tbuckley/cabot-search huggingface dataset:
RXP-E
Authors: Rebecca Lewandowski, Kristina Procida, Ravi Vaidyanathan, Wanda Coombs, José Jalife, Morten S. Nielsen, Steven M. Taffet, Mario Delmar
Journal: Circulation Research (2008)

Gap junctions provide a low-resistance pathway for cardiac electric propagation. The role of GJ regulation in arrhythmia is unclear, partly because of limited availability of pharmacological tools. Recently, we showed that a peptide called "RXP-E" binds to the carboxyl terminal of connexin43 and prevents chemically induced uncoupling in connexin43-expressing N2a cells. Here, pull-down experiments show RXP-E binding to adult cardiac connexin43. Patch-clamp studies revealed that RXP-E prevented heptanol-induced and acidification-induced uncoupling in pairs of neonatal rat ventricular myocytes. Separately, RXP-E was concatenated to a cytoplasmic transduction peptide (CTP) for cytoplasmic translocation (CTP-RXP-E). The effect of RXP-E on action potential propagation was assessed by high-resolution optical mapping in monolayers of neonatal rat ventricular myocytes, containing approximately 20% of randomly distributed myofibroblasts. In contrast to control experiments, when heptanol (2 mmol/L) was added to the superfusate of monolayers loaded with CTP-RXP-E, action potential propagation was maintained, albeit at a slower velocity. Similarly, intracellular acidification (pH(i) 6.2) caused a loss of action potential propagation in control monolayers; however, propagation was maintained in CTP-RXP-E-treated cells, although at a slower rate. Patch-clamp experiments revealed that RXP-E did not prevent heptanol-induced block of sodium currents, nor did it alter voltage dependence or amplitude of Kir2.1/Kir2.3 currents. RXP-E is the first synthetic molecule known to: (1) bind cardiac connexin43; (2) prevent heptanol and acidification-induced uncoupling of cardiac gap junctions; and (3) preserve action potential propagation among cardiac myocytes. RXP-E can be used to characterize the role of gap junctions in the function of multicellular systems, including the heart.
High disease activity of ankylosing spondylitis in the community before the introduction of tumour necrosis factor blockers
Authors: J. Hermann, T. Muller, B. Yazdani-Biuki, M. Aringer, M. Herold, W. Ebner, P. Ofner, W. Graninger
Journal: Annals of the Rheumatic Diseases (2006)

will be more dependent on +2373ARG than on +2035CRG, as this latter SNP was discordant in haplotype 5.This study confirms the association of common SNPs in the DNASE I gene with SLE, although it fails to show a correlation with low DNase I activity or production of antinuclear antibodies in patients' sera.Therefore, other mechanisms should be explored to explain the SLE susceptibility related to DNASE I variation and the low DNase I activity observed in most patients.
Characterization of p53 Wild-Type and Null Isogenic Colorectal Cancer Cell Lines Resistant to 5-Fluorouracil, Oxaliplatin, and Irinotecan
Authors: John Boyer, Estelle G. McLean, Somaiah Aroori, Peter Wilson, Andrea McCulla, P. Declan Carey, Daniel B. Longley, Patrick G. Johnston
Journal: Clinical Cancer Research (2004)

Abstract To elucidate mechanisms of resistance to chemotherapies currently used in the first-line treatment of advanced colorectal cancer, we have developed a panel of HCT116 p53 wild-type (p53+/+) and null (p53−/−) isogenic colorectal cancer cell lines resistant to the antimetabolite 5-fluorouracil (5-FU), topoisomerase I inhibitor irinotecan (CPT-11), and DNA-damaging agent oxaliplatin. These cell lines were generated by repeated exposure to stepwise increasing concentrations of each drug over a period of several months. We have demonstrated a significant decrease in sensitivity to 5-FU, CPT-11, and oxaliplatin in each respective resistant cell line relative to the parental line as determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, with increases in IC50 (72 h) concentrations ranging from 3- to 65-fold. Using flow cytometry, we have also demonstrated compromised apoptosis and cell cycle arrest in 5-FU-, oxaliplatin-, and CPT-11-resistant cell lines compared with the parental lines after exposure to each drug. In addition, we found that resistance to 5-FU and oxaliplatin was higher in parental p53−/− cells compared with parental p53+/+ cells, with an ∼5-fold increase in IC50 (72 h) for each drug. In contrast, the IC50 (72 h) doses for CPT-11 were identical in the p53 wild-type and null cell lines. Furthermore, apoptosis after treatment with 5-FU and oxaliplatin, but not CPT-11, was significantly reduced in parental p53−/− cells compared with parental p53+/+ cells. These data suggest that p53 may be an important determinant of sensitivity to 5-FU and oxaliplatin but not CPT-11. Using semiquantitative reverse transcription-PCR, we have demonstrated down-regulation of thymidine phosphorylase mRNA in both p53+/+ and p53−/− 5-FU-resistant cells, suggesting that decreased production of 5-FU active metabolites may be an important resistance mechanism in these lines. In oxaliplatin-resistant cells, we noted increased mRNA levels of the nucleotide excision repair gene ERCC1 and ATP-binding cassette transporter breast cancer resistance protein. In CPT-11-resistant cells, we found reduced mRNA levels of carboxylesterase, the enzyme responsible for converting CPT-11 to its active metabolite SN-38, and topoisomerase I, the SN-38 target enzyme. In addition, we noted overexpression of breast cancer resistance protein in the CPT-11-resistant lines. These cell lines are ideal tools with which to identify novel determinants of drug resistance in both the presence and absence of wild-type p53.
Cardiac cellular heterogeneity and remodelling
Authors: P KOHL
Journal: Cardiovascular Research (2004)

See article by Zorn-Pauly et al.  [17]  (pages 250–259) in this issue. 

Uniform cardiac pump function requires well-coordinated myocardial heterogeneity at the cellular level. This insight was eloquently presented some 15 years ago by Katz and Katz [9], who likened the serial and parallel summation of mechanical activity in various regions of cardiac muscle to the combined action of oarsmen on ancient Greek triremes. These battleships were powered by 170 men, placed in three tiers along both sides of the ship. In order to synchronise mechanical action and to achieve optimal propulsion, their rowing gear was ingeniously fine-tuned to match positional requirements from bow to stern (a kind of ‘base–apex gradient’) and between rows (‘trans-mural gradient’).

Indeed, recent research has confirmed the existence of complex regional differences in electro-mechanical cell properties in healthy ventricle [2], and highlighted pronounced alterations of this heterogeneity in pathological states [12]. Thus, in normal heart, the time-to-peak of contraction decreases from endocardium to epicardium which, in the presence of a corresponding delay in transmural activation timing, supports synchronised peak force development of the tissue as a whole [6]. Mechanical heterogeneity in ventricular cardiomyocyte properties is accompanied by differences in calcium handling, metabolic activity, electrophysiology, cell coupling and structure. In their combination, these physiological heterogeneities … 

*Tel.: +44 1865 272 114; fax: +44 1865 272 554. Email address: peter.kohl{at}physiol.ox.ac.uk
Characterisation of patients with primary biliary cirrhosis responding to long term ursodeoxycholic acid treatment
Authors: M Leuschner
Journal: Gut (2000)

In some patients with primary biliary cirrhosis, ursodeoxycholic acid causes full biochemical normalisation of laboratory data; in others, indexes improve but do not become normal.To characterise complete and incomplete responders.Seventy patients with primary biliary cirrhosis were treated with ursodeoxycholic acid 10-15 mg/kg/day and followed up for 6-13 years.In 23 patients (33%) with mainly stage I or II disease, cholestasis indexes and aminotransferases normalised within 1-5 years, except for antimitochondrial antibodies. Histological findings improved. Indexes were not normalised in 47 patients (67%) although the improvement of their biochemical functions parallelled the trend in the first group. In these incomplete responders histological findings improved to a lesser extent. The only difference between the two groups before treatment was higher levels of alkaline phosphatase and gamma glutamyl transpeptidase in the incomplete responders. At onset of treatment the discriminant value separating responders from incomplete responders was 660 U/l for alkaline phosphatase and 131 U/l for gamma glutamyl transpeptidase. One year later it was 239 and 27 U/l (overall predictive value for responders 92%, for incomplete responders 81%). There were no differences between the two groups concerning immune status, antimitochondrial antibody subtypes, liver histology, or any other data. HLA-B39, DRB1*08, DQB1*04 dominated in both groups.In patients with mainly early stages of primary biliary cirrhosis, higher values of alkaline phosphatase and gamma glutamyl transpeptidase are the only biochemical indexes which allow discrimination between patients who will completely or incompletely respond to ursodeoxycholic acid treatment.
Cardiovascular nuclear magnetic resonance: basic and clinical applications
Authors: John R. Forder, Gerald M. Pohost
Journal: Journal of Clinical Investigation (2003)

magnetic resonance (MR); echo-planar imaging (EPI); cardiovascular MR (CMR); volume of interest (VOI); chemical shift imaging (CSI); image-selected in vivo spectroscopy (ISIS); spatial response function (SRF); radiofrequency (RF); gadolinium-diethyleneaminepentaacetate (Gd-DTPA); phosphocreatine (PCr); inorganic phosphate (Pi); tricarboxylic acid (TCA); spin-lattice relaxation time (T1); spin-spin relaxation time (T2)
Inhibition of restenosis by tissue factor pathway inhibitor: in vivo and in vitro evidence for suppressed monocyte chemoattraction and reduced gelatinolytic activity
Authors: Christoph W. Kopp, Thomas Hölzenbein, Sabine Steiner, Rodrig Marculescu, Helga Bergmeister, Daniela Seidinger, Isabella Mosberger, Christoph Kaun, Manfred Cejna, Reinhard Horvat, Johann Wojta, Gerald Maurer, Bernd R. Binder, Johannes M. Breuss, Rupert C. Ecker, Rainer de Martin, Erich Minar
Journal: Blood (2003)
Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis
Authors: Jordan W. Smoller, Kenneth Kendler, Nicholas John Craddock, Phil Hyoun Lee, Benjamin M. Neale, John I. Nurnberger, Stephan Ripke, Susan Santangelo, Patrick F. Sullivan, Shaun Purcell, Richard Anney, Jan Buitelaar, Ayman Fanous, Stephen V. Faraone, Witte Hoogendijk, Klaus-Peter Lesch, Douglas F. Levinson, Roy H. Perlis, Marcella Rietschel, Brien Riley, Edmund Sonuga-Barke, Russell Schachar, Thomas G. Schulze, Anita Thapar, Michael Neale, Patrick Bender, Sven Cichon, Mark J. Daly, John Kelsoe, Thomas Lehner, Michael Conlon O'Donovan, Pablo Gejman, Jonathan Sebat, Pamela Sklar
Journal: The Lancet (2013)
Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis
Authors: A. Y. Walley, Z. Xuan, H. H. Hackman, E. Quinn, M. Doe-Simkins, A. Sorensen-Alawad, S. Ruiz, A. Ozonoff
Journal: BMJ (2013)

To evaluate the impact of state supported overdose education and nasal naloxone distribution (OEND) programs on rates of opioid related death from overdose and acute care utilization in Massachusetts.Interrupted time series analysis of opioid related overdose death and acute care utilization rates from 2002 to 2009 comparing community-year strata with high and low rates of OEND implementation to those with no implementation.19 Massachusetts communities (geographically distinct cities and towns) with at least five fatal opioid overdoses in each of the years 2004 to 2006.OEND was implemented among opioid users at risk for overdose, social service agency staff, family, and friends of opioid users.OEND programs equipped people at risk for overdose and bystanders with nasal naloxone rescue kits and trained them how to prevent, recognize, and respond to an overdose by engaging emergency medical services, providing rescue breathing, and delivering naloxone.Adjusted rate ratios for annual deaths related to opioid overdose and utilization of acute care hospitals.Among these communities, OEND programs trained 2912 potential bystanders who reported 327 rescues. Both community-year strata with 1-100 enrollments per 100,000 population (adjusted rate ratio 0.73, 95% confidence interval 0.57 to 0.91) and community-year strata with greater than 100 enrollments per 100,000 population (0.54, 0.39 to 0.76) had significantly reduced adjusted rate ratios compared with communities with no implementation. Differences in rates of acute care hospital utilization were not significant.Opioid overdose death rates were reduced in communities where OEND was implemented. This study provides observational evidence that by training potential bystanders to prevent, recognize, and respond to opioid overdoses, OEND is an effective intervention.
Leukocyte response integrin and integrin-associated protein act as a signal transduction unit in generation of a phagocyte respiratory burst.
Authors: M Zhou, E J Brown
Journal: The Journal of Experimental Medicine (1993)

The leukocyte response integrin (LRI) is a phagocyte integrin which recognizes the basement membrane protein entactin and the synthetic peptide Lys-Gly-Ala-Gly-Asp-Val (KGAGDV). The function of LRI is intimately associated with that of a distinct membrane protein, integrin-associated protein (IAP), as antibodies which recognizes IAP can inhibit all known functions of LRI. When adherent to surface, the LRI ligands entactin and KGAGDV activate the respiratory burst in polymorphonuclear leukocytes (PMN) and monocytes, as do monoclonal antibodies (mAb) directed at either LRI or IAP. When added in solution, peptides and antibodies specific for LRI, and some, but not all, anti-IAP antibodies, can inhibit the respiratory burst activated by any of these surface-adherent ligands. Only monoclonal anti-IAP antibodies which can inhibit LRI function when added in solution are competent to activate the respiratory burst when adherent to a surface. KGAGDV peptide and anti-LRI added in solution can inhibit anti-IAP-stimulated respiratory burst. The LRI-IAP-initiated respiratory burst is independent of CD18, as judged by: (a) blockade of inhibition by anti-CD18 mAb with the protein kinase A inhibitor HA1004; (b) enhanced sensitivity of CD18-dependent respiratory burst compared with LRI/IAP-dependent respiratory burst to the tyrosine kinase inhibitors genestein and herbimicin; and (c) generation of a respiratory burst in response to KGAGDV, anti-LRI, and anti-IAP coated surfaces in PMN from a patient with LAD. Despite its apparent CD18 independence, LRI/IAP-initiated respiratory burst requires a solid phase ligand and is sensitive to cytochalasin B. These data suggest a model in which LRI and IAP act together as a single signal transduction unit to activate the phagocyte respiratory burst, in a manner that requires CD18-independent cell adhesion.
Effector mechanisms in organ-specific autoimmunity. I. Characterization of a CD8+ T cell line that mediates murine interstitial nephritis.
Authors: C M Meyers, C J Kelly
Journal: Journal of Clinical Investigation (1991)

To further investigate mechanisms of cell-mediated tissue destruction in an organ-specific autoimmune disease, we have established and characterized a nephritogenic CD8+ T cell line. This target antigen-specific effector T cell line, M52, was derived from bulk populations of CD8+ T cells isolated from susceptible animals immunized to produce anti-tubular basement membrane (alpha TBM) disease. Our studies show that M52 retains the phenotypic and functional characteristics of nephritogenic T cells induced in vivo. M52 mediates antigen-specific delayed-type hypersensitivity (DTH) responses to the target antigen 3M-1, it is cytotoxic to 3M-1-expressing renal tubular epithelial cells in vitro, and it adoptively transfers interstitial nephritis to naive syngeneic recipients. Clonal analysis of these nephritogenic CD8+ T cells reveals distinct functional phenotypes within the M52 cell line. We have isolated a cytotoxic CD8+ clone, M52.26, which is not DTH-reactive to 3M-1, and multiple DTH-reactive clones which mediate less efficient cytotoxicity to 3M-1-expressing target cells. Cytofluorographic analysis of four randomly selected clones reveals alpha beta T cell receptor expression. Further characterization of these functionally distinct CD8+ T cell clones will help to define their respective roles in mediating tubular epithelial cell injury and the inflammatory lesion of autoimmune interstitial nephritis.
Total parenteral nutrition in infancy: effect on the liver and suggested pathogenesis
Authors: C A Hughes, I C Talbot, D A Ducker, M J Harran
Journal: Gut (1983)

Biochemical, histological, and electron-microscopic investigation of seven preterm infants who became jaundiced after prolonged total parenteral nutrition showed conjugated hyperbilirubinaemia apparently due to cholestasis without significant primary liver cell injury. In the absence of evidence indicating a direct toxic effect on the liver of this form of nutrition the necropsy findings in one child and analogy with the effects of total parenteral nutrition in animals suggest that the cholestasis is the result of suppression of trophic and/or secretion-stimulating hormone(s) normally produced by the gut, due to absent enteral nutrition. Biochemical and electron-microscopic findings suggest that liver cell damage occurs after resumption of enteral nutrition.
Proteinase-antiproteinase balance in tracheal aspirates from neonates
Authors: KB Sluis, BA Darlow, MC Vissers, CC Winterbourn
Journal: European Respiratory Journal (1994)

We wanted to identify the inhibitors of neutrophil elastase, quantify their activities in the upper airways of neonates, and relate these to the presence of active elastase and the likelihood of elastolytic injury occurring due to inhibitory capacity being overwhelmed. Activities of neutrophil elastase and its inhibitors were measured in tracheal aspirates from 17 infants, 10 of whom subsequently developed bronchopulmonary dysplasia. All aspirates contained immunologically detectable alpha 1-proteinase inhibitor (alpha 1-PI), but their inhibitory capacity against neutrophil elastase ranged from being undetectable to being in excess of the amount of alpha 1-PI detected immunologically. When the alpha 1-PI was removed from each of the aspirates, using a specific antibody, from 0-50% of the original activity remained, indicating the presence of another elastase inhibitor. Its properties were consistent with it being the low molecular mass, secretory leucoproteinase inhibitor (SLPI), also known as bronchial antileucoproteinase. The alpha 1-PI was from 0-100% active. Most of the inactive inhibitor was shown by western blotting to be complexed with elastase, with a small amount of cleaved material. There was no evidence of major oxidative inactivation. Free elastase was detected in only three of the aspirates; these had little or no detectable elastase inhibitory capacity, and most of their alpha 1-PI was complexed. Elastase load, comprising the sum of free and complexed elastase, correlated closely with myeloperoxidase activity, a recognized marker of inflammatory activity. Active SLPI levels showed a positive correlation with gestational age (r = 0.66). We conclude that most neutrophil elastase in the upper airways of ventilated infants is complexed.(ABSTRACT TRUNCATED AT 250 WORDS)
Serum -Tocopherol and -Tocopherol in Relation to Prostate Cancer Risk in a Prospective Study
Authors: S. J. Weinstein, M. E. Wright, P. Pietinen, I. King, C. Tan, P. R. Taylor, J. Virtamo, D. Albanes
Journal: JNCI Journal of the National Cancer Institute (2005)

The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study demonstrated a 32% reduction in prostate cancer incidence in response to daily α-tocopherol supplementation. We examined baseline serum concentrations of α-tocopherol and γ-tocopherol to compare their respective associations with prostate cancer risk. From the ATBC Study cohort of 29 133 Finnish men, 50–69 years old, we randomly selected 100 incident prostate cancer case patients and matched 200 control subjects. Odds ratios and 95% confidence intervals (CIs) were estimated for the serum tocopherols (measured by high-performance liquid chromatography) using logistic regression models. All P values were two-sided. Odds ratios for the highest versus the lowest tertiles were 0.49 (95% CI = 0.24 to 1.01, Ptrend = .05) for α-tocopherol and 0.57 (95% CI = 0.31 to 1.06, Ptrend = .08) for γ-tocopherol. Further analyses indicated that the association of high serum tocopherols with low prostate cancer risk was stronger in the α-tocopherol–supplemented group than in those not receiving α-tocopherol. Participants with higher circulating concentrations of the major vitamin E fractions, α-tocopherol and γ-tocopherol, had similarly lower prostate cancer risk.
Actin polymerization in neutrophils from donors of peripheral blood stem cells: Divergent effects of glycosylated and nonglycosylated recombinant human granulocyte colony‐stimulating factor
Authors: Giovanni Carulli, Letizia Mattii, Antonio Azzarà, Stefania Brizzi, Sara Galimberti, Alessandra Zucca, Edoardo Benedetti, Mario Petrini
Journal: American Journal of Hematology (2006)

Abstract Neutrophil functions can be modified by Recombinant human G‐CSF (rhG‐CSF) treatment, with divergent effects on phagocytosis, motility, bactericidal activity, and surface molecule expression. Neutrophil morphology is modified by treatment with filgrastim (the nonglycosylated form of rhG‐CSF), while it is not affected by lenograstim (the glycosylated type of rhG‐CSF). Little information is available about actin polymerization in neutrophils from subjects treated with the two types of rhG‐CSF. In the current paper we evaluated two groups of donors of peripheral blood stem cells (PBSC) for allogeneic transplantation. Ten subjects were treated with filgrastim and 10 with lenograstim to mobilize PBSC; 15 blood donors were evaluated as a control group. Actin polymerization (both spontaneous and fMLP‐stimulated) was studied by a flow cytometric assay. A microscopic fluorescent assay was also carried out to evaluate F‐actin distribution in neutrophils. We found that filgrastim induced an increased F‐actin content in resting neutrophils, along with morphologic evidence for increased actin polymerization distributed principally at the cell membrane and frequently polarized in focal areas; in addition, fMLP was not able to induce further actin polymerization. On the contrary, treatment with lenograstim was associated with F‐actin content, distribution, and polymerization kinetics indistinguishable from those displayed by control neutrophils. Such experimental results show that filgrastim and lenograstim display divergent effects also on neutrophil actin polymerization and provide further explanation for previous experimental findings. Am. J. Hematol. 81:318–323, 2006. © 2006 Wiley‐Liss, Inc.
Cytisine versus Nicotine for Smoking Cessation
Authors: Natalie Walker, Colin Howe, Marewa Glover, Hayden McRobbie, Joanne Barnes, Vili Nosa, Varsha Parag, Bruce Bassett, Christopher Bullen
Journal: New England Journal of Medicine (2014)

Placebo-controlled trials indicate that cytisine, a partial agonist that binds the nicotinic acetylcholine receptor and is used for smoking cessation, almost doubles the chances of quitting at 6 months. We investigated whether cytisine was at least as effective as nicotine-replacement therapy in helping smokers to quit.