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The TBC1 domain family member 10B (EPI64B/TBC1D10B), a member of the RabGAP EPI64 subfamily, contains a TBC domain that confers GTPase-activating protein activity. Even though overexpression of TBC1D10B has been reported to promote tumor invasion and metastasis in gastric adenocarcinoma, the prognostic value of TBC1D10B and its correlation with DNA methylation and immune infiltration in hepatocellular carcinoma are still not known. Transcriptional expression profiles of TBC1D10B between hepatocellular carcinoma tissues and normal tissues were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus. The Clinical Proteomic Tumor Analysis Consortium and the Human Protein Atlas were used to assess the TBC1D10B protein expression. The biological functions of TBC1D10B were evaluated by the Metascape database and by Gene Set Enrichment Analysis (GSEA). Receiver operating characteristic (ROC) curve analysis was used to distinguish hepatocellular carcinoma from adjacent normal tissues. The effect of TBC1D10B on survival was estimated using the Kaplan–Meier method. DNA methylation in the TBC1D10B gene was assessed using the online MEXPRESS and MethSurv tools. The association between TBC1D10B mRNA expression and immune cell infiltration was investigated by the TIMER2 web server, tumor immune estimation resource and single-sample GSEA. This study found that TBC1D10B is highly expressed in hepatocellular carcinoma and that increased TBC1D10B mRNA expression is associated with female sex, lower Body Mass Index, high level of alpha fetal protein, and worse clinical stages. The mRNA and protein levels of TBC1D10B were verified in cells. Functional annotation indicated enrichment with negative regulation of the cell cycle, extracellular matrix, and corresponding pathways in the high-TBC1D10B phenotype. The ROC curve analysis showed that, with a cutoff level of 2.912, the accuracy, sensitive, and specificity in differentiate TBC1D10B hepatocellular carcinoma from adjacent controls were 0.931, 0.920, and 0.802, respectively. Kaplan–Meier survival analysis showed that hepatocellular carcinoma patients with high TBC1D10B had a worse prognosis than those with low TBC1D10B, especially in patients with a weight below 70 kg, height above 170 cm, and histological G2 and G3. We also found that the methylation of TBC1D10B was associated with the prognosis in patients with hepatocellular carcinoma. Moreover, correlation analysis indicated that TBC1D10B mRNA expression was positively correlated with infiltration levels of most immune cells, but negatively correlated with Th17 and cytotoxic cells infiltration. Our study indicates that increased TBC1D10B expression in hepatocellular carcinoma may play a role in tumorigenesis by regulating the cell cycle and extracellular matrix. TBC1D10B may be a novel prognostic and predictive marker and immune therapeutic target in hepatocellular carcinoma patients. [ABSTRACT FROM AUTHOR]

Background: Apigenin effectively inhibits the growth of human gastric carcinoma SGC-7901 cells and induces apoptosis as well. This study investigated the effects of ATF6 and PERK signaling pathways in unfolded protein response (UPR) and endoplasmic reticulum stress (ERS) on the apoptosis induced by apigenin in human gastric carcinoma SGC-7901 cells. Materials and Methods: SGC-7901 cells were cultured with apigenin and tunicamycin for 48 h or with apigenin for 12–48 h. CCK-8 was used to determine cell viability. The mRNA expression level was detected by RT-qPCR. The expression of related proteins was explored by Western blot. The apoptosis rate of cells and cell-cycle arrest were evaluated by flow cytometer. Results: The results of CCK-8 confirmed that apigenin could induce apoptosis of SGC-7901 cells. In the apigenin -treated cells group, the protein and mRNA levels of GRP78 and GRP94 dose- and time-dependently increased. Additionally, apigenin -activated UPR components PERK and ATF6. However, apigenin exerted no influence on CHOP expression or JNK activation. Pretreatment with 4-PBA significantly increased the apigenin -triggered apoptosis in SCG-7901 cells (p < 0.05). Conclusion: The results revealed the protective effect of UPR performance on apigenin -triggered apoptosis in SGC-7901 cells. [ABSTRACT FROM AUTHOR]

Objective: The use of growth factors to achieve closure of human traumatic tympanic membrane perforations (TMPs) has recently been demonstrated. However, pretreatment factors affecting healing outcomes have seldom been discussed. The objective of this study was to evaluate pretreatment factors contributing to the success or failure of healing of TMPs using fibroblast growth factor-2 (FGF-2).Design and participants: A retrospective cohort study of 99 patients (43 males, 56 females) with traumatic TMPs who were observed for at least 6 months after FGF-2 treatment between March 2011 and December 2012. Eleven factors considered likely to affect the outcome of perforation closure were evaluated statistically using univariate and multivariate logistic regression analysis.Interventions: Each traumatic TMP was treated by direct application of FGF-2.Main outcome measures: Complete closure versus failure to close.Results:In total, 99 patients were analyzed. The total closure rate was 92/99 (92.9%) at 6 months; the mean closure time was 10.59 ±  6.81 days. The closure rate did not significantly differ between perforations with or without inverted edges (100.0% vs. 91.4%,p = 0.087), among different size groups (p = 0.768), or among different periods of exposure to injury (p = 0.051). However, the closure rate was significantly different between the high- and low-dose FGF-2 groups (85.0% vs. 98.3%,p = 0.010) and between perforations where the umbo or malleus was or was not involved in perforation (85.4% vs. 98.3%,p = 0.012). Additionally, univariate logistic regression analysis tests showed that it was difficult to achieve healing of these perforations with a history of chronic otitis media or residual TM calcification (p = 0.006), the umbo or malleus was involved in perforation (p = 0.038), and with a high dose of FGF-2 (p = 0.035) compared with control groups. Multivariate logistic regression analysis showed that only a history of chronic otitis media and residual TM calcification and perforation close to the umbo or malleus were associated with non-healing of the TM perforation (p = 0.03 andp = 0.017, respectively) with relative risk factors.Conclusions: Direct application of FGF-2 can be used in all traumatic TMPs, the size of the perforation and inverted edges did not affect the closure rate, and the most beneficial dose was sufficient to keep the residual eardrum environment moist, but without adding liquid. Additionally, multivariate logistic regression analysis revealed that a large perforation was not a major risk factor for nonhealing of TM perforations. However, a history of chronic otitis media, residual TM calcification and involvement of the umbo or malleus in perforation were significant risk factors. [ABSTRACT FROM PUBLISHER]

A series of 1-phenyl-3,4-dihydroisoquinoline-3-carboxamide analogues 6 – 21 as selective PDE4B inhibitors were designed and synthesized based on structure-based drug design and fragment identification. Currently, it is in urgent need to develop novel selective PDE4 inhibitors with novel structural scaffolds to overcome the adverse effects and improve the efficacy. Novel 1-phenyl-3,4-dihydroisoquinoline amide derivatives were developed as potential PDE4 inhibitors based on the structure-based drug design and fragment identification strategy. A SARs analysis was performed in substituents attached in the C-3 side chain phenyl ring, indicating that the attachment of methoxy group or halogen atom substitution at the ortho -position of the phenyl ring was helpful to enhance both inhibitory activity toward PDE4B and selectivity. Compound 15 with excellent selectivity, exhibited the most potent inhibition in vitro and in vivo , which is a promising lead for development of a new class of selective PDE4 inhibitors. [ABSTRACT FROM AUTHOR]

This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNF α release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC 50 of 0.88 µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH 3 O group or CF 3 O group to the phenyl ring at the para- position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation. [ABSTRACT FROM AUTHOR]

Oligosaccharides have been used for an environmentally friendly insect control in the agricultural industry. In order to discover novel eco-friendly pesticides, a series of partially acetylated oligorhamnoses mezzettiasides, 2-8, and their analogues, 9-14, with biosurfactant characteristics were designed and synthesized, some of which exhibited comparable to or even stronger aphicidal activity than pymetrozine. Preliminary SAR studies demonstrated that the aphicidal activity of mezzettiasides analogs is highly dependent on their structures, including both the sugar length and the substitutes on the sugar. Among them, trirhamnolipid 9 displayed the strongest aphicidal activity, with an LC50 of 0.019 mmol/L, indicating that the biosurfactant 9 may have potential for use as an environmentally friendly agricultural pesticide. [ABSTRACT FROM AUTHOR]

[Display omitted] • Two series of cardo polyimides with high T g s and high transparency were prepared. • A new method to prepare PIs with alicyclic diamine to avoid salt formation was provided. • The DMPF base polyimide PI-IIa displayed high thermal properties with T g of 350 ℃ and high transparency with transmittance of 86% at 400 nm. Two series of transparent cardo polyimides (PIs) derived from bisphenol fluorenes and 1,4-bis(4-fluorophthalimide)cyclohexanes (BFCH) with different ratios of trans- and cis - 1,4-diaminocyclohexane were prepared via aromatic nucleophilic substitution. These PIs exhibited high glass transition temperatures (T g s) of 271–352 °C, 5% weight loss temperatures (T d 5%) of 400–433 °C in nitrogen, mechanical properties of tensile strengths of 62–107 MPa, tensile moduli of 3.0–4.4 GPa and elongations at break of 1.7–4.5% and great solubility in a variety of organic solvents. These PI films appeared excellent optical transparency, which displayed the cut-off wavelengths from 323 to 355 nm and high transmittance at 450 nm with more than 85 %. The steric effects of different substituent groups on bisphenol fluorene and different ratios of trans / cis configuration were also investigated. [ABSTRACT FROM AUTHOR]