tbuckley/cabot-search huggingface dataset:
Lead Times and Overdetection Due to Prostate-Specific Antigen Screening: Estimates From the European Randomized Study of Screening for Prostate Cancer
Authors: G. Draisma, R. Boer, S. J. Otto, I. W. van der Cruijsen, R. A. M. Damhuis, F. H. Schroder, H. J. de Koning
Journal: JNCI Journal of the National Cancer Institute (2003)

Background: Screening for prostate cancer advances the time of diagnosis (lead time) and detects cancers that would not have been diagnosed in the absence of screening (overdetection). Both consequences have considerable impact on the net benefits of screening. Methods: We developed simulation models based on results of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which enrolled 42 376 men and in which 1498 cases of prostate cancer were identified, and on baseline prostate cancer incidence and stage distribution data. The models were used to predict mean lead times, overdetection rates, and ranges (corresponding to approximate 95% confidence intervals) associated with different screening programs. Results: Mean lead times and rates of overdetection depended on a man’s age at screening. For a single screening test at age 55, the estimated mean lead time was 12.3 years (range = 11.6–14.1 years) and the overdetection rate was 27% (range = 24%–37%); at age 75, the estimates were 6.0 years (range = 5.8–6.3 years) and 56% (range = 53%–61%), respectively. For a screening program with a 4-year screening interval from age 55 to 67, the estimated mean lead time was 11.2 years (range = 10.8–12.1 years), and the overdetection rate was 48% (range = 44%–55%). This screening program raised the lifetime risk of a prostate cancer diagnosis from 6.4% to 10.6%, a relative increase of 65% (range = 56%–87%). In annual screening from age 55 to 67, the estimated overdetection rate was 50% (range = 46%–57%) and the lifetime prostate cancer risk was increased by 80% (range = 69%–116%). Extending annual or quadrennial screening to the age of 75 would result in at least two cases of overdetection for every clinically relevant cancer detected. Conclusions: These model-based lead-time estimates support a prostate cancer screening interval of more than 1 year.
The Cancer and Leukemia Group B Respiratory Committee
Authors: Everett E. Vokes, Michael C. Perry, Hedy L. Kindler, Mark R. Green
Journal: Clinical Cancer Research (2006)

Abstract The Cancer and Leukemia Group B Respiratory Committee has a 30-year track record of clinical investigation in patients with small-cell lung cancer and non–small-cell lung cancer (NSCLC) and mesothelioma. The most widely recognized contributions of the Committee include the early confirmation of the role of concurrent chemoradiotherapy in LD-SCLC, the effect of combination chemotherapy followed by radiation in stage III NSCLC, the introduction of third-generation agents into concurrent chemoradiation for stage III disease, the prospective demonstration of the benefit of treating older (70 years old) and poorer performance status (performance status = 2) patients with first-line combinations for stage IV disease, and the development of the “Herndon prognostic index” to normalize patient characteristics and outcomes in sequential phase II trials of new agents in patients with mesothelioma. Many other contributions have also emerged from the Committee's clinical trials and correlative science programs. We look forward to making additional critical contributions during future decades of Cancer and Leukemia Group B Respiratory Committee research.
Sputum eosinophils and exhaled nitric oxide during late asthmatic reaction in patients with western red cedar asthma
Authors: H Obata, M Dittrick, H Chan, M Chan-Yeung
Journal: European Respiratory Journal (1999)

Examination of sputum for eosinophils and measurement of exhaled nitric oxide have been proposed as noninvasive methods of assessing airway inflammation in asthma. The use of these tests in the evaluation of patients with occupational asthma has not been reported. This study investigated the changes in sputum eosinophils and exhaled NO before and at intervals after inhalation challenge with plicatic acid in patients with suspected western red cedar asthma. Of 17 subjects who underwent challenge, nine had a positive bronchoconstrictor reaction (responders) and eight had a negative reaction (nonresponders). At 6 and 24 h after plicatic acid challenge, there was a significant increase in sputum eosinophils among responders, which was inversely related to the fall in forced expiratory volume in one second (FEV1) at 6 h. An increase in sputum eosinophils was also found in three nonresponders. Levels of exhaled NO increased at 24 h after challenge with plicatic acid in both responders and nonresponders, being significant only in nonresponders. No correlation was found between the increase in nitric oxide and the magnitude of the functional changes in the airways. There were significant correlations between the degree of sputum eosinophilia and the level of exhaled NO before and after methacholine and plicatic acid challenge. In conclusion, the late asthmatic reaction induced by plicatic acid in patients with western red cedar asthma is associated with an increase in sputum eosinophils. The usefulness of measuring sputum eosinophils and exhaled nitric oxide in the clinical evaluation of patients with suspected occupational asthma caused by low molecular weight compounds has yet to be determined.
γ-Aminobutyric Acid (GABA) Stimulates Pancreatic Cancer Growth through Overexpressing GABAA Receptor π Subunit
Authors: Akio Takehara, Masayo Hosokawa, Hidetoshi Eguchi, Hiroaki Ohigashi, Osamu Ishikawa, Yusuke Nakamura, Hidewaki Nakagawa
Journal: Cancer Research (2007)

Abstract γ-Aminobutyric acid (GABA) functions primarily as an inhibitory neurotransmitter in the mature central nervous system, and GABA/GABA receptors are also present in nonneural tissues, including cancer, but their precise function in nonneuronal or cancerous cells has thus far been poorly defined. Through the genome-wide cDNA microarray analysis of pancreatic ductal adenocarcinoma (PDAC) cells as well as subsequent reverse transcription-PCR and Northern blot analyses, we identified the overexpression of GABA receptor π subunit (GABRP) in PDAC cells. We also found the expression of this peripheral type GABAA receptor subunit in few adult human organs. Knockdown of endogenous GABRP expression in PDAC cells by small interfering RNA attenuated PDAC cell growth, suggesting its essential role in PDAC cell viability. Notably, the addition of GABA into the cell culture medium promoted the proliferation of GABRP-expressing PDAC cells, but not GABRP-negative cells, and GABAA receptor antagonists inhibited this growth-promoting effect by GABA. The HEK293 cells constitutively expressing exogenous GABRP revealed the growth-promoting effect of GABA treatment. Furthermore, GABA treatment in GABRP-positive cells increased intracellular Ca2+ levels and activated the mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/Erk) cascade. Clinical PDAC tissues contained a higher level of GABA than normal pancreas tissues due to the up-regulation of glutamate decarboxylase 1 expression, suggesting their autocrine/paracrine growth-promoting effect in PDACs. These findings imply that GABA and GABRP could play important roles in PDAC development and progression, and that this pathway can be a promising molecular target for the development of new therapeutic strategies for PDAC. [Cancer Res 2007;67(20):9704–12] [Cancer Res 2007;67(20):9704–12]
Differences in LDL Oxidizability by Glycemic Status
Authors: Dawn C. Schwenke, Ralph B. D’Agostino, David. C. Goff, Andrew J. Karter, Marian J. Rewers, Lynne E. Wagenknecht
Journal: Diabetes Care (2003)

OBJECTIVE—To investigate differences in LDL oxidizability by glycemic status within the Insulin Resistance Atherosclerosis Study cohort. RESEARCH DESIGN AND METHODS—LDL oxidizability (lag time and oxidation rate) after exposure to copper was compared among 352 subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), newly diagnosed type 2 diabetes, and known type 2 diabetes. RESULTS—After adjustment for age, clinic, ethnicity, sex, and smoking status, LDL oxidation rates differed by glycemic status (P = 0.001), with a strong trend (P = 0.0001) for reduced LDL oxidation rate with increasing extent and duration of glucose intolerance (2,378 ± 54, 2,208 ± 65, 2,145 ± 71, and 2,115 ± 48 arbitrary units [mean ± SE] for NGT, IGT, newly diagnosed type 2 diabetes, and known type 2 diabetes, respectively). Differences in LDL oxidation rate among groups were relatively unaltered by adjustment for lipids and lipoproteins, hypertension, BMI, and waist-to-hip ratio (WHR) and remained significant even after further adjustment for dietary antioxidants and fatty acids, as well as medications. LDL lag times differed marginally by glycemic status (P = 0.058), with similar values for NGT, IGT, and newly diagnosed type 2 diabetes (57–60 min) but higher values for known type 2 diabetes (65 ± 2). These differences were eliminated by further adjustment for lipids and lipoproteins, hypertension, BMI, and WHR. CONCLUSIONS—We found that glycemic status influenced LDL oxidizability, with a paradoxical reduction in LDL oxidizability, as indicated by a lower LDL oxidation rate with increased extent and duration of glucose intolerance. This difference was only slightly attenuated by adjustment for relevant demographic, metabolic, dietary, and pharmacological factors that potentially influence LDL oxidation.
Microscopic Imaging and Spectroscopy with Scattered Light
Authors: Nada N. Boustany, Stephen A. Boppart, Vadim Backman
Journal: Annual Review of Biomedical Engineering (2010)

Optical contrast based on elastic scattering interactions between light and matter can be used to probe cellular structure, cellular dynamics, and image tissue architecture. The quantitative nature and high sensitivity of light scattering signals to subtle alterations in tissue morphology, as well as the ability to visualize unstained tissue in vivo, has recently generated significant interest in optical-scatter-based biosensing and imaging. Here we review the fundamental methodologies used to acquire and interpret optical scatter data. We report on recent findings in this field and present current advances in optical scatter techniques and computational methods. Cellular and tissue data enabled by current advances in optical scatter spectroscopy and imaging stand to impact a variety of biomedical applications including clinical tissue diagnosis, in vivo imaging, drug discovery, and basic cell biology.
The Safety of Tiotropium — The FDA's Conclusions
Authors: Theresa M. Michele, Simone Pinheiro, Solomon Iyasu
Journal: New England Journal of Medicine (2010)

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, and the rate of COPD-related death is increasing.1 No current drug therapy alters the progressive decline in lung function that characterizes this disease. In 2004, the Food and Drug Administration (FDA) approved the use of tiotropium delivered by the HandiHaler device, the first long-acting anticholinergic bronchodilator for treatment of COPD. Trials supporting tiotropium's approval demonstrated sustained bronchodilation over a 24-hour period. More recent studies have shown that treatment with the tiotropium HandiHaler reduces COPD exacerbations. Concerns have been raised, however, about tiotropium's safety. In particular, disparate sources have . . .
Transcription Factor Ets-1 Regulates Gelatinase A Gene Expression in Mesangial Cells
Authors: Julia Reisdorff, Abdelaziz En-Nia, Ioannis Stefanidis, Jürgen Floege, David H. Lovett, Peter R. Mertens
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Ets transcription factors are involved in cell growth and angiogenesis. Ets-1 targets include members of the matrix metalloproteinase superfamily. In inflammatory glomerular diseases, the patterns and regulation of Ets expression have not been fully characterized. In the present study, nuclear binding activities to the consensus Ets-1/PEA3 motif were detected in mesangial cells (MC), and the Ets-1 protein was positively identified by Western blotting, reverse transcription PCR (RT-PCR), and DNA-binding studies. The 5′ flanking regions of the human and rat gelatinase A genes contain clusters of potential Ets-1 binding motifs, one of which is evolutionarily conserved. Using a series of 5′ deletion reporter constructs of the rat gelatinase A gene and an Ets-1 expression plasmid, a concentration-dependent threefold trans-activation of gene expression mapped to the conserved Ets-1 binding motif at −1004/−1053 bps, designated responsive element-2 (RE-2). The RE-2 was operative within the context of the homologous gelatinase A promoter but not with a heterologous simian virus 40 promoter. Specific Ets-1 binding to this sequence was demonstrated by DNA-binding studies. Transient expression of an Ets-1 expression plasmid increased gelatinase A protein expression. Our findings identify an additional matrix metalloproteinase family member, gelatinase A, as an Ets-1 responsive gene in MC that may play a role in the high level expression of this enzyme in inflammatory glomerular diseases.
International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the Recognition and Nomenclature of G Protein-Coupled Receptor Heteromultimers
Authors: Jean-Philippe Pin, Richard Neubig, Michel Bouvier, Lakshmi Devi, Marta Filizola, Jonathan A. Javitch, Martin J. Lohse, Graeme Milligan, Krzysztof Palczewski, Marc Parmentier, Michael Spedding
Journal: Pharmacological Reviews (2007)

G protein-coupled receptors (GPCRs) have long been considered to be monomeric membrane proteins. Although numerous recent studies have indicated that GPCRs can form multimeric complexes, the functional and pharmacological consequences of this phenomenon have remained elusive. With the discovery that the functional GABA<sub>B</sub> receptor is an obligate heterodimer and with the use of energy transfer technologies, it is now accepted that GPCRs can form heteromultimers. In some cases, specific properties of such heteromers not shared by their respective homomers have been reported. Although in most cases these properties have only been observed in heterologous expression systems, there are a few reports describing data consistent with such heteromultimeric GPCR complexes also existing in native tissues. The present article illustrates well-documented examples of such native multimeric complexes, lists a number of recommendations for recognition and acceptance of such multimeric receptors, and gives recommendations for their nomenclature.
NHS is staring into a financial "abyss" as new levels of rationing emerge, clinicians warn
Authors: A. O'Dowd
Journal: BMJ (2014)

The NHS is reaching new levels of financial trouble, and signs are emerging of dangerous rationing of care, clinicians have warned MPs.

Concerns included deficits in trusts that have always managed to achieve surpluses previously, difficulties in recruiting permanent staff, and restrictions on care for some patients, said witnesses appearing before the parliamentary health committee on 26 November.

During the evidence session for their inquiry into public expenditure on health and social care the committee’s MPs asked if the witnesses recognised the scale of the funding challenges facing the NHS as set out in the Five Year Forward View published by NHS England and other national bodies last month.1 2

Mark Porter, BMA chair, giving evidence, said that this scale was in line with BMA estimates and added, “At present in the NHS, demand …
Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age
Authors: I Heier, K Malmstrom, A S Pelkonen, L P Malmberg, M Kajosaari, M Turpeinen, H Lindahl, P Brandtzaeg, F L Jahnsen, M J Makela
Journal: Thorax (2008)

In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3(+) Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways.Immunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4-23 months of age, under investigation for airway disease.A well developed HLA-DR(+) network of APC was present in all samples, approximately 50% of the cells being CD68(+) macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR(+) cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a(+) dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3(+) Treg were located primarily within these isolated lymphoid follicles.A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy.
Long-term Feeding of Sodium Saccharin to Nonhuman Primates: Implications for Urinary Tract Cancer
Authors: S. Takayama, S. M. Sieber, R. H. Adamson, U. P. Thorgeirsson, D. W. Dalgard, L. L. Arnold, M. Cano, S. Eklund, S. M. Cohen
Journal: JNCI Journal of the National Cancer Institute (1998)

It was observed in the early 1970s that saccharin produced bladder cancer in rats. However, it has been unclear whether sodium saccharin when consumed by humans poses a substantial carcinogenic hazard. Numerous epidemiologic studies have not shown any evidence of increased urothelial proliferation associated with ingestion of sodium saccharin.Our purpose was to determine the effects of long-term feeding of sodium saccharin to three species of nonhuman primates.Twenty monkeys of three species (six African green, seven rhesus, six cynomolgus, and one hybrid [of rhesus male and cynomolgus female parentage]) were treated with sodium saccharin (25 mg in the diet/kg body weight daily for 5 days a week) beginning within 24 hours after birth and continuing for up to 24 years. Sixteen monkeys (seven rhesus and nine cynomolgus) served as controls. During their last 2 years of life, urine was collected from selected treated and control animals and evaluated for various urinary chemistries and for the presence of calculi, microcrystalluria, and precipitate. Urinary bladders were examined by light microscopy and by scanning electron microscopy.Sodium saccharin treatment had no effect on the urine or urothelium in any of these monkeys. There was no evidence of increased urothelial cell proliferation, and there was no evidence of formation of solid material in the urine.Although the dose of sodium saccharin administered to these monkeys was only five to 10 times the allowable daily intake for humans, the results provide additional evidence that sodium saccharin is without a carcinogenic effect on the primate urinary tract.
Critical amino acids in the lymphocyte function-associated antigen-1 I domain mediate intercellular adhesion molecule 3 binding and immune function.
Authors: Y van Kooyk, M E Binnerts, C P Edwards, M Champe, P W Berman, C G Figdor, S C Bodary
Journal: The Journal of Experimental Medicine (1996)

We have identified amino acid residues within the evolutionarily conserved I domain of the alpha-chain (CD11a) of the leukocyte integrin leukocyte function-associated antigen (LFA) 1 that are critical for intercellular adhesion molecule (ICAM) 3 (CD50) binding. ICAM-3, a ligand of LFA-1, is thought to mediate intercellular adhesion essential for the initiation of immune responses. Using a panel of human/murine I domain chimeras and point mutants, we observed that the Ile-Lys-Gly-Asn motif, located in the NH2-terminal part of the CD11a I domain, is required for ICAM-3 but not ICAM-1 binding. These findings demonstrate that the I domain of CD11a contains distinct functional subdomains for ligand specific binding. An aspartic acid located at position 137, which is essential to ICAM-1/LFA-1 interactions (Edwards, C.P., M. Champe, T. Gonzalez, M.E. Wessinger, S.A. Spencer, L.G. Presta, P.W. Berman, and S.C. Bodary. 1995. J. Biol. Chem. 270:12635-12640), was also critical for ICAM-3 binding, whereas Ser at position 139 did not effect ICAM-1 or ICAM-3 binding. A synthetic peptide containing the Ile-Lys-Gly-Asn motif inhibited ICAM-3-dependent adhesion and proliferation of T cells at micromolar concentrations, suggesting that this peptide interferes with immune recognition. These observations underscore the importance of ICAM-3 in leukocyte function, and may lead to development of a new category of immunosuppressive agents.
Dissemination and evaluation of the ASAS/EULAR recommendations for the management of ankylosing spondylitis: results of a study among 1507 rheumatologists
Authors: L Gossec, M Dougados, C Phillips, M Hammoudeh, K de Vlam, K Pavelka, T Pham, J Braun, J Sieper, I Olivieri, D van der Heijde, E Collantes, M Stone, T K Kvien
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Background:</h3> Ten ASAS/EULAR recommendations for the management of ankylosing spondylitis (AS) were published in 2006. <h3>Objectives:</h3> (<i>a</i>) To disseminate and (<i>b</i>) to evaluate conceptual agreement with, and (<i>c</i>) application of, these recommendations as well as (<i>d</i>) potential barriers to the application. <h3>Methods:</h3> A questionnaire was sent to rheumatologists in 10 countries. It included (<i>a</i>) the text of the recommendations; (<i>b</i>) rheumatologists' demographic variables; (<i>c</i>) two numerical rating scales from 1 to 10 for each recommendation: conceptual agreement with, and application of, the recommendation (10 indicates maximal agreement and maximal application); and (<i>d</i>) a list of potential barriers to the application of the recommendation. Statistical analysis included descriptive and multivariate analyses. <h3>Results:</h3> 7206 questionnaires were sent out; 1507 (21%) were returned. Of the 1507 answering rheumatologists, 62% were men, mean (SD) age 49 (9) years, and 34% had an academic position. Conceptual agreement with the recommendations was high (mean (SD) for all recommendations 8.9 (0.9)). Self-reported application was also high (8.2 (1.0)). The difference between agreement and application varied across recommendations and countries. The most pronounced discrepancies were reported for use of anti-tumour necrosis factor drugs in a few countries, with funding as the most commonly reported barrier for application of this recommendation. <h3>Conclusion:</h3> This large project has helped the dissemination of the ASAS/EULAR recommendations for the management of AS and shows that conceptual agreement with the recommendations is very high. The project also highlights inequalities in access to healthcare for European citizens with AS.