tbuckley/cabot-search huggingface dataset:
Cyclooxygenase Isoforms and Platelet Vessel Wall Interactions in the Apolipoprotein E Knockout Mouse Model of Atherosclerosis
Authors: Orina A. Belton, Angela Duffy, Sinead Toomey, Desmond J. Fitzgerald
Journal: Circulation (2003)

Cyclooxygenase (COX) activity is induced in human atherosclerosis, and the products formed may modify the disease directly or through an effect on platelets. We examined the role of COX-1 and -2 on platelet vessel wall interactions and development of atherosclerosis in a murine model.Apolipoprotein E-deficient (apoE-/-) mice fed a 1% cholesterol diet were treated with a selective COX-1 inhibitor (SC-560), a selective COX-2 inhibitor (SC-236), or vehicle. Urinary prostacyclin and thromboxane metabolites (2,3-dinor-6-keto-PGF1alpha and 2,3-dinor-TXB2) were increased in the apoE-/- knockout mouse. There was also induction of both COX isoforms in the vascular lesions formed, which stained for CD41, a platelet-specific marker, and for CD40L. Selective inhibition of COX-2 had no effect on lesion formation and, despite selective reduction in prostacyclin generation, had no effect on platelet activity, as measured by thromboxane formation or platelet deposition. Selective inhibition of COX-1 reduced 2,3-dinor-TXB2 generation and lesion formation. However, platelet deposition on the vessel wall persisted, with well-defined monolayers seen. There was also persistent expression of the macrophage marker CD68 and increased expression of the cell death protein Bax. In contrast to lesion development, the selective COX-1 inhibitor had no effect on the regression of evolving lesions.COX-1 plays an important role in the early stages of lesion development in the apoE-/- knockout model of atherosclerosis, preventing gross lesion formation in the face of continued vascular injury and inflammation. Despite the inhibition of prostacyclin, COX-2 inhibition had no effect on lesion development or platelet-vessel wall interactions.
Dacomitinib as first-line treatment in patients with clinically or molecularly selected advanced non-small-cell lung cancer: a multicentre, open-label, phase 2 trial
Authors: Pasi A Jänne, Sai-Hong I Ou, Dong-Wan Kim, Geoffrey R Oxnard, Renato Martins, Mark G Kris, Frank Dunphy, Makoto Nishio, Joseph O'Connell, Cloud Paweletz, Ian Taylor, Hui Zhang, Zelanna Goldberg, Tony Mok
Journal: The Lancet Oncology (2014)
Complex sleep apnoea in congestive heart failure
Authors: T. Bitter, N. Westerheide, M. S. Hossain, R. Lehmann, C. Prinz, A. Kleemeyer, D. Horstkotte, O. Oldenburg
Journal: Thorax (2011)

<h3>Background</h3> Sleep disordered breathing is common and of prognostic significance in patients with congestive heart failure (CHF). Complex sleep apnoea (complexSA) is defined as the emergence of central sleep apnoea during continuous positive airway pressure (CPAP) treatment in patients with obstructive sleep apnoea (OSA). This study aims to determine the prevalence and predictors for complexSA in patients with CHF with OSA, and to assess the effects of treatment with adaptive servoventilation. <h3>Methods</h3> 192 patients with CHF (left ventricular ejection fraction (LVEF) ≤45%, New York Heart Association (NYHA) class ≥2) and OSA (apnoea–hypopnoea index (AHI) ≥15) were investigated using echocardiography, cardiopulmonary exercise testing, measurement of hyperoxic, hypercapnic ventilatory response, 6 min walk test and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) prior to CPAP introduction. If patients demonstrated complexSA (AHI &gt;15/h with &lt;10% obstructive events) during CPAP titration, adaptive servoventilation was introduced and the investigations were repeated at 3 monthly follow-up visits. <h3>Results</h3> ComplexSA developed in 34 patients (18%) during CPAP titration. After adjustment for demographic and cardiac parameters, measures of CO<sub>2</sub> sensitivity (higher hyperoxic, hypercapnic ventilatory response) were independently associated with complexSA. Patients using adaptive servoventilation had improved AHI, NYHA class, NT-proBNP concentration, LVEF, hyperoxic, hypercapnic ventilatory response, oxygen uptake during cardiopulmonary exercise testing and the relationship between minute ventilation and the rate of CO<sub>2</sub> elimination (VE/Vco<sub>2</sub> slope) at last individual follow-up (14±4 months). <h3>Conclusion</h3> There is a high prevalence of complexSA in patients with OSA and CHF, and those who develop complexSA have evidence of higher respiratory controller gain before application of CPAP. Treatment with adaptive servoventilation effectively suppressed complexSA and had positive effects on cardiac function and respiratory stability.
Phase I and Pharmacokinetic Study of Gefitinib in Children With Refractory Solid Tumors: A Children’s Oncology Group Study
Authors: Najat C. Daw, Wayne L. Furman, Clinton F. Stewart, Lisa C. Iacono, Mark Krailo, Mark L. Bernstein, Janet E. Dancey, Rose Anne Speights, Susan M. Blaney, James M. Croop, Gregory H. Reaman, Peter C. Adamson
Journal: Journal of Clinical Oncology (2005)

Purpose Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. Patients and Methods Gefitinib (150, 300, 400, or 500 mg/m 2 ) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). Results Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m 2 and elevated ALT and AST in one patient treated with 400 mg/m 2 . The maximum-tolerated dose was 400 mg/m 2 /d. The most frequent non–dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing’s sarcoma had a partial response. Disease stabilized for 8 to ≥ 60 weeks in two patients with Wilms’ tumor and two with brainstem glioma (one exophytic). At 400 mg/m 2 , the median peak gefitinib plasma concentration was 2.2 μg/mL (range, 1.2 to 3.6 μg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m 2 (range, 3.8 to 24.8 L/h/m 2 ) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. Conclusion Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.
Identification of anti-tumour biologics using primary tumour models, 3-D phenotypic screening and image-based multi-parametric profiling
Authors: Alan M. Sandercock, Steven Rust, Sandrine Guillard, Kris F. Sachsenmeier, Nick Holoweckyj, Carl Hay, Matt Flynn, Qihui Huang, Kuan Yan, Bram Herpers, Leo S. Price, Jo Soden, Jim Freeth, Lutz Jermutus, Robert Hollingsworth, Ralph Minter
Journal: Molecular Cancer (2015)

Monolayer cultures of immortalised cell lines are a popular screening tool for novel anti-cancer therapeutics, but these methods can be a poor surrogate for disease states, and there is a need for drug screening platforms which are more predictive of clinical outcome. In this study, we describe a phenotypic antibody screen using three-dimensional cultures of primary cells, and image-based multi-parametric profiling in PC-3 cells, to identify anti-cancer biologics against new therapeutic targets.ScFv Antibodies and designed ankyrin repeat proteins (DARPins) were isolated using phage display selections against primary non-small cell lung carcinoma cells. The selected molecules were screened for anti-proliferative and pro-apoptotic activity against primary cells grown in three-dimensional culture, and in an ultra-high content screen on a 3-D cultured cell line using multi-parametric profiling to detect treatment-induced phenotypic changes. The targets of molecules of interest were identified using a cell-surface membrane protein array. An anti-CUB domain containing protein 1 (CDCP1) antibody was tested for tumour growth inhibition in a patient-derived xenograft model, generated from a stage-IV non-small cell lung carcinoma, with and without cisplatin.Two primary non-small cell lung carcinoma cell models were established for antibody isolation and primary screening in anti-proliferative and apoptosis assays. These assays identified multiple antibodies demonstrating activity in specific culture formats. A subset of the DARPins was profiled in an ultra-high content multi-parametric screen, where 300 morphological features were measured per sample. Machine learning was used to select features to classify treatment responses, then antibodies were characterised based on the phenotypes that they induced. This method co-classified several DARPins that targeted CDCP1 into two sets with different phenotypes. Finally, an anti-CDCP1 antibody significantly enhanced the efficacy of cisplatin in a patient-derived NSCLC xenograft model.Phenotypic profiling using complex 3-D cell cultures steers hit selection towards more relevant in vivo phenotypes, and may shed light on subtle mechanistic variations in drug candidates, enabling data-driven decisions for oncology target validation. CDCP1 was identified as a potential target for cisplatin combination therapy.
A model study of the effects of the discrete cellular structure on electrical propagation in cardiac tissue.
Authors: Y Rudy, W L Quan
Journal: Circulation Research (1987)

The effects of the discrete cellular structure on propagation of electrical excitation in cardiac muscle were studied in a one-dimensional fiber model containing a periodic intercalated disk structure. Globally, the macroscopic velocity of propagation follows the behavior associated with propagation in a continuous tissue (except for high values of disk resistance). In addition, the computed spatial extracellular potential along the fiber is a smooth biphasic waveform and does not reflect the underlying discrete cellular structure of the tissue. Other results of the simulations demonstrate the discontinuous nature of propagation and the importance of the structure in arrhythmogenesis. Vmax displays a biphasic behavior as a function of increasing intercalated disk resistance. An initial "paradoxical" increase in Vmax (with a simultaneous decrease in conduction velocity) is followed by a decrease that leads to decremental propagation and conduction block. The time constant of the foot of the action potential (tau foot) increases monotonically with increasing intercalated disk resistance. An increase in the leakage current to extracellular space brings about a significant decrease in the action potential duration and a loss of the plateau. This major effect is accompanied by a relatively smaller decrease in conduction velocity. Collision of two activation wavefronts results in a significant (100%) increase in Vmax and a very small (0.6%) decrease in tau foot.
Opioids in the UK: what's the problem?
Authors: C. Stannard
Journal: BMJ (2013)

In many cases, doses are too high and treatment is too long 

The extensive misuse of prescription drugs in the United States has brought into sharp focus the role of opioids for persistent pain. The US has seen a marked and progressive rise in the prescription of opioid analgesics over the past two decades. This has been paralleled by an increase in deaths from these drugs—now a leading cause of accidental death in the US.1 Prescription data from the United Kingdom show comparable trends in the use of opioids for non-cancer pain.2 3 However, prescribing statistics don’t tell the whole story, and we need to look at UK statistics on addiction and opioid related mortality to understand exactly what the problems are.

The UK has fewer sources of data on opioid misuse than the US, but there are places to look for indications of a problem. Drug related deaths are reported by the Office of National Statistics (ONS), and its most recent data (2011) show an overall downward trend in deaths from analgesics. A notable exception is a steady rise in deaths from tramadol (154 in 2010-11). There has also been a rise …
Linking ventilation heterogeneity and airway hyperresponsiveness in asthma
Authors: J. Venegas
Journal: Thorax (2007)

<h3>Background</h3> Systemic Lupus Erythematosus (SLE) patients show higher Red blood cells Distribution Width (RDW) regardless of anaemia status<sup>1</sup>. RDW has been found to positively correlate with serum IgM, CRP, ESR, and SLE Disease Activity Index 2000 (SLEDAI-2K), and glucocorticoid treatment decreased both SLEDAI-2K and RDW<sup>2</sup>. <h3>Objectives</h3> To determine whether RDW levels in SLE are associated with damage accrual. <h3>Methods</h3> This cross-sectional study was conducted in 276 SLE patients, 257 females and 19 males. Evaluations included interview, medical records review, physical examination and laboratory tests. Disease activity was measured with the SLEDAI. Damage accrual was ascertained with the SLICC/ACR damage index (SDI). Univariable and multivariable Poisson regression models were performed to determine if RDW levels were associated with damage accrual. These models were stratified by tertiles of RDW. The multivariable model was adjusted for variables known to be associated with this outcome [age at diagnosis, gender, socioeconomic status, ethnicity, tobacco use, disease duration, SLEDAI, anemia, antimalarials and immunosuppressive drugs use, average daily dose and time of exposure to prednisone (PDN)]. <h3>Results</h3> The patients mean (SD) age at diagnosis was 34.38 (13.33) years; nearly all patients were mestizo. Disease duration was 7.04 (6.16) years. The SLEDAI was 5.24 (4.67) and the SDI 0.92 (1.28). The average daily dose of PDN was 6.90 (6.07) mg/d and the time of exposure to PDN was 6.58 (9.59) years. RDW levels were 14.57 (1.52)%. Hemoglobin levels were 12.4 (1.7) g/dl. We divided the RDW levels into tertiles with cut points in 13.8 and 14.0; the highest tertiles were associated with disease damage; with a Rate Ratio (RR) 1.57 (1.07–2.28; p: 0.020 for the highest tertile, and 1.67 (1.15–2.42; p: 0.007) for the medium tertile. <h3>Conclusions</h3> Higher RDW levels are associated with damage accrual in SLE patients independent of other well-known risk factors for such occurrence. <h3>References</h3> Vayá A, Alis R, Hernández J-L, et al. RDW in patients with systemic lupus erythematosus. Influence of anaemia and inflammatory markers. Clin Hemorheol Microcirc 2013; 54: 333–9. Hu Z-D, Chen Y, Zhang L, et al. Red blood cell distribution width is a potential index to assess the disease activity of systemic lupus erythematosus. Clin Chim Acta 2013; 425: 202–205. <h3>Disclosure of Interest</h3> None declared
Irritable bowel syndrome in general practice: prevalence, characteristics, and referral
Authors: W G Thompson, K W Heaton, G T Smyth, C Smyth
Journal: Gut (2000)

Little is known about the prevalence, symptoms, diagnosis, attitude, and referral to specialists of patients with irritable bowel syndrome (IBS) in general practice. This study aimed to determine these characteristics.3111 patients attending 36 general practitioners (GPs) at six varied locations in and near Bristol, UK, were screened to identify those with a gastrointestinal problem. These patients (n=255) and their doctors were given questionnaires. Six months later the case notes were examined to reach criteria based diagnoses of functional bowel disorders.Of 255 patients with a gastrointestinal complaint, 30% were judged to have IBS and 14% other functional disorders. Compared with 100 patients with an "organic" diagnoses, those with IBS were more often women and more often judged by their GP to be polysymptomatic and to have unexplained symptoms. The majority of patients with IBS (58%) were diagnosed as such by the GP; 22% had other functional diagnoses. Conversely, among 54 patients diagnosed as having IBS by the GPs, the criteria based diagnosis was indeed functional in 91%; only one patient had organic disease (proctitis). More patients with IBS than those with organic disease feared cancer. In most some fear remained after the visit to the doctor. On logistic regression analysis, predictors of referral to a specialist (29% referred) were denial of a role for stress, multiple tests, and frequent bowel movements.Half the patients with gut complaints seen by GPs have functional disorders. These are usually recognised, and few patients are referred. In IBS, cancer fears often remain, suggesting unconfident diagnosis or inadequate explanation.
Genetic validation of a therapeutic target in a mouse model of ALS
Authors: A. Sophie de Boer, Kathryn Koszka, Evangelos Kiskinis, Naoki Suzuki, Brandi N. Davis-Dusenbery, Kevin Eggan
Journal: Science Translational Medicine (2014)

The DP1 receptor mediates toxicity of microglia in human stem cell and transgenic animal models of amyotrophic lateral sclerosis.
A novel genetic strategy reveals unexpected roles of the Swi–Snf–like chromatin-remodeling BAF complex in thymocyte development
Authors: Anant Jani, Mimi Wan, Jianmin Zhang, Kairong Cui, Jie Wu, Paula Preston-Hurlburt, Rohini Khatri, Keji Zhao, Tian Chi
Journal: The Journal of Experimental Medicine (2008)

We have developed a general strategy for creating littermates bearing either a tissue-specific point mutation or deletion in any target gene, and used the method to dissect the roles of Brg, the ATPase subunit of the chromatin-remodeling Brg-associated factor (BAF) complex, in early thymocyte development. We found that a point mutation that inactivates the Brg ATPase recapitulates multiple defects previously described for Brg deletion (Chi, T.H., M. Wan, P.P. Lee, K. Akashi, D. Metzger, P. Chambon, C.B. Wilson, and G.R. Crabtree. 2003. Immunity. 19:169–182). However, the point mutant helps reveal unexpected roles of Brg in CD25 repression and CD4 activation. Surprisingly, CD4 activation occurs independently of the Brg ATPase and is perhaps mediated by physical interactions between Brg and the CD4 locus. Our study thus suggests that the BAF complex harbors novel activities that can be necessary and even sufficient for stimulating transcription from an endogenous chromatin template in the absence of Brg-dependent remodeling of that template. We conclude that conditional point mutants, rarely used in mammalian genetics, can help uncover important gene functions undetectable or overlooked in deletion mutants.
Absence of Histological Lesions in Primate Models of ECT and Magnetic Seizure Therapy
Authors: Andrew J. Dwork, Victoria Arango, Mark Underwood, Boro Ilievski, Gorazd Rosoklija, Harold A. Sackeim, Sarah H. Lisanby
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The authors present preliminary findings from the first nonhuman primate neuropathological study of ECT to use perfusion fixation and adequate controls and the first to compare ECT with magnetic seizure therapy, to their knowledge. METHOD: Twelve Macaca mullata received 6 weeks of daily ECT, magnetic seizure therapy, or anesthesia alone. After perfusion fixation, their brains were examined while masked to intervention. RESULTS: No identified lesions were attributable to the interventions. Cortical and hippocampal immunoreactivity for glial fibrillary acidic protein (an astrocytic marker) was most intense in the group that received ECT. CONCLUSIONS: This small but rigorous primate study supports the view that ECT does not produce histological lesions in the brain and provides the first comparable safety data on magnetic seizure therapy.
Chemotherapy for Elderly Patients With Advanced Non-Small-Cell Lung Cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) Phase III Randomized Trial
Authors: C. Gridelli, F. Perrone, C. Gallo, S. Cigolari, A. Rossi, F. Piantedosi, S. Barbera, F. Ferrau, E. Piazza, F. Rosetti, M. Clerici, O. Bertetto, S. F. Robbiati, L. Frontini, C. Sacco, F. Castiglione, A. Favaretto, S. Novello, M. R. Migliorino, G. Gasparini, D. Galetta, R. V. Iaffaioli, V. Gebbia
Journal: JNCI Journal of the National Cancer Institute (2003)

Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-small-cell lung cancer (NSCLC). Some studies have also suggested that gemcitabine is well tolerated and effective in such patients. We compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label, randomized phase III trial in elderly patients with advanced NSCLC.Patients aged 70 years and older, enrolled between December 1997 and November 2000, were randomly assigned to receive intravenous vinorelbine (30 mg/m(2) of body surface area), gemcitabine (1200 mg/m(2)), or vinorelbine (25 mg/m(2)) plus gemcitabine (1000 mg/m(2)). All treatments were delivered on days 1 and 8 every 3 weeks for a maximum of six cycles. The primary endpoint was survival. Survival curves were drawn using the Kaplan-Meier method and analyzed by the Mantel-Haenszel test. Secondary endpoints were quality of life and toxicity.Of 698 patients available for intention-to-treat analysis, 233 were assigned to receive vinorelbine, 233 to gemcitabine, and 232 to vinorelbine plus gemcitabine. Compared with each single drug, the combination treatment did not improve survival. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI] = 0.95 to 1.44) that of patients receiving vinorelbine and 1.06 (95% CI = 0.86 to 1.29) that of patients receiving gemcitabine. Although quality of life was similar across the three treatment arms, the combination treatment was more toxic than the two drugs given singly.The combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC.
Thoracic Aortic Aneurysm and Dissection
Authors: Christian Olsson, Stefan Thelin, Elisabeth Ståhle, Anders Ekbom, Fredrik Granath
Journal: Circulation (2006)

Background— Current knowledge of prevalence, incidence, and survival in thoracic aortic diseases (aneurysm and dissection) is based on small studies from a dated era of treatment and diagnostic procedures. The objective of the present study was to reappraise epidemiology and long-term outcomes in subjects with thoracic aortic disease in a large contemporary population. Methods and Results— All subjects with thoracic aortic aneurysm or dissection identified in Swedish national healthcare registers from 1987 to 2002 were included in the present study. Of 14 229 individuals with thoracic aortic disease, 11 039 (78%) were diagnosed before death. Incidence of thoracic aortic disease rose by 52% in men and by 28% in women to reach 16.3 per 100 000 per year and 9.1 per 100 000 per year, respectively. Operations increased 7-fold in men and 15-fold in women over time. Of the 2455 patients who underwent operation, 389 (16%) died within 30 days, with older age and thoracic aortic rupture as risk factors. In Cox analysis, increasing age was the only variable associated with long-term mortality. Both short- and long-term mortality improved over time. In patients who underwent operation, actuarial survival (95% CI) at 1, 5, and 10 years was 92% (91% to 93%), 77% (75% to 80%), and 57% (53% to 61%), respectively. The cumulative incidence of thoracic aortic reoperations was 7.8% at 10 years. Conclusions— The prevalence and incidence of thoracic aortic disease was higher than previously reported and increasing. The annual number of operations increased substantially. Surgical (30-day) and long-term survival improved significantly over time to form a growing cohort of patients needing counseling, management decisions, operations, and extended postoperative surveillance.