Prognostic prediction using a gene signature developed based on exhausted T cells for liver cancer patients.

Background: Liver hepatocellular carcinoma (LIHC) is a solid primary malignancy with poor prognosis. This study discovered key prognostic genes based on T cell exhaustion and used them to develop a prognostic prediction model for LIHC. Methods: SingleR's annotations combined with Seurat was used to automatically annotate the single-cell clustering results of the LIHC dataset GSE166635 downloaded from the Gene Expression Omnibus (GEO) database and to identify clusters related to exhausted T cells. Patients were classified using ConsensusClusterPlus package. Next, weighted gene co-expression network analysis (WGCNA) package was employed to distinguish key gene module, based on which least absolute shrinkage and selection operator (Lasso) and multi/univariate cox analysis were performed to construct a RiskScore system. Kaplan-Meier (KM) analysis and receiver operating characteristic curve (ROC) were employed to evaluate the efficacy of the model. To further optimize the risk model, a nomogram capable of predicting immune infiltration and immunotherapy sensitivity in different risk groups was developed. Expressions of genes were measured by quantitative real-time polymerase chain reaction (qRT-PCR), and immunofluorescence and Cell Counting Kit-8 (CCK-8) were performed for analyzing cell functions. Results: We obtained 18,413 cells and clustered them into 7 immune and non-immune cell subpopulations. Based on highly variable genes among T cell exhaustion clusters, 3 molecular subtypes (C1, C2 and C3) of LIHC were defined, with C3 subtype showing the highest score of exhausted T cells and a poor prognosis. The Lasso and multivariate cox analysis selected 7 risk genes from the green module, which were closely associated with the C3 subtype. All the patients were divided into low- and high-risk groups based on the medium value of RiskScore, and we found that high-risk patients had higher immune infiltration and immune escape and poorer prognosis. The nomogram exhibited a strong performance for predicting long-term LIHC prognosis. In vitro experiments revealed that the 7 risk genes all had a higher expression in HCC cells, and that both liver HCC cell numbers and cell viability were reduced by knocking down MMP-9. Conclusion: We developed a RiskScore model for predicting LIHC prognosis based on the scRNA-seq and RNA-seq data. The RiskScore as an independent prognostic factor could improve the clinical treatment for LIHC patients.

Ti-40Al-10Nb-10Cr Porous Microfiltration Membrane with Hierarchical Pore Structure for Particulate Matter Capturing from High-Temperature Flue Gas.

TiAl-based porous microfiltration membranes are expected to be the next-generation filtration materials for potential applications in high-temperature flue gas separation in corrosive environments. Unfortunately, the insufficient high-temperature oxidation resistance severely limits their industrial applications. To tackle this issue, a Ti-40Al-10Nb-10Cr porous alloy was fabricated for highly effective high-temperature flue gas purification. Benefited from microstructural changes and the formation of two new phases, the Ti-40Al-10Nb-10Cr porous alloy demonstrated favorable high-temperature anti-oxidation performance with the incorporation of Nb and Cr high-temperature alloying elements. By the separation of a simulated high-temperature flue gas, we achieved an ultra-high PM-removal efficiency (62.242% for PM<2.5 and 98.563% for PM>2.5). These features, combined with our experimental design strategy, provide a new insight into designing high-temperature TiAl-based porous materials with enhanced performance and durability.

A stemness-based eleven-gene signature correlates with the clinical outcome of hepatocellular carcinoma.

BACKGROUND: Cumulative evidences have been implicated cancer stem cells in the tumor environment of hepatocellular carcinoma (HCC) cells, whereas the biological functions and prognostic significance of stemness related genes (SRGs) in HCC is still unclear. METHODS: Molecular subtypes were identified by cumulative distribution function (CDF) clustering on 207 prognostic SRGs. The overall survival (OS) predictive gene signature was developed, internally and externally validated based on HCC datasets including The Cancer Genome Atlas (TCGA), GEO and ICGC datasets. Hub genes were identified in molecular subtypes by protein-protein interaction (PPI) network analysis, and then enrolled for determination of prognostic genes. Univariate, LASSO and multivariate Cox regression analyses were performed to assess prognostic genes and construct the prognostic gene signature. Time-dependent receiver operating characteristic (ROC) curve, Kaplan-Meier curve and nomogram were used to assess the performance of the gene signature. RESULTS: We identified four molecular subtypes, among which the C2 subtype showed the highest SRGs expression levels and proportions of immune cells, whereas the worst OS; the C1 subtype showed the lowest SRGs expression levels and was associated with most favorable OS. Next, we identified 11 prognostic genes (CDX2, PON1, ADH4, RBP2, LCAT, GAL, LPA, CYP19A1, GAST, SST and UGT1A8) and then constructed a prognostic 11-gene module and validated its robustness in all three datasets. Moreover, by univariate and multivariate Cox regression, we confirmed the independent prognostic ability of the 11-gene module for patients with HCC. In addition, calibration analysis plots indicated the excellent predictive performance of the prognostic nomogram constructed based on the 11-gene signature. CONCLUSIONS: Findings in the present study shed new light on the role of stemness related genes within HCC, and the established 11-SRG signature can be utilized as a novel prognostic marker for survival prognostication in patients with HCC.

Patterns of CSF Inflammatory Markers in Non-demented Older People: A Cluster Analysis.

OBJECTIVE: In this study, we aimed to examine if patterns of CSF inflammatory markers are correlated with global cognition, episodic memory, hippocampal volume, and CSF AD-related pathologies among non-demented older people. METHODS: We included 217 non-demented older individuals, including 87 subjects with normal cognition (NC) and 130 subjects with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Hierarchical cluster analysis including nine inflammatory markers in CSF [Tumor necrosis factor-α(TNF-α), TNF-R1, TNF-R2, transforming growth factor-ß1 (TGF-ß1), TGF-ß2, TGF-ß3, Interleukin-21 (IL-21), IL-6, and IL-7] was conducted. RESULTS: We identified two clusters among non-demented older people based on nine inflammatory markers in CSF. Compared to the first cluster, the second cluster showed significantly higher levels of CSF inflammatory markers (TNF-R1, TNF-R2, TGF-ß1, TGF-ß3, and IL-6). Further, the second cluster was also associated with higher levels of t-tau and p-tau levels in CSF. CONCLUSION: We observed a subgroup of non-demented older people characterized by increased levels of inflammatory markers in CSF. Further, this subgroup showed higher levels of t-tau and p-tau levels in CSF.

Knockdown of FOXO6 Inhibits Glycolysis and Reduces Cell Resistance to Paclitaxel in HCC Cells via PI3K/Akt Signaling Pathway.

PURPOSE: Previous studies have reported that FOXO6 is highly expressed in hepatocellular carcinoma (HCC) tissues and is associated with the prognosis of HCC patients. However, little research has been carried out to explore the role of FOXO6 in glycolysis of HCC cells and paclitaxel resistance. Today, along with the increasing incidence and mortality of HCC, chemotherapy resistance of HCC also poses a serious challenge. Therefore, this study was set out to investigate the effect of FOXO6 on glycolysis and cytotoxicity of paclitaxel in HCC cells and its potential mechanism. PATIENTS AND METHODS: The levels of FOXO6 mRNA and protein were detected by qRT-PCR and Western blot, respectively. In addition, paclitaxel-resistant cell lines of HCC cells were established, whose activity was assessed by CCK-8 assay, among which the invasion ability was assessed by Transwell and the apoptosis rate by flow cytometry. What is more, glycolysis levels were evaluated by measuring glucose consumption and lactic acid production, and the protein levels of p-PI3K and p-protein kinase B (Akt) were determined by Western blot. RESULTS: Compared with normal human hepatocytes, FOXO6 was highly expressed in HCC cells, which was of high real value for HCC. FOXO6 knockdown inhibited the proliferation and invasion and induced apoptosis of HCC cells. In addition, FOXO6 knockdown suppressed glycolysis, reversed resistance to chemotherapy in Hep3B/PTX cells and inactivated PI3K and Akt proteins, thus inhibiting the PI3K/Akt signaling pathway. Furthermore, it was found that when activated by 740Y-P, PI3K/Akt signaling pathway could resist the effects of FOXO6 knockdown on the cytotoxicity and glycolysis of paclitaxel in HCC cells. Vice versa, inhibition of PI3K/Akt pathway by LY294002 could resist the effect of FOXO6 overexpression on chemotherapy, cytotoxicity and glycolysis of HCC cells. CONCLUSION: FOXO6 knockdown can inhibit glycolysis of HCC cells and reduce their resistance to chemotherapy by inhibiting the PI3K/Akt signaling pathway, which may be a new target for the treatment of HCC.

Expression Analysis of Long Non-Coding RNA HAR1A and HAR1B in HBV-Induced Hepatocullular Carcinoma in Chinese Patients.

OBJECTIVE: To determine the clinical relevance of long noncoding RNA (lncRNA) HAR1A and HAR1B expression in hepatocellular carcinoma (HCC). METHODS: In this study, we enrolled 50 cases of chronic hepatitis B (CHB) without cirrhosis, 50 cases of CHB and liver cirrhosis (LC), and 100 cases of HBV and HCC. The expression profiles of lncRNA HAR1A and HAR1B were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: The expression levels of HAR1A and HAR1B were significantly lower in the HCC group, compared with the CHB and LC groups (P <.01). HAR1A and HAR1B were negatively associated with histologic grade and TNM (tumor/nodes/metastasis) stage (all P <.05). Univariable multivariable analysis showed that decreased HAR1A (HR = 0.753, P = .02) and HAR1B (HR = 0.551, P = .01) levels were independent predictors for shorter overall survival (OS) in HCC. CONCLUSION: Decreased HAR1A and HAR1B expression in HCC indicates poor prognosis.

Safety and efficacy analysis of DEB-TACE treatment in elderly patients with hepatocellular carcinoma: a comparative cohort study.

The aim of this study was to explore the difference of liver function change, safety profiles and efficacy of drug-eluting bead transarterial chemoembolization (DEBTACE) therapy between elderly and middle-aged hepatocellular carcinoma (HCC) patients. 91 HCC patients were enrolled in this prospective cohort study. They were treated by DEB-TACE therapy and divided into elderly group (age >= 65 years, n=30) and middle-aged group (age < 65 years, n=61), liver function, safety profiles and treatment response were recorded. No difference of liver function was found between two groups before operation and at 1 week post DEB-TACE treatment. While the portion of abnormal total protein (TP) in elderly group was elevated than that in middleage group at 1-3 months after operation. During operation, elderly group presented with raised incidence of vomiting compared with middle-aged group, whereas elderly patients displayed lower incidence of pain than middle-aged patients at 1 month post treatment. No other difference of safety profiles was found between the two groups. At 1-3 months after treatment, elderly patients achieved complete response (CR) of 26.7% and overall response rate (ORR) of 93.3%, meanwhile, middle-aged patients obtained CR of 23.0% and ORR of 90.2%. No difference of CR and ORR was found between elderly and middle-aged patients, in addition, no difference of OS was observed between the two groups. In conclusion, DEB-TACE therapy was well tolerated in elderly HCC patients, and it possessed equal efficacy in elderly patients compared with middle-aged patients.