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Find video protocols related to scientific articles indexed in Pubmed.
The Impact of Ischemia on Long-Term Renal Function After Partial Nephrectomy in the Two Kidney Model.
J. Endourol.
PUBLISHED: 09-30-2014
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Abstract Purpose: To determine whether on-clamp partial nephrectomy (ON-PN) has any significant impact on long-term renal function in a two kidney model. Patients and Methods: From November 1999 to July 2013, 607 patients underwent PN at our institution. After excluding patients with solitary kidneys, multiple renal masses, and follow-up less than 90 days, 331 remained. Patient demographics were assessed, as was renal function based on pre- and postoperative mercaptoacetyltriglycine (MAG-3) renal scans and change in estimated glomerular filtration rate (eGFR) using the preoperative and most recent recorded creatinine levels. Results: There were a total of 236 patients who underwent ON-PN and 95 who underwent off-clamp PN (OFF-PN) during the study period. The longest follow-up was 12.6 years with mean follow-up of 3 years. Mean ischemia time of patients undergoing ON-PN was 25 minutes (range 8-63?min). No differences were noted between the ON-PN and OFF-PN cohorts with respect to estimated change in eGFR (ON-PN: -6.07?mL/min/1.73?m(2) vs OFF-PN: -6.00?mL/min/1.73?m(2), P=0.69). No differences were noted in the % change in the MAG-3 renal scans (ON-PN: -0.77% vs OFF-PN: -1.1%, P=0.94). A post hoc sensitivity analysis of the same two variables stratified by age revealed no differences in change in estimated GFR or % change in differential function on renal scan. Conclusions: In the two kidney model, ischemia does not appear to affect long-term renal function outcomes after PN. These data provide evidence that ON-PN is perfectly acceptable in the appropriately selected patient with two kidneys.
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Modelling biological behaviours with the unified modelling language: an immunological case study and critique.
J R Soc Interface
PUBLISHED: 08-22-2014
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We present a framework to assist the diagrammatic modelling of complex biological systems using the unified modelling language (UML). The framework comprises three levels of modelling, ranging in scope from the dynamics of individual model entities to system-level emergent properties. By way of an immunological case study of the mouse disease experimental autoimmune encephalomyelitis, we show how the framework can be used to produce models that capture and communicate the biological system, detailing how biological entities, interactions and behaviours lead to higher-level emergent properties observed in the real world. We demonstrate how the UML can be successfully applied within our framework, and provide a critique of UML's ability to capture concepts fundamental to immunology and biology more generally. We show how specialized, well-explained diagrams with less formal semantics can be used where no suitable UML formalism exists. We highlight UML's lack of expressive ability concerning cyclic feedbacks in cellular networks, and the compounding concurrency arising from huge numbers of stochastic, interacting agents. To compensate for this, we propose several additional relationships for expressing these concepts in UML's activity diagram. We also demonstrate the ambiguous nature of class diagrams when applied to complex biology, and question their utility in modelling such dynamic systems. Models created through our framework are non-executable, and expressly free of simulation implementation concerns. They are a valuable complement and precursor to simulation specifications and implementations, focusing purely on thoroughly exploring the biology, recording hypotheses and assumptions, and serve as a communication medium detailing exactly how a simulation relates to the real biology.
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Proton beam therapy for localized prostate cancer 101: basics, controversies, and facts.
Rev Urol
PUBLISHED: 07-11-2014
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Proton beam therapy for prostate cancer has become a source of controversy in the urologic community, and the rapid dissemination and marketing of this technology has led to many patients inquiring about this therapy. Yet the complexity of the technology, the cost, and the conflicting messages in the literature have left many urologists ill equipped to counsel their patients regarding this option. This article reviews the basic science of the proton beam, examines the reasons for both the hype and the controversy surrounding this therapy, and, most importantly, examines the literature so that every urologist is able to comfortably discuss this option with inquiring patients.
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Massive renal size is not a contraindication to a laparoscopic approach for bilateral native nephrectomies in autosomal dominant polycystic kidney disease (ADPKD).
BJU Int.
PUBLISHED: 06-07-2014
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To determine if massive renal size should be a contraindication for attempting a laparoscopic approach to bilateral native nephrectomies in patients with autosomal dominant polycystic kidney disease (ADPKD).
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Robot-assisted retroperitoneal lymph node dissection: technique and initial case series of 18 patients.
BJU Int.
PUBLISHED: 05-15-2014
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To evaluate outcomes of the first 18 patients treated with robot-assisted retroperitoneal lymph node dissection (RA-RPLND) for non-seminomatous germ cell tumours (NSGCT) and paratesticular rhabdomyosarcoma (RMS) at our institution.
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Long-term renal function after donor nephrectomy: secondary follow-up analysis of the randomized trial of ketorolac vs placebo.
Urology
PUBLISHED: 04-03-2014
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To evaluate the long-term safety of a novel continuous infusion of ketorolac vs placebo after laparoscopic donor nephrectomy.
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Venous thromboembolism after urological surgery.
J. Urol.
PUBLISHED: 02-20-2014
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We determined the rates of deep venous thromboembolism and pulmonary embolism after common urological procedures in the United States.
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The role of the parasympathetic nervous system in visually induced motion sickness: systematic review and meta-analysis.
Exp Brain Res
PUBLISHED: 02-11-2014
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The parasympathetic nervous system (PNS) has been implicated in the development of visually induced motion sickness. The objective of this study was to perform a systematic review and meta-analysis of the effect of visually induced motion sickness on validated parameters of PNS tone. Methods followed PRISMA recommendations. Controlled trials reporting validated measures of PNS tone in visually induced motion sickness in healthy adults were included. One reviewer performed the screening of articles and data extraction, and two reviewers independently performed methodological evaluation. Data were synthesised using standardised mean differences (SMDs) for all relevant outcomes using a random-effects model. Publication bias was assessed via funnel plots and Egger's test. The search strategy identified seven citations comprising 237 healthy individuals. The mean quality score was 4/10 (range 3-7). There was no difference between baseline PNS tone between individuals who developed visually induced motion sickness and those that did not. Visually induced motion sickness (VIMS)-sensitive individuals had a reduction in PNS tone, following exposure to the stimulus (mean weighted SMD = -0.45, 95% confidence interval -0.64 to -0.27, Z = -4.8, p < 0.0001). There was no evidence of heterogeneity or publication bias. These data suggest that baseline PNS parameters do not provide a useful measure of predicting the probability of developing visually induced motion sickness. However, a fall in PNS tone, as indicated by cardiac activity, is characteristic in sensitive individuals. Further work is needed to characterise these responses in clinical populations, in conjunction with improvements and standardisation in study design.
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The use of artificial crabs for testing predatory behavior and health in the octopus.
ALTEX
PUBLISHED: 01-28-2014
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The willingness of the cephalopod mollusc Octopus vulgaris to attack a live crab is traditionally used as a method to assess the overall health and welfare of octopuses in the laboratory. This method requires placing a crab in the home tank of an animal, measuring the time (latency) taken for the octopus to initiate an attack and withdrawing the crab immediately prior to capture. The same crab is commonly used to assess multiple octopuses as part of daily welfare assessment. Growing concern for the welfare of crustaceans and a review of all laboratory practices for the care and welfare of cephalopods following the inclusion of this taxon in 2010/63/EU prompted a study of the utility of an artificial crab to replace a live crab in the assessment of octopus health. On consecutive days O. vulgaris (N=21) were presented with a live, a dead or an artificial crab, and the latency to attack measured. Despite differences in the predatory performance towards the three different crab alternatives, octopuses readily attacked the artificial (and the dead) crab, showing that they can generalize and respond appropriately towards artificial prey. Researchers should consider using an artificial crab to replace the use of a live crab as part of the routine health assessment of O. vulgaris.
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Cephalopods in neuroscience: regulations, research and the 3Rs.
Invert. Neurosci.
PUBLISHED: 01-03-2014
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Cephalopods have been utilised in neuroscience research for more than 100 years particularly because of their phenotypic plasticity, complex and centralised nervous system, tractability for studies of learning and cellular mechanisms of memory (e.g. long-term potentiation) and anatomical features facilitating physiological studies (e.g. squid giant axon and synapse). On 1 January 2013, research using any of the about 700 extant species of "live cephalopods" became regulated within the European Union by Directive 2010/63/EU on the "Protection of Animals used for Scientific Purposes", giving cephalopods the same EU legal protection as previously afforded only to vertebrates. The Directive has a number of implications, particularly for neuroscience research. These include: (1) projects will need justification, authorisation from local competent authorities, and be subject to review including a harm-benefit assessment and adherence to the 3Rs principles (Replacement, Refinement and Reduction). (2) To support project evaluation and compliance with the new EU law, guidelines specific to cephalopods will need to be developed, covering capture, transport, handling, housing, care, maintenance, health monitoring, humane anaesthesia, analgesia and euthanasia. (3) Objective criteria need to be developed to identify signs of pain, suffering, distress and lasting harm particularly in the context of their induction by an experimental procedure. Despite diversity of views existing on some of these topics, this paper reviews the above topics and describes the approaches being taken by the cephalopod research community (represented by the authorship) to produce "guidelines" and the potential contribution of neuroscience research to cephalopod welfare.
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Measuring the bright side of being blue: a new tool for assessing analytical rumination in depression.
PLoS ONE
PUBLISHED: 01-01-2014
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Diagnosis and management of depression occurs frequently in the primary care setting. Current diagnostic and management of treatment practices across clinical populations focus on eliminating signs and symptoms of depression. However, there is debate that some interventions may pathologize normal, adaptive responses to stressors. Analytical rumination (AR) is an example of an adaptive response of depression that is characterized by enhanced cognitive function to help an individual focus on, analyze, and solve problems. To date, research on AR has been hampered by the lack of theoretically-derived and psychometrically sound instruments. This study developed and tested a clinically meaningful measure of AR.
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Population-level effects of suppressing fever.
Proc. Biol. Sci.
PUBLISHED: 01-01-2014
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Fever is commonly attenuated with antipyretic medication as a means to treat unpleasant symptoms of infectious diseases. We highlight a potentially important negative effect of fever suppression that becomes evident at the population level: reducing fever may increase transmission of associated infections. A higher transmission rate implies that a larger proportion of the population will be infected, so widespread antipyretic drug use is likely to lead to more illness and death than would be expected in a population that was not exposed to antipyretic pharmacotherapies. We assembled the published data available for estimating the magnitudes of these individual effects for seasonal influenza. While the data are incomplete and heterogeneous, they suggest that, overall, fever suppression increases the expected number of influenza cases and deaths in the US: for pandemic influenza with reproduction number , the estimated increase is 1% (95% CI: 0.0-2.7%), whereas for seasonal influenza with , the estimated increase is 5% (95% CI: 0.2-12.1%).
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Development of novel dual binders as potent, selective, and orally bioavailable tankyrase inhibitors.
J. Med. Chem.
PUBLISHED: 12-11-2013
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Tankyrases (TNKS1 and TNKS2) are proteins in the poly ADP-ribose polymerase (PARP) family. They have been shown to directly bind to axin proteins, which negatively regulate the Wnt pathway by promoting ?-catenin degradation. Inhibition of tankyrases may offer a novel approach to the treatment of APC-mutant colorectal cancer. Hit compound 8 was identified as an inhibitor of tankyrases through a combination of substructure searching of the Amgen compound collection based on a minimal binding pharmacophore hypothesis and high-throughput screening. Herein we report the structure- and property-based optimization of compound 8 leading to the identification of more potent and selective tankyrase inhibitors 22 and 49 with improved pharmacokinetic properties in rodents, which are well suited as tool compounds for further in vivo validation studies.
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A novel human receptor involved in bitter tastant detection identified using Dictyostelium discoideum.
J. Cell. Sci.
PUBLISHED: 09-04-2013
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Detection of substances tasting bitter to humans occurs in diverse organisms including the social amoeba Dictyostelium discoideum. To establish a molecular mechanism for bitter tastant detection in Dictyostelium, we screened a mutant library for resistance to a commonly used bitter standard, phenylthiourea. This approach identified a G-protein-coupled receptor mutant, grlJ(-), which showed a significantly increased tolerance to phenylthiourea in growth, survival and movement. This mutant was not resistant to a structurally dissimilar potent bitter tastant, denatonium benzoate, suggesting it is not a target for at least one other bitter tastant. Analysis of the cell-signalling pathway involved in the detection of phenylthiourea showed dependence upon heterotrimeric G protein and phosphatidylinositol 3-kinase activity, suggesting that this signalling pathway is responsible for the cellular effects of phenylthiourea. This is further supported by a phenylthiourea-dependent block in the transient cAMP-induced production of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in wild-type but not grlJ(-) cells. Finally, we have identified an uncharacterized human protein ?-aminobutyric acid (GABA) type B receptor subunit 1 isoform with weak homology to GrlJ that restored grlJ(-) sensitivity to phenylthiourea in cell movement and PIP3 regulation. Our results thus identify a novel pathway for the detection of the standard bitter tastant phenylthiourea in Dictyostelium and implicate a poorly characterized human protein in phenylthiourea-dependent cell responses.
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Discovery of novel, induced-pocket binding oxazolidinones as potent, selective, and orally bioavailable tankyrase inhibitors.
J. Med. Chem.
PUBLISHED: 05-23-2013
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Tankyrase (TNKS) is a poly-ADP-ribosylating protein (PARP) whose activity suppresses cellular axin protein levels and elevates ?-catenin concentrations, resulting in increased oncogene expression. The inhibition of tankyrase (TNKS1 and 2) may reduce the levels of ?-catenin-mediated transcription and inhibit tumorigenesis. Compound 1 is a previously described moderately potent tankyrase inhibitor that suffers from poor pharmacokinetic properties. Herein, we describe the utilization of structure-based design and molecular modeling toward novel, potent, and selective tankyrase inhibitors with improved pharmacokinetic properties (39, 40).
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Simultaneous kidney transplantation and bilateral native nephrectomy for polycystic kidney disease.
J. Urol.
PUBLISHED: 05-21-2013
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Bilateral native nephrectomy with simultaneous kidney transplantation is becoming more common for patients with polycystic kidney disease in the living donor nephrectomy era. Single center reports evaluating the short-term and long-term outcomes of simultaneous kidney transplantation have been published but are generally limited by small sample sizes. We examined population level data to broadly define the complications of simultaneous kidney transplantation.
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Predicting response to bacillus Calmette-Guérin (BCG) in patients with carcinoma in situ of the bladder.
Urol. Oncol.
PUBLISHED: 05-02-2013
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Currently, there is no reliable tool to predict response to intravesical bacillus Calmette-Guérin (BCG). Based on the fact that BCG is a Th1-polarizing immunotherapy, we attempt to correlate the pretreatment immunologic tumor microenvironment (Th1 or Th2) with response to therapy.
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In silico investigation into dendritic cell regulation of CD8Treg mediated killing of Th1 cells in murine experimental autoimmune encephalomyelitis.
BMC Bioinformatics
PUBLISHED: 04-17-2013
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Experimental autoimmune encephalomyelitis has been used extensively as an animal model of T cell mediated autoimmunity. A down-regulatory pathway through which encephalitogenic CD4Th1 cells are killed by CD8 regulatory T cells (Treg) has recently been proposed. With the CD8Treg cells being primed by dendritic cells, regulation of recovery may be occuring around these antigen presenting cells. CD4Treg cells provide critical help within this process, by licensing dendritic cells to prime CD8Treg cells, however the spatial and temporal aspects of this help in the CTL response is currently unclear.
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Marital status and prostate cancer outcomes.
Can J Urol
PUBLISHED: 04-17-2013
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To evaluate the influence of marriage on the survival outcomes of men diagnosed with prostate cancer.
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Nausea and the quest for the perfect anti-emetic.
Eur. J. Pharmacol.
PUBLISHED: 04-15-2013
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The discovery of anti-emetic agents is reviewed to illustrate the large database (>129,000 papers in PubMed) available for potential data mining and to provide a background to the shift in interest to nausea from vomiting. Research on nausea extends to identification of biomarkers for diagnosis/clinical trials and to understanding why nausea is such a common dose-limiting toxicity of diverse therapeutic agents. The lessons learned for translation from animals to humans, from the discovery of the anti-vomiting effects of 5-HT3 and NK1 receptor antagonists, is discussed in terms of the similarities between the emetic pathways and their pharmacology, and also in terms of the limitations of rodent models of "nausea" (pica, conditioned taste aversion, conditioned gaping and disgust). The review focuses on the established view that anti-emetics are more efficacious against vomiting than nausea. In particular we examine studies of 5-HT3, NK1 and D2 receptor antagonists, gabapentin and various receptor agonists. The potential for targeting anti-nausea agents is then considered, by targeting mechanisms which correct delayed gastric emptying (prokinetics), the rise in plasma vasopressin (AVP) and/or act at central targets revealed by the growing knowledge of cortical regions activated/inhibited in subjects reporting nausea. Modulation of the projections from the brainstem to the cortical areas responsible for the genesis of the sensation of nausea provides the most likely approach to a target at which an anti-nausea drug could be targeted with the expectation that it would affect nausea from multiple causes.
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Considerations for the nonclinical safety evaluation of antibody drug conjugates for oncology.
Regul. Toxicol. Pharmacol.
PUBLISHED: 04-02-2013
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Antibody drug conjugates (ADCs) include monoclonal antibodies that are linked to cytotoxic small molecules. A number of these agents are currently being developed as anti-cancer agents designed to improve the therapeutic index of the cytotoxin (i.e., cytotoxic small molecule or cytotoxic agent) by specifically delivering it to tumor cells. This paper presents primary considerations for the nonclinical safety evaluation of ADCs and includes strategies for the evaluation of the entire ADC or the various individual components (i.e., antibody, linker or the cytotoxin). Considerations are presented on how to design a nonclinical safety assessment program to identify the on- and off-target toxicities to enable first-in-human (FIH) studies. Specific discussions are also included that provide details as to the need and how to conduct the studies for evaluating ADCs in genetic toxicology, tissue cross-reactivity, safety pharmacology, carcinogenicity, developmental and reproductive toxicology, biotransformation, toxicokinetic monitoring, bioanalytical assays, immunogenicity testing, test article stability and the selection of the FIH dose. Given the complexity of these molecules and our evolving understanding of their properties, there is no single all-encompassing nonclinical strategy. Instead, each ADC should be evaluated on a case-by-case scientifically-based approach that is consistent with ICH and animal research guidelines.
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In silico investigation of novel biological pathways: the role of CD200 in regulation of T cell priming in experimental autoimmune encephalomyelitis.
BioSystems
PUBLISHED: 03-07-2013
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The use of simulation to investigate biological domains will inevitably lead to the need to extend existing simulations as new areas of these domains become more fully understood. Such simulation extensions can entail the incorporation of additional cell types, molecules or molecular pathways, all of which can exert a profound influence on the simulation behaviour. Where the biological domain is not well characterised, a structured development methodology must be employed to ensure that the extended simulation is well aligned with its predecessor. We develop and discuss such a methodology, relying on iterative simulation development and sensitivity analysis. The utility of this methodology is demonstrated using a case study simulation of experimental autoimmune encephalomyelitis (EAE), a murine T cell-mediated autoimmune disease model of multiple sclerosis, where it is used to investigate the activity of an additional regulatory pathway. We discuss how application of this methodology guards against creating inappropriate simulation representations of the biology when investigating poorly characterised biological mechanisms.
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Spartan: a comprehensive tool for understanding uncertainty in simulations of biological systems.
PLoS Comput. Biol.
PUBLISHED: 02-28-2013
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Integrating computer simulation with conventional wet-lab research has proven to have much potential in furthering the understanding of biological systems. Success requires the relationship between simulation and the real-world system to be established: substantial aspects of the biological system are typically unknown, and the abstract nature of simulation can complicate interpretation of in silico results in terms of the biology. Here we present spartan (Simulation Parameter Analysis RToolkit ApplicatioN), a package of statistical techniques specifically designed to help researchers understand this relationship and provide novel biological insight. The tools comprising spartan help identify which simulation results can be attributed to the dynamics of the modelled biological system, rather than artefacts of biological uncertainty or parametrisation, or simulation stochasticity. Statistical analyses reveal the influence that pathways and components have on simulation behaviour, offering valuable biological insight into aspects of the system under study. We demonstrate the power of spartan in providing critical insight into aspects of lymphoid tissue development in the small intestine through simulation. Spartan is released under a GPLv2 license, implemented within the open source R statistical environment, and freely available from both the Comprehensive R Archive Network (CRAN) and http://www.cs.york.ac.uk/spartan. The techniques within the package can be applied to traditional ordinary or partial differential equation simulations as well as agent-based implementations. Manuals, comprehensive tutorials, and example simulation data upon which spartan can be applied are available from the website.
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Age-period-cohort analysis of renal cell carcinoma in United States adults.
Urology
PUBLISHED: 02-24-2013
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To determine the extent to which the year of diagnosis, year of birth, and age at diagnosis influence the incidence trends of kidney cancer in the United States.
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The relationship between gastric motility and nausea: gastric prokinetic agents as treatments.
Eur. J. Pharmacol.
PUBLISHED: 02-15-2013
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Nausea is one of a cluster of symptoms described subjectively by patients with delayed gastric emptying. The mechanisms and treatments are unclear (anti-emetic drugs are not fully effective against nausea). Can nausea be relieved by stimulating gastric emptying? Physostigmine (together with atropine) has been shown experimentally to stimulate gastric motility, relieve nausea and restore normal gastric motility. Is this mimicked by gastric prokinetic drugs? The answer is complicated by mixed pharmacology. Metoclopramide increases gastric motility by activating myenteric 5-HT4 receptors but also directly inhibits vomiting via D2 and 5-HT3 receptor antagonism; relationships between increased gastric motility and relief from nausea are therefore unclear. Similarly, the D2 receptor antagonist domperidone has direct anti-emetic activity. Nevertheless, more selective 5-HT4 and motilin receptor agonists (erythromycin, directly stimulating gastric motility) inhibit vomiting in animals; low doses of erythromycin can also relieve symptoms in patients with gastroparesis. Ghrelin stimulates gastric motility and appetite mostly via vagus-dependent pathways, and inhibits vomiting in animals. To date, ghrelin receptor activation has failed to consistently improve gastric emptying or symptoms in patients with gastroparesis. We conclude that nausea can be relieved by gastric prokinetic drugs, but more clinical studies are needed using drugs with selective activity. Other mechanisms (e.g. ghrelin, vagal and central pathways, influencing a mechanistic continuum between appetite and nausea) also require exploration. These and other issues will be further explored in a forthcoming special issue of the European Journal of Pharmacology, which focusses on mechanisms of nausea and vomiting.
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Outcome and toxicity for patients treated with intensity modulated radiation therapy for localized prostate cancer.
J. Urol.
PUBLISHED: 02-06-2013
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We evaluate long-term disease control and chronic toxicities observed in patients treated with intensity modulated radiation therapy for clinically localized prostate cancer.
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Functional complexity of the Leishmania granuloma and the potential of in silico modeling.
Front Immunol
PUBLISHED: 01-30-2013
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In human and canine visceral leishmaniasis and in various experimental models of this disease, host resistance is strongly linked to efficient granuloma development. However, it is unknown exactly how the granuloma microenvironment executes an effective antileishmanial response. Recent studies, including using advanced imaging techniques, have improved our understanding of granuloma biology at the cellular level, highlighting heterogeneity in granuloma development and function, and hinting at complex cellular, temporal, and spatial dynamics. In this mini-review, we discuss the factors involved in the formation and function of Leishmania donovani-induced hepatic granulomas, as well as their importance in protecting against inflammation-associated tissue damage and the generation of immunity to rechallenge. Finally, we discuss the role that computational, agent-based models may play in answering outstanding questions within the field.
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Determining disease intervention strategies using spatially resolved simulations.
PLoS ONE
PUBLISHED: 01-01-2013
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Predicting efficacy and optimal drug delivery strategies for small molecule and biological therapeutics is challenging due to the complex interactions between diverse cell types in different tissues that determine disease outcome. Here we present a new methodology to simulate inflammatory disease manifestation and test potential intervention strategies in silico using agent-based computational models. Simulations created using this methodology have explicit spatial and temporal representations, and capture the heterogeneous and stochastic cellular behaviours that lead to emergence of pathology or disease resolution. To demonstrate this methodology we have simulated the prototypic murine T cell-mediated autoimmune disease experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. In the simulation immune cell dynamics, neuronal damage and tissue specific pathology emerge, closely resembling behaviour found in the murine model. Using the calibrated simulation we have analysed how changes in the timing and efficacy of T cell receptor signalling inhibition leads to either disease exacerbation or resolution. The technology described is a powerful new method to understand cellular behaviours in complex inflammatory disease, permits rational design of drug interventional strategies and has provided new insights into the role of TCR signalling in autoimmune disease progression.
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Why cant rodents vomit? A comparative behavioral, anatomical, and physiological study.
PLoS ONE
PUBLISHED: 01-01-2013
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The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity-key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed.
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Impact of margin status at 37 months after robot assisted radical prostatectomy.
Can J Urol
PUBLISHED: 12-15-2011
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We evaluate the impact of margin length, location, and pathologic stage on biochemical recurrence (BCR) after robot assisted radical prostatectomy (RARP) at 37 months of follow up.
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Comparing the portable laparoscopic trainer with a standardized trainer in surgically naïve subjects.
J. Endourol.
PUBLISHED: 10-14-2011
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To evaluate the effectiveness of the portable laparoscopic trainer in improving skills in subjects who have had no previous laparoscopic experience.
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Ubiquitin ligase substrate identification through quantitative proteomics at both the protein and peptide levels.
J. Biol. Chem.
PUBLISHED: 10-10-2011
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Protein ubiquitination is a key regulatory process essential to life at a cellular level; significant efforts have been made to identify ubiquitinated proteins through proteomics studies, but the level of success has not reached that of heavily studied post-translational modifications, such as phosphorylation. HRD1, an E3 ubiquitin ligase, has been implicated in rheumatoid arthritis, but no disease-relevant substrates have been identified. To identify these substrates, we have taken both peptide and protein level approaches to enrich for ubiquitinated proteins in the presence and absence of HRD1. At the protein level, a two-step strategy was taken using cells expressing His(6)-tagged ubiquitin, enriching proteins first based on their ubiquitination and second based on the His tag with protein identification by LC-MS/MS. Application of this method resulted in identification and quantification of more than 400 ubiquitinated proteins, a fraction of which were found to be sensitive to HRD1 and were therefore deemed candidate substrates. In a second approach, ubiquitinated peptides were enriched after tryptic digestion by peptide immunoprecipitation using an antibody specific for the diglycine-labeled internal lysine residue indicative of protein ubiquitination, with peptides and ubiquitination sites identified by LC-MS/MS. Peptide immunoprecipitation resulted in identification of over 1800 ubiquitinated peptides on over 900 proteins in each study, with several proteins emerging as sensitive to HRD1 levels. Notably, significant overlap exists between the HRD1 substrates identified by the protein-based and the peptide-based strategies, with clear cross-validation apparent both qualitatively and quantitatively, demonstrating the effectiveness of both strategies and furthering our understanding of HRD1 biology.
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Discovering small molecules to control stem cell fate.
Future Med Chem
PUBLISHED: 09-03-2011
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Pluripotent stem cells promise to revolutionize drug discovery and offer new modes of therapy. The ease with which they can be grown in bulk and their differentiation controlled in vitro is of importance for their widespread adoption by industry and their clinical efficacy. Small molecules have already had a positive impact on several areas of stem cell biology, from maintenance of pluripotency, the promotion of single cell survival and steering differentiation to involvement in reprogramming somatic cells. High-throughput technology has played an important role in identifying novel compounds, however to date there are few published examples of medicinal chemistry input in this area. This review discusses the potential of pluripotent stem cells, the successful uses of small molecules and future prospects.
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Pharmacokinetics of diazepam administered intramuscularly by autoinjector versus rectal gel in healthy subjects: a phase I, randomized, open-label, single-dose, crossover, single-centre study.
Clin Drug Investig
PUBLISHED: 07-05-2011
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Acute repetitive seizures (ARS) are a debilitating part of episodic seizure activity that can sometimes progress to status epilepticus. Currently approved treatment that can be administered by non-medical personnel to patients with ARS is a diazepam rectal gel. While effective, rectal administration can be difficult, inconvenient and objectionable. A diazepam autoinjector has been developed to deliver diazepam via an intramuscular (IM) injection. This study evaluated the dose proportionality of the diazepam autoinjector and the consequent diazepam bioavailability relative to an equivalent dose of diazepam administered rectally as a commercial gel.
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A retrospective study of a modified 1-minute formocresol pulpotomy technique part 2: effect on exfoliation times and successors.
Pediatr Dent
PUBLISHED: 06-28-2011
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The purposes of this study were to evaluate the: effect of a 1-minute application of full-strength Buckleys formocresol with concur- rent hemostasis using the medicated cotton pledget in human primary teeth on their successors; and exfoliation times compared to the contralateral nonpulpotomized tooth.
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A retrospective study of a modified 1-minute formocresol pulpotomy technique part 1: clinical and radiographic findings.
Pediatr Dent
PUBLISHED: 06-28-2011
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The purpose of this study was to assess the clinical and radiographic outcomes of a 1-minute application of full-strength Buckleys formocresol with concurrent hemostasis using the medicated cotton pledget in human primary teeth.
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Urologic surgical simulation: an endoscopic bladder model.
Simul Healthc
PUBLISHED: 06-07-2011
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With the explosion of endoscopic techniques in urology as well as the increasing work restrictions with resident duty hours, training programs are faced with the challenges of how to adequately train residents while still being proficient and safe in the operating room. Surgical simulation with models is an excellent tool to help bridge the gap between practice and experience and allow residents to learn basic skills in a low stress environment that can be later transferred to the operating room.
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Incidental prostate cancer revisited: early outcomes after holmium laser enucleation of the prostate.
Int. J. Urol.
PUBLISHED: 05-18-2011
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Incidental prostate cancer (PCa) after treatment of benign prostate hyperplasia (BPH) is becoming less common. This is a result of the changing patterns of BPH treatment. The purpose of the present research was to re-examine the clinical outcomes and importance of cT1a and cT1b PCa in a contemporary cohort after holmium laser enucleation of the prostate (HoLEP). All patients with newly diagnosed PCa after HoLEP were retrospectively identified. Pre- and postoperative prostate-specific antigen (PSA), biopsy history, pathological features and disease progression were examined. Patients were matched to a control group with benign pathology for outcome comparisons. The database consisted of 240 consecutive patients, aged 52-90 years with prostate sizes from 25 to 375?cm(3) . A total of 28 patients were identified with incidental PCa (14 cT1a and 14 cT1b). Median follow up was 11 months and 13 months for cT1a and cT1b, respectively. Hospitalization time, catheterization time, complications and functional outcomes were similar. Three patients with cT1b required additional treatment as a result of PSA progression. All other cancers are being closely followed. The functional benefits of HoLEP are well established. The incidental PCa detection rate of 11.7% shows the potential benefit of pathological analysis. Just 10.7% of these patients received additional treatment, but this might be significant as these patients would otherwise go untreated. The impact on disease-specific survival and progression requires a longer follow up.
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Blue again: perturbational effects of antidepressants suggest monoaminergic homeostasis in major depression.
Front Psychol
PUBLISHED: 05-10-2011
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Some evolutionary researchers have argued that current diagnostic criteria for major depressive disorder (MDD) may not accurately distinguish true instances of disorder from a normal, adaptive stress response. According to disorder advocates, neurochemicals like the monoamine neurotransmitters (serotonin, norepinephrine, and dopamine) are dysregulated in major depression. Monoamines are normally under homeostatic control, so the monoamine disorder hypothesis implies a breakdown in homeostatic mechanisms. In contrast, adaptationist hypotheses propose that homeostatic mechanisms are properly functioning in most patients meeting current criteria for MDD. If the homeostatic mechanisms regulating monoamines are functioning properly in these patients, then oppositional tolerance should develop with prolonged antidepressant medication (ADM) therapy. Oppositional tolerance refers to the forces that develop when a homeostatic mechanism has been subject to prolonged pharmacological perturbation that attempt to bring the system back to equilibrium. When pharmacological intervention is discontinued, the oppositional forces cause monoamine levels to overshoot their equilibrium levels. Since depressive symptoms are under monoaminergic control, this overshoot should cause a resurgence of depressive symptoms that is proportional to the perturbational effect of the ADM. We test this prediction by conducting a meta-analysis of ADM discontinuation studies. We find that the risk of relapse after ADM discontinuation is positively associated with the degree to which ADMs enhance serotonin and norepinephrine in prefrontal cortex, after controlling for covariates. The results are consistent with oppositional tolerance, and provide no evidence of malfunction in the monoaminergic regulatory mechanisms in patients meeting current diagnostic criteria for MDD. We discuss the evolutionary and clinical implications of our findings.
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Athermal nerve sparing robot-assisted radical prostatectomy: initial experience with microporous polysaccharide hemospheres as a topical hemostatic agent.
World J Urol
PUBLISHED: 04-26-2011
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Microporous polysaccharide hemospheres (MPH) are hemostatic beads engineered from plant starch to accelerate the natural clotting cascade. The purpose of this report is to detail our initial experience with MPH as a topical hemostatic agent during robot-assisted radical prostatectomy (RARP).
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Natural orifice transluminal endoscopic radical prostatectomy: initial perioperative and pathologic results.
Urology
PUBLISHED: 04-14-2011
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To describe the first clinical experience, pathologic, and perioperative outcomes of natural orifice transluminal endoscopic surgery (NOTES) radical prostatectomy. NOTES represents the evolution of minimally invasive surgery. The conceptual feasibility has been shown in careful laboratory and animal studies, but a scarcity of information regarding clinical applications exists.
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The translational value of rodent gastrointestinal functions: a cautionary tale.
Trends Pharmacol. Sci.
PUBLISHED: 03-18-2011
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Understanding relationships between gene complements and physiology is important, especially where major species-dependent differences are apparent. Molecular and functional differences between rodents (rats, mice, guinea pigs) and humans are increasingly reported. Recently, the motilin gene, which encodes a gastrointestinal hormone widely detected in mammals, was found to be absent in rodents where the receptors are pseudogenes; however, actions of motilin in rodents are sometimes observed. Although ghrelin shares common ancestry with motilin, major species-dependent abberations are not reported. The apparently specific absence of functional motilin in rodents is associated with specialised digestive physiology, including loss of ability to vomit; motilin is functional in mammals capable of vomiting. The exception is rabbit, the only other mammal unable to vomit, in which motilin might be conserved to regulate caecotrophy, another specialised digestive process. Motilin illustrates a need for caution when translating animal functions to humans. Nevertheless, motilin receptor agonists are under development as gastroprokinetic drugs.
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Investigating the effect of emetic compounds on chemotaxis in Dictyostelium identifies a non-sentient model for bitter and hot tastant research.
PLoS ONE
PUBLISHED: 03-11-2011
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Novel chemical entities (NCEs) may be investigated for emetic liability in a range of unpleasant experiments involving retching, vomiting or conditioned taste aversion/food avoidance in sentient animals. We have used a range of compounds with known emetic /aversive properties to examine the possibility of using the social amoeba, Dictyostelium discoideum, for research into identifying and understanding emetic liability, and hence reduce adverse animal experimentation in this area. Twenty eight emetic or taste aversive compounds were employed to investigate the acute (10 min) effect of compounds on Dictyostelium cell behaviour (shape, speed and direction of movement) in a shallow chemotaxic gradient (Dunn chamber). Compound concentrations were chosen based on those previously reported to be emetic or aversive in in vivo studies and results were recorded and quantified by automated image analysis. Dictyostelium cell motility was rapidly and strongly inhibited by four structurally distinct tastants (three bitter tasting compounds--denatonium benzoate, quinine hydrochloride, phenylthiourea, and the pungent constituent of chilli peppers--capsaicin). In addition, stomach irritants (copper chloride and copper sulphate), and a phosphodiesterase IV inhibitor also rapidly blocked movement. A concentration-dependant relationship was established for five of these compounds, showing potency of inhibition as capsaicin (IC(50) = 11.9 ± 4.0 µM) > quinine hydrochloride (IC(50) = 44.3 ± 6.8 µM) > denatonium benzoate (IC(50) = 129 ± 4 µM) > phenylthiourea (IC(50) = 366 ± 5 µM) > copper sulphate (IC(50) = 1433 ± 3 µM). In contrast, 21 compounds within the cytotoxic and receptor agonist/antagonist classes did not affect cell behaviour. Further analysis of bitter and pungent compounds showed that the effect on cell behaviour was reversible and not cytotoxic, suggesting an uncharacterised molecular mechanism of action for these compounds. These results therefore demonstrate that Dictyostelium has potential as a non-sentient model in the analysis of the molecular effects of tastants, although it has limited utility in identification of emetic agents in general.
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Different approaches to an inguinal hernia repair during a simultaneous robot-assisted radical prostatectomy.
J. Endourol.
PUBLISHED: 02-28-2011
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To determine if different approaches to an inguinal hernia repair (robotic, laparoscopic, or open) results in different outcomes during a simultaneous robot-assisted radical prostatectomy (RARP).
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Comparison of 2 cell-based phosphoprotein assays to support screening and development of an ALK inhibitor.
J Biomol Screen
PUBLISHED: 02-08-2011
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Anaplastic lymphoma kinase (ALK) when expressed as a fusion protein with nucleophosmin (NPM) has been implicated as a driving oncogene in a subset of lymphomas. Recent reports of ALK expression in a number of other cancers have raised the possibility that an ALK inhibitor may benefit patients with these diseases as well. In a campaign to identify and develop a selective ALK inhibitor, 2 assays were devised to measure the phosphorylation of tyrosine residue 1604 of ALK (pY(1604) ALK). Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen(®)) and phosflow platforms were used to detect modulation of pY(1604) ALK to determine the relative potency of a set of small-molecule inhibitors. Prior to making use of these assays in diverse settings, the authors attempted to ensure their equivalence with a direct comparison of their performance. The pY(1604) ALK assays correlated well both with each other and with assays of ALK enzyme activity or ALK-dependent cell proliferation. The AlphaScreen(®) assay was amenable to automation and enabled rapid, high-throughput compound assessment in an NPM-ALK-driven cell line, whereas the phosflow assay enabled the authors to characterize the activity of compounds with respect to their impact on targeted enzymes and pathways. Results show that both AlphaScreen(®) and phosflow ALK assays exhibited diverse characteristics that made them desirable for different applications but were determined to be equally sensitive and robust in the detection of inhibition of pY(1604) ALK.
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Discovery of triazine-benzimidazoles as selective inhibitors of mTOR.
Bioorg. Med. Chem. Lett.
PUBLISHED: 01-28-2011
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mTOR is part of the PI3K/AKT pathway and is a central regulator of cell growth and survival. Since many cancers display mutations linked to the mTOR signaling pathway, mTOR has emerged as an important target for oncology therapy. Herein, we report the discovery of triazine benzimidazole inhibitors that inhibit mTOR kinase activity with up to 200-fold selectivity over the structurally homologous kinase PI3K?. When tested in a panel of cancer cell lines displaying various mutations, a selective inhibitor from this series inhibited cellular proliferation with a mean IC(50) of 0.41 ?M. Lead compound 42 demonstrated up to 83% inhibition of mTOR substrate phosphorylation in a murine pharmacodynamic model.
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High-content screening of feeder-free human embryonic stem cells to identify pro-survival small molecules.
Biochem. J.
PUBLISHED: 09-22-2010
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The propensity of human embryonic stem cells to die upon enzymatic disaggregation or low-density plating is an obstacle to their isolation and routine use in drug discovery and basic research. Equally, the very low rate of establishment of implanted cells hinders cell therapy. In the present study we have developed a high-content assay for human embryonic stem cell survival and used this to screen a range of libraries of lead-like small molecules and known bioactives. From this we identified 18 confirmed hits with four structural classes being represented by multiple compounds: a series of 5-(acyl/alkyl-amino)indazoles, compounds with a 4-(acylamino)pyridine core, simple N?,N?-dialkyladenines and compounds with a 5-(acylamino)indolinone core. In vitro kinase profiling indicated that the ROCK (Rho-associated kinase)/PRK2 (protein kinase C-related kinase 2) protein kinases are of pivotal importance for cell survival and identified previously unreported compound classes that inhibited this important biological activity. An evaluation using an extensive panel of protein kinases showed that six of our hit compounds exhibited better selectivity for ROCK inhibition than the routinely used commercially available ROCK inhibitor Y-27632. In this screen we also identified the K(+)-ATP channel opener pinacidil and show that it probably promotes cell survival, by off-target inhibition of ROCK/PRK2. We have therefore identified novel pro-survival compounds of greater specificity, equivalent potency and reduced toxicity relative to the routinely employed ROCK inhibitor Y-27632.
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Natural orifice translumenal endoscopic surgery: radical prostatectomy in the canine model.
J. Endourol.
PUBLISHED: 09-01-2010
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The goal of this study is to demonstrate the feasibility of transurethral radical prostatectomy in the canine model. We describe the surgical procedure for natural orifice translumenal endoscopic surgery-radical prostatectomy (NOTES-RP).
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Identification of substrates of SMURF1 ubiquitin ligase activity utilizing protein microarrays.
Assay Drug Dev Technol
PUBLISHED: 09-01-2010
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The ubiquitin proteasome pathway (UPP) has been implicated in a number of pathogenic diseases: cancer, inflammation, metabolic disorders, and viral infection. The human genome contains well over 500 genes encoding proteins involved in the UPP. Ubiquitin ligases (E3s) comprise the largest subset of these genes, and together with an E2 partner, provide the substrate selectivity required for regulating cellular proteins through the covalent attachment of ubiquitin. Many ligases that have been identified in critical cellular pathways have no known substrates. Even those E3s with known substrates may have a yet unidentified role in the pathways on which they lie and as such may have additional substrates. It is critical to identify these substrates for discovery of selective small molecule inhibitors aimed at therapeutic intervention. Other methods, such as mass spectrometry, have been utilized for identifying ligase substrates, but these are labor-intensive and require a significant investment. In this study, we utilized protein microarrays for the identification of substrates of the HECT domain E3, Smurf1. Smurf1 is a critical regulator of TGF-beta and bone morphogenic protein signaling, and has been demonstrated to play a role in regulating cell polarity through the degradation of RhoA. We set out to identify novel Smurf1 substrates involved in the regulation of the aforementioned pathways. Proof-of-principle experiments with known Smurf1 substrates demonstrated efficient ubiquitination thereby validating this approach. Assaying a human protein microarray for ubiquitination with Smurf1 and the partner E2 ubiquitin ligase Ubch5 or Ubch7 identified 89 potential substrates of the Smurf1 E3 activity, which spanned a number of different biological pathways. Substrates identified utilizing protein microarray technology have been validated in vitro. Here we demonstrate the utility of this approach for identifying substrates of particular E2/E3 complexes.
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Practical approaches to dose selection for first-in-human clinical trials with novel biopharmaceuticals.
Regul. Toxicol. Pharmacol.
PUBLISHED: 06-09-2010
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Recent advances in our understanding of disease biology, biomarkers, new therapeutic targets, and innovative modalities have each fueled a dramatic expansion in the development of novel human therapeutics. Many are biotechnology-derived biologics possessing high selectivity and affinity for their intended target; as such they often pose challenges in the development path to approval. One challenge is the selection of the first-in-human (FIH) dose. This process has come under increased scrutiny as a result of a FIH trial with a super-agonist monoclonal antibody (TGN1412), which resulted in significant injury to healthy volunteers. Regulatory agencies have responded with supplemental guidance for the development of novel therapeutics. The intent of this paper is to provide experience-based insight, with relevant examples, for those planning the first administration of novel biopharmaceuticals in humans.
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Surgical margin status after robot assisted radical cystectomy: results from the International Robotic Cystectomy Consortium.
J. Urol.
PUBLISHED: 05-15-2010
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Positive surgical margins at radical cystectomy confer a poor prognosis. We evaluated the incidence and predictors of positive surgical margins in patients who underwent robot assisted radical cystectomy for bladder cancer.
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Does previous robot-assisted radical prostatectomy experience affect outcomes at robot-assisted radical cystectomy? Results from the International Robotic Cystectomy Consortium.
Urology
PUBLISHED: 04-21-2010
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To evaluate the effect of previous robot-assisted radical prostatectomy (RARP) case volume on the outcomes of robot-assisted radical cystectomy. Little is known regarding the effect of previous robotic surgical experience on the implementation and execution of robot-assisted radical cystectomy.
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Telemetry in a motion-sickness model implicates the abdominal vagus in motion-induced gastric dysrhythmia.
Exp. Physiol.
PUBLISHED: 04-01-2010
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In humans, motion sickness is associated with disruption of normal gastric myoelectric activity, and it has been proposed that this results from an imbalance of autonomic nervous system activity. We used the established Suncus murinus (house musk shrew) model of motion-induced emesis to investigate the effect of horizontal motion on gastric myoelectric activity (recorded using telemetry) and the involvement of the abdominal vagi. Surgical vagotomy increased baseline dysrhythmia and reduced the dominant power of the gastric myoelectric signals. In response to motion, normal gastric myoelectric activity was reduced in sham-operated animals but not in vagotomized animals. Vagotomy, however, failed to affect motion-induced emesis. In conclusion, motion had a differential effect in sham-operated and vagotomized animals, which is consistent with the hypothesis that motion-induced dysrhythmia arises from an autonomic nervous system imbalance.
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Living donor kidney transplantation with multiple renal arteries in the laparoscopic era.
Urology
PUBLISHED: 03-26-2010
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To compare the postoperative complications and survival metrics after multiple renal arteries (MRA) and single renal artery (SRA) laparoscopically procured living donor kidney transplantation (LLDKT). MRA are the most frequently encountered anatomic variation during kidney transplantation. The long-term outcomes of LLDKT with MRA are not well characterized.
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Accuracy of ultrasound in estimation of prostate weight: comparison of urologists and radiologists.
Can J Urol
PUBLISHED: 02-17-2010
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Measurements of prostate size are obtained to contribute in the diagnosis and follow up of patients with a variety of diseases. Since its introduction, transrectal ultrasonography (TRUS) of the prostate has become the most common method for assessment of prostate volumes. Ultrasonography, in general, has been associated with concerns of operator dependent variability. Herein, we analyze the accuracy of urologists and radiologists performing TRUS.
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Early graft function after laparoscopically procured living donor kidney transplantation.
J. Urol.
PUBLISHED: 02-06-2010
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We determined predictors of poor early graft function after laparoscopic living donor kidney transplantation.
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Evaluation of central serotonin sensitivity in breast cancer survivors with cancer-related fatigue syndrome.
J Pain Symptom Manage
PUBLISHED: 01-15-2010
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Increased central serotonin sensitivity is hypothesized to contribute toward the development of cancer-related fatigue syndrome (CRFS).
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Successful transplantation of a split crossed fused ectopic kidney into a patient with end-stage renal disease.
J Transplant
PUBLISHED: 01-13-2010
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Potential donors with congenital renal anomalies but normal renal function are often overlooked because of a possible increase in technical difficulty and complications associated with the surgery. However, as the waiting list for a deceased donor kidney transplant continues to grow, it is important to consider these kidneys for potential transplant. This paper describes the procurement of a crossed fused ectopic kidney, and subsequent parenchymal transection prior to transplantation as part of a combined simultaneous kidney pancreas transplant. The transplant was uncomplicated, and the graft had immediate function. The patient is now two years from transplant with excellent function.
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Reduced normogastric electrical activity associated with emesis: a telemetric study in ferrets.
World J. Gastroenterol.
PUBLISHED: 12-23-2009
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To characterize the gastric myoelectric activity (GMA) and intra-abdominal pressure changes induced by emetic stimuli (apomorphine and cisplatin) in the ferret.
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Nonclinical safety assessment of the histone deacetylase inhibitor vorinostat.
Int. J. Toxicol.
PUBLISHED: 11-10-2009
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Vorinostat (SAHA, Zolinza), a histone deacetylase inhibitor, is assessed in nonclinical studies to support its approval for cutaneous T-cell lymphoma. Vorinostat is weakly mutagenic in the Ames assay; is clastogenic in rodent (ie, CHO) cells but not in normal human lymphocytes; and is weakly positive in an in vivo mouse micronucleus assay. No effects are observed on potassium ion currents in the hERG assay up to 300 microM (safety margin approximately 300-fold the approximately 1 microM serum concentration associated with the 400 mg/d maximum recommended human dose. No rat respiratory or central nervous system effects are found at 150 mg/kg (>2-fold maximum recommended human dose). No cardiovascular effects, including effects on QTc interval, are observed after a single oral dose (150 mg/kg) in dogs. Vorinostat is orally dosed daily in rats (controls, 20, 50, or 150 mg/kg/d) and dogs (controls, 60, 80, or 100/125/160 mg/kg/d) for 26 weeks with a 4-week recovery. Rat vorinostat-related adverse findings are decreased food consumption, weight loss, and hematologic changes; a no observed adverse effects level is not established. In dogs, adverse effects are primarily gastrointestinal; the no observed adverse effects level is 60 mg/kg/d (approximately 6-fold maximum recommended human dose). Toxicities are reversible and can be monitored in the clinic.
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Robot-assisted radical cystectomy: intermediate survival results at a mean follow-up of 25 months.
BJU Int.
PUBLISHED: 11-09-2009
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To assess the overall and disease-specific survival rates of patients undergoing robot-assisted radical cystectomy (RARC) compared with historical open cystectomy.
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Discovery and optimization of chromenotriazolopyrimidines as potent inhibitors of the mouse double minute 2-tumor protein 53 protein-protein interaction.
J. Med. Chem.
PUBLISHED: 10-28-2009
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Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that is frequently disabled in human tumors. In many tumor types, p53 is deleted or mutated, but in others p53 is inactivated by overexpression or amplification of its negative regulator mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as a potent inhibitor of the MDM2-p53 protein-protein interaction. This screening hit was found to be chemically unstable and difficult to handle due to poor DMSO solubility. Co-crystallization with the target protein helped to direct further optimization and provided a tractable lead series of novel MDM2-p53 inhibitors. In cellular assays, these compounds were shown to upregulate p53 protein levels and p53 signaling and to cause p53-dependent inhibition of proliferation and apoptosis.
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Radiation dose escalation for localized prostate cancer: intensity-modulated radiotherapy versus permanent transperineal brachytherapy.
Cancer
PUBLISHED: 08-12-2009
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In the current study, the effects of dose escalation for localized prostate cancer treatment with intensity-modulated radiotherapy (IMRT) or permanent transperineal brachytherapy (BRT) in comparison with conventional dose 3-dimensional conformal radiotherapy (3D-CRT) were evaluated.
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Olvanil: a non-pungent TRPV1 activator has anti-emetic properties in the ferret.
Neuropharmacology
PUBLISHED: 08-04-2009
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Anti-emetic drugs such as the tachykinin NK(1) receptor antagonists are useful to control emesis induced by diverse challenges. Evidence suggests pungent capsaicin-like TRPV1 activators also have broad inhibitory anti-emetic activity. However, pungent compounds are associated with undesirable effects including adverse actions on the cardiovascular system and on temperature homeostasis. In the present investigations using the ferret, we examine if the non-pungent vanilloid, olvanil, has useful anti-emetic properties without adversely affecting behaviour, blood pressure or temperature control. Olvanil (0.05-5 mg/kg, s.c.) was compared to the pungent vanilloid, resiniferatoxin (RTX; 0.1 mg/kg, s.c.), and to the anandamide reuptake inhibitor, AM404 (10 mg/kg, s.c.), for a potential to inhibit emesis induced by apomorphine (0.25 mg/kg, s.c.), copper sulphate (50 mg/kg, intragastric), and cisplatin (10 mg/kg, i.p.). Changes in blood pressure and temperature were also recorded using radiotelemetry implants. In peripheral administration studies, RTX caused transient hypertension, hypothermia and reduced food and water intake, but also significantly inhibited emesis induced by apomorphine, copper sulphate, or cisplatin. Olvanil did not have a similar adverse profile, and antagonised apomorphine- and cisplatin-induced emesis but not that induced by copper sulphate. AM404 reduced only emesis induced by cisplatin without affecting other parameters measured. Following intracerebral administration only olvanil antagonised cisplatin-induced emesis, but this was associated with transient hypothermia. In conclusion, olvanil demonstrated clear anti-emetic activity in the absence of overt cardiovascular, homeostatic, or behavioural effects associated with the pungent vanilloid, RTX. Our studies indicate that non-pungent vanilloids may have a useful spectrum of anti-emetic properties via central and/or peripheral mechanisms after peripheral administration.
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The bright side of being blue: depression as an adaptation for analyzing complex problems.
Psychol Rev
PUBLISHED: 07-22-2009
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Depression is the primary emotional condition for which help is sought. Depressed people often report persistent rumination, which involves analysis, and complex social problems in their lives. Analysis is often a useful approach for solving complex problems, but it requires slow, sustained processing, so disruption would interfere with problem solving. The analytical rumination hypothesis proposes that depression is an evolved response to complex problems, whose function is to minimize disruption and sustain analysis of those problems by (a) giving the triggering problem prioritized access to processing resources, (b) reducing the desire to engage in distracting activities (anhedonia), and (c) producing psychomotor changes that reduce exposure to distracting stimuli. As processing resources are limited, sustained analysis of the triggering problem reduces the ability to concentrate on other things. The hypothesis is supported by evidence from many levels-genes, neurotransmitters and their receptors, neurophysiology, neuroanatomy, neuroenergetics, pharmacology, cognition, behavior, and efficacy of treatments. In addition, the hypothesis provides explanations for puzzling findings in the depression literature, challenges the belief that serotonin transmission is low in depression, and has implications for treatment.
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Interval from prostate biopsy to robot-assisted radical prostatectomy: effects on perioperative outcomes.
BJU Int.
PUBLISHED: 06-22-2009
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To determine whether shorter intervals (<4 and 6 weeks) between prostate biopsy and robot-assisted radical prostatectomy (RARP) have a detrimental effect on perioperative outcomes, as recent studies showed that open RP shortly after prostate biopsy does not adversely influence surgical difficulty or efficacy, but RARP relies solely on visual cues rather than tactile sensation to determine posterior surgical planes of dissection.
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The delayed phase of cisplatin-induced emesis is mediated by the area postrema and not the abdominal visceral innervation in the ferret.
Neurosci. Lett.
PUBLISHED: 05-05-2009
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The anti-cancer chemotherapeutic agent cisplatin induces an acute (approximately 24 h) and delayed (approximately 24-72 h+) emetic response in humans; whereas the mechanism mediating the acute phase has been characterised, the delayed phase is relatively poorly understood. We have used nerve lesions (abdominal vagus, VX; greater splanchnic nerve, GSNX) and area postrema ablation (APX) in the ferret model of cisplatin (5 mg/kg, i.p.) delayed emesis and demonstrated that VX and VX+GSNX did not significantly modify the delayed emetic response (24-72 h), which consisted of 276.0+/-62.8 retches+vomits (R+V) in sham-operated ferrets and 167.2+/-34.0R+V and 214.8+/-40.2R+V, in the VX and VX+GSNX groups, respectively. APX virtually abolished the delayed phase of emesis and sham-operated ferrets had 93.0+/-22.9R+V whilst only 6.0+/-3.6R+V (p=0.009) were observed in APX animals. These data suggest that, in contrast to the acute emetic response triggered by cisplatin, the delayed phase does not rely on abdominal visceral afferents but is mediated via the area postrema.
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A novel and ergonomic patient position for laparoscopic kidney surgery.
Can J Urol
PUBLISHED: 04-15-2009
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Flank positioning with the patients ipsilateral arm elevated over the head on an arm board is often used during laparoscopic kidney surgery. There have been reports of brachial plexus neuropraxia, rhabdomyolysis and other complications related to this positioning. Herein we describe our modified positioning technique for laparoscopic renal surgery.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.