dimensional phononic crystal, are introduced to verify the effectiveness and efficiency of the proposed method.

Proteome-wide Lysine Glutarylation Profiling of the Mycobacterium tuberculosis H37Rv.

Lysine glutarylation, a new protein posttranslational modification (PTM), was recently identified and characterized in both prokaryotic and eukaryotic cells. To explore the distribution of lysine glutarylation in Mycobacterium tuberculsosis, by using a comprehensive method combining the immune affinity peptide enrichment by the glutaryl-lysine antibody with LC-MS, we finally identified 41 glutarylation sites in 24 glutarylated proteins from M. tuberculosis. These glutarylated proteins are involved in various cellular functions such as translation and metabolism and exhibit diverse subcellular localizations. Three common glutarylated proteins including 50S ribosomal protein L7/L12, elongation factor Tu, and dihydrolipoamide succinyltransferase are shared between Escherichia coli and M. tuberculosis. Moreover, comparison with other PTMs characterized in M. tuberculosis, 15 glutarylated proteins, are found to be both acetylated and succinylated. Notably, several stress-response-associated proteins including HspX are glutarylated. Our data provide the first analysis of M. tuberculosis lysine glutarylated proteins. Further studies on the role of the glutarylated proteins will unveil the molecular mechanisms of glutarylation underlying M. tuberculosis physiology and pathogenesis.

Mycobacteriophage putative GTPase-activating protein can potentiate antibiotics.

The soaring incidences of infection by antimicrobial resistant (AR) pathogens and shortage of effective antibiotics with new mechanisms of action have renewed interest in phage therapy. This scenario is exemplified by resistant tuberculosis (TB), caused by resistant Mycobacterium tuberculosis. Mycobacteriophage SWU1 A321_gp67 encodes a putative GTPase-activating protein. Mycobacterium smegmatis with gp67 overexpression showed changed colony formation and biofilm morphology and supports the efficacy of streptomycin and capreomycin against Mycobacterium. gp67 down-regulated the transcription of genes involved in cell wall and biofilm development. To our knowledge, this is the first report to show that phage protein in addition to lysin or recombination components can synergize with existing antibiotics. Phage components might represent a promising new clue for better antibiotic potentiators.

First succinyl-proteome profiling of extensively drug-resistant Mycobacterium tuberculosis revealed involvement of succinylation in cellular physiology.

Protein lysine succinylation, an emerging protein post-translational modification widespread among eukaryotic and prokaryotic cells, represents an important regulator of cellular processes. However, the extent and function of lysine succinylation in Mycobacterium tuberculosis, especially extensively drug-resistant strain, remain elusive. Combining protein/peptide prefractionation, immunoaffinity enrichment, and LC-MS/MS analysis, a total of 686 succinylated proteins and 1739 succinylation sites of M. tuberculosis were identified, representing the first global profiling of M. tuberculosis lysine succinylation. The identified succinylated proteins are involved in a variety of cellular functions such as metabolic processes, transcription, translation, and stress responses and exhibit different subcellular localization via GO, protein interaction network, and other bioinformatic analysis. Notably, proteins involved in protein biosynthesis and carbon metabolism are preferred targets of lysine succinylation. Moreover, two prevalent sequence patterns: EK(suc) and K*****K(suc), can be found around the succinylation sites. There are 109 lysine-succinylated homologues in E. coli, suggesting highly conserved succinylated proteins. Succinylation was found to occur at the active sites predicted by Prosite signature including Rv0946c, indicating that lysine succinylation may affect their activities. There is extensive overlapping between acetylation sites and succinylation sites in M. tuberculosis. Many M. tuberculosis metabolic enzymes and antibiotic resistance proteins were succinylated. This study provides a basis for further characterization of the pathophysiological role of lysine succinylation in M. tuberculosis.

Roles of Protein N-Myristoylation and Translational Medicine Applications.

Protein N-myristoylation is a ubiquitous cotranslational and posttranslational modification catalyzed by myristoyl CoA:protein N-myristoyltransferase (NMT), which attaches myristate, a rare 14-carbon saturated fatty acid, to an N-terminal glycine of some eukaryotic and virus proteins. This protein modification triggers dynamic protein-protein and protein-membrane interactions implicated in diverse physiological processes. This review summarizes the NMT catalytic mechanism and demyristoylation. Of special interest are the primary roles of N-myristoylated protein in signaling, protein targeting, tumorigenesis, apoptosis, virus assembly, and morphology change, as well as the regulation of N-myristoylation and NMT inhibitors.

Implications of Mycobacterium Major Facilitator Superfamily for Novel Measures against Tuberculosis.

Major facilitator superfamily (MFS) is an important secondary membrane transport protein superfamily conserved from prokaryotes to eukaryotes. The MFS proteins are widespread among bacteria and are responsible for the transfer of substrates. Pathogenic Mycobacterium MFS transporters, their distribution, function, phylogeny, and predicted crystal structures were studied to better understand the function of MFS and to discover specific inhibitors of MFS for better tuberculosis control.