Yes-associated protein (YAP) is a downstream effector of the Hippo signaling pathway, which controls organ expansion and tissue development. We have recently defined the tumorigenic potential and ...clinical significance of the YAP1 oncogene in human hepatocellular carcinoma (HCC). The present study aims to define the tumorigenic properties of YAP in HCC and elucidate the related downstream signaling mechanism. In a gain-of-function study, we demonstrated that ectopic increased expression of YAP in the immortalized non-tumorigenic hepatocyte cell line MIHA confers tumorigenic and metastatic potentials, as evidenced by (1) enhanced aptitudes in cell viability, anchorage-independent growth, migration and invasion; (2) tumor formation in a xenograft mouse model; and (3) induction of HCC biomarker α-fetoprotein and activation of mitogen-activated protein kinase. Furthermore, we have identified AXL, a receptor tyrosine kinase, as a key downstream target that drives YAP-dependent oncogenic functions. RNAi-mediated knockdown of AXL expression decreased the ability of YAP-expressing MIHA cells and of the primary HCC cell line to proliferate and invade. These results indicate that AXL is a mediator of YAP-dependent oncogenic activities and implicates it as a potential therapeutic target for HCC.
Practical, efficient synthesis of metal oxide nanocrystals with good crystallinity and high specific surface area by a modified polymer-network gel method is demonstrated, taking ZnO nanocrystals as ...an example. A novel stepwise heat treatment yields significant improvement in crystal quality. Such nanophase materials can effectively degrade common organic dyes under solar radiation and can perform very well in photo-assisted detection of NO
gas. Other typical metal oxide nanocrystals with good crystallinity and high specific surface area were also synthesized successfully under similar conditions. This work provides a general strategy for the synthesis of metal oxide nanocrystals, balancing the crystallinity and specific surface area.
Two types of scanning strategies were adopted to study the effect of scanning strategy, i.e., bidirectional scanning without (SS-X) and with 45° deviation from X/Y-axis and 90° rotation (SS-XY45) ...between adjacent layers, on microstructure and mechanical properties of reduced activation ferritic/martensitic (RAFM) steel fabricated by selective laser melting (SLM). The SLM-built RAFM steel exhibited a better combination of strength and ductility than the previously reported counterparts. The SS-X had higher yield strength of 911 MPa and higher elongation of 18.7% than the SS-XY with yield strength of 893 MPa and elongation of 15.0%. The results reveal that the variation in the yield strength was mainly ascribed to the different grain size and the improved ductility was associated with the modified grain structure that altered the tensile fracture mode with concurrent occurrence of intergranular brittle and transgranular ductile fracture. This finding provides an alternative to fabricate high-performance RAFM steel by tailoring the microstructure with different scanning strategies.
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•The SLMed CLF-1 steel exhibited a superior combination of strength and ductility.•Scanning strategy modified the grain size and morphology of bimodal microstructure.•The variation in yield strength was mainly ascribed to different grain size.•The improved ductility was associated with altered tensile fracture mode.
In addition to protein-coding genes, the human genome makes a large amount of noncoding RNAs, including microRNAs and long noncoding RNAs (lncRNAs). Both microRNAs and lncRNAs have been shown to have ...a critical role in the regulation of cellular processes such as cell growth and apoptosis, as well as cancer progression and metastasis. Although it is well known that microRNAs can target a large number of protein-coding genes, little is known whether microRNAs can also target lncRNAs. In the present study, we determine whether miR-21 can regulate lncRNA expression. Using the lncRNA RT-PCR (reverse transcription-polymerase chain reaction) array carrying 83 human disease-related lncRNAs, we show that miR-21 is capable of suppressing the lncRNA growth arrest-specific 5 (GAS5). This negative correlation between miR-21 and GAS5 is also seen in breast tumor specimens. Of interest, GAS5 can also repress miR-21 expression. Whereas ectopic expression of GAS5 suppresses, GAS5-siRNA increases miR-21 expression. Importantly, there is a putative miR-21-binding site in exon 4 of GAS5; deletion of the miR-21-binding site abolishes this activity. Experiments with in vitro cell culture and xenograft mouse model suggest that GAS5 functions as a tumor suppressor. We further show that the biotin-labeled GAS5-RNA probe is able to pull down the key component (AGO2) of the RNA-induced silencing complex (RISC) and we subsequently identify miR-21 in this GAS5-RISC complex, implying that miR-21 and GAS5 may regulate each other in a way similar to the microRNA-mediated silencing of target mRNAs. Together, these results suggest that miR-21 targets not only tumor-suppressive protein-coding genes but also lncRNA GAS5.
Highlights • Tourette syndrome is associated with reduced interneurons in the striatum. • We performed targeted ablation of parvalbumin neurons in the striatum in adult mice. • Interneuronal ablation ...produced increased grooming after acute stress. • Interneuronal ablation also produced elevated anxiety-like behavior. • This supports a causal contribution of interneuronal deficits to movement disorders.
This randomized, double‐blind, placebo‐controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. ...Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26–30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine‐treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo‐treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine‐treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine‐treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.
Purpose
To investigate whether growth hormone (GH) could improve pregnancy rates of patients with thin endometrium by clinical study and laboratory experiments.
Materials and methods
Ninety-three ...patients were randomized to either the GH-received group (40) or the routine exogenous administration of estrogens control group (53) for clinical study. The human endometrial carcinoma cell line RL95-2 was used for testing the role of GH with Western blot and real-time PCR by exposure to various concentrations of GH (0.1 nM,1 nM,10 nM,100 nM).
Results
Patients treated with GH had a significantly (
P
< 0.05) greater endometrium thickness on day 3 (7.87±0.72 vs 6.34±0.86), higher implantation rates (24.4% vs 10.5%) and greater clinical pregnancy rates (42.5% vs 18.9%) compared with the control group. No adverse events were associated with the use of GH. Administration of GH significantly up-regulated the expression of VEGF, ItgB3 and IGF-I expression in RL95-2 cells at both mRNA and protein levels (
P
< 0.05). AG490, an inhibitor of JAK2, nearly completely inhibited the up-regulative effect of GH through the JAK2-STAT5 pathway, and GH-induced effects could be mediated through autocrine IGF-I together with its hepatic counterpart. IGF-I mRNA was detected in the RL95-2 cells.
Conclusion
GH may improve pregnancy outcomes of patients with thin endometrium who undergo frozen embryo transfer by acting on human endometrial cells to promote proliferation and vascularization and to up-regulate receptivity-related molecular expression.
The role that changes in DNA methylation and histone modifications have in human malignancies is poorly understood. p300 and CREB-binding protein (CBP), two distinct but highly homologous lysine ...acetyltransferases, are mutated in several cancers, suggesting their role as tumor suppressors. In the current study, we found that deletion of p300, but not CBP, markedly accelerated the leukemogenesis ofNup98-HoxD13 (NHD13) transgenic mice, an animal model that phenotypically copies human myelodysplastic syndrome (MDS). p300 deletion restored the ability of NHD13 expressing hematopoietic stem and progenitor cells (HSPCs) to self-renew in vitro, and to expand in vivo, with an increase in stem cell symmetric self-renewal divisions and a decrease in apoptosis. Furthermore, loss of p300, but not CBP, promoted cytokine signaling, including enhanced activation of the MAPK and JAK/STAT pathways in the HSPC compartment. Altogether, our data indicate that p300 has a pivotal role in blocking the transformation of MDS to acute myeloid leukemia, a role distinct from that of CBP.
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