tbuckley/cabot-search huggingface dataset:
Comparative In Vitro Cellular Data Alone Are Insufficient to Predict Clinical Responses and Guide the Choice of BCR-ABL Inhibitor for Treating Imatinib-Resistant Chronic Myeloid Leukemia
Authors: Pierre Laneuville, Clifford DiLea, Ophelia Q.P. Yin, Richard C. Woodman, Jürgen Mestan, Paul W. Manley
Journal: Journal of Clinical Oncology (2010)

Recently, Redaelli et al 1 reported the development of a table to help guide physicians in their choice of which tyrosine kinase inhibitor (TKI) to use to treat their patients with chronic myeloid leukemia (CML).This table presents the in vitro inhibitory activity of imatinib, dasatinib, nilotinib, and bosutinib against a panel of 18 mutant forms of BCR-ABL, expressed in transfected Ba/F3 cells, known to be associated with imatinib resistance.The authors concluded that this table will help physicians develop rational, patient-tailored therapy and help them select TKIs in the most efficient way for their patients.Although the concept of developing a tool for tailoring patient therapy based on mutation status is notable, the use of in vitro data alone to guide the choice of TKI for patients is insufficient.Such an approach neglects several other impor-tant variables, so that predicting comparative clinical efficacies based on in vitro data can be very misleading.To translate in vitro potency into in vivo efficacy, drug exposure must be adequate to inhibit the BCR-ABL kinase located in the cytoplasm of leukemic cells, located primarily within the patient's bone marrow and/or peripheral blood.This process requires satisfactory pharmacokinetics, which are affected by independent variables that might be related to molecular structure.A comparison of nilotinib and dasatinib illustrates this complexity.For example, in Ba/F3 cells transfected to express 210-kDa wild-type (WT), M351T, or E255K BCR-ABL, respective antiproliferative mean GI 50 values (values that result in 50% growth inhibition) were shown to be 25, 38, and 548 nmol/L for nilotinib and 6.4, 8, and 83 nmol/L for dasatinib. 2In patients, steady-state peak and trough plasma concentrations of nilotinib were shown to be 4.27 and 1.95 mol/L, respectively, after oral administration of 400 mg nilotinib twice daily. 3 For comparative purposes, day 8 peak and trough plasma concentrations were shown to be approximately 90 and 10 nmol/L, respectively, after an oral regimen of 70 mg dasatinib twice daily. 4Thus, at currently approved doses, nilotinib is present at concentrations 171-, 112-, and 7.8-fold greater than its GI 50 value and dasatinib is present at concentrations 14-, 11-, and 1.1-fold greater than its GI 50 value for the inhibition of WT, M351T, and E255K BCR-ABL, respectively.At trough levels, the ratios of nilotinib
Moving from the Oslerian paradigm to the post-genomic era: are asthma and COPD outdated terms?
Authors: Lowie E G W Vanfleteren, Janwillem W H Kocks, Ian S Stone, Robab Breyer-Kohansal, Timm Greulich, Donato Lacedonia, Roland Buhl, Leonardo M Fabbri, Ian D Pavord, Neil Barnes, Emiel F M Wouters, Alvar Agusti
Journal: Thorax (2013)

In the majority of cases, asthma and chronic obstructive pulmonary disease (COPD) are two clearly distinct disease entities. However, in some patients there may be significant overlap between the two conditions. This constitutes an important area of concern because these patients are generally excluded from randomised controlled trials (mostly because of smoking history in the case of asthma or because of significant bronchodilator reversibility in the case of COPD). As a result, their pathobiology, prognosis and response to therapy are largely unknown. This may lead to suboptimal management and can limit the development of more personalised therapeutic options. Emerging genetic and molecular information coupled with new bioinformatics capabilities provide novel information that can pave the way towards a new taxonomy of airway diseases. In this paper we question the current value of the terms 'asthma' and 'COPD' as still useful diagnostic labels; discuss the scientific and clinical progress made over the past few years towards unravelling the complexity of airway diseases, from the definition of clinical phenotypes and endotypes to a better understanding of cellular and molecular networks as key pathogenic elements of human diseases (so-called systems medicine); and summarise a number of ongoing studies with the potential to move the field towards a new taxonomy of airways diseases and, hopefully, a more personalised approach to medicine, in which the focus will shift from the current goal of treating diseases as best as possible to the so-called P4 medicine, a new type of medicine that is predictive, preventive, personalised and participatory.
The minimal important difference of exercise tests in severe COPD
Authors: M.A. Puhan, D. Chandra, Z. Mosenifar, A. Ries, B. Make, N.N. Hansel, R.A. Wise, F. Sciurba
Journal: European Respiratory Journal (2010)

Our aim was to determine the minimal important difference (MID) for 6-min walk distance (6MWD) and maximal cycle exercise capacity (MCEC) in patients with severe chronic obstructive pulmonary disease (COPD). 1,218 patients enrolled in the National Emphysema Treatment Trial completed exercise tests before and after 4–6 weeks of pre-trial rehabilitation, and 6 months after randomisation to surgery or medical care. The St George's Respiratory Questionnaire (domain and total scores) and University of California San Diego Shortness of Breath Questionnaire (total score) served as anchors for anchor-based MID estimates. In order to calculate distribution-based estimates, we used the standard error of measurement, Cohen's effect size and the empirical rule effect size. Anchor-based estimates for the 6MWD were 18.9 m (95% CI 18.1–20.1 m), 24.2 m (95% CI 23.4–25.4 m), 24.6 m (95% CI 23.4–25.7 m) and 26.4 m (95% CI 25.4–27.4 m), which were similar to distribution-based MID estimates of 25.7, 26.8 and 30.6 m. For MCEC, anchor-based estimates for the MID were 2.2 W (95% CI 2.0–2.4 W), 3.2 W (95% CI 3.0–3.4 W), 3.2 W (95% CI 3.0–3.4 W) and 3.3 W (95% CI 3.0–3.5 W), while distribution-based estimates were 5.3 and 5.5 W. We suggest a MID of 26±2 m for 6MWD and 4±1 W for MCEC for patients with severe COPD.
Exercise during acute myocardial infarction: an experimental study
Authors: P. L. THOMPSON, H. R. JENZER, B. LOWN, L. A. LOHRBAUER
Journal: Cardiovascular Research (1973)

Journal Article Exercise during acute myocardial infarction: an experimental study Get access P. L. THOMPSON, P. L. THOMPSON From the Cardiovascular Research Laboratories, Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar H. R. JENZER, H. R. JENZER From the Cardiovascular Research Laboratories, Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar B. LOWN, B. LOWN From the Cardiovascular Research Laboratories, Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar L. A. LOHRBAUER L. A. LOHRBAUER From the Cardiovascular Research Laboratories, Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, U.S.A. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 7, Issue 5, September 1973, Pages 642–648, https://doi.org/10.1093/cvr/7.5.642 Published: 01 September 1973
High-Dose Atorvastatin vs Usual-Dose Simvastatin for Secondary Prevention After Myocardial Infarction&lt;SUBTITLE&gt;The IDEAL Study: A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: Terje R. Pedersen
Journal: JAMA (2005)

Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol (LDL-C) than is commonly applied clinically will provide further benefit in stable coronary artery disease.To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction (MI).The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at 190 ambulatory cardiology care and specialist practices in northern Europe between March 1999 and March 2005 with a median follow-up of 4.8 years, which enrolled 8888 patients aged 80 years or younger with a history of acute MI.Patients were randomly assigned to receive a high dose of atorvastatin (80 mg/d; n = 4439), or usual-dose simvastatin (20 mg/d; n = 4449).Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation.During treatment, mean LDL-C levels were 104 (SE, 0.3) mg/dL in the simvastatin group and 81 (SE, 0.3) mg/dL in the atorvastatin group. A major coronary event occurred in 463 simvastatin patients (10.4%) and in 411 atorvastatin patients (9.3%) (hazard ratio [HR], 0.89; 95% CI, 0.78-1.01; P = .07). Nonfatal acute MI occurred in 321 (7.2%) and 267 (6.0%) in the 2 groups (HR, 0.83; 95% CI, 0.71-0.98; P = .02), but no differences were seen in the 2 other components of the primary end point. Major cardiovascular events occurred in 608 and 533 in the 2 groups, respectively (HR, 0.87; 95% CI, 0.77-0.98; P = .02). Occurrence of any coronary event was reported in 1059 simvastatin and 898 atorvastatin patients (HR, 0.84; 95% CI, 0.76-0.91; P<.001). Noncardiovascular death occurred in 156 (3.5%) and 143 (3.2%) in the 2 groups (HR, 0.92; 95% CI, 0.73-1.15; P = .47). Death from any cause occurred in 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (HR, 0.98; 95% CI, 0.85-1.13; P = .81). Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 (1.0%) vs 5 (0.1%) withdrawals (P<.001). Serious myopathy and rhabdomyolysis were rare in both groups.In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions.Trial Registration ClinicalTrials.gov Identifier: NCT00159835.
Automated pattern-guided principal component analysis vs expert-based immunophenotypic classification of B-cell chronic lymphoproliferative disorders: a step forward in the standardization of clinical immunophenotyping
Authors: E S Costa, C E Pedreira, S Barrena, Q Lecrevisse, J Flores, S Quijano, J Almeida, M del Carmen García- Macias, S Bottcher, J J M Van Dongen, A Orfao
Journal: Leukemia (2010)

Immunophenotypic characterization of B-cell chronic lymphoproliferative disorders (B-CLPD) is becoming increasingly complex due to usage of progressively larger panels of reagents and a high number of World Health Organization (WHO) entities. Typically, data analysis is performed separately for each stained aliquot of a sample; subsequently, an expert interprets the overall immunophenotypic profile (IP) of neoplastic B-cells and assigns it to specific diagnostic categories. We constructed a principal component analysis (PCA)-based tool to guide immunophenotypic classification of B-CLPD. Three reference groups of immunophenotypic data files-B-cell chronic lymphocytic leukemias (B-CLL; n = 10), mantle cell (MCL; n = 10) and follicular lymphomas (FL; n = 10)--were built. Subsequently, each of the 175 cases studied was evaluated and assigned to either one of the three reference groups or to none of them (other B-CLPD). Most cases (89%) were correctly assigned to their corresponding WHO diagnostic group with overall positive and negative predictive values of 89 and 96%, respectively. The efficiency of the PCA-based approach was particularly high among typical B-CLL, MCL and FL vs other B-CLPD cases. In summary, PCA-guided immunophenotypic classification of B-CLPD is a promising tool for standardized interpretation of tumor IP, their classification into well-defined entities and comprehensive evaluation of antibody panels.
S107 Treatment and outcomes for locally advanced (stage IIIA) lung cancer; 4 year experience from the National Lung Cancer Audit
Authors: I Woolhouse, R Stanley, M Callister, S Barnard, R Page, P Beckett, Md Peake
Journal: Thorax (2013)

<h3>Background</h3> Surgery for lung cancer patients with mediastinal lymph node involvement (N2 disease) remains controversial. In one study (Albain 2009), progression-free (but not overall) survival was higher for patients who received induction chemo- radiotherapy followed by lobectomy but post operative mortality was high in pneumonectomy patients. We describe treatment and outcomes for patients with pre-treatment IIIA disease using data submitted from England to the National Lung Cancer Audit (NLCA) 2008–2011. <h3>Methods</h3> Patients with pre-treatment staging of T1–3, N2, M0 were included. Small cell cancer, mesothelioma and carcinoid were excluded. The extent and histological nature of pre-treatment N2 disease is not recorded in the NLCA. Survival analyses were performed according to treatment received. <h3>Results</h3> 6,775 of 98,403 (6.9%) patients met the inclusion criteria. 2,669 (39%) patients had either chemotherapy or radiotherapy recorded and 2,250 (33%) patients had no treatment recorded. 948 (14%) patients received chemotherapy and radiotherapy however radiotherapy treatment intent was recorded as curative in only 12%. 907 (13%) patients had surgery recorded as part of their treatment plan. Of these, 70% had post operative pathological nodal status recorded (25<b>%</b> N0, 14<b>%</b> N1, 30<b>% </b>N2). Median survival following surgery for the 271 patients with pathological N2 disease was 806 days, with 30 day survival of 99% and 1 year survival 76%. <h3>Conclusions</h3> Lung cancer patients with stage IIIA disease make up a very small proportion of the overall lung cancer population. Only a small proportion of these patients receive surgery and there is significant discrepancy between the recorded pre and post operative nodal status. In patients with pathological confirmed N2 disease survival is similar to the 713 days reported in the Albain study. The automated collection of detailed radiotherapy/chemotherapy treatment data in future will allow a more reliable comparison between surgical and non-surgical treatments.
Don't count your chickens before they're hatched: Elaborative encoding in REM dreaming in face of the physiology of sleep stages
Authors: Gaétane Deliens, Sophie Schwartz, Philippe Peigneux
Journal: Behavioral and Brain Sciences (2013)

Abstract Llewellyn suggests that episodic memories undergo “elaborative encoding” during rapid eye movement (REM) dreams, generating novel associations between recent and remote memories that are then instantiated during non-REM (NREM) sleep. This hypothesis conflicts with our knowledge of the physiology of NREM and then REM sleep stages and their ordered succession. Moreover, associations during sleep might also involve the extraction of hidden patterns rather than de novo associations.
Blocking of lung endothelial cell adhesion molecule-1 (Lu-ECAM-1) inhibits murine melanoma lung metastasis.
Authors: D Zhu, C F Cheng, B U Pauli
Journal: Journal of Clinical Investigation (1992)

The 90-kD lung endothelial cell adhesion molecule-1 (Lu-ECAM-1) selectively promotes Ca(2+)-dependent adhesion of lung-metastatic B16 melanoma cells. Corresponding with their metastatic performance, high lung-metastatic B16-F10 melanoma cells bind in significantly higher numbers to Lu-ECAM-1 than their intermediate and low lung-metastatic counterparts B16-L8-F10 and B16-F0, respectively. Maximum attachment is observed at a density of approximately 2.4 x 10(2) Lu-ECAM-1 sites/microns2 of plastic surface. B16 melanoma cell binding to Lu-ECAM-1 is blocked by mAb 6D3 and is competitively inhibited by soluble Lu-ECAM-1. C57B1/6 mice passively immunized with anti-Lu-ECAM-1 mAb 6D3 or actively immunized with purified Lu-ECAM-1 exhibit an anti-Lu-ECAM-1 antibody titer-dependent reduction in the number of B16 experimental metastases. Lu-ECAM-1 promotes neither binding nor metastasis of other lung-metastatic tumor cells (e.g., KLN205). Our data indicate that an "antiadhesion" therapy directed at interfering with the adherence of blood-borne tumor cells to organ-specific vascular endothelium is efficient in the control of metastasis formation in selective organ sites.
Lymphodepletion in the ApcMin/+ mouse model of intestinal tumorigenesis
Authors: P. Louise Coletta, Albrecht M. Müller, Elena A. Jones, Bettina Mühl, Sarah Holwell, Deborah Clarke, Josephine L. Meade, Graham P. Cook, Gillian Hawcroft, Frederique Ponchel, Wai K. Lam, Ken A. MacLennan, Mark A. Hull, Constanze Bonifer, Alexander F. Markham
Journal: Blood (2003)
Lung function after preterm birth: development from mid-childhood to adulthood
Authors: Maria Vollsæter, Ola Drange Røksund, Geir Egil Eide, Trond Markestad, Thomas Halvorsen
Journal: Thorax (2013)

<h3>Background</h3> As a result of advances in perinatal care, more small preterm infants survive. There are concerns that preterm birth and its treatments may harm pulmonary development and thereby lead to chronic airway obstruction in adulthood. <h3>Objective</h3> To assess the development of spirometric lung function variables from mid-childhood to adulthood after extreme preterm birth. <h3>Methods</h3> Two population-based cohorts born at gestational age ≤28 weeks or with birth weight ≤1000 g performed lung function tests at 10 and 18 and at 18 and 25 years of age, respectively, together with matched term-born controls. The results are presented as z scores, normalised for age, sex and height. Longitudinal development was compared for groups born at term and preterm, split by a history of absence (n=20), mild (n=38) or moderate/severe (n=25) neonatal bronchopulmonary dysplasia (BPD). <h3>Results</h3> The preterm-born cohorts, particularly those with neonatal BPD, had significantly lower forced expiratory volume in 1 s and mid-expiratory flow than those born at term at all assessments (z scores in the range −0.40 to −1.84). Within each of the subgroups the mean z scores obtained over the study period were largely similar, coefficients of determination ranging from 0.64 to 0.82. The pattern of development for the BPD subgroups did not differ from each other or from the groups born at term (tests of interaction). <h3>Conclusions</h3> Airway obstruction was present from mid-childhood to adulthood after extreme preterm birth, most evident after neonatal BPD. Lung function indices were tracking similarly in the preterm and term-born groups.
Smoking cessation interventions in COPD: a network meta-analysis of randomised trials
Authors: R. Strassmann, B. Bausch, A. Spaar, J. Kleijnen, O. Braendli, M. A. Puhan
Journal: European Respiratory Journal (2009)

The aim of this study was to rank order the effectiveness of smoking cessation interventions for chronic obstructive pulmonary disease (COPD) patients. We searched 10 databases to identify randomised trials of smoking cessation counselling (SCC) with or without pharmacotherapy or nicotine replacement therapy (NRT). We conducted a network meta-analysis using logistic regression analyses to assess the comparative effectiveness of smoking cessation interventions while preserving randomisation of each trial. The analysis of 7,372 COPD patients from six out of eight identified trials showed that SCC in combination with NRT had the greatest effect on prolonged abstinence rates versus usual care (OR 5.08, p&lt;0.0001) versus SCC alone (2.80, p = 0.001) and versus SCC combined with an antidepressant (1.53, p = 0.28). The second most effective intervention was SCC combined with an antidepressant (3.32, p = 0.002) versus SCC alone (1.83, p = 0.007), with no difference between antidepressants. SCC alone was of borderline superiority compared with usual care (1.81, p = 0.07). A small body of evidence suggests that SCC combined with NRT is more effective than other combinations and single smoking cessation treatments in COPD, but substantially more research is needed for this most important COPD treatment.
Additive Interaction of Hyperglycemia and Albuminuria on Risk of Ischemic Stroke in Type 2 Diabetes
Authors: Xilin Yang, Gary T.C. Ko, Wing Yee So, Ronald C.W. Ma, Alice P.S. Kong, Christopher W.K. Lam, Chung Shun Ho, Chun-Chung Chow, Peter C.Y. Tong, Juliana C.N. Chan
Journal: Diabetes Care (2008)

OBJECTIVE—The study aims to test whether biological interaction between hyperglycemia and albuminuria can explain the inconsistent findings from epidemiological studies and clinical trials about effects of hyperglycemia on stroke in type 2 diabetes. RESEARCH DESIGN AND METHODS—A total of 6,445 Hong Kong Chinese patients with type 2 diabetes and free of stroke at enrollment were followed up for a median of 5.37 years. Spline Cox proportional hazard regression was used to obtain hazard ratio curves, which were used to identify cutoff points of A1C and spot urinary albumin–to–creatinine ratio for increased ischemic stroke risk. The identified cutoff point of A1C was used to check biological interaction between A1C and albuminuria (micro- and macroalbuminuria). The biological interaction was estimated using relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP), and synergy index. RESULTS—During the follow-up period, 4.45% (n = 287) of patients developed ischemic stroke. A1C was associated with increased hazard ratios of ischemic stroke in a near-linear manner except for two points—6.2 and 8.0%—where the slope between these two points accelerated. For A1C values &amp;lt;6.2%, the presence of micro/macroalbuminuria did not confer additional risk, while significant biological interaction between A1C and micro/macroalbuminuria for values ≥6.2% was observed (RERI 0.92, 95% CI 0.16–1.68, and AP 0.40, 0.01–0.78). CONCLUSIONS—A1C ≥6.2% and micro/macroalbuminuria interact to markedly increase the ischemic stroke risk, which explains a large proportion of risk in patients with type 2 diabetes harboring both risk factors.
Supernetwork Identifies Multiple Events of Plastid trnF(GAA) Pseudogene Evolution in the Brassicaceae
Authors: Marcus A. Koch, Christoph Dobeš, Christiane Kiefer, Roswitha Schmickl, Leoš Klimeš, Martin A. Lysak
Journal: Molecular Biology and Evolution (2006)

The occurrence of nonfunctional trnF pseudogenes has been rarely described in flowering plants. However, we describe the first large-scale supernetwork for the Brassiccaeae built from gene trees for 5 loci (adh, chs, matK, trnL-F, and ITS) and report multiple independent origins for trnF pseudogenes in crucifers. The duplicated regions of the original trnF gene are comprised of its anticodon domain and several other highly structured motifs not related to the original gene. Length variation of the trnL-F intergenic spacer region in different taxa ranges from 219 to 900 bp as a result of differences in pseudocopy number (1-14). It is speculated that functional constraints favor 2-3 or 5-6 copies, as found in Arabidopsis and Boechera. The phylogenetic distribution of microstructural changes for the trnL-F region supports ancient patterns of divergence in crucifer evolution for some but not all gene loci.