tbuckley/cabot-search huggingface dataset:
Clinical Implications of <i>CYP2D6</i> Genotyping in Tamoxifen Treatment for Breast Cancer
Authors: Vincent O. Dezentjé, Henk-Jan Guchelaar, Johan W.R. Nortier, Cornelis J.H. van de Velde, Hans Gelderblom
Journal: Clinical Cancer Research (2008)

Abstract In October 2006 the Food and Drug Administration recommended an update in the tamoxifen label to reflect the increased risk of recurrence in breast cancer patients who are cytochrome P450 2D6 (CYP2D6) poor metabolizers. This recommendation was based on only a few studies at that time. More clinical studies addressing the relation between the CYP2D6 genotype and tamoxifen efficacy have been published since, mostly describing Caucasian populations in the adjuvant treatment setting. An updated analysis of the literature is presented. Furthermore, the possibility to implement CYP2D6 genotyping in clinical practice is evaluated by analyzing the results of six studies on mainly Caucasian patients using adjuvant tamoxifen. Three studies were consistent with the FDA advice, but the three other studies showed contradictory results. Although some of the published criticism on the negative studies is justified, this does not imply that these results should be discarded. The reviewed literature is put in perspective acknowledging the limiting effect of Mendelian randomization on confounding and the limitations of the various study designs. The current accumulation of data showing worse clinical outcome in patients with decreased CYP2D6 metabolism in other types of populations still indicates that the CYP2D6 genotype may well become a clinically relevant predictive marker. The CYP2D6 genotype might be one of the first predictors of therapeutic response in cancer care based on germline DNA creating the possibility to analyze blood instead of tumor.
The A-G polymorphism in exon 1 of the CTLA-4 gene is not associated with systemic lupus erythematosus
Authors: J. Heward, C. Gordon, A. Allahabadia, A. H Barnett, J. A Franklyn, S. C L Gough
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVES</h3> Factors contributing to the development of systemic lupus erythematosus (SLE) remain largely unknown although are likely to include both environmental and genetic components. Studies on murine lupus have indicated a role for an antibody that blocks binding of cytotoxic T lymphocyte associated-4 (CTLA-4) to B7 on antigen presenting cells in the treatment of disease, suggesting that CTLA-4 may play an important part in the disease process. This study, therefore, investigated the frequency of a previously described A-G polymorphism in exon 1 of the<i>CTLA-4</i> gene, the G allele of which has shown to be associated with both Graves' disease and type I diabetes, to determine whether this polymorphism was playing a part in the development of SLE. <h3>METHODS</h3> One hundred and twenty six SLE patients and 363 control subjects were genotyped for the A-G polymorphism in exon 1 of the<i>CTLA-4</i> gene. Target DNA was amplified using the polymerase chain reaction and the resulting product was digested using the BbvI restriction enzyme. <h3>RESULTS</h3> No differences in allele or genotype frequencies were observed between patients with SLE and control subjects. <h3>CONCLUSION</h3> These data suggest that the A-G polymorphism in exon 1 of the<i>CTLA-4</i> gene does not play a part in the genetic susceptibility to the development of SLE.
Cost-effectiveness of adjuvant systemic therapy in low-risk breast cancer patients with nodal isolated tumor cells or micrometastases
Authors: M de Boer, E M M Adang, K C G Van Dycke, J A A M van Dijck, G F Borm, S C Seferina, C H M van Deurzen, P J van Diest, P Bult, A R T Donders, V C G Tjan-Heijnen
Journal: Annals of Oncology (2012)
A multicentre study of air pollution exposure and childhood asthma prevalence: the ESCAPE project
Authors: Anna Mölter, Angela Simpson, Dietrich Berdel, Bert Brunekreef, Adnan Custovic, Josef Cyrys, Johan de Jongste, Frank de Vocht, Elaine Fuertes, Ulrike Gehring, Olena Gruzieva, Joachim Heinrich, Gerard Hoek, Barbara Hoffmann, Claudia Klümper, Michal Korek, Thomas A.J. Kuhlbusch, Sarah Lindley, Dirkje Postma, Christina Tischer, Alet Wijga, Göran Pershagen, Raymond Agius
Journal: European Respiratory Journal (2014)

The aim of this study was to determine the effect of six traffic-related air pollution metrics (nitrogen dioxide, nitrogen oxides, particulate matter with an aerodynamic diameter &lt;10 μm (PM 10 ), PM 2.5 , coarse particulate matter and PM 2.5 absorbance) on childhood asthma and wheeze prevalence in five European birth cohorts: MAAS (England, UK), BAMSE (Sweden), PIAMA (the Netherlands), GINI and LISA (both Germany, divided into north and south areas). Land-use regression models were developed for each study area and used to estimate outdoor air pollution exposure at the home address of each child. Information on asthma and current wheeze prevalence at the ages of 4–5 and 8–10 years was collected using validated questionnaires. Multiple logistic regression was used to analyse the association between pollutant exposure and asthma within each cohort. Random-effects meta-analyses were used to combine effect estimates from individual cohorts. The meta-analyses showed no significant association between asthma prevalence and air pollution exposure ( e.g. adjusted OR (95%CI) for asthma at age 8–10 years and exposure at the birth address (n=10377): 1.10 (0.81–1.49) per 10 μg·m -3 nitrogen dioxide; 0.88 (0.63–1.24) per 10 μg·m -3 PM 10 ; 1.23 (0.78–1.95) per 5 μg·m -3 PM 2.5 ). This result was consistently found in initial crude models, adjusted models and further sensitivity analyses. This study found no significant association between air pollution exposure and childhood asthma prevalence in five European birth cohorts.
Exploring Unconscious Bias in Disparities Research and Medical Education
Authors: Michelle van Ryn, Somnath Saha
Journal: JAMA (2011)

The evidence that physician behavior and decision making may contribute to racial inequalities in health care [1][2][3][4][5] is difficult to reconcile with the fact that most physicians are genuinely motivated to provide good care to all their patients. 6This apparent contradiction can cause considerable cognitive dissonance, the uncomfortable feeling that occurs when holding 2 conflicting ideas simultaneously.Cognitive dissonance has been shown to be so aversive that people are highly motivated to resolve it, often by discounting the evidence supporting one of the conflicting beliefs.For scientists, however, cognitive dissonance motivates inquiry into how 2 seemingly contradictory sets of facts can coexist.The study by Haider and colleagues 7 in this issue of JAMA is part of a growing body of work applying concepts and methods from cognitive and social psychology to medical care and education research to understand and inform interventions to eliminate the physician contribution to racial inequalities in care.Current explanations for the paradox of well-intentioned physicians providing inequitable care are rooted in strong evidence that humans have at least 2 cognitive systems. 8One system involves conscious, controlled, and effortful processing of stimuli and produces explicit beliefs and attitudes.The second system responds to stimuli by rapidly, effortlessly, and automatically applying implicit knowledge, beliefs, attitudes, and skills that have been stored, through repeated exposures, in long-term memory.The 2 systems can have significantly different responses to external stimuli such as social group category.For example, although most US residents explicitly (consciously) hold egalitarian attitudes about race, 80% of white Americans may still have implicit (unconscious) attitudes favoring whites over blacks. 9Implicit racial attitudes have been proposed as one explanation for the evidence that sometimes clinicians provide worse technical or interpersonal care to nonwhite patients, even when they fully intend to provide equitable care. 1,5
Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial
Authors: J. Bourbeau, P. Christodoulopoulos, F. Maltais, Y. Yamauchi, R. Olivenstein, Q. Hamid
Journal: Thorax (2007)

<h3>Background:</h3> Airway inflammation in chronic obstructive pulmonary disease (COPD) is characterised by infiltration of CD8+ T cells and CD68+ macrophages and an increased number of neutrophils, whereas few studies have described the presence of eosinophils. Although the anti-inflammatory effects of corticosteroids in stable COPD are unclear, recent studies suggest that combination therapy could be beneficial. A study was therefore undertaken to evaluate combined salmeterol/fluticasone propionate (SFC) and fluticasone propionate (FP) alone on inflammatory cells in the airways of patients with COPD. <h3>Methods:</h3> Patients were treated in a randomised, double blind, parallel group, placebo-controlled trial with either a combination of 50 µg salmeterol and 500 µg FP twice daily (SFC, n = 19, 19 men, mean age 62 years), 500 µg FP twice daily (n = 20, 15 men, mean age 64 years) or placebo (n = 21, 17 men, mean age 66 years) for 3 months. At the start and end of treatment bronchoscopy with bronchial biopsies was performed and the numbers of CD8+ T lymphocytes, CD68+ macrophages, neutrophils and eosinophils were measured. <h3>Results:</h3> CD8+ cells were significantly reduced by SFC compared with placebo (difference −98.05 cells/mm<sup>2</sup>; 95% CI −143.14 to −52.9; p&lt;0.001). Such a marked effect was not seen with FP alone (−44.67 cells/mm<sup>2</sup>; 95% CI −90.92 to 1.57; p = 0.06). CD68+ macrophages were also reduced by SFC compared with placebo (difference −31.68 cells/mm<sup>2</sup>; 95% CI −61.07 to −2.29; p = 0.03) but not by FP. SFC did not significantly change neutrophils and eosinophils compared with placebo. <h3>Conclusions:</h3> SFC has airway anti-inflammatory effects not seen with inhaled corticosteroids alone.
Acute gastric dilatation with infarction and perforation: Report of fatal outcome in patient with anorexia nervosa
Authors: S H Saul, A Dekker, C G Watson
Journal: Gut (1981)

This is a report of a 22-year-old woman with treated anorexia nervosa who died of complications of acute gastric dilatation-that is, infarction and perforation with severe and irreversible shock. Binge eating and drinking, precipitated by emotional crises, contributed to her acute gastric dilatation. This complication of anorexia nervosa has been previously reported, but, unlike the others, this case ended fatally. The literature is reviewed.
Effects of curcumin or dexamethasone on lung ischaemia-reperfusion injury in rats
Authors: J. Sun, D. Yang, S. Li, Z. Xu, X. Wang, C. Bai
Journal: European Respiratory Journal (2008)

The present study aimed to investigate potential effects of curcumin (CUR) and dexamethasone (DXM) on ischaemia–reperfusion (I/R) induced lung injury in rats. Experimental rats were pre-treated with a single i.p. dose of vehicle, CUR (50 mg·kg −1 or 200 mg·kg −1 ) or DXM (5 mg·kg −1 ), 2 h before anaesthesia and subjected to left lung hilus clamping with 90-min ischaemia followed by 4 h of reperfusion. Pre-treatment with CUR (200 mg·kg −1 ) or DXM markedly attenuated I/R-induced barrier disruption, lung oedema, tissue inflammation, hypoxaemia 4 h after reperfusion, and overactivation of nuclear factor-κB, inflammatory cytokines, myeloperoxidase and malondialdehyde. It appears that curcumin attenuates acute lung injury, probably through improving oxidative stress and inhibiting nuclear factor-κB-mediated expression of inflammatory cytokines. Thus, curcumin may be an alternative therapy for improving the outcomes of ischaemia–reperfusion-induced lung injury.
Progress towards tuberculosis elimination: secular trend, immigration and transmission
Authors: M.W. Borgdorff, S. Van Den Hof, K. Kremer, L. Verhagen, N. Kalisvaart, C. Erkens, D. Van Soolingen
Journal: European Respiratory Journal (2009)

This study aimed to determine to what extent tuberculosis trends in the Netherlands depend on secular trend, immigration and recent transmission. Data on patients in the Netherlands Tuberculosis Register in the period 1993–2007 were matched with restriction fragment length polymorphism (RFLP) patterns of Mycobacterium tuberculosis isolates. Index patients were defined as patients with pulmonary tuberculosis whose isolates had RFLP patterns not observed in another patient in the previous 2 yrs. Among 8,330 patients with pulmonary tuberculosis the isolates of 56% of native and 50% of foreign-born patients were clustered. Of these, 5,185 were included in detailed analysis: 1,376 native index patients, 2,822 foreign-born index patients and 987 secondary cases within 2 yrs of diagnosis of the index case. The incidence of native and foreign-born index patients declined by 6% and 2% per year, respectively. The number of secondary cases per index case was 0.24. The decline of native cases contributed most to the overall decline of tuberculosis rates and was largely explained by a declining prevalence of latent infection. Tuberculosis among immigrants was associated with immigration figures. Progress towards elimination of tuberculosis would benefit from intensifying diagnosis and treatment of latent infection among immigrants and global tuberculosis control.
Cell Biology of Cytotoxic and Helper T Cell Functions: Immunofluorescence Microscopic Studies of Single Cells and Cell Couples
Authors: A Kupfer, S J Singer
Journal: Annual Review of Immunology (1989)

This review deals with certain important features of the cell biology of natural killer (NK) cells, cytotoxic T lymphocytes (CTL), and helper T (Th) cells. These features appeared originally in studies of the cell biology of cells other than immunological cells, and their relevance to immune cell interactions was then appreciated and explored. This brief review is therefore meant to be selective rather than exhaustive, and it focuses primarily on problems that have been intensively studied in our laboratory over the past decade. At the outset, it should be emphasized that we concentrate on investigations of single (generally cloned) T cells and cell couples, rather than of cell populations. Recent reviews have appeared that deal with other aspects of the cell biology of T cells and their interactions (1-7). The entree to this work stemmed from our investigations of eukaryotic cell motility; these have been separately reviewed (8). These studies are considered briefly first, since they not only introduce the ideas that have played a prominent part in our immunological work, but they also demon-
Comedo-like openings in dermoscopy: An essential diagnostic clue for lichen sclerosus, even in children
Authors: Celia Horcajada-Reales, Minia Campos-Domínguez, Elena Conde-Montero, Verónica Parra-Blanco, Ricardo Suárez-Fernández
Journal: Journal of the American Academy of Dermatology (2014)
High resolution computed tomographic assessment of airway wall thickness in chronic asthma: reproducibility and relationship with lung function and severity
Authors: S A Little
Journal: Thorax (2002)

Background: In some patients chronic asthma results in irreversible airflow obstruction. High resolution computed tomography (HRCT) has been advocated for assessing the structural changes in the asthmatic lung and permits investigation of the relationships between airway wall thickening and clinical parameters in this condition. Methods: High resolution CT scanning was performed in 49 optimally controlled asthmatic patients and measurements of total airway and lumen diameter were made by two independent radiologists using electronic callipers. Wall area as % total airway cross sectional area (WA%) and wall thickness to airway diameter ratio (T/D) were calculated for all airways clearly visualised with a transverse diameter of more than 1.5 mm, with a mean value derived for each patient. Intra- and inter-observer variability was assessed for scope of agreement in a subgroup of patients. Measurements were related to optimum forced expiratory volume in 1 second (FEV<sub>1</sub>), forced mid expiratory flow, carbon monoxide gas transfer, two scores of asthma severity, airway inflammation as assessed with induced sputum, and exhaled nitric oxide. Results: Neither observer produced a statistically significant difference between measurements performed on two occasions but there was a significant difference between observers (limits of agreement –2.6 to 6.8 for WA%, p&lt;0.0001). However, mean WA% measured on two occasions differed by no more than 5.4% (limits of agreement –4.0 to 5.4; mean (SD) 0.7 (2.4)). Statistically significant positive associations were observed between both WA% and T/D ratio and asthma severity (<i>r</i><sub>S</sub>=0.29 and 0.30, respectively, for ATS score), and an inverse association with gas transfer coefficient was observed (<i>r</i><sub>S</sub>=–0.43 for WA% and <i>r</i><sub>S</sub>=–0.41 for T/D). No association was identified with FEV<sub>1</sub> or airway inflammation. Conclusions: The airway wall is thickened in more severe asthma and is associated with gas transfer coefficient. This thickening does not relate directly to irreversible airflow obstruction as measured with FEV<sub>1</sub>.
Therapeutic strategy in p47-phox deficient chronic granulomatous disease presenting as inflammatory bowel disease
Authors: Folke Freudenberg, Uwe Wintergerst, Angela Roesen-Wolff, Michael H. Albert, Christine Prell, Brigitte Strahm, Sibylle Koletzko, Stephan Ehl, Dirk Roos, Alberto Tommasini, Alessandro Ventura, Bernd H. Belohradsky, Reinhard Seger, Joachim Roesler, Tayfun Güngör
Journal: Journal of Allergy and Clinical Immunology (2010)
Exogenous Natural Surfactant for Treatment of Acute Lung Injury and the Acute Respiratory Distress Syndrome
Authors: Jozef Kesecioglu, Richard Beale, Thomas E. Stewart, George P. Findlay, Jean-Jacques Rouby, Laurent Holzapfel, Peter Bruins, Edmee J. Steenken, Ole K. Jeppesen, Burkhard Lachmann
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Compositional changes in surfactant and/or decreased surfactant content of the lungs are common features in patients with acute respiratory failure. Instillation of exogenous surfactant into the lungs of neonates with respiratory distress syndrome or pediatric patients with acute respiratory distress syndrome (ARDS) has resulted in improved survival.We conducted this trial to determine whether the instillation of exogenous surfactant would improve the Day 28 outcome of adult patients with acute lung injury (ALI) or ARDS.A total of 418 patients with ALI and ARDS were included in an international, multicenter, stratified, randomized, controlled, open, parallel-group study. We randomly assigned 418 patients to receive usual care either with or without instillation of exogenous natural porcine surfactant HL 10 as large boluses.The primary endpoint was death rate before or on Day 28. Secondary endpoints were adverse event and death rate on day 180. The 28-day death rate in the usual care group was 24.5% compared with 28.8% in the HL 10 group. The estimated odds ratio for death at Day 28 in the usual care group versus the HL 10 group was 0.75 (95% CI, 0.48-1.18; P = 0.22). The most common adverse events related to HL 10 administration were temporary hypoxemia defined as oxygen saturation less than 88% (51.9% in HL 10 group vs. 25.2% in usual care) and hypotension defined as mean arterial blood pressure less than 60 mm Hg (34.1% in HL 10 group vs. 17.1% in usual care).In this study, instillation of a large bolus of exogenous natural porcine surfactant HL 10 into patients with acute lung injury and ARDS did not improve outcome and showed a trend toward increased mortality and adverse effects. Clinical trial registered with www.clinicaltrials.gov (NCT 00742482).
Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements
Authors: Arvind Dasari, Janine N. Bartholomew, Daniela Volonte, Ferruccio Galbiati
Journal: Cancer Research (2006)

Abstract Cellular senescence is believed to represent a natural tumor suppressor mechanism. We have previously shown that up-regulation of caveolin-1 was required for oxidative stress–induced premature senescence in fibroblasts. However, the molecular mechanisms underlying caveolin-1 up-regulation in senescent cells remain unknown. Here, we show that subcytotoxic oxidative stress generated by hydrogen peroxide application promotes premature senescence and stimulates the activity of a (−1,296) caveolin-1 promoter reporter gene construct in fibroblasts. Functional deletion analysis mapped the oxidative stress response elements of the mouse caveolin-1 promoter to the sequences −244/−222 and −124/−101. The hydrogen peroxide–mediated activation of both Cav-1 (−244/−222) and Cav-1 (−124/−101) was prevented by the antioxidant quercetin. Combination of electrophoretic mobility shift studies, chromatin immunoprecipitation analysis, Sp1 overexpression experiments, as well as promoter mutagenesis identifies enhanced Sp1 binding to two GC-boxes at −238/−231 and −118/−106 as the core mechanism of oxidative stress–triggered caveolin-1 transactivation. In addition, signaling studies show p38 mitogen-activated protein kinase (MAPK) as the upstream regulator of Sp1-mediated activation of the caveolin-1 promoter following oxidative stress. Inhibition of p38 MAPK prevents the oxidant-induced Sp1-mediated up-regulation of caveolin-1 protein expression and development of premature senescence. Finally, we show that oxidative stress induces p38-mediated up-regulation of caveolin-1 and premature senescence in normal human mammary epithelial cells but not in MCF-7 breast cancer cells, which do not express caveolin-1 and undergo apoptosis. This study delineates for the first time the molecular mechanisms that modulate caveolin-1 gene transcription upon oxidative stress and brings new insights into the redox control of cellular senescence in both normal and cancer cells. (Cancer Res 2006; 66(22): 10805-14)
Randomized Controlled Trial to Evaluate Transdermal Testosterone in Female Cancer Survivors With Decreased Libido; North Central Cancer Treatment Group Protocol N02C3
Authors: D. L. Barton, D. B. Wender, J. A. Sloan, R. J. Dalton, E. P. Balcueva, P. J. Atherton, A. M. Bernath, W. L. DeKrey, T. Larson, J. D. Bearden, P. C. Carpenter, C. L. Loprinzi
Journal: JNCI Journal of the National Cancer Institute (2007)

Decreased libido is one of several changes in sexual function that are often experienced by female cancer patients. Transdermal testosterone therapy has been associated with increased libido among estrogen-replete women who report low libido. In a phase III randomized, placebo-controlled crossover clinical trial, we evaluated whether transdermal testosterone would increase sexual desire in female cancer survivors. Postmenopausal women with a history of cancer and no current evidence of disease were eligible if they reported a decrease in sexual desire and had a sexual partner. Eligible women were randomly assigned to receive 2% testosterone in Vanicream for a testosterone dose of 10 mg daily or placebo Vanicream for 4 weeks and were then crossed over to the opposite treatment for an additional 4 weeks. The primary endpoint was sexual desire or libido, as measured using the desire subscales of the Changes in Sexual Functioning Questionnaire, as assessed at baseline and at the end of 4 and 8 weeks of treatment. Serum levels of bioavailable testosterone were measured at the same times. All statistical tests were two-sided. We enrolled 150 women. Women who were on active testosterone cream had higher serum levels of bioavailable testosterone than women on placebo (mean change from baseline, testosterone versus placebo, week 4, 11.57% versus 0%, difference = 11.57%, 95% confidence interval [CI] = 8.49% to 14.65%; week 8, 10.21% versus 0.28%, difference = 9.92%, 95% CI = 5.42% to 14.42%; P <.001 for all). However, the average intrapatient libido change from baseline to weeks 4 and 8 was similar on both arms. Increased testosterone level did not translate into improved libido, possibly because women on this study were estrogen depleted.