tbuckley/cabot-search huggingface dataset:
ONX0912, a novel proteasome inhibitor for the treatment of lung fibrosis?
Authors: Nora Pfister, Nunja Habel, Oliver Eickelberg, Tobias Stöger, Silke Meiners
Journal: European Respiratory Journal (2012)

Background: Proteasome inhibition has been shown to prevent development of fibrosis in several organs. Effects of proteasome inhibitors (PI) on lung fibrosis are controversial and cytotoxic side effects of the inhibition of proteasomal protein degradation in the cell cannot be excluded.  Hypothesis: Local administration of PI allows efficient drug delivery to the lung and prevents development of pulmonary fibrosis without systemic toxicity.  Methods and results: ONX0912 (ONX), a new irreversible PI, was evaluated in comparison to bortezomib, the only FDA approved PI, with regard to cytotoxicity and proteasomal inhibition in the cell line A549. Primary lung fibroblasts were isolated from proteasome reporter mice (ODD-luc) and characterized using MTT survival, and proteasome activity assays. The ODD-luc reporter accumulates upon proteasome inhibition and can be quantified via bioluminescence reflecting the actual degree of proteasome inhibition in the cell.  While bortezomib had strong cytotoxic effects, ONX only partially inhibited the proteasome at low doses but efficiently blocked fibroblast function without affecting cell viability of fibroblasts or epithelia cells. An optimal nontoxic dose of ONX was obtained after intratracheal instillation into ODD-luc mice. This dose then was applied locally into the lung of ODD-luc mice with bleomycin induced fibrosis and therapeutic effects were investigated by histochemical analysis of the lungs.  Conclusion: ONX provides antifibrotic effects in murine lung fibroblasts in a non-toxic dose range. Local administration of ONX into the lungs partially inhibits the proteasome without toxic side effects and can be regarded as a promising approach to inhibit pulmonary fibrosis.
Tiotropium Respimat® Add-On Therapy Reduces Airflow Obstruction In Patients With Symptomatic Moderate Asthma, Independent Of TH2 Inflammatory Status
Authors: Thomas B. Casale, Eric Donn Bateman, Ronald Dahl, Emilio Pizzichini, Mark L. Vandewalker, Johann Christian Virchow, Michael Engel, Petra Moroni-Zentgraf, Hendrik Schmidt, Huib A.M. Kerstjens
Journal: Journal of Allergy and Clinical Immunology (2014)
Walking, cycling and transport safety: an analysis of child road deaths
Authors: B. Sonkin
Journal: Journal of the Royal Society of Medicine (2006)

DesignAnalysis of road traffic injury death rates per 100 000 children and death rates per 10 million passenger miles travelled. Main outcome measuresDeath rates per 100 000 children and per 10 million child passenger miles for pedestrians, cyclists and car occupants. ResultsDeath rates per head of population have declined for child pedestrians, cyclists and car occupants but pedestrian death rates remain higher (0.55 deaths/100 000 children; 95% confidence interval [CI] 0.42 to 0.72 deaths) than those for car occupants (0.34 deaths; 95% CI 0.23 to 0.48 deaths) and cyclists (0.16 deaths; 95% CI 0.09 to 0.27 deaths). Since 1985, the average distance children travelled as a car occupant has increased by 70%; the average distance walked has declined by 19%; and the average distance cycled has declined by 58%. Taking into account distance travelled, there are about 50 times more child cyclist deaths (0.55 deaths/10 million passenger miles; 0.32 to 0.89) and nearly 30 times more child pedestrian deaths (0.27 deaths; 0.20 to 0.35) than there are deaths to child car occupants (0.01 deaths; 0.007 to 0.014). In 2003, children from families without access to a vehicle walked twice the distance walked by children in families with access to two or more vehicles. ConclusionsMore needs to be done to reduce the traffic injury death rates for child pedestrians and cyclists. This might encourage more walking and cycling and also has the potential to reduce social class gradients in injury mortality.
Five years' experience of treating port wine stains with the flashlamp-pumped pulsed dye laser
Authors: G.A. KATUGAMPOLA, S.W. LANIGAN
Journal: British Journal of Dermatology (1997)

During the last 5 years, 640 patients had treatment to their port wine stains (PWS) with a flashlamp-pumped pulsed dye laser. One hundred and fifty-six patients have been discharged for varying reasons, of which 59 (38%) achieved excellent (at least 75%) lightening of their birthmark. Of the remaining patients, those who attended the clinic for the sixth and 12th time for treatment were also assessed to determine the degree of fading achieved in the port wine stain. Our findings confirm that flashlamp-pumped dye laser treatment is safe and effective for the treatment of PWS and that complications are rare. However, the degree of fading achieved is variable and often unpredictable. Fifty-two per cent of facial lesions of different colours achieved over 75% fading as against 18% of non-facial lesions. Sixty-four per cent of those over the age of 50 years had an excellent response whereas only 19% of those below the age of 5 years were able to achieve a similar result. The colour of the port wine stain was found to be of no prognostic value. A search for an accurate and non-invasive method to predict the outcome of flashlamp-pumped pulsed dye laser therapy for PWS is warranted.
Solutions to global health challenges: no more Band-Aids
Authors: Warner C. Greene
Journal: Journal of Clinical Investigation (2013)

Thank you very much. It’s a pleasure to be here. I would like to describe to you an alternate career. It might seem strange. Why would a professed molecular biologist, who has spent an entire career studying the basic mechanisms of HIV pathogenesis, be talking to you today about global health? Well, let me tell you a story. This story begins with Merle Sande (Figure ​(Figure1),1), who was Chief of Medicine at San Francisco General Hospital, a close and dear friend. He was one of the main reasons I moved to the University of California, San Francisco, and to Gladstone.
Long term changes in lung function after surgical treatment of bullous emphysema in smokers and ex-smokers.
Authors: J A Hughes, A M MacArthur, D C Hutchison, P Hugh-Jones
Journal: Thorax (1984)

Eleven patients who had received surgical treatment for bullous emphysema had regular assessment of lung function for a minimum of four years (mean 8.8, range 4-20 years). For each patient we estimated the annual rate of change in FEV1 and "relaxed" vital capacity (before and after bronchodilator aerosol) and in carbon monoxide transfer factor (TLCO), transfer coefficient (KCO), and arterial carbon dioxide and oxygen tensions (Paco2 and Pao2). Among the 11 who had undergone operation, all lung function variables declined at a faster rate in those who continued to smoke than in ex-smokers, the difference in rate being significant (p less than 0.05) for FEV1 (before bronchodilator), TLCO and KCO. In ex-smokers the rate of change in most lung function indices was not significantly different from zero--that is, no change; in smokers all lung function indices except Paco2 declined at a rate significantly greater than zero. These findings suggest that long term results of surgical treatment for bullous emphysema are likely to be greatly improved if patients abandon smoking.
Long term outcomes in men screened for abdominal aortic aneurysm: prospective cohort study
Authors: J. L. Duncan, K. A. Harrild, L. Iversen, A. J. Lee, D. J. Godden
Journal: BMJ (2012)

<b>Objective</b> To determine whether there is a relation between aortic diameter and morbidity and mortality in men screened for abdominal aortic aneurysm. <b>Design</b> Prospective cohort study. <b>Setting</b> Highland and Western Isles (a large, sparsely populated area of Scotland). <b>Participants</b> 8146 men aged 65-74. <b>Main outcome measures</b> Morbidity and mortality in relation to presence of abdominal aortic aneurysm and three categories of aortic diameter (≤24 mm, 25-29 mm, and ≥30 mm). <b>Results</b> When screened, 414 men (5.1%) had an aneurysm (diameter ≥30 mm), 669 (8.2%) an aortic diameter of 25-29 mm, and 7063 (86.7%) an aortic diameter of ≤24 mm. The cohort was followed up for a median of 7.4 (interquartile range 6.9-8.2) years. Mortality was significantly associated with aortic diameter: 512 (7.2%) men in the ≤24 mm group died compared with 69 (10.3%) in the 25-29 mm group and 73 (17.6%) in the ≥30 mm group. The mortality risk in men with an aneurysm or with an aorta measuring 25-29 mm was significantly higher than in men with an aorta of ≤24 mm. The increased mortality risk in the 25-29 mm group was reduced when taking confounders such as smoking and known heart disease into account. After adjustment, compared with men with an aortic diameter of ≤24 mm, the risk of hospital admission for cardiovascular disease and chronic obstructive pulmonary disease was significantly higher in men with aneurysm and those with aortas measuring 25-29 mm. Men with an aneurysm also had an increased risk of hospital admission for cerebrovascular disease, atherosclerosis, peripheral arterial disease, and respiratory disease. In men with aortas measuring 25-29 mm, the risk of hospital admission with abdominal aortic aneurysm was significantly higher than in men with an aorta of ≤24 mm (adjusted hazard ratio 6.7, 99% confidence interval 3.4 to 13.2) and this increased risk became apparent two years after screening. <b>Conclusions</b> Men with abdominal aortic aneurysm and those with aortic diameters measuring 25-29 mm have an increased risk of mortality and subsequent hospital admissions compared with men with an aorta diameter of ≤24 mm. Consideration should be given to control of risk factors and to rescreening men with aortas measuring 25-29 mm at index scanning.
ATM Mediates Cytotoxicity of a Mutant Telomerase RNA in Human Cancer Cells
Authors: Bradley A. Stohr, Elizabeth H. Blackburn
Journal: Cancer Research (2008)

Abstract Telomeres are elongated by the enzyme telomerase, which contains a template-bearing RNA (TER or TERC) and a protein reverse transcriptase. Overexpression of a particular mutant human TER with a mutated template sequence (MT-hTer-47A) in telomerase-positive cancer cells causes incorporation of mutant telomeric sequences, telomere uncapping, and initiation of a DNA damage response, ultimately resulting in cell growth inhibition and apoptosis. The DNA damage pathways underlying these cellular effects are not well understood. Here, we show that the ataxia-telangiectasia mutated (ATM) protein is activated and forms telomeric foci in response to MT-hTer-47A expression. Depletion of ATM from two cancer cell lines, including the p53-mutant UM-UC-3 bladder cancer line, rendered the cells largely unresponsive to MT-hTer-47A. Relative to ATM-competent controls, ATM-depleted cells showed increased proliferation and clonogenic survival and reduced cell death following MT-hTer-47A treatment. In contrast, ATM depletion sensitized the cancer cells to treatment with camptothecin, a topoisomerase inhibitor that induces DNA double-strand breaks. We show that the effects of ATM depletion on the MT-hTer-47A response were not due to decreased expression of MT-hTer-47A or reduced activity of telomerase at the telomere. Instead, ATM depletion allowed robust cancer cell growth despite the continued presence of dysfunctional telomeres containing mutant sequence. Notably, the number of end-to-end telomere fusions induced by MT-hTer-47A treatment was markedly reduced in ATM-depleted cells. Our results identify ATM as a key mediator of the MT-hTer-47A dysfunctional telomere response, even in cells lacking wild-type p53, and provide evidence that telomere fusions contribute to MT-hTer-47A cytotoxicity. [Cancer Res 2008;68(13):5309–17]
Effects of inhaled furosemide on platelet-activating factor challenge in mild asthma
Authors: A.l Echazarreta, F.p Gómez, J Ribas, M Achaval, J.a Barberà, J Roca, K.f Chung, R Rodriguez-Roisin
Journal: European Respiratory Journal (1999)

Furosemide (Fur) may have an anti-inflammatory effect on airways in patients with asthma although its intrinsic mechanism remains elusive. Platelet-activating factor (PAF) is a potent proinflammatory mediator that induces systemic and respiratory effects in normal control subjects and asthmatics. The aim of this study was to assess whether pretreatment with nebulized Fur (40 mg) was able to modulate PAF-induced systemic and respiratory effects in asthma. Eleven patients were studied (mean+/-sem 22+/-0.8 yrs) with mild asthma (forced expiratory volume in one second, 95+/-4%) in a randomized, double-blind, placebo-controlled, cross-over fashion, one week apart. PAF challenge (18 microg) was carried out 15 min after administration of Fur or placebo. Peripheral blood neutrophils, respiratory system resistance, and arterial blood gases were measured at baseline, and 5, 15 and 45 min after PAF; urinary cysteinyl leukotriene E4 (uLTE4) was also measured, at baseline and 120 min after PAF challenge. Although Fur did not alter PAF-induced systemic and respiratory effects, it did partially inhibit (63%; p&lt;0.04) the increments of uLTE4 levels shown after PAF inhalation. It is concluded that furosemide is not effective in protecting against platelet-activating factor challenge in patients with asthma despite its potential inhibition of leukotriene synthesis. These findings reinforce the view that the pulmonary effects of platelet-activating factor are mediated through different pathways.
Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials
Authors: Hai T Tran, Yuan Liu, Amado J Zurita, Ying Lin, Katherine L Baker-Neblett, Anne-Marie Martin, Robert A Figlin, Thomas E Hutson, Cora N Sternberg, Rafael G Amado, Lini N Pandite, John V Heymach
Journal: The Lancet Oncology (2012)
Nasal application of the cationic liposome DC-Chol:DOPE does not alter ion transport, lung function or bacterial growth
Authors: PG Middleton, NJ Caplen, X Gao, L Huang, H Gaya, DM Geddes, EW Alton
Journal: European Respiratory Journal (1994)

Liposome-mediated gene transfer is commonly used for in vitro transfection of deoxyribonucleic acid (DNA) into mammalian cells. We and others have recently demonstrated that this can be an effective method for in vivo delivery of plasmid DNA containing the human cystic fibrosis transmembrane conductance regulator (CFTR) gene to mouse models of cystic fibrosis (CF). This suggests that cationic liposomes may be useful for transferring CFTR complementary DNA (cDNA) into the airways of CF subjects. In such trials, measurement of nasal potential difference (PD) will be used to monitor the efficacy of correction of the CF bioelectric defect and to provide a sensitive assay of epithelial integrity [corrected]. We therefore assessed whether the cationic liposome DC-Chol: DOPE altered nasal ion transport parameters, in six normal and three CF subjects. Lung function was also measured as a further marker of safety. Finally, as CF airways are chronically infected, we studied whether DC-Chol:DOPE or DC-Chol:DOPE-DNA complexes altered the bacterial growth and sensitivities of CF sputum. No significant effect was seen on any of these parameters, suggesting that DC-Chol:DOPE may be appropriate for use in human trials of liposome-mediated gene therapy for CF.
Preoperative CYFRA 21-1 level as a prognostic indicator in resected nonsmall cell lung cancer
Authors: J Niklinski, T Burzykowski, W Niklinska, J Laudanski, L Chyczewski, M Rapellino, M Furman
Journal: European Respiratory Journal (1998)

Cytokeratin 19 is particularly abundant in carcinoma of the lung. The CYFRA 21-1 assay has recently been developed for detection of a cytokeratin 19 fragment in serum. In the current study, the prognostic information provided by the CYFRA 21-1 assay in operable nonsmall cell lung cancer (NSCLC) was analysed. Serum levels of CYFRA 21-1 were measured using an immunoradiometric assay (DiaSorin) in 94 patients with operable NSCLC. Survival and disease-free survival curves related to initial levels of this marker were estimated using the Kaplan-Meier method. Elevated preoperative CYFRA 21-1 levels were identified in 42% of patients with NSCLC. The number of patients with elevated levels of this marker increased with tumour node metastasis (TNM) stage (p=0.02). In univariate analysis elevated levels of CYFRA 21-1 were significantly associated with poor overall survival (p&lt;0.001) and with disease-free survival (p&lt;0.001). The results remained significant when the comparisons were adjusted, using the stratified log-rank test, for patient's TNM stage (p&lt;0.001 for both overall and disease-free survival). Elevated preoperative levels of CYFRA 21-1 decreased the probability of survival or surviving without recurrence 15 months or more after the operation. This was confirmed by the results of the multivariate analysis. In conclusion, CYFRA 21-1 may be an independent prognostic parameter of survival and tumour relapse in nonsmall cell lung cancer and may be useful in identifying resected cancer patients at high risk for treatment failure.
Transcriptional Regulation of the Human Reduced Folate Carrier in Childhood Acute Lymphoblastic Leukemia Cells
Authors: Mingjun Liu, Yubin Ge, Scott G. Payton, Amro Aboukameel, Stephen Buck, Robin M. Flatley, Christina Haska, Ramzi Mohammad, Jeffrey W. Taub, Larry H. Matherly
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The transcriptional regulation of the human reduced folate carrier (hRFC), involved in cellular uptake of methotrexate and reduced folates, was studied in childhood acute lymphoblastic leukemia (ALL). The hRFC gene is regulated by six noncoding exons (A1/A2 and A to E) and multiple promoters. In ALL, hRFC-A1/A2 and hRFC-B are the major transcript forms. Experimental Design: RNAs from 18 ALL lymphoblast specimens and 10 nonobese diabetic/severe combined immunodeficient ALL xenografts were assayed by real-time reverse transcription-PCR for hRFC-A1/A2 and hRFC-B transcripts and for transcripts encoding USF1, GATA1, Sp1, and Ikaros transcription factors. For the xenografts, gel shift and chromatin immunoprecipitation assays assessed transcription factor binding to the hRFC-A1/A2 and hRFC-B promoters. CpG methylation density within a 334-bp region, including the core hRFC-B promoter, was established by bisulfite sequencing. hRFC-A1/A2 and hRFC-B promoter polymorphisms were assayed by DNA sequencing. Results: For the 28 ALLs, hRFC-A1/A2 and hRFC-B transcripts spanned a 546-fold range. By chromatin immunoprecipitation and gel shift assays, binding was confirmed for USF1 and GATA1 for hRFC-A1/A2, and for Sp1, USF1, and Ikaros for hRFC-B. hRFC transcript levels correlated with those for GATA1 and USF1 for hRFC-A1/A2 and with Sp1 and USF1 transcripts for hRFC-B. CpG methylation in ALL did not correlate with hRFC-B transcripts. In 40 ALL and 17 non-ALL specimens, 2 cosegregating high-frequency polymorphisms (T-1309/C-1217 and C-1309/T-1217; allelic frequencies of 36% and 64%, respectively) were detected in the A1/A2 promoter; none were detected in promoter B. The hRFC-A1/A2 polymorphisms only slightly affected promoter activity. Conclusions: Our results show a complex regulation of hRFC in ALL involving the hRFC-A1/A2 and hRFC-B promoters and noncoding exons. Although Sp1, USF1, and GATA1 levels are critical determinants of hRFC transcription in ALL, neither DNA methylation nor promoter polymorphisms contribute to differences in hRFC expression.
Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma
Authors: Salvia Jain, Dina Stroopinsky, Li Yin, Jacalyn Rosenblatt, Maroof Alam, Parul Bhargava, Rachael A. Clark, Thomas S. Kupper, Kristen Palmer, Maxwell D. Coll, Hasan Rajabi, Athalia Pyzer, Michal Bar-Natan, Katarina Luptakova, Jon Arnason, Robin Joyce, Donald Kufe, David Avigan
Journal: Blood (2015)
Diastolic Fractional Flow Reserve to Assess the Functional Severity of Moderate Coronary Artery Stenoses
Authors: Masayuki Abe, Hirofumi Tomiyama, Hideo Yoshida, Nobutaka Doba
Journal: Circulation (2000)

Coronary blood flow occurs mainly during the diastolic phase of each cardiac cycle and is mainly dependent on diastolic driving pressure, especially in the left anterior descending coronary artery (LAD). We hypothesized that calculation of the ratio of the diastolic driving pressure of a stenotic LAD to its normal value, namely diastolic FFR (d-FFR), might provide precise insight into the mechanism of FFR for assessment of the functional severity of the stenosis. We compared d-FFR with FFR, coronary flow reserve (CFR), and exercise myocardial thallium scintigraphy in an lesion of intermediate severity.The study population consisted of 46 consecutive patients with a moderate stenosis in the LAD in whom simultaneous measurements of aortic pressure, left ventricular pressure, and coronary pressure distal to the stenosis were obtained. Coronary flow velocity was successfully measured with a Doppler guidewire in 37 of the 46 patients. Values for FFR, d-FFR, and CFR in the noninvasive test-positive group were significantly lower than those in the negative group. With cutoff values of 0.75, 0.76, and 2.0 for FFR, d-FFR, and CFR, sensitivities were 83.3%, 95.8%, and 88.2% and specificities were 100%, 100%, and 95.0%, respectively.The close similarity of the sensitivity and specificity of FFR and d-FFR, around almost identical cutoff values (0.75 versus 0.76), confirms the physiological validity of FFR as a clinical standard. In clinical practice, FFR remains the index of choice for assessment of the functional severity of moderate coronary artery stenoses.
Serum Selenium Levels in Relation to Markers of Neoplastic Progression Among Persons With Barrett's Esophagus
Authors: R. E. Rudolph, T. L. Vaughan, A. R. Kristal, P. L. Blount, D. S. Levine, P. C. Galipeau, L. J. Prevo, C. A. Sanchez, P. S. Rabinovitch, B. J. Reid
Journal: JNCI Journal of the National Cancer Institute (2003)

Persons with Barrett's esophagus have a substantially greater risk of esophageal adenocarcinoma than the general population. Higher serum selenium levels have been associated with a reduced risk of several cancers; however, their association with the risk of esophageal adenocarcinoma is unknown. We used a cross-sectional study to investigate the relationship between serum selenium levels and markers of neoplastic progression among persons with Barrett's esophagus.
An in vitro model for cyclosporin A-induced interference of intrathymic clonal elimination.
Authors: H Kosaka, H Matsubara, S Sogoh, M Ogata, T Hamaoka, H Fujiwara
Journal: The Journal of Experimental Medicine (1990)

The effects of cyclosporin A (CsA) on influencing the intrathymic clonal deletion were investigated by using our established thymic stromal cell clone with capacities to express Ia antigens and to produce a unique T cell growth factor. The following were revealed: (a) T cell clone with a given specificity was killed on the Ia+ stromal cell monolayer in the presence of the relevant antigens, a process depending on T cell receptor (TCR) stimulation; and (b) CsA allowed the T cell clone to continuously proliferate even during TCR stimulation by virtue of the stromal cell-derived T cell growth factor. This paper describes an in vitro model of a mechanism by which CsA is responsible for the generation of normally "forbidden" T cell clones.