Immunodominant PstS1 antigen of mycobacterium tuberculosis is a potent biological response modifier for the treatment of bladder cancer

BACKGROUND: Bacillus Calmette Guérin (BCG)-immunotherapy has a well-documented and successful clinical history in the treatment of bladder cancer. However, regularly observed side effects, a certain degree of nonresponders and restriction to superficial cancers remain a major obstacle. Therefore, alternative treatment strategies are intensively being explored. We report a novel approach of using a well defined immunostimulatory component of Mycobacterium tuberculosis for the treatment of bladder cancer. The phosphate transport protein PstS1 which represents the phosphate binding component of a mycobacterial phosphate uptake system is known to be a potent immunostimulatory antigen of M. tuberculosis. This preclinical study was designed to test the potential of recombinant PstS1 to serve as a non-viable and defined immunotherapeutic agent for intravesical bladder cancer therapy. METHODS: Mononuclear cells (PBMCs) were isolated from human peripheral blood and stimulated with PstS1 for seven days. The activation of PBMCs was determined by chromium release assay, IFN-γ ELISA and measurement of lymphocyte proliferation. The potential of PstS1 to activate monocyte-derived human dendritic cells (DC) was determined by flow cytometric analysis of the marker molecules CD83 and CD86 as well as the release of the cytokines TNF-α and IL-12. Survival of presensitized and intravesically treated, tumor-bearing mice was analyzed by Kaplan-Meier curve and log rank test. Local and systemic immune response in PstS1-immunotherapy was investigated by anti-PstS1-specific ELISA, splenocyte proliferation assay and immunohistochemistry. RESULTS: Our in vitro experiments showed that PstS1 is able to stimulate cytotoxicity, IFN-γ release and proliferation of PBMCs. Further investigations showed the potential of PstS1 to activate monocyte-derived human dendritic cells (DC). In vivo studies in an orthotopic murine bladder cancer model demonstrated the therapeutic potential of intravesically applied PstS1. Immunohistochemical analysis and splenocyte restimulation assay revealed that local and systemic immune responses were triggered by intravesical PstS1-immunotherapy. CONCLUSION: Our results demonstrate profound in vitro activation of human immune cells by recombinant PstS1. In addition, intravesical PstS1 immunotherapy induced strong local and systemic immune responses together with substantial anti-tumor activity in a preclinical mouse model. Thus, we have identified recombinant PstS1 antigen as a potent immunotherapeutic drug for cancer therapy

The activation of eco-driving mental models: can text messages prime drivers to use their existing knowledge and skills?

Eco-driving campaigns have traditionally assumed that drivers lack the necessary knowledge and skills and that this is something that needs rectifying. Therefore, many support systems have been designed to closely guide drivers and fine-tune their proficiency. However, research suggests that drivers already possess a substantial amount of the necessary knowledge and skills regarding eco-driving. In previous studies, participants used these effectively when they were explicitly asked to drive fuel-efficiently. In contrast, they used their safe driving skills when they were instructed to drive as they would normally. Hence, it is assumed that many drivers choose not to engage purposefully in eco-driving in their everyday lives. The aim of the current study was to investigate the effect of simple, periodic text messages (nine messages in 2 weeks) on drivers’ eco- and safe driving performance. It was hypothesised that provision of eco-driving primes and advice would encourage the activation of their eco-driving mental models and that comparable safety primes increase driving safety. For this purpose, a driving simulator experiment was conducted. All participants performed a pre-test drive and were then randomly divided into four groups, which received different interventions. For a period of 2 weeks, one group received text messages with eco-driving primes and another group received safety primes. A third group received advice messages on how to eco-drive. The fourth group were instructed by the experimenter to drive fuel-efficiently, immediately before driving, with no text message intervention. A post-test drive measured behavioural changes in scenarios deemed relevant to eco- and safe driving. The results suggest that the eco-driving prime and advice text messages did not have the desired effect. In comparison, asking drivers to drive fuel-efficiently led to eco-driving behaviours. These outcomes demonstrate the difficulty in changing ingrained habits. Future research is needed to strengthen such messages or activate existing knowledge and skills in other ways, so driver behaviour can be changed in cost-efficient ways

Antimicrobial peptides of the Cecropin-family show potent antitumor activity against bladder cancer cells

<p>Abstract</p> <p>Background</p> <p>This study evaluated the cytotoxic and antiproliferative efficacy of two well-characterized members of the Cecropin-family of antimicrobial peptides against bladder tumor cells and benign fibroblasts.</p> <p>Methods</p> <p>The antiproliferative and cytotoxic potential of the Cecropins A and B was quantified by colorimetric WST-1-, BrdU- and LDH-assays in four bladder cancer cell lines as well as in murine and human fibroblast cell lines. IC₅₀values were assessed by logarithmic extrapolation, representing the concentration at which cell viability was reduced by 50%. Scanning electron microscopy (SEM) was performed to visualize the morphological changes induced by Cecropin A and B in bladder tumor cells and fibroblasts.</p> <p>Results</p> <p>Cecropin A and B inhibit bladder cancer cell proliferation and viability in a dose-dependent fashion. The average IC₅₀values of Cecropin A and B against all bladder cancer cell lines ranged between 73.29 μg/ml and 220.05 μg/ml. In contrast, benign fibroblasts were significantly less or not at all susceptible to Cecropin A and B. Both Cecropins induced an increase in LDH release from bladder tumor cells whereas benign fibroblasts were not affected. SEM demonstrated lethal membrane disruption in bladder cancer cells as opposed to fibroblasts.</p> <p>Conclusion</p> <p>Cecropin A and B exert selective cytotoxic and antiproliferative efficacy in bladder cancer cells while sparing targets of benign murine or human fibroblast origin. Both peptides may offer novel therapeutic strategies for the treatment of bladder cancer with limited cytotoxic effects on benign cells.</p

Item Development and Face Validity of the Rheumatoid Arthritis Patient Priorities in Pharmacological Interventions Outcome Measures

© 2015, Springer International Publishing Switzerland. Background: The assessment of rheumatoid arthritis (RA) is dominated by core sets and indices that have been developed by RA professionals. Previous research developed a set of eight priority treatment outcomes generated by patients to complement the professionally developed core sets for RA. Objective: This study aimed to facilitate quantitative measurement of these outcomes. Methods: Two consultation meetings with patient research partners diagnosed with RA (n=18) were held to identify face validity in existing instruments (Phase 1) at the Bristol Royal Infirmary. Where validated measures did not exist, new numerical rating scales (NRS) were constructed and discussed at two focus groups with patients diagnosed with RA (n=8) at the Bristol Royal Infirmary and the Royal National Hospital for Rheumatic Diseases (Phase 2). Feedback on the stem question, time frame, anchors and layout was recorded and transcribed verbatim. Results: Of the eight priorities, existing NRS for pain, activities of daily living and fatigue were voted as acceptable (Phase 1), but new NRS were required for five priorities. The partners strongly recommended that the three separate domains of severity, effect and ability to cope in each measurement area be assessed, as in the existing validated fatigue NRS. Focus group participants (Phase 2) made significant contributions to the phrasing of questions, for example how to ensure ‘mobility’ could be uniformly understood and how changes in valued activities be judged appropriately. Conclusion: Through extensive patient feedback, 24 NRS were constructed based on priorities identified by patients and encompassing domains where existing questionnaires contain many more items and do not address three important concepts endorsed by patients: severity, effect and coping. The Rheumatoid Arthritis Patient Priorities in Pharmacological Interventions patient-reported outcome measures are now ready for the evaluation of comprehension, construct validity and sensitivity through an observational study

Pain in elderly people with severe dementia: A systematic review of behavioural pain assessment tools

BACKGROUND: Pain is a common and major problem among nursing home residents. The prevalence of pain in elderly nursing home people is 40–80%, showing that they are at great risk of experiencing pain. Since assessment of pain is an important step towards the treatment of pain, there is a need for manageable, valid and reliable tools to assess pain in elderly people with dementia. METHODS: This systematic review identifies pain assessment scales for elderly people with severe dementia and evaluates the psychometric properties and clinical utility of these instruments. Relevant publications in English, German, French or Dutch, from 1988 to 2005, were identified by means of an extensive search strategy in Medline, Psychinfo and CINAHL, supplemented by screening citations and references. Quality judgement criteria were formulated and used to evaluate the psychometric aspects of the scales. RESULTS: Twenty-nine publications reporting on behavioural pain assessment instruments were selected for this review. Twelve observational pain assessment scales (DOLOPLUS2; ECPA; ECS; Observational Pain Behavior Tool; CNPI; PACSLAC; PAINAD; PADE; RaPID; Abbey Pain Scale; NOPPAIN; Pain assessment scale for use with cognitively impaired adults) were identified. Findings indicate that most observational scales are under development and show moderate psychometric qualities. CONCLUSION: Based on the psychometric qualities and criteria regarding sensitivity and clinical utility, we conclude that PACSLAC and DOLOPLUS2 are the most appropriate scales currently available. Further research should focus on improving these scales by further testing their validity, reliability and clinical utility

Modelling the Costs and Effects of Selective and Universal Hospital Admission Screening for Methicillin-Resistant Staphylococcus aureus

Background: Screening at hospital admission for carriage of methicillin-resistant Staphylococcus aureus (MRSA) has been proposed as a strategy to reduce nosocomial infections. The objective of this study was to determine the long-term costs and health benefits of selective and universal screening for MRSA at hospital admission, using both PCR-based and chromogenic media-based tests in various settings. Methodology/Principal Findings: A simulation model of MRSA transmission was used to determine costs and effects over 15 years from a US healthcare perspective. We compared admission screening together with isolation of identified carriers against a baseline policy without screening or isolation. Strategies included selective screening of high risk patients or universal admission screening, with PCR-based or chromogenic media-based tests, in medium (5%) or high nosocomial prevalence (15%) settings. The costs of screening and isolation per averted MRSA infection were lowest using selective chromogenic-based screening in high and medium prevalence settings, at $4,100 and$10,300, respectively. Replacing the chromogenic-based test with a PCR-based test costs $13,000 and$36,200 per additional infection averted, and subsequent extension to universal screening with PCR would cost $131,000 and$232,700 per additional infection averted, in high and medium prevalence settings respectively. Assuming $17,645 benefit per infection averted, the most cost-saving strategies in high and medium prevalence settings were selective screening with PCR and selective screening with chromogenic, respectively. Conclusions/ Significance: Admission screening costs$4,100-$21,200 per infection averted, depending on strategy and setting. Including financial benefits from averted infections, screening could well be cost saving