tbuckley/cabot-search huggingface dataset:
Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer
Authors: Eric Raymond, Jérôme Alexandre, Sandrine Faivre, Karina Vera, Eric Materman, Joseph Boni, Cathie Leister, Joan Korth-Bradley, Axel Hanauske, Jean-Pierre Armand
Journal: Journal of Clinical Oncology (2004)

Purpose To establish the safety, tolerability, and pharmacokinetic parameters of CCI-779, a selective inhibitor of the mammalian target of rapamycin, in patients with advanced cancer. Patients and Methods Using a modified continuous reassessment method, we performed a phase I with pharmacokinetic study of CCI-779 given as a weekly 30 minutes intravenous (IV) infusion. Results Twenty-four patients received CCI-779 at doses ranging 7.5 to 220 mg/m 2 . No immunosuppressive effect was reported. Dose-limiting thrombocytopenia occurred in two patients at 34 or 45 mg/m 2 . At 220 mg/m 2 , dose-limiting toxicities consisted of manic-depressive syndrome, stomatitis, and asthenia in two of nine patients, preventing further dose escalation. The most frequent drug-related toxicities were acne-like, maculopapular rashes and mucositis or stomatitis. All toxicities were reversible on treatment discontinuation. Maximum concentration and area under the concentration-time curve increase sub-proportionally with dose. Mean steady-state volume of distribution ranged from 127 to 385L. Sirolimus was a major metabolite (metabolite-to-parent ratio range, 2.5 to 3.5). Whole blood clearance was nonlinear, ranging from 19 to 51 L/h (34 to 220 mg/m 2 ). Variability predicted with flat doses appears comparable with data based on body-surface area–normalized treatment. Partial responses were observed in one patient with renal clear-cell carcinoma and in one patient with breast adenocarcinoma. Conclusion CCI-779 displayed no immunosuppressive effects with manageable and reversible adverse events at doses up to 220 mg/m 2 , the highest dose tested. Based on our results, weekly doses of 25, 75, and 250 mg CCI-779 not based on classical definitions of maximum-tolerated dose are being tested in phase II trials in patients with breast and renal cancer.
A randomised trial to evaluate the self-administered standardised chronic respiratory questionnaire
Authors: H. J. Schünemann, R. Goldstein, M. J. Mador, D. McKim, E. Stahl, M. Puhan, L. E. Griffith, B. Grant, P. Austin, R. Collins, G. H. Guyatt
Journal: European Respiratory Journal (2005)

The original chronic respiratory questionnaire (CRQ), one of the most widely used measures of health-related quality of life (HRQL) in chronic respiratory disease (CRD), is traditionally interviewer administered (IA) and includes an individualised dyspnoea domain. The present authors studied the impact of self-administered (SA) and standardised dyspnoea questions on CRQ measurement properties. In a factorial design multicentre trial, 177 patients with CRD (mean age 67.7 yrs; mean forced expiratory volume in one second per cent predicted 44.6%) were randomised to CRQ-IA (n = 86) or CRQ-SA (n = 91), and to initially complete the standardised or individualised items before and after respiratory rehabilitation. While maintaining validity, the CRQ-SA proved more responsive to changes in HRQL than the CRQ-IA in all domains. Compared with the standardised dyspnoea domain, the individualised dyspnoea domain indicated greater responsiveness. The correlations of baseline scores and change scores with other HRQL instruments indicated good validity of the CRQ-SA. In conclusion, self-administration and standardisation of the chronic respiratory questionnaire maintains validity and responsiveness relative to the interviewer-administered chronic respiratory questionnaire. These results challenge the assumption that interviewer-administered questionnaires are superior to self-administered questionnaires in older patients with chronic respiratory disease.
Therapeutic use exemptions (TUEs) at the Olympic Games 1992–2012
Authors: Kenneth D Fitch
Journal: British Journal of Sports Medicine (2013)

The need for therapeutic use exemptions (TUEs) or the permitted use of Prohibited Substances and Prohibited Methods by athletes to treat significant medical conditions arose when several classes of drugs used commonly in medicine were prohibited in sport by the International Olympic Committee (IOC) during the 1980s. However, although the IOC Medical Commission (IOC-MC) gave qualified support for the concept to formally start at the 1992 Barcelona Olympics, the Commission's fears that athletes might abuse the mechanism resulted in minimal publicity and its non-inclusion in the Medical Code of the Olympic Movement for 8 years. TUEs would not be widely publicised until the advent of the World Anti-Doping Agency which not only approved the principles of TUEs as developed by the IOC's Medications Advisory Committee (MAC) in 1991, but also introduced the name of TUE. Several changes to the Prohibited List have resulted in TUEs being necessary for substances that were permitted 20 years ago as disclosed in a review of TUEs approved at the 11 Olympic Games that the IOC's MAC, later the TUE Committee (TUEC), has operated. The IOC and its TUEC played a pivotal role in developing the concept of TUE which is now globally accepted.
The influence of breathhold on peak expiratory flow in normal and asthmatic children
Authors: I. Matsumoto, S. Walker, P.D. Sly
Journal: European Respiratory Journal (1996)

We have previously demonstrated a 10% reduction in peak expiratory flow (PEF) in healthy adults following a breathhold at total lung capacity (TLC). This fall was attributed to dissipation of airway wall viscoelasticity, increasing airway wall compliance (Caw). To investigate this phenomenon in children and to determine whether the effect of breathhold would be greater in asthmatics than in normal children, 15 asthmatics and 14 normal children (aged 10-15 yrs) performed maximal post expirations (MFE) with and without a 5 s breathhold at TLC. The entire study was repeated following the inhalation of salbutamol (800 micrograms) to relax the airway smooth muscle (and to increase Caw). Breathhold at TLC resulted in a significant decrease in PEF both in the asthmatics (group mean fall 5.8%; p &lt; 0.01) and normal children (group mean fall 10.3%; p &lt; 0.05). Salbutamol diminished this fall, becoming nonsignificant in the normal children. Similar patterns were also seen in forced expiratory volume in one second (FEV1) and in maximal expiratory flow at 50% vital capacity (V950). These data are consistent with the proposal that breathhold at total lung capacity dissipated viscoelastic energy (increasing airway compliance) and decreased maximal expiratory flows both in normal and asthmatic children. They also demonstrate the need to standardize the forced vital capacity manoeuvre to decrease the variability in the flows recorded during the subsequent forced expiration.
Chimeric Smooth Muscle–Specific Enhancer/Promoters
Authors: Sébastien Ribault, Pascal Neuville, Agnès Méchine-Neuville, Fabrice Augé, Ara Parlakian, Giulio Gabbiani, Denise Paulin, Valérie Calenda
Journal: Circulation Research (2001)

Abstract —Gene transfer with adenoviral vectors is an attractive approach for the treatment of atherosclerosis and restenosis. However, because expression of a therapeutic gene in nontarget tissues may have deleterious effects, artery-specific expression is desirable. Although expression vectors containing transcriptional regulatory elements of genes expressed solely in smooth muscle cells (SMCs) have proved efficient to restrict expression of the transgene, their use in the clinical setting can be limited by their reduced strength. In the present study, we show that low levels of transgene expression are obtained with the smooth muscle (SM)-specific SM22α promoter compared with the viral cytomegalovirus (CMV) enhancer/promoter. We have generated chimeric transcriptional cassettes containing either a SM (SM-myosin heavy chain) or a skeletal muscle (creatine kinase) enhancer combined with the SM22α promoter. With both constructs we observed significantly stronger expression that remains SM-specific. In vivo, reporter gene expression was restricted to arterial SMCs with no detectable signal at remote sites. Moreover, when interferon-γ expression was driven by one of these two chimeras, SMC growth was inhibited as efficiently as with the CMV promoter. Finally, we demonstrate that neointima formation in the rat carotid balloon injury model was reduced to the same extent by adenoviral gene transfer of interferon-γ driven either by the SM-myosin heavy chain enhancer/SM22α promoter or the CMV promoter. These results indicate that such vectors can be useful for the treatment of hyperproliferative vascular disorders.
Experimental Rhinovirus 16 Infection
Authors: KATRIEN GRÜNBERG, HERMELIJN H. SMITS, MIEKE C. TIMMERS, ERIK P. A. de KLERK, RADBOUD J. E. M. DOLHAIN, ELLIOT C. DICK, PIETER S. HIEMSTRA, PETER J. STERK
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Asthma exacerbations are often associated with respiratory virus infections, particularly with rhinovirus. In the present study we investigated the effect of experimental rhinovirus 16 (RV16) infection on airway inflammation as assessed by analysis of hypertonic saline-induced sputum. Twenty-seven nonsmoking atopic, mildly asthmatic subjects participated in a placebo-controlled parallel study. RV16 (n = 19) or its diluent (n = 8) was nasally administered. Sputum inductions were performed at entry and on Days 2 and 9 after inoculation, and airway responsiveness to histamine (PC20) was measured on Days 4 and 11. Cell differentials and levels of albumin, eosinophil cationic protein (ECP), IL-8, and IL-6 were determined. The cellular origin of IL-8 was investigated by intracellular staining. RV infection was confirmed by culture and/or by antibody titer rise in each of the RV16-treated subjects. There were no significant changes in the sputum differentials of nonsquamous cells (MANOVA, p ⩾ 0.40). In the RV16 group, there was a significant increase in the levels of ECP, IL-8, and IL-6 at Day 2 after infection (p < 0.05), whereas the albumin levels did not change (p = 0.82). The levels of IL-8 and IL-6 remained elevated for as long as 9 d after infection (p < 0.05). The increase in the percentage of IL-8 positive cells at Day 2 after infection could be attributed to the increase in IL-8 positive neutrophils (p < 0.02). There was a significant decrease in PC20 at Day 4 (p = 0.02), which was no longer significant at Day 11 (p = 0.19). The decrease in PC20 correlated significantly with the increase in ECP in the first week (r = − 0.60) and with the change in the percentage eosinophils in the second week after inoculation (r = − 0.58). We conclude that experimental RV16 infection in atopic asthmatic subjects increases airway hyperresponsiveness in conjunction with augmented airway inflammation, as reflected by an increase in ECP, IL-8, and IL-6 in sputum. Our results suggest that the RV16-enhanced airway hyperresponsiveness is associated with eosinophilic inflammation.
Public-health impact of accelerated measles control in the WHO African Region 2000–03
Authors: M Otten, R Kezaala, A Fall, B Masresha, R Martin, L Cairns, R Eggers, R Biellik, M Grabowsky, P Strebel, J-M Okwo-Bele, D Nshimirimana
Journal: The Lancet (2005)
Hazards of chemical weapons release during war: new perspectives.
Authors: S Reutter
Journal: Environmental Health Perspectives (1999)

The two major threat classes of chemical weapons are mustard gas and the nerve agents, and this has not changed in over 50 years. Both types are commonly called gases, but they are actually liquids that are not remarkably volatile. These agents were designed specifically to harm people by any route of exposure and to be effective at low doses. Mustard gas was used in World War I, and the nerve agents were developed shortly before, during, and after World War II. Our perception of the potency of chemical weapons has changed, as well as our concern over potential effects of prolonged exposures to low doses and potential target populations that include women and children. Many of the toxicologic studies and human toxicity estimates for both mustard and nerve agents were designed for the purpose of quickly developing maximal casualties in the least sensitive male soldier. The "toxicity" of the chemical weapons has not changed, but our perception of "toxicity" has.
Travel-associated Legionnaires’ disease in residents from England and Wales travelling to Corfu, Greece, August to October 2011
Authors: R Maini, F Naik, T  G Harrison, M Mentasti, G Spala, E Velonakis, C Hadjichristodoulou, B de Jong, A Vatopoulos, N Phin
Journal: Eurosurveillance (2012)

Binary file ES_Abstracts_Final_ECDC.txt matches
Methylenetetrahydrofolate reductase 677 T allele protects against persistent HBV infection in West Africa
Authors: Jean-Pierre Bronowicki, Idrissia Abdelmouttaleb, Laurent Peyrin-Biroulet, Véronique Venard, Hacène Khiri, Nicodème Chabi, Emile K. Amouzou, Hélène Barraud, Philippe Halfon, Ambaliou Sanni, Marc-André Bigard, Alain Le Faou, Jean-Louis Guéant
Journal: Journal of Hepatology (2008)
Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma
Authors: P Bhavsar, M Hew, N Khorasani, A Torrego, P J Barnes, I Adcock, K F Chung
Journal: Thorax (2008)

About 5-10% of patients with asthma suffer from poorly controlled disease despite corticosteroid (CS) treatment, which may indicate the presence of CS insensitivity. A study was undertaken to determine whether relative CS insensitivity is present in alveolar macrophages from patients with severe asthma and its association with p38 mitogen-activated protein kinase (MAPK) activation and MAPK phosphatase-1 (MKP-1).Fibreoptic bronchoscopy and bronchoalveolar lavage (BAL) were performed in 20 patients with severe asthma and 19 with non-severe asthma and, for comparison, in 14 normal volunteers. Alveolar macrophages were exposed to lipopolysaccharide (LPS, 10 mug/ml) and dexamethasone (10(-8) and 10(-6) M). Supernatants were assayed for cytokines using an ELISA-based method. p38 MAPK activity and MKP-1 messenger RNA expression were assayed in cell extracts.The inhibition of LPS-induced interleukin (IL)1beta, IL6, IL8, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha release by dexamethasone (10(-6) M) was significantly less in macrophages from patients with severe asthma than in macrophages from patients with non-severe asthma. There was increased p38 MAPK activation in macrophages from patients with severe asthma. MKP-1 expression induced by dexamethasone and LPS, expressed as a ratio of LPS-induced expression, was reduced in severe asthma.Alveolar macrophages from patients with severe asthma demonstrate CS insensitivity associated with increased p38 MAPK activation that may result from impaired inducibility of MKP-1.
Melanocortin 1 Receptor Agonists Reduce Proteinuria
Authors: Annika Lindskog, Kerstin Ebefors, Martin E. Johansson, Bergur Stefánsson, Anna Granqvist, Margret Arnadottir, Anna-Lena Berg, Jenny Nyström, Börje Haraldsson
Journal: Journal of the American Society of Nephrology (2010)

Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. Recent reports suggest that treatment with adrenocorticotropic hormone (ACTH) reduces proteinuria, but the mechanism of action is unknown. Here, we identified gene expression of the melanocortin receptor MC1R in podocytes, glomerular endothelial cells, mesangial cells, and tubular epithelial cells. Podocytes expressed most MC1R protein, which colocalized with synaptopodin but not with an endothelial-specific lectin. We treated rats with passive Heymann nephritis (PHN) with MS05, a specific MC1R agonist, which significantly reduced proteinuria compared with untreated PHN rats ( P < 0.01). Furthermore, treatment with MC1R agonists improved podocyte morphology and reduced oxidative stress. In summary, podocytes express MC1R, and MC1R agonism reduces proteinuria, improves glomerular morphology, and reduces oxidative stress in nephrotic rats with PHN. These data may explain the proteinuria-reducing effects of ACTH observed in patients with membranous nephropathy, and MC1R agonists may provide a new therapeutic option for these patients.
Recombination-Associated Sequence Homogenization of Neighboring Alu Elements: Signature of Nonallelic Gene Conversion
Authors: A. Aleshin, D. Zhi
Journal: Molecular Biology and Evolution (2010)

Recently, researchers have begun to recognize that, in order to establish neutral models for disease association and evolutionary genomics studies, it is crucial to have a clear understanding of the genomic impact of nonallelic gene conversion.Drawing on previous successes in characterizing this phenomenon over protein-coding gene families, we undertook a computational analysis of neighboring Alu sequences in the genome scale.For this purpose, we developed adjusted comutation rate (aCMR), a novel statistical method measuring the excess number of identical point mutations shared by adjacent Alu sequences, vis-a `-vis random pairs.Using aCMR, we uncovered a remarkable genome-wide sequence homogenization of neighboring Alus, with the strongest signal observed in the pseudoautosomal regions of the X and Y chromosomes.The magnitude of sequence homogenization between Alu pairs is greater with shorter interlocus distance, higher sequence identity, and parallel orientation.Moreover, shared substitutions show a strong directionality toward GC nucleotides, with multiple substitutions tending to cluster within the Alu sequence.Taken together, these observed recombination-associated sequence homogenization patterns are best explained by frequent ubiquitous gene conversion events between neighboring Alus.We believe that these observations help to illuminate the nature and impact of the enigmatic phenomenon of gene conversion.
Utilization of I-domain of LFA-1 to Target Drug and Marker Molecules to Leukocytes
Authors: Prakash Manikwar, Bimo A. Tejo, Heather Shinogle, David S. Moore, Tahl Zimmerman, Francisco Blanco, Teruna J. Siahaan
Journal: Theranostics (2011)

The long-term objective of this project is to utilize the I-domain protein for the α-subunit of LFA-1 to target drugs to lymphocytes by binding to ICAM receptors on the cell surface. The short-term goal is to provide proof-of-concept that I-domain conjugated to small molecules can still bind to and uptake by ICAM-1 on the surface of lymphocytes (i.e., Raji cells). To accomplish this goal, the I-domain protein was labeled with FITC at several lysine residues to produce the FITC-I-domain and CD spectroscopy showed that the FITC-I-domain has a secondary structure similar to that of the parent I-domain. The FITC-I-domain was taken up by Raji cells via receptor-mediated endocytosis and its uptake can be blocked by anti-I-domain mAb but not by its isotype control. Antibodies to ICAM-1 enhance the binding of I-domain to ICAM-1, suggesting it binds to ICAM-1 at different sites than the antibodies. The results indicate that fluorophore modification does not alter the binding and uptake properties of the I-domain protein. Thus, I-domain could be useful as a carrier of drug to target ICAM-1-expressing lymphocytes.
CELLULAR EVENTS IN THE IMMUNE RESPONSE
Authors: Donald J. Raidt, R. I. Mishell, Richard W. Dutton
Journal: The Journal of Experimental Medicine (1968)

Cell suspensions from the spleens of normal mice or mice injected with sheep erythrocytes were separated on a discontinous bovine serum albumin density gradient. Four bands or subpopulations were obtained and were assayed for antibody-forming cells, and for antigen-sensitive precursor cells. The antibody-forming cells were assayed by the hemolytic plaque assay and the antigen-sensitive precursors were assayed by the number of plaque-forming cells which developed after 3 or 5 day's culture with antigen. It was found that both antibody-forming cells and their precursors were present in the denser region of the gradient when spleen cell suspensions were taken from unimmunized mice. In contrast, both antibody-forming cells and precursors floated to the top in cell suspensions from mice sacrificed 1, 2, or 3 days after antigen injection. The change in density was detectable as early as 12 hr and was complete by 18 hr. The cell which changed in density was specific for the antigen that brought about that change. The significance of these findings is discussed.
Uropepsinogen Level in Post-gastrectomy Cases
Authors: J. M. Cameron
Journal: BMJ (1960)

hospitals throughout Wales in the five years and who did not subsequently commit suicide.One important fact which the death of these 92 ex-mental-hospital patients does demonstrate is the need for vigilance by family doctors and psychiatric out-patient clinics in the months immediately after patients' discharge from hospital, for nearly two-thirds of the 92 died within a year of their discharge.The examination of the 881 suicides suggests that the number of suicides could be reduced now by medical means; for (1) signs of emotional abnormality were commonly present for some time before death, (2) com- paratively few had received psychiatric treatment, (3) signs of profound depression sometimes did not receive the urgent attention which would have been given to a medical or surgical emergency, and (4) com- paratively few of the large population "at risk" in mental hospitals later commit suicide.
Multicentre phase I/II study of PI-88, a heparanase inhibitor in combination with docetaxel in patients with metastatic castrate-resistant prostate cancer
Authors: M. Khasraw, N. Pavlakis, S. McCowatt, C. Underhill, S. Begbie, P. de Souza, A. Boyce, F. Parnis, V. Lim, R. Harvie, G. Marx
Journal: Annals of Oncology (2009)
Physical Association of HDAC1 and HDAC2 with p63 Mediates Transcriptional Repression and Tumor Maintenance in Squamous Cell Carcinoma
Authors: Matthew R. Ramsey, Lei He, Nicole Forster, Benjamin Ory, Leif W. Ellisen
Journal: Cancer Research (2011)

Squamous cell carcinoma (SCC) is a treatment-refractory subtype of human cancer arising from stratified epithelium of the skin, lung, esophagus, oropharynx, and other tissues. A unifying feature of SCC is high-level expression of the p53-related protein p63 (TP63) in 80% of cases. The major protein isoform of p63 expressed in SCC is ΔNp63α, an N-terminally truncated form which functions as a key SCC cell survival factor by mechanisms that are unclear. In this study, we show that ΔNp63α associates with histone deacetylase 1 (HDAC1) and HDAC2 to form an active transcriptional repressor complex that can be targeted to therapeutic advantage. Repression of proapoptotic Bcl-2 family member genes including p53 upregulated modulator of apoptosis (PUMA) by p63/HDAC is required for survival of SCC cells. Cisplatin chemotherapy, a mainstay of SCC treatment, promotes dissociation of p63 and HDAC from the PUMA promoter, leading to increased histone acetylation, PUMA activation, and apoptosis. These effects are recapitulated upon targeting the p63/HDAC complex selectively with class I/II HDAC inhibitors using both in vitro and in vivo models. Sensitivity to HDAC inhibition is directly correlated with p63 expression and is abrogated in tumor cells that overexpress endogenous Bcl-2. Together, our results elucidate a mechanism of p63-mediated transcriptional repression and they identify the ΔNp63α/HDAC complex as an essential tumor maintenance factor in SCC. In addition, our findings offer a rationale to apply HDAC inhibitors for SCC treatment.
Congestive Heart Failure in the Diabetic
Authors: Timothy J. Regan
Journal: Annual Review of Medicine (1983)

Heart failure seems to occur in adult-onset diabetics with a greater frequency than in the nondiabetic population, particularly in women. A number of such patients do not have significant occlusive disease of the major coronary arteries, or convincing small-vessel disease. A subclinical abnormality of myocardium in experimental diabetes and asymptomatic human diabetics supports the concept of a diabetic cardiomyopathy.