tbuckley/cabot-search huggingface dataset:
P254 NVA237 once daily improves exercise endurance in patients with COPD from the first dose: the GLOW3 trial
Authors: D. Singh, K. Beeh, A. Drollmann, L. Di Scala, R. Smith
Journal: Thorax (2011)

<h3>Introduction</h3> The fundamental characteristics of COPD are exertional dyspnoea and exercise limitation, which are associated with dynamic hyperinflation. We assessed the effects of NVA237 (glycopyrronium bromide), a once-daily long-acting muscarinic antagonist (LAMA), on exercise endurance in patients with moderate-to-severe COPD. <h3>Methods</h3> Patients with COPD were randomised to a cross-over design of NVA237 50 μg or placebo once daily for 3 weeks, with a 14-day washout. The primary endpoint was endurance time during a submaximal constant-load cycle ergometry test (SMETT) on Day 21 of treatment. Endurance time after first dose, dynamic hyperinflation (inspiratory capacity [IC] at isotime during exercise), and morning trough FEV<sub>1</sub> and plethysmographic lung volumes were also measured. <h3>Results</h3> 108 patients were randomised; mean age was 60.5 years, mean post-bronchodilator FEV<sub>1</sub> was 57.1% predicted. 88.0% completed the study. Endurance time on Day 21 significantly increased by 21% with NVA237 vs placebo; the effect was significant from Day 1, with an increase of 10%. Both dynamic IC at exercise isotime and trough FEV<sub>1</sub> showed significant and clinically relevant improvements from Day 1 that were maintained for the study duration (Abstract P254 table 1). This was accompanied by inverse decreases in residual volume and functional residual capacity (Abstract P254 table 1). Overall, the safety profile of NVA237 was similar to that of placebo. <h3>Conclusion</h3> Once-daily NVA237 provided immediate and significant improvement in exercise endurance from Day 1. This was accompanied by sustained and significant improvements in IC at isotime, meaningful improvements in trough FEV<sub>1</sub>, and sustained reductions of lung hyperinflation. There was an improvement in endurance time during the study period, suggesting that mechanisms beyond improved lung function play a part in superior exercise tolerance.
Occupational asthma caused by dry metabisulphite.
Authors: J L Malo, A Cartier, A Desjardins
Journal: Thorax (1995)

A case is described of occupational asthma in a worker with no previous history of asthma who sprinkled dried metabisulphite powder onto potatoes and developed work-related symptoms. Occupational asthma was confirmed by specific inhalation challenges.
New Data on Aspirin and Colorectal Cancer Brings Calls for New Guidelines, More Research
Authors: C. McNeil
Journal: JNCI Journal of the National Cancer Institute (2012)

T hree large studies in the past 14 months have reopened a longstanding issue in colorectal cancer: Can aspirin prevent it? Or more precisely, is the evidence for preventive benefit in people at average risk strong enough to outweigh the known risks of regular aspirin use? Up to now, the committees that draw up cancer prevention guidelines have concluded that the evidence for aspirin ’ s benefi ts was insuffi cient when weighed against the risk of gastrointestinal bleeding, a common side effect that can be severe; aspirin can also cause hemorrhagic stroke. But the new studies, though not perfect, could tip the scales in favor of aspirin, say some experts. The accumulated data now “arguably support more general recommendations to consider aspirin for prevention of colorectal cancer in the context of individualized risk-benefi t assessments,” wrote Andrew Chan, M.D. Harvard Medical School, Boston, and Scott Lippman, M.D. at the M.D. Anderson Cancer Center in Houston, in their Lancet editorial on December 17 th . “We ’ re in a situation where no single study will settle all the questions for everyone,” Chan said in an interview. “But a lot of evidence is in and we’ve reached a point where there is a suffi cient body of evidence for us to no longer question if aspirin can prevent colorectal cancer, but to decide what kind of risk stratifi cation we need.” Others argue that the evidence is still not strong enough, pointing to weaknesses in the new studies. Nevertheless, it seems certain that guideline committees will revisit the issue in 2012 and that ongoing research on aspirin ’ s risks and benefi ts in cancer prevention has taken on new visibility.
Induction of Metalloproteinases by Glomerular Mesangial Cells Stimulated by Proteins of the Extracellular Matrix
Authors: JOHN MARTIN, LISA EYNSTONE, MALCOLM DAVIES, ROBERT STEADMAN
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Human glomerular mesangial cells (HMC) are embedded in the mesangial matrix (MM) and control its turnover through a dynamic equilibrium between synthesis and degradation. Degradation is controlled by matrix metalloproteinases (MMP), whose activity has been causally implicated in the progression of glomerular disease. In other systems, MMP secretion may be directly affected by exposure to specific matrix proteins. The present study, therefore, investigated the effect of different matrix components on the adherence of HMC and on their secretion and activation of the gelatinases MMP2 and MMP9. HMC adhered strongly (quantified using crystal violet staining) to collagen IV and collagen I ( P &lt; 0.01, relative to binding to control, bovine serum albumin (BSA)-coated wells) and to a lesser extent to gelatin IV and fibronectin ( P &lt; 0.05). Binding to vitronectin and laminin was not statistically different to control wells. After the addition of these matrix proteins (0.1 μg/ml to 100 μg/ml) to growth-arrested HMC for 72 h, zymography of the conditioned medium established that only fibronectin and collagens I and IV dose-dependently increased latent (72 kD) MMP2 secretion and activation. Fibronectin, however, also induced the secretion of MMP9. Membranes from HMC that had been co-cultured with fibronectin for 72 h were prepared to investigate whether the activation of MMP2 in this system was due to the action of membrane-type (MT)-MMP. When incubated with latent MMP2 for times up to 24 h, these membranes activated the enzyme in a time- and dose-dependent manner. The results demonstrate that specific matrix components increased the secretion of MMP2 and MMP9 from HMC. In addition, MT-MMP activity, selectively induced by fibronectin, was implicated in the activation of the secreted proteinases.
Inappropriate ADH secretion caused by oat cell carcinoma and relieved by lung resection.
Authors: C Robinson, R C Jeffries, G C Walsh
Journal: Thorax (1980)

In this case report we describe a patient with an early oat cell carcinoma and inappropriate antidiuretic hormone (ADH) secretion, whose symptoms were cured by resecting the tumour.The follow-up period is four and a half years.Another unusual feature, the presence of thrombocytopaenia, was greatly improved by the lung resection.Case report
Lung consequences in adults born prematurely
Authors: Charlotte E Bolton, Andrew Bush, John R Hurst, Sailesh Kotecha, Lorcan McGarvey
Journal: Thorax (2015)

Although survival has improved significantly in recent years, prematurity remains a major cause of infant and childhood mortality and morbidity. Preterm births (&lt;37 weeks of gestation) account for 8% of live births representing &gt;50 000 live births each year in the UK. Preterm birth, irrespective of whether babies require neonatal intensive care, is associated with increased respiratory symptoms, partially reversible airflow obstruction and abnormal thoracic imaging in childhood and in young adulthood compared with those born at term. Having failed to reach their optimal peak lung function in early adulthood, there are as yet unsubstantiated concerns of accelerated lung function decline especially if exposed to noxious substances leading to chronic respiratory illness; even if the rate of decline in lung function is normal, the threshold for respiratory symptoms will be crossed early. Few adult respiratory physicians enquire about the neonatal period in their clinical practice. The management of these subjects in adulthood is largely evidence free. They are often labelled as asthmatic although the underlying mechanisms are likely to be very different. Smoking cessation, maintaining physical fitness, annual influenza immunisation and a general healthy lifestyle should be endorsed irrespective of any symptoms. There are a number of clinical and research priorities to maximise the quality of life and lung health in the longer term not least understanding the underlying mechanisms and optimising treatment, rather than extrapolating from other airway diseases.
Inhibition of G9a induces DUSP4-dependent autophagic cell death in head and neck squamous cell carcinoma
Authors: Kai-Chun Li, Kuo-Tai Hua, Yi-Shen Lin, Chia-Yi Su, Jenq-Yuh Ko, Michael Hsiao, Min-Liang Kuo, Ching-Ting Tan
Journal: Molecular Cancer (2014)

Head and neck squamous cell carcinoma (HNSCC) is a common cancer worldwide. Emerging evidence indicates that alteration of epigenetics might be a key event in HNSCC progression. Abnormal expression of histone methyltransferase G9a, which contributes to transcriptional repression of tumor suppressors, has been implicated in promoting cancerous malignancies. However, its role in HNSCC has not been previously characterized. In this study, we elucidate the function of G9a and its downstream mechanism in HNSCC. We investigated the clinical relevance of G9a in HNSCC using immunohistochemistry (IHC) staining. In vitro cell proliferation and tumorigenesis ability of G9a-manipulated HNSCC cells were examined with MTT assays, clonogenic assays, and soft agar assays. We examined different routes of cell death in HNSCC cells induced by G9a-depletion or enzymatic inhibition by immunoblot, flow cytometry, fluorescent and transmission electron microscopy analysis. Specific targets of G9a were identified by affymetrix microarray and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Lastly, functions of G9a in vivo were confirmed with a xenograft tumor model. G9a expression is positively correlated to proliferation marker Ki-67 and to poor prognosis in HNSCC patients. Genetic or pharmacological inhibition of G9a reduced cell proliferation without inducing necrosis or apoptosis. Instead, autophagic cell death was the major consequence, and our investigation of mechanisms suggested it is mediated via the dual specificity phosphatase-4 (DUSP4) dependent ERK inactivation pathway. An orthotopic tumor model further confirmed the growth inhibiting effect and induction of autophagy that followed suppression of G9a. In this study, we provide evidence that G9a confers the survival advantage of HNSCC. Genetic or pharmacological inhibition of G9a induces autophagic cell death; this finding provides a basis for new therapeutic targets for treating HNSCC.
Albumin and Fibrinogen Synthesis and Insulin Effect in Type 2 Diabetic Patients With Normoalbuminuria
Authors: Paolo Tessari, Edward Kiwanuka, Renato Millioni, Monica Vettore, Lucia Puricelli, Michela Zanetti, Antonella Gucciardi, Marina Tosolini, Paola Cogo, Virgilio Carnielli, Antonio Tiengo, Rocco Barazzoni
Journal: Diabetes Care (2006)

OBJECTIVE—Insulin stimulates albumin synthesis but inhibits that of fibrinogen in both type 1 diabetic and healthy subjects. In type 2 diabetes, fibrinogen production is increased both in the postabsorptive state and in response to hyperinsulinemia. No data exist on the rate of albumin synthesis and its response to insulin in type 2 diabetes. RESEARCH DESIGN AND METHODS—We measured fractional synthesis rates (FSRs) and absolute synthesis rates (ASRs) of both albumin and fibrinogen in postabsorptive normoalbuminuric type 2 diabetic patients at their spontaneous glucose levels (study A), as well as albumin FSR and ASR before and after a hyperinsulinemic-euglycemic euaminoacidemic clamp (study B), using leucine isotope methods. RESULTS—In postabsorptive type 2 diabetes (study A), albumin FSR (11.2 ± 0.9%/day) and albumin ASR (15.4 ± 1.2 g/day) were not different from control values (albumin FSR: 9.4 ± 0.7%/day; albumin ASR: 13.8 ± 1.2 g/day, P &amp;gt; 0.1 for both). In contrast, in the type 2 diabetic subjects, both fibrinogen FSR (24.9 ± 2.1%/day) and ASR (2.4 ± 0.2 g/day) were greater (P &amp;lt; 0.025 and P &amp;lt; 0.007, respectively) compared with the control subjects (FSR: 18.6 ± 1.51%/day; ASR: 1.6 ± 0.2 g/day). Worse metabolic control in the type 2 diabetic patients was associated with hyperfibrinogenemia and increased leucine rate of appearance, whereas neither the (increased) fibrinogen ASR nor the (normal) albumin production was affected. In study B, after hyperinsulinemia (raised to ∼860 nmol/l), albumin FSR and ASR increased by ∼25% versus basal (P &amp;lt; 0.04) and to the same extent in both type 2 diabetic and control subjects. CONCLUSIONS—In normoalbuminuric type 2 diabetic patients, postabsorptive albumin synthesis and its response to insulin were normal, whereas fibrinogen synthesis was increased, irrespective of metabolic control. Furthermore, in normoalbuminuric type 2 diabetic patients, a normal insulin sensitivity with respect to albumin production but a selective hepatic dysregulation of fibrinogen metabolism were present.
Limitation of Excessive Extracellular Matrix Turnover May Contribute to Survival Benefit of Spironolactone Therapy in Patients With Congestive Heart Failure
Authors: Faiez Zannad, François Alla, Brigitte Dousset, Alfonso Perez, Bertram Pitt
Journal: Circulation (2000)

Background —In congestive heart failure (CHF), extracellular matrix turnover is a major determinant of cardiac remodeling. It has been suggested that spironolactone may decrease cardiac fibrosis. We investigated the interactions between serum markers of cardiac fibrosis and the effect of spironolactone on outcome in patients with CHF. Methods and Results —A sample of 261 patients from the Randomized Aldactone Evaluation Study (RALES) were randomized to placebo or spironolactone (12.5 to 50 mg daily). Serum procollagen type I carboxy-terminal peptide, procollagen type I amino-terminal peptide, and procollagen type III amino-terminal peptide (PIIINP) were assessed at baseline and at 6 months. Baseline PIIINP &gt;3.85 μg/L was associated with an increased risk of death (relative risk [RR] 2.36, 95% CI 1.34 to 4.18) and of death+hospitalization (RR 1.83, 95% CI 1.18 to 2.83). At 6 months, markers decreased in the spironolactone group but remained unchanged in the placebo group. The spironolactone effect on outcome was significant only in patients with above-median baseline levels of markers. RR (95% CI) values for death among patients receiving spironolactone were 0.44 (0.26 to 0.75) and 1.11 (0.66 to 1.88) in subgroups of PIIINP levels above and below the median, respectively. Similarly, RR (95% CI) values for death+hospitalization among patients receiving spironolactone were 0.45 (0.29 to 0.71) and 0.85 (0.55 to 1.33), respectively. Conclusions —In patients with CHF, high baseline serum levels of markers of cardiac fibrosis synthesis are significantly associated with poor outcome and decrease during spironolactone therapy. The benefit from spironolactone was associated with higher levels of collagen synthesis markers. These results suggest that limitation of the excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with CHF.
MEK1/2 Inhibition Elicits Regression of Autochthonous Lung Tumors Induced by KRASG12D or BRAFV600E
Authors: Christy L. Trejo, Joseph Juan, Silvestre Vicent, Alejandro Sweet-Cordero, Martin McMahon
Journal: Cancer Research (2012)

Abstract Genetically engineered mouse (GEM) models of lung tumorigenesis allow careful evaluation of lung tumor initiation, progression, and response to therapy. Using GEM models of oncogene-induced lung cancer, we show the striking similarity of the earliest stages of tumorigenesis induced by KRASG12D or BRAFV600E. Cre-mediated expression of KRASG12D or BRAFV600E in the lung epithelium of adult mice initially elicited benign lung tumors comprising cuboidal epithelial cells expressing markers of alveolar pneumocytes. Strikingly, in a head-to-head comparison, oncogenic BRAFV600E elicited many more such benign tumors and did so more rapidly than KRASG12D. However, despite differences in the efficiency of benign tumor induction, only mice with lung epithelium expression of KRASG12D developed malignant non–small cell lung adenocarcinomas. Pharmacologic inhibition of mitogen-activated protein (MAP)–extracellular signal-regulated kinase (ERK) kinase (MEK)1/2 combined with in vivo imaging showed that initiation and maintenance of both BRAFV600E- or KRASG12D-induced lung tumors was dependent on MEK→ERK signaling. Although the tumors dramatically regressed in response to MEK1/2 inhibition, they regrew following cessation of drug treatment. Together, our findings show that RAF→MEK→ERK signaling is both necessary and sufficient for KRASG12D-induced benign lung tumorigenesis in GEM models. The data also emphasize the ability of KRASG12D to promote malignant lung cancer progression compared with oncogenic BRAFV600E. Cancer Res; 72(12); 3048–59. ©2012 AACR.
Endothelin, vasopressin, and substance P like immunoreactivity in cultured and intact epithelium from rabbit trachea.
Authors: R E Rennick, A Loesch, G Burnstock
Journal: Thorax (1992)

The control of airways reactivity is essential to our understanding of disease processes such as asthma. Many studies have examined the neural control of the airways, but more recently there has been evidence to show that the epithelium lining the airways may influence airways reactivity.Rabbit tracheal epithelial cells were dispersed with enzymes, grown in primary culture and fixed. Tissue from intact tracheas was also sampled and fixed. Localisation of the vasoactive substances endothelin-1, arginine-vasopressin, and substance P was investigated by immunolabelling techniques.Scattered immunolabelling to endothelin-1, arginine-vasopressin, and substance P was found throughout the cultures (with < 20% of cells staining positively to each antibody). At the ultrastructural level this immunoreactivity was found in the cytoplasmic matrix. In addition, immunoreactivity of intact tissue to endothelin-1, arginine-vasopressin, and substance P was examined and positively staining cells were found to be scattered through the epithelium.The presence of these vasoactive substances within the epithelium lining the airways supports the view that epithelial cells may provide an additional mechanism in the control of airways reactivity.
AUTOLOGOUS BLOOD STEM CELL TRANSPLANTATION IN ACUTE MYELOID LEUKAEMIA
Authors: J Reiffers, G Marit, B David, PH Bernard, A Broustet, C.A Juttner, P.G Dyson, L.B To, J.Q.K Ho, D.N Haylock, M.M Roberts
Journal: The Lancet (1988)
Obesity in patients with COPD, an undervalued problem?
Authors: L van den Bemt, C A M van Wayenburg, I J M Smeele, T R J Schermer
Journal: Thorax (2009)

Franssen et al reported potential links between obesity and chronic obstructive pulmonary disease (COPD).1 In their review, the authors use obesity prevalence estimates for COPD patient populations from only two studies with a relatively small sample sizes.2 3 Therefore, in our view, whether or not obesity is actually more prevalent in patients with COPD is still a matter of debate. Moreover, the current evidence of a possible association between obesity and a worse COPD disease state is inconclusive. This information is crucial before considering any potential underlying mechanisms of this presumed association.

In order to contribute to the discussion on the role of obesity …
Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial
Authors: Gerald S Falchook, Georgina V Long, Razelle Kurzrock, Kevin B Kim, Tobias H Arkenau, Michael P Brown, Omid Hamid, Jeffrey R Infante, Michael Millward, Anna C Pavlick, Steven J O’Day, Samuel C Blackman, C Martin Curtis, Peter Lebowitz, Bo Ma, Daniele Ouellet, Richard F Kefford
Journal: The Lancet (2012)
Minor Histocompatibility Antigen DBY Elicits a Coordinated B and T Cell Response after Allogeneic Stem Cell Transplantation
Authors: Emmanuel Zorn, David B. Miklos, Blair H. Floyd, Alex Mattes-Ritz, Luxuan Guo, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz
Journal: The Journal of Experimental Medicine (2004)

We examined the immune response to DBY, a model H-Y minor histocompatibility antigen (mHA) in a male patient with chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplant from a human histocompatibility leukocyte antigen (HLA)-identical female sibling. Patient peripheral blood mononuclear cells were screened for reactivity against a panel of 93 peptides representing the entire amino acid sequence of DBY. This epitope screen revealed a high frequency CD4(+) T cell response to a single DBY peptide that persisted from 8 to 21 mo after transplant. A CD4(+) T cell clone displaying the same reactivity was established from posttransplant patient cells and used to characterize the T cell epitope as a 19-mer peptide starting at position 30 in the DBY sequence and restricted by HLA-DRB1*1501. Remarkably, the corresponding X homologue peptide was also recognized by donor T cells. Moreover, the T cell clone responded equally to mature HLA-DRB1*1501 male and female dendritic cells, indicating that both DBY and DBX peptides were endogenously processed. After transplant, the patient also developed antibodies that were specific for recombinant DBY protein and did not react with DBX. This antibody response was mapped to two DBY peptides beginning at positions 118 and 536. Corresponding DBX peptides were not recognized. These studies provide the first demonstration of a coordinated B and T cell immune response to an H-Y antigen after allogeneic transplant. The specificity for recipient male cells was mediated by the B cell response and not by donor T cells. This dual DBX/DBY antigen is the first mHA to be identified in the context of chronic GVHD.
“Efforts to Reprioritise the Agenda” in China: British American Tobacco's Efforts to Influence Public Policy on Secondhand Smoke in China
Authors: Monique E Muggli, Kelley Lee, Quan Gan, Jon O Ebbert, Richard D Hurt
Journal: PLoS Medicine (2008)

Background Each year, 540 million Chinese are exposed to secondhand smoke (SHS), resulting in more than 100,000 deaths. Smoke-free policies have been demonstrated to decrease overall cigarette consumption, encourage smokers to quit, and protect the health of nonsmokers. However, restrictions on smoking in China remain limited and ineffective. Internal tobacco industry documents show that transnational tobacco companies (TTCs) have pursued a multifaceted strategy for undermining the adoption of restrictions on smoking in many countries. Methods and Findings To understand company activities in China related to SHS, we analyzed British American Tobacco's (BAT's) internal corporate documents produced in response to litigation against the major cigarette manufacturers to understand company activities in China related to SHS. BAT has carried out an extensive strategy to undermine the health policy agenda on SHS in China by attempting to divert public attention from SHS issues towards liver disease prevention, pushing the so-called "resocialisation of smoking" accommodation principles, and providing "training" for industry, public officials, and the media based on BAT's corporate agenda that SHS is an insignificant contributor to the larger issue of air pollution. Conclusions The public health community in China should be aware of the tactics previously used by TTCs, including efforts by the tobacco industry to co-opt prominent Chinese benevolent organizations, when seeking to enact stronger restrictions on smoking in public places.