tbuckley/cabot-search huggingface dataset:
High-Throughput Cell-Based Screening of 4910 Known Drugs and Drug-like Small Molecules Identifies Disulfiram as an Inhibitor of Prostate Cancer Cell Growth
Authors: Kristiina Iljin, Kirsi Ketola, Paula Vainio, Pasi Halonen, Pekka Kohonen, Vidal Fey, Roland C. Grafström, Merja Perälä, Olli Kallioniemi
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically explore most currently marketed drugs and drug-like molecules for their efficacy against a panel of prostate cancer cells. Experimental Design: We carried out a high-throughput cell-based screening with proliferation as a primary end-point using a library of 4,910 drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial cell lines (RWPE-1 and EP156T). The EC50 values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper or zinc were done in vitro for mechanistic exploration. Results: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations. DSF reduced tumor growth in vivo, induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF was potentiated by copper in vitro. Conclusions: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs. We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically well-known molecules can be readily translated to in vivo preclinical studies and clinical trials. (Clin Cancer Res 2009;15(19):6070–8)
Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment
Authors: S De Flora, C Grassi, L Carati
Journal: European Respiratory Journal (1997)

N-acetylcysteine (NAC), an analogue and precursor of reduced glutathione, has been in clinical use for more than 30 yrs as a mucolytic drug. It has also been proposed for and/or used in the therapy and/or prevention of several respiratory diseases and of diseases involving an oxidative stress, in general. The objective of the present study was to evaluate the effect of long-term treatment with NAC on influenza and influenza-like episodes. A total of 262 subjects of both sexes (78% &gt; or = 65 yrs, and 62% suffering from nonrespiratory chronic degenerative diseases) were enrolled in a randomized, double-blind trial involving 20 Italian Centres. They were randomized to receive either placebo or NAC tablets (600 mg) twice daily for 6 months. Patients suffering from chronic respiratory diseases were not eligible, to avoid possible confounding by an effect of NAC on respiratory symptoms. NAC treatment was well tolerated and resulted in a significant decrease in the frequency of influenza-like episodes, severity, and length of time confined to bed. Both local and systemic symptoms were sharply and significantly reduced in the NAC group. Frequency of seroconversion towards A/H1N1 Singapore 6/86 influenza virus was similar in the two groups, but only 25% of virus-infected subjects under NAC treatment developed a symptomatic form, versus 79% in the placebo group. Evaluation of cell-mediated immunity showed a progressive, significant shift from anergy to normoergy following NAC treatment. Administration of N-acetylcysteine during the winter, thus, appears to provide a significant attenuation of influenza and influenza-like episodes, especially in elderly high-risk individuals. N-acetylcysteine did not prevent A/H1N1 virus influenza infection but significantly reduced the incidence of clinically apparent disease.
Organization and evolution of transposable elements along the bread wheat chromosome 3B
Authors: Josquin Daron, Natasha Glover, Lise Pingault, Sébastien Theil, Véronique Jamilloux, Etienne Paux, Valérie Barbe, Sophie Mangenot, Adriana Alberti, Patrick Wincker, Hadi Quesneville, Catherine Feuillet, Frédéric Choulet
Journal: Genome biology (2014)

The 17 Gb bread wheat genome has massively expanded through the proliferation of transposable elements (TEs) and two recent rounds of polyploidization. The assembly of a 774 Mb reference sequence of wheat chromosome 3B provided us with the opportunity to explore the impact of TEs on the complex wheat genome structure and evolution at a resolution and scale not reached so far.We develop an automated workflow, CLARI-TE, for TE modeling in complex genomes. We delineate precisely 56,488 intact and 196,391 fragmented TEs along the 3B pseudomolecule, accounting for 85% of the sequence, and reconstruct 30,199 nested insertions. TEs have been mostly silent for the last one million years, and the 3B chromosome has been shaped by a succession of bursts that occurred between 1 to 3 million years ago. Accelerated TE elimination in the high-recombination distal regions is a driving force towards chromosome partitioning. CACTAs overrepresented in the high-recombination distal regions are significantly associated with recently duplicated genes. In addition, we identify 140 CACTA-mediated gene capture events with 17 genes potentially created by exon shuffling and show that 19 captured genes are transcribed and under selection pressure, suggesting the important role of CACTAs in the recent wheat adaptation.Accurate TE modeling uncovers the dynamics of TEs in a highly complex and polyploid genome. It provides novel insights into chromosome partitioning and highlights the role of CACTA transposons in the high level of gene duplication in wheat.
Relationship between Particle Size and Biological Activity of E. coli Boivin Endotoxin*
Authors: Hermann Beer, Theophil Staehelin, Herndon Douglas, Abraham I. Braude
Journal: Journal of Clinical Investigation (1965)

Many investigators have tried unsuccessfully to demonstrate that a specific chemical structure is responsible for the toxic action of bacterial endotoxins.Practically all of the protein (or peptide) and lipid constituents of the endotoxin molecule may be removed without affecting significantly its biological activities, and the carbo- hydrate moiety loses toxicity after it is depolymerized by even mild acid hydrolysis (1-4).Recent studies have also shown that toxicity does not depend upon the presence of the polysaccharide side chains that give the endotoxin its O-antigenic specificity (5).Other observations indicate that the size of the molecule, or molecular aggregate, is a more prominent determinant of toxicity than the chem- ical composition (6-7).Variations in particle size were noted by Schramm, Westphal, and Luderitz (8) in studies involving electron micros- copy, sedimentation in the ultracentrifuge, and viscosity measurements.They demonstrated that endotoxins in solution are polydisperse, and the average particle weight was estimated at 24 mil- lion.The larger particles are formed by aggre- gation of identical subunits with a molecular weight of about 1 million.The purpose of the present work was to get more quantitative information about the polydispersity of a Boivin endotoxin by sucrose density gradient centrifugation of endotoxin labeled uni- *
Intra-individual variability of the metabolic effect of inhaled insulin together with an absorption enhancer.
Authors: L Heinemann, W Klappoth, K Rave, B Hompesch, R Linkeschowa, T Heise
Journal: Diabetes Care (2000)

OBJECTIVE: To study the metabolic effect and the variability of the effect elicited by inhalation of 87.2 U insulin powder combined with an absorption enhancer. The metabolic effect was compared with that of 10.2 U regular insulin injected subcutaneously and of 5.5 U regular insulin given intravenously RESEARCH DESIGN AND METHODS: In this single-center open euglycemic glucose clamp study 13 healthy male volunteers received 5 insulin administrations on separate study days: once as an intravenous dose, once as a subcutaneous injection, and 3 times by inhalation, in randomized order. Glucose infusion rates (GIRs) necessary to keep blood glucose concentrations constant at 5.0 mmol/l were determined over an 8-h period after administration. RESULTS: After inhalation of the insulin powder aerosol, the onset of action was substantially more rapid than after subcutaneous insulin injection, and maximal action was reached earlier (86+/-47 vs. 182+/-53 min, P&amp;lt;0.0001). The maximal glucose infusion rate after inhalation of insulin was comparable to that after subcutaneous insulin injection (9.2+/-2.6 vs. 8.8+/-2.8 mg x kg(-1) x min(-1), NS). The metabolic effect in the first 2 h after inhalation was significantly greater than that after subcutaneous insulin injection (amount of glucose infused: 0.88+/-0.25 vs. 0.59+/-0.20 g x kg(-1) x 120 min(-1), P&amp;lt;0.0001). However, the total metabolic effect after inhalation and subcutaneous injection was comparable (2.50+/-0.76 vs. 2.56+/-0.69 g x kg(-1) x 480 min(-1), NS). The relative bioefficacy of inhaled insulin calculated in relation to the data from the subcutaneous insulin application was 12.0+/-3.5% (absolute bioefficacy 10.1+/-3.1%) but was highest in the first 2 h after application (18.5+/-3.7%; absolute bioefficacy 8.2+/-4.1%). The intraindividual variability of the metabolic response induced by insulin inhalation was 14+/-9% for the maximal glucose infusion rate, 15+/-10% for the time-to-maximal effect, and 16+/-12% for the total amount of glucose infused. CONCLUSIONS: This feasibility study shows that inhaled insulin with an absorption enhancer has a pronounced metabolic effect compared with the results of a previous study of inhaled insulin without an enhancer. The intraindividual variability of the metabolic effect was comparable with that of inhaled and subcutaneously injected insulin.
End Points and Trial Design in Geriatric Oncology Research: A Joint European Organisation for Research and Treatment of Cancer–Alliance for Clinical Trials in Oncology–International Society of Geriatric Oncology Position Article
Authors: Hans Wildiers, Murielle Mauer, Athanasios Pallis, Arti Hurria, Supriya G. Mohile, Andrea Luciani, Giuseppe Curigliano, Martine Extermann, Stuart M. Lichtman, Karla Ballman, Harvey Jay Cohen, Hyman Muss, Ulrich Wedding
Journal: Journal of Clinical Oncology (2013)

Selecting the most appropriate end points for clinical trials is important to assess the value of new treatment strategies. Well-established end points for clinical research exist in oncology but may not be as relevant to the older cancer population because of competing risks of death and potentially increased impact of therapy on global functioning and quality of life. This article discusses specific clinical end points and their advantages and disadvantages for older individuals. Randomized or single-arm phase II trials can provide insight into the range of efficacy and toxicity in older populations but ideally need to be confirmed in phase III trials, which are unfortunately often hindered by the severe heterogeneity of the older cancer population, difficulties with selection bias depending on inclusion criteria, physician perception, and barriers in willingness to participate. All clinical trials in oncology should be without an upper age limit to allow entry of eligible older adults. In settings where so-called standard therapy is not feasible, specific trials for older patients with cancer might be required, integrating meaningful measures of outcome. Not all questions can be answered in randomized clinical trials, and large observational cohort studies or registries within the community setting should be established (preferably in parallel to randomized trials) so that treatment patterns across different settings can be compared with impact on outcome. Obligatory integration of a comparable form of geriatric assessment is recommended in future studies, and regulatory organizations such as the European Medicines Agency and US Food and Drug Administration should require adequate collection of data on efficacy and toxicity of new drugs in fit and frail elderly subpopulations.
Increased number of activated lymphocytes in human lung following swine dust inhalation
Authors: C Muller-Suur, K Larsson, P Malmberg, PH Larsson
Journal: European Respiratory Journal (1997)

Inhalation of swine dust causes intense alveolar inflammation, with recruitment of inflammatory cells, predominantly neutrophils, but also alveolar macrophages and lymphocytes. The present study focuses on the lymphocyte response to inhaled swine dust. Twenty four healthy, nonsmoking, nonallergic subjects were exposed to swine dust for 3 h in a swine confinement building. Bronchoalveolar lavage (BAL) was performed before and 24 h after the start of exposure, and blood samples were drawn before, and at 7 and 24 h after exposure. Total and differential cell counts were carried out. Monoclonal antibodies recognizing T-cells, T-cell subsets, T-cell activation markers, and B-cells were analysed by flow cytometry. The number of granulocytes increased more than 50 times and alveolar macrophages and lymphocytes increased two- to three-fold in BAL fluid. The exposure did not alter the proportion of T-cells but increased the number of activated T-cells in BAL fluid. The interleukin-2 (IL-2) receptor (CD25), human leucocyte antigen-DR (HLA-DR) major histocompatibility complex (MHC) class II and the early activation marker CD69 were expressed by 8.4% (25-75th percentiles 6.4-9.6%), 9.9% (8.2-21.6%) and 22.0% (18.1-24.3%) of the lymphocytes prior to exposure, and 11.6% (9.0-16.4%) (p &lt; 0.01), 18.8% (12.9-30.4%) (p &lt; 0.01) and 42.1% (38.4-47.3%) (p &lt; 0.05), respectively, after the exposure. In peripheral blood, the concentration of T-cells decreased after exposure and B-cells increased slightly but significantly. The ratio naive/memory T-cells (CD45RA/RO) did not change in blood. In conclusion, 3 h of swine dust inhalation led to an influx of lymphocytes into the lower airways and increased expression of lymphocyte activation markers on the cell surface in previously unexposed subjects. The finding suggests a role for T-cells, in conjunction with other cells, in the inflammatory response to inhaled swine dust.
Evaluation of Liver Iron Content by Computed Tomography: Its Value in the Follow-Up of Treatment in Patients with Idiopathic Hemochromatosis†
Authors: Françoise Roudot-Thoraval, Marc Halphen, Dominique Larde, Martine Galliot, Jean-Claude Rymer, Frederic Galacteros, Daniel Dhumeaux
Journal: Hepatology (1983)

The therapeutic management of patients with idiopathic hemochromatosis (IH) implies the evaluation of excess hepatic iron. This work was undertaken to confirm the value of computed tomography for the assessment of liver iron overload in such patients and to evaluate this technique during the course of treatment by phlebotomy. The study included 24 patients with initially untreated IH and 7 patients previously treated by phlebotomy for 10 months to 7 years. Follow-up was obtained in 15 subjects. In patients with untreated IH, liver attenuation coefficient (LAC) was always markedly increased (92.4 +/- 7.1 Hounsfield units) as compared with LAC of subjects with normal liver (60.2 +/- 3.1 Hounsfield units) and that of patients with chronic liver disease (53.8 +/- 4.8 Hounsfield units), and was found to be specific for liver iron overload. LAC decreased progressively during phlebotomy, and this diminution was correlated with the amount of mobilized iron (r = 0.79, p less than 0.001); it returned to normal values only after complete removal of iron overload. LAC was closely correlated with liver iron concentration (r = 0.83, p less than 0.001), better than usual biochemical parameters, especially serum ferritin (r = 0.70, p less than 0.01). This study confirms that the determination of LAC on computed tomography provides a reliable index of hepatic iron stores in patients with IH, without requiring a liver biopsy, and shows that this noninvasive method is of particular interest for the follow-up of patients treated by phlebotomy.
Noninvasive Imaging of the Transcriptional Activities of Human Telomerase Promoter Fragments in Mice
Authors: Thomas Groot-Wassink, Eric O. Aboagye, Yaohe Wang, Nicholas R. Lemoine, W. Nicol Keith, Georges Vassaux
Journal: Cancer Research (2004)

We have assessed the feasibility of positron emission tomography (PET) and ex vivo gamma-counting to measure the pattern of expression of telomerase promoter fragments in vivo. Promoter fragments from either the RNA [human telomerase RNA (hTR)] or the catalytic components [human telomerase reverse transcriptase (hTERT)] of the telomerase genes were used to drive the expression of the sodium iodide symporter PET reporter gene in recombinant adenoviruses. Both promoter fragments provided cancer-selective expression that could be visualized and quantitated by PET. The transcriptional activity of the hTR promoter was found to be consistently stronger than that of the hTERT promoter. Both promoters appear therefore to be good candidates for safe use in gene therapy, and PET imaging can be used to assess the selectivity of promoters in vivo. Given that this methodology is directly scalable to humans, imaging gene expression using the sodium iodide symporter PET reporter gene could be applied to measure telomerase promoter activity in humans.
Keratinocyte growth factor and hepatocyte growth factor/scatter factor are heparin-binding growth factors for alveolar type II cells in fibroblast-conditioned medium.
Authors: R J Panos, J S Rubin, K G Csaky, S A Aaronson, R J Mason
Journal: Journal of Clinical Investigation (1993)

Epithelial-mesenchymal interactions mediate aspects of normal lung growth and development and are important in the restoration of normal alveolar architecture after lung injury. To determine if fibroblasts are a source of soluble growth factors for alveolar type II cells, we investigated the effect of fibroblast-conditioned medium (CM) on alveolar type II cell DNA synthesis. Serum-free CM from confluent adult human lung fibroblasts was concentrated fivefold by lyophilization. Type II cells were isolated from adult rats by elastase dissociation and incubated with [3H]thymidine and varying dilutions of concentrated CM and serum from day 1 to 3 of culture. Stimulation of type II cell DNA synthesis by fibroblast-CM was maximal after 48 h of conditioning and required the presence of serum. The activity of the CM was eliminated by boiling and by treatment with trypsin, pepsin, or dithiothreitol and was additive with saturating concentrations of acidic fibroblast growth factor, epidermal growth factor, and insulin. The growth factor activity bound to heparin-Sepharose and was eluted with 0.6 and 1.0 M NaCl. Neutralizing antibody studies demonstrated that the primary mitogens isolated in the 0.6 and 1.0 M NaCl fractions were keratinocyte growth factor (KGF, fibroblast growth factor 7) and hepatocyte growth factor/scatter factor (HGF/SF), respectively. HGF/SF was demonstrated in the crude CM and KGF was detected in the 0.6 M NaCl eluent by immunoblotting. Northern blot analysis confirmed that the lung fibroblasts expressed both KGF and HGF/SF transcripts. Human recombinant KGF and HGF/SF induced a concentration- and serum-dependent increase in rat alveolar type II cell DNA synthesis. We conclude that adult human lung fibroblasts produce at least two soluble heparin-binding growth factors, KGF and HGF/SF, which promote DNA synthesis and proliferation of rat alveolar type II cells in primary culture. KGF and HGF/SF may be important stimuli for alveolar type II cell proliferation during lung growth and after lung injury.
Are Suicide Attempters Who Self-Mutilate a Unique Population?
Authors: Barbara Stanley, Marc J. Gameroff, Venezia Michalsen, J. John Mann
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Individuals who mutilate themselves are at greater risk for suicidal behavior. Clinically, however, there is a perception that the suicide attempts of self-mutilators are motivated by the desire for attention rather than by a genuine wish to die. The purpose of this study was to determine differences between suicide attempters with and without a history of self-mutilation. METHOD: The authors examined demographic characteristics, psychopathology, objective and perceived lethality of suicide attempts, and perceptions of their suicidal behavior in 30 suicide attempters with cluster B personality disorders who had a history of self-mutilation and a matched group of 23 suicide attempters with cluster B personality disorders who had no history of self-mutilation. RESULTS: The two groups did not differ in the objective lethality of their attempts, but their perceptions of the attempts differed. Self-mutilators perceived their suicide attempts as less lethal, with a greater likelihood of rescue and with less certainty of death. In addition, suicide attempters with a history of self-mutilation had significantly higher levels of depression, hopelessness, aggression, anxiety, impulsivity, and suicide ideation. They exhibited more behaviors consistent with borderline personality disorder and were more likely to have a history of childhood abuse. Self-mutilators had more persistent suicide ideation, and their pattern for suicide was similar to their pattern for self-mutilation, which was characterized by chronic urges to injure themselves. CONCLUSIONS: Suicide attempters with cluster B personality disorders who have a history of self-mutilation tend to be more depressed, anxious, and impulsive, and they also tend to underestimate the lethality of their suicide attempts. Therefore, clinicians may be unintentionally misled in assessing the suicide risk of self-mutilators as less serious than it is.
Comparison of cyclosporin A pharmacokinetics of a new microemulsion formulation and standard oral preparation in patients with psoriasis
Authors: P. ERKKO, H. GRANLUND, M. NUUTINEN, S. REITAMO
Journal: British Journal of Dermatology (1997)

Cyclosporin A (CyA) is a potent immunosuppressive drug which has shown efficacy in various skin disorders. The bioavailability of the oral CyA formulation (Sandimmun) is approximately 30%, showing high interpatient and intrapatient variability. The steady-state pharmacokinetics, efficacy and tolerability of CyA in two formulations: commercial Sandimmun soft gelatin capsules (CyA-SGC) and a newer oral formulation (Sandimmun Neoral: CyA-NOF), were compared in an open prospective study with a crossover between the two treatments in 19 patients with psoriasis. Each patient received a twice-daily treatment of CyA with a clinically effective dose of 2-5 mg/kg per day. The individual dosages were kept unchanged for at least 2 weeks before study entry and over the 42-day course of the study. At entry, patients were switched to CyA-NOF for 4 weeks and then back to CyA-SGC for another 2 weeks. Pharmacokinetic profiles were assessed at steady-state on day 14 while the patients were on CyA-NOF, and on day 42 while on CyA-SGC. Switching from CyA-SGC to CyA-NOF using 1:1 dose conversion resulted in an increased absorption of the drug. On average there was a 61% increase in maximum drug concentration (Cmax) and a 32% increase in the area under the steady-state blood concentration-time curve (AUC): Cmin was comparable in the two formulations. The increases in Cmax and AUC were associated with some increase in the clinical efficacy of the treatment. The number of adverse events reported by the patients and observed by the investigators were increased during CyA-NOF; the mean serum creatinine levels were not affected. An increased and a more consistent and predictable absorption of CyA is achieved with the new oral microemulsion formulation.