Ral GEF with the PH Domain and SH3 Binding Motif 1 Regulated by Splicing Factor Junction Plakoglobin and Pyrimidine Metabolism Are Prognostic in Uterine Carcinosarcoma.

Uterine carcinosarcoma (UCS) is a highly invasive malignant tumor that originated from the uterine epithelium. Many studies suggested that the abnormal changes of alternative splicing (AS) of pre-mRNA are related to the occurrence and metastasis of the tumor. This study investigates the mechanism of alternative splicing events (ASEs) in the tumorigenesis and metastasis of UCS. RNA-seq of UCS samples and alternative splicing event (ASE) data of UCS samples were downloaded from The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases, several times. Firstly, we performed the Cox regression analysis to identify the overall survival-related alternative splicing events (OSRASEs). Secondly, a multivariate model was applied to approach the prognostic values of the risk score. Afterwards, a coexpressed network between splicing factors (SFs) and OSRASEs was constructed. In order to explore the relationship between the potential prognostic signaling pathways and OSRASEs, we fabricated a network between these pathways and OSRASEs. Finally, validations from multidimension platforms were used to explain the results unambiguously. 1,040 OSRASEs were identified by Cox regression. Then, 6 OSRASEs were incorporated in a multivariable model by Lasso regression. The area under the curve (AUC) of the receiver operator characteristic (ROC) curve was 0.957. The risk score rendered from the multivariate model was corroborated to be an independent prognostic factor (P < 0.001). In the network of SFs and ASEs, junction plakoglobin (JUP) noteworthily regulated RALGPS1-87608-AT (P < 0.001, R = 0.455). Additionally, RALGPS1-87608-AT (P = 0.006) showed a prominent relationship with distant metastasis. KEGG pathways related to prognosis of UCS were selected by gene set variation analysis (GSVA). The pyrimidine metabolism (P < 0.001, R = -0.470) was the key pathway coexpressed with RALGPS1. We considered that aberrant JUP significantly regulated RALGPS1-87608-AT and the pyrimidine metabolism pathway might play a significant part in the metastasis and prognosis of UCS.

Identification of prognostic and metastasis-related alternative splicing signatures in hepatocellular carcinoma.

As the most common neoplasm in digestive system, hepatocellular carcinoma (HCC) is one of the most important leading cause of cancer deaths worldwide. Its high-frequency metastasis and relapse rate lead to the poor survival of HCC patients. However, the mechanism of HCC metastasis is still unclear. Alternative splicing events (ASEs) have a great effect in cancer development, progression and metastasis. We downloaded RNA sequencing and seven types of ASEs data of HCC samples, in order to explore the mechanism of ASEs underlying tumorigenesis and metastasis of HCC. The data were taken from the The Cancer Genome Atlas (TCGA) and TCGASpliceSeq databases. Univariate Cox regression analysis was used to determine a total of 3197 overall survival-related ASEs (OS-SEs). And based on five OS-SEs screened by Lasso regression, we constructed a prediction model with the Area Under Curve of 0.765. With a good reliability of the model, the risk score was also proved to be an independent predictor. Among identified 390 candidate SFs, Y-box protein 3 (YBX3) was significantly correlated with OS and metastasis. Among 177 ASEs, ATP-binding cassette subfamily A member 6 (ABCA6)-43162-AT and PLIN5-46808-AT were identified both associated with OS, bone metastasis and co-expressed with SFs. Then we identified primary bile acid biosynthesis as survival-related (KEGG) pathway by Gene Set Variation Analysis (GSVA) and univariate regression analysis, which was correlated with ABCA6-43162-AT and PLIN5-46808-AT. Finally, we proposed that ABCA6-43162-AT and PLIN5-46808-AT may contribute to HCC poor prognosis and metastasis under the regulation of aberrant YBX3 through the pathway of primary bile acid biosynthesis.

Structure of a fucose-rich polysaccharide derived from EPS produced by Kosakonia sp. CCTCC M2018092 and its application in antibacterial film.

A novel exopolysaccharide (EPS) with high molecular weight (3.65 × 105 Da) and film-forming ability was produced by the strain Kosakonia sp. CCTCC M2018092. Partially acid hydrolyzed EPS (AH-EPS) with high content of fucose was prepared and exhaustively characterized. The molecular weight of AH-EPS was determined to be 3.47 × 104 Da. GC-MS and HPLC analyses indicated that AH-EPS is composed of L-fucose, d-glucose, D-galactose, D-glucuronic acid and pyruvic acid in the molar ratio of 2.03:1.00:1.18:0.64:0.67. Chemical and NMR analyses revealed that AH-EPS is an anionic heteropolysaccharide, with a major linkage structural motif as follows. Utilizing AH-EPS as reducing and stabilizing agent, silver nanoparticles (AH-EPS@Ag NPs) with uniform size (diameter about 20 nm) were synthesized through a green method. A hybrid film containing EPS and AH-EPS@Ag NPs was further prepared, and its antibacterial effectiveness to Staphylococcus aureus was confirmed. Taken together, this work revealed the structural characteristics of a novel fucose-rich polysaccharide, with good potential in developing new biodegradable antibacterial film.

A self-assembled, ROS-responsive Janus-prodrug for targeted therapy of inflammatory bowel disease.

A self-assembled and oxidation-degradable Janus-prodrug, termed as Bud-ATK-Tem (B-ATK-T), was fabricated by ROS-responsive aromatized thioketal (ATK) linked anti-inflammatory drug budesonide (Bud) and antioxidant tempol (Tem). Benefiting from the hydrophobic interactions and π-π stacking interactions of ATK, prodrug B-ATK-T could self-assemble into nanoparticles (NP) in water containing lecithin and DSPE-PEG2K. The morphology of B-ATK-T NP (approximate 100-120nm) was confirmed to be regular spherical by transmission electron microscope. B-ATK-T NP was endowed high drug loading content with 41.23% for Bud and 15.55% for Tem. The rapid drug release from B-ATK-T NP proceeded in an extensive reactive oxygen species (ROS)-dependent manner. More than 98% of Bud and Tem in B-ATK-T NP could release in the mimic inflammation microenvironment or phorbol-12-myristate-13-acetate (PMA)-stimulated macrophages within short time. The release of drugs in a simultaneous and proportional manner ensures that B-ATK-T NP can increase the combined efficacy of anti-inflammation and anti-oxidation. It is worth noting that B-ATK-T NP could be passively accumulated and dramatically increasing the maximum drugs concentration in the inflamed colon of mice with inflammatory bowel disease (IBD) by oral route, and avoiding potential systemic side effects. B-ATK-T NP could not only relieve colitis via inhibiting the expression of oxidative and proinflammatory mediators more than combination of free drugs, but also significantly reduce colitis-caused death. Taken together, the self-assembled, Janus-prodrug B-ATK-T NP is a promising candidate therapies for IBD, even for other inflammatory diseases.