tbuckley/cabot-search huggingface dataset:
The Fitness Effects of Synonymous Mutations in DNA and RNA Viruses
Authors: José M. Cuevas, Pilar Domingo-Calap, Rafael Sanjuán
Journal: Molecular Biology and Evolution (2011)

Despite being silent with respect to protein sequence, synonymous nucleotide substitutions can be targeted by natural selection directly at the DNA or RNA level. However, there has been no systematic assessment of how frequent this type of selection is. Here, we have constructed 53 single random synonymous substitution mutants of the bacteriophages Qβ and ΦX174 by site-directed mutagenesis and assayed their fitness. Analysis of this mutant collection and of previous studies undertaken with a variety of single-stranded (ss) viruses demonstrates that selection at synonymous sites is stronger in RNA viruses than in DNA viruses. We estimate that this type of selection contributes approximately 18% of the overall mutational fitness effects in ssRNA viruses under our assay conditions and that random synonymous substitutions have a 5% chance of being lethal to the virus, whereas in ssDNA viruses, these figures drop to 1.4% and 0%, respectively. In contrast, the effects of nonsynonymous substitutions appear to be similar in ssRNA and ssDNA viruses.
Hypertonic saline alters ion transport across the human airway epithelium
Authors: P.G. Middleton, K.A. Pollard, J.R. Wheatley
Journal: European Respiratory Journal (2001)

Aerosolized hypertonic saline is currently being investigated as a new agent for the treatment of impaired mucociliary clearance which occurs in many respiratory diseases. Mannitol aerosols, in particular dry powder inhalers, have been proposed as an alternative treatment to saline, offering the same osmotic load with other benefits. However, the effects of these hypertonic aerosols on airway epithelial ion transport processes have not been tested in human subjects in vivo . This report examines the effect of these solutions on airway ion transport using the nasal potential difference (PD) technique. Seven healthy nonsmoking adult volunteers were studied. On different days, a dose-response curve was constructed for the saline added to Krebs N-[2-hydroxyethyl] piperazine-N′-[2-ethanesulphonic acid] (HEPES) diluent. The reversibility of this saline effect was measured, and the response to additional saline (500 mM) and mannitol (1 M) compared. Hypertonic saline decreased nasal PD in a dose-related manner, with mean (sem) decreases in PD (less negative) of 6.6 (1.5), 7.6 (1.6), 10.0 (2.0), 13.1 (2.9) and 14.8 (3.2) mV (n=4) for addition of 150 mM, 250 mM, 500 mM, 1,200 mM and 2,000 mM NaCl to the Krebs HEPES diluent, respectively. The effect of hypertonic saline was fully reversible with washout for 3 min (presaline 15.9 (0.5) mV, postwashout 15.8 (1.1) mV, (n=4)). The hypertonic saline response was rapid in onset, sustained for at least 4 min, and decreased PD from 13.7 (1.7) mV to 5.1 (1.3) mV (n=7, p&lt;0.001). In contrast, addition of mannitol to the perfusate did not significantly alter nasal PD, with a nonsignificant trend towards an increase (more negative) in the PD, (premannitol 13.9 (1.6) mV, postmannitol 15.3 (2.0) mV, n=7). As the osmotic stimulus of the 1 M mannitol is similar to that of the 500 mM sodium chloride, the divergent nasal potential difference responses suggest that the response to the saline was specific to the sodium chloride itself and not the simultaneous change in osmolarity. This demonstrates that the human airway epithelium in vivo can respond to topical hypertonic saline independent of the altered osmolarity.
Src Tyrosine Kinase Regulates Adhesion and Chemotaxis in Waldenstrom Macroglobulinemia
Authors: Hai T. Ngo, Abdel Kareem Azab, Mena Farag, Xiaoying Jia, Molly M. Melhem, Judith Runnels, Aldo M. Roccaro, Feda Azab, Antonio Sacco, Xavier Leleu, Kenneth C. Anderson, Irene M. Ghobrial
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma characterized by widespread involvement of the bone marrow. Despite different options of therapy, Waldenstrom macroglobulinemia is still incurable. Src tyrosine kinase has been shown to play a central role in the regulation of a variety of biological processes, such as cell proliferation, migration, adhesion, and survival in solid tumors. We sought to determine whether the protein tyrosine kinase Src regulates adhesion, migration, and survival in Waldenstrom macroglobulinemia. Experimental Design: We tested the expression of Src tyrosine kinase in Waldenstrom macroglobulinemia and normal cells, and the effect of the specific Src inhibitor AZD0530 on the adhesion, migration, cell cycle, and survival of a Waldenstrom macroglobulinemia cell line and patient samples. Moreover, we tested the effect of AZD0530 on cytoskeletal and cell cycle signaling in Waldenstrom macroglobulinemia. Results: We show that Src is overexpressed in Waldenstrom macroglobulinemia cells compared with control B cells, and that the use of the Src inhibitor AZD0530 led to significant inhibition of adhesion, migration, and cytoskeletal signaling induced by SDF1. Moreover, inhibition of Src activity induced G1 cell cycle arrest; however, it had minimal effect on survival of Waldenstrom macroglobulinemia cells, and no significant effect on survival of normal cells. Conclusions: Taken together, these results delineate the role of Src kinase activity in Waldenstrom macroglobulinemia and provide the framework for future clinical trials using Src inhibitors in combination with other drugs to improve the outcome of patients with Waldenstrom macroglobulinemia. (Clin Cancer Res 2009;15(19):6035–41)
Subcutaneous Ghrelin Enhances Acute Food Intake in Malnourished Patients Who Receive Maintenance Peritoneal Dialysis
Authors: Katie Wynne, Kalli Giannitsopoulou, Caroline J. Small, Michael Patterson, Gary Frost, Mohammad A. Ghatei, Edwina A. Brown, Stephen R. Bloom, Peter Choi
Journal: Journal of the American Society of Nephrology (2005)

Anorexia and malnutrition confer significant morbidity and mortality to patients with end-stage kidney disease but are resistant to therapy. The aim of this study was to determine whether subcutaneous administration of ghrelin, an appetite-stimulating gut hormone, could enhance food intake in patients who are receiving maintenance peritoneal dialysis and have evidence of malnutrition. The principal outcome measure was energy intake during a measured study meal. Secondary outcome measures were BP and heart rate and 3-d food intake after intervention. Nine peritoneal dialysis patients with mild to moderate malnutrition (mean serum albumin 28.6 ± 5.0 g/L, total cholesterol 4.4 ± 0.6 mmol/L, subjective global assessment score of 5.7 ± 1.7) were given subcutaneous ghrelin (3.6 nmol/kg) and saline placebo in a randomized, double-blind, crossover protocol. Administration of subcutaneous ghrelin significantly increased the group mean absolute energy intake, compared with placebo, during the study meal (690 ± 190 versus 440 ± 250 kcal; P = 0.0062). When expressed as proportional energy increase for each individual, ghrelin administration resulted in immediate doubling of energy intake (204 ± 120 versus 100%; P = 0.0319). Administration of ghrelin maintained a nonsignificant increase in energy intake over 24 h after intervention (2009 ± 669 versus 1579 ± 330 kcal) and was not followed by subsequent underswing (1790 ± 370 versus 1670 ± 530 and 1880 ± 390 versus 1830 ± 530 kcal on days 2 and 3, respectively). Ghrelin administration resulted in a significant fall in mean arterial BP (P = 0.0030 by ANOVA). There were no significant adverse events during the study. Subcutaneous ghrelin administration enhances short-term food intake in dialysis patients with mild to moderate malnutrition.
Relation of atrial natriuretic peptides to left ventricular systolic and diastolic function in heart failure
Authors: Anke A.M. Wijbenga, Aggie H.M.M. Balk, Fokke A.M. Jonkman, Frans Boomsma, Maarten L. Simoons, Arie J. Man in 't Veld
Journal: European Journal of Heart Failure (1999)
Population Genetics in Nonmodel Organisms: II. Natural Selection in Marginal Habitats Revealed by Deep Sequencing on Dual Platforms
Authors: R. Zhou, S. Ling, W. Zhao, N. Osada, S. Chen, M. Zhang, Z. He, H. Bao, C. Zhong, B. Zhang, X. Lu, D. Turissini, N. C. Duke, J. Lu, S. Shi, C.-I. Wu
Journal: Molecular Biology and Evolution (2011)

Population genetics of species living in marginal habitats could be particularly informative about the genetics of adaptation, but such analyses have not been readily feasible until recently. Sonneratia alba, a mangrove species widely distributed in the Indo-West Pacific, provides a very suitable system for the study of local adaptation. In this study, we analyzed DNA variation by pooling 71 genes from 85–100 individuals for DNA sequencing. For each of the two nearby S. alba populations, we obtained ∼2,500 × coverage on the Illumina GA platform and for the Sanya population, an additional 5,400 × coverage on the AB SOLiD platform. For the Sanya sample, although each sequencing method called many putative single nucleotide polymorphisms, the two sets of calls did not overlap, suggesting platform-dependent errors. Conventional sequencing corroborated that each population is monomorphic. The two populations differ by 54 bp of 79,000 sites, but 90% of the variants are found in 10% of the genes. Strong local adaptation and high migration may help to explain the extensive monomorphism shared by the two populations in the presence of a small number of highly differentiated loci.
ATM Kinase Inhibition Preferentially Sensitizes p53-Mutant Glioma to Ionizing Radiation
Authors: Laura Biddlestone-Thorpe, Muhammad Sajjad, Elizabeth Rosenberg, Jason M. Beckta, Nicholas C.K. Valerie, Mary Tokarz, Bret R. Adams, Alison F. Wagner, Ashraf Khalil, Donna Gilfor, Sarah E. Golding, Sumitra Deb, David G. Temesi, Alan Lau, Mark J. O'Connor, Kevin S. Choe, Luis F. Parada, Sang Kyun Lim, Nitai D. Mukhopadhyay, Kristoffer Valerie
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia–telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro. Experimental Design: Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump. Results: Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma. Conclusions: Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers. Clin Cancer Res; 19(12); 3189–200. ©2013 AACR.
Budesonide — A New Steroid for Intranasal Use
Authors: A. Warland, P. Møller, N. Lindqvist
Journal: Allergy (1981)

Twenty‐nine patients with seasonal rhinitis completed a double‐blind study comparing budesonide nasal spray 200 μg b.i.d. with placebo. The patients were randomly assigned into two parallel groups. Symptoms were assessed over a treatment period of 3 weeks. There were statistically significant differences in favour of budesonide on all measurements. Side effects were mild and the incidence was low.
Induction of Inflammation in Vascular Endothelial Cells by Metal Oxide Nanoparticles: Effect of Particle Composition
Authors: Andrea Gojova, Bing Guo, Rama S. Kota, John C. Rutledge, Ian M. Kennedy, Abdul I. Barakat
Journal: Environmental Health Perspectives (2006)

The mechanisms governing the correlation between exposure to ultrafine particles and the increased incidence of cardiovascular disease remain unknown. Ultrafine particles appear to cross the pulmonary epithelial barrier into the bloodstream, raising the possibility of direct contact with the vascular endothelium.Because endothelial inflammation is critical for the development of cardiovascular pathology, we hypothesized that direct exposure of human aortic endothelial cells (HAECs) to ultrafine particles induces an inflammatory response and that this response depends on particle composition.To test the hypothesis, we incubated HAECs for 1-8 hr with different concentrations (0.001-50 mug/mL) of iron oxide (Fe(2)O(3)), yttrium oxide (Y(2)O(3)), and zinc oxide (ZnO) nanoparticles and subsequently measured mRNA and protein levels of the three inflammatory markers intra-cellular cell adhesion molecule-1, interleukin-8, and monocyte chemotactic protein-1. We also determined nanoparticle interactions with HAECs using inductively coupled plasma mass spectrometry and transmission electron microscopy.Our data indicate that nanoparticle delivery to the HAEC surface and uptake within the cells correlate directly with particle concentration in the cell culture medium. All three types of nanoparticles are internalized into HAECs and are often found within intracellular vesicles. Fe(2)O(3) nanoparticles fail to provoke an inflammatory response in HAECs at any of the concentrations tested; however, Y(2)O(3) and ZnO nanoparticles elicit a pronounced inflammatory response above a threshold concentration of 10 mug/mL. At the highest concentration, ZnO nanoparticles are cytotoxic and lead to considerable cell death.These results demonstrate that inflammation in HAECs following acute exposure to metal oxide nanoparticles depends on particle composition.
Doctors who become chief executives in the NHS: from keen amateurs to skilled professionals
Authors: Chris Ham, John Clark, Peter Spurgeon, Helen Dickinson, Kirsten Armit
Journal: Journal of the Royal Society of Medicine (2011)

Summary Objectives To investigate the experiences of doctors who become chief executives of NHS organizations, with the aim of understanding their career paths and the facilitators and barriers encountered along the way. Design Twenty-two medical chief executives were identified and of these 20 were interviewed. In addition two former medical chief executives were interviewed. Information was collected about the age at which they became chief executives, the number of chief executive posts held, the training they received, and the opportunities, challenges and risks they experienced. Setting All NHS organizations in the United Kingdom in 2009. Results The age of medical chief executives on first appointment ranged from 36 to 64 years, the average being 48 years. The majority of those interviewed were either in their first chief executive post or had stepped down having held only one such post. The training and development accessed en route to becoming chief executives was highly variable. Interviewees were positive about the opportunity to bring about organizational and service improvement on a bigger scale than is possible in clinical work. At the same time, they emphasized the insecurities associated with being a chief executive. Doctors who become chief executives experience a change in their professional identity and the role of leaders occupying hybrid positions is not well recognized. Conclusions Doctors who become chief executives are self-styled ‘keen amateurs’ and there is a need to provide more structured support to enable them to become skilled professionals. The new faculty of medical leadership and management could have an important role in this process.
SHAPE-directed Discovery of Potent shRNA Inhibitors of HIV-1
Authors: Justin T Low, Stefanie A Knoepfel, Joseph M Watts, Olivier ter Brake, Ben Berkhout, Kevin M Weeks
Journal: Molecular Therapy (2012)

The RNA interference (RNAi) pathway can be exploited using short hairpin RNAs (shRNAs) to durably inactivate pathogenic genes. Prediction of optimal target sites is notoriously inaccurate and current approaches applied to HIV-1 show weak correlations with virus inhibition. In contrast, using a high-content model for disrupting pre-existing intramolecular structure in the HIV-1 RNA, as achievable using high-resolution SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemical probing information, we discovered strong correlations between inhibition of HIV-1 production in a quantitative cell-based assay and very simple thermodynamic features in the target RNA. Strongest inhibition occurs at RNA target sites that both have an accessible "seed region" and, unexpectedly, are structurally accessible in a newly identified downstream flanking sequence. We then used these simple rules to create a new set of shRNAs and achieved inhibition of HIV-1 production of 90% or greater for up to 82% of designed shRNAs. These shRNAs inhibit HIV-1 replication in therapy-relevant T cells and show no or low cytotoxicity. The remarkable success of this straightforward SHAPE-based approach emphasizes that RNAi is governed, in significant part, by very simple, predictable rules reflecting the underlying RNA structure and illustrates principles likely to prove broadly useful in understanding transcriptome-scale biological recognition and therapeutics involving RNA.
Static linear and nonlinear elastic properties of normal and arterialized venous tissue in dog and man.
Authors: R L Wesly, R N Vaishnav, J C Fuchs, D J Patel, J C Greenfield
Journal: Circulation Research (1975)

Ten normal and four transplanted canine jugular vein segments and four human saphenous vein segments were studied to determine the in vitro static elastic properties of venous tissue and their modification by transplantation into the arterial system. Both the intraluminal pressure and the longitudinal force were varied, and the resulting dimensions were recorded photographically. Venous segments manifested a hysteresis response but showed minimum tendency to creep. The pressure-strain relationships were curvilinear with an initial, highly compliant phase over the physiological venous pressure range followed by a relatively noncompliant phase. This transition occurred at lower pressures for jugular segments than it did for saphenous segments. In contrast, comparable-sized canine carotide artery segments did not show this essentially noncompliant phase over the pressure range studied (0 to 200 cm H2O). At comparable pressures and strains, the jugular vein segments were stiffer than the saphenous vein segments in both the circumferential and the longitudinal directions. At comparable strains, the saphenous vein moduli were similar to those in the carotid artery segments. Jugular segments transplanted into arterial circuits became virtually noncompliant and markedly inhomogeneous, with wall thickening and a histologic picture of intimal proliferation. They showed no tendency to "arterialize," that is, they failed to assume either the elastic or the histologic characteristics of arterial tissue.
Inhibitory effects of vesnarinone in the progression of myocardial damage in experimental autoimmune myocarditis in rats
Authors: S Ishiyama
Journal: Cardiovascular Research (1999)

Objectives: Vesnarinone, a positive inotropic and immunomodulatory agent, diminishes nitric oxide (NO) levels by suppressing the induction of inducible NO synthase (iNOS) expressed in cytokine-stimulated macrophages and cardiomyocytes. We examined whether vesnarinone exerts inhibitory effects on the progression of myocardial damage in experimental autoimmune myocarditis in rats through suppression of iNOS. Methods: Myocarditis was induced in 30 Lewis rats by injection of porcine cardiac myosin and vesnarinone was orally administered to 20 of the 30 rats. On day 21 after immunization (the climax of inflammation), the hemodynamics were examined and the severity of myocarditis was evaluated by determining the area ratio (%) [affected/entire area] of myocardial lesions in histological sections. Levels of serum CK-MB, NOx (NO2−+NO3−), TNF-α and IL-1β, and cyclic GMP, iNOS mRNA, TNF-α and IL-1β in heart tissues were determined. Expression of iNOS and TNF-α protein were examined by immunohistochemical methods. Results: Histopathological examination revealed extensive myocardial destruction and massive infiltration of inflammatory cells in the vesnarinone-untreated rats. The area ratio of the lesions in the treated rats was significantly lower than that in the untreated ones. Levels of CK-MB, NOx, cyclic GMP, cytokines and iNOS mRNA were significantly lower in the vesnarinone-treated rats. Infiltrating macrophages and cardiomyocytes in the untreated rats showed much higher levels of expression of iNOS and TNF-α than those in the vesnarinone-treated rats. Conclusions: Vesnarinone may prove to be useful in the treatment of myocarditis by attenuating NO production through suppression of iNOS induced by cytokines.
Cardiotoxicity of Histone Deacetylase Inhibitor Depsipeptide in Patients with Metastatic Neuroendocrine Tumors
Authors: Manisha H. Shah, Philip Binkley, Kenneth Chan, Jim Xiao, Daria Arbogast, Minden Collamore, Yasser Farra, Donn Young, Michael Grever
Journal: Clinical Cancer Research (2006)

Abstract Purpose: This phase II study was undertaken to assess objective response and toxicity of histone deacetylase inhibitor depsipeptide in patients with neuroendocrine tumors. Experimental Design: A total of 15 patients with metastatic neuroendocrine tumors received a 4-hour i.v. infusion of depsipeptide at 14 mg/m2 on days 1, 8, and 15 every 28 days. Tumor response was assessed at 8-week intervals using Response Evaluation Criteria in Solid Tumors. Most patients were chemo-naïve (n = 12) but receiving long-acting octreotide for carcinoid syndrome (n = 11). All patients had Eastern Cooperative Oncology Group performance status of 0 to 1. Results: The study was terminated prematurely due to an unexpected high number of serious cardiac adverse events so the objective response rate could not be determined. A total of 77 doses of depsipeptide with a median of four doses (range, 2-13) per patient were administered. The most common adverse events included nausea (86%), anorexia (73%), vomiting (66%), and fatigue (73%). A sudden death attributed to possible fatal ventricular arrhythmia occurred within 24 hours after the fifth dose of depsipeptide. Furthermore, asymptomatic grade 2 ventricular tachycardia (n = 2) and prolonged QTc (n = 3) probably related to depsipeptide were observed. Plasma depsipeptide levels measured in a subset of patients failed to reveal differences among patients with or without cardiac adverse events. Conclusions: Depsipeptide was associated with a high number of potentially serious cardiac adverse events in patients with metastatic neuroendocrine tumor. As sudden death possibly associated with depsipeptide was observed in this trial, the risks for potentially life-threatening arrhythmia associated with this agent need to be comprehensively evaluated.