Discovering patterns in drug-protein interactions based on their fingerprints

<p>Abstract</p> <p>Background</p> <p>The discovering of interesting patterns in drug-protein interaction data at molecular level can reveal hidden relationship among drugs and proteins and can therefore be of paramount importance for such application as drug design. To discover such patterns, we propose here a computational approach to analyze the molecular data of drugs and proteins that are known to have interactions with each other. Specifically, we propose to use a data mining technique called <it>Drug-Protein Interaction Analysis </it>(<it>D-PIA</it>) to determine if there are any commonalities in the fingerprints of the substructures of interacting drug and protein molecules and if so, whether or not any patterns can be generalized from them.</p> <p>Method</p> <p>Given a database of drug-protein interactions, <it>D-PIA </it>performs its tasks in several steps. First, for each drug in the database, the fingerprints of its molecular substructures are first obtained. Second, for each protein in the database, the fingerprints of its protein domains are obtained. Third, based on known interactions between drugs and proteins, an interdependency measure between the fingerprint of each drug substructure and protein domain is then computed. Fourth, based on the interdependency measure, drug substructures and protein domains that are significantly interdependent are identified. Fifth, the existence of interaction relationship between a previously unknown drug-protein pairs is then predicted based on their constituent substructures that are significantly interdependent.</p> <p>Results</p> <p>To evaluate the effectiveness of <it>D-PIA</it>, we have tested it with real drug-protein interaction data. <it>D-PIA </it>has been tested with real drug-protein interaction data including enzymes, ion channels, and protein-coupled receptors. Experimental results show that there are indeed patterns that one can discover in the interdependency relationship between drug substructures and protein domains of interacting drugs and proteins. Based on these relationships, a testing set of drug-protein data are used to see if <it>D-PIA </it>can correctly predict the existence of interaction between drug-protein pairs. The results show that the prediction accuracy can be very high. An AUC score of a ROC plot could reach as high as 75% which shows the effectiveness of this classifier.</p> <p>Conclusions</p> <p><it>D-PIA </it>has the advantage that it is able to perform its tasks effectively based on the fingerprints of drug and protein molecules without requiring any 3D information about their structures and <it>D-PIA </it>is therefore very fast to compute. <it>D-PIA </it>has been tested with real drug-protein interaction data and experimental results show that it can be very useful for predicting previously unknown drug-protein as well as protein-ligand interactions. It can also be used to tackle problems such as ligand specificity which is related directly and indirectly to drug design and discovery.</p

Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): Study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Laparoscopic cholecystectomy in acute calculous cholecystitis in high risk patients can lead to significant morbidity and mortality. Percutaneous cholecystostomy may be an alternative treatment option but the current literature does not provide the surgical community with evidence based advice.</p> <p>Methods/Design</p> <p>The CHOCOLATE trial is a randomised controlled, parallel-group, superiority multicenter trial. High risk patients, defined as APACHE-II score 7-14, with acute calculous cholecystitis will be randomised to laparoscopic cholecystectomy or percutaneous cholecystostomy. During a two year period 284 patients will be enrolled from 30 high volume teaching hospitals. The primary endpoint is a composite endpoint of major complications within three months following randomization and need for re-intervention and mortality during the follow-up period of one year. Secondary endpoints include all other complications, duration of hospital admission, difficulty of procedures and total costs.</p> <p>Discussion</p> <p>The CHOCOLATE trial is designed to provide the surgical community with an evidence based guideline in the treatment of acute calculous cholecystitis in high risk patients.</p> <p>Trial Registration</p> <p>Netherlands Trial Register (NTR): <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2666">NTR2666</a></p

In vivo Bioluminescence Imaging of Ca(2+) Signalling in the Brain of Drosophila

Many different cells' signalling pathways are universally regulated by Ca(2+) concentration [Ca(2+)] rises that have highly variable amplitudes and kinetic properties. Optical imaging can provide the means to characterise both the temporal and spatial aspects of Ca(2+) signals involved in neurophysiological functions. New methods for in vivo imaging of Ca(2+) signalling in the brain of Drosophila are required for probing the different dynamic aspects of this system. In studies here, whole brain Ca(2+) imaging was performed on transgenic flies with targeted expression of the bioluminescent Ca(2+) reporter GFP-aequorin (GA) in different neural structures. A photon counting based technique was used to undertake continuous recordings of cytosolic [Ca(2+)] over hours. Time integrals for reconstructing images and analysis of the data were selected offline according to the signal intensity. This approach allowed a unique Ca(2+) response associated with cholinergic transmission to be identified by whole brain imaging of specific neural structures. Notably, [Ca(2+)] transients in the Mushroom Bodies (MBs) following nicotine stimulation were accompanied by a delayed secondary [Ca(2+)] rise (up to 15 min. later) in the MB lobes. The delayed response was sensitive to thapsigargin, suggesting a role for intra-cellular Ca(2+) stores. Moreover, it was reduced in dunce mutant flies, which are impaired in learning and memory. Bioluminescence imaging is therefore useful for studying Ca(2+) signalling pathways and for functional mapping of neurophysiological processes in the fly brain

Pharmacological adjuncts to stop bleeding: options and effectiveness

Severe trauma and massive haemorrhage represent the leading cause of death and disability in patients under the age of 45 years in the developed world. Even though much advancement has been made in our understanding of the pathophysiology and management of trauma, outcomes from massive haemorrhage remain poor. This can be partially explained by the development of coagulopathy, acidosis and hypothermia, a pathological process collectively known as the “lethal triad” of trauma. A number of pharmacological adjuncts have been utilised to stop bleeding, with a wide variation in the safety and efficacy profiles. Antifibrinolytic agents in particular, act by inhibiting the conversion of plasminogen to plasmin, therefore decreasing the degree of fibrinolysis. Tranexamic acid, the most commonly used antifibrinolytic agent, has been successfully incorporated into most trauma management protocols effectively reducing mortality and morbidity following trauma. In this review, we discuss the current literature with regard to the management of haemorrhage following trauma, with a special reference to the use of pharmacological adjuncts. Novel insights, concepts and treatment modalities are also discussed

Respiratory Syncytial Virus (RSV): Targeting the G Protein Provides a New Approach for an Old Problem.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection (LRTI) annually affecting >2 million children in the US 65 years old), RSV results in ∼175,000 hospitalizations annually in the US with worldwide incidence ∼34 million. There is no approved RSV vaccine and treatments are limited. Recently, a Phase 3 trial in the elderly using a recombinant RSV F protein vaccine failed to meet its efficacy objectives, namely prevention of moderate-to-severe RSV-associated LRTI and reduced incidence of acute respiratory disease. Moreover, a recent Phase 3 trial evaluating suptavumab (REGN2222), an antibody to RSV F protein, did not meet its primary endpoint of preventing medically attended RSV infections in pre-term infants. Despite these setbacks, numerous efforts targeting the RSV F protein with vaccines, antibodies, and small molecules continue based on the commercial success of a monoclonal antibody (mAb) against the RSV F protein (palivizumab). As the understanding of RSV biology has improved, the other major coat protein, the RSV G protein, has re-emerged as an alternative target reflecting progress in understanding its roles in infecting bronchial epithelial cells and in altering the host immune response. In mouse models, a high-affinity, strain-independent human mAb to the RSV G protein has shown potent direct antiviral activity combined with the alleviation of virus-induced immune system effects that contribute to disease pathology. This mAb, being prepared for clinical trials, provides a qualitatively new approach to managing RSV for populations not eligible for prophylaxis with palivizumab