tbuckley/cabot-search huggingface dataset:
Nilotinib alone or in combination with selumetinib is a drug candidate for neurofibromatosis type 2
Authors: S. Ammoun, M. C. Schmid, J. Triner, P. Manley, C. O. Hanemann
Journal: Neuro-Oncology (2011)

Loss of the tumor suppressor merlin is a cause of frequent tumors of the nervous system, such as schwannomas, meningiomas, and ependymomas, which occur spontaneously or as part of neurofibromatosis type 2 (NF2). Because there is medical need for drug therapies for these tumors, our aim is to find therapeutic targets. We have studied the pathobiology of schwannomas, because they are the most common merlin-deficient tumors and are a model for all merlin-deficient tumors. With use of a human schwannoma in vitro model, we previously described strong overexpression/activation of platelet-derived growth factor receptor-β (PDGFR-β) leading to strong, long-lasting activation of extracellular-signal-regulated kinase (ERK1/2) and AKT and increased schwannoma growth, which we successfully inhibited using the PDGFR/Raf inhibitor sorafenib. However, the benign character of schwannomas may require long-term treatment; thus, drug tolerability is an issue. With the use of Western blotting, proliferation assays, viability assays, and a primary human schwannoma cell in vitro model, we tested the PDGFR/c-KIT inhibitors imatinib (Glivec; Novartis) and nilotinib (Tasigna; Novartis). Imatinib and nilotinib inhibited PDGF-DD-mediated ERK1/2 activation, basal and PDGF-DD-mediated activation of PDGFR-β and AKT, and schwannoma proliferation. Nilotinib is more potent than imatinib, exerting its maximal inhibitory effect at concentrations lower than steady-state trough plasma levels. In addition, nilotinib combined with the MEK1/2 inhibitor selumetinib (AZD6244) at low concentrations displayed stronger efficiency toward tumor growth inhibition, compared with nilotinib alone. We suggest that therapy with nilotinib or combinational therapy that simultaneously inhibits PDGFR and the downstream Raf/MEK1/2/ERK1/2 pathway could represent an effective treatment for schwannomas and other merlin-deficient tumors.
Health of men, women, and children in post-trafficking services in Cambodia, Thailand, and Vietnam: an observational cross-sectional study
Authors: Ligia Kiss, Nicola S Pocock, Varaporn Naisanguansri, Soksreymom Suos, Brett Dickson, Doan Thuy, Jobst Koehler, Kittiphan Sirisup, Nisakorn Pongrungsee, Van Anh Nguyen, Rosilyne Borland, Poonam Dhavan, Cathy Zimmerman
Journal: The Lancet Global Health (2015)

Background Traffi cking is a crime of global proportions involving extreme forms of exploitation and abuse.Yet little research has been done of the health risks and morbidity patterns for men, women, and children traffi cked for various forms of forced labour.Methods We carried out face-to-face interviews with a consecutive sample of individuals entering 15 post-traffi cking services in Cambodia, Thailand, and Vietnam.We asked participants about living and working conditions, experience of violence, and health outcomes.We measured symptoms of anxiety and depression with the Hopkins Symptoms Checklist and post-traumatic stress disorder with the Harvard Trauma Questionnaire, and used adjusted logistic regression models to estimate the eff ect of traffi cking on these mental health outcomes, controlling for age, sector of exploitation, and time in traffi cking.Findings We interviewed 1102 people, of whom 1015 reached work destinations.Participants worked in various sectors including sex work (329 [32%]), fi shing (275 [27%]), and factories (136 [13%]).481 (48%) of 1015 experienced physical violence, sexual violence, or both, with 198 (35%) of 566 women and girls reporting sexual violence.478 (47%) of 1015 participants were threatened and 198 (20%) were locked in a room.685 (70%) of 985 who had data available worked 7 days per week and 296 (30%) of 989 worked at least 11 hours per day.222 (22%) of 983 had a serious injury at work.61•2% (95% CI 58•2-64•2) of participants reported symptom of depression, 42•8% (39•8-45•9) reported symptoms of anxiety, and 38•9% (36•0-42•0) reported symptoms of post-traumatic stress disorder.5•2% (4•0-6•8) had attempted suicide in the past month.Participants who experienced extremely excessive overtime at work, restricted freedom, bad living conditions, threats, or severe violence were more likely to report symptoms of depression, anxiety, and post-traumatic stress disorder.Interpretation This is the fi rst health study of a large and diverse sample of men, women, and child survivors of traffi cking for various forms of exploitation.Violence and unsafe working conditions were common and psychological morbidity was associated with severity of abuse.Survivors of traffi cking need access to health care, especially mental health care.
Implantable Cardioverter-Defibrillator Therapy for Prevention of Sudden Death in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia
Authors: Domenico Corrado, Loira Leoni, Mark S. Link, Paolo Della Bella, Fiorenzo Gaita, Antonio Curnis, Jorge Uriarte Salerno, Diran Igidbashian, Antonio Raviele, Marcello Disertori, Gabriele Zanotto, Roberto Verlato, Giuseppe Vergara, Pietro Delise, Pietro Turrini, Cristina Basso, Franco Naccarella, Francesco Maddalena, N.A. Mark Estes, Gianfranco Buja, Gaetano Thiene
Journal: Circulation (2003)

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a condition associated with the risk of sudden death (SD).We conducted a multicenter study of the impact of the implantable cardioverter-defibrillator (ICD) for prevention of SD in 132 patients (93 males and 39 females, age 40+/-15 years) with ARVC/D. Implant indications were a history of cardiac arrest in 13 patients (10%), sustained ventricular tachycardia in 82 (62%), syncope in 21 (16%), and other in 16 (12%). During a mean follow-up of 39+/-25 months, 64 patients (48%) had appropriate ICD interventions, 21 (16%) had inappropriate interventions, and 19 (14%) had ICD-related complications. Fifty-three (83%) of the 64 patients with appropriate interventions received antiarrhythmic drug therapy at the time of first ICD discharge. Programmed ventricular stimulation was of limited value in identifying patients at risk of tachyarrhythmias during the follow-up (positive predictive value 49%, negative predictive value 54%). Four patients (3%) died, and 32 (24%) experienced ventricular fibrillation/flutter that in all likelihood would have been fatal in the absence of the device. At 36 months, the actual patient survival rate was 96% compared with the ventricular fibrillation/flutter-free survival rate of 72% (P<0.001). Patients who received implants because of ventricular tachycardia without hemodynamic compromise had a significantly lower incidence of ventricular fibrillation/flutter (log rank=0.01). History of cardiac arrest or ventricular tachycardia with hemodynamic compromise, younger age, and left ventricular involvement were independent predictors of ventricular fibrillation/flutter.In patients with ARVC/D, ICD therapy provided life-saving protection by effectively terminating life-threatening ventricular arrhythmias. Patients who were prone to ventricular fibrillation/flutter could be identified on the basis of clinical presentation, irrespective of programmed ventricular stimulation outcome.
Immunological abnormalities in cystic fibrosis: chicken or egg?
Authors: M E Hodson
Journal: Thorax (1980)

Immunological abnormalities in cystic fibrosis: chicken or egg?Cystic fibrosis (CF) is a disease characterised by malabsorption, chronic bronchopulmonary infection, and a high sweat sodium concentration.In 1938 about 80% of patients died within the first year of life' but now many are surviving into adult life,2-4 and are being transferred from the care of the paediatrician to that of the thoracic physician.This increased survival is probably accounted for by improved paediatric care, increased understanding of the importance of efficient postural drainage, and the advent of antibiotics.Patients with CF may develop either pulmonary infection in the neonatal period which persists throughout life or neonatal infection which may respond to treatment only to recur in adolescence.A few patients develop pulmonary infection for the first time in late adolescent or early adult life.Once bronchopulmonary infection with a given organism is established in a patient with CF it is often impossible to eradicate this organism.While antibiotics may improve the patient's clinical state, respiratory function tests, and chest radiograph for a period, most patients eventually die of overwhelm- ing bronchopulmonary infection by pathogens which appear in the laboratory to be sensitive to the antibiotics with which the patient is being treated.This therefore gives rise to the question as to whether the immune defences of patients with CF may be defective.In recent years new techniques have been developed to explore both quantitatively and qualitatively the various components of the immune response.These techniques have now been applied to the study of the immune response in cystic fibrosis. T cell systemFifty to sixty per cent of peripheral blood lymphocytes are thymus-dependent T cells.They have antigen recognition sites on their surfaces and on stimulation they release lymphokines.These lymphokines have many actions including the activation of macrophages.T cells will transform with phytohaemagglutinin, will help or suppress B
A three-arms phase III randomised trial comparing combinations of platinum derivatives, ifosfamide and/or gemcitabine in stage IV non-small cell lung cancer (NSCLC)
Authors: Jean-Paul Sculier, Jean-Jacques Lafitte, Marianne Paesmans, Jean-Paul Lecomte, Thierry Berghmans, M.C. Florin, George Koumakis, Constantinos Alexopoulos, P Recloux, Paul Mommen, Vincent Ninane, Jean Klastersky
Journal: European Respiratory Journal (2001)
Insomnia in the Context of Cancer: A Review of a Neglected Problem
Authors: Josée Savard, Charles M. Morin
Journal: Journal of Clinical Oncology (2001)

This article reviews the evidence on the diagnosis, epidemiology, etiology, and treatment of insomnia in the context of cancer and proposes several areas for future research. Clinical and diagnostic features of insomnia are described and prevalence estimates of insomnia complaints in cancer patients are summarized. Then, potential etiologic factors (ie, predisposing, precipitating, and perpetuating factors) and consequences of insomnia (ie, psychologic, behavioral, and health impact) in the context of cancer are discussed. Finally, pharmacologic and psychologic treatments previously shown effective to treat insomnia in healthy individuals are discussed as valuable treatment options for cancer patients as well. Because long-term use of hypnotic medications is associated with some risks (eg, dependence), it is argued that psychologic interventions (eg, stimulus control, sleep restriction, cognitive therapy) are the treatment of choice for sleep disturbances in the context of cancer, especially when it has reached a chronic course. However, the efficacy of these treatments has yet to be verified specifically in cancer patients.
Characterization of Sialyltransferase in Noncancerous and Neoplastic Human Liver Tissue<xref ref-type="fn" rid="FN2">2</xref>
Authors: Holly A. Ingraham, Jack A. Alhadeff
Journal: JNCI Journal of the National Cancer Institute (1978)

When compared to uninvolved adjacent tissue, metastatic tumors in human liver appear to have significantly reduced sialyltransferase activity. No significant kinetic differences (Michaelis constants, thermostability, and pH optima) between noncancerous and cancerous tissue sialyltransferase were found. Mixing experiments between cancerous and noncancerous tissues indicated that inhibitors of sialyltransferase activity were present in cancerous tissue. Subsequent experiments demonstrated increased levels of bound sialic acid in the tumor tissues. Inasmuch as fetuin, a sialoglycoprotein, inhibits sialyltransferase activity, the increased levels of bound sialic acid in tumor tissue may be responsible for the reduced enzyme activity in these tissue.
The clinical and genetic features of COPD-asthma overlap syndrome
Authors: Megan Hardin, Michael Cho, Merry-Lynn McDonald, Terri Beaty, Joe Ramsdell, Surya Bhatt, Edwin J.R. van Beek, Barry J. Make, James D. Crapo, Edwin K. Silverman, Craig P. Hersh
Journal: European Respiratory Journal (2014)

Individuals with chronic obstructive pulmonary disease (COPD) and asthma are an important but poorly characterised group. The genetic determinants of COPD and asthma overlap have not been studied. The aim of this study was to identify clinical features and genetic risk factors for COPD and asthma overlap. Subjects were current or former smoking non-Hispanic whites or African–Americans with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40 years. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the non-Hispanic whites and African–American populations, and combined these results in a meta-analysis. More females and African–Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema and greater airway wall thickness compared to subjects with COPD alone. The non-Hispanic white GWAS identified single nucleotide polymorphisms in the genes CSMD1 (rs11779254, p=1.57×10 −6 ) and SOX5 (rs59569785, p=1.61×10 −6 ) and the meta-analysis identified single nucleotide polymorphisms in the gene GPR65 (rs6574978, p=1.18×10 −7 ) associated with COPD and asthma overlap. Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD and asthma overlap is an important syndrome and may require distinct clinical management.
Address in Obstetric Medicine
Authors: J. G. S. Coghill
Journal: BMJ (1881)

trtuth ?From the CGre(o to the S&ero, in this instance the step is very easy, for they are almost phases of the same sentiment.I ha*ve just enumerated very briefly a very few of the countless encomragements to hope which those conversant with the history of our profession may easily find in the records of the last half-century.Can any (o ubt that they are but an earnest of far greater triumphs to come ?The &irk that is before us spreads out in a sort of threefold division.\Ve have to apply in the best practicable manner our present know- ledge for the benefit of those around us. \We have to do our best to increase that knowledge, and, thirdly, we have to find the best means for trallsferring it to the new generation which will soon succeed to our duties.'Medical practice, the advancement of the knowledge of the naturle of disease, and the training of our sons-such are our three great spheres of duty.Some of us wvork in one, some in another, most of us to some extent in all.Let us all seek to love the great final obo- ject at which we aim, to believe in the means which we are employing, and to hope confidently of their results.
Randomized Phase III Trial of Gemcitabine-Based Chemotherapy With In Situ RRM1 and ERCC1 Protein Levels for Response Prediction in Non–Small-Cell Lung Cancer
Authors: Craig Reynolds, Coleman Obasaju, Michael J. Schell, Xueli Li, Zhong Zheng, David Boulware, John R. Caton, Linda C. DeMarco, Mark A. O'Rourke, Gail Shaw Wright, Kristi A. Boehm, Lina Asmar, Jane Bromund, Guangbin Peng, Matthew J. Monberg, Gerold Bepler
Journal: Journal of Clinical Oncology (2009)

We evaluated the efficacy of gemcitabine versus gemcitabine and carboplatin in patients with advanced non-small-cell lung cancer (NSCLC) and a performance status (PS) of 2 and assessed if tumoral RRM1 and ERCC1 protein levels are predictive of response to therapy.A randomized phase III trial was conducted in community-based oncology practices. Tumor specimens were collected a priori and shipped to a single laboratory for blinded determination of in situ RRM1 and ERCC1 protein expression levels by an automated quantitative immunofluorescent-based technology.One hundred seventy patients were randomly assigned. Overall median survival was 5.1 months for gemcitabine and 6.7 months for gemcitabine and carboplatin (P = .24). RRM1 (range, 5.3 to 105.6; median, 34.1) and ERCC1 (range, 5.2 to 131.3; median, 34.7) values were significantly and inversely correlated with disease response (r = -0.41; P = .001 for RRM1; r = -0.39; P = .003 for ERCC1; ie, response was better for patients with low levels of expression). A model for response prediction that included RRM1, ERCC1, and treatment arm, was highly predictive of the treatment response observed (P = .0005). We did not find statistically significant associations between survival and RRM1 or ERCC1 levels.Single-agent chemotherapy remains the standard of care for patients with advanced NSCLC and poor PS. Quantitative analysis of RRM1 and ERCC1 protein expression in routinely collected tumor specimens in community oncology practices is predictive of response to gemcitabine and gemcitabine and carboplatin therapy. Oncologists should consider including in situ expression analysis for these proteins into their therapeutic decisions.
An analysis of the learning curve to achieve competency at colonoscopy using the JETS database
Authors: Stephen Thomas Ward, Mohammed A Mohammed, Robert Walt, Roland Valori, Tariq Ismail, Paul Dunckley
Journal: Gut (2014)

The number of colonoscopies required to reach competency is not well established. The primary aim of this study was to determine the number of colonoscopies trainees need to perform to attain competency, defined by a caecal intubation rate (CIR) ≥90%. As competency depends on completion, we also investigated trainee factors that were associated with colonoscopy completion.The Joint Advisory Group on GI Endoscopy in the UK has developed a trainee e-portfolio from which colonoscopy data were retrieved. Inclusion criteria were all trainees who had performed a total of ≥20 colonoscopies and had performed ≤50 colonoscopies prior to submission of data to the e-portfolio. The primary outcome measure was colonoscopy completion. The number of colonoscopies required to achieve CIR ≥90% was calculated by the moving average method and learning curve cumulative summation (LC-Cusum) analysis. To determine factors which determine colonoscopy completion, a mixed effect logistic regression model was developed which allowed for nesting of patients within trainees and nesting of patients within hospitals, with various patient, trainee and training factors entered as fixed effects.297 trainees undertook 36 730 colonoscopies. By moving average analysis, the cohort of trainees reached a CIR of 90% at 233 procedures. By LC-Cusum analysis, 41% of trainees were competent after 200 procedures. Of the trainee factors, the number of colonoscopies, intensity of training and previous flexible sigmoidoscopy experience were significant factors associated with colonoscopy completion.This is the largest study to date investigating the number of procedures required to achieve competency in colonoscopy. The current training certification benchmark in the UK of 200 procedures does not appear to be an inappropriate minimum requirement. The LC-Cusum chart provides real time feedback on individual learning curves for trainees. The association of training intensity and flexible sigmoidoscopy experience with colonoscopy completion could be exploited in training programmes.
Von Hippel-Lindau–dependent polycythemia is endemic on the island of Ischia: identification of a novel cluster
Authors: Silverio Perrotta, Bruno Nobili, Marcella Ferraro, Carmela Migliaccio, Adriana Borriello, Valeria Cucciolla, Vincenzo Martinelli, Francesca Rossi, Francesca Punzo, Paola Cirillo, Giuseppe Parisi, Vincenzo Zappia, Bruno Rotoli, Fulvio Della Ragione
Journal: Blood (2005)
P-Selectin Expression on Platelets Determines Size and Stability of Platelet Aggregates
Authors: Michael Merten, Perumal Thiagarajan
Journal: Circulation (2000)

Background —P-selectin mediates rolling of platelets and leukocytes on activated endothelial cells. After platelet activation, P-selectin is translocated from intracellular granules to the external membrane, whereas fibrinogen aggregates platelets by bridging glycoprotein (GP) IIb/IIIa between adjacent platelets. Methods and Results —In this study, we define a novel role for P-selectin in platelet aggregation. Expression of P-selectin on the platelet surface correlated strongly with the mean platelet aggregate size. Inhibition of P-selectin binding to its ligand by either monoclonal anti–P-selectin antibodies directed against the lectin domain or soluble human P-selectin reversed platelet aggregation even when added up to 5 minutes after activation; however, fibrinogen binding to platelets was not affected. This deaggregating effect significantly reduced the maximal size and number of platelet aggregates. When added 1 minute after platelet activation, anti–P-selectin antibody achieved 95% to 100% of the deaggregating effect of EDTA, whereas the anti-GP IIb/IIIa antibody abciximab had no effect. Monoclonal antibodies against known P-selectin ligands, such as P-selectin GP ligand-1 (PSGL-1) or GP Ib, had no effect on platelet aggregation, suggesting a different ligand for P-selectin in platelet aggregate stabilization. In kinetic studies, P-selectin was maximally expressed 10 minutes after platelet activation, whereas maximal activation of GP IIb/IIIa occurred within the first 10 seconds, suggesting that P-selectin operates after fibrinogen binding to activated GP IIb/IIIa. Conclusions —These results indicate that P-selectin interaction with a ligand, different from PSGL-1 or GP Ib, stabilizes initial GP IIb/IIIa–fibrinogen interactions, allowing the formation of large stable platelet aggregates.
Resting Regional Cerebral Blood Flow and Gambling Task Performance in Cocaine-Dependent Subjects and Healthy Comparison Subjects
Authors: Bryon Adinoff, Michael D. Devous, Douglas B. Cooper, Susan E. Best, Patricia Chandler, Thomas Harris, Carole Anne Cervin, C. Munro Cullum
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: Orbitofrontal cortex regional cerebral blood flow (rCBF) is lower in cocaine-dependent subjects than in non-cocaine-dependent subjects. Performance on the Gambling Task, a test of decision making, is a putative correlate of orbitofrontal cortex activity and is reportedly impaired in drug-dependent subjects. The authors tested the hypothesis that lower Gambling Task scores would be associated with lower resting orbitofrontal cortex rCBF in cocaine-dependent subjects. METHOD: Fifteen healthy comparison subjects and 13 abstinent cocaine-dependent subjects underwent resting single photon emission computed tomography to measure rCBF, after which they completed the Gambling Task. RESULTS: Resting anterior cingulate and left dorsolateral prefrontal cortex rCBF significantly correlated with performance on the Gambling Task, but orbitofrontal cortex rCBF did not. Left dorsolateral prefrontal cortex rCBF was lower in the cocaine-dependent subjects than in the comparison subjects. CONCLUSIONS: Resting anterior cingulate and dorsolateral prefrontal cortex rCBF is significantly related to decision making, as assessed by the Gambling Task.