Surface exploration of Amphibalanus amphitrite cyprids on microtextured surfaces

Microtopography is one of several strategies used by marine organisms to inhibit colonization by fouling organisms. While replicates of natural microtextures discourage settlement, details of larval interactions with the structured surfaces remain scarce. Close-range microscopy was used to quantify the exploration of cyprids of Amphibalanus amphitrite on cylindrical micropillars with heights of 5 and 30 μm and diameters ranging from 5 to 100 μm. While 5 μm-high structures had little impact, 30 μm-high pillars significantly influenced cyprid exploration. An observed step length decrease and step duration increase on 5 μm diameter pillars is attributed to the small dimensions of the voids excluding the cyprid's attachment disc and consequently reducing the area of adhesive contact. When exploring larger diameter pillars, cyprids preferred using the voids to form temporary attachment points. This may enhance their resistance to flow. No-choice assay settlement patterns mirrored this exploration behaviour, albeit in a pattern counter to what was predicted.     

Preclinical pharmacokinetics,pharmacodynamics, tissue distribution,and tumor penetration of anti-PD-L1 monoclonal antibody,an immune checkpoint inhibitor

MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose of the study reported here was to characterize the pharmacokinetics, pharmacodynamics, tissue distribution and tumor penetration of MPDL3280A and/or a chimeric anti-PD-L1 antibody PRO304397 to help further clinical development.

The pharmacokinetics of MPDL3280A in monkeys at 0.5, 5 and 20 mg·kg^?1 and the pharmacokinetics / pharmacodynamics of PRO304397 in mice at 1, 3 10 mg·kg^?1 were determined after a single intravenous dose. Tissue distribution and tumor penetration for radiolabeled PRO304397 in tumor-bearing mouse models were determined.

The pharmacokinetics of MPDL3280A and PRO304397 were nonlinear in monkeys and mice, respectively. Complete saturation of PD-L1 in blood in mice was achieved at serum concentrations of PRO304397 above ～0.5 µg·mL^?1. Tissue distribution and tumor penetration studies of PRO304397 in tumor-bearing mice indicated that the minimum tumor interstitial to plasma radioactivity ratio was ～0.3; saturation of target-mediated uptake in non–tumor tissues and desirable exposure in tumors were achieved at higher serum concentrations, and the distribution into tumors was dose-and time-dependent.

The biodistribution data indicated that the efficacious dose is mostly likely higher than that estimated based on simple pharmacokinetics/pharmacodynamics in blood. These data also allowed for estimation of the target clinical dose for further development of MPDL3280A.     

Circular RNA circABCC4 as the ceRNA of miR‐1182 facilitates prostate cancer progression by promoting FOXP4 expression

In recent years, circular RNAs (circRNAs) have been identified to be essential regulators of various human cancers. However, knowledge of the functions of circRNAs in prostate cancer remains very limited. The correlation between circABCC4 and human cancer is largely unknown. This study aims to investigate the biological functions of circABCC4 in prostate cancer progression and illustrate the underlying mechanism. We found that circABCC4 was remarkably up‐regulated in prostate cancer tissues and cell lines and promoted FOXP4 expression by sponging miR‐1182 in prostate cancer cells. CircABCC4 knockdown markedly suppressed prostate cancer cell proliferation, cell‐cycle progression, migration and invasion in vitro. Furthermore, silencing of the circRNA also delayed tumor growth in vivo. Taken together, our findings indicated that circABCC4 facilitates the malignant behaviour of prostate cancer by promoting FOXP4 expression through sponging of miR‐1182. The circABCC4–miR‐1182‐FOXP4 regulatory loop may be a promising therapeutic target for prostate cancer intervention.     

The mechanism involved in the loss of PTEN expression in NSCLC tumor cells

Loss of PTEN expression is observed in most non-small cell lung cancers (NSCLC). However, the mechanism by which PTEN expression is regulated in NSCLC has not been fully elucidated. In this study, we investigated the role of DNA methyltransferases (Dnmts), microRNA-29b (miR-29b), and anti-miR-29b inhibitor in PTEN promoter methylation and PTEN gene expression in H358 NSCLC cells in vitro and in vivo. PTEN mRNA was measured by RT-PCR. PTEN and Dnmts protein levels were measured by Western blot. miR-29b expression was detected by Northern blot. A xenograft H358 tumor mouse model was established by subcutaneously inoculating H358 cells into the right hind limbs of nude mice. We found that radiation induced cell apoptosis and hypomethylation in PTEN promoter, PTEN and miR-29b expression, and downregulation of Dnmt1, 3a and 3b expression in H358 tumor cells. The effect of radiation on gene expression and apoptosis was blocked by anti-miR-29b inhibitor. In the xenograft H358 tumor model, anti-miR-29b inhibitor reversed radiation-induced tumor growth delay, PTEN reexpression and downregulation of Dnmts expression. Our study suggested that miR-29b is an upstream molecule of PTEN. miR-29b regulates PTEN gene expression through downregulating Dnmts expression and subsequently induces hypomethylation in PTEN promoter. Targeting therapy could be established in NSCLC by upregulating miR-29b expression.     

Differential promoter activities of functional haplotypes in the 5′‐flanking region of human Sulfotransferase 1A1

Previously, we reported five common single nucleotide polymorphisms (SNPs), ?624G>C, ?396G>A, ?358A>C, ?341C>G, and ?294T>C, and six common haplotypes (CGACT, GAACT, GGAGC, GGACC, CAACT, and GAACC) in the 5′‐flanking region of the SULT1A1 gene that were associated with altered enzymatic activity. In the present study, we performed in vitro assays to determine the functional impact of these genetic variations on the promoter activity. Dual luciferase reporter assays revealed that these SNPs are located in a negative regulatory fragment of the SULT1A1 gene. Further experiments demonstrated that these SNPs and haplotypes affected promoter activities of SULT1A1. Electrophoretic mobility shift assays showed distinctive binding patterns for the SNPs ‐396G>A and ‐294T>C, due to differential binding affinities of the G/A alleles and the T/C alleles to nuclear proteins extracted from the liver carcinoma cell lines, HepG2 and Huh7. © 2012 Wiley Periodicals, Inc. J Biochem Mol Toxicol 26:422–428, 2012; View this article online at wileyonlinelibrary.com . DOI 10:1002/jbt.21437     

Cloning, sequence analysis and identification of a nonsense mutation-mediated mRNA decay of porcine GSTM2 gene

The glutathione S-transferase mu 2 gene （GSTM2） encodes a GST functioning in the elimination of electrophilic compounds and the regulation of cell growth. In this study, the sequence of porcine GSTM2 gene that contains the complete sequence encoding a protein of 218 amino acids was cloned. The deduced amino acid sequence shared 76%, 78% and 76% identity with that of human, mouse and rat, respectively, mRNA expression analysis showed that the porcine GSTM2 gene was expressed at a high level in liver and testis, at a medium level in longissimus dorsi muscle, adipose tissue, spleen and lung, at a low level in kidney, and at a very low level in heart and embryo. A nonsense mutation （CGA→TGA） resulted from C27T substitution in the fifth exon to produce a premature translation termination codon was identified, and it was discovered that nonsense-mediated mRNA decay might have an effect on the regulation of porcine GSTM2 gene expression. This polymorphism was analyzed in Large White, Landrace, Meishan and Qingping pig populations using the Taq I-polymerase chain reaction-restriction fragment length polymorphism method. The result showed that allele C had a higher frequency than allele T in each population.     

巴东过路黄中三萜皂苷及其体外抗肿瘤活性研究

从巴东过路黄(Lysimachia patungensis)95%乙醇提取物的正丁醇萃取部位中,分离到2个齐墩果烷型三萜皂苷,经光谱鉴定,分别为ardicrenin(1)和ardisiacrispinA(2)。体外抗肿瘤实验显示ardicrenin(1)对人脑胶质瘤(SWO-38)、口腔上皮癌(KB)、人乳腺癌(MCF-7)和人宫颈癌(Hela)细胞的半数毒性浓度(TC50)分别为3.16、3.16、2.97、2.42μmol/L,ArdisiacrispinA(2)对上述细胞的TC50分别为3.96、3.01、1.98、2.73μmol/L。