tbuckley/cabot-search huggingface dataset:
Effect of Hypoxia-Inducible Factor-1α Gene Therapy on Walking Performance in Patients With Intermittent Claudication
Authors: Mark A. Creager, Jeffrey W. Olin, Jill J.F. Belch, Gregory L. Moneta, Timothy D. Henry, Sanjay Rajagopalan, Brian H. Annex, William R. Hiatt
Journal: Circulation (2011)

Background— Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional regulatory factor that orchestrates cellular responses to hypoxia. It increases collateral vessel growth and blood flow in models of hind-limb ischemia. This study tested whether intramuscular administration of Ad2/HIF-1α/VP16, an engineered recombinant type 2 adenovirus vector encoding constitutively active HIF-1α, improves walking time in patients with peripheral artery disease and intermittent claudication. Methods and Results— Two hundred eighty-nine patients with claudication were randomized in a double-blind manner to 1 of 3 doses of Ad2/HIF-1α/VP16 (2×10 9 , 2×10 10 , or 2×10 11 viral particles) or placebo, administered by 20 intramuscular injections to each leg. Graded treadmill tests were performed at baseline and then 3, 6, and 12 months after treatment. The primary end point was the change in peak walking time from baseline to 6 months. The secondary end point was change in claudication onset time, and tertiary end points included changes in ankle-brachial index and quality-of-life assessments. Median peak walking time increased by 0.82 minutes (interquartile range, −0.05–1.93 minutes) in the placebo group and by 0.82 minutes (interquartile range, −0.07–2.12 minutes), 0.28 minutes (interquartile range, −0.37–1.70 minutes), and 0.78 minutes (interquartile range, −0.02–2.10 minutes) in the HIF-1α 2×10 9 , 2×10 10 , and 2×10 11 viral particle groups, respectively ( P =NS between placebo and each HIF-1α treatment group). There were no significant differences in claudication onset time, ankle-brachial index, or quality-of-life measurements between the placebo and each HIF-1α group. Conclusions— Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00117650.
Improving Mutation Screening in Familial Hematuric Nephropathies through Next Generation Sequencing
Authors: Vincent Morinière, Karin Dahan, Pascale Hilbert, Marieline Lison, Said Lebbah, Alexandra Topa, Christine Bole-Feysot, Solenn Pruvost, Patrick Nitschke, Emmanuelle Plaisier, Bertrand Knebelmann, Marie-Alice Macher, Laure-Hélène Noel, Marie-Claire Gubler, Corinne Antignac, Laurence Heidet
Journal: Journal of the American Society of Nephrology (2014)

Alport syndrome is an inherited nephropathy associated with mutations in genes encoding type IV collagen chains present in the glomerular basement membrane. COL4A5 mutations are associated with the major X-linked form of the disease, and COL4A3 and COL4A4 mutations are associated with autosomal recessive and dominant forms (thought to be involved in 15% and 1%–5% of the families, respectively) and benign familial hematuria. Mutation screening of these three large genes is time-consuming and expensive. Here, we carried out a combination of multiplex PCR, amplicon quantification, and next generation sequencing (NGS) analysis of three genes in 101 unrelated patients. We identified 88 mutations and 6 variations of unknown significance on 116 alleles in 83 patients. Two additional indel mutations were found only by secondary Sanger sequencing, but they were easily identified retrospectively with the web-based sequence visualization tool Integrative Genomics Viewer. Altogether, 75 mutations were novel. Sequencing the three genes simultaneously was particularly advantageous as the mode of inheritance could not be determined with certainty in many instances. The proportion of mutations in COL4A3 and COL4A4 was notably high, and the autosomal dominant forms of Alport syndrome appear more frequently than reported previously. Finally, this approach allowed the identification of large COL4A3 and COL4A4 rearrangements not described previously. We conclude that NGS is efficient, reduces screening time and cost, and facilitates the provision of appropriate genetic counseling in Alport syndrome.
Relationship between lung functions and extent of emphysema as assessed by high-resolution computed tomography in patients with COPD
Authors: Muzaffer Sariaydin, Nejat Altintas, Ozgur Ince
Journal: European Respiratory Journal (2014)

Background: To investigate whether the extent of emphysema, visually confirmed by high resolution computed tomography (HRCT) in patients with COPD were associated with different indices of lung functions.

Methods: Eighty-two patients with COPD underwent HRCT scanning, visual assessment of HRCT scan was used in the calculation of extent of emphysematous destruction. The patients were clinically stable at the time of the evaluation. All subjects were smokers or past smokers who had smoked>10 pack-years.

Results: The mean visual emphysema score in all patients was 2.21±1.11. While the mean emphysema score in patients with COPD GOLD (Global Initiative for Chronic Obstructive Lung Disease) stage 3 was 2.88 ±1.03, it was 1.54 ±1.16 in COPD GOLD stage 2 (p<0.001). There was a significant correlation between the emphysema score and the numbers of pack/years smoked (R=0.58, p<0.001). The visual emphysema score was inversely correlated with the FEV1(r = -0.56, p<0.0001), FVC ( r= -0.38, p=0.001), FEV1/FVC ( r=-0.43, p<0.001),PEF(r=-0.44, p<0,001) and with carbon monoxide diffusion capacity (DLCO)( r = -0.50, p<0.001). In our study population, patients had a limited expression of the disease as represented by low scores in Saint George Respiratory Questionnaire (SGRQ), and there was no correlation between emphysema score and SGRQ.

Conclusions: HRCT visual scores correlated with functional indices of airflow obstruction and impaired lung diffusing capacity in patients with stable COPD of varying severity, the presence of pulmonary emphysema is best represented by the FEV1 and DLCO .
Granulocyte Macrophage Colony-Stimulating Factor–Secreting Allogeneic Cellular Immunotherapy for Hormone-Refractory Prostate Cancer
Authors: Eric J. Small, Natalie Sacks, John Nemunaitis, Walter J. Urba, Eugene Dula, Arthur S. Centeno, William G. Nelson, Dale Ando, Catherine Howard, Flavia Borellini, Minh Nguyen, Kristen Hege, Jonathan W. Simons
Journal: Clinical Cancer Research (2007)

Abstract Purpose: This trial evaluated the safety, clinical activity, and immunogenicity of an allogeneic cellular immunotherapy in 55 chemotherapy-naïve patients with hormone-refractory prostate cancer (HRPC). The immunotherapy, based on the GVAX platform, is a combination of two prostate carcinoma cell lines modified with the granulocyte macrophage colony-stimulating factor (GM-CSF) gene. Experimental Design: HRPC patients with radiologic metastases (n = 34) or rising prostate-specific antigen (PSA) only (n = 21) received a prime dose of 500 million cells and 12 boost doses of either 100 million cells (low dose) or 300 million cells (high dose) biweekly for 6 months. End points were changes in PSA, time to progression, and survival. Results: Median survival was 26.2 months (95% confidence interval, 17, 36) in the radiologic group: 34.9 months (8, 57) after treatment with the high dose (n = 10) of immunotherapy and 24.0 months (11, 35) with the low dose (n = 24). The median time to bone scan progression in the radiologic group was 5.0 months (2.6, 11.6) with the high dose and 2.8 months (2.8, 5.7) with the low dose. In the rising-PSA group (n = 21) receiving the low dose, the median time to bone scan progression was 5.9 months (5.6, not reached), and median survival was 37.5 months (29, 56). No dose-limiting or autoimmune toxicities were seen; the most common adverse events were injection site reaction and fatigue. Conclusions: These results suggest that this GM-CSF–secreting, allogeneic cellular immunotherapy is well tolerated and may have clinical activity in patients with metastatic HRPC. Phase 3 trials to confirm these results are under way.
Hemodynamic Effects of <scp>l</scp> - and <scp>d</scp> - <i>S</i> -Nitrosocysteine in the Rat
Authors: Robin L. Davisson, Mark D. Travis, James N. Bates, Stephen J. Lewis
Journal: Circulation Research (1996)

The vasorelaxant effects of the endothelium-derived relaxing factor S -nitrosocysteine (SNC) may not be simply due to its decomposition to NO. The biological actions of SNC may also involve the transnitrosation of amino acids in the blood and in plasma membranes. The possibility that the SNC moiety possesses biological activity prompted us to examine whether the hemodynamic effects of this S -nitrosothiol involves the activation of stereoselective S -nitrosothiol receptors within the cardiovascular system. We examined (1) the hemodynamic effects produced by intravenous injections of the l and d isomers of SNC ( l - and d -SNC, respectively; 100 to 800 nmol/kg), the l and d isomers of the parent thiols ( l - and d -cysteine, respectively; 100 to 800 nmol/kg), the oxidized thiol l -cystine (100 to 800 nmol/kg), and the NO donor sodium nitroprusside (SNP, 1 to 36 μg/kg) in conscious freely moving rats, (2) the baroreceptor reflex–mediated changes in heart rate elicited in response to the falls in arterial pressure produced by l - and d -SNC and SNP in conscious rats, and (3) the relative decomposition of l - and d -SNC to NO upon addition to heparinized rat blood or upon direct application to cultured porcine aortic smooth muscle (PASM) cells. We now report that (1) l -SNC is a more potent hypotensive and vasodilator agent within the mesenteric bed and sympathetically intact and sympathetically denervated hindlimb beds of conscious rats than is d -SNC, (2) l - and d -SNC markedly inhibit baroreceptor reflex–mediated tachycardia in conscious rats and d -SNC is considerably more effective than l -SNC, (3) the intravenous injections of l - and d -cysteine or l -cystine do not affect arterial blood pressure or vascular resistances, and (4) l - and d -SNC decompose equally to NO upon application to rat blood or cultured PASM cells. These results suggest that the hemodynamic effects of endogenous SNC may involve its interaction with stereoselective S -nitrosothiol recognition sites within the vasculature and the baroreflex arc. These findings provide tentative evidence that membrane-bound S -nitrosothiol receptors may exist within the cardiovascular system.
Acetylcholine via Muscarinic Receptors Inhibits Histamine Release from Human Isolated Bronchi
Authors: TORSTEN REINHEIMER, DIRK BAUMGÄRTNER, KARL-DIETER HÖHLE, KURT RACKÉ, IGNAZ WESSLER
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Human bronchi were incubated in organ baths to measure histamine release. The calcium ionophore A23187 (10 mumol/L; 1 min) stimulated histamine release by 148 +/- 28% (n = 11) above the prestimulation level but was ineffective in epithelium-denuded bronchi. Neither bradykinin (0.1 mumol/L) nor compound 48/80 (10 micrograms/ml) triggered the release of histamine from epithelium-intact bronchi. Acetylcholine did not affect spontaneous histamine release (about 2 nmol/g x 5 min) but inhibited A23187-evoked histamine release in an atropine-sensitive manner. Already a concentration as low as 0.1 nmol/L acetylcholine was effective, the maximal inhibition (by 89%) occurred at 100 nmol/L, whereas a concentration of 10 mumol/L acetylcholine was ineffective. Oxotremorine (1 nmol/L), a stable agonist at muscarinic receptors, suppressed stimulated histamine release completely. Physostigmine (0.1 mumol/L), an acetylcholinesterase inhibitor, reduced A23187-evoked histamine release by 58%. Antihuman IgE antibody stimulated histamine release by 127 +/- 30% (n = 6) above the prestimulation level. Acetylcholine (100 nmol/L) inhibited also the immunologically evoked histamine release by 70%. In conclusion, the present experiments provide a model to characterize mast cells that are localized in or close to the airway surface epithelium. Acetylcholine via muscarinic receptors strongly inhibits the releasability of these mucosal mast cells being among the first cells to interact with inhaled antigens and environmental agents. The inhibitory action of physostigmine indicates the involvement of endogenous, probably non-neuronal acetylcholine expressed in airway epithelial cells.
A memorable patient: Fear of tuberculosis
Authors: B. Yule
Journal: BMJ (1998)

<h3>Objective</h3> Although portrayal of television (TV) and movie tobacco use has been linked with initiation of cigarette smoking in adolescents, its association with smoking in adults has not been assessed. Therefore, we examined long-term and annual changes in tobacco portrayal in popular US TV dramas and their associations with comparable trends in national adult cigarette consumption. <h3>Methods</h3> Tobacco use in 1838 h of popular US TV dramas was coded from 1955–2010. The long-term trend and annual deviations from trend were studied in relation to comparable trends in adult per capita cigarette consumption using correlational and time-series methods that controlled for other potential predictors. <h3>Results</h3> TV tobacco portrayal has trended downward since 1955 in line with the historical trend in cigarette consumption. Controlling for changes in cigarette prices and other factors, annual changes of one tobacco instance per episode hour across 2 years of programming were associated with annual change of 38.5 cigarettes per US adult. The decline in TV tobacco portrayal was associated with nearly half the effect of increases in cigarette prices over the study period. <h3>Conclusions</h3> The correlation between tobacco portrayal in TV dramas and adult cigarette consumption is consistent with well-established effects of exposure to tobacco cues that create craving for cigarettes in adult smokers. Although tobacco use in TV dramas along with movies has declined over time, portrayal of smoking on screen media should be a focus for future adult tobacco control research and policy.
Airway Mucus Function and Dysfunction
Authors: John V. Fahy, Burton F. Dickey
Journal: New England Journal of Medicine (2010)

Pulmonary defense against environmental injury depends on airway mucus, which traps inhaled toxins that are then cleared from the lungs by ciliary beating and cough. This review examines the normal and abnormal formation and clearance of mucus, as well as the therapy of mucus dysfunction.
The Effects of Psychopharmacological Agents on Central Nervous System Amine Metabolism in Man
Authors: J W Maas
Journal: The Annual Review of Pharmacology and Toxicology (1977)

In assessing the effects of psychopharmacological agents on the disposition and turnover of biogenic amines in the ceritral nervous system (CNS) of man, investiga­ tors are ethically limited to the use of indirect experimental approaches. Most investigators have focused on changes in concentrations of amine metabolites in cerebrospinal fluid (CSF) that are associated with drug administration, and the greatest attention has been paid to 3-methoxy-4-hydroxyphenethyleneglycol (MHPG), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) as these are the principal metabolites of norepinephrine (NE), dopamine (DA), and serotonin (S-HT), respectively, in the CNS. To a lesser extent, changes in the concentration of urinary MHPG in relationship to drug administration have also been studied in an attempt to understand the effects of psychotropic agents upon CNS NE metabolism. Each of these approaches has certain advantages and inherent limitations, which are briefly reviewed below. It is thought that such comments will help to place in better perspective the data obtained by using these techniques with human subjects. There is a gradient between ventricular CSF HV A and lumbar CSF HV A of approximately 10:1 (1). Obstructions to flow between the cistern and lumbar spaces are associated with a marked reduction in the concentration of CSF HVA (2-4). DA is found in the spinal cord in very low concentrations (5, 6) and there is a barrier to the movement of HVA from blood into CSF (7, 8). As a group, these studies suggest that HV A in lumber CSF originates principally in structures within brain. The degree to which various structures in brain contribute to lumber CSF HV A is
Activation of the Flt3 signal transduction cascade rescues and enhances type I interferon–producing and dendritic cell development
Authors: Nobuyuki Onai, Aya Obata-Onai, Roxane Tussiwand, Antonio Lanzavecchia, Markus G. Manz
Journal: The Journal of Experimental Medicine (2006)

Flt3 ligand (Flt3L) is a nonredundant cytokine in type I interferon–producing cell (IPC) and dendritic cell (DC) development, and IPC and DC differentiation potential is confined to Flt3+ hematopoietic progenitor cells. Here, we show that overexpression of human Flt3 in Flt3− (Flt3−Lin−IL-7Rα−Thy1.1−c-Kit+) and Flt3+ (Flt3+Lin−IL-7Rα−Thy1.1−c-Kit+) hematopoietic progenitors rescues and enhances their IPC and DC differentiation potential, respectively. In defined hematopoietic cell populations, such as Flt3− megakaryocyte/erythrocyte-restricted progenitors (MEPs), enforced Flt3 signaling induces transcription of IPC, DC, and granulocyte/macrophage (GM) development–affiliated genes, including STAT3, PU.1, and G-/M-/GM-CSFR, and activates differentiation capacities to these lineages. Moreover, ectopic expression of Flt3 downstream transcription factors STAT3 or PU.1 in Flt3− MEPs evokes Flt3 receptor expression and instructs differentiation into IPCs, DCs, and myelomonocytic cells, whereas GATA-1 expression and consecutive megakaryocyte/erythrocyte development is suppressed. Based on these data, we propose a demand-regulated, cytokine-driven DC and IPC regeneration model, in which high Flt3L levels initiate a self-sustaining, Flt3-STAT3– and Flt3-PU.1–mediated IPC and DC differentiation program in Flt3+ hematopoietic progenitor cells.
RNA Interference Screen to Identify Pathways That Enhance or Reduce Nonviral Gene Transfer During Lipofection
Authors: Gregory A Barker, Scott L Diamond
Journal: Molecular Therapy (2008)

Some barriers to DNA lipofection are well characterized; however, there is as yet no method of finding unknown pathways that impact the process. A druggable genome small-interfering RNA (siRNA) screen against 5,520 genes was tested for its effect on lipofection of human aortic endothelial cells (HAECs). We found 130 gene targets which, when silenced by pooled siRNAs (three siRNAs per gene), resulted in enhanced luminescence after lipofection (86 gene targets showed reduced expression). In confirmation tests with single siRNAs, 18 of the 130 hits showed enhanced lipofection with two or more individual siRNAs in the absence of cytotoxicity. Of these confirmed gene targets, we identified five leading candidates, two of which are isoforms of the regulatory subunit of protein phosphatase 2A (PP2A). The best candidate siRNA targeted the PPP2R2C gene and produced a 65% increase in luminescence from lipofection, with a quantitative PCR-validated knockdown of approximately 76%. Flow cytometric analysis confirmed that the silencing of the PPP2R2C gene resulted in an improvement of 10% in transfection efficiency, thereby demonstrating an increase in the number of transfected cells. These results show that an RNA interference (RNAi) high-throughput screen (HTS) can be applied to nonviral gene transfer. We have also demonstrated that siRNAs can be co-delivered with lipofected DNA to increase the transfection efficiency in vitro.
Abstract LB-238: Antitumor activity of mini-IGFBP-3, a protease-resistant derivative of human IGF binding protein-3
Authors: François Godeau, Patricia Leneuve, Laetitia D. Costa, Yves L. Bouc, Jack-Michel Renoir
Journal: Cancer Research (2014)

Abstract Insulin-like growth factors (IGF) are polypeptide hormones with potent anabolic and mitogenic properties that regulate cell growth and differentiation. Dysregulation of the IGF axis has been well documented in the development and progression of multiple types of cancer. Consequently, targeting the IGF axis has become an area of intense preclinical and clinical research through the development of 3 major classes of therapeutic compounds: antibodies that target IGF-IR, dual IGF-IR and IR tyrosine kinase inhibitors (TKI), and IGF ligands (IGF-I and IGF-II) neutralizing antibodies. Due to their high affinities for IGF-I and IGF-II, six IGFBPs regulate IGF bioavailability and IGFBP-3 is the main carrier of circulating IGFs in postnatal serum. In order to efficiently neutralize the excess of free IGF ligand maintaining tumor progression, we have produced, using the baculovirus insect cell system, a protease-resistant mutein of human IGFBP-3 with conserved affinities towards both IGF-I and IGF-II that was fused to the human IgG1 Fc fragment. In vitro, the resulting immunoadhesin (mIGFBP-3-Fc), evaluated in both regular and 3D culture, was found to block proliferation, arrest cell cycle and induce apoptosis in various types of cancer cell lines (Colon Adenocarcinoma, Ewing's Sarcoma, Adrenocortical Carcinoma and Multiple Myeloma (MM). mIGFBP-3-Fc antitumor activity was evaluated in vivo using RPMI-8226 luciferase-expressing MM cells xenografts. When MM cells were grafted subcutaneouly, daily mIGFBP-3-Fc injections drastically reduced tumor growth and induced tumor cell apoptosis. Similarly, after iv tumor cell injection, bone marrow localization of MM cells was substantially reduced in the mIGFBP-3-Fc-treated group. Furthermore, when used in association with the proteasome inhibitor Bortezomib, mIGFBP-3-Fc was shown to enhance the antitumor effect of Bortezomib used as single agent. Altogether, these data support the concept that mIGFBP-3-Fc could improve MM treatment either as a single agent or in association with proteasome inhibitors. Citation Format: François Godeau, Patricia Leneuve, Laetitia Da Costa, Yves Le Bouc, Jack-Michel Renoir. Antitumor activity of mini-IGFBP-3, a protease-resistant derivative of human IGF binding protein-3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-238. doi:10.1158/1538-7445.AM2014-LB-238
The Brown and Williamson Documents
Authors: James S. Todd
Journal: JAMA (1995)

There is a massive body of evidence, derived from many scientific disciplines, that tobacco is addictive and kills smokers. Up to half of those who continue to smoke cigarettes will die prematurely from diseases caused by smoking, half of these deaths occurring in middle age.<sup>1</sup>Peto et al<sup>2</sup>have calculated that of the 1.25 billion people now living in developed countries, 250 million will, if present tobacco consumption patterns are maintained, die from tobacco. With 3 million deaths worldwide each year currently due to tobacco use, the consequences of tobacco to the public health have been, and will continue to be, staggering, and the importance of bringing this hazard under control is correspondingly great. It is against this background that<i>JAMA</i>publishes several highly unusual articles this week. <h3>The Documents</h3> On May 12, 1994, Stanton A. Glantz, PhD, a professor of medicine in the Division of Cardiology at
Novel encapsulation technology for the preparation of core–shell microparticles
Authors: A.T. ten Cate, G. Pieterse, J. Eversdijk, L.A.M. Brouwers, E.G.M. Craenmehr, R.J. van Ee, A. Rijfers, N.E. Papen-Botterhuis, R.J. Houben, K.J.C. van Bommel
Journal: Journal of Controlled Release (2010)