Inhibition of yes-associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model.

Yes-associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030-BrM3(K-rasG12C mutation) and PC9-BrM3 (EGFRΔexon19 mutation) had a significantly decreased p-YAP(S127)/YAP ratio compared to parental H2030 (K-rasG12C mutation) and PC9 (EGFRΔexon19 mutation) cells (P < .05). H2030-BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P < .05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030-BrM3 cells (P < .05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030-BrM3 cells (P < .05). We are first to show that mice inoculated with YAP shRNA-transfected H2030-BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P < .05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030-BrM3 cell brain metastasis in a murine model

Ample Pairs

We show that the ample degree of a stable theory with trivial forking is preserved when we consider the corresponding theory of belles paires, if it exists. This result also applies to the theory of $H$-structures of a trivial theory of rank $1$.Comment: Research partially supported by the program MTM2014-59178-P. The second author conducted research with support of the programme ANR-13-BS01-0006 Valcomo. The third author would like to thank the European Research Council grant 33882

Selection and environmental adaptation along a path to speciation in the Tibetan frog Nanorana parkeri.

Tibetan frogs, Nanorana parkeri, are differentiated genetically but not morphologically along geographical and elevational gradients in a challenging environment, presenting a unique opportunity to investigate processes leading to speciation. Analyses of whole genomes of 63 frogs reveal population structuring and historical demography, characterized by highly restricted gene flow in a narrow geographic zone lying between matrilines West (W) and East (E). A population found only along a single tributary of the Yalu Zangbu River has the mitogenome only of E, whereas nuclear genes of W comprise 89-95% of the nuclear genome. Selection accounts for 579 broadly scattered, highly divergent regions (HDRs) of the genome, which involve 365 genes. These genes fall into 51 gene ontology (GO) functional classes, 14 of which are likely to be important in driving reproductive isolation. GO enrichment analyses of E reveal many overrepresented functional categories associated with adaptation to high elevations, including blood circulation, response to hypoxia, and UV radiation. Four genes, including DNAJC8 in the brain, TNNC1 and ADORA1 in the heart, and LAMB3 in the lung, differ in levels of expression between low- and high-elevation populations. High-altitude adaptation plays an important role in maintaining and driving continuing divergence and reproductive isolation. Use of total genomes enabled recognition of selection and adaptation in and between populations, as well as documentation of evolution along a stepped cline toward speciation

The distinct role of orbitofrontal and medial prefrontal cortex in encoding impulsive choices in an animal model of attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder affecting up to 5% of children worldwide. The lack of understanding of ADHD etiology prevented the development of effective treatment for the disease. Here, using in vivo electrophysiology recordings, we have recorded and analyzed the neuronal encoding of delay discounting behavior in prefrontal and orbitofrontal cortex of spontaneously hypertensive rat (SHR). We found that in the presence of rewards, neurons in the orbitofrontal cortex (OFC) were activated regardless to the value of the rewards and OFC neurons in SHR exhibited significantly higher rates of neuronal discharging towards the presence of rewards. While in the medial prefrontal cortex (mPFC), neurons of SHR responded similarly in the presence of large rewards compared with control rats whereas they displayed higher firing rates towards smaller rewards. In addition, the reward-predicting neurons in the OFC encodes for value of rewards in control animals and they were strongly activated upon receiving a small immediate reinforcer in the SHR whereas the reward-predicting neurons in the mPFC neurons generally did not respond to the value of the rewards. Our study characterized the neuronal discharging patterns of OFC and mPFC neurons in the SHR and the control animals and provided novel insights for further understanding the neuronal basis of ADHD pathology

Cytochrome P450 Metabolism of Betel Quid-Derived Compounds: Implications for the Development of Prevention Strategies for Oral and Pharyngeal Cancers

Betel quid (BQ) products, with or without tobacco, have been classified by the International Agency for Research on Cancer (IARC) as group I human carcinogens that are associated with an elevated risk of oral potentially malignant disorders (OPMDs) and cancers of the oral cavity and pharynx. There are estimated 600 million BQ users worldwide. In Taiwan alone there are 2 million habitual users (approximately 10% of the population). Oral and pharyngeal cancers result from interactions between genes and environmental factors (BQ exposure). Cytochrome p450 (CYP) families are implicated in the metabolic activation of BQ- and areca nut-specific nitrosamines. In this review, we summarize the current knowledge base regarding CYP genetic variants and related oral disorders. In clinical applications, we focus on cancers of the oral cavity and pharynx and OPMDs associated with CYP gene polymorphisms, including CYP1A1, CYP2A6, CYP2E1, and CYP26B1. Our discussion of CYP polymorphisms provides insight into the importance of screening tests in OPMDs patients for the prevention of oral and pharyngeal cancers. Future studies will establish a strong foundation for the development of chemoprevention strategies, polymorphism-based clinical diagnostic tools (e.g., specific single-nucleotide polymorphism (SNP) “barcodes”), and effective treatments for BQ-related oral disorders

Improving thermal stability and efficacy of BCNU in treating glioma cells using PAA-functionalized graphene oxide

Yu-Jen Lu1,2,#, Hung-Wei Yang1,#, Sheng-Che Hung3, Chiung-Yin Huang2, Shin-Ming Li4, Chen-Chi M Ma4, Pin-Yuan Chen2, Hong-Chieh Tsai2, Kuo-Chen Wei2, Jyh-Ping Chen1 1Department of Chemical and Materials Engineering, Chang Gung University, Kwei-San, Taoyuan, Taiwan; 2Department of Neurosurgery, Chang Gung Memorial Hospital, Kwei-San, Taoyuan, Taiwan; 3Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan; 4Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan#These authors contributed equally to this workBackground: 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a commercial chemotherapeutic drug for treating malignant brain tumors, has poor thermal stability and a short half-life. Immobilization of BCNU on a nanocarrier might increase the thermal stability of BCNU and extend its half-life.Methods: Nanosized graphene oxide (GO) could be modified by polyacrylic acid (PAA) to improve the aqueous solubility and increase the cell penetration efficacy of the nanocarrier. PAA–GO intended as a drug carrier for BCNU was prepared and characterized in this study. The size and thickness of PAA–GO was investigated by transmission electron microscopy and atomic force microscopy, and the presence of PAA functional groups was confirmed by electron spectroscopy for chemical analysis and thermogravimetric analysis. BCNU was conjugated to PAA–GO by covalent binding for specific killing of cancer cells, which could also enhance the thermal stability of the drug.Results: Single layer PAA–GO (about 1.9 nm) with a lateral width as small as 36 nm was successfully prepared. The optimum drug immobilization condition was by reacting 0.5 mg PAA–GO with 0.4 mg BCNU, and the drug-loading capacity and residual drug activity were 198 µg BCNU/mg PAA–GO and 70%, respectively. This nanocarrier significantly prolonged the half-life of bound BCNU from 19 to 43 hours compared with free drug and showed efficient intracellular uptake by GL261 cancer cells. The in vitro anticancer efficacy of PAA–GO–BCNU was demonstrated by a 30% increase in DNA interstrand cross-linking and a 77% decrease in the IC50 value toward GL261 compared with the same dosage of free drug.Conclusion: Nanosized PAA–GO serves as an efficient BCNU nanocarrier by covalent binding. This nanocarrier will be a promising new vehicle for an advanced drug delivery system in cancer therapy.Keywords: graphene oxide, BCNU, glioma cells, drug delivery, thermal stabilit

Trends and associated factors of HIV, HCV and syphilis infection among different drug users in the China-Vietnam border area: an 11-year cross-sectional study (2010-2020)

BACKGROUND: Data on recent human immunodeficiency virus (HIV), hepatitis C virus (HCV) and syphilis prevalence among drug users in the Southwest China are sparse despite the high burden of drug use. This study aims at assessing the prevalence trends and related factors of HIV, HCV and syphilis infection among different drug users in the China-Vietnam border area. METHODS: A continuous cross-sectional survey was conducted among drug users from 2010 to 2020 in the China-Vietnam border area. Chi-square trend tests were used to assess the trend of HIV, HCV and syphilis prevalence and the proportion for drug type used by drug users. Multivariate logistic regression was used to identify associated factors of HIV, HCV and syphilis infection in different drug users. RESULTS: In this study, a total of 28,951 drug users were included, of which 27,893 (96.45%) male, 15,660 (54.09%) aged 13-34 years, 24,543 (84.77%) heroin-only users, 2062 (7.12%) synthetic drug-only (SD-only) users and 2346 (8.10%) poly-drug users. From 2010 to 2020, the proportion of heroin-only users decreased from 87.79% to 75.46%, whereas SD-only users and poly-drug users increased from 5.16% to 16.03%, and from 7.05% to 8.52%, respectively. The prevalence of HIV, HCV, and syphilis during the study period declined from 12.76%, 60.37% and 5.72% to 4.35%, 53.29% and 4.53%, respectively, among heroin-only users and declined from 18.30%, 66.67% and 15.69% to 6.95%, 27.81% and 5.35%, respectively, among poly-drug users; however, the prevalence of HIV and HCV among SD-only users increased from 0.89% and 8.93% to 2.84% and 18.75%, respectively. Having ever injected drugs and needle sharing were common associated factors for both HIV and HCV infection among poly-drug users and heroin-only users. Aged ≥ 35 years old was an associated factor for HIV, HCV and syphilis infection among the SD-only users. Female drug users were at high risk of contracting syphilis among three different drug users. CONCLUSIONS: The prevalence of HIV, HCV and syphilis among heroin-only users and poly-drug users decreased during the study period. However, the prevalence of HIV and HCV among SD-only users increased. Comprehensive intervention strategies, particularly focusing on the SD-only users are needed in order to bring down the disease burden in this population in the China-Vietnam border areas

Crystallinity Improvement of ZnO Thin Film on Different Buffer Layers Grown by MBE

The material and optical properties of ZnO thin film samples grown on different buffer layers on sapphire substrates through a two-step temperature variation growth by molecular beam epitaxy were investigated. The thin buffer layer between the ZnO layer and the sapphire substrate decreased the lattice mismatch to achieve higher quality ZnO thin film growth. A GaN buffer layer slightly increased the quality of the ZnO thin film, but the threading dislocations still stretched along the c-axis of the GaN layer. The use of MgO as the buffer layer decreased the surface roughness of the ZnO thin film by 58.8% due to the suppression of surface cracks through strain transfer of the sample. From deep level emission and rocking curve measurements it was found that the threading dislocations play a more important role than oxygen vacancies for high-quality ZnO thin film growth