Mitochondrial uncoupling reveals a novel therapeutic opportunity for p53-defective cancers.

There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.

Acceptability of HPV vaccines and associations with perceptions related to HPV and HPV vaccines among male baccalaureate students in Hong Kong.

OBJECTIVES: The highly infectious human papillomavirus (HPV) causes both genital warts and cervical cancer in women. In 2009, the prevalence of genital warts in Hong Kong was 203.7 per 100,000 person-years. Cervical cancer, more seriously, was the eight most common cancer among women and girls in Hong Kong, accounting for 2.3% of all new cancer cases in females in 2014. Cervical cancer is a significant global public health problem and HPV is a major risk factor leading to the development of cervical cancer. HPV is also the most common sexually transmitted disease among university students. This is the first study to examine the acceptability of HPV vaccines and associations with perceptions related to HPV and HPV vaccines among the male baccalaureate student population locally. METHODS: A self-administrative cross-sectional survey was used to assess whether male baccalaureate students from eight local Hong Kong universities intended to be immunized for HPV. The study also asked questions concerning how its subjects perceived HPV and HPV vaccines using the Health Belief Model. Data collection spanned from June to September 2015. A multiple stepwise regression model was used to examine associations between cognitive factors and subjects' intention to take up the HPV vaccine. RESULTS: A total of 1,004 (83.7%) students aged 18 and 26 participated in this study. 23.3% found vaccinating for HPV acceptable, a level correlating with a number of indicators. Subjects were more likely to find vaccinating acceptable if 1) they knew something about HPV vaccines; 2) they understood that men were susceptible to infection by HPV; 3) they realised they could benefit by HPV vaccination, and 4) they were aware of the arguments for and against HPV vaccination, as disseminated by either the media or peers. CONCLUSIONS: HPV remains a significant public health concern in Hong Kong and China more broadly. This study's findings show a disconnect between the perceived and actual risk of being infected with the HPV vaccine among male baccalaureate students. This disconnect may be bridged by informing young men of the benefits of their being vaccinated against HPV, by removing the psychological and financial barriers that prevent them from taking up the vaccine and by improving how primary healthcare providers motivate them to get immunized.

Genomic and Phenotypic Analyses Reveal the Emergence of an Atypical Salmonella enterica Serovar Senftenberg Variant in China.

Human infections with Salmonella enterica subspecies enterica serovar Senftenberg are often associated with exposure to poultry flocks, farm environments, or contaminated food. The recent emergence of multidrug-resistant isolates has raised public health concerns. In this study, comparative genomics and phenotypic analysis were used to characterize 14 Salmonella Senftenberg clinical isolates recovered from multiple outbreaks in Shenzhen and Shanghai, China, between 2002 and 2011. Single-nucleotide polymorphism analyses identified two phylogenetically distinct clades of S Senftenberg, designated SC1 and SC2, harboring variations in Salmonella pathogenicity island 1 (SPI-1) and SPI-2 and exhibiting distinct biochemical and phenotypic signatures. Although the two variants shared the same serotype, the SC2 isolates of sequence type 14 (ST14) harbored intact SPI-1 and -2 and hence were characterized by possessing efficient invasion capabilities. In contrast, the SC1 isolates had structural deletion patterns in both SPI-1 and -2 that correlated with an impaired capacity to invade cultured human cells and also the year of their isolation. These atypical SC1 isolates also lacked the capacity to produce hydrogen sulfide. These findings highlight the emergence of atypical Salmonella Senftenberg variants in China and provide genetic validation that variants lacking SPI-1 and regions of SPI-2, which leads to impaired invasion capacity, can still cause clinical disease. These data have identified an emerging public health concern and highlight the need to strengthen surveillance to detect the prevalence and transmission of nontyphoidal Salmonella species.

Loss of Fas apoptosis inhibitory molecule leads to spontaneous obesity and hepatosteatosis.

Altered hepatic lipogenesis is associated with metabolic diseases such as obesity and hepatosteatosis. Insulin resistance and compensatory hyperinsulinaemia are key drivers of these metabolic imbalances. Fas apoptosis inhibitory molecule (FAIM), a ubiquitously expressed antiapoptotic protein, functions as a mediator of Akt signalling. Since Akt acts at a nodal point in insulin signalling, we hypothesize that FAIM may be involved in energy metabolism. In the current study, C57BL/6 wild-type (WT) and FAIM-knockout (FAIM-KO) male mice were fed with normal chow diet and body weight changes were monitored. Energy expenditure, substrate utilization and physical activities were analysed using a metabolic cage. Liver, pancreas and adipose tissue were subjected to histological examination. Serum glucose and insulin levels and lipid profiles were determined by biochemical assays. Changes in components of the insulin signalling pathway in FAIM-KO mice were examined by immunoblots. We found that FAIM-KO mice developed spontaneous non-hyperphagic obesity accompanied by hepatosteatosis, adipocyte hypertrophy, dyslipidaemia, hyperglycaemia and hyperinsulinaemia. In FAIM-KO liver, lipogenesis was elevated as indicated by increased fatty acid synthesis and SREBP-1 and SREBP-2 activation. Notably, protein expression of insulin receptor beta was markedly reduced in insulin target organs of FAIM-KO mice. Akt phosphorylation was also lower in FAIM-KO liver and adipose tissue as compared with WT controls. In addition, phosphorylation of insulin receptor substrate-1 and Akt2 in response to insulin treatment in isolated FAIM-KO hepatocytes was also markedly attenuated. Altogether, our data indicate that FAIM is a novel regulator of insulin signalling and plays an essential role in energy homoeostasis. These findings may shed light on the pathogenesis of obesity and hepatosteatosis.

Object tracking mask-based NLUT on GPUs for real-time generation of holographic videos of three-dimensional scenes.

A new object tracking mask-based novel-look-up-table (OTM-NLUT) method is proposed and implemented on graphics-processing-units (GPUs) for real-time generation of holographic videos of three-dimensional (3-D) scenes. Since the proposed method is designed to be matched with software and memory structures of the GPU, the number of compute-unified-device-architecture (CUDA) kernel function calls and the computer-generated hologram (CGH) buffer size of the proposed method have been significantly reduced. It therefore results in a great increase of the computational speed of the proposed method and enables real-time generation of CGH patterns of 3-D scenes. Experimental results show that the proposed method can generate 31.1 frames of Fresnel CGH patterns with 1,920 × 1,080 pixels per second, on average, for three test 3-D video scenarios with 12,666 object points on three GPU boards of NVIDIA GTX TITAN, and confirm the feasibility of the proposed method in the practical application of electro-holographic 3-D displays.

Highly cited articles in health care sciences and services field in Science Citation Index Expanded. A bibliometric analysis for 1958 - 2012.

OBJECTIVE: This study aimed to identify and analyze characteristics of highly cited articles published in the Web of Science category of health care sciences and services from 1958 to 2012. METHODS: Articles that have been cited at least 100 times were assessed regarding publication outputs, distribution of outputs in journals, publications of authors, institutions, countries as well as citation life cycles of the articles with the highest total citations since its publication up to 2012 and the highest citations in 2012. Six bibliometric indicators were used to evaluate source countries, institutions, and authors. Total citations from the time the articles were first published to the end of 2012 and citations in 2012 only were applied. Additionally, Y-index was applied to evaluate publication characteristics of authors. A high percentage of authors had the same numbers of first author and corresponding author status of highly cited articles in health care sciences and services field. RESULTS: RESULTS showed that 890 of the most highly referenced articles, published between 1977 and 2009, had been cited at least 100 times. Medical Care and Journal of General Internal Medicine published the most highly cited articles. The United States produced 76% of highly cited articles and also published the most number of independent, internationally collaborative, first authored, corresponding authored, and single author highly cited articles. The Harvard University was the most productive institute and was number one for the total highly cited articles, inter-institutionally collaborative articles, single institution articles, first author articles, and corresponding author articles. CONCLUSIONS: The application of quantitative techniques in the analysis of highly cited articles can improve the researchers' understanding of the directions in health care sciences and services field. Y-index is useful for the evaluation of contributing authors.

Neuroprotective effects of minocycline on double-stranded RNA-induced neurotoxicity in cultured cortical neurons.

1. Minocycline, memantine,and glycoconjugate were assessed for their ability to protect cultured primary cortical neurons against double-stranded RNA-induced neurotoxicity. 2. Minocycline but not memantine or glycoconjugate protected cultured cells and warrants further investigation.

A systemic review of human papillomavirus studies: global publication comparison and research trend analyses from 1993 to 2008.

The term "human papillomavirus" has been used as the keyword during searching titles, abstracts, and keywords based on the online version of Science Citation Index (SCI), Web of Science from 1993 to 2008. Twelve document types were found among the 14,943 papers published in 1,072 journals that were listed in 99 SCI subject categories. All the articles referring to human papillomavirus were assessed by using the following aspects: characteristics of publication output, distribution of output in journals, publication output of source country, source institute, and analysis of word clusters in title, author keywords, and keywords plus. The results have shown that the USA ranked first using five publication indicators including total, single country, international, first author, and corresponding author publications. China has had the sharpest rise of publications since 2004. The top four European countries in 2008 were France, Germany, the UK, and Italy, respectively. Trend studies with word cluster analysis were performed with regards to the areas of immunology, screening methodology, behavioral sciences, economics, and meta-analysis. All those areas have shown a sharp upward rise since 2004. In addition, hypermethylation-induced inactivation of the p16 gene in the early stages of oncogenesis has been getting more interest in recent years.

Functional recovery of diabetic mouse hearts by glutaredoxin-1 gene therapy: role of Akt-FoxO-signaling network.

Recent studies suggest that glutaredoxin-1 (Glrx-1) may serve as therapeutic target for diabetic hearts. As the level of reactive oxygen species (ROS) is increased in the pathologic hearts including ischemia/reperfusion (I/R) and diabetes, we assumed that upregulation of Glrx-1 could reduce the cardiac risk factors associated with I/R and/or diabetes. Diabetes was induced in mice by i.p. injection of streptozotocin (150 mg kg(-1)). Eight days after when the blood glucose was elevated to 400 mg per 100 ml, the animals were randomly assigned to one of the following three groups, which received either empty vector, or LacZ or Glrx-1 adenoviral construct. Four days later, isolated working hearts were subjected to 30 min ischemia followed by 2 h reperfusion. Glrx-1 gene therapy significantly enhanced the Glrx-1 level, which prevented I/R-mediated reduction of ventricular recovery, increased myocardial infarct size and cardiomyocyte apoptosis in diabetic myocardium. In concert, Glrx-1 prevented diabetes and ischemia-reperfusion induced reduction of cardioprotective proteins including Akt, FoxO-1, and hemeoxygenase-1, and abolished the death signal triggered by Jnk, p38 mitogen-activated protein kinase, and c-Src. Glrx-1 gene therapy seems to prevent cardiac complications in diabetic heart due to the I/R by switching the death signal into survival signal by activating Akt-FoxO-signaling network.

Porphyromonas gingivalis fimbriae-dependent interleukin-6 autocrine regulation by increase of gp130 in endothelial cells.

BACKGROUND AND OBJECTIVE: Local persistent infection by Porphyromonas gingivalis leads to inflammatory systemic diseases, such as atherosclerosis. We have reported previously that avirulent P. gingivalis fimbriae-dependent invasion into endothelial cells might be involved in progression of atherosclerosis. Although interleukin-6 (IL-6) regulates progression of atherosclerosis, little is known about the relationship of P. gingivalis fimbriae-dependent invasion to IL-6 regulation in endothelial cells. MATERIAL AND METHODS: We examined the secretion of IL-6 and the expression of the IL-6 signal transducer gp130 in human umbilical vein endothelial cells (HUVEC) infected with the wild-type FDC381 strain of P. gingivalisand a fimbriae-deficient mutant (fimA) by enzyme-linked immunosorbent assay, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry (fluorescence-activated cell sorting, FACS) analysis. RESULTS: Coculture of HUVEC with P. gingivalis resulted in increase of IL-6 secretion at 24 h postinfection. Interestingly, the increase was inhibited significantly in HUVEC infected with the P. gingivalis fimA mutant. In addition, the increase of IL-6 secretion induced by P. gingivalis infection was significantly impaired by the meiosis specific kinase 1 inhibitor, PD98059, or the nuclear factor kappaB inhibitor, Bay11-7082. Furthermore, we demonstrated that gp130 expression increased with P. gingivalis infection. Importantly, gp130 expression was significantly impaired by P gingivalis fimA mutant infection compared with wild-type P. gingivalis infection, as assessed by both quantitative RT-PCR and FACS analysis. CONCLUSION: Our findings indicate that P. gingivalis fimbriae are important factors in the autocrine regulation of IL-6, by increasing gp130 in endothelial cells.

Removal of Cr(VI) from aqueous solutions using agricultural waste 'maize bran'.

Novel biosorbent 'maize bran' has been successfully utilized for the removal of Cr(VI) from aqueous solution. The effect of different parameters such as contact time, sorbate concentration, pH of the medium and temperature were investigated and maximum uptake of Cr(VI) was 312.52 (mgg(-1)) at pH 2.0, initial Cr(VI) concentration of 200mgL(-1) and temperature of 40 degrees C. Effect of pH showed that maize bran was not only removing Cr(VI) from aqueous solution but also reducing toxic Cr(VI) into less toxic Cr(III). The sorption kinetics was tested with first order reversible, pseudo-first order and pseudo-second order reaction and it was found that Cr(VI) uptake process followed the pseudo-second order rate expression. Mass transfer of Cr(VI) from bulk to the solid phase (maize bran) was studied at different temperatures. Different thermodynamic parameters, viz., DeltaG degrees , DeltaH degrees and DeltaS degrees have also been evaluated and it has been found that the sorption was feasible, spontaneous and endothermic in nature. The Langmuir and Freundlich equations for describing sorption equilibrium were applied and it was found that the process was well described by Langmuir isotherm. Desorption studies was also carried out and found that complete desorption of Cr(VI) took place at pH of 9.5.

Age-dependent modulation of hippocampal long-term potentiation by antioxidant enzymes.

Oxidative stress has long been associated with normal aging and age-related neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, it is now evident that reactive oxygen species (ROS) such as superoxide (O(2-*)) and hydrogen peroxide (H(2)O(2)) also play pivotal roles in normal cell signaling. The focus of the present study was to examine the effects of the antioxidant enzymes CuZnSOD (SOD1) and catalase, which produce and remove H(2)O(2), respectively, on long-term potentiation (LTP) forms of synaptic plasticity during aging. Consistent wth previous studies, LTP, when induced in vitro in CA1 of the hippocampus with a high-frequency stimulation protocol, is significantly reduced in slices from older mice (22-26 months) relative to younger mice (2-4 months). Neither knockout of the endogenous catalase gene (Cat KO) nor acute enzymatic treatment with SOD1 altered LTP in slices from adult mice. Conversely, enzymatic applications of SOD1 inhibited LTP in slices from older mice. A much different set of results emerges with exogenous applications of catalase to hippocampal slices. Catalase significantly inhibited LTP in slices from adult mice but reversed age-related LTP deficits in slices from older mice. Measurements of H(2)O(2) showed that exogenous treatments with catalase lowered H(2)O(2) in synapse-enriched synaptoneurosome (SN) fractions prepared from adult mice. Notably, SNs from both Cat KO and old mice were deficient in removing extracellular challenges of H(2)O(2). Overall, the results suggest that dynamic alterations in extracellular H(2)O(2) metabolism affect synaptic plasticity in the hippocampus during aging.