Drought legacy interacts with wildfire to alter soil microbial communities in a Mediterranean climate-type forest.

Mediterranean forest ecosystems will be increasingly affected by hotter drought and more frequent and severe wildfire events in the future. However, little is known about the longer-term responses of these forests to multiple disturbances and the forests' capacity to maintain ecosystem function. This is particularly so for below-ground organisms, which have received less attention than those above-ground, despite their essential contributions to forest function. We investigated rhizosphere microbial communities in a resprouting Eucalyptus marginata forest, southwestern Australia, that had experienced a severe wildfire four years previously, and a hotter drought eight years previously. Our aim was to understand how microbial communities are affected over longer-term trajectories by hotter drought and wildfire, singularly, and in combination. Fungal and bacterial DNA was extracted from soil samples, amplified, and subjected to high throughput sequencing. Richness, diversity, composition, and putative functional groups were then examined. We found a monotonic decrease in fungal, but not bacterial, richness and diversity with increasing disturbance with the greatest changes resulting from the combination of drought and wildfire. Overall fungal and bacterial community composition reflected a stronger effect of fire than drought, but the combination of both produced the greatest number of indicator taxa for fungi, and a significant negative effect on the abundance of several fungal functional groups. Key mycorrhizal fungi, fungal saprotrophs and fungal pathogens were found at lower proportions in sites affected by drought plus wildfire. Wildfire had a positive effect on bacterial hydrogen and bacterial nitrogen recyclers. Fungal community composition was positively correlated with live tree height. These results suggest that microbial communities, in particular key fungal functional groups, are highly responsive to wildfire following drought. Thus, a legacy of past climate conditions such as hotter drought can be important for mediating the responses of soil microbial communities to subsequent disturbance like wildfire.

Patient-reported outcomes predict survival and adverse events following anticancer treatment initiation in advanced HER2-positive breast cancer.

BACKGROUND: The prognostic value of patient-reported outcomes (PROs) has been minimally explored in advanced breast cancer (BC), and their comparative prognostic performance against Eastern Cooperative Oncology Group performance status (ECOG PS) is largely unknown. PATIENTS AND METHODS: This study pooled individual participant data from clinical trials CLEOPATRA, EMILIA, and MARIANNE. Pre-treatment PRO associations with overall survival (OS), progression-free survival (PFS), and grade ≥3 adverse events were evaluated via Cox proportional hazards regression. Prognostic performance was assessed with the C-statistic (c). PRO values were collected via the Functional Assessment of Cancer Therapy-Breast (FACT-B) questionnaire. All analyses were stratified by study and treatment arms. Analyses adjusted for known prognostic variables were conducted. Exploratory analysis of the prognostic performance of PROs compared to ECOG PS was undertaken. RESULTS: The study included data from 2894 patients initiated on contemporary therapies including pertuzumab (n = 765), trastuzumab (n = 1173), trastuzumab emtansine (n = 1225), taxanes (n = 1173), lapatinib (n = 496), and capecitabine (n = 496). On univariable and adjusted analysis, patient-reported physical well-being, functional well-being, and BC subscale were all identified to be associated with OS, PFS, and grade ≥3 adverse events (P < 0.05). Patient-reported physical well-being was the most prognostic PRO for all assessed outcomes. The OS prognostic performance of physical well-being (c = 0.58) was superior to ECOG PS (c = 0.56) (P < 0.05), with multivariable analysis indicating that both provide independent information (P < 0.0001). CONCLUSIONS: PROs were identified as independent prognostic factors for OS, PFS, and grade ≥3 adverse events in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced BC initiating contemporary treatment options. Further, patient-reported physical well-being was more prognostic of OS than ECOG PS and contained independent information. PROs have value as prognostic and stratification factors for clinical use and research trials of anticancer treatment in HER2-positive ABC.

Fluopyram Suppresses Population Densities of Heterodera glycines in Field and Greenhouse Studies in Michigan.

The soybean cyst nematode (SCN), Heterodera glycines Ichinohe, causes significant damage to soybean production annually. Fluopyram is a fungicide commonly used in soybean seed treatments intended to control soilborne fungal pathogens; however, recent studies have also suggested inhibitory effects on SCN. We examined the effects of a fluopyram seed treatment, ILeVO, on SCN reproduction, sudden death syndrome (SDS) development, and yield in a 3-year field study. Overall, fluopyram had a significant effect on yield (P = 0.046) and end-of-season SCN eggs and second-stage juveniles (Pf, P = 0.033) but no significant effect on SCN reproduction (Rf) or SDS disease index (P > 0.05). Post hoc tests indicated that fluopyram increased yield and suppressed SCN quantities. However, Rf was consistently greater than 1 whether or not the seed was treated with fluopyram, indicating that SCN populations were still increasing in the presence of fluopyram. A follow-up greenhouse study indicated that fluopyram reduced SCN relative to nontreated controls, as observed in the field, but only reduced SCN DNA within roots of a susceptible cultivar. These results indicate that fluopyram can suppress SCN quantities relative to nontreated seed but may not successfully reduce nematode populations without the use of additional management strategies.

Efficacy of Proximal Resin Infiltration on Caries Inhibition: Results from a 3-Year Randomized Controlled Clinical Trial.

This study reports 3-y outcomes of a split-mouth randomized clinical trial. Resin infiltration's capacity to arrest caries lesion progression in noncavitated proximal lesions is affirmed. Forty-two consented young adults, blinded to tooth surface allocation, were treated with resin infiltration on 1 randomly selected surface and concurrently experienced a mock infiltration procedure on another. Both treatments were provided as an adjunct to the currently accepted standard-of-care regimen (periodic prophylaxis and serial fluoride varnish applications) appropriate for the management of high caries risk. Challenging periods of low oral hygiene compliance were expected. The primary outcome measure was 3-y radiographic lesion progression. Blinded investigators evaluated each study surface for lesion progression with a series of images obtained at intervals over the 3-y course of study. Proportions of progressing lesions were compared with McNemar's test. Twenty-nine noncavitated lesion pairs in permanent posterior teeth demonstrating caries penetrating into inner enamel or outer dentin were included in the analyses. No adverse events were reported. Radiographic progression was recorded in 4 of 29 infiltrated lesions (14%) and 14 of 29 control lesions (48%, P < .003). Adjunct resin infiltration demonstrated a high 3-y efficacy of 71% (relative risk reduction). The prevented fraction was 86% for infiltration versus 52% for controls. Resin infiltration was 100% successful in arresting caries progression in inner enamel lesions (E2) and 64% in outer dentin lesions (D1). Supplementary microinvasive resin infiltration is significantly more efficacious in reducing proximal lesion progression than management by standard noninvasive therapy alone. Long-term results may shed light on whether this represents the arrest or delay of the caries disease process (ClinicalTrials.gov NCT01584024).

Dose-response of intrathecal morphine when administered with intravenous ketorolac for post-cesarean analgesia: a two-center, prospective, randomized, blinded trial.

BACKGROUND: The appropriate dose of intrathecal morphine for post-cesarean analgesia is unclear. With the inclusion of routine non-steroidal anti-inflammatory drugs, the required dose of morphine may be significantly less than the 200-300µg common a decade ago. We performed a two-center, prospective, randomized, blinded trial comparing three doses of intrathecal morphine, combined with routine intravenous ketorolac, in 144 healthy women undergoing elective cesarean delivery. METHODS: Patients received an intrathecal injection of hyperbaric bupivacaine 12mg, fentanyl 15µg and a randomized dose of 50, 100, or 150µg morphine in a volume of 2.2mL. Patients received intravenous ketorolac 30mg before leaving the operating room and 15mg intravenously every 6h for the duration of the study (24h). All received postoperative patient-controlled intravenous morphine. The primary endpoint was total intravenous morphine administered postoperatively over 24h, analyzed using mixed model regression. RESULTS: There were no differences between dose groups (or institutions) in intravenous morphine use over 24h. Visual analog scale scores for pain and nausea did not differ. Pruritus was greater in the 100 and 150µg groups than the 50µg group at 6h and 12h, but there was no difference between groups in nausea or pruritus treatments. Respiratory depression or significant sedation did not occur. CONCLUSION: The dose-response relationship of intrathecal morphine for multimodal post-cesarean analgesia suggests that 50µg produces analgesia similar to that produced by either 100µg or 150µg.

Interactive Pharmacometric Applications Using R and the Shiny Package.

Interactive applications, developed using Shiny for the R programming language, have the potential to revolutionize the sharing and communication of pharmacometric model simulations. Shiny allows customization of the application's user-interface to provide an elegant environment for displaying user-input controls and simulation output-where the latter simultaneously updates with changing input. The flexible nature of the R language makes simulations of population variability possible thus promoting the combination of Shiny with R in model visualization.

Semiphysiologically Based Pharmacokinetic Model of Leflunomide Disposition in Rheumatoid Arthritis Patients.

A semiphysiologically based pharmacokinetic (semi-PBPK) population model was used to evaluate the influence of enterohepatic recycling and protein binding, as well as the effect of genetic variability in CYP1A2, CYP2C19, and ABCG2, on the large interindividual variability of teriflunomide (active metabolite) concentrations following leflunomide administration in rheumatoid arthritis (RA) patients. The model was developed with total and free teriflunomide concentrations determined in RA patients taking leflunomide, as well as mean teriflunomide concentrations following the administration of leflunomide or teriflunomide extracted from the literature. Once developed, the 15-compartment model was able to predict total and free teriflunomide concentrations and was used to screen demographic and genotypic covariates, of which only fat-free mass and liver function (ALT) improved prediction. This approach effectively evaluated the effects of multiple covariates on both total and free teriflunomide concentrations, which have only been explored previously through simplistic one-compartment models for total teriflunomide.

Onchocerciasis control in the Democratic Republic of Congo (DRC): challenges in a post-war environment.

OBJECTIVE: To evaluate onchocerciasis control activities in the Democratic Republic of Congo (DRC) in the first 12 years of community-directed treatment with ivermectin (CDTI). METHODS: Data from the National Programme for Onchocerciasis (NPO) provided by the National Onchocerciasis Task Force (NOTF) through the annual reports of the 21 CDTI projects for the years 2001-2012 were reviewed retrospectively. A hypothetical-inputs-process-outputs-outcomes table was constructed. RESULTS: Community-directed treatment with ivermectin expanded from 1968 communities in 2001 to 39 100 communities by 2012 while the number of community-directed distributors (CDD) and health workers (HW) multiplied. By 2012, there were ratios of 1 CDD per 262 persons and 1 HW per 2318 persons at risk. More than 80% of the funding came from the fiduciary funds of the African Programme for Onchocerciasis Control. The cost of treatment per person treated fell from US$ 1.1 in 2001 to US$ 0.1 in 2012. The therapeutic coverage increased from 2.7% (2001) to 74.2% (2012); the geographical coverage, from 4.7% (2001) to 93.9% (2012). Geographical coverage fell in 2005 due to deaths in loiasis co-endemic areas, and the therapeutic coverage fell in 2008 due to insecurity. CONCLUSIONS: Challenges to CDTI in DRC have been serious adverse reactions to ivermectin in loiasis co-endemic areas and political conflict. Targets for personnel or therapeutic and geographical coverages were not met. Longer term funding and renewed efforts are required to achieve control and elimination of onchocerciasis in DRC.

Frameless stereotactic radiosurgery for the treatment of primary intracranial tumours in dogs.

Stereotactic radiosurgery (SRS) is a procedure that delivers a single large radiation dose to a well-defined target. Here, we describe a frameless SRS technique suitable for intracranial targets in canines. Medical records of dogs diagnosed with a primary intracranial tumour by imaging or histopathology that underwent SRS were retrospectively reviewed. Frameless SRS was used successfully to treat tumours in 51 dogs with a variety of head sizes and shapes. Tumours diagnosed included 38 meningiomas, 4 pituitary tumours, 4 trigeminal nerve tumours, 3 gliomas, 1 histiocytic sarcoma and 1 choroid plexus tumour. Median survival time was 399 days for all tumours and for dogs with meningiomas; cause-specific survival was 493 days for both cohorts. Acute grade III central nervous system toxicity (altered mentation) occurred in two dogs. Frameless SRS resulted in survival times comparable to conventional radiation therapy, but with fewer acute adverse effects and only a single anaesthetic episode required for therapy.

The rheumatoid arthritis susceptibility polymorphism PTPN22 C1858T is not associated with leflunomide response or toxicity.

WHAT IS KNOWN AND OBJECTIVE: A common polymorphism (C1858T) in the gene that encodes the protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with altered T-cell responses and increased susceptibility to rheumatoid arthritis (RA) and other autoimmune diseases. Teriflunomide, the active metabolite of leflunomide, reduces T-cell responses through inhibition of tyrosine kinase p56LCK. We examined a potential association between PTPN22 genotype and response or toxicity to leflunomide in Caucasian RA patients taking leflunomide in combination with other disease-modifying antirheumatic drugs (DMARDs). METHODS: Patients enrolled in the Royal Adelaide Hospital RA inception cohort and taking leflunomide were eligible for inclusion. Participants were followed for 12 months after leflunomide initiation or until either another DMARD was added or leflunomide was ceased. Clinical response according to change in 28-joint Disease Activity Score (DAS28) and cessation due to toxicity were assessed. RESULTS AND DISCUSSION: A total of 94 participants were included in the study, 75 of whom carried the CC genotype, 18 the CT, whereas one individual carried the TT genotype. Over the first 12 months of leflunomide treatment, there was no statistically significant relationship between carrying the T allele and change in DAS28 (-0·84 vs. -1·15, P = 0·446) nor with cessation of leflunomide treatment due to side effects (P = 0·433). These results indicate that PTPN22 C1858T genotype has no effect on response or toxicity outcomes in leflunomide-treated RA patients. WHAT IS NEW AND CONCLUSION: This is the first study to evaluate the biologically plausible hypothesis that PTPN22 genotype might be a predictor of response/toxicity to leflunomide therapy. Despite this, PTPN22 genotype was not associated with leflunomide response or toxicity in patients with RA.

An in vitro investigation of the cardiovascular effects of the 5-HT(4) receptor selective agonists, velusetrag and TD-8954.

The 5-HT(4) receptor agonists, and gastrointestinal (GI) prokinetic agents, cisapride and tegaserod, lack selectivity for the 5-HT(4) receptor. Cisapride is a potent human ether-à-go-go-related gene (hERG) potassium channel inhibitor while cisapride and tegaserod have significant affinity for 5-HT(1) and 5-HT(2) receptor subtypes. Marketing of both compounds was discontinued due to cardiovascular concerns (cardiac arrhythmias with cisapride and ischemic events with tegaserod). The reported association of tegaserod with ischemia has been postulated to involve coronary artery constriction or augmentation of platelet aggregation. This in vitro study investigated the effects of two of the new generation of highly selective 5-HT(4) receptor agonists, velusetrag and TD-8954, on canine, porcine and human coronary artery tone, human platelet aggregation and hERG potassium channel conductance. No significant off-target actions of velusetrag or TD-8954 were identified in these, and prior, studies. While cisapride inhibited potently the hERG channel currents, tegaserod failed to affect platelet aggregation, and had only a small contractile effect on the canine coronary artery at high concentrations. Tegaserod inhibited the 5-HT-induced contractile response in the porcine coronary artery. New generation 5-HT(4) receptor agonists hold promise for the treatment of patients suffering from GI motility disorders with a reduced cardiovascular risk.

Junctional adhesion molecule-A is co-expressed with HER2 in breast tumors and acts as a novel regulator of HER2 protein degradation and signaling.

Junctional adhesion molecule-A (JAM-A) is a membranous cell-cell adhesion protein involved in tight-junction formation in epithelial and endothelial cells. Its overexpression in breast tumors has recently been linked with increased risk of metastasis. We sought to identify if JAM-A overexpression was associated with specific subtypes of breast cancer as defined by the expression of human epidermal growth factor receptor-2 (HER2), estrogen receptor (ER) and progesterone receptor. To this end, JAM-A immunohistochemistry was performed in two breast cancer tissue microarrays. In parallel, cross-talk between JAM-A, HER2 and ER was examined in several breast cell lines, using complementary genetic and pharmacological approaches. High JAM-A expression correlated significantly with HER2 protein expression, ER negativity, lower patient age, high-grade breast cancers, and aggressive luminal B, HER2 and basal subtypes of breast cancer. JAM-A and HER2 were co-expressed at high levels in vitro in SKBR3, UACC-812, UACC-893 and MCF7-HER2 cells. Knockdown or functional antagonism of HER2 did not alter JAM-A expression in any cell line tested. Interestingly, however, JAM-A knockdown decreased HER2 and ER-α expression, resulting in reduced levels of phospho-(active) AKT without an effect on the extracellular signal-related kinase phosphorylation. The downstream effects of JAM-A knockdown on HER2 and phospho-AKT were partially reversed upon treatment with the proteasomal inhibitor MG132. We conclude that JAM-A is co-expressed with HER2 and associates with aggressive breast cancer phenotypes. Furthermore, we speculate that JAM-A may regulate HER2 proteasomal degradation and activity, potentially offering a promise as a therapeutic target in HER2-positive breast cancers.

Effects of oligosaccharides in a soybean meal-based diet on fermentative and immune responses in broiler chicks challenged with Eimeria acervulina.

Fermentable oligosaccharides, particularly those found in soybean meal (SBM), may modulate fermentation in the ceca, thus affecting intestinal immune responses to intestinal pathogens. We hypothesized that fermentable oligosaccharides found in SBM would positively affect cecal fermentation and intestinal immune status in chicks challenged with an acute coccidiosis (Eimeria acervulina) infection and fed either a SBM-based diet or a semi-purified soy protein isolate- (SPI) based diet. Using a completely randomized design, 1-d-old broiler chicks (n = 200; 5 replications/treatment; 5 chicks/replication) were assigned to 1 of 4 SBM- or SPI-based diets containing either dietary cellulose (4%) or a fermentable carbohydrate, galactoglucomannan oligosaccharide-arabinoxylan (GGMO-AX) complex (4%). On d 9 posthatch, an equal number of chicks on each diet were inoculated with either distilled water (sham control) or E. acervulina (1 × 10(6) oocysts) and then euthanized on d 7 postinoculation. Overall, body weight gain and feed intake were greater (P < 0.01) for SBM-fed chicks, regardless of infection status. Gain:feed ratio was greater (P ≤ 0.05) for SPI-fed chicks except during d 3-7 postinoculation. Infection status, but not fiber source, affected propionate, isobutyrate, isovalerate, and total branched-chain fatty acid concentrations (P ≤ 0.02). Soybean meal-based diets resulted in greater (P ≤ 0.04) short-chain fatty acid and branched-chain fatty acid concentrations than SPI-based diets. Messenger RNA fold changes relative to uninfected SBM-cellulose-fed chicks of all duodenal cytokines were greater (P ≤ 0.01) for infected chicks, and SBM-fed chicks had greater (P < 0.01) interferon-γ and interleukin-12ß expression compared with SPI-fed chicks. Cecal tonsil cytokine expression was also affected (P ≤ 0.02) by infection; however, protein source only affected (P < 0.01) interleukin-1ß expression in this tissue. Overall, a SBM-based diet, compared with a semi-purified SPI-based diet with a different ingredient composition, resulted in greater weight gain, feed intake, and short-chain fatty acid production regardless of infection status, and also greater duodenal cytokine expression in E. acervulina- infected chicks, which is hypothesized to be related to the nutrients and oligosaccharides found in SBM.

Ingestion of a novel galactoglucomannan oligosaccharide-arabinoxylan (GGMO-AX) complex affected growth performance and fermentative and immunological characteristics of broiler chicks challenged with Salmonella typhimurium.

Fermentable carbohydrates may enhance the ability of the gastrointestinal tract to defend against a pathogenic infection. We hypothesized that a galactoglucomannan oligosaccharide-arabinoxylan (GGMO-AX) complex would positively affect immune status and prevent colonization and shedding in Salmonella typhimurium-infected chicks. Using a completely randomized design, 1-d-old commercial broiler chicks (n = 240 chicks; 4 replications/treatment; 5 chicks/replication) were assigned to 1 of 6 dietary treatments differing in concentration of GGMO-AX (0, 1, 2, or 4%) or containing 2% Safmannan or 2% short-chain fructooligosaccharides. Cellulose was used to make diets iso-total dietary fiber. On d 10 posthatch, an equal number of chicks on each diet were inoculated with either phosphate-buffered saline (sham control) or Salmonella typhimurium (1 × 10(8) cfu). All birds were euthanized on d 10 postinoculation (PI) for collection of intestinal contents and select tissues. Body weight gain and feed intake of chicks were greater (P < 0.05) in infected chicks PI for all time periods, except for weight gain on d 0 to 3 PI. Gain:feed was affected (P < 0.05) by diet, with Safmannan-fed chicks having the highest G:F and 1% GGMO-AX-fed chicks having the lowest. The GGMO-AX substrate demonstrated effects similar to a prebiotic substrate as indicated by increased cecal short-chain fatty acid concentrations, decreased cecal pH, and increased populations of Lactobacillus spp. and Bifidobacteria spp. as dietary GGMO-AX concentration increased. Excreta Salmonella typhimurium populations on d 5 and 10 PI, and ileal and cecal Salmonella typhimurium populations, tended to be affected (P < 0.10) by the main effect of diet. Messenger RNA expression of IFN-γ in the cecal tonsils was the only cytokine independently affected by infection and diet (P < 0.01). Chicks fed 2 and 4% GGMO-AX had similar expressions of IFN-γ and IL-1ß, regardless of infection, suggesting that Salmonella typhimurium virulence was suppressed. Dietary supplementation with GGMO-AX resulted in prebiotic-like effects but did not limit Salmonella typhimurium intestinal colonization or shedding, but possibly decreased the virulence of Salmonella typhimurium within the digestive tract.

The effects of a galactoglucomannan oligosaccharide-arabinoxylan (GGMO-AX) complex in broiler chicks challenged with Eimeria acervulina.

Fermentable carbohydrates may enhance the ability of the gastrointestinal tract to defend against pathogenic infection. We hypothesized that a mannose-rich, galactoglucomannan oligosaccharide-arabinoxylan (GGMO-AX) complex would positively impact immune status and prevent weight loss resulting from acute coccidiosis (Eimeria acervulina) infection of chicks. Using a completely randomized design, 1-d-old commercial broiler chicks (n = 160; 4 replications/treatment; 5 chicks/replication) were assigned to one of 4 corn-soybean meal-based diets containing supplemental GGMO-AX (0, 1, 2, or 4%) that replaced dietary cellulose. On d 9 posthatch, an equal number of chicks on each diet were inoculated with either distilled water (sham control) or E. acervulina (1 × 10(6) oocysts). All birds were euthanized on d 7 postinoculation (PI) for collection of cecal contents and duodenal tissue. Overall, BW gain of chicks was not affected by diet PI, whereas infection decreased (P < 0.01) weight gain on d 0 to 7 PI. Feed intake was not affected by dietary treatment, but infection decreased (P < 0.01) feed intake on d 0 to 7 PI. Overall, infection, but not diet, decreased (P < 0.01) G:F on d 0 to 7 PI. Cecal propionate concentrations were independently affected by infection and diet, while butyrate concentrations were affected only by infection (P = 0.02). Cecal Bifidobacterium spp. populations were affected (P < 0.01) by diet, with the 2% GGMO-AX resulting in the highest cfu/g of cecal contents (on a DM basis). Messenger RNA expression of all duodenal cytokines evaluated was affected by infection status (P ≤ 0.02) but not by dietary treatment alone. Supplementing 4% GGMO-AX consistently resulted in the greatest fold change in proinflammatory cytokine expression, while inhibiting antiinflammatory cytokine expression, which indicates a more robust innate immune response. Despite decreasing performance, 4% dietary GGMO-AX improved select fermentation indices and the innate intestinal immune response to an acute E. acervulina infection.

Identification and evaluation of a potent novel ATR inhibitor, NU6027, in breast and ovarian cancer cell lines.

BACKGROUND: The ataxia telangiectasia mutated and Rad3-related kinase (ATR) has a key role in the signalling of stalled replication forks and DNA damage to cell cycle checkpoints and DNA repair. It has long been recognised as an important target for cancer therapy but inhibitors have proved elusive. As NU6027, originally developed as a CDK2 inhibitor, potentiated cisplatin in a CDK2-independent manner we postulated that it may inhibit ATR. METHODS: Cellular ATR kinase activity was determined by CHK1 phosphorylation in human fibroblasts with inducible dominant-negative ATR-kinase dead expression and human breast cancer MCF7 cells. Cell cycle effects and chemo- and radiopotentiation by NU6027 were determined in MCF7 cells and the role of mismatch repair and p53 was determined in isogenically matched ovarian cancer A2780 cells. RESULTS: NU6027 is a potent inhibitor of cellular ATR activity (IC(50)=6.7 µM) and enhanced hydroxyurea and cisplatin cytotoxicity in an ATR-dependent manner. NU6027 attenuated G2/M arrest following DNA damage, inhibited RAD51 focus formation and increased the cytotoxicity of the major classes of DNA-damaging anticancer cytotoxic therapy but not the antimitotic, paclitaxel. In A2780 cells sensitisation to cisplatin was greatest in cells with functional p53 and mismatch repair (MMR) and sensitisation to temozolomide was greatest in p53 mutant cells with functional MMR. Importantly, NU6027 was synthetically lethal when DNA single-strand break repair is impaired either through poly(ADP-ribose) polymerase (PARP) inhibition or defects in XRCC1. CONCLUSION: NU6027 inhibits ATR, impairing G2/M arrest and homologous recombination thus increasing sensitivity to DNA-damaging agents and PARP inhibitors. It provides proof of concept data for clinical development of ATR inhibitors.

SIMS(DAIRY): a modelling framework to identify sustainable dairy farms in the UK. Framework description and test for organic systems and N fertiliser optimisation.

Multiple demands are placed on farming systems today. Society, national legislation and market forces seek what could be seen as conflicting outcomes from our agricultural systems, e.g. food quality, affordable prices, a healthy environmental, consideration of animal welfare, biodiversity etc., Many of these demands, or desirable outcomes, are interrelated, so reaching one goal may often compromise another and, importantly, pose a risk to the economic viability of the farm. SIMS(DAIRY), a farm-scale model, was used to explore this complexity for dairy farm systems. SIMS(DAIRY) integrates existing approaches to simulate the effect of interactions between farm management, climate and soil characteristics on losses of nitrogen, phosphorus and carbon. The effects on farm profitability and attributes of biodiversity, milk quality, soil quality and animal welfare are also included. SIMS(DAIRY) can also be used to optimise fertiliser N. In this paper we discuss some limitations and strengths of using SIMS(DAIRY) compared to other modelling approaches and propose some potential improvements. Using the model we evaluated the sustainability of organic dairy systems compared with conventional dairy farms under non-optimised and optimised fertiliser N use. Model outputs showed for example, that organic dairy systems based on grass-clover swards and maize silage resulted in much smaller total GHG emissions per l of milk and slightly smaller losses of NO(3) leaching and NO(x) emissions per l of milk compared with the grassland/maize-based conventional systems. These differences were essentially because the conventional systems rely on indirect energy use for 'fixing' N compared with biological N fixation for the organic systems. SIMS(DAIRY) runs also showed some other potential benefits from the organic systems compared with conventional systems in terms of financial performance and soil quality and biodiversity scores. Optimisation of fertiliser N timings and rates showed a considerable scope to reduce the (GHG emissions per l milk too).

Public-private partnerships in neglected tropical disease control: the role of nongovernmental organisations.

Successful public-private partnerships for health control have usually included nongovernmental development organisations (NGDOs), and these have long been in the forefront of pinpointing particular social and health issues. The immensely successful control and elimination programmes for onchocerciasis are a case in point. NGDOs were the driving force in early advocacy for onchocerciasis control in West Africa, leading eventually to the remarkably effective and long lasting partnership of the Onchocerciasis Control Programme (OCP). With the donation of Mectizan(®), NGDOs were the driving force in developing onchocerciasis control in non-OCP countries, especially programmes for community based action. These were, further modified by the African Programme for Onchocerciasis Control (APOC) to become the successful Community Directed Interventions. NGDOs came together to coordinate activities in partnership with the World Health Organisation (WHO). Innovations by NGDOs led to integration of mass drug administration for Vitamin A deficiency and then for other parasitic diseases, leading to the current trend of preventive chemotherapy. The success of the NGDO Group for Onchocerciasis Control has led to the creation of similar groups for trachoma control and lymphatic filariasis elimination. These groups have now come together to form an NGDO Network for Neglected Tropical Disease control.