tbuckley/cabot-search huggingface dataset:
Phase III Trial Comparing Vinflunine With Docetaxel in Second-Line Advanced Non–Small-Cell Lung Cancer Previously Treated With Platinum-Containing Chemotherapy
Authors: Maciej Krzakowski, Rodryg Ramlau, Jacek Jassem, Aleksandra Szczesna, Petr Zatloukal, Joachim Von Pawel, Xushan Sun, Jaafar Bennouna, Armando Santoro, Bonne Biesma, François M. Delgado, Yacine Salhi, Nathalie Vaissiere, Olfred Hansen, Eng-Huat Tan, Elisabeth Quoix, Pilar Garrido, Jean-Yves Douillard
Journal: Journal of Clinical Oncology (2010)

To compare vinflunine (VFL) to docetaxel in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) who have experienced treatment failure with first-line platinum-based chemotherapy.Randomized, multicenter, phase III study, 551 patients received either vinflunine 320 mg/m(2) or docetaxel 75 mg/m(2) every 21 days until disease progression or serious toxicity. The primary end point was progression-free survival (PFS). The noninferiority analysis was based on a 10% difference (types I/II error rates: 5%/20%). Secondary end points included response rate (ORR), response duration, overall survival (OS), clinical benefit, quality of life (QOL), and safety.Median PFS was 2.3 months for each arm (HR, 1.004; 95% CI, 0.841 to 1.199). ORR, stable disease, median OS, were 4.4% versus 5.5%, 36.0% versus 39.6%, 6.7 versus 7.2 months (HR, 0.973; 95% CI, 0.805 to 1.176), respectively. No significant difference in patient benefit and QOL (Functional Assessment of Cancer Therapy-Lung). No unexpected adverse events were observed. Grade higher than 0 (vinflunine v docetaxel) anemia (82.1% v 79.8%), neutropenia (49.3 v 39.02%), thrombocytopenia (30.6% v 14.3%), febrile neutropenia (3.3% v 4.7%), constipation (39.2% v 11.7%), fatigue (36.6% v 33.9%), injection site reaction (31.9% v 0.7%), nausea (26.7% v 23.7%), vomiting (23.8% v 14.2%), alopecia (19.8% v 35.4%), stomatis (19.4% v 12.4%), abdominal pain (20.1% v 3.6%), myalgia (14.7% v 6.6%), peripheral neuropathy (10.7% v 15.0%), arthralgia (7.0% v 7.7%), diarrhea (6.2% v 12.4%), edema (1.5% v 5.4%), and nail disorders (1.1% v 5;1%) were observed.This noninferiority phase III study showed similar efficacy end points for vinflunine and docetaxel. Despite higher rates of some adverse effects (anemia, abdominal pain, constipation, fatigue) the overall toxicity profile of vinflunine was manageable. Therefore, VFL may be another option in the second-line treatment of patients with advanced NSCLC.
Divergent changes to muscarinic and serotonergic signalling following colitis
Authors: R W Wells
Journal: Gut (2005)

<b>Background:</b> The altered motility of the inflamed intestine derives in part from changes to the contractility of the intestinal smooth muscle cell. While modifications to the muscarinic receptor system are identified, changes to 5-hydroxytryptamine (5-HT; serotonin) receptors that also mediate contraction are less well studied. <b>Methods:</b> In the trinitrobenzene sulphonic acid model of rat colitis, we used receptor antagonists to identify changes in receptor utilisation that accompany the selective reversal of the impaired contractile response to acetylcholine (ACh) and 5-HT during colitis (day 4 (D4)) and following resolution of inflammation (day 36 (D36)). <b>Results:</b> In isolated circular smooth muscle cells, challenged with ACh, the muscarinic 3 receptor (M<sub>3</sub>R) antagonists 4-DAMP and pF-HSD each showed a 50% decrease in antagonism on D4 while the M<sub>2</sub>R antagonist methoctramine more than doubled its potency, showing a decreased role of M<sub>3</sub>R and an increased role of M<sub>2</sub>R, respectively. These changes were fully reversed by D36. In contrast, the 5-HT<sub>2</sub> receptor (5-HT<sub>2</sub>R) antagonist ketanserin was sharply decreased in effectiveness on D4, with a further decrease by D36, when the contribution of 5-HT<sub>2A</sub>R was only 22% of control. There were no changes in response to the 5-HT<sub>4</sub>R antagonist SDZ-205-557 at any time. Western blotting identified decreased expression of 5-HT<sub>2A</sub>R on D36 versus controls, further supporting the conclusion that the persistence of the impaired response to 5-HT was due to decreased expression of the excitatory 5-HT<sub>2A</sub>R. <b>Conclusions:</b> Thus the lasting decrease in receptor expression and resulting impairment of the contractile response will compromise the capacity for an appropriate response to 5-HT, which may contribute to the intestinal dysfunction seen in post-enteritis syndromes.
Indicator condition-guided HIV testing in Europe: a step forward to HIV control:
Authors: Francesco Blasi, Alberto Matteelli
Journal: European Respiratory Journal (2013)

by ''HIV in Europe'', a pan-European initiative constituted by an independent group of experts with representation from civil society, policymakers, health professionals and European public health institutions.This initiative was started in Brussels in 2007 to promote early diagnosis and earlier care of the HIV infection across Europe.The document, ''HIV indicator conditions: guidance for implementing HIV testing in health care settings'' is an important step to ensure that people living with HIV enter care earlier in the course of their infection [1].It was developed by a multidisciplinary panel of experts, because the active commitment of several medical specialties was considered an essential prerequisite for the successful implementation of the recommended approach.
Arsenic Exposure and Age- and Sex-Specific Risk for Skin Lesions: A Population-Based Case–Referent Study in Bangladesh
Authors: Mahfuzar Rahman, Marie Vahter, Nazmul Sohel, Muhammad Yunus, Mohammad Abdul Wahed, Peter Kim Streatfield, Eva-Charlotte Ekström, Lars Åke Persson
Journal: Environmental Health Perspectives (2006)

BackgroundThe objective of this population-based case–referent study in Matlab, Bangladesh, was to assess the susceptibility to arsenic-induced skin lesions by age and sex, in a population drinking water from As-contaminated tube wells.MethodsIdentification of As-related skin lesions was carried out in three steps: a) screening of the entire population > 4 years of age (n = 166,934) by trained field teams; b) diagnosis of suspected As-related cases by physicians; and c) confirmation by experts based on physicians' records and photographs. A total of 504 cases with skin lesions were confirmed. We randomly selected 2,201 referents from the Matlab health and demographic surveillance system; 1,955 were eligible, and 1,830 (94%) were available for participation in the study. Individual history of As exposure was based on information obtained during interviews and included all drinking-water sources used since 1970 and concentrations of As (assessed by atomic absorption spectrophotometry) in all the tube wells used.ResultsCases had been exposed to As more than referents (average exposure since 1970: male cases, 200 μg/L; female cases, 211 μg/L; male referents, 143 μg/L; female referents, 155 μg/L). We found a dose–response relationship for both sexes (p < 0.001) and increased risk with increasing socioeconomic status. Males had a higher risk of obtaining skin lesions than females (odds ratio 10.9 vs. 5.78) in the highest average exposure quintile (p = 0.005). Start of As exposure (cumulative exposure) before 1 year of age was not associated with higher risk of obtaining skin lesions compared to start of As exposure later in life.ConclusionsThe results demonstrate that males are more susceptible than females to develop skin lesions when exposed to As in water from tube wells.
The Allergic Rhinitis Clinical Investigator Collaborative (AR-CIC) – a Multicentre Pilot Study to Optimize a Standard Nasal Allergen Challenge Protocol
Authors: Anne K. Ellis, Louis-Philippe Boulet, Harissios Vliagoftis, Paul Keith, Susan Waserman, Marie-Eve Boulay, Lisa Steacy, Helen Neighbour
Journal: Journal of Allergy and Clinical Immunology (2013)
TRAIL Signalling Is Pro-Inflammatory in Eosinophilic Esophagitis
Authors: Adam M. Collison, Leon A. Sokulsky, Joseph D. Sherrill, Scott Nightingale, Luke Hatchwell, Nicholas J. Talley, Marjorie M. Walker, Marc E. Rothenberg, Joerg Mattes
Journal: Journal of Allergy and Clinical Immunology (2015)
Adeno-Associated Virus Vectors as Therapeutic and Investigational Tools in the Cardiovascular System
Authors: Serena Zacchigna, Lorena Zentilin, Mauro Giacca
Journal: Circulation Research (2014)

The use of vectors based on the small parvovirus adeno-associated virus has gained significant momentum during the past decade. Their high efficiency of transduction of postmitotic tissues in vivo, such as heart, brain, and retina, renders these vectors extremely attractive for several gene therapy applications affecting these organs. Besides functional correction of different monogenic diseases, the possibility to drive efficient and persistent transgene expression in the heart offers the possibility to develop innovative therapies for prevalent conditions, such as ischemic cardiomyopathy and heart failure. Therapeutic genes are not only restricted to protein-coding complementary DNAs but also include short hairpin RNAs and microRNA genes, thus broadening the spectrum of possible applications. In addition, several spontaneous or engineered variants in the virus capsid have recently improved vector efficiency and expanded their tropism. Apart from their therapeutic potential, adeno-associated virus vectors also represent outstanding investigational tools to explore the function of individual genes or gene combinations in vivo, thus providing information that is conceptually similar to that obtained from genetically modified animals. Finally, their single-stranded DNA genome can drive homology-directed gene repair at high efficiency. Here, we review the main molecular characteristics of adeno-associated virus vectors, with a particular view to their applications in the cardiovascular field.
GTP Cyclohydrolase I Phosphorylation and Interaction With GTP Cyclohydrolase Feedback Regulatory Protein Provide Novel Regulation of Endothelial Tetrahydrobiopterin and Nitric Oxide
Authors: Li Li, Amir Rezvan, John C. Salerno, Ahsan Husain, Kihwan Kwon, Hanjoong Jo, David G. Harrison, Wei Chen
Journal: Circulation Research (2009)

GTP cyclohydrolase I (GTPCH-1) is the rate-limiting enzyme involved in de novo biosynthesis of tetrahydrobiopterin (BH(4)), an essential cofactor for NO synthases and aromatic amino acid hydroxylases. GTPCH-1 undergoes negative feedback regulation by its end-product BH(4) via interaction with the GTP cyclohydrolase feedback regulatory protein (GFRP). Such a negative feedback mechanism should maintain cellular BH(4) levels within a very narrow range; however, we recently identified a phosphorylation site (S81) on human GTPCH-1 that markedly increases BH(4) production in response to laminar shear.We sought to define how S81 phosphorylation alters GTPCH-1 enzyme activity and how this is modulated by GFRP.Using prokaryotically expressed proteins, we found that the GTPCH-1 phospho-mimetic mutant (S81D) has increased enzyme activity, reduced binding to GFRP and resistance to inhibition by GFRP compared to wild-type GTPCH-1. Using small interfering RNA or overexpressing plasmids, GFRP was shown to modulate phosphorylation of GTPCH-1, BH(4) levels, and NO production in human endothelial cells. Laminar, but not oscillatory shear stress, caused dissociation of GTPCH-1 and GFRP, promoting GTPCH-1 phosphorylation. We also found that both GTPCH-1 phosphorylation and GFRP downregulation prevents endothelial NO synthase uncoupling in response to oscillatory shear. Finally oscillatory shear was associated with impaired GTPCH-1 phosphorylation and reduced BH(4) levels in vivo.These studies provide a new mechanism for regulation of endothelial GTPCH-1 by its phosphorylation and interplay with GFRP. This mechanism allows for escape from GFRP negative feedback and permits large amounts of BH(4) to be produced in response to laminar shear stress.
Physical activity throughout life reduces the atherosclerotic wall process in the carotid artery
Authors: M Sandrock, C Schulze, D Schmitz, H-H Dickhuth, A Schmidt-Trucksaess
Journal: British Journal of Sports Medicine (2008)

Good cardiorespiratory fitness has been associated with a reduced risk for clinical events of atherosclerotic vascular diseases. It is still unclear how this relates to a slower progression of the early atherosclerosis wall process.Using a dynamic model, we generated new parameters for describing the pathologic wall process in the carotid artery, based on an automatic layer detection system. In this study, we scrutinised the influence of two ultrasonographic parameters, intima-media thickness (IMT) and roughness, by comparing two groups: a healthy inactive group (PIP) (mean (SD) age 64.37 (5.10) years; n = 50) and a healthy lifelong physically active group (PA) (mean (SD) age 64.48 (3.45) years; n = 51). All subjects underwent a blood test, spiroergometry, echocardiography and carotid ultrasound examination.There was a significant difference in the well known risk factors for cardiovascular disease (for example, high density lipoprotein cholesterol, triglyceride) between groups. PIP compared to PA had a significantly higher roughness (PIP 0.073 (0.015) vs PA 0.065 (0.0156); p<0.01). No significantly higher IMT was found for PIP (PIP 0.89 (0.18) vs PA 0.90 (0.22); p = 0.63) compared to PA. In this cross sectional study of middle aged men, Vo(2)max was inversely associated with carotid atherosclerotic parameters.In this study, good cardiorespiratory fitness was associated with an increase of the proven risk factors and a reduction of atherosclerosis in the common carotid artery. Roughness seems to be significantly more sensitive than IMT for characterising the changes of the arterial wall. We suggest measuring roughness in addition to IMT to gain additional information about the atherosclerotic wall.
Ploidy, expression of erbB1, erbB2, P53 and amplification of erbB1, erbB2 and erbB3 in non-small cell lung cancer
Authors: N Reinmuth, B Brandt, WP Kunze, K Junker, M Thomas, R Achatzy, HH Scheld, M Semik
Journal: European Respiratory Journal (2000)

The aim of this study was to assess the prognostic value of deoxyribonucleic acid analysis, expression oferbB1, erbB2 and P53, and amplification levels of erbB1, erbB2 and erbB3 in non-small cell lung cancer (NSCLC). Consecutive patients with NSCLC who underwent treatment with curative intention (118) were included. In 108 cases, the cell cycle was analysed using flow cytometry and double-staining with propidium iodide and anticytokeratin. In another 108 cases, expression of erbB1, erbB2 and P53 was assessed immunhistochemically. Amplification of the erbB family was determined in the tumours of 53 patients using double-differential polymerase chain reaction. Of the tumours, 81% were aneuploid and 14% showed positive staining for erbB1, 18% for erbB2 and 41% for P53. There were normal mean gene copy numbers in 86% for erbB1, 94% for erbB2 and in 96% for erbB3. No significant correlations were noted between erbB1, erbB2 and P53 expression, ploidy status and tumour stage. In a Cox regression model, only tumour stage was shown to be prognostically significant. It seems that ploidy and expression status of erbB1, erbB2 and P53 are not prognostic parameters in non-small cell lung cancer. Amplification of the erbB family does not seem to be a frequent event in non-small cell lung cancer.
Glutathione S-transferase copy number variation alters lung gene expression
Authors: M.W. Butler, N.R. Hackett, J. Salit, Y. Strulovici-Barel, L. Omberg, J. Mezey, R.G. Crystal
Journal: European Respiratory Journal (2011)

The glutathione S -transferase (GST) enzymes catalyse the conjugation of xenobiotics to glutathione. Based on reports that inherited copy number variations (CNVs) modulate some GST gene expression levels, and that the small airway epithelium (SAE) and alveolar macrophages (AMs) are involved early in the pathogenesis of smoking-induced lung disease, we asked: do germline CNVs modulate GST expression levels in SAE and AMs? Microarrays were used to survey GST gene expression and determine CNVs genotypes in SAE and AMs obtained by bronchoscopy from current smokers and nonsmokers. 26% of subjects were null for both GSTM1 alleles, with reduced GSTM1 mRNA levels seen in both SAE and AMs. 30% of subjects had homozygous deletions of GSTT1 , with reduced mRNA levels in both tissues. Interestingly, GSTT2B exhibited homozygous deletion in the blood of 27% of subjects and was not expressed in SAE in the remainder of subjects, but was expressed in AMs of heterozygotes and wild-type subjects, proportionate to genotype. These data show a germline CNV-mediated linear relationship of genotype with expression level, suggesting minimal compensation of gene expression levels in heterozygotes, consistent with GST polymorphisms playing a role in the risk of smoking-associated, xenobiotic-induced lung disease.
Late Outcomes of a Randomized Trial of High-Frequency Oscillation in Neonates
Authors: Sanja Zivanovic, Janet Peacock, Mireia Alcazar-Paris, Jessica W. Lo, Alan Lunt, Neil Marlow, Sandy Calvert, Anne Greenough
Journal: New England Journal of Medicine (2014)

Results from an observational study involving neonates suggested that high-frequency oscillatory ventilation (HFOV), as compared with conventional ventilation, was associated with superior small-airway function at follow-up. Data from randomized trials are needed to confirm this finding.
PCTs seek to restrict GPs prescribing high cost drugs
Authors: A. O'Dowd
Journal: BMJ (2011)

General practitioners’ ability to prescribe expensive drugs that are officially approved for use on the NHS is being scaled back by primary care trusts to try and save money.

Some doctors are coming under increasing pressure to stop prescribing high cost drugs even though they are approved by medicines watchdog the National Institute for Health and Clinical Excellence (NICE).

The Department of Health has questioned the development and insisted that GPs are entitled to prescribe medicines based on a patient’s clinical need and trusts are legally obliged to fund treatments and drugs recommended by NICE.

A survey with responses from 134 primary care organisations in England, Scotland, and Wales carried out by Pulse magazine found that more than half had created new lists of drugs in the past year, which they recommended doctors no longer prescribe.

Of the 134 …
Transfer of Olanzapine Into Breast Milk, Calculation of Infant Drug Dose, and Effect on Breast-Fed Infants
Authors: Sharon J. Gardiner, Judith H. Kristensen, Evan J. Begg, L. Peter Hackett, Debbie A. Wilson, Kenneth F. Ilett, Rolland Kohan, Jonathan Rampono
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: This study characterized infant drug doses and breast-milk-to-plasma area-under-the-curve ratios for olanzapine and determined plasma concentrations and effects of this drug on breast-feeding infants. METHOD: Seven mother-infant nursing pairs were studied. Olanzapine was measured in plasma and milk with high-performance liquid chromatography over a dose interval (for six patients) or at a single time after dose ingestion (for one patient) at steady state. Infant drug exposure was estimated as the product of an assumed milk production rate and average drug concentration in milk, normalized to body weight, and expressed as a percentage of maternal drug dose, normalized to body weight. RESULTS: The median infant dose of olanzapine ingested through milk was 1.02% of the maternal dose; the median milk-to-plasma area-under-the-curve ratio was 0.38 for the six patients with data collected over the dose interval. Corresponding values in the patient with single-point data were 1.13% and 0.75. Olanzapine was not detected in the plasma of the six infants with an evaluable plasma sample. All of the infants were healthy and experienced no side effects. CONCLUSIONS: Breast-fed infants were exposed to a calculated olanzapine dose of approximately 1%—well below the 10% notional level of concern. In infant plasma, olanzapine was below the detection limit; there were no adverse effects on the infants. These data support the use of olanzapine during breast-feeding. However, the authors recommend that breast-fed infants be monitored closely and the decision to breast-feed be made after individual risk-benefit analysis.
Action Schools! BC implementation: from efficacy to effectiveness to scale-up
Authors: Heather A McKay, Heather M Macdonald, Lindsay Nettlefold, Louise C Masse, Meghan Day, Patti-Jean Naylor
Journal: British Journal of Sports Medicine (2014)

Objectives To describe Action Schools! BC (AS! BC) from efficacy to scale-up. Participants/setting Education and health system stakeholders and children in grades 4–6 from elementary schools in British Columbia, Canada. Intervention At the provincial level, the AS! BC model reflected socioecological theory and a partnership approach to social change. Knowledge translation and exchange were embedded as a foundational element. At the school level, AS! BC is a comprehensive school health-based model providing teachers and schools with training and resources to integrate physical activity (PA) and healthy eating (HE) into the school environment. Our research team partnered with key community and government stakeholders to deliver and evaluate AS! BC over efficacy, effectiveness and implementation trials. Results On the basis of significant increases in PA, cardiovascular fitness, bone and HE in AS! BC schools during efficacy trials, the BC government supported a provincial scale-up. Since its inception, the AS! BC Support Team and &gt;225 trained regional trainers have delivered 4677 teacher-focused workshops (training approximately 81 000 teachers), reaching approximately 500 000 students. After scale-up, PA delivery was replicated but the magnitude of change appeared less. One (HE) and 4 (PA) years after scale-up, trained AS! BC teachers provided more PA and HE opportunities for students even in the context of supportive provincial policies. Conclusions Whole school models like AS! BC can enhance children's PA and health when implemented in partnership with key stakeholders. At the school level, adequately trained and resourced teachers and supportive school policies promoted successful scale-up and sustained implementation. At the provincial level, multisectoral partnerships and embedded knowledge exchange mechanisms influenced the context for action at the provincial and school level, and were core elements of successful implementation. Trial registration number Clinical Trials Registry NCT01412203 .