Stemness And Chemotherapeutic Drug Resistance Induced By Eif5a2 Overexpression In Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies of the digestive tract in East Asian countries. Multimodal therapies, including adjuvant chemotherapy and neo-adjuvant chemotherapy, have become more often used for patients with advanced ESCC. However, the chemotherapy effect is often limited by patients' drug resistance. This study demonstrated that EIF5A2 (eukaryotic translation initiation factor 5A2) overexpression induced stemness and chemoresistance in ESCC cells. We showed that EIF5A2 overexpression in ESCC cells resulted in increased chemoresistance to 5-fluorouracil (5-FU), docetaxel and taxol. In contrast, shRNAs suppressing eIF5A2 increased tumor sensitivity to these chemotherapeutic drugs. In addition, EIF5A2 overexpression was correlated with a poorer overall survival in patients with ESCC who underwent taxane-based chemotherapy after esophagectomy (P > 0.05). Based on these results, we suggest that EIF5A2 could be a predictive biomarker for selecting appropriate chemo-treatment for ESCC patients and EIF5A2 inhibitors might be considered as combination therapy to enhance chemosensitivity in patients with ESCC.published_or_final_versio

Comprehensive analysis of a novel RNA modifications-related model in the prognostic characterization, immune landscape and drug therapy of bladder cancer

Background: Bladder cancer (BCa) is the leading reason for death among genitourinary malignancies. RNA modifications in tumors closely link to the immune microenvironment. Our study aimed to propose a promising model associated with the “writer” enzymes of five primary RNA adenosine modifications (including m6A, m6Am, m1A, APA, and A-to-I editing), thus characterizing the clinical outcome, immune landscape and therapeutic efficacy of BCa.Methods: Unsupervised clustering was employed to categorize BCa into different RNA modification patterns based on gene expression profiles of 34 RNA modification “writers”. The RNA modification “writers” score (RMS) signature composed of RNA phenotype-associated differentially expressed genes (DEGs) was established using the least absolute shrinkage and selection operator (LASSO), which was evaluated in meta-GEO (including eight independent GEO datasets) training cohort and the TCGA-BLCA validation cohort. The hub genes in the RMS model were determined via weighted gene co-expression network analysis (WGCNA) and were further validated using human specimen. The potential applicability of the RMS model in predicting the therapeutic responsiveness was assessed through the Genomics of Drug Sensitivity in Cancer database and multiple immunotherapy datasets.Results: Two distinct RNA modification patterns were determined among 1,410 BCa samples from a meta-GEO cohort, showing radically varying clinical outcomes and biological characteristics. The RMS model comprising 14 RNA modification phenotype-associated prognostic DEGs positively correlated with the unsatisfactory outcome of BCa patients in meta-GEO training cohort (HR = 3.00, 95% CI = 2.19–4.12) and TCGA-BLCA validation cohort (HR = 1.53, 95% CI = 1.13–2.09). The infiltration of immunosuppressive cells and the activation of EMT, angiogenesis, IL-6/JAK/STAT3 signaling were markedly enriched in RMS-high group. A nomogram exhibited high prognostic prediction accuracy, with a concordance index of 0.785. The therapeutic effect of chemotherapeutic agents and antibody-drug conjugates was significantly different between RMS-low and -high groups. The combination of the RMS model and conventional characteristics (TMB, TNB and PD-L1) achieved an optimal AUC value of 0.828 in differentiating responders from non-responders to immunotherapy.Conclusion: We conferred the first landscape of five forms of RNA modifications in BCa and emphasized the excellent power of an RNA modifications-related model in evaluating BCa prognosis and immune landscape

Polysaccharide from Fruits of Physalis Alkekengi L. Enhances Antitumor Efficacy by a DNA Vaccine

 Physalis. alkekengi fruit has long been used in traditional Chinese medicine for tumor therapy. In the present study, using plasmids that encode ovalbumin (OVA) gene, we investigate the adjuvant activity of a polysaccharide fraction (PPSB) isolated from P.alkekengi fruit. Formulation by simple procedures of mixing of the OVA-encoding pCI-neo-sOVA plasmid with PPSB not only induced specific antibody responses, but also induced antigen-specific cytotoxic T lymphocyte (CTL) responses (Graph abstract). Furthermore, immunization using this vaccine prevented the growth of OVA-expressing B16-OVA tumor cell growth in the immunized mice. Thus, we provide evidence supporting the adjuvant activity of PPSB in DNA vaccine against tumor

Immunosuppressive Tumor Microenvironment and Immunotherapy of Epstein–Barr Virus-Associated Malignancies

The Epstein–Barr virus (EBV) can cause different types of cancer in human beings when the virus infects different cell types with various latent patterns. EBV shapes a distinct and immunosuppressive tumor microenvironment (TME) to its benefit by influencing and interacting with different components in the TME. Different EBV-associated malignancies adopt similar but slightly specific immunosuppressive mechanisms by encoding different EBV products to escape both innate and adaptive immune responses. Strategies reversing the immunosuppressive TME of EBV-associated malignancies have been under evaluation in clinical practice. As the interactions among EBV, tumor cells, and TME are intricate, in this review, we mainly discuss the epidemiology of EBV, the life cycle of EBV, the cellular and molecular composition of TME, and a landscape of different EBV-associated malignancies and immunotherapy by targeting the TME

Effect of Tailings Fine Content on the Properties of Cemented Paste Backfill from the Perspective Packing Density

In order to quantitatively study the influence of tailings fine content on the properties of cemented paste backfill (CPB) and further understand the mechanism of tailings fine content acting, the concept of packing density was introduced in this study. The packing density of each tailings sample was measured by the wet packing method after the samples with various fine contents were prepared. Moreover, CPBs with different tailings fine contents were tested by the mini slump test, rheological test, uniaxial compressive strength (UCS) test, and mercury intrusion porosimetry test. The results demonstrated that the flow spread and UCS both increase first and then decrease with the increase of tailings fine content, while the yield stress shows an opposite trend. The fine content of tailings affects the flowability of fresh CPB mainly through the packing density. When the fine content is high, the influence of the specific surface area of tailings cannot be ignored. The packing density is an important factor affecting the strength of CPB, and there is an obvious linear relationship between the packing density and UCS. The pore structure of CPB samples with different tailing fine contents is significantly different, and the macroscopic packing density changes the strength of CPB by affecting the microscopic pores

Low SIRT3 Expression Correlates with Poor Differentiation and Unfavorable Prognosis in Primary Hepatocellular Carcinoma

<div><p>SIRT3, a mitochondrial sirtuin belonging to nicotinamide adenine nucleotide (NAD) dependent deacetylases, is implicated in metabolism, longevity and carcinogenesis. SIRT3 expression and its significance in hepatocellular carcinoma (HCC) remain largely unclear. In this study, we demonstrated that SIRT3 expression in HCC tissue was much lower than that in paracarcinoma tissue, at both mRNA and protein levels. The cutoff value for low SIRT3 expression in HCC was defined according to receiver operating characteristic curve (ROC) analysis. As disclosed by immunohistochemistry (IHC) results, low SIRT3 expression was present in 67.3% (167/248) of HCC cases. Furthermore, low expression of SIRT3 was significantly correlated to differentiation (<em>P</em> = 0.013), clinical stage (<em>P</em> = 0.005), serum AFP level (<em>P</em><0.01), tumor multiplicity (<em>P</em> = 0.026) and relapse (<em>P</em> = 0.028). Moreover, Kaplan-Meier analysis indicated that low SIRT3 expression associated with unfavorable overall survival (<em>P</em><0.01) and recurrence-free survival (<em>P</em> = 0.004). The prognostic impact of SIRT3 was further confirmed by stratified survival analysis. Importantly, multivariate analysis revealed that low SIRT3 expression was an independent poor prognostic marker for overall survival (Hazard Ratio (HR) 0.555, 95% confidence interval (95% CI) 0.344–0.897, <em>P</em> = 0.016). Collectively, we conclude that SIRT3 is decreased in HCC and is a novel unfavorable marker for prognosis of patients with this fatal disease.</p> </div

Univariate analysis of SIRT3 expression and clinicopathologic variables in 248 patients with primary hepatocellular carcinoma (log-rank test).

a<p>Mean age;</p><p>NR, not reached; HbsAg, hepatitis B surface antigen; AFP, alpha-fetoprotein.</p

Wafer−Scale Growth of Fe−Doped Hexagonal Boron Nitride (hBN) Films via Co−Sputtering

Fe−doped hBN film has great potential for use in spintronic applications. The wafer scale preparation of Fe−doped hBN films and their material properties are crucial for application in devices. In this work, Fe−doped films with 2−inch wafer scale were fabricated by magnetron co−sputtering, and the properties of the films were characterized. The crystal quality decreased, but the electrical performance was greatly improved. The average square resistance of Fe−doped film was 0.34 KΩ/sqr. Meanwhile, the Fe−doped films kept the characteristics of hBN well. The wavelength of absorption edge was 216 nm, and the corresponding optical band gap of 5.76 eV