A novel Hsp90 inhibitor AT13387 induces senescence in EBV-positive nasopharyngeal carcinoma cells and suppresses tumor formation

Background: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy strongly associated with Epstein-Barr virus (EBV). AT13387 is a novel heat shock protein 90 (Hsp90) inhibitor, which inhibits the chaperone function of Hsp90 and reduces expression of Hsp90-dependent client oncoproteins. This study aimed to evaluate both the in vitro and in vivo antitumor effects of AT13387 in the EBV-positive NPC cell line C666-1.Results: Our results showed that AT13387 inhibited C666-1 cell growth and induced cellular senescence with the downregulation of multiple Hsp90 client oncoproteins EGFR, AKT, CDK4, and restored the protein expression of negative cell cycle regulator p27. We also studied the ability of AT13387 to restore p27 expression by downregulation of AKT and the p27 ubiquitin mediator, Skp2, using AKT inhibitor and Skp2 siRNA. In the functional study, AT13387 inhibited cell migration with downregulation of a cell migration regulator, HDAC6, and increased the acetylation and stabilization of α-tubulin. We also examined the effect of AT13387 on putative cancer stem cells (CSC) by 3-D tumor sphere formation assay. AT13387 effectively reduced both the number and size of C666-1 tumor spheres with decreased expression of NPC CSC-like markers CD44 and SOX2. In the in vivo study, AT13387 significantly suppressed tumor formation in C666-1 NPC xenografts.Conclusion: AT13387 suppressed cell growth, cell migration, tumor sphere formation and induced cellular senescence on EBV-positive NPC cell line C666-1. Also, the antitumor effect of AT13387 was demonstrated in an in vivo model. This study provided experimental evidence for the preclinical value of using AT13387 as an effective antitumor agent in treatment of NPC. © 2013 Chan et al.; licensee BioMed Central Ltd.published_or_final_versio

Does China's public assistance scheme create welfare dependency? An assessment of the welfare of the Urban Minimum Living Standard Guarantee

In China, there are increasing concerns among the public and academics on welfare dependency caused the 'generous' of benefits of the Urban Minimum Living Standard Scheme (UMLSS). This study examines this issue by analysing the levels of the UMLSS according to international poverty measurements as well as reporting the life experiences of MLSS beneficiaries in Guangzhou city. It concludes that the UMLSS assistance is actually too low to reduce claimants’ work motivation. Instead, supplementary benefits associated with the UMLSS contributing to the recipients’ staying in China’s public assistance scheme in order to gain access to basic housing, health and educational services

Advances in Antisense Oligonucleotide Development for Target Identification, Validation, and as Novel Therapeutics

Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18–21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normally occurs only once. The potential applications of As-ODNs are numerous because mRNA is ubiquitous and is more accessible to manipulation than DNA. With the publication of the human genome sequence, it has become theoretically possible to inhibit mRNA of almost any gene by As-ODNs, in order to get a better understanding of gene function, investigate its role in disease pathology and to study novel therapeutic targets for the diseases caused by dysregulated gene expression. The conceptual simplicity, the availability of gene sequence information from the human genome, the inexpensive availability of synthetic oligonucleotides and the possibility of rational drug design makes As-ODNs powerful tools for target identification, validation and therapeutic intervention. In this review we discuss the latest developments in antisense oligonucleotide design, delivery, pharmacokinetics and potential side effects, as well as its uses in target identification and validation, and finally focus on the current developments of antisense oligonucleotides in therapeutic intervention in various diseases

Está insatisfeito com o seu chefe? Será devido a ele ou a si? O efeito que o locus de controlo tem na relação entre liderança e satisfação

Dissertação de Mestrado apresentada no ISPA - Instituto Universitário para a obtenção de grau de Mestre na especialidade de Psicologia Social e das Organizações.A presente investigação teve como objetivo estudar a relação que existe entre as variáveis Liderança, Satisfação com o Líder e Locus de Controlo, no âmbito organizacional. Sendo assim, o principal objetivo da investigação é estudar se a relação entre Liderança e Satisfação com o Supervisor é positiva ou negativa, e se o Locus de Controlo tem um efeito moderador nessa mesma relação. A amostra desta dissertação é composta por 149 trabalhadores (dos quais 68% são do género feminino) recrutados através do método snowball, e que têm supervisão direta. A avaliação da Liderança Transformacional e Transacional foi feita através do Questionário Multifatorial de Liderança (Salanova, Lorente, Chambel, & Martínez, 2011); a Satisfação com o Supervisor foi avaliada com recurso a parte do Questionário de Satisfação Laboral S20/23, (Pocinho e Garcia, 2008); e o Locus de Controlo foi medido através da escala MASLOC (Multidimensional Academic-Specific Locus of Control) (Barros, 1992). Os resultados indicam que existe uma relação positiva entre os dois estilos de Liderança e a Satisfação com o Supervisor. No entanto, o efeito de moderação do Locus de Controlo entre a Liderança e a Satisfação com o Supervisor não se verificou. No fim foram discutidas as implicações e limitações consideradas no presente estudo e foram feitas sugestões para estudos futuros.This research aimed to examine the relationship between Leadership, Satisfaction with Leadership, and Locus of Control in organizations. Specifically, this research tested if the relationship between leadership style and employees satisfaction with leadership is moderated by employees’ locus of control. Participants were 149 employees (68% of which were female), engaged in the current research through a snowball participant’s recruitment procedure. All participants had a direct supervisor. Transformational and transactional Leadership styles were measured using the Multifactorial Leadership Questionnaire (Salanova, Lorente, Chambel, & Martínez, 2011); Satisfaction with supervisor was assessed using part of the Satisfaction with Work Questionnaire (Pocinho & Garcia, 2008); and Locus of Control was measured using the MASLOC (Multidimensional Academic-Specific Locus of Control), (Barros, 1992). The research findings suggest that there is a positive relationship between supervisor’s Leadership style, and employees’ satisfaction with leadership. However, locus of control did not have any effect on this relationship. The study’s limitations and implications were also debated in the end of the dissertation

External Cesium-137 doses to humans from soil influenced by the Fukushima and Chernobyl nuclear power plants accidents: a comparative study

© 2020, The Author(s). External exposure to gamma-photon irradiation from soil contamination due to nuclear power plant (NPP) accidents has significant contribution to human radiation exposure in the proximity of the NPP. Detailed absorbed doses in human organs are rarely reported in the literature. We applied the Monte Carlo Neutron Particle (MCNP) transport code to calculate and compare the absorbed doses in different human organs. The absorbed doses by gamma-photon radiation were from cesium-137 (137Cs) in soil contaminated by the two major NPP accidents. More serious and wide-spread impacts of the Chernobyl NPP accident on soil contamination in Ukraine, Belarus, Russia and countries as far as Sweden and Greece were due to the inland location, radiative plume transport pathway and high 137Cs emission strength (9 times the Fukushima emission). Based on our MCNP calculations, the largest absorbed dose was found in skin. The maximum calculated external 137Cs annual effective dose received from the Chernobyl accident was 10 times higher relative to the Fukushima accident. Our calculated effective doses at various influenced areas were comparable to those available in the literature. The calculated annual effective doses at areas near the Fukushima and Chernobyl NPPs exceeded the ICRP recommendation of 1 mSv yr−1