Prevailing I292V PB2 mutation in avian influenza H9N2 virus increases viral polymerase function and attenuates IFN-β induction in human cells

Adaptation of PB2 protein is important for the establishment of avian influenza viruses in mammalian hosts. Here, we identify I292V as the prevalent mutation in PB2 of circulating avian H9N2 and pandemic H1N1 viruses. The same dominant PB2 mutation is also found in most human isolates of emergent avian H7N9 and H10N8 viruses. In human cells, PB2-292V in H9N2 virus has the combined ability of conferring higher viral polymerase activity and stronger attenuation of IFN-β induction than that of its predecessor PB2-292I. IFN-β attenuation is accompanied by higher binding affinity of PB2-292V for host mitochondrial antiviral signalling protein, an important intermediary protein in the induction of IFN-β. In the mouse in vivo model, PB2-292V mutation increases H9N2 virus replication with ensuing increase in disease severity. Collectively, PB2-292V is a new mammalian adaptive marker that promotes H9N2 virus replication in mammalian hosts with the potential to improve transmission from birds to humans

Identification of Hub Genes Associated With Progression and Prognosis in Patients With Bladder Cancer

Given that most bladder cancers (BCs) are diagnosed in advanced stages with poor prognosis, this study aims to find novel biomarkers associated with the progression and prognosis in patients with BC. 1,779 differentially expressed genes (DEGs) between BC samples and normal bladder tissues were identified in total. Then, 24 DEGs were regarded as candidate hub genes by constructing a protein–protein interaction (PPI) network and a random forest model. Among them, six genes (BUB1B, CCNB1, CDK1, ISG15, KIF15, and RAD54L) were eventually identified by using five analysis methods (one-way Analysis of Variance analysis, spearman correlation analysis, distance correlation analysis, receiver operating characteristic curve, and expression values comparison), which were correlated with the progression and prognosis of BC. Moreover, the validation of hub genes was conducted based on GSE13507, Oncomine, and CBioPortal. Results of univariate Cox regression analysis showed that the expression levels of all the hub genes were influence features of overall survival (OS) and cancer specific survival (CSS) based on GSE13507, and we further established a six-gene signature based on the expression levels of the six genes and their Cox regression coefficients. This signature showed good potential for clinical application suggested by survival analysis (OS: Hazard Ratio = 0.484, 95%CI: 0.298–0.786; P = 0.0034; CSS: Hazard Ratio = 0.244, 95%CI: 0.121–0.493, P < 0.0001) and decision curve analysis. In conclusion, our study indicates that six hub genes have great predictive value for the prognosis and progression of BC and may contribute to the exploration of further basic and clinical research of BC

Construction and Validation of an Autophagy-Related Prognostic Signature and a Nomogram for Bladder Cancer

ObjectiveBladder cancer (BC) is one of the top ten cancers endangering human health but we still lack accurate tools for BC patients’ risk stratification. This study aimed to develop an autophagy-related signature that could predict the prognosis of BC. In order to provide clinical doctors with a visual tool that could precisely predict the survival probability of BC patients, we also attempted to establish a nomogram based on the risk signature.MethodsWe screened out autophagy-related genes (ARGs) combining weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) in BC. Based on the screened ARGs, we performed survival analysis and Cox regression analysis to identify potential prognostic biomarkers. A risk signature based on the prognostic ARGs by multivariate Cox regression analysis was established, which was validated by using seven datasets. To provide clinical doctors with a useful tool for survival possibility prediction, a nomogram assessed by the ARG-based signature and clinicopathological features was constructed, verified using four independent datasets.ResultsThree prognostic biomarkers including BOC (P = 0.008, HR = 1.104), FGF7(P = 0.030, HR = 1.066), and MAP1A (P = 0.001, HR = 1.173) were identified and validated. An autophagy-related risk signature was established and validated. This signature could act as an independent prognostic feature in patients with BC (P = 0.047, HR = 1.419). We then constructed two nomograms with and without ARG-based signature and subsequent analysis indicated that the nomogram with ARG signature showed high accuracy for overall survival probability prediction of patients with BC (C-index = 0.732, AUC = 0.816). These results proved that the ARG signature improved the clinical net benefit of the standard model based on clinicopathological features (age, pathologic stage).ConclusionsThree ARGs were identified as prognosis biomarkers in BC. An ARG-based signature was established for the first time, showing strong potential for prognosis prediction in BC. This signature was proven to improve the clinical net benefit of the standard model. A nomogram was established using this signature, which could lead to more effective prognosis prediction for BC patients

Molecular vasculogenic mimicry–Related signatures predict clinical outcomes and therapeutic responses in bladder cancer: Results from real-world cohorts

Bladder cancer (BLCA) is a heterogeneous disease, and there are many classical molecular subtypes that reflect tumor immune microenvironment (TME) heterogeneity but their clinical utility is limited and correct individual treatment and prognosis cannot be predicted based on them. To find reliable and effective biomarkers and tools for predicting patients’ clinical responses to several therapies, we developed a new systemic indicator of molecular vasculogenic mimicry (VM)–related genes mediated by molecular subtypes based on the Xiangya cohort and additional external BLCA cohorts using a random forest algorithm. A correlation was then done between the VM_Score and classical molecular subtypes, clinical outcomes, immunophenotypes, and treatment options for BLCA. With the VM_Score, it is possible to predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic potential of BLCA with high accuracy. The VM_Scores of high levels indicate a more anticancer immune response but a worse prognosis due to a more basal and inflammatory phenotype. The VM_Score was also found associated with low sensitivity to antiangiogenic and targeted therapies targeting the FGFR3, β-catenin, and PPAR-γ pathways but with high sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy. A number of aspects of BLCA biology were reflected in the VM_Score, providing new insights into precision medicine. Additionally, the VM_Score may be used as an indicator of pan-cancer immunotherapy response and prognosis

HLA-matched sibling transplantation with G-CSF mobilized PBSCs and BM decreases GVHD in adult patients with severe aplastic anemia

<p>Abstract</p> <p>Background</p> <p>Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for severe aplastic anemia (SAA). However, graft failure and graft-versus-host disease (GVHD) are major causes of the early morbidity in Allo-HSCT.</p> <p>Methods</p> <p>To reduce graft failure and GVHD, we treated fifteen patients with SAA using high- dose of HSCT with both G-CSF mobilized PB and BMSCs from HLA-identical siblings to treat patients with SAA.</p> <p>Results</p> <p>All patients had successful bone marrow engraftment. Only one patient had late rejection. Median time to ANC greater than 0.5 × 10⁹/L and platelet counts greater than 20 × 10⁹/L was 12 and 16.5 days, respectively. No acute GVHD was observed. The incidence of chronic GVHD was 6.67%. The total three-year probability of disease-free survival was 79.8%.</p> <p>Conclusion</p> <p>HSCT with both G-CSF mobilized PB and BMSCs is a promising approach for heavily transfused and/or allo-immunized patients with SAA.</p

The Role of COL5A2 in Patients With Muscle-Invasive Bladder Cancer: A Bioinformatics Analysis of Public Datasets Involving 787 Subjects and 29 Cell Lines

Bladder cancer (BC) is one of the most common malignancies. Two previous studies identified collagen type V alpha 2 (COL5A2) as a potential biomarker in BC, both are simple reanalysis of a single transcriptomic dataset without subgroup analysis for muscle-invasive BC (MIBC). We focused in MIBC patients and explored the role of COL5A2 from an integration perspective, using refined methodology covering individual participant data meta-analysis and bioinformatics analysis. Eight transcriptomic datasets of 787 MIBC patients (including one dataset containing genomic mutation information) and two drug sensitivity datasets of 29 cell lines in which more than 250 compounds were analyzed. We found subjects with increased COL5A2 gene expression exhibited poorer prognosis, and the power analysis confirmed adequate sample size. FGFR3 was the only gene differential mutated between the COL5A2 high and low expression groups. Differential expression and co-expression network analysis suggested potential association between COL5A2 expression and essential pathways involved in cancer invasion and dissemination, including cell adhesion, extracellular matrix organization, and epithelial-mesenchymal transition. Coordinately, analysis of drug screening datasets and gene-drug interaction also revealed COL5A2 expression linked to cell morphogenesis, angiogenesis, blood vessel development, and urogenital development. The utility and feasibility of COL5A2 for clinically applicable prognosis prediction and risk classification and the exact underlying molecular mechanism should be further investigated in subsequent studies

The CHR promoter element controls cell cycle-dependent gene transcription and binds the DREAM and MMB complexes

Cell cycle-dependent gene expression is often controlled on the transcriptional level. Genes like cyclin B, CDC2 and CDC25C are regulated by cell cycle-dependent element (CDE) and cell cycle genes homology region (CHR) promoter elements mainly through repression in G0/G1. It had been suggested that E2F4 binding to CDE sites is central to transcriptional regulation. However, some promoters are only controlled by a CHR. We identify the DREAM complex binding to the CHR of mouse and human cyclin B2 promoters in G0. Association of DREAM and cell cycle-dependent regulation is abrogated when the CHR is mutated. Although E2f4 is part of the complex, a CDE is not essential but can enhance binding of DREAM. We show that the CHR element is not only necessary for repression of gene transcription in G0/G1, but also for activation in S, G2 and M phases. In proliferating cells, the B-myb-containing MMB complex binds the CHR of both promoters independently of the CDE. Bioinformatic analyses identify many genes which contain conserved CHR elements in promoters binding the DREAM complex. With Ube2c as an example from that screen, we show that inverse CHR sites are functional promoter elements that can bind DREAM and MMB. Our findings indicate that the CHR is central to DREAM/MMB-dependent transcriptional control during the cell cycle