Phosphodiesterase-4 Inhibition Alters Gene Expression and Improves Isoniazid – Mediated Clearance of Mycobacterium tuberculosis in Rabbit Lungs

Tuberculosis (TB) treatment is hampered by the long duration of antibiotic therapy required to achieve cure. This indolent response has been partly attributed to the ability of subpopulations of less metabolically active Mycobacterium tuberculosis (Mtb) to withstand killing by current anti-TB drugs. We have used immune modulation with a phosphodiesterase-4 (PDE4) inhibitor, CC-3052, that reduces tumor necrosis factor alpha (TNF-α) production by increasing intracellular cAMP in macrophages, to examine the crosstalk between host and pathogen in rabbits with pulmonary TB during treatment with isoniazid (INH). Based on DNA microarray, changes in host gene expression during CC-3052 treatment of Mtb infected rabbits support a link between PDE4 inhibition and specific down-regulation of the innate immune response. The overall pattern of host gene expression in the lungs of infected rabbits treated with CC-3052, compared to untreated rabbits, was similar to that described in vitro in resting Mtb infected macrophages, suggesting suboptimal macrophage activation. These alterations in host immunity were associated with corresponding down-regulation of a number of Mtb genes that have been associated with a metabolic shift towards dormancy. Moreover, treatment with CC-3052 and INH resulted in reduced expression of those genes associated with the bacterial response to INH. Importantly, CC-3052 treatment of infected rabbits was associated with reduced ability of Mtb to withstand INH killing, shown by improved bacillary clearance, from the lungs of co-treated animals compared to rabbits treated with INH alone. The results of our study suggest that changes in Mtb gene expression, in response to changes in the host immune response, can alter the responsiveness of the bacteria to antimicrobial agents. These findings provide a basis for exploring the potential use of adjunctive immune modulation with PDE4 inhibitors to enhance the efficacy of existing anti-TB treatment

Impact of lenalidomide dose on progression-free survival in patients with relapsed or refractory multiple myeloma

This analysis assessed the effect of lenalidomide on progression-free survival (PFS). Patients with relapsed or refractory multiple myeloma (RRMM) who received lenalidomide plus dexamethasone in the MM-009 and MM-010 trials were pooled and those who had not progressed and were still receiving lenalidomide at 12 months were included. The median follow-up of surviving patients was 48 months. Of 353 patients who received lenalidomide plus dexamethasone, 116 (33%) had not progressed. Overall, 52 patients (45%) had no dose reductions, 25 (22%) had dose reductions ⩾12 months and 39 (34%) had dose reductions before 12 months. Patients who had dose reductions ⩾12 months had a significantly longer median PFS than those who had reductions before 12 months (P=0.007) or no dose reductions (P=0.039) (not reached vs 28.0 vs 36.8 months, respectively). In a multivariate Cox regression model, dose reduction ⩾12 months was an independent predictor of improved PFS (hazard ratio, 0.47; 95% confidence interval, 0.23–0.98) after adjusting for patient characteristics. The data suggest that to achieve maximum PFS benefit, patients with RRMM should be treated for ⩾12 months with full-dose lenalidomide plus dexamethasone. Thereafter, patients may benefit from lower-dose continued therapy; prospective studies are needed to confirm these findings

The effectiveness of e-Learning on biosecurity practice to slow the spread of invasive alien species

Online e-Learning is increasingly being used to provide environmental training. Prevention measures including biosecurity are essential to reducing the introduction and spread of invasive alien species (IAS) and are central to international and national IAS policy. This paper is the first to evaluate the effectiveness of e-Learning as a tool to increase awareness, risk perception and biosecurity behaviour in relation to IAS among individuals conducting work activities or research (fieldwork) in the field. We surveyed participants (a mixture of students and professionals) before, and 6 months after undertaking an e-Learning course on IAS and biosecurity practices. Awareness of IAS and self-reported biosecurity behaviour increased after e-Learning among students and professionals. Students had a lower awareness of IAS than professionals before training (20% of students vs 60% of professionals), but after training students showed a greater increase in awareness which led to similar levels of awareness post-training (81%). Prior to training, risk perception was also lower amongst students than professionals (33% of students and 59% of professionals were aware of the risk that their activities posed to the accidental spread of IAS). There was no change in risk perception amongst professionals after training, however training led to a doubling of risk perception in students. E-Learning also led to an increase in reported biosecurity behaviour and cleaning practices and there were higher levels of biosecurity cleaning amongst professionals. The higher awareness and better biosecurity amongst professionals is likely to reflect their familiarity with the issues of IAS and day-to-day activities in the field. Our results suggest that e-Learning is an effective tool to raise awareness and encourage behaviour change among field workers and researchers in an attempt to reduce the risk of accidental introduction and spread of IAS

Rapidity and Centrality Dependence of Proton and Anti-proton Production from Au+Au Collisions at sqrt(sNN) = 130GeV

We report on the rapidity and centrality dependence of proton and anti-proton transverse mass distributions from Au+Au collisions at sqrt(sNN) = 130GeV as measured by the STAR experiment at RHIC. Our results are from the rapidity and transverse momentum range of |y|<0.5 and 0.35 <p_t<1.00GeV/c. For both protons and anti-protons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y|<0.5. Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton(anti-proton) yields and transverse mass distributions the possibility of pre-hadronic collective expansion may have to be taken into account.Comment: 4 pages, 3 figures, 1 table, submitted to PR

Phosphodiesterase 4 Inhibition Reduces Innate Immunity and Improves Isoniazid Clearance of Mycobacterium tuberculosis in the Lungs of Infected Mice

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is one of the leading infectious disease causes of morbidity and mortality worldwide. Though current antibiotic regimens can cure the disease, treatment requires at least six months of drug therapy. One reason for the long duration of therapy is that the currently available TB drugs were selected for their ability to kill replicating organisms and are less effective against subpopulations of non-replicating persistent bacilli. Evidence from in vitro models of Mtb growth and mouse infection studies suggests that host immunity may provide some of the environmental cues that drive Mtb towards non-replicating persistence. We hypothesized that selective modulation of the host immune response to modify the environmental pressure on the bacilli may result in better bacterial clearance during TB treatment. For this proof of principal study, we compared bacillary clearance from the lungs of Mtb-infected mice treated with the anti-TB drug isoniazid (INH) in the presence and absence of an immunomodulatory phosphodiesterase 4 inhibitor (PDE4i), CC-3052. The effects of CC-3052 on host global gene expression, induction of cytokines, and T cell activation in the lungs of infected mice were evaluated. We show that CC-3052 modulates the innate immune response without causing generalized immune suppression. Immune modulation combined with INH treatment improved bacillary clearance and resulted in smaller granulomas and less lung pathology, compared to treatment with INH alone. This novel strategy of combining anti-TB drugs with an immune modulating molecule, if applied appropriately to patients, may shorten the duration of TB treatment and improve clinical outcome

HelexKids:a word frequency database for Greek and Cypriot primary school children

In this article, we introduce HelexKids, an online written-word database for Greek-speaking children in primary education (Grades 1 to 6). The database is organized on a grade-by-grade basis, and on a cumulative basis by combining Grade 1 with Grades 2 to 6. It provides values for Zipf, frequency per million, dispersion, estimated word frequency per million, standard word frequency, contextual diversity, orthographic Levenshtein distance, and lemma frequency. These values are derived from 116 textbooks used in primary education in Greece and Cyprus, producing a total of 68,692 different word types. HelexKids was developed to assist researchers in studying language development, educators in selecting age-appropriate items for teaching, as well as writers and authors of educational books for Greek/Cypriot children. The database is open access and can be searched online at www.helexkids.org

Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers

We assessed the safety, tolerability and efficacy of the immunomodulatory drug, CC-5013 (REVIMID(TM)), in the treatment of patients with metastatic malignant melanoma and other advanced cancers. A total of 20 heavily pretreated patients received a dose-escalating regimen of oral CC-5013. Maximal tolerated dose, toxicity and clinical responses were evaluated and analysis of peripheral T-cell surface markers and serum for cytokines and proangiogenic factors were performed. CC-5013 was well tolerated. In all, 87% of adverse effects were classified as grade 1 or grade 2 according to Common Toxicity Criteria and there were no serious adverse events attributable to CC-5013 treatment. Six patients failed to complete the study, three because of disease progression, two withdrew consent and one was entered inappropriately and withdrawn from the study. The remaining 14 patients completed treatment without dose reduction, with one patient achieving partial remission. Evidence of T-cell activation was indicated by significantly increased serum levels of sIL-2 receptor, granulocyte- macrophage colony-stimulating factor, interleukin-12 (IL-12), tumour necrosis factor-alpha and IL-8 in nine patients from whom serum was available. However, levels of proangiogenic factors vascular endothelial growth factor and basic foetal growth factor were not consistently affected, This study demonstrates the safety, tolerability and suggests the clinical activity of CC-5013 in the treatment of refractory malignant melanoma. Furthermore, this is the first report demonstrating T-cell stimulatory activity of this class of compound in patients with advanced cancer

Exploring knowledge, perception of risk and biosecurity practices among researchers in the UK: a quantitative survey

Accidental introduction and/or spread of Invasive Non-Native Species (INNS) can result from a range of activities including agriculture, transport, trade and recreation. Researchers represent an important group of stakeholders who undertake activities in the field that could potentially facilitate the spread of INNS. Biosecurity is key to preventing the introduction and spread of INNS. Risk perceptions are a fundamental component in determining behaviour, so understanding how researchers perceive the risks associated with their activities can help us understand some of the drivers of biosecurity behaviour in the field. The aim of this study was to investigate researchers’ perceptions of risk in relation to their field activities and whether risk perceptions influenced behaviour. We gathered quantitative data on perceptions of risk and biosecurity practices using an online questionnaire. Only 35% of all respondents considered their field activities to pose some risk in terms of spreading INNS. Higher risk perception was found in those who undertook high risk activities or where INNS were known/expected to be present. However, whilst respondents with experience of INNS were more likely to report consciously employing biosecurity in the field, this did not translate into better actual biosecurity practices. Awareness of biosecurity campaigns did in fact increase perception of risk, perceived and actual biosecurity behaviour. However, there remains a disconnect between reported and actual biosecurity practices, including a lack of understanding about what constitutes good biosecurity practice. These findings should be used to improve targeted awareness raising campaigns and help create directed training on biosecurity practices