tbuckley/cabot-search huggingface dataset:
Engineered Botulinum Neurotoxins as New Therapeutics
Authors: Geoffrey Masuyer, John A. Chaddock, Keith A. Foster, K. Ravi Acharya
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Botulinum neurotoxins (BoNTs) cause flaccid paralysis by inhibiting neurotransmission at cholinergic nerve terminals. Each BoNT consists of three domains that are essential for toxicity: the binding domain, the translocation domain, and the catalytic light-chain domain. BoNT modular architecture is associated with a multistep mechanism that culminates in the intracellular proteolysis of SNARE (soluble N-ethylmaleimide-sensitive-fusion-protein attachment protein receptor) proteins, which prevents synaptic vesicle exocytosis. As the most toxic proteins known, BoNTs have been extensively studied and are used as pharmaceutical agents to treat an increasing variety of disorders. This review summarizes the level of sophistication reached in BoNT engineering and highlights the diversity of approaches taken to utilize the modularity of the toxin. Improved efficiency and applicability have been achieved by direct mutagenesis and interserotype domain rearrangement. The scope of BoNT activity has been extended to nonneuronal cells and offers the basis for novel biomolecules in the treatment of secretion disorders.
Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial
Authors: Alexander MM Eggermont, Stefan Suciu, Mario Santinami, Alessandro Testori, Wim HJ Kruit, Jeremy Marsden, Cornelis JA Punt, François Salès, Martin Gore, Rona MacKie, Zvonko Kusic, Reinhard Dummer, Axel Hauschild, Elena Musat, Alain Spatz, Ulrich Keilholz
Journal: The Lancet (2008)
Tiotropium improves walking endurance in COPD
Authors: M.-E. Bedard, C. Brouillard, V. Pepin, S. Provencher, J. Milot, Y. Lacasse, P. Leblanc, F. Maltais
Journal: European Respiratory Journal (2011)

The primary objective of this study was to evaluate the effects of a 3-week treatment with tiotropium on walking capacity in chronic obstructive pulmonary disease (COPD). After familiarisation with study procedures, 36 patients were randomised to receive tiotropium 18 μg once daily or a matching placebo in a double-blind, parallel-group study. Pre- (trough) and 2-h post-dose pulmonary function was measured. An endurance shuttle walk was then completed. The same procedures were repeated after 3 weeks of treatment. Ventilatory parameters were monitored during exercise. At 3 weeks, tiotropium significantly improved walking endurance time in comparison with placebo, with a mean±sd between-group difference of 128±141 s (p=0.017). At 3 weeks, trough values for forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were significantly improved with tiotropium in comparison with placebo. The post-dose response to tiotropium was statistically superior to placebo after the first dose and after 3 weeks of treatment for FEV(1), FVC and inspiratory capacity. Ventilation and tidal volume at the end of walking were significantly improved with tiotropium. 3 weeks of tiotropium resulted in a greater walking endurance in patients with COPD. Improvements in FEV(1), maximal ventilation and tidal volume may contribute to this enhanced exercise capacity.
Rapid dendritic cell recruitment to the bronchial mucosa of patients with atopic asthma in response to local allergen challenge
Authors: F.L. Jahnsen, E.D. Moloney, T. Hogan, J.W. Upham, C.M. Burke, Patrick Holt
Journal: Thorax (2001)

Airway dendritic cells (DC) play an important role in chronic allergic airway inflammation in experimental animals, but a similar role for DC in human allergic asthma has been difficult to define. This pilot study was undertaken to elucidate the role of DC in allergic asthma by examining their potential to migrate to the lower airways in response to bronchial challenge with specific allergen.Bronchial biopsy specimens were obtained from seven patients with allergic asthma before and 4-5 hours after allergen challenge. Multicolour immunofluorescence staining was performed on mucosal cryosections to identify changes in the number and phenotypes of DC.A dramatic increase in the number of CD1c+HLA-DR+ DC were observed in the lamina propria after challenge compared with baseline (22.4 v 7.8 cells/mm(2)). The rapid accumulation (within 4-5 hours) of these cells strongly suggests that they were directly recruited from peripheral blood.We have shown for the first time that a specific DC subset rapidly emigrates into the human bronchial mucosa during allergic inflammation. While this study is based on relatively few patients, the consistency of the overall results strongly suggests that the rapid population dynamics of human airway DC closely parallel those in animal models of acute inflammation. These findings support suggestions that DC have an important role in human airway allergy.
Novel targeted therapies: the future of rheumatoid arthritis? Mavrilumab and tabalumab as examples
Authors: Bernard Combe, Ronald van Vollenhoven
Journal: Annals of the Rheumatic Diseases (2013)

Rheumatoid arthritis (RA) control and outcome has greatly improved with the efficacy of biologic disease-modifying antirheumatic drugs (DMARDs)1 combined with early effective management and treatment targeting remission or low disease activity.2 ,3

However, although biologic therapy-blocking key molecules involved in the pathogenesis of RA has greatly improved RA management, some needs are still unmet. About 30% of patients with RA show inadequate response to the first biologic therapy,4–8 which is usually a tumour necrosis factor (TNF) blocker, currently considered with methotrexate (MTX) as the ‘gold standard’ in RA therapy.1 After failure of at least one TNF inhibitor, the response rate of biological agents is 20–40% after adjustment for the placebo response.9 In addition, the response may decrease over time in some patients. Finally, only a few patients achieve remission or low disease activity, the rate being lower for established than early RA.2

Since the remarkable but partial success of TNF inhibitors, tremendous efforts have been made to offer additional treatment options for RA patients. Thus, several biologics drugs with other modes of action have been developed, which block cytokines other than TNF or cells involved in the pathogenesis of RA.10 This has led to the licensing of biological DMARDs inhibiting interleukin 1 (IL-1) (anakinra), IL-6 receptor (tocilizumab), B cells (rituximab) and T-cell costimulation (abatacept).1 ,3 The availability of this variety of biological drugs has offered additional strategies for rheumatologists in daily practice, but refractory patients remain, and many still have active disease and progressive disability. Another ‘fashionable’ and more recent strategy has been to try to identify biomarkers that could identify subpopulations of patients with better response to a specific drug.11 However, biomarkers, so far, have failed to predict the clinical response to any biological or synthetic DMARD at …
Chronic hepatitis E infection in children with liver transplantation
Authors: Ugur Halac, Kathie Béland, Pascal Lapierre, Natacha Patey, Pierre Ward, Julie Brassard, Alain Houde, Fernando Alvarez
Journal: Gut (2011)

Chronic hepatitis E virus (HEV) infection has been described in immunosuppressed adult patients. A study was undertaken to establish the presence of HEV infection in children after orthotopic liver transplantation (OLT).Children undergoing liver transplantation between 1992 and 2010 with available serum were classified into two groups: group 1 (control group, n=66) with normal serum aminotransferases and group 2 (n=14) with persistently increased serum aminotransferases and histological features of chronic hepatitis. Patients were tested for HEV RNA by reverse transcription-polymerase chain reaction (RT-PCR). HEV amplicons were sequenced and compared with published sequences. Antibody titres (IgG and IgM) to 12 HEV immunodominant regions were measured by enzyme-linked immunosorbent assays.In group 1 (control group), 15% of children were anti-HEV IgG-positive during follow-up. No anti-HEV IgM antibodies were detected in any of these children. After OLT, 86% of patients in group 2 had anti-HEV IgG compared with 36% pre-OLT. Thus, two-thirds of children acquired anti-HEV IgG after OLT. Seven anti-HEV IgG-positive patients (58%) were also anti-HEV IgM-positive more than once during follow-up after OLT. Eight years post-OLT, one girl presented with anti-HEV IgG and IgM that remained positive afterwards. In this patient, HEV RNA was found in five different annual samples from 10 years post-OLT, concomitantly with increased serum aminotransferases and cirrhosis development during that period. Phylogenetic analysis revealed two different HEV strains (detected 3 years apart) that were highly similar to swine genotype 3, suggesting a possible case of zoonotic re-infection.The diagnosis of HEV infection is technically challenging and should be made simultaneously with RT-PCR methods, viral load quantification and serological markers. In immunosuppressed children who develop chronic hepatitis, the prevalence of HEV is high and could explain the chronic liver inflammation potentially leading to cirrhosis. Re-infection by different HEV strains from zoonotic transmission can result in progressive liver disease in immunocompromised children.
Exposure to Juniperus Ashei (Mt. Cedar) Pollen in a Pollen Challenge Chamber Elicits Changes in White Blood Cell Counts and Cytokines in Mountain Cedar Positive and Negative Subjects
Authors: Weijing He, Andrew Carrillo, Nathan Harper, Fabio Jimenez, Hernan Martinez, Seema Ahuja, Cynthia Rather, Daniel Ramirez, Charles Andrews, Robert L. Jacobs, Sunil Ahuja
Journal: Journal of Allergy and Clinical Immunology (2013)
Hydraulic Power Associated with Pulmonary Blood Flow and its Relation to Heart Rate
Authors: WILLIAM R. MILNOR, DEREK H. BERGEL, JACK D. BARGAINER
Journal: Circulation Research (1966)

Pulmonary vascular input impedance and hydraulic power were measured at various heart rates in 29 anesthetized and 5 unanesthetized dogs. Hydraulic power at the pulmonary veno-atrial junction was measured in 5 dogs. The pulmonary vascular impedance spectrum in the unanesthetized dogs did not differ significantly from that in the anesthetized dogs. Average pulmonary arterial power in the anesthetized dogs was 157 milliwatts (mw), of which 108 mw was associated with mean pressure and flow, and 49 mw with the pulsations around these means. Seventy-eight per cent of this input power was dissipated in passage through the pulmonary bed. Kinetic energy accounted for 7% of the total input power. Because of a steep fall in impedance between zero and 3 cycles/sec, and a rate-dependent change in the harmonic structure of flow pulsations, there was an inverse relationship between heart rate and the input power for a given mean flow, up to 180 beats/min. Pulmonary vascular dimensions and elasticity, which determine impedance, thus embody a mechanism whereby tachycardia can increase pulmonary blood flow by as much as 35% with an increase in pulmonary arterial input power of less than 5%, without the intervention of vasomotor activity.
Comparative effects of three class I antiarrhythmic drugs on plateau and pacemaker currents of sheep cardiac Purkinje fibres
Authors: E. CORABOEUF, E. DEROUBAIX, D. ESCANDE, A. COULOMBE
Journal: Cardiovascular Research (1988)

The electrophysiological effects of three class I antiarrhythmic drugs, lignocaine, disopyramide, and penticainide, were compared in sheep cardiac Purkinje fibres. Action potential duration was shortened with all three drugs, the effect being small with disopyramide, moderate with penticainide, and greatest with lignocaine. Slowing down of the early phase of repolarisation was greatest with disopyramide, smaller with penticainide, and did not occur with lignocaine. Automaticity recorded in low potassium media was unaltered (disopyramide), depressed (penticainide), or stopped (lignocaine). Ionic currents were recorded in short fibres using the two microelectrode voltage clamp technique. The tetrodotoxin sensitive slow component of the sodium current was suppressed (lignocaine) or reduced (penticainide and disopyramide) and the instantaneous background potassium current slightly reduced (disopyramide more than penticainide), unaffected, or slightly increased (lignocaine). The three drugs depressed moderately and similarly the slow inward calcium current. The amplitude of the 4-aminopyridine sensitive transient outward potassium current was almost unaffected (lignocaine) or appreciably depressed (disopyramide more than penticainide). The pacemaker current was reduced greatly by lignocaine, moderately by penticainide, and slightly by disopyramide. Changes in ionic currents may explain the effects of the three drugs on action potential plateau and automaticity of sheep Purkinje fibres. It is concluded that the pronounced differences observed in the effects of these three class I antiarrhythmic drugs on pacemaker depolarisation and on initial repolarisation may justify a more discriminative subdivision of class I antiarrhythmic drugs.
Mammalian phylogeny: comparison of morphological and molecular results.
Authors: J Shoshani
Journal: Molecular Biology and Evolution (1986)

In an attempt to resolve the "bushy" part at the root of the eutherian tree, 182 nondental morphological characters from 100 species (79 extant and 21 extinct; 98 mammalian and 2 nonmammalian) were analyzed using two maximum-parsimony tree-building algorithms. Parallel analyses of 2,258 pairwise immunodiffusion comparisons with chicken antisera on 101 mammalian species and of amino acid sequence data of alpha and beta hemoglobins and other published protein sequences were also carried out. The morphological and molecular phylogenies agree in depicting the infraclass Eutheria as consisting of five major clades (thus resolving part of the "bush"). Rates of evolution were also found to be similar in the two types of phylogenies.
GIV/Girdin Links Vascular Endothelial Growth Factor Signaling to Akt Survival Signaling in Podocytes Independent of Nephrin
Authors: Honghui Wang, Taro Misaki, Vanessa Taupin, Akiko Eguchi, Pradipta Ghosh, Marilyn G. Farquhar
Journal: Journal of the American Society of Nephrology (2014)

Podocytes are critically involved in the maintenance of the glomerular filtration barrier and are key targets of injury in many glomerular diseases. Chronic injury leads to progressive loss of podocytes, glomerulosclerosis, and renal failure. Thus, it is essential to maintain podocyte survival and avoid apoptosis after acute glomerular injury. In normal glomeruli, podocyte survival is mediated via nephrin-dependent Akt signaling. In several glomerular diseases, nephrin expression decreases and podocyte survival correlates with increased vascular endothelial growth factor (VEGF) signaling. How VEGF signaling contributes to podocyte survival and prevents apoptosis remains unknown. We show here that Gα-interacting, vesicle-associated protein (GIV)/girdin mediates VEGF receptor 2 (VEGFR2) signaling and compensates for nephrin loss. In puromycin aminonucleoside nephrosis (PAN), GIV expression increased, GIV was phosphorylated by VEGFR2, and p-GIV bound and activated Gαi3 and enhanced downstream Akt2, mammalian target of rapamycin complex 1 (mTORC1), and mammalian target of rapamycin complex-2 (mTORC2) signaling. In GIV-depleted podocytes, VEGF-induced Akt activation was abolished, apoptosis was triggered, and cell migration was impaired. These effects were reversed by introducing GIV but not a GIV mutant that cannot activate Gαi3. Our data indicate that after PAN injury, VEGF promotes podocyte survival by triggering assembly of an activated VEGFR2/GIV/Gαi3 signaling complex and enhancing downstream PI3K/Akt survival signaling. Because of its important role in promoting podocyte survival, GIV may represent a novel target for therapeutic intervention in the nephrotic syndrome and other proteinuric diseases.
Dispositional Predictors of Problem Gambling in Male Adolescents
Authors: Frank Vitaro, Louise Arseneault, Richard E. Tremblay
Journal: American Journal of Psychiatry (1997)

This study investigated the possible relationship between impulsivity in early adolescence and gambler status in late adolescence.Impulsivity measures consisting of self-reports and teacher ratings were gathered from 754 boys in early adolescence, and their gambling status in late adolescence was assessed with a self-report measure.On both measures of impulsivity, nongamblers had the lowest scores, recreational gamblers had the next higher scores, low problem gamblers had still higher scores, and high problem gamblers had the highest scores.These findings support the DSM-IV classification of problem gambling as a deficit in impulse control.
<i>Salmonella typhimurium</i> Persists within Macrophages in the Mesenteric Lymph Nodes of Chronically Infected <i>Nramp1</i>+<i>/</i>+ Mice and Can Be Reactivated by IFNγ Neutralization
Authors: Denise M. Monack, Donna M. Bouley, Stanley Falkow
Journal: The Journal of Experimental Medicine (2004)

Host-adapted strains of Salmonella are capable of establishing a persistent infection in their host often in the absence of clinical disease. The mouse model of Salmonella infection has primarily been used as a model for the acute systemic disease. Therefore, the sites of long-term S. typhimurium persistence in the mouse are not known nor are the mechanisms of persistent infection clearly understood. Here, we show that S. typhimurium can persist for as long as 1 yr in the mesenteric lymph nodes (MLNs) of 129sv Nramp1+/+ (Slc11a1+/+) mice despite the presence of high levels of anti–S. typhimurium antibody. Tissues from 129sv mice colonized for 60 d contain numerous inflammatory foci and lesions with features resembling S. typhi granulomas. Tissues from mice infected for 365 d have very few organized inflammatory lesions, but the bacteria continue to persist within macrophages in the MLN and the animals generally remain disease-free. Finally, chronically infected mice treated with an interferon-γ neutralizing antibody exhibited symptoms of acute systemic infection, with evidence of high levels of bacterial replication in most tissues and high levels of fecal shedding. Thus, interferon-γ, which may affect the level of macrophage activation, plays an essential role in the control of the persistent S. typhimurium infection in mice.
The Role of α-Folate Receptor-Mediated Transport in the Antitumor Activity of Antifolate Drugs
Authors: Davinder S. Theti, Ann L. Jackman
Journal: Clinical Cancer Research (2004)

Raltitrexed, pemetrexed, lometrexol, and ZD9331 are antifolate drugs transported into cells via the ubiquitously expressed reduced-folate carrier. They display also high affinity for the alpha-folate receptor (alpha-FR), a low capacity folate transporter that is highly overexpressed in some epithelial tumors. The role of alpha-FR in the activity of the antifolates has been evaluated in two alpha-FR-overexpressing cell lines grown in a physiological concentration of folate (20 nM R,S-Leucovorin).A431-FBP cells (transfected with the alpha-FR) were 3-5-fold more sensitive to the antifolates than A431 cells. KB cells (constitutive alpha-FR overexpression) were less sensitive to the drugs when coexposed to 1 microM folic acid to competitively inhibit binding to the alpha-FR. Raltitrexed, pemetrexed, and lometrexol are polyglutamated in cells leading to drug retention, e.g., the raltitrexed 4- and 24-h IC(50)s in A431 cells were approximately 0.6 and 0.008 microM, respectively, compared with 0.003 microM for 72-h continuous exposure. A431-FBP cells were approximately 3-fold more sensitive to raltitrexed and pemetrexed at all exposure times. ZD9331 is not polyglutamated, and the 4- and 24-h IC(50)s in A431 cells were >100 and approximately 100 microM, respectively, reducing to 2 and 0.1 microM, respectively, in A431-FBP cells. The ZD9331 4- and 24-h IC(50)s in KB cells were 20 and 1 microM, respectively, and reversible by coaddition of 1 microM folic acid. An in situ thymidylate synthase assay demonstrated continued thymidylate synthase inhibition after ZD9331-treated A431-FBP and KB, but not A431, cells were placed in drug-free medium for 16 h. A model is proposed in which the antifolates accumulate in the alpha-FR/endosomal apparatus, leading to slow release into the cytoplasm. In particular, this leads to cellular retention of the nonpolyglutamatable ZD9331.Antifolate drugs, particularly ZD9331, have the potential for increased efficacy in tumors that highly overexpress the alpha-FR.
ABERRANT DNA METHYLATION AS A CANCER-INDUCING MECHANISM
Authors: Manel Esteller
Journal: The Annual Review of Pharmacology and Toxicology (2005)

Aberrant DNA methylation is the most common molecular lesion of the cancer cell. Neither gene mutations (nucleotide changes, deletions, recombinations) nor cytogenetic abnormalities are as common in human tumors as DNA methylation alterations. The most studied change of DNA methylation in neoplasms is the silencing of tumor suppressor genes by CpG island promoter hypermethylation, which targets genes such as p16(INK4a), BRCA1, and hMLH1. There is a profile of CpG island hypermethylation according to the tumor type, and genes silent by methylation represent all cellular pathways. The introduction of bisulfite-PCR methodologies combined with new genomic approaches provides a comprehensive spectrum of the genes undergoing this epigenetic change across all malignancies. However, we still know very little about how this aberrant DNA methylation "invades" the previously unmethylated CpG island and how it is maintained through cell divisions. Furthermore, we should remember that this methylation occurs in the context of a global genomic loss of 5-methylcytosine (5mC). Initial clues to understand this paradox should be revealed from the current studies of DNA methyltransferases and methyl CpG binding proteins. From the translational standpoint, we should make an effort to validate the use of some hypermethylated genes as biomarkers of the disease; for example, it may occur with MGMT and GSTP1 in brain and prostate tumors, respectively. Finally, we must expect the development of new and more specific DNA demethylating agents that awake these methyl-dormant tumor suppressor genes and prove their therapeutic values. The expectations are high.
Alternative pathway of complement: demonstration and characterization of initiating factor and its properdin-independent function.
Authors: R D Schreiber, O Götze, H J Müller-Eberhard
Journal: The Journal of Experimental Medicine (1976)

A novel component of the properdin system has been discribed which represents a heretofore unrecognized human serum protein. The protein has been tentatively termed the initiating factor (IF) because it functions in the initial reaction of the properdin pathway. IF is a 170,000 dalton beta-pseudoglobulin which is composed of two presumably identical 85,000 dalton chains linked by disulfide bonds. The protein reacts with antibody to nephritic factor, which is defined by its activity and is found in the serum of patients with certain nephritides. The activity of IF is heat stable. Upon treatment of serum with activators of the alternative pathway, the initial C3 convertase is assembled from IF, Factors D and C, C3, and magnesium without participation of properdin. It is the function of the enzyme to deposit C3b on the surface of the activator particles, thereby affording generation of the solid phase enzymes of the pathway, a process that is a prerequisite for properdin activation. By exposure to low pH, IF assumed the electrophoretic mobility of psi-globulin and acquired the ability to generate without activators a fluid phase C3 convertase in serum. Serum depleted of IF did not allow activation of the properdin pathway. Serum depleted of properdin did permit activation of the pathway and expression of cytolytic activity. These results raise the possibility that IF represents the recognition unit of the pathway.