BRD4 facilitates replication stress-induced DNA damage response.

Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. Here we describe a novel role for BRD4 in DNA damage response (DDR). BRD4 associates with and regulates the function of pre-replication factor CDC6 and plays an indispensable part in DNA replication checkpoint signaling. Inhibition of BRD4 by JQ1 or AZD5153 resulted in a rapid, time-dependent reduction in CHK1 phosphorylation and aberrant DNA replication re-initiation. Furthermore, BRD4 inhibition sensitized cancer cells to various replication stress-inducing agents, and synergized with ATR inhibitor AZD6738 to induce cell killing across a number of cancer cell lines. The synergistic interaction between AZD5153 and AZD6738 is translatable to in vivo ovarian cell-line and patient-derived xenograft models. Taken together, our study uncovers a new biological function of BRD4 and provides mechanistic rationale for combining BET inhibitors with DDR-targeted agents for cancer therapy

Chemical Analysis of Cellular and Extracellular Carbohydrates of a Biofilm-Forming Strain Pseudomonas aeruginosa PA14

Background: Pseudomonas aeruginosa is a Gram-negative bacterium and an opportunistic pathogen, which causes persisting life-threatening infections in cystic fibrosis (CF) patients. Biofilm mode of growth facilitates its survival in a variety of environments. Most P. aeruginosa isolates, including the non-mucoid laboratory strain PA14, are able to form a thick pellicle, which results in a surface-associated biofilm at the air-liquid (A\ufffdL) interface in standing liquid cultures. Exopolysaccharides (EPS) are considered as key components in the formation of this biofilm pellicle. In the non-mucoid P. aeruginosa strain PA14, the \ufffd\ufffdscaffolding\ufffd\ufffd polysaccharides of the biofilm matrix, and the molecules responsible for the structural integrity of rigid A\ufffdL biofilm have not been identified. Moreover, the role of LPS in this process is unclear, and the chemical structure of the LPS O-antigen of PA14 has not yet been elucidated. Principal Findings: In the present work we carried out a systematic analysis of cellular and extracellular (EC) carbohydrates of P. aeruginosa PA14. We also elucidated the chemical structure of the LPS O-antigen by chemical methods and 2-D NMR spectroscopy. Our results showed that it is composed of linear trisaccharide repeating units, identical to those described for P. aeruginosa Lanyi type O:2a,c (Lanyi-Bergman O-serogroup 10a, 10c; IATS serotype 19) and having the following structure: -4)-a-L-GalNAcA-(1\ufffd3)-a-D-QuiNAc-(1\ufffd3)- a-L-Rha-(1-. Furthermore, an EC O-antigen polysaccharide (EC O-PS) and the glycerol-phosphorylated cyclic b-(1,3)-glucans were identified in the culture supernatant of PA14, grown statically in minimal medium. Finally, the extracellular matrix of the thick biofilm formed at the A-L interface contained, in addition to eDNA, important quantities (at least ,20% of dry weight) of LPS-like material. Conclusions: We characterized the chemical structure of the LPS O-antigen and showed that the O-antigen polysaccharide is an abundant extracellular carbohydrate of PA14. We present evidence that LPS-like material is found as a component of a biofilm matrix of P. aeruginosa.Peer reviewed: YesNRC publication: Ye

Monitoring of risk perceptions and correlates of precautionary behaviour related to human avian influenza during 2006 - 2007 in the Netherlands: results of seven consecutive surveys

BACKGROUND: Avian influenza (AI) is a public health challenge because of ongoing spread and pandemic potential. Non-pharmaceutical measures are important to prevent the spread of AI and to contain a pandemic. The effectiveness of such measures is largely dependent on the behaviour of the population. Risk perception is a central element in changing behaviour. This study aimed to investigate perceived vulnerability, severity and precautionary behaviour related to AI in the Netherlands during seven consecutive surveys in 2006 - 2007 as well as possible trends in risk perception and self-reported precautionary behaviours. METHODS: Seven web-based surveys were conducted including 3,840 respondents over a one-year period. Time trends were analyzed with linear regression analyses. Multivariate analysis was used to study determinants of precautionary behaviour. RESULTS: While infection with AI was considered a very severe health problem with mean score of 4.57 (scale 1 - 5); perceived vulnerability was much lower, with a mean score of 1.69. While perceived severity remained high, perceived vulnerability decreased slightly during a one-year period covering part of 2006 and 2007. Almost half of the respondents (46%) reported taking one or more preventive measures, with 36% reporting to have stayed away from (wild) birds or poultry. In multivariate logistic regression analysis the following factors were significantly associated with taking preventive measures: time of the survey, higher age, lower level of education, non-Dutch ethnicity, vaccinated against influenza, higher perceived severity, higher perceived vulnerability, higher self efficacy, lower level of knowledge, more information about AI, and thinking more about AI. Self efficacy was a stronger predictor of precautionary behaviour for those who never or seldom think about AI (OR 2.3, 95% CI 1.9 - 2.7), compared to those who think about AI more often (OR 1.5, 95% CI 1.2 - 1.9). CONCLUSIONS: The fact that perceived severity of AI appears to be high and remains so over time offers a good point of departure for more specific risk communications to promote precautionary actions. Such communications should aim at improving knowledge about the disease and preventive actions, and focus on perceived personal vulnerability and self efficacy in taking preventive measures

Perceived risk, anxiety, and behavioural responses of the general public during the early phase of the Influenza A (H1N1) pandemic in the Netherlands: Results of three consecutive online surveys

Background: Research into risk perception and behavioural responses in case of emerging infectious diseases is still relatively new. The aim of this study was to examine perceptions and behaviours of the general public during the early phase of the Influenza A (H1N1) pandemic in the Netherlands. Methods. Two cross-sectional and one follow-up online survey (survey 1, 30 April-4 May; survey 2, 15-19 June; survey 3, 11-20 August 2009). Adults aged 18 years and above participating in a representative Internet panel were invited (survey 1, n = 456; survey 2, n = 478; follow-up survey 3, n = 934). Main outcome measures were 1) time trends in risk perception, feelings of anxiety, and behavioural responses (survey 1-3) and 2) factors associated with taking preventive measures and strong intention to comply with government-advised preventive measures in the future (survey 3). Results. Between May and August 2009, the level of knowledge regarding Influenza A (H1N1) increased, while perceived severity of the new flu, perceived self-efficacy, and intention to comply with preventive measures decreased. The perceived reliability of information from the government decreased from May to August (62% versus 45%). Feelings of anxiety decreased from May to June, and remained stable afterwards. From June to August 2009, perceived vulnerability increased and more respondents took preventive measures (14% versus 38%). Taking preventive measures was associated with no children in the household, high anxiety, high self-efficacy, more agreement with statements on avoidance, and paying much attention to media information regarding Influenza A (H1N1). Having a strong intention to comply with government-advised preventive measures in the future was associated with higher age, high perceived severity, high anxiety, high perceived efficacy of measures, high self-efficacy, and finding governmental information to be reliable. Conclusions. Decreasing tren

The dynamics of risk perceptions and precautionary behavior in response to 2009 (H1N1) pandemic influenza

<p>Abstract</p> <p>Background</p> <p>The trajectory of an infectious disease outbreak is affected by the behavior of individuals, and the behavior is often related to individuals' risk perception. We assessed temporal changes and geographical differences in risk perceptions and precautionary behaviors in response to H1N1 influenza.</p> <p>Methods</p> <p>1,290 US adults completed an online survey on risk perceptions, interests in pharmaceutical interventions (preventive intervention and curative intervention), and engagement in precautionary activities (information seeking activities and taking quarantine measures) in response to H1N1 influenza between April 28 and May 27 2009. Associations of risk perceptions and precautionary behaviors with respondents' sex, age, and household size were analyzed. Linear and quadratic time trends were assessed by regression analyses. Geographic differences in risk perception and precautionary behaviors were evaluated. Predictors of willingness to take pharmaceutical intervention were analyzed.</p> <p>Results</p> <p>Respondents from larger households reported stronger interest in taking medications and engaged in more precautionary activities, as would be normatively predicted. Perceived risk increased over time, whereas interest in pharmaceutical preventive interventions and the engagement in some precautionary activities decreased over time. Respondents who live in states with higher H1N1 incidence per population perceived a higher likelihood of influenza infection, but did not express greater interests in pharmaceutical interventions, nor did they engage in a higher degree of precautionary activities. Perceived likelihood of influenza infection, willingness to take medications and engagement in information seeking activities were higher for women than men.</p> <p>Conclusions</p> <p>Perceived risk of infection and precautionary behavior can be dynamic in time, and differ by demographic characteristics and geographical locations. These patterns will likely influence the effectiveness of disease control measures.</p

Outcomes and factors influencing survival in cirrhotic cases with spontaneous rupture of hepatocellular carcinoma: a multicenter study

<p>Abstract</p> <p>Background</p> <p>Spontaneous rupture is rare complication of hepatocellular carcinoma (HCC) with high mortality rate in cirrhotic cases. The aim of this study was to determine the factors influencing prognosis in cases of spontaneously ruptured HCC and to investigate the outcomes of the treatments employed, especially transcatheter arterial embolization (TAE).</p> <p>Methods</p> <p>A retrospective multicenter study was conducted in 48 cirrhotic patients with spontaneous rupture of HCC. Conservative treatment was employed in 32 patients (ConT group) and TAE was performed in 16 patients (TAE group).</p> <p>Results</p> <p>The median survival time (MST) in the ConT group was only 13.1 days and the survival rate was extremely poor: 59.4% at 7 days, 37.5% at 14 days, and 6.3% at 30 days. On the other hand, the MST in the TAE group was 244.8 days and the survival rate was 87.5% at 1 month, 56.3% at 3 months, 23.4% at 12 months, and 15.6% at 24 months. According to the results of univariate analyses, factors associated with poor hepatic function and poor suitability for TAE was important determinants of short-term death (less than 3 weeks) among the patients (<it>p </it>< 0.05). On the other hand, among the patients in whom initial TAE was successfully performed (<it>n </it>= 15), a multivariate analysis showed that a maximum tumor size not exceeding 7 cm was the only independent factor determining long-term survival (<it>p </it>= 0.0130).</p> <p>Conclusion</p> <p>Despite the inherent limitations of this retrospective study, TAE appears to be a useful treatment strategy for cirrhotic patients with spontaneous HCC rupture, as it yielded a longer survival period compared with conservative treatment in patients with ruptured HCC. Among the patients with ruptured HCC in whom initial TAE was successfully performed, the maximum tumor size was an important factor influencing survival.</p

Factors associated with influenza vaccination status of residents of a rural community in Japan

<p>Abstract</p> <p>Background</p> <p>The rate of influenza vaccination in Japan has declined over the past several decades. It is essential to identify community-specific factors that affect attitudes toward vaccination, but such parameters have not yet been fully determined in Japan. The present study used the Health Belief Model (HBM) to identify perceptions of influenza vaccination in a rural Japanese community.</p> <p>Methods</p> <p>All subjects were residents of a rural town in the southern part of Kyoto, Japan. An anonymous self-administered questionnaire was mailed to 846 randomly chosen households (containing 2,665 subjects). The survey explored gender, age, history of influenza, and factors associated with obtaining influenza vaccination, based on the HBM.</p> <p>Results</p> <p>A total of 1,182 valid responses (response rate, 44.4%) were received. Sources of information that were associated with vaccination decisions were medical facilities for children (OR = 4.21; 95% CI: 1.17-15.1), workplaces for adults (OR = 2.40; 95% CI: 1.22-4.75), medical facilities, town office and family for elderly subjects (OR = 6.18; 95% CI: 2.42-15.7, OR = 5.59; 95% CI: 2.26-13.8 and OR = 3.29; 95%CI: 1.01-10.6). Subjects, in all age groups, who strongly agreed that the vaccine was effective were significantly more likely to be vaccinated (OR = 10.5; 95%CI: 2.68-41.7 for children; OR = 8.85; 95%CI: 4.61-16.9 for adults; OR = 19.9; 95%CI: 8.28-48.0 for the elderly). The vaccination rate of elderly subjects who expressed concerns regarding adverse vaccine effects (OR = 0.34, 95% CI: 0.15-0.78) or who were worried about practical barriers to the vaccination process (OR = 0.13; 95% CI: 0.05-0.31) was significantly lower than in other populations.</p> <p>Conclusions</p> <p>Our results indicate that vaccination coverage can be increased if accurate information on personal risk, severity of influenza illness, and efficacy of vaccination are provided by responsible information sources that are easily accessible. Such sources include medical facilities and municipal offices. In addition, barriers and inconveniences associated with vaccination should be removed, especially if they impact on elderly people.</p

Mutual trust between leader and subordinate and employee outcomes

Stable and enduring cooperative relationships among people are primarily based on mutual trust. However, little evidence exists about the effects of mutual trust between supervisor and subordinate on work outcomes. To understand better the dynamics of trust in supervisor–subordinate relationships, we examined how mutual trust between supervisor and subordinate is associated with work outcomes. Based on a sample of 247 subordinate–supervisor pairs, multilevel analyses revealed a positive effect of perceived mutual trust on task performance and interpersonal facilitation after controlling for trust in leader and felt trust. In addition, task performance and interpersonal facilitation increased as trust in leader and felt trust or trust in subordinate both increased