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  • 1
    In: Neurology, 2014, Vol.82(1), pp.77-79
    Description: Randomization is the standard means for addressing known and unknown confounders within the patient population in clinical trials. Although random assignment to treatment arms on a 1:1 basis has long been the norm, many 2-armed confirmatory trials now use unequal allocation schemes where the number of patients receiving investigational interventions exceeds those in the comparator arm. In what follows, we offer 3 arguments for why investigators, institutional review boards, and data and safety monitoring boards should exercise caution when planning or reviewing 2-armed confirmatory trials involving unequal allocation ratios. We close by laying out some of the conditions where uneven allocation can be justified ethically.
    Keywords: Medicine;
    ISSN: 0028-3878
    E-ISSN: 1526632X
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  • 2
    Language: English
    In: Eukaryotic Cell, 2010, Vol. 9(10), p.1557
    Description: AprA and CfaD are secreted proteins that function as autocrine signals to inhibit cell proliferation in Dictyostelium discoideum. Cells lacking AprA or CfaD proliferate rapidly, and adding AprA or CfaD to cells slows proliferation. Cells lacking the ROCO kinase QkgA proliferate rapidly, with a doubling time 83% of that of the wild type, and overexpression of a QkgA-green fluorescent protein (GFP) fusion protein slows cell proliferation. We found that qkgA(-) cells accumulate normal levels of extracellular AprA and CfaD. Exogenous AprA or CfaD does not slow the proliferation of cells lacking qkgA, and expression of QkgA-GFP in qkgA(-) cells rescues this insensitivity. Like cells lacking AprA or CfaD, cells lacking QkgA tend to be multinucleate, accumulate nuclei rapidly, and show a mass and protein accumulation per nucleus like those of the wild type, suggesting that QkgA negatively regulates proliferation but not growth. Despite their rapid proliferation, cells lacking AprA, CfaD, or QkgA expand as a colony on bacteria less rapidly than the wild type. Unlike AprA and CfaD, QkgA does not affect spore viability following multicellular development. Together, these results indicate that QkgA is necessary for proliferation inhibition by AprA and CfaD, that QkgA mediates some but not all of the effects of AprA and CfaD, and that QkgA may function downstream of these proteins in a signal transduction pathway regulating proliferation.
    Keywords: Autocrine Communication ; Cell Proliferation -- Drug Effects ; Dictyostelium -- Cytology ; Protein Kinases -- Metabolism ; Protozoan Proteins -- Metabolism;
    ISSN: 1535-9778
    ISSN: 15359778
    ISSN: 15359786
    E-ISSN: 15359786
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  • 3
    Language: English
    In: European Journal of Pharmacology, 2010, Vol.643(2), pp.274-281
    Description: A strategy to overcome the side effect liabilities of oral PDE4 inhibitors has been to deliver the drugs by inhalation. In this report, we identify 1-[[5-(1(S)-aminoethly)-2-[8-methoxy-2-(triflurormethyl)-5-quinolinyl]-4-oxazolyl] carbonyl]-4(R)-[(cyclopropylcarbonyl)amino]-L-proline, ethyl ester xinafoate salt, (COMPOUND 1) as a potent and selective inhibitor of PDE4 with biological and pharmacokinetic properties suitable for delivery by the inhaled route. COMPOUND 1 potently inhibits human PDE4 (IC = 70 pM) with little or no activity against other PDEs. It is highly potent against PDE4B and PDE4D which are important isoforms of PDE4 controlling inflammation and airway functions. In an allergen-challenged Brown Norway rat model of asthma, COMPOUND 1 inhibited the late phase influx of inflammatory cells and reductions in lung function following its administration by the intratracheal or nose-only routes of administration. Important differences were seen between intratracheal COMPOUND 1 and our previously published results with the oral PDE4 inhibitor roflumilast (Celly et al., 2005), as COMPOUND 1 rapidly (within 1 h) reversed the decline in lung function when it was given therapeutically to rats already challenged with antigen. COMPOUND 1 was weakly active by the oral route which is a finding consistent with results showing this compound has poor oral bioavailability in animals. Positive interactions between COMPOUND 1 and albuterol, and COMPOUND 1 and mometasone furoate were seen on the improvement in lung functions in allergen-challenged rats. These results identify COMPOUND 1 as a potent and selective inhibitor of PDE4 with properties suitable for delivery by inhalation.
    Keywords: Inhaled Pde4 Inhibitor ; Dry Powder Aerosol ; Lung Function ; Corticosteroid ; Β-Adrenoceptor Agonist ; Combination Therapy ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0014-2999
    E-ISSN: 1879-0712
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  • 4
    Language: English
    In: Inflammation & Allergy-Drug Targets, 2013, Vol.12(2), p.124-131
    Description: Animal models are vital instruments of the drug discovery process. In addition to assessing the efficacy of candidate molecules, in vivo disease models also help validate the therapeutic potential of molecular targets. Over recent years, several molecules that have shown efficacy in preclinical models of respiratory diseases have failed to translate into new medicines for chronic respiratory conditions such as asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. As such, many scientists have argued that these systems are of limited value; however, we propose that a more careful and thorough approach to the characterization of these models and the interpretation of data generated using these systems would improve their translational utility. Herein, we describe two key elements of our strategy aiming to improve the predictive nature of these models: 1) Novel bioinformatics methods that can be used to identify animal models that best represent specific patient populations; and 2) Innovative physiological techniques that will improve our ability to discover drugs that can restore the functional capacity of lungs damaged during the course of the disease.
    Keywords: Animal Models ; Asthma ; Bioinformatics ; Copd ; Ipf ; Lung Physiology ; Respiratory Disease ; Translational Research.
    ISSN: 1871-5281
    E-ISSN: 2212-4055
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  • 5
    Language: English
    In: Journal of visualized experiments : JoVE, 06 April 2017(122)
    Description: Obstructive respiratory diseases like asthma and chronic obstructive pulmonary disease (COPD) are currently treated by inhaled anti-inflammatory and bronchodilator drugs. Despite the availability of multiple treatments, both diseases are growing public health concerns. The majority of asthma patients are well controlled on current inhaled therapies but a substantial number of patients with severe asthma are not. Asthma affects an estimated 300 million people worldwide and approximately 20 percent have a severe form of the disease. In contrast to asthma, there are few effective therapies for COPD. An estimated 10% of the population has COPD and the trend in death rates is increasing for COPD while decreasing for other major diseases. Although developing drugs for inhaled delivery is challenging, the nose-only inhalation unit enables direct delivery of novel drugs to the lung of rodents for pre-clinical efficacy and safety/toxicology studies. Inhaled drug delivery has multiple advantages for respiratory diseases, where high concentration in the lung improves efficacy and minimizes systemic side effects. Inhaled corticosteroids and bronchodilators benefit from these advantages and inhaled delivery may also hold potential for future biologic therapies. The inhalation unit described herein can generate, sample for characterization, and uniformly deposit a drug aerosol in the lungs of rodents. This enables the pre-clinical determination of the efficacy and safety of drug doses deposited in the lungs of rodents, key data required before initiating clinical development.
    Keywords: Equipment Design ; Nose ; Bronchodilator Agents -- Administration & Dosage ; Drug Delivery Systems -- Instrumentation
    E-ISSN: 1940-087X
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  • 6
    Language: English
    In: Disease Models & Mechanisms, 01 February 2015, Vol.8(2), pp.147-156
    Description: Neuronal ceroid lipofuscinosis (NCL) is the most common childhood-onset neurodegenerative disease. NCL is inevitably fatal, and there is currently no treatment available. Children with NCL show a progressive decline in movement, vision and mental abilities, and an accumulation of autofluorescent deposits in neurons and other cell types. Late-infantile NCL is caused by mutations in the lysosomal protease tripeptidyl peptidase 1 (TPP1). TPP1 cleaves tripeptides from the N-terminus of proteins in vitro, but little is known about the physiological function of TPP1. TPP1 shows wide conservation in vertebrates but it is not found in Drosophila, Caenorhabditis elegans or Saccharomyces cerevisiae. Here, we characterize ddTpp1, a TPP1 ortholog present in the social amoeba Dictyostelium discoideum. Lysates from cells lacking ddTpp1 show a reduced but not abolished ability to cleave a TPP1 substrate, suggesting that other Dictyostelium enzymes can perform this cleavage. ddTpp1 and human TPP1 localize to the lysosome in Dictyostelium, indicating conserved function and trafficking. Cells that lack ddTpp1 show precocious multicellular development and a reduced ability to form spores during development. When cultured in autophagy-stimulating conditions, cells lacking ddTpp1 rapidly decrease in size and are less viable than wild-type cells, suggesting that one function of ddTpp1 could be to limit autophagy. Cells that lack ddTpp1 exhibit strongly impaired development in the presence of the lysosome-perturbing drug chloroquine, and this phenotype can be suppressed through a secondary mutation in the gene that we name suppressor of tpp1− A (stpA), which encodes a protein with some similarity to mammalian oxysterol-binding proteins (OSBPs). Taken together, these results suggest that targeting specific proteins could be a viable way to suppress the effects of loss of TPP1 function.
    Keywords: Neuronal Ceroid Lipofuscinosis ; Batten Disease ; Tpp1 ; Tripeptidyl Peptidase 1 ; Dictyostelium ; Medicine ; Biology
    ISSN: 1754-8403
    E-ISSN: 1754-8411
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  • 7
    Language: English
    In: PLoS ONE, 01 January 2013, Vol.8(4), p.e59348
    Description: The preclinical model of bleomycin-induced lung fibrosis, used to investigate mechanisms related to idiopathic pulmonary fibrosis (IPF), has incorrectly predicted efficacy for several candidate compounds suggesting that it may be of limited value. As an attempt to improve the predictive nature of this model, integrative bioinformatic approaches were used to compare molecular alterations in the lungs of bleomycin-treated mice and patients with IPF. Using gene set enrichment analysis we show for the first time that genes differentially expressed during the fibrotic phase of the single challenge bleomycin model were significantly enriched in the expression profiles of IPF patients. The genes that contributed most to the enrichment were largely involved in mitosis, growth factor, and matrix signaling. Interestingly, these same mitotic processes were increased in the expression profiles of fibroblasts isolated from rapidly progressing, but not slowly progressing, IPF patients relative to control subjects. The data also indicated that TGFβ was not the sole mediator responsible for the changes observed in this model since the ALK-5 inhibitor SB525334 effectively attenuated some but not all of the fibrosis associated with this model. Although some would suggest that repetitive bleomycin injuries may more effectively model IPF-like changes, our data do not support this conclusion. Together, these data highlight that a single bleomycin instillation effectively replicates several of the specific pathogenic molecular changes associated with IPF, and may be best used as a model for patients with active disease.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Sci Rep, 2016, Vol.6(1), pp.26013-26013
    Description: CLARITY enables immunofluorescent labelling and imaging of large volumes of tissue to provide a better insight into the three dimensional relationship between cellular morphology and spatial interactions between different cell types. In the current study, we optimise passive CLARITY and immunofluorescent labelling of neurons and mitochondrial proteins in mouse and human brain tissues to gain further insights into mechanisms of neurodegeneration occurring in mitochondrial disease. This is the first study to utilise human cerebellum fixed in paraformaldehyde and cryoprotected in conjunction with formalin-fixed tissues opening up further avenues for use of archived tissue. We optimised hydrogel-embedding and passive clearance of lipids from both mouse (n = 5) and human (n = 9) cerebellum as well as developing an immunofluorescent protocol that consistently labels different neuronal domains as well as blood vessels. In addition to visualising large structures, we were able to visualise mitochondrial proteins in passively cleared tissues to reveal respiratory chain deficiency associated with mitochondrial disease. We also demonstrate multiple use of tissues by stripping antibodies and re-probing the cerebellum. This technique allows interrogation of large volumes intact brain samples for better understanding of the complex pathological changes taking place in mitochondrial disease.
    Keywords: Article;
    ISSN: 2045-2322
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  • 9
    Language: English
    In: American journal of physiology. Regulatory, integrative and comparative physiology, 01 January 2018, Vol.314(1), pp.R12-R21
    Description: Care of premature infants often requires parental and caregiver separation, particularly during hypoxic and hypothermic episodes. We have established a neonatal rat model of human prematurity involving maternal-neonatal separation and hypoxia with spontaneous hypothermia prevented by external heat. Adults previously exposed to these neonatal stressors show a sex difference in the insulin and glucose response to arginine stimulation suggesting a state of insulin resistance. The current study used this cohort of adult rats to evaluate insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)], plasma adipokines (reflecting insulin resistance states), and testosterone. The major findings were that daily maternal-neonatal separation led to an increase in body weight and HOMA-IR in adult male and female rats and increased plasma leptin in adult male rats only; neither prior neonatal hypoxia (without or with body temperature control) nor neonatal hypothermia altered subsequent adult HOMA-IR or plasma adiponectin. Adult male-female differences in plasma leptin were lost with prior exposure to neonatal hypoxia or hypothermia; male-female differences in resistin were lost in the adults that were exposed to hypoxia and spontaneous hypothermia as neonates. Exposure of neonates to daily hypoxia without spontaneous hypothermia led to a decrease in plasma testosterone in adult male rats. We conclude that neonatal stressors result in subsequent adult sex-dependent increases in insulin resistance and adipokines and that our rat model of prematurity with hypoxia without hypothermia alters adult testosterone dynamics.
    Keywords: Homa-IR ; Adipokines ; Androgens ; Leptin ; Neonatal Stress ; Sex Difference ; Insulin Resistance ; Maternal Deprivation ; Adiponectin -- Blood ; Anxiety, Separation -- Blood ; Hypothermia -- Blood ; Hypoxia -- Blood ; Insulin -- Blood ; Leptin -- Blood ; Resistin -- Blood ; Testosterone -- Blood
    ISSN: 03636119
    E-ISSN: 1522-1490
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  • 10
    Language: English
    In: Journal of applied physiology (Bethesda, Md. : 1985), September 2002, Vol.93(3), pp.873-81
    Description: Submucosal glands secrete macromolecules and liquid that are essential for normal airway function. To determine the mechanisms responsible for airway gland secretion and the interaction between gland secretion and epithelial ion transport, studies were performed in porcine tracheal epithelia by using the hillocks and Ussing techniques. No significant baseline gland fluid flux (J(G)) was measured by the hillocks technique after 3 min, and the epithelia had an average potential difference of 7.5 +/- 0.5 mV (lumen negative) with a short-circuit current of 73 +/- 4 microA/cm(2), as measured by the Ussing technique. The secretagogue methacholine induced concentration-dependent increases in J(G) after 3 min from 0.003 microl. min(-1). cm(-2) at 0.1 microM to 0.41 +/- 0.04 microl. min(-1). cm(-2) at 1,000 microM, with a 0.9 +/- 0.1 mV hyperpolarization of the epithelium at 1,000 microM. When the epithelium was pretreated for 3 min with the sodium channel blocker amiloride, the methacholine (1,000 microM)-induced J(G) increased to 0.67 +/- 0.09 microl. min(-1). cm(-2), and the hyperpolarization increased to 2.2 +/- 0.5 mV over the amiloride-pretreated level. When pretreated for 3 min with the chloride channel blocker diphenylamine-2-carboxylic acid, the methacholine (1,000 microM)-induced J(G) was inhibited to 0.20 +/- 0.06 microl. min(-1). cm(-2), and the methacholine-induced hyperpolarization was abolished. These data indicate that, in porcine airways, methacholine-induced J(G) may be increased by inhibition of sodium absorption and decreased by inhibition of chloride secretion.
    Keywords: Amiloride -- Pharmacology ; Chloride Channels -- Antagonists & Inhibitors ; Methacholine Chloride -- Pharmacology ; Muscarinic Agonists -- Pharmacology ; Respiratory Mucosa -- Drug Effects ; Sodium Channel Blockers -- Pharmacology ; Ortho-Aminobenzoates -- Pharmacology
    ISSN: 8750-7587
    E-ISSN: 15221601
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