Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites

N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex

Peptidomimetic inhibitors of N-myristoyltransferase from human malaria and leishmaniasis parasites

N-Myristoyltransferase (NMT) has been shown to be essential in Leishmania and subsequently validated as a drug target in Plasmodium. Herein, we discuss the use of antifungal NMT inhibitors as a basis for inhibitor development resulting in the first sub-micromolar peptidomimetic inhibitors of Plasmodium and Leishmania NMTs. High-resolution structures of these inhibitors with Plasmodium and Leishmania NMTs permit a comparative analysis of binding modes, and provide the first crystal structure evidence for a ternary NMT-Coenzyme A/myristoylated peptide product complex

Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity

In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy.We also thank the University of Cambridge, Cancer Research UK, the CRUK Cambridge Institute Core Facilities, and Hutchison Whampoa Limited. This work was also supported by the Lustgarten Foundation for Pancreatic Cancer Research, the Ludwig Institute for Cancer Research, the NIHR Biomedical Research Centre, and the Cambridge ECMC. T.R.F. was supported by the Rosetrees Trust and the Cambridge School of Clinical Medicine’s MB/PhD Programme, T.J. was supported by the Wellcome Trust Translational Medicine and Therapeutics Programme and the University of Cambridge Department of Oncology (RJAG/076), C.M.C. was supported by the Cambridge University Hospitals NHS Foundation Trust, E.W.R. was supported by the CRI Irvington Postdoctoral Fellowship Program, and A.P.C. was supported by the Medical Research Council (MRC) Metabolic Diseases Unit (MRC_MC_UU_12012/1). D.T.F. is a Distinguished Scholar of the Lustgarten Foundation

Chimpanzees modify intentional gestures to coordinate a search for hidden food

Humans routinely communicate to coordinate their activities, persisting and elaborating signals to pursue goals that cannot be accomplished individually. Communicative persistence is associated with complex cognitive skills such as intentionality, because interactants modify their communication in response to another's understanding of their meaning. Here we show that two language-trained chimpanzees effectively use intentional gestures to coordinate with an experimentally naive human to retrieve hidden food, providing some of the most compelling evidence to date for the role of communicative flexibility in successful coordination in nonhumans. Both chimpanzees (named Panzee and Sherman) increase the rate of nonindicative gestures when the experimenter approaches the location of the hidden food. Panzee also elaborates her gestures in relation to the experimenter's pointing, which enables her to find food more effectively than Sherman. Communicative persistence facilitates effective communication during behavioural coordination and is likely to have been important in shaping language evolution

Structure-Based Design of Potent and Selective Leishmania N-Myristoyltransferase Inhibitors

Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme

Persistence and Availability of Web Services in Computational Biology

We have conducted a study on the long-term availability of bioinformatics Web services: an observation of 927 Web services published in the annual Nucleic Acids Research Web Server Issues between 2003 and 2009

Between-centre differences and treatment effects in randomized controlled trials: A case study in traumatic brain injury

BACKGROUND: In Traumatic Brain Injury (TBI), large between-centre differences in outcome exist and many clinicians believe that such differences influence estimation of the treatment effect in randomized controlled trial (RCTs). The aim of this study was to assess the influence of between-centre differences in outcome on the estimated treatment effect in a large RCT in TBI. METHODS: We used data from the MRC CRASH trial on the efficacy of corticosteroid infusion in patients with TBI. We analyzed the effect of the treatment on 14 day mortality with fixed effect logistic regression. Next we used random effects logistic regression with a random intercept to estimate the treatment effect taking into account between-centre differences in outcome. Between-centre differences in outcome were expressed with a 95% range of odds ratios (OR) for centres compared to the average, based on the variance of the random effects (tau2). A random effects logistic regression model with random slopes was used to allow the treatment effect to vary by centre. The variation in treatment effect between the centres was expressed in a 95% range of the estimated treatment ORs. RESULTS: In 9978 patients from 237 centres, 14-day mortality was 19.5%. Mortality was higher in the treatment group (OR = 1.22, p = 0.00010). Using a random effects model showed large between-centre differences in outcome (95% range of centre effects: 0.27- 3.71), but did not substantially change the estimated treatment effect (OR = 1.24, p = 0.00003). There was limited, although statistically significant, between-centre variation in the treatment effect (OR = 1.22, 95% treatment OR range: 1.17-1.26). CONCLUSION: Large between-centre differences in outcome do not necessarily affect the estimated treatment effect in RCTs, in contrast to current beliefs in the clinical area of TBI

Recognition of delirium in ICU patients: a diagnostic study of the NEECHAM confusion scale in ICU patients

BACKGROUND: A delirium, is a serious, high-frequency complication in intensive care unit (ICU) patients. The consequences of this complication range from high morbidity and mortality to greater need for nursing care. Despite these, delirium is often not recognized and there for not treated. In this study a nursing screening instrument, the NEECHAM confusion scale, was studied for early recognition of delirium ICU patients. This scale proved valid and reliable in several studies in the general hospital population. METHODS: In this study validity and reliability were tested in a prospective cohort of 105 patients. Gold standard for delirium was an independent DSM-IV diagnosis. User friendliness was tested by structured evaluation of nurses' experiences working with the scale. RESULTS: The NEECHAM confusion scale showed high internal consistency (Cronbach's alpha 0.88) and an interrater reliability of Cohen's Kappa 0.60. The concurrent validity with the DSM-IVcriteria showed a strong link (chi-square 67.52, p [less than or equal to] 0.001). Sensitivity was high, 97% and specificity was good 83%. ICU nurses completed the NEECHAM confusion rating in 3.69, ± 1.21 minutes average. In general the nurses were positive about the NEECHAM confusion scale. They were able to collect data during regular care, but experienced problems in rating the scale in intubated patients. The items in themselves were clear, the content validity, measured by the language used was rated good. CONCLUSION: The psychometric characteristics of the NEECHAM confusion scale of this ICU study are generally consistent with validity research previously reported for the general hospital population. The psychometric characteristics and the ease of use of the NEECHAM confusion scale enables ICU nurses to early recognize delirium. Further study, especially in intubed patients is recommended

The science of clinical practice: disease diagnosis or patient prognosis? Evidence about "what is likely to happen" should shape clinical practice.

BACKGROUND: Diagnosis is the traditional basis for decision-making in clinical practice. Evidence is often lacking about future benefits and harms of these decisions for patients diagnosed with and without disease. We propose that a model of clinical practice focused on patient prognosis and predicting the likelihood of future outcomes may be more useful. DISCUSSION: Disease diagnosis can provide crucial information for clinical decisions that influence outcome in serious acute illness. However, the central role of diagnosis in clinical practice is challenged by evidence that it does not always benefit patients and that factors other than disease are important in determining patient outcome. The concept of disease as a dichotomous 'yes' or 'no' is challenged by the frequent use of diagnostic indicators with continuous distributions, such as blood sugar, which are better understood as contributing information about the probability of a patient's future outcome. Moreover, many illnesses, such as chronic fatigue, cannot usefully be labelled from a disease-diagnosis perspective. In such cases, a prognostic model provides an alternative framework for clinical practice that extends beyond disease and diagnosis and incorporates a wide range of information to predict future patient outcomes and to guide decisions to improve them. Such information embraces non-disease factors and genetic and other biomarkers which influence outcome. SUMMARY: Patient prognosis can provide the framework for modern clinical practice to integrate information from the expanding biological, social, and clinical database for more effective and efficient care